PMID- 30516271 TI - Spatial scale modulates the inference of metacommunity assembly processes. AB - The abundance and distribution of species across the landscape depend on the interaction between local, spatial and stochastic processes. However, empirical syntheses relating these processes to spatio-temporal patterns of structure in metacommunities remains elusive. One important reason for this lack of synthesis is that the relative importance of the core assembly processes (dispersal, selection and drift) critically depends on the spatial grain and extent over which communities are studied. To illustrate this, we simulated different aspects of community assembly on heterogeneous landscapes, including the strength of response to environmental heterogeneity (inherent to niche theory) versus dispersal and stochastic drift (inherent to neutral theory). We show that increasing spatial extent leads to increasing importance of niche selection, whereas increasing spatial grain leads to decreasing importance of niche selection. The strength of these scaling effects depended on environment configuration, dispersal capacity and niche breadth. By mapping the variation observed from the scaling effects in simulations, we could recreate the entire range of variation observed within and among empirical studies. This means that variation in the relative importance of assembly processes among empirical studies is largely scale dependent and cannot be directly compared. The scaling coefficient of the relative contribution of assembly processes, however, can be interpreted as a scale-integrative estimate to compare assembly processes across different regions and ecosystems. This emphasizes the necessity to consider spatial scaling as an explicit component of studies intended to infer the importance of community assembly processes. This article is protected by copyright. All rights reserved. PMID- 30516272 TI - Linked Matrix Factorization. AB - Several recent methods address the dimension reduction and decomposition of linked high-content data matrices. Typically, these methods consider one dimension, rows or columns, that is shared among the matrices. This shared dimension may represent common features measured for different sample sets (horizontal integration) or a common sample set with features from different platforms (vertical integration). We introduce an approach for simultaneous horizontal and vertical integration, Linked Matrix Factorization (LMF), for the general case where some matrices share rows (e.g., features) and some share columns (e.g., samples). Our motivating application is a cytotoxicity study with accompanying genomic and molecular chemical attribute data. The toxicity matrix (cell lines * chemicals) shares samples with a genotype matrix (cell lines * SNPs) and shares features with a molecular attribute matrix (chemicals * attributes). LMF gives a unified low-rank factorization of these three matrices, which allows for the decomposition of systematic variation that is shared and systematic variation that is specific to each matrix. This allows for efficient dimension reduction, exploratory visualization, and the imputation of missing data even when entire rows or columns are missing. We present theoretical results concerning the uniqueness, identifiability, and minimal parametrization of LMF, and evaluate it with extensive simulation studies. This article is protected by copyright. All rights reserved. PMID- 30516273 TI - Temporal clustering of extreme climate events drives a regime shift in rocky intertidal biofilms. AB - Research on regime shifts has focused primarily on how changes in the intensity and duration of press disturbances precipitate natural systems into undesirable, alternative states. By contrast, the role of recurrent pulse perturbations, such as extreme climatic events, has been largely neglected, hindering our understanding of how historical processes regulate the onset of a regime shift. We performed field manipulations to evaluate whether combinations of extreme events of temperature and sediment deposition that differed in their degree of temporal clustering generated alternative states in rocky intertidal epilithic microphytobenthos (biofilms) on rocky shores. The likelihood of biofilms to shift from a vegetated to a bare state depended on the degree of temporal clustering of events, with biofilm biomass showing both states under a regime of non-clustered (60 days apart) perturbations while collapsing in the clustered (15 days apart) scenario. Our results indicate that time since the last perturbation can be an important predictor of collapse in systems exhibiting alternative states and that consideration of historical effects in studies of regime shifts may largely improve our understanding of ecosystem dynamics under climate change. This article is protected by copyright. All rights reserved. PMID- 30516274 TI - Multiple drivers of contrasting diversity-invasibility relationships at fine spatial grains. AB - The diversity-invasibility hypothesis and ecological theory predict that high diversity communities should be less easily invaded than species-poor communities, but empirical evidence does not consistently support this prediction. While fine-scale experiments tend to yield the predicted negative association between diversity and invasibility, broad-scale observational surveys generally report a positive correlation. This conflicting pattern between experiments and observational studies is referred to as the invasion paradox, and is thought to arise because different processes control species composition at different spatial scales. Here, we test empirically the extent to which the strength and direction of published diversity-invasibility relationships depend on spatial scale and on the metrics used to measure invasibility. Using a meta analytic framework, we explicitly separate the two components of spatial scale: grain and extent, by focusing on fine-grain studies that vary in extent. We find evidence of multiple drivers of the paradox. When we consider only fine-grain studies, we still observe conflicting patterns between experiments and observational studies. In contrast, when we examine studies that are conducted at both a fine grain and fine extent, there is broad overlap in effect sizes between experiments and observation, suggesting that comparing studies with similar extents resolves the paradox at local scales. However, we uncover systematic differences in the metrics used to measure invasibility between experiments, which use predominantly invader performance, and observational studies, which use mainly invader richness. When we consider studies with the same metric (i.e., invader performance), the contrasting associations between study types also disappears. It is not possible, at present, to fully disentangle the effect of spatial extent and metric on the paradox because both variables are systematically associated in different directions with study type. There is therefore an urgent need to conduct experiments and observational studies that incorporate the full range of variability in spatial extent and invasibility metric. This article is protected by copyright. All rights reserved. PMID- 30516275 TI - Belowground plant parts are crucial for comprehensively estimating total plant richness in herbaceous and woody habitats. AB - Most studies consider aboveground plant species richness as a representative biodiversity measure. This approach inevitably assumes that the partitioning of total plant species richness into above- and belowground components is constant or at least consistent within and across vegetation types. However, with studies considering belowground plant richness still scarce and completely absent along vegetation gradients, this assumption lacks experimental support. Novel DNA sequencing techniques allow economical, high-throughput species identification of belowground environmental samples, enabling the measurement of the contributions of both above- and belowground plant components to total plant richness. We investigated above- and belowground plant species richness in four vegetation types (birch forest, heath, low alpine tundra, high alpine tundra) at the scale of herbaceous plant neighborhoods (dm) using 454 sequencing of the chloroplast trnL (UAA) intron to determine the plant species richness of environmental root samples and combined it with aboveground data from vegetation surveys to obtain total plant species richness. We correlated the measured plant species richness components with each other and with their respective plant biomass components within and across vegetation types. Total plant species richness exceeded aboveground richness twice on average and by as much as three times in low alpine tundra, indicating that a significant fraction of belowground plant richness cannot be recorded aboveground. More importantly, no consistent relationship among richness components (above- and belowground) was found within or across vegetation types, indicating that aboveground richness alone cannot predict total plant richness in contrasting vegetation types. Finally, no consistent relationship between plant richness and the corresponding biomass component was found. Our results clearly show that aboveground plant richness alone is a poor estimator of total plant species richness within and across different vegetation types. Consequently, it is crucial to account for belowground plant richness in future plant ecological studies in order to validate currently accepted plant richness patterns, as well as to measure potential changes in plant community composition in a changing environment. This article is protected by copyright. All rights reserved. PMID- 30516276 TI - Temperamental Emotionality Attributes as Antecedents of Children's Social Information Processing. AB - This study examined temperament dimensions of emotion as precursors of children's social information processing (SIP) of stressful peer events. Two hundred and forty-three preschool children (M = 4.60 years) and their primary caregivers participated in two measurement occasions spaced 2 years apart. Observations of temperamental anger, fearful distress, positive affect, and effortful control were assessed in multiple laboratory tasks across two visits at Wave 1. SIP assessments from vignettes of peer challenges were repeated across two waves and included: eye tracking measures of attention to peer emotion displays, hostile attribution bias, hostile solutions, and subjective distress. Findings from structural equation models with inclusion of autoregressive controls indicated that effortful control, fear, and anger predicted subsequent changes in specific SIP dimensions. PMID- 30516277 TI - The Modification of In Situ SiOx Chitosan Coatings by ZnO/TiO2 NPs and Its Preservation Properties to Silver Carp Fish Balls. AB - The composite chitosan coatings were prepared and characterized to evaluate their preservation properties for silver carp fish balls, and the microstructures and physicochemical properties of the coatings were improved by in situ nano silicon oxide (SiOx) and zinc oxide/titania (ZnO/TiO2 ) nano-particles (NPs). In the chitosan coatings, when the chitosan combines with NPs by chemical bonds, the crystal lattice is slightly changed due to the modification of NPs. The chitosan coatings modified by NPs showed few cracks, among which sodium hexametaphosphate (SHMP) modified ZnO/TiO2 /SiOx-chitosan (ZTS-CS) coating is proved to be the optimal one. The change of the freshness index and the texture of the fish balls are delayed by the coatings due to their gas permeability and antibacterial properties. The preservation properties of the chitosan coatings for Silver Carp fish balls are improved by in situ SiOx, and further improved by co-modification of ZnO/TiO2 NPs. Furthermore, the surface modification of ZnO/TiO2 NPs enhances the preservation properties of the chitosan coating. PRACTICAL APPLICATION: In our previous study, in situ SiOx was found to improve antibacterial and preservation properties of chitosan coating, leading to extending shelf time of Sciaenops ocellatus. In order to further improve properties of chitosan coatings, we added nontoxic edible nano materials to the in situ SiOx chitosan coatings. In situ SiOx modified by ZnO/TiO2 NPs were synthesized, measured, and characterized in this study, and were applied for the preservation of silver carp fish balls. It could serve as a potential preservation material due to the increasing mechanical preservation properties. Through the results, the ZnO/TiO2 /SiOx chitosan (ZTS-CS) coatings have potential as application in the food industry to guarantee food quality and extend shelf life of products. PMID- 30516278 TI - Migraine and Markers of Carotid Atherosclerosis in Middle-Aged Women: A Cross Sectional Study. AB - OBJECTIVE: This study evaluated the association between migraine and the markers of carotid artery disease. BACKGROUND: Migraine increases the risk of cardiovascular events, but its relationship with vascular dysfunction is unclear. METHODS: In this cross-sectional study, middle-aged women with no known cardiovascular diseases underwent clinical, neurological, and laboratory evaluations; pulse wave velocity (PWV) assessment; and carotid artery ultrasonography. We divided the participants based on the presence of migraine and, further, based on the type of migraine. Associations between migraine and carotid thickening (intima-media thickness >0.9 mm), carotid plaques, or arterial stiffening (PWV >10 m/s) were evaluated using a multiple regression analysis. RESULTS: The study comprised 112/277 (40%) women with migraine, of whom 46/277 (17%) reported having an aura. Compared to the non-migraineurs, the migraine with aura group had an increased risk of diffuse carotid thickening (3/46 [6.8%] vs 2/165 [1.3%], adjusted OR = 7.12, 95% CI 1.05-48.49). Migraine without aura was associated with a low risk of carotid plaques (3/66 [4.7%] vs 26/165 [16.7%], adjusted OR = 0.28, 95% CI 0.08-0.99) and arterial stiffening (21/66 [34.4%] vs 82/165 [51.2%], adjusted OR = 0.39, 95% CI 0.19-0.79). There were no correlations between migraine characteristics and arterial stiffness or carotid thickness measurements. CONCLUSION: Migraine with aura is associated with an increased risk of carotid thickening, and migraine without aura is associated with a low risk of carotid plaques and arterial stiffening. PMID- 30516279 TI - Mass medusae release and temporal reproductive segregation among the three Red Sea fire coral species. AB - The reproductive patterns of coral communities with many of the same species can vary geographically (Shlesinger and Loya 1985), raising interesting questions of natural selection and ecology. Species of the colonial cnidarian genus Millepora have received the common name "fire corals" due to the painful sting inflicted to humans by the release of venom from their stinging cells. Despite their popular name and some similarities with scleractinian stony corals of the class Anthozoa, fire corals belong to a different class of organisms (i.e., Hydrozoa) and are therefore known as hydrocorals. The genus Millepora has a circum-tropical distribution, incorporating about 15 known species (Razak and Hoeksema 2003, Lewis 2006, Amaral et al. 2008, Ruiz-Ramos et al. 2014, de Souza et al. 2017). In some localities milleporids may be rare while in others they may be abundant and serve as important reef-framework builders (Lewis 2006, Amaral et al. 2008). This article is protected by copyright. All rights reserved. PMID- 30516280 TI - Melatonin attenuates myocardial ischemia reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. AB - Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1-related mitochondrial fusion/mitophagy. At the molecular level, OPA1-related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function and blocked cardiomyocyte caspase-9-involved mitochondrial apoptosis. However, genetic approaches with cardiac-specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1 related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK-OPA1 mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury. This article is protected by copyright. All rights reserved. PMID- 30516281 TI - Atlas of the telencephalon based on cytoarchitecture, neurochemical markers, and gene expressions in Rhinogobius flumineus [Mizuno, 1960]. AB - Gobiida is a basal subseries of percomorphs in teleost fishes, holding a useful position for comparisons with other orders of Percomorpha as well as other cohort of teleosts. Here, we describe a telencephalic atlas of a Gobiida species Rhinogobius flumineus (Mizuno, Memoirs of the College of Science, University of Kyoto, Series B: Biology, 1960; 27, 3), based on cytoarchitectural observations, combined with analyses of the distribution patterns of neurochemical markers and transcription factors. The telencephalon of R. flumineus shows a number of features distinct from those of other teleosts. Among others, the followings were of special note. (a) The lateral part of dorsal telencephalon (Dl), which is known as a visual center in other teleosts, is composed of as many as seven regions, some of which are conspicuous, circumscribed by cell plates. These subdivisions of the Dl can be differentiated clearly by differential soma size and color with Nissl-staining, and distribution patterns of neural markers. (b) Cell populations continuous with the ventral region of dorsal part of ventral telencephalon (vVd) exhibit extensive dimension. Especially, portion 1 of the central part of ventral telencephalon appears to represent a cell population laterally translocated from the vVd, forming a large cluster of small cells that penetrate deep into the central part of dorsal telencephalon. (c) The magnocellular subdivision of dorsal part of dorsal telencephalon (Ddmg) contains not only large cells but also vglut2a-positive clusters of small cells that cover a wide range of the caudal Ddmg. Such clusters of small cells have not been observed in the Ddmg of other teleosts. PMID- 30516282 TI - Na+ /H+ exchanger type-1: a shepherd for cellular transhumance. PMID- 30516283 TI - Preparation of allyl isothiocyanate nanoparticles, their anti-inflammatory activity towards RAW 264.7 macrophage cells and anti-proliferative effect on HT1376 bladder cancer cells. AB - BACKGROUND: Allyl isothiocyanate (AITC), a volatile and water-insoluble compound present in several cruciferous vegetables, has been shown to possess several biological activities such as anti-bacteria, anti-fungi and anti-cancer. In this study, water-soluble allyl isothiocyanate nanoparticles (AITC-NPs) were prepared by O/W microemulsion and complex coacervation techniques and evaluated for their anti-inflammatory and anti-cancer effects on human bladder cancer cell HT1376. RESULTS: The AITC-NPs with a particle size of 9.4 nm were stable during heating up to 110 degrees C or 3 freeze-thawing cycles. No significant cytotoxicity was shown on both Caco-2 and intestine epithelial IEC-6 cells at AITC-NPs dose ranging from 0.25-2 g/L (8.75-70 mg/L AITC). However, at 2 g/L dosage, AITC-NPs could inhibit the growth of human bladder cancer cells HT1376 by 90%, while a low dosage of 0.25 g/L could inhibit the migration ability by 83.7, 71.3, 58.4 and 31.4% after 4, 8, 12 and 24 h of incubation, respectively. Compared to AITC and NPs, AITC-NPs showed a better inhibition on lipopolysaccharide (LPS)-induced TNF alpha, IL-6, NO and iNOS production in RAW 264.7 macrophage cells. CONCLUSION: The results demonstrate the potential of AITC-NPs as a therapeutic agent for treatment of bladder cancer and enhancement of immune function. This article is protected by copyright. All rights reserved. PMID- 30516284 TI - Comment on "Transcatheter Aortic Valve Replacement in Patients with Pure Native Aortic Valve Regurgitation: A Systematic Review and Meta-analysis". AB - The timely publication by Haddad et al. entitled "Transcatheter Aortic Valve Replacement in Patients with Pure Native Aortic Valve Regurgitation: A Systematic Review and Meta-analysis" in the journal Clinical Cardiology addresses one of the topics which is receiving increasing attention in cardiovascular intervention field [1]. PMID- 30516285 TI - Response letter to the editor entitled "Transvenous lead extraction, only once or repeatable?" PMID- 30516286 TI - Coercive control during the transition to parenthood: An overlooked factor in intimate partner violence and family wellbeing? AB - A key criticism of research on intimate partner violence (IPV) is that a sole focus on physical or psychological acts of aggression fails to account for other forms of manipulative behavior that may have serious consequences for partner and family functioning. The current study examines coercive control, or behavior designed to constrain or compel an intimate partner in some way, in a longitudinal community sample of 98 heterosexual couples assessed in the third trimester of pregnancy as well as at 1 and 2 years postpartum. We found that the majority of couples reported at least some coercive controlling behavior during the transition to parenthood, that coercive control was highly bi-directional between partners, and that women were more likely than men to engage in coercive control before parenthood. Using multilevel actor-partner interdependence modeling, we found that women's coercive control predicted their own as well as men's perpetration of IPV across the transition to parenthood. Controlling for IPV perpetration by both partners, women's coercive control was longitudinally predictive of men's depression, harmful alcohol use, relationship dissatisfaction, poor co-parenting, low perceived parenting competence, and perceptions of toddler problem behavior. Men's coercive control was longitudinally predictive of women's relationship dissatisfaction and parenting stress, as well as women's perceptions of infant problem behavior. Men's coercive control was associated with their own use of ineffective parenting behavior. These findings suggest that coercive control is common in community samples during the transition to parenthood and that coercive control predicts lower early family functioning. PMID- 30516287 TI - Social determinants of health and adverse maternal and birth outcomes in adolescent pregnancies: A systematic review and meta-analysis. AB - BACKGROUND: Adverse outcomes in adolescent pregnancies have been attributed to both biological immaturity and social determinants of health (SDOH). The present systematic review evaluated the evidence on the association between SDOH and adverse maternal and birth outcomes in adolescent mothers. METHODS: Comprehensive literature searches were conducted to identify observational studies evaluating the relationship between SDOH and adverse adolescent pregnancy outcomes. Study selection, risk of bias appraisal, and data extraction of study characteristics were independently performed by two reviewers. Pooled odds ratios (pOR) with 95% confidence intervals (95% CI) were calculated to assess the association between SDOH and adverse birth outcomes. RESULTS: Thirty-one studies met the inclusion criteria. The most frequently evaluated SDOH was race while the most commonly reported maternal and birth outcomes were caesarean section and preterm birth (PTB), respectively. The risk of bias of included studies was fair on the Newcastle-Ottawa Scale. Meta-analyses of retrospective cohort studies showed that, compared to White adolescent mothers, African American teens had increased odds of PTB (pOR 1.67; 95% CI 1.59, 1.75) and low birthweight (pOR 1.53; 95% CI 1.45, 1.62). Rural residence was consistently linked with PTB while low maternal socio-economic (SES) and illiteracy were found to increase the risk of adolescent maternal mortality and LBW infants. CONCLUSION: Social determinants of health contribute to the risk of adverse pregnancy outcomes in adolescent mothers. African American race, rural residence, inadequate education, and low SES are markers for poor pregnancy outcomes in adolescent mothers. Further research needs to be done to understand the underlying causal pathways to inequalities in adolescent pregnancy outcomes. PMID- 30516288 TI - A Pedagogical Response to Decoloniality: Decolonial Atmospheres and Rising Subjectivity. AB - The neoliberal academy is, at its core, an apparatus through which coloniality sustains itself. Despite the academy's self-promotion as a catalyzing institution that prepares students to become agents of social change and transformation, some students and faculty experience it as a crucible of oppression. In this essay I trace the beginnings of a project I was a part of in which I worked alongside students who demanded that a psychology program in the university be transformed into a force for decoloniality. I reflect on some of the conditions of coloniality that students actively resisted at one college and that exist elsewhere within the university. Juxtaposed against manifestations of coloniality in the university are synopses of student's experience of them. These synopses provide insight into why students have chosen to resist coloniality in the academy. I also outline a pedagogical response to coloniality that I created given students' desire for decoloniality. Finally, and with the permission of student artists, two liberation psychology student art projects are included to make visible the rise in subjectivity that becomes possible when a decolonial atmosphere is created within the university. PMID- 30516289 TI - Generalized pustular psoriasis complicated with bullous pemphigoid. PMID- 30516290 TI - Post-fire forest regeneration shows limited climate tracking and potential for drought-induced type conversion. AB - Disturbance such as wildfire may create opportunities for plant communities to reorganize in response to climate change. The interaction between climate change and disturbance may be particularly important in forests, where many of the foundational plant species (trees) are long-lived and where poor initial tree establishment can result in conversion to shrub- or graminoid-dominated systems. The response of post-disturbance vegetation establishment to post-disturbance weather conditions-particularly to extreme weather-could therefore provide useful information about how forest communities will respond to climate change. We examined the effect of post-fire weather conditions on post-fire tree, shrub, and graminoid recruitment in fire-adapted forests in northern California, USA by surveying regenerating vegetation in severely burned areas 4-5 years after 14 different wildfires that burned between 2004 and 2012. This time period (2004 2016) encompassed a wide range of post-fire weather conditions, including a period of extreme drought. For the most common tree species, we observed little evidence of disturbance-mediated community reorganization or range shifts but instead either (a) low sensitivity of recruitment to post-fire weather or (b) weak but widespread decreases in recruitment under unusually dry post-fire conditions, depending on the species. The occurrence of a single strong drought year following fire was more important than a series of moderately dry years in explaining tree recruitment declines. Overall, however, post-fire tree recruitment patterns were explained more strongly by long-term climate and topography and local adult tree species abundance than by post-fire weather conditions. This observation suggests that surviving adult trees can contribute to a "biological inertia" that restricts the extent to which tree community composition will track changes in climate through post-disturbance recruitment. In contrast to our observations in trees, we observed substantial increases in shrub and graminoid establishment under post-fire drought, suggesting that shifts in dominance between functional groups may become more likely in a future with more frequent and intense drought. This article is protected by copyright. All rights reserved. PMID- 30516291 TI - Content of Poorly Absorbed Short-Chain Carbohydrates (FODMAP) in Enteral Homemade Diets. AB - BACKGROUND: Recent studies have shown that commercial enteral formulas with low FODMAP (FO, fermentable oligosaccharides; D, disaccharides; M, monosaccharides; AP, and polyols) content decrease diarrhea of individuals receiving enteral nutrition therapy (ENT). There is no information, however, regarding the content of FODMAP in homemade enteral formula. The objective of this study was to assess energy and macronutrient content, and to quantify the amount of FODMAP content in homemade enteral formula, commonly prescribed for home use after hospital discharge. METHODS: Recipes of homemade enteral formula were requested from all hospitals and healthcare centers in a Brazilian city, totaling 24 recipes. The diets were quantified in relation to their energy content, macronutrients, and FODMAP content. RESULTS: Of the 19 hospitals, 68.4% prescribe only commercial enteral formulas at the time of hospital discharge, and 31.6% prescribe homemade enteral formula, both conventional and commercial. The homemade enteral formula showed a variation from 700 to 3000 kcal/d. The macronutrient levels of carbohydrates, proteins, and fats were 49.0% +/- 6.8%, 17.4% +/- 3.1%, and 33.5% +/- 6.2%, respectively. On average, homemade enteral formula had 58.5% of high FODMAP content, 7.1% of moderate content, and 34.5% of low FODMAP content, considering that milk is the main food responsible for the high content of FODMAP. CONCLUSIONS: Homemade enteral formula presented adequate nutrition characteristics and is rich in FODMAP. It is important to consider FODMAP in enteral diets prescribed for individuals intolerant to these carbohydrates by individualizing the diet prescription. PMID- 30516292 TI - Reaching Milestones in the Oxygenation Chemistry of Magnesium Alkyls: Towards Intimate States of O2 Activation and the First Monomeric Well-Defined Magnesium Alkylperoxide. AB - Despite decades of extensive studies on the reactivity of magnesium alkyls towards O2, the isolation and structural characterization of discrete products of these reactions still remains a challenge. Although the formation of the most frequently encountered magnesium alkoxides via unstable alkylperoxide intermediates has commonly been accepted, the latter species have been elusive for over 100 years. Probing the oxygenation of a well-defined neo-pentylmagnesium complex stabilized by a beta-diketminate ligand, (dippBDI)MgCH2CMe3, we report on the isolation and structure characterization of both a dimeric magnesium alkoxide [(dippBDI)Mg(u-OCH2CMe3)]2 and the first example of monomeric magnesium alkylperoxide [(dippBDI)Mg(thf)OOCH2CMe3] (dippBDI = [(ArNCMe)2CH]- and Ar = C6H3iPr2-2,6). The formation of monomeric magnesium alkylperoxide demonstrate a crucial role of an additional Lewis base for stabilizing the most elusive oxygenation products likely due to increasing of the electron density on the metal centre. Moreover, the 1H NMR studies at - 80 degrees C revealed that the dissociation of a coordinated Lewis base from the solvated complex (dippBDI)Mg(L)CH2CMe3 (where L = thf or 4-methylpyridine) is likely not required prior to the effective attack of an O2 molecule on the metal centre and the four coordinate alkylmagnesium complex reacts smoothly with O2 under these conditions. The results can be expected to aid future engineering of various organomagnesium/O2-based reaction systems. PMID- 30516293 TI - Does DRG funding encourage hospital specialization? Evidence from the Italian National Health Service. AB - The impact of diagnosis-related group (DRG)-based funding has been analyzed along a wide range of dimensions. Its effects on hospital specialization, however, have been investigated only sparsely. This paper examines such effects in the context of the Italian National Health Service, where decentralization has produced a significant degree of variation in funding arrangements. To this end, a 9-year panel data set covering 762 Italian public and private hospitals was analyzed using a finite mixture model approach. Hospital specialization was measured by the internal Herfindahl-Hirschman Index. Three variables were introduced as proxies for the choices made by Italian Regions with respect to the development and use of their DRG systems. The best finite mixture model identified three groups of hospitals, two of which sizeable. Of these, one included nearly all public hospitals, while the other was composed almost exclusively of small and medium-sized investor-owned hospitals. Averagely, private and smaller hospitals showed a stronger tendency to specialize over time. The positive impact of DRG funding on the hospitals' propensity to specialize found only limited empirical support. Moreover, it emerged as comparatively much smaller for public hospitals vis a vis private ones. PMID- 30516294 TI - Probing the Regioselectivity by Encapsulated H2: Diels-Alder Reaction of a Cage Opened C60 Derivative with Anthracene. AB - We have studied the resioselectivity in the Diels-Alder reaction of an unsymmetrical open-cage C60 derivative with anthracene. By using an encapsulated H2 molecule as a magnetic probe, we successfully evaluated the product population in detail, indicating the formation of ca. 10 compounds as major components. The NICS calculations showed the close resemblance to the observed 1H NMR spectrum, which realizes facile characterization of the products. We further performed theoretical studies on the formation of all 29 possible anthracene-adducts. The results indicated that the regioselectivity is strongly governed by steric factor, value of frontier orbital coefficients, and thermodynamic stabilities. The single crystal X-ray analysis of the most dominant compound exhibited the supramolecular architecture between the anthracene moiety and the pi-sphere of a neighbouring molecule. PMID- 30516295 TI - Investigating unmet health care needs under the National Health Insurance program in Taiwan: A latent class analysis. AB - OBJECTIVES: In Taiwan, although the implementation of the National Health Insurance (NHI) program reduced financial barriers and enhanced accessibility for individuals to utilize health care services, an unequal distribution of medical care resources still exists. This paper is focusing on analyzing factors that are associated with unmet health care needs among the middle-aged and elderly under the NHI in Taiwan. METHODS: Statistical analysis from the 2007 Survey of Health and Living Status of the Elderly in Taiwan. We firstly adopted latent class analysis to classify individuals' observable reasons for feeling unwell but not seeing a doctor within the last 3 months into three latent perceived barriers classes. We further used a multinomial probit regression model to analyze factors that are associated with each perceived barrier class to the access of health care service. RESULTS: Results indicate relative to the "relatively no barriers" class, individuals with a high level of educational attainment tend to more likely to be in the "accommodation barriers" class, and individuals live in the most developed areas with the densest medical facilities tend to less likely to be in the "accessibility barriers" class. CONCLUSIONS: We identified possible risk factors for each perceived barrier, which could provide important insights for health authorities and medical providers when targeting policies and interventions to efficiently assist people in need. PMID- 30516296 TI - Multivalent thiosialosides and their synergistic interaction with pathogenic sialidases. AB - Sialidases (SA) hydrolyze sialyl residues from glycoconjugates of the eukaryotic cell surface and are virulence factors expressed by pathogenic bacteria, viruses and parasites. The catalytic domain of SA are often flanked with carbohydrate binding module(s) previously shown to bind sialosides and to enhance enzymatic catalytic efficiency. Here we designed non-hydrolyzable multivalent thiosialosides as probes and inhibitors of V. cholerae, T. cruzi and S. pneumoniae (NanA) sialidases. NanA was truncated from the catalytic and lectinic domains (NanA-L and NanA-C) to probe their respective roles when interacting with sialylated surfaces and the synthetically designed di-, and polymeric thiosialosides. NanA-L domain was shown to fully drive NanA binding, improving affinity for the thiosialylated surface and compounds by more than two orders of magnitude. Importantly, each thiosialoside grafted onto the polymer was also shown to reduce NanA and NanA-C catalytic activity with a 3000-fold higher efficiency compared to the monovalent thiosialoside reference. These results extend the concept of multivalency for designing potent bacterial and parasitic sialidase inhibitors. PMID- 30516297 TI - Strength in Numbers: Development of a Fluorescence Sensor Array for Secondary Structures of DNA. AB - High-throughput assessment of secondary structures adopted by DNA oligonucleotides is currently hampered by the lack of suitable biophysical methods. Fluorescent sensors hold great potential in this respect; however, the moderate selectivity that they display for one DNA conformation over the others constitutes a major drawback to the development of accurate assays. Moreover, the use of single sensors impedes a comprehensive classification of the tested sequences. Herein, we propose to overcome these limitations through the development of a fluorescence sensor array constituted by easily accessible, commercial dyes. Multivariate analysis of the emission data matrix produced by the array allows to explore the conformational preferences of DNA sequences of interest, either by calculating the probability of group membership in the six predefined structural categories (three G-quadruplex groups, double-stranded, and two groups of single-stranded forms), or by revealing their particular structural features. The assay enables rapid screening of synthetic DNA oligonucleotides in a 96-wells plate format. PMID- 30516298 TI - Impact of Intravenous Lipid Emulsions Containing Fish Oil on Clinical Outcomes in Critically Ill Surgical Patients: A Literature Review. AB - A fish oil (FO)-containing intravenous lipid emulsion (ILE; FO ILE) has been approved for use in the United States; however, similar formulations have been used throughout Europe and China in intensive care units since the 1990s. This literature review evaluates the evidence regarding the effectiveness of FO ILE on clinical outcomes in the critically ill surgical patient population. The review of available evidence demonstrates that ILEs containing FO lower triglyceride concentrations, inflammatory markers, and liver function enzymes, and improve morbidity and mortality outcomes in critically ill surgical patients. PMID- 30516299 TI - Percutaneous lead extraction and repositioning: An effective and safe therapeutic strategy for early ventricular lead perforation with dislocation both inside and outside the pericardial sac following a cardiac device implantation. AB - INTRODUCTION: Cardiac perforation of the right ventricle associated with pacemaker or implantable cardioverter-defibrillator (ICD) leads' implantation is an uncommon, albeit potentially life-threatening, complication. The aim of this study is to further identify the optimal therapeutic strategy especially when lead dislocation has occurred outside the pericardial sac. METHODS AND RESULTS: The study population included 10 consecutive patients (6 female, mean age: 66.5 years-old) diagnosed with early ventricular lead perforation following a pacemaker or ICD implantation, with significant protrusion inside the pericardial sac (n=2) or migration of the lead at the pleural space (n=3), the diaphragm (n=1) or the abdominal cavity (n=4), during the period 2013-2017. All patients were symptomatic; however, individuals presenting with haemodynamic instability were excluded. The outcome of the percutaneous therapeutic approach was retrospectively assessed. All patients underwent a successful removal of the perforating lead percutaneously at the electrophysiology lab, by direct traction, and repositioning in another location of the right ventricle. The operation was performed by a multi-disciplinary team, under continuous hemodynamic and transesophageal echocardiographic monitoring and cardiac surgical backup. The periprocedural period was uneventful. Subjects were followed-up for at least one year. Interestingly, all patients developed a type of post cardiac injury syndrome, successfully treated with a 3-month scheme of ibouprofen and colchicine. CONCLUSION: Percutaneous traction and repositioning of the perforating ventricular lead is an effective, safe and less invasive compared to thoracotomy method in hemodynamically stable patients when dislocation has occurred outside the pericardial sac provided that there is no visceral organs injury. This article is protected by copyright. All rights reserved. PMID- 30516300 TI - K2p 3.1 Protein is Expressed as a Transmural Gradient across the Rat Left Ventricular Free Wall. AB - INTRODUCTION: K2p 3.1, also known as TASK-1, is a twin-pore acid-sensitive repolarizing K+ channel, responsible for a background potassium current that significantly contributes to setting the resting membrane potential of cardiac myocytes. Inhibition of IK2p3.1 alters cardiac repolarization and is pro arrhythmogenic. In this study, we have examined the expression of K2p 3.1 and function of this channel in tissue and myocytes from across the left ventricular free wall. METHODS AND RESULTS: Using fluorescence immunocytochemistry, the expression of K2p 3.1 protein in myocytes from the sub-endocardial region was found to be twice (205 +/- 13.5 %) that found in myocytes from the sub-epicardial region of the left ventricle (100 +/- 5.3 %). The left ventricular free-wall exhibited a marked transmural gradient of K2p 3.1 protein expression. Western blot analysis confirmed significantly higher K2p 3.1 protein expression in sub endocardial tissue (156 +/- 2.5 %) than sub-epicardial tissue (100 +/- 5.0 %); however, there was no difference in K2p 3.1 mRNA expression. Whole-cell patch clamp identified IK2p3.1 current density to be significantly greater in myocytes isolated from the sub-endocardium (7.66 +/- 0.53 pA/pF) compared with those from the sub-epicardium (3.47 +/- 0.74 pA/pF). CONCLUSIONS: This is the first study to identify a transmural gradient of K2p 3.1 in the left ventricle. This gradient has implications for understanding ventricular arrhythmogenesis under conditions of ischemia but also in response to other modulatory factors such as adrenergic stimulation and the presence of anesthetics which inhibit or activate this channel. This article is protected by copyright. All rights reserved. PMID- 30516301 TI - Feasibility and Utility of Intraoperative Epicardial Scar Characterization During Left Ventricular Assist Device Implantation for Destination Therapy. AB - INTRODUCTION: Ventricular arrhythmias (VA) after left ventricular assist device (LVAD) placement are associated with increased morbidity and mortality. We sought to assess epicardial voltage characteristics at the time of LVAD implantation and investigate relationships between scar burden and post-implant VA. METHODS AND RESULTS: Consecutive patients underwent open-chest epicardial electroanatomic mapping immediately prior to LVAD implantation. Areas of low voltage and sites with local abnormal potentials were identified. Patients were followed prospectively for post-implant VA and clinical outcomes. Between 2015 and 2017, 36 patients underwent high-density intraoperative epicardial voltage mapping; 15 had complete maps suitable for analysis. Mapping required a median of 11.8 minutes (interquartile range: 8.5 - 12.7 minutes), with a median of 2650 (IQR 2139-3191) points sampled per patient. Over a median follow-up of 311 (IQR 168 469) post-operative days, 4 patients (27%) experienced sustained VA. Patients with post-implant VA were more likely to have had pre-implant ICD shocks (100% vs 27%; P=0.03), VT storm (75% vs 9%; P=0.03), and lower ejection fraction (13.5 vs 19.0%, P=0.05). Patients with post-implant VA also had a significantly higher burden of epicardial low bipolar voltage points: 55.4% vs 24.9% of points were <0.5 mV (P=0.01), and 88.9% vs 63.7% of points <1.5 mV (P=0.004). CONCLUSIONS: Intraoperative high-density epicardial mapping during LVAD implantation is safe and efficient, facilitating characterization of potentially arrhythmogenic substrate. Increased burden of epicardial scar may be associated with a higher incidence of post-implant VA. The role of empiric intraoperative epicardial ablation to mitigate risk of post-implant VA requires further study. This article is protected by copyright. All rights reserved. PMID- 30516302 TI - Selective ablation of ligament of Marshall inhibits ventricular arrhythmias during acute myocardial infarction: Possible mechanisms. AB - INTRODUCTION: Our recent study found that selective ablation of the distal part of the ligament of Marshall (LOMLSPV ) could suppress ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study was to investigate the possible underlying mechanisms. METHODS: Dogs were randomly subjected into the sham operated group (SO, n=6), AMI group (AMI, n=8) and the group undergoing LOMLSPV ablation ahead of AMI (LOMD+AMI, n=8). Incidence of VAs, serum levels of malondialdehyde (MDA) and superoxide diamutas (SOD), expression of connexin (Cx43), Bcl-2, Bax, Caspase-3, tumor necrosis factor (TNF)-alpha, IL-6 and high mobility group box (HMGB)1 were compared. Anatomic and immunostaining examinations of LOMLSPV were performed. RESULTS: Compared with MI group, incidence of VAs was reduced in LOMD+AMI group. Compared with SO group, Cx43, SOD, Bcl-2 were decreased, MDA, Bax, Caspase-3, TNF-alpha, IL-6 and HMGB1 were increased in MI group, all the alterations were significantly restrained in LOMD+AMI group. A visual nerve fiber communication between the left stellate ganglion (LSG) and LOM, and abundant sympathetic nerve bundles distribution in LOMLSPV were revealed. CONCLUSIONS: LOMLSPV ablation could suppress VAs during AMI. The possible mechanism may be associated to disconnection of the sympathetic conduit from LSG to the ventricles. Preservation of Cx43, inhibition of cardiac oxidative stress, apoptosis and inflammation may be involved. This article is protected by copyright. All rights reserved. PMID- 30516303 TI - Distal-to-proximal delay for ablation of premature ventricular contractions. AB - INTRODUCTION: Ablation of premature ventricular contractions has emerged as a safe and effective treatment in patients experiencing a high premature ventricular contractions burden. Mapping of premature ventricular contractions origin may sometimes be challenging. We sought to evaluate the accuracy of a new electrophysiological criterion, the Distal-to-Proximal Delay, at localizing the optimal site for ablation of ventricular ectopic foci. METHODS AND RESULTS: Consecutive patients with ablation attempts of symptomatic premature ventricular contractions were included. Prematurity and Distal-to-Proximal Delay - i.e., time duration between the onset of ablation catheter distal bipolar electrogram and the onset of proximal bipolar electrogram - were measured at successful and unsuccessful ablation sites by 3 blinded experienced electrophysiologists. Mean Distal-to-Proximal Delay at effective ablation sites (N=30) was significantly higher than at ineffective sites (N=55) (23+/-9 vs 11+/-8 ms, p<0.0001). Distal to-Proximal Delay had good to excellent interrater reliability. A Distal-to Proximal Delay >=15 ms had the highest accuracy at predicting a successful ablation site (sensitivity 0.97, area under ROC curve 0.87, p<0.0001). CONCLUSION: Distal-to-Proximal Delay is an additional, simple and effective electrophysiological parameter to accurately localize premature ventricular contractions foci. This article is protected by copyright. All rights reserved. PMID- 30516304 TI - Australian primary school student's attitudes to changing from traditional school uniforms to sports uniforms and association with student characteristics. PMID- 30516305 TI - The prevalence and protective factors for resilience in adolescent Aboriginal Australians living in urban areas: a cross-sectional study. AB - OBJECTIVES: To estimate the prevalence and determine protective factors for resilience in urban Aboriginal adolescents. METHODS: Cross-sectional survey data was collected from 119 Aboriginal adolescents participating in the Study of Environment on Aboriginal Resilience and Child Health (SEARCH). Resilience was defined as having 'low-risk' Strengths and Difficulties Questionnaire scores on the total difficulties (range: 0-40) or the prosocial scale (range: 0-10). RESULTS: Most adolescents scored in the low-risk range of the total difficulties (n=85, 73%) and prosocial scales (101, 86%). Family encouragement to attend school was associated with a 4.3-point reduction in total difficulties scores (95%CI, 0.22-8.3). Having someone to talk to if there was a problem and regular strenuous exercise were associated with higher scores on the prosocial behaviour scale, increasing scores by 1.2 (95%CI, 0.45-2.0) and 1.3 (95%CI, 0.26-2.3) points, respectively. CONCLUSIONS: Most adolescents in SEARCH displayed resilience. Resilience was associated with nurturing family environments, social support and regular exercise. Implications for public health: Our data accords with previous research that demonstrates resilience, but also a higher prevalence of emotional and behaviour problems among Aboriginal youth. Supporting Aboriginal young people to build resilience may promote better mental health outcomes leading to important public health benefits. PMID- 30516306 TI - Use of data linkage to improve communicable disease surveillance and control in Australia: existing practices, barriers and enablers. AB - OBJECTIVES: To review the use of data linkage by Australian state and territory communicable disease control units, and to identify barriers to and enablers of data linkage to inform communicable disease surveillance and control activities. METHODS: Semi-structured telephone interviews were carried out with one key informant from communicable disease control units in all eight Australian states and territories between October 2017 and January 2018. RESULTS: Key informants from all Australian states and territories participated in the interview. A variety of existing practices were identified, with few jurisdictions making systematic use of available data linkage infrastructure. Key barriers identified from the review included: a lack of perceived need; system factors; and resources. Existing regulatory tools enable data linkage to enhance communicable disease surveillance and control. CONCLUSIONS: We identified considerable variation in the use of data linkage to inform communicable disease surveillance and control activities between jurisdictions. We suggest that routinely collected, disparate data are systematically integrated into existing surveillance and response policy cycle to improve communicable disease prevention and control efforts. Implications for public health: Existing gaps in communicable disease surveillance data may affect prevention and control efforts. Data linkage is recognised as a valuable method to close surveillance gaps and should be used to enhance the value of publicly held health data. PMID- 30516307 TI - Isolated left atrial posterior wall tachycardia. AB - A case of macroreentry tachycardia of the isolated posterior left atrium is presented after surgical and subsequent catheter ablation. This article is protected by copyright. All rights reserved. PMID- 30516308 TI - Sexuality and sexual health: Policy in Australian residential aged care. AB - OBJECTIVE: To examine the extent and scope of written policies about sexuality and sexual health for older people living in Australian residential aged care facilities. METHODS: Postal survey sent to all 2766 Australian residential aged care facilities. Respondents were asked to indicate whether the facility had written policies on sexuality and sexual health and to return copies. Content analysis was performed on policies returned. RESULTS: Surveys were returned by 1094 facilities. Less than one-quarter reported having a policy regarding sexuality (n = 237/1049; 23%) or sexual health (n = 129/985; 13%). Less than one tenth (n = 74/1049; 7%) returned a written policy; only two-thirds of these policies were dedicated to sexuality or sexual health. CONCLUSION: Most residential aged care staff do not have access to policies on sexuality or sexual health to guide their practice resident intimacy and sexual health needs are at risk of being ignored. PMID- 30516309 TI - The Closing the Gap (CTG) Refresh: Should Aboriginal and Torres Strait Islander culture be incorporated in the CTG framework? How? PMID- 30516310 TI - Culture-positive shigellosis cases are epidemiologically different to culture negative/PCR-positive cases. AB - OBJECTIVE: To review the epidemiological differences between culture-positive and culture-negative (but ipaH PCR-positive) cases of shigellosis in Sydney Local Health District (SLHD), NSW, to inform whether changes to the national case definition for shigellosis are required. METHODS: An audit of all cases of shigellosis (culture-positive vs. culture-negative/PCR-positive) in SLHD from 1 January 2013 to 30 June 2015 was conducted and demographic, clinical and risk factors were analysed and compared between these groups. RESULTS: Of the 148 shigellosis cases notified to SLHD, 122 cases (85 culture-positive vs. 37 culture negative) were included for analysis. Culture-positive cases were more likely than culture-negative/PCR-positive cases to have experienced at least three symptoms (OR 3.18, 95%CI 1.3-7.5), been hospitalised (OR 4.2, 95%CI 1.4-13.2), and have had men-who-have-sex-with-men exposure identified as the source of their infection (OR 28.7, 95%CI 6.2-132.6). CONCLUSIONS: This study has identified that culture-positive vs. culture-negative/PCR-positive shigellosis cases in NSW differ by clinical severity and risk factors for infection. Implications for public health: The study findings warrant further research to determine the true diagnostic prevalence of Shigella in the culture-negative/PCR-positive group in the Australian context, in order to inform further changes to the national case definition for shigellosis. PMID- 30516311 TI - "No-one's driving this bus" - qualitative analysis of PrEP health promotion for Aboriginal and Torres Strait Islander gay and bisexual men. AB - OBJECTIVE: HIV prevention tools such as pre-exposure prophylaxis require equitable access and uptake to protect all at-risk populations. This project assessed the perceived barriers to accessible HIV prevention for Aboriginal and Torres Strait Islander gay and bisexual men (GBM) and evaluated the presence of health promotion for pre-exposure prophylaxis (PrEP) for this population from the perspective of service providers. METHODS: Eighteen semi-structured interviews with healthcare providers, researchers and AIDS Council employees were qualitatively analysed for themes and concepts related to PrEP-specific health promotion. RESULTS: Respondents noted AIDS Councils and affiliated sexual health clinics had been instrumental in promoting PrEP to at-risk GBM. However, many Aboriginal gay and bisexual men who are not well connected with these communities and services may not have been exposed to this health promotion and therefore have not accessed PrEP effectively. CONCLUSIONS: Aboriginal community and gay community controlled health organisations need to collaborate to ensure they deliver effective and tailored health promotion to Aboriginal communities. Implications for public health: The rising HIV notification rates in Aboriginal Australians is an example of the health gap experienced by First Nation people. Effective HIV prevention is required to ensure this gap does not widen further, and that Australia meets its goal of preventing all new HIV infections. However, these efforts will be hampered by ineffective health promotion of HIV prevention tools, such as PrEP, for Aboriginal Australians. PMID- 30516313 TI - Population woods and clinical trees. A commentary on 'Evidence-based pathways to intervention for children with language disorders'. PMID- 30516312 TI - Myocardial viability as shown by left ventricular lead pacing threshold and improved dyssynchrony by QRS narrowing predicts the response to cardiac resynchronization therapy. AB - INTRODUCTION: Patients with advanced heart failure and dyssynchrony can benefit from cardiac resynchronization therapy (CRT). To predict the response to CRT, myocardial viability and improved dyssynchrony are suggested to be important. METHODS: We retrospectively investigated 93 patients who underwent CRT implantation in Nagoya University Hospital. We assessed QRS narrowing the day after implantation to measure the improvement in dyssynchrony and measured the left ventricular pacing threshold (LVPT) to determine the local myocardial viability in all patients. Responders to CRT were defined as those having a >=15% decrease in left ventricular end-systolic volume by echocardiography at their 6 month follow-up. RESULTS: Sixty-two patients (67%) were classified as responders. The QRS width before CRT implantation, QRS narrowing after implantation, left atrial diameter, septal-to-posterior wall motion delay, left ventricular end diastolic diameter, radial strain, and LVPT were significantly different between the responder and non-responder groups. On multivariate analysis, QRS narrowing (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05, p = 0.005) and LVPT (OR 0.42, 95% CI 0.22-0.82, p = 0.011) were independent predictors of a response to CRT. We calculated the cutoff values from the receiver operating characteristic curves as 22.5 msec of QRS narrowing and 1.55 V of LVPT. The response rates in patients with both predictive factors (QRS narrowing >= 22.5 msec and LVPT <= 1.55 V), one factor, and no factors were 91%, 61%, and 25%, respectively (p < 0.001). CONCLUSION: Both myocardial viability and improved electrical dyssynchrony may be essential to predict a good response to CRT. This article is protected by copyright. All rights reserved. PMID- 30516314 TI - Radiochemistry in a flash: photochemical conjugation and one-pot radiolabelling of antibodies for immuno-PET. AB - Monoclonal antibodies (mAbs), immunoglobulin fragments and other proteins are important scaffolds in the development of radiopharmaceuticals for diagnostic immuno-positron emission tomography (immuno-PET) and targeted radioimmunotherapy (RIT). Conventional methods for radiolabelling proteins with metal ions like 68Ga, 64Cu, 89Zr, and 90Y etc require multi-step procedures involving pre purification, functionalisation with a chelate, and subsequent radiolabelling. Standard coupling chemistries are time consuming, difficult to automate, and involve synthesis, isolation and storage of an intermediate, new molecular entity (the conjugated mAb) whose biochemical properties can differ from those of the parent protein. To circumvent these issues, we developed a photoradiochemical approach that uses fast, chemoselective, light-induced protein modification under mild conditions with novel metal ion binding chelates derivatised with arylazide (ArN3) groups. Experiments show that one-pot photochemical conjugation and radiolabelling of formulated mAbs can be achieved in <20 min. PMID- 30516315 TI - Learning to read facilitates the retrieval of phonological representations in rapid automatized naming: Evidence from unschooled illiterate, ex-illiterate, and schooled literate adults. AB - Rapid automatized naming (RAN) of visual items is a powerful predictor of reading skills. However, the direction and locus of the association between RAN and reading is still largely unclear. Here we investigated whether literacy acquisition directly bolsters RAN efficiency for objects, adopting a strong methodological design, by testing three groups of adults matched in age and socioeconomic variables, who differed only in literacy/schooling: unschooled illiterate and ex-illiterate, and schooled literate adults. To investigate in a fine-grained manner whether and how literacy facilitates lexical retrieval, we orthogonally manipulated the word-form frequency (high vs. low) and phonological neighborhood density (dense vs. spare) of the objects' names. We observed that literacy experience enhances the automaticity with which visual stimuli (e.g., objects) can be retrieved and named: relative to readers (ex-illiterate and literate), illiterate adults performed worse on RAN. Crucially, the group difference was exacerbated and significant only for those items that were of low frequency and from sparse neighborhoods. These results thus suggest that, regardless of schooling and age at which literacy was acquired, learning to read facilitates the access to and retrieval of phonological representations, especially of difficult lexical items. This article is protected by copyright. All rights reserved. PMID- 30516316 TI - How many fingers am I holding up? The answer depends on children's language background. AB - Monolingual English-speaking preschool children tend to process number gestures as unanalyzed wholes rather than use the one-to-one (finger-to-quantity) correspondence. By school age, however, children can use the one-to-one correspondence. The purpose of the present studies was to test whether children learn one-to-one correspondence through exposure to a variety of finger configurations to convey a single quantity. In Study 1, we compared children with exposure to multiple one-to-one configurations, that is, French-English and German-English bilingual children, to English monolingual children who see consistent representations. As predicted, the bilingual children performed better in interpreting unconventional number gestures. In Study 2, we compared Chinese English bilingual children who knew arbitrary one-handed Chinese numbers gestures for quantities six through ten to Chinese-English bilingual children who did not know these gestures, as well as to monolingual English speakers. Chinese-English bilinguals who knew the arbitrary gestures were more likely to interpret unconventional gestures arbitrarily (i.e., influenced by the written and/or Chinese gesture forms). These children did not differ from English monolinguals in the interpretation of unconventional gestures. These results are consistent with the argument that children can become sensitive to the one-to-one correspondence in number gestures with exposure to multiple configurations for the same quantity. This article is protected by copyright. All rights reserved. PMID- 30516318 TI - Current Resources for Evidence-Based Practice, January/February 2019. PMID- 30516317 TI - Simple Estimates for Eutectic Behavior. AB - A simple formula is derived for the eutectic point of an A-B system in terms of the monomer melting points and melting enthalpies. This estimate is tested on several non-ionic or ionic systems, with or without common ions, including choline chloride/urea mixtures. The results are compared with the Schroder-van Laar equation. PMID- 30516319 TI - 'Leave Well Enough Alone': A New Mantra for Management of Diabetes in the Elderly. AB - A multitude of epidemiological cross-sectional and case-control studies have now indicated that overly-stringent or 'tight' glycaemic control in the elderly is at best of no benefit to the patient and at worst a reckless endeavour. Rodiguez Poncelas et al. recently demonstrated that this issue remains unresolved by presenting data in the International Journal of Clinical Practice on this somewhat under-acknowledged aspect of diabetes care.1 Perhaps now is the time for physicians to take note and implement a mantra of 'leave well enough alone' in the case of the diabetic elderly. This article is protected by copyright. All rights reserved. PMID- 30516320 TI - On the Role of Mindfulness and Compassion Skills in Students' Coping, Well-being and Development across the Transition to College: A Conceptual Analysis. AB - In this paper, we aim to integrate the current conceptual approaches to stress and coping processes during the college transition with the potential role of mindfulness and compassion skills on students' well-being and development. First, we provide an overview of the issues and challenges emerging adults are facing during the transition to college, drawing on the revised version of the transactional stress model by Lazarus and Folkman (1984). Second, we introduce a conceptual model of adaptive stress and coping processes enhanced by mindfulness and compassion (MC) skills to positively impact the appraisal and coping resources and emerging adults' mental health. Specifically, mindfulness and compassion skills may play an important role in promoting a healthy stress response by strengthening emerging adults' socioemotional competencies and supporting the development of adaptive appraisal and coping resources, including processes antecedent and consequent to a coping encounter. In particular, MC skills were hypothesized to enhance (1) preparedness to cope, (2) productive stress response through adaptive appraisals and skillful deployment of coping resources; and (3) healthy post-coping reflections. Therefore, MC skills may be a useful preventive tool to strengthen emerging adults' ability to adjust to a new academic environment and fulfill the developmental tasks of this period. PMID- 30516321 TI - Australian Association of Gerontology Position Paper: Older women who are experiencing, or at risk of, homelessness. PMID- 30516322 TI - Considerations for Implementing Precision Therapeutics for Children. AB - Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life-long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contribute to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age-specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on response rather than only the dose-exposure relationship. The amount of drug target receptors and the relative affinity for binding at that target site may require different levels of systemic exposure to achieve a desired response. Concentration-controlled studies can identify the needed exposure for a response at the drug target, the level of expression of the target site in an individual patient, and the tools required to individualize response. Although pediatrics represents a large spectrum of growth and development, developing tools to improve drug delivery for each individual patient across the spectrum of the ages treated by clinicians remains valuable. This article is protected by copyright. All rights reserved. PMID- 30516323 TI - Nurse telephone education for promoting a treat-to-target approach in recently diagnosed rheumatoid arthritis patients: A pilot project. AB - OBJECTIVE: The aim of the present study was to implement a nurse telephone education programme for patients with recently diagnosed rheumatoid arthritis (RA) that promotes shared decision-making and a treat-to-target approach. METHODS: This was a pilot project of newly diagnosed adult RA patients conducted between November 2015 and December 2016. A rheumatology clinic nurse telephoned patients to offer disease education. A toolkit was mailed to patients. Measures included call attempts, call time, a qualitative description of free-text notes and the proportion of patients who adhered to their next clinic visit. Data were analysed descriptively and qualitatively. RESULTS: Twenty-six patients participated in the nurse calls. Most patients were female (65%), with a median age of 54 years (range 22-78 years). Median call length was 14.5 min, with a range of 8-23 min. Qualitative notes indicated that patients overwhelmingly supported the nurse calls. Nineteen patients (73%) were adherent to their follow up visit. CONCLUSION: This preliminary project successfully implemented an educational programme that included a nurse-facilitated, RA-specific, telephone call and toolkit. This educational programme could be a model for similar educational efforts by other clinics. PMID- 30516324 TI - Re: Outcome of fetuses with prenatal diagnosis of isolated severe bilateral ventriculomegaly: systematic review and meta-analysis. PMID- 30516327 TI - Reply. PMID- 30516328 TI - Long-term analysis of children with metastatic neuroblastoma treated in the ENSG5 randomised clinical trial. AB - BACKGROUND: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long term outcomes of the ENSG5 trial were analysed. PROCEDURE: Patients with metastatic neuroblastoma aged >=12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. RESULTS: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. CONCLUSION: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described. PMID- 30516329 TI - Garcinol Reduces Obesity in High-Fat Diet-Fed Mice by Modulating Gut Microbiota Composition. AB - SCOPE: Obesity has become a major health problem worldwide and is associated with low-grade chronic inflammation and intestinal dysbiosis. This study was conducted to investigate the chemopreventive effects of garcinol, a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica. We sought to delineate how garcinol protects against obesity in high-fat diet (HFD) induced mice and determine whether its anti-obesity effects are related to gut microbiota. METHODS AND RESULTS: The results showed that garcinol reduced HFD-fed mice body weight gain and relative visceral adipose tissue fat weight in a dose dependent manner. Furthermore, garcinol markedly reduced the plasma levels of glutamate pyruvate transaminase, total cholesterol, and triacylglycerol. The 16S rRNA gene sequence data indicated that garcinol not only reversed HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios-but also controlled inflammation by increasing the intestinal commensal bacteria, Akkermansia. In addition, the AMP-activated protein kinase alpha signaling pathway involved in adipocyte adipogenesis was also affected by garcinol. CONCLUSION: Taken together, these results demonstrate for the first time that garcinol can prevent HFD-induced obesity and may be used as a novel gut microbiota moderator to prevent HFD-induced gut dysbiosis and obesity-related metabolic disorders. This article is protected by copyright. All rights reserved. PMID- 30516330 TI - A Single-center Experience with Methotrexate in the Treatment of Chinese Crohn's Disease. AB - OBJECTIVE: Methotrexate (MTX) can be used as an alternative for Crohn's disease (CD) patients intolerant to thiopurine. Although some studies have reported the efficacy of MTX administration in treating CD, few studies have included Asian patients. This retrospective study aimed to provide some clues regarding MTX treatment in Chinese CD patients. METHODS: We included 27 patients (>18 years) with CD treated with MTX between 2012 and 2017 at Renji Hospital, School of Medicine, Shanghai Jiao Tong University. MTX was administered at 15 mg or 20 mg intramuscularly once per week. The efficacy and adverse reactions of MTX were recorded and analyzed. RESULTS: Over two years, 13 (48.1%) patients who received intramuscular MTX achieved remission for more than 12 months, whereas 4 (14.8%) patients responded to MTX treatment. Eight patients (29.6%) discontinued MTX due to the adverse events. The mean age of those who maintained remission was significantly lower than that of those who did not (35.62 +/- 10.99 years vs 45.43 +/- 11.93 years, P < 0.05). CONCLUSIONS: Intramuscular MTX administration is safe and effective for patients from a single center in China at doses of 15 or 20 mg/week and can be an alternative therapy for patients intolerant to thiopurine. Elderly CD patients and patients with normal pretreatment C-reaction protein may have reduced response to MTX. PMID- 30516332 TI - Issue Information - ToC. PMID- 30516331 TI - Improving police conceptual knowledge of Mexico's law on cannabis possession: Findings from an assessment of a police education program. AB - BACKGROUND AND OBJECTIVES: Policing practices do not reflect recent decriminalization of drug possession in Mexico. We assessed knowledge of cannabis law as part of a police education program (PEP) post-drug law reform in Tijuana. METHODS: Officers took pre-/post-PEP surveys; random subsample (n = 759) received follow-up assessments. Longitudinal logistic regression (pre-, post-, 3-months post-PEP) measured knowledge of cannabis law. RESULTS: PEP increased conceptual knowledge of cannabis law from baseline to post-training (AOR = 56.1, CI: 41.0 76.8) and 3 months post-PEP (AOR = 11.3, CI: 9.0-14.2). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: PEPs improve police knowledge of cannabis law. Reforms should be bundled with PEPs to improve policy implementation. (Am J Addict 2018;XX:XX-XX). PMID- 30516333 TI - Ayahuasca: From the Amazon to a city near you. PMID- 30516334 TI - Issue Information - Editorial Board. PMID- 30516335 TI - E-cigarettes and the Nicotine Epidemic. PMID- 30516336 TI - Attitudes toward defendants with substance-related charges: An analysis of a national sample of criminal defense attorneys. AB - BACKGROUND AND OBJECTIVES: While a large percentage of criminal offenders suffer from substance use disorders (SUDs), virtually nothing is known about the attitudes criminal defense attorneys possess toward their clients who are facing substance-related charges. This is a serious concern, as the burden of steering individuals with SUDs into treatment often falls to criminal defense attorneys. The goal of this study was to examine the attitudes of criminal defense attorneys toward individuals who have been accused of drug crimes. METHODS: A questionnaire was sent to criminal defense attorneys (N = 1,933) from all 50 U.S. states and the District of Columbia. It was comprised of (i) demographic information and (ii) a version of the 11-item Medical Condition Regard Scale (MCRS). RESULTS: Criminal defense attorneys held generally positive attitudes toward clients with substance-related charges, but there was a significant divergence in attitudes between private and public attorneys, with the latter showing both greater familiarity with and better attitudes toward this same group of clients. These differences were impactful: worse attitudes toward clients strongly correlated with greater predictions that the clients would reoffend. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Given the magnitude of the incarcerated population with SUDs and the centrality of defense attorneys in the treatment process, especially its initiation, the divergence in attitudes between private and public criminal defense attorneys is concerning. There is a clear need for increased collaboration between physicians and attorneys, with an aim of increasing the number of individuals with SUDs receiving proper treatment (Am J Addict 2018;XX:1 7). PMID- 30516337 TI - Women and opioid use disorders. PMID- 30516338 TI - High-throughput isolation of circulating tumor DNA:a comparison of automated platforms. AB - The emerging interest in circulating tumor DNA (ctDNA) analyses for clinical trials has necessitated the development of a high-throughput method for fast, reproducible and efficient isolation of ctDNA. Currently, the majority of ctDNA studies use the manual QIAamp (QA) platform to isolate DNA from blood. The purpose of this study is to compare two competing automated DNA isolation platforms (Maxwell (MX) and QIAsymphony (QS)) to the current 'gold standard' QA to facilitate high-throughput processing of samples in prospective trials. We obtained blood samples from healthy blood donors and metastatic cancer patients for plasma isolation. Total cell free DNA (cfDNA) quantity was assessed by TERT quantitative PCR. Recovery efficiency was investigated by quantitative PCR analysis of spiked-in synthetic plant DNA. In addition, a beta-actin fragmentation assay was performed to determine the amount of contamination by genomic DNA from lysed leukocytes. ctDNA quality was assessed by digital PCR for somatic variant detection. cfDNA quantity and recovery efficiency were lowest using the MX platform, whereas QA and QS showed a comparable performance. All platforms preferentially isolated small (136 bp) DNA fragments over large (420 and 2000 bp) DNA fragments. Detection of the number variant and wild type molecules was most comparable between QA and QS. However, there was no significant difference in variant allele frequency comparing QS and MX to QA. In summary, we show that the QS platform has comparable performance to QA, the 'gold standard', and outperformed the MX platform. We conclude that the QS can replace the more laborious QA platform, especially when high-throughput cfDNA isolation is needed. PMID- 30516339 TI - Independent links between plasma xanthine oxidoreductase activity and levels of adipokines. AB - AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR), a rate-limiting and catalyzing enzyme of uric acid formation in the purine metabolism, is involved in an increase in reactive oxygen species. Plasma XOR activity has been shown to be associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia and insulin resistance. MATERIALS AND METHODS: The association between plasma XOR activity measured by using liquid chromatography and mass spectrometry and levels of adipokines, including adiponectin, fatty acid-binding protein 4 (FABP4) and fibroblast growth factor 21 (FGF21), were investigated in 282 subjects (male/female: 126/156) with no medication of the Tanno-Sobetsu Study. RESULTS: Female subjects had lower plasma XOR activity than did male subjects. Smoking habit was associated with the increased activity. Plasma XOR activity was positively correlated with concentrations of FABP4 (r = 0.192, P < 0.001) and FGF21 (r = 0.208, P < 0.001), HOMA-R as an index of insulin resistance and uric acid and was negatively correlated with adiponectin level (r = -0.243, P = 0.001). Multivariate regression analyses demonstrated that levels of adiponectin, FABP4 and FGF21 were independent determinants of plasma XOR activity after adjusting age, gender, uric acid and HOMA-R. With additional adjustment of smoking habit, the level of FABP4, but not that of adiponectin or FGF21, remained as an independent predictor of plasma XOR activity. CONCLUSIONS: Plasma XOR activity is independently associated with levels of adipokines in a general population of subjects without medication. This article is protected by copyright. All rights reserved. PMID- 30516340 TI - Confronting Challenges in Reducing Heart Failure 30-Day Readmissions: Lessons Learned With Implications for Evidence-Based Practice. AB - BACKGROUND: Heart failure (HF) is considered a condition in which a portion of hospital admissions are preventable if timely and appropriate outpatient care management occurs. Facility readmission rates for HF are reportable and subject to penalty. Both military and civilian healthcare systems have fiscal responsibility and are accountable for successful disease management. Therefore, best practices and evidence-based strategies to reduce readmissions are in critical demand. However, translating best evidence into practice can be challenging due to the complexities of the healthcare system. AIMS: This crosswalk paper provides strategies and considerations for nurses planning HF readmission reduction initiatives. METHODS: Insight regarding implementation strategies, challenges, successes, and lessons learned is shared through a framework-guided description of two separate but similar HF readmission reduction projects conducted in military and civilian healthcare facilities. RESULTS: Lessons learned suggest defined and attainable outcomes, multidisciplinary inclusivity, redundancy in roles, greater collaboration, and engagement with stakeholders are most beneficial when initiated before dedicating resources and continuously throughout practice change implementation, maintenance, and sustainment. LINKING EVIDENCE TO ACTION: The authors advocate for interdisciplinary evidence-based practice consortiums to share lessons learned that may promote success potential and optimize return on invested time and efforts in the same or similar initiatives-in this instance, reducing 30-day readmissions for HF patients. PMID- 30516341 TI - Facile Synthesis of Resveratrol Nanogels with Enhanced Fluorescent Emission. AB - Herein, a kind of fluorescent resveratrol nanogels via one-pot thiol-ene Michael addition polymerization of resveratrol triacrylate, 1,6-hexanedithiol, and methoxyl poly(ethylene glycol) acrylate is prepared. The resultant nanogels can be well-dispersed in water with a hydrodynamic radius of around 68 nm, and the nanogels are stable in both water and organic solvents. Moreover, the resveratrol nanogels exhibit elevated fluorescence intensity compared to free resveratrol, and the quantum yield of resveratrol nanogels is estimated to be 5.8 times as that of free resveratrol dispersed in water. Fluorescence image results also demonstrate that the resveratrol nanogels can be used for cell imaging in MCF-7 human breast cancer cells. Therefore, the resveratrol nanogels are expected to be used as a trackable drug delivery system. PMID- 30516342 TI - Rapid Assembly of Saturated Nitrogen Heterocycles in One-Pot: Diazo-Heterocycle 'Stitching' by N-H Insertion and Cyclization. AB - Methods that provide rapid access to new heterocyclic structures in biologically relevant chemical space provide important opportunities in drug discovery. Here, a strategy is described for the preparation of 2,2-disubstituted azetidines, pyrrolidines, piperidines and azepanes bearing ester and diverse aryl substituents. A one-pot rhodium catalyzed N-H insertion and cyclization sequence uses diazo compounds to stitch together linear 1,m-haloamines (m = 2 to 5) to rapidly assemble 4-, 5-, 6- and 7-membered saturated nitrogen heterocycles in excellent yields. Over fifty examples are demonstrated, including with diazo compounds derived from biologically active compounds. The products can be functionalized to afford alpha,alpha-disubstituted amino acids and applied to fragment synthesis. PMID- 30516343 TI - Construction of a Luminogen Exhibiting High Contrast and Multicolored Emission Switching through Combination of a Bulky Conjugation Core and Toly Groups. AB - Stimuli responsive luminogens may find application in highly sensitive sensors, memories and security inks. However, few examples exhibiting both high contrast and multi-colored emission switching have been reported due to the absence of molecular design strategy. Through combination of large conjugation core and peripheral phenyl rings, we obtained ditolyldibenzofulvene (1). Luminogen 1 is AIE active and exhibits tetracolored emission depending on its morphology. Its three single crystals emit blue, yellow and dark orange light upon excitation, exhibiting a maximal emission of 461 nm, 545 nm and 586 nm, respectively, and its amorphous solid emits at 557 nm. All the four aggregates exhibit enhanced emission intensity at lower temperature, but only the orange emissive crystals exhibit blue-shifted emission. The emission of 1 can be switched reversibly between any two of the four states through morphology tuning. Finally, the potential application of 1 in optical data storage was also investigated. PMID- 30516344 TI - Geographic Variation in Obesity, Behavioral Treatment, and Bariatric Surgery for Veterans. PMID- 30516345 TI - Relationship between EGFR mutation and computed tomography characteristics of the lung in patients with lung adenocarcinoma. AB - BACKGROUND: The aim of this study was to investigate the relationship between EGFR mutation and computed tomography (CT) features in patients with adenocarcinoma of the lung. METHODS: One hundred and ninety two lung adenocarcinoma patients who underwent surgery were retrospectively included in this study. Examination of EGFR gene mutation was performed on all resected tumor samples. The 192 recruited lung adenocarcinoma patients were divided into groups according to EGFR mutation status: patients with mutations in exons 18-21 (effective mutated, n = 61) and non-mutated (n = 131). The clinical characteristics and lung CT imaging features of the two groups were recorded and compared. Univariate and logistic regression analysis were performed to identify the independent risk factors relevant to effective EGFR gene mutation. RESULTS: The independent risk factors relevant to effective EGFR mutation were evaluated by logistic regression test. The results indicated that female gender (odds ratio [OR] 3.23), lung CT features of lymphangitis carcinomatosa (OR 2.66), semi-solid lesion density (OR 3.56), and spicule sign (OR 1.61) were independent risk factors relevant to EGFR mutation. CONCLUSION: Female patients with lung CT features of lymphangitis carcinomatosa, semi-solid lesion density, and spicule sign are more prone to harbor EGFR gene mutations and are more likely to benefit from targeted therapy. PMID- 30516346 TI - Incorporating digital anorectal examinations for anal cancer screening into routine HIV care for men who have sex with men living with HIV: a prospective cohort study. AB - INTRODUCTION: Men who have sex with men (MSM) living with HIV have a high risk of anal cancer, which is often detected at late stages, when morbidity and mortality are high. The objective of this study was to describe the feasibility and challenges to incorporating regular digital anorectal examination (DARE) into routine HIV care for MSM living with HIV, from the perspective of patients, physicians and the health service. METHODS: In 2014, we recruited 327 MSM living with HIV, aged 35 and above from one major sexual health centre (n = 187), two high HIV caseload general practices (n = 118) and one tertiary hospital (n = 22) in Melbourne, Australia. Men were followed up for two years and DARE was recommended at baseline, year 1 and year 2. Data were collected regarding patient and physician experience, and health service use. An ordered logit model was used to assess the relationship between sociodemographic factors and the number of DAREs performed. RESULTS: Mean age of men was 51 (SD +/- 9) years, 69% were Australian born, 32% current smokers, and mean CD4 was 630 (SD +/- 265) cells per mm3 , with no significant differences between clinical sites. Overall, 232 (71%) men received all three DAREs, 71 (22%) received two DAREs, and 24 (7%) had one DARE. Adverse outcomes were rarely reported: anal pain (1.2% of total DAREs), bleeding (0.8%) and not feeling in control of their body during the examination (1.6%). Of 862 DAREs performed, 33 (3.8%) examinations resulted in a referral to a colorectal surgeon. One Stage 1 anal cancer was detected. CONCLUSION: Incorporation of an early anal cancer detection programme into routine HIV clinical care for MSM living with HIV showed high patient acceptability, uncommon adverse outcomes and specialist referral patterns similar to other cancer screening programmes. PMID- 30516347 TI - Using Electronic Health Records To Generate Phenotypes For Research. AB - Electronic health records contain patient-level data collected during and for clinical care. Data within the electronic health record include diagnostic billing codes, procedure codes, vital signs, laboratory test results, clinical imaging, and physician notes. With repeated clinic visits, these data are longitudinal, providing important information on disease development, progression, and response to treatment or intervention strategies. The near universal adoption of electronic health records nationally has the potential to provide population-scale real-world clinical data accessible for biomedical research, including genetic association studies. For this research potential to be realized, high-quality research-grade variables must be extracted from these clinical data warehouses. We describe here common and emerging electronic phenotyping approaches applied to electronic health records, as well as current limitations of both the approaches and the biases associated with these clinically collected data that impact their use in research. (c) 2018 by John Wiley & Sons, Inc. PMID- 30516348 TI - Divergent Synthesis of 3-Deoxy-D-manno-oct-2-ulosonic Acid (Kdo) Glycosides Containing alpha-(2->4)-Linked Kdo-Kdo Unit. AB - A convenient and divergent approach was developed to prepare diverse bacterial Kdo oligosaccharides containing Kdo-alpha-(2->4)-Kdo fragment. The orthogonal protected alpha-(2->4) linked Kdo-Kdo disaccharide 3, serving as a common precursor, was divergently transformed into the corresponding 8-, 8'-, and 4' hydroxy disaccharides 5, 7, and 14, respectively. Then, these alcohols were glycosylated, respectively, with the 5,7-O-di-tert-butylsilylene (DTBS) protected Kdo thioglycoside donors 1 or 2 in an alpha-stereoselective and high-yielding manner to afford a range of Kdo oligosaccharides. Finally, removal of all protecting groups of the newly formed glycosides resulted in the desired free Kdo oligomers. PMID- 30516349 TI - DNA-Based Biomaterials for Immunoengineering. AB - Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNA-based biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage associated molecular patterns (DAMPs), or pathogen-associated molecular patterns (PAMPs), by immune cell receptors, activating either proinflammatory signaling pathways or immunosuppressive cell functions. Although extracellular DNA promotes protective immune responses during early inflammation such as bacterial killing, recent advances demonstrate that unresolved and elevated DNA concentrations may contribute to the pathogenesis of autoimmune diseases, cancer, and fibrosis. Therefore, addressing the immunogenicity of DNA enables immune responses to be engineered by optimizing their activating and suppressive performance per application. To this end, emerging biology relevant to the generation of extracellular DNA, DNA sensors, and its role concerning existing and future synthetic DNA biomaterials are reviewed. PMID- 30516351 TI - Adenosine 2a receptor signals block autoimmune arthritis by inhibiting pathogenic germinal center T follicular helper cells. AB - OBJECTIVE: CD4 germinal center (GC)-T follicular helper (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR, Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. Therefore, we examined the effects of A2aR signaling on CD4 T cells during the recognition of a self-antigen using a mouse model of autoimmune arthritis. METHODS: Wild type and Adora2a-deficient KRN TCR-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-Ag7 were transferred into immunodeficient Tcra-/- I-Ag7 -expressing mice to induce arthritis. Recipients were then treated with either the selective A2aR agonist CGS-21680 (CGS) or PBS vehicle alone. Severity of disease, autoantibody titers, KRN T cell numbers and phenotype, and GPI-specific isotype class-switched plasmablasts were tracked. RESULTS: CGS treatment inhibited arthritis development and KRN GC-Tfh cell differentiation, blocked the appearance of high affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in anti GPI IgG1 titers. Additionally, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reduced KRN GC-Tfh cell numbers and anti-GPI IgG1 titers. CONCLUSION: Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. Therefore, our data suggest that the A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets to interfere with autoreactive GC-Tfh cell differentiation. This article is protected by copyright. All rights reserved. PMID- 30516352 TI - Association of renal arteriosclerosis and hypertension with renal and cardiovascular outcomes in Japanese type 2 diabetic patients with diabetic nephropathy. AB - AIMS/INTRODUCTION: This retrospective study investigated the impact of renal arteriosclerosis (AS) and hypertension (HT) on long-term renal and cardiovascular outcomes in Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy. MATERIALS AND METHODS: A total of 185 patients were enrolled. Patients were divided into four groups stratified by renal AS status and presence of HT. The outcomes for this study were the first occurrence of renal events (a need for dialysis or a 30% decline in estimated glomerular filtration rate from baseline) and cardiovascular events (cardiovascular death, nonfatal myocardial infarction, coronary intervention, or nonfatal stroke). RESULTS: The proportion of renal AS score >=1 was 88.3% among normal-range blood pressure (BP) and 95.4% among HT. During a mean follow-up period was 7.6 years, 129 episodes of renal composite events and 55 of cardiovascular events were observed. Compared with patients with no renal AS and normal-range BP, renal AS score >=1 increased the risk of renal composite events with multivariable-adjusted hazard ratio (HR) of 3.21 (1.27-8.14) in patients with normal-range BP and 4.99 (1.98-12.54) in patients with HT, whereas renal AS score >=1 increased the risk of cardiovascular events with a multivariable-adjusted HR of 6.06 (1.24-29.61) in patients with normal-range BP and 10.02 (1.92-52.39) in patients with HT. CONCLUSIONS: Renal AS was associated with increasing risks for renal composite events and cardiovascular events in both normal-range BP and HT. The risks of renal composite events and cardiovascular events were the highest in both renal AS and HT. This article is protected by copyright. All rights reserved. PMID- 30516353 TI - Renal Resistive Index Predicts Post-Bariatric Surgery Renal Outcome in Nondiabetic Individuals with Severe Obesity. AB - OBJECTIVE: Bariatric surgery may ameliorate renal function through vascular mechanisms. This study tested surgery's ability to improve measured glomerular filtration rate (mGFR) and identified clinical, renal, and systemic vascular predictors of such improvement. METHODS: Twenty-five nondiabetic subjects with severe obesity were studied before and 1 year after Roux-en-Y gastric bypass, evaluating mGFR and renal plasma flow, basal renal resistive index (RI) and dynamic renal RI, renal visceral fat, and systemic vascular parameters, including flow-mediated dilation, aortic pulse wave velocity, and carotid intima media thickness and stiffness. RESULTS: After Roux-en-Y gastric bypass, BMI decreased by 31%. At follow-up, body surface area (BSA)-adjusted mGFR increased (from 86.9 +/- 15.2 to 109.0 +/- 18.2 mL/min/1.73 m2 , P < 0.001), whereas the absolute mGFR did not change. Renal plasma flow did not vary. RI decreased; flow-mediated dilation, pulse wave velocity, carotid intima media thickness, and carotid stiffness improved. mGFR changes after surgery (DeltamGFR/BSA) were associated with younger age and lower fasting glucose. Among vascular variables, an improved DeltamGFR/BSA was associated with smaller brachial artery diameter, lower intima media thickness, and lower RI; this latter association remained after adjusting for covariates. No measure of adiposity was associated with DeltamGFR. CONCLUSIONS: In subjects with obesity and normal renal function, bariatric surgery improves mGFR/BSA (although absolute mGFR is unchanged) and renal and systemic vascular function. Lower renal intravascular resistance can predict these improvements, maximizing them in relatively young individuals. PMID- 30516354 TI - Proteomics of Uterosacral Ligament Connective Tissue from Women With and Without Pelvic Organ Prolapse. AB - PURPOSE: Damage to the uterosacral ligaments is an important contributor to uterine and vaginal prolapse. The aim of this study was to identify differentially expressed proteins in the uterosacral ligaments of women with and without pelvic organ prolapse and analyze their relationships to cellular mechanisms involved in the pathogenesis of pelvic organ prolapse. EXPERIMENTAL DESIGN: Uterosacral ligament connective tissue from four patients with pelvic organ prolapse and four control women underwent iTRAQ analysis followed by Ingenuity Pathway Analysis of differentially expressed proteins. Differentially expressed proteins were validated using western blot analysis. RESULTS: A total of 1789 unique protein sequences were identified in the uterosacral ligament connective tissues. The expression levels of 88 proteins were significantly different between prolapse and control groups (>=1.2-fold, p<0.05). Ingenuity pathway analysis demonstrated the association of 14 differentially expressed proteins with "Connective Tissue Function". Among them, fibromodulin (FMOD), Collagen alpha-1 (XIV) chain (COL14A1), Calponin-1 (CNN-1), Tenascin (TNC), and Galectin-1 (LGALS1) appeared most likely to play a role in the etiology of pelvic organ prolapse. Data are available via ProteomeXchange with identifier PXD011467. CONCLUSIONS AND CLINICAL RELEVENCE: We identified at least 6 proteins not previously associated with the pathogenesis of pelvic organ prolapse with biologic functions that suggest a plausible relationship to the disorder. These results may be helpful for furthering our understanding of the pathophysiological mechanisms of pelvic organ prolapse. This article is protected by copyright. All rights reserved. PMID- 30516355 TI - Ex Vivo Tumor-on-a-Chip Platforms to Study Intercellular Interactions within the Tumor Microenvironment. AB - The emergence of immunotherapies and recent FDA approval of several of them makes them a promising therapeutic strategy for cancer. While these advancements underscore the potential of engaging the immune system to target tumors, this approach has so far been efficient only for certain cancers. Extending immunotherapy as a widely acceptable treatment for various cancers requires a deeper understanding of the interactions of tumor cells within the tumor microenvironment (TME). The immune cells are a key component of the TME, which also includes other stromal cells, soluble factors, and extracellular matrix based cues. While in vivo studies function as a gold standard, tissue-engineered microphysiological tumor models can offer patient-specific insights into cancer immune interactions. These platforms, which recapitulate cellular and non cellular components of the TME, enable a systematic understanding of the contribution of each component toward disease progression in isolation and in concert. Microfluidic-based microphysiological platforms recreating these environments, also known as "tumor-on-a-chip," are increasingly being utilized to study the effect of various elements of TME on tumor development. Herein are reviewed advancements in tumor-on-a-chip technology that are developed and used to understand the interaction of tumor cells with other surrounding cells, including immune cells, in the TME. PMID- 30516356 TI - The Influence of Physicochemical Properties of Biomimetic Hydroxyapatite on the In Vitro Behavior of Endothelial Progenitor Cells and Their Interaction with Mesenchymal Stem Cells. AB - Calcium phosphate (CaP) substrates are successfully used as bone grafts due to their osteogenic properties. However, the influence of the physicochemical features of CaPs in angiogenesis is frequently neglected despite it being a crucial process for bone regeneration. The present work focuses on analyzing the effects of textural parameters of biomimetic calcium deficient hydroxyapatite (CDHA) and sintered beta-tricalcium phosphate (beta-TCP), such as specific surface area, surface roughness, and microstructure, on the behavior of rat endothelial progenitor cells (rEPCs) and their crosstalk with rat mesenchymal stem cells (rMSCs). The higher reactivity of CDHA results in low proliferation rates in monocultured and cocultured systems. This effect is especially pronounced for rMSCs alone, and for CDHA with a fine microstructure. In terms of angiogenic and osteogenic gene expressions, the upregulation of particular genes is especially enhanced for needle-like CDHA compared to plate-like CDHA and beta TCP, suggesting the importance not only of the chemistry of the substrate, but also of its textural features. Moreover, the coculture of rEPCs and rMSCs on needle-like CDHA results in early upregulation of osteogenic modulator, i.e., protein deglycase 1 might be a possible cause of overexpression of osteogenic related genes on the same substrate. PMID- 30516357 TI - A novel psychosocial factor involved in diabetes self-care in the Japanese cultural context. AB - AIMS/INTRODUCTION: Recent evidence shows that cultural context can influence the management of diabetes mellitus. The aim of this study was to examine the relationship between interdependence, which is valued in the Eastern cultural context, and diabetes self-care behavior in Japanese patients with type 2 diabetes mellitus. MATERIAL AND METHODS: We conducted a cross-sectional survey of 161 Japanese adults with type 2 diabetes mellitus using well-established questionnaires. The association of an interdependent tendency with diabetes self care activities was analyzed using multiple regression analysis. RESULTS: Diabetes self-care activities had a negative correlation with interdependent tendency (r = -0.16, P = 0.047) and they had positive correlations with age (r = 0.42, P < 0.001), emotional support (r = 0.25, P = 0.001) and diabetes self-care support (r = 0.36, P < 0.001). When patients were divided into two groups at the median age (68 y), multiple regressions showed that interdependent tendency (beta= -0.20, P = 0.048), male sex (beta= -0.24, P = 0.023), emotional support (beta= 0.22, P = 0.028) and diabetes self-care support (beta= 0.39, P <0.001) were significant determinants of diabetes self-care activities only in the younger group. CONCLUSIONS: Interdependence may influence diabetes self-care behavior, and intervention focusing on support from close others may lead patients to more successful care in Japanese adults with type 2 diabetes mellitus, especially those under the age of 68. This article is protected by copyright. All rights reserved. PMID- 30516358 TI - Fabricated Elastin. PMID- 30516359 TI - Ultrathin Biomimetic Polymeric Ti3C2Tx MXene Composite Films for Electromagnetic Interference Shielding. AB - Lightweight, ultrathin and flexible electromagnetic interference (EMI) shielding materials with high electromagnetic shielding effectiveness and excellent mechanical robustness are greatly desired for miniaturized and highly integrated electronics. Herein, for the first time, a freestanding, ultrathin and flexible Ti3C2Tx/PEDOT:PSS composite film with "brick-and-mortar" structure is biomimetically designed and fabricated via a vacuum-assisted filtration process. The ultrathin polymeric composite film with a weight ratio of Ti3C2Tx to PEDOT: PSS for 7:1 is only 11.1 MUm in thickness, but exhibits a high EMI shielding effectiveness (SE) value of 42.10 dB. Meanwhile, the tensile strength increases considerably from 5.62 to 13.71 MPa and the corresponding ruptured strain increases from 0.18 to 0.29% compared with pure Ti3C2Tx MXene film, respectively. Moreover, the hybrid film displays a superior conductivity of 340.5 S/cm and outstanding specific EMI shielding efficiency of 19497.8 dB cm2 g-1. The superior electrical conductivity and specific EMI shielding efficiency imply the excellent potential of the Ti3C2Tx/PEDOT:PSS composite films for ultrathin, lightweight, and flexible EMI shielding materials. PMID- 30516360 TI - Headspace Gas Monitoring of Gut Microbiota Using Targeted and Globally Optimized Targeted Secondary Electrospray Ionization Mass Spectrometry. AB - This study aimed to develop and incorporate a secondary electrospray ionization (SESI) setup in combination with both targeted tandem mass spectrometry (MS/MS) and a hybrid metabolomics technique, globally optimized targeted mass spectrometry (GOT-MS), to sensitively detect volatile metabolites from the headspace of in vitro gut microbial culture in a human colonic model (HCM). Two SESI- tandem mass spectrometry panels with a comparable number of targeted metabolites/features (77 compounds in the targeted SESI-MS/MS panel, and 75 features in the SESI-GOT-MS/MS panel) were established. The analytical performance of SESI-GOT-MS/MS method, as well as its biological capability, were examined and compared with the targeted SESI-MS/MS method. As a result, SESI-GOT MS/MS method detected a similar number of metabolic features with good reproducibility (coefficient of variation < 10%) comparing to the targeted SESI MS/MS method. Both methods showed a comparable ability to differentiate the gut microbial culture with or without the addition of green tea extract (GTE) to a human colonic model (HCM). The results from analysis of variance (ANOVA) showed that similar numbers of compounds from targeted SESI-MS/MS and metabolic features from SESI-GOT-MS/MS have significant differences when comparing samples collected from different HCM treatment stages. Partial least squares discriminant analysis (PLS-DA) indicated that both methods could clearly differentiate the stages of GTE treatment. In summary, we demonstrated that SESI-MS/MS in combination with either targeted or GOT approaches can be a useful tool for monitoring gut microbial metabolism and their response to perturbations. PMID- 30516361 TI - The Effect of Crystal Grain Orientation on the Rate of Ionic Transport in Perovskite Polycrystalline Thin Films. AB - In this work, we examine the effect of microstructure on ion migration induced photoluminescence (PL) quenching in methylammonium lead iodide perovskite films. Thin films were fabricated by two methods: spin-coating, which results in randomly oriented perovskite grains, and zone-casting, which results in aligned grains. As an external bias is applied to these films, migration of ions causes a quenching of the PL signal in the vicinity of the anode. The evolution of this PL quenched zone is less uniform in the spin-coated devices than in the zone-cast ones, suggesting that the relative orientation of the crystal grains plays a significant role in the migration of ions within polycrystalline perovskite. We simulate this effect via a simple Ising model of ionic motion across grains in the perovskite thin film. The results of this simulation align closely with the observed experimental results, further solidifying the correlation between crystal grain orientation and the rate of ionic transport. PMID- 30516362 TI - Superhard Tungsten Diboride-Based Solid Solutions. AB - Solid solutions of tungsten diboride (WB2) with increasing substitution of tungsten (W) by tantalum (Ta) and niobium (Nb)-ranging from 0 to 50 at. % on a metals basis-were synthesized through resistive arc melting. Samples were characterized using a combination of powder X-ray diffraction (PXRD) for phase identification, energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy for elemental composition, Vickers microindentation for hardness measurements, and thermogravimetric analysis for thermal stability. The solubility limit was found to be less than 8 at. % for Nb and less than 10 at. % for Ta, as determined by PXRD. Vickers hardness ( Hv) values were measured to be 40.3 +/- 1.6 and 41.0 +/- 1.2 GPa at 0.49 N for 6 at. % Nb and for 8 at. % Ta substitution, respectively. In addition, the hardest solid solution (W0.92Ta0.08B2) showed oxidation resistance up to ~570 degrees C, approximately 70 degrees C higher than that of tungsten carbide (WC). Although pure WB2 is known not to be superhard, these results demonstrate the formation of superhard solid solutions through the substitution of tungsten by small amounts of transition metals. This increase in hardness can be attributed to solid solution hardening. PMID- 30516363 TI - Negative-Ion Mode Capillary Isoelectric Focusing-Mass Spectrometry for Charge Based Separation of Acidic Oligosaccharides. AB - Glycosaminoglycans (GAGs) are biologically and pharmacologically important linear, anionic polysaccharides containing various repeating disaccharides sequences. The analysis of these polysaccharides generally relies on their chemical or enzymatic breakdown to disaccharide units that are separated, by chromatography or electrophoresis, and detected, by UV, fluorescence or mass spectrometry (MS). Isoelectric focusing (IEF) is an important analytical technique with high resolving power for the separation of analytes exhibiting differences in isoelectric points. One format of IEF, the capillary isoelectric focusing (cIEF), is an attractive approach, in that it can be coupled with mass spectrometry (cIEF-MS) to provide on-line focusing and detection of complex mixtures. In the past three decades, numerous studies have applied cIEF-MS methods to the analysis of protein and peptide mixtures by positive-ion mode mass spectrometry. However, polysaccharide chemists largely rely on negative-ion mode mass spectrometry for the analysis of highly sulfated GAGs. The current study reports a negative-ion mode cIEF-MS method using an electrokinetically pumped sheath liquid nanospray capillary electrophoresis - mass spectrometry (CE-MS) coupling technology. The feasibility of this negative-ion cIEF-MS method and its potential applications are demonstrated using chondroitin sulfate and heparan sulfate oligosaccharides mixtures. PMID- 30516364 TI - A wearable fluid capture device for electrochemical sensing of sweat. AB - Wearable sensing technologies are vital for realizing personalized health monitoring. Non-invasive human sweat sampling is essential for monitoring an individual's physical state using rich physiological data. However, existing wearable sensing technologies lack the controlled capture of body sweats and in performing on-device measurement without inflammatory contact. Herein, we report the development of a wearable sweat-capture device using patterned graphene arrays with controlled superwettability and electrical conductivity for simultaneously capturing and electrochemically measuring the sweat droplets. The sweat droplets exhibited strong attachment on the superhydrophilic graphene patterns, even during moderate exercising. The captured sweat droplets present strong electrochemical signals using graphene films as the working electrode and metal pins as the counter electrode arrays assembled on 3D printed holders, at the detection limit of 6 uM detection limit for H2O2 sensing. This research enables full-body spatiotemporal mapping of sweat, beneficial for a broad range of personalized monitoring applications, such as drug abuse detection, athletics performance optimization, and physiological wellness tracking. PMID- 30516365 TI - Aerobic and Anaerobic Bacterial Mercury Uptake is Driven by Algal Organic Matter Composition and Molecular Weight. AB - The biological mobilization of mercury (Hg) into microbes capable of Hg methylation is one of the limiting steps in the formation of the neurotoxin methylmercury (MeHg). Although algal dissolved organic matter (DOM) has been associated with increased MeHg production, the relationship between bacterial Hg uptake and algal DOM remains unexplored. In this study, we aimed to address how the quantity and quality of DOM freshly harvested from several algae affected the bacterial uptake of Hg using a biosensor capable of functioning both aerobically and anaerobically. We combined biosensor measurements with high resolution mass spectrometry and field-flow fractionation to elucidate how DOM composition and molecular weight influence microbial Hg uptake. We showed that freshly harvested DOM from Chlorophyte and Euglena mutabilis strongly inhibited aerobic and anaerobic Hg uptake, whereas DOM harvested from Euglena gracilis did not exhibit this same pronounced effect. Once fractionated, we found that amino acids and polyamines, most abundant in Euglena gracilis DOM, were positively correlated to increase Hg uptake, suggesting that these molecules are potentially underappreciated ligands affecting Hg bioavailability. As water quality is affected by eutrophication, algal community assemblages will change, leading to variations in the nature of autochthonous DOM released in aquatic systems. Our results highlight that variations in the emergent properties of DOM originating from varying algal species can have a profound effect on bacterial Hg uptake and thus methylation. PMID- 30516366 TI - Molybdenum Complexes that Contain a Calix[6]azacryptand Ligand as Catalysts for Reduction of N2 to Ammonia. AB - [CAC(OMe)6]Mo(N) (3, where [CAC]3- is a calix[6]azacryptand ligand derived from a [6]calixarene) has been prepared in a reaction between Li3[CAC(OMe)6] and ( t BuO)3Mo(N). An X-ray structural study showed 3 to have a structure similar to that of [HIPTN3N]Mo(N) (where [HIPTN3N]3- is [(3,5-(2,4,6 triisopropylphenyl)2C6H3NCH2CH2)3N]3-). The relatively rigid [CAC(OMe)6]3- ligand in 3 forms a bowl-shaped cavity defined by a 24-atom macrocyclic ring. The Mo Namido-Cipso angles are ~8 degrees smaller in 3 than they are in [HIPTN3N]Mo(N). Methoxides on the three linking units point into the cavity above the nitride in 3, whereas the three methoxides on phenyl rings attached to the amido nitrogen atoms point away from the cavity. An analogous [CAC(OMe)3(H)3]Mo(N) complex (9) was prepared in which the three methoxides pointing into the cavity in 3 have been replaced by protons. Its structure differs little from that of 3. The nitride could be protonated in 3 to give {[CAC(OMe)6]Mo(NH)}+, which could be reduced (reversibly) to [CAC(OMe)6]Mo(NH). Catalytic reduction of molecular nitrogen under a variety of conditions with either Ph2NH2OTf or HBArf (BArf- = {B[3,5(CF3)2C5H3]4}-) as the acid and a Co metallocene or KC8 as the reducing agent between -78 and 22 degrees C in diethyl ether shows that 1.20-1.34 equivalents of ammonia are formed starting with either [CAC(OMe)6]Mo(N) (50% 15N) or [CAC(OMe)3(H)3]Mo(N) (50% 15N). PMID- 30516367 TI - Revealing the degradation mechanism of LiMnxFe1-xPO4 by single particle electrochemistry method. AB - The commercial application of LiMnxFe1-xPO4 materials has always been a great challenge due to its unsatisfactory structure stability during cycling and the safety issue. Herein, single-particle (SP) electrodes, where aggregated LiMnxFe1 xPO4 is dispersed into SPs so they can distribute homogeneously in the carbon nanotube networks, has been prepared and characterized to probe its degradation mechanism for the first time. Compared with conventionally prepared cathode, the SP LiMnxFe1-xPO4 cathode shows prominent capacity fading with cycle numbers, which can be attributed to the formation of the MnF2 nanocrystals on the surface of LiMnxFe1-xPO4 due to the reaction between F- and dissolved Mn2+ at the interface between the electrolyte and LiMnxFe1-xPO4. The different electrochemical behaviors can be ascribed to LiMnxFe1-xPO4 SPs surface reconstruction with MnF2 nucleation and growth by the interfacial reactions. In addition, by applying a thin protecting layer of Al2O3 on the surface of LiMnxFe1 xPO4, the interfacial side-reactions can be suppressed. This work demonstrates that SP method is a powerful tool to extract the information of interfacial reactions, which sometimes appear to be negligible compared with bulk reactions. PMID- 30516368 TI - Ratiometric Monitoring of Thorium Contamination in Natural Water using a Dual Emission Luminescent Europium Organic Framework. AB - Traditional analytical methods of thorium contamination suffer from several disadvantages such as time-consuming procedure and equipment-intensive nature, leading to substantial challenges in rapid and onsite monitoring of thorium concentration in complex natural water systems. We report here the first case of luminescent metal organic framework based probe (ThP-1) for highly sensitive and selective self-calibrated sensing of Th4+ contamination in natural fresh water media with a notably facilitated detection procedure. The detection limit of ThP 1 was determined to be 24.2 ppb, much lower than the thorium contamination standard of 246 ppb in drinking water defined by the World Health Organization. Importantly, the detection procedure based on the rarely reported self calibration manner is greatly beneficial on improving the detection accuracy. The self-calibrated luminescence evolution process is of great anti-interference ability capable of detecting thorium contamination in a wide concentration range from 24.2 ppb to 300 ppm, which can not be achieved directly by the traditional methods. The Th4+-selective luminescence response originates from the selective uptake and efficient enrichment of Th4+ by the host framework of ThP-1 through inner-sphere coordination, which is further confirmed by batch experiments, X-ray absorption spectroscopic study, and DFT calculations. PMID- 30516369 TI - Abnormal Ionic Current Rectification Caused by Reversed Electroosmotic Flow under Viscosity Gradients across Thin Nanopores. AB - Single nanopores have attracted much scientific interest due to their versatile applications. The majority of experiments have been performed with nanopores being in contact with the same electrolyte on both sides of the membrane, while solution gradients across semi-permeable membranes are omnipresent in natural systems. In this manuscript, we studied ionic and fluidic movement through thin nanopores under viscosity gradients both experimentally and using simulations. Ionic current rectification was observed under these conditions, due to solutions with different conductivities filled across the pore under different biases caused by electroosmotic flow. We found that a pore filled with high viscosity solutions exhibited current increase with applied voltage in a steeper slope beyond a threshold voltage, which abnormally reduced the current rectification ratio. Through simulations, we found reversed electroosmotic flow that filled the pore with aqueous solutions of lower viscosities was responsible for this behavior. The reversed electroosmotic flow could be explained by slower depletion of coions than counterions along the pore. By increasing the surface charge density of pore surfaces, current rectification ratio could reach the value of the viscosity gradient across thin nanopores. Our findings shed light on fundamental aspects to be considered when performing experiments with viscosity gradients across nanopores and nanofluidic channels. PMID- 30516370 TI - Injectable, magnetically-orienting electrospun fiber conduits for neuron guidance. AB - Magnetic electrospun fibers are of interest to biomaterial applications that strive to provide cell guidance that can be delivered using minimally invasive techniques. Magnetic electrospun fibers can be injected then magnetically positioned in situ, and the aligned fiber scaffolds provide consistent topographical guidance to cells. We developed and tested magnetically-responsive aligned poly-L-lactic acid (PLLA) electrospun fiber scaffolds for neural applications. Incorporating oleic-acid-coated iron oxide nanoparticles significantly increased neurite outgrowth, reduced the fiber alignment, and increased the surface nanotopography of the electrospun fibers. After verifying neuron viability on two-dimensional scaffolds, the system was tested as an injectable three-dimensional scaffold. Small conduits of aligned magnetic fibers were easily injected in a collagen or fibrinogen hydrogel solution and repositioned using an external magnetic field. The aligned magnetic fibers provided internal directional guidance to neurites within a three-dimensional collagen or fibrin model hydrogel, supplemented with Matrigel. Neurites growing from a dorsal root ganglia explant extended 1.4-3x farther on the aligned fibers compared to neurites extending in the hydrogel alone. Overall, these results show that magnetic electrospun fiber scaffolds can be injected and manipulated with a magnetic field in situ to provide directional guidance to neurons inside an injectable hydrogel. Most importantly, this injectable guidance system increased both neurite alignment and neurite length within the hydrogel scaffold. PMID- 30516371 TI - Release and Transformation of BTBPE During the Thermal Treatment of Flame Retardant ABS Plastics. AB - Thermal scenarios inevitably occur during the lifecycle of engineering plastics laden with brominated flame retardants (BFRs). However, little information on the fate of embedded BFRs during the thermal processes is available. In this study, we measured the release and transformation of a typical BFR, 1,2-bis-(2,4,6 tribromophenoxy)ethane (BTBPE), during the thermal treatment of acrylonitrile butadiene styrene (ABS) plastics. The possible thermal scenarios were simulated by varying the heating temperature and atmosphere. The maximum release rate of BTBPE was observed at 350 degrees C. A release kinetic model was developed to explore the mechanism of BTBPE release while heating ABS. Material-phase diffusion was found to be the rate-determining step during release. According to the developed release model, it was estimated that 0.04-0.17% of embedded BTBPE could be released to air during the industrial processing of ABS plastics. When the heating temperature was >= 350 degrees C, approximately 15-56% of embedded BTBPE decomposed to bromophenols (BPs) and 1,3,5-tribromo-2-(vinyloxy) benzene (TBVOB), and the decomposition followed a first-order kinetics at 350 degrees C. Polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) were also significantly formed at >= 350 degrees C from BPs and TBVOB via a precursor mechanism. A higher temperature (>= 450 degrees C) was favorable for the formation of PBDFs. PMID- 30516372 TI - Silicon-Mediated Selective Homo- and Hetero-Coupling of Carbon Monoxide. AB - While the transformation of carbon monoxide to multicarbon compounds (fuels and organic bulk chemicals) via reductive scission of the enormously strong CO bond is dominated by transition-metals, splitting and deoxygenative reductive coupling of CO under nonmatrix conditions using silicon, the second most abundant nonmetal of the Earth's crust, is extremely scarce and mechanistically not well understood. Herein we report the selective deoxygena-tive homocoupling of carbon monoxide by divalent silicon utilizing the (LSi:)2Xant 1a (Xant = 9,9-dimethyl xanthene-4,5-diyl; L = PhC(NtBu)2) and (LSi:)2Fc 1b (Fc = 1,1'-ferrocenyl) as four-electron reduction reagents under mild reaction conditions (RT, 1 atm), affording the corresponding disilylketenes, Xant(LSi)2(u-O)(u-CCO) 2a and Fc(LSi)2(u-O)(u-CCO) 2b, respectively. However, the dibenzofuran analogue of 1b, compound 1c, was unreactive towards CO due to the longer distance between the two SiII atoms, which demonstrated the crucial role of the Si???Si distance on cooperative CO binding and activation. This is confirmed by Density Functional Theory (DFT) calculations and further theoretical investigations on CO homocoupling with 1a and 1b revealed that the initial step of CO binding and scission involved CO acting as a Lewis acid (four-electron acceptor), in sharp contrast to CO activation mediated by transition-metals where CO serves as a Lewis base (two-electron donor). This mechanism was strongly reinforced by the reaction of 1a with isocyanide Xyl-NC (Xyl = 2, 6-Me2C6H3), isoelectronic with CO. Treatment of 1a with one or two molecules of Xyl-NC furnished the unique (silyl)(imido)silene 3a and the C=C coupled bis(Xyl-NC) product 5, respectively, via the isolable doubly-bridged Xant(LSi)2(u-XylNC)2 intermediate 4. Moreover, compound 3a reacts with one molar equiv of CO to give the disilylketenimine Xant(LSi)2(u-O)(u-CCNR) 6, representing, for the first time, a selective heterocou-pling product of CO with isoelectronic isocyanide (CNR). PMID- 30516373 TI - Lipid-based inhibitors act directly on GlyT2. AB - The endogenous lipids N-arachidonylglycine and oleoyl-L-carnitine, are potential therapeutic leads in the treatment of chronic pain through their inhibition of the glycine transporter GlyT2. However, their mechanism of action is unknown. It has been hypothesised that these "bioactive" lipids either inhibit GlyT2 indirectly, by significantly perturbing the biophysical properties of the membrane; or directly, by binding directly to the transporter (either from a membrane-exposed or solvent-exposed binding site). Here, we used molecular dynamics simulations to study the effects of the lipids anandamide, N arachidonylglycine and oleoyl-L-carnitine on a) the biophysical properties of the bilayer, and b) direct binding interactions with GlyT2. During the simulations, the biophysical properties of the bilayer itself-for example the area per lipid, bilayer thickness and order parameters-were not significantly altered by the presence or type of bioactive lipid, regardless of the presence of GlyT2. Our work, together with previous computational and experimental data, suggests that these acyl-inhibitors of GlyT2 inhibit the transporter by directly binding to it. However, these bioactive lipids bound to various parts of GlyT2 and did not prefer a single binding site during 4.5 MUs of simulation. We postulate that the binding site is located at the solvent-exposed regions of GlyT2. Understanding the mechanism of action of these, and related bioactive lipids is essential in effectively developing high-affinity GlyT2 inhibitors for the treatment of pain. PMID- 30516374 TI - Metal-Organic Framework Showing Selective and Sensitive Detection of Exogenous and Endogenous Formaldehyde. AB - In this work, we report a new hydrazine-functionalized Al(III)- based metal organic framework having MIL-53 (MIL = Material of Institute Lavoisier) framework topology for the sensitive and selective detection of formaldehyde (FA). The phase purity of the thermally activated and as-synthesized forms of the material was examined by X-ray powder diffraction experiments, Fourier transform infrared spectroscopy, and thermogravimetric analysis. The desolvated material (1') showed great potential for the selective sensing of FA in the existence of other potentially competitive aldehydes in both aqueous and 10 mM HEPES buffer (pH = 7.4) media. The fluorescence "turn-on" behavior of the reaction-based probe can be ascribed to the inhibition of the photoinduced electron transfer process (from the hydrazine group to the phenyl ring) because of the formation of the hydrazone moiety. The detection limit of the probe toward FA in HEPES buffer is 8.37 MUM (0.25 ppm), which lies below the intracellular concentration of FA (100-400 MUM). A very short response time (1 min) has been displayed by 1' for FA sensing. Moreover, a remarkable enhancement in the emission intensity (sevenfold and fourfold in aqueous and HEPES buffer media, respectively) of 1' was observed after 1 min of FA addition. Furthermore, the ability of the probe to detect FA in the vapor phase was demonstrated. Interestingly, the material is also capable to detect endogenous FA in cancer cells. All the above discussed features clearly reveal that the present material has a huge potential for selective recognition of FA in both real water and biological samples. PMID- 30516375 TI - Humic Acids Limit the Precipitation of Cadmium and Arsenate at the Brushite-Fluid Interface. AB - Bioavailability and mobility of cadmium (Cd2+) and arsenate (As5+) in soils can be effectively lowered through the dissolution of brushite (dicalcium phosphate dihydrate, CaHPO4?2H2O) coupled with the precipitation of a more stable mineral phase containing both Cd and As. Due to the ubiquitous presence of humic acid (HA) in soil environments, it is more complex to predict the fate of dissolved Cd and As during such sequestration. Here, we used in situ atomic force microscopy (AFM) to image the kinetics of simultaneous precipitation of Cd and As at the brushite-fluid interface in the presence of HA. Results show that HA inhibits the formation of both amorphous and crystalline Cd(5-x)Cax(PO4)(3-y)(AsO4)y(OH) on the (010) face of brushite. A combination of X-ray photoelectron spectroscopy (XPS) and real-time surface-enhanced Raman spectroscopy (SERS) reveals that part of As5+ reduction into As3+ with HA and [HA-Cd] complexation occur, modulating the concentrations of free Cd2+ and As5+ ions to inhibit subsequent precipitation of a Cd(5-x)Cax(PO4)(3-y)(AsO4)y(OH) phase on the dissolving brushite surface. A combination of AFM imaging, SERS analyses and PhreeqC simulations suggests that environmentally relevant humic substances can limit the precipitation of Cd and As at mineral surfaces through a mechanism of oxidation/reduction and aqueous/surface complexation. This may exacerbate the transportation of these contaminants into waters by subsurface fluid flow. PMID- 30516376 TI - Correction to Acrylamide Induces Senescence in Macrophages through a Process Involving ATF3, ROS, p38/JNK, and a Telomerase-Independent Pathway. PMID- 30516377 TI - Amphiphile-Mediated Depalmitoylation of Proteins in Living Cells. AB - Post-translational S-palmitoylation plays a central role in protein localization, trafficking, stability, aggregation, and cell signaling. Dysregulation of palmitoylation pathways in cells can alter protein function and is the cause of sev-eral diseases. Considering the biological and clinical im-portance of S palmitoylation, tools for direct, in vivo mod-ulation of this dynamic lipid modification would be ex-tremely valuable. Here, we describe a method for the rapid cleavage of native S-palmitoyl groups from proteins in living cells. Using a cell permeable, cysteine-functionalized amphiphile, we demonstrate the direct de-palmitoylation of cellular proteins. We show that am-phiphile-mediated depalmitoylation (AMD) can effective-ly cleave S-palmitoyl groups from the native GTPase HRas, triggering its release from the plasma membrane. We also demonstrate that AMD successfully depal-mitoylates mislocalized proteins in an infantile neuronal ceroid lipofuscinosis (INCL) disease model. AMD ena-bles direct and facile depalmitoylation of proteins in live cells and has potential therapeutic applications for diseases such as INCL, where native protein thioesterase activity is deficient. PMID- 30516378 TI - Rational Design of an Amphiphilic Coordination Cage-based Emulsifier. AB - Self-assembled, porous coordination cages with a functional interior find application in controlled guest inclu-sion/release, drug delivery, separation processes, and catalysis. However, only few studies exist that describe their utilization for the development of self-assembled materials based on their 3 dimensional shape and external functional-ization. Here, dodecyl chain containing, acridone-based ligands (LA) and shape-complementary phenanthrene derived ligands (LB) are shown to self-assemble to heteroleptic coordination cages cis-[Pd2(LA)2(LB)2]4+ acting as a gemini amphiphile (CGA-1; Cage-based Gemini Amphiphile-1). Owing to their anisotropic decoration with short polar and long non-polar side chains, the cationic cages were found to assemble into vesicles with diameters larger than 100 nm in suitable polar solvents, visualized by cryo-TEM and Liquid-Cell Transmission Electron Microscopy (LC-TEM). LC-TEM reveals that these vesicles aggregate into chains and necklaces via long-range interac-tions. In addition, the cages show a rarely described ability to stabilize oil-in-oil emulsions. PMID- 30516379 TI - Development of the Smartphone-Assisted Colorimetric Detection of Thorium by Using New Schiff's Base and Its Applications to Real Time Samples. AB - In this paper, a new Th4+ ion-selective chromogenic sensor (L) was developed by reacting 1,10-phenanthroline-2,9-dicarbohydrazide with 2-hydroxy naphthaldehyde. The sensing ability of L toward Th4+ was investigated in solution and paper strips loaded with L using spectrophotometric and colorimetric methods. The selective interaction of L was examined with various f-metal ions and other selected metal ions from s-block and d-block elements. Results show that by the colorimetric method in solution-phase dimethyl sulfoxide/H2O (7:3, v/v) and paper strip methods, the naked-eye detectable color change of L occurred from colorless solution to yellow-orange and pale yellow colour upon interacting with Th4+ and Al3+, respectively, whereas other metal ions did not interfere. The ligand L exhibits two absorbance bands at 320 and 375 nm because of ligand-to-ligand charge transfer. Upon interaction with Th4+, L undergoes red shift of both absorption bands and the formation of a new UV-vis band at 335 and 440 nm. The UV visible spectral studies indicate the formation of a 1:1 host-guest complex between L and Th4+ with an association constant of 4.7 * 103 M-1. The limit of quantification and limit of detection of L for the analysis of Th4+ are found to be 167 and 50 nM, respectively. The visually detectable color change of L has been well integrated with a smartphone RGB color value to make it an analytical signal for real-time analysis of Th4+ with the detection limit down to 116 nM. Besides, L was applied for the analysis of Th4+ content present in various real water samples, monazite, and lantern mantle samples by spectrophotometry and RGB color values. The binding mode of L with Th4+ is investigated by 1H NMR, electrospray ionization-mass, and theoretical studies. PMID- 30516380 TI - Hydrogen Activation by Silica Supported Metal Ion Catalysts: Catalytic Properties of Metals and Performance of DFT Functionals. AB - Single-site heterogeneous catalysts (SSHC) have received increasing attention due to their well-defined active sites and potentially high specific activity. Detailed computational studies were carried out on a set of potential SSHC's i.e., silica supported metal ions, to investigate the reactivity of these catalysts with H2 as well as to evaluate the performance of density functional theory (DFT) methods in conjunction with triple-zeta quality basis sets (i.e., cc pVTZ) on reaction energetics. The ions considered include 4d and 5d metals as well as several post-transition metal ions. A representative cluster model of silica is used to calculate reaction free energies of the metal hydride formation that results from the heterolytic cleavage of H2 on the M-O bond. The hydride formation free energy is previously shown to be strongly correlated with the catalytic activity of such catalysts for alkene hydrogenation. ONIOM calculations (CCSD(T)//MP2) are used to assess the accuracy and reliability of the MP2 results and it is found that MP2 is a suitable level of theory for gauging the performance of DFT functionals. The performance of various DFT functionals is assessed relative to MP2 results and it is found that the wB97xd and PBE0 functionals have the lowest standard deviation (STD) value while the MN12SX and PBE functionals have the lowest mean absolute deviation (MAD) values. The B3LYP functional is shown to have the similar MAD and STD values as the top performing functionals. Potential active SSHC's for exergonic hydrogen activation predicted in this study include mostly late and post transition metal ions, i.e., Au3+, Pd2+, Pt4+, Pd4+, Tl3+, Ir4+, Hg2+, Rh3+, Pb4+, In3+, Ir3+, Os4+, Cd2+, Ru2+, and Ga3+. This study provides important guidance to future computational studies of such catalyst systems. PMID- 30516381 TI - NMR Quantification of Hydrogen-bond Activating Effects for Organocatalysts including Boronic Acids. AB - The hydrogen-bonding activation for 66 organocatalysts has been quantified using a 31P NMR binding experiment with triethylphosphine oxide (TEPO). Diverse structural classes, including phenols, diols, silanols, carboxylic acids, boronic acids, and phosphoric acids, were examined with a variety of steric and electronic modifications to understand how the structure and secondary effects contribute to hydrogen-bonding ability and catalysis. Hammett plots demonstrate high correlation for the Deltadelta 31P NMR shift to Hammett parameters establishing the ability of TEPO binding to predict electronic trends. Upon correlation to catalytic activity in a Friedel-Crafts addition reaction, data demonstrate that 31P NMR shifts correlate to catalytic activity better than pKa values. Boronic acids were investigated and 31P NMR binding experiments predicted strong H-bonding ability, for which catalytic activity was confirmed, resulting in the greatest rate enhancement observed in the Friedel-Crafts addition of all organocatalysts studied. A detailed investigation supports that boronic acid activation proceeds through hydrogen-bonding interactions and not coordination with the Lewis acidic boron center. Using 31P NMR spectroscopy offers a simple and rapid tool to quantify and predict H-bonding abilities for the design and applications of new organocatalysts and supramolecular synthons. PMID- 30516382 TI - Conformational states of E7010 is complemented by micro-clusters of water inside the alpha,beta-Tubulin core. AB - The alpha,beta-tubulin is the building block of the microtubules, which gets associated with and dissociated from the microtubular architecture complying with the dynamic instability of the microtubules. This dynamics has direct relation with the spindle formation by the microtubules and cell division kinetics. E7010 is one of the promising ligands of alpha,beta-tubulin protein that binds at the core of this protein and can diminish the protein's ability to fit to a growing microtubule; thus frustrates the cell division. Although x-ray crystallography has reported a specific binding conformation of E7010 in PDB, molecular dynamics (MD) simulations have revealed two other conformational states of the ligand capable to bind to tubulin with stabilities close to that state reported in PDB. To rationalize this quasi degeneracy of ligand binding modes, MD simulations have further revealed that the understanding of the mechanism of E7010-tubulin binding remains incomplete unless the role of water molecules to bridge this interaction is taken into consideration; a very critical insight that was not visible from the PDB structure. Further, these water molecules differ from the standard examples of 'bridging' waters which generally exists as isolated water molecules between receptor and ligand. In the present case the water molecules sandwiched between ligand and protein, sequestered from the bulk solvent, integrate with each other by HBonds network forming a group, which appear as micro clusters of water. The structural packing with the ligand binding pocket and the bridging of interactions between protein and ligand take place through such clusters. The presence of this micro-cluster of water is not just cosmetic, instead they have crucial impact on the ligand binding thermodynamics. Only with the explicit consideration of these water clusters in the binding energy calculations (MMGBSA), the stability of the native mode of ligand binding reported in PDB is rationalized. At the same time the two other binding modes are elucidated to be quasi degenerate with the native state and that indicates the further possibility in gaining more entropic stabilization of the complex. The role of such 'bridging' water clusters to enhance the protein-ligand interaction will be insightful for designing next generation prospective compounds in the field of cancer therapeutics. PMID- 30516383 TI - pi-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions. AB - The origins of pi-facial selectivities in the borohydride reduction of endocyclic iminium ions have been elucidated by density functional theory (DFT) calculations. In reductions of conjugated ("thermodynamic") iminium ions, the pi facial preference of the hydride attack was found to be due to torsional steering. Attack at the favored pi-face leads to a lower-energy "half-chair"-like conformation of the tetrahydropyridine product, whereas attack at the other pi face results in an unfavorable "twist-boat" conformation. In reductions of non conjugated ("kinetic") iminium ions, torsional distinction is small between the top- and bottom-face attacks, and the pi-facial selectivity of the hydride approach is primarily due to steric hindrance. PMID- 30516384 TI - Paper-based Versatile SERS Chip with Smartphone-based Raman Analyzer for Point of Care Application. AB - With the advanced development of the miniaturized Raman spectroscopy, surface enhanced Raman spectroscopy (SERS) has extended its applications into the field of Point of Care Testing (POCT) and demonstrated its great significance in virtue non-invasive property and capability of fingerprint identification. In the SERS based analysis and/or sensing system, the preparation of low cost, high performance SERS substrate is critically important. In this manuscript, vacuum filtration is utilized to fabricate the silver nanoparticles (AgNPs) embedded nylon filter membrane (ANFM) as flexible paper-based SERS chips. By characterizing the typical analytes with the miniaturized smartphone-based Raman analyzer, the proposed SERS chips have successfully demonstrated good sensitivity, repeatability and stability. The lowest concentration as detected can approach 1 pmol for Rhodamine 6G (RH6G) and 10 pmol for both crystal violet (CV) and malachite green (MG), respectively. With the help of microporous structure of the membrane, the ANFM based SERS chips can implement the separation of small molecules from complex mixture and can achieve "purified" SERS signals of targeted molecules. Besides, with the function of anti-friction resistance and flexibility, the ANFM can serve as SERS papers to pre-concentrate the contaminates by multiple swapping and further enhance the SERS signals for point of care analysis. Therefore, we demonstrate multi-functions of the flexible ANFM based SERS chips, which provides a promising solution for the POCT analysis with SERS technique on account of its flexibility and low fabrication cost. PMID- 30516385 TI - In-situ formed shields enabling Li2CO3-free solid electrolytes: A new route to uncover the intrinsic lithiophilicity of garnet electrolytes for dendrite-free Li metal batteries. AB - Introduction of inorganic solid electrolytes is believed to be an ultimate strategy to dismiss dendritic Li in high-energy Li-metal batteries (LMBs), and garnet-type Li7La3Zr2O12 (LLZO) electrolytes are impressive candidates. However, the current density for stable Li plating/stripping in LLZO is still quite limited. Here we create in-situ formed Li-deficient shields by the high temperature calcination at 900 degrees C. By this novel process, the formation of Li2CO3 on LLZO is restrained, and then we successfully obtain Li2CO3-free LLZO after removing the Li-deficient compounds. Without any surface modification, Li2CO3-free LLZO shows an intrinsic "lithiophilicity" characteristic. The contact angles of metallic Li on LLZO garnets are assessed by the first-principle calculation to confirm the "lithiophilicity" characteristic of LLZO electrolytes. The wetting of metallic Li on the Li2CO3-free LLZO surface leads to a continuous and tight Li/LLZO interface, resulting in an ultra-low interfacial resistance of 49 Omega cm2 and a homogenous current distribution in the charge/discharge processes of LMBs. Consequently, the current density for the stable Li plating/stripping in LLZO increases to 900 MUA cm-2 at 60 degrees C, one of the highest current density for LMBs based on garnet-type LLZO electrolytes. Our findings not only offer insight into the "lithiophilicity" characteristics of LLZO electrolytes to suppress dendritic Li at high current densities, but also expand the avenue towards high-performance, safe and long-life energy storage systems. PMID- 30516386 TI - Highly conductive 2D metal-organic framework thin film fabricated by liquid liquid interfacial reaction using one-pot synthesized benzenehexathiol. AB - Metal-organic frameworks (MOF) are studied extensively in applications like catalysts, gas storage and sensors due to their various functional groups and porous structures. Two-dimensional (2D) MOFs such as triphenylene-based materials show excellent charge transport properties but thin film fabrication and organic ligand synthesis are difficult. In this work, we synthesize thiol-based organic ligand, benzenehexathiol (BHT), by a simple one-pot reaction. This facile method is safer and faster than conventional synthesis procedure that requires using liquid ammonia as solvent. We also fabricate two novel 2D MOF materials by coordinating BHT either with Ag or Au ions using liquid-liquid interfacial reaction to obtain Ag3BHT2 and Au3BHT2 respectively. The Ag3BHT2 thin film reaches high electrical conductivity of 363 Scm-1, which has potential applications in electronic devices and sensors. PMID- 30516387 TI - Charged polystyrene nanoparticles near a SiO2/water interface. AB - Quartz crystal microbalance with dissipation (QCM-D) monitoring is traditionally used to investigate adsorption processes at liquid-solid interfaces but has also been applied increasingly to characterize the viscoelastic properties of complex liquids. Here, we contribute new insights to the latter field by using QCM-D to investigate the structure near an interface and high-frequency viscoelastic properties of charge stabilized polystyrene particles (radius 37 nm) dispersed in pure water. The study reveals changes with increasing ionic-strength from the crystalline order at low salt concentration to that with a less-structured particle distribution at high ionic strength. Replacing pure water with an aqueous particle dispersion is due to an increased mass load expected to give rise to a decrease in frequency, f. In the present work increases in both f and dissipation, D, were observed on exchanging pure water for the particle dispersion at low ionic strength. However, the QCM-D data are still well represented by a viscoelastic Voigt model, with the viscosity increasing from 1.0 to 1.3 mPa s as the particle volume fraction changed from 0.005 to 0.07. This increase is higher than predicted for dilute dispersions according to Einstein's equation for the viscosity of non-interacting hard spheres particles in liquids but can be explained by the charge repulsion between the particles giving rise to a higher effective volume fraction. It is also concluded that the polystyrene particles did not adhere to the solid surface but rather were separated by a layer of pure dispersion medium. The QCM-D response was successfully represented using a viscoelastic Kelvin-Voigt model, from which it was concluded that the thickness of the Newtonian dispersion medium layer was of the order of the particle-particle bulk separation, in the range 50 to 250 nm and was observed to decrease with both particle concentration and with addition of salt. Similar anomalous frequency and dissipation responses have been seen previously for colloidal systems containing weakly adherent colloidal particles and bacteria and in these cases interpreted in terms of coupled resonators. We here demonstrate that surface attachment is not required for such phenomena to occur, but that a viscoelastic liquid separated from the oscillating surface by a thin Newtonian layer can give rise to very similar responses. PMID- 30516388 TI - DNA-functionalized Nanoceria for Probing Oxidation of Phosphorus Compounds. AB - Chemical reactions without an obvious optical signal change, such as fluorescence or color, are difficult to monitor. Often, more advanced analytical techniques such as HPLC and mass spectroscopy are needed. It would be useful to convert such reactions to changes in optical signals. In this work, we demonstrate that fluorescently labeled DNA oligonucleotides adsorbed on nanomaterials can probe such reactions, and oxidation of phosphorus containing species was used as an example. Various metal oxides were tested and CeO2 nanoparticles were found to be the most efficient for this purpose. Among phosphate, phosphite, and hypophosphite, only phosphate produced a large signal, indicating its strongest adsorption on CeO2 to displace the DNA. This was further used to screen oxidation agents to convert lower oxidation state compounds to phosphate, and bleach was found to be able to oxidize phosphite. Canonical discriminant analysis was performed to discriminate various phosphorus species using a sensor array containing different metal oxides. Based on this, glyphosate was studied for its adsorption and oxidation. Although this method is not specific enough to be selective biosensors, it is useful as a tool to produce sensitive optical signals to follow important chemical transformations. PMID- 30516389 TI - Substituted Dihydroisoquinolinones by Iodide-Promoted Cyclocarbonylation of Aromatic alpha-Amino Acids. AB - Imidazolidinone derivatives of a range of aromatic alpha-amino acids, on treatment with phosgene and potassium iodide, undergo a mild Bischler-Napieralski style cyclocarbonylation reaction that generates a tricyclic lactam by insertion of a C?O group between amino acid nitrogen and the ortho position of the aryl substituent. Regio- and diastereoselective functionalization of the lactam generates a library of substituted dihydroisoquinolinones and their congeners in enantioenriched form. PMID- 30516391 TI - Index to Volume 235. PMID- 30516390 TI - Multisite vascular disease in acute coronary syndromes: increased in-hospital mortality and no improvement over time. AB - INTRODUCTION:: Limited data are available on the impact of multisite artery disease in patients with acute coronary syndromes. In particular, it is unknown whether the outcomes of those high-risk patients have improved over time. Therefore, we addressed the multisite artery disease patient population enrolled in the Swiss nationwide prospective acute coronary syndromes cohort study AMIS Plus over two decades. METHODS:: All patients enrolled from January 1999 to October 2016 were stratified according to the presence of isolated coronary artery disease or multisite artery disease, defined as coronary artery disease with known concomitant vascular disease (i.e. cerebrovascular disease and/or peripheral artery disease). Multisite artery disease 1 (MSAD1) and multisite artery disease 2 (MSAD2) defined patients with one and two additional vascular conditions, respectively. Primary outcome measures were in-hospital mortality and major adverse cardiovascular events (defined as re-infarction, stroke or death). RESULTS:: Among a total of 44,157 patients, 39,613 (89.7%) had coronary artery disease only while 4544 (10.3%) had multisite artery disease (4097 (9.3%) had MSAD1 and 447 (1.0%) had MSAD2). Compared with patients with coronary artery disease only, multisite artery disease patients were older, had a longer delay from symptom onset to hospital admission, had more frequently atypical presentation, presented more frequently with non-ST-segment elevation acute coronary syndromes, were more frequently in Killip class III/IV, had higher Charlson comorbidity index, more frequently had three-vessel coronary artery disease and were treated less frequently with evidence-based treatments such as aspirin, P2Y12 inhibitors, or beta-blockers. Similarly, multisite artery disease benefitted less frequently from coronary angiography as well as percutaneous coronary revascularisation. In-hospital mortality was 10.9% in multisite artery disease patients and 4.4% in coronary artery disease-only patients ( P<0.001). Corresponding major adverse cardiovascular events rates were 13.4% and 5.4% ( P<0.001). Cardiogenic shock, re-infarction and cerebrovascular events were significantly more frequent in multisite artery disease patients compared with coronary artery disease-only patients. In multivariable logistic regression analysis, multisite artery disease was identified as an independent predictor of in-hospital mortality (odds ratio 1.69, 95% confidence interval 1.47-1.94, P<0.001). Among multisite artery disease patients, mortality was the highest in MSAD2 individuals (15.4% vs. 10.4% among MSAD1 patients, P=0.001), the same was true for the major adverse cardiovascular events rates (19.1% in MSAD2 patients vs. 12.7% in MSAD1 patients, P<0.001). When stratified for the decade of enrollment, no improvement in mortality or major adverse cardiovascular events rates was observed in multisite artery disease patients. CONCLUSION:: Patients presenting with multisite artery disease were less likely to receive evidence based therapies than coronary artery disease-only patients and had increased in hospital morbidity and mortality, with no improvement over time. The worse outcomes were observed among MSAD2 patients. These results should prompt awareness for multisite artery disease as a high-risk condition in the setting of multisite artery disease. PMID- 30516392 TI - Clinical trial on the effects of amantadine on traumatic brain injury outcome. Is there more than meets the eye? PMID- 30516393 TI - Perioperative safety in patient under oral anticoagulation during holmium laser enucleation (HoLEP) of the prostate. AB - Introduction & Objectives To evaluate the safety of holmium laser enucleation of the prostate (HoLEP) in patients on oral anticoagulation (OA) with respect to intra- and postoperative bleeding complications. Methods Between 01/2013 and 10/2016, 2178 patients were included in this study, of whom 94 received direct oral anticoagulants (DOACs) and 151 received Vitamin K antagonists (VKAs) before HoLEP. All patients either ceased OA (DOACs) or were bridged subtherapeutically (VKAs, INR<2) during surgery. These patients were compared to a sample size of 1933 non-anticoagulated patients. Results A significant longer postoperative stay was noted for the patients on DOACs (5.2 (4-6) days) and VKAs (5.3 (4-5) days) compared to the control group (4.5 (4-4) days). The mean drop in haemoglobin was significantly higher in the VKA group compared to the DOAC and control group. There was a significant higher rate of postoperative bladder tamponades/secondary coagulation in patients on OA with 6 (7.9%)/3 (3.9%) patients in the DOAC group, 10 (7.4%)/6 (4.4%) patients in the VKA group compared to 37 (2.2%)/21 (2.1%) patients in the control group, respectively (p<0.001). 8 patients required blood transfusions with a distribution of 1 (1.3%), 3 (2.2%) and 4 (0.2%) patients in the DOAC, VAK and control group, respectively (p<0.001). Conclusions Our findings indicate that bridged patients who's DOACs and VKAs were ceased before HoLEP are at higher risk of intra- and postoperative bleeding complications. Nonetheless, HoLEP appears to be a safe and effective procedure in those patients. PMID- 30516394 TI - Summary for Clinicians: Clinical Practice Guideline for Management of Malignant Pleural Effusions. PMID- 30516395 TI - Phlebotomy Methods May Affect QuantiFERON Gold Plus Assay Results. PMID- 30516396 TI - Is emotion regulation associated with cancer-related psychological symptoms? AB - OBJECTIVES: This study examined the cross-sectional and prospective relationships between subjective (cognitive reappraisal, expressive suppression and experiential avoidance) and objective (high-frequency heart rate variability [HF HRV]) measures of emotion regulation (ER) and a set of psychological symptoms (anxiety, depression, fear of cancer recurrence [FCR], insomnia, fatigue, pain, and cognitive impairments) among women receiving radiation therapy for non metastatic breast cancer. DESIGN: Eighty-one participants completed a battery of self-report scales within 10 days before the start of radiotherapy (T1) and within 10 days after its end (T2; approximately 6 weeks after T1). HF-HRV at rest was measured at T1. RESULTS: Canonical correlation analyses revealed that higher levels of experiential avoidance and expressive suppression were cross sectionally associated with higher levels of all symptoms, except pain, at T1 and at T2 (both p's < 0.0001). Higher levels of suppression and reappraisal at T1 were marginally associated with reduced FCR and with increased depression and fatigue between T1 and T2 (p = 0.07). HF-HRV was not associated with symptoms cross-sectionally or prospectively. CONCLUSIONS: Although preliminary, these results are consistent with the hypothesis that maladaptive ER strategies, assessed subjectively, may cross-sectionally act as a transdiagnostic mechanism underlying several cancer-related psychological symptoms. PMID- 30516397 TI - Scared or Attached? Unraveling Important Links in Strain-Crime Relationships Among School Students. AB - Drawing on general strain theory of crime, the study employs the survey data from a random sample of 600 school students in Lviv, Ukraine, to examine how sanction risks and social bonds mediate and moderate the relationship between strain and adolescent delinquency. Findings from negative binomial regressions and the KHB decomposition procedure demonstrate that fear of sanctions and levels of social control mediate the relationships between strain and delinquency to a different degree, depending on the type of strain experienced. Results concerning conditioning effects are mixed, with only parental monitoring found to be a moderator of the strain-delinquency link. However, the direction of the interaction effect is unexpected. Future research needs to improve the specification of strain models and evaluate them in other sociocultural contexts. PMID- 30516398 TI - The toxicology of air pollution predicts its epidemiology. AB - The epidemiologic investigation has successively delineated associations of air pollution exposure with non-malignant and malignant lung disease, cardiovascular disease, cerebrovascular disease, pregnancy outcomes, perinatal effects and other extra-pulmonary disease including diabetes. Defining these relationships between air pollution exposure and human health closely parallels results of an earlier epidemiologic investigation into cigarette smoking and environmental tobacco smoke (ETS), two other particle-related exposures. Humic-like substances (HULIS) have been identified as a chemical component common to cigarette smoke and air pollution particles. Toxicology studies provide evidence that a disruption of iron homeostasis with sequestration of host metal by HULIS is a fundamental mechanistic pathway through which biological effects are initiated by cigarette smoke and air pollution particles. As a result of a common chemical component and a shared mechanistic pathway, it should be possible to extrapolate from the epidemiology of cigarette smoking and ETS to predict associations of air pollution exposure with human disease, which are currently unrecognized. Accordingly, it is anticipated that the forthcoming epidemiologic investigation will demonstrate relationships of air pollution with COPD causation, peripheral vascular disease, hypertension, renal disease, digestive disease, loss of bone mass/risk of fractures, dental disease, eye disease, fertility problems, and extrapulmonary malignancies. PMID- 30516399 TI - Source-apportioned coarse particulate matter exacerbates allergic airway responses in mice. AB - Exposure to coarse particulate matter (PM) is associated with lung inflammation and exacerbation of respiratory symptoms in sensitive populations, but the degree to which specific emission sources contribute to these effects is unclear. We examined whether coarse PM samples enriched with diverse sources differentially exacerbate allergic airway responses. Coarse PM was collected weekly (7/2009 6/2010) from urban (G.T. Craig [GTC]) and rural (Chippewa Lake Monitor [CLM]) sites in the Cleveland, Ohio area. Source apportionment results were used to pool GTC filter PM extracts into five samples dominated by traffic, coal, steel (two samples), or road salt sources. Five CLM samples were prepared from corresponding weeks. Control non-allergic and house dust mite (HDM)-allergic Balb/cJ mice were exposed by oropharyngeal aspiration to 100 MUg coarse GTC or CLM, control filter extract, or saline only, and responses were examined 2 d after PM exposures. In allergic mice, CLM traffic, CLM road salt and all GTC samples except steel-1 significantly increased airway responsiveness to methacholine (MCh) compared with control treatments. In non-allergic mice, CLM traffic, CLM steel-2 and all GTC samples except coal significantly increased bronchoalveolar lavage fluid (BALF) neutrophils, while only CLM traffic PM increased eosinophils in allergic mice. In non-allergic mice, CLM coal PM increased BALF interleukin (IL)-13 and GTC steel-1 PM increased TNF-alpha levels. These results demonstrate that equal masses of GTC and CLM coarse PM enriched with a variety of sources exacerbate allergic airway disease. Greater PM concentrations at the urban GTC site signify a greater potential for human health effects. PMID- 30516400 TI - Intestinal metaplasia at the gastroesophageal junction is associated with gastroesophageal reflux but not with Helicobacter pylori infection. AB - OBJECTIVE: Studies of the etiology of intestinal metaplasia (IM) at a normal appearing gastroesophageal junction (GEJ) are conflicting as associations with both H. Pylori (HP) infection and gastroesophageal reflux has been reported. The aim of this study was to investigate whether IM at the GEJ is associated with gastroesophageal reflux or HP infection. MATERIAL AND METHODS: Fifty asymptomatic volunteers and 149 patients with reflux symptoms underwent endoscopy with biopsies obtained from the gastric antrum and the squamocolumnar junction (SCJ). All subjects underwent wireless 48 h pH monitoring with the electrode placed immediately above the SCJ and a fecal antigen test for HP infection. Clinical characteristics and the pattern of reflux were compared in subjects with and without IM. RESULTS: Three asymptomatic volunteers and 35 patients who had clearly irregular SCJs with short extensions of columnar mucosa were excluded from the study. In the remaining 47 asymptomatic volunteers and 114 patients, variables that reached a significance level of 0.1 or less on univariate analyses were used in a binomial regression analysis to assess their relative importance for the finding of IM. IM at the GEJ was significantly associated with abnormal distal esophageal acid exposure (5.5 (1.2-24.6), p = .026), the frequency of reflux episodes/hour (1.5 (1.1-2.2), p = .031), and an endoscopic appearance of the SCJ corresponding to ZAP grade I (4.6 (1.4-15.6), p = .013). There was no association with HP infection. CONCLUSION: The finding of IM at an endoscopically normal-appearing GEJ is associated with gastroesophageal reflux but not with HP infection. PMID- 30516401 TI - Long term outcome of EUS-based strategy for suspected choledocholithiasis but negative CT finding. AB - OBJECTIVES: The American Society for Gastrointestinal Endoscopy (ASGE) guidelines offered the risk-stratified approach in suspected choledocholithiasis. Previous studies have raised concern about the insufficient accuracy of the guideline, especially in high probability group. The purposes of this study were to authenticate the stratification and clinical predictors of the guidelines for suspected choledocholithiasis with no visible choledocholithiasis on computed tomography (CT) and to make clear the clinical strategy of endoscopic ultrasonography (EUS). MATERIALS AND METHODS: We carried out the retrospective single-center study of 156 patients with suspected choledocholithiasis but negative findings on CT who underwent EUS for about 8 years at Samsung Medical Center. We assessed the clinical predictors of the ASGE guidelines in predicting the presence of choledocholithiasis and the outcome of the EUS. RESULTS: Fifty three of the 156 patients had positive findings on EUS that included choledocholithiasis (n = 43, 27.6%) or obstructive papillitis (n = 10, 6.4%). Among the 53 patients, 51 (96.2%) had choledocholithiasis or obstructive papillitis on ERCP. The 101 patients of 103 patients with negative finding on EUS did not show biliary events during follow-up period. EUS accuracy was 98.7% (sensitivity 100%; specificity 98.1%). Among the 49 patients with high probability, 21 (42.9%) had choledocholithiasis on ERCP. In 107 patients who were classified as intermediate probability, 30 (27.3%) had choledocholithiasis. There were no complications related to EUS. CONCLUSIONS: Not only intermediate probability group but also high probability group without definite acute cholangitis may require EUS. Application of EUS for suspected choledocholithiasis is highly accurate, safe and reduces unnecessary invasive ERCP in 57.1% of patients with high probability group. PMID- 30516402 TI - Fast-track hip and knee arthroplasty - have we reached the goal? PMID- 30516403 TI - Many Ways-One Destination: Different Types of Neutrophils Death. AB - Neutrophils constitute the most numerous populations of peripheral blood leukocytes, fulfilling the fundamental role in the development of the innate immune response. As the cells of the first line of defense, they guard the organism against the spread of pathogenic microorganisms. Neutrophils, similar to the other cells of the immune system, enter the path of death after fulfilling their biological function. Depending on the conditions that they are found in, they may undergo different types of cell death which requires the involvement of numerous signaling pathways. In this review article, we summarize the current state of knowledge regarding the different forms of neutrophil death, such as apoptosis, necrosis, necroptosis, autophagy, NETosis and pyroptosis. PMID- 30516404 TI - Peripheral blood lymphocyte subset repertoires are biased and reflect clinical features in patients with dermatomyositis. AB - OBJECTIVE: Dermatomyositis (DM) is an idiopathic inflammatory myopathy which often involves the lungs. DM is likely to be associated with aberrant T- and B cell activation in the pathogenesis because of the proven effectiveness of T- and B-cell-targeted treatments. Assuming that the aberrant activation is reflected by biases in the lymphocyte subset repertoires, we aimed to elucidate these biases, especially in relation to clinical features of DM. METHOD: Based on the immunophenotyping standardized by the Human Immunology Project Consortium, untreated 13 DM patients, including seven patients with interstitial lung disease (ILD), and 18 age-matched healthy donors (HDs) were examined for proportions of peripheral blood lymphocyte subsets. Six DM patients were examined before and after successful induction of remission. RESULTS: Naive CD4+ T cells and naive B cells were more abundant, while there were fewer naive CD8+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, Th1 cells, Tfh cells, and memory B cells in DM patients than in HDs. When the patients were subgrouped according to the presence of ILD, the lymphocyte subset repertoires in the patients with ILD contributed to the statistical differences in all the biased lymphocyte subset proportions. After treatment, transitional B cells vanished and there was an increase in memory B cells. CONCLUSION: The lymphocyte subset repertoires in the DM patients were biased, and were associated with the presence of ILD and disease activity of DM. PMID- 30516405 TI - Recurrent natural killer/T-cell lymphoma of the lacrimal sac and nasolacrimal duct in a 59-year-old Caucasian woman. AB - A 59-year-old Caucasian woman with past medical history significant for Natural Killer (NK)/T-cell lymphoma of the right nasal septum in remission for nine months presented after surveillance PET-CT imaging revealed increased metabolic activity in the right nasolacrimal duct. She also reported ipsilateral epiphora starting around this time. The lacrimal sac and nasolacrimal ductal mucosa were biopsied via an external approach. Pathologic evaluation revealed a proliferation of lymphoid cells with necrotic tissue. Immunohistochemical staining demonstrated predominantly CD3+, EBER+, and CD56+ cells indicating recurrent NK/T-cell lymphoma. This case describes an unusual presentation of recurrent NK/T-cell lymphoma involving the lacrimal excretory system in a Caucasian adult. Recurrent malignancy should be considered in the differential of any patient with a history of a lymphoproliferative disorder near the lacrimal drainage system who presents with new onset epiphora. PMID- 30516406 TI - Overexpression of LH3 reduces the incidence of hypertensive intracerebral hemorrhage in mice. AB - Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention. PMID- 30516407 TI - An update on the cutaneous manifestations of coeliac disease and non-coeliac gluten sensitivity. AB - INTRODUCTION: Coeliac disease is a gluten-induced immune-mediated enteropathy, characterised by the expression of specific genotypes and the production of autoantibodies. The inflammatory process specifically targets the intestinal mucosa, but gastrointestinal and extraintestinal signs and symptoms can also be present. Non-coeliac gluten sensitivity (NCGS) can be diagnosed in individuals who have intestinal and/or extraintestinal symptoms related to the ingestion of gluten, but do not have autoantibodies and do not suffer from lesions in the duodenal mucosa. Among the extraintestinal manifestations, cutaneous manifestations are the most common for both diseases. PURPOSE: We conducted this review to illustrate the common and uncommon features underlying the association of coeliac disease and NCGS with cutaneous manifestations related to gluten ingestion. Areas covered: The roles of innate and adaptive immunity in the cutaneous appearance of gluten sensitivity will be discussed. PMID- 30516408 TI - Weight affects survival of primary total knee arthroplasty: study based on the Danish Knee Arthroplasty Register with 67,810 patients and a median follow-up time of 5 years. AB - Background and purpose - Obesity is a rising issue worldwide and growing evidence supports poor outcome amongst obese patients following total knee arthroplasty (TKA). Using nationwide registries we investigated the association between bodyweight and risk of revision of primary TKA. Patients and methods - All primary TKA performed during 1997-2015, weight at time of primary TKA and subsequent TKA revisions were identified in the Danish Knee Arthroplasty Register (DKR). Data on comorbidities and a priori selected confounding variables were collected from nationwide registries. The association between weight and 1st time TKA revision was calculated as both crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) using Cox regression. Results - Of 67,810 identified primary TKAs, 4.8% were revised within a median follow-up time of 5.4 years. No association between weight and risk of any revision in patients aged 18 54 and 55-70 years was found. Increased risk of any revision was seen in patients >70 years, 80-89 kg (aHR =1.5, CI 1.2-1.8), 90-99 kg (aHR =1.7, CI 1.3-2.1) and patients >99 kg (aHR =1.6, CI 1.3-2.1), as well as those weighing 45-60 kg (aHR =1.4, CI 1.1-1.9) compared with same aged patients weighing 70-79 kg. Interpretation - We found a complex association between weight and knee arthroplasty survival. There was an increased risk of any revision in patients older than 70 years of age weighing <60 kg and >80 kg. Patients aged 18-55 years weighing 60-69 kg had a lower risk of revision compared with all other weight groups, whereas weight was not found to affect risk of any revision in patients aged 55-70 years. PMID- 30516409 TI - Acute fulminant myocarditis in a patient with primary Sjogren's syndrome. PMID- 30516410 TI - A new perspective in oculoplastic surgical management of symptomatic distichiasis in lymphedema-distichiasis syndrome. AB - Lymphedema-distichiasis syndrome (LDS) is an autosomal dominant condition associated with FOXC2 mutations. Patients with distichiasis are mostly symptomatic, and efforts to deal with their ocular complaints comprise of electrolysis, cryotherapy and a variety of surgical techniques. We describe an enhanced surgical technique for a case of symptomatic distichiasis of the right eye with scarred, irregular eyelid margins secondary to initial cryotherapy, whereby the distorted tarsus was excised to remove the aberrant hair follicles, the levator palpebrae superioris was released to extend the upper lid and prevent lagophthalmos and a mucous membrane graft was used to cover the exposed portion of the tarsal plate. At 14 months follow up, the lid cosmesis and position remained satisfactory, with no infection or rejection of the mucous membrane graft. Therefore, this surgical technique provides a sound option for symptomatic distichiasis, where cryotherapy can cause lid irregularity and keratinization. PMID- 30516411 TI - "Leaving Was a Process, Not an Event": The Lived Experience of Dating and Domestic Violence in 140 Characters. AB - One of the most frequent refrains heard in the public discourse on intimate partner violence (IPV) is why do they stay? The literature has demonstrated that IPV victims face multiple barriers to safely exiting their relationships. Currently, there has been a limited examination of the role social media can play in elucidating the lived experience of IPV. With 25% of the population using Twitter, there are opportunities to examine its utility for deepening understandings of IPV. Using data generated from the #WhyIStayed Twitter campaign, the purpose of this study is to examine Twitter users' reasons for staying in their abusive relationships. The study sample ( n = 3,086) is composed of a random sample of 61,725 English speaking tweets globally that employed the #WhyIStayed and #WhyILeft hashtags. We analyzed all tweets using thematic content analysis methods. This process involved multiple rounds of coding. In response to #WhyIStayed, Tweeters worldwide shared the barriers they faced that made leaving their abusive partners difficult. Seven primary themes emerged that influenced their decision-making processes: (a) impact of IPV on personal well-being, (b) lack of awareness regarding the dynamics of abusive relationships, (c) not identifying as a stereotypical IPV victim, (d) fear of reinforcing racial stereotypes, (e) internalizing social scripts regarding relationships, (f) structural barriers, and (g) leaving takes time. Twitter messages have the capacity to function as micronarratives that recount the complex barriers IPV victims confront when negotiating their relationships. This analysis provides a multifaceted description of the challenges associated with leaving abusive relationships that can augment existing theoretical frameworks on victim readiness. Furthermore, these findings demonstrate the myriad ways that societal representations of domestic violence (DV) serve as impediments for victims leaving their abusive relationships. Therefore, social media has the potential to provide a platform for capturing the lived experience of IPV. PMID- 30516412 TI - In Vivo Study of mPEG-PCL as a Nanocarriers for Anti-Inflammatory Drug Delivery of Simvastatin. AB - PURPOSE: In this study, methoxy poly (ethylene glycol) -poly (epsilon caprolactone) (mPEG-PCL) di block copolymers were synthesized. The purpose of this work is to investigate the in vivo anti-inflammatory effects of simvastatin loaded micelles. METHODS: The structure of synthesized copolymers were characterized by using HNMR, FTIR and GPC techniques. Simvastatin was encapsulated in micelles through a single-step nano-precipitation method, leading to formation of simvastatin-loaded mPEG-PCL (simvastatin-mPEG-PCL) micelles. In this study the anti-inflammatory effects of simvastatin/mPEG-PCL micelles versus indomethacin were investigated in acute inflammation induced rats. The paw edema thickness was measured 1, 2, 3 and 4 hours after injection of formulation. The inhibition of edema in various groups were calculated and reported by percentages. RESULTS: The results showed that the zeta potential of micelles were about -14.9 +/- 0.47 mV and the average size was in 66.10 +/- 0.34 nm range. Simvastatin was encapsulated in mPEG-PCL micelles with loading capacity of 9.63 +/- 0.87% and encapsulation efficiency of 64.20 +/- 0.79%. Simvastatin and simvastatin-mPEG-PCL micelles showed significant anti-inflammatory activity in the present study. CONCLUSIONS: This study revealed that simvastatin and simvastatin/mPEG-PCL micelles both have anti-inflammatory effects and suggested that statins have potential anti-inflammatory activity along with their lipid lowering properties. PMID- 30516413 TI - A randomized controlled trial of a power brush/irrigator/mouthrinse routine on plaque and gingivitis reduction in orthodontic patients. AB - OBJECTIVES:: To assess plaque and gingivitis reduction in orthodontic patients after 4 weeks' use of an oscillating-rotating power brush, irrigator, and mouthrinse. MATERIALS AND METHODS:: This was a randomized, examiner-blind, clinical trial comparing plaque and gingivitis outcomes for an experimental power brush/irrigator/mouthrinse oral hygiene routine vs a dental prophylaxis followed by regular manual brushing (positive control). Fifty-one participants with fixed orthodontic appliances in the upper and lower jaw and a minimum of 15 gingival bleeding sites were randomly assigned to experimental or positive control treatment. Both groups were instructed to use their products at least twice daily. At baseline, week 1, and week 4, plaque was evaluated using digital plaque imaging analysis and a conventional subjective index. Gingival inflammation and bleeding were also measured. Analysis of covariance was used to compare groups. RESULTS:: Fifty-one participants (mean age = 13.9 years) were randomized; 50 (25 per group) completed the study. At baseline, group means were not statistically different ( P > .1) for gingival inflammation or bleeding. At week 4, the experimental and control groups had a 10.0% to 32.7% and 5.9% to 6.7% reduction vs baseline, respectively, in plaque (across both methods); 12.6% and 8.3% reduction, respectively, in gingival inflammation; and 50.6% and 37.8% reduction, respectively, in bleeding. At week 4, group differences favoring the experimental group were statistically significant ( P < .05) for gingival inflammation, gingival bleeding, and plaque (by conventional and digital imaging indexes). CONCLUSIONS:: Use of a power brush/irrigator/mouthrinse resulted in statistically significantly greater plaque and gingivitis reductions than prophylaxis followed by manual brushing in patients with fixed appliances over 4 weeks. PMID- 30516414 TI - A randomized clinical trial to evaluate the plaque removal efficacy of an oscillating-rotating toothbrush versus a sonic toothbrush in orthodontic patients using digital imaging analysis of the anterior dentition. AB - OBJECTIVE:: To compare the plaque removal efficacy of an oscillating-rotating electric toothbrush with an orthodontic brush head versus a sonic toothbrush in adolescent patients with fixed orthodontic appliances. MATERIALS AND METHODS:: This was a randomized, examiner-blind, replicate single-use, two-treatment, four period, crossover study with a washout period between visits of approximately 24 hours. Forty-four adolescent patients with fixed orthodontic appliances in both arches were randomized based on a computer-generated randomization schedule to one of four toothbrush treatment sequences. The primary outcome was plaque score change from baseline, measured using digital plaque imaging analysis. RESULTS:: Baseline plaque levels for both brush treatments were high, covering more than 50% of the tooth area. Effective plaque removal was observed with both brush treatments ( P < .001); however, the reduction in plaque with the oscillating rotating toothbrush was statistically significantly greater ( P = .017) compared with the sonic toothbrush. CONCLUSIONS:: The study provides evidence for more effective plaque-removing efficacy of the oscillating-rotating toothbrush versus the sonic toothbrush among orthodontic patients. PMID- 30516415 TI - Differences in heritability of craniofacial skeletal and dental characteristics between hypo- and hyper-divergent patterns using Falconer's method and principal component analysis. AB - OBJECTIVES:: To investigate the difference in heritability of craniofacial skeletal and dental characteristics between hypodivergent and hyperdivergent patterns. MATERIALS AND METHODS:: 53 Korean adult monozygotic (MZ) and dizygotic (DZ) twins and their siblings were divided into a hypodivergent group (Group 1, SN-MP < 35 degrees , 17 MZ pairs; 11 DZ and sibling [DS] pairs of the same gender) and hyper-divergent group (Group 2, SN-MP > 35 degrees , 16 MZ pairs; 9 DS pairs of the same gender). A total of 56 cephalometric variables were measured using lateral cephalographs. Craniofacial structures were divided into anteroposterior, vertical, dental, mandible, and cranial base characteristics. Falconer's method was used to calculate heritability (h2 > 0.8, high). After principal component analysis (PCA), the mean h2 value of each component was calculated. RESULTS:: Group 1 exhibited high heritability values in shape and position of the mandible, vertical angular/ratio variables, cranial base shape, and maxillary incisor inclination. Group 2 showed high heritability values in anteroposterior position of the maxilla, intermaxillary relationship, vertical angular variables, cranial base length, and mandibular incisor inclination. Occlusal plane inclination showed high heritability in both groups. Although vertical structure presented a high overall mean h2 value in Group 1, there were no structures that exhibited a high overall mean h2 value in Group 2. PCA derived 10 components with 91.2% and 92.7% of cumulative explanation in Groups 1 and 2, respectively. CONCLUSIONS:: It is necessary to estimate or predict growth according to vertical pattern for providing differential diagnosis and orthodontic/orthopedic treatment planning. PMID- 30516416 TI - Effect of automated messaging on oral hygiene in adolescent orthodontic patients: A randomized controlled trial. AB - OBJECTIVE:: To determine whether automated text messages sent daily to adolescent orthodontic patients improves oral hygiene more than weekly reminders. MATERIALS AND METHODS:: A blinded, prospective, randomized controlled trial was designed to evaluate the effects of automated messages on oral hygiene. Subjects were recruited from patients undergoing orthodontic treatment at the Texas A&M University College of Dentistry, Department of Orthodontics. They were being treated with a variety of fixed full appliances in both arches. Subjects were randomly assigned to either a once-a-week text message group or a daily text message group. There were 52 females and 27 males who were 12 to 17 years of age. Oral hygiene was measured at the beginning of the study and again 8.6 +/- 0.9 weeks later. RESULTS:: The daily reminder group (N = 42) had significantly greater improvements in oral hygiene compliance than the weekly reminder group (N = 37). The daily score decreases were 48%, 21% and 19% for the bleeding index (BI), plaque index (PI), and gingival index (GI), respectively. The weekly score decreases were 27%, 14% and 13% for the BI, PI, and GI. There were no sex differences in hygiene changes during the study. The 42% of patients who completed the survey at the end of the study wanted more frequent messages and reported that messages related to decreasing treatment time were the most effective, while those related to oral hygiene were the least effective. CONCLUSIONS:: Daily text messages are more effective at improving oral hygiene than weekly text messages. PMID- 30516417 TI - Finite element analysis of stresses on adjacent teeth during the traction of palatally impacted canines. AB - OBJECTIVE:: To evaluate stresses on maxillary teeth during alignment of a palatally impacted canine (PIC) under different loading conditions with forces applied in vertical and buccal directions. MATERIALS AND METHODS:: A three dimensional finite element model of the maxilla was developed from a cone beam computed tomographic scan of a patient with a left PIC. Traction was simulated under different setups: (1) palatal spring extending from a transpalatal bar (TPB) anchored on the first molars (M1) and alternatively combined with different archwires (0.016 * 0.022-inch; 0.018 * 0.025-inch) with and without engaging second molars and (2) a buccal force against 0.018-inch, 0.016 * 0.022-inch, and 0.018 * 0.025-inch archwires with and without engaging the left lateral incisor (I2). RESULTS:: Without fixed appliances, stresses were assumed by M1; with fixed appliances, stresses were distributed on all teeth, decreasing mesially toward the midline. Direct buccal pull exerted most stress on neighboring I2 (19-20% with different wire sizes) and first premolar (12-17%), decreasing distally, along a similar pattern with different archwire sizes. When I2 was bypassed, stresses on adjacent teeth increased only by 3-6%. Higher stresses occurred with the lighter round wire. CONCLUSIONS:: This first research on stresses on adjacent teeth during PIC traction provided needed quantitative data on the pattern of stress generation, suggesting the following clinical implications: use of distal vertical pull from posterior anchorage (TPB) as initial movement and when using a buccal force, bypassing the lateral incisor and using heavier wires that would minimize side effects. PMID- 30516418 TI - Time and pattern of the fusion of the spheno-occipital synchondrosis in patients with skeletal Class I and Class III malocclusion. AB - OBJECTIVES:: To investigate the time and pattern of fusion of the spheno occipital synchondrosis in patients with skeletal Class I and Class III malocclusion using cone-beam computed tomography (CBCT). MATERIALS AND METHODS:: A total of 262 CBCT images were collected: 140 skeletal Class I (0 degrees < ANB < 4 degrees ; 71 males, 69 females) and 122 skeletal Class III (ANB <= 0 degrees ; 61 males and 61 females). The fusion stages were identified using CBCT images of a six-stage system defined by the appearance of osseous cores and ossifying vestige in the synchondrosis. The age distributions of each stage and the pattern of fusion were evaluated. RESULTS:: The stages of fusion progressed with increasing age ( P < .05, r = .824), and the age distributions in the female groups were generally 1 to 3 years younger than those in the male groups. However, no significant differences were observed between the skeletal Class I and Class III groups regarding the time of ossification of the synchondrosis. The osseous cores appeared most frequently in the supero-center part, followed by the mid-center part of the synchondrosis. CONCLUSIONS:: The time and pattern of fusion of the spheno-occipital synchondrosis are not apparently different between patients with Class I malocclusion and those with Class III malocclusion. The osseous cores appear frequently in the supero-center and mid-center of the synchondrosis with various patterns before the end of the pubertal growth spurt period. PMID- 30516419 TI - A prospective, split-mouth, clinical study of orthodontic titanium miniscrews with machined and acid-etched surfaces. AB - OBJECTIVES:: To determine whether the success rate and primary stability of surface-treated miniscrews differ from those of nontreated miniscrews. MATERIALS AND METHODS:: Patients who required one or more miniscrews for the same reason in each quadrant were recruited into a single-blinded, split-mouth, randomized, controlled trial with a 1:1 allocation ratio. Self-drilling miniscrews with two surface types were used: those with no surface treatment, and those with an acid etched surface treatment. The cumulative success rate and primary stability of each type of miniscrew were examined, and factors potentially affecting the success and failure of miniscrews were investigated. RESULTS:: Forty patients were included in the study, with a total of 98 orthodontic miniscrews. The overall success rate was 88.8%, and the respective success rates for acid-etched and machined surface miniscrews were 91.8% and 85.7%. The respective mean insertion torques were 13.62 +/- 5.95 N.cm and 13.38 +/- 4 N.cm, and periotest values measured immediately after insertion were -0.50 +/- 2.77 for acid-etched miniscrews and -0.28 +/- 3.36 for machined surface miniscrews. There was no significant difference in the mean insertion torques and periotest values according to surface treatment and jaw. CONCLUSIONS:: Neither the success rate nor the primary stability of acid-etched surface miniscrews and machined surface miniscrews differed significantly. There is a high possibility that miniscrews will fall out in patients who have an open bite or those who require total distalization. PMID- 30516420 TI - High-fat diet withdrawal modifies alcohol preference and transcription of dopaminergic and GABAergic receptors. AB - The bidirectional and positive relation between the ingestion of fat and alcohol has become the subject of extensive discussion. However, this relation is more studied in animal models of binge eating with intermittent access of high-fat diet or in a model of short period of this diet consumption. Here, we developed a model to elucidate how chronic high-fat diet and its withdrawal influence alcohol intake (two-bottle choice) and anxiety behavior (marble burying test). In the first experimental stage, animals were fed on standard (AIN93G) or high sugar and butter (HSB) diet for 8 weeks. Then, a protocol of free-choice between water and a 10% alcohol solution was introduced, and the HSB diet was replaced with AIN93G in two experimental groups. The result obtained with this model point out that the relation among high-fat diet consumption and alcohol intake appears to depend on the presence or absence of the diet when alcohol intake is evaluated, and that an imbalance in the mesocorticolimbic dopaminergic pathway, observed by the transcriptional regulation of the dopamine receptors (Drd1/Drd2) and GABAB receptors subunit (Gabbr1/Gabbr2), can be driving the alcohol intake. PMID- 30516421 TI - Sex-dependent differences in the adverse renal changes induced by an early in life exposure to a high fat diet. AB - This study examines whether the intake of a high fat diet very early in life leads to changes in arterial pressure and renal function and evaluates whether the mechanisms involved in these changes are sex-dependent. Experiments were performed in male and female SD rats with normal or high fat diet from weaning to four months of age. This exposure to a high fat diet lead to an angiotensin II dependent elevation in arterial pressure and to significant increments in fat abdominal volume and plasma leptin that were similar in both sexes. In addition, the angiotensin II-induced increment in renal vascular resistance was greater (P<0.05) in male (106 +/- 14%) and female (97 +/- 15%) rats with high fat diet than in rats with normal fat diet (51 +/- 8%). However, the high fat intake during early life induced increments in albuminuria, interleukin-6 and infiltration of CD3 lymphocytes in the renal parenchyma that were greater (P<0.05) in male than in female rats. Other sex-dependent differences in response to high fat intake were that adiponectin levels only decreased in females (21%, P<0.05) and renal NFkB expression only increased in males (31%, P<0.05). In summary, the early exposure to a high fat diet leads to angiotensin II-dependent arterial pressure elevations, and to increments in abdominal fat and in the renal sensitivity to angiotensin II that are similar in both sexes. However, the mechanisms involved in the renal changes associated to the early exposure to a high fat diet are different in males and females. PMID- 30516422 TI - Renal Advances in Renal Epithelial Transport. PMID- 30516423 TI - Klotho deficiency aggravates sepsis-related multiple organ dysfunction. AB - Sepsis-induced organ failure is characterized by a massive inflammatory response and oxidative stress. Acute kidney injury (AKI) occurs in approximately half of patients in septic shock, and the mortality associated with sepsis-induced AKI is unacceptably high. Klotho is a protein expressed by renal cells and has anti senescence properties. Klotho has also been shown to protect the kidneys in ischemia-reperfusion injury and to have antioxidant properties. To analyze the role of Klotho in sepsis-related organ dysfunction and AKI, we used a cecal ligation and puncture (CLP) model of sepsis in heterozygous Klotho haploinsufficient mice and their wild-type littermates (CLP-Kl+/- and CLP-WT mice, respectively). In comparison with the CLP-WT mice, CLP-Kl+/- mice showed lower survival, impaired renal function, impaired hepatic function, greater oxidative stress, upregulation of inflammatory pathways (at the systemic and kidney tissue levels), and increased NF-kappaB activation. It is noteworthy that CLP-Kl+/- mice also showed lower heart rate variability, less sympathetic activity, impaired baroreflex sensitivity to sodium nitroprusside, and a blunted blood pressure response to phenylephrine. We also demonstrated that sepsis creates a state of acute Klotho deficiency. Given that low Klotho expression exacerbates sepsis and multiple organ dysfunction, Klotho might play a protective role in sepsis, especially in elderly individuals, in whom Klotho expression is naturally reduced. PMID- 30516424 TI - Fructose acutely stimulates NKCC2 activity in rat thick ascending limbs (TALs) by increasing surface NKCC2 expression. AB - The thick ascending limb (TAL) reabsorbs 25% of the filtered NaCl through the Na+/K+/2Cl- cotransporter (NKCC2). NKCC2 activity is directly related to surface NKCC2 expression and phosphorylation. Higher NaCl reabsorption by TALs is linked to salt-sensitive hypertension. Consumption of fructose is linked to salt sensitive hypertension. However, little is known about the effects of fructose on renal NaCl reabsorption. We hypothesized that fructose but not glucose acutely enhances TAL-dependent NaCl reabsorption by increasing NKCC2 activity via stimulation of surface NKCC2 levels and phosphorylation. We found that fructose (5 mM) increased transport-related oxygen consumption in TALs by 11.1 +/- 3.2% (p<0.05). The effect of fructose on oxygen consumption was blocked by furosemide. To study the effect of fructose on NKCC2 activity, we measured the initial rate of NKCC2-dependent thallium influx. We found that fructose (5 mM) for 20 min increased NKCC2 activity by 58.5 +/- 16.9 % (p<0.05). We then used surface biotinylation to measure surface NKCC2 levels in rat TALs. Fructose increased surface NKCC2 expression in a concentration dependent manner (fructose 1mM = 22 +/- 5%, 5mM = 49 +/- 10%, 10mM = 101 +/- 59% of baseline; p<0.05) whereas glucose or a glucose metabolite did not. Fructose did not change NKCC2 phosphorylation at Thre96/101, nor total NKCC2 expression. We concluded that acute fructose treatment increases NKCC2 activity by enhancing surface NKCC2 expression rather than NKCC2 phosphorylation. Our data suggest that fructose consumption could contribute to salt-sensitive hypertension by stimulating NKCC2-dependent NaCl reabsorption in TALs. PMID- 30516425 TI - L-NIL prevents the ischemia and reperfusion injury involving TRL4, GST, clusterin and NFAT5 in mice. AB - Upon renal ischemia-reperfusion (IR) injury, recruitment of neutrophils during the inflammatory process promotes local generation of oxygen and nitrogen reactive species which, in turn, are likely to exacerbate tissue damage. The mechanism by which iNOS is involved in IR has not been completely elucidated. In this work, the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) and the NOS substrate L-Arginine (L-Arg), were employed to understand the role of NOS activity on the expression of particular target genes and the oxidative stress elicited after a 30 min of bilateral renal ischemia, followed by 48h reperfusion in BALB/c mice. The main findings of the present study were that pharmacological inhibition of iNOS with L-NIL during an IR challenge of mice kidney decreased renal injury, prevented tissue loss of integrity, and improved renal function. Several novel findings regarding the molecular mechanism by which iNOS inhibition led to these protective effects: i) a prevention the IR-related increase in expression of TLR4, and its downstream target, IL1b; ii) reduced oxidative stress following the IR challenge; noteworthy, this study shows the first evidence of GST inactivation following kidney IR, a phenomenon fully prevented by iNOS inhibition; iii) increased expression of clusterin, a survival autophagy component; and iv) increased expression of NFAT5 and its target gene AQP-1. In conclusion, prevention of renal damage following IR by the pharmacological inhibition of iNOS with L-NIL was associated with the inactivation of proinflammatory pathway triggered by TRL4, oxidative stress, renoprotection (autophagy inactivation) and NFAT5 signaling pathway. PMID- 30516426 TI - Dynamic contrast-enhanced (DCE) MRI promotes early detection of toxin-induced acute kidney injury (AKI). AB - Acute kidney injury (AKI) is a common cause of morbidity and mortality in hospitalized patients. Nevertheless, there is limited ability to diagnose AKI in its earliest stages through the collection of structural and functional information. Imaging modalities such as magnetic resonance imaging (MRI) are increasingly being utilized to provide structural and functional data that characterize the injured kidney. Dynamic contrast-enhanced (DCE) MRI is an imaging modality that measures changes in kidney structure and contrast transit times; however, its ability to detect these parameters following AKI has not been determined. We hypothesized that DCE MRI would detect a prolongation in contrast transit time following toxin-induced AKI earlier than commonly used serum and tissue biomarkers. To test our hypothesis, we injected mice with either vehicle or cisplatin (30 mg/kg) and performed DCE MRI at multiple timepoints. We found that commonly used kidney injury biomarkers including creatinine, BUN, and NGAL did not rise until day 2 following cisplatin. Tissue levels of the pro inflammatory cytokines and chemokines, TNFa, IL-1b, IL-1a, IL-6, CCL2, and CXCL2 similarly did not upregulate until day 2 following cisplatin. However, the time to peak intensity of contrast in the renal collecting system was already prolonged at day 1 following cisplatin compared to vehicle-treated mice; and this intensity mirrored changes in kidney injury as measured by histologic analysis. Taken together, DCE MRI is a promising pre-clinical imaging modality that is useful for assessing both structural integrity and functional capacity of the kidney in the earliest stages following AKI. PMID- 30516427 TI - Novel ImPACT validity indices in collegiate student-athletes with and without histories of ADHD or academic difficulties. AB - OBJECTIVE: Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) assesses neurocognitive functioning in sports-related concussion. Previous work demonstrates ImPACT's validity indices detect poor effort at disproportionately higher rates in athletes with histories of attention deficit hyperactivity disorder (ADHD) or academic difficulties. The present study examines whether previously suggested 'dormant' validity indices, Word Memory Correct Distractors (WMCD), and Design Memory Correct Distractors (DMCD), reduce disproportionate invalidity in collegiate athletes with such histories. METHOD: Six seasons of ImPACT protocols were examined (n = 1727). Athletes were grouped by self-reported histories of ADHD, academic difficulties, or comorbid ADHD and academic difficulties. Chi-square analyses compared invalidity rates using existing validity indices and both standard and conservative cutoffs for WMCD and DMCD. RESULTS: Using standard cutoffs for dormant indices (WMCD < 22, DMCD < 16) produced significant differences in rates of athletes identified as having an invalid protocol, with the comorbid group exhibiting the highest invalidity rate (63.2%) and the no history group producing the lowest (42.0%), chi2 (3) = 11.57, p < .01, Cramer's V = 0.08. This difference remained when utilizing conservative cutoffs (WMCD < 18, DMCD < 10), with the comorbid group again producing the highest (26.3%) and the no history group producing the lowest (10.4%), chi2 (3) = 15.64, p < .005, Cramer's V = 0.10. CONCLUSIONS: Student-athletes with self reported histories of ADHD and academic difficulties are more likely to produce invalid protocols, even with dormant indices. These findings emphasize the difficulty in assessing validity in special populations of athletes and encourage further work in this area. PMID- 30516428 TI - Measuring the road safety performance of Iranian provinces: a double-frontier DEA model and evidential reasoning approach. AB - Road traffic accidents are critical public issue in developing countries, and they annually waste a significant amount of Gross Domestic Product (GDP). In order to urgently consider how this problem is related to the current policies, a proper safety evaluation of regional programmes in crash reduction is fundamental to the governments. The current research aims to employ a double-frontier Data Envelopment Analysis (DEA) model to assess the productivity of Iranian regional safety programmes in reducing the number of road fatalities. The safety efficiencies of Iranian provinces are simultaneously estimated using the double frontier DEA to reflect both the optimistic and pessimistic points of view. Then, the Evidential Reasoning (ER) approach is applied to aggregate the obtained efficiency values. These provinces are ranked based on the data panel for 2014 2016. Finally, a double-frontier Malmquist productivity index (MPI) is used to comprehensively measure the safety performance of Iranian roads over a period of time. PMID- 30516429 TI - Perpetration of Electronic Intrusiveness Among Adolescent Females: Associations With In-Person Dating Violence. AB - Electronic intrusiveness is a form of cyber dating abuse that includes monitoring a partners' location, whom a partner is talking to, and other private information via technology and social networking sites. The aim of this study was to further explore the prevalence of electronic intrusiveness, as well as to assess how electronic intrusiveness relates to in-person dating violence while controlling for known risk factors for in-person dating violence, namely, depression, emotion regulation, and acceptance of couple violence. Data for this study were drawn from the baseline assessment of a larger clinical trial. A sample of high-risk adolescent females between the ages of 14 and 17 with a lifetime history of prior dating violence victimization or perpetration was used. Participants completed self-report measures for all study variables. Findings demonstrate that perpetration of electronic intrusiveness within the past 3 months is common among a sample of high-risk adolescent females, with rates across various modes of technology ranging from 30% to 57%. Results also revealed electronic intrusiveness is associated with in-person dating violence perpetration after accounting for known risk factors. This study highlights the need to increase awareness of electronic intrusiveness and to better incorporate electronic intrusiveness into theoretical and empirical models of dating violence. PMID- 30516430 TI - SUMOylation of Periplakin is critical for efficient re-organization of Keratin filament network. AB - The architecture of the cytoskeleton and its remodeling are tightly regulated by dynamic reorganization of keratin-rich intermediate filaments. Plakin family proteins associate with the network of intermediate filaments (IFs) and affect its reorganization during migration, differentiation, and response to stress. The smallest plakin, periplakin (PPL), interacts specifically with intermediate filament proteins K8, K18, and vimentin via its C-terminal linker domain. Here, we show that periplakin is SUMOylated at a conserved lysine in its linker domain (K1646) preferentially by SUMO1. Our data indicate that PPL SUMOylation is essential for the proper reorganization of the keratin IF network. Stresses perturbing intermediate-filament and cytoskeletal architecture induce hyper SUMOylation of periplakin. Okadaic acid induced hyper-phosphorylation dependent collapse of the keratin IF network results in a similar hyper-SUMOylation of PPL. Strikingly, exogenous over-expression of a non-SUMOylatable periplakin mutant (K1646R) induced aberrant bundling and loose network interconnections of the keratin filaments. Time-lapse imaging of cells expressing the K1646R mutant showed the enhanced sensitivity of keratin filament collapse upon okadaic acid treatment. Our data identify an important regulatory role for periplakin SUMOylation in dynamic reorganization and stability of keratin IFs. Movie S1 Movie S1 Movie of GFP-PPL-C transfected HeLa cells, recorded for 3.5hr at 100X. Movie S2 Movie S2 Movie of GFP-PPL-C K1646R transfected HeLa cells, recorded for 3.5hr 100X. Movie S3 Movie S3 Movie of GFP-PPL-C transfected HeLa cells, recorded for 3.5hr in the presence of 0.5MUM OA. Movie S4 Movie S4 Movie of GFP-PPL-C K1646R transfected HeLa cells, recorded for 3.5hr in the presence of 0.5MUM OA. Movie S5 Movie S5 Movie of GFP-PPL-C transfected HeLa cells, recorded for 3.5hr at 100X in the presence of 0.25MUM OA. Movie S6 Movie S6 Movie of GFP-PPL-C K1646R transfected HeLa cells, recorded for 3.5hr at 100X in the presence of 0.25MUM OA. Movie S7 Movie S7 Movie of GFP-PPL-C transfected HEK293T cells, recorded for 2hr in the presence of 0.5MUM OA. Movie S8 Movie S8 Movie of GFP-PPL C K1646R transfected HEK293T cells, recorded for 2hr in the presence of 0.5MUM OA. Movie S9 Movie S9 Movie of GFP-PPL-C transfected MCF7a cells, recorded for 2hr in the presence of 0.5MUM OA. Movie S10 Movie S10 Movie of GFP-PPL-C K1646R transfected MCF7a cells, recorded for 2hr in the presence of 0.5MUM OA. PMID- 30516431 TI - Questioning the Questionnaire: Methodological Challenges in Measuring Subjective Quality of Life in Nursing Homes Using Cognitive Interviewing Techniques. AB - Although the concept of subjective quality of life in the nursing home setting is seen as a promising approach to discovering opportunities for improvement from the resident's perspective, it appears problematic in classical surveys that self reported quality ratings on the basis of satisfaction questions tend to turn out overly positive. The aim of this article is to analyze how people in residential care facilities interpret and process response stimuli received from a questionnaire on subjective quality of life. In this analysis, we aim to gain methodological insights into the way a survey instrument on subjective quality of life can adequately represent individual ratings, as well as expectations regarding different aspects of quality of life. To test the feasibility of the proposed approach, we employed a range of probing techniques from the cognitive interviewing approach. The result is a promising design principle for constructing survey instruments to measure subjective quality of life. PMID- 30516432 TI - Antibodies to watch in 2019. AB - For the past 10 years, the annual 'Antibodies to watch' articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, we expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. Our data indicate that: 1) antibody therapeutics are entering clinical study, and being approved, in record numbers; 2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and 3) Phase 1 to approval success rates are favorable, ranging from 17-25%, depending on the therapeutic area (cancer vs. non-cancer). In 2018, a record number (12) of antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United States (US). As of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) were in regulatory review in China. In addition, our data show that 3 product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019. Finally, we found that approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab, spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018 and in 2019, and are thus 'antibodies to watch'. We look forward to documenting progress made with these and other 'antibodies to watch' in the next installment of this article series. PMID- 30516433 TI - Cyclin C directly stimulates Drp1 GTP affinity to mediate stress-induced mitochondrial hyper-fission. AB - Mitochondria exist in an equilibrium between fragmented and fused that shifts heavily toward fission in response to cellular damage. Nuclear to cytoplasmic cyclin C relocalization is essential for dynamin-related protein 1 (Drp1) dependent mitochondrial fission in response to oxidative stress. This study finds that cyclin C directly interacts with the Drp1 GTPase domain, increases its affinity to GTP and stimulates GTPase activity in vitro. In addition, the cyclin C domain that binds Drp1 is contained within the non-Cdk binding second cyclin box domain common to all cyclin family members. This interaction is important as this domain is sufficient to induce mitochondrial fission when expressed in mouse embryonic fibroblasts in the absence of additional stress signals. Using gel filtration chromatography and negative stain electron microscopy, we found that cyclin C interaction changes the geometry of Drp1 oligomers in vitro. High molecular weight low GTPase activity oligomers in the form of short filaments and rings were diminished while dimers and elongated filaments were observed. Our results support a model that cyclin C binding stimulates the reduction of low GTPase-activity Drp1 oligomers into dimers capable of producing high GTPase activity filaments. PMID- 30516434 TI - Light priming of thermotolerance development in plants. AB - It is widely perceived that plant responses to environmental temperatures are profoundly influenced by light conditions. However, it is unknown how light signals modulate plant thermal responses and what photoreceptors are responsible for the light regulation of thermal adaptive process. We have recently reported that phytochrome B (phyB)-mediated red light signals prime the ASCORBATE PEROXIDASE 2 (APX2)-mediated detoxification reaction of reactive oxygen species (ROS), a well-known biochemical process that mediates the acquisition of thermotolerance under high temperature conditions. It is interesting that red light influences the HEAT SHOCK FACTOR A1 (HSFA1)-stimulated activation of the APX2 transcription, which is otherwise responsive primarily to stressful high temperatures. Blue light also efficiently primes the APX2-mediated induction of thermotolerance. In natural habitats, temperatures fluctuate according to the light/dark cycles with temperature peaks occurring during the daytime. It is thus apparent that plants utilize light information to prepare for upcoming high temperature spells. PMID- 30516435 TI - A break from pain! Interruption management in the context of pain. AB - Activity interruptions, namely temporary suspensions of an ongoing task with the intention to resume it later, are common in pain. First, pain is a threat signal that urges us to interrupt ongoing activities in order to manage the pain and its cause. Second, activity interruptions are used in chronic pain management. However, activity interruptions by pain may carry costs for activity performance. These costs have recently started to be systematically investigated. We review the evidence on the consequences of activity interruptions by pain for the performance of the interrupted activity. Further, inspired by literature on interruptions from other research fields, we suggest ways to improve interruption management in the field of pain, and provide a future research agenda. PMID- 30516436 TI - Fer1l6 Is Essential for the Development of Vertebrate Muscle Tissue in Zebrafish. AB - The precise spatial and temporal expression of genes is essential for proper organismal development. Despite their importance however, many developmental genes have yet to be identified. We have determined that Fer1L6, a member of the ferlin family of genes, is a novel factor in zebrafish development. We find that Fer1L6 is expressed broadly in the trunk and head of zebrafish larvae and is more restricted to gills and female gonads in adult zebrafish. Using both genetic mutant and morpholino knockdown models, we found that loss of Fer1L6 led to deformation of striated muscle tissues, delayed development of the heart, and high morbidity. Further, expression of genes associated with muscle cell proliferation and differentiation were affected. Fer1L6 was also detected in the C2C12 cell line, and unlike other ferlin homologues, we found Fer1L6 expression was independent of the myoblast-to-myotube transition. Lastly, analysis of cell and recombinant protein-based assays indicate that Fer1L6 colocalizes with syntaxin 4 and vinculin, and that the putative C2 domains interact with lipid membranes. We conclude that Fer1L6 has diverged from other vertebrate ferlins to play an essential role in zebrafish skeletal and cardiac muscle development. Movie S1 Movie S1 Representative video of z-slices of sarcomere myosin labeled 4 dpf heart from control sample. Movie S2 Movie S2 Representative video of z-slices of sarcomere myosin labeled 4 dpf heart from Fer1L6 morphant sample. PMID- 30516437 TI - Belief in memories may be relinquished as often for adulthood as for childhood events, but for different reasons. AB - The age distribution of nonbelieved memories (NBMs) reported by young and older adults typically reflects a large proportion of events dated to childhood. The present study aimed to further investigate the age of origin of NBMs by using instructions that include an NBM related to adulthood. Participants aged from 40 to 80 years were asked to describe an NBM, to explain why they had stopped believing their memory, and to rate its phenomenal characteristics. Participants also described and rated an age-matched believed memory (BM). The results revealed a similar proportion of nonbelieved events experienced in childhood and adulthood, thus calling into question the hypothesis that NBMs are mainly related to childhood events. We also found that NBMs might emerge for different reasons depending on the time of events. Additional analyses indicated that, overall, the influence of temporal distance on the ratings of phenomenal characteristics was similar for BMs and NBMs. PMID- 30516438 TI - Cancer pain: where are we now? AB - Increasing numbers of those living with and beyond cancer presents a clinical challenge for pain specialists. A large proportion of these patients experience pain secondary to their disease or its treatment, impeding rehabilitation and significantly impacting upon their quality of life. The successful management of this pain presents a considerable challenge. This review aims to outline current concepts and treatment options, while considering nuances within pain assessment and the use of large-scale data to help guide further advances. PMID- 30516439 TI - STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) belongs to the ATP binding cassette (ABC) transporter superfamily but functions as an anion channel crucial for salt and water transport across epithelial cells. CFTR dysfunction, because of mutations, causes cystic fibrosis (CF). The anion-selective pore of the CFTR protein is formed by its two transmembrane domains (TMDs) and regulated by its cytosolic domains: two nucleotide binding domains (NBDs) and a regulatory (R) domain. Channel activation requires phosphorylation of the R domain by cAMP dependent protein kinase (PKA), and pore opening and closing (gating) of phosphorylated channels is driven by ATP binding and hydrolysis at the NBDs. This review summarizes available information on structure and mechanism of the CFTR protein, with a particular focus on atomic-level insight gained from recent cryo electron microscopic structures and on the molecular mechanisms of channel gating and its regulation. The pharmacological mechanisms of small molecules targeting CFTR's ion channel function, aimed at treating patients suffering from CF and other diseases, are briefly discussed. PMID- 30516440 TI - A new way of thinking about pain. PMID- 30516441 TI - Transcranial direct current stimulation to prevent and treat surgery-induced opioid dependence: a systematic review. AB - Opioid misuse leading to dependence is a major health issue. Recent studies explored valid alternatives to treat pain in postsurgical settings. This systematic review aims to discuss the role of transcranial direct current stimulation (tDCS) in preventing and treating postoperative pain and opioid dependence. PubMed and Embase databases were screened, considering studies testing tDCS effects on pain and opioid consumption in surgical settings and opioid addiction. Eight studies met our inclusion criteria. Results showed a reduction of postoperative pain, opioid consumption and cue-induced craving following cortical stimulation. Despite the limited number of studies, this review shows preliminary encouraging evidence regarding the analgesic role of tDCS. However, future studies are needed to further investigate the application of tDCS in postsurgical settings. PMID- 30516442 TI - Visual gossiping: non-consensual 'nude' sharing among young people in Denmark. AB - The practice of sending and receiving nude and semi-nude images without consent is gaining increasing public attention and has been identified as a new form of digital sexual violence, framing sexting as a risk behaviour. In order to account for the existence of non-consensual nude sharing among young people in Denmark, we set out to conduct an ethnographic exploration of the social processes, gender dynamics and social implications of the practice. Our analysis suggests that non consensual sharing acts as a form of visual gossip to maintain social bonds and gendered recognition. The practice often has gendered implications as it rests on and reproduces gendered values, forming the basis for judging girls' and boys' sexual activities differently. By using the framework of visual gossip, we draw attention to how the social dynamics of gossiping shape the different violating actions tied to the nude across time and context. PMID- 30516443 TI - Contemporary Surgical Techniques for Mitral Valve Repair: A Pathoanatomic Appraisal. AB - Mitral valve surgery has evolved over 4 decades from one based on the principles of prosthetic replacement to a subspecialty with a foundation based on the principles of repair. This review will attempt to enumerate the contemporary techniques of mitral valve repair and a pathoanatomically directed approach with which to apply them by focusing on degenerative disease and associated complexities. PMID- 30516444 TI - Proanthocyanidin and anthocyanins from the hulls and beards of red-kerneled rice and their antiglycation properties. AB - In the current study, we isolated a proanthocyanidin oligomer from the hulls of red-kerneled rice. The structure of the oligomer was characterized based on spectral data and chemical reaction. Furthermore, two anthocyanins were isolated from the beards of the same source. The proanthocyanidins and beard extract showed more potent inhibitory and cleaving activities than those of positive controls, respectively. PMID- 30516445 TI - Screening of healthcare workers for latent tuberculosis infection in the low tuberculosis burden country: QuantiFERON-TB gold in tube test or tuberculin skin test? AB - Healthcare workers (HCWs) are an important group at increased risk for exposure to various infectious agents including Mycobacterium tuberculosis. Unfortunately, there is very limited data on the prevalence of latent tuberculosis infection (LTBI) among HCWs in Iran. The aim of this study was to analyze the prevalence of LTBI among HCW's of Children Medical Center (CMC), an Iranian referral hospital, and to compare the feasibility of using tuberculin skin test (TST) and QuantiFERON-TB gold in tube test (QFT-GIT) to screen the LTBI among this population. Informed consent was obtained before the study questionnaire was completed. Participants were then evaluated for LTBI using QFT-GIT test followed immediately by TST. The prevalence of latent TB infection in the 101 HCWs, based on QFT-GIT positivity, was 47% (n = 47), while based on TST test a higher prevalence was observed (n = 57, 57%). Forty-five (45%) subjects were positive for both tests, whereas 14 (14%) were positive by either test. Among the TST positive cases, 21% (n = 12) were negative for QFT-GIT. The overall agreement of TST and QFT-GIT was 86% ([45 + 42]/101] and a moderate correlation between these two tests was observed (Kappa value 0.72). The use of QFT-GIT test as a second step in TST-positive cases offers an appropriate tool for LTBI detection in our country where all HCWs are BCG-vaccinated. To enable the effective control and prevention of TB in healthcare settings in Iran, specific and detailed guidelines for dealing with LTBI are highly required. All newly hired HCWs should receive baseline testing for LTBI before commencing employment. In addition, HCWs who work in high-risk departments should receive regular follow-up screening for LTBI. PMID- 30516446 TI - A sexual rejection peptide: potential use for controlling mouse overpopulation. AB - Exocrine gland-secreting peptide 22 (ESP22) is a 10-kDa protein secreted in tears of juvenile mice. ESP22 inhibits sexual behaviors in adults, leading to a reduction in reproduction rate. We herein identified the 24 amino acid sequence within ESP22 that was essential for exhibiting sexual rejection activity. This synthesizable peptide can be useful for controlling mouse overpopulation. PMID- 30516447 TI - [Preparedness to provide care in relation to the satisfaction with hospital discharge planning and level of knowledge of relatives to elderly patients]. AB - : Preparedness to provide care in relation to the satisfaction with hospital discharge planning and level of knowledge of relatives to elderly patients Abstract. BACKGROUND: Relatives are a great resource for older people who are discharged after hospitalization. Studies have so far shown very little about the readiness of relatives to aid in caregiving. AIM: The study examined if relatives showed a relationship between readiness to provide care and satisfaction with hospital discharge management as well as group differences between well-informed and less informed relatives. METHOD: In addition to demographic data, the preparedness to provide care, satisfaction and extent of knowledge of relatives were surveyed using a retrospective cross-sectional study. Analyses were made of the relationship between preparedness to provide care and satisfaction with hospital discharge management, as well as group differences between informed and less informed relatives in terms of their preparedness to provide care. RESULTS: Of the 111 relatives, the majority were adult offspring (55.9 %) and partners (32.4 %) that participated in the study. A weak correlation was detected between the satisfaction with the hospital discharge planning of relatives and their willingness to provide care (rs = -0.113, p = 0.267). The group differences between well-informed and less informed relatives were significant (t(102) = 2.301, p = 0.023). CONCLUSION: Relatives that evaluated themselves as well informed are more likely to be in the position to provide informal care. Therefore, it is necessary to involve relatives more in the planning of hospital discharges and to inform them better. Experimental studies are necessary to find out if the preparedness to provide care can be increased through good discharge planning and specific information provision. PMID- 30516448 TI - Evaluation of maltose on conformation and activity parameters of trypsin. PMID- 30516449 TI - Generation by phage display and characterization of drug-target complex-specific antibodies for pharmacokinetic analysis of biotherapeutics. AB - Anti-idiotypic antibodies play an important role in pre-clinical and clinical development of therapeutic antibodies, where they are used for pharmacokinetic studies and for the development of immunogenicity assays. By using an antibody phage display library in combination with guided in vitro selection against various marketed drugs, we generated antibodies that recognize the drug only when bound to its target. We have named such specificities Type 3, to distinguish them from the anti-idiotypic antibodies that specifically detect free antibody drug or total drug. We describe the generation and characterization of such reagents for the development of ligand binding assays for drug quantification. We also show how these Type 3 antibodies can be used to develop very specific and sensitive assays that avoid the bridging format. Abbreviations: BAP: bacterial alkaline phosphatase; CDR: complementarity-determining regions in VH or VL; Fab: antigen binding fragment of an antibody; HRP: horseradish peroxidase; HuCAL(r): Human Combinatorial Antibody Libraries; IgG: immunoglobulin G; LBA: ligand binding assay; LOQ: limit of quantitation; NHS: normal human serum; PK: pharmacokinetics; VH: variable region of the heavy chain of an antibody; VL: variable region of the light chain of an antibody. PMID- 30516450 TI - Recombinant manganese peroxidase reduces A2E burden in age related and Stargardt's macular degeneration models. AB - Macular degeneration is hallmarked by retinal accumulation of toxic retinoid species (e.g. A2E) for which there is no endogenous mechanism to eliminate. This ultimately results in progressive dysfunction and loss of vision either in advanced age for genetically normal patients (age-related macular degeneration), or in adolescence for those with inherited genetic mutations (Stargardt's disease). Here, we present a proof-of-concept study for an enzyme-based therapy to remove these retinoids, modeled on traditional enzyme replacement therapy. Recombinant manganese peroxidase (rMnP) is produced in Pichia pastoris. In vitro, we demonstrate that rMnP breaks down A2E and other lipofuscin fluorophores with limited cellular toxicity, and as this enzyme is mannosylated, it can be taken up into cells via mannose receptor-dependent endocytosis. In vivo we demonstrate that rMnP can significantly reduce the A2E burden when administered by intravitreal injections. Together, these data provide encouraging results towards the development of an enzyme-based therapy for macular degeneration and indicate the need for additional work to characterize the molecular mechanism of A2E breakdown and to improve the pharmacological parameters of the enzyme. PMID- 30516451 TI - Gender Differences in Attitudes Toward Sexual Harassment of Health Care Employees: A Turkish Case Study. AB - The purpose of the study was to examine differences in sexual harassment attitudes between male and female labor force in health care organizations. A total of 571 employees working in various health care organizations in Turkey participated in the study. Sexual harassment was measured using 22 items and three-factor structure with constructs "Provocative Behavior," "Normal Flirtations," and "Trivial Matter" developed by Turgut. The data were collected using percentage, frequency, mean, standard deviation, independent sample t tests, and multivariate analysis of variance and covariance (MANOVA and MANCOVA). The results of the study revealed that a significant gender difference exists in sexual harassment attitudes with respect to "Provocative Behavior" and "Normal Flirtations" factors, while "Trivial Matter" factor was not statistically significant at the probability level of .05 as part of the sexual harassment scale. After controlling for variables such as age, marital status, monthly income level, education level, profession, institution, length of working time in the organization, and length of time in the health care sector; it was seen that most gender differences remained significant. PMID- 30516452 TI - Examining Social and Organizational Predictors of Nurses' Safety Motivation. AB - Medication errors are common in health care settings. Safety motivation, such as willingness to report error, is needed to contain medication errors. Limited evidence exists about measures to enforce nurses' safety motivation. The purpose of this study was to test a proposed model explaining the mechanism by which organizational and social factors influence nurses' safety motivation. Survey for this cross-sectional study was mailed to a random sample of 500 acute care nurses. Data collection started in January 2014 and lasted 6 months. Path analysis results showed a good fitting final model with 15% of explained variance on nurses' safety motivation. Safety climate dimensions of error feedback (beta = .38, p ? .00) and nonpunitive response to errors (beta = .22, p = .01) significantly predicted the outcome. There is a need for both organizational and social factors to motivate nurses to report errors. Leadership practices emphasizing safety as a priority is needed to enhance nurses' safety motivation. PMID- 30516453 TI - Does the meiotic spindle really predicts embryo implantation and live birth rates? An update. AB - SummaryThe aim of this study was to determine the capacity of the meiotic spindle (MS) to predict embryo implantation and live birth rates. For this purpose, we performed a broad systematic literature search. Of all publications retrieved, only those in which the implantation rates were related to some characteristics of the MS were evaluated. Despite the different methodology used in all the chosen studies, presence of the MS in oocytes was found to be positively associated with embryo implantation. Moreover, high retardance values, as well as strict criteria of normality in the MS structure, are significantly related to higher embryo implantation numbers and live birth rates. PMID- 30516454 TI - Reducing Door-to-Needle Times for Ischaemic Stroke to a Median of 30 Minutes at a Community Hospital. AB - BACKGROUND: Alteplase is an effective treatment for ischaemic stroke patients, and it is widely available at all primary stroke centres. The effectiveness of alteplase is highly time-dependent. Large tertiary centres have reported significant improvements in their door-to-needle (DTN) times. However, these same improvements have not been reported at community hospitals. METHODS: Red Deer Regional Hospital Centre (RDRHC) is a community hospital of 370 beds that serves approximately 150,000 people in their acute stroke catchment area. The RDRHC participated in a provincial DTN improvement initiative, and implemented a streamlined algorithm for the treatment of stroke patients. During this intervention period, they implemented the following changes: early alert of an incoming acute stroke patient to the neurologist and care team, meeting the patient immediately upon arrival, parallel work processes, keeping the patient on the Emergency Medical Service stretcher to the CT scanner, and administering alteplase in the imaging area. Door-to-needle data were collected from July 2007 to December 2017. RESULTS: A total of 289 patients were treated from July 2007 to December 2017. In the pre-intervention period, 165 patients received alteplase and the median DTN time was 77 minutes [interquartile range (IQR): 60-103 minutes]; in the post-intervention period, 104 patients received alteplase and the median DTN time was 30 minutes (IQR: 22-42 minutes) (p < 0.001). The annual number of patients that received alteplase increased from 9 to 29 in the pre intervention period to annual numbers of 41 to 63 patients in the post intervention period. CONCLUSION: Community hospitals staffed with community neurologists can achieve median DTN times of 30 minutes or less. PMID- 30516455 TI - Comparison of national cross-sectional breast-feeding surveys by maternal education in Europe (2006-2016). AB - OBJECTIVE: Breast-feeding is an important determinant of health of mothers and their offspring. The present study aimed to compare breast-feeding rates across Europe disaggregated by maternal education and establish what proportion achieves at least 50 % exclusive breast-feeding (EBF) at 6 months.Design/SettingSecondary analysis of national or sub-national studies' breast-feeding data for EU Member States plus Norway and Iceland, published in 2006-2016. Nineteen EU Member States plus Norway reported rates of EBF and any breast-feeding disaggregated by maternal education, of which only thirteen could be matched to the International Standard Classification of Education.ParticipantsMothers and their infants aged 0 12 months. RESULTS: Data on EBF rates at 6 and 4 months were found in only four and six countries, respectively. At 6 months, EBF rates of 49 % in Slovakia and 44 % in Hungary were closest to WHO's target of at least 50 % EBF. At 4 months, mothers with high education level in Denmark, the Netherlands and Germany had the highest EBF rates (71, 52 and 50 %, respectively). Mothers with low education level were less likely to initiate breast-feeding and cessation occurred early. The inequality gap ranged from 63 % in Irish mothers to no gap or very low levels of inequality in Poland, Sweden and Norway. CONCLUSIONS: More mothers with high, compared with low, education initiate breast-feeding and practise EBF for longer. More European policies should be targeted to protect, support and promote breast feeding, especially among mothers with only mandatory education. PMID- 30516456 TI - Insights into soy lecithin and egg yolk-based extenders for chilling canine spermatozoa. AB - SummaryThe aim of this study was to compare different concentrations of soy lecithin (LEC0.01%, LEC0.05% and LEC0.1%) with egg yolk (Control) in cooling extenders during the storage of semen at 5oC for 5 days. Twelve dogs (n = 12) were selected, and semen was cooled and assessed after 2, 24, 48, 72, 96 or 120 h. At each time point, sperm were analyzed for kinetic patterns (using computer assisted sperm analysis), mitochondrial activity (3'3- diaminobenzidine assay), lipid peroxidation (TBARS assay), DNA fragmentation (SCSA(r)) and plasma and acrosome membrane integrity (eosin/nigrosin and fast green/rose Bengal stains, respectively). The Control group (1814.4 +/- 197.2) presented the highest rates of lipid peroxidation at 120 h. Conversely, progressive motility (42.8 +/- 4%), linearity (45.4 +/- 1%), and VAP (88 +/- 3%) were higher in the Control group. In addition, there was lower mitochondrial activity in the Control group at 72 h. Therefore, our data show that lecithin used at these concentrations was not able to maintain sperm viability at as high qualities as would egg yolk. Moreover, the decrease in high mitochondrial activity and the persistence of sperm motility may indicate a compensatory mechanism in canine spermatozoa (i.e., glycolytic pathway). Furthermore, these higher lipid peroxidation indexes could indicate the necessity for future therapy using extenders and antioxidants over a long cooling time for dog sperm. PMID- 30516457 TI - Characterization of first blastomeres in Patagonian blenny (Eleginops maclovinus) (Perciformes: Eleginopidae). AB - SummaryThere is no information about the characteristics of early cleavage in the Patagonian blennie (Eleginops maclovinus), which can be used as a diagnostic tool for embryo quality. The purpose of this investigation, therefore, was to characterize the first blastomeres of E. maclovinus morphologically. Of a 'pool' of incubated eggs at 10.7 +/- 0.5 degrees C, 100 microphotographs of blastodiscs were extracted at different incubation periods from 0.25 to 5 h after fertilization and analyzed. Blastodiscs taken at 3.5, 4.0 and 5.0 h were characterized and classified into symmetric or asymmetric groups according to their morphology. The proportions of length (L) and width (W) of each blastomere were determined to establish its symmetry. Additionally, 20 microphotographs of blastodiscs of normal appearance were analyzed morphologically (control blastodisc: CB) and compared other blastodiscs (4.0 and 5.0 h). The results showed that before fertilization oocytes presented a somehow turgid aspect (maximum average diameter of 987 +/- 41 um) and after fertilization and hydration, their diameter increased to 1001.5 +/- 11 um (but not statistically significant) and presented a spherical shape. First cleavage ends after 3.5 h of development, forming two blastomeres 467 +/- 45 MUm length (L) and 328 +/- 21 MUm width (W) with a L/W ratio of 1.43 +/- 0.19. The second cleavage ends after development at 4.5 h forming four blastomeres 238 +/- 65 MUm length and 227 +/- 65 MUm width with a ratio L/W of 1.06 +/- 0.09. Five categories were identified during the blastomere characterization: 70% normal or symmetric; 8% with odd numbers of blastomeres; 6% unequal; 6% 'pie shaped' and 10% amorphous. PMID- 30516458 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 68, part 9, of the IJSEM. PMID- 30516459 TI - Hyphobacterium indicum sp. nov., isolated from deep seawater, and emended description of the genus Hyphobacterium. AB - A novel aerobic, Gram-stain-negative bacterium, designated strain 2ED5T, was isolated from a deep seawater sample in the north-west Indian Ocean. Cells of the strain were oval- to rod-shaped, and motile by a polar flagellum or sessile by a prostheca. The strain formed creamy white colonies on 2216E marine agar plates. It grew at 10-40 degrees C (optimum 28 degrees C) and pH 5.0-8.0 (optimum pH 6.0-7.0). The strain required 1-6 % (w/v) NaCl for growth and grew optimally in the presence of 2-3 % NaCl. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain 2ED5T was affiliated with the genus Hyphobacterium in the family Hyphomonadaceae of the class Alphaproteobacteria, sharing 95.1 % similarity at the 16S rRNA gene sequence level with the type strain of Hyphobacterium vulgare, the only species in the genus Hyphobacterium. The major fatty acids of the strain were C18 : 1omega7c and iso-C17 : 1omega9c, and the polar lipids included monoglycosyl diglyceride, sulfoquinovosyl diacylglycerol, glucuronopyranosyl diglyceride, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and an unidentified glycolipid. The strain contained ubiquinone Q-10 as the predominant respiratory quinone. The G+C content of the genomic DNA of the strain was 60.9 mol%. Based on the results of this polyphasic analysis, strain 2ED5T represents a novel species in the genus Hyphobacterium, for which the name Hyphobacterium indicum sp. nov. is proposed. The type strain is 2ED5T (=CGMCC 1.16466T=JCM 32612T). PMID- 30516460 TI - Leucothrix arctica sp. nov., isolated from Arctic seawater. AB - A Gram-stain-negative, non-motile, oxidase- and catalase-positive, rod-shaped bacterium was isolated from a coastal seawater sample from the Arctic Circle and designated strain IMCC9719T. On the basis of 16S rRNA gene sequence analysis, it was shown that strain IMCC9719T belonged to the genus Leucothrix and was closely related to the type strains of Leucothrix pacifica (97.6 % similarity) and Leucothrix mucor (95.1 %), while the strain shared <90.6 % sequence similarity with other bacterial species. The average nucleotide identity and genome-to genome distance values between strain IMCC9719T and L. pacifica JCM 18388T were 71.7 and 16.9 %, respectively. The DNA G+C content of strain IMCC9719T was 43.5 mol%. Optimum growth of strain IMCC9719T was observed at 15 degrees C, at pH 7.5 8.5 and in the presence of 2.0-2.5 % (w/v) NaCl. The major fatty acids were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c) and C16 : 0. Cells of strain IMCC9719T contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, an unidentified polar lipid, an unidentified aminophospholipid and two unidentified phospholipids. The major respiratory quinone was ubiquinone-8 (Q-8). Based on the taxonomic data collected in this study, strain IMCC9719T represents a novel species of the genus Leucothrix, for which the name Leucothrix arctica sp. nov. is proposed. The type strain is IMCC9719T (=KACC 18010T=NBRC 110382T). PMID- 30516461 TI - DORA Editorial. PMID- 30516462 TI - Hepatitis C virus NS5A inhibitor daclatasvir allosterically impairs NS4B-involved protein-protein interactions within the viral replicase and disrupts the replicase quaternary structure in a replicase assembly surrogate system. AB - Daclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non structural protein 5A (NS5A) of hepatitis C virus (HCV) and has been used with great clinical success. Previous studies have demonstrated its impact on viral replication complex assembly. However, the precise mechanisms by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system in which the HCV NS3-5B polyprotein is expressed to mimic the viral replicase assembly, we assessed the impact of DCV on the aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase. We found that DCV did not affect aggregation and tertiary structure of NS5A. DCV induced a quaternary structural change of the viral replicase, as evidenced by selective increase of NS4B's sensitivity to proteinase K digestion. Mechanically, DCV impaired the NS4B-involved protein protein interactions within the viral replicase. These phenotypes were consistent with the phenotypes of several reported NS4B mutants that abolish the viral replicase assembly. The DCV-resistant mutant Y93H was refractory to the DCV induced reduction of the NS4B-involved protein interactions and the quaternary structural change of the viral replicase. In addition, Y93H reduced NS4B-involved protein-protein interactions within the viral replicase and attenuated viral replication. We propose that DCV may induce a positional change of NS5A, which allosterically affects protein interactions within the replicase components and disrupts replicase assembly. PMID- 30516463 TI - Corrigendum: Natronolimnobius aegyptiacus sp. nov., an extremely halophilic alkalithermophilic archaeon isolated from the athalassohaline Wadi An Natrun, Egypt. PMID- 30516464 TI - DORA Editorial. PMID- 30516465 TI - Prevalence and genome characteristics of atypical porcine pestivirus in southwest China. AB - Atypical porcine pestivirus (APPV) causes congenital tremor (CT) in piglets and has a wide geographical distribution. In this study, we evaluated APPV prevalence using 165 piglet sera from southwest China. Viral RNA was detectable by qRT-PCR in 43.6 % (17/39, 95 % CI 27.8-60.4 %) of piglets with CT, while viral RNA was not detected in the sera of any healthy piglets. The seven complete APPV genomes were obtained from distinct farms and were 11 269-11 459 nucleotides in length. The genomes of the seven strains shared 82.8-98 % identity with the APPV reference strains. Phylogenetic analysis of the complete genomes as well as E2 and Nrpo sequences revealed that the seven APPVs clustered into two groups: four strains belonged to genogroups A and D and three strains belonged to a novel APPV genotype, tentatively called genogroup E. This study provides important insights into the epidemiological features and genetic diversity of APPV. PMID- 30516466 TI - DORA Editorial. PMID- 30516467 TI - DORA Editorial. PMID- 30516468 TI - DORA Editorial. PMID- 30516469 TI - Molecular epidemiology of multidrug-resistant Acinetobacter baumannii infection in two hospitals in Central Brazil: the role of ST730 and ST162 in clinical outcomes. AB - PURPOSE: Acinetobacter baumannii is a major cause of multidrug-resistant nosocomial infections. The characteristics of A. baumannii at two hospitals in a city in Central Brazil are described by analysing the phenotypes and molecular profiles of isolates recovered from 87 patients. METHODOLOGY: The isolates were identified and their antimicrobial susceptibility was evaluated using the the Bact/Alert 3D and Vitek2 methods. Patients' clinical data were obtained from medical files. Genes associated with resistance to carbapenems were analysed by multilocus sequence typing, clinical and bacteriological variables were analysed by descriptive statistics, and logistic models were generated to adjust the associations. RESULTS: Sixty-four (73.5 %) out of 87 A. baumannii isolates analysed were from patients in intensive care. The mortality rate was 43.7 %. Eighty (91.9 %) isolates were resistant to imipenem and 86 were susceptible to colistin (98.8 %). The blaOXA-23 gene (78.2 %) and its upstream insertion ISAba1 (55.2 %) were predominant, followed by blaOXA-24 (55.2 %) and blaOXA-143 (28.7 %). The blaOXA-23 gene and ISAba1 were independently associated with resistance to imipenem (P<0.05). There were 13 different sequence types (STs) among the 35 isolates. ST1 (nine; 25.7 %), ST162 (eight; 22.8 %) and ST730 (six; 17.1 %) were the most common, and four new STs were identified. The isolates were grouped into five clonal complexes (CC1, CC15, CC79, CC108 and CC162) plus a singleton using eburst. CONCLUSION: Respiratory infection, age >60 years and use of noradrenaline were factors associated with fatality. ST730 (CC79) was associated with higher mortality (P<0.05) and ST162 (CC162) was associated with increased survival probability (P<0.05). PMID- 30516470 TI - Glucose intake hampers PKA-regulated HSP90 chaperone activity. AB - Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2Delta or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity. PMID- 30516471 TI - Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment. AB - A normal endowment of nephrons in the mammalian kidney requires a balance of nephron progenitor self-renewal and differentiation throughout development. Here, we provide evidence for a novel action of ureteric branch tip-derived Wnt11 in progenitor cell organization and interactions within the nephrogenic niche, ultimately determining nephron endowment. In Wnt11 mutants, nephron progenitors dispersed from their restricted niche, intermixing with interstitial progenitors. Nephron progenitor differentiation was accelerated, kidneys were significantly smaller, and the nephron progenitor pool was prematurely exhausted, halving the final nephron count. Interestingly, RNA-seq revealed no significant differences in gene expression. Live imaging of nephron progenitors showed that in the absence of Wnt11 they lose stable attachments to the ureteric branch tips, continuously detaching and reattaching. Further, the polarized distribution of several markers within nephron progenitors is disrupted. Together these data highlight the importance of Wnt11 signaling in directing nephron progenitor behavior which determines a normal nephrogenic program. PMID- 30516472 TI - Spliceosome factors target timeless (tim) mRNA to control clock protein accumulation and circadian behavior in Drosophila. AB - : Transcription-translation feedback loops that comprise eukaryotic circadian clocks rely upon temporal delays that separate the phase of active transcription of clock genes, such as Drosophila period (per) and timeless (tim), from negative feedback by the two proteins. However, our understanding of the mechanisms involved is incomplete. Through an RNA interference screen, we found that pre mRNA processing 4 (PRP4) kinase, a component of the U4/U5.U6 triple small nuclear ribonucleoprotein (tri-snRNP) spliceosome, and other tri-snRNP components regulate cycling of the molecular clock as well as rest:activity rhythms. Unbiased RNA-Sequencing uncovered an alternatively spliced intron in tim whose increased retention upon prp4 downregulation leads to decreased TIM levels. We demonstrate that the splicing of tim is rhythmic with a phase that parallels delayed accumulation of the protein in a 24 hr cycle. We propose that alternative splicing constitutes an important clock mechanism for delaying the daily accumulation of clock proteins, and thereby negative feedback by them. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30516473 TI - [Autoimmune diseases in dogs and their impact for breeding programs with special reference of the Nova Scotia Duck Tolling Retriever]. AB - INTRODUCTION: Autoimmune diseases are of considerable importance in dog breeding. An increased risk of diseases with genetic predisposition is present especially in breeds with a limited genetic diversity. Strict breeding regulations and a high degree of self responsibility of the breeders are essential to prevent these diseases. There are only a few DNA tests available for detecting carriers of genes predisposing for autoimmune diseases. In this review, we describe the special situation in the Nova Scotia Duck Tolling Retriever, who has a special predisposition for Systemic Lupus Erythematosus (SLE) and for Immune-mediated Rheumatoid Disease (IMRD), as well as for Steroid-Responsive Meningitis Arteritis (SRMA) and Juvenile Addison's Disease (JADD). In addition a short overview on the pathogenesis of autoimmune disease is presented. PMID- 30516474 TI - [Evaluation of three-dimensional sonography for antral follicle count in cycling dairy cows]. AB - INTRODUCTION: The objective of the present study was to investigate reliability of transrectal three-dimensional ultrasound (3D-S) for antral follicle count (AFC) in dairy cows. Furthermore individual differences of AFC between cows and the fluctuation of AFC within and between different cycles were evaluated. To test the reliability of 3D-S, AFC was determined on the ovaries of 10 cows in vivo and compared with counts obtained after slaughter using computer tomography. To evaluate cyclic follicle dynamics, six cows were repeatedly examined with 3D-S over a period of two cycles. Using 3D-S, follicles with a mean diameter greater than 2 mm could be recorded. AFC determined with 3D-S and computer tomography showed a significant correlation (r >= 0.86, p < 0.05) and values were similar (p >= 0.05). AFC differed between individuals (p < 0.0001) and a moderate fluctuation within and between two cycles within the same cow was apparent (p < 0.05). In conclusion, 3D-S is a suitable method for determination of AFC in cattle. AFC differs between cows and cyclic fluctuations are apparent in a lesser extent. PMID- 30516475 TI - [Milk production without use of -antibiotics]. AB - INTRODUCTION: At present, the usage of antimicrobial agents in organic dairy farming is a subject of controversial public debate because of its impact on animals, humans and the environment. This study shows how farms can be successfully managed without using antimicrobials for udder diseases. Thereby, animal welfare and targeted low bulk tank somatic cell counts should not be neglected. The operating data analysed in this study was collected during feeding and milking time on 18 swiss dairy farms that have not been treating diseased udders with antibiotics for at least 3 years. This study is a cross-sectional study. Farmers put the focus on breed characteristics such as a high life performance, low bulk tank somatic cell counts over several lactations, animals with a calm character, and small-formed cows with a deep flank. A trend towards dual-purpose breeds was observed. Few persons were involved in the milking process. Moreover, 94% of the farmers were raising their own young cattle directly on the farm. Consequently, animal transport has been minimized. Furthermore, clear management practices and work processes as well as a good animal observation influenced decisively the production success. additionally some farmers used phytotherapy, homeopathy and tried and true home remedies. PMID- 30516476 TI - [The frequency of abnormal ultrasonographic findings in the lungs of 129 calves with bronchopneumonia]. AB - INTRODUCTION: The goal of this study was to analyse the frequency of ultrasonographic findings in 129 calves with bronchopneumonia and to determine how often multiple abnormalities occur in individual calves. The frequency of abnormal ultrasonographic findings ranged from 4 to 88%. Comet-tail artifacts were the most common finding (88%) followed in decreasing order by scattered echogenic foci (69%), air bronchograms (44%), superficial alveolograms (29%), pleural effusion (26%), hepatisation (23%), pleural lesions (18%), fluid bronchograms (14%), lung abscesses (6%) and fibrin deposits or fibrin strands (4%). Thoracic ultrasonography yielded a mean of 3.3 +/- 1.55 abnormal findings (range, 1-6) per calf. Ultrasonography of the lungs in calves with bronchopneumonia is a useful adjunct to clinical examination and allows the determination of the type and severity of lesions. PMID- 30516477 TI - Brucella canis infection in a young dog with epididymitis and orchitis. AB - INTRODUCTION: The following case report describes the clinical and diagnostic procedure for suspected brucellosis infection in a dog. A 21 month old intact male Border Collie was presented with an enlarged right testicle and epididymis. The dog was imported to Switzerland from Germany at the age of three months, but was never abroad since then. Clinical and laboratory diagnostic investigation included bacteriology and histology. An initial serological evaluation by means of rapid slide agglutination test (RSAT) was negative. Repeated examination of the same serum by a chromatographic immunoassay (ICT) revealed a positive result. Brucella canis infection was confirmed by culture. The present case is intended to underline the importance of the suspected diagnosis of 'brucellosis' in the presence of reproductive tract problems in dogs. In addition, Brucella canis has zoonotic potential and it is imperative to comply with strict hygiene management. PMID- 30516478 TI - Early and Late Closure of Loop Ileostomies: A Retrospective Comparative Outcomes Analysis. AB - : The optimal timing of loop ileostomy reversal remains largely unknown, but evidence that delayed ileostomy closure may increase postoperative complication rates is increasing. PURPOSE: Retrospective research was conducted to compare outcomes between patients who had early (<6 months) or late (>6 months) loop ileostomy closure. METHODS: Records of patients >18 years of age who underwent circumstomal reversal of a loop ileostomy over a period of 5 years in 1 hospital's colorectal unit were abstracted and analyzed. Data from patients who had a planned or conversion to laparotomy, a concurrent bowel resection, reversal of double-barrel small bowel and colonic stomas, or closure of an end ileostomy or patients whose records were incomplete were excluded. Demographic information, American Society of Anesthesiologists (ASA) grade, primary operation indication, surgery and inpatient dates, readmission within 30 days of discharge, reasons for readmission, complication type, and Clavien-Dindo classification were extracted and compared between early and late closure groups using independent-sample t test and Fisher's exact test. RESULTS: Among the 75 study participants, 25 had an early closure (mean age 68.6 [range 26 - 93] years, mean time since primary surgery 3.8 months) and 50 had a late closure procedure (mean age 71.6 [range 46 93] years, mean time since primary surgery 12.8 months). Gender distribution, ASA grades, primary surgery indication, and total number of readmissions were similar between the 2 groups. Hospital length of stay was significantly shorter (5.5 days vs 9.4 days; P = .01) and average number of complications was significantly lower (0.33 vs 0.61; P = .04) in the early closure group. Rates of postoperative ileus, anastomotic bleed, and wound-related complications were not significantly different. CONCLUSION: Hospital length of stay and average number of postoperative complications following circumstomal loop ileostomy closure were significantly lower in the early than in the late closure group. Additional studies are warranted to help guide practice. PMID- 30516479 TI - Cultivating Incontinence-associated Dermatitis Prevention Practices in an Australian Local Health District: A Quasi-experimental Study. AB - : Incontinence-associated dermatitis (IAD) is a common, painful, difficult-to treat skin condition. PURPOSE: A 2-part, quasi-experimental, post-test study was conducted to evaluate the impact of prevention initiatives on IAD prevalence and incontinence practices. METHOD: In part 1, from May 2017 to November 2017, a quasi-experimental post-test study design was conducted in a health district in Australia. Following an audit of IAD prevalence and identification of evidence practice gaps in 4 hospitals in a local health district (12 wards, 250 patients), an implementation science approach was used to implement evidence-based initiatives. An IAD committee was formed, staff were educated about correct incontinence pad sizing, washable and disposable underpads and plastic sheets were removed from the care setting, and barrier cream cloths for cleansing, moisturizing, and protecting skin were introduced. Patients admitted to 1 of the 12 wards who were >=18 years of age were recruited for participation and evaluation in the post-intervention implementation IAD and incontinence care practices audit. Post-intervention data were entered into a software program and compared to pre-implementation data using descriptive and bivariate statistics. In part 2, nurses from the 12 wards were asked to participate in 1 of 6 focus groups to share their impressions about the barrier cream cloths. Discussions were transcribed verbatim and analyzed using descriptive content analysis. RESULTS: The rate of incontinence among audited patients (N= 259, 132 men, 124 women; mean age 73.2 +/- 16.8 years) was 47.2% (119/252) and 2/259 (0.8%) had a pressure injury (PI). IAD prevalence was significantly lower in the post- than in the pre-implementation audit (6/259 vs 23/250, P = .015), as was hospital acquired pressure injury (9/250 [3.6%] vs 2/259 [0.08%]) and the use of bed protection layers (154/238 vs 6/259; P <.01). The focus groups included 31 nurses (25 women, 6 men). Four (4) themes emerged: 1) benefits to the patient (eg, improved skin condition), 2) usability (eg, fewer steps), 3) problems encountered (eg, not seeing the barrier in place), and 4) related factors. Patient comfort was cited frequently as an important benefit. CONCLUSION: Evidence-based initiatives led to a significant reduction in IAD prevalence and improved incontinence care practices. . PMID- 30516480 TI - A Descriptive, Qualitative Study to Explore the Pain Experience During Negative Pressure Wound Therapy for Postsurgical Abdominal Wounds. AB - : Pain during negative pressure wound therapy (NPWT) has been reported in the literature. PURPOSE: The study was conducted to describe patients' pain experience, pain-coping skills, and the effect of NPWT-related pain on daily life activities following abdominal surgery. METHOD: Using a descriptive, qualitative design, semi-structured face-to-face interviews were conducted between April 3, 2016 and December 26, 2016, in the surgical ward of a university hospital in Edirne, Turkey. Patients aged >=18, receiving NPWT, who had at least 1 dressing change, and with no diagnosis of diabetes mellitus or neurological disease were included. Interviews were conducted at the patients' bedside 1 day after wound debridement. All wounds were covered with the NPWT black foam dressing, and NPWT settings were -50 mm Hg to -125 mm Hg. One (1) researcher led the interviews using a voice-recorder while 2 researchers observed and took notes. Data were analyzed using Colaizzi's phenomenological method. RESULTS: The themes identified were: 1) pain experience, 2) pain coping, 3) pain prevention, and 4) affects daily life activity. Patients mostly reported pain during foam dressing changes and wrap removal unless the dressing change occurred while receiving anesthesia. Self-applied pain-coping strategies between dressing changes included limiting mobility, trying not to cough, applying pressure, or walking; these strategies were mostly ineffective. The results are supported by many findings from other studies investigating the effects of NPWT on patient pain. CONCLUSION: This study provides further insight into the patients' wound pain experiences during NPWT and its effect on daily activities. Increased awareness about NPWT-associated pain and pain control measures as well as qualitative and controlled quantitative studies are needed. Inservice training and educational meetings should be conducted at surgical clinics to expand surgical nurse and physician knowledge and awareness of how to efficiently manage pain during NPWT treatment and related procedures. PMID- 30516481 TI - IMPROVEMENT OF THE DERMATENSION METHOD IN THE RECONSTRUCTIVE-RECOVERY SURGERY OF DEFECTS OF SOFT TISSUES OF VARIOUS ETIOLOGY. AB - The problem of treating patients with loss of the skin and with a complicated course of the wound process remains topical. The problem is that, despite the relative technical simplicity of the dermatension method, the most significant complication is the decubitus of the stretchable flap, which is associated with a relatively high incidence of acute blood circulatory disturbances in the stretch tissues due to vascular compression with an excessive amount of injected fluid. The aim of the work is to improve the method of dermatension in reconstructive and recovery surgery of soft tissue defects of various genesis by planning and implementing dermatension at all its steps with instrumental control of the process using ultrasound and ICT in a complex. The results of surgical treatment of patients with a wound defect of different etiology of the scalp with which dermatension was performed in order to obtain additional plastic material in the burn center of the Kharkov City Clinical Hospital of Emergency and Urgent Care. prof. A.I. Meshchaninov for the period 2016-2018. There were only men aged 30 to 60 years among the patients. The average age of the operated patients was 45 years. In the first stage of dermatension, after filling the implanted expander with NaCl 0.9% physiological solution to achieve hemostasis, ultrasound was performed on the first day to measure the thickness of the cutaneous flap above the balloon and ICT (using the FLIR ONE Gen3 Pro thermal imager), to determine the state of the blood circulation above its dome. 10 days after the implantation of the expander, the second stage of dermatension was started (filling the tissue expander with 0.9% NaCl solution), taking into account the blood circulation parameters of the stretched flap with the help of a thermal imager and with constant monitoring of the thickness of the cutaneous flap over the balloon by ultrasound. There were stopped injecting fluid to the expander when the temperature in the center of the flap was reduced by more than 10C. With a further decrease in temperature, some of the liquid from the expander was evacuated. The results of ultrasound and ICT in the course of the operation planning (step I of dermatension), when filling the expander (step II of dermatension) and at the completion of dermatension (step III), according to the change in the thickness of the stretch flap and the formed connective tissue capsule, the dynamics of thermoreaction in the dermatitis flap allow to assess the state of blood circulation (perfusion) with a high probability, which is undoubtedly important for the prevention of such serious complications as ischemia, decubitus, necrosis of the flap, which carries stretches. PMID- 30516482 TI - DISORDERS OF CARBOHYDRATE METABOLISM IN PATIENTS WITH GASTRIC CANCER. AB - Object study carbohydrate metabolism state in patient with GC during the surgical treatment period, and the detection of factors that influence these kind of disorders. The results of investigations of 270 patients with GC were analyzed. The rest of patients were males - 193 (71.48%). 239 patients underwent different surgical involvements. The state of carbohydrate metabolism was evaluated based on the study of the level of glucose in blood serum and urine at various stages of surgical treatment. The results of carbohydrate metabolism in 270 patients with gastric cancer in the perioperative period are analyzed. Factors that have an effect on the changes in glucose and insulin levels in the blood and its appearance in the urine before the specific treatment, as well as at various periods of staying patients in the surgical department, was the duration of the anamnesis, advanced stages of the oncological process, complicated clinical course of the underlying disease.. It was established that surgical intervention itself, its extension, and also postoperative period have a direct negative effect on the disorders in carbohydrate metabolism. In 65.3% of cases operations were accompanied by hyperglycemia, and in 25.9% of cases glucosuria was detected. The duration of a surgical operation for more than two hours lead to an almost twofold increase in the incidence of cases of hyperglycemia, and tripled increase in glucosuria. Intensive correction of blood glucose level along with enteral feeding led to a decrease in levels of hyperglycemia and glucosuria. Complicated postoperative period did not lead to an increase in the incidence of carbohydrate metabolism disorders, but had an effect on the longer retention of elevated levels of glucose in the blood and urine. PMID- 30516483 TI - VARIANTS OF ENDOVASCULAR REVASCULARIZATION OF LOWER LIMBS WITH CRITICAL ISSHEMIA DOE EXTENSIVE ATEROSCLEROSIS AND ASSESSMENT OF THEIR EFFECTIVENESS. AB - A retrospective analysis of the results of endovascular operations on the arteries of the lower extremities was performed in 209 patients, of which 45 (21.5%) were patients with chronic ischemia of the 2nd stage, category 4, 138 (66.1%) of patients with ischemia of the lower extremities of the third stag, category 5 and 26 (12.4%) of patients with IV stage, category 6 (by classification Rutherford et al., 1997) 17, 187 men, 22 women. The average age of patients was 63.7+/-9.3 years. Based on clinical and angiographic data, several variants of endovascular revascularization of the lower extremities were used: the vasoballoone segmentation followed by its stenting with a self-expanding stent of Terumo Misago (Japan) or a stent of Palmas Cordis (USA), one stent or two end-to-end stents (the stenting of the artery was supplemented by vasoballoone dilatation of the segment over the stents, between stents or under stents), sub intimal angioplasty was performed under the condition of Re-Entry Outback (Cordis, USA), balloon angioplasty was used using IN cylinders. PACT Admiral (Medtronic Inc. USA) with Free Pac coating containing urea and paclitaxel, the method of SAFARI (Subintimal Arterial Flossing with Antegrade Retrograde Intervention). After analyzing the results of restorative opera-tions, we noted that clinical success in the first 6 months was achieved in 171 (81.8%) patients. Among them, a significant improvement in the limb was reported in 94 (45.0%) patients, moderate improvement was noted in 73 (34.9%) patients, unchanged in 26 (12.4%) cases, and a moderate deterioration at 16 (7.7%) patients. Cumulative vascular passage after endovascular operations was: 1-st month - 94.5%, 2-nd month - 92.3%, 6 month - 87.4%, one year later - 78.1%, in 2 years - 69.8%. According to our observations, the highest frequency of restenosis and reocclusion occurs in the first 6 months. All patients had a successful repeated endovascular reconstruction of the lesion area. Cumulative limb preservation after endovascular surgery was: 1 month - 100%, 2 months - 94.3%, 6 months - 90.6%, in 2 years - 84.1%. PMID- 30516484 TI - [COMPARISON OF ULTRASOUND INVESTIGATION METHODS IN POSTMENOPAUSE]. AB - The aim of the study is to improve the diagnostic approach in assessing the state of the endometrium with the help of ultrasonic endometrial diagnostics in accordance with the IETA criteria in combination with three-dimensional Doppler indices, calculating the volume of the endometrium, and the 3D reconstruction in postmenopausal women. 167 postmenopausal women underwent a 2D pelvic ultrasound examination and a combined three-dimensional complex pelvic ultrasound examination that included calculation of the volume of the endometrium, three dimensional dopplerometric indices (vascularization index, blood flow index and vascularization ratio), and 3D-reconstruction mode. In the second stage, the patients underwent hysteroscopy/endometrial bipyroscopy with morphological evaluation of tissue samples, which retrospectively performed analysis of echographic and dopplerometric criteria in patients with benign changes in the endometrium and their comparison with atrophic endometrium. In addition, a comparative analysis of the 2D ultrasound method and its combination with a complex 3D study was carried out. Most of the echographic criteria between the groups of hyperproliferative pathology and endometrial atrophy had statistical differences, but there were no significant differences in comparison with the group of synechia of the uterine cavity and cystic atrophy. While the analysis of Dopplerometric criteria both in the two-dimensional mode and with its combination with trimer techniques demonstrated a statistical difference between the indices in the groups of the endometrial hyperpliphyral pathology and the endometrium atrophy, including its cystic form, and also the synechia of the uterine cavity. Based on the results of the comparative analysis of the ultrasound modes, the combination of 2D study with a complex 3D study increases the sensitivity of the method by 12%, and the specificity by 13%. Three-dimensional echography with the determination of dopplerometric indices and volume of endometrium and 3D reconstruction is highly accurate in the diagnosis of endometrial pathology, its wide practical application at the preoperative stage will allow to improve the quality of diagnostics and to formulate clear criteria for hysteroscopy in postmenopausal women. The results of the study show that the thickness of the endometrium is not an absolute criterion in determining the pathology of the endometrium. The main criterion in the diagnosis of hyperproliferative changes in the endometrium in postmenopause is the presence in it of vascularization. PMID- 30516485 TI - [CLINICAL FEATURES OF ENDOMETRIOSIS IN WOMEN IN PERIMENOPAUSE]. AB - The aim of the research is the assessment of the features of the course of endometriosis in women in perimenopause. The exanimated group of patients consisted of 106 women with endometriosis and climacteric syndrome and 64 women with endometriosis without climacteric syndrome. The comparison group consisted of 70 women without endometriosis and symptoms of climacteric syndrome. The age of the examined women was from 39 to 55 years. We analyzed the leading complaints, the menstrual function and the severity of the pain manifestations in the examined patients. The results of the studies have shown that the main manifestations of endometriosis, such as hyperpolimenorrhea and pain syndrome, tend to fade with the onset of climacteric syndrome. The psycho-emotional disorders are on the first place in patients with endometriosis in perimenopause. PMID- 30516486 TI - THE ORTHODONTIC APPLIANCES FOR TREATMENT OF OPEN BITE PROPRIETARY CONSTRUCTION. AB - In orthodontic practice, removable orthodontic devices are used to treat anomalies and deformations of the dentoalveolar apparatus during the period of the transition occlusion. The creation of new orthodontic appliances or the modification of existing appliances is actual today. The aim is to create easy-to use therapeutical-prophilaxis orthodontic appliances that can be used to treat open bite and anomalies of the individual teeth position. The mechanism of action of the proposed appliance by P. Flis - V. Filonenko for the treatment of open bite (Ukraine's declarative patent No. 69548 for the utility model A61C7 / 00) is to expand the dentition; stimulation of growth of the apical bases of the jaws by moving the upper frontal teeth orally; correction of the tooth-alveolar height; normalization of the position of tongue. The clinical experience of the use of the orthodontic apparatus by P. Flis - V. Filonenko pointed to the drawbacks of its use in the case of retrusion or normal torque of upper frontal teeth. This goal is achieved by introducing into the design a lingual arc and lip bumper (Ukraine's declarative patent No. 115089 for the utility model A61C7 / 00). Orthodontic appliances of P. Flis - V. Filonenko and P. Flis - O.Tsyzh - V. Filonenko are advisable to use for the treatment and prevention of dentoalveolar anomalies and deformations, in particular, open bite and anomalies of individual teeth position. Conducted clinical studies indicate the feasibility of widespread introduction of appliances in orthodontic practice. PMID- 30516487 TI - [EFFECTIVENESS AND SAFETY OF METHOTREXATE MONOTHERAPY IN PATIENTS WITH PULMONARY SARCOIDOSIS]. AB - Immunosuppressants are traditionally administered in sarcoidosis patients with contraindications for the use of glucocorticosteroids (GCS), or in those with serious adverse reactions on GCS, as well as in the cases of GCS-therapy resistance. Aim - to study the effectiveness and safety of methotrexate monotherapy in pulmonary sarcoidosis patients with either GCS contraindication or adverse reactions. We examined 33 patients with st. II pulmonary sarcoidosis, 20 men and 13 women, 23-67 years of age. In all cases a general physical examination; chest computed tomography and spirometry were performed. Oral methotrexate 10 mg once per week was administered to all patients. Blood tests, including total blood count with platelet count, blood chemistry (ALT, AST, bilirubin, creatinin) were done before the start of the therapy and monthly afterwards. Methotrexate monotherapy appeared to be effective in 24 (72,7%) study patients (clinical cure or regression of lung lesions). Adverse reactions were registered in 10 (30,3%) patients. In 1 case treatment was stopped because of the serious adverse event. As it was confirmed by our study results, methotrexate should be considered a medication of choice in pulmonary sarcoidosis patients with contraindications for use or adverse reactions to GCS. A research of combination therapy of methotrexate with first-line drugs should be continued. PMID- 30516488 TI - [LASER CORRECTION OF MYOPIC ASTIGMATISM USING FEMTO LASIK AND RELEX SMILE TECHNOLOGIES - EFFICIENCY AND SAFETY]. AB - The purpose of the study is a comparative analysis of the efficacy and safety of the Femto LASIK and ReLEx SMILE technologies in correcting myopic astigmatism. Materials and methods: The study included 1212 results of interventions in patients with myopic astigmatism, incl. 721 (59.5%) using ReLEx SMILE technology and 491 (40.5%) Femto LASIK technology. Visionometry and refraction investigation were performed at the time of 3, 6, 9, 12 months after the operation, as well as an analysis of the incidence of complications. Results of the study: As a result of the study, it was determined that in patients with myopic astigmatism, laser correction of refractive error using ReLEx SMILE technology gives similar results to Femto LASIK in the presence of a combination of moderate myopia and mild astigmatism. With medium-level astigmatism, the clinical results of Femto LASIK decrease (the difference in this category of patients after 1 week was 12.7% (p=0.04), they were also significant after 3 months (11.9%, p=0.042) and 9 months (8.9%, p=0.048)), which, nevertheless, remain quite satisfactory. The use of the ReLEx SMILE technique provides a significant reduction in the number of complications of laser correction of refractive errors, with both light astigmatism (3.2 times) and more pronounced violations (2.6 times). Significant differences were revealed in the frequency of dry eye syndrome (4.7 times, chi2=23.22, p=0.001), hypercorrection 14.3 times (chi2 = 34.52, p <0.001) in favor of the ReLEx SMILE technique. PMID- 30516489 TI - [THE ROLE OF INSULIN IN THE ASSESSMENT OF BONE HEALTH IN TYPE 2 DIABETES]. AB - The purpose of this study was to identify complex relationships between the mineral, organic component of bone and the risk of fractures under the influence of metabolic changes associated with type 2 diabetes. A cross-sectional study of patients diagnosed with T2DM (n=96) was conducted; control group, consisted of 82 individuals. All patients were studied calcitropic homons, serum bone remodeling markers and bone mineral density with (DXA). In the course of this study, there was a correlation between serum insulin levels, bone metabolism markers and bone mass density determined by lumbar DXA in patients with type 2 diabetes. This allows us to believe that the presence of type 2 diabetes mellitus aggravates the disturbances of bone remodeling, thereby contributing to the development of osteoporosis. This study found that increased insulin resistance and/or hyperinsulinemia may affect the anabolic response of bone tissue, adversely affecting bone strength. Study suggests that obesity and hyperinsulinemia not be bone-protective factors, which complements the growing body of evidence that points to the importance of measuring bone remodeling markers in combination with bone mineral density in assessing and predicting the risk of fractures. Further studies are needed to determine the pathophysiological mechanisms by which insulin resistance can adversely affect bone metabolism. PMID- 30516490 TI - AN ALGORITHM FOR PROGNOSIS OF RECURRENT MYOCARDIAL INFARCTION IN TYPE 2 DIABETES MELLITUS PATIENTS FOLLOWING DETERMINATION OF ENDOTHELIAL DYSFUNCTION MARKERS. AB - The combination of cardiac pathology and metabolic disorders, namely type 2 diabetes mellitus, is one of the most frequent comorbid pathologies and the main cause of death from cardiovascular complications at an early stage of the disease. Despite the wide range of antithrombogenic measures, prevention of thrombotic complications of acute myocardial infarction remains an urgent problem of cardiology. The study involved examination of 73 patients with acute myocardial infarction with concomitant type 2 diabetes mellitus, who were distributed into clusters according to severity by the main indices of lipid and carbohydrate metabolism using hierarchical analysis. 43 patients (3 persons from Cluster 1 and 40 from Cluster 2) had complications in the form of recurrent myocardial infarction. The study implied elaboration of the system of recurrent myocardial infarction in patients with type 2 diabetes mellitus, involving a group of classifiers based on a discriminant model and a scoring system of prediction. Routine indices (insulin, cholesterol, EDV, creatinine phosphokinase) and specific markers (asymmetric dimethylarginine and type 1 plasminogen activator inhibitor) were used as predictors. The system of mathematical prediction of recurrent myocardial infarction has a high sensitivity (84.1%) and specificity (93.1%) with a total accuracy of 87.7%, which allows it to be used in modern clinical practice to prevent the occurrence of undesirable cardiovascular events. PMID- 30516491 TI - CONNECTION BETWEEN SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR LEVELS AND SEVERITY OF MICROANGIOPATHY IN PATIENTS WITH TYPE 2 DIABETES AND OBSTRUCTIVE SLEEP APNEA. AB - Our aim was to evaluate the serum vascular endothelial growth factor (VEGF) level in type 2 diabetes patients with comorbid obstructive sleep apnea (OSA) and to compare it in connection with diabetic retinopathy and chronic kidney disease severity. In the prospective cohort study following data were collected: medical anamnesis; demographic and anthropometric data; laboratory (serum VEGF, complete blood count, biochemistry, immunology, complete urine test, including microalbuminuria) and instrumental investigation data (fundoscophy, laboratory polysomnography). From 232 analyzed patients 54 (23.27%) were placed in OSA+ group, 178-OSA- group Mean VEGF value in OSA+ group was significantly higher, than in OSA- group. Serum VEGF level in patients with diabetic retinopathy was signifcantly higher with OSA comorbidity. Pearson correlation coefficient between VEGF and diabetic retinopathy stages, VEGF and CKD stages was significant in both groups. Our study suggests, that the blood VEGF play an important role in microangiopathy severity in patients with T2DM, especially with OSA comorbily. PMID- 30516492 TI - SERUM VASCULAR ENDOTHELIAL GROWTH FACTOR CONCENTRATION DECREASES IN CORRELATION WITH GLYCATED HEMOGLOBIN LEVELS IN PATIENTS WITH TYPE 2 DIABETES. AB - Our aim was to compare serum vascular endothelial growth factor (VEGF) level in type 2 diabetes mellitus (T2DM) patients with comorbid OSA at screening and 6 month follow up visits. In the prospective cohort study following data were collected at screening visit: medical anamnesis; demographic and anthropometric data; Epworth sleepiness score data; laboratory (serum VEGF, complete blood count, biochemistry, immunology, complete urine test, including microalbuminuria) and instrumental investigation data (fundoscophy, laboratory polysomnography). At 6 months follow up visit we evaluated anthropometric data; Epworth sleepiness score; serum VEGF. Comparing VEGF level at screening and 6 month follow up visits showed significant decrease in VEGF level in both groups (P=0.0281 OSA+ and P=0.0278 OSA-). It was established direct correlation between decreased VEGF level and decreased HbA1c level (P=0.04696) and between decreased VEGF level and Epworth sleepiness score (P=0.0153) at 6 month follow up visit in OSA+ group. Our the study suggests that VEGF level decreases in parallel with diabetes compensation quality. Future researches are necessary to support this research. PMID- 30516493 TI - ASSOCIATION OF DYSADIPOKINEMIA WITH TLR4 SERUM CONCENTRATION IN GOUT PATIENTS. AB - Study objective was to estimate the levels of TLR4 in gout patients and evaluate their association with the dysadipokinemia. The study involved 65 gout patients and 24 healthy individuals. All study subjects proceeded clinical and laboratory examination. Levels of adipokines and TLR4 concentration were estimated by commercial ELISA kits. The statistical information was processed using MS Excel and Statistica SPSS22 utility programs for Windows. Our study revealed that gout patients had elevated leptin and TLR4 levels, decreased adiponectin concentration and lg A/L dysadipokinemia indicator compared to apparently healthy individuals. More prominend disturbance of adipokines status was estimated in patients with high level of TLR4. The adipokine status disturbances were associated with elevated TLR4 serum concentrations. PMID- 30516494 TI - [IMPROVEMENT OF ETIOLOGICAL DIAGNOSIS OF THE CEREBRAL TOXOPLASMOSIS IN HIV INFECTED PERSONS]. AB - The objective of the study was to determine the diagnostic value of the parallel detection of the avidity index of the IgG to Toxoplasma gondii in the blood and cerebrospinal fluid by a three-step solid-phase enzyme immunoassay using T. gondii antigen, protein dissociating agent and monoclonal antibodies against human IgG at HIV-infected individuals with a focal damage of the brain. The results of the study showed that conducting of the enzyme-linked immunosorbent assay by a direct and dissociated method makes it possible to detect specific intrathecal and serum immunoglobulins, which is proposed in terms of improving diagnosis of cerebral toxoplasmosis in HIV-infected individuals. The high informative ability of the test system for detecting the avidity index of IgG antibodies to T. gondii allows the possibility to apply it in the algorithm for diagnosing an etiological factor of neuroinfection in HIV-infected individuals. PMID- 30516495 TI - VISCERAL GNATHOSTOMIASIS WITH SIMULTANEOUS DAMAGE TO THE UPPER AND LOWER PARTS OF THE GASTROINTESTINAL TRACT. AB - In this article, we described a rare atypical clinical case of tropical helminthiasis - a visceral gnathostomiasis with simultaneous damage of the upper and lower parts of the gastrointestinal tract. The visceral form is the rarest variant and among the literary data, only single cases of this form are described in the world. Therefore the management of such patients requires an individual and balanced approach since it is almost impossible to predict the consequences of any medical interventions. This determines the clinical uniqueness of this case and requires further research of clinical guidelines for the management of such injuries. PMID- 30516496 TI - [THE LOCAL REGISTRY DATA ON MYOCARDIAL INFARCTION IN WOMEN: THE RISK FACTOR ANALYSIS, CLINICAL CHARACTERISTICS AND SURVIVAL]. AB - The clinical experience implies poor prognosis in women with myocardial infarction (MI). We performed a retrospective cohort study of 1395 patients - 987 (70,75%) men and 408 (29,25%) women) aged of 64,63+/-11,43 years with myocardial infarction and comorbidity hospitalized between 2010-2016. This study shows an increase of mortality in women with myocardial infarction during the last 4 years from 23,1% to 34,2%. We observed more frequent cases of non-STEMI (p=0,014) and recurrent myocardial infarction in females compared with males (r<0,0001). Arterial hypertension with elevated diastolic pressure was more common women than in men (86,4% vs 68,7%, p=0,0001). Being overweight (p<0,0001), abdominal obesity (p=0,019), hypercholesterolemia, elevated low-density lipoprotein (p=0,005) were more common in females than in males. Type 2 diabetes mellitus was more frequent in women (32,6% compared with men 20,1%), the duration of the disease was also longer in females 10,3+/-0,8 years vs 7,3+/-0,5 years in men. Thyroid problems were observed more often in male (r<0,0001). Gastrointestinal ulcer was more common in men - 10,6% vs 6,6% compared with woman, p=0,019, while the bile duct diseases were more frequent in women - 8,3% vs 3,9 % compared with men, p=0,003. The mortality rate in acute myocardial infarction was 1.5-fold more frequent in women and due to age, heart rate, oxygen saturation at first day of myocardial infarction, NYHA functional class, left ventricular end-diastolic dimension index. The survival analyses after myocardial infarction was performed with the Kaplan-Meier method. It showed higher mortality level in females (chi2=26,73; r<0,0001). PMID- 30516497 TI - [FEATURES OF EARLY REPOLARIZATION SYNDROME DEPENDING ON EVIDENCES OF HEART HYPERTROPHY IN PROFESSIONAL ATHLETES]. AB - A syndrome of early repolarization, common in professional athletes, has recently been considered as a possible predictor of acute arrhythmias. It is known that for this category of young people the development of compensatory hypertrophy of the heart is also common. The aim of the study was to investigate the features of early ventricular repolarization in professional athletes, depending on the presence of signs of cardiac hypertrophy. The study included 28 high-level competition athletes who had regular intensive physical activity for at least six months. Syndrome of early repolarization was diagnosed on the basis of ECG registration, in case of elevation of the J-point on 1 mm and more above the isoelectric line in the lower or lateral leads was detected. Diagnosis of cardiac hypertrophy was established by electrocardiography and echocardiography. On the background of high prevalence of early repolarization syndrome in professional athletes, we did not reveal the statistically significant relationship between its presence and cardiac hypertrophy. However, the combination of these two syndromes in the examined athletes was accompanied by a statistically significant shortening of the corrected QT interval, the last, in a case of the presence of certain anamnestic data, may be one of the risk factors for acute arrhythmias. This necessitates a deeper examination of such patients and monitoring of them. Further studies are needed to determine the prognostic value of early repolarization in athletes with cardiac hypertrophy. PMID- 30516498 TI - EFFECTIVENESS OF NONALCOHOLIC STEATOHEPATITIS CORRECTION ON THE BASKGROUND OF OBESITY WITH CONCOMITANT CHRONIC KIDNEY DISEASE. AB - The article presents a theoretical generalization of the research results the effectiveness of heparisin on the state of the carbohydrate-protein components of the extracellular matrix of connective tissue in liver in patients with non alcoholic steatohepatitis with obesity I-II degree and chronic kidney disease I II stage. The purpose of the study is to find out the effectiveness of heparisin (glycyrizine 40 mg, glycine 400 mg, L-cysteine hydrochloride 20 mg) on the state of the carbohydrate-protein components of the extracellular matrix in connective tissue of the liver in patients with non-alcoholic steatohepatitis (NASH) with obesity I-II degree and chronic kidney disease (CKD) I-II stage. 98 patients with NASH on the background of obesity of the I-II degree were examined, including: 52 patients with NASH (I group) (without accompanying CKD), 46 patients with NASH with comorbid CKD I-II stage (II group). The control group consisted of 20 practically healthy persons (PHPs) of the corresponding age and sex. Biopsy of the liver was performed on 32 NASH patients with CKD I-II, 28 patients with NASH without CKD. Patients on both groups of NASH received heparisin treatment (glycyrizine 40 mg, glycine 400 mg, L-cysteine hydrochloride 20 mg) (Valartin Pharma) by intravenous administration of 20 ml of the drug for 10 days followed by enteral administration of 2 tablets of heparysin (1 tablet : glycyrizine 25 mg, glycine - 25 mg, methionine - 25 mg) 3 times a day for 80 days. Patients with NASH and a comorbid flow of obesity and CKD of the I-II stages, except for heparisin, received baseline therapy of CKD I-II stage: chronic pyelonephritis. Heparizin therapy for 3 months contributed to the achievement of a collagen anabolic and catabolic balance by activating collagenase, inhibiting the activity of proteolytic inhibitors and collagenase, inhibition of fibroblast growth factor secretion, acute phase inflammation, reducing extracellular matrix fucoglycoproteinsdegradation in liver, and in general, reducing the activation of connective tissue components, by evidence which led to a decrease in the liver fibrosisindex according to the fibrotest in the range of 1.5-2.0 times. PMID- 30516499 TI - PATHOGENETIC LINKS OF THE COMBINED COURSE OF CHRONIC PANCREATITIS AND HYPERTENSIVE DISEASE AND THEIR ROLE IN THE FORMATION OF COMPLICATIONS. AB - Objective the purpose of the study the relationship between the gene polymorphism of vitamin D receptors (VDR) and biochemical markers of bone metabolism in the risk of osteoporosis in patients with chronic pancreatitis (CP) and hypertensive disease (HD). 110 patients with CP were examined, in which it proceeded against the background of HD in 70 cases, and in 40 cases it was isolated. The polymorphism of the VDR gene, the content of osteocalcin, total acid phosphatase (TAP), and tartrate-resistant acid phosphatase (TRAP) were studied to determine the possible effect of these parameters on the course of the disease and the formation of complications. The obtained results show that in persons with combined course of CP and HD, a decrease in serum osteocalcin content (bone tissue synthesis index) and an increase in the content of TAP and TRAP - markers of bone destruction were revealed. The polymorphism of the VDR gene was characterized by the predominance of individuals with the B-allele, against which the reliability of changes in biochemical markers of osteoporosis was noted, which can be considered as a predictor of the development of osteoporotic conditions. The combined course of CP and HD is characterized by an increase in the number of persons with B-alleles of the VDR gene (84.3%), the carriers of which have an increased risk of osteopenic conditions. Reduction of osteocalcin content, increase in the level of TAP and TPKF in the blood serum of patients with HP and HD often occur against the background of an unfavorable B-allele of VDR gene polymorphism. Combined course of CP and HD is the basis for early diagnosis of secondary osteoporosis. PMID- 30516500 TI - CLINICAL-PATHOGENETICAL ROLE OF DYNAMICS OF CONCENTRATION OF INTERLEUKIN-6 DEPENDING ON POLYMORPHISM OF ITS GENE IN CONDUCTING ANTIVIRAL THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C. AB - The study included 83 patients with CHC who received antiviral therapy according to the EASL 2016 recommendations on a 12-week peg-IFN+SOF+RBV schedule. The aim of the study was to determine the role of IL-6 concentration dynamics in relation to the polymorphism of the gene that encodes it, in achieving a SVR during therapy. Based on the results of the study, it was established that the polymorphism of the IL-6 gene (rs1800795) in patients with CHC influenced the dynamics of IL-6 concentration and the effectiveness of AVT. In patients with CHC, the genotype CC of the polymorphism of the IL-6 gene was associated with fluctuations in the concentration of IL-6 in the blood within the reference range, which was prognostically favorable for the formation of SVR 24 for AVT according to the peg-IFNalpha + SOF + RBV. With the presence of CG/GG genotypes in patients with CHC, the efficacy of this treatment was lower than in patients with CC genotypes (85,5% vs. 100%). The ineffectiveness of AVT according to the scheme peg-IFNalpha+SOF+RBV was associated with the presence of CG/GG genotypes and the highest concentration of IL-6 in the blood. PMID- 30516501 TI - [SUBSTANTIATION OF INDICATIONS FOR BIOFEEDBACK THERAPY AND CYTOFLAVIN APPLICATION IN TREATMENT OF OSTEOCHONDROSIS NEUROLOGICAL COMPLICATIONS IN ELDERLY PATIENTS]. AB - The aim of the study was to assess the impact of cytoflavin and bioflavin therapy on the dynamics of clinical and psychophysiological status of patients with Osteochondrosis. 150 patients with osteochondrosis of a backbone were investigated. The patients were divided into two groups using method of randomization: the main group - 75 patients - and control group -75 patients. All patients received a standard treatment (non-steroidal anti-inflammatory drugs, myorelaxants, chondroprotectors, as well as physiotherapy). The main group in addition to standard treatment received biofeedback therapy and cytoflavin. The results showed that cytoflavin and biofeedback therapy significantly enhanced the positive effect of standard treatment and significantly increased the quality of life of patients. It is recommended to treat elderly patients with neurological complications of spinal osteochondrosis with Cytoflavin in combination with biofeedback therapy Before prescribing biofeedback therapy and Cytoflavin it is necessary to take into account a number of positive and negative predictors of their effectiveness in reducing severity of pain syndrome. PMID- 30516502 TI - [THE STRUCTURE AND RISK OF CHRONIC MORBIDITY IN SOME VILLAGES OF THE UPPER IMERETI REGION OF WEST GEORGIA AND THEIR MOLECULAR AND CYTOGENETIC MARKERS]. AB - The purpose of our study was to identify the nature of the cause-effect relationship between the risks of developing of Chronic Obstructive Pulmonary Disease (COPD) and Cardio-vascular Disease (CVD) in patients residing in the villages of Chiatura district, characterized by varying degrees of environmental stress. The residents (n=400) of the Chiatura district living in the villages, Khreiti, Perevisa and Rgani were examined. The villages are characterized by different degrees of ecological tension (the villages differ both in their remoteness from sources of environmental pollution - manganese mining quarries and the scale of its extraction, which allows them to rank according to the degree of environmental tension: Khreiti - low, Perevis - medium, Rgani - high). In the patients the blood general redox balance and genetic parameters (the number of micronuclei in the scrapings of the oral mucosa) were studied. In the zone of moderate environmental stress (the village of Perevisa), a significant increase in the indicator of the total antiradical activity of blood plasma and an increase in the frequency of micronucleated buccal cells were revealed in comparison with the zone of low environmental stress (the village of Khreiti). In residents of the village of Rgani, characterized by the highest level of pollution, the indicator of the total antiradical activity of blood plasma decreases sharply, the number of micronuclei decreases, the presence of various types of damage to the nucleus is noted, which is characteristic of intensive apoptosis. Under the conditions of moderate air pollution, observed mobilization of protective anti-radical and replication mechanisms in the body are aimed at preserving the stability of the somatic cell genome. Identified oxidative stress can also act as mediators of secondary alteration and the development of the inflammatory process in the circulatory bed, resulting in an increased risk of arterial hypertension (AH) against the background of a relatively high risk of chronic nonspecific obstructive pulmonary diseases (COPD). High level of environmental pollution contributes to the development of permanent intense oxidative stress in the affected tissues of the respiratory tract. That contributes to the development of predominantly nonreparable changes in the cell genome, apoptosis and intensification of secondary oxidative stress, which, under conditions of depletion of antiradical protection, causes preferential defeat of the microenvironment of apoptotic cells, the development of local effects, reflected in a sharp increase in the risk of COPD. PMID- 30516503 TI - [ANALYSIS OF MORBIDITY WITH TEMPORARY DISABILITY OF WORKERS IN THE ORE BENEFICIATION ON CHRYSOTILE PRODUCTION]. AB - This study is aimed at studying the morbidity with temporary disability (MTD) of employee working in ore beneficiation at chrysotile production of JSC "Kostanay Minerals" . It was found that the incidence of MTD is higher among male male workers than in men in the control group, and the incidence of MTD in the compared professional groups decreases with an increase in work experience. This is possibly due to the fact that the organism of the trained workers is more stable due to the formation of protective adaptive mechanisms to the current production hazards. However, the revealed reliable differences between the main and control groups in the trainees group for 30 years or more rank them at risk. When analyzing the morbidity by class of disease in the compared groups, respiratory diseases take the first place. In the main group, the second place is occupied by diseases of the musculoskeletal system, in the control group - the class of illnesses "traumas and poisonings" with the share of domestic injuries accounting for 95,2%. The third place in the main group was occupied by the class of "trauma and poisoning", and in the control group - diseases of the musculoskeletal system. The obtained research results allow us to conclude that in the current conditions of industrial development of industry in the Republic of Kazakhstan, the continuous improvement of the most important preventive measures for labor protection and the prevention of occupational diseases on the basis of studying the morbidity with MTD remain relevant, they should be aimed at establishing the relationship between the kind of activity of workers with risks development of occupational diseases. PMID- 30516504 TI - THE RELATIONSHIP BETWEEN THERMAL PAIN SENSATION, FREE TESTOSTERONE, TRPV1, MOR LEVELS AND VARIOUS DEGREES OF HOSTILITY IN YOUNG HEALTHY MALES. AB - Large number of studies consider gonadal hormones as factors influencing pain perception by changing the activity of nociceptive and antinociceptive systems. Recent studies indicate that testosterone, along with some other gonadal hormones, plays a key role in the regulation of TRPV1 and MOR expression. In addition, some works focus on the relationship between pain sensation and hostility indices, as well as their interaction with gonadal hormones. The purpose of this study is to elucidate the relationship of thermal sensation and pain threshold with free testosterone, transient receptor potential cation channel subfamily V member 1(TRPV1) and u-opioid receptor (MOR) protein levels as well as various degrees of hostility in young healthy males. Significant positive correlation is found between heat pain threshold, free testosterone and MOR levels. Each of these parameters significantly correlates positively with various degrees of assault and insignificantly with that of verbal and indirect hostility. They also significantly correlate negatively with various degrees of irritability, resentment, suspicion and guilt. Significant negative correlation is detected between heat pain threshold and TRPV1 level as well as free testosterone and TRPV1 level. The relationship among cold pain threshold, free testosterone, TRPV1, MOR levels and hostility indices is insignificant. Consequently, we consider it to the purpose to further studies in this direction including interaction among other forms of pain sensation and psychological indices. PMID- 30516505 TI - ASTHMA CONTROL STATUS AND LUNG FUNCTION IN RELATION TO VITAMIN D LEVEL IN CHILDREN WITH BRONCHIAL ASTHMA. AB - The aim of the study - low circulating vitamin D level maybe related to poor asthma control status and decreased lung function. The aim of our research is to establish correlation between serum vitamin D level, asthma control status and lung function. The study was performed in children aged 6-15 years old, including patients with asthma (n=50), who referred to Sachkhere medical center for a visit. The status of asthma control in the basic group was classified as controlled (n=31) and uncontrolled (n=19). The children underwent serum vitamin D and IgE level, spirometry and skin prick tests for the study. Using the multivariate logistic regression analysis, the presence of asthma was associated with the reduced level of vitamin D (OR = 1.35, 95% CI (1,14-1.58) P = 0.011; chi2=6.78; F-0.022) in children with uncontrolled bronchial asthma. 48% of the patients in the group- controlled asthma (n=15) had vitamin D deficit, and in 52% of the cases (n=16) was confirmed with vitamin D insufficient. In the group uncontrolled asthma - 5% of the patients (n=1) had Vitamin D insufficiency in blood serum. In 95% (n=18) of the patients vitamin D level was significantly low <20 ng/ml. According the results, decreased pulmonary function (p-0.039; chi2 3.12) is strongly associated with low level of vitamin D; but neither serum IgE level (p-0.54; chi2-10.9), nor skin prick test result on dust mite (p-0.50, chi2 5.12 ) was correlations with serum vitamin D low level. The presence of vitamin D deficiency effectively predict increased risk of uncontrolled bronchial asthma in children. Serum vitamin D level is related to lung function too. Therefore, the normalization of the serum levels of Vitamin D may have beneficial effect on improvement of asthma control in the complex of asthma management and preventive measures. PMID- 30516506 TI - [PROBLEMS OF IMPROVING ANTENATAL MONITORING OF PREGNANT WOMEN IN THE PRIMARY HEALTH CARE SYSTEM IN GEORGIA]. AB - The purpose of the above work is to study the trends of mothers' health condition according to the implementation of antenatal monitoring of primary healthcare programs in 1996 - 2016 in Georgia. The methodology basis of the research is the qualitative investigation, so called Desk Research: collecting statistical data, description, systematization, comparison, analyses and interpretation. Data about mothers' health indicators were derived from National Center for Disease Control and Social Health and National Service of Georgian Statistics. Dynamic of the following indicators were studied: Number of births at home and the share of births at medical institution received by the qualified medical personnel, percentage of pregnant women's timely application, covering 4 antenatal visits, full time pregnancy, timely births, physiologic and pathologic births, Caesarean sections (planned, urgent); Number and indicator of mother's deaths. In order to study the law basis, the Statements of Georgian Government, normative acts of Labour, Health and Social Security of Georgia have been used for studying. In 1996 - 2016, as the result of Healthcare reforms, implemented in Georgia up to now, several parameters of antenatal monitoring were improved. The share of timely application and covering full, 4 antenatal visits increased; Share of births, received by qualified medical personnel increased; Number of mothers' mortality significantly decreased, but it is much higher when compared with the developed countries. Following the improvement in monitoring parameters and financial and geographical availability of antenatal care services, the unfavorable outcome of the pregnancy was revealed: the percentage of pathologic births increased, share of physiologic births decreased. The share of Caesarean sections is increasing and critically high. The share of early deliveries and incomplete period pregnancies increased. The above mentioned conditions indicate that there are systemic problems in the primary healthcare: In the preconception and then antenatal period, the quality of medical service does not meet the international standard. Assessment of pregnancy and fetal risks, prevention and management are inadequate. PMID- 30516507 TI - CHARACTERISTICS OF DIARRHEAL DISEASE COMPLICATED WITH HEMOLYTIC UREMIC SYNDROME AMONG CHILDREN IN GEORGIA, 2009-2016. AB - Shiga toxin-producing Escherichia coli (STEC) causes illness ranging from mild diarrhea to bloody diarrhea, to the hemolytic uremic syndrome (HUS), which manifests with a triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. Surveillance of HUS and bloody diarrhea is not performed in Georgia. The primary objective of our study was to determine the annual incidence of diarrheal diseases. The secondary objective was to assess epidemiological characteristics, etiology and risk factors of diarrhea and HUS in Georgia among children under 15. We collected a retrospective data on diarrheal diseases particularly bloody diarrhea and HUS among children in Georgia in 2009-2016 years. Laboratory, clinical and epidemiological data was entered into electronic database. Descriptive statistics, proportions, incidence rates, means and medians were calculated in R statistical language using statistical package R for windows v 3.4.3. A total of 316 cases of bloody diarrhea including 64 (20.2%) cases complicated with HUS under age 15 were identified from 2009 until 2016. From 316 patients 5 (1.6%) have died, all of them with diagnosis and severe complications of HUS. Average rate of HUS per 100,000 populations during 2009-2016 was 0.3 and for bloody diarrhea 2 per 100,000. High RR for food products consumed by children with bloody diarrhea either complicated with HUS or not were various ice-creams produced locally (RR 4.23 P<0.001), dairy products (RR 2.79 P = 0.01), ground beef products (RR 4.52 P<0.001). The another highest attack ratio was identified for fruits (RR 6.19 P<0.001) and vegetables (RR 3.45 P < 0.001). Different enteric pathogens including shiga toxin producing E. coli was detected as etiology of diarrheal diseases and HUS. Epidemiological data suggests that inadequately washed fruits, vegetables and eating undercooked food and ice-cream could be a possible risk factors of exposure with enteric pathogens and developing diarrhea and HUS among children. Further investigations of food products are required to determine epidemiology and source food products of bloody diarrhea and HUS among children in Georgia. PMID- 30516508 TI - DISTRIBUTION AND DEMOGRAPHIC CHARACTERISTICS OF DUCTAL INVASIVE BREAST CARCINOMA SUBTYPES IN GEORGIAN POPULATION. AB - The analysis of prevalence of each specific subtypes of the ductal invasive breast carcinoma according to age group categories showed that Luminal A subtype is observed in every age group as dominant subtype, although in different intensity: two peaks were demonstrated in group III and group IV, and in relatively less amount, in V group as well. Its considerable that Her2(+)/ER subtype was second most prevalent subtype in almost all age groups. It also must be noted that there was no direct correlation found between pre- or post menopausal period and HER2+ state, except for group IV (60-69 year old range), where it was almost 2 times less frequently found than Basal-like subtype. The frequency of Her2(+)/ER tumor subtype was identical to Luminal A subtype frequency. In age group I (30-39 year old) and all others its frequency was found to be markedly decreasing along with the frequency of Luminal A subtype (if in age group I their frequency was 1.2, in the age group IV it accounted for 9.4, which means that Her2(+)/ER subtype prevalence decreases with increasing age until the age group V (70-79 year old), after which it increases again (age group V and VI demonstrated the frequency of 2.0 and 5.0 respectively). Basal-like tumor was not found in age groups I and VI, and its frequency was gradually increasing except for age group II, where it was approximately 1.5 less frequent than in other age group categories. Triple-negative subtype was not found in age groups I and VI, however, its frequency was gradually increasing with increasing age. The prevalence of triple-negative tumor in age group V was 4.5 times higher than in age group II. The frequency of Luminal B subtype tumor was almost 2 times decreased in age group III, while in age group V it was almost 3 times increased. However, it disappeared in age group VI completely. Consideration of the age related specificities of ductal invasive breast carcinoma subtypes (phenotypes) is important both for diagnostic aspect and treatment strategy selection, as well as adequate planning of breast cancer screening programs. Thus, in all age groups of the studied population, IIIA and B stages of tumor were identified, with tumor sizes ranging between 2.8-4.7mm. There was no stable direct correlation between breast cancer and family history, as the presence of such data requires additional research with more focus on anamnesis details. PMID- 30516509 TI - CHANGES OF PROTEINURIA AND ACID-REGULATING KIDNEY FUNCTION IN MATURE RATS WITH SLOW AND RAPID ACETYLATION TYPE UNDER CONDITIONS OF SUBACUTE CADMIUM-NITRATE INTOXICATION. AB - The experiments conducted on non-linear mature laboratory albino rats determined that under conditions of subacute cadmium-nitrate intoxication the indices of proteinuria and acid-regulating renal function depend on acetylation phenotype. Unlike rapid acetylators considerable increase of protein concentration in urine (192,8%, r<0,05) and standardized by glomerular filtration protein excretion (141,7%, r<0,05) are indicative of higher susceptibility of rats with slow acetylation type to nephrotoxic action of cadmium chloride and sodium nitrate. Lack of protein loss with urine and adaptive-compensative character of acid regulating renal function changes directed to elimination of hydrogen ions excess from the body give evidence concerning less intensive damage of the nephron tubular portion in rats with rapid acetylation type, and at the same time do not exclude development of nephropathy. In order to confirm the significance of acetylation phenotype for assessment of susceptibility and degree of cadmium nitrate damage of the kidneys the condition of other renal functions should be examined with analysis of biochemical criteria of nephrotoxicity, which is of an important practical value for the selection of appropriate pharmacotherapy. PMID- 30516510 TI - [PROTECTIVE PROPERTIES OF DRUGS OF PLANT ORIGION IN ACUTE EMOTIONAL AND PAINFUL STRESS IN RATS]. AB - The aim of the investigation was to study the protective properties of the herbal preparation - biotrite and tranquilizer diazepam under the modeling of emotional and painful stress in rats. Materials and methods. The experiment was conducted on 24 white male rats of 5 months of age. Animals (6 rats in the group) were kept on the standard diet of the vivarium: 1st group was intact; rats of the 2nd, 3rd and 4th groups were reproduced acute painful emotional stress for 3 hours. 60 minutes before the stress, rats received per os: the 2nd group - water, the 3rd group - diazepam in a dose of 1.25 mg / kg body weight of rats; 4th group - a preparation of biotrite in a dose of 50 mg / kg. Results and conclusion. The conducted studies demonstrated significant adaptive properties of the biotrite preparation, and the degree of their manifestations was higher than the stress protective effects of diazepam. PMID- 30516511 TI - THE INFLUENCE OF SODIUM SALTS OF CARBOXYMETHYLATES OF OXYETHYLATED ISONONYLPHENOLS ON THE NEUTRALIZING FUNCTION OF THE LIVER IN A SUBACUTE TOXICOLOGICAL EXPERIMENT. AB - The study was conducted as a part of research work "Biochemical mechanisms of the development of dismetabolic processes under the influence of chemical environmental factors". The purpose of the present work was to study the effects produced by sodium salts of carboxymethylates of oxyethylated isononylphenols on the state of the microsomal monooxygenase system of hepatocyte detoxification and on the conjugation reaction in conditions of a subacute experiment and to reveal a potential danger for homoitherms and human beings. The object of the study were the white rats of WAG population. The effects produced by sodium salts of carboxymethylates of oxyethylated isononylphenols of such brands as AFS 9-4 KM, AFS 9-6 KM, AFS 9-10 KM on the state of the microsomal monooxygenase system of hepatocyte detoxification and on the conjugation reaction in conditions of a subacute experiment were studied. It was set that studied compounds during their subacute influence in a toxicological experiment stimulated the hydroxyling microsomal monooxygenase system of hepatocytes and inhibited reactions of the formation of glucuronid and glutathione conjugations against a background of more active processes of the formation of acetyl conjugation, higher levels in the content of CoA-SH, acetyl-CoA and ketone bodies. PMID- 30516512 TI - THE INFLUENCE OF MONOSODIUM GLUTAMATE ADMINISTRATION ON GENERATION OF REACTIVE OXYGEN SPECIES AND APOPTOSIS OF BLOOD LEUKOCYTES IN RATS. AB - The use of food additives in food manufacturing has been a public health issue for many years. Currently, more than 3000 food additives have been approved and estimates has shown that each person may consume 3.6 to 4.5 kg of food additives per year on average. One of the most common food additives in Ukraine and in Europe is monosodium glutamate (MSG). This paper reports the effect of monosodium glutamate administration at "safe" (allowed) doses on the generation of reactive oxygen species and apoptosis in leukocyte blood suspension of rats. Experimental studies were conducted on 32 non-linear, male, white rats weighing 180-200 g. The experimental animals were administered MSG (Sigma-Aldrich, USA) at a dose of 15, 30 and 45 mg/kg body weight. Control group of animals received normal saline. We have found that consumption of MSG at low dosage was associated with development of excessive reactive oxygen species generation and apoptotic processes in blood leukocytes of rats. Therefore it is advisable not only to investigate the established dangerous doses of E621, but also to study the molecular mechanisms of the "safe" (allowed) doses of MSG effect on a living organism. PMID- 30516513 TI - EXPERIMENTAL STUDY OF PAIN-RELIEVING MECHANISMS OF 4-[4-OXO-(4H)-QUINAZOLIN-3-YL] BENZOIC ACID (PK-66 COMPOUND). AB - An in-depth study of the pharmacological properties of 4-[4-oxo-(4h)-quinazolin-3 yl]-benzoic acid as an analgesic agent established that it had a sufficiently high analgesic effect on models of somatic and neuropathic pain syndromes. Study objective was to study the mechanisms of analgesic action of PK-66 compound in rats using the pharmacological analysis. We evaluated the mechanisms of analgesic effect of PK-66 (1 mg/kg, intraperitoneal) compound on the thermal irritation model on Hours 1, 2, 4 and 6 after administration of study compounds. To evaluate the mechanisms of PK-66 compound pain killing, we determined the changes in its efficacy against the effects of pharmacological analyzers - Naloxon, Tramadolum, Clophelinum (Clonidine), Yohimbine, Noraepinephrine, Reserpinum, Chlorpromazine (Aminazin), Levodopa, Diazepam, and Memantine). The anti-nociceptive effect of PK 66 compound was virtually unchanged during all study terms with underlying administration of Naloxon, an opioid receptor antagonist. The results of administration of Reserpinum in rats and the concomitant administration of Noradrenaline, Clophelinum, Yohimbine and quinazoline derivative demonstrated that the adrenergic system, in particular alpha-2 adrenergic receptors, was involved in the mechanisms of PK-66 activity. Changes in the PK-66 compound effect with underlying previous administration of Levodopa and Chlorpromazine suggested that the dopaminergic system was unquestionably involved in the analgesic activity of the compound. Further study of the involvement of inhibitory and exhilarating amino acids, GABA and glutamate, showed that administration of Diazepam potentiated and extended the PK-66 analgesic effect on the thermal nociception models throughout the experiment. At the same time, increased antinociception with underlying Memantine administration preceding PK 66 was observed only in the first hours of the experiment. Therefore, the studies conducted have shown that the adrenergic system, in particular alpha-2 adrenergic receptors, dopaminergic and GABAergic systems, is involved in the mechanisms of analgesic action of 4-[4-oxo-(4h) -quinazolin-3-yl]-benzoic acid (PK-66) without any effect of PK-66 on opioid receptors. PMID- 30516514 TI - MEDICAL BASIS OF DIABETIC NEUROPATHY FORMATION (REVIEW). AB - Nowadays, chronic diseases are leading cause of death worldwide. One of popular chronic disease of 21 century is Diabetes Mellitus (DM) that affected 422 million people around the world in 2014; its prevalence is expected to increase to 592 million by the year 2035. Diabetic neuropathy (DN) seems to be the most common and least understood complication being present in over 50% of chronic diabetics. As the latest date explain the pathogenesis of DN is not fully understood. Therefore, considering the widespread of DN, severity of its consequences, it is vital to investigate details of its pathophysiology and find therapeutic strategies to improve patients' condition. Generally two mechanisms have been suggested to be involved in the pathogenesis of diabetic neuropathy. The first mechanism is the activation of the Renin Angiotensin Aldosterone System (RAAS) in the presence of hyperglycemia with increased tissue level of Angiotenzin II (Ang II). Ang II stimulates Nicotin Adenine Dinucleotide (Phosphate) (NAD (P)) oxidase which enhances oxidative stress and vascular damage and leading to DN. The other mechanism is linked with disturbance in the metabolism and vasculature of nerve tissue in the presence of excessive uptake of glucose. Conclusion: In our review we have discussed different mechanisms involved in formation of DM and DN. Based on the latest research studies the main component in the big picture of DN formation is hyperglycemia.The list of mechanisms are associated with high glucose level leading inflammation, oxidative stress, hypoxia and apoptosis through the activation of several pathogenic pathways induced by Tumor Necrosis Factor alfa (TNFa), AgII, (pro)renin, Protein Kinase C (PKC), glycolysis intermediated products, Cyclooxygenase 2 (COX2) and reactive nitrogen species (RNS). Therefore to use drugs linked with above discussed pathological processes would be effective solution in the treatment of DM and its complications. PMID- 30516515 TI - ISOLATION OF FLAVONOID EXTRACT FROM GEORGIAN CITRUS SINENSIS PEEL AND ITS ANTIOXIDATIVE PROPERTIES. AB - A method for isolation of polyphenol extract with significant amounts of flavonoid compounds (GOF) from precocious Georgian Citrus sinensis peels (Citrus sinensis (L.) Osbeck ,,Seike Navel", form N26) was established by multistage process based on producing water-associated fraction (WAF). Recent study describes the impact of GOF on altered cellular metabolism patterns of cardiac muscle cells and changes in blood induced by psycho-emotional stress. Markedly, GOF-treated animals show positive changes in certain antioxidant enzymes (SOD, catalase) activity and normalization of lipid peroxidation, whereas the concentration of Ca2+ and nitric oxide are approximated to the control value. Similar impacts were also observed in comparison with nobiletin, mainly found in citrus peels. It is notable that in terms of certain parameters, implication of GOF shows more effectiveness than nobiletin. PMID- 30516516 TI - [TIME SINCE DEATH ESTIMATION BY USING THE METHOD OF POLYCRYSTALLINE CEREBROSPINAL FLUID FILMS IMAGES MUTUAL POLARIZATION DEGREE LEVELS DISTRIBUTIONS TWO DIMENSIONAL MAPPING WITH FINE-SCALE SPATIAL FREQUENCY FILTRATION]. AB - Objective - to develop a method of two-dimensional Stokes-polarimetric spatial frequency mapping of small-scale components of cerebrospinal fluid to improve the accuracy of post-mortem interval estimation. The object of the study was polycrystalline cerebrospinal fluid films taken from 69 corpses (the main study group) and 20 healthy volunteers (comparison group). For each sample, the coordinate distribution of the values of the complex degree of mutual polarization was determined in the optical arrangement of the Stokes polarimeter. The value of the statistical moments of 1 - 4 orders with further statistical processing was calculated. Time dependences of the variation of the value of the most sensitive statistical moments were built to achiev of values stabilization. The interval and the accuracy of the post-mortem interval were estimated by generalizing of the time dependences of the third and fourth order statistical moments of the polarization maps obtained by the two-dimensional mapping of the values distributions of the complex degree of mutual polarization of the small scale component of polycrystalline networks of cerebrospinal fluid films. An interval of 10 h and the accuracy of post-mortem interval estimation DeltaT = +/- 12.5 min was established. PMID- 30516517 TI - CLINICAL ETHICS COMMITTEES: OVERVIEW OF THE EUROPEAN EXPERIENCE. AB - Making appropriate medical decisions in the best interest of the patient and in a line with the patient's autonomy, rights, dignity and plurality of values, are very important. In order to reach those goals and develop patient-oriented health service, Clinical Ethics Committees (CECs) support could make a great contribution. European countries (Netherland, Belgium, Italy, Germany, Norway, UK) are experiencing an exponential rise in the number of CECs as a mechanism to address the new ethical dilemmas in clinical settings, however the practice of CECs are facing barriers in transitional countries in central, eastern, and southeastern Europe. Despite the differences across the European countries we have found many similarities in groundwork trends of CECs development in studied countries, which have the most important impetus on the implementation and development of CECs. The most important and common ones are: enforcement of human rights doctrine, pluralistic civil movement, progressive development of medical science and new technologies, transfer of human rights movement in health care, development of bioethics, CECs educational capacity building, arising of complex moral, legal and ethical dilemmas in physicians' daily clinical practice, shifting medical care paradigm from the physician's single obligation to the shared responsibilities with respect of patient's rights, autonomy and dignity. Exploring those trends will lead to the opportunity to identify the most important factors that impact on the strengthening of the CECs practice in transitional countries as well. PMID- 30516518 TI - [THE STATE OF INTERNATIONAL LEGAL REGULATION OF CADAVERIC DONATION: ON THE PATH TO UNIFICATION (REVIEW)]. AB - The purpose of this study is to assess the current state of international legal regulation of cadaveric donation and determine the possibility of its further unification. Therefore, the subject of the study was the legal regulation of cadaveric donation as a certain part of medicine. In particular, the work examined the norms of international law, as well as the separate provisions of the national legislation of different countries, aimed at regulating relations in the field of cadaveric donation. Also analyzed the results of scientific research on this subject. During the study, different methods of cognition were used. In particular, the historical method allowed to establish trends in the development of legal regulation of cadaveric donation. The comparative-legal method has given an opportunity to highlight the peculiarities of national regulation of relations associated with cadaveric retrieval of organs in some individual countries and correlated them to international legal experience. The statistical method has given an opportunity to establish the effectiveness of the application of a legal construct, its ability to overcome the "deficit" of the bodies and a fair distribution between the recipients. On the basis of the dialectical method, the conclusion was drawn about the possibility of developing common standards for the legal regulation of relations in the area of cadaveric donation. Other methods were used in this work, including: formal-logical, dogmatic, modeling, analysis and synthesis. The result of the study was the conclusion about the need and the possibility of forming a single international standards for the legal regulation of cadaveric donation, and in the context of globalization, there is an urgent need to create a universal Model code on donation and transplantation. PMID- 30516519 TI - PROBLEM-ORIENTED MEDICAL RECORD AS A CHALLENGE FOR NARRATOLOGICAL ANALYSIS. AB - The paper examines the narrative arrangement of the problem-oriented medical record (POMR) as an effective method of registering and assessing clinical data. The aim of the research is to examine the types of narrators and focalization, as well as the hierarchy and interaction of narrative levels in the analyzed discourse. The research has demonstrated the presence of several types of narrators within the analyzed discourse: (1) the omniscient hetero-extradiegetic narrator with transient internal focalization (the third-person narration, represented by the physician) and (2) homo-intradiegetic narration (patient's first-person narration) in the "Subjective Observation" section; (3) the "estranged" heterodiegetic narrator with external focalization (the "Objective Observation" part); (4) the "uncertain" type of narrator (the "Assessment" part); (5) and the imperative mode of narration (the "Plan" section). Each section of POMR is characterized by a specific type of narration, and each of them aims to "intertwine" the events, scattered in time and space, into one coherent narrative to ensure the effective communication between physicians and successful treatment of patients. It is highly important for future physicians to develop narrative competence and master the basic mechanisms of producing an effective POMR, in order to be able to accurately document the encounters with patients, elicit the relevant details from case histories, and select the appropriate strategy of treatment. Therefore, in the process of training future doctors, the analysis of the basic mechanisms of writing POMRs should be an integral part of the curricula in English for Specific Purposes at universities. PMID- 30516521 TI - What is the association between obesity and diastolic dysfunction: Obesity or obesity phenotype? PMID- 30516520 TI - Automated nucleic acid isolation methods for HDV viral load quantification can lead to viral load underestimation. AB - BACKGROUND: Hepatitis D virus (HDV) infection is a cause of severe liver disease. Diagnosis and monitoring of HDV RNA are important to patient management. Since 2012 a WHO standard for HDV RNA quantification is available, however, the impact of RNA extraction methods on HDV viral load quantification has never been evaluated. METHODS: Aim of this study was to compare four commonly used automated nucleic acid (NA) extraction methods (AmpliPrep, MagNA Pure, QIAcube QBK and QIAcube VRK) to a manual RNA extraction method (Instant Virus RNA/DNA kit) and evaluate the possible effect of each method on HDV RNA yield with subsequent amplification with the Robogene HDV assay. Serum samples from HDV positive patients taken before treatment with PEG-IFNa-2a and at treatment weeks 12 and 48 were studied. RESULTS: The automated extraction methods MagNA Pure, Ampliprep and QIAcube VRK extraction lead to about 10-fold lower HDV RNA values compared to the manual method of NA extraction, while the difference was smaller with QIAcube QBK (about 6-fold lower). The median viral load was 10,665 IU/ml for the manual method, 445 IU/ml for AmpliPrep, 3209 IU/ml for MagNA Pure, 2060 IU/ml for QIAcube QBK and 3568 IU/ml for QIAcube VRK. Use of MagNA Pure lead to misclassification of two on-treatment samples with low viral load as being false negative. CONCLUSIONS: The NA extraction method has a significant impact on the measured HDV viral loads determined by the commonly used Robogene assay, with the manual RNA method yielding consistently higher values of viral load. PMID- 30516522 TI - Predictive power of different obesity measures for the presence of diastolic dysfunction. AB - OBJECTIVE: Body mass index (BMI) and waist circumference (WC) as measures of obesity have some limitations. The aim of this study was to evaluate whether one measure could predict the presence of diastolic dysfunction (DD) more accurately than the other measures. METHODS: A total of 91 obese patients without any other risk factors for DD were prospectively enrolled. Echocardiographic examination was performed. DD was defined and categorized according to recent guidelines. The study participants were divided into 2 groups according to the presence of DD. Weight, height, and WC were measured; BMI and waist-to-hip ratio (WHR) were calculated; and a body shape index (ABSI) was calculated as WC/(BMI2/3height1/2). The associations between ABSI, BMI, WHR, and WC and the presence of DD were examined using logistic regression analyses. Analysis of covariance was used to examine the differences. RESULTS: WC and BMI were significantly greater in subjects with DD (p=0.049 and 0.051, respectively). A greater BMI, WC, and WHR increased the risk of the presence of DD (BMIDD: odds ratio [OR]=1.096, p=0.024; WC-DD: OR=1.059, p=0.007; WHR-DD: OR=2.363, p=0.007). After adjustment for age and sex, only BMI continued to be significantly associated with DD (p=0.031). ABSI was not associated with DD. CONCLUSION: After adjustment for age and sex, BMI was the only predictor of DD in obesity. Despite its limitations, BMI may still be a potentially more accurate measure of DD compared with other obesity measures. PMID- 30516523 TI - Mid-term clinical outcomes of new generation drug-eluting stents for treatment of diffuse coronary artery disease. AB - OBJECTIVE: Diffuse coronary artery disease (CAD) is a challenging issue in clinical cardiology practice. There are limited data about percutaneous revascularization in these patients. METHODS: This study was an observational clinical evaluation. The records of patients with diffuse CAD revascularized with new-generation drug-eluting stents (DES) were researched retrospectively. Patients treated with multiple, overlapping new-generation DES (at least 60mm in length per vessel) were included. The incidence of major adverse cardiac events (MACE), defined as cardiac death, stent thrombosis, non-fatal myocardial infarction, and target lesion revascularization (TLR), at the end of the first year following the index procedure was recorded. RESULTS: A total of 71 patients (with 75 coronary vessels) treated with new-generation DES for diffuse CAD were enrolled in the study. Zotarolimus-eluting stents were used in 48 vessels and biolimus A9-eluting stents were used in 27 vessels. The median total stent length per vessel was 75.0 mm (60.0-106.0) and the median number of stents implanted was 3 (2-4) for each vessel. The cumulative incidence of MACE at the end of the first year was 11.2% (8 patients). The presence of diabetes mellitus (DM) and ST segment elevated myocardial infarction (STEMI) were defined as independent clinical risk factors related to MACE development. CONCLUSION: Coronary artery revascularization with new-generation drug-eluting stents can be a good choice in the treatment of selected patients with diffuse CAD. DM and STEMI were found to be related to poorer clinical outcomes with this treatment option in our study. PMID- 30516524 TI - [Pulmonary hypertension spectrum: 16 years of experience from a single center]. AB - OBJECTIVE: Pulmonary hypertension (PH) is multidisciplinary disorder that should be diagnosed and treated by specialized centers. Progress in the field of PH diagnosis has led to new classifications of the disease. The aim of this study was to determine the etiological properties of PH diagnosed at one center. METHODS: A retrospective search of the database of the right heart catheterization laboratory was conducted. All of the patients who underwent right heart catheterization (RHC) and were diagnosed with PH were included in the study and grouped according to etiology. RESULTS: A total of 379 patients with PH (23 female; 53.2+/-14.7 years) were included in the current research. There were 82 patients classified as having pulmonary arterial hypertension (PAH). The leading cause among the PAH subgroups was congenital heart disease, and valve disease were found to be most the common reason for postcapillary PH. There was a statistically significant difference in the mean and systolic pulmonary artery pressure and left ventricular ejection fraction between the PH groups (p<0.001, p=0.003, p<0.001, respectively). CONCLUSION: The results of this study indicated that the leading causes of PAH and postcapillary PH were congenital heart disease and valve disease, respectively. Additional research of the etiological properties of PH should be performed by specialized centers in Turkey. PMID- 30516525 TI - Arrhythmia during diagnostic cardiac catheterization in pediatric patients with congenital heart disease. AB - OBJECTIVE: Diagnostic and interventional cardiac catheterization procedures for congenital heart diseases (CHD) are becoming increasingly more popular, and arrhythmia is a well-known complication. This study was an evaluation of the incidence and causative agents of arrhythmia and the subsequent treatment strategies applied during cardiac catheterization. METHODS: The catheterization data of all of the patients who underwent diagnostic cardiac catheterization for CHD between January 2012 and 2018 at a single center were examined retrospectively. RESULTS: A total of 1316 children underwent diagnostic cardiac catheterization due to CHD. The median age and body weight was 18 months (6 days 21 years) and 9.9 kg (2.2-135 kg), respectively. Patients with ventricular septal defect (281 patients) and those with tetralogy of Fallot (257 patients) represented 2 major groups of the study population. In 93 (7%) patients, arrhythmia developed during cardiac catheterization. Among them, there were 58 (62%) cases of bradyarrhythmia and 35 (38%) cases of tachyarrhythmia. Arrhythmia was classified as low, high, or major, according to the adverse event severity score; the rates were 2.7%, 4.3%, and 1.2%, respectively. In 36 (39%) patients, there was no need for therapy, whereas 57 (61%) required treatment to eliminate the arrhythmia. Treatment modalities included catheter manipulation in 15, pharmacological therapy in 24, and cardioversion in 3 patients. Eleven patients required cardiopulmonary resuscitation. Temporary pacemaker implantation was required in 2 patients, while 2 others underwent permanent pacemaker implantation secondary to catheterization-related arrhythmia. There were no cases of mortality secondary to catheterization-related arrhythmia. CONCLUSION: Diagnostic cardiac catheterization in CHD may result in various types of cardiac arrhythmias. The proper management of arrhythmias may reduce morbidity and mortality related to cardiac catheterization. PMID- 30516526 TI - Is there a gender gap in secondary prevention of coronary artery disease in Turkey? AB - OBJECTIVE: It has been reported that women receive fewer preventive recommendations regarding pharmacological treatment, lifestyle modifications, and cardiac rehabilitation compared with men who have a similar risk profile. This study was an investigation of the impact of gender on cardiovascular risk profile and secondary prevention measures for coronary artery disease (CAD) in the Turkish population. METHODS: Statistical analyses were based on the European Action on Secondary and Primary Prevention through Intervention to Reduce Events (EUROASPIRE)-IV cross-sectional survey data obtained from 17 centers in Turkey. Male and female patients, aged 18 to 80 years, who were hospitalized for a first or recurrent coronary event (coronary artery bypass graft, percutaneous coronary intervention, acute myocardial infarction, or acute myocardial ischemia) were eligible. RESULTS: A total of 88 (19.7%) females and 358 males (80.3%) were included. At the time of the index event, the females were significantly older (p=0.003) and had received less formal education (p<0.001). Non-smoking status (p<0.001) and higher levels of depression and anxiety (both p<0.001) were more common in the female patients. At the time of the interview, conducted between 6 and 36 months after the index event, central obesity (p<0.001) and obesity (p=0.004) were significantly more common in females. LDL-C, HDL-C or HbA1c levels did not differ significantly between genders. The fasting blood glucose level was significantly higher (p=0.003) and hypertension was more common in females (p=0.001). There was no significant difference in an increase in physical activity or weight loss after the index event between genders, and there was no significant difference between genders regarding continuity of antiplatelet, statin, beta blocker or ACEi/ARB II receptor blocker usage (p>0.05). CONCLUSION: Achievement of ideal body weight, fasting blood glucose and blood pressure targets was lower in women despite similar reported medication use. This highlights the importance of the implementation of lifestyle measures and adherence to medications in women. PMID- 30516527 TI - The caregiver burden and the psychosocial adjustment of caregivers of cardiac failure patients. AB - OBJECTIVE: This cross-sectional, descriptive study evaluated the relationship between the caregiver burden and the psychosocial adjustment of caregivers to cardiac failure patients. METHODS: Between November 18, 2015 and March 1, 2016, a preliminary information form, the Caregiver Burden Scale, and the Psychosocial Adjustment to Illness Scale were used to assess the caregivers of 200 patients being treated in the cardiology service of a university hospital. RESULTS: Among the caregivers, 75% were primary or secondary school graduates, 36% were housewives, and 43% were the patients' spouse. Of the group, 71% had been caring for the patients for 5 years or less. The caregivers described cardiac failure as "difficulty with inhalation, fatigue, asthenia, insomnia, and swelling in the hands and feet." They reported feelings of sorrow, fear, despair, bewilderment, anger, and guilt when they learned about the diagnosis, and they indicated that they generally managed those feelings by themselves. A total of 94% of the caregivers remarked that after the diagnosis they experienced physical, psychological, social, occupational, or economic changes. Of the respondents, 74% felt sad and adversely affected, 71.5% faced difficulties with care provision, and 84% felt anxiety about the possibility of losing the patient while under their care, the disease prognosis, surgery (pacemaker implantation), and adjustment to the treatment. The study participants' caregiver burden and psychosocial adjustment scale scores were below average. There were moderate statistically significant relationships between 3 subdimensions of the caregiver burden and psychosocial adjustment to illness scales (p<0.05). CONCLUSION: The participating caregivers of cardiac failure patients described moderate difficulties due to caregiving and adjusting to the illness. It was determined that as the distress felt due to caregiving increased, psychosocial adjustment to illness deteriorated. PMID- 30516528 TI - Acute anterior myocardial infarction in the 36th week of pregnancy: A successful stepwise treatment approach. AB - Acute myocardial infarction (AMI) is associated with a high incidence of maternal and fetal complications when it develops during pregnancy or the early postpartum period. The pathophysiology involves various factors, including alterations in the vascular wall and hypercoagulability as a result of the hormonal and hemodynamic effects of pregnancy. It frequently occurs due to the development of a thrombus following a ruptured plaque. In addition, coronary artery dissection constitutes a significant cause of AMI in pregnancy. In the literature, the therapeutic approach covers a wide spectrum, ranging from conservative follow-up to percutaneous coronary intervention, urgent bypass surgery, and occasionally, thrombolytic therapy. The success rate is often low; however, maternal and fetal complications are seen more frequently during invasive interventions and bypass surgeries because of the structural changes in the coronary intima and media wall. Presently described is the case of a woman in the 36th week of pregnancy who presented with AMI. The occlusion could not be detected during the primary percutaneous intervention, and thrombolytic treatment and a stepwise percutaneous intervention were performed with a successful result. PMID- 30516529 TI - Unilateral leg edema: Is it always vascular? AB - Unilateral lower extremity edema below the knee commonly results from deep venous thrombosis, venous insufficiency, or lymphedema. The patient history, a physical examination, and lower extremity venous duplex ultrasound often reveal the underlying etiology, which is frequently of vascular origin. Presently described is the case of a 23-year-old patient who underwent a diagnostic workup for unilateral leg swelling and was found to have a relatively uncommon cause of edema: lipedema. Lipedema is a disease characterized by subcutaneous adipose tissue deposition, and although diagnosed very rarely in general cardiology outpatient clinics, it has been demonstrated to be a cause of lower extremity edema in approximately one-fifth of cases in specialized clinics. PMID- 30516530 TI - [Removal of a catheter kinked in the radial artery by anchoring the distal part of the catheter with a needle via transcutaneous approach]. AB - Presently described is a case with a twisted catheter in the radial artery during coronary angiography and was removed after stretching it with an external needle tip inserted into the brachial artery. A 77-year-old male patient had undergone coronary artery bypass surgery 10 years earlier and implantation of a permanent pacemaker 2 years prior. He had presented with typical angina and a regional wall motion defect had been observed on echocardiography. Coronary angiography was scheduled. A 5-F sheath (Terumo Corp., Tokyo, Japan) was inserted, and angiography via the right radial artery was initiated. Soon after, the 5-F diagnostic catheter became twisted due to subclavian artery tortuosity. The fold in the catheter could not be flattened with 0.038-mm or 0.035-mm guidewires or rotation movements. With scopy assistance, a 21-gauge, 40-mm, green needle was inserted percutaneously into the catheter through the brachial artery. So, the catheter was stretched and the kink could then be corrected and the catheter was removed from the sheath. Subsequent Images revealed no trauma or deformity of the brachial or radial arteries. It was not possible to straighten the fold until the distal portion of the catheter was fixed in place and stretched. A catheter can be transdermally anchored with a needle if it becomes kinked in the upper extremity vessels. This is a simple and reliable method that is a traumatic. PMID- 30516531 TI - Revascularization of superficial femoral artery due to chronic total occlusion: Collateral approach. AB - Endovascular interventions are now used more frequently in the treatment of femoropopliteal occlusions, and antegrade passage through the occlusion is preferred as the first option. However, when antegrade passage fails for any of several reasons, retrograde, or less frequently, collateral passage may be used. Although collateral passage may present serious complications, it can be successfully applied in selected cases in experienced centers. In the present case, a superficial femoral artery occlusion was successfully opened with a collateral approach. PMID- 30516532 TI - Can flecainide totally eliminate bidirectional ventricular tachycardia in pediatric patients with Andersen-Tawil syndrome? AB - Andersen-Tawil syndrome (ATS) is a disorder that causes episodes of muscle weakness (periodic paralysis), changes in heart rhythm, and developmental abnormalities. QT prolongation and ventricular arrhythmias, including bidirectional ventricular tachycardia (VT) and polymorphic VT, may occur. About 60% of all cases of the disorder arecaused by mutations in the KCNJ2 gene. A 13 year-old female patient was referred for frequent premature ventricular contractions. Suspicion of ATS due to dysmorphic findings, electrocardiogram changes, and periodic muscle weakness was genetically confirmed. Beta-blocker therapy was initiated as a first-line treatment for bidirectional VT and frequent polymorphic premature ventricular contractions. Despite proper treatment, the VT attacks were not brought under control. Flecainide was added to the treatment regime. The number of premature ventricular contractions was dramatically reduced with flecainide and the VT attacks completely disappeared. This patient is a rare example of ATS in our country. This article provides a description of successful management of rhythm disturbance in a patient with ATS. PMID- 30516533 TI - Vaccination of adults with heart failure and chronic heart conditions: Expert opinion. PMID- 30516534 TI - Case Image: Iatrogenic radial artery psedoaneurysm after cardiac catheterization. PMID- 30516535 TI - Case Image: Endovascular coil treatment of a right coronary artery aneurysm related to atherosclerosis. PMID- 30516536 TI - Case Image: Treatment of a fistula between coronary and pulmonary arteries with simultaneous use of two microcatheters for antegrade coil embolization. PMID- 30516537 TI - Case Image: Disproportionate right heart enlargement in a patient with small atrial septal defect: Hidden abnormal pulmonary venous return. PMID- 30516538 TI - Lipid disorders in Familial Mediterranean Fever patients: Is inflammation the only cause? PMID- 30516539 TI - Authors reply. PMID- 30516540 TI - Authors reply. PMID- 30516541 TI - Implantable cardioverter-defibrillator therapies are associated with increased incidence of depression and mortality. PMID- 30516542 TI - Authors reply. PMID- 30516543 TI - [Is Cardiac Syndrome X associated with altered myocardial energy expenditure?] PMID- 30516544 TI - [Author's reply]. PMID- 30516545 TI - Where is the missing piece of the puzzle? Failed device therapy in patients with left ventricular assist device. PMID- 30516546 TI - Bronchiectasis and asthma: a dangerous liaison? AB - PURPOSE OF REVIEW: To explore the latest insight of the literature on the asthma/bronchiectasis phenotype providing an updated overview about epidemiological, clinical and biological evidence linking these two conditions. RECENT FINDINGS: An increasing body of literature has shown that the association of asthma and bronchiectasis is a frequent phenomenon leading to a more severe disease with frequent exacerbations. The mechanisms by which the two diseases are linked are still not well established but they share several clinical and immunological features and many comorbidities. SUMMARY: The early identification of bronchiectasis through high-definition computer tomography in patients with severe asthma is crucial in order to provide an adequate treatment for both diseases and therefore to better control symptoms, exacerbations and infections. PMID- 30516547 TI - Prostaglandin E2 in NSAID-exacerbated respiratory disease: protection against cysteinyl leukotrienes and group 2 innate lymphoid cells. AB - PURPOSE OF REVIEW: The purpose of this review is to describe the recent advances that have been made in understanding the protective role of prostaglandin E2 (PGE2) in aspirin-exacerbated respiratory disease (AERD), known in Europe as NSAID-exacerbated respiratory disease (N-ERD). RECENT FINDINGS: Decreased PGE2 signaling through the EP2 receptor in patients with AERD leads to an increase in leukotriene synthesis and signaling. Leukotriene signaling not only directly activates group 2 innate lymphoid cells and mast cells, but it also increases production of IL-33 and thymic stromal lymphopoietin. These cytokines drive Th2 inflammation in a suspected feed-forward mechanism in patients with AERD. SUMMARY: Recent discoveries concerning the role of PGE2 in leukotriene synthesis and signaling in AERD, as well as downstream effects on group 2 innate lymphoid cells and mast cells, allow for a more comprehensive understanding of the pathogenesis of this disease. These discoveries also identify new paths of potential investigation and possible therapeutic targets for AERD. PMID- 30516548 TI - Innate lymphoid cells in asthma: pathophysiological insights from murine models to human asthma phenotypes. AB - PURPOSE OF REVIEW: The current review describes the role of different types of innate lymphoid cells (ILCs) in the pathogenesis of asthma inflammatory phenotypes by linking findings from murine asthma models with human studies. Novel treatment options are needed for patients with steroid-insensitive asthma. Strategies targeting ILCs, or their upstream or downstream molecules are emerging and discussed in this review. RECENT FINDINGS: In eosinophilic asthma, ILCs, and especially type 2 ILCs (ILC2s), are activated by alarmins such as IL-33 upon allergen triggering of the airway epithelium. This initiates IL-5 and IL-13 production by ILC2, resulting in eosinophilic inflammation and airway hyperreactivity. Type 3 ILCs (ILC3s) have been shown to be implicated in obesity induced asthma, via IL-1beta production by macrophages, leading ILC3 and release of IL-17. ILC1s might play a role in severe asthma, but its role is currently less investigated. SUMMARY: Several studies have revealed that ILC2s play a role in the induction of eosinophilic inflammation in allergic and nonallergic asthmatic patients mainly via IL-5, IL-13, IL-33 and thymic stromal lymphopoietin. Knowledge on the role of ILC3s and ILC1s in asthmatic patients is lagging behind. Further studies are needed to support the hypothesis that these other types of ILCs contribute to asthma pathogenesis, presumably in nonallergic asthma phenotypes. PMID- 30516549 TI - Ergonomics in endoscopic sinus surgery. AB - PURPOSE OF REVIEW: Awareness of ergonomics is growing into surgical specialties including otolaryngology. Most otolaryngologists experience occupational physical discomfort, and daily incorporation of standard ergonomic principles may alleviate some of this pain. RECENT FINDINGS: Further demonstration of surgery related physical discomfort has been documented based on surveys of general otolaryngologists and subspecialty rhinologists. One study utilized surface electromyography to document physical findings directly associated with the endoscopic sinus surgery procedure. However, relatively little work has been published on interventions to relieve task-related pain and body discomfort in rhinology. SUMMARY: Surgeon fatigue and bodily injury is a surprisingly frequent occurrence and is more likely to occur in procedures that are mentally challenging, prolonged, and require the surgeon to operate in a fixed position. Endoscopic sinus and skull base surgeons appear particularly susceptible to task related physical discomfort, and incorporation of ergonomic principles should be a priority. PMID- 30516550 TI - Weight stigma and its impact on paediatric care. AB - PURPOSE OF REVIEW: This review aims to evaluate current research findings relevant to weight stigmatization, to acknowledge the deleterious impact it has on the health of the paediatric population and to provide insight to optimize future guidelines for the treatment of individuals with overweight and obesity. RECENT FINDINGS: Obesity prevalence continues to rise in the USA with estimates in children from ages 2-19 years of 18.5%, an all-time high. With the increase in obesity, there has been a concomitant increase in weight stigma, which affects both youth and general population across varied levels of socioeconomic status and body sizes. SUMMARY: Weight stigma is a contributing phenomenon to the current obesity epidemic, as individuals with stigmatized experiences (weight based teasing, bullying, victimization) have increased risks for acquiring adverse health outcomes that encompass the physical, behavioural and psychological. Weight stigma can also lead affected individuals to internalize such experiences which decrease their overall quality of life. Sources of stigma may come from peers, family, educators, media, as well as healthcare professionals, as highlighted in this review. Efforts to establish prevention and treatment strategies for weight stigma may generate further traction to help improve global obesity rates. VIDEO ABSTRACT. PMID- 30516551 TI - Tumor risk and surveillance for children with hereditary disorders affecting growth. AB - PURPOSE OF REVIEW: Hereditary disorders affecting growth (both overgrowth and growth retardation) are frequently associated with heightened risk of neoplastic disease. This review summarizes the tumor spectra associated with these conditions and identifies disease-specific screening approaches. RECENT FINDINGS: An understanding of the molecular events underlying many of these growth disorders has evolved significantly over the past several years. Recognition of genotype-phenotype associations, in many cases, informs the cancer risk profile. Additionally, accumulating data suggest a benefit of rational presymptomatic surveillance for at-risk individuals, with a reduction in tumor-associated morbidity. Recent clinical practice recommendations have established risk-driven paradigms for tumor surveillance in the context of hereditary tumor predisposition syndromes, including those affecting growth. SUMMARY: Clinicians caring for children with growth disorders should be aware of syndromic associations and the associated cancer risks. Knowledge of tumor spectra and recommended surveillance strategies may facilitate tumor diagnosis at an early stage and reduce morbidity of the disease and associated treatments. PMID- 30516552 TI - Quickscan Assesses Risk of Long-Term Sickness Absence: A Cross-Sectional Validation Study. AB - OBJECTIVE: Increasing long-term sickness absence in many countries asks for specific measures regarding return-to work. METHODS: The risk of long-term sickness absence was assessed using a questionnaire containing work-related, function-related, stressful life-events -related and person-related factors. Additionally, workers' occupational health physician estimated the worker's chances for work resumption. Reliability, construct and criterion validity of the questionnaire were measured. RESULTS: 276 patients and 35 physicians participated in the study. The reliability was satisfying (alpha>.70) for all scales, except for perfectionism (alpha=.62). The results of the CFAs showed that the hypothesized factor models fitted the data well. Criterion validity tests showed that eight predictors significantly related to the estimation of the occupational physicians (rho<.05). CONCLUSIONS: The scales of the questionnaire are reliable and valid, and may be implemented to assess sick-listed workers at risk who might benefit from a rehabilitation program.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30516553 TI - The Application of Blockchain Technology in Stroke Rehabilitation. PMID- 30516554 TI - Response. PMID- 30516555 TI - Topical Rho-Associated Kinase Inhibitor, Y27632, Accelerates Corneal Endothelial Regeneration in a Canine Cryoinjury Model. AB - PURPOSE: Corneal endothelial cell regeneration varies by species, with nonhuman primates (NHPs) and rabbits displaying low and high proliferative capacities, respectively. Recent studies report that topical application of rho-associated kinase (ROCK) inhibitors accelerates corneal endothelial wound healing in animal models and human patients with endothelial dysfunction. This study determines the regenerative capacity of canine corneal endothelial cells in vivo and their response to a topical ROCK inhibitor, Y27632, after transcorneal freezing. METHODS: Right eyes of 6 beagles underwent transcorneal freezing; 10 mM ROCK inhibitor Y27632 or vehicle control was applied topically to both eyes at least 4 times daily for 56 days. Endothelial cell density was evaluated by in vivo confocal microscopy, and corneal thickness was measured by Fourier-domain optical coherence tomography (FD-OCT) and ultrasound pachymetry. RESULTS: Transcorneal freezing induced severe central corneal edema in dogs, with restoration of transparency occurring within 4 weeks. Y27632 significantly decreased corneal thickness by FD-OCT and ultrasound pachymetry in the acute phase and significantly increased endothelial cell density at days 28 and 42 post cryoinjury, suggesting faster restoration of endothelial cell recovery. CONCLUSIONS: Canine corneal endothelial function recovers at a similar rate as NHPs but more slowly than rabbits after cryoinjury. Faster corneal endothelial wound healing was observed by in vivo confocal microscopy and FD-OCT in dogs treated with Y27632 versus vehicle controls. Thus, a canine cryoinjury model may be a useful alternative to NHPs in detecting a response to therapies directed at endothelial regeneration. PMID- 30516556 TI - Utilization of Anterolateral Thigh Flap and Transverse Cervical Recipient Vessels for Head and Neck Cancer Patients With Former Neck Dissection and Irradiation: A Case Series Study. AB - PURPOSE: Free flap reconstruction in head and neck cancer patients with prior tumor resection, neck dissection, and irradiation is clinically challenging. The purpose of this study was to investigate the reliability and outcome of using the anterolateral thigh (ALT) flap and transverse cervical recipient vessels for microvascular reconstruction in patients with depleted vessels in the head and neck region caused by previous surgery and irradiation. METHODS: Between January 2015 and December 2017, microsurgical head and neck reconstruction was performed using the ALT flap and transverse cervical artery (TCA) as the recipient vessel in 15 patients who had undergone previous neck dissections and irradiation for cancer treatment. All patients had a "vessel-depleted neck" resulting from severe scarring and radiation fibrosis. Clinical data of each patient were recorded. RESULTS: All ipsilateral TCAs were found to be damage free. Subsequently, free ALT flaps were revascularized using the TCAs. One patient developed venous thrombosis, and another patient developed arterial thrombosis. They were both salvaged within 6 hours postoperatively. No flap failure or mortalities were reported within the 30-day postoperative period. Two patients developed orocutaneous fistula and were further managed with wound care. The mean follow-up time was 11.9 +/- 6.0 months (range, 5-23 months). Five patients died during the follow-up period from cancer progression. CONCLUSIONS: The use of the free ALT flap and TCA as the recipient vessel provides favorable microsurgical outcomes in patients with depleted recipient vessels in the head and neck region caused by previous neck dissections and radiation therapy. PMID- 30516557 TI - Linea Arcuate Hernia Following Transversus Abdominis Release Incisional Hernia Repair. AB - Open abdominal surgery continues to be most commonly complicated by postoperative herniation at the incision line. In 2012, Novitsky et al described a novel hernia repair technique that utilized a transversus abdominis release coupled with a posterior (retrorectus) component separation (TAR-PCS) of the ventral abdominal wall. Early reports attest to the versatility and low recurrence rate of this technique, particularly when repairing large and complex defects. We present a rare case of herniation below the linea arcuate (LAH) following repair via TAR PCS. Given its novelty compared with more widely utilized techniques, literature review revealed less discussion regarding potential pitfalls associated with this type of reconstruction, in particular the potential for LAH. To date, only 9 cases of symptomatic LAH have been described, although 2 previously described "suprapubic" herniations following TAR-PCS may represent previously mischaracterized cases of this type of complication. Nonetheless, none of these reports were in the setting of ventral hernia repair. PMID- 30516558 TI - A Systematic Review and Meta-analysis of Functional Shoulder Impairment After Latissimus Dorsi Breast Reconstruction. AB - PURPOSE: The latissimus dorsi flap (LDF) is a very reliable flap and may be used for a multitude of reconstructive purposes. It is widely used for breast reconstruction when performed. It has few complications, except for a possible impact on shoulder function. The aims of this study were to evaluate the validity of the literature by investigating the level of evidence and to perform a meta analysis. METHODS: A systematic literature search was conducted using the databases PubMed, Scopus, and Web of Science. Predictor variables were shoulder function after breast reconstruction with the LDF. Articles were chosen according to 4 different outcomes: shoulder range of motion (ROM), shoulder strength, DASH score, and subjective evaluation. RESULTS: Twenty-six articles were found, including 1045 patients: 8 level II, 16 level III, 1 level IV, and 1 level V articles. The meta-analysis showed that both ROMs for flexion and abduction are significantly impaired at less than or at 3 months of follow-up. CONCLUSIONS: There are several influencing factors, such as age, smoking, obesity, radiotherapy, and physiotherapy. Moreover, the impact on shoulder function seemed influenced by the type of thoracodorsal vessel-based flap. From the level of evidence analysis, there is a tendency that the LDF transfer does affect shoulder function. This limitation seems to be minimal, and few patients experience a major impact on shoulder function. However, the existing literature on total shoulder impairment after breast reconstruction with LDF is insufficient to draw any final conclusion. There is a need for future studies and current articles that suggest that the initial measurement should be performed preoperatively (preferably at the time of diagnosis or initial biopsy) and follow-ups with measurements at 6, 12, and 24 months (long-term effect) after surgery. We recommend measurements of both operated and nonoperated sides. Each measurement should be accompanied by a history with special emphasis on shoulder function. The methods of measuring outcomes of recommendation are DASH score, ROM with use of a goniometer preferably by a physiotherapist or a health care professional trained by a physiotherapist, and strength measured by, for example, a handheld dynamometer. PMID- 30516559 TI - Influence of Recipient Site on the Function and Survival of Fat Grafts. AB - BACKGROUND: Autologous fat grafting has become an increasingly common procedure for soft tissue augmentation throughout the body. However, the long-term outcome is always unpredictable because of inconsistent graft survival. Based on the "law of use and disuse," we speculate that the volume loss of fat grafts will occur when transferred into a site where there is less fat. The purpose of this study is to investigate the cause of high resorption rate from the perspective of fat function after transplantation. METHODS: Adipose aspirates obtained from routine liposuction were injected into the dorsal site of athymic mice, which have no subcutaneous fat layer. The fat grafts were explanted at days 7, 15, and 30 after transplantation. Changes in fat function were evaluated by measuring the adipocyte size and the expression level of adipose differentiation-related protein. RESULTS: After grafting, adipose tissue was replaced by fibrosis, inflammation, and vacuolar tissues gradually over time. The size of fat cells decreased sharply from day 0 to day 7, increased at day 15, and further declined at day 30. Adipose differentiation-related protein expression experienced a dramatic increase at day 7 and then continuously decreased until day 30. CONCLUSIONS: Assuming that the extrinsic factors influencing fat function and distribution remain stable, capabilities of the redistributed fat to handle free fatty acid and store lipid substance are reduced, leading to substantial tissue atrophy and volume decline after grafting. PMID- 30516560 TI - Functional and Aesthetic Outcome of Extensive Orbital Floor and Medial Wall Fracture via Navigation and Endoscope-assisted Reconstruction. AB - BACKGROUND AND PURPOSE: Extensive orbital floor and medial wall fractures compared with isolated orbital wall fractures are more likely to require surgical correction because of a higher possibility of complications like diplopia, enophthalmos, or numbness. The unique and complex contours of the orbital anatomy limit the intraoperative view of the intraorbital anatomy, and complex orbital fractures involving the buttress of the transition zone area all make orbital reconstruction surgery more challenging. The aim of this study was to describe our experience with surgical approaches using navigation- and endoscope-assisted guidance for extensive orbital floor and medial wall fracture reconstruction. PATIENTS AND METHODS: A retrospective study was conducted on consecutive 17 patients from 2015 to 2017 presenting with unilateral extensive orbital floor and medial wall fractures at the Chang Gung Memorial Hospital, Linkou Branch. The fractures were treated surgically with a preformed mesh plate and layered Medpor (Porex Surgical Inc, Atlanta, Ga) through navigation and endoscopy. The preoperative and postoperative functional and aesthetic outcomes were described. RESULTS: All extensive orbital floor and medial wall fractures were successfully reconstructed. Of the 17 patients, 11 experienced diplopia preoperatively, and for 2 of the 11 patients, diplopia improved immediately after surgery. In the remaining 9 patients, diplopia still persisted after surgery; however, diplopia recovered after an average of 3.44 months (range, 1-9 months). Average enophthalmos among the 10 patients, evaluated by postoperative follow-up computed tomography scan, improved from 2.99 to 0.68 mm. There were no major complications during follow-up, and all patients were satisfied with their final appearance and function. CONCLUSIONS: On the basis of the results, our surgical approach using preformed titanium mesh plates and Medpor under the assistance of navigation and endoscopy can be a safe, accurate, and effective method for the management of extensive orbital floor and medial wall fractures and clearly optimizes functional and aesthetic outcomes. PMID- 30516561 TI - Melanocyte Differentiation From Induced Pluripotent Stem Cells Derived From Human Adipose-Derived Stem Cells. AB - The pigment melanin is produced by melanocytes, is primarily responsible for skin color, and protects it against ultraviolet rays that can cause the destruction of genetic material within the keratinocytes. To elucidate the mechanisms of many diseases associated with melanocytes, such as melanoma and albinism, or burns with uneven pigment distribution, the disease model needs to be established first. In this study, we aimed to construct the melanocyte model from patients in a short period.Sandai virus vector containing 4 stemness genes (Oct4, Sox2, Klf4, c-Myc) was transfected into human adipose-derived stem cells to produce induced pluripotent stem cells (iPSCs). Immunofluorescence staining was used to confirm the expression of specific proteins for iPSCs, including Tra-1-60, Tra-1-81, Oct 4, Sox-2, and Nango. polymerase chain reaction results also showed that specific genes of iPSCs with the ability to cause the differentiation of cells into the 3 germ layers were expressed. In our in vivo experiments, iPSCs were subcutaneously injected into nude mice to induce teratoma formation for 2 months. The morphology of the 3 germ layers was confirmed by hematoxylin and eosin staining. Furthermore, melanocytes were purified by serial induction medium, and their presence was confirmed by flow cytometry and the expression of different markers for melanocytes. PMID- 30516562 TI - Maxillofacial Fractures Associated With Laryngeal Injury: A Craniofacial Surgeon Should be Alert. AB - OBJECTIVE: Maxillofacial fractures with concomitant laryngeal injuries put both the quality and maintenance of life in jeopardy. Because of its low incidence, it is often overlooked in the clinical setting. The purpose of this study is to review the incidence, clinical presentations, managements, and outcomes of these patients. METHODS: A retrospective analysis of medical records from 2008 to 2015 was conducted at a single institute. A case series (n = 12, which contributed 22.2% of laryngeal injuries in our institute) of these patients was presented, and propensity score matching was applied for further statistical analysis. RESULTS: When comparing patients who sustained maxillofacial fractures with concomitant laryngeal injuries with patients with only maxillofacial fractures and no laryngeal injuries, subcutaneous emphysema (83.3% vs 4.2%, P < 0.001), neck pain (75.0% vs 6.3%, P < 0.001), dyspnea (75.0% vs 0%, P < 0.001), hoarseness (41.7% vs 0%, P < 0.001), neck swelling (66.7% vs 4.2%, P = 0.012), stridor (16.7% vs 0%, P = 0.037), hemoptysis (16.7% vs 0%, P = 0.037), and thoracic trauma (58.3% vs 10.4%, P = 0.001) all showed significant differences. The length of intensive care unit stay (7.42 days vs 3.21 days, P = 0.008), ventilator use (66.7% vs 18.8%, P = 0.002), and tracheostomy (58.3% vs 0%, P < 0.001) were also significantly different. CONCLUSIONS: A significant portion of laryngeal injuries is concurrent with maxillofacial fractures. As a craniofacial surgeon, we should be alert to the signs of laryngeal injury. Diagnosis of laryngeal injuries should be established before definitive surgery for maxillofacial fractures. PMID- 30516563 TI - Using a Sternocleidomastoid Muscle Flap to Close an Iatrogenic Tracheoesophageal Fistula in a Patient With Advanced Laryngeal Cancer: A Case Report and Literature Review. AB - BACKGROUND: An iatrogenic tracheoesophageal (TE) fistula is one possible complication after total laryngectomy with flap reconstruction. We used sternocleidomastoid (SCM) rotation flap to close a TE fistula. METHODS AND RESULTS: A 69-year-old man with laryngeal cancer underwent total laryngectomy with radial forearm free flap reconstruction. A tracheostoma stenosis was noticed 7 months after the tracheostomy tube was removed. The patient underwent tracheostoma dilatation; the iatrogenic TE fistula was noticed 1 month later. We used SCM rotation flap to close the TE fistula. The postoperative course was uneventful. A barium esophagogram showed no leakage in the esophagus. CONCLUSIONS: Tracheoesophageal fistula can be reconstructed with an SCM rotation flap. If the TE fistula is of a suitable size, this reconstructive strategy is effective and simple to close persistent TE fistula and avoid further airway complications. PMID- 30516564 TI - Perception of Lip Cant as a Sign of Facial Deformity: Assessment by Laypersons and Professionals on Composite Face Photographs. AB - OBJECTIVE: Lip cant is a feature of facial deformity and commonly seen in patients with facial asymmetry. Because of its importance in aesthetic assessment, it is necessary to define the perceptions of lip cant and investigate differences in perception between laypersons and professionals. These data were insufficient in the literature. METHODS: Photographs of 30 male and 30 female individuals with normal faces were collected, and the lip line angles were measured. A composite facial photograph was generated from superimpositions of the normal faces. Lip line angles from 0 degrees to 9 degrees were made, with other facial features remaining unchanged. The test photographs were arranged in random fashion and evaluated by 64 laypersons and 30 professionals. Comparisons and cumulative frequency were performed. RESULTS: The lip line angle from the 60 normal persons was 1.20 degrees +/- 0.94 degrees . From the composite test photographs, the average first perception of lip cant was 3.25 degrees 1+/- 1.36 degrees in the laypersons and 1.70 degrees +/- 0.69 degrees in the professionals. The average first perception of unacceptable lip cant was 6.40 degrees +/- 1.79 degrees in the laypersons and 4.40 degrees 1. +/- 1.65 degrees in the professionals. Significant differences were found between the first perception and perception as unacceptable lip cant, as well as between the laypersons and the professionals. Cumulative data showed that 82.8% of the laypersons perceived lip cant at 4 degrees , and 17.2% of them felt it aesthetically unacceptable. Few laypersons (1.6%) considered less than 4 degrees unacceptable. CONCLUSIONS: The data in this study provide helpful information in the evaluation of lip cant. A lip cant of 4 degrees or more could be considered an indication for clinical management. PMID- 30516565 TI - Prognosis of Traumatic Ulnar Nerve Injuries: A Systematic Review. AB - Ulnar nerve injury (UNI) is not uncommon and often results in incomplete motor recovery after the initial nerve repair and requires secondary functional reconstruction. To clarify the prognosis and predicting factor of UNI, and if it is reasonable to wait after the initial repair, a systematic literature review from PubMed computerized literature database and Google scholar was performed. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist and guidelines were followed to develop the search protocol for this literature review. Two reviewers independently assessed titles, abstracts, and full-text articles, and a third reviewer resolved any disagreements. Seventeen articles with 260 cases were found with sufficient data and enough follow-up. After multiple logistic regression, age, injury level, gap of lesion, and delayed time to surgery were significant prognostic factors in UNI. If considering only high-level injuries (injury at or above proximal forearm), age became the only predicting factor. In cases with likely poor prognosis, their motor recovery tends to be unsatisfactory, and observation for months after the initial repair might not be reasonable. Other surgical interventions such as early nerve transfer may be an option to improve the outcome. PMID- 30516566 TI - Systemic Changes Affecting the Morphology of Calvarial Bone. AB - Plastic surgeons are frequently consulted to evaluate concerns about a patient's skull. Imaging studies often reveal abnormalities in bone morphology, from increased porosity to sclerotic changes. While focal findings imply a benign or malignant neoplasm, the etiology of more diffuse findings can be more varied, making the correct diagnosis challenging. The present review summarizes the differential diagnosis of osseous lesions of the calvarium that affect the bone and contribute to changes seen on imaging studies. PMID- 30516567 TI - Heterogeneity and Variability in Pressure Autoregulation of Organ Blood Flow: Lessons Learned Over 100+ Years. AB - OBJECTIVES: Pressure autoregulation is an organ's intrinsic ability to maintain blood flow despite changes in perfusion pressure. The purpose of this review is to discuss autoregulation's heterogeneity among different organs and variability under different conditions, a very clinically relevant topic. DATA SOURCES: Systematic search of Ovid MEDLINE; nonsystematic search of PubMed, Google Scholar, and reference lists. STUDY SELECTION: Animal or human studies investigating the potency or variation of pressure autoregulation of any organs or the association between autoregulation and outcomes. DATA EXTRACTION: Two authors screened the identified studies independently then collectively agreed upon articles to be used as the basis for this review. DATA SYNTHESIS: Study details, including subjects, organ investigated, methods of blood pressure intervention and blood flow measurement, and values of the lower limit, upper limit, and plateau were examined. Comparative canine studies were used to demonstrate the heterogeneity of pressure autoregulation among different organs and validate the proposed scale for organ categorization by autoregulatory capacity. Autoregulatory variability is discussed per organ. The association between cerebral autoregulation and outcome is summarized. CONCLUSIONS: The organs with robust autoregulation are the brain, spinal cord, heart, and kidney. Skeletal muscle has moderate autoregulation. Nearly all splanchnic organs including the stomach, small intestine, colon, liver, and pancreas possess weak autoregulation. Autoregulation can be readily affected by a variety of clinically relevant factors. Organs with weak or weakened autoregulation are at a greater risk of suboptimal perfusion when blood pressure fluctuates. Cerebral autoregulation and outcomes are closely related. These lessons learned over 100+ years are instructive in clinical care. PMID- 30516568 TI - Concurrent Radiation and Immunotherapy: Survey of Practice Patterns in the United States. AB - OBJECTIVE: The objective of this study was to report on US radiation oncologists' (ROs) practice patterns and perceptions of concurrent radiation (RT) and immunotherapy (IT) (CRI). METHODS: A 22-question survey was emailed to radiation oncologists in February 2018. CRI was defined as RT completed within 1 week before initial IT infusion through 4 weeks after final IT infusion. RESULTS: Of the 323 respondents from 45 states, 88% had experience treating a patient with CRI, including 51% private and 48% academic physicians. The most common reason for not offering CRI was concerns of increased toxicity (50%). Although 84% to 94% of respondents did not change RT dose, more ROs decreased dose when treating central structures (chest/abdomen/pelvis) versus noncentral structures (brain/head and neck/extremities): 13% to 15% versus 4% to 8%, P<0.001. The majority (58% to 80%) of respondents would not delay RT from last IT infusion. Moderate and significant actual toxicities were rare (medical intervention 6%, hospitalization/death <1%). 97.5% of ROs did not routinely prescribed prophylactic steroids for CRI. More ROs believed CRI with SBRT/SRS versus palliative RT had better local control (35% vs. 25%, P<0.05) and higher rates of abscopal responses (41% vs. 25%, P<0.01). CONCLUSIONS: Despite concerns for toxicity, ROs with CRI experience reported minimal toxicities. Most ROs do not alter RT dose, use prophylactic steroids, or delay starting RT from last IT infusion. Uncertainty remains about improved local control outcomes and abscopal responses from CRI, with a perception that concurrent SBRT offers better outcomes than palliative RT. These survey results may help guide ROs until more definitive data are available. PMID- 30516569 TI - Identification of Adenosquamous Carcinoma as a Rare Aggressive HER2-negative Subgroup of Esophageal/Gastroesophageal Junction Adenocarcinoma. AB - BACKGROUND: Our purpose was to evaluate the prognostic impact of pathologically confirmed esophageal adenosquamous carcinoma (ASC) and its association with HER2 status and clinicopathologic characteristics. METHODS: Among 796 patients with esophageal or gastroesophageal junction adenocarcinoma who underwent curative resection, surgical pathology reports were reviewed, and suspected ASC was confirmed utilizing p63 and CK5/6 immunostaining. HER2 status was determined using immunohistochemistry and fluorescence in situ hybridization. Cox models were used to assess the impact of ASC on disease-specific survival and overall survival. RESULTS: Overall, 2.0% (16/796) of patients had esophageal ASC, mostly demonstrating a close intermingling of squamous and adenocarcinoma cells within the same tumor. The percentage of squamous versus adenocarcinoma cells in the primary was generally recapitulated in nodal metastases, and intrapatient internodal heterogeneity was uncommon. Patients with esophageal ASC were statistically significantly more likely to be female (vs. male), have normal (vs. excess) body mass index, and harbor HER2-negative (vs. positive) tumors, as compared with patients with adenocarcinoma only. No ASC tumor was HER2-positive as compared with 16% of adenocarcinoma only tumors (P=0.018). Compared with patients with adenocarcinoma only, those with ASC demonstrated profoundly worse disease-specific survival (5-year event-free rate, 34% vs. 6%; multivariate hazard ratio, 2.87 [95% confidence interval, 1.59-4.76]; P=0.0010) and overall survival (P=0.0027) that was independent of known prognostic factors and HER2 status. CONCLUSION: ASC identifies a rare aggressive HER2-negative subgroup of esophageal/gastroesophageal junction adenocarcinoma. PMID- 30516570 TI - The diagnostic performance of a simplified blood test (SteatoTest-2) for the prediction of liver steatosis. AB - BACKGROUND: Serum biomarkers of steatosis such as the SteatoTest are recommended for large-scale screening studies, because imaging is less accessible and more expensive. AIMS: The primary aim of this retrospective analysis of prospective studies was to construct a new SteatoTest-2 that was not inferior to the reference first-generation SteatoTest, but that did not include BMI or bilirubin, as these two components can increase test variability because of the assessment of weight and height and in case of Gilbert syndrome or hemolysis, respectively. PATIENTS AND METHODS: Five different subsets of 2997 patients with biopsies were evaluated for test construction and validation, and four to assess the prevalence of steatosis in target populations with increasing risks of steatosis. The performance of the SteatoTest-2 was compared with the reference test, using the noninferiority test (0.10 margin) and the Lin concordance coefficient. RESULTS: Areas under the receiver operating characteristic curve of the SteatoTest-2 were noninferior to the reference test (P<0.001). Areas under the receiver operating characteristic curve varied in the SteatoTest-2 and the reference test according to subsets and the prevalence of steatosis, with 0.772 [95% confidence interval (CI): 0.713-0.820] versus 0.786 (95% CI: 0.729-0.832) in the 2997 cases with biopsy and 0.822 (95% CI: 0.810-0.834) versus 0.868 (95% CI: 0.858-0.878) in the 5776 cases including healthy individuals without risk factors of steatosis as controls, respectively. The Lin coefficient was highly concordant (P<0.001), from 0.74 (95% CI: 0.74-0.74) in presumed NAFLD to 0.91 (95% CI: 0.89-0.93) in the construction subset. CONCLUSION: The SteatoTest-2 is simpler and noninferior to the first-generation SteatoTest for the diagnosis of steatosis, without the limitations of BMI and bilirubin.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30516571 TI - Robotic Thoracic Surgery Training for Residency Programs: A Position Paper for an Educational Curriculum. AB - OBJECTIVE: Robotic-assisted surgery is increasingly being used in thoracic surgery. Currently, the Integrated Thoracic Surgery Residency Program lacks a standardized curriculum or requirement for training residents in robotic-assisted thoracic surgery. In most circumstances, because of the lack of formal residency training in robotic surgery, hospitals are requiring additional training, mentorship, and formal proctoring of cases before granting credentials to perform robotic-assisted surgery. Therefore, there is necessity for residents in Integrated Thoracic Surgery Residency Program to have early exposure and formal training on the robotic platform. We propose a curriculum that can be incorporated into such programs that would satisfy both training needs and hospital credential requirements. METHODS: We surveyed all 26 Integrated Thoracic Surgery Residency Program Directors in the United States. We also performed a PubMed literature search using the key word "robotic surgery training curriculum." We reviewed various robotic surgery training curricula and evaluation tools used by urology, obstetrics gynecology, and general surgery training programs. We then designed a proposed curriculum geared toward thoracic Integrated Thoracic Surgery Residency Program adopted from our credentialing experience, literature review, and survey consensus. RESULTS: Of the 26 programs surveyed, we received 17 responses. Most Integrated Thoracic Surgery Residency Program directors believe that it is important to introduce robotic surgery training during residency. Our proposed curriculum is integrated during postgraduate years 2 to 6. In the preclinical stage postgraduate years 2 to 3, residents are required to complete introductory online modules, virtual reality simulator training, and in-house workshops. During clinical stage (postgraduate years 4-6), the resident will serve as a supervised bedside assistant and progress to a console surgeon. Each case will have defined steps that the resident must demonstrate competency. Evaluation will be based on standardized guidelines. CONCLUSIONS: Expansion and utilization of robotic assistance in thoracic surgery have increased. Our proposed curriculum aims to enable Integrated Thoracic Surgery Residency Program residents to achieve competency in robotic-assisted thoracic surgery and to facilitate the acquirement of hospital privileges when they enter practice. PMID- 30516572 TI - Management of Atrial Fibrillation in Patients Undergoing Coronary Artery Bypass Grafting: Review of the Literature. AB - Untreated atrial fibrillation is associated with an increased risk of all-cause mortality and morbidity. Despite the current guidelines recommending surgical ablation of atrial fibrillation at the time of coronary artery bypass surgery, most patients with concomitant atrial fibrillation and coronary artery disease do not receive surgical ablation for their atrial fibrillation. This review reports the efficacy of different surgical ablation techniques used for the treatment of atrial fibrillation during coronary artery bypass. PubMed was systematically searched for studies reporting outcomes of concomitant surgical ablation in coronary artery bypass patients between January 2002 and March 2018. Data were independently extracted and analyzed by two investigators. Twenty-four studies were included. Twelve studies exclusively reported outcomes of surgical ablation in patients undergoing coronary artery bypass, whereas the remaining 12 reported outcomes of concomitant cardiac surgery with subgroup analysis. Only four studies performed the concomitant Cox-Maze procedure. Freedom from atrial tachyarrhythmia was reported as high as 98% at 1 year and 76% at 5 years with Cox-Maze procedure, whereas lesser lesion sets had more variable outcomes, ranging from 35% to 93%. In most studies, the addition of surgical ablation was not associated with increased morbidity and mortality. Although the Cox-Maze procedure had the greatest short- and long-term success rates, most studies comprising the evidence documenting the safety and efficacy of adding surgical ablation were of low or moderate quality. There was a great deal of heterogeneity among study populations, follow-up times, methods, and definition of failure. To establish a consensus regarding a surgical ablation technique for atrial fibrillation in coronary artery bypass population, larger multicenter randomized controlled studies need to be designed. PMID- 30516573 TI - Clinical Psychopharmacology in Switzerland. PMID- 30516574 TI - Switching to Imipramine Versus Add-on Mirtazapine in Venlafaxine-Resistant Major Depression: A 10-Week Randomized Open Study. AB - PURPOSE/BACKGROUND: Newer-generation antidepressants used in monotherapy or in combination with other newer-generation antidepressants or other psychotropic drugs are usually preferred as first- or second-step treatment options in resistant depression. According to our clinical experience, tricyclic antidepressants still are one of our preferred first choices in treatment resistant moderate to severe unipolar major depressive episodes. METHODS: This 10 week open-design randomized study assessed the effectiveness of switching to imipramine (adjusted to plasma levels) compared with add-on mirtazapine (30 mg/d) for treatment of moderate to severe unipolar major depressive episodes after a 10 week unsuccessful venlafaxine regimen (225-300 mg/d). Efficacy analyses examined the change in depressive symptoms severity from baseline visit to endpoint and the comparative remission rate between treatment subgroups. FINDINGS/RESULTS: The randomized sample consisted of 112 venlafaxine-resistant moderate to severe unipolar major depressed patients. Both the percentage of remitters (71.43% vs 39.28%) and the mean reduction of the Hamilton Depression Rating Scale score (76.94% vs 50.72%) were significantly larger in the imipramine subgroup. IMPLICATIONS/CONCLUSIONS: Even though we should be cautious about generalizing these results to patients with a less severe unipolar major episodes, our study suggest that switching to imipramine is a very effective treatment option in unipolar major depressive episodes after an unsuccessful venlafaxine regimen. PMID- 30516575 TI - Effectiveness of Venlafaxine in Selective Serotonin Reuptake Inhibitor-Resistant Obsessive-Compulsive Disorder: Experience From a Specialty Clinic in India. AB - BACKGROUND: Despite its favorable pharmacological profile and efficacy in major depression and anxiety disorders, evidence for the use of venlafaxine in obsessive-compulsive disorder (OCD) is limited. We sought to examine the real world effectiveness of venlafaxine from a large database of an OCD clinic in India. METHODS: A total of 1704 consecutive patients who registered at the OCD clinic between June 2014 and December 2016 were evaluated with structured interviews and scales. Patients with symptomatic OCD (Yale-Brown Obsessive Compulsive Severity >=16) despite treatment with selective serotonin reuptake inhibitors and initiated on venlafaxine were included for analysis. The main outcome measures were response as defined by 35% or more reduction in the Yale Brown Obsessive-Compulsive Severity total score and "all-cause discontinuation." RESULTS: Of a total of 65 patients who were eligible for analysis, 29(45%) were responders at the end of 16 weeks and 27 (42%) continued to remain on venlafaxine. Repeated measures analysis of variance yielded significant reduction in the Yale-Brown Obsessive-Compulsive Severity total score (F(1.29, 82.4) = 56.54, P < 0.001, partial eta = 0.469). On regression analysis, only lower insight (P = 0.048) predicted poor response. CONCLUSIONS: The study suggests that venlafaxine may be useful in a proportion of patients with poor response to selective serotonin reuptake inhibitors and therefore requires to be studied in controlled trials. PMID- 30516576 TI - Statistics Commentary Series: Commentary No. 30: Propensity Scores. PMID- 30516577 TI - The Collaborative Improvement and Innovation Network project to drive quality improvement. AB - PURPOSE OF REVIEW: The purpose is to describe an approach for improvement using an organized collaborative improvement framework where participants learn, apply, and share improvement ideas supported through a 3-year Organ Procurement Transplant Network (OPTN) project called Collaborative Improvement and Innovation Network (COIIN). The COIIN project, proposed as an alternative approach to monitoring transplant performance, supported collaboration, and improvement in 58 transplant hospitals and partner organ procurement organizations. The aim was to increase transplantation with a focus on increasing the utilization of moderate to-high (50-100%) Kidney Donor Profile Index (KDPI) kidneys. RECENT FINDINGS: Preliminary findings show increases in transplant rate and utilization of moderate-to-high KDPI kidneys was achieved in many participating organizations. Preliminary COIIN project results suggest that an improvement approach that supports collaborative improvement can be effective in driving improvement. SUMMARY: The COIIN project involved the development of a change package of key interventions for three key areas: waitlist management, organ-offer acceptance, and care coordination. Additionally, a balanced scorecard approach using outcome, process, and relationship measures, was used and effective in driving improvement. The preliminary COIIN outcome and process results suggest that collaborative improvement does drive improvement and was well received in the transplant community. VIDEO ABSTRACT: In the video, two of the authors describe the content of the review and present the main topics discussed in the article (http://links.lww.com/MOT/A22). PMID- 30516578 TI - Why some organ allografts are tolerated better than others: new insights for an old question. AB - PURPOSE OF REVIEW: There is great variability in how different organ allografts respond to the same tolerance induction protocol. Well known examples of this phenomenon include the protolerogenic nature of kidney and liver allografts as opposed to the tolerance-resistance of heart and lung allografts. This suggests there are organ-specific factors which differentially drive the immune response following transplantation. RECENT FINDINGS: The specific cells or cell products that make one organ allograft more likely to be accepted off immunosuppression than another are largely unknown. However, new insights have been made in this area recently. SUMMARY: The current review will focus on the organ-intrinsic factors that contribute to the organ-specific differences observed in tolerance induction with a view to developing therapeutic strategies to better prevent organ rejection and promote tolerance induction of all organs. PMID- 30516580 TI - Editorial introductions. PMID- 30516579 TI - Quality initiatives in pediatric transplantation. AB - PURPOSE OF REVIEW: Pediatric transplantation faces unique challenges in implementing dynamic quality improvement measures because of proportionally smaller volumes compared to adults, logistics of being integrated successfully within larger or complex hospital systems, lack of adult-affiliated transplant centers, varying focus in prioritization of relevant outcome metrics, and potential lack of sufficient resources. RECENT FINDINGS: To address these challenges, multiinstitutional collaborations have developed which have proven increasingly effective in driving awareness and quality improvement measures to supplement regulatory efforts in the pediatric population. Relevant work from the Pediatric Heart Transplant Society and Studies in Pediatric Liver Transplantation will be highlighted. The introduction of learning networks such as the Improving Renal Outcomes Collaborative and the Starzl Network for Excellence in Pediatric Transplantation have further focused on continuous learning initiatives in renal and liver transplantation using collaboration and patient informed measures. SUMMARY: Optimal transplant performance improvement is fully integrated into health delivery at all points of the patient pathway. Progress in performance improvement will require ongoing integration of big data solutions, improved patient engagement and technology solutions. VIDEO ABSTRACT:. PMID- 30516581 TI - Ablation of persistent atrial fibrillation and beyond. AB - PURPOSE OF REVIEW: Percutaneous catheter ablation is an effective treatment for atrial fibrillation. However, catheter ablation for the treatment of persistent atrial fibrillation or long-standing persistent atrial fibrillation is associated with unsatisfying success rates. This review aims to summarize the recent literature on the progress of catheter ablation among patients with persistent atrial fibrillation RECENT FINDINGS: In this review, we outline the potential future therapeutic techniques of catheter ablation of persistent atrial fibrillation. We highlight the innovative techniques (rotor mapping, substrate mapping, delayed enhancement MRI, and high-resolution mapping catheter) of current approaches and optimal procedural endpoint for persistent atrial fibrillation. SUMMARY: In summary, the optimal catheter ablation strategy for persistent atrial fibrillation remains unknown. Current data highlight the need for a better understanding of the substrate and mechanisms of arrhythmia maintenance in this population. Current mapping technologies offer additional tools (improved automatic algorithm for annotation, multiple electrode mapping, high-resolution mapping, and application of different processing techniques) for identifying the putative mechanism underlying atrial fibrillation. Further prospective studies are needed for the optimal procedural endpoint and the recent innovative techniques and their clinical benefits in ablation strategies. PMID- 30516582 TI - Both the Filler Amount and Columellar Elasticity Are Important in Injection Rhinoplasty in the Columella. PMID- 30516583 TI - Miscarriage Treatment-Related Morbidities and Adverse Events in Hospitals, Ambulatory Surgery Centers, and Office-Based Settings. AB - OBJECTIVE: The aim of the study was to examine whether miscarriage treatment related morbidities and adverse events vary across facility types. METHODS: A retrospective cohort study compared miscarriage treatment-related morbidities and adverse events across hospitals, ambulatory surgery centers (ASCs), and office based settings. Data on women who had miscarriage treatment between 2011 and 2014 and were continuously enrolled in their insurance plan for at least 1 year before and at least 6 weeks after treatment were obtained from a large national private insurance claims database. The main outcome was miscarriage treatment-related morbidities and adverse events occurring within 6 weeks of miscarriage treatment. Secondary outcomes were major events and infections. RESULTS: A total of 97,374 miscarriage treatments met inclusion criteria. Most (75%) were provided in hospitals, 10% ASCs, and 15% office-based settings. A total of 9.3% had miscarriage treatment-related events, 1.0% major events, and 1.5% infections. In adjusted analyses, there were fewer events in ASCs (6.5%) than office-based settings (9.4%) and hospitals (9.6%), but no significant difference between office-based settings and hospitals. There were no significant differences in major events between ASCs (0.7%) and office-based settings (0.8%), but more in hospitals (1.1%) than ASCs and office-based settings. There were fewer infections in ASCs (0.9%) than office-based settings (1.2%) and more in hospitals (1.6%) than ASCs and office-based settings. In analyses stratified by miscarriage treatment type, the difference between ASCs and office-based settings was no longer significant for miscarriages treated with procedures. CONCLUSIONS: Although there seem to be slightly more events in hospitals than ASCs or office based settings, findings do not support limiting miscarriage treatment to particular settings.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30516584 TI - Missing a beat: assessment of circadian rhythm abnormalities in bipolar disorder in the genomic era. AB - Circadian rhythm abnormalities have been recognized as a central feature of bipolar disorder (BD) but a coherent biological explanation for them remains lacking. Using genetic mutation of 'clock genes', robust animal models of mania and depression have been developed that elucidate key aspects of circadian rhythms and the circadian clock-mood connection. However, translation of this knowledge into humans remains incomplete. In recent years, very large genome-wide association studies (GWAS) have been conducted and the genetic underpinnings of BD are beginning to emerge. However, these genetic studies in BD do not match well with the evidence from animal studies that implicate the circadian clock in mood regulation. Even larger GWAS have been conducted for circadian phenotypes including chronotype, rhythm amplitude, sleep duration, and insomnia. These studies have identified a diverse set of associated genes, including a minority with previously well-characterized functions in the circadian clock. Taken together, the data from recent GWAS of BD and circadian phenotypes indicate that the genetic organization of the circadian clock, both in health and in BD is complex. The findings from GWAS elucidate potentially novel circadian mechanism that may be partly distinct from those identified in animal models. Pleiotropy, epistasis and nongenetic factors may play important roles in regulating circadian rhythms, some of which may underlie circadian rhythm disturbances in BD. PMID- 30516585 TI - Noninvasive approach for de novo acute hypoxemic respiratory failure: noninvasive ventilation, high-flow nasal cannula, both or none? AB - PURPOSE OF REVIEW: To summarize the recent evidence regarding the use of noninvasive strategies for de novo acute hypoxemic respiratory failure (AHRF). RECENT FINDINGS: New guidelines for the use of noninvasive ventilation (NIV) in acute respiratory failure have been published. In parallel, high-flow nasal cannula (HFNC) is an emerging noninvasive strategy for AHRF patients. Although some have cautioned against the use of NIV in AHRF, new encouraging data about the use of a helmet interface for NIV in acute respiratory distress syndrome may overcome the limitations of facemask NIV. SUMMARY: In the last two decades, the use of NIV and HFNC in patients with AHRF has considerably expanded, changing the paradigm of management of AHRF. Choice of each technique should be based according to centre experience and patient tolerability. However, when using noninvasive strategies for AHRF, it is crucial to predefine specific criteria for intubation and monitor patients closely for early detection of clinical deterioration to avoid delayed intubation. PMID- 30516586 TI - Causes of acute respiratory failure in the immunocompromised host. AB - PURPOSE OF REVIEW: A wide spectrum of heterogeneous conditions can render a patient immunocompromised. Recent years have seen an increase in the number of immunocompromised patients given the earlier detection of conditions that require immunosuppressive therapies, changes in immunosuppressive regimens leading to increased survival or novel therapeutic advancements in oncologic care. Acute respiratory failure (ARF) is the leading cause of critical illness and mortality in this population. This review highlights the spectrum of causes of ARF in immunocompromised patients with a particular focus on acute toxicities of novel oncologic treatments. RECENT FINDINGS: Recent years have seen improved survival amongst critically ill immunocompromised patients with ARF. This is likely attributable to patient selection of immunosuppressive therapy, improved noninvasive microbiologic diagnostic techniques, improved antimicrobial prophylaxis, treatment, stewardship, and advancements in supportive care including intensive care. Infectious complications remain the leading cause of ARF in this population. However, one of the greatest challenges physicians continue to face is accurate identification of the cause of ARF, given the vast (and increasing) noninfectious causes of ARF across these patients. Emerging therapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR T-cell) have contributed to this problem. Finally, undetermined ARF is reported in approximately 13% of immunocompromised and is associated with a worse prognosis. SUMMARY: Infectious complications are still the leading cause of ARF in immunocompromised patients. However, noninfectious complications, derived from the underlying disease or treatment, should be always considered, including novel therapies, such as ICIs and CAR T cells. Further research should focus in improving the diagnostic rate in this subgroup. PMID- 30516587 TI - Airway pressure release ventilation in children. AB - PURPOSE OF REVIEW: In patients with acute respiratory distress syndrome (ARDS), the airway pressure release ventilation (APRV) has been purported to have several physiological benefits. This review synthesizes recent research evaluating APRV mode and provides perspectives on the utility of this mode in children with ARDS. RECENT FINDINGS: Two single-center clinical trials on APRV, one adult and one pediatric, have been published this year. These two trials have not only elicited editorials and letters that highlight some of their strengths and weaknesses but also rekindled debate on several aspects of APRV. Despite their contradicting results, both trials provide significant insights into APRV strategies that work and those that may not. This review places the newer evidence in the context of existing literature and provides a comprehensive analysis of APRV use in children. SUMMARY: There have been significant recent advancements in our understanding of the clinical utility of APRV in children with ARDS. The recent trial highlights the urgent need to evolve a consensus on definition of APRV and identify strategies that work. Pending further research, clinicians should avoid the use of a zero-PLOW Personalized-APRV strategy as a primary ventilation modality in children with moderate-severe ARDS. PMID- 30516588 TI - Recent advances in venovenous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: To summarize results of the most recent trials on venovenous extracorporeal membrane oxygenation (VV-ECMO) in severe acute respiratory distress syndrome (ARDS) and to elaborate on the unmet needs regarding VV-ECMO management in this setting. RECENT FINDINGS: Although it was terminated early for futility (i.e., failure to demonstrate a difference in 60-day mortality of 20%), the ECMO to Rescue Lung Injury in Severe ARDS trial of VV-ECMO for severe ARDS reported a nonsignificant, but clinically important, reduction in mortality (35 vs. 46%; relative risk 0.76; 95% confidence interval 0.55-1.04, P = 0.09). Refractory hypoxemia led to rescue ECMO in 28% of controls, who had more severe ARDS at inclusion, were extremely sick at the time of ECMO cannulation and for whom mortality was 57%. Beyond the rescue of patients dying of refractory hypoxemia, ECMO may now be used early in severe ARDS patients to reduce the intensity of mechanical ventilation and to minimize ventilator-induced lung injury. Future research in the field should focus on identification of patients who are more likely to benefit from this technique and the right timing for its initiation, optimization of daily management of patients under ECMO to further reduce complications, and selection of optimal ventilator management on ECMO. SUMMARY: VV-ECMO is a reasonable therapeutic option for patients with severe ARDS and major hypoxemia or excessive pressures. Future trials should be designed to optimize patients' management while on VV-ECMO support. PMID- 30516589 TI - Every breath you take...should be monitored. PMID- 30516590 TI - Congenital Internal Auditory Canal Stenosis With Facial Palsy. PMID- 30516591 TI - Superficial Siderosis of the Central Nervous System: Neurotological Findings Related to Magnetic Resonance Imaging. AB - OBJECTIVE: To compare the neurotological results of five patients suffering from progressive hearing loss and ataxia due to superficial siderosis (SS) with the magnetic resonance imaging (MRI) findings. STUDY DESIGN: Retrospective case review. SETTING: Primary and hospital care center. PARTICIPANTS: Five adult patients with neurotological symptoms of SS underwent MRI with acquisition of our temporal bone protocol including 3D-constructive interference in steady state (3D CISS) and susceptibility-weighted imaging (SWI). All patients underwent a complete neurotological examination, the results of which were compared with the imaging findings. MAIN OUTCOME MEASURES: Cochleovestibular deficits were present in all five patients as determined by uni- or bilateral bithermal caloric testing and/or video head impulse tests. Sacculocollic reflex was present with increased P1 and N1 latencies on both sides in all patients. MRI revealed an extensive hypointense SWI signal outlining the surface of the brain and the VIIIth cranial nerve in all five patients. Desynchronization of the brainstem auditory evoked potentials (BAEP) and partial or complete absence of the visual suppression of vestibulo-ocular reflex during the pendular rotatory test was particularly consistent with the lesions of the cochleovestibular nerves as well as the cerebellar atrophy seen on MRI. CONCLUSION: The MRI results with SWI were related to neurotological findings in patients suffering from sensorineural deafness with ataxia due to SS. Our findings support the integration of the SWI and 3D-CISS sequences into the MRI protocol for all patients referred for evaluation of the extent of SS. PMID- 30516592 TI - Methods of Conservative Antibiotic Treatment of Acute Uncomplicated Appendicitis: A Systematic Review. AB - BACKGROUND: Meta-analyses and a recent guideline acknowledge that conservative management of uncomplicated appendicitis with antibiotics can be successful for patients who wish to avoid surgery. However, guidance as to specific management does not exist. METHODS: PUBMED and EMBASE search of trials describing methods of conservative treatment was conducted according to PRISMA guidelines. RESULTS: Thirty-four studies involving 2944 antibiotic-treated participants were identified. The greatest experience with conservative treatment is in persons 5 50 years of age. In most trials, imaging was employed to confirm localized appendicitis without evidence of abscess, phlegmon, or tumor. Antibiotics regimens were generally consistent with intra-abdominal infection treatment guidelines and used for 7-10 days. Approaches ranged from 3-day hospitalization on parenteral agents to same-day hospital or ED discharge of stable patients with outpatient oral antibiotics. Minimal time allowed before response was evaluated varied from 8-72 hours. Although pain was a common criterion for non-response and appendectomy, analgesic regimens were poorly described. Trials differed in use of other response indicators, i.e., WBC, CRP, and re-imaging. Diet ranged from restriction for 48 hours to as tolerated. Initial response rates were generally >90% and most improved by 24-48 hours, with no related severe sepsis or deaths. In most studies, appendectomy was recommended for recurrence, however, in several, patients had antibiotic retreatment with success. CONCLUSION: While further investigation of conservative treatment is ongoing, patients considering this approach should be advised and managed according to study methods and related guidelines to promote informed shared decision-making and optimize their chance of similar outcomes as described in published trials. Future studies that address biases associated with enrollment and response evaluation, employ best practice pain control and antibiotic selection, and explore longer time thresholds for response, minimized diet restriction and hospital stays, and antibiotic re-treatment will further our understanding of the potential effectiveness of conservative management. STUDY TYPE: Systematic review LEVEL OF EVIDENCE: Level IIThis is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30516593 TI - Chemical chaperone 4-phenylbutyrate prevents hearing loss and cochlear hair cell death in Cdh23erl/erl mutant mice. AB - We previously developed Cdh23 mutant mice (erl mice) as a model of hearing loss for otoprotective drug evaluation and showed that the erl mutation leads to hearing loss related to endoplasmic reticulum (ER) stress-induced cochlear hair cell apoptosis. Small molecular chemical chaperones, 4-phenylbutyrate (4PBA), targeting ER stress exert a neuroprotective effect. To evaluate whether 4PBA exerts an otoprotective effect, we intraperitoneally injected erl mice with 4PBA daily from postnatal age day 7 up to 12 weeks. Our results showed that treatment with 4PBA significantly alleviated hearing loss and suppressed hair cell death in erl mice. In addition, ER stress-related proteins were downregulated by 4PBA treatment. Our study showed that 4PBA exerts an otoprotective effect, which provides the potential to repurpose the drug for otoprotection. PMID- 30516594 TI - Etiology of Childhood Otorrhea in Luanda, Angola, and a Review of Otitis Media in African Children. AB - BACKGROUND: In resource-poor settings, otorrhea causes a significant burden of disease in children. Etiologic studies and structured data on otorrhea and chronic otitis media among African children remain scarce. METHODS: Here, we reviewed 678 bacteriologically analyzed otorrhea samples from Luanda Children's Hospital from children <=15 years of age between 2008 and 2015. We then compared these to data from other studies among African children through a literature review of 20 papers published over two decades. RESULTS: Overall, 32 different bacteria were identified among 542 isolates from 654 children in Luanda. Gram negative bacteria constituted the majority of all isolates (85%), whereby Pseudomonas sp was the most common (n = 158, 29%), followed by Proteus sp (n = 134, 25%). Among Staphylococcus aureus (n = 106, 10%), 69% of tested isolates were MRSA, and among Enterobacteriaceae 14% were ESBL isolates. Resistance to quinolones was rare. Furthermore, in a review of the literature, we found a high occurrence of otorrhea and chronic suppurative otitis media (CSOM) in children as well as possible gaps in existing knowledge. CONCLUSIONS: In Angola, Gram negative rods emerged as common causative agents of otorrhea in children followed by S. aureus. The magnitude of chronic otorrhea in Africa represents a cause for public health concern. PMID- 30516595 TI - CONTRIBUTORS. PMID- 30516596 TI - A Critical Look Back and Ahead. PMID- 30516597 TI - Cerebral Edema and Elevated Intracranial Pressure. AB - PURPOSE OF REVIEW: This article reviews the management of cerebral edema, elevated intracranial pressure (ICP), and cerebral herniation syndromes in neurocritical care. RECENT FINDINGS: While corticosteroids may be effective in reducing vasogenic edema around brain tumors, they are contraindicated in traumatic cerebral edema. Mannitol and hypertonic saline use should be tailored to patient characteristics including intravascular volume status. In patients with traumatic brain injury who are comatose, elevated ICP should be managed with an algorithmic, multitiered treatment protocol to maintain an ICP of 22 mm Hg or less. Third-line ICP treatments include anesthetic agents, induced hypothermia, and decompressive craniectomy. Recent clinical trials have demonstrated that induced hypothermia and decompressive craniectomy are ineffective as early neuroprotective strategies and should be reserved for third-line management of refractory ICP elevation in severe traumatic brain injury. Monitoring for cerebral herniation should include bedside pupillometry in supratentorial space occupying lesions and recognition of upward herniation in patients with posterior fossa lesions. SUMMARY: Although elevated ICP, cerebral edema, and cerebral herniation are interrelated, treatments should be based on the distinct pathophysiologic process. Focal lesions resulting in brain compression are primarily managed with surgical decompression, whereas global or multifocal brain injury requires a treatment protocol that includes medical and surgical interventions. PMID- 30516598 TI - Intracerebral Hemorrhage. AB - PURPOSE OF REVIEW: This article describes the advances in the management of spontaneous intracerebral hemorrhage in adults. RECENT FINDINGS: Therapeutic intervention in intracerebral hemorrhage has continued to focus on arresting hemorrhage expansion, with large randomized controlled trials addressing the effectiveness of rapidly lowering blood pressure, hemostatic therapy with platelet transfusion, and other clotting complexes and clot volume reduction both of intraventricular and parenchymal hematomas using minimally invasive techniques. Smaller studies targeting perihematomal edema and inflammation may also show promise. SUMMARY: The management of spontaneous intracerebral hemorrhage, long relegated to the management and prevention of complications, is undergoing a recent evolution in large part owing to stereotactically guided clot evacuation techniques that have been shown to be safe and that may potentially improve outcomes. PMID- 30516599 TI - Subarachnoid Hemorrhage. AB - PURPOSE OF REVIEW: This article reviews the epidemiology, clinical presentation, diagnosis, and management of patients with aneurysmal subarachnoid hemorrhage (SAH). SAH is a type of hemorrhagic stroke and is a neurologic emergency with substantial morbidity and mortality. This article reviews the most common and potentially life-threatening neurologic and medical complications to promote their early recognition and prevent secondary brain injury. RECENT FINDINGS: Over the past 30 years, the incidence of SAH has remained stable; yet, likely because of improved care in specialized neurocritical care units, discharge mortality has considerably decreased. Two consensus guidelines by the American Heart Association/American Stroke Association and the Neurocritical Care Society have outlined best practices for the management of patients with SAH. The most important recommendations include admission of patients to high-volume centers (defined as more than 35 SAH admissions per year) under the management of a multidisciplinary, specialized team; expeditious identification and treatment of the bleeding source with evaluation by a multidisciplinary team consisting of cerebrovascular neurosurgeons, neuroendovascular specialists, and neurointensivists; management of patients in a neurocritical care unit with enteral nimodipine, blood pressure control, euvolemia, and close monitoring for neurologic and medical complications; and treatment of symptomatic cerebral vasospasm/delayed cerebral ischemia with induced hypertension and endovascular therapies. This article also highlights new insights of SAH pathophysiology and provides updates in the management approach. SUMMARY: SAH remains a neurologic emergency. Management of patients with SAH includes adherence to published guidelines, but some areas of SAH management remain understudied. Clinical trials are required to elucidate the role of these controversial management approaches in improving patient outcomes. PMID- 30516600 TI - Management of Stroke in the Neurocritical Care Unit. AB - PURPOSE OF REVIEW: This article provides updated information regarding the diagnosis and treatment (specifically critical care management) of acute ischemic stroke. This article also discusses the increased use of thrombolysis and thrombectomy in clinical practice. RECENT FINDINGS: Stroke is the leading cause of disability in the United States. A significant proportion of patients with acute ischemic stroke require critical care management. Much has changed in the early evaluation and treatment of patients presenting with acute ischemic stroke. The introduction of embolectomy in large vessel occlusions for up to 24 hours post-symptom onset has resulted in one in every three eligible patients with acute ischemic stroke with the potential to lead an independent lifestyle. These patients increasingly require recognition of complications and initiation of appropriate interventions as well as earlier admission to dedicated neurocritical care units to ensure better outcomes. SUMMARY: This article emphasizes issues related to the management of patients with acute ischemic stroke undergoing mechanical thrombectomy and thrombolysis and addresses the complex physiologic changes affecting neurologic and other organ systems. PMID- 30516601 TI - Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus. AB - PURPOSE OF REVIEW: Status epilepticus, refractory status epilepticus, and super refractory status epilepticus can be life-threatening conditions. This article presents an overview of the three conditions and discusses their management and outcomes. RECENT FINDINGS: Status epilepticus was previously defined as lasting for 30 minutes or longer but now is more often defined as lasting 5 minutes or longer. A variety of potential causes exist for status epilepticus, refractory status epilepticus, and super-refractory status epilepticus, but all three ultimately involve changes at the cellular and molecular level. Management of patients with status epilepticus generally requires several studies, with EEG of utmost importance given the pathophysiologic changes that can occur during the course of status epilepticus. Status epilepticus is treated with benzodiazepines as first-line antiepileptic drugs, followed by phenytoin, valproic acid, or levetiracetam. If status epilepticus does not resolve, these are followed by an IV anesthetic and then alternative therapies based on limited data/evidence, such as repetitive transcranial magnetic stimulation, therapeutic hypothermia, immunomodulatory agents, and the ketogenic diet. Scores have been developed to help predict the outcome of status epilepticus. Neurologic injury and outcome seem to worsen as the duration of status epilepticus increases, with outcomes generally worse in super-refractory status epilepticus compared to status epilepticus and sometimes also to refractory status epilepticus. SUMMARY: Status epilepticus can be a life-threatening condition associated with multiple complications, including death, and can progress to refractory status epilepticus and super-refractory status epilepticus. More studies are needed to delineate the best management of these three entities. PMID- 30516602 TI - Coma and Brain Death. AB - PURPOSE OF REVIEW: This article discusses the diagnostic and therapeutic approach to patients who are comatose and reviews the current knowledge on prognosis from various causes of coma. This article also provides an overview of the principles for determination of brain death as well as advice on how to avoid common pitfalls. RECENT FINDINGS: Technologic advances have refined our understanding of the physiology of consciousness and the spectrum of disorders of consciousness; they also promise to improve our prognostic accuracy. Yet the clinical principles for the evaluation and treatment of coma remain unaltered. The clinical standards for determination of death by neurologic criteria (ie, brain death) are also well established, although variabilities in local protocols and legal requirements remain a problem to be resolved. SUMMARY: Effective evaluation of coma demands a systematic approach relying on clinical information to ensure rational use of laboratory and imaging tests. When the cause of coma is deemed irreversible in the setting of a catastrophic brain injury and no clinical evidence exists for brain and brainstem function, patients should be evaluated for the possibility of brain death by following the clinical criteria specified in the American Academy of Neurology guidelines. PMID- 30516603 TI - Management of Comatose Survivors of Cardiac Arrest. AB - PURPOSE OF REVIEW: Because the whole-body ischemia-reperfusion insult associated with cardiac arrest often results in brain injury, neurologists perform an important role in postresuscitation cardiac arrest care. This article provides guidance for the assessment and management of brain injury following cardiac arrest. RECENT FINDINGS: Neurologists have many roles in postresuscitation cardiac arrest care: (1) early assessment of brain injury severity to help inform triage for invasive circulatory support or revascularization; (2) advocacy for the maintenance of a neuroprotective thermal, hemodynamic, biochemical, and metabolic milieu; (3) detection and management of seizures; (4) development of an accurate, multimodal, and conservative approach to prognostication; (5) application of shared decision-making paradigms around the likely outcomes of therapy and the goals of care; and (6) facilitation of the neurocognitive assessment of survivors. Therefore, optimal management requires early neurologist involvement in patient care, a detailed knowledge of postresuscitation syndrome and its complex interactions with prognosis, expertise in bringing difficult cases to their optimal conclusions, and a support system for survivors with cognitive deficits. SUMMARY: Neurologists have a critical role in postresuscitation cardiac arrest care and are key participants in the treatment team from the time of first restoration of a perfusing heart rhythm through the establishment of rehabilitation services for survivors. PMID- 30516604 TI - Critical Care of Neuromuscular Disorders. AB - PURPOSE OF REVIEW: Weakness is a common reason patients are seen in neurologic consultation. This article reviews the differential diagnosis of neuromuscular disorders in the intensive care unit (ICU), discusses the intensive care needs and evaluation of respiratory failure in patients with neuromuscular disorders, and provides a practical guide for management. RECENT FINDINGS: Although primary neuromuscular disorders used to be the most common cause for weakness from peripheral nervous system disease in the ICU, a shift toward ICU-acquired weakness is observed in today's clinical practice. Therefore, determining the cause of weakness is important and may have significant prognostic implications. Guillain-Barre syndrome and myasthenia gravis remain the most common primary neuromuscular disorders in the ICU. In patients with myasthenia gravis, it is important to be vigilant with the airway and institute noninvasive ventilation early in the course of the disease to attempt to avoid the need for intubation. On the other hand, patients with Guillain-Barre syndrome should be intubated without delay if the airway is at risk to avoid further complications. In patients with ICU-acquired weakness, failure to wean from the ventilator is usually the challenge. Early mobility, glucose control, minimizing sedation, and avoiding neuromuscular blocking agents remain the only therapeutic regimen available for ICU-acquired weakness. SUMMARY: Critical care management of neuromuscular disorders requires a multidisciplinary approach engaging members of the ICU and consultative teams. Developing an airway management protocol could have implications on outcome and length of stay for patients with neuromuscular disorders in the ICU. Tending to the appropriate nuances of each patient who is critically ill with a neuromuscular disorder through evidence-based medicine can also have implications on length of stay and outcome. PMID- 30516605 TI - Multimodality Monitoring in the Neurocritical Care Unit. AB - PURPOSE OF REVIEW: This article focuses on the multiple neuromonitoring devices that can be used to collect bedside data in the neurocritical care unit and the methodology to integrate them into a multimodality monitoring system. The article describes how to apply the collected data to appreciate the physiologic changes and develop therapeutic approaches to prevent secondary injury. RECENT FINDINGS: The neurologic examination has served as the primary monitor for secondary brain injury in patients admitted to the neurocritical care unit. However, the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care concluded that frequent bedside examinations are not sufficient to detect and prevent secondary brain injury and that integration of multimodality monitoring with advanced informatics tools will most likely enhance our assessments compared to the clinical examinations alone. This article reviews the invasive and noninvasive technologies used to monitor focal and global neurophysiologic cerebral alterations. SUMMARY: Multimodal monitoring is still in the early stages of development. Research is still needed to establish more advanced monitors with the bioinformatics to identify useful trends from data gathered to predict clinical outcome or prevent secondary brain injury. PMID- 30516606 TI - Ethical Considerations in End-of-life Care in the Face of Clinical Futility. AB - Management of patients with terminal brain disorders can be medically, socially, and ethically complex. Although a growing number of feasible treatment options may exist, there are times when further treatment can no longer meaningfully improve either quality or length of life. Clinicians and patients should discuss goals of care while patients are capable of making their own decisions. However, because such discussions can be challenging, they are often postponed. These discussions are then conducted with patients' health care proxies after patients lose the capacity to make their own decisions. Disagreements may arise when a patient's surrogate desires continued aggressive interventions that are either biologically futile (incapable of producing the intended physiologic result) or potentially inappropriate (potentially capable of producing the patient's intended effect but in conflict with the medical team's ethical principles). This article explores best practices in addressing these types of conflicts in the critical care unit, but these concepts also broadly apply to other sites of care. PMID- 30516607 TI - End-of-life Considerations and Shared Decision Making in Neurocritical Care. AB - The goal of shared decision making in the neurocritical care setting is to form plans of care that are consistent with best medical practice and are respectful of the patient's values. Close cooperation and meaningful interaction must be achieved with family members so that the patient's "person can emerge" through discussions. This article highlights several caveats that can subvert this complex process, including the cognitive biases that affect both clinicians and surrogates. Impact, optimism, and gain-framing biases may be particularly relevant when considering patients who are receiving neurocritical care. Practitioners need to be cognizant of the distorting influences of these biases and make attempts to neutralize them. Quality of survival and the nature and degree of deficits are often the dominant concerns after patients experience acute severe brain injuries. Care should be taken to avoid conflating medical facts and value judgments when discussing prognoses. PMID- 30516608 TI - Neurocritical Care Coding for Neurologists. AB - Coding specifies the work performed when providing patient care. Critical care services mostly use code 99291, and other codes specify additional time and procedures. Current Procedural Terminology defines critically ill as "a high probability of imminent or life-threatening deterioration in the patient's condition," a condition necessary for use of the critical care code. A patient may be critically ill for neurologic reasons even when stable from a cardiorespiratory status. Rules govern who can use these codes, whether they can be used by more than one physician, the locations where the code may be used, and what services are included and excluded. Physicians need to document the medical necessity of visits and nature of critical illness or high-risk medical decision making because auditors may not understand the nature of serious neurologic illness. PMID- 30516609 TI - Instructions for Completing CME and Tally Sheet. PMID- 30516610 TI - Postreading Self-Assessment and CME Test. PMID- 30516611 TI - Postreading Self-Assessment and CME Test-Preferred Responses. PMID- 30516612 TI - Appendix A. PMID- 30516613 TI - Appendix B. PMID- 30516614 TI - ERRATA. PMID- 30516615 TI - Learning Objectives and Core Competencies. PMID- 30516616 TI - Performance Characteristics of Endometrial Sampling in Diagnosis of Endometrial Carcinoma. AB - Outpatient endometrial biopsy can give false-negative results, with a 0.9% reported posttest probability for endometrial carcinoma (EC) after a negative result. Our objective was to determine if there has been any improvement in the performance characteristics of endometrial biopsy over the last 15 yr. All hysterectomy specimens with a diagnosis of EC or atypical hyperplasia (AH), reported between May 2011 and May 2015, were identified and cross-referenced for any negative endometrial sampling results during the 5 yr before hysterectomy. Negative endometrial samples were defined as either benign findings or insufficient/nondiagnostic, excluding those diagnosed as AH or EC and those for which follow-up sampling was recommended because of atypia. Of 1677 hysterectomy specimens showing AH or EC there were previous negative biopsies in 172: 116 benign and 56 insufficient/nondiagnostic. Over the same period 22,875 negative endometrial biopsy specimens were reported in our region. The posttest probability of having EC or AH in the hysterectomy specimen, given a negative endometrial biopsy result, was 0.74%. In a subset of 90 cases in which a negative biopsy was followed by a diagnosis of AH or EC in a hysterectomy specimen, the slides were independently reviewed. There were no cases where a diagnosis of carcinoma was missed. In 12 samples atypia or possible atypia was identified, and the level of agreement with the original diagnosis was excellent kappa=0.83+/ 0.05. In a prospective comparison of examination of 3 levels from each block versus a single slide in 319 cases, the routine preparation of additional slides did not yield clinically significant information. Although there has been evolution in the diagnostic criteria for AH and for recognition of morphologically subtle forms of AH or EC, our results demonstrate a significant lack of sensitivity of outpatient endometrial sampling in the diagnosis of endometrial malignancy/premalignancy. The sensitivity problems are mainly attributable to failure to sample abnormal endometrium. Independent review of slides or examination of additional levels did little to increase the diagnostic yield. PMID- 30516617 TI - Wilms Tumor of the Ovary: Review of the Literature and Report of 2 Cases. AB - Primary extrarenal Wilms tumor of the gynecologic tract is extremely rare with scattered case reports occurring in the ovary, uterine corpus and cervix. Only 9 cases of primary ovarian Wilms tumor have been reported to date. Here, we provide an extensive literature review and describe 2 patients with ovarian Wilms tumor: a 36-yr-old female (patient 1) and a 16-yr-old female (patient 2), both presenting with abdominal pain and suspected ovarian torsion. They were each found to have unilateral ovarian masses measuring >15 cm in size which were removed by unilateral salpingo-oophorectomy. Microscopically, the tumors exhibited the typical triphasic histology of Wilms tumor. In addition, the tumor from patient 1 contained elements of mature cystic teratoma, while an extensive rhabdomyosarcomatous component was identified in patient 2. Both tumors were diffusely and strongly positive for WT1 with variable staining for other biomarkers. The cases were diagnostically challenging and referred to our center for an expert opinion. Teratoid Wilms tumor in patient 1 is the second reported case of ovarian Wilms tumor arising in association with teratoma. Recognition of primary ovarian Wilms tumor requires a high index of suspicion and exclusion of other entities based on tumor morphology and immunohistochemical studies. PMID- 30516618 TI - Primary Angiosarcoma of the Cervix: Case Report of a Rare Lesion. AB - Angiosarcomas of the female genital tract are rare and primary angiosarcoma of the cervix is extremely rare with only one prior case report. We report a case of a primary cervical angiosarcoma in a 43-yr-old woman who presented with heavy vaginal bleeding. Cervical biopsy and subsequent radical hysterectomy showed a malignant vascular tumor which was composed of spindled and epithelioid cells and formed abortive vascular channels. Immunohistochemically, the tumor cells were diffusely positive for CD31, CD34, ERG, and cyclin D1 and focally positive for D2 40. A reverse transcription polymerase chain reaction test for YWHAE-NUTM2 genetic fusion was negative excluding a YWHAE-translocated high-grade endometrial stromal sarcoma. The tumor formed a 5 cm mass within the cervix with microscopic involvement of the endometrium, superficial myometrium, and vagina. Metastatic microscopic tumor deposits were present in both ovaries, left fallopian tube, one paracervical lymph node, and one pelvic lymph node. In reporting this unusual case we discuss the differential diagnosis. PMID- 30516619 TI - Malignant Lymphoma of the Ovary: A Diagnostic Pitfall of Intraoperative Consultation. AB - Primary ovarian lymphomas are rare, but can potentially evoke diagnostic problems. We present a case of ovarian lymphoma, in which an ambiguous intraoperative pathologic report led to overtreatment (unnecessary surgery). A 73 yr-old woman with fatigue and low-grade fever was diagnosed as having a left ovarian tumor by imaging modalities. Exploratory laparotomy was carried out to confirm the diagnosis. The frozen tissue sections of the ovarian tumor showed condensed proliferation of atypical round cells accompanied with a few small lymphocytes. The pathologists could not determine whether this tumor was a lymphoma or another malignancy (eg, dysgerminoma). Hence, they reported it to gynecologists who operated as simply a malignant tumor in order to evade misdiagnosis. On the basis of the inconclusive pathologic report, the gynecologists decided to change the planned laparotomy to total hysterectomy with bilateral salpingo-oophorectomy and pelvic lymph node dissection. A postoperative paraffin section-based pathologic diagnosis was diffuse large B-cell lymphoma of the ovary, which basically does not require surgical treatments. Subsequently, chemotherapy for B-cell lymphoma was initiated, and no lymphoma recurrence has been reported to date. A more robust preoperative discussion between the gynecologists and the pathologists might have avoided the overtreatment. PMID- 30516620 TI - Muir-Torre Syndrome With a Frame-shift Mutation in the MSH2 Gene: A Rare Case Report and Literature Review. AB - Muir-Torre syndrome is a rare subtype of Lynch syndrome characterized by coincidence of skin neoplasm and visceral malignancies. Here, we report a case of this rare disease, whose diagnosis of the syndrome was first suspected by the pathologist. This was a 60-yr-old woman who presented with an axillary skin nodule, which was diagnosed as basal cell carcinoma. Further inquiry revealed that she was hospitalized for evaluation of a recurrent vaginal stump endometrial carcinoma. Histologic workup and immunohistochemistry for mismatch repair proteins of both the skin and vaginal tumor suggested the possibility of Muir Torre syndrome. NexGen sequencing identified a frame-shift mutation in the MSH2 gene. The patient was found to have a metachronous colorectal carcinoma, uterine endometrial carcinoma, and skin cancer from 1998 to 2016. Five family members had also suffered from colorectal cancer or glioma. This case report illustrates the importance of the multidisciplinary care approach, mismatch repair protein and gene testing, and detailed medical history taking into consideration the diagnosis of Muir-Torre syndrome. PMID- 30516622 TI - Leaving a Legacy While Achieving Maximum Impact: JBJS EST Now in PubMed Central. PMID- 30516621 TI - Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer. AB - To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16 negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66 mo [95% confidence interval (CI), 31-96], 34 mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31 mo, P=0.02 and 35 vs 16 mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts. PMID- 30516623 TI - Outcomes of the Ponseti Method for Untreated Clubfeet in Nepalese Patients Seen Between the Ages of One and Five Years and Followed for at Least 10 Years. AB - BACKGROUND: To our knowledge, there are no reports of the Ponseti method initiated after walking age and with >10 years of follow-up. Our goal was to report the clinical findings and patient-reported outcomes for children with a previously untreated idiopathic clubfoot who were seen when they were between 1 and 5 years old, were treated with the Ponseti method, and had a minimum follow up of 10 years. METHODS: A retrospective review of medical records was supplemented by a follow-up evaluation of physical findings (alignment and range of motion) and patient-reported outcomes using the Oxford Ankle Foot Questionnaire for Children (OxAFQ-C). The initial treatment was graded as successful if a plantigrade foot was achieved without the need for an extensive soft-tissue release and/or osseous procedure. RESULTS: We located 145 (91%) of 159 patients (220 clubfeet). The average age at treatment was 3 years (range, 1 to 5 years), and the average duration of follow-up was 11 years (range, 10 to 12 years). The initial scores according to the systems of Pirani et al. and Dimeglio et al. averaged 5 and 17, respectively, and an average of 8 casts were required. Surgical treatment, most commonly a percutaneous Achilles tendon release (197 feet; 90%), was required in 96% of the feet. A plantigrade foot was achieved in 95% of the feet. Complete relapse was rare (3%), although residual deformities were common. Patient-reported outcomes were favorable. CONCLUSIONS: A plantigrade foot was achieved in 95% of the feet initially and was maintained in most of the patients, although residual deformities were common. Patient-reported outcomes were satisfactory, and longer-term follow-up with age-appropriate outcome measures will be required to evaluate function in adulthood. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516624 TI - Functional Outcomes Following Treatment for Clubfoot: Ten-Year Follow-up. AB - BACKGROUND: The purpose of this study was to assess function, at the age of 10 years, of children initially treated nonoperatively for clubfoot with either the Ponseti or French physiotherapy program and to compare outcomes in feet that had undergone only nonoperative treatment with those that required subsequent surgery. METHODS: Gait analysis, isokinetic ankle strength, parent-reported outcomes, and daily step activity data were collected when patients who had been treated for idiopathic clubfoot reached the age of 10 years. Patients who had undergone only nonoperative treatment were compared with those who subsequently underwent extra-articular surgery or intra-articular surgery (posterior release or posteromedial release). The clubfoot groups were compared with age-matched controls. RESULTS: Of 263 treated clubfeet in 175 patients, 148 had only been treated nonoperatively, 29 underwent extra-articular surgery, and 86 underwent intra-articular surgery (posterior release in 42 and posteromedial release in 44). Significant abnormalities were found in ankle kinetics and isokinetic ankle strength in the feet treated with intra-articular surgery compared with the nonoperatively treated feet (p < 0.017). Compared with controls (n = 40 feet), all groups showed reduced ankle plantar flexion during gait, resulting in a deficit of 9% to 14% for dynamic range of motion, 13% to 20% for ankle moment, and 13% to 23% for power (p < 0.013). Within the intra-articular group, feet that underwent posteromedial release had decreased plantar flexion strength (15%; p = 0.008), dorsiflexion strength (6%; p = 0.048), and parent-reported global function scores (p = 0.032) compared with the posterior release group. The patients with clubfoot took 10% fewer steps (p = 0.015) and had 11% less total ambulatory time (p = 0.001) than the controls. CONCLUSIONS: Examination of patients when they had reached the age of 10 years showed better ankle power and isokinetic strength for clubfeet treated without surgery compared with those that underwent intra-articular surgery for residual deformity or recurrence. Compared with controls, both nonoperatively and surgically treated clubfeet had significant limitations in ankle plantar flexion resulting in decreased range of motion, moment, and power. Gastrocnemius-soleus complex strength was decreased after both nonoperative and surgical treatment of clubfeet. Although activity was diminished in the clubfoot population, no differences in function were perceived by the patients' parents. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516625 TI - Tranexamic Acid Is Efficacious at Decreasing the Rate of Blood Loss in Adolescent Scoliosis Surgery: A Randomized Placebo-Controlled Trial. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss. Evidence supporting its efficacy in surgery for adolescent idiopathic scoliosis is not robust. This trial was designed to validate the clinical efficacy of TXA in surgery for adolescent idiopathic scoliosis. METHODS: This institutional review board-approved prospective double-blinded trial involved 111 patients with adolescent idiopathic scoliosis who were randomized to receive either a placebo or TXA (50-mg/kg loading dose and 10-mg/kg/h infusion). Power analysis indicated that 50 patients per group would provide power to detect a >20% difference in blood loss. Two-way analysis of variance (ANOVA) was applied to compare blood loss rates (slopes) using the group-by-time interaction F test. RESULTS: The risk of clinically relevant blood loss (>20 mL/kg) was more than twice as high in the placebo group than in the TXA group (44% versus 21%, relative risk = 2.1, 95% confidence interval = 1.2 to 3.7). Compared with the placebo group, the TXA group had a 27% reduction in intraoperative blood loss, a significantly lower rate of intraoperative bleeding per hour (mean and standard deviation, 190 +/- 73 versus 230 +/- 80 mL, p = 0.01; F = 9.77, p < 0.001) and per fused spinal level (82 +/- 32 versus 110 +/- 40 mL, p < 0.001), less intraoperative blood loss (836 +/- 373 versus 1,031 +/- 484 mL, p = 0.02), and less postoperative bleeding (in the drain) (498 +/- 228 versus 645 +/- 318 mL, p = 0.009). Six patients who received a placebo and no patient who received TXA required an allogenic blood transfusion. No perioperative adverse events, including thromboembolic events or seizures, were observed. Three independent factors were predictive of blood loss: TXA administration, duration of surgery, and number of levels fused. Greater intraoperative blood loss was the only independent variable predictive of a longer hospital stay. CONCLUSIONS: Use of TXA in patients undergoing surgery for adolescent idiopathic scoliosis significantly reduced blood loss, by 27%, compared with that in the placebo group. The rate of intraoperative blood loss per hour and per level fused and the amount of postoperative blood loss were significantly lower in the TXA group. More placebo-treated patients received allogenic blood. Patients with greater intraoperative blood loss spent a longer time in the hospital. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516626 TI - The Effect of Prosthetic Design and Polyethylene Type on the Risk of Revision for Infection in Total Knee Replacement: An Analysis of 336,997 Prostheses from the Australian Orthopaedic Association National Joint Replacement Registry. AB - BACKGROUND: Periprosthetic infection following total knee replacement remains alarmingly frequent, is devastating for patients, and is an increasingly substantial public health burden. While both the prosthetic design elements and type of polyethylene used in total knee replacement can independently affect survivorship of the prosthesis, their influence on the risk of revision for infection is unknown. Therefore, we examined the effects of total knee prosthetic design and type of polyethylene bearing on the long-term revision risk for nonacute infection following total knee replacement by comparing 4 different cohorts: patients who had minimally stabilized total knee prostheses with crosslinked polyethylene (XLPE) bearing surfaces, minimally stabilized total knee prostheses with noncrosslinked polyethylene (NXLPE), posterior stabilized total knee prostheses with XLPE, and posterior stabilized total knee prostheses with NXLPE. METHODS: National registry data on revision procedures for surgeon reported infection following primary total knee replacement for osteoarthritis from September 1999 through December 2015 were obtained for 4 patient cohorts. The cohorts were defined by the total knee prosthetic design and polyethylene type used. Revisions at <=6 months were censored to reduce confounding bias. Hazard ratios (HRs) were adjusted for age, sex, and antibiotic cement usage. RESULTS: A total of 336,997 primary total knee prostheses were included, 1,651 (0.49%) of which underwent revision for periprosthetic infection. Compared with minimally stabilized total knee prostheses that had XLPE bearing surfaces, the revision risk for infection, adjusted for age, sex, and antibiotic cement usage, was 25% higher for minimally stabilized total knee prostheses with NXLPE bearing surfaces (HR = 1.25 [95% confidence interval (CI), 1.07 to 1.45]; p = 0.003), 89% higher for posterior stabilized total knee prostheses with XLPE (HR = 1.89 [95% CI, 1.52 to 2.35]; p < 0.001), and 102% higher for posterior stabilized total knee prostheses with NXLPE (HR = 2.02 [95% CI, 1.72 to 2.37]; p < 0.001). Posterior stabilized total knee prostheses with NXLPE had a 61% higher risk of infection compared with minimally stabilized total knee prostheses with NXLPE (HR = 1.61 [95% CI, 1.43 to 1.83]; p < 0.001). The revision risk for infection for posterior stabilized total knee prostheses with NXLPE was the same as that for posterior stabilized total knee prostheses with XLPE (HR = 1.08 [95% CI, 0.88 to 1.32]; p = 0.481). CONCLUSIONS: Minimally stabilized total knee prostheses with NXLPE bearing surfaces and posterior stabilized total knee prostheses, irrespective of bearing type, had a greater long-term revision risk for periprosthetic infection when compared with the revision risk for minimally stabilized total knee prostheses with XLPE bearing surfaces. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of Levels of Evidence. PMID- 30516627 TI - Medicaid Payer Status Is Associated with Increased 90-Day Morbidity and Resource Utilization Following Primary Total Hip Arthroplasty: A Propensity-Score-Matched Analysis. AB - BACKGROUND: Medicaid payer status has been shown to affect risk-adjusted outcomes and resource utilization across multiple medical specialties. The purpose of this study was to examine resource utilization via readmission rates, length of stay, and total cost specific to Medicaid payer status following primary total hip arthroplasty. METHODS: The Nationwide Readmissions Database (NRD) was utilized to identify patients who underwent total hip arthroplasty in 2013 as well as corresponding "Medicaid" or "non-Medicaid" payer status. Demographic data, 14 individual comorbidities, readmission rates, length of stay, and direct cost were evaluated. A propensity-score-based matching model was utilized to control for baseline confounding variables between payer groups. Following propensity-score matching, the chi-square test was used to compare readmission rates between the 2 payer groups. The relative risk (RR) with 95% confidence interval (CI) was estimated to quantify readmission risk. Length of stay and total cost comparisons were evaluated using the Wilcoxon signed-rank test. RESULTS: A total of 5,311 Medicaid and 144,814 non-Medicaid patients managed with total hip arthroplasty were identified from the 2013 NRD. A propensity score was estimated for each patient on the basis of the available baseline demographics, and 5,311 non Medicaid patients were matched by propensity score to the 5,311 Medicaid patients. Medicaid versus non-Medicaid payer status yielded significant differences in overall readmission rates of 28.8% versus 21.0% (p < 0.001; RR = 1.37 [95% CI, 1.28 to 1.46]) and 90-day hip-specific readmission rates of 2.5% versus 1.8% (p = 0.01; RR = 1.38 [95% CI, 1.07 to 1.78]). Mean length of stay was greater in the Medicaid group than in the non-Medicaid group at 4.5 versus 3.3 days (p < 0.0001), as was the mean total cost at $71,110 versus $65,309 (p < 0.0001). CONCLUSIONS: This study demonstrates that Medicaid payer status is independently associated with increased resource utilization, including readmission rates, length of stay, and total cost following primary total hip arthroplasty. Providers may have a disincentive to treat patient populations who require increased resource utilization following surgery. Risk adjustment models accounting for Medicaid payer status are necessary to avoid decreased access to care for this patient population and to avoid financial penalty for physicians and hospitals alike. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516628 TI - Time-Driven Activity-Based Costing to Identify Patients Incurring High Inpatient Cost for Total Shoulder Arthroplasty. AB - BACKGROUND: As payment models shift toward a focus on value, an accurate understanding of surgical costs and preoperative correlates of high-cost patients is important for effective implementation of cost-saving strategies. This study used time-driven activity-based costing (TDABC) to explore inpatient cost of total shoulder arthroplasty (TSA) and to identify preoperative characteristics of high-cost patients. METHODS: Using TDABC, we calculated the cost of inpatient care for 415 patients undergoing elective primary TSA between 2016 and 2017. Patients in the top decile of cost were defined as high-cost patients. Multivariable logistic regression modeling was employed to determine preoperative characteristics (e.g., demographics, comorbidities, American Society of Anesthesiologists [ASA] score, and American Shoulder and Elbow Surgeons [ASES] score) associated with high-cost patients. RESULTS: Implant purchase price was the main driver (57%) of total inpatient costs, followed by personnel cost from patient check-in through the time in the operating room (20%). There was a 1.3 fold variation in total cost between patients in the 90th percentile for cost and those in the 10th percentile; the widest cost variation was in personnel cost from the post-anesthesia care unit through discharge (2.5-fold) and in medication cost (2.4-fold). High-cost patients were more likely to be women and chronic opioid users and to have diabetes, depression, an ASA score of >=3, a higher body mass index (BMI), and a lower preoperative ASES score than non-high-cost patients. After multivariable adjustment, the 3 predictors of high-cost patients were female sex, an ASA score of >=3, and a lower ASES score. Total inpatient cost correlated strongly with the length of the hospital stay but did not correlate with operative time. CONCLUSIONS: Our study provides actionable data to contain costs in the perioperative TSA setting. From the hospital's perspective, efforts to reduce implant purchase prices may translate into rapid substantial cost savings. At the patient level, multidisciplinary initiatives aimed at reducing length of stay and controlling medication expenses for patients at risk for high cost (e.g., infirm women with poor preoperative shoulder function) may prove effective in narrowing the existing patient-to-patient variation in costs. LEVEL OF EVIDENCE: Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516629 TI - Routine Diagnostic Tests for Periprosthetic Joint Infection Demonstrate a High False-Negative Rate and Are Influenced by the Infecting Organism. AB - BACKGROUND: Current guidelines recommend serum erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as the first-line testing for evaluation of suspected periprosthetic joint infection, in addition to synovial white blood cell (WBC) count and polymorphonuclear percentage. However, the sensitivity and other diagnostic measures of these tests using a standardized definition of periprosthetic joint infection and the influence of organisms on these inflammatory markers remain inadequately investigated. METHODS: A retrospective review of an institutional database of 549 periprosthetic joint infection cases and 653 aseptic total joint arthroplasty revisions was performed. Periprosthetic joint infection was defined using major criteria from the International Consensus Meeting (ICM) on Periprosthetic Joint Infection. The mean inflammatory marker levels were compared among organisms with Student t tests and the proportions of elevated laboratory levels were compared among organisms with chi-square analyses. Receiver operating characteristic curve analyses were performed to calculate new cutoffs, sensitivities, and specificities for each organism and overall for serum CRP and ESR and synovial WBC and polymorphonuclear percentage. RESULTS: The sensitivity of these markers for diagnosing chronic periprosthetic joint infection was 0.85 for ESR, 0.88 for CRP, 0.83 for WBC count, and 0.78 for polymorphonuclear percentage. For ESR, antibiotic-resistant organisms had higher mean values (84.3 mm/hr) than culture-negative cases (57.4 mm/hr), coagulase negative Staphylococcus (68.3 mm/hr), and Streptococcus species (66.1 mm/hr); Staphylococcus aureus (81.0 mm/hr) was higher than culture-negative cases (57.4 mm/hr). For CRP, culture-negative cases had lower mean values (41.0 mg/L) than gram-negative organisms (87.4 mg/L), antibiotic-resistant organisms (86.0 mg/L), S. aureus (112.2 mg/L), and Streptococcus species (114.6 mg/L); S. aureus (112.2 mg/L) was higher than coagulase-negative Staphylococcus (66.0 mg/L). For WBC count, culture-negative cases had lower mean values (27,984.5 cells/mL) than S. aureus (116,250.0 cells/mL) and Streptococcus species (77,933.7 cells/mL). For polymorphonuclear percentage, there were no significant differences in mean values among all organisms. CONCLUSIONS: It appears that serological markers, namely ESR and CRP, have a higher false-negative rate than previously reported. Synovial markers similarly exhibit high false-negative rates. Furthermore, the sensitivity of these tests appears to be related to organism type. Surgeons should be aware of the high rate of false-negatives associated with low-virulence organisms and culture-negative cases. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516630 TI - Posteromedial Elbow Dislocations without Relevant Osseous Lesions: Clinical Characteristics, Soft-Tissue Injury Patterns, Treatments, and Outcomes. AB - BACKGROUND: Although simple posterolateral or posterior elbow dislocations are relatively common and usually stable after closed reduction, simple posteromedial dislocations are extremely rare and poorly characterized. We investigated the clinical characteristics, soft-tissue injury patterns, treatments, and outcomes of a series of posteromedial elbow dislocations without relevant osseous lesions. METHODS: We retrospectively reviewed 20 cases of simple posteromedial elbow dislocations without relevant osseous lesions that were treated at 7 fellowship training hospitals during a 10-year period. Soft-tissue injury patterns in 15 cases were investigated with use of magnetic resonance imaging. Clinical outcomes were evaluated after an average of 56.1 months (range, 24 to 93 months) with use of the Mayo Elbow Performance Score (MEPS) and the Quick-DASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH]) score. Complications were also evaluated. RESULTS: On magnetic resonance imaging, significant tears of the lateral collateral ligament complex and common extensor group were observed in all cases. Seventeen cases (85%) required surgical treatment for acute instability. Fourteen cases underwent only lateral complex repair and 3 underwent repair of both the medial and lateral complexes. At the time of the latest follow-up, the mean MEPS and Quick-DASH scores were 85.8 +/- 15.0 and 10.5 +/- 16.3, respectively. Seventeen patients (85%) had a satisfactory clinical outcome. Complications following treatment included 4 patients with heterotopic ossification; 2 of these patients also experienced posttraumatic elbow stiffness, which was treated with arthrolysis at 8 and 18 months after the initial operation. CONCLUSIONS: Posteromedial elbow dislocations without relevant osseous lesions are associated with a more severe soft-tissue injury, especially to the lateral complex, resulting in a high rate of surgical treatment. With careful post-reduction evaluation, either operative or nonoperative treatment provided satisfactory clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30516632 TI - What's New in Musculoskeletal Basic Science. PMID- 30516631 TI - Clinical Use of Opportunistic Computed Tomography Screening for Osteoporosis. PMID- 30516633 TI - What's Important: Listening and Reasoning: Interactions of Physicians, Patients, and Technology in Making Medical Decisions. PMID- 30516634 TI - The 2018 Austrian-Swiss-German Traveling Fellowship. PMID- 30516636 TI - Clubfoot Treatment in High and Low-Income Regions Produces Functional Feet: Commentary on articles by Kelly A. Jeans, MS, et al.: "Functional Outcomes Following Treatment for Clubfoot. Ten-Year Follow-up," and Bibek Banskota, MRCS, MS, et al.: "Outcomes of the Ponseti Method for Untreated Clubfeet in Nepalese Patients Seen Between the Ages of One and Five Years and Followed for at Least 10 Years". PMID- 30516635 TI - The Critical Portions of Carpal Tunnel Release, Ulnar Nerve Transposition, and Open Reduction and Internal Fixation of the Distal Part of the Radius. AB - BACKGROUND: Overlapping surgery is attracting increased scrutiny. The American College of Surgeons states that the attending surgeon must be present for all critical portions of a surgical procedure; however, critical portions of surgical procedures are not defined. We hypothesized that a Delphi panel process would measure consensus on critical portions of 3 common hand surgical procedures. METHODS: We used a Delphi process to achieve consensus on the critical portions of carpal tunnel release, ulnar nerve transposition, and open reduction and internal fixation of the distal part of the radius. The panelists were 10 hand surgeons (7 fellowship-trained surgeons and 3 fellows). Following an in-person discussion to finalize steps for each procedure, 2 online rounds were completed to rate steps from 1 (not critical) to 9 (extremely critical). We operationalized consensus as >=80% of ratings within the same range: 1 to 3 (not critical), 4 to 6 (somewhat critical), and 7 to 9 (critical). Because of a lack of consensus on some steps after round 2, another in-person discussion and a third online round were conducted to rate only steps involving disagreement or somewhat critical ratings using a dichotomous scale (critical or not critical). RESULTS: Following the first 2 rounds, there was consensus on 19 of 24 steps (including 3 steps being somewhat critical) and no consensus on 5 of 24 steps. At the end of round 3, there was consensus on all but 2 steps (identification of the medial antebrachial cutaneous nerve in ulnar nerve transposition and clinical assessment of joint stability in open reduction and internal fixation of the distal part of the radius), with moderate disagreement (3 compared with 7) for both. CONCLUSIONS: The panel reached consensus on the designation of critical or noncritical for all steps of a carpal tunnel release, all but 1 step of an ulnar nerve transposition, and all but 1 step of open reduction and internal fixation of the distal part of the radius. The lack of consensus on whether 2 of the steps are critical leaves this determination at the discretion of the attending surgeon. The findings of our Delphi panel provide guidance to our division on which portions of the surgical procedure are critical and thus require the attending surgeon's presence. PMID- 30516637 TI - Serum Erythrocyte Sedimentation Rate and C-Reactive Protein Level Have Weaknesses but Are the Best Screening So Far: Commentary on an article by Michael M. Kheir, MD, et al.: "Routine Diagnostic Tests for Periprosthetic Joint Infection Demonstrate a High False-Negative Rate and Are Influenced by the Infecting Organism". PMID- 30516638 TI - Erratum: Continuous Near-Infrared Spectroscopy Demonstrates Limitations in Monitoring the Development of Acute Compartment Syndrome in Patients with Leg Injuries. PMID- 30516639 TI - Management of patients with unruptured intracranial aneurysms. AB - PURPOSE OF REVIEW: Intracranial aneurysms are frequent incidental findings on cranial imaging. The decision for preventive treatment depends on the presumed risk of rupture, the efficacy and risk of complications of preventive treatment, and the quality of life having to live with an unruptured aneurysms. Data on all these factors are still incomplete, and additional data are needed. RECENT FINDINGS: The current review describes advances of the last 2 years in assessment of risk of rupture, on risks of preventive aneurysms occlusion, on follow-up imaging and on medical management of patients with unruptured intracranial aneurysms. SUMMARY: In addition to risk factors used to predict absolute risks of rupture, also aneurysm irregularity and aneurysm growth during follow-up are potential risk factors for rupture. To what extent these factors improve risk prediction in absolute terms is yet uncertain. Uncertainty also continues on whether endovascular or surgical occlusion is the preferred method, but a trial comparing these two strategies is ongoing. Aneurysm growth can now be predicted in absolute risks. Enhancement of the aneurysm wall on MRI probably is also related to aneurysm instability and reflects inflammation. A trial assessing the effects of anti-inflammatory treatment and blood pressure lowering on aneurysm growth and rupture is currently ongoing. PMID- 30516640 TI - Examining the ocular fundus in neurology. AB - PURPOSE OF REVIEW: The funduscopic examination can be a technically difficult, and often omitted, portion of the neurologic examination, despite its great potential to influence patient care. RECENT FINDINGS: Medical practitioners are often first taught to examine the ocular fundus using a direct ophthalmoscope, however, this skill requires frequent practice. Nonmydriatic tabletop and portable fundus photography and even smartphone-based photography offer alternative and practical means for approaching examination of the ocular fundus. These alternative tools have been shown to be practical in a variety of settings including ambulatory clinics and emergency departments. Decreased retinal microvascular density detected with fundus photography has been linked to accelerated rates of cognitive decline. Research has also found optic disc pallor and retinopathy detected via fundus photography to be more prevalent in patients with recent stroke or transient ischemic attack. SUMMARY: Alternative methods of funduscopic examination based on fundus photography have the potential to improve the ease of use, portability, and availability of funduscopy. Recognition of changes in retinal microvasculature has the potential to noninvasively identify patients at the highest risk for cognitive impairment and cerebrovascular disease. However, further research is needed to determine the specific utility of measurements of retinal microvascular changes in clinical care. Innovative funduscopy techniques offer neurologists new approaches to this essential facet of the neurological examination. PMID- 30516641 TI - Diagnostic error and neuro-ophthalmology. AB - PURPOSE OF REVIEW: This review summarizes the recent literature on diagnostic error relevant to the practice of neuro-ophthalmology, and evaluates the potential of increased access to neuro-ophthalmology as a means to decrease rates of diagnostic error, thereby reducing medical harm and spending on unnecessary tests and treatments. RECENT FINDINGS: Despite medical advances, current research continues to show alarmingly high rates of diagnostic error. Research into diagnostic error shows that many of these errors can be traced to cognitive errors. Recent studies on diagnostic problems relevant to neuro-ophthalmology, including studies of misdiagnosis of posterior communicating artery aneurysms, idiopathic intracranial hypertension, optic neuritis, and optic nerve sheath meningiomas, have identified major causes of diagnostic error in these conditions. SUMMARY: Studies on diagnostic error in neuro-ophthalmologic conditions show that prior to evaluation by a neuro-ophthalmologist, patients may undergo unnecessary tests and treatments that are costly and potentially harmful. Further research on diagnostic error will inform better utilization of neuro ophthalmologists as a resource to decrease diagnostic error. PMID- 30516642 TI - Visual function in children with primary brain tumors. AB - PURPOSE OF REVIEW: To review the recent advances in understanding how primary brain tumors affect vision in children. RECENT FINDINGS: Children with primary brain tumors may have vision loss due to involvement of their afferent visual pathways or from papilledema. These vision deficits may go unrecognized until later in life, years after treatment of the primary lesion. Strabismus and cranial nerve palsies may occur as a result of brain tumors. Ophthalmologists can monitor and treat young children at risk for vision loss from amblyopia as a result of effects from their underlying lesion. Advances in imaging techniques have made it possible to quantify damage to the visual pathways with objective tests. SUMMARY: Systematic referrals for evaluation by an ophthalmologist should occur early in the course of treatment of primary brain tumors as these evaluations may improve visual outcomes and quality of life. PMID- 30516643 TI - Ischemic stroke and infectious diseases in low-income and middle-income countries. AB - PURPOSE OF REVIEW: To address the important relationships between stroke and infection, focusing on the most frequent infections found in low-income and middle-income countries. RECENT FINDINGS: Stroke is one of the leading causes of mortality and disability worldwide, with a great proportion of the stroke burden occurring in low-income and middle-income countries. Infectious diseases are still a great health problem in developing countries and it is possible that the proportion of infection-related strokes is greater in these nations. Infectious diseases and stroke have a bidirectional relationship. Common infections may act as risk factors and can trigger stroke through different mechanisms in their acute phase. Several intracranial and systemic infections can cause stroke as a direct complication, such as Chagas disease, neurosyphilis, tuberculous meningitis, and neurocysticercosis. These conditions are of particular interest to low-income and middle-income countries, but also relevant to high-income nations because of increasing migration. Finally, infection is a frequent poststroke complication, with great impact in the patient outcome. SUMMARY: Infectious diseases and stroke are common problems in low-income and middle income countries. More studies are necessary to fully elucidate the real impact of infectious diseases on stroke burden, especially in countries where epidemiological data are still scarce. PMID- 30516644 TI - The changing profile of cerebrovascular diseases. PMID- 30516645 TI - Hot neuro-ophthalmologic topics. PMID- 30516646 TI - Management of intracranial haemorrhage, unruptured aneurysms and arteriovenous malformations during and after pregnancy. AB - PURPOSE OF REVIEW: The absolute risk of pregnancy-associated intracranial haemorrhage (ICH) has been reported to be relatively low and often associated with high risks of life-long disabilities and mortality. The aim of this narrative review was obtaining a better understanding of the current management practices for ICH, unruptured aneurysms and/or arteriovenous malformations during pregnancy, as well as the effects of future pregnancies, and the uses of oral contraceptive or HRT. RECENT FINDING: General guidelines for the management of ICH are used for pregnant women but additional expedient and thorough evaluation of foetal viability and its gestational age are requested. Recent epidemiological data suggest that menopause can be an independent risk factor for the development of aneurysmal subarachnoid haemorrhage. Furthermore, several population-based studies performed on women with aneurysmal subarachnoid haemorrhage observed a lower risk of bleeding with HRT. SUMMARY: The current review observed that the management practices for ICH during pregnancy were seen to be somewhat uniform. Whereas, the practices regarding future pregnancies and the prescriptions of either oral contraceptives or HRT do not follow coherent patterns. In light of this, we recommend the establishment of an international registry that would collect data on women with ICH during pregnancy. PMID- 30516647 TI - Treatment strategies for Leber hereditary optic neuropathy. AB - PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need. RECENT FINDINGS: There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY: Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder. PMID- 30516648 TI - Assessment of vision in concussion. AB - PURPOSE OF REVIEW: To review emerging vision-based assessments in the evaluation of concussion. RECENT FINDINGS: Involvement of the visual pathways is common following concussion, the mildest form of traumatic brain injury. The visual system contains widely distributed networks that are prone to neurophysiologic changes after a concussion, resulting in visual symptoms and ocular motor dysfunction. Vision-based testing is increasingly used to improve detection and assess head injury. Several rapid automatized naming (RAN) tasks, such as the King-Devick test and the Mobile Universal Lexicon Evaluation System, show capacity to identify athletes with concussion. Video-oculography (VOG) has gained widespread use in eye-tracking and gaze-tracking studies of head trauma from which objective data have shown increased saccadic latencies, saccadic dysmetria, errors in predictive target tracking, and changes in vergence in concussed individuals. SUMMARY: RAN tasks demonstrate promise as rapid screening tools for concussion. Further investigation will involve assessment of the role for age, characterization of learning effects over repeated measurements, and identification of optimal thresholds for clinically significant performance decrements. Various RAN tasks are likely to be functionally distinct, engaging different neural networks according to the demands of each task. Measures of saccades, smooth pursuit eye-movements, the vestibulo-ocular reflex and, more recently, disparity vergence are candidate vision-based markers for concussion. Work to adopt these assessments to the sideline or clinical environments is ongoing. PMID- 30516649 TI - Obtaining Actionable Inferences from Epidemiologic Actions. PMID- 30516650 TI - Is the association between pregnancy weight gain and fetal size causal? A re examination using a sibling comparison design. AB - BACKGROUND: Observational cohort studies have consistently shown that maternal weight gain in pregnancy is positively associated with fetal size, but it is unknown whether the association is causal. This study investigated the effect of pregnancy weight gain on fetal growth using a sibling comparison design to control for unmeasured confounding by genetic and shared environmental factors. METHODS: Our study population included 44,457 infants (21,680 women) with electronic medical records in the Stockholm-Gotland Obstetrical Database, 2008 2014. We standardized pregnancy weight gain into gestational age-specific z scores. Fetal size was classified as birthweight (g), and as small- and large-for gestational-age birth (birthweight <10 or >90 percentiles, respectively). Our sibling comparison analyses used multivariable linear fixed effects models for birthweight and hybrid logistic fixed effects models for small- and large-for gestational-age birth (SGA and LGA). We repeated analyses using conventional (unmatched) regression models. RESULTS: Sibling comparison analyses showed a clinically meaningful association between weight gain and fetal size (e.g., adjusted difference of +89g birthweight [95% CI: 82-95g]; adjusted risk ratios (aRR) for SGA of 0.80[0.75-0.86] per 1 z-score increase in weight gain for a woman of body mass index [BMI]=25). These findings were consistent across the range of BMI. Estimates were only modestly attenuated compared with conventional approach (+97g [92-102g], aRR for SGA of 0.70[0.67-0.73] per 1 z-score increase in weight gain). CONCLUSIONS: The positive association between pregnancy weight gain and fetal size we found using a sibling comparison design suggests this relationship has minimal confounding by familial factors that remain constant between pregnancies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30516651 TI - Elite Rowers Demonstrate Consistent Patterns of Hip Cartilage Damage Compared With Matched Controls: A T2* Mapping Study. AB - BACKGROUND: Rowing exposes the femoral head and acetabulum to high levels of repetitive abutment motion and axial loading that may put elite athletes at an increased risk for developing early hip osteoarthritis. QUESTIONS/PURPOSES: Do elite rowers demonstrate characteristic hip cartilage lesions on T2 MRI sequences compared with asymptomatic individuals who do not row? METHODS: This study included 20 asymptomatic rowers (mean age, 23 +/- 3 years; nine females, 11 males) who had a minimum of 5 years of intensive (>= 12 hours/week) training. The recruiting of the rowers took place from the central German federal rowing base, which has inherent intense training and selection requirements to declare these athletes as "elite rowers." We investigated one hip per study participant. MRI was performed on a 3-T scanner. The protocol included standard sequences, a double-echo steady-state sequence, and a multiecho data image combination sequence with inline T2 calculation (= the decay of transverse magnetization arising from molecular interactions [T2] and inhomogeneities in the magnetic field resulting from tissue susceptibility-induced field distortions and variations in the magnet itself), which detects changes in water content and the disruption of collagen structure. Although extrinsic and intrinsic influences on the T2 values including diurnal effects, MR technic-derived variations, and anatomic-related regional disparities need to be taken into account, low T2 values well below 20 ms indicate cartilage degeneration. Cartilage was morphologically analyzed in the anterior, anterosuperior, superoanterior, superior, superoposterior, posterosuperior, and posterior regions of the hip and graded as follows: Grade 0 = normal; Grade 1 = signal changes; Grade 2 = cartilage abrasion; Grade 3 = cartilage loss. Labrum was classified as follows: Grade 0 = normal; Grade 1 = partial tear; Grade 2 = full-thickness tear; Grade 3 = labrum degeneration. The T2 measurement was done through a region of interest analysis. For reliability assessment, morphologic evaluation and T2 measurement were performed by two observers while one observer repeated his analysis with a time interval > 2 weeks. Intra- and interobserver reliability was determined using kappa analysis and intraclass correlation coefficients. Control T2 data were derived from a previous study on 15 hips in 15 asymptomatic volunteers of similar ages (seven males and eight females) who were not competitive rowers with similar MR hardware and imaging sequences. RESULTS: Compared with the control group of asymptomatic volunteers who were not competitive rowers, we noted a high level of labrum and cartilage degeneration in the cohort of elite rowers. In the group of elite rowers, cartilage degeneration was noted in all hips. Regarding the acetabular cartilage, 271 zones could be evaluated. Of those, 44% (120 of 271) were graded normal, 6% (15 of 271) revealed signal alteration, 45% (122 of 271) demonstrated cartilage abrasion, and 5% (14 of 271) were noted to have full thickness cartilage loss. Morphologic cartilage degeneration in the femoral head was less frequent. T2 values were lower than the control hips in all zones except for the posterior central acetabular zone (global T2 acetabular: 20 +/- 6 ms, range, 9-36 ms, 95% confidence interval [CI], 19-21 ms versus 25 +/- 5 ms, range, 14-44 ms, 95% CI, 24-25 ms, p < 0.001; global T2 femoral: 23 +/- 7 ms, range, 9 38 ms, 95% CI, 22-24 ms versus 27 +/- 5 ms, range, 17-45 ms, 95% CI, 26-28 ms, p < 0.001). The difference in T2 between the two study groups was superior in the peripheral zone of the anterosuperior region (16 +/- 3 ms; range, 10-22 ms, 95% CI, 15-18 ms versus 26 ms +/- 5 ms, range, 18-38 ms, 95% CI, 24-29 ms, p < 0.001). CONCLUSIONS: We found signs of hip cartilage degeneration to a much greater degree in elite rowers than in asymptomatic controls. Although causation cannot be inferred, this is concerning, and future investigations including controlled longitudinal studies both on elite and nonelite athletes with sufficient cohort size are warranted to clarify our findings. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 30516652 TI - Cam FAI and Smaller Neck Angles Increase Subchondral Bone Stresses During Squatting: A Finite Element Analysis. AB - BACKGROUND: Individuals with a cam deformity and a decreased (varus) femoral neck shaft angle may be predisposed to symptomatic femoroacetabular impingement (FAI). However, it is unclear what combined effects the cam deformity and neck angle have on acetabular cartilage and subchondral bone stresses during an impinging squat motion. We therefore used finite element analysis to examine the combined effects of cam morphology and femoral neck-shaft angle on acetabular cartilage and subchondral bone stresses during squatting, examining the differences in stress characteristics between symptomatic and asymptomatic individuals with cam deformities and individuals without cam deformities and no hip pain. QUESTIONS/PURPOSES: Using finite element analysis in this population, we asked: (1) What are the differences in acetabular cartilage stresses? (2) What are the differences in subchondral bone stresses? (3) What are the effects of high and low femoral neck-shaft angles on these stresses? METHODS: Six male participants were included to represent three groups (symptomatic cam, asymptomatic cam, control without cam deformity) with two participants per group, one with the highest femoral neck-shaft angle and one with the lowest (that is, most valgus and most varus neck angles, respectively). Each participant's finite element hip models were reconstructed from imaging data and assigned subject-specific bone material properties. Hip contact forces during squatting were determined and applied to the finite element models to examine maximum shear stresses in the acetabular cartilage and subchondral bone. RESULTS: Both groups with cam deformities experienced higher subchondral bone stresses than cartilage stresses. Both groups with cam deformities also had higher subchondral bone stresses (symptomatic with high and low femoral neck-shaft angle = 14.1 and 15.8 MPa, respectively; asymptomatic with high and low femoral neck-shaft angle = 10.9 and 13.0 MPa, respectively) compared with the control subjects (high and low femoral neck-shaft angle = 6.4 and 6.5 MPa, respectively). The symptomatic and asymptomatic participants with low femoral neck-shaft angles had the highest cartilage and subchondral bone stresses in their respective subgroups. The asymptomatic participant with low femoral neck-shaft angle (123 degrees ) demonstrated anterolateral subchondral bone stresses (13.0 MPa), similar to the symptomatic group. The control group also showed no differences between cartilage and subchondral bone stresses. CONCLUSIONS: The resultant subchondral bone stresses modeled here coincide with findings that acetabular subchondral bone is denser in hips with cam lesions. Future laboratory studies will expand the parametric finite element analyses, varying these anatomic and subchondral bone stiffness parameters to better understand the contributions to the pathomechanism of FAI. CLINICAL RELEVANCE: Individuals with a cam deformity and more varus neck orientation may experience elevated subchondral bone stresses, which may increase the risks of early clinical signs and degenerative processes associated with FAI, whereas individuals with cam morphology and normal-to-higher femoral neck-shaft angles may be at lesser risk of disease progression that would potentially require surgical intervention. PMID- 30516653 TI - CORR Insights(r): Which Two-dimensional Radiographic Measurements of Cam Femoroacetabular Impingement Best Describe the Three-dimensional Shape of the Proximal Femur? PMID- 30516654 TI - CORR Insights(r): Chemotherapy Curtails Bone Formation From Compliant Compression Fixation of Distal Femoral Endoprostheses. PMID- 30516655 TI - CORR Insights(r): Proximal Femur Hounsfield Units on CT Colonoscopy Correlate With Dual-energy X-ray Absorptiometry. PMID- 30516656 TI - CORR Insights(r): Acetabular Retroversion and Decreased Posterior Coverage Are Associated With Sports-related Posterior Hip Dislocation in Adolescents. PMID- 30516657 TI - CORR Insights(r): When Do Patients Return to Previous Daily Activity After Arthroscopic Rotator Cuff Repair? PMID- 30516659 TI - CORR Insights(r): To Improve Your Surgical Drilling Skills, Make Use of Your Index Fingers. PMID- 30516658 TI - CORR Insights(r): What Is the Risk of Repeat Revision When Patellofemoral Replacement Is Revised to TKA? An Analysis of 482 Cases From a Large National Arthroplasty Registry. PMID- 30516660 TI - Residency Diary: The Other Side of the Knife. PMID- 30516661 TI - How Common Is Back Pain and What Biopsychosocial Factors Are Associated With Back Pain in Patients With Adolescent Idiopathic Scoliosis? AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is the most common spine deformity in adolescent patients. Although structural deformity may affect spinal biomechanics of patients with AIS, little is known regarding various period prevalence proportions of back pain and chronic back pain and factors associated with back pain in such patients. QUESTIONS/PURPOSES: (1) What are the period prevalence rates of back pain among teenagers with AIS? (2) Is back pain in patients with AIS associated with curve severity? METHODS: A total of 987 patients with AIS who were treated without surgery were recruited from a single center's scoliosis clinic. Between December 2016 and July 2017, this center treated 1116 patients with suspected AIS. During that time, patients were offered surgery when their Cobb angle was at least 50 degrees and had evidence of curve progression between two visits, and most of the patients who were offered surgery underwent it; other patients with AIS were managed nonsurgically with regular observation, brace prescription, posture training, and reassurance. To be included in this prospective, cross-sectional study, a patient needed to be aged between 10 and 18 years with a Cobb angle > 10 degrees . No followup data were required. A total of 1097 patients with AIS were managed nonsurgically (98.3% of the group seen during the period in question). After obtaining parental consent, patients provided data related to their demographics; physical activity levels; lifetime, 12-month, 30-day, 7-day, and current thoracic pain and low back pain (LBP); chronic back pain (thoracic pain/LBP); brace use; and treatments for scoliosis/back pain. Pain was rated on a 10-point numeric rating scale for pain. The Insomnia Severity Index, Epworth Sleepiness Scale, and Depression Anxiety Stress Scales were also assessed. These features and radiologic study parameters between patients with and without back pain were also compared. Factors associated with current and 12-month back pain as well as chronic back pain were analyzed by multivariate analyses. RESULTS: Depending on the types of period prevalence, the prevalence of thoracic pain ranged from 6% (55 of 987) within 12 months to 14% (139 of 987) within 7 days, whereas that of LBP ranged from 6% (54 of 987) to 29% (289 of 987). Specifically, chronic thoracic pain or LBP had the lowest prevalence. Compared with the no pain group, patients with current back pain had more severe insomnia (odds ratio [OR], 1.80; p = 0.02; 95% confidence interval [CI], 1.10-2.93) and daytime sleepiness (OR, 2.41; p < 0.001, 95% CI, 1.43-4.07). Those with chronic back pain had the same problems along with moderate depression (OR, 2.49; p = 0.03; 95% CI, 1.08-5.71). Older age (OR range, 1.17-1.42; all p values <= 0.030) and Cobb angle > 40 degrees (OR range, 2.38 3.74; all p values <= 0.015), daytime sleepiness (OR range, 2.39-2.41; all p values <= 0.011), and insomnia (OR range, 1.76-2.31; all p values <= 0.001) were associated with episodic and/or chronic back pain. Females were more likely to experience back pain in the last 12 months than males. Moderate depression (OR, 3.29; 1.45-7.47; p = 0.004) and wearing a brace (OR, 3.00; 1.47-6.15; p = 0.003) were independently associated with chronic back pain. CONCLUSIONS: Biopsychosocial factors are associated with the presence and severity of back pain in the AIS population. Our results highlight the importance of considering back pain screening/management for patients with AIS with their psychosocial profile in addition to curve magnitude monitoring. In particular, sleep quality should be routinely assessed. Longitudinal changes and effects of psychotherapy should be determined in future studies. LEVEL OF EVIDENCE: Level II, prognostic study. PMID- 30516662 TI - Pleural Mesothelioma Detects by 18F-Choline PET/CT in a Patient With Biochemical Recurrence of Prostate Cancer. AB - A 73-year-old man with a prostate cancer treated by radical prostatectomy in 2006. For a biochemical recurrence of disease (prostate-specific antigen level, 0.1 ng/mL) during hormonal therapy, patient underwent F-choline PET/CT that showed a significant uptake in a diffuse right pleural thickening. The patient was sent to pleurectomy decortication showing an epithelioid pleural mesothelioma. This case highlighted that a histopathological evaluation is mandatory in case of a significant radiolabeled choline uptake in pleural lesions. PMID- 30516663 TI - Gallbladder Metastasis From Conjunctival Melanoma. AB - Malignant conjunctival melanoma is a rare tumor. A 46-year-old woman with a history of locally recurrent left conjunctival melanoma was followed by F-FDG PET/CT. Four years after the local recurrence treated by orbital exenteration, the follow-up PET/CT scan showed an incidental intense FDG uptake mass infiltrating the gallbladder associated with a low uptake of an infracentimetric pulmonary nodule. The patient was completely asymptomatic with no sign of local recurrence. Laparoscopic cholecystectomy was performed, and histopathologic findings were consistent with gallbladder metastasis of melanoma. After almost 2 years of immunotherapy, the patient is still in complete response. PMID- 30516664 TI - Small Primary Cutaneous gammadeltaT-Cell Lymphoma Lesions Successfully Treated With Pralatrexate. AB - Here we report on the treatment of a 38-year-old woman with primary cutaneous gammadeltaT-cell lymphoma, which is a rare subset of cutaneous T-cell lymphoma. She presented with multiple subtle subcutaneous nodules, which were not clearly observed on computed tomography scans or after biopsy. However, F fluorodeoxyglucose positron emission tomography (F-FDG-PET) accurately detected small cutaneous lesions. She achieved a second complete remission, as demonstrated by F-FDG-PET performed after pralatrexate infusion. PMID- 30516665 TI - PET/CT and MR Features of Infiltrating Spinal Angiolipoma. AB - Spinal angiolipomas are benign tumors predominantly found in the epidural space. Infiltrating spinal angiolipoma is an extremely rare type, which tends to invade the surrounding tissue and may mimic an aggressive tumor. Herein, we reported the case of a 64-year-old woman with a thoracic angiolipoma involving the T9 vertebral body and its appendix. The lesion showed long T1 and T2 signal intensity on MRI and slightly increased FDG uptake on PET/CT. After surgery, the pathologic examination demonstrated features consistent with angiolipoma, and the patient was free of symptoms. PMID- 30516666 TI - A Mixed Variant of Castleman Disease Detected by Somatostatin Receptor Scintigraphy with 99mTc-HYNIC-TOC and 18F-FDG PET/CT. AB - A 50-year-old woman was found with a hypervascular abdominal mass in the right lower quadrant in contrast-enhanced CT. Somatostatin receptor scintigraphy with Tc-HYNIC-TOC showed positivity of the abdominal mass and detected additional lesion with moderate increased radioactivity in the right axilla. In F-FDG PET/CT, both of the lesions were FDG-avid. A hypermetabolic node in the right supraclavicular fossa was also noted. The histopathological examination of the abdominal mass after surgical resection revealed Castleman disease, a mixed hyaline vascular and plasma cell variant. The right axillary and supraclavicular lesions were considered involvement of Castleman disease. PMID- 30516667 TI - FDG PET/CT Course of Pembrolizumab-Associated Multiorgan Sarcoidosis. AB - An 80-year-old man with metastatic melanoma had been receiving treatment with pembrolizumab from September 2015 until June 2017. Series FDG PET/CT scans from March 7, 2017, to June 14, 2018, showed the course of biopsy-proven pembrolizumab induced sarcoidosis. Reported here is the first case of multiorgan sarcoidosis induced by pembrolizumab and its self-resolving course on FDG PET/CT. PMID- 30516668 TI - 18F-Choline PET/CT in Leptomeningeal Breast Cancer Metastases. AB - We describe a case of 47-year-old woman affected by human epidermal growth factor receptor-2-positive breast cancer with a diffuse leptomeningeal carcinomatosis. An intense uptake of F-choline was reported at fused PET/MRI images in the brain, compatible with a diffuse leptomeningeal disease. This case highlights that F choline PET would be used for the identification of leptomeningeal involvement in patients affected by breast cancer, as a support of MRI images. PMID- 30516669 TI - Skeletal Superscan on 18F-FDG PET/CT in a Patient With Multiple Myeloma. AB - An F-FDG PET/CT was performed on a 47-year-old man diagnosed as multiple myeloma with diffuse bone marrow infiltration on pathology. PET/CT findings presented as a pattern of skeletal "superscan," including diffuse and prominent hypermetabolism throughout the axial and proximal appendicular skeleton, which all alleviated after 5 cycles of chemotherapy. PMID- 30516670 TI - Chronic Vasitis After Mesh Herniorrhaphy: A Potential Cause of False Positive Results in 18F-FDG PET/CT Studies. AB - We report two cases of supra-scrotal vasitis incidentally detected in patients who had undergone mesh herniorrhaphy. PET/CT in patients undergoing lymphoma work up and health check-up revealed hypermetabolic dilatation of vas deferens in the external iliac area. There were no symptoms, and blood test results did not indicate acute inflammation. Interestingly, both had undergone herniorrhaphy for inguinal hernia. Herniorrhaphy is reported to cause vasal complications such as obstruction or inflammation, although most are asymptomatic and probably under reported. Chronic vasitis after herniorrhaphy may be a potential cause for false positive findings on F-FDG PET/CT in patients undergoing work-up for various oncological indications. PMID- 30516671 TI - Increased 99mTc Pertechnetate Uptake But Unimpressive 131I Activity in the Metastatic Mediastinal Lymph Nodes in a Thyroid Cancer Patient. AB - False negative I accumulation in metastatic lesions of thyroid carcinoma could be due to various etiologies. Here we present a 33-year-old woman with a history of papillary thyroid cancer who had increased Tc pertechnetate activity in the mediastinal metastatic lymph nodes, which was not clearly seen on whole body I scan due to adjacent activity from lung metastases. PMID- 30516672 TI - Incidental 18F-NaF Uptake in Drug-Induced Gynecomastia. AB - Gynecomastia is not uncommon in men older than 50 years of age and is characterized by glandular proliferation of breast tissue. Non-physiologic gynecomastia is mostly caused by a variety of external medical interventions. Medications that belong to classes of antiandrogens, antipsychotics, or antibiotics alter the levels of estrogen and testosterone and are commonly implicated in patients with gynecomastia. We are presenting a case of bilateral F NaF uptake in the breast tissue of a 56-year-old man with known history of prostate cancer. PMID- 30516673 TI - Rationale for Study of the Deep Subfascial Lymphatic Vessels During Lymphoscintigraphy for the Diagnosis of Peripheral Lymphedema. AB - PURPOSE: The current study aimed to determine the utility of including the study of deep subfascial lymphatic vessels in a 2-compartment lymphoscintigraphy for the diagnosis of lymphedema in patients with limb swelling. Lymphoscintigraphy is a valuable imaging tool for the timely diagnosis of peripheral lymphedema. However, there is a lack of standardization in its application, especially regarding which type of lymphatic vessels to examine (superficial, deep, or both). METHODS: Two hundred fifty-eight patients with lymphedema underwent segmental lymphoscintigraphy. The transport index (TI) was calculated to categorize the flow of the superficial and deep vessels as normal (<10) or pathological (>=10). The scores from 248 patients (48 unilateral arm, 86 unilateral leg, 114 bilateral leg) were tested with a 3-way analysis of variance to examine the relationship between affected limb, deep or superficial pathways, and primary or secondary lymphedema. The relationship between clinical presentation and TI was also investigated. RESULTS: In general, primary and secondary lymphedema patients had similar patterns of lymphoscintigraphic lymphatic abnormalities. Patients with unilateral clinical presentation can have bilateral TI abnormalities. The vast majority of patients (88%-98%) had either the deep subfascial vessels alone, or both the superficial and deep vessels, with a pathological TI. CONCLUSIONS: A 2-compartment lymphoscintigraphy is able to accurately detect lymphatic flow abnormalities in patients with limb swelling. Given that the vast majority of patients had deep lymphatic vessels abnormalities, inclusion of these vessels in the lymphoscintigraphic diagnostic protocol is recommended. PMID- 30516674 TI - Unusual Focal Muscle FDG Activity Related to Altered Biomechanics. AB - A 20 year old man suffered severe right knee pain, especially when his right foot touched ground. The MRI findings suggested periosteal osteosarcoma, which led to a staging FDG PET/CT. The images showed not only a hypermetabolic right knee lesion but also focally elevated activity in select muscles, which was attributed to altered biomechanics. The resected lesion was pathologically proven as periosteal chondrosarcoma instead of periosteal osteosarcoma. In a follow-up period of 4 years after the surgery, there was no recurrent disease, nor any abnormality in the muscles which showed focal FDG activity on the initial FDG PET/CT. PMID- 30516675 TI - Hybrid 11C-MET PET/MRI Combined With "Machine Learning" in Glioma Diagnosis According to the Revised Glioma WHO Classification 2016. AB - PURPOSE: With the advent of the revised WHO classification from 2016, molecular features, including isocitrate dehydrogenase (IDH) mutation have become important in glioma subtyping. This pilot trial analyzed the potential for C-methionine (MET) PET/MRI in classifying glioma according to the revised WHO classification using a machine learning model. METHODS: Patients with newly diagnosed WHO grade II-IV glioma underwent preoperative MET-PET/MRI imaging. Patients were retrospectively divided into four groups: IDH wild-type glioblastoma (GBM), IDH wild-type grade II/III glioma (GII/III-IDHwt), IDH mutant grade II/III glioma with codeletion of 1p19q (GII/III-IDHmut1p19qcod) or without 1p19q-codeletion (GII/III-IDHmut1p19qnc). Within each group, the maximum tumor-to-brain-ratio (TBRmax) of MET-uptake was calculated. To gain generalizable implications from our data, we made use of a machine learning algorithm based on a development and validation subcohort. A support vector machine model was fit to the development subcohort and evaluated on the validation subcohort. Receiver operating characteristic (ROC) analysis served as metric to assess model performance. RESULTS: Of a total of 259 patients, 39 patients met the inclusion criteria. TBRmax was highest in the GBM cohort (TBRmax 3.83 +/- 1.30) and significantly higher (P = 0.004) compared to GII/III-IDHmut1p19qnc group, where TBRmax was lowest (TBRmax 2.05 +/- 0.94). ROC analysis showed poor AUC for glioma subtyping (AUC 0.62) and high AUC of 0.79 for predicting IDH status. In the GII/III IDHmut1p19qcod group, TBR values were slightly higher than in the IDHmut1p19qnc group. CONCLUSIONS: MET-PET/MRI imaging in pre-operatively classifying glioma entities appears useful for the assessment of IDH status. However, a larger trial is needed prior to translation into the clinical routine. PMID- 30516676 TI - 18F-FDG PET and Bone Scintigraphy of Epithelioid Hemangioendothelioma. AB - We report the case of a 31-year-old woman with left foot bones located epithelioid hemangioendothelioma. It is a rare type of vascular tumor, locally aggressive with metastatic potential. It was revealed by a chronic isolated left foot pain. Conventional imaging showed multiple osteolytic lesions of the bones, appearing aggressive. Both bone scintigraphy and F-FDG PET showed an increased uptake of these lesions and confirmed the limited extent to distal extremity of the left lower limb. Final diagnosis was given on a surgical biopsy. Patient was treated by hyperthermic chemotherapy using isolated limb perfusion. PMID- 30516677 TI - Arterial Phase 18F-Fluorocholine PET/CT in Hepatocellular Carcinoma. AB - A 57-year-old man was referred to our institution for F-fluorocholine PET/CT to characterize a pulmonary nodule in a context of hepatocellular carcinoma. F-FDG PET/CT did not show any uptake of the pulmonary nodule. F-fluorocholine PET/CT showed high uptake of the pulmonary nodule, confirming its metastatic origin. Furthermore, liver early dynamic acquisitions allowed better visualization of the hepatocellular carcinoma during the "arterial phase" than at equilibrium. PMID- 30516678 TI - 68Ga-DOTA-TOC PET/CT of von Hippel-Lindau Disease. AB - We present a rare case of a 42-year-old man with a long history of von Hippel Lindau disease that was scanned with Ga-DOTA-TOC PET/CT for suspicion of disease relapse. Ga-DOTA-TOC imaging demonstrated increased DOTA-TOC uptake in pancreas tail and intramedullary and extramedullary spinal hemangioblastomas, only some of which have already been highlighted at MRI examination. This case illustrates the significant role the Ga-labeled somatostatin receptor analogs PET/CT in the management of the von Hippel-Lindau disease. PMID- 30516679 TI - Pretreatment Tumor 18F-FDG Uptake Improves Risk Stratification Beyond RECIST 1.1 in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer: FDG Uptake and Risk Stratification. AB - PURPOSE: This study investigated the prognostic role of tumor F-FDG uptake on pretreatment scans as an independent indicator and whether its addition improves risk prediction from Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). METHODS: We measured the SUVmax of the most F-FDG-avid tumor lesions on pretreatment scans from 222 patients (age, 60.5 +/- 9.5 years; males, 55.2%) with advanced nonsquamous non-small-cell lung cancer who were enrolled in a prospective phase II clinical trial. We then examined the prognostic value of SUVmax compared with other clinical factors, including chemotherapy response according to RECIST 1.1 criteria. RESULTS: A multivariable Cox proportional hazards model revealed that an SUVmax greater than 16.3 was an independent predictor of poor progression-free survival (hazards ratio, 3.50; 95% confidence interval, 1.89-6.51; P < 0.000) and overall survival (hazards ratio, 6.87; 95% confidence interval, 2.51-18.76; P < 0.000), whereas RECIST 1.1 did not show a significant association with any survival outcome. Furthermore, improvement was achieved by adding SUVmax to RECIST 1.1, which increased the net reclassification index (27.4%; P = 0.046) and integrated discrimination improvement (integrated discrimination improvement, 10.6%; P = 0.026). Similarly, adding RECIST 1.1 to SUVmax also improved net reclassification index (68.9%, P = 0.006) and integrated discrimination improvement (25.4%, P = 0.006) for prognosis prediction. CONCLUSIONS: High tumor F-FDG uptake on a pretreatment scan is an independent prognostic indicator that can significantly improve risk stratification when added to RECIST 1.1 for patients with advanced nonsquamous non-small-cell lung cancer. PMID- 30516680 TI - Richter Syndrome Presenting With Colon Localization. AB - A 75-year-old man, who had been diagnosed with small lymphocytic lymphoma with cervical localization, underwent F-FDG PET/CT with iodinated contrast medium due to the appearance of cervical swelling suspected of illness relapse. PET/CT revealed intense F-FDG uptake in multiple cervical and subdiaphragmatic lymph nodes and in the left parotid. Moreover, diffuse uptake and wall thickening of the colon were evident; endoscopy with biopsy revealed a diffuse large B-cell lymphoma. Transformation into a more aggressive lymphoma occurs in 2% to 8% of small lymphocytic lymphoma, the so-called Richter syndrome. Extranodal localization in the sigmoid colon is an extremely rare site for transformed lymphoma. PMID- 30516681 TI - Ischemic Complications After High-Grade Glioma Resection Could Interfere With Residual Tumor Detection With 18F-Fluorocholine PET/CT. AB - Ischemic complications after resection of high-grade glioma are frequent and may constitute potential cause of false-positive results in postsurgical evaluation using F-fluorocholine PET/CT. On the other hand, hypoxia caused by ischemia promotes invasive glioma growth. We present 3 cases of patients with different grades of ischemic injury after resection of high-grade glioma. The combined interpretation of diffusion-weighted imaging and apparent diffusion coefficient map on MRI, in this clinical setting, is mandatory to avoid PET/CT misinterpretations. PMID- 30516682 TI - Subacute Venous Infarct Mimicking Cerebral Metastasis in 18F-FDG PET/CT. AB - A 68-year-old woman with colon carcinoma was referred to F-FDG PET/CT imaging for staging. In addition to primary tumor involvement, PET/CT demonstrated focal FDG uptake in the right temporal lobe suggestive of primary brain tumor or metastasis. To delineate the lesion, a brain MRI scan showed sigmoid sinus thrombosis and vasogenic edema in the right temporal lobe. The patient presented a history of right-sided headache that began 1 week before the PET/CT. Neurological examination and MRI findings were concluded as subacute venous infarct due to sigmoid sinus thrombosis and that is a potential cause for false positive FDG uptake on PET/CT. PMID- 30516683 TI - Diffuse Large B-Cell Lymphoma Recurring as Neurolymphomatosis on FDG PET/CT. AB - Two patients with diffuse large B-cell lymphoma relapsing as neurolymphomatosis diagnosed on FDG PET/CT are presented. Both patients were treated initially with chemotherapy and had a complete metabolic response. Patient 1 represented with lower-limb pain. An FDG PET/CT demonstrated intense uptake throughout the sciatic nerves bilaterally extending distally with relapse confirmed on biopsy. Patient 2 represented to hospital with worsening mobility, neuropathic pain, and facial asymmetry. An FDG PET/CT demonstrated relapse within the spinal cord, left sciatic nerve, and facial nerve branches. Neurolymphomatosis is an uncommon finding on FDG PET/CT and can be the only site of relapse. PMID- 30516684 TI - Evaluation of Oxalate Osteopathy Secondary to Hyperoxaluria With 18F-FDG PET/CT and 99mTc-HMDP Bone Scan. AB - We report a case of a 69-year-old woman with primary hyperoxaluria type I, who developed a severe hypercalcemia despite controlled secondary hyperparathyroidism. Bone scintigraphy showed diffuse increased uptake in axial and peripheral skeleton. F-FDG PET/CT showed countless striking hypermetabolic foci, interesting 2 types of lesions (joint calcifications and periosteal resorptions). Bone biopsy demonstrated inflammatory changes around many calcium oxalate crystals; hypercalcemia was then related to oxalate osteopathy. Immunotherapy with denosumab was thus initiated. Eighteen months later, a second PET/CT showed decreased F-FDG uptake, reflecting treatment efficacy on inflammatory reaction secondary to calcium oxalosis skeletal deposits. PMID- 30516685 TI - Juvenile Nasal Angiofibroma on 68Ga-PSMA PET/CT: Opening New Frontiers. AB - The prostate-specific membrane antigen (PSMA) is highly expressed in prostatic cancer. However, PSMA expression is also noted in various benign and malignant nonprostatic neoplasms in the endothelial cells of tumor-associated neovasculature. We performed Ga-PSMA PET/CT in a 14-year-old boy with juvenile nasal angiofibroma (JNA) to explore its theranostic potential. The scan revealed high uptake in the lesion. Performance of PSMA PET/CT in JNA opens up new frontiers with respect to radiological staging, early recurrence identification, and perhaps even radioligand therapy of residual/recurrent JNAs in the future. PMID- 30516686 TI - Voriconazole-Induced Periostitis After Allogeneic Stem Cell Transplantation. AB - A 34-year-old man with history of Hodgkin lymphoma presented 7 months after allogeneic stem cell transplantation with an unexplained severe musculoskeletal pain syndrome. A Tc-MDP bone SPECTCT showed multiple foci with moderate to intense bone uptake across the axial and appendicular skeleton consistent with periostitis. The patient had been on voriconazole daily for 4 months to treat an Aspergillus pneumonia, and in the absence of other causes, a drug-induced periostitis was suspected. Voriconazole was changed to posaconazole with complete resolution of the musculoskeletal symptoms within 3 weeks. PMID- 30516687 TI - Primary Diffuse Leptomeningeal Melanomatosis of Spine: 18F-FDG PET Findings. AB - Primary diffuse leptomeningeal melanomatosis is a rare variant of malignant melanoma of the central nervous system, arising from melanocytes of leptomeninges. It may involve leptomeninges and may invade brain superficially. The diagnosis of the disease with conventional imaging techniques is quite difficult. This case demonstrates the F-FDG uptake of primary diffuse leptomeningeal melanomatosis matching with MRI contrast enhancement regions particularly in the lower thoracic and superior lumbar region. PMID- 30516688 TI - 99mTc-MIBI Uptake in a Benign Thymic Cyst. AB - A 34-year-old man with end-stage renal failure status post rejection of a deceased donor kidney transplant presented with bone pain in the setting of elevated serum parathyroid hormone and calcium levels. A Tc-MIBI SPECT/CT was performed before planned subtotal parathyroidectomy. SPECT/CT imaging revealed a 1.9-cm anterior mediastinal lesion with radiotracer uptake on both the immediate and delayed images. Surgical pathology of the lesion showed a benign thymic cyst with no parathyroid component. PMID- 30516689 TI - FDG-PET/CT for Detecting an Infection Focus in Patients With Bloodstream Infection: Factors Affecting Diagnostic Yield. AB - PURPOSE: To investigate the diagnostic performance of F-fluoro-2-deoxy-D-glucose (FDG) PET/ CT for the detection of an infection focus in patients with a bloodstream infection (BSI) and to identify factors influencing the diagnostic yield of FDG-PET/CT. METHODS: This retrospective single-center study included 185 consecutive patients with a BSI who underwent an FDG-PET/CT scan for the detection of an infection focus between 2010 and 2017. The final diagnosis at hospital discharge was used as reference standard. Diagnostic performance of FDG PET/CT for the detection of an infection focus was assessed, and logistic regression analyses were performed to identify factors associated with FDG-PET/CT yield. RESULTS: An infection focus was identified on FDG-PET/CT in 120 (64.8%) of 185 patients. FDG-PET/CT achieved a sensitivity of 80.2%, specificity of 79.6%, positive predictive value of 90.8%, and a negative predictive value of 61.4% for detecting an infection focus in patients with a BSI. Blood cultures positive for enterococci (odds ratio, 0.14; P = 0.019) and days of antibiotic treatment before FDG-PET/CT (odds ratio, 0.94 per day increase; P = 0.014) were statistically significant independent predictors of a lower odds of detecting an infection focus on FDG-PET/CT. In patients who received antibiotics for less than 7 days before FDG-PET/CT, an infection focus was found in 71% (56/79). In patients who received antibiotics for 8 to 14 days before FDG-PET/CT, an infection focus was found in 52% (22/42). After 15 to 21 days of antibiotic treatment, an infection focus was found in 61% (8/13), and for 22 days or more, this declined to 38% (5/13). CONCLUSIONS: FDG-PET/CT is a useful method for detecting an infection focus in patients with BSI. However, longer duration of antibiotic treatment before FDG-PET/CT and bacteremia with enterococci reduce the diagnostic yield of FDG-PET/CT. These factors should be taken into account when considering an FDG PET/CT scan for this indication. PMID- 30516690 TI - Incidental Finding of Intrathyroid Metastases of Prostatic Cancer on 18F-Choline PET/CT. AB - An 85-year-old man with a 2-year history of prostate cancer, treated with radiotherapy and hormonal therapy, presented increased prostatic-specific antigen levels. F-choline PET/CT showed focal prostatic uptake consistent with known local recurrence, increased uptake of 2 hypodense thyroid nodules and of 2 left cervical lymph nodes, suspected as thyroid cancer. Neck ultrasound confirmed the high risk of malignancy, and a guided biopsy (of a thyroid nodule and cervical lymph node) revealed cellular infiltrates thyroid transcription factor-1 (TTF-1) negative and prostatic-specific antigen positive, confirming intrathyroid and cervical lymph node metastases of prostate cancer. PET/CT changed the disease staging. Chemotherapy was initiated. PMID- 30516691 TI - Synthetic Brain MRI: Review of Current Concepts and Future Directions. AB - Synthetic magnetic resonance imaging is a novel imaging technique that allows generating multiple contrast-weighted images based on relaxivity measurements of tissue properties in a single acquisition using a multiecho, multidelay saturation recovery spin-echo sequence. The synthetic images can be generated postacquisition from the parametric tissue maps, which can be beneficial to reduce scan time and improve patient throughput. Based on relaxometry maps, synthetic magnetic resonance imaging can also perform brain tissue segmentation and myelin quantification without additional scan time. The quantitative analysis may have implications for understanding and monitoring of the evolution of the maturation process. Similarly, the myelination process is vitally important to central nervous system functioning. Measuring myelin volume could provide relevant information for the diagnosis and treatment of patients with myelination disorders. PMID- 30516692 TI - Tubulinopathies. AB - Mutations causing dysfunction of the tubulins and microtubule-associated proteins, otherwise known as tubulinopathies, are a group of recently described entities, that lead to complex brain malformations. An understanding of the fundamental principles of operation of the cytoskeleton and compounds in particular microtubules, actin, and microtubule-associated proteins, can assist in the interpretation of the imaging findings of tubulinopathies. Somewhat consistent morphological imaging patterns have been described in tubulinopathies such as dysmorphic basal ganglia-the hallmark (found in 75% of cases), callosal dysgenesis, cerebellar hypoplasia/dysplasia, and cortical malformations, most notably lissencephaly. Recognizing the common imaging phenotypes present in tubulinopathies can prove invaluable in directing the genetic workup for a patient with brain malformations. PMID- 30516693 TI - Imaging of Childhood Inflammatory Brain Diseases. AB - Brain has been considered as an immune-privileged site for centuries owing to the presence of blood-brain barrier, absent lymphatic drainage, and antigen presenting cells. However, the present prevailing concept is of immune surveillance where brain is continuously surveyed by immune cells. However, the presence of immune cells in central nervous system (CNS) brings the risk of inflammation and autoimmunity involving both T and B cell mediated pathways. These mechanisms form the underlying pathology in a wide spectrum of pediatric CNS diseases manifesting as acquired neurological deficits. Overlapping, heterogenous, and ambiguous clinical features often delays the diagnosis. Although not always pathognomonic, magnetic resonance imaging can be an important biomarker leading to early diagnosis, prognostication, and systematic follow-up pf these diseases. This review describes the spectrum of different pediatric inflammatory disorders and their pertinent imaging features illustrated with clinical examples. PMID- 30516694 TI - The Rare Neurocutaneous Disorders: Update on Clinical, Molecular, and Neuroimaging Features. AB - Phakomatoses, also known as neurocutaneous disorders, comprise a vast number of entities that predominantly affect structures originated from the ectoderm such as the central nervous system and the skin, but also the mesoderm, particularly the vascular system. Extensive literature exists about the most common phakomatoses, namely neurofibromatosis, tuberous sclerosis, von Hippel-Lindau and Sturge-Weber syndrome. However, recent developments in the understanding of the molecular underpinnings of less common phakomatoses have sparked interest in these disorders. In this article, we review the clinical features, current pathogenesis, and modern neuroimaging findings of melanophakomatoses, vascular phakomatoses, and other rare neurocutaneous syndromes that may also include tissue overgrowth or neoplastic predisposition. PMID- 30516695 TI - Imaging Review of Common and Rare Causes of Stroke in Children. AB - Vascular injury is increasingly recognized as an important cause of mortality and morbidity in children (29 days to 18 years of age). Since vascular brain injury in children appears to be less common than in adults, the index of suspicion for vascular brain injury is usually lower. In this review article, we describe frequent and rare conditions underlying pediatric stroke including cardioembolic, viral, autoimmune, post-traumatic, and genetic etiologies. Furthermore, we provide a neuroimaging correlate for clinical mimics of pediatric stroke. This review highlights the role of multimodal noninvasive neuroimaging in the early diagnosis of pediatric stroke, providing a problem-solving approach to the differential diagnosis for the neuroradiologist, emergency room physician, and neurologist. PMID- 30516696 TI - Childhood Medulloblastoma Revisited. AB - Medulloblastoma is the most common malignant solid tumor in childhood and the most common embryonal neuroepithelial tumor of the central nervous system. Several morphological variants are recognized: classic medulloblastoma, large cell/anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity. Recent advances in transcriptome and methylome profiling of these tumors led to a molecular classification that includes 4 major genetically defined groups. Accordingly, the 2016 revision of the World Health Organization's Classification of Tumors of the Central Nervous System recognizes the following medulloblastoma entities: Wingless (WNT) activated, Sonic hedgehog (SHH)-activated, Group 3, and Group 4. This transcriptionally driven classification constitutes the basis of new risk stratification schemes applied to current therapeutic clinical trials. Because additional layers of molecular tumor heterogeneities are being progressively unveiled, several clinically relevant subgroups within the 4 major groups have already been identified. The purpose of this article is to review the recent basic science and clinical advances in the understanding of "medulloblastomas," and their diagnostic imaging correlates and the implications of those on current neuroimaging practice. PMID- 30516697 TI - Ocular and Intracranial MR Imaging Findings in Abusive Head Trauma. AB - Abusive head trauma (AHT) is a form of inflicted head injury. AHT is more frequent in 2-year-old or younger children. It is an important cause of neurological impairment and the major cause of death from head trauma in this age group. Brain magnetic resonance imaging allows the depiction of retinal hemorrhages, injured bridging veins, and identifying and localizing extra- and intra-axial bleeds, contusions, lacerations, and strokes. The diagnosis of AHT is a multidisciplinary team effort which includes a careful evaluation of social, clinical, laboratory, and radiological findings. Notwithstanding, the introduction in the current clinical practice of high-resolution techniques is adding forensic evidence to the recognition of AHT. PMID- 30516698 TI - From the Editor. PMID- 30516699 TI - Guest Editorial. PMID- 30516700 TI - Guest Editorial. PMID- 30516701 TI - Future Proofing: The Nursing Now Campaign. AB - In many Western democracies, nursing consumes a comparatively large proportion of the health service budget and delivers the highest proportion of direct patient care. Therefore, identifying and representing the contribution of nurses to clinical effectiveness as well as the wider social benefit to populations and the economy is crucial. Predictive models on health and social care requirements for the next quarter of a century report a staggering shift in population age, multimorbidity, and complexity of need. This is leading to the widespread realization that change is needed to ensure that health care throughout the world meets the emerging needs of humankind. Currently, 97% of health budgets are spent on treatment, while only 3% are invested in prevention. Targeted initiatives that redistribute a higher proportion of national health policy budgets to the prevention of disease offer opportunities for nurses to address gaps in service provision. Nursing Now is a campaign focused on raising the status and profile of nursing globally while maximizing the contribution that nurses make to the health and well-being of individuals and communities. Nursing Now is a 3-year campaign, launched in 2018. The campaign has a very clear strategic goal to position nursing to optimize the profession's potential to fully contribute and make a real difference to the health of the global population. PMID- 30516702 TI - The Role of Nurses in Advancing the Objectives of the Global Compacts for Migration and on Refugees. AB - Nurses and other health care professionals are in a unique position to shift the paradigm around migration debates. As caregivers and advocates for patients and other providers, nurses are crucial to the health and well-being of individuals, families, and communities. This is especially true for migrants, including increasingly vulnerable refugee populations around the world. As negotiations surrounding the Global Compact for Migration and Global Compact on Refugees come to a close, nurses' roles are becoming more apparent. Nurses are facilitators of migration and can help ensure that the benefits of migration are maximized and the challenges are mitigated. Often, nurses are migrants themselves. Leveraging nurses' knowledge, experience, talents, and compassion is crucial for attaining the objectives of both the Global Compact for Migration and the Global Compact on Refugees. Nurses are large contributors to the United Nations' 2030 Agenda for Sustainable Development and its 17 Sustainable Development Goals. The global nursing workforce has enormous potential to advance the achievement of these goals and objectives. In a world that appears to be increasingly xenophobic and hostile to migrants, nurses stand out as professionals who can change the narrative while providing compassionate care for the most vulnerable. PMID- 30516703 TI - Nursing Leadership in Guam. AB - Guam, an unincorporated territory of the United States, is one of the ten (10) US Affiliated Pacific Islands. The geographic location in the western Pacific Ocean, as well as the ties to the US position Guam as a strategic hub between the continental US, Asia, and the Pacific region. Health disparities in Guam and the Micronesian region are significant, and the non-communicable disease crisis is worsening, threatening the existing poor health infrastructure on the islands. Migration of islanders from the Micronesian region, whose countries also suffer health disparities, adds to the burden of the weak health care system on Guam. A critical nursing workforce shortage plagues the health care community, and strong nursing leadership is needed to address the problems. Nurse leaders, through many organizations, are working to implement strategies to address the issues facing the islands. Increased collaboration with partners on the island, on the US mainland, and globally, are necessary to effectively address Guam's health care concerns. PMID- 30516704 TI - Current Data of Foreign-Educated Nurses in Italy and the Recognition of Their Professional Qualifications. AB - Up-to-date data on foreign-educated nurses (FENs) in Italy and the recognition of their professional qualifications are pivotal to boost international discussion, and to improve the engagement and involvement of multistakeholders in the nursing profession. Currently, FENs in Italy represent roughly 6% of the total number of registered nurses. FENs are predominantly females between 35 and 54 years old. This article discusses FENs' paths to achieve their professional qualification to practice in Italy. It also offers insights for regulators and stakeholders, such as the need to enlarge the scope of practice for nurses. PMID- 30516705 TI - Connecting Communities: The Development of an International Partnership. AB - Addressing health inequities and the social determinants of health for all people of the world is a primary goal of the World Health Organization. This article describes how a "Connecting Communities educational program" enabled nurse leaders from academic institutions from different sides of the globe to develop a reciprocal relationship of mutual interest around the topics of the nursing role in population health and care delivery. Grant funding resulted in the sharing of knowledge, expertise, and experiences directed toward encouraging the development of nurses as global citizens, with a broader view on what influences health and well-being. This initiative demonstrates how nurses can contribute to the improvement of world health and address the social determinants of health while practicing locally but thinking and contributing globally. PMID- 30516706 TI - The CNO US Healthcare Immersion Program, Part 1: A Transformational Leadership Model. AB - As a result of recent global health events, US health care leaders are strengthening international relationships to share best practices, health research, and support of workforce capacity. The Institute for Healthcare Improvement, the National Academies of Sciences, Engineering, and Medicine, the American Nurses Credentialing Center, and the Joint Commission International have all committed to expanding their vision and mission to improve health and health care globally. To support excellence in international health care delivery, the authors embarked on a Chief Nursing Officer (CNO) US Healthcare Immersion Program. The purpose of the program is to introduce the US nursing leadership competences to China CNO colleagues in preparation for their future role with health care reform. PMID- 30516707 TI - The CNO US Healthcare Immersion Program, Part 2: Expanding the Footprint of Professional Nursing. AB - As global leaders, US nurses will have an increasingly recognized role and responsibility in shaping health care in all countries. They should be at the forefront of changing and improving health systems to achieve universal health. Currently, a major health care reform is underway that requires a shift in the professional nursing footprint of China's nurse leaders. These leaders must garner knowledge capital to reinforce ethics, regulations, and standards; use current best practices; implement a comprehensive performance evaluation process; and capture the spirit of caring within their health care environments. Therefore, China is seeking US immersion opportunities for their emerging nurse leaders. Although US Immersion Programs exist, there is scant literature related to international precepting and how transformational learning occurs within this experience. This article introduces a transformational learning experience between US International Nurse Preceptors and a Chief Nursing Officer from Yinchuan, China. PMID- 30516708 TI - Beyond a Single Country's Borders: Trade in Services Uncovered Through Bibliometrics. AB - We live and work in an increasingly connected global environment where actions in one part of the world can have consequences for all of us. This article examines, through the use of bibliometric analysis, the extent to which nursing scholars are engaged in the policy debate surrounding trade in services. Results demonstrate that, in comparison to medical colleagues, the nursing profession is more regionally orientated, focused on more operational-based themes and orientated to Mode 4: Mobility of the Profession. However, with the impetus of initiatives such as Nursing Now, opportunities exist to increase nurses' contribution to policy in today's ever more connected supranational environment. To be effective, and if quantum rather than incremental progress is to be made, more scholarship on policy-oriented topics is needed. An increased output of PhD prepared nurses is essential. Collaborative working in multidisciplinary policy teams must become the norm, so nurses can demonstrate their unique and essential contribution to addressing the many and complex challenges that health systems now face. This is what is required if nurses are to be equipped to make robust evidence-based arguments at national and supranational levels. PMID- 30516709 TI - A Concept Analysis of Organizational Health and Communication. AB - Concepts of communication and organizational health were analyzed using the parameters set forth by Walker and Avant, including conceptual selection; clarification; synthesis; attribute exploration and identification; and review of corresponding events. Concept synthesis was initiated through exploration of medical and social science journals, and current literature regarding communication and organizational health was scrutinized to aid conceptual clarification. Concept analysis was informed by using the search engines CINAHL, PubMed, and PsycINFO, with inclusion criteria of "hospital," "communication," and "organizational health." Reenvisioning communication through the lens of organizational health will illuminate issues of false centrality, thus leading to improved interdisciplinary communication in hospitals. PMID- 30516710 TI - Follow the Leader: Changing the Game of Hierarchy in Health Care. AB - Almost every formal organization has a multilayered hierarchy. The role of the leader has been discussed in the literature for decades. Less well understood, and certainly less well documented, is the role of the follower. Followers make up the majority of any organization but have been overlooked as a worthy component of the team. The first step in breaking this mold is identifying the types of followership that are present within the nursing profession. A population of nurses with 4 or fewer years of experience in a designated hospital setting in Southwest Texas. A descriptive study, using a 20-question, 7-point (0 6) Likert-type, validated questionnaire, was changed to an electronic format in Qualtrics and used to survey the identified nursing population. Data collected within Qualtrics XM were exported into Excel and then into SPSS 20 IBM version that was then used to create a scatterplot. The 2 axes represented the independent thinking and the active engagement of the participants. Correlations between demographics and followership styles were also conducted, using a chi square automatic interaction detector (CHAID) analysis. Using Robert E. Kelley's scatterplot to analyze the data, 3 different types of followers were identified within the respondents. The 3 types were exemplary followers, conformist followers, and pragmatist followers. Of the qualified participants who completed the questionnaire, the majority fell into the exemplary follower category. The results identified that an issue with active engagement exists among all of the participants. PMID- 30516711 TI - From Brainstorming to Strategic Plan: The Framework for the Society for the Advancement of Disaster Nursing: A Work in Progress. AB - Professional health care societies play a critical role in promoting excellence in patient care, educating and certifying their members on evidence-based practices, and pursuing relevant research agendas to advance the science in the field. Disaster nursing is a subspecialty of professional nursing characterized by a unique knowledge base and set of skills and abilities not used in normal daily health care activities. A disaster or large-scale public health emergency creates a sudden, unanticipated surge of patients with health care needs that far exceeds the capacity of the health care system. This creates a significant burden and risk for the nurses participating in the response. Recognizing the critical need to define scope of practice and core standards for disaster nursing and to promote greater nursing leadership in disaster preparedness and response, a group of subject matter experts established a professional society to provide leadership and guidance. The strategic planning process as described by M. Kwestel et al was used as the overarching framework for describing the design, development, and implementation of the new society. Establishment of the Society for the Advancement of Disaster Nursing is a definitive step toward improving national nurse readiness in the United States. PMID- 30516712 TI - Early life exposure to famine and reproductive aging among Chinese women. AB - OBJECTIVE: To assess the effect of early life exposure to famine, as endured during 1959 to 1961 in China, on reproductive aging in adult women. METHODS: Between 2011 and 2012, 2,868 women born around the Chinese famine period (1956 1964) were enrolled in this study from three communities in China. Age at natural menopause was obtained retrospectively from a structured questionnaire. The associations of early life famine exposure with reproductive aging during adulthood were estimated, with adjustment of socioeconomic status, lifestyle factors, and body mass index. RESULTS: Women exposed to prenatal famine had a higher risk of early menopause (ie, natural menopause <45 years, odds ratio: 1.59, 95% confidence interval [CI]: 1.07, 2.36), and a nonsignificant trend of higher risk of premature ovarian failure (ie, natural menopause <40 y, odds ratio: 1.94, 95% CI: 0.93, 4.00), compared to unexposed women. Exposure to famine during childhood was not significantly associated with reproductive aging. In a secondary analysis focusing on the fetal exposure, prenatal famine exposure was associated with a higher risk of premature ovarian failure (odds ratio: 2.07, 95% CI: 1.08, 3.87), and a nonsignificant trend of higher risk of early menopause (odds ratio: 1.37, 95% CI: 0.98, 1.91), compared to those unexposed to prenatal famine. CONCLUSIONS: Our study showed that fetal exposure to famine was associated with an increased risk of early menopause. Such findings provided evidence in favor of the thrifty phenotype theory in reproductive aging and helped better understand the etiology of early menopause. PMID- 30516713 TI - Evaluation of clinical meaningfulness of estrogen plus progesterone oral capsule (TX-001HR) on moderate to severe vasomotor symptoms. AB - OBJECTIVE: The aim of this study was to determine the clinical meaningfulness of TX-001HR in reducing moderate to severe vasomotor symptoms (VMS) in menopausal women with a uterus. METHODS: In the REPLENISH study (NCT01942668), women with moderate to severe hot flushes (>=7/d or >=50/wk) were enrolled in a VMS substudy and randomized to four doses of daily TX-001HR (17beta-estradiol/progesterone) or placebo. Participants assessed improvement of their VMS by the Clinical Global Impression and the Menopause-Specific Quality of Life (MENQOL) questionnaire, which were used to define clinical responders, clinically important differences (CIDs) or minimal CID (MCID) in VMS frequency. Response thresholds were determined by nonparametric discriminant analyses utilizing bootstrapping methods. RESULTS: In the modified intent-to-treat VMS substudy population (n = 726), statistically significantly more Clinical Global Impression-based clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of >=25 moderate to severe VMS: 82-88% vs 69%; all, P < 0.05) and CID (weekly reduction of >=39 VMS: 68%-73% vs 52%; all, P < 0.05) at week 12. Week 4 results were similar. For Menopause Quality of Life-based analysis, significantly more clinical responders were observed with TX-001HR than placebo for MCID (weekly reduction of >=34 VMS: 74%-81% vs 55%; all, P < 0.01) and CID (weekly reduction of >=44 VMS: 61%-69% vs 42%; all, P < 0.01) at week 12. CONCLUSIONS: TX-001HR provided clinically meaningful improvements (as measured by 2 different methods), in addition to statistically significant reductions, in menopausal VMS frequency. TX-001HR may provide a new option, as a single oral capsule of estradiol and progesterone (identical to the hormones naturally occurring in women) for the treatment of moderate to severe VMS in menopausal women with a uterus.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 30516714 TI - Toward a personalized lifestyle intervention approach to prevent Alzheimer's disease. PMID- 30516715 TI - The relationship between serum fibroblast growth factor 23, Klotho, and lumbar spine bone mineral density in northern Chinese postmenopausal women. AB - OBJECTIVES: Changes in serum protein levels of fibroblast growth factor 23 (FGF23) and Klotho resulting from bone metabolism are still controversial. The purpose of this study was to observe the relationship between FGF23 and Klotho serum proteins and lumbar spine bone mineral density (LBMD) in northern Chinese postmenopausal women. METHODS: This was a community-based cross-sectional study carried out in Shenyang, a northern Chinese city. The study included 355 postmenopausal women with an average age of 62.92 +/- 8.78 years. FGF23 and Klotho serum proteins were measured using a sandwich enzyme immunoassay. LBMD was examined using dual-energy X-ray absorptiometry. Pearson's correlation and regression analyses were performed to investigate the associations among them. RESULTS: The LgKlotho was positively correlated with LBMD (r = 0.105). There was a linear relationship between LgKlotho serum levels and LBMD (P = 0.007) after adjusting for BMI, and the relationship still existed after adjustments for many confounding variables (P = 0.045), including age, BMI, systolic blood pressure, diastolic blood pressure, total protein, total bilirubin, high-density lipoprotein cholesterol, fasting blood glucose, serum calcium, estimated glomerular filtration rate, serum uric acid, estradiol, cigarette smoking, alcohol consumption, milk intake, calcium and vitamin D supplements, physical exercise, and fracture history in postmenopausal women. FGF23 serum levels were, however, not significantly associated with LBMD. CONCLUSIONS: Klotho was positively correlated with LBMD, and there was a linear relationship between Klotho serum protein levels and LBMD; however, the levels of serum Klotho were not independently associated with reduced LBMD in northern Chinese postmenopausal women. Moreover, serum FGF23 levels were not significantly related to LBMD in this sample population. PMID- 30516716 TI - Metal Hypersensitivity in Total Joint Arthroplasty. PMID- 30516717 TI - Commonly Missed Injuries in the Patient with Polytrauma and the Orthopaedist's Role in the Tertiary Survey. PMID- 30516718 TI - Comparison of the Effects of Epidural Analgesia and Patient-controlled Intravenous Analgesia on Postoperative Pain Relief and Recovery After Laparoscopic Gastrectomy for Gastric Cancer. AB - PURPOSE: Epidural analgesia (EDA) is an imperative modality for postoperative pain relief after major open abdominal surgery. However, whether EDA has benefits in laparoscopic surgery has not been clear. In this study, the effects of EDA and patient-controlled intravenous analgesia (PCIA) after laparoscopic distal gastrectomy (LDG) were compared. METHODS: This was a retrospective study that included 82 patients undergoing LDG for gastric cancer. Patients received either EDA (n=67) or PCIA (n=15) for postoperative pain relief. Postoperative outcomes and analgesia-related adverse events were compared between the two modalities. RESULTS: EDA and PCIA patients showed no differences in the incidence of complications [9 (13%) vs. 2 (13%); P=0.99] and the length of postoperative hospital stay (9.6+/-4.5 d vs. 9.7+/-4.0 d; P=0.90), although the PCIA included poorer preoperative physical status (PS) patients. The number of additional doses of analgesics was higher in the EDA than in the PCIA (1.8+/-2.4 vs. 0.9+/-1.0; P=0.01), although postoperative pain scores were similar in the 2 groups. Though the time to first passage of flatus was shorter in the EDA (P<0.05), more EDA patients developed postoperative hypotension as an adverse event (P<0.01). The full mobilization day and the day of oral intake tolerance were not significantly different between the 2 groups after surgery. CONCLUSIONS: After LDG, EDA may not be indispensable, while PCIA may be the optimal modality for providing safe and effective postoperative analgesia and recovery. PMID- 30516719 TI - Prospective Comparison of Bleeding Complications Between Right and Left Approaches in Percutaneous Biliary Drainage. AB - PURPOSE: The present study aimed to determine whether the percentage of bleeding complications differs between the right and the left approaches in percutaneous biliary drainage (PBD) in adult patients. MATERIALS AND METHODS: This was a prospective, descriptive, nonrandomized comparative and longitudinal study. We included adult patients over 18 years of age who underwent a PBD. We excluded those with a bilateral PBD for the comparative study. Usually, but not exclusively, we performed the right approach under fluoroscopic guidance and the left one under ultrasound and fluoroscopy. RESULTS: Of 150 cases, 63 were performed using the right approach and 61 with the left; 26 were performed with the bilateral. The right approach faced less dilated biliary ducts and more benign diseases. We experienced 20 bleeding complications (13.33%, confidence intervals of 95%=8.3-19.8), 7 in the bilateral approach, 10 in the right approach, and 3 in the left one. The difference between the right and the left approaches was statistically significant (Fisher P=0,04). No procedures were required to obtain hemostasis, and only one patient (0.66%, confidence intervals of 95%=0.009-3.66) (in the right side) required a red blood cell transfusion. We found no related mortality. CONCLUSIONS: Global bleeding complications are more likely to appear in the right approach in which less dilated biliary ducts and more benign diseases probably contributed to a higher number of needle passes, portal and hepatic vein punctures, and, therefore, to an increase in the risk of bleeding complications. The significant bleeding complication rate was low (0.66%). PMID- 30516720 TI - Clinical Outcomes of Elective Laparoscopic Cholecystectomy: Retrospective Comparative Study Between Patients With and Without Xanthogranulomatous Cholecystitis. AB - AIM: The aim of this study was to evaluate the results of laparoscopic cholecystectomy (LC) in patients with xanthogranulomatous cholecystitis (XGC) compared with patients without XGC. METHODS: A retrospective study was performed including patients who had undergone elective LC between January 2003 and November 2017. Results of patients with XGC (25) were compared with those of patients without XGC (2181) with respect to operative time, conversion rate, drain use, postoperative complications, and postoperative stay. RESULTS: The mean operative times in patients with and without XGC were 112.8 and 66.3 minutes, respectively (P=0.001). The conversion rate was 36% in patients with XGC and 3.89% in patients without XGC (P=0.001). Drains were used in 76% of patients with XGC and in 24% of patients without XGC (P=0.001). Postoperative complication rate was 16% and 9.9% in patients with and without XGC, respectively (P=0.309). Mean postoperative stays in patients with and without XGC were 4.3 and 2.3 days, respectively (P=0.001). CONCLUSIONS: LC in patients with XGC is associated with significantly longer operative time, higher conversion rate, greater drain use, and longer postoperative stay compared with patients without XGC. PMID- 30516721 TI - Symptomatic, Radiological, and Quality of Life Outcome of Paraesophageal Hernia Repair With Urinary Bladder Extracellular Surgical Matrix: Comparison With Primary Repair. AB - INTRODUCTION: Paraesophageal hernia repairs are prone to recurrence and mesh reinforcement is common. Both biologic and prosthetic meshes have been used. We report a comparison of a new type of biologically derived graft, Gentrix Surgical Urinary Bladder Matrix (UBM). METHODS: The medical records of 65 patients who underwent paraesophageal hernia repair (PEHR) were reviewed. Primary data points included demographics, first-time or recurrent hernia, operative approach, graft or primary repair, operative time, and postoperative complications. Patients then underwent upper gastrointestinal series, completed the GERD-HRQL symptom severity questionnaire, and the SF-36 generic quality of life instrument. RESULTS: A total of 32 patients underwent graft-reinforced repair, 33 underwent primary repair. More patients in the UBM group were being treated for recurrent PEH. Demographic data and postoperative complications were similar. There was no difference in recurrence rates, size of recurrence, postoperative symptomatic or quality of life improvement. Patients who suffered recurrence in the primary repair group had more severe symptoms and a higher rate of dissatisfaction. Of the 3 patients with recurrences after Gentrix placement, reoperation demonstrated anterior failure where no reinforcement had occurred because of the posteriorly placed U shaped graft. CONCLUSIONS: The use of UBM was not associated with an increased complications despite use in more difficult patients. Although there appeared to be no difference in recurrence rate or size, it was associated with less severe symptomatic recurrences. The U-shape configuration is prone to recurrence at the site of the repair not covered by the graft, suggesting that a keyhole configuration may be superior. PMID- 30516722 TI - Assessing uncertainty in an anatomical site-specific gonococcal infection transmission model of men who have sex with men. AB - BACKGROUND: Increased gonorrhea detection highlights the need for additional prevention efforts. Gonorrhea may only be acquired when there is contact between infected and uninfected anatomical sites. With three sites of infection this leads to seven plausible routes of MSM transmission: urethra-to-rectum, rectum-to urethra, urethra-to-oropharynx, rectum-to-oropharynx, oropharynx-to-urethra, oropharynx-to-rectum, and oropharynx-to-oropharynx. We characterize the uncertainty and potential importance of transmission from each anatomical site using a deterministic compartmental mathematical model. METHODS: We developed a model of site-specific gonococcal infection, where individuals are infected at zero, one, two, or all three sites. Sexual behavior and infection duration parameters were fixed similar to a recent model analysis of Australian MSM. Markov Chain Monte Carlo methods were used to sample the posterior distribution of transmission probabilities that were consistent with site-specific prevalence in American MSM populations under specific scenarios. Scenarios were defined by whether transmission routes may or may not transmit by constraining specific transmission probabilities to zero rather than fitting them. RESULTS: Transmission contributions from each site have greater uncertainty when more routes may transmit; in the most extreme case, when all routes may transmit, the oropharynx can contribute 0-100% of all transmissions. In contrast, when only anal or oral sex may transmit, transmission from the oropharynx can account for only 0-25% of transmission. Intervention effectiveness against transmission from each site also has greater uncertainty when more routes may transmit. CONCLUSION: Even under ideal conditions (i.e., when site-specific gonococcal prevalence, relative rates of specific sex acts, and duration of infection at each anatomical site are known and do not vary), the relative importance of different anatomical sites for gonococcal infection transmission cannot be inferred with precision. Additional data informing per act transmissibility are needed to understand site specific gonococcal infection transmission. This understanding is essential for predicting population-specific intervention effectiveness. PMID- 30516723 TI - Rapidly spreading HIV epidemic among older males and associated factors: a large scale prospective cohort study in rural southwest China. AB - BACKGROUND: Increasing risk of HIV heterosexual transmission can raise the potential for a more diffuse and generalized epidemic. In response to the paucity of data on HIV incidence among heterosexuals in China, we conducted a large scale, population-based cohort study located in rural southwest China. METHODS: Baseline enrollment for the study was conducted from 2013 to 2014 and follow-up at 12-months was from 2014 to 2015 among adults > 20 years old in three rural counties of Southwest China. Study participants were informed of the study by brochures and leaflets distributed in outreach activities. Interviews and blood collection were conducted in private rooms. Blood samples were tested for HIV infection. RESULTS: The HIV prevalence of the sample was 0.29% (95% CI: 0.27 0.30) (2063/722,795) among the total adult population of 1,090,296 potential participants aged >=20 years at baseline. Of the 720,732 individuals who tested HIV-negative at baseline, 493,990 completed the follow-up (69%). Overall HIV incidence was 2.73 (95% CI: 2.38-3.08) per 10000 person-years (235/860,627 PY). HIV incidence was associated with males, older age, less than secondary schooling and not currently being married. HIV incidence was 71.28 (95% CI: 35.21-107.35) per 10000 person-years among males aged 50-69 years who had less than secondary schooling and were divorced or widowed. Heterosexual sex was the dominant transmission mode for HIV seroconversions (99.0%). CONCLUSIONS: Older heterosexual males were at disproportionate risk of HIV infection. Health authorities in China need to develop and implement innovative interventions suitable for the broader population of older heterosexuals. PMID- 30516724 TI - A Case of Asymptomatic Syphilitic Proctitis. AB - The incidence of syphilis is increasing. Syphilitic proctitis involving the rectal mucosa often presents with pain on defecation, rectal bleeding, or ulceration. We present a case of asymptomatic syphilitic proctitis diagnosed upon a routine screening colonoscopy. PMID- 30516725 TI - Characteristics associated with HIV transmission networks involving adolescent girls and young women in HIV Prevention Trials Network (HPTN) 068 study. AB - We combined behavioral survey data from the HIV Prevention Trials Network 068 study with phylogenetic information to determine if cluster membership was associated with characteristics of young women and their partners. Clusters were more likely to involve young women from specific villages and schools, indicating some localized transmission. PMID- 30516726 TI - Increased Ascertainment of Transgender and Non-Binary Patients using a Two-Step versus One-Step Gender Identity Intake Question in a STD Clinic Setting. AB - BACKGROUND: Transgender inclusive and gender affirmative healthcare includes asking patients about gender identity and sex assigned at birth through what is known as the 'two-step' methodology. In May 2016, the STD clinic in Seattle, WA switched from using a one-step to a two-step gender identity question. We aimed to determine if the updated questions increased ascertainment of transgender and gender nonconforming (TGNC) patients, and used the improved gender identity data to describe the HIV/STD risk profile of TGNC patients. METHODS: We conducted a pre-post analysis comparing the proportion of patients that identified as TGNC during the year prior to and following implementation of the two-step questions. Gender identity and medical history questions were ascertained using a computer assisted self-interview. The two-step question included two new gender response options: non-binary/genderqueer and write-in. RESULTS: Institution of the two step question resulted in a 4.8-fold increase in patients who were identified as TGNC: 36 of 6,635 (0.5%) to 172 of 7,025 (2.4%) of patients (p<0.001). After implementation, 89 patients identified as non-binary/genderqueer (51.7% of TGNC patients). The proportion of patients identified as transgender men and women increased from 0.2% to 0.5% (p=0.002) and 0.4% to 0.6% (p=0.096), respectively. Non-binary patients' HIV/STI risk profile was distinct from that of transgender and cisgender men who have sex with men (MSM), suggesting that distinguishing sub populations within the TGNC population is important for risk stratification. CONCLUSIONS: Using a two-step gender identity question and including non binary/genderqueer options increased our clinic's ascertainment of TGNC patients and more accurately captured gender identity among STD clinic patients. PMID- 30516727 TI - Integrating HIV testing into syphilis partner services in Mississippi to improve HIV case finding. AB - BACKGROUND: Mississippi (MS) has the 10th highest rate of new HIV infections in the United States. The Mississippi State Department of Health (MSDH) integrated partner HIV testing into syphilis partner services (PS) in 2014, but the effectiveness of this as an HIV case-finding strategy has not been evaluated. METHODS: We identified all early syphilis (primary, secondary, and early latent) case records reported from 7/1/2014-12/31/2016, excluding case records for people concurrently newly diagnosed with HIV. Among sex partners of these people, we identified new diagnoses of early syphilis and HIV. We calculated the number needed to interview (NNTI) as the number of syphilis index case-patients interviewed divided by the number of partners newly diagnosed with early syphilis or HIV. RESULTS: A total of 1535 of the 1619 early syphilis index case-patients (95%) were interviewed for PS. These case-patients named 2267 partners, of whom 1868 (82%) were contacted by MSDH. Among partners, 1508 (81%) tested for syphilis and 745/1321 (56%) partners not previously diagnosed with HIV were tested for HIV. PS identified 696 new early syphilis case-patients (46%) and 24 new HIV case patients (3.2%) among partners. Sixty-four index case-patient interviews were needed to identify one new case of HIV, and two interviews were needed to identify one new case of syphilis among partners. CONCLUSION: Syphilis PS allowed MSDH to interact with 1592 MSM over a 30-month period and was effective for identifying people newly infected with early syphilis and HIV. Increasing HIV testing among partners of syphilis case-patients could increase HIV case finding in MS. PMID- 30516728 TI - Treponema pallidum subsp. pallidum DNA and RNA in semen of a syphilis patient without genital or anal lesions. Possible implications for disease transmissibility. AB - Treponema pallidum subsp. pallidum DNA and RNA were detected in a semen specimen of a syphilis patient with no genital or anal sores and no clinically evident orchitis. No nucleic acids were found in a urine sample of the same patient collected immediately before the semen sample. Exposure to the syphilis agent through semen could account for transmission episodes in the absence of direct contact with a syphilitic sore. PMID- 30516729 TI - Detailed Fetal Anatomic Ultrasound Examination: Effect of the 2014 Consensus Report on a Tertiary Referral Center. AB - This study evaluates the impact of extended cardiac views on examination time, repeat imaging, and anomaly detection before and after implementation of 76811 guidelines (American Institute of Ultrasound in Medicine Consensus 2014). It is a retrospective study of singleton pregnancies undergoing detailed ultrasound imaging at 18 weeks' gestation or greater before and after the protocol change in an academic, tertiary care fetal center. Views required prior to 2014: 4-chamber, left outflow tract, right outflow tract. Additional views required after 2014: bicaval, aortic arch, 3-vessel, and 3-vessel trachea. Fetuses with known anomalies were excluded. Rates of detection of congenital heart disease (CHD), examination completion, repeat examination recommendation, fetal echocardiogram recommendation, completion by body mass index, and cardiac examination time were determined. Six hundred twenty-four subjects were included, 217 before and 407 after protocol change. Views obtained were as stated in the American Institute of Ultrasound in Medicine/Society for Maternal-Fetal Medicine consensus. Detection of CHD was not improved. Examination times increased by 20% (6.4 vs 7.7 minutes, P < 0.05). Number of incomplete studies increased by 130% (11% to 26%, P < 0.05). Twice as many patients were referred for repeat examination (6% vs 13%, P < 0.05). Completion rates were negatively correlated with body mass index. Recommendations for fetal echocardiogram were unchanged (5% vs 6%, P = 0.6). Additional imaging did not increase detection rate of CHD (3% vs 2%, P = 0.3). Extended cardiac views resulted in increased examination time, more incomplete examinations, and more repeat examinations without changing detection rates of CHD. PMID- 30516730 TI - Can Presurgical Ultrasound Predict Survival in Women With Ovarian Masses? AB - PURPOSE: This study aimed to determine the ability of ultrasound to predict survival and detect more aggressive tumors in women with ovarian masses. MATERIALS AND METHODS: Institutional review board approval was obtained. A total of 167 patients who presented with adnexal mass/masses were included. These were documented as benign or malignant on ultrasound. Age, date of diagnosis and date of death, type of tumor, and tumor marker cancer antigen 125 (CA-125) values were recorded. A CA-125 value of less than 35 U/mL was considered normal. All cases underwent surgery. Pathologic findings were considered as reference standard. The 2 * 2 cross-tabulations were used to correlate dichotomized CA-125, US diagnosis (benign vs malignant), and pathologic status. Difference of distributions was tested using the Wilcoxon rank sum test, and their association was tested using the Fisher exact test. All tests were 2-sided, and P values of 0.05 or less were considered statistically significant. Kaplan-Meir curves were generated to estimate survival. RESULTS: There was a statistically significant difference in patients with benign versus malignant tumors based on pathology (P < 0.0001) and ultrasound (P < 0.0003). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ultrasound were 55%, 86%, 90% and 46%, and 81%. Patients diagnosed as having malignant tumors based on ultrasound had statistically significant worse overall survival. Probability of survival based on pathologic diagnosis of malignancy was statistically significant at P < 0.0003; based on ultrasound, P < 0.0001; and based on CA-125, P < 0.041. CONCLUSION: Patients who had ultrasound-based prediction of ovarian malignancy had overall worse survival probability (P < 0.0001) compared with CA-125- or pathology-based prediction. PMID- 30516731 TI - A Clinical Study Comparing the Diagnostic Performance of Assist Strain Ratio Against Manual Strain Ratio in Ultrasound Breast Elastography. AB - OBJECTIVE: Strain ratio (SR) is a semiquantitative parameter in differentiating benign from malignant tumors in breast ultrasound elastography. Currently, SR is computed manually and, thus, user dependent. The objective of this study was to evaluate the performance of a new tool assist strain ratio (ASR) and determine how it performs compared with an expert sonologist. METHODS: Ninety-one patients scheduled for breast biopsy were included in this institutional review board approved/Health Insurance Portability and Accountability Act-compliant study. For manual strain ratio (MSR), fat and lesion were manually outlined, whereas for ASR, the clinician indicated the lesion center and the fat-to-lesion ratio is computed automatically. Three measurements were obtained for each lesion. The same raw data were used to calculate the MSR and ASR. RESULTS: The SR thresholds to differentiate benign from malignant tumors were determined using the Youden index. For MSR, the cutoff was 2.7, and for ASR was 2.8. The MSR showed a sensitivity of 88%, specificity of 64%, accuracy of 77%, positive predictive value of 72%, and negative predictive value of 92.1%. Corresponding ASR showed a sensitivity of 86%, specificity of 76%, accuracy of 81%, positive predictive value of 79%, and negative predictive value of 84%. The areas under the curve for the MSR and ASR were 0.83 and 0.85, respectively. The average coefficients of variation for the MSR and ASR measurements were 43% and 30%, respectively. CONCLUSION: Assist strain ratio demonstrated similar diagnostic performance compared with MSR. In addition, the coefficient of variation of ASR is lower, implying lower intraoperator dependency. Thus, ASR may aid less-experienced scanners in obtaining improved results. PMID- 30516732 TI - A Pictorial Review of Sonography of Intramammary Lymph Nodes: When to Care and What to Do About It. AB - This pictorial essay reviews and illustrates benign and malignant features of intramammary lymph nodes on mammography, ultrasound, and magnetic resonance imaging, including a review of the clinical and the prognostic significance in patients with known breast cancer. This pictorial essay discusses management suggestions for intramammary lymph nodes in patients with breast cancer. PMID- 30516733 TI - Ultrasound Imaging of the Brachial Plexus and Nerves About the Neck. AB - This review describes techniques for sonographic evaluation of the brachial plexus and multiple regional nerve branches in the neck, essential for successful implementation of neurosonology in the neck. High-frequency ultrasound transducers have the ability to produce superior, high-resolution images, allowing for superb depiction of nerve fascicular anatomy. Sonographic appearances of normal nerve anatomy and nerve-specific pathology are reviewed. Benefits and limitations of ultrasound nerve imaging compared with magnetic resonance imaging are discussed. PMID- 30516735 TI - Comments on "Microanatomy of sensory nerves in the upper eyelid: A cadaveric anatomical study". PMID- 30516734 TI - The Application of Ultrasound and Fine-Needle Aspiration in Low-Volume Lateral Lymph Nodes of Papillary Thyroid Carcinoma Patients. AB - This research investigates the application of high-frequency ultrasound (US) examination and US-guided fine-needle aspiration (US-FNA) in diagnosing low volume metastatic lateral lymph nodes (LLNs) from papillary thyroid carcinoma patients. This study reviewed the medical records of 996 LLNs from 858 patients with suspicious thyroid nodules or after thyroidectomy from January 2013 to January 2016. All patients took US-FNA. The US characteristics and the malignancy rate of LLNs classified into group A and group B based on size were analyzed and compared (group A, >=6 mm; group B, <6 mm). Size was not an independent predictor for malignancy (P > 0.005) in multiple regression analysis, whereas the malignancy rate in the large LLNs (286/425; 67.3%) was slightly higher than that in the small LLNs (338/571; 59.2%) (P = 0.01). However, no significant difference was observed between the groups in terms of calcification, absence of hilum, and peripheral vascularization. The prevalence of malignant LLNs was slightly higher in the small LLNs than that in the large ones when there were less than 3 suspicious US features (P < 0.05), and there was no significant difference between the small and large LLNs when there were 3 or more suspicious US features (P > 0.05). The results indicate that metastases may occur in the lymph nodes even when they were small. Ultrasound and US-FNA showed excellent performance in the diagnosis of low-volume metastatic lateral lymph nodes from papillary thyroid carcinoma patients. PMID- 30516736 TI - PRS Video Plus: Response: Refinements in Upper Blepharoplasty: The Five-Step Technique. PMID- 30516737 TI - Refinements in Upper Blepharoplasty: The Five-Step Technique. PMID- 30516738 TI - A response to letter PRS-D-18-01390 by Professor Kun Hwang, Comments on "Microanatomy of sensory nerves in the upper eyelid: A cadaveric anatomical study." PMID- 30516740 TI - Arterial Vascularization of the Mandibular Condyle. PMID- 30516739 TI - "Evaluation of Acellular Dermal Matrix Efficacy in Prosthesis-Based Breast Reconstruction." PMID- 30516741 TI - Suggested Refinements in Reply to "A New Composite Eyeball-Periorbital Transplantation Model in Humans: An Anatomical Study in Preparation for Eyeball Transplantation". PMID- 30516742 TI - Comments on "Arterial Vascularization of the Mandibular Condyle and Fractures of the Condyle". PMID- 30516743 TI - Reply: "High-pressure Injection of Heparinized Saline for Reversing Refractory Intraoperative Phenylephrine-induced Venous Vasospasm". PMID- 30516745 TI - "Letter to the Editor: Fournier Gangrene: Association of Mortality with the Complete Blood Count Parameters." PMID- 30516744 TI - Changing the Dialogue on Plastic Surgery: A Visual Representation of the Twitterverse. PMID- 30516746 TI - Changing the Dialogue of Plastic Surgery: A Visual Representation of the Twitterverse. PMID- 30516747 TI - High-pressure Injection of Heparinized Saline for Reversing Refractory Intraoperative Phenylephrine-induced Venous Vasospasm. PMID- 30516748 TI - The external jugular vein anastomosis under the sternocleidomastoid muscle technique for head and neck reconstruction. PMID- 30516749 TI - Response to Letter to the Editor: "Sentinel lymph node positivity in thin melanomas: the 'vertical route' is traced". PMID- 30516750 TI - Sentinel lymph node positivity in thin melanomas: the "vertical route" is traced. PMID- 30516751 TI - Reply: The external jugular vein anastomosis under the sternocleidomastoid muscle technique for head and neck reconstruction. PMID- 30516752 TI - Letter to the editor: Fournier Gangrene: Association of Mortality with the Complete Blood Count Parameters. PMID- 30516753 TI - Response to comments on "A New Composite Eyeball-Periorbital Transplantation Model in Humans: An Anatomical Study in Preparation for Eyeball Transplantation". PMID- 30516754 TI - Reply: Two-Point Discrimination Predicts Pain Relief after Lower Limb Nerve Decompression for Painful Diabetic Peripheral Neuropathy. PMID- 30516755 TI - Two-Point Discrimination Predicts Pain Relief after Lower Limb Nerve Decompression for Painful Diabetic Peripheral Neuropathy. PMID- 30516756 TI - A Clinical Prediction Algorithm to Stratify Pediatric Musculoskeletal Infection by Severity. AB - OBJECTIVE: There are currently no algorithms for early stratification of pediatric musculoskeletal infection (MSKI) severity that are applicable to all types of tissue involvement. In this study, the authors sought to develop a clinical prediction algorithm that accurately stratifies infection severity based on clinical and laboratory data at presentation to the emergency department. METHODS: An IRB-approved retrospective review was conducted to identify patients aged 0 to 18 who presented to the pediatric emergency department at a tertiary care children's hospital with concern for acute MSKI over a 5-year period (2008 to 2013). Qualifying records were reviewed to obtain clinical and laboratory data and to classify in-hospital outcomes using a 3-tiered severity stratification system. Ordinal regression was used to estimate risk for each outcome. Candidate predictors included age, temperature, respiratory rate, heart rate, C-reactive protein (CRP), and peripheral white blood cell count. We fit fully specified (all predictors) and reduced models (retaining predictors with a P-value <=0.2). Discriminatory power of the models was assessed using the concordance (c)-index. RESULTS: Of the 273 identified children, 191 (70%) met inclusion criteria. Median age was 5.8 years. Outcomes included 47 (25%) children with inflammation only, 41 (21%) with local infection, and 103 (54%) with disseminated infection. Both the full and reduced models accurately demonstrated excellent performance (full model c-index 0.83; 95% confidence interval, 0.79-0.88; reduced model 0.83; 95% confidence interval, 0.78-0.87). Model fit was also similar, indicating preference for the reduced model. Variables in this model included CRP, pulse, temperature, and an interaction term for pulse and temperature. The odds of a more severe outcome increased by 30% for every 10 U increase in CRP. CONCLUSIONS: Clinical and laboratory data obtained in the emergency department may be used to accurately differentiate pediatric MSKI severity. The predictive algorithm in this study stratifies pediatric MSKI severity at presentation irrespective of tissue involvement and anatomic diagnosis. Prospective studies are needed to validate model performance and clinical utility. LEVEL OF EVIDENCE: Level II prognostic study. PMID- 30516757 TI - Knowledge gaps in patients with venous thromboembolism: usefulness of a new questionnaire. AB - INTRODUCTION Little is known about the current awareness of venous thromboembolism (VTE) and knowledge of thromboprophylaxis among patients receiving oral anticoagulation therapy (OAC). OBJECTIVES We sought to develop and evaluate the usefulness of the Jessa AF Knowledge Questionnaire (JAKQ) modified for VTE patients. PATIENTS AND METHODS Consecutive patients at least one month since the VTE event (n=273, mean [SD] age 51 [17] years; 52.7% women; 55.9% unprovoked event) were enrolled at the study. RESULTS The median percentage of correct responses was 64.2% (53 - 73%; minimum 12% and maximum 100%). Younger patients had better knowledge about VTE in general, including a higher proportion of correct responses to the question about the definition of PE (71.4 vs. 57.7%, P=0.03), about possible consequence of DVT, including PE (81.1 vs 62%, P=0.001) and VTE risk related to long travels (78.1 vs 59.2%, P=0.002). There was no difference in overall scoring between NOAC and VKA patients (mean, [SD] 64.1%, [16.3] vs 63.9%, [13.8], respectively, P=0.7). Regardless of the type of anticoagulants, 39.3% of patients knew that VTE is not always symptomatic, 33.6% knew what to do when they missed an OAC dose, and 50% did not know which painkillers are the safest in combination with anticoagulants. Education performed in 27 patients, resulted in an increase in the median percentage of correct responses from 60% to 80 % (P=0.0001). CONCLUSIONS Knowledge on VTE and anticoagulation is suboptimal among patients on VKA and NOACs. Education of VTE patients should be improved especially in older individuals on NOACs. PMID- 30516759 TI - Non-erosive reflux disease is more common in patients with a chronic thyroid disease: preliminary results. PMID- 30516758 TI - Prevention of sudden cardiac death by the implantable cardioverter-defibrillator. AB - Sudden cardiac death (SCD) is a leading cause of death. The advent of the implantable cardioverter-defibrillator (ICD) has revolutionized prevention of SCD in high-risk patients with underlying cardiac diseases. However, several challenges remain. Identification of patients at risk that should receive an ICD is suboptimal; sole criterion applied in clinical practice is a severely reduced left ventricular ejection fraction despite the fact that the majority of SCD cases occur in patients with preserved or mildly reduced ejection fraction. Additionally, the majority of patients that do receive the ICD will at the end not benefit from the device. Therefore, improved risk stratification approaches to guide selection of patients for ICD implantation are definitely needed. There are several novel features and developments in the field with the subcutaneous defibrillator being probably the most important one and having the potential to substantially influence clinical practice. The role of catheter ablation of ventricular tachycardia and particularly the potential to abolish the need for ICD implantation at least in selected patient groups needs to be further defined. Internists and general practitioners play a significant role in the management of ICD patients, from identification of candidates for ICD implantation up to early detection and appropriate treatment of complications. PMID- 30516760 TI - Recurrent goiters: risk factors, patient quality of life, and efficacy of radioiodine therapy. AB - INTRODUCTION Goiter recurrence occurs in a substantial number of patients after thyroid resection. OBJECTIVES We aimed to investigate the prevalence and risk factors of recurrent goiters, influence of goiter recurrence on patient quality of life (QoL) and the efficacy of therapy with radioactive iodine (RAI). PATIENTS AND METHODS This was a case-control study. All thyroidectomized patients admitted within the past year to the outpatient department were included in the study and their medical records were analyzed. Recurrence was defined as nodular lesions within the remnant tissue or enlargement of the remaining thyroid tissue which required therapy (reoperation or radioiodine). Clinical and biochemical data were collected. Randomly selected patients were asked to answer ThyPROpl for health related QoL assessment; 30 healthy subjects were recruited for comparison. RESULTS 481 out of 538 patients were included in the study: 68 patients with a recurrent goiter and 413 without recurrence. Higher TSH at follow-up and lobectomy were the strongest risk factors for goiter recurrence, followed by a longer observation period. Postoperative LT4 therapy was associated with a lower risk of recurrence. Efficacy of RAI was similar to secondary thyroidectomy. Scores in all comparable scales for patients with recurrent goiters were significantly worse than those in the general population. CONCLUSIONS Lobectomies should be avoided as a primary surgical treatment for benign thyroid diseases, and levothyroxine therapy should be individually considered in each patient.Radioiodine therapy seems to be a safe and effective treatment option for recurrent goiters. Recurrent goiters, although successfully treated, have a negative impact on QoL. PMID- 30516761 TI - A novel CCK2/gastrin receptor-localizing radiolabeled peptide probe for personalized diagnosis and therapy of patients with progressive or metastatic medullary thyroid carcinoma - GRAN-T-MTC - a multicenter phase I study. PMID- 30516762 TI - Possible B-C bonding in the hydroboration of benzonitrile by an external electric field. AB - Generally, the hydroboration of benzonitrile produces B-N containing compounds. However, an unprecedented B-C bond may be formed in the presence of a suitable external electric field (EEF). In reactions of benzonitrile with borane, when the EEF is oriented parallel to the positive direction (N -> C) of the N[triple bond, length as m-dash]C bond, the barriers to Markovnikov hydroboration are decreased gradually, meaning the pathway for generating B-C bonds becomes more favorable. Accordingly, hydroboration could be influenced and its selectivity could be controlled by changing the magnitude and direction of an applied EEF. PMID- 30516763 TI - On the sensitization of Eu3+ with Ce3+ and Tb3+ by composite structured Ca2LuHf2Al3O12 garnet phosphors for blue LED excitation. AB - This work deals with the photoluminescence of various composite structured Ca2LuHf2Al3O12 garnet type LED phosphors. It is well known that sensitization of Eu3+ with Ce3+ suffers from metal-to-metal charge transfer (MMCT) quenching. Spatial separation of the sensitizer and activator results in a reduced quenching mechanism and thus higher luminescence intensities, when Ce3+ is excited in the blue spectral range and transfers its energy to Eu3+. The phosphor particles were prepared via different synthesis techniques. The phase purity of the synthesized particles was determined by X-ray powder diffraction. Scanning electron microscopy images were obtained to study the particle morphology and composite formation. Photoluminescence properties were determined by recording the emission spectra, excitation spectra and diffuse reflectance spectra. Furthermore, the temperature dependent emission spectra and fluorescence lifetimes were recorded to compare thermal quenching and decay behavior of the samples. External quantum efficiencies (EQEs) were calculated to examine the MMCT quenching behavior. Since the EQE of Ca2LuHf2Al3O12:Ce3+,Tb3+,Eu3+ is lower than 1%, it could be demonstrated that the composite approach significantly increases the EQE due to the spatial separation of Ce3+ and Eu3+. PMID- 30516764 TI - Simple and accurate isochoric differential scanning calorimetry measurements: phase transitions for pure fluids and mixtures in nanopores. AB - Various types of nanopores are encountered in many different engineering and science applications. Due to incomplete understanding of the phase behavior of fluids in nanosize confined space, the improvement of such applications has been largely based on experience and empirical approaches. Therefore, experimental studies on the phase behavior of confined fluids that are simple but accurate are still urgently needed. We recently developed a new isochoric procedure using a Differential Scanning Calorimeter (DSC) to measure the onset of vapor-liquid phase transitions, which has been successfully used in experiments measuring the vapor pressures of pure substances and the dew points of a bulk mixture in the absence of nanopores [Qiu et al., Phys. Chem. Chem. Phys., 2018, 20, 26241 26248]. It is the purpose of this work to extend the new method to confined fluids. To demonstrate the superior ability of the new method, we measure the capillary condensation of CO2 and the dew points of a binary methane/ethane gas mixture confined in SBA-15 with different pore diameters. PMID- 30516765 TI - Photon catalysis of deuterium iodide photodissociation. AB - A catalyst enhances a reaction pathway without itself being consumed or changed. Recently, there has been growing interest in the concept of "photon catalysis" in which nonresonant photons, which are neither absorbed nor scattered, promote reactions. The driving force behind this effect is the interaction between the strong electric field associated with a pulsed, focused laser and the polarizability of the reacting system. In this study, the effect of near infrared, nonresonant radiation on the photodissociation of deuterium iodide is demonstrated. We use nanosecond pulses rather than time-resolved spectroscopy to investigate the average effect of the electric field on the branching ratio for forming D + I(2P3/2) and D + I(2P1/2). Changes in the measured D-atom speeds between field-free and strong-field conditions confirm substantial differences in dissociation dynamics. Both the magnitude and direction of change in the branching ratios are dependent upon the photodissociation wavelength. Experiments and theoretical calculations confirm that the mechanism for photon catalysis under these conditions is dynamic Stark shifting of potential energy surfaces rather than electric-field-induced alignment of reagent molecules. PMID- 30516766 TI - Post synthetic exchange enables orthogonal click chemistry in a metal organic framework. AB - Biphenyl-4,4'-dicarboxylic acid derivatives containing either azide or acetylene functional groups were inserted into UiO-67 metal organic frameworks (MOFs) via post synthetic linker exchange. Sequential and orthogonal click reactions could be performed on these modified MOFs by incubating the crystals with small molecule substrates bearing azide or acetylene groups in the presence of a copper catalyst. 1H NMR of digested MOF samples showed that up to 50% of the incorporated linkers could be converted to their "clicked" triazole products. Powder X-ray diffraction confirmed that the UiO-67 structure was maintained throughout all transformations. The click reaction efficiency is discussed in context of MOF crystallite size and pore size. As the incorporation of clicked linkers could be controlled by post synthetic exchange, this work introduces a powerful method of quickly introducing orthogonal modifications into known MOF architectures. PMID- 30516767 TI - Rice (Oryza sativa L.) tau class glutathione S-transferase (OsGSTU30) overexpression in Arabidopsis thaliana modulates a regulatory network leading to heavy metal and drought stress tolerance. AB - Glutathione S-transferases (GSTs) are well-known enzymes due to their role in detoxification of xenobiotic compounds. However, their biochemical action is still not so clear in imparting tolerance to several abiotic stresses in crop plants. In our previous study, we observed that rice tau class OsGSTU30 plays a significant role in the detoxification of Cr(vi). Interestingly, q-RT PCR analysis also revealed higher expression of OsGSTU30 under drought conditions. In this study, we characterize OsGSTU30 in response to drought as well as heavy metal [Cr(vi)] stresses through overexpression in Arabidopsis thaliana. Biochemical and physiological analyses revealed that OsGSTU30 overexpression lines have improved tolerance against both stresses as compared to wild-type plants. Kinetic analysis and molecular docking confirmed that OsGSTU30 enzyme possesses both GST as well as glutathione peroxidase (GPx) like activity. Differentially expressed stress-responsive genes were also identified by transcriptome analysis, involved in different biological pathways during abiotic stresses. These results suggest the signaling functions of OsGSTU30 apart from its catalytic activity during abiotic stress responses and can be further exploited for improving the stress tolerance in crops. PMID- 30516768 TI - Interfacial structure and electrochemical stability of electrolytes: methylene methanedisulfonate as an additive. AB - The mechanism responsible for widening the electrochemical stability window of methylene methanedisulfonate (MMDS)-containing electrolytes compared to conventional carbonate electrolytes is suggested based on molecular dynamics (MD) simulations and density functional theory (DFT) calculations. We find that MMDS has a stronger reduction ability and higher affinity for the electrode surface than solvents, and these behaviors provide an important condition for priority decomposition of the additive. The addition of MMDS could reduce the probability of finding solvent-ion complexes at the electrolyte-electrode interface, which is especially beneficial for the stability of the solvent electrochemical window. This knowledge of the local electrolyte composition and structure at the surface plays a significant role in advancing our understanding of the relationships between interface structure and battery cycling performance, and expanding the operating windows of electrochemical devices. PMID- 30516769 TI - Exploring the ultrafast dynamics of a diarylethene derivative using sub-10 fs laser pulses. AB - A diarylethene derivative, 1,2-bis(2,4-dimethyl-5-phenyl-3 thienyl)perfluorocyclopentene (DMP), is a photoswitch molecule utilizing a reversible aromatic ring-opening reaction. The quantum yield of the ring-opening reaction is however remarkably low. We investigate the origin of this behaviour by means of ultrafast transient absorption spectroscopy utilizing sub-10 fs pulses, which is an invaluable tool for simultaneously studying both the electronic and the vibrational molecular dynamics. Namely, a noncollinear optical parametric amplifier (NOPA) generating sub-10 fs pulses in the spectral range 605 750 nm is employed. The transient absorption signal is modulated by several vibrational modes, which are compared with experimental and computational Raman spectra and then assigned to the ground or excited electronic state. We observe that the most pronounced vibrational mode - the ethylenic stretching mode at a frequency of 1501 cm-1 - exhibits instantaneous frequency and amplitude modulation. The observed modulations occur due to weak coupling with another 1431 cm-1 stretching mode mediated by a vibrational mode of low frequency, i.e. around 60 cm-1. Fast internal conversion S1 -> S0 originates in a relaxation through a conical intersection (found by density-functional theory computations), facilitated by the two aforementioned stretching modes. PMID- 30516770 TI - Effect of Ho dopant on the ferromagnetic characteristics of MoS2 nanocrystals. AB - Transition-metal dichalcogenides (TMDs) have been widely studied for decades in the spintronic device application. However, designing and tuning the magnetic properties of molybdenum disulphide (MoS2) is still a great challenge. In this work, the as-synthesized MoS2:Ho3+ nanocrystals exhibit robust room-temperature ferromagnetism and the ferromagnetism is controlled by different doping concentrations of Ho3+ ions. The maximum saturation magnetization is 0.055 emu g 1. Based on first-principles calculations, the intrinsic ferromagnetic and the changed electronic properties are introduced by Ho3+ doping. The as-obtained MoS2:Ho3+ nanocrystals with intrinsic ferromagnetism may be a potential candidate in the spintronics field and this approach may be employed in the magnetic applications of other TMDs. PMID- 30516771 TI - Protein structure networks provide insight into active site flexibility in esterase/lipases from the carnivorous plant Drosera capensis. AB - In plants, esterase/lipases perform transesterification reactions, playing an important role in the synthesis of useful molecules, such as those comprising the waxy coatings of leaf surfaces. Plant genomes and transcriptomes have provided a wealth of data about expression patterns and the circumstances under which these enzymes are upregulated, e.g. pathogen defense and response to drought; however, predicting their functional characteristics from genomic or transcriptome data is challenging due to weak sequence conservation among the diverse members of this group. Although functional sequence blocks mediating enzyme activity have been identified, progress to date has been hampered by the paucity of information on the structural relationships among these regions and how they affect substrate specificity. Here we present methodology for predicting overall protein flexibility and active site flexibility based on molecular modeling and analysis of protein structure networks (PSNs). We define two new types of specialized PSNs: sequence region networks (SRNs) and active site networks (ASNs), which provide parsimonious representations of molecular structure in reference to known features of interest. Our approach, intended as an aid to target selection for poorly characterized enzyme classes, is demonstrated for 26 previously uncharacterized esterase/lipases from the genome of the carnivorous plant Drosera capensis and validated using a case/control design. Analysis of the network relationships among functional blocks and among the chemical moieties making up the catalytic triad reveals potentially functionally significant differences that are not apparent from sequence analysis alone. PMID- 30516772 TI - Conversion of aldimines to secondary amines using iron-catalysed hydrosilylation. AB - Iron-catalyzed hydrosilylation of imines to amines using a well-defined iron complex is reported. This method employs relatively mild conditions, by reaction of imine, (EtO)3SiH in a 1 : 2 ratio in the presence of 1 mol% precatalyst ([BIAN]Fe(eta6-toluene), 3, BIAN = bis(2,6-diisopropylaniline)acenaphthene) at 70 degrees C. A broad scope of imines was readily converted into the corresponding secondary amines without the need for precatalyst activators. PMID- 30516773 TI - Thermal insulation with 2D materials: liquid phase exfoliated vermiculite functional nanosheets. AB - Phyllosilicates are layered materials possessing unique thermal properties, commonly exploited in their multilayered crystalline form as refractory insulators and heating elements. A more versatile use of such materials, however, would require their existence in the form of inks and dispersions ready to be patterned. Within this framework, the liquid-phase exfoliation of low-cost, low purity materials such as bulk multiphasic minerals and powders represents an economically advantageous approach for the production of 2D nano-sized objects with a defined composition, size and morphology. Here, ultrasound-assisted exfoliation and shear-mixing of a multi-phasic vermiculite in mild acidic aqueous solutions were employed to successfully obtain dispersions of mono- and few-layer thick clay nanosheets. The exfoliated materials were thoroughly investigated through granulometry, X-Ray Diffraction (XRD), specific surface area measurements and AFM imaging. Despite the fact that the lateral size and the thickness distribution of exfoliated flakes obtained with the two approaches appear similar, the ultrasound-assisted exfoliation process yielded a larger amount of mono- and bi-layer thick flakes as well as materials with a higher specific surface area. XRD analysis revealed that the use of ultrasound waves in an acidic environment results in the complete exfoliation of the vermiculite layer, whereas the use of shear forces under the same conditions results in the exfoliation of hydrobiotite and mica crystalline phases. Thermal conductivity measurements provided clear evidence on how the structural changes - arising from the exfoliation process - have a direct impact on the properties of the exfoliated clay. Remarkably, compared to the raw material, the thermal conductivity of the exfoliated material decreases by 25%, reaching the ultra-low thermal conductivity regime (<0.1 W m-1 K-1). Our approach may enable in the future the generation of patterns of thermal insulators onto different surfaces by applying vermiculite nanosheets in the form of dispersions and printable inks. PMID- 30516774 TI - The shielding effect of metal complexes on the binding affinities of ligands to metalloproteins. AB - Metal ions are important regulatory cofactors in a wide variety of proteins. Conventional wisdom suggests that stronger metal-ligand interactions have a larger effect on the ligand binding affinity. However, some experimental data do not support this conventional wisdom. In this study, we used a theoretical derivation approach to explore the effect of metal-ligand interactions on ligand binding affinities. Both theoretical derivation and experimental data indicate that metal-ligand interactions weaken the original interactions of the metal ions, which reduce the contributions of the metal-ligand interactions to the ligand binding affinities. The shielding effect is so large that some strong metal-ligand interactions contribute little to the ligand binding affinities. The binding free energies contributed by metal-ligand interactions have a limited relationship with the strengths of the interactions. Considering that the shielding effect of metal complexes is essential for accurately modelling metal ligand interactions, our findings challenge the conventional wisdom and represent a significant advance for the design of drugs targeted for metalloproteins and for exploring the enormous catalytic power of metalloproteins. PMID- 30516775 TI - A gold(i) biscarbene complex with improved activity as a TrxR inhibitor and cytotoxic drug: comparative studies with different gold metallodrugs. AB - Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time. A portfolio of other gold complexes (e.g. Auranofin) has been used as references in key biological assays, showing that the novel (NHC)2Au+ complex exhibits substantially lower protein binding in combination with a strongly enhanced cytotoxic activity. PMID- 30516776 TI - Direct (het)arylation of tetrahydroisoquinolines via a metal and oxidant free C(sp3)-H functionalization enabled three component reaction. AB - An unprecedented method for the direct arylation and heteroarylation of tetrahydroisoquinolines under metal and oxidant free conditions is reported. The arylation reactions occurred via a C(sp3)-H functionalization enabled three component condensation of tetrahydroisoquinolines, 9-fluorenone imine, and arenes without involving a pre-functionalization/pre-derivatization step. A wide range of arenes and heteroarenes participated in the reaction to provide structurally diverse arylated tetrahydroisoquinolines with good to excellent yields. PMID- 30516777 TI - The interplay between Zeeman splitting and spin-orbit coupling in InAs nanowires. AB - Coupling of the electron orbital motion and spin, i.e., spin-orbit coupling (SOC) leads to nontrivial changes in energy-level structures, giving rise to various spectroscopies and applications. The SOC in solids generates energy-band inversion or splitting under zero or weak magnetic fields, which is required for topological phases or Majorana fermions. Here, we examined the interplay between the Zeeman splitting and SOC by performing the transport spectroscopy of Landau levels (LLs) in indium arsenide nanowires under a strong magnetic field. We observed the anomalous Zeeman splitting of LLs, which depends on the quantum number of LLs as well as the electron spin. We considered that this observation was attributed to the interplay between the Zeeman splitting and the SOC. Our findings suggest an approach of generating spin-resolved chiral electron transport in nanowires. PMID- 30516778 TI - Cascade reaction based synthetic strategies targeting biologically intriguing indole polycycles. AB - Indole polycycles are common structural frameworks of biologically intriguing small molecules of natural and synthetic origin and therefore remain interesting and challenging synthetic targets. Cascade reactions wherein a number of reactions occur in a sequential manner in the same reaction apparatus are highly efficient chemical processes which quickly build up molecular complexity. Synthetic approaches based on cascade reactions are highly useful as they tend to avoid multiple reaction work-up steps as well as purifications of all intermediary products. Therefore, in the last decade, a number of cascade reaction based approaches to build various molecular scaffolds of biological interest have been reported. However, a relatively smaller number of cascade reaction based synthetic strategies have targeted the indole polycycles. In this article, we have summarized some interesting cascade reaction based synthesis designs leading to complex indole polycycles including some biologically intriguing and natural product inspired indole frameworks. PMID- 30516779 TI - Directed production of aurantizolicin and new members based on a YM-216391 biosynthetic system. AB - Using a highly effective heterologous expression system, the YM-216391 (1) biosynthetic gene cluster was engineered to yield aurantizolicin (2) and the hybrid compound 3. Both of these compounds were isolated and fully structurally characterised and the bioactivity was evaluated. The results indicate that compound 3 exhibits significantly improved antitumor activity. PMID- 30516780 TI - Organocatalytic enantioselective synthesis of acyclic pyrimidine nucleosides by aza-Michael reaction. AB - An efficient diarylprolinol triphenylsilyl ether-catalyzed enantioselective aza Michael reaction of pyrimidines as N-centered nucleophiles to alpha,beta unsaturated aldehydes, followed by reduction, provided chiral acyclic pyrimidine nucleosides in good yields (51-78% yields for two steps) and excellent enantioselectivities (91-98% ee). In addition, the chiral acyclic pyrimidine nucleoside having the tert-butyldiphenylsilyl-protected hydroxyl substituent was successfully applied to the synthesis of the corresponding chiral cyclic pyrimidine nucleoside analogue bearing the tetrahydrofuranyl ring. PMID- 30516781 TI - Meroterpene-like compounds derived from beta-caryophyllene as potent alpha glucosidase inhibitors. AB - Meroterpenoids isolated from guava (Psidium guajava) and Rhodomyrtus tomentosa possess special skeletons which incorporate terpenoids with phloroglucinol derivatives. Most of these meroterpenoids showed high cytotoxicity against cancer cell lines. However, their chemical diversity is very limited. Herein, we employed a biomimetic hetero-cycloaddition starting from ortho-quinone methides and an abundant natural product, beta-caryophyllene, to generate meroterpene-like compounds. Considering that the source plant has hyperglycemic functions, alpha glucosidase was selected as a target for bioassay. Nine compounds were screened out for promising activities (IC50 < 15 MUM), which were better than the positive controls genistein and acarbose. The best inhibitor 12 (IC50 2.73 MUM) possesses two caryophyllene moieties. They represented a new type of skeleton possessing activities against alpha-glucosidase. The kinetic study exhibited that these inhibitors belong to a non-competitive type. All these inhibitors may provide an opportunity to develop a new class of antidiabetic agents. PMID- 30516782 TI - Ring-closing metathesis of unprotected peptides in water. AB - Ring-closing metathesis (RCM) is an attractive reaction for the preparation of artificially designed peptides. Until now, RCM has been used for fully or partially protected peptides. Herein, the first RCM of unprotected peptides in water was achieved using a water-soluble Ru catalyst. PMID- 30516783 TI - Highly dispersed layered double oxide hollow spheres with sufficient active sites for adsorption of methyl blue. AB - The adsorption of dyes in contaminated water is an effective approach to solving the environmental crisis. Layered double hydroxide (LDH) and its calcinated product layered double oxide (LDO) show great potential as adsorbents. However, the conventional preparation of LDH or LDO typically suffers from aggregation and blocked active sites, hampering the adsorption efficiency of the adsorbent. Herein, three-dimensional, hollow MgFe-LDO spheres were constructed through the sacrifice of a carbon template. The hollow structure and the monodisperse state provided MgFe-LDO with sufficient microchannels and abundant active sites for adsorption. Through the memory effect of LDO, the anion methyl blue (MB) can be effectively adsorbed with a high uptake capacity of 398 mg g-1. Isotherm simulations demonstrated the monolayer adsorption of MB and the heterogeneous surfaces of the reconstructed LDHs. Moreover, the adsorbents can be recycled and reutilized at least five times through magnetic separation followed by calcination. Our proposed strategy is expected to provide new possibilities for the construction of adsorbents with well-controlled architecture and abundant active sites to deal with anionic pollutants. PMID- 30516784 TI - Contents list. PMID- 30516785 TI - Back cover. PMID- 30516786 TI - Aldehydes can switch the chemoselectivity of electrophiles in protein labeling. AB - We show that the chemoselectivity of an electrophile in protein labeling can be promiscuous. An aldehyde enables switching of chemoselectivity of an epoxide and a sulfonate ester along with an enhanced rate of reaction. The chemical technology renders single-site installation of diverse probes on a protein and delivers analytically pure tagged proteins. PMID- 30516788 TI - Front cover. PMID- 30516789 TI - Copper-catalyzed three-component synthesis of pyrimidines from amidines and alcohols. AB - An efficient copper-catalyzed one-pot three-component reaction of amidines, primary alcohols and secondary alcohols has been developed to synthesize multisubstituted pyrimidines. The significant merits of this method involve high atom efficiency, good functional group tolerance and operational simplicity. PMID- 30516787 TI - Recent methods for the synthesis of alpha-acyloxy ketones. AB - The present review provides a broad description of the methods reported for the synthesis of alpha-acyloxy ketones and some of their derivatives. alpha-Acyloxy ketones and their derivatives are vital synthetic intermediates and are ubiquitous as biochemical constituents of living organisms, biologically active natural products and pharmaceuticals. Due to their biological importance, new methods for their synthesis are being continuously developed and documented in the recent past. However, the chemical literature lacks a comprehensive summary on the synthetic methodologies targeting alpha-acyloxy ketones. In an attempt to fill this void, this review discusses their synthetic procedures developed over time. The synthetic approaches are systematically classified based on the substrates used. The mechanistic details for certain critical cases are also discussed. In the past, preparation of alpha-acyloxy ketones was reported from functionalized ketones like alpha-haloketones and diazo esters. Later on, among the reactions that formed the acyloxy ketones, oxidative coupling of ketones with carboxylic acids both under metal and metal-free conditions made their synthesis simple and versatile. Specifically, in the last decade, many oxidative coupling reactions emerged as a powerful tool for the synthesis of alpha-acyloxy ketones. Quite recently, acyloxy ketones' synthesis has been reported from commercially available alkenes and alkynes through oxidative addition reactions. Subsequently, the mechanistic details for these coupling reactions became interesting to many organic chemists. The asymmetric version of the title compounds hails from their enzymatic resolution to metal catalysed chiral synthesis. Besides, the synthesis of acyloxy ketones from epoxides, alcohols and enamides using various oxidative reagents has also been documented. PMID- 30516790 TI - Bisphosphine catalyzed sequential [3 + 2] cycloaddition and Michael addition of ynones with benzylidenepyrazolones via dual alpha',alpha'-C(sp3)-H bifunctionalization to construct cyclopentanone-fused spiro-pyrazolones. AB - A bisphosphine-catalyzed sequential [3 + 2] cycloaddition and Michael addition reaction of ynones with benzylidenepyrazolones has been developed. Under the catalysis of DPPB [1,4-bis(diphenylphosphino)butane], the reaction proceeded smoothly to give spiro-[cyclopentanone] pyrazolone derivatives in moderate to good yields with good diastereoselectivities via sequential dual alpha',alpha' C(sp3)-H bifunctionalization annulation. This strategy provides a novel route toward the synthesis of spiro-[cyclopentanone] pyrazolones containing three contiguous stereocenters which possess potential pharmaceutical activities. PMID- 30516791 TI - Improved synthesis of 2,4,6-trialkylpyridines from 1,5-diketoalkanes: the total synthesis of Anibamine. AB - Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6 trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following the above methodology using a reported compound as the starting material to give the product in 12% yield. PMID- 30516792 TI - Efficient synthesis of esters through oxone-catalyzed dehydrogenation of carboxylic acids and alcohols. AB - Since esters are important organic synthesis intermediates, an environmentally friendly oxone catalyzed-esterification of carboxylic acids with alcohols has been developed. A series of carboxylic acid esters are obtained in high yield. This strategy requires mild reaction conditions, providing an attractive alternative for the construction of valuable carbonyl esters. Electron-rich and electron-deficient groups are compatible with the standard conditions and a variety of substrates are demonstrated. Moreover, the reaction could easily be adapted to typical prodrugs, drugs and gram-scale synthesis. PMID- 30516793 TI - Inside front cover. PMID- 30516794 TI - Advance Care Planning in Older Adults With Multiple Chronic Conditions Undergoing High-Risk Surgery. PMID- 30516795 TI - When One Data Set Is Insufficient-Things to Consider When Linking Secondary Data. PMID- 30516796 TI - Use of Prolonged Exposure and Sertraline in the Treatment of Posttraumatic Stress Disorder for Veterans. PMID- 30516797 TI - Efficacy of Prolonged Exposure Therapy, Sertraline Hydrochloride, and Their Combination Among Combat Veterans With Posttraumatic Stress Disorder: A Randomized Clinical Trial. AB - Importance: Meta-analyses of treatments for posttraumatic stress disorder (PTSD) suggest that trauma-focused psychotherapies produce greater benefits than antidepressant medications alone. Objective: To determine the relative efficacy of prolonged exposure therapy plus placebo, prolonged exposure therapy plus sertraline hydrochloride, and sertraline plus enhanced medication management in the treatment of PTSD. Design, Setting, and Participants: The Prolonged Exposure and Sertraline Trial was a randomized, multisite, 24-week clinical trial conducted at the Veterans Affairs Ann Arbor Healthcare System, Veterans Affairs San Diego Healthcare System, Ralph H. Johnson Veterans Affairs Medical Center, and Massachusetts General Hospital Home Base Veterans Program between January 26, 2012, and May 9, 2016. Participants and clinicians were blinded to pill condition, and outcome evaluators were blinded to assignment. Participants completed assessments at weeks 0 (intake), 6, 12, 24, and 52 (follow-up). Participants (N = 223) were service members or veterans of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment (Clinician Administered PTSD Scale score, >=50) of at least 3 months' duration. Analyses were on an intent-to-treat basis. Intervention: Participants completed up to thirteen 90-minute sessions of prolonged exposure therapy by week 24. Sertraline dosage was titrated during a 10-week period and continued until week 24; medication management was manualized. Main Outcomes and Measures: The primary outcome was symptom severity of PTSD in the past month as assessed by the Clinician-Administered PTSD Scale score at week 24. Results: Of 223 randomized participants, 149 completed the study at 24 weeks, and 207 (180 men and 27 women; mean [SD] age, 34.5 [8.3 years]) were included in the intent-to-treat analysis. Modified intent-to-treat analysis using a mixed model of repeated measures showed that PTSD symptoms decreased significantly during the 24 weeks (sertraline plus enhanced medication management, 33.8 points; prolonged exposure therapy plus sertraline, 32.7 points; and prolonged exposure therapy plus placebo, 29.4 points; beta,-9.39; 95% CI, -11.62 to -7.16; P < .001); however, slopes did not differ by treatment group (prolonged exposure therapy plus placebo group, -9.39; sertraline plus enhanced medication management group, -10.37; and prolonged exposure therapy plus sertraline group, -9.99; P = .81). Conclusions and Relevance: No difference in change in PTSD symptoms or symptom severity at 24 weeks was found between sertraline plus enhanced medication management, prolonged exposure therapy plus placebo, and prolonged exposure therapy plus sertraline. Trial Registration: ClinicalTrials.gov Identifier: NCT01524133. PMID- 30516799 TI - Whole-Fat or Nonfat Dairy? The Debate Continues. PMID- 30516798 TI - Association of Hospital Surgical Aortic Valve Replacement Quality With 30-Day and 1-Year Mortality After Transcatheter Aortic Valve Replacement. AB - Importance: Hospital outcomes for transcatheter aortic valve replacement (TAVR) may be dependent on the quality of evaluation, personnel, and procedural and postprocedural care common to patients undergoing cardiac surgery. Objectives: We sought to assess whether those hospitals with better patient outcomes for surgical aortic valve replacement (SAVR) subsequently achieved better TAVR outcomes after launching TAVR programs. Design, Setting, and Participants: This national cohort included US patients 65 years and older. The analysis used the Centers for Medicare and Medicaid Services' Medicare Provider and Review data collected between January 1, 2010, and September 29, 2015. Only hospitals performing at least 1 SAVR prior to September 1, 2011, and performing at least 1 TAVR after this date were included in the analysis. Data analysis was completed from June 2018 to August 2018. Interventions: Isolated aortic valve replacements. Main Outcomes and Measures: Hospital risk-adjusted 30-day mortality for SAVR in the pre-TAVR period was used as a surrogate for SAVR quality. Thirty-day and 1 year TAVR mortality rates were examined after stratification by quartile of baseline hospital risk-adjusted SAVR mortality. Results: A total of 51 924 TAVR procedures were performed in 519 hospitals, of which 19 798 were performed at hospitals in quartile 1 (the lowest risk-adjusted SAVR mortality rate), 7663 were performed in quartile 2, 10 180 were performed in quartile 3, and 14 283 were performed in quartile 4 (the highest risk-adjusted SAVR mortality rate). Observed mortality rates at 30 days consistently increased with increasing baseline hospital SAVR risk-adjusted mortality (quartile 1, 917 patients [4.6%]; quartile 2, 381 [5.0%]; quartile 3, 521 [5.1%]; quartile 4, 800 [5.6%]; P < .001). The same pattern was observed in 1-year mortality (quartile 1, 3359 [17.0%]; quartile 2, 1337 [17.5%]; quartile 3, 1852 [18.2%]; quartile 4, 2652 [18.6%]; P < .001). After multivariable analysis, compared with the lowest quartile of SAVR mortality, undergoing TAVR at a hospital with higher baseline SAVR mortality continued to be associated with higher 30-day mortality (odds ratios: quartile 2, 1.02 [95% CI, 0.87-1.21]; quartile 3, 1.13 [95% CI, 1.02-1.26]; quartile 4, 1.23 [95% CI, 1.07-1.40]; P = .02) and 1-year mortality (hazard ratios: quartile 2, 1.04 [95% CI, 0.92-1.17]; quartile 3, 1.14 [95% CI, 1.02-1.28]; quartile 4, 1.16 [95% CI, 1.05-1.28]; P = .02). Conclusions and Relevance: Hospitals with higher SAVR mortality rates also had higher short-term and long-term TAVR mortality after initiating TAVR programs. Quality of cardiac surgical care may be associated with a hospital's performance with new structural heart disease programs. PMID- 30516800 TI - Unraveling the Mysteries of the Human Placenta. PMID- 30516801 TI - Association of Prevalence of Benign Pathologic Findings After Partial Nephrectomy With Preoperative Imaging Patterns in the United States From 2007 to 2014. AB - Importance: Although the intent of nephron-sparing surgery is to eradicate malignant tumors found on preoperative imaging, benign masses often cannot be differentiated from malignant tumors. However, in the past there have been discrepancies in the reported percentages of benign masses removed by partial nephrectomy (PNx). Objective: To investigate the annual trend of prevalence of benign pathologic findings after PNx and to investigate what potential factors are associated with this prevalence. Design, Setting, and Participants: A total of 18 060 patients who underwent PNx between 2007 and 2014 were selected from Truven Health MarketScan Research Databases. We selected those patients who underwent PNx as an inpatient from 2007 and set the surgery date as the index date. Overall, a total of 21 445 patients with International Classification of Diseases, Ninth Revision, Clinical Modification code of 55.4 were identified from 2007 to 2015. Main Outcomes and Measures: The annual trend of benign pathologic findings was described as an actual number and as a proportion. Univariate and multiple analyses were performed to investigate factors predictive of a benign final pathologic diagnosis, including type of preoperative imaging modality or performance of a renal mass biopsy. Results: Among the 18 060 patients, mean (SD) age was 57 (12) years, and there were 10637 (58.9%) men and 7423 (41.1%) women. The overall prevalence of benign pathologic findings was 30.9% and the annual trends demonstrated a prevalence of over 30% for nearly every year of the study period. On univariate analysis, the performance of magnetic resonance imaging (MRI) and renal mass biopsy was associated with benign pathologic findings (P = .02 and P < .001, respectively). On multivariable analysis, female sex (odds ratio [OR], 0.62; 95% CI, 0.58-0.66; P < .001), older age (>65 years) (OR, 0.99; 95% CI, 0.99-0.99; P < .001), and computed tomography (CT) only preoperative imaging (OR, 1.16; 95% CI, 1.05-1.28; P = .004) were associated with benign pathologic findings after PNx. Conclusions and Relevance: We found that the overall prevalence of benign pathologic findings after PNx was higher than the literature suggests, with consistent year-over-year rates exceeding 30%. Female sex, older age (>65 years), and CT only preoperative imaging were predictive of a benign tumor. Further elucidation concerning covariates associated with a benign diagnosis should be the focus of future investigations to identify a cohort of patients who could potentially avoid unnecessary surgical intervention. PMID- 30516802 TI - Addressing Clinical Significance. PMID- 30516803 TI - Addressing Clinical Significance-Reply. PMID- 30516804 TI - Cyclosporine-Induced Gingival Hypertrophy. PMID- 30516805 TI - Highlights. PMID- 30516806 TI - JAMA Psychiatry. PMID- 30516807 TI - Trends and Outcomes of Cardiovascular Surgery in Patients With Opioid Use Disorders. AB - Importance: Persistent opioid use is currently a major health care crisis. There is a lack of knowledge regarding its prevalence and effect among patients undergoing cardiac surgery. Objective: To characterize the national population of cardiac surgery patients with opioid use disorder (OUD) and compare outcomes with the cardiac surgery population without OUD. Design, Setting, and Participants: In this retrospective population-based cohort study, more than 5.7 million adult patients who underwent cardiac surgery (ie, coronary artery bypass graft, valve surgery, or aortic surgery) in the United States were included. Pregnant patients were excluded. Propensity matching was performed to compare outcomes between cardiac surgery patients with OUD (n = 11 359) and without OUD (n = 5 707 193). The Nationwide Inpatient Sample database was queried from January 1998 to December 2013. Data were analyzed in January 2018. Exposures: Persistent opioid use and/or dependence. Main Outcomes and Measures: In-hospital mortality, complications, length of stay, costs, and discharge disposition. Results: Among the 5 718 552 included patients, 3 887 097 (68.0%) were male; the mean (SD) age of patients with OUD was 47.67 (13.03) years and of patients without OUD was 65.53 (26.14) years. The prevalence of OUD among cardiac surgery patients was 0.2% (n = 11 359), with an 8-fold increase over 15 years (0.06% [262 of 437 641] in 1998 vs 0.54% [1425 of 263 930] in 2013; difference, 0.48%; 95% CI of difference, 0.45-0.51; P < .001). Compared with patients without OUD, patients with OUD were younger (mean [SD] age, 48 [0.30] years vs 66 [0.05] years; P < .001) and more often male (70.8% vs 68.0%; P < .001), black (13.7% vs 4.8%), or Hispanic (9.1% vs 4.8%). Patients with OUD more commonly fell in the first quartile of median income (30.7% vs 17.1%; P < .001) and were more likely to be uninsured or Medicaid beneficiaries (48.6% vs 7.7%; P < .001). Valve and aortic operations were more commonly performed among patients with OUD (49.8% vs 16.4%; P < .001). Among propensity-matched pairs, the mortality was similar between patients with vs without OUD (3.1% vs 4.0%; P = .12), but cardiac surgery patients with OUD had an overall higher incidence of major complications (67.6% vs 59.2%; P < .001). Specifically, the risks of blood transfusion (30.4% vs 25.9%; P = .002), pulmonary embolism (7.3% vs 3.8%; P < .001), mechanical ventilation (18.4% vs 15.7%; P = .02), and prolonged postoperative pain (2.0% vs 1.2%; P = .048) were significantly higher. Patients with OUD also had a significantly longer length of stay (median [SE], 11 [0.30] vs 10 [0.22] days; P < .001) and cost significantly more per patient (median [SE], $49 790 [1059] vs $45 216 [732]; P < .001). Conclusions and Relevance: The population of patients with persistent opioid use or opioid dependency undergoing cardiac surgery has increased over the past decade. Cardiac surgery in patients with OUD is safe but is associated with higher complications and cost. Patients should not be denied surgery because of OUD status but should be carefully monitored postoperatively for complications. PMID- 30516808 TI - Association of Surgical Risk With Exogenous Hormone Use in Transgender Patients: A Systematic Review. AB - Importance: A growing number of transgender patients are receiving gender affirming hormone treatments. It is unclear whether the evidence supports the current practice of routinely discontinuing these hormones prior to surgery. Objective: To determine how medications used in cross-sex hormone treatment (CSHT) affect perioperative risk. Evidence Review: A series of searches were carried out in PubMed and Excerpta Medica Database to identify articles using each of the terms testosterone, estrogen, estradiol, oral contraceptive, spironolactone, cyproterone acetate, finasteride, dutasteride, leuprolide, goserelin, and histrelin, in combination with the terms surgery, perioperative, thrombosis, thromboembolism, and operative. The search was not restricted to perioperative outcomes in transgender populations because many surgeons routinely discontinue hormone use prior to surgery in this population, which makes it impossible to study how hormones affect outcomes. Additional sources were also identified from the texts of reviewed articles. Articles were excluded if they were animal studies or case reports, did not explicitly discuss surgical outcomes, or were restricted to removal of hormonally sensitive tissues. Findings: Eighteen articles addressing perioperative outcomes were identified by this systematic review, including 1 on CSHT, 12 on estrogens and progesterones, 1 on testosterone, and 4 on spironolactone and antiandrogens. Data were limited, but use of exogenous testosterone was not found to be associated with an increased risk of venous thromboembolism or other complications during surgery. Moderate evidence suggests that spironolactone is not associated with negative surgical outcomes. The data linking estrogen use and thrombosis is inconsistent in the perioperative period and does not address the types of estrogens most often used for CSHT. Conclusions and Relevance: Current evidence does not support routine discontinuation of all CSHT prior to surgery, particularly given the lack of information on risks associated with resuming these medications after they have been stopped. Evidence suggests there is no need to discontinue either testosterone or spironolactone, although their association with perioperative outcome quality has not been studied in depth. Most of the evidence that supports discontinuation of estrogen prior to surgery is based on oral estrogen regimens that are not typically used in transgender patients, and even with those formulations, there are conflicting reports on perioperative risk. Further research is needed to determine the safety of continuing hormone treatment and elucidate risks of short-term discontinuation. PMID- 30516810 TI - Comparison of Injuries From Sharps Among Resident Physicians Within Dermatology and Other Medical and Surgical Specialties. PMID- 30516809 TI - Prevention and Treatment of Opioid Misuse and Addiction: A Review. AB - Importance: More than 42 000 Americans died of opioid overdoses in 2016, and the fatalities continue to increase. This review analyzes the factors that triggered the opioid crisis and its further evolution, along with the interventions to manage and prevent opioid use disorder (OUD), which are fundamental for curtailing the opioid crisis. Observations: Opioid drugs are among the most powerful analgesics but also among the most addictive. The current opioid crisis, initially triggered by overprescription of opioid analgesics, which facilitated their diversion and misuse, has now expanded to heroin and illicit synthetic opioids (fentanyl and its analogues), the potency of which further increases their addictiveness and lethality. Although there are effective medications to treat OUD (methadone hydrochloride, buprenorphine, and naltrexone hydrochloride), these medications are underused, and the risk of relapse is still high. Strategies to expand medication use and treatment retention include greater involvement of health care professionals (including psychiatrists) and approaches to address comorbidities. In particular, the high prevalence of depression and suicidality among patients with OUD, if untreated, contributes to relapse and increases the risk of overdose fatalities. Prevention interventions include screening and early detection of psychiatric disorders, which increase the risk of substance use disorders, including OUD. Conclusions and Relevance: Although overprescription of opioid medications triggered the opioid crisis, improving opioid prescription practices for pain management, although important for addressing the opioid crisis, is no longer sufficient. In parallel, strategies to expand access to medication for OUD and improve treatment retention, including a more active involvement of psychiatrists who are optimally trained to address psychiatric comorbidities, are fundamental to preventing fatalities and achieving recovery. Research into new treatments for OUD, models of care for OUD management that include health care, and interventions to prevent OUD may further help resolve the opioid crisis and prevent it from happening again. PMID- 30516811 TI - Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population. AB - Importance: Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations. Objective: To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease. Design, Setting, and Participants: Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1, 2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population. Main Outcomes and Measures: Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations. Results: A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation. Conclusions and Relevance: The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population. PMID- 30516812 TI - Aggressive Squamous Cell Carcinoma in Organ Transplant Recipients. AB - Importance: Squamous cell carcinoma (SCC) is the most frequent malignant neoplasm found in solid organ transplant recipients and is associated with a more aggressive disease course and higher risk of metastasis and death than in the general population. Objectives: To report the clinicopathologic features of and identify factors associated with aggressive SCC in solid organ transplant recipients. Methods: This retrospective multicentric case series included 51 patients who underwent solid organ transplantation and were found to have aggressive SCC, defined by nodal or distant metastasis or death by local progression of primary SCC. Standard questionnaires were completed by the researchers between July 18, 2005, and January 1, 2015. Data were analyzed between February 22, 2016, and July 12, 2016. Results: Of the 51 participants, 43 were men and 8 were women, with a median age of 51 years (range, 19-71 years) at time of transplantation and 62 years (range, 36-77 years) at time of diagnosis of aggressive SCC. The distribution of aggressive SCC was preferentially on the face (34 [67%]) and scalp (6 [12%]), followed by the upper extremities (6 [12%]). A total of 21 tumors (41%) were poorly differentiated, with a median tumor diameter of 18.0 mm (range, 4.0-64.0 mm) and median tumor depth of 6.2 mm (range, 1.0-20.0 mm). Perineural invasion was present in 20 patients (39%), while 23 (45%) showed a local recurrence. The 5-year overall survival rate was 23%, while 5-year disease-specific survival was 30.5%. Conclusions and Relevance: Results of this case series suggest that anatomical site, differentiation, tumor diameter, tumor depth, and perineural invasion are important risk factors in aggressive SCC in solid organ transplant recipients. PMID- 30516813 TI - When One Data Set Is Insufficient-Things to Consider When Linking Secondary Data Reply. PMID- 30516814 TI - A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents. AB - Importance: Infections have been associated with increased risks for mental disorders, such as schizophrenia and depression. However, the association between all infections requiring treatment and the wide range of mental disorders is unknown to date. Objective: To investigate the association between all treated infections since birth and the subsequent risk of development of any treated mental disorder during childhood and adolescence. Design, Setting, and Participants: Population-based cohort study using Danish nationwide registers. Participants were all individuals born in Denmark between January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis were November 2017 to February 2018. Exposures: All treated infections were identified in a time-varying manner from birth until June 30, 2013, including severe infections requiring hospitalizations and less severe infection treated with anti-infective agents in the primary care sector. Main Outcomes and Measures: This study identified all mental disorders diagnosed in a hospital setting and any redeemed prescription for psychotropic medication. Cox proportional hazards regression was performed reporting hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex, somatic comorbidity, parental education, and parental mental disorders. Results: A total of 1 098 930 individuals (51.3% male) were followed up for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91) years. Infections requiring hospitalizations were associated with subsequent increased risk of having a diagnosis of any mental disorder (n = 42 462) by an HRR of 1.84 (95% CI, 1.69 1.99) and with increased risk of redeeming a prescription for psychotropic medication (n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated with anti-infective agents was associated with increased risk of having a diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and with increased risk of redeeming a prescription for psychotropic medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated with particularly increased risk estimates. The risk of mental disorders after infections increased in a dose-response association and with the temporal proximity of the last infection. In particular, schizophrenia spectrum disorders, obsessive-compulsive disorder, personality and behavior disorders, mental retardation, autistic spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder and conduct disorder, and tic disorders were associated with the highest risks after infections. Conclusions and Relevance: Although the results cannot prove causality, these findings provide evidence for the involvement of infections and the immune system in the etiology of a wide range of mental disorders in children and adolescents. PMID- 30516815 TI - Durability Data for Bioprosthetic Surgical Aortic Valve: A Systematic Review. AB - Importance: Although several studies have reported data on surgical aortic valve durability, variability in study methodologies and definitions as well as inadequate follow-up make the interpretation of data from these studies difficult to interpret. Objective: To review available data on structural valve deterioration (SVD) of surgical bioprosthetic aortic valves by examining the published literature as well as data reported to the US Food and Drug Administration (FDA). Evidence Review: A systematic review using Preferred Reporting Items for Systematic Review and Meta-Analysis reporting guidelines to obtain all available data from preexisting literature on the actuarial freedom from SVD and outcomes of SVD. Data were collected from database inception to November 2016. Additionally, data reported to the FDA were obtained. Findings: In total, 167 studies and 12 FDA reports including 101 650 patients and 17 different valve types were analyzed. There were 11 different definitions of SVD used in the studies. Core laboratory data were available for 11 studies. Mean follow-up ranged from less than 1 year to 14 years. Kaplan-Meier estimates were reported for up to 30 years of follow-up, with 0% to 37% of patients remaining at risk at maximum follow-up. Food and Drug Administration-reported data are similarly variable in duration (mean follow-up range, 1.2 to 7 years) and completeness of follow-up, with final follow-up of 0.1% to 95%. Conclusions and Relevance: There is considerable variability in reporting SVD of surgical aortic valves, with different definitions and inadequate long-term systematically collected core laboratory data. Rigorously collected long-term data with standardized definitions for surgical valves are needed to provide a benchmark for the durability of rapidly evolving transcatheter valves. PMID- 30516816 TI - Has a New Determinant of Transcatheter Aortic Valve Replacement Outcomes Been Identified? PMID- 30516817 TI - Harbingers of Mental Disease-Infections Associated With an Increased Risk for Neuropsychiatric Illness in Children. PMID- 30516818 TI - Cross-Sectional Imaging Analysis of Epiretinal Membrane Involvement in Unilateral Open-Angle Glaucoma Severity. AB - Purpose: To determine the relevance of epiretinal membranes (ERMs) in primary open-angle glaucoma (POAG) and potential risk for glaucoma severity. Methods: Sixty eyes of 30 patients with POAG who had a unilateral ERM were analyzed; 60 nonglaucomatous eyes of 30 patients with a unilateral ERM also were recruited in this institutional cross-sectional study. Patients underwent swept-source (SS) optical coherence tomography (OCT) imaging and visual field testing. Intraindividual differences in the SS-OCT retinal nerve fiber layer (RNFL) disc cupping area measurements and visual field outcomes were analyzed in the two groups. Results: In patients with POAG, the mean circumpapillary RNFL thickness in the eyes with an ERM was 75.6 +/- 16.5 MUm superiorly and 71.8 +/- 26.0 inferiorly compared with the fellow eyes without an ERM (87.2 +/- 23.6 MUm, P = 0.0061 and 81.3 +/- 27.7 MUm, P = 0.034, respectively). The areas of disc cupping and cup-to-disc ratio seen on OCT horizontal and vertical B-scans were larger in eyes with an ERM than in the fellow eyes without ERM (P = 0.0004 and P = 0.0011, respectively). The average mean deviations were -11.6 +/- 7.5 dB in the ERM group and -8.19 +/- 6.4 dB in the group with no ERM (P = 0.029). Eyes with an ERM received more antiglaucoma eye drops (P = 0.018). Those differences were not seen between eyes with an ERM or fellow eyes in patients without glaucoma. Conclusions: The presence of an ERM can be a potential risk factor for unilateral severity in eyes with POAG. PMID- 30516820 TI - Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations. AB - Purpose: To compare the phenotype of blue cone monochromacy (BCM) caused by large deletion mutations with those having the C203R missense mutation. Methods: BCM patients with large deletion mutations (n = 21; age range, 5-60 years), and with the C203R missense mutation (n = 13; age range, 5-70 years), were studied with optical coherence tomography, visual acuity, and perimetric sensitivity in a retrospective observational case series. Perceptual estimates of spatial resolution driven by rods, S-cones, and L/M-cones were obtained by the choice of chromatic gratings presented on varied adapting conditions with a modified microperimeter. Results: Both genotypes had abnormal foveal photoreceptor structure early in life. Patients with the C203R mutation, however, had decades longer persistence of foveal photoreceptor outer nuclear layer thickness and a slower rate of development of inner segment/outer segment defects than did patients with large deletion mutations. At late ages, both genotypes had comparably severe losses of central structure. At the rod-rich hot spot, there was no difference in structure between cohorts with age. Grating acuities in all BCM patients were driven by S-cones and rods; the foveal structural differences were not reflected in a difference between cohorts in visual sensitivity and spatial resolution. Conclusions: A difference in structural phenotype due to the C203R mutation versus large deletion mutations in BCM was detected as a more prolonged persistence of foveal photoreceptor structure in patients with the missense mutation. This should be taken into account in planning natural history studies, selecting outcomes for clinical trials, and defining the time window for possible therapies. PMID- 30516821 TI - Feasibility and effectiveness of repetitive gait training early after stroke: A systematic review and meta-analysis. AB - BACKGROUND: Pre-clinical evidence suggests a period early after stroke during which the brain is most receptive to rehabilitation, if it is provided as high dose motor training. OBJECTIVE: To evaluate the feasibility of repetitive gait training within the first 3 months post-stroke and the effects on gait-specific outcomes. METHODS: PubMed, Web of Science, Cochrane Library, Rehab Data and PEDro databases were searched systematically. Randomized controlled trials were included to descriptively analyse the feasibility and quantitatively investigate the effectiveness of repetitive gait training compared with conventional therapy. RESULTS: Fifteen randomized controlled trials were included. Repetitive training can safely be provided through body weight support and locomotor assistance from therapists or a robotic device. No difference in drop-out rates was reported despite the demanding nature of the intervention. The meta-analysis yielded significant, but small, effects on walking independence and endurance. Training with end-effector robots appears most effective. CONCLUSION: Robots enable a substantial, yet feasible, increase in the quantity of walking practice early post-stroke, which might enhance functional recovery. However, the mechanisms underlying these effects remain poorly understood. PMID- 30516822 TI - Construction of Efficient Bio-Electrochemical Devices; An Improved Electricity Production from Cyanobacterium (Leptolyngbia sp.) Based on pi-Conjugated Conducting Polymers/Gold Nanoparticles Composite Interfaces. AB - In this study, gold electrodes (GE) were coated with conducting polymers to obtain high photocurrent using cyanobacteria from a novel bio-electrochemical fuel cell. For this purpose, an electropolymerization process was carried out by using 4- (4H-Dithieno [3,2-b: 2 ', 3'-d] pyrrol-4-yl) aniline, 5-(4H-dithieno [3,2-b:2,'3'-d]pyrol-4-yl) naphtalene-1-amine, monomers onto the gold electrodes. After that, gold nanoparticles (AuNP) were specifically modified by 2 mercaptoethane sulfonic acid and p-aminothiophenol in order attach to the electrode surface. The conducting polymers coated GE was modified with functionalized AuNP using a cross-linker. The resulting electrode structures were characterized by cyclic voltammetry and chronoamperometry under on-off illumination using a fiber optic light source. Cyanobacteria Leptolyngbia sp. was added to the GE/Conducting polymer/AuNP electrode surface and stabilized by using a cellulose membrane. During the illumination the water was oxidized by the photosynthesis, and the oxygen is released. The released oxygen was electro catalytically reduced at the cathode surface and a 25 nA cm-2 photocurrent was observed by GE/Leptolyngbia sp.. After the electrode modifications, a significant improvement in the photocurrent up to 630 nA cm-2 was achieved. This article is protected by copyright. All rights reserved. PMID- 30516819 TI - Potential Role of Ocular Microbiome, Host Genotype, Tear Cytokines, and Environmental Factors in Corneal Infiltrative Events in Contact Lens Wearers. AB - Purpose: The purpose of this study was to explore differences in genotype, ocular surface microbiome, tear inflammatory markers, and environmental and behavioral exposures in soft contact lens (SCL) wearers with and without a history of corneal infiltrative events (CIEs). Methods: Nine SCL wearers with a recent CIE and nine age-, sex-, and SCL material- and modality-matched controls were enrolled. The Contact Lens Risk Survey, slit-lamp examination data, basal tears, conjunctival microbial cultures, and peripheral blood samples were collected. Tear inflammatory mediator concentrations, genomic DNA from swabs, and whole exome sequencing of blood samples were quantified. Results: There were no marked differences in SCL wear behaviors or exposures between case and control subjects. Predominant organisms detected among case and control subjects were Staphylococcus, Propionibacterium, Streptococcus, and Corynebacterium. Marginally higher levels of Neisseria were found in three of nine cases but zero of nine control samples (P = 0.056). A potentially deleterious missense single nucleotide polymorphism (SNP) variant in IL-6 Signal Transducer (IL6ST) was found in seven of eight cases and zero of nine controls (rs2228046; P = 0.03). The concentration of tear IL-6 was significantly higher in cases (4.5 [range, 2.1 to 6.2] pg/mL) versus controls (3.5 [range, 2.5 to 6.6] Pg/mL; = 0.02). Conclusions: Tear IL-6 concentration was higher, and SNP variants were detected in subjects with a history of CIEs compared with healthy controls. The synthesis, signaling, and ocular surface cytokine concentration of IL-6 may be related to susceptibility to CIE. A larger study population is required to further explore relationships between genetic variations, the ocular surface microbiome, inflammatory mediators, and environmental exposures. PMID- 30516823 TI - Socioeconomic status in Danish women with polycystic ovary syndrome. A register based cohort study. AB - INTRODUCTION: Low socioeconomic status (SES) could be associated with increased risk of polycystic ovary syndrome (PCOS) and vice versa. Possible associations between SES, obesity, and ethnicity in PCOS are undetermined MATERIAL AND METHODS: National register-based study including women with PCOS aged 25 years or above (PCOS Denmark and an embedded cohort; PCOS Odense University Hospital (OUH)) and one control population. PCOS Denmark (N=13,891) included women with PCOS in the Danish National Patient Register. Women in PCOS OUH underwent clinical examination (N=814). Three age matched controls were included per patient (N=41,584). The main outcome measure was SES (Personal income, occupational status, and education) RESULTS: The median (Q1; Q3) age of women in PCOS Denmark and controls was 33 (29; 39) years. Women with personal income in the lower tertile had higher probability of a PCOS diagnosis than women in the high-income tertile (adj. odds ratio OR 1.5 (95% CI; 1.4 to 1.6)). Women being unemployed or on welfare payment (adj. OR 1.5 (95% CI; 1.4 to1.6)), or being early retired (OR 1.8 (95% CI; 1.7 to 2.0)) had higher probability of a PCOS diagnosis than women affiliated to the labour market. Women originating from the Middle East more often had PCOS (adj. OR 3.2 (95% CI 2.8 to 3.7)) compared to women originating from Europe. In PCOS OUH, SES was lower in obese vs. normal weight women CONCLUSIONS: A diagnosis of PCOS was associated with lower SES. In PCOS, women of foreign origin and women with obesity, more often had low SES. This article is protected by copyright. All rights reserved. PMID- 30516824 TI - Association between treatment of superficial bladder cancer and 10-year mortality in older adults with multiple chronic conditions. PMID- 30516825 TI - Histone demethylase UTX is a therapeutic target for diabetic kidney disease. AB - KEY POINTS: Diabetic kidney disease (DKD) is a major complication of diabetes. We found that UTX, a histone demethylase, was upregulated in the renal mesangial and tubular cells of diabetic mice and DKD patients. In cultured renal mesangial and tubular cells, UTX overexpression promoted palmitic acid-induced elevation of inflammation and DNA damage; while UTX knockdown or GSK-J4 treatment showed the opposite effects. We found that UTX demethylase activity-dependently regulated the transcription of inflammatory genes and apoptosis; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal abnormalities in db/db mice, an animal model of type 2 diabetes. These results revealed the possible mechanisms underlying the regulation of histone methylation in DKD and suggested UTX as a potential therapeutic target for DKD. ABSTRACT: Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end-stage kidney disease (ESRD) worldwide without effective therapy available. Ubiquitously Transcribed Tetratricopeptide Repeat on chromosome X (UTX, also known as KDM6A), a histone demethylase which removes the di- and tri methyl groups from histone H3K27, plays important biological roles in gene activation, cell fate control, C. elegans life span regulation. Here, we report upregulated UTX in the kidneys of diabetic mice and DKD patients. Administration of GSK-J4, an H3K27 demethylase inhibitor, ameliorated the diabetes-induced renal dysfunction, abnormal morphology, inflammation, apoptosis and DNA damage in db/db mice, an animal model of type 2 diabetes. In cultured renal mesanglial and tubular cells, UTX overexpression promoted palmitic acid induced elevation of inflammation and DNA damage; while UTX knockdown or GSK-J4 treatment showed the opposite effects. Mechanistically, we found that UTX demethylase activity dependently regulated the transcription of inflammatory genes; moreover, UTX bound with p53 and p53-dependently exacerbated DNA damage. Collectively, our results suggest UTX as a potential therapeutic target for DKD. This article is protected by copyright. All rights reserved. PMID- 30516826 TI - Isolation and expression analysis of a candidate gametophyte sex determination gene (sjhmg) of kelp (Saccharina japonica). AB - Saccharina japonica undergoes an alternating life cycle during which the diploid sporophyte generation alternates with the monoploid gametophyte generation. Saccharina japonica uses the UV sex determination system to determine the sex of its haploid gametophytes. However, the sex-determining genes and the sex determining mechanisms of kelp gametophytes have not been thoroughly elucidated to date. In this study, a kelp HMG-box-containing gene (SjHMG), which is located within the sex determination region (SDR) of S. japonica, was isolated and characterized. SjHMG contained an open reading frame (ORF) of 1,266 bp in length and encoded a deduced protein of 421 amino acid residues with two HMG-box domains. Phylogenetic analysis showed the strongest relationship between SjHMG and its orthologs in brown algae. An alternatively spliced transcript (SjHMG isoform-2) encoding a protein of 256 amino acid residues was also identified. The two isoforms were specific for male gametophytes. A real-time quantitative PCR analysis showed significantly higher abundances of two isoforms in immature male gametophytes than in mature ones. These findings suggested that the SjHMG gene is a candidate male gametophyte determination gene of kelp. In addition, the abundance of SjHMG isoform-2 transcripts was significantly lower than that of SjHMG isoform-1 transcripts, and only an HMG-box domain was conserved among species in the order Laminariales, which indicated that the gene is specifically involved in sex regulation in some species of the order Laminariales by alternative splicing. This article is protected by copyright. All rights reserved. PMID- 30516827 TI - Acclimation of the photosynthetic apparatus and alterations in sugar metabolism in response to inoculation with endophytic fungi. AB - The role of an endophytic Zygomycete Mucor sp. in growth promotion and adaptation of the photosynthetic apparatus to increased energy demands of its hosts Arabidopsis arenosa and Arabidopsis thaliana was evaluated. Inoculation with the fungus improved the water use efficiency of the plants and allowed for them to utilize incident light for photochemistry more effectively by upregulating the expression of several photosystem I- and II-related genes and their respective proteins, proteins involved in light harvesting in PSII and PSI and carbon assimilation. This effect was independent of the ability of the plants to acquire nutrients from the soil. We hypothesize that the accelerated growth of the symbiotic plants resulted from an increase in their demand for carbohydrates and carbohydrate turnover (sink strength) that triggered a simultaneous upregulation of carbon assimilation. Arabidopsis plants inoculated with Mucor sp. exhibited upregulated expression in several genes encoding proteins involved in carbohydrate catabolism, sugar transport and relatively smaller starch grains that indicate a significant upregulation of carbohydrate metabolism. PMID- 30516828 TI - Periodontal treatment needs in the Medicaid patient population: a retrospective study in a US dental school. AB - OBJECTIVES: The aim of this study was to use electronic health records (EHRs) from a US dental school clinic to retrospectively investigate associations between periodontal treatment needs and insurance type in a newly insured adult Medicaid population. We hypothesized that newly insured Medicaid patients, covered by the Iowa Dental Wellness Plan (DWP), would display greater need for treatment than patients with other sources of financing. METHODS: A retrospective chart review of EHRs of patients at the University of Iowa College of Dentistry and Dental Clinics (UI COD) from 2014 to 2016 was completed. The outcome of interest whether or not a new patient was indicated for scaling and root planing (SRP) based on clinical examination. Logistic regression models analyzed associations between treatment need and source of financing, adjusting for known periodontal disease risk indicators. RESULTS: A total of 1,259 patient charts were evaluated. SRP was indicated for 56 percent of all patients. Patients with DWP coverage had significantly greater unadjusted odds of being indicated for SRP than privately insured individuals (OR = 1.47, P = 0.009). However, this association did not remain significant after adjusting for known risk indicators. CONCLUSIONS: Although individuals enrolled in DWP were not significantly more likely to need treatment than individuals with other sources of financing when adjusting for risk indicators, their demonstrated clinical need was higher than privately insured adults. Public benefit programs could anticipate greater burden of periodontal need in low-income populations due to increased prevalence of risk factors in this population. PMID- 30516829 TI - The influence of environmental gradients on individual behaviour: Individual plasticity is consistent across risk and temperature gradients. AB - 1.The expression of individual behaviour as a function of environmental variation (behavioural plasticity) is recognised as a means for animals to modify their phenotypes in response to changing conditions. Plasticity has been studied extensively in recent years, leading to an accumulation of evidence for behavioural plasticity within natural populations. 2.Despite the recent attention given to studying individual variation in behavioural plasticity, there is still a lack of consensus regarding its causes and constraints. One pressing question related to this is whether individual plasticity carries over across temporal and environmental gradients. That is, are some individuals more plastic (responsive) than others in general? 3.Here, we examined the influence of temporal and environmental gradients on individual behavioural responses in a marine gastropod, Littoraria irrorata. We measured individual boldness repeatedly over time and in response to tidal cycle (high vs low, an index of risk) and daily temperature fluctuations (known to affect metabolism), in a controlled field experiment. 4.On average, boldness increased from high to low tide and with increasing temperature but decreased marginally over time. Individuals also differed in their responses to variation in tide and temperature, but not over time. Those that were relatively bold at high tide (when predation risk is greater) were similarly bold at low tide, whereas shy individuals became much more 'bold' at low tide. Most notably, individuals that were more responsive to tide (and thus risk) were also more responsive to temperature changes, indicating that plasticity was correlated across contexts (r = 0.57) and that bolder individuals were least plastic overall. 5.This study provides a rare and possibly first example of consistency of individual behavioural plasticity across contexts, suggesting underlying physiology as a common mechanism, and raises the possibility of correlational selection on plasticity. This article is protected by copyright. All rights reserved. PMID- 30516830 TI - Dietary Lipids Differentially Shape NASH Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages. AB - BACKGROUND: A crucial component of non-alcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages METHODS: This hypothesis was tested by using RNA-seq methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol RESULTS: The addition of cholesterol to a high fat diet triggered hepatic pathology reminiscent of advanced non-alcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized LDL, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-seq analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased Kupffer cells and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized LDL recapitulated some of the transcriptional changes observed in the RNA-seq study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that Kupffer cells are purely pro inflammatory in NASH CONCLUSION: This comprehensive view of macrophage populations in NASH indicates novel mechanisms by which cholesterol contribute to NASH progression and identifies potential therapeutic targets for this common disease. This article is protected by copyright. All rights reserved. PMID- 30516831 TI - Fibre degradation of wheat straw by Pleurotus erygnii under low moisture conditions during solid state fermentation. AB - The application of solid state fermentation offers an alternative to conventional, submerged approaches for a variety of bioconversion processes, including animal feeds, biofuels and fungal bioproducts. Optimising solid state fermentation under low moisture conditions could significantly impact the proportion of dry biomass that could be processed and improve the commercial viability of this approach, because of reduced input costs and higher yields of final products. Pleurotus erygnii that appeared to show tolerance to low moisture conditions was grown on saturated and desaturated wheat straw. P. erygnii showed insignificant fibre degradation although showed significantly lower biomass decomposition on desaturated wheat straw. Fibre decomposition by the fungus on wheat straw containing wheat bran showed marginally higher decomposition when saturated although there was no difference in biomass decomposition. The levels of delignification achieved were similar under different saturation conditions. It would appear that the fungus effectively decomposed fibre under low moisture conditions often resulting in lower biomass losses. This article is protected by copyright. All rights reserved. PMID- 30516832 TI - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as a useful tool for the rapid identification of wild flea vectors preserved in alcohol. AB - Flea identification is a significant issue because some species are considered as important vectors of several human pathogens that have emerged or re-emerged recently, such as Bartonella henselae (Rhizobiales: Bartonellaceae) and Rickettsia felis (Rickettsiales: Rickettsiaceae). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been evaluated in recent years for the identification of multicellular organisms, including arthropods. A preliminary study corroborated the usefulness of this technique for the rapid identification of fleas, creating a preliminary database containing the spectra of five species of flea. However, longterm flea preservation in ethanol did not appear to be an adequate method of storage in the context of specimen identification by MALDI-TOF MS profiling. The goal of the present work was to assess the performance of MALDI-TOF MS in the identification of seven flea species [Ctenocephalides felis (Siphonaptera: Pulicidae), Ctenocephalides canis, Pulex irritans (Siphonaptera: Pulicidae), Archaeopsylla erinacei (Siphonaptera: Pulicidae), Leptopsylla taschenbergi (Siphonaptera: Ceratophyllidae), Stenoponia tripectinata (Siphonaptera: Stenoponiidae) and Nosopsyllus fasciatus (Siphonaptera: Ceratophyllidae)] collected in the field and stored in ethanol for different periods of time. The results confirmed that MALDI TOF MS can be used for the identification of wild fleas stored in ethanol. Furthermore, this technique was able to discriminate not only different flea genera, but also the two congeneric species C. felis and C. canis. PMID- 30516833 TI - Monoclonal anti-CD47 interference in red cell and platelet testing. AB - BACKGROUND: Anti-CD47 (Hu5F9-G4) is a human monoclonal immunoglobulin G (IgG)4 antibody that is in clinical trials to treat hematologic or solid malignancies. CD47, a glycoprotein expressed on all cells, binds to signal-regulatory protein alpha on macrophages and regulates phagocytosis. Blocking CD47 is thought to enhance phagocytosis and promote antitumor responses. Here, we evaluate drug interference in pretransfusion testing, determine mitigation strategies, and compare interference with anti-CD38 (Daratumumab). STUDY DESIGN AND METHODS: Samples from four patients were tested by standard methods. Anti-IgG (Immucor monoclonal Gamma-clone and Ortho BioClone) were used, and dithiothreitol and enzyme-treated RBCs were tested. Allo-adsorption was performed with papain treated RBCs, pooled platelets, or with commercial human platelet concentrate. Platelet antibody testing was performed according to manufacturer's instructions. RESULTS: All plasma samples reacted 3+ to 4+ in all phases with all red blood cells (RBCs) by all methods including immediate spin. Stronger reactivity was observed with D- RBCs with titers as high as 16,384 at indirect antiglobulin testing. Reactivity at indirect antiglobulin testing using Gamma-clone anti-IgG (which does not detect IgG4) was only weakly positive and confirmed to be carryover agglutination. Plasma reacted with dithiothreitol, trypsin, papain, alpha-chymotrypsin, or warm autoantibody removal medium (W.A.R.M., Immucor) treated RBCs. Direct antiglobulin testing and autocontrol were negative or weak with 3+ reactive eluates. Reactivity was removed by multiple alloadsorptions with papain-treated cells or pooled platelets. Polyethylene glycol adsorption was invalid due to precipitation of antibody. CONCLUSION: Anti-CD47 (Hu5F9-G4) interferes with all phases of pretransfusion testing, including ABO reverse typing. To remove interference requires multiple RBC alloadsorptions and/or the use of monoclonal Gamma-clone anti-IgG in the indirect antiglobulin testing. PMID- 30516834 TI - Short-term Response to Phenytoin Sodium in Andersen-Tawil Syndrome-1 with a Cardiac-Dominant Phenotype. AB - BACKGROUND: Andersen Tawil Syndrome (ATS) is a rare familial periodic paralysis that typically also affects the heart and skeletal system. Ventricular arrhythmias (VA) are profound, difficult to control but minimally symptomatic. In this report we describe an atypical phenotype of ATS in 2 related families. We also report our experience with phenytoin sodium for the control of resistant ventricular arrhythmias in these patients. METHODS AND RESULTS: Between 2014 and 2018, seven siblings were diagnosed with ATS on the basis of cardiac arrhythmias and genetic evaluation. Heterozygous mutation c.431G > C (p.G144A) in exon 2 of KCNJ2 gene was observed in all patients. Characteristic cardiac manifestations were noted in all patients but periodic paralysis or objective neurological involvement was distinctly absent. Phenytoin was considered for control of symptomatic VA in 3 patients. 1 month of oral phenytoin (5 mg/kg/day) completely suppressed VA (< 1% in 24 hour holter) in 2 patients and significantly in the third (8%/24 hr). Phenytoin was well tolerated in all 3 patients. CONCLUSIONS: We describe a Cardiac- predominant phenotype in ATS. ATS should be suspected in patients with typical cardiac manifestations even in the absence of periodic paralysis. Our initial experience with short-term use of phenytoin for control of resistant ventricular arrhythmias is encouraging. This article is protected by copyright. All rights reserved. PMID- 30516835 TI - Exclusion criteria and adverse events in perioperative trials of tranexamic acid: a systematic review and meta-analysis. AB - BACKGROUND: Tranexamic acid (TXA) is an inexpensive therapy effective at minimizing perioperative blood loss and transfusion. However, it remains underutilized due to safety concerns. To date, no evidence-based guidelines exist identifying which patients should not receive TXA therapy. This study determined patient groups for whom safety information regarding TXA is lacking due to common exclusion from perioperative TXA trials. STUDY DESIGN AND METHODS: A systematic review searching the databases Medline, EMBASE, CENTRAL, and Clinicaltrials.gov was performed. Randomized controlled trials (RCTs) administering systemic TXA perioperatively to elective or emergent surgery patients were eligible. Our primary outcome was to describe exclusion criteria of RCTs, and the secondary outcome was TXA safety. A descriptive synthesis of exclusion criteria was performed, and TXA safety was assessed by meta-analysis. RESULTS: A total of 268 eligible RCTs were included. Meta-analysis showed that systemic TXA did not increase risk of adverse events compared to placebo or no intervention (relative risk, 1.05; 95% confidence interval, 0.99-1.12). Patient groups commonly excluded from perioperative TXA trials, and thus potentially lacking TXA safety data, were those with major comorbidities, a history of thromboembolism, medication use affecting coagulation, TXA allergy, and coagulopathy. Exclusion of patients with major comorbidities may not be necessary; we showed that the risk of adverse events was similar in studies that excluded patients with major comorbidities and those that did not. CONCLUSION: Sufficient evidence exists to develop perioperative guidelines for TXA use in many populations. Further studies evaluating perioperative TXA use in patients with a history of thromboembolism are warranted. PMID- 30516836 TI - VDR rs7975232/ApaI genetic variation predicts sustained HBsAg loss in HBeAg positive chronic hepatitis B patients treated with pegylated interferon. AB - AIM: To evaluate the predictive value of vitamin D and its metabolic pathway gene polymorphisms in response to pegylated interferon (Peg-IFN) in HBeAg-positive CHB patients. METHODS: 119 HBeAg-positive CHB patients who received Peg-IFN monotherapy for 48 weeks and then were followed-up for another 48 weeks were prospectively enrolled; baseline 25-(OH)D and HBV serologic marker levels were detected, 9 critical single nucleotide polymorphisms within vitamin D metabolism were genotyped. RESULTS: 45 (37.8%), 44 (37.0%), 35 (29.4%) and 11 (9.2%) of the patients achieved VR, HBeAg loss, CR and HBsAg level <200 IU/ml at the end of treatment (EOT; week 48), respectively; 42 (35.3%) and 6 (5.0%) people achieved HBeAg and HBsAg loss at the end of follow-up (EOF; week 96). Baseline HBeAg level was independent predictor of VR (OR=0.470, 95% CI: 0.294-0.751, P=0.002), HBeAg loss (OR=0.395, 95% CI: 0.243-0.643, P<0.001), CR (OR=0.392, 95% CI: 0.215-0.714, P=0.002) at EOT and HBeAg loss at EOF (OR=0.334, 95% CI: 0.203-0.559, P<0.001); baseline HBsAg level itself was independent predictor of both HBsAg<200 IU/ml at EOT (OR=0.257, 95% CI: 0.103-0.642, P=0.004) and HBsAg loss at EOF (OR=0.232, 95% CI: 0.077-0.702, P=0.010). Age was also independent predictors of HBsAg loss at EOF (OR=0.775, 95% CI: 0.634-0.948, P=0.013). Concerning genetic variation of VDR rs7975232/ApaI, A allele was the genetic independent predictor of VR at EOT (OR=1.824, 95% CI: 1.024-3.248, P=0.041) and HBsAg loss at EOF (OR=3.566, 95% CI: 1.057-12.029, P=0.040). CONCLUSIONS: Genetic variation of VDR rs7975232/ApaI is a pretreatment predictor of sustained HBsAg loss in HBeAg-positive CHB patients with Peg-IFN monotherapy. This article is protected by copyright. All rights reserved. PMID- 30516837 TI - From high definition precision healthcare to precision public oral health: opportunities and challenges. AB - In anticipation of a major transformation in healthcare, this review provides highlights that anticipate the near future for oral public health (and beyond). Personalized or precision healthcare reflects the expectation that advances in genomics, imaging, and other domains will extend our risk assessment, diagnostic, and prognostic capabilities, and enables more effective prevention and therapeutic options for all Americans. Meanwhile, the current healthcare system does not meet cost, access, or quality criteria for all Americans. It is now an imperative that the success of "smart," quality, and cost-effective high definition precision healthcare requires a public health perspective for several reasons: a) to enhance generalizability, b) to assess methods of implementation, and c) to focus on both risk and prevention in large and small populations, thereby providing a balance between the generation of long-term knowledge and short-term health gains. Sensitivity and resolution, reasonable cost, access to all Americans, coordinated comprehensive care, and advances in whole genome sequencing (WGS) and big data analyses, coupled to other advances in biotechnology and digital/artificial intelligence/machine learning devices, and the behavioral, social, and environmental sciences, offer remarkable opportunities to improve the health and wellness of the American people [genotype + phenotype + environment + behavior = high definition healthcare]. The opportunity is to significantly improve the well-being and life expectancy of all people across the lifespan including the least-advantaged people in our society and potentially increase access, reduce the national costs, and improve health outcomes. PMID- 30516838 TI - Recent advances in biosensors for diagnosis of celiac disease: A review. AB - Celiac disease (CD) is an intestinal issue activated by the inappropriate immune reaction towards gluten protein of wheat, rye, barley, oats, and autoantigen, tissue transglutaminase. Regardless of the accessibility of immunochemical conventions for research facility analysis of CD, there is as yet a need of speedier, less expensive, and simpler devices for diagnosing CD. This review concentrates on progresses in biosensors for diagnosing CD in perspective of the scaled down hardware, multianalyte discovery and low sample volume necessity. Various recently developed biosensors in this field are presented. PMID- 30516839 TI - Levels and patterns of self-reported and objectively-measured free-living physical activity among prostate cancer survivors: A prospective cohort study. AB - BACKGROUND: No prior study has measured or compared self-reported and objectively measured physical activity trajectories in prostate cancer survivors before and after treatment. METHODS: Clinically localized prostate cancer patients treated with radical prostatectomy were recruited between 2011 and 2014. Of the 350 participants enrolled at the main site, 310 provided self-reported physical activity at baseline before radical prostatectomy, and 5 weeks, 6 months, and 12 months after radical prostatectomy. A subset of participants (n = 81) provided objectively measured physical activity at all study time points by wearing an accelerometer for 7 days each. Changes in activity over time were compared using Friedman's test. Agreement between self-reported and objective measures was evaluated using Spearman's rank correlation coefficient. RESULTS: Self-reported moderate-to-vigorous physical activity was high at baseline (median, 32.1 min/day), followed by a decline at 5 weeks (median, 15.0 min/day) and a recovery at 6 and 12 months (median, 32.1-47.1 min/day). In contrast, objectively measured moderate-to-vigorous physical activity was low at all 4 time points (median, 0.0 5.2 min/day), with no overall change across study assessments (global P = .29). Self-reported moderate-to-vigorous physical activity tended to be more closely related to objectively measured light-intensity physical activity (rho = 0.29 0.42) than to objectively measured moderate-to-vigorous physical activity (rho = 0.07-0.27, P = .009-.32). CONCLUSIONS: In our population of prostate cancer survivors with critically low moderate-to-vigorous physical activity levels, self reported measures greatly overestimated moderate-to-vigorous physical activity and may have been more reflective of light-intensity physical activity. Because cancer survivor guidelines are derived from self-reported data, our findings may imply that intensities of physical activity below moderate, such as light intensity, still have health benefits. PMID- 30516840 TI - Dining dangerously: Geophagy by snowshoe hares. PMID- 30516841 TI - Reply to Association between treatment of superficial bladder cancer and 10-year mortality in older adults with multiple chronic conditions. PMID- 30516842 TI - Outcome in dogs with presumptive idiopathic pericardial effusion after thoracoscopic pericardectomy and pericardioscopy. AB - OBJECTIVE: To report the outcome of dogs with presumptive echocardiographic idiopathic pericardial effusion treated with thoracoscopic pericardectomy and pericardioscopy. STUDY DESIGN: Multi-institutional retrospective study (2011 2017). ANIMALS: Eighteen dogs. METHODS: Records were searched for dogs with pericardial effusion and no identified cause by preoperative echocardiography and subsequent thoracoscopic pericardectomy and pericardioscopy. Collected data included presenting complaint, physical examination, laboratory results, imaging, and operative findings. Follow-up was obtained via telephone interview and/or recheck examination. RESULTS: No evidence of mass lesions or cause for the effusion was identified in any of the dogs by preoperative echocardiography. Nine dogs had unremarkable pericardioscopic examination results. Nine dogs had pericardioscopic abnormalities consistent with masses, nodules, or adhesions. Median survival time (MST) for the 9 dogs with abnormalities identified by pericardioscopy was 66 days, whereas MST for the 9 dogs with unremarkable pericardioscopic examination results was not reached (P = .0067). Median survival time for dogs based on histopathologic diagnosis alone was not different between dogs with a diagnosis of neoplasia and dogs with a diagnosis of pericarditis (P = .1056). Among dogs with lesions identified during pericardioscopy, MST did not differ between those with a diagnosis of malignancy and those with a diagnosis of pericarditis (P = .78). CONCLUSION: Dogs with presumptive idiopathic pericardial effusion without evidence of masses, nodules, and/or adhesions during thoracoscopic pericardectomy and pericardioscopy lived longer than dogs in which abnormalities were identified during pericardioscopy. CLINICAL SIGNIFICANCE: Thoracoscopic pericardectomy/pericardioscopy and targeted biopsy of the pericardium and pleura are recommended in dogs with echocardiographic idiopathic pericardial effusion. PMID- 30516843 TI - Managing a moral identity in debt advice conversations. AB - Previous research has found that stigma can be a barrier to service use but there has been little work examining actual service encounters involving members of stigmatized groups. One such group are those with problematic or unmanageable debts. Providing advice to members of this group is likely to be particularly difficult due to the stigma associated with being in debt. Using conversation analysis and discursive psychology, this study examines 12 telephone advice conversations between debt advisors and individuals in debt. Both clients and advisors oriented to the negative moral implications of indebtedness and typically worked collaboratively to manage these issues. Clients often claimed a moral disposition as a way to disclaim any unwanted associations with debt, but could find it difficult to reconcile this with an insolvency agreement. Moreover, the institutional requirements of the interaction could disrupt the collaborative management of stigma and advisors could manage the subsequent resistance from clients in either client-centred or institution-centred ways. The findings suggest that the products offered by debt advice agencies, as well as the manner in which they are offered to clients, can either help or hinder debtors negotiate the stigma-related barriers to service engagement. PMID- 30516844 TI - Multisystemic Therapy for Child Abuse and Neglect: Do Parents Show Improvement in Parental Mental Health Problems and Parental Stress? AB - Multisystemic Therapy for Child Abuse and Neglect (MST-CAN) is an evidence-based program for families with children who experience maltreatment. This clinical trial is the first evaluation of MST-CAN in a German-speaking area. Parental psychological problems and parental stress have been shown to be risk factors for child abuse and neglect. By the end of treatment, parents reported significantly less psychological distress than before the start of MST-CAN. Six months after treatment, this reduction was still evident. However, parents did not report any significant reduction of parental stress at any of the three time points. MST-CAN is an effective intervention for child maltreatment that not only combats child abuse and neglect but also has the potential to alleviate parental psychological distress. PMID- 30516845 TI - Thioesterase Superfamily Member 2 Promotes Hepatic VLDL Secretion by Channeling Fatty Acids into Triglyceride Biosynthesis. AB - In non-alcoholic fatty liver disease (NAFLD), triglycerides accumulate within the liver because the rates of fatty acid accrual by uptake from plasma and de novo synthesis exceed elimination by mitochondrial oxidation and secretion as VLDL triglycerides. Thioesterase superfamily member 2 (Them2) is an acyl-CoA thioesterase that catalyzes the hydrolysis of fatty acyl-CoAs into free fatty acids plus CoASH. Them2 is highly expressed in the liver, as well as other oxidative tissues. Mice globally lacking Them2 are resistant to diet-induced obesity and hepatic steatosis, and exhibit improved glucose homeostasis. These phenotypes are attributable, at least in part, to roles of Them2 in the suppression of thermogenesis in brown adipose tissue and insulin signaling in skeletal muscle. To elucidate the hepatic function of Them2, we created mice with liver-specific deletion of Them2 (L-Them2-/- ). Whereas L-Them2-/- mice were not protected against excess weight gain, hepatic steatosis or glucose intolerance, they exhibited marked decreases in plasma triglyceride and apolipoprotein B100 concentrations. These were attributable to reduced rates of VLDL secretion owing to decreased incorporation of plasma-derived fatty acids into triglycerides. The absence of hepatic steatosis in L-Them2-/- mice fed chow was explained by compensatory increases in rates of fatty acid oxidation and by decreased de novo lipogenesis in high fat fed mice. Consistent with a role for Them2 in hepatic VLDL secretion, THEM2 levels were increased in livers of obese patients with NAFLD characterized by simple steatosis. Conclusion: Them2 functions in the liver to direct fatty acids towards triglyceride synthesis for incorporation into VLDL particles. When taken together with its functions in brown adipose and muscle, these findings suggest Them2 as target for the management of NAFLD and dyslipidemia. This article is protected by copyright. All rights reserved. PMID- 30516846 TI - HELLS regulates chromatin remodeling and epigenetic silencing of multiple tumor suppressor genes in human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third lethal cancer worldwide. Increasing evidence showed that epigenetic alterations play an important role in human carcinogenesis. Deregulation of DNA methylation and histone modifications have recently been characterized in HCC, but the significance of chromatin remodeling in liver carcinogenesis remains to be explored. In this study, by systematically analyzing the expression of chromatin remodeling genes in human HCCs, we found that HELicase, Lymphoid-Specific (HELLS), a SWI2/SNF2 chromatin remodeling enzyme, was remarkably overexpressed in HCC. Overexpression of HELLS correlated with more aggressive clinicopathological features and poorer patient prognosis, compared to those patients with lower HELLS expression. We further showed that up regulation of HELLS in HCC was conferred by hyperactivation of transcription factor SP1. To investigate the functions of HELLS in HCC, we generated both gain- and loss-of-function models by CRISPR activation system, lentiviral shRNA, and CRISPR/Cas9 genome editing system. We demonstrated that overexpression of HELLS augmented HCC cell proliferation and migration. In contrast, depletion of HELLS reduced HCC growth and metastasis both in vitro and in vivo. Moreover, inactivation of HELLS led metabolic reprogramming and reversed Warburg effect in HCC cells. Mechanistically, by integrating analysis of RNA-seq and MNase-seq, we revealed that overexpression of HELLS increased nucleosome occupancy that obstructed the accessibility of enhancers and hindered the formation of nucleosome-free region (NFR) at transcription start site (TSS). Though this mechanism, up-regulation of HELLS mediated epigenetic silencing of multiple tumor suppressor genes including E-Cadherin, FBP1, IGFBP3, XAF1 and CREB3L3 in HCC. CONCLUSION: Our data unravel that HELLS is a key epigenetic driver of HCC. By altering the nucleosome occupancy at NFR and enhancer, HELLS epigenetically suppresses multiple tumor suppressor genes to promote HCC progression. This article is protected by copyright. All rights reserved. PMID- 30516847 TI - Peripheral Blood Biomarkers of Early Immune Reconstitution in Newly Diagnosed Multiple Myeloma. AB - Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and monocyte (AMC) counts at the time of treatment initiation and one month thereafter in 771 newly diagnosed patients. Two hundred and thirty-four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty-seven of these patients (37%) recovered normal biomarkers at one month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61 - 0.97, p = 0.025, n = 771). The absence of immune dysregulation at one month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50 - 0.80, p < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43 0.92, p = 0.016, n = 771). Cytogenetic high-risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit. This article is protected by copyright. All rights reserved. PMID- 30516848 TI - The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly annotated patients with primary myelofibrosis. AB - JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple-negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple-negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high-molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically-inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics-clinical MIPSS70+ version 2.0 model (P = .4). Leukemia-free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2-mutated PMF. PMID- 30516849 TI - Anomalous and Polarization-Sensitive Photoresponse of Td -WTe2 from Visible to Infrared Light. AB - Recently, an emergent layered material Td -WTe2 was explored for its novel electron-hole overlapping band structure and anisotropic inplane crystal structure. Here, the photoresponse of mechanically exfoliated WTe2 flakes is investigated. A large anomalous current decrease for visible (514.5 nm), and mid- and far-infrared (3.8 and 10.6 um) laser irradiation is observed, which can be attributed to light-induced surface bandgap opening from the first-principles calculations. The photocurrent and responsivity can be as large as 40 uA and 250 A W-1 for a 3.8 um laser at 77 K. Furthermore, the WTe2 anomalous photocurrent matches its in-plane crystal structure and exhibits light polarization dependence, maximal for linear laser polarization along the W atom chain a direction and minimal for the perpendicular b direction, with the anisotropic ratio of 4.9. Consistently, first-principles calculations confirm the angle dependent bandgap opening of WTe2 under polarized light irradiation. The anomalous and polarization-sensitive photoresponses suggest that linearly polarized light can significantly tune the WTe2 surface electronic structure, providing a potential approach to detect polarized and broadband lights up to far infrared range. PMID- 30516850 TI - Incidence and clinical signs of owner-reported equine laminitis in a cohort of horses and ponies in Great Britain. AB - BACKGROUND: Previous robust epidemiological studies of equine laminitis have utilised only veterinary-diagnosed episodes of disease, potentially underestimating true disease frequency. OBJECTIVES: To estimate the incidence of, and describe clinical signs associated with, owner-reported active laminitis in horses/ponies, using both veterinary-diagnosed and non-veterinary-diagnosed episodes. STUDY DESIGN: Prospective cohort. METHODS: Data were collected from horse/pony owners in Great Britain between August 2014 and December 2016 using a web-based application. The incidence of owner-reported laminitis was estimated using both first incident and repeat episodes reported during the study period via a previously-validated laminitis reporting form. Owner-reported clinical signs present in these episodes were recorded. RESULTS: A total of 1,070 horses/ponies contributed 1,068 horse-years at risk (HYAR) and 123 active laminitis episodes were reported in 97 animals. Sixty-two of these episodes (50.4%, 95% confidence interval [CI] 41.6, 59.2%) were veterinary-diagnosed and 75.3% (CI 66.7, 83.8%; n = 73) of horses/ponies reported to have laminitis during the study had a previous laminitis history. Overall owner-reported first episode incidence was 9.6 episodes (CI 7.8, 11.7)/100 HYAR while incidence including repeat episodes was 11.5 episodes (CI 9.7, 13.7)/100 HYAR. Laminitis occurred throughout the year with no significant differences between seasonal incidence estimates. Incidence was highest in Connemara and New Forest and lowest in Draught and Cob breed categories. The most prevalent owner-reported clinical signs (>=70%) were difficulty turning and a short/stilted or lame walk. Laminitis was reported in all limbs however; both forelimbs were most commonly affected (62.9%, CI 54.1, 71.7%; n = 73/116). MAIN LIMITATIONS: Self-selection enrolment of participants may limit generalisability of the findings. CONCLUSIONS: Laminitis remains a considerable year-round welfare issue of horses and ponies, with frequency estimates utilising owner-reported data more representative of the true impact of the disease. The clinical signs reported by horse/pony owners were reflective of those previously described by veterinary surgeons. This article is protected by copyright. All rights reserved. PMID- 30516851 TI - N-Doped C@Zn3 B2 O6 as a Low Cost and Environmentally Friendly Anode Material for Na-Ion Batteries: High Performance and New Reaction Mechanism. AB - Na-ion batteries (NIBs) are ideal candidates for solving the problem of large scale energy storage, due to the worldwide sodium resource, but the efforts in exploring and synthesizing low-cost and eco-friendly anode materials with convenient technologies and low-cost raw materials are still insufficient. Herein, with the assistance of a simple calcination method and common raw materials, the environmentally friendly and nontoxic N-doped C@Zn3 B2 O6 composite is directly synthesized and proved to be a potential anode material for NIBs. The composite demonstrates a high reversible charge capacity of 446.2 mAh g 1 and a safe and suitable average voltage of 0.69 V, together with application potential in full cells (discharge capacity of 98.4 mAh g-1 and long cycle performance of 300 cycles at 1000 mA g-1 ). In addition, the sodium-ion storage mechanism of N-doped C@Zn3 B2 O6 is subsequently studied through air-insulated ex situ characterizations of X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared (FT-IR) spectroscopy, and is found to be rather different from previous reports on borate anode materials for NIBs and lithium-ion batteries. The reaction mechanism is deduced and proposed as: Zn3 B2 O6 + 6Na+ + 6e- ? 3Zn + B2 O3 ? 3Na2 O, which indicates that the generated boracic phase is electrochemically active and participates in the later discharge/charge progress. PMID- 30516852 TI - Architected Origami Materials: How Folding Creates Sophisticated Mechanical Properties. AB - Origami, the ancient Japanese art of paper folding, is not only an inspiring technique to create sophisticated shapes, but also a surprisingly powerful method to induce nonlinear mechanical properties. Over the last decade, advances in crease design, mechanics modeling, and scalable fabrication have fostered the rapid emergence of architected origami materials. These materials typically consist of folded origami sheets or modules with intricate 3D geometries, and feature many unique and desirable material properties like auxetics, tunable nonlinear stiffness, multistability, and impact absorption. Rich designs in origami offer great freedom to design the performance of such origami materials, and folding offers a unique opportunity to efficiently fabricate these materials at vastly different sizes. Here, recent studies on the different aspects of origami materials-geometric design, mechanics analysis, achieved properties, and fabrication techniques-are highlighted and the challenges ahead discussed. The synergies between these different aspects will continue to mature and flourish this promising field. PMID- 30516853 TI - Developmental changes in resting-state functional networks among individuals with and without internalizing psychopathologies. AB - BACKGROUND: Three well-established intrinsic connectivity networks (ICNs) involved in cognitive-affective processing include the cognitive control network (CCN), default mode network (DMN), and salience and emotional network (SEN). Despite recent advances in understanding developmental changes in these ICNs, the majority of research has focused on single seeds or networks in isolation with limited age ranges. Additionally, although internalizing psychopathologies (IPs), such as anxiety and depression, are often characterized by maladaptive cognitive affective processing styles, it is not clear how IP history influences age related changes in brain networks. METHOD: The current study aimed to characterize the normative development of the CCN, DMN, and SEN across a large age-span (7-29 year olds) of typically developing (TD) individuals (n = 97). We also explore how age may impact differences in network connectivity between TD individuals and patients with IPs (n = 136). RESULTS: Among TD individuals, DMN and CCN connectivity strengthened with age, whereas connectivity between the SEN and ventromedial prefrontal cortex weakened across development. When exploring group (IP vs. TD) differences, the IP group was characterized by greater connectivity between the CCN and cerebellum and between the SEN and caudate from childhood to early adulthood, relative to TD individuals. In addition, patients with IPs, versus TD individuals, exhibited reduced connectivity between the SEN and medial frontal gyrus from adolescence to adulthood. CONCLUSIONS: The current findings shed light on differential age-related changes in brain network patterns among psychiatrically free, TD individuals and those with internalizing disorders, and may provide plausible targets for novel mechanism-based treatments that differ based on developmental stage. PMID- 30516854 TI - Cocktail Strategy Based on Spatio-Temporally Controlled Nano Device Improves Therapy of Breast Cancer. AB - Metastatic breast cancer may be resistant to chemo-immunotherapy due to the existence of cancer stem cells (CSC). And the control of particle size and drug release of a drug carrier for multidrug combination is a key issue influencing therapy effect. Here, a cocktail strategy is reported, in which chemotherapy against both bulk tumor cells and CSC and immune checkpoint blockade therapy are intergraded into one drug delivery system. The chemotherapeutic agent paclitaxel (PTX), the anti-CSC agent thioridazine (THZ), and the PD-1/PD-L1 inhibitor HY19991 (HY) are all incorporated into an enzyme/pH dual-sensitive nanoparticle with a micelle-liposome double-layer structure. The particle size shrinks when the nanoparticle transfers from circulation to tumor tissues, favoring both pharmacokinetics and cellular uptake, meanwhile achieving sequential drug release where needed. This nano device, named PM@THL, increases the intratumoral drug concentrations in mice and exhibits significant anticancer efficacy, with tumor inhibiting rate of 93.45% and lung metastasis suppression rate of 97.64%. It also declines the proportion of CSC and enhances the T cells infiltration in tumor tissues, thus prolongs the survival of mice. The cocktail therapy based on the spatio-temporally controlled nano device will be a promising strategy for treating breast cancer. PMID- 30516855 TI - Clinical, histopathologic, cystoscopic, and fluorescence in situ hybridization analysis of proliferative urethritis in 22 dogs. AB - BACKGROUND: Proliferative urethritis (PU) is a lower urinary tract disease of dogs characterized by frond-like lesions in the urethra. The etiology of PU is unknown, although an association with bacterial cystitis is reported. OBJECTIVES: Deep-seated bacterial cystitis is associated with PU, particularly in dogs with neutrophilic or granulomatous inflammation. ANIMALS: Twenty-two client-owned dogs with PU and 5 control dogs euthanized for non-urinary disease. METHODS: In retrospective analysis, medical records of dogs with PU from 1986 to 2016 were reviewed. Signalment, clinical signs, cystoscopic findings, antimicrobial use, and results of urine, bladder, or urethral tissue cultures, if available, were recorded. Histopathology was reviewed and classified as lymphocytic-plasmacytic (LP), neutrophilic, LP-neutrophilic (LPN), granulomatous, or pleocellular. Eubacterial fluorescence in situ hybridization (FISH) was performed on 18 tissue samples (13 cases, 5 controls), with subsequent evaluation of bacterial species. RESULTS: Of the 22 dogs, 9 had LP urethritis, 6 had LPN, 4 had pleocellular, and 3 had neutrophilic urethritis. Of note, 7 of 13 PU samples were FISH+ for adherent or invasive bacteria; 1 of 5 controls were FISH+ for adherent bacteria. Five dogs had negative urine and tissue cultures when FISH was positive. There was no association detected between the type of urethral inflammation and the results of urine and tissue culture or FISH. CONCLUSIONS AND CLINICAL IMPORTANCE: The type of inflammation varied widely in these 22 PU cases. Deep-seated bacterial urethritis could be contributing to the inflammatory process in some dogs, regardless of the inflammation type. Urine and tissue cultures likely underestimate bacterial colonization of the urethra in dogs. PMID- 30516856 TI - Durable control of Hepatitis C through interferon-free antiviral combination therapy immediately prior to allogeneic hematopoietic stem cell transplantation. AB - Chronic hepatitis C virus (HCV) infection carries increased risks for morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) but has become curable through the advent of directly acting antiviral compounds. Current guidelines of the American Society for Blood and Marrow Transplantation (ASBMT) recommend that HCV-infected HSCT candidates preferably start and complete therapy prior to transplant. However, this is often not feasible due to time constraints or treatment limiting comorbidities, conditions and treatments. For these reasons, data on the safety of antiviral treatment, its efficacy to achieve durable eradication of the virus until full immune recovery, and late effects of former HCV infection in patients receiving HSCT are unknown. Here we report the course of two pediatric patients with chronic HCV infection who received a full course of directly acting antivirals prior to allogeneic HSCT and achieved and maintained viral eradication throughout transplantation until complete immune recovery. This article is protected by copyright. All rights reserved. PMID- 30516857 TI - Poly(Alkyl Glycidate Carbonate)s as Degradable Pressure Sensitive Adhesives. AB - Polyacrylates are widely used in industry; however, their all aliphatic backbone leads to minimal degradability with challenges in recovery and recyclability. Insertion of CO2 into the backbone, forming poly(carbonate) analogues of poly(acrylate)s provides an environmentally friendly and biocompatible alternative polymer. The synthesis of five poly(carbonate) analogues of poly(methyl acrylate), poly(ethyl acrylate), and poly(butyl acrylate) is described. The polymers are prepared via the copolymerization of CO2 and an oxirane catalyzed by a salen cobalt complex. All the carbonate analogues possess higher glass transition temperatures (Tg = 32 to -5 OC) than alkyl acrylates (Tg = 10 to -50 OC), however, the carbonate analogues (Td=~230 OC) undergo thermal decomposition at lower temperatures than their acrylate counterparts (Td=~380 OC). Additionally, we synthesized constitutionally isomeric poly(alkyl carbonates) in which the pendant ester group is in the reverse orientation to the backbone. Compared to the acrylate derivative, the reverse analogues possess lower glass transition temperatures (Tg = 24 to 0 OC). However, the polymerization reactions are 10X more efficient and with more polymer produced than the cyclic carbonate byproduct. The poly(alkyl carbonates) exhibit compositional dependent adhesivity, and two of the analogues possess comparative peel strength to Duct Tape(r) and Scotch Tape(r). Finally, the poly(carbonate) analogues degrade into glycerol, alcohol, and CO2 in a time and pH dependent manner with the rate of degradation accelerated at higher pH conditions, in contrast to the poly(acrylate)s. PMID- 30516858 TI - Hepatitis C virus genotype 3 was associated with the development of hepatocellular carcinoma in Korea. AB - Although hepatitis C virus (HCV) genotype 3 infection is thought to be an important risk factor for hepatocellular carcinoma (HCC), current evidence is limited because only a few Western studies have evaluated the occurrence of HCC in patients with HCV genotype 3 infection. We evaluated the impact of genotype 3 and non-3 on HCC incidence and on disease progression in chronic HCV patients; this is the first study reporting such findings in an Asian population. We performed a retrospective cohort study using the data of 1448 consecutive chronic HCV patients evaluated at 3 centers in Korea between January 2005 and December 2016. Of these, 604, 675, and 169 had genotype 1, genotype 2, and genotype 3 HCV infections, respectively. Over a mean follow-up period of 53.2 months, 75 and 143 patients of all the patients developed HCC and experienced disease progression, respectively. The incidences of HCC were 1.10, 0.92, and 2.50 per 100 person years, and those of disease progression were 1.95, 1.62, and 6.72 per 100 person years for HCV genotypes 1, 2, and 3, respectively. In multivariate Cox regression analysis, genotype 3 was associated with an increased risk of HCC (hazard ratio [HR] = 4.26, 95% confidence interval [CI] = 2.02-8.97) and an increased risk of disease progression (HR = 4.88, 95% CI = 2.94-8.08). Our study proposes that HCV genotype 3 is an independent risk factor for HCC and disease progression in chronic HCV patients. This article is protected by copyright. All rights reserved. PMID- 30516859 TI - Peculiar Photoinduced Electron Transfer in Porphyrin-Fullerene Akamptisomers. AB - Porphyrin-fullerene dyads are promising candidates for organic photovoltaic devices. Electron transfer (ET) properties of the molecular devices depend significantly on the mutual position of the donor and acceptor. Recently, a new type of molecular isomerism (akamptisomerism) has been discovered. In the present study, we explore how photoinduced ET can be modulated by passing from one akamptisomer to another. To this aim, four akamptisomers of quinoxalinoporphyrin [60]fullerene complex are selected for the computational study. The most striking finding is that, depending on the isomer, the porphyrin unit in the dyad can act as either electron donor or electron acceptor. Thus, the stereoisomeric diversity allows one to change the direction of ET between the porphyrin and fullerene moieties. To understand the effect of akamptisomerism on the photoinduced ET processes a detailed analysis of initial and final states involved in the ET is performed. The computed rate for charge separation is estimated to be in the region of 1-10 ns-1. The formation of a long-living quinoxalinoporphyrin anion radical species is predicted. PMID- 30516860 TI - The National Early Warning Score predicts mortality in hospital ward patients with deviating vital signs: A retrospective medical record review study. AB - AIMS AND OBJECTIVES: To evaluate if the scale used for assessment of hospital ward patients could predict in-hospital and 30-day mortality amongst those with deviating vital signs i.e. that patients classified as medium or high-risk would have increased risk of in-hospital and 30-day mortality compared to patients with low-risk. BACKGROUND: The National Early Warning Score (NEWS) is a widely-adopted scale for assessing deviating vital signs. A clinical risk-scale that comes with the NEWS divides the risk for critical illness into three risk-categories, low, medium and high. DESIGN: Retrospective analysis of vital signs data. METHODS: Logistic regression models for age-adjusted in-hospital and 30-day mortality were used for analyses of 1107 patients with deviating vital signs. RESULTS: Patients classified as medium or high-risk by NEWS experienced a 2,11 or 3,40 increase, respectively, in odds of in-hospital death (95% CI: 1,27-3,51, p=0.004 & 95% CI: 1,90-6,01, p<0.001) compared to low-risk patients. Moreover, those with NEWS medium or high-risk were associated with a 1,98 or 3,19 increase, respectively, in odds of 30-day mortality (95% CI: 1,32-2,97, p=0.001 & 95% CI: 1,97-5,18, p<0.001). CONCLUSION: The NEWS risk classification seems to be a reliable predictor of mortality on patients in hospital wards. RELEVANCE TO CLINICAL PRACTICE: The NEWS risk classification offers a simple way to identify deteriorating patients and can aid the healthcare staff to prioritize among patients. This article is protected by copyright. All rights reserved. PMID- 30516861 TI - Amorphous Quantum Nanomaterials. AB - In quantum materials, macroscopic behavior is governed in nontrivial ways by quantum phenomena. This is usually achieved by exquisite control over atomic positions in crystalline solids. Here, it is demonstrated that the use of disordered glassy materials provides unique opportunities to tailor quantum material properties. By borrowing ideas from single-molecule spectroscopy, single delocalized pi-electron dye systems are isolated in relatively rigid ultrasmall (<10 nm diameter) amorphous silica nanoparticles. It is demonstrated that chemically tuning the local amorphous silica environment around the dye over a range of compositions enables exquisite control over dye quantum behavior, leading to efficient probes for photodynamic therapy (PDT) and stochastic optical reconstruction microscopy (STORM). The results suggest that efficient fine-tuning of light-induced quantum behavior mediated via effects like spin-orbit coupling can be effectively achieved by systematically varying averaged local environments in glassy amorphous materials as opposed to tailoring well-defined neighboring atomic lattice positions in crystalline solids. The resulting nanoprobes exhibit features proven to enable clinical translation. PMID- 30516862 TI - Ultrathin Visible-Light-Driven Mo Incorporating In2 O3 -ZnIn2 Se4 Z-Scheme Nanosheet Photocatalysts. AB - Inspired by natural photosynthesis, the design of new Z-scheme photocatalytic systems is very promising for boosting the photocatalytic performance of H2 production and CO2 reduction; however, until now, the direct synthesis of efficient Z-scheme photocatalysts remains a grand challenge. Herein, it is demonstrated that an interesting Z-scheme photocatalyst can be constructed by coupling In2 O3 and ZnIn2 Se4 semiconductors based on theoretical calculations. Experimentally, a class of ultrathin In2 O3 -ZnIn2 Se4 (denoted as In2 O3 -ZISe) spontaneous Z-scheme nanosheet photocatalysts for greatly enhancing photocatalytic H2 production is made. Furthermore, Mo atoms are incorporated in the Z-scheme In2 O3 -ZISe nanosheet photocatalyst by forming the Mo?Se bond, confirmed by X-ray photoelectron spectroscopy, in which the formed MoSe2 works as cocatalyst of the Z-scheme photocatalyst. As a consequence, such a unique structure of In2 O3 -ZISe-Mo makes it exhibit 21.7 and 232.6 times higher photocatalytic H2 evolution activity than those of In2 O3 -ZnIn2 Se4 and In2 O3 nanosheets, respectively. Moreover, In2 O3 -ZISe-Mo is also very stable for photocatalytic H2 production by showing almost no activity decay for 16 h test. Ultraviolet-visible diffuse reflectance spectra, photoluminescence spectroscopy, transient photocurrent spectra, and electrochemical impedance spectroscopy reveal that the enhanced photocatalytic performance of In2 O3 -ZISe-Mo is mainly attributed to its widened photoresponse range and effective carrier separation because of its special structure. PMID- 30516863 TI - Towards an understanding of compassion from an Islamic perspective. AB - AIMS: Explore the concept of compassion as represented in Islamic virtues and how it influences the practice of nurses. BACKGROUND: Islam is one of the world's major religions. Yet, an Islamic perspective of compassion is not well understood in the Western nursing literature. Current understandings of compassion are largely drawn from a Western or Buddhist perspective. DESIGN: Discursive paper. METHODS: This is a review of literature and Islamic texts on the presence, meaning and practices of compassion that are relevant to our understanding of compassion in the contemporary nursing practice. CONCLUSIONS AND RELEVANCE TO CLINICAL PRACTICE: A compassionate Muslim nurse is a person who gives without asking for something in return, a person who cares without conditions, and a person who seeks to achieve the happiness of others. Therefore, Islam, like many other religions, endorses compassionate care in all aspects, and this is particularly emphasized in nurses. This paper also provides an insight into how a Muslim patient perceives different experiences of health and illness, supported by quotes from the Islamic contextual heritage, and how a nurse within this culture is expected to behave. This article is protected by copyright. All rights reserved. PMID- 30516864 TI - Surface Crystallization of Liquid Au-Si and Its Impact on Catalysis. AB - In situ transmission electron microscopy reveals that an atomically thin crystalline phase at the surface of liquid Au-Si is stable over an unexpectedly wide range of conditions. By measuring the surface structure as a function of liquid temperature and composition, a simple thermodynamic model is developed to explain the stability of the ordered phase. The presence of surface ordering plays a key role in the pathway by which the Au-Si eutectic solidifies and also dramatically affects the catalytic properties of the liquid, explaining the anomalously slow growth kinetics of Si nanowires at low temperature. A strategy to control the presence of the surface phase is discussed, using it as a tool in designing strategies for nanostructure growth. PMID- 30516865 TI - Emergency drills for agricultural drought response: a case study in Guatemala. AB - Drills are an important element of disaster management, helping to increase preparedness and reduce the risk of real-time failure. Yet, they are not applied systematically to slow-onset disasters such as a drought, which causes damage that is not instantly apparent and thus does not solicit immediate action. This case study evaluates how drills inform institutional responses to slow-onset disasters. It spotlights Guatemala, a country where drought has severe impacts on livelihoods and the food security of small farmers. By implementing part of the Ministry of Agriculture, Livestock and Food's institutional response plan for drought, it explores how drills can help to detect issues in emergency response and to foster an institutional focus on improvements in preparedness. The results reveal that drills alone do not trigger institutional improvements if unsupported by a wider strategy that seeks to enhance capacities and protocols. These findings are valuable, however, in making problems transparent and in creating the space for discussion. PMID- 30516866 TI - Management of Sepsis in Patients with Cirrhosis: current evidence and practical approach. AB - Sepsis in patients with cirrhosis is associated with high mortality. An impaired immune response accounts for the increased infection risk observed in these patients. Hemodynamic and systemic changes suggestive of sepsis may be seen in patients with cirrhosis in the absence of infection, therefore diagnosis and treatment of sepsis may be delayed. The optimal management of the critically-ill septic patient with cirrhosis has not been well established and is generally extrapolated from consensus guidelines and expert recommendations made for management of non-cirrhotic patients with sepsis. Despite the lack of strong evidence, we propose a contemporary pragmatic approach to sepsis management in patients with cirrhosis including the choice of fluids, vasopressors and antibiotics. This article is protected by copyright. All rights reserved. PMID- 30516867 TI - 20+ Years and alive with primary myelofibrosis: Phenotypic signature of very long lived patients. AB - In the last decade, several prognostic models for primary myelofibrosis (PMF) have been introduced and shown to be effective in predicting overall survival. The main objective for this study was to identify clinical and genetic markers of very long (20+ years) survival in PMF. A total of 1282 patients with PMF were considered (median age 65 years, range 19-92; 63% males); 26 (2%) patients (median age 51 years, range 28-71; 38% males) survived their disease for at least 20 years (long-lived patients) and 626 (49%) patients (median age 68 years, range 27-92; 66% males) died within 5 years of their diagnosis (short-lived patients). Multivariable logistic regression analysis identified 7 variables that were associated with survival beyond 20 years: age <= 70 years (P = .002); female sex (P = .03); hemoglobin level >= 10 g/dL for women and >= 11 g/dL for men (P = .03), leukocyte count <=25 * 109 /L (P = .009), platelet count >=100 * 109 /L (P = .002), circulating blasts <2% (P = .03) and absence of constitutional symptoms (P = .04). Five-year mortality was independently predicted by high-molecular risk mutations (P < .001); unfavorable or very high risk karyotype (P < .001); absence of type 1/like CALR mutation (P < .001); age > 70 years (P < .001); constitutional symptoms (P < .001); hemoglobin level < 10 g/dL for women and < 11 g/dL for men (P < .001); leukocyte count >25 * 109 /L (P = .004); and circulating blasts >=2% (P = .001). This study suggests that genetic risk factors in PMF are associated with early mortality while survival beyond 20 years could be predicted by easily accessible clinical variables, including age, sex, blood counts, and symptoms. PMID- 30516868 TI - Role of systemic high-dose methotrexate and combined approaches in the management of vitreoretinal lymphoma: A single center experience 1990-2018. AB - Vitreoretinal lymphoma (VRL) management remains a challenge. We present 72 patients with VRL, diagnosed at Mayo Clinic between 1990-2018. Three nondiffuse large B-cell lymphoma (DLBCL) histology cases were excluded. Among 69 DLBCL, 33 patients had primary VRL (PVRL), 18 concurrent intraocular and central nervous system (CNS) or systemic disease and 18 secondary VRL. Patients received intraocular chemotherapy (intraocular injections of rituximab or metothrexate or steroids or in combination), radiotherapy, systemic or combined systemic plus intraocular treatment in 9, 10, 35, and 15 cases, respectively. Among primary and concurrent VRL, median failure free survival (FFS), CNS relapse-free survival (CNS-RFS) and overall survival (OS) were: 1.8, 4.9, and 4.1 years, respectively; among PVRL, median FFS, CNS-RFS, and OS were: 2.6 year, Not Reached and 9.3 year, respectively. No CNS relapse occurred beyond 4 years in PVRL. Median OS for patients diagnosed between 1990 and 1999 vs between 2000 and 2018 was 1.5 vs 9.4 years, respectively (P = .0002). OS was significantly higher in PVRL, as compared with concurrent VRL (P = .04). Previous immunosuppression and poor performance status were predictive of worse outcome. In PVRL, a combined systemic and intraocular therapy showed higher FFS (P = .002) and CNS-RFS (P = .003), but no differences in OS. Among 18 secondary VRL, at a median follow-up of 1.1 year after vitreoretinal relapse, median FFS and OS were 0.3 and 1.3 years. An improvement in survival of VRL has been observed over the decades. PVRL should undergo combined systemic and intraocular chemotherapy to prevent CNS progression. PMID- 30516869 TI - High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer. AB - Recent findings indicate CD169-positive lymph node sinus macrophages (LySMs) in the regional lymph nodes (RLNs) play an important role in anti-cancer immunity. In the present study, we investigated the correlation between CD169 expression in RLNs and clinicopathologic factors. Higher CD169 expression in LySMs was significantly associated with longer cancer-specific survival (CSS). The density of tumor-infiltrating lymphocytes (TILs) in the cancer nest and CD169 expression on LySMs were positively associated in patients who underwent pretreatment. As CD169 expression is thought to reflect a high interferon signature in RLNs, we tried to identify immunity-related genes that are up-regulated by interferon in macrophages as well as CD169. Indoleamine 2,3-dioxygenase (IDO1) was found to be elevated by interferon, and expression of IDO1 was tested using immunohistochemistry. IDO1 expression on LySMs was positively correlated with CD169 expression; however, there was no significant correlation between IDO1 and clinicopathologic factors. These results suggest that high expression of CD169 in LySMs reflects a high potential for anti-cancer immune responses in esophageal cancer patients and that monitoring CD169 expression would be useful for evaluating the potential of anti-cancer immune reactions. PMID- 30516870 TI - The Mystery of ART. AB - One of the first steps towards a successful pregnancy is fertilization, where sperm and oocyte come together to form a zygote. In mammals, this process can occur in vitro, allowing assisted reproductive technologies (ART) to alleviate certain infertilities. ART - which includes in vitro fertilization and gamete donation - accounted for 1.7% of all US births in the US in 2015 (Sunderam et al. 2018). This article is protected by copyright. All rights reserved. PMID- 30516871 TI - A prognostic index for long-term outcome after successful acute phase cognitive therapy and interpersonal psychotherapy for major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) has a highly recurrent nature. After successful treatment, it is important to identify individuals who are at risk of an unfavorable long-term course. Despite extensive research, there is no consensus yet on the clinically relevant predictors of long-term outcome in MDD, and no prediction models are implemented in clinical practice. The aim of this study was to create a prognostic index (PI) to estimate long-term depression severity after successful and high quality acute treatment for MDD. METHODS: Data come from responders to cognitive therapy (CT) and interpersonal psychotherapy (IPT) in a randomized clinical trial (n = 85; CT = 45, IPT = 40). Primary outcome was depression severity, assessed with the Beck Depression Inventory II, measured throughout a 17-month follow-up phase. We examined 29 variables as potential predictors, using a model-based recursive partitioning method and bootstrap resampling in conjunction with backwards elimination. The selected predictors were combined into a PI. Individual PI scores were estimated using a cross validation approach. RESULTS: A total of three post-treatment predictors were identified: depression severity, hopelessness, and self-esteem. Cross-validated PI scores evidenced a strong correlation (r = 0.60) with follow-up depression severity. CONCLUSION: Long-term predictions of MDD are multifactorial, involving a combination of variables that each has a small prognostic effect. If replicated and validated, the PI can be implemented to predict follow-up depression severity for each individual after acute treatment response, and to personalize long-term treatment strategies. PMID- 30516872 TI - Copper-Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates with Phosphaalkynes to Prepare 1,3-Azaphospholes. AB - A novel copper-catalyzed synthetic method is described for phosphorous- and nitrogen-containing heterocycles such as 1,3-azaphospholes. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, dppm, and potassium carbonate afford the corresponding 1,3 azaphospholes in high yields with a complete selectivity. Some dppm-bridged dicopper complexes work as active species for the formation of 1,3-azaphospholes. PMID- 30516873 TI - Reductive Nitric Oxide Coupling at a Dinickel Core: Isolation of a Key cis Hyponitrite Intermediate en route to N2O Formation. AB - Reductive coupling of nitric oxide (NO) to give N2O is an important reaction in the global nitrogen cycle. Here, a dinickel(II) dihydride complex 1 that releases H2 upon substrate binding and serves as a dinickel(I) scaffold is shown to reductively couple two molecules of NO within the bimetallic cleft. The resulting hyponitrite complex 2 features an unprecedented cis-[N2O2]2- binding mode that has been computationally proposed as a key intermediate in flavodiiron nitric oxide reductases (FNORs). NMR and DFT evidence indicates facile rotational fluxionality of the [N2O2]2- unit, which allows to access an isomer that is prone to N2O release. Protonation of 2 is now found to trigger rapid N2O evolution and formation of a hydroxido bridged complex, reminiscent of FNOR reactivity. This work provides fundamental insight into the biologically relevant reductive coupling of two NO molecules and the subsequent trajectory towards N2O formation at bimetallic sites. PMID- 30516874 TI - Clinical effectiveness, cost effectiveness and acceptability of community-based treatment of Hepatitis C Virus infection: a mixed method systematic review. AB - Several community-based models for treating Hepatitis C Virus (HCV) infection have been implemented to improve treatment accessibility and health outcomes. However, there is a lack of knowledge regarding how well these models achieve the desired goals. We conducted a mixed-method systematic review of quantitative and qualitative evidence about clinical effectiveness, cost effectiveness and acceptability of community-based HCV treatment models. Seventeen databases were researched for published and unpublished studies. Methodological quality was assessed using The Joanna Briggs Institute Critical Appraisal tools. Quantitative findings were synthesised in narrative form and qualitative findings were synthesised using meta-synthesis. Forty-two quantitative and six qualitative studies were included. No relevant cost effectiveness studies were found. Five categories of community-based models were identified: telehealth, integration of HCV and addiction services, integration of HCV and HIV services, integration of HCV and primary care, and implementation by a home care and health care management company. The range of reported outcomes included; end of treatment response: 48.7% to 96%, serious side effects: 3.3% to 27.8%, sustained virological response: 22.3% to 95.5%, relapse: 2.2% to 16.7%, and treatment completion: 33.4% to 100%. Inconsistent measures of uptake and adherence were used; uptake ranged from 8.3% to 92%, and 68.4% to 100% of patients received >=80% of prescribed doses. Patient reported experiences included trusted and supportive care providers, safe and trusted services, easily accessible care, and positive psychological and behavioural changes. The clinical effectiveness and acceptability reported from the included studies are similar to or better than reported outcomes from systematic reviews of studies in tertiary settings. Studies of the cost-effectiveness of community-based models for treating HCV are needed. This article is protected by copyright. All rights reserved. PMID- 30516875 TI - The Immunomodulatory Properties of Propyl-Propane Thiosulfonate (PTSO) Contribute to its Intestinal Anti-Inflammatory Effect in Experimental Colitis. AB - SCOPE: Propyl-propane thiosulfonate (PTSO) is a component isolated from garlic (Allium sativum) with antioxidant, anti-inflammatory, immunomodulatory and antimicrobial properties. In consequence, PTSO could be a potential candidate for the treatment of inflammatory bowel diseases. METHODS AND RESULTS: The anti inflammatory effects of PTSO were studied in two mice models of colitis: 2,4 dinitrobenzene sulfonic acid (DNBS) (PTSO doses: 0.01-10 mg/kg) and dextran sodium sulfate (DSS) (PTSO doses: 0.01-0.1 mg/kg). The immunomodulatory effects of PTSO (0.1- 25 MUM) were also shown in vitro in Caco-2 and THP-1 cells, reducing the production of pro-inflammatory mediators and down-regulating mitogen activated protein kinases (MAPKs) signaling pathways. This compound displayed beneficial effects in both models of mouse colitis by reducing the expression of different pro-inflammatory mediators, and improving the intestinal epithelial barrier integrity. Moreover, PTSO ameliorated the altered gut microbiota composition observed in DSS colitic mice. CONCLUSION: PTSO exerted intestinal anti-inflammatory activity in experimental colitis in mice. This anti inflammatory activity could be associated with the immunomodulatory properties of PTSO through the regulation of the activity of cells involved in the inflammatory response. Furthermore, PTSO was able to restore the intestinal epithelial barrier function and to ameliorate the intestinal microbiota homeostasis, thus supporting its future development in human IBD. This article is protected by copyright. All rights reserved. PMID- 30516876 TI - Special education use in elementary school by children with nonsyndromic orofacial clefts. AB - BACKGROUND: Children with nonsyndromic orofacial clefts (NS OFCs) may require exceptional children's (EC) services for academic delays. We examined EC service use of children with and without NS OFCs in NC in elementary school. METHODS: We included 559 children with NS OFCs and 6,822 children without birth defects who had NC educational records. We estimated prevalence ratios, trends in enrollment, and characteristics of eligibility classification using descriptive statistics and logistic regression by cleft subtype and race/ethnicity. We estimated the odds of third grade retention by EC enrollment using logistic regression with inverse probability of treatment weights. RESULTS: Children with NS OFCs were 3.02 (95% CI: 2.50, 3.64) times as likely to receive third grade special education (SE) services compared to unaffected peers. The prevalence odds was highest among children with CL+P (OR: 4.61, 95% CI: 3.49, 6.09) declining by 54% by fifth grade. The prevalence odds of SE for white children was approximately 1.50 times that for African American children in fourth and fifth grades. Approximately 33% of children with NS OFCs within each racial/ethnic group received SE in third grade. African American children were twice as likely to receive services under specific learning disability. Children with NS OFCs receiving EC services were 44% (OR: 0.56; 95% CI: 0.13, 2.38) less likely to be retained in third grade compared to children with NS OFCs who were not receiving services. CONCLUSIONS: Children with NS OFCs are more likely to receive SE services in elementary school compared to their unaffected peers. The eligibility category differed by racial/ethnic group. PMID- 30516877 TI - Access to N-Substituted 2-Pyridones by Catalytic Intermolecular Dearomatization and 1,4-Acyl Transfer. AB - A novel rhodium-catalyzed dearomatization of O-substituted pyridines to access N substituted 2-pyridones has been developed. Computational study suggested a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4-acyl migratory rearrangement from O-to-C. Furthermore, using chiral dirhodium complexes as the catalyst, the asymmetric transformation has been achieved with excellent enantioselective control. DFT calculations indicate the chirality has been established from axial chirality to central stereogenic centre. The stronger pi-pi interaction and CH-pi interaction accounts for the high enantioselectivity. PMID- 30516878 TI - Water and Sodium Chloride: Essential Ingredients for Robust and Fast Pd-catalysed Cross-Coupling Reactions between Organolithiums and (Hetero)aryl halides. AB - Direct palladium-catalysed cross-couplings between organolithiums and (hetero)aryl halides (Br, Cl) proceed fast, cleanly and selectively at room temperature in air, with water as the only reaction medium and in the presence of NaCl as a cheap additive. Under optimised reaction conditions, a water accelerated catalysis is responsible for furnishing Csp3-Csp2, Csp2-Csp2, and Csp Csp2 cross-coupled products, competitively with protonolysis, within a 20 s reaction time, in yields of up to 99%, and in the absence of undesired dehalogenated/homocoupling side-products even if it starts from challenging secondary organolithiums. It is worth noting that the proposed protocol is scalable and the catalyst and water can easily and successfully be recycled up to 10 times, with an E-factor as low as 7.35. PMID- 30516879 TI - Standard abbreviations. PMID- 30516880 TI - Integrating infant and young child feeding learning sessions into saving groups is feasible and acceptable for HIV-positive and HIV-negative women in Malawi. AB - Based on formative research, HIV-positive women in Lilongwe District, Malawi receive little infant and young child feeding (IYCF) counseling postpartum and want more support for IYCF from their husbands. To address these gaps, we implemented a behavior change communication intervention promoting IYCF in village savings and loan associations (VSLAs) that included HIV-positive and HIV negative women. The intervention consisted of 15 IYCF learning sessions facilitated by VSLA volunteers during regular VSLA meetings and included four sessions to which husbands were invited. We assessed the feasibility and acceptability of the intervention through learning session participation logs, structured observations of learning sessions, and in-depth interviews with HIV positive and HIV-negative VSLA members, husbands of members, and VSLA volunteers. Nine VSLA volunteers conducted learning sessions with approximately 300-400 women, about one-quarter of whom were lactating, and 25-35 men. VSLA volunteers consistently communicated technical information correctly, followed the learning session steps, and used visual aids. Sessions averaged 46 minutes, with <20% of observed sessions completed within the recommended time (20-25 minutes). Key themes from interviews were: (1) learning sessions were useful, (2) including HIV positive and HIV-negative women in the sessions was acceptable, (3) information learned during sessions encouraged families to change IYCF practices, (4) IYCF messages were shared with others in the community, and (5) male participation was low because men considered VSLAs and IYCF to be women's activities. In conclusion, integrating IYCF learning sessions into VLSAs was feasible and acceptable for mixed groups of HIV-positive and HIV-negative women. Future research should test other strategies for involving men in IYCF. PMID- 30516881 TI - Hair cortisol concentration in a population without hypothalamic-pituitary adrenal axis disorders. AB - BACKGROUND: Measuring hair cortisol seems to be a good alternative to laboratory tests used thus far in routine endocrine diagnostics, primarily because it is independent of the circadian rhythm of cortisol. Due to the average hair growth of 1 cm per month, the results are related to the average blood cortisol levels over the previous weeks, months or years (depending on the length of the hair sample). OBJECTIVES: The aim of this study is an attempt to apply hair cortisol concentration (HCC) measurements to clinical endocrine diagnostics, based on reference cortisol concentrations in the blood in a population without disorders of the hypothalamic-pituitary-adrenal axis (HPA). MATERIAL AND METHODS: In the final selection process, 44 patients were enrolled in the study, all with negative interviews regarding disorders of the HPA and with reference levels of cortisol concentration obtained in routine laboratory tests. In the pre-analytic phase, we used 1 cm proximal hair strands cut from the posterior vertex area of the head, followed by the incubation of a 20 mg hair sample in methanol. The final cortisol measurement was done using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of HCC ranged from 2 pg/mg up to 51.63 pg/mg. The diurnal decrease in cortisol levels was significantly lower in females than in males (p = 0.031), but we do not consider that difference to be clinically significant. The difference in the HCC between males and females was not statistically significant (p = 0.767). The linear regression coefficient for age was not statistically significant (p = 0.847). Neither the regression coefficients for gender nor the gender and age interactions were statistically significant (p = 0.815). CONCLUSIONS: Hair cortisol concentration measurement, unlike other endocrinological tests, gives information about the cortisol concentration in the long-term perspective. The results obtained in this study may be used as a reference for further research aimed at determining normal values of HCC. PMID- 30516882 TI - DNA methylation analysis of selected genes for the detection of early-stage lung cancer using circulating cell-free DNA. AB - BACKGROUND: Lung cancer is still the deadliest cancer in the world, but early diagnosis cannot be achieved because of the limitations of diagnostic methods. DNA methylation has been proven to be a potentially powerful tool for cancer detection and diagnosis over the past decade. OBJECTIVES: We explored whether free DNA methylation in plasma can be a reliable biomarker for noninvasive lung cancer detection. MATERIAL AND METHODS: We detected the methylation of 8 genes in plasma-free DNA of patients with pulmonary space-occupying lesions using real time quantitative methylation-specific polymerase chain reaction (QMSP). Among the 50 selected patients, 39 were confirmed using pathological analysis as having early lung cancer and 11 had an inflammatory pseudotumor. RESULTS: The QMSP detection showed that the methylation levels of 8 genes in the patients were significantly higher than in the non-lung cancer group. The methylation level of CALCA was the highest and the methylation level of HOXA9 was the lowest. Methylation of RASSF1A, CDKN2A and DLEC1 occured only in lung cancer patients, while methylation of CALCA, CDH13, PITX2, HOXA9, and WT1 occured not only in lung cancer patients, but also in non-lung cancers. The specificity reached 95~100%, whether for a single gene or overall, but the sensitivity was relatively low for each gene. The sensitivity can reach 72% if the methylation of any of the 8 genes is positive and the overall specificity was 91%. The positive and negative predictive values were 96% and 60%, respectively. CONCLUSIONS: Quantitative detection of DNA methylation in plasma is a potential method for early diagnosis of lung cancer. PMID- 30516883 TI - A quantitative method for measuring the transfection efficiency of CD19-directed chimeric antigen receptor in target cells. AB - BACKGROUND: Adoptive cell therapy (ACT) based on chimeric antigen receptors (CARs) expressed on the surface of T cells shows a remarkable clinical outcome, particularly for B-cell malignancies. However, toxicity and side effects of CD19 redirected CAR T cells have been observed concurrently in most cases due to cytokine release and tumor cell lysis. Therefore, strictly controlling the amount of valid T cells re-transfused to patients seems to be an important step in reducing toxicity and side effects of CAR T cells. Transfection efficiency via lentiviral particles varies widely in different cases. OBJECTIVES: The aim of this study was to accurately calculate and control the number of valid CAR T cells through ACT because the restriction antibiotics gene or the fluorescence gene are not suitable for tracking or screening for valid transfected T cells. MATERIAL AND METHODS: We expressed and purified a GFP-CD19 fusion protein as a probe to measure the expression efficiency of CD19-redirected CAR on the cell surface in adherent and suspension cell lines. RESULTS: We can precisely calculate the transfected efficiency of lentiviral particles by counting the number of GFP-labeled cells under a microscope, as well as calculate the percentage by comparing the number of GFP-labeled cells to total cells. CONCLUSIONS: We propose a method to control the number of valid cells in ACT and to reduce toxicity and side effects in clinical use - a convenient technique for monitoring the dosage of CAR T cells for patients. PMID- 30516884 TI - ? PMID- 30516885 TI - [Combined antithrombotic treatment : do we have to add an antiplatelet drug to an anticoagulated-patients ?] AB - Antithrombotic drugs are regularly prescribed for the treatment and prevention of venous or arterial thromboembolic events. The co-prescription of an anticoagulant and antiplatelet drug is frequent in daily practice even if evidence of benefit associated with such an association is limited, while the increased bleeding risk is well established. The aim of this article is to review the situations where antiplatelet drugs are indicated in patients already treated with long-term anticoagulants. The perspective of adapting and personalizing antithrombotic therapy according to each patient's characteristics is also discussed. PMID- 30516886 TI - [Antithrombotics in the management of thrombotic antiphospholipid syndrome]. AB - The thrombotic antiphospholipid syndrome is defined by persistent antiphospholipid antibodies and vascular thrombosis. Recommendations for the secondary thrombotic prevention in the thrombotic antiphospholipid syndrome are weak, based on a low-to-moderate quality of evidence. When the initial event leading to diagnosis is a venous thrombosis, the prevention of recurrence of a thrombotic event is based on anticoagulation with a vitamin K antagonist. When the initial event is an arterial thrombosis, the optimal antithrombotic regimen is more controversial and the role of aspirin is debated. Recent data suggest not to use direct oral anticoagulant in the -setting of the thrombotic antiphospholipid syndrome. The identification of patients with low risk of thrombotic recurrence could help in tailoring antithrombotic therapy. PMID- 30516887 TI - [Best medical treatment of lower extremity arterial disease in 2018]. AB - Lower extremity artery disease is a very common disease, which is frequently associated with consistent disability in terms of both clinical symptoms and functioning. It is also associated with important morbidity and mortality, because of a significant increase in overall cardiovascular risk in affected patients. The establishment of an optimal medical treatment, including a careful management of the different cardiovascular risk factors through a healthy lifestyle, a regular and structured physical activity and the administration (if indicated) of antihypertensive, lipid-lowering, antidiabetic and antithrombotic drugs is a fundamental component in the clinical management of these patients and should always be considered by the clinicians facing the disease. PMID- 30516888 TI - [Antithrombotic treatments and inherited bleeding disorders]. AB - Inherited disorders of haemostasis predisposing to bleeding (platelet defects; deficiencies in von Willebrand and clotting factors) do not fully protect against the occurrence of thrombotic events. For patients affected with such disorders, antithrombotic treatments, which carry an additional haemorrhagic risk, are very challenging. There are no evidence-based recommendations, but only expert consensus at best. In this narrative review, we describe the epidemiology of the thrombotic risk in such a setting, and propose some basic rules for a structured reasoning and examples of the guidance on the utilization of antithrombotic drugs. Antithrombotic therapy for such patients, who are managed by specialized teams on a life-long basis, is performed case-by-case, and should involve all caregivers including GPs in a concerted manner. PMID- 30516889 TI - [Peripherally inserted central catheters : indications, contraindications, complications]. AB - Peripherally inserted central catheter (PICC) can be used for short to medium term administration of intravenous treatments. Their main advantages lie in their ease of insertion and removal, compared with other types of central venous access. Complications of PICC include mechanical complications, infections and vein thrombosis. This review describes the indications, contraindications, methods of insertion and complications of PICC. PMID- 30516890 TI - [Arteriovenous malformations and its complex management]. AB - Congenital arteriovenous malformations (AVM) represent a rare clinical entity. They are present at birth but can remain silent for many years. Due to their potential severity and their complex and specific management, the general practitioner should know when to suspect the presence of an AVM. Anatomic and hemodynamic characteristics of these malformations are well analysed by Doppler ultrasound, which is the first-line diagnostic test. MRI is often used in conjunction with ultrasound to better define the location and extension to neighbouring tissues and organs. Embolisation should be restricted to AVM associated with major functional disability, local complications or systemic cardiac complications in case of high flow volume life-threatening lesions. PMID- 30516892 TI - ? PMID- 30516891 TI - [Gastric cancer : management and multidisciplinary treatment]. AB - Despite a decreasing incidence, gastric cancer remains a burden. Generally discovered at an advanced stage, survival improved with progress in perioperative treatment and surgical management. Preoperative staging is essential to accurately classify the tumor and introduce the appropriate treatment. Tumor location is particularly important because the treatment of tumors of the esophageal junction and the stomach is different. Minimally invasive techniques can probably reduce postoperative morbidity and help to put patients in the best possible conditions for adjuvant treatment. PMID- 30516893 TI - ? PMID- 30516894 TI - ? PMID- 30516895 TI - ? PMID- 30516897 TI - ? PMID- 30516896 TI - ? PMID- 30516898 TI - ? PMID- 30516899 TI - ? PMID- 30516900 TI - ? PMID- 30516901 TI - ? PMID- 30516902 TI - ? PMID- 30516903 TI - ? PMID- 30516904 TI - ? AB - Asthma treatment management strategies. The aim of asthma treatment management strategies is to find the minimum dose of inhaled corticosteroids to achieve disease control, reduce morbidity and mortality, and improve respiratory function in patients with asthma. Assessing asthma control is therefore a key step of the management. The practitioner can use questionnaires such as ACT or ACQ for the evaluation of the patient. Adaptation of drug therapy is achieved by gradually increasing or decreasing the dose of inhaled corticosteroids and by adding or removing any additional therapies (long-acting beta2mimetics, antileukotrienes, tiotropium or theophylline). However, drug therapy is only a part of the global asthma management after confirmation of asthma diagnosis, verification of adherence and inhaled device technique, and investigation for aggravating factors and comorbidities. PMID- 30516905 TI - ? AB - Difficult to treat or severe asthma? Difficult-to-treat asthma is characterized by the need for several controllers including high dose inhaled corticosteroids to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy. Difficult-to-treat asthma can be due to inappropriate diagnosis, non-adherence to treatment, improper inhaler technique, exposition to environmental factors or co-existing conditions. Thus, difficult-to-treat asthma must be distinguished from severe asthma, which one is defined by an " intrinsic " resistance to asthma therapy. The diagnosis of difficult-to-treat asthma is a warning that should encourage to interrupt the step-up therapy process and to initiate a comprehensive approach aiming at checking the accuracy of asthma diagnosis, optimizing therapy adherence and technique, eliminating environmental factors and treating co-existing conditions. If several controllers including high dose inhaled corticosteroids are still required after this comprehensive approach, then asthma is called severe asthma. PMID- 30516907 TI - ? PMID- 30516906 TI - ? PMID- 30516908 TI - ? PMID- 30516909 TI - ? PMID- 30516910 TI - ? AB - Erysipelas. Erysipelas is a non-necrotizing acute dermohypodermitis of streptococcal origin (group A beta-hemolytic streptococcus) that usually affects adults and tends to reoccur. Risk factors recognized by the 2000 Consensus Conference are lymphedema, the existence of a gateway and obesity. Diagnosis is clinical with a classic presentation in the form of a "big red painful leg, acute, febrile and unilateral". Necrotizing fasciitis is the main differential diagnosis, as initial presentation of both may sometimes be similar, but whose severity requires urgent medical and surgical management. Management of erysipelas can be done on an outpatient basis or require hospitalization when parenteral treatment and/or close monitoring is required. Recommended treatment is antibiotherapy with penicillin or macrolides or related in case of allergy, associated with lesions related to skin infection (edema, bubbles) and risk factors (portal of entry and lymphedema) management. PMID- 30516911 TI - ? AB - Iodine deficiency during pregnancy. Iodine is a necessary element to thyroid hormones synthesis, and is essential in neurological development. Iodine needs increases during pregnancy. In developed countries, iodine deficiency is the second cause of mental delay avoidable after foetal alcoholization syndrome. In France, there is a moderate iodine deficiency, according to World Health Organization (WHO) thresholds. The marker used in studies is 24h urinary iodine excretion, but this marker is not applicable at the individual level. European substitution policy is hard to establish considering alimentary customs for each population. Salt fortification has a limited impact because its use has to be limited during pregnancy. Prophylaxis is recommended systematically by WHO in moderate deficiency areas like in France: 150 MUg/ day for women of childbearing age and 250 MUg/ day during pregnancy and breast feeding. Side effects may seem bearable considering benefit/ risk ratio providing not exceeding 500 MUg/day. PMID- 30516912 TI - ? AB - Diabetic retinopathy. Diabetic retinopathy (DR) is a disease whose screening actually can change the functional prognosis for the patients. It makes blindness avoidable. Annual screening using funduscopy or retinography for all diabetic patients is mandatory and yet not sufficiently and systematically performed in France. French Public health authority is developping telemedicine screening programs in different french regions to improve the prevention of DR. The treatment of DR is based on the management of its 2 major complications, that can coexist: preretinal neovascular proliferation (proliferative diabetic retinopathy), and diabetic macular edema (DME). Both of these complications require preventive management through strict control of blood glucose, blood pressure and hyperlipidemia. Once the complication is present, PRP must be performed to treat the neovessels while antiVEGF or corticosteroids intravitreal injections are the best way to treat DME. Surgery is required for more complicated forms of DR, such as intra-vitreous haemorrhage, retinal detachment, or neovascular glaucoma. PMID- 30516913 TI - ? AB - Evidence-based medicine criticism. Evidence-based medicine is now considered as the rule in the practice of clinical medicine. It covers however a lot of issues and limitations, leading to numerous and severe pitfalls. Most are described and discussed in this review. PMID- 30516914 TI - ? AB - Clinical inertia, or the defeat of evidence - based medicine. Often doctors do not follow good practice guidelines that have been widely disseminated, that they know and even approve. Sometimes they do it wisely, considering that the guideline does not apply to the patient they have in front of them: in that case their behaviour would represent an appropriate inaction, of which they can give a reason that is often validated by their peers. But sometimes this is not the case, and this is referred to as clinical inertia. This phenomenon, recently described, seems to defeat evidence-based medicine (EBM). The aim of this article is to propose that it is at least in part caused by a difference in logic: the purely rational logic of EBM, and the complex thought of patients and doctors, which combines rationality and irrationality, linked to the presence in the mental functioning of human beings of rapid circuits of reasoning called heuristics and of emotions. PMID- 30516915 TI - ? AB - An example of clinical controversy related to EBM. The DCCT study for type 1 diabetes (1993) and UKPDS for type 2 (1998) had demonstrated the benefit of the hypoglycemic treatment with, for 1 point of HbA1c less, 30% less microangiopathy events. The cardiovascular benefit was less obvious, as these studies were performed in patients with primary prevention. The benefit became significant only during the follow-up, 10 years after the end of the study. After these results, it became unethical to consider randomized studies in which patients in the control group would have HbA1c greater than or equal to 8%. More recent studies in type 2 diabetics with a very high cardiovascular risk therefore compared "intensive" treatment to "good" treatment. The "super intensive" treatment of the ACCORD study, with an objective of HbA1c lower than 6%, resulted in increased mortality leading to premature discontinuation of the study. The excess cardiovascular mortality was correlated with the occurrence of very severe hypoglycaemia, three times more frequent in the "super intensive" group. In contrast to the concept "the lower is the better", patients with high cardiovascular risk should avoid the risk of severe hypoglycaemia secondary to treatment. In addition, the drug industry was asked to demonstrate the cardiovascular safety of the new antidiabetic molecules, regardless of their hypoglycemic effect, by conducting randomized double-blind studies with an identical target of HbA1c between the two groups. The adaptation of glycemic targets to cardiovascular risk in case of risk of hypoglycemia on the one hand, and the poor understanding of the methodology of cardiovascular safety studies on the other hand, have led to a radical questioning of the benefit of treating hyperglycemia with potentially serious consequences for patients. PMID- 30516917 TI - ? PMID- 30516916 TI - ? AB - Alternatives to evidence based medecine. The evolution of patient-physician relationships, in addition to beneficence, implies to consider patient's autonomy as a relevant ethical factor. This infers to associate to the physician's scientific expertise, patient's wishes and preferences in a genuine personcentered medicine. The alternatives to evidence-based medicine mean here that it should not be considered exclusively or isolated from other factors. The physician should be aware that a fruitful dialogue with his patient include both the benefits of a scientific and sound medicine, based on solid evidences, as well as the careful consideration of patient's preferences, for the good of both.. PMID- 30516918 TI - ? PMID- 30516919 TI - ? PMID- 30516920 TI - ? PMID- 30516921 TI - ? PMID- 30516922 TI - ? PMID- 30516923 TI - ? PMID- 30516925 TI - Microdissection is the best way to perform sperm retrieval in men with non obstructive azoospermy? | Opinion: Yes. PMID- 30516924 TI - The current status of renal cell carcinoma and prostate carcinoma grading. PMID- 30516926 TI - Microdissection is the best way to perform sperm retrieval in men with non obstructive azoospermy? | Opinion: No, there are other options. PMID- 30516927 TI - Prospective Evaluation of Chondroitin Sulfate, Heparan Sulfate and Hyaluronic Acid in Prostate Cancer. AB - PURPOSE: The present study evaluates chondroitin sulfate (CS) and heparan sulfate (HS) in the urine and hyaluronic acid (HA) in the plasma of patients with prostate cancer before and after treatment compared to a control group. MATERIALS AND METHODS: Plasma samples were used for HA dosage and urine for quantification of CS and HS from forty-four cancer patients and fourteen controls. Clinical, laboratory and radiological information were correlated with glycosaminoglycan quantification by statistical analysis. RESULTS: Serum HA was significantly increased in cancer patients (39.68 +/- 30.00 ng/ mL) compared to control group (15.04 +/- 7.11 ng/mL; p=0.004) and was further increased in high-risk prostate cancer patients when compared to lower risk patients (p = 0.0214). Also, surgically treated individuals had a significant decrease in seric levels of heparan sulfate after surgical treatment, 31.05 +/- 21.01 MUg/mL (before surgery) and 23.14 +/- 11.1 MUg/mL (after surgery; p=0.029). There was no difference in the urinary CS and HS between prostate cancer patients and control group. Urinary CS in cancer patients was 27.32 +/- 25.99 MUg/mg creatinine while in the men unaffected by cancer it was 31.37 +/- 28.37 MUg/mg creatinine (p=0.4768). Urinary HS was 39.58 +/- 32.81 MUg/ mg creatinine and 35.29 +/- 28.11 MUg/mg creatinine, respectively, in cancer patients and control group (p=0.6252). CONCLUSIONS: Serum HA may be a useful biomarker for the diagnosis and prognosis of prostate cancer. However, urinary CS and HS did not altered in the present evaluation. Further studies are necessary to confirm these preliminary findings. PMID- 30516928 TI - Prognostic significance of body mass index in patients with localized renal cell carcinoma. AB - OBJECTIVE: To investigate the relationship between the pretreatment body mass index (BMI) and the clinical outcomes in patients with localized stage I - III renal cell carcinoma (RCC) surgically treated. MATERIALS AND METHODS: From January 2000 to December 2012, 798 patients with stage I - III RCC were recruited from First Affiliated Hospital and Cancer Center of Sun Yat - Sen University. Patients were divided into two groups of BMI < 25 kg / m2 or BMI >= 25 kg / m2 according to the World Health Organization classifications for Asian populations. The differences in the long-term survival of these two BMI groups were analyzed. RESULTS: The 5 - year failure - free survival rates for BMI < 25 kg / m2 and BMI >= 25 kg / m2 groups were 81.3% and 93.3%, respectively (P = 0.002), and the 5 - year overall survival rates were 82.5% and 93.8%, respectively (P = 0.003). BMI was a favored prognostic factor of overall survival and failure - free survival in a Cox regression model. CONCLUSIONS: Pretreatment body mass index was an independent prognostic factor for Chinese patients surgically treated, localized stage I - III RCC. PMID- 30516929 TI - Simplified method using kidney / ureter / bladder x-ray to determine the appropriate length of ureteral stents. AB - PURPOSE: To investigate a method to determine the appropriate length of ureteral stents, given that the stent length may lead to exacerbation of urinary symptoms if the stent crosses the bladder midline. MATERIALS AND METHODS: We retrospectively reviewed the position of the distal curl of the ureteral stent using kidney/ureter/bladder (KUB) radiographs after ureteroscopic lithotripsy in 165 patients who underwent placement of 24- or 26-cm ureteral stents. According to the KUB findings, we categorized the position of the distal curl of the ureteral stent into two groups. In Group 1, the stents did not cross the midline (appropriate length); in Group 2, the stents crossed the midline (inappropriate length). We assessed several patient parameters (sex, height, body mass index, and stone side) and the index of ureteral length using KUB radiographs ("C-P") and computed tomography (CT, "PV"). Multivariate analysis was performed to identify the most significant factors affecting the position of ureteral stents. We also calculated the cutoff points of the receiver operating characteristic (ROC) curve of C-P and P-V for the position of ureteral stents. RESULTS: The multivariate analysis showed that C-P was the most significant factor affecting the position of ureteral stents (p < 0.001) in patients with 24- and 26-cm ureteral stents. Comparison of the ROC curves of C-P and P-V showed that C-P was superior to P-V (p < 0.01) in patients with 24- and 26-cm stents. CONCLUSION: The use of KUB radiographs was effective and simple in determining the appropriate length of ureteral stents. PMID- 30516948 TI - Titanosilicate Derived SiO2/TiO2@C Nanosheets with Highly Distributed TiO2 Nanoparticles in SiO2 Matrix as Robust Lithium Ion Battery Anode. AB - Carbon coated SiO2/TiO2 (SiO2/TiO2@C) nanosheets consist of TiO2 nanoparticles uniformly embedded in SiO2 matrix and carbon coating layer are fabricated by using acidified titanosilicate JDF-L1 nanosheets as template and precursor. SiO2/TiO2@C has unique structural features of sheet-like nanostructure, ultrafine TiO2 nanoparticles distributed in SiO2 matrix and carbon coating, which can expedite ion diffusion and electron transfer, and relieve volume expansion efficiently, and thus the synergetic combination of these advantages significantly enhance their Li storage capability. As anode of LIBs, SiO2/TiO2@C nanosheets exhibit a high capacity of 998 mAh g-1 at 100 mA g-1 after 100 cycles. Moreover, an ultrahigh capacity of 410 mAh g-1 retains at 2000 mA g-1 after 400 cycles. A mixed reaction mechanism of capacitance and diffusion-controlled intercalation is revealed by qualitative and quantitative analysis. PMID- 30516949 TI - Anomalous K-Point Phonons in Noble Metal/Graphene Heterostructure Activated by Localized Surface Plasmon Resonance. AB - Metal/graphene interface has been one of the most important research topics with regard to charge screening, charge transfer, contact resistance, and solar cells. Chemical bond formation of metal/graphene can be deduced from the defect induced D-band and its second-order mode, 2D band, measured by Raman spectroscopy, as a simple and non-destructive method. However, a phonon mode located at ~ 1350 cm-1, which is normally known as the defect-induced D-band, is intriguing for graphene deposited with noble metals (Ag, Au, and Cu). We observe anomalous K-point phonons in non-reactive noble metal/graphene heterostructure. The intensity ratio of the mid-frequency mode at ~ 1350 cm-1 over G-band (~1590 cm-1) exhibits non linear but resonant behavior with the excitation laser wavelength and more importantly, the phonon frequency-laser energy dispersion is ~ 10-17 cm-1/eV, which is much less than the conventional range. These phonon modes of graphene at non-zero phonon wave vector (q ? 0) around K points are activated by localized surface plasmon resonance, and not by the defects due to chemical bond formation of metal/graphene. This hypothesis is supported by density function theory (DFT) calculations for noble metals and Cr along with the measured contact resistances. PMID- 30516950 TI - ATP-responsive low-molecular-weight polyethylenimine-based supramolecular assembly via host-guest interaction for gene delivery. AB - In this work, we report on an ATP-responsive low-molecular-weight polyethylenimine (LMW-PEI)-based supramolecular assembly. It formed via host guest interaction between PEI (MW=1.8 kDa)-alpha-cyclodextrin (alpha-CD) conjugates and PEI1.8k-phenylboronic acid (PBA) conjugates. The host-guest interaction between PEI1.8k-alpha-CD and PEI1.8k-PBA was confirmed by the 2D NOESY chromatogram experiment and competition test. The ATP-responsive property of the supramolecular assembly was evaluated by a series of ATP-triggered degradation and siRNA release studies in terms of fluorescence resonance energy transfer, agarose gel electrophoresis assay and the time course monitoring of the particle size and morphology. Confocal laser scanning microscopy confirmed the intracellular disassembly of the supramolecular polymer and the release of siRNA. The supramolecular assembly showed high buffering capability and was capable of protecting siRNA from RNase degradation. It had high cytocompatibility according to in vitro cytotoxicity and hemolysis assays. LMW-PEI-based supramolecular assembly facilitated cellular entry of siRNA via energy-dependent endocytosis. Moreover, the assembly/SR-A siRNA polyplexes at N/P ratio of 30 was most effective in knocking down SR-A mRNA and inhibiting uptake of modified LDL. Taken together, this work shows that ATP-responsive LMW-PEI-based supramolecular assembly is a promising gene vector and has potential application in treating atherosclerosis. PMID- 30516951 TI - Exclusive Magnetic Excitation Enabled by Structured Light Illumination in a Nanoscale Mie Resonator. AB - Recent work has shown that optical magnetism, generally considered a challenging light-matter interaction, can be significant at the nanoscale. In particular, the dielectric nano-structures that support magnetic Mie resonances have been recognized as low-loss and versatile optical magnetic elements that can effectively manipulate the magnetic field of light. However, the usually narrow magnetic resonance band of the dielectric Mie resonators is often overshadowed by the electric response, which prohibits the use of such nano-resonators as efficient magnetic nano-antennas. Here, we design and fabricate a Si disk magnetic Mie resonator at visible frequencies and excite the magnetic mode exclusively by a tightly focused, azimuthally polarized beam. We use photo induced force microscopy to experimentally characterize the local electric near field distribution in the immediate vicinity of the Si disk at the nanoscale, and then computationally convert the electric field distribution to the local magnetic response. We use this approach to visualize the electric near-field profile of the silicon disk with an unprecedented signal-to-noise ratio and infer the magnetic response of the silicon disk at the beam singularity, which agrees with numerical calculations. Such a magnetic excitation is essential for a plethora of optical magnetic applications including magnetic dipole transition characterization, optical magnetic force manipulation, magnetic nano-antennas, etc. PMID- 30516952 TI - Mid-Infrared Chalcogenide Waveguides for Real-Time and Non-Destructive Volatile Organic Compounds Detection. AB - A mid-infrared (mid-IR) sensor chip was demonstrated for volatile organic compounds (VOCs) detection. The sensor con-sisted of As2Se3 optical waveguides built by microelectronic fabrication processes. The VOCs sensing performance was char-acterized by measuring acetone and ethanol vapors at their characteristic C H absorption from lambda = 3.40 to 3.50 um. Continu-ous VOCs detection with < 5 s response time was achieved by measuring the intensity attenuation of the waveguide mode. The miniaturized non-invasive VOCs sensor can be applied to breath analysis and environmental toxin monitoring. PMID- 30516953 TI - NOVEL MATRIX SUBLIMATION DEVICE FOR MALDI MASS SPECTROMETRY IMAGING. AB - Sublimation is a widely used method for matrix deposition in imaging mass spectrometry experiments. Still, most of the time standard glass sublimators are used for this purpose, which do not enable optimal matrix deposition reproducibility, com-promising inter-experiment comparison of the results. Here we present an in-house designed stainless steel sublimator in which the parameters that have the strongest influence over matrix deposition reproducibility can be easily monitored. Using sections of human colon biopsies we demonstrate the capabilities of this new prototype. PMID- 30516954 TI - Influence of bridging groups on the photovoltaic properties of wide bandgap poly(BDTT-alt-BDD)s. AB - To further advance polymer solar cells requires the fast evolution of pi conjugated materials, as well as better understanding of their structure-property relationships. Herein, we present three co-polymers (PT1, PT2, PT3) made through tuning pi-bridges (without any group, thiophene, and 3-hexylthieno[3,2 b]thiophene) between electron rich (D: BDTT) and deficient (A: BDD) units. The comparative studies reveal the unique correlation that the tune of pi-bridge on the polymeric backbone governs the solid stacking and photovoltaic properties of resultant poly(BDTT-alt-BDD)s, which provide an effective way to deliver new and efficient polymer with feasible processability. That is, polymers with either twist zigzag backbone (PT1) or with linear co-planar backbone (PT2) result in both inferior photovoltaic performance upon simple solution casting. Among them, PT3 with extended zigzag backbone and planar segments exhibits suitable processability and retains good efficiency in non-fullerene solar cells through single solvent-cast without involving tedious treatments. This work illustrates the tuning of D-pi-A polymer backbone facilitates efficient materials with feasible processability, promising for scale-up fabrication. PMID- 30516955 TI - Metabolomics reveal that octocrylene accumulates in Pocillopora damicornis tissues as fatty acid conjugates and triggers coral cell mitochondrial dysfunction. AB - Octocrylene (OC) is an ingredient used in many sunscreens and cosmetics worldwide. Our group evaluated the toxicity of OC in corals. Adult Pocillopora damicornis coral was treated with OC at concentrations of 5, 50, 300 and 1000 ug/L. Most polyps were closed at concentrations of 300 ug/L and higher. Further, metabolomic profiling provided crucial information regarding OC accumulation in coral tissues and OC toxicity. First, we demonstrated that OC was transformed into fatty acid conjugates via oxidation of the ethylhexyl chain, yielding very lipophilic OC analogs that accumulate in coral tissues. Second, the differential analysis of coral profiles revealed higher levels of 15 acylcarnitines, suggesting abnormal fatty-acid metabolism related to mitochondrial dysfunction. The formation of OC analogs suggests that OC concentrations measured in the environment and organisms may have been largely underestimated. Overall, these results call for an in-depth evaluation of OC toxicity and the reevaluation of the actual OC accumulation rate in the ocean's food chain, including OC-fatty acid conjugates. PMID- 30516956 TI - Zig-Zag sp2 Carbon Chains Passing through sp3 Framework - A Driving Force toward Room Temperature Ferromagnetic Graphene. AB - Stabilization of ferromagnetic ordering in graphene-based systems up to room temperature remains an important challenge owing to huge scope for applications in electronics, spintronics, biomedicine, and separation technologies. To date, several strategies have been proposed, including edge engineering, introduction of defects and dopants, and covalent functionalization. However, these techniques are usually hampered by limited temperature sustainability of ferromagnetic ordering. Here, we describe a method for the well-controlled sp3 functionalization of graphene to synthesize zig-zag conjugated sp2 carbon chains that can act as communication pathways among radical motifs. Zig-zag sp2/sp3 patterns in the basal plane were clearly observed by high-resolution scanning transmission electron microscopy and provided a suitable matrix for stabilization of ferromagnetic ordering up to room temperature due to combined contributions of itinerant pi-electrons and superexchange interactions. The results highlight the principal role of sp2/sp3 ratio and super-organization of radical motifs in graphene for generating room temperature non-metallic magnets. PMID- 30516957 TI - Consensus Modeling of Median Chemical Intake for the U.S. Population Based on Predictions of Exposure Pathways. AB - Prioritizing the potential risk posed to human health by chemicals requires tools that can estimate exposure from limited information. In this study chemical structure and physicochemical properties were used to predict the probability that a chemical might be associated with any of four exposure pathways leading from sources - consumer (near-field), dietary, far-field industrial, and far field pesticide - to the general population. The balanced accuracies of these source-based exposure pathway models range from 73-81%, with the error rate for identifying positive chemicals ranging from 17-36%. We then used exposure pathways to organize predictions from thirteen different exposure models as well as other predictors of human intake rates. We created a consensus, meta-model using the Systematic Empirical Evaluation of Models (SEEM) framework in which the predictors of exposure were combined by pathway and weighted according to predictive ability for chemical intake rates inferred from human biomonitoring data for 114 chemicals. The consensus model yields an R2 of ~0.8. We extrapolate to predict relevant pathway(s), median intake rate, and credible interval for 479,926 chemicals, mostly with minimal exposure information. This approach identifies 1,880 chemicals for which the median population intake rates may exceed 0.1 mg/kg bodyweight/day, while there is 95% confidence that the median intake rate is below 1 ug/kg BW/day for 478,046 compounds. PMID- 30516958 TI - AF4-UV-MALS-ICP-MS/MS, spICP-MS and STEM-EDX for the characterization of metal containing nanoparticles in gas condensates from petroleum hydrocarbon samples. AB - The coupling of flow field flow fractionation (FlFFF) with ICP-MS/MS for the fractionation and analysis of natural nanoparticles in environmental samples is becoming more popular. However, the applicability of this technique to non aqueous samples such as gas condensates from petroleum hydrocarbon samples has not been reported yet. In this study, an asymmetric flow-field flow fractionation (AF4) system coupled with UV and MALS detectors has been optimized to perform the fractionation of natural nanoparticles present in a gas condensate sample, using THF as the carrier liquid. Prior to this, STEM images indicated the presence of both large (200 nm and more) and smaller (50 nm and less) particles, whose irregular shape is probably due to agglomeration. AF4-UV-MALS-ICP-MS/MS confirmed the presence of various nanoparticles and colloids, some containing aromatic compounds as well as various metals including Hg. The recovery against an injection without crossflow is around 75% for most metals. The presence of Hg containing nanoparticles was confirmed with offline single particle ICP-MS (spICP MS), using THF as a solvent. These NPs were identified as HgS using STEM-EDX. These results highlight for the first time that particulate matter may contaminate gas condensates with a series of elements (Al, P, S, Ti, V, Mn, Fe, Co, Cu, Zn, As, Se, Cd, Hg, Pb) which can make the upstream use problematic, especially for mercury. PMID- 30516959 TI - Forensic analysis and differentiation of black powder and black powder substitute chemical signatures by infrared thermal desorption - DART-MS. AB - The trace detection and forensic analysis of black powders and black powder substitutes, directly from wipe-based sample collections was demonstrated using infrared thermal desorption (IRTD) coupled with direct analysis in real time mass spectrometry (DART-MS). Discrete 15 s heating ramps were generated, creating a thermal desorption profile that desorbed more volatile species (e.g., organic and semivolatile inorganic compounds) at lower temperatures (250 degrees C to 400 degrees C) and nonvolatile inorganic oxidizers at high temperatures (450 degrees C to 550 degrees C). Common inorganic components of black powders (e.g., sulfur and potassium nitrate) as well as the alternative and additional organic and inorganic components of common black powder substitutes (e.g., dicyandiamide, ascorbic acid, sodium benzoate, guanidine nitrate, and potassium perchlorate) were detected from polytetrafluoroethylene-coated fiberglass collection wipes with no additional sample preparation. IRTD-DART-MS enabled the direct detection of intact inorganic salt species as nitrate adducts (e.g., [KClO4+NO3]-) and larger clusters. The larger ion distributions generated by these complex mixtures were differentiated using principal component analysis (PCA) of the mass spectra generated at two points during the thermal desorption profile (low and high temperatures), as well as at high in-source collision induced dissociation (CID). The PCA framework generated by the analysis of two black powders and five black powder substitutes was used to classify samples collected from a commercial firecracker containing both flash powder and black powder. The coupling of IRTD DART-MS and multivariate statistics demonstrated the powerful utility for detection and discrimination of trace fuel-oxidizer mixtures. PMID- 30516960 TI - Biodistribution of Filamentous Plant Virus Nanoparticles: Pepino Mosaic Virus versus Potato Virus X. AB - Nanoparticles with high aspect ratios have favorable attributes for drug delivery and bio-imaging applications based on their enhanced tissue penetration and tumor homing properties. Here, we investigated a novel filamentous viral nanoparticle (VNP) based on Pepino mosaic virus (PepMV), a relative of the established platform Potato virus X (PVX). We studied the chemical reactivity of PepMV, produced fluorescent versions of PepMV and PVX, and then evaluated their biodistribution in mouse tumor models. We found that PepMV can be conjugated to various small chemical modifiers including fluorescent probes via the amine groups of surface-exposed lysine residues, yielding VNPs carrying payloads of up to 1600 modifiers per particle. Although PepMV and PVX share similarities in particle size and shape, PepMV achieved enhanced tumor homing and less non specific tissue distribution compared to PVX in mouse models of triple negative breast cancer and ovarian cancer. In conclusion, PepMV provides a novel tool for nanomedical research but more research is needed to fully exploit the potential of plant VNPs for health applications. PMID- 30516961 TI - Concept and Development of Framework Nucleic Acids. AB - The blooming field of structural DNA nanotechnology harnessing the material properties of nucleic acids has attracted widespread interest. The exploitation of the precise and programmable Watson-Crick base pairing of DNA or RNA has led to the development of exquisite nucleic acid nanostructures from one to three dimensions. The advances of computer-aided tools facilitate automated design of DNA nanostructures with various sizes and shapes. Especially, the construction of shell or skeleton DNA frameworks, or more recently dubbed 'Framework Nucleic Acids' (FNAs) provides a means to organize molecules or nanoparticles with nanometer precision. The intrinsic biological properties and tailorable functionalities of FNAs hold great promise for physical, chemical, and biological applications. This perspective highlights state-of-the-art design and construction, of precisely assembled FNAs, and outlines the challenges and opportunities for exploiting the structural potential of FNAs for translational applications. PMID- 30516962 TI - All solution-based heterogeneous material formation for p-n junction diodes. AB - All solution-based devices have potential as the next class of macroscale and multifunctional electronics on versatile amorphous substrates. Different methods and materials have been studied to control the formation of p-type and n-type semiconducting materials because forming active materials for transistors and sensors remains challenge. This study proposes an approach for solution-based devices in which a p-n junction diode is fabricated using a solution-based InZnO (IZO) thin film for the n-type semiconductor and a carbon nanotube (CNT) network film for the p-type semiconductor. Additionally, the barrier height (~160 meV) is extracted and a p-n junction diode on a plastic film is demonstrated. Although the performance requires further improvements by modifying the interfaces, this printing method may be an interesting approach for all-printed electronics, which can replace conventional Si electronics. PMID- 30516963 TI - Reduction of Nitro Compounds Using 3d-Non-Noble Metal Catalysts. AB - The reduction of nitro compounds to the corresponding amines is one of the most utilized catalytic processes in the fine and bulk chemical industry. The latest development of catalysts with cheap metals like Fe, Co, Ni, and Cu has led to their tremendous achievements over the last years prompting their greater application as "standard" catalysts. In this review, we will comprehensively discuss the use of homogeneous and heterogeneous catalysts based on non-noble 3d metals for the reduction of nitro compounds using various reductants. The different systems will be revised considering both the catalytic performances and synthetic aspects highlighting also their advantages and disadvantages. PMID- 30516964 TI - Metallonanobelt: A Kinetically Stable Shape-Persistent Molecular Belt Prepared by Reversible Self-Assembly Processes. AB - A triptycene-based shape-persistent belt-shaped macrocycle, metallonanobelt, was synthesized by the self-assembly of 2,3,6,7-tetraaminotriptycene L and square planar Pd2+. The pentamer was selectively formed by the complexation of L with Pd2+ in the presence of the pillar[6]arene derivative P6 having triethylene glycol pendant as a template, whereas a mixture of a trimer, tetramer, and pentamer was obtained in the absence of the template. The pentamer was successfully isolated based on the solubility difference between the metallonanobelt and the template. It was also revealed that the isolated pentamer was remarkably stable in solutions such as acetonitrile or methanol thanks to the relatively inert planar chelate metal complex, [Pd( o-phenylenediamine)2] unit. Thus, we can handle the metallonanobelt almost as a static organic nanobelt that is synthesized covalently. PMID- 30516965 TI - Binding of distinct substrate conformations enables hydroxylation of remote sites in thaxtomin D by cytochrome P450 TxtC. AB - Cytochromes P450 (CYPs) catalyze various oxidative transformations in drug metabolism, xenobiotic degradation and natural product biosynthesis. Here we report biochemical, structural and theoretical studies of TxtC, an unusual bifunctional CYP in-volved in the biosynthesis of the EPA-approved herbicide thaxtomin A. TxtC was shown to hydroxylate two remote sites with-in the Phe residue of its diketopiperazine substrate thaxtomin D. The reactions follow a preferred order, with hydroxylation of the ?-carbon preceding functionalization of the phenyl group. To illuminate the molecular basis for remote site functionaliza-tion, X-ray crystal structures of TxtC in complex with the substrate and monohydroxylated intermediate were determined. Electron density corresponding to a diatomic molecule (probably dioxygen) was sandwiched between the heme iron atom and Thr237 in the TxtC-intermediate structure, providing insight into the mechanism for conversion of the ferrous-dioxygen com-plex into the reactive ferryl intermediate. The substrate and monohydroxylated intermediate adopted similar conformations in the active site, with the ?-face of the phenyl group positioned over the heme iron atom. Docking simulations reproduced this observation and identified a second, energetically similar but conformationally distinct binding mode in which the ?-hydrogen of the Phe residue is positioned over the heme prosthetic group. Molecular dynamics simulations confirmed that the ?-hydrogen is sufficiently close to the ferryl oxygen atom to be extracted by it and indicated that the two substrate conformations cannot readily interconvert in the active site. These results indicate that TxtC is able to hydroxylate two spatially remote sites by binding distinct conformations of the substrate and monohydroxylated intermediate. PMID- 30516966 TI - Control of Intra- versus Extracellular Bioorthogonal Catalysis using Surface Engineered Nanozymes. AB - Bioorthogonal transformation of prodrugs and profluorophores using transition metal catalysts (TMC) offers a promising strategy for therapeutic and imaging applications. Here, we report the surface engineering of nanoparticles to specifically localize gold nanoparticles (AuNPs) with encapsulated TMCs (nanozymes) to either the inside or outside of cells. The ability to control nanozyme localization and hence activity was demonstrated by the activation of pro-fluorophores and prodrugs intra- and extracellularly, establishing the potential of engineered nanozyme platforms for both diagnostic and therapeutic purposes. PMID- 30516967 TI - Architecture of Biperovskite-Based LaCrO3/PbTiO3 p-n Heterojunction with a Strong Interface for Enhanced Charge Anti-recombination Process and Visible Light Induced Photocatalytic Reactions. AB - Erection of a resourceful p-n heterojunction is a state-of-the-art tactic to flourish the charge anti-recombination process at the heterojunction interface and boost the photocatalytic activities under visible light irradiation. In the present work, we have engineered a new series of PbTiO3/LaCrO3 (PT/LC) p-n heterojunction through a facile two-step combustion process. The structural, interface, and optical analysis distinctly revealed a strong intact between p type LaCrO3 and n-type PbTiO3, elucidating their electronic channelization and substantial reduction of electron-hole recombination at the PbTiO3/LaCrO3 interface, which extend the lifetime and population of photogenerated charges in the p-n heterojunction material. The asymmetry photocurrent in the opposite directions and an inverted characteristic V-shape Mott-Schottky plot of the optimal PT/LC (7/3) material demonstrated the construction of a p-n heterojunction. The optimal p-n heterojunction possesses excellent photostability, and it revealed the highest photocatalytic activity toward degradation of phenol, that is, 86% and hydrogen generation, that is, 343.57 MUmol in 2 h. The enhanced photocatalytic activities of the p-n heterojunction materials in comparison to pristine ones are due to the higher separation charge carriers across the p-n heterojunction interface, which was deeply elucidated by carrying out electrochemical impedance spectroscopy, time-resolved photoluminescence spectroscopy, and photoluminescence analyses. These materials pave a new way to design the interface intact photocatalyst with an ultrafast approach for migration of photoexcited electrons across the p-n heterojunction and enhance the photocatalytic activities. PMID- 30516968 TI - Interfacial Conformation of Hydrophilic Polyphosphoesters Affects Blood Protein Adsorption. AB - Synthetic polymers are commonly used as protein repelling materials for a variety of biomedical applications. Despite their widespread use, the fundamental mechanism underlying protein repellence is often elusive. Such insights are essential for improving existing, and developing new materials. Here, we investigate how subtle differences in the chemistry of hydrophilic polyphosphoesters influence the adsorption of the human blood proteins serum albumin and fibrinogen. Using thermodynamic measurements, surface-specific vibrational spectroscopy and Brewster angle microscopy, we investigate protein adsorption, hydration as well as the steric repulsion properties of the polyphosphoester polymers. Whereas both surface hydration and polymer conformation of the polymers vary substantially as a consequence of the chemical differences in the polymer structure, the protein repellency ability of these hydrophilic materials appears to be dominated by steric repulsion. PMID- 30516969 TI - Lanthanide-doped Hafnia Nanoparticles for Multimodal Theranostics: Tailoring the Physicochemical Properties and Interactions with Biological Entities. AB - High-Z metal oxide nanoparticles hold promise as imaging probes and radio enhancers. Hafnium dioxide nanoparticles have recently entered clinical evaluation. Despite promising early clinical findings, the potential of HfO2 as a matrix for multimodal theranostics is yet to be developed. Here, we investigate the physicochemical properties and the potential of HfO2-based nanoparticles for multimodal theranostic imaging. Undoped and lanthanide (Eu3+, Tb3+, and Gd3+) doped HfO2 nanoparticles were synthesized and functionalized with various moieties, including poly(vinylpyrrolidone) (PVP), (3-aminopropyl)triethoxysilane (APTES) and folic acid (FA). We show that different synthesis routes, including direct precipitation, microwave-assisted synthesis, and sol-gel chemistry allow preparation of hafnium dioxide particles with distinct physicochemical properties. Sol-gel based synthesis allows preparation of uniform nanoparticles with dopant incorporation efficiencies superior to the other two methods. Both luminescence and contrast properties can be tweaked by lanthanide doping. We show that MRI contrast can be unified with radio-enhancement by incorporating lanthanide dopants in the HfO2 matrix. Importantly, ion leaching from the HfO2 host matrix in lysosomal-like conditions was minimal. For Gd:HfO2 nanoparticles, leaching was reduced >10* compared to Gd2O3 and no relevant cytotoxic effects have been observed in monocyte-derived macrophages for nanoparticle concentrations up to 250 ug/mL. Chemical surface modification allows further tailoring of the cyto- and hemocompatibility and enables functionalization with molecular targeting entities, which lead to enhanced cellular uptake. Taken together, the present study illustrates the manifold properties of HfO2-based nanomaterials with prospective clinical utility beyond radio-enhancement. PMID- 30516970 TI - Stretchable Conjugated Polymers: A Case Study in Topic Selection for New Research Groups. AB - The field of pi-conjugated (semiconducting) polymers has been underwritten largely because of the promise of flexible (and increasingly, stretchable) devices for energy and health care. Our research group has spent much of the past six years studying the mechanical properties of conjugated polymers. Mechanically robust materials can extend the life spans of devices such as solar cells and organic light-emitting diode (OLED) panels and enable high throughput processing techniques such as roll-to-roll printing. Additionally, wearable and implantable devices, including electronic skin, implantable pressure sensors, and haptic actuators, benefit by having moduli and extensibilities close to those of biological tissue. At the time of our laboratory's inception, however, the optoelectronic properties of conjugated polymers were understood in much greater depth than their mechanical properties. We therefore set out, as our laboratory's first research topic, to understand the molecular and microstructural determinants of the mechanical properties of conjugated polymers. This is an Account not only of our scientific findings but also of the pragmatic aspects, including personnel, funding, and time constraints, behind our studies as a nascent research group. We hope that this Account will provide information to newly independent scientists about the process of starting a new research laboratory. We identify three main stages of our scientific growth. (1) We began by conducting proof-of-concept experiments to identify basic correlations between chemical structure and mechanical properties and to determine whether high optoelectronic performance and mechanical robustness were mutually exclusive. (2) We then added new metrological techniques to enable more rapid and robust measurements, such as obtaining full stress-strain curves for conjugated polymer thin films, characterizing modes of thin film failure, and simplified identification of the glass transition temperature. (3) Finally, we incorporated new capabilities, such as organic synthesis and molecular dynamics simulations, into the toolkit of our group. These stages corresponded with increased funding, personnel commitment, and flexibility to take on long-term projects. Our research efforts identified polythiophene-based semiconducting polymers capable of both achieving high power conversion efficiencies and accommodating high degrees of strain. Additionally, we identified several chemical and microstructural determinants of the mechanical properties of conjugated polymer films, such as the chemical composition and structure of side chains and a high degree of dependence on amorphous packing structure. While the field has not yet produced stretchable materials that retain state-of-the-art electronic properties with high elastic range and repeated deformation, we hope that our work and the work of others in the field has provided a foundation for future advances. PMID- 30516971 TI - Design and biosynthesis of dimeric alboflavusins with biaryl linkages via regiospecific C-C bond coupling. AB - Alboflavusins (AFNs) are a group of cyclohexapeptides with moderate antibacterial and antitumor activities from Streptomyces alboflavus sp. 313. In vivo and in vitro studies proposed that AFNs are biosynthesized by a non-ribosomal peptide synthetase machinery, and the 6-Cl-L-Trp precursor is supplied by a tryptophan halogenase gene locating outside the afn gene cluster. Guided by the structure activity relationship knowledge about the AFN-like cyclohexapeptides, two Dimeric AFNs (Di-AFNs) with regiospecific biaryl linkages were designed and generated biotechnologically by expressing the P450 gene hmtS or clpS in S. alboflavus wild type and mutant strains. The Di-AFNs displayed much better antibacterial and antitumor activities than their monomers as anticipated, exemplifying a rational strategy to generate natural product congeners with improved bioactivities. PMID- 30516972 TI - Imaging of endogenous hydrogen peroxide during the process of cell mitosis and mouse brain development with a near-infrared ratiometric fluorescent probe. AB - Hydrogen peroxide (H2O2) is emerging as a new second messenger, which plays vital roles in intracellular signaling, thereby triggering physiological variations in terms of proliferation, differentiation, and migration. As known, cell mitosis has closely association to the intracellular level of H2O2, which contribute to the significant effects on the brain development, especially during the critical period of immaturity. To further investigate the biological roles of endogenous H2O2 in cells mitosis, we develop a near-infrared ratiometric fluorescent probe BCy-PFS for specifically imaging of endogenous H2O2 in cells and in vivo. Employing the probe BCy-PFS, we examine the critical effects of endogenous H2O2 on cells proliferation in live hippo-campal neurons cells, our results provide strong evidences for H2O2 signaling in cell mitosis through growth factor signaling. Furthermore, we successfully demonstrate the close association of endogenous H2O2 level changes with the brain develop-ment at various stages. We envision that this present probe has potential as a promising useful chemical imaging tool for exploring the roles of H2O2 in cell mitosis. PMID- 30516973 TI - High-Rate Nanostructured Pyrite Cathodes Enabled by Fluorinated Surface and Compact Grain Stacking via Sulfuration of Ionic Liquid Coated Fluorides. AB - Metal-polysulfide batteries are attracting broad attentions as conversion reaction systems of high theoretical energy density and low cost. However, their further applications are hindered by low loading of active species, excess conductive additive and loose (nanostructured) electrode network. Herein, we propose that compact grain stacking and surface fluorination are two crucial factors for achieving high-rate and long-life pyrite (FeS2) cathode enabled by sulfurating ionic liquid wrapped open framework fluorides. Both the factors can accelerate the Li- and Na-driven transport across pyrite-electrolyte interface and conversion propagation between adjacent grains. Such an electrode design enables a highly reversible capacity of 425 mAh/g after 1000 cycles at 1C for Li storage and 450 mAh/g after 1200 cycles at 2C for Na-storage even under high loading of pyrite grains and ultrathin carbon coating (< 2 nm). Its cathode energy density can reach to 800 and 350 Wh/kg for Li and Na cells respectively under a high power density of 10000 W/kg. The cross-linkage between ionic liquid and fluoride precursors appears to be a solution to the reinforcement of surface fluorination. PMID- 30516974 TI - Accelerated Blood Clearance of Antibodies by Nanosized Click Antidotes. AB - Long blood half-life is one of the advantages of antibodies over small molecule drugs. At the same time, prolonged half-life is a problem for imaging applications or in the case of antibody-induced toxicities. There is a substantial need for antidotes that can quickly clear antibodies from systemic circulation and peripheral tissues. Engineered nanoparticles exhibit intrinsic affinity for clearance organs (mainly liver and spleen). trans-Cyclooctene (TCO) and methyltetrazine (MTZ) are versatile copper-free click chemistry components that are extensively being used for in vivo bioorthogonal couplings. To test the ability of nanoparticles to eliminate antibodies, we prepared a set of click modified, clinically relevant antidotes based on several classes of drug carriers: phospholipid-PEG micelles, bovine serum albumin (BSA), and cross-linked dextran iron oxide (CLIO) nanoparticles. Mice were injected with IRDye 800CW labeled, click-modified IgG followed by a click-modified antidote or PBS (control), and the levels of the IgG were monitored up to 72 h postinjection. Long-circulating lipid micelles produced a spike in IgG levels at 1 h, decreased IgG levels at 24 h, and did not decrease the area under the curve (AUC) and IgG accumulation in main organs. Long-circulating BSA decreased IgG levels at 1 and 24 h, decreased the AUC, but did not significantly decrease organ accumulation. Long-circulating CLIO nanoworms increased IgG levels at 1 h, decreased IgG levels at 24 h, did not decrease the AUC, and did not decrease the organ accumulation. On the other hand, short-circulating CLIO nanoparticles decreased IgG levels at 1 and 24 h, significantly decreasing the AUC and accumulation in the main organs. Multiple doses of CLIO and BSA were not able to completely eliminate the antibody from blood, despite the click reactivity of the residual IgG, likely due to exchange of IgG between blood and tissue compartments. Pharmacokinetic modeling suggests that short antidote half-life and fast click reaction rate should result in higher IgG depletion efficiency. Short-circulating click-modified nanocarriers are the most effective antidotes for elimination of antibodies from blood. This study sets a stage for future development of antidotes based on nanomedicine. PMID- 30516975 TI - Forensic Investigations of Diesel Oil Spills in the Environment using Comprehensive Two-Dimensional Gas Chromatography - High Resolution Mass Spectrometry and Chemometrics: New perspectives in the Absence of Recalcitrant Biomarkers. AB - Forensic investigations of oil spills aim to find the responsible source(s) of the spill. Oil weathering processes changes the chemical composition of the spilled oil and makes the matching of oil spill samples to potential sources difficult. Diesel oil spill cases are more challenging, because biomarkers recalcitrant to long-term weathering are absent. We developed and tested a new method for the analysis and matching of diesel oil spills using two-dimensional gas chromatography - high resolution mass spectrometry (GC*GC - HRMS) and 2D CHEMSIC (2-Dimensional CHEMometric analysis of Selected Ion Chromatograms), an extension of the CHEMSIC method to GC*GC data. The 2D-CHEMSIC performs pixel based analysis using chemometrics on concatenated sections of 2D extracted ions chromatograms to assess the overall chemical variability of the samples, with potential applications for matching spill-source pairs in forensic investigations. The method was tested on samples from a number of diesel oil spill cases, i) distinguishing chemically similar source diesels, ii) investigating weathering effects on spill samples to determine type and degree of weathering, and iii) to improve matching of diesel oil spill affected by weathering. Positive matches for spill-source pairs were identified after excluding the signals from the hydrocarbons most susceptible to evaporation, and photo-oxidized spills were also matched due to the presence of unaffected hydrocarbons. Forensic diagnostics obtained by the 2D-CHEMSIC were validated by the conventional CEN-Tr method. PMID- 30516976 TI - Can environmentally relevant neuroactive chemicals specifically be detected with the locomotor response test in zebrafish embryos? AB - Chemicals considered as neuroactive (such as certain pesticides, pharmaceuticals and industrial chemicals) are among the largest groups of bioactive substances recently detected in European rivers. However, the determination of nervous system-specific effects has been limited using in vitro tests or conventional endpoints including lethality. Thus, neurobehavioral tests using in vivo models (e.g. zebrafish embryo) have been proposed as complementary approaches. To investigate the specificity and sensitivity of a light-dark transition locomotor response (LMR) test in 4 to 5 days post fertilization zebrafish with respect to different modes of action (MoAs), we analyzed a set of 18 environmentally relevant compounds with various anticipated MoAs. We found that exposure-induced behavioral alterations were reproducible and dependent on concentration and time. Comparative and quantitative analyses of the obtained locomotor patterns revealed that behavioral effects were not restricted to compounds primarily known to target the nervous system. A clear distinction of MoAs based on locomotor patterns was not possible for most compounds. Furthermore, chemicals with an anticipated same MoA did not necessarily provoke similar behavioral phenotypes. Finally, we determined an increased sensitivity (>=10-fold) compared to observed mortality in the LMR assay for 5 of 8 neuroactive chemicals as opposed to non neuroactive compounds. PMID- 30516977 TI - Excited-State Switching between Ligand-Centered and Charge Transfer Modulated by Metal-Carbon Bonds in Cyclopentadienyl Iridium Complexes. AB - Three series of pentamethylcyclopentadienyl (Cp*) Ir(III) complexes with different bidentate ligands were synthesized and structurally characterized, [Cp*Ir(tpy)L] n+ (tpy = 2-tolylpyridinato; n = 0 or 1), [Cp*Ir(piq)L] n+ (piq = 1 phenylisoquinolinato; n = 0 or 1), and [Cp*Ir(bpy)L] m+ (bpy = 2,2'-bipyridine; m = 1 or 2), featuring a range of monodentate carbon-donor ligands within each series [L = 2,6-dimethylphenylisocyanide; 3,5-dimethylimidazol-2-ylidene (NHC); methyl)]. The spectroscopic and photophysical properties of these molecules and those of the photocatalyst [Cp*Ir(bpy)H]+ were examined to establish electronic structure-photophysical property relationships that engender productive photochemical reactivity of this hydride and its methyl analogue. The Ir(III) chromophores containing ancillary CNAr ligands exhibited features anticipated for predominantly ligand-centered (LC) excited states, and analogues bearing the NHC ancillary exhibited properties consistent with LC excited states containing a small admixture of metal-to-ligand charge-transfer (MLCT) character. However, the molecules featuring anionic and strongly sigma-donating methyl or hydride ligands exhibited photophysical properties consistent with a high degree of CT character. Density functional theory calculations suggest that the lowest energy triplet states in these complexes are composed of a mixture of MLCT and ligand-to-ligand CT originating from both the Cp* and methyl or hydride ancillary ligands. The high degree of CT character in the triplet excited states of methyliridium complexes bearing C^N-cyclometalated ligands offer a striking contrast to the photophysical properties of pseudo-octahedral structures fac-Ir(C^N)3 or Ir(C^N)2(acac) that have lowest-energy triplet excited states characterized as primarily LC character with a more moderate MLCT admixture. PMID- 30516978 TI - Matrix Assisted Regulation of Antimicrobial Properties: Mechanistic Elucidation with Ciprofloxacin-Based Polymeric Hydrogel Against Vibrio sp. AB - Design of new drug material through modification of some well known antibiotics to combat pathogenic bacteria must include a complete understanding of matrix regulation, since the human body consists of majorly three types of matrices; solid, semisolid and liquid which has a tendency to regulate antibacterial efficacy along with bactericidal mechanism of several antimicrobial agents. Herein, matrix dependent action of ciprofloxacin based polymeric hydrogel scaffold was explored against a new species of Vibrio, namely Vibrio chemaguriensis Iso1 (V. chemaguriensis), which is resistant to most of the common antibiotics and possess genes that can be linked to pathogenicity. Ciprofloxacin was attached to the polymeric system consisting of hydrophilic polyethylene glycol methyl ether methacrylate (PEGMA) and zwitterionic sulphabetaine methacrylate (SBMA) with antifouling nature via covalent linkage leading to effective polymer antibiotic conjugates (PACs) with linear and hyperbranched architectures. The hyperbranched PAC was transformed to polymeric gel exhibiting greater antibacterial efficacy in solid matrix than that of liquid one with complete bactericidal effect and rod to spherical switching of bacterial cell followed by chain formation via "dual" contact active and release mechanism through sustain removal of thiol terminated ciprofloxacin fragment along with equilibrium swelling and deswelling process. Lower killing efficacy was displayed in liquid matrix with intact cell morphology due to lack of forced contact between cell wall and gel surface as well as entrapment of released bioactive fragment via additional thick exopolysaccharide (EPS) layer, which throws a great challenge to modern medical sciences. PMID- 30516979 TI - Promoting the Delivery of Nanoparticles to Atherosclerotic Plaques by DNA Coating. AB - Many nanoparticle-based carriers to atherosclerotic plaques contain peptides, lipoproteins, and sugars, yet the application of DNA-based nanostructures for targeting plaques remains infrequent. In this work, we demonstrate that DNA coated superparamagnetic iron oxide nanoparticles (DNA-SPIONs), prepared by attaching DNA oligonucleotides to poly(ethylene glycol)-coated SPIONs (PEG SPIONs), effectively accumulate in the macrophages of atherosclerotic plaques following an intravenous injection into apolipoprotein E knockout (ApoE-/-) mice. DNA-SPIONs enter RAW 264.7 macrophages faster and more abundantly than PEG SPIONs. DNA-SPIONs mostly enter RAW 264.7 cells by engaging Class A scavenger receptors (SR-A) and lipid rafts and traffic inside the cell along the endolysosomal pathway. ABS-SPIONs, nanoparticles with a similarly polyanionic surface charge as DNA-SPIONs but bearing abasic oligonucleotides also effectively bind to SR-A and enter RAW 264.7 cells. Near-infrared fluorescence imaging reveals evident localization of DNA-SPIONs in the heart and aorta 30 min post injection. Aortic iron content for DNA-SPIONs climbs to the peak (~60% ID/g) 2 h post-injection (accompanied by profuse accumulation in the aortic root), but it takes 8 h for PEG-SPIONs to reach the peak aortic amount (~44% ID/g). ABS-SPIONs do not appreciably accumulate in the aorta or aortic root, suggesting that the DNA coating (not the surface charge) dictates in vivo plaque accumulation. Flow cytometry analysis reveals more pronounced uptake of DNA-SPIONs by hepatic endothelial cells, splenic macrophages and dendritic cells, and aortic M2 macrophages (the cell type with the highest uptake in the aorta) than PEG-SPIONs. In summary, coating nanoparticles with DNA is an effective strategy of promoting their systemic delivery to atherosclerotic plaques. PMID- 30516980 TI - Characterization of Polysaccharides from Feijoa Fruits ( Acca sellowiana Berg.) and Their Utilization as Growth Substrates by Gut Commensal Bacteroides Species. AB - Polysaccharides from feijoa fruit were extracted and analyzed; the composition of these polysaccharides conforms to those typically found in the primary cell walls of eudicotyledons. The two major polysaccharide extracts consisted of mainly pectic polysaccharides and hemicellulosic polysaccharides [xyloglucan (77%) and arabinoxylan (16%)]. A collection of commensal Bacteroides species was screened for growth in culture using these polysaccharide preparations and placed into five categories based on their preference for each substrate. Most of the species tested could utilize the pectic polysaccharides, but growth on the hemicellulose was more limited. Constituent sugar and glycosyl linkage analysis showed that species that grew on the hemicellulose fraction showed differences in their preference for the two polysaccharides in this preparation. Our data demonstrate that the members of the genus Bacteroides show differential hydrolysis of pectic polysaccharides, xyloglucan, and arabinoxylan, which might influence the structure and metabolic activities of the microbiota in the human gut. PMID- 30516981 TI - Ion-Ion Repulsions and Charge Shielding Effects Dominate the Permeation Mechanism through the OmpF Porin Channel. AB - OmpF is a wide channel bacterial porin frequently employed to study selective ionic translocation. The cationic preference of this porin is mainly determined by electrostatic forces between the translocated ion and the protein, the formation of ion pairs (e.g. K+...Cl-) being previously pointed as the main cause to favor the cationic transport through the constriction zone. Hybrid Quantum Mechanics / Molecular Mechanics - Molecular Dynamics (QM/MM-MD) simulations, which have provided polarization-containing potentials of mean force (PMF) profiles for different permeation scenarios, reveal significant new insights related with the ion translocation mechanism. Results show that the permeation is dominated by electrostatic interactions, which in turn affect ion-protein interactions at the constriction zone. However, it is observed that ion flow is favored by ion-ion repulsions and, in a lesser extent, by charge-shielding effects, instead of the previously pointed ionic pair formation. PMID- 30516982 TI - Experimentally derived and computationally optimized backbone conformational statistics for blocked amino acids. AB - Experimentally derived, amino acid specific backbone dihedral angle distributions are invaluable for modeling data-driven conformational equilibria of proteins and for enabling quantitative assessments of the accuracies of molecular mechanics forcefields. The protein coil library that is extracted from analysis of high resolution structures of proteins, has served as a useful proxy for quantifying intrinsic and context-dependent conformational distributions of amino acids. However, data that go into coil libraries will have hidden biases, and ad hoc procedures must be used to remove these biases. Here, we combine high-resolution biased information from protein structural databases with unbiased low-resolution information from spectroscopic measurements of blocked amino acids to obtain experimentally derived and computationally optimized coil library landscapes for each of the twenty naturally occurring amino acids. Quantitative descriptions of conformational distributions require parsing of data into conformational basins with defined envelopes, centers, and statistical weights. We develop and deploy a numerical method to extract conformational basins. The weights of conformational basins are optimized to reproduce quantitative inferences drawn from spectroscopic experiments for blocked amino acids. The optimized distributions serve as touchstones for assessments of intrinsic conformational preferences and for quantitative comparisons of molecular mechanics forcefields. PMID- 30516983 TI - Spirostaphylotrichin X from a Marine-Derived Fungus as an Anti-influenza Agent Targeting RNA Polymerase PB2. AB - A new spirocyclic gamma-lactam, named spirostaphylotrichin X (1), and three related known spirostaphylotrichins (2-4) were isolated from the marine-derived fungus Cochliobolus lunatus SCSIO41401. Their structures were determined by spectroscopic analyses. Spirostaphylotrichin X (1) displayed obvious inhibitory activities against multiple influenza virus strains, with IC50 values from 1.2 to 5.5 MUM. Investigation of the mechanism showed that 1 inhibited viral polymerase activity and interfered with the production of progeny viral RNA. Homogeneous time-resolved fluorescence, surface plasmon resonance assays, and a molecular docking study revealed that 1 could inhibit polymerase PB2 protein activity by binding to the highly conserved region of the cap-binding domain of PB2. These results suggest that 1 inhibits the replication of influenza A virus by interfering with the activity of PB2 protein and that 1 represents a new type of potential lead compound for the development of anti-influenza therapeutics. PMID- 30516984 TI - One- to Two-Exciton Transitions in Perylene Bisimide Dimer Revealed by Two Dimensional Electronic Spectroscopy. AB - The excited state energy levels of molecular dimers and aggregates play a critical role in their photophysical behavior and an understanding of the photodynamics in such structures is critical when developing applications such as photovoltaics and optoelectronic devices. Here, exciton transitions in two different covalently bound PBI dimers are studied by two-dimensional electronic spectroscopy (2DES), a powerful spectroscopic method, providing the most complete picture of vibronic transitions in molecular systems. The data are accurately reproduced using the equation of motion-phase matching approach. The unambiguous presence of one-exciton to two-exciton transitions are captured in our results and described in terms of a molecular exciton energy level scheme based on the Kasha model. Furthermore, the results are supported by comparative measurements with the PBI monomer and another dimer in which the inter-chromophore distance is increased. PMID- 30516985 TI - Control over Near-Ballistic Electron Transport through Formation of Parallel Pathways in a Single-Molecule Wire. AB - This paper reports highly efficient coherent tunneling in single-molecule wires of oligo-ferrocenes with one to three Fc units. The Fc units were directly coupled to the electrodes, i.e. without chemical anchoring groups between the Fc units and the terminal electrodes. We found that a single Fc unit readily interacts with the metal electrodes of an STM-break junction (STM = scanning tunneling microscope) and that the zero-voltage bias conductance of an individual Fc molecular junction increased 5-fold, up to 80% of the conductance quantum Go (77.4 uS), when the length of the molecular wire was increased from one to three connected Fc units. Our compendium of experimental evidences combined with non equilibrium Green functions calculations contemplate a plausible scenario to explain the exceedingly high measured conductance based on the electrode/molecule contact via multiple Fc units. The oligo-Fc backbone is initially connected through all Fc units and, as one of the junction electrodes is pulled away, each Fc unit is sequentially disconnected from one of the junction terminals resulting in a number of distinct conductance features proportional to the number of Fc units in the backbone. The conductance values are independent of the applied temperature (-10 to 85?C), which indicates that the mechanism of charge transport is coherent tunneling for all measured configurations. These measurements show the direct Fc-electrode coupling provides highly efficient molecular conduits with very low barrier for electron tunneling, and whose conductivity can be modulated near the ballistic regime through the number of Fc units able to bridge and the energy position of the frontier molecular orbital. PMID- 30516986 TI - Identity and activity of 2,4-D metabolites in wild radish ( Raphanus raphanistrum). AB - Synthetic auxin herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D) are widely used for selective control of broadleaf weeds in cereals and transgenic crops. Although the troublesome weed wild radish ( Raphanus raphanistrum) has developed resistance to 2,4-D, no populations have yet displayed an enhanced capacity for metabolic detoxification of the herbicide, with both susceptible and resistant wild radish plants readily metabolizing 2,4-D. Using mass spectrometry and NMR, the major 2,4-D metabolite was identified as the glucose ester, and its structure confirmed by synthesis. As expected, both the endogenous and synthetic compounds retained auxin activity in a bioassay. The lack of detectable 2,4-D hydroxylation in wild radish, and the lability of the glucose ester, suggest that metabolic 2,4-D resistance is unlikely to develop in this species. PMID- 30516987 TI - Chemoselective Aza-[4+3]-annulation of N-Perfluoroalkyl-1,2,3-triazoles with 1,3 Dienes: Access to N-Perfluoroalkyl-Substituted Azepines. AB - Rhodium-catalyzed transannulation of N-perfluoroalkylated 1,2,3-triazoles with 1,3-dienes under microwave heating proceeded chemoselectively via the formal aza [4+3]-pathway, affording N-perfluoroalkyl-substituted 2,5-dihydroazepines. A unique regioselectivity profile was observed in annulation with 1-substituted 1,3 diene, affording unusual 5,6-disubstituted examples. Transannulation of triazoles with 2-trimethylsilyloxybutadiene provided N-perfluoroalkyl-substituted azepinone derivatives. PMID- 30516988 TI - Restricted access volatile supramolecular solvents for single-step extraction/cleanup of benzimidazole anthelmintic drugs in milk prior to LC-MS/MS. AB - In this work, a restricted access volatile supramolecular solvent (RAM-VOL SUPRAS) directly synthesized in milk is proposed for the first time for the simultaneous extraction and cleanup of benzimidazole anthelmintic drugs in milk meant for human consumption. The RAM-VOL-SUPRAS was formed by the self-assembly and coacervation of hexanol in tetrahydrofuran induced by the water content in milk. Benzimidazoles legislated by the European Union were quantitatively extracted (80-110%) Proteins were precipitated by the action of THF and the amphiphile, extraction of carbohydrates was avoided by a size exclusion mechanism and lipids were removed during hexanol evaporation. The analytical methodology was fully validated according to Commission Decision 2002/657/EC. Method detection limits from 0.03 to 0.14 ug L-1 were well below the maximum residue limits legislated in milk for these drugs, with interday precisions at maximum residue levels below 13%. This novel methodology guarantees a rapid and reliable tool for daily and routinely laboratory analyses in the field of food quality control. PMID- 30516989 TI - CO2/O2 Exchange in Magnesium-Water Clusters Mg+(H2O) n. AB - Hydrated singly charged metal ions doped with carbon dioxide, Mg2+(CO2)-(H2O)n, in the gas phase are valuable model systems for the electrochemical activation of CO2. Here, we study these systems by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry combined with ab initio calculations. We show that the exchange reaction of CO2 with O2 proceeds fast with bare Mg+(CO2), with a rate coefficient kabs = 1.2*10-10 cm3 s-1, while hydrated species exhibit a lower rate in the range of kabs = 1.2-2.4*10-11 cm3 s-1 for this strongly exothermic reaction. Water makes the exchange reaction more exothermic but, at the same time, considerably slower. The results are rationalized with a need for proper orientation of the reactants in the hydrated system, with formation of a Mg2+(CO4)-(H2O)n intermediate while the activation energy is negligible. According to our nanocalorimetric analysis, the exchange reaction of the hydrated ion is exothermic by -1.7 +/- 0.5 eV, in agreement with quantum chemical calculations. PMID- 30516990 TI - The journey of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) from lab to clinic. AB - Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies used to treat HIV. Till now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), and rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis and clinical requirements for drugs. PMID- 30516991 TI - Thermodynamic Analysis of n-Hexane/Ethanol Binary Mixtures Using Kirkwood-Buff Theory. AB - A complete thermodynamic analysis of mixtures consisting of molecules with complex chemical constitution can be rather demanding. Kirkwood-Buff theory of solutions allows the estimation of thermodynamic properties which cannot be directly extracted from atomistic simulations, such as the Gibbs energy of mixing (Deltamix G). In this work we perform molecular dynamics simulations of n hexane/ethanol binary mixtures in the liquid state under two temperature-pressure conditions and at various mole fractions. Based on the recently published methodology of Galata et al. [ Fluid Phase Equilib. 2018, 470, 25-37], we first calculate the Kirkwood-Buff (KB) integrals in the isothermal-isobaric ( NpT) ensemble, identifying how system size affects their estimation. We then extract the activity coefficients, excess Gibbs energy, excess enthalpy, and excess entropy for the n-hexane/ethanol binary mixtures we simulate. We employ two approaches for quantifying composition fluctuations: one based on counting molecular centers of mass, and a second one based on counting molecular segments. Results from the two approaches are practically indistinguishable. We compare our results against predictions of vapor-liquid equilibria obtained in a previous simulation work using the same force field, as well as with experimental data, and find very good agreement. In addition, we develop a simple methodology to identify the hydrogen bonds between ethanol molecules and analyze their effects on mixing properties. PMID- 30516992 TI - Ceric ammonium sulfate (CAS) mediated oxidations of benzophenones possessing a phenolic substituent for the synthesis of xanthones and related products. AB - Work previously published by our group described novel methodology for the synthesis of xanthones and related products from phenolic benzophenones in a reaction mediated by ceric ammonium sulfate (CAS). In this paper we further explore this novel reaction by subjecting an additional set of phenolic benzophenones to CAS to afford a range of compounds, including xanthones, 9H xanthen-2,9(4aH)-diones, 3H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4' diones and biaryl compounds. Based on these results, greater insight into the reaction mechanism has been gained. In addition, the conversion of the synthesized xanthen-2,9(4aH)-diones to xanthones by treatment with sodium dithionite is described. PMID- 30516993 TI - Time-Temperature Scaling and Dielectric Modeling of Conductivity Spectra of Single-Ion Conducting Liquid Dendrimer Electrolytes. AB - We discuss here the time-temperature scaling and dielectric modeling of the variation of single-ion conductivity with frequency of first generation (G1) liquid dendrimer electrolyte, viz. (propyl-ether-imine) (PETIM): Li-salt. The PETIM: Li-salt electrolyte exhibits cation/anion transference number close to unity in the liquid state. On switching from an ester (G1-COOR) to cyano (G1-CN) peripheral group, keeping constant the linker (ether) and branching groups (amine), an interesting transformation from cationic (t+ ~1) to an anionic conductor (t- ~1) takes place. The switch in the nature of predominant charge carrier is directly related to the change in the magnitude of anion diffusion (D ), which increases by one order in magnitude from D- = 1.1*10-12 m2 s-1 (at 30 oC) in G1-COOR to D- = 1.3*10-11 m2 s-1 (at 30 oC) in G1-CN. This intriguing ion transport mechanism is probed comprehensively using ac-impedance spectroscopy. The frequency dependent ionic conductivity of G1-CN/G1-COOR, comprising of distinct frequency regimes, is analyzed using time-temperature superposition scaling principle (TTSP) based on Summerfield and Baranovski scaling methods. To gain insight in to the electrical polarization (EP) phenomenon, the relevant frequency regime is converted from conductivity to dielectric versus frequency. The dielectric versus frequency data is modelled using Macdonald and Coelho. The combined approach of TTSP and dielectric modeling provide explicitly the extent of the influence of ion-dendrimer, ion-ion interactions and also the mobile charge carrier density on the effective ion transport in the homogeneous single ion conducting dendrimer electrolytes. The combined analysis suggests that ion transport in PETIM-COOR is only due to enhanced ion mobility whereas in PETIM-CN it is due to both mobile charge carrier concentration and ion mobility. To the best of our knowledge, the scaling and modeling approaches employed here constitute a rare example for validation of such concepts in the context of dendrimer electrolytes. PMID- 30516994 TI - Thermal Stability of Globins: Implications of Flexibility and Heme Coordination Studied by Molecular Dynamics Simulations. AB - Proteins are sensitive to temperature, and abrupt changes in the normal temperature conditions can have a profound impact in both structure and function, leading to protein unfolding. However, adaptation of certain organisms to extreme conditions raises questions about the structural features that permit to preserve the structure and function of proteins in these adverse conditions. To gain insight into the molecular basis of protein thermostability in the globin family, we have examined three representative examples: human neuroglobin, horse heart myoglobin and Drosophila hemoglobin, which differ in their melting temperature and the coordination state of the heme iron in absence of external ligands. In order to elucidate the possible mechanisms that govern the thermostability in these proteins, microsecond-scale classical molecular dynamics simulations were performed at different temperatures. Structural fluctuations and essential dynamics were analyzed, indicating that the flexibility of the CD region, which includes the two short C and D helixes and the connecting CD loop, is directly related with the thermostability. We observe that a larger inherent flexibility of the protein produces higher thermostability, probably concentrating the thermal fluctuations observed at high temperature in flexible regions, preventing unfolding. Globally, the results in this work improve our understanding of thermostability in the globin family. PMID- 30516995 TI - Metallaphotoredox-Catalyzed Cross-Electrophile Csp3-Csp3 Coupling of Aliphatic Bromides. AB - A strategy for the installation of small alkyl fragments onto pharmaceutically relevant aliphatic structures has been established via metallaphotoredox catalysis. Herein, we report that tris(trimethylsilyl)silanol can be employed as an effective halogen abstraction reagent that, in combination with photoredox and nickel catalysis, allows a generic approach to Csp3-Csp3 cross-electrophile coupling. In this study, we demonstrate that a variety of aliphatic drug-like groups can be successfully coupled with a number of commercially available small alkyl electrophiles, including methyl tosylate and strained cyclic alkyl bromides. Moreover, the union of two secondary aliphatic carbon centers, a long standing challenge for organic molecule construction, has been accomplished with a wide array of structural formats. Last, this technology can be selectively merged with Csp2-Csp3 aryl-alkyl couplings to build drug-like systems in a highly modular fashion. PMID- 30516996 TI - Dielectric Behavior as a Screen in Rational Searches for Electronic Materials: Metal Pnictide Sulfosalts. AB - Dielectric screening plays an important role in reducing the strength of carrier scattering and trapping by point defects for many semiconductors such as the halide perovskite solar materials. However, it was rarely considered as a screen to find new electronic semiconductors. We performed a material search study using the dielectric properties as a screen to identify potential electronic materials in the class of metal-pnictide ternary sulfosalts, containing Bi or Sb. These salts are basically ionic due to the electronegativity difference between both the S and both the metal and pnictogen elements. However, we do find significant cross-gap hybridization between the S p derived valence bands and pnictogen p derived conduction bands in many of the materials. This leads to enhanced Born effective charges, and in several cases, highly enhanced dielectric constants. We find a chemical rule for high dielectric constant in terms of the bond connectivity of the pnictogen-chalcogen part of the crystal structure. We additionally find a series of compounds with low effective mass, high dielectric constant and other properties that suggest good performance as electronic materials, and also several potential thermoelectric compounds. Experimental optical data and solar conversion efficiency are reported for Sn-Sb-S samples and results in accord with predicted good performance are found. The results illustrate the utility of dielectric properties as a screen for identifying complex semiconductors. PMID- 30516997 TI - Plant-mediated Horizontal Transmission of Hamiltonella defensa in the Wheat Aphid Sitobion miscanthi. AB - Hamiltonella defensa is mainly vertically transmitted, but evidence suggests that horizontal transmission may occur. Here, the first case of plant-mediated horizontal transmission of H. defensa between wheat aphids, Sitobion miscanthi, is reported. H. defensa was harbored in sheath cells, secondary bacteriocytes and hemolymph. After Hamiltonella-infected aphids fed on wheat leaves, H. defensa was observed in aphid stylets and plant phloem. H. defensa persisted in wheat leaves for at least 10 days. Most Hamiltonella-uninfected aphids became infected with H. defensa after sustained feeding on infected plant leaves and showed almost 100% stable vertical transmission over the next five generations. These horizontal transmission experiments were replicated using two other plants, rice and corn, and two different wheat aphids, Rhopalosiphum padi and Schizaphis graminum. Surprisingly, aphid feeding induced plant infection only locally rather than systemically in leaves. Our findings indicate that plants may act as horizontal transmission intermediaries, contributing to the ubiquity of the otherwise maternally inherited H. defensa. PMID- 30516998 TI - Development of 2-(2-(3-(4-([18F]Fluoromethoxy-d2)phenyl)-7-methyl- 4-oxo-3,4 dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione for Positron Emission Tomography Imaging of Phosphodiesterase 10A (PDE10A) in Brain. AB - Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central nervous system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4 dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron emission tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [18F]5 can accumulate in the brain. In this study, using [18F]5 as a lead compound, we designed four new 18F-labeled ligands ([18F]6-9) to find one more suitable than [18F]5. Of these, 2-(2-(3-(4-([18F]fluoromethoxy-d2)phenyl)-4-oxo-3,4 dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]9) exhibited high in vitro binding affinity (Ki = 2.9 nM) to PDE10A and suitable lipophilicity (LogD = 2.2). In PET studies, the binding potential (BPND) of [18F]9 (5.8) to PDE10A in rat brains was significantly higher than that of [18F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamination with radiolabeled metabolites of [18F]9 in the brain than those of [18F]5. In conclusion, [18F]9 is a useful PET ligand for PDE10A imaging in brain. PMID- 30516999 TI - Boosting quantum machine learning models with multi-level combination technique: Pople diagrams revisited. AB - Inspired by Pople diagrams popular in quantum chemistry, we introduce a hierarchical scheme, based on the multi-level combination (C) technique, to combine various levels of approximations made when calculating molecular energies within quantum chemistry. When combined with quantum machine learning (QML) models, the resulting CQML model is a generalized unified recursive kernel ridge regression which exploits correlations implicitly encoded in training data comprised of multiple levels in multiple dimensions. Here, we have investigated up to three dimensions: Chemical space, basis set, and electron correlation treatment. Numerical results have been obtained for atomization energies of a set of $?sim$7'000 organic molecules with up to 7 atoms (not counting hydrogens) containing CHONFClS, as well as for $?sim$6'000 constitutional isomers of C$_7$H$_{10}$O$_2$. CQML learning curves for atomization energies suggest a dramatic reduction in necessary training samples calculated with the most accurate and costly method. In order to generate milli-second estimates of CCSD(T)/cc-pvdz atomization energies with prediction errors reaching chemical accuracy ($?sim$1 kcal/mol), the CQML model requires only $?sim$100 training instances at CCSD(T)/cc-pvdz level, rather than thousands within conventional QML, while more training molecules are required at lower levels. Our results suggest a possibly favourable trade-off between various hierarchical approximations whose computational cost scales differently with electron number. PMID- 30517001 TI - Low-Energy Photoelectron Spectrum and Dissociative Photoionization of the Smallest Amides: Formamide and Acetamide. AB - The threshold photoelectron spectrum and low-energy dissociative photoionization processes of formamide and acetamide were studied using photoelectron photoion coincidence spectroscopy and vacuum ultraviolet synchrotron radiation. Ab initio calculations and Franck-Condon simulations helped us assign the main vibrational progressions in the spectra and enabled the first conclusive assignment of the first electronically excited states. The adiabatic ionization energies to the X and A states of formamide (10.236 +/- 0.004 eV and 10.643 +/- 0.015 eV) and acetamide (9.734 +/- 0.008 and 10.282 +/- 0.020 eV) have been re-evaluated and spectroscopic transitions were assigned using a Franck-Condon approach. The cationic potential energy surface was explored to rationalize the observed fragmentation patterns and to construct a statistical model, which was fitted to the experimental breakdown diagram. Thermochemical thresholds were measured and calculated for H, CO, and NH2 loss from HCONH2+ as well as for CH3, NH2, CO, HCCO, and NH3 loss from CH3CONH2+. We present the first comprehensive, experimental and theoretical treatise of these fragmentation processes. The statistical model confirms fast internal conversion between the X ^+ and A ^+ states in formamide, as H-transfer in CO loss is shown to take place on the excited state surface. It also explains the five almost simultaneously opening dissociation channels in the acetamide cation quantitatively. The derived 0 K appearance energies have been confirmed by ab initio calculations and by comparison with state-of-the-art thermochemical data, and revise some of the previous results by more than ten times their stated uncertainty. PMID- 30517000 TI - Fish oil emulsions stabilized with caseinate glycated by dextran: Physicochemical stability and gastrointestinal fate. AB - Incorporation of fish oil containing omega-3 polyunsaturated fatty acids (PUFAs) into functional foods remains challenging. In this study, caseinate and glycoconjugates (CD6, CD40, CD70, CD100) of caseinate to dextrans of different molecular weights (D6, D40, D70, D100 kDa) were used to stabilize fish oil emulsions, and the impact on physicochemical stability and gastrointestinal fate was investigated. The glycoconjugate of CD6 exhibited significantly higher conjugation efficiency, lower surface hydrophobicity (H0) and lower surface activity than other glycoconjugates. The glycoconjugate of CD70 displayed the best emulsifying activity and emulsion stability. Except CD6 stabilized emulsions, all other emulsions showed fine storage stability over 14 d at 22 +/- 1 degrees C. The glycoconjugates stabilized emulsions exhibited significantly lower peroxide value (PV) (P < 0.05) than that of caseinate stabilized one. During in vitro gastrointestinal tract digestion, the glycation of caseinate with dextrans changed the zeta-potential, average particle size (D32) and particle size distribution of the emulsions, which influenced flocculation and coalescence of droplets, as demonstrated by confocal microscopy. Caseinate after glycation with dextrans significantly retarded the release of free fatty acids from emulsions (P<0.05) during in vitro lipolysis. These results suggested that the dextrans attached to caseinate by glycation played a vital role in physicochemical stability and gastrointestinal fate of emulsions, mainly by its steric hindrance to effectively prevent flocculation and coalescence of droplets. PMID- 30517002 TI - Identification of G-Quadruplex-Binding Protein from the Exploration of RGG Motif/G-Quadruplex Interactions. AB - The arginine/glycine-rich region termed the RGG domain is usually found in G quadruplex (G4)-binding proteins and is im-portant in G4-protein interactions. Studies on the binding mechanism of RGG domains found that small segments (RGG motif) inside the domain contribute greatly to the G4 binding affinity. However, unlike the entire RGG domains that have been broadly explored, the role of the RGG motif remains obscure, with very limited study. Herein, to clarify the role of the RGG motif in G4-protein interactions, we systematically investigated the binding affinity and mode between RGG-motif peptides and G4s. The internal arrangement of RGG repeats and gap amino acids played a more crucial role in the G4 bind-ing mechanism than a critical amount of RGG repeats. Arginines and phenylalanines at the exact position of the RGG motif might enable additional hydrogen bonding and pi stacking interaction with nucleic acid bases and strengthen the binding of G4. Impressively, proceeding from a G4-binding RGG peptide, 12, discovered above, we identified the cold-inducible RNA-binding protein (CIRBP) as a new G4 DNA-binding protein both in vitro and in cells. In addition, we found that the key ami-no acids for G4 binding in peptide 12 and CIRBP were highly similar, and peptide 12 clearly played a key role in the G4 binding of CIRBP. This report is the first in which a G4-binding protein was identified from exploration of the G4-binding RGG motif. Our findings suggest a novel strategy to discover new G4-binding proteins by exploring key peptide segments. PMID- 30517003 TI - Dynamic imaging of the delay- and tilt-free motion of Neel domain walls in perpendicularly magnetized superlattices. AB - We report on the time-resolved investigation of current- and field-induced domain wall motion in the flow regime in perpendicularly magnetized microwires exhibiting anti-symmetric exchange interaction by means of scanning transmission x-ray microscopy using a time step of 200 ps. The sub-ns time step of the dynamical images allowed us to observe the absence of incubation times for the motion of the domain wall within an uncertainty of 200 ps, together with indications for a negligible inertia of the domain wall. Furthermore, we observed that, for short current and magnetic field pulses, the magnetic domain walls do not exhibit a tilting during its motion, providing a mechanism for the fast, tilt free, current-induced motion of magnetic domain walls. PMID- 30517004 TI - Vegetable signatures derived from human urinary metabolomic data in controlled feeding studies. AB - Examination of changes in urinary metabolomic profiles after vegetable ingestion may lead to new methods of assessing plant food intake. To this regard, we developed a proof-of-principle methodology to identify urinary metabolomic signatures for spinach, celery, and onion. Three feeding studies were conducted. In the first study, healthy individuals were fed with spinach, celery, onion, and no vegetable in four separate experiments with pooled urinary sample for metabolite discovery. The same protocol was used to validate the finding at individual level in the second study and to feed all three vegetables simultaneously in the third study. An LC/MS-based metabolomics approach was adopted to search for indicative metabolites from urine samples collected during multiple time periods before and after the meal. Consequently, a total of 1, 9, and 3 non-overlapping urinary metabolites were associated with the intake of spinach, celery, and onion, respectively. The PCA signature of these metabolites followed a similar "time cycle" pattern, which maximized at approximately 2-4 h after intake. In addition, the metabolite profiles for the same vegetable were consistent across samples, regardless consumed individually or in combination. The developed methodology along with the identified urinary metabolomic signatures were potential tools for assessing plant food intake. PMID- 30517005 TI - Expanding the Reactivity of Donor-Acceptor Cyclopropanes: Synthesis of Benzannulated Five-Membered Heterocycles via Intramolecular Attack of a Pendant Nucleophilic Group. AB - Lewis-acid-induced domino transformations of donor-acceptor cyclopropanes, possessing a nucleophilic center embedded in a donor group, into functionalized 2,3-dihydrobenzo[ b]furans and 2,3-dihydrobenzo[ b]thiophenes are reported herein. An unusual switch of the electrophilic center in the three-membered ring, from the atom bearing a donor substituent to an unsubstituted carbon atom, was achieved by a judicious choice of Lewis acid, which induces the isomerization of a cyclopropane to an electrophilic alkene, and the length of linker, connecting a nucleophilic moiety and the small ring. PMID- 30517006 TI - CYP3A4/5 activity probed with testosterone and midazolam: Correlation between two substrates at the microsomal and enzyme levels. AB - Testosterone (TST) and Midazolam (MDZ) are widely used as probes to detect CYP3A4/5 activity but the data acquired with these two substrates does not correlate well at the microsomal level (per milligram of microsomal protein) and the reason is unclear. In this study, CYP3A4/5 activity was probed with TST and MDZ at the microsomal and enzyme levels (per picomole of CYP3A4/5) in 72 human liver samples. Correlation coefficients were lower in Vmax, CLint at the microsomal level, as compared with those at the enzyme level (Vmax 0.658 vs. 0.883; CLint no correlation vs. 0.796). Compared with TST, MDZ was found to correlate better with content of CYP3A4/5 (no correlation vs. 0.431), CYP3A5 (no correlation vs. 0.447) and huge variations in enzyme content existed among different genotypes, which explained the lower degree of correlation at the microsomal level. In addition, different genotypes had varying effects on activity at the enzyme level, whereas the difference between activity at the enzyme level probed with TST and that probed with MDZ was not obvious (P > 0.05), indicating that the effect of gene polymorphisms on correlation between activity probed with these two substrates was limited at the enzyme level. In conclusion, our study demonstrates a high degree of correlation between CYP3A4/5 activity probed with TST and MDZ at the enzyme level, but not at the microsomal level and allows us to correctly understand the influence of gene polymorphisms on the correlations. PMID- 30517007 TI - Synthesis of 2-Quinolinones via a Hypervalent Iodine(III)-Mediated Intramolecular Decarboxylative Heck-Type Reaction at Room Temperature. AB - A hypervalent iodine(III)-mediated intramolecular decarboxylative Heck-type reaction of 2-vinyl-phenyl oxamic acids has been developed. The unique ring strain-enabled radical decarboxylation mechanism is preliminarily revealed. This protocol features metal-free reaction conditions and operational simplicity, allowing the lactamization of 2-vinylanilines using a readily accessible carbonyl source and the synthesis of various 2-quinolinones with excellent chemoselectivity at room temperature. PMID- 30517008 TI - Cp*Co(III)-Catalyzed Regioselective Synthesis of Cyclopenta[ b]carbazoles via Dual C(sp2)-H Functionalization of 1-(Pyridin-2-yl)-indoles with Diynes. AB - Cp*Co(III)-catalyzed synthesis of cyclopenta[ b]carbazoles from 1-(pyridin-2-yl) indoles and diynes is developed. This reaction involves dual C-H activation of indoles and domino cyclizations with diynes and has excellent regioselectivity, high efficiency, a broad substrate scope, and tolerance for various functional groups. A series of cyclopenta[ b]carbazole molecular scaffolds are obtained in good to excellent yields. PMID- 30517009 TI - Thiazolidin-5-imine Formation as a Catalyst-Free Bioorthogonal Reaction for Protein and Live Cell Labeling. AB - A previously undescribed reaction involving the formation of a thiazolidin-5 imine linkage was developed for bioconjugation. Being highly specific and operating in aqueous media, this simple condensation reaction is used to chemoselectively label peptides, proteins, and living cells under physiological conditions without the need to use toxic catalysts or reducing reagents. PMID- 30517010 TI - Oxide-Polymer Heterojunction Diodes with a Nanoscopic Phase-Separated Insulating Layer. AB - Organic semiconductor-insulator blend films are widely explored for high performance electronic devices enabled by unique phase separation and self assembly phenomena at key device interfaces. Here we report the first demonstration of high-performance hybrid diodes based on p-n junctions formed by a p-type poly(3-hexylthiophene) (P3HT)-poly(methylmethacrylate) (PMMA) blend and n-type indium-gallium-zinc oxide (IGZO). The thin film morphology, microstructure, and vertical phase separation behavior of the P3HT films with varying contents of PMMA are systematically analyzed. Microstructural and charge transport evaluation indicates that the polymer insulator component positively impacts the morphology, molecular orientation, and effective conjugation length of the P3HT films, thereby enhancing the heterojunction performance. Furthermore, the data suggest that PMMA phase segregation creates a continuous nanoscopic interlayer between the P3HT and IGZO layers, playing an important role in enhancing diode performance. Thus, the diode based on an optimal P3HT-PMMA blend exhibits a remarkable 10-fold increase in forward current versus that of a neat P3HT diode, yielding an ideality factor value as low as 2.5, and a moderate effective barrier height with an excellent rectification ratio. These results offer a new approach to simplified manufacturing of low-cost, large-area organic electronics technologies. PMID- 30517011 TI - In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. AB - In vitro and in vivo delivery of RNAs of interest holds promise for gene therapy. Recently, exosomes are considered as the rational vehicle for RNA delivery, especially miRNA and/or siRNA, while the loading efficiency is limited. In this study, we engineered the exosomes for RNA loading by constructing a fusion protein, in which the exosomal membrane protein CD9 was fused with RNA binding protein, while the RNAs of interest either natively harbors or is engineered to have the elements for the binding. By proof-of-principle experiments, we here fused CD9 with HuR, an RNA binding protein interacts with miR-155 with a relatively high affinity. In the exosome packaging cells, the fused CD9-HuR successfully enriches miR-155 into exosomes when miR-155 was excessively expressed. Moreover, miR-155 encapsulated in the exosomes in turn could be efficiently delivered into the recipient cells and recognizes the endogenous targets. In addition, we also revealed that the CD9-HuR exosomes could enrich the functional miRNA inhibitor or CRISPR/dCas9 when the RNAs were engineered to have the AU rich elements. Taken together, we here have established a novel strategy for RNA cargo encapsulation into engineered exosome, which in turn functions in the recipient cells. PMID- 30517012 TI - Suppression of Gold Nanoparticle Aggregation on Lipid Membranes Using Nanosized Liposomes to Increase Steric Hindrance. AB - Suppression of nanoparticle aggregation on a plasma membrane surface may lead to better understanding of the causes of various diseases and development of new drug delivery systems. In this study, we inhibited the aggregation of gold nanoparticles on a lipid membrane in a fluidic liquid-crystalline phase by using nanosized liposomes to increase steric hindrance. Adsorption of liposomes on gold nanoparticles was confirmed by transmission electron microscopy and ultraviolet visible absorption spectroscopy. The ability of the liposomes to suppress gold nanoparticle aggregation strongly depended on the concentration of liposomes providing steric hindrance. The fluidity or rigidity of the liposome membrane also strongly influenced the ability of the liposomes to suppress gold nanoparticle aggregation. PMID- 30517013 TI - Near-infrared Fluorescent Peptides with High Tumor Selectivity: Novel Probes for Image-Guided Surgical Resection of Orthotopic Glioma. AB - The complete excision of glioblastomas with maximal retention of surrounding normal tissues can significantly improve patient prognosis. Near-infrared fluorescence (NIRF) optical imaging of the tumor vasculature offers a non invasive method for detection of early-stage glioblastoma and efficient monitoring of therapeutic responses. The aim of this study was to develop a novel NIRF imaging probe as a visualization tool for image-guided surgical resection of orthotopic glioblastoma. In this study, Cy5.5-RKL, Cy5.5-NKL and Cy5.5-DKL probes were successfully synthesized and their properties investigated in vitro and in vivo. In vivo, Cy5.5-RKL and Cy5.5-NKL were able to detect U87MG xenografts for at least 8 h p.i.. The maximum tumor to muscle ratios of Cy5.5-RKL and Cy5.5-NKL were 7.65 +/- 0.72 and 5.43 +/- 0.72, respectively. Of the probes, Cy5.5-RKL displayed the best delineation of the boundaries between orthotopic glioblastomas and normal brain tissue at 8 h p.i. In conclusion, NIRF imaging using Cy5.5-RKL is promising not only for diagnostic purposes but also for use in image-guided surgery for orthotopic glioblastoma or other superficial tumors. PMID- 30517014 TI - Photocatalytic Hydrogen-Evolving Cross-Coupling of Arenes with Primary Amines. AB - Herein, we described a cooperative catalyst system consisting of an acridinium photoredox catalyst and a cobalt-based proton-reduction catalyst that is effective for the C-H amination of arenes with concomitant generation of hydrogen. This oxidant-free method allows a variety of amines with diverse functional groups to be converted to aromatic amines. Additionally, this protocol can also be extended to hydrolytically unstable benzophenone imines. PMID- 30517015 TI - Imaging the Optical Fields of Functionalized Silver Nanowires through Molecular TERS. AB - We image 4-mercaptobenzonitrile-functionalized silver nanowires (~20 nm diameter) through tip-enhanced Raman scattering (TERS). The enhanced local optical field molecular interactions that govern the recorded hyperspectral TERS images are dissected through hybrid finite-difference time-domain-density functional theory simulations. Our forward simulations illustrate that the recorded spatio-spectral profiles of the chemically functionalized nanowires may be reproduced by accounting for the interaction between orientationally averaged molecular polarizability derivative tensors and enhanced incident/scattered local fields polarized along the tip axis. In effect, we directly map the enhanced optical fields of the nanowire in real space through TERS. The simultaneously recorded atomic force microscopy (AFM) images allow a direct comparison between our attainable spatial resolution in topographic (13 nm) and TERS (5 nm) imaging measurements performed under ambient conditions. Overall, our described protocol enables local electric-field imaging with few nm precision through molecular TERS, and it is therefore generally applicable to a variety of plasmonic nano structures. PMID- 30517016 TI - Ag(I)-Catalyzed Nucleophilic Addition and Friedel-Crafts Alkylation between alpha Oxoketene Dithioacetals and Propargyl Carbonates. AB - Silver-catalyzed nucleophilic addition and intramolecular Friedel-Crafts alkylation between alpha-oxoketene dithioacetals and tertiary propargylic carbonates have been realized. The reactions proceeded in moderate to good yields with broad substrate scope, providing a straightforward method for the synthesis of substituted indenes. PMID- 30517017 TI - Lipidic Mesophase-embedded Palladium Nanoparticles: Synthesis and Tunable Catalysts in Suzuki-Miyaura Cross Coupling Reactions. AB - Lipidic cubic phases (LCPs) can reduce Pd2+-salts to palladium nanoparticles (PdNPs) of ~ 5 nm size in their confined water channels under mild conditions. The resulting PdNP-containing LCPs were used as nanoreactor scaffolds to catalyze Suzuki-Miyaura cross coupling reactions in the aqueous channels of the mesophase. To turn on catalysis, PdNP-containing LCPs are activated by swelling the aqueous channels of the lipidic framework, thereby enabling diffusion of the water soluble substrates to the catalysts. The mesophases play a threefold role: they act as the reducing agent for Pd2+, as a limiting template for their growth, and as a support. The system was characterized and investigated by small-angle X-ray scattering (SAXS), cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and nuclear magnetic resonance (NMR). Bulk LCPs as well as three dispersed palladium/lipid hybrid nanoparticle types were applied in catalysis. The latter - liposomes, hexosomes and cubosomes - can be obtained by design through combination of lipid and additive. The Suzuki-Miyaura cross coupling of 5-iodo-2'-deoxyuridine and phenylboronic acid was used as a model reaction to study these systems. Bulk Pd-LCPs deliver the Suzuki-Miyaura product in 24 h in conversions up to 98 % at room temperature, whereas with palladium/lipid dispersions at 40 degrees C 68 % of the starting material was transformed to the product after 72 h. PMID- 30517018 TI - Ruthenium-Catalyzed Intramolecular Double Hydroalkoxylation of Internal Alkynes. AB - Intramolecular double hydroalkoxylation of internal alkynes could be achieved using a Grubbs-type ruthenium carbene complex or its modified species to deliver a series of bridged- and spiroacetal derivatives in moderate to good yields. This study represents a new example of nonmetathetic reactions catalyzed by Grubbs type ruthenium carbene complexes. PMID- 30517019 TI - Impact of Environmental Stressors on Tolerance to Hemorrhage in Humans. AB - Hemorrhage is a leading cause of death in the military and civilian settings and approximately 85% of potentially survivable battlefield deaths are hemorrhage related. Both Soldiers and civilians are exposed to a number of environmental and physiological conditions that have the potential to alter tolerance to a hemorrhagic insult. The objective of this review article is to summarize the known impact of commonly encountered environmental and physiological conditions on hemorrhagic tolerance, primarily in humans. The majority of the presented studies use lower-body negative pressure (LBNP) to simulate a hemorrhagic insult, although some studies employed incremental blood withdrawal. This review first addresses the use of LBNP as a model of hemorrhage-induced central hypovolemia, and then addresses the effects of the following conditions on tolerance to LBNP: passive and exercise-induced heat stress with and without accompanying hypohydration/dehydration, hypothermic exposure, and altitude/hypoxia exposure. By understanding the effects of these environmental and physiological conditions on responses to a hemorrhagic challenge, including tolerance, targeted strategies and interventions can be developed and applied to reduce the impact of such conditions on tolerance to a hemorrhagic insult, and ultimately improve survival from blood loss injuries. PMID- 30517020 TI - Cost associated with hematopoietic stem cell transplantation: a retrospective claims data analysis in Germany. AB - AIM: Quantify hematopoietic stem cell transplantation (HSCT) costs in German patients with acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). METHODS: The primary outcome was direct and indirect costs in patients with ALL/DLBCL/FL who received HSCT between 2010 and 2014. Costs were evaluated two to four quarters before to eight quarters after HSCT. RESULTS: Among 258 patients with HSCT, direct costs were ?290,125/patient (pediatric ALL), ?246,266/patient (adult ALL), ?230,399/patient (DLBCL/FL allogeneic) and ?107,457/patient (DLBCL/FL autologous). Indirect costs with HSCT were ?52,939/patient (adult ALL), ?20,285/patient (DLBCL/FL allogeneic) and ?29,881/patient (DLBCL/FL autologous). CONCLUSION: Direct and indirect costs associated with HSCT are substantial for patients with ALL, DLBCL and FL. Novel therapies that reduce HSCT use could reduce medical costs. PMID- 30517021 TI - Encoding and Decoding DNA Sequences by Integer Chaos Game Representation. AB - DNA sequences are fundamental for encoding genetic information. The genetic information may be understood not only from symbolic sequences but also from the hidden signals inside the sequences. The symbolic sequences need to be transformed into numerical sequences so the hidden signals can be revealed by signal processing techniques. All current transformation methods encode DNA sequences into numerical values of the same length. These representations have limitations in the applications of genomic signal compression, encryption, and steganography. We propose a novel integer chaos game representation (inter-CGR or iCGR) of DNA sequences and a lossless encoding method DNA sequences by the iCGR. In the iCGR method, a DNA sequence is represented by the iterated function of the nucleotides and their positions in the sequence. Then the DNA sequence can be uniquely encoded and recovered using three integers from iCGR. One integer is the sequence length and the other two integers represent the accumulated distributions of nucleotides in the sequence. The integer encoding scheme can compress a DNA sequence by 2 bits per nucleotide. The integer representation of DNA sequences provides a prospective tool for sequence analysis and operations. PMID- 30517022 TI - Efficiently Mining Recurrent Substructures from Protein Three-Dimensional Structure Graphs. AB - Studying protein structures is a major asset for understanding the molecular mechanisms of life. The number of publicly available protein structures has increasingly become extremely large. Yet, the classification of a protein structure remains a difficult, costly, and time-consuming task. Exploring spatial information on protein structures can provide important functional and structural insights. In this context, spatial motifs may correspond to relevant fragments, which might be very useful for a better understanding of proteins. In this article, we propose AntMot, a fast algorithm, to find spatial motifs from protein three-dimensional structures by extending the Karp-Miller-Rosenberg repetition finder, originally dedicated to sequences. The extracted motifs, termed ant motifs, follow an ant-like shape that is composed of a backbone fragment from the primary structure, enriched with spatial refinements. We show that these motifs are biologically sound, and we used them as descriptors in the classification of several benchmark datasets. Experimental results show that our approach presents a trade-off between sequential motifs and subgraph motifs in terms of the number of extracted substructures, while providing a significant enhancement in the classification accuracy over sequential and frequent-subgraph motifs as well as alignment-based approaches. PMID- 30517023 TI - Emergency Preparedness of Secondary School Athletic Programs in Arizona. AB - CONTEXT: Schools that sponsor athletic programs have an obligation to provide a safe environment with appropriate policies for addressing emergencies. OBJECTIVE: To describe the emergency preparedness of secondary schools in Arizona specific to emergency action plans (EAPs), cardiac arrest, concussion, and heat illness. DESIGN: Cross-sectional study. SETTING: Online survey. PATIENTS OR OTHER PARTICIPANTS: Athletic directors from 143 Arizona secondary schools (response rate = 54%). INTERVENTION(S): A 6-section survey that included questions related to athletic trainer (AT) access, EAPs, automated external defibrillators (AEDs), concussion, heat illness, and other policies. MAIN OUTCOME MEASURE(S): Descriptive statistics were reported. Comparisons of responses between schools with and without AT access were conducted with Mann-Whitney U tests. RESULTS: Most respondents (81%, n = 116) indicated their school had access to an AT, and 95% (n = 125) of respondents reported their school had a written EAP. The AEDs were available at most (93%, n = 121) schools. All respondents were familiar with the interscholastic concussion policy, and 98% (n = 123) indicated they had a school-specific policy. Almost all respondents (99%, n = 121) reported being familiar with the state heat-illness policy. Environmental measures were taken before practices at 48% (n = 60) of schools. Schools with access to an AT were more likely to have an EAP, venue-specific EAPs, physician approval of EAP, AEDs, heat illness policies, and cold-water immersion tubs and to take environmental measures. CONCLUSIONS: Whereas the majority of schools reported AT access, not all schools had adequate EAPs in place. Schools would benefit from educational opportunities regarding best practices and policy development to improve emergency preparedness. PMID- 30517024 TI - The highly efficient power house in the Wistar Audiogenic Rat (WAR), an epileptic rat strain. AB - The Wistar Audiogenic Rat (WAR) is an animal model of tonic-clonic epileptic seizures, developed after genetic selection by sister x brother inbreeding of Wistar rats susceptible to sound stimuli. Although metabolic changes have been described in this strain, nothing, however, is known about its mitochondrial metabolism. Here, we addressed mitochondrial aspects of OXPHOS, oxidative stress, biogenesis and dynamics in liver, skeletal muscle and heart of male WAR, correlating then to physiological aspects of body metabolism. The results showed higher mitochondrial content, respiration rates in phosphorylation and noncoupled states and H2O2 production in WAR. Liver presented higher content of PGC1alpha and mTOR, proteins related to mitochondrial biogenesis. In agreement, isolated liver mitochondria from WAR showed higher respiration rates in phosphorylation state and ADP/O, as well as higher content of proteins related to electron transport chain ATP synthase, Krebs cycle, mitochondrial fusion and fission. Mitochondria with higher area and perimeter, and more variable shapes were found in liver and soleus from WAR, in addition to lower GSH/GSSG. In vivo WAR demonstrated lower body mass and energy expenditure, but higher food and water intake and amino acid oxidation. When exposed to a running test, WAR reached higher speed and resisted for longer time and distance than their Wistar controls. In conclusion, WAR strain has mitochondrial changes in liver, skeletal muscle and heart which improves its mitochondrial capacity of ATP production, making it an excellent rat model to study PGC1alpha overexpression and mitochondrial function in different physiological conditions or facing pathological challenges. PMID- 30517025 TI - A De Novo Robust Clustering Approach for Amplicon-Based Sequence Data. AB - When analyzing microbial communities, an active and computational challenge concerns the categorization of 16S rRNA gene sequences into operational taxonomic units (OTUs). Established clustering tools use a one pass algorithm to tackle high number of gene sequences and produce OTUs in reasonable time. However, all of the current tools are based on a crisp clustering approach, where a gene sequence is assigned to one cluster. The weak quality of the output compared with more complex clustering algorithms forces the user to postprocess the obtained OTUs. Providing a membership degree when assigning a gene sequence to an OTU will help the user during the postprocessing task. Moreover it is possible to use this membership degree to automatically evaluate the quality of the obtained OTUs. So the goal of this study is to propose a new clustering approach that takes into account uncertainty when producing OTUs, and improves both the quality and the presentation of the OTU results. PMID- 30517027 TI - Brief structural insight into the allosteric gating mechanism of BK (Slo) channel. AB - The big conductance Ca2+ dependent K+ channel also known as BK, MaxiK, Slo1 or KCa1.1 is a ligand- and voltage gated K+ channel. Although, structure-function studies of the past decades, involving mutagenesis and electrophysiological measurements revealed fine details of the mechanism of BK channel gating, the exact molecular details remained unknown until the quaternary structure of the protein has been solved at a resolution of 3.5 A using cryo-electron microscopy. In this short review, we are going to summarize these results and interpret the gating model of the BK channel in the light of the recent structural results. PMID- 30517026 TI - Diffusing Capacity of the Lung for Carbon Monoxide in Mexican/Latino Children: Quality Control and Reference Values. AB - RATIONALE: Single breath diffusing capacity of the lung for carbon monoxide (DLCOsb) evaluates gas exchange; however, the quality of maneuvers performed by children has not been evaluated, and reference values for young people living at moderate altitudes are not well established. OBJECTIVES: 1) to determine whether DLCOsb maneuvers performed by a pediatric population would meet 2017 ERS/ATS quality control standards; and 2) to report normal DLCOsb values for Mexican/Latino children and adolescents living at moderate altitudes. METHODS: This study involved healthy young people aged 4-20 years from the metropolitan area of Mexico City (2,240 m above sea level) recruited in schools from July 2014 to August 2017. DLCOsb testing was performed following the 2005 ATS/ERS standards, and the quality control of each maneuver was analyzed according to the 2017 ERS/ATS standards. We constructed models for DLCOsb with linear and quadratic terms for weight, height, and age as independent variables using shrinkage statistics, variance inflation factors, the Akaike information criterion, and R2 to compare the results of different models. RESULTS: They were 420 individuals (53% boys). Mean age was 11.7+/-4.5 (SD) years; 47% of maneuvers from children age 4-6 had grade A (13% grade B), while 90% of those in children older than 13 years had grade A or B. Forty-six percent of the subjects had a DLCOsb repeatability <1 ml/min/mmHg. The mean DLCOsb was higher for boys than that for girls, 32.4+/-13.6(SD) vs. 24.1+/-7.5 ml/min/mmHg, respectively. The reference equation for boys was DLCOsb=exp(1.63469 + (0.03251*age) + (0.00846*height) + (0.00304*weight)), R2=0.87; for girls, the best equation was DLCOsb =exp(1.56516 + (0.0193*age) + (0.00893*height) + (0.00273*weight)), R2=0.75. The transfer coefficient (KCOsb) remained constant with age and height, with a lower limit of normality of 6.5 ml/min/mmHg/L in boys and 5.4 ml/min/mmHg/L in girls. Measured DLCOsb was higher than predicted by other authors (p<0.001 by paired T-test). CONCLUSION: Individuals aged 4-20 years old can complete high-quality DLCOsb tests. Children and adolescents living at 2,240 m have a higher DLCOsb than do those living at sea level. Reference equations for DLCOsb obtained at sea level are poor predictors of the values measured at moderate altitude. PMID- 30517028 TI - An updated normative data-set from the Autonomic Reflex Screen representative of Southwestern Ontario. AB - BACKGROUND: In evaluating autonomic dysfunction, the autonomic reflex screen (ARS) is an established set of standardized tests to evaluate the presence and severity of autonomic dysfunction. Our laboratory previously reported normative data on 121 healthy individuals; however, the sample size in older individuals was reduced compared to other age groups. Therefore, the objective of the current study was to provide updated normative values representative of young, middle aged and older individuals from Southwestern Ontario. METHODS: 252 healthy individuals completed quantitative sudomotor axon reflex testing, heart rate responses to deep breathing (HRDB), and Valsalva maneuver using standard protocols of the ARS. RESULTS: All four sweat sites demonstrated a significant effect of sex (p<0.001). In addition, the proximal leg, distal leg and foot were all significantly affected by age (p<0.001). Cardiovagal parameters, measured via HRDB and Valsalva ratio revealed a significant regression with age (p<0.001). These results show similar trends with previously reported normative datasets. All normative data as a function of age and sex, where appropriate, are expressed as percentiles (2.5th, 5th, 95th, 97.5th). CONCLUSION: The current study provides updated normative data describing autonomic functioning in healthy individuals obtained from the sudomotor and cardiovagal components of the Autonomic Reflex Screen. PMID- 30517029 TI - HMGB1 is mechanistically essential in the development of experimental pulmonary hypertension. AB - Pulmonary hypertension (PH) is a mortal disease featured with pulmonary vascular constriction and remodeling, right heart failure and eventual death. Several reports showed that high mobility group box 1 (HMGB1) appears to be critical for the development of PH, the underlying mechanism, however has not been revealed. Experiments from the current study demonstrated that the HMGB1 level was elevated in the lung tissue and blood plasma of rats after chronic hypoxia exposure and monocrotaline treatment. The HMGB1 was originally located within nucleus and translocated to cytoplasm of pulmonary artery smooth muscle cells (PASMCs) upon hypoxia exposure, a process that appeared mediated by endogenous H2O2. The exposure of HMGB1 mobilized calcium signaling in PASMCs, a response which was attenuated by extracellular Ca2+ removal, toll-like receptor 4 (TLR4) inhibition by TAK-242, or transient receptor potential channel (TRPC) suppression with 2-APB and SKF-96365. The sustained phosphorylation of Akt pathway modulated HMGB1 induced migration of PASMCs. The blockage of HMGB1 with glycyrrhizin, anti-HMGB1 neutralizing antibody attenuated lung inflammation and PH establishment in rats after hypoxia exposure and monocrotaline treatment. The above findings reveal a mechanistic importance for HMGB1 in pulmonary hypertension through TLR4- and TRPC associated Ca2+ influx, and Akt phosphorylation-driven PASMCs migration. PMID- 30517030 TI - Platelet-Endothelial Cell Interactions Modulate Smooth Muscle Cell Phenotype in an vitro Model of Type 2 Diabetes Mellitus. AB - Platelets (PLTs) - endothelial cells (ECs) interaction appears to contribute to phenotypic transition of VSMCs that play an important role in the physiological and pathological process of vascular complications in Type 2 diabetes (DM2). However, the precise mechanisms by which interactions between PLTs and ECs affect VSMCs phenotype, have largely remained unclear. We determined the effect of diabetic PLTs-ECs interaction to influence VSMCs migration, proliferation and phenotypic transformation in triple cell co-culture models using the qRT-PCR, western blot, fluorescence microscopy, wound scratch assays, CCK-8 assays, and gelatine zymography assays. Our results revealed that DM2 PLTs-ECs interaction to be associated with a significant down-regulation of VSMCs specific contractile phenotypic genes and proteins, including SM22alpha, SMA, Smoothelin-B and SM-MHC. Inversely, VSMCs specific proliferative phenotype genes and proteins levels including CCND1/and 2, SMemb, and PCNA were in up-regulation. Further, the DM2 originated PLTs-ECs interaction promoted the expression level of transforming growth factor (TGF)-beta1, and the PI3K/Akt and MMP9 signaling pathway was activated subsequently. Finally, these reactions contributed to a synthetic phenotype of VSMCs, including the proliferation, migration and gelatinolytic activities. These findings suggest that PLTs-ECs interaction modulates the phenotypic transition of VSMCs between a contractile and proliferative/synthetic phenotype under diabetic conditions, conceivably providing important implications regarding the mechanisms controlling the VSMC phenotypic transition and the development of cardiovascular complications. PMID- 30517031 TI - Sex differences in subcutaneous adipose tissue redox homeostasis and inflammation markers in control and high fat diet fed rats. AB - The development of obesity related-metabolic disorders is more evident in male in comparison to female subjects, but the mechanisms are unknown. Several studies have shown that oxidative stress is involved in the pathophysiology of obesity, but the majority of them were performed in male animals. The aim of this study was to evaluate the sex-related differences in the subcutaneous adipose tissue redox homeostasis and inflammation of rats chronically fed a high fat diet. NADPH oxidase (NOX), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase activities were evaluated in the subcutaneous adipose tissue (SC) of adult male and female rats fed either a standard chow (SCD) or a high-fat diet (HFD) for 11 weeks. NOX2 and NOX4 mRNA levels, total reduced thiols, as well as IL-1beta, TNF-alpha, and IL-6 were also determined. Higher antioxidant enzyme activities and total reduced thiol levels were detected in SC of control male compared to female rats. Chronic HFD administration increased NADPH oxidase activity and NOX2 and NOX4 mRNA levels, and decreased SOD and GPx activities only in male animals. IL-1beta, TNF-alpha, and IL-6 levels, as well as Adgre1, CD11b, and CD68 mRNA levels were also higher in male SC adipose tissue after HFD. In females SC, catalase activity was higher after HFD feeding. Taken together, our results show that redox homeostasis and inflammation of SC is sexually dimorphic. Furthermore, males show higher oxidative stress in SC after 11 weeks of HFD due to both increased ROS production through NOX2 and NOX4, and decreased ROS detoxification. PMID- 30517032 TI - Behavioral Changes to Repeated Takeovers in Highly Automated Driving: Effects of the Takeover-Request Design and the Nondriving-Related Task Modality. AB - OBJECTIVE:: We investigated drivers' behavior and subjective experience when repeatedly taking over their vehicles' control depending on the design of the takeover request (TOR) and the modality of the nondriving-related task (NDRT). BACKGROUND:: Previous research has shown that taking over vehicle control after highly automated driving provides several problems for drivers. There is evidence that the TOR design and the NDRT modality may influence takeover behavior and that driver behavior changes with more experience. METHOD:: Forty participants were requested to resume control of their simulated vehicle six times. The TOR design (auditory or visual-auditory) and the NDRT modality (auditory or visual) were varied. Drivers' takeover behavior, gaze patterns, and subjective workload were recorded and analyzed. RESULTS:: Results suggest that drivers change their behavior to the repeated experience of takeover situations. An auditory TOR leads to safer takeover behavior than a visual-auditory TOR. And with an auditory TOR, the takeover behavior improves with experience. Engaging in the visually demanding NDRT leads to fewer gazes on the road than the auditory NDRT. Participants' fixation duration on the road decreased over the three takeovers with the visually demanding NDRT. CONCLUSIONS:: The results imply that (a) drivers change their behavior to repeated takeovers, (b) auditory TOR designs might be preferable over visual-auditory TOR designs, and (c) auditory demanding NDRTs allow drivers to focus more on the driving scene. APPLICATION:: The results of the present study can be used to design TORs and determine allowed NDRTs in highly automated driving. PMID- 30517033 TI - Three-dimensional kinematic corridors of the head, spine, and pelvis for small female driver seat occupants in near- and far-side oblique frontal impacts. AB - OBJECTIVES: Analyses of recent automotive accident data indicate an increased risk of injury for small female occupants compared to males in similar accidents. Females have been shown to be more susceptible to spinal injuries than males. To protect this more vulnerable population, advanced anthropomorphic test devices (ATDs) and computer human body models are being developed and require biofidelity curves for validation. The aim of this study is to generate female-specific 3D kinematic corridors in near- and far-side oblique frontal impacts for the head, spine, and pelvis. METHODS: Eight specimens were procured and prescreened for mass, stature, and quantitative computed tomography bone mineral density and preexisting injuries to minimize biologic variability. Sets of 4 noncolinear retroreflective targets were placed on the back of the head; dorsal spine at T1, T8, and L2; and posterior sacrum. Instrumented computed tomography scans were obtained to measure the orientation and position of the markers relative to anatomic fiducials. The specimens were placed on a buck representative of a generic automotive driver's seat environment designed to minimize lower-extremity and pelvic motion. The buck was oriented such that the buck centerline was seated 30 degrees from the impact vector in either a near- or far-side oblique frontal configuration. Preposition of the occupant was specified to the 50th percentile male H-point location, thigh and tibial angles, and torso angle. Impact was delivered via a servo-acceleration sled to the base of the buck with a 30 km/h 9 g trapezoidal pulse. Occupants were restrained by a standard 3-point belt that had a custom load-limiter device set to 2 kN at the D-ring side of the shoulder belt. Target motion was recorded at 1 kHz using a 3D optical motion capture system. Anatomic motion of the head, spine, and pelvis was calculated relative to the seat, and the average response was determined from 4 near-side and 4 far-side tests. The borders of the corridor were determined by calculating a standard deviational ellipse in the x, y, and z planes at each time step. RESULTS: Plots of the biofidelity corridors for near- and far-side tests are shown in planes parallel to the seat from the lateral, rear, and overhead directions. Averaged peak excursions in the fore/aft and lateral directions are compared for the near- and far-side corridors. Near-side female and male tests are similarly compared. CONCLUSIONS: In general, average peak excursions were greater in the far-side configuration than in the near-side configuration. Peak excursion results compared well with similar tests conducted on male postmortem human subjects (PMHS). The kinematic corridors developed in the current study serve as a set of biofidelity corridors for the development of current and future physical and computational surrogates. PMID- 30517035 TI - Re: "High Altitude and Cancer Mortality" by Thiersch and Swenson (High Alt Med Biol 2018;19:116-123). PMID- 30517034 TI - Therapeutic expression of human clotting factors IX and X following adeno associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques. AB - Adeno-associated viral vectors (AAVs) achieve stable therapeutic expression without long-term toxicity in adults with hemophilia. To avert irreversible complications in congenital disorders producing early pathogenesis, safety and efficacy of AAV-intrauterine gene transfer (IUGT) requires assessment. We therefore performed IUGT of AAV5 or -8 with liver-specific promoter-1 encoding either human coagulation factors IX (hFIX) or X (hFX) into Macaca fascicularis fetuses at ~0.4 gestation. The initial cohort received 1 * 1012 vector genomes (vgs) of AAV5-hFIX ( n = 5; 0.45 * 1013 vg/kg birth weight), resulting in ~3.0% hFIX at birth and 0.6-6.8% over 19-51 mo. The next cohort received 0.2-1 * 1013 vg boluses. AAV5-hFX animals ( n = 3; 3.57 * 1013 vg/kg) expressed <1% at birth and 9.4-27.9% up to 42 mo. AAV8-hFIX recipients ( n = 3; 2.56 * 1013 vg/kg) established 4.2-41.3% expression perinatally and 9.8-25.3% over 46 mo. Expression with AAV8-hFX ( n = 6, 3.12 * 1013 vg/kg) increased from <1% perinatally to 9.8 13.4% >35 mo. Low expressers (<1%, n = 3) were postnatally challenged with 2 * 1011 vg/kg AAV5 resulting in 2.4-13.2% expression and demonstrating acquired tolerance. Linear amplification-mediated-PCR analysis demonstrated random integration of 57-88% of AAV sequences retrieved from hepatocytes with no events occurring in or near oncogenesis-associated genes. Thus, early-IUGT in macaques produces sustained curative expression related significantly to integrated AAV in the absence of clinical toxicity, supporting its therapeutic potential for early onset monogenic disorders.-Chan, J. K. Y., Gil-Farina I., Johana, N., Rosales, C., Tan, Y. W., Ceiler, J., Mcintosh, J., Ogden, B., Waddington, S. N., Schmidt, M., Biswas, A., Choolani, M., Nathwani, A. C., Mattar, C. N. Z. Therapeutic expression of human clotting factors IX and X following adeno-associated viral vector-mediated intrauterine gene transfer in early-gestation fetal macaques. PMID- 30517036 TI - Data driven mathematical modelling reveals the dynamic mechanism of MSC-induced neovascularization. AB - Coculture of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) in vitro leads to the formation of a capillary-like reticular structure by ECs, which has great potential as a better substitute for artificial blood vessels in terms of stability and functionality. To investigate the mechanisms of the early neovascularization induced by MSCs, we analyzed the kinematic features of the motion of ECs and concluded that the dynamic interaction between cells and the extracellular matrix would reveal the capillary-like structure formation. Based on this hypothesis, we proposed a mathematical model to simulate the vascular like migration pattern of ECs in silico, which was confirmed by in vitro studies. These in vitro studies validated that the dynamic secretion and degradation of collagen I is the critical factor for capillary structure formation. The model proposed based on cell tracking, single cell sequencing, and mathematical simulation provides a better understanding of the neovascularization process induced by MSCs and a possible simple explanation guiding this important cellular behavior.-Yu, Y., Situ, Q., Jia, W., Li, J., Wu, Q., Lei, J. Data driven mathematical modelling reveals the dynamic mechanism of MSC-induced neovascularization. PMID- 30517037 TI - Networks for better drug discovery: making optimal use of existing chemical space. PMID- 30517038 TI - Acute Mountain Sickness is Reduced Following 2 Days of Staging During Subsequent Ascent to 4300 m. AB - : Beidleman, Beth A., Charles S. Fulco, Ellen L. Glickman, Allen Cymerman, Robert W. Kenefick, Bruce S. Cadarette, Sean P. Andrew, Janet E. Staab, Ingrid V. Sils, and Stephen R. Muza. Acute mountain sickness is reduced following 2 days of staging during subsequent ascent to 4300 m. High Alt Med Biol 00:000-000, 2018. OBJECTIVE: To determine whether 2 days of staging at 2500-3500 m, combined with either high or low physical activity, reduces acute mountain sickness (AMS) during subsequent ascent to 4300 m. METHODS: Three independent groups of unacclimatized men and women were staged for 2 days at either 2500 m (n = 18), 3000 m (n = 16), or 3500 m (n = 15) before ascending and living for 2 days at 4300 m and compared with a control group that directly ascended to 4300 m (n = 12). All individuals departed to the staging altitudes or 4300 m after spending one night at 2000 m during which they breathed supplemental oxygen to simulate sea level conditions. Half in each group participated in ~3 hours of daily physical activity while half were sedentary. Women accounted for ~25% of each group. AMS incidence was assessed using the Environmental Symptoms Questionnaire. AMS was classified as mild (>=0.7 and <1.5), moderate (>=1.5 and <2.6), and severe (>=2.6). RESULTS: While staging, the incidence of AMS was lower (p < 0.001) in the 2500 m (0%), 3000 m (13%), and 3500 m (40%) staged groups than the direct ascent control group (83%). After ascent to 4300 m, the incidence of AMS was lower in the 3000 m (43%) and 3500 m (40%) groups than the 2500 m group (67%) and direct ascent control (83%). Neither activity level nor sex influenced the incidence of AMS during further ascent to 4300 m. CONCLUSIONS: Two days of staging at either 3000 or 3500 m, with or without physical activity, reduced AMS during subsequent ascent to 4300 m but staging at 3000 m may be recommended because of less incidence of AMS. PMID- 30517039 TI - Dissociation of muscle and cortical response scaling to balance perturbation acceleration. AB - The role of cortical activity in standing balance is unclear. Here we tested whether perturbation-evoked cortical responses share sensory input with simultaneous balance-correcting muscle responses. We hypothesized that the acceleration-dependent somatosensory signals that drive the initial burst of the muscle automatic postural response also drive the simultaneous perturbation evoked cortical N1 response. We measured in healthy young adults (N=16) the initial burst of the muscle automatic postural response (100-200ms), startle related muscle responses (100-200ms), and the perturbation-evoked cortical N1 potential, i.e. a negative peak in cortical EEG activity (100-200ms) over the supplementary motor area. Forward and backward translational support-surface balance perturbations were applied at four levels of acceleration, and were unpredictable in timing, direction, and acceleration. Our results from averaged and single-trial analyses suggest that although cortical and muscle responses are evoked by the same perturbation stimulus, their amplitudes are independently modulated. While both muscle and cortical responses increase with acceleration, correlations between single-trial muscle and cortical responses were very weak. Further, across subjects, the scaling of muscle responses to acceleration did not correspond to scaling of cortical responses to acceleration. Moreover, we observed a reduction in cortical response amplitude across trials that was related to a reduction in startle-related, but not balance-correcting, muscle activity. Therefore, cortical response attenuation may be related to a reduction in perceived threat rather than motor adaptation or changes in sensory inflow. We conclude that the cortical N1 reflects integrated sensory inputs simultaneously related to brainstem-mediated balance-correcting muscle responses and startle reflexes. PMID- 30517040 TI - LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling. AB - Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLIN), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to executing memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High frequency stimulation of the mossy fibers induces LTD of their calcium permeable-AMPA receptor synapses with SLINs; previous work localized site of induction to be postsynaptic and site of expression to be presynaptic. Yet the underlying signaling events and the identity of the retrograde signal are incompletely understood. We used whole cell recordings of SLIN in hippocampal slices from wild type and mutant mice to explore the mechanisms. Genetic and pharmacologic perturbations revealed a requirement for both the receptor tyrosine kinase, TrkB, and its agonist, BDNF, for induction of LTD. Inclusion of inhibitors of Trk receptor kinase and phospholipase C in the patch pipette prevented LTD. Endocannabinoid receptor antagonists and genetic deletion of the CB1 receptor prevented LTD. We propose a model whereby release of BDNF from mossy fiber filopodia activates TrkB and PLCg1 signaling postsynaptically within SLINs, triggering synthesis and release of an endocannabinoid that serves as retrograde signal, culminating in reduced glutamate release. Insights into the signaling pathways by which activity modifies function of these synapses will facilitate understanding their contribution to the local circuit and behavioral consequences of hippocampal granule cell activity. PMID- 30517041 TI - Enhanced visual experience rehabilitates the injured brain in Xenopus tadpoles in an NMDAR-dependent manner. AB - Traumatic brain injuries introduce functional and structural circuit deficits that must be repaired for an organism to regain function. We developed an injury model in which Xenopus laevis tadpoles are given a penetrating stab wound that damages the optic tectal circuit and impairs visuomotor behavior. In tadpoles, as in other systems, injury induces neurogenesis. The newly generated neurons are thought to integrate into the existing circuit, however, whether they integrate via the same mechanisms that govern normal neuronal maturation during development is not understood. Development of the functional visuomotor circuit in Xenopus is driven by sensory activity. We hypothesized that enhanced visual experience would improve recovery from injury and by facilitating integration of newly generated neurons into the tectal circuit. We labeled newly generated neurons in the injured tectum by GFP expression and examined their circuit integration using electrophysiology and in vivo imaging. Providing animals with brief bouts of enhanced visual experience starting 24 hours after injury increased synaptogenesis and circuit integration of new neurons, and facilitated behavioral recovery. To investigate mechanisms of neuronal integration and behavioral recovery after injury, we interfered with NMDA receptor function. Ifenprodil, which blocks GluN2B-containing NMDA receptors, impaired dendritic arbor elaboration. GluN2B blockade inhibited functional integration of neurons generated in response to injury and prevented behavioral recovery. Furthermore, tectal GluN2B knockdown blocked the beneficial effects of enhanced visual experience on functional plasticity and behavioral recovery. We conclude that visual experience-mediated rehabilitation of the injured tectal circuit occurs by GluN2B-containing NMDAR-dependent integration of newly generated neurons. PMID- 30517042 TI - Siponimod for the treatment of secondary progressive multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic central nervous system immune mediated disease with an important inflammatory component associated with focal demyelination and widespread neurodegeneration. In most cases, the clinical presentation is relapsing-remitting, followed by a secondary progressive phase, characterized by disability accrual unrelated to relapses. In a minority, the phenotype is progressive from the beginning. Major therapeutic achievements have been made concerning the relapsing phase but modifying the evolution of progressive MS remains an unmet need. Areas covered: This review covers siponimod (BAF312), a new sphingosine 1-phosphate receptor modulator, and its role in the treatment of secondary progressive MS. The authors reviewed PubMed English literature using the keywords 'siponimod' or 'BAF312' and 'multiple sclerosis.' They also present the pharmacological profile of siponimod, as well as clinical efficacy and safety, with emphasis on the recently published results of a Phase III trial. Phase II data in relapsing MS are also summarized. Expert opinion: Siponimod may reduce the activity of the disease and has a modest effect on the gradual disability accrual. If approved, it may become one of the few available therapy options for secondary progressive MS. PMID- 30517043 TI - Effects of selective strengthening of tibialis posterior and stretching of iliopsoas on navicular drop, dynamic balance, and lower limb muscle activity in pronated feet: A randomized clinical trial. AB - OBJECTIVES: Flexibility and strength are compromised in pronated feet, which could in turn lead to alteration of the dynamic balance and muscle activity in the lower extremities. This study aimed to analyze the effects of selective tibialis posterior strengthening and iliopsoas stretching on navicular drop, dynamic balance, and lower limb muscle activity in young adults with pronated feet. METHODS: Twenty-eight participants with pronated feet were randomly assigned to either the stretching and strengthening group (n = 14) or the conventional exercise group (n = 14). The stretching and strengthening group performed tibialis posterior strengthening exercises and iliopsoas stretching three times a week for 6 weeks in addition to the conventional towel curl exercises. The conventional exercise group performed towel curl exercises only. Navicular drop, dynamic balance, and lower limb muscle activity were assessed at baseline and post-intervention. A mixed model analysis of variance was performed to test the study hypothesis. RESULTS: Significant group effects for the activity of tibialis anterior (p = 0.003) and abductor hallucis muscle (p = 0.010), as well as for the posterolateral (p = 0.036) and composite reach scores (p = 0.018), were detected. Significant group * time interactions were observed for naviculardrop (p < 0.001), all dynamic balance components (p < 0.001), and the activity of tibialis anterior (p < 0.001) and abductor hallucis (p < 0.001). CONCLUSIONS: This study demonstrated that inclusion of selective tibialis posterior strengthening and iliopsoas stretching in addition to the conventional towel curl exercise program could improve important clinical outcomes, such as navicular drop, muscle activity, and dynamic balance in flatfeet. PMID- 30517044 TI - Theta-Gamma Cascades and Running Speed. AB - Oscillations in the hippocampal LFP at theta and gamma frequencies are prominent during awake-behavior and have demonstrated several behavioral correlates. Both oscillations have been observed to increase in amplitude and frequency as a function of running speed. Previous investigations, however, have examined the relationship between speed and each of these oscillation bands separately. Based on energy cascade models where "... perturbations of slow frequencies cause a cascade of energy dissipation at all frequency scales" (Buzsaki 2006), we hypothesized that cross-frequency interactions between theta and gamma should increase as a function of speed. We examined these relationships across multiple layers of the CA1 subregion, which correspond to synaptic zones receiving different afferents. Across layers, we found a reliable correlation between the power of theta and the power of gamma, indicative of an amplitude-amplitude relationship. Moreover, there was an increase in the coherence between the power of gamma and the phase of theta, demonstrating increased phase-amplitude coupling with speed. Finally, at higher velocities, phase entrainment between theta and gamma increases. These results have important implications and provide new insights regarding how theta and gamma are integrated for neuronal circuit dynamics, with coupling strength determined by the excitatory drive within the hippocampus. Specifically, rather than arguing that different frequencies can be attributed to different psychological processes, we contend that cognitive processes occur across multiple frequency bands simultaneously with organization occurring as a function of the amount of energy iteratively propagated through the brain. PMID- 30517045 TI - The role of sensory stimulation on motor learning via action observation: a mini review. AB - Action observation involves the observation of an action followed by an attempt to replicate it. Recent studies show that increased sensorimotor cortical connectivity improves motor performance via observation, and that priming the sensory system before observation enhances the effects of observation-based learning. Understanding the role of the sensory system is, therefore, critical for rehabilitation of movement disorders that have a sensory deficit. PMID- 30517046 TI - Novel pharmacotherapy for burn wounds: what are the advancements. AB - INTRODUCTION: The prognosis for severe burns has improved significantly over the past 50 years. Meanwhile, burns have become an affliction mainly affecting the less well-developed regions of the world. Early excision and skin grafting has led to major improvements in therapeutic outcomes. Areas covered: The purpose of this article is to survey the use of pharmacotherapy to treat different pathophysiological complications of burn injury. The author, herein, discusses the use of drug treatments for a number of systemic metabolic disturbances including hyperglycemia, elevated catabolism, and gluconeogenesis. Expert opinion: Advancements in personalized and molecular medicine will make an impact on burn therapy. Similarities between severe burns and other critically ill patients will lead to cross-fertilization between different medical specialties. Furthermore, advances in stem cells and tissue regeneration will lead to improved healing and less lifelong disability. Indeed, research in new drug therapy for burns is actively progressing for many different complications. PMID- 30517047 TI - Nurse Practitioner-Physician Comanagement of Patients in Primary Care. AB - Current demand for primary care services will soon exceed the primary care provider (PCP) workforce capacity. As patient panel sizes increase, it has become difficult for a single PCP to deliver all recommended care. As a result, provider comanagement of the same patient has emerged in practice. Provider comanagement is defined as two or more PCPs sharing care management responsibilities for the same patient. While physician-physician comanagement of patients has been widely investigated, there is little evidence about nurse practitioner (NP)-physician comanagement. Given the large number of NPs that are practicing in primary care, more evidence is warranted about the PCP perspectives of physicians and NPs comanaging patient care. The purpose of this study was to explore NP-physician comanagement in primary care from the perspectives of PCPs. We conducted in person qualitative interviews of 26 PCPs, including NPs and physicians, that lasted 25 to 45 minutes, were audio recorded, and then professionally transcribed. Transcripts were deidentified and checked for accuracy prior to a deductive and inductive data analysis. Physicians and NPs reported that comanagement increases adherence to recommended care guidelines, improves quality of care, and increases patient access to care. Effective communication, mutual respect and trust, and a shared philosophy of care are essential attributes of NP physician comanagement. Physicians and NPs are optimistic about comanagement care delivery and find it a promising approach to improve the quality of care and alleviate primary care delivery strain. Efforts to promote effective NP-physician comanagement should be supported in clinical practice. PMID- 30517048 TI - Ipsilateral finger representations in the sensorimotor cortex are driven by active movement processes, not passive sensory input. AB - Hand and finger movements are mostly controlled through crossed corticospinal projections from the contralateral hemisphere. During unimanual movements, activity in the contralateral hemisphere is increased while the ipsilateral hemisphere is suppressed below resting baseline. Despite this suppression, unimanual movements can be decoded from ipsilateral activity alone. This indicates that ipsilateral activity patterns represent parameters of ongoing movement, but the origin and functional relevance of these representations is unclear. Here, we asked whether ipsilateral representations are caused by active movement, or whether they are driven by sensory input. Participants alternated between performing single finger presses and having fingers passively stimulated, while we recorded brain activity using high-field (7T) functional imaging. We contrasted active and passive finger representations in sensorimotor areas of ipsilateral and contralateral hemispheres. Finger representations in the contralateral hemisphere were equally strong under passive and active conditions, highlighting the importance of sensory information in feedback control. In contrast, ipsilateral finger representations in the sensorimotor cortex were stronger during active presses. Furthermore, the spatial distribution of finger representations differed between hemispheres: the contralateral hemisphere showed the strongest finger representations in Brodmann areas 3a and 3b, while the ipsilateral hemisphere exhibited stronger representations in premotor and parietal areas. Altogether, our results suggest that finger representations in the two hemispheres have different origins - contralateral representations are driven by both active movement and sensory stimulation, whereas ipsilateral representations are mainly engaged during active movement. PMID- 30517049 TI - Fluoxetine reverses brain radiation and temozolomide-induced anxiety and spatial learning and memory defect in mice. AB - Radiation therapy and concomitant temozolomide chemotherapy are commonly used in treatment of brain tumors, but they may also result in behavioral impairments such as anxiety and cognitive deficit. The present study sought to investigate the effect of fluoxetine on the behavioral impairments caused by radiation and temozolomide treatment. C57BL/6J mice were subjected to a single cranial radiation followed by 6-week cyclic temozolomide administration, and then treated with chronic administration of fluoxetine. Behavioral tests were carried out to determine the anxiety-like behavior and cognition function of these animals. Long term potentiation (LTP) in the hippocampus was measured by electrophysiology and neurogenesis in the dentate gyrus was evaluated by immunohistochemistry. Mice treated with radiation and temozolomide showed increased anxiety-like behavior and cognitive impairment, along with LTP impairment and neurogenesis deficit. Chronic fluoxetine administration could reverse the behavioral dysfunction, enhance LTP and increase neurogenesis in the hippocampus. PMID- 30517050 TI - Response to letter to the editor. PMID- 30517052 TI - Retraction of "Visual Darkness Reduces Perceived Risk of Contagious-Disease Transmission From Interpersonal Interaction". PMID- 30517051 TI - Clinical outcomes and recipient vessel selection for free flap transfer following arteriovenous malformation resection. AB - BACKGROUND: Arteriovenous malformation (AVM) is a rare vascular lesion that is difficult to treat. Radical surgical resection followed by free flap transfer is currently one of the preferred treatments, and this study aimed to assess the selection of recipient vessels and clinical outcomes for free flap transfer after AVM resection to establish better surgical management. METHODS: Data from 22 consecutive patients who underwent free flap transfer after AVM resection were retrospectively reviewed. Of these, AVMs were located at the head and neck of 11 patients and at the extremities of another 11 patients. The first choice for a recipient vessel was a normal artery or vein. However, in the absence of suitable alternatives, the feeding arteries or drainage veins were employed as recipient vessels. Patient backgrounds and postoperative outcomes were evaluated. RESULTS: Two patients required double flap transfer to cover the defects. Hence, a total of 24 flaps were transferred. A normal artery could be used in all cases of head and neck lesions, whereas a feeding artery was used in all cases of extremity lesions. On the other hand, a normal vein could be used in all cases as the recipient vein. No anastomotic failure or flap loss occurred postoperatively. CONCLUSION: Free flap transfer is feasible and safe even after AVM resection. The feeding artery can be used as the recipient artery in the absence of a normal artery especially for AVMs in the extremity although the safety of the drainage vein as the recipient vein remains unclear. ABBREVIATIONS: AVM: arteriovenous malformation; MRI: magnetic resonance imaging; 3DCT: threedimensional computed tomography; HN: head and neck; NR: not reported. PMID- 30517053 TI - Study on the interaction of amprolium HCl and dinitolmide in animal-derived food products with BSA by multiple spectroscopies and molecular modeling techniques. PMID- 30517054 TI - Is It Safe for Trainees to Perform Single-Incision Pediatric Endosurgery Splenectomy? AB - INTRODUCTION: Few centers worldwide have advanced single-incision pediatric endosurgery (SIPES) splenectomy. The safety and feasibility of SIPES performed by trainees were not assessed before. SIPES splenectomy is a demanding technique that needs high level of skills. This is the largest series of 39 SIPES splenectomies performed by 14 trainees in one single center. AIMS: To assess the safety, feasibility, and technical challenges of SIPES splenectomy performed by trainees and to compare it with other published series. MATERIALS AND METHODS: Retrospective study of all patients operated with SIPES splenectomy for 7 years. SIPES port was inserted through 1.5 cm umbilical incision. One type of port and straight regular instruments were used in all cases. RESULTS: Forty-nine patients underwent SIPES splenectomy. Eighty percent was done by our trainees. Six cholecystectomies were done simultaneously. Forty-five patients with sickle cell disease, two with thalassemia, one spherocytosis, and one Fanconi's anemia. Mean operative time (MOT) for splenectomy was 182 minutes (130-190) and 251 minutes for splenectomy with cholecystectomy (230-270) depending on severity of adhesions and size of the spleen; P value <.001. Two conversions have to be opened due to bleeding. There is neither wound infection nor incisional hernia up to date. CONCLUSION: SIPES splenectomy is safe and feasible when performed by surgical trainees without adding any morbidity to the patient. Learning curve can quickly improve with more exposure of trainee to different SIPES procedures and hands-on workshops. More than one procedure could be done at the same time. It has excellent cosmesis and almost invisible scar. PMID- 30517055 TI - Short-Term Sleep Loss Alters Cytokine Gene Expression in Brain and Peripheral Tissues and Increases Plasma Corticosterone of Zebra Finch (Taeniopygia guttata). AB - Lack of sleep incurs physiological costs that include increased inflammation and alterations in the hypothalamic-pituitary-adrenal axis. Specifically, sleep restriction or deprivation leads to increased pro-inflammatory cytokine expression and elevated glucocorticoids in rodent models, but whether birds exact similar costs is unknown. In this study, we examined whether zebra finch (Taeniopygia guttata), an avian model species, exhibits physiological costs of sleep loss by using a novel automated sleep fragmentation/deprivation method, wherein a horizontal wire sweeps across a test cage to disrupt sleep every 120 s. We measured pro-inflammatory (IL-1beta and IL-6) and anti-inflammatory (IL-10) cytokine gene expression in the periphery (fat, liver, spleen, and heart) and brain (hypothalamus, hippocampus, and apical hyperpallium) of captive finches after 12 h of exposure to a moving or stationary (control) bar during the night or the day. Plasma corticosterone, body mass, and behavioral profiles were also assessed. We predicted that birds undergoing sleep loss would exhibit elevated pro-inflammatory and reduced anti-inflammatory gene expression in brain and peripheral tissues compared with control birds. In addition, we predicted an increase in plasma corticosterone levels after sleep loss. As predicted, sleep loss increased pro-inflammatory gene expression, specifically in adipose tissue (IL-6), spleen (IL-1), and hippocampus (IL-6), but a decrease in anti inflammatory expression (IL-10) was not detected. However, sleep loss elevated baseline concentrations of plasma corticosterone. Taken together, these results suggest that a diurnal songbird is sensitive to the costs of sleep loss. PMID- 30517056 TI - Impact of Telemedicine in Pediatric Postoperative Care. AB - BACKGROUND: A shortage of pediatricians and long wait times in the hospitals render more efficient follow-up visits increasingly important. Virtual visits between physician and patient offer a solution to this problem. Increased awareness, improved technology, and efficient scheduling methods will contribute to the quality and adoption of telemedicine programs. INTRODUCTION: The aim of this study was to analyze the impact of pediatric telemedicine on wait times and visit durations, as compared with in-person visits. A secondary goal was to assess the efficiency of different scheduling methods for virtual visits. MATERIALS AND METHODS: The study included >800 postoperative virtual visits from urology, cardiovascular surgery, and ophthalmology, comprising data on wait times, visit duration, and postvisit satisfaction collected through SBR Health and Redcap. In-person visit data were collected on 14 patients in urology, and satisfaction scores were obtained through Press Ganey for urology and ophthalmology. RESULTS: Patients reported very high satisfaction with virtual visits and benefitted from reduced wait times, while receiving care of comparable duration and quality. Longer blocks of time scheduled exclusively for virtual visits correlated with shorter wait times. DISCUSSION: Supplementing health care with telemedicine is a viable way to provide patient-centered care. Implemented effectively, a telemedicine program can contribute greatly to the value a hospital provides to its patients. CONCLUSIONS: Virtual visits provide an efficient way to conduct postoperative visits, reducing wait times and increasing physician efficiency while retaining high satisfaction and quality of care. PMID- 30517057 TI - A Demographic Analysis of Racial/Ethnic Minority Enrollment Into HVTN Preventive Early Phase HIV Vaccine Clinical Trials Conducted in the United States, 2002 2016. AB - OBJECTIVES:: Racial/ethnic minority communities in the United States are overrepresented among new HIV diagnoses, yet their inclusion in preventive HIV vaccine clinical trials is inadequate. An analysis of enrollment demographic characteristics from US preventive HIV vaccine clinical trials from 1988 through 2002 showed that enrollment of racial/ethnic minority groups increased. We analyzed enrollment in preventive HIV vaccine clinical trials from 2002 through 2016 and compared our data with data from the previous study, described demographic characteristics of trial participants, and assessed how well this distribution reflected the racial/ethnic distribution of new HIV diagnoses in the United States. METHODS:: We examined data on demographic characteristics from 43 Phase 1 and Phase 2A preventive HIV vaccine clinical trials conducted in the United States and compared the results with those of the previous study. We also compared racial/ethnic distributions from 2011 through 2015 with Centers for Disease Control and Prevention data on the number of new HIV diagnoses during the same period. RESULTS:: Of 3469 participants, 1134 (32.7%) identified as a racial/ethnic minority, a 94% increase from the previous period (634/3731; 17.0%). Percentage annual enrollment of all racial/ethnic minority participants fluctuated from 17% to 53% from mid-2002 to 2016. Percentages of new HIV diagnoses among the general population were 1.9 to 2.9 times the percentage enrollment of black participants and 1.3 to 6.6 times the percentage enrollment of Hispanic/Latino participants in clinical trials for the same period. CONCLUSIONS:: Although enrollment of racial/ethnic minority groups into HIV vaccine clinical trials has increased, it is not proportional to the number of new HIV diagnoses among these groups. To enhance recruitment of racial/ethnic minority groups, the HIV Vaccine Trials Network has prioritized community partnerships and invested resources into staff training. PMID- 30517058 TI - Phylogenetic and Morphological Reassessment of Mycosphaerella nawae, the Causal Agent of Circular Leaf Spot in Persimmon. AB - Persimmon (Diospyros kaki) fruit production is severely affected by circular leaf spot worldwide. Mycosphaerella nawae causes circular leaf spot of persimmon (CLSP) and can result in leaf spot, defoliation, early fruit maturation, and subsequent softening and abscission. The morphology and phylogenetic position of M. nawae within the family Mycosphaerellaceae is, therefore, of utmost importance given its impact on persimmon production. Based on previous morphological and molecular studies, the phylogenetic position of the anamorphic genera associated with M. nawae remain in confusion. In the present study, 15 isolates of M. nawae were collected from the tissue of living leaves exhibiting leaf spot symptoms. A subsample of three isolates was characterized phylogenetically and morphologically. Isolates were compared based on DNA sequence data for the internal transcribed spacer region (ITS1-5.8S ITS2), part of the 28S nrDNA including domains D1-D3 (LSU), actin (Act), translation elongation factor 1-alpha (EF-1alpha), and RNA polymerase II second largest subunit (rpb2). The anamorph and teleomorph structures, ascospore germination patterns, as well as host specificity were used to describe the isolates. The phylogenetic and morphological analyses revealed that M. nawae requires a new holomorphic genus within Mycosphaerellaceae, described herein as Plurivorosphaerella gen. nov. A host specificity test revealed that Plurivorosphaerella nawae comb. nov. (M. nawae) can superficially colonize, but not infect, apple, peach, cherry, and plum. PMID- 30517059 TI - Expression of Concern: The Decoy Effect as a Nudge: Boosting Hand Hygiene With a Worse Option. PMID- 30517060 TI - Corrigendum: The Decoy Effect as a Nudge: Boosting Hand Hygiene With a Worse Option. PMID- 30517061 TI - Altered A-Type Potassium Channel Function in the Nucleus Tractus Solitarius in Acquired Temporal Lobe Epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarius (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched controls, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9-12 weeks post-treatment. Activity of GABAergic NTS neurons from pilo SE mice showed less sensitivity to 4-aminopyridine (4-AP). Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. PMID- 30517062 TI - Locating primary somatosensory cortex in human brain stimulation studies: Systematic review and meta-analytic evidence. AB - Transcranial magnetic stimulation (TMS) over human primary somatosensory cortex (S1), unlike over primary motor cortex (M1), does not produce an immediate, objective output. Researchers must therefore rely on one or more indirect methods to position the TMS coil over S1. The 'gold standard' method of TMS coil positioning is to use individual functional and structural magnetic resonance imaging (F/SMRI) alongside a stereotactic navigation system. In the absence of these facilities, however, one common method used to locate S1 is to find the scalp location which produces twitches in a hand muscle (e.g., the first dorsal interosseus, M1-FDI), then move the coil posteriorly to target S1. There has been no systematic assessment of whether this commonly-reported method of finding the hand area of S1 is optimal. To do this, we systematically reviewed 124 TMS studies targeting the S1 hand area, and 95 functional magnetic resonance imaging (FMRI) studies involving passive finger and hand stimulation. 96 TMS studies reported the scalp location assumed to correspond to S1-hand, which was on average 1.5 to 2cm posterior to the functionally-defined M1-hand area. Using our own scalp measurements combined with similar data from MRI and TMS studies of M1 hand, we provide the estimated scalp locations targeted in these TMS studies of the S1-hand. We also provide a summary of reported S1 coordinates for passive finger and hand stimulation in FMRI studies. We conclude that S1-hand is more lateral to M1-hand than assumed by the majority of TMS studies. PMID- 30517063 TI - #ThisIsOurLane - Firearm Safety as Health Care's Highway. PMID- 30517064 TI - Unraveling the characteristics of a heteropolysaccharide-protein from an Haloarchaeal strain with flocculation effectiveness in heavy metals and dyes removal. AB - The production, characterization and potential application in heavy metals and dyes removal of a novel heteropolysaccharide-protein named, gpHb, produced by an haloarchaeal strain Halogeometricum borinquense strain A52 were investigated. The highest gpHb yield of 13.96 +/- 0.32 g/L was produced under optimized conditions by response surface methodology. We focused on the characteristics and flocculation performance of gpHb. An important attribute of protein with 16 protein types identified that occupied a total content of 50.2% in the gpHb. Additionally, carbohydrate that occupied 30.4% of the total bioflocculant content consisted of three monosaccharides. Fourier transform infrared spectroscopy indicated the presence of carboxyl, hydroxyl, amine, amide, and sulfate groups. To further study flocculation activities, factors such as bioflocculant dosage, temperature, pH, salinity and cations addition were tested. In comparison to the chemical flocculant poly aluminium chloride, gpHb maintain high activity at large range of salinity and its flocculation activity was higher on both sides of pH 7. Addition of trivalent cation maingly Fe3+ enhances the flocculating rate indicating that the bioflocculant is negatively charged. Its practical applicability was established for heavy metals and dyes removal from saline aqueous solutions. The highest removal efficiency was observed with Cr3+ (91.4%) and Ni2+ (89.60%) and with Basic bleue 3 (83.8%) and Basic red (78.6%). The excellent flocculation activity of gpHb under saline condition suggests its potential industrial utility for treatment of textile and tannery wastewaters. PMID- 30517065 TI - Effectiveness of Dental Bleaching With 37.5% and 6% Hydrogen Peroxide and Its Effect on Quality of Life. AB - OBJECTIVE:: This study investigated whether it is possible to achieve equally satisfactory results between 37.5% hydrogen peroxide (HP) gel and 6% HP gel. We also assessed the psychosocial impact and self-perception of esthetics generated by extracoronal tooth whitening. METHODS AND MATERIALS:: A prospective, double blind, randomized clinical trial was carried out. A total of 33 patients were selected from the clinic of the Faculty of Dentistry at the University of Chile. The patients included men and women over 18 years old without prior tooth whitening treatments, tooth decay, or restorations of the maxillary anterior teeth. The patients had tooth colors of A3 or less according to the Vita Classical scale, which was determined with a Vita Easy Shade spectrophotometer. The study was carried out with a "split-mouth" design. One side of each mouth was randomly treated with 37.5% HP, and the other side was bleached with 6% HP. Each group received 3 to 12 minutes of treatment with the respective gel applications. Two sessions of bleaching were carried out each week. A spectrophotometer was used to measure the total variation of color (DeltaE), and a subjective evaluation was made with Vita Classical scale (DeltaSGU) between the baseline (session 1) and different measurement times. We compared DeltaE and DeltaSGU for both agents using the Mann-Whitney test ( alpha=0.05). RESULTS:: In both groups, there was variation among the initial color and the color in the different measurement times. In the month after the treatment was completed, DeltaE was 9.06 in the 37.5% HP group and 5.69 in the 6% HP group. The difference between the two groups was statistically significant starting in the second session ( p=0.000). CONCLUSION:: There was a significant difference between the effectiveness of the bleaching gel concentrations of 37.5% and 6% HP according to spectrophotometer measurements and subjective evaluations. There was also a positive effect on psychosocial impact and esthetic self-perception among patients. PMID- 30517066 TI - Is Optical Coherence Tomography a Potential Tool to Evaluate Marginal Adaptation of Class III/IV Composite Restorations In Vivo? AB - OBJECTIVE:: Margin analysis of Class III and IV composite restorations in vitro and in vivo occurred by scanning electron microscopy (SEM) and optical coherence tomography (OCT). The results were compared and related to clinical evaluation. METHODS AND MATERIALS:: Eight Class III composite restorations were imaged in vitro using OCT and SEM. The margins were analyzed quantitatively. OCT signals were verified by assignment to the criteria perfect margin, gap, and positive/negative ledge. In vivo quantitative margin analysis of Class III/IV composite restorations made of the micro-hybrid composite Venus combined with the self-etch adhesive iBond Gluma inside (1-SE) or etch-and-rinse adhesive Gluma Comfort Bond (2-ER) (all Heraeus Kulzer) was carried out using OCT and SEM after 90 months of clinical function. The results were compared with clinical evaluation (US Public Health Service criteria; marginal integrity, marginal discoloration). RESULTS:: In vitro, the correlation between OCT and SEM was high for all four margin criteria (Kendall tau b [taub] correlation: 0.64-0.92, pi<=0.026), with no significant differences between OCT and SEM ( pi>=0.63). In vivo, a moderate correlation was observed (taub: 0.38-0.45, pi<0.016). Clinically, the cumulative failure rate in the criterion marginal integrity was higher for the 1-SE group (baseline 90 M, p=0.011). Similarly, OCT and SEM detected higher percentages of the criterion gap in the 1-SE group ( p: 0.027/0.002), in contrast to perfect margin. Both, gap and perfect margin ranged widely between 0.0% and 88.7% (OCT) and between 0.0% and 89.0% (SEM). CONCLUSION:: Despite the positive selection bias after 90 months with only a few patients left, quantitative margin analysis allows for differentiation between the two adhesives at this specific date. OCT in particular offers the possibility to evaluate marginal integrity directly in vivo. PMID- 30517067 TI - Ferrule Design Does Not Affect the Biomechanical Behavior of Anterior Teeth Under Mechanical Fatigue: An In Vitro Evaluation. AB - OBJECTIVES:: To investigate the survival and failure mode of fiber-post resin restorations over preparations with different ferrule designs when submitted to a fatigue load test. METHODS AND MATERIALS:: Fifty bovine incisors were selected and divided into five groups (n=10) according to ferrule design: a no-ferrule group, a 2-mm circumferential ferrule group, a 2-mm buccal ferrule group, a 2-mm lingual ferrule group, and a 2-mm buccal and lingual ferrule group. The fiberglass post was cemented and the composite core was built up and prepared, followed by cementation of a full composite crown. The samples were subjected to a cyclic fatigue test with loading applicator at 135 degrees ; a staircase approach was used until fracture. Survival (cycles to fracture) and failure modes were recorded. Survival data were analyzed with the log-rank test, while Kruskal Wallis and Fisher exact tests were used to analyze failure mode data (alpha=0.05). RESULTS:: The median number of cycles to fracture ranged from 215,000 to 236,153. The log-rank test showed no statistically significant difference in survival rates among the groups ( p=0.82). Regarding failure mode, three types were observed: I, post and/or core fracture; II, root fracture in the cervical third; and III, root fracture in the middle third. No statistical difference was observed among the groups (Kruskal-Wallis test, p=0.147). CONCLUSION:: The ferrule design had no effect on fatigue resistance or failure mode of endodontically treated incisor teeth restored with a fiber post, composite core buildup, and composite crown. PMID- 30517068 TI - A Simple Method for Treating Subgingival Class V Lesions. AB - Noncarious cervical lesions (NCCLs) are steadily increasing. Unfortunately, NCCL restorations represent one of the less durable types of restorations due to problems, including isolation and crevicular moisture control, especially in cases where the cervical margin is covered by soft tissue. This article presents a technique that allows us, through the use of a common metallic matrix, to isolate and make accessible class V cavities with intrasulcular cervical margins. The advantages and disadvantages of the technique are presented. PMID- 30517069 TI - The Use of Different Photoinitiator Systems in Photopolymerizing Resin Cements Through Ceramic Veneers. AB - OBJECTIVE:: To evaluate the effect of different photoinitiator systems on photopolymerizing resin cements through ceramic veneers with different thickness on microshear bond strength (MUSBS), flexural strength (FS), and ultimate tensile strength (UTS) and verify the light attenuation through these ceramic veneers. METHODS AND MATERIALS:: Four photopolymerizing experimental resin cements were produced with the same resin matrix and associated with four different photoinitiator systems: camphorquinone (CQ), diphenyl(2,4,6 trimethylbenzoyl)phosphine oxide (TPO), Ivocerin, and TPO + Ivocerin. Eighty disc shaped ceramic veneers (IPS Empress Esthetic, Ivoclar Vivadent) were fabricated (10-mm diameter) in two different thicknesses: 0.7 and 1.5 mm. A previously characterized multiwave LED (Bluephase G2, Ivoclar Vivadent) was standardized for 40 seconds of photoactivation. Light transmittance through each ceramic veneer thickness (n=5) was measured using a spectrometer (USB 2000, Ocean Optics). The MUSBS of each resin cement (n=15) to the ceramic veneer was evaluated using 0.5 mm cylinders with 0.7-mm diameters photoactivated through the different ceramic veneer thicknesses. Samples for FS and UTS tests were made either with or without ceramics veneers (0.7 and 1.5 mm) fixed to the light-curing tip. Data were submitted to two-way analysis of variance and the Tukey test (alpha=0.05). RESULTS:: The multiwave LED emitted higher irradiance into the blue wavelength spectra than into the violet wavelength spectra ( p=0.0001). Light transmittance through the ceramic veneers was reduced in a systematic manner based on thickness regardless of the wavelength spectra emitted from the multiwave LED ( p=0.00037). The MUSBS was reduced in a systematic manner based on thickness regardless of the photoinitiator system ( p<0.05). However, resin cements with CQ and Ivocerin showed higher bond strength values in comparison to the resin cement with TPO regardless of the ceramic veneer thickness ( p<0.05). The FS and UTS means decreased ( p<0.05) with the interposition of 0.7- and 1.5-mm ceramic veneers for all resin cements. The resin cement containing only TPO showed the lowest FS and UTS means ( p<0.05) for all ceramic veneers. CONCLUSIONS:: The thickness of the ceramic veneers reduced the irradiance of the multiwave LED in all wavelength spectra. Ivocerin alone or associated with TPO showed to be an effective alternative photoinitiator to substitute for CQ. The resin cement containing only TPO had lower bond strength values in comparison to resin cements with CQ, Ivocerin, and Ivocerin + TPO. PMID- 30517070 TI - Impact of Recently Developed Universal Adhesives on Tensile Bond Strength to Computer-Aided Design/Manufacturing Ceramics. AB - OBJECTIVES:: The aim of this investigation was to test the tensile bond strength (TBS) between different computer-aided-design/manufacturing (CAD/CAM) ceramics after conditioning using different universal adhesive systems and resin composite cement. METHODS AND MATERIALS:: Substrates of four CAD/CAM ceramics-1) VITABLOCS Mark II, 2) Initial LRF, 3) Celtra Duo, and 4) IPS e.max CAD (N=648, n=162)-were fabricated. VITABLOCS Mark II and Initial LRF were etched using 9% hydrofluoric acid for 60 seconds, Celtra Duo for 30 seconds, and IPS e.max CAD for 20 seconds. Substrates for conditioning using Monobond Etch & Prime were untreated. The following adhesive systems were used: All-Bond Universal (ABU), Clearfil Universal Bond (CUB), G-Multi Primer (GMP), iBond Universal (IBU), Monobond Etch & Prime (MEP), Monobond Plus (MBP), One Coat 7 Universal (OCU), Prime&Bond Active (PBA), and Scotchbond Universal (SBU). Conditioned substrates were bonded using a resin composite cement (Variolink Esthetic DC), thermal cycled (20,000*, 5 degrees C/55 degrees C), and TBS was measured using a universal testing machine. Data were analyzed using univariate analysis with partial eta-squared, Kolmogorov Smirnov, Kruskal-Wallis, Mann-Whitney U, and Spearman-Rho tests (alpha=0.05). RESULTS:: ABU, MEP, and MBP obtained the significantly highest TBS, while CUB, IBU, and OCO resulted in the lowest, regardless of the CAD/CAM ceramic. SBU showed varying TBS results depending on the CAD/CAM ceramic used. ABU, MEP, and MBP showed no impact of CAD/CAM ceramic on TBS values. ABU, GMP, MEP, and MBP showed predominantly cohesive failure types in luting composite, while CUB and OCU demonstrated adhesive failure types. PMID- 30517071 TI - Clinical Evaluation of Two Different Prevention Programs in Adults Depending on Their Caries Risk Profile: One-Year Results. AB - The aim of this study was to investigate the management of incipient caries lesions in adults with two preventive protocols. A total of 44 adult patients with high, moderate and low caries risk with 516 incipient caries took part in the study. These patients were assessed for caries with International Caries Detection and Assessment System (ICDAS) criteria and were then divided into three groups depending on their caries risk profile: a high-risk group (group A), a moderate-risk group (group B), and a low-risk group (group C). Participants in each group were further divided randomly into two subgroups. In subgroups A1, B1, and C1, an intensive preventive protocol was applied, while in subgroups A2, B2, and C2, the protocol consisted only of instructions in oral hygiene. The invasive intensive protocol included the topical application of fluoride, brushing with 5000-ppm fluoride toothpaste, use of amorphous calcium phosphate-casein phosphopeptide, applications of sealants for occlusal lesions (ICDAS code 2), and minimal resin restorations for occlusal lesions (ICDAS code 3). There was no statistically significant difference in the number of lesions (baseline and after one year) in the high-risk and moderate-risk groups that received the intensive protocol (groups A1 and B1), while the control groups were statistically significant different (groups A2 and B2). In the low-risk group, there was no statistically significant difference in the number of lesions (groups C1 and C2). The two different preventive protocols in the high- and moderate-risk groups presented differences in effectiveness, while in the low-risk group, no significant difference was demonstrated. PMID- 30517072 TI - Multiple-therapy-resistant major depressive disorder: a clinically important concept. AB - SummaryMany novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. PMID- 30517073 TI - An engineered lipocalin that tightly complexes the plant poison colchicine for use as antidote as well as bioanalytical applications. AB - Colchicine is a toxic alkaloid prevalent in autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits polymerization of microtubules. Using combinatorial and rational protein design, we have developed an artificial binding protein based on the human lipocalin 2 that binds colchicine with a dissociation constant of 120 pM, i.e. 10 000-fold stronger than tubulin. Crystallographic analysis of the engineered lipocalin, dubbed Colchicalin, revealed major structural changes in the flexible loop region that forms the ligand pocket at one end of the eight-stranded beta-barrel, resulting in a lid like structure over the deeply buried colchicine. A cis-peptide bond between residues Phe71 and Pro72 in loop #2 constitutes a peculiar feature and allows intimate contact with the tricyclic ligand. Using directed evolution, we achieved an extraordinary dissociation half-life of more than 9 h for the Colchicalin*colchicine complex. Together with the chemical robustness of colchicine and availability of activated derivatives, this also opens applications as a general-purpose affinity reagent, including facile quantification of colchicine in biological samples. Given that engineered lipocalins, also known as Anticalin(r)proteins, represent a class of clinically validated biopharmaceuticals, Colchicalin may offer a therapeutic antidote to scavenge colchicine and reverse its poisoning effect in situations of acute intoxication. PMID- 30517074 TI - Differential expression of DLG1 as a common trait in different human diseases: an encouraging issue in molecular pathology. AB - Human Disc large (DLG1) is a scaffolding protein that through the interaction with diverse cell partners participates in the control of key cellular processes such as polarity, proliferation and migration. Experimental data have mainly identified DLG1 as a tumor suppressor. An outstanding point for DLG1 protein is that altered DLG1 expression and DLG1 gene mutations were observed in different pathologies, including cancer and neurological and immunological disorders. Evident changes in DLG1 abundance and/or cell localization were identified in a number of studies suggesting its participation in molecular mechanisms responsible for the development of such illnesses. In this review, we focus on some of the latest findings regarding DLG1 alterations in different diseases as well as its potential use as a biomarker for pathological progression. We further address the current knowledge on the molecular mechanisms regulating DLG1 expression and the posttranslational modifications that may affect DLG1 cell localization and functions. Despite the advances in this field, there are still open questions about the precise molecular link between alterations in DLG1 expression and the development of each specific pathology. The complete understanding of this concern will give us new scenarios for the design of promising diagnosis and therapeutic tools. PMID- 30517075 TI - Peptide binding affinity redistributes preassembled repeat protein fragments. AB - Designed armadillo repeat proteins (dArmRPs) are modular peptide binders composed of N- and C-terminal capping repeats Y and A and a variable number of internal modules M that each specifically recognize two amino acids of the target peptide. Complementary fragments of dArmRPs obtained by splitting the protein between helices H1 and H2 of an internal module show conditional and specific assembly only in presence of a target peptide (Michel et al., 2018). Here, we investigate dArmRP fragments that already spontaneously assemble with high affinity, e.g. those obtained from splits between entire modules or between helices H2 and H3. We find that the interaction of the peptide with the assembled fragments induces distal conformational rearrangements that suggest an induced fit on a global protein level. A population analysis of an equimolar mixture of an N-terminal and three C-terminal fragments with various affinities for the target peptide revealed predominant assembly of the weakest peptide binder. However, adding target peptide to this mixture altered the population of the protein complexes such that the combination with the highest affinity for the peptide increased and becomes predominant when adding access of peptide, highlighting the feasibility of peptide-induced enrichment of best binders from inter-modular fragment mixtures. PMID- 30517076 TI - Ovarian reserve in adolescent girls born prematurely. AB - Background The objective was to estimate ovarian reserve in adolescent girls born prematurely. Materials and methods Two hundred adolescent girls aged 15-16 years who were born prematurely and full term were studied with laboratory, ultrasound and statistical methods. Results Statistically significant differences of the main parameters that characterize ovarian reserve in adolescent girls born prematurely compared to those born full term were specified. The levels of estradiol (p = 0.027), anti-Mullerian hormone (p = 0.0004) and inhibin V (p = 0.015) were lower in the girls born prematurely and follicle stimulating (p = 0.0001) and lutenizing (p = 0.002) hormone levels were higher. The ultrasound imaging (USI) findings of the uterus and appendages were also different. Adolescent girls born prematurely had longer uterus cervix, smaller sizes of endometrial echo, smaller ovarian sizes and fewer follicles in them. Conclusions Adolescent girls born prematurely have different parameters of ovarian reserve compared to those of girls born full term. PMID- 30517077 TI - Deep Convolutional Neural Networks for the Prediction of Molecular Properties: Challenges and Opportunities Connected to the Data. AB - We present a flexible deep convolutional neural network method for the analysis of arbitrary sized graph structures representing molecules. This method, which makes use of the Lipinski RDKit module, an open-source cheminformatics software, enables the incorporation of any global molecular (such as molecular charge and molecular weight) and local (such as atom hybridization and bond orders) information. In this paper, we show that this method significantly outperforms another recently proposed method based on deep convolutional neural networks on several datasets that are studied. Several best practices for training deep convolutional neural networks on chemical datasets are also highlighted within the article, such as how to select the information to be included in the model, how to prevent overfitting and how unbalanced classes in the data can be handled. PMID- 30517078 TI - Status and trends in the use of insulin analogs, insulin delivery systems and their association with glycemic control: comparison of the two consecutive recent cohorts of Japanese children and adolescents with type 1 diabetes mellitus. AB - Background Treatment for type 1 diabetes mellitus (T1DM) has greatly changed by the general use of insulin analogs and continuous subcutaneous insulin infusion (CSII). To investigate whether these advances have been translated into continued improvement in glycemic control in Japanese children and adolescents, we analyzed the registration data of the two consecutive recent cohorts of Japanese childhood onset T1DM patients. Methods The registration data including hemoglobin A1c (HbA1c), hypoglycemia and insulin regimen were compared between the two cohorts (862 patients in the 2008 cohort and 1090 in the 2013 cohort). Results The proportion of subjects with multiple daily insulin injection therapy (MDI) and CSII significantly increased (p<0.0001) from 67.4% and 9.7% to 71.8% and 23.4%, respectively. In the 2013 cohort, almost all patients were treated with basal bolus treatment using insulin analogs. The use of CSII increased in all age groups, especially in the age group 0-5 years. The rates of overall, moderate and severe hypoglycemia significantly declined from 10.24, 10.18 and 0.056 events/100 persons/period in the 2008 cohort to 0.66, 0.62 and 0.033 in the 2013 cohort (p<0.0001, <0.0001, 0.04), respectively. Contrarily, there were no significant changes in HbA1c values between the two cohorts. Conclusions The popularization of the basal-bolus treatment using insulin analogs hascontributed to a significant decrease in hypoglycemia. In contrast, the intensive insulin treatment may not be enough for the satisfactory improvement of glycemic control in Japanese children and adolescents with T1DM. Considerable points remain, such as diabetic education and support to motivate patients. PMID- 30517079 TI - A Turkish girl with H syndrome: stunted growth and development of autoimmune insulin dependent diabetes mellitus in the 6th year of diagnosis. AB - Background H syndrome ([OMIM] 602782) is an autosomal recessive disorder with systemic manifestations and characteristic skin lesions, caused by mutations of the SLC29A3 gene. Short stature and diabetes mellitus are the major endocrine problems related to H syndrome, however, clear data from clinical follow-up of H syndrome patients is lacking in the literature. Case presentation Here, we present follow-up of a Turkish girl diagnosed with H syndrome at the age of 10 with a homozygous 310(c.933T>A, p.C310X) early stop codon mutation on exon 6 of the SLC29A3 gene. She had severe short stature non-responsive to growth hormone (GH) treatment and gluten-free diet despite low GH levels and celiac antibody positivity. She developed insulin dependent diabetes mellitus (IDDM) symptoms 6 years after the initial diagnosis. Conclusions H syndrome patients can develop IDDM years after characteristic symptoms. Short stature in H syndrome patients may not respond to GH replacement or gluten-free diet alone. PMID- 30517080 TI - ERCP practice beyond the training period - bridging the gap between guidelines and real-life practice: a single operator experience of 679 procedures. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography has evolved significantly in recent years. The increase in complexity and range of applications has not been adequately reflected in an improvement of training methods for ERCP, with many endoscopists failing to meet required performance standards during their training period and limited available data on their performance immediately after completing training. We aimed to analyze the performance of an independent operator from a developing country after the completion of formal training with regard to procedure and patient-related outcomes. METHODS: We conducted an observational study of ERCPs performed by a young endoscopist from a referral center. Data about the procedure, cannulation technique (including use of precut), trainee involvement and procedure-related outcomes was retrieved and analyzed from a prospectively maintained database on quality in ERCP (the QUASIE initiative). RESULTS: Data from 679 consecutive ERCPs conducted or supervised by one endoscopist with < 200 independent procedures prior to the study period were included in the final analysis. Cannulation rates significantly improved over time, from 90% to 96% (p=0.016). Use of precut techniques changed significantly over time, with an initial increase followed by a subsequent decrease as overall cannulation rates improved. Trainee involvement was significantly associated with prolonged cannulation times (p=0.003) and use of precut (p=0.001), but did not impact on technical success or patient safety. CONCLUSIONS: Independent practice of ERCP after the training period is characterized by on-going changes in technique, especially with regard to cannulation and use of precut, showing significant improvements in performance over time. PMID- 30517081 TI - Eosinophil count (EC) as a diagnostic and prognostic marker for infection in the internal medicine department setting. AB - INTRODUCTION: Eosinopenia has been previously investigated as a marker to differentiate infectious from non-infectious diagnoses and as a prognostic marker. Most previous studies were conducted in intensive care unit patients. Our study focuses on the value of eosinopenia in patients admitted to the Internal Medicine department. METHODS: We retrospectively analyzed 271 consecutive patients with infection and 31 patients presenting with fever or inflammatory syndrome and a non-infectious diagnosis. We evaluated and compared the following markers for differentiating infectious from non-infectious diagnoses: eosinophil count [EC], CRP, WBC and neutrophil-to-lymphocyte count ratio [NLCR]. We also evaluated the value of eosinopenia as a monitoring parameter in patients with infections. RESULTS: Eosinopenia at admission was found in 71% of patients with infection compared to 32% in the non-infection group. EC and NLCR were moderate markers for discriminating infection from non-infection, with an area under the receiver operating characteristic curve of 0.789 and 0.718 respectively. Significant eosinopenia (<=10/ul) had a high specificity (90%) for diagnosing infections. High EC at admission (>400/ul) was rare in the infection group (1.5%) but not uncommon in the non-infection group (25.8%). Persistent eosinopenia was noted in non-survivors, compared to the rapid normalization of EC in survivors. CONCLUSIONS: Among patients presenting with fever and/or high inflammatory markers a low EC is supportive of infection, while a high EC may suggest non infectious diagnoses. The persistence/resolution of eosinopenia may be a useful monitoring parameter to predict response to therapy. PMID- 30517082 TI - Fast water desalination by carbon-doped boron nitride monolayer: transport assisted by water clustering at pores. AB - The well-being of the ever-escalating world population hinges largely upon the adequacy of clean, fresh water. Desalination is one of the most promising approaches in such an endeavor. Using molecular dynamics simulations, we take a close look at nanoporous hexagonal boron nitride nanosheets as desalination membranes, and study how C dopants affect their performance. The calculations predict that the desalination performance of C-doped BN membranes compares favorably to that of MoS2 membranes: the water flux through the 0% (0CB-0CN), 25% (3CB-0CN), 75% (3CB-6CN), and 100% C terminated BN membrane (6CB-6CN) is 29.9, 47.5, 95.3, and 81.5 molecules ns-1 per pore, respectively, and there is a strong correlation between the water flux and the axial diffusion coefficient. Through our study of the effect of C content on the desalination performance, it is found that more clustering of water molecules at membrane pores due to a smaller hydration free energy and pore energy barrier assists water transport through the pores, and allows a greater water flux. PMID- 30517083 TI - Non-power-driven organic photodiode via junction engineering. AB - Here we introduce a junction engineering approach to realize a high performance non-power-driven organic photodiode. To overcome the external power source dependency of conventional photodiodes, in this work, we try not only to implement an inherently large built-in-potential of the junction but also to utilize an inherently low charge carrier concentration of the semiconductor. The strategically designed ITO/plasma-treated ZnO/poly[2-methoxy-5-(2'-ethylhexyloxy) p-phenylene vinylene] (MEH-PPV)/MoO3/Ag geometry showed near-ideal Schottky junction properties with a high zero-bias built-in potential of 0.54 eV, leading to a zero-bias depletion width of 470 nm. As a result, a green-selective polymeric photodiode with high zero-bias detectivity up to 5 * 1011 Jones and a low noise equivalent power of 2.98 * 10-12 W Hz-1/2 are demonstrated, revealing the possibility of a thin film, color-selective and non-power-driven polymeric photodiode for battery-free application. PMID- 30517084 TI - Tuning adatom mobility and nanoscale segregation by twin formation and polytypism. AB - Nanoscale variations in the composition of an Al x Ga1-x As shell around a GaAs nanowire affect the nanowire functionality and can lead to the formation of localized quantum emitters. These composition fluctuations can be the consequence of variations of crystal phase and/or nanoscale adatom mobility. By applying electron-microscopy-related techniques we correlate the optical, compositional and structural properties at the nanoscale on the same object. The results indicate a clear correlation between the twin density in the nanowire and the quantum-emitter density as well as a significant redshift in the emission. We propose that twinning increases nanoscale segregation effects in ternary alloys. An additional redshift in the emission can be explained by the staggered band alignment between wurtzite and zinc-blende phases. This work opens new avenues in the achievement of homogeneous ternary and quaternary alloys in nanowires and in the engineering of the segregation effects at the nanoscale. PMID- 30517085 TI - High performance acetone sensor based on gamma-Fe2O3/Al-ZnO nanocomposites. AB - Ternary nanocomposites made of gamma-iron oxide and aluminum-doped zinc oxide (gamma-Fe2O3/Al-ZnO NCs), with different metal oxides ratio (0%-100%) were prepared through a solvothermal sol-gel process. The synthesized materials were characterized by x-ray diffraction, UV-vis spectroscopy, photoluminescence (PL), scanning electron microscope and BET analysis. Characterization results demonstrated that the ternary gamma-Fe2O3/Al-ZnO NCs are mainly constituted by gamma-Fe2O3 and Al-ZnO individual phases, while structural and physical properties like surface area, pore size, optical band gap, PL and electrical conductivity were deeply affected by the composition of nanocomposite. The synthesized gamma-Fe2O3/Al-ZnO NCs were employed to prepare conductometric gas sensors, then their sensing performances toward acetone were also investigated. Results revealed enhanced sensing performance of nanocomposites than both pure gamma-Fe2O3 and Al-ZnO phases. In particular, the gamma-Fe2O3(33%)/Al-ZnO based gas sensor showed the best sensing properties, like a high response of R air/R gas = 29, a short response time of 3 s, in addition to an improved selectivity toward acetone versus ethanol at an operating temperature of 200 degrees C. Overall, ternary gamma-Fe2O3/Al-ZnO NCs appear to be promising for the development of conductometric acetone sensors. PMID- 30517086 TI - Enhancement of transport properties in single ZnSe nanowire field-effect transistors. AB - Wide-gap semiconductors are excellent candidates for next-generation optoelectronic devices, including tunable emitters and detectors. ZnSe nanowire based devices show great promise in blue emission applications, since they can be easily and reproducibly fabricated. However, their utility is limited by deep level defect states that inhibit optoelectronic device performance. The primary objective of this work is to show how the performance of ZnSe nanowire devices improves when nanowires are subjected to a post-growth anneal treatment in a zinc rich atmosphere. We use low temperature photoluminescence spectroscopy to determine the primary recombination mechanisms and associated defect states. We then characterize the electronic properties of ZnSe nanowire field effect transistors fabricated from both as-grown and Zn-annealed nanowires, and measure an order-of-magnitude improvement to the electrical conductivity and mobility after the annealing treatment. We show that annealing reduces the concentration of zinc vacancies, which are responsible for strong compensation and high amounts of scattering in the as-grown nanowires. PMID- 30517087 TI - Low intensity resistance exercise reduces hyperglycemia and enhances glucose control over a 24-hour period in women with type 2 diabetes. AB - The study herein aimed to compare glucose concentration and hyperglycemic responses of 24-hours after resistance exercise (RE) performed in different intensities in patients with type-2 diabetes (T2D). Twelve women with T2D (55.2+/ 4.0 years; 70.1+/-11.4 kg; 155.7+/-3.3 cm) performed four experimental sessions divided into two blocks separated by 7 days and in randomized order: block-A (session-1: control-CONT40% and session-2: RE40% of one repetition maximum test 1RM) and block-B (session-3: CONT80% and session-4: RE80%1RM). The RE sessions were performed over 40min with three circuits of seven exercises each, with 40%1RM and 80%1RM with 16 and 8 repetitions for each set, respectively. Glucose was monitored over 24-hours after each experimental session through continuous glucose monitoring system. One-way ANOVA for repeated measures showed that AUC glucose was reduced (p<0.05) after RE40%1RM (193.738+/-33.186 mg.dL x 1.380 min) when compared to CONT40% (263.937+/-26.665 mg.dL x 1.380 min), CONT80% (254.721+/ 35.836 mg.dL * 1.380 min), and RE80%1RM (263.966+/-62.795 mg.dL * 1.380 min). Hyperglycemia (>160 mg.dL) was less prevalent (p<0.05) during the total period after RE40%1RM (20.8+/-21.2%) when compared to CONT40% (77.4+/-18.3%), CONT80% (69.4+/-24.6%), and RE80%1RM (66.0+/-33.7%). There was a lower hyperglycemic state in RE40%1RM (p<0.05) vs. CONT40%, CONT80%, and RE80%1RM after breakfast (1:25+/-0:54 h vs. 4:00+/-0:00 h, 3:40+/-0:53 h and 3:25+/-1:09 h, respectively), lunch (1:25+/-2:03 h vs. 4:55+/-0:17 h, 4:25+/-1:26 h and 3:40+/-2:06 h, respectively) and dinner (0:15+/-0:27 h vs. 3:15+/-0:45 h, 3:25+/-0:47 h and 2:50+/-1:31 h, respectively). During the sleeping period, there was a lower hyperglycemic state (p<0.05) in RE40%1RM (0:20+/-0:39 h) vs. RE80%1RM (4:05+/ 3:08 h). A single low intensity RE40%1RM decreases hyperglycemic prevalence over a 24-hour period and ameliorates glucose control after meals and in sleeping periods in T2D women. PMID- 30517088 TI - IP3-Mediated Calcium Signaling Is Involved in the Mechanism of Fractalkine Induced Hyperalgesia Response. AB - BACKGROUND Fractalkine is widely expressed throughout the brain and spinal cord, where it can exert effects on pain enhancement and hyperalgesia by activating microglia through CX3C chemokine receptor 1 (CX3CR1), which triggers the release of several pro-inflammatory cytokines in the spinal cord. Fractalkine has also been shown to increase cytosolic calcium ([Ca2+]i) in microglia. MATERIAL AND METHODS Based on the characteristics of CX3CR1, a G protein-coupled receptor, we explored the role of inositol 1,4,5-trisphosphate (IP3) signaling in fractalkine induced inflammatory response in BV-2 cells in vitro. The effect and the underlying mechanism induced by fractalkine in the brain were observed using a mouse model with intracerebroventricular (i.c.v.) injection of exogenous fractalkine. RESULTS [Ca2+]i was significantly increased and IL-1beta and TNF alpha levels were higher in the fractalkine-treated cell groups than in the farctalkine+ 2-APB groups. We found that i.c.v. injection of fractalkine significantly increased p-p38MAPK, IL-1beta, and TNF-alpha expression in the brain, while i.c.v. injection of a fractalkine-neutralizing antibody (anti CX3CR1), trisphosphate receptor (IP3R) antagonist (2-APB), or p38MAPK inhibitor (SB203580) prior to fractalkine addition yielded an effective and reliable anti allodynia effect, following the reduction of p-p38MAPK, IL-1beta, and TNF-alpha expression. CONCLUSIONS Our results suggest that fractalkine leads to hyperalgesia, and the underlying mechanism may be associated with IP3/p38MAPK mediated calcium signaling and its phlogogenic properties. PMID- 30517089 TI - Trypanosoma cruzi-specific IFN-gamma-producing cells in chronic Chagas disease associate with a functional IL-7/IL-7R axis. AB - BACKGROUND: The severity of cardiac disease in chronic Chagas disease patients is associated with different features of T-cell exhaustion. Here, we assessed whether the ability of T cells to secrete IFN-gamma in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: PBMCs from chronic Chagas disease patients and uninfected controls were examined for frequencies of T. cruzi-responsive IFN-gamma-producing cells by ELISPOT and cellular expression and function of IL-7R using flow cytometry. Serum levels of IL-7, IL-21, IL-27, soluble IL-7R, and inflammatory cytokines were also evaluated by ELISA or CBA techniques. Patients possessing T. cruzi-specific IFN-gamma-producing cells (i.e. IFN-gamma producers) had higher levels of memory T cells capable of modulating the alpha chain of IL-7R and an efficient response to IL-7 compared to that in patients lacking (i.e. IFN-gamma nonproducers) parasite-specific T-cell responses. IFN-gamma producers also showed low levels of soluble IL-7R, high basal expression of Bcl-2 in T cells and low basal frequencies of activated CD25+ T cells. Modulation of IL-7R was inversely associated with serum IL-6 levels and positively associated with serum IL-8 levels. Circulating IL-21 and IL-27 levels were not associated with the frequency of IFN-gamma producing cells but were reduced in less severe clinical forms of the disease. In vitro stimulation of PBMCs with IL-7 or IL-27 enhanced IFN-gamma production in IFN-gamma producers but not in IFN-gamma nonproducers. CONCLUSIONS/SIGNIFICANCE: Alterations of the IL 7/IL-7R axis and in the levels of inflammatory cytokines were linked to impaired T. cruzi-specific IFN-gamma production. These alterations might be responsible of the process of immune exhaustion observed in chronic Chagas disease. PMID- 30517090 TI - Pyrethroids resistance intensity and resistance mechanisms in Anopheles gambiae from malaria vector surveillance sites in Nigeria. AB - Anopheles gambiae, An. coluzzii and An. arabiensis are the three major vectors of malaria in Nigeria. These mosquitoes have developed resistance to different insecticides. Insecticides resistance intensity assay was recently introduced to provide insight into the potential operational significance of insecticide resistance. Here, we present data on pyrethroids resistance intensity and resistance mechanisms from six vector surveillance sites (Lagos, Ogun, Edo, Anambra, Kwara and Niger) in Nigeria. Adult Anopheles reared from larval collections were tested using WHO insecticides susceptibility protocol with 1x concentration of permethrin and deltamethrin followed with intensity assays with 5x and 10x concentrations of both insecticides. Synergistic and biochemical assays were carried out and underlying resistance mechanisms determined following standard protocols. Anopheles gambiae constituted >50% samples tested in five sites. Permethrin and deltamethrin resistance was observed at all the sites. The Kdt50 varied from 15 minutes (CI = 13.6-17.2) in deltamethrin to 42.1 minutes (CI = 39.4-44.1) in permethrin. For both insecticides, Kdt95 was >30 minutes with 25% to 87% post exposure mortality at the different sites. The West Africa knock down resistance (kdr-w) mechanism was found at each site. Resistant An. gambiae from Lagos, Ogun and Niger synergized prior to permethrin or deltamethrin exposure showed significant mortality (89-100%) compared to unsynergized mosquitoes (Lagos, p = 0.031; Ogun, p = 0.025; Niger, p = 0.018). Biochemical analyses revealed significant increased levels of P450 enzymes in resistant Anopheles gambiae from Lagos (p = 0.038); Ogun (p = 0.042) and Niger (p = 0.028) in addition to GST in Lagos (p = 0.028) and Ogun (p = 0.033). Overall, the results revealed high pyrethroid resistance associated with increased activities of metabolic enzymes (P450 + GST) in An. gambiae and An. coluzzii from Lagos and Ogun. The presence of kdr + P450 conferred moderate resistance whereas low resistance was the case where kdr was the sole resistance mechanism. Findings thus suggests that elevated levels of cytochrome P450 enzymes together with GST were responsible for high or severe pyrethroid resistance. PMID- 30517091 TI - Assessing impact of exogenous features on biotic phenomena in the presence of strong spatial dependence: A lake sturgeon case study in natural stream settings. AB - Modeling spatially explicit data provides a powerful approach to identify the effects of exogenous features associated with biological processes, including recruitment of stream fishes. However, the complex spatial and temporal dynamics of the stream and the species' reproductive and early life stage behaviors present challenges to drawing valid inference using traditional regression models. In these settings it is often difficult to ensure the spatial independence among model residuals-a key assumption that must be met to ensure valid inference. We present statistical models capable of capturing complex residual anisotropic patterns through the addition of spatial random effects within an inferential framework that acknowledges uncertainty in the data and parameters. Proposed models are used to explore the impact of environmental variables on Lake sturgeon (Acipenser fulvescens) reproduction, particularly questions about patterns in egg deposition. Our results demonstrate the need to apply valid statistical methods to identify relationships between response variables, e.g., egg counts, across locations, and environmental covariates in the presence of strong and anisotropic autocorrelation in stream systems. The models may be applied to other settings where gamete distribution or, more generally, other biotic phenomena may be associated with spatially dynamic and anisotropic processes. PMID- 30517092 TI - Bioinformatics: A rational combine approach used for the identification and in vitro activity evaluation of potent beta-Glucuronidase inhibitors. AB - Identification of hotspot drug-receptor interactions through in-silico prediction methods (Pharmacophore mapping, virtual screening, 3DQSAR, etc), is considered as a key approach in drug designing and development process. In the current design study, advanced in-silico based computational techniques were used for the identification of lead-like molecules against the targeted receptor beta glucuronidase. The binding pattern of a potent inhibitor in the ligand-receptor X ray co-crystallize complex was used to identify and extract the structure-base Pharmacophore features. Based on these observations; five structure-based pharmacophore models were derived to conduct the virtual screening of ICCBS in house data-base. Top-ranked identified Hits (33 compounds) were selected to subject for in-vitro biological activity evaluation against beta-glucuronidase enzyme; out of them, twenty compounds (61% of screened compounds) evaluated as actives, however eleven compounds were found to have significantly higher inhibitory activity, including compounds 1, 5-8, 10, 12-13, and 17-19 with IC50 values ranging from 1.2 MUM to 34.9 MUM. Out of the eleven potent inhibitors, seven compounds 1, 5, 6, 7, 8, 13, and 19 were found new, and evaluated first time for the beta-glucuronidase inhibitory activity. Compounds 1, 5 and 19 exhibited a highly potent inhibition in uM of beta-glucuronidase enzyme with non cytotoxic behavior against the mouse fibroblast (3T3) cell line. Our combined in silico and in-vitro results revealed that the binding pattern analysis of the eleven potent inhibitors, showed almost similar non-covalent interactions, as observed in case of our validated pharmacophore model. The obtained results thus demonstrated that the virtual screening minimizes false positives, and provide a template for the identification and development of new and more potent beta glucuronidase inhibitors with non-toxic effects. PMID- 30517093 TI - The association between cigarette affordability and consumption: An update. AB - OBJECTIVES: This study calculates cigarette affordability for 78 countries worldwide from 2001 to 2014 using the Relative Income Price (RIP) ratio defined as the percentage of per capita GDP required to purchase 100 packs of cigarettes using the lowest price from Economist Intelligence Unit (EIU) database, examine the association between cigarette affordability and cigarette consumption, and calculate the affordability elasticity of demand. DESIGN AND METHODS: RIP (2001 2014) was calculated for 16 low-income economies, 19 lower middle-income economies, 13 upper middle-income economies, and 30 high-income economies. Ordinary least square regressions were used to analyze the association between cigarette affordability and consumption. RESULTS: Per capita consumption continued to rise in low-income countries and decreased slightly in lower middle income countries as the RIP of cigarette consistently declined in low- and lower middle-income economies from 2001 to 2014. The real cigarette prices continued to decline in low- and lower middle-income countries and continued to rise in upper middle- and high-income countries. Though cigarettes were more expensive in HICs than were in LMICs, cigarettes were more affordable in HICs than were in LMICs. The regression results show a 10% increase in the RIP of cigarettes led to a 2% decrease in per capita consumption. The affordability elasticity of demand differed significantly between HICs and LMICs. However, the effect of cigarette affordability on consumption has not changed over time. CONCLUSIONS: To control the smoking epidemic, low- and lower middle-income countries should further increase cigarette prices. The rate of price increase should exceed the rate of economic growth and outpace the inflation rate to make cigarettes less affordable and thereby reducing tobacco use. PMID- 30517094 TI - The predictive value of quantitative nucleic acid amplification detection of Clostridium difficile toxin gene for faecal sample toxin status and patient outcome. AB - BACKGROUND: Laboratory diagnosis of Clostridium difficile infection (CDI) remains unsettled, despite updated guidelines. We investigated the potential utility of quantitative data from a nucleic acid amplification test (NAAT) for C. difficile toxin gene (tg) for patient management. METHODS: Using data from the largest ever C. difficile diagnostic study (8853 diarrhoeal samples from 7335 patients), we determined the predicative value of C. difficile tgNAAT (Cepheid Xpert C.diff) low cycle threshold (CT) value for patient toxin positive status, CDI severity, mortality and CDI recurrence. Reference methods for CDI diagnosis were cytotoxicity assay (CTA) and cytotoxigenic culture (CTC). RESULTS: Of 1281 tgNAAT positive faecal samples, 713 and 917 were CTA and CTC positive, respectively. The median tgNAAT CT for patients who died was 25.5 vs 27.5 for survivors (p = 0.021); for toxin-positivity was 24.9 vs 31.6 for toxin-negative samples (p<0.001) and for patients with a recurrence episode was 25.6 vs 27.3 for those who did not have a recurrent episode (p = 0.111). Following optimal cut-off determination, low CT was defined as <=25 and was significantly associated with a toxin-positive result (P<0.001, positive predictive value 83.9%), presence of PCR ribotype 027 (P = 0.025), and mortality (P = 0.032). Recurrence was not associated with low CT (p 0.111). CONCLUSIONS: Low tgNAAT CT could indicate CTA positive patients, have more severe infection, increased risk of mortality and possibly recurrence. Although, the limited specificity of tgNAAT means it cannot be used as a standalone test, it could augment a more timely diagnosis, and optimise management of these at-risk patients. PMID- 30517095 TI - More diversity in epithelial cell polarity: A fruit flies' gut feeling. AB - Multicellular animals face the principle challenge to deal with two distinct compartments: the internal organismal compartment and the external environment. This challenge is met by the differentiation of cell sheets into epithelia, which provide a dynamic barrier in tissues, organs, and organisms. Cell polarity is key to all functions of epithelia, and compromising polarity causes many severe diseases. Within the past 20 years, research on Drosophila melanogaster discovered a conserved molecular machinery that controls epithelial polarity. Recent findings suggest that the textbook Drosophila-based paradigm of the control of epithelial polarity may not be as universal as previously assumed. PMID- 30517096 TI - Characterisation of morphological differences in well-differentiated nasal epithelial cell cultures from preterm and term infants at birth and one-year. AB - BACKGROUND: Innate immune responses of airway epithelium are important defences against respiratory pathogens and allergens. Newborn infants are at greater risk of severe respiratory infections compared to older infants, while premature infants are at greater risk than full term infants. However, very little is known regarding human neonatal airway epithelium immune responses and whether age related morphological and/or innate immune changes contribute to the development of airway disease. METHODS: We collected nasal epithelial cells from 41 newborn infants (23 term, 18 preterm) within 5 days of birth. Repeat sampling was achieved for 24 infants (13 term, 11 preterm) at a median age of 12.5 months. Morphologically- and physiologically-authentic well-differentiated primary paediatric nasal epithelial cell (WD-PNEC) cultures were generated and characterised using light microscopy and immunofluorescence. RESULTS: WD-PNEC cultures were established for 15/23 (65%) term and 13/18 (72%) preterm samples at birth, and 9/13 (69%) term and 8/11 (73%) preterm samples at one-year. Newborn and infant WD-PNEC cultures demonstrated extensive cilia coverage, mucous production and tight junction integrity. Newborn WD-PNECs took significantly longer to reach full differentiation and were noted to have much greater proportions of goblet cells compared to one-year repeat WD-PNECs. No differences were evident in ciliated/goblet cell proportions between term- and preterm derived WD-PNECs at birth or one-year old. CONCLUSION: We describe the successful generation of newborn-derived WD-PNEC cultures and their revival from frozen. We also compared the characteristics of WD-PNECs derived from infants born at term with those born prematurely at birth and at one-year-old. The development of WD PNEC cultures from newborn infants provides a powerful and exciting opportunity to study the development of airway epithelium morphology, physiology, and innate immune responses to environmental or infectious insults from birth. PMID- 30517097 TI - The administration of high-mobility group box 1 fragment prevents deterioration of cardiac performance by enhancement of bone marrow mesenchymal stem cell homing in the delta-sarcoglycan-deficient hamster. AB - OBJECTIVES: We hypothesized that systemic administration of high-mobility group box 1 fragment attenuates the progression of myocardial fibrosis and cardiac dysfunction in a hamster model of dilated cardiomyopathy by recruiting bone marrow mesenchymal stem cells thus causing enhancement of a self-regeneration system. METHODS: Twenty-week-old J2N-k hamsters, which are delta-sarcoglycan deficient, were treated with systemic injection of high-mobility group box 1 fragment (HMGB1, n = 15) or phosphate buffered saline (control, n = 11). Echocardiography for left ventricular function, cardiac histology, and molecular biology were analyzed. The life-prolonging effect was assessed separately using the HMGB1 and control groups, in addition to a monthly HMGB1 group which received monthly systemic injections of high-mobility group box 1 fragment, 3 times (HMGB1, n = 11, control, n = 9, monthly HMGB1, n = 9). RESULTS: The HMGB1 group showed improved left ventricular ejection fraction, reduced myocardial fibrosis, and increased capillary density. The number of platelet-derived growth factor receptor-alpha and CD106 positive mesenchymal stem cells detected in the myocardium was significantly increased, and intra-myocardial expression of tumor necrosis factor alpha stimulating gene 6, hepatic growth factor, and vascular endothelial growth factor were significantly upregulated after high-mobility group box 1 fragment administration. Improved survival was observed in the monthly HMGB1 group compared with the control group. CONCLUSIONS: Systemic high mobility group box 1 fragment administration attenuates the progression of left ventricular remodeling in a hamster model of dilated cardiomyopathy by enhanced homing of bone marrow mesenchymal stem cells into damaged myocardium, suggesting that high-mobility group box 1 fragment could be a new treatment for dilated cardiomyopathy. PMID- 30517098 TI - Insights on the impact of mitochondrial organisation on bioenergetics in high resolution computational models of cardiac cell architecture. AB - Recent electron microscopy data have revealed that cardiac mitochondria are not arranged in crystalline columns but are organised with several mitochondria aggregated into columns of varying sizes often spanning the cell cross-section. This raises the question-how does the mitochondrial arrangement affect the metabolite distributions within cardiomyocytes and their impact on force dynamics? Here we employed finite element modelling of cardiac bioenergetics, using computational meshes derived from electron microscope images, to address this question. Our results indicate that heterogeneous mitochondrial distributions can lead to significant spatial variation across the cell in concentrations of inorganic phosphate, creatine (Cr) and creatine phosphate (PCr). However, our model predicts that sufficient activity of the creatine kinase (CK) system, coupled with rapid diffusion of Cr and PCr, maintains near uniform ATP and ADP ratios across the cell cross sections. This homogenous distribution of ATP and ADP should also evenly distribute force production and twitch duration with contraction. These results suggest that the PCr shuttle, and associated enzymatic reactions, act to maintain uniform force dynamics in the cell despite the heterogeneous mitochondrial organization. However, our model also predicts that under hypoxia-activity of mitochondrial CK enzyme and diffusion of high-energy phosphate compounds may be insufficient to sustain uniform ATP/ADP distribution and hence force generation. PMID- 30517099 TI - Preliminary development of an assay for detection of TERT expression, telomere length, and telomere elongation in single cells. AB - The telomerase enzyme enables unlimited proliferation of most human cancer cells by elongating telomeres and preventing replicative senescence. Despite the critical importance of telomerase in cancer biology, challenges detecting telomerase activity and expression in individual cells have hindered the ability to study patterns of telomerase expression and function across heterogeneous cell populations. While sensitive assays to ascertain telomerase expression and function exist, these approaches have proven difficult to implement at the single cell level. Here, we validate in situ RNAscope detection of the telomerase TERT mRNA and couple this assay with our recently described TSQ1 method for in situ detection of telomere elongation. This approach enables detection of TERT expression, telomere length, and telomere elongation within individual cells of the population. Using this assay, we show that the heterogeneous telomere elongation observed across a HeLa cell population is in part driven by variable expression of the TERT gene. Furthermore, we show that the absence of detectable telomere elongation in some TERT-positive cells is the result of inhibition by the telomeric shelterin complex. This combined assay provides a new approach for understanding the integrated expression, function, and regulation of telomerase at the single cell level. PMID- 30517100 TI - Organised sports participation and adiposity among a cohort of adolescents over a two year period. AB - BACKGROUND: Overweight and obesity among young people is alarmingly high. While hundreds of millions of children participate in organised sports worldwide, it is currently unknown whether time spent in organised sports is associated with levels of adiposity among young people. This study aimed to investigate bidirectional associations between participation in organised sports and adiposity over a two year period. METHOD: Data were drawn from the Longitudinal Study of Australian Children. In total, 4033 participants (51% male) reported time spent in organised sports and had their body mass index, body fat percentage, and waist circumference measured at age 12, and again two years later. A cross-lagged panel model was used to examine bidirectional relationships over time, as well as interaction effects. RESULTS: Total sport participation at age 12 was not associated with subsequent BMI-z scores (beta = 0.01 [95% CI, 0.02, 0.04]), body fat (beta = 0.01 [95% CI, -0.02, 0.03]), or waist circumference (beta = -0.01 [95% CI, -0.05, 0.02]). Similarly, measure of adiposity at age 12 were not associated with subsequent sports participation (BMI z score: beta = -0.01 [95% CI, -0.02, 0.04]; body fat percentage: beta = -0.02 [95% CI, -0.05, 0.02]; waist circumference: beta = -0.01 [95% CI, -0.01, 0.03]). There were no differences in the strength or direction of the relationships by type of sport or by sex (p < .05). CONCLUSION: Policy and programmatic changes may be needed before organised youth sports are considered a preventative strategy for overweight and obesity. However, a more nuanced understanding of why organised youth sports are not associated with adiposity is needed before evidence-based changes can be made. PMID- 30517101 TI - Prevalence and type of artefact with spectral domain optical coherence tomography macular ganglion cell imaging in glaucoma surveillance. AB - PURPOSE: The ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma. METHOD: A total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined. RESULTS: A total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes. CONCLUSION: The macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results. PMID- 30517102 TI - Automatic classification of pediatric pneumonia based on lung ultrasound pattern recognition. AB - Pneumonia is one of the major causes of child mortality, yet with a timely diagnosis, it is usually curable with antibiotic therapy. In many developing regions, diagnosing pneumonia remains a challenge, due to shortages of medical resources. Lung ultrasound has proved to be a useful tool to detect lung consolidation as evidence of pneumonia. However, diagnosis of pneumonia by ultrasound has limitations: it is operator-dependent, and it needs to be carried out and interpreted by trained personnel. Pattern recognition and image analysis is a potential tool to enable automatic diagnosis of pneumonia consolidation without requiring an expert analyst. This paper presents a method for automatic classification of pneumonia using ultrasound imaging of the lungs and pattern recognition. The approach presented here is based on the analysis of brightness distribution patterns present in rectangular segments (here called "characteristic vectors") from the ultrasound digital images. In a first step we identified and eliminated the skin and subcutaneous tissue (fat and muscle) in lung ultrasound frames, and the "characteristic vectors"were analyzed using standard neural networks using artificial intelligence methods. We analyzed 60 lung ultrasound frames corresponding to 21 children under age 5 years (15 children with confirmed pneumonia by clinical examination and X-rays, and 6 children with no pulmonary disease) from a hospital based population in Lima, Peru. Lung ultrasound images were obtained using an Ultrasonix ultrasound device. A total of 1450 positive (pneumonia) and 1605 negative (normal lung) vectors were analyzed with standard neural networks, and used to create an algorithm to differentiate lung infiltrates from healthy lung. A neural network was trained using the algorithm and it was able to correctly identify pneumonia infiltrates, with 90.9% sensitivity and 100% specificity. This approach may be used to develop operator-independent computer algorithms for pneumonia diagnosis using ultrasound in young children. PMID- 30517103 TI - Development of a PCR algorithm to detect and characterize Neisseria meningitidis carriage isolates in the African meningitis belt. AB - Improved methods for the detection and characterization of carried Neisseria meningitidis isolates are needed. We evaluated a multiplex PCR algorithm for the detection of a variety of carriage strains in the meningitis belt. To further improve the sensitivity and specificity of the existing PCR assays, primers for gel-based PCR assays (sodC, H, Z) and primers/probe for real-time quantitative PCR (qPCR) assays (porA, cnl, sodC, H, E, Z) were modified or created using Primer Express software. Optimized multiplex PCR assays were tested on 247 well characterised carriage isolates from six countries of the African meningitis belt. The PCR algorithm developed enabled the detection of N. meningitidis species using gel-based and real-time multiplex PCR targeting porA, sodC, cnl and characterization of capsule genes through sequential multiplex PCR assays for genogroups (A, W, X, then B, C, Y and finally H, E and Z). Targeting both porA and sodC genes together allowed the detection of meningococci with a sensitivity of 96% and 89% and a specificity of 78% and 67%, for qPCR and gel-based PCR respectively. The sensitivity and specificity ranges for capsular genogrouping of N. meningitidis are 67% - 100% and 98%-100% respectively for gel-based PCR and 90%-100% and 99%-100% for qPCR. We developed a PCR algorithm that allows simple, rapid and systematic detection and characterisation of most major and minor N. meningitidis capsular groups, including uncommon capsular groups (H, E, Z). PMID- 30517104 TI - Plant epithelia: What is the role of the mortar in the wall? AB - In a growing plant root, the inner vascular system is sealed off by an epithelium, the endodermis. The space between all of the cells in the endodermal layer is filled with an impermeable mass called the Casparian strip, which closes the spaces between cells in the endodermal layer. The role of the Casparian strip has been proposed to prevent backflow of water and nutrients into the soil, but as mutant plants lacking the Casparian strip only have weak phenotypes, the view that it serves an essential function in plants has been challenged. In an accompanying paper, it is shown that loss of the Casparian strip impacts the ability of the plant to take up ammonium and allocate it to the shoots. PMID- 30517105 TI - Base composition is the primary factor responsible for the variation of amino acid usage in zebra finch (Taeniopygia guttata). AB - In the present study, we carried out an examination of the amino acid usage in the zebra finch (Taeniopygia guttata) proteome. We found that tRNA abundance, base composition, hydrophobicity and aromaticity, protein second structure, cysteine residue (Cys) content and protein molecular weight had significant impact on the amino acid usage of the zebra finch. The above factors explained the total variability of 22.85%, 25.37%, 10.91%, 5.06%, 4.21%, and 3.14%, respectively. Altogether, approximately 70% of the total variability in zebra finch could be explained by such factors. Comparison of the amino acid usage between zebra finch, chicken (Gallus gallus) and human (Homo sapiens) suggested that the average frequency of various amino acid usage is generally consistent among them. Correspondence analysis indicated that base composition was the primary factor affecting the amino acid usage in zebra finch. This trend was different from chicken, but similar to human. Other factors affecting the amino acid usage in zebra finch, such as isochore structure, protein second structure, Cys frequency and protein molecular weight also showed the similar trends with human. We do not know whether the similar amino acid usage trend between human and zebra finch is related to the distinctive neural and behavioral traits, but it is worth studying in depth. PMID- 30517107 TI - Traumatic insemination is not the case in three Orius species (Heteroptera: Anthocoridae). AB - Traumatic insemination (TI) is an extraordinary style of mating behavior wherein the female integument is pierced by the male extragenital structure to transfer the spermatozoa into the female's body through wounding. Flower bugs of the genus Orius belong to the family Anthocoridae (Heteroptera), which is referred to as the "TI family". Males possess sharp shaped extragenitalia, and females receive the extragenitalia using the copulatory tubes, which are specialized extragenital structures in Orius species. Since TI is not well studied in insects possessing the copulatory tube, we examined the genital structures and copulatory processes of three species, Orius strigicollis, O. sauteri, and O. minutus. Scanning electron microscopic observations revealed the positions of male extragenital structures during copulation. A needle-like flagellum was deeply inserted into the female intersegment between the abdominal VII and VIII segments, while the curved part of a sickle-like cone forced the intersegment to expand. No scars were detected around the copulation region after copulation. The copulatory tube adhered to the interior of segment VII, and the interior integument around the copulatory tube remained intact after copulation. On the basis of these results, TI does not occur in these Orius species. A pair of seminal conceptacles, which exists in typical TI insects, was found at the base of the oviducts in O. strigicollis. The distal end of the copulatory tube connected to a closed bag with a double-membrane, termed the sperm pouch. The sperm pouch was filled with filamentous structures after copulation and structures with equivalent forms were observed in adult male testis. These structures, considered to be spermatozoa, persisted in the pouch for at least two weeks after copulation, suggesting that the pouch is a long-term spermatozoa storage organ. PMID- 30517106 TI - Ancestral origin of ApoE epsilon4 Alzheimer disease risk in Puerto Rican and African American populations. AB - The ApoE epsilon4 allele is the most significant genetic risk factor for late onset Alzheimer disease. The risk conferred by epsilon4, however, differs across populations, with populations of African ancestry showing lower epsilon4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE epsilon4 allele in both populations (Puerto Rican: p value = 0.019; African American: p-value = 0.005). ApoE epsilon4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene epsilon4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors. PMID- 30517108 TI - Relationship of peripheral blood mononuclear cells miRNA expression and parasitic load in canine visceral leishmaniasis. AB - Visceral leishmaniasis (VL) in humans is a chronic and often fatal disease if left untreated. Dogs appear to be the main reservoir host for L. infantum infection, however, in many regions other canids such as jackals, foxes, wolves and other mammals, such as hares or black rats, have been implicated as wild reservoirs. Most dogs cannot form an effective immune response against this infection, and this could be modulated by small non-coding RNAs, called microRNAs, responsible for post-transcriptional control of gene expression. Here, we evaluated the expression of miRNAs in peripheral blood mononuclear cells (PBMC) of symptomatic dogs naturally infected with Leishmania (L.) infantum (n = 10) and compared to those of healthy dogs (n = 5). Microarray analysis revealed that miR-21, miR-424, miR-194 and miR-451 had a 3-fold increase in expression, miR-192, miR-503, and miR-371 had a 2-fold increase in expression, whereas a 2 fold reduction in expression was observed for miR-150 and miR-574. Real-time PCR validated the differential expression of miR-21, miR-150, miR-451, miR-192, miR 194, and miR-371. Parasite load of PBMC was measured by real-time PCR and correlated to the differentially expressed miRNAs, showing a strong positive correlation with expression of miR-194, a regular positive correlation with miR 371 expression, and a moderate negative correlation with miR-150 expression in PBMC. These findings suggest that Leishmania infection interferes with miRNAs expression in PBMC, and their correlation with parasite load may help in the identification of therapeutic targets in Canine Visceral Leishmaniasis (CVL). PMID- 30517109 TI - Diet and prey selection by snow leopards in the Nepalese Himalayas. AB - Visual attractiveness and rarity often results in large carnivores being adopted as flagship species for stimulating conservation awareness. Their hunting behaviour and prey selection can affect the population dynamics of their prey, which in turn affects the population dynamics of these large carnivores. Therefore, our understanding of their trophic ecology and foraging strategies is important for predicting their population dynamics and consequently for developing effective conservation programs. Here we concentrate on an endangered species of carnivores, the snow leopard, in the Himalayas. Most previous studies on snow leopard diet lack information on prey availability and/or did not genetically check, whether the identification of snow leopard scats is correct, as their scats are similar to those of other carnivores. We studied the prey of snow leopard in three Himalayan regions in Nepal (Sagarmatha National Park (SNP), Lower Mustang (LM) and Upper Manang (UM) in the Annapurna Conservation Area, during winter and summer in 2014-2016. We collected 268 scats along 139.3 km linear transects, of which 122 were genetically confirmed to belong to snow leopard. Their diet was identified by comparing hairs in scats with our reference collection of the hairs of potential prey. We determined prey availability using 32-48 camera-traps and 4,567 trap nights. In the SNP, the most frequent prey in snow leopard faeces was the Himalayan tahr in both winter and summer. In LM and UM, its main prey was blue sheep in winter, but yak and goat in summer. In terms of relative biomass consumed, yak was the main prey everywhere in both seasons. Snow leopard preferred large prey and avoided small prey in summer but not in winter, with regional differences. It preferred domestic to wild prey only in winter, and in SNP. Unlike most other studies carried out in the same area, our study uses genetic methods for identifying the source of the scat. Studies solely based on visual identification of samples may be strongly biased. Diet studies based on frequency of occurrence of prey tend to overestimate the importance of small prey, which may be consumed more often, but contribute less energy than large prey. However, even assessments based on prey biomass are unlikely to be accurate as we do not know whether the actual size of the prey consumed corresponds to the average size used to calculate the biomass eaten. For example, large adults may be too difficult to catch and therefore mostly young animals are consumed, whose weight is much lower. We show that snow leopard consumes a diverse range of prey, which varies both regionally and seasonally. We conclude that in order to conserve snow leopards it is also necessary to conserve its main wild species of prey, which will reduce the incidence of losses of livestock. PMID- 30517110 TI - Pulmonary high-resolution computed tomography findings in patients with synovitis, acne, pustulosis, hyperostosis and osteitis syndrome. AB - OBJECTIVE: To characterize the high-resolution computed tomography (HRCT) pulmonary abnormalities in patients with synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS: Pulmonary HRCT images were reconstructed from whole-spine computed tomography (CT) images of 67 patients with SAPHO syndrome. HRCT images of 58 healthy controls were also obtained and reviewed. Patients with pneumonia and tuberculosis were excluded. Demographic and clinical data such as gender, age, onset age, disease duration, erythrocyte sedimentation rate (ESR), highly sensitive C-reactive protein (hs-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were collected from the SAPHO syndrome patients. Demographic characteristics, ESR and hs-CRP data from the healthy controls were also recorded. Student's t test, Mann-Whitney U test, chi-squared test and logistic regression were employed to compare the HRCT findings of the two groups of patients. RESULTS: The median age of the SAPHO syndrome patients was 47.0 years, interquartile range [38.0-53.0]; that of the healthy controls was 37.0[30.8-53.8]. From the detailed HRCT evaluations, abnormalities were identified in 45 patients. We found irregular linear opacities in 29 (43.3%) patients, opacities in 22 (32.8%), ground-glass opacity in 11 (16.4%), pleural thickening in 9 (13.4%), solitary nodules in 6 (9%), bronchiectasis in 3 (4.5%), pulmonary bulla in 2 (3%), multiple nodules in 1 (1.5%), and reticular patterns in 1 (1.5%). Compared to the healthy controls, the SAPHO syndrome patients had a significantly higher rate of opacities but a significantly lower percentage of nodules (especially multiple nodules), although the overall rates of abnormal HRCT findings were similar in the two groups. According to the multivariate logistic regression analysis, increased age and BASDAI < 4 were significant predictors of abnormal HRCT findings. CONCLUSION: Our study is the first to address HRCT pulmonary abnormalities in SAPHO syndrome patients. SAPHO syndrome patients have a significantly higher percentage of opacities and a significantly lower rate of pulmonary nodules than healthy controls. BASDAI and age are possible good predictors of abnormal HRCT pulmonary findings. PMID- 30517111 TI - Adaptive and dynamic RFID tag anti-collision based on secant iteration. AB - Radio frequency identification (RFID) has recently experienced unprecedented development. Among many other areas, it has been widely applied in blood station management, automatic supermarket checkout, and logistics. In the application of RFID for large-scale passive tags, tag collision is inevitable owing to the non cooperation mechanism among tags. Therefore, a tag anti-collision method is a key factor affecting the identification efficiency. In this paper, we propose a tag anti-collision method based on Aloha technology for RFID. It estimates the number of remaining tags using the secant iteration method. To achieve optimal identification efficiency, it adaptively and dynamically adjusts the lengths of the subsequent frames according to the principle that the length of a frame should be the same as the number of tags to be identified. For pseudo-solutions of tag population estimation while using secant iteration, we present an elimination method by two probing frames. The simulation results show that the estimation precision of our method can reach above 97%. Thus, it can meet the requirement of the tag anti-collision estimation accuracy. Its global throughput is obviously superior to the Q algorithm adopted by the current international standard, and it is close to the ideal system. It consequently outperforms existing schemes. PMID- 30517112 TI - Changes in brain white matter structure are associated with urine proteins in urologic chronic pelvic pain syndrome (UCPPS): A MAPP Network study. AB - The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates. Results identified a brainstem region that showed a strong correlation between both ADC (R2 = 0.49, P<0.0001) and FA (R2 = 0.39, P = 0.0002) with urinary MMP9 levels as well as a correlation between both ADC (R2 = 0.42, P = 0.0001) and FA (R2 = 0.29, P = 0.0020) and urinary MMP9/NGAL complex. Results also identified significant correlations between FA and urinary MMP9 in white matter adjacent to sensorimotor regions (R2 = 0.30, P = 0.002; R2 = 0.36, P = 0.0005, respectively), as well as a correlation in similar sensorimotor regions when examining ADC and urinary MMP2 levels (R2 = 0.42, P<0.0001) as well as FA and urinary MMP9/NGAL complex (R2 = 0.33, P = 0.0008). A large, diffuse cluster of white matter was identified as having a strong correlation between both ADC (R2 = 0.35, P = 0.0006) and FA (R2 = 0.43, P<0.0001) with urinary NGAL levels. In contrast, no significant association between DTI measurements and VEGF was observed. Results suggest that elevated MMP9 or MMP9/NGAL in UCPPS may be related to degenerative neuronal changes in brainstem nuclei through excitotoxicity, while also facilitating synaptic plasticity in sensorimotor regions. PMID- 30517113 TI - Summer shifts of bacterial communities associated with the invasive brown seaweed Sargassum muticum are location and tissue dependent. AB - Seaweed-associated microbiota experience spatial and temporal shifts in response to changing environmental conditions and seaweed physiology. These shifts may result in structural, functional and behavioral changes in the host with potential consequences for its fitness. They, thus, may help the host to adapt to changing environmental conditions. The current knowledge of seasonal variation of seaweed-associated microbiota is however still limited. In this study, we explored temporal and spatial variation of microbial communities associated with the invasive brown seaweed S. muticum. We sampled in northern and southern Portugal, in September, March and July-August (summer). In addition, as (pseudo )perennial seaweeds display seasonal reproductive phenology, we sampled various parts of the individuals to disentangle the effect of temporal changes from those due to structural development variations. The diversity and structure of associated microbial communities were determined using next generation sequencing of the variable regions V5-7 of the 16S rDNA. We expected to find differentiation in associated microbial communities between regions and sampling months, but with differences depending on the seaweed structure examined. As expected, the study revealed substantial temporal shifts in S. muticum microbiome, for instance with large abundance of Rhodobacteraceae and Loktanella in September-March but prevalence of Pirellulales during the summer months. Variations between regions and tissues were also observed: in northern Portugal and on basal structures, bacterial diversity was higher as compared to the South and apical parts. All examined seaweed structures showed temporal differences in associated microbial community structure over time, except for holdfasts between September and March. Bacteria contributing to these changes varied spatially. Conversely to all other structures, the holdfast also did not show differences in associated community structure between southern and northern regions. Our study highlights the importance of structural microscale differentiations within seaweeds hosts with regard to their associated microbial communities and their importance across temporal and spatial dimensions. PMID- 30517114 TI - Traveling pulse emerges from coupled intermittent walks: A case study in sheep. AB - Monitoring small groups of sheep in spontaneous evolution in the field, we decipher behavioural rules that sheep follow at the individual scale in order to sustain collective motion. Individuals alternate grazing mode at null speed and moving mode at walking speed, so cohesive motion stems from synchronising when they decide to switch between the two modes. We propose a model for the individual decision making process, based on switching rates between stopped / walking states that depend on behind / ahead locations and states of the others. We parametrize this model from data. Next, we translate this (microscopic) individual-based model into its density-flow (macroscopic) equations counterpart. Numerical solving these equations display a traveling pulse propagating at constant speed even though each individual is at any moment either stopped or walking. Considering the minimal model embedded in these equations, we derive analytically the steady shape of the pulse (sech square). The parameters of the pulse (shape and speed) are expressed as functions of individual parameters. This pulse emerges from the non linear coupling of start/stop individual decisions which compensate exactly for diffusion and promotes a steady ratio of walking / stopped individuals, which in turn determines the traveling speed of the pulse. The system seems to converge to this pulse from any initial condition, and to recover the pulse after perturbation. This gives a high robustness to this coordination mechanism. PMID- 30517115 TI - Life satisfaction favors reproduction. The universal positive effect of life satisfaction on childbearing in contemporary low fertility countries. AB - Do people with higher life satisfaction have more children? Having children requires considerable energy and investment on the part of parents. However, even in countries where contraceptives are easily available and widely used, where having children is optional and most of time the result of an intended action, parenthood has not gone "out of fashion". This paper tests the hypothesis that higher life satisfaction fosters reproductive behavior. We argue that people satisfied with their overall life feel better prepared to start the monumental task of childrearing. If, it is suggested, life satisfaction facilitates fertility, then this positive link should be observable in contemporary low fertility societies. The hypothesis is tested by taking overall life satisfaction as a determinant of fertility behavior using long longitudinal data available for developed countries: namely for Australia, Germany, Russia, South Korea, Switzerland, the United Kingdom, and the United States. We find that higher levels of subjective well-being are, indeed, associated with a higher probability of having children in all the countries considered. We, therefore, conclude that life satisfaction favors reproduction, at least in low fertility societies. PMID- 30517117 TI - Gene expression profiling of the early pathogenesis of wooden breast disease in commercial broiler chickens using RNA-sequencing. AB - Wooden Breast Disease (WBD), a myopathy in commercial broiler chickens characterized by abnormally firm consistency of the pectoral muscle, impacts the poultry industry negatively due to severe reduction in meat quality traits. To unravel the molecular profile associated with the onset and early development of WBD in broiler chickens, we compared time-series gene expression profiles of Pectoralis (P.) major muscles between unaffected and affected birds from a high breast-muscle-yield, purebred broiler line. P. major biopsy samples were collected from the cranial and caudal aspects of the muscle belly in birds that were raised up to 7 weeks of age (i.e. market age). Three subsets of biopsy samples comprising 6 unaffected (U) and 10 affected (A) from week 2 (cranial) and 4 (caudal), and 4U and 11A from week 3 (cranial) were processed for RNA sequencing analysis. Sequence reads generated were processed using a suite of bioinformatics programs producing differentially expressed (DE) genes for each dataset at fold-change (A/U or U/A) >1.3 and False Discovery Ratio (FDR) <0.05 (week 2: 41 genes; week 3: 618 genes and week 4: 39 genes). Functional analysis of DE genes using literature mining, BioDBnet and IPA revealed several biological processes and pathways associated with onset and progress of WBD. Top among them were dysregulation of energy metabolism, response to inflammation, vascular disease and remodeling of extracellular matrix. This study reveals that presence of molecular perturbations involving the vasculature, extracellular matrix and metabolism are pertinent to the onset and early pathogenesis of WBD in commercial meat-type chickens. PMID- 30517116 TI - Discontinuities in quinoa biodiversity in the dry Andes: An 18-century perspective based on allelic genotyping. AB - History and environment shape crop biodiversity, particularly in areas with vulnerable human communities and ecosystems. Tracing crop biodiversity over time helps understand how rural societies cope with anthropogenic or climatic changes. Exceptionally well preserved ancient DNA of quinoa (Chenopodium quinoa Willd.) from the cold and arid Andes of Argentina has allowed us to track changes and continuities in quinoa diversity over 18 centuries, by coupling genotyping of 157 ancient and modern seeds by 24 SSR markers with cluster and coalescence analyses. Cluster analyses revealed clear population patterns separating modern and ancient quinoas. Coalescence-based analyses revealed that genetic drift within a single population cannot explain genetic differentiation among ancient and modern quinoas. The hypothesis of a genetic bottleneck related to the Spanish Conquest also does not seem to apply at a local scale. Instead, the most likely scenario is the replacement of preexisting quinoa gene pools with new ones of lower genetic diversity. This process occurred at least twice in the last 18 centuries: first, between the 6th and 12th centuries-a time of agricultural intensification well before the Inka and Spanish conquests-and then between the 13th century and today-a period marked by farming marginalization in the late 19th century likely due to a severe multidecadal drought. While these processes of local gene pool replacement do not imply losses of genetic diversity at the metapopulation scale, they support the view that gene pool replacement linked to social and environmental changes can result from opposite agricultural trajectories. PMID- 30517118 TI - Patients' sense of responsibility to healthcare providers and its predictors: A national cross-sectional survey in China. AB - OBJECTIVES: To evaluate patients' sense of responsibility to healthcare providers and to determine its predictors using on a national sample in China. METHODS: We conducted a national cross-sectional survey in China with a stratified cluster sample of patients treated in 77 hospitals between July 2014 and April 2015. Patients' sense of responsibility to healthcare providers was measured with four questions assessing patients' perceptions regarding their responsibilities to respect doctors, respect nurses, coordinate with health professionals, and comply with hospital rules. Predictors included patient sociodemographic characteristics and their past hospitalization experience. RESULTS: Small proportions of respondents reported that they perceived having no responsibility to respect doctors (8.9%), respect nurses (7.9%), comply with hospital rules (6.7%), or coordinate with health professionals (6.3%). Multivariate regression analyses showed that the strongest predictor of patients' sense of responsibility to healthcare providers was patinets' trust in health professionals, followed by patients' education level. Familiarity with healthcare professionals and past hospitalization frequency were inversely associated with patients' sense of responsibility to healthcare providers. CONCLUSIONS: Although only a small proportion of the patients reported feeling no or low sense of responsibility to healthcare providers, the lack of respect and collaboration from these patients can negatively affect patient-provider relationships. Healthcare administrators need to communicate clearly with the patients and the public about the role of patients and the limitations of medicine in order to instill a sense of patients' responsibility. PMID- 30517119 TI - Estimating everyday risk: Subjective judgments are related to objective risk, mapping of numerical magnitudes and previous experience. AB - We aimed to investigate individual differences that associate with peoples' acute risk perception for activities such as walking and giving birth, including objective risk and the mapping of numerical magnitudes. The Amazon Mechanical Turk platform was used, with 284 participants recruited (40% female) ranging between 19 and 68 years. Participants had to indicate the positions of (1) the relative death risk of activities on a horizontal-line with 'very low risk of death' and 'very high risk of death' as left and right anchors respectively and (2), numerical magnitudes on a horizontal-line ranging 0-1000. The MicroMort framework was used to index acute risk of death (one/million chance of dying from an accident). Previous experience with the activities, handedness, along with risk propensity and unrealistic optimism were also measured. Linear mixed-effects modelling was used to investigate predictors of subjective MicroMort judgments. Individuals subjectively judged activities to be riskier if the activity was objectively riskier, if they over-estimated on the numerical task (more so for low-risk activities as compared to high-risk), or if they had not experienced the activity previously. The observed relationship between the number line task and everyday risk judgments is in keeping with the idea of a common magnitude representation system. In conclusion, individuals are able to discriminate between activities varying in risk in an absolute sense, however intuition for judging the relative differences in risk is poor. The relationship between the misjudging of both risks and numerical magnitudes warrants further investigation, as may inform the development of risk communication strategies. PMID- 30517120 TI - Point-of-care, smartphone-based, dual-modality, dual-view, oral cancer screening device with neural network classification for low-resource communities. AB - Oral cancer is a growing health issue in a number of low- and middle-income countries (LMIC), particularly in South and Southeast Asia. The described dual modality, dual-view, point-of-care oral cancer screening device, developed for high-risk populations in remote regions with limited infrastructure, implements autofluorescence imaging (AFI) and white light imaging (WLI) on a smartphone platform, enabling early detection of pre-cancerous and cancerous lesions in the oral cavity with the potential to reduce morbidity, mortality, and overall healthcare costs. Using a custom Android application, this device synchronizes external light-emitting diode (LED) illumination and image capture for AFI and WLI. Data is uploaded to a cloud server for diagnosis by a remote specialist through a web app, with the ability to transmit triage instructions back to the device and patient. Finally, with the on-site specialist's diagnosis as the gold standard, the remote specialist and a convolutional neural network (CNN) were able to classify 170 image pairs into 'suspicious' and 'not suspicious' with sensitivities, specificities, positive predictive values, and negative predictive values ranging from 81.25% to 94.94%. PMID- 30517121 TI - Subclinical parameters of arterial stiffness and arteriosclerosis correlate with QRISK3 in systemic lupus erythematosus. AB - : It is well known that cardiovascular diseases (CVD) are a major contributor of death in systemic lupus erythematosus (SLE) as well in other rheumatic illness. In the last decades, there has been a growing development of different methodologies with the purpose of early detection of CVD. OBJECTIVE: The aim of this study is to correlate the usefulness of subclinical parameters of vascular aging and QRISK 3-2017 score for early detection of CVD in SLE. METHODS: Clinical assessment including systemic lupus erythematosus disease activity index (SLEDAI) and systemic lupus international collaborating clinics / american college of rheumatology damage index (SLICC/ACR DI), laboratory measurements, carotid ultrasound examination, carotid intima media thickness (cIMT) measurement, carotid distention and diameter analysis, arterial stiffness measurement measured by tonometry and QRISK 3-2017 were done. All results were analyzed by SPSS 24 software. RESULTS: We observed correlation between QRISK3 and mean cIMT (rs = 0.534, P < 0.001), PWV (rs = 0.474, P < 0.001), cfPWV (rs = 0.569, P < 0.001) and distensibility (rs = -0.420, P = 0.006). Consistent with above, SLE patients in middle and high risk QRISK 3-2017 showed increased arterial stiffness versus low risk group. CONCLUSIONS: We encourage to the rheumatology community to assess cardiovascular risk in SLE patients with QRISK 3-2017 risk calculator as an alternative method at the outpatient clinic along a complete cardiovascular evaluation when appropriate. PMID- 30517122 TI - Listener characteristics modulate the semantic processing of native vs. foreign accented speech. AB - Foreign accents have been shown to have considerable impact on how language is processed [1]. However, the impact of a foreign accent on semantic processing is not well understood. Conflicting results have been reported by previous event related potential (ERP) studies investigating the impact of foreign-accentedness on the N400 effect elicited by semantic violations. Furthermore, these studies have only examined a subset of the four characteristics of the N400 (i.e. onset latency, latency, amplitude, and scalp distribution), and have been conducted in linguistic environments where foreign-accented speech is relatively uncommon. The current study therefore compared the N400 effect elicited by semantic violations in native Australian English vs. Mandarin-accented English, in a context where foreign-accented speech is common. Factors which may be responsible for individual variability in N400 amplitude were also investigated. The results showed no differences between the N400s elicited by native and foreign-accented speech in any of the four aforementioned characteristics. However, the analysis of individual variability revealed an effect of familiarity with foreign-accented speech on the amplitude of N400 effects for semantic violations. An effect of working memory capacity on N400 amplitude was also found. These findings highlight the relevance of the ambient linguistic environment for studies of speech processing, and demonstrate the interacting influences of both speaker- and listener-related factors on semantic processing. PMID- 30517123 TI - Bilateral delayed endolymphatic hydrops evaluated by bilateral intratympanic injection of gadodiamide with 3T-MRI. AB - The purpose of this study was to assess the diagnostic performance of 3T MRI after intratympanic injection of gadodiamide for delayed endolymphatic hydrops (DEH), and assess the relationship between endolymphatic hydrops (ELH) and vestibular function in patients diagnosed with DEH and confirmed by 3T MRI. Nineteen patients clinically diagnosed with DEH (11 ipsilateral DEH, 8 contralateral DEH) participated in this study. Diluted gadodiamide was administered to the bilateral tympanic cavity by injection through the tympanic membrane. At 24 hours post-injection, the ELH was evaluated by MRI. Patient vestibular functions were evaluated by caloric testing and cVEMP. ELH was observed in all patients (19/19: positive rate 100%). The distribution patterns of ELH varied between the cochlear or vestibular region. Vestibular ELH was observed in the affected ear in all ipsilateral DEH patients. In the contralateral DEH patients, however, there were individual differences in the distribution patterns of ELH. Six patients (1 ipsilateral DEH, 5 contralateral DEH) had bilateral ELH. No obvious relationships were observed between ELH and vestibular function. ELH distribution was complicated, particularly in the contralateral DEH cases. It was difficult to identify the existence of ELH by vestibular functional testing alone; therefore, 3T MRI is thought to be useful for identifying the affected ear. A significant number of cases had "bilateral" DEH, particularly among the contralateral DEH cases, indicating that we should pay careful attention to this pathology when treating DEH. PMID- 30517124 TI - Description of an extant salamander from the Gulf Coastal Plain of North America: The Reticulated Siren, Siren reticulata. AB - The salamander family Sirenidae is represented by four extant species that are restricted to North America. Sirens are abundant throughout the southern United States and are among the world's largest amphibians, yet the biology, ecology, and phylogeography of this group is poorly-known. In this study we use morphological and genetic evidence to describe a previously unrecognized species from southern Alabama and the Florida panhandle. We name this species the Reticulated Siren, Siren reticulata. Future studies will enable more precise phylogenetic information about S. reticulata and will almost surely reveal additional undescribed species within the family. PMID- 30517125 TI - Modeling the effects of atmospheric pressure on suicide rates in the USA using geographically weighted regression. AB - Low atmospheric pressure may increase depression and suicide through inducing hypoxia. Previous studies have not evaluated the geographic variation of this relationship across the United States. Analyses were based on three groupings of age-adjusted completed suicide rates (all suicide, firearm-related suicide, non firearm-related suicide) from 2286 counties in the United States. Multiple regression was used to determine the overall relationship between atmospheric pressure and completed suicide rates. Geographically weighted regression (GWR) models were used to obtain local coefficient estimates. A negative correlation between atmospheric pressure and completed suicide rates was observed for all three suicide groupings (p-value <0.0001). Significant, negative GWR coefficient estimates were located in the West and Northeast for the all suicides and firearm related suicides, and in the Midwest for non-firearm-related suicides. PMID- 30517126 TI - The association between workplace violence and physicians' and nurses' job satisfaction in Macau. AB - BACKGROUND: This paper describes the association between workplace violence and job satisfaction among physicians and nurses in Macau. Convenience sampling was sourced from six health centers under the Macau Health Bureau. METHODS: This study uses a cross-sectional self-administrative survey. The study used case studies research instruments for workplace violence in the health sector by country (from the ILO, ICN, WHO, PSI), the Minnesota Satisfaction Questionnaire and Perceived Stress Scale. The data collection period spanned from August to December, 2014. DATA ANALYSIS: Multiple logistic regression examines levels of intrinsic and extrinsic satisfaction in physicians and nurses and significant correlates affecting their job satisfaction. RESULTS: A total of 720 (14.9% physicians) participants were recruited. 57.2% of participants reported physical and psychological workplace violence in the preceding year. The most common forms of workplace violence were verbal abuse (53.4%), physical assault (16.1%), bullying / harassment (14.2%), sexual harassment (4.6%) and racial harassment (2.6%). Nurses were at a significantly higher risk of physical assault and verbal abuse compared to physicians. Patients, patients' relatives, and colleagues were the main perpetrators. Worry about WPV, on-call duty and shift work, experience of bullying and verbal abuse and employment sector emerged as significant correlates affecting the intrinsic and extrinsic job satisfaction of physicians and nurses. Frontline staff, aged 30 and 39, coming from an ethnic minority, and perceived stress were significant correlates affecting nurses' job satisfaction. CONCLUSIONS: WPV remains a significant concern in healthcare settings in Macau. Stakeholders should legally enforce a zero-tolerance policy towards WPV within healthcare workplaces. WPV is detrimental to healthcare professionals' mental wellbeing, risking irreversible physical and psychological harm for its victims. PMID- 30517128 TI - Provider knowledge and performance in medication injection safety in anesthesia: A mixed method prospective crosses sectional study. AB - OBJECTIVES: Injection safety during anesthesia is a challenging health care issue in Iranian hospitals. Anesthesia is one of the most medication-intensive procedures in healthcare and injecting patients are an integral part of that care. The present study aimed to assess the status of medication injection safety practice in a teaching center. DESIGN, SETTING, PARTICIPANTS: A prospective cross sectional study was done in 2014-2015 at a 500-bed secondary level teaching hospital affiliated with Urmia University of Medical Sciences, Iran. The study population included providers of anesthesia in two groups of operating rooms (ORs) with different types of surgeries at the center. Data were collected using valid and reliable observation and a questionnaire instruments in two consecutive phases. Mann-Whitney U, Kruskal-Wallis, and Spearman correlation tests were used for data analyses. RESULTS: A total of 345 injections were observed and recorded during the study period, 53% in group A ORs, and 47% in group B ORs. Eighty-two questionnaires were completed (96.5% response rate) to determine hospital injection practices and personal knowledge of injection safety. Adherence to safety requirements was observed in 58.5% of injections. Fifty five percent of respondents knew that hepatitis B, C, and HIV are blood borne diseases. Observed compliance with injection safety requirements was determined significant by OR groups (P = 0.00). Correlation was significant between observed injection safety practices by age and work experience (P = 0.00). The Kruskal-Wallis test showed a significant difference (P = 0.000) in observed safe injection practices among four job groups but not in reported adherence. Knowledge of respondents was significant by job groups about blood borne diseases and receiving three doses of hepatitis B vaccine. CONCLUSIONS: The study revealed that some of safe injection procedures were well carried out in our ORs, but that others were not. The reported adherence of staff was acceptable but their actual practices were unsafe. It is suggested to implement audits, provide safer supplies, and complete Hepatitis B vaccination of injection providers. PMID- 30517127 TI - Distribution of HCV genotypes in Belgium from 2008 to 2015. AB - BACKGROUND: The knowledge of circulating HCV genotypes and subtypes in a country is crucial to guide antiviral therapy and to understand local epidemiology. Studies investigating circulating HCV genotypes and their trends have been conducted in Belgium. However they are outdated, lack nationwide representativeness or were not conducted in the general population. METHODS: In order to determine the distribution of different circulating HCV genotypes in Belgium, we conducted a multicentre study with all the 19 Belgian laboratories performing reimbursed HCV genotyping assays. Available genotype and subtype data were collected for the period from 2008 till 2015. Furthermore, a limited number of other variables were collected: some demographic characteristics from the patients and the laboratory technique used for the determination of the HCV genotype. RESULTS: For the study period, 11,033 unique records collected by the participating laboratories were used for further investigation. HCV genotype 1 was the most prevalent (53.6%) genotype in Belgium, with G1a and G1b representing 19.7% and 31.6%, respectively. Genotype 3 was the next most prevalent (22.0%). Further, genotype 4, 2, and 5 were responsible for respectively 16.1%, 6.2%, and 1.9% of HCV infections. Genotype 6 and 7 comprise the remaining <1%. Throughout the years, a stable distribution was observed for most genotypes. Only for genotype 5, a decrease as a function of the year of analysis was observed, with respectively 3.6% for 2008, 2.3% for 2009 and 1.6% for the remaining years. The overall M:F ratio was 1.59 and was mainly driven by the high M:F ratio of 3.03 for patients infected with genotype 3. Patients infected with genotype 3 are also younger (mean age 41.7 years) than patients infected with other genotypes (mean age above 50 years for all genotypes). The patients for whom a genotyping assay was performed in 2008 were younger than those from 2015. Geographical distribution demonstrates that an important number of genotyped HCV patients live outside the Belgian metropolitan cities. CONCLUSION: This national monitoring study allowed a clear and objective view of the circulating HCV genotypes in Belgium and will help health authorities in the establishment of cost effectiveness determinations before implementation of new treatment strategies. This baseline characterization of the circulating genotypes is indispensable for a continuous surveillance, especially for the investigation of the possible impact of migration from endemic regions and prior to the increasing use of highly potent direct-acting antiviral (DAA) agents. PMID- 30517129 TI - GradientScanSurv-An exhaustive association test method for gene expression data with censored survival outcome. AB - Accurate assessment of the association between continuous variables such as gene expression and survival is a critical aspect of precision medicine. In this report, we provide a review of some of the available survival analysis and validation tools by referencing published studies that have utilized these tools. We have identified pitfalls associated with the assumptions inherent in those applications that have the potential to impact scientific research through their potential bias. In order to overcome these pitfalls, we have developed a novel method that enables the logrank test method to handle continuous variables that comprehensively evaluates survival association with derived aggregate statistics. This is accomplished by exhaustively considering all the cutpoints across the full expression gradient. Direct side-by-side comparisons, global ROC analysis, and evaluation of the ability to capture relevant biological themes based on current understanding of RAS biology all demonstrated that the new method shows better consistency between multiple datasets of the same disease, better reproducibility and robustness, and better detection power to uncover biological relevance within the selected datasets over the available survival analysis methods on univariate gene expression and penalized linear model-based methods. PMID- 30517130 TI - Investigating clinical handover and healthcare communication for outpatients with chronic disease in India: A mixed-methods study. AB - OBJECTIVES: Research concentrating on continuity of care for chronic, non communicable disease (NCD) patients in resource-constrained settings is currently limited and focusses on inpatients. Outpatient care requires attention as this is where NCD patients often seek treatment and optimal handover of information is essential. We investigated handover, healthcare communication and barriers to continuity of care for chronic NCD outpatients in India. We also explored potential interventions for improving storage and exchange of healthcare information. METHODS: A mixed-methods design was used across five healthcare facilities in Kerala and Himachal Pradesh states. Questionnaires from 513 outpatients with cardiovascular disease, chronic respiratory disease, or diabetes covered the form and comprehensiveness of information exchange between healthcare professionals (HCPs) and between HCPs and patients. Semi-structured interviews with outpatients and HCPs explored handover, healthcare communication and intervention ideas. Barriers to continuity of care were identified through triangulation of all data sources. RESULTS: Almost half (46%) of patients self referred to hospital outpatient clinics (OPCs). Patient-held healthcare information was often poorly recorded on unstructured sheets of paper; 24% of OPC documents contained the following: diagnosis, medication, long-term care and follow-up information. Just 55% of patients recalled receiving verbal follow-up and medication instructions during OPC appointments. Qualitative themes included patient preference for hospital visits, system factors, inconsistent doctor patient communication and attitudes towards medical documents. Barriers were hospital time constraints, inconsistent referral practices and absences of OPC medical record-keeping, structured patient-held medical documents and clinical handover training. Patients and HCPs were in favour of the introduction of patient-held booklets for storing and transporting medical documents. CONCLUSIONS: Deficiencies in communicative practices are compromising the continuity of chronic NCD outpatient care. Targeted systems-based interventions are urgently required to improve information provision and exchange. Our findings indicate that well-designed patient-held booklets are likely to be an acceptable, affordable and effective part of the solution. PMID- 30517131 TI - Recycling 115,369 mobile phones for gorilla conservation over a six-year period (2009-2014) at Zoos Victoria: A case study of 'points of influence' and mobile phone donations. AB - More than seven billion mobile phones are estimated to be in service globally, with more than a billion older phones likely to be retired. A major barrier to a sustainable circular economy for mobile phones is people's hoarding of their retired phones. Old mobile phones may be refurbished for re-use or ultimately dismantled for possible extraction of elements, including 'conflict' metals such as coltan (containing elements tantalum and niobium), mined in eastern Democratic Republic of Congo and threatening wild populations of eastern Grauer's gorillas (Gorilla beringei graueri). Zoos Victoria cares for western gorillas (Gorilla gorilla gorilla) who served as ambassadors for their Grauer's gorilla counterparts in this community-based social marketing initiative. Through tracking of barcodes on satchels of recycled mobile phones, efficiency of ten different points of influence could be calculated for the 'They're Calling on You' mobile phone recycling community campaign at Zoos Victoria in Australia. Over a six-year period (2009-2014), a total of 115,369 mobile phones were donated. The Courier Collect initiative resulted in 50,883 mobile phone donations (44% of total), followed by the Static Display at Melbourne Zoo, resulting in 29,778 mobile phone donations (26% of total). The number of phones collected for Keeper Talks (at Melbourne Zoo and Werribee Open Range Zoo) was 12,684 (11% of total), and in terms of fostering close connections between visitors and the conservation campaign, keeper talks were effective as one phone was donated for every four people attending a keeper talk at Werribee Open Range Zoo and one phone was donated for every 28 people who attended a keeper talk at Melbourne Zoo. We provide suggestions for future campaigns, so that accurate data capture can allow cost-benefit analyses to be conducted. Our results demonstrate that a conservation-based organisation, in partnership with corporate sponsors and community groups can effectively influenced people's mobile phone recycling behavior, paving the way for international collaborations to maximize scale and impact. PMID- 30517132 TI - Semantic algorithms can detect how media language shapes survey responses in organizational behaviour. AB - Research on sensemaking in organisations and on linguistic relativity suggests that speakers of the same language may use this language in different ways to construct social realities at work. We apply a semantic theory of survey response (STSR) to explore such differences in quantitative survey research. Using text analysis algorithms, we have studied how language from three media domains-the business press, PR Newswire and general newspapers-has differential explanatory value for analysing survey responses in leadership research. We projected well known surveys measuring leadership, motivation and outcomes into large text samples from these three media domains significantly different impacts on survey responses. Business press language was best in explaining leadership-related items, PR language best at explaining organizational results and "ordinary" newspaper language seemed to explain the relationship among motivation items. These findings shed light on how different public arenas construct organizational realities in different ways, and how these differences have consequences on methodology in research on leadership. PMID- 30517133 TI - The palatability of sugar-sweetened beverage taxation: A content analysis of newspaper coverage of the UK sugar debate. AB - BACKGROUND: Excess sugar consumption, including sugar-sweetened beverages (SSBs), contributes to a variety of negative health outcomes, particularly for young people. The mass media play a powerful role in influencing public and policy makers' perceptions of public health issues and their solutions. We analysed how sugar and SSB policy debates were presented in UK newspapers at a time of heightened awareness and following the announcement of the UK Government's soft drinks industry levy (SDIL), to inform future public health advocacy. METHODS & FINDINGS: We carried out quantitative content analysis of articles discussing the issues of sugar and SSB consumption published in 11 national newspapers from April 2015 to November 2016. 684 newspaper articles were analysed using a structured coding frame. Coverage peaked in line with evidence publication, campaigner activities and policy events. Articles predominantly supportive of SSB taxation (23.5%) outnumbered those that were predominantly oppositional (14.2%). However, oppositional articles outnumbered supportive ones in the month of the announcement of the SDIL. Sugar and SSB consumption were presented as health risks, particularly affecting young people, with the actions of industry often identified as the cause of the public health problem. Responsibility for addressing sugar overconsumption was primarily assigned to government intervention. CONCLUSION: Our results suggest that the policy landscape favouring fiscal solutions to curb sugar and SSB consumption has benefited from media coverage characterising the issue as an industry-driven problem. Media coverage may drive greater public acceptance of the SDIL and any future taxation of products containing sugar. However, future advocacy efforts should note the surge in opposition coinciding with the announcement of the SDIL, which echoes similar patterns of opposition observed in tobacco control debates. PMID- 30517134 TI - Reproductive site selection in a bromeliad breeding treefrog suggests complex evolutionary trade-offs. AB - Reproductive site selection is a key determinant of fitness in many taxa. However, if the site characteristics that enhance offspring survival are detrimental to the parent's survival or mating success, then complex evolutionary trade-offs occur. In the Brazilian Atlantic Forest, males of the treefrog species Aparasphenodon arapapa use the temporary water bodies in forest-floor bromeliads to court and mate. Males fit tightly into the plant with the head blocking the access and after mating, stay in the bromeliad with the offspring. Since evaporation of the temporary water body inside the bromeliad results in reproductive failure, we expected that males would simply choose the largest bromeliad tanks with the most water. We found that although this was generally true, males seemed to avoid both very large bromeliads and very high water volumes. Field observations suggested a trade-off mechanism for this pattern, whereby very large and water-filled tanks would reduce the male's ability to effectively seal the tank entrance, avoid predation, or call to mating females. Males also avoided bromeliads with leaf litter and preferred slightly inclined plants. Our results indicate that during reproductive site selection, this bromeliad-breeder needs to engage in complex trade-offs between selection pressures, balancing water requirements against the need for defense and potentially, the ability to attract a mate. PMID- 30517135 TI - Bird diversity along elevational gradients in the Dry Tropical Andes of northern Chile: The potential role of Aymara indigenous traditional agriculture. AB - Understanding diversity patterns along environmental gradients lies at the heart of community ecology and conservation. Previous studies have found variation in bird diversity and density along "natural" elevational gradients in the Tropical Andes Hotspot. However, there is still a lack of knowledge about how bird communities respond to traditional land-use patterns, in association with other multiple drivers, along elevations. In the present study, we investigated biotic, abiotic and anthropogenic sources of variation associated with bird species diversity, density and turnover along a 3000-m elevational gradient, in southern limit of the Tropical Andes Hotspot, northern Chile. Over four seasons, we conducted 472 bird point count surveys and established 118 plots distributed across the Desert, Pre-Puna, Puna and High-Andean belts, where biotic, abiotic and anthropogenic factors were measured. We used mixed-effects models to estimate alpha diversity and multinomial Poisson mixture models to estimate species density, accounting for detectability. Species diversity and density increased until 3300 masl and then declined. This type of elevational pattern is characteristic of dry-based mountains, where environmental conditions are suitable at mid-elevations. Habitats shaped by traditional Aymara indigenous agriculture, associated with relatively high vegetation heterogeneity, hosted the highest values of bird diversity and density. Species turnover was structured by habitat type, while elevational ranges of most species were restricted to three relatively discrete assemblages that replaced each other along the gradient. Our study revealed a hump-shaped relationship between elevation and bird diversity and density in the Dry Tropical Andes Biodiversity Hotspot, supporting a diversity pattern characteristic of dry-based mountains of the world. Traditional Aymara agriculture may have constructed ecological niches for biodiversity at mid elevations, enhancing vegetation heterogeneity, thus providing resources for resident and rare species. Increasing loss of traditional land-use may present a threat to the bird community in the Tropical Andes Hotspot. PMID- 30517136 TI - Essentiality of Plasmodium falciparum plasmepsin V. AB - The malaria parasite replicates within erythrocytes. The pathogenesis of clinical malaria is in large part due to the capacity of the parasite to remodel its host cell. To do this, intraerythrocytic stages of Plasmodium falciparum export more than 300 proteins that dramatically alter the morphology of the infected erythrocyte as well as its mechanical and adhesive properties. P. falciparum plasmepsin V (PfPMV) is an aspartic protease that processes proteins for export into the host erythrocyte and is thought to play a key role in parasite virulence and survival. However, although standard techniques for gene disruption as well as conditional protein knockdown have been previously attempted with the pfpmv gene, complete gene removal or knockdown was not achieved so direct genetic proof that PMV is an essential protein has not been established. Here we have used a conditional gene excision approach combining CRISPR-Cas9 gene editing and DiCre mediated recombination to functionally inactivate the pfpmv gene. The resulting mutant parasites displayed a severe growth defect. Detailed phenotypic analysis showed that development of the mutant parasites was arrested early in the ring-to trophozoite transition in the erythrocytic cycle following gene excision. Our findings are the first to elucidate the effects of PMV gene disruption, showing that it is essential for parasite viability in asexual blood stages. The mutant parasites can now be used as a platform to further dissect the Plasmodium protein export pathway. PMID- 30517137 TI - Overexpression of ScMYBAS1 alternative splicing transcripts differentially impacts biomass accumulation and drought tolerance in rice transgenic plants. AB - Drought is the most significant environmental stress for agricultural production worldwide, and tremendous efforts have been made to improve crop yield under the increasing water scarcity. Transcription factors are major players in the regulation of water stress-related genes in plants. Recently, different MYB transcription factors were characterized for their involvement in drought response. A sugarcane R2R3-MYB gene (ScMYBAS1) and its four alternative forms of transcript (ScMYAS1-2, ScMYBAS1-3, ScMYBAS1-4 and ScMYBAS1-5) were identified in this study. The subcellular localization, in Nicotiniana benthamiana, of the TFs fused in frame with GFP revealed that ScMYBAS1-2-GFP and ScMYBAS1-3-GFP were observed in the nucleus. The overexpression of ScMYBAS1-2 and ScMYBAS1-3 spliced transcripts in rice promoted change in plant growth under both well-watered and drought conditions. The ScMYBAS1-2 and ScMYBAS1-3 transgenic lines revealed a higher relative water content (RWC) compared to the wild type before maximum stress under drought conditions. The ScMYBAS1-2 transgenic lines showed a reduction in biomass (total dry weight). Conversely, ScMYBAS1-3 showed an increased biomass (total dry weight) relative to the wild-type. The overexpression of ScMYBAS1-3 in rice transgenic lines showed involvement with drought tolerance and biomass and, for this reason, was considered a good target for plant transformation, particularly for use in developing genotypes with drought tolerance and biomass accumulation. PMID- 30517138 TI - Phylogeny, character evolution and spatiotemporal diversification of the species rich and world-wide distributed tribe Rubieae (Rubiaceae). AB - The Rubiaceae tribe Rubieae has a world-wide distribution with up to 1,000 species. These collectively exhibit an enormous ecological and morphological diversity, making Rubieae an excellent group for macro- and microevolutionary studies. Previous molecular phylogenetic analyses used only a limited sampling within the tribe or missed lineages crucial for understanding character evolution in this group. Here, we analyze sequences from two plastid spacer regions as well as morphological and biogeographic data from an extensive and evenly distributed sampling to establish a sound phylogenetic framework. This framework serves as a basis for our investigation of the evolution of important morphological characters and the biogeographic history of the Rubieae. The tribe includes three major clades, the Kelloggiinae Clade (Kelloggia), the Rubiinae Clade (Didymaea, Rubia) and the most species-rich Galiinae Clade (Asperula, Callipeltis, Crucianella, Cruciata, Galium, Mericarpaea, Phuopsis, Sherardia, Valantia). Within the Galiinae Clade, the largest genera Galium and Asperula are para- and polyphyletic, respectively. Smaller clades, however, usually correspond to currently recognized taxa (small genera or sections within genera), which may be used as starting points for a refined classification in this clade. Life-form (perennial versus annual), flower shape (long versus short corolla tube) and fruit characters (dry versus fleshy, with or without uncinate hairs) are highly homoplasious and have changed multiple times independently. Inference on the evolution of leaf whorls, a characteristic feature of the tribe, is sensitive to model choice. Multi-parted leaf whorls appear to have originated from opposite leaves with two small interpetiolar stipules that are subsequently enlarged and increased in number. Early diversification of Rubieae probably started during the Miocene in western Eurasia. Disjunctions between the Old and the New World possibly are due to connections via a North Atlantic land bridge. Diversification of the Galiineae Clade started later in the Miocene, probably in the Mediterranean, from where lineages reached, often multiple times, Africa, eastern Asia and further on the Americas and Australia. PMID- 30517139 TI - Characterization of biodegradation in a 17th century easel painting and potential for a biological approach. AB - It is important to characterize the microorganisms involved in biodeterioration processes to understand their effects on cultural assets and to define an efficient strategy for protecting artworks, monuments, and buildings from microbiological recolonization. In this study, we analyzed the microbial communities dwelling on the verso (front) and recto (back) sides of a 17th century easel painting attributed to Carlo Bononi, an Italian artist of the first Baroque period. Cultivable bacteria and fungi colonizing the painting were isolated and identified in order to characterize the microbial community possibly involved in deteriorating the pictorial layer of the painting. The isolated bacterial strains belonged to the Staphylococcus and Bacillus genera. Furthermore, culture-dependent techniques and SEM/EDS analyses revealed the presence of filamentous fungi of the genera Aspergillus, Penicillium, Cladosporium, and Alternaria. The chemical compositions of pigments were consistent with typical 17th century paintings, and some of the identified pigments, namely red lac and red and yellow earths, could be exploited as nutrient sources by painting-associated microorganisms. The study also evaluated, in vitro, the potential decontaminating activity of a biocompound, containing spores of Bacillus subtilis, Bacillus pumilus, and Bacillus megaterium. The results indicated the ability of this biocompound to counteract the growth of contaminating microorganisms that are potentially dangerous to the painting, suggesting the potential use of these microorganisms to prevent biodeterioration of artworks. PMID- 30517140 TI - Traces of history conserved over 600 years in the geographic distribution of genetic variants of an RNA virus: Bovine viral diarrhea virus in Switzerland. AB - The first records of smallpox and rabies date back thousands of years and foot and-mouth disease in cattle was described in the 16th century. These diseases stood out by their distinct signs, dramatic way of transmission from rabid dogs to humans, and sudden appearance in cattle herds. By contrast, infectious diseases that show variable signs and affect few individuals were identified only much later. Bovine viral diarrhea (BVD), endemic in cattle worldwide, was first described in 1946, together with the eponymous RNA virus as its cause. There is general agreement that BVD was not newly emerging at that time, but its history remains unknown. A search for associations between the nucleotide sequences of over 7,000 BVD viral strains obtained during a national campaign to eradicate BVD and features common to the hosts of these strains enabled us to trace back in time the presence of BVD in the Swiss cattle population. We found that animals of the two major traditional cattle breeds, Fleckvieh and Swiss Brown, were infected with strains of only four different subgenotypes of BVDV-1. The history of these cattle breeds and the events that determined the current distribution of the two populations are well documented. Specifically, Fleckvieh originates from the Bernese and Swiss Brown from the central Alps. The spread to their current geographic distribution was determined by historic events during a major expansion of the Swiss Confederation during the 15th and 16th centuries. The association of the two cattle populations with different BVD viral subgenotypes may have been preserved by a lack of cattle imports, trade barriers within the country, and unique virus-host interactions. The congruent traces of history in the distribution of the two cattle breeds and distinct viral subgenotypes suggests that BVD may have been endemic in Switzerland for at least 600 years. PMID- 30517141 TI - Risk factors for acute unplanned tracheostomy during panendoscopy in HNSCC patients. AB - BACKGROUND: Despite of careful pre-operative risk evaluation some patients require an acute unplanned tracheostomy during panendoscopy. METHODS: Risk factors of patients requiring an unplanned tracheostomy during panendoscopy (n = 32) were compared to a control group with panendoscopy without tracheostomy (n = 180). RESULTS: 2131 panendoscopies for Head and Neck squamous cell carcinoma were performed at our Department between 2000 and 2014. Unplanned tracheostomies were necessary in 1.6% of all panendoscopies. Patients with laryngeal cancer (p = 0.001) or abnormal activated partial thromboplastin time (aPTT) (p = 0.03) had a statistically significant higher risk of unplanned tracheostomy. Regression analysis showed that patients with advanced laryngeal cancer had an almost 6 times higher risk for tracheostomy than patients with early stage oropharyngeal cancer. CONCLUSIONS: We identified abnormal aPTT and laryngeal carcinoma as significant predictors for unplanned tracheostomy during panendoscopy. The results of our study could improve preoperative risk evaluation in HNSCC patients. PMID- 30517142 TI - Components of the antepartum, intrapartum, and postpartum exposome impact on distinct short-term adverse neonatal outcomes of premature infants: A prospective cohort study. AB - We aimed to test the hypothesis that determinants of the perinatal clinical exposome related to the underlying etiology of premature birth (PTB) impact differently on select neonatal outcomes. We conducted a prospective longitudinal study of 377 singleton preterm neonates [gestational age (GA) at birth: 23-34 weeks] separated into three distinct contemporaneous newborn cohorts: i) spontaneous PTB in the setting of intra-amniotic infection/inflammation (yes-IAI, n = 116); ii) spontaneous PTB in the absence of IAI (no-IAI, n = 130), and iii) iatrogenic PTB for preeclampsia (iPTB-PE, n = 131). Newborns (n = 372) were followed until death or discharge. Amniotic fluid defensins 1&2 and calgranulins A&C were used as biomarkers of IAI. An algorithm considering cord blood interleukin-6 (IL-6) and haptoglobin (Hp switch-on) was used to assess fetal exposure to IAI. Intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), early-onset neonatal (EONS) and late-onset (LOS) sepsis, death. Independent risk factors for adverse outcomes were: i) IVH (n = 53): histologic chorioamnionitis, GA, fetal growth restriction, male sex, Hp switch-on; ii) PVL (n = 11): cord blood IL-6; iii) NEC (n = 25), GA; iv) BPD (n = 53): ventilator support, need for surfactant, GA; v) ROP (n = 79): ventilator support, Hp switch-on, GA; vi) fetal and neonatal death (n = 31): GA, amniotic fluid IL-6; vii) suspect EONS (n = 92): GA, Hp switch-on; viii) LOS (n = 81): GA. Our findings are applicable to pregnancies delivered between 23 and 34 weeks' gestation in the setting of IAI and PE, and suggest that GA and inflammatory intrauterine environment play key roles in occurrence of IVH, PVL, ROP, death, EONS and LOS. Postnatal determinants seem to play major role in NEC and BPD. PMID- 30517143 TI - Genotyping-by-sequencing identifies date palm clone preference in agronomics of the State of Qatar. AB - Understanding the genetic diversity in a crop population is key to its targeted breeding for desired traits, such as higher yields, better fruit quality and resistance to disease and changing climates. Date fruits represent a major crop in the Middle East and are key to achieving future food independence in arid countries like Qatar. We previously determined the genome of the date palm Phoenix dactylifera and showed that date palm trees world-wide divide into two distinct subpopulations of Eastern and Western origins. Here we applied a resource of SNPs from 179 commercially available date fruits to assess the genetic diversity of date palm trees grown in the State of Qatar. We found that palm trees in Qatar are mainly of Eastern origin, and that their genetic diversity doesn't associate with regions of the State. Together with targeted genetic assays, our resource can be used in the future for date palm cultivar identification, to aid selecting suitable cultivars for targeted breeding, to improve a country's date palm genetic diversity, and to certify the origin of date fruits and trees. PMID- 30517144 TI - Estimation of paddy rice leaf area index using machine learning methods based on hyperspectral data from multi-year experiments. AB - The performance of three machine learning methods (support vector regression, random forests and artificial neural network) for estimating the LAI of paddy rice was evaluated in this study. Traditional univariate regression models involving narrowband NDVI with optimized band combinations as well as linear multivariate calibration partial least squares regression models were also evaluated for comparison. A four year field-collected dataset was used to test the robustness of LAI estimation models against temporal variation. The partial least squares regression and three machine learning methods were built on the raw hyperspectral reflectance and the first derivative separately. Two different rules were used to determine the models' key parameters. The results showed that the combination of the red edge and NIR bands (766 nm and 830 nm) as well as the combination of SWIR bands (1114 nm and 1190 nm) were optimal for producing the narrowband NDVI. The models built on the first derivative spectra yielded more accurate results than the corresponding models built on the raw spectra. Properly selected model parameters resulted in comparable accuracy and robustness with the empirical optimal parameter and significantly reduced the model complexity. The machine learning methods were more accurate and robust than the VI methods and partial least squares regression. When validating the calibrated models against the standalone validation dataset, the VI method yielded a validation RMSE value of 1.17 for NDVI(766,830) and 1.01 for NDVI(1114,1190), while the best models for the partial least squares, support vector machine and artificial neural network methods yielded validation RMSE values of 0.84, 0.82, 0.67 and 0.84, respectively. The RF models built on the first derivative spectra with mtry = 10 showed the highest potential for estimating the LAI of paddy rice. PMID- 30517145 TI - CBF-dependent and CBF-independent regulatory pathways contribute to the differences in freezing tolerance and cold-regulated gene expression of two Arabidopsis ecotypes locally adapted to sites in Sweden and Italy. AB - Arabidopsis thaliana (Arabidopsis) increases in freezing tolerance in response to low nonfreezing temperatures, a phenomenon known as cold acclimation. The CBF regulatory pathway, which contributes to cold acclimation, includes three genes CBF1, CBF2 and CBF3-encoding closely-related transcription factors that regulate the expression of more than 100 genes-the CBF regulon-that impart freezing tolerance. Here we compare the CBF pathways of two Arabidopsis ecotypes collected from sites in Sweden (SW) and Italy (IT). Previous studies showed that the SW ecotype was more freezing tolerant than the IT ecotype and that the IT ecotype had a nonfunctional CBF2 gene. Here we present results establishing that the difference in CBF2 alleles contributes to the difference in freezing tolerance between the two ecotypes. However, other differences in the CBF pathway as well as CBF-independent pathways contribute the large majority of the difference in freezing tolerance between the two ecotypes. The results also provided evidence that most cold-induced CBF regulon genes in both the SW and IT ecotypes are coregulated by CBF-independent pathways. Additional analysis comparing our results with those published by others examining the Col-0 accession resulted in the identification of 44 CBF regulon genes that were conserved among the three accessions suggesting that they likely have important functions in life at low temperature. The comparison further supported the conclusion that the CBF pathway can account for a large portion of the increase in freezing tolerance that occurs with cold acclimation in a given accession, but that CBF-independent pathways can also make a major contribution. PMID- 30517146 TI - New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy. AB - Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15-25% of cases). In this report all known NM related genes were screened by Next Generation Sequencing in five Spanish patients in order to genetically confirm the clinical and histological diagnosis of NM. Four mutations in NEB (c.17779_17780delTA, c.11086A>C, c.21076C>T and c.2310+5G>A) and one mutation in ACTA1 (c.871A>T) were found in four patients. Three of the four mutations in NEB were novel. A cDNA sequencing assay of the novel variants c.17779_17780delTA, c.11086A>C and c.2310+5G>A revealed that the intronic variant c.2310+5G>A affected the splicing process. Mutations reported here could help clinicians and geneticists in NM diagnosis. PMID- 30517147 TI - Infected cyst in patients with autosomal dominant polycystic kidney disease: Analysis of computed tomographic and ultrasonographic imaging features. AB - PURPOSE: To investigate the imaging features of cyst infection in autosomal dominant polycystic kidney disease (ADPKD) patients using computed tomography (CT) and ultrasonography (US). MATERIALS & METHODS: The institutional review board approved this retrospective study. Fifty-one episodes with proven cyst infection in forty-three ADPKD patients were included. Two experienced abdominal radiologists reviewed CT and US images and evaluated the following imaging features in consensus: cyst size, location, cyst shape, intracystic attenuation, intracystic echogenicity, intracystic heterogeneity, wall thickness, the presence of fluid-fluid level, septation, intracystic gas, pericystic fat infiltration, and pericystic hyperemia. Intracystic attenuation was measured for all infected cysts and two presumed normal cysts and compared using the Wilcoxon rank-sum test. RESULTS: On CT scans, the median size of infected cysts was 5.5 cm (range: 2.3-18.8 cm) and 46 of 51 (90.2%) infected cysts were located in the subcapsular region. Most (48 of 51, 94.1%) infected cysts showed lobulated, focal bulging or irregular shape. Discernible wall thickening (84.1%) was the most frequently found imaging feature of infected cysts followed by relatively higher intracystic attenuation compared to normal cysts (79.1%) and pericystic fat infiltration (52.9%). Fluid/fluid level was found in 3 of 51 (5.9%) infected cysts and intracystic gas was found in 3 of 51 (5.9%) infected cysts, respectively. For hepatic cysts, 11 of 14 (78.6%) infected cysts showed pericystic hyperemia. Intracystic attenuation was significantly higher in infected cysts (median; 19.0 HU) than in presumed normal cysts (median; 8.5 HU) (P<0.001), and exceeded 25 HU in 18 (35.3%) of 51 infected cysts. Among the 41 infected cysts for which US images were available, 35 (85.1%) showed heterogeneous echogenicity. CONCLUSION: Minute imaging features such as minimal wall thickening or relatively high attenuation compared to normal cysts would be helpful to detect infected cysts in ADPKD patients. PMID- 30517148 TI - Predictive factors of Clostridioides difficile infection in hospitalized patients with new diarrhea: A retrospective cohort study. AB - INTRODUCTION AND OBJECTIVE: Diagnostic testing for Clostridioides difficile infection (CDI) by nucleic acid amplification test (NAAT) cannot distinguish between colonization and infection. A positive NAAT may therefore represent a false positive for infection, since diarrhea due to various aetiologies may occur in hospitalized patients. Our objective was to help answer the question: "does this medical inpatient with diarrhea have CDI?" DESIGN: We conducted a retrospective cohort study (n = 248) on the Clinical Teaching Units of the Royal Victoria Hospital (Montreal, Canada). Patients were included if they had a NAAT between January 2014 and September 2015 and their admission diagnosis was not CDI. CDI cases and non-CDI cases were compared, and independent predictors of CDI were determined by logistic regression. RESULTS: Several factors were independently associated with CDI, including: hemodialysis (OR: 13.5, 95% CI: 2.85-63.8), atrial fibrillation (OR: 3.70, 95% CI: 1.52-9.01), whether the patient received empiric treatment (OR: 3.01, 95% CI: 1.04-8.68), systemic antibiotic therapy prior to testing (OR: 4.23, 95% CI: 1.71-10.5), previous positive NAAT (OR: 3.70, 95% CI: 1.41-9.72), and a leukocyte count of 11x109/L or higher (OR: 3.43, 95% CI: 1.42-8.26). The area under the curve was 0.80. CONCLUSION: For patients presenting with hospital-onset diarrhea, various parameters can help differentiate between CDI and other causes. A clinical prediction calculator derived from our cohort (http://individual.utoronto.ca/leet/cdiff.html) might assist clinicians in estimating the risk of CDI for inpatients; those with low pre-test probability may not require immediate testing, treatment, nor prolonged isolation. PMID- 30517149 TI - Altering alpha-frequency brain oscillations with rapid analog feedback-driven neurostimulation. AB - Oscillations of the brain's local field potential (LFP) may coordinate neural ensembles and brain networks. It has been difficult to causally test this model or to translate its implications into treatments, because there are few reliable ways to alter LFP oscillations. We developed a closed-loop analog circuit to enhance brain oscillations by feeding them back into cortex through phase-locked transcranial electrical stimulation. We tested the system in a rhesus macaque with chronically implanted electrode arrays, targeting 8-15 Hz (alpha) oscillations. Ten seconds of stimulation increased alpha oscillatory power for up to 1 second after stimulation offset. In contrast, open-loop stimulation decreased alpha power. There was no effect in the neighboring 15-30 Hz (beta) LFP rhythm or on a neighboring array that did not participate in closed-loop feedback. Analog closed-loop neurostimulation might thus be a useful strategy for altering brain oscillations, both for basic research and the treatment of neuro psychiatric disease. PMID- 30517151 TI - The conservation landscape of the human ribosomal RNA gene repeats. AB - Ribosomal RNA gene repeats (rDNA) encode ribosomal RNA, a major component of ribosomes. Ribosome biogenesis is central to cellular metabolic regulation, and several diseases are associated with rDNA dysfunction, notably cancer, However, its highly repetitive nature has severely limited characterization of the elements responsible for rDNA function. Here we make use of phylogenetic footprinting to provide a comprehensive list of novel, potentially functional elements in the human rDNA. Complete rDNA sequences for six non-human primate species were constructed using de novo whole genome assemblies. These new sequences were used to determine the conservation profile of the human rDNA, revealing 49 conserved regions in the rDNA intergenic spacer (IGS). To provide insights into the potential roles of these conserved regions, the conservation profile was integrated with functional genomics datasets. We find two major zones that contain conserved elements characterised by enrichment of transcription associated chromatin factors, and transcription. Conservation of some IGS transcripts in the apes underpins the potential functional significance of these transcripts and the elements controlling their expression. Our results characterize the conservation landscape of the human IGS and suggest that noncoding transcription and chromatin elements are conserved and important features of this unique genomic region. PMID- 30517150 TI - Hypervirulent group A Streptococcus emergence in an acaspular background is associated with marked remodeling of the bacterial cell surface. AB - Inactivating mutations in the control of virulence two-component regulatory system (covRS) often account for the hypervirulent phenotype in severe, invasive group A streptococcal (GAS) infections. As CovR represses production of the anti phagocytic hyaluronic acid capsule, high level capsule production is generally considered critical to the hypervirulent phenotype induced by CovRS inactivation. There have recently been large outbreaks of GAS strains lacking capsule, but there are currently no data on the virulence of covRS-mutated, acapsular strains in vivo. We investigated the impact of CovRS inactivation in acapsular serotype M4 strains using a wild-type (M4-SC-1) and a naturally-occurring CovS-inactivated strain (M4-LC-1) that contains an 11bp covS insertion. M4-LC-1 was significantly more virulent in a mouse bacteremia model but caused smaller lesions in a subcutaneous mouse model. Over 10% of the genome showed significantly different transcript levels in M4-LC-1 vs. M4-SC-1 strain. Notably, the Mga regulon and multiple cell surface protein-encoding genes were strongly upregulated-a finding not observed for CovS-inactivated, encapsulated M1 or M3 GAS strains. Consistent with the transcriptomic data, transmission electron microscopy revealed markedly altered cell surface morphology of M4-LC-1 compared to M4-SC-1. Insertional inactivation of covS in M4-SC-1 recapitulated the transcriptome and cell surface morphology. Analysis of the cell surface following CovS-inactivation revealed that the upregulated proteins were part of the Mga regulon. Inactivation of mga in M4-LC-1 reduced transcript levels of multiple cell surface proteins and reversed the cell surface alterations consistent with the effect of CovS inactivation on cell surface composition being mediated by Mga. CovRS inactivating mutations were detected in 20% of current invasive serotype M4 strains in the United States. Thus, we discovered that hypervirulent M4 GAS strains with covRS mutations can arise in an acapsular background and that such hypervirulence is associated with profound alteration of the cell surface. PMID- 30517152 TI - Analysis of the transcriptome data in Litopenaeus vannamei reveals the immune basis and predicts the hub regulation-genes in response to high-pH stress. AB - Soil salinization erodes the farmlands and poses a serious threat to human life, reuse of the saline-alkali lands as cultivated resources becomes increasingly prominent. Pacific white shrimp (Litopenaeus vannamei) is an important farmed aquatic species for the development and utilization of the saline-alkali areas. However, little is known about the adaptation mechanism of this species in terms of high-pH stress. In the present study, a transcriptome analysis on the gill tissues of L. vannamei in response to high-pH stress (pH 9.3 +/- 0.1) was conducted. After analyzing, the cyclic nucleotide gated channel-Ca2+ (CNGC-Ca2+) and patched 1 (Ptc1) were detected as the majority annotated components in the cAMP signaling pathway (KO04024), indicating that the CNGC-Ca2+ and Ptc1 might be the candidate components for transducing and maintaining the high-pH stress signals, respectively. The immunoglobulin superfamily (IgSF), heat shock protein (HSP), glutathione s-transferase (GST), prophenoloxidase/phenoloxidase (proPO/PO), superoxide dismutase (SOD), anti-lipopolysaccharide factor (ALF) and lipoprotein were discovered as the major transcribed immune factors in response to high-pH stress. To further detect hub regulation-genes, protein-protein interaction (PPI) networks were constructed; the genes/proteins "Polymerase (RNA) II (DNA directed) polypeptide A" (POLR2A), "Histone acetyltransferase p300" (EP300) and "Heat shock 70kDa protein 8" (HSPA8) were suggested as the top three hub regulation-genes in response to acute high-pH stress; the genes/proteins "Heat shock 70kDa protein 4" (HSPA4), "FBJ murine osteosarcoma viral oncogene homolog" (FOS) and "Nucleoporin 54kDa" (NUP54) were proposed as the top three hub regulation-genes involved in adapting endurance high-pH stress; the protein interactions of "EP300-HSPA8" and "HSPA4-NUP54" were detected as the most important biological interactions in response to the high-pH stress; and the HSP70 family genes might play essential roles in the adaptation of the high-pH stress environment in L. vannamei. These findings provide the first insight into the molecular and immune basis of L. vannamei in terms of high-pH environments, and the construction of a PPI network might improve our understanding in revealing the hub regulation-genes in response to abiotic stress in shrimp species and might be beneficial for further studies. PMID- 30517153 TI - Illegal logging as a disincentive to the establishment of a sustainable forest sector in the Amazon. AB - Brazil recently began granting timber concessions in public forests to promote sustainable forest use. The effectiveness of this strategy hinges on the design and implementation of the concessions themselves as well as their competitive position within the logging sector as a whole. There is, however, a lack of information on the competitive interaction between legal and illegal logging and its effects on concessions profits. We address this knowledge gap by using a spatially explicit simulation model of the Amazon timber industry to examine the potential impact of illegal logging on timber concessions allocation and profits in a 30-year harvest cycle. In a scenario in which illegal logging takes place outside concessions, including private and public "undesignated" lands, concession harvested area would decrease by 59% due to competition with illegal logging. Moreover, 29 out of 39 National Forests (~74%) would experience a decrease in harvested area. This "leakage" effect could reduce concession net rents by up to USD 1.3 Billion after 30 years. Federal and State "undesignated" lands, if not adequately protected, could have 40% of their total volume illegally harvested in 30 years. Our results reinforce the need to invest in tackling illegal logging, if the government wants the forest concessions program to be successful. PMID- 30517154 TI - Artificial tactile and proprioceptive feedback improves performance and confidence on object identification tasks. AB - Somatosensory feedback of the hand is essential for object identification. Without somatosensory feedback, individuals cannot reliably determine the size or compliance of an object. Electrical nerve stimulation can restore localized tactile and proprioceptive feedback with intensity discrimination capability similar to natural sensation. We hypothesized that adding artificial somatosensation improves object recognition accuracy when using a prosthesis. To test this hypothesis, we provided different forms of sensory feedback-tactile, proprioceptive, or both-to two subjects with upper limb loss. The subjects were asked to identify the size or mechanical compliance of different foam blocks placed in the prosthetic hand while visually and audibly blinded. During trials, we did not inform the subjects of their performance, but did ask them about their confidence in correctly identifying objects. Finally, we recorded applied pressures during object interaction. Subjects were free to use any strategy they chose to examine the objects. Object identification was most accurate with both tactile and proprioceptive feedback. The relative importance of each type of feedback, however, depended on object characteristics and task. Sensory feedback increased subject confidence and was directly correlated with accuracy. Subjects applied less pressure to the objects when they had tactile pressure feedback. Artificial somatosensory feedback improves object recognition and the relative importance of tactile versus proprioceptive feedback depends on the test set. We believe this test battery provides an effective means to assess the impact of sensory restoration and the relative contribution of different forms of feedback (tactile vs. kinesthetic) within the neurorehabilitation field. PMID- 30517155 TI - High genetic diversity and distinct ancient lineage of Asiatic black bears revealed by non-invasive surveys in the Annapurna Conservation Area, Nepal. AB - Asiatic black bears (Ursus thibetanus) have a widespread distribution in mountain landscapes, and are considered vulnerable globally, but are low-priority species for conservation in Nepal. Habitat fragmentation, illegal hunting, and human-bear conflict are the major threats to Asiatic black bears across their global range. Having an adequate level of genetic variation in a population helps with adapting to rapidly changing environments, and thus is important for the long-term health of bear populations. Accordingly, we conducted non-invasive surveys of bear populations in the Annapurna Conservation Area (ACA) to elucidate genetic diversity, genetic structure, and the phylogenetic relationship of Asiatic black bears from this region of Nepal to other subspecies. To assess levels of genetic diversity and population genetic structure, we genotyped eight microsatellite loci using 147 samples, identifying 60 individuals in an area of approximately 525 km2. We found that the Asiatic black bear population in the ACA has maintained high levels of genetic diversity (HE = 0.76) as compared to other bear populations from range countries. We did not detect a signature of population substructure among sampling localities and this suggests that animals are moving freely across the landscape within the ACA. We also detected a moderate population size that may increase with the availability of suitable habitat in the ACA, so bear-related conflict should be addressed to ensure the long-term viability of this expanding bear populations. Primers specific to bears were designed to amplify a 675 bp fragment of the mitochondrial control region from the collected samples. Three haplotypes were observed from the entire conservation area. The complete mitochondrial genome (16,771 bp), the first obtained from wild populations of the Himalayan black bear (U. t. laniger), was also sequenced to resolve the phylogenetic relationships of closely related subspecies of Asiatic black bears. The resulting phylogeny indicated that Himalayan black bear populations in Nepal are evolutionary distinct from other known subspecies of Asiatic black bears. PMID- 30517156 TI - Improving the calling of non-invasive prenatal testing on 13-/18-/21-trisomy by support vector machine discrimination. AB - With the advance of next-generation sequencing (NGS) technologies, non-invasive prenatal testing (NIPT) has been developed and employed in fetal aneuploidy screening on 13-/18-/21-trisomies through detecting cell-free fetal DNA (cffDNA) in maternal blood. Although Z-test is widely used in NIPT NGS data analysis, there is still necessity to improve its accuracy for reducing a) false negatives and false positives, and b) the ratio of unclassified data, so as to lower the potential harm to patients as well as the induced cost of retests. Combining the multiple Z-tests with indexes of clinical signs and quality control, features were collected from the known samples and scaled for model training using support vector machine (SVM). We trained SVM models from the qualified NIPT NGS data that Z-test can discriminate and tested the performance on the data that Z-test cannot discriminate. On screenings of 13-/18-/21-trisomies, the trained SVM models achieved 100% accuracies in both internal validations and unknown sample predictions. It is shown that other machine learning (ML) models can also achieve similar high accuracy, and SVM model is most robust in this study. Moreover, four false positives and four false negatives caused by Z-test were corrected by using the SVM models. To our knowledge, this is one of the earliest studies to employ SVM in NIPT NGS data analysis. It is expected to replace Z-test in clinical practice. PMID- 30517157 TI - Automated algorithms combining structure and function outperform general ophthalmologists in diagnosing glaucoma. AB - PURPOSE: To test the ability of machine learning classifiers (MLCs) using optical coherence tomography (OCT) and standard automated perimetry (SAP) parameters to discriminate between healthy and glaucomatous individuals, and to compare it to the diagnostic ability of the combined structure-function index (CSFI), general ophthalmologists and glaucoma specialists. DESIGN: Cross-sectional prospective study. METHODS: Fifty eight eyes of 58 patients with early to moderate glaucoma (median value of the mean deviation = -3.44 dB; interquartile range, -6.0 to -2.4 dB) and 66 eyes of 66 healthy individuals underwent OCT and SAP tests. The diagnostic accuracy (area under the ROC curve-AUC) of 10 MLCs was compared to those obtained with the CSFI, 3 general ophthalmologists and 3 glaucoma specialists exposed to the same OCT and SAP data. RESULTS: The AUCs obtained with MLCs ranged from 0.805 (Classification Tree) to 0.931 (Radial Basis Function Network, RBF). The sensitivity at 90% specificity ranged from 51.6% (Classification Tree) to 82.8% (Bagging, Multilayer Perceptron and Support Vector Machine Gaussian). The CSFI had a sensitivity of 79.3% at 90% specificity, and the highest AUC (0.948). General ophthalmologists and glaucoma specialists' grading had sensitivities of 66.2% and 83.8% at 90% specificity, and AUCs of 0.879 and 0.921, respectively. RBF (the best MLC), the CSFI, and glaucoma specialists showed significantly higher AUCs than that obtained by general ophthalmologists (P<0.05). However, there were no significant differences between the AUCs obtained by RBF, the CSFI, and glaucoma specialists (P>0.25). CONCLUSION: Our findings suggest that both MLCs and the CSFI can be helpful in clinical practice and effectively improve glaucoma diagnosis in the primary eye care setting, when there is no glaucoma specialist available. PMID- 30517158 TI - Cranio-caudal and medio-lateral navicular translation are representative surrogate measures of foot function in asymptomatic adults during walking. AB - INTRODUCTION: The translation of the navicular bone is thought to be a representative surrogate measure to assess foot pronation and hence foot function; however, it is not known how it is related to multi-segment foot kinematics. METHODS: Cranio-caudal (NCC) and medio-lateral (NML) navicular translation and multi-segment foot kinematics from the Oxford Foot Model (OFM) were simultaneously assessed during the stance phase of walking in 20 healthy adults. Relationships to forefoot to hindfoot (FFtoHF), hindfoot to tibia (HFtoTBA) and global hindfoot (HFL) motion were explored by cross-correlations at zero phase shift. RESULTS: FFtoHF sagittal, transversal and frontal plane angles showed median cross correlations of -0.95, 0.82 and 0.53 with NCC and of 0.78, 0.81 and -0.90 with NML. HFtoTBA transversal and frontal plane angles had correlations of 0.15 and 0.74 with NCC and of -0.38 and -0.83 with NML. The HFL frontal plane angle showed correlations of 0.41 and -0.44 with NCC and NML, respectively. DISCUSSION: The strongest relationships were found between FFtoHF sagittal plane angles and NCC and between FFtoHF frontal plane angles and NML. However, cranio-caudal and medio-lateral navicular translation seem to be reasonable surrogates for the triplanar motion between the fore- and hindfoot. The medial longitudinal arch dropped and bulged medially, while the forefoot dorsiflexed, abducted and everted with respect to the hindfoot and vice-versa. The lower cross-correlation coefficients between the rear foot parameters and NCC/NML indicated no distinct relationships between rearfoot frontal plane and midfoot kinematics. The validity of rearfoot parameters, like Achilles tendon or Calcaneal angle, to assess midfoot function must be therefore questioned. The study could also not confirm a systematic relationship between midfoot kinematics and the internal/external rotation between the hindfoot and the tibia. The measurement of navicular translation is suggested as an alternative to more complex multi-segment foot models to assess foot function. PMID- 30517159 TI - Health problems during childhood and school achievement: Exploring associations between hospitalization exposures, gender, timing, and compulsory school grades. AB - AIMS: To investigate while accounting for health at birth 1) associations between health problems during childhood, measured as hospitalizations, and school achievement in the final year of compulsory school, measured as overall grade points and eligibility for upper secondary education, 2) if and how gender moderates the association between health problems and school achievement, 3) if and how the timing of a health problem during childhood is associated with later school achievement. METHODS: Analyzes were performed on a population-based cohort (n = 115 196) born in 1990 in Sweden (51.3% boys, 48.7% girls) using data from several national registries. Multiple linear regression and logistic regression were used to analyze associations between study variables. RESULTS: Overall grade points and eligibility for continuation to upper secondary school were lower for individuals exposed to hospitalizations. Only the association between hospitalizations and overall grade points was moderated by gender and only for ages 13-16 years. Exposure close to actual grading had worst outcomes. CONCLUSIONS: Health problems, measured through hospitalizations, was significantly associated with lower school achievements among Swedish children. Girls exposed to health problems requiring hospitalizations had relatively poorer school achievements as compared to boys. Health problems requiring hospitalization during junior high school had the greatest negative association with final achievement at compulsory school. PMID- 30517160 TI - Quantitative study of the somatosensory sensitization underlying cross-modal plasticity. AB - Loss of one sensory modality can cause other types to become more perceptive (cross-modal plasticity). To test the hypothesis that the loss of vision changes the perceptual threshold in the somatosensory system, we applied optogenetics to directly manipulate the afferent inputs involved in the whisker-barrel system using a transgenic rat (W-TChR2V4) that expresses channelrhodopsin-2 (ChR2) selectively in the large mechanoreceptive neurons in the trigeminal ganglion (TG) and their peripheral nerve terminals. The licking behavior of W-TChR2V4 rat was conditioned to a blue LED light cue on the whisker area while the magnitude and duration of light pulses were varied. The perceptual threshold was thus quantitatively determined for each rat according to the relationship between the magnitude/duration of light and the reaction time between the LED light cue and the first licking event after it. We found that the perceptual threshold was more significantly reduced than the control non-deprived rats when the rats were visually deprived at postnatal 26-30 days (P26-30, early VD group), but not at P58-66 (late VD group). However, the sensory threshold of a late VD animal was similar to that of a control. Our results suggest the presence of cross-modal plasticity by which the loss of vision at the juvenile period increased the sensitivity of the somatosensory system involved in the touch of whiskers. PMID- 30517161 TI - High plasma resistin associates with severe acute kidney injury in Puumala hantavirus infection. AB - BACKGROUND: Puumala hantavirus (PUUV) infected patients typically suffer from acute kidney injury (AKI). Adipokines have inflammation modulating functions in acute diseases including AKI. We examined plasma levels of three adipokines (resistin, leptin, and adiponectin) in acute PUUV infection and their associations with disease severity. METHODS: This study included 79 patients hospitalized due to acute PUUV infection. Plasma resistin, leptin, adiponectin, as well as IL-6 and CRP, were measured at the acute phase, recovery phase and one year after hospitalization. RESULTS: Plasma resistin levels were significantly higher in the acute phase compared to the recovery phase and one year after (median resistin 28 pg/mL (11-107) vs. 17 pg/mL (7-36) vs. 14 pg/mL (7-31), p<0.001). Maximum resistin concentration correlated with maximum plasma creatinine levels (r = 0.63; p<0.001). The higher the amount of albuminuria in the urine dipstick test (0-1+, 2+ or 3+) at admission, the higher the median of maximum resistin (24.7 pg/mL, 25.4 pg/mL and 39.6 pg/mL, respectively, p = 0.002). High resistin was also an independent risk factor for severe AKI (creatinine >=353.6MUmol/L) (OR 1.08, 95% CI 1.02-1.14). Neither plasma leptin nor adiponectin level had any correlation with creatinine concentration or the amount of albuminuria. CONCLUSIONS: Plasma resistin independently associates with the severity of AKI in acute PUUV infection. The association of resistin with the amount of albuminuria suggests that the level of plasma resistin is not only influenced by renal clearance but could have some role in the pathogenesis of AKI during PUUV infection. PMID- 30517162 TI - The Radiation-Transmission-Reception (RTR) model of propagation: Implications for the effectiveness of network interventions. AB - Propagating phenomena in networks have received significant amount of attention within various domains, ranging from contagion in epidemiology, to diffusion of innovations and social influence on behavior and communication. Often these studies attempt to model propagation processes in networks to create interventions that steer propagation dynamics towards desired or away from undesired outcomes. Traditionally, studies have used relatively simple models of the propagation mechanism. In most propagation models this mechanism is described as a monolithic process and a single parameter for the infection rate. Such a description of the propagation mechanism is a severe simplification of mechanisms described in various theoretical exchange theories and phenomena found in real world settings, and largely fails to capture the nuances present in such descriptions. Recent work has suggested that such a simplification may not be sufficient to explain observed propagation dynamics, as nuances of the mechanism of propagation can have a severe impact on its dynamics. This suggests a better understanding of the role of the propagation mechanism is desired. In this paper we put forward a novel framework and model for propagation, the RTR framework. This framework, based on communication theory, decomposes the propagation mechanism into three sub-processes; Radiation, Transmission and Reception (RTR). We show that the RTR framework provides a more detailed way for specifying and conceptually thinking about the process of propagation, aligns better with existing real world interventions, and allows for gaining new insights into effective intervention strategies. By decomposing the propagation mechanism, we show that the specifications of this mechanism can have significant impact on the effectiveness of network interventions. We show that for the same composite single-parameter specification, different decompositions in Radiation, Transmission and Reception yield very different effectiveness estimates for the same network intervention, from 30% less effective to 70% more effective. We find that the appropriate choice for intervention depends strongly on the decomposition of the propagation mechanism. Our findings highlight that a correct decomposition of the mechanism is a prerequisite for developing effective network intervention strategies, and that the use of monolithic models, which oversimplify the mechanism, can be problematic of supporting decisions related to network interventions. In contrast, by allowing more detailed specification of the propagation mechanism and enabling this mechanism to be linked to existing interventions, the RTR framework provides a valuable tool for those designing interventions and implementing interventions strategies. PMID- 30517163 TI - Direct CNS delivery of proteins using thermosensitive liposome-in-gel carrier by heterotopic mucosal engrafting. AB - Delivering therapeutics across the blood-brain barrier (BBB) for treating central nervous system (CNS) diseases is one of the biggest challenges today as the BBB limits the uptake of molecules greater than 500 Da into the CNS. Here we describe a novel trans-nasal mucosal drug delivery as an alternative to the intranasal drug delivery to overcome its limitations and deliver high molecular weight (HMW) therapeutics efficiently to the brain. This approach is based on human endoscopic skull base surgical techniques in which a surgical defect is repaired by engrafting semipermeable nasal mucosa over a skull base defect. Based on endoscopic skull based surgeries, our groups has developed a trans-nasal mucosal rodent model where we have evaluated the permeability of ovalbumin (45 kDa) as a model protein through the implanted mucosal graft for delivering HMW therapeutics to the brain. A thermo sensitive liposome-in-gel (LiG) system was developed for creating a drug depot allowing for a sustained release from the site of delivery to the brain through the implanted nasal graft. We would like to report this as an exploratory pilot study where we are using this novel surgical model to show that the implanted nasal mucosal graft and the LiG delivery system result in an efficient and a sustained brain delivery of HMW proteins. Hence, this study demonstrates that the trans-nasal mucosal engrafting technique could overcome the limitations for intranasal drug delivery and enable the uptake of HMW protein therapeutics into the CNS for the treatment of a wide range of neurodegenerative diseases. PMID- 30517164 TI - Cluster randomised trial on the effectiveness of a computerised prompt to refer (back) patients with type 2 diabetes. AB - AIMS: Information and communications technology (ICT) could support care organisations to cope with the increasing number of patients with diabetes mellitus. We aimed to aid diabetes care providers in allocating patients to the preferred treatment setting (hospital outpatient clinic or primary care practice), by using the Electronic Medical Record (EMR). METHODS: A cluster randomised controlled trial. Physicians in primary and secondary care practices of the intervention group received an advisory message in the EMR during diabetes consultations if patients were treated in the 'incorrect' setting according to national management guidelines. Primary outcome: the proportion of patients that shifted to the correct treatment setting at one year follow-up. RESULTS: 47 (38 primary care and 9 internist) practices and 2778 patients were included. At baseline, 1197 (43.1%) patients were in the correct treatment setting (intervention 599; control 598). Advice most often (68.4%) regarded a consultation with the internist. After one year 12.4% of the patients in the intervention and 10.6% in the control group (p = 0.30) had shifted to the correct setting. Main reasons for not following advice were: 1. physician's preference to consider other treatment options; 2. patients' preferences. CONCLUSIONS: We could not find evidence that using the EMR to send consultation-linked advice to physicians resulted in a shift in patients. Physicians will not follow the advice, at least partly due to patients' preferences. PMID- 30517165 TI - Cost-effectiveness analyses and cost analyses in castration-resistant prostate cancer: A systematic review. AB - BACKGROUND: Treatment of metastatic prostate cancer is associated with high personal and economic burden. Recently, new treatment options for castration resistant prostate cancer became available with promising survival advantages. However, cost-effectiveness of those new treatment options is sometimes ambiguous or given only under certain circumstances. The aim of this study was to systematically review studies on the cost-effectiveness of treatments and costs of castration-resistant prostate cancer (CRPC) and metastasizing castration resistant prostate cancer (mCRPC) on their methodological quality and the risk of bias. METHODS: A systematic literature search was performed in the databases PubMed, CINAHL Complete, the Cochrane Library and Web of Science Core Collection for costs-effectiveness analyses, model-based economic evaluations, cost-of illness analyses and budget impact analyses. Reported costs were inflated to 2015 US$ purchasing power parities. Quality assessment and risk of bias assessment was performed using the Consolidated Health Economic Evaluation Reporting Standards checklist and the Bias in Economic Evaluations checklist, respectively. RESULTS: In total, 38 articles were identified by the systematic literature search. The methodological quality of the included studies varied widely, and there was considerable risk of bias. The cost-effectiveness treatments for CRPC and mCRPC was assessed with incremental cost-effectiveness ratios ranging from dominance for mitoxantrone to $562,328 per quality-adjusted life year gained for sipuleucel T compared with prednisone alone. Annual costs for the treatment of castration resistant prostate cancer ranged from $3,067 to $77,725. CONCLUSION: The cost effectiveness of treatments of CRPC strongly depended on the willingness to pay per quality-adjusted life year gained/life-year saved throughout all included costs-effectiveness analyses and model-based economic evaluations. High-quality cost-effectiveness analyses based on randomized controlled trials are needed in order to make informed decisions on the management of castration-resistant prostate cancer and the resulting financial impact on the healthcare system. PMID- 30517166 TI - Assessment of dietary patterns, physical activity and obesity from a national survey: Rural-urban health disparities in older adults. AB - BACKGROUND: Obesity is a critical public health issue, affecting over one-third of all Americans, and is an underlying cause of numerous health issues across the lifespan. For older adults, obesity is linked to premature declines in physical and mental health and cognitive functioning. The occurrence of obesity and related health behaviors and chronic diseases are higher in rural areas than in urban areas. Furthermore, rural areas of the United States have a higher proportion of older adults than urban areas. Few studies, to date, have explored rural-urban differences in the relationships between dietary patterns and obesity among older adults. Therefore, the purpose of this study is to assess rural-urban differences in obesity rates in older adults, and the potential for the associations between obesity and physical activity and dietary patterns to vary by rural-urban status. METHODS: Data were abstracted from respondents aged 65 and above from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) database linked to Census-based county-level information on rural-urban status and socioeconomic status. Generalized linear models were utilized to assess rural urban disparities in obesity, and the potential for associations between obesity and known risk factors (fruit consumption, green vegetable consumption and physical activity) to vary by rural-urban status, accounting for complex sampling and confounders. RESULTS: Obesity rates were highest and fruit consumption was lowest in the most rural areas. However, for older adults in the most urban areas, there was a significant negative association between obesity and fruit and green vegetable consumption. This association was not observed in more rural older adults. CONCLUSION: These findings underscore the need to take into account place-based factors such as rural-urban status, when designing and implementing policies and interventions designed to reduce obesity through risk factor mitigation in older adults. To reduce rural-urban disparities in older adults, all policies, programs, and interventions should address the unique barriers and needs specific to rural and urban older adults. PMID- 30517167 TI - Power-system protection device with IoT-based support for integration in smart environments. AB - This paper proposes a power-system protection device designed to be integrated in smart environments based on Internet-of-Things technologies. The proposed system enhances electrical safety by fast disconnection of the power supply in case of fault events like leakage current, electrical arc, overcurrent or overvoltage and has been designed with the goal to be integrated in smart environments like smart homes or smart cities for protecting the electrical equipment. The system also enables real-time monitoring and notification events through an advanced communication interface using a data concentrator architecture. This paper provides an extended description of the proposed system's design and implementation, as well as the experimental validation results. PMID- 30517168 TI - Heated humidification did not improve compliance of positive airway pressure and subjective daytime sleepiness in obstructive sleep apnea syndrome: A meta analysis. AB - INTRODUCTION: We performed a meta-analysis on whether heated humidification during positive airway pressure (PAP) could improve compliance and subjective daytime sleepiness in obstructive sleep apnea syndrome (OSAS) patients. MATERIALS AND METHODS: We searched PubMed, EMBASE, Medline, Cochrane Library, Clinical Trials, Web of Science and Scopus from inception to Oct 29, 2017. We made meta analysis on the all available randomized controlled trials (RCTs) which assessed effects of heated humidification intervention on PAP compliance and subjective daytime sleepiness, by subgroups of automatic adjusting positive airway pressure/ continuous positive airway pressure (APAP/CPAP) usage and patients with/without upper airway symptoms prior to PAP therapy. RESULTS: A total of nine RCTs were evaluated finally in this meta-analysis. When all the studies were pooled, heated humidification did not improve PAP usage time [weighted mean difference(WMD) = 13.28, 95% confidence interval(CI): -5.85 to 32.41, P = 0.17] or Epworth sleepiness scale (ESS) score (WMD = -0.63, 95% CI: -1.32 to 0.07, P = 0.08). In terms of PAP usage time, heated humidification failed to enhance compliance in both APAP (WMD = 22.34, 95%CI: -21.08 to 65.77, P = 0.31) or CPAP subgroup (WMD = 11.09, 95%CI: -10.21 to 32.40, P = 0.31) and it was also ineffective among patients with upper airway symptoms prior to PAP therapy (WMD = 22.74, 95% CI: 7.77 to 53.24, P = 0.14) or without (WMD = 13.22, 95%CI: -35.84 to 62.29, P = 0.60). In terms of ESS score, heated humidification did not reduce ESS scores in both APAP (WMD = -1.59, 95% CI: -3.81 to 0.64, P = 0.16) or CPAP subgroup (WMD = 0.39, 95% CI: -1.16 to 0.37, P = 0.32) and it was also helpless among patients with upper airway symptoms prior to PAP therapy (WMD = -1.17, 95% CI: -3.10 to 0.75, P = 0.23) or without (WMD = -0.30, 95%CI: -2.25 to 1.66, P = 0.76). CONCLUSION: Heated humidification during PAP therapy improves neither the compliance nor ESS scores in OSAS patients, no matter what types of PAP or whether the patients had upper airway symptoms prior to PAP therapy. But to the population with upper airway symptoms and the APAP users, the conclusions were limited because of small sample size and possible selection bias. More attentions should be paid to these potentially possible benefited subgroups. PMID- 30517169 TI - Comparative genomics of transport proteins in seven Bacteroides species. AB - The communities of beneficial bacteria that live in our intestines, the gut microbiome, are important for the development and function of the immune system. Bacteroides species make up a significant fraction of the human gut microbiome, and can be probiotic and pathogenic, depending upon various genetic and environmental factors. These can cause disease conditions such as intra-abdominal sepsis, appendicitis, bacteremia, endocarditis, pericarditis, skin infections, brain abscesses and meningitis. In this study, we identify the transport systems and predict their substrates within seven Bacteroides species, all shown to be probiotic; however, four of them (B. thetaiotaomicron, B. vulgatus, B. ovatus, B. fragilis) can be pathogenic (probiotic and pathogenic; PAP), while B. cellulosilyticus, B. salanitronis and B. dorei are believed to play only probiotic roles (only probiotic; OP). The transport system characteristics of the four PAP and three OP strains were identified and tabulated, and results were compared among the seven strains, and with E. coli and Salmonella strains. The Bacteroides strains studied contain similarities and differences in the numbers and types of transport proteins tabulated, but both OP and PAP strains contain similar outer membrane carbohydrate receptors, pore-forming toxins and protein secretion systems, the similarities were noteworthy, but these Bacteroides strains showed striking differences with probiotic and pathogenic enteric bacteria, particularly with respect to their high affinity outer membrane receptors and auxiliary proteins involved in complex carbohydrate utilization. The results reveal striking similarities between the PAP and OP species of Bacteroides, and suggest that OP species may possess currently unrecognized pathogenic potential. PMID- 30517170 TI - Influence of reward learning on visual attention and eye movements in a naturalistic environment: A virtual reality study. AB - Rewards constitute crucial signals that motivate approach behavior and facilitate the perceptual processing of objects associated with favorable outcomes in past encounters. Reward-related influences on perception and attention have been reliably observed in studies where a reward is paired with a unidimensional low level visual feature, such as the color or orientation of a line in visual search tasks. However, our environment is drastically different and composed of multidimensional and changing visual features, encountered in complex and dynamic scenes. Here, we designed an immersive virtual reality (VR) experiment using a 4 frame CAVE system to investigate the impact of rewards on attentional orienting and gaze patterns in a naturalistic and ecological environment. Forty-one healthy participants explored a virtual forest and responded to targets appearing on either the left or right side of their path. To test for reward-induced biases in spatial orienting, targets on one side were associated with high reward, whereas those on the opposite side were paired with a low reward. Eye-movements recording showed that left-side high rewards led to subsequent increase of eye gaze fixations towards this side of the path, but no such asymmetry was found after exposure to right-sided high rewards. A milder spatial bias was also observed after left-side high rewards during subsequent exploration of a virtual castle yard, but not during route turn choices along the forest path. Our results indicate that reward-related influences on attention and behavior may be better learned in left than right space, in line with a right hemisphere dominance, and could generalize to another environment to some extent, but not to spatial choices in another decision task, suggesting some domain- or context-specificity. This proof-of-concept study also outlines the advantages and the possible drawbacks of the use of the 3D CAVE immersive platform for VR in neuroscience. PMID- 30517171 TI - Training intensity quantification of core stability exercises based on a smartphone accelerometer. AB - Although core stability (CS) training is largely used to enhance motor performance and prevent musculoskeletal injuries, the lack of methods to quantify CS training intensity hinders the design of CS programs and the comparison and generalization of their effects. The aim of this study was to analyze the reliability of accelerometers integrated into smartphones to quantify the intensity of several CS isometric exercises. Additionally, this study analyzed to what extent the pelvic acceleration data represent the local stability of the core structures or the whole-body postural control. Twenty-three male and female physically-active individuals performed two testing-sessions spaced one week apart, each consisting of two 6-second trials of five variations of frontal bridge, back bridge, lateral bridge and bird-dog exercises. In order to assess load intensity based on the postural control challenge of CS exercises, a smartphone accelerometer and two force platforms were used to measure the mean pelvic linear acceleration and the mean velocity of the centre of pressure displacement, respectively. Reliability was assessed through the intra-class correlation coefficient (ICC3,1) and the standard error of measurement (SEM). In addition, Pearson coefficient was used to analyze the correlation between parameters. The reliability analysis showed that most CS exercise variations obtained moderate-to-high reliability scores for pelvic acceleration (0.71 90% in 5 min) in pH 1.2 medium. In contrast, the dissolution of the optimized TPC-loaded SMEDDS was pH independent and reached over 90% within 5 min in all the media tested. Thus, we suggested that phospholipid complex formation and SMEDDS formulation using the experimental design method might be a promising approach to enhance the dissolution of poorly soluble drugs. PMID- 30517188 TI - Analysis of NK cell clones obtained using interleukin-2 and gene-modified K562 cells revealed the ability of "senescent" NK cells to lose CD57 expression and start expressing NKG2A. AB - In this work, we analyzed the phenotype and growth of human NK cell clones obtained by the stimulation of individual NK cells with IL-2 and gene-modified K562 feeder cells expressing membrane-bound IL-21 (K562-mbIL21). We generated clones from NK cells at distinct differentiation and activation stages, determined by CD56, CD57 and HLA-DR expression levels. Less differentiated CD56bright NK cell subsets showed higher cloning efficiency compared with more differentiated CD56dim subsets, especially with the CD57bright subset. However, clones from the CD56dimCD57- subset lived longer on average than other subsets. Moreover, several clones with the highest cell numbers were derived from CD56dimCD57-HLA-DR-cells. Most of the clones including those derived from more differentiated CD56dimCD57+/-NKG2A- NK cells showed a less-differentiated NKG2A+ phenotype. Also, CD57- cells were frequently observed in clones derived from CD57+ NK cells suggesting the loss of CD57 during the cloning process. On the other hand, KIR surface expression once detected for a clone never disappeared entirely, confirming irreversibility of the KIR expression. In summary, we have demonstrated that in specific conditions terminally differentiated CD57+ human NK cells are able to acquire the CD57- phenotype that was previously not observed and, thus, was considered impossible. PMID- 30517189 TI - Correction: Preserved endothelial function in young adults with type 1 diabetes. AB - [This corrects the article DOI: 10.1371/journal.pone.0206523.]. PMID- 30517190 TI - Correction: Influence of the fixation/permeabilization step on peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) for the detection of bacteria. AB - [This corrects the article DOI: 10.1371/journal.pone.0196522.]. PMID- 30517191 TI - Gene expression profiling of spontaneously occurring canine mammary tumours: Insight into gene networks and pathways linked to cancer pathogenesis. AB - Spontaneously occurring canine mammary tumours (CMTs) are the most common neoplasms of unspayed female dogs leading to thrice higher mortality rates than human breast cancer. These are also attractive models for human breast cancer studies owing to clinical and molecular similarities. Thus, they are important candidates for biomarker studies and understanding cancer pathobiology. The study was designed to explore underlying molecular networks and pathways in CMTs for deciphering new prognostic factors and therapeutic targets. To gain an insight into various pathways and networks associated with the development and pathogenesis of CMTs, comparative cDNA microarray expression profiling was performed using CMT tissues and healthy mammary gland tissues. Upon analysis, 1700 and 1287 differentially expressed genes (DEGs, P <= 0.05) were identified in malignant and benign tissues, respectively. DEGs identified from microarray analysis were further annotated using the Ingenuity Systems Pathway Analysis (IPA) tool for detection of deregulated canonical pathways, upstream regulators, and networks associated with malignant, as well as, benign disease. Top scoring key networks in benign and malignant mammary tumours were having central nodes of VEGF and BUB1B, respectively. Cyclins & cell cycle regulation and TREM1 signalling were amongst the top activated canonical pathways in CMTs. Other cancer related significant pathways like apoptosis signalling, dendritic cell maturation, DNA recombination and repair, Wnt/beta-catenin signalling, etc. were also found to be altered. Furthermore, seven proteins (ANXA2, APOCII, CDK6, GATC, GDI2, GNAQ and MYH9) highly up-regulated in malignant tissues were identified by two-dimensional gel electrophoresis (2DE) and MALDI-TOF PMF studies which were in concordance with microarray data. Thus, the study has uncovered ample number of candidate genes associated with CMTs which need to be further validated as therapeutic targets and prognostic markers. PMID- 30517192 TI - Correction: Predictive modeling for odor character of a chemical using machine learning combined with natural language processing. AB - [This corrects the article DOI: 10.1371/journal.pone.0198475.]. PMID- 30517194 TI - Correction: Dynasore protects the ocular surface against damaging oxidative stress. AB - [This corrects the article DOI: 10.1371/journal.pone.0204288.]. PMID- 30517193 TI - Patient and provider perceptions of a comprehensive care program for HIV-positive adults over 50 years of age: The formation of the Golden Compass HIV and aging care program in San Francisco. AB - OBJECTIVE: People living with HIV (PLWH) are living longer and developing comorbidities and aging-related syndromes. New care models are needed to address the combined burden and complexity of HIV and its comorbidities in this group. The goal of this study is to describe qualitative data from patients and providers that informed the development of a comprehensive care model for older PLWH. METHODS: Patient and provider perspectives on the clinical care and service needs of patients living and aging with HIV were explored via surveys and focus groups at a safety net HIV clinic in San Francisco. We surveyed 77 patients and 26 providers and conducted separate focus groups of older patients living with HIV (n = 31) and staff (n = 20). Transcripts were analyzed using thematic analysis. Themes for a care program were additionally explored using findings from the literature on HIV and aging. FINDINGS: Themes from surveys and focus groups emphasized (a) the need for knowledge expertise in HIV and aging, (b) focus on medical conditions and determinants of health of particular import (e.g. marginal housing) among older PLWH, (c) co-locating specialty services (e.g. cardiology, geriatrics) with primary care, and (d) addressing social isolation. Findings informed the design of a comprehensive, multidisciplinary care model for PLWH called the Golden Compass program composed of four "points": Heart and Mind (North), Bones and Strength (East), Network and Navigation (South), and Dental, Hearing, and Vision (West). CONCLUSION: Based on patient and clinic staff perspectives from surveys and focus groups, we designed a multidisciplinary program of integrated primary and specialty care, as well as housing and social support, to address the needs of older PLWH within a safety-net infrastructure. Golden Compass launched in 2017 for PLWH older than 50 years. Future research to evaluate the effectiveness of this care program in improving patient outcomes and satisfaction is ongoing. PMID- 30517195 TI - Rapid and highly-specific generation of targeted DNA sequencing libraries enabled by linking capture probes with universal primers. AB - Targeted Next Generation Sequencing (NGS) is being adopted increasingly broadly in many research, commercial and clinical settings. Currently used target capture methods, however, typically require complex and lengthy (sometimes multi-day) workflows that complicates their use in certain applications. In addition, small panels for high sequencing depth applications such as liquid biopsy typically have low on-target rates, resulting in unnecessarily high sequencing cost. We have developed a novel targeted sequencing library preparation method, named Linked Target Capture (LTC), which replaces typical multi-day target capture workflows with a single-day, combined 'target-capture-PCR' workflow. This approach uses physically linked capture probes and PCR primers and is expected to work with panel sizes from 100 bp to >10 Mbp. It reduces the time and complexity of the capture workflow, eliminates long hybridization and wash steps and enables rapid library construction and target capture. High on-target read fractions are achievable due to repeated sequence selection in the target-capture-PCR step, thus lowering sequencing cost. We have demonstrated this technology on sample types including cell-free DNA (cfDNA) and formalin-fixed, paraffin-embedded (FFPE) derived DNA, capturing a 35-gene pan-cancer panel, and therein detecting single nucleotide variants, copy number variants, insertions, deletions and gene fusions. With the integration of unique molecular identifiers (UMIs), variants as low as 0.25% abundance were detected, limited by input mass and sequencing depth. Additionally, sequencing libraries were prepared in less than eight hours from extracted DNA to loaded sequencer, demonstrating that LTC holds promise as a broadly applicable tool for rapid, cost-effective and high performance targeted sequencing. PMID- 30517196 TI - Comparative effectiveness and safety of interventions for acute diarrhea and gastroenteritis in children: A systematic review and network meta-analysis. AB - BACKGROUND: Many interventions have shown effectiveness in reducing the duration of acute diarrhea and gastroenteritis (ADG) in children. Yet, there is lack of comparative efficacy of interventions that seem to be better than placebo among which, the clinicians must choose. Our aim was to determine the comparative effectiveness and safety of the pharmacological and nutritional interventions for reducing the duration of ADG in children. METHODS: Data sources included Medline, Embase, CENTRAL, CINAHL, LILACS, and Global-Health up to May 2017. Eligible trials compared zinc (ZN), vitamin A, micronutrients (MN), probiotics, prebiotics, symbiotics, racecadotril, smectite(SM), loperamide, diluted milk, lactose-free formula(LCF), or their combinations, to placebo or standard treatment (STND), or among them. Two reviewers independently performed screening, review, study selection and extraction. The primary outcome was diarrhea duration. Secondary outcomes were stool frequency at day 2, diarrhea at day 3, vomiting and side effects. We performed a random effects Bayesian network meta analysis to combine the direct and indirect evidence for each outcome. Mean differences and odds ratio with their credible intervals(CrI) were calculated. Coherence and transitivity assumptions were assessed. Meta-regression, subgroups and sensitivity analyses were conducted to explore the impact of effect modifiers. Summary under the cumulative curve (SUCRA) values with their CrI were calculated. We assessed the evidence quality and classified the best interventions using the Grading of Recommendations, Assessment, Development & Evaluation (GRADE) approach for each paired comparison. RESULTS: A total of 174 studies (32,430 children) proved eligible. Studies were conducted in 42 countries of which most were low-and middle-income countries (LMIC). Interventions were grouped in 27 categories. Most interventions were better than STND. Reduction of diarrhea varied from 12.5 to 51.1 hours. The combinations Saccharomyces boulardii (SB)+ZN, and SM+ZN were considered the best interventions (i.e., GRADE quality of evidence: moderate to high, substantial superiority to STND, reduction in duration of 35 to 40 hours, and large SUCRA values), while symbiotics (combination of probiotics+prebiotics), ZN, loperamide and combinations ZN+MN and ZN+LCF were considered inferior to the best and better than STND [Quality: moderate to high, superior to STND, and reduction of 17 to 25 hours]. In subgroups analyses, effect of ZN was higher in LMIC and was not present in high income countries (HIC). Vitamin A, MN, prebiotics, kaolin-pectin, and diluted milk were similar to STND [Quality: moderate to high]. The remainder of the interventions had low to very-low evidence quality. Loperamide was the only intervention with more side effects than STND [Quality: moderate]. DISCUSSION/CONCLUSION: Most interventions analyzed (except vitamin A, micronutrients, prebiotics, and kaolin-pectin) showed evidence of superiority to placebo in reducing the diarrhea. With moderate-to high-quality of evidence, SB+ZN and SM+ZN, demonstrated the best combination of evidence quality and magnitude of effect while symbiotics, loperamide and zinc proved being the best single interventions, and loperamide was the most unsafe. Nonetheless, the effect of zinc, SB+ZN and SM+ZN might only be applied to children in LMIC. Results suggest no further role for studies comparing interventions against no treatment or placebo, or studies testing loperamide, MN, kaolin-pectin, vitamin A, prebiotics and diluted milk. PROSPERO REGISTRATION: CRD42015023778. PMID- 30517197 TI - The aquaporin 5 -1364A/C promoter polymorphism impacts on resolution of acute kidney injury in pneumonia evoked ARDS. AB - BACKGROUND: Aquaporin 5 (AQP5) expression impacts on cellular water transport, renal function but also on key mechanisms of inflammation and immune cell migration that prevail in sepsis and ARDS. Thus, the functionally relevant AQP5 1364A/C promoter single nucleotide polymorphism could impact on the development and resolution of acute kidney injury (AKI). Accordingly, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with AKI in patients suffering from pneumonia evoked ARDS. METHODS: This prospective study included 136 adult patients of Caucasian ethnicity with bacterially evoked pneumonia resulting in ARDS. Blood sampling was performed within 24 hours of ICU admission and patients were genotyped for the AQP5 promoter -1364A/C single nucleotide polymorphism. The development of an AKI and the cumulative net fluid balance was described over a 30-day observation period and compared between the AA and AC/CC genotypes, and between survivors and non-survivors. RESULTS: Incidence of an AKI upon admission did not differ in AA (58%) and AC/CC genotype carriers (60%; p = 0.791). However, on day 30, homozygous AA genotypes (57%) showed an increased prevalence of AKI compared to AC/CC genotypes (24%; p = 0.001). Furthermore, the AA genotype proved to be a strong, independent risk factor for predicting AKI persistence (odds-ratio: 3.35; 95%-CI: 1.2-9.0; p = 0.017). While a negative cumulative fluid balance was associated with increased survival (p = 0.001) the AQP5 promoter polymorphism had no impact on net fluid balance (p = 0.96). CONCLUSIONS: In pneumonia evoked ARDS, the AA genotype of the AQP5 promoter polymorphism is associated with a decreased recovery rate from AKI and this is independent of fluid balance. Consequently, the role of AQP5 in influencing AKI likely rests in factors other than fluid balance. PMID- 30517198 TI - The Transcriptional landscape of Streptococcus pneumoniae TIGR4 reveals a complex operon architecture and abundant riboregulation critical for growth and virulence. AB - Efficient and highly organized regulation of transcription is fundamental to an organism's ability to survive, proliferate, and quickly respond to its environment. Therefore, precise mapping of transcriptional units and understanding their regulation is crucial to determining how pathogenic bacteria cause disease and how they may be inhibited. In this study, we map the transcriptional landscape of the bacterial pathogen Streptococcus pneumoniae TIGR4 by applying a combination of high-throughput RNA-sequencing techniques. We successfully map 1864 high confidence transcription termination sites (TTSs), 790 high confidence transcription start sites (TSSs) (742 primary, and 48 secondary), and 1360 low confidence TSSs (74 secondary and 1286 primary) to yield a total of 2150 TSSs. Furthermore, our study reveals a complex transcriptome wherein environment-respondent alternate transcriptional units are observed within operons stemming from internal TSSs and TTSs. Additionally, we identify many putative cis-regulatory RNA elements and riboswitches within 5'-untranslated regions (5'-UTR). By integrating TSSs and TTSs with independently collected RNA Seq datasets from a variety of conditions, we establish the response of these regulators to changes in growth conditions and validate several of them. Furthermore, to demonstrate the importance of ribo-regulation by 5'-UTR elements for in vivo virulence, we show that the pyrR regulatory element is essential for survival, successful colonization and infection in mice suggesting that such RNA elements are potential drug targets. Importantly, we show that our approach of combining high-throughput sequencing with in vivo experiments can reconstruct a global understanding of regulation, but also pave the way for discovery of compounds that target (ribo-)regulators to mitigate virulence and antibiotic resistance. PMID- 30517199 TI - Genomic characterization of the Braque Francais type Pyrenees dog and relationship with other breeds. AB - The evaluation of genetic variability is a useful research tool for the correct management of selection and conservation strategies in dog breeds. In addition to pedigree genealogies, genomic data allow a deeper knowledge of the variability and genetic structure of populations. To date, many dog breeds, such as small regional breeds, still remain uncharacterized. Braque Francais type Pyrenees (BRA) is a dog breed originating from a very old type of gun-dog used for pointing the location of game birds to hunters. Despite the ancient background, the knowledge about levels of genetic diversity, degree of inbreeding and population structure is scarce. This may raise concerns on the possibility that few inbred bloodlines may dominate the breed, and on its future health. The aim of this work was therefore to provide a high-resolution representation of the genome-wide diversity and population structure of BRA dogs, using the 170K genome wide SNP array. Genome-wide polymorphisms in BRA were compared with those of other worldwide dog breeds. Between-dog relationships estimated from genomic data were very similar to pedigree relationships (Pearson correlation rg,a = 0.92). Results showed that BRA generally presents moderate levels of genetic diversity when compared with the major canine breeds. The estimated effective population size (recent Ne = 51) shows a similar declining pattern over generations as all other dog breeds, pointing at a common demographic history of modern canine breeds, clearly different from the demography of feral wolves. Multidimensional scaling (MDS), Bayesian clustering and Neighbor Joining tree were used to visualize and explore the genetic relationships among breeds, and revealed that BRA was highly differentiated and presented only low levels of admixture with other breeds. Brittany Spaniel, English Setter, Gordon Setter and Weimaraner dogs are the closest breeds to BRA. The exact reason for BRA being so divergent from other dog breeds, based on these results, is not yet clear. Further studies including additional ?braccoid? breeds will be needed to refine the results presented here and to investigate the origin of the BRA breed. Nonetheless, the genome-wide characterization reported here provides a comprehensive insight into the genome diversity and population structure of the Braque Francais, type Pyrenees breed. PMID- 30517200 TI - Idea density in Japanese for the early detection of dementia based on narrative speech. AB - BACKGROUND: Idea density (ID), a natural language processing-based index, was developed to aid in the detection of dementia through the analysis of English narratives. However, it has not been applied to non-English languages due to the difficulties in translating grammatical concepts. In this study, we defined rules to count ideas in Japanese narratives based on a previous study and proposed a novel method to estimate ID in Japanese text using machine translation. MATERIALS: The study participants comprised 42 Japanese patients with dementia aged 69-98 years (mean: 84.95 years). We collected free narratives from the participants to build a speech corpus. The narratives of the patients were translated into English using three machine translation systems: Google Translate, Bing Translator, and Excite Translator. The ID in the translated text was then calculated using the Dependency-based Propositional ID (DEPID), an English ID scoring tool. RESULTS: The maximum correlation coefficient between ID calculated using DEPID-R-ADD (a modified DEPID method to calculate ID after removing vague sentences) and the Mini-Mental State Examination score was 0.473, indicating a moderate correlation. DISCUSSION: The results demonstrate the feasibility of machine translation-based ID measurement. We believe that the basic concept of this translation approach can be applied to other non-English languages. PMID- 30517201 TI - Vectored delivery of anti-SIV envelope targeting mAb via AAV8 protects rhesus macaques from repeated limiting dose intrarectal swarm SIVsmE660 challenge. AB - Gene based delivery of immunoglobulins promises to safely and durably provide protective immunity to individuals at risk of acquiring infectious diseases such as HIV. We used a rhesus macaque animal model to optimize delivery of naturally arising, autologous anti-SIV neutralizing antibodies expressed by Adeno Associated Virus 8 (AAV8) vectors. Vectored transgene expression was confirmed by quantitation of target antibody abundance in serum and mucosal surfaces. We tested the expression achieved at varying doses and numbers of injections. Expression of the transgene reached a saturation at about 2 x 1012 AAV8 genome copies (gc) per needle-injection, a physical limitation that may not scale clinically into human trials. In contrast, expression increased proportionately with the number of injections. In terms of anti-drug immunity, anti-vector antibody responses were universally strong, while those directed against the natural transgene mAb were detected in only 20% of animals. An anti-transgene antibody response was invariably associated with loss of detectable plasma expression of the antibody. Despite having atypical glycosylation profiles, transgenes derived from AAV-directed muscle cell expression retained full functional activity, including mucosal accumulation, in vitro neutralization, and protection against repeated limiting dose SIVsmE660 swarm challenge. Our findings demonstrate feasibility of a gene therapy-based passive immunization strategy against infectious disease, and illustrate the potential for the nonhuman primate model to inform clinical AAV-based approaches to passive immunization. PMID- 30517202 TI - Establishing trust in HIV/HCV research among people who inject drugs (PWID): Insights from empirical research. AB - BACKGROUND: The establishment of trust between researchers and participants is critical to advance HIV and HCV prevention particularly among people who inject drugs (PWID) and other marginalized populations, yet empirical research on how to establish and maintain trust in the course of community health research is lacking. This paper documents ideas about trust between research participants and researchers amongst a sub-sample of PWID who were enrolled in a large, multi-year community health study of social networks and HIV/HCV risk that was recently conducted in rural Puerto Rico. METHODS: Qualitative research was nested within a multi-year Social Network and HIV/HCV Risk study involving N = 360 PWID > 18 years of age living in four small, rural Puerto Rican communities. Semi structured interviews were conducted between March 2017 and April 2017 with a subset of 40 active PWID who had been enrolled in the parent study. Interview questions invited participants to draw upon their recent experience as research participants to better understand how PWID perceive and understand participant researcher trust within the context of HIV/HCV-related epidemiological research. RESULTS: Fear of police, stigma and concerns regarding confidentiality and anonymity were identified as structural factors that could compromise participation in HIV/HCV-related research for PWID. While monetary compensation was an important motivation, participants also valued the opportunity to learn about their HIV/HCV status. During their participation in the study, gaining knowledge of safe injection practices was perceived as a valuable benefit. Participant narratives suggested that PWID may adopt an incremental and ongoing approach in their assessment of the trustworthiness of researchers, continuously assessing the extent to which they trust the research staff throughout the course of the research. Trust was initially generated through peer Respondent Driven Sampling recruitment. Research staff who maintained a presence in the community for the entire duration of the prospective study reinforced trust between participants and the research team. CONCLUSION: Although PWID face numerous structural barriers to research-related trust in HIV/HCV research, we found that using a peer-based recruitment method like RDS, and employing a research staff who are knowledgeable about the targeted population, culturally sensitive to their needs, and who maintain a long-term presence in the community may help mitigate many of these barriers. The reputation of the research is built incrementally as participants join the study. This contributes to a "street reputation" that grows as current or former participants vouch for the study. Establishing trust was identified as only the first step towards building a collaborative relationship with participants, and our findings suggest that steps to address criminalization and stigmatization also are necessary to support research trust. PMID- 30517203 TI - How do pregnant and lactating women, and young children, experience religious food restriction at the community level? A qualitative study of fasting traditions and feeding behaviors in four regions of Ethiopia. AB - Maternal and child feeding behaviors are often rooted in family and sociocultural context, making these an important point of inquiry for improving nutrition and health over the life course. The present study explored the practice of fasting during religious periods in relation to eating patterns of pregnant and lactating women and young children in four regions of Ethiopia, a nation which has experienced rapid economic growth and marked improvement in health and nutrition outcomes over the last two decades. Qualitative data collection and analysis at community level illustrated conflicting areas of understanding and practice related to diets of children and pregnant and lactating women during fasting times, potentially leading to gaps in nutrition. Community participants described different understandings of fasting requirements for these vulnerable populations and associated social norms and doxa, not always in accordance with religious texts or published guidance. Useful behavior change strategies may be developed through these results to address the potential barriers to appropriate feeding patterns for pregnant and lactating women and young children in Ethiopia. This will include continuing to work with communities and religious leaders to clarify that religious doctrine promotes improved nutrition outcomes. PMID- 30517204 TI - Higher prevalence of viral control in HIV-1-infected women in serodiscordant relationships. AB - BACKGROUND: HIV-1-discordant couples that remain discordant despite repeated exposure may differ from the general population in their distribution of transmission risk factors, including low plasma viral load (PVL) in the infected partner even in the absence of antiretroviral therapy (ART). METHODS: We followed two cohorts of HIV-1-infected Kenyan women: females in discordant couples (FDC) and female sex workers (FSW). We compared the distribution of undetectable (<150 copies/mL) and low PVL (<1,000 copies/mL) between the cohorts using bootstrap methods and exact Poisson regression. RESULTS: We evaluated 296 FDC and 220 FSW. At baseline, FDC were more likely to have undetectable (RR = 6.94, bootstrap 95% CI: 3.47, 20.81) and low PVL (RR = 3.53, bootstrap 95% CI: 2.57, 5.65) than FSW. Similarly, both repeat undetectable PVL (RR = 9.36, bootstrap 95% CI: 6.04, 10.97) and repeat low (RR = 4.99, bootstrap 95% CI: 2.33, 14.04) PVL were more likely among FDC than FSW during follow-up. DISCUSSION: We observed higher prevalence of viral control in FDC compared to FSW in the absence of ART, suggesting potentially higher prevalence of biological HIV resistance factors among discordant couples. PMID- 30517205 TI - Chromium(III) substitution inhibits the Fe(II)-accelerated transformation of schwertmannite. AB - Schwertmannite is an Fe(III)-oxyhydroxysulfate which is common in acid mine drainage (AMD) and acid sulfate soil (ASS) environments. Natural schwertmannite is often enriched in Cr(III), yet the effects of Cr(III) substitution on schwertmannite transformation to more stable Fe(III) minerals has not been addressed. Here we examine, for the first time, the effects of Cr(III) substitution on the Fe(II)-accelerated transformation of schwertmannite. X-ray diffraction (XRD) and Fe K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy shows that Cr(III) substitution inhibits schwertmannite transformation. Substitution at a Cr(III):Fe(III) ratio of 0.025 decreased schwertmannite transformation (at pH 6.5) by 18-49% (depending on Fe(II) concentrations) relative to that of Cr(III)-free schwertmannite. Formation of crystalline secondary phases (predominantly goethite) caused associated decreases in solid-phase Fe and Cr extractability by 1 M HCl. The extractability of Cr was consistently greater than that of Fe, suggesting some accumulation of Cr(III) at the residual schwertmannite surface-a phenomenon which passivates the surface against Fe(II)/Fe(III) electron transfer and atom exchange required for the Fe(II)-accelerated transformation process. The finding that Cr(III)-substitution inhibits schwertmannite transformation implies that it may also significantly impact associated Fe, S and trace metal(loid) behaviour. PMID- 30517206 TI - Treatment with a fixed dose combination antiretroviral therapy drug containing tenofovir, emtricitabine and efavirenz is associated with cardioprotection in high calorie diet-induced obese rats. AB - HIV-infection, certain antiretroviral drug classes, especially protease inhibitors (PI), and obesity are associated with increased ischaemic heart disease (IHD) risk. However, the effect of PI-free fixed dose combination (FDC) antiretroviral therapy (ART) on hearts exposed to ischaemia-reperfusion injury (I/R) is unknown, particularly in obesity. This is becoming relevant as World Health Organisation guidelines recommend a FDC ART containing (non-) nucleoside reverse transcriptase inhibitors (tenofovir (TDF), emtricitabine (FTC) and efavirenz (EFV)) as first-line HIV treatment. Additionally, obesity rates are rising in HIV-infected populations, not only in ART-experienced individuals, but also at the time of ART initiation, which may further increase the risk of IHD. Therefore, we investigated the effects of PI-free FDC ART in myocardial I/R exposed hearts from obese rats. Obesity was induced in male wistar rats via a 16 week high calorie diet. At week 10, treatment with a FDC ART drug containing TDF/FTC/EFV was initiated. Biometric and metabolic parameters, as well as myocardial functional recovery and infract size (IS), and myocardial signalling proteins following I/R were assessed after 16 weeks. Obese rats presented with increased body and intraperitoneal fat mass, elevated triglyceride and TBARS levels, whilst the hearts responded to I/R with impaired functional performance and increased IS. The FDC ART treatment did not alter biometric and metabolic parameters in obese rats. In a novel finding, ART protected obese hearts against I/R as shown by improved functional performance and smaller IS vs. untreated obese hearts. Cardioprotection was underscored by increased myocardial phosphorylated endothelial nitric oxide synthase (eNOS) and reduced AMP-kinase levels. In conclusion, these results demonstrate for the first time, that 6-weeks treatment of obese rats with a FDC ART drug specifically containing TDF/FTC/EFV conferred cardioprotection against I/R. The FDC ART-induced cardioprotection was seemingly unrelated to metabolic changes, but rather due to direct cardiac mechanisms including the up-regulation of myocardial eNOS. PMID- 30517207 TI - Longer TOMM40 poly-T variants associated with higher FDDNP-PET medial temporal tau and amyloid binding. AB - BACKGROUND: The translocase of outer mitochondrial membrane 40 (TOMM40), which lies in linkage disequilibrium with the apolipoprotein E (APOE) gene, has been implicated in Alzheimer's disease (AD). TOMM40 influences AD pathology through mitochondrial neurotoxicity, and the medial temporal lobe (MTL) is the most likely brain region for identifying early manifestations of AD-related morphology changes. While early reports indicated that the longer length poly-T allele of TOMM40 increases risk for AD, these findings have not been consistently replicated in further studies. We examined the effect of TOMM40 and APOE on regional brain positron emission tomography (PET) 2-(1-{6-[(2 [F18]fluoroethyl) (methyl) amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) binding values in MTL. METHODS: A total of 73 non-demented older adults (42 females; mean age: 62.9(10.9) completed genotyping for both APOE and TOMM40 and received FDDNP-PET scans. For TOMM40, the lengths of the poly-T sequence were classified as short (14-20 repeats; S), long (21-29 repeats, L) or very long (>29 repeats, VL). Using general linear models, we examined medial temporal lobe FDDNP binding and cognitive functioning between TOMM40 and APOE-4 groups, with age, sex, and education as covariates. RESULTS: Data from 30 individuals with APOE-4 and L TOMM40 poly-T length, 11 non E4 TOMM40 S/S, 14 non E4 TOMM40 S/VL and 13 non E4 TOMM40 VL/VL were analyzed. Medial temporal FDDNP binding differed significantly between TOMM40/APOE groups (F(3,62) = 3.3,p = .03). Participants with TOMM40 S/S exhibited significantly lower binding compared to TOMM40 S/VL and APOE-4 carriers. We did not find a significant relationship between TOMM40 poly-T lengths/APOE risk groups and cognitive functioning. CONCLUSIONS: This is the first report to demonstrate a significant association between longer TOMM40 poly T lengths and higher medial temporal plaque and tangle burden in non-demented older adults. Identifying biomarkers that are risk factors for AD will enhance our ability to identify subjects likely to benefit from novel AD treatments. PMID- 30517208 TI - Lower Extremity Injuries in Ice Hockey: Current Concepts. AB - Ice hockey is a fast-paced, collision sport requiring tremendous skill and finesse, yet ice hockey can be a harsh and violent game. It has one of the highest musculoskeletal injury rates in all of competitive sports. Razor sharp skates, aluminum sticks and boards made from high density polyethylene (HDPE), all contribute to the intrinsic hazards of the game. The objective of this article is to review evaluation, management, and return-to-the-rink guidelines after common lower extremity ice hockey injuries. PMID- 30517209 TI - Safety and Efficacy of Percutaneous Injection of Lipogems Micro-Fractured Adipose Tissue for Osteoarthritic Knees. AB - The aim of this study was to evaluate the safety and efficacy of using autologous, micro-fractured, minimally manipulated adipose tissue in patients with refractory knee osteoarthritis (OA). A total of 17 subjects (26 knees) with a median age of 72 years (range: 54-78 years) and a history of knee OA (Kellgren Lawrence, grade of 3 or 4) underwent treatment with ultrasound-guided injection of micro-fractured adipose tissue. Micro-fractured fat was obtained using a minimal manipulation technique in a closed system (Lipogems), without the addition of enzymes or any other additives. The study subjects were clinically evaluated using the numerical pain rating scale (NPRS), the 100-point Knee Society Score (KSS) with its functional component (FXN), and the lower extremity activity scale (LEAS) at 6 weeks, 6 months, and 12 months following this procedure. When compared with baseline, significant improvements were noted in the mean values of NPRS, FXN, and LEAS at 6 weeks, 6 months, and 12 months. The mean KSS significantly improved at 6 weeks and 12 months. In particular, the average KSS score improved from 74 to 82, the FXN score improved from 65 to 76, and the LEAS score improved from 36 to 47. These values were significantly greater than the previously published minimal clinically important difference described for KSS and FXN in patients who underwent total knee arthroplasty for primary OA. No serious adverse events were reported. The injection of autologous, micro-fractured, minimally manipulated adipose tissue appears to be a safe and effective treatment option for patients with refractory, severe (grade 3 or 4) knee OA. This study demonstrated significant improvements in pain, quality of life, and function for at least 12 months in this study population. This intervention may represent a nonsurgical treatment option to avoid knee joint replacement in this population; however, further investigation is needed. PMID- 30517210 TI - Novel variants of human herpesvirus 2 from Brazilian HIV-1 coinfected subjects. AB - BACKGROUND Human herpesvirus 2 (HHV-2) have DNA genome with a limited genetic variability and have been classified into two clades. OBJECTIVES To identify and characterise six HHV-2 isolates derived from Brazilian women. METHODS HHV-2 isolates were performed polymerase chain reaction (PCR) and sequencing of 2250 pb of the glycoprotein B (gB) coding regions. FINDINGS Four HHV-2 isolates were classified into clade B, while the remaining two, derived from HIV-1 co-infected women, showed a notable genetic divergence (> 1%). MAIN CONCLUSION The results reveal novel HHV-2 variants. The impact of these novel variants on HHV-2 pathogenesis and HIV/HHV-2 coinfection need to be investigated. PMID- 30517212 TI - A Dangerous Mistake: Research as a Commodity in University Institutions. PMID- 30517211 TI - Nyssorhynchus dunhami: bionomics and natural infection by Plasmodium falciparum and P. vivax in the Peruvian Amazon. AB - BACKGROUND Nyssorhynchus dunhami, a member of the Nuneztovari Complex, has been collected in Brazil, Colombia, and Peru and described as zoophilic. Although to date Ny. dunhami has not been documented to be naturally infected by Plasmodium, it is frequently misidentified as other Oswaldoi subgroup species that are local or regional malaria vectors. OBJECTIVES The current study seeks to verify the morphological identification of Nuneztovari Complex species collected in the peri Iquitos region of Amazonian Peru, to determine their Plasmodium infection status, and to describe ecological characteristics of their larval habitats. METHODS We collected Ny. nuneztovari s.l. adults in 2011-2012, and Ny. nuneztovari s.l. larvae and adults in 2016-2017. When possible, samples were identified molecularly using cytochrome c oxidase subunit I (COI) barcode sequencing. Adult Ny. nuneztovari s.l. from 2011-2012 were tested for Plasmodium using real-time PCR. Environmental characteristics associated with Ny. nuneztovari s.l. larvae positive water bodies were evaluated. FINDINGS We collected 590 Ny. nuneztovari s.l. adults and 116 larvae from eight villages in peri-Iquitos. Of these, 191 adults and 111 larvae were identified by COI sequencing; all were Ny. dunhami. Three Ny. dunhami were infected with P. falciparum, and one with P. vivax, all collected from one village on one night. Ny. dunhami larvae were collected from natural and artificial water bodies, and their presence was positively associated with other Anophelinae larvae and amphibians, and negatively associated with people living within 250m. MAIN CONCLUSIONS Of Nuneztovari Complex species, we identified only Ny. dunhami across multiple years in eight peri-Iquitos localities. This study is, to our knowledge, the first report of natural infection of molecularly identified Ny. dunhami with Plasmodium. We advocate the use of molecular identification methods in this region to monitor Ny. dunhami and other putative secondary malaria vectors to more precisely evaluate their importance in malaria transmission. PMID- 30517213 TI - Plant densities and harvesting times on productive and physiological aspects of Stevia rebaudiana Bertoni grown in southern Brazil. AB - Stevia (stevia rebaudiana Bertoni) is a species characterized by producing non caloric substances with high sweetening potential. Among these substances, rebaudioside A and stevioside are produced in greater quantity. Plant density and harvesting time are factors that affects biomass and sweetening compounds yield in this species. The objective of this research was to evaluate the effect of plant densities and harvesting times on the productive and physiological characteristics of stevia in southern Brazil. The experimental design was in randomized blocks, in a split-plot scheme, with 9 treatments comparing the effect of three planting densities (166 667, 83 333 and 33 333 plants ha-1) in the plots and three harvesting periods (before, in the beginning and in full flowering) in the subplots. Harvesting at the beginning of flowering promoted higher dry leaf biomass yield and, when associated with the lowest planting density, promoted higher levels of rebaudioside A and stevioside. The lowest planting density resulted in greater leaves biomass accumulation, whereas the highest density promoted higher yields per area. Interaction between density of 166 667 plants ha 1 and the harvest at the onset of flowering promoted higher yields of rebaudioside A (43.22 kg ha-1) as well as higher rebaudioside A/stevioside ratio (0.60). PMID- 30517214 TI - Plant growth, radiation use efficiency and yield of sugarcane cultivated in agroforestry systems: An alternative for threatened ecosystems. AB - Sugarcane (Sacharum officinarum L.) monocropping has had a great socio-economic and environmental impact in Brazil, and agroforestry systems have been considered as an alternative for more sustainable production; however, there is a lack of field research under such conditions. The aim of this study was to evaluate the growth rates, radiation use efficiency and yield traits in sugarcane cultivated in the understory of Aleurites fordii, in two agroforestry arrangements and monocropping systems. A field experiment was conducted from July 2015 to June 2016 in the city of Frederico Westphalen, Rio Grande do Sul, Brazil. The radiation use efficiency, assimilate partitioning, leaf area index, absolute growth rate, net assimilation rate, number of tillers, plant height, % of intercepted solar radiation, extinction coefficient, and yield in each system was evaluated. In agroforestry systems, the dynamic interactions between multiple plant species change with the time and can result in unique microclimates. The use of agroforestry systems in 12 x 12m arrangements should be prioritized because it enables greater yields and radiation availability in the understory. This study sought to provide new sustainable alternatives for farmers in order to increase the diversification of the rural property and maintain the preservation of existing agroecosystems. PMID- 30517215 TI - Free phenolic compounds extraction from Brazilian halophytes, soybean and rice bran by ultrasound-assisted and orbital shaker methods. AB - In several countries halophytes are commercially cultivated in low saline or even irrigated with seawater, as well as with saline aquaculture effluent, like a sea asparagus Sarcocornia ambigua, that show a biotechnological potential for bioactive compounds production. However, their recovery from matrix is sometimes inefficient because the lignocellulosic materials difficult the solvent action when drastic conditions are not applied. The ultrasound-assisted extraction (UAE) was optimized by a central composite rotational design for recovery free phenolic compounds (FPC) from the sea asparagus S. ambigua. Optimum conditions were validated and compared with orbital shaker extraction for S. ambigua, other Brazilian halophytes (Apium graveolens, Myrsine parvifolia, Paspalum vaginatum, and Schinus terebinthifolius), soybean and rice bran. Except for P. vaginatum, soybean and rice bran, UAE yielded 18-29% higher FPC than that of the orbital shaker. Besides this analytical performance UAE method optimized is faster than the orbital shaker, providing shorter exposure of the analyst to the extractor solvent and applicable in matrices with different compositions. It was also demonstrated that halophytes species showed to be good natural sources of FPC in a better way as soybean and rice bran. This work was the first to report FPC in M. parvifolia and P. vaginatum. PMID- 30517216 TI - Potentialities and limitations of agricultural use in soils of semi-arid region of the state of Bahia. AB - The objective of this study was to evaluate the potentialities and limitations of the agricultural use of representative classes of semi-arid regions of the state of Bahia, based on the pedological and evaluation of their soil characteristics. Five areas were selected where trenches were opened to collect samples for the analyses: Eutric Haplustept which presents vulnerability to physical and chemical degradation due to poor drainage with risks of erosion, waterlogging, salinization and compaction but having good natural fertility; Abrupt Kandiustalf with high vulnerability to physical degradation due to the presence of gravel and pebbles which may limit the development of deep rooting plants and mechanization but also with good natural fertility; Typic quartzipsaments and Typic Eutrustalf with no limitations related to drainage as low risk of compaction but featuring limitation of low moisture-holding capacity and nutrients; and Arenic Haplustulf wose characteristics are high vulnerability to degradation due to the drainage limitation related to the Btx horizon cementing in addition to low natural fertility and therefore is not recommended to agricultural use. However, in general, they feature no serious impediments for agricultural use. The amounts of OM is low in all soils but the use of management systems aiming at their accumulation and maintenance in appropriate levels will contribute to the CEC increase as well as to improve the chemical and physical properties. PMID- 30517217 TI - Physical-mechanical characterization of two amazon woods coming from the second cutting cycle. AB - Due to changes in the Amazon forest dynamics after the first cutting cycle, non exploited species become dominant in the forest. The lack of technological knowledge makes it hard to commercialize these woods, making the understanding of their physical-mechanical properties a fundamental step to properly define their applications. This study aimed to characterize physically and mechanically the wood of Pseudopiptadenia psilostachya and Eschweilera ovata from the second cutting cycle of the Tapajos National Forest, intending to commercially promote and to identify usages for them, as well as to evaluate the viability of replacement of highly commercialized species. The tests were performed accordingly to the Brazilian standard NBR 7190. P. psilostachya, presented bulk density of 0.683 g.cm-3, medium levels of shrinkage and anisotropy, as well as medium hardness (7366 N) and high strength on compression parallel to grain (71.63 MPa) and on static bending (103.9 MPa). It was generally superior to Euxylophora paraensis, but inferior when compared to Bagasssa guianensis and Apuleia leiocarpa, with possibilities to replace these three species. E. ovata, on the other hand, presented bulk density of 0.798 g.cm-3, high shrinkage and anisotropy values, but high values for hardness (12089 N) and strength on compression parallel to grain (68.67 MPa) and on static bending (127.1 MPa). This species exhibited, in general, similarities with Mezilaurus itauba, although it is a little inferior in relation to Hymenaea sp. and Astronium lecointei. Both species, P. psilostachya and E. ovata fit in the highest strength class described on the Brazilian Standard NBR7190, C60. By means of the results found, it was concluded that although the species studied were unknown, they presented timber with enough quality to replace some Amazon timber species widely commercialized on both national and international market. PMID- 30517218 TI - Sequential sampling plan for fruit fly species of the Genus Anastrepha (Diptera: Tephritidae) in guava orchards. AB - This study aimed to elaborate a sequential sampling plan for Anastrepha species in commercial orchards of guava Psidium guajava Novo Milenio cultivar. Samplings were carried out in three orchards in the State of Mato Grosso do Sul. Fruit flies were sampled for 23 weeks. Data were subjected to the sequential probability ratio test. We adopted the mean of 0.3 Anastrepha individuals for the safety level and 0.7 for the control level and the observed frequency was adjusted to the negative binomial expected frequency (Bn) for the equation of the line. The condition of adopting a control method recommended by S1 = 6.5554 + 0.5362n was observed in the upper line. In turn, the lower line, which does not require the use of a control method, is defined by So = -2.8229 + 0.5362n. The sequential sampling plan predicted the expected maximum number of 37 sampling units to decide whether or not to use control method(s). This sequential plan was defined with mean number of 0.54 adults for each McPhail trap unit (sample). The sequential plan generated is unprecedented and will contribute to the rapid and safe decision making in the control of Anastrepha species of economic importance in guava farming. PMID- 30517219 TI - Consortium of five fungal isolates conditioning root growth and arbuscular mycorrhiza in soybean, corn, and sugarcane. AB - Plant growth and arbuscular mycorrhizal colonization were studied in sugarcane, corn and soybean by applying five plant growth promoting fungi: Beauveria bassiana, Metarhizium anisopliae, Pochonia chlamydosporia, Purpureocillium lilacinum, and Trichoderma asperella. Sugarcane, corn and soybean were grown in pots under two treatments: (1) inoculation with the fungal consortium and (2) control without inoculation. In the inoculated treatment, fungal spore suspension were applied to the seeds and shoots were sprayed every 28 days. Means were analyzed by analysis of variance and Tukey's test at 5% probability level. The experiment was arranged in a completely randomized design, with six replications. Fungi consortium mediate root growth in soybean and corn, and arbuscular mycorrhizal colonization in soybean and sugarcane. These findings are probably caused by the fungi producing phytohormones and inducing the plants to synthesize phytohormones: auxins for root growth; and jasmonic, abscisic, and salicylic acids with a role in the regulation of mycorrhizal colonization. These effects are important when seeking conservation strategies in agriculture and livestock production, since Fungi consortium can better mediate soil resource acquisition, promoting greater absorption of nutrients and water. PMID- 30517220 TI - Effects of maternal artificial vocalization on hyperprolific lactating sows and piglets behavior. AB - The objective of this trial was to evaluate the behavioral patterns and performance of lactating sows and their litters under the effect of artificial vocalization. Twenty-eight sows and their litters were distributed in a completely randomized design in a 2x2 factorial scheme (artificial vocalization x lactation week). The behavior of the animals was monitored during 24 hours on the 7th and 15th days of lactation, analyzing the number, interval, and frequency of nursings. The body condition and performance of the sows were also evaluated. Artificial vocalization promoted higher frequencies of eating for sow and nursing for piglets (P <0.05), increased inactive sow behavior (P <0.05), and reduced sow alert in activity (P <0.05). The number and duration of suckling sessions at the 15thday of lactation were reduced (P <0.05). The use of artificial vocalization did not affect the body condition or milk production of the lactating sows, or the performance of the litter during lactation (P> 0.05). The use of maternal artificial vocalization during lactation of sows promoted greater lactation efficiency and longer rest time, favoring the sows' welfare. PMID- 30517221 TI - Impact of percentage and particle size of sugarcane biochar on the sorption behavior of clomazone in Red Latosol. AB - Biochar is a carbonaceous material that has excellent potential as a fertilizer and soil conditioner. However, there is a lack of information concerning the effects of the amount and particle size of this pyrogenic material on the soil sorption capacity. In this work, evaluation was made of changes in clomazone (CMZ) sorption in a Red Latosol following soil conditioning using different percentages (0.25, 0.5, and 1% w/w) of sugarcane biochar in three particle sizes (<106, 106-508, and 508-610 um). The conditioned soils presented apparent sorption coefficients (Kd) up to 1300 times higher than that of pure soil, besides changes in the behavior of CMZ sorption. The biochar particle size and percentage influenced sorption of the herbicide as well as its retention in the amended soil during desorption processes. Both sorption and desorption Freundlich constants were linearly correlated with the external surface area of the biochar present in the soil. PMID- 30517222 TI - Sunflower protein concentrate and crambe protein concentrate in diets for silver catfish Rhamdia quelen (Quoy and Gaimard, 1824): use as sustainable ingredients. AB - The objective of this study was to evaluate growth and metabolic parameters of silver catfish fed with protein concentrates of sunflower meal (SMPC) and crambe meal (CrMPC). The study evaluated two levels of substitution, where 25 or 50% of animal protein was replaced with plant-based protein. A total of 300 silver catfish (14 +/- 0.26 g) were used in five treatments and three replications, in fifteen 280-liter experimental units. The results were submitted to analysis of variance and the means of the control diet was compared to the remaining treatments by Dunnett's test at 5% significance level. At the end of the trial, no differences were observed for the variables final weight and daily weight gain. However, minor feed conversion was observed in the groups Control and SMPC 25%. Metabolic parameters were analyzed in the plasma and liver, where no significant differences were found for any of the blood parameters analyzed. In the analyzed liver parameters (ammonia, protein, amino acids and ALAT), the liver protein content was lower in fish consuming SMPC-50%, CrMPC-50% and 25% CrMPC diets. The amino acids content was higher in fish receiving the SMPC-25% diet. It can be concluded that sunflower meal protein concentrate is better utilized by fish and more efficient metabolically than crambe meal. This study demonstrated that a newly developed protein concentrate SMPC and CrMPC can effectively replace 25% and 50% the animal protein in a diet free of FM. PMID- 30517223 TI - Welfare indicators for laying Japanese quails caged at different densities. AB - In the way to reduce costs in the poultry production, high densities of birds are adopted in the production systems. Such high densities can lead to an inappropriate environment, compromising the welfare and decreasing the animal performance. In this work we aimed to evaluate the effects of different densities on the productive yield, egg quality and immunological aspects of Japanese quails. It was used 816 Japanese quails, during egg production phase, in a random design, with four treatments (121.43 cm2/bird; 106.25 cm2/bird; 94.44 cm2/bird and 85.00 cm2/bird) with six repetitions each. Results indicate density did not interfere on egg quality and all treatments can be considered excellent, once the Haugh Unit was 88.03. Therefore, higher densities decline the yield, decreasing the eggs weight (10.35 g), the laying percentage (88%), egg mass (9.16 g) and the week average feed consumption (157.35 g). IgY values were higher at smaller cage density, suggesting birds in this condition presented better immunological condition, related to welfare and stress factors, all linked to immunoglobulins IgY. PMID- 30517224 TI - Combination of fixative agents and fixation times to visually differentiate the cortical from the medullary layer in bovine adrenal glands. AB - Chronic stress exposure commonly increases adrenals weight and changes their morphology. This study aimed to compare four methods to delimitate the cortical and medullary layers of adrenals glands in Nelore bulls. Fresh adrenals did not present differentiation between layers. Then, frozen adrenals were distributed in plastics bags with fixative Bouin (G1), 96oGL ethylic alcohol (G2), 10% formaldehyde (G3), or 2.5% glutaraldehyde (G4). After 12 hours of fixation, the G1 adrenal glands did not show the entire cortical layer marked by Bouin's solution. For G2 and G3 there was a poor contrast, while for G4 there was a reasonable contrast. After 24 hours of fixation, G1 had an excellent contrast between layers, while G2 and G4 had a reasonable contrast and G3 a very bad contrast. After 48 hours it was difficult to differentiate cortical and medullar layers for G1; for Group 2 we get a reasonable contrast; and for G3 the contrast was bad. For G4 the contrast was not as sharp due to the medulla became dark. It was concluded that fixation of adrenals must be done in Bouin's solution for 24 hours to obtain an effective evaluation of the adrenals' morphometry. PMID- 30517225 TI - Growth of cactus pear cv. Miuda under different salinity levels and irrigation frequencies. AB - Soil and water salinity are considered the main limiting factors of plant production. This work aimed to evaluate the influences of irrigation frequency and soil salinity on the development of cactus pear cv. Miuda (Nopalea cochenillifera Salm Dyck). The experiment was conducted in factorial arrangement of four salinity levels: 0.3 (control), 0.5 (low), 1.5 (medium) and 3.6 (high salinity) (ds m-1), associated with four irrigation frequencies (each 7, 14, 21 and 28 days) and two soil textures (sandy and sandy loam) in a randomized block design with four replicates. One cladode was planted in each polyethylene pot containing 10 kg of soil. The soil texture influenced some of the morphological characteristics of the cactus pear, so that plants grown in sandy loam soil yielded higher number of cladodes (9.47) and higher productivity (62.1 g plant 1). The sandy soil produced plants with fewer cladodes (4.50). Irrigation water with a salinity level of 3.6 ds m-1 and an irrigation frequency of 7 days showed higher soil electrical conductivity (48.65 dS m-1) and plants with a higher damage (5.0) and lower productivity (32.51 g plant-1), indicating a low tolerance of the cv. Miuda to salt stress. PMID- 30517226 TI - Relationship between biochemical and photosynthetic traits with Asian soybean rust. AB - Asian soybean rust (Phakopsora pachyrhizi - ASR) is one of the major diseases that occur in soybean and causes great damage to commercial crops. Therefore, the goal of this work was to investigate the relationship between biochemical and photosyntetic parameters in soybean with ASR. Two experiments were performed in a randomized complete block with three treatments (water, Tween 20, and methyl jasmonate). The evaluated traits were: severity, chlorophyll pools, concentration of phenolic compounds content, enzyme activity, and photosyntetic parameters. Based on Pearson correlation, correlation network and path analysis it was verified that the severity had high correlation with almost all traits evaluated meanwhile photosynthesis is weakly related with almost all traits. Therefore, the occurrence of ASR affects directly the traits related to enzymatic activity and phenolic compounds content in soybean plants inoculated with ASR. The management of ASR is important to keep in normal levels the rates of photosynthesis carried out by the plant, and thus not affect the yield. Besides that, understanding the biochemical mechanisms and ecophysiological responses that occur during the soybean-P. pachyrhizi interaction has a great importance for breeding programs, as it will help for obtaining resistant cultivars or efficient methods in fungus control. PMID- 30517227 TI - Population suppression of Ceratitis capitata (Wiedemann) on table grapes using toxic baits. AB - To provide alternatives to the use of spraying synthetic insecticides in C. capitata management, was evaluated the effect of "attract and kill" toxic baits on population suppression of C. capitata in three commercial areas producing table grapes. Toxic baits of GelsuraTM (4.5 L ha-1) and SuccessTM 0.02 CB (4.0 L ha-1) resulted in lower population levels of C. capitata adults in monitoring traps after five sequential applications at weekly intervals during the maturation period of the grapes when compared with control plots with or without insecticidal spray. In addition, plots with GelsuraTM and SuccessTM 0.02 CB applications showed a significant reduction in damage (%) by C. capitata on grape berries and grape bunches when compared with control plots without or with insecticidal spray. However, when compared with a plot treated by conventional management with sprays of etofenprox (SafetyTM, 100 g c.p. (commercial product) 100 L-1) and applications of spinosad (SuccessTM 0.02 CB toxic bait) with a brush, only GelsuraTM (4.5 L ha-1) showed a lower level of damage of grape berries and grape bunches. Toxic baits GelsuraTM (4.5 L ha-1) and SuccessTM 0.02 CB (4.0 L ha-1) are promising alternatives for the population suppression of C. capitata on table grapes. PMID- 30517228 TI - Soil Physical Quality in Agricultural Systems on the Cerrado of Piaui State, Brazil. AB - Soil quality is essential for maintaining the sustainability of agro-ecosystems and ecosystem services provided by this natural resource. The present study aimed to assess the physical quality of soil through the characterization of the physical properties in grain production systems in the Southwest region of Piaui State, Brazil. The study was carried out in the Cerrado region of Piaui in four cities in areas of expansion of the agricultural frontier of the state: Baixa Grande do Ribeiro, Sebastiao Leal, Urucui and Bom Jesus. Soil samples were collected in April 2012, in areas of grain production under conventional and no tillage systems. Adjacent areas with native vegetation were also sampled as reference. Bulk density, effective saturation, hydraulic conductivity, penetration resistance, porosity and aggregation were measured. Regardless of the type of soil management used, agricultural systems degrade soil physical quality. No-tillage showed higher bulk density, penetration resistance and aggregation, with lower total porosity, macroporosity and hydraulic conductivity. The physical quality of soil in the agricultural areas of the Cerrado region of Piaui was dependent on the soil texture, while silt, clay and organic matter were determinant for soil aggregation, mechanical resistance, total porosity and microporosity. PMID- 30517229 TI - Erratum: Incontinence-associated dermatitis: a cohort study in critically ill patients. AB - [This corrects the article doi: 10.1590/1983-1447.2016.esp.68075]. PMID- 30517230 TI - Over-the-counter medications potentially inappropriate for the elderly. PMID- 30517231 TI - Challenges and perspectives in the treatment of patients with haemophilia in Brasil. PMID- 30517232 TI - Benign prostatic hyperplasia. AB - The minimally invasive procedures (mips) for the treatment of symptoms of benign prostatic hyperplasia (bph) are presented as attractive techniques due to their ease of accomplishment and the possibility of outpatient treatment. This guideline aims to present recommendations that may assist in decision making in patients with benign prostatic hyperplasia and indication of the different minimally invasive therapies. For this, a systematic review of the literature was performed, with the descriptors according to the pico: patient with benign prostatic hyperplasia, minimally invasive therapy, clinical outcome and adverse events. With no time restriction, in medline, cochrane central and lilacs databases via vhl, 1,007 papers were retrieved, of which 16 were selected to respond to clinical doubt. Details of the methodology and results of this guideline are set out in annex I. PMID- 30517233 TI - Wernicke's encephalopathy in a patient with non-Hodgkin's lymphoma post Autologous HSCT. AB - Wernick's Encephalopathy (WE) is an acute neuropsychiatric syndrome caused by thiamine deficiency post hematopoietic stem cell transplant (HSCT). WE is associated with high mortality and morbidity rates, but due to its rare occurrence, it is rarely considered in patients submitted to this procedure. Considering that, the manuscript reports the clinical characteristics and the possible factors that predisposed the occurrence of WE in a patient with non Hodgkin's lymphoma post-Autologous HSCT. We conclude that WE should be considered in patients submitted to autologous HSCT associated with prolonged use of TPN and malnutrition. PMID- 30517234 TI - Application of confocal endomicroscopy in the diagnostic elucidation of pancreatic cyst. PMID- 30517235 TI - Assessment of oxidative damage and enzymatic antioxidant system activity on the umbilical cord blood and saliva from preterm newborns with risk factors for early onset neonatal sepsis. AB - BACKGROUND: To determine the concentration of the Lipid Peroxidation Marker: Malondialdehyde (MDA), and Antioxidant Markers: Superoxide Dismutase (SOD), Glutathione Peroxidase (GPX), Catalase (CAL) in umbilical cord blood and in unstimulated saliva in the first 24 and 48 hours of life in the PTNB of mothers with and without risk factors for early-onset neonatal sepsis. METHODS: Cross sectional study with the signing of informed consent by the pregnant women and application of a standard questionnaire classifying the PTNB in Group 1 or 2. RESULTS: Twenty-one PTNB were studied. Regarding gender, birth weight, need for oxygen, use of phototherapy, diagnosis of assumed sepsis, presence of fetal distress, number of pregnancies, type of delivery, use of corticosteroids, premature rupture of membranes, maternal fever, chorioamnionitis, APGAR at the 5th and 10th minute of life. Statistical analysis was performed with the Mann Whitney test (p = 0.019) on the GPX variable of umbilical cord blood in the group of mothers with risk factors for early-onset neonatal sepsis. There was no statistical difference in the MDA, SOD, and CAT variables of the group with risk factors and in any variable of the group without risk factors. CONCLUSION: There was an increase of the GPX concentration in the blood from the umbilical vein in the group with risk factors for early-onset neonatal sepsis. There was no statistical significance in the comparison of saliva and umbilical cord blood. There was no statistically significant difference in MDA, SOD, CAT. PMID- 30517236 TI - Growth achieved and correlation with blood pressure levels in schoolchildren. AB - INTRODUCTION: The prevalence of systemic arterial hypertension in childhood has increased progressively. OBJECTIVE: To analyze blood pressure and height reached by children in public schools in the South of Brazil. METHODS: This is a sectional study of a randomized sample of 1,082 students of six to seven and nine to ten years old used to evaluate blood pressure and height. Blood pressure levels were classified by percentile for gender, age and stature according to the North American reference of National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. RESULTS: Schoolchildren presented adequate growth, which was, on average, higher than the WHO reference values. Blood pressure levels were altered in 13.8% of children, with a higher frequency in the nine and ten year olds (17.6%). The isolated analysis of systolic and diastolic Blood pressure revealed a similar trend, with blood pressure levels higher than the greater the value of the Z-score for stature. CONCLUSION: The schoolchildren in the study evidenced adequate growth and an elevated prevalence of pre-hypertension and arterial hypertension, which tended to be higher in older children and/or those that achieved a greater stature growth. PMID- 30517237 TI - Comparison of students' motivation at different phases of medical school. AB - INTRODUCTION: Knowledge about student motivation allows educators to broaden their understanding and to establish strategies that make it possible to enhance motivation. OBJECTIVES: To investigate the levels of student motivation at different phases of medical education, comparing incoming students' motivation with that of those at the end of their studies, as well as during the different preclinical, clinical, and clerkship cycles. METHOD: Cross-sectional study including students from a Brazilian public university. The questionnaire included sociodemographic data and the Academic Motivation Scale (AMS). Student motivation was compared at different phases of the medical course. RESULTS: 710 students were included. Students in the preclinical phase (1st-2nd years) had higher levels of integrated regulation AMS (e.g.,"Education is a privilege."), introjected regulation AMS (e.g."I come because it is what is expected of me."), and intrinsic motivation AMS (e.g."School is a pleasure"). Students in the clinical phase (3rd-4th years) had higher levels of amotivation (e.g., "I'm wasting my time at school.") and external regulation AMS (e.g., "I'm coming to school to earn a degree"). AMS levels of external regulation, introjected relation, and integrated regulation were different for Clerkship students (5th 6th years) compared to preclinical students, but not for clinical students. Comparing only the first and last years, incoming students had higher levels of integrated regulation AMS and lower levels of amotivation AMS and external regulation AMS. CONCLUSION: Important motivational changes were found during different phases of medical school, with higher levels of motivation during the course's initial semesters. These findings can aid in developing educational strategies to stimulate self-determined education. PMID- 30517238 TI - Opioid tapering and weaning protocols in pediatric critical care units: a systematic review. AB - OBJECTIVE: Opioid abstinence syndrome is common in the pediatric intensive care environment because sedation is often needed during the children's treatment. There is no specific guideline regarding the management of these patients; and lately, methadone is an important drug for the prevention of abstinence symptoms during the weaning of opioids. This study gathers the available research to establish the initial dose of methadone, the rate of taper and tools to recognize this syndrome and act promptly. METHODS: A systematic review was made from data of four different databases. Forty-nine articles of observational and experimental studies were selected based on the inclusion criteria (critical pediatric patients in acute use of opioids) and exclusion criteria (previous chronic use of opioids, other medications). The data regarding specific themes were separated in sections: initial dose of methadone, use of protocols in clinical practice, abstinence scales and adjuvant drugs. RESULTS: The articles showed a great heterogeneity of ways to calculate the initial dose of methadone. The pediatric intensive care units of the study had different weaning protocols, with a lower incidence of abstinence when a pre-defined sequence of tapering was used. The Withdrawal Assessment Tool - 1 was the most used scale for tapering the opioids, with good sensitivity and specificity for signs and symptoms. CONCLUSION: There is still little evidence of other medications that can help prevent the abstinence syndrome of opioids. This study tries to promote a better practice during opioid weaning. PMID- 30517239 TI - The artery of Mouchet: blood supply of the septomarginal trabecula in 50 human hearts. AB - The septomarginal trabecula is a muscular structure which transmits the right branch of the atrioventricular bundle. It is usually supplied by a branch from the second anterior septal artery. Anastomoses between the right and left coronary arteries may happen on the septomarginal trabecula. They are of great significance in order to prevent ischemia during a myocardial infarction. Surgeries such as Konno's and Ross' procedures implies in knowledge of these vessels anatomy. The coronary arteries of 50 human hearts were injected with latex and subsequentely dissected with the purpose of identifying the arterial branch that supplied the septomarginal trabecula. The trabecular branch arose from the second anterior septal artery in 38% of cases, and the branch arose from the first anterior septal artery in 26%. One of the hearts had its septomarginal trabecula supplied by the conus arteriosus arteryliterature. Anastomoses between the right and left coronary arteries were found inside the septomarginal trabecula. The right branch of the atrioventricular bundle is subject to a great number of clinical conditions and is often manipulated during surgery, thus, the study of the septal branches of the coronary arteries and the trabecular branch is essential. PMID- 30517240 TI - Cognition, functionality and symptoms in patients under home palliative care. AB - OBJECTIVE: Evaluating the degree of cognition, functionality, presence of symptoms and medications prescribed for patients under palliative home care. METHOD: Descriptive, cross-sectional study where 55 patients under palliative home care were interviewed. Cognition was evaluated using the Mini-Mental state examination (MM), with patients being separated into two groups: with preserved cognitive ability (MM>24), or altered (MM <24). The functionality was verified by the Palliative Performance Scale (PPS) and the patients were divided into two groups: PPS<=50 and PPS>=60. The symptoms presence was evaluated by ESAS (Edmonton Symptom Assessment System) being considered as mild (ESAS 1-3), moderate (ESAS 4-6) or severe (ESAS 7-10) symptoms. Medications prescribed to control the symptoms were registered. Statistical analysis used Student's t test (p <0.05). RESULTS: Most of the 55 patients were women (63.6%), 70.9% of these had MM> 24, 83.6% had PPS <50 and 78.2% presented chronic non-neoplastic degenerative disease. There was a significant relationship between PPS<=50 and MM<=24. Symptoms were present in 98% of patients. Asthenia was more frequently reported and was not treated in 67% of the cases. Severe pain was present in 27.3%: 46% without medication and 13% with medication, if necessary. Most patients with severe dyspnea used oxygen. CONCLUSIONS: Most of the analysed patients had their cognition preserved, presented low functionality and 98% reported the presence of symptoms. Severe pain was present in almost 1/3 of the patients without effective treatment. Re-evaluate palliative home care is suggested to optimize patient's quality of life. PMID- 30517241 TI - Detection of intracellular Helicobacter pylori in Candida. SPP from neonate oral swabs. AB - BACKGROUND: There is evidence of detection of Helicobacter pylori (H. pylori) in the stool of newborns and in the yeast that colonizes the oral cavity of this age group. However, there is a lack of research to confirm it. This study proposes to determine the existence of the bacteria at an early age, specifically in newborns. OBJECTIVE: To identify intracellular H. pylori in oral yeasts and to detect antigens of the bacteria in newborn stools. METHODOLOGY: Cross-sectional and descriptive study. Samples were obtained from infants (oral swab and meconium). Identification of yeast species was performed using the following techniques: CHROMagar Candida, Germinal Tube Test and API Candida Identification System, then the yeasts were observed by light microscopy and fluorescence. Detection of H. pylori antigen in meconium and PCR were performed to amplify specific genes of the bacterium (rRNA16S, cagA, vacA s1a, vacA s1b, vacA s2, vacA m1, vacA m2 and dupA). RESULTS: Intracellular H. pylori was detected in yeast of the species Candida glabrata (C. glabrata) isolated from an oral swab of a newborn. CONCLUSION: The results of this study evidenced the existence of intracellular H. pylori in newborns. PMID- 30517242 TI - Ultrasonography features of abdominal perimuscular connective tissue in elite and amateur basketball players: an observational study. AB - The purpose of this study was to assess and compare with rehabilitative ultrasound imaging (RUSI) the perimuscular connective tissue (PMCT) and interrecti distance (IRD) between elite and amateur basketball players. A sample of 22 healthy basketball players was included and divided into two groups: elite basketball players from Spanish 1st division (n = 11) and amateur basketball players from an entertainment Spanish division (n = 11). Ultrasound images of the external oblique (EO), internal oblique (IO), transversus abdominis (TrAb), rectus anterior (RA) and IRD PMCT were measured and analysed by the ImageJ software. Measurements of abdominal wall muscles PMCT present statistically differences (P < .05) for an increase of perimuscular connective tissue of external oblique (PMCTEO), perimuscular connective tissue of transversus abdominis (PMCTTA) of the left side and an increase of PMCTEO on the right side in favor of the elite group. Rather, the study showed statistically differences (P < .05) for a decrease of perimuscular connective tissue between the internal oblique and transversus abdominis (PMCTIO-TA), and a decrease in PMCT total summation of the left side with elite group in respect to amateur group. This study reported an increase of left PMCTEO, left PMCTTAA, right PMCTEO as well as a decrease of left PMCTIO-TA and in PMCT total summation on the left side. PMID- 30517243 TI - Relevance of hMLH1 -93G>A, 655A>G and 1151T>A polymorphisms with colorectal cancer susceptibility: a meta-analysis based on 38 case-control studies. AB - OBJECTIVE: There has been increasing interest in the study of the association between human mutL homolog 1 (hMLH1) gene polymorphisms and risk of colorectal cancer (CRC). However, results from previous studies are inconclusive. Thus, a meta-analysis was conducted to derive a more precise estimation of the effects of this gene. METHODS: A comprehensive search was conducted in the PubMed, EMBASE, Chinese Biomedical Literature databases until January 1, 2018. Odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. RESULTS: Finally, 38 case-control studies in 32 publications were identified met our inclusion criteria. There were 14 studies with 20668 cases and 19533 controls on hMLH1 -93G>A, 11 studies with 5,786 cases and 8,867 controls on 655A>G and 5 studies with 1409 cases and 1637 controls on 1151T>A polymorphism. The combined results showed that 655A>G and 1151T>A polymorphisms were significantly associated with CRC risk, whereas -93G>A polymorphism was not significantly associated with CRC risk. As for ethnicity, -93G>A and 655A>G polymorphisms were associated with increased risk of CRC among Asians, but not among Caucasians. More interestingly, subgroup analysis indicated that 655A>G might raise CRC risk in PCR-RFLP and HB subgroups. CONCLUSION: Inconsistent with previous meta-analyses, this meta-analysis shows that the hMLH1 655A>G and 1151T>A polymorphisms might be risk factors for CRC. Moreover, the -93G>A polymorphism is associated with the susceptibility of CRC in Asian population. PMID- 30517245 TI - Erratum. AB - [This corrects the article doi: 10.1590/1518-8345.2378.3020]. PMID- 30517244 TI - Mourning and Takotsubo cardiomyopathy: neuroendocrine implications and nutritional management. AB - This article aims to make reference to some recent mourning aspects considered risk factors for cardiovascular disease, specifically the Takotsubo cardiomyopathy. The objective was to describe the stress from the death of a loved one combining it to the possibility of occurrence of Takotsubo cardiomyopathy through the perception of a traumatic event by the cortex, which triggers the subcortical brain circuit affecting the endocrine response. Given the growing acknowledgement of this cardiomyopathy, it is possible to contextualize the nutritional behaviours and decisions surrounding it, whose benefits must exceed the condition of temporary cardiac dysfunction and extend to food choices that have some influence in the limbic system. It is a descriptive analysis that aims to problematize the theme into reflections based on this experience, considering the foundation with the science of nutrition. PMID- 30517246 TI - A survey of freshwater and terrestrial snails in a predominantly urban municipality of Rio de Janeiro State, Brazil, with emphasis on human parasites vectors. AB - Many snail species act as intermediate hosts of helminths that transmit diseases to humans and animals, such as schistosomiasis and angiostrongyliasis. Sao Goncalo, a mostly urban municipality in Rio de Janeiro State, Brazil, has undergone fundamental environmental impacts, which favor the establishment of a range of diseases, for which snails act as the intermediate hosts of the etiological agents. In the present study, freshwater and terrestrial snail populations were surveyed in different environments within five city districts, and the presence of helminths was determined in the collected specimens. A total of 287 individuals were collected, six species from freshwater environment, Pomacea sp. (Ampullariidae), Melanoides tuberculata (Thiaridae), Biomphalaria tenagophila (Planorbidae), Dysopeas muibum (Subulinidae), Physa marmorata, and Physa acuta (Physidae), and two from terrestrial environment, Achatina fulica (Achatinidae) and Bradybaena similaris (Bradybaenidae). Snails were found in only two districts, Centro, an urban area, and Ipiiba, a rural area. Thirteen percent of the specimens of A. fulica eliminated larvae of the nematode Angiostrongylus cantonensis. None of the analyzed freshwater snails contained helminths.The most abundant and frequent snails were B. tenagophila, M. tuberculataand A. fulica, and the latter two species are exotic. The disturbance and degradation of natural areas adjacent to residential zones favor the proliferation of helminths, jeopardizing the local residents health. The abundance of A. fulica and B. tenagophila in the study area reinforces the need for a continuous and systematic monitoring of the snail fauna in this region. PMID- 30517247 TI - An alternative storage method for characterization of the intestinal microbiota through next generation sequencing. AB - Gut microbiota has been the subject of various molecular studies mainly due to its importance and wide-ranging relationships with human hosts. However, the storage of fecal samples prior to DNA extraction is critical when characterizing the composition of intestinal microbiota. Therefore, we aimed to understand the effects of different fecal storage methods to characterize intestinal microbiota using Next Generation Sequencing (NGS) as well as to establish an alternative conservation method of bacterial genetic material in these samples using guanidine. Stool samples from 10 healthy volunteers were collected. Each sample was divided into five aliquots: one aliquot was extracted immediately after collection (fresh) and two aliquots were subjected to freezing at -20 degrees C or -80 degrees C and extracted after 48 h. The other two aliquots were stored in guanidine at room temperature or 4 degrees C and extracted after 48 h. The V4 hypervariable regions of the bacterial and archeal 16S rRNA gene were amplified by PCR and sequenced using an Ion Torrent PGM platform for NGS. The data were analyzed using QIIME software. Statistical significance was determined using a non-parametric Kruskal-Wallis test. A total of 11,494,688 reads with acceptable quality were obtained. Unweighted principal coordinate analysis (PCoA) revealed that the samples were clustered based on the host rather than by the storage group. At the phylum and genus levels, we observed statistically significant differences between two genera, Proteobacteria (p=0.013) and Suterella (p=0.004), comparing frozen samples with guanidine-stored samples. Our data suggest that the use of guanidine can preserve bacterial genetic materials as well as freezing, providing additional conveniences. PMID- 30517248 TI - Biological Aortic Heart Valve Prosthesis in Patients Under 65 Years Old: Are the Paradigms Changing? PMID- 30517249 TI - Coronary Artery Bypass Grafting in Acute Ischemic Heart Failure: Where do We Stand? (And Where Should We Go?). PMID- 30517250 TI - Hydrodynamic Evaluations of Four Mock Femoral Venous Cannulas. AB - OBJECTIVE: To report the results of four mock femoral venous cannulas and the hydrodynamical superiority of one of them, which is the completely punched (CP) model, upon the other three. METHODS: Four simulated femoral venous cannulas (single-stage, two-stage, multi-stage, and CP model) were designed from a 1/4" x 1/16" x 68 cm polyvinyl chloride (PVC) tubing line for testing. Holes on the PVC tubes were opened by a 5 mm aortic punch. In order to evaluate the cannulas' drainage performance, gelofusine was used as fluid. The fluid was drained for 60 seconds by gravitation and then measured for each model separately. RESULTS: Mean drained volumes of single-stage, two-stage, and multi-stage cannulas were 2.483, 2.561, and 2.603 mL, respectively. However, the CP cannula provided us a mean drained volume of 2.988 mL. There were significant differences among the variables of the CP cannula and the other three mock cannulas concerning the drained fluid flow (P<0.01). CONCLUSION: In our study, the measured mean volumes showed us that more drainage surface area provides better fluid drainage. PMID- 30517251 TI - Mid-Term Results of Peripheral Cannulation After Robotic Cardiac Surgery. AB - INTRODUCTION: Various surgical procedures for minimally invasive cardiac surgery have been described in recent decades as alternatives to median sternotomy. Cardiopulmonary bypass via femoral arterial and venous cannulation is the foundation of these procedures. In this study, we evaluated the mid-term outcomes of femoral cannulation performed with U-suture technique in patients undergoing robotic heart surgery. METHODS: A total of 216 patients underwent robotic assisted cardiac surgery between January 2013 and April 2017. Cardiopulmonary bypass was performed via femoral artery, jugular, and femoral vein cannulation, and a Chitwood clamp was used for aortic occlusion. A total of 192 patients attended the outpatient follow-up, and femoral arterial and venous flow pattern was examined using Doppler ultrasound (DUS) in 145 patients. RESULTS: Hospital mortality occured in 4 of the 216 (1.85%) cases, but there was no late mortality in this patient group. Postoperatively, seroma (n=9, 4.69%) and cannulation site infection (n=3, 1.56%) were managed with outpatient treatment. DUS in 145 patients revealed triphasic flow pattern in the common femoral arteries in all patients except for 2 (1.38%). These patients were determined to have asymptomatic arterial stenosis. Chronic recanalized thrombus in the common femoral vein was also detected in 2 (1.38%) patients. CONCLUSION: Femoral artery cannulation with the U-suture technique can be successfully performed in robotic assisted cardiac surgery, with good mid-term results. PMID- 30517252 TI - Comparison of the Efficacy of Oral versus Intravascular Magnesium in the Prevention of Hypomagnesemia and Arrhythmia after CABG. AB - OBJECTIVE: Cardiac arrhythmias are a common challenge following open-heart surgeries. Hypomagnesemia is believed to be correlated with this condition. Prophylactic intravenous magnesium supplementation has been practiced for a long time in patients undergoing CABG. This study was designed in an attempt to compare the efficacy of oral versus intravenous routes in the prevention of hypomagnesemia and arrhythmia. METHODS: In this interventional clinical study, 82 patients were randomly assigned to 2 groups. All patients were evaluated for baseline serum magnesium level and arrhythmias. One group received 1,600 mg of oral magnesium hydroxide through nasogastric (NG) tube prior to surgery, while the other group received 2 g of magnesium sulfate during the induction of anesthesia. The serum magnesium level was monitored for 48 hours after the operation. The difference in preoperative hypomagnesemia was non-significant (Sig: 0.576). RESULTS: During the operation, the serum magnesium level peaked around 4 mg/dL, and no hypomagnesemia was detected in any patient. Although the curve of oral group declined parallel and below that of intravenous (IV) group, no significant differences were detected during postoperative monitoring. In addition, a prevalence of arrhythmia of 13.9% and 6.5% was noticed in IV and oral groups, respectively (OR: 0.428). CONCLUSION: Providing 1,600 mg of oral magnesium supplement to patients is as effective as 2,000 mg of magnesium sulfate IV in preventing hypomagnesemia and arrhythmia after CABG. Thus, the authors introduce this treatment regimen as a promising and cost-effective method. PMID- 30517253 TI - Acute Kidney Injury after Cardiac Surgery in Patients Without Chronic Kidney Disease. AB - INTRODUCTION: Among patients undergoing cardiac surgery, the occurrence of acute renal injury appears to be associated with worse prognosis and increased mortality. The objective of this study was to evaluate risk factors and the impact this complication on mortality and survival after cardiac surgery among patients without chronic kidney disease. METHODS: In this retrospective study, we reviewed the medical records of 142 patients who underwent elective coronary artery bypass grafting, valve replacement (single or multiple), or both (simultaneously) at a tertiary care hospital. RESULTS: Among the 142 patients evaluated, the mean age was 58.28+/-13.87 years and 80 (56.33%) were female. The postoperative incidence of acute renal injury was 43.66%. Univariate analysis between the groups with and without acute renal injury revealed no significant differences, whereas multivariate analysis showed that risk factors for acute renal injury included valve replacement (OR=4.7, P=0.002, 95% CI=1.76-12.62, age (OR=1.044, P=0.012, 95% CI=1.01-1.07), previous cardiac surgery (OR=36.1, P=0.015, 95% CI=1.99-653.85), postoperative use of the vasoactive drug norepinephrine (OR=3.32, P=0.013, 95% CI=1.29-8.58) and dobutamine (OR=5.3, P=0.019, 95% CI=1.32-21.64). In our sample, there were 30 deaths, of which 25 had acute kidney injury. Survival was also lower among the patients with this complication, especially those who had required hemodialysis (OR=2.60, P<0.001, 95% CI=1.01-6.70) or had previously undergone cardiac surgery (OR=3.68, P<0.001, 95% CI=1.09-12.37). CONCLUSION: Our findings underscore the importance of identifying risk factors for developing acute renal injury after cardiac surgery, which can further the development of effective renoprotective strategies. PMID- 30517254 TI - Consequence of Ischemic Stroke after Coronary Surgery with Cardiopulmonary Bypass According to Stroke Subtypes. AB - INTRODUCTION: The aim of this study was to determine the outcomes of patients developing ischemic stroke after coronary artery bypass grafting (CABG). METHODS: From March 2012 to January 2017, 5380 consecutive patients undergoing elective coronary surgery were analyzed. Ninety-five patients who developed ischemic strokes after on-pump coronary surgery were included in the study, retrospectively. The cohort was divided into four subgroups [total anterior circulation infarction (TACI), partial anterior circulation infarction (PACI), posterior circulation infarction (POCI), and lacunar infarction (LACI)] according to the Oxfordshire Community Stroke Project (OCSP) classification. The primary endpoints were in-hospital mortality, total mortality, and survival analysis over an average of 30 months of follow-up. The secondary endpoints were the extent of disability and dependency according to modified Rankin Scale (mRS). RESULTS: The incidence of stroke was 1.76% (n=95). The median age was 62.03+/-10.06 years and 68 (71.6%) patients were male. The groups were as follows: TACI (n=17, 17.9%), PACI (n=47, 49.5%), POCI (n=20, 21.1%), and LACI (n=11, 11.6%). Twenty-eight (29.5%) patients died in hospital and 34 (35.8%) deaths occurred. The overall mortality rate of the TACI group was significantly higher than that of the LACI group (64.7% vs. 27.3%, P=0.041). The mean mRS score of the TACI group was significantly higher than that of the other groups (P=0.003). CONCLUSION: Patients in the TACI group had higher in-hospital and cumulative mortality rates and higher mRS scores. We believe that use of the OCSP classification and the mRS may render it possible to predict the outcomes of stroke after coronary surgery. PMID- 30517255 TI - Hemodynamic Changes During Heart Displacement in Aorta No-Touch Off-Pump Coronary Artery Bypass Surgery: A Pilot Study. AB - OBJECTIVE: To evaluate the sequential changes of hemodynamic and metabolic parameters in patients who underwent aorta no-touch off-pump coronary artery bypass surgery (OPCAB). METHODS: Prospective study involving twenty-seven consecutive patients who underwent aorta no-touch OPCAB. The FloTrac/PreSep/VigileoTM system (Edwards Lifesciences) was used to continuously record heart rate (HR), mean arterial blood pressure (MABP), central venous pressure (CVP), continuous cardiac index (FCI), stroke volume (SV), stroke volume variation (SVV), and central venous oxygen saturation (ScvO2). The parameters were assessed 5 min before, during and 5 min after each anastomosis (left anterior descending [LAD], posterior descending [PD], obtuse marginal [OM] and diagonal [Dg]). Postoperative lactate was also evaluated. RESULTS: There was no significant change in HR and MABP for all anastomoses, except for MABP during PD grafting (-10.1+/-2.7 mmHg, P=0.03). There was a significant decrease in ScvO2 only during PD and OM anastomoses (-9.4+/-0.4, P=0.03; -4.4+/-0.4, P=0.02; respectively). CVP drop after PD manipulation was strongly associated with a higher lactate during the first hours after surgery (r=-0.82; P=0.001). These hemodynamic changes were transient and entirely recovered after the heart was returned to its anatomical position. No significant differences were observed in FCI, SVV, or the systemic vascular resistance index (SVRI) during all anastomoses, except for a drop in SVRI during PD grafting (-8.03+/-2.3, P=0.007). SV tended to decrease during the procedure in all territories, but with statistically significant drop only in PD and OM grafting (-10.4+/-1.2, P=0.02; 13.6+/-5.1, P=0.007; respectively). CONCLUSION: Heart displacement for performing aorta no-touch OPCAB is well tolerated, with transient and endurable hemodynamic variations. PMID- 30517256 TI - Quality of Life in Cardiovascular Surgery: Elaboration and Initial Internal Validation of a Quality of Life Questionnaire. AB - OBJECTIVE: Elaboration and internal validation of the Quality of Life in Cardiovascular Surgery (QLCS) questionnaire adapted to the reality of Brazilian cardiovascular surgery. METHODS: Cross-sectional pilot study of a prospective cohort included in the Documentation and Surgical Registry Center (CEDREC) for internal validation of the QLCS questionnaire. Four hundred forty-five patients submitted to cardiovascular surgery and who answered a QLCS questionnaire 30 days after hospital discharge were included. It was applied via telephone. To verify the questions' internal consistency, Cronbach's alpha was used. The total QLCS score was calculated as the sum of 5 questions, ranging from 5 to 25 points. Mann U-Whitney test was used to relate the symptoms with the quality of life (QoL). Level of significance was 5%. RESULTS: After 30 days of surgery, about 95% of the patients had already returned to normal routine and 19% of them were already performing physical activity. In the evaluation of the QLCS's internal consistency, a Cronbach's alpha of 0.74 was found, suggesting that this was probably an adequate questionnaire to evaluate QoL in this population. In the comparison between the presence and absence of symptoms and the median of QoL, the presence of pain at the incision (P=0.002), chest pain (P<0.001), shortness of breath (P<0.001), and return to physical activity (P<0.001) were statistically significant. CONCLUSION: The process of elaboration and validation of questionnaires includes a series of steps. The QLCS questionnaire is probably an adequate tool for the evaluation of QoL in the postoperative patient of cardiovascular surgery, in this first stage of internal validation. PMID- 30517257 TI - Combined Off-Pump Coronary Artery Bypass Grafting and Lung Resection in Patients with Lung Cancer Accompanied by Coronary Artery Disease. AB - INTRODUCTION: Optimal surgical approach for the treatment of resectable lung cancer accompanied by coronary artery disease (CAD) remains a contentious issue. In this study, we present our cases that were operated simultaneously for concurrent lung cancer and CAD. METHODS: Simultaneous off-pump coronary artery bypass surgery (OPCABG) and lung resection were performed on 10 patients in our clinic due to lung cancer accompanied by CAD. Demographic features of patients, operation data and postoperative results were evaluated retrospectively. RESULTS: Mean patient age was 63.3 years (range 55-74). All patients were male. Six cases of squamous cell carcinoma, three of adenocarcinoma and one case of large cell carcinoma were diagnosed. Six patients had single-vessel CAD and 4 had two-vessel CAD. Three patients underwent OPCABG at first and then lung resection. The types of resections were one right pneumonectomy, three right upper lobectomies, one right lower lobectomy, three left upper lobectomies, and two left lower lobectomies. Reoperation was performed in one patient due to hemorrhage. One patient developed intraoperative contralateral tension pneumothorax. One patient died due to acute respiratory distress syndrome at the early postoperative period. CONCLUSION: Simultaneous surgery is a safe and reliable option in the treatment of selected patients with concurrent CAD and operable lung cancer. PMID- 30517258 TI - Use of 3D Printing in Preoperative Planning and Training for Aortic Endovascular Repair and Aortic Valve Disease. AB - INTRODUCTION: Three-dimensional (3D) printing has become an affordable tool for assisting heart surgeons in the aorta endovascular field, both in surgical planning, education and training of residents and students. This technique permits the construction of physical prototypes from conventional medical images by converting the anatomical information into computer aided design (CAD) files. OBJECTIVE: To present the 3D printing feature on developing prototypes leading to improved aortic endovascular surgical planning, as well as transcatheter aortic valve implantation, and mainly enabling training of the surgical procedure to be performed on patient's specific condition. METHODS: Six 3D printed real scale prototypes were built representing different aortic diseases, taken from real patients, to simulate the correction of the disease with endoprosthesis deployment. RESULTS: In the hybrid room, the 3D prototypes were examined under fluoroscopy, making it possible to obtain images that clearly delimited the walls of the aorta and its details. The endovascular simulation was then able to be performed, by correctly positioning the endoprosthesis, followed by its deployment. CONCLUSION: The 3D printing allowed the construction of aortic diseases realistic prototypes, offering a 3D view from the two-dimensional image of computed tomography (CT) angiography, allowing better surgical planning and surgeon training in the specific case beforehand. PMID- 30517259 TI - Comparison of del Nido Cardioplegia with Blood Cardioplegia in Coronary Artery Bypass Grafting Combined with Mitral Valve Replacement. AB - OBJECTIVE: To compare del Nido cardioplegia (DNC) with blood cardioplegia (BC) in coronary artery bypass grafting (CABG) combined with mitral valve replacement. METHODS: A 3-year single-center retrospective cohort study was carried out. Subjects who underwent CABG (up to triple bypass) combined with mitral valve replacement were divided into DNC and BC groups. Each group had thirty subjects. RESULTS: Both groups demonstrated similar baseline characteristics, including age, gender, cardiac/non-cardiac comorbidity, and preoperative echocardiographic parameters. Compared with the BC group, the DNC group demonstrated significantly lower cardioplegia volume (BC = 1130.00+/-194.1 mL, DNC = 884.33+/-156.8 mL, P=0.001), cardiopulmonary bypass time (DNC = 110.90+/-12.52 min, BC = 121.70+/ 13.57 min, P=0.002), aortic clamp time (DNC = 91.37+/-11.58 min, BC = 101.37+/ 13.87 min, P=0.004), and need for intraoperative defibrillation (DNC = 6 events, BC = 21 events, P=0.001). Postoperative creatine kinase-MB levels and troponin levels were significantly lower in the DNC group than in the BC group. Postoperative haemoglobin and haematocrit levels were significantly higher in the DNC group than in the BC group. The intubation period (hours) in intensive care unit (ICU) was significantly small in the BC group (DNC = 8.13+/-12.21, BC = 6.82+/-1.57, P=0.037); however, ICU stay, total hospital stay, and postoperative complication rates were not significantly different between them. At pre discharge echocardiography, the DNC group demonstrated significantly higher ejection fraction rates than the BC group (47.79+/-5.50 and 45.72+/-5.86, respectively, P=0.005). CONCLUSION: DNC presented better intraoperative and postoperative parameters and it is an effective and safe alternative to BC for CABG combined with mitral valve replacement. PMID- 30517260 TI - When is the Best Time for Corrective Surgery in Patients with Tetralogy of Fallot between 0 and 12 Months of Age? AB - OBJECTIVE: To identify the best time for corrective surgery of tetralogy of Fallot (TF) in children aged 0-12 months and to report the most frequent complications during the first 3 years postoperatively. METHODS: Systematic review of studies published between 2000 and 2017 on corrective surgery for TF. Articles were selected through search of electronic databases (PubMed, SciELO, Scopus, Lilacs, Google Scholar, and Cochrane). Length of stay in intensive care unit, duration of mechanical ventilation, and peri/postoperative complications were analyzed for data discussion and research interpretation. CONCLUSION: Definitive corrective surgery is the best alternative, and the earlier it is performed, the lower the occurrence of harmful effects and the greater the chances of cardiorespiratory recovery. This systematic review suggests that the best time to perform definitive corrective surgery for TF in the first year of life is during 3-6 months of age in children with no or mild symptoms. Children with severe symptoms should undergo surgery immediately. PMID- 30517262 TI - Ruptured Abdominal Aortic Aneurysm with a Suprarenal Tumor. AB - This paper presents a case study of a patient that underwent surgery for a ruptured abdominal aneurysm. The postoperative course was complicated by resistant hypertension and tachycardia. A suprarenal mass was detected in the computed tomography scan with radiological suspicion of pheochromocytoma. Few cases of pheochromocytoma coexisting with aneurysms have been reported. Management of cardiovascular stability is crucial in such cases. Despite the lack of evidence, pheochromocytomas might have a role in the etiology of aortic aneurysms. PMID- 30517261 TI - Updated Meta-analysis on the Closure of Patent Foramen Ovale in Reduction of Stroke Rates: the DEFENSE-PFO Trial Does not Change the Scenario. AB - OBJECTIVE: We aimed to analyze whether patent foramen ovale (PFO) closure reduces the risk of stroke, assessing also some safety outcomes after the publication of a new trial. INTRODUCTION: The clinical benefit of closing a PFO has been an open question, so it is necessary to review the current state of published medical data in regards to this subject. METHODS: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were used to search for randomized controlled trials (RCTs) that reported any of the following outcomes: stroke, death, major bleeding or atrial fibrillation. Six studies fulfilled our eligibility criteria and included 3560 patients (1889 for PFO closure and 1671 for medical therapy. RESULTS: The risk ration (RR) for stroke in the "closure" group compared with the "medical therapy" showed a statistically significant difference between the groups, favouring the "closure" group (RR 0.366; 95%CI 0.171-0.782, P=0.010). There was no statistically significant difference between the groups regarding the safety outcomes, death and major bleeding, but we observed an increase in the risk of atrial fibrillation in the "closure" group (RR 4.131; 95%CI 2.293-7.443, P<0.001). We also observed that the larger the proportion of effective closure, the lower the risk of stroke. CONCLUSION: This meta-analysis found that stroke rates are lower with percutaneously implanted device closure than with medical therapy alone, being these rates modulated by the rates of hypertension, atrial septal aneurysm and effective closure. The publication of a new trial did not change the scenario in the medical literature. PMID- 30517263 TI - Primary Cardiac Angiosarcoma with Rare Presenting Feature and Successful Surgical Treatment. AB - Primary angiosarcoma is a rare clinical entity, it's typically located within the right atrium and known to be rapidly fatal. A 37-year-old female was presented with a history of recurrent facial paralysis and left hemiparesis. A cranial mass was identified at cranial magnetic resonance imaging and she underwent neurosurgery operation. The immunohistochemical examination was determined as metastatic cardiac angiosarcoma. The tumor, as well as part of the right pericardium, were resected. A piece of bovine pericardium was used to reconstruct the right atrial wall. Tricuspid valve was reconstructed with ring annuloplasty. Due to resection of right coronary artery with the tumor, coronary bypass surgery was performed successfully. The patient is currently healthful without any recurrence and complaint 12 months after the diagnosis as followed up. PMID- 30517264 TI - Lobectomy with ECMO Support in an Infant Who Developed Pulmonary Interstitial Emphysema Following Repair of Hypoplastic Aortic Arch. AB - Pulmonary interstitial emphysema (PIE) is a common problem in premature neonates with respiratory distress syndrome. This condition is often related to barotrauma caused by mechanical ventilation or continuous positive airway pressure applied to low birth weight neonates. The clinical diagnosis can be challenging. However, after proper diagnosis, several interventions are available for successful management. We describe an infant who developed severe PIE with recurrent pneumothoraces and development of a persistent bronchopleural fistula shortly after repair of a hypoplastic aortic arch and description of successful lobectomy with the assistance of extracorporeal support (ECMO). PMID- 30517265 TI - Red wine consumption, coronary calcification, and long-term clinical evolution. AB - Coronary artery calcification (CAC) is associated with atherosclerotic complications. However, elevated CAC may not always imply a worse prognosis. Herein, we report the clinical evolution of long-term red wine (RW) drinkers in relation to CAC. We followed 200 healthy male habitual RW drinkers and compared them to 154 abstainers for a period of 5.5 years. The initial evaluation included coronary computed tomography angiography (CTA), clinical, demographics, and laboratory data. CAC was quantified by the Agatston score. The follow-up process was conducted by telephone calls and/or hospital record review. The composite end point of total death, acute myocardial infarction (AMI), or coronary revascularization (or major adverse cardiac event - MACE) was assessed. The RW drinkers ingested 28.9+/-15 g of alcohol/day for 23.4+/-12.3 years. They had higher high-density lipoprotein and low-density lipoprotein, but lower C-reactive protein than abstainers. Age, total cholesterol, triglycerides, glucose, and liver enzymes were similar. History of diabetes was lower among drinkers, but other risk factors were similar. However, drinkers had higher CAC than abstainers; the mean value was 131.5+/-362 in drinkers vs 40.5+/-320 in abstainers (P<0.001). The median and interquartile range were 15 (0.0-131.5) in RW drinkers and 1 (0.0-40.5) in abstainers (P=0.003). During the follow-up, MACE was significantly lower in drinkers than in abstainers, despite their higher CAC. The difference was driven mainly by AMI (0 vs 6; P<0.03). Greater CAC values in this setting did not predict worse prognosis. A possible underlying mechanism is lesion calcification, which leads to plaque stabilization and less clinical events. PMID- 30517266 TI - Pseudowords to the Phonological Therapy: a new therapeutic approach. AB - The pseudowords are a resource rarely used in clinical practice, but may be an excellent option for phonological therapy. This study aimed to verify the therapeutic progress of children with phonological disorder, treated from a new therapeutic approach, considering the favorable linguistic environment in pseudowords and words. The sample consisted of three children, aged between 4 and 8 years old, who submitted to a new therapeutic approach to phonological basis. The children were treated with different targets involving pseudowords and real words in favorable and neutral linguistic environments. In the results, it can be observed that the therapy involving favorable linguistic environment the best results when compared to realize in neutral environment. Regarding the target words, subject treated simultaneously with pseudowords and real words presented satisfactory results, indicating that the targets were appropriate to therapy. The new therapeutic approach involving pseudowords and real words in favorable environments proved to be effective for the treatment of phonological disorders. PMID- 30517267 TI - Association of facial massage, dry needling, and laser therapy in Temporomandibular Disorder: case report. AB - This case report aims to evaluate the treatment of Temporomandibular Disorder (TMD) of muscular origin by associating facial massage (FM), dry needling (DN), and low-level laser therapy (LLLT). The pre- and post-treatment evaluations consisted of clinical examinations based on the Research Diagnostic Criteria (RDC) for TMD, pain intensity quantification by means of the Visual Analog Scale (VAS), mandibular movement measurement, and electromyographic (EMG) analysis of the masseter and temporal muscles. Post-therapy assessment indicated a decrease in pain sites of 58%, in pain intensity mean (1.3), and an increase in the maximum aperture of 10 mm, in addition to normalization of EMG signals. We conclude that, after application of the treatment protocol, there was a decrease in painful sites, gain in amplitude of mandibular movements, and normalization of EMG activity. PMID- 30517268 TI - Effects of cochlear implantation on adulthood. AB - PURPOSE: To understand the benefits of cochlear implantation in adulthood under the perspective of users. METHODS: Qualitative study using Symbolic Interactionism and Straussian Grounded Theory as theoretical and methodological frameworks, respectively. The project was approved by the Research Ethics Committee of the aforementioned Institution (Opinion no. 482,019). Sixteen adult cochlear implant (CI) users aged 28-58 years participated in the study. The data collection instrument was a semi-structured interview with questions about changes caused by CI in the social relations, communication, family system, and personal, academic and professional spheres of life of users. RESULTS: The category Cochlear Implant Effects on Adulthood is part of a more comprehensive theoretical study that addresses how adult CI users cope with deafness. Together with its subcategories, it shows that CI intervenes in a revolutionary way in the lives of its users, because it increases their sense of security, enables them to see life from a new perspective, rescues self-confidence and self-esteem, enables them to communicate and interact more effectively, enjoy music and other entertainment, rescue old projects, and make plans for the future; thus assisting with the process of recovering independence in adult life. CONCLUSION: Subjective impressions of the users showed that cochlear implants not only improve their auditory performance, but also bring several positive changes to their social insertion and quality of life. Therefore, this intervention is highly beneficial to deaf adults. PMID- 30517269 TI - Identification of swallowing disorders: the perception of patients with neurodegenerative diseases. AB - PURPOSE: To verify the perception of patients with neurodegenerative diseases regarding swallowing changes and to know the perceptions of swallowing sensations that can promote the early identification of dysphagia. METHODS: It is a cross sectional study with 44 patients with neurodegenerative diseases. All of them answered a questionnaire to know the sensation perceived during swallowing and its intensity. The Fatigue Severity Scale was applied to measure fatigue and the Swallowing Disturbance Questionnaire was applied to detect swallowing complaints. The Functional Oral Intake Scale was used to classify the swallowing functionality. Videofluoroscopic swallowing study (VFSS) was performed to verify the correspondence between the patient's perceptions and swallowing physiopathology. A descriptive and exploratory statistical analysis was performed. RESULTS: There was correspondence between VFSS findings and the patient's perception in 76.5% of the cases. Sensations such as discomfort and fatigue were perceived during swallowing, especially with solids. Such feelings have predominantly been reported in the throat, from the half to the end of the meal. There was association between fatigue and odynophagia. Fatigue during swallowing was associated with worse functionality of oral intake. CONCLUSION: Most participants perceived the disorders in their swallowing. Sensations such as burning, discomfort, tiredness, pain, cramp, or irritation were perceived by participants and were associated with symptoms that may suggest risk of aspiration due to fatigue resulting from weakness, incoordination, and/or stiffness of muscles. PMID- 30517270 TI - Surface electromyographic biofeedback for behavioral dysphonia in adult people: a systematic review. AB - PURPOSE: To review systematically the literature and to analyze the effectiveness of surface electromyographic biofeedback in the rehabilitation of adults with behavioral dysphonia. RESEARCH STRATEGIES: Two authors performed an independent search in the following databases: Clinical Trials, Cochrane Library, Embase, LILACS, PubMed, and Web of Science. A specific search strategy was developed for each database. SELECTION CRITERIA: The review included studies that examined the effectiveness of surface electromyographic biofeedback compared to other direct vocal therapy intervention in adults with behavioral dysphonia. There were no restrictions in regard to language or date of publication. DATA ANALYSIS: Analysis of the risk of bias, heterogeneity, quantitative and qualitative data, sensitivity, subgroups, and publication bias. RESULTS: 51 studies were identified, but only two cohort studies remained as prospects for analysis. The studies showed 100% uncertain risk of selection, performance, and detection bias. There was a high degree of clinical heterogeneity. The descriptive analysis showed a reduction in muscle electrical activity and improvement in vocal self assessment using electromyographic biofeedback; however, it was not possible to calculate the effect size of the interventions. The present study was limited by the fact that it was unable to show a consensus for the majority of data analyzed. CONCLUSION: The available literature does not support a conclusive finding about the effectiveness of surface electromyographic biofeedback compared to other direct interventions used in the rehabilitation of adults with behavioral dysphonia. The studies analyzed vary widely in their clinical procedures and methodology, making it impossible to determine the procedure's effectiveness. PMID- 30517271 TI - Relation among the knowledge of teachers about hearing loss degree, technological devices and communication strategies. AB - PURPOSE: To analyze the relations among the knowledge of teachers about hearing loss degree, technological devices, hearing aids (HA), cochlear implant (CI), frequency modulation system (FM), and communication strategies. METHODS: Forty two (42) teachers that taught students with hearing impairment participated in this study. This sample included 24 middle school teachers, 11 elementary school teachers, and 7 preschool teachers, whose taught in the second semester of the school year and in the first semester of the following year. The data was obtained through the Knowledge and Experience Questionnaire developed by Delgado Pinheiro & Omote (2010). The questionnaire answers were categorized, and the frequency of occurrence was analyzed. Statistical analysis was performed using the chi-square test. RESULTS: There was a statistically significant difference between the answers which showed that the teachers do not know about the degree of hearing loss, but they modify the communication strategies to keep the attention of the students. In addition, the results also showed that teachers do not know the technological devices and communication strategies most appropriate for the student with hearing impairment. CONCLUSION: The results showed that teachers do not have sufficient knowledge about hearing impairment and as a result they modify their communication strategies for the student, even though they are unaware of the most appropriate communication strategies. PMID- 30517272 TI - A mapping of the Speech Language Pathology practice pathway in verbal expressivity in the work of communicative competence. AB - PURPOSE: Present a mapping of the Speech-language Pathology (SLP) practice pathway in verbal expressivity in the work of communicative competence. METHODS: Study participants were 40 volunteer speech-language pathologists with extensive experience in the area of voice. They responded to questions about duration of work, number of participants, evaluation instruments, and training of the speech language pathologists who work in this area. They discussed specific issues related to the strategies of expressivity proposed and the vocal resources, exercises and terminology used. RESULTS: The group agreed that communicative competence work is practical, conducted with small groups and preferably guided by a voice specialist. Expressivity exercises comprise a large part of the work and aim to promote communication consistent with the context and intention of discourse. Oral reading of texts with different emotions, simulations, and exercises of connected speech were mentioned as frequently-used strategies. Some points to be considered are associated with duration of communicative competence work, teaching-learning and andragogy issues involved in this process, and use of specific terminology in this area. CONCLUSION: Further discussions involving such aspects seem to be fundamental for the systematic organization of information on the theme. PMID- 30517273 TI - Evaluation of the sensitivity of the Psychosocial Scale of Facial Appearance in peripheral facial paralysis. AB - PURPOSE: To investigate the sensitivity and internal consistency of the Psychosocial Scale of Facial Appearance (PSFA) based on the comparison between its results and those from other facial functional assessment instruments: House Brackmann scale (HBS) and Facial Grading System - and the psychosocial implications measured by the Hospital Anxiety and Depression Scale (HADS). METHODS: The study was approved by the Research Ethics Committee of the aforementioned Institution under protocols no. 196.977 and 230.982. Thirty-eight adult individuals with Peripheral Facial Palsy (PFP) were submitted to closed interviews in order to evaluate the sensitivity of the questionnaire. Statistical analyses were conducted for each stage of this study. Data were entered in Excel(r) spreadsheet and analyzed using SPSS 17.0 and AMOS 22.0 for Windows(r). RESULTS: Study participants were 38 individuals with PFP aged 19-78 years with predominance of idiopathic paralysis (44.7%). Results of the Cronbach's Alpha coefficient showed strong internal consistency between the thematic groups and the questions; however, Confirmatory Factor Analysis indicated some questions with week causal relationship between thematic groups, namely, questions 5 and 6 of the group Functional Aspects of Face, question 17 of the group Social Aspects, and question 23 of the group Emotional Aspects. CONCLUSION: This study provided the first steps for the subsidy and support of an instrument designed to investigate the psychosocial aspects associated with PFP, enabling the preparation of questions and their organization into thematic groups. However, further studies are needed to conclude the validation processes. PMID- 30517274 TI - Impact of autocorrelation in the time analysis of HIV mortality coefficients in Brazil. PMID- 30517275 TI - Reply to comment on the article "HIV/AIDS Mortality in Brazil, 2000-2015: Are there reasons for concern? PMID- 30517276 TI - Protists and other organisms on a minute snail periostracum. AB - Since the foundation of the Malacological Center in 1980, Universidad Centro Americana (UCA), Managua-Nicaragua, has been monitoring and collecting the marine, terrestrial, fluvial and lake mollusk population of the country. Many specimens have been photographed by Scanning Electronic Microscope (SEM), and in one of these, observation of the hairy periostracum reveals a seemingly thriving population of minute protists in possible symbiosis with their host. Adequate magnification and comparison with previous studies allowed the determination of these hosts as diatoms, testaceous amoebae, yeast, phacus, spores and other undetermined organisms which occur in tropical forests on rocks, trees and leaves. Here illustrated are diatoms and other organisms detected for the first time on the periostracum of a tropical rainforest mollusk. PMID- 30517277 TI - Laparoscopic splenectomy: a new approach. AB - OBJECTIVES: To introduce a new laparoscopic splenectomy (LS) approach. METHODS: Sixteen patients underwent LS with general anaesthesia and carbon dioxide pneumoperitoneum. The details of the surgery are as follows: 1. The omentum was incised along the greater curvature and retracted as much as possible to expose the pancreatic body and tail. 2. The right arteriovenous root in the gastric omentum was ligated to sufficiently expose the pancreatic body and tail. 3. The pancreatic capsula was opened along the inferior margin of the pancreatic tail, elevated and separated until the superior margin of the pancreas was grasped. The entire splenic pedicle was retracted using a string. The branching blood vessels in the splenic hilus were ligated using clamps and separated. The splenogastric and splenophrenic ligaments were transected proximally using an ultrasonic knife, and the thick short gastric blood vessels were clamped. This procedure allows complete exposure of the area above the pancreatic tail where the splenic hilus is located. The splenoportal vasculature was suspended using a 7-0 silk suture to easily manipulate this tissue. The splenic portal vessels were dissected using an ultrasonic knife, and the portal vessels were isolated individually using vascular clamps and transected. The splenogastric and lienorenal ligaments were also transected. The spleen was then placed into a bag, and the surgical port was slightly enlarged. Finally, the spleen was sectioned for removal. RESULTS: Fifteen surgeries were successfully performed from March 2015 to January 2016. One patient underwent laparotomy. No patients developed postoperative intra abdominal haemorrhage or infection. One patient developed subcutaneous emphysema, and one developed a wound infection. No deaths occurred. CONCLUSIONS: Active exposure of the area dorsal to the pancreatic tail is a safe and simple splenectomy method. PMID- 30517278 TI - Transcatheter Closure of Perimembranous Ventricular Septal Defects in Children using a Wire-Drifting Technique. AB - OBJECTIVE: Explore the feasibility and safety of transcatheter closure of perimembranous ventricular septal defects using a wire-drifting technique (WT) in children. METHODS: We retrospectively analyzed 121 pediatric patients diagnosed with perimembranous ventricular septal defects who underwent interventional treatment at the First Affiliated Hospital of Xi'an Jiaotong University from Dec 2011 to Dec 2014. Based on the method used for arteriovenous loop establishment during the procedure, the patients were divided into a conventional technique (CT) group and a WT group. RESULTS: In total, 51 of the 53 patients (96.2%) in the CT group and 66 of the 68 patients (97.1%) in the WT group achieved procedural success, with no significant difference between the two groups (p>0.05). The CT group showed a nonsignificantly higher one-time success rate of arteriovenous loop establishment (94.3% vs. 91.2%, p>0.05). The procedure time was 46.0 (14.0) min and 46.5 (10.0) min in the CT and WT groups, respectively. The CT procedure was discontinued in the 2 cases (3.8%) of intraprocedural atrioventricular block in the CT group. In the one case (1.9%) of postprocedural atrioventricular block in the CT group, a permanent pacemaker was implanted to resolve third-degree atrioventricular block three months after the procedure. In the WT group, no cases of intraprocedural atrioventricular block occurred, and one case (1.5%) of postprocedural atrioventricular block occurred. In this case, intravenous dexamethasone injection for three days returned the sinus rhythm to normal. Aggravated mild to moderate tricuspid regurgitation was observed in 2 patients (3.8%) in the CT group during the 2-year follow-up period; aggravated tricuspid regurgitation was not observed in the WT group. During the 2-year follow-up period, there was no evidence of residual shunting in either group. CONCLUSION: Transcatheter closure of perimembranous ventricular septal defects with the WT is safe and effective in children. PMID- 30517279 TI - Ongoing maturation in the time-compressed speech test. AB - OBJECTIVES: To verify the neuromaturational influence in the ability of auditory closure, that is, to verify the performance of children and young adults in the ability of auditory closure, through the time compressed speech test (TCS). METHODS: Thirty children (8 to 10 years old) and 30 young adults (16 to 24 years old) with normal hearing without complaints (neurological, cognitive, auditory processing) who performed TFC (monosyllables and disyllables) with a compression ratio of 60% in both ears. Statistical analysis was performed using analysis of variance (ANOVA) and ANOVA with repeated measures with a significance level of 0.05. The minimum statistical power was 80%. RESULTS: In the comparison between ears, there was no significant difference between groups for the monosyllables. For disyllables, the second ear tested was better in children, and the right ear was better than the left ear for young adults. In the comparison between modalities (monosyllables and disyllables), children did not show significant differences. The performance of the young adults was better in the disyllables in both ears. Comparing the age groups, the young adults were better than the children for both modalities and ears. CONCLUSION: The study has demonstrated the influence and impact of age (maturational factor) on TCS test performance, showing the importance of establishing normality patterns for various age groups to provide a standardized tool for evaluation of auditory closure ability. PMID- 30517280 TI - Preanalytical conditions can interfere with M. tuberculosis detection by PCR in respiratory samples. AB - OBJECTIVES: Tuberculosis is one of the most prevalent infections in humans. Although culture is the reference for diagnosis, its sensitivity is compromised, especially in paucibacillary samples. Because polymerase chain reaction (PCR) amplifies mycobacterial DNA, it is more sensitive than culture for the diagnosis of Mycobacterium tuberculosis (Mtb). However, its performance can be affected by intrinsic sample inhibitors and by the extraction/detection techniques used. METHODS: We evaluated the influence of preanalytical conditions on Mtb detection in samples of sputum (SPU), bronchoalveolar lavage (BAL), and pleural fluid (PF) using combinations of extraction/detection methods. Respiratory samples were prepared to contain different concentrations of red blood cells and nucleated cells to which increasing amounts of Mtb colonies were inoculated and submitted to PCR. RESULTS: Up to 102 CFU/ml of Mtb were detected in the SPU in all methods, except for the Roche extraction/detection method, regardless of the preanalytical sample condition. In BAL samples, medium and high concentrations of cells and high concentrations of red blood cells contributed to a lower Mtb detection, regardless of the extraction method used. In PF, red blood cells were the variable that most interfered with Mtb detection, with better recovery (102 CFU/ml) observed with the Qiagen/Nanogen combination. CONCLUSION: The choice of Mtb extraction and detection method is of fundamental importance for PCR analytical sensitivity, especially when paucibacillary samples and/or samples containing potential PCR inhibitors are analyzed. PMID- 30517281 TI - Relationship between food perceptions and health-related quality of life in a prospective study with breast cancer patients undergoing chemotherapy. AB - OBJECTIVE: To correlate the perceptions related to dietary intake with the domains and subscales of health-related quality of life (HRQL) in women with breast neoplasms receiving chemotherapy. METHODS: In this prospective study, 55 women with breast cancer were followed up during chemotherapy at three different times (T0, T1, T2). Before chemotherapy, perceptions related to food consumption were evaluated. HRQL was analyzed with the EORTC QLQ-C30 and Br23 instruments 21 days after each investigated cycle. The differences (T2-T0) in the subscales and HRQL domains were correlated with the differences (T2-T0) in the appetite scores. Spearman's correlation was used to verify a possible correlation between differences in functional and overall HRQL domains (T2-T0) and differences in appetite scores for certain foods and between the differences in some subscales of EORTC QLQ-C30 and Br23 (T2-T0) and differences in appetite scores for certain food groups (T2-T0). RESULTS: Correlations between pain and appetite for bitter taste and between an increased appetite for juices and pain intensification or fatigue were identified, and pain was correlated with an appetite for starchy foods. An appetite for vegetables, legumes and meat/eggs was correlated with physical function. The only significant correlation with social functions occurred between the appetite for sweet foods and these functions. We found a correlation between overall health, emotional function, social function and physical function and the appetite for juices. CONCLUSION: Chemotherapy alters the individual's relationship with food and, consequently, the individual's HRQL. PMID- 30517282 TI - Prevalence of overweight and obesity and associated factors in school children and adolescents in a medium-sized Brazilian city. AB - OBJECTIVES: The objective of this study was to describe the prevalence of overweight and obesity in school children and adolescents in a medium-sized Brazilian city. METHODS: In total, 1,125 children and adolescents between the ages of 5.6 and 18 years from public and private schools participated in the study. The sample included 681 girls and 444 boys. Each subject's weight and height were obtained according to Brazilian guidelines (SISVAN). The triceps (TSF), subscapular (SSF), biceps, suprailiac, femoral and calf skinfolds were measured in triplicate. Body mass index (BMI) was classified as the BMI percentile (BMIP) according to the World Health Organization (WHO) 2007 criteria. The percentage body fat (%BF) was obtained using the equations by Slaughter et al., 1998. Categorical variables were analyzed using the chi-squared test. RESULTS: Overall, 364 participants with excess weight were identified: 17.3% were overweight, and 15.0% were obese. Among the girls, 18.0% were overweight, and 12.5% were obese; among the boys, 15.3% were overweight, and 18.0% were obese. These prevalence rates were higher when the time spent watching TV or participating in media-related activities surpassed 5 hrs/day, when individuals belonged to a higher economic class and when the head of the family had a higher education level (>=12 years). CONCLUSION: It is important to emphasize the need to increase our understanding of factors associated with overweight and obesity, and it is essential to implement measures and policies aimed at reversing this trend, such as stimulating healthy eating habits and physical activity and reducing time spent watching TV and participating in other media activities, including video games and social networking. PMID- 30517283 TI - Influence of dental occlusion on the athletic performance of young elite rowers: a pilot study. AB - OBJECTIVES: The present study aimed to assess the influence of dental occlusion on body posture and the competitive performance of young elite rowers. METHOD: Dental occlusion disturbance devices were used to simulate dental malocclusions. We assessed the influence of malocclusion on the body balance, paravertebral muscle contraction symmetry, and muscular power of young elite rowers. A nonparametric permutation test for repeated measures ANOVA, a Cochran's Q test for paired data and a paired Student's t-test were used in order to statistically evaluate the influence of artificial occlusal disturbance on each factor. A force platform and a Dyno Concept 2 machine were used as measuring instruments. RESULTS: A total of 7 members of the "Pole France Aviron" (age range of 15-17 years) were enrolled in the study. None of the body balance parameters was significantly influenced by the artificial occlusal disturbance. The interposition of an occlusal silicone splint significantly increased the proportion of athletes presenting asymmetric muscular contractions from 14.3% to 85.7% (p=0.025) and induced a significant 17.7% decrease in the athletes' muscular power (p=0.030). CONCLUSIONS: This study shows the negative impacts of an occlusal disturbance on the athletic performance of young elite rowers. The detection of malocclusion traits by regular occlusal monitoring would be of great interest in this population. PMID- 30517285 TI - The diagnosis and treatment of tibial intercondylar chondroblastoma. AB - OBJECTIVES: To investigate the diagnosis and treatment of tibial intercondylar chondroblastoma. METHODS: We retrospectively analyzed the diagnosis and treatment of 12 patients with tibial intercondylar chondroblastoma admitted to the orthopedics department from May 2011 to February 2016; among them were 4 males and 3 females aged 10-19 years, with an average age of 15.7 years. Tibial intercondylar chondroblastoma was on the left and right side in 7 and 5 cases, respectively. The preoperative average Lysholm score of the knee joint was 68 (42 87). A posteromedial approach was applied in all cases. The incisions were approximately 5-8 cm in length. Complete curettage and inactivation were performed after fenestration, and allogeneic bone grafts were transplanted. Then, the posterior cruciate ligament insertion was fixed with 5.0 suture anchors. All patients were followed up with regularly to monitor for tumor recurrence, observe bone graft healing, and reassess the Lysholm score of the knee. RESULTS: Patients were followed for 7-55 months, and the median follow-up time was 19 months. One patient experienced tumor relapse 4 months after the operation. Incision, inactivation and cementation were performed. Then, the bone was fixed with anchors. In the other 11 patients, the bone graft healed over an average period of 6.2 months (4-10 months), with good functional recovery postoperatively. The average postoperative Lysholm score of the knee was 91 (81-95). CONCLUSION: Tibial intercondylar chondroblastoma has unique clinical and imaging characteristics and can effectively be treated by curettage followed by the inactivation, transplantation and fixation of allogeneic bone grafts with suture anchors through a posteromedial approach. PMID- 30517284 TI - Instruments for augmentative and alternative communication for children with autism spectrum disorder: a systematic review. AB - New technologies designed to improve the communication of autistic children can also help to promote interaction processes and cognitive and social development. The aim of this study was to analyze the instruments used to improve the communication skills of children with autism spectrum disorder. We searched the PubMed and Web of Science databases using the descriptors "autism", "Asperger", "education", "children" and "assistive technology" and selected articles that met the following inclusion criteria: (i) original research; (ii) written in English; (iii) based on participants with a primary diagnosis of autism spectrum disorder; and (iv) tested an instrument designed to promote communication in children with autism spectrum disorder. Our search retrieved 811 articles, of which 34 met the inclusion criteria. Data on 26 instruments were extracted, and the measurement properties of the instruments were combined with information about their outcomes and presentation. The most commonly used interventions were the Treatment and Education of Autistic and Related Communication Handicapped Children program and the Picture Exchange Communication System. The Treatment and Education of Autistic and Related Communication Handicapped Children program was shown to produce improvements in the communication skills, socialization and self-care skills of children with autism spectrum disorder. The Picture Exchange Communication System produced inconsistent results. The results of the identified studies confirm the significant importance of these instruments in improving the communicative process of autistic children. PMID- 30517286 TI - Proposal for a New Histological Scoring System for Cartilage Repair. AB - OBJECTIVE: This study aimed to develop a new histological scoring system for use in a partial-thickness cartilage repair animal model. Although previous papers have investigated the regeneration of articular cartilage, the good results achieved in small animals have not been replicated in large animal models or humans, possibly because of the frequent use of models with perforation of the subchondral bone plates. Partial-thickness lesions spare the subchondral bone, and this pattern is the most frequent in humans; therefore, new therapies should be tested using this model. However, no specific histological score exists to evaluate partial-thickness model results. METHODS: Histological sections from 30 ovine knees were reviewed to develop a new scoring system. The sections were subjected to H&E, Safranin O, and Masson's trichrome staining. RESULTS: This paper describes a new scoring tool that is divided into sections in detail: repair of tissue inside the lesion, cartilage around the lesion and degenerative changes at the base of the lesion. Scores range from 0 to 21; a higher score indicates better cartilage repair. DISCUSSION: Unlike existing tools, this new scale does not assign points for the positioning of a tidemark; we propose evaluation of the degenerative changes to the subchondral bone and calcified cartilage layer. It is necessary to remove the whole joint to access and study the evolution of the lesion as well as the surrounding tissue. CONCLUSION: This article emphasizes the importance of a partial-thickness animal model of cartilage repair and presents a new histological scoring system. PMID- 30517287 TI - Anti-ophidian activity of Bredemeyera floribunda Willd. (Polygalaceae) root extract on the local effects induced by Bothrops jararacussu venom. AB - Bredemeyera floribunda roots are popularly used to treat snakebites in the semiarid region of Northeast Brazil, and previous studies indicate the anti ophidian actions of triterpenoid saponins found in its roots. To assess B. floribunda root extract (BFRE) activity against the effects of Bothrops jararacussu venom (BjuV), antiphospholipasic, antiproteolytic, antihemorrhagic, antinecrotic, and anti-edematogenic activities were investigated in mice. Phytochemical analysis revealed the presence of saponins, flavonoids, and sugars, with rutin and saccharose being the major constituents of BFRE. Acute toxicity was determined and BFRE was nontoxic to mice. Phospholipase A2 and proteolytic activities induced by BjuV were inhibited in vitro by BFRE at all concentrations tested herein. BFRE (150 mg/kg) inhibited paw edema induced by BjuV (50 ug/animal), reducing total edema calculated by area under the curve, but carrageenan-induced paw edema was unchanged. Hemorrhagic and necrotizing actions of BjuV (50 ug/animal) were considerably decreased by BFRE treatment. Thus, BFRE blocked the toxic actions of B. jararacussu venom despite having no anti inflammatory activity, which points to a direct inhibition of venom's toxins, as demonstrated in the in vitro assays. The larger amounts of rutin found in BFRE may play a role in this inhibition, since 3',4'-OH flavonoids are known inhibitors of phospholipases A2. PMID- 30517288 TI - Effects of nanoparticles of hydroxy-aluminum phthalocyanine on markers of liver injury and glucose metabolism in diabetic mice. AB - Photodynamic therapy, by reducing pain and inflammation and promoting the proliferation of healthy cells, can be used to treat recurrent lesions, such as diabetic foot ulcers. Studies using the photosensitizer phthalocyanine, together with the nanostructured copolymeric matrix of Pluronic(r) and Carbopol(r) for the treatment of diabetic foot ulcers and leishmaniosis lesions, are showing promising outcomes. Despite their topical or subcutaneous administration, these molecules are absorbed and their systemic effects are unknown. Therefore, we investigated the effect of the subcutaneous administration of the hydroxy aluminum phthalocyanine hydrogel without illumination on systemic parameters, markers of liver injury, and liver energy metabolism in type 1 diabetic Swiss mice. Both the hydrogel and the different doses of phthalocyanine changed the levels of injury markers and the liver glucose release, sometimes aggravating the alterations caused by the diabetic condition itself. However, the dose of 2.23 ug/mL caused less marked plasmatic and metabolic changes and did not change glucose tolerance or insulin sensitivity of the diabetic mice. These results are indicative that the use of hydroxy-aluminum phthalocyanine hydrogel for the treatment of cutaneous ulcers in diabetic patients is systemically safe. PMID- 30517289 TI - Representations of resident professionals regarding the pedagogical strategies used in the multiprofessional residency training process. AB - OBJECTIVE: To evaluate the social representations of residents regarding the pedagogical strategies of a Multiprofessional Health Residency program. METHOD: A case study with a qualitative approach supported by the Theory of Social Representations. Data collection was performed by applying a questionnaire to the resident professionals. ALCESTE software was used for the lexical content analysis. RESULTS: Questionnaires were applied to 15 resident professionals. The analysis showed the educational potential of a Distance Education tool, the need to prioritize theoretical content and its planning, aligning it with the experience in the territory, and the preference of the subjects for dynamic spaces that favor communication and critical-reflective analysis of day-to-day routines. CONCLUSION: There is a need to value strategies and teaching-learning methodologies that are significant for the resident professional and which contribute to health education. PMID- 30517290 TI - Dressings used to prevent surgical site infection in the postoperative period of cardiac surgery: integrative review. AB - OBJECTIVE: To identify and describe which dressings are recommended to prevent surgical site infection in hospitalized adult patients after cardiac surgeries. METHOD: Integrative review carried out in the databases MEDLINE, LILACS, CINAHL, Web of Science, Cochrane and Scopus. Studies related to dressing in the postoperative period of cardiac surgery were selected. RESULTS: Seven articles were included, with the following dressings: negative pressure wound therapy, silver nylon dressing, transdermal delivery of continuous oxygen and impermeable adhesive drape. The dressings that led to reduction of infection were negative pressure and silver nylon dressings. CONCLUSION: It was not possible to identify which dressing is most recommended, however, some studies show that certain types of dressings were related to the reduction of infection. Clinical trials with a rigorous methodological design and representative samples able to minimize the risk of bias should be conducted to evaluate the effectiveness of dressings in the prevention of surgical site infection. PMID- 30517291 TI - Compression therapy: Unna boot applied to venous injuries: an integrative review of the literature. AB - OBJECTIVE: To analyze the literature related to the types of therapies for venous injuries with emphasis on use of the Unna boot, and to investigate and discuss the main aspects related to its use compared to other techniques. METHOD: Integrative review of the literature of the last five years through searches in the following databases: VHL, LILACS, BDENF, SciELO, MEDLINE/PubMed. RESULTS: Twenty-two publications were identified, with 15,931 cases among adult or elderly individuals, whose mean age was 60 (35-78) years or greater with no sex differences. The Unna boot presented a shorter healing time than the single and two-layer elastic bandage. CONCLUSION: Although other compression techniques may prove to be more efficient than the Unna boot by adding more technology, the boot stands out as a traditional low-cost dressing. Multilayer bandage is a gold standard technique. This review demonstrated the best option may not be the Unna boot, because it requires a higher healing time compared to the multilayer bandage, but it meets the expectation with a high rate of treatment efficiency, also when compared to simple dressing, single or two-layer bandage. PMID- 30517292 TI - [Empowerment evaluation: theoretical and methodological considerations applied to the health area]. AB - The objective of this article is to discuss the empowerment evaluation as a theoretical and methodological framework and its applications to the health area. This is a theoretical article that presents the conceptual and methodological aspects and the principles of the empowerment evaluation. This evaluation is regarded as an approach that allows the participation of interest groups in the process, in order to improve the qualification and transformation of the knowledge and practices of the context evaluated. In the health area, the possible articulations between this framework and the complexity of the practices are discussed, aiming to increase the sense of belonging and responsibility of the participants in the evaluation process. Empowerment evaluation is a viable and powerful theoretical and methodological alternative in the health area, which, in addition to producing knowledge applied to the reality of interest groups, also provides a better understanding of work processes and institutional arrangements in the field of health management and health care. PMID- 30517293 TI - Reemerging arboviruses: clinical-epidemiological profile of hospitalized elderly patients. AB - OBJECTIVE: Describe the clinical-epidemiological profile of hospitalized elderly patients with arbovirus. METHOD: A documentary retrospective population-based descriptive study that used a quantitative approach with hospitalized elderly patients diagnosed with arbovirus was conducted in a teaching hospital. Data were collected from medical records and investigation forms. RESULTS: Thirty-three elderly patients participated in this study. A prevalence of dengue was observed, with fever, myalgia, and arthralgia. Arterial hypertension and diabetes were the comorbidities. Statistically significant correlations were obtained between arbovirus and schooling, employment situation, marital status, test results, and use of analgesics; and between the site of arthralgia and Chikungunya. CONCLUSION: The results support nursing care to hospitalized elderly patients with arbovirus, allowing the development of a proper and humanized care plan. PMID- 30517294 TI - Comparison between near miss criteria in a maternal intensive care unit. AB - OBJECTIVE: The aim of this study was to compare the incidence of different criteria of maternal near miss in women admitted to an obstetric intensive care unit and their sensitivity and specificity in identifying cases that have evolved to morbidity. METHOD: A cross-sectional analytical epidemiological study was conducted with women admitted to the intensive care unit of the Maternity School Assis Chateaubriand in Ceara, Brazil. The Chi-square test and odds ratio were used. RESULTS: 560 records were analyzed. The incidence of maternal near miss ranged from 20.7 in the Waterstone criteria to 12.4 in the Geller criteria. The maternal near-miss mortality ratio varied from 4.6:1 to 7.1:1, showing better index in the Waterstone criteria, which encompasses a greater spectrum of severity. The Geller and Mantel criteria, however, presented high sensitivity and low specificity. Except for the Waterstone criteria, there was an association between the three other criteria and maternal death. CONCLUSION: The high specificity of Geller and Mantel criteria in identifying maternal near miss considering the World Health Organization criteria as a gold standard and a lack of association between the criteria of Waterstone with maternal death. PMID- 30517295 TI - Evaluation of social support and stress in nursing students. AB - OBJECTIVE: To analyze the perception of stress and social support of nursing students considering the number of supporters and the satisfaction with them. METHOD: Quantitative, cross-sectional study performed with nursing students from a public university in the state of Sao Paulo, Brazil. We used the Stress Evaluation in Nursing Students scale and the Social Support Questionnaire. We performed the chi-squared test and analyzed the structure of the support network using software Gephi version 0.9.1. RESULTS: 192 students participated. Family and friends were the most mentioned supporters. Despite counting on a low number of supporters, most participants were satisfied with the perceived support. The students presented high intensity of stress in the "professional training" domain. Furthermore, the students who were pleased with the perceived social support presented low intensity of stress in accomplishing the theoretical activities of the undergraduate course. CONCLUSION: The creation of more welcoming spaces in the academic environment, the qualification of the social support, and the employment of strategies to improve the transition from the student stage to the professional stage are important recommendations that will contribute for positive outcomes regarding the coping with student stress. PMID- 30517296 TI - Factors associated with non-adherence to outpatient follow-up of neonatal intensive care discharge. AB - OBJECTIVE: To analyze the factors associated with non-adherence to the outpatient follow-up of infants discharged from the Neonatal Intensive Care Unit. METHOD: A cross-sectional study that included 596 children who were discharged between October 1, 2014 and September 30, 2015 and who were referred to outpatient follow up. The data were collected by evaluating the discharge report and attendance to the consultations. RESULTS: Of the 596 children referred for follow-up, 118 (19.80%) did not attend any outpatient care in the 12 months after discharge. Children with gestational age at birth >=37 weeks (odds ratio 1.97, p=0.013), who were not resuscitated at birth (odds ratio 1.79, p=0.032) and those without continuous use of medications at home (odds ratio 1.69, p=0.046) were more likely to not adhere to outpatient follow-up. CONCLUSION: The expressive number of non adherence to follow-up indicates the need for actions to ensure care continuity to newborns at risk after hospital discharge. Although the differences pointed out cannot be defined as predictors of non-follow-up, evidence of these variables allows us to recognize risks and seek to reduce factors that influence abandoning follow-up care. PMID- 30517297 TI - Rural workload and factors associated with the use of medication by elderly people. AB - OBJECTIVE: Identify the prevalence and factors associated with the use of medication by elderly rural workers and verify the association between the use of medication and rural workload. METHOD: Cross-sectional, exploratory study, conducted among elderly rural workers from the state of Rio Grande do Sul. The data was collected through interviews, using a structured questionnaire. RESULTS: Ninety-five elderly people participated in the study. Prevalence of medication use was 32% higher among women than men, and the type of medication most used by women was for the nervous and musculoskeletal systems. One additional degree in the frustration level with farm work resulted in a 1% increase in the probability of elderly people using medication. CONCLUSION: It is necessary to consider strategies that seek to reduce the physical and mental demand of rural work, through investments in public policies that enable elderly people to reduce rural labor for subsistence purposes and, consequently, their workload. PMID- 30517298 TI - Nursing Care Systematization in a basic health unit: perception of the nursing team. AB - OBJECTIVE: To conduct a situational diagnosis of the Nursing Care Systematization (NCS) in a Basic Health Unit from the perception of the nursing team. METHOD: This was a quantitative, descriptive-exploratory study, conducted in a Basic Health Unit in the interior of Sao Paulo state, Brazil. A structured questionnaire containing Likert scale was used for data collection, previously validated by specialists. RESULTS: The questionnaire was applied to 21 nursing professionals. It was verified that implementation of NCS and the nursing process is still incipient in the Basic Health Units. Regarding its use in all nursing actions: 19% of respondents believe that it is never used, 38% thought that it is rarely implemented, and 29% responded sometimes. The main difficulties identified were related to the lack of institutional structure, highlighting a lack of capacity by the institution (81%). The team has a reasonable understanding about the subject, but pointed out that professional education does not prepare them for performing NCS in primary care. CONCLUSION: Institutional interest in NCS is necessary to enable implementation. The study can contribute to the effective implementation in this unit and point out guidelines for its implementation in other similar contexts. PMID- 30517299 TI - Reflective practice and the development of competencies for health promotion in nurses' training. AB - OBJECTIVE: To analyze the insertion in reflective professional practice as a strategy for the development of competencies for health promotion in nurses' training. METHOD: Case study, qualitative approach anchored in the theoretical methodological framework of the Marxist dialectic. Data were obtained from documents, interviews with graduated students and focus groups with teachers from a nursing higher education institution located in the state of Minas Gerais, Brazil. Data were examined by critical discourse analysis. RESULTS: The most favorable contexts to reflective practice in the development of competencies for health promotion involve the practice of teaching-service-community integration, teacher-student interaction and teamwork. The discourse of early insertion is hegemonically constructed as a social practice of the study scenario. CONCLUSION: The characteristics of the curricular proposal of the study scenario favor the 'learning to do' mediated by experience and reflexivity by mobilizing the development of competencies for health promotion. In addition to insertion, students' immersion in the reality of services generates experiences in a reflective-critical process. PMID- 30517300 TI - Quality of life related to clinical aspects in people with chronic wound. AB - OBJECTIVE: To evaluate the quality of life of people with chronic wounds and to compare this index with clinical parameters. METHOD: A cross-sectional study conducted between July 2014 and February 2015, evaluating people with chronic wounds in outpatient care during a nursing consultation, in the city of Guarapuava, Parana. Quality of life was assessed by the Quality of Life Index - wounds version. Data were analyzed using the Mann Whitney test and T-test. RESULTS: 53 people participated. The mean quality of life score was 22.65+/-3.08. The most significant scores in the analyzes were the family domain (27.71+/-2.94) with the highest mean score, and the health domain (18.91+/-4.58) had the lowest. Pain in walking (p=0.031) and using pain medication (p=0.002) presented a significant relation with overall score. There was a significant difference between the groups for the items pain at rest (p=0.022), pain in moving (p=0.006), using pain medication (p<0.001) and presence of infection (p=0.004), in the rest item (p=0.015) in the socioeconomic domain, and type of wound (p=0.05) and rest (p=0.041) in the psychological domain. CONCLUSION: The overall Quality of Life Index and by domains was classified as good and very good, where the family domain was better evaluated to the deriment of the health domain due to the clinical parameter of pain. PMID- 30517301 TI - Profile of medicines used via oral and gastrointestinal catheter in a Walk-in Service. AB - OBJECTIVE: To identify the profile of drugs prescribed via oral and gastrointestinal catheter in a Walk-in Service of a University Hospital. METHOD: Quantitative cross-sectional study in which data were collected from the medical records of hospitalized patients using medication via oral or gastrointestinal catheter at least once a day between April and October 2015. The analysis was performed through descriptive statistics. RESULTS: Out of 568 prescriptions (total), there were 143 different medications. The pharmaceutical form with the greatest number of prescriptions was solid (95.8%), of which 46.1% were simple tablets. The oral route had the highest number of administrations (97.3%). The most prescribed drug class was of anti-infectives (25.9%), but the Omeprazole drug was the most prescribed in the study (40%). CONCLUSION: There are indications that enable rethinking the care practice and establishing criteria and norms for contributing to the safety and efficacy of services provided in healthcare, especially regarding the preparation and administration of medications via gastrointestinal catheter. PMID- 30517302 TI - Relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer in China. AB - OBJECTIVES: To study the relationship between the Asp1104His polymorphism of the nucleotide excision repair gene ERCC5 and treatment sensitivity to oxaliplatin in patients with advanced colorectal cancer (CRC) in China. METHODS: A group of 226 patients in the Department of Gastrointestinal Oncology at Zhejiang Xiaoshan Hospital from July 2011~December 2016 and a control group of 226 normal healthy individuals were involved in this study. All patients were first diagnosed with advanced CRC and were treated with oxaliplatin-based chemotherapy. The genotype of ERCC5 at the site of amino acid 1104 was determined by a TaqMan probe-based real-time PCR approach. RESULTS: There were no differences in age or gender between the groups, but the percentages of smokers and individuals with a family history of cancer were significantly higher in the patient group than in the control group. Analysis of the G/C polymorphism frequency among the patients and the healthy controls showed that the frequencies of the CC genotype and the CC+GC genotype were significantly related to CRC, but no significant difference in these frequencies was found between genders. The analysis of the relationship between the 5-year survival rate and different genotypes showed that in the total patient group, regardless of gender, the 5-year survival rate was significantly associated with the Asp1104His polymorphism of ERCC5. CONCLUSIONS: The Asp1104His polymorphism of ERCC5 was associated with the risk and 5-year survival rate of CRC as well as treatment sensitivity to oxaliplatin. PMID- 30517303 TI - Audiometric evaluation in individuals with mucopolysaccharidosis. AB - OBJECTIVES: To characterize the audiometric evaluation and acoustic immittance measures in different types of mucopolysaccharidosis. METHOD: Fifty-three mucopolysaccharidosis patients were evaluated. The classification consisted of type I (Hurler syndrome, Hurler-Scheie and Scheie syndrome), type II (Hunter syndrome), type III (Sanfilippo syndrome), type IV (Morquio syndrome), and type VI (Maroteaux-Lamy syndrome). Immittance audiometry and play or conventional threshold tone audiometry were used to obtain auditory thresholds and were chosen according to the patient's chronological age and ability to understand/respond to the procedure. The findings were analyzed using descriptive statistics and considering the recommendations for research involving human beings contained in Resolution CNE N degrees 466/2012. RESULTS: Fifty-one subjects (96.2%) had hearing loss, and the conductive type was the most frequent. Only two (3.8%) patients presented bilateral thresholds within normal limits, one with type IV mucopolysaccharidosis and the other with type VI. There were 11 individuals (20.8%) with mucopolysaccharidosis type I with mixed hearing loss, 9 (16.9%) individuals with type I with conductive hearing loss and 9 (16.9%) with type VI with conductive hearing loss. Mild hearing loss was most common (37.3%), followed by moderately severe hearing loss (36.3%). The type B tympanometric curve (80.4%) was the most frequent. CONCLUSIONS: Most of the individuals with mucopolysaccharidosis types I, II, III, IV and VI presented mixed or conductive hearing losses of mild to moderately severe degree, type B tympanograms and an absence of contralateral acoustic reflexes. PMID- 30517304 TI - Normal values for sagittal spinal alignment: a study of Brazilian subjects. AB - OBJECTIVES: The purpose of this study is to investigate the normal values of and chain of correlations between spinopelvic parameters in a Brazilian population. METHODS: This is a prospective observational study including asymptomatic adult subjects who had full spinal radiographs performed. The subjects were stratified by age into 3 groups (18-39 years old, 40-59 years old, and >60 years old), and radiographic parameters were compared across age groups and gender using ANOVA and Student's t-test, respectively. The relationships between various radiographic parameters were evaluated with Pearson correlation coefficients. RESULTS: One hundred and thirty asymptomatic volunteers (mean age, 48 years) met the inclusion criteria. The mean sagittal parameters in a normal Brazilian population were as follows: lumbar lordosis (LL) of 56.8 degrees , pelvic tilt (PT) of 12.4 degrees , pelvic incidence (PI) of 49.4 degrees , PI-LL of -7.4 degrees , T1 pelvic angle (TPA) of 8 degrees , sagittal vertical axis (SVA) of 0.54 cm and T1 slope of 25.2 degrees . Subjects >=60 years old had significantly higher values of SVA (p=0.024) and TPA (p=0.009) than the two younger age groups. The TPA was significantly correlated with the following spinopelvic parameters: LL (r=-0.172, p=0.005), PT (r=0.776, p<0.001), PI (r=0.508, p<0.001), PI-LL (r=0.717, p<0.001), SVA (r=0.409, p<0.001) and T1 slope (r=0.172, p=0.050). CONCLUSION: This study demonstrated significant physiologic trunk inclination with increasing age. The TPA, an angular parameter of global spinal alignment, presented a chain of correlations with different spinal segments. PMID- 30517305 TI - Relationships of interleukin-10 with the regulatory T cell ratio and prognosis of cervical cancer patients. AB - OBJECTIVE: This study investigated serum interleukin-10 (IL-10) levels, changes in peripheral blood CD4+CD25+ regulatory T cell (PBCDT) ratios, and the prognosis of cervical cancer (CC) patients. METHODS: Seventy patients with CC composed the observation group, and 70 healthy subjects composed the control group. The PBCDT ratios in the CC patients and healthy subjects were calculated. Serum IL-10 levels were detected with a double antibody sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The PBCDT ratio was higher in the patients with active CC [12.16+/-2.41%] than in the control subjects [6.34+/-1.05%]. Serum IL-10 levels were higher in the patients with CC [384+/-106 pg/ml] than in the control subjects [104+/-50 pg/ml]; the differences in both PBCDT ratio and IL-10 level were statistically significant (p<0.01). Serum IL-10 levels were positively correlated with PBCDT ratios (r=0.375, p<0.05). The 5-year patient survival rate was significantly higher in the low serum IL-10 group (64.2%) than in the high serum IL-10 group (42.8%, p=0.012). CONCLUSIONS: PBCDT ratios and serum IL-10 levels are related to CC activity. These factors are reciprocally related and influence one another, and both are involved in the development and progression of CC. Low IL-10 expression is beneficial regarding the survival of patients with CC. PMID- 30517306 TI - Review of a three-year study on the dental care of onco-hematological pediatric patients. AB - The aim of this study was to provide an updated review of dental procedures undertaken at the dental unit of the Onco-hematology service of the Instituto da Crianca at the Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (ICr/HC-FMUSP). We retrospectively reviewed 565 of 1902 medical and dental records of patients diagnosed with onco-hematological diseases who were seen in a 3-year study (January 2015 to December 2017). We assessed data regarding population characteristics, onco-hematological diagnosis and dental procedures performed. Of the selected medical records, preventive dentistry was the most common procedure undertaken in this population, followed by oral maxillofacial surgeries, restorative dentistry and oral mucositis treatment. The most prevalent malignant diagnosis was acute lymphocytic leukemia, and the most prevalent nonmalignant diagnosis was sickle-cell anemia. Preventive dental procedures represent most of the dental procedures undertaken in hospitalized onco hematological pediatric patients. PMID- 30517308 TI - Familiar factors and illicit drug use among Brazilian adolescents: an analysis of the Brazilian National Survey of School Health (PeNSE, 2015). AB - Illicit drug use is related to individual characteristics; however, social and family environments seem to be associated with this consumption. The aim of this study was to analyze the association of the relationships between parents or guardians and Brazilian adolescents that use illicit drugs. This is a cross sectional study with data from the Brazilian National Survey of School Health (PeNSE, 2015), in which the target population was school children from the ninth grade (eighth year). A total of 102,072 students were included in the current research, being 52,782 females and 49,290 males. Illicit drug use was the outcome and family relationship factors were the exposure. For adjustments, factors as sociodemographic characteristics, mental health, as well as tobacco and alcohol use were established. Univariate and multivariate analysis stratified by sex was conducted through Poisson regression, with a robust variance estimator to calculate the prevalence ratio and the 95% confidence interval. The general prevalence of illicit drug use was 3.8%; 3.3% among females and 4.4% among males. The following factors increase the prevalence ratio for illicit drug use in adolescents: not living with their parents, not feeling supervised by parents, and skipping classes without parents' consent. Never feeling understood by parents and frequent physical aggressions by family members were also associated with illicit drug use. Family relationships collaborate to illicit drug use among Brazilian adolescents, considering their sociodemographic factors, alcohol and smoking habits and parents and friends' profiles. PMID- 30517307 TI - Precision Medicine: Changing the way we think about healthcare. AB - Health care has changed since the decline in mortality caused by infectious diseases as well as chronic and non-contagious diseases, with a direct impact on the cost of public health and individual health care. We must now transition from traditional reactive medicine based on symptoms, diagnosis and treatment to a system that targets the disease before it occurs and, if it cannot be avoided, treats the disease in a personalized manner. Precision Medicine is that new way of thinking about medicine. In this paper, we performed a thorough review of the literature to present an updated review on the subject, discussing the impact of the use of genetics and genomics in the care process as well as medical education, clinical research and ethical issues. The Precision Medicine model is expanded upon in this article to include its principles of prediction, prevention, personalization and participation. Finally, we discuss Precision Medicine in various specialty fields and how it has been implemented in developing countries and its effects on public health and medical education. PMID- 30517309 TI - Cascade of care for people living with HIV infection in Southern Brazil: results from a public health network. AB - The cascade of care for people living with HIV infection (PLHIV) describes steps in diagnosis, linkage and retention in care, as well as the provision and success of combination antiretroviral therapy (cART). The aim of this study was to evaluate the rates regarding the retention in care, on cART, and suppressed viral load for PLHIV attended at a Brazilian public health network. Data on PLHIV from 116 cities of Parana, Southern Brazil, attended from 2012 to 2015, were retrospectively collected through the Laboratory Tests Control System (SISCEL). The number of PLHIV related to care increased about 22.5% from 2012 to 2015 (4,106 to 5,030 individuals). The proportion of PLHIV retained in care showed a trend toward stabilization around 81.7-86.9%. Every year, the use of cART increased up to 90.3% for PLHIV retained in care. Viral load suppression was achieved by 72.8% of patients on cART and 57.1% by those linked to care. Retention in care and HIV viral suppression were more likely to occur in older PLHIV than younger ones; similarly, patients living in medium-sized cities were more susceptible to these factors than in large- or small-sized cities. In conclusion, the study showed a high level of retention in care and HIV suppression on cART, as well as emphasized that current efforts for treating already-infected PLHIV remain a challenge for our health public institutions and may contribute to highlight steps for improvement of the HIV cascade of care in our population. PMID- 30517310 TI - [The Brazilian market for monoclonal antibodies used in cancer treatment]. AB - Monoclonal antibodies (mABs) have been indicated as an innovative technology for the treatment of some types of cancer, since they are capable of targeting and selectively killing tumor cells. However, the high costs of these therapies raise questions as to the sustainability of access. This study aimed to identify the principal characteristics of monoclonal antibodies used in cancer treatment with active marketing authorization in Brazil as of 2016. This was a descriptive retrospective analysis based on consultation of the Brazilian Health Regulatory Agency (Anvisa) website, in which these mABs were characterized according to the target antigen, type of antibody, year of registration, therapeutic indications, and applicant. A total of 14 antibodies were identified with action on seven different target antigens. The most frequent clinical indications were for lymphomas, leukemias, breast cancer, and colorectal cancer. As for type, the study identified three chimeric, six humanized, and five human antibodies. Roche was the applicant in 6 of the 14 mABs, or 43% of the marketing authorization. It was possible to discuss the idea of me-too medicines in the biological market and the idea of a differentiated oligopoly, as well as to think about the tensions in this kind of market. It is expected that the development of new products, although to act on the same biological target, represent the possibility of a competitive increase and, as a result, a decrease in prices practiced by companies. However, this becomes a problem when it is the same pharmaceutical industry that launches on the market new antibodies directed to the same target, with no relevant changes. PMID- 30517311 TI - Homicides and socio-environmental determinants of health in Brazil: a systematic literature review. AB - Brazil currently has the highest absolute number of homicides in the world, which results from a complex range of factors. This study aimed at understanding the associations between socio-environmental determinants of health (SDH) and homicides in Brazil through a systematic literature review. The review followed PRISMA guidelines, selecting quantitative and qualitative studies published in Portuguese, English, and Spanish carried out between 2002 and 2017, available in the PubMed, MEDLINE, LILACS, SciELO and BVS-BIREME databases. Two trilingual reviewers tracked studies independently by basing on the eligibility criteria. We critically assessed the selected studies with the Critical Appraisal Skills Programme (CASP) or the Checklist for Analytical Cross-Sectional Studies, depending on the study design. We considered 60 studies and grouped their SDH into categories to develop a narrative synthesis about each SDH. These categories were: territory; race/ethnicity; gender; age; social inequalities and economic factors; development; education; work and employment; drugs and trafficking; other SDH. We found some SDH were more associated with homicides, such as being young, black, male, of low education level, and also people who lived in places of high social inequality, such as urban suburbs and agricultural frontiers. Unemployment and drug trafficking, as well as intersections between various SDH were also prominent. Education seems to be a protective factor for homicide. Despite the limited capacity of interpretation due to the high range of methodological approaches, this review shows the importance of considering SDH and their intersections when developing homicide prevention policies. PMID- 30517312 TI - The food environment of Brazilian public and private schools. AB - This study's aim was to characterize the food environment of Brazilian public and private schools. This was a national school-based cross-sectional study with 1,247 schools - among which 81.09% were public and 18.91% were private - in 124 Brazilian municipalities. The data originated from the Questionnaire on Aspects of the School Environment, used in the Study of Cardiovascular Risk in Adolescents (ERICA) in 2013 and 2014. Data analysis was conducted in 2017. The chi-square test was used to compare proportions. A greater proportion of public schools offered school meals (98.15%) in comparison to private schools (8.07%) (p < 0.001). The internal sale of food and beverages was more prevalent in private schools (97.75% vs. 45.06%, p < 0.001). Also, sale and advertisement of processed and ultra-processed foods (sodas, cookies, savory snacks, sandwiches and pizza), as well as the presence of vending machines for industrialized products (18.02% vs. 4%) (p < 0.001) were more common in private schools. Street vendors at the school gate or surroundings were identified in 41.32% of the public schools and 47.75% of the private schools (p > 0.05). These findings reveal the predominance of obesogenic environments mainly in private schools, and can contribute to the design of Brazilian public policies to promote a healthy school food environment. PMID- 30517313 TI - [Validity of self-reported high cholesterol in the city of Sao Paulo, Brazil, and factors associated with this information's sensitivity]. AB - The study aimed to validate self-report of high cholesterol in Sao Paulo, Brazil, and verify factors associated with this information's sensitivity. Data were used from the Health Survey of the City of Sao Paulo 2015, a cross-sectional population-based study with a probabilistic sample of the city's residents. The sample included 886 individuals with information from the structured questionnaire, blood measurements of total cholesterol and fractions or who reported being on medication for high cholesterol. The validity of self-reported information on high cholesterol was measured according to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa index, considering total cholesterol and LDL-c and pharmacological treatment as the gold standard. Logistic regression models were developed to investigate factors associated with the sensitivity of this information. The sensitivity of information on high cholesterol using total cholesterol as the reference was 50.6%, specificity 90.19%, PPV 51.64%, NPV 89.82%, and kappa 0.41. Taking LDL-c as the gold standard, sensitivity was 53.52%, specificity 89.93%, PPV 49.22%, NPV 91.39%, and kappa 0.43. Using total cholesterol as the reference, age (OR = 1.69; 95%CI: 1.24-2.29) and having a private health plan (OR = 2.91; 95%CI: 1.06-7.99) were associated with the information's sensitivity. With LDL-c as the gold standard, age (OR = 1.71; 95%CI: 1.13-2.57), smoking (OR = 3.33; 95%CI: 1.08-10.27), and having a private health plan (OR = 3.64; 95%CI: 1.10 12.08) were associated with the information's sensitivity. The results suggest low sensitivity and low PPV of self-reported high cholesterol in residents of Sao Paulo. PMID- 30517314 TI - [Costs of an Aedes aegypti vector control program in municipalities in Colombia: a case study in Giron and Guadalajara de Buga, 2016]. AB - The aim of this study was to measure the costs of vector-borne disease control programs at the local level in Colombia (2016). A cost analysis was performed for this purpose from the policymaker's perspective in the municipalities (counties) of Giron and Guadalajara de Buga, specifically for the Aedes aegypti control program, the principal mosquito vector of dengue, Zika, and chikungunya. The analysis involved the quantification of all the costs required for each of the prevention and control strategies in vector-borne diseases. The costs were classified as operating and capital costs, and for purposes of comparison the costs were also calculated per case and per capita. The programs' total estimated costs were USD 146,651 in Giron and USD 97,936 in Guadalajara de Buga. Per capita cost was USD 0.88 in Giron and USD 0.99 in Guadalajara de Buga. In general, the predominant cost strategies were chemical spraying of adult mosquitos, accounting for 26% of the total costs in Giron and 47% in Guadalajara de Buga, with personnel representing 40% of the total costs for this strategy in Giron and 66% of the operating costs in Guadalajara de Buga. PMID- 30517315 TI - Sarcopenia and its association with changes in socioeconomic, behavioral, and health factors: the EpiFloripa Elderly Study. AB - This study aimed to verify the prevalence of sarcopenia and its association with changes in socioeconomic, behavioral, and health factors in the elderly. The longitudinal population-based study included 598 elderly (>= 60 years) in Florianopolis, Santa Catarina State, in the South of Brazil. Sarcopenia was defined on the basis of appendicular skeletal mass index (ASMI) according to gender (ASMI < 7.26kg/m2 for men and < 5.5kg/m2 for women). We assessed changes that occurred between the two study waves (2009/2010 and 2013/2014) in relation to socioeconomic, behavioral, and health factors. Crude and adjusted logistic regression analyses were performed. Prevalence of sarcopenia was 17% in women (95%CI: 12.4-22.9) and 28.8% in men (95%CI: 21.3-37.7). In the final model, women that continued to consume or that started consuming alcohol (OR = 0.31; 95%CI: 0.11-0.91) showed lower odds of sarcopenia. Women who continued to smoke or that started smoking (OR = 2.55; 95%CI: 1.16-5.58) and/or that remained inactive or became insufficiently active (OR = 2.90; 95%CI: 1.44-5.84) showed higher odds of sarcopenia. For men, no change variable was associated with sarcopenia. The results suggest that continuing or starting to smoke and remaining or becoming physically inactive are preventable and modifiable risk factors for sarcopenia. PMID- 30517316 TI - [Meteorites, dinosaurs, butterflies... and also health]. PMID- 30517317 TI - [The National Museum and its role in the history of science and health in Brazil]. PMID- 30517318 TI - "Hello + invitation: 'How Collections End'": the fire at the Brazilian National Museum and shared stories. PMID- 30517319 TI - Adverse drug events identified in hospitalized patients in Brazil by International Classification of Diseases (ICD-10) code listings. AB - Studies of adverse drug events (ADEs) are important in order not to jeopardize the positive impact of pharmacotherapy. These events have substantial impact on the population morbidity profiles, and increasing health system operating costs. Administrative databases are an important source of information for public health purposes and for identifying ADEs. In order to contribute to learning about ADE in hospitalized patients, this study examined the potential of applying ICD-10 (10th revision of the International Classification of Diseases) codes to a national database of the public health care system (SIH-SUS). The study comprised retrospective assessment of ADEs in the SIH-SUS administrative database, from 2008 to 2012. For this, a list of ICD-10 codes relating to ADEs was built. This list was built up by examining lists drawn up by other authors identified by bibliographic search in the MEDLINE and LILACS and consultations with experts. In Brazil, 55,604,537 hospital admissions were recorded in the SIH-SUS, between 2008 and 2012, of which 273,440 (0.49%) were related to at least one ADE. The proportions and rates seem to hold constant over the study period. Fourteen out of 20 most frequent ADEs were identified in codes relating to mental disorders. Intoxications figure as the second most frequently recorded group of ADEs in the SIH-SUS, comprising 76,866 hospitalizations. Monitoring of ADEs in administrative databases using ICD-10 codes is feasible, even in countries with information systems under construction, and can be an innovative tool to complement drug surveillance strategies in place in Brazil, as well as in others countries. PMID- 30517320 TI - [Laziness as the single explanation for physical inactivity: commentary and reflections on discrepancies between scientific evidence and media discourse]. AB - This essay aims to suggest food for thought on discrepancies between scientific evidence on physical inactivity and the associated factors and determinants and information communicated by the media on this topic. We specifically examine a case in which "laziness" was used as the "explanatory" factor for the high levels of physical inactivity in the Brazilian population. We use as examples a scientific article published in Nature and two news stories published in mainstream Brazilian media channels (Veja magazine and O Globo newspaper) that commented on the former. There were important inconsistencies between the scientific content in the Nature article and the news stories, which took a simplistic approach to a real and complex problem (high levels of physical inactivity in Brazil), suggesting that "laziness" explains why Brazil ranks so poorly in the world in terms of physical activity. We highlight the need for mass communications media to better contextualize the information they republish, because otherwise the impact can be more negative than positive, especially when they build or reinforce misconceptions. This is particularly serious in the case of physical inactivity, since such news coverage can lend legitimacy to the lack of investments in measures to deal adequately with the problem. If physical inactivity is interpreted merely as a matter of "laziness", it makes much less sense to invest in modifying various determinants of this serious public health problem. PMID- 30517321 TI - Oxymatrine alleviates periodontitis in rats by inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression1. AB - PURPOSE: To investigate the effect of oxymatrine on periodontitis in rats and related mechanism. Methods: Ninety SD rats were divided into control, model, 10, 20 and 40 mg/kg oxymatrine and tinidazole groups. The periodontitis model was established in later 5 groups. The 10, 20 and 40 mg/kg oxymatrine groups were intragastrically administrated with 10, 20 and 40 mg/kg oxymatrine, respectively. The tinidazole group was intragastrically administrated with 100 mg/kg tinidazole. The treatment duration was 4 weeks. The tooth mobility, gingival and plaque indexes, serum inflammatory factor levels and gingival tissue matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) protein levels were detected. Results: After treatment, compared with model group, in 40 mg/kg oxymatrine group the rat general conditions were obviously improved, the tooth mobility, gingival index and plaque index were significantly decreased (P<0.05), the serum tumor necrosis factor-alpha, interleukin-1beta and prostaglandin E2 levels were significantly decreased (P<0.05), the MMP-2 and MMP 9 protein levels were significantly decreased (P<0.05), and the TIMP-2 protein level was significantly increased (P<0.05). Conclusions: Oxymatrine can alleviate the experimental periodontitis in rats. The mechanism may be related to its inhibiting inflammatory factor secretion and regulating MMPs/TIMP protein expression. PMID- 30517322 TI - Prevention of rocuronium induced mast cell activation with prophylactic oleuropein rich diet in anesthetized rabbits1. AB - PURPOSE: The effect of a prophylactic oleuropein-rich diet before anesthesia accompanied by the widely-used steroid-based neuromuscular drug rocuronium on mast cell activation was investigated in the study. METHODS: 14 rabbits used in the study. The rabbits in the oleuropein group were given oleuropein-rich extract added to the animals' water at doses of 20 mg/kg oleuropein for 15 days orally. After 15 days, all rabbits in the two groups were given general anesthesia with rocuronium of 1 mg/kg. After 1 day, animals were sacrificed and the liver tissue sections stained with H&E, toluidine blue and tryptase for immunohistochemical study. RESULTS: There was no statistically significant difference between ALT, AST and albumin averages of the oleuropein and control groups (p> 0.05). The tryptase average of the control group was higher than the tryptase average of the oleuropein group and this difference was statistically significant (p=0.003). The T. blue average in the oleuropein group was higher than the control group. However, there was no statistically significant difference between groups (p=0.482). CONCLUSIONS: Rocuronium adverse effects, like hypersensitivity and anaphylaxis, may limit routine use of this substance. The use of oleuropein reduced the number of inflammatory cells and prevented degranulation. PMID- 30517323 TI - Effects of different periods of gastric ischemia on liver as a remote organ1. AB - PURPOSE: To evaluate the hepatic changes associated with gastric ischemia. METHODS: Thirty male rabbits were studied, distributed in 3 groups (n=10). Group 1: ligature and section of the gastric vasculature and removal of the liver after three hours; Group 2: ligature and section of the gastric vasculature and removal of the liver after 6 hours; Group 3: ligature and section of the gastric vasculature and removal of the liver after 12 hours. Blood samples were collected immediately before surgery and after the determined time of ischemia in each group to evaluate the hepatic function. After the death of the rabbits, the liver was removed for macro and microscopic study. RESULTS: An increase in aminotransferases and bilirubin occurred in groups 2 and 3. Total protein and albumin diminished in all of the animals. All of the rabbits from groups 2 and 3 presented hepatocellular necrosis. CONCLUSION: The devascularization of the stomach for a period of above three hours is associated with hepatic morphological and functional disorders. PMID- 30517324 TI - Hepatic retractor in an ex vivo model1. AB - PURPOSE: To discuss the use of models of hepatic retraction by laparoscopy, to present a new Hepatic Retractor (HR) and to evaluate its practicality, efficacy and safety in Esophageal Hiatus Exposure (EHE). METHODS: Experimental cross - sectional study with a quantitative character. It was carried out in the Laboratory of Health Training of Christus University Center. The sample consisted of 12 livers of adult pigs weighing between 30 and 45 kg. A circular-shaped HR, 5 cm diameter and deformable materials was developed with a polypropylene cloth, metallic guide wire, epidural needle plastic guide and nylon string. The practicality of HR management was measured by the time required to use the instrument, efficacy by exposure to the operative field and safety by macroscopic assessment of liver damage. RESULTS: The average time to complete the procedure was 3.24 minutes and reached less than 2 minutes after 12 repetitions. In eight experiments the maximum degree of EHE was obtained. No macroscopic lesions were observed. CONCLUSION: The use of HR described can broaden the operative field, without causing macroscopic liver lesions and prolonging the surgical time. PMID- 30517325 TI - Effectual components of Polygonum ciliinerve protects against Staphylococcus aureus infection with immunomodulatory functions in C57BL/6 mice1. AB - PURPOSE: To investigate the efficacy and mechanisms of root tuber of Polygonum ciliinerve (Nakai) ohwi (rPC) which has been used to treat bacterial infection in traditional Chinese medicine. METHODS: With the mouse model of Staphylococcus aureus (S. aureus) pneumonia, the phenotype of rPC treated mice, including body weight, mortality, lung slices and bacterial burden were evaluated. Furthermore, inflammatory factors in bronchoalveolar lavage (BAL) were determined by ELISA and the distribution of T cells in lung was assessed by immunofluorescence assay. RESULTS: rPC treatment could dose-dependently reduce weight loss and mortality in S. aureus-infected mice. Upon 10 mg/ml rPC treatment, S. aureus-infected mice showed about 8 grams increase in body weight (P<0.001) and 50% enhancement in mortality. The integrity of lung tissue and bacterial burden were also improved by rPC treatment. Moreover, rPC was found to modulate the immune response in infection. CONCLUSION: rPC has therapeutic potential for S. aureus infections and pneumonia with immunomodulatory functions. PMID- 30517326 TI - Knockdown of transglutaminase-2 prevents early age-induced vascular changes in mice1. AB - PURPOSE: To determine whether the absence of transglutaminase 2 enzyme (TG2) in TG2 knockout mice (TG2-/-) protect them against early age-related functional and histological arterial changes. METHODS: Pulse wave velocity (PWV) was measured using non-invasive Doppler and mean arterial pressure (MAP) was measured in awake mice using tail-cuff system. Thoracic aortas were excised for evaluation of endothelial dependent vasodilation (EDV) by wire myography, as well as histological analyses. RESULTS: PWV and MAP were similar in TG2-/-mice to age matched wild type (WT) control mice. Old WT mice exhibited a markedly attenuated EDV as compared to young WT animals. The TG2-/-young and old mice had enhanced EDV responses (p<0.01) as compared to WT mice. There was a significant increase in TG2 crosslinks by IHC in WT old group compared to Young, with no stain in the TG2-/-animals. Optical microscopy examination of Old WT mice aorta showed thinning and fragmentation of elastic laminae. Young WT mice, old and young TG2-/ mice presented regularly arranged and parallel elastic laminae of the tunica media. CONCLUSION: The genetic suppression of TG2 delays the age-induced endothelial dysfunction and histological modifications. PMID- 30517327 TI - Healing effect of andiroba-based emulsion in cutaneous wound healing via modulation of inflammation and transforming growth factor beta 31. AB - PURPOSE: To evaluate the effects and mechanisms of andiroba-based emulsion (ABE) topical treatment on full-thickness cutaneous wounds in rats. METHODS: The wounds were harvested on days 3, 7, 15, and 20 post-surgery. Wound contraction rate, quantitative immunohistochemistry [macrophages, myofibroblasts, capillaries, collagens (col) I and III, transforming growth factor beta3beta (TGFbeta3)], and tensile strength were assessed. RESULTS: Treated wounds were smaller, contracted earlier and had increased angiogenesis, fewer CD68+ and M2 macrophages on days 7 and 15, but higher on day 20. Myofibroblasts appeared on days 3 to 7 in untreated wounds and on days 7 to 15 in treated wounds. TGFbeta3 levels were higher in the treated wounds, less dense collagen fibers, lower col I/III ratios and a higher tensile strength. CONCLUSION: These results demonstrate the important anti inflammatory role of treatment and the associated modulation of macrophages, myofibroblasts, and TGFbeta3 levels. Collagen fibers in the treated wounds were more organized and less dense, similar to unwounded skin, which likely contributed to the higher tensile strength. PMID- 30517328 TI - Adipose tissue derived mesenchymal stem cell transplantation in the treatment of ischemia/reperfusion induced acute kidney injury in rats. Application route and therapeutic window1. AB - PURPOSE: To evaluate renal repair in rats who had renal infarction induced by the obstruction of blood flow in the renal artery and were treated with transplantation of adipose tissue derived mesenchymal stem cell. METHODS: 16-week old Wistar rats (n=72) were used, submitted to celiotomy and had of the renal artery and vein clipped for 24 hours. The animals were randomly assigned to 10 experimental homogeneous groups, corresponding to the treatments with phosphate buffered saline (PBS) or adipose tissue derived mesenchymal stem cell (ADSC), duration of application (24 or 48 hours), and site of transplantation (lateral vein of the tail or intrarenal). After the treatments were performed, at 8 and 31 days, four animals in each group were subjected to left nephrectomy for histological studies. RESULTS: Histologically, a higher amount of cell debris and tubules devoid of the epithelium and a higher degree of necrosis were observed in the groups treated with PBS, as opposed to a low degree of necrosis and higher tubular vascularization in the groups treated with ADSC, particularly in the group treated with intrarenal ADSC 48 hours after injury. CONCLUSION: The transplantation of ADSC positively contributed to the replacement of necrotic tissue by renal tubular cells, vascularization of the renal parenchyma, and restoration of the organ function. PMID- 30517329 TI - Absorbable suture. Best aesthetic outcome in cesarian scar1. AB - PURPOSE: To compare two suture threads, poliglecaprone 25 and nylon, used as intradermal suture for skin closure in women undergoing their first cesarean section. METHODS: This is a randomized clinical trial. A total of 60 women undergoing their first cesarean section were enrolled and prospectively assessed. They were randomly allocated to group I (n=30), which received an intradermal suture with nylon 4.0 or to group II (n=30), which had an intradermal suture with poliglecaprone 25, 4.0. The main author took standardized photographs of the scar 6 months after the operation. Four independent raters, two senior obstetricians and two senior plastic surgeons (a male and a female physician from each specialty) assessed the photographs.The panelists rated the scar according to Trimbos scale, composed by the subscales hypertrophy, color and width of the scar. RESULTS: At baseline, patients in both groups were similar regarding age and body mass index. Five patients withdraw the study, four from group and one from group II. Scars of patients from group II were significantly less hypertrophic (p=0.001), thinner (p=0.019) and had more acceptable color (p=0.019). CONCLUSION: The intradermal suture with poliglecaprone 25 for skin closure after cesarean incision provides better aesthetic result. PMID- 30517330 TI - The cardiopulmonary bypass and cancer dissemination puzzle1. AB - Early cancer diagnosis, new therapies that increased survival of patients, besides the increasingly elderly population are some factors would be associated with possible cancer dissemination in patients under cardiopulmonary bypass (CPB) cardiac surgery. Also, the benefits, and risks, regarding long-term survival, have not yet been established. Therefore, cardiac surgery morbimortality may be superior in patients with cancer disease. Also, immunologic and inflammatory changes secondary to CPB can also increase tumor recurrence. After a brief introduction and CPB immunologic the two main topic subjects included: 1) Combined heart surgery and lung resection and; 2) Possible influence of neoplasia type. After observing the relative literature scarcity, we keep the opinion that "CPB has a modest association with cancer progression" and that "CPB and cancer dissemination should be a logical but unlikely association." PMID- 30517331 TI - Epidemiology of asthma: it is necessary to expand our concepts. PMID- 30517332 TI - Getting to know our pneumococcus. PMID- 30517333 TI - Electronic cigarettes - the new playbook and revamping of the tobacco industry. PMID- 30517334 TI - ? PMID- 30517335 TI - Paravertebral mass. PMID- 30517336 TI - Meeting the assumptions of statistical tests: an important and often forgotten step to reporting valid results. PMID- 30517337 TI - Asthma mortality in Brazil, 1980-2012: a regional perspective. AB - OBJECTIVE: To estimate asthma mortality rates in Brazil for the period 1980-2012. METHODS: On the basis of data from the Brazilian National Ministry of Health Mortality Database, we estimated mortality rates by calculating moving averages from a municipal perspective that would allow an evaluation differentiating between urban, rural, and intermediate (rurban) Brazil during the period 2002 2012. Trends were assessed using simple linear regression. RESULTS: On average, 2,339 asthma-related deaths were reported per year during the study period. Asthma ranged from the 53rd to 95th leading cause of death. There was a decrease in asthma mortality rates in the country, from 1.92/100,000 population in 1980 to 1.21/100,000 population in 2012. From the municipal perspective, rates fell in urban and rurban Brazil, but increased in rural Brazil, except in the 5-34-year age group. Asthma mortality rates fell in the population under 25 years of age and increased among those over 74 years of age. Rates were always higher in females. CONCLUSIONS: Asthma mortality rates in Brazil have been decreasing slightly, with the decrease being more marked in the decade 2002-2012. Only the northeastern region of Brazil showed the opposite trend. Asthma mortality rates in urban and rurban Brazil showed a downward trend similar to that of the national scenario, whereas rural Brazil showed the opposite behavior. Analysis by age group showed that rates decreased among younger individuals and increased among the elderly aged >= 75 years. PMID- 30517338 TI - Does methylene blue attenuate inflammation in nonischemic lungs after lung transplantation? AB - OBJECTIVE: To evaluate whether methylene blue (MB) could minimize the effects of ischemia-reperfusion injury in the nonischemic lung on a lung transplantation rodent model. METHODS: Forty female Sprague-Dawley rats were divided into 20 donors and 20 recipients. The 20 recipient rats were divided into two groups (n = 10) according to the treatment (0.9% saline vs. 1% MB solutions). All animals underwent unilateral lung transplantation. Recipients received 2 mL of saline or MB intraperitoneally prior to transplantation. After 2 h of reperfusion, the animals were euthanized and histopathological and immunohistochemical analyses were performed in the nonischemic lung. RESULTS: There was a significant decrease in inflammation-neutrophil count and intercellular adhesion molecule-1 (ICAM-1) expression in lung parenchyma were higher in the saline group in comparison with the MB group-and in apoptosis-caspase-3 expression was higher in the saline group and Bcl-2 expression was higher in MB group. CONCLUSIONS: MB is an effective drug for the protection of nonischemic lungs against inflammation and apoptosis following unilateral lung transplantation in rats. PMID- 30517339 TI - The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil. AB - OBJECTIVE: The clinical, functional, radiological and genotypic descriptions of patients with an alpha-1 antitrypsin (A1AT) gene mutation in a referral center for COPD in Brazil. METHODS: A cross-sectional study of patients with an A1AT gene mutation compatible with deficiency. We evaluated the A1AT dosage and genotypic, demographic, clinical, tomographic, and functional characteristics of these patients. RESULTS: Among the 43 patients suspected of A1AT deficiency (A1ATD), the disease was confirmed by genotyping in 27 of them. The A1AT median dosage was 45 mg/dL, and 4 patients (15%) had a normal dosage. Median age was 54, 63% of the patients were male, and the respiratory symptoms started at the age of 40. The median FEV1 was 1.37L (43% predicted). Tomographic emphysema was found in 77.8% of the individuals. The emphysema was panlobular in 76% of them and 48% had lower lobe predominance. The frequency of bronchiectasis was 52% and the frequency of bronchial thickening was 81.5%. The most common genotype was Pi*ZZ in 40.7% of participants. The other genotypes found were: Pi*SZ (18.5%), PiM1Z (14.8%), Pi*M1S (7.4%), Pi*M2Z (3.7%), Pi*M1I (3.7%), Pi*ZMnichinan (3.7%), Pi*M3Plowell (3.7%), and Pi*SF (3.7%). We did not find any significant difference in age, smoking load, FEV1, or the presence of bronchiectasis between the groups with a normal and a reduced A1AT dosage, neither for 1 nor 2-allele mutation for A1ATD. CONCLUSIONS: Our patients presented a high frequency of emphysema, bronchiectasis and bronchial thickening, and early-beginning respiratory symptoms. The most frequent genotype was Pi*ZZ. Heterozygous genotypes and normal levels of A1AT also manifested significant lung disease. PMID- 30517340 TI - Impact of adherence to long-term oxygen therapy on patients with COPD and exertional hypoxemia followed for one year. AB - OBJECTIVE: To determine the impact of adherence to long-term oxygen therapy (LTOT) on quality of life, dyspnea, and exercise capacity in patients with COPD and exertional hypoxemia followed for one year. METHODS: Patients experiencing severe hypoxemia during a six-minute walk test (6MWT) performed while breathing room air but not at rest were included in the study. At baseline and after one year of follow-up, all patients were assessed for comorbidities, body composition, SpO2, and dyspnea, as well as for anxiety and depression, having also undergone spirometry, arterial blood gas analysis, and the 6MWT with supplemental oxygen. The Saint George's Respiratory Questionnaire (SGRQ) was used in order to assess quality of life, and the Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity (BODE) index was calculated. The frequency of exacerbations and the mortality rate were noted. Treatment nonadherence was defined as LTOT use for < 12 h per day or no LTOT use during exercise. RESULTS: A total of 60 patients with COPD and exertional hypoxemia were included in the study. Of those, 10 died and 11 experienced severe hypoxemia during follow-up, 39 patients therefore being included in the final analysis. Of those, only 18 (46.1%) were adherent to LTOT, showing better SGRQ scores, higher SpO2 values, and lower PaCO2 values than did nonadherent patients. In all patients, SaO2, the six-minute walk distance, and the BODE index worsened after one year. There were no differences between the proportions of adherence to LTOT at 3 and 12 months of follow-up. CONCLUSIONS: Quality of life appears to be lower in patients with COPD and exertional hypoxemia who do not adhere to LTOT than in those who do. In addition, LTOT appears to have a beneficial effect on COPD symptoms (as assessed by SGRQ scores). (Brazilian Registry of Clinical Trials - ReBEC; identification number RBR-9b4v63 [http://www.ensaiosclinicos.gov.br]). PMID- 30517341 TI - 2018 recommendations for the management of community acquired pneumonia. AB - Community-acquired pneumonia (CAP) is the leading cause of death worldwide. Despite the vast diversity of respiratory microbiota, Streptococcus pneumoniae remains the most prevalent pathogen among etiologic agents. Despite the significant decrease in the mortality rates for lower respiratory tract infections in recent decades, CAP ranks third as a cause of death in Brazil. Since the latest Guidelines on CAP from the Sociedade Brasileira de Pneumologia e Tisiologia (SBPT, Brazilian Thoracic Association) were published (2009), there have been major advances in the application of imaging tests, in etiologic investigation, in risk stratification at admission and prognostic score stratification, in the use of biomarkers, and in the recommendations for antibiotic therapy (and its duration) and prevention through vaccination. To review these topics, the SBPT Committee on Respiratory Infections summoned 13 members with recognized experience in CAP in Brazil who identified issues relevant to clinical practice that require updates given the publication of new epidemiological and scientific evidence. Twelve topics concerning diagnostic, prognostic, therapeutic, and preventive issues were developed. The topics were divided among the authors, who conducted a nonsystematic review of the literature, but giving priority to major publications in the specific areas, including original articles, review articles, and systematic reviews. All authors had the opportunity to review and comment on all questions, producing a single final document that was approved by consensus. PMID- 30517342 TI - Hamman's syndrome. PMID- 30517343 TI - Clinical aspects of the Mycobacterium abscessus complexAuthors' replyClinical aspects in patients with pulmonary infection caused by mycobacteria of the Mycobacterium abscessus complex, in the Brazilian AmazonBurden of non-tuberculous mycobacterial pulmonary disease in GermanyBritish Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). PMID- 30517344 TI - Smoking cessation before initiation of chemotherapy in metastatic non-small cell lung cancer: influence on prognosis. PMID- 30517345 TI - Omalizumab as add-on therapy in patients with asthma and allergic bronchopulmonary aspergillosis. PMID- 30517346 TI - Lung transplantation with extracorporeal membrane oxygenation as intraoperative support. PMID- 30517347 TI - Investigation of schistosomiasis cases and deaths in the city of Recife, Pernambuco, Brazil, 2005-2013. AB - OBJECTIVE: to describe schistosomiasis cases and deaths among residents of the city of Recife, Pernambuco, Brazil, from 2005 to 2013. METHODS: this was a descriptive epidemiological study using data from the Mortality Information System (SIM) (2005-2013) and the Notifiable Diseases Information System (SINAN) (2007-2013); active tracing of the relatives of the dead was undertaken and probabilistic linkage of the databases (2007-2013) was performed using the Reclink program. RESULTS: 297 schistosomiasis deaths were recorded on the SIM system; through active tracing, 130 relatives were contacted and 20.8% autochthony was identified; 388 cases resident in Recife were registered on the SINAN system; through probabilistic linkage, 23 matching records were identified on SIM and SINAN. CONCLUSION: investigation of deaths showed that some individuals had never traveled outside Recife and progressed to the chronic stage of the disease; 23.8% of the cases registered on SINAN had Recife as the municipality in which infection occurred. PMID- 30517348 TI - The impact of pneumococcal vaccine in reducing pneumonia hospitalizations in children under 5 years old, in Santa Catarina, Brazil, 2006 a 2014. AB - OBJECTIVE: to analyze the impact of pneumococcal conjugate vaccine (PCV10) on pneumonia hospital admissions among children in Santa Catarina, Brazil, 2006 2014. METHODS: this was an ecological study using data obtained from Brazilian National Health System Information Technology Department (Datasus) for 2006-2009 (pre-vaccination period) and 2010-2014 (post-vaccination period); time trends were evaluated using the Poisson regression coefficient. RESULTS: in the comparison between pre- and post-vaccination periods, the percentage difference in the hospitalization rate for children under 1 year old ranged from -44.1% in the Western region to -1.4% in the Serrano Plateau region, and in children between 1-4 years old it ranged from -37.1% in the Northern Plateau region to 16.9% in the Serrano Plateau region (p<0.05); hospitalization rates in the state reduced by 23.3% in children under 1 year old and by 8.4% in those aged 1-4 years. CONCLUSION: a significant reduction in the rate of pneumonia hospitalization in children under 1 year old age was found, suggesting the effectiveness of the vaccine in reducing hospitalizations. PMID- 30517349 TI - National Dengue Control Program implementation evaluation in two border municipalities in Mato Grosso do Sul State, Brazil, 2016. AB - OBJECTIVE: to evaluate the degree of implementation of the National Dengue Control Program (PNCD) in two border municipalities in Mato Grosso do Sul State (Corumba and Ponta Pora), Brazil, 2016. METHODS: This was a normative evaluation based on indicators of service structure and work process; questionnaires were answered by health professionals involved in dengue prevention and control; the cut-off points used to determine the degree of implementation were 'implemented' (>75% of the activities implemented), 'partially implemented' (50 to 75%), 'low level of implementation' (25 to 49%), and 'not implemented' (<25%). RESULTS: 383 health professionals participated in this study, 227 of whom were from Corumba and 156 from Ponta Pora; the degree of PNCD implementation was 63.1% and 66.4% for Corumba and Ponta Pora, respectively, thus being classified as partially implemented in both municipalities. CONCLUSION: PNCD implementation was partial in both municipalities; problems observed indicate the need for program enhancement. PMID- 30517350 TI - Spatial study of leprosy in Bahia, Brazil, 2001-2012: an approach based on the local empirical Bayesian model. AB - OBJECTIVE: to compare the temporal evolution and spatial distribution of epidemiological indicators of leprosy, both crude and also corrected using the empirical Bayesian model, Bahia, Brazil, 2001-2012. METHODS: this was an ecological study using data from the Notifiable Diseases Information System; all 417 municipalities in Bahia were included and the following indicators per 100,000 inhabitants were analyzed - detection rate of new cases in the general population, in those <15 years old, and in those with grade 2 physical disability -; the local empirical Bayesian model was used to smoothen the indicators, and Student's t-test was used to compare means. RESULTS: indicators estimated by the model were higher than crude indicators; estimated detection rates in the general population and in those <15 years old were higher than crude rates in 253 (60.7%) and 209 (50.1%) municipalities, respectively; areas of greatest risk were concentrated in the northwestern and southern regions of the state. CONCLUSION: spatial distribution of the disease was heterogeneous and there was possible underreporting of cases. PMID- 30517351 TI - Human rabies: evaluation of post-exposure prophylaxis prevalence in Ceara, Brazil, 2007-2015. AB - OBJECTIVE: to analyze the prevalence of inadequate human anti-rabies post exposure prophylaxis in patients attacked by animals in the state of Ceara, Brazil, 2007-2015. METHODS: this was a study of the prevalence of inadequate prophylaxis procedures, using data on reported cases of accidents involving animals potentially capable of transmitting rabies registered on the Notifiable Diseases Information System (SINAN) from January 2007 to December 2015. RESULTS: of the 231,694 reported cases, 95.8% were found to have inadequate procedures, especially in young people aged under 19 (37.6%), with no difference between the sexes (p=0.04); higher prevalence rate of inadequate procedures occurred with regard to exposure to bites (PR=1.03 - 95%CI 1.02;1.03), multiple injuries (PR=1.07 - 95%CI 1.06;1.07), accidents involving dead/missing animals (RP=1.05 - 95%CI 1.05;1.06), and vaccine treatments (RP=1.03 - 95%CI 1.02;1.03). CONCLUSION: high prevalence of inadequate procedures indicates the need for a better epidemiological evaluation of cases and compliance with the Human Rabies Prophylaxis Technical Standards, in order to ensure adequate anti-rabies prophylaxis procedures. PMID- 30517352 TI - Evolution of socioeconomic inequalities in conducting prenatal consultations among Brazilian parturient women: analysis of the period 2000-2015. AB - OBJECTIVE: to analyze evolution as to conducting seven or more prenatal consultations with pregnant women in Brazil, in the period 2000-2015 according to maternal education level and race/skin color of the newborn baby. METHODS: this was a time series study based on Live Births Information System (SINASC) data; relative and absolute inequalities were investigated, adjusted for maternal age and gestational week in which childbirth occurred. RESULTS: we analyzed approximately 48 million births; the proportion of seven or more prenatal consultations increased nationally (from 46.0% to 66.9%) in all groups analyzed; the relative difference between the extremes of education level ranged from 3.0 to 2.0, while the absolute difference ranged from 53.1 to 47.7 percentage points; the adjusted ratio between White/Black race/skin color was 1.4 in 2000 and 1.2 in 2015. CONCLUSION: the proportion of pregnant women having seven or more prenatal consultations has increased in Brazil, although inequalities are still found. PMID- 30517353 TI - Improvement of data quality on the underlying cause of death from external causes using Health, Public Security and Press sector database linkage in the State of Rio de Janeiro, Brazil, 2014. AB - OBJECTIVE: to describe improvement of the quality of data on the underlying cause of death from external causes, after performing Health, Public Security and Press sector database linkage in the State of Rio de Janeiro, Brazil, 2014. METHODS: deterministic data linkage on deaths from external causes of undetermined intent and deaths from undetermined natural causes held on the Mortality Information System (SIM), Forensic Institute, Civil Police, Urgent Mobile Care Service (SAMU) and press databases. RESULTS: of the 13,916 deaths from external causes, deaths from causes of undetermined intent were reduced from 5,836 (41.9%) to 958 (6.9%); while 222 (10.7%) of the 2,069 deaths from undetermined natural causes were reclassified to external causes; there was an increase in mortality due to traffic accidents (93.0%), assault (71.6%), legal intervention (744.7%), intentional self-harm (112%) and other accidents (29.9%). CONCLUSION: there was an improvement in the quality of the information by type of underlying cause of death from external causes, using a strategy that can be reproduced by other services. PMID- 30517355 TI - TOO MUCH INFORMATION. WHAT TO DO? PMID- 30517354 TI - Syphilis in pregnancy and congenital syphilis and their relationship with Family Health Strategy coverage, Goias, Brazil, 2007-2014: an ecological study. AB - OBJECTIVE: to analyze the incidence of syphilis in pregnant women (SPW) and congenital syphilis (CS) and the correlation of these indicators with Family Health Strategy (FHS) coverage in Goias, Brazil, from 2007 to 2014. METHODS: this was an ecological study using Notifiable Diseases Information System (SINAN) data and data from the Health Ministry's Department of Primary Care; Spearman's correlation was used to evaluate the relationship between FHS coverage and syphilis incidence. RESULTS: SPW incidence increased from 2.8 to 9.5/1,000 live births, while CS incidence increased from 0.3 to 2.5/1,000 live births (p<0.05) in the period 2007-2014; there was a significant increase in CS cases in municipalities with percentage FHS coverage below 75% (p<0.001). CONCLUSION: the concomitant increase in SPW and CS incidence suggests failures in the prevention of vertical transmission of syphilis, especially in regions with lower FHS coverage. PMID- 30517356 TI - SHORT-TERM RESULTS OF MINIMALLY INVASIVE TREATMENT OF GASTROESOPHAGEAL REFLUX DISEASE BY RADIOFREQUENCY (STRETTA): FIRST BRAZILIAN SERIES OF CASES. AB - BACKGROUND: New endoscopic treatments for gastroesophageal reflux (GERD) are developed every year and are indicated in cases that are refractory to conventional therapies as well as after surgical treatment failure. OBJECTIVE: To present the first cases of endoscopic therapy for GERD performed in Brazil. METHODS: Use of radiofrequency with the Stretta procedure in symptomatic volunteers diagnosed with GERD. RESULTS: The technique was performed in three patients after they were included in the study protocol. No patient had complications, and all patients were discharged on the same day, either without medication or taking it sporadically for symptom control. CONCLUSION: Endoscopic treatment for GERD using radiofrequency was effective in the cases presented herein with no technical complications. PMID- 30517357 TI - Level VI lymph nodes: an anatomic study of lymph nodes located between the recurrent laryngeal nerve and the right common carotid artery. AB - OBJECTIVE: to describe the presence of lymph nodes and their relationships with demographic and anthropometric characteristics in a specific region, not yet described in anatomy compendiums, called by us Recurrent Carotid Recess (RCR) and located among the right recurrent laryngeal nerve, the right common carotid artery, and the right inferior thyroid artery. METHODS: 32 right cervical regions were harvested from cadavers within 24 hours post-mortem. The fibro-fatty tissue of the RCR was resected and prepared with formalin fixation. It was then subjected to an increasing sequence of alcohols (70%, 80%, and 90%), subsequently to a solution of Xylol, and finally to a solution of Methyl Salicylate, respecting the time required for each step. The macroscopic study was carried out on the diaphanized piece, observing the presence or not of lymph nodes. When present, they were photographed and their measurements were gauged with a digital caliper. In the microscopic study, hematoxylin-eosin staining was used to confirm the lymph node. RESULTS: the presence of lymph nodes was observed in 22 (68.75%) of the 32 specimens. The number of lymph nodes ranged from zero to six (mean of 1.56+/-0.29), per cadaver, and their mean size was 7.82mmx3.86mm (longitudinal x transversal diameters). CONCLUSION: the relationship between anthropometric data and presence of lymph nodes in the RCR (Fisher's exact test) was significant for medium-height individuals (p=0.03) and also white ones (p=0.04). PMID- 30517358 TI - Trauma and early blood transfusion: the challenging hemorrhage management in Jehovah's Witnesses. AB - The management of patients, such as Jehovah's Witnesses, who refuse to receive blood transfusions, is often a medical challenge, not only because of the ethical dilemma, but also because it creates a major obstacle to rapid hemorrhage control in a setting of trauma. This article explores the reasons for this conflict between the physician's duty of care and the respect for the patient's autonomy, and draws a panorama of the main understandings of the Judiciary on the subject. Finally, it is concluded that the manifestation of the patient's will, although free, is not enough to release the doctor from his (her) duty of care. In case of danger to life, the doctor must carry out a blood transfusion, regardless of the patient's consent or the permission of those responsible for the patient. PMID- 30517359 TI - Epidemiological study of bucomaxilofacial trauma in a Paraiba reference hospital. AB - OBJECTIVE: to study the epidemiological data of patients suffering from buccomaxillofacial trauma treated at a referral hospital in the State of Paraiba. METHODS: we conducted a cross-sectional study of inductive approach, with a comparative statistical procedure and research technique by field direct documentation. The sample comprised hospital records obtained from January 2016 to December 2017 of patients attended by the Service of Buccomaxillofacial Surgery and Traumatology of this hospital, and consisted of 332 patients according to the study's eligibility criteria. Two previously calibrated examiners collected and analyzed the data, both descriptively and inferentially. RESULTS: males sustained the majority of facial trauma (83.1%), mainly in the third decade of life (32.2%). Motorcycle accidents were the most common etiology of trauma for both genders. In relation to inferential statistics with a margin of error of 5%, there was no significant association (p>0.05) between the genders and the trauma etiological factors. The bones of the nose (38.2%) were the most affected bones and the most frequent soft tissue injury was edema, in 50.9% of cases. Only 20.8% of the patients with bone fractures were polytraumatized. CONCLUSION: the victims of oral and maxillofacial trauma attended at our hospital are predominantly men in the third decade of life, involved in motorcycle accidents and sustaining lesions in the nose bones nose. PMID- 30517360 TI - Immunohistochemical analysis of tissue factor expression in gastric carcinoma: correlations with prognosis and survival. AB - OBJECTIVE: to study the expression of the tissue factor (TF) and its correlation with prognosis and survival in patients with gastric carcinoma. METHODS: we measured the immunohistochemical expression of TF in 50 specimens of gastric adenocarcinomas from patients submitted to curative surgery. We then compared the intensity of its expression with clinical and pathological data, TNM staging, prognostic factors and survival. RESULTS: all tumors displayed TF expression; the intensity of TF expression was not associated with TNM stage, clinical or pathological variables or general survival. CONCLUSION: TF has a high expression in gastric carcinoma, but that it is not useful as a prognostic marker. PMID- 30517361 TI - Percutaneous laser ablation of benign thyroid nodules: a one year follow-up study. AB - OBJECTIVE: To evaluate safety and effectiveness of nodule volume reduction and thyroid function after percutaneous laser ablation treatment in patients with benign nonfunctioning thyroid nodules. METHODS: Prospective single-center study, from January 2011 to October 2012, which evaluated 30 euthyroid and thyroid antibodies negative patients with benign solitary or dominant nodule with indication of treatment due to compressive symptoms and aesthetic disturbances. The clinical and laboratory (thyroid ultrasound, TSH, FT4, TG, TG-Ab, TPO-Ab and TRAb levels) evaluations were performed before the procedure, and periodically 1 week, 3 months and 6 months after. The ablation technique was performed under local anesthesia and sedation. In each treatment, one to three 21G spinal needle were inserted into the thyroid nodule. The laser fiber was positioned through the needle, which was then withdrawn 10mm to leave the tip in direct contact with the nodule tissue. Patients were treated with a ND: Yag-laser output power of 4W and 1,500 to 2,000J per fiber per treatment. The entire procedure was performed under US guidance. RESULTS: Thirty patients, with a total of 31 nodules submitted to laser ablation were evaluated. The median volumetric reduction of the nodule was approximately 60% after 12 months. No statistical significance was observed on thyroid function and antibodies levels. There was a peak on the level of thyroglobulin after the procedure due to tissue destruction (p<0.0001). No adverse effects were observed. CONCLUSION: Percutaneous laser ablation is a promising outpatient minimally invasive treatment of benign thyroid nodule. PMID- 30517362 TI - Is quality of life affected by temporomandibular disorders? AB - OBJECTIVE: To determine the impact of temporomandibular disorders in quality of life. METHODS: A total of 102 volunteer patients (68 female) aged 19 to 86 years, who sought medical care in health clinics of the university and were evaluated in the period from September to December 2013. The subjects were examined according to the Research Diagnostic Criteria for Temporomandibular Disorders, using a mechanical algometer (Palpeter(r)) with standardized pressure of 0.5 and 1.0kg, and Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) questionnaire, to assess quality of life. The data were tabulated for statistical analysis and the variables were correlated with the clinical findings of the temporomandibular disorders and quality of life. RESULTS: Fifty percent of patients were positive for temporomandibular disorders and 39.2% classified as myofascial pain group. The temporomandibular disorder group was significantly associated with uncomfortable bite (p=0.0000), temporomandibular joint clicking (p=0.0001) and tooth clenching (p=0.0001). The Mann Whitney test used to analyze the SF-36 revealed that the domains of pain (mean score of 47.80%; p<0.0001) and mental health (62.67%; p<0.05) were strongly associated with temporomandibular disorders. CONCLUSION: The quality of life of individuals with temporomandibular disorders was negatively affected by the presence of pain and mental health disorders. PMID- 30517363 TI - Effect of auditory-motor training on auditory processing of school children. AB - OBJECTIVE: To compare performance in Avaliacao Simplificada do Processamento Auditivo Central and Scale of Auditory Behaviors scores before and after auditory and motor training. METHODS: Sample comprising 162 children aged 9 to 11 years and attending public schools in the city of Sao Paulo (SP), Brazil; 122 out of 162 children were allocated to one of three experimental groups: Multisensory; Auditory/Motor and Motor/Auditory. Experimental groups were submitted to 8 hours of auditory, visuospatial and motor stimulation over the course of 8 weeks. The remaining 40 children formed the Control Group and received no stimulation. RESULTS: Relation between child behavior as perceived by school teachers and auditory test responses revealed that the better the performance in auditory processing assessment, the higher the Scale of Auditory Behaviors scores. CONCLUSION: Auditory and motor training led to improvements in auditory processing skills as rated by Avaliacao Simplificada do Processamento Auditivo Central and Scale of Auditory Behaviors; this intervention model proved to be a good tool for use in school settings. PMID- 30517364 TI - Clinical, dietary and demographic characteristics interfering on quality of life of cancer patients. AB - OBJECTIVE: To estimate the dietary intake of cancer patients and its relation with clinical and demographic characteristics, and to assess the contribution of dietary intake, appetite/symptoms and clinical and demographic characteristics to their quality of life. METHODS: The consumption of energy and macronutrients of patients was estimated. The relation between dietary intake and clinical and demographic characteristics was evaluated by analysis of variance. The intake of energy and macronutrient of the patients was compared to the nutritional recommendations using 95% confidence interval. The Cancer Appetite and Symptom Questionnaire (CASQ) and the European Organization for Research and Treatment of Cancer (EORTC QLQ C-30) were used to assess appetite/symptoms and quality of life, respectively. The psychometric properties of the instruments were estimated. A structural equation model was prepared. RESULTS: In this study, 772 cancer patients (63.1% women) participated. There was a significant relation between dietary intake and work activity, economic class, specialty field of cancer, type of treatment and nutritional status. Patients' energy and macronutrients intake was below recommended values. Both CASQ and EORTC QLQ C-30 were refined to fit the data. In the structural model, impaired appetite, more symptoms, presence of metastasis, being female and of higher economic classes were characteristics that significantly contributed to interfering in patients' quality of life. CONCLUSION: The dietary intake of oncology patients did not reach the recommended values. Different characteristics impacted on quality of life of patients and should be considered in clinical and epidemiological protocols. PMID- 30517365 TI - Profile of drugs used for self-medication by elderly attended at a referral center. AB - OBJECTIVE: To determine the profile of medications used for self-medication by the elderly. METHODS: A cross-sectional study based on interviews with elderly seen at a reference center for Elderly Health of a teaching hospital, from July 2014 to July 2015. Clinical, demographic and pharmacotherapeutic data were collected. RESULTS: A total of 170 elderly were interviewed, 85.9% female, and the median age was 76 years. The frequency of self-medication was 80.5%. The most used medications for self-medication were central acting muscle relaxants, analgesics and antipyretics, non-steroidal anti-inflammatory and antirheumatic agents. Among the elderly who practiced self-medication, 55.5% used drugs that were inappropriate for the elderly, according to Beers criteria of 2015, and 56.9% used medications that showed therapeutic duplicity with the prescribed drugs. We identified 57 drugs used for self-medication, of which 30 (52.6%) were classified as over-the-counter and 27 (47.4%) as prescription drugs. Approximately 68.6% of elderly had at least one interaction involving drugs prescribed and those used for self-medication. CONCLUSION: The practice of self medication was frequent in the elderly studied. The widespread use of over-the counter drugs and/or potentially inappropriate medications for elderly increases the risk of drug interactions and adverse events. PMID- 30517366 TI - Facial nerve hemangioma in the middle ear. AB - Facial nerve hemangioma is a rare and benign vascular tumor, and accounts for 0.7% of intratemporal tumors. We report the second case described in the literature of a facial nerve hemangioma in its tympanic segment. A 14-year-old male patient presented with a history of progressive right ear hearing loss with preserved facial mimicry. Pure tone audiometry showed a right ear moderate conductive hearing loss. Magnetic resonance imaging demonstrated an expansive lesion involving the tympanic segment of the right facial nerve, suggestive of hemangioma. Watchful waiting was chosen as management. In the first case of middle ear facial hemangioma described in the literature, facial palsy was the symptom that led the patient to seek medical care. In the present case, it can be inferred that the first symptom was conductive hearing loss ipsilateral to the lesion. Facial palsy may not be present and the clinical presentation may resemble otosclerosis, ossicular chain disruption, and third window abnormalities, among other differential diagnoses of conductive hearing loss. The second case of tympanic portion facial nerve hemangioma is reported, describing the specificity of conductive hearing loss as its only clinical manifestation. PMID- 30517368 TI - What is the future of the Brazilian Public Health System? PMID- 30517367 TI - Polyclonal anti T-lymphocyte antibody therapy monitoring in kidney transplant recipients: comparison of CD3+ T cell and total lymphocyte counts. AB - OBJECTIVE: To investigate the correlation between total lymphocyte and CD3+ T cell counts in peripheral blood in renal transplant patients treated with anti thymocyte globulin, and discuss related outcomes. METHODS: A single-center, retrospective study involving 226 patients submitted to kidney transplant between 2008 and 2013, and treated with anti-thymocyte globulin for induction or treatment of cellular rejection. Doses were adjusted according to CD3+ T cell or total lymphocyte counts in peripheral blood. RESULTS: A total of 664 paired samples were analyzed. The Spearman's correlation coefficient was 0.416 (p<0.001) for all samples combined; the overall Kappa coefficient was 0.267 (p<0.001). Diagnostic parameters estimated based on total lymphocyte counts were also calculated using the number of CD3+ T cells (gold standard), with a cut off of >20 cells/mm3. CONCLUSION: Total lymphocyte and CD3+ T cell counts in peripheral blood are not equivalent monitoring strategies in anti-thymocyte globulin therapy. PMID- 30517369 TI - Nanotechnology and multipotent adult progenitor cells in Reparative Medicine: therapeutic perspectives. AB - The biology of stem cells is one of the most dynamic and promising fields of the biological sciences, since it is the basis for the development of organisms. Its biological complexity demands efforts from several lines of research aimed mainly at its therapeutic use. Nanotechnology has been emerging as a new field of study, which shows great potential in the treatment of various diseases. This new area of health has been called "Nanomedicine" or "Bionanotechnology", which can be applied in Medicine by transport and drug delivery systems, robotic tools to be used in diagnostic and surgical processes, nanobiomaterials, gene therapies, nanobiomedical devices, among others. Because stem cells and Nanotechnology are two areas of extremely promising science, a new field of study, called "stem cell Nanotechnology", has gradually emerged. In this, Nanotechnology is used to help the stem cells apply their therapeutic potential in the treatment, cure, and repair of the damaged tissues, in an effective and safe way. In this way, stem cell Nanotechnology has generated great interest, since it may result in significant contributions to Regenerative Medicine and tissue engineering. The present work aims to present the state-of-the-art regarding its therapeutic use in Human Medicine. PMID- 30517370 TI - Severe iron-deficiency anemia as initial manifestation of pulmonary hemosiderosis in a child. AB - Idiopathic pulmonary hemosiderosis is a potentially fatal disease that results from episodes of alveolar hemorrhage of unknown origin. The clinical spectrum is varied, and anemia may constitute the only manifestation of illness, preceding other signs and symptoms by several months. We present the case of a 4 year-old child presenting with fever, vomiting and prostration, associated with pallor. He had microcytic and hypochromic anemia refractory to iron therapy. Gastrointestinal bleeding was ruled out after negative extensive etiological investigation. Subsequently, pulmonary infiltrates suggestive of alveolar hemorrhage were observed in the chest radiography. The cytological exam of the bronchoalveolar lavage showed hemosiderin-laden macrophages. After the etiological study, the diagnosis of idiopathic pulmonary hemosiderosis was made by exclusion. He was initiated on corticosteroid therapy, later associated to an immunosuppressive agent, with subsequent correction of anemia and of the radiological pattern. The patient is currently asymptomatic. PMID- 30517371 TI - From Evidence-Based Medicine to Precision Health: Using Data to Personalize Care. PMID- 30517372 TI - Warning Against Low-Density Lipoprotein Oxidation in Users of Oral Combined Contraceptives. PMID- 30517373 TI - The Nature of Cardiac Remodeling Due to Physical Exercise: More Evidence Towards to the Normal Adaptive Responses of the Heart. PMID- 30517375 TI - Myocardial Perfusion Scintigraphy after Percutaneous Coronary Intervention in Asymptomatic Patients: Useful or Futile? PMID- 30517374 TI - The Prognostic Value and Clinical Use of Myocardial Perfusion Scintigraphy in Asymptomatic Patients after Percutaneous Coronary Intervention. AB - BACKGROUND: The role of myocardial perfusion scintigraphy (MPS) in the follow-up of asymptomatic patients after percutaneous coronary intervention (PCI) is not established. OBJECTIVES: To evaluate the prognostic value and clinical use of MPS in asymptomatic patients after PCI. METHODS: Patients who underwent MPS consecutively between 2008 and 2012 after PCI were selected. The MPS were classified as normal and abnormal, the perfusion scores, summed stress score (SSS), and summed difference score (SDS) were calculated and converted into percentage of total perfusion defect and ischemic defect. The follow-up was undertaken through telephone interviews and consultation with the Mortality Information System. Primary endpoints were death, cardiovascular death, and nonfatal acute myocardial infarction (AMI), and secondary endpoint was revascularization. Logistic regression and COX method were used to identify the predictors of events, and the value of p < 0.05 was considered statistically significant. RESULTS: A total of 647 patients were followed for 5.2 +/- 1.6 years. 47% of MPS were normal, 30% were abnormal with ischemia, and 23% were abnormal without ischemia. There were 61 deaths, 27 being cardiovascular, 19 non fatal AMI, and 139 revascularizations. The annual death rate was higher in those with abnormal perfusion without ischemia compared to the groups with ischemia and normal perfusion (3.3% * 2% * 1.2%, p = 0.021). The annual revascularization rate was 10.3% in the ischemia group, 3.7% in those with normal MPS, and 3% in those with abnormal MPS without ischemia. The independent predictors of mortality and revascularization were, respectively, total perfusion defect greater than 6%, and ischemic defect greater than 3%. Forty-two percent of the patients underwent MPS less than 2 years after PCI, and no significant differences were observed in relation to those who underwent it after that period. CONCLUSION: Although this information is not contemplated in guidelines, in this study MPS was able to predict events in asymptomatic after PCI patients, regardless of when they were performed. PMID- 30517376 TI - Cystatin C as a Candidate Biomarker of Cardiovascular Outcomes: Too Near, but too Far from Reality. PMID- 30517377 TI - Can Non-Pharmacological Treatment Promote Additional Benefit for Children with Familial Hypercholesterolemia Treated with Statins? PMID- 30517378 TI - Paroxysmal Atrial Fibrillation Catheter Ablation of Pulmonary Veins: does Anatomy Influence the Outcome? PMID- 30517379 TI - CADE-Q SV: Practical and Relevant in the Assessment of Patients with Cardiovascular Diseases regarding their Health Condition. PMID- 30517380 TI - Cardiovascular Manifestations of Erdheim-Chester's Disease: A Case Series. AB - Erdheim-Chester Disease is a rare entity, classified as an inflammatory myeloid neoplasm, with an unknown incidence, occurring preferentially in men after 50 years of age. Classically, it has a multisystemic presentation, with the skeletal system being the most frequently affected (90% of the patients), followed by genitourinary involvement in 60% of cases and central nervous system in the pituitary and diabetes insipidus in 25% of the cases. Cardiovascular manifestations are present in more than half of the patients, with aortic infiltration and atrial pseudotumor being the most common forms. PMID- 30517382 TI - Case 6 - Woman with Ischemic Heart Disease Admitted due to Chest Pain and Shock. PMID- 30517381 TI - Sudden Death in Young Brazilian Athletes: Isn't It Time We Created a Genuinely National Register? AB - Young competitive athletes (<= 35 years old) with or without a previous diagnosis of cardiovascular disease may suddenly die in competitive activities, potentially leading to an impact in society through the media. Although the relative risk for sudden death (SD) in athletes is twice as high as for their counterparts, the absolute incidence is low. While there is consensus among medical societies worldwide that early detection of causal factors is highly desirable, there is debate among different screening schemes to that end. In Brazil, the recommendations of the Brazilian Society of Cardiology mirror the guidelines of the European Society of Cardiology (ESC), which indicate a clinical examination combined with a 12-lead resting electrocardiogram, regardless of the presence of risk factors. The possibility of genetic screening is also plausible, since most clinical entities that cause SD in young competitive athletes are related to genotype. Finally, considering the diversity of practiced sports, and the population miscegenation, we emphasize the need to a national registry of cases. PMID- 30517383 TI - Myocarditis with Cardiogenic Shock as the First Manifestation of Systemic Lupus Erythematosus. PMID- 30517384 TI - Anxiety and Depression and their Association with Low Quality of Life in Patients with Metabolic Syndrome. PMID- 30517385 TI - Evidence-Based Nursing Setting and image. PMID- 30517386 TI - Scientific production of the International Classification for Nursing Practice: a bibliometric study. AB - OBJECTIVE: To describe the scientific production of the International Classification for Nursing Practice throughout dissertations and theses published by nurses in Brazil from 1996 to 2016. METHOD: A bibliometric, descriptive, quantitative documentary study, carried out from October/2015 to July/2016 on the sites of the Center of Studies and Research in Nursing (CEPEn), at the thesis and dissertation banks of the Coordination of Improvement of Higher Education Personnel and of the Plataforma Sucupira (Sucupira Platform). RESULTS: There were 108 productions, 30 theses and 78 dissertations. In 2014, there was the largest number of publications (19). The Graduate Program in Nursing of the Universidade Federal da Paraiba had the highest number of productions (23). Regarding the theme, the use in clinical practice was highlighted (69), followed by the elaboration of terminology subsets (17). CONCLUSION: The Brazilian scientific production setting on ICNP(r) is expressive, evidencing this system as a tool that allows the provision of systematic care. PMID- 30517387 TI - The body marked by the arteriovenous fistula: a phenomenological point of view. AB - OBJECTIVE: To understand the experience of people with chronic kidney disease using arteriovenous fistula. METHOD: Qualitative and exploratory study based on Social Phenomenology, conducted on 30 adults undergoing hemodialysis by using the fistula, interviewed in 2017. The interviews were analyzed according to the empirical-comprehensive model proposed by Amedeo Giorgi. RESULTS: We found the categories "The changed body aesthetics"; "The perception of the other about my body"; and "The fistula as an inseparable condition for life maintenance." FINAL CONSIDERATIONS: The experience of people using fistula showed that this venous access leaves marks that change the body aesthetics, making the body imperfect. Such changes cause low self-esteem and attract the look of the other, causing embarrassment in those who have the body changed. Thus, they react by camouflaging the fistula, without which there is no life. This perception arises from the fear that works as a catalyst for self-care. PMID- 30517388 TI - Predictive factors of the interruption of exclusive breastfeeding in premature infants: a prospective cohort. AB - OBJECTIVE: to evaluate the incidence of exclusive breastfeeding and the risk factors associated to its interruption in premature infants after hospital discharge. METHOD: this is a prospective cohort with 113 premature infants in a neonatal unit, whom were followed-up from 7 to 15 days after hospital discharge. The outcome was the interruption of exclusive breastfeeding. Maternal and neonatal exposure variables were evaluated by a regression model and described by the confidence interval (95%) and risk ratio. RESULTS: exclusive breastfeeding rate was 81.4% at discharge and 66.4% at 7 to 15 days after discharge. Double gestation, time of mechanical ventilation and birth weight were associated with higher risks of interruption of exclusive breastfeeding after discharge. CONCLUSION: there is a need for the implementation of actions that promote the early onset and maintenance of exclusive breastfeeding of premature infants. PMID- 30517389 TI - Clinical-epidemiological aspects of patients submitted to Percutaneous Coronary Intervention in a university hospital. AB - OBJECTIVE: To outline the clinical-epidemiological profile of patients submitted to Percutaneous Coronary Intervention in a Reference Hospital in Urgent Cardiology Clinic of the state of Rio Grande do Norte. METHOD: This is a descriptive, exploratory, prospective study with a quantitative approach developed in a Brazilian University Hospital with patients submitted to Percutaneous Coronary Intervention. Data collection occurred between April and October 2017. RESULTS: The sample consisted of 222 patients, of whom 58.10% underwent Elective Percutaneous Coronary Intervention and 41.89% were primary, 65.3% males, with a mean age of 62.7. In comorbidities "Hypertension", "Acute Myocardial Infarction", "Current Smoking" and "Physical Inactivity" were highlighted. CONCLUSION: In the elective patients, there was a high prevalence of risk factors and in patients with urgent cases, high time of total ischemia. It is necessary to create strategies to structure the care line, to improve the effectiveness of treatment and to minimize adverse outcomes. PMID- 30517390 TI - Experience of adults with cystic fibrosis: a perspective based on social phenomenology. AB - OBJECTIVE: To understand the experience of adults living with cystic fibrosis. METHOD: A qualitative study based on the social phenomenology by Alfred Schutz, carried out with 12 adults interviewed in 2016. The statements were analyzed and organized into concrete categories. RESULTS: The following categories were evidenced: "The biopsychosocial impact of the disease on daily life", "Social prejudice as a generator of embarrassment", "Coping strategies" and "Fear, uncertainties and the desire to carry out life projects". FINAL CONSIDERATIONS: The understanding of the experience lived by adults with cystic fibrosis allowed unveiling intersubjective aspects experienced by this public that should be considered by health professionals in the care of this group. It is up to the professionals involved in assisting these people to develop care strategies aimed at completeness, respect for the world of meanings of each individual, their life history, and intersubjectivity that is specially built in the relationship between professionals and people with cystic fibrosis. PMID- 30517391 TI - Family Health Strategies: Profile/quality of life of people with diabetes. AB - OBJECTIVE: To evaluate the quality of life and to analyze the epidemiological profile of people with diabetes treated in Family Health Strategies. METHOD: A cross-sectional study carried out with 350 people with diabetes. RESULTS: Most people with diabetes are women, elderly, married, white, with low educational level, retired/pensioners, family income of up to two minimum wages. As the time of people with the disease increases, their quality of life decreases. People with complications from diabetes have a lower quality of life, with a statistically significant difference. CONCLUSION: Knowledge of the sociodemographic characteristics, clinical evaluation and quality of life of people with diabetes can improve the care process provided to this population. PMID- 30517392 TI - Violence against women: historical trajectory of a care program (Curitiba - 1997 2014). AB - OBJECTIVE: To analyze the historical trajectory and the contributions of the Programa de Atencao as Mulheres em Situacao de Violencia (Program of Care to Women Victims of Violence) of Curitiba. METHOD: Research with documentary and local approach, inspired by the Dimension of Political History, to unveil power relations, political representations, symbols and discourses. Eighty-eight sources were used for the period 1997-2014. The data collection was performed in May 2016 and presented in the timeline modality. RESULTS: The historical trajectory of the program indicates intersectoral and interinstitutional experience that has been increasing and originating important innovations in care to women based on humanization and from the perspective of comprehensiveness. FINAL CONSIDERATIONS: Historicizing the Program contributed to the reflection on the construction of practices aimed at confronting violence, the need for intersectoral actions and looks that involve its complexity. PMID- 30517393 TI - Impact of breast cancer and quality of life of women survivors. AB - OBJECTIVE: To evaluate the impact of breast cancer and the quality of life of women survivors and to identify associations between sociodemographic and clinical variables. METHOD: This was a cross-sectional, analytical, quantitative study conducted with women receiving outpatient post-treatment care at a public institution of the city of Sao Paulo, state of Sao Paulo, Brazil. Instruments: sociodemographic and clinical questionnaires; Impact of Cancer scale; Functional Assessment of Cancer Therapy-Breast Cancer scale. Descriptive and analytical statistical analysis were performed. RESULTS: One hundred women were included in the study with a mean age of 60 years (SD = 11.3); most with less than 5 years of follow-up, low purchasing power, and low education levels. Negative Impact of Cancer: Health Worry, Body Changes, Feelings, and Meaning of Cancer. Quality of life: 81.9 (18.3), specific: 105.6 (24.6). The following subscales of the impact of cancer scale predicted lower quality of life scores: Body Changes, Negative Self-Evaluation, and Concerns about Cancer (p <0.05). CONCLUSION: Although they presented high scores for quality of life, patients reported negative impacts of cancer, enhanced by vulnerabilities. PMID- 30517394 TI - VER-SUS project: Influences on the training and performance of nurses. AB - OBJECTIVE: To analyze the influences of the Vivencias e Estagios na Realidade do Sistema Unico de Saude (Brazilian Unified Health System), in the training and performance of nurses. METHOD: A qualitative study was carried out with 14 nurses who participated in the VER-SUS project in Rio Grande do Sul State. The data were collected through a semi-structured interview technique. The data were analyzed, interpreted and discussed, through the technique of Content Analysis. RESULTS: The categories "VER-SUS Influences on Nursing Training for SUS" and "VER-SUS Contributions for Nurses Performance in the SUS" were highlighted. FINAL CONSIDERATIONS: It was possible to identify the influences of the VER-SUS project in the training and performance of the nursing professionals, pointing out the revision of the Pedagogical Projects of Course and the preparation of the teachers, as a way to carry out the training with emphasis in the Brazilian Unified Health System. PMID- 30517395 TI - The waiting room: potential for people with arterial hypertension to learn. AB - OBJECTIVE: To analyze the meanings assigned by people with systemic arterial hypertension to health education actions in the waiting room. METHOD: This is an analytical qualitative study, held in 2016 with 19 people with arterial hypertension from a health unit. The data were collected in households, through a semi-structured interview and field notes, recorded on audio, transcribed and organized by thematic analysis, being analyzed considering Vygostky's Cultural Historical Learning Theory. RESULT: Meanings of attention, interest, pleasure and learning assigned to educational practice denote the importance of interaction and mediation to reconstruct knowledge about blood pressure control and to attribute a new meaning to self-care. FINAL CONSIDERATIONS: The waiting room became an environment that promoted interaction, favoring the construction of meanings and internalization of knowledge with potential for lifestyle changes. PMID- 30517396 TI - Educational program for coronary artery disease patients: results after one year. AB - OBJECTIVE: To evaluate the long-term results of an educational program compared to usual care. METHOD: A longitudinal study in which 56 participants from a previous study (randomized controlled clinical trial) were evaluated twelve months after the percutaneous coronary intervention (PCI). Health-related quality of life (HRQoL) was assessed by the Medical Outcomes Study: 36-item Short Form (SF-36), and anxiety and depression symptoms were assessed by the Hospital Anxiety and Depression Scale (HADS). A repeated measures analysis of variance was performed (significance level 0.05). RESULTS: Participants in the educational program showed improvement of HRQoL in the Role-Emotional domain, while those in the usual care did not present changes (p=0.05). Both groups showed improvement in the Role-Physical (p = 0.001) and Bodily Pain (p=0.01) domains over time. There were no differences in the symptoms of anxiety and depression. CONCLUSION: One year after the PCI, there were significant differences between groups only for the Role-Emotional domain of the SF-36. PMID- 30517397 TI - Diffusion of the e-SUS Primary Care innovation in Family Health Teams. AB - OBJECTIVE: To analyze the diffusion of e-SUS Primary Care innovation in Family Health Teams. METHOD: A qualitative approach case study, based on Innovation Diffusion Theory and Technology Acceptance Model. We conducted 62 interviews and observation of professionals from Family Health Teams in six municipalities of Minas Gerais State, between March 2016 and January 2017. The data were treated through Categorical Thematic Content Analysis and, systematized, with Atlas.ti software . RESULTS: It was verified that although the e-SUS Primary Care strategy is recognized as a technological innovation, situations predominate that weaken its acceptance as: incompatibilities with the work process; sudden deployment, poor training; work overload; resistance; and negative impacts on health care. CONCLUSION: The diffusion of the e-SUS Primary Care strategy as a technological innovation has presented potential situations of its rejection, conforming as challenges to be overcome. PMID- 30517398 TI - Knowledge of healthcare professionals about breastfeeding and supplementary feeding. AB - OBJECTIVE: To analyze the knowledge of breastfeeding (BF) and supplementary feeding (SF) of professionals in the Primary Health Care. METHOD: Cross-sectional study, with 168 professionals, conducted between June and September 2016. The Kruskal Wallis test was used to compare means of percentage of knowledge about BF and SF, by professional category and contingency testing, for association between variables. RESULTS: From the total of professionals, 39.29% of them demonstrated good knowledge about BF and 2.38% about SF; 74.4% of respondents reported not knowing the program Brazilian Breastfeeding and Feeding Strategy (EAAB - Estrategia Amamenta e Alimenta Brasil). There was a positive association between professionals' level of knowledge about BF and education (p=0.04), occupation (p=0.05) and healthcare in BF (p=0.04). Regarding the level of knowledge about SF, there was association between education (p<0.01) and healthcare in SF (p=0.04). CONCLUSION: The professionals have greater knowledge about breastfeeding when compared to supplementary feeding. PMID- 30517399 TI - Nursing diagnoses in primary health care consultations to newborns. AB - OBJECTIVE: To describe and analyze nursing diagnoses established on newborns' medical consultations in a primary health care service. METHOD: Descriptive, analytical and quantitative study performed in a primary health care clinic in Sao Paulo. Data were collected from the medical records of 37 children treated in 39 nursing consultations during their neonatal period. The identified nursing diagnoses were analyzed regarding: frequency, classification in strengthening or exhaustion in light of the health-disease process, and the correspondence with the essential needs of infants. RESULTS: 372 diagnoses were identified, most of them of strengthening (71%), such as efficient development (n = 37) and effective growth (n = 36). Among the exhaustion diagnoses (29%), there was a predominance of risk for suffocation (n = 15) and impaired tissue integrity (n = 14). Most diagnoses corresponded to the need of physical protection and security. CONCLUSION: Families are strengthened in the care of the essential needs of newborns, however, preventing diseases is necessary. PMID- 30517400 TI - Breastfeeding self-efficacy among blind mothers. AB - OBJECTIVE: To evaluate breastfeeding self-efficacy among blind mothers. METHOD: This is a descriptive and exploratory research carried out in Fortaleza-Ceara, with ten blind mothers. Data were collected through an interview with the application of a socioeconomic and obstetric questionnaire and the Breastfeeding Self-Efficacy Scale - Short Form. RESULTS: The majority of blind mothers presented high breastfeeding self-efficacy, but there were also mothers with low breastfeeding self-efficacy. CONCLUSION: It is necessary to follow-up mothers throughout the entire breastfeeding period to maintain or improve breastfeeding self-efficacy in this specific public. PMID- 30517401 TI - Importance of health guidance for family members of children with sickle cell disease. AB - OBJECTIVE: To know the main health guidance needs of family members of children with sickle cell disease. METHOD: Qualitative research, developed in a pediatric reference hospital of Ceara State, between April and May 2017, through the participation of 12 family members of children with sickle cell disease. The data were collected through semi-structured interviewees and analyzed according to the Bardin's Thematic Categorical Analysis. RESULTS: The relatives had divergent opinions about what this pathology would be and expressed the expectation of being broadly guided, from general information (signs and symptoms) to more complex ones about the disease, including major complications and ways of preventing them. FINAL CONSIDERATIONS: The health fragility due to the punctual and/or meager guidance provided to family members reflects the importance of increasing knowledge and clarifying doubts of these relatives about the disease, which makes it urgent to develop health education strategies by multiprofessional teams. PMID- 30517402 TI - Hypermedia on peripheral venipuncture: effectiveness in teaching nursing students. AB - OBJECTIVE: To assess the effectiveness of an educational hypermedia in the knowledge of Nursing academics on peripheral venipuncture. METHOD: Quasi experimental study with pre and post-test design. RESULTS: The mean number of right answers of the 73 individuals who participated in the study, in the pre test, was 7.7 (DP = 1.05), and 8.3 in the post-test (DP = 0.74). The comparation of pre and post hypermedia mean number of right answers showed significant difference (p < 0.001). CONCLUSION: Hypermedia is a strategy that increases knowledge and is feasible in the teaching-learning process, being useful as a support tool for teachers and for the development of undergraduate Nursing students. PMID- 30517403 TI - Overweight and associated factors in young adult student girls. AB - OBJECTIVE: To analyze overweight and associated factors in young adult student girls children in a capital city of Northeast Brazil. METHOD: An analytical, quantitative study was conducted with 546 young adults from 26 schools in a capital city of the Brazilian Northeast. After obtaining the data by the application of a specific questionnaire, the hierarchical logistic regression was used to identify the confounding variables and predictors of overweight. RESULTS: The frequency of cases of overweight in this group was 36.6%. In the bivariate analysis, Overweight presented a statistically significant association with ethnicity, marital status, weight in childhood and overweight in adolescence, overweight in the family and exposure to alcohol, number of children, and age of menarche. In the final regression model, overweight remained associated with weight in childhood and age of menarche. CONCLUSION: Characteristics related to nutritional status in earlier life stages and gynecological issues were associated with Overweight during the young adult stage of the woman. PMID- 30517404 TI - Cross-cultural adaptation of the General Comfort Questionnaire to Brazilian patients with myocardial infarction. AB - OBJECTIVE: Describe the first stages of the cross-cultural adaptation process of the General Comfort Questionnaire for myocardial infarction patients in intensive care units. METHOD: This is a study of qualitative and quantitative research and analysis techniques. Conceptual, item, semantic and operational equivalence was performed. Fifteen items were added to the original instrument to better represent the comfort experienced by myocardial infarction patients in intensive care units. The content validity index was applied to analyze the answers of the experts; it was considered adequate above 0.78. RESULTS: Some changes suggested by the experts for better understanding were adopted. All items were kept, obtaining a scale of sixty-three items. In the pre-test conducted with 30 subjects, the instrument was considered adequate to the target audience. CONCLUSION: The adapted version of the General Comfort Questionnaire for people with myocardial infarction is adequate to the target audience. PMID- 30517405 TI - Association between follow-up in health services and antihypertensive medication adherence. AB - OBJECTIVE: To analyze the association between the characteristics of follow-up in health services and adherence to antihypertensive medication in patients with cardiovascular disease. METHOD: Analytical study carried out with 270 patients suffering from hypertension and hospitalized due to cardiovascular complications. Data collection occurred between November 2015 and April 2016, involving sociodemographic variables, presence of self-reported diabetes, accessibility and use of health services, blood pressure levels and medication adherence (analyzed through the Morisky-Green Test). RESULTS: The rate of adherence to antihypertensive therapy was 63.0%. Enrollment in the Hiperdia program had no statistical significance to medication adherence. People who attended at least between 4 and 6 nursing consultations throughout the data collection period (p = 0.02) had better adherence. CONCLUSION: The study's findings provide support for the reorientation of health services and their public policies towards improving adherence to antihypertensive therapeutics. PMID- 30517406 TI - Influence of socio-demographic, clinical and surgical variables on the Aldrete Kroulik Scoring System. AB - OBJECTIVE: To identify the influence of the variables sex, age, type of anesthesia, occurrence of intraoperative complications, pain and surgical complexity on the Aldrete-Kroulik Scoring System in patients in the immediate postoperative period, in the post-anesthesia care unit. METHOD: Non-experimental, longitudinal study, with a quantitative approach, conducted with 241 surgical patients. Descriptive analysis, Student's t-test, Pearson and Spearman Correlation Indexes and multiple linear regression were used to analyze the data. RESULTS: Correlations between the Aldrete-Kroulik Scoring System and pain (r= 0.13; p=0.05) and surgical complexity (r=-0.12; p=0.05) were statistically significant. The type of anesthesia and pain (p<0.01) influenced the decrease of the Aldrete-Kroulik System's scores. CONCLUSION: Considering the vulnerability of patients in the immediate postoperative period, it is essential for the nurse to know the factors that can influence the Aldrete-Kroulik Scoring System to provide a safe and optimal post-anesthesia recovery. PMID- 30517407 TI - Creation and validation of a checklist for blood transfusion in children. AB - OBJECTIVE: To describe the process for creating and validating a checklist for blood transfusion in children. METHOD: Methodological study, conducted from November 2016 to May 2017, developed in two stages. The content of the items that compose the instrument was based on scientific evidence and submitted to specialized nurses for content validation. We applied the Content Validity index, considering the value >= 0.80. RESULTS: The content was considered valid with global CVI of 0.87. Suggestions for adjustments, such as deletion, replacement, and addition of terms, were included in the final version, which consisted of 14 items and 56 subitems. CONCLUSION: The checklist for blood transfusion in children was considered a technology with valid content to be used in the transfusion performed by nurses, thus contributing to transfusion safety in children. PMID- 30517408 TI - Pressure Ulcer in Intensive Care Units: a case-control study. AB - OBJECTIVE: To evaluate the relationship between presence/absence of Pressure Ulcer, socio-demographic factors and hospitalization. METHOD: Case-control study, performed through multiple logistic regression based on information from the adverse event reporting system and the hospital information system, between September/2014 and August/2015. RESULTS: Among the risk factors, after adjustment, age greater than or equal to 60 years, hospitalization due to infectious, parasitic and neoplastic diseases, periods of hospitalization longer than seven days and being hospitalized in ICU other than ICU covenant were highlighted. Most of ulcers were reported with mild damage degree and Stage II classification. CONCLUSION: Age and days of hospitalization presented a dose response effect, the longer the age or the number of days of hospitalization, the greater the chances of Pressure Ulcer. There was a significant association among higher occurrences of death in patients with ulcer. PMID- 30517409 TI - Alarm fatigue and the implications for patient safety. AB - OBJECTIVE: To measure the response time of health professionals before sound alarm activation and the implications for patient safety. METHOD: This is a quantitative and observational research conducted in an Adult Intensive Care Unit of a teaching hospital. Three researchers conducted non-participant observations for seven hours. Data collection occurred simultaneously in 20 beds during the morning shift. When listening the alarm activation, the researchers turned on the stopwatches and recorded the motive, the response time and the professional conduct. During collection, the unit had 90% of beds occupied and teams were complete. RESULT: We verified that from the 103 equipment activated, 66.03% of alarms fatigued. Nursing was the professional category that most provided care (31.06%) and the multi-parameter monitor was the device that alarmed the most (66.09%). CONCLUSION: Results corroborate the absence or delay of the response of teams, suggesting that relevant alarms might have been underestimated, compromising patient safety. PMID- 30517410 TI - Degree of risk for foot ulcer due to diabetes: nursing assessment. AB - OBJECTIVE: To classify the level of risk for foot ulcers in people with diabetes mellitus and identify their main predictive risk factors. METHOD: Exploratory, descriptive study, in which patients were assessed in a municipal ambulatory of Sao Paulo through nursing consultation, following the guidelines of the International Consensus on the Diabetic Foot. Data were descriptively analyzed. RESULTS: The analyzed population was composed of 50 longevous and retired people, with household income of up to two minimum wages, with dermato-neurofunctional risk factors and unfavorable clinical indicators, and 66% had Risk 1; 16% Risk 2; 6% Risk 3 and 12% Risk 4. Of this analyzed total, 96% never had their feet examined with the Semmes-Weinstein monofilament. CONCLUSION: The data found indicate the importance of careful feet examination in people with diabetes by the nursing staff to identify future risks of ulcers and, thus, prevent them. PMID- 30517411 TI - Impact of anxiety and depression on morbidity and mortality of patients with coronary syndrome. AB - OBJECTIVE: Evaluate the impact of anxiety and depression on morbidity and mortality of patients with acute coronary syndrome. METHOD: Retrospective cohort study, with follow-up of two years, conducted with 94 patients. The morbidity and mortality (readmission, myocardial revascularization, and death) was evaluated immediately after discharge and after one and two years. Anxiety and depression were evaluated by the State-Trait Anxiety Inventory and by Beck's Depression Inventory. The Kaplan-Meier estimator and the Logrank test were used. The significance level adopted was 0.05. RESULTS: We observed that 76.6% of the patients did not present symptoms of depression or had mild signs, while 78.8% had low to moderate anxiety. The symptoms of depression and anxiety were not related to morbidity (need for MR p=0.098 and 0.56, respectively; readmission p=0.962 and 0.369, respectively) and mortality (p=0.434 and 0.077, respectively). CONCLUSION: No relationship was found between levels of anxiety and depression with the morbidity and mortality of patients. PMID- 30517412 TI - Management of elderly people with Stroke: strategies based on action research. AB - OBJECTIVE: To elaborate and implement, through an educational intervention with the nursing team of the Emergency Unit, strategies that contribute to the management of elderly people suspected/affected by Stroke. METHOD: Action research with eighteen nursing professionals working in the Emergency Unit of a reference hospital. The data were collected through five pedagogical workshops and systematized through the thematic analysis. RESULTS: After a situational analysis and identification of the difficulties in the management of these elderly, a synthesis chart was prepared with strategic actions, responsible professionals and perspectives for implementation in the short, medium and long term. Short-term strategies had, for the most part, immediate implementation; the others were agreed on the need for further implementation. FINAL CONSIDERATIONS: The educational intervention allowed the construction of strategies that were implemented or agreed with the management for later applicability, sensitizing the group regarding the importance of the qualification and prompt care in the management of the elderly suspected/affected by Stroke. PMID- 30517413 TI - Impaired Verbal Communication: diagnosis review in patients with Amyotrophic Lateral Sclerosis. AB - OBJECTIVE: To review the contents of the nursing diagnosis of Impaired Verbal Communication in patients with Amyotrophic Lateral Sclerosis. METHOD: For the review of this diagnosis we used the integrative review. The 21 selected articles were submitted to a careful concept analysis for the definition of the diagnostic concept and review of its elements. RESULTS: It is recommended, in addition to a new definition for the diagnosis of Impaired Verbal Communication, the incorporation of twelve Risk Factors, the maintenance of three others and the relocation of a Defining Characteristic for Risk Factor. It is also recommended the incorporation of nine Defining Characteristics and the modification of the nomenclature of the other three that already make up the NANDA-I. CONCLUSION: The content review process subsidized a clarification of the chosen concept, contributing to a future refinement and improvement of the study diagnosis and its components present in NANDA-I. PMID- 30517414 TI - Diagnostic validity of biomarkers in Parkinson's Disease: systematic review and meta-analysis. AB - OBJECTIVE: To identify biomarkers for Parkinson's disease, cerebrospinal fluid, blood, saliva, and urine. METHOD: The studies were collected from the Cochrane, LILACS, PubMed, SCOPUS, WEB OF SCIENCE, OpenGrey, ProQuest and Google Scholar databases starting from May 3, 2016 and updated on March 20, 2017. Twenty-two studies were evaluated, by the Quality Assessment Tool for Diagnostic Accuracy Studies and Review Manager 5.3. RESULTS: Evidence shows that serum antibodies can be used as highly specific and accurate biomarkers for the diagnosis of Parkinson's disease at the outset. Biomarkers in the cerebrospinal fluid are related to increased motor severity, postural instability, gait abnormality, and cognitive impairment. CONCLUSION: Serum and cerebrospinal antibodies can be used as diagnostic biomarkers at the onset of the disease. PMID- 30517415 TI - Needlesticks with safety devices and accident prevention: an integrative review. AB - OBJECTIVE: To identify in the literature the efficacy of needlesticks with safety devices to reduce the occurrence of occupational accidents with exposure to biological material among health workers. METHOD: Integrative literature review, structured in the stages: Guiding question, search, categorization of studies, evaluation, discussion and interpretation of results, and synthesis of knowledge. Search for original articles and systematic reviews on the main bases of the Health area, published from 2000 to 2016 in Portuguese, English and Spanish, with descriptors: needlesticks injuries, exposure to biological agents, needles, protective devices, occupational accidents, accident prevention and health personnel. RESULTS: We selected eleven articles, most characterized the passive safety devices as more effective in reducing the occurrence of injuries by needlesticks. CONCLUSION: The use of needlesticks with safety devices reduces the occurrence of accidents, bringing greater solvency when combined with the training of workers. PMID- 30517416 TI - Adductor Pollicis Muscle Thickness for nutritional assessment: a systematic review. AB - OBJECTIVE: The aim of this study is to systematically review the scientific findings about the efficacy of the measure of the Adductor Pollicis Muscle Thickness for nutritional assessment of individuals in various clinical conditions. METHOD: Systematic review study performed according to the methodology Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: 13 original articles published between 2004 and 2016 were included. The measure was associated/correlated to parameters of nutritional status (such as weight, body mass index and Global Subjective Assessment) and muscle mass markers (such as circumference brachial muscle circumference, brachial muscle area, calf circumference, and muscle mass). All these correlations were weak or moderate. CONCLUSION: The measurement can be used in different populations, being able to estimate nutritional status and muscle mass. However, it is suggested that it be used in a complementary way to the nutritional evaluation, not constituting a single diagnostic/monitoring parameter. PMID- 30517417 TI - Nursing consultation for people with diabetes mellitus: experience with an active methodology. AB - OBJECTIVE: to describe our experience with a methodology for teaching nursing consultation in support of people with diabetes mellitus at a Family Health Unit. METHOD: experience report with four moments-submission of the proposal to the team; theorizing; nursing care for people with diabetes mellitus at home and at the health unit, and evaluation of learning. RESULTS: the pedagogical process favored the integration between service and users, contributed to implement and apply the nursing process and strengthened professional training, based on the epidemiological profile of chronic diseases and its implications for nursing in primary care. FINAL CONSIDERATIONS: the active methodology discussed here allowed for a resignification of knowledge and a qualification of nursing care, demonstrating to be an important instrument for integrating clinical practice and epidemiology in accordance to experienced reality. PMID- 30517418 TI - Promotion of health, sustainability and social development of a vulnerable community. AB - OBJECTIVE: to report the experience of research phases on promoting sustainable development based on social technologies with palm fiber artifacts in a vulnerable community. METHOD: this is an experience report that describes the phases of a multiprofessional project that sought sustainable development, and was conducted with inhabitants from a vulnerable community. RESULTS: the actions were developed in four phases: exploratory, planning, implementation and evaluation. These phases encompassed a situational diagnosis, planning and performing health education workshops, training meetings, production of handcrafted window shutters with insulation and acoustic comfort. The most emphatic result was the possibility of a new source of income. FINAL CONSIDERATIONS: the project actions favored the individual and collective empowerment of the participants regarding their health, especially considering the recovery of self-esteem, valuation of traditional knowledge and a new source of income. PMID- 30517419 TI - Professor training in health postgraduate studies: analysis of an experience. AB - OBJECTIVE: To analyze a professor training experience for higher education. METHOD: This is a descriptive case report on the professor training process in the postgraduate course of the College of Nursing of Ribeirao Preto, University of Sao Paulo. An evaluative activity was performed to capture the perceptions and experiences of 21 graduate students who were interns of an educational improvement program. The data were analyzed following the thematic content analysis guidelines. RESULTS: Three thematic categories were identified: 1) knowledge necessary for teaching practice; 2) teaching routines and practices; 3) the essentiality of mentoring. FINAL CONSIDERATIONS: This article provides a critical approach on the formative process of human resources for higher education in health, identifying potentials and challenges. Its innovative character resides in understanding pedagogical work articulated with graduate research training. PMID- 30517420 TI - Validation in grounded theory: conversation circles as a methodological strategy. AB - OBJECTIVE: To present the validation of a theoretical model through conversation circles in a qualitative research guided by the Grounded Theory. METHOD: Study carried out from a thesis developed in a reference hospital in the south region of Brazil. Two conversation circles happened, with participation of representatives of the "Training Prism", in the months of October and November, 2016. RESULTS: The conversation circle enabled an in depth dialogic approach of the subject of research, broadening the vision on the phenomenon and on the research. The circle also mobilized thinking as it highlighted the subjectivity of individuals, expanding the group's ability of understanding and assisting in the validation process of a theoretical model. CONCLUSION: The conversation circle emerges as a powerful strategy for the development of qualitative research in nursing, more specifically in the validation step of the Grounded Theory. PMID- 30517421 TI - Neutrophils, eosinophils, and mast cells in the intestinal wall of dogs naturally infected with Leishmania infantum. AB - Visceral leishmaniasis (VL) is a disease caused by the protozoa Leishmania infantum and can cause an inflammatory reaction in the gastrointestinal tract, however the role of granulocytic cells (neutrophils, eosinophils, and mast cells) in the intestine of dogs infected is not fully understood. We performed a quantitative analysis these cells in the intestinal wall of dogs with canine visceral leishmaniasis (CVL). Twenty dogs were assigned to one of three groups: group 1 (G1, n=8), dogs with CVL and L. infantum amastigotes in the intestine; group 2 (G2, n=9), dogs with CVL but without intestinal amastigotes; and group 3 (G3, n=3), uninfected dogs (control group). Granulocytic cells were counted in the crypt-villus unit (mucosa), submucosa, and muscle layer of the intestinal mucosa. Cell counts were higher in the intestinal wall of dogs from G2 followed by G1 and G3 (p<=0.05). In G1, there was a low inverse correlation between parasite burden of the small intestine and granulocyte counts (r= -0.1, p<=0.01). However, in G2 dogs, mast cell and eosinophil numbers showed positive correlation (r=0.85, p<=0.01). The granulocytic cell hyperplasia observed in the intestine of L. infantum-infected dogs suggests that these cells may be involved in the cell mediated immune response for parasite elimination. PMID- 30517422 TI - Serological diagnosis and risk factors for Coxiella burnetii in goats and sheep in a semi-arid region of Northeastern Brazil. AB - Coxiella burnetii is a zoonotic agent transmitted mainly by small ruminants. In Brazil the disease has been classified as a notifiable disease since 2013, when human cases were reported. This study aimed to identify risk factors associated with the presence of anti- Coxiella burnetii antibodies in goats and sheep in a semiarid region of Northeastern Brazil. Sera of 412 goats and 403 sheep from municipality of Petrolina, Pernambuco, were examined by the Indirect Fluorescent Antibody Test (IFAT) against antigens of C. burnetii. Information about management variables (independent variables) that could be associated with the presence of the microorganism (dependent variables) were obtained from the supervisor of each farm. It was determined that 2.2% (9/412) of the goats and 2.1% (9/403) of the sheep had antibodies reactive to C. burnetii. The presence of anti-C. burnetii antibodies was associated with the dry area of the Sequeiro (a region in the northern part of the municipality of Petrolina) (P = 0.025), male sheep (P = 0.020), and intensive goat breeding (P = 0.005). This study therefore showed the presence of anti-C. burnetii antibodies in goat and sheep, confirming for the first time that this agent is likely circulating among goat herds in the Caatinga Biome, semi-arid of Brazil. PMID- 30517423 TI - In vivo effect of diflubenzuron, administered via mineral salt supplementation, against Haematobia irritans and Rhipicephalus microplus parasitizing cattle. AB - This study involved two field trials with the aim of evaluating the efficacy of diflubenzuron, via mineral supplementation, against Haematobia irritans parasitizing cattle. Concomitantly with the main trial, a stall test was conducted to ascertain the effects of a different formulation with the same active ingredient against Rhipicephalus microplus, along with the action of diflubenzuron on the reproductive parameters of R. microplusfemales that had naturally detached from cattle. Against H. irritans, it was observed that the efficacy indexes fordiflubenzuron were low (<= 31.3% or 44.6%) or null (0.0%) throughout the study. The anti- R. microplus efficacy of diflubenzuron, at weekly intervals, ranged from 0.0 to 13.7% over the entire experimental period. Null efficacy (0.0%) was registered for diflubenzuron in relation to the reproductive parameters of R. microplusfemales that had naturally detached from cattle. The different diflubenzuron formulations, administered via mineral salt supplementation, did not show satisfactory efficacy indexes against H. irritans and R. microplus parasitizing cattle, within the experimental design of the present study. In addition, this agent did not present any deleterious effects on the reproductive parameters of R. microplus females. PMID- 30517424 TI - Morphological, molecular and phylogenetic characterization of Borrelia theileri in Rhipicephalus microplus. AB - This study aimed to perform a morphological, molecular and phylogenetic characterization of Borrelia theileri obtained from infected Rhipicephalus microplus in Brazil. Fifty engorged R. microplus females from cattle in the municipality of Seropedica, Rio de Janeiro, were analyzed for spirochetes by hemolymph smear. Macerated eggs and positive ticks, as well as blood from the bovine infested by these ticks, were analyzed the glpQ, flaB and hpt genes by PCR. The PCR products were purified and sequenced for analysis and construction of a phylogenetic tree. Only 2% (1/50) of the ticks generated a positive result by both smear and PCR. The spiral forms (n = 50) had (media +/- SD) a mean length of 19.17 +/- 4.12 um, diameter of 0.2935 +/- 0.0469 and number of turns 8.44 +/- 2.59. Sequence alignments of the three evaluated genes exhibited 98% similarity to B. theileri isolates, occurring in a clade highly related to B. theileri strain KAT. Egg maceration samples were positive for the three evaluated genes, whereas bovine blood was negative by PCR. This is the most detailed characterization of B. theileri in the Americas to-date, presenting morphological, molecular and phylogenetic data, including the transovarial transmission of the spirochete in the host tick. PMID- 30517425 TI - ERRATUM. AB - [This corrects the article doi: 10.1590/S1984-29612014089]. PMID- 30517426 TI - Quality of life and mastication in denture wearers and cleft lip and palate adults. AB - The impact of oral rehabilitation on masticatory function and oral health-related quality of life (OHRQoL) may vary with the experience of the individual with tissue loss. Our hypothesis is that patient-centered outcomes vary among adults who have experienced large defects in the maxilla due to congenital or acquired conditions even after oral rehabilitation to restore aesthetics and function. This study compared OHRQoL, perceived masticatory ability, maximum bite force (MBF), and symptoms of pain and depression among subjects with acquired (edentulous maxilla) and congenital (cleft lip and palate) loss of oral tissues in the maxilla after dental treatment. A gender-matched sample (n = 60) of cleft lip and palate (CLP), maxillary denture wearers (DENT) and controls (CONT) was recruited. OHRQoL was assessed using OHIP-14. Chewing was evaluated through a masticatory ability questionnaire and by MBF. The RDC/TMD Axis II questionnaire was used to assess symptoms of pain and depression. Data were analyzed by Fisher's test, Kruskal Wallis test, and Spearman correlation coefficients. CLP showed higher OHIP-14 and depression scores than DENT and CONT (p < 0.05). Sub analysis by OHIP-14 items (%FOVO) showed higher prevalence of psychological impact for CLP and of functional impacts for DENT. The number of foods difficult to chew, of food textures difficult to chew, and avoided foods were similar between CLP and DENT. OHIP-14, MBF, and depression scores showed significant correlation (p < 0.05). The results suggest that adults with treated CLP or maxillary DENT have chewing impairment and lower MBF than healthy subjects, with different psychological and functional impacts. PMID- 30517427 TI - Influence of ceramic material, thickness of restoration and cement layer on stress distribution of occlusal veneers. AB - The aim of this study was to evaluate stress distribution in an occlusal veneer according to the restorative material, restoration thickness, and cement layer thickness. A tridimensional model of a human maxillary first molar with an occlusal veneer preparation was constructed using a modeling software of finite element analysis. The model was replicated 9 times to evaluate the factors: restoration thickness (0.6, 1.2, and 1.8 mm) and cement layer thickness (100, 200, and 300 MUm). Then, each model received different restorative materials (High Translucency Zirconia - [YZHT], Lithium Disilicate - [LD], Zirconia Reinforced Lithium Silicate - [ZLS], Feldspathic - [F], and Hybrid Ceramic - [HC]), totaling forty-five groups. An axial load (600 N) was applied on the occlusal face for static structural analysis. Solids were considered isotropic, homogeneous, and linearly elastic. Contacts were considered perfectly bonded. Fixation occurred in the dental root and a mechanical static structural analysis was performed. Descriptive statistical analysis and one-way ANOVA (alpha =10%) were performed for tensile stress peak values in the restoration and cement layer. The difference between groups was compared using the Tukey's test with 10% significance to match the percentage of the mesh convergence test. According to the results, the cement layer thickness did not influence stress distribution in the restoration (p >= 0.10). The thicker the restoration, the higher the tensile stress concentration in the restoration. The graphs showed higher stress concentration in the YZHT, followed by LD, F, ZLS, and HC. Also, the restorative material influenced stress concentration on the cement layer, which decreased according to the sequence HC>YZHT>ZLS>LD>F. HC stood out for causing the least stress concentration in the restoration. Cement layer thickness did not interfere in the mechanical performance of the restorations. PMID- 30517428 TI - Assessment of toxicity and oxidative DNA damage of sodium hypochlorite, chitosan and propolis on fibroblast cells. AB - The objective of this study was to evaluate and compare the cytotoxicity and genotoxicity on human fibroblast cell lines of sodium hypochlorite (NaOCl), chitosan and propolis as root canal irrigating solutions. Human fibroblast cells were exposed to chitosan, propolis and NaOCl for 4 and 24 h. Cell viability was assessed by 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide, and oxidative DNA damage was assessed by determination of 8 hydroxydeoxyguanosine (8-OHdG) level with an ELISA kit. The data of cell cytotoxicity were analysed statistically using a test of one-way analysis of variance at a significance level of p < 0.05. In the NaOCI group, the 8-OHdG level was higher than in the chitosan group, but there was no statistical difference when compared with the other groups (p < 0.05). It was determined that the irrigation solutions were cytotoxic, depending on the dose and time. NaOCl was the most toxic solution after both 4 and 24 h of exposure (p < 0.05). Chitosan and propolis may be alternatives to NaOCl for irrigation solutions, because they are both less toxic and produce less oxidative DNA damage. PMID- 30517429 TI - Evaluation of chemokines and receptors in gnotobiotic root canal infection by F. nucleatum and E. faecalis. AB - The present study aims to evaluate the longitudinal effects of induced experimental infections in gnotoxenic animals on the expression of inflammatory chemokines and their receptors in periradicular tissues. The null hypothesis tested was that Enterococcus faecalis and Fusobacterium nucleatum had no effect on CCR5, CCL5, CXCL10, CCL2/MCP-1, CXCR2 and CCR1 expression. Two groups of five animals (n = 5) aged between 8 and 12 weeks were used in this study. The animals were anaesthetized, and coronary access was performed in the first molar on the right and left sides. Microorganisms were inoculated into the left molar, and the right molar was sealed without contamination to function as a control. Animals were sacrificed 7 and 14 days after infection, and periapical tissues were collected. The cytokine mRNA expression levels were assessed using real-time PCR. The chemokine mRNA expression levels demonstrated that the experimental infection was capable of inducing increased chemokine expression on day 7 compared to that on day 14, except for CCR5 and CCL5, which showed no changes. The gnotoxenic animal model proved to be effective and allowed evaluation of the immune response against a known infection. Additionally, this study demonstrates that gene expression of chemokines and their receptors against the experimental infection preferentially prevailed during the initial phase of induction of the periradicular alteration (i.e., on day 7 post-infection). PMID- 30517430 TI - How to improve root canal filling in teeth subjected to radiation therapy for cancer. AB - The aim of this study was to evaluate the influence of radiation therapy on root canal sealer push-out bond strength (BS) to dentin and the sealer/dentin interface after different final irrigation solutions (NaOCl, EDTA, and chitosan). Sixty-four maxillary canines were distributed into two groups (n=30): non irradiated and irradiated with 60 Gy. Canals were prepared with Reciproc-R50 and subdivided (n=10) for final irrigation (NaOCl, EDTA, chitosan) and filled. Three dentin slices were obtained from each root third. The first slice of each third was selected for BS evaluation, and the failure mode was determined by stereomicroscopy. SEM analysis of the sealer-dentin interface was performed in the remaining slices. Two-way ANOVA and Tukey's tests (alpha=0.05) were used. Lower BS (P<0.0001) was obtained after irradiation (2.07+/-0.79 MPa), regardless of the final irrigation solution used. The NaOCl group (P<0.001) had the lowest BS in the irradiated (1.68+/-0.72) and non-irradiated (2.39+/-0.89) groups, whereas the EDTA (irradiated: 2.14+/-0.77 and non-irradiated: 3.92+/-1.54) and chitosan (irradiated: 2.37+/-0.73 and non-irradiated: 3.51+/-1.47) groups demonstrated a higher BS (P<0.05). The highest values were observed in the coronal third (3.17+/-1.38) when compared to the middle (2.74+/-1.36) and apical ones (2.09+/-0.97)(P<0.0001). There were more cohesive failures and more gaps in irradiated specimens, regardless of the final solution. The present study showed that radiation was associated with a decrease in BS, regardless of the final solution used, whereas chitosan increased BS in teeth subjected to radiation therapy. PMID- 30517431 TI - Effects of nursing care on patients in an educational program for prevention of diabetic foot. AB - OBJECTIVES: Identify in patients with type 2 diabetes what changes in the feet would be associated with demographic, clinical, biochemical and treatment characteristics and which would increase the risk of mortality. METHODS: Retrospective longitudinal study evaluating the alterations in feet of outpatients attended at a nursing visit. Data from the clinical history and foot exam were collected from 918 medical records of a convenience sample. RESULTS: At 10 years, the cumulative mortality attributable to peripheral polyneuropathy was 44.7%, to peripheral artery disease was 71.7%, to both conditions were 62.4%, and to amputation was 67.6%. After multivariate analysis, duration of nursing follow up remained as the only protective factor against death (p < 0.001). CONCLUSIONS: The risk of death in these patients decreased when they had consultations with a nurse educator. Ischemic feet, amputation, and coronary artery disease remained independent risk factors. PMID- 30517432 TI - Validation of parameters to fill in the Perroca's patient classification system. AB - OBJECTIVE: To propose parameters to qualify the filling of the Patient Classification System proposed by Perroca. METHOD: Validation study by consensus held in 2014, in a university hospital. The sample included 10 specialist nurses, four teachers and a computer science professional, all knowledgeable in the Classification System. The information was collected and analyzed through meetings registration, where strategies were discussed to enable the systematic application of the instrument in the institution. For the construction, it was considered a consensus of 100% among the experts. RESULTS: The computerized parameter guide was elaborated with a description of what to evaluate in each item of the Perroca's instrument, standardizing the filling by the nurses. CONCLUSIONS: The parameter guide made it possible to minimize the subjectivity of the evaluators when applying the classification instrument, provided guiding elements to fill it in and qualified the nursing care benchmarking. PMID- 30517433 TI - Evaluation of prenatal care in primary care in the perception of pregnant women. AB - OBJECTIVE: To evaluate prenatal care in primary health care in the perception of pregnant women. METHOD: This cross-sectional study analyzes the association and statistical significance of the expectations and satisfaction of pregnant women receiving prenatal care in a municipality of southeast Brazil. We evaluated the association using simple logistic regression and statistical significance between variables and the expectation and satisfaction domains. RESULTS: A predominance of low expectations, with 279 (74%), and high satisfaction, with 220 (58.8%), was identified among the pregnant women regarding their perceptions of prenatal care. Tests showed an association and a statistical significance between the variable "to have used the same prenatal service" with the satisfaction domain. No differences were found between the two service models for both domains. CONCLUSION: The low expectation and high satisfaction of the pregnant women for the two care models can reveal ways of improving the quality of care in both services. PMID- 30517434 TI - Accountability and participation: how to overcome the tutelary character in the psychosocial care center for alcohol and drug users? AB - OBJECTIVE: Analyze the degree of accountability and participation of user under treatment at the Psychosocial Care Center for Alcohol and Drug Users (CAPS-ad) from the harm reduction policy perspective. METHODS: It is a qualitative approach study, case study type, with 12 users and four professionals from CAPS-ad in a county of Minas Gerais state. Data were collected from April to September 2017, by means of semi-structured interview, participant observation and documental analysis. RESULTS: Based on content analysis, information was organized in two thematic categories: treatment objectives and motivation for treatment. Conclusions: the study's findings revealed that users should be more held accountable and empowered with regard to their treatment. CONCLUSIONS: More professional listening is suggested, favoring the constructions of goals befitting users' interests, as contracts. PMID- 30517435 TI - Adverse reactions on day zero of hematopoietic stem cell transplantation: integrative review. AB - OBJECTIVE: To identify the adverse reactions associated with the infusion of hematopoietic stem cells on day zero of hematopoietic stem cell transplantation. METHODOLOGY: Integrative literature review, without temporal cut, with search in the following databases: PubMed, CINAHL, SCOPUS, BVS, SciELO, Web of Science and CAPES; the final sample consisted of 18 scientific articles, published between 1998 and 2017, based on the inclusion and exclusion criteria. RESULTS: Mild and moderate adverse reactions were the most frequent in studies that used the classification by severity, and nausea and emesis had the highest incidence; the most affected organ systems were the cardiovascular, respiratory and gastrointestinal. CONCLUSION: The main adverse reactions identified in the studies were nausea and emesis. Those classified as mild and moderate were the most frequent in the studies that used the severity classification; and the cardiovascular, respiratory and gastrointestinal systems were the most affected in those that used the classification by organic systems. PMID- 30517436 TI - Care transition strategies in Latin American countries: an integrative review. AB - OBJECTIVE: To identify and analyze available literature on care transition strategies in Latin American countries. METHODS: Integrative literature review that included studies indexed in PubMed, LILACS, Web of Science Core Collection, CINAHL, SCOPUS databases, and the Scientific Electronic Library Online (SciELO), published in Portuguese, Spanish or English, between 2010 and 2017. RESULTS: Eleven articles were selected and the strategies were grouped into components of care transition: discharge planning, advanced care planning, patient education and promotion of self-management, medication safety, complete communication of information, and outpatient follow-up. These strategies were carried out by multidisciplinary team members, in which nurses play a leading role in promoting safe care transitions. CONCLUSIONS: Care transition activities are generally initiated very close to patient discharge, this differs from recommendations of care transition programs and models, which suggest implementing care transition strategies from the time of admission until discharge. PMID- 30517437 TI - Detection of tuberculosis: the structure of primary health care. AB - OBJECTIVE: To analyze the structure of primary health care for the detection of tuberculosis cases in two municipalities of Rio Grande do Sul. METHOD: Descriptive, evaluative mixed methods research, with direct observation of the physical structure of 69 primary health care units; and semi-structured interviews with 10 subjects. Conducted between 2014 and 2016. Using descriptive statistics and content analysis for data analysis. RESULTS: In the 50 units in Pelotas there was an absence of: pots (24%); forms (53.1%), register books (48%) and of transportation of material to the laboratory (86%). In the 19 units of Sapucaia do Sul, these inputs were available. The absence of professionals, the turnover of human resources and the lack of training, emerged as the main structural deficiencies. CONCLUSION: There are structural differences between municipalities. The study suggests that Pelotas should adopt tuberculosis care coordination. PMID- 30517438 TI - Alternative to Avoid Tooth Discoloration after Regenerative Endodontic Procedure: A Systematic Review. AB - This systematic review aimed to evaluate whether alternative materials to conventional triple antibiotic paste (TAP - metronidazole, ciprofloxacin, and minocycline) and grey mineral trioxide aggregate (GMTA) could avoid tooth discoloration in teeth submitted to Regenerative Endodontic Procedure (REP). It was also investigated if dental bleaching is able to reverse the color of darkened teeth due to REP. The search was conducted in four databases (Medline via PubMed, Scopus, ISI Web of Science and BVS - Virtual health library), following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The retrieved papers were uploaded in the software EndNoteTM and two reviewers independently selected the studies and extracted the data. Only studies in humans (case reports, case series, clinical trials) were included in the review. From 1,122 potentially eligible studies, 83 were selected for full-text analysis, and 38 were included in the review. The included studies were mainly case reports (76.3 %). The studies described a total of 189 teeth submitted to REP. From these, about 54% of teeth presented some degree of discoloration. Most teeth presenting color alteration were treated with TAP, especially when combined with GMTA. Only three studies performed dental bleaching to restore the color of teeth and neither bleaching technique was able to restore the original color of the crowns. The use of alternative materials to TAP and GMTA, such as double antibiotic paste or Ca(OH)2 pastes and white mineral trioxide aggregate or BiodentineTM, reduces the occurrence of tooth discoloration. PMID- 30517439 TI - Dental Pulp Fibroblasts Response after Stimulation with HEMA and Adhesive System. AB - This study evaluated in vitro cell viability and metabolism, nitric oxide release and production of chemokines by cultured human dental pulp fibroblasts (DPF) under contact with HEMA and Single Bond. Cultures of DPF were established by means of an explant technique. Once plated, cells were kept under contact with increasing concentrations of HEMA (10, 100 and 1000 nM) or Single Bond (SB) [10 fold serially diluted in culture medium (10-4, 10-3 and 10-2 v/v)] and also with polymerized SB components. Cytotoxicity was assessed by Trypan Blue exclusion method and MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Nitric oxide release on cell supernatant was detected by Griess Method whereas chemokines (CXCL12 and CXCL8) were detected by ELISA. RT-qPCR was employed for chemokines gene expression analysis. Cytotoxic tests showed significant differences for SB 10-2. None of the tested materials significantly altered NO levels. Protein levels of CXCL12 were significantly decreased only by HEMA. On the other hand, while CXCL12 mRNA remained unaltered, gene expression of CXCL8 had significant decrease with all materials, except for polymerized SB. In conclusion, Single Bond and HEMA at various concentrations, decreased expression and production of molecules involved in inflammatory processes and, therefore, the use of adhesive systems such as pulp capping materials must be viewed with caution due to its large cytotoxic effect when in close contact with the pulp. PMID- 30517440 TI - Characteristics of Human Natal Stem Cells Cultured in Allogeneic Medium. AB - Recently, human natal dental pulp stem cells (hNDP-SCs) have been characterized in vitro and it has been shown that they satisfy criteria defining human mesenchymal stromal cells (MSCs), as proposed by the International Society for Cellular Therapy. However, these results were reached in the presence of xenogeneic expansion medium, which has the potential to alter the cells' functional capacity. To determine the validity of the previously reported hNDP SCs characteristics for human cell therapy, we have cultured hNDP-SCs in allogeneic expansion medium. Two hNDP-SC lineages were isolated from vital natal teeth, donated by a healthy newborn female and cultured in 2% platelet rich plasma (PRP). Analysis of the phenotypic expressions, proliferation rates, viability, telomerase length and in vitro adipogenic, osteogenic and chondrogenic differentiation potentials of two hNDP-SCs lineages (Zn001 and Zn002) were performed. Both lineages displayed similar morphology, proliferation rates, adipogenic, chondrogenic and osteogenic differentiation potential. Telomere shortening by 41.0% and 13.49% occurred from 3rd till 14th passage for lineages Zn001 and Zn002 respectively. Viability of both lineages was higher than 90%. Flow cytometry demonstrated that both lineages were positive to the majority of tested markers, including markers, which were negatively, expressed when hNDP-SCs were cultured previously in xenogeneic medium. Using immune-cytochemistry the cells were shown to express beta III-tubulin, nestin, neurofilaments and Nanog. PRP used as allogeneic medium is suitable for cultivation of hNDP-SCs. PMID- 30517441 TI - Effect of Local Application of Alendronate and Parathyroid Hormone on Craniofacial Bone Repair - a Preliminary Study. AB - This study aimed to evaluate the effect of two methods of local application of alendronate and parathyroid hormone (PTH) on bone repair and the systemic implications. A critically sized defect (5 mm) was created in the cranial region of twenty-five male Wistar rats, and the bone removed was particulated, and grafted back to the defect with different treatments. The animals were randomly divided into five groups: A1- bone graft immersion in alendronate solution (3 mg/kg) for 5 minutes; P1- bone graft immersion in PTH solution (20 ug); A2- weekly local applications of alendronate 1 mg/kg; P2- weekly local applications of PTH (20 ug); C- no drugs were used. The animals were euthanized 60 days after surgery. Cranial bone blocks were removed for histological, histomorphometric, and immunohistochemical analyses. MMP-2 and MMP-9 were used for immunolabeling. The kidneys, liver, and brain were also removed from all the rats for histological analysis. The data were submitted for statistical analysis with a level of significance of 0.05 (One-way ANOVA). The group C and group P2 presented a higher quantity of viable bone particles than the remaining groups. Groups A1, A2, and P1 presented with fewer viable bone particles than the control group, with a predominance of non-mineralized connective tissue. The histomorphometric analysis revealed no differences in relative bone area or MMP-2 or MMP-9 immunolabeling between the groups (p>0.05). Group A2 showed presence of fat in the liver consistent with hepatic steatosis. Changes in brain tissue were observed in groups A1 and P1. PMID- 30517442 TI - Effect of Post-Space Irrigation with NaOCl And CaOCl at Different Concentrations on the Bond Strength of Posts Cemented with a Self-Adhesive Resin Cement. AB - The aim of this study was to evaluate the effect of post-space irrigation with NaOCl and CaOCl at different concentrations on the bond strength of posts cemented with a self-adhesive resin cement. Eighty premolars were sectioned 14 mm from the apex, and endodontically treated. The root canal filling was partially removed. Specimens were randomly assigned into 8 groups (n=10), according to the irrigant for post-space irrigation: SS - 0.9% saline solution (control group); CHX - 2% chlorhexidine; 1% NaOCl - 1% sodium hypochlorite; 2.5% NaOCl - 2.5% sodium hypochlorite; 5% NaOCl - 5% sodium hypochlorite; 1% CaOCl - 1% calcium hypochlorite; 2.5% CaOCl - 2.5% calcium hypochlorite; and 5% CaOCl - 5% calcium hypochlorite. For each group, irrigation was performed continuously with 2 ml of solution. The post-spaces were dried with paper points (#80), and glass fiber posts were cemented using a self-adhesive resin cement. The specimens were sectioned perpendicularly and the push-out test was performed. Optical microscopy was used to analyze the failure mode. ANOVA and Bonferroni tests analyzed the bond strength data. NaOCl and CaOCl presented similar bond strength regardless the concentration used to irrigate the post-space (p>0.05). SS showed the highest bond strength (11.47 MPa) (p<0.05). Adhesive failures at the cement/dentin interface were predominant (58.33%). Saline solution should be irrigant of choice to irrigate the post-space before fiber post cementation with self-adhesive resin cement. NaOCl and CaOCl negatively affect the bond strength values. PMID- 30517443 TI - Ytterbium Oxide as Radiopacifier of Calcium Silicate-Based Cements. Physicochemical and Biological Properties. AB - This study evaluated physicochemical properties, cytotoxicity and bioactivity of MTA Angelus (MTA), calcium silicate-based cement (CSC) and CSC with 30% Ytterbium oxide (CSC/Yb2O3). Setting time was evaluated using Gilmore needles. Compressive strength was evaluated in a mechanical machine. Radiopacity was evaluated using radiographs of materials and an aluminum scale. Solubility was evaluated after immersion in water. Cell viability was evaluated by means of MTT assay and neutral red staining, and the mineralization activity by using alkaline phosphatase activity and Alizarin Red staining. The data were submitted to ANOVA, Tukey and Bonferroni tests (5% significance). The bioactive potential was evaluated by scanning electron microscopy. The materials presented similar setting time. MTA showed the lowest compressive strength. MTA and CSC/Yb2O3 presented similar radiopacity. CSC/Yb2O3 showed low solubility. Saos-2 cell viability tests showed no cytotoxic effect, except to 1:1 dilution in NR assay which had lower cell viability when compared to the control. ALP at 1 and 7 days was similar to the control. MTA and CSC had greater ALP activity at 3 days when compared to control. All the materials present higher mineralized nodules when compared with the control. SEM analysis showed structures suggesting the presence of calcium phosphate on the surface of materials demonstrating bioactivity. Ytterbium oxide proved to be a properly radiopacifying agent for calcium silicate based cement since it did not affected the physicochemical and biological properties besides preserving the bioactive potential of this material. PMID- 30517444 TI - Antibacterial Efficacy of Synthetic and Natural-Derived Novel Endodontic Irrigant Solutions. AB - The aim of this study was to compare the efficacy of grape seed extract (GSE), calcium hypochlorite [Ca(ClO)2], and sodium hypochlorite (NaOCl) irrigant solutions with rotary or reciprocating instrumentation for disinfection of root canals inoculated with Enterococcus faecalis. The mesiobuccal root canals of mandibular molars were prepared and inoculated with Enterococcus faecalis for 21 days. The roots were then randomly divided into the following eight experimental groups (n=11) according to the instrumentation technique and disinfection protocol: ProTaper Next or Reciproc R25 with sodium chloride (control group), 6% NaOCl, 6% Ca(ClO)2, or 50% GSE used for irrigation during instrumentation. The antimicrobial activity was determined on the basis of a reduction in colony forming units (CFUs) counted on bacterial samples collected before and after root canal instrumentation and expressed as a percentage of reduction. Data were evaluated by two-way ANOVA followed by Tukey HSD post-hoc tests (p<0.05). No significant differences were observed in bacterial reduction between the ProTaper Next and Reciproc R25 systems (p>0.05), regardless of the irrigant solution used. Furthermore, all active solutions (6% NaOCl, 50% GSE, and 6% Ca(ClO)2) showed similar potential to reduce bacterial counts (p>0.05) and were significantly more effective than sodium chloride (control) (p<0.05). The results suggest that the GSE and Ca(ClO)2 have potential clinical application as irrigant solutions in endodontic therapy since they present bactericidal efficacy against Enterococcus faecalis. PMID- 30517445 TI - Timing of Permanent Tooth Emergence is Associated with Overweight/Obesity in Children from the Amazon Region. AB - The aim of this study was to evaluate the association between timing of permanent tooth emergence with overweight and obesity in children from Brazilian Amazon region. The studied population consisted of 192 children, 09 to 12 year-old, from public schools at Manaus, Amazonas-Brazil. Clinical examination was performed and the tooth emergence was evaluated according to the number of permanent erupted teeth. Body mass index z-score was calculated. For the statistical analysis 'Overweight/obese' group was compared with 'Normal weight' group in a case to control ratio 1:2. The t-test based on age was used for means comparison between the groups. A linear regression analysis using age and gender as co-variants was used. The established alpha was 5%. One hundred twenty-seven children were classified as normal weight and 65 were classified as overweight/obese (49 were overweight and 16 were obese). Overweight/obesity condition was associated with the gender, in which boys had a higher chance to present higher weight conditions (OR=1.84; CI 95% 1.06-3.37; p=0.04). The mean number of permanent teeth was higher in the overweight/obesity group (p<0.001). Linear regression analysis demonstrated that nutritional status, gender and age were strongly associated with number of permanent erupted teeth (p<0.05). In conclusion, our study demonstrated that timing of permanent tooth emergence is associated with overweigh/obesity in children from Manaus, Brazil. PMID- 30517446 TI - ? AB - This study determined the reduction threshold in thickness of the dentin shade composite necessary to result in perceptible and acceptable color changes on simulated restorations. Three composite systems (Charisma Diamond, IPS Empress Direct, and Filtek Z350 XT) were evaluated using cylinder-shaped specimens built up with dentin and enamel shades. The opacity of the composites was assessed using 1.0 mm thick specimens over black and white backgrounds. A baseline color was established for each system by combining 1.0 mm thick enamel shade with 3.0 mm of dentin shade cylinders over a dark background (n = 9). Then, the color changes (?E00) caused by sequential 0.1 mm reductions on dentin shade cylinders were calculated. Opacity changes on dentin shade cylinders and combined enamel dentin pair cylinders were also assessed after each thickness reduction. Polynomial regression was performed with averages of ?E00 as a function of thickness of dentin shade cylinders; and acceptability (?E = 1.77) and perceptibility (?E = 0.81) thresholds were calculated. Linear regressions were also performed for ?E00 as function of opacity of dentin shade cylinders and combined enamel-dentin pair of cylinders. Except for Charisma, enamel shades presented the lowest opacity than dentin one. Perceptible and acceptable color changes were observed for dentin shade cylinders thinner than 2.0-2.4 mm and 1.1 1.4 mm, respectively, were used. No difference among the composite systems was observed. In conclusion, reductions on dentin shade composite lower than 0.6-mm did not yield perceptible color changes, and clinically significant color changes only were observed within reductions higher than 1.6-mm. PMID- 30517447 TI - Influence of Fluoridated Groundwater and 1,100 Ppm Fluoride Dentifrice on Biomarkers of Exposure to Fluoride. AB - This research aimed to determine the influence of fluoridated groundwater and 1,100 ppm fluoride dentifrice on biomarkers of exposure to fluoride in preschoolers. A cross-sectional study was performed on thirty preschoolers recruited from naturally fluoridated and non-fluoridated areas (n=15). Total Daily Fluoride Intake (TDFI) from diet and dentifrice, and Daily Urinary Fluoride Excretion (DUFE) was measured over 24 h. Nails samples were collected twice during 30 days. Fluoride analyses were performed using a fluoride-ion-specific electrode. Data were evaluated using the Student and paired t-test, Pearson correlation analysis, multiple linear regression analysis (alpha<=0.05). Fluoridated groundwater and dentifrice were the dominant sources (r2 > 0.83) of TDFI in children from a naturally fluoridated and a non-fluoridated area, respectively. A positive correlation between TDFI and DUFE (r=0.50), and between [F] in fingernails and toenails (r=0.60) were found in children from a naturally fluoridated area. The [F] in nails of finger and toe were not correlated to TDFI. The consumption of fluoridated groundwater influenced the fluoride concentration in urine. In addition, the use of 1,100 ppm fluoride dentifrice did not influence the fluoride concentration in urine and fingernails. PMID- 30517448 TI - Polishing of Ground Y-TZP Ceramic is Mandatory for Improving the Mechanical Behavior. AB - It evaluated the effect of aging by Low Temperature Degradation (LTD), executed after post- processing surface treatments (polishing, heat treatment and glazing), on the surface characteristics (micromorphology and roughness) and on the structural stability (phase transformation and mechanical behavior-flexural strength and structural reliability) of a ground yttrium-stabilized tetragonal zirconia polycrystal (Y-TZP) ceramic. Discs of Y-TZP (VITA In-Ceram YZ) were manufactured (ISO:6872-2015; 15 mm in diameter and 1.2 +/- 0.2 mm in thickness) and randomly assigned into 10 groups according two factors: "aging" in 2 levels (with or without) and "surface treatment" in 5 levels (Ctrl: as-sintered; Gr: grinding with coarse diamond bur; Gr + HT: grinding plus heat treatment; Gr + Pol: grinding plus polishing; Gr + Gl: grinding plus glazing). Roughness (n=30), biaxial flexural test (n=30), phase transformation (n=2), and surface topography (n=2) analyses were performed. Aging led to an intense increase in monoclinic (m) phase content for all the tested conditions, being the as-sintered samples (Ctrl= 65.6%) more susceptible to the t-m phase transformation. Despite of increasing the m-phase content, aging was not detrimental for characteristic strength (except to the grinding condition). There was no significant reduction in the Weibull modulus after surface treatments. Additionally, heat treatment and glazing after grinding led to a decrease in characteristic strength, while polishing presented the highest characteristic strength values. Thus, polishing is mandatory after grinding the Y-TZP ceramic, while performing glazing or heat treatment alone after grinding lead to the worst mechanical performance. PMID- 30517449 TI - Adhesion to a Lithium Disilicate Glass Ceramic Etched with Hydrofluoric Acid at Distinct Concentrations. AB - This study evaluated the effect of different hydrofluoric acid (HF) concentrations on the bond strength between a lithium disilicate-based glass ceramic and a resin cement. Eighty ceramic-blocks (12*7*2 mm) of IPS e.Max CAD (Ivoclar Vivadent) were produced and randomly assigned to 8 groups, considering 2 study factors: HF concentration in 4 levels, i.e., 1% (HF1), 3% (HF3), 5% (HF5), and 10% (HF10), and storage in 2 levels, i.e., baseline (tests were performed 24 h after cementation), and aged (storage for 150 days + 12,000 thermal-cycles at 5 degrees C and 55 degrees C). Acid etching (20 s) was performed, followed by washing, drying, and silanization. Four resin cement cylinders (phi= 0.96 mm) were built-up from starch matrices on each ceramic sample (n= 40). Additional ceramic samples were etched and analyzed for contact angle, micro-morphology, and roughness. In baseline condition (without aging), the HF3, HF5, and HF10 groups showed similar bond strength values (13.9 - 15.9 MPa), and HF1 (11.2 MPa) presented lower values than HF5, being that statistically different (p= 0.012). After aging, all the mean bond strengths statistically decreased, being that HF3, HF5, and HF10 (7.8 - 11 MPa) were similar and higher than HF1 (1.8 MPa) (p= 0.0001). For contact angle, HF3, HF5, and HF10 presented similar values (7.8 - 10.4 degrees ), lower than HF1 and CTRL groups. HF5 and HF10 presented rougher surfaces than other conditions. For better bond strength results, the tested ceramic may be etched by HF acid in concentrations of 3%, 5%, and 10%. PMID- 30517450 TI - A Survey About Dental Instruments at the Primary Health Care in Brazil. AB - This study describes the structure of oral health services in primary health care in Brazil and the instruments available for the provision of oral health care and to compare the number of instruments according to organizational characteristics of health services and among the macroregions. Of the 23,251 oral health teams (OHTs) in the Public Health System, 17,513 (75.3%) participated in this study. Trained researchers observed the structures of the health services and determined the presence of and whether a sufficient quantity of 36 dental instruments existed. The score of each oral health service was determined by the sum of the number of dental instruments present in sufficient quantity (0 to 36). Central tendency measures were compared along with the variability in these scores according to the organizational characteristics of the services and according to the Brazilian macroregion. No instrument was found to be present in all evaluated services. Basic, surgical and restorative instruments were the most frequently found. Periodontal, endodontic and prosthetic instruments exhibited the lowest percentages. The mean and median numbers of dental instruments were higher for teams that operated over more shifts, those with an oral health technician and those in the South and Southeast regions. The oral health services were equipped with basic, surgical and restorative instruments. Instruments designed for periodontal diagnosis, emergency care and denture rehabilitation were less frequently found in these services. The worst infrastructure conditions existed in the OHTs with the worst forms of care organization and in regions with greater social issues. PMID- 30517451 TI - In Vitro Analysis of the Cytotoxicity of Indirect Restorative Materials. AB - This study aimed to compare the cytotoxicity of the Vita AC12, Lava Ultimate, Vita Enamic and InSync indirect restorative materials. Extracts of each material were prepared by incubation for 1, 7 and 40 days, with daily washing. Human gingival fibroblasts were exposed to the extracts, and cell viability was evaluated by sequential assessment of mitochondrial activity (XTT), membrane integrity (NRU) and cell density (CVDE). Extracts of polystyrene beads and latex fragments were used as negative and positive controls, respectively. Differences between groups and experimental times were evaluated by analysis of variance. At the 24 h extraction, significant differences between the control and both Vita AC 12 and InSync were observed in the XTT assay (p<0.05), and between the control and both Enamic and Lava Ultimate, in the CVDE assay (p<0.05). AC12, Lava Ultimate, and InSync presented significantly lower cell viability than Enamic and the control group, in the NRU assay (p<0.05). The Vita Enamic and Lava Ultimate hybrid ceramic-like materials presented better biocompatibility at the 24 h extraction time point than the AC12 and InSync ceramic materials. However, a simulation of the removal of toxic components by biological fluids, conducted by using longer extraction times and daily washing, led to the absence of cytotoxicity in all the tested restorative materials. These findings can be viewed as positive for the clinical indication of these restorative materials, considering their contact with adjacent soft tissues for extended periods of time. PMID- 30517452 TI - Editorial PeNSE 2015. PMID- 30517453 TI - Risk and protection factors for chronic noncommunicable diseases in adolescents in Brazilian capitals. AB - OBJECTIVE: To analyze trend estimates on the prevalence of risk and protective behaviors for chronic noncommunicable diseases in adolescents, according to data from the National School Health Survey in 2009, 2012 and 2015. METHODS: Data from the three cross-sectional studies in Brazilian capitals and the Federal District were used. In total, 173,310 adolescents enrolled in the ninth grade of elementary school were interviewed, with average age of 14 years. The prevalence of indicators of protective (consumption of beans and fruit; physical education classes at school; practice of physical activity for 60 minutes or more) and risk factors (consumption of candies and soft drinks; use of cigarettes and alcohol in the last 30 days; drug testing) were estimated through linear regression. RESULTS: There was a significant increase (p < 0.05) in the prevalence of fruit consumption and in the reduction of bean, soft drinks and candies consumption, as well as the consumption of alcoholic beverages and cigarettes. However, an increase in the prevalence of illicit drug experimentation was observed. Discussion: Despite the tendency to reduce risk factors, prevalences are high when compared with other sociocultural realities. CONCLUSION: The school is an important area of access to the adolescent public, and it is necessary to encourage school health promotion programs to reduce health risk behaviors, as well as to stimulate protective ones. PMID- 30517454 TI - Demand for health services or professionals among Brazilian adolescents according to the National School Health Survey 2015. AB - INTRODUCTION: Knowing the profile of individuals who demand health services or professionals could help in the improvement and reorganization of services. However, this subject is still underexplored among adolescents. This study aimed to describe and identify characteristics related to the demand for health services or professionals by Brazilian students. METHODS: Using data from the 2015 National School Health Survey, the prevalence and respective 95% confidence intervals (95%CI) of the demand for health services or professionals among students were estimated, and Poisson regression adjusted by age and region of residence was used to identify the associated factors. RESULTS: More than half of the students demanded for health services or professionals in the last year, with a higher demand among females. The characteristics associated with the outcome were sociodemographic (female, white, private school), family (maternal schooling of 12 years or more, having meals with parents/guardians and parents' knowledge of the adolescent's activities in their free time), risk behaviors (alcohol consumption and sexual intercourse without a condom) and health-related issues (physical violence, wheezing, toothache, hygiene habits, and attitude to one's own weight). CONCLUSION: Organizing health services in a way that takes the particularities of this population into account may provide a space to deal with subjects related to the risks to which it is exposed. PMID- 30517455 TI - Use of psychoactive substances among Brazilian adolescents and associated factors: National School-based Health Survey, 2015. AB - AIM: To analyze the consumption of tobacco, alcohol and illicit drugs among schoolchildren according to demographic factors, family context and mental health. METHODS: We used data from the National School-based Health Survey 2015 and included in the sample 102,301 schoolchildren in the 9th grade. We estimated the prevalence of tobacco and alcohol use in the last 30 days and drug experimentation according to demographic, mental health and family context variables. Then, a bivariate analysis was performed using Pearson's chi2 test and the unadjusted odds ratio (OR) was calculated. Finally, we conducted a multivariate analysis including independent variables with an unadjusted association (p < 0.20), for each outcome, estimating the adjusted OR with a 95% confidence interval. RESULTS: The prevalence of tobacco consumption was 5.6%; alcohol consumption, 23.8%; and drug experimentation, 9.0%. Multivariate analysis has indicated that living with parents, having meals with parents or guardian, and family supervision were associated with lower substance consumption; whereas missing classes without parental consent has increased the chances of substance use. Increased chance of substance use was also associated with white skin color, increasing age, to work, feeling lonely and having insomnia. Not having friends was associated with drug and tobacco use, but this was protective for alcohol consumption. CONCLUSIONS: Family supervision was protective for psychoactive substance use among Brazilian schoolchildren, whereas work, loneliness and insomnia have increased their chances of use. PMID- 30517456 TI - Parental supervision and alcohol use among Brazilian adolescents: analysis of data from National School-based Health Survey 2015. AB - OBJECTIVE: To evaluate the relation between parental supervision and sociodemographic factors and alcohol use by Brazilian adolescents. METHODS: This is a cross-sectional study with data from National School-based Health Survey (PeNSE) 2015, which included 16,608 adolescents aged 13 to 17 years, students from Brazilian public and private schools. Variables related to alcohol use, sociodemographic factors and parental supervision were evaluated. In order to analyze the relation between sociodemographic variables, parental supervision and use of alcohol among adolescents, prevalence ratios stratified by sex were used. RESULTS: It was observed that 61.4% of the adolescents had tried alcohol, 27.2% had a drunken episode in their lifetime, 9.3% have had problems with alcohol and 29.3% reported alcohol use in last 30 days. The lack of parental supervision was associated with increased use of alcohol. The proportion of alcohol use was higher for girls, and also among those who were older than 16 years, worked, did not live with one or both parents, and lived in the South, regardless of sex. CONCLUSION: The results showed early alcohol experimentation and occurrence of problems due to its use among Brazilian adolescents. In addition, the lack of monitoring by parents and guardians shows a risk of alcohol use in this age. PMID- 30517457 TI - Factors associated with the use of waterpipe and other tobacco products among students, Brazil, 2015. AB - OBJECTIVE: To identify the frequency and factors associated with the use of waterpipe and other tobacco products among Brazilian students. METHODS: This is a cross-sectional study based on data from the National Adolescent Student Health Survey. The sample consisted of 9th-grade students from elementary school. We conducted a descriptive analysis of the use of tobacco products in 2012 and 2015. To explore the relationship between the use of other tobacco products and factors such as sociodemographic characteristics, family, mental health, and life habits, we calculated the adjusted odds ratio. RESULTS: The use of other tobacco products increased from 4.8% (95%CI 4.6 - 5.0) in 2012 to 6.1% (95%CI 5.7 - 6.4) in 2015, with a higher proportion among boys. Waterpipe was the most commonly used product in 2015 (71.6%; 95%CI 68.8 - 74.2), especially among girls. Factors positively associated with the use of other tobacco products were: attending private school, living with father/mother, working, not having friends, suffering domestic violence, skipping classes, consuming cigarettes and alcohol, experimenting drug, having had sex, having smoker parents or guardians, and seeing people smoking. The protective factors were: female gender, increasing age, multiracial or indigenous people, having meals with a guardian, family supervision, and practicing physical activity. CONCLUSION: The use of other tobacco products was high and has been increasing in recent years, particularly waterpipe. It is important to raise awareness of the risks and monitor the use of these products, as well as improve public policies of tobacco control in the country. PMID- 30517458 TI - Prevalence and factors associated with illicit drug use throughout life: National School Health Survey 2015. AB - INTRODUCTION: The use of illicit drugs is a public health concern. This paper describes the prevalence and factors associated with the use of illicit drugs throughout life among 9th grade students attending public and private schools in daylight period in Brazil. METHOD: Data from the Brazilian Adolescent School based Health Survey (PeNSE) were analyzed. Use of illicit drugs at some point in life was assessed considering marijuana, cocaine, crack, solvent-based glue, ether-based inhalants, ecstasy, and oxy. Data were analized descriptively and by the Poisson's regression model. RESULTS: The use of illicit drugs at least once in life was reported by 9,0% of participants, being more prevalent among girls and associated with alcohol or tobacco use, active sexual life, feeling of loneliness, little or no contact between school and parents, and the experience of familial aggressions. The outcome was inversely associated with close contact with parents and their supervision. Prevalence was higher among participants whose mothers had higher educational levels and had, who had a payed job, and who attended public schools. DISCUSSION: The prevalence of lifetime use of illicit drugs was stable when the three PeNSE samples were compared, but it resulted more common among girls in 2015 for the first time and was associated with the same conditions found in prior studies. CONCLUSION: Family and school appear to be protective factors, especially when there is direct supervision and care. It is important that both girls and boys are given the same attention when it comes to this this subject. PMID- 30517459 TI - Nutritional status of Brazilian schoolchildren: National Adolescent School-based Health Survey 2015. AB - INTRODUCTION: Obesity has increased in Brazil for all age groups. Overweight at the end of adolescence indicates a high probability of unhealthy weight in adulthood. OBJECTIVE: To describe anthropometric data of the National Adolescent School-based Health Survey (PeNSE) 2015 and its distribution according to geographic and socioeconomic strata. METHODS: Data from the PeNSE 2015 was used. The analysis sample consisted of adolescents aged 11 to 19 years old from public and private schools with available anthropometric data. Nutritional status was classified according to the body mass index, with reference values proposed by the International Obesity Task Force (IOTF). The prevalence estimates of underweight and overweight and their respective standard errors were presented. The association between anthropometric indicators and demographic or social characteristics of adolescents was estimated by odds ratio, and the respective 95% confidence intervals were presented. RESULTS: The prevalence of underweight was less than 3%. Elevated prevalence of overweight was observed in adolescents from the South region, from the urban area, from the lowest fifths of income, and those who declared themselves to be black or indigenous. In general, the prevalence of overweight was higher among adolescents attending private schools. CONCLUSION: Overweight is more frequent among adolescents from low-income strata. Besides being an indicator of nutritional status, overweight may indicate social inequality in Brazil. PMID- 30517460 TI - Dietary patterns, sociodemographic and behavioral characteristics among Brazilian adolescents. AB - INTRODUCTION: Inadequate dietary patterns in childhood and adolescence are a major risk factor for the early onset of obesity and other chronic diseases. Objectives: To identify and to analyze dietary patterns among Brazilian adolescents. METHODS: Data from the Brazilian National School Health Survey (PeNSE) of 2015 were used (n = 10,926 adolescents). The identification and analyses of dietary patterns were calculated using principal component analysis and linear regression, respectively. RESULTS: Two dietary patterns were identified. The first one was characterized by the presence of markers of unhealthy eating, and the second one by markers of healthy eating. The adherence to the unhealthy pattern was positively associated with female adolescents, which mothers had completed, at least, the elementary school, residents in developed regions and urban areas, as well as those students who usually chose to skip breakfast, to not have meals with their parents/guardians, and who usually had meals while watching TV/studying, and at fast food restaurants. DISCUSSION: Analyses of the consumption of isolated food groups, which do not consider the diet in all its complexity, have been insufficient in explaining the main outcomes of the public health nutrition area. CONCLUSION: Our findings contributed to the identification of the most vulnerable population groups to unhealthy dietary patterns and to the understanding of the coexistence of different food habit determinants among adolescents. PMID- 30517461 TI - Soft drink consumption and body mass index in Brazilian adolescents: National Adolescent Student Health Survey. AB - OBJECTIVE: To estimate the association between soft drink consumption and body mass index (BMI) in eutrophic and overweight adolescents. METHODS: We used data from the National Adolescent Student Health Survey (Pesquisa Nacional de Saude do Escolar - PeNSE) of 2009. The dependent variable (outcome) was the tertiles of BMI score (zBMI), and the main independent variable (exposure) was the consumption of sugar-sweetened soft drinks. The models included age, school type, home goods and services score, and maternal schooling as adjustment variables. We estimated the association between exposure and outcome by using multinomial regression models, stratified by gender, and eutrophic and overweight subgroups. RESULTS: 23.8% of the adolescents evaluated were overweight, and 21.7% reported consuming soft drinks daily. For eutrophic boys, those who consumed soft drinks had a greater chance of being in higher zBMI tertiles than non-consumers. For overweight adolescents, both male and female, soft drink consumption was associated with a lower chance of being in the highest tertile of zBMI score. CONCLUSION: The results show the possibility of reverse causality between consumption of sweetened soft drinks and zBMI in the overweight adolescents group. For eutrophic male adolescents, soft drink consumption can potentially increase the chances of having higher zBMI, which reinforces the need for measures to significantly reduce the consumption of this beverage. PMID- 30517462 TI - Nutritional status, body image, and their association with extreme weight control behaviors among Brazilian adolescents, National Adolescent Student Health Survey 2015. AB - INTRODUCTION: This study aimed to analyze the association between nutritional status, body image perception, and extreme weight control behaviors among adolescents. METHODS: This is an analytical cross-sectional study conducted in Brazil based on the National Adolescent Student Health Survey (Pesquisa Nacional de Saude do Escolar - PeNSE) of 2015, with adolescents aged 13 to 17 years. Nutritional status and body image perception were the independent variables. The two dependent variables were vomiting or laxative use and use of medicines and other formulas for weight control in the 30 days prior to data collection. We used Poisson regression models for association, with demographic variables for control. RESULTS: 7.4% of adolescents (95%CI 6.7 - 8.2) reported vomiting or using laxatives, with no difference between genders. The prevalence of use of medicines and formulas was higher among boys (7.8%; 95%CI 6.6 - 8.9). The association between nutritional status and extreme behaviors was not significant. However, the prevalence of vomiting or laxative use for adolescents who considered themselves very fat was 2.3 (95%CI 1.1 - 4.7) times higher for boys and 5.3 (95%CI 3.3 - 8.6) times higher for girls, while the use of medicines and formulas was 4.0 (95%CI 2.3 - 7.1) times higher for girls who considered themselves very fat. CONCLUSION: Body image perception seems to have a greater influence on extreme behaviors than nutritional status. Strategies involving health services and schools have great potential to impact the self-esteem and health of students positively. PMID- 30517463 TI - Prevalence of physically active adolescents in Brazilian capitals: National Adolescent School-based Health Survey 2012 and 2015. AB - OBJECTIVE: To compare the prevalence of physically active adolescents living in Brazilian capitals, using 2012 and 2015 National Adolescent School-based Health Survey. METHOD: The sample consisted of 61,145 (2012) and 51,192 (2015) adolescents who were residents in 27 Brazilian capitals and were attending the 9th year of elementary school. The globally estimated physical activity indicator with the cutoff point of 300 minutes or more per week was used to determine the prevalence of physically active adolescents in both surveys. The prevalence rates were stratified by socio-demographic characteristics (gender, age, maternal schooling and skin color) and by capital of residency. Descriptive statistics were used for comparisons considering 95% confidence intervals. RESULTS: The respective prevalence rates of physically active adolescents observed in 2012 (21.0%; 95%CI 20.3 - 21.7) and 2015 (20.7%; 95%CI 20.1 - 21.3) were similar, independently of the sociodemographic characteristics. In considering the 27 capitals, a reduction in the prevalence of physically active adolescents from 2012 to 2015 was observed only in Belem. CONCLUSION: Overall, no changes in the prevalence of physically active adolescents residing in urban centers was observed from 2012 to 2015. These findings evidence the need for new public policies in order to enhance and promote the practice of physical activity among Brazilian adolescents, as well as the expansion of existing ones. PMID- 30517464 TI - Analysis of sexual and reproductive health indicators of Brazilian adolescents, 2009, 2012 and 2015. AB - OBJECTIVE: To analyze sexual and reproductive health indicators of adolescents based on data from the National School-based Health Survey (PeNSE) in 2015, comparing them to the data from 2009 and 2012. METHODS: Cross-sectional study that has analyzed data from 9th grade students from PeNSE 2015, 2012 and 2009. We estimated prevalence and 95% confidence intervals for the following indicators: sexual initiation, condom use in the last sexual intercourse, counseling for pregnancy, sexually transmitted infections and free condoms in the three rounds of the survey. Prevalence of all indicators accessed in 2015 was estimated according to sex, type of school and region. Pearson's chi2 test was used. RESULTS: The prevalence of sexual initiation reported by adolescents has decreased from 30.5%, in 2009, to 27.5%, in 2015, as well as the use of condom in the last intercourse, from 75.9 to 66.2%, respectively. In respect to counseling, there was a reduction regarding pregnancy prevention in public schools, from 81.1 to 79.3% and in relation to free condom in private schools, from 65.4 to 57.3%. About 30% reported using both condom and another contraceptive method, and 19.5% did not use any method. Boys presented greater prevalence of sexual initiation, higher number of partners and reduced prevalence of condom use. Adolescents living in North, Northeast and Central-West regions presented worse indicators. CONCLUSION: There was a reduction in sexual initiation and condom use among Brazilian adolescents, boys were more vulnerable to sexually transmitted infections, and girls from public schools were more vulnerable to pregnancy. PMID- 30517465 TI - Trends in violent situations experienced by Brazilian adolescents: National Adolescent Student Health Survey 2009, 2012, and 2015. AB - OBJECTIVE: To present trends found in the last three editions of the National Adolescent Student Health Survey (Pesquisa Nacional de Saude do Escolar - PeNSE) on violent situations experienced by Brazilian students. METHODS: Time-series study with a focus on the Brazilian state capitals, using PeNSE databases of 2009, 2012, and 2015. The indicators evaluated were: missing classes due to insecurity in the home-school route or at school; involvement in a fight with firearm or melee weapon; and physical assault by an adult of the family. We estimated the prevalence of indicators according to the total number of adolescents, gender, school type, and capital. Trends in prevalence were estimated by linear regression, adjusted for age. RESULTS: We identified a trend in increasing prevalence, with statistical significance, for all selected violence indicators in the period from 2009 to 2015, in Brazilian state capitals. DISCUSSION: The most vulnerable groups were public schools students; male adolescents for involvement in fights with melee weapons or firearms; and female adolescents for physical assault by family members. CONCLUSION: PeNSE contributed to identifying the increase in the prevalence of violence experienced by adolescents, which alerts to the need of planning and implementing policies that help to prevent violence, and promote health and a culture of peace. PMID- 30517466 TI - Evolution of the report of suffering bullying among Brazilian schoolchildren: National Scholl Health Survey - 2009 to 2015. AB - INTRODUCTION: The purpose of this paper was to compare the tendency of bullying across Brazilian capitals, considering the editions of National Scholl Health Survey (PeNSE) 2009, 2012 and 2015, and to describe the prevalence of bullying by sex, age and administrative dependence of the school in the 2015 sample. METHODOLOGY: The prevalence of bullying and its 95% confidence interval (95%CI) were assessed per State capital and for all capitals. 95%CI was used to check for differences in the period. In the last edition, two samples were analyzed: sample 1 represents the students of the 9th year of Elementary School and sample 2 holds students from 13 to 17 years of age, from the 6th to 9th grade of Elementary and High Schools. RESULTS: The report of suffering bullying by 9th graders in Brazilian capitals increased from 5.4% (95%CI 5.1 - 5.7), in 2009, to 7.2% (95%CI 6.6 - 7.8), in 2012, staying at 7.4% (95%CI 7.1 - 7.7) in 2015. Descriptive analysis for Brazil showed variation by age, as adolescents aged 13 years suffered more bullying than those aged 14, 15 and 16 years. Boys usually report more this problem than girls, as well as public school students, but with overlapping CI. DISCUSSION: The study pointed 37% increase in the prevalence of bullying between 2009 and 2015 in Brazilian capitals by. CONCLUSION: This study reiterates that Brazilian schools are still a space for violence reproduction, which makes it urgent to make progress in prevention and minimization of bullying at schools based on the concept of health promotion and integral care. PMID- 30517467 TI - Profile and trend of risk factors for traffic accidents in schoolchildren in Brazilian capitals: PeNSE 2009, 2012 and 2015. AB - INTRODUCTION: Land transport accidents (LTA) are the second cause of death in schoolchildren aged 13 to 17 years. The study aims to describe the risk factors for LTA in schoolchildren from the National School Health Survey (PeNSE) of 2015 and to evaluate the trend of selected indicators in the last three editions of PeNSE. METHODOLOGY: A descriptive study on risk factors for LTA in 2015, with PeNSE data and time series trends analysis, with age-adjusted regression tests of the 2009, 2012 and 2015 editions, in Brazilian capitals. RESULTS: In 2015, 26.3% of ninth grade schoolchildren, mostly between 13 and 15 years of age, reported having been in a motor vehicle driven by someone who consumed alcohol and 32.4% had driven a motor vehicle; 30.7% of adolescents did not use seat belts in the back seat; and 16.8% of schoolchildren who ride motorcycles did not wear helmets. There was also a worsening of the indicators between 2009 and 2015, regarding driving a motor vehicle (1.0 percentage points) and having been driven by vehicle for consumption of alcoholic beverages (1.1 percentage points). DISCUSSION: The LTA occurrence results from the interaction between roads, vehicles and users, and has a strong correlation with behavior. CONCLUSIONS: The results show the need to invest in educational measures, associated with supervision, the improvement of road infrastructure, research and improvement of legislation. The monitoring of risk factors in schoolchildren substantially contributes to support intersectoral public policies interventions to reduce morbidity and mortality in traffic. PMID- 30517468 TI - Asthma trend in adolescence in Brazil: results of the National Adolescent School based Health Survey (PeNSE 2012-2015). AB - OBJECTIVE: To compare the evolution of asthma indicators in the editions of the National School Health Survey (PeNSE 2012 and 2015). METHODS: Cross-sectional study including Brazilian 9th grade students from public and private schools. Wheezing was assessed through the question: "In the past 12 months, did you have wheezing (or chirping) chest? (yes/no)", and to assess lifetime presence of asthma, the question was "Have you ever had asthma? (yes/no)". RESULTS: Of the students, 23,52% reported wheezing or chirping chest in the past 12 months, with prevalences ranging from 16,80% (in Salvador, Bahia) to 27,43% (in Porto Alegre, Rio Grande do Sul). Lifetime presence of asthma was reported by 17,92% of the students, ranging from 13,98% (in Campo Grande, Mato Grosso do Sul) to 30,35% (in Porto Alegre, Rio Grande do Sul). There was also a decrease in the prevalence of self-report of wheezing/chirping chest in the last 12 months between the two editions of the survey (2012/2015) in 20 of the 27 Brazilian state capitals, especially in Belo Horizonte, Florianopolis, Cuiaba and Goiania. However, prevalence of lifetime diagnostic of asthma increased from 2012 to 2015 in 26 of the 27 Brazilian state capitals. CONCLUSION: There was a decrease in the prevalence of self-report of asthma symptoms and an increase of self-reported lifetime presence of asthma. Certainly, monitoring indicators of asthma prevalence is of high importance for health knowledge and the development of public policies. PMID- 30517469 TI - Characteristics associated to a poor self-rated health in Brazilian adolescents, National Adolescent School-based Health Survey, 2015. AB - INTRODUCTION: Health self-assessment (HSA) is a widely studied indicator among adults and the elderly, but not often explored in adolescents. This study aimed to estimate the prevalence of poor self-rated health in Brazilian schoolchildren and associated factors. METHODS: Data from the 2015 National Adolescent School based Health Survey (PeNSE) were analyzed; prevalences and their 95% confidence intervals (95%CI) were estimated for poor self-rated health and associated factors. Multiple logistic regression analysis was performed. RESULTS: A total of 7.1% (95%CI 7.0 - 7.3) of the schoolchildren reported a poor self-assessed health status. Sociodemographic characteristics, such as female gender, 15 years of age or older, yellow, brown and indigenous race/skin color; risk behaviors such as regular alcohol consumption and drug experimentation, and issues related to physical and emotional health remained positively associated with the outcome studied. Protective factors identified were maternal schooling and demand for health services. CONCLUSION: The impact of risky behaviors on physical and emotional health need to be addressed among students. The school presents itself as a safe and opportune space for promoting a healthy lifestyle. PMID- 30517470 TI - Simultaneous oral health risk behaviors among adolescents: evidence from the National School-based Student Health Survey. AB - OBJECTIVE: To investigate the prevalence of simultaneous oral health risk behaviors and associated factors among Brazilian adolescents. METHODS: The study comprised data of 109,104 adolescents participating in the Brazilian National School-based Student Health Survey. The simultaneous presence of less frequent toothbrushing (E), current smoking (C), no visits to the dentist (D), low fruit intake (F), and high sugar intake (A) was assessed by comparison of observed/expected prevalence (OP/EP). Logistic regression was used to assess sociodemographic and family factors associated with the clustering patterns of oral health risk behaviors. RESULTS: The simultaneous occurrence of two or more oral health risk behaviors was of 60.40%. The highest prevalence values were found for the following patterns with OP/EP over 1.20: EDF, CFA, and EDFA. The odds for two or more combined oral health risk behaviors were higher for adolescents whose parents did not participate in homework, from public schools, males, and of Asian or Indigenous ethnicity (OR > 1.00; p < 0.05). Low family affluence level (FAL) acted as a risk factor for the pattern ECDFA (OR = 2.58; p = 0.009), while low and mean FAL functioned as protection factors for the pattern CFA (OR = 0.71; p < 0.001, and OR = 0.76; p = 0.011). CONCLUSION: The prevalence of simultaneous oral health risk behaviors was low and negatively associated with sociodemographic and family factors. Interventions aiming at reducing these behavior patterns should prioritize the groups that have been identified as being at most risk. PMID- 30517471 TI - Trends in risk and protective factors for non-communicable diseases in the population with health insurance in Brazil from 2008 to 2015. AB - OBJECTIVE: To analyze trends in risk and protective factors for non-communicable diseases (NCD) and access to preventive tests in the population with health insurance in Brazilian state capitals between 2008 and 2015. METHODS: This is a cross-sectional study that analyzed data collected from the Surveillance of Risk and Protective Factors for non-communicable diseases (NCD) Telephone Survey (Sistema Nacional de Vigilancia de Doencas Cronicas por Inquerito Telefonico - Vigitel) on adults aged 18 years and older. We analyzed trends in NCD indicators among health insurance users in approximately 30 thousand interviews done between 2008 and 2015. We used the simple linear regression model to calculate the trends. RESULTS: Health insurance users showed an increase in the prevalence of protective factors such as fruit and vegetable consumption, and physical activity in leisure time. Also, there was a decrease in risk factors such as smoking and soft drink consumption, increase in mammography coverage, and a drop in smoking prevalence. However, overweight, obesity, and diabetes increased. CONCLUSION: There are differences according to gender, and, in general, women accumulate more protective factors and men, more risk factors. PMID- 30517472 TI - Prevalence of arterial hypertension according to different diagnostic criteria, National Health Survey. AB - OBJECTIVE: To determine the population prevalence of arterial hypertension in adults according to different diagnostic criteria. METHODS: This is a cross sectional study, analyzing information from the Brazilian National Health Survey in 2013, consisted of interviews, physical and laboratory measurements (n = 60,202). The prevalence of hypertension was defined according to three diagnostic criteria: self-reported; measured by instrument (blood pressure >= 140/90 mmHg); measured and/or using medication. Prevalence and 95% confidence interval (95%CI) were estimated by the three diagnostic criteria of hypertension. RESULTS: The high blood pressure measurements were: 21.4% (95%CI 20.8 - 22.0) using the criterion self-reported; 22.8% (95%CI 22.1 - 23.4) by measured hypertension; and 32.3% (95%CI 31.7 - 33.0) by measured hypertension and/or reported use of medication. Women presented higher prevalence for the self-reported criterion (24.2%; 95%CI 23.4 - 24.9) and men, for the measured criterion (25.8%; 95%CI 24.8 - 26.8). Hypertension increases with age and is more frequent in urban areas. Using these three criteria, the hypertension was higher in the Southeast and South regions, in relation to the average of the country and the other regions. Using these three criteria, hypertension increased with age, was more frequent in urban areas and in the Southeast and South regions, in relation to the average of the country and the other regions. CONCLUSION: These findings are important to support policies that aim to achieve the World Health Organization's goal of reducing hypertension by 25% over the next decade. PMID- 30517473 TI - Development of a New Cone-Beam Computed Tomography Software for Endodontic Diagnosis. AB - Cone-beam computed tomography (CBCT) has promoted changes in approaches in Endodontics, and enhanced decision-making in complex clinical cases. Despite the technological advancements in CBCT hardware, the interpretation of the acquired images is still compromised by viewing software packages that often have limited navigational tools and lack adequate filters to overcome some challenges of the CBCT technology such as artefacts. This study reviews the current limitations of CBCT and the potential of a new CBCT software package (e-Vol DX, CDT- Brazil) to overcome these aspects and support diagnosing, planning and managing of endodontic cases. This imaging method provide high resolution images due to submillimeter voxel sizes, dynamic multi-plane imaging navigation and ability to change the volume parameters such as slice thickness and slice intervals and data correction applying imaging filters and manipulating brightness and contrast. The main differences between e-Vol DX and other software packages are: compatibility with all current CBCT scanners with the capacity to export DICOM Data, a more comprehensive brightness and contrast library, as other applications, in which adjustments are limited, do not usually support all the DICOM dynamic range features; Custom slice thickness adjustment, often limited and pre-defined in other applications; Custom Sharpening adjustment, often limited in other applications; advanced noise reduction algorithm that enhances image quality; preset imaging filters, dedicated endodontic volume rendering filters with the ability to zoom the image over 1000x (3D reconstructions) without loss of resolution and automatic imaging parameters customization for better standardization and opportunities for research; capture screen resolution of 192 dpi, with a 384 dpi option, in contrast to the 96 dpi of most similar applications. This new CBCT software package may support decision-making for the treatment of complex endodontic cases and improve diagnosis and treatment results. Effective improvement of image quality favors the rational prescription and interpretation of CBCT scans. PMID- 30517474 TI - Effect of Aging on Dentinal Crack Formation after Treatment and Retreatment Procedures: a Micro-CT Study. AB - In order to evaluate the volume of dentinal cracks taking into account the age of the dentin and the type of file system used for endodontic procedures, forty freshly extracted single-rooted lower incisive teeth presenting similar root volume, were divided into two groups according to the age of the patient: Group Young (18 - 30 years old) and Group Old (60 years old or more). Each specimen was scanned by microcomputed tomography (micro-CT) in three stages: (i) before any treatment, (ii) after endodontic treatment with Reciproc files (REC), and (iii) after subsequent endodontic retreatment. Each group was subdivided into two subgroups, according to the retreatment technique used: retreatment with REC or with ProTaper Universal Retreatment (PUR) files. For each subgroup, the images were analyzed for differences in the volume of dentinal cracks in the middle and apical thirds of the teeth , according to the dentin age. In both stages (before and after instrumentation), the micro-CT images of the old root dentin presented with higher volume of cracks than those of the young root dentin, statistical significance notwithstanding (p>0.01). The use of REC files appeared to have no statistically significant differences in the generation of cracks in any type of root dentin when compared with PUR files (p>0.01). When retreated with PUR, the old root dentin presented with a significantly higher volume of cracks (p<0.01) when compared with the old root dentin initially. PMID- 30517475 TI - Evaluation of Physicochemical Properties of New Calcium Silicate-Based Sealer. AB - This study aimed to evaluate the physicochemical properties of a calcium silicate based sealer (Sealer Plus BC; MK Life, Porto Alegre, Brazil) compared with an epoxy-resin sealer (AH Plus; Dentsply DeTrey GmbH, Konstanz, Germany). Initial and final setting time was assessed based on ISO 6876:2012 and ASTM C266:03. Calcium ion release and pH were evaluated by filling polyethylene tubes with sealers and then immersing them in 10 mL of deionized water. Following experimental periods of 1, 24, 72 and 168 hours, the samples were measured regarding pH and calcium ion release with a pH meter and a colorimetric spectrophotometer, respectively. The flow was examined based on ISO 6876:2012. Rings of 10 mm in diameter with 1 mm thickness were prepared to analyze the radiopacity (ISO 6876:2012 and ADA n.57) and solubility (ISO 6876:2012). The data were analyzed by variance analysis, Student-T and Tukey tests (p<0.05). The calcium ion release and pH values were significantly higher for the Sealer Plus BC compared with the AH Plus (p<0.05). Lower setting time, flow and radiopacity were observed for the bioceramic sealer than for AH Plus (p<0.05). Sealer Plus BC exhibited higher solubility compared with AH Plus (p<0.05). Sealer Plus BC showed physicochemical properties as setting time, pH, calcium release, flow, and radiopacity following the required standards, but higher solubility than the minimum values required by ISO 6876:2012. PMID- 30517476 TI - Effect of At-Home Bleaching on Oxygen Saturation Levels in the Dental Pulp of Maxillary Central Incisors. AB - The present study assessed oxygen saturation (SaO2) levels before, during, and after at-home bleaching treatment in the pulps of healthy maxillary central incisors. SaO2 levels were measured in 136 healthy maxillary central incisors using a pulse oximeter. The bleaching protocol consisted of 10% carbamide peroxide gel placed in individual trays and used for four hours daily for 14 days. SaO2 levels were assessed before bleaching (T0), immediately after the first session (T1), on the 7th day of treatment (T2), on the 15th day (the day following the last session) (T3), and 30 days after completion of the bleaching protocol (T4). Data were statistically analyzed using generalized estimating equations (GEE), Student's t test (p<0.05) and Pearson's correlation. Mean pulp SaO2 levels were 85.1% at T0, 84.9% at T1, 84.7% at T2, 84.3% at T3, and 85.0% at T4. Gradual reductions in SaO2 levels were observed, with significant differences (p<0.001) during the course of home bleaching treatment. However, 30 days after the end of the bleaching protocol, SaO2 levels returned to baseline levels. Home bleaching caused a reversible transient decrease in SaO2 levels in the pulps. PMID- 30517477 TI - Survival, Reasons for Failure and Clinical Characteristics of Anterior/Posterior Composites: 8-Year Findings. AB - This retrospective study aimed to compare the annual failure rate (AFR), reasons for failure and factors influencing survival of posterior and anterior composite restorations placed by undergraduate students. Composite restorations placed by undergraduate students were evaluated. The restorations should be in occlusion, with at least one adjacent tooth; and patients should have been present for check up, with at least 1 annual recall. The investigation was performed in two separate analysis: 1) dental electronic records of 100 patients (n=333 restorations) were selected to assess factors influencing survival; 2) clinical evaluation of 30 patients by examining restorations (n=123) to assess clinical characteristics and failure type distribution. Data were subjected to Kaplan Meier method, Log-rank test, Cox regression and Fisher's Exact test (p<0.05). After 8-year period, the AFR was 2.62%. There was difference between anterior and posterior restorations (p=0.005), with anterior showing a higher AFR. The patient caries-risk (p<0.001) and the number of surfaces restored (p=0.010) affected restoration survival. The superficial brightness (p=0.029), fracture (p=0.025) and retention (p=0.011) were clinical criteria with differences between anterior and posterior restorations. Income (p<0.001), caries activity (p<0.001), caries risk (p<0.001) and oclusal risk (p<0.001) also influenced on the restorations survival. After 8-year, the AFR of restorations placed by undergraduate students was acceptable and affected by patient risk factors and the position of the tooth in the arch: anterior restorations failed more than posterior. PMID- 30517478 TI - In Vivo Study of the Action of a Topical Anti-Inflammatory Drug In Rat Teeth Submitted To Dental Bleaching. AB - Bleaching gel containing hydrogen peroxide (H2O2) cause damages in pulp tissue. This study investigated the action of a topical anti-inflammatory, the Otosporin(r), in rats' bleached teeth with the null hypothesis of which the Otosporin(r) is no able to minimize the pulp inflammation that bleaching gel generates. The rat's molars were divided into groups: BLE: bleached (35% H2O2 concentration /single application of 30 min); BLE-O: bleached followed by Otosporin(r) (10 min); and control: placebo gel. In the second day after dental bleaching, the rats were killed, and the jaws were processed for hematoxylin eosin and immunohistochemistry analysis for tumor necrosis factor alpha (TNF alpha), interleukin (IL)-6 and IL-17. The data collected were subjected to Kruskal-Wallis and Dunn statistical tests with at a 5% level of significance (p<0.05). The BLE group had moderate to strong inflammation in the occlusal third of the coronary pulp, with necrotic areas; and BLE-O, mild inflammation (p<0.05). There was a significant difference in the occlusal and middle thirds of the coronary pulp between the BLE with BLE-O and control groups (p<0.05). There was no difference in the cervical third (p>0.05). The BLE group had a high immunoexpression of TNF-alpha than BLE-O and control groups (p<0.05), with moderate and mild immunoexpression, respectively. Regarding IL-6 and IL-17, the BLE group had higher immunoexpression than control (p<0.05); the BLE-O was similar to the control (p>0.05). The topical anti-inflammatory Otosporin(r) can reduce pulp inflammation after dental bleaching in the rat teeth. PMID- 30517479 TI - Dentoalveolar Evaluation of Lower Incisors by CBCT after Treatment with Herbst Appliance. AB - This study aimed to evaluate the effects of the Herbst appliance on the proclination and protrusion of the lower incisors, and to verify if the device causes alveolar bone loss in the anterior region of the mandible. This is a retrospective study. The sample consisted of 35 individuals. The treatment group consisted of 22 individuals (8 girls and 14 boys; initial mean age of 8.2 years) who used the Cantilever Herbst appliance for a period of 12 months. The control group consisted of 13 individuals (3 girls and 10 boys; initial mean age of 8.9 years) who received no treatment and were followed up for a period of approximately 18 months. Cone-beam computed tomography scans were performed at the beginning and at the end of the observational period. The medullary bone thickness (MT), buccal cortical bone thickness (BCT), lingual cortical bone thickness (LCT), and lower incisors proclination and protrusion were evaluated. Data were submitted to statistical analysis (ANCOVA and Student's t-test) with a significance level of 5%. There was no significant difference in MT, BCT, LCT and incisor proclination between groups. Incisor proclination increased in the treated group with no statistical significance. The treatment group showed a significant increase in the protrusion of the incisors (p = 0.02). The Herbst appliance promoted a small proclination and protrusion of the lower incisors, without relevant clinical implications. The Herbst appliance did not cause bone loss in the anterior region of the mandible during Class II treatment. PMID- 30517480 TI - Toothache and Non-Clinical Individual and School Factors in Five-Year-Old Children: Multilevel Analysis. AB - The objective of the present study was to evaluate the influence of individual and contextual factors on the occurrence of toothache in five-year-old children. A cross-sectional study was conducted with 756 five-year-old children from public and private preschools in a city in the countryside of the northeast of Brazil. The sample was determined through probabilistic sampling in two stages (preschools and children). The children included could not have systematic diseases, permanent tooth or orthodontic treatment. Parents/caregivers were required to spend at least 12 hours per day with their children. The history of toothache during the life of the child was reported by parents/guardians. Socioeconomic and psychological questionnaires were completed by parents/guardians. Variables related to social context were obtained from the preschools in which the children studied and the official publications of the municipal region. Unadjusted and adjusted multilevel Poisson regression models were used to investigate the association between individual and contextual characteristics and history of toothache. The history of toothache was found for 23.8% of the children. Among the individual determinants, gender of the child, order of birth, and schooling of parent/guardian were associated with toothache in children. The individual variables remained associated with the outcome after the addition of the contextual variables to the model. The type of preschool was the contextual determinant associated with toothache in the final model. Both individual (gender, order of birth and schooling of parents/guardians) and contextual (type of preschool) determinants were associated with history of toothache in five-year-old children. PMID- 30517481 TI - Retention Force and Wear Characteristics of three Attachment Systems after Dislodging Cycles. AB - Several attachment systems for mandibular implant-supported overdentures are currently available and studies are required to understand their mechanical properties. The objective of this study was to evaluate the retention force and wear characteristics of three attachment systems in a simulation of the cyclic dislodging of implant-supported overdentures. Thirty samples were fabricated and divided into 3 groups: 1-O-ring; 2-Mini Ball; and 3-Equator. A mechanical fatigue test was applied to the specimens using a servo-hydraulic universal testing machine performing 5500 insertion/removal cycles (f=0.8 Hz), immersed in artificial saliva. Retention force values were obtained before and after 1500, 3000, and 5500 cycles using a speed of 1 mm/min and a load cell of 1 kN. One specimen from each group was randomly selected and analyzed by scanning electron microscopy. Two-way repeated measures ANOVA and the Bonferroni post hoc test were used for statistical analyses (alpha=0.05). The O-ring system remained stable during all periods tested and exhibited significantly lower retention force values than the Mini Ball and Equator systems. The Mini Ball system exhibited a significant increase in retention force after the mechanical test (baseline=21.04+/-3.29N; 5500 cycles=24.01+/-3.30N).The Equator system exhibited a significant decrease in retention force after each period tested, but the values were higher than the other systems. The type of attachment was found to influence retention force in different ways after mechanical tests. The Equator system exhibited the highest retention force values. The Mini Ball and Equator matrices produced deformation and wear on the surfaces without breakage of the polyamide rings. PMID- 30517482 TI - Preservation of Dental Sockets Filled with Composite Bovine Bone. A Single-Blind Randomized Clinical Trial. AB - The purpose of this study was to evaluate the preservation of alveolar dimensions in human fresh extraction sockets filled with a composite bovine bone graft by means of design of single-blind randomized clinical trial. Forty participants had monoradicular teeth extracted (one teeth in each participant), and after were randomly divided into 2 groups: individuals whose fresh sockets were filled with the composite heterologous bone graft (Biomaterial Group), or with blood clot (Control Group). After extraction, the fresh sockets were measured at their greatest mesiodistal (MD) and bucco-lingual/palatal (BL/P) distance. Primary closure of the soft tissue was performed with a fibro-mucosal plug. After 120 post-operative days, the re-entry procedure was performed and the largest MD and BL/P measurements were again obtained to calculate the remodeling of the alveolar bone measured in percentage. In the biomaterial group, a percentage reduction of 1.62% and 3.29% in the MD and BL/P dimensions was observed 120 days after the extractions, whereas a reduction of 4.97% and 7.18% in the MD and BL/P dimensions occurred in the control group. There was a statistically significant difference (p<0.05) between the two groups for the bucco-palatal and mesiodistal measurements in the maxilla. In view of the results obtained, it can be concluded that composite bovine bone graft limited but did not impede alveolar bone remodeling. PMID- 30517483 TI - Sexing the Cranium from the Foramen Magnum Using Discriminant Analysis in a Brazilian Sample. AB - In the identification process, the foramen magnum has shown controversial results in sex estimation. The present study aimed to analyze the morphometric variables of the foramen magnum in Brazilian adult cranium for sex estimation. The sample was composed of 100 craniums (53 males and 47 females) from the documented collection of the Institute of Teaching and Research in Forensic Sciences. The protocol measurement was constituted of two linear measurements: maximum length of the foramen magnum and maximum breadth of the foramen magnum and two formulas to calculate the area, method one (M1) and method two (M2). Descriptive statistics showed statistically significant differences between sex (p<0.05) for all variables. The univariate discriminant functions showed an accuracy between 56.0-62.0%, and the multivariate analysis showed a percentage of accuracy between 60.0-65.0%, the greatest accuracy was found combining the two linear measurements with M1(71.7%), even after cross-validation (66%). Receiver Operating Characteristic (ROC) curve analysis showed that M2 is the best parameter for estimating sex (AUC=0.693). A reference table for Brazilians using the foramen magnum parameters was developed based on the results of the ROC curve analysis. In conclusion, the foramen magnum should be used with caution to estimate sex in forensic cases of fragmentary craniums, due to the limited accuracy. PMID- 30517484 TI - Antimicrobial and Anti-Caries Effect of New Glass Ionomer Cement on Enamel Under Microcosm Biofilm Model. AB - The occurrence of caries lesions adjacent to restorations is a serious problem in Dentistry. Therefore, new antimicrobial restorative materials could help to prevent recurrent carious lesions. This study evaluated the effect of a new glass ionomer cement (Ion Z) on the viability of a microcosm biofilm and on the development of enamel demineralization. Enamel samples were filled with the following materials (n=9): A) Ion-Z (FGM Ltda); B) Maxxion R (FGM Ltda); C) Ketac Fil Plus (3M ESPE) and D) no restoration (control). The samples were then exposed to human saliva mixed with McBain saliva (1:50) containing 0.2% sucrose for 14 days. The live and dead bacteria were quantified by fluorescence using a confocal laser-scanning microscope. The enamel demineralization was analyzed using transverse microradiography (TMR). The data were submitted to ANOVA/Tukey or Kruskal-Wallis/Dunn test (p<0.05). Ion Z induced a higher percentage of dead bacteria (60.96+/-12.0%) compared to the other groups (Maxxion R: 39.8+/-6.7%, Ketac Fil Plus: 43.7+/-9.71% and control 46.3+/-9.5%). All materials significantly reduced the average mineral loss compared to control (Ion-Z 25.0+/ 4.2%vol, Maxxion R 23.4+/-8.0%vol, Ketac Fil Plus 30.7+/-7.7 and control 41.2+/ 6.6%vol). Ion-Z was the only material able to significantly improve the mineral content at the surface layer (Zmax: 63.5+/-18.2%vol) compared to control (38.9+/ 11.3%vol). Ion-Z shows antimicrobial potential, but its anti-caries effect was similar to the other materials, under this model. PMID- 30517485 TI - How Common is Dry Mouth? Systematic Review and Meta-Regression Analysis of Prevalence Estimates. AB - The aim of this paper is to systematically review the literature to estimate the overall prevalence of xerostomia/hyposalivation in epidemiological studies. An electronic search was carried out up to February 2018 with no language restrictions. A total of 5760 titles were screened and just twenty-nine papers were included in review and the meta-analysis after a two independently reviewers applied the selection criteria. Data were extracted from PubMed and Web of Science databases. Eligibility criteria included original investigations from observational population-based studies that reported the prevalence of xerostomia or data that allowed the calculation of prevalence of xerostomia and/or hyposalivation. Studies conducted in samples with specific health conditions, literature reviews, case reports and anthropological studies, as conferences or comments were excluded. Sample size, geographic location of the study, study design, age of the studied population, diagnosis methods, and evaluation criteria used to determine xerostomia e/or hyposalivation were extracted for meta-analysis and meta-regression. Multivariate meta-regression analysis was performed to explore heterogeneity among studies. The overall estimated prevalence of dry mouth was 22.0% (95%CI 17.0-26.0%). Higher prevalence of xerostomia was observed in studies conducted only with elderly people. Despite diverse approaches to the condition's measurement, just over one in four people suffer from xerostomia, with higher rates observed among older people. Moreover, the measurement methods used currently may over- or underestimate xerostomia. These findings highlight the need for further work on existing and new clinical measure and will be useful to determine which one is more reliable in clinical and epidemiological perspectives. PMID- 30517486 TI - Photoanthropometry of the Face in the Young White Brazilian Population. AB - The aim of the present study is to describe the simplified facial pattern of young Brazilian men and women using the facial index (FI), upper face index (UFI), and nasal index (NI) in indirect anthropometric measurements applied to frontal photographic images. The images were obtained from 660 adult white men and 689 adult white women aged 30 years +/- 6 months, and classified according to regions of birth, as follows: south (S), southeast (SE), midwest (MW), northeast (NE), and north (N). The nasion, zygion, gnathion, stomion, subnasale, and alare landmarks were labeled on the images using the SAFF 2D(r) software. Based on the coordinates, the linear distances between the landmarks of interest were calculated and presented as indices. The analysis of variance and Student's t test were used for assessing the regions of birth and gender, respectively. The collected data allowed obtaining the facial profile of the young adult Brazilian population. There were differences in the facial profiles between men and women and also between some regions, especially between the N and the other Brazilian regions (p<0.05). The UFI did not show a statistically significant difference (p>0.05) between genders for any of the regions. The discriminant analysis for gender assessment demonstrated higher accuracy when the three indices were analyzed together. In the decision tree for gender assessment, the NI showed better results than the other indices. PMID- 30517487 TI - [Continuum of care of people living with HIV and gaps in achieving the 90-90-90 goals in Peru]. AB - In 2013, the Joint United Nations Programme on HIV/AIDS (UNAIDS) proposed, in terms of public health, to end the HIV epidemic by 2030 by achieving the so called 90-90-90 targets by 2020. This goal will only be possible if coverage in the HIV care continuum indicators is increased. With the methodology proposed by PAHO/WHO, this paper estimates the indicators of the continuum of care in Peru for 2014, consisting of diagnostic coverage, antiretroviral treatment (ART), and viral suppression in people living with HIV (PLHIV). Of the 72,000 PLHIV estimated in Peru for 2014, 64% were diagnosed, 56% and 55% were linked and retained in the system, respectively; 46% were receiving ART, and 36% had viral suppression. The main gaps identified were: 19,917 PLHIV did not know their diagnosis, 25,078 had no access to treatment, and 25,633 did not achieve viral suppression at study closing. This is the first estimation exercise of the continuum of care indicators in Peru. These indicators will serve as a baseline for the monitoring progress toward the 90- 90-90 Targets. It is also the starting point for analysis and research on the determinants of each gap and new proposals by authorities and actors involved in the fight against HIV in Peru. PMID- 30517488 TI - [Preliminary results of the strengthening of the national death registry information system]. AB - Peru has a low coverage of deaths with a cause of death (54%) and a poor-quality registration of causes of death, as about 30% of causes of death are classified as poorly-defined or not very useful for the formulation of public policies. In response to these problems, the Ministry of Health, together with other government agencies, with the support of the Bloomberg Philanthropies "Data for Health Initiative," is implementing the National Death Registry Information System (SINADEF). The objective of this article is to describe the process of strengthening the mortality information system in Peru, focused on the implementation of SINADEF. The activities that have been carried out are described in the following areas: a) Management of the mortality information system, b) Process standardization, c) Use of information and communication technology, d) Coverage of deaths with medical certificate, e) Improvement of the quality of information, f) Development of studies, and g) Monitoring of processes. Since the implementation of SINADEF in August 2016 until July 2018, 28,407 users of the SINADEF application have been created and a total of 122,411 deaths have been registered. The quality of data recording, including the cause of death, has been improved, while low coverage of deaths with a cause of death still persists. PMID- 30517489 TI - [Invasive Fusariosis: Report of Three Cases in Peru]. AB - Fusarium species are a group of fungi that cause superficial infections, locally invasive and disseminated disease, which occur mainly in immunocompromised hosts, and occasionally in immunocompetent individuals. We present three cases that show three different clinical forms of Fusarium spp. disease that affected different types of patients (patients with hematological malignancy, chronic kidney disease in peritoneal dialysis and post-surgical for osteoarticular pathology), each with its own characteristics that merit discussion. These cases show different clinical forms of invasive fusariosis caused by Fusarium solani complex species in patients with different pathologies and therapeutic management that could be risk factors for the development of the disease. The clinical recognition of fusariosis, not only in oncohematological patients, together with a timely diagnosis and treatment contribute to the success of the treatment and a reduction in mortality. PMID- 30517490 TI - [Iron Supplementation Reported by Parents of Children Aged 6 to 23 Months in Peru, 2015-2016]. PMID- 30517491 TI - [Lutzomyia shannoni a potential vector of Leishmania chagasi in Madre de Dios, Peru]. PMID- 30517492 TI - [Registration of Patients with Primary Immunodeficiencies in the Three Main Reference Centers in Peru]. PMID- 30517493 TI - [Reply: on the evaluation of post- traumatic stress disorder in individuals affected by el nino]. PMID- 30517494 TI - [Reply: New case of duplicate or redundant publication in different languages]. PMID- 30517495 TI - [Health research policy and systems for management based on evidences]. PMID- 30517496 TI - [Epidemiological surveillance activities for malaria in the colombian-peruvian border diagnostic network]. AB - OBJECTIVE.: To describe the activities of the malaria diagnostic network and its quality control in the Colombian-Peruvian border to characterize the functioning of the epidemiological surveillance system. MATERIALS AND METHODS.: Descriptive study with a research focus on implementation. We visited border communities with health care centers or volunteers trained to diagnose malaria. The visited sites were georeferenced to know their distribution. With information from departmental public health laboratories, the quality component was analyzed and compliance with the national guidelines for malaria diagnostic networks in the border area of the two countries was evidenced. RESULTS.: Twenty-five Colombian and 18 Peruvian sites were visited, of which 25% had only microscopy posts, 56% made a diagnosis for malaria, and 19% only took samples and the plates were sent to a reference point for diagnosis. The Ministry of Health of the Amazon (Colombia) did not carry out direct supervision visits to the malaria diagnostic network during 2016-2017; the Regional Health Directorate of Loreto (Peru) has not carried out visits since 2015. Sixty percent of the diagnosis points in the Amazon and 29% in Loreto participated in quality assurance. CONCLUSIONS.: Lack of opportunity in the diagnosis was identified in 44% of the visited sites and deficiencies in the quality component of the border diagnostic network. PMID- 30517497 TI - [Knowledge of malaria and long-lasting insecticidal net use practices in two departments of colombia]. AB - OBJECTIVES: To determine the knowledge about malaria and use practice of insecticide-treated mosquito nets in the departments of Antioquia and Choco in Colombia, 2013. MATERIALS AND METHODS: Cross-sectional and descriptive study with probability sampling of clusters, stratified and two-staged. The head of household survey was developed using ten questions on knowledge, transmission, symptoms and preventive measures against malaria, used in the questionnaires of the 2007 National Health Survey in Colombia, as well as 13 questions on long lasting insecticidal nets, tenure, use, reasons for non-use, short-term health side effects, washing and drying. RESULTS: 2078 residents responded to the survey. 89% (95% CI: 87.5-89.9) in Antioquia and 94% (95% CI: 93.0-94.0) in Choco recognized the causes, symptoms, treatment and prevention methods. In Antioquia, 86% (95% CI: 84.9-87.3) had at least one mosquito net and 72% (95% CI: 70.0-73.4) used it daily; and for the department of Choco, it was 93% (95% CI: 92.2-94.4) and 73% (95% CI: 72.0-74.4), respectively. CONCLUSIONS: There are high levels of knowledge about malaria; however, the care of the mosquito nets does not follow the recommendations to increase their useful life, therefore, specific social strategies are required for each department. PMID- 30517498 TI - [Health-related out-of-pocket expenses in older peruvian adults: analysis of the national household survey on living conditions and poverty 2017]. AB - OBJECTIVES: . To estimate out-of-pocket spending on health (GBS) and identify its associated factors in Peruvian older adults. MATERIALS AND METHODS.: Analytical cross-sectional study of the National Household Survey on Living Conditions and Poverty (ENAHO) 2017. Older adults were considered to be all individuals aged 60 and over and the GBS was considered the main study variable. Prevalence ratios (PR) and adjusted prevalence ratios (PRa) were estimated for each of the factors associated with GBS. GBS means were estimated using a generalized linear model with gamma distribution and log binding function. All confidence intervals (95%) of the estimators were calculated by bootstrapping with the normal-based method. RESULTS: . Eighteen 386 older adults were included, of which 56.5% reported GBS. The mean and median GBS is S/. 140.8 (USD 43.2) and S/. 34.5 (USD 10.6), respectively. Factors such as urban origin, a higher level of education, chronic diseases and higher per capita expenses increase the probability of GBS by up to 1.6 times. In those affiliated to the Integral Health Insurance (SIS), the GBS is reduced by 63.0 soles (USD 19.3) compared to those without any health insurance. CONCLUSIONS: . Six out of ten older Peruvian adults reported GBS to attend to their health needs. This generates an access inequity in terms of health services, mainly for socially-vulnerable groups. We suggest researching into the economic impact of health insurance and the preventive-promotional approach to chronic diseases, in order to reduce GBS and improve the efficiency of the Peruvian health system. PMID- 30517499 TI - [Prevalence and factors associated with over-the-counter antimicrobial purchases, Peru 2016]. AB - OBJECTIVES: To describe the prevalence and factors associated with the purchase of antimicrobials without a prescription (CASRM) in drugstore/pharmacy users according to the National Health User Satisfaction Survey (ENSUSALUD). MATERIALS AND METHODS: A secondary analysis of ENSUSALUD 2016 was carried out; a study with two-stage probabilistic sampling in the Health Service Providers of the public and private subsector. The CASRM was evaluated by self-report. Crude (PR) and adjusted (PRa) prevalence ratios with 95% confidence intervals (95% CI) were estimated. RESULTS: The study included 1.165 users who purchased antimicrobials. The mean age was 38.0 years (standard deviation: 13.4). The prevalence of CASRM was 53.4% (95% CI: 48.0-58.8). The prevalence of CASRM in the highlands was (PRa 1.66, 95% CI 1.37-2.02) and in the jungle (PRa 1.61, 95% CI 1.31-1.99); and in pharmacy users (PRa 1.25, 95% CI 1.13-1.39). People with Comprehensive Health Insurance (SIS) had a lower prevalence of CASRM (RP 0.73, 95% CI 0.60-0.88). The prevalence was lower if the antimicrobial was for the spouse (RP 0.65, 95% CI 0.55-0.77) or child (RP 0.70, 95% CI 0.52-0.93). CONCLUSIONS: A 53.4% of drugstore/pharmacy users, who bought antimicrobials, did so without a doctor's prescription. The prevalence of CASRM was higher in the highlands and jungle and in pharmacy users, as well as lower in those who had SIS and those who bought for their spouse or child. We suggest reinforcing the interventions, mainly regulatory and educational, in the highlands and in the jungle, as well as, in the population not affiliated to a health insurance. PMID- 30517500 TI - [Mortality from chronic kidney disease in Peru: national trends 2003-2015]. AB - OBJECTIVES.: To describe the mortality trend due to chronic kidney disease (CKD) in Peru in the period 2003-2015. MATERIALS AND METHODS.: Analysis of secondary data and ecological design. National mortality registries based on death certificates were analyzed. ERC was defined as CIE code 10: N18 in the basic cause. Absolute and relative frequencies of death by ERC are described. To estimate the proportion of deaths by CKD in each region of Peru, a generalized mixed linear model was used. The outcome variable was the proportion of deaths, the independent variables were each region of the country and the year. RESULTS.: The analysis included 1,086,778 deaths, of which 25,091 (2.0 % age- and sex adjusted) were by CKD. During the study period, the average age at death increased by 2.6 years (p<0.001); in addition, the proportion of age- and sex adjusted CKD deaths was always higher in women. In the observation period, the region with the highest mortality from CKD was Puno (4.1%), and with the lowest mortality was Amazonas (1.1%). Those regions that showed a significantly greater increase than the others were Tacna, La Libertad, Tumbes, Apurimac, Cusco, Ica, Moquegua, Ayacucho, Huancavelica and Puno. CONCLUSIONS.: In the 2003-2015 period, mortality from CKD in Peru has increased; this trend is observed in several regions of the country. Preventive measures, early identification, and access to treatment must be implemented to control this trend. PMID- 30517501 TI - [Global and disease-free survival in a peruvian cohort of patients with acute lymphoblastic leukemia]. AB - OBJECTIVE: To know the five-year survival and its associated factors in patients with Acute Lymphoblastic Leukemia (ALL) in Peru. MATERIALS AND METHODS: A retrospective cohort of patients with ALL treated with chemotherapy in a Peruvian hospital for 13 years was studied. The dependent variables were overall survival (OS) and disease-free survival (DFS). Possible factors that might be associated with diagnosis and response to treatment were evaluated using the Cox proportional risk method. RESULTS: The mortality rate was 32.5% and the relapse rate was 66.1%. The factors associated with lower overall survival were leukocyte count at diagnosis (HR: 1.01; 95% CI: 1.01-1.03), lineage other than B (HR: 2.15; 95% CI: 1,06-4,41), age at diagnosis (HR: 1,09; 95% CI: 1,03-1,16), bone marrow relapse (HR: 6,81; 95% CI: 4,14- 11,21) and induction failure (HR: 3,04; 95% CI: 1,47-6,32). Factors associated with lower disease-free survival: male gender (HR: 1.43; 95% CI: 1.10-1.86), age at diagnosis (HR: 1.06; 95% CI: 1.02-1.10) and leukocytes at diagnosis (HR: 1.01; 95% CI: 1.002-1.011). CONCLUSIONS: The five year OS and DFS figures for our population are lower than those for the world. More studies are needed to know the factors involved in this reality and thus generate interventions aimed at improving the survival and quality of life of our patients. The variables associated with the decrease in both survival indicators were age and leukocyte count at the time of diagnosis, so the process of disease diagnosis must be improved. PMID- 30517502 TI - [Presence of multidrug resistant Enterobacteriaceae and Escherichia coli in meat purchased in traditional markets of Lima]. AB - OBJECTIVE.: The objective of this study was to describe the presence of Enterobacteriaceae in meat samples collected in traditional markets of Lima and to establish the levels of antimicrobial resistance and the presence of extended spectrum beta-lactamases (BLEE) and AmpC in Escherichia coli. MATERIALS AND METHODS.: A total of 138 meat samples, 64 (46.4%) chicken, 44 (31.9%) beef and 30 (21.7%) pork were collected. The isolated bacteria belonged to 17 different genera and, specifically, 14 were classified as Enterobacteriaceae. Sensitivity to ten antimicrobial agents was analyzed using the Kirby-Bauer disc diffusion method, BLEE and AmpC were determined by double disc and imipenem-ceftazidime induction tests, respectively. RESULTS.: Antimicrobial resistance levels were high against trimethoprim-sulfamethoxazole, ampicillin, tetracycline, nalidixic acid, ciprofloxacin and chloramphenicol. There are significant differences in antibiotic resistance levels depending on the type of meat (chicken, beef and pork) (p <0.05). Multiple drug resistance (MDR) levels were particularly high in chicken and pork (98.2% and 86.4%, respectively). In addition, the presence of BLEE in Escherichia coli isolated from chicken meat was 59.4%. CONCLUSIONS.: Multiple drug resistance levels were high compared to antibiotics frequently used in humans; chicken and beef are highlighted as potential reservoirs of BLEE and pAmpC-producing Escherichia coli, respectively. PMID- 30517503 TI - [Molecular diagnosis of multidrug-resistant tuberculosis in sputum samples by melting curve analysis]. AB - OBJECTIVES.: To analyze melting curves for the diagnosis of multidrug-resistant tuberculosis from sputum samples. MATERIALS AND METHODS.: Sputum samples (n = 250) were collected from patients with clinical suspicion of pulmonary tuberculosis as a result of bacilloscopy and cultured in solid medium Lowenstein Jensen. According to the reference method, 124 samples sensitive to rifampicin and isoniazid, 24 resistant to rifampicin, 33 resistant to isoniazid, and 69 multidrug-resistant were used. It was evaluated by real-time PCR and then by melting curves, the rpoB gene was used as a biomarker of rifampicin resistance, and the katG gene and inhA promoter region were used as biomarkers of isoniazid resistance. The H37Rv strain was considered a drug-sensitive control. The results of the reference method and the results of the melting curve analysis were compared to evaluate the parameters of sensitivity, specificity, positive predictive value and negative predictive value. RESULTS.: Rifampicin resistance showed a sensitivity of 90.3%, specificity of 90.4%, positive predictive value of 84.8% and negative predictive value of 94.0%. Isoniazid resistance showed a sensitivity of 90.2%, specificity of 93.9%, positive predictive value of 91.1% and negative predictive value of 93.3%. The detection of multidrug-resistant tuberculosis showed values of 89.9%, 90.6%, 78.5% and 95.9% for sensitivity, specificity, positive predictive value and negative predictive value, respectively. CONCLUSIONS.: The melting curve analysis showed to be safe and reliable to be used in the rapid diagnosis of multidrug-resistant tuberculosis in sputum samples. PMID- 30517504 TI - [Osteoarticular protection of Zea mays L. purple variety (purple corn) in experimental arthritis in rats]. AB - OBJECTIVES.: To evaluate the protective effect of Zea mays L., purple variety (purple corn) against inflammatory response and osteoarticular damage in rats with experimental arthritis. MATERIALS AND METHODS.: Sixty-five Holtzman rats were used, assigned to seven groups: G1 (n=5): control; G2 (n=10): pristane (PIA) + distilled water; G3 (n=10): PIA + methotrexate 0.1 mg/kg; G4 (n=10): PIA + indomethacin 0.6 mg/kg; G5 (n=10): PIA + Zea mays 100 mg/kg; G6 (n=10): PIA + Zea mays 1000 mg/kg, and G7 (n=10): PIA + methotrexate 0.1 mg/kg + Zea mays 1000 mg/kg. Treatments were administered by orogastric cannula daily for 21 days; pristane was administered subdermal only on day 1. Volume of hind leg was recorded with a digital plethysmometer. The radiological analysis of the legs was evaluated according to the modified Clark criteria. RESULTS.: The percentage of inflammation at the end of the experiment was: (G1) 1.50 +/- 0.5; (G2) 13.73 +/- 8.4; (G3) 14.76 +/- 8.8; (G4) 14.22 +/- 9.0; (G5) 10.81 +/- 9.1; (G6) 5.31 +/- 1.4; (G7) 6.38 +/- 0.5. The radiological scores of the affected areas were: (G1) 0.6; (G2) 3.5; (G3) 0.6; (G4) 1.7; (G5) 1.9; (G6) 1.4; (G7) 1.0. Only the groups Zea mays L. 1000 mg/kg and methotrexate + Zea mays L. 1000 mg/kg showed a significantly lower inflammatory response (p<0.05) and showed significantly lower joint scores in relation to PIA. CONCLUSIONS.: Zea mays L. (purple corn) reduces the inflammatory process and radiological modifications of PIA-induced arthritis in rats in a dose-dependent manner. PMID- 30517505 TI - [Effect of oxytocin on the levels of malondialdehyde, nitric oxide, and s100b protein in newborns]. AB - OBJECTIVES: To assess the effects of the administration of oxytocin during labor management on the levels of malondialdehyde (MDA), nitric oxide (NO), and S100B protein in newborns. MATERIALS AND METHODS: We selected 80 term pregnant women without obstetric and fetal pathology, forming two groups: pregnant women with normal delivery and pregnant women conducted with oxytocin. Blood was collected immediately after delivery from the umbilical cord vein to measure MDA, ON and from the artery for protein S100B. The concentration of MDA and ON was quantified by spectroscopic methods and the protein S100B by ELISA. RESULTS: Values of 3.4 uMol/L and 3.6 uMol/L of MDA and 1.4 uMol/L and 1.8 uMol/L of NO were obtained in the oxytocin and control group, respectively, without significant difference; S100B levels were higher in the oxytocin managed group, with a median of 1.36 MUg/L compared to the normal delivery group 1.11 MUg/L (p=0.03). There was no relationship between the dose of oxytocin administered and the levels of MDA, ON, and S100B. CONCLUSIONS: There is no difference between MDA and NO levels between pregnant women undergoing a normal or managed birth. There is a significant difference in S100B protein levels in newborns born via an oxytocin-managed delivery. There is no relationship between oxytocin dose and levels of oxidative stress and S100B protein. PMID- 30517506 TI - [Spanish adaptation and validation of The Institutional Review Board Researcher Assessment Tool (IRB-RAT)]. AB - OBJECTIVE.: To assess the reliability and validity of the translated and culturally-adapted Institutional Review Board Researcher Assessment Tool (IRB RAT) for Peruvian research ethics committees (RECs). MATERIALS AND METHODS.: The IRB-RAT is an instrument that determines how RECs are perceived by researchers based on eight factors, using two formats: 1) importance in the work of the researcher and 2) descriptive of the REC being evaluated. Its original English version was translated and culturally adapted into Spanish, with the support of experts and representatives of the target population. Then, according to the responses of 113 users, the heterogeneous items were identified and eliminated until a final version of 29 items was obtained. The reliability of this version was reviewed using Cronbach's alpha and omega coefficient, its internal structure validity through a confirmatory factor analysis with the unweighted least squares method. RESULTS.: Translation and cultural adaptation complied with internationally recommended steps. Reliability at the level of the eight factors was moderate for format 1 (0.67=18 years, and advanced fibrosis (F>=3) patients. Samples were collected at baseline and after 12 weeks (W12) of TT. Six cytokines were analyzed by flow cytometry. RESULTS: Of 31 patients, four were excluded (two deaths, one interrupted TT, and one F2 patient). Of the 27 remaining patients, 21 (78%) were cirrhotic. SVR was achieved in 63% of the patients. The patients had a mean age of 55.11 +/- 10.03 years. Analyses at baseline showed that the chemokine CCL5/Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) (p=0.04) and interleukin (IL)-6 (p=0.02), which was associated with SVR. RANTES (p=0.04) and IL-8 (p=0.01) levels were associated with SVR at W12. CONCLUSIONS: Similar to patterns observed during double therapy, IL-6, IL-8, and RANTES levels were associated with SVR in TT, indicating the potential role of interferon in immune response to hepatitis C virus. PMID- 30517526 TI - Fluctuations in serological hepatitis C virus levels in HIV patients. AB - INTRODUCTION: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have identical transmission routes, explaining the high prevalence of coinfections. The main aim of this study was to detect fluctuations in serological HCV levels in HIV patients. METHODS: We analyzed samples of 147 patients who attended an outpatient service that supports HIV/AIDS patients in Sao Paulo city. We also recruited 22 HCV-monoinfected patients who attended the Instituto Adolfo Lutz Laboratory in Sao Paulo city, to compare the test results. Serological testing of the blood samples was performed for the detection of HCV antibodies. The samples were then analyzed using real-time PCR for RNA viral quantification and sequencing. RESULTS: We found that 13.6% of the study population was coinfected with HIV and HCV. In 20% of coinfected patients, fluctuations in serology results were detected in samples collected during the follow-up. No changes in anti-HCV serological markers were observed in HCV-monoinfected patients. An HCV viral load was detected in 9,5% of the samples collected from HIV patients. CONCLUSIONS: Our findings provide important clinical data to public health professionals and highlight the importance of periodic monitoring of HCV/HIV coinfected patients. PMID- 30517527 TI - Quality of life predictors for people living with HIV/AIDS in an impoverished region of Brazil. AB - INTRODUCTION: Quality of life (QoL) is important for people living with HIV/AIDS, particularly as the disease progresses. This study evaluated the QoL of people living with HIV/AIDS (PLWHA), as well as its predictors, in one of the most impoverished regions of Brazil. METHODS: This cross-sectional study was conducted with patients older than 18 years with HIV/AIDS from two specialized HIV/AIDS care centers in the city of Montes Claros between 2013 and 2014. Sample size was calculated considering the estimates of mean scores for various dimensions of the European Portuguese version of the World Health's Organization Quality of Life Instrument in HIV Infection (WHOQOL-HIV Bref). The following parameters were adopted: CI of 95%, estimated mean scores for QoL equal to 15, estimated variance for QoL scores equal to 16, and 5% relative margin of error. An increase of 20% was established to compensate for possible non-responses or losses, and correcting any design effect, adopting a deff equal to 2.0. Calculations revealed the need to interview at least 221 patients. Therefore, 226 patients living with HIV/AIDS were randomly selected. RESULTS: A total of 226 patients with mean age 43.7 years were evaluated: 51.8% men, 51.8% unemployed, 51.8% with low schooling level, 89.8% used antiretrovirals, and 43.3% experienced depression. Despite this, data indicated that 65% self-assessed their QoL as good and very good. Low QoL was associated with sociodemographic variables and some clinical variables. CONCLUSIONS: Depression was the main predictor of low QoL in all domains evaluated. PMID- 30517528 TI - Predictive factors of dengue severity in hospitalized children and adolescents in Rio de Janeiro, Brazil. AB - INTRODUCTION: Dengue is one of the most important mosquito-borne infections. Severe cases are more frequently observed in adults. However, in 2008, the State of Rio de Janeiro, Brazil, experienced a severe dengue epidemic that primarily affected children and caused many cases of dengue hemorrhagic fever (DHF) and death. METHODS: A cross-sectional analytical study was conducted to examine laboratory diagnosis and clinical epidemiologic factors for confirmed dengue cases in patients aged less than 16 years, from January to June 2008, at a municipal hospital in the City of Rio de Janeiro, Brazil. Variables associated with severe outcomes and P values less than .05 were evaluated by means of a logistic regression model. RESULTS: Of the 419 dengue cases studied, 296 were classified as DHF and 123 as classical dengue. Six patients who had DHF died. In multivariate analysis, some laboratory and clinical variables were independently associated with DHF: age 5 years or older (odds ratio [OR], 4.94; 95% confidence interval [CI], 1.30-18.71), abdominal pain (OR, 8.59; 95% CI, 3.17-23.27), hepatomegaly (OR, 15.87; 95% CI, 5.38-46.85), and positive tourniquet test (OR, 10.84; 95% CI, 3.96-29.71). Hypoalbuminemia occurred more frequently than hemoconcentration in DHF cases, and high aminotransferase levels were associated with severity. CONCLUSIONS: Age greater than 5 years, abdominal pain, painful hepatomegaly, and positive tourniquet test were predictors of DHF. The high frequency of hepatic impairment suggests that acetaminophen should be avoided in severe cases of dengue. PMID- 30517529 TI - Assessment of different methods for the detection of biofilm production in coagulase-negative staphylococci isolated from blood cultures of newborns. AB - INTRODUCTION: Coagulase-negative staphylococci (CoNS) are a frequent cause of bacteremia, especially in neonates. The major virulence determinant in CoNS is the ability to produce biofilms, which is conferred by the icaADBC genes. This study aimed to assess different methods for the detection of biofilm formation in 176 CoNS isolates from blood cultures of newborns. METHODS: The presence of the icaACD genes was assessed by polymerase chain reaction (PCR), and biofilm formation was assessed on congo red agar (CRA), by the tube method (TM), and on tissue culture plates (TCP). RESULTS: Of the 176 CoNS isolates, 30.1% expressed icaACD and 11.4% expressed icaAD. The CRA assay and TM showed that 42% and 38.6% of the isolates were biofilm producing, respectively. On TCP, 40.9% of the isolates produced biofilms; 21% were weakly adherent and 19.9% were strongly adherent. When compared to the gold standard technique (PCR), the CRAassay showed 79% sensitivity and 84% specificity (kappa = 0.64), TM showed 78% sensitivity and 89% specificity (kappa = 0.68), and TCP showed 99% sensitivity and 100% specificity (kappa = 0.99). CONCLUSIONS: In this study, ~42% of CoNS isolates produced biofilms, and the presence of icaACD was associated with a greater capacity to form biofilms. Compared to the other phenotypic methodologies, TCP is an ideal procedure for routine laboratory use. PMID- 30517530 TI - Favorable responses to treatment with 5 mg Sbv/kg/day meglumine antimoniate in patients with American tegumentary leishmaniasis acquired in different Brazilian regions. AB - INTRODUCTION: Favorable responses in American tegumentary leishmaniasis (ATL) patients to treatment with 5 mg Sbv/kg/day meglumine antimoniate (MA) has been reported in Rio de Janeiro, but little is known regarding the therapeutic response to low doses in patients from other locations. METHODS: A retrospective review of medical records was conducted to compare the therapeutic response to 5 mg Sbv/kg/day MA treatment among 36 patients who acquired ATL in Brazilian states other than Rio de Janeiro (OS group) and 72 patients from Rio de Janeiro (RJ group). RESULTS: One course of 5 mg Sbv/kg/day MA cured 72.8% of 81 cutaneous (CL) and 66.6% of 27 mucosal (ML) leishmaniasis-infected patients: 70% in the CL/RJ group, 81% in the CL/OS group, 50% in the ML/RJ group, and 80% in the ML/OS group. After up to two additional treatment courses at the same dose, 88.9% and 85.2% of the CL and ML patients were cured, respectively. Adverse events were observed in 40% of patients in the CL/RJ group, 57% of the CL/OS group, 58% of the ML/RJ group, and 80% of the ML/OS group. No significant differences were observed in the cure rates or adverse effects between the RJ and OS groups. No patients required permanent discontinuation of treatment due to adverse events. CONCLUSIONS: Patients with ATL acquired in both RJ and OS may respond to low-dose MA. While high-dose MA should remain the standard treatment for ATL, low-dose MA might be preferred when toxicity is a primary concern. PMID- 30517531 TI - Prevalence and risk factors of toxoplasmosis among adults in a small Brazilian city. AB - INTRODUCTION: The prevalence of Toxoplasma gondii infection varies markedly among different populations, especially depending on factors related to socioeconomic development and eating habits. Cassia dos Coqueiros is a small city in Brazil with rural characteristics and increased risk factors traditionally associated with T. gondii infection. METHODS: We carried out a cross-sectional study involving 970 inhabitants aged 18 years or more, selected from patients of the local health unit and home visits in urban and rural areas. Each participant completed a survey with questions regarding demographic, socioeconomic, and risk factors for toxoplasmosis. Blood samples from participants were tested for presence of IgG and IgM antibodies against T. gondii using a chemiluminescent microparticle immunoassay. RESULTS: The prevalence of IgG and IgM antibodies was 62.3% and 2.5%, respectively. Variables that proved to be independent predictors of infection were age, low levels of education, and previous diagnosis of toxoplasmosis. CONCLUSIONS: The high prevalence of toxoplasmosis serological markers in this adult population highlights the need to promote preventive practices, especially those directed toward women of childbearing age, in this part of Brazil. PMID- 30517532 TI - Factors associated with leprosy in a municipality of the Pre-Amazon region, state of Maranhao, Brazil. AB - INTRODUCTION: The Integrated Program of Leprosy Control was initiated in the municipality of Buriticupu, Maranhao, Brazil, an area considered hyperendemic for leprosy in 2003. It aims at assessing the clinical and epidemiological characteristics of the disease to reduce the detection rate of new cases until 2015. Here, we present the evolution of the indicators of leprosy within the period from 2003 to 2015. METHODS: We conducted a descriptive analytical study based on the active search for and voluntary referral of cases of leprosy. The detection rate of new cases was analyzed over time. We included individuals diagnosed with leprosy between January 2003 and December 2015. The association between categorical variables was assessed using the chi-square test of independence, considering a level of significance of 5%. When the association was significant, the detection rate (with a confidence interval of 95%) was calculated. RESULTS: Overall, 879 new leprosy cases were detected; the majority of the affected individuals were men (65.9%). Multibacillary leprosy was the most common type of the disease, according to the operational classification (55.5%); it showed the strongest association with an age >=60 years. We also detected an association between the male sex and both, lepromatous and multibacillary leprosy. The detection rate reduced from 211.09/100,000 population in 2003 to 50.26/100,000 population in 2015. CONCLUSIONS: We found an improvement in leprosy control, with a reduction in the detection rate and the absolute number of cases. Strengthening of disease control measures should be prioritized to eliminate leprosy as a public health concern in this municipality. PMID- 30517533 TI - Alterations in the lipid profiles and circulating liver enzymes in individuals infected by Schistosoma mansoni. AB - INTRODUCTION: Portal hypertension and periportal fibrosis commonly occur in severe Schistosoma mansoni infection. Changes in lipid profile and elevated levels of circulating liver enzymes have also been described in infected individuals. The present study sought to assess the alterations in laboratory parameters associated with liver disorder in individuals infected by S. mansoni who visited a private routine laboratory service. Levels of circulating liver enzymes (gamma-glutamyl transferase [gamma-GT], aspartate transaminase [AST], alanine transaminase [ALT], and alkaline phosphatase [ALP]) and a lipid panel (total cholesterol [COL], high-density lipoprotein [HDL], low-density lipoprotein [LDL], very low-density lipoprotein [VLDL], and triglycerides [TRI]) were evaluated in both infected and non-infected individuals and relative risk was used to measure associations. METHODS: Data were collected for analysis from a total of 1,078 cases identified in 379,600 individuals who submitted samples to the Datalab Laboratory (Salvador, Bahia) between 2004 and 2008. RESULTS: S. mansoni infection led to increased circulating levels of gamma-GT in both women and men, AST (women), and ALP (men). S. mansoni infection was a protective factor against increased levels of TRI, CHO, and VLDL for individuals aged 19 years or older. The results of our analysis indicate that alterations in lipid metabolism and circulating liver enzymes in asymptomatic S. mansoni-infected individuals might be attributed to eggs lodged in the hepatic sinusoids. CONCLUSIONS: Parasitological testing for S. mansoni should be indicated in endemic areas when this pattern of alterations is detected. PMID- 30517534 TI - Hepatitis E virus infection among rural Afro-descendant communities from the eastern Brazilian Amazon. AB - INTRODUCTION: The prevalence, public health impact, and epidemiological characteristics of hepatitis E virus (HEV) are poorly understood in Brazil. METHODS: Serum samples from 535 individuals from three rural Afro-descendant communities located in eastern Brazilian Amazon were collected in October 2015 and tested for presence of anti-HEV IgM and IgG antibodies. Serologically positive samples were also tested for HEV-RNA. RESULTS: Two cases were confirmed for anti-HEV IgM (0.3 %) and two cases for anti-HEV IgG (0.3 %). No sample was positive for HEV-RNA. CONCLUSIONS: Results indicated low prevalence of HEV infection in Afro-descendant rural communities from the eastern Brazilian Amazon. PMID- 30517535 TI - Absence of cytomegalovirus in gingivitis and chronic periodontitis in HIV-1 patients in Northern Brazil. AB - INTRODUCTION: The influence of cytomegalovirus (CMV) on the progression of chronic periodontitis in HIV patients is poorly investigated. METHODS: ELISA was used for anti-CMV antibody IgG titer measurements and real-time polymerase chain reaction for qualitative and quantitative CMV detection. Data on the CD4 + T lymphocyte count and plasma HIV viral load were obtained from patient records. RESULTS: CMV DNA was detected in samples of subgingival biofilm in only three individuals, two of them with chronic periodontitis (4%) and one with gingivitis (3.3%). CONCLUSIONS: The prevalence of CMV is very low both in HIV-1 patients with gingivitis and chronic periodontitis. PMID- 30517536 TI - Prevalence and risk factors of syphilis and human immunodeficiency virus co infection at a university hospital in Brazil. AB - INTRODUCTION: The incidence of syphilis has increased since the 1970s. METHODS: This was a descriptive and analytical cross-sectional study with a non probabilistic sample. RESULTS: Of 973 patients with human immunodeficiency virus, 179 (18.4%) tested positive for both human immunodeficiency virus and syphilis, 84.8% were men, 50.9% were aged between 36 and 50 years, 47.8% with syphilis were diagnosed with human immunodeficiency virus for 10-20 years, and 40.3% received antiretroviral therapy for 10-20 years. CONCLUSIONS: The prevalence of syphilis in patients with human immunodeficiency virus is higher than expected, making it urgent to adopt efficient public health measures. PMID- 30517537 TI - Syphilis in pregnancy, congenital syphilis, and factors associated with mother-to child transmission in Itapeva, Sao Paulo, 2010 to 2014. AB - INTRODUCTION: This study describes cases of syphilis in pregnancy (SiP) and congenital syphilis (CS) and identifies factors associated with mother-to-child transmission in patients in Itapeva from January 1, 2010 to December 31, 2014. METHODS: Using SiP and CS notification forms and medical records, a cross sectional study involving 149 pregnant women was conducted. RESULTS: Annual SiP detection rates ranged from 16.3-31.4/1000 live births. Most women had prenatal care started at the first trimester of pregnancy with >=6 visits. Mother-to-child transmission rate was 69.7%. CS incidence rates varied from 9.1-22.3/1000 live births. CONCLUSIONS: The results suggest low quality of prenatal care. PMID- 30517538 TI - Echocardiographic Study of the Coronary Sinus in the Indeterminate Form of Chagas Disease. AB - INTRODUCTION: We investigated the occurrence of coronary sinus abnormalities in the indeterminate form of Chagas disease (CD). METHODS: Differences between the maximum and minimum diameters of the coronary sinus (?%) on echocardiography were evaluated in individuals with the indeterminate form of CD (n=14) and those without (n=16) CD. The association of the difference with abnormalities detected by echocardiography and myocardial scintigraphy was assessed. RESULTS: The mean Delta% values did not differ significantly between the groups. There was no correlation of the measurements with echocardiographic and myocardial scintigraphy findings. CONCLUSIONS: The coronary sinus evaluation revealed no differences between the groups. PMID- 30517539 TI - Using a Chagas disease hospital database: a clinical and epidemiological patient profile. AB - INTRODUCTION: Chagas disease (CD) prevention and control rely on studies of its distribution, characteristics of individuals affected and mode of transmission. CD data in Brazil are scarce; a retrospective analysis of the clinical characteristics of 80 patients treated at the Clinical Hospital of UNICAMP, Campinas, Brazil, was performed. METHODS: Patient data records were analyzed. RESULTS: Thirty percent of the patients probably got infected through vector borne transmission, 65% came from endemic areas, a predominance of cardiac and cardiodigestive forms was found among males, and the cardiac form prevailed (51%). CONCLUSIONS: The results update the view on the epidemiology of CD in Campinas, Brazil. PMID- 30517540 TI - American cutaneous leishmaniasis in a northeast Brazilian city: clinical and epidemiological features. AB - INTRODUCTION: This study characterized the clinico-epidemiological profile of American cutaneous leishmaniasis (ACL) cases in Barbalha, Ceara State, Brazil. METHODS: Medical records of 363 patients visiting Federal University of Cariri between 2009 and 2014 were analyzed. RESULTS: ACL was more prevalent in men with low education level from rural zones. The main presentation was a single ulcer, mainly in the lower limbs, and 49.8% also presented lymphadenomegaly. The annual incidence ranged from 2.83 to 22.60 per 10,000 inhabitants. CONCLUSIONS: The rates observed in this study indicate the importance of additional research to contribute to the control of this endemic disease. PMID- 30517541 TI - PCR sensitivity of peripheral blood of dogs co-infected with Leishmania spp. and Ehrlichia spp. in endemic area of Brazil. AB - INTRODUCTION: Peripheral blood of 400 dogs infected with Leishmania and Ehrlichia were analyzed using polymerase chain reaction (PCR), and clinical signs were characterized. METHODS: PCR and parasitological tests were conducted. RESULTS: PCR was positive for Leishmania in 84.75%, and parasitological tests showed that 63.25% and 31.75% were positive for Leishmania and Ehrlichia, respectively. All animals showed more than three clinical signs. PCR results were negative for Leishmania in 15.25% of the samples. CONCLUSIONS: Conventional PCR of peripheral blood can be used for diagnosing canine visceral leishmaniasis in combination with other techniques, especially in uncertain cases that need species identification. PMID- 30517542 TI - Antiprotozoal action of synthetic cinnamic acid analogs. AB - INTRODUCTION: Leishmaniasis, Chagas disease, and malaria cause morbidity globally. The drugs currently used for treatment have limitations. Activity of cinnamic acid analogs against Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum was evaluated in the interest of identifying new antiprotozoal compounds. METHODS: In vitro effects of analogs against L. braziliensis, L. infantum chagasi, T. cruzi, and P. falciparum, and hemolytic and cytotoxic activities on NCTC 929 were determined. RESULTS: Three analogs showed leishmanicidal and tripanocidal activity. No antiplasmodial, hemolytic, or cytotoxic activity was observed. CONCLUSIONS: Antiprotozoal activity of analogs against L. infantum braziliensis, L. infantum chagasi, and T. cruzi was demonstrated. PMID- 30517543 TI - Seroepidemiological aspects of human infection by Strongyloides stercoralis in Alfenas, southern Minas Gerais, Brazil. AB - INTRODUCTION: In most Strongyloides stercoralis infected individuals, nematoidosis occurs asymptomatically, but in immunocompromised patients, it can cause hyperinfection. Serological techniques seem to be a good alternative for detecting this parasite. METHODS: The frequency of seropositivity for strongyloidiasis in Alfenas, MG, was estimated using the enzyme linked immunosorbent assay on blood samples, between May and August of 2015. RESULTS: Out of 258 samples tested, 53.9% were positive, and the frequency of seropositive individuals was higher in the peripheral districts of the municipality. CONCLUSIONS: The results indicate high seropositivity rates for strongyloidiasis among the residents of Alfenas city. PMID- 30517544 TI - Subcutaneous nodules of cysticercosis as a sign of asymptomatic neurocysticercosis in an HIV positive patient. AB - Cysticercosis is caused by the hematogenous dissemination of the larval form (cysticercus) of Taenia solium. It can affect any organ or tissue in the body but commonly affects the subcutaneous tissue, central nervous system, eyes, and skeletal muscle. Skin lesions can assist as a marker in the diagnosis of asymptomatic neurocysticercosis in endemic areas. A 49-year-old HIV positive man presented with multiple cutaneous nodules confirmed as cysticercomas which led to the diagnosis of asymptomatic neurocysticercosis. He was successfully treated with albendazole and steroids at recommended doses with no adverse effects. PMID- 30517545 TI - Diabetes insipidus secondary to tuberculous meningoencephalitis with hypothalamic involvement extending to the hypophysis: a case report. AB - The involvement of Mycobacterium tuberculosis in the central nervous system (CNS) is an uncommon and devastating manifestation of tuberculosis. We report a case of disseminated tuberculosis presenting as meningoencephalitis, hypothalamic involvement with extension to the hypophysis, and secondary insipidus diabetes diagnosed at autopsy. PMID- 30517546 TI - Type 1 cardiorenal syndrome in a patient with an acute infection caused by Trypanosoma cruzi in the Brazilian Amazon region - a case report. AB - Cardiorenal syndrome type 1 (CRS 1) occurs when acute heart failure leads to acute kidney injury. There are several etiologies of CRS 1, including Chagas disease. Here, we present the first case report of CRS 1 in a patient with acute Chagas disease. Electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging showed signs of acute myocarditis. Laboratory examination revealed severe loss of kidney function, with a creatinine clearance of 30 mL/min, which fully normalized after treatment. Due to emergence of Chagas disease in the Brazilian Amazon, it is important to report unique clinical features in order to improve patients' outcomes. PMID- 30517547 TI - Vancomycin-induced severe thrombocytopenia in a young infant. AB - Vancomycin is a first-line drug for treating methicillin-resistant Staphylococcus aureus. Thrombocytopenia is a rare adverse reaction to vancomycin treatment, and there are no reports of vancomycin-induced thrombocytopenia (VIT) in infants. We describe the case of a 3-month-old girl who was diagnosed with purulent meningitis. After 13 days of treatment with vancomycin, her platelet count reduced to 8 * 109/L. Vancomycin was discontinued, and intravenous methylprednisolone was administered. The platelet count returned to normal after 4 days. Patients, especially young children, receiving vancomycin for a long clinical course should undergo careful monitoring of laboratory indicators and blood tests. PMID- 30517548 TI - Jarisch-Herxheimer reaction in a patient with syphilis and human immunodeficiency virus infection. PMID- 30517549 TI - Diabetic foot ulcers with myiasis: a potential route for resistance gene dissemination for enterococci? PMID- 30517550 TI - Letter. PMID- 30517551 TI - [The aborted law: Notes on the debate over the voluntary termination of pregnancy]. PMID- 30517552 TI - [Sexual and reproductive health without freedom?: The conflict over abortion in Argentina]. AB - The feminist movement installed a political debate regarding the right to abortion in 2018, proposing a transformation not only in the praxis of democracy, but also in its substance, through the decriminalization and legalization of abortion. In this context, this article seeks to describe and evaluate the democratic conflict produced based on the reasons and justifications underpinning the disputed content, in favor and against abortion. It also seeks to summarize the principal constitutional and conventional rulings that, by regulating abortion, shed light on the normative universe of what ought to be, in which human rights are inscribed. Lastly, the article attempts to explain how political control over body sovereignty was constructed and implemented in a patriarchal system, with sufficient legitimacy and power to last for centuries. Although there are no legal obstacles to the decriminalization and legalization of abortion, why is that the interests of freedom for women are not fully enabled within their array of rights, including the social right to health? What other interests, other than those of women, does this freedom represent? PMID- 30517553 TI - [The production of the fetus as a "subject of rights": qualitative analysis of medical-Catholic discourses in Chile]. AB - This article presents the results of a study aimed at identifying and analyzing the discursive construction of the fetus as a subject of rights on the part of medical-religious institutions in the discussion of the decriminalization of abortion due to three causes in Chile during the 2013-2016 period. To this end, a triangulation was carried out based on an analysis of thematic content and an analysis of certain discursive strategies from the critical discourse analysis perspective using a textual corpus composed of 16 documents. Four analytical themes were identified: factual construction, female pastoral power, biopolitical management of the female body, and intervention technologies. It is concluded that the medical-religious discourse uses a series of rhetorical strategies and mobilizes meanings with respect to the fetus based on the hybridization of rhetorical strategies such as resources of factualization, connotation, metaphor and others that validate metaphysical beliefs about the body and the subjectivity of women and allow for an authoritative and irrefutable voice. Thus, the biopolitical management of women's reproductive capacities constitutes a filter that obstructs the possibility of incorporating discussions and ethical positions linked to citizenship and the social contract. PMID- 30517554 TI - [Configurations of secularism in debates about the legalization of abortion in Argentina: parliamentary and feminist discourses (2015-2018)]. AB - This article explores the configurations of secularism present in the parliamentary debate on the voluntary termination of pregnancy bill in 2018, and in some specific areas of feminist activism in which secularism is discussed and promoted, collected in the period between 2015 and 2018. Based on the official transcriptions of the speeches of deputies and senators during the debates as well as participant observation in national and regional women's and feminist gatherings, we analyze the ideas that emerge in relation to the State, churches, religions, spiritualities and democracy when sexual and reproductive rights are discussed. The results confirm our hypothesis regarding the expansion of the discourse on secularism in both Chambers during 2018, with different definitions and intensities, as well as the amplification of support for existing feminist campaigns for a secular State and, in parallel, new problematizations regarding the confluence of a feminist identity with religious and/or spiritual identity. PMID- 30517555 TI - [Key arenas in the struggle for abortion rights in Argentina]. AB - The huge mobilization seen in 2018 around the right to legal abortion in Argentina is the crowning point of a struggle that has been going on for many years, and that like any emancipatory movement has had different milestones as well as victories and setbacks, but that has never been abandoned. This article considers some of the actions that have marked that history, beginning with the pioneering women of the seventies, and continuing with the Commission for the Right to Abortion [Comision por el Derecho al Aborto] after the restoration of democracy in the 1980s, followed by the experiences of Women Coming Together for the Right to Choose [Mujeres Autoconvocacadas por el Derecho a Decidir], the Assembly for the Right to Abortion [Asamblea por el Derecho al Aborto], and the present Campaign for the Right to Legal, Safe and Free Abortion [Campana por el Derecho al Aborto Legal, Seguro y Gratuito], which succeeded in getting the bill that decriminalizes and legalizes abortion treated in the National Congress. PMID- 30517556 TI - [Young women: between the "green tide" and the decision to have an abortion]. AB - The work analyzes the characteristics, arguments and conditions of possibility present in the gender activisms carried out in recent years by young women in Argentina, with special attention paid to the generational mark they imprint onto the collective demands and struggles for legal, safe and free abortion. The article reconstructs some of the social and personal circumstances at the base of the motivation or the decision of a group of young women to carry out an abortion with misoprostol, with the purpose of exploring concretely the support networks and the information circulating among these young women in relation to the practice of medical abortion, at a time in which access to this right has not yet been legally instituted in the country. We are interested in putting these realities in dialogue with a broader context of female youth prominence in these demands, condensed in the expression "green tide" and in the idea of a "cultural battle" that has already been won socially. PMID- 30517557 TI - [Abortion, sorority and body autonomy: a conversation with Monica Macha, representative in the Argentine Chamber of Deputies]. AB - Just days after the Argentine Chamber of Deputies approved the bill on the Voluntary Termination of Pregnancy, Salud Colectiva asked Dora Barrancos and Patricia Rosemberg to converse with representative Monica Macha regarding the events leading up to the Chamber's approval of the bill. In the conversation other themes emerged in connection to the energy that flooded the streets all over the country throughout the year. The three women highlighted the activism and sorority present inside and outside of the chamber, the central role of youth, "the revolution of the daughters," the discussion of body autonomy, the role of doctors and how the struggle became a cultural change from which there is no return. This conversation narrates a historical moment in the words of some of its actors. PMID- 30517558 TI - [Medical anthropology in Latin America, 1990-2015: A strictly provisional review]. AB - The article presents a provisional examination of the production of Latin American medical anthropology, especially from Mexico, and to a lesser degree Brazil, from 1990 to 2015, in an attempt to highlight the discipline's principal contributions, orientations and objectives, but also to pose critiques and doubts, especially with respect to the omission of the study of serious collective health problems and processes. The article attempts to put into evidence the importance of the discipline not only for anthropology, but also for biomedicine, suggesting the need for complementation beyond the differences and incompatibilities that exist regarding, for example, the use of qualitative techniques, and interventions -or lack of interventions- regarding the customs of the different social actors with respect to health/disease/care-prevention processes. PMID- 30517559 TI - [Machines and artisanal health workers]. AB - This work discusses the dominant models and tensions within the health field regarding the conceptualization of the human body (as a machine), the process of health work (industrial and artisanal models), institutions (hospitals and health centers) and primary agents (the medical corporation and the medical industrial complex). The context of analysis is the United States from the end of the 19th century to the present. Economic-political, ideological-cultural, and scientific technical dimensions are discussed, which permeate the historicity of the field. The purpose is to illustrate how the health field has transformed over time, as well as the role instrumental reason and financial capital has played in this process, to the detriment of relational aspects. PMID- 30517560 TI - [Subjectivity and autonomy: meanings and narratives with respect to discontinuing psychiatric drugs]. AB - The objective of this work was to reconstruct the meanings and narratives surrounding the process of discontinuing psychiatric drugs, taking into account the strategies used to abandon these drugs and the processes of construction of identity. In 2015, in-depth semi-structured interviews were conducted individually with five people from Santiago, Chile who had experiences of psychiatric diagnosis, who received treatment with psychiatric drugs during eight o more years, and who discontinued the use of psychiatric drugs for at least one year. The results show the existence of institutional barriers which limit the right to abandon treatment; therefore, people do so autonomously through intimate and personal processes utilizing self-help and social support strategies. At the same time, discontinuing psychiatric drugs implies the construction of a "former user" identity, concentrating knowledge in the figure of expert by experience in the mental health field. PMID- 30517561 TI - [Pediatric cardiology health brigades: from medical triage to social triage]. AB - This article explores the sociocultural aspects of a program of pediatric cardiology health brigades that provides care to children from low-income populations in peripheral regions of Colombia. We analyzed the brigades as a humanitarian strategy to close the gaps of inequity in access to health care, and as a particular context of the medical encounter, the experience of heart disease and the definition of care trajectories. Based on ethnographic observation of brigades and interviews with families receiving care and with health personnel, carried out in 2016 in five different cities, we looked at the dynamics that shape the medical encounter and questioned the mechanisms (medical and social) through which it is evaluated and decided which families can access care in Bogota. We conclude that the brigades, as initiatives that continue to be anchored in humanitarism instead of contributing to the transformation of the conditions that generate health inequities, reproduce and exacerbate such inequities by selecting which lives receive priority to be saved. PMID- 30517562 TI - [A comprehensive community model to prevent and address adolescent health problems]. AB - This article presents a model for building a comprehensive community response to adolescent health problems. The approach is comprehensive in that it includes prevention and promotion, assistance and protection, and involves different sectors and areas of the State and the community. We describe the conceptual framework and principles of the model, developed based on debates regarding health promotion and collective health as well as the work experiences of the research team in different communities in Argentina over the last 15 years. We then present the steps developed to help facilitate interventions and analyze certain theoretical, political and practical issues underlying the management of such a model, in an attempt to link critical reflection with the development of social technologies. This model takes into account reflections regarding how to carry out health promotion actions that seek to transform particular realities, respecting their singularities but at the same time acknowledging their connections to others. PMID- 30517563 TI - [Overweight, obesity and perceived health in contexts of poverty in Tucuman, Argentina]. AB - In contexts in which poverty compromises children's health and quality of life, the study of perceived health allows for the identification of aspects of quality of life affected by overweight and obesity. From this perspective, the objectives of this study were: 1) to determine the prevalence of overweight and obesity in schoolchildren aged 8-12 years living in contexts of poverty, 2) to describe and compare the perception of health of children according to the presence or absence of overweight and obesity, and 3) to identify possible factors associated with low quality of life related to health. A quantitative and cross-sectional study was conducted. The KIDSCREEN-52 questionnaire was applied and weight and height were assessed in 666 schoolchildren living in the department of Simoca (province of Tucuman), which has high percentages of structural poverty. The high prevalence of overweight (23.0%) and obesity (27.2%) affect the perception of health among children, especially in psychosocial dimensions such as moods and emotions, autonomy, social acceptance, and financial resources. PMID- 30517564 TI - [Association between food availability and mortality due to colorectal cancer in the Americas]. AB - With the aim of describing the association between food availability and the mortality rate due to colorectal cancer in the countries of the Americas in 2010, data provided by the International Agency for Research on Cancer and the Food and Agriculture Federation were analyzed in an ecological study. Great variability was observed except in caloric supply. Food availability was abundant for calories, total fats, animal fat, red meat and alcoholic beverages. Availability was critically low for fruits and vegetables in 80% of the countries. The countries with the highest colorectal cancer mortality rates were Uruguay, Barbados, Argentina and Cuba, while those with the lowest rates were Guatemala, Canada, Mexico and Honduras. The strongest relationships were found between colorectal cancer mortality rate and the availability of animal fat, red meat, alcoholic beverages and calories. No protective effect of availability of fruits and vegetables on the colorectal cancer mortality rate was found. It would be advisable to improve the records of tumor incidence and direct ways of evaluating diet to be analyzed in future studies instead of the data used here. PMID- 30517566 TI - [Considerations for an epidemiology of food and eating: A genealogy of nutritional studies in Ecuador]. AB - This article analyzes two of the most important studies on nutrition that have been carried out in Ecuador in the last fifty years. The objective is to justify the need for an alimentary epidemiology capable of looking at the entire process of social reproduction and the food system as well as the expressions of each in different ways of life, overcoming a purely individual and biologistic perspective. The article proposes that eating be studied as a total social fact within the school of thought of critical epidemiology, recognizing the existence of three different levels of reality - the general, particular and singular - as well as the existence of a margin of relative autonomy of subjects in the process of determination of food consumption and nutritional status. PMID- 30517565 TI - [Comparative study of the nutritional status of children living in four counties of the province of Buenos Aires (Argentina), in the context of nutrition transition]. AB - The aim of this study was to evaluate and compare the nutritional status of child populations living in four counties of the province of Buenos Aires to observe differences related to particular environmental and socioeconomic contexts in the framework of the nutrition transition. During the school years corresponding to the 2008-2012 period, weight and height were measured and body mass index was calculated for 7,873 school children between the ages of 4 and 12 years from the counties of La Plata, Brandsen, Magdalena and Punta Indio. Information about the contexts of residence was obtained using self-administered structured surveys. About 40% of schoolchildren presented malnutrition, with a prevalence of overweight in La Plata, obesity in Punta Indio and undernutrition in Magdalena. The nutritional status of the study populations was associated with the socioenvironmental conditions of residence, indicating that these populations are at different stages of the nutrition transition process. PMID- 30517567 TI - ["Homo Caloricus": The epistemological construction of lipophobic stigma in public health media discourses]. AB - The case of obesity in Mexico constitutes an emblematic example of how, in the messages emitted by public health television campaigns, strong beliefs regarding the issue of body weight prevail. The main objective is to reflect on certain epistemological effects that abound in biomedical media narratives related to obesity. To do so, aspects of the rhetoric employed in two initiatives of the Ministry of Public Health - Muevete y Metete en Cintura [Move Around and Slim Down] in 2008 and the 5 Steps Program in 2011 - are analyzed, as is the discourse surrounding the tax measure introduced by the Mexican tax service in 2017. This study also looks at other similar practices that, although taking place outside of Mexico, stoke the fires of lipophobism, such as the "Cormillot industry" in Argentina. As a result, a strong discursive influx stemming from a reductionist vision of bodily diversity has been identified, supported by the pathologization of fat bodies through moral prejudices and biased generalizations. PMID- 30517568 TI - [Law 30021 on the Promotion of Healthy Eating for children and adolescents]. PMID- 30517569 TI - [Food labeling in Chile: Comments on the letter regarding Law 30021 in Peru]. PMID- 30517570 TI - [Front-of-package labelling of food products in Argentina]. PMID- 30517571 TI - Obstetric violence in the daily routine of care and its characteristics. AB - OBJECTIVE: to analyze the scientific production on obstetric violence by identifying and discussing its main characteristics in the routine care for the pregnant-puerperal cycle. METHOD: integrative literature review of 24 publications indexed in the Cumulative Index to Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online, SciVerse Scopus, Web of Science and the Scientific Electronic Library Online and Virtual Health Library. RESULTS: the publications are intensified from 2015 onwards and present methodological designs of quantitative and qualitative nature. In the discussion, we first address the concept of obstetric violence and its different forms of occurrence in care. Then, interfaces of the phenomenon are presented with reflections related to the conception of gender, the different actors involved, the institutionalization, and the invisibility and trivialization of the event. Finally, strategies to combat the problem are presented through academic training, women's awareness, proposals of social mobilization, and creation of public policies and laws. CONCLUSION: obstetric violence portrays a violation of human rights and a serious public health problem and is revealed in the form of negligent, reckless, omissive, discriminatory and disrespectful acts practiced by health professionals and legitimized by the symbolic relations of power that naturalize and trivialize their occurrence. PMID- 30517572 TI - Safety of a formulation containing chitosan microparticles with chamomile: blind controlled clinical trial. AB - OBJECTIVE: to evaluate the safety of a topical formulation containing chamomile microparticles coated with chitosan in the skin of healthy participants. METHOD: phase I blind, controlled, non-randomized, single-dose clinical trial with control for skin, base formulation, and formulation with microparticles. The variables analyzed were irritation and hydration by the Wilcoxon and Kruskall Wallis tests. RESULTS: the study started with 35 participants with a mean age of 26.3 years. Of these, 30 (85.71%) were female, 29 (82.90%) were white skinned and 32 (91.40%) had no previous pathologies. One participant was removed from the study reporting erythema at the site of application, and four other participants for not attending the last evaluation. In the 30 participants who completed the study, the tested formulation did not cause erythema, peeling, burning, pruritus or pain; there was an improvement in cutaneous hydration in the site of application of the formulation with microparticles. In the evaluation of the barrier function, there was an increase in transepidermal water loss in all sites. CONCLUSION: the formulation with chamomile microparticles is safe for topical use, not causing irritation and improving skin hydration over four weeks of use. Its effects on barrier function need further investigation. No. RBR 3h78kz in the Brazilian Registry of Clinical Trials (ReBEC). PMID- 30517573 TI - Gender and generation perspectives in the narratives of sexually abused women in childhood. AB - OBJECTIVE: to analyze the narratives of sexually abused women in childhood, identifying issues related to gender and generation. METHOD: descriptive research with a qualitative approach, based on 214 reports selected from the Brazilian campaign #primeiroassedio (first harassment), which took place on Twitter social network, collected from a structured instrument. Thematic content analysis was used. RESULTS: girls were the main victims of sexual abuse. The perpetrators were mostly male and people they knew. Five categories emerged from the narratives: Sexual abuse in the aggressors' discourse; The child as the object of sexual pleasure; Violated childhood; Victims' guilty feelings; and Repercussions of sexual abuse experienced in childhood. CONCLUSION: sexual abuse often occurs in the family context and, even if sometimes veiled, the submission of girls' power in gender relations and of children in generation relationships is evident. Analyzing sexual abuse under the categories of gender and generation contributes to an in-depth understanding of the phenomenon, directing practices more effectively to their coping. PMID- 30517574 TI - Influence of support surfaces on the distribution of body interface pressure in surgical positioning. AB - OBJECTIVE: to evaluate the interface pressure (IP) of support surfaces (SSs) on bony prominences. METHOD: a quasi-experimental study with repeated measures on each SS. Twenty healthy adult volunteers participated in the study. The participants were placed in the supine position on a standard operating table for evaluation of IP on the bony prominences of the occipital, subscapular, sacral, and calcaneal regions using sensors. Seven evaluations were performed for each bony prominence: one on a standard operating table, and the others on tables containing SSs made of viscoelastic polymer, soft foam, or sealed foam. Descriptive statistics and analysis of variance were used to analyze the data. RESULTS: the mean IP was higher on the viscoelastic polymer-based SS compared to the other SSs (p<0.001). The mean IP was relatively lower on the density-33 sealed foam and density-18 soft foam. In addition, this variable was comparatively higher in the sacral region (42.90 mmHg) and the calcaneal region (15.35 mmHg). CONCLUSION: IP was relatively lower on foam-based SSs, especially on density-18 soft foam and density-33 sealed foam. Nonetheless, IP was not reduced on the viscoelastic polymer SS compared to the control SS. PMID- 30517575 TI - Randomized clinical study on radial artery compression time after elective coronary angiography. AB - OBJECTIVE: to compare two compression times of the radial artery after coronary angiography with customized compressive dressing regarding the occurrence of hemostasis and vascular complications. METHOD: a randomized clinical study was carried out in patients undergoing elective transradial coronary angiography in two study groups: (G30), whose compressive dressing was maintained for 30 minutes, and (G60), whose compressive dressing was maintained for 60 minutes, both until the first evaluation of hemostasis. Variables related to patients, procedure, occurrence of hemostasis, and vascular complications were analyzed. Patency of the radial artery was assessed with Doppler vascular ultrasonography, immediately after removing the compressive dressing and 30 days after the procedure. RESULTS: the sample consisted of 152 patients in G30 and 151 in G60. Hemostasis was evidenced in the first evaluation in 76.3% of G30 patients and 84.2% of G60 patients (p = 0.063). There were 91 immediate complications, being 53 hematomas and 38 occlusions of the radial artery. We identified 18 late occlusions, 7 (5.5%) in G30 and 11 (8.2%) in G60. CONCLUSION: the different compression times of the radial artery after coronary angiography did not significantly influence the occurrence of hemostasis and vascular complications. Brazilian Registry of Clinical Trials (Rebec): RBR-7VJYMJ. PMID- 30517577 TI - Validation of vulnerability markers of dysfunctions in the socioemotional development of infants. AB - OBJECTIVES: to validate the vulnerability markers of dysfunctions in the socioemotional development of infants. METHODS: study with a sequential exploratory mixed-method design. The vulnerability markers elaborated in the qualitative phase were analyzed by experts in the quantitative phase using the Delphi technique with a minimum consensus of 70%. Seventeen judges answered the questionnaire in the first round of analysis and 11 answered in the second round. RESULTS: in the first round, two markers did not reach minimum consensus: the presence of instability in family relationships (66%) and delinquency and/or drug abuse by parents/caregivers (65%). In the second round, all markers were validated, with more than 90% agreement in most of the attributes, and reached the minimum consensus of 73%. CONCLUSION: the eight vulnerability markers reached the minimum consensus for validation, and a relevant instrument for infant care can be developed after assessing the reliability and clinically validating these markers. PMID- 30517576 TI - Prevalence of serological markers for hepatitis and potential associated factors in patients with diabetes mellitus. AB - OBJECTIVE: to estimate the prevalence of serological markers for hepatitis B and C in patients with diabetes mellitus and analyze potential associated factors. METHOD: a cross-sectional study with 255 patients with diabetes mellitus. Demographic, clinical, and risk behavior factors for hepatitis B and C were selected. The markers HBsAg, Anti-HBc IgG, Anti-HBc IgM, Anti-HBs, and Anti-HCV were investigated. A questionnaire and venous blood collection and inferential statistical analysis were used. RESULTS: 16.8% of the patients had a total reactive Anti-HBc marker, 8.2% an isolated Anti-HBs, and 75% were non-reactive for all hepatitis B markers. No case of reactive HBsAg was found and 3.3% of the patients had a reactive anti-HCV marker. The prevalence of prior hepatitis B virus infection was directly associated with the time of diabetes mellitus and the prevalence of hepatitis C virus infection was not associated with the investigated variables. The prevalence of hepatitis B and C infection in patients with diabetes mellitus was higher when compared to the national, with values of 16.8% and 3.3%, respectively. CONCLUSION: the results suggest that patients with diabetes are a population of higher vulnerability to hepatitis B and C, leading to the adoption of preventive measures of their occurrence. PMID- 30517578 TI - Patient, cured, victim or survivor of urological cancer? A qualitative study. AB - PURPOSE: to describe the meanings that patients attribute to the term cancer survivor and to analyze the identities assumed by them according to their experience with the disease. METHODS: qualitative study with a narrative method, theoretical framework of the medical anthropology and identity concept. The study included 14 participants, men and women, diagnosed with urologic cancer. The semi structured interviews were performed at the individual's home, after confirming participation. RESULTS: eight participants assumed to be survivors, but five also assumed at least one other identity, in addition to cancer survivor. In contrast, among the six who defined themselves as cured, only one indicated another identity. Four considered themselves as victims and only two as cancer patients. However, the latter - cancer patient and victim - assumed at least one other associated identity. CONCLUSIONS: allowing patients to reflect on themselves and their experience with the disease, as well as attributing themselves a new identity, will be directly related to the wellbeing and momentum the survivor is going through. Therefore, it can direct care in the cancer survivorship phase according to each survivor's individual context. PMID- 30517579 TI - Clinical trial for the control of water intake of patients undergoing hemodialysis treatment. AB - OBJECTIVE: to analyze the impact of an educational and motivational intervention for patients with a chronic kidney disease, undergoing hemodialysis treatment, on the control of fluid intake during interdialytic periods. METHOD: a quasi experimental, non-randomized clinical trial with patients from a Nephrological Unit of the State of Sao Paulo. Participants were included in two groups: Control Group with 106 patients and Intervention Group with 86 patients, totaling 192 participants. The used intervention was an educational and motivational video to control liquid intake, based on the Bandura's Theory. The measure of control of water intake was the percentage of lost weight, also considered the variable outcome of the research. For the data analysis, descriptive analyses and regression analysis of the Inflated Beta Model were used. RESULTS: patients who participated in the intervention had a decrease in the pattern of weight gain in interdialytic periods, with a 3.54 times more chance of reaching the goal of 100% of weight loss when compared to participants from the control group. CONCLUSION: the educational and motivational intervention was effective in reducing the percentage of weight loss in patients undergoing hemodialysis. Brazilian Clinical Trials Registry (ReBEC) under the opinion RBR-4XYTP6. PMID- 30517580 TI - Diagnostic evaluation of risk for bleeding in cardiac surgery with extracorporeal circulation. AB - OBJECTIVE: to identify the risk factors associated with cases of excessive bleeding in patients submitted to cardiac surgery with extracorporeal circulation. METHOD: case-control study on the factors of risk for bleeding based on the analysis of data from the medical charts of 216 patients submitted to cardiac surgery with elective extracorporeal circulation during a three-year period. RESULTS: variables that are commonly associated with excessive bleeding in studies in the field were analyzed, and the following were considered as risk factors for the nursing diagnosis "risk for bleeding" (00206) in cardiac surgery with extracorporeal circulation: Body mass index lower than 26.35kg/m2 (Odds ratio = 3.64); Extracorporeal circulation longer than 90 minutes (Odds ratio = 3.57); Hypothermia lower than 32 degrees C (Odds ratio = 2.86); Metabolic acidosis (Odds ratio = 3.50) and Activated partial thromboplastin time longer than 40 seconds (Odds ratio= 2.55). CONCLUSION: such variables may be clinical indicators of an operational nature for a better characterization of the risk factor "treatment regimen" and a refinement of knowledge related to coagulopathy induced by extracorporeal circulation, which is currently presumably incorporated into the "treatment regimen" category of the nursing diagnostic classification by NANDA International, Inc. PMID- 30517581 TI - Scale of adverse events associated to nursing practices: a psychometric study in Portuguese hospital context. AB - OBJECTIVE: to contribute to the validation study of the Scale of Adverse Events associated with Nursing Practices in the hospital context. METHOD: cross sectional study, in public hospital units, in the central and northern regions of Portugal. The exploratory factor analysis of the Scale of Adverse Events associated to Nursing Practices was conducted with a sample of 165 nurses and the confirmatory factorial analysis was made with a sample of 685 nurses. Reliability, internal consistency and construct validity were estimated. The invariance of the model was evaluated in two subsamples to confirm the stability of the factorial solution. RESULTS: the global sample consisted of 850 nurses aged between 22 and 59, mostly licensed professionals. The model had a good overall fit in the subscales (Nursing Practices: chi2/df = 2.88, CFI = 0.90, GFI = 0.86, RMSEA = 0.05, MECVI = 3.30; Adverse Events: chi2/df = 4.62, CFI = 0.93, GFI = 0.95, RMSEA = 0.07, MECVI = 0.39). There was a stable factor structure, indicating strong invariance in the subscale Nursing Practices and structural invariance in the subscale Adverse Events. CONCLUSION: the refined model of the Scale of Adverse Events associated with Nursing Practices revealed good fit and stability of the factorial solution. The instrument was adjusted to evaluate the perception of nurses about adverse events associated with health care, precisely nursing care, in the hospital setting. PMID- 30517582 TI - Tuberculosis control from the perspective of health professionals working in street clinics. AB - PURPOSE: to present the opinion of professionals about street dwellers undergoing treatment of tuberculosis and identify strategies of control of tuberculosis in this population. METHOD: an exploratory and descriptive study involving 17 health professionals working in street clinics. A semi-structured study composed of closed questions and a guiding question. The statements were analyzed using the discourse analysis technique, resulting in the identification of two analytical categories: 1. Meanings attributed to street dwellers with tuberculosis, and 2. Control of tuberculosis in homeless people. RESULTS: the analysis identified situations that limited adherence to tuberculosis treatment, including the reasons for staying in the streets, living conditions, and risk factors (dependence on alcohol and other drugs, short-sightedness, constant relocations, and lack of perspectives). Street dwellers were knowledgeable about the disease. Furthermore, there were difficulties in solving several problems of people living in the streets, including living conditions and lifestyle, social stigma, relocations, drug abuse, and lack of life project. CONCLUSION: coping with the complexity of situations related to living in the streets limits to the work of health professionals because these situations go beyond health care and require intersectoral actions. PMID- 30517583 TI - Adaptation and validation of the Instrumental Expressive Social Support Scale in Portuguese older individuals. AB - OBJECTIVE: to adapt and validate the Instrumental Expressive Social Support Scale (IESS) in a sample of older people. METHOD: methodological study. The sample of 964 community-dwelling older people was randomly divided into two groups. The first group was used as a calibration sample to study the number of factors underlying social support through Principal Axis Factoring, and the second group as a validation sample to test the "best fit" model through Confirmatory Factor Analysis. RESULTS: exploratory Factor Analysis suggested a three-factor solution, which was confirmed by Confirmatory Factor Analysis. The factors were similar to those in the pre-existing dimensions of the original instrument and were named as Sense of control (alpha = 0.900), Financial support (alpha = 0.802), Familiar and socio-affective support (alpha = 0.778). Confirmatory Factor Analysis showed acceptable fit. The model's goodness-of-fit indexes were satisfactory (chi2/df = 5.418; CFI = 0.903; NFI = 0.884; RMSEA = 0.098). The convergent validity was supported by associations between social support and medication adherence and positive affect. The discriminant validity was evidenced by association with negative affect. The reliability analysis showed high values of internal consistency. CONCLUSION: the instrument proved to be a valid measure for the assessment of social support in older people. PMID- 30517584 TI - Domains of common mental disorders in women reporting intimate partner violence. AB - OBJECTIVE: to verify associations between the types of intimate partner violence and the domains of common mental disorders in women. METHOD: cross-sectional study with 369 women. The information was obtained through the instruments Self Reporting Questionnaire and Conflict Tactic Scales. To analyze the data, Pearson's Chi-Square test, Fisher's exact test and Odds Ratio were used. RESULTS: women who reported physical abuse with and without sequela were respectively 2.58 and 3.7 times more likely to have symptoms of anxious depressed mood. The chances of experiencing symptoms of decreased vital energy increased by 2.27 times with psychological aggression, 3.06 times with physical abuse without sequelae and 3.13 times with physical abuse with sequelae. Somatic symptoms did not show statistical association with the types of violence. The propensity to develop symptoms of depressive thoughts increased 3.11 times with psychological aggression, 6.13 times with physical aggression without sequelae, 2.47 times with sexual coercion and 7.3 times with physical aggression with sequelae. CONCLUSION: the types of intimate partner violence are strongly associated with the domains of common mental disorders in women. This finding may contribute to more accurate interventions by health professionals to women victims of violence. PMID- 30517585 TI - Frailty syndrome among elderly and associated factors: comparison of two cities. AB - OBJECTIVE: to compare the frailty syndrome among elderly people living at home in two Brazilian cities and to identify factors related to sociodemographic and health-related variables. METHOD: population-based cross-sectional study with 480 elderly individuals from the cities of Ribeirao Preto/SP and Joao Pessoa/PB, with application of the Mini Mental State Examination instruments and the Edmonton Frailty, Geriatric Depression and Lawton and Brody scales. Descriptive analysis, Chi-square test, Fisher's test, Student's t-test, Spermann's correlation and Logistic regression were used. In all analyzes, the level of significance was set at p<=0.05. RESULTS: in relation to frailty, it was verified that living in Ribeirao Preto, presenting advanced age, low schooling, multiple chronic diseases, reduced cognitive status and functional capacity, besides depressive symptoms, are factors associated with the frailty syndrome, in both cities. CONCLUSION: we identified that the frailty syndrome in the elderly of both cities has a relation with the place where the elderly person lives, age, schooling, number of diseases, reduction of cognitive status, functional capacity and presence of symptoms depressive. PMID- 30517586 TI - Guided imagery relaxation therapy on preoperative anxiety: a randomized clinical trial. AB - OBJECTIVE: to evaluate the effect of relaxation therapy with guided imagery on state anxiety and cortisol in the immediate preoperative period in patients submitted to bariatric surgery by videolaparoscopy. METHOD: a randomized, triple blind clinical trial in a large teaching hospital in the interior of Minas Gerais. Twenty-four patients who would undergo video-laparoscopic bariatric surgery were randomly allocated in two groups, namely 12 in the control group and 12 in the experimental group. State anxiety was assessed by the State-Trait Anxiety Inventory, and blood cortisol levels were measured before and after the intervention or standard care. Descriptive analyzes were used for the quantitative variables and Student's t-test for independent samples, in the analysis of the differences between the state anxiety scores and cortisol levels. RESULTS: the experimental group presented a statistically significant reduction of the state anxiety scores (p = 0.005) as well as of cortisol levels (p <0.001) after the intervention. CONCLUSION: guided imagery relaxation therapy is an effective nursing intervention for the reduction of state anxiety and blood cortisol levels in the preoperative period in patients undergoing video laparoscopic bariatric surgery. Brazilian Registry of Clinical Trials: RBR 5qywrf. PMID- 30517587 TI - Massive transfusion triggers in severe trauma: Scoping review. AB - OBJECTIVE: to identify the predictive variables or the massive transfusion triggers in severely traumatized patients through the existing scales. METHOD: a review of the literature was carried out using the Scoping Review method across the electronic databases CINAHL, MEDLINE, LILACS, the Cochrane and IBECS libraries, and the Google Scholar search tool. RESULTS: in total, 578 articles were identified in the search and the 36 articles published in the last ten years were included, of which 29 were original articles and 7 review articles. From the analysis, scales for massive transfusion and their predictive triggers were examined. CONCLUSION: the absence of universal criteria regarding the massive transfusion triggers in traumatized patients has led to the development of different scales, and the studies on their validation are considered relevant for the studies about when to initiate this strategy. PMID- 30517588 TI - Conceptual and operational definitions of the defining characteristics of the nursing diagnosis Disturbed Sleep Pattern. AB - OBJECTIVE: to present the knowledge produced about sleep and Acute Coronary Syndrome in order to assist in the elaboration of the operational and conceptual definitions of the defining characteristics of the nursing diagnosis Disturbed Sleep Pattern (00198). METHOD: integrative review in the following databases: COCHRANE; SCOPUS; MEDLINE (Medical Literature Analysis and Retrieval System Online) via Pubmed; LILACS (Latin American and Caribbean Health Science Literature Database); CINAHL (Cumulative Index to Nursing and Allied Health Literature) and EMBASE (The Excerpta Medical Database). At the end of the search, 2827 studies were found, 43 were selected for reading, and 10 were included in the review. The gray literature was also included. RESULTS: important findings related to clinical evidence and contributing factors of sleep were found in the review. However, in order to build definitions of the defining characteristics, it was necessary to use gray literature, such as a Portuguese dictionary and two textbooks about sleep. CONCLUSION: the definitions will help nurses in their practice in the collection of information, in the determination of the nursing diagnosis studied here, and in directing care measures with respect to quantity and quality of sleep of Acute Coronary Syndrome inpatients. They will also assist in the next steps of the validation of this diagnosis to the referred population. PMID- 30517590 TI - Comments on "Preliminary 3-Year Evaluation of Experience With SilkSurface and VelvetSurface Motiva Silicone Breast Implants: A Single-Center Experience With 5813 Consecutive Breast Augmentation Cases". PMID- 30517589 TI - Association of preoperative anxiety and depression symptoms with postoperative complications of cardiac surgeries. AB - OBJECTIVE: to investigate the associations of preoperative anxiety and depression symptoms with postoperative complications and with sociodemographic and clinical characteristics of patients submitted to the first coronary artery bypass graft. METHOD: observational, analytical and longitudinal study. A consecutive non probabilistic sample consisted of patients submitted to coronary artery bypass graft. To evaluate the symptoms, the Hospital Anxiety and Depression Scale was used. tracheal intubation for more than 48 hours, hemodynamic instability, sensorineural deficit, agitation, hyperglycemia, infection, nausea, vomiting, pain and death were classified as complications. The Mann-Whitney and Spearman Correlation tests were used, with a significance level of 0.05. RESULTS: a total of 75 patients participated. The group that presented hemodynamic instability in the postoperative period had a greater median for the anxiety symptoms (p = 0.012), as well as the women (p = 0.028). The median of the depression symptoms was higher in the group presenting nausea (p = 0.002), agitation (p <0.001), tracheal intubation for more than 48 hours (p = 0.018) and sensorineural deficit (p = 0.016). CONCLUSION: there was association of the symptoms of preoperative anxiety with hemodynamic instability in the postoperative period and with the female gender, as well as association of depression symptoms with the following complications: nausea, agitation, time of intubation in the postoperative period and sensorineural deficit. PMID- 30517591 TI - Use of Bone-Cartilaginous Unit in Revision Rhinoplasty. AB - Background: In revision rhinoplasty, insufficient septal cartilage is a common finding. In these cases, harvesting of costal cartilage or conchal cartilage is needed which is time consuming and has morbidity. Use of the septal bone/cartilage composite graft or bony-cartilaginous unit as a graft in rhinoplasty is a new technique. Objectives: The aim of this research was to evaluate subjective and objective effects of using this graft in revision rhinoplasty. Methods: In this clinical trial study, we examined 40 patients lacking sufficient septal cartilage for grafting who referred to a tertiary center and a private setting from January 2016 to March 2017 for revision septorhinoplasty. The patients had complaints of nasal deformity and nasal obstruction. Surgical outcome was assessed using anthropometric measurements and the width of the middle nasal third of the patients' photographs and two patient questionnaires: Nasal Obstruction and Septoplasty Effectiveness (NOSE) and Rhinoplasty Outcome Evaluation (ROE). Results: Nasolabial angles and the middle nasal third improved significantly after surgery (p<0.005). On the NOSE questionnaire, 85% of patients had no or mild nasal obstruction and on the ROE questionnaire 62.5% were completely or very satisfied about nose appearance. Conclusion: The bony-cartilaginous unit is an effective graft in revision rhinoplasty. This graft can be used in place of the rib graft. Harvesting of this graft has no morbidity in skilled hands and is not time consuming. PMID- 30517592 TI - Impact of a Prescriber-driven Antibiotic Time-out on Antibiotic Use in Hospitalized Patients. AB - A multicenter quasi-experimental study of a provider-driven antibiotic "time-out" in 3470 antibiotic courses showed no difference in antibiotic use before and after implementation, but did show a decrease in inappropriate therapy (45% vs 31%, P < .05). Single time-outs without input from antibiotic stewardship teams are insufficient to optimize prescribing. PMID- 30517593 TI - Non-Apis Bee Exposure Workshop: Industry Participants' View. PMID- 30517594 TI - Drug Targetor: a web interface to investigate the human druggome for over 500 phenotypes. AB - Summary: Results from hundreds of genome-wide association studies (GWAS) are now freely available and offer a catalogue of the association between phenotypes across medicine with variants in the genome. With the aim of using this data to better understand therapeutic mechanisms, we have developed Drug Targetor, a web interface that allows the generation and exploration of drug-target networks of hundreds of phenotypes using GWAS data. Drug Targetor networks consist of drug and target nodes ordered by genetic association and connected by drug-target or drug-gene relationship. We show that Drug Targetor can help prioritize drugs, targets and drug-target interactions for a specific phenotype based on genetic evidence. Availability and implementation: Drug Targetor v1.21 is a web application freely available online at drugtargetor.com and under MIT license. The source code can be found at https://github.com/hagax8/drugtargetor. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30517595 TI - Medication Management Capacity and Its Neurocognitive Correlates in Huntington's Disease. AB - Objective: Although medication management is a necessary daily activity for individuals with Huntington's disease (HD), medication management abilities and their relation to cognitive functioning have not been evaluated. Method: Twenty individuals with HD and 20 healthy adults (HA) completed the Medication Management Abilities Assessment (MMAA). Individuals with HD also completed a self report medication management measure and neuropsychological tests assessing executive function, retrospective memory, and prospective memory. Results: Individuals with HD performed significantly poorer and made more undertaking errors on the MMAA as compared to HA. No group differences were found in overtaking errors. In the HD group, significant associations were found between undertaking errors and perceived medication management ability as well as between MMAA task performance and measures assessing prospective memory and executive functions. Conclusions: Medication management capacity was negatively affected in individuals with HD and may be associated with difficulty remembering to take medications in the future. PMID- 30517596 TI - Association of Periodontal Disease and Edentulism With Hypertension Risk in Postmenopausal Women. AB - BACKGROUND: Multiple cross-sectional epidemiologic studies have suggested an association between periodontal disease and tooth loss and hypertension, but the temporality of these associations remains unclear. The objective of our study was to evaluate the association of baseline self-reported periodontal disease and edentulism with incident hypertension. METHODS: Study participants were 36,692 postmenopausal women in the Women's Health Initiative-Observational Study who were followed annually from initial periodontal assessment (1998-2003) through 2015 (mean follow-up 8.3 years) for newly diagnosed treated hypertension. Cox proportional hazards regression with adjustment for potential confounders was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Edentulism was significantly associated with incident hypertension in crude (HR (95% CI) = 1.38 (1.28-1.49)) and adjusted (HR (95% CI) = 1.21 (1.11 1.30)) models. This association was stronger among those <60 years compared to >=60 years (P interaction 0.04) and among those with <120 mm Hg systolic blood pressure, compared to those with >=120 mm Hg (P interaction 0.004). No association was found between periodontal disease and hypertension. CONCLUSIONS: These findings suggest that edentulous postmenopausal women may represent a group with higher risk of developing future hypertension. As such improved dental hygiene among those at risk for tooth loss as well as preventive measures among the edentulous such as closer blood pressure monitoring, dietary modification, physical activity, and weight loss may be warranted to reduce disease burden of hypertension. Further studies are needed to clarify these results and further elucidate a potential role of periodontal conditions on hypertension risk. PMID- 30517597 TI - Expression profiles and characteristics of human lncRNA in normal and asthenozoospermia sperm. AB - Increasing studies have shown that specific mRNAs and miRNAs expressed in mature sperm may be related to sperm motility. However, the expression profiles and roles of lncRNAs in sperm remain unknown. In the present study, numerous lncRNAs were identified in human sperm, and some lncRNAs were expressed exclusively in sperm and testis. Compared with normal sperm, the lncRNA expression profiles in asthenozoospermia (AZS) sperm showed significant differences. Gene ontology and pathway analyses showed that function of differentially expressed lncRNA targets and mRNAs between AZS and normal sperm were closely-linked with many processes involved in spermatogenesis and sperm function. Furthermore, among the up regulated lncRNAs in AZS sperm, lnc32058, lnc09522 and lnc98487, which exhibited specific/enriched sperm and testicular expression, increased simultaneously in the same AZS sperm samples, and their expression levels were correlated with sperm progressive motility. This is the first systematic study of lncRNA expression profiles in human mature sperm indicating an association between lncRNA expression and sperm motility. The study provides a preliminary database for identifying lncRNAs crucial for human spermatogenesis and sperm function, and new insights into our understanding of the regulation of sperm motility and causes of male infertility. PMID- 30517598 TI - Detection of Mild Cognitive Impairment Among Community-Dwelling African Americans Using the Montreal Cognitive Assessment. AB - Objective: To establish a cut score for the Montreal Cognitive Assessment (MoCA) that distinguishes mild cognitive impairment (MCI) from normal cognition (NC) in a community-based African American (AA) sample. Methods: A total of 135 AA participants, from a larger aging study, diagnosed MCI (n = 90) or NC (n = 45) via consensus diagnosis using clinical history, Clinical Dementia Rating score, and comprehensive neuropsychological testing. Logistic regression models utilized sex, education, age, and MoCA score to predict MCI versus NC. Receiver operating characteristic (ROC) curve analysis determined a cut score to distinguish MCI from NC based on optimal sensitivity, specificity, diagnostic accuracy, and greatest perpendicular distance above the identity line. ROC results were compared with previously published MoCA cut scores. Results: The MCI group was slightly older (MMCI = 64.76[5.87], MNC = 62.33[6.76]; p = .033) and less educated (MMCI = 13.07[2.37], MNC = 14.36[2.51]; p = .004) and had lower MoCA scores (MMCI=21.26[3.85], MNC = 25.47[2.13]; p < .001) than the NC group. Demographics were non-significant in regression models. The area under the curve (AUC) was significant (MoCA = .83, p < .01) and an optimal cut score of <24 maximized sensitivity (72%), specificity (84%), and provided 76% diagnostic accuracy. In comparison, the traditional cut score of <26 had higher sensitivity (84%), similar accuracy (76%), but much lower specificity (58%). Conclusions: This study provides a MoCA cut score to help differentiate persons with MCI from NC in a community-dwelling AA sample. A cut score of <24 reduces the likelihood of misclassifying normal AA individuals as impaired than the traditional cut score. This study underscores the importance of culturally appropriate norms to optimize the utility of commonly used cognitive screening measures. PMID- 30517599 TI - The Association between the Montreal Cognitive Assessment and Functional Activity Questionnaire in the Systolic Blood Pressure Intervention Trial (SPRINT). AB - Objective: To examine the association of global cognitive function assessed via the Montreal Cognitive Assessment (MoCA) and deficiencies in instrumental activities of daily living (IADL) on the Functional Activity Questionnaire (FAQ) in hypertensive older adults in the Systolic Blood Pressure Intervention Trial (SPRINT). Methods: In cross-sectional analysis, 9,296 SPRINT participants completed the MoCA at baseline. The FAQ was obtained from 2,705 informants for SPRINT participants scoring <21 or <22 on the MoCA, depending on education. FAQ severity ranged from no dysfunction (Score = 0) to moderate/severe dysfunction (Score = 5+). Results: Participants who triggered FAQ administration were older, less educated, and more likely to be Black or Hispanic (p < 0.001). Sixty-one percent (n = 1,661) of participants' informants reported no functional difficulties in IADLs. An informant report, however, of any difficulty on the FAQ was associated with lower MoCA scores after controlling for age, sex, race/ethnicity, and education (p < 0.05). Partial proportional odds regression indicates that participants scoring lower on the MoCA (in the 10th to <25th, fifth to <10th, and 50% except for the Tanaka formula (43.7%). Conclusions: In our study, Tanaka could offer a plausible alternative of mean populational 24-h sodium estimation for young adolescents. However, the results did not support the use of these equations in pediatrics at individual levels. PMID- 30517606 TI - Reply to Bouiller, et al., and to Lacout, et al. PMID- 30517607 TI - Comparing pulmonary hypertension severity between rat strains suggests right ventricle NK cells are protective. PMID- 30517608 TI - Interspecific differences in how sink-source imbalance causes photosynthetic downregulation among three legume species. AB - Background and Aims: Sink-source imbalance could cause an accumulation of total non-structural carbohydrates (TNC; soluble sugar and starch) in source leaves. We aimed to clarify interspecific differences in how sink-source imbalance and TNC causes the downregulation of photosynthesis among three legume plants. The TNC in source leaves was altered by short-term manipulative treatments, and its effects on photosynthetic characteristics were evaluated. Methods: Soybean, French bean and azuki bean were grown under high nitrogen availability. After primary leaves were fully expanded, they were subjected to additional treatments: defoliation except for two primary leaves; transfer to low nitrogen conditions; transfer to low nitrogen conditions and defoliation; or irradiation by light-emitting diodes. Physiological and anatomical traits such as TNC content, maximum photosynthetic rate, cell wall content and delta13C values of primary leaves and whole-plant growth were examined. Key Results: Among the three legume plants, the downregulation of maximum photosynthesis and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) content was co-ordinated with an increase in TNC only in French bean. Rubisco did not decrease with an increase in TNC in soybean and azuki bean. The defoliation treatment caused an increase in cell wall content especially in soybean, and maximum photosynthesis decreased despite resulting in a higher Rubisco content. This indicates that a decrease in mesophyll conductance could cause photosynthetic downregulation, which was confirmed by an increase in delta13C. Conclusion: The present results suggest that a downregulation of photosynthesis in response to increased levels of TNC in source leaves can result not only from decreases in Rubisco content, but also from anatomical factors, such as an increase in cell wall thickness leading to reduced chloroplast CO2 concentrations. PMID- 30517609 TI - Proceedings from the 2018 Association for Chemoreception Annual Meeting Symposium: Bariatric Surgery and Its Effects on Taste and Food Selection. AB - This article provides a summary of the topics discussed at the symposium titled Bariatric Surgery and Its Effects on Taste and Food Selection which was held at the Fortieth Annual Meeting of the Association for Chemoreception Sciences. Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) is currently one of the most effective treatments available for weight loss and Type-2 diabetes. For this reason, it is of great interest to clinicians as well as to basic scientists studying the controls of feeding and energy balance. Despite the commonly held view by clinicians that RYGB patients change their food preferences away from fats and sugars in favor of less energy dense alternatives such as vegetables, the empirical support for this claim is equivocal. It is currently thought that the taste and palatability of fats and sugars is affected by the surgery. Some key preclinical and clinical findings addressing these issues were evaluated in this symposium. PMID- 30517611 TI - Erratum: Repeated exposure and conditioning strategies for increasing vegetable liking and intake: systematic review and meta-analyses of the published literature. PMID- 30517610 TI - Geriatric health charts for individual assessment and prediction of care needs: a population-based prospective study. AB - Background: Geriatric health charts that are similar to pediatric growth charts could facilitate monitoring health changes and predicting care needs in older adults. We aimed to validate an existing composite score (Health Assessment Tool [HAT]) and provide provisional age-specific reference curves for the general older population. Methods: Data came from the SNAC-K population study (n=3363 participants 60+ years examined clinically at baseline and 3 years later). HAT was validated by exploring its relationship with health indicators (logistic regression) and comparing its ability to predict care consumption with that of two of its components, morbidity and disability (ROC areas). A flowchart was developed to obtain individual-level HAT scores (nominal response method). Sex specific health charts were derived by graphing seven percentile curves of age related HAT change (logistic quantile regression). Results: HAT scores over the age- and sex-specific median were related to good performance in chair-stand tests (OR=2.62, 95% CI: 2.07-3.31), balance and grip tests (interaction balance grip test, OR=1.15, 95% CI: 1.05-1.25), and good self-rated health (OR=2.19, 95% CI: 1.77-2.71). ROC areas (HAT vs. number of chronic disorders) were: formal care, 0.76 vs. 0.58 (p-value<0.001); informal care, 0.74 vs. 0.59 (p value<0.001); hospital admission, 0.70 vs. 0.66 (p-value<0.001); primary care, 0.71 vs. 0.69 (p-value>0.05); and specialty visits, 0.62 vs. 0.65 (p value<0.001). HAT consistently predicted medical and social care service use better than disability. Conclusions: HAT is a valid tool that predicts care consumption well and could be useful in developing geriatric health charts to better monitor health changes in older populations. PMID- 30517612 TI - Performance of Stool Testing Recommendations for Acute Gastroenteritis when Used to Identify Children with Nine Potential Bacterial Enteropathogens. AB - Background: The ability to identify bacterial pathogens that necessitate specific clinical management or public health action in children with acute gastroenteritis is crucial to patient care and public health. However, existing stool testing guidelines offer inconsistent recommendations, and their performance characteristics are unknown. We evaluated six leading gastroenteritis guidelines (e.g. those of the Centers for Disease Control and Prevention and Infectious Disease Society of America) that recommend when to test children's stool for bacterial enteropathogens. Methods: Two emergency departments in Alberta, Canada, enrolled 2,447 children <18 years old who presented with >=3 episodes of diarrhea and/or vomiting in a 24-hour period. All participants were tested for nine bacterial enteropathogens: Aeromonas, Campylobacter, Escherichia coli O157, other Shiga toxin-producing E. coli, enterotoxigenic E. coli, Salmonella, Shigella, Vibrio, and Yersinia. Patient data gathered at the index visit were used to determine if guidelines would recommend testing. Sensitivity and specificity to recommend testing for children with bacterial enteropathogens were calculated for each guideline. Results: Outcome data were available for 2,391 (97.7%) participants. Six percent (144/2391) of participants tested positive for a bacterial enteropathogen. Guideline sensitivity ranged from 25.8% [95% confidence interval (CI) 18.7%, 33.0%] to 66.9% (95% CI 59.3%, 74.6%) and varied for individual pathogens. Guideline specificity for all bacterial enteropathogens ranged from 63.6% (95% CI 61.6%, 65.6%) to 96.5% (95% CI 95.7%, 97.2%). Conclusions: No guideline provided optimally balanced performance. The most sensitive guidelines missed one-third of cases and would drastically increase testing volumes. The most specific guidelines missed almost 75% of cases. PMID- 30517613 TI - Effect of Balance Training After Hip Fracture Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Studies. AB - Background: Although balance impairment after hip fracture surgery (HFS) can constitute a long-term problem of limiting mobility and increasing the risk of falls in older adults, little is known about the effect of balance training (BT) on physical functioning after HFS. Thus, we performed a meta-analysis to evaluate whether BT improved the overall physical functioning of patients after HFS. Methods: We searched the PubMed-Medline, Embase, and Cochrane Library databases in January 2018 and included all randomized controlled trials comparing BT with usual care after HFS. We performed a pairwise meta-analysis using fixed- and random-effects models. Results: Eight randomized controlled trials including a total of 752 participants were retrieved. The BT group showed significantly improved overall physical functioning after HFS compared with the usual care group (overall standardised mean difference [SMD]=0.390; 95% confidence interval [CI], 0.114-0.667; p=0.006). Both balance and gait improved (SMD=0.570; 95% CI, 0.149-0.992; p=0.008 and SMD=0.195; 95% CI, 0.043-0.347; p=0.012, respectively) in the BT group. Lower limb strength, performance task, activity of daily living, and health-related quality of life also improved significantly in the BT group. Conclusion: Our meta-analysis revealed that BT after HFS improved overall physical functioning. Positive effects on balance, gait, lower limb strength, performance task, activity of daily living, and health-related quality of life were evident. Therefore, BT should be specifically included in postoperative rehabilitation programs and balance must be thoroughly checked in elderly patients with hip fractures. PMID- 30517614 TI - Does the Neurological Damage from a Traumatic Brain Injury Invalidate Measures of Psychopathology Such as the MMPI-2? AB - Objective: The Gass correction model removes 14 items from the MMPI-2 which refer to neurological damage when assessing a person suffering a traumatic brain injury (TBI). Previous analysis supported ongoing inclusion of the five correction items from MMPI-2 Hs scale in individuals who suffered a TBI. This study investigates the remaining nine correction model items on the Hy and Sc scales. Participants: A sample of patients with a TBI (n = 242), and the MMPI-2 normative sample (n = 2,600). Design Main Measures: This is a cross-sectional study testing measurement invariance of two MMPI-2 scales (Hy and Sc) between the TBI and normative samples. Results: Factor models for each scale were defined and assessed across multiple samples. The Hy scale generated a four-factor model (CFI range .913 .935, RMSEA range .025-.027). The Sc scale generated a five-factor model (CFI range .911-.962, RMSEA range .013-.018). Both models met the criteria of partial measurement invariance. Sensitivity and specificity analysis supported retaining all correction items when assessing persons with a TBI. Conclusions: These results suggest continued inclusion of all 14 Gass correction model items when assessing a person with a TBI. PMID- 30517615 TI - Editorial for the Thematic Issue on "Industrial Microbiology". PMID- 30517616 TI - Secretion and signalling of bacterial RNAs. PMID- 30517617 TI - Evidence of Aggregation-Sex Pheromone Use by Longhorned Beetles (Coleoptera: Cerambycidae) Species Native to Africa. AB - During field bioassays in Kenya of 10 chemicals that are common pheromone components of cerambycid beetles, six species in the subfamily Cerambycinae were significantly attracted to 3-hydroxyhexan-2-one, and one species in the subfamily Lamiinae was significantly attracted to 2-(undecyloxy)ethanol (known as monochamol). These results further demonstrate that the former compound is highly conserved as a cerambycid pheromone because it has now been identified or implicated in the pheromones of numerous cerambycine species native to all six habitable continents. Similarly, monochamol has been identified or implicated as a pheromone component for species in the subfamily Lamiinae native to Asia, Europe, North America, and now Africa. The eight other compounds tested, including (E)-6,10-dimethyl-5,9-undecadien-2-ol (fuscumol), the corresponding (E) 6,10-dimethyl-5,9-undecadien-2-yl acetate (fuscumol acetate), syn- and anti-(2,3) hexanediols and (2,3)-octanediols, 3-hydroxyoctan-2-one, and 3-hydroxydecan-2 one, did not attract significant numbers of any species. PMID- 30517618 TI - Towards an understanding of resilience: responding to health systems shocks. PMID- 30517619 TI - Male-female differences in characteristics and early outcomes of patients undergoing tricuspid valve surgery: a national cohort study in the Netherlands. AB - OBJECTIVES: This study aims to explore male-female differences in baseline and procedural characteristics, and outcomes of patients undergoing isolated or concomitant tricuspid valve (TV) surgery. METHODS: All TV procedures registered between 2007 and 2016 in the database of the Netherlands Association for Cardio Thoracic Surgery were analysed. Logistic regression analyses with interaction terms were used to determine whether sex was associated with hospital mortality. RESULTS: Five thousand five hundred and eighty-two patients underwent TV surgery [isolated: N = 685 (49% male), TVrepair: N = 5286 (50% male) and TVreplacement: N = 250 (46% male)]. In the TVrepair group, females were significantly older, had less prior percutaneous/surgical coronary interventions, less extracardiac arteriopathies, a lower prevalence of renal impairment, less endocarditis, a lower prevalence of preoperative critical condition, less recent myocardial infarction, less concomitant coronary artery bypass grafting (CABG) and, in case of concomitant mitral valve surgery, less concomitant mitral valve repair compared to males. In the TVreplacement group, females more often had a history of prior valve surgery and less prior CABG. Hospital mortality for males and females was 7.0% (N = 183) and 6.1% (N = 163), P = 0.241 in the TVrepair group and 2.6% (N = 3) and 8.8% (N = 12), P = 0.074 in the TVreplacement group. Sex was not associated with hospital mortality (odds ratio (OR) 1.14, 95% confidence interval (CI) 0.88-1.48; P = 0.322). Sex demonstrated a significant interaction with the parameter 'critical preoperative condition' (OR 0.44, 95% CI 0.22-0.90; P = 0.026). CONCLUSIONS: Substantial differences in patient and procedural characteristics existed between male and female patients undergoing TV surgery, although sex was not a derterminant for hospital mortality. Nevertheless, sex interacted with a critical preoperative condition, indicating the usefulness of separate risk factor models for males and females requiring TV surgery. PMID- 30517621 TI - Unlocking the potential of value-based health care by defining global Standard Sets of outcome measures that matter to patients with cardiovascular diseases. AB - As health systems around the world increasingly look to record and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. Clinicians today gather more data than ever before, but what is measured often has little relationship to the results of care that matter most to patients. Through its working groups of global experts in particular diseases, the International Consortium for Health Outcomes Measurement (ICHOM) aims to define minimum Standard Sets of outcomes, along with case-mix factors to support risk-adjustment and meaningful comparison. These Standard Sets may then be implemented globally empowering patients to select providers with the best outcomes at the lowest cost, empowering providers that deliver superior outcomes at competitive costs to excel, and empowering payers to negotiate contracts based on results. ICHOM has published 24 Standard Sets including coronary artery disease, heart failure, hypertension and stroke and is nearing the completion of its work in atrial fibrillation. PMID- 30517620 TI - Homozygous missense mutation L673P in adenylate kinase 7 (AK7) leads to primary male infertility and multiple morphological anomalies of the flagella but not to primary ciliary dyskinesia. PMID- 30517622 TI - Mid-term results of a randomized trial of tricuspid annuloplasty for less-than severe functional tricuspid regurgitation at the time of mitral valve surgery?. AB - OBJECTIVES: The optimal management of functional tricuspid regurgitation (FTR) in the setting of mitral valve operations remains controversial. The current practice is both centre specific and surgeon specific with guidelines based on non-randomized data. A prospective randomized trial was performed to evaluate the worth of less-than-severe FTR repair during mitral valve procedures. METHODS: A single-centre randomized study was designed to allocate patients with less-than severe FTR undergoing mitral valve surgery to be prophylactically treated with or without tricuspid valve annuloplasty (TVP- or TVP+). These patients were analysed using longitudinal cardiopulmonary exercise capacity, echocardiographic follow-up and cardiac magnetic resonance. The primary outcome was freedom from more than or equal to moderate tricuspid regurgitation with vena contracta >=4 mm. Secondary outcomes were maximal oxygen uptake and right ventricular (RV) dimension and function. RESULTS: A total of 53 patients were allocated to receive concomitant TVP+, and 53 patients were treated conservatively (TVP-). At 5 years, tricuspid regurgitation was observed to be greater than mild in 10 patients in the TVP- group and no patients in the TVP+ group (P < 0.01). Maximal oxygen uptake, RV basal diameter, end-diastolic diameter and end-systolic diameter and fractional area changes were similar in both groups. Cardiac magnetic resonance confirmed no differences in RV end-diastolic volume, RV end-systolic volume and RV ejection fraction. CONCLUSIONS: This single-centre prospective randomized trial demonstrated that prophylactic tricuspid annuloplasty irrespective of annular dilatation at the time of mitral surgery reduced the recurrence of moderate or severe FTR at 5-year follow-up and reduced the pulmonary pressure. Nevertheless, the functional capacity, the RV function and the RV dimension remained similar. PMID- 30517623 TI - Impact of genes and environment on obesity and cardiovascular disease. AB - Obesity and abdominal obesity have been closely related to cardiovascular outcomes, and recent evidence has indicated that environmental and genetic factors act in concert in determining the risks of these conditions. Improving adherence to healthy lifestyle habits and healthy dietary patterns can at least partly counteract genetic variations related risks of obesity and cardiovascular disease (CVD). Other factors, such as epigenetic alterations, may also modulate a relationship between genetic susceptibility and these disorders. In this review, we highlighted data from recent studies on gene and environmental risk factors for obesity and CVD, and described how these findings might inform understanding of the complex roles of interactions between genes and environmental factors in the development of obesity and CVD. PMID- 30517624 TI - Meeting the Emotional Needs of Hospital Patients With Dementia: A Freelisting Study With Ward Staff. AB - Background and Objectives: People with dementia are vulnerable when in hospital, with serious risks to their physical and emotional well-being. Hospital staff are expected to understand and respond to the emotions of the patient; however, it is not known how this can be achieved. We provide a concise description of achievable emotion-focused care for patients with dementia. Design and Methods: Exploratory qualitative interviews were conducted with a whole U.K. hospital ward providing dementia care, constituting 47 staff members. Staff responded to four questions using ethnographic freelisting. They listed (a) all the ways they notice the emotional distress of patients with dementia, (b) the causes of emotional distress, (c) all the ways they respond, and (d) the responses that seem to work. Cultural consensus analysis was applied. Results: A single-factor solution for each question indicated a consensus approach to emotional distress. Emotional distress was noticed from agitation (Smith's saliency score, 0.418), crying (0.350), and increased mobilizing (0.238). The main causes of distress were the unfamiliar hospital environment (0.355) and not knowing what is happening (0.313). The most effective ways to respond to emotional distress required knowing the person (0.299), talking (0.283), and being with the person (0.269). Discussion and Implications: The findings expand what is understood of behavioral and psychological symptoms of dementia; these communicated emotional distress with well-understood causes. Prioritized ways of responding to emotional distress described person-centered care. The results offer a menu of options for providing emotionally responsive care for patients with dementia in hospital. Future research should evaluate the care described. PMID- 30517625 TI - GnRH - a key regulator of FSH. AB - The hypothalamic decapeptide, GnRH, is the gatekeeper of mammalian reproductive development and function. Activation of specific, high affinity cell surface receptors (GnRHR) on gonadotropes by GnRH triggers signal transduction cascades to stimulate the coordinated synthesis and secretion of the pituitary gonadotropins, FSH and LH. These hormones direct gonadal steroidogenesis and gametogenesis, making their tightly regulated production and secretion essential for normal sexual maturation and reproductive health. FSH and LH are glycoprotein heterodimers comprised of a common alpha-subunit and a unique beta-subunit (FSHbeta and LHbeta, respectively), which determines the biological specificity of the gonadotropins. The unique beta-subunit is the rate limiting step for the production of the mature gonadotropins. Therefore, FSH synthesis is regulated at the transcriptional level by Fshb gene expression. The overarching goal of this review is to expand our understanding of the mechanisms and pathways underlying the carefully orchestrated control of FSH synthesis and secretion by GnRH, focusing on the transcriptional regulation of the Fshb gene. Identification of these regulatory mechanisms is not only fundamental to our understanding of normal reproductive function but will also provide a context for the elucidation of the pathophysiology of reproductive disorders and infertility to lead to potential new therapeutic approaches. PMID- 30517626 TI - Hepatic HKDC1 expression contributes to liver metabolism. AB - Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5th HK with expression in the liver. Here, we reveal HKDC1 to have low glucose phosphorylating ability and demonstrate its association with the mitochondria in hepatocytes. As we have shown previously that genetic deletion of HKDC1 leads to altered hepatic triglyceride levels, we also explored the influence of overexpression of HKDC1 in hepatocytes on cellular metabolism observing reduced glycolytic capacity and maximal mitochondrial respiration with concurrent reductions in glucose oxidation and mitochondrial membrane potential. Furthermore, we found that acute in vivo overexpression of HKDC1 in the liver induced significant changes in mitochondrial dynamics. Altogether, these findings suggest overexpression of HKDC1 causes mitochondrial dysfunction in hepatocytes. However, its overexpression was not enough to alter energy storage in the liver, but led to mild improvement in glucose tolerance. We next investigated the conditions necessary to induce HKDC1 expression, observing HKDC1 expression to be elevated in human patients whose livers were at more advanced stages of NAFLD and similarly found high liver expression in mice on diets causing high levels of liver inflammation and fibrosis. Overall, our data suggests HKDC1 expression in hepatocytes results in defective mitochondrial function and altered hepatocellular metabolism and speculate that its expression in liver may play a role in the development of NAFLD. PMID- 30517627 TI - Chronic pain is associated with increased health care use among community dwelling older adults in Brazil: the Pain in the Elderly (PAINEL) Study. AB - Background: Chronic pain is known to increase health care use in high-income countries, but in Brazil, little is known. Objective: To investigate the association between chronic pain and health care use among Brazilian older adults and explore the relationship between pain severity and health care use. Methods: This cross-sectional study was derived from the population-based study Frailty in Brazilian Older People-FIBRA. Chronic pain, pain intensity and pain-related disability were assessed through additional telephone interviews. Health care use was measured by the number of doctor visits, hospitalization events and high health care use (highest quartile of the distribution for number of doctor visits) in the last 12 months. Associations were tested in regression analyses adjusted for predisposing, enabling and illness-level components from the Andersen Model. Results: The 383 participants were predominantly female (71.0%), mean age was 75.6 (6.1 SD). The prevalence of chronic pain was 30.0%. Chronic pain was associated with number of doctor visits [unstandardized B coefficient 1.48; 95% confidence interval (CI) = 0.35-2.62] and high health care use [odds ratios (OR) = 2.27; 95% CI = 1.39-3.72]. Pain intensity was associated with high health care use in univariate (OR = 1.13; 95% CI = 1.06-1.20) but not multivariate analysis (OR = 1.12; 95% CI = 0.94-1.33). Pain-related disability was not associated with any outcome. Conclusion: Chronic pain increased health care use among Brazilian older adults. Improving the quality of primary care management of individuals at greater risk of chronic pain should be a cornerstone of health policies directed towards reducing the personal and societal burden of ageing. PMID- 30517628 TI - The Aging of a Young Nation: Population Aging in Singapore. AB - The juxtaposition of a young city-state showing relative maturity as a rapidly aging society suffuses the population aging narrative in Singapore and places the "little red dot" on the spotlight of international aging. We first describe population aging in Singapore, including the characteristic events that shaped this demographic transition. We then detail the health care and socioeconomic ramifications of the rapid and significant shift to an aging society, followed by an overview of the main aging research areas in Singapore, including selected population-based data sets and the main thrust of leading aging research centers/institutes. After presenting established aging policies and programs, we also discuss current and emerging policy issues surrounding population aging in Singapore. We aim to contribute to the international aging literature by describing Singapore's position and extensive experience in managing the challenges and maximizing the potential of an aging population. We hope that similar graying populations in the region will find the material as a rich source of information and learning opportunities. Ultimately, we aspire to encourage transformative collaborations-locally, regionally, and internationally-and provide valuable insights for policy and practice. PMID- 30517629 TI - Social Support and Preventive Healthcare Behaviors Among Couples in Later Life. AB - Background and Study Objectives: Intimate partners and close friends represent two major sources of social support that are central to one's health and health behaviors in later life. The aim of this study was to examine dyadic linkages between perceived social support (from spouses and friends) and preventive healthcare behaviors among coupled-individuals. Design and Methods: Prospective data from the Health and Retirement Study (2010, 2012) were used to analyze a sample of coupled-individuals (dyad N = 1,902). A series of multilevel logistic regression (actor-partner interdependence) models were estimated to evaluate whether perceived social support from spouses and friends was associated with the likelihood of using two common forms of preventive healthcare services (i.e., influenza vaccination and cancer screenings). Results: Apart from the role of perceived support from spouse on flu vaccinations, wives' preventive healthcare behaviors were unrelated to perceived social support. In contrast, husbands' preventive healthcare behaviors showed consistent associations with perceived social support from friends for the 2-year observation period. Further, husbands' receipt of prostate cancer screening was associated with wives' perceptions of social support from spouse as well as friends. Discussion and Implications: These findings contributed to our understanding of the health advantages associated with being in a marital relationship for preventive healthcare behaviors, especially for men. Future research should unpack the pathways through which social support of various forms is associated with obtaining needed preventive health services. PMID- 30517630 TI - Sleep and cardiovascular risk: how much is too much of a good thing? PMID- 30517631 TI - The course of neuropsychiatric symptoms in patients with dementia in primary care. AB - Background: During the course of dementia, most people develop some type of neuropsychiatric symptoms (NPS), which result in lower quality of life, high caregiver burden, psychotropic drug use and a major risk of institutionalization. Studies on NPS in people with dementia have been mainly conducted in clinical centres or psychiatric services. Objectives: To investigate the course of NPS in people with dementia in primary care. Methods: Analysis of (cumulative) prevalence and incidence, persistence and resolution based on data collected during an assessment at home of a prospective naturalistic cohort study in primary care in a sample of 117 people with dementia and their informal caregivers. Subsyndromes of NPS were assessed with the Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory. Multivariate analyses were used to detect determinants for the course of NPS. Results: The mean age of the people with dementia was 78.6 years, and 52% were female. Mean Mini-Mental State Examination total score was 19.5, mean NPI total score 15.7. The most prevalent clinically relevant subsyndromes of the NPI were hyperactivity and mood/apathy, and the most prevalent individual NPS were aberrant motor behaviour (28%), agitation/aggression (24%) and apathy/indifference (22%). Of the people with dementia, 72.3% had one or more symptoms of the mood/apathy and 75.3% of the hyperactivity subsyndrome. Conclusions: GPs should be aware of NPS in people with dementia and should actively identify them when they visit these patients or when informal caregivers consult them. Timely diagnosing facilitates adequate professional care. PMID- 30517633 TI - Corrigendum. PMID- 30517632 TI - Pre-treatment drug resistance and HIV-1 subtypes in infants from Argentina with and without exposure to antiretroviral drugs for prevention of mother-to-child transmission. AB - Objectives: To assess the prevalence and patterns of pre-treatment HIV drug resistance (PDR) and HIV-1 subtype in infants from Argentina with exposure to different antiretroviral drugs (ARVs) for the prevention of mother-to-child transmission (PMTCT). Patients and methods: HIV-1 genotyping was performed in 115 infants (median age = 2.3 months) born between 2007 and 2014 to screen for drug resistance mutations (DRMs) before starting first-line ART. HIV-1 subtype was characterized by phylogenetic and recombination analysis. Results: Overall, DRMs were found in 34 of 115 infants (PDR level 30% to any ARV, 3.5% to PIs, 12% to NRTIs and 22% to NNRTIs). Of the 115 infants, 22 (19.1%) were ARV-unexposed. Another 93 were ARV-exposed: 28 (24.3%) to short-course zidovudine monotherapy ARV prophylaxis; 25 (21.7%) to nevirapine-based ARV prophylaxis; 12 (10.4%) to perinatal infant zidovudine prophylaxis + maternal combination ART with NNRTIs; and 28 (24.3%) to perinatal infant zidovudine prophylaxis+maternal combination ART with PIs. Transmitted drug resistance among ARV-unexposed infants was 32% (5% to PIs, 9% to NRTIs and 18% to NNRTIs). ART-exposed infants showed multi-class ARV resistance. Importantly, vertical transmission of a triple-class-resistant virus was confirmed in one case. Patterns of DRMs predicted high-level resistance to NNRTIs in a similar and high proportion (>50%) of infants with at least one DRM independently of ARV exposure. BF recombinants were found in 74%, subtype B in 20%, subtype C in 3% and novel AG and AB recombinants in 3%. Conclusions: PDR in HIV-1-infected children from Argentina is among the highest reported, jeopardizing successful lifelong suppressive ART as well as the efficacy of current PMTCT regimens. PMID- 30517634 TI - Can MoCA and MMSE Be Interchangeable Cognitive Screening Tools? A Systematic Review. AB - Background and Objectives: Cognitive disorders may be an early sign of neuropsychiatric disorders; however, it remains unclear whether the screening measures are interchangeable. The aim of this study was to contrast the most commonly used screening tools-Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)-for early detection of neurocognitive disorder (NCD). Research Design and Methods: This study presents a descriptive systematic review and informative literature according to the Cochrane Foundation's guidelines. The keywords "Mini-Mental State Examination" and "Montreal Cognitive Assessment" were searched in the Web of Science, SciELO, and LILACS databases. Results: Fifty-one studies were selected including a total sample of 11,870 participants (8,360 clinical patients and 3,510 healthy controls). Most studies were published in the past 5 years using a cross-sectional design, carried out across the world. They were organized by age ranges (18-69 years and 20-89 years), years of schooling, and mental status (with and without mental and behavior disorders). Sixteen of 18 studies had participants aged 18-69 years, and 21 out of 33 studies within the older set suggested that the MoCA is a more sensitive tool for detecting NCD. Discussion and Implications: Thirty-seven studies suggested that the MoCA is a more sensitive tool for NCD detection because it assesses executive function and visuospatial abilities. Some individuals who demonstrated normal cognitive function on the MMSE had lower performance on the MoCA. However, it seems necessary to establish different cutoffs based on years of schooling to avoid false positives. Future studies should contrast MoCA with other screening tools designed for NCD assessment. PMID- 30517635 TI - Challenging SNP impact on caspofungin resistance by full-length FKS1 allele replacement in Candida lusitaniae. AB - Objectives: A strain of the opportunistic pathogenic yeast Candida lusitaniae was genetically engineered for full-length replacement of the FKS1 gene encoding the target of echinocandin antifungals in order to assess the impact of FKS mutations on echinocandin resistance and reduced echinocandin susceptibility (RES). Methods: FKS1 allelic exchange was achieved by transforming C. lusitaniae with two DNA fragments covering the entire FKS1 ORF. Both fragments overlap a 40 bp region where SNPs or small indels of interest were inserted. To target integration at the FKS1 locus, each DNA fragment was fused with split auxotrophic markers of which complementary truncated parts were previously inserted into the chromosomal regions flanking FKS1, allowing selection on minimal medium. Results: Three SNPs described in the FKS1 hotspot (HS) regions HS1 or HS2 of clinical isolates of Candida albicans were expressed at an equivalent position in C. lusitaniae and were confirmed to confer either reduced susceptibility (F641V) or full resistance (S645P and R1361G) to caspofungin. The F659 deletion reported in an FKS2 allele of Candida glabrata and the naturally occurring P660A substitution in FKS1 of Candida parapsilosis were shown to confer a 256-fold and 6-fold increase in caspofungin MIC, respectively, when introduced into an FKS1 allele of C. lusitaniae. Conclusions: We have successfully developed a C. lusitaniae strain for the expression of full-length FKS1 alleles harbouring known mutations contributing to reduced susceptibility or resistance to caspofungin, thus opening the way for the screening of other FKS1/FKS2 mutations potentially involved in RES. PMID- 30517637 TI - Cardiovascular Medication Stability in Urine for Non-Adherence Screening by LC-MS MS. AB - Biochemical testing in urine is a powerful new tool in the investigation of non adherence to cardiovascular medications Drug testing using liquid chromatography tandem mass spectrometry (LC-MS-MS) is the mainstay of the laboratory test but may be subject to pre-analytical factors that could impact on test results. The stability of cardiovascular medications in urine is one such factor that has not been fully explored in non-adherence testing and has the potential to result in patients appearing falsely non-adherent to their therapy. The stability of 29 cardiovascular medications in patients' urine samples were assessed at room temperature (RT) and at -80 degrees C using a LC-MS-MS screening method. All drugs and drug metabolites were found to be stable under the storage conditions studied. The findings imply that the medication stability in urine samples does not have any impact on non-adherence results and thus allowing samples to be taken and transported without the need for specialist sample handling procedures. The stability of cardiovascular drugs in urine samples will allow adherence testing to be utilized more widely into routine clinics and research. PMID- 30517636 TI - The transcriptomic landscape of yaks reveals molecular pathways for high altitude adaptation. AB - Yak is one of the largest native mammalian species at the Himalayas, the highest plateau area in the world with an average elevation of more than 4,000 meters above the sea level. Yak is well adapted to high altitude environment with a set of physiological features for a more efficient blood flow for oxygen delivery under hypobaric hypoxia. Yet, the genetic mechanism underlying its adaptation remains elusive. We conducted a cross-tissue, cross-altitude and cross-species study to characterize the transcriptomic landscape of domestic yaks. The generated multi-tissue transcriptomic data greatly improved the current yak genome annotation by identifying tens of thousands novel transcripts. We found that among the eight tested tissues (lung, heart, kidney, liver, spleen, muscle, testis and brain), lung and heart are two key organs showing adaptive transcriptional changes and more than 90% of the cross-altitude differentially expressed genes (DEGs) in lung display a non-linear regulation. Pathways related to cell survival and proliferation are enriched, including PI3K-Akt, HIF-1, focal adhesion and ECM-receptor interaction. These findings, in combination with the comprehensive transcriptome dataset, are valuable to understanding the genetic mechanism of hypoxic adaptation in yak. PMID- 30517638 TI - SLP-2 interacts with Parkin in mitochondria and prevents mitochondrial dysfunction in Parkin-deficient human iPSC-derived neurons and Drosophila. PMID- 30517639 TI - Difference in Pathomechanism Between Crohn's Disease and Ulcerative Colitis Revealed by Colon Transcriptome. AB - Background: We aim to identify the differences in colonic mucosal transcriptome between Crohn's disease (CD) and ulcerative colitis (UC) for a better understanding of the molecular pathology. Methods: Differentially expressed genes (DEG) in the colonic mucosa of CD and UC were identified with a global gene expression microarray dataset generated from the colon biopsies of CD and UC patients and normal controls. The DEGs were then processed to identify altered pathways and modularized DEGs and pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis with an independent cohort of samples was performed to validate the microarray data. Results: At the pathway level, virus infection and autoimmune pathways were upregulated in CD but not in UC when compared with controls. Some of the relevant DEGs (such as TAP1 and TAP2) were elevated in both CD and UC, with CD exhibiting more pronounced elevations. Gene expression levels in viral infection pathways were correlated with those of autoimmune pathways. In contrast, pattern recognition-mediated innate immune pathways (TLR4 and TLR2) were significantly elevated in UC but not in CD. Similar results were observed with an independent cohort by qRT-PCR. Conclusions: Our data support the hypothesis that viral infection induced autoimmunity may represent a pathomechanism for IBD, especially CD. However, pattern recognition mediated innate immunity targeting microbiome may play a more important role in UC compared with CD. Our findings identified different intervention targets for CD and UC, which may lead to more effective treatments for IBD patients. PMID- 30517640 TI - Seasonal and Site Differences in Phorid Parasitoidism Rates of Leaf-Cutting Ants. AB - Interspecific interactions are influenced by several environmental factors that may affect spatial and temporal dynamics. Seasonal variations in environmental conditions and differences among sites may affect the intensity of interactions and the abundance of interacting species. In this study, we describe the variability in parasitoids of Atta ants among sites and seasons over a year. More specifically, we studied parasitoidism of Atta sexdens Linnaeus and Atta laevigata Smith nests at a site with native cerrado vegetation and a Eucalyptus monoculture in dry and rainy seasons. Of the 45,147 workers collected, 1,020 (2.2%) were parasitized. We found five parasitoid species of A. sexdens and four species of A. laevigata. The two species of leaf-cutting ants shared similar parasitoid communities, but the infection rate was higher in A. laevigata (5.3%) compared with A. sexdens (0.8%). Parasitoidism rates of A. laevigata increased in the rainy season, but the rate for A. sexdens was consistently low in both seasons. The identity of the host species and the season, therefore, appear to interact to influence the rate of parasitoidism in these leaf-cutting ant species. PMID- 30517641 TI - Evaluation of the ability of linezolid and tedizolid to eradicate intraosteoblastic and biofilm-embedded Staphylococcus aureus in the bone and joint infection setting. AB - Objectives: Prolonged use of linezolid for bone and joint infection (BJI) is limited by its long-term toxicity. The better safety profile of tedizolid, a recently developed oxazolidinone, could offer an alternative. However, its efficacy against biofilm-embedded and intracellular Staphylococcus aureus, the two main bacterial reservoirs associated with BJI chronicity, is unknown. Methods: Using three S. aureus strains (6850 and two clinical BJI isolates), linezolid and tedizolid were compared regarding their ability: (i) to target the S. aureus intracellular reservoir in an in vitro model of osteoblast infection, using three concentrations increasing from the bone concentration reached with standard therapeutic doses (Cbone = 2.5 * MIC; Cplasm = 10 * MIC; Cmax = 40 * MIC); (ii) to eradicate mature biofilm [minimal biofilm eradication concentration (MBEC)]; and (iii) to prevent biofilm formation [biofilm MIC (bMIC) and confocal microscopy]. Results: Linezolid and tedizolid weakly reduced the intracellular inoculum of S. aureus in a strain-dependent manner despite the similar MICs for the tested strains, but improved cell viability even in the absence of an intracellular bactericidal effect. Conversely, linezolid and tedizolid were ineffective in eradicating mature biofilm formed in vitro, with MBEC >2000 and >675 mg/L, respectively. bMICs of tedizolid were 4-fold lower than those of linezolid for all strains. Conclusions: Linezolid and tedizolid alone are not optimal candidates to target bacterial phenotypes associated with chronic forms of BJI. Despite weak intracellular activity, they both reduce infection-related cytotoxicity, suggesting a role in modulating intracellular expression of staphylococcal virulence factors. Although inactive against biofilm-embedded S. aureus, both-but particularly tedizolid-are able to prevent biofilm formation. PMID- 30517643 TI - Foods, macronutrients and breast cancer risk in postmenopausal women: a large UK cohort. PMID- 30517642 TI - Insights into Local Orbital Immunity: Evidence for the Involvement of the Th17 Cell Pathway in Thyroid-Associated Ophthalmopathy. AB - Context: Unique features of local immunity in thyroid-associated ophthalmopathy (TAO) may affect disease progression. Objective: To investigate the association between the orbital immune microenvironment and TAO development. Design/Setting/Participants: TAO and control orbital connective tissues were collected. Main Outcome Measures: Single-cell sequencing examined orbital lymphocytic infiltrates. Multi-color flow cytometry explored the phenotypes of different cell subsets and in vitro models for cell functional studies. Co culture experiment and western blotting assay were used to determine underlying mechanism of the enhanced T helper (Th)17 cell pathway. Results: The TAO orbital microenvironment was composed of natural killer cells, dendritic cells, macrophages, T cells, plasma cells, and CD34+ orbital fibroblasts (OFs), but few B cells. Increases in CD3+CD8- interleukin (IL)-17A-producing and RAR-related orphan receptor (ROR)gammat-expressing T cells and in CD3+CD8- IL-13-producing and GATA3-expressing T cells suggested Th17 cell and Th2 cell responses in TAO orbits. Increased interferon (IFN)-gamma-producing and RORgammat+Tbet+ T cells indicated a Th1-like phenotype of orbital-infiltrating Th17 cells. Higher IL-23R and IL-1R expression and lower IL-21R expression were also observed on Th17 cells in TAO orbits. Multivariate analyses revealed that the Th17 pathway [IL-17A (p=0.001), IFN-gamma (p=0.009), RORgammat (p=0.003), IL-23R (p=0.033), IL-21R (p=0.019)] and Th2 pathway [IL-13 (p=0.015), GATA3 (p=0.012)] were associated with TAO. IL-17A, IL-23R, and IL-1R correlated with clinical activity score and visual acuity. CD34+ OFs exhibited distinct cell surface marker expression and promoted IL-23R and IL-1R expression on T cells to facilitate the Th17-cell phenotype through prostaglandin E2-EP2/EP4-cAMP signaling. Conclusion: Our study addressed the importance of retroorbital immunity and suggests possible means of disrupting TAO pathogenesis. PMID- 30517644 TI - Tilmicosin modulates the innate immune response and preserves casein production in bovine mammary alveolar cells during Staphylococcus aureus infection. AB - Tilmicosin is an antimicrobial agent used to treat intramammary infections against S. aureus and has clinical anti-inflammatory effects. However, the mechanism by which it modulates the inflammatory process in the mammary gland is unknown. We evaluated the effect of tilmicosin treatment on the modulation of the mammary innate immune response after S. aureus infection and its effect on casein production in mammary epithelial cells. To achieve this goal, we used immortalized mammary epithelial cells (MAC-T), pre-treated for 12 h or treated with tilmicosin after infection with S. aureus (ATCC 27543). Our data showed that tilmicosin decreases intracellular infection (P <0.01) and had a protective effect on MAC-T reducing apoptosis after infection by 80% (P <0.01). Furthermore, tilmicosin reduced reactive oxygen species (ROS) (P <0.01), IL-1beta (P <0.01), IL-6 (P <0.01) and TNF-alpha (P <0.05) production. In an attempt to investigate the signaling pathways involved in the immunomodulatory effect of tilmicosin, mitogen-activated protein kinase (MAPK) phosphorylation was measured by fluorescent activated cell sorting (FACS). Pre- treatment with tilmicosin increased ERK1/2 (P <0.05) but decreased P38 phosphorylation (P <0.01). In addition, the anti-inflammatory effect of tilmicosin helped to preserve casein synthesis in mammary epithelial cells (P <0.01). This result indicates that tilmicosin could be an effective modulator inflammation in the mammary gland. Through regulation of MAPK phosphorylation, ROS production and pro-inflammatory cytokine secretion tilmicosin can provide protection from cellular damage due to S. aureus infection and help to maintain normal physiological functions of the bovine mammary epithelial cell. PMID- 30517645 TI - JUNO, the receptor of sperm IZUMO1, is expressed by the human oocyte and is essential for human fertilisation. AB - STUDY QUESTION: Is JUNO protein present at the surface membrane of human oocytes and involved in the fertilisation process? SUMMARY ANSWER: JUNO protein is expressed on the plasma membrane of human oocytes and its inhibition by a monoclonal antibody completely blocks gamete fusion. WHAT IS KNOWN ALREADY: Fusion of gamete membranes is the culminating event of the fertilisation process, but its molecular mechanisms are poorly understood. Until now, three molecules have been shown to be essential: CD9 tetraspanin in the oocyte, Izumo1 protein on the sperm and Juno, its corresponding receptor on the oocyte. Oocyte CD9 and sperm IZUMO1 have been identified in human gametes and their interaction is also well-conserved among several mammalian species. The presence of JUNO on human oocytes, however, has not yet been reported, nor has its role in fertilisation been investigated. STUDY DESIGN, SIZE, DURATION: We selected an anti-human JUNO antibody in order to investigate the presence of JUNO on the oocyte membrane surface and studied its potential involvement in gamete membrane interaction during fertilisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Monoclonal antibodies against human JUNO (anti-hJUNO mAb) were produced by immunisation of mice with HEK cells transfected with the putative human JUNO sequence (HEK hJUNO). These antibodies were used for immunostaining experiments and in vitro fertilisation assays with human gametes (GERMETHEQUE Biobank). MAIN RESULTS AND THE ROLE OF CHANCE: Three hybridoma supernatants, verified by immunostaining, revealed specifically HEK-hJUNO cells. The three purified monoclonal antibodies, FJ2E4 (IgG1), FJ8E8 (IgG1) and FJ4F5 (IgG2a), recognised the soluble recombinant human JUNO protein and, in a western blot of HEK-hJUNO extracts, a protein with an expected MW of 25 kDa. In addition, soluble recombinant human IZUMO protein inhibited the binding of anti-hJUNO mAbs to cells expressing hJUNO. Using these anti-hJUNO mAbs in immunostaining, we identified the presence of JUNO protein at the plasma membrane of human oocytes. Furthermore, we revealed a progressive expression of JUNO according to oocyte maturity. Finally, we showed that human zona-free oocytes, inseminated in the presence of anti-hJUNO mAb, were not fertilised by human sperm. These results suggest that, as seen in the mouse, JUNO is indeed involved in human gamete membrane fusion during fertilisation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In accordance with French bioethics laws, functional tests were performed using zona-free oocytes, which of course does not fully encompass all normal in vivo physiological conditions. However, these in vitro tests do provide direct information regarding sperm oocyte membrane interactions. WIDER IMPLICATIONS OF THE FINDINGS: Mechanisms of gamete fusion appear to be homologous between mice and humans. However, some differences do exist and analysing the human mechanisms is essential. In fact, this is the first report describing the presence of JUNO on human oocytes and its involvement in human fertilisation. This discovery allows further examination of the understanding of molecular mechanisms that drive gamete fusion: a crucial challenge at a time when infertility affects 16% of reproductively active couples. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Agence Nationale pour la Recherche, Grant no. ANR-13-BVS5-0004, and by Association Institut du Cancer et d'Immunogenetique (ICIG). There are no competing interests. PMID- 30517646 TI - Tenascin-C Produced by Intestinal Myofibroblasts Promotes Colitis-associated Cancer Development Through Angiogenesis. AB - Background: Colitis-associated cancer (CAC) is one of the prognostic factors in inflammatory bowel disease (IBD), and prevention of CAC is a critical concern for patients with IBD. Component cells of the microenvironment, especially myofibroblasts, are known to affect tumor development, but the role of intestinal myofibroblasts (IMFs) in CAC has not been clarified. Here, we explored the role of IMFs in CAC and sought to identify candidate genes as novel therapeutic targets for the prevention of CAC. Methods: We used the azoxymethane (AOM)/dextran sodium sulfate (DSS) model for dysplasia and CAC. Flow cytometry and RNA sequencing (RNA-seq) were performed to obtain an unbiased gene expression profile of IMFs. The transcriptome of significantly differentially expressed genes was analyzed by RNA-seq, quantitative reverse transcriptase polymerase chain reaction, and immunohistochemistry. Results: Comparison of normal intestinal fibroblasts and IMFs revealed 1045 genes with significantly differential expression. Among them, we focused on tenascin-C (TNC; q = 0.00232, Log2(Fold Change) = 3.87). Tenascin-C gene expression was markedly increased in the dysplasia model compared with control and CAC model (P < 0.05). Tenascin-C protein was barely expressed in normal and nondysplastic mucosa but strongly expressed in the stroma around dysplastic lesions. Moreover, TNC surrounded and enclosed integrin alphavbeta3-positive microvessels. Administration of ATN-161, an antagonist of alphavbeta3-integrin, significantly suppressed tumorigenesis of CAC through inhibition of angiogenesis (P < 0.05). Conclusions: In the early stages of CAC, TNC produced by IMFs affects tumor development via integrin alphavbeta3-mediated angiogenesis. Intestinal myofibroblasts might be a novel therapeutic target for preventing CAC. PMID- 30517647 TI - Differences in the Phenology of Harmonia axyridis (Coleoptera: Coccinellidae) and Native Coccinellids in Central Europe. AB - Harmonia axyridis (Pallas), an invasive non-native species in central Europe, can outcompete other aphidophagous species. The distribution and abundance of H. axyridis vary depending on different host plants, and its effects on native coccinellid communities may change accordingly. The distribution and abundance of coccinellids in central Europe (50 degrees N, 14 degrees E) were investigated from 2010 to 2016. Coccinellids were counted at regular intervals on cereals (Avena, Hordeum, and Triticum), herbaceous plants (Matricaria and Urtica) and trees (Acer, Betula, and Tilia). Additionally, the occurrence over time of each species on these plants was assessed and used as an index of persistence. Across all years, the adults and larvae of H. axyridis were the dominant species of coccinellid on trees. However, H. axyridis was less abundant on herbaceous plants and cereals than on trees. Populations of native coccinellids and H. axyridis co occurred on trees and persisted for the same length of time, while native coccinellids persisted longer than H. axyridis on herbaceous plants and cereals. Compared to 1976-1986, in the 2010s, the abundance of native species decreased on all plants by 50-70%. The presence of H. axyridis could be considered as a factor driving changes in the assemblages of native coccinellids. PMID- 30517648 TI - Left atrial function in heart failure with mid-range ejection fraction differs from that of heart failure with preserved ejection fraction: a 2D speckle tracking echocardiographic study. AB - Aims: Heart failure (HF) with mid-range ejection fraction (HFmrEF) shares similar diagnostic criteria to HF with preserved ejection fraction (HFpEF). Whether left atrial (LA) function differs between HFmrEF and HFpEF is unknown. We, therefore, used 2D-speckle-tracking echocardiography (2D-STE) to assess LA phasic function in patients with HFpEF and HFmrEF. Methods and results: Consecutive outpatients diagnosed with HF according to current European recommendations were prospectively enrolled. There were 110 HFpEF and 61 HFmrEF patients with sinus rhythm, and 37 controls matched by age. LA phasic function was analysed using 2D STE. Peak-atrial longitudinal strain (PALS), peak-atrial contraction strain (PACS), and PALS-PACS were measured reflecting LA reservoir, pump, and conduit function, respectively. Among HF groups, most of left ventricular (LV) diastolic function measures, and LA volume were similar. Both HF groups had abnormal LA phasic function compared with controls. HFmrEF patients had worse LA phasic function than HFpEF patients even among patients with LA enlargement. Among patients with normal LA size, LA reservoir, and pump function remained worse in HFmrEF. Differences in LA phasic function between HF groups remained significant after adjustment for confounders. Global PALS and PACS were inversely correlated with brain natriuretic peptide, LA volume, E/A, E/e', pulmonary artery systolic pressure, and diastolic dysfunction grade in both HF groups. Conclusion: LA phasic function was worse in HFmrEF patients compared with those with HFpEF regardless of LA size, and independent of potential confounders. These differences could be attributed to intrinsic LA myocardial dysfunction perhaps in relation to altered LV function. PMID- 30517649 TI - Integrity of clinical information in computerized order requisitions for diagnostic imaging. AB - Objective: Assess information integrity (concordance and completeness of documented exam indications from the electronic health record [EHR] imaging order requisition, compared to EHR provider notes), and assess potential impact of indication inaccuracies on exam planning and interpretation. Methods: This retrospective study, approved by the Institutional Review Board, was conducted at a tertiary academic medical center. There were 139 MRI lumbar spine (LS-MRI) and 176 CT abdomen/pelvis orders performed 4/1/2016-5/31/2016 randomly selected and reviewed by 4 radiologists for concordance and completeness of relevant exam indications in order requisitions compared to provider notes, and potential impact of indication inaccuracies on exam planning and interpretation. Forty each LS-MRI and CT abdomen/pelvis were re-reviewed to assess kappa agreement. Results: Requisition indications were more likely to be incomplete (256/315, 81%) than discordant (133/315, 42%) compared to provider notes (p < 0.0001). Potential impact of discrepancy between clinical information in requisitions and provider notes was higher for radiologist's interpretation than for exam planning (135/315, 43%, vs 25/315, 8%, p < 0.0001). Agreement among radiologists for concordance, completeness, and potential impact was moderate to strong (Kappa 0.66-0.89). Indications in EHR order requisitions are frequently incomplete or discordant compared to physician notes, potentially impacting imaging exam planning, interpretation and accurate diagnosis. Such inaccuracies could also diminish the relevance of clinical decision support alerts if based on information in order requisitions. Conclusions: Improved availability of relevant documented clinical information within EHR imaging requisition is necessary for optimal exam planning and interpretation. PMID- 30517650 TI - Effects of vaccination timing against respiratory pathogens on performance, antibody response, and health in feedlot cattle. AB - Angus * Hereford calves (n = 159; 87 heifers and 72 steers) were ranked by sex, body weight (BW), and age, and assigned to 1 of 3 vaccination schemes against bovine respiratory disease (BRD): 1) vaccination at weaning (d 0) and revaccination at feedyard arrival (d 30; CON, n = 53), 2) vaccination 15 d before weaning (d -15) and revaccination 15 d before feedyard arrival (d 15; EARLY, n = 53), and 3) vaccination 15 d after weaning (d 15) and revaccination 15 d after feedyard arrival (d 45; DELAYED, n = 53). Calves were maintained on pasture from d -15 to 29, transported (d 30) for 480 km to a commercial growing feedyard, and moved (d 180) to an adjacent finishing yard where they remained until slaughter (d 306). Calf BW was recorded on 2 consecutive days (d -15, -14, 0, 1, 29, 30, 75, 76, 179, and 180), which were averaged for BW gain calculation. Calves were assessed for BRD signs daily from d 0 to 306. Blood samples were collected on d 15, 0, 15, 30, 45, 60, and 75. No treatment effects were detected (P >= 0.49) for BW responses and carcass characteristics (P >= 0.32). Serum titers against bovine viral diarrhea type-1 were greater (P <= 0.05) in EARLY vs. CON and DELAYED from d 15 to 45, and greater (P < 0.01) in CON vs. DELAYED on d 30 and 45. Serum titers against bovine herpesvirus-1 were greater (P < 0.01) in EARLY vs. CON and DELAYED on d 0 and 30, and greater (P < 0.01) in EARLY and CON vs. DELAYED on d 15 and 45. Serum titers against bovine respiratory syncytial virus were greater (P = 0.05) in EARLY vs. CON on d 0, greater (P = 0.04) in CON vs. DELAYED on d 15, and greater (P <= 0.03) in EARLY and CON vs. DELAYED from d 30 to 60. Serum titers against parainfluenza3 virus were greater (P <= 0.04) in EARLY vs. DELAYED on d 30 and 45, and greater (P < 0.01) in CON vs. DELAYED on d 30. Incidence of BRD was less (P = 0.04) in EARLY vs. CON and DELAYED, and similar (P = 0.99) between CON and DELAYED. Therefore, altering the time of vaccination and revaccination against BRD to provide both doses prior to feedlot entry altered serum antibody responses to BRD pathogens, and alleviated the incidence of this disease in feedlot cattle. PMID- 30517652 TI - A multilevel analysis of overweight and obesity among non-pregnant women of reproductive age in Malawi: evidence from the 2015-16 Malawi Demographic and Health Survey. AB - Background: Overweight and obesity are well-known risk factors for non communicable diseases such as cardiovascular disease, diabetes, some cancers and musculoskeletal disorders. In Malawi, the proportion of women who are overweight/obese has doubled, from 10% in 1992 to 21% in 2015-16. Therefore we aimed to explore the individual- and community-level factors associated with overweight and obesity among non-pregnant women of child-bearing age. Methods: Secondary analysis of the 2015-16 Malawi Demographic and Health Survey was conducted. Overweight was defined as a body mass index (BMI) of 25 to <30 kg/m2, while obesity was defined as a BMI >=30 kg/m2. Two-level multilevel multivariable logistic regression models were constructed using a logit-link function with a binomial distribution on 7326 women living in 850 different communities. Results: At the individual level, the adjusted multilevel regression results showed that women 15-19 y of age as well as women from the poorest households had reduced odds of being overweight/obese. However, women with white collar jobs and women who were affiliated with the Church of Central Africa Presbyterian and the Roman Catholic church had increased odds of being overweight/obese. At the community level, women from urban areas and women who resided in communities with a low percentage of media exposure had increased odds of being overweight or obese. While women from poor communities had reduced odds of being overweight and obese, the proportion change in variance showed that 56, 77 and 78% of total variations in the odds of overweight, obese and overweight/obese across the communities were explained by both individual- and community-level factors. The median odds ratio showed that the likelihood of maternal overweight, obese and overweight/obese increased by 63, 39 and 84% when the women moved from low- to high-risk neighbourhoods. Conclusions: Older women, Christian women, women with white collar jobs and women from the richest households should be targeted during policy formulation. At the community level, media coverage should be spread evenly so that health awareness messages, consequences and means of overweight and obesity prevention are getting to the targeted women. Our study revealed evidence of clustering effects of overweight and obesity at the community level, hence neighbourhood variations with respect to maternal overweight and obesity should be taken into account when designing nutritional policies. PMID- 30517651 TI - Minimally Invasive Saliva Testing to Monitor Norovirus Infection in Community Settings. AB - Background: Norovirus is a leading cause of acute gastroenteritis worldwide. Routine norovirus diagnosis requires stool collection. The goal of this study was to develop and validate a noninvasive method to diagnose norovirus to complement stool diagnostics and to facilitate studies on transmission. Methods: A multiplex immunoassay to measure salivary immunoglobulin G (IgG) responses to 5 common norovirus genotypes (GI.1, GII.2, GII.4, GII.6, and GII.17) was developed. The assay was validated using acute and convalescent saliva samples collected from Peruvian children <5 years of age with polymerase chain reaction (PCR)-diagnosed norovirus infections (n = 175) and controls (n = 32). The assay sensitivity and specificity were calculated to determine infection status based on fold rise of salivary norovirus genotype-specific IgG using norovirus genotype from stool as reference. Results: The salivary assay detected recent norovirus infections and correctly assigned the infecting genotype. Sensitivity was 71% and specificity was 96% across the evaluated genotypes compared to PCR-diagnosed norovirus infection. Conclusions: This saliva-based assay will be a useful tool to monitor norovirus transmission in high-risk settings such as daycare centers or hospitals. Cross-reactivity is limited between the tested genotypes, which represent the most commonly circulating genotypes. PMID- 30517653 TI - Q-PULS, a new quasi-physiological pulsatile extracorporeal model to simulate heart function. AB - OBJECTIVES: The invention of new surgical procedures requires testing at different stages including animal models. To facilitate this process, we have developed a computer-controlled extracorporeal circulation system for testing of an explanted porcine heart simulating a variety of physiological parameters. Mitral valve function can be assessed before and after induced valve insufficiency and after valve repair. Accordingly, techniques and instruments can be modified at early stages of prototype development. METHODS: In the diastole, the left atrium is passively filled through the reservoir. The loading pressure of the atrium and flow rates can be widely adjusted. To simulate the systole, a linear motor-driven piston pump promotes volume into the left ventricle and the aorta. An additional circulatory pump compensates for undesired total emptying of the heart chambers. The processor control of the linear pump allows for various settings of flow rate, velocity and even irregular rhythm. Twenty-one isolated porcine hearts were used. The leaflet movement was filmed using a universal serial bus (USB)-probe camera. RESULTS: With 80 mm stroke and 1 m/s speed, a volume of 150 ml can be pumped at a heart rate of up to 73 bpm. Cardiac outputs of up to 10.9 l/min can be achieved. Constant visualization and continuous measurements of the pressure gradients before and after the induction of mitral insufficiency and after repair allowed quantitative verification of repair quality under beating-heart conditions. CONCLUSIONS: This model allows a controllable pulsation, loading and unloading of a porcine heart in a wide range. Thus, the function of the leaflets and repair results can be qualitatively and quantitatively evaluated under quasiphysiological conditions. PMID- 30517654 TI - RSV and asthma inception - cause and effect or shared susceptibility? PMID- 30517655 TI - The role of intracellular anionic phospholipids in the production of N-acyl phosphatidylethanolamines by cytosolic phospholipase A2epsilon. AB - N-Acyl-phosphatidylethanolamines (NAPEs) represent a class of glycerophospholipids and serve as the precursors of bioactive N acylethanolamines, including arachidonoylethanolamide (anandamide), palmitoylethanolamide and oleoylethanolamide. NAPEs are produced in mammals by N acyltransferases, the enzymes which transfer an acyl chain of glycerophospholipids to the amino group of phosphatidylethanolamine. Recently, the epsilon isoform of cytosolic phospholipase A2 (cPLA2epsilon, also called PLA2G4E) was identified as Ca2+-dependent N-acyltransferase. We showed that the activity is remarkably stimulated by phosphatidylserine (PS) in vitro. In the present study, we investigated whether or not endogenous PS regulates the function of cPLA2epsilon in living cells. When PS synthesis was suppressed by the knockdown of PS synthases in cPLA2E-expressing cells, the cPLA2E level and its N acyltransferase activity were significantly reduced. Mutagenesis studies revealed that all of C2, lipase and polybasic domains of cPLA2E were required for its proper localization as well as the enzyme activity. Liposome-based assays showed that several anionic glycerophospholipids, including PS, phosphatidic acid and phosphatidylinositol 4,5-bisphosphate, enhance the Ca2+-dependent binding of purified cPLA2E to liposome membrane and stimulate its N-acyltransferase activity. Altogether, these results suggested that endogenous PS and other anionic phospholipids affect the localization and enzyme activity of cPLA2E. PMID- 30517656 TI - GhNAC83 inhibits corm dormancy release by regulating ABA signaling and CK biosynthesis in Gladiolus hybridus. AB - Corm dormancy is an important trait for breeding in many bulb flowers, including the most cultivated Gladiolus hybridus. Gladiolus corms are modified underground stems that function as storage organs and remain dormant to survive adverse environmental conditions. Unlike seed dormancy, not much is known about corm dormancy. Here, we characterize the mechanism of corm dormancy release (CDR) in Gladiolus. We identified an important ABA (abscisic acid) signaling regulator, GhPP2C1 (protein phosphatase 2C1), by transcriptome analysis of CDR. GhPP2C1 expression increased during CDR, and silencing of GhPP2C1 expression in dormant cormels delayed CDR. Furthermore, we show that GhPP2C1 expression is directly regulated by GhNAC83, which was identified by yeast one-hybrid library screening. In planta assays show that GhNAC83 is a negative regulator of GhPP2C1, and silencing GhNAC83 promoted CDR. As expected, silencing of GhNAC83 decreased ABA level, but also dramatically increased cytokinin (CK; zeatin) content in cormels. Binding assays demonstrate that GhNAC83 associates with the GhIPT (ISOPENTENYLTRANSFERASE) promoter and negatively regulates zeatin biosynthesis. Taken together, our results reveal that GhNAC83 promotes ABA signaling and synthesis and inhibits CK biosynthesis pathways thereby inhibiting CDR. Our findings show that GhNAC83 regulates the ABA and CK pathways, and therefore control corm dormancy. PMID- 30517657 TI - High-risk human papillomavirus in semen is associated with poor sperm progressive motility and a high sperm DNA fragmentation index in infertile men. AB - STUDY QUESTION: Does the presence of human papillomavirus (HPV) in semen impact seminal parameters and sperm DNA quality in white European men seeking medical help for primary couple's infertility? SUMMARY ANSWER: HPV seminal infections involving high-risk (HR) genotypes are associated with impaired sperm progressive motility and sperm DNA fragmentation (SDF) values. WHAT IS KNOWN ALREADY: HPV is commonly present in semen samples. However, whether the presence of HPV in semen is actually associated with impaired sperm parameters and SDF values have yet to be elucidated. STUDY DESIGN, SIZE, DURATION: In this cross-sectional study, complete demographic, clinical and laboratory data from 729 infertile men were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Health-significant comorbidities were scored with the Charlson comorbidity index (CCI). Serum hormones and SDF index (measured by the sperm chromatin structure assay [SCSA]) were measured in every patient (SDF >=30% was defined as pathological). Semen analysis was based on 2010 World Health Organisation reference criteria. Amplification by nested PCR was used to detect HPV-DNA sequences in semen samples. Descriptive statistics and linear regression models were used to test the association between the presence of HPV and clinical and seminal characteristics in the whole cohort. MAIN RESULTS AND THE ROLE OF CHANCE: The overall rate of HPV positivity was 15.5% (113/729). Overall, 78/729 (10.7%) and 35/729 (4.8%) patients had HR HPV+ and low-risk HPV+, respectively. HPV16 was the most prevalent type (22.1%), followed by HPV43 (10.6%), HPV56 and HPV42 (both 8.8%). No differences were found in terms of clinical and hormonal characteristics between patients with or without seminal HPV. Sperm progressive motility was significantly lower (P = 0.01) while SDF values were higher (P = 0.005) in HPV+ men compared to those with no HPV. In particular, HR HPV+ men had lower sperm progressive motility (P = 0.007) and higher SDF values (P = 0.003) than those with a negative HPV test. Univariable analysis showed that HR HPV+ was associated with impaired sperm progressive motility (P = 0.002) and SDF values (P = 0.003). In the multivariable analysis, age, FSH levels and testicular volume were significantly associated with impaired sperm progressive motility (all P <= 0.04). Conversely BMI, CCI, smoking habits and HPV status were not. Only age (P = 0.02) and FSH (P = 0.01) were significantly associated with SDF, after accounting for BMI, CCI, testicular volume, smoking habits and HPV status. LIMITATIONS, REASONS FOR CAUTION: Main limitations are the cross-sectional design of our study and the relatively small sample size of the subgroups. Additional limitations are the lack of a control group of normal fertile men and the lack of follow-up testing to check the clearance or the persistence of HPV in semen after a 6-12 months. WIDER IMPLICATIONS OF THE FINDINGS: Overall, these observations point out the importance of an accurate investigation of seminal HPV presence in everyday clinical practice in the diagnostic work-up of infertile men. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used. There are no competing interests. PMID- 30517658 TI - Spinal Pleomorphic Xanthoastrocytoma With a QKI-RAF1 Fusion. AB - Pleomorphic xanthoastrocytoma (PXA) is a slow-growing neoplasm that predominantly affects the pediatric and young adult population. This neoplasm has a good prognosis, with a median 10-year survival rate of 70%. The majority of tumors are supratentorial and arise in the temporal lobe, while spinal tumors are extremely rare, with only 8 reported cases. Molecular perturbations involving the MAPK/ERK signaling pathway have been described in PXAs. The most common mutation is BRAF V600E in 60%-80% of cases. Other mechanisms activating this pathway in the absence of this mutation are rare and include CRAF (RAF1) fusion genes. We report a PXA case in the cervical spinal cord of a 49-year-old man with slowly progressive coordination difficulties and extremity numbness. The tumor was negative for the V600E mutation, but 2 RNA sequencing platforms detected a QKI RAF1 fusion (t(6; 3)(q26; p25)), which has not been previously reported in PXAs. This fusion is known to activate MAPK/ERK and PI3K/mTOR signaling. Although first and second-generation RAF inhibitors are predicted to be ineffective, this fusion may be targetable by the novel RAF inhibitor LY3009120 and to some extent by the MEK inhibitor trametinib. Genetic analysis to screen for MAPK/ERK pathway mutations is warranted on PXAs negative for the V600E mutation. PMID- 30517659 TI - Tracking quality: can embryology key performance indicators be used to identify clinically relevant shifts in pregnancy rate? AB - STUDY QUESTION: Can embryology key performance indicators (KPIs) detect shifts in laboratory performance that precede changes in clinical outcomes? SUMMARY ANSWER: Day 5 usable blastocyst rate (D5BUR) is an important embryology KPI that complements total usable blastocyst rate (TBUR) in its ability to rapidly identify adverse embryology outcomes, prior to changes in clinical outcomes. WHAT IS KNOWN ALREADY: The hypothesis that monitoring performance of an IVF laboratory using statistical process controls (SPCs) can act as an early warning signal of shifts in laboratory conditions is a hypothesis that requires validation. The Vienna consensus report recently defined KPIs for monitoring fresh IVF and ICSI cycles, but the effectiveness of using these KPIs for detecting clinically relevant shifts following changes in laboratory processes is unknown. STUDY DESIGN, SIZE, DURATION: A retrospective, multicentre, analysis of KPIs for 1971 fresh IVF and ICSI cycles during three consecutive 5-month periods (P1, P2 and P3) during which the culture medium was changed in the middle period. PARTICIPANTS/MATERIALS, SETTING, METHODS: ICSI fertilisation rate, IVF fertilisation rate, D5BUR, TBUR and clinical pregnancy rate (CPR) were tracked monthly and analysed for SPC using Shewhart control charts. Out-of-control KPIs were identified by warning (2-sigma) and control (3-sigma) limits. The effect of the laboratory culture medium change on embryology KPIs and cumulative CPR was investigated using a one-way ANOVA or Pearson Chi-squared test and logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: D5BUR decreased from 32 to 25% after the culture medium was changed, and the decrease was detected within 1 week after the change (P < 0.0001). D5BUR subsequently increased after a change back to the original medium. A decrease in CPR (51-36%) after the medium change was also observed but was not detected until 3 months after the shift in D5BUR (P = 0.0005). Overall, the change in culture medium independently influenced D5BUR, CPR and cumulative CPR. Importantly, TBUR (41%) was not affected by the change in culture medium, remaining within control limits for all three culture periods, indicating that the overall blastocyst rate alone may not sufficiently monitor embryology laboratory performance. LIMITATIONS REASONS FOR CAUTION: The statistical KPI monitoring system demonstrated by the current study may be less effective at identifying KPI shifts in smaller clinics with lower cycle volumes. Live-birth rate per cycle started was not included as a clinical KPI. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates that statistical KPI monitoring systems have the potential to provide systematic, early detection of adverse outcomes in ART laboratories after planned or unexpected shifts in conditions. STUDY FUNDING/COMPETING INTEREST(S): No external funds were used for the study. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30517660 TI - Prevalence and predictors of tobacco smoking among university students in Sylhet Division, Bangladesh. AB - Background: Among university students, large numbers are involved with smoking and suffer from many chronic diseases. This study examined tobacco smoking prevalence and potential predictors among university students in Sylhet Division, Bangladesh. Methods: A total of 416 students were selected for face-to-face interviews. Logistic regression analysis was used to fulfil the specific objectives of the study. Results: It was discovered that the prevalence of smoking among university students in Sylhet Division was 37% and almost half of current male students were smokers. Mother's occupation and peer smoking status were found to be significant factors. Although data were collected using multistage sampling, the stages (type of university, universities, departments and academic levels) were insignificant with smoking status. There is a 2.1 times greater likelihood of a student becoming a smoker if a close friend is a smoker. The adjusted living expenses (>$100) was a proactive factor, though individually it was a significant factor. Conclusions: This study and previous studies found that smoking initiation among female students is negligible, so gender-specific health promotion and intervention is needed in Bangladesh. Tobacco control awareness programs and 'No smoking' signage should be displayed within university campuses and sanctioned by university authorities. PMID- 30517661 TI - Age at onset of metabolic syndrome among women with and without polycystic ovary syndrome-like status. AB - Context: Women with polycystic ovary syndrome (PCOS) have a higher prevalence of metabolic syndrome (MetS), but whether they develop MetS earlier than women without PCOS is unknown. Understanding the impact of PCOS on the timing of MetS onset is important for screening and clinical care in this population. Design: Women with PCOS-like status ("PCOSp") were identified from participants of the Michigan Bone Health and Metabolism Study based upon history of irregular menstrual cycles, high free-androgen index and high levels of anti-mullerian hormone. MetS was defined according to the Adult Treatment Panel III criteria. Age at MetS onset was compared between women with and without PCOSp using an accelerated failure time model adjusted for baseline education, lifestyle factors and midlife body weight. Results: Among the 496 women in the analysis, 11.7% (n=58) were determined to have PCOSp. Over a mean follow-up of 11 years, 20 women with PCOSp and 136 women without PCOSp developed MetS. After adjusting for smoking, education and physical activity, women with PCOSp developed MetS at an age 14.4% (95% confidence interval (CI) -22.7, -5.2) younger than women without PCOSp. The magnitude of the association was attenuated to 5.4% in models additionally adjusted for BMI (95% CI -12.4, 2.1). Since a typical study participant without PCOSp developed MetS at 51.5, 5.4% translates to almost three years earlier onset of MetS for a comparable woman with PCOSp. Conclusions: Women with PCOSp develop MetS at a younger age. Earlier screening for MetS in women with PCOS may be warranted. PMID- 30517662 TI - Growth and Reproductive Performance of Rangeland Beef-Cattle as Influenced by Controlled and Uncontrolled Populations of Horn Flies (Diptera: Muscidae). AB - A 4-yr study was conducted on native rangeland to assess the growth and reproductive performance of cows (Bos taurus) infested with naturally occurring seasonal populations of horn flies (Haematobia irritans). One hundred five Angus * Hereford cow-calf pairs were evaluated as a randomized complete block that was replicated across 4 yr. Cows were approximately 39 d postpartum at the beginning of each yearly trial and were randomly allocated to either an untreated control (UTC) or an insecticide-treated (TRT) herd. Horn fly populations were monitored throughout each yearly replication and blood serum progesterone levels were used to estimate postpartum interval lengths and days to pregnancy. Initial body weights of cows were collected in May with final body weights and calf weaning weights acquired in October of each year. Monthly horn fly control ranged from 85.55 to 99.57% throughout the 4 yr. Cows within UTC herds maintained on average 530.10 +/- 94.74 more (P = 0.0015) flies per animal than TRT. However, no differences were detected between treatment groups for any of the reproductive parameters evaluated (P > 0.05). Despite a lack of difference in the reproductive parameters measured, TRT cows gained more (P = 0.0492) weight throughout the fly seasons when compared to UTC cattle. Furthermore, calves paired with insecticide treated cows tended (P = 0.0680) to wean 16.28 +/- 8.04 kg heavier than calves paired with cows exposed to naturally occurring horn fly populations. PMID- 30517663 TI - Physician stress and burnout: the impact of health information technology. AB - Objective: To quantify how stress related to use of health information technology (HIT) predicts burnout among physicians. Methods: All 4197 practicing physicians in Rhode Island were surveyed in 2017 on their HIT use. Our main outcome was self reported burnout. The presence of HIT-related stress was defined by report of at least 1 of the following: poor/marginal time for documentation, moderately high/excessive time spent on the electronic health record (EHR) at home, and agreement that using an EHR adds to daily frustration. We used logistic regression to assess the association between each HIT-related stress measure and burnout, adjusting for respondent demographics, practice characteristics, and the other stress measures. Results: Of the 1792 physician respondents (43% response rate), 26% reported burnout. Among EHR users (91%), 70% reported HIT-related stress, with the highest prevalence in primary care-oriented specialties. After adjustment, physicians reporting poor/marginal time for documentation had 2.8 times the odds of burnout (95% CI: 2.0-4.1; P < .0001), compared to those reporting sufficient time. Physicians reporting moderately high/excessive time on EHRs at home had 1.9 times the odds of burnout (95% CI: 1.4-2.8; P < .0001), compared to those with minimal/no EHR use at home. Those who agreed that EHRs add to their daily frustration had 2.4 times the odds of burnout (95% CI: 1.6-3.7; P < .0001), compared to those who disagreed. Conclusion: HIT-related stress is measurable, common (about 70% among respondents), specialty-related, and independently predictive of burnout symptoms. Identifying HIT-specific factors associated with burnout may guide healthcare organizations seeking to measure and remediate burnout among their physicians and staff. PMID- 30517664 TI - The Unreasonable Effectiveness of Convolutional Neural Networks in Population Genetic Inference. AB - Population-scale genomic datasets have given researchers incredible amounts of information from which to infer evolutionary histories. Concomitant with this flood of data, theoretical and methodological advances have sought to extract information from genomic sequences to infer demographic events such as population size changes and gene flow among closely related populations/species, construct recombination maps, and uncover loci underlying recent adaptation. To date most methods make use of only one or a few summaries of the input sequences and therefore ignore potentially useful information encoded in the data. The most sophisticated of these approaches involve likelihood calculations, which require theoretical advances for each new problem, and often focus on a single aspect of the data (e.g. only allele frequency information) in the interest of mathematical and computational tractability. Directly interrogating the entirety of the input sequence data in a likelihood-free manner would thus offer a fruitful alternative. Here we accomplish this by representing DNA sequence alignments as images and using a class of deep learning methods called convolutional neural networks (CNNs) to make population genetic inferences from these images. We apply CNNs to a number of evolutionary questions and find that they frequently match or exceed the accuracy of current methods. Importantly, we show that CNNs perform accurate evolutionary model selection and parameter estimation, even on problems that have not received detailed theoretical treatments. Thus, when applied to population genetic alignments, CNN are capable of outperforming expert-derived statistical methods, and offer a new path forward in cases where no likelihood approach exists. PMID- 30517665 TI - Association of phthalates, parabens and phenols found in personal care products with pubertal timing in girls and boys. AB - STUDY QUESTION: Are in-utero or peripubertal exposures to phthalates, parabens and other phenols found in personal care products associated with timing of pubertal onset in boys and girls? SUMMARY ANSWER: We found some associations of altered pubertal timing in girls, but little evidence in boys. WHAT IS KNOWN ALREADY: Certain chemicals in personal care and consumer products, including low molecular weight phthalates, parabens and phenols, or their precursors, are associated with altered pubertal timing in animal studies. STUDY DESIGN, SIZE, DURATION: Data were from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study which followed 338 children in the Salinas Valley, California, from before birth to adolescence. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnant women were enrolled in 1999 2000. Mothers were mostly Latina, living below the federal poverty threshold and without a high school diploma. We measured concentrations of three phthalate metabolites (monoethyl phthalate [MEP], mono-n-butyl phthalate and mono-isobutyl phthalate), methyl and propyl paraben and four other phenols (triclosan, benzophenone-3 and 2,4- and 2,5-dichlorophenol) in urine collected from mothers during pregnancy and from children at age 9. Pubertal timing was assessed among 179 girls and 159 boys every 9 months between ages 9 and 13 using clinical Tanner staging. Accelerated failure time models were used to obtain mean shifts of pubertal timing associated with concentrations of prenatal and peripubertal biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: In girls, we observed earlier onset of pubic hair development with prenatal urinary MEP concentrations and earlier menarche with prenatal triclosan and 2,4-dichlorophenol concentrations. Regarding peripubertal biomarkers, we observed: earlier breast development, pubic hair development and menarche with methyl paraben; earlier menarche with propyl paraben; and later pubic hair development with 2,5-dichlorophenol. In boys, we observed no associations with prenatal urinary biomarker concentrations and only one association with peripubertal concentrations: earlier genital development with propyl paraben. LIMITATIONS, REASONS FOR CAUTION: These chemicals are quickly metabolized and one to two urinary measurements per developmental point may not accurately reflect usual exposure. Associations of peripubertal measurements with parabens may reflect reverse causality: children going through puberty early may be more likely to use personal care products. The study population was limited to Latino children of low socioeconomic status living in a farmworker community and may not be widely generalizable. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to a growing literature that suggests that exposure to certain endocrine disrupting chemicals may impact timing of puberty in children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Institute of Environmental Health Sciences and the US Environmental Protection Agency. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 30517666 TI - Emergence and rapid global dissemination of CTX-M-15-associated Klebsiella pneumoniae strain ST307. AB - Objectives: Recent reports indicate the emergence of a new carbapenemase producing Klebsiella pneumoniae clone, ST307. We sought to better understand the global epidemiology and evolution of this clone and evaluate its association with antimicrobial resistance (AMR) genes. Methods: We collated information from the literature and public databases and performed a comparative analysis of 95 ST307 genomes (including 37 that were newly sequenced). Results: We show that ST307 emerged in the mid-1990s (nearly 20 years prior to its first report), is already globally distributed and is intimately associated with a conserved plasmid harbouring the blaCTX-M-15 ESBL gene and several other AMR determinants. Conclusions: Our findings support the need for enhanced surveillance of this widespread ESBL clone in which carbapenem resistance has occasionally emerged. PMID- 30517667 TI - Sulfur Dioxide Fumigation for Postharvest Control of Mealybugs on Harvested Table Grapes. AB - Laboratory fumigations with sulfur dioxide (SO2) were conducted under ultralow oxygen (ULO) and normal atmosphere to determine their effects on mortality of grape mealybug, Pseudococcus maritimus (Ehrhorn), and vine mealybug, Planococcus ficus Signoret, and postharvest quality of table grapes. Three- and 4-d fumigation treatments with 100 ppm SO2 under 30 ppm ULO condition and normal atmosphere resulted in 100% mortality of eggs and nymphs/adults of vine mealybug. The 3- and 4-d SO2 fumigations under the ULO condition and the normal atmosphere were also effective against grape mealybug with egg mortalities of 85.8% and 98.8% and nymph/adult mortalities of 99.0% and 100%, respectively. There was no significant difference between SO2 fumigations under ULO and the normal atmosphere in insect mortality. One-day fumigation treatments with 400 and 500 ppm SO2 achieved 89.8% and 95.8% mortality of grape mealybug eggs, respectively, and achieved 100% mortality of grape mealybug nymphs and adults. None of the treatments used in this study adversely affected quality of the six table grape cultivars used in the studies. SO2 fumigation under either ULO or normal atmosphere is potentially a useful means for postharvest control of mealybugs on harvested table grapes. PMID- 30517668 TI - SOX2 in Cancer Stemness: Tumor Malignancy and Therapeutic Potentials. AB - Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition (EMT), ATP-binding cassette (ABC) drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC specific anticancer strategies. PMID- 30517669 TI - Illness Perception in Inflammatory Bowel Disease Patients is Different Between Patients With Active Disease or in Remission: A Prospective Cohort Study. AB - Background: Inflammatory bowel diseases [IBD] are characterised by significant quality of life [QoL] impairment, as well as illness perception. Assessing illness perception may help in optimising the management of IBD patients. Methods: In this single-centre, observational, transversal study, consecutive adult IBD patients were enrolled and stratified according to disease activity [active/remission]. The Revised Illness Perception Questionnaire [IPQ-R], based on identity, opinions, and causes of their disease was administered to all patients. Comparison within IPQ-R parameters was done between clinically active patients and those in remission. Results: A total of 201 patients were enrolled (Crohn's disease [CD] = 47%). The most frequently reported IBD-related symptoms were fatigue [86.9%], loss of strength [83.3%], pain [80%], and weight loss [68.2%]. Active patients reported significantly more frequently fatigue [p = 0.005], sore eyes [p = 0.046], and sleep difficulties [p = 0.001], and reported more symptoms than controls [p = 0.023]. Overall, the patients considered stress [84.1%], altered immunity [69.32%], family problems [49.4%], and emotional status [40.9%] as the main causes of IBD. Work overload was more frequently considered as a disease cause in active patients than in those in remission [p = 0.002]. Smoking, family history, and previous inadequate therapies were considered as a relevant risk factor for illness by only 20% of patients. Active IBD patients had more negative thoughts on prognosis [p = 0.001] and more negative emotions [p < 0.0001]. Patients in remission were significantly more convinced about treatment control [p = 0.007] and had clearer understanding of illness [p = 0.009]. Conclusions: Illness perception is impaired in IBD patients. Adequate educational and psychological support may be helpful in the optimal management of IBD patients. PMID- 30517672 TI - Malaria Modeling to Evaluate Treatment for Severe Disease. PMID- 30517670 TI - Association of estimated sleep duration and naps with mortality and cardiovascular events: a study of 116 632 people from 21 countries. AB - Aims: To investigate the association of estimated total daily sleep duration and daytime nap duration with deaths and major cardiovascular events. Methods and results: We estimated the durations of total daily sleep and daytime naps based on the amount of time in bed and self-reported napping time and examined the associations between them and the composite outcome of deaths and major cardiovascular events in 116 632 participants from seven regions. After a median follow-up of 7.8 years, we recorded 4381 deaths and 4365 major cardiovascular events. It showed both shorter (<=6 h/day) and longer (>8 h/day) estimated total sleep durations were associated with an increased risk of the composite outcome when adjusted for age and sex. After adjustment for demographic characteristics, lifestyle behaviours and health status, a J-shaped association was observed. Compared with sleeping 6-8 h/day, those who slept <=6 h/day had a non-significant trend for increased risk of the composite outcome [hazard ratio (HR), 1.09; 95% confidence interval, 0.99-1.20]. As estimated sleep duration increased, we also noticed a significant trend for a greater risk of the composite outcome [HR of 1.05 (0.99-1.12), 1.17 (1.09-1.25), and 1.41 (1.30-1.53) for 8-9 h/day, 9-10 h/day, and >10 h/day, Ptrend < 0.0001, respectively]. The results were similar for each of all-cause mortality and major cardiovascular events. Daytime nap duration was associated with an increased risk of the composite events in those with over 6 h of nocturnal sleep duration, but not in shorter nocturnal sleepers (<=6 h). Conclusion: Estimated total sleep duration of 6-8 h per day is associated with the lowest risk of deaths and major cardiovascular events. Daytime napping is associated with increased risks of major cardiovascular events and deaths in those with >6 h of nighttime sleep but not in those sleeping <=6 h/night. PMID- 30517673 TI - Inertial Sensor-Based Assessment of Central Sensory Integration for Balance After Mild Traumatic Brain Injury: Corrigendum. PMID- 30517671 TI - Persistence of Lassa Virus Associated With Severe Systemic Arteritis in Convalescing Guinea Pigs (Cavia porcellus). AB - Lassa fever (LF) survivors develop various clinical manifestations including polyserositis, myalgia, epididymitis, and hearing loss weeks to months after recovery from acute infection. We demonstrate a systemic lymphoplasmacytic and histiocytic arteritis and periarteritis in guinea pigs more than 2 months after recovery from acute Lassa virus (LASV) infection. LASV was detected in the arterial tunica media smooth muscle cells by immunohistochemistry, in situ hybridization, and transmission electron microscopy. Our results suggest that the sequelae of LASV infection may be due to virus persistence resulting in systemic vascular damage. These findings shed light on the pathogenesis of LASV sequelae in convalescent human survivors. PMID- 30517674 TI - Single-nucleotide-resolution mapping of DNA gyrase cleavage sites across the Escherichia coli genome. AB - An important antibiotic target, DNA gyrase is an essential bacterial enzyme that introduces negative supercoils into DNA and relaxes positive supercoils accumulating in front of moving DNA and RNA polymerases. By altering the superhelical density, gyrase may regulate expression of bacterial genes. The information about how gyrase is distributed along genomic DNA and whether its distribution is affected by drugs is scarce. During catalysis, gyrase cleaves both DNA strands forming a covalently bound intermediate. By exploiting the ability of several topoisomerase poisons to stabilize this intermediate we developed a ChIP-Seq-based approach to locate, with single nucleotide resolution, DNA gyrase cleavage sites (GCSs) throughout the Escherichia coli genome. We identified an extended gyrase binding motif with phased 10-bp G/C content variation, indicating that bending ability of DNA contributes to gyrase binding. We also found that GCSs are enriched in extended regions located downstream of highly transcribed operons. Transcription inhibition leads to redistribution of gyrase suggesting that the enrichment is functionally significant. Our method can be applied for precise mapping of prokaryotic and eukaryotic type II topoisomerases cleavage sites in a variety of organisms and paves the way for future studies of various topoisomerase inhibitors. PMID- 30517675 TI - Return to Duty Following Open Reduction and Internal Fixation of Unstable Ankle Fractures in the Active Duty Population. AB - Introduction: Literature on functional outcomes after ankle surgery is for the most part limited to return to sport studies. The purpose of this study was to determine occupational and functional outcomes following operative treatment of unstable ankle fractures in the active duty military population. Materials and Methods: All ankle fractures treated with open reduction internal fixation at a single institution from 2013 to 2015 were reviewed. Inclusion criteria included active duty personnel with a single-sided injury requiring operative management. All patients had a minimum of 6 months follow-up. Forty-seven records were reviewed with 43 patients fitting these criteria. Patients were predominantly male (91%) with an average age of 26 years at the time of fracture. Functional outcomes were evaluated using AOFAS and SANE scores. Occupational outcomes were determined in reference to a service member's ability to return to full duty. Results: Of the 43 subjects, 81% (n = 35) returned to active duty. Of the eight individuals who did not return to active duty, six were medically boarded out of the military. Looking at demographic, surgical, and functional variables, only the SANE and AFAOS scores functional outcomes showed a significant correlation with individual return to duty. Individuals who reported less pain and increased functional outcomes had increased return to duty rates. Conclusion: This study sought to determine predictors for return to duty within an active duty military population after ORIF of unstable ankle fractures. Given the paucity of military literature on this subject, the end goal was to provide realistic recovery expectations for both injured service members and their command teams. Overall, 81% of patients were able to return to active duty following operative treatment of unstable ankle fractures. There were no associations found between age, gender, military rank, or fracture patterns and return to duty. PMID- 30517676 TI - Adipose tissue exosomal proteomic profile reveals a role on placenta glucose metabolism in gestational diabetes mellitus. AB - Context: Molecules produced by adipose tissue (AT) function as an endocrine link between maternal AT and fetal growth by regulating placental function in normal and gestational diabetes mellitus (GDM). Objective: We hypothesised that AT derived exosomes from women with GDM carry a specific set of proteins that influences glucose metabolism in placenta. Design: Exosomes were isolated from omental AT-conditioned media from pregnant women with normal glucose tolerance (exo-NGT, n=65) and women with GDM (exo-GDM, n=82). SWATH mass spectrometry (MS) was used to construct a small ion library from AT and exosomal proteins followed by ingenuity pathway analysis (IPA) to determine canonical pathways and biofunctions. The effect of exosomes on human placental cells was determined using a Human Glucose Metabolism RT2 Profiler PCR Array. Results: The number of exosomes (vesicles/MUg-tissue/24h) was significantly (1.7-fold) higher in GDM compared to NGT, and the number of exosomes positively correlated with birthweight Z score. IPA of the exosomal proteins revealed differential expression of the proteins targeting sirtuin (sirt) signalling pathway, oxidative phosphorylation (OXPHOS) and mechanistic target of rapamycin (mTOR) signalling pathways in GDM compared to NGT. Exo-GDM increased the expression of genes associated with glycolysis and gluconeogenesis in placental cells compared to the effect of exo-NGT. Conclusions: Our findings are consistent with the possibility that AT exosomes play an important role in mediating the changes in placental function in GDM, which may be responsible for some of the adverse consequences in this pregnancy complication, such as fetal overgrowth. PMID- 30517677 TI - BMI change during puberty is an important determinant of adult type 2 diabetes risk in men. AB - Objective: The aim of this study was to determine the role of change in body mass index (BMI) during puberty, independent of childhood overweight, for the risk of adult type 2 diabetes in men. Study design, population and outcome: We included 36,176 men who had weight and height measured at age 8 (childhood) and 20 (young adult age) available from the BMI Epidemiology Study (BEST) and the Conscription register. Information on type 2 diabetes (n=1,777) was retrieved from the Swedish National Patient Register. Hazard ratios and 95% Confidence Intervals were estimated by Cox regressions including birth year and country of birth as covariates. Because the assumption of proportional hazards was violated for the association between BMI change during puberty and type 2 diabetes, we split the follow-up time into early (<=55.7 years) and late (>55.7 years). Results: Both childhood overweight and a high BMI increase during puberty associated with risk of adult type 2 diabetes. Men with childhood overweight that normalized during puberty did not have a significantly increased risk of type 2 diabetes (Early type 2 diabetes 1.28[0.89; 1.82]; Late type 2 diabetes 1.35[0.97; 1.87]). Men who developed overweight during puberty (Early 4.67[3.90; 5.58]; Late 2.85[2.25; 3.61]) and men overweight at both childhood and young adult age (Early 4.82[3.84; 6.05]; Late 3.04[2.27; 4.06]) had substantially increased risk of type 2 diabetes compared with men who were never overweight. Conclusion: BMI change during puberty is an important, and childhood BMI a modest, independent determinant of adult type 2 diabetes risk in men. PMID- 30517678 TI - What was the fate of human embryos following long-term cryopreservation (>=12 years) and frozen embryo transfer? AB - STUDY QUESTION: Do human embryos survive long-term cryopreservation (CP) (>=12 years) and implant after frozen embryo transfer (ET)? SUMMARY ANSWER: Human embryos remain usable after long-term CP. WHAT IS KNOWN ALREADY: Several cohort studies have reported the live birth rate or neonatal outcomes of human embryos after CP for up to 5 years. Only a few case reports have described successful live births from human embryos after long-term CP up to 12 years. STUDY DESIGN, SIZE, DURATION: This retrospective observational study in China included 20 patients (128 embryos) from March 2016 to April 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty patients who had at least one live birth during their previous IVF/ICSI treatments and had surplus embryos cryopreserved were observed. Data concerning frozen embryo recovery, pregnancy and obstetric outcomes following frozen ET were recorded. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 128 embryos of 20 patients were observed. The embryo storage duration was 12.0 17.1 years, with a mean of 13.9 +/- 1.73 years. In all, 115 embryos were thawed to transfer, with a survival rate of 74%. Sixty embryos were further cultured, which resulted in 20 blastocysts with a blastocyst formation rate of 33%. There were 21 cleavage-stage embryos and 13 blastocysts transferred in a total of 12 and 11 cycles, respectively, which resulted in one biochemical pregnancy, one first trimester miscarriage, two ectopic pregnancies, three singletons and one case of twins, with a clinical pregnancy rate of 25% (D3 ET) and 36% (blastocyst transfer) and a live birth rate of 17% (D3 ET) and 27% (blastocyst transfer). Two of the four patients who had live birth developed gestational diabetes mellitus. One of the five live births was a preterm delivery. LIMITATIONS, REASONS FOR CAUTION: The sample size was small due to the unique study population, and all the embryos underwent slow freezing. The fate of long-term cryopreserved embryos after vitrification is still unclear. WIDER IMPLICATIONS OF THE FINDINGS: The results provide evidence to support the use of embryos after extended CP to preserve patients' fertility. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the National Key Research and Development Programme of China (2016YC1000205) and the Guangzhou Scientific Programme (201508020006). None of the authors has any conflicts of interest to declare. PMID- 30517680 TI - SLiM 3: Forward genetic simulations beyond the Wright-Fisher model. AB - With the desire to model population genetic processes under increasingly realistic scenarios, forward genetic simulations have become a critical part of the toolbox of modern evolutionary biology. The SLiM forward genetic simulation framework is one of the most powerful and widely used tools in this area. However, its foundation in the Wright-Fisher model has been found to pose an obstacle to implementing many types of models; it is difficult to adapt the Wright-Fisher model, with its many assumptions, to modeling ecologically realistic scenarios such as explicit space, overlapping generations, individual variation in reproduction, density-dependent population regulation, individual variation in dispersal or migration, local extinction and recolonization, mating between subpopulations, age structure, fitness-based survival and hard selection, emergent sex ratios, and so forth. In response to this need, we here introduce SLiM 3, which contains two key advancements aimed at abolishing these limitations. First, the new non-Wright-Fisher or "nonWF" model type provides a much more flexible foundation that allows the easy implementation of all of the above scenarios and many more. Second, SLiM 3 adds support for continuous space, including spatial interactions and spatial maps of environmental variables. We provide a conceptual overview of these new features, and present several example models to illustrate their use. PMID- 30517679 TI - Disseminating a Smoke Free Homes program to low SES households in the US through 2-1-1: Results of a national impact evaluation. AB - Introduction: Given homes are now a primary source of secondhand smoke exposure (SHS) in the US, research-tested interventions that promote smoke-free homes should be evaluated in real-world settings to build the evidence-base for dissemination. This study describes outcome evaluation results from a dissemination and implementation study of a research-tested program to increase smoke-free home rules through US 2-1-1 helplines. Methods: Five 2-1-1 organizations, chosen through a competitive application process, were awarded grants of up to $70,000. 2-1-1 staff recruited participants, delivered the intervention, and evaluated the program. 2-1-1 clients who were recruited into the program allowed smoking in the home, lived in households with both a smoker and a nonsmoker or child, spoke English, and were at least 18 years old. Self reported outcomes were assessed using a pre-post design, with follow-up at two months post baseline. Results: 2,345 households (335 to 605 per 2-1-1 center) were enrolled by 2-1-1 staff. Most participants were female (82%), smokers (76%), and half were African American (54%). Overall, 40.1% (n=940) reported creating a full household smoking ban. Among the nonsmoking adults reached at follow-up (n=389), days of SHS exposure in the past week decreased from 4.9 (SD=2.52) to 1.2 (SD=2.20). Among the 1,148 smokers reached for follow-up, 211 people quit, an absolute reduction in smoking of 18.4% (p<0.0001), with no differences by gender. Conclusions: Among those reached for two-month follow-up, the proportion who reported establishing a smoke-free home was comparable to or higher than smoke free home rates in the prior controlled research studies. Implications: Dissemination of this brief research-tested intervention via a national grants program with support from university staff to five 2-1-1 centers increased home smoking bans, decreased secondhand smoke exposure, and increased cessation rates. While the program delivery capacity demonstrated by these competitively-selected 2-1-1s may not generalize to the broader 2-1-1 network in the US, or social service agencies outside of the US, partnering with 2-1-1s may be a promising avenue for large scale dissemination of this smoke-free homes program and other public health programs to low SES populations in the US. PMID- 30517681 TI - Serum Cystatin C Levels in Twin Pregnancy versus Singleton Pregnancy. AB - Objective: To explore whether there was an increased secretion of cystatin C (Cys C) in twin pregnancy. Methods: Patients with a total of 281 singleton pregnancies (including 38 patients with preeclampsia) and 72 twin pregnancies, as well as 42 patients who were not pregnant, were included in this study. We tested levels of serum Cys C, creatinine, and uric acid, along with the estimated glomerular filtration rate (eGFR), in different groups. Results: The levels of serum Cys C in all 3 trimesters for women with twin pregnancy were much higher than those in the corresponding trimesters for women with singleton pregnancy. However, we observed little change in eGFR in the corresponding trimesters. Cys C/eGFR in the second and third trimester of twin pregnancy increased, compared with the corresponding trimesters of women with singleton pregnancy. Levels of serum Cys C were higher in the third trimester in women with twin pregnancy than that in patients with preeclampsia. Also, Cys C/eGFR in the third trimester of twin pregnancy was close to the level observed in patients with preeclampsia. Conclusions: Increased secretion of Cys C could contribute to the elevated serum Cys C levels that we observed in twin pregnancy. PMID- 30517682 TI - A light-responsive RNA aptamer for an azobenzene derivative. AB - Regulation of complex biological networks has proven to be a key bottleneck in synthetic biology. Interactions between the structurally flexible RNA and various other molecules in the form of riboswitches have shown a high-regulation specificity and efficiency and synthetic riboswitches have filled the toolbox of devices in many synthetic biology applications. Here we report the development of a novel, small molecule binding RNA aptamer, whose binding is dependent on light induced change of conformation of its small molecule ligand. As ligand we chose an azobenzene because of its reliable photoswitchability and modified it with chloramphenicol for a better interaction with RNA. The synthesis of the ligand 'azoCm' was followed by extensive biophysical analysis regarding its stability and photoswitchability. RNA aptamers were identified after several cycles of in vitro selection and then studied regarding their binding specificity and affinity toward the ligand. We show the successful development of an RNA aptamer that selectively binds to only the trans photoisomer of azoCm with a KD of 545 nM. As the aptamer cannot bind to the irradiated ligand (lambda = 365 nm), a light selective RNA binding system is provided. Further studies may now result in the engineering of a reliable, light-responsible riboswitch. PMID- 30517683 TI - Response to the Letter by Weisman et al on: Twenty Thousand Needles Under the Sea: Trigger Point Dry Needling Aboard an Israeli Navy Submarine. A Case Report. PMID- 30517684 TI - Borrelia parkeri in Ornithodoros parkeri (Ixodida: Argasidae) Collected Using Compact Dry Ice Traps in Madera County, California. AB - Tick-borne relapsing fever (TBRF) is a potentially serious vector-borne disease endemic to the western United States. Vector surveillance is compromised by the nidicolous life history of the three Ornithodoros species that transmit TBRF to people in this region. Large-scale stationary trapping methods were developed to survey a wide geographical range of Ornithodoros spp. which are known to vector relapsing fever Borrelia spp. in California. Ninety-six Ornithodoros parkeri were collected from four locations in the foothills of Fresno and Madera Counties. Two of these O. parkeri nymphs were PCR positive for Borrelia parkeri, and their collection at a popular recreation site increases the public health concern. PMID- 30517685 TI - RNA-DNA fibers and polygons with controlled immunorecognition activate RNAi, FRET and transcriptional regulation of NF-kappaB in human cells. AB - Nucleic acid-based assemblies that interact with each other and further communicate with the cellular machinery in a controlled manner represent a new class of reconfigurable materials that can overcome limitations of traditional biochemical approaches and improve the potential therapeutic utility of nucleic acids. This notion enables the development of novel biocompatible 'smart' devices and biosensors with precisely controlled physicochemical and biological properties. We extend this novel concept by designing RNA-DNA fibers and polygons that are able to cooperate in different human cell lines and that have defined immunostimulatory properties confirmed by ex vivo experiments. The mutual intracellular interaction of constructs results in the release of a large number of different siRNAs while giving a fluorescent response and activating NF-kappaB decoy DNA oligonucleotides. This work expands the possibilities of nucleic acid technologies by (i) introducing very simple design principles and assembly protocols; (ii) potentially allowing for a simultaneous release of various siRNAs together with functional DNA sequences and (iii) providing controlled rates of reassociation, stabilities in human blood serum, and immunorecognition. PMID- 30517686 TI - SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency. AB - Context: Multiple autosomal recessive genes have been etiologically linked to Primary Adrenal Insufficiency (PAI). Recently, SGPL1 gene mutations were recognized as causes of steroid-resistant nephrotic syndrome type 14 (NPHS14), a sphingolipidosis with multisystemic manifestations including PAI. Interestingly, this is the only monogenetic form of nephrotic syndrome (NS) and the sole sphingolipidosis causing adrenal disease. Objective: To understand if SGPL1 mutations are involved in the pathogenesis of PAI in patients who do not exhibit NS. Methods: Sequencing of the SGPL1 gene in 21 patients with familial glucocorticoid disease or triple A syndrome. Results: We identified two missense SGPL1 variants in four patients, two being first-cousins. We describe in detail the proband, a boy born to Saudi Arabian consanguineous parents with a homozygous c.665G>A, p.R222Q SGPL1 variant. The patient presented with hypoglycemia and seizures at age two years and was ultimately diagnosed with PAI (isolated glucocorticoid deficiency). A brain MRI showed abnormalities in the basal ganglia consistent with a degenerative process albeit the patient had no neurological symptoms. Conclusions: New genetic causes of PAI continue to be identified. We suggest that screening for SGPL1 mutations should not be reserved only for patients with nephrotic syndrome but may also include patients with PAI that lack other clinical manifestations of NPHS14 since, in certain cases, kidney disease and accompanying features might develop later on. Timely diagnosis of this specific sphingolipidosis, while the kidneys still function normally, can lead to prompt initiation of therapy and improve outcome especially, if a targeted NPHS14 treatment is available in the future. PMID- 30517687 TI - TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity. AB - The microtubule cytoskeleton supports diverse cellular morphogenesis and migration processes during brain development. Mutations in tubulin genes are associated with severe human brain malformations known as 'tubulinopathies'; however, it is not understood how molecular-level changes in microtubule subunits lead to brain malformations. In this study, we demonstrate that missense mutations affecting arginine at position 402 (R402) of TUBA1A alpha-tubulin selectively impair dynein motor activity, and severely and dominantly disrupt cortical neuronal migration. TUBA1A is the most commonly affected tubulin gene in tubulinopathy patients, and mutations altering R402 account for 30% of all reported TUBA1A mutations. We show for the first time that ectopic expression of TUBA1A-R402C and TUBA1A-R402H patient alleles is sufficient to dominantly disrupt cortical neuronal migration in the developing mouse brain, strongly supporting a causal role in the pathology of brain malformation. To isolate the precise molecular impact of R402 mutations, we generated analogous R402C and R402H mutations in budding yeast alpha-tubulin, which exhibit a simplified microtubule cytoskeleton. We find that R402 mutant tubulins assemble into microtubules that support normal kinesin motor activity, but fail to support the activity of dynein motors. Importantly, the level of dynein impairment scales with the expression level of the mutant in the cell, suggesting a 'poisoning' mechanism in which R402 mutant alpha-tubulin acts dominantly by populating microtubules with defective binding sites for dynein. Based on our results, we propose a new model for the molecular pathology of tubulinopathies that may also extend to other tubulin related neuropathies. PMID- 30517688 TI - Errors in estimating usual sodium intake by the Kawasaki formula alter its relationship with mortality: implications for public health. AB - Background: Several cohort studies with inaccurate estimates of sodium reported a J-shaped relationship with mortality. We compared various estimated sodium intakes with that measured by the gold-standard method of multiple non consecutive 24-h urine collections and assessed their relationship with mortality. Methods: We analysed the Trials of Hypertension Prevention follow-up data. Sodium intake was assessed in four ways: (i) average measured (gold standard): mean of three to seven 24-h urinary sodium measurements during the trial periods; (ii) average estimated: mean of three to seven estimated 24-h urinary sodium excretions from sodium concentration of 24-h urine using the Kawasaki formula; (iii) first measured: 24-h urinary sodium measured at the beginning of each trial; (iv) first estimated: 24-h urinary sodium estimated from sodium concentration of the first 24-h urine using the Kawasaki formula. We included 2974 individuals aged 30-54 years with pre-hypertension, not assigned to sodium intervention. Results: During a median follow-up of 24 years, 272 deaths occurred. The average sodium intake measured by the gold-standard method was 3769 +/- 1282 mg/d. The average estimated sodium over-estimated the intake by 1297 mg/d (95% confidence interval: 1267-1326). The average estimated value was systematically biased with over-estimation at lower levels and under-estimation at higher levels. The average measured sodium showed a linear relationship with mortality. The average estimated sodium appeared to show a J-shaped relationship with mortality. The first measured and the first estimated sodium both flattened the relationship. Conclusions: Accurately measured sodium intake showed a linear relationship with mortality. Inaccurately estimated sodium changed the relationship and could explain much of the paradoxical J-shaped findings reported in some cohort studies. PMID- 30517689 TI - High frequency neuronal oscillatory abnormalities in the phospholipase C-beta1 knockout mouse model of schizophrenia. AB - Background: Schizophrenia is a complex neuropsychiatric disorder characterised by psychoses, socioaffective disturbances and cognitive deficits. The phosphodiesterase enzyme phospholipase C-beta1 (PLC-beta1) has been reported to be reduced in post-mortem tissue of schizophrenia patients. Dysregulation of neuronal oscillations, particularly those in the higher frequency range, such as beta (12-30 Hz) and gamma (30-80 Hz), are also associated with this disorder. We investigated the influence of PLC-beta1 gene deletion on cortical oscillatory activity and sensorimotor gating behavior. Methods: Adult PLC-beta1 knock-out (PLC-beta1-/-) and wildtype C57Bl/6J control mice (total n=26) underwent surgical implantation of extradural electrodes to allow electrocorticography (ECoG) recordings. ECoG was recorded during prepulse inhibition (PPI) behavior sessions to measure ongoing and auditory-evoked electrophysiological responses. Mice were also pre-treated with antipsychotic drugs haloperidol (0.25mg/kg), clozapine (2.5mg/kg) and olanzapine (5mg/kg). Results: PLC-beta1-/- mice exhibited reduced PPI, and diminished power and phase synchrony of beta and gamma oscillatory responses to auditory stimuli, as well as elevated ongoing beta oscillations. Reductions in PPI were highly correlated with the power and phase synchrony of evoked oscillations. Clozapine and olanzapine ameliorated the PPI deficit in PLC beta1 -/- mice, but not the electrophysiology abnormalities. Conclusions: PLC beta1 reduction leads to disturbances to beta and gamma oscillatory dynamics, and PPI behavior. The strong relationships between these measures demonstrate the importance of event-related oscillatory activity to sensorimotor gating behavior. However, dissociation of these measures observed in the drug studies suggests that abnormalities in neuronal networks may not necessarily need to be corrected for behavioral improvement. PMID- 30517690 TI - Egg Parasitoids of Dalbulus maidis (Hemiptera: Cicadellidae) Within Maize Agroecosystems and in the Edge Zones of Maize Fields, and on Maize Varieties During the Wet Season in Mexico. AB - Little is known about Dalbulus maidis (DeLong) egg parasitoids within maize fields, in the edge zones that surround these fields, and the parasitism on D. maidis eggs oviposited on different maize varieties. The objectives of the present study were first to understand which egg parasitoid species attack D. maidis eggs within maize fields and in the surrounding edge zones, and second, to compare parasitism on two maize varieties (land race Ancho-pozolero and hybrid Tigre-Asgrow) during the maize-growing wet season. We used maize plants with sentinel eggs to attract the egg parasitoids in two consecutive wet seasons, in 2015 and 2016. In 2015, Anagrus sp. (Hymenoptera: Mymaridae) and Paracentrobia sp. (Hymenoptera: Trichogrammatidae) parasitized D. maidis eggs within the maize field and on its edges. However, much more parasitism was seen within the maize agroecosystem than in the maize edge zones. In 2016, two Mymaridae species, Anagrus columbi Perkins and Anagrus sp, and two Trichogrammatidae genera, Pseudoligosita sp. and Paracentrobia sp., attacked the D. maidis eggs laid on maize hybrids but not those oviposited on the maize land race. Our findings indicate that parasitism of corn leafhopper eggs differs with agroecosystem location and maize varieties. PMID- 30517691 TI - Detection in Italy of a porcine Enterococcus faecium isolate carrying the novel phenicol-oxazolidinone-tetracycline resistance gene poxtA. PMID- 30517692 TI - Simulation Training for Operational Medicine Providers (STOMP): Impact of a Comprehensive Skills-Based Curriculum for Military General Medical Officers. AB - Introduction: A standardized training curriculum designed for general medical officers (GMO) titled Simulation Training for Operational Medicine Providers (STOMP) was recently developed to educate and improve GMOs' procedural skills through directed feedback prior to assuming duties in an operational environment. This study aimed to determine the impact this novel curriculum had on GMOs'confidence levels in 21 core privileges covering eight different subspecialties while stationed at Naval Medical Center Portsmouth (NMCP). Materials and Methods: A cohort study from 2015 to 2017 was designed to address our specific aim to examine if the implementation of the STOMP curriculum increased GMOs' confidence levels. Fifty-seven participants enrolled in the study. The GMO case group completed the STOMP curriculum (n = 22), while the control or GMO self-study group (n = 35) did not complete the curriculum. Six months after starting clinical practice at NMCP, both groups completed an online survey that assessed their confidence level in performing each core privilege using a 5-point Likert scale. Scores were analyzed using a Wilcoxon Mann-Whitney test. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia IRB, protocol number: NMCP.2016.0010. Results: Participants demonstrated a statistically significant increase in self-rated confidence scores (p < 0.05) in nine core privilege skills: punch biopsy, shave biopsy, excisional biopsy, removal of otic foreign body, removal of nasal foreign body, removal of ocular foreign body, tonometry, incision and drainage of a thrombosed hemorrhoid, and reduction of simple closed fractures and dislocations. Conclusions: These findings suggest that a novel and recently developed standardized simulation training curriculum entitled STOMP improves the confidence levels of early career physicians' in several primary care procedural skills and is an ideal adjunct to traditional lecture-based teaching prior to independent practice in a primary care environment. PMID- 30517693 TI - The unique mechanism of functional mitral regurgitation in acute myocardial infarction: a prospective dynamic 4D quantitative echocardiographic study. AB - Aims: Mechanisms of chronic ischaemic mitral regurgitation (IMR) are well characterized by apically tethered leaflet caused by papillary muscles (PMs) displacement and adynamic mitral apparatus. We investigated the unique geometry and dynamics of the mitral apparatus in first acute myocardial infarction (MI) by using quantified 3D echocardiography. Methods and results: We prospectively performed 3D echocardiography 2.3 +/- 1.8 days after first MI, in 174 matched patients with (n = 87) and without IMR (n = 87). 3D echocardiography of left ventricular (LV) volumes and of mitral apparatus dynamics throughout cardiac cycle was quantified. Similar mitral quantification was obtained at chronic post MI stage (n = 44). Mechanistically, acute IMR was associated with larger and flatter annulus (area 9.29 +/- 1.74 cm2 vs. 8.57 +/- 1.94 cm2, P = 0.002, saddle shape 12.7 +/- 4.5% vs. 15.0 +/- 4.6%, P = 0.001), and larger tenting (length 6.36 +/- 1.78 mm vs. 5.60 +/- 1.55 mm, P = 0.003) but vs. chronic MI, mitral apparatus displayed smaller alterations (all P < 0.01) and annular size, PM movement remained dynamic (all P < 0.01). Specific to acute IMR, without PM apical displacement (P > 0.70), greater separation (21.7 +/- 4.9 mm vs. 20.0 +/- 3.4 mm, P = 0.01), and widest angulation of PM (38.4 +/- 6.2 degrees for moderate vs. 33.5 +/- 7.3 degrees for mild vs. 31.4 +/- 6.3 degrees for no-IMR, P = 0.0009) wider vs. chronic MI (P < 0.01). Conclusions: 3D echocardiography of patients with first MI provides insights into unique 4D dynamics of the mitral apparatus in acute IMR. Mitral apparatus remained dynamic in acute MI and distinct IMR mechanism in acute MI is not PM displacement seen in chronic IMR but separation and excess angulation of PM deforming the mitral valve, probably because of sudden-onset regional wall motion abnormality without apparent global LV remodelling. This specific mechanism should be considered in novel therapeutic strategies for IMR complicating acute MI. PMID- 30517694 TI - MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2. AB - The heterotrimeric eukaryotic translation initiation factor (eIF) 2 plays critical roles in delivering initiator Met-tRNAiMet to the 40S ribosomal subunit and in selecting the translation initiation site. Genetic analyses of patients with MEHMO syndrome, an X-linked intellectual disability syndrome, have identified several unique mutations in the EIF2S3 gene that encodes the gamma subunit of eIF2. To gain insights into the molecular consequences of MEHMO syndrome mutations on eIF2 function, we generated a yeast model of the human eIF2gamma-I259M mutant, previously identified in a patient with MEHMO syndrome. The corresponding eIF2gamma-I318M mutation impaired yeast cell growth and derepressed GCN4 expression, an indicator of defective eIF2-GTP-Met-tRNAiMet complex formation, and, likewise, overexpression of human eIF2gamma-I259M derepressed ATF4 messenger RNA translation in human cells. The yeast eIF2gamma I318M mutation also increased initiation from near-cognate start codons. Biochemical analyses revealed a defect in Met-tRNAiMet binding to the mutant yeast eIF2 complexes in vivo and in vitro. Overexpression of tRNAiMet restored Met-tRNAiMet binding to eIF2 in vivo and rescued the growth defect in the eIF2gamma-I318M strain. Based on these findings and the structure of eIF2, we propose that the I259M mutation impairs Met-tRNAiMet binding, causing altered control of protein synthesis that underlies MEHMO syndrome. PMID- 30517695 TI - Sleep and breathing disturbances in patients with chronic obstructive pulmonary disease traveling to altitude: a randomized trial. AB - Study Objectives: Patients with chronic obstructive pulmonary disease (COPD) have impaired pulmonary gas exchange near sea level. The purpose of the current study was to investigate whether exposure to hypobaric hypoxia during a stay at altitude affects nocturnal oxygen saturation, breathing pattern, and sleep in patients with moderate to severe COPD. Methods: Thirty-two patients with COPD, median age 67 years, FEV1 59% predicted, PaO2 68 mmHg, living below 800 m, underwent polysomnography and questionnaire evaluations in Zurich (490 m), and in Swiss Alpine villages at 1650 and 2590 m, for two nights each, in random order. Mean nocturnal oxygen saturation (SpO2), the apnea-hypopnea index (AHI), and sleep structure were compared between altitudes. Results: Polysomnography during the first night at each altitude revealed a reduced SpO2 at 1650 and 2590 m (medians 89% and 85%) compared with 490 m (92%, p <0.05 vs. higher altitudes) and a higher AHI (medians 26.8/hr and 55.7/hr) vs. 490 m (15.4/hr, p <0.05 vs. higher altitudes) due to emergence of frequent central apneas/hypopneas. At 2590 m, sleep efficiency (median 59%) and slow-wave sleep (median 17% of total sleep time) were reduced compared with 490 m (72% and 20%, respectively, p <0.05). In the morning after one night at 2590 m, patients estimated to have spent more time awake (median 110 min) than at 490 m (43 min, p <0.05) and felt slightly less alert. Conclusions: During a stay at moderate altitude, lowlanders with moderate to severe COPD experience nocturnal hypoxemia that induces central sleep apneas, altered sleep structure, and insomnia. These novel findings help us to counsel patients with COPD planning altitude travel. Trial Registration: ClinicalTrials.gov: NCT01870830. PMID- 30517696 TI - Segregational drift and the interplay between plasmid copy number and evolvability. AB - The ubiquity of plasmids in all prokaryotic phyla and habitats and their ability to transfer between cells marks them as prominent constituents of prokaryotic genomes. Many plasmids are found in their host cell in multiple copies. This leads to an increased mutational supply of plasmid-encoded genes and genetically heterogeneous plasmid genomes. Nonetheless, the segregation of plasmid copies into daughter cells during cell division is considered to occur in the absence of selection on the plasmid alleles. We investigate the implications of random genetic drift of multicopy plasmids during cell division - termed here segregational drift - to plasmid evolution. Performing experimental evolution of low- and high-copy non-mobile plasmids in Escherichia coli, we find that the evolutionary rate of multicopy plasmids does not reflect the increased mutational supply expected according to their copy number. In addition, simulated evolution of multicopy plasmid alleles demonstrates that segregational drift leads to increased loss frequency and extended fixation time of plasmid mutations in comparison to haploid chromosomes. Furthermore, an examination of the experimentally evolved hosts reveals a significant impact of the plasmid type on the host chromosome evolution. Our study demonstrates that segregational drift of multicopy plasmids interferes with the retention and fixation of novel plasmid variants. Depending on the selection pressure on newly emerging variants, plasmid genomes may evolve slower than haploid chromosomes, regardless of their higher mutational supply. We suggest that plasmid copy number is an important determinant of plasmid evolvability due to the manifestation of segregational drift. PMID- 30517697 TI - The double burden of diabetes and global infection in low and middle-income countries. AB - Four out of five people in the world with diabetes now live in low- and middle income countries (LMIC), and the incidence of diabetes is accelerating in poorer communities. Diabetes increases susceptibility to infection and worsens outcomes for some of the world's major infectious diseases such as tuberculosis, melioidosis and dengue, but the relationship between diabetes and many neglected tropical diseases is yet to be accurately characterised. There is some evidence that chronic viral infections such as hepatitis B and HIV may predispose to the development of type 2 diabetes by chronic inflammatory and immunometabolic mechanisms. Helminth infections such as schistosomiasis may be protective against the development of diabetes, and this finding opens up new territory for discovery of novel therapeutics for the prevention and treatment of diabetes. A greater understanding of the impact of diabetes on risks and outcomes for infections causing significant diseases in LMIC is essential in order to develop vaccines and therapies for the growing number of people with diabetes at risk of infection, and to prioritise research agendas, public health interventions and policy. This review seeks to give an overview of the current international diabetes burden, the evidence for interactions between diabetes and infection, immune mechanisms for the interaction, and potential interventions to tackle the dual burden of diabetes and infection. PMID- 30517698 TI - Corrigendum. PMID- 30517699 TI - Association of age at first severe RSV disease with subsequent risk of severe asthma: a population-based cohort study. AB - Objective: In a population-based cohort study we determined the association between age at first severe respiratory syncytial viral (RSV) disease and subsequent asthma. Methods: Incidence rates and rate ratios of first asthma hospitalisation beyond 2 years of age in children with RSV hospitalisation at <3 months, 3 - <6 months, 6 - <12 months, and 12 - 24 months were calculated. Results: The incidence/1000 child - years (95% CI) of asthma hospitalisation in children who had RSV hospitalisation at <3 months was 0.5 (0.2 - 0.7), 3 - <6 months was 0.9 (0.5 - 1.3), 6 - <12 months was 2.0 (1.4 - 2.7) and 12 - 24 months was 1.7 (1.0 - 2.5). The rate ratio of asthma hospitalisation was 2 - 7 fold greater in children who had RSV hospitalisation at ages >=6 months compared to those who had RSV at ages 0-<6 months. Conclusions: Although burden of RSV is highest in children aged <6 months, the burden of subsequent asthma is higher in children who develop RSV disease at ages >=6 months. PMID- 30517700 TI - Novel Strategy of Ventral Dural Repair for Idiopathic Thoracic Spinal Cord Herniation: Report of Outcomes and Review of Techniques. AB - BACKGROUND: Idiopathic ventral thoracic spinal cord herniation is a rare condition that usually presents with progressive myelopathy or Brown-Sequard syndrome. More than 100 cases have been reported with significant variance in surgical treatment strategies and likewise, significant variance in patient outcomes. Although laminectomy has often been used, to date, there is no consensus regarding the optimal surgical approach or strategy for ventral dural repair. OBJECTIVE: To report and illustrate a novel approach to repair the ventral dural defect with more than 2 yr of clinical follow-up. The specific approach and graft used are both detailed. METHODS: A retrospective chart review of all known cases of idiopathic spinal cord herniation at the Cleveland Clinic over the last 15 yr was performed. Postoperative outcome scores (including the Japanese Orthopedic Association score, European Myelopathy score, and Nurick) were calculated preoperatively and postoperatively. RESULTS: A total of 5 patients were identified. Four of five patients improved clinically after surgery and 1 patient remained unchanged at last follow-up (average 23.2 mo, range 12-60 mo). There were no complications. All patients had postoperative magnetic resonance imaging demonstrating realignment of the spinal cord and no recurrence of tethering. CONCLUSION: A unilateral dorsolateral, transpedicular approach combined with laminectomy provides excellent exposure for ventral or ventrolateral dural defects associated with idiopathic spinal cord herniation and minimizes spinal cord manipulation. A collagen matrix graft used as an onlay between the spinal cord and ventral dural defect is a safe and effective option for ventral dural repair. PMID- 30517701 TI - EARS to cyber incidents in health care. AB - Background: Connected medical devices and electronic health records have added important functionality to patient care, but have also introduced a range of cybersecurity concerns. When a healthcare organization suffers from a cybersecurity incident, its incident response strategies are critical to the success of its recovery. Objective: In this article, we identify gaps in research concerning cybersecurity response plans in healthcare. Through a systematic literature review, we develop aggregated strategies that professionals can use to construct better response strategies in their organizations. Methods: We reviewed journal articles on cyber incident response plans in healthcare published in PubMed and Web of Science. We sought to collect articles on the intersection of cybersecurity and healthcare that focused on incident response strategies. Results: We identified and reviewed 13 articles for cybersecurity response recommendations. We then extracted information such as research methods, findings, and implications. Finally, we synthesized the recommendations into a framework of eight aggregated response strategies (EARS) that fall under managerial and technological categories. Conclusions: We conducted a systematic review of the literature on cybersecurity response plans in healthcare and developed a novel framework for response strategies that could be deployed by healthcare organizations. More work is needed to evaluate incident response strategies in healthcare. PMID- 30517702 TI - Comparison of Purified beta-glucuronidases in Patient Urine Samples Indicates a Lack of Correlation Between Enzyme Activity and Drugs of Abuse Metabolite Hydrolysis Efficiencies Leading to Potential False Negatives. AB - Pain management laboratories analyze biological fluids (urine, saliva or blood) from patients treated for chronic pain to ensure compliance and to detect undisclosed drug use. The quantitation of multi-panel drugs in urine and tissues utilizes beta-glucuronidase to cleave the glucuronic acid and liberate the parent drug for mass spectrometry analysis. This work focuses on the comparison of three different, purified and commercially available beta-glucuronidases across 83 patient urine samples. One enzyme is genetically modified, expressed in bacteria and the other two enzymes are purified from abalone. The results indicate that the source of beta-glucuronidase plays an important role in substrate specificity which in turn dictates hydrolysis efficiency. Contaminants in the enzyme solutions also interfere with analyte detection. Altogether, these factors impact precision and accuracy of data interpretation, leading up to 13% positive/negative disagreement. PMID- 30517703 TI - A map of direct TF-DNA interactions in the human genome. AB - Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is the most popular assay to identify genomic regions, called ChIP-seq peaks, that are bound in vivo by transcription factors (TFs). These regions are derived from direct TF DNA interactions, indirect binding of the TF to the DNA (through a co-binding partner), nonspecific binding to the DNA, and noise/bias/artifacts. Delineating the bona fide direct TF-DNA interactions within the ChIP-seq peaks remains challenging. We developed a dedicated software, ChIP-eat, that combines computational TF binding models and ChIP-seq peaks to automatically predict direct TF-DNA interactions. Our work culminated with predicted interactions covering >4% of the human genome, obtained by uniformly processing 1983 ChIP-seq peak data sets from the ReMap database for 232 unique TFs. The predictions were a posteriori assessed using protein binding microarray and ChIP-exo data, and were predominantly found in high quality ChIP-seq peaks. The set of predicted direct TF-DNA interactions suggested that high-occupancy target regions are likely not derived from direct binding of the TFs to the DNA. Our predictions derived co binding TFs supported by protein-protein interaction data and defined cis regulatory modules enriched for disease- and trait-associated SNPs. We provide this collection of direct TF-DNA interactions and cis-regulatory modules through the UniBind web-interface (http://unibind.uio.no). PMID- 30517704 TI - Stress-inducible NHEJ in bacteria: function in DNA repair and acquisition of heterologous DNA. AB - DNA double-strand breaks (DSB) in bacteria can be repaired by non-homologous end joining (NHEJ), a two-component system relying on Ku and LigD. While performing a genetic characterization of NHEJ in Sinorhizobium meliloti, a representative of bacterial species encoding several Ku and LigD orthologues, we found that at least two distinct functional NHEJ repair pathways co-exist: one is dependent on Ku2 and LigD2, while the other depends on Ku3, Ku4 and LigD4. Whereas Ku2 likely acts as canonical bacterial Ku homodimers, genetic evidences suggest that Ku3-Ku4 form eukaryotic-like heterodimers. Strikingly, we found that the efficiency of both NHEJ systems increases under stress conditions, including heat and nutrient starvation. We found that this stimulation results from the transcriptional up regulation of the ku and/or ligD genes, and that some of these genes are controlled by the general stress response regulator RpoE2. Finally, we provided evidence that NHEJ not only repairs DSBs, but can also capture heterologous DNA fragments into genomic breaks. Our data therefore suggest that NHEJ could participate to horizontal gene transfer from distantly related species, bypassing the need of homology to integrate exogenous DNA. This supports the hypothesis that NHEJ contributes to evolution and adaptation of bacteria under adverse environmental conditions. PMID- 30517705 TI - Effect of Temperature and Tissue Type on the Development of Myiasis Causing Fly; Chrysomya bezziana (Diptera: Calliphoridae). AB - Chrysomya bezziana Villeneuve is the major human myiasis producer in tropical countries, including Sri Lanka. Although of great medical and veterinary importance, only a single study has been published on the development of C. bezziana. This limitation is due in part to the difficulty of maintaining this species in a colony outside of using a living host. In this study, a novel technique that overcomes this limitation is presented along with development data for C. bezziana fed on three different meat types: swine muscle, swine liver, and bovine muscle at two temperature regimes: 35 and 37 degrees C. The optimum development of C. bezziana was recorded at 35 degrees C in bovine muscle (262.20 h) followed by swine muscle (286.00 h) and swine liver (307.00 h). Data from the current study indicate tissue type significantly impacts change in length and width of larvae over time, whereas the two temperatures examined had no significant effect. PMID- 30517706 TI - The relationship between remission and health-related quality of life in a cohort of SLE patients. AB - Objective: To investigate the relationship between remission and health-related quality of life (HRQoL) in patients with SLE in a longitudinal observational cohort. Methods: HRQoL was measured at cohort visits using the physical and mental component score (PCS and MCS, respectively) of the Short Form 36 questionnaire. Definitions of Remission in SLE remission categories (no remission/remission on therapy/remission off therapy) were applied. Determinants of PCS and MCS were identified with simple linear regression analyses. Association between remission and HRQoL was assessed using generalized estimating equation models. Results: Data from 154 patients with 2 years of follow-up were analysed. At baseline 60/154 (39.0%) patients were in either form of remission. Patients in remission had higher Short Form 36 scores in all subdomains compared with patients not in remission. PCS was positively associated with remission and employment, and negatively associated with SLICC damage index, ESR, medication, patient global assessment and BMI. MCS was positively associated with Caucasian ethnicity and negatively associated with patient global assessment. In generalized estimating equation analysis, a gradual and significant increase of PCS was observed from patients not in remission (mean PCS 36.0) to remission on therapy (41.8) to remission off therapy (44.8). No significant difference in MCS was found between remission states. Conclusion: we show a strong and persistent association between remission and PCS, but not MCS. These results support the relevance (construct validity) of the Definition of Remission in SLE remission definitions and the further development of a treat-to-target approach in SLE. PMID- 30517707 TI - Transient receptor potential ion channels mediate adherens junctions dysfunction in a toluene diisocyanate-induced murine asthma model. AB - Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 (GSK2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E cadherin and beta-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3beta, tyrosine phosphorylation of beta-catenin, as well as activation and nuclear transport of beta-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and beta catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma. PMID- 30517708 TI - Optimal Treatments for Severe Malaria and the Threat Posed by Artemisinin Resistance. AB - Background: Standard treatment for severe malaria is with artesunate; patient survival in the 24 hours immediately posttreatment is the key objective. Clinical trials use clearance rates of circulating parasites as their clinical outcome, but the pathology of severe malaria is attributed primarily to noncirculating, sequestered, parasites, so there is a disconnect between existing clinical metrics and objectives. Methods: We extend existing pharmacokinetic/pharmacodynamic modeling methods to simulate the treatment of 10000 patients with severe malaria and track the pathology caused by sequestered parasites. Results: Our model recovered the clinical outcomes of existing studies (based on circulating parasites) and showed a "simplified" artesunate regimen was noninferior to the existing World Health Organization regimen across the patient population but resulted in worse outcomes in a subgroup of patients with infections clustered in early stages of the parasite life cycle. This same group of patients were extremely vulnerable to resistance emerging in parasite early ring stages. Conclusions: We quantify patient outcomes in a manner appropriate for severe malaria with a flexible framework that allows future researchers to implement their beliefs about underlying pathology. We highlight with some urgency the threat posed to treatment of severe malaria by artemisinin resistance in parasite early ring stages. PMID- 30517709 TI - Homologous pairing activities of Arabidopsis thaliana RAD51 and DMC1. AB - In eukaryotes, homologous recombination plays a pivotal role in both genome maintenance and generation of genetic diversity. Eukaryotic RecA homologues, RAD51 and DMC1, are key proteins in homologous recombination that promote pairing between homologous DNA sequences. Arabidopsis thaliana is a prominent model plant for studying eukaryotic homologous recombination. However, A. thaliana RAD51 and DMC1 have not been biochemically characterized. In the present study, we purified A. thaliana RAD51 (AtRAD51) and DMC1 (AtDMC1). Biochemical analyses revealed that both AtRAD51 and AtDMC1 possess ATP hydrolyzing activity, filament formation activity, and homologous pairing activity in vitro. We then compared the homologous pairing activities of AtRAD51 and AtDMC1 with those of the Oryza sativa and Homo sapiens RAD51 and DMC1 proteins. PMID- 30517710 TI - Survival predictors in biopsy-proven giant cell arteritis: a northern Italian population-based study. AB - Objective: To evaluate the influence of disease-related findings and treatment outcomes on survival in a population-based cohort of Northern Italian patients with GCA. Methods: A total of 281 patients with incident temporal artery biopsy (TAB)-proven GCA, diagnosed over a 26-year period (1986-2012) and living in the Reggio Emilia area, were retrospectively evaluated. We analysed clinical, imaging and laboratory findings at diagnosis, pathological patterns of TAB, CS treatment and therapeutic outcomes, and traditional cardiovascular risk factors as factors predictive of survival. Results: Univariate analysis showed that increased mortality was associated with large vessel involvement at diagnosis [hazard ratio (HR) 5.84], while reduced mortality was associated with female sex (HR 0.66), PMR (HR 0.54), higher haemoglobin levels (HR 0.84) at diagnosis, long-term remission (HR 0.47) and inflammation limited to adventitia or to the adventitial vasa vasorum (HR 0.48) at TAB examination. Multivariate analysis confirmed the association between increased mortality and large vessel involvement (HR 5.14) at diagnosis, between reduced mortality and PMR (HR 0.57) at diagnosis and adventitial inflammation (HR 0.31) at TAB. Conclusion: PMR at diagnosis and inflammation limited to the adventitia at TAB appear to identify subsets of patients with more benign disease, while large vessel involvement at diagnosis is associated with reduced survival. PMID- 30517711 TI - Age may influence the impact of TRAbs on thyroid function and relapse-risk in patients with Graves' disease. AB - Context: Thyrotropin receptor antibodies (TRAbs) play a crucial role in the pathogenesis of Graves' disease (GD). However, factors that influence the association of TRAbs with thyroid hormones and relapse risk in GD remain unclear. Objective: We investigated: (i) the associations of TRAbs at diagnosis with thyroid hormones and relapse risk; (ii) potential factors that can influence these associations in GD. Design and Setting: A prospective study in GD patients from a single endocrine centre in the north-east of England, seen between January 2008 and March 2018. Patients and Main outcome measures: Consecutive GD patients (n=384) who had measurements of TRAbs, free thyroxine and free triiodothyronine at diagnosis. The association of TRAbs with thyroid hormones and relapse risk was assessed through linear regression and Cox proportional hazard models, adjusted for potential confounders. Results: TRAbs were non-linearly associated with thyroid hormones, following a curve with an initial positive slope and a subsequent flattening (p-values <0.0001). Higher TRAbs were also associated with greater relapse risk (Hazard ratio [HR], 1.05; 95% confidence interval [95%CI], 1.02-1.08, per 1 U/L increase in TRAb; p-value 0.001). These associations were modified by age, but not by sex, race, smoking or thyroid peroxidase antibody levels. In younger participants, increasing TRAbs were associated with higher thyroid hormones, and greater relapse risk (HR, 1.13; 95%CI, 1.04-1.23, per 1 U/L increase in TRAb; p-value 0.005). In older participants, increasing TRAbs were not associated with meaningful increases in thyroid hormones or relapse risk (HR, 0.99; 95%CI, 0.93-1.05, per 1 U/L increase in TRAb, p-value 0.7). Conclusions: In GD, age can influence the impact of TRAbs on thyroid function and relapse risk. TRAbs at diagnosis have better predictive value in younger patients with GD. PMID- 30517712 TI - An Experimental Study of Diazepam and Alprazolam Kinetics in Urine and Oral Fluid Following Single Oral Doses. AB - Benzodiazepines are commonly seen in samples submitted for drug testing of patients, people involved in child welfare cases, work-place drug testing, as well as in drug-facilitated assaults. Limited previous experimental studies are available regarding the excretion of benzodiazepines in urine and oral fluid. The aim of this study was to investigate the concentrations of diazepam and alprazolam in oral fluid and urine for up to 2 weeks after ingestion of a single oral dose in healthy volunteers. A total of 11 healthy volunteers ingested 10 mg diazepam at the start of the study and 0.5 mg alprazolam on Day 3 of the study. A total number of 10 oral fluid samples and 17 urine samples were collected from each participant. The samples were analyzed by liquid chromatography with tandem mass spectroscopy and ultra-high performance liquid chromatography tandem mass spectrometry methods. The median detection time was 252 h for the longest detected diazepam metabolite in urine (oxazepam, range 203-322) and 132 h in oral fluid (N-desmethyldiazepam, range 109-136). For alprazolam, the median detection time was 36 h (metabolite alpha-OH-alprazolam, range 26-61) in urine and 26 h (alprazolam, range 4-37) in oral fluid. These results show that detection times are only 36 h for alprazolam in urine after intake of a single therapeutic oral dose. For diazepam in urine, detection times were 11 days. Detection times were generally shorter in oral fluid compared to urine. The results could be helpful in the interpretation of diazepam or alprazolam findings in drug testing cases involving urine or oral fluid. PMID- 30517713 TI - RNA-binding protein RPS3 contributes to hepatocarcinogenesis by post transcriptionally up-regulating SIRT1. AB - Although several studies indicate that RNA-binding proteins (RBPs) contribute to key steps in a variety of physiological processes and cancer, the detailed biological functions and mechanisms remain to be determined. By performing bioinformatics analysis using well-established hepatocellular carcinoma (HCC) datasets, we identified a set of HCC progression-associated RBPs (HPARBPs) and found that the global expression of HPARBPs was significantly correlated with patient prognosis. Among the 42 HPARBPs, human ribosomal protein S3 (RPS3) was one of the most abundant genes whose role remains uncharacterized in HCC. Gain- and loss-of-function analyses demonstrated that RPS3 promoted HCC tumorigenesis both in vitro and in vivo. Mechanistically, we revealed that silent information regulator 1 (SIRT1) was a critical target of RPS3 and was essential for sustaining the RPS3-induced malignant phenotypes of HCC cells. RPS3 stabilized SIRT1 mRNA by binding to AUUUA motifs in the 3448-3530 region of the 3' untranslated region (UTR) of SIRT1 mRNA. In addition, we found that (5 formylfuran-2-yl) methyl 4-hydroxy-2-methylenebutanoate (FMHM) inhibited HCC progression by repressing the RPS3/SIRT1 pathway. Our study unveils a novel extra ribosomal role of RPS3 in facilitating hepatocarcinogenesis via the post transcriptional regulation of SIRT1 expression and proposes that the RPS3/SIRT1 pathway serves as a potential therapeutic target in HCC. PMID- 30517714 TI - Intestinal plasticity in response to nutrition and gastrointestinal surgery. AB - The plasticity of a material corresponds to its capacity to change its feature under the effect of an external action. Intestinal plasticity could be defined as the ability of the intestine to modify its size or thickness and intestinal cells to modulate their absorption and secretion functions in response to external or internal cues/signals. This review will focus on intestinal adaptation mechanisms in response to diet and nutritional status. These physiological mechanisms allow a fine and rapid adaptation of the gut to promote absorption of ingested food, but they can also lead to obesity in response to overnutrition. This plasticity could thus become a therapeutic target to treat not only undernutrition but also obesity. How the intestine adapts in response to 2 types of surgical remodeling of the digestive tract-extensive bowel resection leading to intestinal failure and surgical treatment of pathological obesity (ie, bariatric surgeries)-will also be reviewed. PMID- 30517715 TI - Validation of new potential targets for remission and low disease activity in psoriatic arthritis in patients treated with golimumab. AB - Objectives: Treat to target recommendations for PsA state that the target of treatment should be remission or, at the very least, low disease activity. Different clinical indexes have been proposed to define these disease states including the minimal disease activity criteria and the Disease Activity Index for PsA (DAPSA) scores, which have 7 and 4-5 domains, respectively. Using a Canadian cohort, the objectives were to calculate the proportion of patients achieving these criteria, their prognostic value and the overall patient impact of these disease states. Methods: BioTRAC is an ongoing, prospective registry of inflammatory arthritis patients. 188 PsA patients treated with golimumab were included. Data collected at baseline, 6 and 12 months were used. Results: Between 15.6% and 38.3% of patients achieved remission, and 37.4-77.7% achieved low disease activity at 6 and 12 months' follow-up. Patients achieving any minimal disease activity target and DAPSA low disease activity had significantly lower swollen joint count, tender joint count, psoriasis area and severity index, dactylitis and enthesitis scores compared with non-achievers (P < 0.05). Higher HAQ scores (P < 0.03) were observed in patients achieving remission with remaining dactylitis or active skin disease. Conclusion: Very low disease activity was the most stringent new potential target for remission in PsA. There was a high level of agreement between scores, although residual activity in dactylitis and skin despite DAPSA remission may affect patient function. Patients achieving either DAPSA endpoint, however, did not show a significant reduction in skin disease, indicating that those two criteria are more restricted to joint symptoms. PMID- 30517717 TI - A Cluster of Exertional Rhabdomyolysis Cases in an ROTC Program Engaged in an Extreme Exercise Program: Corrigendum. PMID- 30517718 TI - Stat Bite Prostate Cancer Incidence and Death Rates. PMID- 30517716 TI - Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality. AB - Objectives: To examine the incidence, predictors and outcomes associated with severe gastrointestinal (GI) disease in a large inception SSc cohort. Methods: SSc subjects with <2 years of disease duration were identified from two multicentre cohorts. Severe GI disease was defined as: malabsorption, hyperalimentation, pseudo-obstruction and/or ?10% weight loss in association with the use of antibiotics for bacterial overgrowth or oesophageal stricture. Kaplan Meier, multivariate logistic regression and Cox proportional hazard analyses were performed to determine the cumulative incidence rate, independent clinical correlates and mortality rate associated with severe GI disease. A longitudinal mixed model was used to assess the impact of severe GI disease on the Short Form Health Survey. Results: In this inception SSc cohort, the probability of developing severe GI disease was estimated at 9.1% at 2 years and 16.0% at 4 years. In multivariate analysis, severe GI disease was associated with inflammatory myositis (odds ratio 4.68, 95% CI 1.65, 13.24), telangiectasias (odds ratio 2.45, 95% CI 1.19, 5.04) and modified Rodnan skin score (odds ratio 1.03, 95% CI 1.01, 1.07). Severe GI disease was associated with a >2-fold increase in the risk of death (hazard ratio 2.27, 95% CI 1.27, 4.09) and worse health-related quality of life [Short Form Health Survey physical (beta = -2.37, P = 0.02) and mental (beta = -2.86, P = 0.01) component summary scores]. Conclusion: Severe GI disease is common in early SSc and is associated with significant morbidity and increased mortality. More research is needed to understand, prevent and mitigate severe GI disease in SSc. PMID- 30517719 TI - Fresh transfer of Day 5 slow-growing embryos versus deferred transfer of vitrified, fully expanded Day 6 blastocysts: which is the optimal approach? AB - STUDY QUESTION: In IVF cycles in which the entire embryo cohort is slow growing, is it optimal to perform fresh transfer in Day 5 or to extend the culture and transfer in subsequent vitrified-warmed cycles? SUMMARY ANSWER: The outcomes depend on the degree of embryo development on Day 5. WHAT IS KNOWN ALREADY: Slow growing blastocysts have lower implantation potential when transferred in fresh cycles. It has been suggested that embryo-endometrial asynchrony could explain this finding. However, studies that compared Days 5 and 6 embryos in frozen embryo transfer (FET) cycles showed contradictory results. There is still a lack of evidence regarding the best approach, performing fresh transfer or deferring transfer and continuing culture until fully developed blastocysts are achieved, when the entire cohort of embryos is slow growing. STUDY DESIGN SIZE, DURATION: This was a retrospective study that included 477 women aged <40 years who underwent fresh Day 5 single embryo transfer of slow-growing embryos and subsequent FET cycles of fully expanded blastocysts (FEB) originating from the same IVF cycle between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included cycles in which the embryos either began blastulation by Day 5 of culture but did not reach the fully expanded stage (Gardner Stage III) or had delayed blastulation with only morula embryos present by Day 5 of culture. All of the subjects in the study underwent elective, single embryo transfer (slow or delayed blastocysts) on Day 5 and had at least one embryo that developed into a FEB on extended culture Day 6 that was suitable for vitrification. All subjects, regardless of the outcome of the fresh transfer, returned for at least one subsequent FET cycle of Day 6 embryos. MAIN RESULTS AND ROLE OF CHANCE: A total of 1070 embryo transfer cycles (fresh + FET) were included. Of them, 365 women had elective, fresh, single transfer of slow-growing blastocysts (Group I) and 112 had elective, fresh, single morula transfer (Group II). Groups I and II underwent a subsequent 457 and 136 FET cycles, respectively. The mean age of Group I was 33.8 +/- 2.9 years, the proportion of Day 5 embryos that developed to FEB by Day 6 was 92%, and the number of blastocysts vitrified was 627 (average of 1.71 blastocysts per cycle). The outcomes of fresh and FET cycles were comparable regarding clinical pregnancy rate (CPR) (31.0 vs. 30.4%, P = 0.86) and live birth rate (LBR) (23.3 vs. 20.3%, P = 0.15). In Group II, the mean age was 35.8 +/- 3.4 years and the proportion of morula embryos that developed to FEB by Day 6 was 72%. The number of blastocysts vitrified on Day 6 was 155 (1.38 per cycle). The transfer of fresh embryos in Group II resulted in significantly lower clinical pregnancy (5.3 vs. 30.1%, P < 0.001) and LBRs (1.8 vs. 20.5%, P < 0.001). The results did not change after controlling for possible confounding factors. LIMITATIONS AND REASONS FOR CAUTION: The retrospective design of the study is a major limitation. Although we compared the outcomes of embryos that originated from the same cohort, the FET cycles could have been overrepresented by older patients and those with poorer prognoses. Furthermore, the study included only cycles in which there were blastocysts available for cryopreservation on Day 6; therefore, the results were not be applicable for those who had mandatory Day 5 transfer with no embryos available for vitrification. WIDER IMPLICATIONS OF THE FINDINGS: Fresh transfer of embryos that begin blastulation on Day 5 results in similar outcomes to the transfer of FEB originating from the same cohort. However, in cases where only morula/compacting embryos are available by Day 5, extending culture until FEB are achieved and then performing subsequent FET will result in significantly higher LBRs. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 30517720 TI - Longitudinal associations of childhood bedtime and sleep routines with adolescent body mass index. AB - Study Objectives: Having a regular, age-appropriate bedtime and sufficient sleep from early childhood may be important for healthy weight in adolescence. This study aimed to (1) identify heterogeneous groups of children by bedtime and sleep routines and (2) test longitudinal associations of childhood bedtime and sleep routine groups with adolescent body mass index (BMI). Methods: We analyzed longitudinal data from the Fragile Families and Child Wellbeing Study, a national birth cohort from 20 US cities (N = 2196). Childhood bedtime and sleep routines were assessed by mothers' reports of their children's presence and timing of bedtimes, adherence to bedtimes, and habitual sleep duration at ages 5 and 9. At age 15, these adolescents reported their height and weight, which were used to calculate BMI z-score. Results: Latent Class Analysis revealed four groups of childhood bedtime and sleep routines: No Bedtime Routine Age 5 (Group 1), No Bedtime Routine Age 9 (Group 2), Borderline Bedtimes Ages 5 and 9 (Group 3), and Age-Appropriate Bedtime and Sleep Routines Ages 5 and 9 (Group 4, reference). Compared with adolescents in the reference group, those in the No Bedtime Routine Age 9 (Group 2) had +0.38 SD greater BMI (95% CI = [0.13 to 0.63]), above the level for overweight (1.02 SD BMI/85th percentile). Associations persisted after adjusting for age 3 BMI and sociodemographic characteristics. Conclusions: Results demonstrate heterogeneity in childhood bedtime routine groups and their associations with adolescent BMI. Future studies should focus on whether childhood sleep behavior interventions promote healthier sleep and weight in later life course stages. PMID- 30517721 TI - Incidence of Traumatic Brain Injury in the U.S. Military, 2010-2014. AB - Introduction: Traumatic brain injury (TBI) is a significant health issue that affects U.S. military service members (SM) at home and in combat deployments. We estimated the TBI incidence rate in the deployed and non-deployed setting between 2010 and 2014 and identified subgroups with elevated rates for prevention efforts. Methods: Retrospective population-based study of all active duty U.S. military SM that sustained a first active duty TBI diagnosis between January 2010 and December 2014 collected and analyzed in 2017. Using Armed Forces Health Surveillance Branch data we calculated the Mantel-Haenszel (MH) standardized TBI incidence rate in the deployed and non-deployed setting, adjusting for service and demographic factors. Results: From 2010 to 2014, the MH standardized incidence rate for deployed SMs was 3,265 TBIs per 100 thousand p-yrs (95% CI: 3,222-3,307) and 1,705.2 (95% CI: 1,694.0-1,716.5) for non-deployed SMs. The youngest deployed male Army soldiers, those ages 17-24, especially White and Hispanic soldiers, had the highest TBI incidence rate (IR) of 5,748.7 (95% CI: 5,585.8-5,916.4) and 5,010.3 (95% CI: 4,647.5-5,401.4), respectively. The IR for all branches was 1,972.6 (95% CI: 1,959.5-1,985.7) and 724.0 (95% CI: 714.9 733.0) for Reserve/Guard Service members. Conclusions: Across all years, Marines and Army Soldiers experience the highest rates of injury with deployed SMs having elevated IRs of TBI. The TBI IR among deployed SMs was 91% higher than among those in the non-deployed setting, due to continued exposures to combat. Deployed Reserve/Guard component SMs seem to have an above average rate, a finding with implications for training and prevention. PMID- 30517722 TI - Urine Spot Samples Can Be Used to Estimate 24-Hour Urinary Sodium Excretion in Children. AB - Background: The gold standard to assess salt intake is 24-h urine collections. Use of a urine spot sample can be a simpler alternative, especially when the goal is to assess sodium intake at the population level. Several equations to estimate 24-h urinary sodium excretion from urine spot samples have been tested in adults, but not in children. Objective: The objective of this study was to assess the ability of several equations and urine spot samples to estimate 24-h urinary sodium excretion in children. Methods: A cross-sectional study of children between 6 and 16 y of age was conducted. Each child collected one 24-h urine sample and 3 timed urine spot samples, i.e., evening (last void before going to bed), overnight (first void in the morning), and morning (second void in the morning). Eight equations (i.e., Kawasaki, Tanaka, Remer, Mage, Brown with and without potassium, Toft, and Meng) were used to estimate 24-h urinary sodium excretion. The estimates from the different spot samples and equations were compared with the measured excretion through the use of several statistics. Results: Among the 101 children recruited, 86 had a complete 24-h urine collection and were included in the analysis (mean age: 10.5 y). The mean measured 24-h urinary sodium excretion was 2.5 g (range: 0.8-6.4 g). The different spot samples and equations provided highly heterogeneous estimates of the 24-h urinary sodium excretion. The overnight spot samples with the Tanaka and Brown equations provided the most accurate estimates (mean bias: -0.20 to -0.12 g; correlation: 0.48-0.53; precision: 69.7-76.5%; sensitivity: 76.9-81.6%; specificity: 66.7%; and misclassification: 23.0-27.7%). The other equations, irrespective of the timing of the spot, provided less accurate estimates. Conclusions: Urine spot samples, with selected equations, might provide accurate estimates of the 24-h sodium excretion in children at a population level. At an individual level, they could be used to identify children with high sodium excretion. This study was registered at clinicaltrials.gov as NCT02900261. PMID- 30517723 TI - Men and Women Differ in Gastric Fluid Retention and Neural Activation after Consumption of Carbonated Beverages. AB - Background: The most commonly consumed carbonated beverages are soda and beer. Carbon dioxide increases gastric volume, which can lead to epigastric discomfort. Women are more susceptible to this; however, correlations with neural activity and gastric distention are unknown. Objective: This study sought to determine the subjective, gastric, and neural correlates of epigastric discomfort in men and women. Methods: Thirty-four healthy, normal-weight adults [17 women; mean +/- SD body mass index (BMI; kg/m2): 22.3 +/- 1.9; 17 men; BMI: 22.8 +/- 1.8] participated in a randomized crossover study with 2 treatments: ingestion of 500 mL beer or soda. Before and after consumption, gastric content and brain activity were measured with magnetic resonance imaging (MRI). Participants rated fullness, bloating, hunger, and nausea at baseline and at t = 0, 10, 20, and 30 min together with gastric MRI. Brain activity [cerebral blood flow (CBF)] was measured at baseline and at t = 5 and 35 min. Liquid, gas, and total gastric volume (TGV) were segmented from gastric MRI. Ratings and gastric content areas under the curve (AUCs) were tested with a mixed model with sex and drink as factors. Results: For subjective ratings, only nausea in the beer condition scored significantly greater for women (9.4-point increase; P = 0.045). Liquid stomach content was significantly greater for women (2525 mL * min increase; P = 0.019). In both men and women, the strongest correlation for bloating was with TGV (r = 0.45, P < 0.01) and for nausea was with the liquid fraction AUC (r = 0.45, P < 0.01). CBF changes did not differ between the drinks. Men showed greater CBF than women in the left precentral and postcentral gyri at t = 5 min. Conclusions: There are differences between sexes when it comes to appetite ratings, gastric fluid retention, and neural activation. Discomfort in women may be related to fluid rather than gas in the stomach, because they retain more fluid than men. Differences between men and women should be considered when studying digestion. This study was registered with the Dutch Trial Registry as NTR5418 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5418). PMID- 30517724 TI - Vitamin A Supplementation during Pregnancy Enhances Pandemic H1N1 Vaccine Response in Mothers, but Enhancement of Transplacental Antibody Transfer May Depend on When Mothers Are Vaccinated during Pregnancy. AB - Background: In the growing embryo, the vitamin A requirement is tightly regulated. Maternal vitamin A deficiency during pregnancy may alter maternal immune function to accommodate the fetus. Objective: Our primary objective was to determine the effect of oral vitamin A supplementation (VAS) during pregnancy and until 6 mo postpartum on pandemic H1N1-vaccine responses in mothers and their infants at 6 mo of age. Methods: In this randomized controlled clinical trial, pregnant women (n = 112) during the second trimester (mean +/- SD: 14 +/- 1 wk) were assigned to receive either an oral dose of 10,000 IU vitamin A or placebo weekly until 6 mo postpartum. During the third trimester, mothers received a single dose of inactivated pandemic H1N1-influenza vaccine. Hemagglutination inhibition (HAI) titer was measured in cord, infant, and maternal blood samples. Multivariate regressions with adjustments were used for data analysis. Results: Seventy-six percent of women had low plasma retinol concentrations (<1.05 MUmol/L) in their second trimester. VAS of mothers increased vitamin A concentrations in cord blood by 21.4% and in colostrum by 40.7%. At 6 mo postpartum, women in the vitamin A group had 38.7% higher HAI titers and a higher proportion of HAI titer of >=1:40 of the cutoff compared with the placebo group. A total of 54.5% of infants had an HAI titer >=1:40 at 6 mo of age, but there was no difference in HAI titer in infants between groups. Overall, HAI in cord blood did not differ between groups, but in the placebo group, cord blood HAI was negatively associated with maternal "vaccination-to-delivery intervals" (rs = 0.401; P = 0.5), and maternal VAS increased cord blood HAI 6-fold if antenatal immunization was administered >=10 wk before delivery. Conclusions: In a community with low vitamin A status, weekly maternal VAS during pregnancy and postpartum increases the breast-milk vitamin A concentration and enhances prenatal H1N1-vaccine responses in mothers, but the benefits of maternal VAS in transplacental antibody transfer may depend on the time of gestation when mothers were vaccinated. This trial was registered at clinicaltrials.gov as NCT00817661. PMID- 30517725 TI - Unsaturated Fatty Acid Intakes During Midlife Are Positively Associated with Later Cognitive Function in Older Adults with Modulating Effects of Antioxidant Supplementation. AB - Background: Given the drastic demographic changes characterized as "population aging," the disease burden related to dementia is a major public health problem. The scientific literature documenting the link between mono- and polyunsaturated fatty acids (MUFAs, PUFAs) and cognitive function during aging is plentiful, but findings are inconsistent. Objectives: We aimed to evaluate the association between intakes of unsaturated fatty acids at midlife and cognitive performance 13 y later in French adults, and to test for a modulating effect of antioxidant supplementation. Methods: Fatty acid intakes were estimated with the use of repeated 24-h records (1994-1996) among 3362 subjects (mean +/- SD age: 65.5 +/- 4.6 y) of the SU.VI.MAX (Supplementation with Antioxidant Vitamins and Minerals) study, including an intervention phase (1994-2002) during which participants were randomly assigned to an "antioxidant supplementation" or placebo group. Cognitive performance was assessed at follow-up only (in 2007-2009) via a battery of 6 standardized neuropsychological tests. A global cognitive score was calculated as the sum of T-scores of the 6 tests. Multivariable-adjusted regression analyses were performed to provide regression coefficients and 95% CIs. Results: In multivariable models, total MUFAs, total PUFAs, and n-6 PUFAs (omega-6 PUFAs) were positively associated with overall cognitive functioning. n-3 PUFA (omega-3 PUFA) intakes showed positive associations among supplemented participants only (mean difference Tertile3 versus Tertile1: 1.40; 95% CI: 0.30, 2.51; P-trend = 0.01, P-interaction = 0.01). A detrimental role of arachidonic acid for cognitive functioning was only detected in the placebo group (mean difference Tertile3 versus Tertile1: -1.38; 95% CI: -2.57, -0.18; P-trend = 0.02, P-interaction = 0.07). Conclusion: Whereas higher total MUFA and n-6 PUFA intakes may be generally beneficial for maintaining cognitive health during aging, a higher consumption of n-3 fatty acids may only be beneficial among individuals with an adequate antioxidant status. These findings underline the importance of not only focusing on specific nutrients for dementia prevention, but also considering the complex interaction between consumed nutrients. This trial was registered at clinicaltrials.gov as NCT00272428. PMID- 30517726 TI - Concentrations of Purine Metabolites Are Elevated in Fluids from Adults and Infants and in Livers from Mice Fed Diets Depleted of Bovine Milk Exosomes and their RNA Cargos. AB - Background: Humans and mice absorb bovine milk exosomes and their RNA cargos. Objectives: The objectives of this study were to determine whether milk exosome- and RNA-depleted (ERD) and exosome- and RNA-sufficient (ERS) diets alter the concentrations of purine metabolites in mouse livers, and to determine whether diets depleted of bovine milk alter the plasma concentration and urine excretion of purine metabolites in adults and infants, respectively. Methods: C57BL/6 mice were fed ERD (providing 2% of the microRNA cargos compared with ERS) and ERS diets starting at age 3 wk; livers were collected at age 7 wk. Plasma and 24-h urine samples were collected from healthy adults who consumed (DCs) or avoided (DAs) dairy products. Spot urine samples were collected from healthy infants fed human milk (HM), milk formula (MF), or soy formula (SF) at age 3 mo. Purine metabolites were analyzed in liver, plasma, and urine; mRNAs and microRNAs were analyzed in the livers of female mice. Results: We found that 9 hepatic purine metabolites in ERD-fed mice were 1.76 +/- 0.43 times the concentrations in ERS fed mice (P < 0.05). Plasma concentrations and urine excretion of purine metabolites in DAs was <=1.62 +/- 0.45 times the concentrations in DCs (P < 0.05). The excretion of 13 purine metabolites in urine from SF infants was <=175 +/- 39 times the excretion in HM and MF infants (P < 0.05). mRNA expression of 5' nucleotidase, cytosolic IIIB, and adenosine deaminase in mice fed ERD was 0.64 +/ 0.52 and 0.60 +/- 0.28 times the expression in mice fed ERS, respectively. Conclusion: Diets depleted of bovine-milk exosomes and RNA cargos caused increases in hepatic purine metabolites in mice, and in plasma and urine from human adults and infants, compared with exosome-sufficient controls. These findings are important, because purines play a role in intermediary metabolism and cell signaling. PMID- 30517727 TI - Daily Consumption of Oregon Hazelnuts Affects alpha-Tocopherol Status in Healthy Older Adults: A Pre-Post Intervention Study. AB - Background: Inadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases. Objective: This study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes. Methods: Participants (n = 32 including 22 women; mean +/- SD age: 63 +/- 6 y) consumed hazelnuts (~57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of alpha-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma alpha-tocopherol, 2) urinary alpha-carboxyethyl hydroxychromanol (alpha-CEHC; an alpha-tocopherol metabolite), and 3) serum magnesium. Results: Hazelnut consumption increased concentrations of the urinary alpha-tocopherol metabolite alpha-CEHC (mean +/- SD: 0.84 +/- 0.45 to 1.14 +/- 0.50 umol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (-3.4%, P = 0.03) and LDL cholesterol (-6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (-4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, high-sensitivity C reactive protein, triglyceride, alpha-tocopherol, or HDL cholesterol. Conclusions: Consuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015-2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT03485989. PMID- 30517728 TI - Sickle Cell and alpha+-Thalassemia Traits Influence the Association between Ferritin and Hepcidin in Rural Kenyan Children Aged 14-26 Months. AB - Background: The relation between subclinical hemoglobinopathies and concentrations of the iron-regulatory hormone hepcidin is not well characterized. Objective: We investigated the relation of hepcidin concentration with hemoglobinopathies among young children in Kenya. Methods: We quantified serum hepcidin and ferritin in 435 Kenyan children aged 14-20 mo in a subsample of the Water, Sanitation, and Handwashing (WASH) Benefits Trial. Blood samples were genotyped for alpha+-thalassemia and for sickle cell disorder. Hepcidin was compared across sickle cell and alpha+-thalassemia genotypes separately by using generalized linear models, and children who were normozygous for both conditions were also compared with those who had either of these conditions. In the association between hepcidin and ferritin, we assessed effect modification by genotype. Results: In this population, we found that 16.2% had sickle cell trait and 0.2% had sickle cell disorder, whereas 40.0% were heterozygous for alpha+ thalassemia and 8.2% were homozygous. Hepcidin concentration did not differ by genotype, but effect modification was found by genotype in the association between hepcidin and ferritin (P < 0.1). Among normozygous sickle cell children (HbAA), there was an association between hepcidin and ferritin (beta = 0.92; 95% CI: 0.72, 1.10). However, among those with sickle cell trait (HbAS), the association was no longer significant (beta = 0.31; 95% CI: -0.04, 0.66). Similarly, among children who were normozygous (alphaalpha/alphaalpha) or heterozygous (-alpha/alphaalpha) for alpha+-thalassemia, hepcidin and ferritin were significantly associated [beta = 0.94 (95% CI: 0.68, 1.20) and beta = 0.77 (95% CI: 0.51, 1.03), respectively]; however, in children who were homozygous for alpha+-thalassemia (-alpha/-alpha), there was no longer a significant association (beta = 0.45; 95% CI: -0.10, 1.00). Conclusion: Hepcidin was not associated with hemoglobin genotype, but there may be a difference in the way hepcidin responds to iron status among those with either sickle cell trait or homozygous alpha+ thalassemia in young Kenyan children. This trial was registered at clinicaltrials.gov as NCT01704105. PMID- 30517730 TI - Stable Isotope Ratios: Nutritional Biomarker and More. PMID- 30517729 TI - Body Mass Index Mediates the Association between Dietary Fiber and Symptomatic Knee Osteoarthritis in the Osteoarthritis Initiative and the Framingham Osteoarthritis Study. AB - Background: Dietary fiber reduces body weight and inflammation in clinical trials. It is unclear whether body mass index (BMI) and inflammation might explain the observed association between higher fiber intake and the lower risk of symptomatic knee osteoarthritis (SXKOA). Objectives: We quantified the extent to which BMI and inflammation influenced the relation between dietary fiber and SXKOA. Methods: We used longitudinal data from the Osteoarthritis Initiative (OAI) and the Framingham Offspring Osteoarthritis Study. At baseline of each study, men and women (mean age: 61 y) with or at risk of knee osteoarthritis were followed for 48 mo in the OAI. Adults (mean age: 53 y) were followed for 9.5 y in the Framingham study. Dietary fiber intake was estimated using a validated food frequency questionnaire. Measured weight and height were used to calculate BMI. Serum high-sensitivity C-reactive protein (CRP) was measured in the Framingham study only. Incident SXKOA was defined as new onset of a combination of knee pain and radiographic osteoarthritis. We applied marginal structural models to quantify the mediation through BMI in the OAI and the sequential mediation through BMI and CRP in the Framingham study. Results: Incident SXKOA occurred in 861 knees among 2876 persons in the OAI and in 143 knees among 971 persons in the Framingham study. In persons whose fiber intake was >=21 g/d compared with those with intakes <21 g/d, the OR (95% CI) was 0.70 (0.53, 0.91) for the overall association with SXKOA and was 0.93 (0.92, 0.95) for the mediation via BMI (per kg/m2) in the OAI. In the Framingham study, the overall association was 0.57 (0.30, 1.09), the mediation through BMI (via BMI and the influence of BMI on CRP) was 0.94 (0.85, 1.02), and the mediation through CRP (per milligram per liter) was 0.99 (0.84, 1.19). Conclusion: Our findings suggest that the inverse association of fiber intake and the risk of incident symptomatic knee osteoarthritis is partially mediated by BMI. PMID- 30517731 TI - Adopting a Mediterranean-Style Eating Pattern with Different Amounts of Lean Unprocessed Red Meat Does Not Influence Short-Term Subjective Personal Well-Being in Adults with Overweight or Obesity. AB - Background: Reducing red meat intake is commonly recommended. Limited observational studies suggest that healthy eating patterns with red meat are associated with improved quality of life. Objective: The secondary objectives of this randomized crossover controlled-feeding trial were to assess the effects of following a Mediterranean-style eating pattern (Med-Pattern) with different amounts of red meat on indexes of personal well-being (i.e., perceived quality of life, mood, and sleep) in overweight or obese adults. We hypothesized that following a Med-Pattern would improve these outcomes, independent of red meat intake amount. Methods: Forty-one participants [aged 46 +/- 2 y; body mass index (kg/m2): 30.5 +/- 0.6; n = 28 women, n = 13 men) were provided Med-Pattern foods for two 5-wk periods separated by 4 wk of self-selected eating. The Med-Red Pattern contained ~500 g/wk (typical US intake), and the Med-Control Pattern contained ~200 g/wk (commonly recommended intake in heart-healthy eating patterns) of lean, unprocessed beef or pork compensated with mainly poultry and dairy. Baseline and postintervention outcomes measured were perceived quality of life via the MOS 36-Item Short-Form Health Survey, version 2 (SF-36v2), daily mood states via the Profile of Mood States (POMS), sleep perceptions via the Pittsburgh Sleep Quality Index, and sleep patterns via actigraphy. Data were analyzed via a doubly repeated-measures ANOVA adjusted for age, sex, and body mass at each time point. Results: Following a Med-Pattern did not change domains of physical health, mental health, total mood disturbances, sleep perceptions, and sleep patterns but improved subdomains of physical health role limitations (SF-36v2: 93.6-96.7%; P = 0.038), vitality (SF-36v2: 57.9-63.0%; P = 0.020), and fatigue (POMS: 2.9-2.5 arbitrary units; P = 0.039). There were no differences between the Med-Red and Med-Control Patterns (time * pattern, P-interaction > 0.05). Conclusion: Following a Med-Pattern, independent of lean, unprocessed red meat intake, may not be an effective short-term strategy to meaningfully improve indexes of personal well-being in adults who are overweight or obese. This trial was registered at clinicaltrials.gov as NCT02573129. PMID- 30517732 TI - Golden Orbweavers Ignore Biological Rules: Phylogenomic and Comparative Analyses Unravel a Complex Evolution of Sexual Size Dimorphism. AB - Instances of sexual size dimorphism (SSD) provide the context for rigorous tests of biological rules of size evolution, such as Cope's Rule (phyletic size increase), Rensch's Rule (allometric patterns of male and female size), as well as male and female body size optima. In certain spider groups, such as the golden orbweavers (Nephilidae), extreme female-biased SSD (eSSD, female:male body length >= 2) is the norm. Nephilid genera construct webs of exaggerated proportions, which can be aerial, arboricolous, or intermediate (hybrid). First, we established the backbone phylogeny of Nephilidae using 367 Anchored Hybrid Enrichment (AHE) markers, then combined these data with classical markers for a reference species-level phylogeny. Second, we used the phylogeny to test Cope and Rensch's Rules, sex specific size optima, and the coevolution of web size, type, and features with female and male body size and their ratio, SSD. Male, but not female, size increases significantly over time, and refutes Cope's Rule. Allometric analyses reject the converse, Rensch's Rule. Male and female body sizes are uncorrelated. Female size evolution is random, but males evolve towards an optimum size (3.2-4.9 mm). Overall, female body size correlates positively with absolute web size. However, intermediate sized females build the largest webs (of the hybrid type), giant female Nephila and Trichonephila build smaller webs (of the aerial type), and the smallest females build the smallest webs (of the arboricolous type). We propose taxonomic changes based on the criteria of clade age, monophyly and exclusivity, classification information content, and diagnosability. Spider families, as currently defined, tend to be between 37-98 million years old, and Nephilidae is estimated at 133 Ma (97 - 146), thus deserving family status. We therefore resurrect the family Nephilidae Simon 1894 that contains Clitaetra Simon 1889, the Cretaceous Geratonephila Poinar & Buckley 2012, Herennia Thorell 1877, Indoetra Kuntner 2006, new rank, Nephila Leach 1815, Nephilengys L. Koch 1872, Nephilingis Kuntner 2013, Palaeonephila Wunderlich 2004 from Tertiary Baltic amber, and Trichonephila Dahl 1911, new rank. We propose the new clade Orbipurae to contain Araneidae Clerck 1757, Phonognathidae Simon 1894, new rank, and Nephilidae. Nephilid female gigantism is a phylogenetically-ancient phenotype (over 100 Ma), as is eSSD, though their magnitudes vary by lineage. PMID- 30517733 TI - N6-Hydroxymethyladenine: a hydroxylation derivative of N6-methyladenine in genomic DNA of mammals. AB - In addition to DNA cytosine methylation (5-methyl-2'-deoxycytidine, m5dC), DNA adenine methylation (N6-methyl-2'-deoxyadenosine, m6dA) is another DNA modification that has been discovered in eukaryotes. Recent studies demonstrated that the content and distribution of m6dA in genomic DNA of vertebrates and mammals exhibit dynamic regulation, indicating m6dA may function as a potential epigenetic mark in DNA of eukaryotes besides m5dC. Whether m6dA undergoes the further oxidation in a similar way to m5dC remains elusive. Here, we reported the existence of a new DNA modification, N6-hydroxymethyl-2'-deoxyadenosine (hm6dA), in genomic DNA of mammalian cells and tissues. We found that hm6dA can be formed from the hydroxylation of m6dA by the Fe2+- and 2-oxoglutarate-dependent ALKBH1 protein in genomic DNA of mammals. In addition, the content of hm6dA exhibited significant increase in lung carcinoma tissues. The increased expression of ALKBH1 in lung carcinoma tissues may contribute to the increase of hm6dA in DNA. Taken together, our study reported the existence and formation of hm6dA in genomic DNA of mammals. PMID- 30517734 TI - Mind the gap: Building the psychological capital of travellers. PMID- 30517735 TI - Increases in absolute temperature stimulate free calcium concentration elevations in the chloroplast. AB - Plants need to sense increases in temperature to be able to adapt their physiology and development to survive; however, the mechanisms of heat perception are currently relatively poorly understood. Here we demonstrate that in response to elevated temperature the free calcium concentration of the stroma of chloroplasts increases. This response is specific to the chloroplast, as no corresponding increase in calcium is seen in the cytosol. The chloroplast calcium response is dose-dependent above a threshold. The magnitude of this calcium response is dependent upon absolute temperature, not rate of heating. This response is dynamic: repeated stimulation leads to rapid attenuation of the response, which can be overcome by sensitisation at a higher temperature. More long-term acclimation to different temperatures resets the basal sensitivity of the system, such that plants acclimated to lower temperatures are more sensitive than those acclimated to higher temperatures. The heat-induced chloroplast calcium response was partially dependent upon the calcium-sensing receptor CAS which has been shown previously to regulate other chloroplast calcium signalling responses. Taken together our data demonstrate the ability of chloroplasts to sense absolute high temperature and produce commensurately quantitative stromal calcium response, the magnitude of which is a function of both current temperature and stress history. PMID- 30517736 TI - Extensive CRISPR RNA modification reveals chemical compatibility and structure activity relationships for Cas9 biochemical activity. AB - CRISPR (clustered regularly interspaced short palindromic repeat) endonucleases are at the forefront of biotechnology, synthetic biology and gene editing. Methods for controlling enzyme properties promise to improve existing applications and enable new technologies. CRISPR enzymes rely on RNA cofactors to guide catalysis. Therefore, chemical modification of the guide RNA can be used to characterize structure-activity relationships within CRISPR ribonucleoprotein (RNP) enzymes and identify compatible chemistries for controlling activity. Here, we introduce chemical modifications to the sugar-phosphate backbone of Streptococcus pyogenes Cas9 CRISPR RNA (crRNA) to probe chemical and structural requirements. Ribose sugars that promoted or accommodated A-form helical architecture in and around the crRNA 'seed' region were tolerated best. A wider range of modifications were acceptable outside of the seed, especially D-2' deoxyribose, and we exploited this property to facilitate exploration of greater chemical diversity within the seed. 2'-fluoro was the most compatible modification whereas bulkier O-methyl sugar modifications were less tolerated. Activity trends could be rationalized for selected crRNAs using RNP stability and DNA target binding experiments. Cas9 activity in vitro tolerated most chemical modifications at predicted 2'-hydroxyl contact positions, whereas editing activity in cells was much less tolerant. The biochemical principles of chemical modification identified here will guide CRISPR-Cas9 engineering and enable new or improved applications. PMID- 30517738 TI - Differential evolution of the epidermal keratin cytoskeleton in terrestrial and aquatic mammals. AB - Keratins are the main intermediate filament proteins of epithelial cells. In keratinocytes of the mammalian epidermis they form a cytoskeleton that resists mechanical stress and thereby are essential for the function of the skin as a barrier against the environment. Here, we performed a comparative genomics study of epidermal keratin genes in terrestrial and fully aquatic mammals to determine adaptations of the epidermal keratin cytoskeleton to different environments. We show that keratins K5 and K14 of the innermost (basal), proliferation-competent layer of the epidermis are conserved in all mammals investigated. By contrast, K1 and K10, which form the main part of the cytoskeleton in the outer (suprabasal) layers of the epidermis of terrestrial mammals, have been lost in whales and dolphins (cetaceans) and in the manatee. While in terrestrial mammalian epidermis K6 and K17 are expressed only upon stress-induced epidermal thickening, high levels of K6 and K17 are consistently present in dolphin skin, indicating constitutive expression and substitution of K1 and K10. K2 and K9, which are expressed in a body site-restricted manner in human and mouse suprabasal epidermis, have been lost in cetaceans and manatee but also in some terrestrial mammals. The evolution of alternative splicing of K10 and differentiation dependent upregulation of K23 have increased the complexity of keratin expression in the epidermis of terrestrial mammals. Taken together, these results reveal evolutionary diversification of the epidermal cytoskeleton in mammals and suggest a complete replacement of the quantitatively predominant epidermal proteins of terrestrial mammals by originally stress-inducible keratins in cetaceans. PMID- 30517739 TI - Aberrant splicing in B-cell acute lymphoblastic leukemia. PMID- 30517740 TI - Structural Patching Fosters Divergence of Mitochondrial Ribosomes. AB - Mitochondrial ribosomes (mitoribosomes) are essential components of all mitochondria that synthesize proteins encoded by the mitochondrial genome. Unlike other ribosomes, mitoribosomes are highly variable across species. The basis for this diversity is not known. Here, we examine the composition and evolutionary history of mitoribosomes across the phylogenetic tree by combining three dimensional structural information with a comparative analysis of the secondary structures of mitochondrial rRNAs (mt-rRNAs) and available proteomic data. We generate a map of the acquisition of structural variation and reconstruct the fundamental stages that shaped the evolution of the mitoribosomal large subunit and led to this diversity. Our analysis suggests a critical role for ablation and expansion of rapidly evolving mt-rRNA. These changes cause structural instabilities that are "patched" by the acquisition of pre-existing compensatory elements, thus providing opportunities for rapid evolution. This mechanism underlies the incorporation of mt-tRNA into the central protuberance of the mammalian mitoribosome, and the altered path of the polypeptide exit tunnel of the yeast mitoribosome. We propose that since the toolkits of elements utilized for structural patching differ between mitochondria of different species, it fosters the growing divergence of mitoribosomes. PMID- 30517741 TI - The isoniazid metabolites hydrazine and pyridoxal isonicotinoyl hydrazone modulate heme biosynthesis. AB - In a mouse model, rifampicin and isoniazid combination treatment results in cholestatic liver injury that is associated with an increase in protoporphyrin IX (PPIX), the penultimate heme precursor. Both ferrochelatase (FECH/Fech) and aminolevulinic acid synthase 1 (ALAS1/Alas1) are crucial enzymes in regulating heme biosynthesis. Isoniazid has recently been reported to upregulate Alas1 but downregulate Fech protein levels in mice; however, the mechanism by which isoniazid mediates disruption of heme synthesis has been unclear. Two metabolites of isoniazid, pyridoxal isonicotinoyl hydrazone (PIH, the isoniazid-vitamin B6 conjugate) and hydrazine, have been detected in the urine of humans treated with isoniazid. Here we show that, in primary human hepatocytes and the human hepatocellular carcinoma cell line HepG2/C3A, (1) isoniazid treatment increases Alas1 protein levels but decreases Fech levels; (2) hydrazine treatment upregulates Alas1 protein and Alas1 mRNA levels; (3) PIH treatment decreases Fech protein levels, but not Fech mRNA levels; and (4) PIH is detected after isoniazid treatment, with levels increasing further when exogenous vitamin B6 analogues are co-administered. In addition, the PIH-mediated downregulation of human FECH is associated with iron chelation. Together, these data demonstrate that hydrazine upregulates ALAS1, whereas PIH downregulates FECH, suggesting that the metabolites of isoniazid mediate its disruption of heme biosynthesis by contributing to PPIX accumulation. PMID- 30517742 TI - Engorged forehead veins in constrictive pericarditis. PMID- 30517737 TI - Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide. AB - Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors. Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided. Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001). Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research. PMID- 30517743 TI - A protein shuttle system to target RNA into mitochondria. PMID- 30517744 TI - A single serine to alanine substitution decreases bicarbonate affinity of phosphoenolpyruvate carboxylase in C4Flaveria trinervia. AB - Phosphoenolpyruvate (PEP) carboxylase (PEPc) catalyzes the first committed step of C4 photosynthesis generating oxaloacetate from bicarbonate (HCO3-) and PEP. It is hypothesized that PEPc affinity for HCO3- has undergone selective pressure for a lower KHCO3 (Km for HCO3-) to increase the carbon flux entering the C4 cycle, particularly during conditions that limit CO2 availability. However, the decrease in KHCO3 has been hypothesized to cause an unavoidable increase in KPEP (Km for PEP). Therefore, the amino acid residue S774 in the C4 enzyme, which has been shown to increase KPEP, should lead to a decrease in KHCO3. Several studies reported the effect S774 has on KPEP; however, the influence of this amino acid substitution on KHCO3 has not been tested. To test these hypotheses, membrane inlet mass spectrometry (MIMS) was used to measure the KHCO3 of the photosynthetic PEPc from the C4Flaveria trinervia and the non-photosynthetic PEPc from the C3F. pringlei. The cDNAs for these enzymes were overexpressed and purified from the PEPc-less PCR1 Escherichia coli strain. Our work in comparison with previous reports suggests that KHCO3 and KPEP are linked by specific amino acids, such as S774; however, these kinetic parameters respond differently to the tested allosteric regulators, malate and glucose-6-phosphate. PMID- 30517745 TI - Histologic evidence that mast cells contribute to local tissue inflammation in peripheral spondyloarthritis by regulating interleukin-17A content. AB - Objectives: Synovial mast cells contain IL-17A, a key driver of tissue inflammation in SpA. A recent in vitro study showed that tissue-derived mast cells can capture and release exogenous IL-17A. The present study aimed to investigate if this mechanism could contribute to tissue inflammation in SpA. Methods: Potential activation of mast cells by IL-17A was assessed by gene expression analysis of the Laboratory of Allergic Diseases 2 (LAD2) mast cell line. The presence of IL-17A-positive mast cells was assessed by immunohistochemistry in synovial tissue obtained before and after secukinumab treatment, as well as in skin and gut tissues from SpA-related conditions. Results: IL-17A did not induce a pro-inflammatory response in human LAD2 mast cells according to the canonical IL-17A signalling pathway. In SpA synovial tissue, the percentage of IL-17A-positive mast cells increased upon treatment with secukinumab. IL-17A-positive mast cells were also readily detectable in non inflamed barrier tissues such as skin and gut. In non-inflamed dermis and gut submucosa, IL-17A-positive mast cells are the most prevalent IL-17A-positive cells in situ. Compared with non-inflamed tissues, both total mast cells and IL 17A-positive mast cells were increased in psoriatic skin dermis and in submucosa from inflammatory bowel disease gut. In contrast, the proportion of IL-17A positive mast cells was strikingly lower in the inflamed compared with non inflamed gut lamina propria. Conclusion: IL-17A-positive mast cells are present across SpA target tissues and correlate inversely with inflammation, indicating that their IL-17A content can be regulated. Tissue-resident mast cells may act as IL-17A-loaded sentinel cells, which release IL-17A to amplify tissue inflammation. PMID- 30517746 TI - Long-term Outcome in Heart Failure Patients Treated with Levothyroxine: An Observational Nationwide Cohort Study. AB - Context: Hypothyroidism has detrimental effects on the cardiovascular system, but controversy remains concerning the benefits of levothyroxine (L-T4) substitution in patients with heart failure (HF). Objective: Examining the effects of L-T4 in patients with HF. Design: Retrospective cohort study. Setting and Participants: All Danish citizens aged >= 18 years diagnosed with HF between 1997 and 2012. L T4 treatment was identified from nationwide registers. Incidence rate ratios (IRR) were calculated using Poisson-regression models. Main Outcome Measures: All cause mortality, myocardial infarction (MI), cardiovascular death and major adverse cardiovascular events (MACE). Results: 224,670 patients were diagnosed with HF (mean age 70.7 [SD+/-14.7] years, 53% male). 6,560 patients were treated with L-T4 at baseline, 9,007 patients initiated L-T4 during follow-up. 209,103 patients did not receive L-T4. During a median follow-up of 4.8 years (IQR 9.2) 147,253 patients died. Increased risk of all-cause mortality (IRR 1.25 [95% CI: 1.21-1.29]) (IRR 1.13 [95% CI: 1.10-1.16]), cardiovascular death (IRR 1.23 [95% CI: 1.18-1.27]) (IRR 1.11 [95% CI: 1.08-1.15]), and MACE (IRR 1.26 [95% CI: 1.22 1.31]) (IRR 1.05 [95% CI: 1.02-1.09]), was observed for treatment on-going at baseline and initiated during follow-up, respectively. Increased risk of MI (IRR 1.32 [95% CI: 1.23-1.41]) was observed for on-going treatment, reduced risk (IRR 0.87 [95% CI: 0.81-0.93]) was observed for incident treatment. Conclusion: On going and incident L-T4 treatment in patients with HF was associated with an increased risk of all-cause mortality, cardiovascular death, and MACE. Increased risk of MI was observed for on-going treatment, reduced risk was observed for incident treatment. PMID- 30517747 TI - Allele-specific genome editing using CRISPR-Cas9 is associated with loss of heterozygosity in diploid yeast. AB - Targeted DNA double-strand breaks (DSBs) with CRISPR-Cas9 have revolutionized genetic modification by enabling efficient genome editing in a broad range of eukaryotic systems. Accurate gene editing is possible with near-perfect efficiency in haploid or (predominantly) homozygous genomes. However, genomes exhibiting polyploidy and/or high degrees of heterozygosity are less amenable to genetic modification. Here, we report an up to 99-fold lower gene editing efficiency when editing individual heterozygous loci in the yeast genome. Moreover, Cas9-mediated introduction of a DSB resulted in large scale loss of heterozygosity affecting DNA regions up to 360 kb and up to 1700 heterozygous nucleotides, due to replacement of sequences on the targeted chromosome by corresponding sequences from its non-targeted homolog. The observed patterns of loss of heterozygosity were consistent with homology directed repair. The extent and frequency of loss of heterozygosity represent a novel mutagenic side-effect of Cas9-mediated genome editing, which would have to be taken into account in eukaryotic gene editing. In addition to contributing to the limited genetic amenability of heterozygous yeasts, Cas9-mediated loss of heterozygosity could be particularly deleterious for human gene therapy, as loss of heterozygous functional copies of anti-proliferative and pro-apoptotic genes is a known path to cancer. PMID- 30517749 TI - ORTHOSCOPE: an automatic web tool for phylogenetically inferring bilaterian orthogroups with user-selected taxa. AB - Identification of orthologous or paralogous relationships of coding genes is fundamental to all aspects of comparative genomics. For accurate identification of orthologs among deeply diversified bilaterian lineages, precise estimation of gene trees is indispensable, given the complicated histories of genes over millions of years. By estimating gene trees, orthologs can be identified as members of an orthogroup, a set of genes descended from a single gene in the last common ancestor of all the species being considered. In addition to comparisons with a given species tree, purposeful taxonomic sampling increases the accuracy of gene tree estimation and orthogroup identification. Although some major phylogenetic relationships of bilaterians are gradually being unraveled, the scattering of published genomic data among separate web databases is becoming a significant hindrance to identification of orthogroups with appropriate taxonomic sampling. By integrating more than 250 metazoan gene models predicted in genome projects, we developed a web tool called ORTHOSCOPE to identify orthogroups of specific protein-coding genes within major bilaterian lineages. ORTHOSCOPE allows users to employ several sequences of a specific molecule and broadly accepted nodes included in a user-specified species tree as queries and to evaluate the reliability of estimated orthogroups based on topologies and node support values of estimated gene trees. A test analysis using data from 36 bilaterians was accomplished within 140 seconds. ORTHOSCOPE results can be used to evaluate orthologs identified by other stand-alone programs using genome-scale data. ORTHOSCOPE is freely available at http://orthoscope.jp or https://github.com/jun inoue/orthoscope (last accessed 14 November 2018). PMID- 30517750 TI - BASELINE STUDIES ON RADIONUCLIDE CONCENTRATION IN FOOD MATERIALS AND ESTIMATION OF THE COMMITTED RADIATION DOSE AROUND THE PHOSPHATE INDUSTRIAL AREA OF SOUTH TUNISIA. AB - The activity concentration of natural and anthropogenic radionuclides was determined in different vegetable samples, and foods derived from animal origin, from different locations in the four cities of Southern Tunisia, where large scale phosphate industries are operating. The aim of the studies was to establish a baseline database on radionuclide concentration in food materials and to evaluate the radiation dose to the general population due to its ingestion through the food chain. The activity concentration of 40K, 210Pb, 226Ra, 228Ra and 137Cs was determined by gamma spectrometry using a HPGe detector, and from the measured activity concentration, the doses were estimated using the dose coefficients given by the ICRP. The dose due to intake of radionuclides through mineral water was also determined. The total annual effective doses were found to be 2.2, 1.4, and 0.7 mSv y-1 for 1 y, 5-15 y and adult (>17 y) age groups, respectively. Among the radionuclides studied, 210Po was the highest contributor to the total dose, followed by 210Pb. PMID- 30517748 TI - Genomic Takeover by Transposable Elements in the Strawberry Poison Frog. AB - We sequenced the genome of the strawberry poison frog, Oophaga pumilio, at a depth of 127.5* using variable insert size libraries. The total genome size is estimated to be 6.76 Gb, of which 4.76 Gb are from high copy number repetitive elements with low differentiation across copies. These repeats encompass DNA transposons, RNA transposons, and LTR retrotransposons, including at least 0.4 and 1.0 Gb of Mariner/Tc1 and Gypsy elements, respectively. Expression data indicate high levels of gypsy and Mariner/Tc1 expression in ova of O. pumilio compared with Xenopus laevis. We further observe phylogenetic evidence for horizontal transfer (HT) of Mariner elements, possibly between fish and frogs. The elements affected by HT are present in high copy number and are highly expressed, suggesting ongoing proliferation after HT. Our results suggest that the large amphibian genome sizes, at least partially, can be explained by a process of repeated invasion of new transposable elements that are not yet suppressed in the germline. We also find changes in the spliceosome that we hypothesize are related to permissiveness of O. pumilio to increases in intron length due to transposon proliferation. Finally, we identify the complement of ion channels in the first genomic sequenced poison frog and discuss its relation to the evolution of autoresistance to toxins sequestered in the skin. PMID- 30517751 TI - Deciphering human ribonucleoprotein regulatory networks. AB - RNA-binding proteins (RBPs) control and coordinate each stage in the life cycle of RNAs. Although in vivo binding sites of RBPs can now be determined genome wide, most studies typically focused on individual RBPs. Here, we examined a large compendium of 114 high-quality transcriptome-wide in vivo RBP-RNA cross linking interaction datasets generated by the same protocol in the same cell line and representing 64 distinct RBPs. Comparative analysis of categories of target RNA binding preference, sequence preference, and transcript region specificity was performed, and identified potential posttranscriptional regulatory modules, i.e. specific combinations of RBPs that bind to specific sets of RNAs and targeted regions. These regulatory modules represented functionally related proteins and exhibited distinct differences in RNA metabolism, expression variance, as well as subcellular localization. This integrative investigation of experimental RBP-RNA interaction evidence and RBP regulatory function in a human cell line will be a valuable resource for understanding the complexity of post transcriptional regulation. PMID- 30517752 TI - Associations Between Immune Phenotype and Inflammation in Murine Models of Irritant Contact Dermatitis. AB - Irritant contact dermatitis (ICD), the most common occupational cutaneous illness, is an acute inflammatory response caused by topical irritant exposure. Multiple factors are associated with the manifestation and severity of ICD and contribute to the lack of effective prophylactic and treatment strategies. To determine the pathomechanism of ICD caused by the irritants, benzalkonium chloride (BKC) and JP-8 jet fuel, two mouse strains, C57BL/6 and Balb/c, were assessed due to their differential immune predispositions. Dermatitis lesions were obtained for histological examination, cytokine protein expression analysis, and determination of immune cell infiltration via flow cytometric analysis. Following acute (3-day) BKC exposure C57BL/6 skin displayed increased neutrophils and expression of 19 distinct cytokines, but fewer dendritic cells and lower expression of IL-1alpha and IL-9 as compared to Balb/c skin. Following prolonged (7-day) exposure to BKC, inflammatory cell populations trended similar to 3-day; however, only 6 distinct cytokines were higher in C57BL/6, whereas Balb/c displayed higher expression of IL-27, 28, and 31. Following acute JP-8 exposure, C57BL/6 skin displayed higher levels of gammadelta T cell infiltration, G and M CSF expression, but lower populations of neutrophils, monocytes, and dendritic cells compared to Balb/c skin. As with BKC, skin inflammatory cell populations following 7-day JP-8 exposure trended similar to 3 day. However, C57BL/6 skin displayed higher levels of IL-6 and LIF, whereas Balb/c showed increased IL 1beta, IL-27, G-CSF, TNFalpha and 7 additional chemokines. These findings further define the pathology of ICD, partially explain individual variation of ICD, and offer insight into biomarkers for risk assessment. PMID- 30517753 TI - Cumulative Inequality at the End of Life?: Racial Disparities in Impairment in the Time Before Death. AB - Objectives: Drawing from cumulative inequality (CI) theory, the current study examined racial disparities in impairment as individuals approached death to determine whether proposed mechanisms hypothesized to fuel or diminish racial disparities at late ages were at work at the end of individualized life spans. Method: Black-white disparities were analyzed among decedents using latent growth curves based on the data from the North Carolina Established Populations for Epidemiologic Studies of the Elderly (EPESE) (N = 1,926). Results: Consistent with previous literature, racial inequalities in functional disparities diminish at late ages. However, significant black-white disparities emerge as older adults approach death, exponentially increasing within the 2 years immediately preceding death. Further, these disparities are not fully mediated by socioeconomic status. Discussion: The results confirm that CI in health outcomes is observable in late life among individual life spans, suggesting the years surrounding death may be a particularly vulnerable period for health inequality. Future research should examine how advantaged statuses translate to increased access to health-related resources that aid in maintaining greater functional independence until the last stage of life. PMID- 30517754 TI - Molecular basis for the differential interaction of plant mitochondrial VDAC proteins with tRNAs. PMID- 30517755 TI - Irreversible activation of Rho-activated kinases resulted from evolution of proteolytic sites within disordered regions in coiled-coil domain. AB - Activation of Rho-associated protein kinase 1 (ROCK1) and myotonic dystrophy kinase-related CDC42-binding kinase alpha (MRCKalpha) by caspases during apoptosis in vertebrates represents a prototypical example of co-option of kinases by proteases. How caspases acquired the ability to control these proteins during evolution of vertebrates is still unknown. Here, we report a phylogenetic and molecular study on the acquisition of caspase-cleavage sites in the family of Rho-activated kinases (RaKs). We demonstrate that the acquisition of such sites has more frequently occurred in identifiable intrinsically disordered regions (IDRs) within or flanking the coiled-coil domain. Thanks to computational identification of IDRs in protein sequences of different organisms, we predicted and validated the independent evolution of two caspase-cleavage sites in ROCK of arthropods and the loss of one of the MRCKalpha caspase-cleavage sites in ray finned fishes. In conclusion, we shed light on the propensity of RaKs to evolve novel proteolytic sites, causing kinase activation and uniform subcellular distribution. PMID- 30517756 TI - Magnitude and Chronicity of Environmental Smoke Exposure Across Infancy and Early Childhood in a Sample of Low-Income Children. AB - Introduction: Infants and young children may be at an increased risk for second- and thirdhand exposure to tobacco smoke because of increased respiration rate and exposure to surface residue. However, relatively fewer studies have examined biomarkers of exposure (cotinine) in children under age 4 years. This study examines the magnitude and chronicity of exposure across early childhood among children from low-income families in order to better characterize contextual risk factors associated with exposure. Methods: A total of 1292 families were recruited in six nonurban counties of Pennsylvania and North Carolina. Cotinine was assayed from infant saliva at 6, 15, 24, and 48 months of age (N = 1218), and categorized as low (<=0.45 ng/mL), moderate (0.46-12 ng/mL), or high (>=12 ng/mL) at each time point. Categories were highly correlated across time. Latent class analysis was used to summarize patterns of exposure categories across time. Results: Magnitude of exposure in this sample was high, with approximately 12% of infants registering cotinine values at least 12 ng/mL, consistent with active smoking in adults. Greater exposure was associated with lower income, less education, more residential instability, and more instability in adult occupants in the home, whereas time spent in center-based day care was associated with lower exposure. Conclusions: Young children from low-income, nonurban communities appear to bear a higher burden of secondhand smoke exposure than previous studies have reported. Results contribute to understanding populations at greater risk, as well as specific, potentially malleable, environmental factors that may be examined as direct contributors to exposure. Implications: Results suggest that infants from low-income, nonurban families have higher risk for environmental smoke exposure than data from nationally representative samples. Predictors of exposure offer insights into specific factors that may be targeted for risk reduction efforts, specifically conditions of children's physical space. In addition to considering the increases in risk when an adult smoker lives in a child's home, families should also attend to the possible risk embedded within the home itself, such as residual smoke from previous occupants. For high-risk children, day care appears to mitigate the magnitude of exposure by providing extended time in a smoke-free environment. PMID- 30517757 TI - Bilateral Lens Subluxation in Marfan syndrome. PMID- 30517758 TI - Laser microdissection-based tissue specific transcriptome analyses reveals novel regulatory network of genes involved in heat-induced grain chalk in rice endosperm. AB - Heat stress occurrence during seed filling forms chalky portion in the limited zone of starchy endosperm of rice grains. In this study, isolation of aleurone, dorsal, central and lateral tissues of developing endosperm by laser microdissection (LM) coupled with gene expression analysis of 44K microarray was performed to identify key regulatory genes involved in the formation of milky white (MW) and white-back (WB) grains during heat stress. Gene regulatory network analysis classified the genes changed under heat stress into five modules. The most distinct expression pattern was observed in modules where most of the small heat shock proteins and cellular organization genes being changed under heat stress in dorsal aleurone cells and dorsal starchy endosperm zones. The histological observation supported the significant increase in cell number and size of dorsal aleurone cells in WB grains. With regard to the central starchy endosperm zone, preferential downregulation of high molecular weight heat shock proteins (HMW HSPs) including a prominent member encoding for endoplasmic reticulum (ER) chaperones by heat stress were observed, while changes in expression of starch-biosynthesis genes were minimal. Characterization of transgenic plants supressing endosperm lumenal binding protein (BiP1), an ER chaperone preferentially downregulated at MW zone under heat stress, showed an evidence of forming the chalky grains without disturbing the expression of starch biosynthesis genes. The present LM-based comprehensive expression analyses provides novel inferences that HMW HSPs play important role in controlling redox, nitrogen and amino acid metabolism in endosperm leading to the formation of MW and WB chalky grains under heat stress. PMID- 30517759 TI - Let it snow! Winter conditions affect growth of birch seedlings during the following growing season. AB - Air temperatures and precipitation are predicted to increase in the future, especially at high latitudes and particularly so during winter. In contrast to air temperatures, changes in soil temperatures are more difficult to predict, as the fate of the insulating snow cover is crucial in this respect. Soil conditions can also be affected by rain-on-snow events and warm spells during winter, resulting in freeze-thaw cycles, compacted snow, ice encasement and local flooding. These adverse conditions during winter could counteract the otherwise positive effects of climate change on forest growth and productivity. For studying the effects of different winter and snow conditions on young Downy birch (Betula pubescens Ehrh.) seedlings, we carried out a laboratory experiment with birch seedlings subjected to four different winter scenarios: snow covering the seedlings (SNOW), compressed snow and ice encasement (ICE), flooded and frozen soil (FLOOD) and no snow at all (NO SNOW). After the winter treatments we simulated a spring and early summer period of 9.5 weeks, and monitored the growth by measuring shoot and root biomass of the seedlings, and starch and soluble sugar concentrations. We also assessed the stress experienced by the seedlings by measuring leaf chlorophyll fluorescence and gas exchange. Although no difference in mortality was observed between the treatments, the seedlings in the SNOW and ICE treatments had significantly higher shoot and root biomass compared with those in the FLOOD and NO SNOW treatments. We found higher starch concentrations in roots of the seedlings in the SNOW and ICE treatments, compared with those in the FLOOD and NO SNOW treatments, although photosynthesis did not differ. Our results suggest a malfunction of carbohydrate distribution in the seedlings of the FLOOD and NO SNOW treatments, probably resulting from decreased sinks. The results underline the importance of an insulating and protecting snow cover for small tree seedlings, and that future winters with changed snow pattern might affect the growth of tree seedlings and thus possibly species composition and forest productivity. PMID- 30517760 TI - The changes will not be televised, but.... PMID- 30517761 TI - Ice Pack Test - An Useful Bedside Test to Diagnose Myasthenia Gravis. AB - Myasthenia gravis is a common autoimmune neurological disorder that is frequently encountered in our daily practice. Its presentation can vary from ocular myasthenia, generalized myasthenia to myasthenia crisis. Diagnosing a myasthenia crisis is especially challenging in an intubated patient. Investigations that can be used to diagnose myasthenia gravis include serum acetylcholine receptor antibodies and repetitive nerve stimulation, however, these tests are not widely available. Here, we reported a case of myasthenia crisis which was diagnosed early by ice pack test and it resulted in full recovery of the patient. PMID- 30517762 TI - Histopathological and molecular signatures of a mouse model of acute-on-chronic alcoholic liver injury demonstrate concordance with human alcoholic hepatitis. AB - Human alcoholic hepatitis (AH) carries a high mortality rate. AH is an acute-on chronic form of liver injury characterized by hepatic steatosis, ballooned hepatocytes, neutrophil infiltration, and pericellular fibrosis. We aimed to study the pathogenesis of AH in an animal model which combines chronic hepatic fibrosis with intragastric alcohol administration. Adult male C57BL6/J mice were treated with CCl4 (0.2 ml/kg, 2*weekly by intraperitoneal injections for 6 weeks) to induce chronic liver fibrosis. Then, ethyl alcohol (up to 25 g/kg/day for 3 weeks) was administered continuously to mice via a gastric feeding tube, with or without one-half dose of CCl4. Liver and serum markers and liver transcriptome were evaluated to characterize acute-on-chronic-alcoholic liver disease in our model. CCl4 or alcohol treatment alone induced liver fibrosis or steatohepatitis, respectively, findings that were consistent with expected pathology. Combined treatment resulted in a marked exacerbation of liver injury, as evident by the development of inflammation, steatosis, and pericellular fibrosis, pathological features of human AH. E. coli and Candida were also detected in livers of mice co treated with CCl4 and alcohol, indicating pathogen translocation from gut to liver, similar to human AH. Importantly, liver transcriptomic changes specific to combined treatment group demonstrated close concordance with pathways perturbed in patients with severe AH. Overall, mice treated with CCl4 and alcohol displayed key molecular and pathological characteristics of human AH - pericellular fibrosis, increased hepatic bacterial load, and dysregulation of the same molecular pathways. This model may be useful for developing therapeutics for AH. PMID- 30517763 TI - ITCH nuclear translocation and H1.2 polyubiquitination negatively regulate the DNA damage response. AB - The downregulation of the DNA damage response (DDR) enables aggressive tumors to achieve uncontrolled proliferation against replication stress, but the mechanisms underlying this process in tumors are relatively complex. Here, we demonstrate a mechanism through which a distinct E3 ubiquitin ligase, ITCH, modulates DDR machinery in triple-negative breast cancer (TNBC). We found that expression of a nuclear form of ITCH was significantly increased in human TNBC cell lines and tumor specimens. Phosphorylation of ITCH at Ser257 by AKT led to the nuclear localization of ITCH and ubiquitination of H1.2. The ITCH-mediated polyubiquitination of H1.2 suppressed RNF8/RNF168-dependent formation of 53BP1 foci, which plays important roles in DDR. Consistent with these findings, impaired ITCH nuclear translocation and H1.2 polyubiquitination sensitized cells to replication stress and limited cell growth and migration. AKT activation of ITCH-H1.2 axis may confer TNBC cells with a DDR repression to counteract the replication stress and increase cancer cell survivorship and growth potential. PMID- 30517764 TI - Paradoxical effects of emodin on ANIT-induced intrahepatic cholestasis and herb induced hepatotoxicity in mice. AB - Emodin is an active ingredient in many herbal medicines and has a broad spectrum of pharmacological activities. The current data indicate that emodin exerts its beneficial effect on alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis through its anti-oxidant and anti-inflammatory activities. Emodin has little effect on the concentrations of bile acids (BAs) in livers of ANIT-treated mice. Instead, emodin shows a potential pro-cholestatic effect by interfering with the crosstalk between AMP-activated protein kinase (AMPK) and farnesoid X receptor (Fxr) in the liver, which leads to a suppression of bile salt export pump (Bsep). Two emodin-containing herbs, namely Polygonum multiflorum (PM) and Semen cassiae (SC), markedly aggravate the intrahepatic cholestasis in ANIT treated mice. SC interferes with the AMPK-Fxr crosstalk and suppresses Bsep in livers of mice. ANIT markedly increases the hepatic retention of emodin in SC treated mice. The major SC constituents, in particular three anthraquinones, are able to activate AMPK in HepG2 cells and inhibit Bsep in primary mouse hepatocytes, with emodin showing the strongest activities. Together, the present study identifies a potential pro-cholestatic role of emodin in the hepatotoxicity of herbs. PMID- 30517765 TI - Antimicrobial stewardship programs in long-term care settings: a meta-analysis and systematic review. AB - BACKGROUND: Antimicrobial stewardship programs have been established in hospitals, but less studied in long-term care facilities (LTCFs), a setting with unique challenges related to patient populations and available resources. This systematic review sought to provide a comprehensive assessment of antimicrobial stewardship interventions implemented in LTCFs, using meta-analysis to examine their impact on overall antimicrobial use. METHODS: Electronic searches of MEDLINE, Embase, and CINAHL (1990 to July 2018) identified any antimicrobial stewardship interventions in LTCFs, with no restriction on patient population, study design, or outcomes. Intervention components were categorized using the Cochrane Effective Practice and Organization of Care taxonomy on implementation strategies. Random-effects meta-analysis used ratio of means to facilitate pooling of different metrics of antimicrobial use. RESULTS: Eighteen studies (one randomized controlled trial [RCT], four cluster RCTs, four controlled pre/post studies, and nine uncontrolled pre/post studies) met inclusion, using 13 different antimicrobial stewardship intervention strategies; 15 studies used multifaceted (maximum, seven; median, four) interventions. The three most commonly implemented strategies were educational materials, educational meetings, and guideline implementation. Intervention labor intensity and resource requirements varied considerably among interventions. Meta-analysis of 11 studies demonstrated that antimicrobial stewardship strategies were associated with a 14% reduction in overall antimicrobial use (95% confidence interval = -8% to -20%; P < .0001), with similar results by study design but high heterogeneity (I2 = 86%) for the uncontrolled pre/post study subgroup and no heterogeneity (I2 = 0%) for the cluster RCT and controlled pre/post study subgroups. Funnel plot analysis suggested publication bias, with a lack of publication of smaller studies showing increased antibiotic use. CONCLUSION: Antimicrobial stewardship strategies implemented in long-term care vary considerably in design and resource intensity, but collectively suggest potential to reduce antimicrobial use in this challenging setting. PMID- 30517766 TI - The Accumulation of Risk and Essential Elements in Edible Mushrooms Chlorophyllum rhacodes, Suillus grevillei, Imleria badia, and Xerocomellus chrysenteron Growing in the Czech Republic. AB - Risk and essential elements were determined in fruiting bodies of wild growing edible mushrooms Chlorophyllum rhacodes, Suillus grevillei, Imleria badia, and Xerocomellus chrysenteron collected in an unpolluted site in South Bohemia, the Czech Republic. The elements were also determined in underlying soils and the bioconcentration factors were calculated. The analyses revealed that C. rhacodes accumulated Ag, Cu, Rb, Se, Zn, As, Cd, and Tl. On the other hand, S. grevillei accumulated Cd, Rb, Ag, Se, and Cs. I. badia and X. chrysenteron strongly accumulated Rb, Cs, and Ag; these species showed the ability to accumulate Cu and Zn as well. Contents of detrimental CrVI were in all cases below the quantification limit (0.003 mg kg-1 dry matter). Studied mushroom species (mainly C. rhacodes) accumulated some toxic elements. However, no considerable effect on human health is expected since they are usually consumed as a delicacy and do not represent a major component of diet. PMID- 30517767 TI - Protein Intake and Risk of Falls: A Prospective Analysis in Older Adults. AB - BACKGROUND: The prospective association between protein intake and falls has been little studied. We assessed this association in a Spanish community-dwelling cohort. METHODS: We performed a prospective cohort study of 2464 men and women 60 years or older who were recruited in 2008-2010 and followed up through 2012. At baseline, the habitual protein intake was determined with a validated dietary history. At the end of follow-up, participants reported the number of falls experienced in the preceding year. Participants were stratified by an unintentional weight loss of 4.5 kg or more. Logistic regression was used after adjustment for the main confounders. RESULTS: A total of 522 participants (21.2%) experienced at least one fall. The odds ratios (ORs) and 95% confidence intervals (CIs) of falling for the three increasing tertiles of total protein intake were 1.00, 0.86 (0.66-1.11), and 0.93 (0.70-1.24) (p for trend = 0.14). However, a statistically significant interaction with unintentional weight loss was observed for the association between protein intake and fall risk (p for interaction = 0.004). Among 163 participants (6.6%) who experienced unintentional weight loss, the ORs (95% CI) of falling for the three increasing tertiles of total protein intake were 1.00, 0.68 (0.21-2.23), and 0.23 (0.05-1.08) (p for trend = 0.01). CONCLUSION: No protective association between protein intake and fall risk in older adults was found. However, high total protein intake tended to confer substantial benefits to participants who experienced an unintentional weight loss of 4.5 kg or more in the preceding year. PMID- 30517768 TI - Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications. AB - Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide-binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD-dependent and TLR-dependent signaling pathways; and (iii) interactions at the post-transcriptional level. Potential practical implications of NOD-TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens. PMID- 30517769 TI - Copper Substitution Induced CO Adsorption Site Change of a Ruthenium Catalyst for Highly Enhanced CO Oxidation Activity. AB - Ru is an important catalyst in many types of reactions. Specifically, Ru is well known as the best monometallic catalyst for oxidation of carbon monoxide (CO) and has been practically used in residential fuel cell systems. However, Ru is a minor metal, and the supply risk often causes violent fluctuations in the price of Ru. Here, we report performance-improved and cost-reduced solid-solution alloy nanoparticles of the Cu-Ru system for CO oxidation. Over the whole composition range, all the CuxRu1-x nanoparticles exhibit significantly enhanced CO oxidation activities, even at 70 at% inexpensive Cu, compared to Ru nanoparticles. Only 5 at% replacement of Ru with Cu provided much better CO oxidation activity, and the maximum activity was achieved by 20 at% replacement of Ru by Cu. The origin of the high catalytic performance was found as CO site change by Cu substitution, which was investigated using in situ Fourier transform infrared spectra and theoretical calculation. PMID- 30517770 TI - Ancient herbal component may be a novel therapeutic for gouty arthritis. PMID- 30517771 TI - Tuning Thiol-Based Self-Assembled Monolayer Chemistry on a Gold Surface toward Synthesis of Biochemical Fuel. AB - A proton gradient across the lipid membrane is required for production of biochemical fuel. Much effort has been devoted to reactions involving proton production in biomimetic assembled architectures under mild conditions. Here, we explore thiol-based self-assembled monolayer chemistry on a naked gold surface for production of biochemical fuel. Protons are generated when alkane thiols self assemble on a gold surface and the proton yield can be tuned by the choice of thiol and by variation of the procedure used for the deposition of gold. Consequently, the proton gradient across a lipid membrane above the gold surface can be modulated to vary the production rate of biochemical fuel performed by lipid-embedded motor proteins. Our work presents evidence that a simple and efficient abiotic chemical reaction in a well-defined biohybrid system can convert unnatural chemicals, alkane thiols, into bioenergy molecules, a finding that has a great potential in biofuel-driven catalysis and devices. PMID- 30517772 TI - Enantioselective Aluminum-Free Alkene Hydroarylations via C-H Activation by a Chiral Nickel/JoSPOphos Manifold. AB - Highly enantioselective nickel-catalyzed alkene endo-hydroarylations were accomplished with full selectivity via organometallic C-H activation. The asymmetric assembly of chiral six-membered scaffolds proved viable in the absence of pyrophoric organoaluminum reagents within an unprecedented nickel/JoSPOphos manifold. PMID- 30517773 TI - Frailty and Pulmonary Function in Older Women. PMID- 30517774 TI - Circulating serum level of retinoic acid and hip fractures among postmenopausal women. AB - PURPOSE: The aim of this study was to evaluate the serum levels of retinoic acid (RA), an active form of vitamin A, in postmenopausal women with hip fractures from Zhengzhou, China. METHODS: This was a case-control study from the Affiliated Hospital of Zhengzhou University. Serum samples were drawn from 375 postmenopausal women who were diagnosed as having hip fracture and 750 matched controls without fracture. Serum RA levels were evaluated as both a continuous variable and a categorical variable in quintiles. RESULTS: The results showed that the serum levels of RA were significantly (P = .039) higher in patients with hip fracture compared with controls. In univariate and multivariate logistic regression analysis, for each 1 ng/mL increase of serum level of RA, the unadjusted and adjusted risk of hip fracture would be increased by 5% (odds ratio [OR] = 1.05; 95% confidence interval [CI] = 1.00-1.10; P = .035) and 2% (OR = 1.02; 95% CI = 0.95-1.11; P = .096), respectively. In multivariate models comparing the fifth with the third quintiles of RA, the RA was associated with hip fracture, and adjusted risk of hip fracture would be increased by 52% (OR = 1.52; 95% CI = 1.13-1.42; P = .011). CONCLUSIONS: The results of our study suggest that subclinical higher levels of RA may increase the risk of hip fracture in postmenopausal women, particularly among the top quintile of serum RA. PMID- 30517775 TI - Pattern recognition receptor polymorphisms in early periodontitis. AB - BACKGROUND: Even though bacteria trigger inflammation, most of the tissue destruction in periodontitis is due to the host inflammatory response. In addition to immunological events that drive development of early periodontitis, numerous environmental factors like genetics and smoking play a role. We investigated whether the carriage of selected single nucleotide polymorphisms (SNP) of toll-like receptors (TLR), NOD-like receptors (NLR) and RIG-I-like receptors (RLR) was associated with the diagnosis of early periodontitis in a case-control study. METHODS: Adolescents with positive (n = 87) and negative (n = 73) diagnosis for periodontitis had blood samples taken. All participants were genotyped for 42 SNP in the genes encoding TLR1-10, NOD1-2, DDX58, and IFIH1 using multiplex assays. Associations between SNP and periodontitis diagnosis were tested. RESULTS: TLR1-rs5743611 showed protective effect for periodontitis (CC vs. GG and GC, P = 0.01, OR 0.10, 95%CI 0.01-0.78). Carriage of the TLR4 rs7873784 was associated with higher odds for periodontitis (GG vs. CC and GC, P = 0.05, OR 2.30, 95% CI 1.00-5.63; GG vs. GC, P = 0.05, OR 2.46, 95% CI 1.01 5.99). In male participants, reduced susceptibility to periodontitis was observed in carriers of TLR7-rs3853839 (CC vs. GG and CG, P = 0.02, OR 0.30, 95% CI 0.11 0.85) and TLR8-rs3764879 (CC vs. GG and CG, P = 0.02, OR 0.31, 95% CI 0.12-0.82). Associations were maintained after adjustments for sex, smoking habits and mother's education. CONCLUSIONS: This study demonstrated an association between TLR1-rs5743611, TLR4-rs7873784, TLR7-rs3853839 and TLR8-rs3764879 and susceptibility to periodontitis in adolescents. This article is protected by copyright. All rights reserved. PMID- 30517776 TI - Allograft reconstruction of the humerus: Complications and revision surgery. AB - BACKGROUND AND OBJECTIVES: Allograft reconstruction of the humerus after resection is preferred by many because of bone stock restoration and biologic attachment of ligaments and muscles to the allograft, theoretically obtaining superior stability and functionality. Our aim was to assess the prevalence of complications and the incidence and etiology for revision surgery in humeral allograft reconstructions. METHODS: We included patients 18 years and older who underwent wide resection and allograft reconstruction of the humerus for primary and metastatic lesions at our institution between 1990 and 2013. Our primary outcome measures were complications and revision surgery. We used competing risk regression to assess allograft survival. RESULTS: Of the 84 patients we included, 47 patients (51%) underwent allograft reconstructions of the proximal humerus, 30 (36%) intercalary, and seven (8%) of the distal humerus. Fifty-one patients (61%) had at least one complication after surgery. Eighteen patients (21%) underwent revision surgery. The 5-year allograft survival was 71%. CONCLUSION: Although allograft reconstructions of the humerus are a valuable option in the orthopedic oncologist's armamentarium, surgeons should mind the accompanying complication rates. Allograft fractures seem to be the main issue for proximal and distal allografts, often leading to revision surgery. Intercalary allografts are mostly troubled by nonunions. PMID- 30517777 TI - Reply to: Frailty and Pulmonary Function in Older Women. PMID- 30517778 TI - The Therapeutic Potential of Cannabinoids in Dermatology AB - Cannabinoids have demonstrated utility in the management of cancer, obesity, and neurologic disease. More recently, their immunosuppressive and anti-inflammatory properties have been identified for the treatment of several dermatologic conditions. This review thus assesses the therapeutic potential of phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids in the management of cutaneous disease. The PubMed(r) and Scopus(r) databases were subsequently reviewed in December 2017 using MeSH and keywords, such as cannabinoid, THC, dermatitis, pruritus, and skin cancer. The search yielded reports on the therapeutic role of cannabinoids in the management of skin cancer, acne vulgaris, pruritus, atopic and allergic contact dermatitis, and systemic sclerosis. While cannabinoids have exhibited efficacy in the treatment of inflammatory and neoplastic skin conditions, several reports suggest pro inflammatory and pro-neoplastic properties. Further investigation is necessary to understand the complexities of cannabinoids and their therapeutic potential in dermatology. PMID- 30517779 TI - Afamelanotide in the Treatment of Dermatologic Disease AB - Afamelanotide, an alpha-melanocyte stimulating hormone analogue, has become an emerging therapeutic option for a variety of skin conditions previously refractory to other treatments. Its efficacy has been demonstrated in several dermatologic conditions, including erythropoietic protoporphyria (EPP), solar urticaria, polymorphic light eruption (PMLE), vitiligo, acne, and Hailey-Hailey disease. Its relatively low risk side effect profile makes it an attractive treatment option and also paves the way for innovative use in other disorders. PMID- 30517780 TI - Size-Dependent Fault-Driven Relaxation and Faceting in Zincblende CdSe Colloidal Quantum Dots. AB - Surface chemistry and core defects are known to play a prominent role in governing the photophysical properties of nanocrystalline semiconductors. Nevertheless, investigating them in small nanocrystals remains a complex task. Here, by combining X-ray scattering techniques in the wide- and small-angle regions and using the Debye Scattering Equation (DSE) method of analysis, we unveil a high density of planar defects in oleate-terminated zincblende (ZB) CdSe colloidal quantum dots (QDs) and size-dependent faceting within a square-cuboid morphology. Atomistic models of faulted ZB nanocrystals, based on the probabilistic stacking of CdSe layers in cubic and hexagonal sequences, and data analysis point to the preferential location of faults near the center of nanocrystals. By finely modeling faulting and morphological effects on the X-ray scattering pattern, a relaxation of the Cd-Se bond distance parallel to the stacking direction, up to +3% (2.71 A) with respect to the reference bulk value (2.63 A) is detected, at the cubic/hexagonal transitions. The smallest nanocrystals show cubic {100} facets; {111} facets appear above 4 nm and progressively extend at larger sizes. These structural and morphological features likely vary depending on the synthesis conditions; nevertheless, since planar defects are nearly ubiquitous in CdSe QDs, the modeling approach here presented has a general validity. This work also points to the great potential of combining small- and wide-angle X-ray scattering and DSE-modeling techniques in gaining important knowledge on atomic-scale defects of semiconductor nanocrystals, underpinning the comprehension of the impact of structural defectiveness on the exciting properties of these QDs. PMID- 30517781 TI - Establishing a multivariate model for predictable antisense RNA-mediated repression. AB - Recent advances in our understanding of RNA folding and functions have facilitated the use of regulatory RNAs such as synthetic antisense RNAs (asRNAs) to modulate gene expression. However, despite the simple and universal complementarity rule, predictable asRNA-mediated repression is still challenging due to the intrinsic complexity of native asRNA-mediated gene regulation. To address this issue, we present a multivariate model, based on the change in free energy of complex formation (DeltaGCF) and percent mismatch of the target binding region, which can predict synthetic asRNA-mediated repression efficiency in diverse contexts. First, 69 asRNAs that bind to multiple target mRNAs were designed and tested to create the predictive model. Second, we showed that the same model is effective predicting repression of target genes in both plasmids and chromosomes. Third, using our model, we designed asRNAs that simultaneously modulated expression of a toxin and its antitoxin to demonstrate tunable control of cell growth. Fourth, we tested and validated the same model in two different biotechnologically-important organisms: Escherichia coli Nissle 1917 and Bacillus subtilis 168. Last, multiple parameters, including target locations, the presence of an Hfq binding site, GC contents, and gene expression levels, were revisited to define the conditions under which the multivariate model should be used for accurate prediction. Together, 434 different strain-asRNA combinations were tested, validating the predictive model in a variety of contexts, including multiple target genes and organisms. The result presented in this study is an important step towards achieving predictable tunability of asRNA-mediated repression. PMID- 30517782 TI - InGaAs-GaAs Nanowire Avalanche Photodiodes Toward Single Photon Detection in Free Running Mode. AB - Single photon detection at near-infrared (NIR) wavelengths is critical for light detection and ranging (LiDAR) systems used in imaging technologies such as autonomous vehicle trackers and atmospheric remote sensing. Portable, high performance LiDAR relies on silicon-based single-photon avalanche diodes (SPADs) due to their extremely low dark count rate (DCR) and afterpulsing probability, but their operation wavelengths are typically limited up to 905 nm. Although InGaAs-InP SPADs offer an alternative platform to extend the operation wavelengths to eye-safe ranges, their high DCR and afterpulsing severely limit their commercial applications. Here we propose a new selective absorption and multiplication avalanche photodiode (SAM-APD) platform composed of vertical InGaAs-GaAs nanowire arrays for single photon detection. Among a total of 4400 nanowires constituting one photodiode, each avalanche event is confined in a single nanowire, which means that the avalanche volume and the number of filled traps can be drastically reduced in our approach. This leads to an extremely small afterpulsing probability compared with conventional InGaAs-based SPADs and enables operation in free-running mode. We show DCR below 10 Hz, due to reduced fill factor, with photon count rates of 7.8 MHz and timing jitter less than 113 ps, which suggest that nanowire-based NIR focal plane arrays for single photon detection can be designed without active quenching circuitry that severely restricts pixel density and portability in NIR commercial SPADs. Therefore, the proposed work based on vertical nanowires provides a new degree of freedom in designing avalanche photodetectors and could be a stepping stone for high performance InGaAs SPADs. PMID- 30517783 TI - Graphene oxide hybrid with sulphur-nitrogen polymer for high-performance pseudocapacitors. AB - Towards the introduction of fast faradaic pseudocapacitive behavior and the increase of the specific capacitance of carbon-based electrodes, we have covalently functionalized graphene oxide with a redox active thiourea formaldehyde polymer yield-ing a multifunctional hybrid system. The multiscale physical and chemical characterization of the novel 3-dimensional hy-brid revealed high material's porosity with high specific surface area (402 m2 g-1) and homogeneous element distribution. The presence of multiple functional groups comprising sulphur, nitrogen and oxygen, provide additional contribution of Faradic redox reaction in supercapacity performance, leading to a high effective electrochemical pseudocapacitance. Signifi-cantly, our graphene-based 3 dimensional thiourea-formaldehyde hybrid (G3DTF) exhibited specific capacitance as high as 400 F g-1, areal capacitance of 160 mF cm-2 and an energy density of 11.1 mWh cm-3 at scan rate of 1 mV s-1 with great capacitance retention (100%) after 5000 cycles at scan rate of 100 mV s-1. PMID- 30517784 TI - Development of analysis toolkit to visualize interaction energies generated by fragment molecular orbital calculations. AB - In modern praxis, a knowledge-driven design of pharmaceutical compounds relies heavily on protein structure data. Nonetheless, quantification of the interaction between protein and ligand is of great importance in the theoretical evaluation of the ability of a pharmaceutical compound to comply with certain expectations. The FMO (fragment molecular orbital) method is handy in this regard. However, the physical complexity and the number of the interactions within a protein-ligand complex render analysis of the results somewhat complicated. This situation prompted us to develop the toolkit AnalysisFMO, which should enable a more efficient and convenient workflow with FMO data generated by quantum-chemical packages such as GAMESS, PAICS, and ABINIT-MP. AnalysisFMO consists of two separate units, RbAnalysisFMO, and the PyMOL plugins. The former can extract inter-fragment interaction energies (IFIEs) or pair interaction energies (PIEs) from the FMO output files generated by the aforementioned quantum-chemical packages. The PyMOL plugins enable visualization of IFIEs or PIEs in the protein structure in PyMOL. We demonstrate the use of this tool on a lectin protein from Burkholderia cenocepacia in which FMO analysis revealed the existence of a new interaction between Gly84 and fucose. Moreover, we found that second-shell interactions are crucial in forming the sugar binding site. In the case of bilirubin oxidase from Myrothecium verrucaria (MvBO), we predict that interactions between Asp105 and three His residues (His401, His403, and His136) are essential for optimally positioning the His residues to coordinate Cu atoms to form a Type 2 and two Type 3 Cu ions. PMID- 30517785 TI - Nickel-Catalyzed Reductive [2+2] Cycloaddition of Alkynes. AB - The nickel-catalyzed synthesis of tetrasubstituted cyclobutenes from alkynes is reported. This transformation is uniquely promoted by the use of a primary aminophosphine, an unusual ligand in nickel catalysis. Mechanistic insights for this new transformation are provided, and post-reaction modifications of the cyclobutene products to stereodefined cyclic and acyclic compounds are reported, including the synthesis of epi-truxillic acid. PMID- 30517786 TI - Fluoride-induced dynamic surface self-reconstruction produces unexpectedly efficient oxygen evolution catalyst. AB - Oxygen evolution reaction (OER) is a key process in water splitting systems, fuel cells, and metal-air batteries, but the development of highly active and robust OER catalyst by simple methods is a great challenge. Here, we report an in situ dynamic surface self-reconstruction that can dramatically improve the catalytic activity of electrocatalysts. The fluoride (F-)-incorporated NiFe hydroxide (NiFe OH-F) nanosheets array was initially grown on Ni foam by a one-step hydrothermal method, which requires a 243 mV overpotential (eta) to achieve 10 mA cm-2 current density (j) with a Tafel slope of 42.9 mV dec-1 in alkaline madia. After the surface self-reconstruction induced by fluoride leaching under OER conditions, the surface original NiFe-OH-F was converted into highly mesoporous and amorphous NiFe oxide hierarchical structure and the OER activity increases over 58 folds. The corresponding eta decreases to 176 mV with an extreme low Tafel slope of 22.6 mV dec-1, this performance is superior to the state-of-the-art OER electrocatalysts. PMID- 30517787 TI - Lithium Plating and Stripping on Carbon Nanotube Sponge. AB - Lithium metal is an ideal anode material due to its high specific capacity and low electrochemical potential. However, issues such as dendritic growth and low coulombic efficiency prevent its application in secondary lithium batteries. The use of three-dimensional (3D) porous current collector is an effective strategy to solve these problems. Herein, commercial carbon nanotube (CNT) sponge is used as a 3D current collector for dendrite-free lithium metal deposition to improve the coulombic efficiency and the cycle stability of the lithium metal batteries. The high specific surface area of the CNT increases the density of the lithium nucleation sites and ensures the uniform lithium deposition while the "pre lithiation" behavior of the porous CNT enhances its affinity with the deposited lithium. Meanwhile, the lithium plating/stripping on the sponge maintains high coulombic efficiency and high cycling stability due to the robust structure of graphitic-amorphous carbon composite in the ether-based electrolyte. Our findings exhibit the feasibility of using CNT sponge as a 3D porous current collector for lithium deposition. They shed light on designing and developing advanced current collectors for the lithium metal electrode and will promote the commercialization of the secondary lithium batteries. PMID- 30517788 TI - Computational Investigation of RNA A-Bulges Related to Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism. AB - Mutations in the human tau gene result in alternative splicing of the tau protein, which cause frontotemporal dementia and Parkinsonism. One disease mechanism is linked to the stability of a hairpin within microtubule-associated protein tau (MAPT) mRNA, which contains an A-bulge. Here we employ computational methods to investigate the structural and thermodynamic properties of several A bulge RNAs with different closing base-pairs. We find that the current amber RNA force field has a preference to overstabilize base-triple over stacked states, even though some of the A-bulges are known to prefer stacked states according to NMR studies. We further determined that if the neighboring base-pairs of A-bulges are AU, this situation can lead to base slippage. However, when the 3'-side of the A-bulge has an UA base-pair, the stacked state is stabilized by an extra interaction that is not observed in the other sequences. We suggest that these A bulge RNA systems could be used as benchmarks to improve the current RNA force fields. PMID- 30517789 TI - Vapor-Assisted Ex-Situ Doping of Carbon Nanotube towards Efficient and Stable Perovskite Solar Cells. AB - Single-walled carbon nanotubes (CNTs) has been considered as a promising material for a top electrode of perovskite solar cells owing to its hydrophobic nature, earth-abundance, and mechanical robustness. However, its poor conductivity, a shallow work function, and non-reflective nature have limited further enhancement in power conversion efficiency (PCE) of top CNT electrode-based perovskite solar cells. Here, we introduced a simple and scalable method to address these issues by utilizing an ex-situ vapor-assisted doping method. Trifluoromethanesulfonic acid (TFMS) vapor doping of the free-standing CNT sheet enabled tuning of conductivity and work function of the CNT electrode without damaging underneath layers. The sheet resistance of the CNT sheet was decreased by 21.3% with an increase in work function from 4.75 eV to 4.96 eV upon doping of TFMS. In addition, recently developed 2D perovskite-protected Cs-containing formamidium lead iodide (FACsPbI3) technology was employed to maximize the absorption. Because of the lowered resistance, better energy alignment, and improved absorption, the CNT electrode-based PSCs produced a PCE of 17.6% with a JSC of 24.21 mA/cm2, VOC of 1.005 V, and FF of 0.72. Furthermore, the resulting TFMS doped CNT-PSCs demonstrated higher thermal and operational stability than bare CNT and metal electrode-based devices. PMID- 30517790 TI - Understanding the Air-Exposure Degradation Chemistry at Nanoscale of Layered Oxide Cathodes for Sodium-Ion Batteries. AB - Undesired reactions between layered sodium transition-metal oxide cathodes and air impede their utilization in practical sodium-ion batteries. Consequently, a fundamental understanding of how layered oxide cathodes degrade in air is of paramount importance, but it has not been fully understood yet. Here a comprehensive study on a model material NaNi0.7Mn0.15Co0.15O2 reveals its reaction chemistry with air and the dynamic evolution of the degradation species upon air exposure. We find that besides the extraction of Na+ ions from the crystal lattice to form NaOH, Na2CO3, and Na2CO3*H2O in contact with air, nickel ions gradually dissolve from the bulk to form NiO and accumulate on the particle surface as revealed by sub-nanometer surface sensitive time-of-flight secondary ion mass spectroscopy. The degradation species on the surface are insulating, leading to an increase in interfacial resistance and declined electrochemical performance. We also demonstrate a feasible surface coating strategy for suppressing the unfavorable degradation process. Understanding the degradation mechanism at nanoscale can facilitate future development of high-energy cathodes for sodium-ion batteries. PMID- 30517791 TI - Missing Satellites Problem: Completeness Corrections to the Number of Satellite Galaxies in the Milky Way are Consistent with Cold Dark Matter Predictions. AB - A critical challenge to the cold dark matter (CDM) paradigm is that there are fewer satellites observed around the Milky Way than found in simulations of dark matter substructure. We show that there is a match between the observed satellite counts corrected by the detection efficiency of the Sloan Digital Sky Survey (for luminosities L?340 L_{?}) and the number of luminous satellites predicted by CDM, assuming an empirical relation between stellar mass and halo mass. The "missing satellites problem," cast in terms of number counts, is thus solved. We also show that warm dark matter models with a thermal relic mass smaller than 4 keV are in tension with satellite counts, putting pressure on the sterile neutrino interpretation of recent x-ray observations. Importantly, the total number of Milky Way satellites depends sensitively on the spatial distribution of satellites, possibly leading to a "too many satellites" problem. Measurements of completely dark halos below 10^{8} M_{?}, achievable with substructure lensing and stellar stream perturbations, are the next frontier for tests of CDM. PMID- 30517792 TI - Chaos Signatures in the Short and Long Time Behavior of the Out-of-Time Ordered Correlator. AB - Two properties are needed for a classical system to be chaotic: exponential stretching and mixing. Recently, out-of-time order correlators were proposed as a measure of chaos in a wide range of physical systems. While most of the attention has previously been devoted to the short time stretching aspect of chaos, characterized by the Lyapunov exponent, we show for quantum maps that the out-of time correlator approaches its stationary value exponentially with a rate determined by the Ruelle-Pollicot resonances. This property constitutes clear evidence of the dual role of the underlying classical chaos dictating the behavior of the correlator at different timescales. PMID- 30517794 TI - Photonic Topological Insulating Phase Induced Solely by Gain and Loss. AB - We reveal a one-dimensional topological insulating phase induced solely by gain and loss control in non-Hermitian optical lattices. The system comprises units of four uniformly coupled cavities, where the successive two have loss; the others experience gain, and they are balanced under two magnitudes. The gain and loss parts are effectively dimerized, and a bulk band gap, topological transition, midgap topological edge, and interface states in finite systems can all be achieved by controlled pumping. We also clarify non-Hermitian topological invariants and edge states in gapless conditions. PMID- 30517795 TI - Proton Mass Decomposition from the QCD Energy Momentum Tensor. AB - We report results on the proton mass decomposition and also on related quark and glue momentum fractions. The results are based on overlap valence fermions on four ensembles of N_{f}=2+1 domain wall fermion configurations with three lattice spacings and three volumes, and several pion masses including the physical pion mass. With fully nonperturbative renormalization (and universal normalization on both quark and gluon), we find that the quark energy and glue field energy contribute 32(4)(4)% and 36(5)(4)% respectively in the MS[over -] (modified minimal substraction) scheme at MU=2 GeV. A quarter of the trace anomaly gives a 23(1)(1)% contribution to the proton mass based on the sum rule, given 9(2)(1)% contribution from the u, d, and s quark scalar condensates. The u, d, s, and glue momentum fractions in the MS[over -] scheme are in good agreement with global analyses at MU=2 GeV. PMID- 30517798 TI - Alternating-Phase Focusing for Dielectric-Laser Acceleration. AB - The concept of dielectric-laser acceleration provides the highest gradients among breakdown-limited (nonplasma) particle accelerators. However, stable beam transport and staging have not been shown experimentally yet. We present a scheme that confines the beam longitudinally and in one transverse direction. Confinement in the other direction is obtained by a single conventional quadrupole magnet. Within the small aperture of 420 nm we find the matched distributions, which allow an optimized injection into pure transport, bunching, and accelerating structures. The combination of these resembles the photonics analogue of the radio frequency quadrupole, but since our setup is entirely two dimensional, it can be manufactured on a microchip by lithographic techniques. This is a crucial step towards relativistic electrons in the MeV range from low cost, handheld devices and connects the two fields of attosecond physics and accelerator physics. PMID- 30517799 TI - Chiral Spin Density Wave and d+id Superconductivity in the Magic-Angle-Twisted Bilayer Graphene. AB - We model the newly synthesized magic-angle-twisted bilayer graphene superconductor with two p_{x,y}-like Wannier orbitals on the superstructure honeycomb lattice, where the hopping integrals are constructed via the Slater Koster formulism by symmetry analysis. The characteristics exhibited in this simple model are well consistent with both the rigorous calculations and experiment observations. A van Hove singularity and Fermi-surface (FS) nesting are found in the doping levels relevant to the correlated insulator and unconventional superconductivity revealed experimentally, based on which we identify the two phases as weak-coupling FS instabilities. Then, with repulsive Hubbard interactions turned on, we performed random-phase-approximation based calculations to identify the electron instabilities. As a result, we find chiral d+id topological superconductivity bordering the correlated insulating state near half-filling, identified as noncoplanar chiral spin-density wave ordered state, featuring the quantum anomalous Hall effect. The phase diagram obtained in our approach is qualitatively consistent with experiments. PMID- 30517801 TI - Globulelike Conformation and Enhanced Diffusion of Active Polymers. AB - We study the dynamics and conformation of polymers composed by active monomers. By means of Brownian dynamics simulations we show that, when the direction of the self-propulsion of each monomer is aligned with the backbone, the polymer undergoes a coil-to-globulelike transition, highlighted by a marked change of the scaling exponent of the gyration radius. Concurrently, the diffusion coefficient of the center of mass of the polymer becomes essentially independent of the polymer size for sufficiently long polymers or large magnitudes of the self propulsion. These effects are reduced when the self-propulsion of the monomers is not bound to be tangent to the backbone of the polymer. Our results, rationalized by a minimal stochastic model, open new routes for activity-controlled polymers and, possibly, for a new generation of polymer-based drug carriers. PMID- 30517797 TI - Multispectral Management of the Photon Orbital Angular Momentum. AB - We report on a programmable liquid crystal spatial light modulator enabling independent orbital angular momentum state control on multiple spectral channels. This is done by using electrically controllable "topological pixels" that independently behave as geometric phase micro-optical elements relying on self engineered liquid crystal defects. These results open interesting opportunities in optical manipulation, sensing, imaging, and communications, as well as information processing. In particular, spectral vortex modulation allows considering singular spatiotemporal shaping of ultrashort pulses which may find applications in many areas such as material processing, spectroscopy, or elementary particles acceleration. PMID- 30517802 TI - Circumventing Magnetostatic Reciprocity: A Diode for Magnetic Fields. AB - Lorentz reciprocity establishes a stringent relation between electromagnetic fields and their sources. For static magnetic fields, a relation between magnetic sources and fields can be drawn in analogy to the Green's reciprocity principle for electrostatics. So far, the magnetostatic reciprocity principle remains unchallenged and the magnetostatic interaction is assumed to be symmetric (reciprocal). Here, we theoretically and experimentally show that a linear and isotropic electrically conductive material moving with constant velocity is able to circumvent the magnetostatic reciprocity principle and realize a diode for magnetic fields. This result is demonstrated by measuring an extremely asymmetric magnetic coupling between two coils that are located near a moving conductor. The possibility to generate controlled unidirectional magnetic couplings implies that the mutual inductances between magnetic elements or circuits can be made extremely asymmetric. We anticipate that this result will provide novel possibilities for applications and technologies based on magnetically coupled elements and might open fundamentally new avenues in artificial magnetic spin systems. PMID- 30517803 TI - Decoding the Apparent Horizon: Coarse-Grained Holographic Entropy. AB - When a black hole forms from collapse in a holographic theory, the information in the black hole interior remains encoded in the boundary. We prove that the area of the black hole's apparent horizon is precisely the entropy associated with coarse graining over the information in its interior, subject to knowing the exterior geometry. This is the maximum holographic entanglement entropy that is compatible with all classical measurements conducted outside of the apparent horizon. We identify the boundary dual to this entropy and explain why it obeys the second law of thermodynamics. PMID- 30517804 TI - Two Phase Transitions in the Two-Dimensional Nematic Three-Vector Model with No Quasi-Long-Range Order: Monte Carlo Simulation of the Density of States. AB - The presence of stable topological defects in a two-dimensional (d=2) liquid crystal model allowing molecular reorientations in three dimensions (n=3) was largely believed to induce a defect-mediated Berzenskii-Kosterlitz-Thouless-type transition to a low temperature phase with quasi-long-range order. However, earlier Monte Carlo (MC) simulations could not establish certain essential signatures of the transition, suggesting further investigations. We study this model by computing its equilibrium properties through MC simulations, based on the determination of the density of states of the system. Our results show that, on cooling, the high temperature disordered phase deviates from its initial progression towards the topological transition, crossing over to a new fixed point, condensing into a nematic phase with exponential correlations of its director fluctuations. The thermally induced topological kinetic processes continue, however, limited to the length scales set by the nematic director fluctuations, and lead to a second topological transition at a lower temperature. It is argued that in the (d=2, n=3) system with an attractive biquadratic Hamiltonian, the presence of additional molecular degrees of freedom and local Z_{2} symmetry associated with lattice sites together promote the onset of an additional relevant scaling field at matching length scales in the high temperature region, leading to a crossover. PMID- 30517800 TI - Entropy Inflection and Invisible Low-Energy States: Defensive Alliance Example. AB - Lower temperature leads to a higher probability of visiting low-energy states. This intuitive belief underlies most physics-inspired strategies for addressing hard optimization problems. For instance, the popular simulated annealing (SA) dynamics is expected to approach a ground state if the temperature is lowered appropriately. Here, we demonstrate that this belief is not always justified. Specifically, we employ the cavity method to analyze the minimum strong defensive alliance problem and discover a bifurcation in the solution space, induced by an inflection point in the entropy-energy profile. While easily accessible configurations are associated with the lower-free-energy branch, the low-energy configurations are associated with the higher-free-energy branch within the same temperature range. There is a discontinuous phase transition between the high energy configurations and the ground states, which generally cannot be followed by SA. We introduce an energy-clamping strategy to obtain superior solutions by following the higher-free-energy branch, overcoming the limitations of SA. PMID- 30517805 TI - Gravity as Gauge Theory Squared: A Ghost Story. AB - The Becchi-Rouet-Stora-Tyutin (BRST) transformations and equations of motion of a gravity-two-form-dilaton system are derived from the product of two Yang-Mills theories in a BRST covariant form, to linear approximation. The inclusion of ghost fields facilitates the separation of the graviton and dilaton. The gravitational gauge fixing term is uniquely determined by those of the Yang-Mills factors which can be freely chosen. Moreover, the resulting gravity-two-form dilaton Lagrangian is anti-BRST invariant and the BRST and anti-BRST charges anticommute as a direct consequence of the formalism. PMID- 30517806 TI - Nuclear Charge Radii of ^{229}Th from Isotope and Isomer Shifts. AB - The isotope ^{229}Th is unique in that it possesses an isomeric state of only a few electron volts above the ground state, suitable for nuclear laser excitation. An optical clock based on this transition is expected to be a very sensitive probe for variations of fundamental constants, but the nuclear properties of both states have to be determined precisely to derive the actual sensitivity. We carry out isotope shift calculations in Th^{+} and Th^{2+} including the specific mass shift, using a combination of configuration interaction and all-order linearized coupled-cluster methods and estimate the uncertainty of this approach. We perform experimental measurements of the hyperfine structure of Th^{2+} and isotopic shift between ^{229}Th^{2+} and ^{232}Th^{2+} to extract the difference in root mean-square radii as delta?r^{2}?^{232,229}=0.299(15) fm^{2}. Using the recently measured values of the isomer shift of lines of ^{229m}Th, we derive the value for the mean-square radius change between ^{229}Th and its low-lying isomer ^{229m}Th to be delta?r^{2}?^{229m,229}=0.0105(13) fm^{2}. PMID- 30517807 TI - Observation of Floquet Raman Transition in a Driven Solid-State Spin System. AB - We experimentally observe Floquet Raman transitions in the weakly driven solid state spin system of a nitrogen-vacancy center in diamond. The periodically driven spin system simulates a two-band Wannier-Stark ladder model and allows us to observe coherent spin state transfer arising from a Raman transition mediated by Floquet synthetic levels. It also leads to the prediction of an analog photon assisted Floquet Raman transition and dynamical localization in a driven two level quantum system. The demonstrated rich Floquet dynamics offers new capabilities to achieve effective Floquet coherent control of a quantum system with potential applications in various types of quantum technologies based on driven quantum dynamics. In particular, the Floquet Raman system may be used as a quantum simulator for the physics of periodically driven systems. PMID- 30517808 TI - Hollow Rims from Water Drop Evaporation on Salt Substrates. AB - We report on the observation of thin salt shells that form at the periphery of evaporating pure water drops on salt. Shell shapes range from rings of inclined walls to hollow toroidal rims. We interpret this phenomenon as a consequence of a molecular coffee-stain effect by which the dissolved salt is advected toward the pinned contact line where an increased evaporation takes place. The subsequent salt supersaturation in the vicinity of the triple line drives the crystallization of the shell at the liquid-air interface. This interpretation is supported by a simple model for shell growth. PMID- 30517809 TI - Disentangling Genuine from Matter-Induced CP Violation in Neutrino Oscillations. AB - We prove that, in any flavor transition, neutrino oscillation CP-violating asymmetries in matter have two disentangled components: (i) a CPT-odd T-invariant term, non-vanishing iff there are interactions with matter, and (ii) a T-odd CPT invariant term, non-vanishing iff there is genuine CP violation. As function of the baseline, these two terms are distinct L-even and L-odd observables to separately test (i) matter effects sensitive to the neutrino hierarchy and (ii) genuine CP violation in the neutrino sector. For the golden nu_{MU}->nu_{e} channel, the different energy distributions of the two components provide a signature of their separation. At long baselines, they show oscillations in the low and medium energy regions, with zeros at different positions and peculiar behavior around the zeros. We discover a magic energy E=(0.91+/-0.01) GeV at L=1300 km with vanishing CPT-odd component and maximal genuine CP asymmetry proportional to sindelta, with delta the weak CP phase. For energies above 1.5 GeV, the sign of the CP asymmetry discriminates the neutrino hierarchy. PMID- 30517810 TI - Avoided Crossing and sub-Fourier-sensitivity in Driven Quantum Systems. AB - The response of a linear system to an external perturbation is governed by the Fourier limit, with the inverse of the interaction time constituting a lower limit for the system bandwidth. This does not hold for nonlinear systems, which can thus exhibit sub-Fourier-behavior. The present Letter identifies a mechanism for sub-Fourier-sensitivity in driven quantum systems, which relies on avoided crossing between Floquet states. Features up to three orders of magnitude finer than the Fourier limit are presented. PMID- 30517811 TI - Nonequilibrium Energetics of Molecular Motor Kinesin. AB - Nonequilibrium energetics of single molecule translational motor kinesin was investigated by measuring heat dissipation from the violation of the fluctuation response relation of a probe attached to the motor using optical tweezers. The sum of the dissipation and work did not amount to the input free energy change, indicating large hidden dissipation exists. Possible sources of the hidden dissipation were explored by analyzing the Langevin dynamics of the probe, which incorporates the two-state Markov stepper as a kinesin model. We conclude that internal dissipation is dominant. PMID- 30517812 TI - Analytic Mode Normalization for the Kerr Nonlinearity Parameter: Prediction of Nonlinear Gain for Leaky Modes. AB - Based on the resonant-state expansion with analytic mode normalization, we derive a general master equation for the nonlinear pulse propagation in waveguide geometries that is valid for bound and leaky modes. In the single-mode approximation, this equation transforms into the well-known nonlinear Schrodinger equation with a closed expression for the Kerr nonlinearity parameter. The expression for the Kerr nonlinearity parameter can be calculated on the minimal spatial domain that spans only across the regions of spatial inhomogeneities. It agrees with previous vectorial formulations for bound modes, while for leaky modes the Kerr nonlinearity parameter turns out to be a complex number with the imaginary part providing either nonlinear loss or even gain for the overall attenuating pulses. This nonlinear gain results in more intense pulse compression and stronger spectral broadening, which is demonstrated here on the example of liquid-filled capillary-type fibers. PMID- 30517813 TI - Dipolar Quantum Mixtures of Erbium and Dysprosium Atoms. AB - We report on the first realization of heteronuclear dipolar quantum mixtures of highly magnetic erbium and dysprosium atoms. With a versatile experimental setup, we demonstrate binary Bose-Einstein condensation in five different Er-Dy isotope combinations, as well as one Er-Dy Bose-Fermi mixture. Finally, we present first studies of the interspecies interaction between the two species for one mixture. PMID- 30517814 TI - Scaling Laws for Light Absorption Enhancement Due to Nonrefractory Coating of Atmospheric Black Carbon Aerosol. AB - Black carbon (BC) aerosol, the strongest absorber of visible solar radiation in the atmosphere, contributes to a large uncertainty in direct radiative forcing estimates. A primary reason for this uncertainty is inaccurate parametrizations of the BC mass absorption cross section (MAC_{BC}) and its enhancement factor (E_{MAC_{BC}})-resulting from internal mixing with nonrefractory and nonlight absorbing materials-in climate models. Here, applying scaling theory to numerically exact electromagnetic calculations of simulated BC particles and observational data on BC light absorption, we show that MAC_{BC} and E_{MAC_{BC}} evolve with increasing internal mixing ratios in simple power-law exponents of 1/3. Remarkably, MAC_{BC} remains inversely proportional to the wavelength of light at any mixing ratio. When mixing states are represented using mass equivalent core-shell spheres, as is done in current climate models, it results in significant underprediction of MAC_{BC}. We elucidate the responsible mechanism based on shielding of photons by a sphere's skin depth and establish a correction factor that scales with a 3/4 power-law exponent. PMID- 30517815 TI - Vanishing Density of States in Weakly Disordered Weyl Semimetals. AB - The Brillouin zone of the clean Weyl semimetal contains points at which the density of states (DOS) vanishes. Previous work suggested that below a certain critical concentration of impurities this feature is preserved including in the presence of disorder. This result got criticized for its neglect of rare disorder fluctuations which might bind quantum states and hence generate a finite DOS. We here show that in spite of their existence these states are so fragile that their contribution effectively vanishes when averaged over continuous disorder distributions. This means that the integrity of the nodal points remains protected for weak disorder. PMID- 30517816 TI - 3D Magneto-Optical Trap of Yttrium Monoxide. AB - We report three-dimensional trapping of an oxide molecule (YO), using a radio frequency magneto-optical trap (MOT). The total number of molecules trapped is ~1.5*10^{4}, with a temperature of 4.1(5) mK. This diversifies the frontier of molecules that are laser coolable and paves the way for the second-stage narrow line cooling in this molecule to the microkelvin regime. Futhermore, the new challenges of creating a 3D MOT of YO resolved here indicate that MOTs of more complex nonlinear molecules should be feasible as well. PMID- 30517817 TI - Detailed Fluctuation Relation for Arbitrary Measurement and Feedback Schemes. AB - Fluctuation relations are powerful equalities that hold far from equilibrium. However, the standard approach to include measurement and feedback schemes may become inapplicable in certain situations, including continuous measurements, precise measurements of continuous variables, and feedback induced irreversibility. Here we overcome these shortcomings by providing a recipe for producing detailed fluctuation relations. Based on this recipe, we derive a fluctuation relation which holds for arbitrary measurement and feedback control. The key insight is that fluctuations inferable from the measurement outcomes may be suppressed by postselection. Our detailed fluctuation relation results in a stringent and experimentally accessible inequality on the extractable work, which is saturated when the full entropy production is inferable from the data. PMID- 30517818 TI - First-Principles Calculation of Third-Order Elastic Constants via Numerical Differentiation of the Second Piola-Kirchhoff Stress Tensor. AB - A general method is presented to calculate from first principles the full set of third-order elastic constants of a material of arbitrary symmetry. The method here illustrated relies on a plane-wave density functional theory scheme to calculate the Cauchy stress and the numerical differentiation of the second Piola Kirchhoff stress tensor to evaluate the elastic constants. It is shown that finite difference formulas lead to a cancellation of the finite basis set errors, whereas simple solutions are proposed to eliminate numerical errors arising from the use of Fourier interpolation techniques. Applications to diamond, silicon, aluminum, magnesium, graphene, and a graphane conformer give results in excellent agreement with both experiments and previous calculations based on fitting energy density curves, demonstrating both the accuracy and generality of our new methodology to investigate nonlinear elastic behaviors of materials. PMID- 30517820 TI - Can We Predict Exacerbations of Asthma? PMID- 30517819 TI - Understanding Positive Youth Development in Sport Through the Voices of Indigenous Youth. AB - This study aimed to understand how positive youth development through sport and physical activity is understood and experienced by urban indigenous youth. Research in positive youth development claims that structured physical activities are critical for development. The 5 Cs (i.e., confidence, competence, character, connection, caring) are a gold standard when discussing positive outcomes and are important characteristics for youth to possess to attain the sixth C contribution. Indigenous leaders recognize the value of sport for indigenous children and youth. Recent works in sport psychology have called for research to understand youth sport and physical activity from diverse cultural perspectives. The current study used a community-based participatory framework, and 43 youth from across 3 Canadian settings were recruited. Talking circles were used to collect the data. Results point to some unique understandings of the 5 Cs by the participants-namely, the inclusion of the self within each C. PMID- 30517821 TI - A National Survey on Depression, Internalized Homophobia, College Religiosity, and Climate of Acceptance on College Campuses for Sexual Minority Adults. AB - Sexual minority persons have an increased risk for negative mental health outcomes in adulthood. This seems to largely be due to experiences of stigma in social settings. This study sought to understand the relationship between attending a religiously conservative college, internalized homophobia (a measure of sexual stigma), and depressive symptoms for sexual minority adults. Sexual minority adult participants (n = 384) from across the U.S. were recruited and completed a Web-based, anonymous survey. A mediation model predicting depression through college religious conservatism, college acceptance of sexual minority identities, and internalized homophobia was tested using path analysis. Results revealed an indirect effect of increased religious conservatism of a college predicted higher depression through lower college acceptance and higher internalized homophobia. Implications for the mental health of sexual minority adults and future research are examined. PMID- 30517822 TI - Breastfeeding Self-Efficacy Among Parturient Women in Shanghai: A Cross-Sectional Study. AB - BACKGROUND:: Breastfeeding self-efficacy has been shown to be a strong predictor of breastfeeding initiation and duration; however, factors associated with breastfeeding self-efficacy in China are unclear. RESEARCH AIMS:: The aims were (a) to describe the breastfeeding self-efficacy of parturient women in Shanghai, China and (b) to identify the sociodemographic factors associated with mothers' breastfeeding self-efficacy. METHODS:: This is a cross-sectional retrospective descriptive study. Through convenience sampling, breastfeeding mothers ( N = 801) were recruited to assess breastfeeding self-efficacy before discharge from the hospital. Descriptive statistics were used to analyze the sociodemographic and perinatal characteristics, level of breastfeeding self-efficacy, and correlations between them. RESULTS:: In the process of breastfeeding, 52.2% ( n = 418) of participants encountered breastfeeding problems, 37.1% ( n = 297) perceived an insufficient milk supply, 82.4% ( n = 660) reported attending breastfeeding classes, but only 37.1% ( n = 297) chose exclusive breastfeeding. Chinese mothers reported a moderate level of breastfeeding self-efficacy, with an item mean score of 3.67 (score = 1-5). Whether or not encountering breastfeeding problems, infant feeding pattern (fully breastfeeding, partial breastfeeding, no breastfeeding) in the previous 24 hours, whether or not perceiving insufficient milk, and main caregiver's positive attitude toward breastfeeding (ranging from 1 to10, higher score indicating more positive attitude) were correlated with participants' breastfeeding self-efficacy score. (The correlation coefficients were -0.432, 0.377, -0.364, and 0.353, respectively.). CONCLUSION:: The misperception of insufficient milk and main caregiver's attitude toward breastfeeding were important factors for breastfeeding self-efficacy. Greater efforts should be made during breastfeeding education and support. PMID- 30517823 TI - Harnessing Expert Judgment to Support Clinical Decisions When the Evidence Base Is Weak. AB - PURPOSE: In the process of developing an evidence-based decision dashboard to support treatment decisions for patients with newly diagnosed prostate cancer, we found that the clinical evidence base is insufficient to provide high-quality comparative outcome data. We therefore sought to determine if clinically acceptable outcome estimates could be created using a modified version of the Sheffield Elicitation Framework (SHELF), a formal method for eliciting judgments regarding probability distributions of expected decision outcomes. METHODS: We asked a panel of 3 urologists, 4 radiation oncologists, and 2 medical oncologists to estimate the probabilities of 11 treatment outcomes based on their clinical experience and an annotated evidence summary. The estimates were elicited using a Microsoft Excel spreadsheet containing a self-guided, adapted version of the SHELF Roulette method distributed via email. We created combined outcome estimates by taking the mean values of the panel members' upper and lower 95% bounds for each outcome. The combined estimates were then distributed via email to the panel for final approval. RESULTS: Eight of the 9 responses were judged to be correct applications of the SHELF method and included in the combined outcome estimates. The final set of outcome estimates was unanimously accepted by the clinician panel members and used to create a decision dashboard suitable for clinical use and evaluation. CONCLUSIONS: Many important health care decisions need to be made in situations where the evidence base is inadequate. Use of a formal protocol for eliciting expert judgments is feasible and can be used to promote evidence-based practice by providing a powerful tool to facilitate the combination of professional judgment with research evidence and patient preferences to guide clinical decisions. PMID- 30517824 TI - Multilevel Factors Influencing Young Mothers' Breastfeeding: A Qualitative CBPR Study. AB - BACKGROUND:: Young mothers (age 14-24 years), who are often low income, are less likely than other mothers to breastfeed for 6 months. They also are more likely to be diagnosed with aggressive forms of breast cancer; breastfeeding significantly reduces this risk. While adolescent breastfeeding has been investigated from the perspective of the individual, the social ecological model recognizes the influence of factors at multiple levels. RESEARCH AIM:: The aim was to identify social and structural barriers to and motivators of breastfeeding that young mothers may encounter. METHODS:: Using a cross-sectional prospective qualitative design with a community-based participatory research approach, we sought to identify influential factors at each social ecological level: individual, relationship, community, and societal/structural. We used purposeful sampling, and enlisted snowball sampling. We interviewed stakeholder experts ( n = 9) and dyads ( n = 6) consisting of a young mother and her decision-making partner. Groups of young mothers ( n = 6 groups) collectively created community maps while discussing their feelings about infant feeding in different locations. Using collaborative data analysis, we identified themes and categorized barriers and facilitators according to the social ecological levels. RESULTS:: Four meta themes emerged: roles, place, stigma, and support. While some barriers and facilitators were similar to those experienced by mothers of all ages, participants reported multiple overlapping stigmas, requiring more support. CONCLUSION:: Young mothers who decide to breastfeed encounter barriers at multiple levels. Policies and programs aiming to increase breastfeeding rates in this group must address these barriers and enlist identified facilitators. PMID- 30517825 TI - Colorimetric detection of the beta-agonist ractopamine in animal feed, tissue and urine samples using gold-silver alloy nanoparticles modified with sulfanilic acid. AB - A highly sensitive, selective and simple method was proposed for colorimetric detection of ractopamine on the basis of the interaction between ractopamine and sulfanilic acid-modified gold-silver alloy nanoparticles (AuAgNPs). The AuAgNPs were prepared by the reduction of HAuCl4 and AgNO3 with sodium citrate in aqueous medium and further modified by sulfanilic acid. The interaction of ractopamine with sulfanilic acid induced rapid aggregation of sulfanilic acid-modified AuAgNPs along with an optical colour change, leading to precise quantification which could be detected by absorptiometry. Under the optimum conditions, the absorbance ratio (A600/A435) of sulfanilic acid-modified AuAgNPs exhibited a linear relationship with the concentration of ractopamine in the range of 4.5 31.6 ng/mL. The detection limit of ractopamine was 1.5 ng/mL. The established novel colorimetric detection method showed high selectivity towards ractopamine. The method was successfully applied to detect ractopamine in spiked pork, swine feed and swine urine samples with excellent recoveries from 94.4% to 112.5%. These results demonstrated that the proposed new method has a good potential for practical applications. PMID- 30517826 TI - Intraspinal dermoid and epidermoid cysts: Long-term outcome and risk factors. AB - OBJECTIVE: The literature on long-term outcome after resection of intraspinal dermoid and epidermoid tumors is limited. The purpose of this study was to review the progression-free survival (PFS), overall survival (OS), and long-term outcome in a consecutive series of 57 patients with intraspinal dermoid and epidermoid tumors. DESIGN: Retrospective study. METHODS: A total of 57 patients who underwent surgery at our institution between 2002 and 2010 were reviewed. Patients outcome were determined using the Japanese Orthopaedic Association score (JOA) and the McCormick score. RESULTS: The follow-up data were 100% complete and the median follow-up time was 9.2 years. Gross total resection was performed in 21 patients (36.84%) and subtotal resection in 36 patients (63.16%). The PFS and OS at 8 years were 78.95% and 100% respectively. A good outcome was observed in 56.14% of patients based on the JOA and McCormick score. The univariate analysis showed that a tumor size of more than 4 cm, subtotal resection and sphincter disturbances were the influencing factors of poor outcome. CONCLUSION: The gold standard treatment for intraspinal tumors is gross total resection, but the operation needs to protect the remaining nerve function as much as possible and follow-up should be focused on patients with a high risk of poor outcome. PMID- 30517827 TI - Multiple Paths to Belonging That We Should Study Together. AB - We propose a broadened conceptualization of what it means to belong by reviewing evidence that there is more than one way to achieve a sense of belonging. We suggest four paths-a communal-relationship path, a general-approbation path, a group-membership path, and a minor-sociability path-and review some evidence for the existence of each. We call for researchers to recognize that multiple paths to belonging exist and to study whether and how the paths combine and interact to influence people's sense of belonging. Choosing the communal-relationship path and the general-approbation path as an example, we highlight times when these paths may (a) mesh well and produce additive boosts to a person's sense of belonging, (b) substitute for one another, and (c) conflict with one another and cause ambivalence. We further call for the development of refined measures of the need to belong and of having a sense of achieved belonging as well as new measures of striving to achieve belonging through specific paths. We suggest that broadening the conceptualization of belonging will help integrate existing literature and generate future research. PMID- 30517828 TI - The place of high resolution computed tomography imaging in the investigation of interstitial lung disease. AB - INTRODUCTION: High resolution computed tomography (HRCT) has revolutionized the diagnosis, prognosis, and in some cases the prediction of therapeutic response in interstitial lung disease (ILD). HRCT represents an essential second step to a patient's clinical history, before considering any other investigation, including lung biopsy. Areas covered: This review describes the current place of HRCT in the diagnosis, prognosis and monitoring of ILD. It also lists some perspectives for the near future. Expert commentary: Since the 1980s, HRCT and its interpretation have improved, the diagnosis value of patterns, and the integration of bio-clinical elements to HRCT have been better standardized. The inter-observer agreement has been investigated, allowing a better use of some limits in the interpretation of various signs. It not only takes into account one particular predominant sign, but the combination of patterns and the distribution of findings. Thanks to HRCT, the range of diagnoses and their probability are more accurately identified. The contribution of HRCT has been optimized during the multidisciplinary discussion that a difficult diagnosis calls for. HRCT quantification of the extent of diffuse lung disease becomes possible and is linked to prognosis. In the future, artificial intelligence may significantly modify the practice of radiology. PMID- 30517829 TI - Does blood contamination of urine compromise interpretation of the urine protein to creatinine ratio in dogs? AB - AIMS: To determine the effect of contamination of urine with 0-5% blood, varying in haematocrit and protein concentrations, on the urine protein to creatinine ratio (UPC) in dogs, and to determine whether the colour of urine can be used to aid interpretation of UPC results. METHODS: Urine samples were collected by free catch from 18 dogs, all of which had UPC <0.2. Venous blood samples were also collected from each dog, and the blood from each dog was added to its own urine to produce serial concentrations of 0.125-5% blood. The colour of each urine sample was recorded by two observers scoring them as either yellow, peach, orange, orange/red or red. Protein and creatinine concentrations were determined, and dipstick analysis and sediment examination was carried out on each sample. Based on colour and dipstick analysis, samples were categorised as either having microscopic, macroscopic or gross haematuria. A linear mixed model was used to examine the effect of blood contamination on UPC. RESULTS: The uncontaminated urine of all 18 dogs had a UPC <0.2. Adding blood to the urine samples resulted in an increase in UPC at all contamination concentrations compared to the non contaminated urine (p < 0.001). None of the 54 samples with microscopic haematuria had UPC >0.5. For 108 samples with macroscopic haematuria the UPC was >0.5 in 21 samples (19.4 (95% CI = 13.1-27.9)%), and for 54 samples with gross haematuria 39 (72 (CI = 59.1-82.4)%) had a UPC >0.5. No samples had a UPC >2.0 unless the blood contamination was 5% and only 3/18 (17%) samples at this blood contamination concentration had a UPC >2.0. CONCLUSIONS AND CLINICAL RELEVANCE: This study showed that while blood contamination of >=0.125% does increase the UPC, if the urine remains yellow (microscopic haematuria), then there is negligible chance that a UPC >0.5 will be solely due to the added blood. In that scenario, attributing the proteinuria present to the haematuria in the sample would be inappropriate. However blood contamination that results in discolouration of the urine sample from yellow to red (indicating macroscopic or gross haematuria) could increase the UPC above the abnormal range and would need to be considered as a differential for the proteinuria. Thus knowledge of urine colour, even if limited to simple colour scores (yellow, discoloured, red) could be utilised to aid interpretation of the UPC in samples with haematuria. PMID- 30517830 TI - Can sit-to-stand muscle power explain the ability to perform functional tasks in adults with severe obesity? AB - This study examined the relationship between sit-to-stand (STS) power and physical function in adults with severe obesity. Thirty-eight adults (age: 44 +/- 12 years; body mass index [BMI]: 45.2 +/- 7.8 kg/m2) completed evaluations of STS power, strength and functional performance. STS power was measured with a wearable inertial sensor, strength was assessed with the isometric mid-thigh pull, and function was measured with the timed up-and-go (TUG), six-minute walk test (6MWT) and 30-s chair STS. Power and strength (normalised to body mass) entered regression models in addition to age, gender, BMI and physical activity (daily step count). Power displayed large univariate associations with TUG (r = 0.50) and 30-s chair STS (r = 0.67), and a moderate association with 6MWT (r = 0.49). Forward stepwise regression revealed that power independently contributed to TUG (beta = -0.40, p = 0.010), 30-s chair STS (beta = 0.67, p < 0.001) and 6MWT performance (beta = 0.27, p = 0.007). Power also appeared to be a superior determinant of function compared with strength. Power generated via the STS transfer largely underpins the ability to perform functional tasks in adults with severe obesity, although intervention studies are required to investigate a potentially causal relationship. PMID- 30517831 TI - Annelies Allain: Pioneer of the International Code of Marketing of Breastmilk Substitutes. AB - Annelies Allain has been at the forefront of global efforts to support and promote breastfeeding for more than 30 years. Her accomplishments continue to affect all of us who work with breastfeeding families. Born in the Netherlands in 1945, Annelies Allain-van Elk received a scholarship and completed a BA from the University of Minnesota, Duluth, USA. Back in Europe, she obtained a BA in French language and literature (University of Geneva, Switzerland) as well as a translator's diploma. After 4 years working in West Africa and visits to South America, she returned to Geneva to obtain an MA in development studies. She is fluent in English, French, and Dutch and has working knowledge of Spanish, Portuguese, Italian, and German. Ms. Allain was a co-founder of IBFAN (1979) and the coordinator of IBFAN Europe (1980-1984). In 1984, she moved to Penang, Malaysia, and IBFAN work soon took over as a full-time job. She was instrumental in developing the Code Documentation Centre (1985) and by 1991 it became a foundation (ICDC) registered in the Netherlands. Subsequently, the Centre has trained over 2,000 officials from 148 countries about the International Code, making it the world's top International Code implementation institution. Among her many other education and advocacy activities, Ms. Allain was a co-founder of WABA (1990) and for many years has been a consultant with UNICEF and WHO's Western Pacific Regional Office on International Code implementation and monitoring. In this interview she provides a firsthand account of how most of the major global breastfeeding protection efforts influencing our current situation came into being. (This is a verbatim interview: MA = Maryse Arendt; AA = Annelies Allain.). PMID- 30517832 TI - Chemical and toxicological alterations of zearalenone under ozone treatment. AB - Our work mainly studied the elimination of zearalenone (ZEN) from corn flour by ozone treatment. We found four degradation products, after separation and identification by UPLC-ESI-QTOF-MS, named as Compound 1 (m/z 335.18), Compound 2 (m/z 351.19), Compound 3 (m/z 321.19) and Compound 4 (m/z 367.18). Then, one main transformation pathway was predicted on the basis of molecular weight and the reaction mechanism of ozone. We had also detected two of the degradation products by our modified UPLC-MS/MS method in real samples-contaminated corn flour. We screened the toxicity of the parent ZEN compound as well as the ozone induced decomposition products with BALB/c mice to evaluate the safety of our method in vivo. Therefore, aqueous ozone was demonstrated to effectively degrade ZEN and chemical structure alternations of ZEN after ozone treatment were predicted in both pure ZEN and real contaminated-corn flour samples. Considering the presence of the by-products formed, differences in the toxic effects on mice exposed to ZEN before and after the ozone treatment emphasise the significance of further study on the quality and toxicity of real food samples after ozone treatment. PMID- 30517833 TI - Implicit Memory, Constructive Memory, and Imagining the Future: A Career Perspective. AB - In this article I discuss some of the major questions, findings, and ideas that have driven my research program, which has examined various aspects of human memory using a combination of cognitive, neuropsychological, and neuroimaging approaches. I do so from a career perspective that describes important scientific influences that have shaped my approach to the study of memory and discusses considerations that led to choosing specific research paths. After acknowledging key early influences, I briefly summarize a few of the main takeaways from research on implicit memory during the 1980s and 1990s and then move on to consider more recent ideas and findings concerning constructive memory, future imagining, and mental simulation that have motivated my approach for the past 2 decades. A main unifying theme of this research is that memory can affect psychological functions in ways that go beyond the simple everyday understanding of memory as a means of revisiting past experiences. PMID- 30517834 TI - Interdisciplinary bodyweight management program for persons with SCI. AB - OBJECTIVE: Persons with spinal cord injury (SCI) have a higher prevalence of being overweight than the general population, which is thought to be due to a variety of metabolic, physiologic and psychological changes. The quality improvement project described in this work was designed to help overweight persons with SCI lose bodyweight through nutrition, exercise, and behavioral management strategies. METHODS: Eighteen persons with SCI who were overweight were enrolled in a 12-week interdisciplinary weight management program. Participants were limited to persons at least one-year post-acute SCI with an established overweight status. Measurements, including a person's weight, body mass index, and waist circumference (WaC), were taken at the program's start, at its end, and six months post program. RESULTS: Seventeen out of 18 participants experienced weight loss, (WaC) decreased (P < 0.001), and the program was effective at reducing weight (P < 0.001). Six months following participation in the program participants did experience a significant change in weight or waist size six months post program, thus indicating that subjects did not regain weight after completion of the program. CONCLUSION: This quality improvement project provided indications of the benefits of an SCI-specific interdisciplinary weight management program. Clinical research evaluating methods for helping persons with SCI achieve a healthy bodyweight is indicated. PMID- 30517835 TI - Mindfulness in allied health and social care professional education: a scoping review. AB - BACKGROUND: Investigations into the use of mindfulness with allied health and social care students, many of whom ultimately work in rehabilitation settings, is in the nascent stages and no systematic mapping of the literature has occurred. The purpose of this scoping review was to identify, summarise, and describe the current state of knowledge on mindfulness in allied health and social care professional education. METHODS: Arksey and O'Malley's scoping review methodology was adopted. Five data bases were searched; inclusion and exclusion criteria were applied; and 50 papers were identified for inclusion in the study. RESULTS: Quantitative studies depicted mindfulness interventions as contributing to: improved capacities for mindfulness; decreases in stress, anxiety, and depression; improvements in academic skills, quality of life and well-being, and empathy; improved physiological measures and emotional regulation; and mixed effects on burn-out. Qualitative studies highlighted: 1) mindfulness and self care, 2) mindfulness within professional practice placements, 3) mindfulness in the classroom, and 4) the cultivation of mindful qualities. CONCLUSIONS: The study has important implications for the education of future rehabilitation professions and suggests that learning about mindfulness may be useful in assisting students to: manage academic stress, anxiety, and depression; cultivate a physical and mental state of calm; be more present and empathetic with clients; and be more focused and attentive in professional practice settings. Implications for rehabilitation Further exploration of mindfulness as a promising educational intervention for the professional preparation of future rehabilitation practitioners in allied health and social care fields is recommended. Education and research about mindfulness and its potential opportunities for students in terms of the mediation of stress, anxiety, depression, and the cultivation of empathy, academic skills, quality of life, and resilience are recommended. Education and research about mindfulness and its potential for the cultivation of beneficial qualities of mind such as attention, self-awareness, compassion, non judgment, and acceptance are recommended. Education and research about mindfulness as a potential means to develop capacities related to self-care, professional practice placements, and classroom performance in students is recommended. PMID- 30517836 TI - What information is important for accredited exercise physiologists to facilitate change in clients living with type 2 diabetes mellitus? AB - Accredited Exercise Physiologists (AEPs) prescribe exercise and physical activity interventions for people living with type 2 diabetes mellitus (T2DM). During initial consultations, AEPs face the challenge of collecting enough information to facilitate behaviour change and adherence to treatment recommendations. The objective of this research is to explore the initial consultation practices of AEPs with clients living with T2DM and resultant recommendations provided to clients to promote long-term adherence. This study was an exploratory descriptive qualitative study. Twenty-one AEPs who currently practice in the Townsville Region participated in focus groups or semi-structured interviews. Data were analysed using a thematic and triangulation approach. Results revealed that an interview style consultation is standard practice, which varied based on experience of the AEP. Interviewing techniques facilitating behaviour change were under-utilised, especially among less-experienced AEPs who focused on the medical information. Assessment of the psychosocial wellbeing of the client living with T2DM by AEPs was limited. AEPs recommended that group exercise sessions yielded greater success for clients adopting physical activity. It is recommended that new graduate AEPs develop greater confidence in strategies of gathering information to facilitate behaviour change in clients with T2DM. A mentorship program could ensure the continued development of new graduate AEPs through the transfer of knowledge and skills. PMID- 30517837 TI - Amelioration of sperm immobilisation factor-induced infertility by bacterial antigenic determinants cross-reacting with spermatozoa. AB - A strain of Staphylococcus aureus, capable of in vitro immobilisation of human and mouse spermatozoa, was already present in our laboratory. Therefore, in the present study, the factor responsible (sperm immobilisation factor, SIF) was isolated and purified. It was found to compromise not only motility, but also viability, morphology and Mg2+-ATPase activity of mouse spermatozoa. Also, SIF (250 MUg mL-1), when administered intravaginally in female BALB/c mice before mating, showed 100% contraceptive effect. Moreover, fluorescein isothiocyanate labelled SIF was also found to bind mouse spermatozoa and various motile as well as non-motile bacteria, indicating the presence of common SIF-binding receptors on spermatozoa and bacteria. Further, to demonstrate molecular mimicry, the amelioration of SIF-induced impairment of sperm function by a SIF-binding bacterial receptor was compelling. For this, the SIF-binding receptor from Escherichia coli (E-SBR) was purified and evaluated for its ameliorative effect on SIF-induced sperm impairment in vitro and in vivo. Interestingly, upon the addition of mouse spermatozoa to SIF pre-incubated with E-SBR, an ameliorative effect against SIF-induced impairment of sperm function could be observed through analysis of normal sperm parameters (motility, viability, morphology, Mg2+ dependent ATPase levels). E-SBR also blocked binding of labelled SIF to spermatozoa and bacteria and alleviated SIF-induced infertility in female BALB/c mice. This provided evidence for molecular similarities between bacteria and spermatozoa, owing to which anti-bacterial antibodies cross-reacting with spermatozoa might be produced and infertility might follow. PMID- 30517838 TI - Awareness of and attitudes to sexually transmissible infections among gay men and other men who have sex with men in England: a qualitative study. AB - Background: Rates of sexually transmissible infections (STIs) have increased over recent years among gay men and other men who have sex with men (MSM) in England and Wales. HIV diagnoses remain high in this group and men with diagnosed HIV are disproportionally affected by STIs. MSM are therefore a priority for health promotion efforts to reduce STIs. Understanding awareness of and attitudes towards STIs is essential in developing health promotion interventions to reduce prevalence. Methods: Eight focus group discussions (FGDs) with a total of 61 MSM in four English cities included a ranking exercise to gauge how 'scary' participants thought 11 STIs are. The exercise sought insights into participants' awareness of, knowledge about and attitudes towards STIs and blood-borne viruses (BBVs). FGDs were audio-recorded, transcribed and data analysed thematically. Results: All groups ranked HIV and Hepatitis C virus (HCV) as the scariest infections, and the majority ranked syphilis and herpes as highly scary. Scabies was ranked as the least scary by most groups. Rankings were dependent on how well informed participants felt about an infection, its transmission mechanisms, health affect and the availability of vaccines and treatment. Personal experience or that of friends influenced perceptions of particular infections, as did their prevalence, treatment options, visibility of symptoms and whether an STI could be cleared from the body. Conclusions: The study findings suggest that, although some MSM are well informed, there is widespread lack of knowledge about the prevalence, modes of transmission, health implications and treatment regimens of particular STIs. PMID- 30517839 TI - Factors associated with self-reported anal cancer screening history in men who have sex with men. AB - Background: Men who have sex with men (MSM) are at greater risk of developing anal cancer caused by human papillomavirus (HPV) than the rest of the general population. Currently, there are no formal national guidelines in the US advising men how and when to get anal cancer screening. We sought to assess differences in demographics, familiarity and anxiety about anal cancer among men who report having had anal cancer screening (i.e. anal cytology and/or a digital anorectal examination (DARE)). Methods: MSM were recruited to participate in a study to assess the feasibility of teaching self and partner anal examinations as a means of screening for anal cancer. Data for this secondary analysis were obtained using a written pre-test and a computer-assisted self-interview. Factors associated with screening were assessed with multivariable logistic regression to allow calculation of adjusted odds ratios (aORs). Results: Of the 197 participants with data, 145 (73.6%) reported having had anal cancer screening (either anal cytology, DARE or both) during their lifetime. Men who were younger, Black and HIV-negative were associated with decreased odds of reporting any type of anal cancer screening. For example, compared with White men, Black men were 80% less likely to report screening (aOR 0.2; 95% confidence interval (CI) 0.1 0.5). Self-perception of anal cancer knowledge was not associated with screening in multivariable analysis (aOR 1.6; 95% CI 0.6-3.9). Conclusions: Age, race and HIV status were independently associated with a history of anal cancer screening. PMID- 30517840 TI - Influence of biochar on physico-chemical and microbial community during swine manure composting process. AB - Excessive nutrients and toxic gas emissions from animal manure management are of great global concern, with negative environmental and economic consequences worldwide. Due to biochar recalcitrance and sorption properties, this study investigated the effect of the biochar(BC) derived from bamboo, amendment on swine manure(SM) composting efficiency through physical, physio-chemical, gaseous emissions, microbiological, and phytotoxic analysis during the 56 day process of in-vessel composting. The treatments were set-up from different ratios of biochar to swine manure mixed with sawdust(SD)(i.e. SM + SD + 3%BC(T1), SM:SD + 5 %BC(T2) and SM:SD + 10 %BC (T3)), while treatment without biochar amendment was used as a control, SM:SD(C). The results showed that, compared to the control, biochar amended compost mixtures had significantly reduced (p <= 0.05) bulk density, organic matter(OM), C:N ratio, NH3 emission, pathogenic microorganisms, and phytotoxicity effect (Cress seed, Lepidium sativum Linn.). On the other hand, biochar amendment mixtures had increased total porosity, water holding capacity, rapid thermophilic temperature, and nitrate nitrogen. However, with the most prominent effects in terms of the nutrient quality and degradation rate of compost mixtures, the amendment of 10% biochar is recommended for swine manure management through the composting process. PMID- 30517841 TI - Mass spectrometric imaging of cysteine rich proteins in human skin. AB - Looking insight pathological processes, metallothioneins (MTs) are considered to be potential biomarkers for monitoring of a development of various types of malignant disease, such as cancer. The early identification of the MT biomarkers in biological tissues could be important tool for the estimation of appropriate clinical therapy. Therefore here we investigated the application of matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) together with immunohistochemical analyses (IHC) using MT-1/2 antibody for MT detection in formalin-fixed paraffin-embedded (FFPE) biopsy specimens of human skin. Principal component analyses revealed differences in the peptide/protein profiles separating healthy skin from the carcinoma specimens. Statistically significant ion peaks at m/z 6038, 6300, 6676, and 7026 were more frequently detected in squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and melanoma. Using IHC, we found that MT-1/2 was significantly higher in SCC and melanoma compared to healthy skin. Surprisingly, significantly low levels of MT 1/2 were found in BCC. On one side, the results indicate important role of MTs in melanoma occurrence and progression, as on the second side, there are hidden processes associated with MTs based on differences of the occurrence of the MS peaks, which could be associated with cycling of MTs isoforms. PMID- 30517842 TI - Dimerization ability, denaturation mechanism, and the stability of a staphylococcal phage repressor and its two domains. AB - The lysogenic growth of phage f11 in Staphylococcus aureus is controlled by a repressor (CI) that harbors an N-terminal domain (NTD), and a C-terminal domain (CTD). Previously, NTD, like CI, showed DNA binding activity and dimerized in the aqueous solution. To precisely understand the folding mechanism, function, and the stability of CI, NTD, and CTD, we have investigated their recombinant forms, rCI, rNTD, and rCTD, using various probes. The data reveal that rCTD, like rCI and rNTD, is a well-structured protein and produces dimers in the aqueous environment. However, the stability order of the dimers appears to be rCI > rCTD > rNTD. Interestingly, the stability of rNTD or rCTD looks slightly higher than that of rCI. The urea-induced equilibrium unfolding of these proteins proceeded via the production of two intermediates. The structure, surface hydrophobicity, and the dimeric status of one intermediate mostly differed from those of another intermediate or the native protein. Our MD simulation study on the representative NTD shows the substantial change in its structure and stability at the urea concentrations, which formed rNTD intermediates. Collectively, the computational data have supported the experimental data and indicated that the CI and its domains are folded by a similar multiphasic pathway. PMID- 30517843 TI - pi-pi stacking interaction is a key factor for the stability of GH11 xylanases at low pH. AB - Acidic xylanases possess the unique features necessary for the tolerance of acidic environments, which may have great potentials for industrial purposes. However, factors controlling the pH-dependent stability of xylanases are only partially known. Here we proposed a residue interaction networks based method to analyze the differences of residue interactions between 6 pairs of experimentally verified acidic and neutral xylanases. They had very close numbers of aromatic amino acids, however extremely significant more (p < 0.001) pi-pi stacking interactions existed in acidic xylanases, which has not been reported before. Whereas the interactions between Tyrosine-Phenylalanine (Tyr-Phe) and Phenylalanine-Phenylalanine (Phe-Phe) were the main contributors. An equation quantitatively described the relationship between the optimal pH and the number of pi-pi stacking interactions was proposed. The predicted optimal pHs for three xylanases was 4.13, 6.7 and 6.1, while the experimental values of the optimum pHs were 4.6, 6.5 and 6.5, with an absolute error of 0.47, 0.2 and 0.4 pH unit, respectively. By counting the aromatic residue pairs forming pi-pi stacking in the 3D structure of an acidic (PDB ID: 1BK1, with an optimal pH of 2) and a neutral (PDB ID:1XXN, with an optimal pH of 6.5) xylanase, we found significant differences existed in the positions ranging from 145 to 166 in forming pi-pi stacking. Two phenylalanines at position 149 and 157 in the acidic xylanase, which involved in 7 pi-pi stacking interactions, played an important role in the stability of xylanase at low pH environment, which was further proved by a mutation experiment. A mutated xylanase with Phe149 -> Ala149 and Phe157 -> Ala157 was expressed and purified, resulting the optimal pH shifted from 2 to 4.5. The interaction networks based method paved a new way in underlying and engineering the acid-stability of xylanase, as well as the characteristics of other enzymes. PMID- 30517844 TI - Power and temporal dynamics of alpha oscillations at rest differentiate cognitive performance involving sustained and phasic cognitive control. AB - Resting state neuronal activity in EEG/MEG recordings is primarily characterized by the presence of alpha oscillations (approx. 8-12 Hz). However, their functional significance and link to cognitive task performance remains elusive. We investigated resting state neuronal activity and its relation to task performance by assessing traditional measures of alpha activity (power and individual alpha peak frequency) and dynamic properties of the signal measured by long-range temporal correlations (LRTC). Multichannel EEG was recorded at rest in 82 healthy male adults and compared to their cognitive performance, measured by tests involving executive functions, working memory, short- and long-term memory demands. Our results showed that attention span scores positively correlated with alpha power at rest, with corresponding neuronal sources located primarily in the left-hemispheric anterior cingulate cortex, supplementary motor area, and parietal regions. Furthermore, better working memory performance was related to increased LRTC of alpha oscillations at rest in the right hemispheric fronto parietal, temporal, and occipital regions. Our findings suggest that resting state neuronal activity may reflect properties of brain networks that are functionally relevant for cognitive task performance. While alpha power measured at rest might relate to tasks that employ sustained inhibitory control, LRTC are suggested to reflect the capacity of neuronal networks to perform tasks that require phasic attention and quick adaptation to changing task demands. PMID- 30517845 TI - VEGF-like protein from Apostichopus japonicus promotes cell proliferation and migration. AB - Vascular endothelial growth factor (VEGF) is a key conservative regulator of inflammation response by promoting cell proliferation, migration, and vascular permeability. It also induces the release of inflammatory factors in vertebrates. We previously characterized NLR family pyrin domain containing 3 and HMGB3 homology in Apostichopus japonicus, providing the occurrence of inflammation in this species. However, to our knowledge, other inflammation-related molecules, such as VEGF, have rarely been investigated. In the present study, a novel VEGF homolog was identified from A. japonicus (designated as AjVEGF) by rapid amplification of cDNA ends. Full-length cDNA of AjVEGF was 3181 bp with a putative open reading frame of 1752 bp encoding 583 amino acid (aa) residue protein. Structural analysis revealed that AjVEGF processed characteristic VEGF domains of platelet-derived growth factor domain (132-232 aa) and CXC domain (223 270 aa). Multiple sequence alignment and phylogenetic analysis both supported that AjVEGF belongs to a new member of VEGF protein subfamily. Both Vibrio splendidus challenge in vivo and lipopolysaccharide stimulation in vitro could significantly upregulate mRNA expression of AjVEGF compared with the control group. Functional analysis indicated that recombinant AjVEGF promoted coelomocyte proliferation and migration not only in sea cucumber but also in human colorectal adenocarcinoma cells (HT29). This consistent function was also detected for human VEGFs. Taken together, these findings suggest that AjVEGF has a similar function of VEGF in higher animals and might serve as a candidate cytokine in sea cucumber inflammation. PMID- 30517846 TI - Candidate early predictive plasma protein markers of doxorubicin-induced chronic cardiotoxicity in B6C3F1 mice. AB - Cardiotoxicity is a serious adverse effect of doxorubicin (DOX) treatment in cancer patients. Currently, there is a lack of sensitive biomarkers to predict the risk of DOX-induced cardiotoxicity. Using SOMAmer-based proteomic technology, 1129 proteins were profiled to identify potential early biomarkers of cardiotoxicity in plasma from male B6C3F1 mice given a weekly intravenous dose of 3 mg/kg DOX or saline (SAL) for 2, 3, 4, 6, or 8 weeks (6, 9, 12, 18, or 24 mg/kg cumulative DOX doses, respectively). Also, a group of mice received the cardio protectant, dexrazoxane (DXZ; 60 mg/kg; intraperitoneal) 30 min before a weekly DOX or SAL dose. Proteomic analysis in plasma collected a week after the last dose showed a significant >=1.2-fold change in plasma level of 18 proteins in DOX treated mice compared to SAL-treated counterparts during 8-week exposure. Of these, neurogenic locus notch homolog protein 1 (NOTCH1), von Willebrand factor (vWF), mitochondrial glutamate carrier 2, Wnt inhibitory factor 1, legumain, and mannan-binding lectin serine protease 1 were increased in plasma at 6 mg/kg cumulative dose, prior to the release of myocardial injury marker, cardiac troponin I at 12 mg/kg and higher cumulative doses. These six proteins also remained significantly elevated following myocardial injury or pathology at 24 mg/kg. Pretreatment of mice with DXZ significantly attenuated DOX-induced elevated levels of only NOTCH1 and vWF with mitigation of cardiotoxicity. This suggests NOTCH1 and vWF as candidate early biomarkers of DOX cardiotoxicity, which may help in addressing a clinically important question of identifying cancer patients at risk for cardiotoxicity. PMID- 30517847 TI - Denoising of MR images using Kolmogorov-Smirnov distance in a Non Local framework. AB - Data coming from any acquisition system, such as Magnetic Resonance Imaging ones, are affected by noise. Although modern high field scanners can reach high Signal to Noise Ratios, in some circumstances, for example in case of very weak signals due to a specific acquisition sequence, noise becomes a critical issue that has to be properly handled. In last years methods based on the so called Non Local Mean have proven to be very effective in denoising tasks. The idea of these filters is to find similar patches across the image and to jointly exploit them to obtain the restored image. A critical point is the distance metric adopted for measuring similarity. Within this manuscript, we propose a filtering technique based on the Kolmogorov-Smirnov distance. The main innovative aspect of the proposed method consists in the criteria adopted for finding similar pixels across the image: it is based on the statistics of the points rather then the widely adopted weighted Euclidean distance. More in details, the Cumulative Distribution Functions of different pixels are evaluated and compared in order to measure their similarities, exploiting a stack of images of the same slice acquired with different acquisition parameters. To quantitatively and qualitatively assess the performances of the approach, a comparison with other widely adopted denoising filters in case of both simulated and real datasets has been carried out. The obtained results confirm the validity of the proposed solution. PMID- 30517848 TI - Interaction of Hsp90AA1 with phospholipids stabilizes membranes under stress conditions. AB - During heat shock conditions, structural changes in cellular membranes may lead to cell death. Hsp90AA1 and other heat shock proteins involved in membranes are responsible for protecting membrane stabilization. However, the membrane binding mechanism of Hsp90AA1 remains largely uncharacterized. In this study, we showed Hsp90AA1 interacts with phospholipid membrane with high affinity. Using the depth dependent fluorescence-quenching with brominated lipids, we found Hsp90AA1 penetrated 10.7 A into the hydrocarbon core of the lipid bilayer. Circular dichroism spectra studies showed Hsp90AA1 lost part of its alpha-helical structures upon interaction with phospholipid membrane. By assessing binding properties of the three Hsp90AA1 domains, we found Hsp90AA1 interacted into the lipid bilayer mainly toward its C-terminus domain (CTD). Using scanning electron microscopy, we examined the protection on host cell membrane by overexpressing Hsp90AA1. The results indicated Hsp90AA1 or Hsp90AA1-CTD expressing E. coli cells exhibited better membrane integrity compared to the control after thermal treatment. The following liposome leakage assay suggested the protection of Hsp90AA1 might due to its stabilization of the membrane lipid. Collectively, the present study demonstrates Hsp90AA1 embeds into the lipid bilayer through its C terminal domain and the Hsp90AA1-lipid association potentially has a significant function in keeping membranes stabilization during stress conditions. PMID- 30517849 TI - A light-initiated chemiluminescent assay for rapid quantitation of allergen specific IgG4 in clinical samples. AB - BACKGROUND: An increase in allergen-specific IgG4 (sIgG4), which serves as a blocking antibody, is associated with acquisition of immune tolerance after immunotherapy. In this study, we developed a rapid, sensitive, and homogeneous immunoassay based on the light-initiated chemiluminescent assay (LICA) technology for quantifying allergen sIgG4 in serum samples. METHODS: Allergen sIgG4 was measured in vitro by incubating the sample with biotinylated allergens and chemiluminescent beads coated with anti-human IgG4 antibody, followed by the addition of streptavidin-coated sensitizer beads. Multiple tests were performed to optimize the working conditions of the LICA and evaluate its performance. RESULTS: We established the optimal concentration of biotinylated allergens (250 ng/mL), the optimal dilution range (1:8 for Gal d 1, Gal d 2 sIgG4 and 1:4 for Gal d 3, Gal d 4 sIgG4), and the optimal incubation time (20 min for Gal d 1, Gal d 2 sIgG4 and 40 min for Gal d 3, Gal d 4 sIgG4). The lower limit of quantification (LLOQ) was 0.261 ng/mL. The coefficient variation (CV) of the LICA was <10%. The assay was unaffected by general interfering substances at physiological concentrations. It exhibited excellent accuracy to detect allergen sIgG4 in human serum. Additionally, we demonstrated that the levels of Gal d 1, Gal d 2, and Gal d 3-sIgG4 were significantly higher in the egg allergy group (p < .05), but no differences were found between the groups for Gal d 4-sIgG4. CONCLUSIONS: The LICA demonstrated satisfactory performance and can be used for quantifying allergen sIgG4 in clinical practice. PMID- 30517850 TI - Measurement of urinary matrix metalloproteinase-7 for early diagnosis of acute kidney injury based on an ultrasensitive immunomagnetic microparticle-based time resolved fluoroimmunoassay. AB - The morbidity and mortality associated with acute kidney injury (AKI) remain obstinately high. Early diagnosis is urgently required and should be pursued in at-risk populations. Recently, a newly validated biomarker, matrix metalloproteinase-7 (MMP-7), was reported as a novel indicator for early AKI prediction and a noninvasive surrogate biomarker of kidney function. Monitoring urinary MMP-7 (uMMP-7) levels fills the gaps in early diagnosis of AKI at early onset. However, the lack of available reagents for its rapid detection limits its use. Herein, we established an ultrasensitive and rapid immunomagnetic microparticles-based time-resolved fluoroimmunoassay to measure urinary MMP-7 in AKI patients. The assay time is 30 min. The calibration curve showed high linear correlation (r = 0.9998) with a linearity of detection of 0.063-150 ng mL-1 and lower limit of detection of 0.039 ng mL-1. The coefficient variation of the intra and inter-assay lower than 5.17%, and the analytical recovery was 99.06% 105.60%. Testing of clinical samples using the proposed assay and a DUOSET@ ELISA kit showed good correlations in the comparison of uMMP-7 levels (r = 0.9541) and uMMP-7/uCreatinine (r = 0.9595). The proposed assay has satisfactory analytical performance and may serve as a promising tool for early diagnosis of AKI. PMID- 30517851 TI - A systematic comparison of exercise training protocols on animal models of cardiovascular capacity. AB - Cardiovascular disease (CVD) is a major global cause of mortality, which has prompted numerous studies seeking to reduce the risk of heart failure and sudden cardiac death. While regular physical activity is known to improve CVD associated morbidity and mortality, the optimal duration, frequency, and intensity of exercise remains unclear. To address this uncertainty, various animal models have been used to study the cardioprotective effects of exercise and related molecular mechanism such as the mice training models significantly decrease size of myocardial infarct by affecting Kir6.1, VSMC sarc-KATP channels, and pulmonary eNOS. Although these findings cement the importance of animal models in studying exercise induced cardioprotection, the vast assortment of exercise protocols makes comparison across studies difficult. To address this issue, we review and break down the existent exercise models into categories based on exercise modality, intensity, frequency, and duration. The timing of sample collection is also compared and sorted into four distinct phases: pre-exercise (Phase I), mid exercise (Phase II), exercise recovery (Phase III), and post-exercise (Phase IV). Finally, because the life-span of animals so are limited, small changes in animal exercise duration can corresponded to untenable amounts of human exercise. To address this limitation, we introduce the Life-Span Relative Exercise Time (RETlife span) as a method of accurately defining short-term, medium-term and long-term exercise relative to the animal's life expectancy. Systematic organization of existent protocols and this new system of defining exercise duration will allow for a more solid framework from which researchers can extrapolate animal model data to clinical application. PMID- 30517852 TI - Real-Time Readout of Large-Scale Unsorted Neural Ensemble Place Codes. AB - Uncovering spatial representations from large-scale ensemble spike activity in specific brain circuits provides valuable feedback in closed-loop experiments. We develop a graphics processing unit (GPU)-powered population-decoding system for ultrafast reconstruction of spatial positions from rodents' unsorted spatiotemporal spiking patterns, during run behavior or sleep. In comparison with an optimized quad-core central processing unit (CPU) implementation, our approach achieves an ~20- to 50-fold increase in speed in eight tested rat hippocampal, cortical, and thalamic ensemble recordings, with real-time decoding speed (approximately fraction of a millisecond per spike) and scalability up to thousands of channels. By accommodating parallel shuffling in real time (computation time <15 ms), our approach enables assessment of the statistical significance of online-decoded "memory replay" candidates during quiet wakefulness or sleep. This open-source software toolkit supports the decoding of spatial correlates or content-triggered experimental manipulation in closed-loop neuroscience experiments. PMID- 30517853 TI - Ghrelin Enhances Food Odor Conditioning in Healthy Humans: An fMRI Study. AB - Vulnerability to obesity includes eating in response to food cues, which acquire incentive value through conditioning. The conditioning process is largely subserved by dopamine, theorized to encode the discrepancy between expected and actual rewards known as the reward prediction error (RPE). Ghrelin is a gut derived homeostatic hormone that triggers hunger and eating. Despite extensive evidence that ghrelin stimulates dopamine, it remains unknown in humans whether ghrelin modulates food cue learning. Here, we show using fMRI that intravenously administered ghrelin increased RPE-related activity in dopamine-responsive areas during food odor conditioning in healthy volunteers. Participants responded faster to food odor-associated cues and perceived them to be more pleasant following ghrelin injection. Ghrelin also increased functional connectivity between the hippocampus and the ventral striatum. Our work demonstrates that ghrelin promotes the ability of food cues to acquire incentive salience and has implications for the development of vulnerability to obesity. PMID- 30517854 TI - Shortening the Half-Life of Cas9 Maintains Its Gene Editing Ability and Reduces Neuronal Toxicity. AB - Virus-mediated expression of CRISPR/Cas9 is commonly used for genome editing in animal brains to model or treat neurological diseases, but the potential neurotoxicity of overexpressing bacterial Cas9 in the mammalian brain remains unknown. Through RNA sequencing (RNA-seq) analysis, we find that virus-mediated expression of Cas9 influences the expression of genes involved in neuronal functions. Reducing the half-life of Cas9 by tagging with geminin, whose expression is regulated by the cell cycle, maintains the genome editing capacity of Cas9 but significantly alleviates neurotoxicity. Thus, modification of Cas9 by shortening its half-life can help develop CRISPR/Cas9-based therapeutic approaches for treating neurological disorders. PMID- 30517855 TI - Selective Survival of Embryos Can Explain DNA Methylation Signatures of Adverse Prenatal Environments. AB - An adverse intrauterine environment is associated with long-term physiological changes in offspring. These are believed to be mediated by epigenomic marks, including DNA methylation (DNAm). Changes in DNAm are often interpreted as damage or plastic responses of the embryo. Here, we propose that stochastic DNAm variation, generated during remodeling of the epigenome after fertilization, contributes to DNAm signatures of prenatal adversity through differential survival of embryos. Using a mathematical model of re-methylation in the early embryo, we demonstrate that selection, but not plasticity, will generate a characteristic reduction in DNAm variance at loci that contribute to survival. Such a reduction in DNAm variance was apparent in a human cohort prenatally exposed to the Dutch famine, illustrating that it is possible to detect a signature of selection on epigenomic variation. Selection should be considered as a possible mechanism linking prenatal adversity to subsequent health and may have implications when evaluating interventions. PMID- 30517856 TI - Optical Clearing in the Kidney Reveals Potassium-Mediated Tubule Remodeling. AB - Distal nephron remodeling contributes to the pathophysiology of many clinically relevant scenarios, including diuretic resistance and certain Mendelian disorders of blood pressure. However, constitutive genetic disruptions are likely to have substantial developmental effects in this segment, and whether tubule remodeling upon physiological stimuli is a normal homeostatic mechanism is not known. Since the distal nephron acts as a potassium sensor, we assessed proliferation and tubule length in three dimensions upon dietary or inducible genetic manipulation by using optical clearing of adult mouse kidneys, whole-mount immunolabeling, and advanced light microscopy. We show that dietary potassium restriction leads promptly to proliferation of various nephron segments, including the distal convoluted tubule, whereas disruption of the potassium sensor Kir4.1 causes atrophy, despite ambient hypokalemia. These results provide proof that kidney tubules adapt rapidly to diet and indicate the power of clearing approaches to assess cell number and tubule length in healthy and diseased kidney. PMID- 30517857 TI - tRNA Translocation by the Eukaryotic 80S Ribosome and the Impact of GTP Hydrolysis. AB - Translocation moves the tRNA2?mRNA module directionally through the ribosome during the elongation phase of protein synthesis. Although translocation is known to entail large conformational changes within both the ribosome and tRNA substrates, the orchestrated events that ensure the speed and fidelity of this critical aspect of the protein synthesis mechanism have not been fully elucidated. Here, we present three high-resolution structures of intermediates of translocation on the mammalian ribosome where, in contrast to bacteria, ribosomal complexes containing the translocase eEF2 and the complete tRNA2?mRNA module are trapped by the non-hydrolyzable GTP analog GMPPNP. Consistent with the observed structures, single-molecule imaging revealed that GTP hydrolysis principally facilitates rate-limiting, final steps of translocation, which are required for factor dissociation and which are differentially regulated in bacterial and mammalian systems by the rates of deacyl-tRNA dissociation from the E site. PMID- 30517858 TI - Single-Cell RNA-Seq of Mouse Olfactory Bulb Reveals Cellular Heterogeneity and Activity-Dependent Molecular Census of Adult-Born Neurons. AB - Cellular heterogeneity within the mammalian brain poses a challenge toward understanding its complex functions. Within the olfactory bulb, odor information is processed by subtypes of inhibitory interneurons whose heterogeneity and functionality are influenced by ongoing adult neurogenesis. To investigate this cellular heterogeneity and better understand adult-born neuron development, we utilized single-cell RNA sequencing and computational modeling to reveal diverse and transcriptionally distinct neuronal and nonneuronal cell types. We also analyzed molecular changes during adult-born interneuron maturation and uncovered developmental programs within their gene expression profiles. Finally, we identified that distinct neuronal subtypes are differentially affected by sensory experience. Together, these data provide a transcriptome-based foundation for investigating subtype-specific neuronal function in the olfactory bulb (OB), charting the molecular profiles that arise during the maturation and integration of adult-born neurons and how they dynamically change in an activity-dependent manner. PMID- 30517859 TI - Supramammillary Nucleus Afferents to the Dentate Gyrus Co-release Glutamate and GABA and Potentiate Granule Cell Output. AB - The supramammillary nucleus (SuM) of the hypothalamus projects to the dentate gyrus (DG) and the CA2 region of the hippocampus. Although the SuM-to-hippocampus circuits have been implicated in spatial and emotional memory formation, little is known about precise neural connections between the SuM and hippocampus. Here, we report that axons of SuM neurons make monosynaptic connections to granule cells (GCs) and GABAergic interneurons, but not to hilar mossy cells, in the DG and co-release glutamate and gamma-aminobutyric acid (GABA) at these synapses. Although inputs from the SuM can excite some interneurons, the inputs alone fail to generate spikes in GCs. However, despite the insufficient excitatory drive and GABAergic co-transmission, SuM inputs have net excitatory effects on GCs and can potentiate GC firing when temporally associated with perforant path inputs. Our results indicate that the SuM influences DG information processing by modulating GC outputs. PMID- 30517860 TI - Long-Term Memory Engram Cells Are Established by c-Fos/CREB Transcriptional Cycling. AB - Training-dependent increases in c-fos have been used to identify engram cells encoding long-term memories (LTMs). However, the interaction between transcription factors required for LTM, including CREB and c-Fos, and activating kinases such as phosphorylated ERK (pERK) in the establishment of memory engrams has been unclear. Formation of LTM of an aversive olfactory association in flies requires repeated training trials with rest intervals between trainings. Here, we find that prolonged rest interval-dependent increases in pERK induce transcriptional cycling between c-Fos and CREB in a subset of KCs in the mushroom bodies, where olfactory associations are made and stored. Preexisting CREB is required for initial c-fos induction, while c-Fos is required later to increase CREB expression. Blocking or activating c-fos-positive engram neurons inhibits memory recall or induces memory-associated behaviors. Our results suggest that c Fos/CREB cycling defines LTM engram cells required for LTM. PMID- 30517861 TI - A Primate-Specific Isoform of PLEKHG6 Regulates Neurogenesis and Neuronal Migration. AB - The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development. PMID- 30517862 TI - Inhibiting Stearoyl-CoA Desaturase Ameliorates alpha-Synuclein Cytotoxicity. AB - The lack of disease-modifying treatments for neurodegenerative disease stems in part from our rudimentary understanding of disease mechanisms and the paucity of targets for therapeutic intervention. Here we used an integrated discovery paradigm to identify a new therapeutic target for diseases caused by alpha synuclein (alpha-syn), a small lipid-binding protein that misfolds and aggregates in Parkinson's disease and other disorders. Using unbiased phenotypic screening, we identified a series of compounds that were cytoprotective against alpha-syn mediated toxicity by inhibiting the highly conserved enzyme stearoyl-CoA desaturase (SCD). Critically, reducing the levels of unsaturated membrane lipids by inhibiting SCD reduced alpha-syn toxicity in human induced pluripotent stem cell (iPSC) neuronal models. Taken together, these findings suggest that inhibition of fatty acid desaturation has potential as a therapeutic approach for the treatment of Parkinson's disease and other synucleinopathies. PMID- 30517863 TI - HDAC3 Regulates the Transition to the Homeostatic Myelinating Schwann Cell State. AB - The formation of myelinating Schwann cells (mSCs) involves the remarkable biogenic process, which rapidly generates the myelin sheath. Once formed, the mSC transitions to a stable homeostatic state, with loss of this stability associated with neuropathies. The histone deacetylases histone deacetylase 1 (HDAC1) and HDAC2 are required for the myelination transcriptional program. Here, we show a distinct role for HDAC3, in that, while dispensable for the formation of mSCs, it is essential for the stability of the myelin sheath once formed-with loss resulting in progressive severe neuropathy in adulthood. This is associated with the prior failure to downregulate the biogenic program upon entering the homeostatic state leading to hypertrophy and hypermyelination of the mSCs, progressing to the development of severe myelination defects. Our results highlight distinct roles of HDAC1/2 and HDAC3 in controlling the differentiation and homeostatic states of a cell with broad implications for the understanding of this important cell-state transition. PMID- 30517865 TI - B Cells Produce the Tissue-Protective Protein RELMalpha during Helminth Infection, which Inhibits IL-17 Expression and Limits Emphysema. AB - Emphysema results in destruction of alveolar walls and enlargement of lung airspaces and has been shown to develop during helminth infections through IL-4R independent mechanisms. We examined whether interleukin 17A (IL-17A) may instead modulate development of emphysematous pathology in mice infected with the helminth parasite Nippostrongylus brasiliensis. We found that transient elevations in IL-17A shortly after helminth infection triggered subsequent emphysema that destroyed alveolar structures. Furthermore, lung B cells, activated through IL-4R signaling, inhibited early onset of emphysematous pathology. IL-10 and other regulatory cytokines typically associated with B regulatory cell function did not play a major role in this response. Instead, at early stages of the response, B cells produced high levels of the tissue protective protein, Resistin-like molecule alpha (RELMalpha), which then downregulated IL-17A expression. These studies show that transient elevations in IL-17A trigger emphysema and reveal a helminth-induced immune regulatory mechanism that controls IL-17A and the severity of emphysema. PMID- 30517864 TI - CMV Primes Functional Alternative Signaling in Adaptive Deltag NK Cells but Is Subverted by Lentivirus Infection in Rhesus Macaques. AB - Despite burgeoning evidence demonstrating the adaptive properties of natural killer (NK) cells, mechanistic data explaining these phenomena are lacking. Following antibody sensitization, NK cells lacking the Fc receptor (FcR) signaling chain (Deltag) acquire adaptive features, including robust proliferation, multifunctionality, rapid killing, and mobilization to sites of virus exposure. Using the rhesus macaque model, we demonstrate the systemic distribution of Deltag NK cells expressing memory features, including downregulated Helios and Eomes. Furthermore, we find that Deltag NK cells abandon typical gamma-chain/Syk in lieu of CD3zeta-Zap70 signaling. FCgammaRIIIa (CD16) density, mucosal homing, and function are all coupled to this alternate signaling, which in itself requires priming by rhesus cytomegalovirus (rhCMV). Simian immunodeficiency virus (SIV) infections further expand gut-homing adaptive NK cells but result in pathogenic suppression of CD3zeta-Zap70 signaling and function. Herein, we provide a mechanism of virus-dependent alternative signaling that may explain the acquisition of adaptive features by primate NK cells and could be targeted for future vaccine or curative therapies. PMID- 30517866 TI - ISRE-Reporter Mouse Reveals High Basal and Induced Type I IFN Responses in Inflammatory Monocytes. AB - Type I and type III interferons (IFNs) are critical for controlling viral infections. However, the precise dynamics of the IFN response have been difficult to define in vivo. Signaling through type I IFN receptors leads to interferon stimulated response element (ISRE)-dependent gene expression and an antiviral state. As an alternative to tracking IFN, we used an ISRE-dependent reporter mouse to define the cell types, localization, and kinetics of IFN responding cells during influenza virus infection. We find that measurable IFN responses are largely limited to hematopoietic cells, which show a high sensitivity to IFN. Inflammatory monocytes display high basal IFN responses, which are enhanced upon infection and correlate with infection of these cells. We find that inflammatory monocyte development is independent of IFN signaling; however, IFN is critical for chemokine production and recruitment following infection. The data reveal a role for inflammatory monocytes in both basal IFN responses and responses to infection. PMID- 30517867 TI - The HDAC-Associated Sin3B Protein Represses DREAM Complex Targets and Cooperates with APC/C to Promote Quiescence. AB - The mammalian DREAM complex is responsible for the transcriptional repression of hundreds of cell-cycle-related genes in quiescence. How the DREAM complex recruits chromatin-modifying entities to aid in its repression remains unknown. Using unbiased proteomics analysis, we have uncovered a robust association between the chromatin-associated Sin3B protein and the DREAM complex. We have determined that genetic inactivation of Sin3B results in the de-repression of DREAM target genes during quiescence but is insufficient to allow quiescent cells to resume proliferation. However, inactivation of APC/CCDH1 was sufficient for Sin3B-/- cells, but not parental cells, to re-enter the cell cycle. These studies identify Sin3B as a transcriptional corepressor associated with the DREAM complex in quiescence and reveals a functional cooperation between E2F target repression and APC/CCDH1 in the negative regulation of cell-cycle progression. PMID- 30517868 TI - Polycomb- and Methylation-Independent Roles of EZH2 as a Transcription Activator. AB - Enhancer of Zeste 2 (EZH2) is the enzymatic subunit of Polycomb Repressive Complex 2 (PRC2), which catalyzes histone H3 lysine 27 trimethylation (H3K27me3) at target promoters for gene silencing. Here, we report that EZH2 activates androgen receptor (AR) gene transcription through direct occupancy at its promoter. Importantly, this activating role of EZH2 is independent of PRC2 and its methyltransferase activities. Genome-wide assays revealed extensive EZH2 occupancy at promoters marked by either H3K27ac or H3K27me3, leading to gene activation or repression, respectively. Last, we demonstrate enhanced efficacy of enzymatic EZH2 inhibitors when used in combination with AR antagonists in blocking the dual roles of EZH2 and suppressing prostate cancer progression in vitro and in vivo. Taken together, our study reports EZH2 as a transcriptional activator, a key target of which is AR, and suggests a drug-combinatory approach to treat advanced prostate cancer. PMID- 30517869 TI - Cooperative Transcription Factor Induction Mediates Hemogenic Reprogramming. AB - During development, hematopoietic stem and progenitor cells (HSPCs) arise from specialized endothelial cells by a process termed endothelial-to-hematopoietic transition (EHT). The genetic program driving human HSPC emergence remains largely unknown. We previously reported that the generation of hemogenic precursor cells from mouse fibroblasts recapitulates developmental hematopoiesis. Here, we demonstrate that human fibroblasts can be reprogrammed into hemogenic cells by the same transcription factors. Induced cells display dynamic EHT transcriptional programs, generate hematopoietic progeny, possess HSPC cell surface phenotype, and repopulate immunodeficient mice for 3 months. Mechanistically, GATA2 and GFI1B interact and co-occupy a cohort of targets. This cooperative binding is reflected by engagement of open enhancers and promoters, initiating silencing of fibroblast genes and activating the hemogenic program. However, GATA2 displays dominant and independent targeting activity during the early phases of reprogramming. These findings shed light on the processes controlling human HSC specification and support generation of reprogrammed HSCs for clinical applications. PMID- 30517870 TI - The Dachsous/Fat/Four-Jointed Pathway Directs the Uniform Axial Orientation of Epithelial Cells in the Drosophila Abdomen. AB - The achievement of the final form of an individual requires not only the control of cell size and differentiation but also integrative directional cues to instruct cell movements, positions, and orientations. In Drosophila, the adult epidermis of the abdomen is created de novo by histoblasts. As these expand and fuse, they uniformly orient along the anteroposterior axis. We found that the Dachsous/Fat/Four-jointed (Ds/Ft/Fj) pathway is key for their alignment. The refinement of the tissue-wide expression of the atypical cadherins Ds and Ft result in their polarization and directional adhesiveness. Mechanistically, the axially oriented changes in histoblasts respond to the redesign of the epithelial field. We suggest that the role of Ds/Ft/Fj in long-range oriented cell alignment is a general function and that the regulation of the expression of its components will be crucial in other morphogenetic models or during tissue repair. PMID- 30517871 TI - Histone Deacetylase SIRT1 Targets Plk2 to Regulate Centriole Duplication. AB - The protein deacetylase SIRT1 (Sirtuin 1) regulates many cellular processes, including cell-cycle progression, DNA damage response, and metabolism. Although the centrosome is a key regulator of cell-cycle progression and genome stability, little is known concerning SIRT1 controlled centrosome-associated events. Here we report that the centrosome protein Plk2 is acetylated and undergoes deacetylation by SIRT1. Acetylation protects Plk2 from ubiquitination, and SIRT1-mediated deacetylation promotes ubiquitin-dependent degradation of Plk2. SIRT1 controls centriole duplication by temporally modulating centrosomal Plk2 levels. AURKA phosphorylates SIRT1 and promotes the SIRT1-Plk2 interaction in mitosis. In early mid G1, phosphorylated SIRT1 deacetylates and promotes Plk2 degradation. In late G1, SIRT1 is hypophosphorylated and its affinity to Plk2 is decreased, resulting in a rapid accumulation of centrosomal Plk2, which contributes to the timely initiation of centriole duplication. Collectively, our findings uncover a critical role of SIRT1 in centriole duplication and provide a mechanistic insight into SIRT1-mediated centrosome-associated functions. PMID- 30517872 TI - CSAP Acts as a Regulator of TTLL-Mediated Microtubule Glutamylation. AB - Tubulin glutamylation is a reversible posttranslational modification that accumulates on stable microtubules (MTs). While abnormally high levels of this modification lead to a number of disorders such as male sterility, retinal degeneration, and neurodegeneration, very little is known about the molecular mechanisms underlying the regulation of glutamylase activity. Here, we found that CSAP forms a complex with TTLL5, and we demonstrate that the two proteins regulate their reciprocal abundance. Moreover, we show that CSAP increases TTLL5 mediated glutamylation and identify the TTLL5-interacting domain. Deletion of this domain leads to complete loss of CSAP activating function without impacting its MT binding. Binding of CSAP to TTLL5 promotes relocalization of TTLL5 toward MTs. Finally, we show that CSAP binds and activates all of the remaining autonomously active TTLL glutamylases. As such, we present CSAP as a major regulator of tubulin glutamylation and associated functions. PMID- 30517873 TI - ULK1 O-GlcNAcylation Is Crucial for Activating VPS34 via ATG14L during Autophagy Initiation. AB - Unc-51-like-kinase 1 (ULK1) is a target of both the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), whose role is to facilitate the initiation of autophagy in response to starvation. Upon glucose starvation, dissociation of mTOR from ULK1 and phosphorylation by AMPK leads to the activation of ULK1 activity. Here, we provide evidence that ULK1 is the attachment of O-linked N-acetylglucosamine (O-GlcNAcylated) on the threonine 754 site by O-linked N-acetylglucosamine transferase (OGT) upon glucose starvation. ULK1 O-GlcNAcylation occurs after dephosphorylation of adjacent mTOR-dependent phosphorylation on the serine 757 site by protein phosphatase 1 (PP1) and phosphorylation by AMPK. ULK1 O-GlcNAcylation is crucial for binding and phosphorylation of ATG14L, allowing the activation of lipid kinase VPS34 and leading to the production of phosphatidylinositol-(3)-phosphate (PI(3)P), which is required for phagophore formation and initiation of autophagy. Our findings provide insights into the crosstalk between dephosphorylation and O-GlcNAcylation during autophagy and specify a molecular framework for potential therapeutic intervention in autophagy-related diseases. PMID- 30517874 TI - MadID, a Versatile Approach to Map Protein-DNA Interactions, Highlights Telomere Nuclear Envelope Contact Sites in Human Cells. AB - Mapping the binding sites of DNA- or chromatin-interacting proteins is essential to understanding biological processes. DNA adenine methyltransferase identification (DamID) has emerged as a comprehensive method to map genome-wide occupancy of proteins of interest. A caveat of DamID is the specificity of Dam methyltransferase for GATC motifs that are not homogenously distributed in the genome. Here, we developed an optimized method named MadID, using proximity labeling of DNA by the methyltransferase M.EcoGII. M.EcoGII mediates N6-adenosine methylation in any DNA sequence context, resulting in deeper and unbiased coverage of the genome. We demonstrate, using m6A-specific immunoprecipitation and deep sequencing, that MadID is a robust method to identify protein-DNA interactions at the whole-genome level. Using MadID, we revealed contact sites between human telomeres, repetitive sequences devoid of GATC sites, and the nuclear envelope. Overall, MadID opens the way to identification of binding sites in genomic regions that were largely inaccessible. PMID- 30517875 TI - Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age Related Metabolic Rewiring of Pancreatic beta Cell Function. AB - Pancreatic beta cell physiology changes substantially throughout life, yet the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from juvenile and 1-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from 1-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides an in depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in beta cell function. PMID- 30517876 TI - Development and Application of FASA, a Model for Quantifying Fatty Acid Metabolism Using Stable Isotope Labeling. AB - It is well understood that fatty acids can be synthesized, imported, and modified to meet requisite demands in cells. However, following the movement of fatty acids through the multiplicity of these metabolic steps has remained difficult. To better address this problem, we developed Fatty Acid Source Analysis (FASA), a model that defines the contribution of synthesis, import, and elongation pathways to fatty acid homeostasis in saturated, monounsaturated, and polyunsaturated fatty acid pools. Application of FASA demonstrated that elongation can be a major contributor to cellular fatty acid content and showed that distinct pro inflammatory stimuli (e.g., Toll-like receptors 2, 3, or 4) specifically reprogram homeostasis of fatty acids by differential utilization of synthetic and elongation pathways in macrophages. In sum, this modeling approach significantly advances our ability to interrogate cellular fatty acid metabolism and provides insight into how cells dynamically reshape their lipidomes in response to metabolic or inflammatory signals. PMID- 30517877 TI - Biochemical characterization of the venom of Central American scorpion Didymocentrus krausi Francke, 1978 (Diplocentridae) and its toxic effects in vivo and in vitro. AB - Venoms of medically important scorpions from Buthidae family have been intensively studied, in contrast to non-buthid venoms, for which knowledge is scarce. In this work, we characterized the venom of a Diplocentridae species, Didymocentrus krausi, a small fossorial scorpion that inhabits the Tropical Dry Forest of Central America. D. krausi venom soluble fraction contains proteases with enzymatic activity on gelatin and casein. Mass spectrometry and venomic analysis confirmed the presence of elastase-like, cathepsin-O-like proteases and a neprilysin-like metalloproteinase. We did not detect phospholipase A2, C or D, nor hyaluronidase activity in the venom. By homology-based venom gland transcriptomic analysis, NDBPs, a beta-KTx-like peptide, and other putative toxin transcripts were found, which, together with a p-benzoquinone compound present in the venom, could potentially explain its direct hemolytic and cytotoxic effects in several mammalian cell lines. Cytotoxicity of D. krausi venom was higher than venoms of two buthid scorpion species distributed in Costa Rica, Centruroides edwardsii and Tityus pachyurus. Even though D. krausi venom was not lethal to mice or crickets, when injected in mouse gastrocnemius muscle at high doses it induced pathological effects at 24 h, which include myonecrosis, weak hemorrhage, and inflammatory infiltration. We observed an apparent thrombotic effect in the skin blood vessels, but no in vitro fibrinogenolytic activity was detected. In crickets, D. krausi venom induced toxicity and paralysis in short periods of time. PMID- 30517878 TI - Cervical cancer cell lines are sensitive to sub-erythemal UV exposure. AB - High risk human papillomavirus (HPV) infections are the causative agent in virtually every cervical cancer as well as a host of other anogenital and oropharyngeal malignancies. These viruses must activate DNA repair pathways to facilitate their replication, while avoiding the cell cycle arrest and apoptosis that can accompany DNA damage. HPV oncoproteins facilitate each of these goals, but also reduce genome stability. Our data dissect the cytotoxic and cytoprotective characteristics of HPV oncogenes in cervical cancer cells. These data show that while the transformation of keratinocytes by HPV oncogene leaves these cells more sensitive to UV, the oncogenes also protect against UV-induced apoptosis. Cisplatin and UV resistant cervical cancer cell lines were generated and probed for their sensitivity to genotoxic agents. Cervical cancer cells can acquire resistance to one DNA crosslinking agent (UV or cisplatin) without gaining broad tolerance of crosslinked DNA. Further, cisplatin resistance may or may not result in sensitivity to PARP1 inhibition. PMID- 30517879 TI - The genetic divergences of codon usage shed new lights on transmission of hepatitis E virus from swine to human. AB - Hepatitis E virus (HEV) is an important pathogen causing public health burden. Swine has been recognized as a main reservoir. Interestingly, genotype 1 HEV only infects human; whereas genotype 3 and 4 are zoonotic. However, there is a lack of in-depth understanding in respect to the transmission from swine to human. Codon usage patterns generally participate in viral survival and fitness towards its hosts. We have analyzed codon usage patterns of the three open reading frames (ORFs) for 243 full-length genomes of HEV genotypes 1, 3 and 4. The divergence of synonymous codon usage patterns is different in each ORF for genotypes 1, 3 and 4, but the genotype-specific codon usage bias in genotype 1 is stronger than those of genotypes 3 and 4. In respect to genotypes 3 and 4, compared with strains isolated from human, HEV isolated from swine shows appreciable variation in adaptation of codon usages to human or swine. These results may help to understand the transmission and host adaptation of HEV genotypes 3 and 4 from swine to human. PMID- 30517880 TI - Antigenic relationship among zoonotic flaviviruses from Italy. AB - Here we report studies of the antigenic relationships of West Nile virus (WNV) and Usutu virus (USUV), two zoonotic flaviviruses from Italy, together with a Japanese encephalitis virus (JEV) strain and compared them with their genetic relationships using the immunodominant viral E protein. Thirty-nine isolates and reference strains were inactivated and used to immunize rabbits to produce hyper immune sera. Serum samples were tested by neutralization against all isolates and results visualized by generating antigenic map. Strains of WNV, USUV, and JEV grouped in separate clusters on the antigenic map. JEV was closer antigenically to the USUV (mean of 3.5 Antigenic Unit, AU, equivalent to a 2-fold change in antibody titer) than to the WNV strains (mean of 6 AU). A linear regression model predicted on average one unit of antigenic change, equivalent to a 2-fold change in antibody titer, for every 22 amino acid substitutions in the E protein ectodomain. Overall, antigenic map was demonstrated to be robust and consistent with phylogeny of the E protein. Indeed, the map provided a reliable means of visualizing and quantifying the relationship between these flaviviruses. Further antigenic analysis employing several strains of representative serocomplex are currently underway. This will provide a more in deep analysis of antigenic relationship between flaviviruses. PMID- 30517881 TI - Clethodim exposure induces developmental immunotoxicity and neurobehavioral dysfunction in zebrafish embryos. AB - Clethodim is one of the most widely used herbicides in agriculture, but its potential negative effects on aquatic organisms are still poorly understood. This study examined the effects of clethodim on zebrafish at aspects of early stage embryonic development, immune toxicity, cell apoptosis and locomotor behavior. Firstly, clethodim exposure markedly decreased the survival rate, body length, and heart rate and resulted in a series of morphological abnormalities, primarily spinal deformities (SD) and yolk sac edema, in zebrafish larvae. Secondly, the number of immune cells was substantially reduced but the levels of apoptosis and oxidative stress were significantly increased in a dose-dependent manner upon clethodim exposure. Thirdly, we evaluated the expression of some key genes in TLR signaling including TLR4, MyD88, and NF-kappaB p65 and they were all up-regulated by exposure to 300 MUg/L clethodim. Meanwhile, some proinflammatory cytokines such as TNF-alpha, IL-1beta, IL8, and IFN-gamma were also activated in both the mock and the TLR4-KD conditions. Moreover, the locomotor behaviors and the enzymatic activities of AChE were obviously inhibited but the levels of acetylated histone H3 were greatly increased by clethodim exposure. In addition, incubation of zebrafish larvae with acetylcholine receptor (AChR) agonist carbachol can partially rescue the clethodim-modulated locomotor behavior. Taken together, our results suggest that clethodim has the potential to induce developmental immunotoxicity and cause behavior alterations in zebrafish larvae. The information presented in this study will help to elucidate the molecular mechanisms underlying clethodim exposure in aquatic ecosystems. PMID- 30517882 TI - Evaluation of in-line particle measurement with an SFT-probe as monitoring tool for process automation using a new time-based buffer approach. AB - The Process Analytical Technology (PAT) initiative published by the Food and Drug administration (FDA) describes PAT systems as important tools to optimize pharmaceutical processes in order to ensure the final product quality. Real-time particle size measurements provide a promising approach for process automation of fluid bed granulation processes. This work focuses on the introduction and evaluation of a new time-based buffer approach for in-line spatial filtering technique (SFT) in order to provide a minimum time delay of the real-time measurement. Comparing the new buffer system to the conventionally used number based approach, a reduced influence of the particle rate and a constant response time was found. A performance qualification of the Parsum probe IPP 80 using this buffer approach according to the ICH guideline Q2 was performed to investigate whether common variations of process parameters influence the real-time particle size measurement. Focussing on the main requirements for process control, hereby a good precision and specificity as well as an adequate robustness was found. Summarized, this study identified the time-based buffer system as more suitable buffer system for process automation. PMID- 30517883 TI - A Tail of Phage Adhesins. AB - In this issue of Structure, Dunne et al. (2018) unveil the architecture of Salmonella phage S16 adhesin. The structure unravels a beads-on-a-string topology consisting of three domains of which the C-terminal glycine-rich PGII domain, located at the distal tip of the long tail fiber, mediates cell surface attachment and host recognition. PMID- 30517884 TI - Guiding COMPASS: Dpy-30 Positions SET1/MLL Epigenetic Signaling. AB - In this issue of Structure, Haddad et al. (2018) solve the high-resolution trimeric crystal structure of human COMPASS-like components Dpy-30 and Ash2L (2:1) to unravel an uncharacterized interaction surface required for competent H3K4 methylation in cells and clarify Dpy-30's role in the allosteric regulation of KMT2 enzymes. PMID- 30517885 TI - The How and What of tRNA Mimicry by a Y RNA. AB - In this issue of Structure, Wang et al. (2018) present the crystal structure of a bacterial Y RNA effector-binding domain. The domain is conserved across many bacteria and despite a reordering of key tRNA features, the structure closely mimics the overall fold and base pairing of the tRNA elbow. PMID- 30517886 TI - Validating Resolution Revolution. PMID- 30517887 TI - Neuronal SNARE complex: A protein folding system with intricate protein-protein interactions, and its common neuropathological hallmark, SNAP25. AB - SNARE (Soluble NSF(N-ethylmaleimide-sensitive factor) Attachment Receptor) complex is a trimeric supramolecular organization of SNAP25, syntaxin, and VAMP which mediates fusion of synaptic vesicles with the presynaptic plasma membrane. The functioning of this entire protein assembly is dependent on its tetrahelical coiled coil structure alongside its interaction with a large spectrum of regulatory proteins like synaptotagmin, complexin, intersectin, etc. Defects arising in SNARE complex assembly due to mutations or faulty post-translational modifications are associated to severe synaptopathies like Schizophrenia and also proteopathies like Alzheimer's disease. The review primarily focuses on SNAP25, which is the prime contributor in the complex assembly. It is conceptualized that the network of protein interactions of this helical protein assists as a chaperoning system for attaining functional structure. Additionally, the innate disordered nature of SNAP25 and its amyloidogenic propensities have been highlighted employing computational methods. The intrinsic nature of SNAP25 is anticipated to form higher-order aggregates due to its cysteine rich domain, which is also a target for several post-translational modifications. Furthermore, the aberrations in the structure and expression profile of the protein display common patterns in the pathogenesis of a diverse synaptopathies and proteopathies. This work of SNARE literature aims to provide a new comprehensive outlook and research directions towards SNARE complex and presents SNAP25 as a common neuropathological hallmark which can be a diagnostic or therapeutic target. PMID- 30517888 TI - The weWomen and ourCircle randomized controlled trial protocol: A web-based intervention for immigrant, refugee and indigenous women with intimate partner violence experiences. AB - Intimate partner violence (IPV), including homicides is a widespread and significant public health problem, disproportionately affecting immigrant, refugee and indigenous women in the United States (US). This paper describes the protocol of a randomized control trial testing the utility of administering culturally tailored versions of the danger assessment (DA, measure to assess risk of homicide, near lethality and potentially lethal injury by an intimate partner) along with culturally adapted versions of the safety planning (myPlan) intervention: a) weWomen (designed for immigrant and refugee women) and b) ourCircle (designed for indigenous women). Safety planning is tailored to women's priorities, culture and levels of danger. Many abused women from immigrant, refugee and indigenous groups never access services [WHY?] and research is needed to support interventions that are most effective and suited to the needs of abused women from these populations in the US. In this two-arm trial, 1250 women are being recruited and randomized to either the web-based weWomen or ourCircle intervention or a usual safety planning control website. Data on outcomes (i.e., safety, mental health and empowerment) are collected at baseline and at 3, 6, and 12 months post- baseline. It is anticipated that the findings will result in an evidence-based culturally tailored intervention for use by healthcare and domestic violence providers serving immigrant, refugee and indigenous survivors of IPV. The intervention may not only reduce risk for violence victimization, but also empower abused women and improve their mental health outcomes. PMID- 30517889 TI - Diabetes sleep treatment trial: Premise, design, and methodology. AB - The Diabetes Sleep Treatment Trial (DSTT) is a multi-site, double-blinded, randomized, sham-controlled trial. The study objective is to test whether treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) treatment results in improved glycemic control and diabetes self management behavior compared to participants on a sham-CPAP (sub-therapeutic) device in participants with type 2 diabetes mellitus (T2DM) and co-morbid OSA. The purpose of this paper is to describe the premise for the DSTT, the study design, and the methodology used in this on-going trial. The target enrollment is 210 randomly assigned participants recruited from two sites. The primary outcome for glucose control is HbA1C; additional outcomes for diabetes self-management include objectively measured steps walked and subjectively measured diabetes related distress, diabetes empowerment, and diabetes knowledge. All participants receive individual diabetes education and counseling for 6 weeks over two individual sessions and three telephone calls. Participants are randomized to receive either sham or active CPAP for 12 weeks, after which, they "guess" their group assignment; this will assist in determining the success of blinding participants to treatment group assignment. Participants revealed to be on active CPAP will be encouraged to continue CPAP for an additional 12 weeks; participants who had been on sham devices will be encouraged to have a repeat CPAP titration study and to crossover to active CPAP treatment for 24 weeks. An intention-to treat approach will be used for efficacy analyses. The trial is registered with Clinicaltrials.gov (NCT01901055). PMID- 30517890 TI - Food healthiness versus tastiness: Contrasting their impact on more and less successful healthy shoppers within a virtual food shopping task. AB - A virtual shopping task was employed to illuminate why women who intend to shop healthily are differentially successful in doing so. Female undergraduates (N = 68) performed a modified approach and avoidance task that employed food items differing in healthiness and tastiness, and yielded relative speed to select and reject food items in a stylised supermarket. Participants categorised a food item either in terms of healthiness or tastiness, then pulled (selected) or pushed (rejected) the item using a joystick. Participants showed faster selection of tasty food after categorisation in terms of tastiness, irrespective of the food's healthiness. However, after categorisation in terms of healthiness, only more successful healthy food shoppers showed faster selection of healthy items regardless of tastiness. Less successful healthy food shoppers showed this effect only for tasty food, and displayed faster rejection of food items not considered tasty, regardless of their assessed healthiness. Thus, when participants who reported the greatest gap between their shopping intention and shopping behaviour were judging the healthiness of food items, their speed to select and reject items continued to be influenced by tastiness. This suggests that reducing incidental processing of food tastiness may reduce the intention-behaviour gap in healthy food shopping. PMID- 30517891 TI - Peeking under the Hood of Naive T Cells. AB - Signaling and transcriptional regulation of metabolic reprogramming upon T cell activation has been studied intensively. In this issue of Cell Metabolism, Ricciardi et al. (2018) show that translational regulation of key metabolic enzymes GLUT1 and ACC1 plays a novel role in human naive CD4 T cell activation and subset differentiation. PMID- 30517893 TI - HER2 Signaling Hijacks the Creatine Shuttle to Fuel Breast Cancer Cell Growth. AB - Alteration of cell energy metabolism represents a major determinant of cancer progression; however, our understanding of oncogenic mechanisms underlying this rewiring remains elusive. In this issue of Cell Metabolism, Kurmi et al. (2018) show that HER2 signaling promotes ABL-mediated phosphorylation of the mitochondrial creatine kinase (MtCK1), providing ATP to support breast tumor growth. PMID- 30517892 TI - Cancer-Induced Endoplasmic Reticulum Stress in T Cells Subverts Immunosurveillance. AB - Compelling evidence indicates that tumors may evade immunosurveillance by subverting the metabolism of immune cells. In a recent paper in Nature, Song et al. (2018) demonstrate that ovarian cancers activate IRE1alpha-XBP1 signaling within CD4+ T lymphocytes, thereby disrupting their bioenergetic function and contribution to anticancer immune responses. PMID- 30517894 TI - A Gut Feeling for Metformin. AB - Metformin is a first-line glucose-lowering agent in patients with type 2 diabetes (T2D). Recently in Nature Medicine, Sun et al. (2018) reported that short-term metformin therapy decreases gut Bacteroides fragilis, consequently increasing glycoursodexoycholic acid (GUDCA) levels in humans. As an antagonist of FXR, GUDCA may carry therapeutic potential in the treatment of T2D. PMID- 30517895 TI - Parasitic Behavior of Leukemic Cells in Systemic Host Metabolism. AB - Metabolic reprogramming is a hallmark of cancer cell metabolism. Recently, in Cancer Cell, Ye and colleagues (2018) reported that leukemic cells have the capacity to modulate glucose metabolism in multiple organs of their host, thereby increasing the glucose resources available for malignant cell growth. PMID- 30517896 TI - Can We DECLARE a Victory against Cardio-Renal Disease in Diabetes? AB - Heart failure and renal disease remain significant complications in people with type 2 diabetes (T2D). Recent outcome studies with sodium-glucose cotransporter-2 (SGLT2) inhibitors have provided increasing insights, with the latest reporting trial DECLARE-TIMI 58 (Wiviott et al., 2018), pointing toward a role for these agents in the primary prevention of cardio-renal complications in T2D. PMID- 30517897 TI - The Translational Machinery of Human CD4+ T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling. PMID- 30517898 TI - Dementia care model: Promoting personhood through co-production. AB - BACKGROUND: Despite robust evidence on its effectiveness, current approaches that aspire to person-centred care (PCC) frequently locate people with dementia as passive recipients rather than as active agents in the care process. We define active involvement in care as 'co-production'. In order to investigate co production, we set out to review the evidence concerning personhood and dignity in dementia care. METHOD: We adopted a meta-ethnographic approach to synthesise the predominantly- qualitative literature on personhood and dignity in dementia care using EMBASE, PsycINFO, and ASSIA databases. We also included relevant policy documents. Members of Patient and Public Involvement (PPI) group were consulted throughout. RESULTS: A total of 14 empirical studies were subjected to content analysis. Three themes were identified: dignity and personhood, coping with dementia, and barriers to dignity in care. The findings suggest that positive strategies and coping mechanisms are associated with superior outcomes in relation to: sense of self, dignity and quality of care. The 22 policy documents yielded six themes pertaining to co-production: the part played by the person with dementia, family, environment, behaviour, governance and law, and health care partnership. CONCLUSION: Personhood in dementia care is enhanced through co-production, by actively participating in social, civic and political life. This is promoted through behavioural changes at the micro and macro levels of society, including providers of care being trained in co-producing care and policy makers creating opportunities with, rather than for people with dementia. PMID- 30517899 TI - Private and public willingness to pay for safety: A validity test. AB - Stated preference (SP) methods are often used to elicit an affected population's preferences for, e.g., increased safety or better environmental quality. SP methods are based on hypothetical market scenarios which have advantages, since decision alternatives are known to the analysis, but also necessitate thorough validity tests of the results, since decisions are hypothetical. This study suggests a validity test based on theoretical predictions and empirical findings for private and public safety measures. According to the test, willingness to pay (WTP) for a public safety measure should exceed or be equal to the private one. Based on a rich data set eliciting both private and public WTP the results show that private WTP exceeds public WTP. Hence, the findings in this study highlight the importance of validity tests of preference estimates for safety, and suggest that WTP also for a private safety measure should be elicited in studies eliciting WTP for public safety measures, to allow for the validity test. PMID- 30517900 TI - Identifying the controlling mechanism of geogenic origin chromium release in soils. AB - A laboratory study was conducted to assess the mobility and mechanisms of chromium release from soils obtained from an area of wide spread geogenic contamination. The agricultural soil sample used in this study was taken from the Schimatari area in Asopos River basin in Greece. In order to refine the isolation of minerals contained in the soil, two types of separation analysis were conducted. First, a size fractionation with hydrocyclone and second, a weight fractionation with heavy liquids. The separated fractions were characterized using chemical, mineralogical and surface analysis. The results provided consistent evidence that the heavy fraction of the soil is related directly to the mobile fraction of chromium. At acidic pHs, the clay-sized fraction also plays an additional important role in the mobility of Cr, due to the fact that this fraction has high surface area and chromium reactivity index. In addition, pH-edge leaching studies showed a high correlation between Cr-Ni, Cr-Mn and Cr-Y released from the soil which also suggests that the mobility of chromium is controlled by chromite weathering which is the case observed in Asopos river basin. PMID- 30517901 TI - University students' self-reported reasons for abstinence from prescription and non-prescription stimulants and depressants. AB - BACKGROUND: No previous publication has evaluated whether the importance of university students' reasons for abstinence differs across prescription stimulants, prescription opioids, and two illicit forms of those medications (cocaine and heroin). METHODS: In response to a recruitment email sent to all enrolled undergraduates at a large public university, 768 students who reported no prior recreational use of these four substances rated the importance of 17 reasons for lifelong abstention from each of the four drugs. RESULTS: Based on factor analyses, 16 of the 17 reasons comprised four subscales (Negative Consequences, Difficult to Acquire, Not Enjoyable, Social Disapproval). With few exceptions, importance ratings for each of the four subscales and the single non loading reason (Against My Beliefs) were highest for heroin, followed in descending order by cocaine and the two prescription medications. Female students rated three types of reasons as more important than did males, but previous use of other illicit drugs and past medical use of prescription stimulants or prescription opioids were not typically associated with importance of reasons for abstaining. CONCLUSION: Each type of reason was rated a more important influence on abstention from street drugs than from comparable prescription drugs. Reasons reflecting harmful consequences were rated most important and reasons reflecting acquisition difficulties were rated least important for each drug. To the degree that importance ratings are associated with continued abstinence, education and prevention messages could emphasize negative consequences as one means to reinforce continued abstinence from these drugs. PMID- 30517902 TI - Varicella-zoster virus clades circulating in Spain over two decades. AB - BACKGROUND: Despite childhood universal VZV immunization was introduced in 2015, there are no data on VZV clade distribution in Spain. OBJECTIVES: To characterize the varicella-zoster virus strains circulating in Spain between 1997 and 2016. STUDY DESIGN: In this retrospective study, we determined the VZV clades in 294 patients with different pathologies (mainly encephalitis, zoster and varicella) by sequencing three fragments within ORF 22, ORF 21 and ORF 50 and, subsequently analyzing 7 relevant SNPs. RESULTS: Among these 294 patients, 132(44.9%) patients were infected by clade 1, 42(14.3%) patients by clade 3, 19(6.5%) by clade 5, 29(9.9%) by clade VI and 3(1%) by clade 4. Four patients (1.4%) were infected by clade 2 vOKA strains, who received one dose of live-attenuated varicella vaccine. Putative recombinant clade 1/3 was identified in 6 cases (2.0%). Results obtained from partial sequences were assigned to clade 1 or 3 in 56(19%) patients and clade 5 or VI in 3(1.0%) patients. In the multivariate analysis, encephalitis was independently associated with clades 1 and 3 and age >14y.o. (P = 0.035 and P = 0.021, respectively). Additionally, Madrid had significant fewer cases of encephalitis compared with the rest of regions analyzed (P = 0.001). CONCLUSIONS: Higher prevalence of clades 1 and 3 and their relation with encephalitis and age >14y.o. suggest earlier introduction of this clades in Spain. Putative interclade 1 and 3 recombinants are circulating in patients with encephalitis, herpes zoster and varicella. Several cases were related to vOKA vaccination but vaccine strains do not seem to circulate in the general population. PMID- 30517903 TI - Liquisolid systems: Understanding the impact of drug state (solution or dispersion), nonvolatile solvent and coating material on simvastatin apparent aqueous solubility and flowability. AB - The drug in a solid dosage form must undergo dissolution before it is available for absorption from the gastrointestinal tract. Liquisolid system (LS) is a technology used for increasing aqueous solubility of the drugs, which has an important role in the dissolution and absorption phenomena. However, many factors can influence the performance and success of LS. Therefore this study aimed to evaluate through a factorial design, the factors such as drug state (solution or dispersion), nonvolatile solvent and coating material that influence the increase simvastatin (BSC II drug) apparent aqueous solubility and LS flow properties. Through numerical optimization the best formulation was selected to develop a liquisolid compact (LC) and it was evaluated by dissolution tests over commercial tablets using two dissolution media. Analyzing the data, the type of nonvolatile solvent and the state of the drug (solution or dispersion) were the factors with the greatest effects on the apparent aqueous solubility response (p < 0.0001 for both). Regarding the responses that evaluated the flow properties, the type of coating material and the type of nonvolatile solvent were the factors that influenced the Carr index (p < 0.0006, p < 0.0023, respectively) and Hausner ratio (p < 0.0006, p < 0.0014, respectively), where formulations containing Kollidon(r) CL were more efficient than Aerosil(r) (which is the most commonly used coating material for LS manufacture). These results enabled us to identify which factors were most influential and to move towards the use of new excipients in the case of Kollidon(r) CL. In addition, allowed a wider evaluation and understanding of LS, which is considered an important technological alternative for the increase of drug solubility. PMID- 30517904 TI - Magnetically-propelled hydrogel particle motors produced by ultrasound assisted hydrodynamic electrospray ionization jetting. AB - One of the most promising future applications of hydrogels is drug delivery. The hydrogels act as a biomedical cargo model to reach the target and release drugs to cure diseases. This application requires no side effects of the hydrogel and the ability to pass through porous media (e.g. membranes, interstitial tissue etc.) with nanoscaled channels. At the same time, the hydrogel must be mass producible in an economic way. In this work, we show that hydrodynamic electrospray ionization jetting combined with ultrasound can fulfill these high requirements. This method can produce mucoadhesive micro-/nano-particles, which are small enough to pass through the gastrointestinal epithelium. The average size of the produced particles is exactly predictable by controlling the spraying distance, spraying mode, alginate concentration, ultrasound bath frequency and counter electrode shape. These micro-/nano-particles are loaded with biocompatible magnetite nanoparticles, and propelled by a rotating magnetic field between 5 to 20 m T and a frequency from 1 Hz to 100 Hz. These rotating micro /nano-particle motors perform directional motion in solution, offering a promising possibility for magnetically controlled drug delivery. PMID- 30517905 TI - Rational design of polymer-lipid nanoparticles for docetaxel delivery. AB - In this work, a stable nanocarrier for the anti-cancer drug docetaxel was rational designed. The nanocarrier was developed based on the solid lipid nanoparticle preparation process aiming to minimize the total amount of excipients used in the final formulations. A particular interest was put on the effects of the polymers in the final composition. In this direction, two poloxoamers -Pluronic F127 and F68- were selected. Some poloxamers are well known to be inhibitors of the P-glycoprotein efflux pump. Additionally, their poly ethylene-oxide blocks can help them to escape the immune system, making the poloxamers appealing to be present in a nanoparticle designed for the treatment of cancer. Within this context, a factorial experiment design was used to achieve the most suitable formulations, and also to identify the effects of each component on the final (optimized) systems. Two final formulations were chosen with sizes < 250 nm and PDI < 0.2. Then, using dynamic light scattering and nanotracking techniques, the stability of the formulations was assessed during six months. Structural studies were carried on trough different techniques: DSC, x-ray diffraction, FTIR-AR and Molecular Dynamics. The encapsulation efficiency of the anticancer drug docetaxel (> 90%) and its release dynamics from formulations were measured, showing that the polymer-lipid nanoparticle is suitable as a drug delivery system for the treatment of cancer. PMID- 30517906 TI - Haptic information provided by anchors and the presence of cognitive tasks contribute separately to reducing postural sway in young adults. AB - BACKGROUND: Haptic information provided by the anchors reduces postural sway while standing upright. It is unclear whether this benefit would remain in the presence of cognitive tasks combined with a more challenging postural task. RESEARCH QUESTION: Our aim was to investigate the effects of the anchors and visual and auditory cognitive tasks on postural control in young adults in a challenging balancing task. METHODS: Twenty young adults stood upright on a balance beam with the central portion of each foot placed over the beam and feet at shoulder width without and with the use of the anchors in three cognitive conditions: control, visual Stroop task, and auditory digit-monitoring task. Each anchor consisted of a flexible cable with a light load (125 g) attached at one end of the cable. With the anchors, the participants held the flexible cable in each hand with the light load resting on the ground while keeping tension in the cable. RESULTS: Both visual and auditory cognitive tasks reduced the center of pressure (COP) ellipse area, the root mean square of the margin of dynamic stability (based on the extrapolated center of mass, COM) and increased the COM time-to-contact relative to the boundaries of the base of support in the AP direction. The anchors reduced the COP ellipse area. SIGNIFICANCE: There is a functional integration between postural control and cognitive tasks, such that postural sway was reduced to facilitate the execution of the cognitive tasks. Anchors were effective in reducing postural sway, suggesting that haptic information was able to benefit postural control in a challenging balancing task regardless of the cognitive task. PMID- 30517907 TI - Muscular tension significantly affects stability in standing posture. AB - BACKGROUND: Muscular co-contraction is a strategy commonly used by elders with the aim to increase stability. However, co-contraction leads to stiffness which in turns reduces stability. Some literature seems to suggest an opposite approach and to point out relaxation as a way to improve stability. Teaching relaxation is therefore becoming the aim of many studies letting unclear whether tension or relaxation are the most effective muscular strategy to improve stability. Relaxation is a misleading concept in our society. It is often confused with rest, while it should be addressed during stressing tasks, where it should aim to reduce energetic costs and increase stability. The inability to relax can be related to sub-optimal neuro-motor control, which can lead to increased stresses. RESEARCH QUESTION: The objective of the study is to investigate the effect of voluntary muscle contraction and relaxation over the stability of human standing posture, answering two specific research questions: (1) Does the muscular tension have an impact on stability of standing posture? (2) Could this impact be estimated by using a minimally invasive procedure? METHODS: By using a force plate, we analysed the displacement of the center of pressure of 30 volunteers during state of tension and relaxation in comparison with a control state, and with open and closed eyes. RESULTS: We found that tension significantly reduced the stability of subjects (15 out of 16 parameters, p < 0.003). SIGNIFICANCE: Our results show that daily situations of stress can lead to decreased stability. Such a loss might actually increase the risk of chronic joint overload or fall. Finally, breathing has direct effect over the management of pain and stress, and the results reported here point out the need to explicitly explore the troubling fact that a large portion of population might not be able to properly breath. PMID- 30517908 TI - Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs). AB - Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = -2.12; T (50) = -2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = -2.12; T (50) = -2.47, p = 0.04) and Fatigue (MD = -3.42; T (50) = -2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted. PMID- 30517909 TI - Psychogenic nonepileptic seizures in children and adolescents: An international cross-cultural study. AB - PURPOSE: We compared various clinical characteristics of psychogenic nonepileptic seizures (PNES) between young patients from Iran, Saudi Arabia, and Canada, three nations with significantly different socioeconomic and demographic characteristics. This international cross-cultural comparative study may advance our knowledge and understanding of PNES in children and adolescents across the cultures and borders. METHODS: In this retrospective study, we investigated all patients 16 years of age or younger, with PNES admitted to the epilepsy monitoring units at one center in Iran, one center in Saudi Arabia, and one center in Canada. Age, gender, age at seizure onset, seizure semiology, seizure frequency, factors potentially predisposing to PNES, and video electroencephalography (EEG) recording of all patients were registered routinely and compared between the nations. RESULTS: Fifty-one patients were studied (22 from Iran, 14 from Saudi Arabia, and 15 from Canada). Age at the diagnosis was 13.4 +/- 2.2 years (range: 8-16 years), and age at the onset of seizures was 12.3 +/- 2.7 years (range: 5-16 years). Demographic and clinical characteristics of and associated factors in the patients among the three nations were not significantly different. Twenty-six (51%) patients were taking antiepileptic drugs at the time of diagnosis; the difference was not statistically significant between the nations (13 patients in Iran, 6 in Saudi Arabia, and 7 patients in Canada; P = 0.5). CONCLUSION: Young patients with PNES across borders and between cultures share more similarities than differences with regard to their demographic and clinical characteristics. PMID- 30517910 TI - Analysis of Efficacy and Prognostic Factors of CLAG Treatment in Chinese Patients with Refractory or Relapsed Acute Myeloid Leukemia. AB - BACKGROUND/AIMS: The aim of this work was to investigate the efficacy and predictive factors of CLAG treatment in refractory or relapsed (R/R) acute myeloid leukemia (AML) patients. METHODS: Sixty-seven R/R AML patients were enrolled in this prospective cohort study and treated by a CLAG regimen: 5 mg/m2/day cladribine (days 1-5), 2 g/m2/day cytarabine (days 1-5), and 300 MUg/day filgrastim (days 0-5). The median follow-up duration was 10 months. RESULTS: A total of 57 out of 67 patients were evaluable for remission after CLAG therapy, of whom 57.9% achieved a complete remission (CR) and the overall remission rate was 77.2%. The median overall survival (OS) was 10.0 months, with a 1-year OS of 40.3 +/- 6.0% and 3-year OS of 16.7 +/- 5.7%. CR at first induction after the initial diagnosis was associated with a favorable CR. Age above 60 years, high risk stratification, second or higher salvage therapy, and bone marrow (BM) blasts >=42.1% were correlated with an unfavorable CR. Secondary disease, age >=60 years, high risk stratification, and second or higher salvage therapy were associated with worse OS. Patients developed thrombocytopenia (41, 61%), febrile neutropenia (37, 55%), leukopenia (33, 49%), neutropenia (18, 27%), and anemia (9, 13%). CONCLUSION: CLAG was effective and well tolerated for R/R AML. BM blasts >=42.1%, age >=60 years, high risk stratification, and second or higher salvage therapy were independent factors for a poor prognosis. PMID- 30517911 TI - Modified Intrathoracic Esophagogastrostomy with Minimally Invasive Robot-Assisted Ivor-Lewis Esophagectomy for Cancer. AB - BACKGROUND: Intrathoracic esophagogastrostomy plays an important role in minimally invasive Ivor-Lewis esophagectomy for cancer. Intrathoracic anastomosis with robot-assisted Ivor-Lewis esophagectomy (RAILE) includes hand-sewn and circular stapler methods, which remain technically challenging. In this study, we modified the techniques for intrathoracic anastomosis at RAILE, in order to simplify the complex procedures. METHODS: "Side-insertion" technique was used for anvil placement and purse string suture for intrathoracic anastomosis at RAILE. Medical records for consecutive patients who had undergone robot-assisted minimally invasive Ivor-Lewis esophagectomy for cancer between January 2015 and June 2018 were analyzed. RESULTS: A total of consecutive 31 patients were enrolled. There was no conversion to open thoracotomy in this cohort. Mean operation duration in the robotic group was 387.4 +/- 68.2 min. Median estimated blood loss was 110 mL (range 50-400 mL). Two patients (6.5%) had postoperative anastomotic leak. No postoperative reoperation was needed and there were no mortality. Six patients (19.4%) had anastomotic stricture and 2 patients of them needed endoscopic dilation. CONCLUSION: RAILE is safe and feasible. Our modified procedure highlighting the "side-insertion" method may simplify the process of intrathoracic anvil placement and purse string suture for anastomosis at RAILE. PMID- 30517912 TI - Recognizing Common Skin and Soft Tissue Infections in the Nephrology Clinic. AB - Renal failure patients have an increased risk of infection, including skin and soft tissue infections. This increased susceptibility is multifactorial, due to the conditions causing the renal failure as well as complications of treatment and renal failure's innate effects on patient health. These infections have a significant impact on patient morbidity, increased hospital and procedural demands, and the cost of health care. Many renal failure patients are seen regularly by their nephrology clinic caregivers due to the need for frequent dialysis and transplant monitoring. Familiarity with common skin and soft tissue infections by these caregivers allowing enhanced patient education, optimal infection prevention, and early recognition could significantly reduce the morbidity and cost of these disorders, such as diabetic foot syndrome, necrotizing fasciitis, and herpetic infections. PMID- 30517913 TI - Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine. AB - BACKGROUND: Epigenetic mechanisms such as histone modifications may be involved in the structural and behavioral changes associated with addiction. We studied whether morphine-induced changes in mRNA levels of the catecholamine biosynthesis enzyme, tyrosine hydroxylase (TH), are associated with histone modifications around the promoter of this gene in the locus coeruleus (LC) and ventral tegmental area (VTA) of rats. METHODS: Dependence was induced in rats by intraperitoneal injections of morphine for 11 days. The animals were killed 2 h (chronic morphine), 24 h and 7 days (spontaneous withdrawal) after the last injection of morphine. RESULTS: Analysis of our real-time quantitative reverse transcription PCR results by 1-way ANOVA showed significant upregulation (5.13 +/ 0.39 folds) of LC levels of the TH transcript 24 h after the last injection of morphine to rats, when compared with 2 h and 7 days time points. Chronic morphine and morphine abstinence failed to cause any significant changes in the levels of TH mRNA in the VTA after cessation of morphine. Consistently, chromatin immunoprecipitation real-time quantitative PCR assays revealed that 24 h after the last injection of morphine, levels of H3 acetylation were significantly increased (4.12 +/- 0.38 folds) at the promoter of the TH gene in the LC but not in the VTA. Our data also showed that histone H3 trimethylation failed to change around the TH gene promoter either in the VTA or in the LC after morphine abstinence. CONCLUSIONS: Results of the present study, for the first time, demonstrate the involvement of histone H3 acetylation in the regulation of TH gene expression in the LC of rats during forced abstinence from morphine. PMID- 30517914 TI - Factors Involved in the Selection of Treatment in Patients with Hematological Malignancies. PMID- 30517915 TI - Three-Tiered versus Two-Tiered Classification of Squamous Dysplasia in Cervical Cytology: Results of a Follow-Up Study. AB - OBJECTIVE: Regarding cytological findings of squamous dysplasia, a comparison was made between a three-tiered classification - low-grade squamous intraepithelial lesion (LSIL), high-grade SIL/cervical intraepithelial neoplasia 2 (HSIL/CIN2), and HSIL/CIN3 - and a two-tiered classification - LSIL and HSIL. The respective risk for CIN2+ and CIN3+ was calculated to make decisions regarding management. METHODS: A total of 2,949 women with first-time cytologic findings of squamous dysplasia (LSIL, HSIL/CIN2, or HSIL/CIN3) between January 2013 and June 2016 were enrolled. Subsequent cytological findings and histological diagnoses were evaluated until August 2018. For each category of findings, the risk for CIN2+ and CIN3+ was determined by Kaplan-Meier estimates. The differences in risk between the cytological categories were checked for significance using the log rank test. RESULTS: For the categories LSIL, HSIL/CIN2, and HSIL/CIN3, the risk for CIN2+ after 12, 24, and 60 months was 3.4, 9.4, and 23.3%; 35.2, 44.8, and 59.8%; and 95.5, 97.8, and 98.9%, respectively. For CIN3+ the risk was 2.0, 5.5, and 13.5%; 28.6, 35.6, and 48.3%; 91.3, 95.6, and 97.9%, respectively. The differences in risk between the categories are highly significant, respectively (p < 0.001). CONCLUSION: A three-tiered classification of squamous dysplasia such as the Munich Nomenclature III for cytology is suitable for risk-adapted clinical management, especially to avoid overdiagnosis and overtreatment. PMID- 30517916 TI - End-Stage Kidney Patients Require Hemodialysis Therapy Full Start. AB - Recently the concept that prescription of chronic hemodialysis (HD) start should be tailored based on residual renal function (RRF) and urine output (UO) has been revived from the past and called infrequent or incremental dialysis. It mainly consists in prescribing 1 or 2 HD sessions per week instead of what has become the standard thrice-weekly HD. It is both surprising and fascinating that almost 60 years after the first end-stage kidney disease patient was treated by Scribner et al. [Trans Am Soc Artif Intern Organs 1960; 6: 114-122], the nephrology community still questions the best way to start HD therapy. This comforting process is the result of pieces of evidence accumulated with time such as that RRF is associated with better outcomes that starting HD therapy favors the loss of RRF and/or UO and also results in a high rate of deaths in the first weeks of HD therapy. Through this review, we support the idea that when the decision to start HD therapy is made, ideally with the full collaboration of the patient, it is necessary to be efficient to alleviate uremic symptoms, to correct the fluid overload and to allow a full recovery from the uremic state associated with the late stages of non-dialysis chronic kidney disease. PMID- 30517917 TI - Transcatheter Aortic Valve Replacement for Pure Native Aortic Valve Regurgitation: A Systematic Review. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a recent and an effective treatment option for high- or extreme-surgical-risk patients with symptomatic severe aortic stenosis. However, pure severe native aortic valve regurgitation (NAVR) without aortic stenosis remains a contraindication to TAVR. The aim of our systemic review analysis was to evaluate TAVR in patients with pure NAVR. METHODS: We searched the published articles in the PubMed and Web of Science databases (2002-2017) using the Boolean operators for studies of NAVR patients undergoing TAVR. Reference lists of all returned articles were searched recursively for other relevant citations. Pooled estimates were calculated using a random-effects meta-analysis. RESULTS: Finally, a total of 10 studies were included in this analysis. The CoreValve was more frequently used with a lower rate of device success and a higher rate of residual aortic regurgitation. The new-generation transcatheter heart valves (THVs) performed a significantly higher rate with less residual aortic regurgitation and a success rate close to 100%. The 30-day all-cause mortality rates ranged from 0 to 30% with an estimate summary rate of 9% (95% CI: 5-15%; I2 = 33%). Cerebrovascular events, major or life-threatening bleeding, major vascular complications, acute kidney disease, and new permanent pacemaker implantation occurred similarly in both the new- and old-generation THV devices. CONCLUSIONS: Aortic regurgitation remains a challenging pathology for TAVR. TAVR is a feasible and reasonable option for carefully selected patients with pure aortic regurgitation. PMID- 30517918 TI - Cervical Artery Dissection in Patients of African Ancestry. AB - BACKGROUND AND PURPOSE: The majority of published data in cervical artery dissection (CeAD), a common cause of stroke in young adults, derive from populations of European ancestry (EA), including a recent genome-wide study identifying an association with the rs9349379 polymorphism of the PHACTR1 gene. Little is known about CeAD in individuals of African ancestry (AA) despite robust epidemiological data showing increased risk of stroke at younger ages. We hypothesize that AA patients with CeAD have different epidemiology and clinical profiles compared to those of EA, and a different genetic architecture related to rs9349379 of the PHACTR1 gene. METHODS: We searched a single-center database of CeAD to identify AA and EA patients. We compared differential prevalence of CeAD versus all young stroke between AA and EA patients. We characterized clinical profiles via electronic medical record review. Data include descriptive statistics reported as medians or percentages. We also obtained publicly available allele frequencies of rs9349379 in AA and EA populations. RESULTS: AA patients comprise 7% of CeAD cases and 27% of young stroke cases while EA patients comprise 90% of CeAD cases and 70% of young stroke cases. Prevalence of hypertension, diabetes mellitus, and hyperlipidemia were 74, 30, and 50%, respectively, in AA patients compared to 37, 6, and 25% in EA patients. Allele frequencies for the CeAD risk allele, rs9349379(A), are higher in AA populations compared to EA populations. CONCLUSION: AA patients represent a smaller proportion of CeAD cases compared to young stroke cases at our center. AA patients suffering CeAD have higher prevalence of both vascular risk factors and frequency of the CeAD risk allele compared to EA patients. These findings suggest a complex interplay between traditional vascular risk factors and genetic predisposition underlying CeAD pathogenesis. Further prospective research is needed to clarify these associations and disparities. PMID- 30517919 TI - A Systematic Review and Meta-Analysis of Molecular Biomarkers Associated with Early Neurological Deterioration Following Acute Stroke. AB - BACKGROUND: Early neurological deterioration (END) following acute stroke is associated with poorer long-term outcomes. Identification of patients at risk could assist early monitoring and treatment decisions. This review summarised the evidence describing non-radiological biomarkers for END. SUMMARY: Electronic searches from January 1990 to March 2017 identified studies reporting a blood/cerebrospinal fluid (CSF)/urine biomarker measurement within 24 h of acute stroke and at least 2 serial assessments of clinical neurological status (< 24 h and < 7 days). Out of 12,895 citations, 82 studies were included, mostly focusing on ischaemic stroke. Using higher neurological thresholds, the n-weighted END incidence for ischaemic stroke was 11.9% (95% CI 11.4-12.4%) and 18.6% (17.9 19.2%) for lower thresholds. Incidence decreased with advancing study publication year (Pearson r-squared 0.23 and 0.15 for higher and lower threshold studies). After classification into 3 broad categories, meta-analysis showed that biomarkers associated with increased END risk (n; fixed-effects mean difference; 95% CI) were "metabolic" (glucose [n = 9,481; 0.90 mmol/L; 0.74-1.06], glycosylated haemoglobin [n = 3,146; 0.33%; 0.19-0.46], low-density lipoprotein [n = 4,839; 0.13 mmol/L; 0.06-0.21], total cholesterol [n = 4,762; 0.21 mmol/L; 0.11-0.31], triglycerides [n = 4,820; 0.11 mmol/L; 0.06-0.17], urea [n = 1,351; 0.55 mmol/L; 0.14-0.96], decreasing albumin [n = 513; 0.33 g/dL; 0.05-0.61]); "inflammatory and excitotoxic" (plasma glutamate [n = 688; 60.13 umol/L; 50.04 70.22], CSF glutamate [n = 369; 7.50 umol/L; 6.76-8.23], homocysteine [n = 824; 2.15 umol/L; 0.68-3.61], leucocytes [n = 3,766; 0.54 * 109/L; 0.34-0.74], high sensitivity C-reactive protein [n = 1,707; 3.79 mg/L; 1.23-6.35]); and "coagulation/haematological" (fibrinogen [n = 3,132; 0.32 g/L; 0.25-0.40]; decreasing haemoglobin [n = 3,586; 2.38 g/L; 0.15-4.60]). Key Messages: Declining incidence of END may represent improving care standards; however, it remains a frequent occurrence. Although statistical associations exist between biomarkers and an increased risk of END, the most promising still need prospective evaluation to determine their additional value relative to baseline radiological and clinical characteristics. PMID- 30517920 TI - Body Fluids in End-Stage Renal Disease: Statics and Dynamics. AB - BACKGROUND: Abnormalities in fluid status in hemodialysis (HD) patients are highly prevalent and are related to adverse outcomes. SUMMARY: The inherent discontinuity of the HD procedure in combination with an often compromised cardiovascular response is a major contributor to this phenomenon. In addition, systemic inflammation and endothelial dysfunction are related to extracellular fluid overload (FO). Underlying this relation may be factors such as hypoalbuminemia and an increased capillary permeability, leading to an altered fluid distribution between the blood volume (BV) and the interstitial fluid compartments, compromising fluid removal during dialysis. Indeed, whereas estimates of extracellular volume by bioimpedance spectroscopy are highly predictive of mortality, absolute BV assessed by the saline dilution technique was predictive of intra-dialytic morbidity. Changes in relative BV during HD are positively related to ultrafiltration rate (UFR) and, at least in some studies, negatively to FO. High UFR is also related to changes in central venous oxygen saturation (ScvO2), a marker for tissue perfusion. On the one hand, high UFR and more pronounced declines in ScvO2, but on the other hand, flat relative BV curves are also predictive of mortality; the relation between outcome which statics and dynamics of fluid status appears to be complex. Key Message: While technological developments enable the clinician to monitor statics and dynamics of fluid status and hemodynamics during HD in an accessible way, the role of technology-based interventions needs further study. PMID- 30517921 TI - Best Vascular Access in the Elderly: Time for Innovation? AB - BACKGROUND: Conflicting data continue to surround the optimal dialysis access for the elderly. Many propose that catheters are the best option for this population; others emphasize the creation of an arteriovenous fistula. SUMMARY: While an arteriovenous access is the best available access, it has a high early failure rate, particularly in the elderly. However, significant differences exist in forearm (men >=65 years ~70%; women >=65 years ~80%) versus upper arm (men >=65 years ~40%; women >=65 years ~38%) fistula failure rates in the elderly, with upper arm having much lower failure rates. Two percutaneous innovative techniques that successfully establish fistulas at the upper arm using proximal radial/ulnar -artery as the inflow have been recently introduced. These procedures have been successfully performed in the elderly. Importantly, these techniques bypass the open surgical exploration and as such avoid the surgical manipulation of the juxta-anastomotic region (a common cause for the development of juxta-anastomotic stenosis and early fistula failure). Key Message: This article discusses the arteriovenous fistula creation in the elderly, highlights the factors necessary for successful fistula creation, and describes the 2 innovative techniques that can be used to provide a robust platform for successful fistula creation in this population. PMID- 30517922 TI - Biomaterial Approaches to Modulate Reactive Astroglial Response. AB - Over several decades, biomaterial scientists have developed materials to spur axonal regeneration and limit secondary injury and tested these materials within preclinical animal models. Rarely, though, are astrocytes examined comprehensively when biomaterials are placed into the injury site. Astrocytes support neuronal function in the central nervous system. Following an injury, astrocytes undergo reactive gliosis and create a glial scar. The astrocytic glial scar forms a dense barrier which restricts the extension of regenerating axons through the injury site. However, there are several beneficial effects of the glial scar, including helping to reform the blood-brain barrier, limiting the extent of secondary injury, and supporting the health of regenerating axons near the injury site. This review provides a brief introduction to the role of astrocytes in the spinal cord, discusses astrocyte phenotypic changes that occur following injury, and highlights studies that explored astrocyte changes in response to biomaterials tested within in vitro or in vivo environments. Overall, we suggest that in order to improve biomaterial designs for spinal cord injury applications, investigators should more thoroughly consider the astrocyte response to such designs. PMID- 30517924 TI - The Chick Caudolateral Epiblast Acts as a Permissive Niche for Generating Neuromesodermal Progenitor Behaviours. AB - Neuromesodermal progenitors (NMps) are a population of bipotent progenitors that maintain competence to generate both spinal cord and paraxial mesoderm throughout the elongation of the posterior body axis. Recent studies have generated populations of NMp-like cells in culture, which have been shown to differentiate to both neural and mesodermal cell fates when transplanted into either mouse or chick embryos. Here, we aim to compare the potential of mouse embryonic stem (ES) cell-derived progenitor populations to generate NMp behaviour against both undifferentiated and differentiated populations. We define NMp behaviour as the ability of cells to: (i) contribute to a significant proportion of the anterior posterior body axis, (ii) enter into both posterior neural and somitic compartments, and (iii) retain a proportion of the progenitor population within the posterior growth zone. We compare previously identified ES cell-derived NMp like populations to undifferentiated mouse ES cells and find that they all display similar potentials to generate NMp behaviour in vivo. To assess whether this competence is lost upon further differentiation, we generated anterior and posterior embryonic cell types through the generation of 3D gastruloids and show that NMp competence is lost within the anterior (Brachyury-negative) portion of the gastruloid. Together this suggests that in vitro-derived NMp-like cells maintain an ability to contribute to multiple germ layers that is also present within pluripotent ES cells, rather than acquiring a neuromesodermal competent state through differentiation. PMID- 30517923 TI - The Vermian-Crest Angle: A New Method to Assess Fetal Vermis Position within the Posterior Fossa Using 3-Dimensional Multiplanar Sonography. AB - BACKGROUND: Normal morphometry of the vermis and its relation to the posterior fossa (PF) rule out most major anomalies of the cerebellum. However, accurate categorization of the position and size of the fetal vermis remains a challenge. OBJECTIVE: Our aim was to test a new method to assess the position and size of fetal vermis on 3-dimensional ultrasound (3D-US). METHODS: We measured the vermian-crest angle (VCA) in normal fetuses using multiplanar 3D-US. We also assessed the diameters (superoinferior, anteroposterior, and horizontal) and volume of the vermis. The Spearman rank test and linear and polynomial regression analyses were used for statistical purposes. RESULTS: We included 126 fetuses. Mean +/- SD gestational age (GA) was 26.3 +/- 4.6 (range 17-35.5) weeks. Mean +/- SD superoinferior, anteroposterior, and horizontal diameters were 16.2 +/- 4.9, 11.2 +/- 3.6, and 5.6 +/- 1.6 mm, respectively. Median (range) vermian volume was 0.50 (0.05-2.9) cm3. The VCA was 64.49 degrees +/- 11.45. We found no correlation between GA and VCA (r = 0.15; p = 0.13), a linear correlation between GA and vermian diameters, and a quadratic correlation between GA and vermian volume. CONCLUSIONS: We provide a new method to assess vermian position and size within the PF using 3D-US. The combined information may be of value for screening purposes, particularly to differentiate between the various pathological situations encountered within the PF. PMID- 30517925 TI - Upregulation of Fibroblast Growth Factor 19 Is Associated with the Initiation of Colorectal Adenoma. AB - Fibroblast growth factor 19 (FGF19) promotes tumor growth in various types of cancer, but its function has not been investigated in the context of colorectal adenoma. Here, we report that FGF19 expression was greater in colorectal adenoma than in normal tissues, as measured by an enzyme-linked immunosorbent assay, quantitative reverse-transcription PCR and immunohistochemistry. FGF19 expression was also elevated in a subset of human colon cancer cell lines. Moreover, FGF receptor 4 (FGFR4), the cognate receptor for FGF19, was upregulated in colorectal adenoma tissues. Lipid levels and body mass index values strongly correlated with FGF19 and FGFR4 levels in patients with colon adenomas. These observations indicate that the FGF19/FGFR4 pathway may be involved in the development of neoplasia, and that FGF19 may be a valuable diagnostic marker for the identification of patients with colorectal adenomas. PMID- 30517926 TI - Risk Factors Analysis of Postoperative Pleural Effusion after Liver Resection. AB - BACKGROUND: Pulmonary complications remain relatively high in morbidities that arise after liver surgery and are associated with increased length of hospital stay and higher cost. Identification of possible risk factors in this retrospective analysis may help reduce operative morbidity and achieve better outcomes. METHODS: In all, 363 consecutive patients underwent elective hepatectomies between July 2008 and November 2013 and these were identified and analyzed retrospectively. Patient demographics and perioperative variables were collected. The main outcome was an analysis of risk factors associated with postoperative pleural effusion (PPE). RESULTS: Of 363 patients receiving hepatectomies, 80 patients (22.0%) developed pulmonary complications. The predominant pulmonary complication in this series is pleural effusion (76 patients, 95%). Univariate analysis found that older age, higher body mass index (BMI), chronic obstructive lung disease, asthma, heart disease, hepatitis C infection, heavy smoking, American Society of Anesthesiology class III and IV, hepatectomy site, combined surgeries, perioperative blood transfusion, and cirrhosis of liver were associated with PPE. Only older age, higher BMI, asthma, heavy smoker, combined gastrointestinal surgeries, and perioperative blood transfusion were identified as independent risk factors in multivariate analysis. CONCLUSION: This study identifies 6 risk factors for PPE. Identification and management of some of these factors could possibly reduce morbidity and improve short-term surgical outcomes. PMID- 30517927 TI - Disaster Management in a Nephrology Service: Lessons Learned from Hurricane Maria. AB - BACKGROUND: Puerto Rico suffered a major humanitarian -crisis after Hurricane Maria. We describe our experience with patients with renal disease in an academic medical center. SUMMARY: A comprehensive emergency response plan should be developed, shared and discussed with the team and the patients prior to the hurricane. The needs of the staff should not be ignored to ensure their ability to participate as responders. Physical damage to facilities, lack of basic services, shortage of disposable products, and the inability to get to treatment centers are the most common threats. Preemptive dialysis can avoid serious complications. A contingency plan to move patients to another center should be prearranged in case the unit is rendered nonfunctional after the storm. Patients must receive preventive education about fluid and dietary restrictions and the possible use of potassium binding drugs if they cannot reach a dialysis unit. A list of alternative drugs that could be used if patients are not able to fill their medications is required. The Internet and social media proved to be an invaluable communication tool. A registry of patients with updated contact information, as well as contact information for relatives and a physical address where an emergency rescue team can be dispatched is essential. Water safety should be reinforced. Key Message: Our experience showed us that preparing for the worst is not enough. Advanced planning of a streamlined response is the best tactic to decrease harm. PMID- 30517928 TI - An Animal Model for Wheat Allergy Skin Sensitisation: A Comparative Study in Naive versus Tolerant Brown Norway Rats. AB - BACKGROUND: Allergic sensitisation to foods may occur in infancy without prior oral exposure to the offending food, leading to the assumption that food allergy sensitisation may occur through the skin. Concerns have been raised regarding the safety of use of personal care products containing hydrolysed wheat proteins, since these products have been shown to induce allergy through the skin, and even cause an abrogation of an already established oral tolerance. OBJECTIVE: To establish an animal model for food allergy skin sensitisation and compare the sensitising capacity of an unmodified and an acid-hydrolysed gluten product via slightly damaged skin in naive versus tolerant rats. METHODS: Gluten products were applied on the slightly damaged skin of naive or tolerant Brown Norway (BN) rats without adjuvant 3 times per week for 3 or 5 consecutive weeks. The effect of the skin applications was evaluated by means of different ELISAs and immunoblotting. RESULTS: A robust animal model was developed for food allergy skin sensitisation. In naive rats, both gluten products were able to induce a statistically significant level of specific antibodies and sensitise through the skin, but in the wheat-tolerant rats, only the acid-hydrolysed gluten was able to sensitise through the skin, albeit at a level much lower than in the naive rats. Results showed that new epitopes had been developed as a result of acid hydrolysis but original epitopes were maintained. This may explain why only the acid-hydrolysed gluten could induce specific antibody responses in the tolerant animals. CONCLUSIONS: This study showed that it is possible to sensitise BN rats through slightly damaged skin, and that the sensitising capacity is heavily influenced by the tolerance status of their immune system and the degree of modification of the wheat products. PMID- 30517929 TI - Left-Sided Atrial Septal Pouch as a Risk Factor of Cryptogenic Stroke: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Despite some evidence of left-sided septal pouch (LSSP) involvement in the pathogenesis of cardioembolic stroke, the question of LSSP clinical significance still remains unsolved. In this study, we aimed to determine the association between the LSSP presence and cryptogenic stroke using meta analytical approach. METHODS: We performed a systematic review of electronic databases for studies that compared the presence of LSSP in subjects with cryptogenic stroke and non-stroke control. Data were extracted and pooled into a meta-analysis. RESULTS: Seven studies (400 cryptogenic stroke patients and 1,456 non-stroke controls) were included in the meta-analysis. A total of 138 LSSPs were identified among the cryptogenic stroke patients, with a pooled prevalence of 29.8% (95% CI 17.5-43.7%), and 268 LSSPs were identified in the non-stroke controls, with a pooled prevalence of 21.0% (95% CI 13.7-29.5%). After meta analysis, the risk of cryptogenic stroke was higher in patients with an LSSP than in patients without LSSP (OR 1.52; 95% CI 1.15-2.00; p < 0.001). No significant heterogeneity was detected across the included studies (p > 0.05). CONCLUSION: Our meta-analysis demonstrated association between LSSP and cryptogenic stroke. In our univariate analysis, the risk of cryptogenic stroke is higher among patients with LSSP than in cases without the LSSP. PMID- 30517930 TI - Dialysate Calcium Levels: Do They Matter? AB - BACKGROUND: Calcium (Ca) is an essential element that plays a critical role in many biological processes. In dialysis patients, the regulation of Ca balance is highly complex, given the absence of kidney function, endocrine disturbances and the use of drugs such as phosphate binders, vitamin D analogues, and calcimimetics. Also, the use of different dialysate Ca (DCa) baths has profound effect on Ca balance, which depends both on the difference between the Ca concentration in the bath and the serum of the patients, as on the ultrafiltration volume. SUMMARY: The choice of DCa may have important short- and long-term consequences. While lower DCa (especially < 2.5 mEq/L) concentrations have been associated with an increased risk of sudden cardiac death in observational studies, DCa in the higher ranges (3.0 mEq/L and above) may contribute to vascular pathology. Intra-dialytic hemodynamics may also be affected by the choice of DCa. In general, lower DCa concentrations are associated with an increase, and higher DCa concentrations with a decrease in parathyroid hormone (PTH) levels. Preliminary data has suggested that a DCa of 2.75 mEq/L may help in obtaining a net zero intradialytic Ca balance in individual patients, but clinical experience is still limited. Key Message: The optimal Ca balance depends on multiple parameters including blood Ca levels, PTH and the use of phosphate binders and vitamin D analogues, as well as on the risk of hemodynamic stability and cardiac arrhythmias. Therefore, DCa prescription should be individualised. A DCa of 2.75 mEq/L may be useful adjunct for dialysis providers. PMID- 30517931 TI - Sickle Cell Nephropathy in the Pediatric Population. AB - BACKGROUND: Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. SUMMARY: SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit. PMID- 30517932 TI - Correlation of Ultrasound Findings and Fine-Needle Aspiration Cytology for the Diagnosis of Axillary Lymph Node Metastasis in Patients with Breast Carcinoma. AB - OBJECTIVE: Ultrasound-guided fine-needle aspiration cytology (USG-FNAC) is used for the detection of axillary lymph node (ALN) metastasis in patients with breast carcinoma (BC). US findings have a good diagnostic accuracy with high sensitivity and specificity. The aim of this study is to correlate the detection of ALN metastases on US with FNAC in BC patients. STUDY DESIGN: In 75 BC patients, over a period of 9 months (January to September 2017), the size, cortical thickness (CT), presence or absence of hilar fat, and length/width ratio of ALN on US were reviewed and correlated with FNAC findings. RESULTS: The age range was 29-78 (mean 52) years. There were 38 patients with a single ALN and 37 with multiple ALNs. ALNs with a maximum length of > 2.5 cm were malignant in 100% of cases while those >=1.5 cm were malignant in 80.4%. ALNs with a CT of > 3 mm had metastasis in 78.1% cases. ALNs with absent hilar fat showed tumour in 87.5% cases. A length/width ratio of < 2 showed a metastatic tumour in 66.7% of aspirates. CONCLUSION: An association was seen between metastatic carcinoma on FNAC and axillary US features of a maximum length of >=1.5 cm, the absence of hilar fat, and a CT of > 3 mm (p < 0.05). PMID- 30517933 TI - National Trends and Procedural Complications from Endomyocardial Biopsy: Results from the National Inpatient Sample, 2007-2014. AB - AIM: The aim of this study is to report recent trends in the performance of endomyocardial biopsy (EMB) and its in-hospital complications (and their predictors) in the United States (US). METHOD: We analyzed Nationwide Inpatient Sample (NIS) database from years 2007 through 2014 to identify patients who underwent EMB. Once identified, the patients were subdivided into those with no history of heart transplant (HT) (cohort 1) and those with history of HT (cohort 2). We then studied the major complication of pericardial effusion, hemopericardium or/and cardiac tamponade that required a pericardiocentesis or a pericardial window (CTRPD) following the EMB procedure. RESULTS: We observed a steady increase in the in-patient EMB procedures, with more EMB procedures being performed in males and in Caucasians. In cohort 1, the CTRPD was higher (0.70%) as compared to cohort 2 (0.19; p = 0.01). CTRPD in women was higher compared to men (0.94 vs. 0.53% p = 0.022). Most of the EMB procedures are performed in teaching hospitals. The CTRPD rate was significantly higher in the nonteaching hospitals when compared to teaching hospitals in both cohort 1 and cohort 2 (3.4 vs. 0.53% and 1 vs.0.18%, respectively; p = 0.01 and < 0.001, respectively). The overall mortality in cohort 1 was 4.3% as compared to 2.5% in cohort 2; p = 0.01. In cohort 1, the mortality was significantly higher in the group that had EMB related complications versus the group without the complications (20 vs. 2.5%; p < 0.001). CONCLUSION: There has been an increase in the number of EMB procedures in the US in recent years. Though the overall risk of CTRPD is very low, the risk is significantly higher in cohort 1, women, and in nonteaching hospitals. The study results provide data benchmarks for assessing EMB outcomes in the US. PMID- 30517934 TI - Imaging of Myocardial Fibrosis and Its Functional Correlates in Aortic Stenosis: A Review and Clinical Potential. AB - Patients with severe aortic stenosis (AS) show progressive fibrotic changes in the myocardium, which may impair cardiac function and patient outcomes even after successful aortic valve replacement. Detection of patients who need an early operation remains a diagnostic challenge as myocardial functional changes may be subtle. In recent years, speckle tracking echocardiography (STE) and cardiac magnetic resonance mapping have been shown to provide complementary information for the assessment of left ventricular mechanics and identification of subtle damage by focal or diffuse myocardial fibrosis, respectively. Little is known, however, about how focal and diffuse myocardial fibrosis occurring in severe AS are related to measurable functional changes by echocardiography and to which extent both parameters have prognostic and diagnostic value. The aims of this review are to discuss the occurrence of focal and diffuse myocardial fibrosis in patients with severe AS and to explore their relation with myocardial function, determined by STE, as well as the prognostic and diagnostic potential of both parameters. PMID- 30517935 TI - Involvement of the cAMP-Dependent Pathway in Dextromethorphan-Induced Inhibition of Spontaneous Glutamate Transmission in the Nucleus Tractus Solitarius Neurons of Guinea Pigs. AB - Dextromethorphan (DEX) presynaptically decreases glutamatergic transmission in second-order neurons of the nucleus tractus solitarius (TS). To clarify the inhibitory mechanism of DEX, the present study examined the interaction of DEX with cAMP. The effects of DEX on miniature and TS-evoked excitatory postsynaptic currents (mEPSCs and eEPSCs) were recorded under activation of the cAMP-dependent pathway using the brainstem slices. An increase in cAMP by forskolin counteracted the inhibitory effect of DEX on mEPSCs. Eight-Bromo-cAMP and N-ethylmaleimide also attenuated the DEX effect. However, forskolin had negligible effects on the DEX-induced inhibition of eEPSCs. This suggests that DEX decreases spontaneous glutamate release by inhibiting the cAMP-dependent pathway and synchronous release by another unknown mechanism. PMID- 30517936 TI - Serum Neuroendocrine Markers Predict Therapy Outcome of Patients with Metastatic Castration-Resistant Prostate Cancer: A Meta-Analysis. AB - PURPOSE: To evaluate whether serum neuroendocrine markers could effectively predict treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: The PubMed, Cochrane Library and Embase databases were sought to identify eligible studies concerning serum neuroendocrine markers and the prognosis of post-treatment mCRPC from inception to April 2018. The association between serum neuroendocrine markers, that is, chromogranin A (CgA) and neurone-specific enolase (NSE), levels and the prognosis of post-treatment mCRPC were summarized using a random-effects model and hazard ratio (HR) with 95% CI Sensitivity analyses were conducted to assess potential bias. RESULTS: A total of 234 participants are included in this meta-analysis (mean age = 71.3 years) from 6 studies. The pooled results show that higher markers' levels at baseline in patients were associated with unfavorable overall survival (OS; univariate analysis: HR 3.775, 95% CI 1.469-9.698, p = 0.006; multivariate analysis: HR 3.838, 95% CI 1.774-8.304, p = 0.001), and a similar situation was observed in progression-free survival (PFS; univariate analysis: HR 2.785, 95% CI 1.315-5.898, p = 0.007; multivariate analysis: HR 1.266, 95% CI 1.017-1.577, p = 0.035). Estimates of the total effects were generally consistent in the sensitivity analysis. Publication bias was observed when performing the univariate analysis of PFS, and we have the explanation accordingly. CONCLUSIONS: The results of this pooled analysis confirm serum neuroendocrine markers could be the effective predictor of treatment outcome in patients with mCRPC. In addition, a combination of CgA and NSE is more valuable to predict worse OS. Further randomized case-control trials are required to validate this relationship. PMID- 30517937 TI - Mechanisms of Etomidate-Mediated Decrease of Spontaneous Spike Activity of Mouse Cerebellar Purkinje Cells in vivo. AB - Etomidate is an imidazole, nonbarbiturate hypnotic agent that is increasingly used in procedural sedation. However, the effects of etomidate on the spontaneous activity of cerebellar Purkinje cells (PCs) in living mouse have not been fully understood. In this study, we investigated the effects of etomidate on the spontaneous simple spike (SS) activity of PCs in urethane-anesthetized mice by cell-attached recording and pharmacological methods. Cerebellar surface application of etomidate (50 MUmol?L) reduced the SS firing rate in a concentration-dependent manner (IC50: 43.4 umol?L). Application of either a gamma aminobutyric acid type A (GABAA) receptor antagonist, SR95531 (20 MUmol?L) or a glycine receptor antagonist strychnine (10 MUmol?L) significantly attenuated but not abolished the etomidate-induced decrease in PC SS firing rate. However, co application of SR95531 (20 MUmol?L) and strychnine (10 MUmol?L) abolished the etomidate-induced decrease in PC SS firing rate. Moreover, intraperitoneal injection of etomidate (3 mg/kg body weight) also induced a significant depression in PC SS firing rate, which was blocked by the co-application of SR95531 and strychnine on the cerebellar surface. These results indicate that both GABAA and glycine receptors are involved in the etomidate-induced decrease in PC SS firing rate in vivo in mice. PMID- 30517938 TI - Deep Brain Stimulation Surgery without Sedation. AB - BACKGROUND: Sedatives and opioids used during deep brain stimulation (DBS) surgery interfere with optimal target localization and add to side effects and risks, and thus should be minimized. OBJECTIVE: To retrospectively test the actual need for sedatives and opioids when cranial nerve blocks and specific therapeutic communication are applied. METHODS: In a case series, 64 consecutive patients treated with a strong rapport, constant contact, non-verbal communication and hypnotic suggestions, such as dissociation to a "safe place," reframing of disturbing noises and self-confirmation, were compared to 22 preceding patients under standard general anaesthesia or conscious sedation. RESULTS: With introduction of the protocol the need for sedation dropped from 100% in the control group to 5%, and from a mean dose of 444 mg to 40 mg in 3 patients. Remifentanil originally used in 100% of the patients in an average dose of 813 ug was reduced in the study group to 104 ug in 31% of patients. There were no haemodynamic reactions indicative of stress during incision, trepanation, electrode insertion and closure. CONCLUSION: With adequate therapeutic communication, patients do not require sedation and no or only low-dose opioid treatment during DBS surgery, leaving patients fully awake and competent during surgery and testing. PMID- 30517939 TI - Tauroursodeoxycholic Acid Ameliorates Lipopolysaccharide-Induced Depression Like Behavior in Mice via the Inhibition of Neuroinflammation and Oxido-Nitrosative Stress. AB - Depression is a mental disease that causes severe economic and social burdens. The mechanism for the onset of depression remains largely unknown. Recently, more and more attention is being given to the role of neuroinflammation and oxidative stress in depression. Tauroursodeoxycholic acid (TUDCA), a clinically available agent used to treat cholesterol gallstone and protect neurons against neurodegeneration, has been reported to prevent neuroinflammation and oxidative stress. In this study, we investigated the effect of TUDCA on lipopolysaccharide (LPS)-induced depression-like behavior, neuroinflammation, and oxido-nitrosative stress in mice. Results showed that TUDCA pretreatment (once daily for 7 consecutive days) at the dosage of 200 and 400 mg/kg, but not 100 mg/kg, markedly attenuated LPS (0.83 mg/kg)-induced behavioral abnormalities in the tail suspension test, forced swim test, and sucrose preference test. Further analysis showed that the TUDCA pretreatment (200, 400 mg/kg) not only inhibited the production of proinflammatory cytokines induced by LPS stimulation, such as interleukin-6 and tumor necrosis factor-alpha, but attenuated LPS-triggered oxido nitrosative stress in the hippocampus and prefrontal cortex. Taken together, our results provide evidence to show that the TUDCA could be a potential antidepressant, and its antidepressive mechanism may be associated with the inhibition of the neuroinflammatory response and oxido-nitrosative stress in the brain. PMID- 30517940 TI - Acknowledgement to Reviewers. PMID- 30517941 TI - Suspected Reaction with Cephalosporin May Be a Predictive Factor for beta-Lactam Allergy in Children. AB - BACKGROUND: Most children diagnosed with beta-lactam allergy based only on history are not truly allergic, and mislabeling leads to use of less effective and more costly alternative broader-spectrum antibiotics, significantly increasing drug resistance. OBJECTIVE: To determine the frequency and risk factors of confirmed allergy in patients with beta-lactam allergy reported by parents or their doctors and evaluate cross-reactivity between beta-lactams in children with confirmed allergy. METHOD: Sixty-seven children with suspected beta lactam allergy were evaluated via history, sIgE measurements, skin tests, and drug provocation tests over a period of 5 years. RESULTS: beta-Lactam allergy was confirmed in 10 (14.9%) patients. Six patients had a positive intradermal test result to one or more of the penicillin skin test materials or ceftriaxone, 4 patients with negative skin test results had positive test results with suspected drugs. Age, gender, time interval between evaluation and the initial reaction, personal history of atopy, parental history of drug allergy, reaction type, and multiple drug allergy history were not significantly different between allergic and tolerant patients. For culprit drugs, there was a significant different between the 2 groups; the rate of confirmed diagnosis was significantly higher for cephalosporins such as ceftriaxone, cefuroxime, and cefprozil (p = 0.03). Three patients with allergy to penicillin tolerated cefuroxime; in 4 patients with selective allergy to ceftriaxone tolerated cephalosporins with a dissimilar side chain (cefadroxil, cefuroxime, cefaclor, and cefdinir). CONCLUSION: Our study indicates that most patients with a suspected beta-lactam allergy tolerated this drug. An appropriate diagnostic allergy workup may prevent the use of less effective and more expensive alternatives. PMID- 30517942 TI - Prevalence of Retinal Vein Occlusion in Europe: A Systematic Review and Meta Analysis. AB - PURPOSE: The aim of this study was to examine the prevalence and incidence of retinal vein occlusions (RVO) in Europe. METHODS: A systematic review and meta analysis of the prevalence and incidence of RVO in Europe according to the Meta Analyses of Observational Studies in Epidemiology (MOOSE) guidelines was performed in the databases PubMed, Embase and Web of Science. Based on Eurostat data, the total number of affected individuals in the EU was calculated and projected to the year 2050. RESULTS: The random-effects pooled prevalence of RVO in Europe was 0.7% (95% CI: 0.5-0.9%) in persons aged 55 years and older based on the examination of 25,002 individuals from 4 prevalence studies. No European incidence studies were identified. The total number of affected individuals in the EU was estimated to rise by almost 20% from 900,000 today to 1.1 million in 2050. CONCLUSION: Published articles on the prevalence and incidence of RVO in Europe are limited. With the expected increase in affected persons, further epidemiological research is warranted for adequate healthcare planning. PMID- 30517943 TI - Pericardium in Reconstructive Urologic Surgeries: A Systematic Review and Meta Analysis. AB - INTRODUCTION: The use of pericardium has been expanded into different surgical modalities; however, there are scarce data regarding the feasibility of the pericardium in reconstructive urologic surgeries. We systematically reviewed the literature on the effectiveness of the pericardial tissue for reconstructive urologic surgeries. MATERIALS AND METHODS: PubMed and Scopus were searched online for evidence on the use of the pericardium in urologic surgeries. Through the methodology recommended by the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, 38 of 4,071 studies were identified. RESULTS: A total of 715 patients and 139 animals underwent reconstructive urologic surgeries using the pericardium. Bladder, urethral, and renal reconstructions were successful in 100% of the human cases. The rates of dissatisfaction, glans hypoesthesia, and penile shortening were comparable between the pericardial graft surgeries and the other operations during penile straightening, but there was a trend among the patients with pericardial grafts toward having a more penile curvature at follow-up (risk ratio [RR] 2.03, 95% CI 0.90-4.61, p = 0.09; I2 = 0%). Among the animal studies, there were 4 reports of penile reconstruction, 7 studies of bladder reconstruction, and 1 study of urethroplasty. Bladder reconstruction and urethroplasty were successful in 83 and 20% of the animals, respectively. The pooled result of the stimulated intracorporeal pressure 5 V significantly favored pericardial grafts during penile reconstruction (RR 2.61, 95% CI 1.26-3.97, p = 0.0002; I2 = 0%). CONCLUSIONS: Our systematic review demonstrates the feasibility of the pericardium, regardless of its type, in urologic surgeries. It, however, seems that urethral substitution needs further investigation. Given the lower cost, easier handling, and less immunogenicity of the pericardium, further studies are required to examine its pros and cons. PMID- 30517944 TI - Unmet Needs in the Field of Neuroendocrine Neoplasms of the Gastrointestinal Tract, Pancreas, and Respiratory System: Reports by the ENETS Group. PMID- 30517945 TI - Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System. AB - An extensive microglial-astrocyte-monocyte-neuronal cross talk seems to be crucial for normal brain function, development, and recovery. However, under certain conditions neuroinflammatory interactions between brain cells and neuroimmune cells influence disease outcome and brain pathology. Microglial cells express a range of functional states with dynamically pleomorphic profiles from a surveilling status of synaptic transmission to an active player in major events of development such as synaptic elimination, regeneration, and repair. Also, inflammation mediates a series of neurotoxic roles in neuropsychiatric conditions and neurodegenerative diseases. The present review discusses data on the involvement of neuroinflammatory conditions that alter neuroimmune interactions in four different pathologies. In the first section of this review, we discuss the ability of the early developing brain to respond to a focal lesion with a rapid compensatory plasticity of intact axons and the role of microglial activation and proinflammatory cytokines in brain repair. In the second section, we present data of neuroinflammation and neurodegenerative disorders and discuss the role of reactive astrocytes in motor neuron toxicity and the progression of amyotrophic lateral sclerosis. In the third section, we discuss major depressive disorders as the consequence of dysfunctional interactions between neural and immune signals that result in increased peripheral immune responses and increase proinflammatory cytokines. In the last section, we discuss autism spectrum disorders and altered brain circuitries that emerge from abnormal long-term responses of innate inflammatory cytokines and microglial phenotypic dysfunctions. PMID- 30517946 TI - Digital Follow-Up and the Perspective of Patient-Centered Care in Oncology: What's the PROblem? AB - There is accumulating evidence from randomized trials suggesting that digital patient-centered care allows a more reliable detection of tumour-related symptoms and adverse events - with a direct impact on overall survival. Consequently, a variety of unsynchronized approaches were kicked off to (electronically) measure patient-reported outcomes (PROs). Despite increasing evidence that PRO data are highly relevant for patient care, the data generated in these initial projects lack standardized processing pathways in order to impact clinical routine; therefore, potential future routine PRO assessments require adequate analysis, storage and processing to allow a robust, reproducible and reliable incorporation into routine clinical decision-making. Here, we discuss relevant challenges of digital follow-up that need to be tackled to render PRO data as relevant to physicians as laboratory or biomarker data. PMID- 30517947 TI - Microtonal Variation in Sung Cantonese. AB - BACKGROUND/AIMS: Both music and language impose constraints on fundamental frequency (F0) in sung music. Composers are known to set words of tone languages to music in a way that reflects tone height but fails to include tone contour. This study tests whether choral singers add linguistic tone contour information to an unfamiliar song by examining whether Cantonese singers make use of microtonal variation. METHODS: 12 native Cantonese-speaking non-professional choral singers learned and sang a novel song in Cantonese which included a minimal set of the Cantonese tones to probe whether everyday singers add in missing contour information. RESULTS: Cantonese singers add in a rising F0 contour of less than a semitone when singing syllables with lexical rising tones. This microtonal variation is not observed when singing in a lower register. CONCLUSION: Cantonese singers use microtonal contours to reflect rising contours of Cantonese linguistic tones. PMID- 30517948 TI - Association of Hydrocephalus with Neural Tube Defect: Our Experience with the Surgical Treatment in One or in Two Operative Stages (on Separate Days). AB - BACKGROUND: Neural tube defects (spina bifidas or cephaloceles) are congenital malformations that can be associated with hydrocephalus. Even if the surgical management of each of these pathologies separately is well established, this is not the case for a combination of these conditions. AIM: To report our results of simultaneous or separate surgery for the association of hydrocephalus with neural tube defect in the same patient. METHODS: This was a retrospective study of the association of hydrocephalus with neural tube defect (spina bifida or cephalocele) managed over a period of 7 years at the Department of Neurosurgery, Yalgado Ouedraogo University Hospital, Ouagadougou, Burkina Faso. RESULTS: Thirty eight cases were included. The mean age was 8.1 months, and the sex ratio was 0.81. There were 27 cases of spina bifida and 11 cases of cephalocele associated with hydrocephalus. A cerebral CT scan was performed in all patients. In 30 cases, the operative management of these pathologies was performed at the same operative time. Eight cases were operated in 2 separate operative stages with a mean time of 30 days between the 2 operations. The course was favorable in 22 patients operated by the simultaneous approach and in 3 patients operated by the separate approach (p = 0.07). CONCLUSION: Surgical management of the association of hydrocephalus with neural tube defect in 1 or 2 operative stages gave similar clinical results. However, the treatment in 1 surgical stage would considerably reduce the charges. PMID- 30517949 TI - Over-the-counter Weight-Loss Herbal Supplements in Egypt: Label Claim, Microbiological, Pharmaceutical Quality and Safety Assessments. AB - OBJECTIVES: Nutraceuticals are advertised and sold with the label claim of being natural and safe herbal products. Due to the absence of clear regulations and guidelines for safety assessments of these products, nutraceuticals are commonly adulterated in order to increase sales. The objective of the current study was to design a comprehensive evaluation system to assess the safety, efficacy, authenticity according to label claim and pharmaceutical quality, of herbal slimming products in between 2015 and 2017. METHODS: We designed a comprehensive assessment system to evaluate the safety, authenticity according to label claim, and pharmaceutical quality of slimming nutraceuticals. Six different popular products were evaluated (Zotreem Plus(r), Zotreem Extra(r), Malaysian Super Slim(r), AB Slim(r), Chinese Super Slim(r) and Metabolites(r)). The pharmaceutical evaluation included analyzing the samples via HPLC to determine any possible adulterants. Additionally, physical properties were assessed via pharmacopeial tests. Finally, microbial evaluation and retrospective prevalence cross-sectional observational study was conducted to assess their safety and efficacy. RESULTS: The tested products were found to be adulterated with unreported active pharmaceutical ingredients, such as sibutramine, sildenafil, phenolphthalein and orlistat. Furthermore, they contained heterogeneous amounts of adulterants and exhibited unsatisfactory pharmaceutical and microbial quality. Finally, the observational survey conducted on users showed that high percentages of participants suffered from common side-effects, such as depression, diarrhea and hypertension. CONCLUSIONS: These products threaten the health of consumers. There is a need to raise the awareness on the lethal consequences of illegal nutraceuticals. PMID- 30517950 TI - The Role of Effortful Control in Stuttering Severity in Children: Replication Study. AB - Background: In 2014, Kraft et al. assessed the temperament, home environment, and significant life events of 69 North American children who stutter to examine the combined and compounded effects of these individualized factors on mediating overt stuttering severity. The temperament domain of effortful control was singularly found to be significantly predictive of stuttering severity. Purpose: Because of the clinical significance of the initial study's findings, a replication study with a different, larger cohort of children who stutter was warranted to validate the reported outcomes. Method: The current study assesses 98 children who stutter, ages 2;4 to 12;6 (years; months, M = 6;7), recruited from Perth, Australia. Results: The results support the previous findings of Kraft, Ambrose, and Chon (2014), with effortful control remaining the sole significant contributor to variability in stuttering severity, as rated by both parents and clinicians. Conclusion: These cumulative and consistent outcomes support the need to develop targeted intervention strategies that specifically strengthen aspects of effortful control as a means to support positive therapeutic change in children who stutter. PMID- 30517951 TI - Malnutrition screening in outpatients receiving hyperbaric oxygen therapy: an opportunity for improvement? AB - Outpatients who receive hyperbaric oxygen treatment (HBOT) may represent a group at significant risk of malnutrition owing to the underlying conditions that are often treated with HBOT (e.g., non-healing diabetic wounds and radiation-induced skin injury). In this issue, See and colleagues provide new, preliminary evidence of the prevalence of malnutrition in a small group of HBOT outpatients treated in an Australian hospital, reporting that approximately one-third of patients receiving HBOT were at risk of malnutrition. To our knowledge, routine malnutrition screening is not available in HBOT centres providing outpatient treatment, which may be a key gap in the nutrition care of these patients. Malnutrition screening was developed to identify those at risk of malnutrition across the healthcare continuum. In the outpatient setting, it is recommended that patients are screened at their first clinic appointment and that screening is repeated when there is clinical concern. Malnutrition screening tools are designed to be quick and simple to complete by trained healthcare staff and include questions relating to appetite, oral intake and recent weight loss. The early identification of patients at risk of malnutrition using validated screening tools enables the appropriate and timely referral of patients to dietetic services for assessment and treatment. Why might malnutrition screening in HBOT services be important? It is well documented that the consequences of malnutrition are systemic, with increased morbidity and mortality attributed to malnutrition. Beyond the detrimental impact of malnutrition to the individual, malnutrition also has significant economic ramifications, with medical costs significantly higher in severely malnourished compared to well-nourished patients. Of particular relevance, malnutrition is associated with impaired and prolonged wound healing. This may influence the effectiveness and success of HBOT treatment, although studies in the area of HBOT and concurrent nutrition therapy are lacking. Furthermore, there are no reliable markers of nutrition status that are easily obtainable in the healthcare setting. In the past, prealbumin (transthyretin) and albumin have been used as surrogate markers of nutritional status. However, these serum proteins are acute-phase proteins and, therefore, are reduced during acute inflammation and infection, making them unreliable indicators of nutrition status. Transferrin, retinol binding protein and C reactive protein are similarly not recommended as markers of nutrition status and malnutrition. Therefore, the implementation of malnutrition screening may be the most practical and validated method of identifying patients who would benefit from a comprehensive assessment of their nutrition status and provision of nutrition support in the HBOT setting. The assessment of nutrition status involves the collective evaluation of anthropometric data, biochemical markers, clinical symptoms impacting on nutrition (e.g., nausea) and oral intake. Tools such as the subjective global assessment have been developed and validated to assess nutrition status and diagnose malnutrition by trained staff. In contrast to other outpatient services, HBOT presents a unique opportunity to complete both malnutrition screening and engage a relevant dietetic service for nutrition assessment early in the course of treatment. The frequent contact with outpatients would also lend itself well to group nutrition education sessions to address important nutrition information related to wound healing. Although there is a paucity of data to support the use of malnutrition screening and dietetic assessments in HBOT, current best practice guidelines recommend these services in outpatient settings. The implementation of routine malnutrition screening and referral processes to dietetic services warrants consideration in the HBOT outpatient setting. If going down this path, careful consideration of available resources, how referral systems can be incorporated into current procedures as well as partnership with dietetic departments is integral. In the interim, the referral of patients to dietetic departments who are suspected to be at risk of poor wound healing due to nutrition factors and those failing treatment should be considered by treating hyperbaric physicians. Although further research is required to assess the effectiveness of malnutrition screening and nutrition intervention in the HBOT outpatient population, the data by See and colleagues provides an important starting point in unpacking malnutrition risk in this population. PMID- 30517952 TI - Comparison of tissue oxygenation achieved breathing oxygen from a demand valve with four different mask configurations. AB - INTRODUCTION: High concentration normobaric oxygen (O2) is a priority in treating divers with suspected decompression illness. The effect of different O2 mask configurations on tissue oxygenation when breathing with a demand valve was evaluated. METHODS: Sixteen divers had tissue oxygen partial pressure (PtcO2) measured at six limb sites. Participants breathed O2 from a demand valve using: an intraoral mask (IOM(r)) with and without a nose clip (NC), a pocket face mask and an oronasal mask. In-line inspired O2 (FIO2) and nasopharyngeal FIO2 were measured. Participants provided subjective ratings of mask comfort, ease of breathing and holding in position. RESULTS: PtcO2 values and nasopharyngeal FIO2 (median and range) were greatest using the IOM with NC and similar with the IOM without NC. O2 measurements were lowest with the oronasal mask which also was rated as the most difficult to breathe from and to hold in position. The pocket face mask was reported as the most comfortable to wear. The NC was widely described as uncomfortable. The IOM and pocket face mask were rated best for ease of breathing. The IOM was rated as the easiest to hold in position. CONCLUSION: Of the commonly available O2 masks for use with a demand valve, the IOM with NC achieved the highest PtcO2 values. PtcO2 and nasopharyngeal FIO2 values were similar between the IOM with and without NC. Given the reported discomfort of the NC, the IOM without NC may be the best option. PMID- 30517953 TI - Decompression illness and other injuries in a recreational dive charter operation. AB - INTRODUCTION: Health and safety within the recreational diving industry are poorly described. We aimed to obtain the true prevalence of decompression illness (DCI) and other diving and non-diving injuries, including occupational injuries, in a large recreational diving charter operation. METHODS: A New Zealand recreational diving operator keeps detailed records of diving activity and event/incident reports. We extracted passenger and crew numbers, dive numbers and incident statistics from all boat trips and associated work-related injuries between 01 January 2008 and 31 December 2014. The records of divers referred to the regional hyperbaric unit for suspected DCI were reviewed retrospectively. Using these data the prevalence of DCI and non-diving injuries were calculated. RESULTS: There were 65,536 person-trips to sea and 57,072 divers undertook 97,144 dives. Fifty-five injury events were documented over seven years, 31 in customers and 24 in staff. Four divers (including one staff member) diagnosed with DCI underwent recompression therapy, giving a prevalence of 0.41 cases requiring recompression per 10,000 dives, or one case per 24,386 dives, whilst five other divers were assessed as not having DCI. There was one cardiac-related fatality. Thirty-five non-diving injuries (mainly lacerations and minor musculoskeletal injuries) were documented in 30 people resulting in 10 consulting a general practitioner and seven presenting to the local regional hospital emergency department. CONCLUSIONS: DCI requiring recompression was relatively rare in this supervised recreational diving operation. Minor non-diving injuries were the most common adverse event. Compared to other adventure sports, the prevalence of injury in recreational scuba diving is low. PMID- 30517954 TI - Fatal shark attacks on divers in Australia, 1960-2017. AB - AIM: The aim of this study was to identify the number, location and characteristics associated with fatal shark attacks on divers in Australian waters from 1960 to 2017, inclusive. METHODS: Searches were made of the Divers Alert Network Asia-Pacific Diving Mortality Database; the International Shark Attack File website; the Australian Shark Attack File and the Global Shark Attack File to identify cases of fatal shark attacks on divers in Australia. In addition, a systematic search of published medical and sporting literature was conducted to identify relevant reports. The data collected were scrutinised for relevance and duplication. RESULTS: There were 187 recorded attacks on divers, comprising 112 snorkellers, 62 scuba divers and 13 on divers using surface supplied breathing apparatus. These included 28 verified deaths: 13 involving snorkellers, eight involving scuba divers, and seven divers using surface-supply. The victims' ages ranged from 13-50 years (mean 31 years). All but three were males. The vast majority of attacks were by Carcharodon carcharias (Great White Shark). CONCLUSION: Spearfishing and other seafood collection, as well as diving near fishing activities and/or seals, were identified as major risk factors. However, shark attacks on divers are relatively rare and represent only 3% of diving-related fatalities in Australia over this 57-year period. PMID- 30517955 TI - Assessment of hyperbaric patients at risk of malnutrition using the Malnutrition Screening Tool - a pilot study. AB - BACKGROUND: Nutritional assessment and support is essential for wound management. The hyperbaric oxygen clinic is a unique outpatient service where chronically unwell patients present daily for hyperbaric oxygen treatment (HBOT) over several weeks, allowing time for effective nutritional intervention. This is the first study to examine the prevalence of those at risk of malnutrition in a cohort of hyperbaric medical patients. METHODS: A prospective study was undertaken over six months. Following consent, 39 enrolled patients had the Malnutrition Screening Tool and Baseline Characteristic Collection Form completed. Those at risk of malnutrition were given an option to be assessed by a dietitian to complete a Subjective Global Assessment (SGA). At the completion of treatment, the patients completed a questionnaire. RESULTS: Twelve of the 39 patients screened were at risk of malnutrition using our screening process. Of these, all the patients with available SGA results were diagnosed with moderate to severe malnutrition. Patients receiving HBOT for non-healing wounds and osteoradionecrosis were most at risk of malnutrition. CONCLUSION: The prevalence of patients being at risk of malnutrition in our hyperbaric medical service was about one in three. Malnutrition screening should be part of routine patient assessment in order to ensure patients receive timely nutritional intervention. This may improve wound healing. PMID- 30517956 TI - Preventive effects of ketone ester BD-AcAc2 on central nervous system oxygen toxicity and concomitant acute lung injury. AB - BACKGROUND: Recent studies indicated that ketone ester R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) may be effective in preventing central nervous system oxygen toxicity (CNS-OT) and concomitant acute lung injury, a serious medical problem to be faced when breathing hyperbaric oxygen (HBO). This study aimed to further investigate the protective effects of BD-AcAc2 against CNS-OT and concomitant acute lung injury (ALI) in mice. METHODS: Mice were treated with BD-AcAc2 in peanut oil vehicle (2.5, 5.0 or 10.0 g.kg-2 body weight) by gavage 20 minutes before 600 kPa HBO exposure. Control mice received the vehicle only. Seizure latency was recorded. Malondialdehyde content in brain and lung tissues, total protein level in bronchoalveolar lavage fluid (BLF) and lung water content were measured 60 minutes after the hyperbaric exposure. Histopathology of lung tissue was undertaken. RESULTS: Compared with the vehicle alone, BD-AcAc2 prolonged seizure latency in a dose-dependent manner (P < 0.01). The HBO-induced increase in brain malondialdehyde, BLF protein and lung water were significantly reduced by BD-AcAc2 (P < 0.01). CONCLUSION: Oral administration of the ketone ester BD-AcAc2 significantly protected against CNS-OT and concomitant ALI. Alleviation of oxidative stress may be one underlying mechanism providing this effect. PMID- 30517957 TI - Vibration and bubbles: a systematic review of the effects of helicopter retrieval on injured divers. AB - INTRODUCTION: Vibration from a helicopter during aeromedical retrieval of divers may increase venous gas emboli (VGE) production, evolution or distribution, potentially worsening the patient's condition. AIM: To review the literature surrounding the helicopter transport of injured divers and establish if vibration contributes to increased VGE. METHOD: A systematic literature search of key databases was conducted to identify articles investigating vibration and bubbles during helicopter retrieval of divers. Level of evidence was graded using the Oxford Centre for Evidence-Based Medicine guidelines. A modified quality assessment tool for studies with diverse designs (QATSDD) was used to assess the overall quality of evidence. RESULTS: Seven studies were included in the review. An in vitro research paper provided some evidence of bubble formation with gas supersaturation and vibration. Only one prospective intervention study was identified which examined the effect of vibration on VGE formation. Bubble duration was used to quantify VGE load with no difference found between the vibration and non-vibration time periods. This study was published in 1980 and technological advances since that time suggest cautious interpretation of the results. The remaining studies were retrospective chart reviews of helicopter retrieval of divers. Mode of transport, altitude exposure, oxygen and intravenous fluids use were examined. CONCLUSION: There is some physical evidence that vibration leads to bubble formation although there is a paucity of research on the specific effects of helicopter vibration and VGE in divers. Technological advances have led to improved assessment of VGE in divers and will aid in further research. PMID- 30517958 TI - Validation of algorithms used in commercial off-the-shelf dive computers. AB - INTRODUCTION: Whilst the US Navy has been very systematic about validating Navy dive computer algorithms, there has been little documented or published evidence of rigorous testing of the algorithms in commercial off-the-shelf dive computers. This paper reports the evaluation of four algorithms used in these - Buhlmann ZHL 16C; VPM-B; Suunto-RGBM; EMC-20H - by comparison with US Navy experimental dives with known decompression sickness outcomes. METHODS: Three specific tests were developed to test the algorithms' ability to mitigate decompression sickness: Total decompression time; no stop times and first stop depth. Output of commercial decompression algorithms were compared to either the probability of decompression sickness (PDCS) results from US Navy man-trials or statistical models derived from PDCS data. The algorithms were first tested with default conservative factors, then these factors were adjusted if the tests were not initially passed. The last verification step was to compare the output of the wrist computer with that of the full desktop algorithm. RESULTS: This testing indicated that, whilst none of the four passed all of the proposed tests with factory-default conservatism, ZHL-16C and Suunto-RGBM could be made to pass by adjusting user-defined settings. CONCLUSIONS: Man-trial data on PDCS is available to the non-US Navy scientific community for testing of commercial decompression algorithms. This type of validation testing can be very informative on how to best use available commercial dive computers to improve diver safety. PMID- 30517959 TI - A diver with immersion pulmonary oedema and prolonged respiratory symptoms. AB - Immersion pulmonary oedema (IPE) is particularly associated with an excessive reaction to exercise and/or cold stress. IPE usually resolves without recompression therapy within a day or two. Herein we report a diver diagnosed with IPE, in whom symptoms persisted for five days. A 58-year-old man presented with sudden onset of dyspnoea, cough and haemoptysis after surfacing. He was an experienced diving instructor with a history of moderate mitral valve regurgitation. While IPE was diagnosed and oxygen administered, respiratory symptoms deteriorated, and serum C-reactive protein elevated. No evidence of infection was seen. Three hyperbaric oxygen treatments were given on the basis of suspected decompression sickness, and symptoms subsequently resolved. The recently diagnosed mitral valve regurgitation and inflammatory response were considered to have contributed to the prolongation of symptoms. PMID- 30517960 TI - The on-site differential diagnosis of decompression sickness from endogenous cerebral ischaemia in an elderly Ama diver using ultrasound. AB - Commercial or occupational breath-hold (BH) harvest divers along the coast and islands of Japan are collectively called Ama divers. Repetitive BH diving by Ama divers may place them at risk of developing neurological decompression sickness (DCS). We report a 74-year-old Ama diver who demonstrated right hemiparesis during an ascent after free diving at a depth of 5 metres' sea water. This report suggests the usefulness of on-site ultrasound for making a differential diagnosis of DCS from endogenous cerebral ischaemia. Further clinical studies of this management approach are warranted. PMID- 30517961 TI - Pallister-Killian Syndrome: The Diagnosis is in the Detail. PMID- 30517962 TI - Lhermitte-Duclos Disease with Cervical Arteriovenous Fistula. AB - Lhermitte-Duclos disease is a rare condition with less than 250 cases reported in the literature. It was considered a neoplastic or hamartomatous growth in the cerebellum. It commonly presents with symptoms of high intracranial pressure or obstructive hydrocephalus. Surgical resection is often curative. The lesion is associated with PTEN gene mutation, and it is considered to be one of the diagnostic criteria of Cowden's syndrome. Vascular tumors are reported in this syndrome, including glioblastomas and meningiomas. Furthermore, central nervous system vascular lesions were also reported in Lhermitte-Duclos disease, such as deep venous anomalies and brain arteriovenous fistulas. A report of an asymptomatic spinal cervical AVF in a patient with Lhermitte-Duclos disease was published in 2006. We present the second case of Lhermitte-Duclos disease associated with an asymptomatic spinal cervical AVF in a 17-year-old young woman with literature review of central nervous system vascular lesions in Lhermitte Duclos disease. PMID- 30517963 TI - Improvement of Back and Leg Pain after Lumbar Spinal Decompression without Fusion. AB - BACKGROUND: To evaluate whether decompression in lumbar spinal stenosis without fusion leads to sufficient improvement of back pain and leg pain and whether re decompression alone is sufficient for recurrent lumbar spinal stenosis for patients without signs of instability. MATERIAL AND METHODS: A successive series of 102 patients with lumbar spinal stenosis (with and without previous lumbar surgery) were treated with decompression alone during a 3-year period. Data on pre- and postoperative back pain and leg pain (numerical rating scale [NRS] scale) were retrospectively collected from questionnaires with a return rate of 65% (n = 66). The complete cohort as well as patients with first-time surgery and re-decompression were analyzed separately. Patients were dichotomized to short term follow-up (< 100 weeks) and long-term follow-up (> 100 weeks) postsurgery. RESULTS: Overall, both back pain (NRS 4.59 postoperative versus 7.89 preoperative; p < 0.0001) and leg pain (NRS 4.09 versus 6.75; p < 0.0001) improved postoperatively. The short-term follow-up subgroup (50%, n = 33) showed a significant reduction in back pain (NRS 4.0 versus 6.88; p < 0.0001) and leg pain (NRS 2.49 versus 6.91: p < 0.0001). Similar results could be observed for the long-term follow-up subgroup (50%, n = 33) with significantly less back pain (NRS 3.94 versus 7.0; p < 0.0001) and leg pain (visual analog scale 3.14 versus 5.39; p < 0.002) postoperatively. Patients with previous decompression surgery benefit significantly regarding back pain (NRS 4.82 versus 7.65; p < 0.0024), especially in the long-term follow-up subgroup (NRS 4.75 versus 7.67; p < 0.0148). There was also a clear trend in favor of leg pain in patients with previous surgery; however, it was not significant. CONCLUSIONS: Decompression of lumbar spinal stenosis without fusion led to a significant and similar reduction of back pain and leg pain in a short-term and a long-term follow-up group. Patients without previous surgery benefited significantly better, whereas patients with previous decompression benefited regarding back pain, especially for long-term follow-up with a clear trend in favor of leg pain. PMID- 30517964 TI - [Motivation for Specialisation in General Practice - A Quantitative Study of NRW's Medical Students in Support of Targeted Recruitment]. AB - AIM OF STUDY: Due to forecasted shortage of general practitioners, we conducted an online survey of all medical students in North-Rhine-Westphalia to identify and quantify determinants in medical students' decision to specialize in general practice (GP). METHODOLOGY: To identify the motives driving the choice of GP as a career, responses of 3976 participants (22.6% of medical students invited) were subjected to factor analysis. Relationships between extracted factors and career choice were ascertained via regression analysis adjusted for population characteristics. All participants who had positioned themselves distinctly for/against GP were included in regression analysis (n=2862). RESULTS: Four of five identified factors were significantly associated with the intended choice of GP. "Comprehensive patient contact" (OR 4.02; 95% CI [3.5-4.6]), and "flexible working hours" (OR 1.35; 95% CI [1.2-1.5]) represent factors associated with choosing GP despite the perception of "superior career opportunities, income and status in other specializations" (OR 1.14; 95% CI [1.0-1.3]). Meanwhile, preference for "specialization, research and teamwork in other disciplines" (OR 0.55; 95% CI [0.5-0.6]) obstructs the intended choice of GP. CONCLUSION: GP recruitment can profit from focused sponsorship of students' interest in patient contact within GP clerkships, appropriate GP teaching structure at the universities, enhanced research and teamwork opportunities, and increased flexibility of working hours. PMID- 30517965 TI - An Overview on Genistein and its Various Formulations. AB - Genistein is the natural isoflavone and a phytoestrogen with a broad range of pharmacological properties, such as tyrosine and topoisomerase inhibition. It also induces apoptosis and cell proliferation inhibition, differentiates cancer cells. Added health benefits include the reduction of osteoporosis by suppressing osteoclasts and lymphocyte functions, decreased the risk of cardiovascular attacks and relieved postmenopausal problems. Genistein traditionally used in Chinese and Ayurvedic medicine and are found to be associated with lower risk of breast, prostate and lung cancer. Numerous factors comprising genetic, epigenetic and transcriptomic alterations are evidenced to be responsible for breast, prostate and lung cancer. In present review, an overview on genistein, the various analytical methods and drug delivery approaches to determine genistein in the formulations are discussed. It may help to develop novel formulations with better solubility and bioavailability of genistein. The tumor cell scan may be targeted to form a stable genistein formulation. PMID- 30517966 TI - UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood. AB - INTRODUCTION: Neurodegenerative diseases of childhood present with progressive decline in cognitive, social, and motor function and are frequently associated with seizures in different stages of the disease. Here we report a patient with severe progressive neurodegeneration with drug-resistant epilepsy of unknown etiology from the age of 2 years. METHODS AND RESULTS: Using whole exome sequencing, we found heterozygous missense de novo variant c.628G > A (p.Glu210Lys) in the UBTF gene. This variant was recently described as de novo in 11 patients with similar neurodegeneration characterized by developmental decline initially confined to motor development followed by language regression, appearance of an extrapyramidal movement disorder, and leading to severe intellectual disability. In 3 of the 11 patients described so far, seizures were also present. CONCLUSIONS: Our report expands the complex phenotype of neurodegeneration associated with the c.628G > A variant in the UBTF gene and helps to clarify the relation between this one single recurrent pathogenic variant described in this gene to date and its phenotype. The UBTF gene should be considered a novel candidate gene in neurodegeneration with or without epilepsy. PMID- 30517967 TI - [The Mini-Audio-Test (MAT) - a screening method on hearing impairment to be used by general practitioners and specialized physicians]. AB - BACKGROUND: In Germany, about 15 million people are suffering from hearing loss (HL), whereas only 16 % are using hearing aids. Untreated hearing loss may lead to severe complications (e. g. social isolation, depression, progress of dementia). An early and widespread screening, beginning at the age of 50, is meant to improve this shortage in medical care. By this study, the Mini-Audio Test (MAT), a six-question and three-step answers containing questionnaire on subjective HL, should be verified on a normal collective of subjects (sensitivity (Se), specificity (Sp), positive predictive value (Ppv)). METHODS: 943 subjects (older 50 years) without any history of ear disease answered the MAT and received pure-tone audiometry. The Se, Sp, and Pv to detect a relevant HL with the MAT for the age-group < 60 years (AG1) and >= 60 years (AG2) were determined. RESULTS: The Se for AG1 was 0.66, the Sp 0.61, the Ppv 0.60, for AG2 the Se was 0.47, the Sp 0.80, the Ppv 0,89. CONCLUSION: Following our results, the MAT is recommended as a general screening-tool for HL in patients over 50 years of age for general practitioners. Hereby, severe secondary diseases (loss of cognitive power, risk of fall, depression, dementia) could be influenced positively. PMID- 30517968 TI - [Pressure study of two miniaturised amplatz sheaths of 9.5 F and 12 F outer diameter for minimal invasive percutaneous nephrolithotomy (MIP): An ex vivo organ model measurement]. AB - : Over the last decade, several devices for percutaneous nephrolithotomy with smaller diameters have been introduced in order to reduce renal trauma. Recent studies have found comparable stone free rates but also exhibit the same rate of postoperative fever and septicaemia. One possible cause is the influence of irrigation fluid during stone treatment procedures. The purpose of this ex vivo study was to compare two new miniaturised PNL nephroscopy sheaths with an outer sheath diameter of 9.5 F and 12 F to the well-established MIP M Set (17.5 F) by Karl Storz. MATERIAL AND METHODS: The new devices were tested in a perfused organ model of fresh porcine kidneys with different irrigation pressures, applied either by gravitation or the use of a pressure pump (Uromat E.A.S.I. Pump, Karl Storz, Tuttlingen, Germany).In addition, the 9.5 F sheath was examined for active irrigation evacuation, i. e. suction of irrigation fluid through a mono-J catheter. An urodynamic pressure probe measured intrapelvic pressure levels throughout the procedures. RESULTS: Regardless of the sheath diameters used, the intrapelvic pressure did not exceed 40 cmH2O (30 mmHg) when applying moderate irrigation pressure levels, either by pump or gravitation. The active suction of irrigation fluid from the kidney basin via the mono-J-catheter had no measurable impact on the detected intrarenal pressures. A crucial increase in the intrapelvic pressure was detected only when using the 9.5 F sheath in combination with applying high irrigation pressures. CONCLUSION: The newly designed miniaturised MIP sets maintain the favourable pressure features of the earlier 17.5 MIP sheath. Although the diameter has been reduced to 12F or 9.5 F, the intrapelvic pressures remained below 40 cmH2O when regular irrigation settings by gravitation or pump irrigation were used. PMID- 30517969 TI - Understanding Secure Messaging in the Inpatient Environment: A New Avenue for Communication and Patient Engagement. AB - BACKGROUND: Patient portals, and the secure messaging feature in particular, have been studied in the outpatient setting, but research in the inpatient setting is relatively less mature. OBJECTIVE: To understand the topics discussed in secure messaging in the inpatient environment, we analyzed and categorized messages sent within an inpatient portal. MATERIALS AND METHODS: This observational study examined the content of all secure messages sent from December 2013 to June 2017 within an inpatient portal at a large Midwestern academic medical center (AMC). We analyzed a total of 2,598 messages, categorizing them by sender (patient, family, or care team member), type, and topic, and conducted a descriptive analysis of categories and an examination of code co-occurrence. RESULTS: Patients were the most frequent message senders (63%); family members sent the fewest messages (10%). We identified five types of messages: Alert/Request; Thanks; Response; Question; and Other (typo/test message). Patient messages included Alerts/Requests (38%), Questions (31%), Statements of Thanks (24%), Response (1.2%), and Other (5%). We also identified 14 nonmutually exclusive message topics: Medication; Procedure/Treatment Plan; Schedule; Pain; Results; Diet; Discharge; Non-Medication Questions; Provider Requests; Symptoms; Custodial; Technical Issues; Potential Error; and Contact Information. Patient message topics most commonly discussed Symptoms (18%), Procedure/Treatment Plan (14%), or Pain (12%). CONCLUSION: Our analysis of secure message content suggests certain message types and topics such as Alerts/Requests and Questions about symptoms and treatment plans are particularly important to patients. These findings demonstrate that both patients and family members utilize the secure messaging function to engage in the care process by posing questions, making requests, and alerting staff to problems. As this technology is implemented in additional facilities, future work should examine how use of secure messaging may be influenced by factors including patients' demographics, reasons for hospitalization, and length of stay. PMID- 30517970 TI - Impact of Electronic Physician Order-Set on Antibiotic Ordering Time in Septic Patients in the Emergency Department. AB - BACKGROUND: Sepsis is a serious medical condition that can lead to organ dysfunction and death. Research shows that each hour delay in antibiotic administration increases mortality. The Surviving Sepsis Campaign Bundles created standards to assist in the timely treatment of patients with suspected sepsis to improve outcomes and reduce mortality. OBJECTIVE: This article determines if the use of an electronic physician order-set decreases time to antibiotic ordering for patients with sepsis in the emergency department (ED). METHODS: A retrospective chart review was performed on adult patients who presented to the ED of four community hospitals from May to July 2016. Patients with severe sepsis and/or septic shock were included. Primary outcome was the difference in time to antibiotic ordering in patients whose physicians utilized the order-set versus those whose physicians did not. Secondary outcomes included differences in time to antibiotic administration, time to lactate test, hospital length of stay, and posthospitalization disposition. The institution's Quality Improvement Committee approved the project. RESULTS: Forty-five of 123 patients (36.6%) with sepsis had physicians who used the order-set. Order-set utilization reduced the mean time to ordering antibiotics by 20 minutes (99 minutes, 95% confidence interval [CI]: 69-128 vs. 119 minutes, 95% CI: 91-147), but this finding was not statistically significant. Mean time to antibiotic administration (145 minutes, 95% CI: 108-181 vs. 182 minutes, 95% CI: 125-239) and median time to lactate tests (12 minutes, 95% CI: 0-20 vs. 19 minutes, 95% CI: 8-34), although in the direction of the hypotheses, were not significantly different. CONCLUSION: Utilization of the order-set was associated with a potentially clinically significant, but not statistically significant, reduced time to antibiotic ordering in patients with sepsis. Electronic order-sets are a promising tool to assist hospitals with meeting the Centers for Medicare and Medicaid Services core measure. PMID- 30517971 TI - Autoimmune Thyroid Diseases. PMID- 30517972 TI - Death, TIR, and RHIM: Self-assembling domains involved in innate immunity and cell-death signaling. AB - The innate immune system consists of pattern recognition receptors (PRRs) that detect pathogen- and endogenous danger-associated molecular patterns (PAMPs and DAMPs), initiating signaling pathways that lead to the induction of cytokine expression, processing of pro-inflammatory cytokines, and induction of cell-death responses. An emerging concept in these pathways and associated processes is signaling by cooperative assembly formation (SCAF), which involves formation of higher order oligomeric complexes, and enables rapid and strongly amplified signaling responses to minute amounts of stimulus. Many of these signalosomes assemble through homotypic interactions of members of the death-fold (DF) superfamily, Toll/IL-1 receptor (TIR) domains, or the RIP homotypic interaction motifs (RHIM). We review the current understanding of the structure and function of these domains and their molecular interactions with a particular focus on higher order assemblies. PMID- 30517973 TI - Pharmacokinetics and metabolism of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator, in rats and monkeys. AB - The metabolic profiles and pharmacokinetics of pemafibrate, a novel selective peroxisome proliferator activated receptor-alpha modulator currently launched as an antidyslipidemic drug, were investigated in vitro using hepatocytes from rats, monkeys, and humans and in vivo in rats and monkeys. Hepatocytes from rats, monkeys, and humans all biotransformed pemafibrate to its demethylated form (M1). The bioavailabilities of pemafibrate in Sprague-Dawley rats and cynomolgus monkeys were 15% and 87%, respectively, after a single oral administration of pemafibrate (1 mg/kg). In rat plasma, unmetabolized pemafibrate was the major form, accounting for 29% of the area under the curve (AUC) of total radioactivity. In monkey plasma, in contrast, the major circulating metabolites were M2/3 (dearylated/dicarboxylic acid forms, 15%), M4 (N-dealkylated form, 21%), and M5 (benzylic oxidative form, 9%), but pemafibrate was the notable minor form (3%). These results, in combination with the reported findings in humans, suggest that the metabolite profile of pemafibrate in plasma was different for rats and monkeys, and that monkeys could be a suitable animal model for further pharmacokinetic studies of pemafibrate in humans. PMID- 30517974 TI - Simultaneous quantitation of metformin and dapagliflozin in human plasma by LC MS/MS: Application to a pharmacokinetic study. AB - A single LC-MS/MS assay is developed and validated for simultaneous determination of metformin and dapagliflozin in human plasma using ion-pair solid phase extraction. Chromatographic separation of the analytes and their internal standards was carried out on a reversed-phase ACE 5CN (150 * 4.6 mm, 5 MUm) column using acetonitrile-15 mM ammonium acetate, pH 4.5 (70:30, v/v) as the mobile phase. To achieve higher sensitivity and selectivity for the analytes, mass spectrometric analysis was performed using polarity switching approach. Ion transitions studied using multiple reaction monitoring mode were, m/z 130.1 [M+H]+ /60.1 for metformin and m/z 467.1 [M+CH3 COO]- /329.1 for dapagliflozin in the positive and negative mode, respectively. The linear calibration range of the assay was established from 1.00-2000 ng/mL for metformin and 0.10-200 ng/mL for dapagliflozin to have better assessment of pharmacokinetics of the drugs. The limit of detection (LOD) and limit of quantitation (LOQ) for the analytes were 0.39 and 1.0 ng/mL for metformin and 0.03 and 0.1 ng/mL for dapagliflozin, respectively. There was no interference of plasma matrix obtained from different sources, including haemolysed and lipemic plasma. The method was successfully applied to study the effect of food on the pharmacokinetics of metformin and dapagliflozin in healthy subjects. PMID- 30517975 TI - A randomized clinical trial of cyanoacrylate tissue adhesives in donor site of connective tissue grafts. AB - BACKGROUND: The purpose was to compare patient-centered outcomes, early wound healing and post-operative complications at palatal donor area of subepithelial connective tissue grafts (CTG) between cyanoacrylates tissue adhesives and Polytetrafluoroethylene (PTFE) sutures. METHODS: 36 patients who required harvesting of CTG were enrolled in this randomized clinical trial and assigned to one of two groups. In the "suture" group, wound closure was achieved with standardized continuous interlocking 6-0 PTFE sutures, while in the "cyanoacrylate" group, a high viscosity blend of n-butyl and 2-octyl cyanoacrylate was applied until hemostasis was achieved. The primary outcome was the discomfort (eating, speaking, etc.) from the donor site during the first post operative week; this was self-reported on a visual analogue scale (VAS) questionnaire. Secondary outcomes were the time required for suture placement or cyanoacrylate application, the patient self-reported pain on the first day, and the first week after surgery, the analgesic-intake and the modified early-wound healing index (MEHI). RESULTS: The median value of discomfort was 1.49 in the "suture" group and 1.86 in the "cyanoacrylate" (p = 0.56). The mean time required for suture placement was 7.31 minutes and for cyanoacrylate application 2.16 minutes (p < 0.0001). No statistically significant differences were found between the two methods in reported pain level, analgesic intake, and MEHI. CONCLUSION: Cyanoacrylate performs similarly to sutures and can be used for wound closure of the donor site of CTG. The application was about 5 minutes faster than conventional suture placement, reducing the total time of the surgical procedure. This article is protected by copyright. All rights reserved. PMID- 30517976 TI - The chemokine receptor CXCR2 contributes to murine adipocyte development. AB - Chemokines are members of a large family of chemotactic cytokines that signal through their receptors to mediate leukocyte recruitment during inflammation and homeostasis. The chemokine receptor CXCR2 has largely been associated with neutrophil recruitment. However, there is emerging evidence of roles for chemokines and their receptors in processes other than leukocyte migration. We have previously demonstrated that CXCR2 knockout (KO) mice have thinner skin compared to wild-type mice. Herein we demonstrate that this is due to a thinner subcutaneous adipose layer, as a result of fewer and smaller individual adipocytes. We observe a similar phenotype in other fat depots and present data that suggests this may be due to reduced expression of adipogenesis related genes associated with adipocyte specific CXCR2 signaling. Interestingly, this phenotype is evident in female, but not male, CXCR2 KO mice. These findings expand our understanding of nonleukocyte related chemokine receptor functions and help to explain some previously observed adipose-related phenotypes in CXCR2 KO mice. PMID- 30517977 TI - Hospital dental hygienist intervention improves activities of daily living, home discharge and mortality in post-acute rehabilitation. AB - AIM: To examine the effects of oral management provided by dental hygienists (DH) on patient outcomes in post-acute rehabilitation. METHODS: We carried out a retrospective cohort study with 1056 patients newly admitted to a post rehabilitation hospital in Japan. DH care was defined as two or more consecutive instances of oral management provided by a ward DH during hospitalization. The primary outcome was the motor domain of Functional Independence Measure score at discharge. Other outcomes included the rate of home discharge; length of stay, all-cause in-hospital mortality, and oral, swallowing and nutritional status at discharge. Propensity score matching was carried out to control and adjust for patients' backgrounds to compare outcomes between patients who did or did not receive DH care. RESULTS: Of 1056 patients enrolled (mean age 71 years; 52.0% women; 73.1% with oral problems), 415 (39.3%) received DH care. Multivariate analyses using pair-matched patients showed that DH care was significantly associated with higher motor domain of Functional Independence Measure score at discharge (beta = 0.281, P = 0.041), shorter length of stay (beta = 0.446, P = 0.044), higher rate of home discharge (odds ratio 1.202, 95% confidence interval 1.026-1.491, P = 0.037) and lower mortality (hazard ratio 0.818, 95% confidence interval 0.738-0.952, P = 0.037) after adjusting for potential covariates. CONCLUSIONS: DH oral management improves patient outcomes, including activities of daily living, home discharge and in-hospital mortality in post-acute rehabilitation. Early detection of oral problems, early oral treatment by dental professionals, and cooperation between medical and dental professionals should be implemented. Geriatr Gerontol Int 2018; **: **-**. PMID- 30517978 TI - Glucose homeostasis in statin users - the LIFESTAT study. AB - Background Statins are widely used to lower cholesterol concentrations in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) and of type 2 diabetes. However, the underlying mechanisms remain disputed. Methods We investigated whether statin induced myalgia is coupled to impaired glucose homeostasis using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT) and the hyperinsulinemic euglycemic clamp. We performed a cross-sectional study of statin users without CVD (primary prevention) stratified into a statin myalgic (M; n=25) and a non-myalgic (NM; n=39) group as well as a control group (C; n=20) consisting of non-statin users. Results A reduction in the insulin secretion rate during the OGTT was observed in the myalgic group compared to the non-myalgic group (AUC ISROGTT , C: 1032 (683 - 1500); M: 922 (678 - 1091); NM: 1089 (933 - 1391) pmol.L-1 .min (median with 25-75% percentiles) but no other measurements indicated impaired beta-cell function. We found no other differences between the three groups for other measurements in the OGTT, IVGTT and euglycemic clamp. Muscle protein content of GLUT4 and hexokinase II was similar between the three groups. Conclusions We conclude that statin users in primary prevention experiencing myalgia do not have impaired glucose homeostasis compared to other statin users or non-users. We consider this an important aspect in the dialog between physician and patient regarding statin treatment and adverse effects. PMID- 30517979 TI - SOX11 regulates apoptosis and cell cycle in hepatocellular carcinoma via Wnt/beta catenin signaling pathway. AB - Hepatocellular carcinoma (HCC) is the most common type of liver cancer with high mortality. Identifying key molecules involved in the regulation of HCC development is of great clinical significance. SOX11 is a transcription factor belonging to group C of Sry-related HMG box family whose abnormal expression is frequently seen in many kinds of human cancers. Here, we reported that the expression of SOX11 was decreased in human HCC tumors than that in matched normal tissues. Overexpression of SOX11 promoted growth inhibition and apoptosis in HCC cell line HuH-7. Mechanistically, SOX11 enhanced the expression of NLK and the phosphorylation of TCF4, thereby blunting the activation of oncogenic Wnt/beta catenin signaling pathway in HuH-7 cells. Finally, SOX11 was also found to sensitize HuH-7 cells to chemotherapy drugs cisplatin and 5-fluorouraci. Therefore, our study identifies SOX11 as a potential tumor suppressor in HCC and may hopefully be beneficial for the clinical diagnosis or treatment of HCC. This article is protected by copyright. All rights reserved. PMID- 30517980 TI - The ISFA wishes to acknowledge the following 2018 Corporate Sponsors. PMID- 30517981 TI - Acknowledgment of Reviewers. PMID- 30517982 TI - Upcoming Meetings Therapeutic Apheresis and Dialysis December 2018. PMID- 30517983 TI - Uraemic tumoral calcinosis in a peritoneal dialysis patient. PMID- 30517985 TI - A case of syphilitic aortitis. PMID- 30517984 TI - Improving service delivery for neuromuscular diseases: a survey of consumers at a tertiary Australian hospital. AB - Patients with neuromuscular diseases benefit from coordinated multidisciplinary care to achieve best outcomes. The integration of multi-specialty healthcare delivered in a single clinic can be challenging for service providers due to cost and resource limitation. Our cross-sectional survey of 53 adult patients with neuromuscular disease across Queensland revealed only 27% support the introduction of an integrated multidisciplinary clinic. The most cited reason for opposition to a multidisciplinary clinic was a perceived loss of contact with one's usual doctor. Modifying service delivery in neuromuscular disease is a complex undertaking and will need input from numerous stakeholders. PMID- 30517987 TI - Fosfomycin: what was old is new again. PMID- 30517986 TI - Cluster of invasive Mycobacteria chimaera infections following cardiac surgery demonstrating novel clinical features and risks of aortic valve replacement. AB - There is a global outbreak of infections due to Mycobacterium chimaera associated with cardiac surgery. The most serious infections involve prosthetic material implantation, and all have followed surgical procedures involving cardiopulmonary bypass. We describe a cluster of four cases following cardiac surgery at a tertiary referral centre in Sydney, Australia. We report novel clinical findings, including haemolysis and kidney rupture possibly related to immune reconstitution inflammatory syndrome. The positive effect of corticosteroids on haemodynamic function in two cases and the failure of currently recommended antimicrobial therapy to sterilise prosthetic valve material in the absence of surgery despite months of treatment are also critically examined. Positron emission tomography was positive in two cases despite normal transoesophageal echocardiograms. The proportion of cases with M. chimaera infection after aortic valve replacement (4/890, 0.45%; 95% confidence interval 0.18-1.15%) was significantly higher than after all other cardiothoracic surgical procedures (0/2433, 0%; 95% confidence interval 0-0.16%). PMID- 30517988 TI - Changing procedures for resolving medical disputes in China. PMID- 30517989 TI - Immune checkpoint inhibitor-induced lymphocytic fasciitis. PMID- 30517990 TI - Permanent peritoneal ports for the management of recurrent malignant ascites: a retrospective review of safety and efficacy. AB - Large volume paracentesis is effective in relieving the symptoms of malignant ascites, but frequent procedures are often required. Permanent peritoneal ports are an alternative to repeated procedures. We describe our experience with the use of peritoneal ports in patients at Middlemore Hospital (Auckland, New Zealand) who had a port inserted for the drainage of malignant ascites. Twenty eight ports were inserted in 26 patients and accessed a total of 257 times with acceptably low rates of complications including cellulitis, peritonitis and wound dehiscence. PMID- 30517991 TI - Does continuing professional development make good doctors? PMID- 30517992 TI - Erratum. PMID- 30517993 TI - Managing patients with severe asthma in Australia: Current challenges with the existing models of care. AB - Severe asthma leads to debilitating symptoms for patients and excessive socioeconomic burden for the community. Comprehensive models of care are required to address complex issues, risk factors and comorbidities in patients with severe asthma, and to identify patients most appropriate for specialised treatments. Dedicated severe asthma services improve asthma control, reduce asthma exacerbations and hospital admissions, and improve quality of life. Currently, diverse models of care exist for managing severe asthma across Australia. Most referrals to severe asthma services are from respiratory physicians seeking a second opinion or from primary care for poorly controlled asthma. Despite benefits of specialised severe asthma services, many patients are not referred and resources are limited, often resulting in long waiting times. Patient referral is often unstructured and there are considerable variations in the management of severe asthma with limited access to other health care professionals such as speech pathologists and dieticians, and restricted scope to optimise patient work-up before referral. Ongoing communication between the specialist and referring clinician is essential for continuity of care but is often lacking. Referral pathways can be optimised by developing referral criteria and guidelines to triage patients with severe asthma and to improve resource efficiency. Additional education and tools for assessing and managing severe asthma are needed, and mechanisms should be developed for involving primary care in the management of stabilised patients. Strategies to increase patient access to multidisciplinary services are recommended. PMID- 30517994 TI - Gastrografin: a diagnostic and therapeutic agent. PMID- 30517995 TI - Retrospective audit of neutropenic fever after chemotherapy: how many patients could benefit from oral antibiotic management? AB - Guidelines suggest that carefully selected patients with neutropenic fever (NF) may be suitable for early discharge on oral antibiotics. Despite these recommendations, many centres manage NF with intravenous antibiotic protocols and inpatient care. We have conducted a retrospective audit of patients with NF, and found that 12 of 40 (30%) patients were eligible for early discharge on oral antibiotics and ambulatory care. Further studies into the barriers to ambulatory management in NF are warranted. PMID- 30517996 TI - Hypersomnia as an isolated symptom of neuromyelitis optica. PMID- 30517997 TI - Lumbar spine fusion: what is the evidence? AB - Lumbar spine fusion is a common procedure associated with a high cost burden and risk of serious complications. We aimed to summarise systematic reviews on the effectiveness of lumbar spine fusion for most diagnoses. We found no high-quality systematic reviews and the risk of bias of the randomised controlled trials in the reviews was generally high. The available evidence does not support a benefit from spine fusion compared to non-operative alternatives for back pain associated with degeneration. The available evidence does not support a clinical benefit from spine fusion compared to non-operative treatment or stabilisation without fusion for thoracolumbar burst fractures. Benefits of spine fusion compared to non-operative treatment for isthmic spondylolisthesis are unclear (one trial at high risk of bias). Surgical intervention for metastatic carcinoma of the spine associated with spinal cord compromise improves mobility and neurological outcome (based on a single trial). Better evidence is required to determine more accurately the effectiveness of spine fusion surgery for all indications. Patients contemplating spinal fusion should be fully informed about the evidence base for their particular problem, including the relative potential benefits and harms of fusion compared with non-operative treatments. PMID- 30517998 TI - Safety of pembrolizumab while commencing treatment for hepatitis C with Harvoni (ledipasvir and sofosbuvir). PMID- 30517999 TI - High diabetes prevalence and insulin medication errors in hospital patients. AB - We conducted three single-day point type 2 diabetes prevalence surveys of all inpatient clinical records in November 2013, 2014 and 2016. The prevalence of diabetes was 19.7-25.3%. The majority (63.4-76%) had type 2 diabetes. Twenty-one percent (n = 21) in 2013, 12% (n = 9) in 2014 and 22.6% (n = 21) in 2016 were diagnosed with diabetes during hospital admission; 41.8% (n = 41) in 2013, 46.7% (n = 35) in 2014 and 51.6% (n = 48) in 2016 required insulin. The high prevalence of diabetes among inpatients mandates active detection and specialist management of diabetes during the admission. PMID- 30518000 TI - Lambert-Eaton myasthenic syndrome developing post-diagnosis of small-cell lung cancer. PMID- 30518001 TI - [Curbing bacterial resistance, pediatricians in action]. PMID- 30518002 TI - [Abridged translation of recommendations of ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition (2016)]. PMID- 30518003 TI - [Investigation on the rational use of antibacterial agents by Chinese pediatricians in 2016]. AB - Objective: To obtain baseline data of pediatricians' clinical use of antibacterial agents in children in China, and provide evidence for the follow-up of guidelines for the diagnosis and treatment of children's clinical medications and the development of rational drug management measures and norms. Methods: A multi-center cross-sectional study was designed to conduct a network electronic questionnaire survey of doctors with child prescription rights in hospitals of all provinces, municipalities and autonomous regions across the country through cluster sampling to understand the current status of antibacterial drugs use in 2016. Results: The survey information of 3 494 pediatricians in tertiary hospitals was finally included. (1) Ranking of the importance of children's medication focus: 54.5% of doctors ranked first the "safety" and 43.5% ranked second the "efficacy" . (2) The most urgent antibacterial agents for children are reported as macrolides (11.9%), third-generation cephalosporins (4.8%), penicillins (4.2%), sulfonamides (2.5%), and carbapenems (2.4%). (3) The top five drugs that are urgently needed to obtain children's indications are: macrolides (26.4%), quinolones (19.9%), aminoglycosides (10.4%), and other antibacterials (9.0%) and the 3rd generation cephalosporins (5.1%). (4) For children with bacterial upper respiratory tract infections, antibacterial drugs should be used in the order of penicillins, second-generation cephalosporins, third-generation cephalosporins, azithromycin or erythromycin, medicamycin or unscented erythromycin or ester erythromycin. (5) The most important basis for empirical use of antibacterials, 42.0% of doctors chose "clinical signs and symptoms", followed by "imaging results" (41.0%). (6) 87.0% of the doctors chose" to read the drug instructions manual before using the drug" as the main way to understand the drug; for the adverse reactions of the antibacterial drugs, the top three rankings of the surveyed doctors were "allergic reactions" (93.3%). "hepatic/kidney functional side effects" (91.1%) and "myelosuppression" (48.2%). (7) The three main problems of children's drug risk selected by the surveyed doctors are "lack of indications for children's medication" (85.5%), "abuse of antimicrobials" (71.2%) and"formulations and specifications for lack of children's drugs". (69.2%). (8) The key link for children's rational drug use, the choice of the doctors to investigate is "clarifying and improving the indications for children's medication" (89.0%), "strengthening the rational use of drugs and clinical guidelines for children" (66.2%) and "developing and producing pharmaceutical dosage form for children and its specifications" (62.6%). Conclusions: Pediatricians are generally reasonable in the basic concepts and knowledge, attitudes and practices of rational use of antibiotics: they can put the safety of medications first, pay attention to reading the instructions before using drugs, and pay attention to the adverse reactions of children. For the drugs that result in adverse reactions in children, it is urgent to understand their indications. Pediatricians use clinical symptoms, signs and imaging findings as an empirical basis for the selection of drugs for bacterial upper respiratory tract infections and antimicrobial agents. The investigation found that macrolides, third-generation cephalosporins, penicillins and other drugs are the most urgent antibacterial drugs in pediatrics, and found that a considerable number of antibacterials lack the indications for children, lack of dosage forms and specifications for children, presence of abuse, etc. The problem is that there are hidden dangers in the use of antibiotics in children. The survey concluded that for pediatricians, the basic concepts and knowledge, attitudes and practices of the rational use of antimicrobials continue to be strengthened. It is necessary to clarify and improve the indications for children's medications, strengthen the training of rational medications and clinical guidelines, and vigorously develop and produce children's medicine dosage forms and their specifications for existing antibacterial drugs. All these are the key links for children's rational use of antibacterials. PMID- 30518004 TI - [Antimicrobial resistance changes of carbapenem-resistant Enterobacteriaceae strains isolated from children]. AB - Objective: To investigate the prevalence and resistance changes of carbapenem resistant Enterobacteriaceae (CRE) strains isolated from children patients of Chinese Bacterial Resistance Surveillance Network (CHINET) from 2005 to 2017. Methods: Antimicrobial susceptibility testing was carried out by disk diffusion method (KB method) and automated systems. Results were analyzed according to the Clinical and Laboratory Standards Institute (CLSI) 2017 edition standards. Results: Among the 4 481 CRE clinical strains, the overall prevalence of CRE in children was 6.4%, including 8.8% in neonatal period, 7.3% in infancy, 3.8% in early childhood, 4.0% in preschool, 4.7% at school age and 7.4% of puberty. The CRE prevalence of citrobacter spp. remained stable in 2005-2017, whereas other bacteria showed an upward trend, which was higher than that of the adult group (P<0.01). Among the 4 481 CRE strains, there were 2 905 strains of Klebsiella spp. (64.8%), 813 strains of Escherichia coli (18.1%), 549 strains of Enterobacter spp.(12.3%), and 65 strains of Citrobacter spp.(1.5%). Among the 4 481 CRE strains, 20.7%, 13.3%, and 11.8% were from the intensive care unit (ICU), neonatal department and internal medicine wards, respectively. Specimens were distributed as respiratory (42.8%), urine (26.3%), and blood (14.9%). The results of antimicrobial susceptibility testing exhibited that the CRE strains were highly resistant to most commonly used antimicrobial agents in clinical practice, such as imipenem, meropenem and ertapenem, as well as penicillins and cephalosporins, etc. Conclusion: The prevalence of CRE strains in children is increasing year by year, and their antimicrobial resistance to common antibacterial agents in clinical practice is extremely serious, to which serious attention needs to be paid. According to the results of antimicrobial susceptibility testings, the antibacterial agents should be rationally selected to effectively control the spread of CRE. PMID- 30518006 TI - [Survey on gross motor development of infants in nine cities of China in 2015]. AB - Objective: To analyze the current situation of gross motor development of infants in nine cities of China and their relationship with physical growth. Methods: Healthy full-term infants aged 1-24 months were investigated by cross-sectional survey, which was carried out in nine cities (Beijing, Harbin, Xi'an in northern, Shanghai, Nanjing, Wuhan in central, and Guangzhou, Fuzhou, Kunming in southern regions of China) from June to October in 2015. Subjects were grouped into 12 age groups (1-<2, 2-<3, 3-<4, 4-<5, 5-<6, 6-<8, 8-<10, 10-<12, 12-<15, 15-<18, 18 <21, 21-<24 months). Gross motor development of infants was examined by fieldworkers and the information on parental education, family income and birth status were obtained by questionnaire. Weight, length and head circumference was measured by fieldworkers according to standard methods in the fields and their Z scores were calculated by using WHO growth standard. Z scores of weight (WZ), length (LZ) and head circumference (HCZ) <-2 s was considered as lower group, -2 s-<-1 s as medium-lower group, -1 s-1 s as medium group, 1 s-<2 s as medium higher group and >=2 s as higher group. The age of gross motor development was calculated by Probit regression analysis and chi(2) test was used for comparison of categorical data. Results: (1) The number of infants whose gross motor development was examined were 88 968 in the nine cities. The proportion of achievement of motor development became larger with the chronological age, i.e. it was 11.1% (800/7 236) at 5-<6 months, 65.2% (4 921/7 545) at 6-<8 months and 98.5% (7 417/7 531) at 8-<10 months for sitting alone without support. There was no gender difference in the proportion of achievement of sitting alone without support, hand-knee crawl, stand alone and walk alone (chi(2)=2.873, 0.275, 0.250, 0.576, all P>0.05). (2) The median age of achievement of sitting alone without support, hand-knee crawl, stand alone, walk alone was respectively 5.9, 7.8, 10.8, 13.0 months, and their ranges from 1(st) to 99(th) percentile were respectively 4.2-8.3 months, 4.9-12.6 months, 7.6-15.4 months, 9.8-17.4 months. The gender difference of median age of gross motor development was 0.0-0.1 months and their regional difference was 0.0-0.7 months. (3) In the lower weight group, their median age of sitting alone without support and walk alone were 0.2-0.6 months later than the medium weight group, while their median age of hand-knee crawl and stand alone were similar to those of the medium weight group. In higher weight group, the median age of sitting alone without support and stand alone were similar to that of the medium weight group, while their median age of hand knee crawl was 0.3 later months and their median age of walk alone was 0.3 months earlier than that of the medium weight group. There was no significant relationship between length and the age of sitting alone or standing alone (the difference was 0.0-0.2 months in each group). The median age of hand-knee crawl and walk alone was 0.4-0.7 months later in lower length group than in other length groups. The median age of gross motor development was similar among different head circumference groups (0.0-0.2 months). The relationship between weight/length and motor development was similar to that between weight and motor development. Conclusions: There were no gender difference and slightly regional difference in the age of achievement of gross motor skills. The percentile age of gross motor skills helps to understand the population variation in healthy infants. The gross motor development is related with weight, length and body proportion. PMID- 30518005 TI - [A multicenter clinical study on 1 138 cases of invasive pneumococcal disease in children from 2012 to 2017]. AB - Objective: To explore the clinical features, the serotype distribution and drug resistance of the isolates in patient with invasive pneumococcal disease (IPD). Methods: By retrieving the laboratory information system in 18 children's hospitals from 2012 to 2017, the children with IPD were enrolled. Streptococcus pneumoniae (Spn) must be isolated from the sterile sites (blood, cerebrospinal fluid, hydrothorax and joint effusion etc.). The clinical characteristics, serotype, drug resistance, treatment and prognosis were reviewed and analyzed. According to the telephone follow up results, the patients were divided into death group and recovered group. The index as an independent risk factor of mortality was demonstrated by multivariate logistic regression analysis. Results: There were 1 138 children with IPD, including 684 male and 454 female. The proportion of male to female was 1.5?1. The age ranged from one day to 16 years. The median age was 1 year 3 month. The majority was under 5 years of age (89.3%, n= 1 016), especially under 2 years of age (61.9%, n=704). In all cases, 88.2% (n=1 004) were community acquired infection. The infections included meningitis (n=446, 39.2%), pneumonia with bacteremia (n=339, 29.8%), and bacteremia without focus (n=232, 20.4%). Underlying diseases were found in 242 cases (21.3%). Co infections were determined in 62 cases (5.4%) with mycoplasma, 27 cases (2.4%) with adenovirus and 34 cases with influenza virus (3.0%). The penicillin insensitivity (PNSP) rates in meningitis and non-meningitis isolates were 69.5% (276/397) and 35.9% (221/615), respectively. There were 81 strains serotyped, in which 93.8% (76/81) were covered by 13-valent protein-polysaccharide conjugate vaccine (PCV13). In the 965 patients who were followed up by phone call, 156 cases (16.2%) were confirmed dead. The independent risk factors for the death were under 2 years of age (OR=2.143, 95%CI 1.284-3.577, P=0.004), meningitis (OR=3.066, 95%CI 1.852-5.074, P<0.01), underlying disease (OR=4.801, 95%CI 2.953 7.804, P<0.01), septic shock(OR=3.542, 95%CI 1.829-6.859, P<0.01), disseminated intravascular coagulation (DIC) (OR=4.150, 95%CI 1.468-11.733, P=0.007), multiple organ failure (OR=12.693, 95%CI 6.623-24.325, P<0.01) and complications of central nervous system (OR=1.975, 95%CI 1.144-3.410, P=0.015). Conclusions: Most children with IPD were under 5 years of age, having underlying diseases and acquired the infection in community. The independent risk factors for death were under two years old, meningitis, underlying diseases and multiple organ failure. The problem of drug resistance was severe. The universal immunization of PCV13 would be effective to prevent IPD in Chinese children. PMID- 30518007 TI - [Multicenter investigation of extracorporeal membrane oxygenation application in pediatric intensive care unit in China]. AB - Objective: To survey the conduction and evaluate the effectiveness of extracorporeal membrane oxygenation (ECMO) therapy in pediatric intensive care unit (PICU) in China mainland. Methods: In a questionnaire-based survey, we retrospectively reviewed the application of ECMO in children's hospital and general hospital in China mainland to summarize and analyze the categories of diseases and prognosis of children treated with ECMO therapy. Results: By December 31, 2017, a total of 23 hospitals using ECMO, including 22 tertiary referral hospitals and 1 secondary hospital, among which 16 were children's hospitals and 7 were general hospitals. Thirty-seven ECMO equipment was available. A total of 518 patients treated with ECMO, within whom 323 (62.4%) successfully weaned from ECMO and 262 (50.6%) survived to discharge. Among 375 pediatric patients, 233 (62.1%) were successfully weaned from ECMO and 186 (49.6%) survived to discharge. Among 143 newborn patients, 90 (62.9%) successfully weaned from ECMO, 76 (53.1%) survived to discharge. ECMO was applied in veno-arterial (VA) mode to 501 (96.7%) patients, veno-venous (VV) mode to 14 (2.7%) patients, and VV-VA conversion mode to 3 (0.6%) patients. Sixty-nine patients required extracorporeal cardiopulmonary resuscitation (ECPR), including 20 newborn patients (29.0%) and 38 pediatric patients (71.0%), who were all with cardiovascular disease. Neonatal respiratory distress syndrome (26/61), persistent pulmonary hypertension of the newborn (PPHN) (12/61), and meconium aspiration syndrome (MAS) (11/61) are the most common pulmonary diseases in newborn patients; among whom, infants with PPHN had highest survival rate (10/12), followed by MAS (9/11). Among newborn patients with cardiovascular diseases, those who admitted were after surgery for congenital cardiac disease were the most common (54/82), while those with septic shock had the highest survival rate (2/3). In pediatric pulmonary diseases, acute respiratory distress syndrome was the most common (42/93), while plastic bronchitis was with the highest survival rate (4/4), followed by viral pneumonia (13/16). Among pediatric cardiovascular diseases, congenital cardiac defect was the most common (124/282), while fulminant myocarditis had the highest survival rate (54/77). Conclusion: The application of ECMO as a rescue therapy for children with severe cardiopulmonary failure has dramatically developed in China mainland. PMID- 30518008 TI - [Application of the five-level pediatric emergency triage system: a single center study]. AB - Objective: To assess the effectiveness in optimizing resources and shortening critical children's waiting time in pediatric emergency department (PED) with five-level pediatric emergency triage system (PETS). Methods: This retrospective study was conducted in the First Affiliated Hospital of Xiamen University after PETS was applied. The data of patients who visited the pediatric emergency department from January 2015 to December 2017 were collected and analyzed, including age, sex, diseases, visiting time, triage rate and destination. Results: A total of 375 985 patients were included, among whom males were 225 308 (59.9%) and females were 150 677 (40.1%), all younger than 14 years of age. The number of critical cases (level I, level II and level III) was increased from 4 719 (3.7%) in 2015, 12 209 (10.2%) in 2016 to 16 188 (12.7%) in 2017. The number of non-critical patients (level V) decreased year by year, as from 98 213 (76.8%) in 2015 to 75 210 (62.6%) in 2016 and 78 857 (61.7%) in 2017. The patients who classified as level I or levelIIaccording to the PETS were seen immediately by physician (n=1855, 0.5%). Overall, 119 738 patients (98.3%) who were classified as level III or level IV could be seen by physician in a timely manner according to triage guidelines, while 2 112 patients (1.7%) could not. The mean waiting time was 9.09 min in level III, 17.7 min in level IV, and 55.76 min in level V patients, respectively. The critical cases admitted to the intensive care units were 175 (36.2%) in 2015, 350 (62.8%) in 2016 and 374 (66.2%) in 2017. The etiologies were respiratory diseases (73.3%), gastrointestinal diseases (15.8%) and infectious diseases (3.1%). Conclusion: The application of PETS could optimize emergency resources and shorten the waiting time of critically ill children. PMID- 30518009 TI - [Effect of miR-21 on the expression of interleukin-10 in B cell of patients with Henoch-Schonlein purpura]. AB - Objective: To investigate the effect of microRNAs (miR)-21 on the expression of interleukin (IL)-10 in B cell of patients with Henoch-Schonlein purpura (HSP). Methods: From March 2016 to January 2017, twenty-four children with HSP hospitalized in rheumatology and immunology department of Shenzhen Children's Hospital were enrolled into the study, including 12 males and 12 females. Patients were divided into purpura nephritis group (HSPN, 14 cases) and non nephritis group (NHSPN, 10 cases). The age-matched 34 healthy children were included as the control group for prospective cohort study. The expression levels of IL-10 in peripheral blood B cells (CD19(+)), transitional B cells (CD19(+) CD24(hi)CD38(hi)) and naive B cells (CD19(+)CD24(int)CD38(int)) from patients with HSP and healthy children were detected by flow cytometry (FCM). Expression of microRNAs related to IL-10 in B cells were quantitated by real-time PCR, including miR-21-5p, miR-106a-5p, miR-98-3p, miR-142-3p, miR-142-5p, miR-98-5p, miR-155-5p and miR-let7b-5p. Agomir negative control-FAM and agomir-21-5p-FAM were transfected into B cells from patients with HSP. The uptake of miRNA by B cells was observed by laser scanning confocal microscope and FCM, and the expression of IL-10 was detected by FCM after transfection. For quantitative data of normal distribution, t test was used for two samples comparison and multiple comparisons among three groups were conducted by ANOVA. Spearman test was used for correlation analysis. Results: (1) The CD19(+) B cells and its two populations at different differentiation stages all could express IL-10. The expression levels of IL-10 in three B cell populations in patients were significantly lower than those in healthy controls (1.4+/-0.2 vs. 2.4+/-0.3, t=3.501, P<0.01; 1.2+/-0.2 vs. 2.2+/-0.3, t=2.688, P<0.05; 1.6+/-0.3 vs. 2.7+/ 0.4, t=2.498, P<0.05). Compared with healthy control and NHSPN groups, the expression of IL-10 in CD19(+) B cells from patients within HSPN group was the lowest, and the difference was statistically significant (1.1+/-0.2 vs. 2.4+/ 0.3, 1.8+/-0.3, t=4.006, 2.362, P<0.001, P<0.05). (2) The expression of miR-21-5p in B cell in patients with HSPN was lower than that in healthy control group (1.2+/-0.9 vs. 3.5+/-2.8, t=2.962, P<0.01). There was no significant change in the other microRNAs. (3) The expression of IL-10 was positively correlated with the expression of miR-21-5p in the B cells of patients with HSP (r=0.778, P<0.001). (4) The expression of IL-10 in B cells of miR-21-5p group was significantly higher than that in negative control group (2.7+/-0.2 vs. 1.6+/ 0.3, t=3.091, P<0.05). Conclusion: The insufficient expression of miR-21-5p in peripheral blood B cells of patients with HSP is one of the reasons for the reduction of IL-10 expression in B cells. PMID- 30518011 TI - [Mycoplasma pneumoniae pneumonia complicated with cardiac thrombosis in children: report of 2 cases]. PMID- 30518010 TI - [Correlation between human bocavirus 2 infection in children and acute diarrhea in Beijing]. AB - Objective: To investigate the relationship between human bocavirus 2 (HBoV2) infection and acute diarrhea in children younger than 5 years of age in a case control study. Methods: This was a prospective case-control study. During May 2016 to December 2016, fecal specimens were collected from children <=5 years of age with acute diarrhea who visited the Affiliated Children's Hospital of Capital Institute of Pediatrics (case group), or from children <=5 years of age without diarrhea from Longtan Community Medical Service Center, Beijing (control group). The case group (n=240) and the control group (n=240) were divided into 8 age subgroups: <=1 month old, >1-3 months old, >3-6 months old, >6-12 months old,>1-2 years old,>2-3 years old,>3-4 years old and >4-5 years old, and there were 30 cases in each age subgroup. The specimens were tested for 7 types of diarrhea associated viruses, especially for HBoV2 by real-time PCR method. The HBoV2 viral load was predicted according to the cycle threshold (Ct). Finally, t-test was used to compare the differences between groups. Results: In the case group (n=240), the positive rate of norovirus was 16.7% (40 cases); rotavirus, 10.8% (26 cases); HBoV2, 7.5% (18 cases); adenovirus, 7.1% (17 cases); astrovirus, 6.3% (15 cases); parachovirus, 3.8% (9 cases); and Aich virus, 0.4% (1 case). The positive rates of HBoV2 in case group (7.5%, 18 cases) and control group (5.0%, 12 cases) showed no significant difference (chi(2)=1.280, P=0.258), as well as in different age groups (all P>0.05) . However, the mean viral load of the HBoV2 in the case group (1*10(9)copies/L with cycle threshold (Ct) 25.8) was higher than that of control group (1*10(5)copies/L with Ct 33.8), showing a significant difference (t=0.597, P=0.000). Conclusions: Norovirus and rotavirus are still the important viral pathogens in children with acute diarrhea. A higher load of HBoV2 may indicate a higher risk of acute diarrhea in children <=5 years of age in Beijing. PMID- 30518012 TI - [Pediatric pancreoblastoma with Cushing syndrome]. PMID- 30518013 TI - [As a small molecular hormone: the role of Elabela in the cardiovascular development]. PMID- 30518014 TI - [Research advance in the role of microbiota in gut-brain-axis and childhood disease]. PMID- 30518016 TI - Lichen-associated bacterium, a novel bioresource of polyhydroxyalkanoate (PHA) production and simultaneous degradation of naphthalene and anthracene. AB - Lichens are generally known as self-sufficient symbiotic life-form between fungus and algae/cyanobacteria, also provide shelter for a wide range of beneficial bacteria. Besides, bacterial derived biodegradable polyhydroxyalkanoate (PHA) is currently grabbing the attention of many researchers as a promising alternative of non-degradable plastics. This study was conducted to develop a new method of PHA production using unexplored lichen-associated bacteria, which can simultaneously degrade two ubiquitous industrial toxins, anthracene and naphthalene. Here, 49 lichen-associated bacteria were isolated and tested for PHA synthesis. During the GC-MS analysis, a potential strain of EL19 was found to be 3-hydroxyhexanoate (3-HHx) accumulator and identified as Pseudomonas sp. based on the 16S rRNA sequencing. GC analysis revealed that EL19 was capable of accumulating 30.62% and 19.63% of 3-HHx from naphthalene and anthracene, respectively, resulting in significant degradation of 98% and 96% of naphthalene and anthracene, respectively within seven days. Moreover, the highly expressed phaC gene verified the genetic basis of PHAmcl production under nitrogen starvation condition. Thus, this study strongly supports the hypothesis that lichen-associated bacteria can detoxify naphthalene and anthracene, store energy for extreme conditions, and probably help the associated lichen to live in extreme condition. So far, this is the first investigation of lichen-associated bacteria that might utilize harmful toxins as the feasible supplements and convert anthracene and naphthalene into eco-friendly 3-HHx. Implementation of the developed method would reduce the production cost of PHAmcl while removing harmful waste products. PMID- 30518015 TI - Characteristics of bacterial communities in biological filters of full-scale drinking water treatment plants. AB - The taxomonic and functional characteristics of bacterial communities in the pre chlorinated rapid filters and ozonated biological activated carbon (BAC) filters were compared using Illumina MiSeq sequencing of 16S rRNA gene and community level physiological profiling (CLPP) based on sole carbon utilization patterns. Both the rapid filters and BAC filters were dominated by Rhizobiales within alpha proteobacteria, but other abundant orders and genera were significantly different in both types of filter. Firmicutes were abundant only in the intermediate chlorinated rapid filter, while Acidobacteria were abundant only in the BAC filters. Bacterial communities in the rapid filter showed high utilization of carbohydrates, while those in the BAC filters showed high utilization of polymers and carboxylic acids. These different characteristics of the bacterial communities could be related to the different substrates in the influents, filling materials, and residual disinfectants. Chlorination and ozonation inactivated the existing bacteria in the influent and formed different bacterial communities, which could be resistant to the oxidants and effectively utilize different substrates produced by the oxidant, including Phreatobacter in the rapid filters and Hyphomicrobium in the BAC filters. Bradyrhizobium and Leptothrix which could utilize compounds adsorbed on the GAC were abundant in the BAC filters. Ozonation increased taxonomic diversity but decreased functional diversity of the bacterial communities in the BAC filters. This study provides some new insights into the effects of oxidation processes and filling materials on the bacterial community structure in the biological filters of drinking water treatment plants. PMID- 30518017 TI - The antimicrobial peptide CopA3 inhibits Clostridium difficile toxin A-induced viability loss and apoptosis in neural cells. AB - Numerous studies have reported that enteric neurons involved in controlling neurotransmitter secretion and motility in the gut critically contribute to the progression of gut inflammation. Clostridium difficile toxins, which cause severe colonic inflammation, are also known to affect enteric neurons. Our previous study showed that C. difficile toxin A directly induces neural cell toxicities, such as viability loss and apoptosis. In the current study, we attempted to identify a potent inhibitor of toxin A-induced neural cell toxicity that may aid in managing toxin A-induced gut inflammation. In our recent study, we found that the Korea dung beetle-derived antimicrobial peptide CopA3 completely blocked neural cell apoptosis caused by okadaic acid or 6-OHDA. Here, we examined whether the antimicrobial peptide CopA3 inhibited toxin A-induced neural cell damage. In neuroblastoma SH-SY5Y cells, CopA3 treatment protected against both apoptosis and viability loss caused by toxin A. CopA3 also completely inhibited activation of the pro-apoptotic factor, caspase-3. Additionally, CopA3 rescued toxin A-induced downregulation of neural cell proliferation. However, CopA3 had no effect on signaling through ROS/p38 MAPK/p27kip1, suggesting that CopA3 inhibits toxin A induced neural cell toxicity independent of this well-characterized toxin A pathway. Our data further suggest that ability of CopA3 to rescue toxin A-induced neural cell damage may also ameliorate the gut inflammation caused by toxin A. PMID- 30518018 TI - Dexamethasone Facilitates NF-kappaB Signal Pathway in TNF-alpha stimulated Rotator Cuff Tenocytes. AB - Corticosteroids are commonly used for pain control in rotator cuff tear. Deregulated NF-kappaB activation is a hallmark of chronic inflammatory diseases and has been responsible for the pathogenesis of rotator cuff tear. The purpose of this study was to examine the exact effect of DEXA on NF-kappaB signaling in rotator cuff tear. We measured NF-kappaB expression in four groups: control, TNF alpha-treated, DEXA-treated, and combined treatment with TNF-alpha and DEXA. Tenocytes were isolated from patients with rotator cuff tears and pre-incubated with TNF-alpha (10 ng/mL), DEXA (1 MUM), or both of them for 10 min, 1 h, and 2 h. Expression of p65, p50, and p52 in the nuclei and cytosol was analyzed by western blotting and immunofluorescence imaging using confocal microscopy. We also evaluated nucleus/cytosol (N/C) ratios of p65, p50, and p52. In our study, the combined treatment with DEXA and TNF-alpha showed increased N/C ratios of p65, p50, and p52 compared with those in the TNF-alpha group at all time points. Additionally, in the DEXA group, N/C ratios of p65, p50, and p52 gradually increased from 10 min to 2 h. In conclusion, DEXA promoted the nuclear localization of p65, p50, and p52, but was not effective in inhibiting the inflammatory response of TNF-alpha-stimulated rotator cuff tear. PMID- 30518019 TI - Simple and Novel Assay of the Host-Guest Complexation of Homocysteine with Cucurbit[7]uril. AB - This paper introduces three ways to determine host-guest complexation of cucurbit[7]uril (CB[7]) with homocysteine (Hcy). After preincubating Hcy and cysteine (Cys) with CB[7], Ellman's reagent (DTNB) was used to detect Hcy and Cys. Only Cys reacted with DTNB and Hcy gave a retarded color change. This suggests that the -SH group of Hcy is buried inside CB[7]. Human cystathionine gamma-lyase (hCGL) decreased the level of Hcy degradation after preincubating Hcy and CB[7]. These results suggest that the amount of free Hcy available was decreased by the formation of a Hcy-CB[7] complex. The immunological signal of anti-Hcy monoclonal antibody was decreased significantly by preincubating CB[7] with Hcy. The ELISA results also show that ethanethiol group (-CH2CH2SH) of Hcy, which is an epitope of anti-Hcy monoclonal antibody, was blocked by the cavity in CB[7]. Overall, CB[7] can act as a host by binding selectively with Hcy, but not Cys. The calculated half-complexation formation concentration of CB[7] was 58.2 nmol using Ellman's protocol, 97.9 nmol using hCGL assay and 87.7 nmol using monoclonal antibody. The differing binding abilities of Hcy and Cys towards the CB[7] host may offer a simple and useful method of determination of the Hcy concentration in plasma or serum. PMID- 30518020 TI - Development of an RNA expression platform controlled by viral internal ribosome entry sites. AB - Since 1990, many nucleic acid expression platforms consisting of DNA or RNA have been developed. However, RNA expression platforms have been neglected. Several such platforms capped at the 5' end of RNA by an anti-reverse cap analog have now been developed. However, the capping reaction is a bottleneck in the production of such platforms, with a high cost and low efficiency. Here, we investigated several viral and eukaryotic internal ribosome entry sites (IRESs) to develop an optimal RNA expression platform, because IRES-dependent translation does not require a capping step. RNA expression platforms constructed with IRESs from the 5' untranslated regions of the encephalomyocarditis virus (EMCV) and the intergenic region of the cricket paralysis virus (CrPV) showed sufficient expression efficiency compared with cap-dependent RNA expression platforms. However, eukaryotic IRESs exhibited a lower viral IRES expression efficiency. Interestingly, the addition of a poly(A) sequence to the 5' end of the coxsackievirus B3 (CVB3) IRES (pMA-CVB3) increased the expression level compared with the CVB3 IRES without poly(A) (pCVB3). Therefore, we developed two multiexpression platforms (termed pMA-CVB3-EMCV and pCrPV-EMCV) by combining the IRESs of CVB3, CrPV, and EMCV in a single-RNA backbone. The pMA-CVB3-EMCV-derived RNA platform showed the highest expression level. Moreover, it clearly exhibited expression in mouse muscles in vivo. These RNA expression platforms prepared using viral IRESs will be useful in developing potential RNA-based prophylactic or therapeutic vaccines, because they have better expression efficiency and do not need a capping step. PMID- 30518021 TI - Ecklonia cava Extract Containing Dieckol Suppresses RANKL-induced Osteoclastogenesis via MAP Kinase/NF-kappaB Pathway Inhibition and Heme oxygenase 1 Induction. AB - Ecklonia cava, edible marine brown alga (Laminariaceae), is a rich source of bioactive compounds such as fucoidan and phlorotannins. Ecklonia cava extract (ECE) was prepared using 70% ethanol extraction and ECE contained 67% and 10.6% of total phlorotannins and dieckol, respectively. ECE treatment significantly inhibited receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation of RAW 264.7 cells and pit formation in bone resorption assay (P <0.05). Moreover, it suppressed RANKL-induced NF-kappaB and mitogen activated protein kinase signaling in a dose dependent manner. Downregulated osteoclast-specific gene (tartrate-resistant acid phosphatase, cathepsin K, and matrix metalloproteinase-9) expression and osteoclast proliferative transcriptional factors (nuclear factor of activated T cells-1 and c-fos) confirmed ECE-mediated suppression of osteoclastogenesis. ECE treatment (100 MUg/mL) increased heme oxygenase-1 expression by 2.5-fold and decreased intercellular reactive oxygen species production during osteoclastogenesis. The effective inhibition of RANKL-stimulated osteoclast differentiation and oxidative stress by ECE suggest that ECE has therapeutic potential in alleviating osteoclast-associated disorders. PMID- 30518022 TI - Highly Selective Production of Compound K from Ginsenoside Rd by Hydrolyzing Glucose at C-3 Glycoside Using beta-glucosidase of Bifidobacterium breve ATCC 15700. AB - To investigate a novel beta-glucosidase from Bifidobacterium breve ATCC 15700 (BbBgl) to produce compound K (CK) via ginsenoside F2 by highly selective and efficient hydrolysis of the C-3 glycoside from ginsenoside Rd. BbBgl gene was cloned and expressed in E. coli BL21. The recombinant BbBgl was purified by Ni NTA magnetic beads to obtain an enzyme with specific activity of 37 U/mg protein using pNP-Glc as substrate. The enzyme activity was optimized at pH 5.0, 35 degrees C, 2 or 6 U/ml, and its activity was enhanced by Mn2+ significantly. Under the optimal conditions, the half-life of the BbBgl is 180 h, much longer than the characterized beta-glycosidases, and the Km and Vmax values are 2.7 mM and 39.8 MUmol/mg/min for ginsenoside Rd. Moreover, the enzyme exhibits strong tolerance against high substrate concentration (up to 40 g/L ginsenoside Rd) with a molar biotransformation rate of 96% within 12 h. The good enzymatic properties and gram-scale conversion capacity of BbBgl provide an attractive method for large-scale production rare ginsenoside CK using a single enzyme or a combination of enzymes. PMID- 30518023 TI - Plasma Branched-Chain Amino Acids and Risk of Incident Type 2 Diabetes: Results from the PREVEND Prospective Cohort Study. AB - Plasma branched-chain amino acids (BCAAs) are linked to metabolic disease, but their relevance for prediction of type 2 diabetes development is unclear. We determined the association of plasma BCAAs with type 2 diabetes risk in the prevention of renal and vascular end-stage disease (PREVEND) cohort. The BCAAs were measured by means of nuclear magnetic resonance spectroscopy. We evaluated the prospective associations of BCAAs with type 2 diabetes in 6244 subjects. The BCAAs were positively associated with HOMA-IR after multivariable adjustment (p < 0.0001). During median follow-up for 7.5 years, 301 cases of type 2 diabetes were ascertained. The Kaplan-Meier plot demonstrated that patients in the highest BCAA quartile presented a higher risk (p log-rank < 0.001). Cox regression analyses revealed a positive association between BCAA and type 2 diabetes; the hazard ratio (HR) for the highest quartile was 6.15 (95% CI: 4.08, 9.24, p < 0.0001). After adjustment for multiple clinical and laboratory variables, the association remained (HR 2.80 (95% CI: 1.72, 4.53), p < 0.0001). C-statistics, Net reclassification improvement, and -2 log likelihood were better after adding BCAAs to the traditional risk model (p = 0.01 to <0.001). In conclusions, high concentrations of BCAAs associate with insulin resistance and with increased risk of type 2 diabetes. This association is independent of multiple risk factors, HOMA-IR and beta cell function. PMID- 30518024 TI - The Progress of Tobacco Control Research in Sub-Saharan Africa in the Past 50 Years: A Systematic Review of the Design and Methods of the Studies. AB - Over one billion of the world's population are smokers, with increasing tobacco use in low- and middle-income countries. However, information about the methodology of studies on tobacco control is limited. We conducted a literature search to examine and evaluate the methodological designs of published tobacco research in Sub-Saharan Africa (SSA) over the past 50 years. The first phase was completed in 2015 using PubMed, Embase, CINAHL, and Cochrane Central Register of Controlled Trials. An additional search was completed in February 2017 using PubMed. Only tobacco/smoking research in SSA countries with human subjects and published in English was selected. Out of 1796 articles, 447 met the inclusion criteria and were from 26 countries, 11 of which had one study each. Over half of the publications were from South Africa and Nigeria. The earliest publication was in 1968 and the highest number of publications was in 2014 (n = 46). The majority of publications used quantitative methods (91.28%) and were cross-sectional (80.98%). The commonest data collection methods were self-administered questionnaires (38.53%), interviews (32.57%), and observation (20.41%). Around half of the studies were among adults and in urban settings. We conclud that SSA remains a "research desert" and needs more investment in tobacco control research and training. PMID- 30518025 TI - Ethnic Differences in Magnesium Intake in U.S. Older Adults: Findings from NHANES 2005-2016. AB - Magnesium plays a crucial role in hundreds of bodily processes relevant to aging, but consumption of dietary magnesium intake has been shown to be inadequate in a large proportion of older adults. Identifying groups at risk of low magnesium intake is important for informing targeted advice. Using data from the National Health and Nutrition Examination Survey (NHANES) 2005-2016, we examined the association between ethnicity (Caucasian/African American/Hispanic/other) and magnesium intake in a large representative sample of U.S. older adults (>=65 y, n = 5682, mean (SD) 72.9 (0.10) y). Analyses adjusted for total energy intake and a range of relevant covariates. Overall, 83.3% of participants were not meeting the recommended level of dietary magnesium intake, ranging from 78.1% of other ethnic groups to 90.6% of African Americans. In the fully adjusted model, magnesium intake was lower among African American older adults (-13.0 mg/d, 95% CI: -18.8 to -7.2), and higher among Hispanics (14.0 mg/d, 95% CI: 7.5 to 20.5) and those from other ethnic groups (17.2, 95% CI: 3.8 to 30.5) compared with Caucasian older adults. These results highlight the need for targeted interventions to increase magnesium intake in U.S. older adults, with a focus on African Americans, in order to reduce the burden of morbidity and ethnic inequalities in health in later life. PMID- 30518026 TI - A Combined Approach of Double Network Hydrogel and Nanocomposites Based on Hyaluronic Acid and Poly(ethylene glycol) Diacrylate Blend. AB - In this study, an innovative polymer blend, based on double network (DN) approach, has been developed by integrating a poly(ethylene glycol) diacrylate (PEGDA) network into a chemically modified hyaluronic acid sodium salt (HAs) hydrogel matrix. Here, the HAs was chemically functionalized with photocrosslinkable moieties by reacting with maleic anhydride (MAA) to obtain a maleated hyaluronic acid (MaHA). Furthermore, nanocomposite DN hydrogels were suitably prepared by physical blending of hydroxyapatite nanoparticles (HAp), obtained by sol-gel synthesis, within the hydrogel. Physico-chemical, thermal, morphological and mechanical analyses were performed. Results showed enhanced mechanical properties and a homogenous microstructure as highlighted by mechanical and morphological investigations. This suggests that nanocomposite DN hydrogels are promising candidates for biomedical applications. PMID- 30518027 TI - A Promising Biocompatible Platform: Lipid-Based and Bio-Inspired Smart Drug Delivery Systems for Cancer Therapy. AB - Designing new drug delivery systems (DDSs) for safer cancer therapy during pre clinical and clinical applications still constitutes a considerable challenge, despite advances made in related fields. Lipid-based drug delivery systems (LBDDSs) have emerged as biocompatible candidates that overcome many biological obstacles. In particular, a combination of the merits of lipid carriers and functional polymers has maximized drug delivery efficiency. Functionalization of LBDDSs enables the accumulation of anti-cancer drugs at target destinations, which means they are more effective at controlled drug release in tumor microenvironments (TMEs). This review highlights the various types of ligands used to achieve tumor-specific delivery and discusses the strategies used to achieve the effective release of drugs in TMEs and not into healthy tissues. Moreover, innovative recent designs of LBDDSs are also described. These smart systems offer great potential for more advanced cancer therapies that address the challenges posed in this research area. PMID- 30518028 TI - Effect of Different Light Spectrum in Helicoverpa armigera Larvae during HearNPV Induced Tree-Top Disease. AB - Lepidopteran larvae upon infection by baculovirus show positive photo-tactic movement during tree-top disease. In light of many insects exploiting specific spectral information for the different behavioral decision, each spectral wavelength of light is an individual parsimonious candidate for such behavior stimulation. Here, we investigated the responses of third instar Helicoverpa armigera larvae infected by Helicoverpa armigera nucleopolyhedrovirus (HearNPV) to white (broad-spectrum), blue (450-490 nm), UVA (320-400 nm), and UVB (290-320 nm) lights for the tree-top disease. Our findings suggest that tree-top phenomenon is induced only when the light is applied from above. Blue, white and UVA lights from above induced tree-top disease, causing infected larvae to die in an elevated position compared to those larvae living in the complete dark. In contrast, UVB from above did not induce tree-top disease. Blue light exerted the maximum photo-tactic response, significantly (p < 0.01) higher than white light. The magnitude of the response decreased with decreasing wavelength to UVA, and no response at UVB. Our results suggested that the spectral wavelength of the light has a significant effect on the induction of the tree-top disease in H. armigera third instar larvae infected with HearNPV. PMID- 30518029 TI - Disordered Eating Attitudes and Behavioral and Neuroelectric Indices of Cognitive Flexibility in Individuals with Overweight and Obesity. AB - Impairment in cognitive flexibility is a trait characteristic among individuals with diagnosed eating disorders. However, the extent to which these relationships exist in individuals with overweight or obesity remains unclear. Furthermore, there is a lack of knowledge characterizing the neural underpinnings of these relationships. The current study aimed to investigate disordered eating attitudes and cognitive flexibility among adults with overweight and obesity. The Eating Attitudes Test (EAT-26) and a task-switching paradigm were collected from 132 adults (50 males, Body Mass Index (BMI) = 32.0 +/- 5.8 kg/m2). Behavioral measures (accuracy and reaction time (RT)) and neuroelectric indices (amplitude and latency) of the P3 component were assessed. Hierarchical linear regressions, following adjustment of age, sex, intelligence quotient (IQ), weight status, and diet quality were developed using summative and subscale scores of the EAT-26. Higher EAT-26 summative scores, and the Dieting subscale, were related to longer RT. Only the Bulimia and Food Preoccupation subscale was related to longer P3 latency. The relationship between disordered eating attitudes and cognitive flexibility extends to individuals with overweight and obesity and is independent of age, sex, IQ, weight status, and diet quality. These findings are important, as differences in cognitive flexibility can lead to behavioral rigidity. Future work should aim to examine other neuroelectric components to identify where differences driving behavioral latencies may be occurring. PMID- 30518030 TI - Stress-Triggered Long-Distance Communication Leads to Phenotypic Plasticity: The Case of the Early Root Protoxylem Maturation Induced by Leaf Wounding in Arabidopsis. AB - Root architecture and xylem phenotypic plasticity influence crop productivity by affecting water and nutrient uptake, especially under those environmental stress, which limit water supply or imply excessive water losses. Xylem maturation depends on coordinated events of cell wall lignification and developmental programmed cell death (PCD), which could both be triggered by developmental- and/or stress-driven hydrogen peroxide (H2O2) production. Here, the effect of wounding of the cotyledonary leaf on root protoxylem maturation was explored in Arabidopsis thaliana by analysis under Laser Scanning Confocal Microscope (LSCM). Leaf wounding induced early root protoxylem maturation within 3 days from the injury, as after this time protoxylem position was found closer to the tip. The effect of leaf wounding on protoxylem maturation was independent from root growth or meristem size, that did not change after wounding. A strong H2O2 accumulation was detected in root protoxylem 6 h after leaf wounding. Furthermore, the H2O2 trap N,N1-dimethylthiourea (DMTU) reversed wound-induced early protoxylem maturation, confirming the need for H2O2 production in this signaling pathway. PMID- 30518031 TI - Both Intrinsically Disordered Regions and Structural Domains Evolve Rapidly in Immune-Related Mammalian Proteins. AB - Eukaryotic proteins consist of structural domains (SDs) and intrinsically disordered regions (IDRs), i.e., regions that by themselves do not assume unique three-dimensional structures. IDRs are generally subject to less constraint and evolve more rapidly than SDs. Proteins with a lower number of protein-to-protein interactions (PPIs) are also less constrained and tend to evolve fast. Extracellular proteins of mammals, especially immune-related extracellular proteins, on average have relatively high evolution rates. This article aims to examine if a high evolution rate in IDRs or that in SDs accounts for the rapid evolution of extracellular proteins. To this end, we classified eukaryotic proteins based on their cellular localizations and analyzed them. Moreover, we divided proteins into SDs and IDRs and calculated the respective evolution rate. Fractional IDR content is positively correlated with evolution rate. For their fractional IDR content, immune-related extracellular proteins show an aberrantly high evolution rate. IDRs evolve more rapidly than SDs in most subcellular localizations. In extracellular proteins, however, the difference is diminished. For immune-related proteins in mammals in particular, the evolution rates in SDs come close to those in IDRs. Thus high evolution rates in both IDRs and SDs account for the rapid evolution of immune-related proteins. PMID- 30518032 TI - Statins and Cardiovascular Disease Outcomes in Chronic Kidney Disease: Reaffirmation vs. Repudiation. AB - Cardiovascular disease (CVD) burden is several-fold higher in patients with chronic kidney disease (CKD). Although statins have been shown to provide significant CVD benefits in both the general population and patients with CKD, this has not translated into survival advantage in patients with advanced CKD or on dialysis. It has been reported that CVD risk continues to escalate as CKD progresses to end-stage kidney disease (ESKD); however, the CVD risk reduction by statins appears to decline as patients' progress from the early to later stages of CKD. Statins have also been associated with a higher incidence of stroke in ESKD patients. Thus, the CVD benefits of statins in ESKD remain questionable. PMID- 30518033 TI - Differences in Anxiety Levels of Various Murine Models in Relation to the Gut Microbiota Composition. AB - Psychobiotics are probiotic strains that confer mental health benefits to the host through the modulation of the gut microbial population. Mounting evidence shows that the gut microbiota play an important role in communication within the gut-brain axis. However, the relationship between the host genetics and the gut microbiota and their influence on anxiety are still not fully understood. Hence, in our research, we attempted to draw a connection between host genetics, microbiota composition, and anxiety by performing an elevated plus maze (EPM) test on four genetically different mice. Four different breeds of 5-week-old mice were used in this experiment: Balb/c, Orient C57BL/6N, Taconic C57BL/6N, and Taconic C57BL/6J. After 1 week of adaptation, their initial anxiety level was monitored using the EPM test via an EthoVision XT, a standardized software used for behavorial testing. Significant differences in the initial anxiety level and microbial composition were detected. Subsequently, the microbiota of each group was modulated by the administration of either a probiotic, fecal microbiota transplantation, or antibiotics. Changes were observed in host anxiety levels in correlation to the shift of the gut microbiota. Our results suggest that the microbiota, host genetics, and psychological symptoms are strongly related, yet the deeper mechanistic links need further exploration. PMID- 30518034 TI - Biological and Evolutionary Significance of Terminal Extensions of Mitochondrial Translation Initiation Factor 3. AB - Protein biosynthesis in mitochondria is organized in a bacterial manner. However, during evolution, mitochondrial translation mechanisms underwent many organelle specific changes. In particular, almost all mitochondrial translation factors, being orthologous to bacterial proteins, are characterized by some unique elements of primary or secondary structure. In the case of the organellar initiation factor 3 (IF3), these elements are several dozen amino acids long N- and C-terminal extensions. This study focused on the terminal extensions of baker's yeast mitochondrial IF3, Aim23p. By in vivo deletion and complementation analysis, we show that at least one extension is necessary for Aim23p function. At the same time, human mitochondrial IF3 is fully functional in yeast mitochondria even without both terminal extensions. While Escherichia coli IF3 itself is poorly active in yeast mitochondria, adding Aim23p terminal extensions makes the resulting chimeric protein as functional as the cognate factor. Our results show that the terminal extensions of IF3 have evolved as the "adaptors" that accommodate the translation factor of bacterial origin to the evolutionary changed protein biosynthesis system in mitochondria. PMID- 30518035 TI - Green Synthesis of High Temperature Stable Anatase Titanium Dioxide Nanoparticles Using Gum Kondagogu: Characterization and Solar Driven Photocatalytic Degradation of Organic Dye. AB - The present study reports a green and sustainable method for the synthesis of titanium dioxide (TiO2) nanoparticles (NPs) from titanium oxysulfate solution using Kondagogu gum (Cochlospermum gossypium), a carbohydrate polymer, as the NPs formation agent. The synthesized TiO2 NPs were categorized by techniques such as X-Ray Diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy analysis, Raman spectroscopy, scanning electron microscope- Energy-dispersive X-ray spectroscopy (SEM-EDX), Transmission electron microscopy (TEM), High-resolution transmission electron microscopy (HR-TEM), UV-visible spectroscopy, Brunauer Emmett-Teller (BET) surface area and particle size analysis. Additionally, the photocatalytic actions of TiO2 NPs were assessed with regard to their ability to degrade an organic dye (methylene blue) from aqueous solution in the presence of solar light. Various parameters affecting the photocatalytic activity of the TiO2 NPs were examined, including catalyst loading, reaction time, pH value and calcination temperature of the aforementioned particles. This green synthesis method involving TiO2 NPs explores the advantages of inexpensive and non-toxic precursors, the TiO2 NPs themselves exhibiting excellent photocatalytic activity against dye molecules. PMID- 30518036 TI - Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy. AB - Cancer drug resistance is an enormous problem. It is responsible for most relapses in cancer patients following apparent remission after successful therapy. Understanding cancer relapse requires an understanding of the processes underlying cancer drug resistance. This article discusses the causes of cancer drug resistance, the current combination therapies, and the problems with the combination therapies. The rational design of combination therapy is warranted to improve the efficacy. These processes must be addressed by finding ways to sensitize the drug-resistant cancers cells to chemotherapy, and to prevent formation of drug resistant cancer cells. It is also necessary to prevent the formation of cancer progenitor cells by epigenetic mechanisms, as cancer progenitor cells are insensitive to standard therapies. In this article, we emphasize the role for the rational development of combination therapy, including epigenetic drugs, in achieving these goals. PMID- 30518037 TI - Bicellular Tight Junctions and Wound Healing. AB - Bicellular tight junctions (TJs) are intercellular junctions comprised of a variety of transmembrane proteins including occludin, claudins, and junctional adhesion molecules (JAMs) as well as intracellular scaffold proteins such as zonula occludens (ZOs). TJs are functional, intercellular structures that form a barrier between adjacent cells, which constantly seals and unseals to control the paracellular passage of molecules. They are primarily present in the epithelial and endothelial cells of all tissues and organs. In addition to their well recognized roles in maintaining cell polarity and barrier functions, TJs are important regulators of signal transduction, which modulates cell proliferation, migration, and differentiation, as well as some components of the immune response and homeostasis. A vast breadth of research data is available on TJs, but little has been done to decipher their specific roles in wound healing, despite their primary distribution in epithelial and endothelial cells, which are essential contributors to the wound healing process. Some data exists to indicate that a better understanding of the functions and significance of TJs in healing wounds may prove crucial for future improvements in wound healing research and therapy. Specifically, recent studies demonstrate that occludin and claudin-1, which are two TJ component proteins, are present in migrating epithelial cells at the wound edge but are absent in chronic wounds. This indicates that functional TJs may be critical for effective wound healing. A tremendous amount of work is needed to investigate their roles in barrier function, re-epithelialization, angiogenesis, scar formation, and in the interactions between epithelial cells, endothelial cells, and immune cells both in the acute wound healing process and in non healing wounds. A more thorough understanding of TJs in wound healing may shed new light on potential research targets and reveal novel strategies to enhance tissue regeneration and improve wound repair. PMID- 30518038 TI - Effects of Arachidonic and Docosohexahenoic Acid Supplementation during Gestation in Rats. Implication of Placental Oxidative Stress. AB - Arachidonic and docosahexaenoic acids (ARA and DHA) are important during pregnancy. However, the effects of dietary supplementation on fetal growth and oxidative stress are inconclusive. We aimed to assess the effect of high ARA and DHA diet during rat gestation on: (1) ARA and DHA availability in plasma and placenta, (2) fetal growth, and (3) placental oxidative stress, analyzing the influence of sex. Experimental diet (ED) was prepared by substituting soybean oil in the control diet (CD) by a fungi/algae-based oil containing ARA and DHA (2:1). Rats were fed with CD or ED during gestation; plasma, placenta, and fetuses were obtained at gestational day 20. DHA, ARA, and their precursors were analyzed in maternal plasma and placenta by gas chromatography/mass spectrophotometry. Fetuses and placentas were weighed, the proportion of fetuses with intrauterine growth restriction (IUGR) determined, and placental lipid and protein oxidation analyzed. ED fetuses exhibited lower body weight compared to CD, being >40% IUGR; fetal weight negatively correlated with maternal plasma ARA, but not DHA. Only ED female placenta exhibited higher lipid and protein oxidation compared to its CD counterparts; lipid peroxidation is negatively associated with fetal weight. In conclusion, high ARA during gestation associates with IUGR, through placental oxidative stress, with females being more susceptible. PMID- 30518039 TI - Effect of Long-Term Strontium Exposure on the Content of Phytoestrogens and Allantoin in Soybean. AB - Abiotic stress, including metal excess, can modify plant metabolism. Here we investigated the influence of long-term strontium exposure (12 weeks, 0.5-4.0 mM Sr) on the content of phytoestrogens and allantoin as well as the mineral composition in soybean. Seven phytoestrogens were identified in the soybean: daidzin, glycitin, genistin, malonyldaidzin, malonylgenistin, daidzein, and coumestrol. The results showed that both malonyldaidzin and malonylgenistin were dominant phytoestrogens; however, the roots contained a relatively high amount of daidzein. It was found that strontium reduced the phytoestrogen content and decreased the antioxidant capacity. Strontium evoked depletion of the sum of all phytoestrogens by 40-70% in the leaves, 25-50% in the stems and in the seeds, depending on the strontium concentration. In the roots, 0.5 and 4.0 mM of strontium decreased the total phytoestrogen content by 25 and 55%, respectively, while 2.0 mM of strontium did not exert an effect on their accumulation. On the other hand, strontium ions induced allantoin accumulation mainly in the roots. Strontium was preferentially accumulated in the leaves, with a slight impact on macro- and micro-nutrients. Our research showed strontium-secondary metabolites interaction in the soybean, which can be useful for obtaining a natural pharmaceutical product containing both strontium and phytoestrogens for remediation of postmenopausal osteoporosis. PMID- 30518040 TI - Comparison of the Allergenicity and Immunogenicity of Camel and Cow's Milk-A Study in Brown Norway Rats. AB - BACKGROUND: When breastfeeding is impossible or insufficient, the use of cow's milk-based hypoallergenic infant formulas is an option for infants suffering from or at risk of developing cow's milk allergy. As the Camelidae family has a large evolutionary distance to the Bovidae family and as camel milk differs from cow's milk protein composition, there is a growing interest in investigating the suitability of camel milk as an alternative to cow's milk-based hypoallergenic infant formulas. METHODS: The aim of the study was to compare the allergenicity and immunogenicity of camel and cow's milk as well as investigating their cross reactivity using a Brown Norway rat model. Rats were immunised intraperitoneally with one of four products: camel milk, cow's milk, cow's milk casein or cow's milk whey fraction. Immunogenicity, sensitising capacity, antibody avidity and cross-reactivity were evaluated by means of different ELISAs. The eliciting capacity was evaluated by an ear swelling test. RESULTS: Camel and cow's milk showed similarity in their inherent immunogenicity, sensitising and eliciting capacity. Results show that there was a lower cross-reactivity between caseins than between whey proteins from camel and cow's milk. CONCLUSIONS: The study showed that camel and cow's milk have a low cross-reactivity, indicating a low protein similarity. Results demonstrate that camel milk could be a promising alternative to cow's milk-based hypoallergenic infant formulas. PMID- 30518041 TI - An Eight-Direction Scanning Detection Algorithm for the Mapping Robot Pathfinding in Unknown Indoor Environment. AB - Aiming at the problem of how to enable the mobile robot to navigate and traverse efficiently and safely in the unknown indoor environment and map the environment, an eight-direction scanning detection (eDSD) algorithm is proposed as a new pathfinding algorithm. Firstly, we use a laser-based SLAM (Simultaneous Localization and Mapping) algorithm to perform simultaneous localization and mapping to acquire the environment information around the robot. Then, according to the proposed algorithm, the 8 certain areas around the 8 directions which are developed from the robot's center point are analyzed in order to calculate the probabilistic path vector of each area. Considering the requirements of efficient traverse and obstacle avoidance in practical applications, the proposal can find the optimal local path in a short time. In addition to local pathfinding, the global pathfinding is also introduced for unknown environments of large-scale and complex structures to reduce the repeated traverse. The field experiments in three typical indoor environments demonstrate that deviation of the planned path from the ideal path can be kept to a low level in terms of the path length and total time consumption. It is confirmed that the proposed algorithm is highly adaptable and practical in various indoor environments. PMID- 30518042 TI - Active Image-Assisted Food Records in Comparison to Regular Food Records: A Validation Study against Doubly Labeled Water in 12-Month-Old Infants. AB - Overreporting of dietary intake in infants is a problem when using food records (FR), distorting possible relationships between diet and health outcomes. Image assisted dietary assessment may improve the accuracy, but to date, evaluation in the pediatric setting is limited. The aim of the study was to compare macronutrient and energy intake by using an active image-assisted five-day FR against a regular five-day FR, and to validate image-assistance with total energy expenditure (TEE), was measured using doubly labeled water. Participants in this validation study were 22 healthy infants randomly selected from the control group of a larger, randomized intervention trial. The parents reported the infants' dietary intake, and supplied images of main course meals taken from standardized flat-surfaced plates before and after eating episodes. Energy and nutrient intakes were calculated separately using regular FR and image-assisted FRs. The mean (+/- standard deviations) energy intake (EI) was 3902 +/- 476 kJ/day from the regular FR, and 3905 +/- 476 kJ/day from the FR using active image assistance. The mean EI from main-course meals when image-assistance was used did not differ (1.7 +/- 55 kJ, p = 0.89) compared to regular FRs nor did the intake of macronutrients. Compared to TEE, image-assisted FR overestimated EI by 10%. Without validation, commercially available software to aid in the volume estimations, food item identification, and automation of the image processing, image-assisted methods remain a more costly and burdensome alternative to regular FRs in infants. The image-assisted method did, however, identify leftovers better than did regular FR, where such information is usually not readily available. PMID- 30518043 TI - TAS1R1 and TAS1R3 Polymorphisms Relate to Energy and Protein-Rich Food Choices from a Buffet Meal Respectively. AB - Eating behaviour in humans is a complex trait that involves sensory perception. Genetic variation in sensory systems is one of the factors influencing perception of foods. However, the extent that these genetic variations may determine food choices in a real meal scenario warrants further research. This study investigated how genetic variants of the umami taste receptor (TAS1R1/TAS1R3) related to consumption of umami-tasting foods. Thirty normal-weight adult subjects were offered "ad libitum" access to a variety of foods covering the full range of main taste-types for 40 min using a buffet meal arrangement. Buccal cell samples were collected and analysed for six single nucleotide polymorphisms (SNPs) reported previously related to the TAS1R1/TAS1R3 genes. Participants identified with the CC alleles of the TAS1R3 rs307355 and rs35744813 consumed significantly more protein from the buffet than T carriers. In addition, participants with GG genotype of the TAS1R1 SNP rs34160967 consumed more fat and calories as compared to the genotype group having the A alleles. In summary, these findings revealed a link between the SNPs variations of umami taster receptor gene and fat and protein intake from a buffet meal. PMID- 30518044 TI - Changes in Dietary Intake and Adherence to the NU-AGE Diet Following a One-Year Dietary Intervention among European Older Adults-Results of the NU-AGE Randomized Trial. AB - BACKGROUND: The Mediterranean Diet has been proposed as an effective strategy to reduce inflammaging, a chronic low grade inflammatory status, and thus, to slow down the aging process. We evaluated whether a Mediterranean-like dietary pattern specifically targeting dietary recommendations of people aged over 65 years (NU AGE diet) could be effective to shift dietary intake of older adults towards a healthful diet. METHODS: Adults aged 65-80 years across five EU-centers were randomly assigned to a NU-AGE diet group or control group. The diet group followed one year of NU-AGE dietary intervention specifying consumption of 15 food groups plus the use of a vitamin D supplement. Participants in the diet group received counselling and individually tailored dietary advice, food products and a vitamin D supplement. Dietary intake was assessed by means of seven-day food records at baseline and one-year follow-up. A continuous NU-AGE index (0-160 points) was developed to assess NU-AGE diet adherence. RESULTS: In total 1296 participants were randomized and 1141 participants completed the intervention (571 intervention, 570 control). After one year, the diet group improved mean intake of 13 out of 16 NU-AGE dietary components (p < 0.05), with a significant increase in total NU-AGE index (difference in mean change = 21.3 +/- 15.9 points, p < 0.01). CONCLUSIONS: The NU-AGE dietary intervention, based on dietary recommendations for older adults, consisting of individual dietary counselling, free healthy foods and a vitamin D supplement, may be a feasible strategy to improve dietary intake in an aging European population. PMID- 30518045 TI - Carbon and Nitrogen Burial and Response to Climate Change and Anthropogenic Disturbance in Chaohu Lake, China. AB - Lakes are a crucial component of the global carbon and nitrogen cycle. As a trend of enhanced human activities and climate change, the mechanisms of burial remain poorly understood. In this study, diverse biogeochemical techniques were applied to analyze the temporal variation of organic carbon and nitrogen burial rates in Chaohu Lake. The results showed that burial rates have ranged from 9.39 to 35.87 g C m-2 yr-1 for carbon and from 1.66 to 5.67 g N m-2 yr-1 for nitrogen since the 1860s. The average rates were 19.6 g C m-2 yr-1 and 3.14 g N m-2 yr-1 after the 1970s, which were significantly higher than the rate before the 1970s, showing an increasing trend. The decrease of C/N ratios as well as organic matter delta13C values indicates that the major organic matter source in sediment has been algal production since the 1970s. The increase of delta15N values indicated that the promotion in productivity was stimulated by nutrient input from sewage and agricultural runoff. The burial rates of organic carbon and nitrogen were significantly positively related to socio-economics and temperature, indicating that Chaohu Lake will become an increasing carbon and nitrogen pool under conditions of enhanced human activities and intensive precipitation. PMID- 30518046 TI - Characterization of the Intrinsic Phospholipase A1 Activity of Bordetella pertussis Adenylate Cyclase Toxin. AB - Adenylate cyclase toxin (ACT, CyaA) is one of the important virulence factors secreted by the whooping cough bacterium Bordetella pertussis, and it is essential for the colonization of the human respiratory tract by this bacterium. Cytotoxicity by ACT results from the synergy between toxin's two main activities, production of supraphysiological cAMP levels by its N-terminal adenylate cyclase domain (AC domain), and cell membrane permeabilization, induced by its C-terminal pore-forming domain (hemolysin domain), which debilitate the host defenses. In a previous study we discovered that purified ACT is endowed with intrinsic phospholipase A1 (PLA) activity and that Ser in position 606 of the ACT polypeptide is a catalytic site for such hydrolytic activity, as part of G-X-S-X G catalytic motif. Recently these findings and our conclusions have been directly questioned by other authors who claim that ACT-PLA activity does not exist. Here we provide new data on ACT phospholipase A1 characteristics. Based on our results we reaffirm our previous conclusions that ACT is endowed with PLA activity; that our purified ACT preparations are devoid of any impurity with phospholipase A activity; that ACT-S606A is a PLA-inactive mutant and thus, that Ser606 is a catalytic site for the toxin hydrolytic activity on phospholipids, and that ACT PLA activity is involved in AC translocation. PMID- 30518048 TI - High Electrochemical Performance from Oxygen Functional Groups Containing Porous Activated Carbon Electrode of Supercapacitors. AB - Carbon electrode materials for double layer capacitors have attracted much attention, due to their low cost and abundant sources. Their low specific capacitance, however, hinders the development of carbon electrode materials. In this paper, the large specific surface area commercial activated carbons, rich in micropores, were initially oxygen-functionalized by treatment using concentrated H2SO4, saturated (NH4)2S2O8, and H2SO4/(NH4)2S2O4 mixed oxidants, respectively. The as-prepared samples were analyzed using N2 adsorption/desorption isotherms, X ray photoelectron spectroscopy, and Boehm titration, and used as electrode materials for supercapacitors. Characterization results displayed that the oxidation treatment decreased the specific surface area along with increasing oxygen content. The electrode test showed that the electrochemical activity increased as oxygen content increased. The result that oxygen-functionalized activated carbon, even with a lower specific surface area but much more oxygen content, had higher capacity than pristine activated carbon, tells of the critical role of oxygen functional groups. The excellent capacitive performance suggests a good potential for oxygen functional carbon material to be a highly promising electrode material for supercapacitors. PMID- 30518047 TI - Comparative Effectiveness of the Core Components of Cardiac Rehabilitation on Mortality and Morbidity: A Systematic Review and Network Meta-Analysis. AB - A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating the core components of cardiac rehabilitation (CR), nutritional counseling (NC), risk factor modification (RFM), psychosocial management (PM), patient education (PE), and exercise training (ET)) was undertaken. Published RCTs were identified from database inception dates to April 2017, and risk of bias assessed using Cochrane's tool. Endpoints included mortality (all-cause and cardiovascular (CV)) and morbidity (fatal and non-fatal myocardial infarction (MI), coronary artery bypass surgery (CABG), percutaneous coronary intervention (PCI), and hospitalization (all-cause and CV)). Meta regression models decomposed treatment effects into the main effects of core components, and two-way or all-way interactions between them. Ultimately, 148 RCTs (50,965 participants) were included. Main effects models were best fitting for mortality (e.g., for all-cause, specifically PM (hazard ratio HR = 0.68, 95% credible interval CrI = 0.54-0.85) and ET (HR = 0.75, 95% CrI = 0.60-0.92) components effective), MI (e.g., for all-cause, specifically PM (hazard ratio HR = 0.76, 95% credible interval CrI = 0.57-0.99), ET (HR = 0.75, 95% CrI = 0.56 0.99) and PE (HR = 0.68, 95% CrI = 0.47-0.99) components effective) and hospitalization (e.g., all-cause, PM (HR = 0.76, 95% CrI = 0.58-0.96) effective). For revascularization (including CABG and PCI individually), the full interaction model was best-fitting. Given that each component, individual or in combination, was associated with mortality and/or morbidity, recommendations for comprehensive CR are warranted. PMID- 30518049 TI - It Is Time to Make Policy for Healthier Food Environments in Australian Universities. AB - The obesogenic food environment is likely driving excessive weight gain in young adults. Our study aimed to investigate the nutritional quality of current food and drink offerings in an Australian university. This cross-sectional study included baseline environmental audits of 30 food outlets and 62 vending machines across campus. A recent food and drink benchmark for health facilities by state government was used to classify the food and beverage offerings. It recommended food outlets and vending machines to offer at least 75% 'Everyday' (healthy) and less than 25% 'Occasional' (less healthy) foods and drinks. Sugary drinks and options with large portion sizes and unhealthy ingredients should be removed from sale. Only two beverage vending machines and none of the food outlets met the full recommendations. The overall proportions of Everyday and Occasional foods in food outlets were 35% and 22%, respectively with 43% falling into the category that should not be sold. Sugary drinks occupied a third of beverage varieties in outlets and 38% of beverage slots in vending machines. The current university food environment was poorly compliant with the existing benchmark. Specific food policy in the university setting may be needed to make healthier choices more accessible to young adults. PMID- 30518050 TI - Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial. AB - Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63-79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time * intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power. PMID- 30518051 TI - Dual Path Lock-In System for Elimination of Residual Amplitude Modulation and SNR Enhancement in Photoacoustic Spectroscopy. AB - A technique for elimination of residual amplitude modulation (ERAM) in photoacoustic spectroscopy based on dual path lock-in was proposed and experimentally demonstrated. There are two lock-in amplifiers, one is for gas concentration demodulation and another for residual amplitude modulation (RAM) measurement by tuning the reference signal in different phases, and then a dual path lock-in technique based on subtraction is applied to RAM removal, improving the second harmonic profile significantly. In this system, the signal to noise ratio (SNR) increases about two times based on our dual path lock-in technique compared to one distributed feedback laser diode (DFB-LD). The system achieved a good linear response (R-square = 0.99887) in a concentration range from 100 ppmv to 2400 ppmv and a minimum detection limit (MDL) of 1.47 ppmv. PMID- 30518052 TI - Maternal Pre-Pregnancy Obesity Attenuates Response to Omega-3 Fatty Acids Supplementation During Pregnancy. AB - Maternal obesity is associated with adverse offspring outcomes. Inflammation and deficiency of anti-inflammatory nutrients like omega(n)-3 polyunsaturated fatty acids (PUFA) may contribute to these associations. Fetal supply of n-3 PUFA is dependent on maternal levels and studies have suggested that improved offspring outcomes are associated with higher maternal intake. However, little is known about how maternal obesity affects the response to n-3 supplementation during pregnancy. We sought to determine (1) the associations of obesity with PUFA concentrations and (2) if the systemic response to n-3 supplementation differs by body mass index (BMI). This was a secondary analysis of 556 participants (46% lean, 28% obese) in the Maternal-Fetal Medicine Units Network trial of n-3 (Docosahexaenoic acid (DHA) + Eicosapentaenoic acid (EPA)) supplementation, in which participants had 2g/day of n-3 (n = 278) or placebo (n = 278) from 19 to 22 weeks until delivery. At baseline, obese women had higher plasma n-6 arachidonic acid concentrations (beta: 0.96% total fatty acids; 95% Confidence Interval (CI): 0.13, 1.79) and n-6/n-3 ratio (beta: 0.26 unit; 95% CI: 0.05, 0.48) compared to lean women. In the adjusted analysis, women in all BMI groups had higher n-3 concentrations following supplementation, although obese women had attenuated changes (beta = -2.04%, CI: -3.19, -0.90, interaction p = 0.000) compared to lean women, resulting in a 50% difference in the effect size. Similarly, obese women also had an attenuated reduction (beta = 0.94 units, CI: 0.40, 1.47, interaction p = 0.046) in the n-6/n-3 ratio (marker of inflammatory status), which was 65% lower compared to lean women. Obesity is associated with higher inflammation and with an attenuated response to n-3 supplementation in pregnancy. PMID- 30518053 TI - Homologous Recombination: To Fork and Beyond. AB - Accurate completion of genome duplication is threatened by multiple factors that hamper the advance and stability of the replication forks. Cells need to tolerate many of these blocking lesions to timely complete DNA replication, postponing their repair for later. This process of lesion bypass during DNA damage tolerance can lead to the accumulation of single-strand DNA (ssDNA) fragments behind the fork, which have to be filled in before chromosome segregation. Homologous recombination plays essential roles both at and behind the fork, through fork protection/lesion bypass and post-replicative ssDNA filling processes, respectively. I review here our current knowledge about the recombination mechanisms that operate at and behind the fork in eukaryotes, and how these mechanisms are controlled to prevent unscheduled and toxic recombination intermediates. A unifying model to integrate these mechanisms in a dynamic, replication fork-associated process is proposed from yeast results. PMID- 30518054 TI - Direct Single-Molecule Observation of Sequential DNA Bending Transitions by the Sox2 HMG Box. AB - Sox2 is a pioneer transcription factor that initiates cell fate reprogramming through locus-specific differential regulation. Mechanistically, it was assumed that Sox2 achieves its regulatory diversity via heterodimerization with partner transcription factors. Here, utilizing single-molecule fluorescence spectroscopy, we show that Sox2 alone can modulate DNA structural landscape in a dosage dependent manner. We propose that such stoichiometric tuning of regulatory DNAs is crucial to the diverse biological functions of Sox2, and represents a generic mechanism of conferring functional plasticity and multiplicity to transcription factors. PMID- 30518055 TI - The Effectiveness of Nutrition Education for Overweight/Obese Mother with Stunted Children (NEO-MOM) in Reducing the Double Burden of Malnutrition. AB - (1) Background: In households experiencing the double burden of malnutrition, stunted children are in a better position for growth improvement when parents are able to direct their resources to support nutrition requirements. This study assesses the effectiveness of maternal nutrition education to reduce child stunting. (2) Methods: This was a Randomized Controlled Trial involving pairs of overweight/obese mothers with stunted children aged 2 to 5 years old in urban Indonesia. Methods: Seventy-one mother-child pairs were randomly assigned to receive either a 12-week nutrition education or printed educational materials. Mixed factorial ANOVA was used to test for between-group differences over time in relation to child's height, weight, maternal self-efficacy, outcome expectation, and caloric intake. (3) Results: Across groups, there was a significant effect of time on child height and weight but no significant differences were observed between-groups. Maternal self-efficacy, outcome expectations in providing animal protein for the children (p-value = 0.025) and mother's total caloric intake (p value = 0.017) favored the intervention group over the comparison group. (4) Conclusions: The behavioral intervention produced strong improvement in maternal self-efficacy to engage in physical activity, eat fruits and vegetables and to provide children with growth-promoting animal protein, but did not significantly influence child height gain. PMID- 30518056 TI - Porous Carrageenan-Derived Carbons for Efficient Ciprofloxacin Removal from Water. AB - Porous carbon materials derived from biopolymers are attractive sorbents for the removal of emerging pollutants from water, due to their high specific surface area, high porosity, tunable surface chemistry, and reasonable cost. However, carrageenan biopolymers were scarcely investigated as a carbon source to prepare porous carbon materials. Herein, hydrochars (HCs) and porous activated carbons (ACs) derived from natural occurring polysaccharides with variable sulfate content (kappa-, iota- and lambda-carrageenan) were prepared and investigated in the uptake of ciprofloxacin, which is an antibiotic detected in water sources and that poses serious hazards to public health. The materials were prepared using hydrothermal carbonization and subsequent chemical activation with KOH to increase the available surface area. The activated carbons were markedly microporous, presenting high specific surface area, up to 2800 m2/g. Activated carbons derived from kappa- and lambda-carrageenan showed high adsorption capacity (422 and 459 mg/g, respectively) for ciprofloxacin and fast adsorption kinetics, reaching the sorption equilibrium in approximately 5 min. These features place the ACs investigated here among the best systems reported in the literature for the removal of ciprofloxacin from water. PMID- 30517793 TI - Observation of Centrality-Dependent Acoplanarity for Muon Pairs Produced via Two Photon Scattering in Pb+Pb Collisions at sqrt[s_{NN}]=5.02 TeV with the ATLAS Detector. AB - This Letter presents a measurement of gammagamma->MU^{+}MU^{-} production in Pb+Pb collisions recorded by the ATLAS detector at the Large Hadron Collider at sqrt[s_{NN}]=5.02 TeV with an integrated luminosity of 0.49 nb^{-1}. The azimuthal angle and transverse momentum correlations between the muons are measured as a function of collision centrality. The muon pairs are produced from gammagamma through the interaction of the large electromagnetic fields of the nuclei. The contribution from background sources of muon pairs is removed using a template fit method. In peripheral collisions, the muons exhibit a strong back-to back correlation consistent with previous measurements of muon pair production in ultraperipheral collisions. The angular correlations are observed to broaden significantly in central collisions. The modifications are qualitatively consistent with rescattering of the muons while passing through the hot matter produced in the collision. PMID- 30518057 TI - Enhancing Output Power of Textured Silicon Solar Cells by Embedding Indium Plasmonic Nanoparticles in Layers within Antireflective Coating. AB - In this study, we sought to enhance the output power and conversion efficiency of textured silicon solar cells by layering two-dimensional indium nanoparticles (In NPs) within a double-layer (SiNx/SiO2) antireflective coating (ARC) to induce plasmonic forward scattering. The plasmonic effects were characterized using Raman scattering, absorbance spectra, optical reflectance, and external quantum efficiency. We compared the optical and electrical performance of cells with and without single layers and double layers of In NPs. The conversion efficiency of the cell with a double layer of In NPs (16.97%) was higher than that of the cell with a single layer of In NPs (16.61%) and greatly exceeded that of the cell without In NPs (16.16%). We also conducted a comprehensive study on the light trapping performance of the textured silicon solar cells with and without layers of In NPs within the double layer of ARC at angles from 0 degrees to 75 degrees . The total electrical output power of cells under air mass (AM) 1.5 G illumination was calculated. The application of a double layer of In NPs enabled an impressive 53.42% improvement in electrical output power (compared to the cell without NPs) thanks to the effects of plasmonic forward scattering. PMID- 30518058 TI - Ultrasonic Transmission Tomography Sensor Design for Bubble Identification in Gas Liquid Bubble Column Reactors. AB - Scientists require methods to monitor the distribution of gas bubbles in gas liquid bubble column reactors. One non-destructive method that can potential satisfy this requirement in industrial situations is ultrasonic transmission tomography (UTT). In this paper, an ultrasonic transmission tomography sensor is designed for measuring bubble distribution in a reactor. Factors that influence the transducer design include transmission energy loss, the resonance characteristics and vibration modes of the transducer, and diffusion angles of the transducers, which are discussed. For practical application, it was found that an excitation frequency of 300 kHz could identify the location and size of gas bubbles. The vibration mode and diffusion also directly affect the quality of the imaging. The geometric parameters of the transducer (a cylinder transducer with a 10 mm diameter and 6.7 mm thickness) are designed to achieve the performance requirements. A UTT system, based on these parameters, was built in order to verify the effectiveness of the designed ultrasonic transducer array. A Sector-diffusion-matrix based Linear Back Projection (SLBP) was used to reconstruct the gas/liquid two-phase flow from the obtained measurements. Two other image processing methods, based on SLBP algorithm named SLBP-HR (SLBP Hybrid Reconstruction) and SLBP-ATF (SLBP-Adaptive Threshold Filtering), were introduced, and the imaging results are presented. The imaging results indicate that a gas bubble with a 3 mm radius can be identified from reconstructed images, and that three different flow patterns, namely, single gas bubble, double gas bubble with different diameters, and eccentric flow, can be identified from reconstructed images. This demonstrates that the designed UTT sensor can effectively measure bubble distribution in gas-liquid bubble column reactors. PMID- 30518066 TI - Energy-Balancing Unequal Clustering Approach to Reduce the Blind Spot Problem in Wireless Sensor Networks (WSNs). AB - Wireless Sensor Networks (WSNs) have become a significant part of surveillance techniques. With unequal clustering approaches and multi-hop communication, WSNs can balance energy among the clusters and serve a wide monitoring area. Recent research has shown significant improvements in unequal clustering approaches by forming clusters prior to the selection of cluster heads. These improvements adopt different geometric fractals, such as the Sierpinski triangle, to divide the monitoring area into multiple clusters. However, performance of such approaches can be improved further by cognitive partitioning of the monitoring area instead of adopting random fractals. This paper proposes a novel clustering approach that partitions the monitoring area in a cognitive way for balancing the energy consumption. In addition, the proposed approach adopts a two-layered scrutinization process for the selection of cluster heads that ensures minimum energy consumption from the network. Furthermore, it reduces the blind spot problem that escalates once the nodes start dying. The proposed approach has been tested in terms of number of alive nodes per round, energy consumption of nodes and clusters, and distribution of alive nodes in the network. Results show a significant improvement in balancing the energy consumption among clusters and a reduction in the blind spot problem. PMID- 30518068 TI - Graphene Reinforced Composites as Protective Coatings for Oil and Gas Pipelines. AB - Corrosion and corrosion-induced damage have resulted mostly in malfunctions and sometimes even in failures of metallic structures, including oil and gas pipelines. In this study, new high-performance composite coatings were developed by incorporating nanoparticles in the polymer resins with applications to oil and gas pipelines. The graphene nanoplatelets under different concentrations were used to prepare the epoxy-based nanocomposites and were then evaluated through mechanical and electrical tests. The integration of high-speed disk and ultrasonication were adopted as the dispersion technique to overcome nanoparticle agglomeration. Electron microscopy techniques were used to investigate the agglomeration. The new composites were qualitatively and quantitatively evaluated in terms of contact angle, surface roughness, adhesion to the substrate, corrosion resistance, and abrasion resistance. The results suggested that the composite with 0.5~1.0 wt.% of the graphene nanofillers led to the largest improvement in both mechanical and electrochemical properties. Distribution of nanoparticles in the matrix was observed using scanning electron microscopy and surface roughness using atomic force microscopy. Large agglomeration that was observed at the higher concentrations mainly resulted in the reduction of corrosion resistance and abrasion resistance. PMID- 30518059 TI - A Metabolomics Approach to the Identification of Urinary Biomarkers of Pea Intake. AB - A significant body of evidence demonstrates that isoflavone metabolites are good markers of soy intake, while research is lacking on specific markers of other leguminous sources such as peas. In this context, the objective of our current study was to identify biomarkers of pea intake using an untargeted metabolomics approach. A randomized cross-over acute intervention study was conducted on eleven participants who consumed peas and couscous (control food) in random order. The urine samples were collected in fasting state and postprandially at regular intervals and were further analysed by ultra-performance liquid chromatography coupled to quadrupole time of flight mass spectrometry (UPLC-QTOF MS). Multivariate statistical analysis resulted in robust Partial least squares Discriminant Analysis (PLS-DA) models obtained for comparison of fasting against the postprandial time points (0 h vs. 4 h, (R2X = 0.41, Q2 = 0.4); 0 h vs. 6 h, ((R2X = 0.517, Q2 = 0.495)). Variables with variable importance of projection (VIP) scores >=1.5 obtained from the PLS-DA plot were considered discriminant between the two time points. Repeated measures analysis of variance (ANOVA) was performed to identify features with a significant time effect. Assessment of the time course profile revealed that ten features displayed a differential time course following peas consumption compared to the control food. The interesting features were tentatively identified using accurate mass data and confirmed by tandem mass spectrometry (MS using commercial spectral databases and authentic standards. 2-Isopropylmalic acid, asparaginyl valine and N-carbamoyl-2-amino-2-(4 hydroxyphenyl) acetic acid were identified as markers reflecting pea intake. The three markers also increased in a dose-dependent manner in a randomized intervention study and were further confirmed in an independent intervention study. Overall, key validation criteria were met for the successfully identified pea biomarkers. Future work will examine their use in nutritional epidemiology studies. PMID- 30518060 TI - Additive and Substractive Surface Structuring by Femtosecond Laser Induced Material Ejection and Redistribution. AB - A novel additive surface structuring process is devised, which involves localized, intense femtosecond laser irradiation. The irradiation induces a phase explosion of the material being irradiated, and a subsequent ejection of the ablative species that are used as additive building blocks. The ejected species are deposited and accumulated in the vicinity of the ablation site. This redistribution of the material can be repeated and controlled by raster scanning and multiple pulse irradiation. The deposition and accumulation cause the formation of um-scale three-dimensional structures that surpass the initial surface level. The above-mentioned ablation, deposition, and accumulation all together constitute the proposed additive surface structuring process. In addition, the geometry of the three-dimensional structures can be further modified, if desirable, by a subsequent substractive ablation process. Microstructural analysis reveals a quasi-seamless conjugation between the surface where the structures grow and the structures additively grown by this method, and hence indicates the mechanic robustness of these structures. As a proof of concept, a sub-mm sized re-entrant structure and pillars are fabricated on aluminum substrate by this method. Single units as well as arrayed structures with arbitrary pattern lattice geometry are easily implemented in this additive surface structuring scheme. Engineered surface with desired functionalities can be realized by using this means, i.e., a surface with arrayed pillars being rendered with superhydrophobicity. PMID- 30518061 TI - Cooperative Jammer Selection for Secrecy Improvement in Cognitive Internet of Things. AB - Smart homes can improve the quality of life and be implemented by Internet of Things (IoT) technologies. However, security is a very important issue in smart homes. For this reason, we propose a secrecy transmission protocol for primary user (PU) by selecting friendly jammer in cognitive IoT model. In particular, a secondary transmitter (ST) is selected to transmit secondary signals by the PU's frequency spectrum, while another ST is chosen to transmit artificial noise to protect the transmission confidentiality of the PU against eavesdropping. Moreover, two selection schemes are presented to confirm the former and the latter ST, and the goal is to optimize the secondary transmission performance and the primary security performance, respectively. For the non-security model and the proposed protocol, we derive the closed-form expressions of the intercept probability and the outage probability for the PU. We also obtain the closed-form expression of outage probability for the secondary user. The numerical results show that the security performance of the PU is significantly enhanced in our protocol compared to the non-security model. In addition, the outage performance of the secondary users is also improved in high secondary transmit SNR region. PMID- 30518064 TI - iTRAQ-Based Comparative Proteomic Analysis Provides Insights into Molecular Mechanisms of Salt Tolerance in Sugar Beet (Beta vulgaris L.). AB - Salinity is one of the major abiotic stress factors that limit plant growth and crop yield worldwide. To understand the molecular mechanisms and screen the key proteins in response of sugar beet (Beta vulgaris L.) to salt, in the present study, the proteomics of roots and shoots in three-week-old sugar beet plants exposed to 50 mM NaCl for 72 h was investigated by isobaric Tags for Relative and Absolute Quantitation (iTRAQ) technology. The results showed that 105 and 30 differentially expressed proteins (DEPs) were identified in roots and shoots of salt-treated plants compared with untreated plants, respectively. There were 46 proteins up-regulated and 59 proteins down-regulated in roots; and 13 up regulated proteins and 17 down-regulated proteins found in shoots, respectively. These DEPs were mainly involved in carbohydrate metabolism, energy metabolism, lipid metabolism, biosynthesis of secondary metabolites, transcription, translation, protein folding, sorting, and degradation as well as transport. It is worth emphasizing that some novel salt-responsive proteins were identified, such as PFK5, MDH, KAT2, ACAD10, CYP51, F3H, TAL, SRPR, ZOG, V-H+-ATPase, V-H+ PPase, PIPs, TIPs, and tubulin alpha-2/beta-1 chain. qRT-PCR analysis showed that six of the selected proteins, including BvPIP1-4, BvVP and BvVAP in root and BvTAL, BvURO-D1, and BvZOG in shoot, displayed good correlation between the expression levels of protein and mRNA. These novel proteins provide a good starting point for further research into their functions using genetic or other approaches. These findings should significantly improve the understanding of the molecular mechanisms involved in salt tolerance of sugar beet plants. PMID- 30518065 TI - Dietary Composition and Cardiovascular Risk: A Mediator or a Bystander? AB - The role of nutrition in the pathogenesis of cardiovascular disease has long been debated. The established notion of the deleterious effects of fat is recently under question, with numerous studies demonstrating the benefits of low carbohydrate, high-fat diets in terms of obesity, diabetes, dyslipidemia, and metabolic derangement. Monounsaturated and polyunsaturated fatty acids, especially n-3 PUFAs (polyunsaturated fatty acids), are the types of fat that favor metabolic markers and are key components of the Mediterranean Diet, which is considered an ideal dietary pattern with great cardioprotective effects. Except for macronutrients, however, micronutrients like polyphenols, carotenoids, and vitamins act on molecular pathways that affect oxidative stress, endothelial function, and lipid and glucose homeostasis. In relation to these metabolic markers, the human gut microbiome is constantly revealed, with its composition being altered by even small dietary changes and different microbial populations being associated with adverse cardiovascular outcomes, thus becoming the target for potential new treatment interventions. This review aims to present the most recent data concerning different dietary patterns at both the macro- and micronutrient level and their association with atherosclerosis, obesity, and other risk factors for cardiovascular disease. PMID- 30518063 TI - The Role of Glucocorticoid Receptor Signaling in Bladder Cancer Progression. AB - Previous preclinical studies have indicated that the activation of glucocorticoid receptor signaling results in inhibition of the growth of various types of tumors. Indeed, several glucocorticoids, such as dexamethasone and prednisone, have been prescribed for the treatment of, for example, hematological malignancies and castration-resistant prostate cancer. By contrast, the role of glucocorticoid-mediated glucocorticoid receptor signaling in the progression of bladder cancer remains far from being fully understood. Nonetheless, emerging evidence implies its unique functions in urothelial cancer cells. Moreover, the levels of glucocorticoid receptor expression have been documented to significantly associate with the prognosis of patients with bladder cancer. This review summarizes the available data suggesting the involvement of glucocorticoid mediated glucocorticoid receptor signaling in urothelial tumor outgrowth and highlights the potential underlying molecular mechanisms. The molecules/pathways that contribute to modulating glucocorticoid receptor activity and function in bladder cancer cells are also discussed. PMID- 30518067 TI - Quantification of Total Phenolic and Carotenoid Content in Blackberries (Rubus Fructicosus L.) Using Near Infrared Spectroscopy (NIRS) and Multivariate Analysis. AB - A rapid method to quantify the total phenolic content (TPC) and total carotenoid content (TCC) in blackberries using near infrared spectroscopy (NIRS) was carried out aiming to provide reductions in analysis time and cost for the food industry. A total of 106 samples were analysed using the Folin-Ciocalteu method for TPC and a method based on Ultraviolet-Visible Spectrometer for TCC. The average contents found for TPC and TCC were 24.27 mg.g-1 dw and 8.30 ug.g-1 dw, respectively. Modified partial least squares (MPLS) regression was used for obtaining the calibration models of these compounds. The RPD (ratio of the standard deviation of the reference data to the standard error of prediction (SEP)) values from external validation for both TPC and TCC were between 1.5 < RPDp < 2.5 and RER values (ratio of the range in the reference data to SEP) were 5.92 for TPC and 8.63 for TCC. These values showed that both equations were suitable for screening purposes. MPLS loading plots showed a high contribution of sugars, chlorophyll, lipids and cellulose in the modelling of prediction equations. PMID- 30518062 TI - Marine Biomaterial-Based Bioinks for Generating 3D Printed Tissue Constructs. AB - Biologically active materials from marine sources have been receiving increasing attention as they are free from the transmissible diseases and religious restrictions associated with the use of mammalian resources. Among various other biomaterials from marine sources, alginate and fish gelatin (f-gelatin), with their inherent bioactivity and physicochemical tunability, have been studied extensively and applied in various biomedical fields such as regenerative medicine, tissue engineering, and pharmaceutical products. In this study, by using alginate and f-gelatin's chemical derivatives, we developed a marine-based interpenetrating polymer network (IPN) hydrogel consisting of alginate and f gelatin methacryloyl (f-GelMA) networks via physical and chemical crosslinking methods, respectively. We then evaluated their physical properties (mechanical strength, swelling degree, and degradation rate) and cell behavior in hydrogels. Our results showed that the alginate/f-GelMA hydrogel displayed unique physical properties compared to when alginate and f-GelMA were used separately. These properties included high mechanical strength, low swelling and degradation rate, and an increase in cell adhesive ability. Moreover, for the first time, we introduced and optimized the application of alginate/f-GelMA hydrogel in a three dimensional (3D) bioprinting system with high cell viability, which breaks the restriction of their utilization in tissue engineering applications and suggests that alginate/f-GelMA can be utilized as a novel bioink to broaden the uses of marine products in biomedical fields. PMID- 30518069 TI - Combination of Posaconazole and Amphotericin B in the Treatment of Candida glabrata Biofilms. AB - Candidemia cases have been increasing, especially among immunosuppressed patients. Candida glabrata is one of the most resistant Candida species, especially to the azole drugs, resulting in a high demand for therapeutic alternatives. The minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and minimum biofilm eradication concentration (MBEC) were determined for posaconazole (Pcz) and amphotericin B (AmB). The drug combinations of both drugs were evaluated on pre-formed biofilms of C. glabrata ATCC 2001, through XTT (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5 carboxanilide) assay, colony forming units (CFU), crystal violet, and the fractional inhibitory concentration index (FICI). C. glabrata revealed higher susceptibility and biofilm reduction in the presence of AmB alone, but both drugs revealed a good capacity in the biomass elimination. In the majority of the tested combinations, the interactions were defined as indifferent (FICI <= 4). The combination of the two drugs does not seem to bring a clear advantage in the treatment of biofilms of C. glabrata. PMID- 30518071 TI - Similar Strength and Power Adaptations between Two Different Velocity-Based Training Regimens in Collegiate Female Volleyball Players. AB - This study investigated the effects of two different velocity-based training (VBT) regimens on muscular adaptations. Fifteen female college volleyball players were randomly assigned into either progressive velocity-based training (PVBT) or optimum training load (OTL). Both groups trained three times a week for seven weeks. PVBT performed a 4-week strength block (e.g., 0.55-0.70 m.s-1) followed by a 3-week power block (e.g., 0.85-1.0 m.s-1), whereas OTL performed training at ~0.85-0.9 m.s-1. 1RM and peak power output (PP) assessments on the back squat (BS), bench press (BP) and deadlift (DL) exercises were assessed pre and post training. There was a main time effect (p <= 0.05) for BS and BP 1RM, (PVBT: 19.6%, ES: 1.72; OTL: 18.3%, ES: 1.57) and (PVBT: 8.5%, ES: 0.58; OTL: 10.2%, ES: 0.72), respectively. OTL increased DL 1RM to a greater extent than PVBT (p <= 0.05), (OTL: 22.9%, ES: 1.49; PVBT: 10.9%, ES: 0.88). Lastly, there was a main time effect (p <= 0.05) for BS, BP and DL PP, (PVBT: 18.3%, ES: 0.86; OTL: 19.8%, ES: 0.79); (PVBT: 14.5%, ES: 0.81; OTL: 27.9%, ES: 1.68); (PVBT: 15.7%, ES: 1.32; OTL: 20.1%, ES: 1.77) respectively. Our data suggest that both VBT regimens are effective for improving muscular performance in college volleyball players during the offseason period. PMID- 30518072 TI - Regulation of Oxidative Stress in Corneal Endothelial Cells by Prdx6. AB - The inner layer of the cornea, the corneal endothelium, is post-mitotic and unable to regenerate if damaged. The corneal endothelium is one of the most transplanted tissues in the body. Fuchs' endothelial corneal dystrophy (FECD) is the leading indication for corneal endothelial transplantation. FECD is thought to be an age-dependent disorder, with a major component related to oxidative stress. Prdx6 is an antioxidant with particular affinity for repairing peroxidised cell membranes. To address the role of Prdx6 in corneal endothelial cells, we used a combination of biochemical and functional studies. Our data reveal that Prdx6 is expressed at unusually high levels at the plasma membrane of corneal endothelial cells. RNAi-mediated knockdown of Prdx6 revealed a role for Prdx6 in lipid peroxidation. Furthermore, following induction of oxidative stress with menadione, Prdx6-deficient cells had defective mitochondrial membrane potential and were more sensitive to cell death. These data reveal that Prdx6 is compartmentalised in corneal endothelial cells and has multiple functions to preserve cellular integrity. PMID- 30518073 TI - A Facile Method to Construct MXene/CuO Nanocomposite with Enhanced Catalytic Activity of CuO on Thermal Decomposition of Ammonium Perchlorate. AB - In this work, a mixing-calcination method was developed to facilely construct MXene/CuO nanocomposite. CuO and MXene were first dispersed in ethanol with sufficient mixing. After solvent evaporation, the dried mixture was calcinated under argon to produce a MXene/CuO nanocomposite. As characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), and X-ray photoelectron spectra (XPS), CuO nanoparticles (60-100 nm) were uniformly distributed on the surface and edge of MXene nanosheets. Furthermore, as evaluated by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA), the high-temperature decomposition (HTD) temperature decrease of ammonium perchlorate (AP) upon addition of 1 wt% CuO (hybridized with 1 wt% MXene) was comparable with that of 2 wt% CuO alone, suggesting an enhanced catalytic activity of CuO on thermal decomposition of AP upon hybridization with MXene nanosheets. This strategy could be further applied to construct other MXene/transition metal oxide (MXene/TMO) composites with improved performance for various applications. PMID- 30518074 TI - mRNA-Mediated Duplexes Play Dual Roles in the Regulation of Bidirectional Ribosomal Frameshifting. AB - In contrast to -1 programmed ribosomal frameshifting (PRF) stimulation by an RNA pseudoknot downstream of frameshifting sites, a refolding upstream RNA hairpin juxtaposing the frameshifting sites attenuates -1 PRF in human cells and stimulates +1 frameshifting in yeast. This eukaryotic functional mimicry of the internal Shine-Dalgarno (SD) sequence-mediated duplex was confirmed directly in the 70S translation system, indicating that both frameshifting regulation activities of upstream hairpin are conserved between 70S and 80S ribosomes. Unexpectedly, a downstream pseudoknot also possessed two opposing hungry codon mediated frameshifting regulation activities: attenuation of +1 frameshifting and stimulation of a non-canonical -1 frameshifting within the +1 frameshift-prone CUUUGA frameshifting site in the absence of release factor 2 (RF2) in vitro. However, the -1 frameshifting activity of the downstream pseudoknot is not coupled with its +1 frameshifting attenuation ability. Similarly, the +1 frameshifting activity of the upstream hairpin is not required for its -1 frameshifting attenuation function Thus, each of the mRNA duplexes flanking the two ends of a ribosomal mRNA-binding channel possesses two functions in bi directional ribosomal frameshifting regulation: frameshifting stimulation and counteracting the frameshifting activity of each other. PMID- 30518075 TI - Copper Tridentate Schiff Base Complex Supported on SBA-15 as Efficient Nanocatalyst for Three-Component Reactions under Solventless Conditions. AB - The anchorage of a supported copper Schiff base complex on SBA-15 materials provides highly efficient heterogeneous catalysts towards the solvent-free synthesis of dihydropyrimidinones derivatives via the Biginelli condensation reaction. The novel nanocatalysts exhibited a highly ordered mesostructure with a surface area of 346 m2g-1 and an average pore diameter of 8.6 nm. Additionally, the supported copper nanocatalysts were reused at least ten times, remaining almost unchanged from the initial activity. Both the mesoporous scaffold and the tridentate Schiff base ligand contributed to the stabilization of copper species. PMID- 30518070 TI - A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability. AB - Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin participates in distinct regulatory mechanisms depending on the type of TA system. Recently, peptides designed by mimicking the interfaces between TA complexes showed its potential to activate the activity of toxin by competing its binding counterparts. Type II TA systems occur more often in pathogenic bacteria than in their nonpathogenic kin. Therefore, they can be possible drug targets, because of their high abundance in some pathogenic bacteria, such as Mycobacterium tuberculosis. In addition, recent bioinformatic analyses have shown that type III TA systems are highly abundant in the intestinal microbiota, and recent clinical studies have shown that the intestinal microbiota is linked to inflammatory diseases, obesity and even several types of cancer. We therefore focused on exploring the putative relationship between intestinal microbiota related human diseases and type III TA systems. In this paper, we review and discuss the development of possible druggable materials based on the mechanism of type II and type III TA system. PMID- 30518076 TI - A Regularized Weighted Smoothed L0 Norm Minimization Method for Underdetermined Blind Source Separation. AB - Compressed sensing (CS) theory has attracted widespread attention in recent years and has been widely used in signal and image processing, such as underdetermined blind source separation (UBSS), magnetic resonance imaging (MRI), etc. As the main link of CS, the goal of sparse signal reconstruction is how to recover accurately and effectively the original signal from an underdetermined linear system of equations (ULSE). For this problem, we propose a new algorithm called the weighted regularized smoothed L 0 -norm minimization algorithm (WReSL0). Under the framework of this algorithm, we have done three things: (1) proposed a new smoothed function called the compound inverse proportional function (CIPF); (2) proposed a new weighted function; and (3) a new regularization form is derived and constructed. In this algorithm, the weighted function and the new smoothed function are combined as the sparsity-promoting object, and a new regularization form is derived and constructed to enhance de-noising performance. Performance simulation experiments on both the real signal and real images show that the proposed WReSL0 algorithm outperforms other popular approaches, such as SL0, BPDN, NSL0, and L p -RLSand achieves better performances when it is used for UBSS. PMID- 30518077 TI - A Stellar Imaging Error Correction Method Based on an Ellipsoid Model: Taking Ziyuan 3-02 Satellite Data Analysis as an Example. AB - Stellar point image coordinates are one of the important observations needed for high-precision space attitude measurement with a star sensor. High-coupling imaging errors occur under dynamic imaging conditions. Using the results of preliminary star point extraction from star sensor imaging data combined with a superimposed time series, we analyze the relative motion and trajectory based on the star point image, establish an image error ellipsoid fitting model based on the elliptical orbit of a satellite platform, and achieve geometric error correction of a star sensors' image star point using multi-parameter screening of the ambiguous solutions of intersection of the elliptic equations. The simulation data showed that the accuracy of the correction error of this method reached 89.8%, and every star point coordinate required 0.259 s to calculate, on average. In addition, it was applied to real data from the satellite Ziyuan 3-02 to carry out the correction of the star points. The experiment shows that the mean of attitude quaternion errors for all its components was reduced by 52.3%. Our results show that the estimation parameters of dynamic imaging errors can effectively compensate for the star point image observation value and improve the accuracy of attitude calculation. PMID- 30518080 TI - Circularly Polarized Broadband Printed Antenna for Wireless Applications. AB - A simple, compact sickle-shaped printed antenna with a slotted ground plane is designed and developed for broadband circularly polarized (CP) radiation. The sickle-shaped radiator with a tapered feed line and circular slotted square ground plane are utilized to realize the wideband CP radiation feature. With optimized dimensions of 0.29lambda * 0.29lambda * 0.012lambda at 2.22 GHz frequency for the realized antenna parameters, the measured results display that the antenna has a 10 dB impedance bandwidth of 7.70 GHz (126.85%; 2.22-9.92 GHz) and a 3 dB axial ratio (AR) bandwidth of 2.64 GHz (73.33%; 2.28-4.92 GHz). The measurement agrees well with simulation, which proves an excellent circularly polarized property. For verification, the mechanism of band improvement and circular polarization are presented, and the parametric study is carried out. Since, the proposed antenna is a simple design structure with broad impedance and AR bandwidth, which is a desirable feature as a candidate for various wireless communication systems. Because of the easy printed structure and scaling the dimension with broadband CP characteristics, the realized antenna does incorporate in a number of CP wireless communication applications. PMID- 30518079 TI - Characterization of Recombinant His-Tag Protein Immobilized onto Functionalized Gold Nanoparticles. AB - The recombinant polyhistidine-tagged hemoglobin I ((His)6-rHbI) from the bivalve Lucina pectinata is an ideal biocomponent for a hydrogen sulfide (H2S) biosensor due to its high affinity for H2S. In this work, we immobilized (His)6-rHbI over a surface modified with gold nanoparticles functionalized with 3-mercaptopropionic acid complexed with nickel ion. The attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) analysis of the modified-gold electrode displays amide I and amide II bands characteristic of a primarily alpha-helix structure verifying the presence of (His)6-rHbI on the electrode surface. Also, X-ray photoelectron spectroscopy (XPS) results show a new peak after protein interaction corresponding to nitrogen and a calculated overlayer thickness of 5.3 nm. The functionality of the immobilized hemoprotein was established by direct current potential amperometry, using H2S as the analyte, validating its activity after immobilization. The current response to H2S concentrations was monitored over time giving a linear relationship from 30 to 700 nM with a corresponding sensitivity of 3.22 * 10-3 nA/nM. These results confirm that the analyzed gold nanostructured platform provides an efficient and strong link for polyhistidine tag protein immobilization over gold and glassy carbon surfaces for a future biosensors development. PMID- 30518078 TI - Validity of the Mediterranean Diet and Culinary Index (MediCul) for Online Assessment of Adherence to the 'Traditional' Diet and Aspects of Cuisine in Older Adults. AB - The Mediterranean diet is associated with multiple health benefits. Yet, no tool has been specifically developed to assess adherence to the 'traditional' Mediterranean diet and cuisine within a Western cohort, and validated for online use. We tested the reliability and validity of online administration of the Mediterranean Diet and Culinary Index (MediCul) among middle-aged and older adults. Participants were recruited in January-March 2017 from the 45 and Up Study, completing MediCul twice. Test-retest reliability was assessed using the paired t-test, intra-class correlation coefficient (ICC) and Bland-Altman plot. Validity was tested against a three-day food record (FR)-derived MediCul score using Bland-Altman and nutrient trends across the MediCul score tertiles. Participants (n = 84; 60% female; 65.4 years (SD = 5.9)), were overweight (BMI 26.1; SD = 4.0) with 1.7 (SD = 1.5) chronic illnesses/conditions. Sequential MediCul tool scores were 56.1/100.0 and 56.8/100.0, respectively (t = -1.019; p = 0.311). Reliability via ICC (ICC = 0.86, 95% CI: 0.789, 0.910, p < 0.0001) and Bland-Altman was good. In Bland-Altman validity analyses, the tool over-reported FR MediCul score by 5.6 points with no systematic bias ((y = 8.7 - 0.06*x) (95% CI: -0.278, 0.158, p = 0.584)). Nutrient trends were identified for MediCul consistent with expected Mediterranean patterns. Online MediCul administration demonstrated good reliability and moderate validity for assessing adherence to a 'traditional' Mediterranean pattern among older Australians. PMID- 30518081 TI - The Impact of Tumor Eco-Evolution in Renal Cell Carcinoma Sampling. AB - Malignant tumors behave dynamically as cell communities governed by ecological principles. Massive sequencing tools are unveiling the true dimension of the heterogeneity of these communities along their evolution in most human neoplasms, clear cell renal cell carcinomas (CCRCC) included. Although initially thought to be purely stochastic processes, very recent genomic analyses have shown that temporal tumor evolution in CCRCC may follow some deterministic pathways that give rise to different clones and sub-clones randomly spatially distributed across the tumor. This fact makes each case unique, unrepeatable and unpredictable. Precise and complete molecular information is crucial for patients with cancer since it may help in establishing a personalized therapy. Intratumor heterogeneity (ITH) detection relies on the correctness of tumor sampling and this is part of the pathologist's daily work. International protocols for tumor sampling are insufficient today. They were conceived decades ago, when ITH was not an issue, and have remained unchanged until now. Noteworthy, an alternative and more efficient sampling method for detecting ITH has been developed recently. This new method, called multisite tumor sampling (MSTS), is specifically addressed to large tumors that are impossible to be totally sampled, and represent an opportunity to improve ITH detection without extra costs. PMID- 30518082 TI - Clinical Trials and Administration of Zika Virus Vaccine in Pregnant Women: Lessons (that Should Have Been) Learned from Excluding Immunization with the Ebola Vaccine during Pregnancy and Lactation. AB - As evidenced from recent epidemics, both Ebola and Zika virus infection are potentially catastrophic when occurring in pregnant women. Ebola virus causes extremely high rates of mortality in both mothers and infants; Zika virus is a TORCH infection that produces a congenital malformation syndrome and pediatric neurodevelopmental abnormalities. Production of efficacious vaccines has been a public health priority for both infections. Unfortunately, during the clinical trials and subsequent deployment of a vaccine for the Ebola virus, pregnant and lactating women were, and continue to be, excluded from receiving the life-saving vaccine. The most serious consequence of Zika virus infection, congenital Zika syndrome, results from fetal infection during pregnancy. Thus, pregnant women have a major stake in the ongoing development of a vaccine for Zika virus. The exclusion of pregnant women from the development, clinical trials and administration of a potential Zika vaccine unfairly deprives them and their infants of the protection they need against this potentially catastrophic intrauterine infection. When creating policy about these issues, it is important to critically evaluate vaccine safety in pregnancy in the context of the substantial risk of infection for the pregnant woman and her fetus in the absence of immunization. PMID- 30518083 TI - Silica Aerogel Monoliths Derived from Silica Hydrosol with Various Surfactants. AB - Owing to their ultra-low thermal conductivity, silica aerogels are promising thermal insulators; however, their extensive application is limited by their high production cost. Thus, scientists have started to explore low-cost and easy preparation processes of silica aerogels. In this work, a low-cost method was proposed to prepare silica aerogels with industrial silica hydrosol and a subsequent ambient pressure drying (APD) process. Various surfactants (cationic, amphoteric, or anionic) were added to avoid solvent exchange and surface modification during the APD process. The effects of various surfactants on the microstructure, thermal conductivity, and thermal stability of the silica aerogels were studied. The results showed that the silica aerogels prepared with a cationic or anionic surfactant have better thermal stability than that prepared with an amphoteric surfactant. After being heated at 600 degrees C, the silica aerogel prepared with a cationic surfactant showed the highest specific surface area of 131 m2?g-1 and the lowest thermal conductivity of 0.038 W?m-1?K-1. The obtained low-cost silica aerogel with low thermal conductivity could be widely applied as a thermal insulator for building and industrial energy-saving applications. PMID- 30518084 TI - Infiltrated Photonic Crystal Fibers for Sensing Applications. AB - Photonic crystal fibers (PCFs) are a special class of optical fibers with a periodic arrangement of microstructured holes located in the fiber's cladding. Light confinement is achieved by means of either index-guiding, or the photonic bandgap effect in a low-index core. Ever since PCFs were first demonstrated in 1995, their special characteristics, such as potentially high birefringence, very small or high nonlinearity, low propagation losses, and controllable dispersion parameters, have rendered them unique for many applications, such as sensors, high-power pulse transmission, and biomedical studies. When the holes of PCFs are filled with solids, liquids or gases, unprecedented opportunities for applications emerge. These include, but are not limited in, supercontinuum generation, propulsion of atoms through a hollow fiber core, fiber-loaded Bose Einstein condensates, as well as enhanced sensing and measurement devices. For this reason, infiltrated PCF have been the focus of intensive research in recent years. In this review, the fundamentals and fabrication of PCF infiltrated with different materials are discussed. In addition, potential applications of infiltrated PCF sensors are reviewed, identifying the challenges and limitations to scale up and commercialize this novel technology. PMID- 30518085 TI - Association of Low Lead Levels with Behavioral Problems and Executive Function Deficits in Schoolers from Montevideo, Uruguay. AB - The negative effect of lead exposure on children's intelligence is well documented. Less is known about the impact of lead on the use of executive functions to self-regulate behavior. We measured blood lead level (BLL) in a sample of first grade children from Montevideo, Uruguay (n = 206, age 6.7 +/- 0.5 years, 59.7% boys). Behavior was assessed with teacher versions of the Conners Rating Scale (CRS) and the Behavior Rating Inventory of Executive Functions (BRIEF). Mean BLL was 4.2 +/- 2.1 MUg/dL; 10% had mild-to-severe ratings of Attentional Deficit with Hyperactivity Disorder (ADHD) (T score > 65). In negative binomial regression, BLL was not associated with CRS sub-scales, but was associated with a poorer ability to inhibit inappropriate behaviors, prevalence ratio (PR) [95% CI]: 1.01 [1.00, 1.03] as measured by the BRIEF. In covariate adjusted models, the association with BLL was attenuated. When stratified by sex, the covariate-adjusted association between BLL, hyperactivity, poorer inhitibion, emotional control, and behavioral regulation was marginally significant for girls but not boys. In summary, among children with low lead-exposure, we found some, but nonetheless modest, evidence of a relationship between higher BLL and child behavior. If confirmed by larger studies and other objective measures of behavior, such links could have implications for learning and social interaction, particularly among girls. PMID- 30518086 TI - Combining Actigraph Link and PetPace Collar Data to Measure Activity, Proximity, and Physiological Responses in Freely Moving Dogs in a Natural Environment. AB - Although several studies have examined the effects of an owner's absence and presence on a dog's physiological responses under experimental conditions over short periods of time (minutes), little is known about the effects of proximity between humans and freely moving dogs under natural conditions over longer periods of time (days). The first aim of our study was to determine whether the combined data generated from the PetPace Collar and Actigraph Link accelerometer provide reliable pulse, respiration, and heart rate variability results during sedentary, light-moderate, and vigorous bouts in 11 freely moving dogs in a foster caretaker environment over 10-15 days. The second aim was to determine the effects of proximity (absence and presence of caretaker) and distance (caretaker and dog within 0-2 m) on the dogs' physiological responses. Aim 1 results: Pulse and respiration were higher during light-moderate bouts compared to sedentary bouts, and higher at rest while the dogs were standing and sitting vs. lying. Heart rate variability (HRV) was not different between activity levels or position. Aim 2 results: During sedentary bouts, pulse and respiration were higher, and HRV lower, when there was a proximity signal (caretaker present) compared to no proximity signal (caretaker absent). Using multiple regression models, we found that activity, position, distance, and signal presence were predictors of physiological response in individual dogs during sedentary bouts. Our results suggest that combining data collected from Actigraph GT9X and PetPace monitors will provide useful information, both collectively and individually, on dogs' physiological responses during activity, in various positions, and in proximity to their human caretaker. PMID- 30518087 TI - Performance Evaluation of a Magnetically Actuated Capsule Microrobotic System for Medical Applications. AB - The paper aims to propose a magnetic actuated capsule microrobotic system, which is composed of a magnetically actuated microrobot with a screw jet mechanism, a driving system, and a positioning system. The magnetically actuated microrobot embedded an O-ring magnet as an actuator has potential for achieving a particular task, such as medical diagnose or drug delivery. The driving system composes of a three axes Helmholtz coils to generate a rotational magnetic field for controlling the magnetically actuated microrobot to realize the basic motion in pipe, e.g., forward/backward motion and upward/downward motion. The positioning system is used to detect the pose of the magnetically actuated microrobot in pipe. We will discuss the shape of the Helmholtz coils and the magnetic field around the O-ring magnet to obtain an optimal performance of the magnetically actuated microrobot. The experimental result indicated that the microrobot with screw jet motion has a flexible movement in pipe by adjusting the rotational magnetic field plane and the magnetic field changing frequency. PMID- 30518088 TI - Glycodelin as a Serum and Tissue Biomarker for Metastatic and Advanced NSCLC. AB - A major part of non-small cell lung cancer (NSCLC) patients treated with mono- or multimodal concept develop therapy resistance. Despite the abundance of biomarkers investigated in the past, there is still a need for valid NSCLC biomarkers. Glycodelin, an immunosuppressive endometrial protein, has been shown to be also expressed in NSCLC. Here, we investigated its potential as a biomarker in metastatic and advanced stage NSCLC. Glycodelin gene and protein expression were measured in 28 therapy-naive resected tumors as well as in corresponding brain (n = 16) and adrenal gland (n = 12) metastasis by qPCR and IHC. Moreover, we correlated glycodelin gene expression of cryoconserved therapy-naive biopsies (n = 55) of advanced stage patients with glycodelin serum concentrations and patient survival. Using follow-up samples of the patients, we monitored glycodelin serum concentrations during therapy. Glycodelin expression correlated between primary tumor and distant metastases within the same patients. The gene expression of glycodelin in therapy-naive biopsies also correlated with the serum concentrations of the patients (r = 0.60). Patients with elevated serum concentrations showed a tendency in lower overall survival (p = 0.088) and measuring of glycodelin indicated a progression of the disease earlier compared to clinical diagnostic. Taken together, we demonstrate that glycodelin is a promising prognostic and follow-up biomarker for metastatic and advanced NSCLC. PMID- 30518089 TI - Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. AB - Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors. PMID- 30518090 TI - The Biological Significance and Regulatory Mechanism of c-Myc Binding Protein 1 (MBP-1). AB - Alternatively translated from the ENO gene and expressed in an array of vertebrate and plant tissues, c-Myc binding protein 1 (MBP-1) participates in the regulation of growth in organisms, their development and their environmental responses. As a transcriptional repressor of multiple proto-oncogenes, vertebrate MBP-1 interacts with other cellular factors to attenuate the proliferation and metastasis of lung, breast, esophageal, gastric, bone, prostrate, colorectal, and cervical cancer cells. Due to its tumor-suppressive property, MBP-1 and its downstream targets have been investigated as potential prognostic markers and therapeutic targets for various cancers. In plants, MBP-1 plays an integral role in regulating growth and development, fertility and abiotic stress responses. A better understanding of the functions and regulatory factors of MBP-1 in plants may advance current efforts to maximize plant resistance against drought, high salinity, low temperature, and oxidative stress, thus optimizing land use and crop yields. In this review article, we summarize the research advances in biological functions and mechanistic pathways underlying MBP-1, describe our current knowledge of the ENO product and propose future research directions on vertebrate health as well as plant growth, development and abiotic stress responses. PMID- 30518091 TI - Exploring Protein-Inorganic Hybrid Nanoflowers and Immune Magnetic Nanobeads to Detect Salmonella Typhimurium. AB - Early screening of pathogenic bacteria is key to preventing and controlling outbreaks of foodborne diseases. In this study, protein-inorganic hybrid nanoflowers were synthesized for signal amplification and used with a calcium ion selective electrode (Ca-ISE) to establish a new enzyme-free assay for rapid and sensitive detection of Salmonella. Calcium hydrophosphate crystals were first conjugated with polyclonal antibodies against Salmonella to synthesize immune calcium nanoflowers (CaNFs), and streptavidin modified magnetic nanobeads (MNBs) were conjugated with biotinylated monoclonal antibodies against Salmonella to form immune MNBs. After target bacteria were separated using immune MNBs to form magnetic bacteria, immune CaNFs were conjugated with magnetic bacteria to form nanoflower conjugated bacteria. Then, hydrogen chloride was used to release calcium ions from nanoflower conjugated bacteria. After magnetic separation, the supernatant was finally injected as a continuous-flow to fluidic chip with Ca-ISE for specific detection of calcium ions. The supernatant's potential had a good linear relationship with bacteria concentration, and this assay was able to detect the S. Typhimurium cells as low as 28 colony forming units/mL within two hours. The mean recovery of target bacteria in spiked chicken samples was 95.0%. This proposed assay shows the potential for rapid, sensitive, and on-line detection of foodborne pathogens. PMID- 30517796 TI - Combination of the Searches for Pair-Produced Vectorlike Partners of the Third Generation Quarks at sqrt[s]=13 TeV with the ATLAS Detector. AB - A combination of the searches for pair-produced vectorlike partners of the top and bottom quarks in various decay channels (T->Zt/Wb/Ht, B->Zb/Wt/Hb) is performed using 36.1 fb^{-1} of pp collision data at sqrt[s]=13 TeV with the ATLAS detector at the Large Hadron Collider. The observed data are found to be in good agreement with the standard model background prediction in all individual searches. Therefore, combined 95% confidence-level upper limits are set on the production cross section for a range of vectorlike quark scenarios, significantly improving upon the reach of the individual searches. Model-independent limits are set assuming the vectorlike quarks decay to standard model particles. A singlet T is excluded for masses below 1.31 TeV and a singlet B is excluded for masses below 1.22 TeV. Assuming a weak isospin (T,B) doublet and |V_{Tb}|?|V_{tB}|, T and B masses below 1.37 TeV are excluded. PMID- 30518092 TI - Nanoclay Intercalation During Foaming of Polymeric Nanocomposites Studied in-Situ by Synchrotron X-Ray Diffraction. AB - The intercalation degree of nanoclays in polymeric foamed nanocomposites containing clays is a key parameter determining the final properties of the material, but how intercalation occurs is not fully understood. In this work, energy dispersive X-ray diffraction (ED-XRD) of synchrotron radiation was used as an in-situ technique to deepen into the intercalation process of polymer/nanoclay nanocomposites during foaming. Foamable nanocomposites were prepared by the melt blending route using low-density polyethylene (LDPE), polypropylene (PP), and polystyrene (PS) with surface treated nanoclays and azodicarbonamide (ADC) as the blowing agent. Foaming was induced by heating at atmospheric pressure. The time and temperature evolution of the interlamellar distance of the clay platelets in the expanding nanocomposites was followed. Upon foaming, interlamellar distances of the nanocomposites based on LDPE and PP increase by 18% and 16% compared to the bulk foamable nanocomposite. Therefore, the foaming process enhances the nanoclay intercalation degree in these systems. This effect is not strongly affected by the type of nanoclay used in LDPE, but by the type of polymer used. Besides, the addition of nanoclays to PP and PS has a catalytic effect on the decomposition of ADC, i.e., the decomposition temperature is reduced, and the amount of gas released increases. This effect was previously proved for LDPE. PMID- 30518094 TI - Sensor Distribution Optimization for Structural Impact Monitoring Based on NSGA II and Wavelet Decomposition. AB - Optimal sensor placement is a significant task for structural health monitoring (SHM). In this paper, an SHM system is designed which can recognize the different impact location and impact degree in the composite plate. Firstly, the finite element method is used to simulate the impact, extracting numerical signals of the structure, and the wavelet decomposition is used to extract the band energy. Meanwhile, principal component analysis (PCA) is used to reduce the dimensions of the vibration signal. Following this, the non-dominated sorting genetic algorithm (NSGA-II) is used to optimize the placement of sensors. Finally, the experimental system is established, and the Product-based Neural Network is used to recognize different impact categories. Three sets of experiments are carried out to verify the optimal results. When three sensors are applied, the average accuracy of the impact recognition is 59.14%; when the number of sensors is four, the average accuracy of impact recognition is 76.95%. PMID- 30518093 TI - Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells. AB - Parkinson's disease (PD) and atypical parkinsonian syndromes are age-dependent multifactorial neurodegenerative diseases, which are clinically characterized by bradykinesia, tremor, muscle rigidity and postural instability. Although these diseases share several common clinical phenotypes, their pathophysiological aspects vary among the disease categories. Extensive animal-based approaches, as well as postmortem studies, have provided important insights into the disease mechanisms and potential therapeutic targets. However, the exact pathological mechanisms triggering such diseases still remain elusive. Furthermore, the effects of drugs observed in animal models are not always reproduced in human clinical trials. By using induced pluripotent stem cell (iPSC) technology, it has become possible to establish patient-specific iPSCs from their somatic cells and to effectively differentiate these iPSCs into different types of neurons, reproducing some key aspects of the disease phenotypes in vitro. In this review, we summarize recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome. Furthermore, we discuss future challenges and prospects for modeling and understanding PD and atypical parkinsonian syndromes. PMID- 30518096 TI - Incentive Strategies for Low-Carbon Supply Chains with Asymmetric Information of Carbon Reduction Efficiency. AB - Information concerning carbon reduction efficiency is of great significance to supply chain operations. Considering the impact of information asymmetry on the performance of low-carbon supply chain, we therefore analyze a chain system with a single product designer and a single manufacturer. The manufacturer owns information on carbon reduction efficiency, whereas the product designer only knows that the carbon reduction efficiency of the manufacturer is either high or low. To induce the manufacturer to reveal his true private information of carbon reduction efficiency to the product designer, we devise the pooling and separating equilibrium models to compare the impacts of these two models on supply chain performance, respectively. We find that the high-efficiency manufacturer gets his first-best choice at the equilibrium decision in the separating model, and obtains the information rent in the pooling model. The information rent increases in the efficiency difference between the two emission reduction types. Additionally, we examine how the probability of the high (or low)-efficiency manufacturer being chosen impacts on both the profits of chain members and carbon-reduction levels. The research provides a reference for companies about how to cooperate with partner who possess private information of carbon emissions. PMID- 30518101 TI - Lifetime Spousal Violence Victimization and Perpetration, Physical Illness, and Health Risk Behaviours among Women in India. AB - The aim of this study was to assess the association between lifetime spousal violence victimization, spousal violence perpetration, and physical health outcomes and behaviours among women in India. In the 2015-2016 National Family Health Survey, a sample of ever-married women (15-49 years) (N = 66,013) were interviewed about spousal violence. Results indicate that 29.9% of women reported lifetime spousal physical violence victimization and 7.1% lifetime spousal sexual violence victimization (31.1% physical and/or sexual violence victimization), and 3.5% lifetime spousal physical violence perpetration. Lifetime spousal violence victimization and lifetime spousal violence perpetration were significantly positively correlated with asthma, genital discharge, genital sores or ulcers, sexually transmitted infections (STIs), tobacco use, alcohol use, and termination of pregnancy, and negatively associated with daily consumption of dark vegetables. In addition, lifetime spousal violence victimization was positively associated with being underweight, high random blood glucose levels, and anaemia, and negatively correlated with being overweight or obese. Lifetime spousal violence perpetration was marginally significantly associated with hypertension. The study found in a national sample of women in India a decrease of lifetime physical and/or sexual spousal violence victimization and an increase of lifetime spousal physical violence perpetration from 2005/5 to 2015/6. The results support other studies that found that, among women, lifetime spousal physical and/or sexual spousal violence victimization and lifetime spousal physical violence perpetration increase the odds of chronic conditions, physical illnesses, and health risk behaviours. PMID- 30518103 TI - Perturbing the Dynamics and Organization of Cell Membrane Components: A New Paradigm for Cancer-Targeted Therapies. AB - Cancer is a multi-process disease where different mechanisms exist in parallel to ensure cell survival and constant adaptation to the extracellular environment. To adapt rapidly, cancer cells re-arrange their plasma membranes to sustain proliferation, avoid apoptosis and resist anticancer drugs. In this review, we discuss novel approaches based on the modifications and manipulations that new classes of molecules can exert in the plasma membrane lateral organization and order of cancer cells, affecting growth factor signaling, invasiveness, and drug resistance. Furthermore, we present azurin, an anticancer protein from bacterial origin, as a new approach in the development of therapeutic strategies that target the cell membrane to improve the existing standard therapies. PMID- 30518095 TI - Three-Year Chronic Consumption of Low-Carbohydrate Diet Impairs Exercise Performance and Has a Small Unfavorable Effect on Lipid Profile in Middle-Aged Men. AB - The objective of this research was to determine whether chronic (average 3.58 +/- 1.56 years) deliberate adherence to low carbohydrate diets (LCDs) is associated with selected markers of metabolism, risk factors of cardiovascular disease (CVD), body mass and physical performance in apparently healthy middle-aged men (n = 12). The control group comprised age, body mass and height matched men using mixed diets (MDs). The diets used were registered for 7 days and analyzed in terms of the energy, carbohydrate, fat and protein contents. It was found that the diets used were isoenergetic, yet varied considerably in carbohydrate and fat content. The LCDs significantly intensified the ketogenesis process, increased resting blood total cholesterol (TC), high-density lipoprotein cholesterol (HDL C), and heart rate, (HR) and decreased respiratory exchange ratio (RER) in relation to MD subjects. An exercise trial revealed significant impairment of exercise in subjects following the LCDs. The results showed that in the case where the subjects of two investigated groups did not differ in their somatic variables, long-term adherence to the LCDs was associated with substantially reduced exercise performance in apparently healthy subjects, along with an association with a small unfavorable effect on their lipid profile. PMID- 30518102 TI - MAPLE Assembled Acetylcholinesterase-Polyethylenimine Hybrid and Multilayered Interfaces for Toxic Gases Detection. AB - Developing a controlled method for obtaining hybrid enzymatic-based interfaces for sensing application require the use of a multiuse, reusable sensor. By controlling the interface characteristics in terms of the surface chemistry, thickness, and roughness, a tailored response toward various toxic compounds can be obtained, regarding both materials used as active surfaces and fabrication methods. Herein, we report a preliminary study on using a laser-based method (i.e., matrix-assisted pulsed laser evaporation, or MAPLE) for obtaining active polymeric-enzymatic interfaces as hybrid or layered coatings for detecting toxic vapors. The MAPLE fabrication consisted of the simultaneous alternating evaporation of layers of polyethylenimine (PEI) and acetylcholinesterase (AchE) in order to obtain active surfaces as both hybrid PEI-AchE and a PEI/AchE layered coating, respectively. The deposition processes of the polymer and enzyme were carried out using a double-target system and a Nd:YAG pulsed laser, operating at 0.45 J/cm2 fluences with a wavelength of 266 nm and a repetition rate of 10 Hz. Fourier transform infrared spectroscopy revealed no significant changes in the functional groups of both hybrid and layered coatings compared with the initial material. The thickness and roughness, as well as the morphologies of the coatings revealed by atomic force microscopy and scanning electron microscopy showed coatings thicker than two MUm that had smooth surfaces and average roughness values below six nm. The sensors were tested with simulants for nerve gases and pesticides containing phosphonate ester groups, namely dimethyl methylphosphonate (DMMP) and diisopropyl methylphosphonate (DIMP), and a different sensitivity was shown to the selected chemical agents for each of the sensors. The best sensitivities for DMMP and DIMP obtained by using a PEI-AchE coated sensor are 65 kHz and 200 kHz, respectively, whereas the best sensitivity when using multilayered interfaces is 30 kHz and 10 KHz for DIMP and DMMP, respectively. PMID- 30518104 TI - Pharmacological Inhibition of LSD1 for Cancer Treatment. AB - Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. Pharmacological inhibition of LSD1 has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of LSD1, its role in carcinogenesis, a comparison of currently available approaches for screening LSD1 inhibitors, a classification of LSD1 inhibitors, and its potential as a drug target in cancer therapy. PMID- 30518098 TI - Appropriate Imaging Modality for the Etiologic Diagnosis of Congenital Single Sided Deafness in Children. AB - We aimed to compare the diagnostic yield between temporal bone computed tomography (TBCT) and internal auditory canal MRI (IAC MRI) for the etiologic diagnosis of children with congenital single-sided deafness (SSD) and the evaluation of cochlear implant (CI) candidacy. In the original cohort, 24 subjects with congenital SSD were enrolled and underwent both TBCT and IAC MRI. We recruited an additional 22 consecutive infants with congenital SSD (the supplementary cohort) and evaluated in particular the cochlear nerve (CN) integrity using IAC MRI. Cochlear nerve deficiency (CND) was classified as 'absent', 'small', and 'indeterminate' via mutual comparison between optical and parameters based on the MRI results. The most common etiologies were CND in the original cohort (19 out of 24). Notably, accurate evaluations of CN status ('small CN' = 2, 'indeterminate CN' = 2), inner ear malformations, and brain abnormalities were possible only with MRI. The 'indeterminate CN' tended to be more frequently detected in SSD ears than in unaffected ears. MRI appeared to be more accurate than TBCT in a meticulous differentiation of CN, which is crucial for the selection of appropriate CI candidacy among congenital SSD children. Additionally, we introduced the novel concept of 'indeterminate CN', of which the causal relationship with SSD awaits confirmation. PMID- 30518097 TI - The Role of Tumor Necrosis Factor alpha in the Biology of Uterine Fibroids and the Related Symptoms. AB - Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. The incidence of UFs has been estimated at 25-80% depending on selected population. The pathophysiology of UFs remains poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is the main component of all pathways leading to UF tumor formation and tumor necrosis factor alpha (TNF-alpha) is believed to be one of the key factors in this field. TNF-alpha is a cell signaling protein involved in systemic inflammation and is one of the cytokines responsible for the acute phase reaction. This publication presents current data about the role of tumor necrosis factor alpha in the biology of UFs and the related symptoms. TNF alpha is an extremely important cytokine associated with the biology of UFs, UF related symptoms and complaints. Its concentration has been proven to be elevated in women with clinically symptomatic UFs. The presented data suggest the presence of an "inflammation-like" state in women with UFs where TNF-alpha is a potent inflammation inducer. The origin of numerous symptoms reported by women with UFs can be traced back to the TNF-alpha influence. Nevertheless, our knowledge on this subject remains limited and TNF-alpha dependent pathways in UF pathophysiology should be investigated further. PMID- 30518099 TI - Adverse Drug Reaction Predictions Using Stacking Deep Heterogeneous Information Network Embedding Approach. AB - Inferring potential adverse drug reactions is an important and challenging task for the drug discovery and healthcare industry. Many previous studies in computational pharmacology have proposed utilizing multi-source drug information to predict drug side effects have and achieved initial success. However, most of the prediction methods mainly rely on direct similarities inferred from drug information and cannot fully utilize the drug information about the impact of protein-protein interactions (PPI) on potential drug targets. Moreover, most of the methods are designed for specific tasks. In this work, we propose a novel heterogeneous network embedding approach for learning drug representations called SDHINE, which integrates PPI information into drug embeddings and is generic for different adverse drug reaction (ADR) prediction tasks. To integrate heterogeneous drug information and learn drug representations, we first design different meta-path-based proximities to calculate drug similarities, especially target propagation meta-path-based proximity based on PPI network, and then construct a semi-supervised stacking deep neural network model that is jointly optimized by the defined meta-path proximities. Extensive experiments with three state-of-the-art network embedding methods on three ADR prediction tasks demonstrate the effectiveness of the SDHINE model. Furthermore, we compare the drug representations in terms of drug differentiation by mapping the representations into 2D space; the results show that the performance of our approach is superior to that of the comparison methods. PMID- 30518105 TI - Evaluation of Continuous Lactate Monitoring Systems within a Heparinized In Vivo Porcine Model Intravenously and Subcutaneously. AB - We present an animal model used to evaluate the in vivo performance of electrochemical amperometric continuous lactate sensors compared to blood gas instruments. Electrochemical lactate sensors were fabricated, placed into 5 Fr central venous catheters (CVCs), and paired with wireless potentiostat devices. Following in vivo evaluation and calibration, sensors were placed within the jugular and femoral veins of a porcine subject as a preliminary assessment of in vivo measurement accuracy. The mobile electronic circuit potentiostat devices supplied the operational voltage for the sensors, measured the resultant steady state current, and recorded the sensor response values in internal memory storages. An in vivo time trace of implanted intravenous (IV) sensors demonstrated lactate values that correlated well with the discrete measurements of blood samples on a benchtop point-of-care sensor-based instrument. Currents measured continuously from the implanted lactate sensors over 10 h were converted into lactate concentration values through use of a two-point in vivo calibration. Study shows that intravenously implanted sensors had more accurate readings, faster peak-reaching rates, and shorter peak-detection times compared to subcutaneously placed sensors. IV implanted and subcutaneously placed sensors closer to the upper body (in this case neck) showed faster response rates and more accurate measurements compared to those implanted in the lower portion of the porcine model. This study represents an important milestone not only towards continuous lactate monitoring for early diagnosis and intervention in neonatal patients with congenital heart disease undergoing cardiopulmonary bypass surgeries, but also in the intervention of critical ill patients in the Intensive Care Units or during complex surgical procedures. PMID- 30518100 TI - Decreased Bioelectrical Impedance Phase Angle in Hospitalized Children and Adolescents with Newly Diagnosed Type 1 Diabetes: A Case-Control Study. AB - The aim of this study was to assess the body composition and nutritional status of hospitalized pediatric patients with newly diagnosed type 1 diabetes by using bioelectrical impedance analysis (BIA) with phase angle (PA) calculation. PA is considered to be a useful and very sensitive indicator of the nutritional and functional status, and it has not yet been evaluated in such a population. Sixty three pediatric patients aged 4 to 18 years, with newly diagnosed type 1 diabetes, were included in the study. The control group consisted of 63 healthy children and adolescents strictly matched by gender and age in a 1:1 case: control manner. In both groups, BIA with PA calculation was performed. Diabetic patients, in comparison to control subjects, had a highly significantly lower PA of 4.85 +/- 0.86 vs. 5.62 +/- 0.81, p < 0.001. They also demonstrated a lower percentage of body cell mass (BCM%), 46.89 +/- 5.67% vs. 51.40 +/- 4.19%, p < 0.001; a lower body cell mass index (BCMI), 6.57 +/- 1.80% vs. 7.37 +/- 1.72%, p = 0.004; and a lower percentage of muscle mass (MM%), 44.61 +/- 6.58% vs. 49.40 +/- 7.59%, p < 0.001, compared to non-diabetic controls. The significantly lower PA value in diabetic patients indicate their worse nutritional and functional status compared to healthy subjects. To assess the predictive and prognostic value of this finding in this population, further prospective studies involving larger sample of patients are required. PMID- 30518106 TI - Intracellular Accumulation of Linezolid and Florfenicol in OptrA-Producing Enterococcus faecalis and Staphylococcus aureus. AB - The optrA gene, which confers transferable resistance to oxazolidinones and phenicols, is defined as an ATP-binding cassette (ABC) transporter but lacks transmembrane domains. The resistance mechanism of optrA and whether it involves antibiotic efflux or ribosomal protection remain unclear. In this study, we determined the MIC values of all bacterial strains by broth microdilution, and used ultra-high performance liquid chromatography-tandem quadrupole mass spectrometry to quantitatively determine the intracellular concentrations of linezolid and florfenicol in Enterococcus faecalis and Staphylococcus aureus. Linezolid and florfenicol both accumulated in susceptible strains and optrA carrying strains of E. faecalis and S. aureus. No significant differences were observed in the patterns of drug accumulation among E. faecalis JH2-2, E. faecalis JH2-2/pAM401, and E. faecalis JH2-2/pAM401+optrA, but also among S. aureus RN4220, S. aureus RN4220/pAM401, and S. aureus RN4220/pAM401+optrA. ANOVA scores also suggested similar accumulation conditions of the two target compounds in susceptible strains and optrA-carrying strains. Based on our findings, the mechanism of optrA-mediated resistance to oxazolidinones and phenicols obviously does not involve active efflux and the OptrA protein does not confer resistance via efflux like other ABC transporters. PMID- 30518107 TI - Synthesis and Gas Transport Properties of Poly(2,6-dimethyl-1,4-phenylene oxide) Silica Nanocomposite Membranes. AB - The emulsion polymerized mixed matrix (EPMM) method is a new approach to prepare nanocomposite membranes, in which inorganic nanoparticles are synthesized in situ at the interface of a dispersed aqueous phase in a continuous phase of polymer solution. In this paper, we report the synthesis and characterization of poly(2,6 dimethyl-1,4-phenylene oxide) (PPO)-based EPMM membranes, in which silica nanoparticles are synthesized by the polymerization of tetraethylorthosilicate (TEOS) in the presence of two different co-solvents, ethanol and acetone, which are soluble in both the aqueous phase and the polymer solution. The EPPM membranes prepared in the presence of acetone show greater conversions of TEOS and a different structure of the synthesized silica nanoparticles compared to the EPMM membranes prepared in the presence of ethanol. The former membranes are both more permeable and more selective for O2/N2 and CO2/CH4. Both types of EPMM membranes are more permeable than the reference PPO membranes. However, while their O2/N2 selectivity is practically unchanged, their CO2/CH4 selectivity is decreased compared to the reference PPO membranes. PMID- 30518108 TI - Intensity Modulated Radiotherapy (IMRT) + Carbon Ion Boost for Adenoid Cystic Carcinoma of the Minor Salivary Glands in the Oral Cavity. AB - BACKGROUND: Adenoid cystic carcinoma (ACC) are more common in the minor salivary glands (MiSGs) than the major salivary glands, and are characterized by slow tumor progression and frequently local recurrence. The main treatment option is surgery followed by combined radiotherapy. METHODS: A retrospective analysis contained 67 patients with ACC of MiSGs in the oral cavity who underwent surgery followed by radiotherapy. The median cumulative IMRT dose was 50 Gy followed by 24 Gy for carbon ion (C12) boost. Median follow-up was 40 months. RESULTS: Median 5-years overall survival (OS), progression-free survival (PFS) and local disease free survival (LDFS) rates were 85.5%, 57.4% and 74.9%. Median time until progression was detected was 32 months (range: 2-205 months). Early grade >=3 mucositis, dermatitis, and dysphagia were detected in 52.2%, 7.5% and 11.9% respectively. Besides common toxicities, two patients (3.0%) developed grade 3 toxicities with osteoradionecrosis of the jaw after 18 and 66 months. Higher grade late toxicity (CTCAE grade 4) was not detected. No treatment-related death was detected. CONCLUSIONS: Our results demonstrate that postoperative combined radiotherapy with IMRT plus C12 boost seems to be a feasible and effective treatment method in ACC of MiSGs in the oral cavity, with good control and survival rates and adequate toxicity. PMID- 30518109 TI - Bystander Phage Therapy: Inducing Host-Associated Bacteria to Produce Antimicrobial Toxins against the Pathogen Using Phages. AB - Brevibacillus laterosporus is often present in beehives, including presence in hives infected with the causative agent of American Foulbrood (AFB), Paenibacillus larvae. In this work, 12 B. laterosporus bacteriophages induced bactericidal products in their host. Results demonstrate that P. larvae is susceptible to antimicrobials induced from field isolates of the bystander, B. laterosporus. Bystander antimicrobial activity was specific against the pathogen and not other bacterial species, indicating that the production was likely due to natural competition between the two bacteria. Three B. laterosporus phages were combined in a cocktail to treat AFB. Healthy hives treated with B. laterosporus phages experienced no difference in brood generation compared to control hives over 8 weeks. Phage presence in bee larvae after treatment rose to 60.8 +/- 3.6% and dropped to 0 +/- 0.8% after 72 h. In infected hives the recovery rate was 75% when treated, however AFB spores were not susceptible to the antimicrobials as evidenced by recurrence of AFB. We posit that the effectiveness of this treatment is due to the production of the bactericidal products of B. laterosporus when infected with phages resulting in bystander-killing of P. larvae. Bystander phage therapy may provide a new avenue for antibacterial production and treatment of disease. PMID- 30518110 TI - Context/Resource-Aware Mission Planning Based on BNs and Concurrent MDPs for Autonomous UAVs. AB - This paper presents a scalable approach to model uncertainties within a UAV (Unmanned Aerial Vehicle) embedded mission manager. It proposes a concurrent version of BFM models, which are Bayesian Networks built from FMEA (Failure Mode and Effects Analysis) and used by MDPs (Markov Decision Processes). The models can separately handle different applications during the mission; they consider the context of the mission including external constraints (luminosity, climate, etc.), the health of the UAV (Energy, Sensor) as well as the computing resource availability including CPU (Central Processing Unit) load, FPGA (Field Programmable Gate Array) use and timing performances. The proposed solution integrates the constraints into a mission specification by means of FMEA tables in order to facilitate their specifications by non-experts. Decision-making processes are elaborated following a "just enough" quality management by automatically providing adequate implementation of the embedded applications in order to achieve the mission goals, in the context given by the sensors and the on-board monitors. We illustrate the concurrent BFM approach with a case study of a typical tracking UAV mission. This case also considers a FPGA-SoC (FPGA-System on Chip) platform into consideration and demonstrates the benefits to tune the quality of the embedded applications according to the environmental context. PMID- 30518111 TI - Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression. AB - We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson's disease and Alzheimer's disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS) stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-kappaB). We found that pseudane-VII attenuated LPS induced phosphorylation of MAPK and NF-kappaB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane VII may represent a potential novel target for treatment for neurodegenerative diseases. PMID- 30518112 TI - Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA). AB - Unravelling the complex molecular pathways responsible for motor neuron degeneration in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) remains a persistent challenge. Interest is growing in the potential molecular similarities between these two diseases, with the hope of better understanding disease pathology for the guidance of therapeutic development. The aim of this study was to conduct a comparative analysis of published proteomic studies of ALS and SMA, seeking commonly dysregulated molecules to be prioritized as future therapeutic targets. Fifteen proteins were found to be differentially expressed in two or more proteomic studies of both ALS and SMA, and bioinformatics analysis identified over-representation of proteins known to associate in vesicles and molecular pathways, including metabolism of proteins and vesicle-mediated transport-both of which converge on endoplasmic reticulum (ER)-Golgi trafficking processes. Calreticulin, a calcium-binding chaperone found in the ER, was associated with both pathways and we independently confirm that its expression was decreased in spinal cords from SMA and increased in spinal cords from ALS mice. Together, these findings offer significant insights into potential common targets that may help to guide the development of new therapies for both diseases. PMID- 30518113 TI - Presyncodon, a Web Server for Gene Design with the Evolutionary Information of the Expression Hosts. AB - In the natural host, most of the synonymous codons of a gene have been evolutionarily selected and related to protein expression and function. However, for the design of a new gene, most of the existing codon optimization tools select the high-frequency-usage codons and neglect the contribution of the low frequency-usage codons (rare codons) to the expression of the target gene in the host. In this study, we developed the method Presyncodon, available in a web version, to predict the gene code from a protein sequence, using built-in evolutionary information on a specific expression host. The synonymous codon usage pattern of a peptide was studied from three genomic datasets (Escherichia coli, Bacillus subtilis, and Saccharomyces cerevisiae). Machine-learning models were constructed to predict a selection of synonymous codons (low- or high frequency-usage codon) in a gene. This method could be easily and efficiently used to design new genes from protein sequences for optimal expression in three expression hosts (E. coli, B. subtilis, and S. cerevisiae). Presyncodon is free to academic and noncommercial users; accessible at http://www.mobioinfor.cn/presyncodon_www/index.html. PMID- 30518114 TI - Isoamericanoic Acid B from Acer tegmentosum as a Potential Phytoestrogen. AB - Phytoestrogens derived from plants have attracted the attention of the general public and the medical community due to their potentially beneficial role in relieving menopausal symptoms. The deciduous tree Acer tegmentosum Maxim (Aceraceae) has long been utilized in Korean folk medicine to alleviate many physiological disorders, including abscesses, surgical bleeding, and liver diseases. In order to explore structurally and/or biologically new constituents from Korean medicinal plants, a comprehensive phytochemical study was carried out on the bark of A. tegmentosum. One new phenolic compound with a 1,4-benzodioxane scaffold, isoamericanoic acid B (1), as well as with nine known phenolic compounds (2-10), were successfully isolated from the aqueous extracts of the bark of A. tegmentosum. A detailed analysis using 1D and 2D NMR spectroscopy, electronic circular dichroism (ECD) spectral data, and LC/MS afforded the unambiguous structural determination of all isolated compounds, including the new compound 1. In addition, compounds 2, 4, 5, and 9 were isolated and identified from the bark of A. tegmentosum for the first time. All isolated compounds were tested for their estrogenic activities using an MCF-7 BUS cell proliferation assay, which revealed that compounds 1, 2, and 10 showed moderate estrogenic activity. To study the mechanism of this estrogenic effect, a docking simulation of compound 1, which showed the best estrogenic activity, was conducted with estrogen receptor (ER) -alpha and ER-beta, which revealed that it interacts with the key residues of ER-alpha and ER-beta. In addition, compound 1 had slightly higher affinity for ER-beta than ER-alpha in the calculated Gibbs free energy for 1:ER-alpha and 1:ER-beta. Thus, the present experimental evidence demonstrated that active compound 1 from A. tegmentosum could be a promising phytoestrogen for the development of natural estrogen supplements. PMID- 30518115 TI - Experimental Evaluation of Interfacial Surface Cracks in Friction Welded Dissimilar Metals through Image Segmentation Technique (IST). AB - Surface cracks on the friction welded interface of dissimilar metals are one of the earliest indications of degradation of the joint, which is a critical aspect for the welding strength. By manual inspection of the friction welded joint, observations of irregularities, porosity voids, crack lengths, cracked surfaces, and depth penetrations of two dissimilar metals can be made. Manual inspection purely depends on a quality expert's experience of quantitative analysis and knowledge. In this research, an attempt has been made to effectively utilize the image segmentation technique (IST) in the estimation of the welded surface quality of a dissimilar joint by friction welding. The bonding strength between dissimilar metals in friction welding is more dependent on the coefficient of friction between the metallic surfaces. To demonstrate the capability of the image segmentation technique, experiments were conducted with various parameters, such as friction pressure, friction time, coefficient of friction, and torque speed of the rotating work piece. The effect of the coefficient of friction on friction welded surface quality by considering process parameters is estimated by using the proposed technique. Experiments were validated and the results claimed that the proposed image processing approach is efficient in fractured surface crack detection, reducing the computation cost, and providing a high-speed method with greater accuracy in the identification of welded surface defects. It was found that the friction coefficient is dependent mostly on the friction pressure and friction time. Its values range from 0.21 to 0.71, with the highest value of friction pressure at 120 MPa and 500 rpm. The present work deals with the detection of welding defects by means of segmentation based analysis of the welded interface. This method has a significant improvement in the fractured surface, crack detection, and non-welded areas' detection in terms of pixels at the desired region, and is easy when compared to conventional detection techniques by using an operator's decisions. PMID- 30518116 TI - Chlorogenic Acid (CGA) Isomers Alleviate Interleukin 8 (IL-8) Production in Caco 2 Cells by Decreasing Phosphorylation of p38 and Increasing Cell Integrity. AB - The objective of this study was to determine the effect of six chlorogenic acid (CGA) isomers known to be present in coffee and other plant foods on modulating the inflammatory response induced by pro-inflammatory cytokines in the Caco-2 human intestinal epithelial cell line. Compared to caffeoylquinic acids (CQA), dicaffeoylquinic acids (DiCQA) had significantly stronger (p < 0.05) capacities to reduce phosphorylation of one of mitogen-activated protein kinases (MAPK) cascades, namely p38. Compared to the control, CQA isomers treatment resulted in around 50% reduction in an interleukin-8 (IL-8) secretion, whereas DiCQA, at the same concentration, resulted in a 90% reduction in IL-8 secretion, compared to the control cells. CGA isomer treatment also showed a significant effect (p < 0.05) on the up-regulation of NFkappaB subunit p65 nuclear translocation by more than 1.5 times, compared to the control. We concluded that CGA isomers exert anti inflammatory activity in a mixture of interferon gamma (IFNgamma) and phorbol myristate acetate (PMA)-challenged Caco-2 cells, by decreasing the phosphorylation of p38 cascade and up-regulating NFkappaB signaling. PMID- 30518117 TI - Growth Behavior of Human Adipose Tissue-Derived Stromal/Stem Cells at Small Scale: Numerical and Experimental Investigations. AB - Human adipose tissue-derived stromal/stem cells (hASCs) are a valuable source of cells for clinical applications, especially in the field of regenerative medicine. Therefore, it comes as no surprise that the interest in hASCs has greatly increased over the last decade. However, in order to use hASCs in clinically relevant numbers, in vitro expansion is required. Single-use stirred bioreactors in combination with microcarriers (MCs) have shown themselves to be suitable systems for this task. However, hASCs tend to be less robust, and thus, more shear sensitive than conventional production cell lines for therapeutic antibodies and vaccines (e.g., Chinese Hamster Ovary cells CHO, Baby Hamster Kidney cells BHK), for which these bioreactors were originally designed. Hence, the goal of this study was to investigate the influence of different shear stress levels on the growth of humane telomerase reversed transcriptase immortalized hASCs (hTERT-ASC) and aggregate formation in stirred single-use systems at the mL scale: the 125 mL (= SP100) and the 500 mL (= SP300) disposable Corning(r) spinner flask. Computational fluid dynamics (CFD) simulations based on an Euler Euler and Euler-Lagrange approach were performed to predict the hydrodynamic stresses (0.06-0.87 Pa), the residence times (0.4-7.3 s), and the circulation times (1.6-16.6 s) of the MCs in different shear zones for different impeller speeds and the suspension criteria (Ns1u, Ns1). The numerical findings were linked to experimental data from cultivations studies to develop, for the first time, an unstructured, segregated mathematical growth model for hTERT-ASCs. While the 125 mL spinner flask with 100 mL working volume (SP100) provided up to 1.68.105 hTERT-ASC/cm2 (= 0.63 * 106 living hTERT-ASCs/mL, EF 56) within eight days, the peak living cell density of the 500 mL spinner flask with 300 mL working volume (SP300) was 2.46 * 105 hTERT-ASC/cm2 (= 0.88 * 106 hTERT-ASCs/mL, EF 81) and was achieved on day eight. Optimal cultivation conditions were found for Ns1u < N < Ns1, which corresponded to specific power inputs of 0.3-1.1 W/m3. The established growth model delivered reliable predictions for cell growth on the MCs with an accuracy of 76-96% for both investigated spinner flask types. PMID- 30518118 TI - Tracing of Listeria monocytogenes Contamination Routes in Fermented Sausage Production Chain by Pulsed-Field Gel Electrophoresis Typing. AB - In this study, the presence of Listeria monocytogenes was assessed along the production process of fermented sausages in a small-scale facility. Following the isolation of the pathogen from the final product (ISO 11290-1), retrospective sampling was performed during the production of a new batch of sausages, including raw materials, casings, additives, sausage mixtures, sausages during fermentation, and environmental samples. L. monocytogenes was recovered from the following sampling points: the defrosting room and the cuttering, mixing, stuffing, and fermentation phases. Ten strains were isolated, molecularly confirmed as L. monocytogenes by means of a molecular detection system, and subjected to pulsed-field gel electrophoresis (PFGE) typing. On the basis of an unweighted pair group method with arithmetic mean (UPGMA) dendrogram from Ascl pulsotypes, the strains were indistinguishable (no band difference). The same pulsotypes of strains present in both batches of sausages, as well as in environmental samples, indicated the persistence of L. monocytogenes in the sausage production unit. PMID- 30518119 TI - Lightweight Workload Fingerprinting Localization Using Affinity Propagation Clustering and Gaussian Process Regression. AB - Fingerprinting localization approach is widely used in indoor positioning applications owing to its high reliability. However, the learning procedure of radio signals in fingerprinting is time-consuming and labor-intensive. In this paper, an affinity propagation clustering (APC)-based fingerprinting localization system with Gaussian process regression (GPR) is presented for a practical positioning system with the reduced offline workload and low online computation cost. The proposed system collects sparse received signal strength (RSS) data from the deployed Bluetooth low energy beacons and trains them with the Gaussian process model. As the signal estimation component, GPR predicts not only the mean RSS but also the variance, which indicates the uncertainty of the estimation. The predicted RSS and variance can be employed for probabilistic-based fingerprinting localization. As the clustering component, the APC minimizes the searching space of reference points on the testbed. Consequently, it also helps to reduce the localization estimation error and the computational cost of the positioning system. The proposed method is evaluated through real field deployments. Experimental results show that the proposed method can reduce the offline workload and increase localization accuracy with less computational cost. This method outperforms the existing methods owing to RSS prediction using GPR and RSS clustering using APC. PMID- 30518120 TI - Structural and Functional Insights into Human Nuclear Cyclophilins. AB - The peptidyl prolyl isomerases (PPI) of the cyclophilin type are distributed throughout human cells, including eight found solely in the nucleus. Nuclear cyclophilins are involved in complexes that regulate chromatin modification, transcription, and pre-mRNA splicing. This review collects what is known about the eight human nuclear cyclophilins: peptidyl prolyl isomerase H (PPIH), peptidyl prolyl isomerase E (PPIE), peptidyl prolyl isomerase-like 1 (PPIL1), peptidyl prolyl isomerase-like 2 (PPIL2), peptidyl prolyl isomerase-like 3 (PPIL3), peptidyl prolyl isomerase G (PPIG), spliceosome-associated protein CWC27 homolog (CWC27), and peptidyl prolyl isomerase domain and WD repeat-containing protein 1 (PPWD1). Each "spliceophilin" is evaluated in relation to the spliceosomal complex in which it has been studied, and current work studying the biological roles of these cyclophilins in the nucleus are discussed. The eight human splicing complexes available in the Protein Data Bank (PDB) are analyzed from the viewpoint of the human spliceophilins. Future directions in structural and cellular biology, and the importance of developing spliceophilin-specific inhibitors, are considered. PMID- 30518121 TI - Multiple Sequence Alignments Enhance Boundary Definition of RNA Structures. AB - Self-contained structured domains of RNA sequences have often distinct molecular functions. Determining the boundaries of structured domains of a non-coding RNA (ncRNA) is needed for many ncRNA gene finder programs that predict RNA secondary structures in aligned genomes because these methods do not necessarily provide precise information about the boundaries or the location of the RNA structure inside the predicted ncRNA. Even without having a structure prediction, it is of interest to search for structured domains, such as for finding common RNA motifs in RNA-protein binding assays. The precise definition of the boundaries are essential for downstream analyses such as RNA structure modelling, e.g., through covariance models, and RNA structure clustering for the search of common motifs. Such efforts have so far been focused on single sequences, thus here we present a comparison for boundary definition between single sequence and multiple sequence alignments. We also present a novel approach, named RNAbound, for finding the boundaries that are based on probabilities of evolutionarily conserved base pairings. We tested the performance of two different methods on a limited number of Rfam families using the annotated structured RNA regions in the human genome and their multiple sequence alignments created from 14 species. The results show that multiple sequence alignments improve the boundary prediction for branched structures compared to single sequences independent of the chosen method. The actual performance of the two methods differs on single hairpin structures and branched structures. For the RNA families with branched structures, including transfer RNA (tRNA) and small nucleolar RNAs (snoRNAs), RNAbound improves the boundary predictions using multiple sequence alignments to median differences of 6 and -11.5 nucleotides (nts) for left and right boundary, respectively (window size of 200 nts). PMID- 30518122 TI - Effects of Protein Supplementation Combined with Exercise Intervention on Frailty Indices, Body Composition, and Physical Function in Frail Older Adults. AB - Aging poses a high risk of lean mass loss, which can be effectively improved through resistance exercise training (RET), or multicomponent exercise training (MET) as well as nutrition supplementation, such as protein supplementation (PS). This study investigated the effects of PS plus exercise training on frail older individuals. A comprehensive search of online databases was performed to identify randomized controlled trials (RCTs) that reported the efficacy of PS combined with RET or MET in frail older individuals. The included RCTs were analyzed through a meta-analysis and risk-of-bias assessment. We finally included 22 RCTs in the meta-analysis, with a mean (range/total) Physiotherapy Evidence Database score of 6.7 (4-9/10). PS plus exercise training significantly improved the frailty status (odds ratio = 2.77; p = 0.006), lean mass (standard mean difference (SMD) = 0.52; p < 0.00001), leg strength (SMD = 0.37; p < 0.00001), and walking speed (SMD = 0.32; p = 0.002). Subgroup analyses revealed that PS plus MET exert significant effects on frailty indices, whereas PS plus RET further improves lean mass. Our findings suggest that PS plus RET as well as MET is effective in improving frailty status, lean mass, muscle strength, and physical mobility in frail older individuals. PMID- 30518123 TI - Finding the Right Way to Target EGFR in Glioblastomas; Lessons from Lung Adenocarcinomas. AB - The EGFR gene is one of the most frequently mutated and/or amplified gene both in lung adenocarcinomas (LUAD) and in glioblastomas (GBMs). Although both tumor types depend on the mutation for growth, clinical benefit of EGFR tyrosine kinase inhibitors (TKIs) has only been observed in LUAD patients and, thus-far, not in GBM patients. Also in LUAD patients however, responses are restricted to specific EGFR mutations only and these 'TKI-sensitive' mutations hardly occur in GBMs. This argues for mutation-specific (as opposed to tumor-type specific) responses to EGFR-TKIs. We here discuss potential reasons for the differences in mutation spectrum and highlight recent evidence for specific functions of different EGFR mutations. These mutation-specific effects likely underlie the differential treatment response between LUAD and GBMs and provide new insights into how to target EGFR in GBM patients. PMID- 30518124 TI - Hybrid Blockchain and Internet-of-Things Network for Underground Structure Health Monitoring. AB - The Internet-of-things (IoT) and blockchain are growing realities of modern society, and both are rapidly transforming civilization, either separately or in combination. However, the leverage of both technologies for structural health monitoring (SHM) to enable transparent information sharing among involved parties and autonomous decision making has not yet been achieved. Therefore, this study combines IoT with blockchain-based smart contracts for SHM of underground structures to define a novel, efficient, scalable, and secure distributed network for enhancing operational safety. In this blockchain-IoT network, the characteristics of locally centralized and globally decentralized distribution have been activated by dividing them into core and edge networks. This division enhances the efficiency and scalability of the system. The proposed system was effective in simulation for autonomous monitoring and control of structures. After proper design, the decentralized blockchain networks may effectively be deployed for transparent and efficient information sharing, smart contracts-based autonomous decision making, and data security in SHM. PMID- 30518125 TI - Bioactive Secondary Metabolites from Octocoral-Associated Microbes-New Chances for Blue Growth. AB - Octocorals (Cnidaria, Anthozoa Octocorallia) are magnificent repositories of natural products with fascinating and unusual chemical structures and bioactivities of interest to medicine and biotechnology. However, mechanistic understanding of the contribution of microbial symbionts to the chemical diversity of octocorals is yet to be achieved. This review inventories the natural products so-far described for octocoral-derived bacteria and fungi, uncovering a true chemical arsenal of terpenes, steroids, alkaloids, and polyketides with antibacterial, antifungal, antiviral, antifouling, anticancer, anti-inflammatory, and antimalarial activities of enormous potential for blue growth. Genome mining of 15 bacterial associates (spanning 12 genera) cultivated from Eunicella spp. resulted in the identification of 440 putative and classifiable secondary metabolite biosynthetic gene clusters (BGCs), encompassing varied terpene-, polyketide-, bacteriocin-, and nonribosomal peptide-synthase BGCs. This points towards a widespread yet uncharted capacity of octocoral associated bacteria to synthetize a broad range of natural products. However, to extend our knowledge and foster the near-future laboratory production of bioactive compounds from (cultivatable and currently uncultivatable) octocoral symbionts, optimal blending between targeted metagenomics, DNA recombinant technologies, improved symbiont cultivation, functional genomics, and analytical chemistry are required. Such a multidisciplinary undertaking is key to achieving a sustainable response to the urgent industrial demand for novel drugs and enzyme varieties. PMID- 30518126 TI - Impact of Blood Collection Tubes and Sample Handling Time on Serum and Plasma Metabolome and Lipidome. AB - Background: Metabolomics is emerging as a valuable tool in clinical science. However, one major challenge in clinical metabolomics is the limited use of standardized guidelines for sample collection and handling. In this study, we conducted a pilot analysis of serum and plasma to determine the effects of processing time and collection tube on the metabolome. Methods: Blood was collected in 3 tubes: Vacutainer serum separator tube (SST, serum), EDTA (plasma) and P100 (plasma) and stored at 4 degrees for 0, 0.5, 1, 2, 4 and 24 h prior to centrifugation. Compounds were extracted using liquid-liquid extraction to obtain a hydrophilic and a hydrophobic fraction and analyzed using liquid chromatography mass spectrometry. Differences among the blood collection tubes and sample processing time were evaluated (ANOVA, Bonferroni FWER <= 0.05 and ANOVA, Benjamini Hochberg FDR <= 0.1, respectively). Results: Among the serum and plasma tubes 93.5% of compounds overlapped, 382 compounds were unique to serum and one compound was unique to plasma. There were 46, 50 and 86 compounds affected by processing time in SST, EDTA and P100 tubes, respectively, including many lipids. In contrast, 496 hydrophilic and 242 hydrophobic compounds differed by collection tube. Forty-five different chemical classes including alcohols, sugars, amino acids and prenol lipids were affected by the choice of blood collection tube. Conclusion: Our results suggest that the choice of blood collection tube has a significant effect on detected metabolites and their overall abundances. Perhaps surprisingly, variation in sample processing time has less of an effect compared to collection tube; however, a larger sample size is needed to confirm this. PMID- 30518127 TI - Genome-Wide Identification and Analysis of U-Box E3 Ubiquitin-Protein Ligase Gene Family in Banana. AB - The U-box gene family is a family of genes which encode U-box domain-containing proteins. However, little is known about U-box genes in banana (Musa acuminata). In this study, 91 U-box genes were identified in banana based on its genome sequence. The banana U-box genes were distributed across all 12 chromosomes at different densities. Phylogenetic analysis of U-box genes from banana, Arabidopsis, and rice suggested that they can be clustered into seven subgroups (I-VII), and most U-box genes had a closer relationship between banana and rice relative to Arabidopsis. Typical U-box domains were found in all identified MaU box genes through the analysis of conserved motifs. Four conserved domains were found in major banana U-box proteins. The MaU-box gene family had the highest expression in the roots at the initial fruit developmental stage. The MaU-box genes exhibited stronger response to drought than to salt and low temperatures. To the best of our knowledge, this report is the first to perform genome-wide identification and analysis of the U-box gene family in banana, and the results should provide valuable information for better understanding of the function of U box in banana. PMID- 30518128 TI - Fibroinflammatory Liver Injuries as Preneoplastic Condition in Cholangiopathies. AB - The cholangipathies are a class of liver diseases that specifically affects the biliary tree. These pathologies may have different etiologies (genetic, autoimmune, viral, or toxic) but all of them are characterized by a stark inflammatory infiltrate, increasing overtime, accompanied by an excess of periportal fibrosis. The cellular types that mount the regenerative/reparative hepatic response to the damage belong to different lineages, including cholagiocytes, mesenchymal and inflammatory cells, which dynamically interact with each other, exchanging different signals acting in autocrine and paracrine fashion. Those messengers may be proinflammatory cytokines and profibrotic chemokines (IL-1, and 6; CXCL1, 10 and 12, or MCP-1), morphogens (Notch, Hedgehog, and WNT/beta-catenin signal pathways) and finally growth factors (VEGF, PDGF, and TGFbeta, among others). In this review we will focus on the main molecular mechanisms mediating the establishment of a fibroinflammatory liver response that, if perpetuated, can lead not only to organ dysfunction but also to neoplastic transformation. Primary Sclerosing Cholangitis and Congenital Hepatic Fibrosis/Caroli's disease, two chronic cholangiopathies, known to be prodrome of cholangiocarcinoma, for which several murine models are also available, were also used to further dissect the mechanisms of fibroinflammation leading to tumor development. PMID- 30518129 TI - The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension. AB - Hypertension is a growing global epidemic. Developmental programming resulting in hypertension can begin in early life. Maternal nutrition status has important implications as a double-edged sword in the developmental programming of hypertension. Imbalanced maternal nutrition causes offspring's hypertension, while specific nutritional interventions during pregnancy and lactation may serve as reprogramming strategies to reverse programming processes and prevent the development of hypertension. In this review, we first summarize the human and animal data supporting the link between maternal nutrition and developmental programming of hypertension. This review also presents common mechanisms underlying nutritional programming-induced hypertension. This will be followed by studies documenting nutritional interventions as reprogramming strategies to protect against hypertension from developmental origins. The identification of ideal nutritional interventions for the prevention of hypertension development that begins early in life will have a lifelong impact, with profound savings in the global burden of hypertension. PMID- 30518130 TI - Effect of a Whey Protein Supplement on Preservation of Fat Free Mass in Overweight and Obese Individuals on an Energy Restricted Very Low Caloric Diet. AB - The obesity epidemic has caused a widespread interest in strategies to achieve a healthy "high quality" weight loss, where excess fat is lost, while fat free mass (FFM) is preserved. In this study, we aimed to examine the effect of whey protein supplementation given before night sleep on FFM preservation during a 4-week (wk) period on a very low caloric diet (VLCD). Twenty-nine obese subjects (body mass index (BMI) > 28 kg/m2) completed a 4-week intervention including a VLCD and a walking program (30 min walking * 5 times per week). Subjects were randomly assigned to either control (CON, n = 15) or a whey protein supplement (PRO, 0.4 g protein/kg/day, n = 14), ingested before bedtime. Body composition (dual-energy X ray absorptiometry, DXA), blood analysis and physical test were performed pre and post intervention. We measured nitrogen excretion in three 24 h urine collections (Day 0, 7 and 28) to assess nitrogen balance. Changes in nitrogen balance (NB) after 7 and 28 days was different between treatment groups (interaction p < 0.05). PRO was in NB after 7 days and in positive NB at day 28. In contrast, CON was in negative NB at day 7, but in NB at day 28. Nevertheless, no significant group differences were observed in the change in pre- and post-FFM measurements ( 2.5 kg, [95% CI: 1.9; 3.1], p = 0.65). In conclusion, ingestion of a whey protein supplement before bedtime during a 4-week period on a VLCD improved nitrogen balance, but did not lead to any significant improvement in the quality of the weight loss in regard to observed changes in body composition and health parameters compared with controls. PMID- 30518131 TI - Foreground Detection with Deeply Learned Multi-Scale Spatial-Temporal Features. AB - Foreground detection, which extracts moving objects from videos, is an important and fundamental problem of video analysis. Classic methods often build background models based on some hand-craft features. Recent deep neural network (DNN) based methods can learn more effective image features by training, but most of them do not use temporal feature or use simple hand-craft temporal features. In this paper, we propose a new dual multi-scale 3D fully-convolutional neural network for foreground detection problems. It uses an encoder-decoder structure to establish a mapping from image sequences to pixel-wise classification results. We also propose a two-stage training procedure, which trains the encoder and decoder separately to improve the training results. With multi-scale architecture, the network can learning deep and hierarchical multi-scale features in both spatial and temporal domains, which is proved to have good invariance for both spatial and temporal scales. We used the CDnet dataset, which is currently the largest foreground detection dataset, to evaluate our method. The experiment results show that the proposed method achieves state-of-the-art results in most test scenes, comparing to current DNN based methods. PMID- 30518132 TI - Driver's Facial Expression Recognition in Real-Time for Safe Driving. AB - In recent years, researchers of deep neural networks (DNNs)-based facial expression recognition (FER) have reported results showing that these approaches overcome the limitations of conventional machine learning-based FER approaches. However, as DNN-based FER approaches require an excessive amount of memory and incur high processing costs, their application in various fields is very limited and depends on the hardware specifications. In this paper, we propose a fast FER algorithm for monitoring a driver's emotions that is capable of operating in low specification devices installed in vehicles. For this purpose, a hierarchical weighted random forest (WRF) classifier that is trained based on the similarity of sample data, in order to improve its accuracy, is employed. In the first step, facial landmarks are detected from input images and geometric features are extracted, considering the spatial position between landmarks. These feature vectors are then implemented in the proposed hierarchical WRF classifier to classify facial expressions. Our method was evaluated experimentally using three databases, extended Cohn-Kanade database (CK+), MMI and the Keimyung University Facial Expression of Drivers (KMU-FED) database, and its performance was compared with that of state-of-the-art methods. The results show that our proposed method yields a performance similar to that of deep learning FER methods as 92.6% for CK+ and 76.7% for MMI, with a significantly reduced processing cost approximately 3731 times less than that of the DNN method. These results confirm that the proposed method is optimized for real-time embedded applications having limited computing resources. PMID- 30518133 TI - A Review of Wearable Solutions for Physiological and Emotional Monitoring for Use by People with Autism Spectrum Disorder and Their Caregivers. AB - The goal of real-time feedback on physiological changes, stress monitoring and even emotion detection is becoming a technological reality. People in their daily life experience varying emotional states, some of which are negative and which can lead to decreased attention, decreased productivity and ultimately, reduced quality of life. Therefore, having a solution that continuously monitors the physiological signals of the person and assesses his or her emotional well-being could be a very valuable tool. This paper aims to review existing physiological and motional monitoring devices, highlight their features and compare their sensing capabilities. Such technology would be particularly useful for certain populations who experience rapidly changing emotional states such as people with autism spectrum disorder and people with intellectual disabilities. Wearable sensing devices present a potential solution that can support and complement existing behavioral interventions. This paper presents a review of existing and emerging products in the market. It reviews the literature on state-of-the-art prototypes and analyzes their usefulness, clinical validity, and discusses clinical perspectives. A small number of products offer reliable physiological internal state monitoring and may be suitable for people with Autism Spectrum Disorder (ASD). It is likely that more promising solutions will be available in the near future. Therefore, caregivers should be careful in their selection of devices that meet the care-receiver's personal needs and have strong research support for reliability and validity. PMID- 30518134 TI - The Shape-Memory Effect of Hindered Phenol (AO-80)/Acrylic Rubber (ACM) Composites with Tunable Transition Temperature. AB - To broaden the types and scope of use of shape-memory polymers (SMPs), we added the hindered phenol 3,9-bis[1,1-dimethyl-2-{b-(3-tert-butyl-4-hydroxy-5 methylphenyl)propionyloxy}ethyl]-2,4,8,10-tetraoxaspiro-[5,5]-undecane (AO-80), which comprises small organic molecules, to acrylic rubber (ACM) to form a series of AO-80/ACM rubber composites. The structural, thermal, mechanical property, and shape-memory properties of the AO-80/ACM rubber composites were investigated. We identified the formation of intra-molecular hydrogen bonding between -OH of AO-80 and the carbonyl groups and the ether groups of ACM molecules. The amount of AO 80 used can be adjusted to tailor the transition temperature. AO-80/ACM rubber composites showed excellent shape recovery and fixity. The approach for adjusting the transition temperature of AO-80/ACM rubber composites provides remarkable ideas for the design and preparation of new SMPs. PMID- 30518135 TI - Vitamin E Metabolic Effects and Genetic Variants: A Challenge for Precision Nutrition in Obesity and Associated Disturbances. AB - Vitamin E (VE) has a recognized leading role as a contributor to the protection of cell constituents from oxidative damage. However, evidence suggests that the health benefits of VE go far beyond that of an antioxidant acting in lipophilic environments. In humans, VE is channeled toward pathways dealing with lipoproteins and cholesterol, underlining its relevance in lipid handling and metabolism. In this context, both VE intake and status may be relevant in physiopathological conditions associated with disturbances in lipid metabolism or concomitant with oxidative stress, such as obesity. However, dietary reference values for VE in obese populations have not yet been defined, and VE supplementation trials show contradictory results. Therefore, a better understanding of the role of genetic variants in genes involved in VE metabolism may be crucial to exert dietary recommendations with a higher degree of precision. In particular, genetic variability should be taken into account in targets concerning VE bioavailability per se or concomitant with impaired lipoprotein transport. Genetic variants associated with impaired VE liver balance, and the handling/resolution of oxidative stress might also be relevant, but the core information that exists at present is insufficient to deliver precise recommendations. PMID- 30518136 TI - Ultralow Interlayer Friction of Layered Electride Ca2N: A Potential Two Dimensional Solid Lubricant Material. AB - Dispersion-corrected density functional theory (DFT) calculations reveal that the layered electride of dicalcium nitride (Ca2N) exhibits stronger interlayer binding interactions but lower interlayer friction behavior than that of traditional layered lubricants weakly bonded by van der Waals (vdW) interactions, such as graphite, h-BN, and MoS2. These results are attributed to the two dimensional (2D) homogeneous conduction electrons distribution in the middle of the interlayer space of Ca2N, which yields a smooth sliding barrier and hence ultralow friction behavior. The interesting results obtained in this study have not only broadened the scope of 2D solid lubricants but also enriched the physical understanding of ultralow friction mechanism for 2D systems. PMID- 30518137 TI - Fluorescently Tagged CCL19 and CCL21 to Monitor CCR7 and ACKR4 Functions. AB - Chemokines are essential guidance cues orchestrating cell migration in health and disease. Cognate chemokine receptors sense chemokine gradients over short distances to coordinate directional cell locomotion. The chemokines CCL19 and CCL21 are essential for recruiting CCR7-expressing dendritic cells bearing pathogen-derived antigens and lymphocytes to lymph nodes, where the two cell types meet to launch an adaptive immune response against the invading pathogen. CCR7-expressing cancer cells are also recruited by CCL19 and CCL21 to metastasize in lymphoid organs. In contrast, atypical chemokine receptors (ACKRs) do not transmit signals required for cell locomotion but scavenge chemokines. ACKR4 is crucial for internalizing and degrading CCL19 and CCL21 to establish local gradients, which are sensed by CCR7-expressing cells. Here, we describe the production of fluorescently tagged chemokines by fusing CCL19 and CCL21 to monomeric red fluorescent protein (mRFP). We show that purified CCL19-mRFP and CCL21-mRFP are versatile and powerful tools to study CCR7 and ACKR4 functions, such as receptor trafficking and chemokine scavenging, in a spatiotemporal fashion. We demonstrate that fluorescently tagged CCL19 and CCL21 permit the visualization and quantification of chemokine gradients in real time, while CCR7 expressing leukocytes and cancer cells sense the guidance cues and migrate along the chemokine gradients. PMID- 30518138 TI - Review of Ocular Manifestations of Joubert Syndrome. AB - Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic "molar tooth" sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations. PMID- 30518139 TI - Bioactive Nanoparticles for Cancer Immunotherapy. AB - Currently, immunotherapy is considered to be one of the effective treatment modalities for cancer. All the developments and discoveries in this field up to the recent Nobel Prize add to the interest for research into this vast area of study. Targeting tumor environment as well as the immune system is a suitable strategy to be applied for cancer treatment. Usage of nanoparticle systems for delivery of immunotherapeutic agents to the body being widely studied and found to be a promising area of research to be considered and investigated further. Nanoparticles for immunotherapy would be one of the effective treatment options for cancer therapy in the future due to their high specificity, efficacy, ability to diagnose, imaging, and therapeutic effect. Among the many nanoparticle systems, polylactic-co-glycolic acid (PLGA) nanoparticles, liposomes, micelles, gold nanoparticles, iron oxide, dendrimers, and artificial exosomes are widely used for immunotherapy of cancer. Moreover, the combination therapy found to be the more effective way of treating the tumor. Here, we review the current trends in nanoparticle therapy and efficiency of these nanosystems in delivering antigens, adjuvants, therapeutic drugs, and other immunotherapeutic agents. This review summarizes the currently available bioactive nanoparticle systems for cancer immunotherapy. PMID- 30518140 TI - An Improved YOLOv2 for Vehicle Detection. AB - Vehicle detection is one of the important applications of object detection in intelligent transportation systems. It aims to extract specific vehicle-type information from pictures or videos containing vehicles. To solve the problems of existing vehicle detection, such as the lack of vehicle-type recognition, low detection accuracy, and slow speed, a new vehicle detection model YOLOv2_Vehicle based on YOLOv2 is proposed in this paper. The k-means++ clustering algorithm was used to cluster the vehicle bounding boxes on the training dataset, and six anchor boxes with different sizes were selected. Considering that the different scales of the vehicles may influence the vehicle detection model, normalization was applied to improve the loss calculation method for length and width of bounding boxes. To improve the feature extraction ability of the network, the multi-layer feature fusion strategy was adopted, and the repeated convolution layers in high layers were removed. The experimental results on the Beijing Institute of Technology (BIT)-Vehicle validation dataset demonstrated that the mean Average Precision (mAP) could reach 94.78%. The proposed model also showed excellent generalization ability on the CompCars test dataset, where the "vehicle face" is quite different from the training dataset. With the comparison experiments, it was proven that the proposed method is effective for vehicle detection. In addition, with network visualization, the proposed model showed excellent feature extraction ability. PMID- 30518141 TI - Erratum: Polge, C., et al. UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment. Cells 2018, 7, 214. AB - Change in author names (order). [...]. PMID- 30518142 TI - Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System. AB - Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression. PMID- 30518143 TI - Study of Size Effect on Microstructure and Mechanical Properties of AlSi10Mg Samples Made by Selective Laser Melting. AB - The macroscopic mechanical performance of additive manufactured structures is essential for the design and application of multiscale microlattice structure. Performance is affected by microstructure and geometrical imperfection, which are strongly influenced by the size of the struts in selective laser melting (SLM) lattice structures. In this paper, the effect of size on microstructure, geometrical imperfection, and mechanical properties was systemically studied by conducting experimental tests. A series of AlSi10Mg rod-shaped samples with various diameters were fabricated using SLM. The uniaxial tensile test results show that with the decrease in build diameter, strength and Young's modulus of strut decreased by 30% more than the stable state. The main reasons for this degradation were investigated through microscopic observation and micro X-ray computed tomography (MU-CT). In contrast with large-sized strut, the inherent porosity (1.87%) and section geometrical deviation (3%) of ponysize strut is greater because of the effect of thermal transform and hydrogen evolution, and the grain size is 0.5 MUm. The discrepancy in microstructure, geometrical imperfection, and mechanical properties induced by size effect should be considered for the design and evaluation of SLM-fabricated complex structures. PMID- 30518144 TI - Manufacturing of All Inkjet-Printed Organic Photovoltaic Cell Arrays and Evaluating their Suitability for Flexible Electronics. AB - The generation of electrical energy depending on renewable sources is rapidly growing and gaining serious attention due to its green sustainability. With fewer adverse impacts on the environment, the sun is considered as a nearly infinite source of renewable energy in the production of electrical energy using photovoltaic devices. On the other end, organic photovoltaic (OPV) is the class of solar cells that offers several advantages such as mechanical flexibility, solution processability, environmental friendliness, and being lightweight. In this research, we demonstrate the manufacturing route for printed OPV device arrays based on conventional architecture and using inkjet printing technology over an industrial platform. Inkjet technology is presently considered to be one of the most matured digital manufacturing technologies because it offers inherent additive nature and last stage customization flexibility (if the main goal is to obtain custom design devices). In this research paper, commercially available electronically functional inks were carefully selected and then implemented to show the importance of compatibility between OPV material stacks and the device architecture. One of the main outcomes of this work is that the manufacturing of the OPV devices was accomplished using inkjet technology in massive numbers ranging up to 1500 containing different device sizes, all of which were deposited on a flexible polymeric film and under normal atmospheric conditions. In this investigation, it was found that with a set of correct functional materials and architecture, a manufacturing yield of more than 85% could be accomplished, which would reflect high manufacturing repeatability, deposition accuracy, and processability of the inkjet technology. PMID- 30518145 TI - Genetic Polymorphisms Associated with Spontaneous Intracerebral Hemorrhage. AB - Differences in the incidence of spontaneous intracerebral hemorrhage (ICH) between ethnicities exist, with an estimated 42% of the variance explained by ethnicity itself. Caucasians have a higher proportion of lobar ICH (LICH, 15.4% of all ICH) than do Asians (3.4%). Alterations in the causal factor exposure between countries justify part of the ethnic variance in ICH incidence. One third of ICH risk can be explained by genetic variation; therefore, genetic differences between populations can partly explain the difference in ICH incidence. In this paper, we review the current knowledge of genetic variants associated with ICH in multiple ethnicities. Candidate gene variants reportedly associated with ICH were involved in the potential pathways of hypertension, vessel wall integrity, lipid metabolism, endothelial dysfunction, inflammation, platelet function, and coagulopathy. Furthermore, variations in APOE (in multiple ethnicities), PMF1/SLC25A44 (in European), ACE (in Asian), MTHFR (in multiple ethnicities), TRHDE (in European), and COL4A2 (in European) were the most convincingly associated with ICH. The majority of the associated genes provide small contributions to ICH risk, with few of them being replicated in multiple ethnicities. PMID- 30518147 TI - Preparation of Nano-SiO2/Al2O3/ZnO-Blended PVDF Cation-Exchange Membranes with Improved Membrane Permselectivity and Oxidation Stability. AB - Ion exchange membranes are used in practically every industry; however, most of them have defects such as low permeability and poor oxidation resistance. In this paper, cation-exchange membranes were prepared with poly (vinylidene fluoride) (PVDF) blended with nano-SiO2, nano-Al2O3 and nano-ZnO. Sulfonic acid groups were injected into the membrane prepared by styrene grafting and sulfonation. The methods used for characterizing the prepared membranes were Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and electrochemical measurements. Membrane performance, such as the ion exchange capacity (IEC), water uptake (WU), transport number, membrane permselectivity, membrane resistance, functional groups, and morphology were also evaluated. The hydrophilia, IEC, and permselectivity of cation-exchange membranes depended on the nanoparticle content of the membrane matrix. High transport property values were obtained, which increased with increasing nano-SiO2/Al2O3/ZnO weight fractions. Finally, the cation-exchange membranes prepared with 1.5% nano-SiO2, 2.0% nano-Al2O3 or 2.0% nano-ZnO all exhibited excellent membrane properties, including membrane permselectivity (PVDF/2% ZnO-g-PSSA membranes, 94.9%), IEC (PVDF/2% Al2O3-g-PSSA membranes, 2.735 mmol.g-1), and oxidation resistance (PVDF/1.5% SiO2-g-PSSA membranes, 2.33%). They can be used to separate applications in a variety of different areas, such as water treatment, electro driven separation, heavy metal smelting, or other electrochemical processes. PMID- 30518146 TI - Direct van der Waals Epitaxy of Crack-Free AlN Thin Film on Epitaxial WS2. AB - Van der Waals epitaxy (vdWE) has drawn continuous attention, as it is unlimited by lattice-mismatch between epitaxial layers and substrates. Previous reports on the vdWE of III-nitride thin film were mainly based on two-dimensional (2D) materials by plasma pretreatment or pre-doping of other hexagonal materials. However, it is still a huge challenge for single-crystalline thin film on 2D materials without any other extra treatment or interlayer. Here, we grew high quality single-crystalline AlN thin film on sapphire substrate with an intrinsic WS2 overlayer (WS2/sapphire) by metal-organic chemical vapor deposition, which had surface roughness and defect density similar to that grown on conventional sapphire substrates. Moreover, an AlGaN-based deep ultraviolet light emitting diode structure on WS2/sapphire was demonstrated. The electroluminescence (EL) performance exhibited strong emissions with a single peak at 283 nm. The wavelength of the single peak only showed a faint peak-position shift with increasing current to 80 mA, which further indicated the high quality and low stress of the AlN thin film. This work provides a promising solution for further deep-ultraviolet (DUV) light emitting electrodes (LEDs) development on 2D materials, as well as other unconventional substrates. PMID- 30518148 TI - Algal Oxylipins Mediate the Resistance of Diatoms against Algicidal Bacteria. AB - Algicidal bacteria can lyse microalgal blooms and trigger shifts within plankton communities. Resistant algal species can escape lysis, and have the opportunity to dominate the phytoplankton after a bacterial infection. Despite their important function in ecosystem regulation, little is known about mechanisms of resistance. Here, we show that the diatom Chaetoceros didymus releases eicosanoid oxylipins into the medium, and that the lytic algicidal bacterium, Kordia algicida, induces the production of several wound-activated oxylipins in this resistant diatom. Neither releases nor an induction occurs in the susceptible diatom Skeletonema costatum that is lysed by the bacterium within a few days. Among the upregulated oxylipins, hydroxylated eicosapentaenoic acids (HEPEs) dominate. However, also, resolvins, known lipid mediators in mammals, increase upon exposure of the algae to the algicidal bacteria. The prevailing hydroxylated fatty acid, 15-HEPE, significantly inhibits growth of K. algicida at a concentration of approximately 1 uM. The oxylipin production may represent an independent line of defense of the resistant alga, acting in addition to the previously reported upregulation of proteases. PMID- 30518149 TI - Coagulotoxic Cobras: Clinical Implications of Strong Anticoagulant Actions of African Spitting Naja Venoms That Are Not Neutralised by Antivenom but Are by LY315920 (Varespladib). AB - Snakebite is a global tropical disease that has long had huge implications for human health and well-being. Despite its long-standing medical importance, it has been the most neglected of tropical diseases. Reflective of this is that many aspects of the pathology have been underinvestigated. Snakebite by species in the Elapidae family is typically characterised by neurotoxic effects that result in flaccid paralysis. Thus, while clinically significant disturbances to the coagulation cascade have been reported, the bulk of the research to date has focused upon neurotoxins. In order to fill the knowledge gap regarding the coagulotoxic effects of elapid snake venoms, we screened 30 African and Asian venoms across eight genera using in vitro anticoagulant assays to determine the relative inhibition of the coagulation function of thrombin and the inhibition of the formation of the prothrombinase complex through competitive binding to a nonenzymatic site on Factor Xa (FXa), thereby preventing FXa from binding to Factor Va (FVa). It was revealed that African spitting cobras were the only species that were potent inhibitors of either clotting factor, but with Factor Xa inhibited at 12 times the levels of thrombin inhibition. This is consistent with at least one death on record due to hemorrhage following African spitting cobra envenomation. To determine the efficacy of antivenom in neutralising the anticoagulant venom effects, for the African spitting cobras we repeated the same 8-point dilution series with the addition of antivenom and observed the shift in the area under the curve, which revealed that the antivenom performed extremely poorly against the coagulotoxic venom effects of all species. However, additional tests with the phospholipase A2 inhibitor LY315920 (trade name: varespladib) demonstrated a powerful neutralisation action against the coagulotoxic actions of the African spitting cobra venoms. Our research has important implications for the clinical treatment of cobra snakebites and also sheds light on the molecular mechanisms involved in coagulotoxicity within Naja. As the most coagulotoxic species are also those that produce characteristic extreme local tissue damage, future research should investigate potential synergistic actions between anticoagulant toxins and cytotoxins. PMID- 30518150 TI - Design of Linear and Cyclic Mutant Analogues of Dirucotide Peptide (MBP82-98) against Multiple Sclerosis: Conformational and Binding Studies to MHC Class II. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system. MS is a T cell-mediated disease characterized by the proliferation, infiltration, and attack of the myelin sheath by immune cells. Previous studies have shown that cyclization provides molecules with strict conformation that could modulate the immune system. METHODS: In this study, we synthesized peptide analogues derived from the myelin basic protein (MBP)82-98 encephalitogenic sequence (dirucotide), the linear altered peptide ligand MBP82 98 (Ala91), and their cyclic counterparts. RESULTS: The synthesized peptides were evaluated for their binding to human leukocyte antigen (HLA)-DR2 and HLA-DR4 alleles, with cyclic MBP82-98 being a strong binder with the HLA-DR2 allele and having lower affinity binding to the HLA-DR4 allele. In a further step, conformational analyses were performed using NMR spectroscopy in solution to describe the conformational space occupied by the functional amino acids of both linear and cyclic peptide analogues. This structural data, in combination with crystallographic data, were used to study the molecular basis of their interaction with HLA-DR2 and HLA-DR4 alleles. CONCLUSION: The cyclic and APL analogues of dirucotide are promising leads that should be further evaluated for their ability to alter T cell responses for therapeutic benefit against MS. PMID- 30518151 TI - lncRNA-Six1 Is a Target of miR-1611 that Functions as a ceRNA to Regulate Six1 Protein Expression and Fiber Type Switching in Chicken Myogenesis. AB - Emerging studies indicate important roles for non-coding RNAs (ncRNAs) as essential regulators in myogenesis, but relatively less is known about their function. In our previous study, we found that lncRNA-Six1 can regulate Six1 in cis to participate in myogenesis. Here, we studied a microRNA (miRNA) that is specifically expressed in chickens (miR-1611). Interestingly, miR-1611 was found to contain potential binding sites for both lncRNA-Six1 and Six1, and it can interact with lncRNA-Six1 to regulate Six1 expression. Overexpression of miR-1611 represses the proliferation and differentiation of myoblasts. Moreover, miR-1611 is highly expressed in slow-twitch fibers, and it drives the transformation of fast-twitch muscle fibers to slow-twitch muscle fibers. Together, these data demonstrate that miR-1611 can mediate the regulation of Six1 by lncRNA-Six1, thereby affecting proliferation and differentiation of myoblasts and transformation of muscle fiber types. PMID- 30518152 TI - Crystal Structures and Cytotoxicity of ent-Kaurane-Type Diterpenoids from Two Aspilia Species. AB - A phytochemical investigation of the roots of Aspilia plurisetaled to the isolation of ent-kaurane-type diterpenoids and additional phytochemicals (1-23). The structures of the isolated compounds were elucidated based on Nuclear Magnetic Resonance (NMR) spectroscopic and mass spectrometric analyses. The absolute configurations of seven of the ent-kaurane-type diterpenoids (3-6, 6b, 7 and 8) were determined by single crystal X-ray diffraction studies. Eleven of the compounds were also isolated from the roots and the aerial parts of Aspilia mossambicensis. The literature NMR assignments for compounds 1 and 5 were revised. In a cytotoxicity assay, 12alpha-methoxy-ent-kaur-9(11),16-dien-19-oic acid (1) (IC50 = 27.3 +/- 1.9 uM) and 9beta-hydroxy-15alpha-angeloyloxy-ent-kaur 16-en-19-oic acid (3) (IC50 = 24.7 +/- 2.8 uM) were the most cytotoxic against the hepatocellular carcinoma (Hep-G2) cell line, while 15alpha-angeloyloxy 16beta,17-epoxy-ent-kauran-19-oic acid (5) (IC50 = 30.7 +/- 1.7 uM) was the most cytotoxic against adenocarcinomic human alveolar basal epithelial (A549) cells. PMID- 30518153 TI - Semisynthesis and Inhibitory Effects of Solidagenone Derivatives on TLR-Mediated Inflammatory Responses. AB - A series of nine derivatives (2-10) were prepared from the diterpene solidagenone (1) and their structures were elucidated by means of spectroscopic studies. Their ability to inhibit inflammatory responses elicited in peritoneal macrophages by TLR ligands was investigated. Compounds 5 and 6 showed significant anti inflammatory effects, as they inhibited the protein expression of nitric oxide synthase (NOS-2), cyclooxygenase-2 (COX-2), and cytokine production (TNF-alpha, IL-6, and IL-12) induced by the ligand of TLR4, lipopolysaccharide (LPS), acting at the transcriptional level. Some structure-activity relationships were outlined. Compound 5 was selected as a representative compound and molecular mechanisms involved in its biological activity were investigated. Inhibition of NF-kappaB and p38 signaling seems to be involved in the mechanism of action of compound 5. In addition, this compound also inhibited inflammatory responses mediated by ligands of TLR2 and TLR3 receptors. To rationalize the obtained results, molecular docking and molecular dynamic studies were carried out on TLR4. All these data indicate that solidagenone derivative 5 might be used for the design of new anti-inflammatory agents. PMID- 30518154 TI - Binding Efficacy and Thermogenic Efficiency of Pungent and Nonpungent Analogs of Capsaicin. AB - (1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor-transient receptor potential vanilloid subfamily 1 (TRPV1)-to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (+/- 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans. PMID- 30518155 TI - Data Compression Based on Stacked RBM-AE Model for Wireless Sensor Networks. AB - Data compression is very important in wireless sensor networks (WSNs) with the limited energy of sensor nodes. Data communication results in energy consumption most of the time; the lifetime of sensor nodes is usually prolonged by reducing data transmission and reception. In this paper, we propose a new Stacked RBM Auto Encoder (Stacked RBM-AE) model to compress sensing data, which is composed of a encode layer and a decode layer. In the encode layer, the sensing data is compressed; and in the decode layer, the sensing data is reconstructed. The encode layer and the decode layer are composed of four standard Restricted Boltzmann Machines (RBMs). We also provide an energy optimization method that can further reduce the energy consumption of the model storage and calculation by pruning the parameters of the model. We test the performance of the model by using the environment data collected by Intel Lab. When the compression ratio of the model is 10, the average Percentage RMS Difference value is 10.04%, and the average temperature reconstruction error value is 0.2815 degrees C. The node communication energy consumption in WSNs can be reduced by 90%. Compared with the traditional method, the proposed model has better compression efficiency and reconstruction accuracy under the same compression ratio. Our experiment results show that the new neural network model can not only apply to data compression for WSNs, but also have high compression efficiency and good transfer learning ability. PMID- 30518156 TI - Transfer of Deoxynivalenol (DON) through Placenta, Colostrum and Milk from Sows to Their Offspring during Late Gestation and Lactation. AB - Deoxynivalenol (DON) contamination of feed may result in reduced growth, feed refusal, immunosuppression, and health problems in swine. Piglets can be exposed to DON via placenta before birth and via milk during lactation. The extent of early-life exposure of piglets to DON is, however, not fully known. This study was therefore aimed at investigating DON uptake in sows fed with naturally contaminated diets, DON transfer across placenta during late gestation, and transfer of DON to piglets via colostrum and milk. Forty-four crossbred sows were evaluated from day 93 +/- 1 of gestation until weaning of piglets and fed with feed made from naturally DON-contaminated oats at three concentration levels: (1) control (DON < 0.2 mg/kg), (2) DON level 1 (1.4 mg DON/kg), and (3) DON level 2 (1.7 mg DON/kg). The transfer of DON to the piglets was evaluated in 15 sows, with repeated sampling of blood and milk from the sows and blood samples from five piglets of each litter. The piglet/sow plasma DON ratio and milk/plasma (M/P) DON ratio in sows were calculated to estimate the degree of transfer. Piglet/sow plasma ratios were 2.14 at birth, 2.30 within 12-36 h after parturition, 0.08 on day 7, 0.16 on day 21, and 0.20 at weaning. M/P ratios were 0.92, 1.11, 0.94, 1.21, and 0.90, respectively. The results indicate that DON is efficiently transferred across placenta and into milk. However, the low piglet/sow plasma ratios at mid-lactation to weaning indicate that the piglets were most strongly exposed to DON in early life, despite the high M/P ratios and efficient secretion of DON in milk throughout the entire lactation. PMID- 30518157 TI - The Interleukin-17 Family of Cytokines in Breast Cancer. AB - Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments. PMID- 30518158 TI - Tissue-Specific Down-Regulation of the Long Non-Coding RNAs PCAT18 and LINC01133 in Gastric Cancer Development. AB - Gastric cancer (GC) is the fifth most common cancer and the third most frequent cause of cancer deaths worldwide. The high death rate associated with GC, and lack of appropriate biomarkers for diagnosis, prognosis, and treatment emphasize the need for identification of novel molecules. Given the emerging roles for long non-coding RNAs (lncRNAs) in cancer development, we studied novel lncRNA candidates involved in gastric carcinogenesis. LncRNA candidate discovery was performed using analyses of available datasets and literature. Validation was done using an internal sample set of GC/normal tissues, and external independent datasets. Network analysis and functional annotation of co-expressed protein coding genes were performed using the weighted gene correlation network analysis (WGCNA) and ingenuity pathway analysis. Two novel lncRNAs, PCAT18 and LINC01133, associated with GC development were identified by analysis of the discovery Gene Expression Omnibus (GEO) datasets. The down-regulation of these genes in GC tissues was successfully validated internally and externally. The results showed a tissue-specific down-regulation of PCAT18 and LINC01133 in gastrointestinal tissues. WGCNA and ingenuity pathway analyses revealed that the genes co expressed with the two lncRNAs were mostly involved in metabolic pathways and networks of gastrointestinal disease and function. Our findings of a tissue specific down-regulation of PCAT18 and LINC01133 in gastric and other gastrointestinal cancers imply that these lncRNAs may have a tumor suppressive function in the development of these tumor entities. The two lncRNA biomarkers may contribute to a better understanding of the complex mechanisms of gastric carcinogenesis. PMID- 30518159 TI - pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain. AB - Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par 4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer's disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl 2 and NF-kB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non aggregated conformation at acidic pH. PMID- 30518160 TI - Microfluidic Deformability Study of an Innovative Blood Analogue Fluid Based on Giant Unilamellar Vesicles. AB - Blood analogues have long been a topic of interest in biofluid mechanics due to the safety and ethical issues involved in the collection and handling of blood samples. Although the current blood analogue fluids can adequately mimic the rheological properties of blood from a macroscopic point of view, at the microscopic level blood analogues need further development and improvement. In this work, an innovative blood analogue containing giant unilamellar vesicles (GUVs) was developed to mimic the flow behavior of red blood cells (RBCs). A natural lipid mixture, soybean lecithin, was used for the GUVs preparation, and three different lipid concentrations were tested (1 * 10-3 M, 2 * 10-3 M and 4 * 10-3 M). GUV solutions were prepared by thin film hydration with a buffer, followed by extrusion. It was found that GUVs present diameters between 5 and 7 um which are close to the size of human RBCs. Experimental flow studies of three different GUV solutions were performed in a hyperbolic-shaped microchannel in order to measure the GUVs deformability when subjected to a homogeneous extensional flow. The result of the deformation index (DI) of the GUVs was about 0.5, which is in good agreement with the human RBC's DI. Hence, the GUVs developed in this study are a promising way to mimic the mechanical properties of the RBCs and to further develop particulate blood analogues with flow properties closer to those of real blood. PMID- 30518161 TI - Larger Workplaces, People-Oriented Culture, and Specific Industry Sectors Are Associated with Co-Occurring Health Protection and Wellness Activities. AB - Employers are increasingly interested in offering workplace wellness programs in addition to occupational health and safety (OHS) activities to promote worker health, wellbeing, and productivity. Yet, there is a dearth of research on workplace factors that enable the implementation of OHS and wellness to inform the future integration of these activities in Canadian workplaces. This study explored workplace demographic factors associated with the co-implementation of OHS and wellness activities in a heterogenous sample of Canadian workplaces. Using a cross-sectional survey of 1285 workplaces from 2011 to 2014, latent profiles of co-occurrent OHS and wellness activities were identified, and multinomial logistic regression was used to assess associations between workplace demographic factors and the profiles. Most workplaces (84%) demonstrated little co-occurrence of OHS and wellness activities. Highest co-occurrence was associated with large workplaces (odds ratio (OR) = 3.22, 95% confidence interval (CI) = 1.15-5.89), in the electrical and utilities sector (OR = 5.57, 95% CI = 2.24-8.35), and a high people-oriented culture (OR = 4.70, 95% CI = 1.59-5.26). Promoting integrated OHS and wellness approaches in medium to large workplaces, in select industries, and emphasizing a people-oriented culture were found to be important factors for implementing OHS and wellness in Canadian organizations. Informed by these findings, future studies should understand the mechanisms to facilitate the integration of OHS and wellness in workplaces. PMID- 30518162 TI - "A Lot of People Are Struggling Privately. They Don't Know Where to Go or They're Not Sure of What to Do": Frontline Service Provider Perspectives of the Nature of Household Food Insecurity in Scotland. AB - This qualitative study explored frontline service providers' perceptions of the nature of food insecurity in Scotland in 2015 to inform national policy and the provision of locally-based support for 'at risk' groups. A country-wide in-depth interview study was undertaken with informants from 25 health, social care, and third sector organisations. The study investigated informants' perspectives associated with how food insecurity was manifesting itself locally, and what was happening at the local level in response to the existence of food insecurity. Data analysis revealed three key themes. First, the multiple faces and factors of food insecurity involving not only increased concern for previously recognised 'at risk of food insecurity' groups, but also similar concern held about newly food insecure groups including working families, young people and women. Secondly, respondents witnessed stoicism and struggle, but also resistance amongst some food insecure individuals to external offers of help. The final theme identified community participation yet pessimism associated with addressing current and future needs of food insecure groups. These findings have important implications for the design and delivery of health and social policy in Scotland and other countries facing similar challenges. PMID- 30518163 TI - Population Genomic Analysis of North American Eastern Wolves (Canis lycaon) Supports Their Conservation Priority Status. AB - The threatened eastern wolf is found predominantly in protected areas of central Ontario and has an evolutionary history obscured by interbreeding with coyotes and gray wolves, which challenges its conservation status and subsequent management. Here, we used a population genomics approach to uncover spatial patterns of variation in 281 canids in central Ontario and the Great Lakes region. This represents the first genome-wide single nucleotide polymorphism (SNP) dataset with substantial sample sizes of representative populations. Although they comprise their own genetic cluster, we found evidence of eastern wolf dispersal outside of the boundaries of protected areas, in that the frequency of eastern wolf genetic variation decreases with increasing distance from provincial parks. We detected eastern wolf alleles in admixed coyotes along the northeastern regions of Lake Huron and Lake Ontario. Our analyses confirm the unique genomic composition of eastern wolves, which are mostly restricted to small fragmented patches of protected habitat in central Ontario. We hope this work will encourage an innovative discussion regarding a plan for managed introgression, which could conserve eastern wolf genetic material in any genome regardless of their potential mosaic ancestry composition and the habitats that promote them. PMID- 30518164 TI - Geographic Imputation of Missing Activity Space Data from Ecological Momentary Assessment (EMA) GPS Positions. AB - This research presents a pilot study to develop and compare methods of geographic imputation for estimating the location of missing activity space data collected using geographic ecological momentary assessment (GEMA). As a demonstration, we use data from a previously published analysis of the effect of neighborhood disadvantage, captured at the U.S. Census Bureau tract level, on momentary psychological stress among a sample of 137 urban adolescents. We investigate the impact of listwise deletion on model results and test two geographic imputation techniques adapted for activity space data from hot deck and centroid imputation approaches. Our results indicate that listwise deletion can bias estimates of place effects on health, and that these impacts are mitigated by the use of geographic imputation, particularly regarding inflation of the standard errors. These geographic imputation techniques may be extended in future research by incorporating approaches from the non-spatial imputation literature as well as from conventional geographic imputation and spatial interpolation research that focus on non-activity space data. PMID- 30518165 TI - Mucolytic Agents and Statins Use is Associated with a Lower Risk of Acute Exacerbations in Patients with Bronchiectasis-Chronic Obstructive Pulmonary Disease Overlap. AB - BACKGROUND: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap (BCO) is a neglected area of trials, and it is not covered by guidelines for clinical practice. METHODS: Using the National Health Insurance Research Database of Taiwan, COPD patients with or without bronchiectasis from 2000 to 2009 were enrolled as the BCO and COPD alone cohorts, respectively. Patients followed for <28 days, diagnosed with COPD who were not prescribed with COPD medications, and those diagnosed with bronchiectasis who did not receive a chest X-ray or computed tomography were excluded. The primary endpoints were acute exacerbations and mortality. RESULTS: There were 831 patients in the BCO cohort and 3321 patients in the COPD alone cohort, covering 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. The BCO cohort had higher risk for exacerbations (adjusted hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.94-2.63) and mortality (HR 1.46, 95% CI 1.24-1.73) than the COPD alone cohort. In the patients overall, the use of statins, macrolides, and mucolytic agents was associated with significantly lower risks of acute exacerbations (statins, HR 0.37, 95% CI 0.29 0.46; macrolides, HR 0.65, 95% CI 0.45-0.93; mucolytic agents, HR 0.68, 95% CI 0.59-0.78). Statins were associated with a significantly lower risk of mortality (HR 0.32, 95% CI 0.25-0.41). In the BCO group, statins and mucolytic agents use was associated with significantly lower risks of acute exacerbations (statins, HR 0.44, 95% CI 0.29-0.65; mucolytic agents, HR 0.58, 95% CI 0.45-0.75). CONCLUSION: Statins and mucolytic agents use may lower risk of acute exacerbation in patients with BCO. PMID- 30518166 TI - Evaluation of Antioxidant Capacity, Protective Effect on Human Erythrocytes and Phenolic Compound Identification in Two Varieties of Plum Fruit (Spondias spp.) by UPLC-MS. AB - Plum edible part was used to obtained extracts by during a 4 h maceration process using three different solvents (ethanol, methanol and water) for the determination of total phenols and flavonoids, antioxidant capacity by (2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), 2,2 diphenyl-1-picrylhydrazyl (DPPH) and hemolysis inhibition in human blood assays. Subsequently, phenolic compounds were identified using ultra-performance liquid chromatography (UPLC-MS). The results indicated that the ethanolic extract of plum fruit being a good source of phenolic (12-18 mg GAE/g FW) and flavonoids (2.3-2.5 mg QE/g FW) content in both varieties of plum. Also, the fruits proved a good source of antioxidants as measured by DPPH and ABTS; likewise, plum aqueous extracts showed the highest protective effect on human erythrocytes with 74.34 and 64.62% for yellow and red plum, respectively. A total of 23 bioactive compounds were identified by UPLC-MS, including gallic acid, rutin, resorcinol, chlorogenic acid, catechin, and ellagic acid, and the antioxidant capacity can be attributed to these species. The edible part of plum contains compounds of biological interest, suggesting that this fruit has antioxidant potential that can be exploited for various technologies. PMID- 30518167 TI - Robust Lane-Detection Method for Low-Speed Environments. AB - Vision-based lane-detection methods provide low-cost density information about roads for autonomous vehicles. In this paper, we propose a robust and efficient method to expand the application of these methods to cover low-speed environments. First, the reliable region near the vehicle is initialized and a series of rectangular detection regions are dynamically constructed along the road. Then, an improved symmetrical local threshold edge extraction is introduced to extract the edge points of the lane markings based on accurate marking width limitations. In order to meet real-time requirements, a novel Bresenham line voting space is proposed to improve the process of line segment detection. Combined with straight lines, polylines, and curves, the proposed geometric fitting method has the ability to adapt to various road shapes. Finally, different status vectors and Kalman filter transfer matrices are used to track the key points of the linear and nonlinear parts of the lane. The proposed method was tested on a public database and our autonomous platform. The experimental results show that the method is robust and efficient and can meet the real-time requirements of autonomous vehicles. PMID- 30518168 TI - Assessment of P values of demographic data in randomized controlled trials reported in Korean Journal of Anesthesiology between 2010 to 2017. AB - In large number of randomized controlled trials, many of researchers would like to provide P values of demographic data which commonly described in table 1 for the purpose of emphasizing no difference between groups. The authors would intend to demonstrate that statistically insignificant P value in demographic data implicate randomization has been well performed between groups. However, insignificant P value does not necessarily reflect the successful randomization. It is more important to establish a statistical analysis plan thoroughly in the stage of the designing and planning study and to consider if any of the variables included in the demographic data may affect the research results. If a researcher designed and planned a study well and performed it exactly and nicely, the study results would not be influenced by the P values no matter what the p-values are significant or not. The most important steps should be on the stage of designing and planning study. Although well planned and performed, controlled variables might affect results in some studies. In this situation, the researcher can provide both results with initial method and second stage of analysis including such variables. For the brief conclusion, it would be useless to exhibit P values in baseline data table. PMID- 30518169 TI - Sinonasal teratocarcinosarcoma treated with surgery followed by volumetric modulated radiotherapy: a case report with review of literature. AB - Surgical excision along with use of postoperative radiotherapy forms an integral management of sinonasal teratocarcinosarcoma (SNTCS). However, given the rarity of the tumor, no standardised guidelines, dose, technique and target delineation exist especially in the era of modern radiation delivery techniques. This is a case of 55-year-old male diagnosed as SNTCS treated with radical ethmoidectomy followed by volumetric modulated radiotherapy, showing good local control and acceptable toxicity profile. PMID- 30518170 TI - The Relationship of Clinical Symptoms with Social Cognition in Children Diagnosed with Attention Deficit Hyperactivity Disorder, Specific Learning Disorder or Autism Spectrum Disorder. AB - OBJECTIVE: One of the areas of social cognition is Theory of Mind (ToM) is defined as the capacity to interpret, infer and explain mental states underlying the behavior of others. When social cognition studies on neurodevelopmental disorders are examined, it can be seen that this skill has not been studied sufficiently in children with Specific Learning Disorder (SLD). METHODS: In this study, social cognition skills in children diagnosed with attention deficit hyperactivity disorder (ADHD), SLD or Autism Spectrum Disorder (ASD) evaluated before puberty and compared with controls. To evaluate the ToM skills, the first and secondorder false belief tasks, the Hinting Task, the Faux Pas Test and the Reading the Mind in the Eyes Task were used. RESULTS: We found that children with neurodevelopmental disorders as ADHD, ASD, and SLD had ToM deficits independent of intelligence and language development. There was a significant correlation between social cognition deficits and problems experienced in many areas such as social communication and interaction, attention, behavior, and learning. CONCLUSION: Social cognition is an important area of impairment in SLD and there is a strong relationship between clinical symptoms and impaired functionality. PMID- 30518171 TI - Frontal Alpha Asymmetry, Heart Rate Variability, and Positive Resources in Bereaved Family Members with Suicidal Ideation after the Sewol Ferry Disaster. AB - OBJECTIVE: After the Sewol ferry disaster, bereavement with suicidal ideation was a critical mental health problem that was accompanied by various neuropsychological symptoms. This study examined the frontal alpha asymmetry (FAA), heart rate variability (HRV), and several psychological symptoms in bereaved family members (BFM) after the Sewol ferry disaster. METHODS: Eighty three BFM after the Sewol ferry disaster were recruited. We assessed FAA, HRV, and psychological symptoms, including depression, post-traumatic stress, post traumatic growth factor, anxiety, grief, and positive resources, between BFM with the presence and absence of current suicidal ideation. RESULTS: Compared to BFM without suicidal ideation, BFM with suicidal ideation showed a higher FAA with right dominance. Significant differences in psychological symptoms were observed between the groups. In BFM with suicidal ideation, the low: high frequency (LF:HF) ratio correlated with social resources and support. CONCLUSION: The FAA and LF:HF ratio may be biomarkers that represent the pathological conditions of BFM with suicidal ideation. If researched further, they may shed light on the interaction between bereavement with suicidal ideation and social resources for therapeutic intervention. PMID- 30518172 TI - Decreased Aquaporin 4 and 6 mRNAs in Patients With Chronic Otitis Media With Otorrhea. AB - Objectives: Aquaporins (AQPs) are integral membrane proteins engaged in the modulation of water homeostasis, but the roles they play in chronic otitis media (COM) have not been well investigated. Accordingly, we undertook document relations between the mRNA expressions of AQPs and COM, and explored the relation between these expressions and otorrhea, which is one of the most common symptoms of COM. Methods: Levels of the mRNAs of AQP 1, 2, 3, 4, 5, 6, 8, and 10 were assayed by real-time polymerase chain reaction in inflammatory tissue samples from 81 patients with COM with or without otorrhea. Relationships between AQP mRNA levels and the presence or absence of otorrhea, the presence or absence of bacteria, hearing threshold levels, types of hearing loss, and clinical manifestations were also evaluated. Results: AQP 1, 2, 3, 4, 5, 6, 8, and 10 mRNAs were expressed in inflammatory tissues obtained from all 81 patients with COM with or without otorrhea. AQP 5 mRNA was most expressed in, followed in descending order by AQP 3, 1, 10, 6, 8, 2, and 4. There were no significant intergroup differences in terms of age, sex, duration of illness, levels of hearing loss in both ears, or incidences of conductive or sensorineural hearing loss. However, AQP 4 (P=0.035) and 6 (P=0.085) mRNA levels were significantly lower in the otorrhea group. In addition, bacteria culture positivity (P=0.014) and the incidence of sensorineural hearing loss (P=0.020) were higher in the otorrhea group. Conclusion: AQP 1, 2, 3, 4, 5, 6, 8, and 10 are involved in the development of COM. Specifically, it shows reductions in AQP 4 and 6 mRNA levels, as observed in the otorrhea group, have an effect on the clinical manifestations of COM. PMID- 30518173 TI - RAV1 Negatively Regulates Seed Development by Directly Repressing MINI3 and IKU2 in Arabidopsis. AB - A plant-specific B3 domain and AP2 domain-containing transcription factor, RAV1 acts as a negative regulator of growth in many plant species and its transcription was downregulated by BR and ABA. In this study, we found that RAV1 overexpressing transgenic plants showed abnormally developed ovules, resulting in reduced seed size, weight, and number in a silique. Interestingly, the endogenous expression of RAV1 fluctuated during seed development; it remained low during the early stage of seed development and sharply increased in the seed maturation stage. In plants, seed development is a complex process that requires coordinated growth of the embryo, endosperm, and maternal integuments. Among many genes that are associated with endosperm proliferation and embryo development, three genes consisting of SHB1, MINI3, and IKU2 form a small unit positively regulating this process, and their expression was regulated by BR and ABA. Using the floral stage specific RNAs, we found that the expression of MINI3 and IKU2, the two downstream genes of the SHB1-MINI3-IKU2 cascade in the seed development pathway, were particularly reduced in the RAV1-overexpressing transgenic plants. We further determined that RAV1 directly binds to the promoter of MINI3 and IKU2, resulting in their repression. Direct treatment with brassinolide (BL) improved seed development of RAV1-overexpressing plants, but treatment with ABA severely worsened it. Overall, these results suggest that RAV1 is an additional negative player in the early stages of seed development, during which ABA and BR signaling are coordinated. PMID- 30518174 TI - Hepatitis B Virus X Protein Stimulates Virus Replication Via DNA Methylation of the C-1619 in Covalently Closed Circular DNA. AB - Methylation of HBV cccDNA has been detected in vivo and in vitro; however, the mechanism and its effects on HBV replication remain unclear. HBx derived from a 1.2-mer HBV replicon upregulated protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), 3a, and 3b, resulting in methylation of the negative regulatory region (NRE) in cccDNA, while none of these effects were observed with an HBx-null mutant. The HBx-positive HBV cccDNA expressed higher levels of HBc and produced about 4-fold higher levels of HBV particles than those from the HBx null counterpart. For these effects, HBx interrupted the action of NRE binding protein via methylation of the C-1619 within NRE, resulting in activation of the core promoter. Treatment with 5-Aza-2'dC or DNMT1 knock-down drastically impaired the ability of HBx to activate the core promoter and stimulate HBV replication in 1.2-mer HBV replicon and in vitro infection systems, indicating the positive role of HBx-mediated cccDNA methylation in HBV replication. PMID- 30518176 TI - Photodynamic therapy in dermatology. PMID- 30518175 TI - Crystal Structure of LysB4, an Endolysin from Bacillus cereus-Targeting Bacteriophage B4. AB - Endolysins are bacteriophage-derived enzymes that hydrolyze the peptidoglycan of host bacteria. Endolysins are considered to be promising tools for the control of pathogenic bacteria. LysB4 is an endolysin produced by Bacillus cereus-infecting bacteriophage B4, and consists of an N-terminal enzymatic active domain (EAD) and a C-terminal cell wall binding domain (CBD). LysB4 was discovered for the first time as an Lalanoyl-D-glutamate endopeptidase with the ability to breakdown the peptidoglycan among B. cereus-infecting phages. To understand the activity of LysB4 at the molecular level, this study determined the X-ray crystal structure of the LysB4 EAD, using the full-length LysB4 endolysin. The LysB4 EAD has an active site that is typical of LAS-type enzymes, where Zn2+ is tetrahedrally coordinated by three amino acid residues and one water molecule. Mutational studies identified essential residues that are involved in lytic activity. Based on the structural and biochemical information about LysB4, we suggest a ligand docking model and a putative endopeptidase mechanism for the LysB4 EAD. These suggestions add insight into the molecular mechanism of the endolysin LysB4 in B. cereusinfecting phages. PMID- 30518177 TI - Clinical and instrumental evaluation of the efficacy of an emollient cream and a cleansing cream in the management of mild to moderate adulthood atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disorder which may persist or directly start in adults. This is an open-label prospective study to clinically and instrumentally evaluate the effects of an emollient glycerin and paraffin-based cream and a gentle refatting cleanser in the management of mild to moderate adulthood AD. METHODS: Fifty adult patient with mild to moderate AD were recruited at the Professional Dermatology and Allergology Outpatient Clinic of the San Gallicano Dermatological Institute of Rome, between November 2016 and January 2018. The patients applied the emollient cream twice daily for 2 months. To assess the efficacy of the cream, two different areas of treatment were identified in each patient's limbs. The outcome was evaluated at 30 days (T1) and 60 days (T2) of treatment comparing to baseline (T0) by means of clinical evaluation, Dermatology Life Quality Index (DLQI) questionary, transepidermal waterloss (TEWL) and corneometry measurements. RESULTS: Clinical evaluation showed significative improvement of skin xerosis, fissuring, itching and erythema. Consistently, a significative reduction of TEWL and an improvement in skin hydration was also detected. A significative improvement of DLQI score was also detected. CONCLUSIONS: Study treatment was well tolerated and showed significative improvement of clinical and instrumental parameters evaluated. The topical daily use of an emollient glycerin and paraffin based cream and a gentle refatting cleanser seems to be a useful tool in the treatment of mild to moderate adulthood AD improving quality of life. PMID- 30518178 TI - Reassurance on the safety of biotin in dermatology. PMID- 30518179 TI - Dermoscopic features of conjunctival melanocytic lesions. PMID- 30518180 TI - A case of co-occurence of Dowling-Degos disease and psoriasis: association or a rarely-seen coincidence? PMID- 30518181 TI - Sensitization and Geographical Distribution of Main Aeroallergens in Iran. AB - N0 Abstract. PMID- 30518182 TI - Modulation of Macrophage Polarization for Bone Tissue Engineering Applications. AB - Innate immune cells play a crucial role in bone development and repair. Macrophages are the main effector cells in immune responses to implants and are indispensable for bone healing success. The heterogeneity and plasticity of macrophages make them a prime target for immune system modulation to enhance bone repair and regeneration. It is believed that the polarization of macrophage phenotype towards the anti-inflammatory M2, rather than the inflammatory M1 phenotype, promotes osteogenesis. Tissue-engineered bioimplants are potentially capable of producing signals to modulate macrophage polarization. Therefore, development of smart immunomodulatory bioimplants via manipulation of their properties seem a promising strategy for tuning immune responses to optimize bone repair without any unwanted inflammatory reactions. The purpose of the present review is to summarize the currently available studies performed on the effects of macrophage polarization, especially towards M2 phenotype, both in bone repair and in bioimplant-stimulated osteogenesis. Moreover, this literature highlights the need to focus future studies on the development of smart immunomodulatory implants capable of switching macrophage polarization-enhancing bone implant-host tissue integration. PMID- 30518183 TI - Effects of Viola tricolor Flower Hydroethanolic Extract on Lung Inflammation in a Mouse Model of Chronic Asthma. AB - Asthma is a chronic inflammatory disease of the lungs driven by T cell activation. Viola tricolor L. as a traditional medical herb could suppress activated T lymphocytes and has been used empirically for asthma remedy. In the present study, we investigated the anti-inflammatory effect of Viola tricolor and its underlying mechanism on asthma characteristics induced by ovalbumin (OVA) in mice. BALB/c mice were randomly divided into six groups: normal control, Ovalbumin (OVA) control, OVA mice treated with Viola tricolor (50, 100 and 200 mg/kg) and dexamethasone (3 mg/kg). All mice except normal controls were sensitized and challenged with OVA. Asthmatic mice were treated orally in the last 7 days of OVA challenge. The total and differential leukocyte counts, Interleukin (IL)-4 and interferon (IFN)-gamma levels in bronchoalveolar lavage fluid (BALF) were determined. H and E staining for lung inflammation was performed. Viola tricolor treatment at 200 mg/kg significantly decreased IL-4 level but did not considerably affect the IFN-gamma level. Therefore, it effectively reduced asthma characteristics including infiltration of leukocytes particularly eosinophil and peribronchial inflammation as compared to dexamethasone. However, Viola tricolor at 100 mg/kg had the most prominent inhibitory effect on the IL-4 level and also markedly increased IFN-gamma level. As result, it prevented further reduction of inflammatory parameters in this group compared to the Viola tricolor-treated group at 200 mg/kg. Our study demonstrated that Viola tricolor has anti-inflammatory effects via inhibition of T-helper type 2 (Th2) cytokine production and validated its empirical usage in traditional medicine. PMID- 30518184 TI - Modulation of Vascular Endothelial Growth Factor and Annexin A2 in Response to 4 (Methylnitrosamino)-1-(3-pyridyl)-1-Butanone -Induced Inflammation via Swimming Training. AB - The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; nicotine derived nitrosamine ketone) is one of the strongest carcinogens in tobacco which is involved in induction of lung cancer by changing the stimulation of vascular endothelial growth factor (VEGF) and annexin A2 expression. The aim of this study was to investigate the changes in resting levels of annexin A2 and VEGF in lung tissues of rats exposed NNK after 12 weeks of aerobic submaximal swimming training. For this purpose, 46 Wistar rats were randomly divided into five groups consist of training, training + NNK, NNK, saline and control. NNK-induced groups received NNK subcutaneously one day per week at a rate of 12/5 mg per kg body weight and the training groups performed submaximal swimming training for 12 weeks. The levels of VEGF and annexin A2 in lung tissue were measured respectively by ELISA and immunohistochemistry. To analyze the data; ANOVA and Tukey's test were used at a significance level of p<0.05. Findings indicated that 12 weeks submaximal swimming training decreased the levels of VEGF and annexin A2 in lung tissue significantly when compared to NNK group (p<0.001). There was no significant correlation between VEGF and annexin A2 levels in all study groups (p>=0.05). Generally, it could be confirmed that regular submaximal aerobic training plays an important role in inhibition of the effects of lung inflammation induced by NNK via decreased levels of VEGF and annexin A2. PMID- 30518185 TI - Effect of Kaempferol on Cyclooxygenase 2 (Cox2) and Cytosolic Phospholipase A2 (cPLA2) Protein Expression in BALB/c Mice. AB - Kaempferol, a phytochemical found in many edible plants, is known to alleviate diseases such as cancer, allergy, and inflammation. The objective of this study was to investigate whether kaempferol could reduce omega-6 and ovalbumin-mediated allergic reactions at lung and trachea in BALB/c mice. Mice were allocated into five groups: 1) control group (CON); 2) positive control group with orally administration of omega-6 (POS); 3) bovine serum albumin (BSA) sensitization group (with BSA injection and ovalbumin inhalation); 4) BSA+K10 group: BSA injection, 10 MUg/g of kaempferol administration and ovalbumin inhalation; and 5) BSA+K20 group: BSA injection, 20 MUg/g of kaempferol administration and ovalbumin inhalation. Results revealed that serum histamine level was the highest (p<0.01) in BSA group. In lung tissue and trachea, cyclooxygenase 2 (Cox2) expression was significantly (p<0.05) higher in the BSA group compared to that in other groups. However, phosphorylated cytosolic phospholipase A2 (p-cPLA2) expression in the trachea was not significantly different among groups. Taken together, results of this study suggest that kaempferol might be useful for alleviating inflammation reaction associated with Cox2 expression. However, the exact mechanism of action involved in the effect of kaempferol on inflammatory response remains unclear. PMID- 30518186 TI - Assessment of the Inhibitory Effects of Ficin-hydrolyzed Gelatin Derived from Squid (Uroteuthis duvauceli) on Breast Cancer Cell Lines and Animal Model. AB - Marine novel natural products have been applied for cancer therapy. Enzyme digested gelatin hydrolysates have proven to serve as promising sources of potent biologically active peptides. Potential anti-breast cancer properties of the extracted Ficin-digesterd gelatin hydrolysate from Indian squid (Uroteuthis duvauceli) was extensively characterized by cellular and animal models. Gelatin was extracted from squid skin, hydrolyzed by Ficin, and characterized by standard physico-chemical methods. Ficin-digested gelatin hydrolysate was used at various doses of 0-0.1 mg/mL for assessment of MCF-7 and MDA-MB-231 breast cancer cells versus HUVEC normal cells. Cytotoxicity, phase-contrast morphological examination, apoptosis/necrosis, clonal-growth, cell-migration, Matrix metalloproteinases (MMPs) zymography, and Western blotting were used for cellular assessments. For animal studies, breast tumor-induced BALB/c mice received hydrolyzed gelatin regimen, followed by tumor size/growth and immune histochemical analyses. Significant inhibition of MCF-7 and MDA-MB-231 with no cytotoxicity on HUVEC cells were detected. Apoptosis was increased in cancer cells, as revealed by elevated ratio of cleaved caspase-3 and PARP. MMP-2 and MMP 9 activities in both cancer cells were diminished. In mice, gelatin hydrolysate prevented weight loss, decreased tumor size, induced p53, and down-regulated Ki67 levels. These findings suggest that Ficin-digested gelatin hydrolysate could be a beneficial candidate for novel breast cancer therapies. PMID- 30518187 TI - Evaluation of IL-17 Producing Memory Regulatory and Effector T Cells Expressing CD26 Molecule in Patients with Psoriasis. AB - Memory regulatory T cells (Tregs) has been demonstrated to produce IL-17 in Psoriasis. Forkhead box P3 (Foxp3) has been demonstrated not to be reliable marker to evaluate Treg cells. Effector CD4+T cells also express Foxp3 after activation. Human T helper-17 cells (Th-17) express high level of surface CD26, while regulatory T cells are CD26 negative or low and this phenotype is stable even after activation of Treg cells. In this study, we aimed to analyze IL-17 producing Treg cells using CD26. Memory T cells were isolated from 10 patients with psoriasis and 10 controls. Ex vivo stimulated IL-17 producing regulatory (Forkhead Box P3 (Foxp3)+CD25+CD26-/low) and effector (Foxp3+CD25+CD26hi) memory T cells were analyzed by flow cytometry. IL-23, IL-6, TNFalpha, TGFbeta and IL-17 cytokine levels were also evaluated. No significant difference in IL-17+memory regulatory T cells was seen between patients and controls (p=0.19). A significant decrease in the percentage of IL-17 producing CD26hi effector memory T cells was observed in patients (p=0.04). However, the percentage of these cells was not different between patients with mild or severe form of psoriasis compared to controls (p=0.13). We could not find any significant difference regarding IL-23, IL-6, TNFalpha, TGFbeta and IL-17 cytokine levels in plasma and cell culture supernatant samples between patients and controls. Taken together, our results showed a reduced IL-17 producing effector memory CD26hi T cells in patients with psoriasis compared to controls. However, IL-17 producing memory regulatory CD4+T cells of patients showed no significant difference from that of controls. PMID- 30518188 TI - Evaluation of ERAP1 Gene Single Nucleotide Polymorphism in Impressing the Inflammatory Cytokine Profile of Ankylosing Spondylitis Patients. AB - Ankylosing spondylitis (AS), an autoinflammatory disease, has been associated with impaired Endoplasmic reticulum aminopeptidase (ERAP) 1 activity, which is involved in priming antigenic peptides. The purpose of this study was to evaluate if the genetic variant of ERAP1 gene could impress the inflammation status of the AS patients. For genotyping, 140 AS cases and 140 healthy controls were enrolled. After isolation of peripheral blood mononuclear cells (PBMCs) and DNA extraction, all the subjects were genotyped for rs27044 polymorphism using SSP-PCR assay. Total RNA of PBMCs was isolated, cDNA was synthesized, and quantitative analyses of mRNA expression of cytokines were performed via Real-time PCR using the SYBR Green Gene Expression MasterMix. To measure the concentration of cytokines in serum of subjects, Enzyme-linked immunosorbent assay (ELISA) was used. It was observed that the G allele of rs27044 polymorphism was significantly prevalent in AS patients. Moreover, the GG genotype and the GG+GC dominant model had significantly different distribution between study groups. There was a significant overexpression of mRNAs of IL-17A, IL-6, IL-33, TNF-alpha, and IFN gamma, while IL-10 was significantly downregulated in AS patients. The ELISA results were in line with that of the gene expression analysis. No significant differences in mRNA expression and concentration of cytokine were identified among AS patients with three genotypes for rs27044 SNP. This study replicated the association of polymorphisms in ERAP1 gene with the risk of AS in a population from Iranian. However, it did not directly determine the inflammatory profile of the AS patients. PMID- 30518189 TI - Genetic Variation in Intergenic and Exonic miRNA Sequence and Risk of Multiple Sclerosis in the Isfahan Patients. AB - MicroRNAs (miRNAs), have been documented to perform a key role in the pathogenesis of multiple sclerosis (MS), a chronic inflammatory and autoimmune disease. Recent studies have shown that single nucleotide polymorphism in the sequence of the miRNA may change their production and expression which can lead to miRNA dysfunction and pathogenicity. Some studies have reported the relationship between miRNA polymorphism and the increased risk of autoimmune disease. This study was conducted to investigate the association between mir155 rs767649, mir196a2 rs11614913 and mir23a rs3745453 polymorphism and the risk of multiple sclerosis in the Iranian MS patients in Isfahan. A population of 80 patients and the same number control were selected. After DNA extraction, genotyping was performed through tetra amplification refractory mutation system PCR method (T ARMS PCR). The frequencies of TT, TC and CC genotypes of mir23a were 46, 35 and 20% in MS patients and 42, 14 and 24 in healthy subjects respectively. These results showed that individuals carrying the genotypes of rs3745453 TC had a 2.3-fold increased risk of MS (OR=2.3, p=0.048). There was no significant difference between genotypes and allele frequency of mir155 and mir196a2 in patients and healthy controls (p>0.05). Our findings specified that CT heterozygosity in mir23a gene significantly related with risk of MS. Unlike mir155 and mir196a2, mir23a rs3745453 may have contributed to the etiology of MS in Isfahan patients. However, extensive studies are required to gain more reliable and authentic results. PMID- 30518190 TI - Effect of Progesterone on Expression of MMP7 and MMP13 in Lungs of Female Mice. AB - Gender medicine is a new era of science which focuses on the impact of sex hormones and gender on normal physiology, pathobiology and clinical features of diseases. In this study we investigated the impact of pregnancy doses of progesterone hormone on the expression of a couple of matrix metalloproteinase (MMPs), which are known to be involved in tissue remodeling of lungs in health and disease, namely MMP7 and 13. Pregnancy maintenance dose of progesterone was administered to female BALB/c mice for 21 and 28 days, the control group received PBS for the same days. After removal of the lungs and RNA extraction, quantitative real-time PCR was done using specific primers for MMP7 and MMP13. We found that progesterone can slightly (not significantly) decrease the expression of MMP13 but had no effect on MMP7. Our results shows that progesterone has minimal effect on the expression of matrix metalloproteinase7 and matrix metalloproteinase 13, but it may still have an effect on corresponding tissue inhibitor of matrix metalloproteinases (TIMPs) or other components of the Extracellular matrix which remains to be elucidated. Also, the effect of progesterone on these MMPs can be further studied in a fibrosis model. PMID- 30518191 TI - Increased Total Serum Immunoglobulin E in Children Developing Mycoplasma pneumoniae-related Extra-pulmonary Diseases. AB - Mycoplasma pneumoniae has been recognized to be involved in several extra pulmonary diseases, but the underlying immunologic mechanisms are still largely unknown. Recently, we observed a significant elevation of serum Immunoglobulin E (IgE) in a small group of these children. Here, we assessed total serum IgE levels in children affected with Mycoplasma pneumoniae-related extra-pulmonary diseases. We prospectively collected the data of 162 children admitted to the hospital (because of respiratory infections or extra-pulmonary diseases) who were evaluated for Mycoplasma pneumoniae serology and total serum IgE levels, concomitantly. Based upon clinical and serology aspects, 3 groups of children were identified: I) with non-mycoplasma respiratory disease; II) with mycoplasma related respiratory diseases; III) with extra-pulmonary diseases related to concomitant/recent Mycoplasma pneumoniae infection. Interestingly, children with Mycoplasma pneumoniae-related extra-pulmonary diseases showed a significant elevation of total serum IgE. In particular, patients developing Mycoplasma pneumoniae-related extra-pulmonary diseases (group III) showed significantly higher level of IgE than both previous groups (p<0.001 vs. group I; p<0.01 vs. group II). In conclusion, hospitalized children diagnosed with Mycoplasma pneumoniae-related extra-pulmonary diseases resulted to have significantly increased serum IgE compared to children developing respiratory illnesses only. PMID- 30518192 TI - Auditory Localization Performances in Subjects with Simulated Unilateral Conductive Hearing Loss. PMID- 30518193 TI - Comparison between Subjective Scoring and Computer-Based Asymmetry Assessment in Facial Nerve Palsy. AB - Background and Objectives: : The aim of the present study was to assess the feasibility of a PC-based facial asymmetry assessment program (PC-FAAP) and to compare the results of PC-FAAP with subjective regional scoring by raters in acute unilateral peripheral facial nerve paralysis (FNP). Subjects and Methods: : Participants were divided into 3 groups with 8 participants per group: group I, normal; group II, mild to moderate FNP; and group III, severe FNP. Using the PC FAAP, the mouth asymmetry ratio (MAR), eyebrow asymmetry ratio (EAR), and complete eye closure asymmetry ratio (CAR) were calculated by comparing the movement of tracking points on both sides. The FNP grading scale (FGS) integrated each score, and the scores were weighted with a ratio of 5:3:2 (MAR:CAR:EAR). Subjective regional scoring was measured on a 0-100 scale score by three otologists. PC-FAAP and subjective scoring were compared in each group regarding the consistency of the results. Results: : The mean scores of the MAR, EAR, CAR, and FGS of each group were significantly different. PC-FAAP showed significant differences between the three groups in terms of MAR, EAC, CAR, and FGS. PC-FAAP showed more consistent results than subjective assessment (p<0.001). The PC-FAAP was significantly more consistent in group I and group III (p<0.001 and p=0.002, respectively). FGS in group III was the only parameter that showed a more consistent result in PC-FAAP than the subjective scoring (p=0.008). Conclusions: : An FNP grading system using a PC-based program may provide more consistent results, especially for severe forms. PMID- 30518194 TI - Evaluation of Saccule Function in Patients with Vitamin D Deficiency. AB - Background and Objectives: : Considering important role of vitamin D in many physiological processes including vestibular system in the ear, aim of present study is to evaluate saccule function via cervical vestibular evoked myogenic potential (cVEMP), in patients with vitamin D deficiency. Subjects and Methods: : After routine audiological tests, cVEMP were recorded in 15 patients with vitamin D deficiency and 16 normal subjects. The short tone burst (95 dB nHL, 500 Hz) was presented to ears. cVEMP was recorded with surface electromyography over the contracted ipsilateral sternocleidomastoid muscle. Results: : Mean of p13, n13, interpeak latencies and amplitude ratios were measured in both groups. Statistical analysis did not show differences between two groups. Conclusions: : Maybe serum 25-hydroxyvitamin D concentration was not low enough to have effect on saccule in the patients in present study or saccule have had low susceptibility to effects of vitamin D deficiency. For better judgment about effect of vitamin D deficiency on saccular function planning studies with high sample size is recommended. PMID- 30518195 TI - Single Dose Topical Application of Clotrimazole for the Treatment of Otomycosis: Is This Enough? AB - Background and Objectives: : To determine the efficacy of filling the external auditory meatus with 1% clotrimazole at a single visit for the treatment of otomycosis. Subjects and Methods: : This prospective study included 40 patients who were referred to our clinic with complaints of ear itching, pain, and fullness, and were diagnosed with unilateral otomycosis. After cleaning the mycotic hyphae from the external auditory meatus, the ear canal was filled with 1% clotrimazole, using an intravenous catheter and syringe. The patients received follow-up examinations on post-treatment days 7, 15, and 45. Results: : The follow-up otomicroscopic examinations revealed that 95% of the ear canals were entirely clean and that all symptoms had resolved. The post-treatment scores of pain, aural fullness and itching were significantly lower than the pre-treatment scores (p<0.01). Conclusions: : Filling the external auditory meatus with 1% clotrimazole at a single visit is an easy, efficient, and cost-effective treatment for otomycosis. Additionally, high patient compliance makes this treatment superior to long-term topical therapy. PMID- 30518196 TI - Comparison of McGurk Effect across Three Consonant-Vowel Combinations in Kannada. AB - Background and Objectives: : The influence of visual stimulus on the auditory component in the perception of auditory-visual (AV) consonant-vowel syllables has been demonstrated in different languages. Inherent properties of unimodal stimuli are known to modulate AV integration. The present study investigated how the amount of McGurk effect (an outcome of AV integration) varies across three different consonant combinations in Kannada language. The importance of unimodal syllable identification on the amount of McGurk effect was also seen. Subjects and Methods: : Twenty-eight individuals performed an AV identification task with ba/ ga, pa/ka and ma/n. a consonant combinations in AV congruent, AV incongruent (McGurk combination), audio alone and visual alone condition. Cluster analysis was performed using the identification scores for the incongruent stimuli, to classify the individuals into two groups; one with high and the other with low McGurk scores. The differences in the audio alone and visual alone scores between these groups were compared. Results: : The results showed significantly higher McGurk scores for ma/n. a compared to ba/ga and pa/ka combinations in both high and low McGurk score groups. No significant difference was noted between ba/ga and pa/ka combinations in either group. Identification of /n. a/ presented in the visual alone condition correlated negatively with the higher McGurk scores. Conclusions: : The results suggest that the final percept following the AV integration is not exclusively explained by the unimodal identification of the syllables. But there are other factors which may also contribute to making inferences about the final percept. PMID- 30518197 TI - Recovery Phase Spontaneous Nystagmus, Its Existence and Clinical Implication. AB - Background and Objectives: : Determination of the lesion side based on the direction of the nystagmus could result in confusions to the clinicians due to mismatch between the vestibular function tests and also between vestibular and audiologic features. To minimize these mistakes, we elucidated the clinical manifestation and vestibular function test results in cases with recovery spontaneous nystagmus (rSN). Subjects and Methods: : Patients who visited ENT clinic of tertiary referral hospital for acute onset continuous vertigo from January 2008 to December 2011 were enrolled. In these patients, we assessed onset time of vertigo, time point of paralytic spontaneous nystagmus (SN) and time point of rSN. At each time point of SN, vestibular function tests and hearing function tests were performed. Results: : We confirmed the rSN among patients with unilateral vestibulopathy and demonstrated that high gain of the rotatory chair test (slow harmonic acceleration) and/or mismatch of the SN direction and contralateral caloric weakness could indicate the recovery state of patients and nystagmus observed in this stage is recovery phase nystagmus. Conclusions: : In acute vestibulopathy patients, recovery phase nystagmus was observed and on this stage of disease vestibular function tests shows several features that could predict recovery state. PMID- 30518198 TI - Mutations in GJB2 as Major Causes of Autosomal Recessive Non-Syndromic Hearing Loss: First Report of c.299-300delAT Mutation in Kurdish Population of Iran. AB - Background and Objectives: : Autosomal recessive non-syndromic hearing loss (ARNSHL) with genetic origin is common (1/2000 births). ARNSHL can be associated with mutations in gap junction protein beta 2 (GJB2). To this end, this cohort investigation aimed to find the contribution of GJB2 gene mutations with the genotype-phenotype correlations in 45 ARNSHL cases in the Kurdish population. Subjects and Methods: : Genomic DNA was extracted from a total of 45 ARNSHL families. The linkage analysis with 3 short tandem repeat markers linked to GJB2 was performed on 45 ARNSHL families. Only 9 of these families were linked to the DFNB1 locus. All the 45 families who took part were sequenced for confirmation linkage analysis (to perform a large project). Results: : A total of three different mutations were determined. Two of which [c.35delG and c.-23+1G>A (IVS1+1G>A)] were previously reported but (c.299-300delAT) mutation was novel in the Kurdish population. The homozygous pathogenic mutations of GJB2 gene was observed in nine out of the 45 families (20%), also heterozygous genotype (c.35delG/N)+(c.-23+1G>A/c.-23+1G>A) were observed in 4/45 families (8.8%). The degree of hearing loss (HL) in patients with other mutations was less severe than patients with c.35delG homozygous mutation (p<0.001). Conclusions: : Our data suggest that GJB2 mutations constitute 20% of the etiology of ARNSHL in Iran; moreover, the c.35delG mutation is the most common HL cause in the Kurdish population. Therefore, these mutations should be included in the molecular testing of HL in this population. PMID- 30518199 TI - Posterior Sublaminar Wiring and/or Transarticular Screw Fixation for Reducible Atlantoaxial Instability Secondary to Symptomatic Os Odontoideum: A Neglected Technique? AB - Study Design: Retrospective case analysis. Purpose: We retrospectively evaluated the clinical and radiological outcomes of posterior sublaminar wiring (PSLW) and/or transarticular screw fixation (TASF) for reducible atlantoaxial instability (AAI) secondary to os odontoideum. Overview of Literature: Limited information is available about the surgical outcomes of symptomatic os odontoideum with AAI. Methods: We examined 23 patients (12 women and 11 men) with os odontoideum and reducible AAI. The average age of the patients at the time of the operation was 44.2 years. The average follow-up duration was 4.5 years. Thirteen patients with anterior AAI underwent PSLW alone, while 10 patients with combined (anterior+posterior) AAI underwent PSLW and TASF. An autogenous iliac bone graft was used for all patients. Nine patients complained of neck or suboccipital pain, and 14 complained of myelopathy. Results: Angulational instability (preoperative 18.7 degrees +/-8.9 degrees vs. postoperative 2.1 degrees +/-4.6 degrees , p<0.001), translational instability (16.3+/-4.9 mm vs. 1.8+/-2.2 mm, p<0.001), and segmental angle of the C1-C2 joint (23.7 degrees +/ 7.2 degrees vs. 28.4 degrees +/-3.8 degrees , p<0.05) showed significant improvement postoperatively. Neck Visual Analog Scale score (6.2+/-2.4 vs. 2.5+/ 1.8, p<0.05) and the modified Japanese Orthopedic Association (9.1+/-3.1 vs. 13.2+/-2.6, p<0.05) score also improved, with a recovery rate of 51.8%. Among the three patients who developed nonunion and/or wire breakage, one underwent revision surgery with repeat PSLW and was finally able to achieve fusion. The final fusion rate was 91.3%. Conclusions: PSLW and/or TASF provided satisfactory clinical and radiological outcomes in reducible AAI secondary to os odontoideum without significant neurological complications. Our results suggest that PSLW and/or TASF can be considered a viable surgical option over segmental fixation in highly selected cases of os odontoideum with reducible AAI. PMID- 30518200 TI - Does the Cage Position in Transforaminal Lumbar Interbody Fusion Determine Unilateral versus Bilateral Screw Placement?: A Review of the Literature. AB - This literature review examines the relative placement of the interbody cage with respect to the unilateral screw construct to address the need for bilateral screw placement versus unilateral screw placement. Transforaminal lumbar interbody fusion (TLIF) has become a widely used technique for correcting lumbar intervertebral pathologies. This review addresses the necessity for further study on the effects of the relative position of intervertebral cage placement on the outcome of lumbar spine surgery after TLIF with unilateral pedicle screw fixation. Previous studies have addressed various factors, including posterior screw fixation, cage size, cage shape, and number of levels fused, that impact the biomechanics of the lumbar spine following TLIF. A simple survey of the literature was conducted. A search of the English literature was conducted using the keywords 'TLIF,' 'transforaminal lumbar interbody fusion,' 'graft placement,' 'graft position,' 'cage position,' 'cage placement,' 'unilateral pedicle screw,' 'unilateral TLIF cage placement,' 'lumbar biomechanics,' 'lumbar stability,' 'lumbar fusion,' and 'lumbar intervertebral cage' with various combinations of the operators 'AND' and 'OR' and no date restrictions. Seventeen articles in the English literature that were most relevant to this research question were identified. To the best of our knowledge, there are no published data addressing the effects of cage placement relative to the unilateral screw on lumbar stability in TLIF with unilateral pedicle screw fixation. Investigation of the effects of cage placement is, thus, warranted to achieve optimal clinical outcomes in patients undergoing TLIF with unilateral pedicle screw fixation. PMID- 30518202 TI - Medical Professionalism: Promoting Patient and Physician Safety PMID- 30518201 TI - Short-term effects of a dietary supplement on lower urinary tract symptoms. AB - Benign prostatic hyperplasia (BPH) is one of the most common conditions affecting men over 40 years of age, typically manifesting itself with lower urinary tract symptoms (LUTS). Recently, research interest has focused in discovering a viable nutraceutical alternative to the drugs that are currently the first line of treatment for BPH. The aim of this study was to investigate the efficacy and safety of a dietary supplement containing curcumin, beta-sitosterol and oligomeric proanthocyanidins in a group of BPH/LUTS patients. One-hundred men with LUTS caused by BPH were enrolled in this study and agreed to take one tablet a day of the test dietary supplement for three months. Several parameters, such as International Prostate Symptom Score (IPSS), degree of urinary obstruction and average urinary flow were evaluated at different time points. Significant improvement in LUTS was seen after one month of treatment and a significant decrease in mean IPSS index was evident after three months of treatment. Moreover, a comparison of the mean urinary flow and of the number of subjects with bladder obstruction at three months versus one month of treatment shows a significant improvement. The study results suggest that the dietary supplement is effective for almost all the symptoms investigated, including the reduction of IPSS score and the increase of urinary flow. Moreover, the dietary supplement proved to be safe and well tolerated by the great majority of the enrolled subjects. . PMID- 30518203 TI - Quality Improvement of Clinical Handover in a Liaison Psychiatry Department: A Three-Phase Audit AB - AimsTo audit and improve quality of clinical handover in a Liaison Psychiatry Department.MethodsAn 11-item Handover Checklist was used to carry out a baseline audit and immediate and delayed post-intervention re-audits. The intervention consisted of checklist posters, an electronic database and staff training.ResultsThere was an immediate and sustained improvement in most areas, including baseline demographics and components of SBAR communication (Situation, Background, Assessment, Recommendation). The improvement between baseline and delayed re-audit was statistically significant (P=0.007).ConclusionPoor handover practices contribute to negative outcomes in healthcare but there remains a dearth of guidelines in most specialties.This audit is important as it describes an intervention which improved clinical handover at a time of significant clinical risk. This practice could be applied effectively to other services and is relevant to all specialties. Six to twelve-monthly re-audit and longitudinal assessment of clinical outcomes are recommended to maintain the practices implemented in this audit. PMID- 30518204 TI - Exploiting Substrate Promiscuity to Develop Activity-Based Probes for TET Family Enzymes. AB - TET enzymes catalyze the repeated oxidation of 5-methylcytosine in genomic DNA. Due to the challenges of tracking reactivity within a complex DNA substrate, chemical tools to probe TET activity are limited, despite these enzyme's crucial role in epigenetic regulation. Here, building on precedents from related Fe(II)/alpha-ketoglutarate-dependent dioxygenases, we show that TET enzymes can promiscuously act upon cytosine bases with unnatural 5-position modifications. Oxidation of 5-vinylcytosine (vC) in DNA results in the predominant formation of a 5-formylmethylcytosine product that can be efficiently labeled to provide an endpoint read-out for TET activity. The reaction with 5-ethynylcytosine (eyC), moreover, results in the formation of a high-energy ketene intermediate that can selectively trap any active TET isoform as a covalent enzyme-DNA complex, even in the complex milieu of a total cell lysate. Exploiting substrate promiscuity therefore offers a new and needed means to directly track TET activity in vitro or in vivo. PMID- 30518205 TI - Insight into the Thermophilic Mechanism of a Glycoside Hydrolase Family 5 beta Mannanase. AB - To study the molecular basis for thermophilic beta-mannanase of glycoside hydrolase family 5, two beta-mannanases, TlMan5A and PMan5A, from Talaromyces leycettanus JCM12802 and Penicillium sp. WN1 were used as models. The four residues, His112 and Phe113 located near the antiparallel beta-sheet at the barrel bottom and Leu375 and Ala408 from loop 7 and loop 8 of PMan5A, were inferred to be key thermostability contributors through module substitution, truncation, and site-directed mutagenesis. The effects of these four residues on the thermal properties followed the order H112Y>A408P>L375H>F113Y and were strongly synergetic. These results were interpreted structurally using molecular dynamics (MD) simulations, which showed that improved hydrophobic interactions in the inner wall of the beta-barrel and the rigidity of loop 8 were caused by the outside domain of the barrel bottom and proline, respectively. The TIM barrel bottom and four specific residues responsible for the thermostability of GH5 beta mannanases were elucidated. PMID- 30518206 TI - Room temperature iron-catalyzed transfer hydrogenation and regioselective deuteration of carbon-carbon double bonds. AB - An iron catalyst has been developed for the transfer hydrogenation of carbon carbon multiple bonds. Using a well-defined beta-diketiminate iron(II) pre catalyst, a sacrificial amine and a borane, even simple, unactivated alkenes such as 1-hexene undergo hydrogenation within 1 hour at room temperature. Tuning the reagent stoichiometry allows for semi- and complete hydrogenation of terminal alkynes. It is also possible to hydrogenate amino-alkenes and amino-alkynes without poisoning the catalyst through competitive amine ligation. Furthermore, by exploiting the separate protic and hydridic nature of the reagents it is possible to regioselectively prepare mono-isotopically labeled products. DFT calculations define a mechanism for the transfer hydrogenation of propene with nBuNH2 and HBpin that involves the initial formation of an iron(II)-hydride active species, 1,2-insertion of propene and rate-limiting protonolysis of the resultant alkyl by the amine N-H bond. This mechanism is fully consistent with the selective deuteration studies, although the calculations also highlight alkene hydroboration and amine-borane dehydrocoupling as competitive processes. This was resolved by re-assessing the nature of the active transfer hydrogenation agent: experimentally a gel is observed in catalysis and calculations suggest this can be formulated as an oligomeric species comprising H-bonded amine-borane adducts. Gel formation serves to reduce the effective concentrations of free HBpin and nBuNH2 and so disfavors both hydroboration and dehydrocoupling while allowing alkene migratory insertion (and hence transfer hydrogenation) to dominate. PMID- 30518207 TI - Organic fluorophore coated polycrystalline ceramic LSO:Ce scintillators for x-ray bioimaging. AB - The current effort demonstrates that lutetium oxyorthosilicate doped with 1-10% cerium (Lu2SiO5:Ce, LSO:Ce) radioluminescent particles can be coated with a single dye or multiple dyes and generate an effective energy transfer between the core and dye(s) when excited via x-rays. LSO:Ce particles were surface modified with an alkyne modified naphthalimide (6-piperidin-1-yl-2-prop-2-yn-1-yl-1 H- benzo[ de]isoquinoline-1,3-(2 H)-dione, AlNap) and alkyne modied rhodamine B ( N (6-diethylamino)-9-{2-[(prop-2-yn-1-yloxy)carbonyl]phenyl}-3 H-xanthen-3-ylidene) N-ethylethanaminium, AlRhod) derivatives to tune the x-ray excited optical luminescence from blue to green to red using F?orster Resonance Energy Transfer (FRET). As x-rays penetrate tissue much more effectively than UV/visible light, the fluorophore modied phosphors may have applications as bio-imaging agents. To that end, the phosphors were incubated with rat cortical neurons and imaged after 24 hours. The LSO:Ce surface modified withAlNap were able to be successfully imaged in vitro with a low-output x-ray tube. To use the LSO:Ce fluorophore modied particles as imaging agents, they must not induce cytotoxicity. Neither LSO:Ce nor LSO:Ce modied with AlNap showed any cytotoxicity toward normal human dermal broblast cells or mouse cortical neurons, respectively. PMID- 30518208 TI - Highly Efficient Abiotic Assay Formats for Methyl Parathion - MINA as Alternative to ELISA. AB - Enzyme-linked immunosorbent assay (ELISA) is a widely used standard method for sensitive detection of analytes of environmental, clinical or biotechnological interest. However, ELISA has clear drawbacks related to the use of relatively unstable antibodies and enzyme conjugates, and need in several steps such as washing of non-bound conjugates and add-ing dye reagents. Herein we introduce a new completely abiotic assay where antibodies and enzymes are replaced with fluorescent molecularly imprinted polymer nanoparticles (nanoMIPs) and target conjugated magnetic nanoparticles, which acted as both reporter probes and binding agents. The components of the molecularly imprinted polymer nanoparticles assay (MINA) are assembled in microtiter plates fitted with magnetic inserts. We have compared the performance of the new magnetic assay with MIP-based ELISA for the detection of methyl parathion (MP). Both assays have shown high sensitivity toward allowing detection of MP at picomolar concentrations without any cross reactivity against chlorpyriphos and fenthion. The fully abiotic assays were also proven to detect analyte in real samples such as tap water and milk. Unlike ELISA based systems the novel assay required no washing steps or addition of enzyme substrates, making it more user-friendly and suitable for high throughput screening. PMID- 30518209 TI - Background-free fluorescence decay time sensing and imaging of pH with highly photostable diazaoxotriangulenium dyes. AB - Novel fluorescent diazaoxatriangulenium (DAOTA) pH indicators for lifetime-based self-referenced pH sensing are reported. The DAOTA dyes were decorated with phenolic receptor groups inducing fluorescence quenching via photoinduced electron transfer mechanism. Electron-withdrawing chlorine substituents ensure response in the most relevant pH range (apparent pK'a values ~5 and 7.5 for the p,p-dichlorophenol- and the p-chlorophenol-substituted dyes, respectively). The dyes feature long fluorescence lifetime (17-20 ns), high quantum yield (~60%) and high photostability. Planar optodes are prepared upon immobilization of the dyes into polyurethane hydrogel D4. Apart from the response in the fluorescence intensity, the optodes show pH-dependent lifetime behaviour which makes them suitable for studying 2D pH distribution with help of fluorescence lifetime imaging technique. The lifetime response is particularly pronounced for the sensors with high dye concentration (0.5-1% wt. in respect to the polymer) and is attributed to efficient homo-FRET mechanism. PMID- 30518210 TI - A Chemoproteomic Strategy for Direct and Proteome-wide Covalent Inhibitor Target site Identification. AB - Despite recent clinical successes for irreversible drugs, potential toxicities mediated by unpredictable modification of off-target cysteines represents a major hurdle for expansion of covalent drug programs. Understanding the proteome-wide binding profile of covalent inhibitors can significantly accelerate their development; however, current mass spectrometry strategies typically do not provide a direct, amino acid level readout of covalent activity for complex, selective inhibitors. Here we report the development of CITe-Id, a novel chemoproteomic approach that employs covalent pharmacologic inhibitors as enrichment reagents in combination with an optimized proteomic platform to directly quantify dose-dependent binding at cysteine-thiols across the proteome. CITe-Id analysis of our irreversible CDK inhibitor THZ1 identified dose-dependent covalent modification of several unexpected kinases, including a previously unannotated cysteine (C840) on the understudied kinase PKN3. These data streamlined our development of JZ128 as a new selective covalent inhibitor of PKN3. Using JZ128 as a probe compound, we identified novel potential PKN3 substrates, thus offering an initial molecular view of PKN3 cellular activity. CITe-Id provides a powerful complement to current chemoproteomic platforms to characterize the selectivity of covalent inhibitors, identify new, pharmacologically-addressable cysteine-thiols, and inform structure-based drug design programs. PMID- 30518211 TI - Cu-substituted NiF2 as Cathode Material for Li-ion Batteries. AB - Metal fluorides have usually a large electronegativity and are promising electrode materials for high power lithium-ion batteries. However, like other conversion reaction based materials, large volumetric expansions and large capacity losses in cycling are major issues for metal fluorides. Here, we explore substitution of Ni with Cu for binary NiF2 and its effects to the electrochemical properties. By in-situ transmission electron microscopy (TEM), the structural evolutions of the several ternary metal fluorides with different Cu/Ni ratios are observed and correlated to their electrochemical properties. With increased Cu substitution from zero to 25 wt%, the areal expansion in the first lithiation reduced. Meanwhile, the fluorine loss (due to reaction irreversibility) in delithiation cycle is also reduced. This provides an explanation on the benefit of Cu substitution on the improved cycling stability and capacity. We believe our observations provide insight in the development of better ternary metal fluorides as cathodes for high power density lithium-ion batteries. PMID- 30518212 TI - Tissue-specific Accumulation and Body Burden of Parabens and Their Metabolites in Small Cetaceans. AB - Parabens have been of global concern due to their endocrine disrupting properties. However, few studies have reported tissue-specific distribution of parabens in wildlife. In this study, we measured parabens and their metabolites in organs and tissues (blubber, muscle, melon, stomach, kidney, liver, gonad, brain, uterus, and umbilical cord, total n=94) of common dolphins (Delphinus capensis) and finless porpoises (Neophocaena asiaeorientalis), to investigate tissue-specific accumulation and body burden. Among the target compounds, methyl paraben (MeP) and para-hydroxybenzoic acid (4-HB) were detected in all organs. Compared to common dolphins, finless porpoises had significantly higher concentrations of MeP and 4-HB due to their near-shore habitat. Higher concentrations of MeP and 4-HB were found in the kidney, liver, and stomach than in other organs, indicating selective accumulation of parabens in certain organs. Significant correlations between MeP and 4-HB in liver/kidney suggested metabolic transformation of the former to the latter. Detection of parabens in brains, umbilical cord, and uterus suggests that these chemicals cross biological barriers such as the blood-brain and placental barriers. The body burdens of total parabens were in the ranges of 13000-90600 MUg and 19800-81500 MUg for common dolphins and finless porpoises, respectively. PMID- 30518213 TI - Visible-light-Driven External-Reductant-Free Cross-Electrophile Couplings of Tetraalkyl Ammonium Salts. AB - Cross-electrophile couplings between two electrophiles are powerful and economic methods to generate C?C bonds in the presence of stoichiometric external reductants. Herein, we report a novel strategy to realize the first external reductant-free cross-electrophile coupling via visible-light photoredox catalysis. A variety of tetraalkyl ammonium salts, bearing primary, secondary, and tertiary C?N bonds, undergo selective couplings with aldehydes/ketone and CO2. Notably, the in situ generated byproduct, trimethylamine, is efficiently utilized as the electron donor. Moreover, this protocol exhibits mild reaction conditions, low catalyst loading, broad substrate scope, good functional group tolerance, and facile scalability. Mechanistic studies indicate that benzyl radicals and anions might be generated as the key intermediates via photocatalysis, providing a new direction for cross-electrophile couplings. PMID- 30518214 TI - Temperature-Dependent Transport in Ultrathin Black Phosphorus Field-Effect Transistors. AB - This paper studies the temperature-dependent transport properties of ultrathin black phosphorus (BP). We present measurements of BP Schottky-barrier (SB) metal oxide-semiconductor field-effect-transistors (MOSFETs) with various channel lengths, constructed from a single BP sample with nanoscale uniformity in thickness and width. The electrical characterization reveals a reversal in the temperature dependence of drain current as a function of gate voltage. This reversal indicates a transition in the charge conduction limiting mechanisms as the device is swept from the off-state into the on-state. In the off-state, charge transport is limited by thermionic emission over the energy barriers at the source/drain SB contacts, and drain current increases with temperature. In the on-state, carriers can easily tunnel across the SB at the contacts, and charge transport is limited by scattering in the channel. As a result, drain current decreases with temperature in the on-state, as scattering increases with temperature. Using Landauer transport theory we derive a closed-form expression for thermionic emission current in SB-MOSFETs with 2-D channels. We use this expression to extract the SB height at metal contact interface with BP, and demonstrate the impact of scattering on the extraction. We then use a comprehensive BP SB-MOSFET model to analyze on-state current as a function of temperature, and demonstrate the effects of charged impurity and phonon scattering on the transport properties of BP through extractions of mobility at fixed carrier density. KEYWORDS: black phosphorus, MOSFET, transistor, transport, two-dimensional, 2D materials. PMID- 30518215 TI - Probing the interface structure of adhering cells by contrast variation neutron reflectometry. AB - Cellular adhesion is a central element in tissue mechanics, biological cell-cell signaling, and cell motility. In this context, the cell-substrate distance has been investigated in the past by studying natural cells and biomimetic cell models adhering on solid substrates. The amount of water in the membrane substrate gap, however, is difficult to determine. Here, we present a neutron reflectivity (NR) structural study of confluent epithelial cell monolayers on silicon substrates. In order to assure valid in-vitro conditions, we developed a cell culture sample chamber allowing to grow and cultivate cells under proper cell culture conditions while performing in-vitro neutron reflectivity measurements. The cell chamber also enabled perfusion with cell medium and hence allowed for contrast variation in-situ by sterile exchange of buffer with different H2O-to-D2O ratio. Contrast variation reduces the ambiguity of data modelling for determining the thickness and degree of hydration of the interfacial cleft between the adherent cells and the substrate. Our data suggest a three-layer interfacial organization. The first layer bound to the silicon surface interface is in agreement with a very dense protein film with a thickness of 9+/-2 nm, followed by a highly hydrated 24+/-4 nm thick layer, and a several ten nm thick layer attributed to the composite membrane. Hence, the results provide clear evidence of a highly hydrated intermediate region between the composite cell membrane and the substrate, reminiscent of the basal lamina. PMID- 30518216 TI - A Tale of Two Stabilities: How One Boron Atom Affects a Switch in Bonding Motifs in CeO2Bx- (x = 2, 3) Complexes. AB - Boronyl (B=O) ligands have garnered much attention as isoelectronic and isolobal analogues of CO and CN-, yet successful efforts in synthesizing metal boronyl complexes remain scarce. Anion photoelectron (PE) spectroscopy and DFT calculations were employed to investigate two small CeO2Bx- (x = 2, 3) complexes generated from laser ablation of a mixed Ce/B pressed powder target. The spectra reveal markedly different bonding upon incorporation of an additional B atom. Most interestingly, CeO2B2- was found to have a Ce(I) center coordinated to two monoanionic boronyl ligands in a bent geometry. This result was unexpected as previous studies suggest electron-rich metals are most suitable for stabilizing such ligands; furthermore, it is one of the first examples of an experimental metal-polyboronyl complex. Introducing another boron atom, however, favors a much different geometry in which Ce(II) coordinates an O2B33- unit through both the O and B atoms, which was evident in the markedly different PE spectra. PMID- 30518217 TI - Multitechnique investigation into the aqueous behavior of plasma polymers. AB - Plasma polymers are often used in applications requiring aqueous immersion; therefore, it is important to understand how this exposure affects the physical and chemical properties of the films. Three different plasma polymer films were deposited at different distances from the electrode, and the film properties were characterized using contact angle, ellipsometry, and x-ray photoelectron spectroscopy. The film behaviors in aqueous solutions were studied via quartz crystal microbalance with dissipation (QCM-D). Exposure to buffer solutions produced significant swelling of the plasma polymerized acrylic acid films, with swelling increasing with distance from the powered electrode, results that could be correlated with changes in film chemistry. Plasma polymerized octadiene and allylamine exhibited little swelling. These films exhibited changes in thickness and contact angle with respect to distance from the electrode, but this had little influence on their behavior in aqueous solution. By combining QCM-D with the more traditional surface chemical analysis techniques, the authors have been able to explore both swelling behavior and the effect that sample position and thus deposition parameters have on film properties and aqueous behavior. This approach gives the authors the basis to define deposition parameters to assist the engineering of thin films for applications such as biosensing and tissue engineering applications where specific chemistries and film behaviors are desired. PMID- 30518218 TI - Probable Roles of Coagulation Cascade and Fibrinolysis System in the Development of Allergic Rhinitis. AB - BACKGROUND: Dysregulation of the coagulation cascade and fibrinolysis system may play an etiologic role in many diseases. Allergic diseases such as bronchial asthma, atopic dermatitis, and conjunctivitis are also associated with fibrin accumulation caused by a change in hemostasis. However, only a few studies have dealt with the relationship between allergic rhinitis (AR) and the coagulation system. OBJECTIVE: We investigated the difference of coagulation and fibrinolysis cascade components between an AR mouse model and a control mice. METHODS: BALB/c mice were sensitized and challenged with ovalbumin. Multiple parameters of coagulation cascade and fibrinolysis system such as factors II, V, VII, X, and XIII; tissue-type plasminogen activator; urokinase-type plasminogen activator (u PA); plasminogen activator inhibitor-1 (PAI-1); and fibrin were compared between the AR model group and the control group. RESULTS: The symptom scores and eosinophil counts were higher in the AR group than in the control group ( P < .01). The mRNA expression level of u-PA ( P = .040) was significantly lower, and the expression levels of factor II ( P = .038) and factor X ( P = .036) were significantly higher, in the AR group. Immunohistochemical staining revealed that most of the fibrinolysis system and coagulation cascade components were localized to the epithelium, endothelium, and submucosal glands of the nasal mucosa. u-PA was downregulated in the AR group, whereas fibrin deposition was more prominent in the AR group than in the control group. CONCLUSION: In AR, particular components of the coagulation cascade were increased and fibrinolysis system was decreased compared to normal control. This difference may be associated with the fibrin deposition in the mucosa of AR mouse model. PMID- 30518219 TI - Predictors of Mortality After Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction. PMID- 30518220 TI - The need for smarter tools to guide suicide prevention. PMID- 30518221 TI - Relationships Between Cognitive Dysfunction and Health-Related Quality of Life Among Older Persons in Taiwan: A Nationwide Population-Based Survey. AB - BACKGROUND:: To examine the relationships between cognitive dysfunction status and quality of life. METHODS:: Secondary analysis of a nationwide population based survey (>=65 years) in Taiwan. The 5-dimension EuroQoL questionnaire (EQ 5D) was completed by 10 013 participants. RESULTS:: Participants with mild cognitive impairment (MCI; odds ratio = 4.88), very mild dementia (VMD; 7.96), or dementia (32.85) were more likely than those with normal cognition to report self care problems. Participants with MCI (3.86), VMD (9.26), or dementia (31.61) were more likely to have usual-activity problems, and those with MCI (3.04), VMD (3.82), or dementia (9.23) were more likely to have mobility problems. Participants with MCI (2.10 and 2.14), VMD (2.77 and 2.18), or dementia (3.04 and 3.02) were more likely to report pain/discomfort and anxiety/depression. CONCLUSION:: Dementia was negatively associated with EQ-5D, especially self-care, usual activities, and mobility. Mild cognitive impairment or VMD was also negatively associated, with VMD more negatively associated. Developing interventions for patients with specific cognitive dysfunctions is critical. PMID- 30518222 TI - Neurofibromatosis and psychosis: coincidence or co-occurrence? PMID- 30518223 TI - Challenges in identifying behavioural markers of bipolar disorder through objective smartphone data. PMID- 30518224 TI - Will the RANZCP clinical practice guidelines for the treatment of anxiety disorders assist in making adequate treatment decisions for panic disorder? PMID- 30518225 TI - Competence and Compassion: Key Elements of Professional Care at the End of Life From Caregiver's Perspective. AB - In the act of caring for and helping people in the end-of-life process, the professional who provides care and assistance must know how to maintain a relationship of closeness, empathy, and compassion for the pain and suffering of the person who is going to die. The objective was to understand, elaborate on, and characterize the key elements of end-of-life care of patients from a caregiver's perspective through a qualitative phenomenological multicenter study. Participants were caregivers who had lost a family member at least 2 months but less than 2 years in the past. The techniques used were 5 discussion groups and 41 in-depth interviews, which included a total of 81 participants. To analyze the information, a protocol developed by Giorgi was followed. Two dimensions or units of meaning, with subdimensions, emerged: (1) Technical competence, with the subdimensions "Control of symptoms" and "Continuity of care," and (2) Compassion, with the subdimensions "Effective/affective communication," "Attitudes of kindness and closeness toward the patient and the family," and "Generosity and personalized flexibility of care." Assistance at the end of life requires the proper preparation of professionals who care for these patients, in addition to a compassionate attitude on the part of professionals and the people accompanying the dying person, that fosters a more humanized and dignified treatment in the dying process. PMID- 30518226 TI - Endogenous cannabinoids and suicide. PMID- 30518227 TI - Is the reported increase in young female hospital-treated intentional self-harm real or artefactual? AB - BACKGROUND:: The Australian Institute of Health and Welfare has reported an increased rate of hospital-treated intentional self-harm in young females (2000 2012) in Australia. These reported increases arise from institutional data that are acknowledged to underestimate the true rate, although the degree of underestimation is not known. OBJECTIVE:: To consider whether the reported increase in young females' hospital-treated intentional self-harm is real or artefactual and specify the degree of institutional underestimation. METHODS:: Averages for age- and gender-standardised event rates for hospital-treated intentional self-harm (national: Australian Institute of Health and Welfare; state: New South Wales Ministry of Health) were compared with sentinel hospital event rates for intentional self-poisoning (Hunter Area Toxicology Service, Calvary Mater Newcastle) in young people (15-24 years) for the period 2000-2012. A time series analysis of the event rates for the sentinel hospital was conducted. RESULTS:: The sentinel hospital event rates for young females of 444 per 100,000 were higher than the state (378 per 100,000) and national (331 per 100,000) rates. There was little difference in young male event rates - sentinel unit: 166; state: 166 and national: 153 per 100,000. The sentinel hospital rates showed no change over time for either gender. CONCLUSION:: There was no indication from the sentinel unit data of any increase in rates of intentional self-poisoning for young females. The sentinel and state rates were higher than the national rates, demonstrating the possible magnitude of underestimation of the national data. The reported increases in national rates of hospital-treated self-harm among young females might be due to artefactual factors, such as changes in clinical practice (greater proportion admitted), improved administrative coding of suicidal behaviours or possibly increased hospital presentations of community self-injury cases, but not intentional self-poisoning. A national system of sentinel units is needed for the accurate and timely monitoring of all hospital-treated self-harm. PMID- 30518228 TI - What Does Death Preparedness Mean for Family Caregivers of Persons With Dementia? AB - PURPOSE:: The purpose of this study was to clarify the concept of death preparedness for family caregivers in dementia. Conceptualization was required to support the assessment, promotion, and operationalization (ie, measurement) of death preparedness through palliative care interventions such as advance care planning. METHODS:: Rodgers evolutionary method of concept analysis was selected to guide this study because of the dynamic nature of death preparedness influenced by context, setting, and time. A comprehensive literature search was conducted. Authors performed constant comparative analysis to identify and interpret surrogate/related concepts, attributes, antecedents, and consequences of death preparedness. RESULTS:: Most importantly attributes included (1) knowing and recognizing the symptoms of decline in dementia and what dying looks like; (2) understanding emotions and grief responses; (3) accessing and appraising supports needed to manage and care for dying; (4) organizing affairs and completing tasks in advance; (5) accepting that losses are inevitable and imminent; (6) reflecting on caregiving and finding meaning, "a silver-lining"; and (7) closing, reconciling, and renewing relationship bonds and completing the family member's life. DISCUSSION:: This study contributed a full definition of death preparedness in dementia. Findings aligned with/expanded upon Hebert et al Theoretical Framework of Preparedness for End-of-Life. The use of problem- and emotion-based coping strategies by caregivers with support from health-care providers to promote feelings of death preparedness (including self-efficacy and control) and minimize uncertainty was the implication of this study. Development of a holistic preparedness instrument is underway. PMID- 30518229 TI - Thirty-year cardiovascular risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives. AB - OBJECTIVES:: Bipolar disorder is associated with a decreased life expectancy of 8 12 years. Cardiovascular disease is the leading cause of excess mortality. For the first time, we investigated the Framingham 30-year risk score of cardiovascular disease in patients with newly diagnosed/first-episode bipolar disorder, their unaffected first-degree relatives and healthy individuals. METHODS:: In a cross-sectional study, we compared the Framingham 30-year risk score of cardiovascular disease in 221 patients with newly diagnosed/first episode bipolar disorder, 50 of their unaffected first-degree relatives and 119 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. Among patients with bipolar disorder, we further investigated medication- and illness-related variables associated with cardiovascular risk. RESULTS:: The 30-year risk of cardiovascular disease was 98.5% higher in patients with bipolar disorder ( p = 0.017) and 85.4% higher in unaffected first-degree relatives ( p = 0.042) compared with healthy individuals in models adjusted for age and sex. When categorizing participants in low cardiovascular risk without considering age and sex distribution among participants, 81% of patients were at low risk, versus 92% of unaffected relatives and 89% of healthy individuals. Of the patients 209 (94.6%) were diagnosed within the preceding 2 years. Smoking was more prevalent among patients with bipolar disorder (45.2%) and their unaffected first-degree relatives (20.4%) compared with healthy individuals (12.8%). Similarly, dyslipidemia was more common among patients with bipolar disorder compared with healthy individuals. Treatment with psychotropic medication with metabolic adverse effects was associated with higher 30-year cardiovascular disease risk score, whereas we did not find illness-related variables associated with cardiovascular risk among patients with bipolar disorder. CONCLUSION:: We found an enhanced cardiovascular disease risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives, which points to a need for specific primary preventive interventions against smoking and dyslipidemia in these populations. PMID- 30518230 TI - Trends of Cardiovascular Risk Factors in Patients With Acute Myocardial Infarction: Soroka Acute Myocardial Infarction II (SAMI II) Project. AB - CONCLUSIONS:: The last decade, patients with AMI became older with increased burden of CVRFs. Framingham risk score increased among patients with NSTEMI and decreased in patients with STEMI. These trends impact on risk stratification and secondary prevention programs. PMID- 30518231 TI - The lipid peroxidation in patients with nephrolithiasis before and after extracorporeal shock wave lithotripsy. AB - AIM: To evaluate the level of lipid peroxidation in patients with nephrolithiasis before and after extracorporeal shock wave lithotripsy (ESWL). MATERIALS & METHODS: Isoprostane concentration (8-isoPGF2alpha) was measured in urine, and thiobarbituric acid reactive substance production in serum and erythrocytes. In addition, the concentrations of selected compounds (uric acid, glucose and creatinine) were measured in serum. RESULTS: The patients (before and after ESWL) demonstrated significantly higher levels of two different biomarkers of lipid peroxidation compared with the control group. A correlation was identified between increased amounts of uric acid and biomarkers of lipid peroxidation in patients with nephrolithiasis, both before and after ESWL. CONCLUSION: Uric acid may be associated with lipid peroxidation in patients with nephrolithiasis. PMID- 30518232 TI - M2C Polarization by Baicalin Enhances Efferocytosis via Upregulation of MERTK Receptor. AB - Baicalin is the main active ingredient primary isolated from the Chinese herb, Scutellaria baicalensis Georgi. Although baicalin can induce M2 macrophage polarization, we still do not know the subtype of macrophages polarized by baicalin. In this study, we characterized that murine bone marrow derived macrophages induced by M-CSF can be further polarized into M2C phenotype by baicalin. The signatures of M2C macrophages for mRNA expression like interferon regulatory factor 4 (IRF4), interleukin-10 (IL-10), MERTK and PTX3 were up regulated. Moreover, we observed the concomitantly decreasing of tumor necrosis factor alpha (TNF- alpha ), interferon regulatory factor 5 (IRF5), IL-6. In contrast, M2 macrophages polarized by IL-4 increased gene transcript of arginase 1 (Arg-1) and surface marker of CD206 indicates that their identity as M2A rather than M2C subtypes. Interestingly, the phagocytosis as well as efferocytosis activity were significantly enhanced in M2C macrophage polarized by baicalin and these capacities were associated with the expression of MERTK receptor. Finally, we conclude that baicalin induced M2C macrophages polarization with both elevations of efferocytosis and anti-inflammatory activity. PMID- 30518233 TI - Fermented Red Ginseng Alleviates Cyclophosphamide-Induced Immunosuppression and 2,4,6-Trinitrobenzenesulfonic Acid-Induced Colitis in Mice by Regulating Macrophage Activation and T Cell Differentiation. AB - A variety of products have been developed with red ginseng (RG, the steamed roots of Panax ginseng Meyer). To clarify the immunomodulating effects of water extracted RG (wRG), 50% ethanol-extracted RG (eRG), enzyme-treated eRG (ERG) and probiotic-fermented eRG (FRG), we examined their immunopotentiating and immunosuppressive effects in mice with cyclophosphamide (CP)-induced immunosuppression (CI) or 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis (TC). Oral administration of RG in CI mice significantly increased blood IFN- gamma levels. Treatment with RG also increased the tumoricidal effects of CI mouse splenic cytotoxic T (Tc) and NK cells against YAC-1 cells. Treatment with RGs, in particular FRG and wRG, significantly increased Th1 cell differentiation. Treatment with RG except wRG increased Treg cell differentiation. However, wRG alone increased IL-6 and IL-17 expression in the colon of CI mice. Furthermore, RG alleviated colitis in TC mice. FRG most potently suppressed TNBS-induced colon shortening, NF- kappa B activation and TNF- alpha and IL-17 expression and increased IL-10 expression. RGs inhibited TNF- alpha expression and increased IL 10 expression in lipopolysaccharide-stimulated primary macrophages in vitro while the differentiation of splenic T cells into type 1 T (Th1) and regulatory T (Treg) cells was increased by FRG in vitro. In conclusion, FRG can alleviate immunosuppression and inflammation by inhibiting macrophage activation and regulating Th1 and Treg cell differentiation. PMID- 30518234 TI - Calotropis gigantea Promotes Neuritogenesis and Synaptogenesis through Activation of NGF-TrkA-Erk1/2 Signaling in Rat Hippocampal Neurons. AB - Calotropis gigantea (L.) R. Br (Apocynaceae) (commonly known as milkweed or crown flower) is a large shrub native to temperate regions of Asia, including China, Bangladesh and India and has a long history of use in traditional medicines. In this study, we investigated the neuromodulatory effects of the ethanol extracts of C. gigantea leaves (CGE) during synaptogenesis in the late stage of neuronal development and during early stage neuritogenesis in cultured rat hippocampal neurons. Maximum neuritogenic activity was achieved at a CGE concentration of 7.5 MU g/ml. At this concentration, CGE facilitated the early development of cytoarchitecture, as evidenced by increases in morphometric parameters, such as, the numbers, lengths, and number of branches of initial neurites, axon and dendrites. During the synaptogenic stage (DIV 14), immunocytochemistry (ICC) showed that CGE upregulated synaptic vesicle 2 (SV2, a marker of axon terminals) and postsynaptic density-95 (PSD-95, a postsynaptic marker) and their colocalization. CGE upregulated nerve growth factor (NGF) and activated extracellular signal-regulated kinase 1/2 (Erk1/2), which is blocked by a TrkA specific inhibitor suggesting the neuritogenic and synaptogenic potential of CGE was due to the activation of NGF-TrkA-Erk1/2 signaling. Moreover, UPLC of CGE did not detect stigmasterol, an active component of C. gigantea. However, the chloroform-methanol and ethyl acetate subfractions of CGE exhibited initial neuritogenic activity, suggesting that multiple active components were responsible for the neurotrophic-mimetic properties of CGE. Our data prove the neuromodulatory ability of CGE and provide a means of identifying new active phytochemicals with potential nootropic, preventative or therapeutic effects on the human brain. PMID- 30518235 TI - A Systematic Review of the Medicinal Potential of Mulberry in Treating Diabetes Mellitus. AB - Diabetes mellitus (DM) is a serious metabolic disorder which has reached epidemic proportions all over the world. Despite tremendous developments in medicinal chemistry, traditional medicine is still commonly used for the prevention and treatment of DM. Traditional herbal medicines have played a major role in the management of DM in Asian countries. In particular, mulberry has commonly been utilized in China for the treatment of DM for thousands of years. In the last decade, numerous preclinical findings have suggested that mulberry is a promising therapeutic agent for the treatment of DM, and the polyhydroxylated alkaloids, flavonoids and polysaccharides from mulberry may be the potential active components. The present review systematically summarizes the chemical composition of mulberry and the pharmacological effects of different medicinal parts on DM; these effects include influences on glucose absorption, insulin (INS) production/secretion, anti-oxidation and anti-inflammation processes. After summarizing our research findings, we will discuss the challenges and opportunities and explore the direction of future research and the potential for developing mulberry into pharmaceuticals for the widespread treatment of DM. PMID- 30518236 TI - Oriental Herbal Medicine for Neurological Disorders in Children: An Overview of Systematic Reviews. AB - Oriental herbal medicine (OHM) has been widely used in pediatric neurological disorders and has attracted attention as a safe and effective treatment. We aim to summarize and evaluate the evidence for OHM in pediatric neurological disorders for evidence-based decision-making. Without language restrictions, up to-date research data were obtained from nine electronic databases. Systematic reviews (SRs) assessing the efficacy of OHM for pediatric neurological disorders were included. The methodological quality of each review was assessed using the AMSTAR instrument. The quality of evidence for the main findings was evaluated using the GRADE approach. Sixteen SRs comprising 169 randomized controlled trials with 19,542 participants were included. In epilepsy (six SRs, n=5,341 ), OHM as an adjunctive or alternative therapy to antiepileptic drugs showed higher clinical symptom improvements than did antiepileptic drugs alone. The Activities of Daily Living scale score was significantly higher in children with cerebral palsy (one SR, n=508 ) when OHM was added to rehabilitation. There were inconsistent results for tic disorder (four SRs, n=9,870 ) and enuresis (two SRs, n=1,995 ) and unclear results for attention deficit hyperactivity disorder (two SRs, n=1,261 ) and autism spectrum disorder (one SR, n=567 ). Eleven SRs reported adverse events, but no fatal adverse reaction was reported. The methodological quality of the included reviews was medium-to-high. The overall quality of evidence ranged from "very low" to "moderate." In conclusion, the efficacy of OHM is promising for some pediatric neurological disorders such as epilepsy and cerebral palsy. However, more high-quality evidence is needed to make clinical recommendations on OHM use. PMID- 30518237 TI - A Comparative Single-Blind Randomized Controlled Trial With Language Training in People With Mild Cognitive Impairment. AB - BACKGROUND:: Although cognitive training is effective for people with mild cognitive impairment (MCI), it is not clear which format is more effective. OBJECTIVE:: To compare the effectiveness of the same language programs when carried out via computer, paper/pencil and orally in people with MCI. METHODS:: Seventy-one participants with MCI were randomly classified in 3 experimental and 2 control groups. The experimental groups attended 48 sessions of language training for 6 months. The control groups attended either unstructured sessions or they were on waiting list. RESULTS:: Mixed measures analysis of variance, at the follow-up, showed a significant cognitive abilities improvement among the experimental versus control groups. At the end of the language training, the 3 groups presented improvement in cognitive abilities and daily function, while the control groups remained at the same performance level. CONCLUSION:: All 3 cognitive language training methods were equally significantly effective. PMID- 30518238 TI - Correlation Between ROTEM FIBTEM Maximum Clot Firmness and Fibrinogen Levels in Pediatric Cardiac Surgery Patients. AB - This study evaluated whether rotational thromboelastometry (ROTEM; Tem International GmbH, Munich, Germany) FIBTEM maximum clot firmness (MCF) can be used to predict plasma fibrinogen level in pediatric patients undergoing cardiac surgery. Linear regression was conducted to predict plasma fibrinogen level using FIBTEM MCF (0.05 level of significance). Scatter plot with the regression line for the model fit was created. Fifty charts were retrospectively reviewed, and 87 independent measurements of FIBTEM MCF paired with plasma fibrinogen levels were identified for analysis. Linear regression analysis suggested a significant positive linear relationship ( P < .0001) between plasma fibrinogen levels and MCF. Both MCF intercept and slope were significantly correlated with fibrinogen level ( P < .0001). The estimated regression equation (predicted fibrinogen = 78.6 + 12.4 * MCF) indicates that a 1-mm increase in MCF raises plasma fibrinogen level by an average of 12.4 mg/dL. The statistically significant positive linear relationship observed between MCF and fibrinogen levels ( P < .001) suggests that MCF can be used as a surrogate for fibrinogen level. This relationship is of clinical relevance in the calculation of patient-specific dosing of fibrinogen supplementation in this setting. PMID- 30518239 TI - Suspension culture of Marek's disease virus and evaluation of its immunological effects. AB - Marek's disease virus (MDV) is a cell-associated alpha-herpesvirus of chickens. It is difficult to perform its complete suspension culture. Therefore, MDV vaccines are currently produced using adherent primary chicken embryo fibroblasts and on a large scale is labor intensive and costly. In this study, the CVI988 strain of MDV was inoculated into chicken fibroblast cell line UMNSAH/DF-1 (DF-1) cultured by microcarrier suspension for proliferation experiment. Moreover, the effects of culture conditions, such as inoculation method, MOI, microcarrier concentration, and pH value, on the proliferation of MDV were investigated. The results demonstrated that the maximum viral load 64.76 +/- 2.64 * 106 PFU/flask in a working volume of 100 mL could be obtained using synchronous cell seeding and inoculation method at an MOI of 0.02 and a microcarrier concentration of 5 g/L at pH 7.2. At the same time, the CVI988/DF-1 vaccines prepared by the microcarrier culture process and the traditional adherent cell culture process (CVI988/Rispense) were compared through animal experiments. We found a protective rate of 94.4% using the CVI988/DF-1 vaccine with specific pathogen free chickens that was equivalent to that of the commercial vaccine CVI988/Rispens (protection rate of 94.1%). In this study, the MDV CVI988/DF-1 vaccine prepared by the microcarrier suspension culture of DF-1 cells could provide effective immune protection for SPF chickens, providing a reference for the prevention and control of MD and further development of a large-scale bioreactor for producing the MD vaccine. PMID- 30518240 TI - Review for Analytical Methods for the Determination of Sodium Cephalothin. AB - Infections are the second leading cause of global morbidity and mortality, therefore it is highly important to study the antimicrobial agents such as cephalosporins. Cephalothin, an antimicrobial agent that belongs to the class of cephalosporins, has bactericidal activity and it is widely used in the Brazilian health system. In literature, some analytical methods are found for the identification and quantification of this drug, which are essential for its quality control, which ensures maintaining the product characteristics, therapeutic efficacy and patient's safety. The aim of this article is to review the available information on analytical methods for cephalothin. Thus, this study presents a literature review on cephalothin and the analytical methods developed for the analysis of this drug in official and scientific papers. It is essential to note that most of the developed methods used toxic and hazardous solvents, which makes necessary industries and researchers choose to develop environmental friendly techniques, which will contribute to the harmonization of science, human, and environmental health. PMID- 30518241 TI - Neighborhood social cohesion and cognitive function in U.S. Chinese older adults findings from the PINE study. AB - OBJECTIVES: The projected increase in the population of older adults in the United States entails a pressing need to examine risk and protective factors associated with cognitive function. This study aims to examine the association between neighborhood social cohesion and cognitive function among older Chinese adults in the United States. METHOD: Using the first epidemiological survey of older Chinese Americans and applying ordinary least squares and quantile regressions, this study examines the association between neighborhood social cohesion and various domains of cognitive function. RESULTS: Results show that neighborhood social cohesion is independently associated with most domains of cognitive function (i.e. global cognition score, and its components such as the Chinese Mini-Mental State Examination and executive function and episodic memory measures). CONCLUSION: This study represents one of a few initial efforts that examined the association between neighborhood social cohesion and cognitive function for Chinese older adults in the United States. Our findings suggest that socially cohesive neighborhoods can provide enriched environments where active lifestyles can be encouraged, and cognitive skills and abilities can be stimulated, practiced, and preserved for older adults. PMID- 30518242 TI - Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 inhibitors: Do we have a vanquishing new strategy? PMID- 30518243 TI - Impact of Interplaying and Compounding Factors in the Novice Nurse Journey: A Basic Qualitative Research Study. AB - PURPOSE: This study explores the impact of interplaying and often compounding factors and the resulting ability to thrive as a novice nurse. Novice nurse attrition rates continue to be high, compounding concerns of an impending nursing shortage. There is currently a lack of research that seeks to understand how the interplay of contextual factors impacts novice nurses' ability to manage the stressors endemic in the field. DESIGN: The study was performed using a Basic Qualitative Research approach. Eight western Canadian novice nurses underwent multiple iterative interviews to explore the impact of interplaying contextual factors. Findings: While participant experiences and contexts vary, common patterns of interplay among factors were clear. The interplay between previous life experience factors and the workplace context has a significant impact on the perception and management of workplace stimuli. Those with more developmental assets, garnered through life experience, are less likely to experience workplace stimuli as stressful, reducing their risk of emotional exhaustion and improving their ability to thrive. Implications for nursing: Understanding how interplay impacts the ability to thrive versus survive informs new graduate transition support efforts and enables an ability to articulate the compounding nature of common novice nurse stressors. PMID- 30518245 TI - Dopamine receptor heteromers: biasing antipsychotics. PMID- 30518244 TI - Do caregiver profiles predict the use of dementia care services? Findings from the Actifcare study. AB - OBJECTIVES: Previously developed dementia caregiver profiles defined by caregiver age and burden, have been associated with caregiver quality of life, depression and perseverance time. The current aim was to investigate whether these caregiver profiles could predict subsequent service use. In addition, non-personal (e.g. meals on wheels) and supportive services (e.g. Alzheimer cafe) in early dementia were investigated as predictors. METHODS: A total of 451 dyads of people with dementia and their informal caregivers from eight European countries were followed for one year. People were included if they did not use formal (personal) care but were expected to do so within 1 year. Logistic regression analyses were used with four clusters of service use as dependent variables (home social care, home personal care, day care and admission). The independent variables were caregiver profiles, and non-personal and supportive services at baseline. RESULTS: Caregiver profiles were significant predictors of service use; those experiencing high strain were more likely to use formal care. The use of low intensity, less intrusive services at baseline significantly predicted the use of home personal care and admission at follow-up. The use of day care at follow-up was predicted by the baseline use of supportive services. CONCLUSION: Caregiver profiles are valuable predictors for service use: this knowledge can aid professionals in ensuring optimal access to services, which is important for maintaining independence at home. In addition, the use of supportive and less intrusive, non-personal services in the early stages of dementia is to be advised. PMID- 30518246 TI - Treatment fidelity evidence for BE-ACTIV - a behavioral intervention for depression in nursing homes. AB - OBJECTIVES: Evidence-based depression therapies are difficult to implement in nursing homes. We present data for BE-ACTIV, a 10-week depression treatment designed for implementation in nursing homes, to address questions of treatment fidelity (delivery, receipt, and enactment) in that context. METHOD: Participants were 41 patients from 13 nursing homes in the treatment arm of a clinical trial, treated by graduate student therapists. Therapists and their supervisor rated their audio-recorded sessions for adherence to treatment protocol and session quality. RESULTS: Delivery of core program elements averaged from 80-94% across all sessions; mean quality was 5.6 (SD 0.61) out of 6 points. Delivery of core components to nursing home activities staff who collaborated in the treatment was similarly high. Patients received an average of 7.32 sessions (SD 3.39); 17 completed 10 sessions. The theoretical basis of BE-ACTIV is behavioral activation; therapist-client dyads planned new pleasant events weekly, from a mean of 3.66 (SD 1.35) after the first session to a mean of between 5 and 6 activities a week across sessions 6-9, with a similar progression in percent activities completed. Activities enactment was significantly related to the likelihood of remission at post-treatment, and of maintaining improvement at 3 month follow-up. Treatment receipt and enactment were also related to improved mood from baseline to 3 months. CONCLUSION: Results demonstrate delivery, receipt, and successful enactment of BE-ACTIV core components in diverse nursing homes and patients, and support the theoretical premise of the intervention. These findings support further implementation work for the BE-ACTIV intervention. PMID- 30518247 TI - Role of perceived stress in postoperative delirium: an investigation among elderly patients. AB - OBJECTIVES: This study examined levels of perceived stress (PS), postoperative delirium (POD) and associated factors among Thai elderly patients undergoing elective noncardiac surgery. BACKGROUND AND AIMS: Preoperative PS and change after operation have not been widely studied. Moreover, psychological factors associated with PS and POD has been poorly investigated. MATERIALS AND METHODS: In total, 429 elderly patients were recruited at a university hospital. The preoperative evaluation included sociodemographic data, health behaviors at risk, Perceived Stress Scale (PSS-10), Neuroticism Inventory (NI), Mental State Examination T10 (MSET10), Montreal Cognitive Assessment (MoCA) and Geriatric Depression Scale (GDS-15). Three-day postoperative evaluation included PSS-10 and Confusion Assessment Method Algorithm (CAM) or CAM-ICU for Delirium. Multiple regression and logistic regression analysis were performed to determine potential predictors. RESULTS: Females were 58.97%, and the mean age was 69.93 +/- 6.87 years. Mean pre- and postoperative PS were 12.77 +/- 5.41 and 13.39 +/- 5.26, respectively (P < 0.05). Multiple regression revealed that neuroticism, depression, and BMI predicted PS significantly. None of the independent variables was found to predict postoperative PS except for preoperative PS (p <.001). POD at the recovery room was predicted by preoperative PS (odds ratio = 1.181, 95% CI = 1.019-1.369), whereas overall POD was predicted by MoCA (odds ratio = .864, 95% CI = .771 -.968). CONCLUSION: Preoperative PS was significant in that it was associated with postoperative PS and POD. A careful assessment of preoperative PS as well as providing brief interventions for patients with high levels of this condition may reduce the risk of POD. PMID- 30518248 TI - Induction of IBV strain-specific neutralising antibodies and broad spectrum protection in layer pullets primed with IBV Massachusetts (Mass) and 793B vaccines prior to injection of inactivated vaccine containing Mass antigen. AB - In an initial study in SPF chickens, a heterologous virus neutralising (VN) antibody response to IBV variants Q1, Variant 2 (Var 2), D388/QX (D388), D274 and Arkansas (DPI) was observed using a vaccination programme incorporating two different live-attenuated IBV vaccines, followed by boosting with an inactivated vaccine containing IBV Massachusetts (Mass) antigen. Therefore, a more detailed study was undertaken in SPF layer-type chickens previously primed with IBV Mass and 793B live-attenuated vaccines. The efficacy of single or repeated vaccination with a multivalent inactivated vaccine containing IBV antigen was determined against challenge with 5 virulent IBVs: Mass (M41), 793B (4/91), D388, Q1 and Var 2. The parameters assessed were serological response, respiratory signs, egg production, post mortem abnormalities in the reproductive organs and abdomen and incidence of IBV antigen in kidneys. Increased VN titres were recorded against the 5 IBV challenge strains, with a significantly higher level of protection against drops in egg production following challenge. The difference between one or two vaccinations with inactivated vaccine was not significant in terms of egg production. However, a significantly increased level of protection was seen in the lower percentage of hens with free yolk in the abdomen and/or peritonitis post challenge with IBV variants, D388, Q1 and Var 2 that were heterologous to the vaccines included in the vaccination programme. A lower incidence of acute, degenerated ovaries was found in the groups given one injection of inactivated vaccine following live priming and this was significantly lower than in groups that had only received live priming. PMID- 30518249 TI - Optimising the treatment of doctors with mental illness. PMID- 30518250 TI - Social isolation, cognitive reserve, and cognition in older people with depression and anxiety. AB - OBJECTIVES: Poor social connections may be associated with poor cognition in older people who are not experiencing mental health problems, and the trajectory of this association may be moderated by cognitive reserve. However, it is unclear whether this relationship is the same for older people with symptoms of depression and anxiety. This paper aims to explore social relationships and cognitive function in older people with depression and anxiety. METHOD: Baseline and two-year follow-up data were analysed from the Cognitive Function and Ageing Study-Wales (CFAS-Wales). We compared levels of social isolation, loneliness, social contact, cognitive function, and cognitive reserve at baseline amongst older people with and without depression or anxiety. Linear regression was used to assess the relationship between isolation and cognition at baseline and two year follow-up in a subgroup of older people meeting pre-defined criteria for depression or anxiety. A moderation analysis tested for the moderating effect of cognitive reserve. RESULTS: Older people with depression or anxiety perceived themselves as more isolated and lonely than those without depression or anxiety, despite having an equivalent level of social contact with friends and family. In people with depression or anxiety, social isolation was associated with poor cognitive function at baseline, but not with cognitive change at two-year follow up. Cognitive reserve did not moderate this association. CONCLUSION: Social isolation was associated with poor cognitive function at baseline, but not two year follow-up. This may be attributed to a reduction in mood-related symptoms at follow-up, linked to improved cognitive function. PMID- 30518251 TI - Ion mobility-mass spectrometry analysis of diarylquinoline diastereomers: Drugs used for tuberculosis treatment. AB - Mycobacterium tuberculosis infection results in more than two million deaths per year and is the leading cause of mortality in people infected with HIV. A new structural class of antimycobacterials, the diarylquinolines, has been synthesized and is being highly effective against both M. tuberculosis and multidrug-resistant tuberculosis. As diarylquinolines are biologically active only under their ( R,S) stereoisomeric form, it is essential to differentiate the stereoisomers ( R,S) and ( R,R). To achieve this, tandem mass spectrometry and ion mobility spectrometry-mass spectrometry have been performed with 10 diarylquinoline diastereomers couples. In this study, we investigated cationization with alkali metal cations and several ion mobility drift gases in order to obtain diastereomer differentiations. We have shown that diastereomers of the diarylquinolines family can be differentiated separately by tandem mass spectrometry and in mixture by ion mobility spectrometry-mass spectrometry. However, although the structure of each diastereomer is close, several behaviors could be observed concerning the cationization and the ion mobility spectrometry separation. The ion mobility spectrometry isomer separation efficiency is not easily predictable; it was however observed for all diastereomeric couples with a significant improvement of separation using alkali adducts compared to protonated molecules. With the use of drift gas with higher polarizability only an improvement of separation was obtained in a few cases. Finally, a good correlation of the experimental collision cross section (relative to three dimensional structure of ions) and the theoretical collision cross section has been shown. PMID- 30518252 TI - Secondary metabolites from the fermented rice of the fungus Monascus purpureus and their bioactivities. AB - Phytochemical investigation of the EtOAc-soluble fraction of the ethanolic extract of a yellow mutant of the fungus Monascus purpureus BCRC 38110 (Eurotiaceae) grown on rice resulted in the isolation of one new azaphilone derivative, monapurpureusone (1), one acetophenone metabolite isolated for the first time from natural source, monapurpureusin (2), along with four known compounds, TW94a (3), ergosterol (4), monascin (5), and ankaflavin (6). The structures and relative configurations of these compounds were elucidated by spectroscopic analyses, including 1D- and 2D-NMR spectroscopy and mass spectrometry, and by the comparison of their NMR data with those of related compounds. Some phytochemicals were evaluated for both anti-inflammatory activity through the measurement of nitric oxide (NO) production levels in lipopolysaccharide (LPS)-stimulated murine-derived macrophages RAW264.7 cell lines and antioxidant activities. PMID- 30518253 TI - Effects of acute ingestion of caffeine on team sports performance: a systematic review and meta-analysis. AB - The aim of this investigation was to perform a systematic review and meta analysis to determine the efficacy of the acute ingestion of caffeine (from 3 to 6 mg/kg) to increase performance on variables related to team sports. A systematic review was performed in scientific databases from January to April 2018. All studies included had cross-over experimental designs comparing caffeine to an identical placebo condition. A meta-analysis was performed using the random effects model and pooled standardized mean differences (Glass's Delta). Thirty four studies published between 2001 and 2018 were included in the analysis. The meta-analysis revealed that caffeine increased single (Delta;95% confidence intervals = 0.19;0.14-0.25; p < 0.01) and repeated jump height (0.29;0.16-0.42; p < 0.01), single (0.16;0.02-0.30; p = 0.03) and repeated sprint velocity (0.14;0.03-0.25; p = 0.02), and reduced the time to complete agility tests (0.41;0.04-0.77; p = 0.03). During team sport matches, caffeine increased total running distance (0.41;0.20-0.62; p < 0.01), distance covered at sprint velocity (0.36;0.12-0.59; p < 0.01) and the number of sprints (0.44;0.18-0.69; p < 0.01). The acute ingestion of a moderate dose of caffeine had a small but significant positive effect on several aspects related to physical performance in team sports. PMID- 30518254 TI - "In vitro" activity of Melaleuca cajuputi against mycobacterial species. AB - The increasing incidence of resistance in tuberculosis and in atypical mycobacterial infections has prompted the search for alternative agents. We explored the antimycobacterial activity of Melaleuca cajuputi essential oil against tubercular and non tubercular mycobacterials isolates. The good activity observed towards M. cajuputi indicated that this essential oil might represent a promising antimicrobial agents, particularly in the management of microbial resistance. PMID- 30518255 TI - A survey of the role of nitrile groups in protein-ligand interactions. AB - In classical medicinal chemistry, nitrile groups were commonly considered as bioisosteres of carbonyl, hydroxyl and carboxyl groups, as well as halogen atoms. However, there is a lack of in-depth understanding about the structural and energetic characteristics of nitrile groups in protein-ligand interactions. Here, we have surveyed the Protein Data Bank and ChEMBL databases with the goal of characterizing such protein-ligand interactions for nitrile-containing compounds. We discuss the versatile roles of nitrile groups in improving binding affinities, and give special attention to examples of displacing and mimicking binding-site waters by nitrile groups. We expect that this review article will further inspire medicinal chemists to exploit nitrile groups rationally in structure-based drug design. PMID- 30518256 TI - Two new triterpenoids from Gardenia jasminoides fruits. AB - A new cycloartane triterpenoid, named gardenolic acid C (1), a new ursane triterpenoid, named 3beta,16beta,21beta,23,24-pentahydroxy urs-12,18,20-trien-28 oic acid gamma-lactone (2), together with three know triterpenoids, gardenolic acid A (3), gardenolic acid B (4), and 3alpha,16beta,23,24-tetrahydroxy-28-nor ursane-12,17,19,21-tetraen (5) were isolated from the fruits of Gardenia jasminoides Ellis. The structures of these compounds were elucidated by analyses of spectroscopic data. All isolates were evaluated for their neuroprotective effects in vitro. [Formula: see text]. PMID- 30518257 TI - A new indole-type alkaloid from the roots of Clematis florida var. plena. AB - One new indole-type alkaloid, alpha-L-rhamnopyranosyl-(1->6)-beta-D- glucopyranosyl 6-methoxy-3-indolecarbonate (1), together with three known alkaloids (2-4), one aromatic acid (5) and five known saponins (6-10), was isolated from the roots of Clematis florida var. plena. Their structures were established by NMR spectroscopic analysis and acid hydrolysis. In in vivo anti inflammatory activity, n-butanol extract was found to be potent against ear edema in mice, with inhibition rate of 48.7% at a dose of 800 mg/kg. Furthermore, compounds 8 and 9 obtained from the n-butanol extract exhibited significant anti inflammatory activities with inhibition rates of 50.9% and 54.7% at a dose of 200 mg/kg. PMID- 30518258 TI - Effect of encapsulation on the stability and survivability of Enterococcus faecium in a non-dairy probiotic beverage. AB - The main objectives of this work were to study the survivability of five probiotic lactobacilli strains in sour cherry juice and citrate buffer with similar pH values (pH 3.5) during storage at 4 C as well as to encapsulate the strain with the least survival in calcium alginate beads. Enterococcus faecium from probiotic strains in sour cherry juice exhibited the least survival; therefore, this strain was selected for studying the protective effect of microencapsulation in calcium alginate beads. Microencapsulated probiotic cells were incorporated into sour cherry juice and then exposed to harsh conditions (e.g. heat treatment, low pH, and simulated gastrointestinal fluids). Changes in the probiotic survivability, pH and titratable acidity of sour cherry juice were monitored during 60 d. D-values of free cells, calculated at 60, 70 and 80 C, were 4.87, 1.48 and 0.43 min, respectively; while, those of microencapsulated cells were 9.41, 3.73 and 1.26 min, respectively. The decrease in the number of free E. faecium after exposure to low pH values (e.g. 2.5, 2 and 1.5) was 2.81, 3.74 and 4.18 log CFU/mL, respectively. Freshly prepared and 30-d old microencapsulated cells, maintained at 4 C in sour cherry juice, showed 1.31, 2.13, 2.37 and 2.19, 2.46, 3.26 log CFU/mL reduction after exposure to similar pH conditions, respectively. The number of free and encapsulated probiotic cells after incubation in simulated gastric and gastrointestinal fluids was 5.86 and 4.81 and 8.05 and 6.61 log CFU/mL, respectively. The sensory attributes of probiotic sour cherry juice samples containing encapsulated cells were better than those fortified with free probiotics. PMID- 30518259 TI - On-line screening and identification of polyphenolic antioxidant compounds of Convolvulus trabutianus. AB - Convolvulus trabutianus Schweinf. & Muschl. is an endemic plant from northern Sahara used in folk medicine. Herein we report, the isolation, characterization and evaluation of the radical scavenging properties of twenty three compounds from different extracts of this species by on-line HPLC-ABTS*+ screening. These compounds include nine phenolic acids: 2, 6, 10-16, two phytosterols: 3-4, four coumarins: 5, 7-9, two quinic acids: 21 and 22 and six flavonoids: 1, 17-20 and 23 among which the most active were: 10, 16, 21 and 22. All the extracts showed a significant antioxidant activity on-line. These results were validated off-line by ORAC and TEAC assays. Four compounds: 1, 5, 18 and 19 were described for the first time from the Convolvulaceae family, whereas compounds 2, 6, 8, 10, 13 and 21 were new for the genus Convolvulus. PMID- 30518260 TI - Anti-inflammatory indomethacin analogs endowed with preferential COX-2 inhibitory activity. AB - AIM: The undeniable indomethacin potency has always suffered serious obstacles such as gastric damage. Continuous attempts to develop potent yet safe indomethacin analogs have never ceased. RESULTS: Herein are new indole derivatives 4a-h and 5a-c, which were synthesized via Fisher indole reaction, evaluated for both their in vivo anti-inflammatory activities using rat paw edema method and their in vitro cyclooxygenase inhibitory activities. Then ulcerogenic liability, physicochemical parameters and molecular docking modeling were performed for the most potent ones. CONCLUSION: Promising results were obtained, where compound 4f was the best anti-inflammatory agent and preferential COX-2/COX 1 inhibitor (90.5% edema inhibition, selective index = 65.71, ulcer index = 7.3), if compared with indomethacin (86.7% edema inhibition, selective index = 0.079, ulcer index = 20.20). PMID- 30518261 TI - First report of antioxidant abeo-labdane type diterpenoid from intertidal red seaweed Gracilaria salicornia with 5-lipoxygenase inhibitory potential. AB - Phytochemical investigation on the biologically active compounds of seaweed Gracilaria salicornia {(C. Agardh) E.Y. Dawson} (family Gracilariaceae) guided to the separation of a previously unreported abeo-labdane class of diterpenoid. The compound was characterized as methyl-16(13->14)-abeo-7-labdene-(12-oxo) carboxylate by extensive spectroscopic experiments, and comparison with the related compounds. The studied compound registered significantly greater activities against pro-inflammatory 5-lipoxygenase (IC50 0.86 mg/mL) than that exhibited by non-steroidal anti-inflammatory agent ibuprofen (IC50 0.92 mg/mL, P < 0.05). Likewise, this compound exhibited comparable radical quenching (1, 1 diphenyl-2-picryl-hydrazil) activity (IC50 0.66 mg/mL) as standard antioxidant agent alpha-tocopherol (IC50 0.62 mg/mL). PMID- 30518262 TI - (+/-) Gancochlearols A and B: cytotoxic and COX-2 inhibitory meroterpenoids from Ganoderma cochlear. AB - (+)- and (-)-gancochlearols A (1) and B (2), two pairs of dimeric mertoterpenoid enantiomers were isolated from the fruiting bodies of Ganoderma cochlear. Their structures were identified by spectroscopic methods. Biological assessments show that the enantiomers of 1 and 2 are cytotoxic against three human cancer cell lines (A549, K562, Huh-7) and could inhibit COX-2 expression with IC50 values less than 10 MUM. PMID- 30518263 TI - Improving Strength and Quality of Epitendinous Repairs. AB - BACKGROUND: Epitendinous sutures not only join the 2 severed tendon edges but also supply strength and support to the repair. Multiple techniques have been described, but none of them include another thread of suture. This could potentially increase the strength of the repair without affecting gliding. METHODS: Caprine tendons were harvested, transected, and sutured with 6-0 Prolene. Four groups were created: single thread running (SR), single thread locking (SL), double thread running (DR), and double thread locking (DL). An Instron 5542 was used to pull the repaired tendons apart, and the energy at the break was calculated (gf/mm). For gliding resistance, we harvested a human A2 pulley. A pre- and postrepair value was obtained, and a ratio was elaborated. A single-factor analysis of variance and independent sample t tests were performed. RESULTS: The SR group had a mean energy at break of 9339.71 +/- 1630.212 gf/mm; the SL group, 9629.96 +/- 1476.45 gf/mm; and the DR group, 9600.221 +/- 976.087 gf/mm, with no statistical significance. The DL group was significantly higher at 14 740.664 +/- 2596.586 gf/mm ( P < .05). When comparing SR with DL for gliding, SR had less than half of the resistance than DL (0.018 +/- 0.004 and 0.049 +/- 0.015 N/mm, respectively), with statistical significance ( P < .05). CONCLUSION: Using a single suture thread for running epitendinous repair is no different than locking with a single thread or using an extra thread in a running fashion. Performing a double suture thread with a locking technique is significantly stronger than the previously mentioned repairs, with the disadvantage of more resistance at the pulley. PMID- 30518264 TI - A layered computer-interpretable guideline model for easing the update of locally adapted clinical guidelines. AB - Maintenance of computer-interpretable guidelines is complicated by evolving medical knowledge and by the requirement to customize content to local practice settings. We developed a framework to support knowledge engineers in customization and maintenance of computer-interpretable guidelines specified in the PROforma formalism. In our layered approach, the computer-interpretable guidelines containing the original clinical guideline serves as the primary layer and local customizations form secondary layers that adhere to its schema while augmenting it. Java code unifies the layers into a single enactable computer interpretable guidelines. We performed a pilot experiment to verify the effectiveness of a layered framework. In this first attempt, we evaluated the hypothesis that the layered computer-interpretable guidelines framework supports knowledge engineers in maintenance of customized computer-interpretable guidelines. Participants who used the layered framework completed an update process of the primary knowledge in less time and made fewer errors as compared to those using the single-layer framework. PMID- 30518265 TI - Challenges of Edible Oils From Farm to Industry: Views of Stakeholders. AB - OBJECTIVE:: The purpose of this study is to explore stakeholders' views about quality and safety of edible oils from farm to industry and propose policy options to address these challenges. METHODS:: Semistructured, face-to-face interviews were conducted with 11 experts in edible oil industry. Participants were selected through purposive sampling and snowballing. Open-ended interview questions were used to identify the edible oil's challenges from farm to industry. All interviews were recorded and final transcripts were re-read to obtain categories until themes were developed using directed content analysis and constant comparison methods. RESULTS:: Six categories in 14 themes with 49 sub themes were explored based on the perspectives of the stakeholders who were responsible for edible oil industry: (1) safety, (2) imports, (3) factory, (4) edible oils' monitoring, (5) edible oil industry, and (7) building consumer trust. The participants' views showed that to increase the quality and safety of edible oils, the following approaches are required: updating food safety regulations, effective inspection, monitoring and surveillance systems, updating laboratory equipment, and controlling the media advertising. CONCLUSIONS:: In order to build and maintain effective edible oil safety systems, strong links must be established between all sectors responsible. The key players need to have access to reliable and up-to-date information so that timely collective action can be taken. It is recommended that governments face up to this task and lead the way. The research findings seek to offer policy options for government and the stakeholders for challenging future strategies for edible oil industry. PMID- 30518266 TI - Smart fluorescent probes for in situ imaging of enzyme activity: design strategies and applications. AB - Enzymes play critical roles in the physiological and pathological processes of living systems. To provide detailed pictures of enzyme activity at the molecular and cellular levels, interdisciplinary studies of chemistry and biology have led to the emergence of many smart fluorescent probes, which emit fluorescence or show a shifted signal only upon interaction with their targets. With distinct advantage of a higher signal-to-noise ratio than traditional 'always on' probes, smart fluorescent probes enable sensitive detection of enzymes with clinical significance. In this review, we summarize the design strategies and selected applications of smart fluorescent probes for in situ imaging of enzyme activity. Current challenges and future developments in this field are also discussed. PMID- 30518267 TI - Management of bacterial skin and skin structure infections with polymicrobial aetiology. AB - INTRODUCTION: Skin and Soft Tissue Infections (SSTIs) are some of the most commonly occurring bacterial infections, with a wide range of possible aetiological pathogens and a considerable variety of clinical presentations and severity; from mild to severe life-threatening infections. Several classifications have been proposed based on a specific variable, such as anatomical localization, skin extension, progression rate, clinical presentation, severity and etiological agent. Areas covered: The last criteria allows the differentiation of SSTIs as mono-microbial and poly-microbial. Among them, especially those infections with a long lasting or chronic course can be sustained by multiple microbial aetiology. Most polymicrobial SSTIs can be included in the following: diabetes foot infections (DFIs), pressure ulcers infection, burn infection, and infected chronic ulcers. Expert commentary: The medical management of these infections comprises the administration of wide a spectrum antibiotic, taking into consideration the frequent occurrence of multidrug resistant microorganisms as responsible agents. An appropriate deep tissue specimen for microbiological examination is a very important issue, especially for polymicrobial infections, sometimes permitting the distinction between real pathogens and contaminants avoiding more complex antibiotic treatments. This aspect must be strongly emphasized, as frequently superficial swabs remain the specimen of choice because they are easy to obtain. PMID- 30518268 TI - A review on the effects of extremely low frequency electromagnetic field (ELF EMF) on cytokines of innate and adaptive immunity. AB - Extremely low frequency electromagnetic field (ELF-EMF) is produced extensively in modern technologies. Numerous in vitro and in vivo studies have shown that ELF EMF has both stimulatory and inhibitory effects on the immune system response. This review was conducted on effects of ELF-EMF on cytokines of innate and adaptive immunity. Mechanisms of ELF-EMF, which may modulate immune cell responses, were also studied. Physical and biological parameters of ELF-EMF can interact with each other to create beneficial or harmful effect on the immune cell responses by interfering with the inflammatory or anti-inflammatory cytokines. According to the studies, it is supposed that short-term (2-24 h/d up to a week) exposure of ELF-EMF with strong density may increase innate immune response due to an increase of innate immunity cytokines. Furthermore, long-term (2-24 h/d up to 8 years) exposure to low-density ELF-EMF may cause a decrease in adaptive immune response, especially in Th1 subset. PMID- 30518269 TI - Self-silencing and women's health: A review. AB - The connection between gender and health has intrigued health professionals in the last few decades. Silencing-the-self theory has brought a considerable clarity in this matter. After around three decades of the theory, the literature related to the theory has immensely flourished and has covered different branches of psychology. The aim of the present work is to provide a comprehensive picture of the qualitative and quantitative research findings that have connected self silencing to health and well-being of women. This article presents a critical review of relevant articles. These articles have used the self-silencing theory as an explanation of women's higher vulnerability to certain diseases as well as their experience with them. Self-silencing has been found to explain the gender gap in psychiatric disorders like depression, eating disorders and so on. It also influences the resilience and therapeutic effects among female patients with chronic conditions such as cancer, AIDS and so on. Moreover, self-silencing has also been found to be associated with women's health issues such as pre-menstrual dysphoric disorder. The present study discusses the existing literature in a narrative manner along with suggesting some relevant research gaps that can be worth exploring in the future. PMID- 30518270 TI - A clinical update on the mid-term clinical performance of the Ovation endograft. AB - INTRODUCTION: The Ovation stent-graft uncouples the steps of fixation and sealing via a pair of polymer-filled inflatable rings. Apart from the well-documented early results, newer data emerged for mid-term results of Ovation and are presented in this review. Areas covered: Aim of this article was to report all current studies with the mid-term results of the particular endograft, the incidence of complications and failure and discuss their management. Expert Commentary: The Ovation stent-graft exhibits very satisfactory clinical mid-term results in abdominal aortic aneurysms treated within the instructions-for-use. It can also have a very promising role in challenging neck anatomies with conical shape and presence of thrombus or calcification. However, this should be not considered a panacea and long-term results are needed to validate this intriguing aspect. PMID- 30518271 TI - Platelet reactivity in patients with chronic kidney disease undergoing percutaneous coronary intervention. AB - This study aimed to evaluate the platelet reactivity in real-world patients with different chronic kidney disease (CKD) stages after percutaneous coronary intervention (PCI), and to examine whether high residual platelet reactivity (HRPR) is associated with higher incidence of adverse cardiovascular events in a 2-year follow up. A total of 10 724 consecutive patients receiving DAPT with aspirin and clopidogrel after PCI throughout 2013 were enrolled. We applied modified thromboelastography (mTEG) in 6745 patients. Kaplan-Meier analysis and Cox proportional regression analysis were applied to illustrate end points for patients. The prevalence of HRPR for adenosine diphosphate (ADP) was higher in patients with CKD3-5 than patients with CKD1-2 (47.0% vs. 37.3%, p = 0.002), but not for arachidonic acid (AA). No significant difference was observed for MACCE between patients with or without HRPR for ADP (HR 1.004, 95%CI: 0.864-1.167, p = 0.954). Patients with HRPR for ADP was associated with less bleeding events than patients without HRPR for ADP (HR 0.795, 95%CI: 0.643-0.982, p = 0.034). In this large cohort of real-world patients after PCI, the deterioration of renal function was linked to HRPR for ADP. HRPR was not associated with MACCE in patients with CKD in a 2-year follow up. Bleeding risks were significantly lower in PCI patients with versus without HRPR for ADP. PMID- 30518272 TI - Matriptase-2: monitoring and inhibiting its proteolytic activity. AB - Matriptase-2 (MT2) is a membrane-anchored proteolytic enzyme. It acts as the proteolytic key regulator in human iron homeostasis. A high expression level can lead to iron overload diseases, whereas mutations in the gene encoding MT2, TMPRSS6, may result in various forms of iron deficiency anemia. Recently, MT2 has been reported as a positive prognostic factor in breast and prostate cancers. However, the exact functions of MT2 in various pathophysiological conditions are still not fully understood. In this review, we describe the synthetic tools designed and synthesized to regulate or monitor MT2 proteolytic activity and present the latest knowledge about the role of MT2 in iron homeostasis and cancer. PMID- 30518273 TI - Optimization techniques for novel c-Met kinase inhibitors. AB - INTRODUCTION: c-Met kinase plays an important part in the regulation of cell growth, invasion and anti-apoptosis. This enzyme is also an important target in cancer treatment. Through structural optimization and structure-activity studies of drugs currently on the market and those still in clinical trials, a great number of novel c-Met kinase inhibitors have been developed. This review focuses on recent developments in research regarding novel c-Met inhibitor synthesis, optimization, and structure-activity relationship (SAR) studies. Area covered: In this review, the authors discuss the representative research of c-Met inhibitors published in recent years. Furthermore, it provides background research of c-Met kinase inhibitors, the introduction of drugs on the market and in clinical research, and the research progress of novel small molecule inhibitors. In particular, this review emphasizes the important role of '5-atoms linker' in the design of some novel c-Met enzyme inhibitors. Expert opinion: Discovering novel c Met kinase inhibitors via natural product chemistry may become a new research field. Though it is difficult, the key to developing better c-Met kinase inhibitors is structural optimization. PMID- 30518274 TI - Folded large-bore central catheter in the right internal jugular vein as shown by ultrasound: a case report. AB - Central venous catheters are used for various purposes in the operating room. Generally, the use of ultrasound to insert a central venous catheter is rapid and minimally complicated. An advanced venous access (AVA) catheter is used to gain access to the pulmonary artery and facilitate fluid resuscitation through the internal jugular vein. The present report describes a case in which ultrasound was used in a 43-year-old man to avoid complications during insertion of an AVA catheter with a relatively large diameter. The sheath of the catheter was so thin that a dilator was essential to prevent it from folding upon insertion. Despite the use of ultrasound guidance, the AVA catheter sheath became folded within the patient's internal jugular vein. Mechanical complications of central venous catheter insertion are well known, but folding of a large-bore catheter in the internal jugular vein has rarely been reported. PMID- 30518275 TI - Machine learning for identification of surgeries with high risks of cancellation. AB - Surgery cancellations waste scarce operative resources and hinder patients' access to operative services. In this study, the Wilcoxon and chi-square tests were used for predictor selection, and three machine learning models - random forest, support vector machine, and XGBoost - were used for the identification of surgeries with high risks of cancellation. The optimal performances of the identification models were as follows: sensitivity - 0.615; specificity - 0.957; positive predictive value - 0.454; negative predictive value - 0.904; accuracy - 0.647; and area under the receiver operating characteristic curve - 0.682. Of the three models, the random forest model achieved the best performance. Thus, the effective identification of surgeries with high risks of cancellation is feasible with stable performance. Models and sampling methods significantly affect the performance of identification. This study is a new application of machine learning for the identification of surgeries with high risks of cancellation and facilitation of surgery resource management. PMID- 30518276 TI - Laterally-positioned placenta in placenta previa. AB - OBJECTIVES: To clarify perinatal outcomes of patients with placenta previa (PP) with the placenta mainly positioned in the lateral uterine wall (lateral PP), thereby clinically characterizing this condition. STUDY DESIGN: The retrospective cohort study was performed involving patients with lateral PP between January 2006 and December 2016. The placental position was determined and classified by magnetic resonance imaging. RESULTS: This study included 98 patients with PP, which was classified into three types according to the main placental position sites: lateral (n = 30), anterior (n = 32), and posterior (n = 36) PP. Overall, the median blood loss at cesarean section (CS) was 1808 mL and transfusion was performed for 78 patients (80%). Univariate analysis showed that patients with lateral PP bled less at CS than those with nonlateral PP (anterior + posterior PP) [median 1,510 (interquartile range 1080-2168) versus 1975 (1570-2860) mL: p = 0.02]. The other parameters including rates of conception by assisted reproductive technology, prior CS, antepartum bleeding, and placenta accreta spectrum did not show the significances. Among the 3 groups of PP (lateral versus anterior versus posterior), patients with lateral PP bled less than those with anterior (p = 0.05) or posterior (p = 0.13) PP, but this was nonsignificant [lateral 1510 (1080-2168) versus anterior 2145 (1580-3348) versus posterior 1808 (1533-2555) mL]. When dividing into lateral PP to two types: placenta showing anterior dominancy versus posterior dominancy, patients with lateral PP and anterior dominancy bled more those with posterior dominancy [2430 (1410-3400) versus 1170 (1050-1588) mL: p = 0.002]. CONCLUSION: Patients with lateral PP bled significantly less than those with nonlateral (anterior or posterior) PP. Patients with lateral PP and anterior dominancy bled more than those with posterior dominancy. PMID- 30518277 TI - Adherence to treatment in allergic respiratory diseases. AB - INTRODUCTION: Asthma and allergic rhinitis (AR) are chronic conditions in which management needs adherence to prescribed drugs. Despite the benefits of regular maintenance of asthma and AR therapy, low adherence is a frequent issue in clinical practice. Areas covered: The aim of this review is to provide a targeted analysis of the more recent literature on adherence in asthma and AR, focused on the following areas: adherence extent, barriers and consequences, effects of educational interventions and use of new technologies to improve the level of adherence. Expert commentary: Despite the extent, reasons and effects of this problem being well known, non-adherence in asthma and allergic AR remains worryingly high. Poor adherence leads to unsatisfactory health outcomes, with a negative impact on patients and society. Recent literature suggests that successful programs to improve adherence should include a combination of strategies. The new technologies represent a promising tool to improve adherence. PMID- 30518278 TI - Epidemiology of lower respiratory tract infections in adults. AB - INTRODUCTION: Lower respiratory tract infections (LRTIs) are the leading infectious disease cause of death in the world and the fifth overall cause of death. From an epidemiological point of view, most consider pneumonia, influenza, bronchitis (including acute exacerbations in chronic obstructive pulmonary disease [AECOPD]), and bronchiolitis to be the most important LRTIs. Areas covered: This review will describe the epidemiology of LRTIs in adults focusing on community-acquired pneumonia, influenza, and AECOPD, utilizing data from the more recent literature. Expert commentary: LRTIs remain exceedingly common, although there have been significant changes in their epidemiology over recent years, both with regard to their frequency and the infecting pathogens. Part of the change in the epidemiology may relate to changing population demographics, the varying prevalence of smoking, and the introduction of the pneumococcal conjugate vaccine in children and patterns of vaccine usage. Furthermore, antigenic variations in the influenza viruses dictate the frequency and characteristics of the influenza epidemics and pandemics. PMID- 30518279 TI - Bereaved Parents More Satisfied With the Care Given to Their Child With Severe Spinal Muscular Atrophy Than Nonbereaved. AB - BACKGROUND AND AIMS:: Children with severe spinal muscular atrophy have complex care needs due to progressive muscle weakness, eventually leading to respiratory failure. To design a care system adapted to families' needs, more knowledge about parents' experience of care and its coordination between settings is required. This study explores (1) whether parents felt that health professionals took every opportunity to help the child feel as good as possible, (2) parents' satisfaction with various care settings, and (3) parents' satisfaction with coordination between settings. METHODS:: Data derive from nationwide Swedish and Danish surveys of bereaved and nonbereaved parents of children with severe spinal muscular atrophy born between 2000 and 2010 in Sweden and 2003 and 2013 in Denmark (N = 95, response rate = 84%). Descriptive statistics and content analysis were used. RESULTS:: Although most of the parents reported that care professionals had taken every opportunity to help the child feel as good as possible, one-third reported the opposite. Bereaved parents were significantly more satisfied with care than nonbereaved (81% vs 29%). The children received care at many different locations, for all of which parents rated high satisfaction. However, some were dissatisfied with care coordination, describing lack of knowledge and communication among staff, and how they as parents had to take the initiative in care management. CONCLUSIONS:: This study highlights the importance of improving disease-specific competence, communication and knowledge exchange among staff. For optimal care for these children and families, parents should be included in dialogues on care and staff should be more proactive and take care management initiatives. PMID- 30518280 TI - 'They love me, but they don't understand me': Family support and stigmatisation of mental health service users in Gujarat, India. AB - BACKGROUND:: Family life is a near-universal condition and a fundamental human right. It can also have a significant impact on mental health, including recovery from mental health conditions. In India, families play a considerable role, representing a source of social, cultural, religious and, often, financial support. However, families can also play a stigmatising role. AIM:: To examine the experiences of mental health service users (MHSUs) relating to stigma and support provided by family members and to consider ways in which family support can be improved. METHOD:: This is a qualitative study. A total of 17 residential MHSUs at the Ahmedabad Hospital for Mental Health were interviewed. The results were evaluated using thematic content analysis. RESULTS:: The results revealed that all 17 MHSUs considered their families to be important sources of support, while 14 of the 17 MHSUs also experienced stigma emanating from their families. A total of 11 experienced lack of knowledge, 4 spoke of prejudicial attitudes and 5 mentioned discriminatory behaviours. There were important gender differences in experiences. MHSUs mentioned needs ranging from education and peer support for family members to financial support. CONCLUSIONS:: Families act both as sources of support and stigmatisation. Education needs are considerable, while the need for peer support for families and resources to aid families in supporting people with mental health conditions are also important considerations. PMID- 30518281 TI - The Evolut R and Evolut PRO Transcatheter Aortic Valve Systems. AB - INTRODUCTION: Transcatheter aortic valves have evolved over the last 15 years. Second- and third- generation devices have considerably improved, and a range of newer devices have also been introduced with the aim of decreasing the incidence of paravalvular leak, reducing the need for permanent pacemaker implantation and minimising procedure- and device-related complications. Areas covered: In this review, we highlight the special features of the latest generation of self expanding Evolut PRO (Medtronic, Minneapolis, Minnesota) transcatheter aortic valve system. A detailed literature search on the Medtronic Evolut R and Evolut PRO transcatheter aortic valves was undertaken using Ovid, PubMed and Web of Science. Expert Commentary: In a single, small study, the Evolut PRO has shown significant improvement over the Evolut R in terms of reduced paravalvular leak and pacemaker implantation. Larger scaled studies are needed to ascertain the performance of the Evolut PRO. PMID- 30518282 TI - Neighborhood social cohesion and viral suppression after HIV diagnosis. AB - Social cohesion has varying effects on health. We investigated the association of perceived neighborhood social cohesion with HIV viral suppression using individual-level data from the New York City HIV registry and surveillance-based interviews ( n = 92). Suppression was achieved within 12 months of HIV diagnosis by 60 percent of persons perceiving low cohesion and 71 percent of those perceiving high ( p = 0.31). Controlling for demographic and clinical characteristics and neighborhood poverty, per proportional hazards regression, cohesion was not associated with suppression (adjusted hazards ratio (95% confidence interval) for high versus low cohesion: 0.79 (0.49-1.28)). Cohesion may have heterogeneous effects on HIV medication adherence. PMID- 30518283 TI - Postural Control Entropy Is Increased When Adopting an External Focus of Attention. AB - Falls in older adults are a public health challenge due to their influence on well-being and health-care costs. One way to address this challenge is to discover new methods to enhance postural control in older adults so they are better prepared to maintain an upright stance. Older and younger adults (N = 32) performed a static balance task on a force plate with no instructions, internal focus instructions, or external focus instructions. Center of pressure displacement time series were analyzed using sample entropy and standard deviation. Only the external focus condition significantly increased postural control entropy, which was observed across both age groups. This study showed that an external focus of attention can be used to increase postural control entropy within a single session of testing. PMID- 30518284 TI - Surgical anatomy of the dorsal cutaneous branch of the ulnar nerve and its clinical significance in surgery at the ulnar side of the wrist. AB - The dorsal cutaneous branch of the ulnar nerve can be easily injured during surgery at the ulnar side of the wrist. We sought to identify the surgical anatomy, the pathway around the ulnar styloid process and the safe zone of the dorsal cutaneous branch of the ulnar nerve. In 44 forearm dissections, we found that the dorsal cutaneous branch of the ulnar nerve originated at a median distance of 6.8 cm proximal to the tip of the ulnar styloid. We classified the crossing pattern of the dorsal cutaneous branch of the ulnar nerve at a vertical axis into three types. The most common type featured the dorsal cutaneous branch of the ulnar nerve crossing the vertical axis at a median distance of 10.0 mm distal to the tip of the ulnar styloid. In 14% of specimens, the dorsal cutaneous branch of the ulnar nerve crossed the vertical axis at the level of the tip of the ulnar styloid. By mapping the course of the nerve using a Cartesian coordinate system, it was found that the areas located proximal and palmar to the tip of the ulnar styloid had a very high density of dorsal cutaneous branches of the ulnar nerve. We were unable to establish a safe zone. We recommend identifying the dorsal cutaneous branch of the ulnar nerve in every patient undergoing surgery at the ulnar side of the wrist. PMID- 30518285 TI - Effects of Foot Placement on Postural Sway in the Anteroposterior and Mediolateral Directions. AB - The common practice of standardizing foot placement in postural research and in clinical practice may serve to increase postural sway. The focus of this study was to investigate foot placement strategies in the tandem (anteroposterior, AP) and side-to-side (mediolateral, ML) stance in healthy adults. Foot placement was either experimenter-controlled or selected by the participant. Greater sway was observed for the AP stance than the ML stance, where sway was minimal. When foot placement was self-selected, participants recruited additional degrees of freedom by rotating both feet outward to expand the base of support; they narrowed their stance width in the AP stance only. Self-selection served to decrease AP sway for the AP stance and increase ML sway for both the AP and ML stances. A dynamical measure, the largest Lyapunov exponent, supported the finding that self-selection of foot placement serves to stabilize posture. The implication is that improvements in postural control were due primarily to self-selection of foot placement and not to adjustments in stance width. Experimental and perhaps clinical procedures should be revised to allow participants to self-select foot placement during postural tasks. PMID- 30518286 TI - Associations of Accumulated Time in Bouts of Sedentary Behavior and Moderate-to Vigorous Physical Activity With Cardiometabolic Health in 10- to 13-Year-Old Boys. AB - BACKGROUND: Little is known about the impact of sedentary and moderate-to vigorous physical activity (MVPA) bouts on cardiometabolic health. The aim was to examine how the accumulation of bouts of sedentary time and MVPA associates to cardiometabolic health in children independently of total sedentary and MVPA time. METHODS: In a cross-sectional study with 123 boys (10-13 y), sedentary and MVPA bouts were determined using 7-day accelerometry. Each bout was compared with cardiometabolic risk factors and with the risk score that was calculated using standardized values of body mass index, waist circumference, homeostasis model assessment for insulin resistance, triglycerides, and total cholesterol/high density cholesterol ratio. RESULTS: Time in 10- to 14-minute sedentary bouts was negatively associated with continuous cardiometabolic risk score in weekdays and weekend days and with triglycerides in a weekend (P < .05). Time accumulated in >=30-minute sedentary bouts was associated with higher insulin and homeostasis model assessment for insulin resistance values in weekend (P < .05). Weekday total MVPA and time accumulated in >=10-minute MVPA bouts were negatively associated with continuous cardiometabolic risk score and body mass index in weekdays (P < .05). No associations were found between total sedentary time and metabolic health. CONCLUSION: Significant associations between sedentary and MVPA bouts with cardiometabolic risk factors suggest the need of the more detailed analysis for sedentary behavior and its effects on health risks. PMID- 30518287 TI - Human papillomaviruses' proteins with clinical utility. AB - Cervical cancer, the fourth leading cause of cancer-associated deaths among women worldwide, is associated with human papilloma virus (HPV) infection. Despite the prophylactic HPV vaccination and the implementation of cervical and HPV-based screening programs, a significant increase in cervical cancer incidence is estimated by the year 2020. Thus, further development of diagnostic tools that allow detection and risk assesment in genital HPV infection is necessary. A special interest is focused on the HPV viral proteins whose expression might be of use either as primary screening tool or in conjunction with other markers (cellular proteins, HPV DNA, PAP test). PMID- 30518288 TI - The Perceived Stress Scale-10 (PSS-10) is reliable and has construct validity in Chinese patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus is a chronic, progressive, autoimmune disease that causes significant stress on patients. There is no specific instrument for assessing stress in Chinese systemic lupus erythematosus patients. The objective of this study was to test the reliability and validity of the 10-item Perceived Stress Scale in Chinese systemic lupus erythematosus patients. Validity evaluation included structural and construct validity (convergent and discriminant validity). Structural validity was assessed by exploratory factor analysis. Convergent validity was assessed by correlating the total score of the 10-item Perceived Stress Scale with the Patient Health Questionnaire-9, Self Efficacy for Managing Chronic Disease 6-Item Scale, the Simplified Coping Style Questionnaire, and the Systemic Lupus Erythematosus Disease Activity Index. Discriminant validity was determined by the statistically significant differences in perceived stress scores among patients with different education levels and disease activity. Reliability was assessed by internal consistency and test retest reliability. The test-retest reliability was measured at 1-week intervals. Exploratory factor analysis extracted two dimensions that explained 66.45% of the variation. Moderate-to-strong correlations were also found between the 10-item Perceived Stress Scale and the Patient Health Questionnaire-9, Self-Efficacy for Managing Chronic Disease 6-Item Scale, the Simplified Coping Style Questionnaire, and Systemic Lupus Erythematosus Disease Activity Index. Excellent test-retest reliability (intraclass correlation coefficient = 0.954) and internal consistency (Cronbach's alpha = 0.810) were demonstrated. In conclusion, the 10-item Perceived Stress Scale can be used to measure stress among Chinese systemic lupus erythematosus patients and serve as a basis for further research. PMID- 30518289 TI - Differences in Career Satisfaction, Work-life Balance, and Stress by Gender in a National Survey of Pharmacy Faculty. AB - INTRODUCTION:: The percentage of women pharmacy students and pharmacy faculty has greatly increased over the last 40 years. However, it is not known whether gender differences exist in terms of career satisfaction, work-life balance, and stress in the pharmacy academia workplace. METHODS:: Results from a national web-based survey administered to American Association of Colleges of Pharmacy (AACP) members were utilized. Bivariate analyses were conducted to compare differences among faculty according to gender (men vs women). A series of multivariate models controlling for demographic and other faculty and school-level factors were created to explore the impact of gender on satisfaction with current position, satisfaction with work-life balance, and perceived stress. RESULTS:: Among the 802 survey respondents, 457 (57.0%) women were more likely to be younger, hold a lower academic rank, and be in a pharmacy practice department, relative to 345 (43.0%) men. In adjusted results, men pharmacy faculty were more likely to report being extremely satisfied with their current job, more likely to report being extremely satisfied with their work-life balance, and score lower on a standardized stress measure relative to women. CONCLUSION:: While primarily descriptive, the results suggest women pharmacy faculty in the United States are less satisfied with their current academic position, less satisfied with their current work-life balance, and have higher stress levels compared to men even after controlling for age, academic rank, and department (along with other factors). Further research is needed to explore and address causes of the observed gender-related differences among pharmacy faculty. PMID- 30518290 TI - The Yersinia pseudotuberculosis Cpx envelope stress system contributes to transcriptional activation of rovM. AB - The Gram-negative enteropathogen Yersinia pseudotuberculosis possesses a number of regulatory systems that detect cell envelope damage caused by noxious extracytoplasmic stresses. The CpxA sensor kinase and CpxR response regulator two component regulatory system is one such pathway. Active Cpx signalling upregulates various factors designed to repair and restore cell envelope integrity. Concomitantly, this pathway also down-regulates key determinants of virulence. In Yersinia, cpxA deletion accumulates high levels of phosphorylated CpxR (CpxR~P). Accumulated CpxR~P directly repressed rovA expression and this limited expression of virulence-associated processes. A second transcriptional regulator, RovM, also negatively regulates rovA expression in response to nutrient stress. Hence, this study aimed to determine if CpxR~P can influence rovA expression through control of RovM levels. We determined that the active CpxR~P isoform bound to the promoter of rovM to directly induced its expression, which naturally associated with a concurrent reduction in rovA expression. Site directed mutagenesis of the CpxR~P binding sequence in the rovM promoter region desensitised rovM expression to CpxR~P. These data suggest that accumulated CpxR~P inversely manipulates the levels of two global transcriptional regulators, RovA and RovM, and this would be expected to have considerable influence on Yersinia pathophysiology and metabolism. PMID- 30518291 TI - A Cautionary Research Note on Standard Versus Extended Release Tacrolimus. PMID- 30518292 TI - Public responses to scientific research: Does disciplinary attribution matter? AB - Research has shown that the form and content of science communications can influence individuals' responses. This study examines whether individuals' perceptions of scientific research are influenced by the discipline to which the research is attributed. Two vignette experiments find that neither the perceived scientific-ness nor trustworthiness of a study originating from sociology is affected by attributing the study to a different social science or to a natural or medical science. These null findings contrast with surveys showing sizable disciplinary differences in public attitudes. It is possible that disciplinary attribution is a less salient cognitive shortcut when presented in longer communications as compared to survey questions that only provide the name of a discipline. We conclude with suggestions for further research on the role of disciplinary attribution on public perceptions of science. PMID- 30518293 TI - Multifractal Analysis Differentiates Postural Sway in Obese and Nonobese Children. AB - Multifractal analyses have been used in recent years as a way of studying balance, with the goal of understanding the patterns of movement of the center of pressure at different spatial scales. A multifractal detrended fluctuation analysis was used to compare obese and nonobese children to investigate the cause of previously demonstrated deficiencies in balance for obese children. Twenty-two children (11 obese and 11 nonobese), aged 8-15 years, performed 30-s trials of bilateral static balance on a plantar pressure distribution measuring device. Both the obese and nonobese groups demonstrated greater persistence for small fluctuations, but the effect was greater in the obese group. This was particularly evident with the eyes closed, where significant differences between the obese and nonobese were observed for small fluctuations. These results demonstrate that balance deficiencies in obese children may be the result of decreased proprioceptive abilities in obese children. PMID- 30518294 TI - Accuracy of Children's Perceived Skill Competence and its Association With Physical Activity. AB - BACKGROUND: Perceived movement competence is important in the relationship between actual competence and physical activity (PA). This study examines the accuracy of children's perceptions and investigates the relationship between perceived competence (PC) and PA. METHODS: Data collected were part of Project Spraoi, a PA and nutrition-based intervention. Participants (N = 419) were senior infant/first class (n = 202, mean age: 6.5 [0.6] y) and fourth/fifth class (n = 217, mean age: 10.4 [0.6] y) children from 3 schools in Cork, Ireland. The Test of Gross Motor Development-2 and Pictorial Scale of Perceived Movement Skill Competence for Young Children assessed actual and PC in 6 locomotor and 6 object control fundamental movement skills. Moderate to vigorous PA levels were measured by accelerometry. Wilcoxon signed-rank tests assessed the accuracy of PC. Hierarchical regression analysis investigated relationships between PC and both actual competence and moderate to vigorous PA. RESULTS: Children had greater perceived overall and object-control competence than actual. Among younger children, there was no difference between perceived locomotor and actual, while older children had lower perceived locomotor competence than actual. PC did not predict actual competence. Perceived object-control and total PC were significant predictors of moderate to vigorous PA. CONCLUSIONS: Children have inflated perceptions of their overall and object-control movement skill competency. Perceived object-control and total FMS is associated with PA and thus, interventions aimed at increasing PA among children should target PC. PMID- 30518295 TI - Climate Change Action Requires Unity Among Movements for Justice and Peace. PMID- 30518296 TI - Length and secondary structure of the 5' non-coding regions of mouse p53 mRNA transcripts - mouse as a model organism for p53 gene expression studies. AB - Transcription initiation sites of Trp53 gene in mice were determined using the 5'RACE method. Based on sequence alignment of the 5'-terminal regions of p53 mRNA in mammals, the site for the most abundant transcript turned out to be essentially identical with that determined for human TP53 gene and slightly differed for the longest transcripts, in mice and humans. Secondary structures of the 5' -terminal regions of the shorter, most abundant and the longest mouse transcripts were determined in vitro and the shorter transcript was also mapped in transfected mouse cells. For the first time, secondary structure models of the 5' terminus of two mouse p53 mRNAs were proposed. Comparing these models with the conservativeness of the nucleotide sequence of the 5'-terminal region of mRNA in mouse and other mammals, the possible function of the selected structural domains of this region was discussed. To elucidate the translation mechanisms, the two studied mRNAs were translated in the presence of an increasing concentration of the cap analog. For the longest transcript, the data suggested that IRES element(s) was/were involved in translation initiation. Additionally, changes in p53 synthesis under genotoxic and endoplasmic reticulum stress conditions in mouse cells were analyzed. PMID- 30518297 TI - Early Experiences With PEGylated Carboxyhemoglobin Bovine in Anemic Jehovah's Witnesses: A Case Series and Review of the Literature. AB - Jehovah's Witnesses (JW) represent a complex patient population due to their refusal to accept blood transfusions on religious grounds. Pharmacologic management of anemic JW patients is limited to stimulation of hematopoiesis by iron and erythropoietin supplementation and reduction of blood loss by prothrombin complex concentrates (PCCs). Hemoglobin-based oxygen carriers (HBOCs) represent the only pharmacologic modality for JW patients capable of acutely increasing a patient's oxygen carrying capacity in the setting of organ failure, yet clinical safety and efficacy data are lacking in this population. We report 3 cases in which the HBOC, PEGylated carboxyhemoglobin bovine (Sanguinate(r)), was requested under emergent circumstances for severely anemic (hemoglobin <5 g/dL) JW patients who refused blood transfusions. Two patients received PEGylated carboxyhemoglobin infusions for severe anemia, while the third patient died prior to receiving the medication. One patient who received Sanguinate died after 5 units of medication. The other patient's hemoglobin recovered and she was discharged in stable condition. This series demonstrates the complex nature of the critically anemic JW population and highlights the clinical considerations of using HBOCs in clinical practice and the critical need for further research before they can be broadly recommended. PMID- 30518298 TI - Zebrafish embryos exposed to deltamethrin exhibited abnormalities in spite of induced expression of related genes ( you, you-too, momo and u-boot). AB - Evaluation of the toxic effects of a widely used synthetic pyrethroid, deltamethrin (DM), was carried out in this study. This pesticide is preferred for pest control because of its low environmental persistence and toxicity. We investigated the expression pattern of four genes, namely, you ( you), yot ( you too), momo ( mom) and ubo ( u-boot) during early development of zebrafish, that is, from 12 hpf to 48 hpf stages. These stages are selected as most of the important developmental aspects take place during this period. All four genes are known to play a vital role in development of notochord and somites. To understand the effect of DM on development, embryos of 4 hpf stage were exposed to two concentrations (100 and 200 ug/L) of DM, and observations were made at 12, 24 and 48 hpf stages. Our earlier studies have shown phenotypic abnormalities such as notochord bending, tail deformation, yolk sac and pericardial edema, lightening of body and eye pigmentation and interfered in somite patterning, during these stages of development. Understanding the relationship of phenotypic abnormalities with these four genes has been our primary objective. These four genes were analyzed by Reverse transcription (RT)-polymerase chain reaction and intensity of the bands has shown induction in their expression after exposure to the toxicant. In spite of the expression of genes, it was noticed that DM caused abnormalities. It can be said from the results that translational pathway could have been affected. PMID- 30518299 TI - Active Transportation: The Role of Parent Attitude, The Physical Environment, and Social Capital. AB - BACKGROUND: Despite recommendation and confirmed physical activity benefits, participation in active transportation to school (ATS) has continued to decline. This study's purpose was to create and test a model of ATS that is directly explained by the constructs of parent attitude, the physical environment, and social capital controlling for age and gender. METHODS: Participants were parents (N = 248) of children at 6 elementary and 2 middle schools in 1 district in the Southwestern United States. The survey included previously validated behavior, environmental, attitude, and social items (eg, Safe Routes to School Parent Survey/U.S. General Social Survey). Structural equation modeling was used to test the fit of the model and whether parent attitude, the physical environment, and social capital were associated with active transportation. RESULTS: An adjusted measurement model was a good fit for the data. The physical environment (beta = 0.391; P < .01) as well as parent attitude (beta = 0.535; P < .001) were positively associated with ATS. CONCLUSION: This study supports a model of ATS, affirming that parent attitude, the physical environment, and social capital are effective constructs from which to conceptualize associations with walking and biking to school. PMID- 30518300 TI - The Disease Phenotype of Adenomyosis-Affected Women Correlates With Specific Serum Cytokine Profiles. AB - BACKGROUND:: Adenomyosis (ADE) is an enigmatic uterine disorder. Several types have been previously described: diffuse adenomyosis (DIF-ADE), focal adenomyosis (FOC-ADE), and association of focal and diffuse lesions (FOC/DIF-ADE). Abnormal immune phenomena have been described that may provide an understanding of the pathophysiology of adenomyosis. However, the immune imbalance in adenomyosis is however still poorly understood. OBJECTIVE:: To compare serum cytokine profiles for the various adenomyosis phenotypes in adenomyosis versus disease-free women. MATERIALS AND METHODS:: This cohort study included 80 women. Based on the magnetic resonance imaging (MRI) findings, the women were allocated to the ADE group (n = 60) and the control group (n = 20). The ADE group was further subdivided according to the phenotype: DIF-ADE, FOC-ADE, and FOC/DIF-ADE. For all of the women, serum cytokine levels were assayed by multiplex immunoassay. RESULTS:: Serum levels of interleukin (IL) 23 (237.77 pg/mL +/- 70.97 in the ADE group versus 1855.04 +/- 1411.33 in the control group, P = .019), IL25 (31.98 +/- 8.54 vs 222.08 +/- 170.90, respectively, P = .006), IL31 (10.13 +/- 3.83 vs 91.51 +/- 71.21, respectively, P = .034), IL33 (3.77 +/- 1.23 vs 17.86 +/- 11.49, respectively, P = .016), and IL17F (16.29 +/- 2.35 vs 30.12 +/- 8.29, respectively, P = .042) were significantly lower in the women with adenomyosis when compared to the controls In the FOC/DIF-ADE group, the serum levels of IL23, IL31, IL25, and IL33 were significantly lower when compared to the control group. CONCLUSION:: Serum levels of IL23, IL31, IL25, and IL33 were lower in women exhibiting adenomyosis forms with associated diffuse and focal lesions when compared with controls. The pathogenesis of adenomyosis may be associated with an immunotolerant process that is more pronounced in associated FOC/DIF-ADE. PMID- 30518301 TI - CYP2C9*61, a rare missense variant identified in a Puerto Rican patient with low warfarin dose requirements. AB - Warfarin continues to be the mainstay therapy for preventing thrombus formation. Although pharmacogenetic algorithms have shown higher predictability of the optimal warfarin dose and lower occurrence of bleeding episodes, they often do not include ethno-specific genetic variants relevant to non-Europeans. This case report describes a rare missense variant at exon 9 of CYP2C9 (rs202201137; c.1370A>G transition; p.Asn457Ser) found in a Puerto Rican patient with low warfarin dose requirements (3 mg/day). The haplotype characterized by two amino acid changes, Asn457Ser and Arg144Cys (rs1799853; c.430C>T), has been designated CYP2C9*61 by the Pharmacogene Variation Consortium. According to prediction scores assessed with the Combined Annotation Dependent Depletion tool, CYP2C9*61 (p.Asn457Ser) was classified as nondeleterious, therefore its impact on CYP2C9 enzymatic activity cannot be postulated. PMID- 30518302 TI - Sumter County on the Move! Evaluation of a Walking Group Intervention to Promote Physical Activity Within Existing Social Networks. AB - BACKGROUND: Social network-driven approaches have promise for promoting physical activity in community settings. Yet, there have been few direct investigations of such interventions. This study tested the effectiveness of a social network driven, group-based walking intervention in a medically underserved community. METHODS: This study used a quasi-experimental pretest-posttest design with 3 measurement time points to examine the effectiveness of Sumter County on the Move! in communities in Sumter County, SC. A total of 293 individuals participated in 59 walking groups formed from existing social networks. Participants were 86% females, 67% black, and 31% white, with a mean age of 49.5 years. Measures included perceptions of the walking groups; psychosocial factors such as self-regulation, self-efficacy, and social support; and both self reported and objectively measured physical activity. RESULTS: The intervention produced significant increases in goal setting and social support for physical activity from multiple sources, and these intervention effects were sustained through the final measurement point 6 months after completion of the intervention. Nonetheless, few of the desired changes in physical activity were observed. CONCLUSION: Our mixed results underscore the importance of future research to better understand the dose and duration of intervention implementation required to effect and sustain behavior change. PMID- 30518303 TI - Comparative Effects of Estrogen and Phytoestrogen, Genistein on Testicular Activities of Streptozotocin-Induced Type 2 Diabetic Mice. AB - The aim of this study was to compare the effect of synthetic estrogen (E2) with a phytoestrogen and genistein in ameliorating type 2 diabetes mellitus (T2D) mediated testicular dysfunction in mice. The streptozotocin (STZ)-induced type 2 diabetic mice were treated exogenously with either E2 or genistein for 2 durations and compared their effects on testicular activities, serum glucose, and insulin level. Type 2 diabetic mice treated with E2 for only short term (14 days) improved regressive changes in the testicular histology by increasing testosterone synthesis and improving insulin sensitivity, whereas those treated for longer duration (28 days) failed to improve testicular dysfunctions. On the other hand, genistein treated for both short- and long term was useful in improving T2D-induced adverse effects on testicular functions. This study further suggests that treatment with genistein improves spermatogenesis in type 2 diabetic mice by increasing insulin-induced formation of lactate and antioxidative enzymes, which contributes to prevent germ cell apoptosis. Thus, genistein can be used to ameliorate T2D-induced testicular dysfunction. PMID- 30518304 TI - Distraction by deviant sounds during reading: An eye-movement study. PMID- 30518305 TI - Author accepted manuscript: What is the Role of Episodic Foresight in Planning for Future needs? Theory and two experiments. PMID- 30518306 TI - Evaluation of anti-infectives prescriptions in a pediatric hemato-oncological center: A retrospective study. AB - INTRODUCTION: A few years after the discovery and development of anti-infectives, this therapeutic feat gave way to bacterial resistance because of the overconsumption of antibiotics, most often with unjustified prescriptions. The objective was to evaluate the compliance of the prescription of antibiotherapy in the pediatric onco-hematology unit of Rabat Children's Hospital and to determine the drug interactions. MATERIAL AND METHODS: This is a retrospective study of anti-infectives prescriptions in pediatric onco-hematology. All prescriptions containing an antibiotic or antimycotic were isolated at the end of each month for analysis according to the ANSM standard. The variables of compliance analyzed in the prescriptions were: form, indication, posology, duration of the treatment, drug interactions and number of antibiotics which were prescribed. RESULTS: The prescriptions containing at least one anti-infective were 195. All the prescriptions were in conformity with their indications; 111 (57%) of the cases were conform with respect to all criteria; 20 (12%) prescriptions were not conform in their form, 12 (6.6%) contained at least one over-dosed drug and 52 (26.7%) contained at least one under-dosed drug. A drug interaction was found in 15 (7.7%) of cases, of which 12 (6.2%) are precautions for use. A drug interaction is present in 1(6,7%) cases when a single antibiotic is prescribed against 3 (20%) cases when 4 antibiotics are prescribed. ( p = 0.007). CONCLUSION: The number of non-compliances in our study was high. It would therefore be advisable to recommend the establishment of an information system to minimize the non-compliances and to ensure a training program for young doctors on international recommendations. PMID- 30518307 TI - FLAG/FLAG-IDA regimen for children with relapsed/refractory acute leukemia in the era of targeted novel therapies. AB - BACKGROUND: Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG +/- IDA) as salvage therapy compared with recent published results of novel therapies. METHODS: This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG +/- IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. RESULT: Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG +/- IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG +/- IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% +/- 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001). CONCLUSION: Despite a 68% complete remission rate using FLAG +/- IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens. PMID- 30518308 TI - Comparative study of the circumferential and volumetric analysis between conventional casting and three-dimensional scanning methods for transtibial socket: A preliminary study. AB - Transtibial prosthetic sockets can be fabricated either by the conventional way, which involve using plaster of Paris bandages for casting. This will include modifications through hand, scanning and digital imaging of software. The aim of this study is to determine the circumferential profiles and conduct a volumetric analysis of a conventional socket that has fabrication using biosculptor technology. In doing this, a male transtibial amputee, age 28 years old with stable health condition was studied, where circumferential measurements were taken at intervals of 1 cm from the distal end of the residual limb to the medial tibial plateau level. Furthermore, the interior volume of both sockets and residuum were determined directly using water displacement method. A comparative value for the calculation of volume was also carried out using engineering mathematical equations. From these measurements, a total surface bearing transtibial sockets was fabricated to compare the changes of circumferential values of both sockets. The finding shows a percentage of the difference between the volume of the residual limb and conventional sockets to be 6.09%, whereas the biosculptor fabrication socket was 7.84% using the water displacement method. A comparison of circumferential profiles and volumetric analysis findings on the contrary showed that socket fabricated using the biosculptor technology is interchangeable with the conventional socket with more advantages, where biosculptor technology produces cheaper sockets and faster process with digital function in the procedure, unlike the conventional manual technique. PMID- 30518309 TI - Reconstruction of calvarial bone defects using poly(amino acid)/hydroxyapatite/calcium sulfate composite. AB - The aim of this study was to evaluate the thermal properties and in vivo interface performance of poly(amino acid) (PAA) and a composite containing PAA, hydroxyapatite (HA), and calcium sulfate (CS), with respect to their suitability for skull repair. Biocompatibility was evaluated by implantation of materials into muscles of rabbits for eight weeks. Skull repair was assessed by implanting PAA, the compact PAA/HA/CS composite (c-PAA/HA/CS), and a one-side-porous PAA/HA/CS composite (p-PAA/HA/CS) into rabbit calvarial defects. The results showed that the PAA/HA/CS composite possessed good heat resistance and possessed excellent biocompatibility and osteoconductivity. Guided bone regeneration and calvarial repair were observed, with excellent integration between calvarial tissue and implant. The p-PAA/HA/CS composite performed best in terms of stability and bone bonding between implant and host bone tissue. Thus, the present work provides new information for the potential use of osteoconductive PAA/HA/CS composites with a macrostructure in calvarial bone repair. PMID- 30518310 TI - Burnout and Quality of Work Life Among Nurse Practitioners in Ventricular Assist Device Programs in the United States. AB - BACKGROUND:: A mixed-method study of role stress and work intensity among nurse practitioners (NPs) in mechanical circulatory support (MCS) programs in the United States reported a qualitative data related to burnout. We empirically investigated this phenomenon by pursuing the following specific aims: (1) describe levels of personal burnout (PB), work-related (WB) burnout, and client related burnout (CB) and quality of work life (QOWL) among MCS-NPs; (2) determine the relationship between burnout and QOWL variables; and (3) identify which type of burnout is a predictor of QOWL. METHODS:: We employed an exploratory correlational research design. Demographics, work characteristics, and psychometrically robust measures of burnout and QOWL were completed by 47 MCS-NPs from various regions of the United States. Data were analyzed with descriptive and inferential statistics. RESULTS:: Higher levels of burnout (PB, WB, and CB) were associated with lower levels of QOWL ( r = -.52 to -.64, P < .001). Of the 3 types of burnout, WB burnout showed a significant predictor of QOWL ( R2 = .44, P < .01). Multiple regression models showed that a 1 point increase in mean score of WB would decrease a mean QOWL score by 0.64 after controlling the effect of PB and CB. Some dimensions of QOWL were associated with work/hospital characteristics ( r > -.30, P values <.05). CONCLUSION:: Work-related burnout is negatively associated with low QOWL among NPs. Hospital/work environment was contributing factors to high burnout and low QOWL. Further research is needed to confirm the findings including the effect of burnout and QOWL on patient and ventricular assist device program outcomes. PMID- 30518311 TI - Comparing protein structures and inferring functions with a novel three dimensional Yau-Hausdorff method. AB - Structures and functions of proteins play various essential roles in biological processes. The functions of newly discovered proteins can be predicted by comparing their structures with that of known-functional proteins. Many approaches have been proposed for measuring the protein structure similarity, such as the template-modeling (TM)-score method, GRaphlet (GR)-Align method as well as the commonly used root-mean-square deviation (RMSD) measures. However, the alignment comparisons between the similarity of protein structure cost much time on large dataset, and the accuracy still have room to improve. In this study, we introduce a new three-dimensional (3D) Yau-Hausdorff distance between any two 3D objects. The (3D) Yau-Hausdorff distance can be used in particular to measure the similarity/dissimilarity of two proteins of any size and does not need aligning and superimposing two structures. We apply structural similarity to study function similarity and perform phylogenetic analysis on several datasets. The results show that (3D) Yau-Hausdorff distance could serve as a more precise and effective method to discover biological relationships between proteins than other methods on structure comparison. Communicated by Ramaswamy H. Sarma. PMID- 30518312 TI - Preparation of low shrinkage stress Bis-GMA free dental resin composites with a synthesized urethane dimethacrylate monomer. AB - A new urethane dimethacrylate TMA was synthesized through a typical urethane reaction. TMA was used to replace 1,6-bis(methacryloxy-2-ethoxycarbonyl- amino) 2,4,4- trimethylhexane (UDMA) in UDMA based composite partially or totally to prepare TMA containing composites. Critical properties of TMA containing composites were investigated. 2,2-bis[4(2-hydroxy-3-methacryloy- propyloy)phenyl]propane (Bis-GMA) based and UDMA based composites were used as references. FT-IR and 1H-NMR confirmed the structure of TMA. All of experimental dental resin composites had the similar double bond conversion (p > 0.05). With a certain amount of TMA, TMA containing composites could have lower volumetric shrinkage (p < 0.05) and shrinkage stress (p < 0.05) than control groups. Water sorption, solubility, flexural strength and modulus of TMA containing composites were not worse than those of control groups. All of TMA containing composites and UDMA based composite had the same fracture toughness (p > 0.05), which was higher than that of Bis-GMA based composite (p < 0.05). TMA has potential as Bis-GMA substitute to prepare Bis-GMA free dental resin composites with low shrinkage stress. PMID- 30518313 TI - An Oculus Rift Assessment of Dynamic Balance by Head Mobility in a Virtual Park Scene: A Pilot Study. AB - Postural sway does not differentiate between balance disorders. Head kinematics within a salient, immersive environment could potentially help identifying movement patterns that are unique to vestibular dysfunction. We describe a virtual park scene, where participants are asked to avoid a virtual ball approaching their head, to target dynamic balance and quantify head movement strategy. Sixteen patients with vestibular dysfunction and 16 healthy controls were wearing the Oculus Rift and performed the "park" scene on floor and stability trainers. Significant between-group differences emerged in head path (patients rotated their head sideways more), head acceleration (controls had higher acceleration, especially on translation movements), and peak frequency (controls peaked around the frequency of the ball whereas patients were variable). Those findings demonstrated good to excellent test-retest reliability. There were no significant between-group differences in postural sway parameters. Future studies should establish norms across different levels of balance dysfunction and investigate the underlying mechanism leading to the movement strategy observed. PMID- 30518314 TI - Intensive Care Clinicians' Views on the Role of Chaplains. AB - There is evidence that addressing the religious and spiritual needs of patients has positive effects on patient satisfaction and health care utilization. However, in the intensive care unit (ICU), chaplains are often consulted only at the very end of life, thereby leaving patients' spiritual needs unmet. This study looked at the views of 219 ICU clinicians on the role of chaplains. We found that all clinicians find chaplains helpful when a patient is dying or when the chaplain brings up religious or spiritual topics. Physicians find chaplains less helpful in other clinical scenarios such as challenging family meetings or when patients are recovering. Nurses are more likely to consult chaplains for a difficult family meeting or when patients are recovering from critical illness. Communication between clinicians and chaplains, both directly and indirectly through electronic health record notes, remains infrequent, highlighting the need for interventions aimed at improving multidisciplinary spiritual care. PMID- 30518315 TI - Diagnostic and prognostic value of the optic nerve sheath diameter with respect to the intracranial pressure and neurological outcome of patients following hemicraniectomy. AB - BACKGROUND: In cases showing cerebrospinal fluid (CSF) redistribution as a compensatory mechanism in acute intracranial hypertension, the optic nerve sheath diameter (ONSD) can be used to estimate intracranial pressure (ICP). However, it remains unclear whether the ONSD can be applied in patients with skull defects after a craniectomy, because the primary injury or surgical craniectomy may alter the dynamics of the CSF circulation or structure of the optical nerve sheath. This study explored the value of the ONSD in patients after a hemicraniectomy. METHODS: This prospective observational study enrolled patients after a hemicraniectomy. All patients underwent invasive ICP monitoring and ocular ultrasound within 6 h postoperatively. We followed the patients for 6 months and evaluated them using the Glasgow Outcome Score (GOS), classifying the outcome as favorable (GOS 4-5) or unfavorable (GOS 1-3). We evaluated the ONSD in both according to the ICP and neurological outcome. RESULTS: Of the 33 enrolled patients, 20 (60.6%) had an unfavorable outcome at 6 months. Disagreement was seen in the ONSD measurements between the eyes [craniectomy side (ONSDips) and opposite side (ONSDcon)]. The intraclass correlation coefficient between ONSDips and ONSDcon was 0.745 (p < 0.001). ONSD had no significant correlation with ICP in Spearman correlation analysis (ONSDips r = 0.205, p = 0.252; ONSDcon r = 0.164, p = 0.362). Receiver operator characteristic (ROC) curve analysis revealed that the GCS, Helsinki computed tomography (CT) score, pupil reaction, and ONSDcon measured after the craniectomy were significantly associated with a poor outcome. ONSDcon > 5.5 mm predicted a poor outcome, with an area under the ROC curve of 0.717 (95% confidence interval, 0.534-0.860, p = 0.02), 70% sensitivity, and 69.2% specificity. CONCLUSIONS: After hemicraniectomy, the ONSD measured on ultrasound was unreliable for evaluating ICP, but showed potential prognostic value for a poor neurological outcome. PMID- 30518316 TI - Wheat TaMs1 is a glycosylphosphatidylinositol-anchored lipid transfer protein necessary for pollen development. AB - BACKGROUND: In flowering plants, lipid biosynthesis and transport within anthers is essential for male reproductive success. TaMs1, a dominant wheat fertility gene located on chromosome 4BS, has been previously fine mapped and identified to encode a glycosylphosphatidylinositol (GPI)-anchored non-specific lipid transfer protein (nsLTP). Although this gene is critical for pollen exine development, details of its function remains poorly understood. RESULTS: In this study, we report that TaMs1 is only expressed from the B sub-genome, with highest transcript abundance detected in anthers containing microspores undergoing pre meiosis through to meiosis. beta-glucuronidase transcriptional fusions further revealed that TaMs1 is expressed throughout all anther cell-types. TaMs1 was identified to be expressed at an earlier stage of anther development relative to genes reported to be necessary for sporopollenin precursor biosynthesis. In anthers missing a functional TaMs1 (ms1c deletion mutant), these same genes were not observed to be mis-regulated, indicating an independent function for TaMs1 in pollen development. Exogenous hormone treatments on GUS reporter lines suggest that TaMs1 expression is increased by both indole-3-acetic acid (IAA) and abscisic acid (ABA). Translational fusion constructs showed that TaMs1 is targeted to the plasma membrane. CONCLUSIONS: In summary, TaMs1 is a wheat fertility gene, expressed early in anther development and encodes a GPI-LTP targeted to the plasma membrane. The work presented provides a new insight into the process of wheat pollen development. PMID- 30518317 TI - USA300 Staphylococcus aureus persists on multiple body sites following an infection. AB - BACKGROUND: USA300 methicillin-resistant Staphylococcus aureus (MRSA) is a community- and hospital-acquired pathogen that frequently causes infections but also can survive on the human body asymptomatically as a part of the normal microbiota. We devised a comparative genomic strategy to track colonizing USA300 at different body sites after an initial infection. We sampled ST8 S. aureus from subjects at the site of a first known MRSA infection. Within 60 days of this infection and again 12 months later, each subject was tested for asymptomatic colonization in the nose, throat and perirectal region. 93 S. aureus strains underwent whole genome shotgun sequencing. RESULTS: Among 28 subjects at the initial sampling time, we isolated S. aureus from the nose, throat and perirectal sites from 15, 11 and 15 of them, respectively. Twelve months later we isolated S. aureus from 9 subjects, with 6, 3 and 3 strains from the nose, throat and perirectal area, respectively. Genome sequencing revealed that 23 patients (ages 0-66 years) carried USA300 intra-subject lineages (ISLs), defined as having an index infection isolate and closely related colonizing strains. Pairwise distance between strains in different ISLs was 48 to 162 single nucleotide polymorphisms (SNPs) across the core regions of the chromosome, whereas within the same ISL it was 0 to 26 SNPs. Strains in ISLs from the same subject differed in plasmid and prophage content, and contained deletions that removed the mecA-containing SCCmec and ACME regions. Five strains contained frameshift mutations in agr toxin regulating genes. Persistence of an ISL was not associated with clinical or demographic subject characteristics. We inferred that colonization with the ISL occurred about 18 weeks before the first assessment of asymptomatic colonization. CONCLUSIONS: Clonal lineages of USA300 may continue to colonize people at one or more anatomic sites up to a year after an initial infection and experience loss of the SCCmec, loss and gain of other mobile genetic elements, and mutations in the agr operon. PMID- 30518318 TI - Differentiation of haploid and diploid fertilities in Gracilaria chilensis affect ploidy ratio. AB - BACKGROUND: Algal isomorphic biphasic life cycles alternate between free-living diploid (tetrasporophytes) and haploid (dioicious gametophytes) phases and the hypotheses explaining their maintenance are still debated. Classic models state that conditional differentiation between phases is required for the evolutionary stability of biphasic life cycles while other authors proposed that the uneven ploidy abundances observed in the field are explained by their cytological differences in spore production. RESULTS: We monitored the state and fate of individuals of the red seaweed Gracilaria chilensis periodically for 3 years in five intertidal pools from two sites with distinct conditions. We tested for differentiation in fecundity and spore survival among the gametophyte males and females (haploids) and the tetrasporophytes (diploids). We tested for the influence of fecundity and spore survival on the observed uneven ploidy abundances in recruits. The probability of a frond becoming fecund was size dependent, highest for the haploid males and lowest for the haploid females, with the diploids displaying intermediate probabilities. Fecund diploids released more tetraspores than carpospores released by the haploid females. Spore survival depended on ploidy and on the local density of co-habiting adult fronds. An advantage of diploid over haploid germlings was observed at very low and very high adult fronds densities. CONCLUSIONS: Neither spore production nor spore survival determined the highly variable ploidy ratio within G. chilensis recruits. This result invalidates the hypothesis of natural cytological differences in spore production as the only driver of uneven field ploidy abundances in this species. Diploid spores (carpospores) survived better than haploid spores (tetraspores), especially in locations and time periods that were associated with the occurrence of strong biotic and abiotic stressors. We hypothesise that carpospore survival is higher due to support by their haploid female progenitors passing-on nutrients and chemical compounds improving survival under stressful conditions. PMID- 30518319 TI - A statistical measure for the skewness of X chromosome inactivation based on family trios. AB - BACKGROUND: X chromosome inactivation (XCI) is an important gene regulation mechanism in females to equalize the expression levels of X chromosome between two sexes. Generally, one of two X chromosomes in females is randomly chosen to be inactivated. Nonrandom XCI (XCI skewing) is also observed in females, which has been reported to play an important role in many X-linked diseases. However, there is no statistical measure available for the degree of the XCI skewing based on family data in population genetics. RESULTS: In this article, we propose a statistical approach to measure the degree of the XCI skewing based on family trios, which is represented by a ratio of two genotypic relative risks in females. The point estimate of the ratio is obtained from the maximum likelihood estimates of two genotypic relative risks. When parental genotypes are missing in some family trios, the expectation-conditional-maximization algorithm is adopted to obtain the corresponding maximum likelihood estimates. Further, the confidence interval of the ratio is derived based on the likelihood ratio test. Simulation results show that the likelihood-based confidence interval has an accurate coverage probability under the situations considered. Also, we apply our proposed method to the rheumatoid arthritis data from USA for its practical use, and find out that a locus, rs2238907, may undergo the XCI skewing against the at-risk allele. But this needs to be further confirmed by molecular genetics. CONCLUSIONS: The proposed statistical measure for the skewness of XCI is applicable to complete family trio data or family trio data with some paternal genotypes missing. The likelihood-based confidence interval has an accurate coverage probability under the situations considered. Therefore, our proposed statistical measure is generally recommended in practice for discovering the potential loci which undergo the XCI skewing. PMID- 30518320 TI - Simultaneously maximizing root/mycorrhizal growth and phosphorus uptake by cotton plants by optimizing water and phosphorus management. AB - BACKGROUND: There are two plant phosphorus (P)-uptake pathways, namely the direct P uptake by roots and the indirect P uptake through arbuscular mycorrhizal fungi (AMF). Maximizing the efficiency of root and AMF processes associated with P acquisition by adjusting soil conditions is important for simultaneously ensuring high yields and the efficient use of available P. RESULTS: A root box experiment was conducted in 2015 and 2016. The aim was to investigate the effects of different P and soil water conditions on root/mycorrhizal growth and P uptake by cotton plants. Hyphal growth was induced in well-watered soil, but decreased with increasing P concentrations. Additionally, P fertilizers regulated root length only under well-watered conditions, with the longest roots observed in response to 0.2 g P2O5 kg- 1. In contrast, root elongation was essentially unaffected by P fertilizers under drought conditions. And soil water in general had more significant effects on root and hyphal growth than phosphorus levels. In well watered soil, the application of P significantly increased the cotton plant P uptake, but there were no differences between the effects of 0.2 and 1 g P2O5 kg- 1. So optimizing phosphorus inputs and soil water can increase cotton growth and phosphorus uptake by maximizing the efficiency of phosphorus acquisition by roots/mycorrhizae. CONCLUSIONS: Soil water and P contents of 19-24% and 20-25 mg kg- 1, respectively, simultaneously maximized root/mycorrhizal growth and P uptake by cotton plants. PMID- 30518321 TI - Development and use of an index for measuring implementation of a weight management program in children in primary care clinics in Texas. AB - BACKGROUND: The Texas Childhood Obesity Research Demonstration study was an integrated, systems-oriented intervention that incorporated primary and secondary obesity prevention approaches targeting multiple sectors, including primary care clinics, to address childhood obesity. The primary care clinic component included the American Academy of Pediatrics' Next Steps weight management counseling materials that support brief healthy lifestyle-focused visits. The current study describes the methodology and assesses the implementation of the Next Steps program in the participating primary care clinics, as well as the association of implementation with enrollment of children with overweight and obesity in the secondary prevention intervention. METHODS: The study used a serial cross sectional study design to collect data from 11 primary care clinics in Houston (n = 5) and Austin (n = 6), Texas, in 2013-2014. Responses of primary care providers on 42 self-reported survey questions assessing acceptability, adoption, appropriateness, and feasibility of the program were utilized to create a mean standardized clinic implementation index score. Provider scores were aggregated to represent Next Steps implementation scores at the clinic level. A mixed effects logistic regression test was conducted to determine the association between program implementation and the enrollment of children in the secondary prevention. RESULTS: Mean implementation index score was lower at Year 2 of implementation (2014) than Year 1 (2013) although the decrease was not significant [63.2% (12.2%) in 2013 vs. 55.3% (16.5%) in 2014]. There were no significant associations between levels of implementation of Next Steps and enrollment into TX CORD secondary prevention study. CONCLUSIONS: The development of an index using process evaluation measures can be used to assess the implementation and evaluation of provider-based obesity prevention tools in primary care clinics. PMID- 30518322 TI - Downstream components of the calmodulin signaling pathway in the rice salt stress response revealed by transcriptome profiling and target identification. AB - BACKGROUND: Calmodulin (CaM) is an important calcium sensor protein that transduces Ca2+ signals in plant stress signaling pathways. A previous study has revealed that transgenic rice over-expressing the calmodulin gene OsCam1-1 (LOC_Os03g20370) is more tolerant to salt stress than wild type. To elucidate the role of OsCam1-1 in the salt stress response mechanism, downstream components of the OsCam1-1-mediated response were identified and investigated by transcriptome profiling and target identification. RESULTS: Transcriptome profiling of transgenic 'Khao Dawk Mali 105' rice over-expressing OsCam1-1 and wild type rice showed that overexpression of OsCam1-1 widely affected the expression of genes involved in several cellular processes under salt stress, including signaling, hormone-mediated regulation, transcription, lipid metabolism, carbohydrate metabolism, secondary metabolism, photosynthesis, glycolysis, tricarboxylic acid (TCA) cycle and glyoxylate cycle. Under salt stress, the photosynthesis rate in the transgenic rice was slightly lower than in wild type, while sucrose and starch contents were higher, suggesting that energy and carbon metabolism were affected by OsCam1-1 overexpression. Additionally, four known and six novel CaM interacting proteins were identified by cDNA expression library screening with the recombinant OsCaM1. GO terms enriched in their associated proteins that matched those of the differentially expressed genes affected by OsCam1-1 overexpression revealed various downstream cellular processes that could potentially be regulated by OsCaM1 through their actions. CONCLUSIONS: The diverse cellular processes affected by OsCam1-1 overexpression and possessed by the identified CaM1-interacting proteins corroborate the notion that CaM signal transduction pathways compose a complex network of downstream components involved in several cellular processes. These findings suggest that under salt stress, CaM activity elevates metabolic enzymes involved in central energy pathways, which promote or at least maintain the production of energy under the limitation of photosynthesis. PMID- 30518323 TI - Molecular characterization of Mannheimia haemolytica isolates associated with pneumonic cases of sheep in selected areas of Central Ethiopia. AB - BACKGROUND: Mannheimia haemolytica has been recognized as the principal cause of pneumonic pasteurellosis in sheep and goats. It is one of the important diseases of small ruminants in Ethiopia. While annual vaccination using a monovalent vaccine (inactivated Pasteurella multocida biotype A) is common, respiratory diseases are still reported in various parts of Ethiopia. This suggests the need for further investigation into the species and strains responsible for the disease, which is vital information for development of a multivalent vaccine. The objective of the current study was to isolate M. heamolytica associated with pneumonic cases of sheep in selected areas of Central Ethiopia, determine its role and the strains/genotypes of the bacterium circulating in the study area. RESULTS: Bacteriological analysis of nasal swab samples collected from a total of 76 pneumonic cases of sheep showed that M. haemolytica was isolated from 26 of them while B.trehalosi from two cases. Further molecular analyses of the isolates using M. haemolytica species-specific and M.haemolytica serotype-1 antigen specific PCR assays revealed, 26 of the isolates were identified as M. haemolytica of which 21 of them were M. haemolytica serotype-1. Both M. haemolytica and B.trehalosi isolates were not detected in a PCR assay targeting capsular biosynthesis gene (capA) of P.multocida despite the non-specific products observed in M. haemolytica isolates. Phylogenetic analysis of M. haemolytica isolates included in this study in comparison with the reference strains with respect to PHSSA and Rpt2 genes revealed that the Ethiopian M. haemolytica isolates constituted three distinct genotypes consistent with site of origin. CONCLUSION: The study indicated that M.haemolytica is commonly associated with cases of pneumonia in sheep in the study areas of central Ethiopia although the remaining other pathogens responsible for majority of the cases are yet to be determined. Molecular characterization revealed the existence of three genotypes of M. haemolytica circulating in the study areas consistent to the site of isolation. The findings suggest further extensive work to determine all pathogens associated with sheep pneumonia and the strain distribution of M. heamolytica to understand its molecular epidemiology at national level and design cost effective prevention and control methods. PMID- 30518324 TI - Application of the CRISPR/Cas9 system for modification of flower color in Torenia fournieri. AB - BACKGROUND: CRISPR/Cas9 technology is one of the most powerful and useful tools for genome editing in various living organisms. In higher plants, the system has been widely exploited not only for basic research, such as gene functional analysis, but also for applied research such as crop breeding. Although the CRISPR/Cas9 system has been used to induce mutations in genes involved in various plant developmental processes, few studies have been performed to modify the color of ornamental flowers. We therefore attempted to use this system to modify flower color in the model plant torenia (Torenia fournieri L.). RESULTS: We attempted to induce mutations in the torenia flavanone 3-hydroxylase (F3H) gene, which encodes a key enzyme involved in flavonoid biosynthesis. Application of the CRISPR/Cas9 system successfully generated pale blue (almost white) flowers at a high frequency (ca. 80% of regenerated lines) in transgenic torenia T0 plants. Sequence analysis of PCR amplicons by Sanger and next-generation sequencing revealed the occurrence of mutations such as base substitutions and insertions/deletions in the F3H target sequence, thus indicating that the obtained phenotype was induced by the targeted mutagenesis of the endogenous F3H gene. CONCLUSIONS: These results clearly demonstrate that flower color modification by genome editing with the CRISPR/Cas9 system is easily and efficiently achievable. Our findings further indicate that this system may be useful for future research on flower pigmentation and/or functional analyses of additional genes in torenia. PMID- 30518326 TI - Alpha shapes: determining 3D shape complexity across morphologically diverse structures. AB - BACKGROUND: Following recent advances in bioimaging, high-resolution 3D models of biological structures are now generated rapidly and at low-cost. To use this data to address evolutionary and ecological questions, an array of tools has been developed to conduct shape analysis and quantify topographic complexity. Here we focus particularly on shape techniques applied to irregular-shaped objects lacking clear homologous landmarks, and propose a new 'alpha-shapes' method for quantifying 3D shape complexity. METHODS: We apply alpha-shapes to quantify shape complexity in the mammalian baculum as an example of a morphologically disparate structure. Micro- computed-tomography (MUCT) scans of bacula were conducted. Bacula were binarised and converted into point clouds. Following application of a scaling factor to account for absolute size differences, a suite of alpha-shapes was fitted per specimen. An alpha shape is formed from a subcomplex of the Delaunay triangulation of a given set of points, and ranges in refinement from a very coarse mesh (approximating convex hulls) to a very fine fit. 'Optimal' alpha was defined as the refinement necessary in order for alpha-shape volume to equal CT voxel volume, and was taken as a metric of overall 'complexity'. RESULTS: Our results show that alpha-shapes can be used to quantify interspecific variation in shape 'complexity' within biological structures of disparate geometry. The 'stepped' nature of alpha curves is informative with regards to the contribution of specific morphological features to overall 'complexity'. Alpha-shapes agrees with other measures of complexity (dissection index, Dirichlet normal energy) in identifying ursid bacula as having low shape complexity. However, alpha-shapes estimates mustelid bacula as being most complex, contrasting with other shape metrics. 3D fractal dimension is identified as an inappropriate metric of complexity when applied to bacula. CONCLUSIONS: Alpha-shapes is used to calculate 'optimal' alpha refinement as a proxy for shape 'complexity' without identifying landmarks. The implementation of alpha-shapes is straightforward, and is automated to process large datasets quickly. We interpret alpha-shapes as being particularly sensitive to concavities in surface topology, potentially distinguishing it from other shape complexity metrics. Beyond genital shape, the alpha-shapes technique holds considerable promise for new applications across evolutionary, ecological and palaeoecological disciplines. PMID- 30518325 TI - Multiple environmental stressors induce complex transcriptomic responses indicative of phenotypic outcomes in Western fence lizard. AB - BACKGROUND: The health and resilience of species in natural environments is increasingly challenged by complex anthropogenic stressor combinations including climate change, habitat encroachment, and chemical contamination. To better understand impacts of these stressors we examined the individual- and combined stressor impacts of malaria infection, food limitation, and 2,4,6-trinitrotoluene (TNT) exposures on gene expression in livers of Western fence lizards (WFL, Sceloporus occidentalis) using custom WFL transcriptome-based microarrays. RESULTS: Computational analysis including annotation enrichment and correlation analysis identified putative functional mechanisms linking transcript expression and toxicological phenotypes. TNT exposure increased transcript expression for genes involved in erythropoiesis, potentially in response to TNT-induced anemia and/or methemoglobinemia and caused dose-specific effects on genes involved in lipid and overall energy metabolism consistent with a hormesis response of growth stimulation at low doses and adverse decreases in lizard growth at high doses. Functional enrichment results were indicative of inhibited potential for lipid mobilization and catabolism in TNT exposures which corresponded with increased inguinal fat weights and was suggestive of a decreased overall energy budget. Malaria infection elicited enriched expression of multiple immune-related functions likely corresponding to increased white blood cell (WBC) counts. Food limitation alone enriched functions related to cellular energy production and decreased expression of immune responses consistent with a decrease in WBC levels. CONCLUSIONS: Despite these findings, the lizards demonstrated immune resilience to malaria infection under food limitation with transcriptional results indicating a fully competent immune response to malaria, even under bio energetic constraints. Interestingly, both TNT and malaria individually increased transcriptional expression of immune-related genes and increased overall WBC concentrations in blood; responses that were retained in the TNT x malaria combined exposure. The results demonstrate complex and sometimes unexpected responses to multiple stressors where the lizards displayed remarkable resiliency to the stressor combinations investigated. PMID- 30518327 TI - The incidentally diagnosed adult congenital heart disease during routine medical health checkups in 27,897 Koreans at a single center over seven years. AB - BACKGROUND: The rate of incidentally diagnosed congenital heart disease (CHD) in adulthood has not been reported. The aim of this study was to investigate the detection rate of CHD in adults by routine, general health checkups. METHODS: Data was acquired from 222,401 patients older than 19 years who participated in general health checkups from January 2010 to December 2016. We excluded persons who did not undergo echocardiography during the general health checkups, who underwent echocardiography prior to the health checkups, and who were previously diagnosed with CHD. RESULTS: Among the 27,897 patients, who were included in the final analysis, 293 cases were newly diagnosed as CHD, and the overall detection rate was 1.05%. The mean age of patients with CHD was 48.7 +/- 21.5 years, and most of them were female (n = 187, 63.8%). More than two-thirds were between the third and fifth decade of life, and only six patients (2.04%) were older than 70 years. The most common type was bicuspid aortic valve (n = 155). Interestingly, Ebstein's anomaly that required surgical repair was detected in five persons. CONCLUSIONS: During general health checkup, there were cases of severe CHD that required cardiac surgery upon diagnosis. PMID- 30518328 TI - Methods for trustworthy nutritional recommendations NutriRECS (Nutritional Recommendations and accessible Evidence summaries Composed of Systematic reviews): a protocol. AB - BACKGROUND: Recent systematic reviews and editorials suggest that many organizations that produce nutritional guideline recommendations do not adhere to internationally recognized standards set forth by the Institute of Medicine (IoM), Guidelines International Network (GIN), Appraisal of Guidelines Research and Evaluation (AGREE), and Grading Recommendations, Assessment, Development and Evaluation (GRADE). METHODS: The potential solution is an independent group with content expertise and skilled in the methodology of systematic reviews and practice guidelines to produce trustworthy guideline recommendations, recommendations that are supported by publication in a top tier journal. The BMJ Rapid Recommendations project has recently demonstrated the feasibility and utility of this approach. Here, we are proposing trustworthy nutritional guideline recommendations based on internationally accepted guideline development standards, recommendations that will be informed by rigorous and novel systematic reviews of the benefits and harms associated with nutritional exposures, as well as studies on the values and preferences related to dietary behaviors among members of the international community. DISCUSSION: Adhering to international guideline standards, conducting high quality systematic reviews, and actively assessing the values and preferences of key stakeholders is expected to improve the quality of nutritional guidelines and their relevance to end-users, particularly patients and community members. We will send our work for peer review, and if found acceptable, we will publish our nutritional recommendations in top-tier general medicine journals. PMID- 30518329 TI - Epidemiological features and spatial clusters of hand, foot, and mouth disease in Qinghai Province, China, 2009-2015. AB - BACKGROUND: Hand, Foot, and Mouth Disease (HFMD) is most frequently caused by Enterovirus71 (EV-A71) or Coxsackie virus A16 (CV-A16), infants and young children are at greatest risk. Describing the epidemiology of HFMD can help develop and better target interventions, including the use of pediatric EV-A71 vaccination. METHODS: We obtained data from the national surveillance system for HFMD cases with onset dates from 2009 to 2015. We defined probable cases as patient with skin papular or vesicular rashes on the hands, feet, mouth, or buttocks and confirmed cases as patients with the above symptoms along with laboratory-based enterovirus detection. We generated overall and age-specific annual incidence rates and described the temporal variability and seasonality of HFMD in Qinghai Province. We identified spatial clustering of HFMD incidence at the county level using the Local Indicator of Spatial Associationand an alpha level of 0.05. RESULTS: During the study period, 14,480 HFMD probable or confirmed cases were reported in Qinghai Province. Of the 2158 (14.9%) with laboratory confirmation, 924 (42.6%) were caused by CV-A16 and 830 (38.2%) were caused by EV-A71. The majority (89%) of all case-patients were <= 5 years of age and male (61.5%). The overall mean annual HFMD incidence rate was 36.4 cases per 100,000 populations, while the incidence rate for children <=5 years of age was 379.5 cases per 100,000. Case reports peaked during the months of May through July. HFMD was predominantly caused by EV-A71, except in 2010 and 2014 when CV A16 was the predominant causative agent. High incidence rates of HFMD were clustered (Moran's I = 0.59, P < 0.05) in the eastern region of the province. CONCLUSION: HFMD remains an important cause of childhood disease in Qinghai Province, occurring in an acyclical pattern of increased incidence, primarily due to CV-A16 circulation every three years. Incidence is also seasonal and tends to spatially cluster in the eastern region of the province. Since approximately 40% of confirmed HFMD cases were due to EV-A71, EV-A71 vaccination is likely to have a positive impact on the HFMD disease burden. Routine analysis of local surveillance data is crucial for describing disease occurrence and changes in etiology. PMID- 30518330 TI - Ultrasonic assessment of liver stiffness and carotid artery elasticity in patients with chronic viral hepatitis. AB - BACKGROUND: This study investigated the relationship between liver stiffness and carotid artery elasticity in patients with chronic viral hepatitis. We used an acoustic radiation force impulse (ARFI) technique to measure stiffness, and a radio frequency (RF) vascular quantitative ultrasound technique to measure changes in common carotid artery elasticity and vascular function. METHODS: Two hundred seventeen patients with chronic viral hepatitis caused by either hepatitis B virus (HBV) or hepatitis C virus (HCV) were enrolled. We divided the patients into two groups, one comprising 147 patients with chronic hepatitis B (CHB) (98 men and 49 women, average age 46.5 +/- 12.2 years) and another comprising 70 patients with chronic hepatitis C (CHC) (47 men and 23 women, average age 47.6 +/- 12.1 years). Additionally, 64 healthy age- and sex-matched participants (43 men and 21 women, average age 47.8 +/- 5.1 years) were selected as the control group. The ARFI technique was used to measure liver stiffness and the RF ultrasound technique was used to measure carotid artery elasticity parameters including intima-media thickness (IMT), pulse wave velocity (PWV), arterial wall dilation coefficient (DC), compliance coefficient (CC), sclerosis indices alpha and beta, and augmentation index (Aix). Clinical indicators, liver stiffness, and carotid artery elasticity parameters were observed and compared between the different age groups to investigate the correlation between carotid artery elasticity parameters and liver stiffness. RESULTS: The ARFI values for the CHB and CHC groups were significantly higher than those for the control group (1.84 +/- 0.52 vs. 1.04 +/- 0.11 m/s; 1.86 +/- 0.37 vs. 1.04 +/- 0.11 m/s, respectively; P < 0.001). When compared to the control group, both CHB and CHC groups showed an IMT of the same order, but had significantly higher elasticity parameters, such as alpha and beta, as well as lower DC and CC values (P < 0.001). The PWV of the CHC group was significantly higher than that of the control group (7.98 +/- 1.42 vs. 6.09 +/- 0.90 m/s, P < 0.001). In the CHB group, all parameters including ARFI, IMT, PWV, DC, CC, alpha and beta, were significantly different between the two age groups (P < 0.05). Within the CHC group, all parameters including IMT, PWV, DC, alpha and beta, were significantly different between the two age groups (P < 0.05), except for ARFI, wherein the difference was not statistically significant. The correlation analysis and stepwise multiple linear regression analysis indicated that for patients with CHB, age was an independent predictor of common carotid artery IMT (R2 = 0.468, F = 54.635, and P < 0.001). For patients with CHC, age and blood sugar were independent predictors of common carotid artery IMT (R2 = 0.465, F = 29.118, and P < 0.001). CONCLUSION: Although based on ARFI and RF ultrasound, the carotid artery IMT in patients with CHB and CHC was not significantly higher than that in the control group, their functional elasticity parameters had already changed. This finding serves as a useful reference for the clinical diagnosis of vascular diseases in patients with viral hepatitis. TRIAL REGISTRATION: ClinicalTrials: ChiCTR1800015859 25/04/2018. PMID- 30518331 TI - Immunogenicity and safety of a tetanus-diphtheria vaccine and a 13-valent pneumococcal conjugate vaccine after concomitant vaccination in >= 50-year-old adults. AB - BACKGROUND: When two or more vaccines are administered concurrently, there is concern about safety and immunogenicity from vaccine interaction. METHODS: Subjects aged >=50 years were randomized 1:1:1 to receive tetanus-diphtheria (Td) + 13-valent pneumococcal conjugate vaccine (PCV13; Group 1), PCV13 alone (Group 2), or Td alone (Group 3). After single or concomitant vaccination, enzyme-linked immunosorbent assay and opsonophagocytic assay (OPA) were performed to compare immunogenicity for Td and PCV13, respectively. RESULTS: A total of 448 subjects were available for the assessment. After concomitant administration, the non inferiority criteria of geometric mean titer (GMT) ratios were met for tetanus, diphtheria, and all four pneumococcal serotypes (1, 5, 18C, and 19A). However, subjects in Group 3 (Td alone) were more likely to have a high IgG anti-tetanus antibody titer (>= 0.5 U/mL) than those in Group 1 (Td + PCV13) (p < 0.01). As for the pneumococcal serotype 1, the OPA GMT was significantly higher in Group 1 (PCV13 + Td) compared to Group 2 (PCV13 alone) (p = 0.02). No serious adverse event occurred. CONCLUSIONS: Concomitant Td and PCV13 administration induced sufficient immunity without significant interference and showed good safety profiles. TRIALS REGISTRATION: NCT03552445 registered at http://www.clinicaltrials.gov on June 11, 2018 (retrospectively registered). PMID- 30518332 TI - Quantity and quality of nucleic acids extracted from archival formalin fixed paraffin embedded prostate biopsies. AB - BACKGROUND: In Sweden, human tissue samples obtained from diagnostic and surgical procedures have for decades been routinely stored in a formalin-fixed, paraffin embedded, form. Through linkage with nationwide registers, these samples are available for molecular studies to identify biomarkers predicting mortality even in slow-progressing prostate cancer. However, tissue fixation causes modifications of nucleic acids, making it challenging to extract high-quality nucleic acids from formalin fixated tissues. METHODS: In this study, the efficiency of five commercial nucleic acid extraction kits was compared on 30 prostate biopsies with normal histology, and the quantity and quality of the products were compared using spectrophotometry and Agilent's BioAnalyzer. Student's t-test's and Bland-Altman analyses were performed in order to investigate differences in nucleic acid quantity and quality between the five kits. The best performing extraction kits were subsequently tested on an additional 84 prostate tumor tissues. A Spearman's correlation test and linear regression analyses were performed in order to investigate the impact of tissue age and amount of tissue on nucleic acid quantity and quality. RESULTS: Nucleic acids extracted with RNeasy(r) FFPE and QIAamp(r) DNA FFPE Tissue kit had the highest quantity and quality, and was used for extraction from 84 tumor tissues. Nucleic acids were successfully extracted from all biopsies, and the amount of tumor (in millimeter) was found to have the strongest association with quantity and quality of nucleic acids. CONCLUSIONS: To conclude, this study shows that the choice of nucleic acid extraction kit affects the quantity and quality of extracted products. Furthermore, we show that extraction of nucleic acids from archival formalin-fixed prostate biopsies is possible, allowing molecular studies to be performed on this valuable sample collection. PMID- 30518333 TI - Assessment of HIV prevalence among MSM in Tokyo using self-collected dried blood spots delivered through the postal service. AB - BACKGROUND: Men who have sex with men (MSM) are at high risk of HIV infection. However, there are only few data on HIV prevalence in MSM in Japan. The objective of this study was to explore the HIV prevalence in MSM at Shinjuku 2-chome, a well known gay quarter in Tokyo. METHODS: MSM directly collected the dried blood spot (DBS) self-collection HIV test kit from a drop-in center in Shinjuku 2-chome between August 2015 and December 2016. The participants collected their own blood by finger-prick and anonymously posted the kit to the laboratory. The participants accessed the study website and checked the results of their tests using unique ID and password. DBS was soaked in phosphate buffered saline overnight and the eluted sample was examined by the fourth generation HIV Ag/Ab test of LUMIPULSE (FUJIREBIO INC.), and followed by HISCL (Sysmex Corp.) when the first assay was positive. The result was defined provisionally positive if both were positive. RESULTS: A total of 1702 HIV test kits were distributed and 1403 DBS were returned (return rate: 82.4%). Since 20.2% of participants collected the test kit more than once, the estimated number of actual test kit users was 1120. Based on the results of the test kit, 34 cases were provisionally diagnosed with HIV. The estimated prevalence was 3.04% (95% confidence interval: 2.03-4.04). Of these 34, 24 (70.6%) were later confirmed to be HIV-positive in the hospital, while the remaining 10 were lost to follow-up. Among the participants, 34.5% received HIV test for the first time. Especially in those aged 20-29, 46.0% were first time HIV testers. CONCLUSIONS: The prevalence of HIV infection in the study population was 3.04%. The high collection suggested a demand for this type of testing in MSM. The test should be expanded further to difficult-to-reach or hidden populations. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network Clinical Trial Registry in August 20th, 2015 (Registry number: UMIN000018699 ). PMID- 30518334 TI - Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non inferiority trial (FORECAST). AB - BACKGROUND: Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000 mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment. METHODS: The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (>=18 years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3 g every 24 h) or ciprofloxacin (500 mg every 12 h) for a total antibiotic duration of 10 days. The primary endpoint is clinical cure (resolution of symptoms) 6-10 days post treatment. Secondary endpoints are microbiological cure 6-10 days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35 days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of < 0.05 and a power of 80%. DISCUSSION: The study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI. TRIAL REGISTRATION: Registered at the Nederlands trial register (Dutch trial register) on 4-10-2017. TRIAL REGISTRATION NUMBER: NTR6449 . Secondary ID (national authority): NL60186.041.17. PMID- 30518335 TI - Norm values and psychometric properties of the brief symptom inventory-18 regarding individuals between the ages of 60 and 95. AB - OBJECTIVE: The SCL-90 and the SCL-90-R are the most applied measures regarding psychological distress. To reduce and prevent an overload to of the individuals, the Brief Symptom Inventory with 18 items (BSI-18) was developed based on the SCL 90. Since psychological disorders more frequently occur at an older age, there is a growing need for efficient instruments to measure distress in the elderly. However, the BSI-18's psychometric properties, norm values, and factorial structure have not yet been investigated in this age group. METHODS: The aim of this study was to evaluate the BSI-18 in a sample of elderly people and to establish norm values for this specific population. Subsequently, demographic information and BSI-18 results were collected from a sample totaling 884 (55% female, mean age of 70.75 years, SD = 7.08, age range = 60-95 years). The questionnaire contains three six-item scales: somatization (SOMA), anxiety (ANX), and depression (DEPR), which form a general symptom index (GSI). RESULTS: We found an acceptable to good model fit for a three-factor-model with a general GSI factor. The BSI-18's psychometric properties were satisfactory. Strict measurement invariance was shown for age and gender. Additionally, we found differences in psychological distress based on sociodemographic variables. CONCLUSIONS: These findings underline the growing need for preventive mechanisms for elderly people such as, e.g., (re)activating their social networks and strengthening their physical and psychological well-being. PMID- 30518336 TI - Trajectories of early secondary insults correlate to outcomes of traumatic brain injury: results from a large, single centre, observational study. AB - BACKGROUND: Secondary insults (SI), such as hypotension, hypoxia, and intracranial hypertension frequently occur after traumatic brain injury (TBI), and have a strong impact on patients' clinical outcomes. The aim of this study is to examine the trajectories of SI from the early phase of injury in the prehospital setting to hospital admission in a cohort of TBI patients. METHODS: This is a retrospective, observational, single centre study on consecutive patients admitted from 1997 to 2016 to the Neuro Intensive Care Unit (NICU) at San Gerardo Hospital, in Monza, Italy. Trajectories of SI from the prehospital to hospital settings were defined as "sustained", "resolved", "new event", and "none". Univariate and multivariate logistic regression analyses were performed to correlate SI trajectories to a 6-months outcome. RESULTS: Nine hundred sixty seven patients were enrolled in the final analysis. About 20% had hypoxic or hypotensive events and 30.7% of patients had pupillary abnormalities. Hypotension and hypoxia were associated with an unfavourable outcome when "sustained" and "resolved", while pupillary abnormalities were associated with a poor outcome when "sustained" and as "new events". After adjusting for confounding factors, 6 month mortality strongly correlated with "sustained" hypotension (OR 11.25, 95% CI, 3.52-35.99), "sustained" pupillary abnormalities (OR 2.8, 95% CI, 1.51-5.2) and "new event" pupillary abnormalities (OR 2.8, 95% CI, 1.16-6.76). CONCLUSIONS: After TBI, sustained hypotension and pupillary abnormalities are important determinants for patients' outcomes. Early trajectories define the dynamics of SI and contribute to a better understanding of how early recognition and treatments in emergency settings could impact on 6-month outcomes and mortality. PMID- 30518337 TI - A systematic review of the association between delayed appropriate therapy and mortality among patients hospitalized with infections due to Klebsiella pneumoniae or Escherichia coli: how long is too long? AB - BACKGROUND: Temporal relationships between the time to appropriate antibiotic therapy and outcomes are not well described. METHODS: A systematic literature review and meta-analysis was performed to examine this relationship in patients hospitalized with Klebsiella pneumoniae or Escherichia coli infections. RESULTS: Twenty identified studies contained data for patients who received delayed appropriate therapy (DAT) versus appropriate antibiotic therapy for these pathogens. Of the 20 included studies, the majority (19/20) focused on patients with bloodstream infections, and only 1 study evaluated patients with pneumonia. When all DAT results were combined (any delay > 24 h from culture collection or any delay after culture and susceptibility reporting [C& SR]), there was an increased risk of mortality (odds ratio [OR], 1.60 [95% CI, 1.25-2.50]). The risk of mortality was greater when DAT > 48 h from culture collection or DAT > C&SR results were combined (OR, 1.76 [95% CI, 1.27-2.44]). CONCLUSIONS: Our findings suggest there is a need to shift current treatment practices away from antibiotic escalation strategies that contribute to delayed appropriate therapy and toward early, relatively aggressive and comprehensive, antibiotic therapy, especially among patients with bloodstream infections due to K. pneumoniae or E. coli. PMID- 30518338 TI - Association of lecithin-cholesterol acyltransferase activity and low-density lipoprotein heterogeneity with atherosclerotic cardiovascular disease risk: a longitudinal pilot study. AB - BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is believed to be involved in reverse cholesterol transport, which is known to play a key role in suppression of atherosclerosis. However, recent investigations have demonstrated that higher LCAT activity, measured in terms of the serum cholesterol esterification rate by an endogenous substrate method, is associated with increased formation of triglyceride (TG)-rich lipoproteins (TRLs), leading to a decrease in the low-density lipoprotein (LDL) particle size. The purpose of this hospital-based longitudinal study was to clarify the causal relationship between changes in the LCAT activity and changes in the LDL-particle size. METHODS: The subjects were a total of 335 patients, derived from our previous study cohort, with one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). For this study, we measured the LDL-particle size (relative LDL migration [LDL-Rm value]) by polyacrylamide gel electrophoresis in the subjects, along with the changes in the LCAT activity, at the end of a follow-up period of at least 1 year. RESULTS: The results revealed that the absolute change (Delta) in the LDL particle size increased significantly as the quartile of Delta LCAT activity increased (p = 0.01). A multi-logistic regression adjusted-analysis revealed that Delta LCAT activity in the fourth quartile as compared to that in the first quartile was independently predictive of an increased LDL-particle size (odds ratio [95% confidence interval]: 2.03 [1.02/4.04], p = 0.04). Moreover, the ? LCAT activity was also positively correlated with ? TRL-related markers (i.e., TG, remnant particle-like cholesterol [RLP-C], apolipoprotein B, apolipoprotein C 2, and apolipoprotein C-3). CONCLUSIONS: The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in the LDL-particle size in patients at a high risk for ASCVD. To reduce the risk of ASCVD, it may be important to focus not only on the quantitative changes in the serum LDL-cholesterol levels, but also on the LCAT activity. TRIAL REGISTRATION: UMIN ( https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi ) Study ID: UMIN000033228 retrospectively registered 2 July 2018. PMID- 30518339 TI - Diversity of Salmonella serotypes from humans, food, domestic animals and wildlife in New South Wales, Australia. AB - BACKGROUND: Salmonella is an important human pathogen in Australia and annual case rates continue to increase. In addition to foodborne exposures, cases have been associated with animal and contaminated environment contact. However, routine surveillance in Australia has tended to focus on humans and food, with no reported attempts to collate and compare Salmonella data from a wider range of potential sources of exposure. METHODS: Salmonella data from humans, food, animals and environments were collated from a range of surveillance and diagnostic sources in New South Wales (NSW). Data were categorised to reflect one of 29 sample origins. Serotype diversity was described for each category, and the distribution of serotypes commonly isolated from humans was examined for each sample origin. The distribution of serotypes along the livestock-food-human continuum and at the companion animal-wildlife interface was also examined. RESULTS: In total, 49,872 Salmonella isolates were included in this analysis, comprising 325 serotypes. The vast majority of these isolates were from humans (n = 38,106). Overall S. Typhimurium was the most frequently isolated serotype and was isolated from all sample categories except natural environment and game meat. S. Enteriditis was not isolated from any livestock animal, however sporadic cases were documented in food, companion animals and a reptile. Many serotypes that were frequently isolated from livestock animals and associated food products were only rarely isolated from humans. In addition, a number of key human serotypes were only sporadically isolated from livestock and food products, suggesting alternative sources of infection. In particular, S. Paratyphi B Java and S. Wangata were more often isolated from wild animals. Finally, there was some overlap between serotypes in companion animals and wildlife, with cats in particular having a large number of serotypes in common with wild birds. CONCLUSIONS: This is the most comprehensive description of Salmonella data from humans, food, livestock, wildlife, companion animals and various environments in Australia reported to date. Results confirm that livestock and food are important sources of salmonellosis in humans but that alternative sources - such as contact with wildlife and environments - warrant further investigation. Surveillance in NSW is largely human-focussed: major knowledge gaps exist regarding the diversity and frequency of serotypes in animals. More systematic surveillance of domestic animals and wildlife is needed to inform targeted control strategies and quantitative source attribution modelling in this state. PMID- 30518340 TI - Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis. AB - BACKGROUND: Myeloid-derived suppressor cells (MDSCs) is a heterogeneous population of immature myeloid cells, inhibiting both the innate and adaptive immunity. Recent studies validated that MDSCs caused immune suppression and promoted cancer progression through various mechanisms. However, the prognostic value of MDSCs in cancer remains controversial. METHODS: Here, we performed this meta-analysis to evaluate the prognostic value of MDSCs in various types of cancer. The electric databases, such as Pubmed, Embase and Web of Science, were searched for relevant publications. Hazards ratios (HRs) with the corresponding 95% confidence intervals (95%CIs) were calculated to evaluate the prognostic role of MDSCs in cancer. RESULTS: A total of 16 studies with 1864 patients were enrolled in our meta-analysis. Elevated MDSCs frequency was shown to be associated with shorter overall survival (OS) (HR = 2.46, 95%CI: 1.87-3.23), and poor disease-free survival / recurrence-free survival (DFS / RFS) (HR = 3.26, 95%CI: 2.10-5.04) after treatment. Furthermore, similar results were also observed in the stratified subgroup analysis, which included the analysis by region, sample size, cancer type, NOS scores, subtype and cut-off value of MDSCs. CONCLUSION: High MDSCs might be related to poor clinical outcomes of patients with cancer, that is, MDSCs might be a potential prognostic biomarker in cancer. PMID- 30518341 TI - The experience of gestational diabetes for indigenous Maori women living in rural New Zealand: qualitative research informing the development of decolonising interventions. AB - BACKGROUND: Although early detection and management of excess rates of gestational diabetes mellitus (GDM) among Indigenous women can substantially reduce maternal and offspring complications, current interventions seem ineffective for Indigenous women. While undertaking a qualitative study in a rural community in Northland, New Zealand about the complexities of living with diabetes, we observed a common emotional discourse about the burden of diabetic pregnancies. Given the significance of GDM and our commitment to give voice to Indigenous Maori women in ways that could potentially inform solutions, we aimed to explore the phenomenon of GDM among Maori women in a rural context marked by high area-deprivation. METHOD: A qualitative and Kaupapa Maori methodology was utilised. A sub-sample of women (n = 10) from a broader study designed to improve type 2 diabetes mellitus (T2DM) who had experienced GDM or pre-existing diabetes during pregnancy and/or had been exposed to diabetes in utero were interviewed. Participants in the broader study were recruited via the local primary care clinic. Experiences of GDM, in relation to their current T2DM, was sought. Narrative data was analysed for themes. RESULTS: Intergenerational experiences informed perceptions that GDM was an inevitable heritable illness that "just runs in the family." The cumulative effects of deprivation and living with GDM compounded the complexities of participant' lives including perceptions of powerlessness and mental health deterioration. Missed opportunities for health services to detect and manage diabetes had ongoing health consequences for the women and their offspring. Positive relationships with healthcare providers facilitated management of GDM and helped women engage with self-management. CONCLUSION: Maori women living with T2DM were clear that health providers had failed to intervene in ways that would have potentially slowed or prevented progression of GDM to T2DM. Participants revealed missed opportunities for appropriate diagnostic testing, treatment and health promotion programmes for GDM. Poor collaboration between health services and social services meant psychosocial issues were rarely addressed and the cycle of intergenerational poverty and disadvantage prevailed. These data highlight opportunities for extended case management to include whanau (family) engagement, input from social services, and evidence-based medicine and/or long-term management and prevention of T2DM. PMID- 30518342 TI - A phylogenetic framework of the legume genus Aeschynomene for comparative genetic analysis of the Nod-dependent and Nod-independent symbioses. AB - BACKGROUND: Among semi-aquatic species of the legume genus Aeschynomene, some have the property of being nodulated by photosynthetic Bradyrhizobium lacking the nodABC genes necessary for the synthesis of Nod factors. Knowledge of the specificities underlying this Nod-independent symbiosis has been gained from the model legume Aeschynomene evenia but our understanding remains limited due to the lack of comparative genetics with related taxa using a Nod factor-dependent process. To fill this gap, we combined different approaches to perform a thorough comparative analysis in the genus Aeschynomene. RESULTS: This study significantly broadened previous taxon sampling, including in allied genera, in order to construct a comprehensive phylogeny. In the phylogenetic tree, five main lineages were delineated, including a novel lineage, the Nod-independent clade and another one containing a polytomy that comprised several Aeschynomene groups and all the allied genera. This phylogeny was matched with data on chromosome number, genome size and low-copy nuclear gene sequences to reveal the diploid species and a polytomy containing mostly polyploid taxa. For these taxa, a single allopolyploid origin was inferred and the putative parental lineages were identified. Finally, nodulation tests with different Bradyrhizobium strains revealed new nodulation behaviours and the diploid species outside of the Nod-independent clade were compared for their experimental tractability and genetic diversity. CONCLUSIONS: The extended knowledge of the genetics and biology of the different lineages sheds new light of the evolutionary history of the genus Aeschynomene and they provide a solid framework to exploit efficiently the diversity encountered in Aeschynomene legumes. Notably, our backbone tree contains all the species that are diploid and it clarifies the genetic relationships between the Nod independent clade and the Nod-dependent lineages. This study enabled the identification of A. americana and A. patula as the most suitable species to undertake a comparative genetic study of the Nod-independent and Nod-dependent symbioses. PMID- 30518343 TI - Risk factor for steatorrhea in pediatric chronic pancreatitis patients. AB - BACKGROUND: Pediatric patients always suffer from chronic pancreatitis (CP), especially those with steatorrhea. This study aimed to identify the incidence of and risk factors for steatorrhea in pediatric CP. To our best knowledge, there is no pediatric study to document the natural history of steatorrhea in CP. METHODS: CP patients admitted to our center from January 2000 to December 2013 were enrolled. Patients were assigned to the pediatric (< 18 years old) and adult group according to their age at onset of CP. Cumulative rates of steatorrhea in both groups were calculated. Risk factors for both groups were identified, respectively. RESULTS: The median follow-up duration for the whole cohort was 7.6 years. In a total of 2153 patients, 13.5% of them were pediatrics. The mean age at the onset and the diagnosis of CP in pediatrics were 11.622 and 19.727, respectively. Steatorrhea was detected in 46 patients (46/291, 15.8%) in the pediatric group and in 447 patients (447/1862, 24.0%) in the adult group. Age at the onset of CP (hazard ratio [HR], 1.121), diabetes mellitus (DM, HR, 51.140), and severe acute pancreatitis (SAP, HR, 13.946) was identified risk factor for steatorrhea in the pediatric group. CONCLUSIONS: Age at the onset of CP, DM and SAP were identified risk factors for the development of steatorrhea in pediatric CP patients. The high-risk populations were suggested to be followed up closely. They may benefit from a full adequate pancreatic exocrine replacement therapy. PMID- 30518344 TI - Determinants of the willingness to participate in biobanking among Malaysian stakeholders in the Klang Valley. AB - BACKGROUND: The demand in biobanking for the collection and maintenance of biological specimens and personal data from civilians to improve the prevention, diagnosis and treatment of diseases has increased notably. Despite the advancement, certain issues, specifically those related to privacy and data protection, have been critically discussed. The purposes of this study are to assess the willingness of stakeholders to participate in biobanking and to determine its predictors. METHODS: A survey of 469 respondents from various stakeholder groups in the Klang Valley region of Malaysia was carried out. Based on previous research, a multi-dimensional instrument measuring willingness to participate in biobanking, and its predictors, was constructed and validated. A single step Structural Equation Modelling was performed to analyse the measurements and structural model using the International Business Machines Corporation Software Package for Social Sciences, Analysis of Moment Structures (IBM SPSS Amos) version 20 with a maximum likelihood function. RESULTS: Malaysian stakeholders in the Klang Valley were found to be cautious of biobanks. Although they perceived the biobanks as moderately beneficial (mean score of 4.65) and were moderately willing to participate in biobanking (mean score of 4.10), they professed moderate concern about data and specimen protection issues (mean score of 4.33). Willingness to participate in biobanking was predominantly determined by four direct predictors: specific application-linked perceptions of their benefits (beta = 0.35, p < 0.001), issues of data and specimen protection (beta = - 0.31, p < 0.001) and religious acceptance (beta = 0.15, p < 0.05) and trust in key players (beta = 0.20, p < 0.001). The stakeholders' willingness to participate in biobanking also involves the intricate relationships between the above-mentioned factors and other predictors, such as attitudes regarding technology, religiosity and engagement. CONCLUSIONS: The findings of this study reaffirmed that stakeholders' willingness to participate in biobanking is a complex phenomenon that should be viewed from a multidimensional perspective. Stakeholder willingness to participate in biobanking is warranted when direct predictors (benefits, issues of data and specimen protection, religious acceptance, and trust in key players) as well as indirect factors are well accounted for. PMID- 30518345 TI - Advance care planning after hospital discharge: qualitative analysis of facilitators and barriers from patient interviews. AB - BACKGROUND: Patients who engage in Advance Care Planning (ACP) are more likely to get care consistent with their values. We sought to determine the barriers and facilitators to ACP engagement after discharge from hospital. METHODS: Prior to discharge from hospital eligible patients received a standardized conversation about prognosis and ACP. Each patient was given an ACP workbook and asked to complete it over the following four weeks. We included frail elderly patients with a high risk of death admitted to general internal medicine wards at a tertiary care academic teaching hospital. Four weeks after discharge we conducted semi-structured interviews with patients. Interviews were transcribed, coded and analysed with thematic analysis. Themes were categorized according to the theoretical domains framework. RESULTS: We performed 17 interviews. All Theoretical Domain Framework components except for Social/Professional Identity and Behavioral Regulation were identified in our data. Poor knowledge about ACP and physician communication skills were barriers partially addressed by our intervention. Some patients found it difficult to discuss ACP during an acute illness. For others acute illness made ACP discussions more relevant. Uncertainty about future health motivated some participants to engage in ACP while others found that ACP discussions prevented them from living in the moment and stripped them of hope that better days were ahead. CONCLUSIONS: For some patients acute illness resulting in admission to hospital can be an opportunity to engage in ACP conversations but for others ACP discussions are antithetical to the goals of hospital care. PMID- 30518346 TI - Public knowledge of dehydration and fluid intake practices: variation by participants' characteristics. AB - BACKGROUND: Dehydration results from a decrease in total body water content either due to less intake or more fluid loss. Common symptoms of dehydration are dry mouth/tongue, thirst, headache, and lethargy. The aim of this study was to assess knowledge of dehydration definition, symptoms, causes, prevention, water intake recommendations and water intake practices among people living in Riyadh, Saudi Arabia. METHODS: A cross-sectional study using self-reported questionnaire was employed. Participants were invited during their visit to shopping malls. The shopping malls were selected based on geographical location covering east, west, north and southern part of the city. Self-filled questionnaires were distributed to 393 participants, using systematic sampling technique. Variables recorded included demographics, past medical history, knowledge of dehydration definition, symptoms, causes, prevention and daily water intake practices. Descriptive statistics were summarised as mean, standard deviation and proportions. Negative binomial model was used to identify the predictors of water intake. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). RESULTS: Out of 393 participants, 273(70%) were Saudi, 209(53%) were female, average age was 32.32 +/- 8.78 years. Majority 366(93%) had good knowledge of dehydration definition, 332(84%) for dehydration prevention, and 293(74%) of water intake recommendation. Top three recognized dehydration symptoms were: dry lips (87%), thirst (84%), dry tongue (76%) and recognized dehydration causes were: diarrhoea (81%), sweating (68%) and vomiting (62%). The less recognized symptoms were fatigue 176(44.78%), lack of focus 171(43.5%), headache/dizziness 160(40.71%), light headedness 117(29.7%), muscle weakness 98(24.94%), rapid breathing 90(22.9%), and muscle cramps 64(16.28%).The participants had reported an average of 5.39 +/- 3.32 water glasses intake per day. The total volume of water intake was significantly different between males n = 184 (3.935 +/- 2.10 l) and females n = 209 (3.461 +/- 2.59 l) (p = 0.046). The participants' weight status, intake of juice or tea were the significant predictors of more water intake. CONCLUSION: The participants displayed good knowledge of dehydration definition, prevention, and water intake recommendation. The participants also displayed good knowledge of the common symptoms, however knowledge was lacking for uncommon symptoms. Moreover, participants had reported adequate water intake, meeting the daily water intake recommendation of >=3.7 l for men and >= 2.7 l for women. PMID- 30518347 TI - Synovial cysts of the hip joint: a single-center experience. AB - BACKGROUND: Synovial cyst of the hip joint is a rare clinical condition in need of evidence-based guidelines for its diagnosis and management. Normally, synovial cyst of the hip joint requires no treatment, but when it intrudes into surrounding structures, various clinical symptoms appear. Because of its rarity, a symptomatic synovial cyst is often confounded with a tumor as a space-occupying lesion or with other diseases, depending on its various clinical presentations. Therefore, guidelines for the precise diagnosis and appropriate management for synovial cyst of the hip joint are required. METHODS: We retrospectively studied 7 cases of symptomatic synovial cyst of the hip joint, some of which showed lower limb edema due to mass effect. We compared physical exam findings on presentation, imaging findings, and size and location of the cyst. RESULTS: All cases were managed successfully with surgical excision. We found that, instead of the size of the cyst, the location of the cyst was an important contributor to venous compression. The recurrence rate was 0%, and some patients have significantly long follow-up of 2 years, 4 years, 6 years and 10 years, respectively. CONCLUSIONS: For symptomatic synovial cyst of the hip joint, surgical excision can successfully resolve the symptoms without recurrence. This retrospective study discusses the clinical presentations, diagnostic approaches, and surgical treatment of symptomatic synovial cyst of the hip joint, hence shedding more light on the clinical management of this condition. PMID- 30518348 TI - Public health emergency preparedness: a framework to promote resilience. AB - BACKGROUND: Emergencies and disasters impact population health. Despite the importance of upstream readiness, a persistent challenge for public health practitioners is defining what it means to be prepared. There is a knowledge gap in that existing frameworks lack consideration for complexity relevant to health systems and the emergency context. The objective of this study is to describe the essential elements of a resilient public health system and how the elements interact as a complex adaptive system. METHODS: This study used a qualitative design employing the Structured Interview Matrix facilitation technique in six focus groups across Canada. Focus group participants were practitioners from public health and related sectors. Data collection generated qualitative data on the essential elements, and interactions between elements, for a resilient public health system. Data analysis employed qualitative content analysis and the lens of complexity theory to account for the complex nature of public health emergency preparedness (PHEP). The unit of study was the local/regional public health agency. Ethics and values were considered in the development of the framework. RESULTS: A total of 130 participants attended the six focus groups. Urban, urban rural and rural regions from across Canada participated and focus group size ranged from 15 to 33 across the six sites. Eleven elements emerged from the data; these included one cross-cutting element (Governance and leadership) and 10 distinct but interlinked elements. The essential elements define a conceptual framework for PHEP. The framework was refined to ensure practice and policy relevance for local/regional public health agencies; the framework has ethics and values at its core. CONCLUSIONS: This framework describes the complexity of the system yet moves beyond description to use tenets of complexity to support building resilience. This applied public health framework for local/regional public health agencies is empirically-derived and theoretically-informed and represents a complex adaptive systems approach to upstream readiness for PHEP. PMID- 30518349 TI - Cariogenicity of Candida albicans of distinct genotypes among 3-5-year-old Uygur children in Kashgar, China- a case-control study. AB - BACKGROUND: In recent years, the opportunistic fungus C.albicans has been linked to ECC.It is important to investigate the relationship between the distribution of C.albicans and early childhood caries (ECC) in 3-5-year-old Uygur and Han children in Kashgar, and the role of C.albicans of distinct genotypes in caries. METHODS: Two hundred fifty-six Uygur and 141 Han children were enrolled in the study. The identified C.albicans isolates were genotyped based on 25S rDNA Polymerase Chain Reaction(PCR) amplification, and their acidogenicity, aciduricity, and adhesiveness were examined. Moreover, secreted aspartic protease (Sap) activity and SAP1-5 transcriptional levels were compared in the ECC and caries-free (CF) groups of Uygur children. RESULTS: C.albicans detection rate was significantly higher in Uygur children than in Han children (44. 5% vs. 31. 2%; chi2= 6.739, P = 0.009);the A genotype was dominant in Uygur and Han children with ECC, the C genotype was dominant in Uygur CF children(P = 0.022). C.albicans acidogenicity and growth were more pronounced in the Uygur ECC group than in CF group, especially at pH 4.0 and 4. 5(pH 4.0, P = 0.012; pH 4. 5, P = 0.029); the average ratios of glass-wall adhesion and the Sap activity was higher in ECC group than in CF group(P < 0.01), and SAP2(P < 0.001) and SAP5(P = 0.001) were expressed more robustly in ECC group. CONCLUSIONS: The strong acidogenicity and aciduricity, Sap activity, and high SAP2 and SAP5 expression might be closely associated with ECC. C.albicans potentially plays a key role in the progression of caries, which most readily affects genotype A carriers and could be attributed to person-to-person environmental variation. PMID- 30518350 TI - Internationally educated nurses' and medical graduates' experiences of getting a license and practicing in Sweden - a qualitative interview study. AB - BACKGROUND: The Swedish healthcare system has an increased need for nurses and physicians, and the number of International Educated Nurses (IENs) and International Medical Graduates (IMGs) seeking job opportunities and a license to practice in Sweden is rising. This study explored how IENs and IMGs describe their experience of getting a license to practice, their perceptions of working in Sweden and of how their intercultural competence is utilized. METHOD: A qualitative study based on semi-structured interviews with 11 IENs and 11 IMGs. The interviews were conducted between 2015 and 2017. The data were analyzed using qualitative content analysis. RESULTS: Three main themes were identified: 'Getting a license - a different story,' 'The work is familiar, yet a lot is new,' 'Trying to master a new language.' The time to obtain a license to practice and finding a job was shorter for IENs and IMGs coming from European countries than for those from non-European countries. Some of the experiences of getting a license to practice and of entering a new workplace in another country were the same for nurses and physicians. In general, both IENs and IMGs felt welcomed and used their intercultural competence at work. Lack of language skills was regarded as the main problem for both professions, while workplace introduction was shorter for IMGs than for IENs. CONCLUSIONS: Problems related to language and culture are often underestimated, therefore organizations and managers employing IENs and IMGs should provide longer workplace introduction to facilitate the acculturation process. More time-efficient language courses specifically adapted to IENs and IMGs could make the transition easier and shorten the time to obtain a license to practice for both professions. PMID- 30518351 TI - Mechanisms associated with maternal adverse childhood experiences on offspring's mental health in Nairobi informal settlements: a mediational model testing approach. AB - BACKGROUND: Adverse childhood experiences (ACEs) is a significant public health and social welfare problem in low-and middle income countries (LMICs). However, most ACEs research is based on developed countries, and little is known about mechanisms of early ACEs on adulthood health and offspring's wellbeing for populations in LMICs. This area is needed to guide social welfare policy and intervention service planning. This study addresses these research gaps by examining patterns of ACEs and understanding the role of ACEs on adulthood health (i.e., physical, mental health, experience of underage pregnancy) and offspring's mental health in Kenya. The study was guided by an Integrated Family Stress and Adverse Childhood Experiences Mediation Framework. METHODS: Three hundred ninety four mothers from two informal communities in Kariobangi and Kangemi in Nairobi were included in this study. The Adverse Childhood Experiences International Questionnaire (ACE-IQ), the Kessler Psychological Distress Scale (K10), Overall Health and Quality of Life items, and Child Behavior Checklist were used to study research questions. Data was gathered through a one-time interview with mothers. Structural Equational Modeling (SEM) was applied for mediational mechanism testing. RESULTS: Among 13 ACE areas, most mothers experienced multiple adversity during their childhood (Mean (SD) = 4.93 (2.52)), with household member treated violently (75%) as the most common ACE. SEM results showedthat all domains of ACEs were associated with some aspects of maternal health, and all three domains of maternal health (maternal mental health, physical health, and adolescent pregnancy) were significantly associated with development of offspring's mental health problems. CONCLUSION: ACEs are highly prevalent in Kenyan informal settlements. Consistent with cross cultural literature on family stress model, maternal ACEs are robust predictors for poor child mental health. Preventive interventions for child mental health need to address maternal adverse childhood traumatic experiences as well as their current health in order to effectively promote child mental health. PMID- 30518352 TI - The composition of a bioprocessed shiitake (Lentinus edodes) mushroom mycelia and rice bran formulation and its antimicrobial effects against Salmonella enterica subsp. enterica serovar Typhimurium strain SL1344 in macrophage cells and in mice. AB - BACKGROUND: Human infection by pathogenic Salmonella bacteria can be acquired by consuming of undercooked meat products and eggs. Antimicrobial resistance against antibiotics used in medicine is also a major concern. To help overcome these harmful effects on microbial food safety and human health, we are developing novel antimicrobial food-compatible formulations, one of which is described in the present study. METHODS: The composition of a bioprocessed (fermented) rice bran extract (BPRBE) from Lentinus edodes liquid mycelia culture was evaluated using gas chromatography and mass spectrometry, and the mechanism of its antibacterial effect against Salmonella Typhimurium, strain SL1344 was investigated in macrophage cells and in mice. RESULTS: BPRBE stimulated uptake of the bacteria into RAW 264.7 murine macrophage cells. Activation of the cells was confirmed by increases in NO production resulting from the elevation of inducible nitric oxide synthase (iNOS) mRNA, and in protein expression. Salmonella infection down-regulated the expression of the following protein biomarkers of autophagy (a catabolic process for stress adaptation of cellular components): Beclin-1, Atg5, Atg12, Atg16, LC3-I and LC3-II. BPRBE promoted the upregulation of protein expressions that induced bacterial destruction in autolysosomes of RAW 264.7 cells. ELISA analysis of interferon IFN-beta showed that inflammatory cytokine secretion and bactericidal activity had similar profiles, suggesting that BPRBE enhances cell-autonomous and systemic bactericidal activities via autophagic capture of Salmonella. The treatment also elicited increased excretion of bacteria in feces and their decreased translocation to internal organs (cecum, mesenteric lymph node, spleen, and liver). CONCLUSIONS: The antibiotic mechanism of BPRBE involves the phagocytosis of extracellular bacteria, autophagic capture of intracellular bacteria, and prevention of translocation of bacteria across the intestinal epithelial cells. The new bioprocessing combination of mushroom mycelia and rice brans forms a potentially novel food formulation with in vivo antimicrobial properties that could serve as a functional antimicrobial food and medical antibiotic. PMID- 30518353 TI - Cognitive function in adolescence and the risk for premature diabetes and cardiovascular mortality in adulthood. AB - BACKGROUND: Epidemiological studies have demonstrated a relationship between cognitive function in youth and the future risk of death. Less is known regarding the relationship with diabetes related death. This study assessed the relationship between cognitive function in late adolescence and the risk for diabetes, cardiovascular- (CVD) and all-cause mortality in adulthood. METHODS: This retrospective study linked data from 2,277,188 16-19 year olds who had general intelligence tests (GIT) conducted during pre-military recruitment assessment with cause of death as coded by the Israel Central Bureau of Statistics. The associations between cognitive function and cause-specific mortality were assessed using Cox models. RESULTS: There were 31,268 deaths that were recorded during 41,916,603 person-years of follow-up, with a median follow up of 19.2 (IQR 10.7, 29.5) years. 3068, 1443, 514 and 457 deaths were attributed to CVD, CHD, stroke, and diabetes, respectively. Individuals in the lowest GIT vs. highest GIT quintiles in unadjusted models had the highest risk for all-cause mortality (HR 1.84, 95% CI 1.78, 1.91), total CVD (HR 3.32, 95% CI 2.93, 3.75), CHD (HR 3.49 95% CI 2.92, 4.18), stroke (HR 3.96 95% CI 2.85, 5.5) and diabetes related (HR 6.96 95% CI 4.68, 10.36) mortality. These HRs were attenuated following adjustment for age, sex, birth year, body-mass index, residential socioeconomic status, education and country of origin for all-cause (HR 1.23, 95% CI 1.17, 1.28), CVD (HR 1.76, 95% CI 1.52, 2.04), CHD (HR 1.7 95% CI 1.37, 2.11), stroke (HR 2.03, 95% CI 1.39, 2.98) and diabetes-related (HR 3.14 95% CI 2.00, 4.94) mortality. Results persisted in a sensitivity analyses limited to participants with unimpaired health at baseline and that accounted competing risk. CONCLUSIONS: This analysis of over 2 million demonstrates a strong relationship between cognitive function at youth and the risk for diabetes, all cause and CVD-related mortality independent of adolescent obesity. PMID- 30518354 TI - Discrimination and avoidance due to disability in Australia: evidence from a National Cross Sectional Survey. AB - BACKGROUND: Across most high-income countries, populations are ageing. With this demographic change is an increase in the number of people living with disabilities. In this context, we sought to examine the prevalence of disability discrimination and disability avoidance in Australia, the demographic and health correlates of exclusion and the contexts in which disability discrimination and avoidance are experienced. METHODS: Utilising newly released measures from the 2015 ABS Survey of Disability, Ageing and Carers, we calculate the prevalence of people living with a disability who have experienced discrimination and engage in avoidance behaviours, and the contexts in which they occur. Logistic regression models were fitted to examine the correlates of discrimination and avoidance behaviours, once controls and complex survey design were accounted for. RESULTS: Approximately 9% (95% CI = 8.1, 9.2) of people with a disability experienced disability discrimination in 2015 and 31% (95% CI = 30.9, 32.9) engaged in avoidance behaviours because of their disability. With controls included, the prevalence of avoidance and discrimination declined with age, was higher for divorced people (versus married), the unemployed (versus employed) and was lower for people with lower levels of education (versus a degree) and those born overseas. Having a psychosocial or physical disability significantly increased the odds of experiencing discrimination or avoidance, as did having an increasing number of long-term health conditions. We further find that disability discrimination and avoidance occurs in contexts critical to human capital, such as the workforce, education and healthcare. CONCLUSIONS: Despite protections in legislation and international accords, significant proportions of Australians with a disability experience discrimination or engage in avoidance behaviours in various settings with potentially important human capital implications. Recently, sectoral responses (eg., in education and the workplace) have been offered by Government reports, providing direction for future research and evaluation. PMID- 30518355 TI - Lipoxin A4 receptor agonist BML-111 induces autophagy in alveolar macrophages and protects from acute lung injury by activating MAPK signaling. AB - BACKGROUND: Acute lung injury (ALI) is a life-threatening lung disease where alveolar macrophages (AMs) play a central role both in the early phase to initiate inflammatory responses and in the late phase to promote tissue repair. In this study, we examined whether BML-111, a lipoxin A4 receptor agonist, could alter the phenotypes of AM and thus present prophylactic benefits for ALI. METHODS: In vitro, isolated AMs were treated with lipopolysaccharide (LPS) to induce ALI. In response to BML-111 pre-treatment, apoptosis and autophagy of AMs were examined by flow cytometry, and by measuring biomarkers for each process. The potential involvement of MAPK1 and mTOR signaling pathway was analyzed. In vivo, an LPS-induced septic ALI model was established in rats and the preventative significance of BML-111 was assessed. On the cellular and molecular levels, the pro-inflammatory cytokines TNF-alpha and IL-6 from bronchoalveolar lavage were measured by ELISA, and the autophagy in AMs examined using Western blot. RESULTS: BML-111 inhibited apoptosis and induced autophagy of AMs in response to ALI inducer, LPS. The enhancement of autophagy was mediated through the suppression of MAPK1 and MAPK8 signaling, but independent of mTOR signaling. In vivo, BML-111 pre-treatment significantly alleviated LPS-induced ALI, which was associated with the reduction of apoptosis, the dampened production of pro inflammatory cytokines in the lung tissue, as well as the increase of autophagy of AMs. CONCLUSIONS: This study reveals the prophylactic significance of BML-111 in ALI and the underlying mechanism: by targeting the MAPK signaling but not mTOR pathway, BML-111 stimulates autophagy in AMs, attenuates the LPS-induced cell apoptosis, and promotes the resolution of ALI. PMID- 30518356 TI - Intestinal microbiota mediates Enterotoxigenic Escherichia coli-induced diarrhea in piglets. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) causes diarrhea in humans, cows, and pigs. The gut microbiota underlies pathology of several infectious diseases yet the role of the gut microbiota in the pathogenesis of ETEC-induced diarrhea is unknown. RESULTS: By using an ETEC induced diarrheal model in piglet, we profiled the jejunal and fecal microbiota using metagenomics and 16S rRNA sequencing. A jejunal microbiota transplantation experiment was conducted to determine the role of the gut microbiota in ETEC-induced diarrhea. ETEC-induced diarrhea influenced the structure and function of gut microbiota. Diarrheal piglets had lower Bacteroidetes: Firmicutes ratio and microbiota diversity in the jejunum and feces, and lower percentage of Prevotella in the feces, but higher Lactococcus in the jejunum and higher Escherichia-Shigella in the feces. The transplantation of the jejunal microbiota from diarrheal piglets to uninfected piglets leaded to diarrhea after transplantation. Microbiota transplantation experiments also supported the notion that dysbiosis of gut microbiota is involved in the immune responses in ETEC-induced diarrhea. CONCLUSION: We conclude that ETEC infection influences the gut microbiota and the dysbiosis of gut microbiota after ETEC infection mediates the immune responses in ETEC infection. PMID- 30518357 TI - Practice of emergency obstetric care signal functions and reasons for non provision among health centers and hospitals in Lake and Western zones of Tanzania. AB - BACKGROUND: The Lake and Western Zones of Tanzania that encompass eight regions namely; Kagera, Geita, Simiyu, Shinyanga, Mwanza, Mara Tabora and Kigoma have consistently been reported with the poorest Maternal Newborn and Child Health (MNCH) indicators in the country. This study sought to establish the provision of Emergency Obstetric Care (EmOC) signal functions and reasons for the failure to do so among health centers and hospitals in the two zones. METHODS: All the 261 public and private hospitals and health centers providing Obstetric Care services in Lake and Western Zones were surveyed in 2014. Data were collected using questionnaires adapted from the Averting Maternal Deaths and Disabilities (AMDD) tool to assess EmOC indicators. Managers in all facilities were interviewed and services, medicines and equipment were observed. Spatial Mapping was done using a calibrated Global Positioning System (GPS) Essential Software for Android and coordinates represented on digitalized map with Arc Geographical Information System (GIS) software. Population data were according to the 2012 Housing and Population National Census. RESULTS: In total 261 health facilities were identified as providers of Obstetric care services, including 69 hospitals and 192 health centres which constitute an overall facility density of 8 per 500,000 population. The three most common EmOC signal functions available in the 3 months preceding the survey were oxytocics (95.7%), injectable antibiotics (88.9%) and basic newborn resuscitation (83.4%). The lowest proportions of facilities performed Cesarean section (25.7%) and blood transfusion (34.6%). Policy restrictions were the most frequent reasons given in relation to nonperformance of blood transfusion and Cesarean section when needed. Lack of training and supplies were the most common reasons for non availability of assisted vaginal delivery and uterine evacuation. Overall the Direct Case fatality Rate for direct obstetric causes was 3%. The referral system highly depended on hired or shared ambulance. CONCLUSION: The provision of EmOC signal functions in Lake and Western zones of Tanzania is inconsistent, being mainly compromised by policy restrictions, lack of supplies and professional development, and by operating under lowly developed referral services. PMID- 30518358 TI - Vitamin D status in Kancheepuram District, Tamil Nadu, India. AB - BACKGROUND: Vitamin D has multifarious roles in maintenance of health and prevention of disease. The present study was undertaken to assess the vitamin D status of a rural adult south Indian population and to identify its associations with socioeconomic status and cultural practices. METHODS: Between June 2015 and July 2016, 424 healthy adults residing in Kattankulathur block in Tamil Nadu, India, provided venous blood samples and answered questions by personal interview. 25-hydroxy vitamin D was estimated by ELISA. RESULTS: Fifty nine (13.9%) of the 424 participants had 25OHD levels below 12 ng/mL (vitamin D deficient) and 175 (41.3%) had 25OHD levels between 12 to 20 ng/mL (vitamin D insufficiency). In univariate analysis, demographic factors associated with vitamin D status included education, occupation, socioeconomic class, and birthplace; lifestyle factors included sun exposure time, skin surface exposed to sunlight, use of sunscreen, awareness of vitamin D, and consumption of fish; and hygiene related factors included source of drinking water, availability of tap water at home, and closed toilet at home. In ordinal logistic regression, the following variables were found to be independently associated with vitamin D sufficiency: Duration of daily sun exposure below 30 min (Odds ratio 0.31, 95% confidence intervals 0.14-0.71, P = 0.006), sun exposure 30-60 min (OR 0.49, 95% CI 0.30-0.80, P = 0.004), male gender (OR 2.00, 95% CI 1.30-3.09, P = 0.002), higher level of education (OR 0.80, 95% CI 0.69-0.94, P = 0.005), non-consumption of fatty fish (OR 0.48, 95% CI 0.24-0.85, P = 0.035) and presence of closed toilet system at home (OR 0.59, 95% CI 0.37-0.93). CONCLUSION: VDD and VDI are highly prevalent in this rural Indian community. The study identifies socioeconomic and behavior patterns that negatively impact vitamin D sufficiency, thus providing a basis for targeted intervention. PMID- 30518359 TI - Inter-individual consistency in habitat selection patterns and spatial range constraints of female little bustards during the non-breeding season. AB - BACKGROUND: Identifying the factors that affect ranging behavior of animals is a central issue to ecology and an essential tool for designing effective conservation policies. This knowledge provides the information needed to predict the consequences of land-use change on species habitat use, especially in areas subject to major habitat transformations, such as agricultural landscapes. We evaluate inter-individual variation relative to environmental predictors and spatial constraints in limiting ranging behavior of female little bustards (Tetrax tetrax) in the non-breeding season. Our analyses were based on 11 females tracked with GPS during 5 years in northeastern Spain. We conducted deviance partitioning analyses based on different sets of generalized linear mixed models constructed with environmental variables and spatial filters obtained by eigenvector mapping, while controlling for temporal and inter-individual variation. RESULTS: The occurrence probability of female little bustards in response to environmental variables and spatial filters within the non-breeding range exhibited inter-individual consistency. Pure spatial factors and joint spatial-habitat factors explained most of the variance in the models. Spatial predictors representing aggregation patterns at ~ 18 km and 3-5 km respectively had a high importance in female occurrence. However, pure habitat effects were also identified. Terrain slope, alfalfa, corn stubble and irrigated cereal stubble availability were the variables that most contributed to environmental models. Overall, models revealed a non-linear negative effect of slope and positive effects of intermediate values of alfalfa and corn stubble availability. High levels of cereal stubble in irrigated land and roads had also a positive effect on occurrence at the population level. CONCLUSIONS: Our results provide evidence that female little bustard ranging behavior was spatially constrained beyond environmental variables during the non-breeding season. This pattern may result from different not mutually exclusive processes, such as cost-benefit balances of animal movement, configurational heterogeneity of environment or from high site fidelity and conspecific attraction. Measures aimed at keeping alfalfa availability and habitat heterogeneity in open landscapes and flat terrains, in safe places close to breeding grounds, could contribute to protect little bustard populations during the non-breeding season. PMID- 30518360 TI - The effect of freeze-dried Carica papaya leaf juice treatment on NS1 and viremia levels in dengue fever mice model. AB - BACKGROUND: Carica papaya leaf juice (CPLJ) was well known for its thrombocytosis activity in rodents and dengue patients. However, the effect of CPLJ treatment on other parameters that could contribute to dengue pathogenesis such as nonstructural protein 1 (NS1) production and viremia level have never been highlighted in any clinical and in vivo studies. The aim of this study is to investigate the effect of freeze-dried CPLJ treatment on NS1 and viremia levels of dengue fever mouse model. METHODS: The dengue infection in mouse model was established by inoculation of non-mouse adapted New Guinea C strain dengue virus (DEN-2) in AG129 mice. The freeze-dried CPLJ compounds were identified by Ultra High Performance Liquid Chromatography High Resolution Accurate Mass Spectrometry analysis. The infected AG129 mice were orally treated with 500 mg/kg/day and 1000 mg/kg/day of freeze-dried CPLJ, starting on day 1 post infection for 3 consecutive days. The blood samples were collected from submandibular vein for plasma NS1 assay and quantitation of viral RNA level by quantitative reverse transcription PCR. RESULTS: The AG129 mice infected with dengue virus showed marked increase in the production of plasma NS1, which was detectable on day 1 post infection, peaked on day 3 post-infection and started to decline from day 5 post infection. The infection also caused splenomegaly. Twenty-four compounds were identified in the freeze-dried CPLJ. Oral treatment with 500 mg/kg/day and 1000 mg/kg/day of freeze-dried CPLJ did not affect the plasma NS1 and dengue viral RNA levels. However, the morbidity level of infected AG129 mice were slightly decreased when treated with freeze-dried CPLJ. CONCLUSION: Oral treatment of 500 mg/kg/day and 1000 mg/kg/day of freeze-dried CPLJ at the onset of viremia did not affect the plasma NS1 and viral RNA levels in AG129 mice infected with non-mouse adapted New Guinea C strain dengue virus. PMID- 30518361 TI - Retrospective evaluation of perioperative and short term clinical outcomes in appendicular long bone skeleton fractures repaired via the string of pearls (SOP) locking plate system. AB - BACKGROUND: Internal plate fixation and, more recently, locking plate fixation are commonly used in the repair of fractures in small animal surgery. This retrospective study reviewed the use of the String of Pearls locking plate system in the fixation/repair of appendicular long bone skeleton fractures in 31 small animal veterinary patients (33 fractures). RESULTS: Major complications necessitating revision surgery occurred in 7/33 (21%), with implant failure as the inciting cause in all cases. Variables corresponding to an unsuccessful outcome were evaluated, and a correlation was found with plates placed in a bridging manner (placed without rigid anatomic reconstruction, p = 0.02) and length of follow-up (p = 0.01). CONCLUSIONS: The SOP plating system can be used in the repair of appendicular longbone skeletal fractures, however, the authors propose that adjunct fixation, such as intramedullary pin, double plating, or external coaptation would likely improve results and should be considered imperative in cases in which anatomic reconstruction is either not desirable or achievable. PMID- 30518362 TI - Drug overdose in the ED: a record linkage study examining emergency department ICD-10 coding practices in a cohort of people who inject drugs. AB - BACKGROUND: Drug overdose is a leading cause of mortality and morbidity amongst people who inject drugs (PWID). Drug overdose surveillance typically relies on the International Classification of Diseases (ICD-10) coding system, however its real world utilisation and the implications for surveillance have not been well characterised. This study examines the patterns of ICD-10 coding pertaining to drug overdoses within emergency departments for a cohort of known PWID. METHODS: Cohort data from 688 PWID was linked to statewide emergency department administrative data between January 2008 and June 2013. ICD-10 diagnostic codes pertaining to poisonings by drugs, medicaments and biological substances (T-codes T36-T50) as well as mental and behavioural disorders due to psychoactive substance use (F-codes F10-F19) were examined. RESULTS: There were 449 unique ED presentations with T or F code mentions contributed by 168 individuals. Nearly half of the T and F codes used were non-specific and did not identify either a drug class (n = 160, 36%) or clinical reaction (n = 46, 10%) and 8% represented withdrawal states. T and F codes could therefore be used to reasonably infer an illicit drug overdose in only 42% (n = 188) of cases. Majority of presentations with T or F overdose codes recorded only one diagnostic code per encounter (83%) and representing multiple-drug overdose (F19.- = 18%) or unidentified substances (T50.9 = 17%) using a single, broad diagnostic code was common. CONCLUSIONS: Reliance on diagnoses alone when examining ED data will likely significantly underestimate incidence of specific drug overdose due to frequent use of non specific ICD-10 codes and the use of single diagnostic codes to represent polysubstance overdose. Measures to improve coding specificity should be considered and further work is needed to determine the best way to use ED data in overdose surveillance. PMID- 30518363 TI - Field application of an indirect gE ELISA on pooled milk samples for the control of IBR in free and marker vaccinated dairy herds. AB - BACKGROUND: The aim of the present study was to assess the reliability of a new strategy for monitoring the serological response against Bovine Herpesvirus 1 (BoHV1), the causative agent of infectious bovine rhinotracheitis (IBR). Bulk milk samples have already been identified as cost effective diagnostic matrices for monitoring purposes. Nevertheless, most eradication programs are still based on individual standard assays. In a region of northwestern Italy (Piedmont), the voluntary eradication program for IBR has become economically unsustainable. Being the prevalence of infection still high, glycoprotein E-deleted marker vaccines are commonly used but gE blocking ELISAs are less sensitive on bulk milk samples compared to blood serum. RESULTS: A recently developed indirect gE ELISA showed high versatility when applied to a wide range of matrices. In this study, we applied a faster, cost effective system for the concentration of IgG from pooled milk samples. The IgG enriched fractions were tested using a gE indirect ELISA for monitoring purposes in IBR-positive and IBR-marker-vaccinated herds. Official diagnostic tests were used as gold standard. During a 3 years study, a total 250 herds were involved, including more than 34,500 lactating cows. The proposed method showed a very good agreement with official diagnostic protocols and very good diagnostic performances: only 37 positive animals were not detected across the entire study. CONCLUSIONS: The results highlighted the ability of the proposed method to support the surveillance of IBR in the Piedmont region, reducing the costs without affecting the diagnostic performances. PMID- 30518364 TI - Effect of statins on fasting glucose in non-diabetic individuals: nationwide population-based health examination in Korea. AB - BACKGROUND: Increasing evidence suggest that statin therapy has a diabetogenic effect. Individual types of statin may have a different effect on glucose metabolism. Using the repeated nationwide population-based health screening data in Korea, we investigated the longitudinal changes in fasting glucose level of non-diabetic individuals by use of statins. METHODS: From the National Health Screening Cohort, we included 379,865 non-diabetic individuals who had >= 2 health screening examinations with fasting blood glucose level measured in 2002 2013. Using the prescription records of statins in the database, we calculated the proportion of days covered (PDC) and average number of defined daily doses per day (anDDD) by statins. We constructed multivariate linear mixed models to evaluate the effects of statins on the changes in fasting glucose (Deltaglu). RESULTS: High PDC by statins had a significant positive effect on Deltaglu (coefficient for PDC 0.093 mmol/L, standard error 0.007, p < 0.001). anDDD by statins was also positively associated with Deltaglu (coefficient for anDDD 0.119 mmol/L, standard error 0.009, p < 0.001). Unlike statins, the PDC by fibrate and ezetimibe were not significantly associated with Deltaglu. There was no significant interaction effect on Deltaglu between time interval and statin. Considering individual types of statins, use of atorvastatin, rosuvastatin, pitavastatin, and simvastatin were significantly associated with increase of Deltaglu. Pravastatin, lovastatin, and fluvastatin were also positively associated with Deltaglu, but were not statistically significant. CONCLUSIONS: More adherent and intensive use of statins was significantly associated with an increase in fasting glucose of non-diabetic individuals. In subgroup analysis of individual statins, use of atorvastatin, rosuvastatin, pitavastatin and simvastatin had significant association with increase in fasting glucose. Pravastatin, lovastatin, and fluvastatin had non-significant trend toward an increased fasting glucose. Our findings suggest the medication class effect of statins inducing hyperglycemia. PMID- 30518365 TI - Nationwide school malaria parasitaemia survey in public primary schools, the United Republic of Tanzania. AB - BACKGROUND: A nationwide, school, malaria survey was implemented to assess the risk factors of malaria prevalence and bed net use among primary school children in mainland Tanzania. This allowed the mapping of malaria prevalence at council level and assessment of malaria risk factors among school children. METHODS: A cross-sectional, school, malaria parasitaemia survey was conducted in 25 regions, 166 councils and 357 schools in three phases: (1) August to September 2014; (2) May 2015; and, (3) October 2015. Children were tested for malaria parasites using rapid diagnostic tests and were interviewed about household information, parents' education, bed net indicators as well as recent history of fever. Multilevel mixed effects logistic regression models were fitted to estimate odds ratios of risk factors for malaria infection and for bed net use while adjusting for school effect. RESULTS: In total, 49,113 children were interviewed and tested for malaria infection. The overall prevalence of malaria was 21.6%, ranging from < 0.1 to 53% among regions and from 0 to 76.4% among councils. The malaria prevalence was below 5% in 62 of the 166 councils and above 50% in 18 councils and between 5 and 50% in the other councils. The variation of malaria prevalence between schools was greatest in regions with a high mean prevalence, while the variation was marked by a few outlying schools in regions with a low mean prevalence. Overall, 70% of the children reported using mosquito nets, with the highest percentage observed among educated parents (80.7%), low land areas (82.7%) and those living in urban areas (82.2%). CONCLUSIONS: The observed prevalence among school children showed marked variation at regional and sub regional levels across the country. Findings of this survey are useful for updating the malaria epidemiological profile and for stratification of malaria transmission by region, council and age groups, which is essential for guiding resource allocation, evaluation and prioritization of malaria interventions. PMID- 30518366 TI - Propolis improves pregnancy outcomes and placental oxidative stress status in streptozotocin-induced diabetic rats. AB - BACKGROUND: This study assessed the effects of propolis alone or combined with insulin on maternal status, pregnancy outcomes and placental oxidative stress in streptozotocin-induced diabetic rats. METHODS: Forty female rats were randomly assigned into five groups (n = 8/group) i.e. non-DM (non-diabetes), DM (diabetes), DM + Propolis (diabetes on propolis orally); DM + Insulin (diabetes on insulin subcutaneously) and DM + Combined (diabetes on propolis and insulin) groups. Propolis and insulin were given at 300 mg/kg/day orally and 5.0 IU/kg/day subcutaneously, respectively, for 4 weeks. RESULTS: Fasting blood glucose, conception period, implantation losses, foetal blood glucose and placental oxidative stress markers such as malonaldehyde and protein carbonyl were significantly higher while maternal weight gain, foetal body weight and total antioxidant capacity were significantly lower in DM group compared with non-DM group. These changes were significantly improved in rats treated with propolis or insulin alone with greater significant effects in rats treated with both propolis and insulin. CONCLUSION: This study may suggest the protective effects of propolis against DM-induced impaired pregnancy outcomes and placental oxidative stress with greater effects when combined with insulin. PMID- 30518367 TI - Electric stimulation of ears accelerates body weight loss mediated by high-fat to low-fat diet switch accompanied by increased white adipose tissue browning in C57BL/6 J mice. AB - BACKGROUND: Weight reduction frequently occurs in patients receiving vagus nerve stimulation (VNS) therapy. Therefore, we hypothesized that during dietary intervention for weight loss, auricular electric stimulation (AES), an alternative of VNS, accelerates weight loss by increasing white adipose tissue (WAT) browning and increases energy expenditure. METHODS: C57BL/6J male mice were fed a high-fat diet for 5 wk. to induce obesity, then switched to a low-fat diet for 5 wk. and allocated into 3 groups to receive 2 Hz electric stimulation on ears, electrode clamps only, or nothing (AES, Sham and Ctrl, respectively). RESULTS: Switching to a low-fat diet reduced body weight progressively in all 3 groups, with the greatest reduction in the AES group. In accordance with a mild decrease in feed intake, hypothalamus mRNA levels of Npy, AgRP tended to be reduced, while Pomc tended to be increased by AES. Mice in the AES group had the highest concentrations of norepinephrine in serum and inguinal WAT, and expression levels of uncoupling protein-1 (UCP-1) and tyrosine hydroxylase in inguinal WAT. Furthermore, their subcutaneous adipocytes had multilocular and UCP 1+ characteristics, along with a smaller cell size. CONCLUSION: AES, by increasing WAT browning, could be used in conjunction with a low-fat diet to augment weight loss in addition to suppressing appetite. PMID- 30518368 TI - Magnitude, trends and causes of maternal mortality among reproductive aged women in Kersa health and demographic surveillance system, eastern Ethiopia. AB - BACKGROUND: Despite efforts at curbing maternal morbidity and mortality, developing countries are still burdened with high rates of maternal morbidity and mortality. Ethiopia is not an exception and has one of the world's highest rates of maternal deaths. Reducing the huge burden of maternal mortality remains the single most serious challenge in Ethiopia. There is a paucity of information with regards to the local level magnitude and causes of maternal mortality. We assessed the magnitude, trends and causes of maternal mortality using surveillance data from the Kersa Health and Demographic Surveillance System (HDSS), in Eastern Ethiopia. METHOD: The analysis used surveillance data extracted from the Kersa HDSS database for the duration of 2008 to 2014. Data on maternal deaths and live births during the seven year period were used to determine the maternal mortality ratio in the study. The data were mainly extracted from a verbal autopsy database. The sample was comprised of all reproductive aged women who died during pregnancy, childbirth or 42 days after delivery. Chi-squared test for linear trend was used to examine the significance of change in rates over time. RESULTS: Out of the total 311 deaths of reproductive aged women during the study period, 72 (23.2%) died during pregnancy or within 42 days of delivery. The overall estimated maternal mortality ratio was 324 per 100,000 live births (95% CI: 256, 384). The observed maternal mortality ratio has shown a declining trend over the seven years period though there is no statistical significance for the reduction (chi2 = 0.56, P = 0.57). The estimated pregnancy related mortality ratio was 543 per 100,000 live births (95% CI: 437, 663). Out of those who died due to pregnancy and related causes, only 26% attended at least one antenatal care service. The most common cause of maternal death was postpartum haemorrhage (46.5%) followed by hypertensive disorders of pregnancy (16.3%). CONCLUSION: The magnitude of maternal mortality is considerably high but has shown a decreasing trend. Community-based initiatives that aim to improve maternal health should be strengthened further to reduce the prevailing maternal mortality. Targeted information education and communication should be provided. PMID- 30518369 TI - Anti-metastatic and anti-proliferative activity of eugenol against triple negative and HER2 positive breast cancer cells. AB - BACKGROUND: Eugenol is a natural phenolic compound and possesses anticancer and antibacterial activities. Breast cancer is a major global health problem, and most of the chemotherapeutic agents are highly toxic with long-term side effects. Therefore, this study aimed to explore the possibility of using eugenol as an anti-metastatic and anti-proliferative agent against MDA-MB-231 and SK-BR-3 breast cancer cells. METHODS: Breast cancer cell lines MDA-MB-231 and SK-BR-3 were treated with eugenol and cell proliferation was measured using a real-time cell electronic sensing system. Annexin V analysis with flow cytometry was used to detect the effect of eugenol on cell death. In MDA-MB-231 and SK-BR-3 cells, metastatic potential after eugenol treatment was examined using a wound-healing assay. Real-time PCR was used to study the effect of eugenol on the expression of anti-metastatic genes such as MMP2, MMP9, and TIMP-1, and genes involved in apoptosis including Caspase3, Caspase7, and Caspase9. RESULTS: Treatment with 4 MUM and 8 MUM eugenol for 48 h significantly inhibited cell proliferation of MDA MB-231, with an inhibition rate of 76.4%, whereas 5 MUM and 10 MUM of eugenol for 48 h significantly inhibited the proliferation of SK-BR-3 cells with an inhibition rate of 68.1%. Eugenol-treated cells showed significantly decreased MMP2 and MMP9 expression and an insignificant increase in TIMP1 expression in HER2 positive and triple negative breast cancer cells. Eugenol significantly increased the proportion of MDA-MB-231 and SK-BR-3 cells in late apoptosis and increased the expression of Caspase3, Caspase7, and Caspase9. CONCLUSION: To the best of our knowledge, this is the first study to describe the anti-metastatic effect of eugenol against MDA-MB-231 and SK-BR-3 breast cancer cell lines. PMID- 30518370 TI - Efficient treatment of chronic endometritis through a novel approach of intrauterine antibiotic infusion: a case series. AB - BACKGROUND: Early diagnosis and efficient management of Chronic Endometritis (CE) in patients seeking fertility treatment are two components every practitioner wishes to address. With respect to endometrial restoration, antibiotic treatment appears to perform well. However, regarding the improvement of In Vitro Fertilization (IVF) success rates, literature evidence is inconclusive, and consensus on optimal treatment has yet to be reached. This manuscript uniquely brings to literature the first report on effective employment of intrauterine antibiotic infusion to treat CE and contribute to addressing the infertility related to it. CASE PRESENTATION: In this case series, we present 3 patients reporting numerous previous failed IVF attempts accompanied with diagnosed CE which failed to be properly treated in the past. Following initial assessment in our clinic and verification of CE findings, an oral antibiotic regime was administered based on the infectious agent detected. Re-evaluation concluded slightly improved microbiological environment in the endometrium but persisting inflammation. Antibiotic intrauterine infusion was proposed to the patients as an alternative practice. All our patients achieved a pregnancy shortly following intrauterine treatment with one patient reporting a live birth of twin babies and two patients currently reporting an ongoing pregnancy. CONCLUSIONS: The implications of this case series contribute to medical knowledge and extend to both effective treatment of CE and subsequent management of related infertility. The current line of treatment of CE through oral antibiotic regimes highlights the need for exploring new options and calls for larger studies on the clinical implication of their use. This novel approach enabled natural conception for patients presenting with established Recurrent Implantation Failure (RIF) having undergone numerous futile IVF attempts. The clinical impact from the practitioner's perspective is considerable allowing for an alternative line of treatment that merits further investigation. PMID- 30518371 TI - Seroprevalence of diphtheria and pertussis immunoglobulin G among children with pneumonia in Ji'nan, China. AB - BACKGROUND: Vaccination is still one of the most important methods to control and prevent childhood infections including diphtheria and pertussis. This study evaluated the level of diphtheria (DT) and pertussis (PT)-related antibodies among children with pneumonia in Ji'nan, China. METHODS: A total of 484 sera of children from 1 day to 13 years of age were collected from 2014 to 2015 in Ji'nan. Children with recent history of pertussis were excluded from this study. Anti-DT and PT IgG concentrations were measured by ELISA (Euroimmun, Lubeck, Germany). RESULTS: Of the 484 subjects tested, the overall positivity rate of anti-DT IgG (>=0.1 IU/ml) was 48.97%, and the highest positivity rate of anti-DT IgG (68.55%) and proportion with long term protection (23.27%) were observed in children aged 6 m- < 3 y. For anti-PT IgG, 334 subjects (69.01%) had anti-PT IgG levels below the lower limit of detection (5 IU/ml). Even with detectable anti-PT antibodies, the majority (115/150, 76.67%) of them had antibody levels of 5- < 40 IU/ml. The highest proportion of subjects with detectable anti-PT IgG (>=5 IU/ml) was observed in children aged < 6 m (44.36%), then the proportion continually decreased to 15.0% at 3 y- < 6 y (chi2 = 24.05, p < 0.0001). The highest positivity rate (>=40 IU/ml) was only 8.27% in children aged < 6 m. Subjects with an anti-PT IgG >=100 IU/ml were observed in all the groups and there were no significant differences in the proportions of subjects with a level >= 100 IU/ml among these age groups (chi2 = 2.572, p = 0.4624). A total of 5 subjects had anti PT IgG >=100 IU/ml (>=1 years post pertussis vaccination) which was considered to be indicative of a recent pertussis infection. CONCLUSIONS: We demonstrated low antibody levels and protection against pertussis in our study population. The anti-PT IgG maintained a low level throughout all age groups, and even no immune responses were observed after the basic immunization and booster. Our study supported the need to reevaluate the immune response of DTP vaccine which was used in Shandong province after 2010. PMID- 30518372 TI - Predictors of positive airway pressure therapy termination in the first year: analysis of big data from a German homecare provider. AB - BACKGROUND: There is a lack of robust data about factors predicting continuation (or termination) of positive airway pressure therapy (PAP) for sleep apnea. This analysis of big data from a German homecare provider describes patients treated with PAP, analyzes the therapy termination rate over the first year, and investigates predictive factors for therapy termination. METHODS: Data from a German homecare service provider were analyzed retrospectively. Patients who had started their first PAP therapy between September 2009 and April 2014 were eligible. Patient demographics, therapy start date, and the date of and reason for therapy termination were obtained. At 1 year, patients were classified as having compliance-related therapy termination or remaining on therapy. These groups were compared, and significant predictors of therapy termination determined. RESULTS: Of 98,329 patients included in the analysis, 11,702 (12%) terminated PAP therapy within the first year (after mean 171 +/- 91 days). There was a U-shaped relationship between therapy termination and age; therapy termination was higher in the youngest (< 30 years, 15.5%) and oldest (>= 80 years, 19.8%) patients, and lower in those aged 50-59 years (9.9%). Therapy termination was significantly more likely in females versus males (hazard ratio 1.48, 95% confidence interval 1.42-1.54), in those with public versus private insurance (1.75, 1.64-1.86) and in patients whose first device was automatically adjusting or fixed-level continuous positive airway pressure versus bilevel or adaptive servo-ventilation (1.28, 1.2-1.38). CONCLUSIONS: This analysis of the largest dataset investigating PAP therapy termination identified a number of predictive factors. These can help health care providers chose the most appropriate PAP modality, identify specific patient phenotypes at higher risk of stopping PAP and target interventions to support ongoing therapy to these groups, as well as allow them to develop a risk stratification tool. PMID- 30518373 TI - Prenatal exposure to phthalates and autism spectrum disorder in the MARBLES study. AB - BACKGROUND: Evidence from experimental and observational studies suggests that prenatal phthalate exposures may be associated with autism spectrum disorder (ASD). We examined whether prenatal phthalate exposures were associated with an increased risk of ASD. METHODS: We quantified 14 metabolites of eight phthalates in 636 multiple maternal urine samples collected during 2nd and 3rd trimesters of pregnancy from 201 mother-child pairs in MARBLES (Markers of Autism Risk in Babies - Learning Early Signs), a high-risk ASD longitudinal cohort. At 3 years old, children were clinically assessed for ASD and classified into three diagnostic categories: ASD (n = 46), non-typical development (Non-TD, n = 55), and typical development (TD, n = 100). We used multinomial logistic regression to evaluate the association of phthalate metabolite concentrations with ASD and Non TD. RESULTS: Most associations of phthalate biomarkers with both ASD and Non-TD were null, with the exception that monoethyl phthalate (MEP) was significantly associated with an increased risk of Non-TD (per 2.72-fold relative increase in concentration: Relative risk ratio (RRR) = 1.38; 95% confidence interval (CI): 1.01, 1.90). When stratified by prenatal vitamin use during the first month of pregnancy, among mothers who took vitamins, ASD risk was inversely associated with mono-isobutyl phthalate (MiBP, RRR = 0.44; 95% CI: 0.21, 0.88), mono(3 carboxypropyl) phthalate (MCPP, RRR = 0.41; 95% CI: 0.20, 0.83) and mono carboxyisooctyl phthalate (MCOP, RRR = 0.49; 95% CI: 0.27, 0.88), but among mothers who did not take prenatal vitamins, Non-TD risk was positively associated with MCPP (RRR = 5.09; 95% CI: 2.05, 12.6), MCOP (RRR = 1.86; 95% CI: 1.01, 3.39), and mono-carboxyisononyl phthalate (MCNP, RRR = 3.67; 95% CI: 1.80, 7.48). When stratified by sex, among boys, MEP, monobenzyl phthalate, MCPP, MCNP, and sum of di(2-ethylhexyl) phthalate metabolites (SigmaDEHP) were positively associated with Non-TD risk, but associations with ASD were null. Among girls, associations with both ASD and Non-TD were null. CONCLUSIONS: Our study showed that phthalate exposures in mid- to late pregnancy were not associated with ASD in children from this high-risk ASD cohort. Further studies should be conducted in the general population without high-risk genes to confirm our findings. PMID- 30518374 TI - Persistent reduction in sialylation of cerebral glycoproteins following postnatal inflammatory exposure. AB - BACKGROUND: The extension of sepsis encompassing the preterm newborn's brain is often overlooked due to technical challenges in this highly vulnerable population, yet it leads to substantial long-term neurodevelopmental disabilities. In this study, we demonstrate how neonatal neuroinflammation following postnatal E. coli lipopolysaccharide (LPS) exposure in rat pups results in persistent reduction in sialylation of cerebral glycoproteins. METHODS: Male Sprague-Dawley rat pups at postnatal day 3 (P3) were injected in the corpus callosum with saline or LPS. Twenty-four hours (P4) or 21 days (P24) following injection, brains were extracted and analyzed for neuraminidase activity and expression as well as for sialylation of cerebral glycoproteins and glycolipids. RESULTS: At both P4 and P24, we detected a significant increase of the acidic neuraminidase activity in LPS-exposed rats. It correlated with significantly increased neuraminidase 1 (Neu1) mRNA in LPS-treated brains at P4 and with neuraminidases 1 and 4 at P24 suggesting that these enzymes were responsible for the rise of neuraminidase activity. At both P4 and P24, sialylation of N-glycans on brain glycoproteins decreased according to both mass-spectrometry analysis and lectin blotting, but the ganglioside composition remained intact. Finally, at P24, analysis of brain tissues by immunohistochemistry showed that neurons in the upper layers (II-III) of somatosensory cortex had a reduced surface content of polysialic acid. CONCLUSIONS: Together, our data demonstrate that neonatal LPS exposure results in specific and sustained induction of Neu1 and Neu4, causing long-lasting negative changes in sialylation of glycoproteins on brain cells. Considering the important roles played by sialoglycoproteins in CNS function, we speculate that observed re-programming of the brain sialome constitutes an important part of pathophysiological consequences in perinatal infectious exposure. PMID- 30518375 TI - Immunological effects of the intraparenchymal administration of allogeneic and autologous adipose-derived mesenchymal stem cells after the acute phase of middle cerebral artery occlusion in rats. AB - BACKGROUND: Adipose-derived mesenchymal stem cell (ADMSC) therapy can promote recovery from cerebral ischemia; however, more information regarding appropriate sources of ADMSCs is required. This study was aimed at analyzing the immunogenicity of rat ADMSCs by comparing the immunological effects of intraparenchymal administration of allogeneic ADMSCs (allo-ADMSCs) and autologous ADMSCs (auto-ADMSCs) after the acute phase of middle cerebral artery occlusion (MCAO) in rats. METHODS: Allo- or auto-ADMSCs from rats (1 * 106 cells) were transplanted into Lewis rats 8 days post MCAO. The immunogenicity of ADMSCs was analyzed using coculture with T lymphocytes. The in vivo immune response induced by rat ADMSCs and the viability, migration, and differentiation of transplanted ADMSCs were detected using immunohistochemistry. Apoptosis within the populations of transplanted cells were detected using a TUNEL assay. Infarct volume was detected by 2,3,5-triphenyltetrazolium chloride staining. Post-treatment neurological function was evaluated using a modified neurological severity score and rotarod test. Data were analyzed using Kruskal-Wallis and Mann-Whitney U tests. RESULTS: Compared with allo-ADMSCs, auto-ADMSCs showed lower immunogenicity and evoked weaker immunological responses. Allo-ADMSCs evoked significantly stronger protein expression of interleukin-2 and interferon-gamma, as well as the local accumulation of CD4+ T lymphocytes, CD8+ T lymphocytes, and microglial cells. This indicates that auto-ADMSCs may contribute to higher survival rates, longer survival time, wider migratory scope, and fewer apoptotic cells. In addition, a small number of transplanted auto-ADMSCs expressed astrocyte-like and neuron-like markers 28 days after transplantation. We did not observe surviving transplanted allo-ADMSCs at this time point. We also found that auto-ADMSCs induced a greater degree of functional recovery and a greater reduction in infarct volume than allo-ADMSCs 28 days after transplantation. CONCLUSIONS: Auto-ADMSCs were more effective than allo-ADMSCs in promoting recovery and reducing the infarct volume of MCAO rats. This could be associated with better viability, migratory ability, and differentiation potential, as well as a lower rate of apoptosis. Confirmation of the superiority of auto-ADMSCs and clarification of the underlying mechanisms will provide a theoretical basis for the improved clinical treatment of cerebral infarction. PMID- 30518376 TI - Villainous role of estrogen in macrophage-nerve interaction in endometriosis. AB - Endometriosis is a complex and heterogeneous disorder with unknown etiology. Dysregulation of macrophages and innervation are important factors influencing the pathogenesis of endometriosis-associated pain. It is known to be an estrogen dependent disease, estrogen can promote secretion of chemokines from peripheral nerves, enhancing the recruitment and polarization of macrophages in endometriotic tissue. Macrophages have a role in the expression of multiple nerve growth factors (NGF), which mediates the imbalance of neurogenesis in an estrogen dependent manner. Under the influence of estrogen, co-existence of macrophages and nerves induces an innovative neuro-immune communication. Persistent stimulation by inflammatory cytokines from macrophages on nociceptors of peripheral nerves aggravates neuroinflammation through the release of inflammatory neurotransmitters. This neuro-immune interaction regulated by estrogen sensitizes peripheral nerves, leading to neuropathic pain in endometriosis. The aim of this review is to highlight the significance of estrogen in the interaction between macrophages and nerve fibers, and to suggest a potentially valuable therapeutic target for endometriosis-associated pain. PMID- 30518377 TI - Treatments used for malaria in young Ethiopian children: a retrospective study. AB - BACKGROUND: In Ethiopia, medicinal plants have been used to treat different diseases, including malaria, for many centuries. People living in rural areas are especially noted for their use of medicinal plants as a major component of their health care. This study aimed to study treatment-seeking and prioritize plants/plant recipes as anti-malarials, in Dembia district, one of the malarious districts in Northwest Ethiopia. METHODS: Parents of children aged under 5 years who had had a recent episode of fever were interviewed retrospectively about their child's treatment and self-reported outcome. Treatments and subsequent clinical outcomes were analysed using Fisher's exact test to elicit whether there were statistically significant correlations between them. RESULTS AND DISCUSSION: Of 447 children with malaria-like symptoms, only 30% took the recommended first line treatment (ACT) (all of whom were cured), and 47% took chloroquine (85% cured). Ninety-nine (22.2%) had used medicinal plants as their first-choice treatment. Allium sativum (Liliaceae), Justicia schimperiana (Acanthaceae), Buddleja polystachya (Scrophulariaceae) and Phytolacca dodecandra (Phytolaccaceae) were the most frequently used. Justicia schimperiana was the one associated with the best clinical outcomes (69% self-reported cure rate). However, the difference in clinical outcomes between the plants was not statistically significant. CONCLUSION: In this study, only 30% of children took the recommended first-line treatment. 22% of children with presumed malaria were first treated with herbal medicines. The most commonly used herbal medicine was garlic, but J. schimperiana was associated with the highest reported cure rate of the plants. Further research is warranted to investigate its anti-malarial properties. PMID- 30518378 TI - Accrediting private providers with National Health Insurance to better serve low income populations in Kenya and Ghana: a qualitative study. AB - BACKGROUND: Small private providers in low- and middle-income countries (LMICs) are well positioned to fill gaps in services to low-income populations using Social Health Insurance (SHI) schemes. However, we know little about the practical challenges both private providers and patients face in the context of SHI that may ultimately limit access to quality services for low-income populations. In this paper, we pull together data collected from private providers, patients, and SHI officials in Kenya and Ghana to answer the question: does participation in an SHI scheme affect private providers' ability to serve poorer patient populations with quality health services? METHODS: In-depth interviews were held with 204 providers over three rounds of data collection (2013, 2015, 2017) in Kenya and Ghana. We also conducted client exit interviews in 2013 and 2017 for a total of 106 patient interviews. Ten focus group discussions (FGDs) were conducted in Kenya and Ghana respectively in 2013 for a total of 171 FGD participants. A total of 13 in-depth interviews also were conducted with officials from the Ghana National Health Insurance Agency (NHIA) and the Kenya National Hospital Insurance Fund (NHIF) across four rounds of data collection (2013, 2014, 2016, 2017). Provider interviews covered reasons for (non) enrollment in the health insurance system, experiences with the accreditation process, and benefits and challenges with the system. Client exit interviews covered provider choice, clinic experience, and SHI experience. FGDs covered the local healthcare landscape. Interviews with SHI officials covered officials' experiences working with private providers, and the opportunities and challenges they faced both accrediting providers and enrolling members. Transcripts were coded in Atlas.ti using an open coding approach and analyzed thematically. RESULTS: Private providers and patients agreed that SHI schemes are beneficial for reducing out-of-pocket costs to patients and many providers felt they had to become SHI-accredited in order to keep their facilities open. The SHI officials in both countries corroborated these sentiments. However, due to misunderstanding of the system providers tended to charge clients for services they felt were above and beyond reimbursable expenses. Services were sometimes limited as well. Significant delays in SHI reimbursement in Ghana exacerbated these problems and compromised providers' abilities to cover basic expenses without charging patients. While patients recognized the potential benefits of SHI coverage and many sought it out, a number of patients reported allowing their enrollment to lapse for cost reasons or because they felt the coverage was useless when they were still asked to pay for services out-of-pocket at the health facility. CONCLUSIONS: Our data point to several major barriers to SHI access and effectiveness for low-income populations in Ghana and in Kenya, in addition to opportunities to better engage private providers to serve these populations. We recommend using fee-for-service payments based on Diagnosis Related Group rather than a capitation payment system, as well as building more monitoring and accountability mechanisms into the SHI systems in order to reduce requests for informal out-of-pocket payments from patients while also ensuring quality of care. However, particularly in Ghana, these reforms should be accompanied by financial reform within the SHI system so that small private providers can be adequately funded through government financing. PMID- 30518379 TI - Jumu is required for circulating hemocyte differentiation and phagocytosis in Drosophila. AB - BACKGROUND: The regulatory mechanisms of hematopoiesis and cellular immunity show a high degree of similarity between insects and mammals, and Drosophila has become a good model for investigating cellular immune responses. Jumeau (Jumu) is a member of the winged-helix/forkhead (FKH) transcription factor family and is required for Drosophila development. Adult jumu mutant flies show defective hemocyte phagocytosis and a weaker defense capability against pathogen infection. Here, we further investigated the role of jumu in the regulation of larval hemocyte development and phagocytosis. METHODS: In vivo phagocytosis assays, immunohistochemistry, Real-time quantitative PCR and immunoblotting were performed to investigate the effect of Jumu on hemocyte phagocytosis. 5-Bromo-2 deoxyUridine (BrdU) labeling, phospho-histone H3 (PH3) and TdT-mediated dUTP Nick End Labeling (TUNEL) staining were performed to analyze the proliferation and apoptosis of hemocyte; immunohistochemistry and Mosaic analysis with a repressible cell marker (MARCM) clone analysis were performed to investigate the role of Jumu in the activation of Toll pathway. RESULTS: Jumu indirectly controls hemocyte phagocytosis by regulating the expression of NimC1 and cytoskeleton reorganization. The loss of jumu also causes abnormal proliferation and differentiation in circulating hemocytes. Our results suggest that a severe deficiency of jumu leads to the generation of enlarged multinucleate hemocytes by affecting the normal cell mitosis process and induces numerous lamellocytes by activating the Toll pathway. CONCLUSIONS: Jumu regulates circulating hemocyte differentiation and phagocytosis in Drosophila. Our findings provide new insight into the mechanistic roles of cytoskeleton regulatory proteins in phagocytosis and establish a basis for further analyses of the regulatory mechanism of the mammalian ortholog of Jumu in mammalian innate immunity. PMID- 30518380 TI - Reflection paper on copyright, patient-reported outcome instruments and their translations. AB - With the growth of patient-reported outcome (PRO) measurement, questions arise regarding how copyright protection applies to PRO instruments in general and to their translations in particular. The main objectives of this reflection paper are: 1) to help authors of PRO instruments understand basic rules of intellectual property and copyright that protect the integrity of their instruments and derivatives; and 2) to provide recommendations to authors and users of PRO instruments to prevent misuse or abuse.National laws on intellectual property (IP) and the international Berne Convention fully apply to PRO instruments since they are creations of the mind. Therefore, the copyright holder / owner / claimant of a PRO instrument, i.e., the person or legal entity who owns the copyright of the instrument, is granted exclusive rights that are divided into two main categories: moral and economic rights. Moral rights are: 1) the right of attribution (or right of paternity), i.e., the right to claim authorship of the work, 2) the right against false attribution, and 3) the right of integrity, i.e., the right to object to any mutilation, deformation or modification of the work. Economic rights represent the exclusive rights of the author to make or authorize reproduction, development of derivative works, distribution and communication to the public. In other words, the PRO instrument's copyright holder controls access (distribution, reproduction), and authorizes all derivative works, i.e., adaptations (e.g., electronic formats), modifications (e.g., shorter versions), and translations. Hence, the access to and use of an original PRO instrument and its derivatives in any kind of research should always be associated with the identification of its copyright holder. However, in some cases, this identification may be challenging, in particular when copyright ownership is not clearly defined. To prevent ownership conflicts as well as misuse or abuse of PRO instruments, the ISOQOL Translation and Cultural Adaptation Special Interest Group (TCA-SIG) provides recommendations to authors of PRO instruments and their users. In particular, the TCA-SIG recommends that the ownership of PRO instruments and their derivatives should be defined from the beginning (i.e., from the development of the instrument) and along the life cycle of the instrument between all parties involved. These recommendations apply not only to PRO instruments but also to all the other clinical outcome assessments (COAs), since they are also creations of the mind. PMID- 30518381 TI - Voxel-based automatic multi-criteria optimization for intensity modulated radiation therapy. AB - BACKGROUND: Automatic multi-criteria optimization is necessary for intensity modulated radiation therapy (IMRT) because of low planning efficiency and large plan quality uncertainty in current clinical practice. Most studies focused on imitating dosimetrists' planning procedures to automate this process and ignored the fact that organ-based objective functions typically used in commercial treatment planning systems (such as dose-volume function) usually lead to sub optimal plans. To guarantee the optimum results and to automate this process, we incorporate an improved automation strategy and a voxel-based optimization algorithm to generate a novel automatic multi-criteria optimization framework. We then evaluate it in clinical cases. METHODS: This novel automatic multi-criteria optimization framework incorporates a ranked priority-list based automatic constraints adjustment strategy and an in-house developed voxel-based optimization algorithm. Constraints are sequentially adjusted following a pre defined priority list. Afterward, a voxel-based fluence map optimization (FMO) with an orientation to the newly updated constraints is launched to find a Pareto optimal solution. Loops of constraints adjustment are repeated until each of them could not be relaxed or tightened. The feasibility of the framework is evaluated with 10 automatic generated gynecology (GYN) cancer IMRT cases by comparing the dosimetric performance with the original. RESULTS: Plan quality improvement is observed for our automatic multi-criteria optimization method. Comparable DVHs are found for the planning target volume (PTV), but with better organs-at-risk (OAR) dose sparing. Among 13 evaluated dosimetric endpoints, 5 of them show significant improvements in automatically generated plans compared with the original plans. Investigation of improvement tendency during optimization exhibits gradual change as the optimization stage proceeds. An initial voxel based optimization stage and in-low-priority dosimetric criteria tighten can significantly contribute to the optimization procedure. CONCLUSIONS: We have successfully developed an automatic multi-criteria optimization framework that can dramatically reduce the current trial-and-error patterned planning workload while affording an efficient method to assure high plan quality consistency. This optimization framework is expected to greatly facilitate precise radiation therapy because of its advantages of planning efficiency and plan quality improvement. PMID- 30518382 TI - Overuse injuries in sport: a comprehensive overview. AB - BACKGROUND: The absence of a single, identifiable traumatic cause has been traditionally used as a definition for a causative factor of overuse injury. Excessive loading, insufficient recovery, and underpreparedness can increase injury risk by exposing athletes to relatively large changes in load. The musculoskeletal system, if subjected to excessive stress, can suffer from various types of overuse injuries which may affect the bone, muscles, tendons, and ligaments. METHODS: We performed a search (up to March 2018) in the PubMed and Scopus electronic databases to identify the available scientific articles about the pathophysiology and the incidence of overuse sport injuries. For the purposes of our review, we used several combinations of the following keywords: overuse, injury, tendon, tendinopathy, stress fracture, stress reaction, and juvenile osteochondritis dissecans. RESULTS: Overuse tendinopathy induces in the tendon pain and swelling with associated decreased tolerance to exercise and various types of tendon degeneration. Poor training technique and a variety of risk factors may predispose athletes to stress reactions that may be interpreted as possible precursors of stress fractures. A frequent cause of pain in adolescents is juvenile osteochondritis dissecans (JOCD), which is characterized by delamination and localized necrosis of the subchondral bone, with or without the involvement of articular cartilage. The purpose of this compressive review is to give an overview of overuse injuries in sport by describing the theoretical foundations of these conditions that may predispose to the development of tendinopathy, stress fractures, stress reactions, and juvenile osteochondritis dissecans and the implication that these pathologies may have in their management. CONCLUSIONS: Further research is required to improve our knowledge on tendon and bone healing, enabling specific treatment strategies to be developed for the management of overuse injuries. PMID- 30518383 TI - Impact of anti-doping education and doping control experience on anti-doping knowledge in Japanese university athletes: a cross-sectional study. AB - BACKGROUND: This study was conducted to elucidate the anti-doping (AD) education, doping control experience, and AD knowledge according to the World Anti-doping Code (Code) of Japanese university athletes. METHODS: We collected data from 514 male athletes (Mage = 19.53 years, SD = 1.13) and 629 female athletes (Mage = 20.99 years, SD = 1.07). We asked them about their experience undergoing doping control and the AD education they had received. Then, we assessed their AD knowledge using the World Anti-Doping Agency's Athlete Learning Program about Health and AD (ALPHA) test. RESULTS: The results showed that 2.54% of the participants had undergone doping control. Further, 30.10% received AD education at least once, and 20.82% received AD education more than once. When comparing the ALPHA scores of athletes with/without doping test experience, we observed no significant difference. However, the ALPHA scores of athletes with/without AD education were significantly different; specifically, athletes who received AD education more than once had significantly higher ALPHA scores than non-educated athletes. CONCLUSION: These results revealed that doping control experience was not related to AD knowledge and that AD education was associated with AD knowledge, suggesting that athletes who receive AD education more than once have more accurate AD knowledge than less educated athletes on this topic. The importance of AD education in promoting understanding of AD according to the Code in sports is highlighted in this study. PMID- 30518384 TI - Prognostic factors affecting clinical outcomes after arthroscopic rotator cuff repair: importance of functional recovery by 3 months after surgery. AB - BACKGROUND: To examine important factors that affect clinical outcomes following arthroscopic rotator cuff repair (ARCR). METHODS: Among 163 patients who underwent ARCR, we included 71 shoulders in 71 patients whose progress was monitored for > 2 years, postoperatively. We divided the patients into groups A (scores >= 83 points, 59 patients) and B (scores < 83 points, 12 patients) using the Japanese Orthopedic Association (JOA) score at 24 months. We then conducted univariate and multivariate analyses of pre- and postoperative (2 and 3 months, respectively) factors. RESULTS: The mean JOA score for all patients significantly improved from 63.7 +/- 11.5 points preoperatively to 90.3 +/- 9.6 points at 24 months postoperatively (P < 0.05). However, there were no significant between group differences in the preoperative scores. In addition, there were no significant differences in the postoperative re-tear rate. Univariate analysis revealed that the range of motion (preoperative abduction and postoperative elevation, abduction, internal rotation, and external rotation), muscle strength (external rotation 3 months postoperatively), postoperative pain level [visual analog scale (VAS) maximum score, 10 points], partial repair, Cofield classification, and preoperative width were significant factors (P < 0.05 for all factors). Multivariate and receiver operating characteristic curve analyses showed that VAS at 2 months postoperatively and elevation at 3 months postoperatively were significant factors. CONCLUSIONS: To obtain a JOA score of >= 83 points at 24 months postoperatively, following ARCR, a postoperative VAS of < 5 points at 2 months and postoperative elevation of >= 110 degrees at 3 months should be achieved. PMID- 30518385 TI - All that is silver is not toxic: silver ion and particle kinetics reveals the role of silver ion aging and dosimetry on the toxicity of silver nanoparticles. AB - BACKGROUND: When suspended in cell culture medium, nano-objects composed of soluble metals such as silver can dissolve resulting in ion formation, altered particle properties (e.g. mass, morphology, etc.), and modulated cellular dose. Cultured cells are exposed not just to nanoparticles but to a complex, dynamic mixture of altered nanoparticles, unbound ions, and ion-ligand complexes. Here, three different cell types (RAW 264.7 macrophages and bone marrow derived macrophages from wild-type C57BL/6 J mice and Scavenger Receptor A deficient (SR A(-/-)) mice) were exposed to 20 and 110 nm silver nanoparticles, and RAW 264.7 cells were exposed to freshly mixed silver ions, aged silver ions (ions incubated in cell culture medium), and ions formed from nanoparticle dissolution. The In Vitro Sedimentation, Diffusion, Dissolution, and Dosimetry Model (ISD3) was used to predict dose metrics for each exposure scenario. RESULTS: Silver nanoparticles, freshly mixed ions, and ions from nanoparticle dissolution were toxic, while aged ions were not toxic. Macrophages from SR-A(-/-) mice did not take up 20 nm silver nanoparticles as well as wild-types but demonstrated no differences in silver levels after exposure to 110 nm nanoparticles. Dose response modeling with ISD3 predicted dose metrics suggest that amount of ions in cells and area under the curve (AUC) of ion amount in cells are the most predictive of cell viability after nanoparticle and combined nanoparticle/dissolution-formed-ions exposures, respectively. CONCLUSIONS: Results of this study suggest that the unbound silver cation is the ultimate toxicant, and ions formed extracellularly drive toxicity after exposure to nanoparticles. Applying computational modeling (ISD3) to better understand dose metrics for soluble nanoparticles allows for better interpretation of in vitro hazard assessments. PMID- 30518386 TI - Diffusion-weighted imaging and diffusion kurtosis imaging for early evaluation of the response to docetaxel in rat epithelial ovarian cancer. AB - BACKGROUND: To investigate diffusion-weighted magnetic imaging (DWI) and diffusion kurtosis magnetic imaging (DKI) for the early detection of the response to docetaxel (DTX) chemotherapy in rat epithelial ovarian cancer (EOC). METHODS: 7,12-Dimethylbenz[A]anthracene was applied to induce orthotopic EOC in Sprague Dawley rats. Rats with EOC were treated with DTX on day 0 (treatment group) or were left untreated (control group). DWI and DKI were performed on days 0, 3, 7, 14 and 21 after treatment. On day 21, the tumors were categorized into the sensitive and insensitive groups according to the size change. The cutoff values of the DWI and DKI parameters for the early response were determined. The experiment was repeated, and the treatment group was divided into the sensitive and insensitive groups according to the initially obtained cutoff values. The DWI and DKI parameters were correlated with tumor size, proliferation, apoptosis and tumor necrosis. RESULTS: In the sensitive vs. insensitive or control group, significant differences were found in the Delta% of the DWI and DKI parameters (ADC, D and K) from day 3 and in tumor size from day 14. Early on day 7, the Delta% of K had an AUC of 1 and sensitivity and specificity values of 100% and 100%, respectively, to detect the response to DTX using a cutoff value of 19.03% reduction in K. From day 7, significant differences were found in the Delta% of Ki-67 and CA125 in the sensitive vs. control group and from day 14 in the sensitive vs. insensitive group. From day 14, there were significant differences in the Delta% of Bcl-2, apoptosis and tumor necrosis in the sensitive vs. control or insensitive group. The Delta% values of ADC and D were negatively correlated with the Delta% values of tumor size, Ki-67, CA125 and Bcl-2 and were positively correlated with the Delta% values of apoptosis and tumor necrosis. The Delta% of K was positively correlated with the Delta% values of tumor size, Ki-67, CA125 and Bcl-2 and was negatively correlated with the Delta% values of apoptosis and tumor necrosis. CONCLUSIONS: DWI and DKI parameters, especially K, are superior for imaging tumor size for the early detection of the response to DTX chemotherapy in induced rat EOC. PMID- 30518387 TI - Uniqueness of local myocardial strain patterns with respect to activation time and contractility of the failing heart: a computational study. AB - BACKGROUND: Myocardial deformation measured by strain is used to detect electro mechanical abnormalities in cardiac tissue. Estimation of myocardial properties from regional strain patterns when multiple pathologies are present is therefore a promising application of computer modelling. However, if different tissue properties lead to indistinguishable strain patterns ('degeneracy'), the applicability of any such method will be limited. We investigated whether estimation of local activation time (AT) and contractility from myocardial strain patterns is theoretically possible. METHODS: For four different global cardiac pathologies local myocardial strain patterns for 1025 combinations of AT and contractility were simulated with a computational model (CircAdapt). For each strain pattern, a cohort of similar patterns was found within estimated measurement error using the sum of least-squared differences. Cohort members came from (1) the same pathology only, and (2) all four pathologies. Uncertainty was calculated as accuracy and precision of cohort members in parameter space. Connectedness within the cohorts was also studied. RESULTS: We found that cohorts drawn from one pathology had parameters with adjacent values although their distribution was neither constant nor symmetrical. In comparison cohorts drawn from four pathologies had disconnected components with drastically different parameter values and accuracy and precision values up to three times higher. CONCLUSIONS: Global pathology must be known when extracting AT and contractility from strain patterns, otherwise degeneracy occurs causing unacceptable uncertainty in derived parameters. PMID- 30518388 TI - microRNA expression pattern as an ancillary prognostic signature for radiotherapy. AB - BACKGROUND: In view of the limited knowledge of plasma biomarkers relating to cancer resistance to radiotherapy, we have set up screening, training and testing stages to investigate the microRNAs (miRNAs) expression profile in plasma to predict between the poor responsive and responsive groups after 6 months of radiotherapy. METHODS: Plasma was collected prior to and after radiotherapy, and the microRNA profiles were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) arrays. Candidate miRNAs were validated by single qRT-PCR assays from the training and testing set. The classifier for ancillary prognosis was developed by multiple logistic regression analysis to correlate the ratios of miRNAs expression levels with clinical data. RESULTS: We revealed that eight miRNAs expressions had significant changes after radiotherapy and the expression levels of miR-374a-5p, miR-342-5p and miR-519d-3p showed significant differences between the responsive and poor responsive groups in the pre-radiotherapy samples. The Kaplan-Meier curve analysis also showed that low miR-342-5p and miR-519d-3p expressions were associated with worse prognosis. Our results revealed two miRNA classifiers from the pre- and post-radiotherapy samples to predict radiotherapy response with area under curve values of 0.8923 and 0.9405. CONCLUSIONS: The expression levels of miR-374a-5p, miR-342-5p and miR 519d-3p in plasma are associated with radiotherapy responses. Two miRNA classifiers could be developed as a potential non-invasive ancillary tool for predicting patient response to radiotherapy. PMID- 30518389 TI - Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions. AB - Recurrent implantation failure (RIF) refers to cases in which women have had three failed in vitro fertilization (IVF) attempts with good quality embryos. The definition should also take advanced maternal age and embryo stage into consideration. The failure of embryo implantation can be a consequence of uterine, male, or embryo factors, or the specific type of IVF protocol. These cases should be investigated to determine the most likely etiologies of the condition, as this is a complex problem with several variables. There are multiple risk factors for recurrent implantation failure including advanced maternal age, smoking status of both parents, elevated body mass index, and stress levels. Immunological factors such as cytokine levels and presence of specific autoantibodies should be examined, as well as any infectious organisms in the uterus leading to chronic endometritis. Uterine pathologies such as polyps and myomas as well as congenital anatomical anomalies should be ruled out. Sperm analysis, pre-implantation genetic screening and endometrial receptivity should be considered and evaluated, and IVF protocols should be tailored to specific patients or patient populations. Treatment approaches should be directed toward individual patient cases. In addition, we suggest considering a new initial step in approach to patients with RIF, individualized planned activities to activate the brain's reward system in attempt to improve immunological balance in the body. PMID- 30518390 TI - Real-time assessment of right and left ventricular volumes and function in children using high spatiotemporal resolution spiral bSSFP with compressed sensing. AB - BACKGROUND: Real-time cardiovascular magnetic resonance (CMR) assessment of ventricular volumes and function enables data acquisition during free-breathing. The requirement for high spatiotemporal resolution in children necessitates the use of highly accelerated imaging techniques. METHODS: A novel real-time balanced steady state free precession (bSSFP) spiral sequence reconstructed using Compressed Sensing (CS) was prospectively validated against the breath-hold clinical standard for assessment of ventricular volumes in 60 children with congenital heart disease. Qualitative image scoring, quantitative image quality, as well as evaluation of biventricular volumes was performed. Standard BH and real-time measures were compared using the paired t-test and agreement for volumetric measures were evaluated using Bland Altman analysis. RESULTS: Acquisition time for the entire short axis stack (~ 13 slices) using the spiral real-time technique was ~ 20 s, compared to ~ 348 s for the standard breath hold technique. Qualitative scores reflected more residual aliasing artefact (p < 0.001) and lower edge definition (p < 0.001) in spiral real-time images than standard breath hold images, with lower quantitative edge sharpness and estimates of image contrast (p < 0.001). There was a small but statistically significant (p < 0.05) overestimation of left ventricular (LV) end-systolic volume (1.0 +/- 3.5 mL), and underestimation of LV end-diastolic volume (- 1.7 +/- 4.6 mL), LV stroke volume (- 2.6 +/- 4.8 mL) and LV ejection fraction (- 1.5 +/- 3.0%) using the real-time technique. We also observed a small underestimation of right ventricular stroke volume (- 1.8 +/- 4.9 mL) and ejection fraction (- 1.4 +/- 3.7%) using the real-time imaging technique. No difference in inter-observer or intra-observer variability were observed between the BH and real-time sequences. CONCLUSIONS: Real-time bSSFP imaging using spiral trajectories combined with a compressed sensing reconstruction showed good agreement for quantification of biventricular metrics in children with heart disease, despite slightly lower image quality. This technique holds the potential for free breathing data acquisition, with significantly shorter scan times in children. PMID- 30518391 TI - bFGF-mediated pluripotency maintenance in human induced pluripotent stem cells is associated with NRAS-MAPK signaling. AB - BACKGROUND: Human pluripotent stem cells (PSCs) open new windows for basic research and regenerative medicine due to their remarkable properties, i.e. their ability to self-renew indefinitely and being pluripotent. There are different, conflicting data related to the role of basic fibroblast growth factor (bFGF) in intracellular signal transduction and the regulation of pluripotency of PSCs. Here, we investigated the effect of bFGF and its downstream pathways in pluripotent vs. differentiated human induced (hi) PSCs. METHODS: bFGF downstream signaling pathways were investigated in long-term culture of hiPSCs from pluripotent to differentiated state (withdrawing bFGF) using immunoblotting, immunocytochemistry and qPCR. Subcellular distribution of signaling components were investigated by simple fractionation and immunoblotting upon bFGF stimulation. Finally, RAS activity and RAS isoforms were studied using RAS assays both after short- and long-term culture in response to bFGF stimulation. RESULTS: Our results revealed that hiPSCs were differentiated into the ectoderm lineage upon withdrawing bFGF as an essential pluripotency mediator. Pluripotency markers OCT4, SOX2 and NANOG were downregulated, following a drastic decrease in MAPK pathway activity levels. Notably, a remarkable increase in phosphorylation levels of p38 and JAK/STAT3 was observed in differentiated hiPSCs, while the PI3K/AKT and JNK pathways remained active during differentiation. Our data further indicate that among the RAS paralogs, NRAS predominantly activates the MAPK pathway in hiPSCs. CONCLUSION: Collectively, the MAPK pathway appears to be the prime signaling pathway downstream of bFGF for maintaining pluripotency in hiPSCs and among the MAPK pathways, the activity of NRAS-RAF-MEK-ERK is decreased during differentiation, whereas p38 is activated and JNK remains constant. PMID- 30518393 TI - Socio-economic and age variations in response to supermarket-led checkout food policies: a repeated measures analysis. AB - BACKGROUND: Dietary inequalities between population groups are common with older and more affluent individuals tending to have healthier diets. Differential responses to health interventions may exacerbate inequalities. Changing what foods are displayed at supermarket checkouts is one intervention that has the potential to change diets. The aim of this study was to assess whether differences in purchases of common checkout foods from supermarkets with different checkout food policies varied according to age group and social grade. METHODS: We analysed annual household purchase data for 2013-17 from nine leading UK supermarkets, split according to age of the main household shopper and household social grade. Checkout food policies were categorised as clear and consistent, vague or inconsistent, and none. Policies were heterogeneous but all included removal of confectionery and/or chocolate from checkouts. Mixed effects linear regression models were used to assess differences in purchases of common checkout foods (sugary confectionery, chocolate and potato crisps) by checkout food policy and whether these varied by age group or occupational social grade. RESULTS: Relative to supermarkets with no checkout food policy, 14% (95% CI: 4 22%) fewer purchases of common checkout foods per household per percentage market share were made in supermarkets with a clear and consistent policy. Adjusted mean numbers of purchases were higher in older age groups than the youngest, but there were no differences between the highest and other social grades. There were significant interactions between checkout food policy and both age group and social grade. In supermarkets with clear and consistent policies, 23% (6-36%), 20% (2-34%), and 23% (7-37%) fewer purchases were made in age groups 45-54, 55-64 and 65+ years respectively, compared to all groups combined. In supermarkets with clear and consistent policies, there were 21% (4-35%), 26% (9-39%) and 21% (3 35%) fewer purchases made by households in the highest two and lowest social grades respectively, compared to all groups combined. CONCLUSIONS: Households with older main shoppers and those in the most and least affluent social grades may be most responsive to supermarket checkout food policies. As older and more affluent groups tend to have healthier diets overall, it is unlikely that supermarket checkout food policies contribute to greater dietary equity. PMID- 30518392 TI - Increased risk of chronic fatigue syndrome following burn injuries. AB - BACKGROUND: The overlapping symptoms and pathophysiological similarities between burn injury and chronic fatigue syndrome (CFS) are noteworthy. Thus, this study explores the possible association between burn injury and the subsequent risk of CFS. METHOD: We used data from the Taiwan National Health Insurance system to address the research topic. The exposure cohort comprised of 17,204 patients with new diagnoses of burn injury. Each patient was frequency matched according to age, sex, index year, and comorbidities with four participants from the general population who did not have a history of CFS (control cohort). Cox proportional hazards regression analysis was conducted to estimate the relationship between burn injury and the risk of subsequent CFS. RESULT: The incidence of CFS in the exposure and control cohorts was 1.61 and 0.86 per 1000 person-years, respectively. The exposure cohort had a significantly higher overall risk of subsequent CFS than did the control cohort (adjusted hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.41-1.56). The risk of CFS in patients with burn injury in whichever stratification (including sex, age, and comorbidity) was also higher than that of the control cohort. CONCLUSION: The findings from this population-based retrospective cohort study suggest that thermal injury is associated with an increased risk of subsequent CFS and provided a point of view suggesting burn injuries in sun- exposed areas such as the face and limbs had greater impact on subsequent development of CFS compared with trunk areas. In addition, extensively burned areas and visible scars were predictors of greater physiological and psychosocial that are needed to follow-up in the long run. PMID- 30518394 TI - Higher dietary magnesium intake is associated with lower body mass index, waist circumference and serum glucose in Mexican adults. AB - BACKGROUND: Obesity and diabetes mellitus (DM) are public health concerns in Mexico of top-level priority due to their high prevalence and their growth rate in recent decades. The accumulation of adipose tissue leads to an unbalanced release of pro-oxidant factors, which causes cellular damage and favors the development of comorbidities. Recent evidence suggests that oxidative stress also promotes the accumulation of adipose tissue and the development of insulin resistance. The objective of this study is to evaluate the association between usual intake of antioxidant nutrients, specifically vitamins A, C, E and magnesium with body mass index (BMI), waist circumference (WC) and serum glucose concentrations in a representative sample of Mexican adults. METHODOLOGY: We analyzed data on diet, BMI, WC and serum glucose from the Mexican National Health and Nutrition Survey 2012. Analysis included 20- to 65-year-old adults without a known diagnosis of DM (n = 1573). Dietary information was obtained using the five step multiple-pass method developed by the United States Department of Agriculture and adapted to the Mexican context. Nutrient usual intake distributions were estimated using the Iowa State University method, through the "Software for Intake Distribution Estimation" (PC-Side) v.1.02. Associations were analyzed using multivariate regression models. RESULTS: Higher dietary magnesium intake was associated with lower markers of adiposity, so that an increase in 10 mg per 1000 kcal/day of magnesium was associated with an average decrease in BMI of 0.72% (95% CI: -1.36, - 0.08) and 0.49 cm (95% CI: -0.92, - 0.07) of WC. Additionally, in women with normal glucose concentrations, an increase in magnesium intake was associated with an average decrease in serum glucose by 0.59% (95% CI: -1.08, - 0.09). CONCLUSION: The results suggest that magnesium intake is associated with lower BMI, WC and serum glucose in Mexican population. However, more studies are required to elucidate the nature of this association. PMID- 30518395 TI - Reshaping the vector control strategy for malaria elimination in Ethiopia in the context of current evidence and new tools: opportunities and challenges. AB - The core vector control measures, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), reduce the risk of malaria infection by targeting indoor biting mosquitoes. These two interventions are found to be effective in malaria control, but not sufficient to eliminate malaria. The main challenges with LLINs and IRS are insecticide resistance, misuse of the interventions, host behaviour, such as staying out-door during early night or sleeping outdoor without using protective measures, and vector behaviour including feeding on bovine blood, outdoor biting and outdoor resting. Therefore, for complete interruption of malaria transmission in a defined area there is a need to consider a variety of interventions that can help prevent out-door as well as indoor malaria transmission. In Ethiopia, to achieve the malaria elimination goal, a mix of vector control tools, such as intensifying the use of LLINs and IRS, and supplemented by use of ivermectin administration, zooprophylaxis, odour baited mosquito trapping, improving housing and larva control measures tailored to the local situation of malaria transmission, may be needed. PMID- 30518396 TI - Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis. AB - BACKGROUND: Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma. PATIENTS AND METHODS: We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency > 5% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method. RESULTS: Six out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P < 0.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P = 0.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P = 0.035). CONCLUSIONS: Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms. PMID- 30518398 TI - Performance of gimbal-based dynamic tumor tracking for treating liver carcinoma. AB - BACKGROUND: Since the introduction of tumor tracking in radiotherapy, it is possible to ensure a precise irradiation of moving targets. To follow the tumor movement, most systems rely on the detection of implanted markers and correlation models between the internal and external patient movement. This study reports the clinical workflow and first results of the dynamic tumor tracking (DTT) performance for patients with liver carcinoma at the Vero SBRT system of the University Hospital Erlangen regarding the detection of the internal marker and the changes of the determined correlation models. METHODS: So far 13 liver patients were treated with DTT. For each patient, two fiducial markers (FM), which are monitored with X-rays during treatment, were implanted in the vicinity of the tumor. All patients received a fraction dose of 4-6 Gy with 8 to 12 fractions. Treatment and patient data is evaluated by processing the acquired log files of the DTT treatment. Based on this, the marker detection and the changes of the correlation model between the internal and external movement is investigated. RESULTS: The median treatment time was 19:42 min. During treatment a median of 173 X-ray stereoscopic images were acquired. The marker detection was successful in 64.6% of the images. The FM detection is independent of the relative angle between the marker and the imager, but shows a dependency on the average intensity surrounding the FM position within the kV images. The number of correlation models needed during treatment increases in the presence of baseline shifts. The comparison of the correlation models shows large differences in the internal-external correlation between the different models acquired for one patient. CONCLUSION: Thirteen liver patients were treated with DTT at the Vero SBRT system and the marker detection was analyzed. Furthermore, the importance of regularly monitoring the internal target motion could be shown, since the correlation between the internal and external motion changes considerably over the course of the treatment. PMID- 30518397 TI - The natural polyphenol curcumin induces apoptosis by suppressing STAT3 signaling in esophageal squamous cell carcinoma. AB - BACKGROUND: We and others have previously shown that the STAT3 signaling pathway is activated in some esophageal squamous cell carcinoma (ESCC) cells and is required for the survival and growth of these primary ESCC-derived xenografts. It has also been shown that the natural polyphenol curcumin is an effective anti tumor agent. METHODS: Luciferase assay and immunoblotting were performed to examine whether curcumin suppressed STAT3 signaling. CCK-8 assay and xenografts were utilized for analyzing ESCC cell growth in culture and mice. Soft agar assay was carried out to determine the colony formation ability of ESCC cells in the presence or absence of curcumin. Cell death and cell cycle were assessed by In CELL Analyzer 2000. Immunohistochemistry and TUNEL assay were used for detecting apoptosis in ESCC tisuses. Molecular docking was performed to evaluate the interaction of curcumin with JAK2. JAK2 activity was assessed using an in vitro cell-free system. HE staining was used to evaluate the ESCC tissues. RESULTS: The natural polyphenol curcumin inhibited STAT3 phosphorylation rapidly and blocked STAT3-mediated signaling in ESCC cells. It also induced growth arrest and apoptosis in cultured ESCC cells, which were attenuated by enforced expression of STAT3. Furthermore, curcumin preferentially blocked the growth of primary ESCC derived xenografts that harbored activated STAT3. CONCLUSIONS: Curcumin is able to exert anti-tumor action through inhibiting the STAT3 signaling pathway. Giving its wide use in traditional medicines with low toxicity and few adverse reactions, it is conceivable that curcumin might be further explored as a unique STAT3 inhibitor for anti-cancer therapies. PMID- 30518399 TI - Using mixed effects logistic regression models for complex survey data on malaria rapid diagnostic test results. AB - BACKGROUND: The effect of malaria in Nigeria is still worrisome and has remained a leading public health issue in the country. In 2016, Nigeria was the highest malaria burden country among the 15 countries in sub-Saharan Africa that accounted for the 80% global malaria cases. The purpose of this study is to utilize appropriate statistical models in identifying socio-economic, demographic and geographic risk factors that have influenced malaria transmission in Nigeria, based on malaria rapid diagnostic test survey results. This study contributes towards re-designing intervention strategies to achieve the target of meeting the Sustainable Development Goals 2030 Agenda for total malaria elimination. METHODS: This study adopted the generalized linear mixed models approach which accounts for the complexity of the sample survey design associated with the data. The 2015 Nigeria malaria indicator survey data of children between 6 and 59 months are used in the study. RESULTS: From the findings of this study, the cluster effect is significant [Formula: see text] which has suggested evidence of heterogeneity among the clusters. It was found that the vulnerability of a child to malaria infection increases as the child advances in age. Other major significant factors were; the presence of anaemia in a child, an area where a child resides (urban or rural), the level of the mother's education, poverty level, number of household members, sanitation, age of head of household, availability of electricity and the type of material for roofing. Moreover, children from Northern and South-West regions were also found to be at higher risk of malaria disease and re-infection. CONCLUSION: Improvement of socio-economic development and quality of life is paramount to achieving malaria free Nigeria. There is a strong link of malaria risk with poverty, under-development and the mother's educational level. PMID- 30518400 TI - Assessment of chiropractic care on strength, balance, and endurance in active duty U.S. military personnel with low back pain: a protocol for a randomized controlled trial. AB - BACKGROUND: Low back pain (LBP) is a common cause of disability among U.S. military personnel. Approximately 20% of all diagnoses resulting in disability discharges are linked to back-related conditions. Because LBP can negatively influence trunk muscle strength, balance, and endurance, the military readiness of active-duty military personnel with LBP is potentially compromised. Chiropractic care may facilitate the strengthening of trunk muscles, the alteration of sensory and motor signaling, and a reduction in pain sensitivity, which may contribute to improving strength, balance, and endurance for individuals with LBP. This trial will assess the effects of chiropractic care on strength, balance, and endurance for active-duty military personnel with LBP. METHODS/DESIGN: This randomized controlled trial will allocate 110 active-duty military service members aged 18-40 with non-surgical acute, subacute, or chronic LBP with pain severity of >=2/10 within the past 24 h. All study procedures are conducted at a single military treatment facility within the continental United States. Participants are recruited through recruitment materials approved by the institutional review board, such as posters and flyers, as well as through provider referrals. Group assignment occurs through computer-generated random allocation to either the study intervention (chiropractic care) or the control group (waiting list) for a 4-week period. Chiropractic care consists primarily of spinal manipulation at a frequency and duration determined by a chiropractic practitioner. Strength, balance, and endurance outcomes are obtained at baseline and after 4 weeks. The primary outcome is a change between baseline and 4 weeks of peak isometric strength, which is measured by pulling on a bimanual handle in a semi-squat position. Secondary outcomes include balance time during a single leg standing test and trunk muscle endurance with the Biering-Sorensen test. Patient-reported outcomes include pain severity, disability measured with the Roland Morris Disability Questionnaire, symptom bothersomeness, PROMIS-29, Fear Avoidance Beliefs Questionnaire, expectations of care, physical activity, and global improvement. DISCUSSION: This trial may help inform further research on biological mechanisms related to manual therapies employed by chiropractic practitioners. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02670148 Registered on 1 February 2016. PMID- 30518401 TI - Pulmonary veno-occlusive disease as a cause of severe pulmonary hypertension in a dog. AB - BACKGROUND: Pulmonary veno-occlusive disease (PVOD) is a rare cause of pulmonary arterial hypertension (PAH) in humans and can be classified in idiopathic, heritable, drug and radiation-induced, and associated with connective tissue disease or human immunodeficiency virus infection. Recently, biallelic mutations of the EIF2AK4 gene have been discovered as a cause for an autosomal recessive form of PVOD in humans. In dogs, PAH is poorly characterized and is generally considered to be idiopathic or secondary to (for example) congenital left-to right cardiovascular shunts or heartworm disease. However, recently, the pathologic features resembling human PVOD were retrospectively described in post mortem lung samples of dogs presenting with respiratory distress and idiopathic pulmonary hypertension (PH), which suggests that PVOD contributes to an unknown percentage of cases with unexplained PH. In dogs, information on the clinical presentation of PVOD is scarce and the cause and pathogenesis of this disease is still unknown. CASE PRESENTATION: An 11-year-old, intact male German Shepherd dog (GSD) was presented with a 2-day history of acute-onset dyspnea and generalized weakness. Physical examination, laboratory analysis, thoracic radiography, echocardiography, a computed tomography scan and an ante mortem lung biopsy demonstrated severe arterial hypoxemia and severe PH but were not diagnostic for a known disease syndrome. Based on the poor reaction to therapy with oxygen, sildenafil, pimobendan and dexamethasone the dog was euthanized. Histopathology of the lungs showed venous and arterial remodelling, segmental congestion of alveolar capillaries and foci of vascular changes similar to human pulmonary capillary hemangiomatosis, indicating that the dog suffered from PVOD. Whole genome sequencing analysis was performed on the case and a healthy GSD. Validation was performed by Sanger sequencing of five additional GSD's unknown for any form of respiratory stress and aged >= 10 years. No causal variants were found in the genes that are known to be involved in human PVOD and PAH. CONCLUSIONS: This case report confirms that PVOD should be a diagnostic consideration in dogs presenting with dyspnea and unexplained PH. In the present case, no casual genetic mutations known to be involved in humans with PVOD and PAH were found. PMID- 30518402 TI - Tumour associated lymphocytes in the pleural effusions of patients with mesothelioma express high levels of inhibitory receptors. AB - OBJECTIVE: Pleural effusion (PE) is a common feature of malignant pleural mesothelioma. These effusions typically contain lymphocytes and malignant cells. We postulated that the PE would be a source of lymphocytes for analysis of tumor immune milieu. The aim of this study was to compare the phenotype and T cell receptor usage of pleural effusion T cells with paired concurrently drawn peripheral blood lymphocytes. We used multi-parameter flow cytometry and high throughput T cell receptor sequencing to analyse peripheral blood and pleural effusion mononuclear cells. RESULTS: Both CD8+ and CD4+ T cells from effusion showed increased expression of T cell inhibitory receptors PD-1, LAG-3 and Tim-3 compared to blood. Comprehensive T cell receptor sequencing on one of the patients showed a discordant distribution of clonotypes in the antigen experienced (PD-1+) compartment between effusion and blood, suggesting an enrichment of antigen specific clonotypes in the effusion, with potential as an immunological response biomarker. PMID- 30518403 TI - Associations of greenness, greyness and air pollution exposure with children's health: a cross-sectional study in Southern Italy. AB - BACKGROUND: Due to the complex interplay among different urban-related exposures, a comprehensive approach is advisable to estimate the health effects. We simultaneously assessed the effect of "green", "grey" and air pollution exposure on respiratory/allergic conditions and general symptoms in schoolchildren. METHODS: This study involved 219 schoolchildren (8-10 years) of the Municipality of Palermo, Italy. Data were collected through questionnaires self-administered by parents and children. Exposures to greenness and greyness at the home addresses were measured using the normalized difference vegetation index (NDVI), residential surrounding greyness (RSG) and the CORINE land-cover classes (CLC). RSG was defined as the percentage of buffer covered by either industrial, commercial and transport units, or dump and construction sites, or urban fabric related features. Two specific categories of CLC, namely "discontinuous urban fabric - DUF" - and "continuous urban fabric - CUF" - areas were found. Exposure to traffic-related nitrogen dioxide (NO2) was assessed using a Land-Use Regression model. A symptom score ranging from 0 to 22 was built by summing affirmative answers to twenty-two questions on symptoms. To avoid multicollinearity, multiple Logistic and Poisson ridge regression models were applied to assess the relationships between environmental factors and self reported symptoms. RESULTS: A very low exposure to NDVI <=0.15 (1st quartile) had a higher odds of nasal symptoms (OR = 1.47, 95% CI [1.07-2.03]). Children living in CUF areas had higher odds of ocular symptoms (OR = 1.49, 95% CI [1.10-2.03]) and general symptoms (OR = 1.18, 95% CI [1.00-1.48]) than children living in DUF areas. Children living in proximity (<=200 m) to High Traffic Roads (HTRs) had increased odds of ocular (OR = 1.68, 95% CI [1.31-2.17]) and nasal symptoms (OR = 1.49, 95% CI [1.12-1.98]). A very high exposure to NO2 >= 60 MUg/m3 (4th quartile) was associated with a higher odds of general symptoms (OR = 1.28, 95% CI [1.10-1.48]). No associations were found with RGS. A Poisson ridge regression model on the symptom score showed that children living in proximity to HTRs (<=200 m) had a higher symptoms score (RR = 1.09, 95% CI [1.02-1.17]) than children living > 200 m from HTRs. Children living in CUF areas had a higher symptoms score (RR = 1.11, 95% CI [1.03-1.19]) than children living in DUF areas. CONCLUSIONS: Multiple exposures related to greenness, greyness (measured by CORINE) and air pollution within the urban environment are associated with respiratory/allergic and general symptoms in schoolchildren. No associations were found when considering the individual exposure to greyness measured using the RSG indicator. PMID- 30518404 TI - Attempted use of PACE for riboswitch discovery generates three new translational theophylline riboswitch side products. AB - OBJECTIVE: The purpose of this project was to use an in vivo method to discover riboswitches that are activated by new ligands. We employed phage-assisted continuous evolution (PACE) to evolve new riboswitches in vivo. We started with one translational riboswitch and one transcriptional riboswitch, both of which were activated by theophylline. We used xanthine as the new target ligand during positive selection followed by negative selection using theophylline. The goal was to generate very large M13 phage populations that contained unknown mutations, some of which would result in new aptamer specificity. We discovered side products of three new theophylline translational riboswitches with different levels of protein production. RESULTS: We used next generation sequencing to identify M13 phage that carried riboswitch mutations. We cloned and characterized the most abundant riboswitch mutants and discovered three variants that produce different levels of translational output while retaining their theophylline specificity. Although we were unable to demonstrate evolution of new riboswitch ligand specificity using PACE, we recommend careful design of recombinant M13 phage to avoid evolution of "cheaters" that short circuit the intended selection pressure. PMID- 30518405 TI - IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways. AB - BACKGROUND: Inosine 5'-monophosphate dehydrogenase type II (IMPDH2) was originally identified as an oncogene in several human cancers. However, the clinical significance and biological role of IMPDH2 remain poorly understood in colorectal cancer (CRC). METHODS: Quantitative real-time polymerase chain reaction (qPCR), western blotting analysis, the Cancer Genome Atlas (TCGA) data mining and immunohistochemistry were employed to examine IMPDH2 expression in CRC cell lines and tissues. A series of in-vivo and in-vitro assays were performed to demonstrate the function of IMPDH2 and its possible mechanisms in CRC. RESULTS: IMPDH2 was upregulated in CRC cells and tissues at both mRNA and protein level. High IMPDH2 expression was closely associated with T stage, lymph node state, distant metastasis, lymphovascular invasion and clinical stage, and significantly correlated with poor survival of CRC patients. Further study revealed that overexpression of IMPDH2 significantly promoted the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and accelerated xenograft tumour growth in nude mice. On the contrary, knockdown of IMPDH2 achieved the opposite effect. Gene set enrichment analysis (GSEA) showed that the gene set related to cell cycle was linked to upregulation of IMPDH2 expression. Our study verified that overexpressing IMPDH2 could promote G1/S phase cell cycle transition through activation of PI3K/AKT/mTOR and PI3K/AKT/FOXO1 pathways and facilitate cell invasion, migration and EMT by regulating PI3K/AKT/mTOR pathway. CONCLUSIONS: These results suggest that IMPDH2 plays an important role in the development and progression of human CRC and may serve as a novel prognostic biomarker and therapeutic target for CRC. PMID- 30518406 TI - First demonstration of the circulation of a pneumovirus in French pigs by detection of anti-swine orthopneumovirus nucleoprotein antibodies. AB - The presence of pneumoviruses in pigs is poorly documented. In this study, we used the published sequence of the nucleoprotein (N) of the recently identified Swine Orthopneumovirus (SOV) to express and purify SOV N as a recombinant protein in Escherichia coli. This protein was purified as nanorings and used to set up an enzyme-linked immunosorbent assay, which was used to analyse the presence of anti pneumovirus N antibodies in swine sera. Sera collected from different pig farms in the West of France and from specific pathogen free piglets before colostrum uptake showed indirectly that a pneumovirus is circulating in pig populations with some variations between animals. Piglets before colostrum uptake were sero negative for anti-pneumovirus antibodies while most of the other pigs showed positivity. Interestingly, in two farms presenting respiratory clinical signs and negative or under control for some common respiratory pathogens, pigs were detected positive for anti-pneumovirus antibodies. Globally, anti-pneumovirus N antibody concentrations were variable between and within farms. Further studies will aim to isolate the circulating virus and determine its potential pathogenicity. SOV could potentially become a new member of the porcine respiratory complex, important on its own or in association with other viral and bacterial micro-organisms. PMID- 30518407 TI - NmeCas9 is an intrinsically high-fidelity genome-editing platform. AB - BACKGROUND: The development of CRISPR genome editing has transformed biomedical research. Most applications reported thus far rely upon the Cas9 protein from Streptococcus pyogenes SF370 (SpyCas9). With many RNA guides, wildtype SpyCas9 can induce significant levels of unintended mutations at near-cognate sites, necessitating substantial efforts toward the development of strategies to minimize off-target activity. Although the genome-editing potential of thousands of other Cas9 orthologs remains largely untapped, it is not known how many will require similarly extensive engineering to achieve single-site accuracy within large genomes. In addition to its off-targeting propensity, SpyCas9 is encoded by a relatively large open reading frame, limiting its utility in applications that require size-restricted delivery strategies such as adeno-associated virus vectors. In contrast, some genome-editing-validated Cas9 orthologs are considerably smaller and therefore better suited for viral delivery. RESULTS: Here we show that wildtype NmeCas9, when programmed with guide sequences of the natural length of 24 nucleotides, exhibits a nearly complete absence of unintended editing in human cells, even when targeting sites that are prone to off-target activity with wildtype SpyCas9. We also validate at least six variant protospacer adjacent motifs (PAMs), in addition to the preferred consensus PAM (5'-N4GATT-3'), for NmeCas9 genome editing in human cells. CONCLUSIONS: Our results show that NmeCas9 is a naturally high-fidelity genome-editing enzyme and suggest that additional Cas9 orthologs may prove to exhibit similarly high accuracy, even without extensive engineering. PMID- 30518408 TI - Association between autophagy and inflammation in patients with rheumatoid arthritis receiving biologic therapy. AB - BACKGROUND: Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. METHODS: In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. RESULTS: Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p < 0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p < 0.05; and 13.1, p < 0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-alpha inhibitors or interleukin-6 receptor inhibitor. CONCLUSIONS: Elevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression. PMID- 30518409 TI - Treatment duration with immune-based therapies in Cancer: an enigma. AB - Unlike chemotherapy treatments that target the tumor itself (rather nonspecifically), immune-based therapies attempt to harness the power of an individual patient's immune system to combat cancer. Similar to chemotherapeutic agents, the dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors (immunotherapy) recommends duration of treatment until disease progression or unacceptable toxicity. Overactivation or constitutive activation of the immune system with immune based therapies can lead to T-cell exhaustion and activation induced cell death (AICD) in T- and B-cells. Examples of immune exhaustion and T-cell depletion is noted in preclinical and clinical studies. Overactivation or constitutive activation leading to Immune exhaustion is a real phenomenon and of profound concern as immune cells are the true arsenal for control of the tumor growth. Designing trials rigorously to address the optimum treatment duration with immune based therapies is critical. By addressing this concern now, not only we may improve patient outcomes, but also gather a deeper understanding of the role and mechanisms of the immune system in the control of tumor growth.Chemotherapy and immune-based therapies provide antitumor effects through completely different mechanisms. Chemotherapeutic agents are cytotoxic in that they directly inhibit basic cellular mechanisms, killing both malignant and nonmalignant cells (hopefully with a preference for malignant cells), while immune based therapies wake-up the host immune system to recognize malignant cells and eliminate them.While there is a burgeoning excitement surrounding development of immune based therapies for the treatment of cancer, the optimal duration for these therapies need to be explored with equal fervor. Dosing for chemotherapy has been determined over years through large-scale prospective randomized trials to pinpoint the dose which maximizes therapeutic effect while minimizing side effects. Also, due to the mechanism of chemotherapeutic action, the duration of treatment with these agents is generally until disease progression or patient intolerance. However, experience with immune based therapies is limited, with current dosing and duration guidelines based primarily on initial trials required for approval of the agents. Since immune based therapies work by activating the body's own immune system, there is concern that overactivation or constitutive activation of the immune system may lead to immune exhaustion and depletion of effector T-cells thereby causing decreased anti-tumor effects and possible allowing for tumor progression.Similar to chemotherapeutic agents, the Dosage and Administration section of labeling for all five currently approved PD-1/PD-L1 inhibitors recommends duration of treatment until disease progression or unacceptable toxicity. However, since immune based therapies work with a completely different mechanism compared to chemotherapy, using the same therapy duration may not be the optimal approach.In exploring treatment duration with immune based therapies, we need to answer the following: (1) does indefinite treatment with immune based therapies exhaust the immune system counteracting its own mechanism of action leading to tumor progression and (2) how can clinical trials be designed to identify the optimal duration of immune-based therapy that prevents immune cell exhaustion but supports anti-tumor immunity. PMID- 30518410 TI - Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor induced colitis: a multi-center study. AB - BACKGROUND: Immune-mediated diarrhea and colitis (IMDC) can limit immune checkpoint inhibitors (ICIs) treatment, which is efficacious for advanced malignancies. Steroids and infliximab are commonly used to treat it. These agents induce systemic immunosuppression, with its associated morbidity. We assessed clinical outcomes of vedolizumab as an alternative treatment for IMDC. METHODS: We analyzed a retrospective case series of adults who had IMDC refractory to steroids and/or infliximab and received vedolizumab from 12/2016 through 04/2018. RESULTS: Twenty-eight patients were included. The median time from ICI therapy to IMDC onset was 10 weeks. Fifteen patients (54%) had grade 2 and 13 (46%) had grade 3 or 4 IMDC. Mucosal ulceration was present in 8 patients (29%), and nonulcerative inflammation was present in 13 (46%). All patients had features of active histologic inflammation; 14 (50%) had features of chronicity, and 10 (36%) had features of microscopic colitis concurrently. The mean duration of steroid therapy was 96 days (standard deviation 74 days). Nine patients received infliximab in addition to steroids and their IMDC was refractory to it. Among these, the duration of steroid use was 131 days compared with 85 days in patients who did not receive infliximab. Likewise, patients who failed infliximab before vedolizumab had a clinical success rate of 67% compared to 95% for patients that did not receive infliximab. The median number of vedolizumab infusions was 3 (interquartile range 1-4). The mean duration of follow-up was 15 months. Twenty four patients (86%) achieved and sustained clinical remission. Repeat endoscopic evaluation was performed in 17 patients. Endoscopic remission was attained in 7 (54%) of the 13 patients who had abnormal endoscopic findings initially; 5/17 patients (29%) reached histologic remission as well. CONCLUSIONS: Vedolizumab can be appropriate for the treatment of steroid-refractory IMDC, with favorable outcomes and a good safety profile. PMID- 30518411 TI - Diagnostic accuracy of molecular methods for detecting markers of antimalarial drug resistance in clinical samples of Plasmodium falciparum: protocol for an update to a systematic review and meta-analysis. AB - BACKGROUND: Each year, infection with Plasmodium causes millions of clinical cases of malaria and hundreds of thousands of deaths. Resistance to different antimalarial medications continues to develop and spread, threatening effective prophylaxis and treatment. Surveillance of resistance is required to inform health policy and preserve effective antimalarial drugs; molecular methods can be used to surveil likely parasite resistances. However, there is no consensus on the most accurate molecular methods, and large variation exists in practice. The objective of this update to this systematic review is to improve and update identification of the sensitivity and specificity of each molecular method for detecting selected antimalarial drug resistance markers. METHODS: We will include diagnostic accuracy studies that compare at least two of any molecular methods to examine blood samples from patients diagnosed with, or suspected of having malaria, to detect at least one selected marker of antimalarial drug resistance. We will search PubMed, EMBASE, BIOSIS, and Web of Science from 2000 to present. Two reviewers will independently screen all results, extract data, consider applicability, and evaluate the methodological quality of included studies using QUADAS-2. We will carry out a meta-analysis and use statistical methods to compare results from homogenous studies. We will use narrative to synthesise and compare results of heterogeneous studies. DISCUSSION: This review will help to identify sub-optimal molecular methods for antimalarial marker detection which may be discontinued and identify more sensitive and specific methods which may be adopted. More sensitive and specific detection of drug resistance can be used to improve the breadth and accuracy of surveillance. This would enable the identification of previously undiscovered areas of antimalarial resistances and susceptibilities, improve the precision of estimates of the prevalence of resistances, and improve our ability to detect smaller changes in these patterns. Higher-quality evidence generated by more accurate and detailed surveillance can be used to inform guidelines on the use of antimalarial drugs, leading to better outcomes for more patients. SYSTEMATIC REVIEW REGISTRATION: This systematic review protocol was registered with PROSPERO on 22 November 2017 (registration number CRD42017082101 ). PMID- 30518412 TI - A randomized, blinded, controlled trial to assess sand fly mortality of fluralaner administered orally in dogs. AB - BACKGROUND: Leishmania infantum is the parasite responsible for the disease in humans known as zoonotic visceral leishmaniasis (ZVL). Dogs are considered the main domestic reservoir of ZVL and sand flies are the proven vectors. The use of systemic insecticides in dogs has been studied as an alternative strategy to control ZVL in endemic areas. One systemic insecticide in dogs, fluralaner, has a proven anti-sand fly effect in membrane-fed studies. However, the efficacy and duration on sand flies directly feeding from dogs treated with fluralaner remains unknown. METHODS: Direct feeding bioassays were performed on 10 beagle dogs that had been randomly assigned to two groups: one with five dogs orally treated with Bravecto(r) (fluralaner) and other five as a control. About 30 females of Phlebotomus papatasi were allowed to directly feed from dogs at seven days before the administration of the treatment and Days 3, 17, 31, 45 and 73 post-treatment. Sand fly mortality after feeding was observed every 24 h for 5 days. The Kaplan Meyer method, Henderson-Tilton formula and a negative binomial mixed model were used to respectively calculate: (i) mortality and its 95% confidence interval (CI); (ii) efficacy of the insecticide at killing sand flies in 24 h; and (iii) differences in the risk of sand fly death at 24 h after feeding. RESULTS: Control sand fly mortality 24 h after feeding was always <= 20% and mortality in the fluralaner group ranged from 2% (95% CI: 0-4%) 7 days before treatment to 100% at 3 days post-treatment. Fluralaner efficacy was 100, 93, 94 and 75% at Days 3, 17, 31 and 45, respectively (P < 0.0001). The increase in the risk of sand fly death was 32.9 (95% CI: 4-263), 76 (95% CI: 8-705), 95.8 (95% CI: 9-1029) and 10.6 times (95% CI: 1.43-79) on Days 3, 17, 31 and 45, respectively CONCLUSIONS: The efficacy of fluralaner, orally administered to dogs, against sand-flies was above 90% for 31 days. Fluralaner administered to dogs should be further evaluated as a control strategy in ZVL endemic areas. PMID- 30518413 TI - Isolation and characterization of camelid single-domain antibodies against HER2. AB - OBJECTIVE: To isolate and characterize novel high-affinity llama single-domain antibodies against human HER2. RESULTS: We immunized a llama with human HER2, constructed a phage-displayed VHH library from the lymphocytes of the animal, and isolated six unique HER2-specific VHHs by panning. All six VHHs were unique at the amino acid level and were clonally unrelated, as reflected by their distinct CDR3 lengths. All six VHHs recognized recombinant human HER2 ectodomain with monovalent affinities ranging from 1 to 51 nM, had comparable affinities for cynomolgus monkey HER2, and bound HER2+ SKOV3 cells by flow cytometry. Three of the VHHs recognized recombinant murine HER2 with no loss of affinity compared with human and cynomolgus monkey HER2. The VHHs recognized three major epitopes on HER2 (including one conserved across the human, simian and murine orthologues), all of which were distinct from that of trastuzumab. These VHHs may be useful in the design of modular cancer immunotherapeutics. PMID- 30518414 TI - Validation of extracellular ligand-receptor interactions by Flow-TriCEPS. AB - OBJECTIVE: The advent of ligand-based receptor capture methodologies, allows the identification of unknown receptor candidates for orphan extracellular ligands. However, further target validation can be tedious, laborious and time-consuming. Here, we present a methodology that provides a fast and cost-efficient alternative for candidate target verification on living cells. RESULTS: In the described methodology a ligand of interest (e.g. transferrin, epidermal growth factor or insulin) was conjugated to a linker (TriCEPS) that carries a biotin. To confirm ligand/receptor interactions, the ligand-TriCEPS conjugates were first added onto living cells and cells were subsequently labeled with a streptavidin fluorophore and analyzed by flow cytometry (thus referred as Flow-TriCEPS). Flow TriCEPS was also used to validate identified receptor candidates when combined with a siRNA knock down approach (i.e. reduction of expression levels). This approach is versatile as it can be applied for different classes of ligands (proteins, peptides, antibodies) and different cell lines. Moreover, the method is time-efficient since it takes advantage of the large variety of commercially available (and certified) siRNAs. PMID- 30518415 TI - Rock substrate rather than black stain alterations drives microbial community structure in the passage of Lascaux Cave. AB - BACKGROUND: The World-famous UNESCO heritage from the Paleolithic human society, Lascaux Cave (France), has endeavored intense microclimatic perturbations, in part due to high touristic pressure. These perturbations have resulted in numerous disturbances of the cave ecosystem, including on its microbial compartment, which resulted in the formation of black stains especially on the rock faces of the passage. We investigated the cave microbiome in this part of Lascaux by sampling three mineral substrates (soil, banks, and inclined planes) on and outside stains to assess current cave microbial assemblage and explore the possibility that pigmented microorganisms involved in stain development occur as microbial consortia. METHODS: Microbial abundance and diversity were assessed by means of quantitative PCR and high-throughput sequencing (Illumina MiSeq) of several DNA and cDNA taxonomic markers. Five sampling campaigns were carried out during winter and summer to embrace potential seasonal effect in this somewhat stable environment (based on measurements of temperature and CO2 concentration). RESULTS: While the season or type of mineral substrate did not affect the abundances of bacteria and micro-eukaryotes on or outside stains, mineral substrate rather than stain presence appears to be the most significant factor determining microbial diversity and structuring microbial community, regardless of whether DNA or cDNA markers were considered. A phylogenetic signal was also detected in relation to substrate types, presence of stains but not with season among the OTUs common to the three substrates. Co-occurrence network analyses showed that most bacterial and fungal interactions were positive regardless of the factor tested (season, substrate, or stain), but these networks varied according to ecological conditions and time. Microorganisms known to harbor pigmentation ability were well established inside but also outside black stains, which may be prerequisite for subsequent stain formation. CONCLUSIONS: This first high throughput sequencing performed in Lascaux Cave showed that black stains were secondary to mineral substrate in determining microbiome community structure, regardless of whether total or transcriptionally active bacterial and micro-eukaryotic communities were considered. These results revealed the potential for new stain formation and highlight the need for careful microbiome management to avoid further cave wall degradation. PMID- 30518416 TI - Giant prolactinoma, germline BRCA1 mutation, and depression: a case report. AB - BACKGROUND: Giant prolactinomas are very rare pituitary tumors that may exhibit an aggressive behavior and present with a life-threatening condition. CASE PRESENTATION: A 25-year-old white woman was admitted to our hospital with a headache, psychomotor retardation, reduced vision, and loss of autonomy in daily activities. Her past medical history was significant for having oligomenorrhea and a depressive syndrome since her mother's death. She also had a breast cancer gene 1 (BRCA1) mutation and a family history of breast cancer. She had marked hyperprolactinemia (7615 ng/dL), central hypocortisolism, growth hormone deficiency, and a giant pituitary tumor (52 * 30 * 33 mm) which was shown in magnetic resonance imaging with obstructive hydrocephalus, requiring emergency surgery. Treatment with cabergoline led to a 99.8% reduction in serum prolactin levels and significant tumor shrinkage. Her depressive symptoms progressively improved and psychiatric drugs were withdrawn after 3 months of cabergoline treatment. Currently, she is being followed in Endocrinology, Neurosurgery, and Neurophthalmology out-patient clinics and in a breast cancer unit. Careful monitoring, support, and follow-up will be essential throughout this patient's life. CONCLUSIONS: This case is a rare presentation of a giant prolactinoma in a young woman, who presented a life-threatening event. She also had an unexpected association between diseases or symptoms that may have contributed to the delay in diagnosis. Given the concomitant presence of a giant prolactinoma, a BRCA1 mutation, and depressive symptoms, a possible association was hypothesized. The breast cancer risk in a BRCA1 mutation carrier and the possible interference of hyperprolactinemia and life events were also discussed. However this hypothesis requires further investigation. PMID- 30518417 TI - Sex-related differences in the association between plasma fibrinogen and non calcified or mixed coronary atherosclerotic plaques. AB - BACKGROUND: Plasma fibrinogen (FIB) has been demonstrated to be a risk factor for cardiovascular disease. Patients with non-calcified plaque (NCP) or mix plaque (MP) have a higher risk of poor outcomes. However, the association between FIB and the presence of NCP or MP (NCP/MP) remains unclear, and if present, whether sex has any impact on this association remains unknown. The aim of this study was to investigate the role of FIB in predicting the presence of NCP/MP and evaluate whether sex has any impact on this association. METHODS: A total of 329 subjects were recruited, and the clinical and laboratory data were collected. Plasma FIB was detected by enzyme-linked immunosorbent assay. According to whether they had coronary atherosclerotic plaques and the characteristics of the most stenotic plaque, we divided them into three groups: no plaque (NP), calcified plaque (CP), and NCP/MP. RESULTS: Patients with NCP/MP had significantly higher FIB level in females, but not in males. Multiple logistic regression analysis showed that FIB was an independent risk factor for the presence of NCP/MP (odds ratio [OR] = 3.677, 95% CI 1.539-8.785, P = 0.003) in females. Receiver operating characteristic (ROC) curve analysis showed that the optimal cut-off value FIB for predicting the presence of NCP/MP was 3.41 g/L (area under curve [AUC] = 0.73, 95% CI 0.63-0.82, P < 0.001) in females. CONCLUSIONS: FIB is independently associated with the presence of NCP/MP in females, but not in males. These results suggest that the potential significance of FIB-lowering regimens in females with NCP/MP. PMID- 30518418 TI - Professional learning and development of postdoctoral scholars: a scoping review protocol. AB - BACKGROUND: A growing number of postdoctoral scholars are following diverse career paths that require broad skill sets to ensure success. Yet, most postdoctoral professional learning and development initiatives are intended for academic careers and seldom include professional skills needed to succeed in non academic settings. Given that fewer than 20% of postdoctoral scholars will obtain tenure-track academic positions, there is a great need for postdoctoral scholars to prepare for a range of future careers. Creating professional learning and development strategies to address these concerns requires an understanding of current approaches, yet there is a distinct lack of literature exploring and synthesizing sources of evidence on the professional learning and development of postdoctoral scholars. The purpose of this scoping review is to examine, synthesize, and map the sources of evidence on professional learning and development pertaining to postdoctoral scholars. METHODS: We will perform a scoping review to identify sources of evidence around professional learning and development of postdoctoral scholars. Our search strategy, limited to English language, will include searching relevant disciplinary and interdisciplinary databases with no limitation on date of publication. We will conduct forward and backward citation chasing of included articles. Gray literature will be searched in electronic databases and websites of national postdoctoral associations. Search strategies will be developed using controlled vocabulary and keyword terms related to postdoctoral scholars and professional development. Two reviewers will independently screen titles and abstracts for inclusion, and two reviewers will independently screen full text to determine final inclusion. These data will be summarized quantitatively (using a simple numerical count) and qualitatively using thematic analysis methods. Through this process, we will summarize the current state of evidence around professional development and learning of postdoctoral scholars and identify current gaps in the literature, as well as the research areas requiring systematic reviews and/or primary research. DISCUSSION: Despite the growing numbers of postdoctoral scholars, there has been no synthesis of the sources of evidence of postdoctoral scholars' professional learning and development. In reviewing a wide range of evidence and integrating it into a manageable and meaningful whole, this scoping review will be a critical first step in understanding the professional learning and development of postdoctoral scholars. Our results will help inform future research and the development of a framework for postdoctoral scholar's professional learning and development. PMID- 30518419 TI - Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 (MSP-1) among Plasmodium knowlesi samples from Malaysia. AB - BACKGROUND: The merozoite surface protein-1 (MSP-1) gene encodes for a leading malaria vaccine candidate antigen. However, its extensive polymorphic nature represents a major obstacle to the development of a protective vaccine. Previously, a pilot study was carried out to explore the sequence variation of the C-terminal 42 kDa fragment within P. knowlesi MSP-1 gene (PkMSP-142) based on 12 clinical samples; however, further study on an adequate sample size is vital in estimating the genetic diversity of the parasite population. METHODS: In the present study, we included a larger sample size of P. knowlesi (83 samples) covering eight states of Malaysia to determine the genetic polymorphism, natural selection and haplotype groups of the gene fragment coding PkMSP-142. The region flanking PkMSP-142 was amplified by PCR and directly sequenced. Genetic diversity, haplotype diversity, population genetic differentiation and natural selection were determined in order to study the polymorphic characteristic of PkMSP-142. RESULTS: A high level of genetic diversity (Hd = 0.970 +/- 0.007; l = 0.01079 +/- 0.00033) was observed among the 83 P. knowlesi samples, confirming the extensive genetic polymorphism exhibited among the P. knowlesi population found in Malaysia. A total of 18 distinct haplotypes with 17 amino acid changes were identified, whereby 15 were new haplotypes. High population differentiation values were observed within samples from Peninsular Malaysia and Malaysian Borneo. The 42 kDa fragments of P. knowlesi from Malaysian Borneo were found to be acting on balancing selection whilst purifying selection was suggested to act on isolates from Peninsular Malaysia. The separation of PkMSP-142 haplotypes into two main groups based on geographical separation has further supported the existence of two distinct P. knowlesi lineages. CONCLUSIONS: A high level of genetic diversity was observed among PkMSP-142 in Malaysia, whereby most of the polymorphisms were found within the 33 kDa region. Taken together, these data will be useful in order to understand the nature of P. knowlesi population in Malaysia as well as the design and development of a MSP-142 based knowlesi malaria vaccine. PMID- 30518420 TI - Risk factors for human brucellosis among a pastoralist community in South-West Kenya, 2015. AB - OBJECTIVE: Brucellosis is one of the top five priority zoonosis in Kenya because of the socio-economic burden of the disease, especially among traditional, livestock keeping communities. We conducted a 1 year, hospital based, unmatched case-control study to determine risk factors for brucellosis among Maasai pastoralists of Kajiado County in 2016. A case was defined by a clinical criteria; fever or history of fever and two clinical signs suggestive of brucellosis and a positive competitive enzyme-linked immunosorbent assay test (c ELISA). A control was defined as patients visiting the study facility with negative c-ELISA. Unconditional logistic regression was used to study association between exposure variables and brucellosis using odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Forty-three cases and 86 controls were recruited from a population of 4792 individuals in 801 households. The mean age for the cases was 48.7 years while that of the controls was 37.6 years. The dominant gender for both cases (62.7%) and controls (58.1%) groups was female. Regular consumption of un-boiled raw milk and assisting animals in delivery were significantly associated with brucellosis by OR 7.7 (95% CI 1.5-40.1) and OR 3.7 (95% CI 1.1-13.5), respectively. PMID- 30518421 TI - Is KingVision videolaryngoscope with a bougie really an effective solution for emergency intubation? PMID- 30518422 TI - Oral vaccination with Trichinella spiralis DNase II DNA vaccine delivered by attenuated Salmonella induces a protective immunity in BALB/c mice. AB - Trichinellosis is one of the most serious foodborne parasitic zoonosis with worldwide distribution, and it is necessary to develop a vaccine to interrupt transmission from animals to humans. Trichinella spiralis adult-specific DNase II 1 (TsDNase II) were identified by immunoproteomics in surface or excretory/secretory proteins of adult worms (AW) and intestinal infective larvae (IIL). The aim of this study was to investigate the systemic, mucosal responses and immune protection elicited by oral vaccination with TsDNase II DNA vaccine delivered by attenuated Salmonella typhimurium strain?cyaSL1344. Oral vaccination with TsDNase II DNA vaccine triggered an obvious mucosal sIgA response and a systemic IgG response in mice, and IgG1 was predominant. Th1 (IFN-gamma) and Th2 (IL-4, 10) cytokines were distinctly increased in the spleen and mesenteric lymph node (MLN) cells of vaccinated mice. An indirect immunofluorescent test revealed that native TsDNase II is present at the cuticle of this nematode after the 2nd molting, further confirming that TsDNase II is adult-specific and expressed at AW and pre-adult stages. Oral immunization of mice with TsDNase II exhibited a 53.85% reduction in AW and a 59.26% reduction in ML after larval challenge. The in vitro NBL production of adult females from TsDNase II-vaccinated mice was also reduced in comparison with pcDNA3.1 or the PBS control group (P < 0.01). Our results show that oral immunization of mice with TsDNase II produced an intestinal and systematic concurrent Th1/Th2 immune response, and a significant immune protection against challenge. PMID- 30518423 TI - Didn't inhale? Time to reconsider aerosolized antibiotics in the treatment of ventilator-associated pneumonia. PMID- 30518424 TI - STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway. AB - BACKGROUND: Cancer stem cells (CSCs) possess abilities of self-renewal and differentiation, have oncogenic potential and are regarded to be the source of cancer recurrence. However, the mechanism by which CSCs maintain their stemness remains largely unclear. METHODS: In this study, the cell line-derived ovarian CSCs (OCSCs), 3AO and Caov3, were enriched in serum-free medium (SFM). Differentially expressed proteins were compared between the OCSC subpopulation and parental cells using liquid chromatography (LC)-mass spectrometry (MS)/MS label-free quantitative proteomics. Sphere-forming ability assays, flow cytometry, quantitative real-time polymerase chain reaction (qPCR), western blotting, and in vivo xenograft experiments were performed to evaluate stemness. RNA-sequencing (RNA-seq) and pyrosequencing were used to reveal the mechanism by which STON2 negatively modulates the stem-like properties of ovarian cancer cells. RESULTS: Among the 74 most differentially expressed proteins, stonin 2 (STON2) was confirmed to be down-regulated in the OCSC subpopulation. We show that STON2 negatively modulates the stem-like properties of ovarian cancer cells, which are characterized by sphere formation, a CD44+CD24- ratio, and by CSC- and epithelial mesenchymal transition (EMT)-related markers. STON2 knockdown also accelerated tumorigenesis in NOD/SCID mice. Further investigation revealed a downstream target, mucin 1 (MUC1), as up-regulated upon the down regulation of STON2. A decrease in both DNA methyltransferase 1 (DNMT1) expression and methylation in the promoter region of MUC1 was associated with subsequently elevated MUC1 expression, as detected in STON2 knockdown in 3AO and Caov3 cells. Direct DNMT1 knockdown simultaneously elevated MUC1 expression. The functional significance of this STON2-DNMT1/MUC1 pathway is supported by the observation that STON2 overexpression suppresses MUC1-induced sphere formation of OCSCs. The paired expression of STON2 and MUC1 in ovarian cancer specimens was also detected revealing the prognostic value of STON2 expression to be highly dependent on MUC1 expression. CONCLUSIONS: Our results imply that STON2 may negatively regulate stemness in ovarian cancer cells via DNMT1-MUC1 mediated epigenetic modification. STON2 is therefore involved in OCSC biology and may represent a therapeutic target for innovative treatments aimed at ovarian cancer eradication. PMID- 30518425 TI - Immunological analysis of phase II glioblastoma dendritic cell vaccine (Audencel) trial: immune system characteristics influence outcome and Audencel up-regulates Th1-related immunovariables. AB - Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via "danger signals". The recent phase II "GBM-Vax" trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel's effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel's general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up regulation of the Th1-related immunovariables ELISPOT IFNgamma, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNgamma and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further - with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers. PMID- 30518427 TI - Cost-effectiveness of vaccination of immunocompetent older adults against herpes zoster in the Netherlands: a comparison between the adjuvanted subunit and live attenuated vaccines. AB - BACKGROUND: The newly registered adjuvanted herpes zoster subunit vaccine (HZ/su) has a higher efficacy than the available live-attenuated vaccine (ZVL). National decision-makers soon need to decide whether to introduce HZ/su or to prefer HZ/su above ZVL. METHODS: Using a Markov model with a decision tree, we conducted a cost-effectiveness analysis of vaccination with HZ/su (two doses within 2 months) or zoster vaccine live (ZVL) (single dose, or single dose with a booster after 10 years) for cohorts of 50-, 60-, 70- or 80-year-olds in the Netherlands. The model was parameterized using vaccine efficacy data from randomized clinical trials and up-to-date incidence, costs and health-related quality of life data from national datasets. We used a time horizon of 15 years, and the analysis was conducted from the societal perspective. RESULTS: At a coverage of 50%, vaccination with two doses of HZ/su was estimated to prevent 4335 to 10,896 HZ cases, depending on the cohort age. In comparison, this reduction was estimated at 400-4877 for ZVL and 427-6466 for ZVL with a booster. The maximum vaccine cost per series of HZ/su to remain cost-effective to a willingness-to-pay threshold of ?20,000 per quality adjusted life year (QALY) gained ranged from ?109.09 for 70-year-olds to ?63.68 for 50-year-olds. The cost-effectiveness of ZVL changed considerably by age, with corresponding maximum vaccine cost per dose ranging from ?51.37 for 60-year-olds to ?0.73 for 80-year-olds. Adding a ZVL booster after 10 years would require a substantial reduction of the maximum cost per dose to remain cost-effective as compared to ZVL single dose. Sensitivity analyses on the vaccine cost demonstrated that there were scenarios in which vaccination with either HZ/su (two doses), ZVL single dose or ZVL + booster could be the most cost-effective strategy. CONCLUSIONS: A strategy with two doses of HZ/su was superior in reducing the burden of HZ as compared to a single dose or single dose + booster of ZVL. Both vaccines could potentially be cost-effective to a conventional Dutch willingness-to-pay threshold for preventive interventions. However, whether HZ/su or ZVL would be the most cost-effective alternative depends largely on the vaccine cost. PMID- 30518426 TI - Molecular characterization of a 31 kDa protein from Trichinella spiralis and its induced immune protection in BALB/c mice. AB - BACKGROUND: Trichinella spiralis is an important foodborne zoonotic parasite and it is necessary to develop a vaccine in order to interrupt transmission from animals to humans. A 31 kDa protein from T. spiralis (Ts31) is an antigen targeted by protective antibodies, and Ts31 contains a domain of trypsin-like serine protease that might have the function of serine protease. The purpose of this study was to investigate the molecular characteristics of Ts31 and its induced immune protection. METHODS: Expression and localization of Ts31 in various T. spiralis phases were investigated using qPCR and immunofluorescent test (IFT). The specific binding between Ts31 and intestinal epithelium cells (IECs) was analyzed by Far-Western blotting, ELISA and IFT, and the cellular localization of binding sites was examined on confocal microscopy. The mice were subcutaneously vaccinated with recombinant Ts31 protein (rTs31), serum specific IgG was determined by ELISA, and immune protection induced by immunization with rTs31 was evaluated. Inhibition of anti-rTs31 IgG on IL1 invasion of IECs and ADCC-mediated killing of newborn larvae (NBL) was also determined. RESULTS: Ts31 was expressed at different life-cycle stages and located principally at the stichosome and cuticle of this parasite. rTs31 was capable to specially bond to IECs, and binding site was located in the cytoplasm of IECs. Immunization of mice with rTs31 elicited a significant humoral response and protection, as demonstrated by a 56.93% reduction of adult worms at 6 days post-infection (dpi) and a 53.50% reduction of muscle larvae at 42 dpi after larval challenge. Anti rTs31 antibodies impeded T. spiralis penetration of enterocytes in a dose dependent pattern, and participated in the destruction of NBL by an ADCC-mediated manner. CONCLUSIONS: Ts31 facilitated the T. spiralis penetration of intestinal epithelium, which could make it a vaccine candidate target molecule against Trichinella infection. PMID- 30518428 TI - Using operating room turnover time by anesthesia trainee level to assess improving systems-based practice milestones. AB - BACKGROUND: Operating room (OR) metrics are frequently cited when optimizing cost efficacy and quality of care (Weiss et al, Characteristics of operating room procedures in U.S. hospitals, 2011: Statistical brief #170, 2013; Macario A, Anesthesiology 105:237-240, 2006; Childers et al, JAMA Surg 153:e176233, 2018). Little has been reported to evaluate how anesthesia trainees change anesthesia related efficiencies in the OR. Statistical correlation may demonstrate awareness and implementation of efficient systems-based practice. METHODS: Utilizing computerized OR information systems, specific data regarding anesthesia controlled turnover times were collected (546 data points) over the course of 4 months. The type of surgery performed, patient's American Society of Anesthesiologists (ASA) physical status and OR turnover times were compared for clinical anesthesia (CA) trainee levels CA1, CA2, CA3 and CRNAs. Standard descriptive statistics were computed. Analysis of variance (ANOVA) was performed to compare the average turnover time. RESULTS: Average OR turnover time was 31 min ranging from 8 to 60 min. There was a significant difference between the OR turnover time of CA-1 (32 min) compared to CA-3 (29 min) (p = 0.017) and CA-1 compared to CRNA (30 min) (p = 0.016). OR turnover time was significantly shorter in CA-3 and CRNA. The analysis showed no differences between OR turnover time of ASA categories. CONCLUSIONS: These findings posit that trainees improve efficiency over time, but that education may for a time come at the expense of productivity. This trend may demonstrate a more profound understanding and mastery of a learner progressing in the graduate medical education system. This interplay plays a key role in clinical and academic shared success. PMID- 30518429 TI - Heavy drinking and contextual risk factors among adults in South Africa: findings from the International Alcohol Control study. AB - BACKGROUND: There is limited information about the potential individual-level and contextual drivers of heavy drinking in South Africa. This study aimed to identify risk factors for heavy drinking in Tshwane, South Africa. METHODS: A household survey using a multi-stage stratified cluster random sampling design. Complete consumption and income data were available on 713 adults. Heavy drinking was defined as consuming >=120 ml (96 g) of absolute alcohol (AA) for men and >= 90 ml (72 g) AA for women at any location at least monthly. RESULTS: 53% of the sample were heavy drinkers. Bivariate analyses revealed that heavy drinking differed by marital status, primary drinking location, and container size. Using simple logistic regression, only cider consumption was found to lower the odds of heavy drinking. Persons who primarily drank in someone else's home, nightclubs, and sports clubs had increased odds of heavy drinking. Using multiple logistic regression and adjusting for marital status and primary container size, single persons were found to have substantially higher odds of heavy drinking. Persons who drank their primary beverage from above average-sized containers at their primary location had 7.9 times the odds of heavy drinking as compared to persons who drank from average-sized containers. Some significant associations between heavy drinking and age, race, and income were found for certain beverages. CONCLUSION: Rates of heavy drinking were higher than expected giving impetus to various alcohol policy reforms under consideration in South Africa. Better labeling of the alcohol content of different containers is needed together with limiting production, marketing and serving of alcohol in large containers. PMID- 30518430 TI - Economic evaluation of the NET intervention versus guideline dissemination for management of mild head injury in hospital emergency departments. AB - BACKGROUND: Evidence-based guidelines for the management of mild traumatic brain injury (mTBI) in the emergency department (ED) are now widely available, and yet, clinical practice remains inconsistent with the guidelines. The Neurotrauma Evidence Translation (NET) intervention was developed to increase the uptake of guideline recommendations and improve the management of minor head injury in Australian emergency departments (EDs). However, the adoption of this type of intervention typically entails an upfront investment that may or may not be fully offset by improvements in clinical practice, health outcomes and/or reductions in health service utilisation. The present study estimates the cost and cost effectiveness of the NET intervention, as compared to the passive dissemination of the guideline, to evaluate whether any improvements in clinical practice or health outcomes due to the NET intervention can be obtained at an acceptable cost. METHODS AND FINDINGS: Study setting: The NET cluster randomised controlled trial [ACTRN12612001286831]. STUDY SAMPLE: Seventeen EDs were randomised to the control condition and 14 to the intervention. One thousand nine hundred forty three patients were included in the analysis of clinical practice outcomes (NET sample). A total of 343 patients from 14 control and 10 intervention EDs participated in follow-up interviews and were included in the analysis of patient reported health outcomes (NET-Plus sample). OUTCOME MEASURES: Appropriate post traumatic amnesia (PTA) screening in the ED (primary outcome). Secondary clinical practice outcomes: provision of written information on discharge (INFO) and safe discharge (defined as CT scan appropriately provided plus PTA plus INFO). Secondary patient-reported, post-discharge health outcomes: anxiety (Hospital Anxiety and Depression Scale), post-concussive symptoms (Rivermead), and preference-based health-related quality of life (SF6D). METHODS: Trial-based economic evaluations from a health sector perspective, with time horizons set to coincide with the final follow-up for the NET sample (2 months post-intervention) and to 1-month post-discharge for the NET-Plus sample. RESULTS: Intervention and control groups were not significantly different in health service utilisation received in the ED/inpatient ward following the initial mTBI presentation (adjusted mean difference $23.86 per patient; 95%CI - $106, $153; p = 0.719) or over the longer follow-up in the NET-plus sample (adjusted mean difference $341.78 per patient; 95%CI - $58, $742; p = 0.094). Savings from lower health service utilisation are therefore unlikely to offset the significantly higher upfront cost of the intervention (mean difference $138.20 per patient; 95%CI $135, $141; p < 0.000). Estimates of the net effect of the intervention on total cost (intervention cost net of health service utilisation) suggest that the intervention entails significantly higher costs than the control condition (adjusted mean difference $169.89 per patient; 95%CI $43, $297, p = 0.009). This effect is larger in absolute magnitude over the longer follow-up in the NET-plus sample (adjusted mean difference $505.06; 95%CI $96, $915; p = 0.016), mostly due to additional health service utilisation. For the primary outcome, the NET intervention is more costly and more effective than passive dissemination; entailing an additional cost of $1246 per additional patient appropriately screened for PTA ($169.89/0.1363; Fieller's 95%CI $525, $2055). For NET to be considered cost-effective with 95% confidence, decision-makers would need to be willing to trade one quality-adjusted life year (QALY) for 25 additional patients appropriately screened for PTA. While these results reflect our best estimate of cost-effectiveness given the data, it is possible that a NET intervention that has been scaled and streamlined ready for wider roll-out may be more or less cost effective than the NET intervention as delivered in the trial. CONCLUSIONS: While the NET intervention does improve the management of mTBI in the ED, it also entails a significant increase in cost and-as delivered in the trial-is unlikely to be cost-effective at currently accepted funding thresholds. There may be a scope for a scaled-up and streamlined NET intervention to achieve a better balance between costs and outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612001286831 , date registered 12 December 2012. PMID- 30518431 TI - Altered pain processing in people with type I and II diabetes: a protocol for a systematic review and meta-analysis of pain threshold and pain modulation mechanisms. AB - BACKGROUND: Peripheral neuropathies are a common complication in patients with diabetes. Changes in nerve function and central pain processing can be quantified by assessing pain thresholds and pain modulation mechanisms. AIM: To summarise the literature which compares pain thresholds and pain modulation mechanisms in people with diabetes without neuropathies, with non-painful diabetic neuropathies and with painful diabetic neuropathies, and in people without diabetes. METHODS: A systematic review and meta-analysis will be conducted. Terms related to diabetes, pain thresholds and pain modulation mechanisms will be combined in a structured search in MEDLINE, CINAHL, EMBASE, the Cochrane Library, SPORTDiscus, Web of Science and PEDro. Publications on adults (18 years and older) with diabetes and at least one pain threshold measure following thermal, mechanical or electrical stimuli and/or at least one pain modulation mechanisms (temporal summation or conditioned pain modulation) with a comparison group will be considered. There will be no restriction regarding language or year of publication. One investigator will screen records based on title and abstract (ESS). Two independent investigators (ESS and MC) will select full-text papers and assess risk of bias using a modified Downs and Black checklist. Potential disagreements will be resolved with a third investigator (LB). One investigator (ESS) will extract all data and a second investigator (MS) will extract data for 20% of the papers to verify accuracy of the process. A sensitivity analysis for publication bias will be conducted. DISCUSSION: This systematic review and meta analysis will summarise the evidence on pain threshold profiles and pain modulation mechanisms in people with diabetes without and with neuropathies (both painful and non-painful). This will provide more insight in the clinical presentation and progression of diabetic neuropathies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018088173. PMID- 30518432 TI - The GLP-1 analog, liraglutide prevents the increase of proinflammatory mediators in the hippocampus of male rat pups submitted to maternal perinatal food restriction. AB - BACKGROUND: Perinatal maternal malnutrition is related to altered growth of tissues and organs. The nervous system development is very sensitive to environmental insults, being the hippocampus a vulnerable structure, in which altered number of neurons and granular cells has been observed. Moreover, glial cells are also affected, and increased expression of proinflammatory mediators has been observed. We studied the effect of Glucagon-like peptide-1 receptor (GLP 1R) agonists, liraglutide, which have very potent metabolic and neuroprotective effects, in order to ameliorate/prevent the glial alterations present in the hippocampus of the pups from mothers with food restriction during pregnancy and lactation (maternal perinatal food restriction-MPFR). METHODS: Pregnant Sprague Dawley rats were randomly assigned to 50% food restriction (FR; n = 12) or ad libitum controls (CT, n = 12) groups at day of pregnancy 12 (GD12). From GD14 to parturition, pregnant FR and CT rats were treated with liraglutide (100 MUg/kg) or vehicle. At postnatal day 21 and before weaning, 48 males and 45 females (CT and MPFR) were sacrificed. mRNA expression levels of interleukin-1beta (IL1beta), interleukin-6 (IL-6), nuclear factor-kappabeta, major histocompatibility complex II (MHCII), interleukin 10 (IL10), arginase 1 (Arg1), and transforming growth factor (TGFbeta) were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 and GFAP-immunoreactivity were assessed by immunocytochemistry. RESULTS: The mRNA expression IL1beta, IL6, NF-kappaB, and MHCII increased in the hippocampus of male but not in female pups from MPFR. In addition, there was an increase in the percentage of GFAP and Iba1-immupositive cells in the dentate gyrus compared to controls, indicating an inflammatory response in the brain. On the other hand, liraglutide treatment prevented the neuroinflammatory process, promoting the production of anti-inflammatory molecules such as IL10, TGFbeta, and arginase 1, and decreasing the number and reactivity of microglial cells and astrocytes in the hippocampus of male pups. CONCLUSION: Therefore, the GLP-1 analog, liraglutide, emerges as neuroprotective drug that minimizes the harmful effects of maternal food restriction, decreasing neuroinflammation in the hippocampus in a very early stage. PMID- 30518433 TI - Utilization of long acting reversible contraceptive methods and associated factors among female college students in Gondar town, northwest Ethiopia, 2018: institutional based cross-sectional study. AB - OBJECTIVES: Family planning is achieved through use of different contraceptive methods among which the most effective methods are modern family planning methods like long acting reversible contraceptive which includes intra-uterine contraceptive device and Implants. The objective of this primary study was to assess utilization of long acting reversible contraceptive methods among female college students in Gondar town, northwest Ethiopia. RESULTS: The overall utilization of long acting reversible contraceptive methods among students was 20.4% (95% CI 18.1, 22.7) and the most commonly utilized long acting reversible contraceptive method was Implants 96.5% (95% CI 95.50, 97.50) followed by intra uterine contraceptive device 3.5% (95% CI 2.97, 4.00). Marital status of the respondents [AOR = 3.97 (95% CI 2.05, 7.67)], discussion about long acting reversible contraceptive methods utilization with husbands or boyfriends [AOR = 2.20 (95% CI 1.19-4.06)] and attitude towards implants [AOR = 0.365 (95% CI 0.14, 0.93)] were found to be significantly associated with utilization of long acting reversible contraceptive among students. PMID- 30518434 TI - The effect of depression management on diabetes and hypertension outcomes in low- and middle-income countries: a systematic review protocol. AB - BACKGROUND: Depression and non-communicable diseases (NCDs) account for a growing burden on health systems in low- and middle-income countries (LMICs). Depression is generally associated with the outcomes of NCDs and is an important barrier to consistent NCD care management. There is great need to understand the efficacy of interventions to treat depression for people with NCDs, but there is a paucity of evidence of the efficacy of the interventions in LMICs. Therefore, the broad objective of this review is to systematically review the literature on the effectiveness of depression management among patients with diabetes and hypertension to improve outcomes. METHODS: This is a systematic review to assess the evidence of the effect of depression management in diabetic and hypertensive patients on diabetes and hypertension outcomes in LMICs. Two independent reviewers will search articles on PubMed, EMBASE, PsycINFO, and Global Index Medicus. Two reviewers will then screen the articles independently based on predefined criteria. We will use standard methods as recommended by the Cochrane Collaboration of assessing quality of evidence and publish our report using the PRISMA guidelines. DISCUSSION: The findings from this review will provide evidence to be used in guiding practice and policy on how to integrate depression management in diabetes and hypertension clinics. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017068257. PMID- 30518435 TI - Bioactive scaffolds in stem-cell-based therapies for cardiac repair: protocol for a meta-analysis of randomized controlled preclinical trials in animal myocardial infarction models. AB - BACKGROUND: Acute myocardial infarction (MI) remains one of the leading causes of death worldwide with no curative therapy available. Stem cell therapies have been gaining interest as a means to repair the cardiac tissue after MI and prevent the onset of heart failure. Many in vivo reports suggest that the use of stem cells is promising, yet clinical trials suggest that the cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function and repair. To battle this limitation, the combination of using stem cells embedded in a bioactive scaffold that promotes cell retention is growing in interest. Yet, a systematic review of the literature on the use of stem cells embedded in bioactive scaffolds for cardiac repair has not yet been performed. In this protocol, we outline a systematic review and meta-analysis of preclinical trials in animal MI models that utilize stem cell-embedded scaffolds for cardiac repair and compare their effects to stem cell-treated animals without the use of a scaffold. METHODS/DESIGN: We will search the following electronic databases: Cochrane Library, MEDLINE, Embase, PubMed, Scopus and Web of Science, and gray literature: Canadian Agency for Drugs and Technologies in Health and Google Scholar. We will only include randomly controlled preclinical trials that have directly investigated the effects of stem cells embedded in a scaffold for cardiac repair in an animal MI model. Two investigators will independently review each article included in the final analysis. The primary endpoint that will be investigated is left ventricular ejection fraction. Secondary endpoints will include infarct size, end systolic volume, end diastolic volume, fractional shortening and left ventricular wall thickness. Pooled analyses will be conducted using the DerSimonian-Laird random effects and Mantel-Haenszel fixed-effect models. Between-studies heterogeneity will be quantified and determined using the Tau2 and I2 statistics. Publication bias will be assessed using visual inspection of funnel plots and complemented by Begg's and Egger's statistical tests. Possible sources of heterogeneity will be assessed using subgroup-meta analysis and meta-regression. DISCUSSION: To date, the use of scaffolds in myocardial repair has not yet been systematically reviewed. The results of this meta analysis will aid in determining the efficacy of stem cell-embedded scaffolds for cardiac repair and help bring this therapy to the clinic. PMID- 30518436 TI - Tumor heterogeneity in gastrointestinal stromal tumors of the small bowel: volumetric CT texture analysis as a potential biomarker for risk stratification. AB - BACKGROUND: To explore whether volumetric CT texture analysis (CTTA) can serve as a potential imaging biomarker for risk stratification of small bowel gastrointestinal stromal tumors (small bowel-GISTs). METHODS: A total of 90 patients with small bowel-GISTs were retrospectively reviewed, of these, 26 were rated as high risk, 13 as intermediate risk, and 51 as low or very low risk. Histogram parameters extracted from CT images were compared among small bowel GISTs with different risk levels by using one-way analysis of variance. Receiver operating characteristics (ROCs) and areas under the curve (AUCs) were analyzed to determine optimal histogram parameters for stratifying tumor risk. RESULTS: Significant differences in mean attenuation, 10th, 25th, 50th, 75th and 90th percentile attenuation, and entropy were found among high, intermediate, and low risk small bowel-GISTs (p <= 0.001). Mean attenuation, 10th, 25th, 50th, 75th and 90th percentile attenuation, and entropy derived from arterial phase and venous phase images correlated significantly with risk levels (r = 0.403-0.594, r = 0.386-0.593, respectively). Entropy in venous phase reached the highest accuracy (AUC = 0.830, p < 0.001) for differentiating low risk from intermediate to high risk small bowel-GISTs, with a cut-off value of 5.98, and the corresponding sensitivity and specificity were 82.4 and 74.4%, respectively. CONCLUSIONS: Volumetric CT texture features, especially entropy, may potentially serve as biomarkers for risk stratification of small bowel-GISTs. PMID- 30518437 TI - Effects of folic acid food fortification scenarios on the folate intake of a multi-ethnic pregnant population. AB - OBJECTIVE: To simulate effects of different scenarios of folic acid fortification of food on dietary folate equivalents (DFE) intake in an ethnically diverse sample of pregnant women. DESIGN: A forty-four-item FFQ was used to evaluate dietary intake of the population. DFE intakes were estimated for different scenarios of food fortification with folic acid: (i) voluntary fortification; (ii) increased voluntary fortification; (iii) simulated bread mandatory fortification; and (iv) simulated grains-and-rice mandatory fortification. SETTING: Ethnically and socio-economically diverse cohort of pregnant women in New Zealand.ParticipantsPregnant women (n 5664) whose children were born in 2009 2010. RESULTS: Participants identified their ethnicity as European (56.0 %), Asian (14.2 %), Maori (13.2 %), Pacific (12.8 %) or Others (3.8 %). Bread, breakfast cereals and yeast spread were main food sources of DFE in the two voluntary fortification scenarios. However, for Asian women, green leafy vegetables, bread and breakfast cereals were main contributors of DFE in these scenarios. In descending order, proportions of different ethnic groups in the lowest tertile of DFE intake for the four fortification scenarios were: Asian (39 60 %), Others (41-44 %), European (31-37 %), Pacific (23-26 %) and Maori (23-27 %). In comparisons within each ethnic group across scenarios of food fortification with folic acid, differences were observed only with DFE intake higher in the simulated grains-and-rice mandatory fortification v. other scenarios. CONCLUSIONS: If grain and rice fortification with folic acid was mandatory in New Zealand, DFE intakes would be more evenly distributed among pregnant women of different ethnicities, potentially reducing ethnic group differences in risk of lower folate intakes. PMID- 30518438 TI - It is ethical to diagnose a public figure one has not personally examined - CORRIGENDUM. PMID- 30518439 TI - Potential Anatomic Markers of Obstructive Sleep Apnea in Prepubertal Children. AB - STUDY OBJECTIVES: Adenotonsillar hypertrophy is the major cause of obstructive sleep apnea (OSA) in prepubertal children, but children without enlarged lymphoid tissues may still suffer from OSA. This study aimed to identify other potential anatomic features associated with childhood OSA. METHODS: This prospective study took place between January 2010 and April 2014. Prepubertal children suspected to have OSA, aged 6 to 11 years, were recruited. They underwent anthropometric measurements, nocturnal polysomnography, tonsil size evaluation, x-ray cephalometry, and sonographic measurement of lateral parapharyngeal wall (LPW) thickness. Linear regression analyses were used to test for the association between anatomic measurements and OSA severity. Logistic regression analyses were used to identify potential anatomic markers for different cutoffs (obstructive apnea-hypopnea index (OAHI) >= 1 and >= 5 events/h) for OSA. RESULTS: Forty-seven children with OSA (20 with moderate to severe disease) and 43 children for the control group were recruited. Sonographic measurement of LPW thickness and position of hyoid bone taken from x-ray cephalometry were risk factors associated with OSA. Linear regression analyses found that these two phenotypes were associated with OAHI. Multivariate models adjusted for age, sex, body mass index, z score, and tonsil size revealed that lower position of hyoid bone was independently associated with higher risk for OSA, whereas both lower position of hyoid bone and greater LPW thickness were associated with higher OAHI and also a higher risk for moderate to severe OSA. CONCLUSIONS: Position of hyoid bone and LPW thickness are anatomical markers of childhood OSA independent of obesity and tonsil size. Screening tools may include cephalometry and sonographic measurement of LPW to allow better delineation of OSA risk. PMID- 30518440 TI - Objectively Measured Disrupted Sleep Is Independently and Directly Associated With Low Exercise Capacity in Males: A Structural Equation Model. AB - STUDY OBJECTIVES: We investigated the interaction between objective sleep disturbance and obesity, sedentary lifestyle, and lung dysfunction and whether it is negatively associated with cardiorespiratory fitness. METHODS: In this community cohort study of 521 men (age 46.6 +/- 7.5 years), measures of anthropometry, pulmonary function, overnight sleep polysomnography, and cardiopulmonary exercise testing were processed stepwise using structural equation modeling (SEM). RESULTS: A univariate correlation analysis was used to group the corresponding variables (in parentheses) into the following eligible latent variables for lower exercise capacity: obesity (body mass index, waist-to hip ratio), irregular exercise, impaired lung function (predicted values of forced expiratory volume in the first second, forced vital capacity, maximal ventilatory volume, and lung diffusion capacity for carbon monoxide), disrupted sleep (total sleep time, percentage of slow-wave sleep, sleep efficiency), and sleep-disordered breathing (apnea-hypopnea index, lowest oxygen saturation, percentage of total period of oxygen saturation < 90%). Advanced SEM analyses produced a well-fitted final confirmatory model that obesity (direct strength betad = .366, P< .001), irregular exercise (betad = .274, P< .001), and impaired lung function (betad = .152, P< .001), with their mutual interactions, as well as disrupted sleep (betad = .135, P = .001) were independently and directly associated with low exercise capacity. By contrast, sleep-disordered breathing (betad = 0, P = .215) was related to low exercise capacity indirectly through obesity into the mutual interaction cycle of obesity, irregular exercise, and impaired lung function. Sleep-disordered breathing was robustly and mutually correlated with obesity (mutual relationship index = .534, P< .001). CONCLUSIONS: Objectively measured disrupted sleep is directly and independently associated with low exercise capacity; however, sleep-disordered breathing is indirectly mediated by obesity and mutual interactions among obesity, lung dysfunction, and sedentary lifestyle and is linked to low exercise capacity. Our findings indicate that individuals with limited exercise capacity without definite causes should undertake a sleep study, particularly in those describing symptoms of sleep disordered breathing or insomnia. PMID- 30518441 TI - Comparison of Commonly Used Questionnaires to Identify Obstructive Sleep Apnea in a High-Risk Population. AB - STUDY OBJECTIVES: Sleep apnea is associated with adverse health outcomes. Despite being an important comorbidity in obesity, type 2 diabetes, heart failure, and resistant hypertension, it is underdiagnosed in these patient groups. An inexpensive and readily accessible sleep apnea screening tool would help address this problem. We sought to compare three commonly used screening tools. METHODS: We recruited 812 patients who had not previously been investigated for sleep apnea from our institution's diabetes (n = 512), obesity (n = 129), resistant hypertension (n = 74) and heart failure (n = 43) clinics. Patients completed three frequently used sleep apnea screening questionnaires (STOP-BANG, Berlin, and OSA50). A total of 758 patients had a valid (> 4 hours' duration) level 3 home sleep study. Studies were reported by a sleep physician and were deemed positive if they recorded a respiratory event index (REI) >= 15 events/h. RESULTS: The 758 patients with valid sleep studies were age 59 +/- 11 years and 63% were male. A total of 38% of patients had a positive test. The respective sensitivities and specificities of the screening questionnaires at the recommended screening thresholds (REI >= 15 events/h) were STOP-BANG >= 3 (95% and 19%), STOP-BANG >= 5 (60% and 69%), Berlin (75% and 38%), and OSA50 (88% and 21%). We identified six independent predictors (age, sex, body mass index, neck circumference, snoring >= 3 days per week, observed apnea >= 3 days per week). However, combining these factors was no better than the STOP-BANG in predicting sleep apnea. All patients with a STOP-BANG < 3 had an REI < 30 events/h. CONCLUSIONS: There is a high prevalence of undiagnosed symptomatic sleep apnea in high-risk patient groups. The STOP-BANG questionnaire appeared superior, though all questionnaires had significant limitations. Incorporation of STOP-BANG >= 3 in this high-risk population might reduce the need for sleep testing in a resource-constrained setting. PMID- 30518442 TI - Long Sleep Duration, Insomnia, and Insomnia With Short Objective Sleep Duration Are Independently Associated With Short Telomere Length. AB - STUDY OBJECTIVES: We aimed to determine the association between short telomere length, sleep parameters, and sleep disorders in an adult general population sample. METHODS: As part of the EPISONO cohort (Sao Paulo, Brazil), 925 individuals answered questionnaires, underwent a full-night polysomnography and clinical assessment, and had peripheral blood collected for DNA extraction. Insomnia was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition; and obstructive sleep apnea was defined according to apnea-hypopnea index. For the objective insomnia phenotype, we combined insomnia diagnosis with total sleep time from polysomnography with a cutoff of 360 minutes, allowing the classification of six groups. Self-reported sleep duration was used to classify the individuals as short (< 6 hours), average (6 to 8 hours) and long (> 8 hours) sleepers. The leukocyte telomere length was measured using quantitative real-time polymerase chain reaction. Based on its distribution, we considered leukocyte telomere length < 10th percentile as short telomere and leukocyte telomere length >= 10th percentile as non-short telomere. RESULTS: After adjusting for sex, age, and body mass index, only insomnia disorder (odds ratio [OR] = 2.654, 95% confidence interval [CI] = 1.025-6.873, P = .044), insomnia disorder total sleep time < 360 minutes (OR = 4.205, 95% CI = 1.097 16.117, P = .036) and long sleepers (OR = 2.177, 95% CI = 1.189-3.987, P = .012) were associated with short telomere. CONCLUSIONS: Our findings support the existence of an association among insomnia, insomnia phenotype, and self-reported long sleep duration with the maintenance of telomere length. PMID- 30518444 TI - The Accuracy of an Ambulatory Level III Sleep Study Compared to a Level I Sleep Study for the Diagnosis of Sleep-Disordered Breathing in Children With Neuromuscular Disease. AB - STUDY OBJECTIVES: Polysomnography (PSG) surveillance recommendations are not being met for children with neuromuscular disease (NMD) because of limited diagnostic facilities. We evaluated the diagnostic accuracy of an ambulatory level III device as compared to a level I PSG. METHODS: A cross-sectional study was conducted at a tertiary pediatric institution. Eligibility criteria included: (1) children with NMD; (2) age 6 to 18 years; (3) booked for a clinically indicated overnight level I PSG. Participants were randomized to an overnight level I PSG followed by an ambulatory level III study with end tidal carbon dioxide (etCO2) or vice versa. Sensitivity and specificity of the ambulatory level III device to diagnose sleep-disordered breathing (SDB) at an apnea hypopnea index (AHI) cutoff of > 1.0 events/h was the primary outcome. RESULTS: Moderate to severe SDB was found in 46% of participants (13/28). The device's sensitivity and specificity to detect SDB was 61.5% and 86.7%, respectively. The positive predictive value of the level III study was 80.0% and the negative predictive value was 72.0%. Fifty percent of the cohort were either missing or had incomplete or falsely low ambulatory etCO2 data. CONCLUSIONS: A level III device with etCO2 is not yet able to be implemented in clinical practice as a diagnostic tool for SDB in pediatric patients with NMD. PMID- 30518443 TI - The Evolution of Sleep Apnea Six Months After Acute Ischemic Stroke and Thrombolysis. AB - STUDY OBJECTIVES: Our goal was to investigate the evolution of prevalence, severity, and type of sleep apnea among patients who had an ischemic stroke, with or without treatment with thrombolysis after 6 months. METHODS: We prospectively studied 204 patients who had an ischemic stroke (110 in the thrombolysis and 94 in the non-thrombolysis group). After follow-up, 177 patients were eligible for a final analysis (98 in the thrombolysis group and 79 in the non-thrombolysis group). An unattended sleep study with a three-channel portable device was performed both on admission and after the 6-month follow-up. RESULTS: The patients receiving thrombolysis were younger than those in the non-thrombolysis group (mean 65.5 versus 69.6 years P = .039). Sleep apnea, defined as a respiratory event index (REI) >= 5 events/h, was diagnosed in 92.7% patients, 93.9% versus 91.1% (P = .488) in the thrombolysis and non-thrombolysis groups, respectively. The prevalence remained unchanged during follow-up. Mild sleep apnea progressed to moderate or severe sleep apnea in 69.2% of the patients. Globally, mean central apneas per hour increased by 2.2% (P = .002), whereas obstructive apneas declined by 1.7% (P = .014). The mean change of oxygen desaturation index was -6.1% (P< .001) in the thrombolysis group, -1.8% (P = .327) in the non-thrombolysis group, and 4.2% (P = .001) in the whole group. In the non-thrombolysis group, the risk for new sleep apnea incidence increased by 6.1-fold (P = .024) at follow-up when compared to the thrombolysis group. CONCLUSIONS: Sleep apnea prevalence remained high in patients who had an ischemic stroke at 6 months post-stroke. The risk for developing sleep apnea after stroke was significantly lower among patients undergoing thrombolysis. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Ischaemic Stroke and Sleep Apnea in Northern Part of Finland; Identifier: NCT01861275; URL: https://clinicaltrials.gov/ct2/show/NCT01861275. PMID- 30518445 TI - Varying Hypopnea Definitions Affect Obstructive Sleep Apnea Severity Classification and Association With Cardiovascular Disease. AB - STUDY OBJECTIVES: To compare clinical features and cardiovascular risks in patients with obstructive sleep apnea (OSA) based on >= 3% desaturation or arousal, and >= 4% desaturation hypopnea criteria. METHODS: This is a cross sectional analysis of 1,400 veterans who underwent polysomnography for suspected sleep-disordered breathing. Hypopneas were scored using >= 4% desaturation criteria per the American Academy of Sleep Medicine (AASM) 2007 guidelines, then re-scored using >= 3% desaturation or arousal criteria per AASM 2012 guidelines. The effect on OSA disease categorization by these two different definitions were compared and correlated with symptoms and cardiovascular associations using unadjusted and adjusted logistic regression. RESULTS: The application of the >= 3% desaturation or arousal definition of hypopnea captured an additional 175 OSA diagnoses (12.5%). This newly diagnosed OSA group (OSAnew) was symptomatic with daytime sleepiness similarly to those in whom OSA had been diagnosed based on >= 4% desaturation criteria (OSA4%). The OSAnew group was more obese and more likely to be male than those without OSA based on either criterion (No-OSA). However, the OSAnew group was younger, less obese, more likely female, and had a lesser smoking history compared to the OSA4% group. Those with any severity of OSA4% had an increased adjusted odds ratio for arrhythmias (odds ratio = 1.95 [95% confidence interval 1.37-2.78], P = .0155). The more inclusive hypopnea definition (ie, >= 3% desaturation or arousal) resulted in recategorization of OSA diagnosis and severity, and attenuated the increased odds ratio for arrhythmias observed in mild and moderate OSA4%. However, severe OSA based on >= 3% desaturation or arousals (OSA3%/Ar) remained a significant risk factor for arrhythmias. OSA based on any definition was not associated with ischemic heart disease or heart failure. CONCLUSIONS: The most current AASM criteria for hypopnea identify a unique group of patients who are sleepy, but who are not at increased risk for cardiovascular disease. Though the different hypopnea definitions result in recategorization of OSA severity, severe disease whether defined by >= 3% desaturation/arousals or >= 4% desaturation remains predictive of cardiac arrhythmias. PMID- 30518446 TI - Oximetry as an Accurate Tool for Identifying Moderate to Severe Sleep Apnea in Patients With Acute Stroke. AB - STUDY OBJECTIVES: Sleep-disordered breathing (SDB) is highly prevalent in patients with acute stroke. SDB is often underdiagnosed and associated with neurological deterioration and stroke recurrence. Polysomnography or home sleep apnea testing (HSAT) is typically used as the diagnostic modality; however, it may not be feasible to use regularly in patients with acute stroke. We investigated the predictive performance of pulse oximetry, a simpler alternative, to identify SDB. METHODS: The records of 254 patients, who were admitted to Boston Medical Center for acute stroke and underwent HSAT, were retrospectively reviewed. Oxygen desaturation index (ODI) from pulse oximetry channel were compared to respiratory event index (REI) obtained from HSAT devices. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ODI were calculated, and different ODI cutoff values to predict SDB were proposed. RESULTS: ODI had a strong correlation (r = .902) and agreement with REI. ODI was accurate in predicting SDB at different REI thresholds (REI >= 5, REI >= 15, and REI >= 30 events/h) with the area under the curve (AUC) of .965, .974, and .951, respectively. An ODI >= 5 events/h rules in the presence of SDB (specificity 91.7%, PPV 96.3%). An ODI >= 15 events/h rules in moderate to severe SDB (specificity 96.4%, PPV 95%) and an ODI < 5 events/h rules out moderate to severe SDB (sensitivity 100%, NPV 100%). CONCLUSIONS: Nocturnal pulse oximetry has a high diagnostic accuracy in predicting moderate to severe SDB in patients with acute stroke. Oximetry can be a simple modality to rapidly recognize patients with more severe SDB and facilitate the referral to the confirmation sleep study. PMID- 30518447 TI - Evaluating Transfer of Modafinil Into Human Milk During Lactation: A Case Report. AB - ABSTRACT: We present a case of a 27-year-old woman in whom idiopathic hypersomnolence was diagnosed in adolescence with adequate symptomatic control on daily dosage of 250 mg of modafinil. She maintained this dosage throughout her pregnancy and during the peripartum period, but did not breastfeed her newborn because of a lack of information on the transmission of modafinil in human breast milk. Samples of her breast milk were obtained at various times over a 24-hour period and analyzed using liquid chromatography mass spectrometry. The relative infant dose was calculated to be 5.3%, below the threshold of concern for drug passage via breast milk. This is the first reported case of modafinil transfer into human breast milk. Given the drug's use in a variety of sleep disorders, the results of this case can be used to advise breastfeeding mothers prescribed modafinil. PMID- 30518448 TI - Practical Implementation of a Single-Night Split-Titration Protocol With BPAP-ST and AVAPS in Patients With Neuromuscular Disease. AB - STUDY OBJECTIVES: At the sleep laboratory, noninvasive positive pressure ventilation titration protocols in patients with neuromuscular disease (NMD) are based on standard pressure cycle devices in a spontaneous/timed mode (BPAP-ST). Experience integrating protocols on average volume-assured pressure support (AVAPS) mode is limited, prompting us to develop a practical single-night titration protocol that provides information to assist clinicians and patients as they decide between BPAP-ST and AVAPS modes. METHODS: We implemented a sequential titration protocol of BPAP-ST followed by AVAPS during a single-night polysomnography study in patients with NMD and reported polysomnographic and clinical metrics. RESULTS: There were 27 patients who completed the protocol: 14 (52%) were male with median and interquartile range (IQR) 64 (59 to 70) years of age and body mass index of 29.6 (25.6-32) kg/m2. They had median (IQR) maximal percent predicted inspiratory and expiratory pressures, and percent vital capacity of 33 (24 to 54), 34 (22 to 47) and 60 (47 to 74), respectively. At final titration of each device, average tidal volume and nadir non-rapid eye movement sleep oxyhemoglobin saturation (SpO2) were higher and respiratory rate/tidal volume, transcutaneous CO2, and arousal index were lower on AVAPS (P< .05) in comparison with BPAP-ST. Full face mask was used in 23 patients (85%). None of the other ventilatory or sleep parameters differed significantly between BPAP-ST and AVAPS (P > .05) sessions. CONCLUSIONS: A practical single-night split titration protocol with BPAP-ST and AVAPS can successfully be implemented in patients with NMD, assisting clinicians and patients with the decision on initial treatment modalities and settings. PMID- 30518449 TI - Association of Adverse Pregnancy Outcomes With Self-Reported Measures of Sleep Duration and Timing in Women Who Are Nulliparous. AB - STUDY OBJECTIVES: To examine the relationship of self-reported sleep during pregnancy with adverse pregnancy outcomes. A secondary objective was to describe the concordance between self-reported and objectively assessed sleep during pregnancy. METHODS: In this prospective cohort, women completed a survey of sleep patterns at 6 to 13 weeks' gestation (visit 1) and again at 22 to 29 weeks' gestation (visit 3). Additionally, at 16 to 21 weeks (visit 2), a subgroup completed a week-long sleep diary coincident with an actigraphy recording. Weekly averages of self-reported sleep duration and sleep midpoint were calculated. A priori, sleep duration < 7 hours was defined as "short," and sleep midpoint after 5:00 am was defined as "late." The relationship of these sleep abnormalities with hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) was determined. RESULTS: Of the 10,038 women enrolled, sleep survey data were available for 7,524 women at visit 1 and 7,668 women at visit 3. A total of 752 women also provided >= 5 days of sleep diary data coincident with actigraphy at visit 2. We did not observe any consistent relationship between self-reported short sleep and HDP or GDM. There was an association between self-reported late sleep midpoint and GDM (visit 1 adjusted odds ratio 1.67, 95% confidence interval 1.17, 2.38; visit 2 adjusted odds ratio 1.73, 95% confidence interval 1.23, 2.43). At visit 2, 77.1% of participants had concordance between their diary and actigraphy for short sleep duration, whereas 94.3% were concordant for sleep midpoint. CONCLUSIONS: Self-reported sleep midpoint, which is more accurate than self-reported sleep duration, is associated with the risk of GDM. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Title: Pregnancy as a Window to Future Cardiovascular Health: Adverse Pregnancy Outcomes as Predictors of Increased Risk Factors for Cardiovascular Disease, Identifier: NCT02231398, URL: https://clinicaltrials.gov/ct2/show/NCT02231398. PMID- 30518451 TI - A Case of Nocturnal Headache. PMID- 30518450 TI - Increased Risk of Benign Paroxysmal Positional Vertigo in Patients With Non-Apnea Sleep Disorders: A Nationwide, Population-Based Cohort Study. AB - STUDY OBJECTIVES: To investigate the association between non-apnea sleep disorders (NSD) and subsequent benign paroxysmal positional vertigo (BPPV) risk. METHODS: This retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2013. We established an NSD group (n = 24,624) and an age-, sex- and index year-matched comparison group (n = 98,496). The primary outcome was the occurrence of BPPV. The incidence rates of BPPV in the two cohorts were compared with a 14-year follow-up. Cox proportional hazard regression analysis was used to evaluate the effects of NSD on BPPV risk. RESULTS: The incidence rate of BPPV was 43.33 per 100,000 person-years for the NSD cohort and 29.33 per 100,000 person-years for the comparison cohort. NSD significantly increased the risk of BPPV (adjusted hazard ratio [HR] = 2.487; 95% confidence interval = 1.996-3.099, P< .001). Subgroup analysis revealed that NSD increase the risk of development of BPPV by 2.357- to 3.658-fold in patients with hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and hyperlipidemia. Furthermore, when comparing different types of NSD, chronic insomnia carries the highest risk of BPPV (adjusted HR = 3.563), followed by organic sleep disorders (adjusted HR = 2.763), sleep disturbance (adjusted HR = 2.506), and acute insomnia (adjusted HR = 2.237). CONCLUSIONS: We demonstrate that NSD are associated with an increased risk of BPPV. Relative to other types of NSD, patients with chronic insomnia are at the highest risk for development of BPPV. PMID- 30518452 TI - Adult With PHOX2B Mutation and Late-Onset Congenital Central Hypoventilation Syndrome. AB - ABSTRACT: PHOX2B 20/27 polyalanine repeat mutation (PARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally associated with full-time ventilator dependence, Hirschsprung disease, and increased risk for cardiac asystole. We follow a 14-year-old boy with CCHS PHOX2B 20/27 PARM who is full-time ventilator dependent via tracheostomy and has Hirschsprung disease. His mother, age 52 years, has a history of prolonged recovery from anesthesia and an elevated serum bicarbonate level of 45 mEq/L discovered on routine blood chemistry. PHOX2B gene mutation analysis was performed and showed an identical 20/27 PARM, diagnostic of CCHS. Late-onset CCHS has been reported in those with 20/24, 20/25 PHOX2B PARM, and in nonpolyalanine repeat mutations. This is the first report of a patient with PHOX2B 20/27 PARM with a mild phenotype diagnosed during adulthood. This unusual presentation supports the screening for PHOX2B mutations in parents of children with CCHS. PMID- 30518453 TI - The Value of a Well-Trained Ear: Incidental Detection of Catathrenia on Home Sleep Apnea Tests in Patients With Low Probability for Obstructive Sleep Apnea. AB - ABSTRACT: Catathrenia is a rare sleep-related breathing disorder marked by nocturnal groaning during prolonged exhalation. Home sleep apnea tests are growing in popularity, but no prior case reports exist documenting catathrenia detected by a home sleep apnea test. We report two cases of catathrenia incidentally detected in patients with low to intermediate risk of obstructive sleep apnea, in which diagnostic polysomnography was recommended but denied by insurers. Events were automatically scored as central apneas, leading to diagnostic uncertainty. The key to identification of catathrenia in both patients was combination of audio review of events, pattern of expiratory air trapping, and mismatch between central apnea flow signal attenuation and increased sound noted on audio amplitude signal. Diagnostic polysomnography was ordered in both cases for confirmation of diagnosis, leading to increased care costs. PMID- 30518454 TI - Fear of Sleep May Be a Core Symptom of Sympathetic Activation and the Drive for Vigilance in Posttraumatic Stress Disorder. PMID- 30518455 TI - Further Exploring the Associations Between Sympathetic Activation, Fear of Sleep, and Insomnia Symptoms in Posttraumatic Stress Disorder. PMID- 30518457 TI - Best and Safest Care Versus Care Closer to Home. PMID- 30518456 TI - Clinical Use of a Home Sleep Apnea Test: An Updated American Academy of Sleep Medicine Position Statement. AB - ABSTRACT: The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. It is the position of the American Academy of Sleep Medicine (AASM) that only a medical provider can diagnose medical conditions such as OSA and primary snoring. Throughout this statement, the term "medical provider" refers to a licensed physician and any other health care professional who is licensed to practice medicine in accordance with state licensing laws and regulations. A home sleep apnea test (HSAT) is an alternative to polysomnography for the diagnosis of OSA in uncomplicated adults presenting with signs and symptoms that indicate an increased risk of moderate to severe OSA. It is also the position of the AASM that: the need for, and appropriateness of, an HSAT must be based on the patient's medical history and a face-to-face examination by a medical provider, either in person or via telemedicine; an HSAT is a medical assessment that must be ordered by a medical provider to diagnose OSA or evaluate treatment efficacy; an HSAT should not be used for general screening of asymptomatic populations; diagnosis, assessment of treatment efficacy, and treatment decisions must not be based solely on automatically scored HSAT data, which could lead to sub-optimal care that jeopardizes patient health and safety; and the raw data from the HSAT device must be reviewed and interpreted by a physician who is either board-certified in sleep medicine or overseen by a board-certified sleep medicine physician. PMID- 30518458 TI - Short Telomere Length and Endophenotypes in Sleep Medicine. PMID- 30518459 TI - The (Still) Elusive Definition of Hypopnea. PMID- 30518461 TI - ? PMID- 30518460 TI - Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation. AB - BACKGROUND: Diagnosis of lung cancer frequently occurs in its later stages. Low dose computed tomography (LDCT) could detect lung cancer early. OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations. DATA SOURCES: Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. METHODS: Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm. RESULTS: Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with <= 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of L20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of L30,000/QALY. The incremental cost effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is L28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of L20,000/QALY in only a minority of analyses. LIMITATIONS: Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. CONCLUSIONS: LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. FUTURE WORK: Clinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial]. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016048530. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 30518462 TI - ? PMID- 30518463 TI - ? PMID- 30518464 TI - [Treatment algorithm for non-melanoma skin cancer]. AB - Non-melanoma skin cancers are the most common malignant neoplasms in Denmark. The majority of cases are basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). The choice of treatment depends on tumour, area, histology and patient specific factors. Superficial and low-risk BCC can be treated with curettage, photodynamic therapy, imiquimod cream or cryotherapy. High-risk BCC and SCC should be treated by surgical excision or radiotherapy. PMID- 30518465 TI - [PANDAS and PANS in children and adolescents are still controversial diagnoses]. AB - Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and paediatric acute-onset neuropsychiatric syndrome (PANS) have been suggested to be a result of a disordered immune response following an infection causing neuropsychiatric symptoms. Although the diagnosis PANDAS/PANS has been controversial, an increasing attention has been paid to the diagnosis, pathophysiology and treatment during the recent years. This review provides an update on knowledge of aetiology, recommended investigations and treatment in children with suspected PANDAS/PANS. PMID- 30518466 TI - [Paraffin oil injecions due to bigorexia may cause hypercalcaemia]. AB - Paraffin oil injections may cause severe hypercalcaemia, likely due to development of granulomas at injection sites, activating 1,25 dihydroxyvitamin D and increasing calcium uptake from gut, kidney and bone. This is a case report of a 39-year-old male with severe hypercalcaemia and renal failure due to paraffin oil injections. He was treated with prednisolone (25-50 mg daily), but the disease recurred the next two summers probably due to erroneous vitamin D supplement and sun exposure. The disease course and prognosis are unknown. Treatment options are discussed, and paraffin oil injections should be avoided. PMID- 30518467 TI - [A low risk of ileus, incisional hernia and impact on female fertility after appendectomy]. AB - Appendicitis is a common condition, which is often seen by the general practitioners as well as in the emergency departments. It is normally treated with laparoscopic appendectomy. This review gives an overview of the long-term surgical complications ileus and incisional hernia and of the impact of appendicitis and appendectomy on female fertility. The literature shows, that there is a low risk of ileus and incisional hernia after appendectomy, and that there is no change in female fertility after appendectomy, not even in cases where the appendix was perforated. PMID- 30518468 TI - [HPV self-sampling for cervical cancer screening in Denmark]. AB - In Denmark, 45% of all incident cervical cancers are detected in underscreened women. High-level evidence supports, that non-participants in cervical cancer screening are better reached by HPV self-sampling than by regular physician-based screening, including increased uptake among un- or underscreened women. A high compliance to follow-up among HPV-positive self-samplers has been reported. In the new Danish cervical cancer screening guidelines, the regions are endorsed to offer HPV self-sampling to women, who are due to receive the second screening reminder, and in this manner potentially improve cervical cancer prevention. PMID- 30518469 TI - [Women with groin hernias should be referred to surgery]. AB - In females, approximately 75% of groin hernias are inguinal hernias, and 25% are femoral. However, all groin hernias in women should be considered potential femoral hernias due to the difficult preoperative diagnosis of hernia type and the high incidence of femoral hernias. Complications following an untreated femoral hernia are unacceptable, which is why, watchful waiting is not recommended in women. Timely repair is desirable, and the laparoscopic approach is recommended due to lower recurrence rates and fewer femoral recurrences than in open repair methods. PMID- 30518470 TI - Invitation to Screening Colonoscopy in the Population at Familial Risk for Colorectal Cancer. AB - BACKGROUND: Screening colonoscopy can lower the incidence of colorectal cancer (CRC), yet participation rates are low even in groups at high risk. The goal of this study was to double the rate of participation in screening colonoscopy among persons at familial risk and then to determine the frequency of neoplasia in this risk group. METHODS: In a nationwide, cluster-randomized, multicenter study, first-degree relatives (FDR) of patients with CRC across Germany received written informational materials concerning the familial risk of CRC, along with an invitation to undergo colonoscopy. Participants in the intervention group were additionally counseled by nurses over the telephone. The primary endpoint of the study was colonoscopy uptake within 30 days. RESULTS: The participants' mean age was 50.8 years. The colonoscopy uptake rates were 99/125 (79%) in the intervention group and 97/136 (71%) in the control group (RR = 1.11; 95% confidence interval [0.97; 1.28]). A polypectomy was performed in 72 of 196 asymptomatic persons (37%). In 13 cases (7%), an advanced neoplasia was detected; two of these persons had colon cancer (stages T0 and T1). 42% of the participants expressed barriers against colonoscopy. 22 reported mild side effects; there were no serious side effects. CONCLUSION: Additional counseling by nurses over the telephone does not increase the participation rate. Approaching patients who have CRC is an opportunity to increase the participation of their first-degree relatives in screening colonoscopy. The frequency of neoplasia that was found in this study underscores the need to screen relatives even before they reach the usual age threshold for screening. PMID- 30518471 TI - Measles Status-Barriers to Vaccination and Strategies for Overcoming Them. AB - BACKGROUND: The World Health Organization (WHO) set the year 2020 as a target date for the eradication of measles in Europe, yet Germany is still far away from this goal. In this article, we provide an overview of current vaccination gaps and barriers to vaccination among children and adults in Germany, as well as potential strategies for overcoming them. METHODS: This review is based on pertinent publications identified by a selective literature search in PubMed (Medline). RESULTS: Measles vaccinations are not carried out in the appropriate timely fashion in Germany. Moreover, current vaccination rates among both children and adults are too low to achieve the goal of measles eradication. For example, among children born in 2014, the recommended vaccination rate of more than 95% was only reached when these children were 24 months old. Primary care physicians bear the responsibility for this situation, as they have the greatest influence on the decision to vaccinate. The main causes of vaccination gaps are safety worries and complacen- cy on the patients' part, and partial skepticism regarding vaccination on the part of the caregivers. We identified promising strategies for overcoming these problems: an instructive talk to provide evidence based information to patients in an atmos- phere of mutual trust, reminder systems, multifactorial interventions, and facilitated access to vaccination, or, as a last resort, the reintroduction of compulsory vacci- nation. CONCLUSION: Primary care physicians play a key role in vaccination. The focus of further strategies should lie above all in improved patient education and in targeted reminders for patients who neglect to vaccinate themselves and/or their children. PMID- 30518472 TI - Validity of Exercise ECG. PMID- 30518473 TI - Degree of Physical Performance Capacity. PMID- 30518474 TI - Exercise Testing in Sports Medicine. PMID- 30518475 TI - In Reply. PMID- 30518476 TI - Predicting Costs Exceeding Bundled Payment Targets for Total Joint Arthroplasty. AB - BACKGROUND: The Center for Medicare and Medicaid Services has instituted bundled reimbursement models for total joint arthroplasty (TJA), which includes target prices for each procedure. Some patients exceed these targets; however, currently there are no tools to accurately predict this preoperatively. We hypothesized that a validated comorbidity index combined with patient demographics would adequately predict excess cost-of-care prior to hospitalization. METHODS: Two thousand eighty-four primary unilateral TJAs performed at a single tertiary center were retrospectively examined. Data were extracted from medical records and a predictive model was built from 30 comorbidities and 7 patient demographic factors (age, gender, race, body mass index, American Society of Anesthesiologists score, smoking status, and marital status). Following parameter selection, a final multivariable model was created, with a corresponding nomogram for interactive visualization of probability for excess cost. RESULTS: Six hundred twelve patients (29%) had cost-of-care exceeding the target price. The final model demonstrated adequate predictive discrimination for cost-of-care exceeding the target price (area under the receiver operator characteristic curve: 0.747). Factors associated with excess cost included age, gender, marital status, American Society of Anesthesiologists score, body mass index, and race, as well as 7 Elixhauser comorbidities (alcohol use, rheumatoid arthritis, diabetes, electrolyte disorders, neurodegenerative disorders, psychoses, and pulmonary circulatory disorders). CONCLUSION: A novel patient model composed of a subset of validated comorbidities and demographic variables provides adequate discrimination in predicting excess cost within bundled payment models for TJA. This not only helps identify patients who would benefit from preoperative optimization, but also provides evidence for modification of future bundled reimbursement models to adjust for nonmodifiable risk factors. PMID- 30518477 TI - Tolerance to Sodium in Patients With CKD-Induced Metabolic Acidosis: Does the Accompanying Anion Matter? AB - Patients with chronic kidney disease (CKD) continue to produce endogenous acids but have a reduction in net acid excretion, resulting in a primary decrease in serum bicarbonate concentration, which is termed chronic metabolic acidosis. Recent prospective studies, along with retrospective cohort analyses, demonstrate a higher risk for CKD progression with untreated metabolic acidosis. To normalize serum bicarbonate levels, acidemic patients are often treated with sodium bicarbonate (NaHCO3) or sodium citrate, which have been shown to slow the progression of CKD. However, studies using this approach have routinely excluded patients with common sodium-sensitive comorbid conditions, such as poorly controlled hypertension, congestive heart failure, volume overload, or edema. This article examines the effect of the anion that accompanies sodium delivered with these therapies. Do the negative effects on blood pressure (BP) and sodium retention, as measured by an increase in edema, weight gain, and congestive heart failure, observed with oral administration of sodium chloride (NaCl) differ when a similar amount of sodium is given with bicarbonate or citrate in this patient population? A review of the literature suggests that NaHCO3 does not increase BP or sodium retention when administered to patients with CKD during a concurrent severe NaCl dietary restriction (~10 mEq/d). However, this degree of NaCl restriction is feasible only under strict control in clinical research environments. In contrast, when NaHCO3 is given to patients without severe dietary NaCl restriction, there is an increase in BP and sodium retention. Thus, unless patients with CKD can tolerate a diet virtually devoid of NaCl, additional sodium, regardless of the accompanying anion, appears to increase BP and sodium retention. PMID- 30518478 TI - In vivo blood metal ion levels in patients after total shoulder arthroplasty. AB - BACKGROUND: Products from metal wear have been identified as a potential cause of adverse local tissue reactions and implant failure in total hip arthroplasty. However, the role of metal ion exposure in patients after total shoulder replacement is unclear. The objective of the present study was to determine in vivo blood metal ion levels of cobalt, chromium, and titanium in patients after anatomic total shoulder arthroplasty (TSA) or reverse TSA. METHODS: A consecutive series of patients after anatomic TSA or reverse TSA was evaluated retrospectively. After exclusion of patients with additional metal implants, 40 patients with unilateral anatomic TSA (n = 20) or reverse TSA (n = 20) were available for whole-blood metal ion analysis at a mean follow-up of 28 +/- 9.6 months. Twenty-three healthy individuals without metal implants served as a control group. RESULTS: Mean cobalt ion concentrations were 0.18 ug/L (range, 0.1 0.66 ug/L), 0.15 ug/L (range, 0.03-0.48 ug/L), and 0.11 ug/L (range, 0.03-0.19 ug/L), mean chromium ion levels were 0.48 ug/L (range, 0.17-2.41 ug/L), 0.31 ug/L (range, 0.09-1.26 ug/L), and 0.14 ug/L (range, 0.04-0.99 ug/L), and mean titanium ion concentrations were 1.31 ug/L (range, 0.75-4.52 ug/L), 0.84 ug/L (range, 0.1 1.64 ug/L), and 0.62 ug/L (range, 0.32-2.14 ug/L) in the reverse TSA group, the anatomic TSA group, and the control group, respectively. CONCLUSIONS: TSA resulted in elevated metal ion levels compared with healthy controls, although overall metal ion concentrations measured in this study were relatively low. The role of local metal ion exposure in patients with total shoulder replacements should be further investigated. PMID- 30518479 TI - Cost-effectiveness of rivaroxaban versus warfarin for treatment of nonvalvular atrial fibrillation in patients with worsening renal function. AB - BACKGROUND: Nonvalvular atrial fibrillation (NVAF) is highly prevalent and increases the risks of cardiovascular events. In a recent subgroup analysis, treatment response was shown to vary for patients exhibiting worsening renal function (WRF) on-treatment. It is important to understand the cost-effectiveness of novel oral anticoagulant (NOAC) use in this population. METHODS: A cost effectiveness analysis (CEA) was conducted using a Markov model to determine whether NOAC rivaroxaban treatment is cost-effective relative to warfarin in NVAF patients with on-treatment WRF. Input parameters were sourced from clinical literature including a multicenter clinical trial and subgroup analysis. We studied elderly US male patients at increased risk for stroke (CHADS2 score >= 2) undergoing treatment for NVAF and exhibiting WRF. Main outcome measures included total healthcare costs in 2017 US dollars (societal perspective), total quality adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental net monetary benefits (INMB) per-patient. RESULTS: The remaining lifetime use of rivaroxaban is associated with 5.69 QALYs at a cost of $66,075 per patient, while warfarin produced 5.22 QALYs with costs of $78,504 per patient. At a willingness-to-pay (WTP) of $150,000 per QALY, incremental net monetary benefits (INMB) per patient are $83,590. In our population, treatment with warfarin was dominated by rivaroxaban in 99.4% of 10,000 simulations. CONCLUSIONS: Rivaroxaban is likely a dominant treatment over warfarin in elderly US male NVAF patients exhibiting WRF, providing increased QALYs at a decreased overall cost. Application of these findings may require healthcare providers to predict which patients are likely to exhibit WRF. PMID- 30518480 TI - A survey of robotic surgery training curricula in general surgery residency programs: How close are we to a standardized curriculum? AB - BACKGROUND: Robotic surgery is increasingly adopted into surgical practice, but it remains unclear what level of robotic training general surgery residents receive. The purpose of our study was to assess the variation in robotic surgery training amongst general surgery residency programs in the United States. METHODS: A web-based survey was sent to 277 general surgery residency programs to determine characteristics of resident experience and training in robotic surgery. RESULTS: A total of 114 (41%) programs responded. 92% (n = 105) have residents participating in robotic surgeries; 68%(n = 71) of which have a robotics curriculum, 44%(n = 46) track residents' robotic experience, and 55%(n = 58) offer formal recognition of training completion. Responses from university affiliated (n = 83) and independent (n = 31) programs were not significantly different. CONCLUSIONS: Many general surgery residencies offer robotic surgery experience, but vary widely in requisite components, formal credentialing, and case tracking. There is a need to adopt a standardized training curriculum and document resident competency. PMID- 30518481 TI - Minimally invasive McKeown's vs open oesophagectomy for cancer: A meta-analysis. AB - BACKGROUND: The effectiveness of minimally invasive oesophagectomy (MIO) compared to open oesophagectomy (OO) remains controversial. Various techniques for performing MIO are currently used, but the evidence for them is lacking. The objective of this meta-analysis was to compare the safety, efficacy and oncological outcomes of McKeown's minimally invasive oesophagectomy (McKeown's MIO) to OO. METHODS: PubMed, Embase and Cochrane Library databases were searched up to December 2016 for relevant articles comparing McKeown's-MIO to OO. As no randomised control trials (RCTs) currently exist, only cohort and case control studies were included. Fixed or random-effects models were used to calculate summary odds ratios (ORs) or relative risks (RRs) for binary outcomes, and hazard ratios (HRs) for time-to-event outcomes. Heterogeneity among studies were evaluated using I2 statistics. RESULTS: Four studies, which consisted a total of 573 patients, were included in the meta-analysis. In comparison to patients undergoing OO, those who were treated with McKeown's-MIO had a reduced incidence of pneumonia and total respiratory complications, however, there were no statistically significant differences for other measures of safety such as RLN palsy and anastomotic leak. In terms of efficacy data, MIO had significantly less blood loss and a shorter duration of hospital stay but a longer operating time. Lymph node retrieval trended towards favouring McKeown's-MIO, but was not statistically significant. There was insufficient data to report on other oncological outcomes. CONCLUSIONS: McKeown's-MIO is a safe and effective procedure that has comparable outcomes to OO. However, RCTs with large sample sizes are needed to confirm these results. PMID- 30518482 TI - Q63, a novel DENV2 RdRp non-nucleoside inhibitor, inhibited DENV2 replication and infection. AB - Dengue virus (DENV) annually infects 400 million people worldwide. Unfortunately, there is lack of widely protective vaccine or drugs against DENV. The viral RNA dependent RNA polymerase (RdRp) of NS5 protein is highly conserved among different DENV subtypes, thus presenting itself as an attractive target for drug design. In the current research, SPRi was performed to screen compounds against DENV2 RdRp and 5(1H)-Quinazolinone,2-(4-bromophenyl)-2,3,4,6,7,8-hexahydro-7,7 dimethyl-1,3-diphenyl (Q63) was successfully screened out with a KD of 0.9 MUM. Then, ITC and molecular docking assay was performed to access the binding mechanism between Q63 and DENV2 RdRp. Meanwhile, Q63 also decreased the intermediate dsRNA production, which was the product of RdRp. Further the antiviral effects of Q63 were evaluated on mosquito C6/36 cells and mammalian BHK 21 cells. Q63 reduced CPE and cell toxicity effect after DENV2 infection on C6/36 and BHK-21 cells, with an EC50 of 2.08 MUM. Time of addition assay revealed that Q63 affected the early genome RNA replication stage, including genome RNA replication. In addition, Q63 down-regulated STAT1 phosphorylation, ISG15 and ISG54 after DENV2 infection. In summary, Q63 was found to be a novel RdRp non nucleoside inhibitor and a potential lead compound for coping with DENV infectious disease in the future. PMID- 30518483 TI - Comparison of efficacy and safety of transpancreatic septotomy, needle-knife fistulotomy or both based on biliary cannulation unintentional pancreatic access and papillary morphology. AB - BACKGROUND: Precut sphincterotomy has been widely performed to facilitate selective biliary access when standard cannulation attempts failed during endoscopic retrograde cholangiopancreatography (ERCP). However, scarce data are available on different precut techniques for difficult biliary cannulation. This study aimed to evaluate the efficacy and safety of transpancreatic septotomy (TPS), needle-knife fistulotomy (NKF) or both based on the presence of unintentional pancreatic access and papillary morphology. METHODS: Between March 2008 and December 2016, 157 consecutive patients undergoing precutting for an inaccessible bile duct during ERCP were identified. Precut techniques were chosen depending on repetitive inadvertent pancreatic cannulation and the papillary morphology. We retrospectively assessed the rates of cannulation success and procedure-related complications among three groups, namely TPS, NKF, and TPS followed by NKF. RESULTS: The baseline characteristics of the three groups were comparable. The overall success rate of biliary cannulation reached 98.1%, including 111 of 113 (98.2%) with TPS, 35 of 36 (97.2%) with NKF and 8 of 8 (100%) with NKF following TPS, without significant difference among groups. The incidences of total complications and post-ERCP pancreatitis were 9.6% and 7.6%, respectively. There was a trend towards less frequent post-ERCP pancreatitis after NKF (0%) compared with 11 cases (9.7%) after TPS and one case (12.5%) after NKF following TPS, but not significantly different (P = 0.07). No severe adverse event occurred during this study period. CONCLUSIONS: The choice of precut techniques by the presence of unintended pancreatic access and the papillary morphology brought about a high success rate without increasing risk in difficult biliary cannulation. PMID- 30518484 TI - Emergency ABO-incompatible living donor liver transplant for patients with ultrahigh MELD scores. PMID- 30518485 TI - Unexplained infertility: Is it over-diagnosed and over-treated? AB - Unexplained infertility is defined as the absence of conception despite 12 months of unprotected intercourse, not explained by anovulation, poor sperm quality, tubal pathology or any known cause of infertility. The two most applied treatments for unexplained infertility are intra-uterine insemination and in vitro fertilisation. As these treatments do not target a specific mechanism but rather increase the probability of conception as compared to natural conception chances, they should be weighed against the prognosis of natural conception. The use of prognostic models could facilitate in identifying who benefits from treatment and who can delay treatment for 6 months, thus aiming for natural conception. This is important, as treatments can have side effects for the woman and her offspring, and their cost may jeopardise access to care. PMID- 30518486 TI - High-accuracy Detection of Preoperative Thyroid Nodules Using Combination of BRAFV600E Mutation and TMPRSS4 mRNA Level. AB - BACKGROUND: Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Though the fine needle aspiration biopsy (FNAB) represents as the golden standard for the diagnostics of thyroid nodules, there is a ~25% risk of indeterminate cytological features. TMPRSS4 is a newly found transmembrane serine protease which was overexpressed in papillary thyroid cancer (PTC). AIMS: The aim of this study was to determine its potential as a diagnostic marker to improve the diagnostic accuracy of thyroid cancer. METHODS: We used pyrosequencing and quantitative real time PCR (qRT-PCT) approaches to examine BRAFV600E mutation and TMPRSS4 mRNA level in FNAB specimens of thyroid nodules. The detection and analysis were respectively applied to training group with 91, and test group with 88 samples. RESULTS: We demonstrated that PTC patients had an increased TMPRSS4 mRNA level as compared with benign subjects. The diagnostic sensitivity, specificity, and accuracy of TMPRSS4 were 93.33, 100, and 96.70%, respectively. Notably, compared with BRAFV600E mutation testing alone, combining with TMPRSS4 mRNA level significantly increased the diagnostic sensitivity and accuracy. CONCLUSIONS: Our findings indicated BRAFV600E mutation combination with TMPRSS4 mRNA analysis can dramatically improve the sensitivity and accuracy of preoperative diagnosis of thyroid nodules. PMID- 30518487 TI - Incidence of surgical wound infection in renal surgery. The effect of antibiotic prophylaxis appropriateness. A prospective cohort study. AB - OBJECTIVE: To assess compliance with the antibiotic prophylaxis protocol for patients who underwent renal surgery and its effect on the incidence of surgical wound infection. MATERIAL AND METHODS: We performed a prospective cohort study and assessed the overall compliance and each aspect of the antibiotic prophylaxis (start, administration route, antibiotic of choice, duration and dosage) and reported the compliance rates. The qualitative variables were compared with the chi-squared test, and the quantitative variables were compared with Student's t test. We studied the effect of antibiotic prophylaxis compliance on the incidence of surgical wound infection in renal surgery, with the relative risk. RESULTS: The study included 266 patients, with an overall compliance rate of 90.6%. The major cause of noncompliance (3.8%) was the start of the prophylaxis, and the incidence rate of surgical wound infections was 3.4%. We found no relationship between antibiotic prophylaxis noncompliance and surgical wound infections (RR=0.26; 95%CI: 0.1-1.2; P>.05). Laparoscopic surgery had a lower incidence of surgical wound infections than open surgery (RR=0.10; 95%CI: 0.01-0.79). CONCLUSIONS: The antibiotic prophylaxis compliance was high. The incidence of surgical site infection was low, and there was no relationship between the incidence of surgical site infection and antibiotic prophylaxis compliance. The incidence of infection was lower in laparoscopic surgery. PMID- 30518488 TI - Polycystosis of the renal sinus or polycystic kidney disease Controversies, challenges and history of a shared discovery. AB - OBJECTIVE: To recall the history of the discovery of non-nephron cystic disease, detected simultaneously in 2 hospitals in Madrid, and the vicissitudes that the authors endured during the process of recognising this disease, while being ignored by the international scientific literature. MATERIAL AND METHOD: We analysed the authors' first publications and presentations, their correspondence relaying the difficulties in reporting the confusion with adult polycystic kidney disease (APKD) and the subsequent nosological identification of the process. We consulted with individuals who worked with the 2 authors to increase the accuracy and objectivity of the history report. RESULTS: We confirmed the authors' remarkable efforts in getting the process definitively recognised despite the notable difficulties. CONCLUSIONS: Rigorous clinical observation recognises processes ignored by the medical literature, and the correct application of the scientific method helps identify and reveal new nosological entities, confirming with this story's example that, in medicine, there are no exhausted issues. PMID- 30518489 TI - Zebrafish assay development for cardiovascular disease mechanism and drug discovery. PMID- 30518490 TI - Five-year native liver survival analysis in biliary atresia from a single large Chinese center: The death/liver transplantation hazard change and the importance of rapid early clearance of jaundice. AB - PURPOSE: This study aimed to analyze the change of death/liver transplantation hazard and biochemical indexes over time after Kasai procedure (KP) based on a retrospective biliary atresia (BA) cohort, and to evaluate the predictive value of early jaundice clearance rate to 5-year native liver survival (NLS). METHODS: A retrospective cohort with follow-up results of 139 BA patients from January 2009 to December 2012 was established, and the pre- and postoperative data were collected. NLS rates were estimated with Kaplan-Meier curves, and any differences between groups were tested by log-rank test. Hazard curve of death/liver transplantation was fitted with Weibull distribution, and hazards at certain time points were calculated. Trend charts of biochemical indexes were drawn to show any changes over time. Rate of jaundice clearance was indicated as the proportion of decreased total bilirubin level at a certain postoperative time point to preoperative total bilirubin level. In multivariate analysis for prediction of 5 year NLS, COX proportional hazard regression model was used and results were expressed as hazard ratios with 95% confidence intervals (CIs). The predictive value of early jaundice clearance rates for 5-year NLS was analyzed by receiver operating characteristic (ROC) curve, and a cut-off value of 4-week jaundice clearance rate was determined. RESULTS: The estimated 5-year NLS rate of the 139 patients was 58.0%. The patients had a high hazard of death/liver transplantation early after KP, which gradually decreased and stabilized at a lower level 1 year later. Most death/liver transplantation events occurred within 1 year after KP. The total bilirubin (TBIL), direct bilirubin (DBIL) and total bile acid (TBA) levels of successful Kasai group decreased continuously after KP, and the biggest decline was seen in the first month. The aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) levels increased during the first month after KP and decreased continuously thereafter. All the biochemical indexes of successful Kasai group tended to stabilize within/close to normal range 1 year after KP. On the contrary, all the biochemical indexes of failed Kasai group fluctuated at obvious abnormal levels after KP. The estimated 5-year NLS rates of successful Kasai group and failed Kasai group were 90.1% and 10.7% (p = 0.000). The most significant clinical protective factor of 5-year NLS was 4-week jaundice clearance rate, revealed by COX proportional hazard regression model, and the HR was 0.089 (95%CI 0.018 0.432, p = 0.003). In predicting 5-year native liver survival, the largest area under ROC (AUROC) curve belonged to 4-week jaundice clearance rate, which was 0.731 (p = 0.000). A cut-off value of 0.457 was determined, with sensitivity 0.827, specificity 0.552, positive predictive value 0.720, and negative predictive value 0.696. NLS rates of patients divided by cut-off value showed significant statistical difference demonstrated by Kaplan-Meier curve and log rank test (p = 0.000). CONCLUSIONS: The 5-year death/liver transplantation hazard of biliary atresia patients reduces greatly and stabilizes 1 year after KP. A successful KP enables patients to achieve long-term stable normal biochemical indexes. A rapid clearance of jaundice is of great positive significance to 5 year NLS, and the 4-week jaundice clearance rate is of some predictive value. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level II, retrospective study. PMID- 30518491 TI - Aortopexy for tracheomalacia via a suprasternal incision. AB - AIM: Tracheomalacia is flaccidity of the tracheal wall leading to tracheal collapse, particularly on expiration. When severe it can warrant surgical intervention. Aortopexy is one surgical option and has been described using a variety of approaches. We report outcomes of aortopexy performed via a suprasternal incision in a single centre by a single surgeon. METHODS: All patients undergoing aortopexy between February 2016 and May 2018 were prospectively included. Patients were managed by a multi-disciplinary team (MDT) and underwent standardized work-up, including dynamic flexible bronchoscopy (DFB) and contrast enhanced CT. Aortopexy was performed via a suprasternal skin crease incision. Surgery was guided by intra-operative flexible bronchoscopy. Data regarding pre-operative symptoms, degree of tracheomalacia, and outcomes were recorded. RESULTS: Twenty-two patients were included, 18 boys, median age 5 months (range 1 month-5 years). Two aortopexy sutures were used in all cases, and three patients required an additional tracheopexy suture. Median operating time was 1 h 24 min (range 47 min-2 h 35 min). Median pre-operative tracheal collapse on DFB was 85% (range 80-95%), improving to 35% (35-80%) intra-operatively. Median length of stay was 4 days (range 1-118). CONCLUSIONS: Aortopexy via a suprasternal incision is a useful treatment modality for tracheomalacia with short operating times and rapid recovery. Outcomes vary with the best results in the TOF and premature groups. Careful patient selection and MDT work-up are essential to optimize outcomes. LEVEL OF EVIDENCE: Level 3 (Case Series). PMID- 30518492 TI - Transamniotic stem cell therapy (TRASCET) in a rabbit model of spina bifida. AB - PURPOSE: Transamniotic stem cell therapy (TRASCET) with select mesenchymal stem cells (MSCs) has been shown to induce partial or complete skin coverage of spina bifida in rodents. Clinical translation of this emerging therapy hinges on its efficacy in larger animal models. We sought to study TRASCET in a model requiring intra-amniotic injections 60 times larger than those performed in the rat. METHODS: Rabbit fetuses (n = 65) with surgically created spina bifida were divided into three groups. One group (untreated) had no further manipulations. Two groups received volume-matched intra-amniotic injections of either saline or a concentrated suspension of amniotic fluid MSCs (afMSCs) at the time of operation. Infused afMSCs consisted of banked heterologous rabbit afMSCs with mesenchymal identity confirmed by flow cytometry, labeled with green fluorescent protein. Defect coverage at term was blindly categorized only if the presence of a distinctive neoskin was confirmed histologically. Statistical comparisons were by logistic regression and the likelihood ratio test. RESULTS: Among survivors with spina bifida (n = 19), there were statistically significant higher rates of defect coverage (all partial) in the afMSC group when compared with the saline and untreated groups (0-50%; p = 0.022-0.036), with no difference between the saline and untreated groups (p = 1.00). Donor afMSCs were identified locally, though sparsely and not in the neoskin. CONCLUSIONS: Concentrated intra-amniotic injection of amniotic mesenchymal stem cells can induce partial coverage of experimental spina bifida in a leporine model. Transamniotic stem cell therapy may become a feasible strategy in the prenatal management of spina bifida. LEVEL OF EVIDENCE: N/A (animal and laboratory study). PMID- 30518493 TI - Not all neonates with oesophageal atresia and tracheoesophageal fistula are a surgical emergency. AB - AIM: Infants with oesophageal atresia and distal tracheoesophageal fistula (OA TOF) occasionally require endotracheal intubation prior to definitive surgery. This creates the risk of preferential ventilation of the fistula leading to gastric distention and subsequent perforation. We aimed to reassess the risk of preoperative positive-pressure ventilation and update recommendations for emergency surgery in this cohort. METHODS: A single centre retrospective review of all cases of OA-TOF from 2008 to 2018 was performed. Data were collected on birth demographics, presence and duration of preoperative intubation, timing of surgery, and outcome. Outcomes considered were gastric perforation and perioperative death. Data are expressed as median (range) unless otherwise stated. RESULTS: Sixty-two neonates with OA-TOF were identified (mean birthweight 2559 g, median gestational age 38 weeks). Seventeen were intubated for respiratory symptoms prior to surgery (1840 g, 34 weeks). The duration of intubation preoperatively was 19 (5-48) h. Seven cases were ventilated for >24 h. Three underwent emergency surgery 'out of hours'. Two were born at 28 weeks' gestation and developed gastric distention requiring urgent surgery. Both were intubated for 10 h preoperatively and underwent fistula ligation with no attempt at oesophageal reconstruction. The third had congenital heart disease and was intubated prior to transfer to our unit. There were no cases of gastric perforation. Five ventilated cases died prior to discharge from hospital from associated conditions. CONCLUSIONS: The risk of gastric perforation is lower than perceived. Ventilated babies with OA-TOF do not necessarily require emergency surgery. This is only indicated in the presence of gastric distention or other instability. LEVEL OF EVIDENCE: IV. PMID- 30518494 TI - The conus medullaris ratio: A new way to identify tethered cord on MRI. AB - PURPOSE: Approximately 25% of patients with anorectal malformation have tethered cord. The traditional way of determining conus medullaris level on magnetic resonance imaging (MRI) relies on counting vertebrae, which may be challenging due to vertebral numeric variation, segmentation anomalies, as well as transitional vertebral body anatomy. The purpose of this study was to utilize more reliable anatomic landmarks (foramen magnum, conus termination, and the upper limit of the iliac crest) to establish a consistent ratio that may differentiate patients with normal and low-lying conus. METHODS: A single institution database search identified two groups of patients: 255 with normal and 85 with abnormal spinal MRI, who underwent tethered cord release. The conus medullaris ratio was calculated in both groups. The ratio was obtained by dividing the distance between the conus level and the iliac crest by the distance between the foramen magnum and the conus level (IRB # 16-2330). RESULTS: The mean ratio was significantly higher in the non-tethered group compared to the tethered patients (0.184 [sd 0.03] versus 0.118 [sd 0.09]; P < .0001). The ratio proved to be a good discriminator between normal and abnormal patients, with area under the curve (AUC) equal to 0.749, meaning that at random, there is a 75% chance that the tethered cord patient will have a lower ratio than the non-tethered cord patient. CONCLUSION: "The Conus Medullaris Ratio" is a good predictor of low lying conus level on MRI and offers an easy alternative to counting vertebral body levels, particularly in patients with variant or abnormal vertebral body anatomy. LEVEL OF EVIDENCE: II, Study of Diagnostic Test. PMID- 30518495 TI - Physical Activity Program Improves Functional Exercise Capacity and Flexibility in Extremely Preterm Children With Bronchopulmonary Dysplasia Aged 4-6 Years: A Randomized Controlled Trial. AB - INTRODUCTION: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme preterm delivery, and is associated with reduced exercise tolerance and exercise capacity. The aim of this study was to assess the effects of a physical activity programme on exercise tolerance, exercise capacity, flexibility, and lung function in prematurely born children with BPD. METHODS: This was a randomized controlled trial. Preterm children with BPD (4-6 years) were randomized to intervention (IG) and control (CG) groups. The CG did not participate in any physical activity during the study period. The IG performed a 4-week exercise programme based on aerobic interval and resistance training. Outcomes were based on the 6-minute walk test (6MWT), incremental shuttle walk test (ISWT), modified sit and reach test (MSRT) and spirometry results. RESULTS: Twenty individuals were recruited. In the IG (n=10), statistical and clinical improvement was observed in the 6MWT (316.3+/-31.4m vs 376.2+/-39.5m; P=.002). Significant improvements were also seen in the IG in the ISWT (248.0+/-45.2m vs 465.3+/-58.2m; P=.013), MSRT (14.5+/-7.7cm vs 22.8+/-6.9cm; P=.003), and FEV1 (102%+/-16% pred vs 104%+/-17% pred; P=.004). No significant differences between pre- and post-intervention were observed in the CG for all outcomes (n=10). CONCLUSION: This 4-week programme resulted in statistical and clinical improvements in exercise tolerance, exercise capacity and flexibility in preterm children with BPD. PMID- 30518496 TI - Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish Experience. AB - BACKGROUND: The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs. METHODS: We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1<40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months. RESULTS: The mean age was 26.65 (range of 10-45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p=0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p=0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment. CONCLUSIONS: While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found. PMID- 30518497 TI - Demographic and facility volume related outcomes in radiofrequency ablation for early-stage hepatocellular carcinoma. AB - BACKGROUND: To evaluate outcomes related to disparities in facility volume and patient demographics in patients with early-stage hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA). METHODS: This is a retrospective study of patients with stage I/II HCC treated with RFA in the National Cancer Database. Independent contributors to overall survival were determined with Cox regression analysis. The Kaplan-Meier method and log-rank analyses were used to estimate overall survival and compare survival curves. A propensity score matched cohort analysis was performed. P-values < 0.05 were considered statistically significant. RESULTS: In total, 2911 patients were included. Stage II disease (p value = 0.006), increasing alpha fetoprotein (p-value = 0.007), and increasing bilirubin (p-value < 0.001) were associated with worse survival. Improved survival was seen in patients treated at high-volume centers (p-value = 0.004), which persisted following propensity score adjustment (p-value = 0.003). Asian race was associated with significantly improved survival (p-value < 0.001), while governmental insurance was associated with a significant decrease in survival (p value < 0.001). CONCLUSION: Treatment at a high-volume center and Asian race were significantly associated with improved survival following RFA for early-stage HCC. Governmental insurance, increasing alpha fetoprotein, increasing bilirubin, and higher disease stage were significantly associated with worse survival. PMID- 30518499 TI - Chromosomal translocations and semen quality: A study on 144 male translocation carriers. AB - RESEARCH QUESTION: Chromosomal translocations are known genetic causes of male infertility. Are certain translocations or chromosomal regions more directly associated with sperm defects? Is there a threshold of sperm impairment that can be relevant for detection of translocations? DESIGN: This is a monocentric retrospective observational study covering a 10-year period. Eighty-one patients carrying a reciprocal translocation (RCT) and 63 carrying a Robertsonian translocation (ROBT) were compared with 105 fertile patients. Semen quality before and after sperm migration was compared. The aims were to define whether a threshold based on sperm analysis could be proposed for detection of translocations and to identify whether some redundant chromosomal regions might be associated with sperm quality defects. RESULTS: The number of progressive spermatozoa retrieved after sperm preparation (NPS-ASP) was altered in both RCT and ROBT carriers compared with controls, with a stronger alteration in ROBT. Based on the NPS-ASP results in this large group of translocation carriers, a relatively robust threshold, fixed at less than 5 million, may be proposed for detection of translocations. The alteration of NPS-ASP was independent of the chromosome involved in ROBT, while in RCT, four redundant chromosomal regions (1q21, 6p21, 16q21, 17q11.2) were associated with poor or very poor NPS-ASP. CONCLUSIONS: The NPS-ASP appears to be a good parameter to assess sperm function and would be a useful tool to detect chromosomal translocations. Four redundant regions have been identified on four chromosomes, suggesting that they may contain genes of interest to study sperm functions. PMID- 30518500 TI - Construction and validation of a prediction model to minimize twin rates at preserved high live birth rates after IVF. AB - RESEARCH QUESTION: Elective single-embryo transfer (eSET) at blastocyst stage is widely used to reduce the frequency of multiple pregnancies after IVF. There are, however, concerns about increased risks for the offspring with prolonged embryo culture. Is it possible to select embryos for transfer at the early cleavage stage and still achieve low twin rates at preserved high live birth rates? DESIGN: A prediction model (PM) was developed to optimize eSET based on variables known 2 days after oocyte retrieval (fresh day 2 embryo transfers; double-embryo transfers 1999-2002 (n=2846) and SET 1999-2003 (n=945); n total=3791). Seventy five variables were analysed for association with pregnancy chance and twin risk and combined for PM construction. This PM was validated in 2004-2016 including frozen-thawed transfers (FET), to compare cumulative live birth rate (CLBR) and twin rate before (1999-2002 fresh embryo transfers plus FET from the same oocyte retrievals until the end of 2007, n=3495) and after (2004-2011 fresh embryo transfers plus FET from the same oocyte retrievals until the end of 2016, n=11195) implementing the model. RESULTS: The PM was constructed from four independent variables: female age, embryo score, ovarian sensitivity and treatment history. The calibration, i.e. the fit of observed versus predicted results, was excellent both at construction and at validation. Without compromising CLBR, twin rate was reduced from 25.2% to 3.8%, accompanied by profound improvements in perinatal outcome. CONCLUSION: The results provide the first successful construction, validation and impact analysis of a day 2 transfer PM to reduce multiple pregnancies. PMID- 30518498 TI - Beliefs About Medication and Uptake of Preventive Therapy in Women at Increased Risk of Breast Cancer: Results From a Multicenter Prospective Study. AB - INTRODUCTION: Uptake of preventive therapies for breast cancer is low. We examined whether women at increased risk of breast cancer can be categorized into groups with similar medication beliefs, and whether belief group membership was prospectively associated with uptake of preventive therapy. PATIENTS AND METHODS: Women (n = 732) attending an appointment to discuss breast cancer risk were approached; 408 (55.7%) completed the Beliefs About Medicines and the Perceived Sensitivity to Medicines questionnaires. Uptake of tamoxifen at 3 months was reported in 258 (63.2%). The optimal number of belief groups were identified using latent profile analysis. RESULTS: Uptake of tamoxifen was 14.7% (38/258). One in 5 women (19.4%; 78/402) reported a strong need for tamoxifen. The model fit statistics supported a 2-group model. Both groups held weak beliefs about their need for tamoxifen for current and future health. Group 2 (38%; 154/406 of the sample) reported stronger concerns about tamoxifen and medicines in general, and stronger perceived sensitivity to the negative effects of medicines compared with group 1 (62%; 252/406). Women with low necessity and lower concerns (group 1) were more likely to initiate tamoxifen (18.3%; 33/180) than those with low necessity and higher concerns (group 2) (6.4%; 5/78). After adjusting for demographic and clinical factors, the odds ratio was 3.37 (95% confidence interval, 1.08-10.51; P = .036). CONCLUSION: Uptake of breast cancer preventive therapy was low. A subgroup of women reported low need for preventive therapy and strong medication concerns. These women were less likely to initiate tamoxifen. Medication beliefs are targets for supporting informed decision-making. PMID- 30518501 TI - Ultrasound promoted transition metal doped polyaniline nanofibers: Enhanced electrode material for electrochemical energy storage applications. AB - Here in, we report a simple and facile method to synthesis morphology oriented transition metal (Nickel) doped polyaniline (Ni2+/PANI) by chemical oxidative polymerization with the assistance of ultrasonic irradiation. Physicochemical property of the materials examined through XRD and FT-IR. The morphological feature exposed that the sonochemical assisted Ni2+ doped PANI is differing from the conventional method and it reveals a notable electrochemical property as in the form of specific capacitance (370 F g-1 at 0.5 A g-1) with improved rate capability and sustained cycling performance due to its typical interconnected nano-fibrillar morphology than the other synthesized materials. These intriguing features realized from the properly arranged nanostructure with perfect doping and make as a promising candidate as an electrode material in supercapacitor applications. PMID- 30518503 TI - CD19-directed CAR T cells gain traction. PMID- 30518504 TI - Corrigendum. PMID- 30518502 TI - Long-term safety and activity of axicabtagene ciloleucel in refractory large B cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. AB - BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15.4 months (IQR 13.7-17.3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 * 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27.1 months (IQR 25.7 28.8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11.1 months (4.2-not estimable). The median overall survival was not reached (12.8-not estimable), and the median progression free survival was 5.9 months (95% CI 3.3-15.0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program. PMID- 30518505 TI - [Celebrating 50 years of the Anales de Pediatria: Maintaining the tradition while promoting changes]. PMID- 30518506 TI - Modified Masquelet's technique with nail and allograft: A case report. AB - The large bone defect treatment is a challenge issue in modern orthopaedic trauma surgery. One of the most used technique is the Masquelet's technique. In this case report we used a modified Masquelet technique to fill a six centimeters bone gap in the proximal femur. A 18-year-old boy with a septic pseudoarthrosis was treated with a two stages procedure: in the first step we used a hollow antibiotic spacer and an intramedullary nail. In the second step, we used both omologous (6 cm of bone allograft) and autologous bone graft with a new intramedullary nail. Immediate partial weight bearing was allowed and after 3 months the patient started walking with complete weight bearing. A year later the fracture had healed uneventfully. The modification of the Masquelet Technique that we have made allows the patient to immediately weight bearing safely, speeding up the functional recovery. Further studies are needed to standardize this type of combined technique. PMID- 30518507 TI - Masquelet technique to treat a septic nonunion after nailing of a femoral open fracture. AB - Septic nonunion is one of the most serious complications after an open fracture because both the infection and the bone defect need to be dealt with. Treatment is always protracted and expensive, and the result is uncertain. In the 1980s, Masquelet first described the technique of the induced membrane and autologous bone grafting to manage critical bone defects. In septic nonunions, the described approach, characterised by two different surgical steps, allows a radical approach to the infection, and gives a significant biological stimulus to bone healing. In this case, we present a 35-year-old male patient with an open grade II femoral shaft fracture (AO / OTA 32C3). The patient was initially treated with an intramedullary nail and the resulting septic nonunion was subsequently managed with the induced membrane technique and a double-plate osteosynthesis to protect the biological chamber. PMID- 30518508 TI - Treatment of distal clavicle nonunion with and without bone grafting. AB - The management of distal clavicle nonunion represents a challenging task for orthopaedic trauma surgeon. Both the choice of the implant and whether a bone graft is needed are controversial points which must be addressed. Particularly, in the case of a hypertrophic nonunion, grafting may not necessarily be needed, but given a poor underlying biological environment, a bone graft becomes necessary in order to enhance fracture healing. We report the case of a 62-year old patient who came to us with a hypertrophic nonunion of the left distal clavicle. She was initially treated with a hook plate without bone grafting. After an early peri-implant fracture she was treated again with anatomical S shaped locking plate associated with autologous cancellous bone graft. PMID- 30518509 TI - Intercalary allograft reconstruction in a patient with large tibial defect: Case report. AB - A fit 26 year-old-man presented to our Department with an open fracture of the left tibial shaft (AO 42-C3). The fracture was initially treated with an External Fixator, which was replaced by an intramedullary Grosse Kempf nail after 4 months. In the following year he developed an atrophic non-union and we witnessed the increasing bone resorption at the fracture site which led to the nail breakage. An accurate CT pre-operative planning was made and a revision surgery was successfully performed: the broken nail was removed and intercalary allograft reconstruction was made, using a compressible intramedullary nail. Whereas in literature it is well described how intercalary allografts can be used to fill the massive diaphyseal defects after tumor resections, we assumed it could also be an adequate technique to treat a large bone defect at a non-union site. PMID- 30518510 TI - Debridement, internal fixation and staged autogenous bone graft for the management of infected femoral non-union. AB - An infected non-union is a major and potentially devastating complication following bone fractures. It is often debilitating for the patients, physically and psychologically, because of its long healing period and emotional toll on patient and caregivers. Different surgical procedures (in one or two stages) are described in literature for its treatment. These range from external fixation (axial or circular) to internal fixation (nails or plates) associated or not with different types of biological support/augmentation (iliac crest bone graft, platelet rich plasma, bone morphogenic protein, etc.). This case report is about a 19 y.o. man affected by an infected non-union of the femoral shaft, who had to undergo a revision surgery a year after his accident. The treatment chosen by the senior author was the following one stage procedure: external fixator removal, surgical debridement, reduction and fixation of the fracture with a locked plate (internal fixator), bone graft and antibiotic cement usage. The use of new iliac crest bone graft after three months was necessary to obtain radiographic and clinical healing with great patient's satisfaction. The autologous iliac bone graft was chosen because it was necessary to give the patient the highest chance of healing. Despite the great experimental and clinical efforts to stimulate the biological healing process through the use of growth factors, stem cells, tissue scaffolds and other methods, today the gold standard of bone graft is still the autologous cancellous bone from the iliac crest. PMID- 30518511 TI - Risk of Post-polypectomy Bleeding With Uninterrupted Clopidogrel Therapy in an Industry-independent, Double-blind, Randomized Trial. AB - BACKGROUND & AIMS: Guidelines recommend withholding clopidogrel 7 days before polypectomy to reduce bleeding risk, but these were written based on limited evidence. We investigated whether uninterrupted clopidogrel therapy increases the risk of delayed post-polypectomy bleeding in patients undergoing colonoscopy. METHODS: We identified patients receiving clopidogrel for cardiovascular disease undergoing elective colonoscopies in Hong Kong, from 28 February 2012 through 11 April 2018. Eligible patients were instructed to stop taking clopidogrel 7 days before colonoscopy. They were then randomly assigned to groups given clopidogrel (75 mg) or placebo, daily until the morning of colonoscopy. All patients resumed their usual prescriptions of clopidogrel after colonoscopy. The primary endpoint was delayed post-polypectomy bleeding that required hospitalization or intervention up to 30 days after colonoscopy. Secondary endpoints were immediate post-polypectomy bleeding and serious cardio-thrombotic events for as long as 6 months after colonoscopy, according to anti-thrombotic trialist's criteria. All events were adjudicated by an independent, masked committee. RESULTS: A total of 387 patients underwent colonoscopy and 216 required polypectomies (106 patients in the clopidogrel group and 110 patients in the placebo group). The cumulative incidence of delayed post-polypectomy bleeding was 3.8% (95% CI, 1.4%-9.7%) in the clopidogrel group and 3.6% (95% CI, 1.4%-9.4%) in the placebo group (log-rank test P=.945). There were no significant differences in immediate post-polypectomy bleeding (8.5% vs 5.5%, P=.380) and cardio-thrombotic events (1.5% vs 2%, P=.713). CONCLUSIONS: In a randomized controlled trial of clopidogrel users undergoing colonoscopy, a slightly higher proportion of patients continuing clopidogrel developed delayed and immediate post-polypectomy bleeding, although this difference was not statistically significant. ClinicalTrials.gov: NCT01806090. PMID- 30518512 TI - Multimodal Transgastric Local Pancreatic Hypothermia Reduces Severity of Acute Pancreatitis in Rats and Increases Survival. AB - BACKGROUND & AIMS: Acute pancreatitis (AP) of different etiologies is associated with activation of different signaling pathways in pancreatic cells, posing challenges to development of targeted therapies. We investigated whether local pancreatic hypothermia, without systemic hypothermia, can reduce severity of AP, induced by different methods in rats. METHODS: A urethane balloon, with two polyurethane tubes was placed inside the stomach of the rats. AP was induced in Wistar rats by administration of caerulein or glyceryl-trilinoleate (GTL). Cold water was then infused into the balloon to cool the pancreas. Pancreatic temperatures were selected based on those found to reduce acinar cell injury. An unperfused balloon was used as a control. Pancreatic and rectal temperatures were monitored, and an infrared lamp and/or heating pad were used to avoid generalized hypothermia. We collected blood, pancreas, kidney, and lung tissues and analyzed them by histology, immunofluorescence, immunoblot, cytokine and chemokine magnetic bead, and DNA damage assays. The effect of hypothermia on signaling pathways initiated by caerulein and GTL was studied in acinar cells. RESULTS: Rats with pancreatic cooling developed less severe GTL-induced AP compared with rats that received the control balloon. In acinar cells, cooling reduced the lipolysis induced by GTL, increased the micellar form of its fatty acid, reduced the increase in cytosolic calcium, prevented loss of mitochondrial membrane potential (by 70%-80%), a and resulted in a 40%-50% reduction in uptake of a fatty acid tracer. In rats with AP, cooling reduced pancreatic necrosis by 48%, reduced serum levels of cytokines and markers of cell damage, decreased markers of lung and renal damage. The pancreatic cooling increased the proportions of rats surviving 6 hrs after induction of AP (to 90%, from less than 10% of rats that received the control balloon). In rats with caerulein-induced AP, pancreatic cooling reduced pancreatic markers of apoptosis and inflammation. CONCLUSIONS: In rats with AP, transgastric local pancreatic hypothermia reduces pancreatic necrosis, apoptosis, inflammation, and markers of pancreatitis severity, and increases survival. PMID- 30518513 TI - eHealth Engagement as a Response to Negative Healthcare Experiences: Cross Sectional Survey Analysis. AB - BACKGROUND: eHealth provides individuals with new means of accessing health information and communicating with providers through online channels. Prior evidence suggests that patients use eHealth to find information online when they receive care that is low in patient centeredness. However, it is unclear how other problems with the healthcare-delivery system motivate the use of eHealth, how these problems relate to different kinds of eHealth activities, and which populations are most likely to use eHealth when they receive low-quality care. OBJECTIVE: We aimed to determine how two types of negative care experiences-low patient centeredness and care coordination problems-motivate the use of different eHealth activities, and whether more highly educated individuals, who may find these tools easier to use, are more likely to use eHealth following negative experiences than less highly educated individuals. METHODS: Using nationally representative data from the 2017 Health Information National Trends Survey, we used factor analysis to group 25 different eHealth activities into categories based on the correlation between respondents' reports of their usage. Subsequently, we used multivariate negative binomial generalized linear model regressions to determine whether negative healthcare experiences predicted greater use of these resulting categories. Finally, we stratified our sample based on education level to determine whether the associations between healthcare experiences and eHealth use differed across groups. RESULTS: The study included 2612 individuals. Factor analysis classified the eHealth activities into two categories: provider-facing (eg, facilitating communication with providers) and independent (eg, patient-driven information seeking and communication with non providers). Negative care experiences were not associated with provider-facing eHealth activity in the overall population (care coordination: P=.16; patient centeredness: P=.57) or among more highly educated respondents (care coordination: P=.73; patient centeredness: P=.32), but respondents with lower education levels who experienced problems with care coordination used provider facing eHealth more often (IRR=1.40, P=.07). Individuals engaged in more independent eHealth activities if they experienced problems with either care coordination (IRR=1.15 P=.01) or patient-centered communication (IRR=1.16, P=.01). Although care coordination problems predicted independent eHealth activity across education levels (higher education: IRR=1.13 P=.01; lower education: IRR=1.19, P=.07), the relationship between low perceived patient centeredness and independent activity was limited to individuals with lower education levels (IRR=1.25, P=.02). CONCLUSIONS: Individuals use a greater number of eHealth activities, especially activities that are independent of healthcare providers, when they experience problems with their healthcare. People with lower levels of education seem particularly inclined to use eHealth when they have negative healthcare experiences. To maximize the potential for eHealth to meet the needs of all patients, especially those who are traditionally underserved by the healthcare system, additional work should be performed to ensure that eHealth resources are accessible and usable to all members of the population. PMID- 30518515 TI - Government's misplaced prevention agenda. PMID- 30518514 TI - How Inclusive, User-Centered Design Research Can Improve Psychological Therapies for Psychosis: Development of SlowMo. AB - BACKGROUND: Real-world implementation of psychological interventions for psychosis is poor. Barriers include therapy being insufficiently usable and useful for a diverse range of people. User-centered, inclusive design approaches could improve the usability of therapy, which may increase uptake, adherence, and effectiveness. OBJECTIVE: This study aimed to optimize the usability of an existing psychological intervention, Thinking Well, which targets reasoning processes in paranoia using a basic digital interface. METHODS: We conducted inclusive, user-centered design research characterized by purposive sampling of extreme users from the margins of groups, ethnographic investigation of the problem context, and iterative prototyping of solutions. The UK Design Council's double diamond method was used. This consisted of 4 phases: discover, including a case series of Thinking Well, stakeholder interviews, desk research, user profiling, system mapping, and a mood board; define, consisting of workshops to synthesize findings and generate the design brief; develop, involving concept workshops and prototype testing; and deliver, in which the final minimal viable product was storyboarded and iteratively coded. RESULTS: Consistent with our previous work, the Thinking Well case series showed medium to large effects on paranoia and well-being and small effects on reasoning. These were maintained at follow-up despite some participants reporting difficulties with the therapy interface. Insights from the discover phase confirmed that usability was challenged by information complexity and poor accessibility. Participants were generally positive about the potential of technology to be enjoyable, help manage paranoia, and provide tailored interpersonal support from therapists and peers, although they reported privacy and security concerns. The define phase highlighted that the therapy redesign should support monitoring, simplify information processing, enhance enjoyment and trust, promote personalization and normalization, and offer flexible interpersonal support. During the develop phase over 60 concepts were created, with 2 key concepts of thoughts visualized as bubbles and therapy as a journey selected for storyboarding. The output of the deliver phase was a minimal viable product of an innovative digital therapy, SlowMo. SlowMo works by helping people to notice their worries and fast thinking habits, and encourages them to slow down for a moment to find ways of feeling safer. A Web app supports the delivery of 8 face-to-face sessions, which are synchronized to a native mobile app. CONCLUSIONS: SlowMo makes use of personalization, ambient information, and visual metaphors to tailor the appeal, engagement, and memorability of therapy to a diversity of needs. Feasibility testing has been promising, and the efficacy of SlowMo therapy is now being tested in a multicentered randomized controlled trial. The study demonstrates that developments in psychological theory and techniques can be enhanced by improving the usability of the therapy interface to optimize its impact in daily life. PMID- 30518516 TI - Sixty seconds on . . . the 10 year plan. PMID- 30518518 TI - Meningococcal meningitis presenting postinfant group B meningococcal immunisation. PMID- 30518519 TI - Examining the effectiveness of examination at 6-8 weeks for developmental dysplasia: testing the safety net. AB - OBJECTIVE: The 'GP check' at 6-8 weeks forms part of the selective surveillance system for developmental dysplasia of the hip (DDH) in the UK. It is imperative to pick up DDH within the first months of life to allow for non-invasive treatment and the avoidance of surgery. We aim to investigate the effectiveness of hip examination at 6-8 weeks. METHODS: This is a longitudinal observational study including all infants born in our region in the 5 years following 2006. Early presentation was defined as diagnosis within 14 weeks of birth and late presentation after 14 weeks. Treatment records for early and late DDH as well as referrals for ultrasound (US) following examination at 6-8 weeks were analysed. Attendance of the examination at 6-8 weeks in those patients who went on to present with a late DDH was also analysed. RESULTS: 23 112 live births occurred during the study period. There were 141 confirmed cases of DDH. 400 referrals for US were received following examination at 6-8 weeks; 6 of these had a positive finding of DDH. 27 patients presented after 14 weeks and were classified as late presentations. 25 of these patients had attended examination at 6-8 weeks and no abnormality had been identified. CONCLUSIONS: The sensitivity of examination at 6 8 weeks was only 19.4%, its specificity was 98% and it had a positive predictive value of 1.5%. For many years the check at 6-8 weeks has been thought of as a means to identify those children not identified as neonates; however, we found that four out of five children with DDH were not identified by the check at 6-8 weeks. Unfortunately, we conclude that the presumed safety net of the examination in its current form is not reliable. PMID- 30518520 TI - Preventing overdiagnosis and the harms of too much sport and exercise medicine. PMID- 30518521 TI - Before and after of major neck surgery. PMID- 30518517 TI - Patient safety after implementation of a coproduced family centered communication programme: multicenter before and after intervention study. AB - OBJECTIVE: To determine whether medical errors, family experience, and communication processes improved after implementation of an intervention to standardize the structure of healthcare provider-family communication on family centered rounds. DESIGN: Prospective, multicenter before and after intervention study. SETTING: Pediatric inpatient units in seven North American hospitals, 17 December 2014 to 3 January 2017. PARTICIPANTS: All patients admitted to study units (3106 admissions, 13171 patient days); 2148 parents or caregivers, 435 nurses, 203 medical students, and 586 residents. INTERVENTION: Families, nurses, and physicians coproduced an intervention to standardize healthcare provider family communication on ward rounds ("family centered rounds"), which included structured, high reliability communication on bedside rounds emphasizing health literacy, family engagement, and bidirectional communication; structured, written real-time summaries of rounds; a formal training programme for healthcare providers; and strategies to support teamwork, implementation, and process improvement. MAIN OUTCOME MEASURES: Medical errors (primary outcome), including harmful errors (preventable adverse events) and non-harmful errors, modeled using Poisson regression and generalized estimating equations clustered by site; family experience; and communication processes (eg, family engagement on rounds). Errors were measured via an established systematic surveillance methodology including family safety reporting. RESULTS: The overall rate of medical errors (per 1000 patient days) was unchanged (41.2 (95% confidence interval 31.2 to 54.5) pre intervention v 35.8 (26.9 to 47.7) post-intervention, P=0.21), but harmful errors (preventable adverse events) decreased by 37.9% (20.7 (15.3 to 28.1) v 12.9 (8.9 to 18.6), P=0.01) post-intervention. Non-preventable adverse events also decreased (12.6 (8.9 to 17.9) v 5.2 (3.1 to 8.8), P=0.003). Top box (eg, "excellent") ratings for six of 25 components of family reported experience improved; none worsened. Family centered rounds occurred more frequently (72.2% (53.5% to 85.4%) v 82.8% (64.9% to 92.6%), P=0.02). Family engagement 55.6% (32.9% to 76.2%) v 66.7% (43.0% to 84.1%), P=0.04) and nurse engagement (20.4% (7.0% to 46.6%) v 35.5% (17.0% to 59.6%), P=0.03) on rounds improved. Families expressing concerns at the start of rounds (18.2% (5.6% to 45.3%) v 37.7% (17.6% to 63.3%), P=0.03) and reading back plans (4.7% (0.7% to 25.2%) v 26.5% (12.7% to 7.3%), P=0.02) increased. Trainee teaching and the duration of rounds did not change significantly. CONCLUSIONS: Although overall errors were unchanged, harmful medical errors decreased and family experience and communication processes improved after implementation of a structured communication intervention for family centered rounds coproduced by families, nurses, and physicians. Family centered care processes may improve safety and quality of care without negatively impacting teaching or duration of rounds. TRIAL REGISTRATION: ClinicalTrials.gov NCT02320175. PMID- 30518522 TI - Paradoxical pulmonary event under tocilizumab treatment for systemic sclerosis associated usual interstitial pneumonia. PMID- 30518524 TI - Five year lung plan calls for wider use of spirometry. PMID- 30518525 TI - Seeing my first death. PMID- 30518523 TI - A phase 1b dose-escalation and expansion study of the BCL-2 inhibitor venetoclax combined with tamoxifen in ER and BCL-2-positive metastatic breast cancer. AB - Venetoclax, a potent and selective BCL-2 inhibitor, synergizes with endocrine therapy in pre-clinical models of ER-positive breast cancer. Using a phase 1b 3+3 dose escalation and expansion study design, 33 patients with ER and BCL-2 positive metastatic disease (mean prior regimens, 2; range 0-8) were treated with daily tamoxifen (20 mg) and venetoclax (200-800 mg). Apart from uncomplicated 'on target' lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase 2 dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and clinical benefit rate 75%. Treatment responses were pre-empted by metabolic responses (FDG PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations. PMID- 30518527 TI - Patient whose GP's religious activities contributed to her mental breakdown is awarded L12 700. PMID- 30518526 TI - Chair ICO/UVIC-UCC of palliative care at the University of Vic - Central University of Catalonia: an innovative multidisciplinary model of education, research and knowledge transfer. AB - OBJECTIVES: Generation and dissemination of knowledge is a relevant challenge of palliative care (PC). The Chair Catalan Institute of Oncology (ICO)/University of Vic (UVIC) of Palliative Care (CPC) was founded in 2012, as a joint project of the ICO and the University of Vic/Central of Catalonia to promote the development of PC with public health and community-oriented vision and academic perspectives. The initiative brought together professionals from a wide range of disciplines (PC, geriatrics, oncology, primary care and policy) and became the first chair of PC in Spain. We describe the experience of the CPC at its fifth year of implementation. METHODS: Data collection from annual reports, publications, training and research activities. RESULTS: Results for period 2012-2017 are classified into three main blocks: (1) Programme: (a) The advanced chronic care model (Palliative needs (NECPAL)); (b) the psychosocial and spiritual domains of care (Psychosocial needs (PSICPAL)); (c) advance care planning and shared decision making (Advance care planning (PDAPAL)); and (d) the compassive communities projects (Society involvement (SOCPAL)). (2) Education and training activities: (a) The master of PC, 13 editions and 550 professionals trained; (b) postgraduate course on psychosocial care, 4 editions and 140 professionals trained; and (c) workshops on specific topics, pregraduate training and online activities with a remarkable impact on the Spanish-speaking community. (3) Knowledge-transfer activities and research projects: (a) Development of 20 PhDs projects; and (b) 59 articles and 6 books published. CONCLUSION: Being the first initiative of chair in PC in Spain, the CPC has provided a framework of multidisciplinary areas that have generated innovative experiences and projects in PC. PMID- 30518528 TI - The Caenorhabditis elegans SMOC-1 Protein Acts Cell Non-autonomously To Promote Bone Morphogenetic Protein Signaling. AB - Bone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) mutants have a small body size, while overexpression of smoc-1 led to a long body size and increased expression of the RAD-SMAD BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFbeta-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell non-autonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1's function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans. PMID- 30518530 TI - Older patients with IBD might have higher risk of Parkinson's disease. PMID- 30518529 TI - Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. PMID- 30518532 TI - Intracranial dural arteriovenous fistula mistaken as cervical transverse myelitis. AB - We describe a man with an intracranial dural arteriovenous fistula that presented as a subacute longitudinally extensive cervical myelopathy. The uncommon location of the fistula and the absence of specific radiological signs resulted in initial misdiagnosis as longitudinally extensive transverse myelitis. Neurologists should have a high index of suspicion for dural arteriovenous fistula in older men, especially those with subacute or chronic symptoms, acellular cerebrospinal fluid and, particularly, if there is neurological deterioration soon after corticosteroid treatment. Patients need early angiography to identify this treatable cause of myelopathy. PMID- 30518531 TI - DNA Methyltransferase 1 Controls Nephron Progenitor Cell Renewal and Differentiation. AB - BACKGROUND: Nephron number is a major determinant of long-term renal function and cardiovascular risk. Observational studies suggest that maternal nutritional and metabolic factors during gestation contribute to the high variability of nephron endowment. However, the underlying molecular mechanisms have been unclear. METHODS: We used mouse models, including DNA methyltransferase (Dnmt1, Dnmt3a, and Dnmt3b) knockout mice, optical projection tomography, three-dimensional reconstructions of the nephrogenic niche, and transcriptome and DNA methylation analysis to characterize the role of DNA methylation for kidney development. RESULTS: We demonstrate that DNA hypomethylation is a key feature of nutritional kidney growth restriction in vitro and in vivo, and that DNA methyltransferases Dnmt1 and Dnmt3a are highly enriched in the nephrogenic zone of the developing kidneys. Deletion of Dnmt1 in nephron progenitor cells (in contrast to deletion of Dnmt3a or Dnm3b) mimics nutritional models of kidney growth restriction and results in a substantial reduction of nephron number as well as renal hypoplasia at birth. In Dnmt1-deficient mice, optical projection tomography and three dimensional reconstructions uncovered a significant reduction of stem cell niches and progenitor cells. RNA sequencing analysis revealed that global DNA hypomethylation interferes in the progenitor cell regulatory network, leading to downregulation of genes crucial for initiation of nephrogenesis, Wt1 and its target Wnt4. Derepression of germline genes, protocadherins, Rhox genes, and endogenous retroviral elements resulted in the upregulation of IFN targets and inhibitors of cell cycle progression. CONCLUSIONS: These findings establish DNA methylation as a key regulatory event of prenatal renal programming, which possibly represents a fundamental link between maternal nutritional factors during gestation and reduced nephron number. PMID- 30518534 TI - Rethinking research reproducibility. PMID- 30518533 TI - Identification of ILK as a critical regulator of VEGFR3 signalling and lymphatic vascular growth. AB - Vascular endothelial growth factor receptor-3 (VEGFR3) signalling promotes lymphangiogenesis. While there are many reported mechanisms of VEGFR3 activation, there is little understanding of how VEGFR3 signalling is attenuated to prevent lymphatic vascular overgrowth and ensure proper lymph vessel development. Here, we show that endothelial cell-specific depletion of integrin-linked kinase (ILK) in mouse embryos hyper-activates VEGFR3 signalling and leads to overgrowth of the jugular lymph sacs/primordial thoracic ducts, oedema and embryonic lethality. Lymphatic endothelial cell (LEC)-specific deletion of Ilk in adult mice initiates lymphatic vascular expansion in different organs, including cornea, skin and myocardium. Knockdown of ILK in human LECs triggers VEGFR3 tyrosine phosphorylation and proliferation. ILK is further found to impede interactions between VEGFR3 and beta1 integrin in vitro and in vivo, and endothelial cell specific deletion of an Itgb1 allele rescues the excessive lymphatic vascular growth observed upon ILK depletion. Finally, mechanical stimulation disrupts the assembly of ILK and beta1 integrin, releasing the integrin to enable its interaction with VEGFR3. Our data suggest that ILK facilitates mechanically regulated VEGFR3 signalling via controlling its interaction with beta1 integrin and thus ensures proper development of lymphatic vessels. PMID- 30518535 TI - NAD(P)H quinone oxidoreductase 1 (NQO1): an enzyme which needs just enough mobility, in just the right places. AB - NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease. PMID- 30518536 TI - Carfilzomib-induced aHUS responds to early eculizumab and may be associated with heterozygous CFHR3-CFHR1 deletion. PMID- 30518537 TI - Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis. AB - Mesenchymal stromal cells (MSCs) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival, and differentiation of hematopoietic stem/progenitor cells (HSPCs) in the stem cell niche. MSCs are functionally altered in myelodysplastic syndromes (MDS) and exhibit an altered methylome compared with MSCs from healthy controls, thus contributing to disease progression. To determine whether MSCs are amenable to epigenetic therapy and if this affects their function, we examined growth, differentiation, and HSPC-supporting capacity of ex vivo-expanded MSCs from MDS patients in comparison with age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). Strikingly, we find that AZA exerts a direct effect on healthy as well as MDS-derived MSCs such that they favor support of healthy over malignant clonal HSPC expansion in coculture experiments. RNA-sequencing analyses of MSCs identified stromal networks regulated by AZA. Notably, these comprise distinct molecular pathways crucial for HSPC support, foremost extracellular matrix molecules (including collagens) and interferon pathway components. Our study demonstrates that the hypomethylating agent AZA exerts its antileukemic activity in part through a direct effect on the HSPC-supporting BM niche and provides proof of concept for the therapeutic potential of epigenetic treatment of diseased MSCs. In addition, our comprehensive data set of AZA-sensitive gene networks represents a valuable framework to guide future development of targeted epigenetic niche therapy in myeloid malignancies such as MDS and acute myeloid leukemia. PMID- 30518538 TI - Robust adaptive immune response against Babesia microti infection marked by low parasitemia in a murine model of sickle cell disease. AB - The intraerythrocytic parasite Babesia microti is the number 1 cause of transfusion-transmitted infection and can induce serious, often life-threatening complications in immunocompromised individuals including transfusion-dependent patients with sickle cell disease (SCD). Despite the existence of strong long lasting immunological protection against a second infection in mouse models, little is known about the cell types or the kinetics of protective adaptive immunity mounted following Babesia infection, especially in infection-prone SCD that are thought to have an impaired immune system. Here, we show, using a mouse B microti infection model, that infected wild-type (WT) mice mount a very strong adaptive immune response, characterized by (1) coordinated induction of a robust germinal center (GC) reaction; (2) development of follicular helper T (TFH) cells that comprise ~30% of splenic CD4+ T cells at peak expansion by 10 days postinfection; and (3) high levels of effector T-cell cytokines, including interleukin 21 and interferon gamma, with an increase in the secretion of antigen (Ag)-specific antibodies (Abs). Strikingly, the Townes SCD mouse model had significantly lower levels of parasitemia. Despite a highly disorganized splenic architecture before infection, these mice elicited a surprisingly robust adaptive immune response (including comparable levels of GC B cells, TFH cells, and effector cytokines as control and sickle trait mice), but higher immunoglobulin G responses against 2 Babesia-specific proteins, which may contain potential immunogenic epitopes. Together, these studies establish the robust emergence of adaptive immunity to Babesia even in immunologically compromised SCD mice. Identification of potentially immunogenic epitopes has implications to identify long-term carriers, and aid Ag-specific vaccine development. PMID- 30518540 TI - Intensive care staff are susceptible to burnout. PMID- 30518539 TI - A Very Oil Yellow1 Modifier of the Oil Yellow1-N1989 Allele Uncovers a Cryptic Phenotypic Impact of Cis-regulatory Variation in Maize. AB - Forward genetics determines the function of genes underlying trait variation by identifying the change in DNA responsible for changes in phenotype. Detecting phenotypically-relevant variation outside protein coding sequences and distinguishing this from neutral variants is not trivial; partly because the mechanisms by which DNA polymorphisms in the intergenic regions affect gene regulation are poorly understood. Here we utilized a dominant genetic reporter to investigate the effect of cis and trans-acting regulatory variation. We performed a forward genetic screen for natural variation that suppressed or enhanced the semi-dominant mutant allele Oy1-N1989, encoding the magnesium chelatase subunit I of maize. This mutant permits rapid phenotyping of leaf color as a reporter for chlorophyll accumulation, and mapping of natural variation in maize affecting chlorophyll metabolism. We identified a single modifier locus segregating between B73 and Mo17 that was linked to the reporter gene itself, which we call very oil yellow1 (vey1). Based on the variation in OY1 transcript abundance and genome wide association data, vey1 is predicted to consist of multiple cis-acting regulatory sequence polymorphisms encoded at the wild-type oy1 alleles. The vey1 locus appears to be a common polymorphism in the maize germplasm that alters the expression level of a key gene in chlorophyll biosynthesis. These vey1 alleles have no discernable impact on leaf chlorophyll in the absence of the Oy1-N1989 reporter. Thus, the use of a mutant as a reporter for magnesium chelatase activity resulted in the detection of expression-level polymorphisms not readily visible in the laboratory. PMID- 30518541 TI - A Multiplex Droplet Digital PCR Assay for Quantification of HTLV-1c DNA Proviral Load and T-Cells from Blood and Respiratory Exudates Sampled in a Remote Setting. AB - During human T-cell leukemia virus type-1 (HTLV-1) infection the frequency of cells harboring an integrated copy of viral cDNA, the proviral load (PVL), is the main risk factor for progression of HTLV-1-associated diseases. Accurate quantification of provirus by droplet digital PCR (ddPCR) is a powerful diagnostic tool with emerging uses for monitoring viral expression. Current ddPCR techniques quantify HTLV-1 PVL in terms of whole genomic cellular material, while the main target of HTLV-1 infection is the CD4+ and CD8+ T-cell. Our understanding of HTLV-1 proliferation and the amount of viral burden present in different compartments is limited. Recently a sensitive ddPCR assay was applied to quantifying T-cells by measuring loss of germline T-cell receptor genes as method of distinguishing non-T-cell from recombined T-cell DNA. In this study, we demonstrated and validated novel applications of the duplex ddPCR assay to quantify T-cells from various sources of human gDNA extracted from frozen material (PBMCs, bronchoalveolar lavage, and induced sputum) from a cohort of remote Indigenous Australians and then compared the T-cell measurements by ddPCR to the prevailing standard method of flow cytometry. The HTLV-1c PVL was then calculated in terms of extracted T-cell gDNA from various compartments. Because HTLV-1c preferentially infects CD4+ T-cells, and the amount of viral burden correlates with HTLV-1c disease pathogenesis, application of this ddPCR assay to accurately measure HTLV-1c-infected T-cells can be of greater importance for clinical diagnostics, prognostics as well as monitoring therapeutic applications. PMID- 30518542 TI - Assessment of Test Performance and Potential for Environmental Contamination Associated with a Point-of-Care Molecular Assay for Group A Streptococcus in an End-User Setting. AB - Although FDA-approved and CLIA-waived point-of-care (POC) molecular systems are being implemented in routine clinical practice, instrument reliability, test performance in the hands of end-users, and the potential for environmental contamination resulting from use of POC molecular systems have not been extensively evaluated. We performed a prospective evaluation of the Roche cobas Liat group A streptococcus (GAS) assay compared to routine real-time PCR. We evaluated test accuracy, instrument failure rate, and monitored for environmental contamination when testing was performed by minimally trained end users in an Express Care Clinic environment. The overall concordance of the Liat GAS assay with routine testing was 97.2% (455/468). The average Liat failure rate across three analyzers was 6.6% (33/501) (range: 3.7 - 11.6%), and no environmental contamination was detected during the course of the study. The cobas Liat platform and GAS assay demonstrated reliable performance in the end-user setting and may serve as a rapid, POC option for routine diagnostic testing for certain infectious diseases, including GAS. PMID- 30518543 TI - Multicenter Clinical Evaluation of the Automated ARIES(r) Bordetella Assay. AB - Molecular methods offer superior sensitivity and specificity, and reduce testing turnaround time from days to hours for detection of Bordetella pertussis and Bordetella parapertussis In this study, we evaluated the performance of the automated PCR-based ARIES Bordetella Assay, which detects both B. pertussis and B. parapertussis directly from nasopharyngeal swab specimens. Limits of detection were 1,800 colony-forming units/mL (CFU.mL-1) for B. pertussis and 213 CFU.mL-1 for B. parapertussis The assay detected 16/18 unique B. pertussis/B. parapertussis strains. Of 71 potential cross-reacting organisms, 5 generated false-positives in 1/6 replicates; none of 6 additional Bordetella spp. were erroneously detected. Specimens were stable at 20-25 degrees C for at least 10 h, 4-8 degrees C for 10 days, and at <= -70 degrees C for 6 months. Of 1,052 nasopharyngeal specimens from patients with suspected pertussis, 3.0% (n=32) were B. pertussis-positive, and 0.2% (n=2) were B. parapertussis-positive. After combining these data with ARIES Bordetella Assay data from 57 nasopharyngeal samples with previously confirmed B. pertussis or B. parapertussis, and from 50 contrived B. parapertussis samples, ARIES assay respective positive and negative percent agreements with the reference assays were 97.1% and 99.0% for B. pertussis, and 100% and 99.7% for B. parapertussis The ARIES Bordetella Assay provides accurate detection and distinction of B. pertussis and B. parapertussis infection within 2 hours. PMID- 30518544 TI - Industry Perspectives on the WHO Essential Diagnostics List. AB - Access to diagnostics is a key component of universal health coverage (UHC). However, healthcare systems in low- and middle-income countries (LMICs) have given little importance to diagnostics and laboratories.1,2 Disease management in such countries largely relies on empirical therapy and syndromic management. This poses challenges for tackling problems such as antimicrobial resistance, outbreaks, and non-communicable diseases.1,2.... PMID- 30518545 TI - CNS phenotype in X linked Charcot- Marie-Tooth disease. PMID- 30518546 TI - Italy's health minister fires country's top health board. PMID- 30518547 TI - T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis. AB - BACKGROUND: T cell dysfunction occurs in many diseases, especially in chronic virus infection and cancers. However, up to now, little is known on the distinctions in T cell exhaustion between cancer and chronic virus infection. The objective of this study is to explore the transcriptional similarities and differences in exhausted CD8 +T cell between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). METHODS: RNA sequencing was performed to compare the transcriptome of CD8 +T cells isolated from healthy donors' blood, tumour tissues of patients with HCC and chronic HBV infected HCC patients' paracancerous tissues. DESeq2 algorithm was used to determine differentially expressed genes. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted for in-depth analysis of these differentially expressed genes. RESULTS: A total number of 2109 and 2203 genes were differentially expressed in patients with chronic HBV infection and HCC, respectively. Comparing these two groups of differentially deregulated genes, we found that nearly half of them were shared, and these shared genes were further classified into several functional categories, such as metabolic process, binding and intracellular organelle. KEGG analysis revealed that these shared deregulated genes were involved in many important pathways such as Parkinson's disease, oxidative phosphorylation and messenger RNA surveillance. Interestingly, we reported that chronic HBV infection specific deregulated genes were mainly enriched in graft versus host disease, allograft rejection, phenylalanine, tyrosine and tryptophan biosynthesis pathways. Whereas, HCC specific deregulated genes were highly enriched in oxidative phosphorylation, thyroid cancer and endometrial cancer pathways. CONCLUSION: Our study demonstrated that T cell dysfunction associated with HCC and chronic HBV infection shares high similarities, however, each possesses its own features in terms of specific genes and signalling pathways. Uncovering the differences of T cells dysfunction would facilitate our understanding the diseases pathogenesis and developing innovative therapies in the future. PMID- 30518548 TI - CAP2 mutation leads to impaired actin dynamics and associates with supraventricular tachycardia and dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a primary myocardial disease leading to contractile dysfunction, progressive heart failure and excessive risk of sudden cardiac death. Around half of DCM cases are idiopathic, and genetic factors seem to play an important role. AIM: We investigated a possible genetic cause of DCM in two consanguineous children from a Bedouin family. METHODS AND RESULTS: Using exome sequencing and searching for rare homozygous variations, we identified a nucleotide change in the donor splice consensus sequence of exon 7 in CAP2 as the causative mutation. Using patient-derived fibroblasts, we demonstrated that the mutation causes skipping of exons 6 and 7. The resulting protein is missing 64 amino acids in its N-CAP domain that should prevent its correct folding. CAP2 protein level was markedly reduced without notable compensation by the homolog CAP1. However, beta-actin mRNA was elevated as demonstrated by real-time qPCR. In agreement with the essential role of CAP2 in actin filament polymerization, we demonstrate that the mutation affects the kinetics of repolymerization of actin in patient fibroblasts. CONCLUSIONS: This is the first report of a recessive deleterious mutation in CAP2 and its association with DCM in humans. The clinical phenotype recapitulates the damaging effects on the heart observed in Cap2 knockout mice including DCM and cardiac conduction disease, but not the other effects on growth, viability, wound healing and eye development. Our data underscore the importance of the proper kinetics of actin polymerization for normal function of the human heart. PMID- 30518549 TI - Converter domain mutations in myosin alter structural kinetics and motor function. AB - Myosins are molecular motors that use a conserved ATPase cycle to generate force. We investigated two mutations in the converter domain of myosin V (R712G and F750L) to examine how altering specific structural transitions in the motor ATPase cycle can impair myosin mechanochemistry. The corresponding mutations in the human beta-cardiac myosin gene are associated with hypertrophic and dilated cardiomyopathy, respectively. Despite similar steady-state actin-activated ATPase and unloaded in vitro motility sliding velocities, both R712G and F750L were less able to overcome frictional loads measured in the loaded motility assay. Transient kinetic analysis and stopped-flow FRET demonstrated that the R712G mutation slowed the maximum ATP hydrolysis and recovery stroke rate constants, while the F750L mutation enhanced these steps. In both mutants, the fast and slow power stroke as well as actin-activated phosphate release rate constants were not significantly different from WT. Time-resolved FRET experiments revealed that R712G and F750L populate the pre- and post-power stroke states with similar FRET distance and distance distribution profiles. The R712G mutant increased the mole fraction in the post-power stroke conformation in the strong actin binding states, while the F750L decreased this population in the actomyosin ADP state. We conclude that mutations in key allosteric pathways can shift the equilibrium and/or alter the activation energy associated with key structural transitions without altering the overall conformation of the pre- and post-power stroke states. Thus, therapies designed to alter the transition between structural states may be able to rescue the impaired motor function induced by disease mutations. PMID- 30518550 TI - Oleate disrupts cAMP signaling, contributing to potent stimulation of pancreatic beta-cell autophagy. AB - Autophagy is critical for maintaining cellular function via clearance of excess nutrients and damaged organelles. In pancreatic beta-cells, it helps counter the endoplasmic reticulum (ER) stress that impairs insulin secretory capacity during Type 2 diabetes. Chronic exposure of beta-cells to saturated fatty acids (FAs) such as palmitate stimulates ER stress and modulates autophagy, but the effects of unsaturated FAs such as oleate which are also elevated during obesity, are less well understood. We therefore treated MIN6 cells and mouse islets for 8-48h with either palmitate or oleate, and then monitored autophagic flux, signaling pathways, lysosomal biology and phospholipid profiles. Compared to palmitate, oleate more effectively stimulated both autophagic flux and clearance of autophagosomes. The flux stimulation occurred independently of ER stress, nutrient-sensing (mTOR) and signaling pathways (protein kinases A, C and D). Instead the mechanism involved the exchange factor directly activated by cAMP 2 (Epac2). Oleate reduced cellular cAMP, and its effects on autophagic flux were reproduced or inhibited respectively by Epac2 knockdown or activation. Oleate also increased lysosomal acidity and increased phospholipid saturation, consistent with improved autophagosomal fusion with lysosomes. We conclude that a potent stimulation of autophagy might help explain the known benefits of unsaturated FAs in countering the toxicity of saturated FAs in beta-cells during obesity and lipid loading. PMID- 30518551 TI - Regulation of SH3PX1 by dNedd4-long at the Drosophila Neuromuscular Junction. AB - Drosophila Nedd4 (dNedd4) is a HECT E3 ubiquitin ligase present in two major isoforms: short (dNedd4S) and long (dNedd4Lo), with the latter containing two unique regions (N-terminus and Middle). While dNedd4S promotes neuromuscular synaptogenesis (NMS), dNedd4Lo inhibits it and impairs larval locomotion. To explain how dNedd4Lo inhibits NMS, mass spectrometry was performed to find its binding partners and identified SH3PX1, which binds dNedd4Lo unique Middle region. SH3PX1 contains SH3, PX and BAR domains and is present at neuromuscular junctions, where it regulates active zone ultrastructure and presynaptic neurotransmitter release. Here, we demonstrate direct binding of SH3PX1 to the dNedd4Lo Middle region (which contains a Pro rich sequence) in vitro and in cells, via the SH3PX1-SH3 domain. In Drosophila S2 cells, dNedd4Lo overexpression reduces SH3PX1 levels at the cell periphery. In vivo overexpression of dNedd4Lo post-synaptically, but not pre-synaptically, reduces SH3PX1 levels at the subsynaptic reticulum and impairs neurotransmitter release. Unexpectedly, larvae that overexpress dNedd4Lo post-synaptically and are heterozygous for a null mutation in SH3PX1 display increased neurotransmission compared to dNedd4Lo or SH3PX1 mutant larvae alone, suggesting a compensatory effect from the remaining SH3PX1 allele. These results suggest a postsynaptic - specific regulation of SH3PX1 by dNedd4Lo. PMID- 30518552 TI - Brain networks' functional connectivity separates aphasic deficits in stroke. AB - OBJECTIVE: To investigate whether different language deficits are distinguished by the relative strengths of their association with the functional connectivity (FC) at rest of the language network (LN) and cingulo-opercular network (CON) after aphasic stroke. METHODS: In a group of patients with acute stroke and left hemisphere damage, we identified 3 distinct, yet correlated, clusters of deficits including comprehension/lexical semantic, grapheme-phoneme knowledge, and verbal executive functions. We computed partial correlations in which the contributions of a behavioral cluster and network FC of no interest were statistically regressed out. RESULTS: We observed a double dissociation such that impairment of grapheme-phoneme knowledge was more associated with lower FC of the LN within the left hemisphere than lower FC of the CON, whereas verbal executive deficits were more related to lower FC of the CON than the LN in the left hemisphere. Furthermore, the specific association between language deficits and FC was independent of the amount of structural damage to the LN and CON. CONCLUSION: These findings indicate that after a left-hemisphere lesion, the type of language impairment is related to the abnormal pattern of correlated activity in different networks. Accordingly, they extend the concept of a neuropsychological double dissociation from structural damage to functional network abnormalities. Finally, current results strongly argue in favor of the behavioral specificity of intrinsic brain activity after focal structural damage. PMID- 30518553 TI - Atrial cardiopathy: A new cause for stroke? PMID- 30518554 TI - Neurology residency training in 2017: A survey of preparation, perspectives, and plans. AB - OBJECTIVE: To survey graduating US neurology residents on the topics of debt, fellowship interview process, future plans, and their readiness for practice and business management tasks. METHODS: An electronic survey was sent to all US American Academy of Neurology member adult and child neurology residents graduating in June 2017. RESULTS: The response rate was 23.4% (n = 159). Of the 143 residents who provided information about student loans, 57% reported having debt (median $180,000). Ninety percent of respondents reported plans to pursue a fellowship after residency; 57% intended to stay at their home institution for additional training. Among respondents from adult neurology programs, 87% preferred to begin the fellowship application process after the first 6 months of the third postgraduate year. Almost half (46%) of adult neurology program residents felt they did not have enough outpatient exposure prior to making fellowship decisions compared to 14% of child neurology trainees. Although reported readiness to perform specific tasks (coding and office management) increased since 2007 (p < 0.05), only 36% of all respondents reported receiving business management training during residency. CONCLUSION: Trainees completing residency report considerable educational debt. A large majority of residents feel the fellowship application process occurs too early. Despite improvements over recent years, the majority of residents continue to feel ill-prepared for specific practice management tasks. These results suggest a need to better understand the effect of educational debt on career choices, an examination of the timing of the fellowship application process, and the incorporation of additional business management training during residency. PMID- 30518555 TI - Naming things: Its importance in youth with epilepsy. PMID- 30518556 TI - Atrial cardiopathy in patients with embolic strokes of unknown source and other stroke etiologies. AB - OBJECTIVE: To investigate the prevalence and clinical determinants of atrial cardiopathy in patients with embolic stroke of unknown source (ESUS) and compare with other established stroke etiologies. METHODS: In a cross-sectional study of 846 consecutive patients with ischemic stroke, we compared the prevalence of atrial cardiopathy (defined by p-wave terminal force in V1 >5,000 uV.ms or severe left atrial enlargement) between ESUS patients and patients with large artery atherosclerosis (LAA) and small vessel disease (SVD) strokes. Baseline characteristics were also compared between ESUS and cardioembolic (CE) patients. RESULTS: Of all, 158 (19%) patients met ESUS diagnostic criteria, while others were classified into LAA (n = 224, 26%), SVD (n = 154, 18%), and CE (n = 310, 37%). The prevalence of atrial cardiopathy was higher in ESUS patients compared to noncardioembolic stroke patients (26.6% vs 12.1% in LAA vs 16.9% in SVD; p = 0.001). ESUS patients were younger, were less hypertensive, and had higher cholesterol and low-density lipoprotein levels, but also had less left ventricular or atrial abnormalities when compared to CE patients. CONCLUSION: The prevalence of atrial cardiopathy was high in ESUS patients compared with patients with nonembolic strokes. Interestingly, ESUS patients were also clinically different from CE patients. While the presence of atrial cardiopathy may reflect a unique mechanism of thromboembolism in ESUS patients, it is still unclear if they may benefit from anticoagulation, or if the presence of atrial cardiopathy in this population could serve as a risk-stratifying marker for stroke recurrence. Further efforts are necessary to provide better characterization of the ESUS population in order to develop better stroke preventive strategies. PMID- 30518557 TI - Noninvasive identification of seizure lateralization in children: Name that thing. AB - OBJECTIVE: With this prospective, observational study, we aimed to determine whether noninvasive language tasks, developed specifically for children, could reliably identify the hemisphere of seizure onset in pediatric epilepsy. METHODS: Seventy-eight children with unilateral epilepsy (44 left), aged 6-15 years (mean age = 11.8, SD = 2.6), completed the Children's Auditory Naming and Visual Naming Tests, the Boston Naming Test, and other verbal and nonverbal tasks. Multivariate analysis of variance was used to compare test performance between left and right hemisphere epilepsy groups, and chi2 analyses and odds ratios were used to examine classification of left vs right hemisphere epilepsy for individual patients based on test performance. RESULTS: Group comparisons revealed poorer auditory naming in children with left hemisphere epilepsy (p = 0.02), yet no significant differences on measures of visual naming, general intelligence, or other cognitive functions. Moreover, chi2 analyses using auditory naming cutoff scores to define intact vs impaired performance correctly classified seizure laterality in a significant proportion of children (p = 0.004). The odds of left hemisphere epilepsy were 4.2 times higher (95% confidence interval 1.4-11.7) than the odds of right hemisphere epilepsy with poor auditory naming performance. In the subset of patients with temporal lobe epilepsy (TLE), the odds of left TLE were 11.3 times higher (95% confidence interval 2.00-63.17) than the odds of right TLE with poor auditory naming performance. CONCLUSION: Contrary to previous findings, naming performance can lateralize hemisphere of seizure onset in children with epilepsy, thereby assisting in the preoperative workup for pediatric epilepsy surgery. PMID- 30518558 TI - Gender differences in cardiovascular risk assessment in elderly adults in Ecuador: evidence from a national survey. AB - The present study aimed to predict the risk of developing cardiovascular disease (CVD) over a 5-year period and how it might vary by sex in an ethnically diverse population of older adults. We used a novel CVD risk model built and validated in older adults named the Systematic Coronary Risk Evaluation in Older Persons (SCORE OP). A population-based study analyzed a total of 1307 older adults. Analyses were done by various risk categories and sex. Of the study population, 54% were female with a mean age of 75+/-7.1 years. According to the SCORE OP model, individuals were classified as having low (9.8%), moderate (48.1%), and high or very high risk (42.1%) of CVD-related mortality. Individuals at higher risk of CVD were more likely to be male compared with females, 53.9% vs 31.8%, respectively (p<0.01). Males were more likely to be younger, living in rural areas, had higher levels of schooling, and with the exception of smoking status and serum triglycerides, had lower values of traditional risk factors than females. In addition, males were less likely to require blood pressure-lowering therapy and statin drugs than females. This gender inequality could be driven by sociocultural determinants and a risk factor paradox in which lower levels of the cardiovascular risk factors are associated with an increase rather than a reduction in mortality. These data can be used to tailor primary prevention strategies such as lifestyle counseling and therapeutic measures in order to improve male elderly health, especially in low-resource settings. PMID- 30518559 TI - Dengue type 1 viruses circulating in humans are highly infectious and poorly neutralized by human antibodies. AB - The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses of humans. The interactions between DENVs and the human host that lead to asymptomatic, mild, or severe disease are poorly understood, in part, because laboratory models are poor surrogates for human DENV disease. Virologists are interested in how the properties of DENVs replicating in people compare with virions propagated on laboratory cell lines, which are widely used for research and vaccine development. Using clinical samples from a DENV type 1 epidemic in Sri Lanka and new ultrasensitive assays, we compared the properties of DENVs in human plasma and after one passage on laboratory cell lines. DENVs in plasma were 50- to 700 fold more infectious than cell culture-grown viruses. DENVs produced by laboratory cell lines were structurally immature and hypersensitive to neutralization by human antibodies compared with DENVs circulating in people. Human plasma and cell culture-derived virions had identical genome sequences, indicating that these phenotypic differences were due to the mature state of plasma virions. Several dengue vaccines are under development. Recent studies indicate that vaccine-induced antibodies that neutralized DENVs in cell culture assays were not sufficient for protecting people from DENV infections. Our results about structural differences between DENVs produced in humans versus cell lines may be key to understanding vaccine failure and developing better models for vaccine evaluation. PMID- 30518560 TI - VIPER is a genetically encoded peptide tag for fluorescence and electron microscopy. AB - Many discoveries in cell biology rely on making specific proteins visible within their native cellular environment. There are various genetically encoded tags, such as fluorescent proteins, developed for fluorescence microscopy (FM). However, there are almost no genetically encoded tags that enable cellular proteins to be observed by both FM and electron microscopy (EM). Herein, we describe a technology for labeling proteins with diverse chemical reporters, including bright organic fluorophores for FM and electron-dense nanoparticles for EM. Our technology uses versatile interacting peptide (VIP) tags, a class of genetically encoded tag. We present VIPER, which consists of a coiled-coil heterodimer formed between the genetic tag, CoilE, and a probe-labeled peptide, CoilR. Using confocal FM, we demonstrate that VIPER can be used to highlight subcellular structures or to image receptor-mediated iron uptake. Additionally, we used VIPER to image the iron uptake machinery by correlative light and EM (CLEM). VIPER compared favorably with immunolabeling for imaging proteins by CLEM, and is an enabling technology for protein targets that cannot be immunolabeled. VIPER is a versatile peptide tag that can be used to label and track proteins with diverse chemical reporters observable by both FM and EM instrumentation. PMID- 30518561 TI - Hybrid prevalence estimation: Method to improve intervention coverage estimations. AB - Delivering excellent health services requires accurate health information systems (HIS) data. Poor-quality data can lead to poor judgments and outcomes. Unlike probability surveys, which are representative of the population and carry accuracy estimates, HIS do not, but in many countries the HIS is the primary source of data used for administrative estimates. However, HIS are not structured to detect gaps in service coverage and leave communities exposed to unnecessary health risks. Here we propose a method to improve informatics by combining HIS and probability survey data to construct a hybrid estimator. This technique provides a more accurate estimator than either data source alone and facilitates informed decision-making. We use data from vitamin A and polio vaccination campaigns in children from Madagascar and Benin to demonstrate the effect. The hybrid estimator is a weighted average of two measurements and produces SEs and 95% confidence intervals (CIs) for the hybrid and HIS estimators. The estimates of coverage proportions using the combined data and the survey estimates differ by no more than 3%, while decreasing the SE by 1-6%; the administrative estimates from the HIS and combined data estimates are very different, with 3-25 times larger CI, questioning the value of administrative estimates. Estimators of unknown accuracy may lead to poorly formulated policies and wasted resources. The hybrid estimator technique can be applied to disease prevention services for which population coverages are measured. This methodology creates more accurate estimators, alongside measured HIS errors, to improve tracking the public's health. PMID- 30518562 TI - Fenestrations control resting-state block of a voltage-gated sodium channel. AB - Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from the membrane phase. Voltage-gated sodium channels initiate action potentials in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia, respectively. LAs and AADs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. The structure of the ancestral bacterial sodium channel NaVAb, which is also blocked by LAs and AADs, revealed fenestrations connecting the lipid phase of the membrane to the central cavity of the pore. We cocrystallized lidocaine and flecainide with NavAb, which revealed strong drug-dependent electron density in the central cavity of the pore. Mutation of the contact residue T206 greatly reduced drug potency, confirming this site as the receptor for LAs and AADs. Strikingly, mutations of the fenestration cap residue F203 changed fenestration size and had graded effects on resting-state block by flecainide, lidocaine, and benzocaine, the potencies of which were altered from 51- to 2.6-fold in order of their molecular size. These results show that conserved fenestrations in the pores of sodium channels are crucial pharmacologically and determine the level of resting-state block by widely used drugs. Fine-tuning drug access through fenestrations provides an unexpected avenue for structure-based design of ion-channel-blocking drugs. PMID- 30518563 TI - Calditol-linked membrane lipids are required for acid tolerance in Sulfolobus acidocaldarius. AB - Archaea have many unique physiological features of which the lipid composition of their cellular membranes is the most striking. Archaeal ether-linked isoprenoidal membranes can occur as bilayers or monolayers, possess diverse polar head groups, and a multiplicity of ring structures in the isoprenoidal cores. These lipid structures are proposed to provide protection from the extreme temperature, pH, salinity, and nutrient-starved conditions that many archaea inhabit. However, many questions remain regarding the synthesis and physiological role of some of the more complex archaeal lipids. In this study, we identify a radical S adenosylmethionine (SAM) protein in Sulfolobus acidocaldarius required for the synthesis of a unique cyclopentyl head group, known as calditol. Calditol-linked glycerol dibiphytanyl glycerol tetraethers (GDGTs) are membrane spanning lipids in which calditol is ether bonded to the glycerol backbone and whose production is restricted to a subset of thermoacidophilic archaea of the Sulfolobales order within the Crenarchaeota phylum. Several studies have focused on the enzymatic mechanism for the synthesis of the calditol moiety, but to date no protein that catalyzes this reaction has been discovered. Phylogenetic analyses of this putative calditol synthase (Cds) reveal the genetic potential for calditol-GDGT synthesis in phyla other than the Crenarchaeota, including the Korarchaeota and Marsarchaeota. In addition, we identify Cds homologs in metagenomes predominantly from acidic ecosystems. Finally, we demonstrate that deletion of calditol synthesis renders S. acidocaldarius sensitive to extremely low pH, indicating that calditol plays a critical role in protecting archaeal cells from acidic stress. PMID- 30518564 TI - Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states. AB - Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG in state or the inactive DFG-out state, but to widely differing extents. Remarkably, these conformational preferences explain broad patterns of inhibitor selectivity across different activation states of Aurora A, with DFG-out inhibitors preferentially binding Aurora A activated by phosphorylation on the activation loop, which dynamically samples the DFG-out state, and DFG-in inhibitors binding preferentially to Aurora A constrained in the DFG-in state by its allosteric activator Tpx2. The results suggest that many inhibitors currently in clinical development may be capable of differentiating between Aurora A signaling pathways implicated in normal mitotic control and in melanoma, neuroblastoma, and prostate cancer. The technology is applicable to a wide range of clinically important kinases and could provide a wealth of valuable structure activity information for the development of inhibitors that exploit differences in conformational dynamics to achieve enhanced selectivity. PMID- 30518565 TI - Habitat fragmentation, biodiversity loss and the risk of novel infectious disease emergence. AB - The number of microbes on Earth may be 1030, exceeding all other diversity. A small number of these can infect people and cause disease. The diversity of parasitic organisms likely correlates with the hosts they live in and the number mammal hosts for zoonotic infections increases with species richness among mammalian orders. Thus, while habitat loss and fragmentation may reduce species diversity, the habitat encroachment by people into species-rich areas may increase the exposure of people to novel infectious agents from wildlife. Here, we present a theoretical framework that exploits the species-area relationship to link the exposure of people to novel infections with habitat biodiversity. We model changes in human exposure to microbes through defined classes of habitat fragmentation and predict that increased habitat division intrinsically increases the hazard from microbes for all modelled biological systems. We apply our model to African tropical forests as an example. Our results suggest that it is possible to identify high-risk areas for the mitigation and surveillance of novel disease emergence and that mitigation measures may reduce this risk while conserving biodiversity. PMID- 30518566 TI - Community dynamics and sensitivity to model structure: towards a probabilistic view of process-based model predictions. AB - Statistical inference and mechanistic, process-based modelling represent two philosophically different streams of research whose primary goal is to make predictions. Here, we merge elements from both approaches to keep the theoretical power of process-based models while also considering their predictive uncertainty using Bayesian statistics. In environmental and biological sciences, the predictive uncertainty of process-based models is usually reduced to parametric uncertainty. Here, we propose a practical approach to tackle the added issue of structural sensitivity, the sensitivity of predictions to the choice between quantitatively close and biologically plausible models. In contrast to earlier studies that presented alternative predictions based on alternative models, we propose a probabilistic view of these predictions that include the uncertainty in model construction and the parametric uncertainty of each model. As a proof of concept, we apply this approach to a predator-prey system described by the classical Rosenzweig-MacArthur model, and we observe that parametric sensitivity is regularly overcome by structural sensitivity. In addition to tackling theoretical questions about model sensitivity, the proposed approach can also be extended to make probabilistic predictions based on more complex models in an operational context. Both perspectives represent important steps towards providing better model predictions in biology, and beyond. PMID- 30518567 TI - Impact of the NHS stop smoking services on smoking prevalence in England: a simulation modelling evaluation. AB - BACKGROUND: The English National Health Service (NHS) Stop Smoking Services (SSS), established in 2001, were the first such services in the world. An appropriate evaluation of the SSS has national and international significance. This modelling study sought to evaluate the impact of the SSS on changes in smoking prevalence in England. METHODS: A discrete time state-transition model was developed to simulate changes in smoking status among the adult population in England during 2001-2016. Input parameters were based on data from national statistics, population representative surveys and published literature. The main outcome was the percentage point reduction in smoking prevalence attributable to the SSS. RESULTS: Smoking prevalence was reduced by 10.8% in absolute terms during 2001-2016 in England, and 15.1% of the reduction could be attributable to the SSS. The percentage point reduction in smoking prevalence each year was on average 0.72%, and 0.11% could be attributable to the SSS. The proportion of SSS supported quit attempts increased from 5.6% in 2001, to as high as 19.3% in 2011, and then reduced to 8.4% in 2016. Quit attempts with SSS support had a higher success rate than those without SSS support (15.1%vs11.7%). Smoking prevalence in England continued to decline after the SSS was much reduced from 2013 onwards. CONCLUSIONS: Approximately 15% of the percentage point reduction in smoking prevalence during 2001-2016 in England may be attributable to the NHS SSS, although uncertainty remains regarding the actual impact of the formal smoking cessation services. PMID- 30518568 TI - Cutting Edge: Dynamic Expression of Id3 Defines the Stepwise Differentiation of Tissue-Resident Regulatory T Cells. AB - Foxp3+ regulatory T (TR) cells are phenotypically and functionally diverse and broadly distributed in lymphoid and nonlymphoid tissues. However, the pathways guiding the differentiation of tissue-resident TR cell populations have not been well defined. By regulating E-protein function, Id3 controls the differentiation of CD8+ effector T cells and is essential for TR cell maintenance and function. We show that dynamic expression of Id3 helps define three distinct mouse TR cell populations: Id3+CD62LhiCD44lo central TR cells, Id3+CD62LloCD44hi effector TR (eTR) cells, and Id3- eTR cells. Adoptive transfer experiments and transcriptome analyses support a stepwise model of differentiation from Id3+ central TR to Id3+ eTR to Id3- eTR cells. Furthermore, Id3- eTR cells have high expression of functional inhibitory markers and a transcriptional signature of tissue-resident TR cells. Accordingly, Id3- eTR cells are highly enriched in nonlymphoid organs but virtually absent from blood and lymph. Thus, we propose that tissue-resident TR cells develop in a multistep process associated with Id3 downregulation. PMID- 30518569 TI - The Noncoding RNA nc886 Regulates PKR Signaling and Cytokine Production in Human Cells. AB - Protein kinase RNA-activated (PKR) is a cytoplasmic receptor for dsRNA, and as such is involved in detection of viral infection. On binding dsRNA, PKR dimerizes, autophosphorylates, and then phosphorylates its substrate, eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha), causing inhibition of mRNA translation and shutdown of viral protein production. However, active PKR has also been found to be involved in the NF-kappaB signaling pathway by inducing phosphorylation of IkappaBalpha. PKR is regulated by the noncoding RNA nc886, which has altered expression in cancer. We have found that expression of nc886 is highly upregulated during activation of human CD4+ T cells. As has been described in other cell types, nc886 bound to PKR in human T cell lysates, preventing PKR phosphorylation by polyinosinic:polycytidylic acid or HIV trans-activation response element RNA in lysates of T cell lines or primary human CD4+ T cells. Using clonal human T cell lines, we found that nc886 expression was strictly required for IFN-gamma and IL-2 expression and secretion after T cell activation but did not affect proliferation or activation-induced cell death. In stimulated human PBMCs, nc886 expression strongly correlated with IFN-gamma expression. Although nc886 inhibited PKR activation by dsRNA, it was required for PKR phosphorylation during T cell stimulation, with subsequent NF-kappaB signaling and CREB phosphorylation. nc886 also regulated PKR phosphorylation during human monocyte-derived macrophage activation. We have therefore identified nc886 as a noncoding RNA marker of T cell activation and regulator of PKR-dependent signaling. PMID- 30518570 TI - Siglec-1 Macrophages and the Contribution of IFN to the Development of Autoimmune Congenital Heart Block. AB - Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjogren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB). Accordingly, three approaches were leveraged to address the association of IFN, IFN-stimulated genes, and the phenotype of macrophages in affected fetal cardiac tissue: 1) cultured healthy human macrophages transfected with hY3, an anti-SSA/Ro-associated ssRNA, 2) RNA isolated from freshly sorted human leukocytes/macrophages after Langendorff perfusion of three fetal hearts dying with CHB and three healthy gestational age matched hearts, and 3) autopsy tissue from three additional human CHB hearts and one healthy heart. TLR ligation of macrophages with hY3 led to the upregulation of a panel of IFN transcripts, including SIGLEC1, a result corroborated using quantitative PCR. Using independent and agnostic bioinformatics approaches, CD45+CD11c+ and CD45+CD11c- human leukocytes flow sorted from the CHB hearts highly expressed type I IFN response genes inclusive of SIGLEC1. Furthermore, Siglec-1 expression was identified in the septal region of several affected fetal hearts. These data now provide a link between IFN, IFN-stimulated genes, and the inflammatory and possibly fibrosing components of CHB, positioning Siglec-1 positive macrophages as integral to the process. PMID- 30518571 TI - Investigating the RAS can be a fishy business: interdisciplinary opportunities using Zebrafish. AB - The renin-angiotensin system (RAS) is highly conserved, and components of the RAS are present in all vertebrates to some degree. Although the RAS has been studied since the discovery of renin, its biological role continues to broaden with the identification and characterization of new peptides. The evolutionarily distant zebrafish is a remarkable model for studying the kidney due to its genetic tractability and accessibility for in vivo imaging. The zebrafish pronephros is an especially useful kidney model due to its structural simplicity yet complex functionality, including capacity for glomerular and tubular filtration. Both the pronephros and mesonephros contain renin-expressing perivascular cells, which respond to RAS inhibition, making the zebrafish an excellent model for studying the RAS. This review summarizes the physiological and genetic tools currently available for studying the zebrafish kidney with regards to functionality of the RAS, using novel imaging techniques such as SPIM microscopy coupled with targeted single cell ablation and synthesis of vasoactive RAS peptides. PMID- 30518572 TI - Age-related response to an acute innate immune challenge in mice: proteomics reveals a telomere maintenance-related cost. AB - Ageing is characterized by the impairment of the acute innate immune response and the upregulation of low-grade inflammation, i.e. inflammaging. At the cellular level, telomeres are considered as a marker of biological ageing as their length is progressively eroded in the absence of repair mechanisms. However, the link between telomeres and inflammaging remains underexplored. We aimed to identify proteins that are differentially expressed between age classes in response to an acute inflammatory challenge. We challenged young (two months) and old (12 months) C57BL/6 mice using bacterial lipopolysaccharide (LPS) and measured telomere length and proteomic profiles in splenocytes. In total, 233 out of the 1966 proteins we quantified differed among experimental groups. A hierarchical clustering analysis revealed that nine of those 233 proteins were differently expressed among the experimental groups. Young mice responded to LPS by increasing the expression of proteins involved in the innate immune response, and interestingly, in telomere length maintenance. However, this regulation was impaired at older ages. These results are in agreement with the assumption that the strength of selection declines with age, potentially explaining the maintenance of costly, dysregulated, immune responses at old age. We suggest that the immune response is competing with the telomere maintenance process, highlighting how telomeres reflect the ageing trade-off even in a species where telomere length is not related to lifespan. PMID- 30518573 TI - Mining and biodiversity: key issues and research needs in conservation science. AB - Mining poses serious and highly specific threats to biodiversity. However, mining can also be a means for financing alternative livelihood paths that, over the long-term, may prevent biodiversity loss. Complex and controversial issues associated with mining and biodiversity conservation are often simplified within a narrow frame oriented towards the negative impacts of mining at the site of extraction, rather than posed as a series of challenges for the conservation science community to embrace. Here, we synthesize core issues that, if better understood, may ensure coexistence between mining and conservation agendas. We illustrate how mining impacts biodiversity through diverse pathways and across spatial scales. We argue that traditional, site-based conservation approaches will have limited effect in preventing biodiversity loss against an increasing mining footprint, but opportunities to improve outcomes (e.g. through long-term strategic assessment and planning) do exist. While future mineral supply is uncertain, projections suggest demand will grow for many metals and shift mining operations towards more dispersed and biodiverse areas. Initiating dialogue between mining companies, policy-makers and conservation organizations is urgent, given the suite of international agendas simultaneously requiring more minerals but less biodiversity loss. PMID- 30518574 TI - Actuarial senescence in a dimorphic bird: different rates of ageing in morphs with discrete reproductive strategies. AB - It is often hypothesized that intra-sexual competition accelerates actuarial senescence, or the increase in mortality rates with age. However, an alternative hypothesis is that parental investment is more important to determining senescence rates. We used a unique model system, the white-throated sparrow (Zonotrichia albicollis), to study variation in actuarial senescence. In this species, genetically determined morphs display discrete mating strategies and disassortative pairing, providing an excellent opportunity to test the predictions of the above hypotheses. Compared to tan-striped males, white-striped males are more polygynous and aggressive, and less parental. Tan-striped females receive less parental support, and invest more into parental care than white striped females, which are also more aggressive. Thus, higher senescence rates in males and white-striped birds would support the intra-sexual competition hypothesis, whereas higher senescence rates in females and tan-striped birds would support the parental investment hypothesis. White-striped males showed the lowest rate of actuarial senescence. Tan-striped females had the highest senescence rate, and tan-striped males and white-striped females showed intermediate, relatively equal rates. Thus, results were inconsistent with sexual selection and competitive strategies increasing senescence rates, and instead indicate that senescence may be accelerated by female-biased parental care, and lessened by sharing of parental duties. PMID- 30518576 TI - Doctors' concerns over universal credit are mounting. PMID- 30518575 TI - Molecular palaeontology illuminates the evolution of ecdysozoan vision. AB - Colour vision is known to have arisen only twice-once in Vertebrata and once within the Ecdysozoa, in Arthropoda. However, the evolutionary history of ecdysozoan vision is unclear. At the molecular level, visual pigments, composed of a chromophore and a protein belonging to the opsin family, have different spectral sensitivities and these mediate colour vision. At the morphological level, ecdysozoan vision is conveyed by eyes of variable levels of complexity; from the simple ocelli observed in the velvet worms (phylum Onychophora) to the marvellously complex eyes of insects, spiders, and crustaceans. Here, we explore the evolution of ecdysozoan vision at both the molecular and morphological level; combining analysis of a large-scale opsin dataset that includes previously unknown ecdysozoan opsins with morphological analyses of key Cambrian fossils with preserved eye structures. We found that while several non-arthropod ecdysozoan lineages have multiple opsins, arthropod multi-opsin vision evolved through a series of gene duplications that were fixed in a period of 35-71 million years (Ma) along the stem arthropod lineage. Our integrative study of the fossil and molecular record of vision indicates that fossils with more complex eyes were likely to have possessed a larger complement of opsin genes. PMID- 30518577 TI - Resource use, characteristics and outcomes of prolonged non-invasive ventilation: a single-centre observational study in China. AB - OBJECTIVE: To report the resource use, characteristics and outcomes of patients with prolonged non-invasive ventilation (NIV). DESIGN: A single-centre observational study. SETTING: An intensive care unit of a teaching hospital. PARTICIPANTS: Patients who only received NIV because of acute respiratory failure were enrolled. Prolonged NIV was defined as subjects who received NIV >=14 days. A total of 1539 subjects were enrolled in this study; 69 (4.5%) underwent prolonged NIV. MAIN OUTCOME MEASURES: Predictors of prolonged NIV and hospital mortality. RESULTS: The rate of do-not-intubate (DNI) orders was 9.1% (140/1539). At the beginning of NIV, a DNI order (OR 3.95, 95% CI 2.25 to 6.95) and pH >=7.35 (2.20, 1.27 to 3.82) were independently associated with prolonged NIV. At days 1 and 7 of NIV, heart rate (1.01 (1.00 to 1.03) and 1.02 (1.00 to 1.03], respectively) and PaO2/FiO2<150 (2.19 (1.25 to 3.85) and 2.05 (1.04 to 4.04], respectively) were other independent risk factors for prolonged NIV. When patients who died after starting NIV but prior to 14 days were excluded, the association was strengthened. Regarding resource use, 77.1% of subjects received NIV<7 days and only accounted for 47.0% of NIV-days. However, 18.4% of subjects received NIV 7-13.9 days and accounted for 33.4% of NIV-days, 2.9% of subjects received NIV 14-20.9 days and accounted for 9.5% of NIV-days, and 1.6% of subjects received NIV>=21 days and accounted for 10.1% of NIV-days. CONCLUSIONS: Our results indicate the resource use, characteristics and outcomes of a prolonged NIV population with a relatively high proportion of DNI orders. Subjects with prolonged NIV make up a high proportion of NIV-days and are at high risk for in-hospital mortality. PMID- 30518578 TI - Can process mining automatically describe care pathways of patients with long term conditions in UK primary care? A study protocol. AB - INTRODUCTION: In the UK, primary care is seen as the optimal context for delivering care to an ageing population with a growing number of long-term conditions. However, if it is to meet these demands effectively and efficiently, a more precise understanding of existing care processes is required to ensure their configuration is based on robust evidence. This need to understand and optimise organisational performance is not unique to healthcare, and in industries such as telecommunications or finance, a methodology known as 'process mining' has become an established and successful method to identify how an organisation can best deploy resources to meet the needs of its clients and customers. Here and for the first time in the UK, we will apply it to primary care settings to gain a greater understanding of how patients with two of the most common chronic conditions are managed. METHODS AND ANALYSIS: The study will be conducted in three phases; first, we will apply process mining algorithms to the data held on the clinical management system of four practices of varying characteristics in the West Midlands to determine how each interacts with patients with hypertension or type 2 diabetes. Second, we will use traditional process mapping exercises at each practice to manually produce maps of care processes for the selected condition. Third, with the aid of staff and patients at each practice, we will compare and contrast the process models produced by process mining with the process maps produced via manual techniques, review differences and similarities between them and the relative importance of each. The first pilot study will be on hypertension and the second for patients diagnosed with type 2 diabetes. ETHICS AND DISSEMINATION: Ethical approval has been provided by East Midlands-Leicester South Regional Ethics Committee (REC reference 18/EM/0284). Having refined the automated production of maps of care processes, we can explore pinch points and bottlenecks, process variants and unexpected behaviour, and make informed recommendations to improve the quality and efficiency of care. The results of this study will be submitted for publication in peer-reviewed journals. PMID- 30518579 TI - Geriatrician-led evidence-based Falls Prevention Clinic: a prospective 12-month feasibility and acceptability cohort study among older adults. AB - OBJECTIVE: We assessed the feasibility and acceptability of delivering a geriatrician-led evidence-based Falls Prevention Clinic to older adults with a history of falls. DESIGN: 12-month prospective cohort study. SETTING: Vancouver Falls Prevention Clinic, Vancouver, British Columbia, Canada (www.fallsclinic.ca). PARTICIPANTS: 188 community-dwelling older adults aged >=70 years who received a baseline assessment at the Vancouver Falls Prevention Clinic due to having had at least one fall resulting in medical attention in the previous 12 months. Fifty-six per cent of participants were also participating in a randomised controlled trial. MEASUREMENTS: Feasibility was ascertained by measuring demand (clinic attendance). Acceptability was measured by compliance with recommendations, completion of monthly fall calendars and patient experience. RESULTS: The attendance was 65% of those eligible and invited. This indicates feasibility for demand. 155 received at least one of the following clinical management recommendations from four domains (compliance reported in %): (1) medication changes (78%); (2) exercise prescription (58%); (3) referrals to other healthcare professionals (78%); and/or (4) lifestyle modifications (35%) excluding exercise. Overall compliance to all recommendations was 69%. Patient experience was related to factors impacting patient perceived physical benefit and attributes influencing patient satisfaction. CONCLUSION: This study demonstrated the feasibility and acceptability of a multifactorial intervention approach based on best available evidence-based medicine. PMID- 30518580 TI - Effect of regional versus general anaesthesia on postoperative delirium in elderly patients undergoing surgery for hip fracture: a systematic review. AB - OBJECTIVE: Older patients with hip fractures who are undergoing surgery are at high risk of significant mortality and morbidity including postoperative delirium. It is unclear whether different types of anaesthesia may reduce the incidence of postoperative delirium. This systematic review will investigate the impact of anaesthetic technique on postoperative delirium. Other outcomes included mortality, length of stay, complications and functional outcomes. DESIGN: Systematic review of randomised controlled trials and non-randomised controlled studies. DATA SOURCES: Bibliographic databases were searched from inception to June 2018. Web of Science and ZETOC databases were searched for conference proceedings. Reference lists of relevant articles were checked, and clinical trial registers were searched to identify ongoing trials. ELIGIBILITY CRITERIA: Studies were eligible if general and regional anaesthesia were compared in patients (aged 60 and over) undergoing hip fracture surgery, reporting primary outcome of postoperative delirium and secondary outcomes of mortality, length of hospital stay, adverse events, functional outcomes, discharge location and quality of life. Exclusion criteria were anaesthetic technique or drug not considered current standard practice; patients undergoing hip fracture surgery alongside other surgery and uncontrolled studies. RESULTS: One hundred and four studies were included. There was no evidence to suggest that anaesthesia type influences postoperative delirium or mortality. Some studies suggested a small reduction in length of hospital stay with regional anaesthesia. There was some evidence to suggest that respiratory complications and intraoperative hypotension were more common with general anaesthesia. Heterogeneity precluded meta-analysis. All findings were described narratively and data were presented where possible in forest plots for illustrative purposes. CONCLUSIONS: While there was no evidence to suggest that anaesthesia types influence postoperative delirium, the evidence base is lacking. There is a need to ascertain the impact of type of anaesthesia on outcomes with an adequately powered, methodologically rigorous study. PROSPERO REGISTRATION NUMBER: CRD42015020166. PMID- 30518581 TI - Observational study of the status of coronary risk biomarkers among Negritos with metabolic syndrome in the east coast of Malaysia. AB - OBJECTIVES: To determine the prevalence of metabolic syndrome (MS), ascertain the status of coronary risk biomarkers and establish the independent predictors of these biomarkers among the Negritos. SETTINGS: Health screening programme conducted in three inland settlements in the east coast of Malaysia and Peninsular Malaysia. SUBJECTS: 150 Negritos who were still living in three inland settlements in the east coast of Malaysia and 1227 Malays in Peninsular Malaysia. These subjects were then categorised into MS and non-MS groups based on the International Diabetes Federation (IDF) consensus worldwide definition of MS and were recruited between 2010 and 2015. The subjects were randomly selected and on a voluntary basis. PRIMARY AND SECONDARY OUTCOME MEASURES: This study was a cross sectional study. Serum samples were collected for analysis of inflammatory (hsCRP), endothelial activation (sICAM-1) and prothrombogenesis [lp(a)] biomarkers. RESULTS: MS was significantly higher among the Malays compared with Negritos (27.7%vs12.0%). Among the Malays, MS subjects had higher hsCRP (p=0.01) and sICAM-1 (p<0.05) than their non-MS counterpart. There were no significant differences in all the biomarkers between MS and the non-MS Negritos. However, when compared between ethnicity, all biomarkers were higher in Negritos compared with Malays (p<0.001). Binary logistic regression analysis affirmed that Negritos were an independent predictor for Lp(a) concentration (p<0.001). CONCLUSIONS: This study suggests that there may possibly be a genetic influence other than lifestyle, which could explain the lack of difference in biomarkers concentration between MS and non-MS Negritos and for Negritos predicting Lp(a). PMID- 30518582 TI - Pregnancy-associated cancers and birth outcomes in children: a Danish and Swedish population-based register study. AB - OBJECTIVES: This study aims to estimate the association between pregnancy associated maternal cancers, diagnosed both prenatally and postnatally, and birth outcomes. DESIGN: Population-based register study. SETTING: National registers of Denmark and Sweden. PARTICIPANTS: A total of 5 523 365 children born in Denmark (1977-2008) and Sweden (1973-2006).Primary and secondary outcome measures: gestational age, birth weight, size for gestational age, Apgar score, caesarean section and sex were the outcomes of interest. ORs and relative risk ratios (RRR) with 95% CIs were estimated using logistic regression and multinomial logistic regression, respectively. RESULTS: In this study, 2% of children were born to mothers with a diagnosis of cancer. Children whose mothers received a prenatal cancer diagnosis had higher risk of being born preterm (RRR: 1.77, 95% CI 1.64 to 1.90); low birth weight (RRR 1.84, 95% CI 1.69 to 2.01); low Apgar score (OR 1.36, 95% CI 1.20 to 1.56); and by caesarean section (OR: 1.69, 95% CI 1.59 to 1.80). Associations moved towards the null for analyses using postnatal diagnoses, but preterm birth (RRR: 1.13, 95% CI 1.09 to 1.17) and low birth weight (RRR: 1.14, 95% CI 1.09 to 1.18) remained statistically significant, while risk of caesarean section became so (OR: 0.95, 95% CI 0.91 to 0.98). Additionally, statistical significance was reached for large for gestational age (RRR: 1.06, 95% CI 1.01 to 1.11), high birth weight (RRR: 1.04, 95% CI 1.01 to 1.06) and caesarean section (OR: 0.95, 95% CI 0.91 to 0.98). CONCLUSIONS: Results suggest an association between pregnancy-associated cancers and adverse birth outcomes in the offspring. While this is strongest for prenatally diagnosed cancers, some smaller associations exist for postnatally diagnosed cancers, indicating that cancer itself could affect fetal development, or that cancer and adverse birth outcomes share risk factors. Future studies on maternal cancer during pregnancy should consider including some postnatal years in their exposure window. PMID- 30518583 TI - Cumulative network-meta-analyses, practice guidelines and actual prescriptions of drug treatments for postmenopausal osteoporosis: a study protocol for cumulative network meta-analyses and meta-epidemiological study. AB - INTRODUCTION: Cumulative network meta-analysis (NMA) is a method to provide a global comparison of multiple treatments with real-time update to evidence users. Several studies investigated the ranking of cumulative NMA and the recommendations of practice guidelines. However, to the best of our knowledge, no study has evaluated the cumulative NMA ranking and prescription patterns. Here, we present a protocol for a meta-epidemiological investigation to compare the results of cumulative NMA with the recommendations in postmenopausal osteoporosis practice guidelines and with the actual prescriptions. METHOD AND ANALYSIS: We will use the data of primary trials from the upcoming postmenopausal osteoporosis clinical practice guideline of the Endocrine Society. We will conduct cumulative NMA using all eligible trials and generate hierarchy of treatment rankings by using the surface under the cumulative ranking curve. We will search practice guidelines in relevant society websites. Two review authors will extract the practice recommendations. We will use data from the Medical Expenditures Panel Survey, a US representative sample of the non-institutionalised population, to determine the prescription patterns. ETHICS AND DISSEMINATION: Because all data will be retrieved from public databases, institutional review board approval is not required. We will publish our findings in a peer-reviewed journal and present key findings at conferences. TRIAL REGISTRATION NUMBER: UMIN000031894: Pre results. PMID- 30518584 TI - Establishment of trauma treatment teams within a regional severe trauma treatment system in China: study protocol for a national cluster-randomised trial. AB - INTRODUCTION: The implementation of first aid processes for patients with trauma in China faces significant challenges. These challenges include long response times of prehospital first aid services, lack of information exchange between prehospital first aid services and in-hospital emergency services, lack of a professional rescue team in the majority of hospitals, and lack of standardised training for prehospital and in-hospital emergency personnel. The purpose of the trial is to guide the establishment of an urban trauma treatment system in China, highlight the construction of a trauma treatment system tailored to the Chinese context and improve levels of medical treatment by selecting approximately 100 counties across China as pilots to establish a regional trauma treatment system. METHODS AND ANALYSIS: A cluster-randomised controlled trial will be performed in 98 county-level research institutes. Included research institutes will be randomised into an experimental group and a control group. Patients in both experimental and control groups will receive basic treatments. A trauma treatment team will be established in the experimental group. The primary outcome measure is in-hospital mortality rate of patients. The secondary outcome measures include mortality rate of patients within 30 days after trauma attack and within 30 days after discharge, the time between arrival in the institution and receiving consultation, and the time from admission to the start of surgery. The effects of establishment of trauma treatment teams on the treatment of severe trauma will be evaluated in all counties. ETHICS AND DISSEMINATION: The procedures have been approved by The Medical Ethics Committee of Peking University People's Hospital (No.2017PHB098-01) and conform to the Declaration of Helsinki. Data will be collected and analysed in accordance with participant privacy laws and regulations. Results will be disseminated through policy briefs, workshops, peer reviewed publications and conferences. TRIAL REGISTRATION NUMBER: NCT03363880; Pre-results. PMID- 30518585 TI - How common are neurocognitive disorders in patients with chronic kidney disease and diabetes? Results from a cross-sectional study in a community cohort of patients in North Wales, UK. AB - OBJECTIVE: Chronic kidney disease (CKD) affects nearly 9% of global populations and is strongly associated with older age. Neurocognitive disorders (NCDs), which include mild cognitive impairment and dementia, are rising as a result of ageing populations throughout the world. This investigation's aim is to report the frequency of mild to major NCD in a clinical cohort of adults with mild to moderate CKD and diabetes. SETTING: Glan Clwyd District general Hospital, North Wales, UK. PARTICIPANTS: We enrolled 178 patients with CKD and diabetes, aged 55 years and over with an estimated glomerular filtration rate <60 >15 mL/min/1.73 m2, attending a specialist renal and diabetic outpatient clinic. OUTCOME MEASURES: Frequency of mild and major NCD and the association with the stage of CKD was assessed in all patients attending the specialist clinic. The diagnosis of NCD was based on patient and informant interview, case note review, neuropsychological assessment and application of Diagnostic and Statistical Manual of Mental Disorders version 5. RESULTS: This investigation found 86/178 (48%) of the cohort with an NCD ranging from mild (n=49) to major symptoms (n=37). No association was found with NCD and the stage of CKD. Mild and major NCD was associated poorer outcomes in several cognitive domains, including, language, executive, memory, fluency and attention function (p<0.05). CONCLUSIONS: This is the first UK investigation to report that cognitive changes occur in a significant number of older adults with CKD and diabetes. The unexpected finding was that prior to cognitive assessment, not any of the cohort had a pre-existing diagnosis of cognitive impairment, suggesting that the current prevalence and incidence rates of NCD in the general population are possibly significantly underestimated. Our findings also suggest that the cognitive function of patients with CKD should be screened and monitored routinely as part of their overall care management. PMID- 30518586 TI - Nonverbal synchrony as a behavioural marker of patient and physician race-related attitudes and a predictor of outcomes in oncology interactions: protocol for a secondary analysis of video-recorded cancer treatment discussions. AB - INTRODUCTION: Racial disparities in cancer treatment contribute to racial disparities in mortality rates. The quality of patient-physician communication during clinical interactions with black patients and non-black physicians (racially discordant) is poorer than communication quality with white patients (racially concordant). Patient and physician race-related attitudes affect the quality of this communication. These attitudes are likely expressed through subtle non-verbal behaviours, but prior research has not examined these behaviours. Nonverbal synchrony, the coordination of physical movement, reflects the preinteraction attitudes of participants in interactions and predicts their postinteraction perceptions of and affect towards one another. In this study, peer reviewed and funded by the National Institute of Minority Health and Health Disparities (R21MD011766), we will investigate non-verbal synchrony in racially concordant and discordant interactions to better understand racial disparities in clinical communication. METHODS AND ANALYSIS: This secondary analysis includes racially concordant (n=163) and racially discordant (n=68) video-recorded oncology interactions, patient and oncologist self-reported race-related attitudes, perceptions of the interaction and observer ratings of physician patient-centred communication and patient and physician affect and rapport. In aim 1, we will assess and compare non-verbal synchrony between physicians and patients in racially concordant and discordant interactions. In aim 2, we will determine the influence of non-verbal synchrony on patient and physician affect and communication. In aim 3, we will examine possible causes (ie, race-related attitudes) and consequences (ie, negative perceptions) of non-verbal synchrony in racially discordant interactions. In aim 4, we will develop and test a mediational model linking physician and patient race-related attitudes to non verbal synchrony and, in turn, interaction outcomes. ETHICS AND DISSEMINATION: The parent and current studies were approved by the Wayne State University Institutional Review Board. Since only archival data will be used, ethical or safety risks are low. We will disseminate our findings to relevant conferences and journals. PMID- 30518587 TI - Non-standard treatment for uncomplicated Chlamydia trachomatis urogenital infections: a systematic review. AB - OBJECTIVES: To review the literature for non-standard treatment options for uncomplicated Chlamydia trachomatis (CT) infections in adolescents and adults. DESIGN: Systematic review. DATA SOURCES: Ovid MEDLINE/PubMed, Ovid EMBASE, Cochrane Trials & Systematic Review Databases, CINAHL Plus with Full Text, Web of Science Core Collection, Scopus, ProQuest Dissertations & Theses Global, ClinicalTrials.gov and Health Canada Trials Database were searched for studies in English or French from 1 January 2006 to 6 August 2017. Keywords included CT, anti-infective or anti-bacterial agents, therapy/pharmacotherapy/management. REVIEW METHODS: Included were primary research studies. Outcome measures included clinical or microbiological cure, treatment failure and adverse events. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were assessed for risk of bias using the Revised Cochrane Risk of Bias V.2.0 tool for randomised and the Newcastle-Ottawa Quality Assessment Scale for non-randomised studies. FUNDING SOURCE: Public Health Agency of Canada. RESULTS: Of the 6899 records identified through the database search, 11 studies were included. One randomised controlled trial reported that delayed release doxycycline was non-inferior to azithromycin. Two studies examined higher doses of azithromycin but reported no additional benefit. One study looked at a 5 day azithromycin treatment regimen and reported a high cure rate. Two studies reported efficacy of sitafloxacin, and a single study supports the use of levofloxacin. Two phase 2 studies reported efficacy of single-dose rifalazil in both men and women. Only one retrospective study was identified that examined treatment in pregnant women and reported that efficacy with single-dose azithromycin exceeded that of amoxicillin and erythromycin. A single study examining the efficacy of a beta-lactam antibiotic was stopped early due to high treatment failures. CONCLUSIONS: The paucity of existing data highlights the need for further adequately powered studies to evaluate rifalazil, delayed release doxycycline, levofloxacin and other agents for the treatment of uncomplicated CT infections. PROSPERO REGISTRATION NUMBER: CRD42017073096. PMID- 30518588 TI - Understanding and evaluating new models of Child and Adolescent Mental Health Services in South-East England: a study protocol for an observational mixed methods study. AB - INTRODUCTION: Increased demand for Child and Adolescent Mental Health Services (CAMHS), alongside concerns that services should be better commissioned to meet the needs of the most vulnerable, has contributed to a requirement to transform services to improve accessibility, quality of care and health outcomes. Following the submission of government-mandated transformation plans for CAMHS, services in England are changing in how, where and by whom they are delivered. This protocol describes the research methods to be applied to understand CAMHS transformations and evaluate the impact on the use of mental health services, patient care, satisfaction, health outcomes and health resource utilisation costs. METHODS AND ANALYSIS: A mixed-methods approach will be taken in an observational retrospective study of CAMHS provided by a large National Health Service (NHS) mental health trust in South-East England (Oxford Health NHS Foundation Trust). Quantitative research will include descriptive analysis of routinely collected data, with difference-in-differences analysis supplemented with propensity score matching performed to assess the impact of CAMHS transformations from 2015 onwards. An economic evaluation will be conducted from a healthcare perspective to provide commissioners with indications of value for money. Qualitative research will include observations of services and interviews with key stakeholders including CAMHS staff, service users and guardians, to help identify mechanisms leading to changes in service delivery, as well as barriers and enabling factors in this phase of transformation. ETHICS AND DISSEMINATION: This project has been registered with NHS Oxford Health Foundation Trust as a service evaluation. Informed consent will be sought from all stakeholders partaking in interviews according to good clinical practice. A local data sharing protocol will govern the transfer of quantitative data. Study findings will be published in professional journals for NHS managers and peer-reviewed scientific journals. They will be discussed in seminars targeting CAMHS providers, managers and commissioners and presented at scientific conferences. PMID- 30518589 TI - Household structure and its association with sexual risk behaviours and sexual health outcomes: evidence from a British probability sample survey. AB - OBJECTIVES: Economic and social changes over the last 20 years have led to changes in the living situations of young people in Britain. A person's home-life context might influence their sexual behaviour, with implications for their sexual healthcare needs; we investigated this hypothesis. METHODS: Britain's third National Survey of Sexual Attitudes and Lifestyles, a probability sample survey undertaken in 2010-2012, interviewed 15 162 men and women aged 16-74 years in Britain (with 3869 aged 16-24 years). We examined household structure by gender and age group. We then focused on sexually experienced young people (aged 16-24 years), and used multivariable models to explore associations between household structure, sexual risk behaviours and sexual health outcomes, independent of confounders including age, relationship status, employment and area of residence. RESULTS: Young people were most likely to be living with parents (women 57.1% (95% CI 54.5% to 59.6%) and men 68.7% (95% CI 65.4% to 71.8%)) or non-relatives (women 10.5% (95% CI 8.5% to 12.9%) and men 12.6% (95% CI 10.1% to 15.6%)). Among the 81.3% of young people who were sexually experienced, compared with young women living with parents (reference category), young women living alone or with non-relatives had a higher likelihood of reporting >=2 sexual partners (adjusted OR 1.54 (95% CI 1.03 to 2.31); 1.76 (95% CI 1.03 to 3.00), respectively). Women living alone were also more likely to have had unsafe sex (2.04 (95% CI 1.38 to 3.02)). Despite these differences in sexually transmitted infection (STI) risk, there was no difference in sexual healthcare-seeking behaviour. Young men and women living with partners reported lower levels of sexual risk behaviours. CONCLUSIONS: Our study suggests household structure may influence the sexual behaviour of young people in Britain. Given changes in their living arrangements, the role of household structure in sexual health research should be further investigated, and also considered as a possible marker for STI risk in clinical consultations. PMID- 30518590 TI - Cohort profile: the Buffalo OsteoPerio microbiome prospective cohort study. AB - PURPOSE: The Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) study is a prospective cohort study focused on the relationship between the microbiome and oral and systemic health outcomes in postmenopausal women. The cohort was established to examine how the oral microbiome is affected by (and how it affects) periodontal disease presence, severity and progression and to characterise the relationship between the microbiome, lifestyle habits and systemic disease outcomes. PARTICIPANTS: Participants (n=1342) were postmenopausal women who were participating in the Women's Health Initiative observational study at the Buffalo, New York clinical centre. There were 1026 participants at the 5-year follow-up visit and 518 at the 15-year visit. FINDINGS TO DATE: Data collected include questionnaires, anthropometric measures, serum blood and saliva samples. At each clinic visit, participants completed a comprehensive oral examination to measure oral health and the oral microbiome. Preliminary findings have contributed to our understanding of risk factors for periodontal disease and the relationship between the oral microbiome and periodontal disease. FUTURE PLANS: The novel microbiome data collected on a large sample of participants at three time points will be used to answer a variety of research questions focused on temporal changes in the microbiome and the relationship between the oral microbiome and oral and systemic disease outcomes. Little is currently known about the relationship between the oral microbiome and health outcomes in older adults; data from the OsteoPerio cohort will fill this gap. Microbiome samples are currently being analysed using next-generation sequencing technology with an anticipated completion date of late 2018. PMID- 30518591 TI - Prognostic accuracy of different disseminated intravascular coagulation criteria in critically ill adult patients: a protocol for a systematic review and meta analysis. AB - INTRODUCTION: Disseminated intravascular coagulation (DIC) is a common and serious condition that can lead to poor outcomes in critically ill patients. To make a correct diagnosis and improve the outcome of patients with DIC, several organisations have put forward DIC scoring systems. However, which criteria is the best to use for diagnosing DIC remains a continuing controversy even though many studies have been conducted to validate the diagnostic accuracy of each DIC scoring system. METHODS AND ANALYSIS: We will conduct a systematic review and meta-analysis of the diagnostic accuracy of DIC criteria for the prediction of mortality in critically ill adult patients. The primary objective is to assess the predictive values of the DIC criteria of Japanese Association for Acute Medicine, International Society on Thrombosis and Haemostasis, Japanese Ministry of Health and Welfare, Korean Society on Thrombosis and Hemostasis and Chinese Diagnostic Scoring System for 28-day mortality. We will search electronic bibliographic databases such as MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials. Two reviewers will independently screen titles and abstracts, perform full article reviews and extract study data. We will report study characteristics and assess methodological quality using the Quality of Diagnostic Accuracy Studies-II tool. If pooling is appropriate, we will compute parameter estimates using bivariate random-effects and hierarchical summary receiver operating characteristic models to produce summary receiver operating curves, summary operating points (pooled sensitivity and specificity) and 95% confidence regions around the summary operating points. Clinical and methodological subgroup and sensitivity analyses will be performed to explore heterogeneity. ETHICS AND DISSEMINATION: This systematic review will help physicians diagnose DIC accurately and improve their clinical practice in critically ill settings. Approval from an ethics committee is not required. The findings will be disseminated through publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42017079350. PMID- 30518593 TI - Combating escalating harms associated with pharmaceutical opioid use in Australia: the POPPY II study protocol. AB - INTRODUCTION: Opioid prescribing has increased 15-fold in Australia in the past two decades, alongside increases in a range of opioid-related harms such as opioid dependence and overdose. However, despite concerns about increasing opioid use, extramedical use and harms, there is a lack of population-level evidence about the drivers of long-term prescribed opioid use, dependence, overdose and other harms. METHODS AND ANALYSIS: We will form a cohort of all adult residents in New South Wales (NSW), Australia, who initiated prescribed opioids from 2002 using Pharmaceutical Benefits Scheme dispensing records. This cohort will be linked to a wide range of other datasets containing information on sociodemographic and clinical characteristics, health service use and adverse outcomes (eg, opioid dependence and non-fatal and fatal overdose). Analyses will initially examine patterns and predictors of prescribed opioid use and then apply regression and survival analysis to quantify the risks and risk factors of adverse outcomes associated with prescribed opioid use. ETHICS AND DISSEMINATION: This study has received full ethical approval from the Australian Institute of Health and Welfare Ethics Committee, the NSW Population and Health Services Research Committee and the ACT Health Human Research Ethics Committee. This will be the largest postmarketing surveillance study of prescribed opioids undertaken in Australia, linking exposure and outcomes and examining risk factors for adverse outcomes of prescribed opioids. As such, this work has important translational promise, with direct relevance to regulatory authorities and agencies worldwide. Project findings will be disseminated at scientific conferences and in peer-reviewed journals. We will also conduct targeted dissemination with policy makers, professional bodies and peak bodies in the pain, medicine and addiction fields through stakeholder workshops and advisory groups. Results will be reported in accordance with the REporting of studies Conducted using Observational Routinely collected Data (RECORD) Statement. PMID- 30518592 TI - Identifying patient-important outcomes in medication-assisted treatment for opioid use disorder patients: a systematic review protocol. AB - INTRODUCTION: Illicit opioid use has become a national crisis in Canada, with over 65 000 people seeking treatment for opioid use disorder (OUD) in Ontario and British Columbia alone. Medication-assisted treatment (MAT) is a common treatment for OUD. There is substantial variability in treatment outcomes used to evaluate effectiveness of MAT, making it difficult to establish clinically and scientifically relevant treatment effect. Furthermore, patients are often excluded from the process of determining these outcomes. The primary objective of this review is to examine outcomes currently used to measure MAT effectiveness and to identify patient-relevant outcomes to enhance effectiveness of treatment options. This review refers to patient-important outcomes as those outcomes patients consider important to or markers of treatment success. METHODS AND ANALYSIS: MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, National Institutes for Health Clinical Trials Registry and WHO International Clinical Trials Registry Platform databases will be searched. We will search databases from inception to the date the search is ran. Studies of interest include those evaluating the effectiveness of MAT for patients with OUD, with or without consultation with patients regarding what they consider to be important as an indicator of treatment success. Results will be analysed using thematic analysis and qualitative analysis where possible. This will result in comprehensive synthesis of all outcomes and measures found related to OUD treatment effectiveness. ETHICS AND DISSEMINATION: We are collaborating with Canadian Addiction Treatment Centres which provide MAT to patients with OUD who will participate in disseminating study results. Dissemination strategies will involve sharing study results through workshops, presentations, peer-reviewed publications, study reports, community presentations and resources in primary care settings. PROSPERO REGISTRATION NUMBER: CRD42018095553. PMID- 30518595 TI - Correction: Treatment effects of systematic two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: rationale and design of a prospective, randomised and multicentre DEFINITION II trial. PMID- 30518594 TI - Diagnostic accuracy of the Geriatric Depression Scale-30, Geriatric Depression Scale-15, Geriatric Depression Scale-5 and Geriatric Depression Scale-4 for detecting major depression: protocol for a systematic review and individual participant data meta-analysis. AB - INTRODUCTION: The 30-item Geriatric Depression Scale (GDS-30) and the shorter GDS 15, GDS-5 and GDS-4 are recommended as depression screening tools for elderly individuals. Existing meta-analyses on the diagnostic accuracy of the GDS have not been able to conduct subgroup analyses, have included patients already identified as depressed who would not be screened in practice and have not accounted for possible bias due to selective reporting of results from only better-performing cut-offs in primary studies. Individual participant data meta analysis (IPDMA), which involves a standard systematic review, then a synthesis of individual participant data, rather than summary results, could address these limitations. The objective of our IPDMA is to generate accuracy estimates to detect major depression for all possible cut-offs of each version of the GDS among studies using different reference standards, separately and among participant subgroups based on age, sex, dementia diagnosis and care settings. In addition, we will use a modelling approach to generate individual participant probabilities for major depression based on GDS scores (rather than a dichotomous cut-off) and participant characteristics (eg, sex, age, dementia status, care setting). METHODS AND ANALYSIS: Individual participant data comparing GDS scores to a major depression diagnosis based on a validated structured or semistructured diagnostic interview will be sought via a systematic review. Data sources will include Medline, Medline In-Process & Other Non-Indexed Citations, PsycINFO and Web of Science. Bivariate random-effects models will be used to estimate diagnostic accuracy parameters for each cut-off of the different versions of the GDS. Prespecified subgroup analyses will be conducted. Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. ETHICS AND DISSEMINATION: The findings of this study will be of interest to stakeholders involved in research, clinical practice and policy. PROSPERO REGISTRATION NUMBER: CRD42018104329. PMID- 30518596 TI - Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-beta Induced Synaptic Dysfunction and Loss. AB - Dozens of genes have been implicated in Late Onset Alzheimer's Disease (AD) risk, but none have a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation nor the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of long term synaptic depression is suppressed in Pyk2 null slices. In contrast, deletion of Pyk2 expression does not alter long term potentiation under control conditions. Of relevance for AD pathophysiology, Pyk2-/- slices are protected from Amyloid-beta-oligomer (Abetao)-induced suppression of long term potentiation in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents Abetao-induced suppression of long term potentiation in wild type slices. Female and male transgenic AD model mice expressing APPswe/PSEN1DeltaE9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter Abeta accumulation or gliosis. Thus, the Pyk2 risk gene is directly implicated in a neuronal Abetao signaling pathway impairing synaptic anatomy and function.SIGNFICANCE STATEMENTGenetic variation at the Pyk2 (PTK2B) locus is a risk for Late Onset Alzheimer's Disease (AD) but the pathophysiological role of Pyk2 is not clear. Here, we studied Pyk2 neuronal function in mice lacking expression, with and without transgenes generating Abeta plaque pathology. Pyk2 is not required for basal synaptic transmission or long term potentiation but participates in long term depression. Hippocampal slices lacking Pyk2 are protected from AD-related Abeta oligomer suppression of synaptic plasticity. In transgenic AD model mice, deletion of Pyk2 rescues synaptic loss and learning/memory deficits. Thus, Pyk2 plays a central role in AD-related synaptic dysfunction mediating Abeta-triggered dysfunction. PMID- 30518597 TI - Intensive care: multidisciplinary group to tackle end of life care. PMID- 30518598 TI - Overdiagnosis and industry influence: how cow's milk protein allergy is extending the reach of infant formula manufacturers. PMID- 30518599 TI - A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets. AB - Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORgammatneg) and MAIT17 (RORgammat+) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1 and NKT17 subsets. The expression of similar programs was further supported by strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT subsets expressed gene signatures associated with tissue residency. Accordingly, parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver. The transcriptional program associated with tissue residency was already expressed in thymus, as confirmed by adoptive transfer experiments. Altogether, shared thymic differentiation processes generate "preset" NKT and MAIT subsets with defined effector functions, associated with specific positioning into tissues. PMID- 30518601 TI - A Year in Review. PMID- 30518600 TI - Distinct metabolic adjustments arise from acclimation to constant hypoxia and intermittent hypoxia in estuarine killifish (Fundulus heteroclitus). AB - Many fish experience daily cycles of hypoxia in the wild, but the physiological strategies for coping with intermittent hypoxia are poorly understood. We examined how killifish adjust O2 supply and demand during acute hypoxia, and how these responses are altered after prolonged acclimation to constant or intermittent patterns of hypoxia exposure. We acclimated killifish to normoxia (~20 kPa O2), constant hypoxia (2 kPa) or intermittent cycles of nocturnal hypoxia (12 h:12 h normoxia:hypoxia) for 28 days, and then compared whole-animal O2 consumption rates (M O2 ) and tissue metabolites during exposure to 12 h of hypoxia followed by reoxygenation in normoxia. Normoxia-acclimated fish experienced a pronounced 27% drop in M O2 during acute hypoxia, and modestly increased M O2 upon reoxygenation. They strongly recruited anaerobic metabolism during acute hypoxia, indicated by lactate accumulation in plasma, muscle, liver, brain, heart and digestive tract, as well as a transient drop in intracellular pH, and they increased hypoxia inducible factor (HIF)-1alpha protein abundance in muscle. Glycogen, glucose and glucose-6-phosphate levels suggested that glycogen supported brain metabolism in hypoxia, while the muscle used circulating glucose. Acclimation to constant hypoxia caused a stable ~50% decrease in M O2 that persisted after reoxygenation, with minimal recruitment of anaerobic metabolism, suggestive of metabolic depression. By contrast, fish acclimated to intermittent hypoxia maintained sufficient O2 transport to support normoxic M O2 , modestly recruited lactate metabolism and increased M O2 dramatically upon reoxygenation. Both groups of hypoxia-acclimated fish had similar glycogen, ATP, intracellular pH and HIF-1alpha levels as normoxic controls. We conclude that different patterns of hypoxia exposure favour distinct strategies for matching O2 supply and O2 demand. PMID- 30518602 TI - Amyloid Imaging. PMID- 30518603 TI - Erratum. PMID- 30518605 TI - Brief Overview of the Fall 2018 SNMMI-TS Board Meeting. PMID- 30518604 TI - SNMMI Procedure Standard for Bone Scintigraphy 4.0. PMID- 30518606 TI - NMTCB Report. PMID- 30518607 TI - Scotland's consultant vacancies are double official tally, BMA finds. PMID- 30518608 TI - Hif-1alpha paralogs play a role in the hypoxic ventilatory response of larval and adult zebrafish (Danio rerio). AB - Hypoxia inducible factor (Hif) 1alpha, an extensively studied transcription factor, is involved in the regulation of many biological processes in hypoxia including the hypoxic ventilatory response. In zebrafish, there are two paralogs of Hif-1alpha (Hif-1A and Hif-1B), but little is known about the specific roles or potential sub-functionalization of the paralogs in response to hypoxia. Using knockout lines of Hif-1alpha paralogs, we examined their involvement in the hypoxic ventilatory response, measured as ventilation frequency (f V) in larval and adult zebrafish (Danio rerio). In wild-type zebrafish, f V increased across developmental time [4 days post fertilization (dpf), 7 dpf, 10 dpf and 15 dpf] in response to hypoxia (55 mmHg). In contrast, the Hif-1B knockout fish did not exhibit an increase in hypoxic f V at 4 dpf. Similar to wild-types, as larvae of all knockout lines developed, the magnitude of f V increased but to a lesser degree than in the wild-type larvae, until 15 dpf at which point there was no difference among the genotypes. In adult zebrafish, only in Hif-1B knockout fish was there an attenuation in f V during sustained exposure to 30 mmHg for 1 h but no effect when exposed for a shorter duration to progressive hypoxia. The mechanism of action of Hif-1alpha, in part, may be through its downstream target, nitric oxide synthase (NOS), and its product, nitric oxide (NO). Overall, the effect of each Hif-1alpha paralog on the hypoxic ventilatory response of zebrafish varies over development and is dependent on the type of hypoxic stress. PMID- 30518609 TI - Erratum for the Research Article: "Engineering a highly elastic human protein based sealant for surgical applications" by N. Annabi, Y.-N. Zhang, A. Assmann, E. S. Sani, G. Cheng, A. D. Lassaletta, A. Vegh, B. Dehghani, G. U. Ruiz-Esparza, X. Wang, S. Gangadharan, A. S. Weiss, A. Khademhosseini. PMID- 30518610 TI - Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis. AB - Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (>=30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues. PMID- 30518611 TI - Wireless, battery-free, flexible, miniaturized dosimeters monitor exposure to solar radiation and to light for phototherapy. AB - Exposure to electromagnetic radiation can have a profound impact on human health. Ultraviolet (UV) radiation from the sun causes skin cancer. Blue light affects the body's circadian melatonin rhythm. At the same time, electromagnetic radiation in controlled quantities has beneficial use. UV light treats various inflammatory skin conditions, and blue light phototherapy is the standard of care for neonatal jaundice. Although quantitative measurements of exposure in these contexts are important, current systems have limited applicability outside of laboratories because of an unfavorable set of factors in bulk, weight, cost, and accuracy. We present optical metrology approaches, optoelectronic designs, and wireless modes of operation that serve as the basis for miniature, low-cost, and battery-free devices for precise dosimetry at multiple wavelengths. These platforms use a system on a chip with near-field communication functionality, a radio frequency antenna, photodiodes, supercapacitors, and a transistor to exploit a continuous accumulation mechanism for measurement. Experimental and computational studies of the individual components, the collective systems, and the performance parameters highlight the operating principles and design considerations. Evaluations on human participants monitored solar UV exposure during outdoor activities, captured instantaneous and cumulative exposure during blue light phototherapy in neonatal intensive care units, and tracked light illumination for seasonal affective disorder phototherapy. Versatile applications of this dosimetry platform provide means for consumers and medical providers to modulate light exposure across the electromagnetic spectrum in a way that can both reduce risks in the context of excessive exposure and optimize benefits in the context of phototherapy. PMID- 30518612 TI - A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis. AB - Mutations in the gene encoding superoxide dismutase 1 (SOD1) lead to misfolding and aggregation of SOD1 and cause familial amyotrophic lateral sclerosis (FALS). However, the implications of wild-type SOD1 misfolding in sporadic forms of ALS (SALS) remain unclear. By screening human memory B cells from a large cohort of healthy elderly subjects, we generated a recombinant human monoclonal antibody (alpha-miSOD1) that selectively bound to misfolded SOD1, but not to physiological SOD1 dimers. On postmortem spinal cord sections from 121 patients with ALS, alpha miSOD1 antibody identified misfolded SOD1 in a majority of cases, regardless of their SOD1 genotype. In contrast, the alpha-miSOD1 antibody did not bind to its epitope in most of the 41 postmortem spinal cord sections from non-neurological control (NNC) patients. In transgenic mice overexpressing disease-causing human SOD1G37R or SOD1G93A mutations, treatment with the alpha-miSOD1 antibody delayed the onset of motor symptoms, extended survival by up to 2 months, and reduced aggregation of misfolded SOD1 and motor neuron degeneration. These effects were obtained whether alpha-miSOD1 antibody treatment was administered by direct brain infusion or peripheral administration. These results support the further development of alpha-miSOD1 antibody as a candidate treatment for ALS involving misfolding of SOD1. PMID- 30518613 TI - Noncoding regions are the main source of targetable tumor-specific antigens. AB - Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs. PMID- 30518614 TI - Predictors of Survival in Patients with Advanced Gastrointestinal Malignancies Admitted to the Intensive Care Unit. AB - BACKGROUND: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). We sought to evaluate the predictors for outcome in patients with gastrointestinal (GI) cancer admitted to the ICU for nonsurgical conditions. PATIENTS AND METHODS: The primary objective was to determine the predictors of hospital mortality. Secondary objectives included investigating the predictors of ICU mortality and hospital overall survival (OS). All patients with GI cancer admitted to the ICU at the University of Texas MD Anderson Cancer Center between November 2012 and February 2015 were retrospectively analyzed. Cancer characteristics, treatment characteristics, and Sequential Organ Failure Assessment (SOFA) scores were analyzed for their effects on survival. RESULTS: The characteristics of the 200 patients were as follows: 64.5% male, mean age of 60 years, median SOFA score of 6.7, and tumor types of intestinal (37.5%), hepatobiliary/pancreatic (36%), and gastroesophageal (24%). The hospital mortality was 41%, and overall 6-month mortality was 75%. In multivariate analysis, high admission SOFA score > 5, poor tumor differentiation, and duration of metastatic disease <=7 months were associated with increased hospital mortality. For OS, high admission SOFA score > 5, poor tumor differentiation, and patients who were not on active chemotherapy because of poor performance had worse outcome. In multivariate analysis, SOFA score remained significant for OS even after excluding patients who died in the ICU. CONCLUSION: For patients with metastatic GI cancer admitted to the ICU, SOFA score was predictive for both acute and long-term survival. A patient's chemotherapy treatment status was not predictive for hospital mortality but was for OS. The SOFA score should be utilized in all patients with GI cancer upon ICU admission for prognostication. IMPLICATIONS FOR PRACTICE: Patients with cancer have a high use of health care utilization at the end of life, which can frequently involve admissions to the intensive care unit (ICU). Although there have been substantial increases in duration of survival for patients with advanced metastatic cancer, their mortality after an ICU admission remains high. GI malignancy is considered one of the top three lethal cancers estimated in 2017. Survival of critically ill patients with advanced GI cancer should be evaluated to help guide treatment planning. PMID- 30518615 TI - Neoadjuvant Chemotherapy Use for Nonmetastatic Breast Cancer at Five Public South African Hospitals and Impact on Time to Initial Cancer Therapy. AB - BACKGROUND: In the U.S., neoadjuvant chemotherapy (NAC) for nonmetastatic breast cancer (BC) is used with extensive disease and aggressive molecular subtypes. Little is known about the influence of demographic characteristics, clinical factors, and resource constraints on NAC use in Africa. MATERIALS AND METHODS: We studied NAC use in a cohort of women with stage I-III BC enrolled in the South African Breast Cancer and HIV Outcomes study at five hospitals. We analyzed associations between NAC receipt and sociodemographic and clinical factors, and we developed Cox regression models for predictors of time to first treatment with NAC versus surgery. RESULTS: Of 810 patients, 505 (62.3%) received NAC. Multivariate analysis found associations between NAC use and black race (odds ratio [OR] 0.49; 95% confidence limit [CI], 0.25-0.96), younger age (OR 0.95; 95% CI, 0.92-0.97 for each year), T-stage (T4 versus T1: OR 136.29; 95% CI, 41.80 444.44), N-stage (N2 versus N0: OR 35.64; 95% CI, 16.56-76.73), and subtype (triple-negative versus luminal A: OR 5.16; 95% CI, 1.88-14.12). Sites differed in NAC use (Site D versus Site A: OR 5.73; 95% CI, 2.72-12.08; Site B versus Site A: OR 0.37; 95% CI, 0.16-0.86) and time to first treatment: Site A, 50 days to NAC versus 30 days to primary surgery (hazard ratio [HR] 1.84; 95% CI, 1.25 2.71); Site D, 101 days to NAC versus 126 days to primary surgery (HR 0.49; 95% CI, 0.27-0.89). CONCLUSION: NAC use for BC at these South African hospitals was associated with both tumor characteristics and heterogenous resource constraints. IMPLICATIONS FOR PRACTICE: Using data from a large breast cancer cohort treated in South Africa's public healthcare system, the authors looked at determinants of neoadjuvant chemotherapy use and time to initiate treatment. It was found that neoadjuvant chemotherapy was associated with increasing tumor burden and aggressive molecular subtypes, demonstrating clinically appropriate care in a lower resource setting. Results of this study also showed that time to treatment differences between chemotherapy and surgery varied by hospital, suggesting that differences in resource limitations were influencing clinical decision making. Practice guidelines and care quality metrics designed for low- and middle-income countries should accommodate heterogeneity of available resources. PMID- 30518616 TI - Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade. AB - BACKGROUND: The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. MATERIALS AND METHODS: In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. RESULTS: Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). CONCLUSION: IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. IMPLICATIONS FOR PRACTICE: This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L. PMID- 30518618 TI - Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. AB - OBJECTIVE: To determine whether use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes. DESIGN: Population based cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS: 154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed until 31 March 2018. MAIN OUTCOME MEASURES: Use of DPP-4 inhibitors and GLP-1 receptor agonists was modelled as a time varying variable and compared with use of other second or third line antidiabetic drugs. All exposures were lagged by one year to account for cancer latency and to minimise reverse causality. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately. A post hoc pharmacovigilance analysis was conducted using the World Health Organization's global individual case safety report database, VigiBase, to estimate reporting odds ratios of cholangiocarcinoma. RESULTS: During 614 274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100 000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively). CONCLUSION: Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes. PMID- 30518617 TI - Treatment Outcomes and Sensitivity to Hormone Therapy of Aggressive Angiomyxoma: A Multicenter, International, Retrospective Study. AB - BACKGROUND: Aggressive angiomyxoma (AA) is a rare, locally aggressive tumor usually arising from pelvis or perineum, with a high local-recurrence rate after complete surgery. Anecdotal responses to hormone therapy have been reported. In the present study we aimed at studying surgical treatment outcomes and sensitivity to hormone therapy of AA. MATERIALS AND METHODS: We conducted a multicenter, international retrospective effort including patients with AA treated at three European referral centers (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and the Italian Rare Cancer Network; Centre Leon Berard, Lyon, France; and Hospital Universitario Virgen del Rocio, Seville, Spain). RESULTS: A total of 36 patients were included. Median follow-up was 51.3 months. Thirty-three patients (92%) underwent complete (R0 + R1) surgery, with a local relapse rate of 50% and a median relapse-free survival of 39 months (95% confidence interval [CI], 27-68.1). Thirteen patients received a first-line systemic treatment with hormone therapy for locally advanced disease, with an overall response rate of 62% and a median progression-free survival of 24.6 months (95% CI, 11.0-39.7). In two patients, adding an aromatase inhibitor (AI) on progression to first-line GnRH agonist (GnRHa) resulted in a new tumor response. CONCLUSION: Our findings confirm that in AA, surgical local control may be challenging, with a significant rate of local relapse despite complete surgery. Hormone therapy is an active treatment option, with a potential of disease control and of being combined with surgery. The addition of an AI to first-line GnRHa could be an effective second-line systemic therapy in premenopausal female patients with AA. IMPLICATIONS FOR PRACTICE: In this retrospective effort including 36 patients with aggressive angiomyxoma, local relapse rate after complete surgery was 50%, with a median relapse-free survival of 39 months, confirming that local control is challenging. Overall response rate to first-line hormone therapy was 62%, with a median progression-free survival of 24.6 months. Thus, hormone therapy has a potential of disease control and of being combined with surgery. PMID- 30518619 TI - Neighbourhoods, networks and pre-exposure prophylaxis awareness: a multilevel analysis of a sample of young black men who have sex with men. AB - OBJECTIVE: Young black men who have sex with men (YBMSM) in the USA represent a subgroup that has the highest HIV incidence among the overall population. In the USA, pre-exposure prophylaxis (PrEP) is an effective prevention intervention to prevent HIV acquisition when taken regularly. Neighbourhood and network factors may relate to PrEP awareness, but have not been studied in YBMSM. This study aimed to examine the relationship of neighbourhood and network characteristics with PrEP awareness among YBMSM. METHODS: We used data collected from a sample of 618 YBMSM in Chicago (2013-2014). Home addresses were collected for participants and enumerated network members. Administrative data (eg, 2014 American Community Survey, Chicago Department of Public Health) were used to describe residence characteristics. Network member characteristics were also collected (eg, sexual partners' sex-drug use, confidant network members who were also MSM). Multilevel analysis was performed to examine the relationships of neighbourhood and network characteristics to PrEP awareness. RESULTS: Higher neighbourhood-level educational attainment (adjusted odds ratio (aOR) 1.02, p=0.03) and greater primary care density (aOR 1.38, p=0.01) were associated with greater PrEP awareness; greater neighbourhood alcohol outlet density (aOR 0.52, p=0.004) was associated with less PrEP awareness. Sexual network members residing in the same neighbourhood as the participants (aOR 2.58, p=0.03) and discussions around avoiding HIV acquisition with confidants (aOR 2.26, p=0.04) were associated with greater PrEP awareness. CONCLUSIONS: The results suggest that neighbourhood and network characteristics can influence PrEP awareness in YBMSM. Additional studies are needed to understand the influences of neighbourhood (eg, MSM serving venues) and network (eg, peer to peer communication) characteristics on dissemination of PrEP information, uptake and adherence and the related mechanisms behind the associations. PMID- 30518620 TI - Results from a cross-sectional sexual and reproductive health study among school girls in Tanzania: high prevalence of bacterial vaginosis. AB - OBJECTIVES: Bacterial vaginosis (BV) increases women's susceptibility to sexually transmitted infections (STIs) and HIV and may partly explain the high incidence of STI/HIV among girls and young women in East and southern Africa. The objectives of this study were to investigate the association between BV and sexual debut, to investigate other potential risk factors of BV and to estimate associations between BV and STIs. METHODS: Secondary school girls in Mwanza, aged 17 and 18 years, were invited to join a cross-sectional study. Consenting participants were interviewed and samples were obtained for STI and BV testing. Factors associated with prevalent BV were analysed using multivariable logistic regression. Y-chromosome was tested as a biomarker for unprotected penile-vaginal sex. RESULTS: Of the 386 girls who were enrolled, 163 (42%) reported having ever had penile-vaginal sex. Ninety-five (25%) girls had BV. The prevalence of BV was 33% and 19% among girls who reported or did not report having ever had penile vaginal sex, respectively. BV was weakly associated with having ever had one sex partner (adjusted odds ratio (aOR) 1.59;95% CI 0.93 to 2.71) and strongly associated with two or more partners (aOR = 3.67; 95% CI 1.75 to 7.72), receptive oral sex (aOR 6.38; 95% CI 1.22 to 33.4) and having prevalent human papillomavirus infection (aOR = 1.73; 95% CI 1.02 to 2.95). Of the 223 girls who reported no penile-vaginal sex, 12 (5%) tested positive for an STI and 7 (3%) tested positive for Y-chromosome. Reclassifying these positive participants as having ever had sex did not change the key results. CONCLUSIONS: Tanzanian girls attending school had a high prevalence of BV. Increasing number of sex partner was associated with BV; however, 19% of girls who reported no penile-vaginal sex had BV. This suggests that penile-vaginal sexual exposure may not be a prerequisite for BV. There was evidence of under-reporting of sexual debut. PMID- 30518621 TI - Use of geosocial networking applications is independently associated with diagnosis of STI among men who have sex with men testing for STIs: findings from the cross-sectional MSM Internet Survey Ireland (MISI) 2015. AB - OBJECTIVES: MSM Internet Survey Ireland (MISI) 2015 was an anonymous, self completed, cross-sectional internet survey assessing sexual behaviours and health needs among men who have sex with men (MSM) in Ireland. We explored factors associated with self-reported STI diagnosis among MSM who were sexually active and had an STI test in the previous year. METHODS: We compared the study population (n=1158; 37% of total population), with the sexually active MISI population not testing for STIs (n=1620; 52% of total population). Within the study population, we identified sociodemographics and sexual behaviours associated with self-reporting STI diagnosis. We used multivariable logistic regression to estimate adjusted odds ratios (aORs). RESULTS: The sociodemographics, lifestyle and sexual behaviours of the study population differed significantly from the sexually active MISI population who did not test for STIs. Within the study population, 65% met a sexual partner via geosocial networking smartphone application (GSNa) and 21% self-reported an STI diagnosis in the previous year. On univariable analysis, factors associated with STI diagnosis included: older age, identifying as gay, HIV-positive status, increasing number of sexual partners in the previous year, condomless anal intercourse (CAI) with >=2 non-steady partners and using GSNa to meet a new sexual partner in the previous year or most recent sexual partner. On multivariable analysis, STI diagnosis was associated with: being aged 25-39 years (aOR 1.8, 95% CI 1.04 to 3.15), CAI with >=2 non-steady partners (aOR 2.8, 95% CI 1.84 to 4.34), total number of sexual partners (aOR 1.02, 95% CI 1.00 to 1.03) and using GSNa to meet a new sexual partner (aOR 1.95, 95% CI 1.12 to 3.39). CONCLUSIONS: STI diagnosis among MSM testing for STIs is associated with GSNa use, as well as sexual behaviours. GSNas are key settings for STI prevention interventions, which should prioritise men with high numbers of sexual partners and those with multiple CAI partners. PMID- 30518622 TI - EGCG protects cardiomyocytes against hypoxia-reperfusion injury via inhibiting OMA1 activation. AB - Mitochondria are important for energy production and cardiomyocytes homeostasis. OMA1, a metalloendopeptidase, initiates the proteolytic process of pro-fusion protein, OPA1, to deteriorate mitochondrial structure and function. In this study, mouse embryonic fibroblasts (MEFs) and neonatal mouse cardiomyocytes (NMCMs) subjected to hypoxia-reperfusion (H/R) and/or H2O2 were used to mimic oxidative stress in the heart following ischemia-reperfusion (I/R). In vitro experiments demonstrated that H/R insult and H2O2 stimulation induced self cleavage of OMA1 and subsequent conversion of OPA1 from long form to short form, leading to mitochondrial fragmentation, cytochrome c release, and apoptosis. By using Molecular Operating Environment (MOE) to simulate the binding interaction of 2295 phytochemicals against OMA1, epigallocatechin gallate (EGCG) and betanin were selected as candidates of OMA1 inhibitor. We found that EGCG directly interacted with OMA1 and potently inhibited self-cleavage of OMA1, leading to attenuated OPA1 cleavage. This study suggests that OMA1 inhibition induced by EGCG can serve as a potential approach to treat cardiac I/R injury. PMID- 30518623 TI - Bexarotene - a novel modulator of AURKA and the primary cilium in VHL-deficient cells. AB - Loss of von Hippel Lindau (VHL) is associated with loss of primary cilia and is causally linked to elevated Aurora Kinase A (AURKA). We developed an image-based HTS assay using a dual-labelling image analysis strategy that identifies both the cilium and the basal body. Using this strategy, we screened small molecule compounds for the targeted rescue of cilia defects associated with VHL-deficiency with high accuracy and reproducibility. Bexarotene was identified and validated as a positive regulator of the primary cilium. Importantly, the inability of an alternate retinoid X receptor (RXR) agonist to rescue ciliogenesis, in contrast to bexarotene, suggested the existence of multiple bexarotene driven mechanisms. We found that bexarotene decreased AURKA expression in VHL-deficient cells, thereby restoring the ability of these cells to ciliate in the absence of VHL Finally, bexarotene treatment reduced the propensity of subcutaneous lesions to develop into tumors in a mouse xenograft model of RCC, with a concomitant decrease in activated AURKA, highlighting the potential of bexarotene as an intervention strategy in the clinic to manage renal cystogenesis associated with VHL-deficiency and elevated AURKA expression. PMID- 30518624 TI - Closed loop peer review. PMID- 30518625 TI - Fetal Leydig cells dedifferentiate and serve as adult Leydig stem cells. AB - Previous studies have established that fetal Leydig cells (FLCs) and adult Leydig cells (ALCs) show distinct functional characteristics. However, the lineage relationship between FLCs and ALCs has not been clarified yet. Here, we reveal that a subset of FLCs dedifferentiate at fetal stages to give rise to ALCs at the pubertal stage. Moreover, the dedifferentiated cells contribute to the peritubular myoid cell and vascular pericyte populations in the neonatal testis, and these non-steroidogenic cells serve as potential ALC stem cells. We generated FLC lineage-specific Nr5a1 (Ad4BP/SF-1) gene-disrupted mice and mice lacking the fetal Leydig enhancer (FLE) of the Nr5a1 gene. Phenotypes of these mice support the conclusion that most of the ALCs arise from dedifferentiated FLCs, and that the FLE of the Nr5a1 gene is essential for both initial FLC differentiation and pubertal ALC redifferentiation. PMID- 30518626 TI - SlMYC1 Regulates Type VI Glandular Trichome Formation and Terpene Biosynthesis in Tomato Glandular Cells. AB - Tomato (Solanum lycopersicum) glandular trichomes function as biochemical factories that synthesize a diverse array of specialized metabolites. Terpenoids are the most diverse class of plant specialized metabolites, with volatile mono- and sesquiterpenes playing important roles in plant defense. Although the biosynthetic pathways of volatile terpenes in tomato glandular trichomes have been well described, little is known about their regulation. Here, we demonstrate that SlMYC1, a basic helix-loop-helix transcription factor, differentially regulates mono- and sesquiterpene biosynthesis in the type VI glandular trichomes of tomato leaves and stems. SlMYC1 functions as a positive regulator of monoterpene biosynthesis in both leaf and stem trichomes but as a negative regulator of sesquiterpene biosynthesis in stem trichomes. SlMYC1 is also essential for type VI glandular trichome development, as knocking down SlMYC1 led to the production of smaller type VI glandular trichomes at lower densities and knocking out this gene led to their absence. Our findings reveal a role for SlMYC1 not only in type VI glandular trichome development, but also in the regulation of terpene biosynthesis in tomato. PMID- 30518627 TI - How Resurrection Plants Survive Being Hung Out to Dry. PMID- 30518628 TI - PDCD4 is an androgen-repressed tumor suppressor that regulates prostate cancer growth and castration resistance. AB - Androgen Receptor (AR) transcriptional activity contributes to prostate cancer (PCa) development and castration resistance. The growth and survival pathways driven by AR remain incompletely defined. Here we found PDCD4 to be a new target of AR signaling, and a potent regulator of PCa cell growth, survival, and castration resistance. The 3' untranslated region of PDCD4 is directly targeted by the androgen-induced miRNA, miR-21. Androgen treatment suppressed PDCD4 expression in a dose-responsive and miR-21-dependent manner. Correspondingly, AR inhibition dose-responsively induced PDCD4 expression. Using data from PCa tissue samples in the Cancer Genome Atlas (TCGA), we found a significant and inverse correlation between miR-21 and PDCD4 mRNA and protein levels. Higher Gleason grade tumors exhibited significantly higher levels of miR-21, and significantly lower levels of PDCD4 mRNA and protein. PDCD4 knockdown enhanced androgen dependent cell proliferation and cell cycle progression, inhibited apoptosis, and was sufficient to drive androgen-independent growth. On the other hand, PDCD4 over-expression inhibited miR-21 mediated growth and androgen-independence. The stable knockdown of PDCD4 in androgen-dependent PCa cells enhanced subcutaneous tumor take rate in vivo, accelerated tumor growth, and was sufficient for castration resistant tumor growth. Implications: This study provides the first evidence that PDCD4 is an androgen-suppressed protein capable of regulating PCa cell proliferation, apoptosis, and castration resistance. These results uncover miR-21 and PDCD4 regulated pathways as potential new targets for castration resistant prostate cancer. PMID- 30518629 TI - Discovery and characterization of recurrent, targetable ALK fusions in leiomyosarcoma. AB - Soft tissue sarcomas such as leiomyosarcoma (LMS) pose a clinical challenge because systemic treatment options show only modest therapeutic benefit. Discovery and validation of targetable vulnerabilities is essential. To discover putative kinase fusions, we analyzed existing transcriptomic data from LMS clinical samples. Potentially oncogenic ALK rearrangements were confirmed by application of multiple RNA-sequencing fusion detection algorithms and fluorescence in situ hybridization (FISH). We functionally validated the oncogenic potential and targetability of discovered kinase fusions through biochemical, cell-based (Ba/F3, NIH3T3 and murine smooth muscle cell) and in vivo tumor modelling approaches. We identified ALK rearrangements in 9 of 377 (2.4%) LMS patients, including a novel KANK2-ALK fusion and a recurrent ACTG2-ALK fusion. Functional characterization of the novel ALK fusion, KANK2-ALK, demonstrates it is a dominant oncogene in Ba/F3 or NIH3T3 model systems, and has tumorigenic potential when introduced into smooth muscle cells. Oral monotherapy with targeted ALK kinase inhibitor lorlatinib significantly inhibits tumor growth and prolongs survival in a murine model of KANK2-ALK leiomyosarcoma. These results provide the first functional validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. Overall, these findings suggest that some soft tissue sarcomas may harbor previously unknown kinase gene translocations, and their discovery may propel new therapeutic strategies in this treatment-refractory cancer. Implications: A subset of leiomyosarcomas harbor previously unrecognized oncogenic ALK fusions that are highly responsive to ALK inhibitors and thus these data emphasize the importance of detailed genomic investigations of leiomyosarcoma tumors. PMID- 30518630 TI - Assessment of in vitro effects of direct thrombin inhibitors and activated factor X inhibitors through clot waveform analysis. AB - AIMS: Clot waveform analysis (CWA) has been reported to extend the interpretation of clotting time measurement. The parameters obtained from successive derivatives of the clotting reaction curves reflect the rates of activation of individual coagulation factors, theoretically dissecting the cascade pathway. This study aims to assess the in vitro effects of direct thrombin inhibitors (DTIs) and activated factor X (FXa) inhibitors. METHODS: CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each drug. For CWA of APTT measurement curves (APTT-CWA), the positive mode of clotting reaction curves was defined as the direction towards fibrin generation. RESULTS: All the maximum positive values in the successive derivatives were decreased dependently on the concentrations of each drug. Moreover, the negative values in the second and third derivatives appeared putatively due to consumption of thrombin and factor FXa, respectively, to form complexes with plasma serine protease inhibitors. The decrease of the maximum negative values observed dependently on the concentrations of each drug appeared to be consistent with the decreased generation of thrombin and factor FXa. The analysis of Hill coefficients of each drug in the dose-response of changes in the APTT-CWA parameters revealed a difference in anticoagulant cooperativity between DTIs versus FXa inhibitors. CONCLUSIONS: The APTT-CWA demonstrated evidence for the blockade of thrombin-positive feedback by DTIs and FXa inhibitors and that for the differences in anticoagulant cooperativity between them. The results demonstrate the usability of CWA for assessment of anticoagulation and provide insights into direct anticoagulants. PMID- 30518631 TI - Deep learning for detecting tumour-infiltrating lymphocytes in testicular germ cell tumours. AB - AIMS: To evaluate if a deep learning algorithm can be trained to identify tumour infiltrating lymphocytes (TILs) in tissue samples of testicular germ cell tumours and to assess whether the TIL counts correlate with relapse status of the patient. METHODS: TILs were manually annotated in 259 tumour regions from 28 whole-slide images (WSIs) of H&E-stained tissue samples. A deep learning algorithm was trained on half of the regions and tested on the other half. The algorithm was further applied to larger areas of tumour WSIs from 89 patients and correlated with clinicopathological data. RESULTS: A correlation coefficient of 0.89 was achieved when comparing the algorithm with the manual TIL count in the test set of images in which TILs were present (n=47). In the WSI regions from the 89 patient samples, the median TIL density was 1009/mm2. In seminomas, none of the relapsed patients belonged to the highest TIL density tertile (>2011/mm2). TIL quantifications performed visually by three pathologists on the same tumours were not significantly associated with outcome. The average interobserver agreement between the pathologists when assigning a patient into TIL tertiles was 0.32 (Kappa test) compared with 0.35 between the algorithm and the experts, respectively. A higher TIL density was associated with a lower clinical tumour stage, seminoma histology and lack of lymphovascular invasion. CONCLUSIONS: Deep learning-based image analysis can be used for detecting TILs in testicular germ cell cancer more objectively and it has potential for use as a prognostic marker for disease relapse. PMID- 30518632 TI - Eradication of central nervous system leukemia of T-cell origin with a brain permeable LSD1 inhibitor. AB - PURPOSE: Lysine-specific demethylase 1 (LSD1) regulates several biological processes via the bifunctional modulation of enhancer functions. Recently, we reported that LSD1 overexpression is a founder abnormality of T-cell leukemogenesis and is maintained in fully transformed T-cell acute lymphoblastic leukemia (T-ALL) cells. On the basis of this finding, we attempted to develop novel LSD1 inhibitors effective for T-ALL with central nervous system (CNS) involvement. EXPERIMENTAL DESIGN: We chemically modified the prototype LSD inhibitor tranylcypromine (TCP) and screened for cytotoxicity against TCP resistant T-ALL cell lines. In vivo efficacy of novel LSD1 inhibitors was examined in immunodeficient mice transplanted with luciferase-expressing T-ALL cell lines, which faithfully reproduce human T-ALL with CNS involvement. RESULTS: We found robust cytotoxicity against T-ALL cells, but not normal bone marrow progenitors, for two N-alkylated TCP derivatives, S2116 and S2157. The two compounds induced apoptosis in TCP-resistant T-ALL cells in vitro and in vivo by repressing transcription of the NOTCH3 and TAL1 genes through increased H3K9 methylation and reciprocal H3K27 deacetylation at super-enhancer regions. Both S2116 and S2157 significantly retarded the growth of T-ALL cells in xenotransplanted mice and prolonged the survival of recipients as monotherapy and in combination with dexamethasone. Notably, S2157 could almost completely eradicate CNS leukemia because of its ability to efficiently pass through the blood-brain barrier. CONCLUSION: These findings provide a molecular basis and rationale for the inclusion of a brain-permeable LSD1 inhibitor, S2157, in treatment strategies for T-ALL with CNS involvement. PMID- 30518634 TI - Gabriel Weston: A surgeon-writer-presenter's story. PMID- 30518633 TI - A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers. AB - PURPOSE: Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas. EXPERIMENTAL DESIGN: The trial was a phase II design with two cohorts, cervical cancers and non cervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin. RESULTS: Objective tumor responses occurred in 5/18 (28%) patients in the cervical cancer cohort and 2/11 (18%) patients in the non-cervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the non-cervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response. Conclusions/Discussion: These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies. PMID- 30518635 TI - Detecting cervical precancer and reaching underscreened women by using HPV testing on self samples: updated meta-analyses. AB - OBJECTIVE: To evaluate the diagnostic accuracy of high-risk human papillomavirus (hrHPV) assays on self samples and the efficacy of self sampling strategies to reach underscreened women. DESIGN: Updated meta-analysis. DATA SOURCES: Medline (PubMed), Embase, and CENTRAL from 1 January 2013 to 15 April 2018 (accuracy review), and 1 January 2014 to 15 April 2018 (participation review). REVIEW METHODS: Accuracy review: hrHPV assay on a vaginal self sample and a clinician sample; and verification of the presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) by colposcopy and biopsy in all enrolled women or in women with positive tests. Participation review: study population included women who were irregularly or never screened; women in the self sampling arm (intervention arm) were invited to collect a self sample for hrHPV testing; women in the control arm were invited or reminded to undergo a screening test on a clinician sample; participation in both arms was documented; and a population minimum of 400 women. RESULTS: 56 accuracy studies and 25 participation trials were included. hrHPV assays based on polymerase chain reaction were as sensitive on self samples as on clinician samples to detect CIN2+ or CIN3+ (pooled ratio 0.99, 95% confidence interval 0.97 to 1.02). However, hrHPV assays based on signal amplification were less sensitive on self samples (pooled ratio 0.85, 95% confidence interval 0.80 to 0.89). The specificity to exclude CIN2+ was 2% or 4% lower on self samples than on clinician samples, for hrHPV assays based on polymerase chain reaction or signal amplification, respectively. Mailing self sample kits to the woman's home address generated higher response rates to have a sample taken by a clinician than invitation or reminder letters (pooled relative participation in intention-to-treat-analysis of 2.33, 95% confidence interval 1.86 to 2.91). Opt-in strategies where women had to request a self sampling kit were generally not more effective than invitation letters (relative participation of 1.22, 95% confidence interval 0.93 to 1.61). Direct offer of self sampling devices to women in communities that were underscreened generated high participation rates (>75%). Substantial interstudy heterogeneity was noted (I2>95%). CONCLUSIONS: When used with hrHPV assays based on polymerase chain reaction, testing on self samples was similarly accurate as on clinician samples. Offering self sampling kits generally is more effective in reaching underscreened women than sending invitations. However, since response rates are highly variable among settings, pilots should be set up before regional or national roll out of self sampling strategies. PMID- 30518636 TI - Murine MPDZ-linked hydrocephalus is caused by hyperpermeability of the choroid plexus. AB - Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straightforward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus. PMID- 30518637 TI - Autophagy in crop plants: what's new beyond Arabidopsis? AB - Autophagy is a major degradation and recycling pathway in plants. It functions to maintain cellular homeostasis and is induced by environmental cues and developmental stimuli. Over the past decade, the study of autophagy has expanded from model plants to crop species. Many features of the core machinery and physiological functions of autophagy are conserved among diverse organisms. However, several novel functions and regulators of autophagy have been characterized in individual plant species. In light of its critical role in development and stress responses, a better understanding of autophagy in crop plants may eventually lead to beneficial agricultural applications. Here, we review recent progress on understanding autophagy in crops and discuss potential future research directions. PMID- 30518638 TI - Insights into GABAAergic system alteration in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disease that is characterized by a triad of motor, psychiatric and cognitive impairments. There is still no effective therapy to delay or halt the disease progress. The striatum and cortex are two particularly affected brain regions that exhibit dense reciprocal excitatory glutamate and inhibitory gamma-amino butyric acid (GABA) connections. Imbalance between excitatory and inhibitory signalling is known to greatly affect motor and cognitive processes. Emerging evidence supports the hypothesis that disrupted GABAergic circuits underlie HD pathogenesis. In the present review, we focused on the multiple defects recently found in the GABAergic inhibitory system, including altered GABA level and synthesis, abnormal subunit composition and distribution of GABAA receptors and aberrant GABAA receptor-mediated signalling. In particular, the important role of cation-chloride cotransporters (i.e. NKCC1 and KCC2) is discussed. Recent studies also suggest that neuroinflammation contributes significantly to the abnormal GABAergic inhibition in HD. Thus, GABAA receptors and cation-chloride cotransporters are potential therapeutic targets for HD. Given the limited availability of therapeutic treatments for HD, a better understanding of GABAergic dysfunction in HD could provide novel therapeutic opportunities. PMID- 30518639 TI - Correction to 'DNA methylation subpatterns at distinct regulatory regions in human early embryos'. PMID- 30518640 TI - A (Not So) Perfectly Designed System: The Paradox of Medical Stewardship and Quality Measurement. PMID- 30518641 TI - Associations between neurochemical receptor genes, 2D:4D, impulsivity and relationship quality. AB - The ratio between the second and fourth digits (2D:4D) has been widely used as a proxy for fetal exposure to androgens and has been linked to a number of sociosexual traits in humans. However, the role of genes in this equation remains unknown. Here (N = 474), we test, firstly, for associations between 2D:4D and single-nucleotide polymorphisms (SNPs) in nine neurochemical receptor genes (AR, OXTR, AVPR1A, OPRM1, DRD1/2, ANKK1, 5HTR1A/2A), and secondly, whether digit ratios mediate the relationship between genetic variation and sociosexuality. We demonstrate significant associations between AR, OPRM1 and AVPR1A and 2D:4D. Moreover, mediation analysis indicates that, in women, AR and OPRM1 variation drives digit ratios, which are related positively to impulsivity and, for OPRM1, negatively to romantic relationship quality. Although these findings are subject to multiple testing issues, this study provides preliminary evidence that in women genetic factors may affect both impulsivity and perceived relationship quality through influencing factors indexed by digit ratios. PMID- 30518642 TI - Prolonged length of stay in the emergency department and increased risk of hospital mortality in patients with sepsis requiring ICU admission. AB - BACKGROUND AND OBJECTIVES: Delayed patient admission to the intensive care unit (ICU) from the ED is common in China. Patients with severe sepsis or septic shock requiring ICU admission are in need of specialised monitoring and tailored treatment. Delayed admission to the ICU might be associated with adverse clinical outcomes for patients with sepsis. METHODS: Patients with sepsis admitted to the ICU from the ED from January 2010 to April 2018 were retrospectively identified from a clinical data warehouse. The primary endpoint was in-hospital mortality. Length of stay in ED (EDLOS) was compared between survivors and non-survivors. A multivariable regression model was employed to adjust for potential confounding due to patient clinical condition. RESULTS: A total of 1997 patients, including 473 non-survivors and 1524 survivors, were included. The crude mortality rate for patients with EDLOS <6 hours was 21.4%, which was significantly lower than patients with EDLOS of 12-24 hours (31.9%), and those with EDLOS >24 hours (31.8%). After adjusting for PaO2/FiO2, serum creatinine, age, Sequential Organ Failure Assessment, body mass index, lactate, comorbidities and infection site, EDLOS continued to be independently associated with increased risk of hospital mortality. Compared with the group with EDLOS <6 hours, those with EDLOS between 12and24 hours (OR 1.82, 95% CI 1.28 to 2.58) and EDLOS >24 hours (OR 1.79, 95% CI 1.27 to 2.52) showed a significantly increased risk of death. CONCLUSIONS: Our study shows that prolonged EDLOS is independently associated with increased risk of hospital mortality in patients with sepsis requiring ICU admission. PMID- 30518643 TI - Histidine-rich glycoprotein inhibits HIV-1 infection in a pH-dependent manner. AB - Histidine-rich glycoprotein (HRG) is an abundant plasma protein with a multidomain structure allowing its interaction with many ligands including phospholipids, plasminogen, fibrinogen, IgG antibodies, and heparan sulfate. HRG has shown to regulate different biological responses such as angiogenesis, coagulation and fibrinolysis. Here, we found that HRG almost completely abrogated the infection of GHOST, Jurkat, CD4+ T cells, and macrophages by HIV-1 at low pH (range 6.5 to 5.5) but not at neutral pH. HRG was shown to interact with heparan sulfate expressed by target cells inhibiting an early post-binding step associated to HIV-1 infection. More importantly, by acting on the viral particle itself, HRG induced a deleterious effect which reduces viral infectivity. Because cervicovaginal secretions in healthy women show low pH values, even after semen deposition, our observations suggest that HRG might represent a constitutive defence mechanism in the vaginal mucosa. Of note, low pH also enabled HRG to inhibit the infection of Hep-2 cells and Vero cells by respiratory syncytial virus (RSV) and herpes simplex virus-type 2 (HSV-2), respectively, suggesting that HRG might display a broad antiviral activity under acidic conditions.IMPORTANCE. Vaginal intercourse represents a high-risk route for HIV-1 transmission. The efficiency of male-to-female HIV-1 transmission has been estimated as 1 in every 1,000 episodes of sexual intercourse, reflecting a high degree of protection conferred by the genital mucosa. However, the contribution of different host factors to the protection against HIV-1 at mucosal surfaces remains poorly defined. Here, we report for the first time that acidic values of pH enable the plasma protein histidine-rich glycoprotein (HRG) to strongly inhibit HIV-1 infection. Because cervicovaginal secretions usually show low pH values, our observations suggest that HRG might represent a constitutive antiviral mechanism in the vaginal mucosa. Interestingly, infection by other viruses such as respiratory syncytial virus and herpes simplex virus-type 2 was also markedly inhibited by HRG at low pH values, suggesting that extracellular acidosis enables HRG to display a broad antiviral activity. PMID- 30518644 TI - Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti CD4 Binding Site Broadly Neutralizing Antibodies against HIV. AB - Attachment inhibitor (AI) BMS-626529 (Fostemsavir) represents a novel class of antiretrovirals which targets human immunodeficiency virus type 1 (HIV-1) gp120 and blocks CD4-induced conformational changes required for viral entry. It is now in Phase III clinical trials and is expected to be approved by the United States Food and Drug Administration (FDA) in the near future. Although Fostemsavir is very potent against HIV in vitro and in vivo, there are already a number of resistant mutants identified. Broadly neutralizing HIV antibodies (bNAbs) can potently inhibit a wide range of HIV-1 strains by binding to viral Env and are very promising candidates for HIV-1 prevention and therapy. Since both target viral Env to block viral entry, we decided to investigate the relationship between these two inhibitors. Our data show that Env mutants resistant to BMS 626529 remained susceptibility to bNAbs. A single treatment of bNAb NIH45-46G54W completely inhibited the replication of these escape mutants. Remarkable synergy was observed between BMS-626529 and CD4 binding site (bs)-targeting bNAbs in neutralizing HIV-1 strains at low concentrations. This synergistic effect was enhanced against virus harboring resistance mutations to BMS-626529. The mechanistic basis of the observed synergy is likely enhanced inhibition of CD4 binding to HIV-1 Env trimer by the combination of BMS-626529 and CD4bs-targeting bNAbs. This work highlights the potential for positive interplay between small and large molecule therapeutics on HIV viral entry, which may prove useful as these agents enter clinical use.IMPORTANCE As the worldwide HIV pandemic continues, there is a continued need for novel drugs and therapies. A new class of drug, Attachment Inhibitor, will soon be approved for the treatment of HIV. Broadly neutralizing antibodies are also promising candidates for HIV prevention and therapy. We investigated how this drug might work with these exciting antibodies that are very potent in blocking HIV infection of cells. These antibodies worked against virus known to be resistant to the new drug. In addition, a specific type of antibody worked really well with the new drug in blocking virus infection of cells. This work has implications for both the new drug and the antibodies that are poised to be used against HIV. PMID- 30518645 TI - Mapping the pH sensors critical for host cell entry by a complex non-enveloped virus. AB - Bluetongue virus (BTV), family Reoviridae, is an insect-borne, double-capsid virus causing haemorrhagic disease in livestock around the world. Here we elucidate how outer capsid proteins VP2 and VP5 coordinate cell entry of BTV. To identify key functional residues, we used atomic-level structural data to guide mutagenesis of VP2 and VP5, and a series of biological and biochemical approaches, including site-directed mutagenesis, reverse genetics-based virus recovery, expression and characterization of individual recombinant mutant proteins and various in vitro and in vivo assays. We demonstrate the dynamic nature of the conformational change process, revealing that a unique zinc finger (CCCH) in VP2 acts as the major low pH sensor, coordinating VP2 detachment, subsequently allowing VP5 to sense low pH via specific histidine residues at key positions. We show that single substitution of only certain histidine residues has lethal effect, indicating location of histidine in VP5 is critical to inducing changes in VP5 conformation that facilitates membrane penetration. Further, we show VP5 anchoring domain alone recapitulates sensing of low pH. Our data reveals a novel, multi-conformational process that overcomes entry barriers faced by this multi-capsid nonenveloped virus.IMPORTANCE Virus entry into a susceptible cell is the first step of infection and a significant point at which infection can be prevented. To enter effectively viruses must sense the cellular environment and, when appropriate, initiate a series of changes that eventually jettison the protective shell and deposit virus genes into the cytoplasm. Many viruses sense pH but how this happens and the events that follow are often poorly understood. Here we address this question for a large multi-layered Bluetongue virus. We show key residues in outer capsid proteins, a pH sensing histidine of a zinc finger within the receptor-binding VP2 protein and certain histidine residues in the membrane-penetrating VP5 protein that detect cellular pH leading to irreversible changes and propel the virus through the cell membrane. Our data reveals a novel mechanism of cell entry for a nonenveloped virus and highlight mechanisms, which may also be used by other viruses. PMID- 30518646 TI - Intrahost dynamics of human cytomegalovirus variants acquired by seronegative glycoprotein B vaccinees. AB - Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, and a frequent cause of hearing loss and debilitating neurologic disease in newborn infants. Thus, a vaccine to prevent HCMV-associated congenital disease is a public health priority. One potential strategy is vaccination of women of child bearing age to prevent maternal HCMV acquisition during pregnancy. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine is the most efficacious tested clinically to date, demonstrating 50% protection against primary HCMV infection in a phase 2 clinical trial. Yet, the impact of gB/MF59-elicited immune responses on the population of viruses acquired by trial participants has not been assessed. In this analysis, we employed quantitative PCR as well as multiple sequencing methodologies to interrogate the magnitude and genetic composition of HCMV populations infecting gB/MF59 vaccinees and placebo recipients. We identified several differences between the viral dynamics of acutely-infected vaccinees and placebo recipients. First, viral load was reduced in the saliva of gB vaccinees, though not in whole blood, vaginal fluid, or urine. Additionally, we observed possible anatomic compartmentalization of gB variants in the majority of vaccinees compared to only a single placebo recipient. Finally, we observed reduced acquisition of genetically-related gB1, gB2, and gB4 genotype "supergroup" HCMV variants among vaccine recipients, suggesting that the gB1 genotype vaccine construct may have elicited partial protection against HCMV viruses with antigenically-similar gB sequences. These findings suggest that gB immunization had a measurable impact on viral intrahost population dynamics and support future analysis of a larger cohort.Importance: Though not a household name like Zika virus, human cytomegalovirus (HCMV) causes permanent neurologic disability in one newborn child every hour in the United States - more than Down syndrome, fetal alcohol syndrome, and neural tube defects combined. There are currently no established effective measures to prevent viral transmission to the infant following HCMV infection of a pregnant mother. However, the gB/MF59 vaccine, which aims to prevent pregnant women from acquiring HCMV, is the most successful HCMV vaccine tested clinically to date. Here, we used viral DNA isolated from patients enrolled in a gB vaccine trial who acquired HCMV, and identified several impacts that this vaccine had on the size, distribution, and composition of the in vivo viral population. These results have increased our understanding of why the gB/MF59 vaccine was partially efficacious, and such investigations will inform future rational design of a vaccine to prevent congenital HCMV. PMID- 30518647 TI - Inhibition of DNA-sensing pathway by Marek's disease virus VP23 protein through suppression of interferon regulatory factor 7 activation. AB - The type I interferon (IFN) response is the first line of host innate immune defense against viral infection; however, viruses have developed multiple strategies to antagonize host IFN responses for efficient infection and replication. Here, we report that Marek's disease virus (MDV), an oncogenic herpesvirus, encodes VP23 protein as a novel immune modulator to block IFN-beta activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) in chicken fibroblasts and macrophages. VP23 overexpression markedly reduces viral DNA-triggered IFN-beta production and promotes viral replication, while knockdown of VP23 during MDV infection enhances the IFN-beta response and suppresses viral replication. VP23 selectively inhibits IFN regulatory factor 7 (IRF7) but not nuclear factor kappaB (NF-kappaB) activation. Furthermore, we found that VP23 interacts with IRF7 and blocks its binding to TANK-binding kinase 1 (TBK1), thereby inhibiting IRF7 phosphorylation and nuclear translocation, resulting in reduced IFN-beta production. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.IMPORTANCE Despite widespread vaccination, Marek's disease (MD) continues to pose major challenges for the poultry industry worldwide. MDV causes immunosuppression and deadly lymphomas in chickens, suggesting that this virus has developed a successful immune evasion strategy. However, little is known regarding the initiation and modulation of the host innate immune response during MDV infection. This study demonstrates that the cGAS-STING DNA-sensing pathway is critical for the induction of the IFN-beta response against MDV infection in chicken fibroblasts and macrophages. An MDV protein, VP23, was found to efficiently inhibit the cGAS-STING pathway. VP23 selectively inhibits IRF7 but not NF-kappaB activation. VP23 interacts with IRF7 and blocks its binding to TBK1, thereby suppressing IRF7 activation and resulting in inhibition of the DNA-sensing pathway. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response. PMID- 30518648 TI - HDAC6 restricts influenza A virus by deacetylation of the RNA polymerase PA subunit. AB - The life cycle of the influenza A virus (IAV) is modulated by various cellular host factors. Although earlier studies indicated that IAV infection is controlled by HDAC6, the deacetylase involved in the regulation of PA remained unknown. Here, we demonstrated that HDAC6 acts as a negative regulator of IAV infection through destabilizing PA. HDAC6 binds to and deacetylates PA, thereby promoting the proteasomal degradation of PA. Through mass spectrometric analysis, Lys(664) of PA can be deacetylated by HDAC6 and this residue is crucial for PA protein stability. The deacetylase activity of HDAC6 is required for anti-IAV activity, because IAV infection was enhanced due to elevated IAV RNA polymerase activity upon HDAC6 depletion and HDAC6 deacetylase dead mutant (HDAC6-DM, H216A;H611A). Finally, we also demonstrated that overexpression of HDAC6 suppresses the IAV RNA polymerase activity, but HDAC6-DM does not. Taken together, our findings provide the initial evidence that HDAC6 plays a negative role in IAV RNA polymerase activity via deacetylating PA and thus restricts IAV RNA transcription and replication.IMPORTANCE Influenza A virus (IAV) continues to threat global public health due to drug resistance and the emergency of frequently mutated strains of IAV. Thus, it is critical to find new strategies to control IAV infection. Here we discovered one host protein, HDAC6, which can inhibit viral RNA polymerase activity through deacetylating PA and thus suppresses virus RNA replication and transcription. Previously, it was reported that IAV can utilize the HDAC6 dependent aggresome formation mechanism to promote virus uncoating, but HDAC6 mediated deacetylation ofalpha-tubulin inhibits viral protein trafficking at late stages of the virus life cycle. These findings together will contribute to a better understanding of the role of HDAC6 in regulating IAV infection. Understanding the molecular mechanisms of HDAC6 in various periods of viral infection may illuminate novel strategies for developing antiviral drugs. PMID- 30518649 TI - The Need for Speed: Run-On Oligomer Filament Formation Provides Maximum Speed with Maximum Sequestration of Activity. AB - Herein we investigate an unusual anti-viral mechanism developed in the bacterium Streptomyces griseus SgrAI is a type II restriction endonuclease which forms run on oligomer filaments when activated, and which possesses both accelerated DNA cleavage activity and expanded DNA sequence specificity. Mutations disrupting the run-on oligomer filament eliminate the robust anti-phage activity of wild type SgrAI, and the observation that even relatively modest disruptions completely abolish this anti-viral activity shows that the greater speed imparted by the run on oligomer filament mechanism is critical to its biological function. Simulations of DNA cleavage by SgrAI uncover the origins of the kinetic advantage of this newly described mechanism of enzyme regulation over more conventional mechanisms, as well as the origin of the sequestering effect responsible for the protection of the host genome against the damaging DNA cleavage activity of activated SgrAI.IMPORTANCE This work is motivated by the interest in understanding the characteristics and advantages of a relatively newly discovered enzyme mechanism involving filament formation. SgrAI is an enzyme responsible for protecting against viral infections in its host bacterium, and was one of the first such enzymes shown to utilize such a mechanism. In this work, filament formation by SgrAI is disrupted and the effects on the speed of the purified enzyme as well as its function in cells are measured. It was found that even small disruptions, which weaken but do not destroy filament formation, eliminate the ability of SgrAI to protect cells from viral infection, its normal biological function. Simulations of enzyme activity were also performed and show how filament formation can greatly speed up an enzyme's activation compared to other known mechanisms, as well as better localize its action to molecules of interest such as invading phage DNA. PMID- 30518650 TI - The Herpesviridae conserved multifunctional infected cell protein 27 (ICP27) is important, but not required for replication and oncogenicity of Marek's disease alphaherpesvirus (MDV). AB - The Herpesviridae conserved infected cell protein 27 (ICP27) is essential for cell culture-based replication of most herpesviruses studied. For members of the Alphaherpesvirinae, ICP27 regulates the expression of many viral genes, including expression of pUL44 (gC), pUL47 (VP13/14), and pUL48 (VP16). These three viral proteins are dysregulated during Marek's disease alphaherpesvirus (MDV) replication in cell culture. MDV replicates in a highly cell-associated manner in cell culture, producing little to no infectious virus. In contrast, infectious cell-free MDV is produced in specialized feather follicle epithelial (FFE) cells of infected chickens where expression of these three genes are abundantly expressed. This led us to hypothesize that MDV ICP27, encoded by gene UL54, is a defining factor for the dysregulation of gC, pUL47, and pUL48 and ultimately, ineffective virus production in cell culture. To address ICP27's role in MDV replication, we generated recombinant MDV with ICP27 deleted (vDelta54). Interestingly, vDelta54 replicated, but plaque sizes were significantly reduced compared to parental viruses. The reduced cell-to-cell spread was due to ICP27 since plaque sizes were restored in rescued viruses, as well as when vDelta54 was propagated in cells expressing ICP27 in trans In chickens, vDelta54 replicated, induced disease, and was oncogenic, but was unable to transmit from chicken-to chicken. To our knowledge, this is the first report in which the Herpesviridae conserved ICP27 protein is dispensable for replication and disease induction in its natural host.IMPORTANCE Marek's disease (MD) is a devastating oncogenic disease that affects the poultry industry and is caused by MD alphaherpesvirus (MDV). Current vaccines block induction of disease, but do not block chicken-to chicken transmission. There is a knowledge gap in our understanding of how MDV spreads from chicken-to-chicken. Here, we studied the Herpesviridae conserved ICP27 regulatory protein in cell culture and during MDV infection in chickens. We determined MDV ICP27 is important, but not required for replication in both cell culture and chickens. In addition, MDV ICP27 was not required for disease induction or oncogenicity, but was required for chicken-to-chicken transmission. This study is important because it addresses the role of ICP27 during infection in the natural host and provides important information for the development of therapies to protect chickens against MD. PMID- 30518651 TI - Hemagglutinin stalk-reactive antibodies interfere with influenza virus neuraminidase activity by steric hindrance. AB - Hemagglutinin (HA) stalk-reactive antibodies are the basis of several current "one-shot" universal influenza vaccine efforts because they protect against a wide spectrum of influenza virus strains. The appreciated mechanism of protection by HA-stalk antibodies is to inhibit HA stalk reconfiguration, blocking viral fusion and entry. This study shows that HA stalk-reactive antibodies also inhibit neuraminidase (NA) enzymatic activity, prohibiting viral egress. NA inhibition (NI) is evident for an attached substrate but not for unattached small molecule cleavage of sialic acid. This suggests that the antibodies inhibit NA enzymatic activity through steric hindrance, thus limiting NA access to sialic acids when adjacent to HA on whole virions. Consistently, F(ab')2 fragments that occupy reduced area without loss of avidity or disrupted HA/NA interactions show significantly reduced NI activity. Notably, HA stalk binding antibodies lacking NI activity were unable to neutralize viral infection via microneutralization assays. This work suggests that NI activity is an important component of HA-stalk antibody mediated protection.IMPORTANCE This study reports a new mechanism of protection that is mediated by influenza hemagglutinin-stalk reactive antibodies: inhibition of neuraminidase activity by steric hindrance, blocking access of neuraminidase to sialic acids when it is abutted next to hemagglutinin on whole virions. PMID- 30518652 TI - Spatio-temporal differences in presentation of CD8 T cell epitopes during HBV infection. AB - Distinct populations of hepatocytes infected with HBV or only harboring HBV-DNA integrations coexist within an HBV chronically infected liver. These hepatocytes express HBV antigens at different levels and with different intracellular localizations but it is not known whether this heterogeneity of viral antigen expression could result in an uneven hepatic presentation of distinct HBV epitopes/HLA class-I complexes triggering different level of activation of HBV specific CD8+ T cells.Using antibodies specific to two distinct HLA-A*02:01/HBV epitope complexes of HBV nucleocapsid and envelope proteins, we mapped their topological distribution in liver biopsies of two anti-HBe+ chronic HBV (CHB) patients. We demonstrated that the core and envelope CD8+T cell epitopes were not uniformly distributed in the liver parenchyma but preferentially located in distinct and sometimes mutually exclusive hepatic zones. The efficiency of HBV epitope presentation was then tested in vitro utilizing HLA-A*02:01/HBV epitope specific antibodies and the corresponding CD8+ T cells, in primary human hepatocyte and hepatoma cell lines either infected with HBV or harboring HBV-DNA integration. We confirmed the existence of a marked variability in the efficiency of HLA-class I/HBV epitope presentation among the different targets that was influenced by presence of IFN-gamma and availability of newly-translated viral antigens. In conclusion, HBV antigen presentation can be heterogeneous within an HBV-infected liver. As a consequence, CD8+ T cells of different HBV specificities might have different antiviral efficacy.Importance The inability of patients with chronic HBV infection to clear HBV is associated with defective HBV-specific CD8+ T cells. Hence, the majority of immunotherapy developments focus on HBV specific T cell function restoration. However, knowledge of whether distinct HBV-specific T cells can equally target all the HBV-infected hepatocytes of a chronically infected liver are lacking. In this work, analysis of CHB patient liver parenchyma and in vitro HBV infection models shows a non-uniform distribution of HBV CD8+ T cells epitopes that is influenced by presence of IFN-gamma and availability of newly-translated viral antigens. These results suggest that CD8+ T cells recognizing different HBV epitopes can be necessary for efficient immune therapeutic control of chronic HBV infection. PMID- 30518653 TI - CRISPR/Cas9-mediated knock-out of DNAJC14 verifies this chaperone as a pivotal host factor for RNA replication of Pestiviruses. AB - Pestiviruses like bovine viral diarrhea virus (BVDV) are a thread to livestock. For pestiviruses cytopathogenic (cp) and non-cytopathogenic (noncp) strains are distinguished in cell culture. The noncp biotype of BVDV is capable of establishing persistent infections which is a major problem in disease control. The noncp biotype rests on temporal control of viral RNA replication, mediated by regulated cleavage of nonstructural protein 2-3 (NS2-3). This cleavage is catalyzed by the autoprotease in NS2 which depends in its activity on its cellular cofactor DNAJC14. Since this chaperone is available in low amounts and binds tightly to NS2, NS2-3 translated later in infection is no longer cleaved. As NS3 is an essential constituent of the viral replicase, this shift in polyprotein processing correlates with downregulation of RNA replication. In contrast, cpBVDV strains arising mostly by RNA recombination, show highly variable genome structures and display unrestricted NS3 release. The functional importance of DNAJC14 for noncp pestiviruses was established so far only for BVDV 1. It was therefore enigmatic whether replication of other noncp pestiviruses is also DNAJC14-dependent. By generating bovine and porcine DNAJC14 knock-out cells we could show that (i) replication of 6 distinct noncp pestivirus species (A-D, F and G) depends on DNAJC14; (ii) the pestiviral replicase NS3-5B can assemble into functional complexes in the absence of DNAJC14; (iii) all cp pestiviruses replicate their RNA and generate infectious progeny independent of host DNAJC14. Together, these findings confirm DNAJC14 as pivotal cellular cofactor for the replication and maintenance of the noncp biotype of pestiviruses.IMPORTANCE Only non-cytopathogenic (noncp) pestivirus strains are capable of establishing life long persistent infections to generate the virus reservoir in the field. The molecular basis for this biotype is only partially understood and only investigated in depth for BVDV-1 strains. Temporal control of viral RNA replication correlates with the noncp biotype and is mediated by limiting amounts of cellular DNAJC14 that activates the viral NS2 protease to catalyze the release of the essential replicase component NS3. Here we demonstrate that several species of noncp pestiviruses depend in their RNA replication on DNAJC14. Moreover, all cp pestiviruses, in sharp contrast to their noncp counterparts, replicate independently of DNAJC14. The generation of a cp BVDV in the persistently infected animal is causative for onset of mucosal disease. Therefore, the observed strict biotype-specific difference in DNAJC14-dependency should be further examined for its role in cell type/tissue tropism and the pathogenesis of this lethal disease. PMID- 30518654 TI - Directed Nucleosome Sliding in SV40 Minichromosomes During the Formation of the Virus Particle Exposes DNA Sequences Required for Early Transcription. AB - Simian Virus 40 (SV40) exists as chromatin throughout its life cycle, and undergoes typical epigenetic regulation mediated by changes in nucleosome location and associated histone modifications. In order to investigate the role of epigenetic regulation during the encapsidation of late stage minichromosomes into virions, we have mapped the location of nucleosomes containing acetylated or methylated lysines in the histone tails of H3 and H4 present in the chromatin from 48-hour post-infection minichromosomes and disrupted virions. In minichromosomes obtained late in infection, nucleosomes were found carrying various histone modifications primarily in the regulatory region with a major nucleosome located within the enhancer and other nucleosomes at the early and late transcriptional start sites. The nucleosome found in the enhancer would be expected to repress early transcription by blocking access to part of the SP1 binding sites and the left side of the enhancer in late stage minichromosomes while also allowing late transcription. In chromatin from virions, the principal nucleosome located in the enhancer was shifted ~ 70 bases in the late direction from what was found in minichromosomes and the level of modified histones was increased throughout the genome. The shifting of the enhancer-associated nucleosome to the late side would effectively serve as a switch to relieve the repression of early transcription found in late minichromosomes while likely also repressing late transcription by blocking access to necessary regulatory sequences. This epigenetic switch appeared to occur during the final stage of virion formation.IMPORTANCE For a virus to complete an infection, it must produce a new virus particle in which the genome is able to support a new infection. This is particularly important for viruses like Simian Virus 40 (SV40) which exist as chromatin throughout their life cycle, since chromatin structure plays a major role in the regulation of their life cycle. In order to determine the role of SV40 chromatin structure late in infection, we have mapped the location of nucleosomes and their histone tail modifications in SV40 minichromosomes and in the SV40 chromatin found in virions using ChIP-Seq. We have identified a novel viral transcriptional control mechanism in which a nucleosome found in the regulatory region of SV40 minichromosome is directed to slide during the formation of the virus particle exposing transcription factor binding sites required for early transcription that were previously blocked by the presence of the nucleosome. PMID- 30518655 TI - ANTIBODY-MEDIATED PROTECTIVE MECHANISMS INDUCED BY A TRIVALENT PARAINFLUENZA VECTORED EBOLAVIRUS VACCINE. AB - Ebolaviruses Zaire (EBOV), Bundibugyo (BDBV) and Sudan (SUDV) cause human disease with high case fatality rates. Experimental monovalent vaccines, which all utilize the sole envelope glycoprotein (GP), do not protect against heterologous ebolaviruses. Human parainfluenza virus type 3-vectored vaccines offer benefits including needle-free administration and induction of mucosal responses in the respiratory tract. Multiple approaches were taken to induce a broad protection against the three ebolaviruses. While GP consensus-based antigens failed to elicit neutralizing antibodies, polyvalent immunization induced neutralizing responses to all three ebolaviruses and protected animals from death and disease caused by EBOV, SUDV and BDBV. As immunization with a cocktail of antigenically related antigens can skew the responses and change the epitope hierarchy, we performed comparative analysis of antibody repertoire and Fc-mediated protective mechanisms in animals immunized with monovalent versus polyvalent vaccines. Compared to the monovalent vaccines, sera from trivalent vaccinated guinea pigs bound and neutralized EBOV and SUDV at equivalent levels and BDBV at only slightly reduced level. Peptide microarrays revealed a preponderance of binding to amino acids 389-403, 397-415 and 477-493, representing three linear epitopes in the mucin-like domain known to induce a protective antibody response. Competition binding assays with monoclonal antibodies isolated from human ebolavirus survivors demonstrated that the immune sera block binding of antibodies specific for the GP glycan cap, GP1-GP2 interface, the mucin-like domain, and the membrane-proximal external region. Thus, cocktail administration of three ebolavirus vaccines induces a desirable broad antibody response, without skewing of the response toward preferential recognition of a single virus.IMPORTANCE Symptoms of the disease caused by ebolaviruses Ebola, Bundibugyo and Sudan are similar, and their endemic areas overlap. However, because of the limited antigenic relatedness of ebolavirus glycoprotein (GP) used in all candidate vaccines against these viruses, they protect only against homologous but not heterologous ebolaviruses. Therefore, a broadly specific pan-ebolavirus vaccine is required, which might be achieved by administration of a cocktail of vaccines. The effects of cocktail administration of ebolavirus vaccines on the antibody repertoire remain unknown. Here in-depth analysis of the antibody responses to cocktail administration of human parainfluenza type 3-vectored vaccines against individual ebolaviruses was performed, which included analysis of binding to GP, neutralization of individual ebolaviruses, epitope specificity, Fc-mediated functions, and protection against the three ebolaviruses. The results demonstrated potent and balanced responses against individual ebolaviruses and no significant reduction of the responses, compared to that induced by individual vaccines. PMID- 30518656 TI - Human papillomavirus 16 E2 regulates keratinocyte gene expression relevant to cancer and the viral life cycle. AB - Human papillomaviruses (HPV) are causative agents in ano-genital and oropharyngeal cancers. The virus must reprogram host gene expression to promote infection, and E6 and E7 contribute to this via targeting of cellular transcription factors including p53 and pRb, respectively. The HPV16 E2 protein regulates host gene expression in U2OS cells and in this study we extend these observations into TERT immortalized oral keratinocytes (NOKs) that are capable of supporting late stages of the HPV16 life cycle. We observed repression of innate immune genes by E2 that are also repressed by the intact HPV16 genome in NOKs. RNA-seq data identified 167 up and 395 downregulated genes by E2; there was a highly significant overlap of the E2 regulated genes with those regulated by the intact HPV16 genome in the same cell type. siRNA targeting of E2 reversed repression of E2 targeted genes. The ability of E2 to repress innate immune genes was confirmed in an ano-genital immortalized keratinocyte cell line, N/Tert-1. We present analysis of data from The Cancer Genome Atlas (TCGA) for HPV16 positive and negative head and neck cancers (HNC) suggesting that E2 plays a role in regulation of the host genome in cancers. Patients with HPV16 positive HNC with a loss of E2 expression exhibit a worse clinical outcome and we discuss how this could, at least partially, be related to the loss of E2 host gene regulation.IMPORTANCE HPV16 positive tumors that retain expression of E2 have a better clinical outcome than those that have lost E2 expression. It has been suggested that this is due to a loss of E2 repression of E6 and E7 expression but this is not supported by data from tumors where there is not more E6 and E7 expression in the absence of E2. Here we report that E2 regulates host gene expression and place this regulation in context of the HPV16 life cycle and HPV16 positive head and neck cancers (the majority of which retain E2 expression). We propose that this E2 function may play an important part in the increased response of HPV16 positive cancers to radiation therapy. Therefore, host gene regulation by E2 may be important for promotion of the HPV16 life cycle, and also for the response of HPV16 positive tumors to radiation therapy. PMID- 30518657 TI - Serotonin receptors of 5-HT2 type in the hypothalamic arcuate nuclei (ARC) positively regulate liver cytochrome P450 via stimulation of the growth hormone releasing hormone - growth hormone (GHRH-GH) hormonal pathway. AB - Our recent study carried out after local injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine into the arcuate nuclei (ARC) of the hypothalamus suggested a positive influence of the serotonergic innervation of the ARC on growth hormone secretion and growth hormone-dependent expression of cytochrome P450. The aim of our present study was to determine the effect of the activation of the 5-HT1 or 5-HT2 type receptors in the ARC on the expression and activity of cytochrome P450 in the liver of male rats. The serotonergic agonists 5-CT (5 carboxyamidotryptamine, a 5-HT1 type receptor agonist) or DOI (2,5-dimethoxy-4 iodoamphetamine, a 5-HT2 type receptor agonist) were injected into the ARC for 5 days. The activity and expression of cytochrome P450 isoenzymes and the levels of serum and pituitary hormones were estimated. DOI significantly increased the activity and expression (both mRNA and protein levels) of CYP2C11, CYP3A1/23 and CYP3A2, which positively correlated with an increase in the pituitary GHRH and serum growth hormone level. The injection of 5-CT into the ARC did not affect the activity of liver CYP isoenzymes or hormone levels. The obtained results indicate that 5-HT2, but not the 5-HT1 type receptors in the ARC, are engaged in the positive neuroendocrine regulation of cytochrome P450, possibly by the stimulation of hypothalamic GHRH release and pituitary GH secretion, and an increase in the serum growth hormone concentration. Further studies are going to identify which of the 5-HT2 receptor subtypes (5-HT2A, 5-HT2B or 5-HT2C) is responsible for the observed neuroendocrine regulation of cytochrome P450. PMID- 30518658 TI - Mycobacteria exploit nitric oxide-induced transformation of macrophages into permissive giant cells. PMID- 30518659 TI - Structural and functional analysis of the GABARAP interaction motif (GIM). PMID- 30518660 TI - The National Glycohemoglobin Standardization Program: Over 20 Years of Improving Hemoglobin A1c Measurement. AB - BACKGROUND: Measurement of hemoglobin A1c (HbA1c) in the blood is integral to and essential for the treatment of patients with diabetes mellitus. HbA1c reflects the mean blood glucose concentration over the preceding 8 to 12 weeks. Although the clinical value of HbA1c was initially limited by large differences in results among various methods, the investment of considerable effort to implement standardization has brought about a marked improvement in analysis. CONTENT: The focus of this review is on the substantial progress that has been achieved in enhancing the accuracy and, therefore, the clinical value of HbA1c assays. SUMMARY: The interactions between the National Glycohemoglobin Standardization Program and manufacturers of HbA1c methods have been instrumental in standardizing HbA1c. Proficiency testing using whole blood has allowed accuracy based assessment of methods in individual clinical laboratories that has made an important contribution to improving the HbA1c measurement in patient samples. These initiatives, supported by the efforts of the IFCC network, have led to a continuing enhancement of HbA1c methods.Many of the factors that previously influenced HbA1c results independently of blood glucose have been eliminated from most modern methods. These include carbamylation, labile intermediates, and common hemoglobin variants. Nevertheless, some factors (e.g., race and aging) may alter HbA1c interpretation, but whether these differences have clinical implications remains contentious. HbA1c has a fundamental role in the diagnosis and management of diabetes. Ongoing improvements in HbA1c measurement and quality will further enhance the clinical value of this analyte. PMID- 30518661 TI - Low-Grade Inflammation in the Association Between Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis: A Study of More Than 115000 Individuals from the General Population. AB - BACKGROUND: How mild-to-moderate hypertriglyceridemia (2-10 mmol/L; 177-886 mg/dL) potentially causes acute pancreatitis is unknown; however, cellular studies indicate that inflammation might be a driver of disease progression. We tested the hypotheses that (a) mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and that (b) the association between mild to-moderate hypertriglyceridemia and risk of acute pancreatitis depends on low grade inflammation. METHODS: From the Copenhagen General Population Study and the Copenhagen City Heart Study, 117865 men and women 20-100+ years of age with measurements of nonfasting plasma triglycerides at baseline were followed prospectively for development of acute pancreatitis. RESULTS: After multivariable adjustment, a 1 mmol/L (89 mg/dL) higher nonfasting triglyceride concentration was associated with 17% (95% CI, 16%-18%, P = 3 * 10-17) higher plasma C-reactive protein (CRP) and a 4.2% (4.0%-4.4%, P = 6 * 10-17) higher blood leukocyte count. Higher concentrations of nonfasting triglycerides were associated almost linearly with higher risk of acute pancreatitis (P for trend = 5 * 10-6), with hazard ratios of 1.5 (95% CI, 0.9-2.5), 2.0 (95% CI, 1.1-3.6), 2.2 (95% CI, 1.0-4.7), 4.2 (95% CI, 1.6-11.5), and 7.7 (95% CI, 3.0-19.8) in individuals with nonfasting triglycerides of 1.00-1.99 mmol/L (89-176 mg/dL; 46% of the population), 2.00 2.99 mmol/L (177-265 mg/dL; 17%), 3.00-3.99 mmol/L (266-353 mg/dL; 6%), 4.00-4.99 mmol/L (354-442 mg/dL; 2%), and >=5mmol/L(443 mg/dL; 2%), respectively, vs individuals with <1 mmol/L (89 mg/dL; 27%). The association with risk of acute pancreatitis appeared more pronounced in individuals with CRP of >=1.39 mg/L (P for trend = 0.001) and leukocytes of >=7 * 109/L (P = 2 * 10-4) than in those with CRP <1.39 mg/L (P = 0.03) and leukocytes <7 * 109/L (P = 0.04); however, there was no formal evidence of statistical interaction (P = 0.38 for CRP and P = 0.41 for leukocytes). CONCLUSIONS: Mild-to-moderate hypertriglyceridemia is associated with low-grade inflammation and higher risk of acute pancreatitis. The association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis is possibly partly mediated by low-grade inflammation. PMID- 30518662 TI - Inflammatory Biomarkers and Clinical Judgment in the Emergency Diagnosis of Urgent Abdominal Pain. AB - BACKGROUND: The early diagnosis of urgent abdominal pain (UAP) is challenging. Most causes of UAP are associated with extensive inflammation. Therefore, we hypothesized that quantifying inflammation using interleukin-6 and/or procalcitonin would provide incremental value in the emergency diagnosis of UAP. METHODS: This was an investigator-initiated prospective, multicenter diagnostic study enrolling patients presenting to the emergency department (ED) with acute abdominal pain. Clinical judgment of the treating physician regarding the presence of UAP was quantified using a visual analog scale after initial clinical and physician-directed laboratory assessment, and again after imaging. Two independent specialists adjudicated the final diagnosis and the classification as UAP (life-threatening, needing urgent surgery and/or hospitalization for acute medical reasons) using all information including histology and follow-up. Interleukin-6 and procalcitonin were measured blinded in a central laboratory. RESULTS: UAP was adjudicated in 376 of 1038 (36%) patients. Diagnostic accuracy for UAP was higher for interleukin-6 [area under the ROC curve (AUC), 0.80; 95% CI, 0.77-0.82] vs procalcitonin (AUC, 0.65; 95% CI, 0.62-0.68) and clinical judgment (AUC, 0.69; 95% CI, 0.65-0.72; both P < 0.001). Combined assessment of interleukin-6 and clinical judgment increased the AUC at presentation to 0.83 (95% CI, 0.80-0.85) and after imaging to 0.87 (95% CI, 0.84-0.89) and improved the correct identification of patients with and without UAP (net improvement in mean predicted probability: presentation, +19%; after imaging, +15%; P < 0.001). Decision curve analysis documented incremental value across the full range of pretest probabilities. A clinical judgment/interleukin-6 algorithm ruled out UAP with a sensitivity of 97% and ruled in UAP with a specificity of 93%. CONCLUSIONS: Interleukin-6 significantly improves the early diagnosis of UAP in the ED. PMID- 30518663 TI - Impact of Hormone Therapy on Laboratory Values in Transgender Patients. AB - BACKGROUND: For transgender individuals taking hormone therapy (HT), data on laboratory values are limited, and the effects on laboratory values cannot be easily predicted. We evaluated the impact on common laboratory analytes in transgender individuals before and after initiation of HT. METHODS: We conducted a retrospective chart review of transgender patients identified at transgender specific clinics at an urban county hospital and community clinic. Laboratory data were collected on hormone concentrations, hematologic parameters, electrolytes, lipids, and liver and renal markers before and after initiation of HT. RESULTS: We identified 183 transgender women (TW) and 119 transgender men (TM) for whom laboratory data were available. In all, 87 TW and 62 TM had baseline laboratory data, and data were also available for 133 TW and 89 TM on HT for >6 months. The most significant changes were seen in red blood cell count, hemoglobin concentration, hematocrit, and creatinine levels after >6 months of HT, which increased in TM and decreased in TW after HT (P < 0.005; d index > 0.6). Alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels increased in TM; however, the effect size was small (d index < 0.5). Calcium, albumin, and alkaline phosphatase levels significantly decreased in TW (P < 0.001; d > 0.6). Additionally, TM were found to have increased triglycerides and decreased HDL levels (P < 0.005; d > 0.6). CONCLUSIONS: Changes occur in several common laboratory parameters for patients on HT. Some laboratory values changed to match the gender identity, whereas others remained unchanged or were intermediate from the baseline values. These findings will help guide interpretation of laboratory test results in transgender patients taking HT. PMID- 30518664 TI - Clinical Microbiology Is Growing Up: The Total Laboratory Automation Revolution. AB - BACKGROUND: Historically, culture-based microbiology laboratory testing has relied on manual methods, and automated methods (such as those that have revolutionized clinical chemistry and hematology over the past several decades) were largely absent from the clinical microbiology laboratory. However, an increased demand for microbiology testing and standardization of sample collection devices for microbiology culture, as well as a dwindling supply of microbiology technologists, has driven the adoption of automated methods for culture-based laboratory testing in clinical microbiology. CONTENT: We describe systems currently enabling total laboratory automation (TLA) for culture-based microbiology testing. We describe the general components of a microbiology automation system and the various functions of these instruments. We then introduce the 2 most widely used systems currently on the market: Becton Dickinson's Kiestra TLA and Copan's WASPLab. We discuss the impact of TLA on metrics such as turnaround time and recovery of microorganisms, providing a review of the current literature and perspectives from laboratory directors, managers, and technical staff. Finally, we provide an outlook for future advances in TLA for microbiology with a focus on artificial intelligence for automated culture interpretation. SUMMARY: TLA is playing an increasingly important role in clinical microbiology. Although challenges remain, TLA has great potential to affect laboratory efficiency, turnaround time, and the overall quality of culture based microbiology testing. PMID- 30518665 TI - Somatic Structural Alterations in Childhood Leukemia Can Be Backtracked in Neonatal Dried Blood Spots by Use of Whole-Genome Sequencing and Digital PCR. PMID- 30518666 TI - Adding the Team into T1 Translational Research: A Case Study of Multidisciplinary Team Science in the Evaluation of Biomarkers of Prostate Cancer Risk and Prognosis. AB - BACKGROUND: Given translational research challenges, multidisciplinary team science is promoted to increase the likelihood of moving from discovery to health effect. We present a case study documenting the utility of multidisciplinary team science in prostate cancer tissue biomarker validation. METHODS: We used primary data generated by a team consisting of a pathologist, cancer biologists, a biostatistician, and epidemiologists. We examined their contributions by phase of biomarker evaluation to identify when, through the practice of team science, threats to internal validity were recognized and solved. Next, we quantified the extent of bias avoided in evaluating the association of Ki67 (immunohistochemistry), stromal cell telomere length (fluorescence in situ hybridization), and microRNA (miRNA) (miR-21, miR-141, miR-221; quantitative RT PCR) with prostate cancer risk or recurrence in nested case-control studies. RESULTS: Threats to validity were tissue storage time (Ki67, miRNA) and laboratory equipment maintenance (telomeres). Solutions were all in the data analysis phase and involved using tissue storage-time specific cutpoints and/or batch-specific cutpoints. Bias in the regression coefficient for quantiles of each biomarker ranged from 24% to 423%, and the coefficient for the test for trend ranged from 15% to 910%. The interpretation of the associations changed as follows: Ki67, null to positive; stromal cell telomere length, null to positive; miR-21 and miR-141 remained null; miR-221, weak to moderate inverse. CONCLUSIONS: In this case study, we documented the inferential benefits of multidisciplinary team science when the team's collaboration and coordination led to the identification of threats to validity and the implementation of appropriate solutions. PMID- 30518667 TI - Single-dose fosfomycin is less effective than 5-day nitrofurantoin in women with uncomplicated urinary tract infection: closing the evidence gap for a new recommendation of an old antibiotic. PMID- 30518668 TI - Optimal anticoagulant treatment of cancer-associated venous thromboembolism remains unclear. PMID- 30518669 TI - Pivmecillinam is more effective than ibuprofen in symptom resolution in women with uncomplicated urinary tract infection: antibiotic treatment for UTI is important. PMID- 30518670 TI - Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants. AB - BACKGROUND: Although caffeine use for apnea of prematurity is well studied, the long-term safety and benefit of routine early caffeine administration has not been explored. Our objective was to determine the association between early (within 2 days of birth) versus late caffeine exposure and neurodevelopmental outcomes in preterm infants. METHODS: Infants of <29 weeks' gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network units and then assessed at Canadian Neonatal Follow-up Network centers were studied. Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months' corrected age. RESULTS: Of 2108 neonates who were eligible, 1545 were in the early-caffeine group and 563 were in the late-caffeine group. Rates of bronchopulmonary dysplasia, patent ductus arteriosus, and severe neurologic injury were lower in the early-caffeine group than in the late-caffeine group. Significant neurodevelopmental impairment (adjusted odds ratio 0.68 [95% confidence interval 0.50-0.94]) and odds of Bayley Scales of Infant and Toddler Development, Third Edition cognitive scores of <85 (adjusted odds ratio 0.67 [95% confidence interval 0.47-0.95]) were lower in the early-caffeine group than in the late-caffeine group. Propensity score-based matched-pair analyses revealed lower odds of cerebral palsy and hearing impairment only. CONCLUSIONS: Early caffeine therapy is associated with better neurodevelopmental outcomes compared with late caffeine therapy in preterm infants born at <29 weeks' gestation. PMID- 30518671 TI - Use of Social Psychology to Improve Adherence to National Bronchiolitis Guidelines. AB - OBJECTIVES: The American Academy of Pediatrics' bronchiolitis guidelines recommend against albuterol and corticosteroids for treating and chest radiographs (CRs) for diagnosing infants with bronchiolitis. However, high rates of nonadherence have been documented. Our objective was to improve guideline adherence in infants with bronchiolitis. METHODS: This quality improvement study was conducted in 1 urban academic pediatric primary care clinic caring for predominately minority and publicly insured children. We tested provider guideline education, display of guidelines in patient care areas, and monthly e mails to all providers documenting deviation rates, with individual e-mails to providers who deviated. P-charts and interrupted time series analysis were used to estimate the effect of the intervention. RESULTS: There were 380 children <2 years of age with a diagnosis of bronchiolitis in the 16 nonsummer months preintervention and 417 in the 15 postintervention months. Rates of prescribed and administered albuterol declined from 45.7% in the baseline period to 13.7% in the intervention period and CR use dropped from a mean of 10.1% to 3.4%, both demonstrating special cause variation. Steroid use did not change significantly. In interrupted time series analyses, the intervention was associated with a significant decrease in albuterol use (P < .001) but not in CR or steroid use. Emergency department visits declined slightly but admissions for bronchiolitis were stable. CONCLUSIONS: Traditional quality improvement efforts coupled with social psychology techniques resulted in improved guideline adherence in outpatient bronchiolitis management. Additional study will help identify which techniques are most effective for increasing guideline adherence in cases of low value care. PMID- 30518673 TI - A methyltransferase trio essential for phosphatidylcholine biosynthesis and growth. AB - Phosphatidylcholine (PC) is a primary class of membrane lipids in most eukaryotes. In plants, the primary PC biosynthetic pathway and its role in plant growth and development remain elusive due to lack of a mutant model with substantially decreased PC content. Recently, a double mutant of Arabidopsis (Arabidopsis thaliana) PHOSPHO-BASE N-METHYLTRANSFERASE 1 (PMT1) and PMT3 was reported with reduced PC content and defective plant growth. However, residual PC content as well as the non-lethal phenotype of the mutant suggests an additional enzyme contributes to PC biosynthesis. Here, we report on the role of three PMTs in PC biosynthesis and plant development, with a focus on PMT2. PMT2 had the highest expression level among the three PMTs, and was highly expressed in roots. The pmt1 pmt2 double mutant enhanced the defects in root growth, cell viability, and PC content of pmt1, suggesting that PMT2 functions together with PMT1 in roots. Chemical inhibition of PMT activity in wild-type roots reproduced the short root phenotype observed in pmt1 pmt2, suggesting that PMT1 and PMT2 are the major PMT isoforms in roots. In shoots, pmt1 pmt2 pmt3 enhanced the phenotype of pmt1 pmt3, showing seedling lethality and further reduced PC content without detectable de novo PC biosynthesis. These results suggest that PMTs catalyze an essential reaction step in PC biosynthesis and that the three PMTs have differential tissue-specific functions in PC biosynthesis and plant growth. PMID- 30518672 TI - Cooperative effect of oncogenic MET and PIK3CA in an HGF-dominant environment in breast cancer. AB - There is compelling evidence that oncogenic MET and PIK3CA signaling pathways contribute to breast cancer. However, the activity of pharmacological targeting of either pathway is modest. Mechanisms of resistance to these monotherapies have not been clarified. Currently commonly used mouse models are inadequate for studying the HGF-MET axis because mouse HGF does not bind human MET. We established human HGF-MET paired mouse models. In this study, we evaluated the cooperative effects of MET and PIK3CA in an environment with involvement of human HGF in vivo. Oncogenic MET/PIK3CA synergistically induced aggressive behavior and resistance to each targeted therapy in an HGF-paracrine environment. Combined targeting of MET and PI3K abrogates resistance. Associated cell signaling changes were explored by functional proteomics. Consistently, combined targeting MET and PI3K inhibited activation of associated oncogenic pathways. We also evaluated the response of tumor cells to HGF-stimulation using breast cancer patient-derived xenografts (PDXs). HGF-stimulation induced significant phosphorylation of MET for all PDX lines detected to varying degrees. However, the levels of phosphorylated MET are not correlated with its expression, suggesting that MET expression level cannot be used as a sole criterion to recruit patients to clinical trials for MET targeted therapy. All together, our data suggests that combined targeting of MET and PI3K could be a potential clinical strategy for breast cancer patients, where phosphorylated MET and PIK3CA mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these co-targeted therapy. PMID- 30518674 TI - Novel and conventional approaches for the analysis of quantitative proteomic data are complementary towards the identification of seminal plasma alterations in infertile patients. AB - Our aim was to define seminal plasma proteome signatures of infertile patients categorized according to their seminal parameters using TMT-LC-MS/MS. To that extent, quantitative proteomic data was analyzed following two complementary strategies: (i) the conventional approach based on standard statistical analyses of relative protein quantification values; and (ii) a novel strategy focused on establishing stable-protein pairs. By conventional analyses, the abundance of some seminal plasma proteins was found to be positively correlated with sperm concentration. However, this correlation was not found for all the peptides within a specific protein, bringing to light the high heterogeneity existing in the seminal plasma proteome due to both the proteolytic fragments and/or the post translational modifications. This issue was overcome by conducting the novel stable-protein pairs analysis proposed herein. A total of 182 correlations comprising 24 different proteins were identified in the normozoospermic-control population, while this proportion was drastically reduced in infertile patients with altered seminal parameters (18 in patients with reduced sperm motility, 0 in patients with low sperm concentration and 3 in patients with no sperm in the ejaculate). These results suggest the existence of multiple etiologies causing the same alteration in seminal parameters. Additionally, the repetition of the stable-protein pair analysis in the control group by adding the data from a single patient at a time enabled to identify alterations in the stable-protein pairs profile of individual patients with altered seminal parameters. These results suggest potential underlying pathogenic mechanisms in individual infertile patients, and might open up a window to its application in the personalized diagnostic of male infertility. PMID- 30518675 TI - A Longitudinal Epidemiology Study of Meningococcal Carriage in Students 13 to 25 Years Old in Quebec. AB - Neisseria meningitidis carriage data are necessary to inform serogroup B (NmB) immunization program implementation. This longitudinal study compared detection methods to measure N. meningitidis throat carriage prevalence in Quebec from November 2010 to December 2013 using cultured swab isolates and direct swab PCR from students in ninth grade (aged 13 to 15 years; n = 534) and eleventh grade/college entry (16 to 18 years; n = 363) and in university students in dormitories (18 to 25 years; n = 360) at 3 time points per group. Meningococcal and NmB carriage rates were lower in ninth- and eleventh-grade/college entry students than university students, regardless of methodology. Genotyping cultured isolates by PCR detected NmB and non-NmB in 2.1% and 7.3% of ninth-grade students, in 1.7% and 7.2% of eleventh-grade/college entry students, and in 7.5% and 21.9% of university students, respectively. NmB acquisition rates were 1.9, 0.7, and 3.3 per 1,000 person-months across respective age groups. Most NmB isolates (94.7%, 76.9%, and 86.8%, respectively) expressed subfamily A factor H binding-protein (fHBP) variants. The most common non-NmB serogroups were NmY (1.7%/1.1%) from ninth grade and eleventh grade/college entry and NmW (2.8%) from university students. Genomic analyses detected disease-associated sequence types in carriage isolates, and carriage could persist for months. This is the largest longitudinal carriage study in Canada and the first to report fHBP variants in NmB carriage isolates in healthy Canadians. These data contribute to identification of the optimal window for NmB vaccination in precollege adolescents and provide a baseline for investigating NmB vaccination effects on carriage in this population.IMPORTANCE Disease caused by Neisseria meningitidis is associated with serious complications and a high fatality rate. Asymptomatic individuals can harbor the bacterium in the throat, a state known as "carriage," which can lead to person-to-person spread of the pathogen. This study examined N. meningitidis carriage from 2010 to 2013 among 2 groups in the Quebec City region: ninth-grade students (aged 13 to 15 years), who were also followed in their last year of high school (eleventh grade/college entry; 16 to 18 years), and university students (18 to 25 years); both groups have been shown in some other geographic regions to have high rates of carriage. This study demonstrated that N. meningitidis carriage rates were higher among university students in dormitories than ninth-grade and eleventh-grade/college entry students. Understanding carriage rates in these age groups leads to better strategies to control N. meningitidis by targeting vaccination to those responsible for transmission within the population. PMID- 30518676 TI - Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome. AB - Extensive research shows that dietary variation and toxicant exposure impact the gut microbiome, yielding effects on host physiology. However, prior work has mostly considered such exposure-microbiome interactions through the lens of single-factor exposures. In practice, humans exposed to toxicants vary in their dietary nutritional status, and this variation may impact subsequent exposure of the gut microbiome. For example, chronic arsenic exposure affects 200 million people globally and is often comorbid with zinc deficiency. Zinc deficiency can enhance arsenic toxicity, but it remains unknown how zinc status impacts the gut microbiome's response to arsenic exposure and whether this response links to host toxicity. Using 16S amplicon sequencing, we examined the combinatorial effects of exposure to environmentally relevant concentrations of arsenic on the composition of the microbiome in C57BL/6 mice fed diets varying in zinc concentration. Arsenic exposure and marginal zinc deficiency independently altered microbiome diversity. When combined, their effects on microbiome community structure were amplified. Generalized linear models identified microbial taxa whose relative abundance in the gut was perturbed by zinc deficiency, arsenic, or their interaction. Further, we correlated taxonomic abundances with host DNA damage, adiponectin expression, and plasma zinc concentration to identify taxa that may mediate host physiological responses to arsenic exposure or zinc deficiency. Arsenic exposure and zinc restriction also result in increased DNA damage and decreased plasma zinc. These physiological changes are associated with the relative abundance of several gut taxa. These data indicate that marginal zinc deficiency sensitizes the microbiome to arsenic exposure and that the microbiome associates with some toxicological effects of arsenic.IMPORTANCE Xenobiotic compounds, such as arsenic, have the potential to alter the composition and functioning of the gut microbiome. The gut microbiome may also interact with these compounds to mediate their impact on the host. However, little is known about how dietary variation may reshape how the microbiome responds to xenobiotic exposures or how these modified responses may in turn impact host physiology. Here, we investigated the combinatorial effects of marginal zinc deficiency and physiologically relevant concentrations of arsenic on the microbiome. Both zinc deficiency and arsenic exposure were individually associated with altered microbial diversity and when combined elicited synergistic effects. Microbial abundance also covaried with host physiological changes, indicating that the microbiome may contribute to or be influenced by these pathologies. Collectively, this work demonstrates that dietary zinc intake influences the sensitivity of the microbiome to subsequent arsenic exposure. PMID- 30518677 TI - Regulation of Yeast-to-Hyphae Transition in Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica undergoes a morphological transition from yeast-to hyphal growth in response to environmental conditions. A forward genetic screen was used to identify mutants that reliably remain in the yeast phase, which were then assessed by whole-genome sequencing. All the smooth mutants identified, so named because of their colony morphology, exhibit independent loss of DNA at a repetitive locus made up of interspersed ribosomal DNA and short 10- to 40-mer telomere-like repeats. The loss of repetitive DNA is associated with downregulation of genes with stress response elements (5'-CCCCT-3') and upregulation of genes with cell cycle box (5'-ACGCG-3') motifs in their promoter region. The stress response element is bound by the transcription factor Msn2p in Saccharomyces cerevisiae We confirmed that the Y. lipolytica msn2 (Ylmsn2) ortholog is required for hyphal growth and found that overexpression of Ylmsn2 enables hyphal growth in smooth strains. The cell cycle box is bound by the Mbp1p/Swi6p complex in S. cerevisiae to regulate G1-to-S phase progression. We found that overexpression of either the Ylmbp1 or Ylswi6 homologs decreased hyphal growth and that deletion of either Ylmbp1 or Ylswi6 promotes hyphal growth in smooth strains. A second forward genetic screen for reversion to hyphal growth was performed with the smooth-33 mutant to identify additional genetic factors regulating hyphal growth in Y. lipolytica Thirteen of the mutants sequenced from this screen had coding mutations in five kinases, including the histidine kinases Ylchk1 and Ylnik1 and kinases of the high-osmolarity glycerol response (HOG) mitogen-activated protein (MAP) kinase cascade Ylssk2, Ylpbs2, and Ylhog1 Together, these results demonstrate that Y. lipolytica transitions to hyphal growth in response to stress through multiple signaling pathways.IMPORTANCE Many yeasts undergo a morphological transition from yeast-to-hyphal growth in response to environmental conditions. We used forward and reverse genetic techniques to identify genes regulating this transition in Yarrowia lipolytica We confirmed that the transcription factor Ylmsn2 is required for the transition to hyphal growth and found that signaling by the histidine kinases Ylchk1 and Ylnik1 as well as the MAP kinases of the HOG pathway (Ylssk2, Ylpbs2, and Ylhog1) regulates the transition to hyphal growth. These results suggest that Y. lipolytica transitions to hyphal growth in response to stress through multiple kinase pathways. Intriguingly, we found that a repetitive portion of the genome containing telomere-like and rDNA repeats may be involved in the transition to hyphal growth, suggesting a link between this region and the general stress response. PMID- 30518678 TI - Erratum for McCarthy et al., "Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug-Induced and Viral Hepatitis". PMID- 30518679 TI - Inhibition of stromal cell-derived factor-1alpha/CXCR4 signaling restores the blood-retina barrier in pericyte-deficient mouse retinas. AB - In diabetic retinopathy (DR), pericyte dropout from capillary walls is believed to cause the breakdown of the blood-retina barrier (BRB), which subsequently leads to vision-threatening retinal edema. While various proinflammatory cytokines and chemokines are upregulated in eyes with DR, their distinct contributions to disease progression remain elusive. Here, we evaluated roles of stromal cell-derived factor-1alpha (SDF-1alpha) and its receptor CXCR4 in the BRB breakdown initiated by pericyte deficiency. After inhibition of pericyte recruitment to developing retinal vessels in neonatal mice, endothelial cells (ECs) upregulated the expression of SDF-1alpha. Administration of CXCR4 antagonists, or EC-specific disruption of the CXCR4 gene, similarly restored the BRB integrity, even in the absence of pericyte coverage. Furthermore, CXCR4 inhibition significantly decreased both the expression levels of proinflammatory genes (P < 0.05) and the infiltration of macrophages (P < 0.05) into pericyte deficient retinas. Taken together, EC-derived SDF-1alpha induced by pericyte deficiency exacerbated inflammation through CXCR4 in an autocrine or paracrine manner and thereby induced macrophage infiltration and BRB breakdown. These findings suggest that the SDF-1alpha/CXCR4 signaling pathway may be a potential therapeutic target in DR. PMID- 30518680 TI - Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis. AB - CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-gamma, TNF alpha, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation. PMID- 30518681 TI - Human bone marrow assessment by single-cell RNA sequencing, mass cytometry, and flow cytometry. AB - New techniques for single-cell analysis have led to insights into hematopoiesis and the immune system, but the ability of these techniques to cross-validate and reproducibly identify the biological variation in diverse human samples is currently unproven. We therefore performed a comprehensive assessment of human bone marrow cells using both single-cell RNA sequencing and multiparameter flow cytometry from 20 healthy adult human donors across a broad age range. These data characterize variation between healthy donors as well as age-associated changes in cell population frequencies. Direct comparison of techniques revealed discrepancy in the quantification of T lymphocyte and natural killer cell populations. Orthogonal validation of immunophenotyping using mass cytometry demonstrated a strong correlation with flow cytometry. Technical replicates using single-cell RNA sequencing matched robustly, while biological replicates showed variation. Given the increasing use of single-cell technologies in translational research, this resource serves as an important reference data set and highlights opportunities for further refinement. PMID- 30518682 TI - Randomized trial of intravenous iron-induced hypophosphatemia. AB - BACKGROUND: Hypophosphatemia can complicate intravenous iron therapy, but no head to-head trials compared the effects of newer intravenous iron formulations on risks and mediators of hypophosphatemia. METHODS: In a randomized, double blinded, controlled trial of adults with iron deficiency anemia from February 2016 to January 2017, we compared rates of hypophosphatemia in response to a single FDA-approved course of ferric carboxymaltose (n = 1,000) or ferumoxytol (n = 997). To investigate pathophysiological mediators of intravenous iron-induced hypophosphatemia, we nested within the parent trial a physiological substudy (ferric carboxymaltose, n = 98; ferumoxytol, n = 87) in which we measured fibroblast growth factor 23 (FGF23), calcitriol, and parathyroid hormone (PTH) at baseline and 1, 2, and 5 weeks later. RESULTS: The incidence of hypophosphatemia was significantly higher in the ferric carboxymaltose versus the ferumoxytol group (<2.0 mg/dl, 50.8% vs. 0.9%; <1.3 mg/dl, 10.0% vs. 0.0%; P < 0.001), and hypophosphatemia persisted through the end of the 5-week study period in 29.1% of ferric carboxymaltose-treated patients versus none of the ferumoxytol-treated patients (P < 0.001). Ferric carboxymaltose, but not ferumoxytol, increased circulating concentrations of biologically active FGF23 (mean within-patient percentage change from baseline to week 2 peak: +302.8 +/- 326.2% vs. +10.1 +/- 61.0%; P < 0.001), which was significantly associated with contemporaneous hypophosphatemia, renal phosphate wasting, and decreased serum calcitriol and calcium, and increased PTH concentrations. CONCLUSIONS: Ferric carboxymaltose rapidly increases biologically active FGF23 in patients with iron deficiency anemia. Paralleling hereditary and other acquired syndromes of hypophosphatemic rickets/osteomalacia, ferric carboxymaltose-induced FGF23 elevation triggers a pathophysiological cascade of renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism that frequently culminates in hypophosphatemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02694978FUNDING. AMAG Pharmaceuticals, Inc.Role of the funding source: This study was supported by AMAG Pharmaceuticals, Inc. The academic investigators designed the clinical trial, performed the analyses, and authored the manuscript with input from the coauthors from AMAG Pharmaceuticals, Inc. PMID- 30518683 TI - CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade. AB - Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these systems in a manner dependent on CD4+ T cells but not reliant on CD8+ T cells. Evaluation of tumor infiltrates and draining lymph nodes after ICB revealed expansion of IFN-gamma-producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-gamma receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-gamma neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-gamma ectopically expressed in the tumor microenvironment was sufficient to inhibit growth of tumors in which the epithelial compartment lacked Ifngr1. Our findings suggest unappreciated CD4+ T cell-dependent mechanisms of ICB activity, principally mediated through IFN-gamma effects on the microenvironment. PMID- 30518684 TI - IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells. AB - In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase-positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC driven by ALDH1A1 expression and activity. We show that platinum induces IL-6 secretion by cancer-associated fibroblasts in the tumor microenvironment, promoting OCSC enrichment in residual tumors after chemotherapy. By activating STAT3 and upregulating ALDH1A1 expression, IL-6 treatment converted non-OCSC to OCSC. Having previously shown altered DNA methylation in OCSC, we show here that IL-6 induces DNA methyltransferase 1 (DNMT1) expression and the hypomethylating agent (HMA) guadecitabine induced differentiation of OCSC and reduced - but did not completely eradicate - OCSC. IL 6 neutralizing antibody (IL-6-Nab) combined with HMA fully eradicated OCSC, and the combination blocked IL-6/IL6-R/pSTAT3-mediated ALDH1A1 expression and eliminated OCSC in residual tumors that persisted in vivo after chemotherapy. We conclude that IL-6 signaling blockade combined with an HMA can eliminate OCSC after platinum treatment, supporting this strategy to prevent tumor recurrence after standard chemotherapy. PMID- 30518685 TI - A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS. METHODS: We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level >=10%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes. RESULTS: No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% +/- 0.7% [cohort 1]; 4.9% +/- 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% +/- 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION: Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT02425579. FUNDING: NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695. PMID- 30518686 TI - AAV CRISPR editing rescues cardiac and muscle function for 18 months in dystrophic mice. AB - Adeno-associated virus-mediated (AAV-mediated) CRISPR editing is a revolutionary approach for treating inherited diseases. Sustained, often life-long mutation correction is required for treating these diseases. Unfortunately, this has never been demonstrated with AAV CRISPR therapy. We addressed this question in the mdx model of Duchenne muscular dystrophy (DMD). DMD is caused by dystrophin gene mutation. Dystrophin deficiency leads to ambulation loss and cardiomyopathy. We treated 6-week-old mice intravenously and evaluated disease rescue at 18 months. Surprisingly, nominal dystrophin was restored in skeletal muscle. Cardiac dystrophin was restored, but histology and hemodynamics were not improved. To determine the underlying mechanism, we evaluated components of the CRISPR-editing machinery. Intriguingly, we found disproportional guide RNA (gRNA) vector depletion. To test whether this is responsible for the poor outcome, we increased the gRNA vector dose and repeated the study. This strategy significantly increased dystrophin restoration and reduced fibrosis in all striated muscles at 18 months. Importantly, skeletal muscle function and cardiac hemodynamics were significantly enhanced. Interestingly, we did not see selective depletion of the gRNA vector after intramuscular injection. Our results suggest that gRNA vector loss is a unique barrier for systemic AAV CRISPR therapy. This can be circumvented by vector dose optimization. PMID- 30518687 TI - Antibody-mediated delivery of VEGF-C potently reduces chronic skin inflammation. AB - VEGF-C is an important mediator of lymphangiogenesis and has been shown to alleviate chronic inflammation in a variety of disease models. In this study, we investigated whether targeted delivery of VEGF-C to sites of inflammation and site-specific activation of lymphatic vessels would represent a clinically feasible strategy for treating chronic skin inflammation. To this end, we generated a fusion protein consisting of human VEGF-C fused to the F8 antibody (F8-VEGF-C), which is specific for the alternatively spliced, angiogenesis marking extradomain A (EDA) of fibronectin. In two mouse models of psoriasis-like skin inflammation, mediated by transgenic VEGF-A overexpression or repeated application of imiquimod, intravenous treatment with F8-VEGF-C but not with untargeted VEGF-C significantly reduced ear skin edema and was as effective as the clinically used TNF-alpha receptor-Fc fusion protein (TNFR-Fc). Treatment with F8-VEGF-C led to a marked expansion of lymphatic vessels in the inflamed skin and significantly improved lymphatic drainage function. At the same time, treatment with F8-VEGF-C significantly reduced leukocyte numbers, including CD4+ and gammadelta T cells. In sum, our results reveal that targeted delivery of VEGF C and site-specific induction of lymphatic vessels represent a potentially new and promising approach for the treatment of chronic inflammatory diseases. PMID- 30518689 TI - A common pathomechanism in GMAP-210- and LBR-related diseases. AB - Biallelic loss-of-function mutations in TRIP11, encoding the golgin GMAP-210, cause the lethal human chondrodysplasia achondrogenesis 1A (ACG1A). We now find that a homozygous splice-site mutation of the lamin B receptor (LBR) gene results in the same phenotype. Intrigued by the genetic heterogeneity, we compared GMAP 210- and LBR-deficient primary cells to unravel how particular mutations in LBR cause a phenocopy of ACG1A. We could exclude a regulatory interaction between LBR and GMAP-210 in patients' cells. However, we discovered a common disruption of Golgi apparatus architecture that was accompanied by decreased secretory trafficking in both cases. Deficiency of Golgi-dependent glycan processing indicated a similar downstream effect of the disease-causing mutations upon Golgi function. Unexpectedly, our results thus point to a common pathogenic mechanism in GMAP-210- and LBR-related diseases attributable to defective secretory trafficking at the Golgi apparatus. PMID- 30518688 TI - FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. AB - Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker. PMID- 30518690 TI - Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus. AB - The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4 KO models have given conflicting results. The role of PAD2 in SLE has not been investigated. The differential roles of PAD2 and PAD4 in TLR-7-dependent lupus autoimmunity were examined. Padi4-/- displayed decreased autoantibodies, type I IFN responses, immune cell activation, vascular dysfunction, and NET immunogenicity. Padi2-/- mice showed abrogation of Th subset polarization, with some disease manifestations reduced compared with WT but to a lesser extent than Padi4-/- mice. RNA sequencing analysis revealed distinct modulation of immune related pathways in PAD-KO lymphoid organs. Human T cells express both PADs and, when exposed to either PAD2 or PAD4 inhibitors, displayed abrogation of Th1 polarization. These results suggest that targeting PAD2 and/or PAD4 activity modulates dysregulated TLR-7-dependent immune responses in lupus through differential effects of innate and adaptive immunity. Compounds that target PADs may have potential therapeutic roles in T cell-mediated diseases. PMID- 30518691 TI - A standardized immune phenotyping and automated data analysis platform for multicenter biomarker studies. AB - The analysis and validation of flow cytometry-based biomarkers in clinical studies are limited by the lack of standardized protocols that are reproducible across multiple centers and suitable for use with either unfractionated blood or cryopreserved PBMCs. Here we report the development of a platform that standardizes a set of flow cytometry panels across multiple centers, with high reproducibility in blood or PBMCs from either healthy subjects or patients 100 days after hematopoietic stem cell transplantation. Inter-center comparisons of replicate samples showed low variation, with interindividual variation exceeding inter-center variation for most populations (coefficients of variability <20% and interclass correlation coefficients >0.75). Exceptions included low-abundance populations defined by markers with indistinct expression boundaries (e.g., plasmablasts, monocyte subsets) or populations defined by markers sensitive to cryopreservation, such as CD62L and CD45RA. Automated gating pipelines were developed and validated on an independent data set, revealing high Spearman's correlations (rs >0.9) with manual analyses. This workflow, which includes pre formatted antibody cocktails, standardized protocols for acquisition, and validated automated analysis pipelines, can be readily implemented in multicenter clinical trials. This approach facilitates the collection of robust immune phenotyping data and comparison of data from independent studies. PMID- 30518692 TI - CD19+IgM+ cells demonstrate enhanced therapeutic efficacy in type 1 diabetes mellitus. AB - We describe a protective effect on autoimmune diabetes and reduced destructive insulitis in NOD.scid recipients following splenocyte injections from diabetic NOD donors and sorted CD19+ cells compared with NOD.scid recipients receiving splenocytes alone. This protective effect was age specific (only CD19+ cells from young NOD donors exerted this effect; P < 0.001). We found that the CD19+IgM+ cell is the primary subpopulation of B cells that delayed transfer of diabetes mediated by diabetogenic T cells from NOD mice (P = 0.002). Removal of IgM+ cells from the CD19+ pool did not result in protection. Notably, protection conferred by CD19+IgM+ cotransfers were not dependent on the presence of Tregs, as their depletion did not affect their ability to delay onset of diabetes. Blockade of IL 10 with neutralizing antibodies at the time of CD19+ cell cotransfers also abrogated the therapeutic effect, suggesting that IL-10 secretion was an important component of protection. These results were strengthened by ex vivo incubation of CD19+ cells with IL-5, resulting in enhanced proliferation and IL 10 production and equivalently delayed diabetes progression (P = 0.0005). The potential to expand CD19+IgM+ cells, especially in response to IL-5 stimulation or by pharmacologic agents, may be a new therapeutic option for type 1 diabetes. PMID- 30518693 TI - Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes. AB - BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Moller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc. PMID- 30518694 TI - Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. AB - PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit. PMID- 30518695 TI - Epigenetic dysregulation of Oxtr in Tet1-deficient mice has implications for neuropsychiatric disorders. AB - OXTR modulates a variety of behaviors in mammals, including social memory and recognition. Genetic and epigenetic dysregulation of OXTR has been suggested to be implicated in neuropsychiatric disorders, including autism spectrum disorder (ASD). While the involvement of DNA methylation is suggested, the mechanism underlying epigenetic regulation of OXTR is largely unknown. This has hampered the experimental design and interpretation of the results of epigenetic studies of OXTR in neuropsychiatric disorders. From the generation and characterization of a new line of Tet1 mutant mice - by deleting the largest coding exon 4 (Tet1Deltae4) - we discovered for the first time to our knowledge that Oxtr has an array of mRNA isoforms and a complex transcriptional regulation. Select isoforms of Oxtr are significantly reduced in the brain of Tet1Deltae4-/- mice. Accordingly, CpG islands of Oxtr are hypermethylated during early development and persist into adulthood. Consistent with the reduced express of OXTR, Tet1Deltae4 /- mice display impaired maternal care, social behavior, and synaptic responses to oxytocin stimulation. Our findings elucidate a mechanism mediated by TET1 protein in regulating Oxtr expression by preventing DNA hypermethylation of Oxtr. The discovery of epigenetic dysregulation of Oxtr in TET1-deficient mouse brain supports the necessity of a reassessment of existing findings and a value of future studies of OXTR in neuropsychiatric disorders. PMID- 30518696 TI - Training the physician-scientist: views from program directors and aspiring young investigators. AB - There is growing concern that the physician-scientist is endangered due to a leaky training pipeline and prolonged time to scientific independence (1). The NIH Physician-Scientist Workforce Working Group has concluded that as many as 1,000 individuals will need to enter the pipeline each year to sustain the workforce (2). Moreover, surveys of postgraduate training programs document considerable variability in disposition and infrastructure (3). Programs can be broadly grouped into two classes: physician-scientist training programs (PSTPs) that span residency and fellowship training, and research-in-residency programs (RiRs), which are limited to residency but trainees are able to match into PSTPs upon transitioning to fellowship (Figure 1). Funding sources for RiRs and PSTPs are varied and include NIH KL2 and T32 awards, charitable foundations, philanthropy, and institutional support. Furthermore, standards for research training and tools for evaluating programmatic success are lacking. Here, we share consensus generated from iterative workshops hosted by the Alliance of Academic Internal Medicine (AAIM) and the student-led American Physician Scientists Association (APSA). PMID- 30518697 TI - HIV-associated sensory polyneuropathy and neuronal injury are associated with miRNA-455-3p induction. AB - Symptomatic distal sensory polyneuropathy (sDSP) is common and debilitating in people with HIV/AIDS, leading to neuropathic pain, although the condition's cause is unknown. To investigate biomarkers and associated pathogenic mechanisms for sDSP, we examined plasma miRNA profiles in HIV/AIDS patients with sDSP or without sDSP in 2 independent cohorts together with assessing related pathogenic effects. Several miRNAs were found to be increased in the Discovery Cohort (sDSP, n = 29; non-DSP, n = 40) by array analyses and were increased in patients with sDSP compared with patients without sDSP. miR-455-3p displayed a 12-fold median increase in the sDSP group, which was confirmed by machine learning analyses and verified by reverse transcription PCR. In the Validation Cohort (sDSP n = 16, non DSP n = 20, healthy controls n = 15), significant upregulation of miR-455-3p was also observed in the sDSP group. Bioinformatics revealed that miR-455-3p targeted multiple host genes implicated in peripheral nerve maintenance, including nerve growth factor (NGF) and related genes. Transfection of cultured human dorsal root ganglia with miR-455-3p showed a concentration-dependent reduction in neuronal beta-III tubulin expression. Human neurons transfected with miR-455-3p demonstrated reduced neurite outgrowth and NGF expression that was reversed by anti-miR-455-3p antagomir cotreatment. miR-455-3p represents a potential biomarker for HIV-associated sDSP and might also exert pathogenic effects leading to sDSP. PMID- 30518698 TI - Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. PMID- 30518700 TI - [The Effectiveness of Counseling Using Preventative Informational Sheets with Climate and Environmental Data from Insurance Pharmacies in Preventing Worsened Asthma Symptoms]. AB - We investigated the possibility that having pharmacists give asthma patients informational sheets on climate and environmental changes at insurance pharmacies during patient counseling might prevent the worsening of asthma symptoms. Patients with hyperlipidemia were comparative subjects. We created informational sheets about climate and environmental changes and their influence on asthma. During patient counseling, pharmacists gave them to all asthma patients who visited insurance pharmacies over a period of 2 months, between November and December 2017. Based on previous studies, we called days which showed certain climate or environmental changes as compared to the previous day "change days". We compared the number of visiting patients on change days after preventative information was provided (between January and March 2018) with the number before information was provided (between January and March 2017). In addition, we compared those numbers with the number of patients who visited the target pharmacies between January and March 2016 in order to examine the influence of yearly climate change. The same procedure was used with hyperlipidemic patients. The number of visiting asthma patients after information was provided significantly decreased (5.1+/-2.1, p=0.03) compared with the number before information was provided, between January and March 2017 (6.1+/-2.8). The number of aforementioned visits compared to those between January and March 2016 also significantly decreased (p=0.01). Our results suggest that preventative information about climate and environmental changes provided by pharmacists during patient counseling might influence the number of asthma patient visits and prevent the exacerbation of their symptoms. PMID- 30518699 TI - Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients. AB - In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of noninvasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in 2 independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis, and overall survival revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential abundance analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume. These findings were validated in longitudinal serum samples from metastatic neuroblastoma patients, where the 9 miRNAs were associated with disease burden and treatment response. PMID- 30518701 TI - Involvement of transient receptor potential melastatin 4 channels in the resting membrane potential setting and cholinergic contractile responses in mouse detrusor and ileal smooth muscles. AB - Here, we investigated the effects of 9-hydroxyphenanthrene (9-phenanthrol), a potent and selective transient receptor potential melastatin 4 (TRPM4) channel blocker, on the resting membrane potential and cholinergic contractile responses to elucidate the functional role of TRPM4 channels in the contractile activities of mouse detrusor and ileal longitudinal smooth muscles. We observed that, 9 phenanthrol (3-30 uM) did not significantly inhibit high K+-induced contractions in both preparations; however, 9-phenanthrol (10 uM) strongly inhibited cholinergic contractions evoked by electrical field stimulation in detrusor preparations compared to inhibitions in ileal preparations. 9-Phenanthrol (10 uM) significantly inhibited the muscarinic agonist, carbachol-induced contractile responses and slowed the maximum upstroke velocities of the contraction in detrusor preparations. However, the agent (10 uM) did not inhibit the contractions due to intracellular Ca2+ release evoked by carbachol, suggesting that the inhibitory effect of 9-phenanthrol may primarily be due to the inhibition of the membrane depolarization process incurred by TRPM4 channels. On the other hand, 9-phenanthrol (10 uM) did not affect carbachol-induced contractile responses in ileal preparations. Further, 9-phenanthrol (10 uM) significantly hyperpolarized the resting membrane potential and decreased the basal tone in both detrusor and ileal muscle preparations. Taken together, our results suggest that TRPM4 channels are constitutively active and are involved in setting of the resting membrane potential, thereby regulating the basal tone in detrusor and ileal smooth muscles. Thus, TRPM4 channels play a significant role in cholinergic signaling in detrusor, but not ileal, smooth muscles. PMID- 30518702 TI - [Content analysis of newspaper reports on passive smoking regulations in Japan]. AB - Objectives Ever since Tokyo was awarded the privilege to host the 2020 Olympic Games, the Japanese Ministry of Health, Labour, and Welfare has worked toward implementing a ban on passive smoking. This study examined the present situation of passive smoking in Japan, and the coverage of passive smoking regulations in newspaper reports, based on a content analysis. This was followed by a comparison with the contents of the "White Paper on Tobacco," published by the Japanese Ministry of Health, Labour, and Welfare in August, 2016.Methods In total, 182 articles published from September 7, 2013 to March 31, 2017 were collected from three major newspapers based in Tokyo (Asahi, Yomiuri, and Mainichi). The article search criteria included the presence of the following keywords in the title or main text: "passive smoking OR entire surface smoking cessation OR indoor smoking OR indoor smoking cessation OR smoking cessation in the site OR smoking cessation in the building." Online posts and articles that did not focus mainly on the regulation of passive smoking were excluded. The 37 coding categories that were developed were classified either as positive or negative (with respect to coverage of passive smoking regulations). The assessment of passive smoking in the White Paper on Tobacco informed the coding categories, to allow the evaluation of the extent to which the contents of the White Paper were reflected in newspaper reports.Results Among the 182 articles examined, 107 addressed only the positive aspects of the regulations, while 7 addressed only the negative aspects. Further, 50 articles addressed both positive and negative aspects, while 18 addressed neither. Among those addressing both positive and negative aspects, 14 (28%) included counterarguments to the negative comments, which consistently reflected the contents of the White Paper on Tobacco.Conclusions Majority of the articles reported only on the positive aspects of the regulations. Persuasive articles that presented both the positive and negative aspects of the issue, which included counterarguments to the negative opinions, were scarce. However, such articles were found to some degree in the editorials of newspapers. The influence of such editorials may increase if newspapers include the pros or cons of this issue, and present counterarguments. Additionally, some topics were not reported sufficiently. Thus, problems were observed in the newspaper reports regarding passive smoking regulations. PMID- 30518703 TI - [The relationship between sleep and subjective mental health at one month postpartum in Japanese women]. AB - Objectives This study aimed to separately ascertain and examine the association between sleep and mental health among primiparas and multiparas at one month postpartum.Methods The subjects were 234 primiparas and 223 multiparas (a total of 457) at one month postpartum who agreed to participate in the questionnaire survey during a health check-up at a maternity hospital. According to the delivery records, they had no history of mental diseases. The survey items of the questionnaire concerned living environment, sleep status, subjective mental health (depressive mood, anxiety, low motivation, irritability) and sleep-related lifestyle. At first, we compared these items between primiparas and multiparas. Next, multiple regression analysis by a general linear model was used to investigate the association between sleep status and mental health. The dependent variables were sleep satisfaction, total sleep time, the existence of sleep problems (difficulty initiating sleep, difficulty maintaining sleep, waking up too early), irregularity of bedtime, and five kinds of sleep-related lifestyle. The independent variables were the four mental health indices according to a visual analog scale.Results In primiparas, total sleep time was shorter, bedtime and sleeping time were later, two kinds of sleep-related lifestyle were worse, and the symptoms of tinnitus and tired feeling were higher than in multiparas. In multiparas, sleep onset latency was longer, the number of times of night awakening was higher, irritability was stronger, and the prevalence of headache was higher than in primiparas. Sleep satisfaction was related to all four indices of mental health for both primiparas and multiparas. In primiparas, the existence of sleep problems was related to depressive mood and anxiety, and the irregularity of bedtime was related to anxiety. "Getting up immediately after awakening" was related to irritability, as well as low motivation, in multiparas. "A nap shorter than 30 minutes before 3 PM" was related to anxiety and low motivation in primiparas. The irregularity of bedtime was negatively related to anxiety, low motivation, and irritability in multiparas.Conclusion It is suggested that sleep problems, which tend to be overlooked, are related to subjective mental health at one month postpartum. Thus, we conclude that sleep education during pregnancy and sleep evaluations at postpartum check-ups are necessary for postpartum women's mental health. PMID- 30518704 TI - [Awareness of harm to others from secondhand smoke and smokers' interest in smoking cessation]. AB - Objectives Because smoking presents various health hazards, smoking cessation is important for health promotion. It is known that awareness of the harm of smoking to smokers themselves is associated with attempts to quit. However, the association between smoking cessation and awareness of harm to others from secondhand smoke has not been well examined. Therefore, in this research, we examined the association between smokers' awareness of the harm to others from secondhand smoke and their interest in smoking cessation, focusing on current smokers in an Internet survey of the general population of Japan.Methods We conducted a cross-sectional Internet survey of the general population of Japan between January 27 and March 13, 2017. A total of 1,586 respondents aged 15-71 years (1,128 men and 458 women) who were current smokers were analyzed. We used multivariable-adjusted logistic regression to examine the association among awareness of smoking's harm to smokers themselves, awareness of harm to others from secondhand smoke, and the smokers' interest in smoking cessation.Results Of current smokers, 81.6% of men and 88.2% of women were aware of the harm caused to others by secondhand smoke; 52.7% of men and 64.6% of women were interested in smoking cessation. Using awareness of harm to smokers themselves and awareness of harm to others from secondhand smoke as predictor variables in multivariable adjusted logistic regression, odds ratios were 2.53 and 2.92, respectively. In the model using both awareness of harm to smokers themselves and harm to others from secondhand smoke, both have a significant independent positive association with smokers' interest in quitting.Conclusions Current smokers aware of the harm caused to others by secondhand smoke were more interested in quitting than those who were not. Awareness of the harm caused to smokers themselves by smoking and awareness of the harm caused to others by secondhand smoke have a significant independent positive association with smokers' interest in quitting. Although this study is a cross-sectional study and did not investigate causal relationships, the findings suggest that raising awareness of the harm to other people from secondhand smoke may lead to more interest in smoking cessation, and the data can be used to promote tobacco control in the future. PMID- 30518705 TI - [Evaluation of real-time surveillance of influenza incidence in Kawasaki City by comparison using the National Epidemiological Surveillance of Infectious Diseases]. AB - Objectives In Japan, nationwide data of the incidence of infectious diseases have been collected via the National Epidemiological Surveillance of Infectious Diseases (NESID) since 1981. In addition, since March 2014, Kawasaki City has operated its own real-time surveillance (RTS) system to collect data of the incidence of influenza from medical institutions across the city. This study aimed to describe the characteristics of the RTS system and compare the two surveillance systems to improve measures against infectious diseases in the future.Methods NESID and RTS data from March 2014 to October 2017 were obtained from the Kawasaki City Institute for Public Health. First, the operating methodologies of the two surveillance systems were compared. Second, RTS data were used to analyze the daily epidemic curve, and then the daily number of influenza cases was converted into weekly data for comparison with NESID data. Pearson's correlation coefficients and 95% confidence intervals (CIs) were calculated. Correlations were also analyzed after data for the last and first weeks of each year were excluded because few hospitals remain open around the New Year holiday, resulting in a disproportionately large number of patients visiting the few institutions that remain open.Results The NESID relies on data provided by a fixed number of medical institutions determined each fiscal year (mean: 56.0+/-4.2 institutions), while the number of institutions providing data for the RTS varies daily or monthly. In September 2017, 691 of the 1,032 eligible institutions (67.0%) were registered for the RTS. Pearson's correlation coefficient for the two surveillance systems was 0.975 (95%CI, 0.967-0.981); when data for the last and first week of each year were excluded, it was 0.989 (95%CI 0.986-0.992). In each of the three seasons that were investigated, an increase in the incidence of type A influenza preceded an increase in the incidence of type B influenza.Conclusion The operating methodologies of the two surveillance systems differed; however, the results identified a strong correlation, confirming the reliability of the RTS. The RTS collects daily data by influenza type; therefore, it detects epidemic onsets at an earlier stage, facilitating more detailed epidemiological analysis, compared with that of the NESID. It is necessary to understand differences in the characteristics between two surveillance systems when we analyze influenza surveillance data. PMID- 30518706 TI - Three-dimensional volumetric magnetic resonance imaging (MRI) analysis of the soft palate and nasopharynx in brachycephalic and non-brachycephalic dog breeds. AB - The purpose of this study was to use magnetic resonance imaging (MRI) to compare the volumes and three-dimensional configurations of the soft palate and nasopharynx in non-brachycephalic and brachycephalic dogs with different body weights, and infer which factors influence nasopharyngeal volume. This was a retrospective observational study. The brain MRI medical records of all dogs referred to the Veterinary Medical Center, Chungbuk National University, between 2013 and 2016, for evaluation of intracranial disease were reviewed. There was a significant difference in the two-dimensional parameters including soft palate length/skull length ratio (P<0.01) and maximum soft palate thickness (P<0.01), and three-dimensional parameters which included soft palate volume (P<0.01), nasopharyngeal volume (P<0.01), soft palate/total upper airway volume ratio (P<0.01), and nasopharyngeal volume/total upper airway volume ratio (P<0.01), between brachycephalic and non-brachycephalic dog breeds. Nasopharyngeal volume correlated positively with the maximum soft palate thickness and body weight in all breeds. The three-dimensional morphologic grades of soft palate were significantly different between the two groups. In brachycephalic breeds, Grade 3 was observed in 33% of cases but was absent in non-brachycephalic breeds, where Grade 1 was present in 85% of the cases. We can conclude that three-dimensional morphology and upper airway volume are significantly different between brachycephalic and non-brachycephalic breeds, and body weight and maximum soft palate thickness are the key factors associated with a decreased nasopharyngeal volume. PMID- 30518707 TI - Silver effects on silkworm, Bombyx mori. AB - Silver nanoparticles (Ag-NPs) are known as a noble metal, and owing to their exclusive properties, their use is widespread in consumer products and they are mostly incorporated into food packaging and food contact products. The aim of this work was to evaluate the effects of direct ingestion of Ag-NPs through food to assess their toxicity effects on the growth and development of silkworms at different concentrations (1 mg.L-1 to 100 mg.L-1), in addition to the examination of the distribution of Ag-NPs in the silkworm body and midgut histopathological analysis. RNA sequencing was performed to investigate the transcriptomic responses to Ag-NPs exposure. Our results show that the highest Ag-NPs' concentrations induced a significant increase in the silkworm body weight with histopathological changes in the midgut compared to the control group. The gene ontology (GO) and pathway enrichment analysis for differentially expressed genes showed that Ag-NPs altered the gene expressions and that they were significantly involved in carbohydrate metabolism, digestive system, and energy metabolism. These findings indicate that the Ag-NPs may induce harmful effects on the primary target organs (alimentary system) with energy deregulation and nutrition digestion and absorption imbalance. This study is an important step in understanding the molecular mechanisms of Ag-NPs' toxicity in vivo. PMID- 30518708 TI - SIRT1 knockdown up-regulates p53 and p21/Cip1 expression in renal adenocarcinoma cells but not in normal renal-derived cells in a deacetylase-independent manner. AB - SIRT1, an NAD+-dependent deacetylase, causes deacetylation and down-regulation of its target p53. Given that p53 is an upstream regulator of the transcription of the cyclin-dependent kinase inhibitor p21/Cip1, SIRT1 is hypothesized to play a stimulatory role in carcinoma cell proliferation. We previously reported that down-regulation of SIRT1 caused the increase in p21/Cip1 in a post transcriptional manner, suggesting that p53 is not involved in the p21/Cip1 increase and raising the question whether SIRT1 exhibits the activity other than deacetylase. In the present study, we examined whether SIRT1 down-regulation and the inhibitor for SIRT1 deacetylase activity affects p21/Cip1 and p53 expression in renal adenocarcinoma cells and normal renal cells. SIRT1 knockdown caused an increase in p53 and p21/Cip1 protein levels in renal adenocarcinoma ACHN cells but not normal renal-derived HK-2 cells. The increase in p53 in ACHN cells is unlikely to contribute to the upregulation of p21/Cip1 expression, given that SIRT1 knockdown did not increase p21/Cip1 mRNA levels in these cells. In contrast to the SIRT1-knock down assay, SIRT1 deacetylase inhibitor did not affect p53 or p21/Cip1 protein levels in ACHN cells. Therefore, SIRT1-knockdown likely stimulates p53 and p21/Cip1 protein expression in a deacetylase-independent manner. PMID- 30518709 TI - Monomethylmercury degradation by the human gut microbiota is stimulated by protein amendments. AB - Monomethylmercury (MMHg) is a potent neurotoxicant that can be bioaccumulated and biomagnified through trophic levels. Human populations whose diets contain MMHg are at risk of MMHg toxicity. The gut microbiota was identified as a potential factor causing variation in MMHg absorption and body burden. However, little is known about the role of gut microbiota on Hg transformations. We conducted a series of in vitro experiments to study the effects of dietary nutrient change on Hg metabolism and the human gut microbiota using anoxic fecal slurry incubations. We used stable Hg isotope tracers to track MMHg production and degradation and characterized the microbiota using high throughput sequencing of the 16S rRNA gene. We show that the magnitude of MMHg degradation is individual dependent and rapidly responds to changes in nutrient amendments, leading to complete degradation of the MMHg present. Although the mechanism involved remains unknown, it does not appear to involve the well-known mer operon. Our data are the first to show a nutrient dependency on the ability of the simulated human gut microbiota to demethylate MMHg. This work provides much-needed insights into individual variations in Hg absorption and potential toxicity. PMID- 30518710 TI - 5-Fluorouracil inhibits neural differentiation via Mfn1/2 reduction in human induced pluripotent stem cells. AB - 5-fluorouracil (5-FU) has been widely used for the treatment of tumors. Regardless of its widespread use as an anti-cancer drug, 5-FU therapy can cause several side effects, including developmental toxicity and neurotoxicity. However, the potential action of 5-FU at the early fetal stage has not yet been completely elucidated. In the present study, we investigated the effect of 5-FU exposure on neural induction, using human induced pluripotent stem cells (iPSCs) as a model of human fetal stage. 5-FU exposure reduced the expression of several neural differentiation marker genes, such as OTX2, in iPSCs. Since the neural differentiation process requires ATP as a source of energy, we next examined intracellular ATP content using iPSCs. We found that 5-FU decreased intracellular ATP levels in iPSCs. We further focused on the effects of 5-FU on mitochondrial dynamics, which plays a role of ATP production. We found that 5-FU induced mitochondrial fragmentation and reduced the level of mitochondrial fusion proteins, mitofusin 1 and 2 (Mfn1/2). Double knockdown of Mfn1/2 genes in iPSCs downregulated the gene expression of OTX2, suggesting that Mfn mediates neural differentiation in iPSCs. Taken together, these results indicate that 5-FU has a neurotoxicity via Mfn-mediated mitochondria dynamics in iPSCs. Thus, mitochondrial dysfunction in iPSCs could be used as a possible marker for cytotoxic effects of drugs. PMID- 30518711 TI - Structure-activity relationship of [1,5]azastibocines in cytotoxicity to vascular endothelial cells. AB - It has been well established that organic-inorganic hybrid molecules can exhibit biological activities that are different from those of either their intramolecular metals in inorganic forms or their organic structures. We have previously reported that organoantimony compound Sb-phenyl-N-methyl-5,?6,7,12 tetrahydrodibenz[c,f][1,5]azastibocine (PMTAS) is nontoxic, but that the compound exhibits cytotoxicity in vascular endothelial cells when the antimony atom is replaced with a bismuth atom. In the present study, we investigated the cytotoxicity and intracellular accumulation of PMTAS and its analogs and found that the cytotoxicity of PMTAS analogs also decrease depending on the electron withdrawing property of the substituent bound to the intramolecular antimony atom. On the other hand, with the exception of the phenyl group, and depending on the carbon number of hydrocarbon group bound to the intramolecular nitrogen atom, cytotoxicity was enhanced. Furthermore, the cytotoxicity of PMTAS analogs correlated with their intracellular accumulation values. These results suggested that the low cytotoxicity effects of PMTAS on vascular endothelial cells is due to the characteristics of substituents bound to intramolecular antimony and nitrogen atoms. PMID- 30518712 TI - The performance of an in vitro skin sensitisation test, IL-8 Luc assay (OECD442E), and the integrated approach with direct peptide reactive assay (DPRA). AB - In all current in vitro skin sensitisation assays, DMSO is used to dissolve water insoluble chemicals. However, our previous study suggested the superiority of the modified IL-8 Luc assay (mIL-8 Luc), in which X-VIVOTM 15 is used to dissolve chemicals, over the original assay using DMSO (oIL-8 Luc). In this study, to confirm the superiority of the mIL-8 Luc, we first increased the number of chemicals examined and demonstrated the superiority of the mIL-8 Luc, in which the mIL-8 Luc provided 87.6% of sensitivity, 74.2% of specificity, and 84.6% of accuracy. Next, to clarify the cause of false negative judgment by the mIL-8 Luc, we examined the effects of physical properties of chemicals on judgment. The results demonstrated that high molecular weight, high LogKo/w, or poor water solubility, did not cause false negative judgment. When it was accepted as an OECD test guideline, the criteria of the mIL-8 Luc to determine sensitisers were modified to further decrease false negative judgment by poor solubility. By applying the new criteria, the test guideline IL-8 Luc assay (tgIL-8 Luc) improved sensitivity but decreased specificity and increased the number of chemicals that cannot be judged. To overcome this problem, we examined a simple combination of the tgIL-8 Luc with direct peptide reactive assay (DPRA), which could improve specificity and decrease the number of the chemicals that cannot be judged. These data suggest that the tgIL-8 Luc is a promising in vitro skin sensitisation assay in combination with other in vitro or in chemico methods. PMID- 30518714 TI - Cardiac Involvement in Emery-Dreifuss Muscular Dystrophy and Related Management Strategies. AB - Emery-Dreifuss muscular dystrophy (EDMD) is a group of hereditary muscular dystrophy syndrome caused by deficiency of genes encoding nuclear envelope proteins. Patients having EDMD show the triad of muscle dystrophy, joint contracture, and cardiac disease. In almost all patients, cardiac involvement is prevalent and is the most severe aspect of EDMD. Cardiac disease is predominantly shown by conduction defects, atrial fibrillation/flutter, and atrial standstill. Sudden death and heart failure because of left ventricular dysfunction are important causes of mortality, particularly in those patients that have the LMNA mutation. Medical treatment of EDMD is limited to addressing symptoms and ambulation support; moreover, pacemaker implantation is necessary when there are severe conduction defects and bradycardia occurs. Note that automated defibrillation devices may be considered for those patients who have a high risk of sudden death, rate, or rhythm control. Also, anticoagulation should be initiated in those patients who have atrial fibrillation/flutter. Thus, for optimal management, a multidisciplinary approach is required. PMID- 30518713 TI - Comparative assessment of 24-hr primary skin irritation test and human patch test data with in vitro skin irritation tests according to OECD Test Guideline 439 (for quasi-drugs in Japan). AB - The Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 439 is an in vitro test method of reconstructed human epidermis (RhE), which was developed for hazard identification of irritating chemicals in accordance with a primary skin irritation test using rabbits with 4-hr exposure. A regulation for quasi-drugs in Japan requires data from primary skin irritation tests using rabbits to undergo 24-hr exposure, and this is used as an evidence for 24-hr closed patch tests in humans. In this study with the same chemicals, primary skin irritation test data using rabbits undergoing 24-hr exposure and a 24-hr occlusive human patch test data were analyzed by comparing the results obtained with four test methods adopted in OECD TG 439. The performances of in vitro test methods showed a positive predictive value of 72.7-85.7% to predict the results of 24-hr primary rabbit skin irritation test knowing that its positive predictive value was 57.1% against humans only. The prediction factors of in vitro test methods were higher for the human patch test data with a sensitivity reaching 60 to 80%. Three surfactants gave false negatives in some of the RhE methods evaluated with the human patch test, but in each case, they were correctly classified as positive when evaluated at double concentration. Therefore, the approach of setting the margin to 2 was effective in eliminating false negatives. This suggests that in vitro test methods are useful for assessing skin irritation potential without animal testing for the application of quasi-drugs in Japan. PMID- 30518715 TI - Natriuretic Peptide Processing in Patients with and Without Left Ventricular Dysfunction. AB - This study aimed to examine the relationship between corin expression and circulating brain natriuretic peptide in patients with left ventricular (LV) dysfunction.Circulating levels of B-type natriuretic peptide (BNP) can be an indicator of LV dysfunction. The 32-amino-acid BNP is cleaved by corin, a cardiac serine protease, from its108-amino-acid pro-brain natriuretic peptide (proBNP) precursor.This study included 25 patients with idiopathic dilated cardiomyopathy (DCMP) and LV dysfunction and 44 heart transplant recipients with normal LV function who underwent diagnostic left and right heart catheterization. Blood samples were used to determine the ratio of plasma proBNP/BNP levels, and LV endomyocardial biopsies were used to determine the expression of NPPB, which encode BNP and corin, respectively, by quantitative reverse transcription polymerase chain reaction.Patients with DCMP revealed worse hemodynamic profiles and higher plasma proBNP and BNP levels than those of the transplant recipients. Myocardial NPPB expression was higher and CORIN expression was lower in the DCMP patients than in the transplant recipients. CORIN expression significantly correlated with NPPB expression (r = -0.585; P < 0.001), ejection fraction (EF; r = 0.694; P < 0.01), LV end-diastolic pressure (r = -0.373; P < 0.05), and indexed end-diastolic LV volume (r = -0.452; P < 0.001). In addition, the plasma proBNP/BNP levels inversely correlated with the CORIN expression (r = -0.362; P < 0.005).Decreased myocardial CORIN expression and the corresponding higher levels of circulating unprocessed proBNP in DCMP may partly account for the relative BNP resistance observed in patients with LV dysfunction. PMID- 30518716 TI - A Modified Loop Snare Technique for Difficult Retrievals of Inferior Vena Cava Filter and Migrated Coil. AB - The aim of this study was to evaluate the safety and efficacy of a modified loop snare technique for retrieval of difficult inferior vena cava (IVC) filters and migrated coils.A retrospective review of Gunther Tulip filter retrievals between January 2014 and February 2017 was performed. A total of 316 IVC filter retrievals were attempted. In 25 cases, the standard technique had failed and our modified loop snare technique was subsequently attempted in 21 of these patients.The retrievals were successful in 20 cases (mean dwell time, 42.6 days, range, 14-102 days). The dwell time of the one failure was 46 days. The retrieval rate increased from 92.1% with the standard technique to 98.4% with the combination of the standard and modified loop snare technique. Unsuccessful retrieval was due to migration and endothelialization of the filter. This technique can also be used to remove migrated coils which cannot be captured by standard techniques. There were no complications from the retrievals.Tilt and endothelialization of filters are the main factors resulting in unsuccessful retrievals with the standard technique. In the present study, we describe an alternative technique for difficult IVC filter retrievals, which can also be used to capture migrated coils and occluders in the aorta and heart. PMID- 30518717 TI - Pressure Overload Impairs Cardiac Function in Long-Chain Fatty Acid Transporter CD36-Knockout Mice. AB - CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure. PMID- 30518718 TI - Characteristics, Mechanism and Long-Term Ablation Outcome of Atrial Tachycardias After Mitral Valvular Surgery and Concomitant Cox-MAZE IV Procedure. AB - The incidence of atrial tachycardia (AT) after rheumatic mitral valvular (RMV) surgery has been well described. However, there have been few reports on the characteristics, mechanism, and long-term ablation outcome of ATs after RMV surgery and concomitant Cox-MAZE IV procedure.The present study reviewed consecutive patients who underwent AT ablation between May 2008 and July 2013. All patients were refractory to antiarrhythmic drugs (AADs) and had a history of RMV surgery and Cox-MAZE IV procedure. A total of 34 patients underwent AT ablation after RMV surgery and concomitant Cox-MAZE IV procedure, and presented 57 mappable and 2 unmappable ATs. The 57 mappable ATs included 14 focal-ATs and 43 reentry-ATs. Ten of the 14 focal-like ATs were located at the pulmonary vein (PV) antrum and border of a box lesion. Of the 43 reentry-ATs, 16 were marco reentrant around the mitral annulus (MA) and 16 around the tricuspid annulus. There were 41 atypical ATs (non-cavotricuspid isthmus related) including 16 ATs related to the box lesion and 21 ATs related to other Cox-MAZE IV lesions. The AT were successfully terminated in 33 (97.1%) patients. After mean follow-up of 46.9 +/- 15.7 months, 25 (73.5%) patients maintained sinus rhythm without AADs after a single procedure and 28 (82.4%) patients after repeated procedures.The recurrent ATs after RMV surgery and concomitant Cox-MAZE IV were mainly reentry mechanism, and largely related to LA. An incomplete lesion or re-conductive gaps in a prior lesion might be the predominant mechanisms for these ATs. Catheter-based mapping and ablation of these ATs seems to be effective and safe during a long-term follow-up. PMID- 30518719 TI - Medical Castration is a Rare but Possible Trigger of Torsade de Pointes and Ventricular Fibrillation. AB - Prostate cancer is the most common non-cutaneous malignancy in men and has been steadily rising in an aging society. Medical castration therapy is effective for metastatic prostate cancer, but the proarrhythmic properties have not been reported. We present a 71-year-old Japanese man with metastasis prostate cancer that, during medical castration therapy, had torsades de pointes (TdP) with a QT prolongation and ventricular fibrillation (VF). His QT interval diminished after discontinuing the medical castration, and he developed no further VF recurrences for 15 months. Medical castration is a rare but possible trigger of TdP with QT prolongation and VF. PMID- 30518720 TI - Involvement of Apelin/APJ Axis in Thrombogenesis in Valve Heart Disease Patients with Atrial Fibrillation. AB - The mechanism underlying thrombosis in atrial fibrillation (AF) is not yet clearly understood. The apelin/APJ axis parallel and counter-regulate with the angiotensin system. The present study hypothesizes that apelin/APJ axis exert its anti-thrombus effect in normal left atrial tissue and is disrupted by up regulated renin-angiotensin-aldosterone system (RAAS) signaling during AF. The specimens of left atrial appendages collected from patients with rheumatic mitral stenosis who underwent valve replacement were divided into 3 groups: sinus rhythm, AF+/thrombus-, and AF+/thrombus+. The amounts of angiotensin II receptor subtype 1 (AT1), apelin/APJ and its downstream plasminogen activator inhibitor-1 (PAI-1) were detected by western blot. The expression of apelin/APJ was significantly decreased in the AF+/thrombus+ group compared with the sinus rhythm and AF+/thrombus- groups. Meanwhile the expressions of AT1 and PAI-1 were highest in the AF+/thrombus+ group compared to the other two groups. Taken together, the present study reveals apelin/APJ axis might be correlated with thrombosis in patients with AF mediated by PAI-1. PMID- 30518721 TI - Risk factors for postoperative cardiovascular morbidity after pheochromocytoma surgery: a large single center retrospective analysis. AB - Surgical resection is the primary treatment strategy for pheochromocytoma; however, it carries a high risk of morbidity and mortality, especially with respect to cardiovascular complications, which is the most common kinds of morbidity. The risk factors for morbidity remain unclear and require further exploration, moreover no studies focus on risk factors for cardiovascular morbidity. Herein we identified the risk factors for cardiovascular morbidity after pheochromocytoma surgery in Chinese patients. We retrospectively reviewed 262 patients who underwent unilateral surgical resection of pheochromocytoma at our center between 1 January 2007 and 31 December 2016. Patient demographics and extensive perioperative data were recorded and evaluated. Adjusted odds ratios and 95% confidence intervals were determined by multivariate logistic regression. Cut-off values and the area under the curve for continuous risk factors were calculated based on receiver operating characteristic curve analysis. A p-value <0.05 was considered statistically significant. Of the 262 patients, 63 (24.0%) had cardiovascular morbidity. The independent risk factors for cardiovascular morbidity were low body mass index, large radiographic tumor size, coronary heart disease, no preoperative crystal/colloid administration, and intraoperative hemodynamic instability; the corresponding odds ratio were 0.762 (p < 0.001), 1.208 (p = 0.010), 2.378 (p = 0.012), 2.720 (p = 0.011), and 4.764 (p = 0.001), respectively. The optimal cut-off values for body mass index and radiographic tumor size were 24.59 kg/m2 and 6.05 cm. We found that cardiovascular morbidity is common in patients after pheochromocytoma surgery. We identified five independent risk factors for cardiovascular morbidity. Identification of these risk factors may help to improve treatment strategies. PMID- 30518722 TI - Ectopic fat, insulin resistance and metabolic disease in non-obese Asians: investigating metabolic gradation. AB - Although metabolic abnormalities commonly occur in non-obese Asians, their pathogenesis is not fully understood. Proton magnetic resonance spectroscopy has been used to analyze intracellular lipids in humans, and results suggest that ectopic fat accumulation in muscle and liver may induce insulin resistance in each tissue independently of obesity. Thus, measurement of ectopic fat currently plays an important role in the study of insulin resistance in non-obese Asians. In addition, studies using 2-step hyperinsulinemic euglycemic clamp with a glucose tracer may clarify how tissue-specific insulin resistance in muscle, liver, and adipose tissue contributes to the development of metabolic disease in non-obese Japanese. Although numerous studies have elucidated the pathophysiology of insulin resistance in obese subjects, research on "metabolic gradation," defined as the gradual transition from an insulin-sensitive to an insulin resistant state, is less common, especially in terms of early metabolic changes. This review addresses a simple question: when and how is insulin resistance induced in non-obese East Asians? Several studies revealed that impaired insulin clearance and hyperinsulinemia not only compensated for insulin resistance, but also secondarily facilitated insulin resistance and weight gain. In this regard, we recently found that impaired insulin clearance and hyperinsulinemia could occur in apparently healthy subjects without significant insulin resistance, suggesting that this change may be an initial trigger that drives subsequent insulin resistance and weight gain. Further research is required to clarify the pathogenesis of metabolic gradation in non-obese Asians. PMID- 30518723 TI - Off- and on-target effects of genome editing in mouse embryos. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas-based genome editing technology has enabled manipulation of the embryonic genome. Unbiased whole genome sequencing comparing parents to progeny has revealed that the rate of Cas9-induced mutagenesis in mouse embryos is indistinguishable from the background rate of de novo mutation. However, establishing the best practice to confirm on-target alleles of interest remains a challenge. We believe that improvement in editing strategies and screening methods for founder mice will contribute to the generation of quality-controlled animals, thereby ensuring reproducibility of results in animal studies and advancing the 3Rs (replacement, reduction, and refinement). PMID- 30518724 TI - Metabolic discrimination of different Rhodiola species using 1H-NMR and GEP combinational chemometrics. AB - Rhodiola is widely consumed in traditional folk medicine and nutraceuticals. To establish a procedure for the hydrogen nuclear magnetic resonance (1H-NMR) spectroscopic fingerprinting of secondary metabolites from three different Rhodiola species, the variation among three Rhodiola species were studied using 1H-NMR metabolomics combined with multivariate data analysis. Gene expression programming (GEP) was used to generate a formula to distinguish Rhodiola crenulata from two other Rhodiola species. Finally, high-performance liquid chromatography (HPLC) was used to demonstrate the results. Same metabolites were compared by quantitative 1H-NMR (qNMR). Three Rhodiola species were clearly discriminated by 1H-NMR fingerprinting involved 22 nuclear magnetic signals of chemical constituents. y=d166*2+C1+d56+d236-d128*C2 can be used to distinguish R. crenulata from two other Rhodiola species by GEP. The gallic acid concentration in R. crenulata was significantly higher than in the other. Rhodiola species as was the level of salidroside. R. crenulata also exhibited substantially higher levels of alpha-glucose. The fatty acid level in Rhodiola kirilowii was lower than the other species. These findings demonstrated that 1H-NMR fingerprinting combined with principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), hierarchical cluster analysis (HCA) and GEP can be used to distinguish different Rhodiola species and these methods were applicable and effective approaches for metabolic analysis, species differentiation, and quality assessment. In addition, gallic acid, salidroside, alpha-D-glucose, glycine, alanine, caffeic acid and tyrosol and are the discriminators. PMID- 30518725 TI - Identifying Risk Factors for Acute Kidney Injury After Pediatric Cardiac Surgery. PMID- 30518726 TI - Identifying Risk Factors for Acute Kidney Injury After Pediatric Cardiac Surgery Reply. PMID- 30518727 TI - Coefficients in the CAVI Equation and the Comparison Between CAVI With and Without the Coefficients Using Clinical Data. AB - AIM: The Cardio-Ankle Vascular Index (CAVI) is a stiffness index of the arterial tree from the origin of the aorta to the ankle, independent of blood pressure at the time of measurement. The CAVI equation includes the coefficients "a" and "b" to adjust it to the value of Hasegawa's pulse wave velocity, which is compensated for at 80 mmHg of diastolic pressure. To verify this adjustment with the coefficients, the clinical significance of CAVI and CAVI without the coefficients (habeta) were compared in both an epidemiological study and an acute clinical study. METHODS: In the epidemiological study, the significances of CAVI and habeta among people with or without coronary risks such as hypertension, dyslipidemia, hyperglycemia, and abnormal electrocardiography change, were compared. In the acute clinical study, nitroglycerin was administered to subjects in a control group and to coronary artery disease patients, observing CAVI and habeta values over a 20-min period. RESULTS: There was no discrepancy in terms of statistically significant differences between CAVI and habeta among subjects with or without risk factors. Furthermore, there was also no discrepancy in terms of statistically significant differences between CAVI and habeta during the changes of those values following nitroglycerin administration over a 20-min period. CONCLUSION: In both the epidemiologic and clinical studies, there was no discrepancy in terms of significant differences between CAVI and habeta. These results suggest that both are valid as indices of stiffness of the arterial tree from the origin of the aorta to the ankle. PMID- 30518728 TI - Investigation into Lipid Management in Acute Coronary Syndrome Patients from the EXPLORE-J Study. AB - AIMS: The EXPLORE-J study aimed to assess lipid management in patients hospitalized for acute coronary syndrome (ACS) and their cardiovascular risk despite undergoing standard therapy. Here, we focused on background characteristics of patients in the EXPLORE-J study to elucidate the current lipid lowering therapy and its issues in Japan. METHODS: In this multicenter, prospective, observational study (UMIN000018946), consecutive Japanese ACS patients who required hospitalization were registered between April 2015 and August 2016. Background and lipid profile data collected within 14 days of hospitalization were analyzed according to risk factors such as diabetes mellitus status. RESULTS: In total, 1944 patients were analyzed (80.3% male). The mean and standard deviation (SD) age and body mass index of all patients were 66.0 years (SD: 12.2) and 24.24 kg/m2 (SD: 3.59), respectively. The most common lipid modifying medication used at the time of ACS was statins (27.3%). The low-density lipoprotein cholesterol (LDL-C) level (first measurement after hospitalization) of patients overall was 121.3 mg/dL (SD: 40.0); 30.3% had an LDL-C level <100 mg/dL (current target level for secondary prevention of cardiovascular events in Japan), compared with 52.1% of patients with a previous history of coronary artery disease (CAD), and 57.2% of patients with a history of diabetes. CONCLUSIONS: Many patients were not meeting Japanese LDL-C target levels at the time of ACS, and a large proportion of patients meeting target levels developed ACS; therefore, more stringent management and further evaluation of the target LDL-C levels is warranted in high-risk patients and those with previous history of CAD. PMID- 30518729 TI - Associations Between Plasma Betatrophin Levels and Coronary and Peripheral Artery Disease. AB - AIM: Betatrophin, a recently identified circulating adipokine, affects lipid and glucose metabolism. However, association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated. METHODS: We investigated plasma betatrophin levels in 457 patients undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening. RESULTS: Of the 457 study patients, CAD was present in 241 patients (53%) (1-vessel [1-VD], n=99; 2 vessel [2-VD], n=71; 3-vessel disease [3-VD], n=71). Compared to 216 patients without CAD, 241 with CAD had higher betatrophin levels (median 1120 vs. 909 pg/mL, p<0.001). A stepwise increase in betatrophin levels was found depending on the number of >50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD, and 1393 pg/ml in 3-VD (p<0.001). Betatrophin levels correlated with the number of >25% stenotic segments (r=0.24,p<0.001). PAD (ABI<0.9) was found in 41 patients (9%). Plasma betatrophin levels were also significantly higher in 41 patients with PAD than in 416 without PAD (1354 vs. 981 pg/mL, p<0.001). In the multivariate analysis, betatrophin levels were not a factor for CAD, but they were a significant factor for 3-VD and PAD independent of atherosclerotic risk factors. The odds ratios for 3-VD and PAD were 1.06 (95%CI=1.01-1.11) and 1.07 (95%CI=1.01-1.13) for a 100-pg/mL increase in betatrophin levels, respectively (p<0.05). CONCLUSION: Plasma betatrophin levels were associated with the presence and severity of CAD and PAD, suggesting betatrophin has a role in atherosclerosis. PMID- 30518730 TI - Early Out-of-Bed Functional Exercise Benefits Elderly Patients Following Hip Fracture: A Retrospective Cohort Study. AB - Hip fracture is a worldwide medical problem with devastating consequences. Older adults are at higher risk for complications and have more mobility limitation. The aim of this study was to assess the impact of delay in out-of-bed functional exercise on one-year mortality and functional outcomes for elderly patients with hip fracture in China. 1,022 cases of patients with hip fracture who were older than 75 were involved in this retrospective cohort study between 2007 and 2017. One-year mortality, follow up Activities of Daily Living (ADL) score, and Harris hip score were collected. Patients with hip fracture experienced an average of 2.9 days of in-bed functional exercise, 41.4% (n = 423) taken out-of-bed functional exercise within 2 days. A Cox proportional regression model showed that after adjustment for age, sex, cardiovascular disease, and urinary disease, delayed out-of-bed functional exercise (> 2 days) associated with higher one-year mortality (OR = 1.38, 95% confidence interval [CI]: 1.09 to 1.69). Ordinary least squares regression showed that delayed out-of-bed functional exercise associated with worsen ADL scores at 1-month (difference of -3.9 points, 95% CI: -6.4 to 1.7), although the long term ADL scores did not have increased. In addition, there were no associations between out-of-bed functional exercise timing and the Harris hip score at 12 months. In conclusion, in elderly patients with hip fracture in China, delayed out-of-bed functional exercise was not associated with improved Harris hip score, but it was associated with worsen ADL capacities at 1 month postoperatively and higher one-year mortality. The present study emphasizes the benefit of early out-of-bed exercise on the majority of elderly patients with hip fracture. PMID- 30518732 TI - Altered Gut Flora and Gut Microbiome-Derived Metabolites in Heart Failure Patients in the Compensated and Decompensated Phases. PMID- 30518731 TI - Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan - Insights From GARFIELD-AF. AB - BACKGROUND: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC+/-antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. CONCLUSIONS: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world. PMID- 30518733 TI - Improved Visualization of Middle Ear Cholesteatoma with Computed Diffusion weighted Imaging. AB - Computed DWI (cDWI) is a mathematical technique that calculates arbitrary higher b value images from at least two different lower b values. In addition, the removal of high intensity noise with image processing on cDWI could improve cholesteatoma-background contrast-to-noise ratio (CNR). In the present study, noise reduction was performed by the cut-off values of apparent diffusion coefficient (ADC) less than 0 and 0.4 * 10-3 s/mm2. The cholesteatoma to non cholesteatoma CNR was increased using a noise reduction algorithm for clinical setting. PMID- 30518734 TI - Regression of White Matter Hyperintensity after Indirect Bypass Surgery in a Patient with Moyamoya Disease. PMID- 30518735 TI - A Pitfall for Diffusion-weighted MR Imaging When Assessing the Response to Neoadjuvant Chemotherapy in Ewing Sarcoma. PMID- 30518736 TI - Intraoperative rapid aspiration cytological method for parathyroid glands identification and protection. AB - To explore new methods for intraoperative identification of parathyroid glands, 86 thyroid cancer patients, admitted to Xijing hospital from July 2017 to July 2018, were included. During lymph node dissection, parathyroid glands were firstly judged by clinician eyeballing, based on his clinical experience. Then, cytological detection was used for rapid identification via Diff-quik staining. PTH monitoring was performed by PTH detection kit. Finally, frozen pathology was examined and regarded as the golden standard. In this study, 172 suspicious parathyroid glands were observed. According to frozen pathology outcome, the accuracy, sensitivity and specificity of clinician eyeballing were calculated as 63.3%, 100%, and 13.9%. Kappa test showed poor consistency (kappa = 0.156), AUC area was 0.569 +/- 0.045, 95%CI = (0.480-0.658), p = 0.123. For cytological and PTH detection, the accuracy, sensitivity and specificity were 91.7% vs. 92.3%, 93.6% vs. 93.8% and 89.0% vs. 90.3%. Kappa value was 0.829 vs. 0.842, indicating good consistency. AUC area was 0.908 +/- 0.027 vs. 0.918 +/- 0.025, 95%CI = (0.856-0.960) vs. (0.869-0.966), p < 0.001, indicating higher diagnositic value. Besides, compared with frozen pathology, cytological detection was easily and rapid. The time-taking between frozen pathology and cytological detection or PTH detection were 39.0 +/- 6.59 min vs. 5.02 +/- 0.78 min and 39.0 +/- 6.59 min vs. 6.1 +/- 1.23 min, p < 0.001. In conclusion, intra-operative cytological detection maybe potential for in-situ preservation of parathyroid glands. PMID- 30518737 TI - Interaction of ovarian steroidogenesis and clock gene expression modulated by bone morphogenetic protein-7 in human granulosa cells. AB - A functional link between clock gene expression and ovarian steroidogenesis was studied using human granulosa KGN cells. Similarities between changes in the mRNA and protein expression levels of Bmal1 and Clock and those of Per2 and Cry1 were found in KGN cells after treatment with forskolin. Among the interrelationships between the expression levels of clock and steroidogenic factors, Clock mRNA had a strongly positive correlation with P450arom and a negative correlation with 3betaHSD. Knockdown of Clock gene by siRNA resulted in a significant reduction of estradiol production by inhibiting P450arom expression, while it induced a significant increase of progesterone production by upregulating 3betaHSD in KGN cells treated with forskolin. Moreover, BMP-7 had an enhancing effect on the expression of Clock mRNA and protein in KGN cells. Thus, the expression levels of Clock, being upregulated by forskolin and BMP-7, were functionally linked to estradiol production and progesterone suppression by human granulosa cells. PMID- 30518738 TI - Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice. AB - BACKGROUND: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of beta-adrenergic receptor (beta-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. CONCLUSIONS: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice. PMID- 30518739 TI - European Society of Cardiology (ESC) Annual Congress Report From Munich 2018. PMID- 30518740 TI - Comparative Analysis of the Genetic Basis of Branched Nonylphenol Degradation by Sphingobium amiense DSM 16289T and Sphingobium cloacae JCM 10874T. AB - Branched nonylphenol (BNP), a degradation product of nonylphenol polyethoxylates, exerts estrogenic effects on various organisms. The genes underlying BNP degradation by Sphingobium amiense DSM 16289T were analyzed by complete genome sequencing and compared with those of the versatile BNP-degrading Sphingobium cloacae JCM 10874T. An opdA homolog (opdADSM16289) encoding BNP degradation activity was identified in DSM 16289T, in contrast with JCM 10874T, possessing both the opdA homolog and nmoA. The degradation profile of different BNP isomers was examined by Escherichia coli transformants harboring opdADSM16289, opdAJCM10874, and nmoAJCM10874 to characterize and compare the expression activities of these genes. PMID- 30518741 TI - Acknowledgment of Reviewers. PMID- 30518742 TI - Zhongfenggao protects brain microvascular endothelial cells from oxygen-glucose deprivation/reoxygenation-induced injury by angiogenesis. AB - Zhongfenggao (ZFG) is prescribed for the treatment of cerebrovascular diseases in critical projects of the State Administration of Traditional Chinese Medicine. ZFG has been found to nourish qi, activate blood circulation, remove blood stasis, dredge collaterals, and strengthen the brain and mind. The present study investigated the effects of ZFG on oxygen-glucose deprivation/reoxygenation (OGD/R) induced injury to brain microvascular endothelial cells (BMECs), and the mechanisms underlying such effects. BMECs are essential target cells of ischemic stroke. In order to simulate ischemic-like conditions in vitro, BMECs were exposed to glucose deprivation and hypoxia for 2 h. Results indicate that ZFG may protect OGD/R-induced injury to BMECs by promoting angiogenesis. Further, we observed that ZFG significantly inhibited apoptosis induced by OGD/R injury. ZFG significantly promoted migration and microtubule formation in BMECs under OGD/R conditions. Additionally, ZFG increased levels of the vascular endothelial growth factor (VEGF) significantly and activated the Notch and Wnt signaling pathways. The results of the present study indicate that ZFG may display a protective effect against OGD/R-induced BMECs injury by promoting angiogenesis via Notch and Wnt signaling pathways. These results provide novel insights into the mechanisms underlying the therapeutic action of ZFG which shows promise as a potential drug candidate for treating cerebral ischemia/reperfusion. PMID- 30518743 TI - Acute Pulmonary Edema in a Pregnant Patient with Undiagnosed Levo-Transposition of the Great Arteries. AB - BACKGROUND Levo-transposition of the great arteries (L-TGA) is a rare form of congenital heart disease that may go unrecognized until adulthood. Parturient women with L-TGA have a high likelihood of developing acute pulmonary edema and cardiac dysrhythmias during the peri-partum period. CASE REPORT We present the case of a 32-year-old primigravida patient with previously unknown diagnosis of L TGA, presenting with preeclampsia, whose peri-partum course was complicated by the development of acute pulmonary edema, complete heart block, and acute hypoxic respiratory failure. CONCLUSIONS This case report highlights the predisposition of parturient women with undiagnosed congenital heart disease to develop acute hypoxic respiratory failure in the perioperative period and the importance of meticulous fluid management in such patients. PMID- 30518744 TI - miR-29 Family Inhibits Resistance to Methotrexate and Promotes Cell Apoptosis by Targeting COL3A1 and MCL1 in Osteosarcoma. AB - BACKGROUND MicroRNAs (miRNAs) play a crucial role in regulating diverse biological processes, including drug resistance. We investigated the potential roles of the miR-29 family in methotrexate (MTX) resistance in osteosarcoma. MATERIAL AND METHODS Two MTX-resistant osteosarcoma cell lines, MG-63/MTX and U2OS/MTX, were generated by continuous exposure to stepwise increasing concentrations of MTX. miR-29abc, COL3A1, and MCL1 mRNA expression levels were determined using quantitative real-time PCR (qRT-PCR). Protein expression levels of COL3A1 and MCL1 were detected by Western blot. Cell viability, IC50 value, and cell apoptosis were assessed by CCK-8 assay and flow cytometry, respectively. The target relationship between the miR-29 family and COL3A1 or MCL1 was confirmed by luciferase reporter assay. RESULTS miR-29a, miR-29b, and miR-29c were significantly downregulated in MG-63/MTX and U2OS/MTX cells and in chemotherapy poor-response osteosarcoma tissues. Overexpression of the miR-29 family sensitized MG-63/MTX and U2OS/MTX cells to MTX and obviously promoted cell apoptosis compared with negative control. COL3A1 and MCL1 were identified to be target genes of the miR-29 family, and transfection with miR-29abc mimics in MG 63/MTX and U2OS/MTX cells decreased COL3A1 and MCL1 mRNA and protein expression. Meanwhile, overexpression of COL3A1 and MCL1 partly neutralized the effects of the miR-29 family on MTX resistance and cell apoptosis. CONCLUSIONS Taken together, our findings suggested a tumor-suppressor role of the miR-29 family in control of MTX resistance and cell apoptosis through regulating COL3A1 or MCL1. Targeting the miR-29 family might provide new strategies to overcome the high dosage MTX-induced cytotoxicity in osteosarcoma treatment. PMID- 30518745 TI - Differential effects of type 1 diabetes mellitus and subsequent osteoblastic beta catenin activation on trabecular and cortical bone in a mouse model. AB - Type 1 diabetes mellitus (T1DM) is a pathological condition associated with osteopenia. WNT/beta-catenin signaling is implicated in this process. Trabecular and cortical bone respond differently to WNT/beta-catenin signaling in healthy mice. We investigated whether this signaling has different effects on trabecular and cortical bone in T1DM. We first established a streptozotocin-induced T1DM mouse model and then constitutively activated beta-catenin in osteoblasts in the setting of T1DM (T1-CA). The extent of bone loss was greater in trabecular bone than that in cortical bone in T1DM mice, and this difference was consistent with the reduction in the expression of beta-catenin signaling in the two bone compartments. Further experiments demonstrated that in T1DM mice, trabecular bone showed lower levels of insulin-like growth factor-1 receptor (IGF-1R) than the levels in cortical bone, leading to lower WNT/beta-catenin signaling activity through the inhibition of the IGF-1R/Akt/glycogen synthase kinase 3beta (GSK3beta) pathway. After beta-catenin was activated in T1-CA mice, the bone mass and bone strength increased to substantially greater extents in trabecular bone than those in cortical bone. In addition, the cortical bone of the T1-CA mice displayed an unexpected increase in bone porosity, with increased bone resorption. The downregulated expression of WNT16 might be responsible for these cortical bone changes. In conclusion, we found that although the activation of WNT/beta-catenin signaling increased the trabecular bone mass and bone strength in T1DM mice, it also increased the cortical bone porosity, impairing the bone strength. These findings should be considered in the future treatment of T1DM related osteopenia. PMID- 30518746 TI - The spatial distribution pattern of Connexin26 expression in supporting cells and its role in outer hair cell survival. AB - Mutations in the GJB2 gene (which encodes Connexin26 (Cx26)) account for about a quarter of all cases of non-syndromic deafness. Previous studies have indicated that knockout (KO) of Gjb2 gene during early postnatal days can cause outer hair cell (OHC) loss in mouse models. However, the postnatal spatial distribution pattern of Cx26 in different types of supporting cells (SCs) and the role of such distributions for the survival of OHCs is still obscure. In this study, the spatial distribution patterns of Cx26 in SCs were observed, and based on these observations different spatial Cx26-null mouse models were established in order to determine the effect of changes in the spatial distribution of Cx26 in SCs on the survival of OHCs. At postnatal day (P)3, unlike the synchronous expression of Cx26 along both longitudinal and radial boundaries of most types of SCs, Cx26 expression was primarily observed along the longitudinal boundaries of rows of Deiter's cells (DCs). From P5 to P7, radial expression of Cx26 was gradually observed between adjacent rows of DCs. When Gjb2 gene was knocked out at random in different types of SCs, about 40% of the total DCs lost Cx26 expression and these Cx26-null DCs were distributed randomly in all three rows of DCs. The mice in this randomly Cx26-null group showed normal hearing and no significant OHC loss. When using a longitudinal KO pattern to induce knockout of Gjb2 gene specifically in the third row of DCs, about 33% of the total DCs lost Cx26 expression in this specific longitudinally Cx26-null group. The mice in this group showed late-onset hearing loss and significant OHC loss, however, the morphology of corresponding DCs was slightly altered. In both experimental groups, no substantial DC loss was observed. These results indicate that longitudinal Cx26-based channels are predominant in DCs during P3-P5. The Cx26 expression along rows of DCs might play a key role in the survival of OHCs, but this longitudinal KO pattern in DCs has a limited effect on DC survival or on its postnatal development. PMID- 30518747 TI - Inactivation of Lon protease reveals a link between mitochondrial unfolded protein stress and mitochondrial translation inhibition. AB - The mitochondrial Unfolded Protein Response (UPRmt) pathway confers protection from misfolded and aggregated proteins by activating factors that promote protein folding and degradation. Our recent work on Lon protease, a member of the mitochondrial ATPase Associated with diverse cellular Activities (AAA+) family of mitochondrial resident proteases, suggests that mitochondrial translational inhibition may also be a feature of the UPRmt pathway. PMID- 30518748 TI - A novel lncRNA, TCONS_00006195, represses hepatocellular carcinoma progression by inhibiting enzymatic activity of ENO1. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies and has an unfavorable prognosis. The hepatitis B virus X (HBx) protein has been reported to be closely associated with hepatocarcinogenesis. Meanwhile, emerging evidence has indicated that long noncoding RNAs (lncRNAs) are involved in the pathogenesis and progression of cancers. Our previous investigation has demonstrated that HBx could promote HCC by regulating the expression levels of various lncRNAs. In this study, we identified an lncRNA, lncRNA-TCONS_00006195 (termed lncRNA-6195), which was downregulated in HBV-related HCC tissues compared with its expression in adjacent noncancerous hepatic tissues. Clinical data showed that a low level of lncRNA-6195 was correlated with a high Edmondson-Steiner grade of the tumor and a poor prognosis in HCC patients. Furthermore, lncRNA-6195 acted as a tumor repressor in the development of hepatitis B-related HCC, inhibiting HCC cell proliferation in vitro and in vivo. Moreover, lncRNA-6195 could combine with alpha-enolase (ENO1) and repress its enzymatic activity, thus further inhibiting the energy metabolism in HCC cells. Our results suggest that lncRNA-6195 represses the growth of HCC by inhibiting the enzymatic activity of ENO1. These findings provide new insights into the mechanisms underlying the lncRNA involvement in hepatocarcinogenesis and can serve as a basis for the development of novel strategies to hinder HCC. PMID- 30518749 TI - Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sezary syndrome. AB - Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sezary syndrome are the most common histological subtypes. Although next generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sezary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such as TP53, PTEN, and RB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found that ZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevant ZEB1 germline variants. The survival analysis shows a worse clinical course for patients with ZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated with ZEB1 depletion in Sezary patients we verified that ZEB1 exerts a role in oxidative response of Sezary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization of ZEB1 abnormalities in Sezary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, that ZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence that ZEB1 activity in Sezary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis. PMID- 30518750 TI - NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells. AB - Accumulating evidence has highlighted the potential role of non-coding RNAs (ncRNAs) and upstream open-reading frames (uORFs) in the biological behaviors of glioblastoma. Here, we elucidated the function and possible molecular mechanisms of the effect of some ncRNAs and NR2C2-uORF on the biological behaviors of gliomas. Quantitative real-time PCR was conducted to profile the cell expression of lnc-UCA1 and microRNA-627-5p (miR-627-5p) in glioma tissues and cells. Western blot assay was used to determine the expression levels of NR2C2, SPOCK1, and NR2C2-uORF in glioma tissues and cells. Stable knockdown of lnc-UCA1 or overexpression of miR-627-5p in glioma cell lines (U87 and U251) were established to explore the function of lnc-UCA1 and miR-627-5p in glioma cells. Further, Dual luciferase report assay was used to investigate the correlation between lnc-UCA1 and miR-627-5p. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate lnc-UCA1 and miR-627-5p function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between NR2C2 and SPOCK1 as well as NR2C2 between lnc-UCA1. This study confirmed that lnc-UCA1 was up-regulated in glioma tissues and cells. UCA1 knockdown inhibited the malignancies of glioma cells by reducing proliferation, migration, and invasion, but inducing apoptosis. We found that lnc-UCA1 acted as miR-627-5p sponge in a sequence-specific manner. Meanwhile, upregulated lnc-UCA1 inhibited miR-627-5p expression. In addition, miR 627-5p targeted 3'UTR of NR2C2 and down-regulated its expression. Moreover, UCA1 knockdown impaired NR2C2 expression by upregulating miR-627-5p. An uORF was identified in mRNA 5'UTR of NR2C2 and overexpression of whom negatively regulated NR2C2 expression. Remarkably, lnc-UCA1 knockdown combined with uORF overepression and NR2C2 knockdown led to severe tumor suppression in vivo. This study demonstrated that the NR2C2-uORF impaired the pivotal roles that UCA1-miR-627-5p NR2C2 feedback loop had in regulating the malignancies of glioma cells by targeting NR2C2 directly. And this may provide a potential therapeutic strategy for treating glioma. PMID- 30518751 TI - Identification of potential genetic risk factors for bipolar disorder by whole exome sequencing. AB - This study aims at assessing the burden of rare (minor allele frequency < 1%) predicted damaging variants in the whole exome of 92 bipolar I disorder (BD) patients and 1051 controls of French ancestry. Patients exhibiting an extreme phenotype (earlier onset and family history of mood disorder) were preferentially included to increase the power to detect an association. A collapsing strategy was used to test the overall burden of rare variants in cases versus controls at the gene level. Only protein-truncating and predicted damaging missense variants were included in the analysis. Thirteen genes exhibited p values exceeding 10-3 and could be considered as potential risk factors for BD. Furthermore, the validity of the association was supported when the Exome Aggregation Consortium database non-Finnish European population was used as controls for eight of them. Their gene products are involved in various cerebral processes, some of which were previously implicated in BD and belong to pathways implicated in the therapeutic effect of lithium, the main mood stabilizer. However, exome-wide threshold for association study was not reached, emphasizing that larger samples are needed. PMID- 30518752 TI - Daily changes in phytoplankton lipidomes reveal mechanisms of energy storage in the open ocean. AB - Sunlight is the dominant control on phytoplankton biosynthetic activity, and darkness deprives them of their primary external energy source. Changes in the biochemical composition of phytoplankton communities over diel light cycles and attendant consequences for carbon and energy flux in environments remain poorly elucidated. Here we use lipidomic data from the North Pacific subtropical gyre to show that biosynthesis of energy-rich triacylglycerols (TAGs) by eukaryotic nanophytoplankton during the day and their subsequent consumption at night drives a large and previously uncharacterized daily carbon cycle. Diel oscillations in TAG concentration comprise 23 +/- 11% of primary production by eukaryotic nanophytoplankton representing a global flux of about 2.4 Pg C yr-1. Metatranscriptomic analyses of genes required for TAG biosynthesis indicate that haptophytes and dinoflagellates are active members in TAG production. Estimates suggest that these organisms could contain as much as 40% more calories at sunset than at sunrise due to TAG production. PMID- 30518753 TI - Wavepacket insights into the photoprotection mechanism of the UV filter methyl anthranilate. AB - Meradimate is a broad-spectrum ultraviolet absorber used as a chemical filter in commercial sunscreens. Herein, we explore the ultrafast photodynamics occurring in methyl anthranilate (precursor to Meradimate) immediately after photoexcitation with ultraviolet radiation to understand the mechanisms underpinning Meradimate photoprotection. Using time-resolved photoelectron spectroscopy, signal from the first singlet excited state of methyl anthranilate shows an oscillatory behavior, i.e., quantum beats. Our studies reveal a dependence of the observed beating frequencies on photoexcitation wavelength and photoelectron kinetic energy, unveiling the different Franck-Condon overlaps between the vibrational levels of the ground electronic, first electronic excited, and ground cationic states of methyl anthranilate. By evaluating the behavior of these beats with increasing photon energy, we find evidence for intramolecular vibrational energy redistribution on the first electronic excited state. Such energy redistribution hinders efficient relaxation of the electronic excited state, making methyl anthranilate a poor choice for an efficient, efficacious sunscreen chemical filter. PMID- 30518754 TI - Population coding of valence in the basolateral amygdala. AB - The basolateral amygdala (BLA) plays important roles in associative learning, by representing conditioned stimuli (CSs) and unconditioned stimuli (USs), and by forming associations between CSs and USs. However, how such associations are formed and updated remains unclear. Here we show that associative learning driven by reward and punishment profoundly alters BLA population responses, reducing noise correlations and transforming the representations of CSs to resemble the valence-specific representations of USs. This transformation is accompanied by the emergence of prevalent inhibitory CS and US responses, and by the plasticity of CS responses in individual BLA neurons. During reversal learning wherein the expected valences are reversed, BLA population CS representations are remapped onto ensembles representing the opposite valences and predict the switching in valence-specific behaviors. Our results reveal how signals predictive of opposing valences in the BLA evolve during learning, and how these signals are updated during reversal learning thereby guiding flexible behaviors. PMID- 30518755 TI - Severity of enterovirus A71 infection in a human SCARB2 knock-in mouse model is dependent on infectious strain and route. AB - Enterovirus A71 (EV-A71) is a major etiological agent of human hand, foot and mouth disease, and it can cause severe neurological complications. Although several genotypes of EV-A71 strains are prevalent in different regions of the world, the genotype C4 has circulated in mainland China for more than 20 years. The pathogenicity of different EV-A71 clinical isolates varies and needs to be explored. In this study, hSCARB2 knock-in mice (N = 181) with a wide range of ages were tested for their susceptibility to two EV-A71 strains with the subgenotypes C4 and C2, and two infection routes (intracranial and venous) were compared. The clinical manifestations and pathology and their relationship to the measured viral loads in different tissues were monitored. We observed that 3 weeks is a crucial age, as mice younger than 3-week-old that were infected became extremely ill. However, mice older than 3 weeks displayed diverse clinical symptoms. Significant differences were observed in the pathogenicity of the two strains with respect to clinical signs, disease incidence, survival rate, and body weight change. We concluded that hSCARB2 knock-in mice are a sensitive model for investigating the clinical outcomes resulting from infection by different EV A71 strains. The intracranial infection model appears to be suitable for evaluating EV-A71 neurovirulence, whereas the venous infection model is appropriate for studying the pathogenicity of EV-A71. PMID- 30518757 TI - A semi-supervised approach for predicting cell-type specific functional consequences of non-coding variation using MPRAs. AB - Predicting the functional consequences of genetic variants in non-coding regions is a challenging problem. We propose here a semi-supervised approach, GenoNet, to jointly utilize experimentally confirmed regulatory variants (labeled variants), millions of unlabeled variants genome-wide, and more than a thousand cell/tissue type specific epigenetic annotations to predict functional consequences of non coding variants. Through the application to several experimental datasets, we demonstrate that the proposed method significantly improves prediction accuracy compared to existing functional prediction methods at the tissue/cell type level, but especially so at the organism level. Importantly, we illustrate how the GenoNet scores can help in fine-mapping at GWAS loci, and in the discovery of disease associated genes in sequencing studies. As more comprehensive lists of experimentally validated variants become available over the next few years, semi supervised methods like GenoNet can be used to provide increasingly accurate functional predictions for variants genome-wide and across a variety of cell/tissue types. PMID- 30518756 TI - uPARAP/Endo180 receptor is a gatekeeper of VEGFR-2/VEGFR-3 heterodimerisation during pathological lymphangiogenesis. AB - The development of new lymphatic vessels occurs in many cancerous and inflammatory diseases through the binding of VEGF-C to its receptors, VEGFR-2 and VEGFR-3. The regulation of VEGFR-2/VEGFR-3 heterodimerisation and its downstream signaling in lymphatic endothelial cells (LECs) remain poorly understood. Here, we identify the endocytic receptor, uPARAP, as a partner of VEGFR-2 and VEGFR-3 that regulates their heterodimerisation. Genetic ablation of uPARAP leads to hyperbranched lymphatic vasculatures in pathological conditions without affecting concomitant angiogenesis. In vitro, uPARAP controls LEC migration in response to VEGF-C but not VEGF-A or VEGF-CCys156Ser. uPARAP restricts VEGFR-2/VEGFR-3 heterodimerisation and subsequent VEGFR-2-mediated phosphorylation and inactivation of Crk-II adaptor. uPARAP promotes VEGFR-3 signaling through the Crk II/JNK/paxillin/Rac1 pathway. Pharmacological Rac1 inhibition in uPARAP knockout mice restores the wild-type phenotype. In summary, our study identifies a molecular regulator of lymphangiogenesis, and uncovers novel molecular features of VEGFR-2/VEGFR-3 crosstalk and downstream signaling during VEGF-C-driven LEC sprouting in pathological conditions. PMID- 30518758 TI - NSD2 is a conserved driver of metastatic prostate cancer progression. AB - Deciphering cell-intrinsic mechanisms of metastasis progression in vivo is essential to identify novel therapeutic approaches. Here we elucidate cell intrinsic drivers of metastatic prostate cancer progression through analyses of genetically engineered mouse models (GEMM) and correlative studies of human prostate cancer. Expression profiling of lineage-marked cells from mouse primary tumors and metastases defines a signature of de novo metastatic progression. Cross-species master regulator analyses comparing this mouse signature with a comparable human signature identifies conserved drivers of metastatic progression with demonstrable clinical and functional relevance. In particular, nuclear receptor binding SET Domain Protein 2 (NSD2) is robustly expressed in lethal prostate cancer in humans, while its silencing inhibits metastasis of mouse allografts in vivo. We propose that cross-species analysis can elucidate mechanisms of metastasis progression, thus providing potential additional therapeutic opportunities for treatment of lethal prostate cancer. PMID- 30518759 TI - Variant of SNP rs1317082 at CCSlnc362 (RP11-362K14.5) creates a binding site for miR-4658 and diminishes the susceptibility to CRC. AB - Genome-wide association studies (GWAS) have identified several loci harboring variants that affected the risk of colorectal cancer; however, the specific mechanisms by which germline variation influenced the tumorigenesis of colorectal cancer (CRC) remains unrevealed. We found the T>C variant of rs1317082, locating at the exon 1 of lncRNA RP11-362K14.5 (CCSlnc362), was predicted to be a protective locus for cancer. However, the specific role of CCSlnc362 and the interaction between CCSlnc362 and rs1317082 variation in colorectal cancer and its mechanisms remain unclear. Here we explored the expression and function of CCSlnc362 in CRC cells and tissues. We found lncRNA CCSlnc362 expression was significantly increased in CRC samples. Follow-up functional experiments elucidated that downregulation of CCSlnc362 inhibited cell proliferation, arrested cell cycle, and promoted apoptosis in CRC cells. The T>C variant of rs1317082 at CCSlnc362 exon 1 created a binding site for miR-4658 to reduce the expression of CCSlnc362 and thus decreased the susceptibility to CRC. Our findings have provided supporting evidence for the protective role of rs1317082 variation and the potential oncogenic role of lncRNA CCSlnc362 in CRC. The data shed new light on the relationship between germline variation, miRNAs, and lncRNAs and opened a new avenue for targeted therapy in CRC. PMID- 30518760 TI - Long non-coding RNA C5orf66-AS1 promotes cell proliferation in cervical cancer by targeting miR-637/RING1 axis. AB - Long non-coding RNA (lncRNA) plays an important role in the development of human malignant tumours. Recently, an increasing number of lncRNAs have been identified and investigated in a variety of tumours. However, the expression pattern and biological function of lncRNAs in cervical cancer still remain largely unexplored. Differentially expressed lncRNAs in cervical cancer and para carcinoma tissues were identified by screening using The Cancer Genome Atlas (TCGA), and candidate lncRNAs were verified by quantitative real-time PCR. We found that lncRNAC5orf66-AS1 was significantly upregulated in cervical cancer tissues and cells. Over-expression of C5orf66-AS1 promoted the proliferation of cervical cancer cells, while downregulation of C5orf66-AS1 promoted the apoptosis of cervical cancer cells. C5orf66-AS1 was identified as the sponge of miR-637 by RNA immunoprecipitation (RIP) and luciferase reporter assays. Exogenous miR-637 and RING1 interventions could reverse the proliferation ability mediated by C5orf66-AS1 in cervical cancer cells. In vivo experiments also confirmed that downregulation of C5orf66-AS1 inhibited the tumour growth. LncRNA C5orf66-AS1, as a competitive endogenous RNA (ceRNA), regulated the effect of RING1 on the proliferation, apoptosis and cell cycle of cervical cancer cells through adsorbing miR-637. Taken together, our findings provided a new theoretical and experimental basis for investigating the pathogenesis and exploring effective therapeutic targets for cervical cancer. PMID- 30518761 TI - SUMO conjugation to the pattern recognition receptor FLS2 triggers intracellular signalling in plant innate immunity. AB - Detection of conserved microbial patterns by host cell surface pattern recognition receptors (PRRs) activates innate immunity. The FLAGELLIN-SENSITIVE 2 (FLS2) receptor perceives bacterial flagellin and recruits another PRR, BAK1 and the cytoplasmic-kinase BIK1 to form an active co-receptor complex that initiates antibacterial immunity in Arabidopsis. Molecular mechanisms that transmit flagellin perception from the plasma-membrane FLS2-associated receptor complex to intracellular events are less well understood. Here, we show that flagellin induces the conjugation of the SMALL UBIQUITIN-LIKE MODIFIER (SUMO) protein to FLS2 to trigger release of BIK1. Disruption of FLS2 SUMOylation can abolish immune responses, resulting in susceptibility to bacterial pathogens in Arabidopsis. We also identify the molecular machinery that regulates FLS2 SUMOylation and demonstrate a role for the deSUMOylating enzyme, Desi3a in innate immunity. Flagellin induces the degradation of Desi3a and enhances FLS2 SUMOylation to promote BIK1 dissociation and trigger intracellular immune signalling. PMID- 30518762 TI - Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities. AB - Clinical studies of non-communicable diseases identify multimorbidities that suggest a common set of predisposing factors. Despite the fact that humans have ~24,000 genes, we do not understand the genetic pathways that contribute to the development of multimorbid non-communicable disease. Here we create a multimorbidity atlas of traits based on pleiotropy of spatially regulated genes. Using chromatin interaction and expression Quantitative Trait Loci (eQTL) data, we analyse 20,782 variants (p < 5 * 10-6) associated with 1351 phenotypes to identify 16,248 putative spatial eQTL-eGene pairs that are involved in 76,013 short- and long-range regulatory interactions (FDR < 0.05) in different human tissues. Convex biclustering of spatial eGenes that are shared among phenotypes identifies complex interrelationships between nominally different phenotype associated SNPs. Our approach enables the simultaneous elucidation of variant interactions with target genes that are drivers of multimorbidity, and those that contribute to unique phenotype associated characteristics. PMID- 30518763 TI - Medullary bone in an Early Cretaceous enantiornithine bird and discussion regarding its identification in fossils. AB - Medullary bone is an ephemeral type of bone tissue, today found only in sexually mature female birds, that provides a calcium reservoir for eggshell formation. The presence of medullary bone-like tissues in extant birds, pterosaurs, and dinosaurs distantly related to birds shows that caution must be exercised before concluding that fossils bear medullary bone. Here we describe a new specimen of pengornithid enantiornithine from the Lower Cretaceous Jiufotang Formation. Consisting of an isolated left hindlimb, the three-dimensional preservation contrasts with the crushed preservation characteristic of most Jehol specimens. Histological examinations suggest this resulted from the presence of a thick layer of highly vascular bone spanning the medullary cavities of the femur and tibiotarsus, consistent with expectations for medullary bone in extant birds. Micro-computed tomographic scans reveal small amounts of the same tissue extending into the pedal phalanges. We consider the tissue to be homologous to the medullary bone of Neornithines. PMID- 30518764 TI - Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice. AB - The pace of repair declines with age and, while exposure to a young circulation can rejuvenate fracture repair, the cell types and factors responsible for rejuvenation are unknown. Here we report that young macrophage cells produce factors that promote osteoblast differentiation of old bone marrow stromal cells. Heterochronic parabiosis exploiting young mice in which macrophages can be depleted and fractionated bone marrow transplantation experiments show that young macrophages rejuvenate fracture repair, and old macrophage cells slow healing in young mice. Proteomic analysis of the secretomes identify differential proteins secreted between old and young macrophages, such as low-density lipoprotein receptor-related protein 1 (Lrp1). Lrp1 is produced by young cells, and depleting Lrp1 abrogates the ability to rejuvenate fracture repair, while treating old mice with recombinant Lrp1 improves fracture healing. Macrophages and proteins they secrete orchestrate the fracture repair process, and young cells produce proteins that rejuvenate fracture repair in mice. PMID- 30518765 TI - Spatial analysis of the geographical distribution of thyroid cancer cases from the first-round thyroid ultrasound examination in Fukushima Prefecture. AB - Following the Fukushima Daiichi Nuclear Power Plant (FNPP) accident on 11 March 2011, there have been concerns regarding the health impacts of the ensuing radioactive environmental contamination, which was spatially heterogeneous. This study aimed to assess the geographical variability of thyroid cancer prevalence among children and adolescents in Fukushima Prefecture. We computed the sex- and age-standardised prevalence ratio using 115 diagnosed or suspected thyroid cancer cases among approximately 300,000 examinees at the first-round ultrasound examination during 2011-2015 from 59 municipalities in the prefecture, under the Fukushima Health Management Survey. We applied flexibly shaped spatial scan statistics and the maximised excess events test on the dataset to detect locally anomalous high-prevalence regions. We also conducted Poisson regression with selected regional indicators. Furthermore, approximately 200 examinees showed positive ultrasound examination results but did not undergo confirmatory testing; thus, we employed simulation-based sensitivity tests to evaluate the possible effect of such undiagnosed cases in the statistical analysis. In conclusion, this study found no significant spatial anomalies/clusters or geographic trends of thyroid cancer prevalence among the ultrasound examinees, indicating that the thyroid cancer cases detected are unlikely to be attributable to regional factors, including radiation exposure resulting from the FNPP accident. PMID- 30518766 TI - Circulating small non-coding RNAs associated with age, sex, smoking, body mass and physical activity. AB - Small non-coding RNAs (sncRNA) are regulators of cell functions and circulating sncRNAs from the majority of RNA classes are potential non-invasive biomarkers. Understanding how common traits influence ncRNA expression is essential for assessing their biomarker potential. In this study, we identify associations between sncRNA expression and common traits (sex, age, self-reported smoking, body mass, self-reported physical activity). We used RNAseq data from 526 serum samples from the Janus Serum Bank and traits from health examination surveys. Ageing showed the strongest association with sncRNA expression, both in terms of statistical significance and number of RNAs, regardless of RNA class. piRNAs were abundant in the serum samples and they were associated to sex. Interestingly, smoking cessation generally restored RNA expression to non-smoking levels, although for some sncRNAs smoking-related expression levels persisted. Pathway analysis suggests that smoking-related sncRNAs target the cholinergic synapses and may therefore potentially play a role in smoking addiction. Our results show that common traits influence circulating sncRNA expression. It is clear that sncRNA biomarker analyses should be adjusted for age and sex. In addition, for specific sncRNAs, analyses should also be adjusted for body mass, smoking, physical activity and technical factors. PMID- 30518767 TI - Rabi splitting and optical Kerr nonlinearity of quantum dot mediated by Majorana fermions. AB - Majorana fermions (MFs), due to their significance in fundamental physics and potential applications in topological quantum computation based on solid-state devices, have drawn widespread attention. Here, we design a hybrid semiconductor/superconductor ring (S/SR) device and put forward an optical method for detecting a pair of MFs in the S/SR device with a quantum dot (QD) with the popular optical pump-probe scheme, which is very different from the present electrical method only considering one nearby MF coupled to the QD. The symmetric and unsymmetric Rabi splitting and optical Kerr nonlinear effect of QD mediated by MFs are investigated under uncoupled and coupled majorana modes, respectively. The coherent optical spectra indicate that a pair of MFs coupled to the QD induced remarkable splitting under different parameters regime and the physical origin of these phenomena are elaborated detailedly. Due to QD-MFs coupling, the probe absorption spectra present the phenomenon of Majorana modes induced transparency (MMIT) which will induce remarkable phenomena of slow light. The coherent optical spectra afford a potential supplement for probing MFs and support Majorana fermions-based topological quantum computation. PMID- 30518768 TI - De novo sequencing and transcriptome assembly of Arisaema heterophyllum Blume and identification of genes involved in isoflavonoid biosynthesis. AB - Arisaema heterophyllum Blume (AhBl) is one of the valued medicinal plants. However, its genetic information is limited, which impedes further studies of this valuable resource. To investigate the genes involved in the isoflavonoid biosynthesis, we deeply performed transcriptome sequencing for AhBl. An average of 10.98 Gb clean reads were obtained based on root, tuber and leaf tissues, and 109,937 unigenes were yielded after de novo assembly. In total, 72,287 of those unigenes were annotated in at least one public database. The numbers of expressed unigenes in each tissue were 35,686, 43,363 and 47,783, respectively. The overall expression levels of transcripts in leaf were higher than those in root and tuber. Differentially expressed genes analysis indicated that a total of 12,448 shared unigenes were detected in all three tissues, 10,215 of which were higher expressed in tuber than that in root and leaf. Besides, 87 candidate unigenes that encode for enzymes involved in biosynthesis of isoflavonoid were identified and analyzed, and some key enzyme genes were experimentally validated by quantitative Real-Time PCR (qRT-PCR). This study provides a unique dataset for the systematic analysis of AhBl functional genes and expression characteristics, and facilitates the future study of the pharmacological mechanism of AhBl. PMID- 30518769 TI - Intra-amniotic Sildenafil Treatment Modulates Vascular Smooth Muscle Cell Phenotype in the Nitrofen Model of Congenital Diaphragmatic Hernia. AB - The etiology of pulmonary vascular abnormalities in CDH is incompletely understood. Studies have demonstrated improvement in pulmonary vasculature with prenatal therapy in animal models. We hypothesize that prenatal sildenafil may attenuate defective pulmonary vascular development via modulation of vSMC phenotype from undifferentiated, proliferative phenotype to differentiated, contractile phenotype. We utilized the nitrofen model of CDH to examine the effect of IA sildenafil on pulmonary vSMC phenotype during lung development. Timed-pregnant CD-1 mice were gavage fed 25 mg nitrofen or olive oil (control) at E8.5 of gestation. Single IA injections of Sildenafil (Revatio; 10 uL of 4 mg/4 ml solution) or dextrose control were performed at E12.5. Mice were sacrificed on various gestational days for embryonic lung harvest. Markers of vSMC development of undifferentiated and differentiated phenotypes were analyzed by immunostaining and western blot. Across all time points in gestation, nitrofen-treated embryonic lungs demonstrated increased vSMC expression of NOTCH3, Hes-5, PDGFR-beta, desmin and alpha-SMA and decreased expression of calponin and SMMHC, compared to oil controls. IA dextrose treatment had no effect on expression levels. However, IA Sildenafil treatment resulted in down-regulation of NOTCH3, Hes-5, PDGFR-beta, desmin and alpha-SMA and upregulation of calponin and SMMHC, comparable to oil controls. In the nitrofen model, vSMC express markers consistent with more undifferentiated proliferative phenotype, resulting in hypermuscularization of intrapulmonary arterioles in CDH. A single dose of IA Sildenafil treatment early in gestation, results in sustained normalization of vSMC phenotype. Pharmacologic modulation of the vSMC phenotype at key gestational points may have therapeutic potential. PMID- 30518770 TI - Analysis of genome-wide variants through bulked segregant RNA sequencing reveals a major gene for resistance to Plasmodiophora brassicae in Brassica oleracea. AB - Two cabbage (Brassica oleracea) cultivars 'Tekila' and 'Kilaherb' were identified as resistant to several pathotypes of Plasmodiophora brassicae. In this study, we identified a clubroot resistance gene (Rcr7) in 'Tekila' for resistance to pathotype 3 of P. brassicae from a segregating population derived from 'Tekila' crossed with the susceptible line T010000DH3. Genetic mapping was performed by identifying the percentage of polymorphic variants (PPV), a new method proposed in this study, through bulked segregant RNA sequencing. Chromosome C7 carried the highest PPV (42%) compared to the 30-34% in the remaining chromosomes. A peak with PPV (56-73%) was found within the physical interval 41-44 Mb, which indicated that Rcr7 might be located in this region. Kompetitive Allele-Specific PCR was used to confirm the association of Rcr7 with SNPs in the region. Rcr7 was flanked by two SNP markers and co-segregated with three SNP markers in the segregating population of 465 plants. Seven genes encoding TIR-NBS-LRR disease resistance proteins were identified in the target region, but only two genes, Bo7g108760 and Bo7g109000, were expressed. Resistance to pathotype 5X was also mapped to the same region as Rcr7. B. oleracea lines including 'Kilaherb' were tested with five SNP markers for Rcr7 and for resistance to pathotype 3; 11 of 25 lines were resistant, but 'Kilaherb' was the only line that carried the SNP alleles associated with Rcr7. The presence of Rcr7 in 'Kilaherb' for resistance to both pathotypes 3 and 5X was confirmed through linkage analysis. PMID- 30518771 TI - Hypertension and chronic kidney disease affect long-term outcomes in patients with stable coronary artery disease receiving percutaneous coronary intervention. AB - Percutaneous coronary intervention (PCI) is commonly used for patients with coronary artery disease (CAD). However, the effects of chronic kidney disease (CKD) and hypertension (HT) on long-term outcomes in patients with stable CAD receiving PCI are still unclear. A total of 1,676 patients treated with PCI were prospectively enrolled and divided into 4 groups according to the presence or absence of HT or CKD. General characteristics, clinical medications, risk factors, angiographic findings, and long-term outcomes were analyzed. Patients with CKD had the highest rate of all-cause and cardiovascular (CV) mortality (both P < 0.01). Patients with CKD alone had the lowest event-free rate of all cause and CV deaths (both P < 0.001). Based on Cox proportional hazard model, patients with CKD alone had the highest risk of all-cause death (HR:2.86, 95% CI:1.73-4.75) and CV death (HR: 3.57,95% CI:2.01-6.33); while patients with both CKD and HT had the highest risk of repeat PCI (HR: 1.42, 95% CI:1.09-1.85).We found that in stable CAD patients after undergoing PCI, those with CKD alone had the highest long-term mortality. Comorbid CKD appears to increase risk in patient with HT, whereas comorbid HT doesn't seem to increase risk in patients with CKD. PMID- 30518772 TI - Effects of near infrared focused laser on the fluorescence of labelled cell membrane. AB - Near infrared (NIR) laser light can have important reactions on live cells. For example, in a macroscopic scale, it is used therapeutically to reduce inflammation and in a single-cell scale, NIR lasers have been experimentally used to guide neuronal growth. However, little is known about how NIR lasers produce such behaviours on cells. In this paper we report effects of focussing a continuous wave 810-nm wavelength laser on in vivo 3T3 cells plasma membrane. Cell membranes were labelled with FM 4-64, a dye that fluoresces when associated to membrane lipids. Confocal microscopy was used to image cell membranes and perform fluorescence recovery after photobleaching (FRAP) experiments. We found that the NIR laser produces an increase of the fluorescence intensity at the location of laser spot. This intensity boost vanishes once the laser is turned off. The mean fluorescence increase, calculated over 75 independent measurements, equals 19%. The experiments reveal that the fluorescence rise is a growing function of the laser power. This dependence is well fitted with a square root function. The FRAP, when the NIR laser is acting on the cell, is twice as large as when the NIR laser is off, and the recovery time is 5 times longer. Based on the experimental evidence and a linear fluorescence model, it is shown that the NIR laser provokes a rise in the number of molecular associations dye-lipid. The results reported here may be a consequence of a combination of induced increments in membrane fluidity and exocytosis. PMID- 30518773 TI - iTRAQ-based quantitative tissue proteomic analysis of differentially expressed proteins (DEPs) in non-transgenic and transgenic soybean seeds. AB - The unintended effects of transgenesis have increased food safety concerns, meriting comprehensive evaluation. Proteomic profiling provides an approach to directly assess the unintended effects. Herein, the isobaric tags for relative and absolute quantitation (iTRAQ) comparative proteomic approach was employed to evaluate proteomic profile differences in seed cotyledons from 4 genetically modified (GM) and 3 natural genotypic soybean lines. Compared with their non-GM parents, there were 67, 61, 13 and 22 differentially expressed proteins (DEPs) in MON87705, MON87701 * MON89788, MON87708, and FG72. Overall, 170 DEPs were identified in the 3 GM soybean lines with the same parents, but 232 DEPs were identified in the 3 natural soybean lines. Thus, the differences in protein expression among the genotypic varieties were greater than those caused by GM. When considering >=2 replicates, 4 common DEPs (cDEPs) were identified in the 3 different GM soybean lines with the same parents and 6 cDEPs were identified in the 3 natural varieties. However, when considering 3 replicates, no cDEPs were identified. Regardless of whether >=2 or 3 replicates were considered, no cDEPs were identified among the 4 GM soybean lines. Therefore, no feedback due to GM was observed at the common protein level in this study. PMID- 30518774 TI - Stable factor structure of the Edinburgh Postnatal Depression Scale during the whole peripartum period: Results from a Japanese prospective cohort study. AB - Early detection of perinatal depression is an urgent issue. Our study aimed to examine the construct validity and factor structure of the Japanese version of the Edinburgh Postnatal Depression Scale (EPDS) from a prospective cohort study from pregnancy to postpartum. A total of 1075 women completed all items of the EPDS at four time points: early pregnancy, late pregnancy, 5 days postpartum and 1 month postpartum. The participants were randomly divided into two sample sets. The first sample set (n = 304) was used for exploratory factor analysis, and the second sample set (n = 771) was used for confirmatory factor analysis. As a result, the Cronbach's alpha coefficients of the EPDS items were 0.762, 0.740, 0.765 and 0.772 at the four time points. From the confirmatory factor analysis of the EPDS in a sample set of Japanese women from pregnancy to postpartum, the following three factors were detected: depression (items 7, 9), anxiety (items 4, 5) and anhedonia (items 1, 2). In conclusion, the EPDS is a useful rating scale, and its factor structure is consistently stable during the whole peripartum period. PMID- 30518775 TI - Generation of a highly efficient and tissue-specific tryptophan hydroxylase 1 knockout mouse model. AB - Recent studies on tissue-autonomous serotonin (5-hydroxytryptamine [5-HT]) function have identified new roles for 5-HT in peripheral organs. Most of these studies were performed by crossing mice carrying the Tph1tm1Kry allele with tissue specific Cre mice. In the present study, we found that 5-HT production was not completely abolished in Tph1tm1Kry KO mice. The residual 5-HT production in Tph1tm1Kry KO mice is attributed to the expression of a truncated form of TPH1 containing the catalytic domain. Hence, in an effort to obtain mice with a Tph1 null phenotype, we generated mice harboring a new Tph1 floxed allele, Tph1tm1c, targeting exons 5 and 6 which encode the catalytic domain of TPH1. By crossing the new Tph1 floxed mice with villin-Cre or insulin-Cre mice, we observed near complete ablation of 5-HT production in the intestine and beta cells. In conclusion, this improved Tph1 floxed mouse model will serve as useful and accurate tool for analyzing peripheral 5-HT system. PMID- 30518777 TI - Boolean Calcium Signalling Model Predicts Calcium Role in Acceleration and Stability of Abscisic Acid-Mediated Stomatal Closure. AB - Inconsistent hypotheses have proposed Ca2+ as either being essential or irrelevant and redundant in ABA induced stomatal closure. This study integrates all available information from literature to define ABA signalling pathway and presents it in a systems view for clearer understanding of the role of Ca2+ in stomatal closure. Importantly, it incorporates into an Asynchronous Boolean model time delays sourced from an extensive literature search. The model predicted the timing of ABA events and mutant behaviour close to biology. It revealed biologically reported timing for Ca2+ activation and Ca2+ dynamics consistent with biology. It also predicts that Ca2+ elevation is not essential in stomatal closure but it can accelerate closure, consistent with previous findings, but our model further explains that acting as a mediator, Ca2+ accelerates stomatal closure by enhancing plasma membrane slowly activating anion channel SLAC1 and actin rearrangement. It shows statistical significance of Ca2+ induced acceleration of closure and that of Ca2+ induced acceleration of SLAC1 activation. Further, the model demonstrates that Ca2+ enhances resilience of closure to perturbation of important elements; especially, ROS pathway, as did previous ABA model, and even to the ABA signal disruption. It goes further to elucidate the mechanisms by which Ca2+ engenders stomatal closure in these perturbations. PMID- 30518776 TI - Extracellular Protein Fibulin-7 and Its C-Terminal Fragment Have In Vivo Antiangiogenic Activity. AB - Angiogenesis is crucial for tissue development and homeostasis; however, excessive angiogenesis can lead to diseases, including arthritis and cancer metastasis. Some antiangiogenic drugs are available, but side effects remain problematic. Thus, alternative angiogenesis inhibition strategies are needed. Fibulin-7 (Fbln7) is a newly discovered member of the fibulin protein family, a group of cell-secreted glycoproteins, that functions as a cell adhesion molecule and interacts with other extracellular matrix (ECM) proteins as well as cell receptors. We previously showed that a recombinant C-terminal Fbln7 fragment (Fbln7-C) inhibits tube formation by human umbilical vein endothelial cells (HUVECs) in vitro. In the present study, we examined the in vivo antiangiogenic activity of recombinant full-length Fbln7 (Fbln7-FL) and Fbln7-C proteins using a rat corneal angiogenesis model. We found that both Fbln7-FL and Fbln7-C inhibited neovascularization. Fbln7-C bound to vascular endothelial growth factor receptor 2 (VEGFR2), inhibiting VEGFR2 and ERK phosphorylation and resulting in reduced HUVEC motility. HUVEC attachment to Fbln7-C occurred through an interaction with integrin alpha5beta1 and regulated changes in cellular morphology. These results suggest that Fbln7-C action may target neovascularization by altering cell/ECM associations. Therefore, Fbln7-C could have potential as a therapeutic agent for diseases associated with angiogenesis. PMID- 30518778 TI - Calponin-3 is critical for coordinated contractility of actin stress fibers. AB - Contractile actomyosin bundles, stress fibers, contribute to morphogenesis, migration, and mechanosensing of non-muscle cells. In addition to actin and non muscle myosin II (NMII), stress fibers contain a large array of proteins that control their assembly, turnover, and contractility. Calponin-3 (Cnn3) is an actin-binding protein that associates with stress fibers. However, whether Cnn3 promotes stress fiber assembly, or serves as either a positive or negative regulator of their contractility has remained obscure. Here, we applied U2OS osteosarcoma cells as a model system to study the function of Cnn3. We show that Cnn3 localizes to both NMII-containing contractile ventral stress fibers and transverse arcs, as well as to non-contractile dorsal stress fibers that do not contain NMII. Fluorescence-recovery-after-photobleaching experiments revealed that Cnn3 is a dynamic component of stress fibers. Importantly, CRISPR/Cas9 knockout and RNAi knockdown studies demonstrated that Cnn3 is not essential for stress fiber assembly. However, Cnn3 depletion resulted in increased and uncoordinated contractility of stress fibers that often led to breakage of individual actomyosin bundles within the stress fiber network. Collectively these results provide evidence that Cnn3 is dispensable for the assembly of actomyosin bundles, but that it is required for controlling proper contractility of the stress fiber network. PMID- 30518779 TI - Simple multi-wavelength imaging of birefringence:case study of silk. AB - Polarised light imaging microscopy, with the addition of a liquid crystal (LC) phase retarder, was used to determine the birefringence of silk fibres with high (~1 MUm) spatial resolution. The measurement was carried out with the silk fibres (the optical slow axis) and the slow axis of the LC-retarder set at parallel angles. The direct fit of the transmission data allowed for high fidelity determination of the birefringence Deltan ~ 1.63 * 10-2 (with ~2% uncertainty) of the brown silk fibre, (Antheraea pernyi) averaged over the wavelength range lambda = (425-625) nm. By measuring retardance at four separate wavelengths, it was possible to determine the true value of the birefringence of a thicker sample when an optical path may include a large number of wavelengths. The numerical procedures and required hardware are described for the do-it-yourself assembly of the imaging polariscope at a fractional budget compared to commercial units. PMID- 30518780 TI - Quantum Annealing for Prime Factorization. AB - We have developed a framework to convert an arbitrary integer factorization problem to an executable Ising model by first writing it as an optimization function then transforming the k-bit coupling (k >= 3) terms to quadratic terms using ancillary variables. Our resource-efficient method uses [Formula: see text] binary variables (qubits) for finding the factors of an integer N. We present how to factorize 15, 143, 59989, and 376289 using 4, 12, 59, and 94 logical qubits, respectively. This method was tested using the D-Wave 2000Q for finding an embedding and determining the prime factors for a given composite number. The method is general and could be used to factor larger integers as the number of available qubits increases, or combined with other ad hoc methods to achieve better performances for specific numbers. PMID- 30518782 TI - BET inhibitor I-BET151 sensitizes GBM cells to temozolomide via PUMA induction. AB - A significant roadblock in treatment of GBM multiforme (GBM) is resistance to temozolomide (TMZ). In this study, we investigated whether I-BET151, a specific BET inhibitor, could sensitize GBM cells to TMZ. Our findings showed that the action of I-BET151 could augment the effect of TMZ on cancer cells U251 and U87 cells. In U251 cells, administration of I-BET151 increased the TMZ-induced apoptosis GBM cells. I-BET151 remarkably enhanced the activities of caspase-3. In addition, I-BET151 promoted TMZ-induced migration and invasion in GBM cells. Moreover, I-BET151 increased the amount of reactive oxygen species as well as superoxide anions with a decrease of activity of SOD and the anti-oxidative properties of GBM cells. I-BET151 also induced increased PUMA expression, which is required for the functions of I-BET151 and regulates the synergistic cytotoxic effects of i-BET151 and TMZ in GBM cells. I-BET151 with TMZ also showed synergistic cytotoxic effects in vivo. These point out to an approach to tackle GBM using TMZ along with BET inhibitors. PMID- 30518781 TI - Correction: Synergistic activation of pro-inflammatory type-2 CD8 + T lymphocytes by lipid mediators in severe eosinophilic asthma. AB - This article was originally published under standard licence, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 30518783 TI - Upregulating microRNA-498 inhibits gastric cancer proliferation invasion and chemoresistance through inverse interaction of Bmi1. AB - This study aimed to analyze the functions of microRNA 498 (miR-498) on gastric cancer (GC) cell proliferation migration and cisplatin chemosensitivity. QTR-PCR found that miR-498 was markedly downregulated in GC cell lines and human GC tumors. It was discover that, lentivirus-mediated miR-498 overexpression inhibited cancer cell proliferations in vitro and in vivo, invasion and cisplatin chemoresistance. Bmi1 was demonstrated to be directly regulated by miR-498 in GC cell lines. Moreover, Bmi1 upregulation was found to reverse the tumor suppressing functions of miR-498 in GC. Therefore, this study presented evidence showing miR-498 expression decreased in GC, and overexpressing miR-498 had significant inhibitory effects on GC development, likely through the inverse interaction of Bmi1. PMID- 30518784 TI - The Doctor Can See You Now: A Key Stakeholder Study Into The Acceptability Of Ambulance Based Telemedicine. AB - Using telecommunications technology it would be possible to link a patient and paramedic to a Doctor in the Emergency Department (ED) at the point of first patient contact. A questionnaire-based study on telemedicine in the pre-hospital environment involving patients, paramedics, doctors and nurses in the ED, was performed to assess if they would want and accept telemedicine in pre-hospital emergency care. When asked 98.5% (55) of patients, 89% (11) of doctors, 76% (14) of nurses and 91% (42) of ambulance personnel saw the potential of an audio visual link from the pre-hospital environment to the ED. The potential benefits were felt to be in diagnosis of time-dependent illnesses, time management, increased hospital preparedness for incoming patients and increased triage efficiency. Stakeholder enthusiasm for pre-hospital telemedicine must be met with the technological requirements to provide such a service. As noted by one patient a pre-hospital audio-visual link to the ED could be "potentially a life saving service". PMID- 30518786 TI - Tender joints might not indicate inflammation. PMID- 30518785 TI - BK channel blocker paxilline attenuates thalidomide-caused synaptic and cognitive dysfunctions in mice. AB - Thalidomide is a widely prescribed immunomodulatory drug (iMiD) for multiple myeloma, but causes reversible memory loss in humans. However, how thalidomide causes cognitive dysfunction at a cellular and molecular level has not been demonstrated. We studied the effect of thalidomide on synaptic functions and cognitive behaviors using a mouse model. Thalidomide led to cognitive deficits in learning behavior in a passive avoidance test and in a novel object recognition test, increased anxiety in an elevated plus maze test, and increased depressive behaviors in a tail suspension test. Interestingly, thalidomide elevated big- or large-conductance, calcium-activated K+ (BK) channel expression in the plasma membrane and BK channel activity in the hippocampus. Thalidomide also increased the paired pulse ratio of excitatory postsynaptic current (EPSC), which suggests a decreased probability of glutamate release. Furthermore, the changes in the paired pulse ratio and in BK channel activity were blocked by paxilline, a BK channel blocker. Finally, we found that thalidomide-induced cognitive dysfunctions were restored by paxilline treatment. These results suggest that thalidomide-mediated BK channel hyperfunction is responsible for the pathological mechanism of thalidomide-associated reversible memory loss. PMID- 30518787 TI - Low-dose IL-2 therapy for autoimmune diseases. PMID- 30518788 TI - Ultrasound thresholds for synovial abnormalities. PMID- 30518789 TI - p73 regulates ependymal planar cell polarity by modulating actin and microtubule cytoskeleton. AB - Planar cell polarity (PCP) and intercellular junctional complexes establish tissue structure and coordinated behaviors across epithelial sheets. In multiciliated ependymal cells, rotational and translational PCP coordinate cilia beating and direct cerebrospinal fluid circulation. Thus, PCP disruption results in ciliopathies and hydrocephalus. PCP establishment depends on the polarization of cytoskeleton and requires the asymmetric localization of core and global regulatory modules, including membrane proteins like Vangl1/2 or Frizzled. We analyzed the subcellular localization of select proteins that make up these modules in ependymal cells and the effect of Trp73 loss on their localization. We identify a novel function of the Trp73 tumor suppressor gene, the TAp73 isoform in particular, as an essential regulator of PCP through the modulation of actin and microtubule cytoskeleton dynamics, demonstrating that Trp73 is a key player in the organization of ependymal ciliated epithelia. Mechanistically, we show that p73 regulates translational PCP and actin dynamics through TAp73-dependent modulation of non-musclemyosin-II activity. In addition, TAp73 is required for the asymmetric localization of PCP-core and global signaling modules and regulates polarized microtubule dynamics, which in turn set up the rotational PCP. Therefore, TAp73 modulates, directly and/or indirectly, transcriptional programs regulating actin and microtubules dynamics and Golgi organization signaling pathways. These results shed light into the mechanism of ependymal cell planar polarization and reveal p73 as an epithelial architect during development regulating the cellular cytoskeleton. PMID- 30518790 TI - Therapeutic faecal microbiota transplantation controls intestinal inflammation through IL10 secretion by immune cells. AB - Alteration of the gut microbiota has been associated with different gastrointestinal disorders. Normobiosis restoration by faecal microbiota transplantation (FMT) is considered a promising therapeutic approach, even if the mechanisms underlying its efficacy are at present largely unknown. Here we sought to elucidate the functional effects of therapeutic FMT administration during experimental colitis on innate and adaptive immune responses in the intestinal mucosa. We show that therapeutic FMT reduces colonic inflammation and initiates the restoration of intestinal homeostasis through the simultaneous activation of different immune-mediated pathways, ultimately leading to IL-10 production by innate and adaptive immune cells, including CD4+ T cells, iNKT cells and Antigen Presenting Cells (APC), and reduces the ability of dendritic cells, monocytes and macrophages to present MHCII-dependent bacterial antigens to colonic T cells. These results demonstrate the capability of FMT to therapeutically control intestinal experimental colitis and poses FMT as a valuable therapeutic option in immune-related pathologies. PMID- 30518791 TI - A screening-level approach to quantifying risk from glacial release of organochlorine pollutants in the Alaskan Arctic. AB - Widespread distribution of atmospherically mobilized organochlorine pollutants (OCPs) has been documented throughout the Arctic. A fraction of these OCPs have become entrained in glacial ice, and during melting, they can be released into downstream reservoirs. Though this remobilization is known, an assessment of risk from glacial meltwater to collocated human communities in the Arctic, including Alaska, had not been accomplished. Here, we use a screening-level risk assessment model for glacial watersheds, based on US Environmental Protection Agency (EPA) methodology, which we apply to the glaciated Jarvis Creek watershed of interior Alaska. Model results indicate that even with low levels of OCPs in glacial meltwater, high fish consumption by subsistence communities in the area increases the risk of cancer and hazard impacts above acceptable limits. Though this model is specific to one watershed, our results imply that further investigation of an increasing OCP signal in glacial meltwater and fish throughout the North American Arctic is warranted. PMID- 30518792 TI - Does soil track-in contribute to house dust concentrations of perfluoroalkyl acids (PFAAs) in areas affected by soil or water contamination? AB - The Minnesota Department of Health measured levels of perfluoroalkyl acids (PFAAs) in house dust at homes in communities impacted by PFAA-contaminated soil and drinking water to determine whether PFAAs in soil outside the home are associated with concentrations in dust. House dust samples from both interior living spaces and entryways to the yard were collected and analyzed separately based on the presumption that PFAAs in entryway dust may better reflect "track in" of PFAAs into the home from contaminated soil or lawns irrigated with contaminated water. PFAA detections and concentrations in living rooms were significantly higher compared to entryways; and concentrations in both sampling locations were higher than corresponding soil concentrations, suggesting that interior sources were the main contributors to PFAAs in house dust. PFAA dust concentrations in entryways were significantly associated with living room dust levels for all analytes except PFBA. Relationships between entryway dust and soil were only seen for one PFAA (PFOA). However, median concentrations of PFOA in entryway and living room dust were 35 and 70 times higher (respectively) than in soil, which highlights the lack of importance of PFAA soil track-in as a contributor to dust concentration in this setting. Due to the small sample size, larger scale studies are needed to further assess the potential for migration of PFAA contaminated soil to indoor dust. PMID- 30518793 TI - Exposure to selected preservatives in personal care products: case study comparison of exposure models and observational biomonitoring data. AB - Exposure models provide critical information for risk assessment of personal care product ingredients, but there have been limited opportunities to compare exposure model predictions to observational exposure data. Urinary excretion data from a biomonitoring study in eight individuals were used to estimate minimum absorbed doses for triclosan and methyl-, ethyl-, and n-propyl- parabens (TCS, MP, EP, PP). Three screening exposure models (European Commission Scientific Commission on Consumer Safety [SCCS] algorithms, ConsExpo in deterministic mode, and RAIDAR-ICE) and two higher-tier probabilistic models (SHEDS-HT, and Creme Care & Cosmetics) were used to model participant exposures. Average urinary excretion rates of TCS, MP, EP, and PP for participants using products with those ingredients were 16.9, 3.32, 1.9, and 0.91 MUg/kg-d, respectively. The SCCS default aggregate and RAIDAR-ICE screening models generally resulted in the highest predictions compared to other models. Approximately 60-90% of the model predictions for most of the models were within a factor of 10 of the observed exposures; ~30-40% of the predictions were within a factor of 3. Estimated exposures from urinary data tended to fall in the upper range of predictions from the probabilistic models. This analysis indicates that currently available exposure models provide estimates that are generally realistic. Uncertainties in preservative product concentrations and dermal absorption parameters as well as degree of metabolism following dermal absorption influence interpretation of the modeled vs. measured exposures. Use of multiple models may help characterize potential exposures more fully than reliance on a single model. PMID- 30518794 TI - A framework for estimating the US mortality burden of fine particulate matter exposure attributable to indoor and outdoor microenvironments. AB - Exposure to fine particulate matter (PM2.5) is associated with increased mortality. Although epidemiology studies typically use outdoor PM2.5 concentrations as surrogates for exposure, the majority of PM2.5 exposure in the US occurs in microenvironments other than outdoors. We develop a framework for estimating the total US mortality burden attributable to exposure to PM2.5 of both indoor and outdoor origin in the primary non-smoking microenvironments in which people spend most of their time. The framework utilizes an exposure response function combined with adjusted mortality effect estimates that account for underlying exposures to PM2.5 of outdoor origin that likely occurred in the original epidemiology populations from which effect estimates are derived. We demonstrate the framework using several different scenarios to estimate the potential magnitude and bounds of the US mortality burden attributable to total PM2.5 exposure across all non-smoking environments under a variety of assumptions. Our best estimates of the US mortality burden associated with total PM2.5 exposure in the year 2012 range from ~230,000 to ~300,000 deaths. Indoor exposure to PM2.5 of outdoor origin is typically the largest total exposure, accounting for ~40-60% of total mortality, followed by residential exposure to indoor PM2.5 sources, which also drives the majority of variability in each scenario. PMID- 30518795 TI - Metabolomic assessment of exposure to near-highway ultrafine particles. AB - Exposure to traffic-related air pollutants has been associated with increased risk of adverse cardiopulmonary outcomes and mortality; however, the biochemical pathways linking exposure to disease are not known. To delineate biological response mechanisms associated with exposure to near-highway ultrafine particles (UFP), we used untargeted high-resolution metabolomics to profile plasma from 59 participants enrolled in the Community Assessment of Freeway Exposure and Health (CAFEH) study. Metabolic variations associated with UFP exposure were assessed using a cross-sectional study design based upon low (mean 16,000 particles/cm3) and high (mean 24,000 particles/cm3) annual average UFP exposures. In comparing quantified metabolites, we identified five metabolites that were differentially expressed between low and high exposures, including arginine, aspartic acid, glutamine, cystine and methionine sulfoxide. Analysis of the metabolome identified 316 m/z features associated with UFP, which were consistent with increased lipid peroxidation, endogenous inhibitors of nitric oxide and vehicle exhaust exposure biomarkers. Network correlation analysis and metabolic pathway enrichment identified 38 pathways and included variations related to inflammation, endothelial function and mitochondrial bioenergetics. Taken together, these results suggest UFP exposure is associated with a complex series of metabolic variations related to antioxidant pathways, in vivo generation of reactive oxygen species and processes critical to endothelial function. PMID- 30518796 TI - Supraglottic airway devices for surfactant treatment: systematic review and meta analysis. AB - OBJECTIVE: To compare surfactant administration via supraglottic airway device (SAD) vs. nasal CPAP alone or INSURE. STUDY DESIGN: A systematic search of PubMed, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials and Clinicaltrials.gov was performed. Articles meeting inclusion criteria (RCT, surfactant administration via SAD, laryngeal mask, I-gel) were assessed RESULTS: Five RCTs were eligible. Surfactant administration via SAD reduced the need for intubation/mechanical ventilation (RR 0.57, 95%CI 0.38-0.85) and short-term oxygen requirements (MD -8.00, 95%CI -11.09 to -4.91) compared to nCPAP alone. Surfactant administration via SAD reduced the need for intubation/mechanical ventilation (RR 0.43, 95%CI 0.31-0.61), but increased short-term oxygen requirements (MD 3.10, 95%CI 0.51-5.69) compared to INSURE approach. CONCLUSIONS: In preterm infants with RDS, surfactant administration via SAD reduces the need for intubation/mechanical ventilation. Overall, available literature includes few, small, poor-quality studies. Surfactant administration via SAD should be limited to clinical trials. PMID- 30518797 TI - Survey of preterm neuro-centric care practices in California neonatal intensive care units. AB - OBJECTIVE: Examine the adoption and presence of preterm, neuro-centric care practices across neonatal intensive care units (NICUs). STUDY DESIGN: Statewide, cross-sectional survey of California NICUs. Data were collected surrounding the timing of adoption and presence of delivery room practices, nursing protocols, provider management practices and quality improvement initiatives. RESULT: Among the 95 NICUs completing the survey (65%), adoption of all surveyed practices increased between 2005 and 2016, though rates of uptake changed over time and varied by practice. Adoption of indomethacin prophylaxis increased 1.8-fold, whereas delayed cord clamping increased 78-fold. Adoption of premedication for intubation and a patent ductus arteriosus management algorithm differed by unit level. Additionally, two underlying practice domains were identified; adoption of delivery room practices and adoption of any preterm practice. CONCLUSION: Adoption of preterm, neuro-centric care practices across California NICUs has increased, though uptake patterns vary by practice and level. PMID- 30518798 TI - Fluid restriction in moderate and severe hypoxemic-ischemic encephalopathy: more evidence is needed. PMID- 30518799 TI - Bronchoscopy in neonates with severe bronchopulmonary dysplasia in the NICU. AB - OBJECTIVES: To describe the findings, resulting changes in management, and safety profile of flexible bronchoscopy in the neonates with severe bronchopulmonary dysplasia. STUDY DESIGN: This was a retrospective case series of twenty-seven neonates with severe bronchopulmonary dysplasia who underwent flexible bronchoscopy in the neonatal intensive care unit. RESULTS: Flexible bronchoscopy revealed airway pathology in 20/27 (74%) patients. Tracheomalacia 13/27 (48%), bronchomalacia 11/27 (40.7%), and airway edema 13/27 (48%) were the most common findings. Bronchoalveolar lavage (BAL) was performed in 17 patients. BAL culture revealed a microorganism in 12/17 (70.5%) cases. Findings from bronchoscopy resulted in change in clinical management in 17/27 (63%) patients. Common interventions included initiation of antibiotics (37%) and treatment of tracheobronchomalacia with bethanechol (22.2%), atrovent (18.5%), and PEEP titration (18.5%). Bronchoscopy was performed without significant complication in 26/27 (97%) patients. CONCLUSION: Flexible bronchoscopy can be a safe and useful tool for the management of neonates with severe bronchopulmonary dysplasia. PMID- 30518800 TI - Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia. AB - OBJECTIVE: Inflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia. STUDY DESIGN: A sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios. RESULTS: Higher 5-alpha-pregnan-3beta,20alpha-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia. CONCLUSIONS: Among women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth. PMID- 30518801 TI - Vascular changes in fetal growth restriction: clinical relevance and future therapeutics. AB - Fetal growth restriction (FGR) affects about 5-10% pregnancies and is associated with poorer outcomes in the perinatal period. Additionally, long standing epidemiological data support its association with chronic diseases such as hypertension and diabetes. Cardiac and vascular adaptations in response to chronic hypoxemia due to utero-placental insufficiency are hallmarks of fetal adaptations. Investigators have attempted to identify these changes in the placenta at the microscopic and molecular level. The ex vivo dual perfusion model of the placenta enables the study of placental haemodynamics in growth-restricted pregnancies. Persistent arterial abnormalities (thickness and stiffness) noted on vascular ultrasound during fetal life through to the young-adult age group for those affected by FGR, seem to be a plausible link between in utero events and chronic circulatory diseases. Using these, this review reflects current thought on vascular maladaptive changes in the FGR cohorts and the role in investigating current and future therapeutics. PMID- 30518802 TI - Genetic variants associated with patent ductus arteriosus in extremely preterm infants. AB - OBJECTIVE: Patent ductus arteriosus (PDA) is a commonly observed condition in preterm infants. Prior studies have suggested a role for genetics in determining spontaneous ductal closure. Using samples from a large neonatal cohort we tested the hypothesis that common genetic variations are associated with PDA in extremely preterm infants. STUDY DESIGN: Preterm infants (n = 1013) enrolled at NICHD Neonatal Research Network sites were phenotyped for PDA. DNA was genotyped for 1634 single nucleotide polymorphisms (SNPs) from candidate genes. Analyses were adjusted for ancestral eigenvalues and significant epidemiologic variables. RESULTS: SNPs in several genes were associated with the clinical diagnosis of PDA and with surgical ligation in extremely preterm neonates diagnosed with PDA (p < 0.01). None of the associations were significant after correction for multiple comparisons. CONCLUSION: We identified several common genetic variants associated with PDA. These findings may inform further studies on genetic risk factors for PDA in preterm infants. PMID- 30518803 TI - Histological chorioamnionitis and developmental outcomes in very preterm infants. AB - OBJECTIVE: To characterize the association of histological chorioamnionitis (HCA) with neurodevelopmental outcomes in children born at <30 weeks gestation. STUDY DESIGN: This retrospective cohort study included infants born 2006-2012 in whom placental histopathology, neonatal outcomes, and Bayley-III assessment at age 2 years were available. We assessed the association of HCA exposure with cognitive, language, and motor delay with logistic regression models adjusted for gestational age, sex, small for gestational age and brain injury. RESULTS: Of 1353 infants, 985 had histological and neonatal data available, and 708 infants had Bayley-III assessments. HCA-exposed infants were at higher risk of some neonatal adverse outcomes, and stage of HCA correlated with low Apgar score and early-onset sepsis. Exposure to HCA was not associated with neurodevelopmental outcomes in adjusted models including stage of HCA. CONCLUSIONS: Exposure to HCA, especially higher stage, was associated with neonatal morbidity but not with adverse neurodevelopmental outcomes at 2 years of age. PMID- 30518804 TI - Prognostic role of masked and white-coat hypertension: 10-Year mortality in treated elderly hypertensives. AB - White-coat uncontrolled hypertension (WUCH) and masked uncontrolled hypertension (MUCH) are common in the elderly. The prognostic role of these hypertension phenotypes is not completely defined in this subpopulation. Our aim is to evaluate the long-term prognostic role of WUCH and MUCH in treated elderly hypertensives. Observational study conducted on 120 consecutive treated elderly hypertensives. Patients were assessed on a first clinical visit in 2006. Subsequently, such patients or their relatives have been recalled after 10 years to evaluate the survival rates. Main inclusion criteria at baseline: age >= 65 years, a previous diagnosis of essential hypertension, a valid 24-h ambulatory blood pressure monitoring (ABPM). All participants received anti-hypertensive drugs during the 10-year period and we considered 10-year mortality for the analysis. General characteristics at baseline: mean age was 71.2 +/- 5.3 years; females were 53.3%; 15.1% of patients had sustained controlled hypertension (SCH), 35.8% had WUCH, 10.8% had MUCH and 38.3% had sustained uncontrolled hypertension (SUCH). Thirty-two patients (26.7%) died during the 10-year period. Deceased patients were older, had lower treatment intensity, HDLc levels and eGFR than survivors. After adjusting for these covariates, MUCH (HR 12.30, p < 0.001) and SUCH (HR 4.84, p = 0.007) were associated with higher risk of death, compared to SCH, while no relationship emerged with WUCH (HR 1.58, p = 0.455). In our real life study on treated elderly hypertensives, MUCH was associated with higher risk of death, compared to SCH and SUCH, while WUCH was not. ABPM is a key tool to improve management and therefore prognosis in this subpopulation. PMID- 30518805 TI - Effects of mineralocorticoid and AT-1 receptor antagonism on the aldosterone renin ratio (ARR) in primary aldosteronism patients (EMIRA Study): rationale and design. AB - Current guidelines recommend withdrawal of treatments that affect the aldosterone/renin ratio (ARR) when screening for primary aldosteronism (PA). However, abandonment of mineralocorticoid-receptor antagonist (MRA) and/or blockers of the renin-angiotensin system can deteriorate control of blood pressure (BP) and hypokalemia. Thus, in consecutive patients with an unambiguous diagnosis of PA in washout from confounding treatments and subtyped by AVS, we will compare within-patient plasma aldosterone and active renin concentration, and the ARR values, measured at baseline, and after a 1-month treatment with MRA alone and combined with an AT-1 receptor blocker (ARB). Patients on a regular salt intake will be treated with canrenone (50-100 mg orally) for 1 month, after which olmesartan (10 or 20 mg orally) will be added for another month with up titration of both treatments over the first 2 weeks to control BP and hypokalemia, while background therapy will be maintained. The biochemical variables and the ARR will be assessed in an identical manner at baseline values and after each month of treatment. With a sample size of 40 patients, the study will have a 95% power to show a clinically significant 20% change in the ARR at a 5% alpha value using a two-sided paired t test. Hence, this study will allow us to determine if an MRA alone, or added to an ARB at doses that control BP and hypokalemia, affects or not the ARR, thus allowing to establish if these agents can be administered or must be forbidden during the screening of PA. PMID- 30518806 TI - Association of uncoupling protein gene polymorphisms with essential hypertension in a northeastern Han Chinese population. AB - Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins and mediate regulated proton leak across the inner mitochondrial membrane. The UCPs play an important role in energy homeostasis and reactive oxygen species (ROS) release, and have been established as candidate genes for obesity, diabetes and hypertension. This study examined the possible association between the single nucleotide polymorphisms (SNPs) of UCP1-3 genes and essential hypertension (EH) in a northeastern Han Chinese population. A total of 2207 Chinese Han subjects were enrolled, including 1045 normotensives and 1162 hypertensives. Genotyping of UCP1 rs1800592, UCP1 rs12502572, UCP2 rs659366, UCP2 rs660339, and UCP3 rs3781907 was detected using Sequenom MassArray System. SHEsis was used to analyze linkage disequilibrium and haplotype. No evident association was observed between the genotype distributions and allele frequencies of individual SNPs and EH. Haplotype analysis showed the haplotype GAATA (rs1800592 rs12502572-rs659366-rs660339-rs3781907) was significantly associated with lower EH risk (p = 0.001, chi2 = 10.861, OR = 0.634, 95% CI = 0.483-0.833), and AGATG was associated with increased EH risk (p = 0.012, chi2 = 6.287, OR = 1.265, 95% CI = 1.052-1.521). These findings suggest haplotypes of UCP1-3 genes are linked to EH risk in a northeastern Han Chinese population. Further investigation with larger sample size in multiethnic population is needed to confirm our results. PMID- 30518807 TI - Estimating the effect of a reduction of sodium intake in childhood on cardiovascular diseases later in life. PMID- 30518808 TI - Autonomic dysfunction in programmed hypertension. AB - Hypertension is an important modifiable risk factor for cardiovascular diseases. Its high prevalence, combined with the significant morbidity and mortality associated with secondary complications, make it a major public health concern. Despite decades of research, over 95% of all cases of hypertension remain of unknown etiology, necessitating that treatments target the established symptoms and not the cause. One of the important recent advances in hypertension research is an understanding that hypertension often may have a developmental origin. A substantial body of evidence indicates that exposure to an adverse intrauterine environment during critical periods of development may predispose an individual to develop hypertension later in life. A causative mechanism has yet to be identified, but may include epigenetic modifications, and/or alterations in renal, vascular or autonomic cardiovascular functions. This review will present evidence regarding changes in autonomic activity as a possible causative pathophysiological mechanism underlying the development of programmed hypertension. In man, low birth weight is the best-known risk factor for hypertension of developmental origins, although this is a broad surrogate measure for intrauterine adversity. This review will include clinical studies across the lifespan that have investigated autonomic function in individuals with fetal growth restriction and those born preterm. A determination of whether altered autonomic function is seen in these individuals in early life is imperative, as hypertensive disorders that have their origins in utero, and that can be identified early, will open the door to risk stratification, and the development of new strategies that prevent or specifically target these mechanisms. PMID- 30518809 TI - A systematic review and network meta-analysis of the comparative efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertension. AB - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are drugs commonly used for the treatment of hypertension. However, studies on their comparative efficacy have not been extensively investigated. The current systematic review and network meta-analysis studied the comparative efficacy of the two antihypertensive treatment categories in reducing blood pressure, mortality, and morbidity in essential hypertension patients. A literature search was carried out in Medline and Cochrane Central Register of Controlled Trials for placebo- and active-controlled, double-blind randomized clinical trials, which had reported blood pressure effects, mortality, and/or morbidity. Blood pressure results were found in 30 studies with 7370 participants and 8 studies with 25,158 participants with mortality/morbidity results included in the analysis. The two drug classes had similar effectiveness in lowering systolic (weighted mean difference (WMD): 0.59, 95% CI: -0.21 to 1.38) and diastolic blood pressure (WMD: 0.62, 95% CI: -0.06 to 1.30), all-cause mortality (risk ratio (RR)): 0.96, 95% CI 0.80 to 1.14), cardiovascular mortality (RR: 0.87, 95% CI 0.67 to 1.14), fatal and non-fatal myocardial infarction (RR: 1.02, 95% CI 0.75 to 1.37) and stroke (RR: 1.13, 95% CI 0.87 to 1.46). Angiotensin-converting enzyme inhibitors were more helpful in the prevention and/or the hospitalization for heart failure than angiotensin receptor blockers (RR: 0.71, 95% CI 0.54 to 0.93). Angiotensin converting enzyme inhibitors and angiotensin receptor blockers were similarly effective in decreasing blood pressure, mortality, and morbidity in essential hypertension. Angiotensin-converting enzyme inhibitors were more protective in the advancement and/or hospitalization of the hypertensive patient for heart failure than angiotensin receptor blockers. PMID- 30518810 TI - Indications and use of therapeutic phlebotomy in polycythemia vera: which role for erythrocytapheresis? PMID- 30518811 TI - Depletion of Ars2 inhibits cell proliferation and leukemogenesis in acute myeloid leukemia by modulating the miR-6734-3p/p27 axis. AB - Ars2 is a component of the nuclear cap-binding complex (CBC) that contributes to microRNA biogenesis and is required for cellular proliferation. Little is known regarding the functional role of Ars2 in cell proliferation and leukemogenesis of acute myeloid leukemia. Here, we show that the elevated expression of Ars2 was observed in acute myeloid leukemia (AML) cell lines and bone marrow samples from AML patients and was correlated with poorer overall survival. Overexpression of Ars2 promoted cell proliferation and colony formation in AML cells, whereas depletion of Ars2 inhibited cell proliferation and colony formation. Mechanistic studies reveal that depletion of Ars2 suppressed the interaction of Ars2 with CBC and led to alterations in miRNA processing. Furthermore, Ars2 depletion reduced the levels of miR-6734-3p, resulting in upregulation of p27 and culminating in cell cycle arrest at the G1 phase. In vivo studies indicate that depletion of Ars2 significantly reduced leukemic cell burden and prolonged the survival time of the leukemia-bearing mice. These findings indicate that Ars2 may not only play a crucial role in the regulation of cell proliferation and leukemogenesis, but could also be identified as a critical therapeutic target for treatment of AML. PMID- 30518812 TI - Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance. AB - Sezary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS. PMID- 30518813 TI - Estimated GFR: time for a critical appraisal. AB - Since 1957, over 70 equations based on creatinine and/or cystatin C levels have been developed to estimate glomerular filtration rate (GFR). However, whether these equations accurately reflect renal function is debated. In this Perspectives article, we discuss >70 studies that compared estimated GFR (eGFR) with measured GFR (mGFR), involving ~40,000 renal transplant recipients and patients with chronic kidney disease (CKD), type 2 diabetes mellitus or polycystic kidney disease. Their results show that eGFR often differed from mGFR by +/-30% or more, that eGFR values incorrectly staged CKD in 30-60% of patients, and that eGFR and mGFR gave different rates of GFR decline. Errors were unpredictable, and comparable for equations based on creatinine and/or cystatin C. We argue, therefore, that the persistence of these errors (despite intensive research) suggests that the problem lies with using creatinine and/or cystatin C as markers of renal function, rather than with the mathematical methods used for GFR estimation. PMID- 30518814 TI - Prisoners of war - host adaptation and its constraints on virus evolution. AB - Recent discoveries of contemporary genotypes of hepatitis B virus and parvovirus B19 in ancient human remains demonstrate that little genetic change has occurred in these viruses over 4,500-6,000 years. Endogenous viral elements in host genomes provide separate evidence that viruses similar to many major contemporary groups circulated 100 million years ago or earlier. In this Opinion article, we argue that the extraordinary conservation of virus genome sequences is best explained by a niche-filling model in which fitness optimization is rapidly achieved in their specific hosts. Whereas short-term substitution rates reflect the accumulation of tolerated sequence changes within adapted genomes, longer term rates increasingly resemble those of their hosts as the evolving niche moulds and effectively imprisons the virus in co-adapted virus-host relationships. Contrastingly, viruses that jump hosts undergo strong and stringent adaptive selection as they maximize their fit to their new niche. This adaptive capability may paradoxically create evolutionary stasis in long-term host relationships. While viruses can evolve and adapt rapidly, their hosts may ultimately shape their longer-term evolution. PMID- 30518815 TI - Cell-based immunotherapy approaches for multiple myeloma. AB - Despite the arrival of novel therapies, multiple myeloma (MM) remains incurable and new treatment options are needed. Chimeric antigen receptor (CAR) T cells are genetically modified T cells that express a CAR directed against specific tumour antigens. CAR T cells are able to kill target tumour cells and may result in long lasting immune responses in vivo. The rapid development of CAR technologies has led to clinical trials in haematological cancers including MM, and CAR T cells might evolve into a standard treatment in the next few years. Only small patient cohorts with relapsed or refractory disease have so far been investigated, but promising preliminary results with high response rates have been obtained in phase I clinical trials with B cell maturation antigen (BCMA), CD19, CD38 and kappa-light-chain CAR T cells. Additional preclinical studies on CD38 and SLAMF7 CAR T cells in MM treatment yielded preclinical results that merit further investigation. Beyond the T cell approach, recent studies have focussed on CAR natural killer (NK) cells in order to increase the reactivity of these effector cells. Finally, to investigate the targeting of intracellular antigens, cellular therapies based on engineered T cell receptors (TCRs) are in development. In this review, we discuss results from preclinical and early-phase clinical trials testing the feasibility and safety of CAR T cell administration in MM, as well as early studies into approaches that utilise CAR NK cell and genetically modified TCRs. PMID- 30518817 TI - Taxonomic and functional heterogeneity of the gill microbiome in a symbiotic coastal mangrove lucinid species. AB - Lucinidae clams harbor gammaproteobacterial thioautotrophic gill endosymbionts that are environmentally acquired. Thioautotrophic lucinid symbionts are related to metabolically similar symbionts associated with diverse marine host taxa and fall into three distinct phylogenetic clades. Most studies on the lucinid bacteria chemosymbiosis have been done with seagrass-dwelling hosts, whose symbionts belong to the largest phylogenetic clade. In this study, we examined the taxonomy and functional repertoire of bacterial endosymbionts at an unprecedented resolution from Phacoides pectinatus retrieved from mangrove-lined coastal sediments, which are underrepresented in chemosymbiosis studies. The P. pectinatus thioautotrophic endosymbiont expressed metabolic gene variants for thioautotrophy, respiration, and nitrogen assimilation distinct from previously characterized lucinid thioautotrophic symbionts and other marine symbionts. At least two other bacterial species with different metabolisms were also consistently identified in the P. pectinatus gill microbiome, including a Kistimonas-like species and a Spirochaeta-like species. Bacterial transcripts involved in adhesion, growth, and virulence and mixotrophy were highly expressed, as were host-related hemoglobin and lysozyme transcripts indicative of sulfide/oxygen/CO2 transport and bactericidal activity. This study suggests the potential roles of P. pectinatus and its gill microbiome species in mangrove sediment biogeochemistry and offers insights into host and microbe metabolisms in the habitat. PMID- 30518816 TI - Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer. AB - BACKGROUND: Advanced cancer causes necrosis and releases damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs activate neutrophils, including generation of neutrophil extracellular traps (NETs), which are injurious, thrombogenic, and implicated in metastasis. We hypothesised that extracellular mitochondrial DNA (mtDNA) in ascites from patients with epithelial ovarian cancer (EOC) would correlate with worse outcomes. METHODS: Banked ascites supernatants from patients with newly diagnosed advanced EOC were analysed for mtDNA, neutrophil elastase, and activation of healthy donor neutrophils and platelets. TCGA was mined for expression of SELP and ELANE. RESULTS: The highest quartile of ascites mtDNA correlated with reduced progression-free survival (PFS) and a higher likelihood of disease progression within 12-months following primary surgery (n = 68, log-rank, p = 0.0178). NETs were detected in resected tumours. Ascites supernatants chemoattracted neutrophils, induced NETs, and activated platelets. Ascites exposure rendered neutrophils suppressive, based on abrogation of ex vivo stimulated T cell proliferation. Increased SELP mRNA expression correlated with worse overall survival (n = 302, Cox model, p = 0.02). CONCLUSION: In this single-centre retrospective analysis, ascites mtDNA correlated with worse PFS in advanced EOC. Mitochondrial and other DAMPs in ascites may activate neutrophil and platelet responses that facilitate metastasis and obstruct anti-tumour immunity. These pathways are potential prognostic markers and therapeutic targets. PMID- 30518819 TI - New in vivo model provides insights into Down syndrome. PMID- 30518818 TI - Marine probiotics: increasing coral resistance to bleaching through microbiome manipulation. AB - Although the early coral reef-bleaching warning system (NOAA/USA) is established, there is no feasible treatment that can minimize temperature bleaching and/or disease impacts on corals in the field. Here, we present the first attempts to extrapolate the widespread and well-established use of bacterial consortia to protect or improve health in other organisms (e.g., humans and plants) to corals. Manipulation of the coral-associated microbiome was facilitated through addition of a consortium of native (isolated from Pocillopora damicornis and surrounding seawater) putatively beneficial microorganisms for corals (pBMCs), including five Pseudoalteromonas sp., a Halomonas taeanensis and a Cobetia marina-related species strains. The results from a controlled aquarium experiment in two temperature regimes (26 degrees C and 30 degrees C) and four treatments (pBMC; pBMC with pathogen challenge - Vibrio coralliilyticus, VC; pathogen challenge, VC; and control) revealed the ability of the pBMC consortium to partially mitigate coral bleaching. Significantly reduced coral-bleaching metrics were observed in pBMC-inoculated corals, in contrast to controls without pBMC addition, especially challenged corals, which displayed strong bleaching signs as indicated by significantly lower photopigment contents and Fv/Fm ratios. The structure of the coral microbiome community also differed between treatments and specific bioindicators were correlated with corals inoculated with pBMC (e.g., Cobetia sp.) or VC (e.g., Ruegeria sp.). Our results indicate that the microbiome in corals can be manipulated to lessen the effect of bleaching, thus helping to alleviate pathogen and temperature stresses, with the addition of BMCs representing a promising novel approach for minimizing coral mortality in the face of increasing environmental impacts. PMID- 30518820 TI - Carbon Nanotube Reinforced Structural Composite Supercapacitor. AB - Carbon nanotubes exhibit mechanical properties ideally suited for reinforced structural composites and surface area and conductivity attractive for electrochemical capacitors. Here we demonstrate the multifunctional synergy between these properties in a composite material exhibiting simultaneous mechanical and energy storage properties. This involves a reinforcing electrode developed using dense, aligned carbon nanotubes grown on stainless steel mesh that is layered in an ion conducting epoxy electrolyte matrix with Kevlar or fiberglass mats. The resulting energy storage composites exhibit elastic modulus over 5 GPa, mechanical strength greater than 85 MPa, and energy density up to 3 mWh/kg for the total combined system including electrodes, current collector, Kevlar or fiberglass, and electrolyte matrix. Furthermore, findings from in-situ mechano-electro-chemical tests indicate simultaneous mechanical and electrochemical functionality with invariant and stable supercapacitor performance maintained throughout the elastic regime. PMID- 30518821 TI - End of the 2018 year: reflections and thanks. PMID- 30518822 TI - Reducing fetal origins of childhood obesity through maternal smoking cessation during pregnancy: an intervention study. AB - Rapid infant weight gain predicts childhood obesity. We aimed to estimate effect size and identify critical timing for intervention-assisted smoking cessation during pregnancy to impact infant weight gain. We followed 25 mother-infant dyads in the UB Pregnancy and Smoking Cessation Study (Buffalo, NY, USA). Maternal smoking status was biochemically verified and monitored through pregnancy. Birth weight and length were extracted from birth records. Research staff measured infant weight and length at 2 weeks and monthly from 1 to 12 months of age. Mixed models were used to fit infant BMI-for-age z-score (ZBMI) trajectories. We found infants of quitters had lower ZBMI gain from birth to 12 months (mean +/- SD, 1.13 +/- 1.16) than infants of persistent smokers (2.34 +/- 1.40; p = 0.035), with Cohen's d effect size being large (0.96). The infant ZBMI gain from birth to 12 months was low (<0.47) if smoking cessation was initiated between 15 and 27 weeks of pregnancy, but started to increase if quitting at 28 weeks (0.65) and accelerated with time (e.g., 3.16 if quitting at 36 weeks). We concluded maternal smoking cessation during pregnancy may reduce fetal origins of obesity through reducing infant weight gain, especially if quitting smoking by 27 weeks of pregnancy. PMID- 30518823 TI - Association between brown adipose tissue and bone mineral density in humans. AB - BACKGROUND: Brown adipose tissue (BAT) seems to play a role in bone morphogenesis. A negative association has been reported between BAT and bone mineral density (BMD) in women, but not in men. A panel of experts has recently published a set of recommendations for BAT assessment, and thus, to re-address previously reported associations is needed. This study aimed to investigate the association between cold-induced BAT 18F-Fluorodeoxyglucose (18F-FDG) uptake and BMD in young healthy adults. METHODS: Ninety-eight healthy adults (68 women; 22 +/- 2.2 years old; 24.3 +/- 4.5 kg/m2) cold-induced BAT was assessed by means of an 18F-FDG positron emission tomography-computed tomography (PET-CT) scan preceded by a personalized cold stimulation. The cold exposure consisted in 2 h in a mild cold room at 19.5-20 degrees C wearing a water perfused cooling vest set 4 degrees C above the individual shivering threshold. Total body and lumbar spine BMD were assessed by a whole-body DXA scan. RESULTS: We found no association between BMD and cold-induced BAT volume, mean, and maximal activity (all P > 0.1) in neither young and healthy men nor women. These results remained unchanged when adjusting by height, by body composition, and by objectively assessed physical activity. Sensitivity analyses using the criteria to quantify cold-induced BAT-related parameters applied in previous studies did not change the results. CONCLUSIONS: In summary, our study shows that there is no association between cold-induced BAT and BMD in young healthy adults. Moreover, our data support the notion that previously shown associations between BAT and BMD in healthy non-calorically restricted individuals, could be driven by methodological issues related to BAT assessment and/or sample size limitations. PMID- 30518824 TI - Parathyroid hormone induces a browning program in human white adipocytes. AB - Energy dissipation through the promotion of brown adipose tissue (BAT) or browning of white adipose tissue has recently evolved as novel promising concept in the fight against metabolic disease. New evidence suggests that hormones can contribute to the thermogenic programming of adipocytes through paracrine or endocrine actions. Recent studies in rodents identified parathyroid hormone (PTH) and PTH-related peptide as mediators of energy wasting in cachexia models due to adipocyte browning. However, the effects of PTH on human adipocyte thermogenesis and metabolic activity are unknown. Here we isolated subcutaneous white adipocyte precursor cells (APCs) from human donors followed by stimulation with recombinant PTH. Our data show that acute and chronic PTH administration in primary in vitro differentiated human subcutaneous adipocytes induces a molecular thermogenic program with increased mitochondrial activity and oxidative respiratory capacity. PTH also enhances hormone sensitive lipase activity and lipolysis in human adipocytes which may contribute to the observed thermogenic effects. In summary, we demonstrate here that PTH is a novel mediator of human adipocyte browning, suggesting a hitherto unknown endocrine axis between the parathyroid gland and adipose tissue in humans. PMID- 30518825 TI - Effects of bariatric surgery on retinal microvascular architecture in obese patients. AB - STUDY AIM: Retinal microvasculature changes reflect systemic small vessel damage from obesity. The impact of bariatric surgery induced weight loss on the microvasculature is relatively unknown. We hypothesized that weight loss following bariatric surgery would be associated with improved structural changes in the retinal microvasculature, reflecting an overall improvement in microvascular health. METHODS: The study included 22 obese subjects scheduled for bariatric surgery (laparoscopic Roux-en-Y gastric bypass or a sleeve gastrectomy) and 15 lean, age-matched controls. Ophthalmic examination, including fundus photography, was performed at baseline and 6-months. Retinal microvasculature caliber was analysed quantitatively using a semi-automated computer program and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE). RESULTS: Mean weight loss at 6 months was 26.1 kg +/- 8 kg in the bariatric surgery group. Retinal artery caliber increased (136.0 +/- 1.4 to 141.4 +/- 1.4 um, p = 0.013) and venular caliber decreased (202.9 +/- 1.9 to 197.3 +/- 1.9 um, p = 0.046) in the bariatric surgery group by 6 months, with no change in arteriolar (136.6 +/- 1.1 to 134.5 +/- 1.2, p = 0.222) or venular (195.1 +/- 2.1 to 193.3 +/- 2.2, p = 0.550) caliber in the control group. The arteriolar to venular ratio increased in the bariatric surgery group, with no change in the control group at 6 months. CONCLUSIONS: The findings suggest obesity-related microvascular changes are reversible after bariatric surgery-induced weight loss. The capacity for the retinal microvasculature to improve following bariatric surgery suggests plasticity of the human microvasculature early in the disease course. PMID- 30518827 TI - Depressive symptoms, perceived stress, and metabolic health: The REGARDS study. AB - OBJECTIVE: To describe the relationship between metabolic health parameters and depressive symptoms and perceived stress, and whether the co-occurrence of these two psychological stressors has an additive influence on metabolic dysregulation in adults at different levels of body mass index (BMI) without diabetes. METHODS: Participants without diabetes (N = 20,312) from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study (recruited between 2003-2007) who had a body mass index (BMI) >= 18.5 kg/m2 were included in this cross-sectional analysis. Mean age of sample was 64.4 years, with 36% African American, and 56% women. Depressive symptoms and perceived stress were measured using brief versions of the Center for Epidemiologic Studies Depression (CES-D-4 item) questionnaire and Cohen Perceived Stress Scale (PSS), respectively. Metabolic health parameters included waist circumference, blood pressure (systolic and diastolic), low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, fasting glucose, and high sensitivity C-reactive protein (hs-CRP). Sequentially adjusted general linear regression models (GLM) for each metabolic parameter were used to assess the association between having both elevated depressive symptoms and stress, either of these psychological risk factors, or none with all analyses stratified by BMI category (i.e., normal, overweight, and obesity). RESULTS: The presence of elevated depressive symptoms and/or perceived stress was generally associated with increased waist circumference, higher CRP, and lower HDL. The combination of depressive symptoms and perceived stress, compared to either alone, was typically associated with poorer metabolic health outcomes. However, sociodemographic and lifestyle factors generally attenuated the associations between psychological factors and metabolic parameters. CONCLUSIONS: Elevated depressive symptoms in conjunction with high levels of perceived stress were more strongly associated with several parameters of metabolic health than only one of these psychological constructs in a large, diverse cohort of adults. Findings suggest that healthy lifestyle factors may attenuate the association between psychological distress and metabolic health impairment. PMID- 30518826 TI - Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts. AB - BACKGROUND AND AIMS: Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. SUBJECTS AND METHODS: The study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use. RESULTS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found. CONCLUSIONS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings. PMID- 30518828 TI - Cryopreservation of primary B cells minimally influences their signaling responses. AB - Phospho flow is a powerful approach to detect cell signaling aberrations, identify biomarkers and assess pharmacodynamics, and can be performed using cryopreserved samples. The effects of cryopreservation on signaling responses and the reproducibility of phospho flow measurements are however unknown in many cell systems. Here, B lymphocytes were isolated from healthy donors and patients with the B cell malignancy chronic lymphocytic leukemia and analyzed by phospho flow using phospho-specific antibodies targeting 20 different protein epitopes. Cells were analyzed both at basal conditions and after activation of cluster of differentiation 40 (CD40) or the B cell receptor. Pharmacodynamics of the novel pathway inhibitor ibrutinib was also assessed. At all conditions, fresh cells were compared to cryopreserved cells. Minimal variation between fresh and frozen samples was detected. Reproducibility was tested by running samples from the same donors in different experiments. The results demonstrate reproducibility across different phospho flow runs and support the use of cryopreserved samples in future phospho flow studies of B lymphocytes. PMID- 30518829 TI - Human pharmacology of positive GABA-A subtype-selective receptor modulators for the treatment of anxiety. AB - Anxiety disorders arise from disruptions among the highly interconnected circuits that normally serve to process the streams of potentially threatening stimuli. The resulting imbalance among these circuits can cause a fundamental misinterpretation of neural sensory information as threatening and can lead to the inappropriate emotional and behavioral responses observed in anxiety disorders. There is considerable preclinical evidence that the GABAergic system, in general, and its alpha2- and/or alpha5-subunit-containing GABA(A) receptor subtypes, in particular, are involved in the pathophysiology of anxiety disorders. However, the clinical efficacy of GABA-A alpha2-selective agonists for the treatment of anxiety disorders has not been unequivocally demonstrated. In this review, we present several human pharmacological studies that have been performed with the aim of identifying the pharmacologically active doses/exposure levels of several GABA-A subtype-selective novel compounds with potential anxiolytic effects. The pharmacological selectivity of novel alpha2-subtype selective GABA(A) receptor partial agonists has been demonstrated by their distinct effect profiles on the neurophysiological and neuropsychological measurements that reflect the functions of multiple CNS domains compared with those of benzodiazepines, which are nonselective, full GABA(A) agonists. Normalizing the undesired pharmacodynamic side effects against the desired on target effects on the saccadic peak velocity is a useful approach for presenting the pharmacological features of GABA(A)-ergic modulators. Moreover, combining the anxiogenic symptom provocation paradigm with validated neurophysiological and neuropsychological biomarkers may provide further construct validity for the clinical effects of novel anxiolytic agents. In addition, the observed drug effects on serum prolactin levels support the use of serum prolactin levels as a complementary neuroendocrine biomarker to further validate the pharmacodynamic measurements used during the clinical pharmacological study of novel anxiolytic agents. PMID- 30518830 TI - Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators. AB - Alterations of hepatic metabolism are critical to the development of liver disease. The peroxisome proliferator-activated receptor-gamma coactivators (PGC1s) are able to orchestrate, on a transcriptional level, different aspects of liver metabolism, such as mitochondrial oxidative phosphorylation, gluconeogenesis and fatty acid synthesis. As modifications affecting both mitochondrial and lipid metabolism contribute to the initiation and/or progression of liver steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), a link between disrupted PGC1 pathways and onset of these pathological conditions has been postulated. However, despite the large quantity of studies, the scenario is still not completely understood, and some issues remain controversial. Here, we discuss the roles of PGC1s in healthy liver and explore their contribution to the pathogenesis and future therapy of NASH and HCC. PMID- 30518831 TI - A phytochrome-B-mediated regulatory mechanism of phosphorus acquisition. AB - Phosphorus (P) is a key macronutrient whose availability has a profound effect on plant growth and productivity. The understanding of the mechanism underlying P availability-responsive P acquisition has expanded largely in the past decade; however, effects of other environmental factors on P acquisition and utilization remain elusive. Here, by imaging natural variation in phosphate uptake in 200 natural accessions of Arabidopsis, we identify two accessions with low phosphate uptake activity, Lm-2 and CSHL-5. In these accessions, natural variants of phytochrome B were found to cause both decreased light sensitivity and lower phosphate uptake. Furthermore, we also found that expression levels of phosphate starvation-responsive genes are directly modulated by phytochrome interacting factors (PIF) PIF4/PIF5 and HY5 transcription factors whose activity is under the control of phytochromes. These findings disclose a new molecular mechanism underlying red-light-induced activation of phosphate uptake, which is responsible for different activity for P acquisition in some natural accessions of Arabidopsis. PMID- 30518832 TI - Moisture pulse-reserve in the soil-plant continuum observed across biomes. AB - The degree to which individual pulses of available water drive plant activity across diverse biomes and climates is not well understood. It has previously only been investigated in a few dryland locations. Here, plant water uptake following pulses of surface soil moisture, an indicator for the pulse-reserve hypothesis, is investigated across South America, Africa and Australia with satellite-based estimates of surface soil and canopy water content. Our findings show that this behaviour is widespread: occurring over half of the vegetated landscapes. We estimate spatially varying soil moisture thresholds at which plant water uptake ceases, noting dependence on soil texture and proximity to the wilting point. The soil type and biome-dependent soil moisture threshold and the plant soil water uptake patterns at the scale of Earth system models allow a unique opportunity to test and improve model parameterization of vegetation function under water limitation. PMID- 30518833 TI - Mechanistic framework for cell-intrinsic re-establishment of PIN2 polarity after cell division. AB - Cell polarity, manifested by the localization of proteins to distinct polar plasma membrane domains, is a key prerequisite of multicellular life. In plants, PIN auxin transporters are prominent polarity markers crucial for a plethora of developmental processes. Cell polarity mechanisms in plants are distinct from other eukaryotes and still largely elusive. In particular, how the cell polarities are propagated and maintained following cell division remains unknown. Plant cytokinesis is orchestrated by the cell plate-a transient centrifugally growing endomembrane compartment ultimately forming the cross wall1. Trafficking of polar membrane proteins is typically redirected to the cell plate, and these will consequently have opposite polarity in at least one of the daughter cells2 5. Here, we provide mechanistic insights into post-cytokinetic re-establishment of cell polarity as manifested by the apical, polar localization of PIN2. We show that the apical domain is defined in a cell-intrinsic manner and that re establishment of PIN2 localization to this domain requires de novo protein secretion and endocytosis, but not basal-to-apical transcytosis. Furthermore, we identify a PINOID-related kinase WAG1, which phosphorylates PIN2 in vitro6 and is transcriptionally upregulated specifically in dividing cells, as a crucial regulator of post-cytokinetic PIN2 polarity re-establishment. PMID- 30518835 TI - Polymers out of sync. PMID- 30518834 TI - Red light means on for phosphorus. PMID- 30518836 TI - Deconstructing Eden. PMID- 30518838 TI - Occupying common ground. PMID- 30518837 TI - Sempervirens. PMID- 30518840 TI - Symbiosis gatekeeper. PMID- 30518839 TI - The CLE9/10 secretory peptide regulates stomatal and vascular development through distinct receptors. AB - The frequency and orientation of cell division are regulated by intercellular signalling molecules; however, tissue-specific regulatory systems for cell divisions are only partially understood. Here, we report that the peptide hormone CLAVATA3/ESR-RELATED 9/10 (CLE9/10) regulates two different developmental processes, stomatal lineage development and xylem development, through two distinct receptor systems in Arabidopsis thaliana. We show that the receptor kinase HAESA-LIKE 1 (HSL1) is a CLE9/10 receptor that regulates stomatal lineage cell division, and BARELY NO MERISTEM (BAM) class receptor kinases are CLE9/10 receptors that regulate periclinal cell division of xylem precursor cells. Both HSL1 and BAM1 bind to CLE9/10, but only HSL1 recruits SOMATIC EMBRYOGENESIS RECEPTOR KINASES as co-receptors in the presence of CLE9/10, suggesting different signalling modes for these receptor systems. PMID- 30518841 TI - Safeguard by root microbiome. PMID- 30518842 TI - CREPT/RPRD1B associates with Aurora B to regulate Cyclin B1 expression for accelerating the G2/M transition in gastric cancer. AB - Gastric cancer, like most of other cancers, has an uncontrolled cell cycle regulated by cyclins and cyclin-dependent kinases (CDKs). In this study, we reported that gastric cancer cells showed an accelerated G2/M transition promoted by CREPT/RPRD1B and Aurora kinase B (Aurora B). We found that CREPT/RPRD1B and Aurora B were coordinately expressed during the cell cycle in gastric cancer cells. Deletion of CREPT/RPRD1B disturbed the cell progression and extended the length of cell cycle, leading to a significant accumulation of mitotic cells. Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1, which is critical for the regulation of gastric tumorigenesis. Our study provides a mechanism by which gastric tumor cells maintain their high proliferation rate via coordination of Aurora B and CREPT/RPRD1B on the expression of Cyclin B1. Targeting the interaction of Aurora B and CREPT/RPRD1B might be a strategy for anti-gastric cancer therapy in the future. PMID- 30518843 TI - Temporal proteomic profiling of postnatal human cortical development. AB - Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR < 5%). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation, and disease. PMID- 30518845 TI - Acetylation takes aim at mRNA. PMID- 30518844 TI - Plasmon induced thermoelectric effect in graphene. AB - Graphene has emerged as a promising material for optoelectronics due to its potential for ultrafast and broad-band photodetection. The photoresponse of graphene junctions is characterized by two competing photocurrent generation mechanisms: a conventional photovoltaic effect and a more dominant hot-carrier assisted photothermoelectric (PTE) effect. The PTE effect is understood to rely on variations in the Seebeck coefficient through the graphene doping profile. A second PTE effect can occur across a homogeneous graphene channel in the presence of an electronic temperature gradient. Here, we study the latter effect facilitated by strongly localised plasmonic heating of graphene carriers in the presence of nanostructured electrical contacts resulting in electronic temperatures of the order of 2000 K. At certain conditions, the plasmon-induced PTE photocurrent contribution can be isolated. In this regime, the device effectively operates as a sensitive electronic thermometer and as such represents an enabling technology for development of hot carrier based plasmonic devices. PMID- 30518846 TI - Reply to 'Deconstructing transport-distribution reconstruction in the nuclear pore complex'. PMID- 30518847 TI - Structural and molecular mechanisms for the control of eukaryotic 5'-3' mRNA decay. AB - 5'-3' RNA decay pathways are critical for quality control and regulation of gene expression. Structural and biochemical studies have provided insights into the key nucleases that carry out deadenylation, decapping, and exonucleolysis during 5'-3' decay, but detailed understanding of how these activities are coordinated is only beginning to emerge. Here we review recent mechanistic insights into the control of 5'-3' RNA decay, including coupling between translation and decay, coordination between the complexes and activities that process 5' and 3' RNA termini, conformational control of enzymatic activity, liquid phase separation, and RNA modifications. PMID- 30518848 TI - Deconstructing transport-distribution reconstruction in the nuclear-pore complex. PMID- 30518849 TI - Structure of a functional obligate complex III2IV2 respiratory supercomplex from Mycobacterium smegmatis. AB - In the mycobacterial electron-transport chain, respiratory complex III passes electrons from menaquinol to complex IV, which in turn reduces oxygen, the terminal acceptor. Electron transfer is coupled to transmembrane proton translocation, thus establishing the electrochemical proton gradient that drives ATP synthesis. We isolated, biochemically characterized, and determined the structure of the obligate III2IV2 supercomplex from Mycobacterium smegmatis, a model for Mycobacterium tuberculosis. The supercomplex has quinol:O2 oxidoreductase activity without exogenous cytochrome c and includes a superoxide dismutase subunit that may detoxify reactive oxygen species produced during respiration. We found menaquinone bound in both the Qo and Qi sites of complex III. The complex III-intrinsic diheme cytochrome cc subunit, which functionally replaces both cytochrome c1 and soluble cytochrome c in canonical electron transport chains, displays two conformations: one in which it provides a direct electronic link to complex IV and another in which it serves as an electrical switch interrupting the connection. PMID- 30518852 TI - Enhancement of photoluminescence efficiency in GeSe ultrathin slab by thermal treatment and annealing: experiment and first-principles molecular dynamics simulations. AB - The effect of thermal treatment and annealing under different temperatures from 100 degrees C to 250 degrees C on the photoluminescence spectroscopy of the GeSe ultrathin slab is reported. After the thermal treatment and annealing under 200 degrees C, we found that the photoluminescence intensity of A exciton and B exciton in GeSe ultrathin slab is increased to twice as much as that in untreated case, while is increased by ~84% in the photoluminescence intensity of C exciton. Combined by our experimental work and theoretical simulations, our study confirms the significant role of thermal treatments and annealing in reducing surface roughness and removing the Se vacancy to form more compact and smoother regions in GeSe ultrathin slab. Our findings imply that the improved quality of GeSe surface after thermal treatments is an important factor for the photoluminescence enhancement. PMID- 30518851 TI - Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer. AB - BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer. PMID- 30518850 TI - Trait determinants of impulsive behavior: a comprehensive analysis of 188 rats. AB - Impulsivity is a naturally occurring behavior that, when accentuated, can be found in a variety of neuropsychiatric disorders. The expression of trait impulsivity has been shown to change with a variety of factors, such as age and sex, but the existing literature does not reflect widespread consensus regarding the influence of modulating effects. We designed the present study to investigate, in a cohort of significant size (188 rats), the impact of four specific parameters, namely sex, age, strain and phase of estrous cycle, using the variable delay-to-signal (VDS) task. This cohort included (i) control animals from previous experiments; (ii) animals specifically raised for this study; and (iii) animals previously used for breeding purposes. Aging was associated with a general decrease in action impulsivity and an increase in delay tolerance. Females generally performed more impulsive actions than males but no differences were observed regarding delay intolerance. In terms of estrous cycle, no differences in impulsive behavior were observed and regarding strain, Wistar Han animals were, in general, more impulsive than Sprague-Dawley. In addition to further confirming, in a substantial study cohort, the decrease in impulsivity with age, we have demonstrated that both the strain and sex influences modulate different aspects of impulsive behavior manifestations. PMID- 30518853 TI - Lecithin-Stabilized Polymeric Micelles (LsbPMs) for Delivering Quercetin: Pharmacokinetic Studies and Therapeutic Effects of Quercetin Alone and in Combination with Doxorubicin. AB - In this study, lecithin-stabilized polymeric micelles (LsbPMs) were prepared to load quercetin (QUE) in order to improve its bioavailability and increase its antitumor activity. Its combination with doxorubicin (DOX) to minimize DOX mediated cardiac toxicity and increase the antitumor activity of QUE-loaded LsbPMs was also examined. LsbPMs were prepared following a previously reported procedure. Results demonstrated that optimal QUE-loaded LsbPMs contained quercetin, D-alpha-tocopheryl polyethylene glycol succinate, and lecithin at a weight ratio of 6:40:80. Drug-release studies showed that QUE released from LsbPMs followed a controlled release pattern. A cytotoxicity assay revealed that QUE-loaded LsbPMs had significant anticancer activities against MCF-7, SKBR-3, and MDA-MB-231 human breast cancer cells and CT26 mouse colon cancer cells. In animal studies, intravenous administration of QUE-loaded LsbPMs resulted in efficient growth inhibition of CT26 colon cancer cells in a Balb/c mice model. In a pharmacokinetics study compared to free QUE, intravenous and oral administration of QUE-loaded LsbPMs was found to have significantly increased the relative bioavailability to 158% and 360%, respectively, and the absolute bioavailability to 5.13%. The effect of QUE-loaded LsbPMs in combination with DOX resulted in efficient growth inhibition of CT26 colon cancer cells and reduced cardiac toxicity in the Balb/c mice model. PMID- 30518854 TI - Inhibition of inflammasome activation by a clinical strain of Klebsiella pneumoniae impairs efferocytosis and leads to bacterial dissemination. AB - Klebsiella pneumoniae is a Gram-negative bacterium responsible for severe cases of nosocomial pneumonia. During the infectious process, both neutrophils and monocytes migrate to the site of infection, where they carry out their effector functions and can be affected by different patterns of cell death. Our data show that clinical strains of K. pneumoniae have dissimilar mechanisms for surviving within macrophages; these mechanisms include modulation of microbicidal mediators and cell death. The A28006 strain induced high IL-1beta production and pyroptotic cell death in macrophages; by contrast, the A54970 strain induced high IL-10 production and low IL-1beta production by macrophages. Pyroptotic cell death induced by the A28006 strain leads to a significant increase in bacterial sensitivity to hydrogen peroxide, and efferocytosis of the pyroptotic cells results in efficient bacterial clearance both in vitro and in vivo. In addition, the A54970 strain was able to inhibit inflammasome activation and pyroptotic cell death by inducing IL-10 production. Here, for the first time, we present a K. pneumoniae strain able to inhibit inflammasome activation, leading to bacterial survival and dissemination in the host. The understanding of possible escape mechanisms is essential in the search for alternative treatments against multidrug-resistant bacteria. PMID- 30518855 TI - A chemical defence against phage infection. AB - The arms race between bacteria and the phages that infect them drives the continual evolution of diverse anti-phage defences. Previously described anti phage systems have highly varied defence mechanisms1-11; however, all mechanisms rely on protein components to mediate defence. Here we report a chemical anti phage defence system that is widespread in Streptomyces. We show that three naturally produced molecules that insert into DNA are able to block phage replication, whereas molecules that target DNA by other mechanisms do not. Because double-stranded DNA phages are the most numerous group in the biosphere and the production of secondary metabolites by bacteria is ubiquitous12, this mechanism of anti-phage defence probably has a major evolutionary role in shaping bacterial communities. PMID- 30518856 TI - Dna2 nuclease deficiency results in large and complex DNA insertions at chromosomal breaks. AB - Insertions of mobile elements1-4, mitochondrial DNA5 and fragments of nuclear chromosomes6 at DNA double-strand breaks (DSBs) threaten genome integrity and are common in cancer7-9. Insertions of chromosome fragments at V(D)J recombination loci can stimulate antibody diversification10. The origin of insertions of chromosomal fragments and the mechanisms that prevent such insertions remain unknown. Here we reveal a yeast mutant, lacking evolutionarily conserved Dna2 nuclease, that shows frequent insertions of sequences between approximately 0.1 and 1.5 kb in length into DSBs, with many insertions involving multiple joined DNA fragments. Sequencing of around 500 DNA inserts reveals that they originate from Ty retrotransposons (8%), ribosomal DNA (rDNA) (15%) and from throughout the genome, with preference for fragile regions such as origins of replication, R loops, centromeres, telomeres or replication fork barriers. Inserted fragments are not lost from their original loci and therefore represent duplications. These duplications depend on nonhomologous end-joining (NHEJ) and Pol4. We propose a model in which alternative processing of DNA structures arising in Dna2-deficient cells can result in the release of DNA fragments and their capture at DSBs. Similar DNA insertions at DSBs are expected to occur in any cells with linear extrachromosomal DNA fragments. PMID- 30518857 TI - Single-cell mapping of lineage and identity in direct reprogramming. AB - Direct lineage reprogramming involves the conversion of cellular identity. Single cell technologies are useful for deconstructing the considerable heterogeneity that emerges during lineage conversion. However, lineage relationships are typically lost during cell processing, complicating trajectory reconstruction. Here we present 'CellTagging', a combinatorial cell-indexing methodology that enables parallel capture of clonal history and cell identity, in which sequential rounds of cell labelling enable the construction of multi-level lineage trees. CellTagging and longitudinal tracking of fibroblast to induced endoderm progenitor reprogramming reveals two distinct trajectories: one leading to successfully reprogrammed cells, and one leading to a 'dead-end' state, paths determined in the earliest stages of lineage conversion. We find that expression of a putative methyltransferase, Mettl7a1, is associated with the successful reprogramming trajectory; adding Mettl7a1 to the reprogramming cocktail increases the yield of induced endoderm progenitors. Together, these results demonstrate the utility of our lineage-tracing method for revealing the dynamics of direct reprogramming. PMID- 30518858 TI - Capture of nebular gases during Earth's accretion is preserved in deep-mantle neon. AB - Evidence for the capture of nebular gases by planetary interiors would place important constraints on models of planet formation. These constraints include accretion timescales, thermal evolution, volatile compositions and planetary redox states1-7. Retention of nebular gases by planetary interiors also constrains the dynamics of outgassing and volatile loss associated with the assembly and ensuing evolution of terrestrial planets. But evidence for such gases in Earth's interior remains controversial8-14. The ratio of the two primordial neon isotopes, 20Ne/22Ne, is significantly different for the three potential sources of Earth's volatiles: nebular gas15, solar-wind-irradiated material16 and CI chondrites17. Therefore, the 20Ne/22Ne ratio is a powerful tool for assessing the source of volatiles in Earth's interior. Here we present neon isotope measurements from deep mantle plumes that reveal 20Ne/22Ne ratios of up to 13.03 +/- 0.04 (2 standard deviations). These ratios are demonstrably higher than those for solar-wind-irradiated material and CI chondrites, requiring the presence of nebular neon in the deep mantle. Furthermore, we determine a 20Ne/22Ne ratio for the primordial plume mantle of 13.23 +/- 0.22 (2 standard deviations), which is indistinguishable from the nebular ratio, providing robust evidence for a reservoir of nebular gas preserved in the deep mantle today. The acquisition of nebular gases requires planetary embryos to grow to sufficiently large mass before the dissipation of the protoplanetary disk. Our observations also indicate distinct 20Ne/22Ne ratios between deep mantle plumes and mid-ocean ridge basalts, which is best explained by addition of a chondritic component to the shallower mantle during the main phase of Earth's accretion and by subsequent recycling of seawater-derived neon in plate tectonic processes. PMID- 30518859 TI - A circuit from hippocampal CA2 to lateral septum disinhibits social aggression. AB - Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal's internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression. PMID- 30518860 TI - Complex mammalian-like haematopoietic system found in a colonial chordate. AB - Haematopoiesis is an essential process that evolved in multicellular animals. At the heart of this process are haematopoietic stem cells (HSCs), which are multipotent and self-renewing, and generate the entire repertoire of blood and immune cells throughout an animal's life1. Although there have been comprehensive studies on self-renewal, differentiation, physiological regulation and niche occupation in vertebrate HSCs, relatively little is known about the evolutionary origin and niches of these cells. Here we describe the haematopoietic system of Botryllus schlosseri, a colonial tunicate that has a vasculature and circulating blood cells, and interesting stem-cell biology and immunity characteristics2-8. Self-recognition between genetically compatible B. schlosseri colonies leads to the formation of natural parabionts with shared circulation, whereas incompatible colonies reject each other3,4,7. Using flow cytometry, whole-transcriptome sequencing of defined cell populations and diverse functional assays, we identify HSCs, progenitors, immune effector cells and an HSC niche, and demonstrate that self-recognition inhibits allospecific cytotoxic reactions. Our results show that HSC and myeloid lineage immune cells emerged in a common ancestor of tunicates and vertebrates, and also suggest that haematopoietic bone marrow and the B. schlosseri endostyle niche evolved from a common origin. PMID- 30518861 TI - Controlling orthogonal ribosome subunit interactions enables evolution of new function. AB - Orthogonal ribosomes are unnatural ribosomes that are directed towards orthogonal messenger RNAs in Escherichia coli, through an altered version of the 16S ribosomal RNA of the small subunit1. Directed evolution of orthogonal ribosomes has provided access to new ribosomal function, and the evolved orthogonal ribosomes have enabled the encoding of multiple non-canonical amino acids into proteins2-4. The original orthogonal ribosomes shared the pool of 23S ribosomal RNAs, contained in the large subunit, with endogenous ribosomes. Selectively directing a new 23S rRNA to an orthogonal mRNA, by controlling the association between the orthogonal 16S rRNAs and 23S rRNAs, would enable the evolution of new function in the large subunit. Previous work covalently linked orthogonal 16S rRNA and a circularly permuted 23S rRNA to create orthogonal ribosomes with low activity5,6; however, the linked subunits in these ribosomes do not associate specifically with each other, and mediate translation by associating with endogenous subunits. Here we discover engineered orthogonal 'stapled' ribosomes (with subunits linked through an optimized RNA staple) with activities comparable to that of the parent orthogonal ribosome; they minimize association with endogenous subunits and mediate translation of orthogonal mRNAs through the association of stapled subunits. We evolve cells with genomically encoded stapled ribosomes as the sole ribosomes, which support cellular growth at similar rates to natural ribosomes. Moreover, we visualize the engineered stapled ribosome structure by cryo-electron microscopy at 3.0 A, revealing how the staple links the subunits and controls their association. We demonstrate the utility of controlling subunit association by evolving orthogonal stapled ribosomes which efficiently polymerize a sequence of monomers that the natural ribosome is intrinsically unable to translate. Our work provides a foundation for evolving the rRNA of the entire orthogonal ribosome for the encoded cellular synthesis of non-canonical biological polymers7. PMID- 30518862 TI - Soft-tissue evidence for homeothermy and crypsis in a Jurassic ichthyosaur. AB - Ichthyosaurs are extinct marine reptiles that display a notable external similarity to modern toothed whales. Here we show that this resemblance is more than skin deep. We apply a multidisciplinary experimental approach to characterize the cellular and molecular composition of integumental tissues in an exceptionally preserved specimen of the Early Jurassic ichthyosaur Stenopterygius. Our analyses recovered still-flexible remnants of the original scaleless skin, which comprises morphologically distinct epidermal and dermal layers. These are underlain by insulating blubber that would have augmented streamlining, buoyancy and homeothermy. Additionally, we identify endogenous proteinaceous and lipid constituents, together with keratinocytes and branched melanophores that contain eumelanin pigment. Distributional variation of melanophores across the body suggests countershading, possibly enhanced by physiological adjustments of colour to enable photoprotection, concealment and/or thermoregulation. Convergence of ichthyosaurs with extant marine amniotes thus extends to the ultrastructural and molecular levels, reflecting the omnipresent constraints of their shared adaptation to pelagic life. PMID- 30518864 TI - Inner ear development in cyclostomes and evolution of the vertebrate semicircular canals. AB - Jawed vertebrates have inner ears with three semicircular canals, the presence of which has been used as a key to understanding evolutionary relationships. Ostracoderms, the jawless stem gnathostomes, had only two canals and lacked the lateral canal1-3. Lampreys, which are modern cyclostomes, are generally thought to possess two semicircular canals whereas the hagfishes-which are also cyclostomes-have only a single canal, which used to be regarded as a more primitive trait1,4. However, recent molecular and developmental analyses have strongly supported the monophyly of cyclostomes5-7, which has left the evolutionary trajectory of the vertebrate inner ear unclear8. Here we show the differentiation of the otic vesicle of the lamprey Lethenteron camtschaticum and inshore hagfish Eptatretus burgeri. This is the first time, to our knowledge, that the development of the hagfish inner ear is reported. We found that canal development in the lamprey starts with two depressions-which is reminiscent of the early developmental pattern of the inner ear in modern gnathostomes. These cyclostome otic vesicles show a pattern of expression of regulatory genes, including OTX genes, that is comparable to that of gnathosomes. Although two depressions appear in the lamprey vesicle, they subsequently fuse to form a single canal that is similar to that of hagfishes. Complete separation of the depressions results in anterior and posterior canals in gnathostomes. The single depression of the vesicle in hagfishes thus appears to be a secondarily derived trait. Furthermore, the lateral canal in crown gnathostomes was acquired secondarily-not by de novo acquisition of an OTX expression domain, but by the evolution of a developmental program downstream of the OTX genes. PMID- 30518865 TI - Author Correction: Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1. AB - In Figs. 1e and 2g of this Letter, the labels 'actin' and 'VGLUT3', respectively, should have been in red instead of green font. This has been corrected online. PMID- 30518863 TI - Consistent success in life-supporting porcine cardiac xenotransplantation. AB - Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-alpha1,3-galactose epitopes (alpha1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that alpha1,3 galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7. PMID- 30518866 TI - Graphene nanoplatelets as nanofillers in mesoporous silicon oxycarbide polymer derived ceramics. AB - Understanding the role of graphene in the thermal stability and pore morphology of polymer derived silicon oxycarbide is crucial for electrochemical energy storage and hydrogen storage applications. Here in this work, we report the synthesis of graphene nanoplatelets dispersed silicon oxycarbide ceramics by the polymer to ceramic synthesis route. Samples containing graphene and without graphene are subjected to different pyrolysis conditions and are characterized using FT-IR, XPS, Raman spectroscopy, XRD, FE-SEM, HR-TEM, and BET. The results show that the graphene dispersed in the ceramic has undergone structural distortions upon pyrolysis and resulted in the formation of nanoclusters of graphene and turbostratic graphene. The XRD results confirm that with the incorporation of higher wt.% of GNP there is resistance to crystallization even at an exceedingly high pyrolysis temperature. The pores are bimodal in nature with specific surface area ranging between 22 and 70 m2/g and are generated in situ during the polymer to ceramic conversion. Our study confirms that upon adjusting the graphene content it is possible to tune the structure and pore morphology of the polymer derived ceramics as per the requirements. PMID- 30518869 TI - Prostate cancer and prostatic diseases Best of China, 2018. PMID- 30518867 TI - Seamless lateral graphene p-n junctions formed by selective in situ doping for high-performance photodetectors. AB - Lateral graphene p-n junctions are important since they constitute the core components in a variety of electronic/photonic systems. However, formation of lateral graphene p-n junctions with a controllable doping levels is still a great challenge due to the monolayer feature of graphene. Herein, by performing selective ion implantation and in situ growth by dynamic chemical vapor deposition, direct formation of seamless lateral graphene p-n junctions with spatial control and tunable doping is demonstrated. Uniform lattice substitution with heteroatoms is achieved in both the boron-doped and nitrogen-doped regions and photoelectrical assessment reveals that the seamless lateral p-n junctions exhibit a distinct photocurrent response under ambient conditions. As ion implantation is a standard technique in microelectronics, our study suggests a simple and effective strategy for mass production of graphene p-n junctions with batch capability and spatial controllability, which can be readily integrated into the production of graphene-based electronics and photonics. PMID- 30518868 TI - m6A-mediated ZNF750 repression facilitates nasopharyngeal carcinoma progression. AB - Nasopharyngeal carcinoma (NPC) progression is regulated by genetic, epigenetic, and epitranscript modulation. As one of the epitranscript modifications, the role of N6-Methyladenosine (m6A) has not been elucidated in NPC. In the present study, we found that the poorly methylated gene ZNF750 (encoding zinc finger protein 750) was downregulated in NPC tumor tissues and cell lines. Ectopic expression of ZNF750 blocked NPC growth in vitro and in vivo. Further studies revealed that m6A modifications maintained the low expression level of ZNF750 in NPC. Chromatin immunoprecipitation sequencing identified that ZNF750 directly regulated FGF14 (encoding fibroblast growth factor 14), ablation of which reversed ZNF750's tumor repressor effect. Moreover, the ZNF750-FGF14 signaling axis inhibited NPC growth by promoting cell apoptosis. These findings uncovered the critical role of m6A in NPC, and stressed the regulatory function of the ZNF750-FGF14 signaling axis in modulating NPC progression, which provides theoretical guidance for the clinical treatment of NPC. PMID- 30518870 TI - Sustainable production of highly conductive multilayer graphene ink for wireless connectivity and IoT applications. AB - Printed electronics offer a breakthrough in the penetration of information technology into everyday life. The possibility of printing electronic circuits will further promote the spread of the Internet of Things applications. Inks based on graphene have a chance to dominate this technology, as they potentially can be low cost and applied directly on materials like textile and paper. Here we report the environmentally sustainable route of production of graphene ink suitable for screen-printing technology. The use of non-toxic solvent Dihydrolevoglucosenone (Cyrene) significantly speeds up and reduces the cost of the liquid phase exfoliation of graphite. Printing with our ink results in very high conductivity (7.13 * 104 S m-1) devices, which allows us to produce wireless connectivity antenna operational from MHz to tens of GHz, which can be used for wireless data communication and energy harvesting, which brings us very close to the ubiquitous use of printed graphene technology for such applications. PMID- 30518871 TI - The extracellular SEMA domain attenuates intracellular apoptotic signaling of semaphorin 6A in lung cancer cells. AB - Semaphorin 6A (SEMA6A), a membrane-bound protein, is downregulated in lung cancer tissue compared to its adjacent normal tissue. However, the functions of SEMA6A in lung cancer cells are still unclear. In the present study, full length SEMA6A and various truncations were transfected into lung cancer cells to investigate the role of the different domains of SEMA6A in cell proliferation and survival, apoptosis, and in vivo tumor growth. SEMA6A-induced cell signaling was explored using gene silencing, co-immunoprecipitation, and co-culture assays. Our results showed that overexpression of SEMA6A reduced the growth of lung cancer cells in vitro and in vivo, and silencing SEMA6A increased the proliferation of normal lung fibroblasts. Truncated SEMA6A lacking the SEMA domain or the extracellular region induced more apoptosis than full length SEMA6A, and reintroducing the SEMA domain attenuated the apoptosis. Fas-associated protein with death domain (FADD) bound to the cytosolic region of truncated SEMA6A and was involved in SEMA6A associated cytosol-induced apoptosis. This study suggests a novel function of SEMA6A in inducing apoptosis via FADD binding in lung cancer cells. PMID- 30518872 TI - Conserved Transcriptional Signatures in Human and Murine Diabetic Peripheral Neuropathy. AB - Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes. In this study, we employed a systems biology approach to identify DPN related transcriptional pathways conserved across human and various murine models. Eight microarray datasets on peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db and ob/ob) diabetes of various ages and human subjects with non-progressive and progressive DPN were collected. Differentially expressed genes (DEGs) were identified between non diabetic and diabetic samples in murine models, and non-progressive and progressive human samples using a unified analysis pipeline. A transcriptional network for each DEG set was constructed based on literature-derived gene-gene interaction information. Seven pairwise human-vs-murine comparisons using a network-comparison program resulted in shared sub-networks including 46 to 396 genes, which were further merged into a single network of 688 genes. Pathway and centrality analyses revealed highly connected genes and pathways including LXR/RXR activation, adipogenesis, glucocorticoid receptor signalling, and multiple cytokine and chemokine pathways. Our systems biology approach identified highly conserved pathways across human and murine models that are likely to play a role in DPN pathogenesis and provide new possible mechanism-based targets for DPN therapy. PMID- 30518873 TI - Correction: Yes and Lyn play a role in nuclear translocation of the epidermal growth factor receptor. AB - In Figure 4C, it was identified that the Histone H3 and alpha-Tubulin purification control blots for YES and LYN overexpressing cells were duplicated. The original Histone H3 control blot was found and confirmed the published results, however, the alpha-Tubulin control blot was not found. This error was determined to not impact the scientific findings of this figure. The authors regret this error. PMID- 30518874 TI - FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma. AB - The fibroblast growth factor 19 gene FGF19 has previously been reported to be amplified in several cancer types and encodes for a key autocrine signaler known to promote tumorigenic growth. Thus, it is imperative to understand which cancers are oncogenically addicted to FGF19 amplification as well as the role it serves in these cancer types. We report for the first time high FGF19 amplification in head and neck squamous cell carcinomas (HNSCC), which is associated with increased autocrine secretion of FGF19 and poor patient outcome in HNSCC. FGF19 amplification corresponded with constitutive activation of FGF receptor 4 (FGFR4) dependent ERK/AKT-p70S6K-S6 signaling activation in HNSCC cells, and addition of human recombinant FGF19 could promote cell proliferation and soft agar colony formation in HNSCC cells with low FGF19 expression through activation of FGFR4 and downstream signaling cascades. In contrast, FGF19 knockout counteracts the observed effects in HNSCC cells carrying high endogenous FGF19, with knockout of FGF19 significantly suppressing tumor growth in an orthotopic mouse model of HNSCC. Collectively, this study demonstrates that FGF19 gene amplification corresponds with an increased dependency upon FGF19/FGFR4 autocrine signaling in HNSCC, revealing a therapeutic target for this cancer type. PMID- 30518875 TI - DHS (trans-4,4'-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). AB - DNA replication machinery is responsible for accurate and efficient duplication of the chromosome. Since inhibition of DNA replication can lead to replication fork stalling, resulting in DNA damage and apoptotic death, inhibitors of DNA replication are commonly used in cancer chemotherapy. Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the biosynthesis of deoxyribonucleoside triphosphates (dNTPs) that are essential for DNA replication and DNA damage repair. Gemcitabine, a nucleotide analog that inhibits RNR, has been used to treat various cancers. However, patients often develop resistance to this drug during treatment. Thus, new drugs that inhibit RNR are needed to be developed. In this study, we identified a synthetic analog of resveratrol (3,5,4'-trihydroxy trans-stilbene), termed DHS (trans-4,4'-dihydroxystilbene), that acts as a potent inhibitor of DNA replication. Molecular docking analysis identified the RRM2 (ribonucleotide reductase regulatory subunit M2) of RNR as a direct target of DHS. At the molecular level, DHS induced cyclin F-mediated down-regulation of RRM2 by the proteasome. Thus, treatment of cells with DHS reduced RNR activity and consequently decreased synthesis of dNTPs with concomitant inhibition of DNA replication, arrest of cells at S-phase, DNA damage, and finally apoptosis. In mouse models of tumor xenografts, DHS was efficacious against pancreatic, ovarian, and colorectal cancer cells. Moreover, DHS overcame both gemcitabine resistance in pancreatic cancer and cisplatin resistance in ovarian cancer. Thus, DHS is a novel anti-cancer agent that targets RRM2 with therapeutic potential either alone or in combination with other agents to arrest cancer development. PMID- 30518876 TI - Obesity-associated inflammation promotes angiogenesis and breast cancer via angiopoietin-like 4. AB - Obesity is a risk factor for breast cancer and also predicts poor clinical outcomes regardless of menopausal status. Contributing to the poor clinical outcomes is the suboptimal efficacy of standard therapies due to dose limiting toxicities and obesity-related complications, highlighting the need to develop novel therapeutic approaches for treating obese patients. We recently found that obesity leads to an increase in tumor-infiltrating macrophages with activated NLRC4 inflammasome and increased interleukin (IL)-1beta production. IL-1beta, in turn, leads to increased angiogenesis and cancer progression. Using Next Generation RNA sequencing, we identified an NLRC4/IL-1beta-dependent upregulation of angiopoietin-like 4 (ANGPTL4), a known angiogenic factor in cancer, in tumors from obese mice. ANGPTL4-deficiency by genetic knockout or treatment with a neutralizing antibody led to a significant reduction in obesity-induced angiogenesis and tumor growth. At a mechanistic level, ANGPTL4 expression is induced by IL-1beta from primary adipocytes in a manner dependent on NF-kappaB- and MAP kinase-activation, which is further enhanced by hypoxia. This report shows that adipocyte-derived ANGPTL4 drives disease progression under obese conditions and is a potential therapeutic target for treating obese breast cancer patients. PMID- 30518877 TI - Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles. AB - The backbone of ovarian cancer treatment is platinum-based chemotherapy and aggressive surgical debulking. New therapeutic approaches using immunotherapy via immune checkpoint blockade, which have demonstrated clinical efficacy in other tumor types, have been less promising in ovarian cancer. To increase their clinical efficacy, checkpoint inhibitors are now being tested in clinical trials in combination with chemotherapy. Here, we evaluated the impact of cisplatin on tumor immunogenicity and its in vivo roles when used alone or in combination with anti-PD-L1, in two novel murine ovarian cancer cell models. The 2F8 and its platinum-resistant derivative 2F8cis model, display distinct inflammatory profiles and chemotherapy sensitivities, and mirror the primary and recurrent human disease, respectively. Acute and chronic exposure to cisplatin enhances tumor immunogenicity by increasing calreticulin, MHC class I, antigen presentation and T-cell infiltration. Cisplatin also upregulates PD-L1 expression in vitro and in vivo, demonstrating a dual, paradoxical immune modulatory effect and supporting the rationale for combination with immune checkpoint blockade. One of the pathways activated by cisplatin treatment is the cGAS/STING pathway. Chronic cisplatin treatment led to upregulation of cGAS and STING proteins in 2F8cis compared to parental 2F8 cells, while acute exposure to cisplatin further increases cGAS and STING levels in both 2F8 and 2F8cis cells. Overexpression of cGAS/STING modifies tumor immunogenicity by upregulating PD-L1, MHC I and calreticulin in tumor cells. Anti-PD-L1 alone in a platinum-sensitive model or with cisplatin in a platinum-resistant model increases survival. These studies have high translational potential in ovarian cancer. PMID- 30518878 TI - Enrichment of the fetal fraction in non-invasive prenatal screening reduces maternal background interference. AB - Measurement of cell-free fetal DNA (cffDNA) is an indispensable process for non invasive prenatal screening (NIPS). According to recent studies, cffDNA in maternal plasma can be enriched for various lengths of fragments, and a sufficient amount of cffDNA can effectively eliminate background interference on the part of maternal DNA. Therefore, we developed a simple and effective separation method, improved NIPS (iNIPS), that enriches the fetal fraction and improves the accuracy of NIPS for fetal aneuploid detection. We adopted a novel strategy to achieve enrichment of 125-135 bp cell-free DNA (cfDNA) by e-gel electrophoresis. To evaluate clinical performance, we compared NIPS and iNIPS results from 2153 retrospective clinical samples. Of the 22 samples with NIPS results of "no call", 17 samples were reclassified as "unaffected" (9 cases of chr13, 5 cases of chr18, and 3 cases of chr21); 2 samples remained classified as "no call" (1 case of chr18 and 1 case of chr21); and 3 samples were identified as T21 by iNIPS. The average increase in abundance of cfDNA fragments of 125-135 bp was 2.5 times, and the average decrease in maternal background interference was 1.3 times. On this basis, the detection of fetal aneuploidy was highly improved with the fetal fraction as low as 2%; iNIPS achieved 100% sensitivity and 99.90% specificity in retrospective samples. PMID- 30518879 TI - HCRP-1 regulates EGFR-AKT-BIM-mediated anoikis resistance and serves as a prognostic marker in human colon cancer. AB - Hepatocellular carcinoma-related protein-1 (HCRP-1), a subunit of mammalian endosomal sorting complex required for transport-I (ESCRT-I), is frequently downregulated in various kinds of malignant tumors. The role of HCRP-1 in colorectal cancer (CRC) remains unknown. We investigate the clinical value of HCRP-1 and its impact on anoikis in CRC. The negative expression of HCRP-1 was significantly correlated with tumor size (P = 0.033), PT status (P = 0.001), TNM stage (P = 0.039), and histological grade (P = 0.01). Univariate and multivariate analyses revealed that HCRP-1 was an independent prognostic factor for CRC (hazard ratio (HR) = 0.237, P < 0.001 for 5-year overall survival). In the in vitro assay, we found that HCRP-1 depletion resulted in cell anoikis resistance. Knockdown of HCRP-1 suppressed Bcl-2 interacting mediator of cell death (BIM) expression, with phosphorylation of AKT and p-FoxO3a, which was reversed by AKT siRNA or AKT inhibitor. Further analysis showed that loss of HCRP-1 obviously increased the activation of EGFR. Inhibition of EGFR blocked si-HCRP1-mediated phosphorylation of EGFR, AKT, FoxO3a, and BIM expression. Moreover, the in vivo results revealed that loss of HCRP-1 promoted cancer metastasis. Our findings implied that reduced HCRP-1 expression in CRC resulted in anoikis resistance and contributed to CRC metastasis and poor prognosis. These data may help design effective therapy targeting HCRP-1 pathway to control colon cancer growth and metastasis. PMID- 30518880 TI - Cardiac parasympathetic activity and ventricular diastolic interactions in individuals with spinal cord injury. AB - STUDY DESIGN: Cohort cross-sectional study. OBJECTIVE: To investigate the relationship between cardiac vagal activity and left ventricular filling at rest and during vagal stimulation, via the cold face test (CFT), in individuals with spinal cord injury (SCI). SETTING: University-based laboratory at Brock University, St. Catharines, ON, Canada. METHODS: A total of 12 able-bodied (age: 40 +/- 8.5 years) and 13 SCI individuals (age: 41 +/- 8.5 years; C4-T6; AIS: A-D) were recruited. Cardiac parasympathetic activity was assessed via heart rate variability (HRV) while LV filling was assessed by conventional echocardiography. All indices of HRV and diastolic function were obtained at rest and during cardiac vagal stimulation via the CFT. RESULTS: At baseline, the able-bodied group demonstrated strong positive correlations between HRV and early diastolic filling; however, such correlations were absent in the SCI group. The CFT resulted in elevated HRV with concomitant bradycardia in the able-bodied group, while the SCI group experienced no change in HRV or heart rate during the CFT. Able-bodied individuals showed a positive correlation between the change in HRV and the change in LV diastole during the CFT, which was attributed to increased cardiac vagal tone and not the change in heart rate, however, no relationships were observed in the SCI group. CONCLUSION: In able-bodied individuals, cardiac parasympathetic activity is associated with LV filling at rest and during elevated cardiac vagal tone. After SCI, there is a discord between vagal and LV diastolic activity, where changes in autonomic function do not influence LV filling, suggesting a disconnect between parasympathetic and cardiac function. PMID- 30518881 TI - Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice. AB - Identification of causal quantitative trait genes (QTGs) governing obesity is challenging. We previously revealed that the lymphocyte antigen 75 (Ly75) gene with an immune function is a putative QTG for Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity found from wild mice (Mus musculus castaneus). The objective of this study was to identify a true QTG for Pbwg1.5 by a combined approach of a quantitative complementation test, qualitative phenotypic analyses and causal analysis using segregating populations. In a four-way cross population among an Ly75 knockout strain, a subcongenic strain carrying Pbwg1.5 and their background strains, the quantitative complementation test showed genetic evidence that the Ly75 locus is identical to Pbwg1.5. Qualitative phenotypic analyses in two intercross populations between knockout and background strains and between subcongenic and background strains suggested that Ly75 may have pleiotropic effects on weights of white fat pads and organs. Causal analysis in the intercross population between knockout and background strains revealed that only variation in fat pad weight is caused by the genotypic difference via the difference in liver Ly75 expression. The results showed that Ly75 is a true Pbwg1.5 QTG for resistance to obesity. The finding provides a novel insight for obesity biology. PMID- 30518882 TI - A critical review of anthropological studies on skeletons from European plague pits of different epochs. AB - In historical times, plague epidemics intermittently ravaged Europe for more than 1,400 years, and still represent a threat in many countries all over the world. A debate is ongoing about the past plague, if it killed randomly in a population or discriminated among persons on the basis of their biological features. To address questions of plague lethality, we reviewed a large number of anthropological studies published in the last twenty years on victims of the past pestilences in Europe. In particular, we focused on data concerning demography (age at death and sex determination), and health status (skeletal biomarkers). We applied to these data a model system based on Multiple Linear Regression, which aimed to discern among possible predictors of sex-selective plague lethality in entire populations, in different periods and regions. Based on available data, we lack evidence for general trends of association between biological features. Differences in sex ratio are more likely due to the original population compositions or to distinct cultural behaviours of the two genders. We concluded that generalizations on biological evidence are not feasible for ancient plagues if we exclude that the infection possibly killed primarily persons between 5-10 and 20-35 years of age. PMID- 30518883 TI - ATP-dependent membrane remodeling links EHD1 functions to endocytic recycling. AB - Endocytic and recycling pathways generate cargo-laden transport carriers by membrane fission. Classical dynamins, which generate transport carriers during endocytosis, constrict and cause fission of membrane tubes in response to GTP hydrolysis. Relatively, less is known about the ATP-binding Eps15-homology domain containing protein1 (EHD1), a dynamin family member that functions at the endocytic-recycling compartment. Here, we show using cross complementation assays in C. elegans that EHD1's membrane binding and ATP hydrolysis activities are necessary for endocytic recycling. Further, we show that ATP-bound EHD1 forms membrane-active scaffolds that bulge tubular model membranes. ATP hydrolysis promotes scaffold self-assembly, causing the bulge to extend and thin down intermediate regions on the tube. On tubes below 25 nm in radius, such thinning leads to scission. Molecular dynamics simulations corroborate this scission pathway. Deletion of N-terminal residues causes defects in stable scaffolding, scission and endocytic recycling. Thus, ATP hydrolysis-dependent membrane remodeling links EHD1 functions to endocytic recycling. PMID- 30518884 TI - High unbound bilirubin for age: a neurotoxin with major effects on the developing brain. AB - Neonatal hyperbilirubinemia is one of the most frequent diagnoses made in neonates. A high level of unconjugated bilirubin that is unbound to albumin is neurotoxic when the level exceeds age-specific thresholds or at lower levels in neonates with neurotoxic risk factors. Lower range of unbound bilirubin results in apoptosis, while moderate-to-high levels result in neuronal necrosis. Basal ganglia and various brain stem nuclei are more susceptible to bilirubin toxicity. Proposed mechanisms of bilirubin-induced neurotoxicity include excessive release of glutamate, mitochondrial energy failure, release of proinflammatory cytokines, and increased intracellular calcium concentration. These mechanisms are similar to the events that occur following hypoxic-ischemic insult in neonates. Severe hyperbilirubinemia in term neonates has been shown to be associated with increased risk for autism spectrum disorders. The neuropathological finding of bilirubin-induced neurotoxicity also includes cerebellar injury with a decreased number of Purkinje cells, and disruption of multisensory feedback loop between cerebellum and cortical neurons which may explain the clinical characteristics of autism spectrum disorders. Severe hyperbilirubinemia occurs more frequently in infants from low- and middle-income countries (LMIC). Simple devices to measure bilirubin, and timely treatment are essential to reduce neurotoxicity, and improve outcomes for thousands of neonates around the world. PMID- 30518885 TI - The Effect of Memory in Inducing Pleasant Emotions with Musical and Pictorial Stimuli. AB - Music is known to evoke emotions through a range of mechanisms, but empirical investigation into the mechanisms underlying different emotions is sparse. This study investigated how affective experiences to music and pictures vary when induced by personal memories or mere stimulus features. Prior to the experiment, participants were asked to select eight types of stimuli according to distinct criteria concerning the emotion induction mechanism and valence. In the experiment, participants (N = 30) evaluated their affective experiences with the self-chosen material. EEG was recorded throughout the session. The results showed certain interaction effects of mechanism (memory vs. stimulus features), emotional valence of the stimulus (pleasant vs. unpleasant), and stimulus modality (music vs. pictures). While effects were mainly similar in music and pictures, the findings suggest that when personal memories are involved, stronger positive emotions were experienced in the context of music, even when the music was experienced as unpleasant. Memory generally enhanced social emotions specifically in pleasant conditions. As for sadness and melancholia, stimulus features did not evoke negative experiences; however, these emotions increased strongly with the involvement of memory, particularly in the condition of unpleasant music. Analysis of EEG-data corroborated the findings by relating frontomedial theta activity to memory-evoking material. PMID- 30518886 TI - Stiff competition. PMID- 30518887 TI - Nonlinear rise in Greenland runoff in response to post-industrial Arctic warming. AB - The Greenland ice sheet (GrIS) is a growing contributor to global sea-level rise1, with recent ice mass loss dominated by surface meltwater runoff2,3. Satellite observations reveal positive trends in GrIS surface melt extent4, but melt variability, intensity and runoff remain uncertain before the satellite era. Here we present the first continuous, multi-century and observationally constrained record of GrIS surface melt intensity and runoff, revealing that the magnitude of recent GrIS melting is exceptional over at least the last 350 years. We develop this record through stratigraphic analysis of central west Greenland ice cores, and demonstrate that measurements of refrozen melt layers in percolation zone ice cores can be used to quantifiably, and reproducibly, reconstruct past melt rates. We show significant (P < 0.01) and spatially extensive correlations between these ice-core-derived melt records and modelled melt rates5,6 and satellite-derived melt duration4 across Greenland more broadly, enabling the reconstruction of past ice-sheet-scale surface melt intensity and runoff. We find that the initiation of increases in GrIS melting closely follow the onset of industrial-era Arctic warming in the mid-1800s, but that the magnitude of GrIS melting has only recently emerged beyond the range of natural variability. Owing to a nonlinear response of surface melting to increasing summer air temperatures, continued atmospheric warming will lead to rapid increases in GrIS runoff and sea-level contributions. PMID- 30518888 TI - Industrial and agricultural ammonia point sources exposed. AB - Through its important role in the formation of particulate matter, atmospheric ammonia affects air quality and has implications for human health and life expectancy1,2. Excess ammonia in the environment also contributes to the acidification and eutrophication of ecosystems3-5 and to climate change6. Anthropogenic emissions dominate natural ones and mostly originate from agricultural, domestic and industrial activities7. However, the total ammonia budget and the attribution of emissions to specific sources remain highly uncertain across different spatial scales7-9. Here we identify, categorize and quantify the world's ammonia emission hotspots using a high-resolution map of atmospheric ammonia obtained from almost a decade of daily IASI satellite observations. We report 248 hotspots with diameters smaller than 50 kilometres, which we associate with either a single point source or a cluster of agricultural and industrial point sources-with the exception of one hotspot, which can be traced back to a natural source. The state-of-the-art EDGAR emission inventory10 mostly agrees with satellite-derived emission fluxes within a factor of three for larger regions. However, it does not adequately represent the majority of point sources that we identified and underestimates the emissions of two-thirds of them by at least one order of magnitude. Industrial emitters in particular are often found to be displaced or missing. Our results suggest that it is necessary to completely revisit the emission inventories of anthropogenic ammonia sources and to account for the rapid evolution of such sources over time. This will lead to better health and environmental impact assessments of atmospheric ammonia and the implementation of suitable nitrogen management strategies. PMID- 30518889 TI - Transformation between meron and skyrmion topological spin textures in a chiral magnet. AB - Crystal lattices with tetragonal or hexagonal structure often exhibit structural transitions in response to external stimuli1. Similar behaviour is anticipated for the lattice forms of topological spin textures, such as lattices composed of merons and antimerons or skyrmions and antiskyrmions (types of vortex related to the distribution of electron spins in a magnetic field), but has yet to be verified experimentally2,3. Here we report real-space observations of spin textures in a thin plate of the chiral-lattice magnet Co8Zn9Mn3, which exhibits in-plane magnetic anisotropy. The observations demonstrate the emergence of a two dimensional square lattice of merons and antimerons from a helical state, and its transformation into a hexagonal lattice of skyrmions in the presence of a magnetic field at room temperature. Sequential observations with decreasing temperature reveal that the topologically protected skyrmions remain robust to changes in temperature, whereas the square lattice of merons and antimerons relaxes to non-topological in-plane spin helices, highlighting the different topological stabilities of merons, antimerons and skyrmions. Our results demonstrate the rich variety of topological spin textures and their lattice forms, and should stimulate further investigation of emergent electromagnetic properties. PMID- 30518891 TI - Berger et al. reply. PMID- 30518893 TI - Satellite pinpoints ammonia sources globally. PMID- 30518890 TI - An experiment to search for dark-matter interactions using sodium iodide detectors. AB - Observations of galaxies and primordial radiation suggest that the Universe is made mostly of non-luminous dark matter1,2. Several new types of fundamental particle have been proposed as candidates for dark matter3, such as weakly interacting massive particles (WIMPs)4,5. These particles would be expected to interact with nuclei in suitable detector materials on Earth, for example, causing them to recoil. However, no definitive signal from such dark-matter interactions has been detected despite concerted efforts by many collaborations6. One exception is the much-debated claim by the DAMA collaboration of a statistically significant (more than nine standard deviations) annual modulation in the rate of nuclear interaction events. Annual modulation is expected because of the variation in Earth's velocity relative to the Galaxy's dark-matter halo that arises from Earth's orbital motion around the Sun. DAMA observed a modulation in the rate of interaction events in their detector7-9 with a period and phase consistent with that expected for WIMPs10-12. Several groups have been working to develop experiments with the aim of reproducing DAMA's results using the same target medium (sodium iodide)13-17. To determine whether there is evidence for an excess of events above the expected background in sodium iodide and to look for evidence of an annual modulation, the COSINE-100 experiment uses sodium iodide as the target medium to carry out a model-independent test of DAMA's claim. Here we report results from the initial operation of the COSINE-100 experiment related to the first task18,19. We observe no excess of signal-like events above the expected background in the first 59.5 days of data from COSINE 100. Assuming the so-called standard dark-matter halo model, this result rules out WIMP-nucleon interactions as the cause of the annual modulation observed by the DAMA collaboration20-23. The exclusion limit on the WIMP-sodium interaction cross-section is 1.14 * 10-40 cm2 for 10-GeV c-2 WIMPs at a 90% confidence level. The COSINE-100 experiment will continue to collect data for two more years, enabling a model-independent test of the annual modulation observed by the DAMA collaboration. PMID- 30518894 TI - Elusive spin textures discovered. PMID- 30518895 TI - Helmholtz mentored many Nobelists. PMID- 30518896 TI - Boost university voices at COP24 UN climate meeting. PMID- 30518898 TI - Plan S will hit some academic societies hard. PMID- 30518897 TI - Brazil's new government threatens food security and biodiversity. PMID- 30518899 TI - Road charges in real time are not a silver bullet. PMID- 30518900 TI - Computer logic meets cell biology: h ow cell science is getting an upgrade. PMID- 30518901 TI - Rules for a safe climate. PMID- 30518902 TI - Global warming will happen faster than we think. PMID- 30518904 TI - The silent epidemic killing more people than HIV, malaria or TB. PMID- 30518903 TI - Emissions are still rising: ramp up the cuts. PMID- 30518905 TI - A beginner's guide to space travel and seafood. PMID- 30518906 TI - Black-hole bounty, Ebola emergency and UK science minister resigns. PMID- 30518907 TI - miR-92b-3p-TSC1 axis is critical for mTOR signaling-mediated vascular smooth muscle cell proliferation induced by hypoxia. AB - Pulmonary artery smooth muscle cells (PASMCs) undergo proliferation by the mammalian target of rapamycin (mTOR) signaling pathway under hypoxia. Hypoxia induces expression of a specific set of microRNAs (miRNAs) in a variety of cell types. We integrated genomic analyses of both small non-coding RNA and coding transcripts using next-generation sequencing (NGS)-based RNA sequencing with the molecular mechanism of the mTOR signaling pathway in hypoxic PASMCs. These analyses revealed hypoxia-induced miR-92b-3p as a potent regulator of the mTOR signaling pathway. We demonstrated that miR-92b-3p directly targets the 3'-UTR of a negative regulator in the mTOR signaling pathway, TSC1. mTOR signaling and consequent cell proliferation were promoted by enforced expression of miR-92b-3p but inhibited by knocking down endogenous miR-92b-3p. Furthermore, inhibition of miR-92b-3p attenuated hypoxia-induced proliferation of vascular smooth muscle cells (VSMCs). Therefore, this study elucidates a novel role of miR-92b-3p as a hypoxamir in the regulation of the mTOR signaling pathway and the pathological VSMC proliferative response under hypoxia. These findings will help us better understand the miRNA-mediated molecular mechanism of the proliferative response of hypoxic VSMCs through the mTOR signaling pathway. PMID- 30518908 TI - A DHX9-lncRNA-MDM2 interaction regulates cell invasion and angiogenesis of cervical cancer. AB - Cervical cancer (CC) is the third most common carcinoma and the fourth leading cause of cancer-associated mortality in women. Here, we report that MDM2-DHX9 interaction mediates CC motility and angiogenesis in a long noncoding RNA dependent fashion. A long noncoding RNA, named lnc-CCDST, is significantly downregulated in CC tissues, and binds to pro-oncogenic DHX9. DHX9 is upregulated in CC tissue, and promotes CC cell motility and angiogenesis. The lnc-CCDST and DHX9 interaction promotes DHX9 degradation through the ubiquitin proteasome pathway. Furthermore, DHX9 bound to E3 ubiquitin ligase MDM2, and this interaction is enhanced by lnc-CCDST. Thus, lnc-CCDST promotes DHX9 degradation by serving as a scaffold to facilitate the formation of MDM2 and DHX9 complexes. Moreover, HPV oncogenes E6 and E7 abolish the expression of lnc-CCDST resulting in the increase of DHX9. Our results have revealed a novel mechanism by which high-risk HPVs promote motility and angiogenesis of CC by inhibiting expression of lnc-CCDST to disrupt MDM2 and DHX9 interaction, and DHX9 degradation, and identified a potential therapeutic target for CC. PMID- 30518909 TI - Author Correction: Efficient genetic engineering of human intestinal organoids using electroporation. AB - The version of this paper originally published shows incorrect units for two plasmid concentrations. In the "Reagent Setup" section, the instructions for sgRNA-Cas9 plasmid should read "Adjust the concentration of each plasmid to 1 MUg MUl-1," rather than "to 1 MUg ml-1." Similarly, all concentrations in the tables in Steps 49A, 49C, and 49D should be in MUg MUl-1 instead of MUg ml-1. Please note that these units have not been corrected in the PDF and HTML versions of the protocol available online. PMID- 30518910 TI - A comprehensive pipeline for translational top-down proteomics from a single blood draw. AB - Top-down proteomics (TDP) by mass spectrometry (MS) is a technique by which intact proteins are analyzed. It has become increasingly popDesalting and concentrating GELFrEEular in translational research because of the value of characterizing distinct proteoforms of intact proteins. Compared to bottom-up proteomics (BUP) strategies, which measure digested peptide mixtures, TDP provides highly specific molecular information that avoids the bioinformatic challenge of protein inference. However, the technique has been difficult to implement widely because of inherent limitations of existing sample preparation methods and instrumentation. Recent improvements in proteoform pre-fractionation and the availability of high-resolution benchtop mass spectrometers have made it possible to use high-throughput TDP for the analysis of complex clinical samples. Here, we provide a comprehensive protocol for analysis of a common sample type in translational research: human peripheral blood mononuclear cells (PBMCs). The pipeline comprises multiple workflows that can be treated as modular by the reader and used for various applications. First, sample collection and cell preservation are described for two clinical biorepository storage schemes. Cell lysis and proteoform pre-fractionation by gel-eluted liquid fractionation entrapment electrophoresis are then described. Importantly, instrument setup and liquid chromatography-tandem MS are described for TDP analyses, which rely on high-resolution Fourier-transform MS. Finally, data processing and analysis are described using two different, application-dependent software tools: ProSight Lite for targeted analyses of one or a few proteoforms and TDPortal for high throughput TDP in discovery mode. For a single sample, the minimum completion time of the entire experiment is 72 h. PMID- 30518911 TI - Differential viral accessibility (DIVA) identifies alterations in chromatin architecture through large-scale mapping of lentiviral integration sites. AB - Alterations in chromatin structure play a major role in the epigenetic regulation of gene expression. Here, we describe a step-by-step protocol for differential viral accessibility (DIVA), a method for identifying changes in chromatin accessibility genome-wide. Commonly used methods for mapping accessible genomic loci have strong preferences toward detecting 'open' chromatin found at regulatory regions but are not well suited to studying chromatin accessibility in gene bodies and intergenic regions. DIVA overcomes this limitation, enabling a broader range of sites to be interrogated. Conceptually, DIVA is similar to ATAC seq in that it relies on the integration of exogenous DNA into the genome to map accessible chromatin, except that chromatin architecture is probed through mapping integration sites of exogenous lentiviruses. An isogenic pair of cell lines are transduced with a lentiviral vector, followed by PCR amplification and Illumina sequencing of virus-genome junctions; the resulting sequences define a set of unique lentiviral integration sites, which are compared to determine whether genomic loci exhibit significantly altered accessibility between experimental and control cells. Experienced researchers will take 6 d to generate lentiviral stocks and transduce the target cells, a further 5 d to prepare the Illumina sequencing libraries and a few hours to perform the bioinformatic analysis. PMID- 30518912 TI - Author Correction: Reminder duration determines threat memory modification in humans. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30518913 TI - UBIAD1 suppresses the proliferation of bladder carcinoma cells by regulating H Ras intracellular trafficking via interaction with the C-terminal domain of H Ras. AB - UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a key role in biosynthesis of vitamin K2 and coenzyme Q10 using geranylgeranyl diphosphate (GGPP). However, the mechanism by which UBIAD1 participates in tumorigenesis remains unknown. This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. In addition, GGPP was required to maintain the function of UBIAD1 in regulating the Ras/ERK signaling pathway. A Drosophila model was employed to confirm the function of UBIAD1/HEIX in vivo. The activation of Ras/ERK signaling at the plasma membrane induced melanotic masses in Drosophila larvae. Our study suggests that UBIAD1 serves as a tumor suppressor in cancer and tentatively reveals the underlying mechanism of melanotic mass formation in Drosophila. PMID- 30518914 TI - Elovl6 regulates mechanical damage-induced keratinocyte death and skin inflammation. AB - Mechanical damage on the skin not only affects barrier function but also induces various immune responses, which trigger or exacerbate skin inflammation. However, how mechanical damage-induced skin inflammation is regulated remains incompletely understood. Here, we show that keratinocytes express the long-chain fatty-acid elongase Elovl6. Mice deficient in Elovl6 showed higher levels of cis-vaccenic acid (CVA) in the epidermis and severe skin inflammation induced by mechanical damage due to tape stripping than did wild-type mice. CVA accelerated tape stripping-triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL 1alpha, which induced production of proinflammatory cytokines and chemokines IL 1beta and CXCL-1 by keratinocytes. Our results demonstrate that Elovl6 regulates mechanical damage-triggered keratinocyte death and the subsequent dermatitis. PMID- 30518915 TI - Mast cells are essential intermediaries in regulating IL-33/ST2 signaling for an immune network favorable to mucosal healing in experimentally inflamed colons. AB - Mast cells (MCs) are potent tissue-resident immune cells that are distributed in the intraepithelial space of the intestine and have been implicated in regulating immune homeostasis and coordinating epithelial responses in inflamed mucosa of inflammatory bowel disease (IBD). IL-33 functions as an endogenous danger signal or alarmin in inflamed intestine segments. MCs highly express the IL-33 receptor ST2. However, the mechanisms underlying the immune regulation of MC-dependent IL 33/ST2 signaling at the barrier surface of the intestine remain largely unknown. We confirmed that MCs are required for the effective resolution of tissue damage using an experimental colitis model that allows for conditional ablation of MCs. After elucidating the IL-33 signaling involved in MC activity in the context of intestinal inflammation, we found that the function of restricted IL-33/ST2 signaling by MCs was consistent with an MC deficiency in response to the breakdown of the epithelial barrier. We observed that a tissue environment with a spectrum of protective cytokines was orchestrated by MC-dependent IL-33/ST2 signaling. Given the significant downregulation of IL-22 and IL-13 due to the loss of MC-dependent IL-33/ST2 signaling and their protective functions in inflammation settings, induction of IL-22 and IL-13 may be responsible for an immune network favorable to mucosal repair. Collectively, our data showed an important feedback loop in which cytokine cues from damaged epithelia activate MCs to regulate tissue environments essential for MC-dependent restoration of epithelial barrier function and maintenance of tissue homeostasis. PMID- 30518916 TI - Long noncoding RNA ATB promotes the epithelial-mesenchymal transition by upregulating the miR-200c/Twist1 axe and predicts poor prognosis in breast cancer. AB - Recent studies indicate that the long noncoding RNA ATB (lncATB) can induce the epithelial-mesenchymal transition (EMT) in cancer cells, but the specific cellular targets of lncATB require further investigation. In the present study, the upregulation of lncATB in breast cancer cells was validated in a TGF-beta induced EMT model. Gain- and loss-of-function studies demonstrated that lncATB enhanced cell migration, invasion and clonogenicity in vitro and in vivo. LncATB promoted the EMT by acting as a sponge for the miR-200 family and restoring Twist1 expression. Subsequently, the clinical significance of lncATB was investigated in a cohort of breast cancer patients (N = 131). Higher lncATB expression was correlated with increased nodal metastasis (P = 0.036) and advanced clinical stage (P = 0.011) as well as shorter disease-free survival (P = 0.043) and overall survival (P = 0.046). These findings define Twist1 as a major target of lncATB in the induction of the EMT and highlight lncATB as a biomarker in breast cancer patients. PMID- 30518917 TI - Antiaromatic character of cycloheptatriene-bis-annelated indenofluorene framework mainly originated from heptafulvene segment. AB - Fully pi-conjugated polycyclic hydrocarbons with antiaromatic character have attracted research attention because of their unique properties such as narrow energy gaps, and thus should find application as optical and electronic materials. Although antiaromatic 16pi-electron frameworks can be constructed by the incorporation of multiple seven-membered rings in a fused fashion to install methylenecycloheptatriene (heptafulvene) segments, the development of corresponding benzo[1,2:4,5]di[7]annulene (BDA)-containing pi-conjugated systems remains challenging due to the difficulty of their molecular design and synthesis. In this study, we develop an unprecedented chemical structure of cycloheptatriene-bis-annelated indenofluorene, which possesses both BDA and indenofluorene frameworks in a fused fashion. Physical measurements and X-ray analyses, along with theoretical calculations, indicated that antiaromaticity appeared in the BDA framework. By using the conjugated polycyclic hydrocarbon possessing both seven-membered and five-membered rings, this study provides fundamental insight into the strong antiaromatic nature of heptafulvene-based BDA framework. PMID- 30518918 TI - Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. AB - Osteoarthritis (OA), a chronic disease characterized by articular cartilage degeneration, is a leading cause of disability and pain worldwide. In OA, chondrocytes in cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring disease progression. Similar to other wound healing disorders, chondrocytes from OA patients show a chronic increase in the gap junction channel protein connexin43 (Cx43), which regulates signal transduction through the exchange of elements or recruitment/release of signalling factors. Although immature or stem-like cells are present in cartilage from OA patients, their origin and role in disease progression are unknown. In this study, we found that Cx43 acts as a positive regulator of chondrocyte mesenchymal transition. Overactive Cx43 largely maintains the immature phenotype by increasing nuclear translocation of Twist-1 and tissue remodelling and proinflammatory agents, such as MMPs and IL-1beta, which in turn cause cellular senescence through upregulation of p53, p16INK4a and NF-kappaB, contributing to the senescence-associated secretory phenotype (SASP). Downregulation of either Cx43 by CRISPR/Cas9 or Cx43-mediated gap junctional intercellular communication (GJIC) by carbenoxolone treatment triggered rediferentiation of osteoarthritic chondrocytes into a more differentiated state, associated with decreased synthesis of MMPs and proinflammatory factors, and reduced senescence. We have identified causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation, redifferentiation and senescence. We propose that chondrocytes undergo chondrocyte-mesenchymal transition where increased Cx43-mediated GJIC during OA facilitates Twist-1 nuclear translocation as a novel mechanism involved in OA progression. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration. PMID- 30518919 TI - Layer-edge device of two-dimensional hybrid perovskites. AB - Two dimensional layered organic-inorganic hybrid perovskites (2D perovskites) are potential candidates for next generation photovoltaic device. Especially, the out of-plane surface perpendicular to the superlattice plane of 2D perovskites (layer edge surface) has presented several exotic behaviors, such as layer-edge states which are found to be crucial for improving the efficiency of 2D perovskite solar cells. However, fundamental research on transport properties of layer-edge surface is still absent. In this report, we observe the electronic and opto electronic behavior in layer-edge device of 2D perovskites. The dark and photo currents are demonstrated to strongly depend on the crystallographic orientation in layer-edge device, and such anisotropic properties, together with photo response, are related to the thickness of inorganic layers. Finally, due to the abundant hydroxyl groups, water molecules are easy to condense on the layer-edge surface, and the conductance is extremely sensitive to the humidity environment, indicating a potential application of humidity sensor. PMID- 30518920 TI - NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. AB - NLRP3 is a cytosolic sensor triggered by different pathogen- and self-derived signals that plays a central role in a variety of pathological conditions, including sterile inflammation. The leucine-rich repeat domain is present in several innate immune receptors, where it is frequently responsible for sensing danger signals and regulation of activation. Here we show by reconstitution of truncated and chimeric variants into Nlrp3-/- macrophages that the leucine-rich repeat domain is dispensable for activation and self-regulation of NLRP3 by several different triggers. The pyrin domain on the other hand is required to maintain NLRP3 in the inactive conformation. A fully responsive minimal NLRP3 truncation variant reconstitutes peritonitis in Nlrp3-/- mice. We demonstrate that in contrast to pathogen-activated NLRC4, the constitutively active NLRP3 molecule cannot engage wild-type NLRP3 molecules in a self-catalytic oligomerization. This lack of signal amplification is likely a protective mechanism to decrease sensitivity to endogenous triggers to impede autoinflammation. PMID- 30518921 TI - Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro. AB - We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. XIST induction in four transgenic clones reproducibly corrected over-production of megakaryocytes and erythrocytes, key to DS myeloproliferative disorder and leukemia. A contrasting increase in neural stem and iPS cells shows cell-type specificity, supporting this approach successfully rebalances the hematopoietic developmental program. Given this, we next used this system to extend knowledge of hematopoietic pathogenesis on multiple points. Results demonstrate trisomy 21 expression promotes over-production of CD43+ but not earlier CD34+/CD43 progenitors and indicates this is associated with increased IGF signaling. This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies. PMID- 30518922 TI - Ferritin heavy subunit enhances apoptosis of non-small cell lung cancer cells through modulation of miR-125b/p53 axis. AB - Ferritin is a nanocage protein composed by the variable assembly of 24 heavy and light subunits. As major intracellular iron storage protein, ferritin has been studied for many years in the context of iron metabolism. However, recent evidences have highlighted its role, in particular that of the heavy subunit (FHC), in pathways related to cancer development and progression, such as cell proliferation, growth suppressor evasion, cell death inhibition, and angiogenesis. At least partly, the involvement in these pathways is due to the ability of FHC to control the expression of a repertoire of oncogenes and oncomiRNAs. Moreover, the existence of a feedback loop between FHC and the tumor suppressor p53 has been demonstrated in different cell types. Here, we show that ectopic over-expression of FHC induces the promoter hypermethylation and the down regulation of miR-125b that, in turn, enhances p53 protein expression in non small cell lung cancer (NSCLC) cell lines. Notably, analysis by absolute quantitative RT-PCR of FHC, miR-125b, and p53 strongly suggests that this axis might be active in human NSCLC tissue specimens. In vitro, FHC over-expression attenuates survival of NSCLC cells by inducing p53-mediated intrinsic apoptosis that is partially abrogated upon miR-125b re-expression. Overall, our findings demonstrate that FHC acts as a tumor suppressor gene, thus providing a potential molecular strategy for induction of NSCLC apoptotic cell death. PMID- 30518923 TI - A downy mildew effector evades recognition by polymorphism of expression and subcellular localization. AB - Pathogen co-evolution with plants involves selection for evasion of host surveillance systems. The oomycete Hyaloperonospora arabidopsidis (Hpa) causes downy mildew on Arabidopsis, and race-specific interactions between Arabidopsis accessions and Hpa isolates fit the gene-for-gene model in which host resistance or susceptibility are determined by matching pairs of plant Resistance (R) genes and pathogen Avirulence (AVR) genes. Arabidopsis Col-0 carries R gene RPP4 that confers resistance to Hpa isolates Emoy2 and Emwa1, but its cognate recognized effector(s) were unknown. We report here the identification of the Emoy2 AVR effector gene recognized by RPP4 and show resistance-breaking isolates of Hpa on RPP4-containing Arabidopsis carry the alleles that either are not expressed, or show cytoplasmic instead of nuclear subcellular localization. PMID- 30518924 TI - A quantitative reverse transcription-polymerase chain reaction for detection of Getah virus. AB - Getah virus (GETV), a mosquito-borne alphavirus, is an emerging animal pathogen causing outbreaks among racehorses and pigs. Early detection of the GETV infection is essential for timely implementation of disease prevention and control interventions. Thus, a rapid and accurate nucleic acid detection method for GETV is highly needed. Here, two TaqMan minor groove binding (MGB) probe based quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays were developed. The qRT-PCR primers and TaqMan MGB probe were designed based on the conserved region of nsP1 and nsP2 genes of 23 GETV genome sequences retrieved from GenBank. Only the qRT-PCR assay using nsP2-specific primers and probe detected all two Malaysia GETV strains (MM2021 and B254) without cross reacting with other closely related arboviruses. The qRT-PCR assay detected as few as 10 copies of GETV RNA, but its detection limit at the 95% probability level was 63.25 GETV genome copies (probit analysis, P <= 0.05). Further validation of the qRT-PCR assay using 16 spiked simulated clinical specimens showed 100% for both sensitivity and specificity. In conclusion, the qRT-PCR assay developed in this study is useful for rapid, sensitive and specific detection and quantification of GETV. PMID- 30518926 TI - Akinetic swept-source optical coherence tomography based on a pulse-modulated active mode locking fiber laser for human retinal imaging. AB - Optical coherence tomography (OCT) is a noninvasive imaging modality that can provide high-resolution, cross-sectional images of tissues. Especially in retinal imaging, OCT has become one of the most valuable imaging tools for diagnosing eye diseases. Considering the scattering and absorption properties of the eye, the 1000-nm OCT system is preferred for retinal imaging. In this study, we describe the use of an akinetic swept-source OCT system based on a pulse-modulated active mode locking (AML) fiber laser at a 1080-nm wavelength for in-vivo human retinal imaging. The akinetic AML wavelength-swept fiber laser was constructed with polarization-maintaining fiber that has an average linewidth of 0.625 nm, a spectral bandwidth of 81.15 nm, and duty ratio of 90% without the buffering method. We successfully obtained in-vivo human retinal images using the proposed OCT system without the additional k-clock and the frequency shifter that provides a wide field of view of 43.1 degrees . The main retina layers, such as the retinal pigment epithelium, can be distinguished from the OCT image with an axial resolution of 6.3 MUm with this OCT system. PMID- 30518925 TI - Induction of immunosuppressive functions and NF-kappaB by FLIP in monocytes. AB - Immunosuppression is a hallmark of tumor progression, and treatments that inhibit or deplete monocytic myeloid-derived suppressive cells could promote anti-tumor immunity. c-FLIP is a central regulator of caspase-8-mediated apoptosis and necroptosis. Here we show that low-dose cytotoxic chemotherapy agents cause apoptosis linked to c-FLIP down-regulation selectively in monocytes. Enforced expression of c-FLIP or viral FLIP rescues monocytes from cytotoxicity and concurrently induces potent immunosuppressive activity, in T cell cultures and in vivo models of tumor progression and immunotherapy. FLIP-transduced human blood monocytes can suppress graft versus host disease. Neither expression of FLIP in granulocytes nor expression of other anti-apoptotic genes in monocytes conferred immunosuppression, suggesting that FLIP effects on immunosuppression are specific to monocytic lineage and distinct from death inhibition. Mechanistically, FLIP controls a broad transcriptional program, partially by NF-kappaB activation. Therefore, modulation of FLIP in monocytes offers a means to elicit or block immunosuppressive myeloid cells. PMID- 30518928 TI - ACNP 57th Annual Meeting: Keyword Index. PMID- 30518929 TI - ACNP 57th Annual Meeting: Author Index. PMID- 30518927 TI - H2 roaming chemistry and the formation of H3+ from organic molecules in strong laser fields. AB - Roaming mechanisms, involving the brief generation of a neutral atom or molecule that stays in the vicinity before reacting with the remaining atoms of the precursor, are providing valuable insights into previously unexplained chemical reactions. Here, the mechanistic details and femtosecond time-resolved dynamics of H3+ formation from a series of alcohols with varying primary carbon chain lengths are obtained through a combination of strong-field laser excitation studies and ab initio molecular dynamics calculations. For small alcohols, four distinct pathways involving hydrogen migration and H2 roaming prior to H3+ formation are uncovered. Despite the increased number of hydrogens and possible combinations leading to H3+ formation, the yield decreases as the carbon chain length increases. The fundamental mechanistic findings presented here explore the formation of H3+, the most important ion in interstellar chemistry, through H2 roaming occurring in ionic species. PMID- 30518930 TI - ACNP 57th Annual Meeting: Panels, Mini-Panels and Study Groups. AB - Sponsorship Statement: Publication of this supplement is sponsored by the ACNP.Individual contributor disclosures may be found within the abstracts.Asterisks in the author lists indicate presenter of the abstract at the annual meeting. PMID- 30518931 TI - ACNP 57th Annual Meeting: Poster Session II. AB - Sponsorship Statement: Publication of this supplement is sponsored by the ACNP.Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. PMID- 30518932 TI - ACNP 57th Annual Meeting: Poster Session III. AB - Sponsorship Statement: Publication of this supplement is sponsored by the ACNP.Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. PMID- 30518933 TI - ACNP 57th Annual Meeting: Poster Session I. AB - Sponsorship Statement: Publication of this supplement is sponsored by the ACNP.Individual contributor disclosures may be found within the abstracts. Asterisks in the author lists indicate presenter of the abstract at the annual meeting. PMID- 30518934 TI - LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA. AB - ABSTACT: Conventional therapies and novel molecular targeted therapies against breast cancer have gained great advances over the past two decades. However, poor prognosis and low survival rate are far from expectation for improvement, particularly in patients with triple negative breast cancer (TNBC). Here, we found that lncRNA DANCR was significantly overregulated in TNBC tissues and cell lines compared with normal breast tissues or other type of breast cancer. Knockdown of DANCR suppressed TNBC proliferation both in vitro and in vivo. Further study of underlying mechanisms demonstrated that DANCR bound with RXRA and increased its serine 49/78 phosphorylation via GSK3beta, resulting in activating PIK3CA transcription, and subsequently enhanced PI3K/AKT signaling and TNBC tumorigenesis. Taken together, Our findings identified DANCR as an pro oncogene and uncoverd a new working pattern of lncRNA to mediate TNBC tumorigenesis, which may be a potential therapeutic target for improving treatment of TNBC. PMID- 30518935 TI - Sleep deprivation alters the time course but not magnitude of locomotor sensitization to cocaine. AB - Repeated exposure to drugs of abuse progressively increases the response to the same stimuli, a process known as sensitization. Behavioral sensitization to cocaine administration is often measured in non-human subjects via locomotor activity which is easily quantifiable. The effects of four hours of sleep deprivation on repeated cocaine (five daily and one challenge) showed attenuated hyperactivity on the first day only, compared to the non-deprived group. Both groups reached the same final level of sensitization, indicating that sleep deprivation altered the time course, but not magnitude of locomotor sensitization. PMID- 30518936 TI - Combination of chemotherapy and physical plasma elicits melanoma cell death via upregulation of SLC22A16. AB - Malignant melanoma is an aggressive cancer that develops drug resistance leading to poor prognosis. Efficient delivery of chemotherapeutic drugs to the tumor tissue remains a major challenge in treatment regimens. Using murine (B16) and human (SK-MEL-28) melanoma cells, we investigated traditional cytotoxic agents in combination with cold physical plasma-derived oxidants. We report synergistic cytotoxicity of doxorubicin and epirubicin, and additive toxicity of oxaliplatin with plasma exposure in coefficient of drug interaction analysis. The combination treatment led to an increased DNA damage response (increased phosphorylation of ATM, gamma-H2AX foci, and micronuclei formation). There was also an enhanced secretion of immunogenic cell death markers ATP and CXCL10 in cell culture supernatants following combination treatment. The observed synergistic effects in tumor cells was due to enhanced intracellular doxorubicin accumulation via upregulation of the organic cationic transporter SLC22A16 by plasma treatment. The doxorubicin uptake was reversed by pretreating cells with antioxidants or calcium influx inhibitor BTP2. Endoribonuclease-prepared siRNAs (esiRNA)-mediated knockdown of SLC22A16 inhibited the additive cytotoxic effect in tumor cells. SK MEL 28 and THP-1 monocytes co-culture led to greater THP-1 cell migration and SK MEL-28 cytotoxicity when compared with controls. Taken together, we propose pro oxidant treatment modalities to sensitize chemoresistant melanoma cells towards subsequent chemotherapy, which may serve as therapeutic strategy in combination treatment in oncology. PMID- 30518937 TI - Transcriptional changes in the Japanese scallop (Mizuhopecten yessoensis) shellinfested by Polydora provide insights into the molecular mechanism of shell formation and immunomodulation. AB - The Japanese scallop (Mizuhopecten yessoensis) is one of the most important aquaculture species in Asian countries; however, it has suffered severe infection by Polydora in northern China in recent years, causing great economic losses. The Polydora parasitizes the shell of scallops, badly destroying the shell's structure. To investigate the molecular response mechanism of M. yessoensis to Polydora infestion, a comprehensive and niche-targeted cDNA sequence database for diseased scallops was constructed. Additionally, the transcriptional changes in the edge mantle, central mantle and hemocytes, tissues directly related to the disease, were first described in this study. The results showed that genes involved in shell formation and immunomodulation were significantly differentially expressed due to the infestation. Different transcriptional changes existed between the two mantle regions, indicating the different molecular functions likely responsible for the formation of different shell layers. The differential expression of genes for immune recognition, signal transduction and pathogen elimination presented an integrated immune response process in scallops. Moreover, neuromodulation and glycometabolism involved in the regulation process with relevant function significantly enriched. The study provides valuable information for mechanism study of shell formation and immunomodulation in scallops. PMID- 30518938 TI - Selective production of phase-separable product from a mixture of biomass-derived aqueous oxygenates. AB - Selective conversion of an aqueous solution of mixed oxygenates produced by biomass fermentation to a value-added single product is pivotal for commercially viable biomass utilization. However, the efficiency and selectivity of the transformation remains a great challenge. Herein, we present a strategy capable of transforming ~70% of carbon in an aqueous fermentation mixture (ABE: acetone butanol-ethanol-water) to 4-heptanone (4-HPO), catalyzed by tin-doped ceria (Sn ceria), with a selectivity as high as 86%. Water (up to 27 wt%), detrimental to the reported catalysts for ABE conversion, was beneficial for producing 4-HPO, highlighting the feasibility of the current reaction system. In a 300 h continuous reaction over 2 wt% Sn-ceria catalyst, the average 4-HPO selectivity is maintained at 85% with 50% conversion and > 90% carbon balance. This strategy offers a route for highly efficient organic-carbon utilization, which can potentially integrate biological and chemical catalysis platforms for the robust and highly selective production of value-added chemicals. PMID- 30518939 TI - Endogenous toxins and the coupling of gregariousness to conspicuousness in Argidae and Pergidae sawflies. AB - Phytophagous insects tend to be either cryptic and solitary, or brightly colored and gregarious, as a defense against vertebrate predators. Here, we tested whether potent defensive chemicals produced de novo by larvae of Argidae and Pergidae sawflies have influenced the evolutionary relationship between larval appearance and levels of gregariousness. Phylogeny-based correlation analyses indicated only a weak trend for solitary species to be cryptic, and for gregarious ones to be conspicuous. Numerous Argidae were cryptic-solitary or conspicuous-gregarious, whereas most Pergidae were conspicuous-gregarious. Both families also included not truly gregarious but aggregated species, i.e. with individuals more evenly distributed on the host plant. By considering two specific morphological traits, predominant body coloration and contrasting spots on body, each one was (weakly) associated with appearance but none with gregariousness, which reflects the functional relevance of appearance as a whole. Furthermore, Argidae can display alternate appearances during successive larval instars. Finally, an independent contrasts test showed no obvious correlation between two major toxic peptides. Our results point towards diversely combined patterns of linked ecological traits in these insects. By assuming that warning coloration is more warranted against vertebrate than invertebrate predators, we suggest that the occurrence itself of toxins allowed this diversity via differing predator guilds and environmental factors, to which these insects were confronted during evolution. PMID- 30518940 TI - Temporal control of gene expression by the pioneer factor Zelda through transient interactions in hubs. AB - Pioneer transcription factors can engage nucleosomal DNA, which leads to local chromatin remodeling and to the establishment of transcriptional competence. However, the impact of enhancer priming by pioneer factors on the temporal control of gene expression and on mitotic memory remains unclear. Here we employ quantitative live imaging methods and mathematical modeling to test the effect of the pioneer factor Zelda on transcriptional dynamics and memory in Drosophila embryos. We demonstrate that increasing the number of Zelda binding sites accelerates the kinetics of nuclei transcriptional activation regardless of their transcriptional past. Despite its known pioneering activities, we show that Zelda does not remain detectably associated with mitotic chromosomes and is neither necessary nor sufficient to foster memory. We further reveal that Zelda forms sub nuclear dynamic hubs where Zelda binding events are transient. We propose that Zelda facilitates transcriptional activation by accumulating in microenvironments where it could accelerate the duration of multiple pre-initiation steps. PMID- 30518941 TI - High Abundance of genus Prevotella in the gut of perinatally HIV-infected children is associated with IP-10 levels despite therapy. AB - Perinatal HIV infection is characterized by faster HIV disease progression and higher initial rate of HIV replication compared to adults. While antiretroviral therapy (ART) has greatly reduced HIV replication to undetectable levels, there is persistent elevated inflammation associated with HIV disease progression. Alteration of gut microbiota is associated with increased inflammation in chronic adult HIV infection. Here, we aim to study the gut microbiome and its role in inflammation in treated and untreated HIV-infected children. Examination of fecal microbiota revealed that perinatally infected children living with HIV had significantly higher levels of genus Prevotella that persisted despite ART. These children also had higher levels of soluble CD14 (sCD14), a marker of microbial translocation, and IP-10 despite therapy. The Prevotella positively correlated with IP-10 levels in both treated and untreated HIV-infected children, while genus Prevotella and species Prevotella copri was inversely associated with CD4 count. Relative abundance of genus Prevotella and species Prevotella copri showed positive correlation with sCD14 in ART-suppressed perinatally HIV-infected children. Our study suggests that gut microbiota may serve as one of the driving forces behind the persistent inflammation in children despite ART. Reshaping of microbiota using probiotics may be recommended as an adjunctive therapy along with ART. PMID- 30518942 TI - An accurate TMT-based approach to quantify and model lysine susceptibility to conjugation via N-hydroxysuccinimide esters in a monoclonal antibody. AB - Conjugation of small molecules to proteins through N-hydroxysuccinimide (NHS) esters results in a random distribution of small molecules on lysine residues and the protein N-terminus. While mass spectrometry methods have improved characterization of these protein conjugates, it remains a challenge to quantify the occupancy at individual sites of conjugation. Here, we present a method using Tandem Mass Tags (TMT) that enabled the accurate and sensitive quantification of occupancy at individual conjugation sites in the NIST monoclonal antibody. At conjugation levels relevant to antibody drug conjugates in the clinic, site occupancy data was obtained for 37 individual sites, with average site occupancy data across 2 adjacent lysines obtained for an additional 12 sites. Thus, altogether, a measure of site occupancy was obtained for 98% of the available primary amines. We further showed that removal of the Fc-glycan on the NIST mAb increased conjugation at two specific sites in the heavy chain, demonstrating the utility of this method to identify changes in the susceptibility of individual sites to conjugation. This improved site occupancy data allowed calibration of a bi-parametric linear model for predicting the susceptibility of individual lysines to conjugation from 3D-structure based on their solvent exposures and ionization constants. Trained against the experimental data for lysines from the Fab fragment, the model provided accurate predictions of occupancies at lysine sites from the Fc region and the protein N-terminus (R2 = 0.76). This predictive model will enable improved engineering of antibodies for optimal labeling with fluorophores, toxins, or crosslinkers. PMID- 30518943 TI - Measurement-Device-Independent Quantum Key Distribution over asymmetric channel and unstable channel. AB - We show that a high key rate of Measurement-Device-Independent Quantum Key Distribution (MDIQKD) over asymmetric and unstable quantum channel can be obtained by full optimization and compensation. Employing a gradient optimization method, we make the full optimization taking both the global optimization for the 12 independent parameters and the joint constraints for statistical fluctuations. We present a loss-compensation method by monitoring the channel loss for an unstable channel. The numerical simulation shows that the method can produce high key rate for both the asymmetric channel and the unstable channel. Compared with the existing results of independent constraints, our result here improves the key rate by 1 to tens of times in typical experimental conditions. PMID- 30518944 TI - Effective nose-to-brain delivery of exendin-4 via coadministration with cell penetrating peptides for improving progressive cognitive dysfunction. AB - In a recent study, we demonstrated the potential of a cell-penetrating peptide (CPP) penetratin to deliver the peptide drug insulin to the brain via nasal administration, and its pharmacological effect on the mild cognitive dysfunction in senescence-accelerated mouse (SAMP8). However, the therapeutic potential of intranasal insulin administration was attenuated when applied to the aged SAMP8 with severe cognitive dysfunction. The present study, therefore, aimed to overcome the difficulty in treating severe cognitive dysfunction using insulin by investigating potential alternatives, glucagon-like peptide-1 (GLP-1) receptor agonists such as exendin-4. Examination using normal ddY mice demonstrated that the distribution of exendin-4 throughout the brain was dramatically increased by intranasal coadministration with the L-form of penetratin. The activation of hippocampal insulin signaling after the simultaneous nose-to-brain delivery of exendin-4 and an adequate level of insulin were confirmed by analyzing the phosphorylation of Akt. Furthermore, spatial learning ability, evaluated in the Morris water maze test after daily administration of exendin-4 with L-penetratin and supplemental insulin for 4 weeks, suggested therapeutic efficacy against severe cognitive dysfunction. The present study suggests that nose-to-brain delivery of exendin-4 with supplemental insulin, mediated by CPP coadministration, shows promise for the treatment of progressive cognitive dysfunction in SAMP8. PMID- 30518945 TI - The effect of copy number variations in chromosome 16p on body weight in patients with intellectual disability. AB - Syndromic monogenic obesity is a rare and severe early-onset form of obesity. It is characterized by intellectual disability, congenital malformations, and/or dysmorphic facies. The diagnosis of patients is challenging due to the genetic heterogenicity of this condition. However, the use of microarray technology in combination with public databases has been successful on genotype-phenotype correlations, especially for body mass index (BMI) alteration. In this study, the relationship between copy number variations (CNVs) detected by microarray mapping on 16p region and BMI alterations in syndromic patients were assessed. In order to achieve this goal, 680 unrelated Spanish children with intellectual disability were included. 16p region was characterized by using microarray platforms. All detected variants were classified as: (I) one previously non-described 10-Mb duplication in 16p13.2p12.3 region considered causal of intellectual disability and severe overweight, and (II) eleven 16p11.2 CNVs of low prevalence but with recurrence in syndromic patients with severe BMI alteration (nine proximal and two distal). Proximal 16p11.2 CNVs have a dose-dependent effect: underweight in carriers of duplication and obesity in carriers of deletion. KCTD13 was identified as a possible candidate gene for BMI alteration on proximal syndromes, whereas SH2B1 gene was identified as candidate for distal syndromes. The results shown in this paper suggest that syndromic patients could constitute a reliable model to evaluate hypothalamic satiety and obesity disorders as well as generate a wide expectation for primary prevention of comorbidities. Furthermore, 16p13.2p12.3 showed to be an important region on the regulation of body fatness. PMID- 30518946 TI - HelixComplex snail mucus exhibits pro-survival, proliferative and pro-migration effects on mammalian fibroblasts. AB - Snail mucus is a mixture of active substances commonly thought to have healthy properties for the treatment of skin disorders. Although snail mucus is an ingredient of several cosmetic and para-pharmaceutic products, a comprehensive characterization of chemical composition and biological effects is still missing. Crude purified extracts from Helix aspersa muller mucus (HelixComplex) were prepared and, after chemical characterization, tested on in vitro experimental models. Differently from what expected, HelixComplex was characterized by the presence of small amounts of glycolic acid and allantoin. By using different in vitro assays on fibroblast cultures, we found that HelixComplex lacked of cytotoxicity, protected cells from apoptosis (p < 0.05) and, importantly, was able to significantly induce cell proliferation and migration through direct and indirect mechanisms. These effects were associated to morphological changes, cytoskeleton re-organization and release of cytokines. In conclusion, our findings suggest that snail mucus biological effects are attributable to cell proliferation and migration, and pave the way for further investigating snail mucus potential as therapeutic agent. PMID- 30518947 TI - Author Correction: The influence of latitude, geographic distance, and habitat discontinuities on genetic variation in a high latitude montane species. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30518948 TI - Publisher Correction: A Pilot Study on Tocilizumab for Treating Refractory Adult Onset Still's Disease. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30518950 TI - Highlights from SfE BES 2018. PMID- 30518949 TI - Sodium selenite inhibits deoxynivalenol-induced injury in GPX1-knockdown porcine splenic lymphocytes in culture. AB - Deoxynivalenol (DON) is a cytotoxic mycotoxin that can cause cell damages. The main effect is to inhibit protein synthesis. Oxidative stress is one of the effects of DON. Selenium (Se) can ameliorate the cell damage caused by DON induced oxidative stress, but it is unclear whether through selenoprotein glutathione peroxidase 1 (GPX1). We established GPX1-knockdown porcine spleen lymphocytes, and treated them with DON and Se. Untransfected porcine splenic lymphocytes (group P) and transfected cells (group M, GPX1 knockdown) were treated with or without DON (0.824, 0.412, 0.206, or 0.103 MUg/mL, group D1-4), Se (Na2SeO3, 2 MUM, group Se), or both (group SD1-4) for 6, 12, or 24 h. The cells were collected and the activities of SOD and CAT, levels of GSH, H2O2, malonaldehyde (MDA), total antioxidant capacity (T-AOC), and the inhibition of free hydroxyl radicals were determined. Levels of ROS were measured at 24 h. Compared with group P, the antioxidant capacity of group M was reduced. DON caused greater oxidative damage to the GPX1-knockdown porcine splenic lymphocytes than to the normal control cells. When Na2SeO3 was combined with DON, it reduced the damage in the GPX1-knockdown porcine splenic lymphocytes, but less effectively than in the normal porcine splenic lymphocytes. PMID- 30518951 TI - Sox2 is associated with cancer stem-like properties in colorectal cancer. AB - Sox2 is known as the undifferentiated cell marker. Recent studies have shown that Sox2 may also be involved in the maintenance of cancer stem cells (CSCs) in skin and bladder cancers. In this study, we aimed to clarify the role of Sox2 in colorectal CSCs. Sox2 expression was measured in colon cancer cells and colorectal clinical samples by qRT-PCR and western blot analysis. To visualize the active Sox2 mRNA production, we generated a Sox2 promoter-dependent DsRed fluorescence emission system. Colon cancer cell lines and colorectal tumor tissues generally expressed the Sox2 protein. Knockdown of Sox2 by siRNA led to increased proliferative activity in Caco2 cells. Kaplan-Meier survival curves showed that the group with high Sox2 mRNA expression had a worse prognosis for relapse-free survival (RFS) than the low expression group (P = 0.045, median follow-up 60.0 months). Time-lapse image analysis revealed that most DsRed+ cells exhibited typical asymmetric cell division and had higher CSC marker expressions. The DsRed+ cells exhibited chemoresistance and they grew slower in vitro, yet they established rather larger tumors in vivo. Our data suggest that Sox2 may be a potential biomarker for colorectal CSCs. PMID- 30518952 TI - Predictors of stent thrombosis and their implications for clinical practice. AB - Stent thrombosis (ST) is a rare but severe complication of coronary procedures with high mortality, high relapse rate and a very complex pathophysiology. An individual's susceptibility to ST is multifactorial and results from interactions between clinical factors, endothelial biology, hypersensitivity and/or inflammatory reactions, blood rheology, platelet reactivity, clotting factors, physical and mechanical properties of the stent and from the effects of these different factors on the fluid dynamics of blood flow. Since the introduction of stents 32 years ago, continuous improvements in our understanding of the pathophysiology of ST have triggered important advances, including new therapies, new technologies and an increased awareness of the implications of implantation techniques. Furthermore, advances in medical imaging and in the mathematical processing of this information have allowed a more detailed assessment of the mechanisms of ST at the time of its onset. Evidence shows that addressing the risk factors for ST leads to a substantial reduction in its incidence, both early and late after stent implantation. A better knowledge of the mechanisms of this complication is, however, necessary to direct the choice of the most appropriate strategy for its prevention and treatment. PMID- 30518953 TI - Mid-term outcomes with CoreValve versus surgery. PMID- 30518954 TI - Nanotherapy for abdominal aortic aneurysm. PMID- 30518955 TI - Benefits of renal denervation in HFrEF. PMID- 30518956 TI - Spatiotemporal clustering of cases of Kawasaki disease and associated coronary artery aneurysms in Canada. AB - Detailed epidemiologic examination of the distribution of Kawasaki disease (KD) cases could help elucidate the etiology and pathogenesis of this puzzling condition. Location of residence at KD admission was obtained for patients diagnosed in Canada (excluding Quebec) between March 2004 and March 2015. We identified 4,839 patients, 164 of whom (3.4%) developed a coronary artery aneurysm (CAA). A spatiotemporal clustering analysis was performed to determine whether non-random clusters emerged in the distributions of KD and CAA cases. A high-incidence KD cluster occurred in Toronto, ON, between October 2004 and May 2005 (116 cases; relative risk (RR) = 3.43; p < 0.001). A cluster of increased CAA frequency emerged in Mississauga, ON, between April 2004 and September 2005 (17% of KD cases; RR = 4.86). High-incidence clusters also arose in British Columbia (November 2010 to March 2011) and Alberta (January 2010 to November 2012) for KD and CAA, respectively. In an exploratory comparison between the primary KD cluster and reference groups of varying spatial and temporal origin, the main cluster demonstrated higher frequencies of conjunctivitis, oral mucosa changes and treatment with antibiotics, suggesting a possible coincident infectious process. Further spatiotemporal evaluation of KD cases might help understand the probable multifactorial etiology. PMID- 30518957 TI - Tuning structure and mechanical properties of Ta-C coatings by N-alloying and vacancy population. AB - Tailoring mechanical properties of transition metal carbides by substituting carbon with nitrogen atoms is a highly interesting approach, as thereby the bonding state changes towards a more metallic like character and thus ductility can be increased. Based on ab initio calculations we could prove experimentally, that up to a nitrogen content of about 68% on the non-metallic sublattice, Ta-C-N crystals prevail a face centered cubic structure for sputter deposited thin films. The cubic structure is partly stabilized by non-metallic as well as Ta vacancies - the latter are decisive for nitrogen rich compositions. With increasing nitrogen content, the originally super-hard fcc-TaC0.71 thin films soften from 40 GPa to 26 GPa for TaC0.33N0.67, accompanied by a decrease of the indentation modulus. With increasing nitrogen on the non-metallic sublattice (hence, decreasing C) the damage tolerance of Ta-C based coatings increases, when characterized after the Pugh and Pettifor criteria. Consequently, varying the non metallic sublattice population allows for an effective tuning and designing of intrinsic coating properties. PMID- 30518958 TI - The potential of substance P to initiate and perpetuate cortical spreading depression (CSD) in rat in vivo. AB - The tachykinin substance P (SP) increases neuronal excitability, participates in homeostatic control, but induces brain oedema after stroke or trauma. We asked whether SP is able to induce cortical spreading depression (CSD) which often aggravates stroke-induced pathology. In anesthetized rats we applied SP (10-5, 10 6, 10-7, or 10-8 mol/L) to a restricted cortical area and recorded CSDs there and in remote non-treated areas using microelectrodes. SP was either applied in artificial cerebrospinal fluid (ACSF), or in aqua to perform a preconditioning. Plasma extravasation in cortical grey matter was assessed with Evans Blue. Only SP dissolved in aqua induced self-regenerating CSDs. SP dissolved in ACSF did not ignite CSDs even when excitability was increased by acetate-preconditioning. Aqua alone elicited as few CSDs as the lowest concentration of SP. Local pretreatment with 250 nmol/L of a neurokinin 1 receptor antagonist prevented the SP-induced plasma extravasation, the initiation of CSDs by 10-5 mol/L SP diluted in aqua, and the initiation of CSDs by aqua alone, but did not suppress KCl-induced CSD. Thus neurokinin 1 receptor antagonists may be used to explore the involvement of SP in CSDs in clinical studies. PMID- 30518960 TI - Gone FISHing. PMID- 30518961 TI - Patchwork subiculum. PMID- 30518959 TI - Non-nociceptive roles of opioids in the CNS: opioids' effects on neurogenesis, learning, memory and affect. AB - Mortality due to opioid use has grown to the point where, for the first time in history, opioid-related deaths exceed those caused by car accidents in many states in the United States. Changes in the prescribing of opioids for pain and the illicit use of fentanyl (and derivatives) have contributed to the current epidemic. Less known is the impact of opioids on hippocampal neurogenesis, the functional manipulation of which may improve the deleterious effects of opioid use. We provide new insights into how the dysregulation of neurogenesis by opioids can modify learning and affect, mood and emotions, processes that have been well accepted to motivate addictive behaviours. PMID- 30518962 TI - Closing the loop. PMID- 30518963 TI - To sleep, to remember. PMID- 30518964 TI - Food intake - feeling the heat. PMID- 30518965 TI - Restoring walking. PMID- 30518966 TI - A neutron tomography study: probing the spontaneous crystallization of randomly packed granular assemblies. AB - We study the spontaneous crystallization of an assembly of highly monodisperse steel spheres under shaking, as it evolves from localized icosahedral ordering towards a packing reaching crystalline ordering. Towards this end, real space neutron tomography measurements on the granular assembly are carried out, as it is systematically subjected to a variation of frequency and amplitude. As expected, we see a presence of localized icosahedral ordering in the disordered initial state (packing fraction ~ 0.62). As the frequency is increased for both the shaking amplitudes (0.2 and 0.6 mm) studied here, there is a rise in packing fraction, accompanied by an evolution to crystallinity. The extent of crystallinity is found to depend on both the amplitude and frequency of shaking. We find that the icosahedral ordering remains localized and its extent does not grow significantly, while the crystalline ordering grows rapidly as an ordering transition point is approached. In the ordered state, crystalline clusters of both face centered cubic (FCC) and hexagonal close packed (HCP) types are identified, the latter of which grows from stacking faults. Our study shows that an earlier domination of FCC gives way to HCP ordering at higher shaking frequencies, suggesting that despite their coexistence, there is a subtle dynamical competition at play. This competition depends on both shaking amplitude and frequency, as our results as well as those of earlier theoretical simulations demonstrate. It is likely that this involves the very small free energy difference between the two structures. PMID- 30518967 TI - Genetic architecture of quantitative flower and leaf traits in a pair of sympatric sister species of Primulina. AB - Flowers and leaves each represent suites of functionally interrelated traits that are often involved in species divergence and local adaptation. However, a major unresolved issue is how the individual component traits that make up a complex trait such as a flower evolve in a coordinated fashion to retain a high degree of functionality. We use a quantitative trait loci (QTL) approach to elucidate the genetic architecture of divergence in flower and leaf traits between the sister species Primulina depressa and Primulina danxiaensis, which grow sympatrically but in contrasting microhabitats. We found that flower traits were controlled by multiple QTL of small effect, while leaf physiological and morphological traits tended to be controlled by QTL of larger effect. The observed floral integration, manifested by a high degree overlap in both individual trait QTL and QTL for principal component scores (PCA QTL), may have been critical for evolutionary divergence of floral morphology in relation to their pollinators. This overlap suggests that direct selection on only one or a few of the component traits could have caused substantial divergence in other floral traits due to genetic correlations, while the low QTL overlap between floral and vegetative traits suggests that these trait suites are genetically unlinked and can evolve independently in response to different selective pressures corresponding to their distinct functions. PMID- 30518969 TI - Reviewer recognition. AB - In this issue we would like to thank all those listed below for taking the time to review for the European Journal of Clinical Nutrition in 2017-your generosity is much appreciated and we hope your association with the journal continues in the future. PMID- 30518968 TI - X-chromosome meiotic drive in Drosophila simulans: a QTL approach reveals the complex polygenic determinism of Paris drive suppression. AB - Meiotic drivers are selfish genetic elements that promote their own transmission into the gametes, which results in intragenomic conflicts. In the Paris sex-ratio system of Drosophila simulans, drivers located on the X chromosome prevent the segregation of the heterochromatic Y chromosome during meiosis II, and hence the production of Y-bearing sperm. The resulting sex-ratio bias strongly impacts population dynamics and evolution. Natural selection, which tends to restore an equal sex ratio, favors the emergence of resistant Y chromosomes and autosomal suppressors. This is the case in the Paris sex-ratio system where the drivers became cryptic in most of the natural populations of D. simulans. Here, we used a quantitative trait locus (QTL) mapping approach based on the analysis of 152 highly recombinant inbred lines (RILs) to investigate the genetic determinism of autosomal suppression. The RILs were derived from an advanced intercross between two parental lines, one showing complete autosomal suppression while the other one was sensitive to drive. The confrontation of RIL autosomes with a reference XSR chromosome allowed us to identify two QTLs on chromosome 2 and three on chromosome 3, with strong epistatic interactions. Our findings highlight the multiplicity of actors involved in this intragenomic battle over the sex ratio. PMID- 30518970 TI - A novel method to evaluate quality of care from the perspective of cataract patients. AB - PURPOSE: To evaluate quality of care from patient's perspective following cataract surgery using a novel questionnaire and to assess validity of the survey in context with the identification of lacks in quality of care. METHODS: Assessment of quality of care in 150 patients (150 eyes) who underwent cataract surgery in an Austrian clinical setting based on a novel "Quality of Care from Patient's perspective following Cataract Surgery" (QCPCS)-questionnaire including 10 subjective, 10 objective and 7 general health care criteria. Quality of care was graded according to importance (range: 1 = not important to 4 = extremely important) and frequency of occurrence (range: 1 = never to 4 = often, 0 = not applicable). Quality-impact indices (QI-respective grading by patient/4) were assessed. RESULTS: Mean performance score was 3.84 (SD = 0.42, range: 1-4). Mean QI was 0.89 for subjective, 0.90 for objective and 0.96 for general health care criteria (p = 0.29). All-over skewness and coefficient of variation were -2.65 and 5.85 respectively. Internal consistency was high (Cronbach's alpha = 0.75) confirming causal taxonomy of disease-specific and generic items. CONCLUSION: A valid new method to reliably and holistically evaluate patient's satisfaction related to cataract surgery including a broad range of patient needs is presented, suitable to assess potential lacks in quality of health care in daily ophthalmological clinical practice. PMID- 30518971 TI - Periocular basal cell carcinoma in under 40's - Is more aggressive treatment warranted? PMID- 30518972 TI - Depth perception in patients with congenital color vision deficiency. AB - PURPOSE: To assess the effect of type and severity of congenital color vision deficiency (CCVD) on depth perception. METHODS: Thirty-one male patients with a known diagnosis of CCVD were included in the study group and 31 age-matched healthy subjects in the control group. After standard ophthalmological examination including best corrected visual acuity (BCVA) testing with Snellen chart, slit-lamp examination, non-contact tonometry, and fundus examination, all patients underwent color perception testing with Hardy-Rand-Rittler (HRR) 4th edition pseudoisochromatic test plates and stereoacuity testing with Titmus stereo test plates. RESULTS: Of the 31 patients with CCVD, 7 were protanope and 24 were deuteranope. Mean stereoacuity was 46.77 +/- 11.3, 105.7 +/- 69.0, and 134.1 +/- 115.2 in the control, protanope, and deuteranope groups, respectively. Stereoacuity was significantly better in the control group than in the protanope and deuteranope groups (p = 0.039, p < 0.001 respectively). No significant difference was observed between protanopes and deuteranopes regarding stereoacuity (p = 0.73). Mean BCVA was -0.01 +/- 0.03, -0.02 +/- 0.07, and -0.10 +/- 0.11 in the control, protanope, and deuteranope groups, respectively. Mean BCVA in deuteranopes was significantly better than the control group (p = 0.004), while mean BCVA in deuteranopes and protanopes did not differ significantly (p = 0.056). No significant difference was observed between the control group and protanopes regarding visual acuity (p = 0.921). CONCLUSIONS: Our study showed that color vision had an important effect on depth perception and CCVD may cause decreased stereoacuity. PMID- 30518973 TI - Reducing health disparities in adult vision loss via interfaces with emerging technology. PMID- 30518974 TI - "PI-less DMEK": results of Descemet's membrane endothelial keratoplasty (DMEK) without a peripheral iridotomy. AB - PURPOSE: To assess Descemet's membrane endothelial keratoplasty (DMEK) without performing a peripheral iridotomy (PI) prior to or during surgery ("PI-less DMEK"). MATERIALS AND METHODS: This retrospective study included consecutive patients that underwent PI-less DMEK by a single surgeon (E.L) between February 2016 and February 2017 at the Rabin Medical Center, a Tertiary Hospital. Intraoperative and postoperative complications were assessed. RESULTS: Thirty-one patients, mean age 75.9 +/- 7.9 years with 58.1% female were included. Leading indications for surgery were pseudophakic bullous keratopathy (18/31) and Fuchs' endothelial dystrophy (9/31). Preoperative best-corrected distance visual acuity was 1.13 +/- 0.59 logMAR (~6/80 Snellen). For 12/31 that had postoperative endothelial cell count measurements, cell loss was 49 +/- 20%. Intraoperative complications included anterior chamber (AC) hyphema during graft insertion requiring reinsertion (n = 1), and minor hyphema from the main corneal incision (n = 1). Partial slit lamp gas evacuation was performed in all patients 1.5 h postoperatively. Postoperative complications included partial graft detachment requiring rebubbling (n = 5), self-resolving minimal peripheral graft detachment (n = 5), uncontrolled intraocular hypertension requiring trabeculectomy in a patient with a history of medically controlled glaucoma (n = 1), postoperative cystoid macular edema that resolved medically (n = 1) and graft failure 5 months postoperatively (n = 1). No patients developed pupillary block. Excluding graft failure (n = 1), preoperative amblyopia (n = 2) and premature loss to follow-up (n = 1), final corrected distance visual acuity was 0.18 +/- 0.14 logMAR (~20/30 Snellen) with 44.4% reaching 6/7.5 (Snellen) or more. CONCLUSIONS: PI-Less DMEK is a safe, technically easy, and effective modification that avoids the time and complications associated with performing a PI before or during surgery. PMID- 30518975 TI - A proposed mechanism influencing structural patterns in X-linked retinoschisis and stellate nonhereditary idiopathic foveomacular retinoschisis. AB - OBJECTIVE: To explore the structural differences between X-linked retinoschisis (XLR) and stellate nonhereditary idiopathic foveomacular retinoschisis (SNIFR) using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: A case series of two patients, a 9-year-old male with XLR and a 58-year-old woman with SNIFR were imaged with swept-source optical coherence tomography angiography (SS-OCTA; PLEX Elite 900, Carl Zeiss Meditec, Inc, Dublin, CA). Automated segmentation was manually adjusted to include the areas of retinoschisis within en face flow and structural slabs. The flow data were binarized using ImageJ 1.51s (Wayne Rasband, National Institutes of Health, USA, http://imagej.nih.gov.ij ) and superimposed onto the structural slab. RESULTS: In the eye with XLR, OCTA flow data superimposed on the structural slab demonstrated flow signal within numerous bridging structures connecting the inner and outer plexiform layers containing the intermediate (ICP) and deep (DCP) capillary plexuses. In contrast, the same technique applied to the eye with SNIFR demonstrated an absence of flow signal in the cystic retinal spaces within Henle's fiber layer. CONCLUSIONS: The vascular pattern of bridging vessels between the ICP and DCP is closely related to the structural "retinoschisis" pattern of XLR and appears to be structurally different from that seen in SNIFR. Moreover, the connecting vessels appear to be highly represented and regularly distributed, thereby supporting a serial arrangement of the retinal capillary plexuses within the perifoveal macula. PMID- 30518976 TI - Quality of life following surgery for congenital glaucoma: findings of the LVPEI congenital glaucoma registry. AB - PURPOSE: To evaluate the health-related quality of life (HRQoL) of children operated for primary congenital glaucoma (PCG) using the Kidscreen-27 questionnaire. METHODS: A total of 121 children (mean age, 11.8 years; SD, 2.8 years; 51% males) with unilateral or bilateral PCG who underwent glaucoma surgery in infancy (mean duration since surgery, 10.2 years; [SD] 4.2 years) by a single surgeon at a tertiary eye care centre were administered the Kidscreen-27 questionnaire (self-or interviewer administered in a face-to-face interview) during their routine follow-up visit. We investigated the measurement properties of Kidscreen-27 questionnaire using Rasch analysis and generated interval-level estimates of HRQoL. The main outcome measure was HRQoL (i.e., Rasch-derived Kidscreen score). Multivariable linear regression analyses assessed the influence of socio-demographic and clinical variables on the HRQoL of children with PCG. RESULTS: Majority (83%) of the children had bilateral PCG and congenital type of the disease (79%). Mean presenting acuity (logMAR) in the better eye was 0.32 (SD, 0.36; median, 0.18). Rasch analysis of Kidscreen-27 questionnaire indicated need for minor modifications following which a psychometrically robust unidimensional 23-item Kidscreen questionnaire emerged. In multivariable model, age of the child was independently associated with a 32% (beta = -0.24 [95% CI, 0.11, -0.36]) increase in the HRQoL score. CONCLUSIONS: Despite undergoing successful glaucoma surgery, children with PCG reported reduced HRQoL. Younger children with PCG are more likely to experience this lowered HRQoL and ophthalmologists will need to be alert to this. Efforts must be made to improve the HRQoL of children with PCG. PMID- 30518977 TI - Safety and efficacy of rituximab-based first line treatment of chronic GVHD. AB - Initial therapy of chronic GVHD (cGvHD) has not changed for over three decades, despite limited efficacy and long-term toxicity. We have previously shown in a small pilot study the feasibility of rituximab-based first-line therapy of cGVHD. To better assess safety and efficacy, we now evaluate 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months. Resolution of cGVHD occurred in 49 patients with median time to IST discontinuation of 349 (138-920) days. The cumulative incidence (CI) of cGHVD resolution was 41%, 69 and 77% at 1-, 2- and 3-years, respectively. No systemic corticosteroids were used in 27 patients, and 67% received <= 10 mg/kg cumulative exposure. Overall survival (OS) at 1-, 2- and 3 years following cGVHD diagnosis was 87, 79 and 77% respectively; corresponding rates of non-relapse mortality (NRM) were 10%, 16 and 19%. The probability of being alive and free of cGVHD at 1-, 2-, and 3-years was 36, 55, and 57% respectively. This study demonstrates the feasibility and efficacy of rituximab based first-line cGVHD treatment. This approach demonstrates significant activity and avoids long courses of corticosteroids in most patients. PMID- 30518978 TI - Donor lymphocyte infusion for BK virus hemorrhagic cystitis and nephropathy: a case report. PMID- 30518979 TI - One single bone marrow harvesting from donors under 3 years of age: assessing safety and efficacy of the procedure. AB - To candidate children as bone marrow donors raises two main concerns: donor safety and adequate marrow cell dose. Data in the field are limited and guidelines for child donor care management are lacking. In this context, we herein report the experience collected in our center by comparing very-young donors (defined as age <= 3 years) with young donors (defined as age > 3 years) who donated bone marrow (BM) for patients affected by beta-globin disorders. PMID- 30518980 TI - A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. AB - The source of CAR T cells can be autologous (autoCAR) or allogeneic (alloCAR). The latter is seen in patients with a history of allogeneic hematopoietic stem cell transplantation, and can be either donor-derived (DD-alloCAR) or recipient derived (RD-alloCAR). While autoCAR is activated by CAR only, alloCAR receives activation signals from both T-cell receptor (TCR) and CAR. As a result, the biological differences could impact clinical outcomes. We retrospectively reviewed 31 patients: 17 received autoCAR, 11 received RD-alloCAR, and 3 received DD-alloCAR. After a median follow-up of 9 months, CR rate was 88.2% (95% CI 63.6 98.5%) in autoCAR and 100% (95% CI 71.5-100%) in RD-alloCAR. The median peak expansion in the autoCAR was significantly higher than the RD-alloCAR group (p = 0.007). RD-alloCAR group had significantly less patients with severe CRS (Grade >= 3) than the autoCAR group (p = 0.049). Acute graft-versus-host disease (GVHD) occurred in 2 (18.2%) of RD-alloCAR patients and 1 (33.3%) of DD-alloCAR patients. Univariate subgroup analysis of alloCAR group showed the presence of cGVHD at the time of T-cell collection was significantly associated with less than 6-month relapses (p = 0.022). RD-alloCAR patients with or without cGVHD at PBMC collection did not differ regarding the peak CAR T-cell expansion, CRS grades and OS. PMID- 30518981 TI - Chemotherapy plus DLI for relapse after haploidentical HSCT: the biological characteristics of relapse influences clinical outcomes of acute leukemia patients. AB - This study investigated the prognostic factors in patients (n = 89) who experienced relapse and received chemotherapy plus donor leukocyte infusion (Chemo-DLI) after haploidentical hematopoietic stem cell transplantation (haplo HSCT). Patients with early relapse (< 6 vs. > 6 months after haplo-HSCT), higher bone marrow blast count before chemo-DLI (> 20% vs. 5-19%), and without chronic graft-versus-host disease (cGVHD) after chemo-DLI had a higher rate of progressive disease (PD) and worse progression-free survival (PFS) and overall survival (OS). In multivariate analysis, non-cGVHD after Chemo-DLI and high blast count predicted a higher risk of PD and poorer PFS, and non-cGVHD after Chemo-DLI and early relapse predicted poorer OS. The patients were stratified into three groups according to these three risk factors. Patients with all three risk factors (n = 14) had the highest PD rate and poorest survival compared with those with one or two risk factors (n = 63) or no risk factors (n = 12). Thus, early relapse, high leukemia burden before Chemo-DLI, and non-cGVHD after Chemo-DLI can predict outcomes in patients who have experienced relapse and received Chemo-DLI after haplo-HSCT. New therapeutic strategies should be identified for these patients. PMID- 30518982 TI - Treatment of Epstein-Barr virus associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation with intrathecal donor lymphocyte infusion. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective measure for the treatment of hematological disease. With the progress and widespread use of allo-HSCT, Epstein-Barr virus (EBV) related central nervous system (CNS) diseases have gotten more and more attention because of its poor prognosis and overall survival. Since currently there is no standard treatment for patients with EBV-associated CNS diseases and reported therapies are heterogeneous with mixed results, we attempted to develop a novel therapeutic method. We applied a regimen of intrathecal donor lymphocyte infusion (IDLI) in three patients with EBV-associated CNS diseases after allo-HSCT in addition to immunosuppressants reduction and combined antiviral therapy. All of three patients were responsive to this therapy: all clinical symptoms and EBV load in CSF were resolved 10, 17, and 12 days after initial IDLI, respectively, and magnetic resonance imaging (MRI) showed that lesions of case 1 and 2 disappeared 15 and 19 days after initial IDLI, respectively. Even more appealing, there were no acute or chronic adverse reactions during the infusion and up to 23 months of follow-up. In conclusion, IDLI seems to be an effective and safe method for EBV associated CNS diseases in allo-HSCT recipients. We recommend this treatment modality for further investigation. PMID- 30518983 TI - Exaggerated blood pressure response to fasudil or nifedipine in hypertensive Ren 2 transgenic rats: role of altered baroreflex. AB - Basal calcium sensitization is decreased in spontaneously hypertensive rats, although their blood pressure (BP) response to acute Rho-kinase inhibition is enhanced. Using fasudil (Rho-kinase inhibitor) or nifedipine (L-VDCC blocker), we evaluated the contribution of calcium sensitization and calcium entry to BP maintenance in hypertensive transgenic Ren-2 rats (TGR) focusing on the influence of major vasoactive systems and/or baroreflex efficiency on BP responses to these two drugs. Homozygous TGR and normotensive Hannover Sprague-Dawley (HanSD) control rats aged 5, 11, or 22 weeks were used. The acute BP-lowering effects of fasudil or nifedipine were studied in intact rats, nitric oxide-deficient L-NAME pretreated rats and rats subjected to combined blockade of the renin-angiotensin system (RAS), sympathetic nervous system (SNS) and nitric oxide synthase (NOS). Fasudil- or nifedipine-induced BP reduction increased during hypertension development in TGR. By contrast, the nifedipine-induced BP response decreased, whereas the fasudil-induced BP response increased with age in HanSD controls. Our data indicated a major contribution of nifedipine-sensitive calcium entry and relative attenuation of calcium sensitization in hypertensive rats compared with normotensive controls. The BP responses to fasudil or nifedipine were enhanced by NOS inhibition and combined blockade in normotensive HanSD rats but not in hypertensive TGR. In conclusion, calcium sensitization is attenuated by endogenous nitric oxide in normotensive HanSD rats but not in hypertensive TGR. Moreover, BP reduction elicited by acute Rho-kinase inhibition is partially compensated by enhanced sympathetic vasoconstriction. The decreased compensation in hypertensive rats with impaired baroreflex efficiency explains their greater BP response to fasudil than in normotensive animals. PMID- 30518984 TI - Sex differences in the awareness, treatment, and control of hypertension in China: a systematic review with meta-analyses. AB - Hypertension is the major cause of preventable disease burden in China. However, limited evidence is available on sex differences in the awareness, treatment, and control of hypertension. We assessed sex differences in the awareness, treatment, and control of hypertension in China. A systematic search of four English language and four Chinese-language databases was conducted to identify studies conducted from 2005 that reported sex-specific data on the awareness, treatment, and control of hypertension in China. Random-effects meta-analysis weighted by the inverse of the variances were used to obtain pooled sex-specific rates and women-minus-men differences, and their 95% confidence intervals (CI). Overall, 57 studies comprising 2,155,829 individuals (55% women) were included. Awareness (53% in women vs. 47% in men), treatment among all (44% vs. 38%), treatment among aware (65% vs. 60%), control among all (17% vs. 14%), and control among treated (27% vs. 27%) were low for both sexes, but more favourable in women than men. The corresponding women-minus men difference was 7% (95% CI: 6; 8%) for awareness, 6% (5; 8%) for treatment among all, 6% (2; 9%) for treatment among aware, 3% (2; 3%) for control among all, and 0% (-2; 1%) for control among treated. Awareness, treatment, and control of hypertension in China is low in both sexes, but greater in women than men. Sex-specific interventions may be needed to efficiently combat the burden of hypertension. PMID- 30518985 TI - Histone deacetylase inhibition disturbs the balance between ACE and chymase expression in endothelial cells: a potential mechanism of chymase activation in preeclampsia. AB - Chymase is a major angiotensin-converting enzyme (ACE)-independent angiotensin convertase, and its expression is upregulated in the maternal vascular endothelium in preeclampsia, a hypertensive disorder in human pregnancy. Increased chymase-dependent angiotensin II generation has been reported in several cardiovascular diseases, including atherosclerosis and aneurysmal lesions. However, it remains unclear how chymase is activated. Histone modification is an important regulatory mechanism that controls gene expression. In this study, using a chymase overexpression cell model, we investigated the mechanisms of chymase activation to test our hypothesis that histone acetylation could promote endothelial chymase expression. Human umbilical vein endothelial cells were transfected with the chymase gene. Trichostatin A was used to inhibit histone deacetylases (HDACs). The expression levels of chymase, ACE, and HDACs were determined by western blotting. Our results showed that ACE was strongly expressed in control cells, but was significantly downregulated in cells transfected to express chymase. Strikingly, we also found that HDAC inhibition resulted in a dose-dependent increase in chymase expression but a dose-dependent decrease in ACE expression in cells transfected with the chymase gene. HDAC inhibition was confirmed by the decreased expression of HDAC1 and HDAC6 in cells treated with trichostatin A. Increased chymase expression associated with reduced histone deacetylase expression was further confirmed by immunostaining of subcutaneous adipose sections from women with preeclampsia. We conclude that aberrant HDAC expression/activity could disturb the balance between ACE and chymase expression in endothelial cells. Our results support the clinical importance of chymase as a new pharmacological target for cardiovascular disorders. PMID- 30518986 TI - Evaluation of sodium intake for the prediction of cardiovascular events in Japanese high-risk patients: the ESPRIT Study. AB - The optimal level of sodium intake remains controversial, and the effects on a broad range of cardiovascular (CV) conditions remain unknown. The Evaluation of sodium intake for the prediction of cardiovascular events in Japanese high-risk patients (ESPRIT) is a prospective observational study designed to investigate whether sodium intake assessed by spot urine testing is associated with adverse CV events. A total of 520 patients who visited our cardiology clinic with various cardiovascular risk profiles were included. Sodium intake was estimated by spot urine testing at the time of entry, and the measurement was repeated at least every 6 months during follow-up. The primary endpoint was composed of (1) hospitalization due to heart failure, (2) acute coronary syndrome, (3) cerebrovascular events, and (4) documented CV deaths. The secondary endpoint was all-cause mortality. During the median follow-up period of 5.2 years, there were 105 composite CV events (3.9%/year), including 60 hospitalizations due to heart failure, 9 acute coronary syndromes, 21 cerebrovascular events, 15 CV deaths, and 26 cases of all-cause mortality. The average sodium excretion (from a median of 14 measurements) during the follow-up period was 3.52 +/- 0.67 g/day. After adjustment for age, sex, and body weight, higher sodium excretion ( >= 4.0 g/day) was associated with composite CV events (hazard ratio 1.79, confidence interval 1.01-3.15 compared with the reference value of 3.0-3.49 g/day) but not all-cause mortality. The ESPRIT study showed that high sodium excretion (>= 4.0 g/day) was associated with the predefined composite CV events (UMIN ID: UMIN000005419). PMID- 30518987 TI - A comprehensive study revealed SNP-SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk. AB - This study investigated whether common polymorphisms of cytochrome P450 2J2 (CYP2J2), a major enzyme that controls the biosynthesis of vasoactive epoxyeicosatrienoic acids, are collectively involved in the molecular basis of essential hypertension (EH). A total of 2314 unrelated Russian subjects from the Kursk (discovery sample: 913 EH patients and 645 controls) and Belgorod (replication sample: 345 EH patients and 411 controls) regions were recruited for this study. Eight single nucleotide polymorphisms (SNPs), including rs890293, rs11572182, rs10493270, rs1155002, rs2280275, rs7515289, rs11572325, and rs10889162, of CYP2J2 were genotyped using the MassARRAY 4 system and TaqMan based assays. Significant associations were identified among the SNPs rs890293 (OR = 2.17, 95%CI 1.30-3.65), rs2280275 (OR = 1.59, 95%CI 1.10-2.37) and rs11572325 (OR = 1.89, 95%CI 1.22-2.95) and the risk of EH in females from the Kursk population. Sixteen CYP2J2 genotype combinations only showed significant associations with EH risk only in females. A common haplotype, T-T-G-C-C-C-T-A, increased the risk of EH in females. The bioinformatic analysis enabled identification of the SNPs that possess regulatory potential and/or are located within the binding sites for multiple transcription factors that play roles in the pathways involved in hypertension pathogenesis. Moreover, the polymorphisms rs890293, rs2280275, and rs11572325 were found to be significantly associated with hypertension risk in the Belgorod population. In conclusion, the rs2280275 and rs11572325 SNPs of CYP2J2 may be considered novel genetic markers of hypertension, at least in Russian women. However, sex-specific associations between CYP2J2 gene polymorphisms and hypertension require further investigation to clarify the specific genetic and/or environmental factors that are responsible for the increased disease susceptibility of women compared to that of men. PMID- 30518988 TI - Temperature Responsive Hydrogel with Reactive Nanoparticles. AB - The application of temperature responsive hydrogels with ion-exchange domain for nanoscale catalytic reactions is an emerging and attractive area because of the combination of individual unique features: temperature responsive tunability by the polymer domain and the high catalytic reactivity of the nanomaterial. Here, we report the entrapment and/or direct synthesis of reactive Fe and Fe/Pd nanoparticles (about 40-70 nm) in a temperature responsive hydrogel network (N isopropylacrylamide (NIPAAm), and NIPAAm-PAA). These nanoparticles are stabilized in the hydrogel network and the dechlorination (using trichloroethylene, TCE, as a model compound) reactivity in water is enhanced and controllable in the temperature range of 30-34 degrees C involving polymer domain transitions at lower critical solution temperature (LCST) from hydrophilic to collapsed hydrophobic state. Water fraction modulation of the network and the enhancement of pollutant partitioning by the thermally responsive polymers play an important role in the catalytic activity. PMID- 30518989 TI - Inside Plectosphaerellaceae. AB - The family Plectosphaerellaceae (Glomerellales, Sordariomycetes) includes numerous plant pathogenic genera and soil-borne fungal species. Ten genera are currently accepted, including several taxa that occupy an unresolved position within the family. To address this issue, a multilocus sequence analysis was carried out using partial gene sequences from the 28S large subunit nrRNA gene (LSU), the internal transcribed spacer (ITS) regions of the nrDNA region, including the 5.8S nrRNA gene, the translation elongation factor 1-alpha (TEF1 alpha), tryptophan synthase (TS), actin (ACT) and the RNA polymerase II second largest subunit (RPB2), based on a large set of isolates mainly from the CBS collection. Results of the molecular data combined with a detailed morphological study resolved 22 genera in the family, of which 12 are newly described. Additionally, 15 new species and 10 new combinations are proposed. An epitype and neotype are also introduced for Stachylidium bicolor and Plectosphaerella cucumerina, respectively. PMID- 30518990 TI - Therapists' techniques in the treatment of adolescent depression. AB - When comparing the relative effectiveness of different psychological treatment approaches using clinical trials, it is essential to establish fidelity to each manualized therapy, and differentiation between the treatment arms. Yet few psychological therapy trials include details about the assessment of treatment integrity and little is known about the specific techniques used by therapists, or to what degree these techniques are shared or distinct across different therapeutic approaches. The aims of this study were: to establish the fidelity of two established psychological therapies - cognitive-behaviour therapy (CBT) and short-term psychoanalytic psychotherapy (STPP) - in the treatment of adolescent depression; and to examine whether they were delivered with adherence to their respective treatment modalities, and if they could be differentiated from each other and from a reference treatment (a brief psychosocial intervention; BPI). The study also aimed to identify shared and distinct techniques used within and across the three treatments. Audio-tapes (N=230) of therapy sessions, collected as part of a trial, were blind double-rated using the Comparative Psychotherapy Process Scale (CPPS), which includes subscales for cognitive-behavioural and psychodynamic-interpersonal techniques. The treatments were delivered with reasonable fidelity and there was clear differentiation in the use of cognitive behavioural and psychodynamic-interpersonal techniques between CBT and STPP, and between these two established psychological therapies and BPI. An item-level analysis identified techniques used across all three treatments, techniques that were shared between BPI and CBT, and techniques that were unique to CBT and STPP. PMID- 30518991 TI - The Length of Surgical Skin Incision in Postoperative Inflammatory Reaction. AB - Background and Objectives: Surgery provokes inflammatory and immune responses, so efforts have been made to reduce host response by using less invasive techniques. The purpose of this experimental study was to investigate the surgical stress induced by skin incision and the role of liver response in this process. Methods: Seventy male anesthetized Wistar rats were subjected to a midline incision confined strictly to the skin (dermis) of either 1 cm long (n = 20), 10 cm long (n = 20), or no incision (n = 20) or served as controls (n = 10). Skin trauma was left open for a 20-minutes period, and then was meticulously sutured. At 3 and 24 hours later, laparotomy was performed on half the rats of each group, for blood and liver sampling. In serum and liver homogenates, cytokine-induced neutrophil chemoattractant (CINC)1/interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha levels were measured with enzyme-linked immunosorbent assays and nitric oxide (NO) using a Griess reaction. Results: Skin trauma was found to significantly (P < .01) increase all inflammatory mediators tested (CINC1/IL-8, TNF-alpha, NO) in serum of operated rats versus controls, the increase being proportionally dependent on the length of skin incision. In liver homogenates, CINC1/IL-8 was significantly (P < .01) increased in operated animals versus controls, similarly to serum levels. In contrast, liver TNF-alpha levels were inversely related to serum levels, and a significant (P < .01) decrease in TNF-alpha was observed in liver homogenates of operated animals compared with the controls, indicating that the increased TNF-alpha in blood reflects liver TNF-alpha secretion. Conclusion: Our findings suggest that inflammatory and immune reactions induced by skin-only surgical trauma are closely correlated to the length of skin incision. PMID- 30518992 TI - Using the Contribution Analysis Approach to Evaluate Science Impact: A Case Study of the National Institute for Occupational Safety and Health. AB - Interest from Congress, executive branch leadership, and various other stakeholders for greater accountability in government continues to gain momentum today with government-wide efforts. However, measuring the impact of research programs has proven particularly difficult. Cause and effect linkages between research findings and changes to morbidity and mortality are difficult to prove. To address this challenge, the National Institute for Occupational Safety and Health program evaluators used a modified version of contribution analysis (CA) to evaluate two research programs. CA proved to be a useful framework for assessing research impact, and both programs received valuable, actionable feedback. Although there is room to further refine our approach, this was a promising step toward moving beyond bibiliometrics to more robust assessment of research impact. PMID- 30518993 TI - Patient-reported outcomes of multifocal and accommodating intraocular lenses: analysis of 117 patients 2-10 years after surgery. AB - Purpose: The purpose of this study was to determine the satisfaction levels of patients at least 2 years after cataract surgery implantation with bilateral accommodating or bilateral multifocal intraocular lenses (IOLs) and to determine the relative rate of spectacle independence and adverse symptoms in that same time frame. Design: Patient questionnaire administered in a single-center private practice at least 2 years after cataract surgery with presbyopia-correcting IOL implantation. Methods: Patients who had undergone uncomplicated cataract surgery with an accommodating or multifocal IOL implant were eligible for inclusion. Patients with visually significant non-IOL-related postoperative morbidity were excluded. Patients with astigmatism or residual refractive error were not excluded. The main outcome measure was patient satisfaction at least 2 years after IOL implantation. Results: Sixty-eight patients who received accommodating lenses and 49 patients who received multifocal lenses completed the questionnaire. The mean age of all patients was 75.7 years at the time of survey; the mean number of years since cataract surgery was 5.4 years. Overall, there were no significant differences between the two groups or within each group between the different lenses used. About 90% of patients in each group were "very satisfied" or "somewhat satisfied" with their vision at least 2 years after the initial surgery. Conversely, only one in eleven patients found his vision to be worse than expected. Conclusions: The majority of patients who received either accommodating or multifocal IOLs remain satisfied with their lens of choice more than 5 years after the original surgery. Glare and halos remain more noticeable in patients who received multifocal lenses. PMID- 30518994 TI - Influence of the level of monovision on visual outcome with an extended range of vision intraocular lens. AB - Purpose: The purpose of this study was to evaluate the influence of different levels of monovision on the clinical outcomes achieved with an extended range of vision (ERV) intraocular lens (IOL). Patients and methods: Subanalysis of 411 patients from the multicenter CONCERTO study aimed at evaluating the outcomes after bilateral implantation of the Tecnis Symfony IOL. Visual acuity, spectacle independence, photic phenomena incidence, and patient satisfaction outcomes were evaluated in six groups defined according to the level of monovision: 0.0 D (75 patients; group 1), 01.0 D (19 patients; group 6). Results: Mean binocular uncorrected distance visual acuity (decimal) ranged from 0.90+/-0.17 in group 6 to 0.97+/-0.20 in group 2. Mean binocular uncorrected intermediate visual acuity (decimal) ranged from 0.77+/-0.25 in group 2 to 0.94+/-0.30 in group 4. Mean binocular uncorrected near visual acuity ranged from 0.64+/-0.23 in group 2 to 0.79+/-0.26 in group 6. The level of spectacle independence was high, with the highest value for near vision in group 6 (94.7%). Less patients reported halos (6.7%) in group 1, whereas only 3.8% of patients in group 4 reported disturbing glare symptoms. For near vision, the highest patient satisfaction was achieved in groups 4, 5, and 6. A total of 96.7% (group 3) and 96.2% (group 4) of patients would recommend the same procedure to their friends and family and would choose the same lens again. Conclusion: Mini-monovision of around 0.75 D after implantation of the Tecnis Symfony IOL provides a complete visual rehabilitation with minimal photic phenomena and high levels of patient satisfaction. PMID- 30518995 TI - Erratum: Short wave-automated perimetry (SWAP) versus optical coherence tomography in early detection of glaucoma [Corrigendum]. AB - [This corrects the article on p. 1819 in vol. 10, PMID: 27698551.]. PMID- 30518996 TI - Analysis of drug utilization and health care resource consumption in patients with psoriasis and psoriatic arthritis before and after treatment with biological therapies. AB - Objectives: To describe the therapeutic pathways of patients with psoriasis (PSO) and psoriatic arthritis (PsA) before and after treatment with biological therapies in a real-world setting and to determine the relative consumption of health care resources. Design: Retrospective observational study. Setting: Real life clinical setting in 5 Italian local health units. Participants: A total of 351 male and female patients with at least 1 prescription for a biological drug from January 1, 2010 to December 31, 2013; patients with concomitant rheumatoid arthritis, ankylosing spondylitis, or Crohn's disease were excluded. Results: The major health care cost (excluding drug costs) was represented by hospitalizations, mainly related to PSO /PsA-associated disorders and cardiometabolic disorders. Use of conventional drugs among biologics-naive patients reached 50% in PSO and 80% in PsA; their use decreased following initiation of biological therapy. After the start of biological treatment, the incidence of hospitalization decreased both for PSO (from 12.3% to 3.2% in day hospital regimen and from 2.4% to 0.4% for conventional admission) and for PsA (from 11.1% to 8.1% and from 10.1% to 3.0%, respectively). Mean annual costs for hospitalization before biological treatment were ?217 and ?537 for PSO and PsA, respectively, while mean annual cost for concomitant drugs slightly increased after biologics initiation: from ?249.8 to ?269.4 for PSO and from ?331.8 to ?346.9 for PsA. The major consumption of health care resources occurred in the quarter preceding the beginning of biological treatment. Conclusion: The consumption of health resources is mostly related to hospitalization, seems to peak during the quarter before the beginning of biologics therapies, and subsequently decreases after biologics initiation. Further studies should focus on prescription scheme and economic burden of PSO and PsA in Italy to help optimize health care resources and potentiate services for patients. PMID- 30518997 TI - The therapeutic effects of traditional Chinese medicine Fusu agent in LPS-induced acute lung injury model rats. AB - Purpose: Acute lung injury (ALI) is a common and fatal oxidative stress in the lung, mainly induced by endothelial injury and capillary leakage. In our previous study, "Fusu agent", a traditional Chinese medicine, was found to exert preventive effect on endothelial damage in lipopoly-saccharide (LPS)-induced ALI model rats partially via inhibiting heparanase1 (HPA1) activation and inhibiting the inflammatory factors. However, it is still unknown whether Fusu agent exerts its therapeutic effect in LPS-induced ALI model rats and its potential mechanism. Materials and methods: Rats were injected with LPS (3 mg/kg, intraperitoneally) to induced ALI, and the prepared Fusu agent was given (2, 4 or 6 g/kg) 2 hours after LPS challenge. Twenty-four or 48 hours after Fusu agent administration, the biochemical changes in the plasma and lung tissues and the morphological/histological changes in the lung associated with inflammation and injury were evaluated. Human umbilical vein endothelial cells (HUVECs) were employed to confirm the therapeutic effects of Fusu agent and investigate its mechanisms, that is, affecting ROS accumulation, mitochondrial transmembrane potential (MTP) maintenance and decreasing the expression levels of HPA1. Results: Administration of Fusu agent obviously improved the lung injury and recovered vascular endothelium loss and injury. CD31 signal, which is a specific marker for endothelial vascular lesions, was decreased after Fusu agent treatment in LPS-induced ALI model rats, indicating its therapeutic effect against endothelial surface layer injury. Meanwhile, Fusu agent also decreased HPA1 expression and inflammatory responses. In vitro, Fusu agent-medicated serum decreased injury and cell death induced by LPS in HUVECs by stabilizing MTP and decreasing the leakage of lactate dehydrogenase. Consistently, Fusu agent medicated serum downregulated HPA1 induced by LPS stimulation. Conclusion: These findings suggest that Fusu agent exerts its therapeutic effect in both LPS induced ALI model rats and HUVECs potentially via suppressing HPA1 expression, and thus exerts prosurvival effect via maintaining MTP and attenuating cell injury. PMID- 30518998 TI - Risankizumab: an anti-IL-23 antibody for the treatment of psoriasis. AB - Risankizumab, a fully human IgG monoclonal antibody inhibitor of IL-23, is a therapeutic agent currently in late stage development for use in the treatment of moderate-to-severe plaque psoriasis. It is a biologic agent similar to guselkumab and tildrakizumab which targets IL-23 specifically, and has been primarily developed for use in moderate-to-severe psoriasis. USA-based pharmaceutical company Abbvie submitted it for a Biologics License Application to the US Food and Drug Administration (FDA) in April 2018. Risankizumab is the result of a collaboration between the German company Boehringer Ingelheim and Abbvie, which together are leading the future development and commercialization of risankizumab globally. The results from Phase I to Phase III clinical trials of risankizumab show it is highly effective and its FDA-approval in 2018 is likely. In this article we provide an independent expert opinion on the efficacy and safety of risankizumab in psoriasis based on a full review of the literature. PMID- 30518999 TI - CTL019 (tisagenlecleucel): CAR-T therapy for relapsed and refractory B-cell acute lymphoblastic leukemia. AB - Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsed/refractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractory/relapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies. PMID- 30519000 TI - A study on screening and antitumor effect of CD55-specific ligand peptide in cervical cancer cells. AB - Background: To improve the targeting ability of antitumor drugs, we identified the antigens with high expression on the surface of tumor cells associated with tumor escape, such as the complement regulatory protein CD55 molecule, which is also known as the decay accelerating factor. In this study, phage display technology was used to screen and identify CD55-specific ligand peptide (CD55sp) bound to CD55 molecule on the surface of cervical cancer HeLa cells. We then explored the role of this peptide in inhibiting the growth of cervical cancer cells in vitro. Our characterization of CD55sp will provide implication for tumor target therapy. Methods: The phage bound to the surface of HeLa cells were isolated by phage display technology. Positive phage clones were identified by ELISA. Phage was then amplified and determined by agarose gel electrophoresis after monoclonal DNA extraction. DNA sequencing and bioinformatical analysis were conducted to obtain specific ligand peptides. Flow cytometry and immunofluorescence were used to measure the expression of CD55 molecule on the surface of tumor and normal cells. Subsequently, the effects of CD55sp on the proliferation and apoptosis of HeLa and SiHa cells were determined by Cell Counting Kit-8 (CCK-8), flow cytometry, and TUNEL assay, respectively. The morphology of apoptotic cells was examined by electron microscope. The distribution of Cleaved caspase-3 was detected by immunofluorescence. The expression of bcl-2 and Cleaved caspase-3 were determined by Western blot. Results: The results showed that the peptide (QVNGLGERSQQM) can bind to the CD55 molecule on the surface of cervical cancer HeLa and SiHa cells as a ligand peptide. It can also effectively inhibit the proliferation of cervical cancer cells and induce cell apoptosis. Conclusion: This study demonstrates that CD55sp screened by phage display technology plays a strong antitumor role. PMID- 30519001 TI - Has the quality of physiotherapy care in patients with Whiplash-associated disorders (WAD) improved over time? A retrospective study using routinely collected data and quality indicators. AB - Purpose: To develop valid quality indicators (QIs) for physiotherapy care based on best available evidence, and to use these QIs to explore trends in the quality of physiotherapy care of patients with Whiplash-associated disorders (WAD) using guideline-based routinely collected data (RCD) gathered between 1996 and 2011. Materials and methods: The study consisted of two phases: 1) development of QIs and 2) analysis of patient records. A set of QIs was developed based on recommendations in the scientific literature and the Dutch Clinical Practice Guideline (CPG) "Physiotherapy Management and WAD". QIs were expressed as percentages, allowing target performance levels to be defined (>=80% or <=30% depending on whether desired performance required a high or low score on a QI). We then analyzed WAD patient data (N = 810) collected over a period of 16 years in two physiotherapy practices, separating patients into two groups defined as before (Group A 1996-2002; n = 353) and after (Group B 2003-2011; n = 457) implementation and transition to the Dutch CPG "Physiotherapy Management and WAD". Results: Using an iterative process and input from both experts and users, 28 QIs were developed and subsequently classified per step of the clinical reasoning process for physiotherapy care. Based on 16 years of RCD, we found that the clinical reasoning process differed significantly (P <= 0.05) between the groups, in favor of Group B. Twelve of the 25 indicators (48.0%) in Group A and 19 of 26 indicators (73.1%) in Group B met predetermined performance targets. The number of target indicators also differed significantly between groups, favoring Group B (P <= 0.05). Conclusion: A preliminary set of novel QIs was developed. Using RCD and these QIs, we conclude that physiotherapy care in our study setting improved over the period 1996-2011. Furthermore, the QIs met the performance targets set for the clinical reasoning process after the transition to the Dutch CPG "Physiotherapy Management and WAD". PMID- 30519002 TI - Disruption in time projection and non-adherence to long-term therapies. AB - Objective: Patients' non-adherence to medical prescriptions is a crucial issue in contemporary medicine because it can jeopardize care efficacy. Non-adherence is especially frequent in patients with chronic diseases. In this article, we propose that a particular condition, which we call disruption in time projection, is a cause of non-adherence to medication therapies in chronic diseases. Methods: A questionnaire was administered to 120 hospitalized people with type 2 diabetes addressing three psychological constructs defining time projection: patience/impatience in a fictive monetary scenario (preferring to receive ?1,500 in 1 year or ?500 today), magnitude of temporal horizon (greater or lesser ability to imagine future events) and perception of the degree of physical similarity of current self to self at 1 year, 5 years and 10 years from the present. In addition, the questionnaire evaluated adherence to medication, social deprivation and depression. Results: In the multivariate analyses, two factors were associated with adherence to medication: patience (P<0.001) and long temporal horizon (P=0.006). Two factors were associated with HbA1c >=8% (64 mmol/mol): non-adherence to medication (P=0.003) and short temporal horizon (P=0.011). Three factors were associated with long temporal horizon: adherence to medication (P<0.001), patience (P<0.001) and the existence of grandchildren (P=0.002). Social deprivation (P<0.001), non-adherence (P<0.001), female gender (P=0.002) and short temporal horizon (P=0.050) were associated with impatience. Finally, an association of adherence to expected similarity in the future to current self, impatience, short temporal horizon, social deprivation and depression was also shown in a multiple correspondence analysis. Conclusion: What we termed a disruption in time projection may be a unique determinant for non adherence to long-term therapy and, therefore, may influence the outcome of chronic diseases. We hypothesize that this is involved in both intentional and unintentional non-adherence and that it represents the loss of a protective mechanism. If this novel concept is to be confirmed in other settings and generalized to other chronic diseases, the recognition of its role in disease prognosis may help orient the teaching and practice of medicine. PMID- 30519003 TI - Association of diabetes-related self-care activities with glycemic control of patients with type 2 diabetes in Pakistan. AB - Objective: Association of various self-care activities on glycemic control of people with diabetes (PWD) in Pakistan is yet to be explored. The current study aimed to evaluate the association of various diabetes-related self-care activities with glycated hemoglobin (HbA1c) levels and to examine the predictive relationship of patients' demographic variables with their self-care activities. Patients and methods: A cross-sectional study was conducted on adult PWD (N=218) who were diagnosed with type 2 diabetes mellitus of at least 1 year duration. Self-care activities were examined by using the Urdu version of Diabetes Self management Questionnaire. Linear regression analysis was conducted to examine the significant predictors for diabetes-related self-care activities and glycemic control. Results: Mean age of the patients was 50.77+/-13.3 years. Poor glycemic control (HbA1c $7%) was observed in majority of the patients (83%). Linear regression analysis revealed that glucose management (beta=-0.44; 95% CI -0.438, 0.209; P<0.001) was the strongest predictor for low levels of patients' HbA1c, followed by dietary control (beta=-0.19; 95% CI -0.248, -0.018; P=0.024) and physical activity (beta=-0.17; 95% CI -0.165, -0.023; P=0.010), respectively. Linear regression analysis showed that use of oral hypoglycemic agents only (beta=-0.218; 95% CI -0.956, -0.200; P=0.003) and higher education level (beta=0.204; 95% CI 0.138, 0.777; P=0.005) were significant predictors for higher scores of patients' self-care activities. Conclusion: The findings support that PWD having better self-reported self-care activities achieve better glycemic control. Patients' self-care activities should be monitored on a regular basis, especially for those who are at risk of poor glycemic control. PMID- 30519005 TI - Delivering bad news: patient's perspective and opinions. AB - Purpose: The aim of our research was to gain knowledge about patients' opinions, experiences, and preferences with regard to the way the news is being delivered to them. Materials and methods: Detailed research was carried out on a group of 314 patients using the CAWI (Computer-Assisted Web Interview) technique. Adult responders who had earlier received bad news were questioned about their opinion about the way the doctor acted while delivering bad news and how he did it. Results: Patients, who define the following aspects of their visit as negative/lacking: 1) doctor's behavior in the moment of delivering bad news, 2) amount of time devoted to the visit, 3) lack of doctor's attention, 4) usage of medical terminology, 5) doctor's honesty, 6) emotional and cognitive support from the doctor, more often tend to change the doctor in charge of their therapy or decide to cease the medical treatment. Conclusion: Doctors' behavior and the way they deliver news to patients are key elements that strongly influence patients' future therapy. It makes an impact on patient's decision whether to continue or cease the treatment. In the first case, it also leads the patient to choose to continue the treatment under the guidance of the same specialist or to find another one. The data that we acquired and that we will discuss below will form the basis for editing a communication protocol concerning delivering bad news. It is necessary to create such a protocol in order to improve the quality of communication with patients, especially as regards delivering bad news to them. PMID- 30519004 TI - Treatment of relapsed refractory multiple myeloma: which new PI-based combination treatments do patients prefer? AB - Background and objectives: This study describes preferences of German relapsed refractory multiple myeloma (RRMM) patients with novel proteasome inhibitor-based combination treatments. Methods: Patients with a minimum age of 18 years and a diagnosis of RRMM were included. Their preferences were assessed using a discrete choice experiment design, which was developed based on a literature review and two patient focus group discussions. The final discrete choice experiment design consisted of four attributes, namely "therapy application regimen," "time without progression of disease," "possibility of grade >=3 adverse events (AEs) affecting the blood," and "possibility of grade >=3 AE heart failure." Results: Analysis was based on 84 patients (36.9% females, mean age 62.7 years, mean multiple myeloma disease duration 5.5 years). Among the tested attributes, "therapy application regimen" was assigned the highest importance for treatment decisions (38.8%), the second important attribute was "time without progression of disease" (38.7%), followed by "possibility of AE heart failure" (13.9%) and "possibility of AEs affecting the blood" (8.6%). Patients preferred oral intake once a day and once a week over other application modes such as oral intake once a day and once a week plus twice-weekly infusions. Furthermore, they preferred longer disease progression-free time and lower risk of grade >=3 AEs. The highest overall utility was derived for ixazomib + lenalidomide + dexamethasone (utility: 3.218), compared with lenalidomide + dexamethasone (2.769), and carfilzomib + lenalidomide + dexamethasone (1.928). Conclusion: RRMM patients prefer treatments with an all-oral application, a longer disease-progression-free time, and a lower probability of AEs. If patients face tradeoffs, they accept a lower progression free time and/or higher AE rates to get an all-oral therapy. PMID- 30519006 TI - The impact of fatwas on patients' acceptance of enamel matrix derivatives for periodontal regeneration in Saudi Arabia. AB - Background: Since the introduction of enamel matrix derivatives (EMD) (Emdogain(r)), it has not been allowed to be used in Saudi Arabia due to the religious restriction on porcine products. This study was conducted to determine the impact of the fatwas permitting the use of EMD and to assess the general perception of using bone-grafting materials in Jeddah, Saudi Arabia. Materials and methods: This cross-sectional survey study included 213 patients seeking dental treatment at the Faculty of Dentistry Clinics of King Abdulaziz University, Jeddah, Saudi Arabia. They were recruited between September and November 2017. Subjects completed a questionnaire to assess their opinions before and after reading the fatwa about using EMD. Results: Majority of the study subjects (70%) did not accept the use of bone-grafting materials and EMD in periodontal regeneration before reading the fatwas. The highest rate of acceptance was observed for the use of tissues from one's own body (84%) while the biomaterials of porcine origin had the lowest acceptance rate (14.1%). Strong religious belief and low education level were the two key factors responsible for the initial refusal of EMD use before reading the fatwas. Around 45.1% of the participants changed their opinions in favor of EMD use after reading the fatwas and their interpretations. McNemar's test found a statistically significant difference in opinions collected before and after reading the fatwas (P<0.001). Conclusion: A significant impact of the fatwas was found on patients' acceptance of EMD use for periodontal regeneration. We believe reliable interpretations of the fatwas may positively shift patients' attitudes toward using new biomaterials. PMID- 30519007 TI - Patient satisfaction, health care resource utilization, and acute headache medication use with galcanezumab: results from a 12-month open-label study in patients with migraine. AB - Background: Effects of galcanezumab, a monoclonal antibody against calcitonin gene-related peptide, on patient satisfaction, health care resource utilization (HCRU), and acute medication use were evaluated in a long-term, open-label study in patients with migraine. Methods: Patients with episodic (78.9%) or chronic migraine (21.1%) were evaluated in the CGAJ study, an open-label study with 12 month treatment period. Galcanezumab 120 mg (with a loading dose of 240 mg) or 240 mg was administered subcutaneously once a month during treatment period. A self-rated scale, Patient Satisfaction with Medication Questionnaire-Modified (PSMQ-M), was used to measure satisfaction levels. Participants reported HCRU for the previous 6 months at baseline and that which occurred since the patient's last study visit during treatment period. Acute headache medication use for migraine or headache for the past month was self-reported by participants at baseline and at each monthly visit during treatment period. Results: At Months 1, 6, and 12, at least 69% of patients treated with galcanezumab responded positively for overall satisfaction, preference over prior treatments, and less impact from side effects. There were within-group reductions from baseline in migraine-specific HCRU (per 100 person-years) with galcanezumab for health care professional visits (173.4 to 59.6), emergency room visits (20.2 to 4.7), and hospital admissions (3.7 to 0.4) during treatment period. Statistically significant reductions in HCRU were observed for some events. There were significant within-group reductions from baseline in mean number of days/month with acute headache medication use for migraine or headache at each monthly visit during treatment period (overall change: -5.1 for galcanezumab 120 mg/240 mg; p<0.001). Conclusion: Results from this long-term, open-label study suggest that treatment with galcanezumab is likely to lead to high patient satisfaction with treatment as well as meaningful reductions in migraine-specific HCRU and acute headache medication use in people with migraine. PMID- 30519008 TI - Postoperative cognitive dysfunction - current preventive strategies. AB - Improving trends in global health care have resulted in a steady increase in the geriatric population. However, as the population ages, surgery is being performed more frequently in progressively older patients and those with higher prevalence of comorbidities. A significant percentage of elderly patients experience transient postoperative delirium following surgery or long-term postoperative cognitive dysfunction (POCD). Increasing age, educational level, pre-existing mental health, and comorbidities are contributory factors. Comprehensive geriatric assessment provides an objective evaluation on overall medical, social, mental, and functional well-being with scope for preoperative optimization. Preventive strategies for POCD target the surgical and patient-related factors as well as the utilization of the concept of stress-free anesthesia and surgery, that is, Enhanced Recovery After Surgery. This includes care bundles and protocols for the perioperative period which improves outcomes in the elderly. Research on biomarkers of neural injury in POCD is gaining momentum. Pharmacologic agents such as acetylcholine esterase inhibitors promise to have a vital role in the management of POCD but exhibit undesired side effects. Interventions to reduce oxidative stress and neuroinflammation could prove beneficial. Preventive strategies, early recognition, and management of perioperative risk factors seems to be, by far, the best modality to deal with POCD till further progress in therapeutic interventions evolve. PMID- 30519009 TI - Concurrent chemoradiation therapy tailored to the older adults with esophageal cancer: state of the art and the future. AB - Purpose: The aim of this study was to review the published literature addressing the question of whether geriatric assessment (GA) should be routinely applied in the treatment of older adults with esophageal cancer (EC) who have received definitive concurrent chemoradiotherapy (dCRT). Materials and methods: A literature search of PubMed, Embase, and Cochrane Library was performed. Studies that contained original data outlining the inclusion and exclusion criteria, treatment compliance rate, and severe toxicity reports were reviewed. Additionally, criteria from ongoing clinical trials in the World Health Organization and National Institutes of Health registries were reviewed to evaluate the utilization of GA-related domains in elderly EC patients who received dCRT. Results: Twenty-nine studies were identified based on the selection criteria: five were single-arm prospective studies, and the other studies were retrospective studies. All studies used chronological age and performance status as basic descriptors for this subpopulation. The comorbidity index and the malnutrition level were mentioned in several studies. However, factors such as "Demographic data and social support," "Psychology," "Polypharmacy," and "Geriatric syndromes" were not described in any of the included studies. Unfortunately, the results were similar for the registered clinical trials. Finally, treatment compliance and toxicity profile were found to be acceptable in selected elderly EC patients. Conclusion: The current experience for older adults with EC receiving dCRT is mainly based on the results of a series of retrospective studies. Ongoing clinical trials should routinely consider GA-related domains to select appropriate treatments for patients in the future. PMID- 30519010 TI - Structured interdisciplinary bedside rounds, in-hospital deaths, and new nursing home placements among older inpatients. AB - Purpose: Ineffective interdisciplinary communication is linked to many adverse consequences of hospitalization. This study evaluated the effect of SIBR, a model of care that encourages interdisciplinary communication and patient and family participations, on in-hospital deaths and new nursing home (NH) placements. Materials and methods: This before-after study included 3,673 consecutive inpatients of mean age 83.8 years, of whom 93.2% were admitted through the emergency department. After each twice-weekly SIBR session, an interdisciplinary care plan was implemented and recorded on a datasheet attached to the bedside record. Staff unable to participate in SIBR were asked to view the datasheet and to follow the care plan. Logistic regression models were computed for in-hospital deaths and new NH placements. Results: Although SIBR implementation had no effect on in-hospital deaths (OR, 1.00; 95% CI, 0.77-1.29), SIBR increased NH placements among those who survived the hospitalization (n=3,346) in both unadjusted (14.6% vs 9.1%; P<0.001) and adjusted (OR, 1.75; 95% CI, 1.38-2.23) analyses. Conclusion: Although the mechanisms between SIBR implementation and NH placement remain uncertain, SIBR may encourage patients and families to make decisions on placement earlier than they would have otherwise. Models of care aiming to improve communication should be evaluated across diverse services and settings to determine effectiveness and to monitor for adverse findings. PMID- 30519011 TI - Frailty and health care use among community-dwelling older adults with diabetes: a population-based study. AB - Purpose: The aims of this study were to investigate the prevalence of frailty and its relationship with health care use among community-dwelling older adults with diabetes. Methods: We analyzed data from a nationally representative sample of people aged 65 years and above (n=3,203) participating in the 2013 National Health Interview Survey in Taiwan. A total of 719 participants had a history of self-reported physician-diagnosed diabetes. The presence of frailty was determined based on the Fatigue, Resistance, Ambulation, Illness, and Loss of weight (FRAIL) scale proposed by the International Association of Nutrition and Aging. FRAIL scores range from 0 to 5 and are categorized as frail (3-5), pre frail (1-2), and robust (0). Participants were asked whether they had been hospitalized or had visited an emergency department in the past year. Results: Among community-dwelling older adults with diabetes, 9.4% of participants were frail and 35.3 % were pre-frail. After adjustment for other factors, being frail was significantly associated with hospitalization during the past year (OR =5.31, 95% CI =1.87-15.10), whereas being pre-frail was not associated with hospitalization. Both being pre-frail and frail were significantly associated with emergency department visits during the past year (OR =2.64, 95% CI =1.35 5.17 and OR =4.05, 95% CI =1.31-12.49, respectively) after adjustment for other factors. Conclusion: Our results highlight the high prevalence of frailty in community-dwelling older adults with diabetes. Furthermore, being frail is associated with a greater burden of hospitalizations and emergency department visits. PMID- 30519012 TI - A posturographic procedure assessing balance disorders in Parkinson's disease: a systematic review. AB - Postural instability is common in Parkinson's disease (PD), often contributing to falls, injuries, and reduced mobility. In the clinical setting, balance disorder is commonly diagnosed using clinical tests and balance scales, but it is suggested that the most sensitive measurement is the force platform. The aim of this systematic review was to summarize the methods and various posturographic procedures used to assess the body balance and gait in PD. A systematic review was conducted of papers published from 2000 to 2017. Databases searched were PubMed and EBSCO. Studies must have involved patients with PD, used force platform or motion analysis system as a measurement tool, and described posturographic procedure. The Physiotherapy Evidence Database (PEDro) scale was used to assess the methodological quality of the included studies. A total of 32 studies met the inclusion criteria. The PEDro scores ranged from 5 to 7 points. The analysis of the objective methods assessing balance disorders revealed a large discrepancy in the duration and procedures of measurements. The number of repetitions of each trial fluctuated between 1 and 8, and the duration of a single trial ranged from 10 to 60 seconds. Overall, there are many scales and tests used to assess the balance disorders and disabilities of people with PD. Although in many included studies the authors have used posturography as a method to evaluate the postural instability of PD patients, the results are contradictory. To solve this issue, it is indicated to establish a "gold standard" of procedures of measures of balance. PMID- 30519013 TI - The association of elevated circulating endocan levels with lung function decline in COPD patients. AB - Background: Endocan is thought to be a novel inflammatory marker that is associated with a variety of inflammatory diseases. However, its role in the pathogenesis of COPD remains unclear. This study aims to explore the potential role of endocan in COPD. Methods: In total, 27 healthy volunteers, 55 COPD patients and 36 acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients were included in the study. Basic demographic characteristics, clinical features and blood samples were collected. Magnetic luminex screening assays were used to detect the concentration of endocan, Fas and Fas ligand (Fas L) in plasma. Differences between groups were compared using an Independent sample t-test, Welch's t-test, chi-squared test and Wilcoxon rank sum test. The correlations of plasma endocan with lung function parameters, Fas and Fas-L were analyzed by Pearson's partial correlation test (adjusted for age, gender, body mass index and smoking history) and multiple linear regression. Results: Plasma endocan levels in COPD patients were significantly higher than those in healthy volunteers (509.7+/-18.25 pg/mL vs 434.8+/-18.98 pg/mL (P=0.0124)), and AECOPD patients had the highest levels of endocan (524.7+/-27.18 pg/mL). Correlation analysis showed that circulating endocan had a negative correlation to FEV1/FVC, FEV1/predictive and FVC (adjusted r=-0.213, P=0.03; adjusted r=-0.209, P=0.034; and adjusted r=-0.300, P=0.002, respectively), and had a positive correlation to Fas (adjusted r=0.280, P=0.004). Conclusion: Our study shows that elevated circulating endocan levels are associated with reduced lung ventilation function in COPD and AECOPD patients. In addition, endocan may influence apoptosis in COPD, suggesting that endocan may play a role in COPD pathogenesis. PMID- 30519014 TI - Mitochondrial functioning abnormalities observed in blood platelets of chronic smoke-exposed guinea pigs - a pilot study. AB - Background: COPD represents a major global health issue, which is often accompanied by cardiovascular diseases. A considerable body of evidence suggests that cardiovascular risk is elevated by the activation of blood platelets, which in turn is exacerbated by inflammation. As reactive oxygen species are believed to be an important factor in platelet metabolism and functioning, the aim of our study was to perform a complex assessment of mitochondrial function in platelets in chronic smoke exposed animals with COPD-like lung lesions. Materials and methods: Eight-week-old, male Dunkin Hartley guinea pigs (the study group) were exposed to the cigarette smoke from commercial unfiltered cigarettes (0.9 mg/cig of nicotine content) or to the air without cigarette smoke (control group), using the Candela Constructions(r) exposure system. The animals were exposed for 4 hours daily, 5 days a week, with 2*70 mL puff/minute, until signs of dyspnea were observed. The animals were bled, and isolated platelets were used to monitor blood platelet respiration. The mitochondrial respiratory parameters of the platelets were monitored in vitro based on continuous recording of oxygen consumption by high-resolution respirometry. Results: An elevated respiration trend was observed in the LEAK-state (adjusted for number of platelets) in the smoke-exposed animals: 6.75 (5.09) vs 2.53 (1.28) (pmol O2/[s ? 1108 platelets]); bootstrap-boosted P 1alpha=0.04. The study group also demonstrated lowered respiration in the ET-state (normalized for protein content): 12.31 (4.84) vs 16.48 (1.72) (pmol O2/[s ? mg of protein]); bootstrap-boosted P 1alpha=0.049. Conclusion: Our results suggest increased proton and electron leak and decreased electron transfer system capacity in platelets from chronic smoke-exposed animals. These observations may also indicate that platelets play an important role in the pathobiology of COPD and its comorbidities and may serve as a background for possible therapeutic targeting. However, these preliminary outcomes should be further validated in studies based on larger samples. PMID- 30519015 TI - Reinforcement of calcium phosphate cement using alkaline-treated silk fibroin. AB - Background: Bone cement plays an important role in the treatment of osteoporotic vertebral compression fractures. Calcium phosphate cement (CPC) is a potential alternative to poly(methyl methacrylate), currently the gold standard of bone cements. However, the poor mechanical properties of CPCs limit their clinical applications. The objective of this study was to develop reinforced CPCs for minimally invasive orthopedic surgeries by compositing silk fibroin (SF) with alpha-tricalcium phosphate. Methods: SF solution was treated with calcium hydroxide and characterized by Zeta potential analyzer and Fourier transform infrared spectroscopy. The alkaline-treated SF (tSF) was com-posited with alpha tricalcium phosphate to obtain tSF/CPC composite, which was characterized using mechanical tests, scanning electron microscopy, handling property and biocompatibility tests, and sheep vertebral augmentation tests. Results: Upon treatment with calcium hydroxide, larger SF particles and more abundant negative charge appeared in tSF solution. The tSF/CPCs exhibited a compact structure, which consisted of numerous SF -CPC clusters and needle-like hydroxyapatite (HAp) crystals. In addition, high transition rate of HAp in tSF/CPCs was achieved. As a result, the mechanical property of tSF/ CPC composite cements was enhanced remarkably, with the compressive strength reaching as high as 56.3+/-1.1 MPa. Moreover, the tSF/CPC cements showed good injectability, anti-washout property, and decent biocompatibility. The tSF/CPCs could be used to augment defected sheep vertebrae to restore their mechanical strength. Conclusion: tSF/CPC may be a promising composite bone cement for minimally invasive orthopedic surgeries. PMID- 30519016 TI - Silica nanoparticles trigger hepatic lipid-metabolism disorder in vivo and in vitro. AB - Background: As a promising nanocarrier in biomedical fields, silica nanoparticles (SiNPs) could transfer from the circulatory system to multiple organs. Among these, blood-liver molecular exchange is a critical factor in biological response to NPs. However, the potential effect of SiNPs on hepatic lipid metabolism is unclear. In this study, we employed three models to attempt discover whether and how SiNPs disturb hepatic lipid metabolism in vivo and in vitro. Methods: Firstly we used ICR mice models to evaulated the effects of SiNPs on the serum and hepatic lipid levels through repeated intravenous administration, meanwhile, the protein expressions of protein markers of lipogenesis (ACC1 and FAS), the key enzyme of fatty acid beta-oxidation, CPT1A,and leptin levels in liver were detected by western blot. For verification studies, the model organism zebrafish and cultured hepatic L02 cells were further performed. The TLR5 and adipocytokine signaling pathway were verified. Results: Inflammatory cell infiltration and mild steatosis induced by SiNPs were observed in the liver. Cholesterol, triglyceride, and low-density lipoprotein cholesterol levels were elevated significantly in both blood serum and liver tissue, whereas the ratio of high-density:low-density lipoprotein cholesterol was markedly decreased. Protein markers of lipogenesis (ACC1 and FAS) were elevated significantly in liver tissue, whereas the key enzyme of fatty acid beta-oxidation, CPT1A, was decreased significantly. Interestingly, leptin levels in the SiNP-treated group were also elevated markedly. In addition, SiNPs caused hepatic damage and steatosis in zebrafish and enhanced hyperlipemia in high-cholesterol diet zebrafish. Similarly, SiNPs increased the release of inflammatory cytokines (IL1beta, IL6, IL8, and TNFalpha) and activated the TLR5-signaling pathway in hepatic L02 cells. Conclusion: In summary, our study found that SiNPs triggered hyperlipemia and hepatic steatosis via the TLR5-signaling pathway. This suggests that regulation of TLR5 could be a novel therapeutic target to reduce side effects of NPs in living organisms. PMID- 30519017 TI - Mechanisms of deformable nanovesicles based on insulin-phospholipid complex for enhancing buccal delivery of insulin. AB - Background: Non-injectable delivery of peptides and proteins are not feasible due to its large molecular, high hydrophilic and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. Purpose: The objective of this study was to propose a novel protein delivery strategy to vanquish the poor efficacy of buccal mucosa delivery systems for protein delivery and then investigate the detailed mechanisms of the enhanced buccal delivery of protein, using insulin as a model drug. Materials and methods: Insulin-phospholipid complex combined with deformable nanovesicles (IPC-DNVs) were prepared, using deformable nanovesicles based on insulin (INS-DNVs) and conventional nanovesicles based on insulin-phospholipid complex (IPC-NVs) as references. Besides, their physicochemical characterization, in vitro transport behavior, in vivo bioactivity and hypoglycemic effect were systematically characterized and compared. Finally, we evaluated the in vivo safety of IPC-DNVs. Results: First, IPC-DNVs increased insulin permeability through deposition of the IPC and deformability of the DNVs, which was revealed by an in vitro mucosal permeation study. Second, DNVs could act as a drug carrier and penetrate the mucosa to reach the receiver medium as intact nanovesicles, which was supported by the observation of intact nanovesicles in the receiver medium through transmission electron microscopy (TEM). Third, IPC-DNVs exhibited both transcellular and paracellular transport in the form of IPC and DNVs, respectively, which was proved by confocal laser scanning microscopy (CLSM). Unlike the other two formulations, IPC-DNVs exhibited a sustained mild hypoglycemic effect, with a relative bioavailability (Fp) of 15.53% (3.09% and 1.96% for INS-DNVs and IPC-NVs, respectively). Furthermore, buccal administration of IPC-DNVs resulted in no visible mucosal irritation to the buccal mucosa. Conclusion: Our work reveals the mechanisms underlying the enhanced buccal delivery of IPC-DNVs: the DNVs facilitate penetration through the main barrier, and the deposition of IPC enhances buccal absorption. Our results and proposed mechanisms could be an important reference to understand other nanocarriers based on protein (peptide)-phospholipid complexes that penetrate the mucosa and provide a theoretical basis for the future development of buccal delivery systems for insulin. PMID- 30519018 TI - A review on nanosystems as an effective approach against infections of Staphylococcus aureus. AB - Staphylococcus aureus (S. aureus) is an important zoonotic bacteria and hazardous for the health of human beings and livestock globally. The characteristics like biofilm forming, facultative intracellular survival, and growing resistance of S. aureus pose a great challenge to its use in therapy. Nanoparticles are considered as a promising way to overcome the infections' therapeutic problems caused by S. aureus. In this paper, the present progress and challenges of nanoparticles in the treatment of S. aureus infection are focused on stepwise. First, the survival and infection mechanism of S. aureus are analyzed. Second, the treatment challenges posed by S. aureus are provided, which is followed by the third step including the advantages of nanoparticles in improving the penetration and accumulation ability of their payload antibiotics into cell, inhibiting S. aureus biofilm formation, and enhancing the antibacterial activity against resistant isolates. Finally, the challenges and future perspective of nanoparticles for S. aureus infection therapy are introduced. This review will help the readers to realize that the nanosystems can effectively fight against the S. aureus infection by inhibiting biofilm formation, enhancing intracellular delivery, and improving activity against methicillin-resistant S. aureus and small colony variant phenotypes as well as aim to help researchers looking for more efficient nano-systems to combat the S. aureus infections. PMID- 30519019 TI - Nanotechnology, an alternative with promising prospects and advantages for the treatment of cardiovascular diseases. AB - Cardiovascular diseases (CVDs) are one of the most important causes of mortality and affecting the health status of patients. At the same time, CVDs cause a huge health and economic burden to the whole world. Although a variety of therapeutic drugs and measures have been produced to delay the progress of the disease and improve the quality of life of patients, most of the traditional therapeutic strategies can only cure the symptoms and cannot repair or regenerate the damaged ischemic myocardium. In addition, they may bring some unpleasant side effects. Therefore, it is vital to find and explore new technologies and drugs to solve the shortcomings of conventional treatments. Nanotechnology is a new way of using and manipulating the matter at the molecular scale, whose functional organization is measured in nanometers. Because nanoscale phenomena play an important role in cell signal transduction, enzyme action and cell cycle, nanotechnology is closely related to medical research. The application of nanotechnology in the field of medicine provides an alternative and novel direction for the treatment of CVDs, and shows excellent performance in the field of targeted drug therapy and the development of biomaterials. This review will briefly introduce the latest applications of nanotechnology in the diagnosis and treatment of common CVDs. PMID- 30519020 TI - Curcumin nanoemulsion as a novel chemical for the treatment of acute and chronic toxoplasmosis in mice. AB - Background: The aim of this study was to prepare curcumin nanoemulsion (CR-NE) to solve the problems associated with poor water solubility and low bioavailability of CR and to test its efficiency in the treatment of acute and chronic toxoplasmosis in mouse models. Materials and methods: CR-NE 1% was prepared using spontaneous emulsification by soybean as oil phase; a mixture of Tween 80 and Tween 85 as surfactant; ethanol as cosurfactant and distilled water. Particle size and zeta potential of NE were assessed using Nano-ZS90 dynamic light scattering. Stability testing of NE was assessed after storage for 2 months at room temperature. In vivo experiments were carried out using 50 BALB/c mice inoculated with virulent RH strain (type I) and 50 BALB/c mice inoculated with avirulent Tehran strain (type II) of Toxoplasma gondii and treated with CR-NE (1% w/v), CR suspension (CR-S, 1% w/v), and NE without CR (NE-no CR). Results: The mean particle size and zeta potential of CR-NE included 215.66+/-16.8 nm and 29.46+/-2.65 mV, respectively, and were stable in particle size after a three freeze-thaw cycle. In acute phase experiment, the survival time of mice infected with RH strain of T. gondii and treated with CR-NE extended from 8 to 10 days postinoculation. The differences were statistically significant between the survival time of mice in CR-NE-treated group compared with negative control group (P<0.001). Furthermore, CR-NE significantly decreased the mean counts of peritoneum tachyzoites from 5,962.5+/-666 in negative control group to 627.5+/-73 in CR-NE-treated mice (P<0.001). Growth inhibition rates of tachyzoites in peritoneum of mice receiving CR-NE, CR-S, and NE-no CR included 90%, 21%, and 11%, respectively, compared with negative control group. In chronic phase experiment, the average number and size of tissue cysts significantly decreased to 17.2+/-15.6 and 31.5+/-6.26 um, respectively, in mice inoculated with bradyzoites of T. gondii Tehran strain and treated with CR-NE compared with that in negative control group (P<0.001). Decrease of cyst numbers was verified by downregulation of BAG1 in treatment groups compared with negative control group with a minimum relative expression in CR-NE (1.12+/-0.28), CR-S (11.76+/-0.87), and NE-no CR (14.67+/-0.77), respectively, (P<0.001). Conclusion: Results from the current study showed the potential of CR-S and CR-NE in treatment of acute and chronic toxoplasmosis in mouse models for the first time. However, CR-NE was more efficient than CR-S, and it seems that CR-NE has a potential formula for the treatment of acute and chronic toxoplasmosis, especially in those with latent bradyzoites in brain. PMID- 30519021 TI - Aerosol-synthesized siliceous nanoparticles: impact of morphology and functionalization on biodistribution. AB - Introduction: Siliceous nanoparticles (NPs) have been extensively studied in nanomedicine due to their high biocompatibility and immense biomedical potential. Although numerous technologies have been developed, the synthesis of siliceous NPs for biomedical applications mainly relies on a few core technologies predominantly intended to produce spherical-shaped NPs. Methods: In this context, the impact of different morphologies of siliceous NPs on biodistribution in vivo is limited. In the present study, we developed a novel technique based on an aerosol silane reactor to produce sintered silicon NPs of similar size but different surface areas due to distinct spherical subunits. Silica-converted particles were functionalized for radiolabeling with copper-64 (64Cu) to systematically analyze their behavior in the passive targeting of A431 tumor xenografts in mice after intravenous injection. Results: While low nonspecific uptake was observed in most organs, the majority of particles were accumulated in the liver, spleen, and lung. Depending on the morphologies and function alization, significant differences in the uptake profiles of the particles were observed. In terms of tumor uptake, spherical shapes with lower surface areas showed the highest accumulation and tumor-to-blood ratios of all investigated particles. Conclusion: This study highlights the importance of shape and fuctionalization of siliceous NPs on organ and tumor accumulation as significant factors for biomedical applications. PMID- 30519022 TI - Nanoparticle-modified chitosan-agarose-gelatin scaffold for sustained release of SDF-1 and BMP-2. AB - Background: Stromal cell-derived factor 1 (SDF-1) is an important chemokine for stem cell mobilization, and plays a critical role in mobilization of mesenchymal stem cells (MSCs). Bone morphogenetic protein 2 (BMP-2) plays a critical role in osteogenesis of MSCs. However, the use of SDF-1 and BMP-2 in bone tissue engineering is limited by their short half-lives and rapid degradation in vitro and in vivo. Methods: The chitosan oligosaccharide/heparin nanoparticles (CSO/H NPs) were first prepared via self-assembly. Chitosan-agarose-gelatin (CAG) Scaffolds were then synthesized via gelation technology using cross-linked chitosan, agarose, and gelatin, and were modified by CSO/H NPs. The encapsulation efficiency and release kinetics of SDF-1 and BMP-2 were quantified using an enzyme-linked immunosorbent assay. A CCK-8 assays were used to evaluate biocompatibility of NP-modified scaffolds. The biological activity of the loaded SDF-1 and BMP-2 was evaluated using the transwell migration assay and osteogenic induction assay. An animal MSC recruitment model was used to study the ability of SDF-1 released from NP-modified scaffolds to induce migration of MSCs. Results: In this study, we developed a novel nanoparticle-modified CAG scaffold for the delivery of SDF-1 and BMP-2. CCK-8 assays demonstrated excellent biocompatibility of NP-modified scaffolds. In addition, we investigated the release of SDF-1 and BMP-2 from NP-modified scaffolds, and evaluated the effect of released SDF-1 on MSC migration. The effect of released BMP-2 on MSC osteogenesis was also examined. In vitro cell migration assays showed that SDF-1 released from NP modified scaffolds retained its migration activity; osteogenesis studies demonstrated that released BMP-2 exhibited a strong ability to induce differentiation towards osteoblasts. Our in vivo recruitment assays showed continuous chemotactic response of MSCs to SDF-1 released from the NP-modified scaffold. Conclusion: The simplicity of synthesizing CSO/H NP-modified CAG scaffolds, combined with its high cytokine loading capacity and sustained release effect, renders NP-modified CAG scaffold an attractive candidate for sustained release of SDF-1 and BMP-2 to promote bone repair and regeneration. PMID- 30519023 TI - Peritumoral implantation of hydrogel-containing nanoparticles and losartan for enhanced nanoparticle penetration and antitumor effect. AB - Background and purpose: Nanoparticle-loaded hydrogels - localized drug delivery devices containing a combination of therapeutic nanoparticles and implantable hydrogel - have been recipients of increased focus and interest for cancer treatment. However, it is difficult for the released nanoparticles to penetrate deeply into tumors because of the dense collagen network in the tumor extracellular matrix, which greatly limits their antitumor effect. We hypothesized that the implantation of a hydrogel loaded with both nanoparticles and losartan (Los) might enhance penetration because Los has been proven to effectively reduce collagen levels in various tumors. Herein, we developed a nanoparticle/Los-loaded hydrogel system and evaluated the intratumoral distribution and anticancer effect after peritumoral implantation of nanoparticles. Methods: Fluorescent polystyrene nanoparticles (FPNPs, size ~100 nm) and Los were simultaneously encapsulated in a polyethylene glycol (PEG) hydrogel to form the FPNP/Los-loaded hydrogel. After peritumoral implantation in 4T1 tumor-bearing mice for 2 weeks, intratumoral distributions of FPNPs and collagen level were determined. Based on the results, liposomal doxorubicin (Doxil, ~100 nm) was subsequently substituted for FPNPs in the hydrogel. The cellular uptake and cytotoxicity of the Doxil/Los-loaded hydrogel were studied, and the in vivo antitumor efficacy after peritumoral implantation was evaluated. Results: Compared with a standard FPNP-loaded hydrogel, the FPNP/Los-loaded hydrogel resulted in enhanced penetration and reduced collagen levels after implantation. Thereafter, the potential of a Doxil/Los-loaded hydrogel for cancer treatment was studied. Doxorubicin was released from the hydrogel and induced effective cytotoxicity against 4T1 cells. The Doxil/Los-loaded hydrogel showed synergistic antitumor effects in 4T1 tumor-bearing mice and was more effective at tumor inhibition than the Doxil-loaded hydrogel. Conclusion: This study provides a proof of principle that the implantation of nanoparticles/Los-loaded hydrogel can increase the intratumoral distribution and antitumor efficacy of nanoparticles, owing to collagen depletion by Los. Future studies may build on this strategy for enhanced tumor penetration of nanoparticles. PMID- 30519024 TI - Intravenous buprenorphine/naloxone and concomitant oral pregabalin misuse: a case report. AB - Opioid misuse and dependence are major medical and social concerns worldwide. Buprenorphine/naloxone combination (BNC) is a drug that has misuse potential and is used to treat opioid dependence, including buprenorphine and naloxone. Buprenorphine shows its pharmacological effects by binding to opioid receptors. Buprenorphine is a partial agonist and has smaller maximal effects compared to those of full agonists (heroin, methadone). Naloxone is a non-selective opiate antagonist added to buprenorphine for the prevention of intravenous diversion. BNC is used in the treatment of opioid dependence for detoxification and maintenance. The drug should be used as a sublingual film tablet. Pregabalin is used in the treatment of neuropathic pain, epilepsy and anxiety disorders. It is increasingly being reported as possessing a potential for misuse. In this article, we present a case of intravenous BNC and concomitant oral pregabalin misuse that developed in a monitored and treated patient for the reason of opioid dependence. PMID- 30519025 TI - The Chinese herbal formula Fuzheng Quxie Decoction attenuates cognitive impairment and protects cerebrovascular function in SAMP8 mice. AB - Purpose: This study was designed to explore the underlying mechanism of action for a Fuzheng Quxie Decoction (FQD) in Alzheimer's disease (AD), to validate its neuroprotective effects, and to provide experimental support for its predicted mechanism of action. Methods: An integrative approach to network pharmacology was performed to predict the mechanism of action for treatment of AD with FQD. The predicted mechanism was validated in SAMP8 mice. Results: With predicted putative FQD targets and a collection of AD-related genes, 245 possible regulatory targets of FQD were identified for the treatment of AD. Pathway-enrichment analysis for the possible regulatory targets indicated that vascular endothelial growth factor (VEGF) and VEGF-receptor signaling were pivotal in the treatment of AD with FQD. In vivo experiments confirmed the neuroprotective effect and the predicted mechanism of action for treatment of AD with FQD. Conclusion: This study contributes to an understanding of the neuroprotective effect of FQD and its potential mechanism of action for the treatment of AD. PMID- 30519026 TI - Economic analysis of acupuncture for migraine prophylaxis. AB - Background: Acupuncture has become a viable option for migraine prophylaxis in Europe; however, despite its wide use, more data on the short- and long-term cost effectiveness are needed when considering the perspectives of a paying third party, the patient, and of society in general. The aim was to evaluate the cost and effectiveness of adjuvant acupuncture to pharmacologic treatment vs pharmacologic treatment alone in migraine patients after a 3-month acupuncture course and a 6-month follow-up from all perspectives. Methods: The study involved an open-label randomized clinical trial of patients receiving acupuncture (n=42), and a waiting list control group (n=44). The number of migraine days during the last 28 days, as well as direct and indirect costs were considered. The trial was registered under DRKS00009803. Results: The total cost per patient reached ?696 vs ?285 after 3 months of acupuncture and ?66 vs ?132 in the acupuncture and control groups after a 6-month follow-up, respectively (P=0.071). The trends observed in effectiveness and costs from all perspectives are discussed. Conclusion: The inclusion of acupuncture in health care results beneficial mainly for its observed trend in reduced losses of productivity and income, with the latter often exceeding the costs of acupuncture treatment. As such, acupuncture may be recommended as an adjuvant treatment in migraine prophylaxis to standard pharmacotherapy. PMID- 30519027 TI - Aripiprazole in acute treatment of children and adolescents with autism spectrum disorder: a systematic review and meta-analysis. AB - Background: Recent randomized controlled trials indicated that aripiprazole was the effective treatment for children and adolescents with autism spectrum disorder (ASD). Objective: This study systematically reviewed the efficacy, acceptability and tolerability of aripiprazole in treatment of ASD children and adolescents. Data sources: Electronic search of databases including, Scopus, PubMed, CINAHL and Cochrane Controlled Trials Register was performed in July 2017. Methods: The full-text versions of included trials were meticulously evaluated and extracted. The main efficacious outcomes consisted of pooled mean change scores of the standardized rating scales for ASD and the pooled response rate. Results: A total of 408 randomized patients from eligible trials were included for synthesizing in this meta-analysis. The pooled mean change scores in aripiprazole-treated group for the Aberrant Behavior Checklist (ABC) Irritability, ABC-Hyperactivity/noncompliance, ABC-Inappropriate speech and ABC Stereotypic behavior were significantly greater than those of the placebo-treated group. Unfortunately, the significant difference between two groups was not found for ABC-Lethargy/social withdrawal. The overall pooled response rate of the aripiprazole-treated group was significantly higher than that of the placebo treated group. The pooled overall discontinuation rate in aripiprazole-treated group was significantly better than that of placebo-treated group. The pooled discontinuation rates due to adverse events in aripiprazole-treated group significantly differed from the placebo-treated group (RR [95% CI] of 1.43 [0.65, 3.18], I 2=0%). Limitation: A small number of studies were gathered in this review. Conclusion: Aripiprazole has efficacy in the treatment of behavioral disturbances, including irritability, hyperactivity/noncompliance, inappropriate speech and stereotypic behavior found in ASD children and adolescents; however, it could not improve the lethargy/social withdrawal in such patients. The present evidence also indicates that it is safe, acceptable and tolerable in such treatment. As a small sample size, further well-defined and large sample size studies should be conducted to warrant those findings. PMID- 30519028 TI - Prevalence of poststroke depression in Iranian patients: a systematic review and meta-analysis. AB - Background: Poststroke depression (PSD) is the most common and important neuropsychiatric consequences of stroke, which can result in longer hospital stay, compromise the effectiveness of rehabilitation, and reduce the patients' quality of life. However, Iranian studies have reported different and conflicting prevalence rates for PSD. Objective: The present systematic review and meta analysis aimed to evaluate the overall prevalence of PSD in Iranian patients. Patients and methods: A systematic search was conducted in 2018 for Persian or English articles on PSD, published in the Scientific Information Database (SID), MagIran, PubMed, Scopus, and Web of Science, using the following keywords: depression, depressive disorder, stroke, cerebrovascular disorder, and Iran and all of their possible combinations. Heterogeneity across the studies was evaluated using the Cochran's Q test. According to the heterogeneity results, a random effects model was used to estimate the overall prevalence of PSD. The data were analyzed using the Stata 12 software. Results: Overall, six articles with a total sample size of 641 patients were included in the analysis. The overall prevalence of PSD in Iran was 46.9% (95% CI: 30.1-63.7). In addition, the prevalence of PSD was higher in women (50.4%, 95% CI: 17.9-82.9) than in men (29.5%, 95% CI: 17.2-41.8). According to the results of univariate meta regression, there was a significant relationship between PSD prevalence and sample size (P=0.010). Conclusion: Around half of the stroke patients in Iran suffer from PSD. Given the overlap between neurological symptoms of stroke and depression, efforts should be made to quickly and accurately diagnose depression so that it can be effectively managed with minimum complications. PMID- 30519029 TI - Abnormal prefrontal brain activation during a verbal fluency task in bipolar disorder patients with psychotic symptoms using multichannel NIRS. AB - Purpose: Bipolar disorder (BD) patients with psychotic symptoms (BDp) worsens prognosis and decreases rates of recovery. The study investigated cognitive performance and brain function between BD patients in depressive episode with and without psychotic symptoms to find potential neurobiological markers associated with psychotic features of BD patients in depressive episode. Patients and methods: Thirty-one patients without psychotic symptoms and 29 patients with psychotic symptoms diagnosed with bipolar I disorder with a current depressive episode were included in the present study. The neural function of prefrontal cortex (PFC) and cognitive performance among BDp, BD patients without psychotic symptoms, and 23 healthy controls (HC) were examined using near-infrared spectroscopy during verbal fluency task (VFT). Results: 1) Both the BD groups exhibited significantly worse performance of VFT and lower activation of oxygenated hemoglobin (oxy-Hb) changes in the bilateral ventrolateral PFC compared with the HC group. 2) Within the BD group, VFT performance was not significantly different. 3) The prefrontal activation of oxy-Hb changes in the BDp patients was significantly lower than that in the BD patients without psychotic symptoms in the right dorsolateral PFC. 4) Activation of oxy-Hb changes in right dorsolateral PFC was negatively correlated with the severity of psychotic symptoms in BDp patients. Conclusion: The prefrontal function differs between BD patients in depressive episode with or without psychotic symptoms measured with near-infrared spectroscopy. PMID- 30519030 TI - Complex calculation or quick glance? Mean platelet volume - new predictive marker for pulmonary embolism. AB - Background: Wells and Geneva scores are widely used in the assessment of pretest probability of pulmonary embolism (PE). Objective: The objective of this study was to examine the hypothesis that mean platelet volume (MPV) may better predict PE than the clinical prediction rules. Methods: A study was performed among patients with PE. Baseline characteristics and complete blood counts including MPV were prospectively recorded upon admission. To assess clinical probability in patients with PE risk, we used Wells and Geneva scores. Results: Data records of 136 patients (males: 44%) with median age of 66 years (interquartile range [IQR] 57.5-78.0) diagnosed with PE at the Intensive Cardiac Therapy Clinic in Lodz (Poland) were analyzed. Baseline characteristics indicate that patients suffered from arterial hypertension (65%), obesity (32%), and diabetes mellitus (24%). Furthermore, they reported active smoking (21%), prolonged immobilization (20%), major surgery (21%), pregnancy (4%), and oral contraceptives (9%). Patients presented with various symptoms. The MPV, plateletcrit, and D-dimer values on admission were respectively as follows: 10.71 (IQR 3.29-13.67), 0.2 (IQR 0.15 0.24), and 9.23 (IQR 8.5-9.85). The study revealed that Wells score correlated significantly with an elevated MPV value (P<0.05) per contra to Geneva score (P>0.05). According to our results, there is a lack of coherence between Wells and Geneva scores (P>0.05). Finally, we determined that the optimum MPV level cutoff point for PE on admission with reference to the original Wells score is 9.6 fL. Conclusion: MPV may be considered useful as an adjunctive or independent predictive marker for PE used in lieu of clinical prediction rules. PMID- 30519031 TI - Comparative study of antiretroviral drug regimens and drug-drug interactions between younger and older HIV-infected patients at a tertiary care teaching hospital in South Korea. AB - Background: With the advent of combination antiretroviral therapy (ART), people living with HIV have lived to older age. So they have experienced age-related illnesses and have taken non-antiretroviral (ARV) medications to manage these illnesses. The aims of this study were to investigate the use patterns of ARV agents in HIV-positive patients by age and to evaluate potential or contraindicated drug-drug interactions (DDIs) between ARV and non-ARV. Methods: This study was retrospectively conducted with HIV-infected patients receiving ART medications between October 2011 and September 2017 at Chonbuk National University Hospital in South Korea. Data were collected by reviewing patients' electronic medical charts. Results: Among 207 patients diagnosed with HIV infection, 183 (86.9% males; 104 aged <50 years and 79 aged >=50 years) were selected based on inclusion criteria. In 2017, the most frequently prescribed ART regimen was nucleoside reverse transcriptase inhibitors (NRTIs)/integrase strand transfer inhibitors (INSTIs; total, 66.3%; <50 years, 36.3%; >=50 years, 30.0%) followed by NRTIs/protease inhibitors (PIs; total, 23.8%; <50 years, 15.0%; >=50 years, 8.8%). In 2017, the most frequently prescribed NRTI combination was abacavir/lamivudine (total, 34.4%; <50 years, 20.6%; >=50 years, 13.8%) followed by tenofovir alafenamide/emtricitabine (FTC; total, 31.3%; <50 years, 16.3%; >=50 years, 15.0%) and tenofovir disoproxil fumarate/FTC (total, 28.1%; <50 years, 16.9%; >=50 years, 11.3%). In 2017, elvitegravir (EVG)/cobicistat (COBI; total, 57.1%; <50 years, 30.4%; >=50 years, 26.8%) was most frequently prescribed followed by dolutegravir (total, 32.1%; <50 years, 19.6%; >=50 years, 12.5%). Potential or contraindicated DDIs between boosted PIs with ritonavir or EVG/COBI and coprescribed drugs occurred most frequently. Conclusion: Currently, NRTIs/INSTIs is the most frequently prescribed ARV combination. Abacavir/lamivudine, tenofovir alafenamide/FTC, and tenofovir disoproxil fumarate/FTC are the most used NRTIs, and EVG/COBI followed by dolutegravir is the most prescribed INSTIs. Potential or contraindicated DDIs occur mainly between boosted PIs or EVG/COBI and non-ARV medications. PMID- 30519032 TI - Walking activity during ambulant cardiac rehabilitation is related to maximum working capacity, age, and smoking behavior. AB - Background: A total of 6,500 to 8,000 steps per day are recommended for cardiovascular secondary prevention. The aim of this research was to examine how many steps per day patients achieve during ambulant cardiac rehabilitation (CR), and if there is a correlation between the number of steps and physical and cardiological parameters. Methods: In all, 192 stable CR patients were included and advised for sealed pedometry. The assessed parameters included maximum working capacity and heart rate, body mass index (BMI), New York Heart Association (NYHA) class, ejection fraction (EF), coronary artery disease status, beta-blocker medication, age, sex, smoking behavior, and laboratory parameters. A regularized regression approach called least absolute shrinkage and selection operator (LASSO) was used to detect a small set of explanatory variables associated with the response for steps per day. Based on these selected covariates, a sparse additive regression model was fitted. Results: The model noted that steps per day had a strong positive correlation with maximum working capacity (P=0.001), a significant negative correlation with higher age (P=0.01) and smoking (smoker: P<0.05; ex-smoker: P=0.01), a positive correlation with high density lipoprotein (HDL), and a negative correlation with beta-blockers. Correlation between BMI and walking activity was nonlinear (BMI 18.5-24: 7,427+/ 2,730 steps per day; BMI 25-29: 6,448+/-2,393 steps/day; BMI 30-34: 6,751+/-2,393 steps per day; BMI 35-39: 5,163+/-2,574; BMI >40: 6,077+/-1,567). Conclusion: Walking activity during CR is reduced in patients who are unfit, older, smoke, or used to smoke. In addition to training recommendations, estimated steps per day during CR could be seen as a baseline orientation that helps patients to stay generally active or even to increase activity after CR. PMID- 30519033 TI - Positive placement experience and future rural practice intentions: findings from a repeated cross-sectional study. AB - Objective: To identify the constituents of positive placement experience and explore the association between positive placement experiences and rural and remote practice intentions. Methods: A repeated cross-sectional study was conducted between January 2014 and December 2017. Medical, nursing, dentistry, and allied health students who completed a rural/remote placement were invited to complete a survey questionnaire on placement experience. Information on students' sociodemographic factors, discipline, placement experience, placement satisfaction, and rural/remote practice intentions was collected. Modified Poisson regression was performed to determine the relationships between placement satisfaction and future rural practice intentions. Qualitative data were analyzed by thematic analysis. Results: A total of 873 students responded. The majority of the survey respondents were females (70.06%), with a median age of 22 years (IQR 21-25 years), and 44.46% of respondents were medical students. Students satisfied with their placement were 2.10 times more likely to have rural/remote practice intention than their counterparts. Of all components of rural/remote placement experience, satisfaction with the placement supervision had the highest impact on changing students' rural/remote practice intentions from negative to positive. The major themes from qualitative analysis were as follows: "wide variety of experience and hands-on learning opportunities," "multidisciplinary exposure at home and workplace," "support from the local University Department of Rural Health (UDRH)," "learning of indigenous culture," and "experiencing challenges of rural health care services." Conclusion: There is a strong association between positive placement experience and future rural/remote practice intentions. Therefore, facilitation of positive placement experiences in remote and rural locations could be a key strategy in addressing rural health workforce maldistribution. PMID- 30519034 TI - Involving "authentic" cancer patients, their caregivers, and multidisciplinary professionals in a quality improvement trajectory in a hospital cancer pathway: a study protocol. AB - Introduction: The implementation of oncology care pathways that standardize organizational procedures has improved cancer care in recent years. However, the involvement of "authentic" patients and caregivers in quality improvement of these predetermined pathways is in its infancy, especially the scholarly reflection on this process. We, therefore, aim to explore the multidisciplinary challenges both in practice, when cancer patients, their caregivers, and a multidisciplinary team of professionals work together on quality improvement, as well as in our research team, in which a social scientist, health care professionals, health care researchers, and experience experts design a research project together. Methods and design: Experience-based co-design will be used to involve cancer patients and their caregivers in a qualitative research design. In depth open discovery interviews with 12 colorectal cancer patients, 12 breast cancer patients, and seven patients with cancer-associated thrombosis and their caregivers, and focus group discussions with professionals from various disciplines will be conducted. During the subsequent prioritization events and various co-design quality improvement meetings, observational field notes will be made on the multidisciplinary challenges these participants face in the process of co-design, and evaluation interviews will be done afterwards. Similar data will be collected during the monthly meetings of our multidisciplinary research team. The data will be analyzed according to the constant comparative method. Discussion: This study may facilitate quality improvement programs in oncologic care pathways, by increasing our real-world knowledge about the challenges of involving "experience experts" together with a team of multidisciplinary professionals in the implementation process of quality improvement. Such co creation might be challenging due to the traditional paternalistic relationship, actual disease-/treatment-related constraints, and a lack of shared language and culture between patients, caregivers, and professionals and between professionals from various disciplines. These challenges have to be met in order to establish equality, respect, team spirit, and eventual meaningful participation. PMID- 30519035 TI - MicroRNA-18a promotes hepatocellular carcinoma proliferation, migration, and invasion by targeting Bcl2L10. AB - Background: Hepatocellular carcinoma (HCC) is known to feature several microRNA dysregulations. This study aimed to determine and investigate the prognostic value of microRNA (miRNA/miR)-18a and its role in regulating the progression of HCC. Methods: miR-18a expressions in human HCC tissues, pair-matched adjacent normal liver tissues as well as in HCC cell lines were determined by quantitative real-time PCR. The prognostic value of miR-18a was determined using Kaplan-Meier survival analysis and multivariable Cox regression assay. The ability of miR-18a in promoting HCC progression was verified in vitro. Results: miR-18a expressions in HCC tissues and cells were more than twice those of the normal control group (P<0.05). miR-18a expression was associated with the alpha-fetoprotein (AFP) level, TNM stage, tumor size, and intrahepatic vascular invasion (P<0.05). Kaplan Meier survival analysis revealed that HCC patients with high expression of miR 18a possessed a more unfavorable prognosis (log-rank P<0.001). Overexpression of miR-18a promoted cell apoptosis and proliferation, induced S phase transition, as well as enhanced the migration and invasion ability of HCC cells. miR-18a was found to directly target the downstream molecule Bcl2L10. Furthermore, overexpressing Bcl2L10 was able to partly reverse the promoting effects of miR 18a on HCC cell progression. Conclusion: miR-18a may serve as a prognostic biomarker of HCC as it is demonstrated to carry out a decisive role in HCC progression by promoting HCC cell invasion, migration, and proliferation through targeting Bcl2L10. PMID- 30519036 TI - Matched-pair analysis of survival in the patients with T3 laryngeal squamous cell carcinoma treated with supracricoid partial laryngectomy or total laryngectomy. AB - Background: The survival outcomes between supracricoid partial laryngectomy (SCPL) and total laryngectomy (TL) were compared in the groups of matched-pair patients with T3 laryngeal squamous cell carcinoma (LSCC). Methods: Patients with T3 LSCC were matched based on prognostic factors. The Kaplan-Meier curve and the Cox proportional hazards model were used for analysis on survival. Results: A total of 212 patients with T3 LSCC were included after matching (106 underwent SCPL and 106 underwent TL). Multivariable analysis showed no differences in overall survival (hazard risk [HR]=1.15; 95% CI: 0.79-1.67; P=0.47), disease specific survival (HR=1.11; 95% CI: 0.69-1.80; P=0.66), and recurrence-free survival (HR=1.07; 95% CI: 0.68-1.68; P=0.77) between the SCPL group and TL group. Conclusion: SCPL provides reliable therapeutic outcomes and can be used to avoid a TL surgery in some patients with advanced primary laryngeal cancer. PMID- 30519037 TI - lncRNA differentiation antagonizing nonprotein coding RNA overexpression accelerates progression and indicates poor prognosis in pancreatic ductal adenocarcinoma. AB - Background: lncRNA differentiation antagonizing nonprotein coding RNA (lncRNA DANCR) has been suggested to play an oncogenic role in multiple cancers. However, to the best of our knowledge, the clinical significance and role of DANCR in pancreatic ductal adenocarcinoma (PDAC) has not been illuminated till now. The present study aims to identify the functional role of DANCR in PDAC. Methods: The expression of DANCR was detected in PDAC cells and tissues. The correlation of DANCR expression and PDAC clinicopahological features was analysed. Kaplan-Meier method was used to depict the overall survival (OS) rate and shorter progression free survival (PFS) of PDAC patients, and Log-rank test was performed to analyse the difference. Univariate and multivariate COX regression model were utilized to analyse the risk factors for prognosis. Transwell assay and Matrigel assay were conducted to detect the effect of DANCR on the migration and invasion of PDAC cells, respectively. Colony formation assay and Cell Counting Kit-8 (CCK-8) assay were performed to evaluate the function of DANCR on proliferation. The mechanisms of DANCR exerting its function were also explored. Results: DANCR was revealed to promote PDAC progression, with relatively higher expression levels in PDAC cell lines and tissues. Correlation analysis of the clinicopathological features and DANCR expression found that high DANCR expression was statistically correlated with vascular invasion (P=0.013), advanced T stage (P=0.005), lymph node metastasis (P<0.001) and advanced TNM stage (P<0.001). Notably, survival analysis discovered that high DANCR expression predicted lower OS rate and shorter PFS period. In addition, high DANCR expression was identified as an independent risk factor for poor OS (HR=1.199, 95% CI=1.113-1.290, P<0.001) and PFS (HR=1.199, 95% CI=1.114-1.290, P<0.001) of PDAC. Moreover, in vitro assays detected that the migration and invasion of Panc1 cells with DANCR deficiency were significantly suppressed in the Transwell assay and the Matrigel assay. However, the motility of BxPC3 cells with DANCR overexpression was obviously increased. In addition, the loss of DANCR suppressed the proliferation of Panc1 cells in the CCK-8 assay and the colony formation assay, while ectopic expression of DANCR in BxPC3 cells promoted the proliferation. Besides, microRNA-33a-5p/AXL signaling pathway may be involved in mediating the function of DANCR. Conclusion: Overexpression of lncRNA DANCR in PDAC is associated with cancer progression and predicts poor OS and PFS. DANCR could promote the proliferation and metastasis of PDAC cells. DANCR may serve as a potential prognostic marker and therapeutic target in PDAC. PMID- 30519038 TI - miR-185 suppresses progression of Ewing's sarcoma via inhibiting the PI3K/AKT and Wnt/beta-catenin pathways. AB - Background: miRNAs are confirmed to play essential roles in tumorigenesis and progression of cancers, including Ewing's sarcoma. miR-185 has been reported to be downregulated in some tumors, whereas the role of miR-185 in Ewing's sarcoma remains unclear. Purpose: The objective of this study was to investigate the role of miR-185 in the progression and metastasis of Ewing's sarcoma and explore the associated mechanism. Materials and methods: Ewing's sarcoma cell line RD-ES was transfected with pCMV-MIR-miR185 vector to upregulate the expression of miR-185. Cell Counting Kit 8 and colony formation assays were used to assess the effect of miR-185 on cell proliferation. The effect of miR-185 on cell migration and invasion was detected by transwell assay. Flow cytometry assay was performed to detect apoptosis rate of RD-ES cells. The protein levels of apoptosis-related proteins was determined using Western blot assay or immunohistochemistry assay. Dual-luciferase reporter assay was used to validate the regulation between miR 185 and its target gene. Results: Upregulation of miR-185 caused significant inhibition on cell growth capacity, migration and invasion of Ewing's sarcoma cell RD-ES. Besides, upregulation of miR-185 was observed to accelerate cell apoptosis in a mitochondrial pathway through regulating Bcl-2/Bax, Caspase 3, and Caspase 9 in Ewing's sarcoma in vitro. Moreover, upregulation of miR-185 was found to suppress the PI3K/Akt/mTOR and Wnt/beta-catenin pathways in RD-ES cells. Furthermore, we identified that E2F6 was a target gene for miR-185, and the suppression on cell proliferation caused by overexpression of miR-185 was significantly rescued by the upregulation of E2F6 in RD-ES cells. Conclusion: miR 185 is involved in cell growth, motility and survival of Ewing's sarcoma as a tumor suppressor via suppressing PI3K/Akt/mTOR and Wnt/beta-catenin pathways and targeting E2F6. PMID- 30519039 TI - The prognostic roles of mRNAs of the exosomes derived from bone marrow stromal cells in common malignancies: a bioinformatic study. AB - Background: The inclusion of exosomes enters the recipient cells by means of endocytosis or direct fusion for information exchange between cells and cells. The inclusion of BMSCs-exo helps to guide the diagnosis and prognosis of cancer, especially cancer. Purpose: This research was to systematically elucidate the prognostic value of mRNAs of the exosomes derived from bone marrow stromal cells (BMSCs) in common malignant neoplasms, such as breast cancer, ovarian cancer, lung cancer, and gastric cancer. Methods: Gene expression data (GSE78235) for the exosomes derived from BMSCs were extracted from the Gene Expression Omnibus database. Firstly, the differentially expressed genes were detected by comparing the RNA expression from exosomes derived from BMSCs between four tumor patients and two healthy controls using the limma package. Subsequently, functional enrichment analysis, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes of differentially expressed genes, was performed using the Functional Enrichment analysis tool (FunRich v3.1.3) software followed by the construction of a protein-protein interaction (PPI) network via STRING v3.6.0. Molecular Complex Detection was used to screen the hub proteins by setting up the following threshold score >=4 and nodes >=10. Cytoscape v3.6.1 was used to for visualizing PPI network. Finally, Kaplan-Meier analysis for hub proteins was performed by Kaplan-Meier plotter online platform. Results: A total of 386 genes originating from the exosomes derived from BMSCs were identifed as statistically signifcant (P < 0.05, FDR <0.05), which consisted of 150 upregulated genes and 236 downregulated genes. Also, 32 pathways were identifed as signifcant (P < 0.05, FDR < 0.05). The PPI network of exosomes derived from BMSC proteins included 100 protein nodes with 579 interaction edges. The hub proteins, including PODN, ZNF521, and CFI, which interacted with ten or more other proteins, were indicated as the hub proteins of PPN of exosomes derived from BMSCs. Conclusion: Taken together, our findings revealed the prognostic roles of mRNAs of exosomes derived from BMSCs and provided implications for targeted therapy for common malignant neoplasms. However, further studies require large samples and experimental verification. PMID- 30519040 TI - Lupeol inhibits growth and migration in two human colorectal cancer cell lines by suppression of Wnt-beta-catenin pathway. AB - Background: Lupeol, a triterpene isolated from various herbal plants, possesses an anti-inflammatory function and has been proposed as a candidate for anticancer agents. The purpose of this research was to investigate the effect of lupeol on the viability, apoptosis, cell-cycle distribution, and migration of colorectal cancer cell lines and its molecular mechanism. Methods: Lupeol was assessed for its anticancer effect using two human colorectal cancer cell lines: SW480 and HCT116. These cells were treated with lupeol, and their viability, apoptosis, migration, and cycle distribution were detected by CCK8, flow cytometry, and the transwell method. Quantitative PCR, Western blot, and immunofluorescence were applied to detect the expressions of CTNNB1, TCF4, cMYC, CCND1, CLDN1, and CCNA2. Results: Lupeol suppressed cell viability and migration and induced cellular apoptosis of both cell lines, with increased p53 and decreased Bcl2 protein levels (P<0.05). Cell cycles of both lupeol-treated cell lines were arrested in the S phase (P<0.05). Quantitative PCR and Western blot analyses showed significantly reduced expressions of CTNNB1, TCF4, and downstream genes of the Wnt-beta-catenin pathway, including the cell-cycle-regulated genes of cMYC and CCND1 of both cell lines upon lupeol treatment (P<0.05). mRNA and protein levels of CLDN1 decreased in HCT116 cells, plus the expression of CCNA2 mRNA and protein decreased in SW480 cells (P<0.05). Immunofluorescence analysis confirmed decreased expression of Wnt-beta-catenin signaling. Conclusion: Our findings indicate that lupeol effectively inhibits proliferation and migration and induces apoptosis and cell-cycle arrest of two colorectal cell lines by inactivation of the Wnt-beta-catenin signaling pathway and downregulation of cMYC, CCND1, CCNA2, and CLDN1, thereby making it a promising anticancer candidate. PMID- 30519041 TI - Long noncoding RNA H19 mediated the chemosensitivity of breast cancer cells via Wnt pathway and EMT process. AB - Background: Breast cancer is still one of the major public health burdens worldwide, although there is tremendous progress in early diagnosis and treatment of breast cancer. Tamoxifen was one of the most popular endocrine therapies for early-stage estrogen receptor (ER) + breast cancer patients. However, a high incidence of drug resistance develops along with poor prognosis in breast cancer. Currently, long noncoding RNAs (lncRNAs) are emerging and are well suited to play a role in the development of cancer and tamoxifen resistance. However, there is little reported about the relationship of breast cancer resistance to tamoxifen and lncRNA H19. Here, we validated that lncRNA H19 was highly expressed in breast cancer especially in patients with late stage (III and IV), compared to normal tissues and early stage cancers (I and II). Methods: Quantitative polymerase chain reaction (qPCR) was utilized for comparison of lncRNA H19 expression level in breast cancers with different stages. qPCR and Western blotting were used to detect gene and protein, respectively. Results: We found that lncRNA H19 expression level manipulated breast cancer cell proliferation both in parental breast cancer cell lines and tamoxifen-resistant cell lines. Knockdown of lncRNA H19 elevated tamoxifen sensitivity for promoting cell growth and inhibiting apoptosis in tamoxifen-resistant breast cancer cells. Moreover, knockdown of H19 inhibited Wnt pathway and epithelia-mesenchymal transition in tamoxifen resistance breast cancer cells. Conclusion: Taken together, the results of this study provided the evidence for H19 in regulating tamoxifen-resistant breast cancer and might provide novel options in the future treatment of tamoxifen resistance breast cancer patients. PMID- 30519042 TI - Erratum: SNHG8 is identified as a key regulator in non-small-cell lung cancer progression sponging to miR-542-3p by targeting CCND1/CDK6 [Erratum]. AB - [This corrects the article on p. 6081 in vol. 11, PMID: 30275712.]. PMID- 30519043 TI - Patterns of regional nodal relapse after D2 lymphadenectomy in gastric cancer: rethinking the target volume. AB - Purpose: This study mapped the localization of regional nodal recurrence to determine whether the clinical target volume (CTV) should be redefined in adjuvant radiotherapy. Patients and methods: Between January 2004 and October 2015, a total of 129 patients with gastric cancer following D2 resection who experienced regional recurrence were retrospectively examined. The lymph nodes (LNs) were hand-drawn proportionally on template computed tomography (CT) images of a standard patient by referencing surrounding anatomic landmarks. The association between clinicopathologic factors and LNs at risk was further investigated. Results: Based on the contour of the recurrent LNs, the authors observed high-risk regions for relapse and drew a density distribution map of 16 LN stations on the CT images. The most commonly involved recurrent LNs were stations 16b (51.2%) and 16a (39.5%). Stations 13, 12, 9, and 14 were involved in 36.4%, 33.3%, 28.7%, and 27.9% of recurrences, respectively. Other regions, including stations 1-6 (perigastric LNs) and station 10 (splenic hilar LN), were of low risk. Notably, 72% (83/116) of recurrent 16b LNs were located in the upper half of 16b1. Analysis within subgroups showed that the pathologic N stage was the only independent risk factor for LN 16 relapse. Conclusion: This mapping suggests a new method for vessel-guided delineation of regional LNs when defining the CTV in patients after standard D2 resection. LNs around the abdominal aorta and its main branches, as well as regions around the hepatic hilar area and pancreatic head, should be the most important radiotherapeutic targets. PMID- 30519044 TI - miR-517a promotes Warburg effect in HCC by directly targeting FBP1. AB - Purpose: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide. Our aim is to explore the expression and biological function of miR-517a in HCC. Materials and methods: We performed qRT-PCR to detect the expression of miR-517a in clinical samples and cell lines. CKK-8 assay and colony formation assay were employed to detect the miR-517a regulated cell proliferation. Glucose uptake and lactate production were examined to determine the Warburg effect. We also performed ECAR assay using Seahorse system. Luciferase acitivy assay was used to examine the binding of FBP1 3'UTR by miR 517a. Results: miR-517a was upregulated in HCC samples in both genomic and mRNA levels. Moreover, overexpression of miR-517a promoted cell proliferation and Warburg effect. Mechanically, miR-517a could directly target the 3'-UTR of FBP1. In addition, restoring the expression of FBP1 inhibited cell growth. Conclusion: We demonstrated that miR-517a acts as an oncogene to promote Warburg effect in HCC, favoring tumor growth, and miR-517a/FBP1 could be a novel target for HCC treatment. PMID- 30519045 TI - Knockdown of HOXA transcript at the distal tip suppresses the growth and invasion and induces apoptosis of oral tongue squamous carcinoma cells. AB - Background: Oral tongue squamous cell carcinoma (OTSCC) is an aggressive cancer which has high mortality rates. HOXA transcript at the distal tip (HOTTIP) is a lncRNA that can be used as a prognostic marker in multiple carcinomas. The expression of HOTTIP is found to be elevated in OTSCC tissues, and such elevation is correlated with poor prognosis. However, its functional role in regulating the growth and metastasis of OTSCC cells remains elusive and requires further investigation. Methods: HOTTIP-silenced OTSCC cells were established by inhibiting HOTTIP expression via its exclusive shRNA. Whether HOTTIP knockdown affected the aggressive tumor behaviors of OTSCC cells was investigated in vitro and in vivo. Results: We found that HOTTIP shRNA restrained the cell proliferation and arrested the cell cycle at G1 phase in TSCCA and TCA8113 cells. The expression levels of cyclins B, D1, and E were downregulated in HOTTIP silenced cells. HOTTIP silencing suppressed the growth of xenograft tumors. Moreover, the silencing of HOTTIP triggered apoptosis in TSCCA and TCA8113 cells and altered the expression of a group of apoptosis-related molecules: downregulated Bcl-2, upregulated Bax, and enhanced the cleavage of caspase 3 and PARP. Knockdown of HOTTIP also suppressed the migration, invasion, and epithelial mesenchymal transition (EMT) of both TSCCA and TCA8113 cell lines. Conclusion: Our findings suggest that HOTTIP is required by the OTSCC cells to maintain their growth and metastasis in vitro. It may serve as a promising potential candidate for OTSCC therapy. PMID- 30519046 TI - Potential clinical application of lncRNAs in non-small cell lung cancer. AB - Lung cancer has been identified as one of the most prevalent and deadly tumors worldwide. In recent years, lncRNAs have been demonstrated to play a significant role in the development of lung cancer. Specifically, lncRNAs act as a regulator of cancer-critical genes, and they regulate the biological behavior of tumors at the transcriptional and posttranscriptional levels. Recent studies have shown that lncRNAs possess great potential in the treatment of non-small cell lung cancer patients because of their roles in diverse cellular processes, such as proliferation, metastasis, stem cell maintenance, and epithelial to mesenchymal transition, and they serve as signaling biomarkers. Compared to other invasive diagnostic methods, detection of lncRNAs may become a very useful noninvasive methodology. Moreover, lncRNAs can serve as potential therapeutic targets in non small cell lung cancer due to their roles in regulating many signaling pathways associated with lung carcinoma. In this review, we discuss the roles and expression profile of lncRNAs. We also discuss the promising application of lncRNAs as predictors of clinical diagnosis, prognosis, and as potential therapeutic targets, aiming to demonstrate their practical value for clinical treatment. PMID- 30519047 TI - Clinicopathological and prognostic significance of circulating tumor cells in patients with esophageal cancer: a meta-analysis. AB - Background: The aim of this meta-analysis was to assess the clinicopathological and prognostic significance of circulating tumor cells (CTCs) in patients with esophageal cancer (EC). Methods: We searched PubMed, EMBASE, Science Citation Index Expanded, Cochrane library (from inception to July 2018) with the keywords "esophageal cancer", "circulating tumor cells", "prognosis", and "peripheral blood". HR, risk ratio (RR), OR, and their 95% CIs were set as effect measures. All analyses were performed by STATA 12.0. Results: Eighteen studies were retrieved; CTC-positive patients were significantly associated with poor progression-free survival (PFS) (HR=2.61; 95% CI=2.08-3.28) and overall survival (OS) (HR=2.50; 95% CI=2.12-2.94). CTC-positive patients were also associated with high recurrence (OR=2.84; 95% CI=1.81-4.44) and poor response of chemoradiotherapy (RR=0.64; 95% CI=0.43-0.96). For clinicopathological characteristics, CTC-positive patients were significantly associated with TNM staging, depth of infiltration, regional lymph nodes metastasis, distant metastasis, lymphatic invasion, and venous invasion. Conclusion: The meta analysis has confirmed the significant clinicopathological and prognostic value of CTC-positive patients for both PFS and OS in patients with EC. PMID- 30519048 TI - Celecoxib suppresses cutaneous squamous-cell carcinoma cell migration via inhibition of SDF1-induced endocytosis of CXCR4. AB - Background: Cutaneous squamous cell carcinoma (CSCC), the main type of non melanoma skin cancer (NMSC), contributes to 20-30% of the overall number of NMSC cases. Some CSCCs are observed to have metastatic potential induced by solar ultra violet (UV) radiation. Celecoxib, a nonsteroidal anti-inflammatory drug, has been largely associated with prevention of many cancer types. However, the relationship between celecoxib and CSCC cell migration has yet to be determined. Methods: To determine the association between celecoxib and CSCC, we performed a series of studies in human samples and in vitro models to assess the influence of celecoxib in CSCC cell migration. Results: In the present study, we found that celecoxib suppresses CSCC cell migration via inhibition of SDF1-induced endocytosis of CXCR4. In addition, ERK/AKT signaling pathways were found to play a key role in this biological process. Conclusion: Our study provides promising evidence that celecoxib could serve as a potential preventative agent for the metastasis of CSCC cells. PMID- 30519049 TI - Expression of CLIC1 as a potential biomarker for oral squamous cell carcinoma: a preliminary study. AB - Purpose: CLIC1, a member of the highly conserved class ion-channel protein family, is frequently upregulated in multiple human malignancies and has been demonstrated to play a critical role in cell proliferation, apoptosis, and invasion. However, limited is known about its expression, biological functions, and action mechanism in oral malignancies. We aimed to evaluate whether CLIC1 could be a biomarker for oral squamous cell carcinoma (OSCC). Methods: Immunohistochemistry was used to analyze the expression of CLIC1 in tissue. CLIC1 protein and mRNA were measured through Western immunoblotting and quantitative real-time PCR. CLIC1 protein expression in plasma was detected via ELISA. A total of 72 OSCC specimens were recruited in this study for evaluation of correlations of CLIC1 with clinicopathological features and survival. Results: CLIC1 was significantly overexpressed in tissue and plasma of OSCC patients. It was found that upregulated CLIC1 was distinctly correlated with histological grade, TNM stage, and tumor size. Meanwhile, Kaplan-Meier survival analysis showed that OSCC patients with high CLIC1 expression had remarkably poorer overall survival rate than those with low CLIC1 expression. Multivariate Cox regression analysis revealed that CLIC1 was the independent prognostic factor for overall survival rate of OSCC patients. In addition, Pearson correlation analysis showed that CLIC1 was associated with multiple tumor-associated genes. Conclusion: These results indicated that CLIC1 acts as a molecular target in OSCC and may present a novel diagnostic marker and therapeutic target for OSCC. PMID- 30519050 TI - Association of MLH1 single nucleotide polymorphisms with clinical outcomes of first-line irinotecan-based chemotherapy in colorectal cancer. AB - Purpose: Several studies have proved that single nucleotide polymorphisms (SNPs) of mismatch repair system genes are closely related to the development of colorectal cancer (CRC) by causing microsatellite instability, while effects of the SNPs of MMR system-related genes on the clinical outcomes of cytotoxic chemotherapy are less understood. The aim of this study explored the influence of MLH1 SNPs on clinical outcomes of first-line irinotecan-based chemotherapy in CRC. Patients and methods: A total of 125 metastatic colorectal cancer (mCRC) patients who received first-line irinotecan-based chemotherapy (none of them combined with bevacizumab or cetuximab) were enrolled in this study. Blood samples or formalin-fixed paraffin-embedded tissues of study population were taken. DNA isolation and genotyping analyzed were obtained for potential functional polymorphisms of MLH1 rs1800734 by real-time PCR. Progression-free survival (PFS) was the primary endpoint and tumor response rate (RR) was the secondary endpoint of this study. Results: Of all the assessable population, the result showed no statistical difference among the three types SNPs of MLH1 rs1800734 (AA, AG, GG) for RR (P=0.859), and also without significant difference for AA + AG combined variants vs GG variant (P=0.849). The median PFS for AA, AG, and GG variants of MLH1 rs1800734 SNPs were 9.4 months, 7.0 months, and 6.9 months, respectively (log-rank P=0.031). Interestingly, compared with AA variant of MLH1 rs1800734 SNPs, GG variant showed a shorter PFS (HR: 3.49; 95 CI: 1.02 11.94; P=0.046). Furthermore, the median PFS of AA + AG combined variants and GG variant were 8.3 months and 6.9 months (log-rank P=0.037), and GG variant have a decreased trend with no significant difference (HR: 1.57; 95 CI: 0.98-2.53; P=0.061). Conclusion: The AA variant of MLH1 rs1800734 SNPs has a longer PFS in first-line irinotecan-based chemotherapy for mCRC patients, and the result needs to be further confirmed by prospective studies in the future. PMID- 30519051 TI - High expression of TFEB is associated with aggressive clinical features in colorectal cancer. AB - Objectives: The transcription factor EB (TFEB), a member of the micropthalmia family, has been found to be associated with autophagy and upregulated in some kinds of tumors. However, very few studies focused on TFEB in colorectal cancer (CRC). TFEB expression status and its relevance to clinical features in CRC would be analyzed in this study. Materials and methods: Real-time PCR, Western blot, and immunohistological staining were used to evaluate TFEB expression in CRC tissues and adjacent normal tissues, and the role of TFEB in CRC cell lines was investigated in vitro and in vivo. Results: TFEB was expressed at lower level in CRC tissues than normal in both mRNA and protein level. However, there were significantly positive correlations between TFEB expression in cancer tissues and malignant progression of CRC. Cancers with TFEB overexpression always had deeper infiltration and higher lymphatic metastasis rate. Furthermore, patients with high TFEB levels always had poor survival, and higher TFEB expression could be a predictor of survival in multivariate analysis. Meanwhile, knockdown TFEB by shRNA or knockout TFEB by sgRNA in CRC cell lines could significantly inhibit cell proliferation and migration in amino acid-free medium. In addition, we found a positive relationship between TFEB and Beclin1 expression, and silencing TFEB inhibited Beclin1 expression in CRC cells. Conclusion: TFEB expression correlated with aggressive clinical features in CRC, and higher TFEB expression could be a prognostic factor and potential treatment target of CRC. PMID- 30519052 TI - Lipocalin 2: a potential therapeutic target for breast cancer metastasis. AB - Although systematic therapeutic approaches have reduced cancer-associated mortality, metastatic breast cancer can still evade therapy, particularly triple negative breast cancer, which remains associated with high rates of cancer metastasis and has the worst clinical prognosis. Lipocalin 2 (LCN2) is a secreted glycoprotein that transports small lipophilic ligands. Its abnormal expression serves critical roles in the epithelial-to-mesenchymal transition process, angiogenesis, and cell migration and invasion in breast cancer. Notably, LCN2 functions as an initiator of carcinogenesis and metastasis by involving multiple signaling pathways. The present review aims to summarize research findings on the abnormal expression of LCN2 in breast cancer progression. Furthermore, the review highlights the latest developments of potential LCN2-targeting agents and proposed LCN2-associated molecular mechanisms with regard to breast cancer invasion and metastasis. PMID- 30519053 TI - A functional human motor unit platform engineered from human embryonic stem cells and immortalized skeletal myoblasts. AB - Background: Although considerable research on neuromuscular junctions (NMJs) has been conducted, the prospect of in vivo NMJ studies is limited and these studies are challenging to implement. Therefore, there is a clear unmet need to develop a feasible, robust, and physiologically relevant in vitro NMJ model. Objective: We aimed to establish a novel functional human NMJs platform, which is serum and neural complex media/neural growth factor-free, using human immortalized myoblasts and human embryonic stem cells (hESCs)-derived neural progenitor cells (NPCs) that can be used to understand the mechanisms of NMJ development and degeneration. Methods: Immortalized human myoblasts were co-cultured with hESCs derived committed NPCs. Over the course of the 7 days myoblasts differentiated into myotubes and NPCs differentiated into motor neurons. Results: Neuronal axon sprouting branched to form multiple NMJ innervation sites along the myotubes and the myotubes showed extensive, spontaneous contractile activity. Choline acetyltransferase and betaIII-tubulin immunostaining confirmed that the NPCs had matured into cholinergic motor neurons. Postsynaptic site of NMJs was further characterized by staining dihydropyridine receptors, ryanodine receptors, and acetylcholine receptors by alpha-bungarotoxin. Conclusion: We established a functional human motor unit platform for in vitro investigations. Thus, this co culture system can be used as a novel platform for 1) drug discovery in the treatment of neuromuscular disorders, 2) deciphering vital features of NMJ formation, regulation, maintenance, and repair, and 3) exploring neuromuscular diseases, age-associated degeneration of the NMJ, muscle aging, and diabetic neuropathy and myopathy. PMID- 30519054 TI - Bacterial profile, antibiotic resistance pattern and associated factors among cancer patients at University of Gondar Hospital, Northwest Ethiopia. AB - Introduction: Cancer is alarmingly increased in developing countries like Ethiopia, where multidrug resistant bacterial infection is rampant. The aim of this study was to determine the bacterial profile, antimicrobial resistance pattern, and associated factors among cancer patients attending University of Gondar Hospital. Methods: A consecutive 216 cancer patients were recruited from February to April, 2017. Socio-demographic and clinical data were collected using a structured questionnaire. Culture and antibiotic resistance were done following standard microbiological procedures. Result: The overall prevalence of bacterial infection was 19.4%. The predominant bacterial isolates were Staphylococcus aureus (28.6%), followed by coagulase negative staphylococci (26.2%) and Escherichia coli (21.4%). Multidrug resistance was detected in 46.5% bacterial isolates. Methicillin resistance was detected in 25% of S. aureus and in 45.5% of coagulase negative staphylococci. Fluoroquinolone resistance was detected in 33.3% of E. coli isolates. Cancer patients with solid tumor, started cancer therapy, and being symptomatic had higher odds of culture positivity. Conclusion: The overall burden of bacterial infection among cancer patients is considerably high. The findings of this study inform baseline information for policymakers and call for additional studies with large isolates in different cancer treatment centers in the region and in the country to better understand the bacterial isolate and resistance pattern. PMID- 30519055 TI - Poor adherence is a contributor to viral breakthrough in patients with chronic hepatitis B. AB - Objective: The objective of this study was to explore the risk factors of poor adherence of nucleoside analogs (NUC) treatment in chronic hepatitis B (CHB) patients and the virological changes in patients with poor adherence. Subjects and methods: A total of 205 CHB patients were enrolled. The patients' demographic data and family history were collected. NUC adherence was calculated every 12 weeks as follows: number of NUC tablets taken by the patients was divided by the number of NUC tablets prescribed. NUC adherence > 90% was defined as good adherence of NUC treatment. Results: NUC adherence of male patients was significantly lower than that of female patients. Adherence among patients with previous NUC treatment was poorer than that of patients without previous NUC treatment. Multivariate analysis indicated that female gender (OR =0.367, P=0.013) was the protective factor for NUC adherence in CHB patients, while pretreatment with NUC was the risk factor for NUC adherence (OR =3.209, P=0.002). A total of six patients in the good adherence group experienced virological breakthroughs while 15 of 77 patients in the poor adherence group experienced virological breakthroughs (P=0.001). Similar trends were observed in NUC resistance. Four of the 128 patients with good adherence developed NUC resistance while nine of the 77 patients with poor adherence developed resistance (P=0.015). Multivariate analysis suggested that pretreatment with NUC (OR =3.133, P=0.031), NUC drugs (OR = 3.951, P=0.010), and adherence (OR =2.749, P=0.046) were independent risk factors associated with virological breakthroughs and that NUC drugs (OR =7.083, P=0.005) and poor adherence (OR =4.951, P=0.009) were independent risk factors for NUC resistance. Conclusion: Male gender and pretreatment with NUC were risk factors associated with NUC adherence. Poor NUC adherence is more likely to induce virological breakthroughs and NUC resistance. For patients with poor NUC adherence, it is necessary to give timely education to improve treatment adherence. PMID- 30519056 TI - Extensively drug-resistant Acinetobacter baumannii and Proteeae association in a Romanian intensive care unit: risk factors for acquisition. AB - Purpose: The purpose of this study was to identify risk factors for extensively drug-resistant (XDR) Acinetobacter baumannii (AB) and XDR Proteeae association in the largest intensive care unit (ICU) in Western Romania. Materials and methods: This retrospective case-controlled study was conducted between January 2016 and December 2016 in the ICU of the "Pius Brinzeu" County Emergency Clinical Hospital of Timi oara. Data were collected, in strict confidentiality, from the electronic database of the Microbiology Laboratory and the hospital's electronic medical records. Risk factors were s investigated by logistic regression. Independent variables with P<=0.05 and OR >1 (95% CI >1) in the univariate analysis were entered into multivariate sequenced analysis. Findings: The incidence density of coinfection with XDR AB and XDR Proteeae was 5.31 cases per 1,000 patient-days. Independent risk factors for the association of XDR AB and XDR Proteeae were represented by the presence of tracheostomy and naso-/orogastric nutrition >= 8 days. In addition, pressure ulcers were independent predictive factors for infections with all three infection types. Previous antibiotic therapy was an independent risk factor for the acquisition of XDR-AB strains, alone or in association, while the prolonged hospitalization in the ICU, blood transfusion, and hemodialysis appear as independent risk factors for single infections. Conclusion: This association of XDR AB and XDR Proteeae may well not be limited to our hospital or our geographical area. PMID- 30519057 TI - Antibiotic prescriptions to adults with acute respiratory tract infections by Italian general practitioners. AB - Purpose: The overuse, misuse, and underuse of antimicrobial agents often lead to the spread of antibiotic-resistant microorganisms. The aim of our study was to describe the pattern of antibiotic prescriptions for acute respiratory tract infections (RTIs) among the adult population and the factors associated with antibiotic prescribing. Patients and methods: The study involved patients who visited a general practitioner with suspected acute RTI. Patients with diagnosis of acute sinusitis, acute pharyngitis, acute bronchitis, and influenza were included in the study. We evaluated the presence of an indication for antibiotic therapy for selected diseases according to international guidelines. The appropriateness of any prescribed molecule was also evaluated. Results: A total of 1,979 cases of acute RTIs were included: 1,196 (60.4%) pharyngitis, 359 (18.2%) bronchitis, 234 (11.8%) influenza, and 190 (9.6%) sinusitis. An antibiotic prescription was given in 67.3% of the consultations and was not indicated by the guidelines in 66.5% of the total RTIs. Macrolides were the most frequently prescribed antibiotics accounting for 32.5% of all those prescribed, followed by amoxicillin with clavulanic acid (31.1%) and fluoroquinolones (14.2%). The highest overprescription was associated with pharyngitis (65.9%) and the lowest with influenza (4.9%). A throat swab was performed only in 11 of all the patients with a diagnosis of acute pharyngitis. Conclusion: The present study showed a very high frequency of nonevidence-based prescription of antibiotics at the primary care level. Future improvement programs should focus on development of evidence-based guidelines, access to postgraduate training, and better availability of diagnostic tools. PMID- 30519058 TI - Baseline hepatitis C virus resistance-associated substitutions present at frequencies lower than 15% may be clinically significant. AB - Background: Controversy is ongoing about whether a minority mutant present at frequencies below 15% may be clinically relevant and should be considered to guide treatment. Methods: Resistance-associated substitution (RAS) studies were performed in patients before and at failure of antiviral treatments using Next generation hepatitis C virus (HCV) sequencing (NGS). Results: We have found two patients with genotype 1a infection having RAS in 3.5%-7.1% of the viral population at baseline that were selected during ledipasvir + sofosbuvir treatment. Co-selection of RAS located in a region not directly affected by the antiviral treatment also occurred. This observation calls into question, the recommendations to guide RAS-based direct-acting antiviral (DAA) treatment only when RAS are present in >15% of the sequences generated. Conclusion: Our results suggests that RAS study should include all three HCV DAA target proteins and minority mutants should be considered as clinically relevant. PMID- 30519059 TI - First reported nosocomial outbreak of Serratia marcescens harboring bla IMP-4 and bla VIM-2 in a neonatal intensive care unit in Cairo, Egypt. AB - Introduction: Serratia marcescens is a significant hospital-acquired pathogen, and many outbreaks of S. marcescens infection have been reported in neonates. We report a sudden breakout of S. marcescens harboring the bla IMP-4 and bla VIM-2 metallo-beta-lactamase (MBL) genes that occurred from March to August 2015 in the neonatal intensive care unit of Cairo University Hospital, Cairo, Egypt. Methods: During the study period, 40 nonduplicate clinical isolates of S. marcescens were collected from blood culture samples. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to identify each isolate. Then, minimum inhibitory concentrations of different antibiotics were assessed by the Vitek 2 compact system. Screening of the MBL genes bla IMP, bla VIM, bla SIM-1, bla SPM 1, and bla GIM-1 as well as the carbapenemase genes KPC, NDM, OXA-48, SME-1, and SME-2 were evaluated. Pulsed field gel electrophoresis was preformed to detect the genetic relationship of the isolates. Results: Analysis showed that 37.5% of the S. marcescens clinical isolates were resistant to meropenem (minimum inhibitory concentrations >= 2 ug/mL), and bla IMP-4 and bla VIM-2 were the most prevalent MBL genes (42.5% and 37.5%, respectively). None of the other investigated genes were observed. Pulsed field gel electrophoresis typing revealed two discrete clones; 33/40 (82.5%) were pulsotype A and 7/40 (17.5%) were pulsotype B. Conclusion: Here, we report for the first time the detection of MBL-producing S. marcescens isolates, particularly IMP-4 and VIM-2 recovered from inpatients with bacteremias from the intensive care unit at Cairo University Hospital. PMID- 30519061 TI - The inflammasome in leprosy skin lesions: an immunohistochemical evaluation. AB - Objective: Leprosy is a chronic infectious disease presenting with a spectrum of clinical manifestations that correspond to the type of immune response that develops in the host. Factors that may be involved in this process include inflammasomes, cytosolic proteins responsible for the activation of caspase 1, IL 1beta and IL-18 secretion, and induction of a type of death called pyroptosis. Patients and methods: We evaluated the expression of inflammasome markers (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 1 [NLRP1], nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 [NLRP3], caspase 1, IL-1beta, and IL-18) by immunohistochemistry in 43 samples of skin lesions of leprosy patients from the groups indeterminate (I) leprosy (13 patients), tuberculoid (TT) leprosy (15 patients), and lepromatous leprosy (LL; 15 patients). Results: The evaluated markers were most upregulated in LL lesions, followed by lesions of TT leprosy and I leprosy. Differences were statistically significant between the I leprosy and LL leprosy forms and between the I leprosy and TT leprosy forms. Positive and significant correlations were found between IL-18 and caspase 1 in LL (r=0.7516, P=0.0012) and TT leprosy (r=0.7366, P=0.0017). In I leprosy, correlations were detected between caspase 1 and IL-1beta (r=0.6412, P=0.0182), NLRP1 and IL-18 (r=0.5585, P=0.473), NLRP3 and IL-18 (r=0.6873, P=0.0094), and NLRP1 and NLRP3 (r=0.8040, P=0.0009). Conclusion: The expression of inflammasome markers in LL lesions indicates the ineffectiveness of this protein complex in controlling the infection. Caspase 1 may be involved in the pyroptotic cell death in the lepromatous form of the disease. Inflammasomes may act together in the initial phase of I leprosy; this phenomenon may influence the clinical outcome of the disease. PMID- 30519060 TI - Drug-resistance profiling and transmission dynamics of multidrug-resistant Mycobacterium tuberculosis in Saudi Arabia revealed by whole genome sequencing. AB - Background: In Saudi Arabia, cross-border transmission of multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains might be particularly fostered by high immigration rates. Herein, we aimed to elucidate the transmission dynamics of MDR-MTBC strains and reveal a detailed prediction of all resistance-conferring mutations for the first- and second-line drugs. Methods: We investigated all MDR-MTBC strains collected between 2015 and 2017 from provincial mycobacteria referral laboratories and compared demographic and clinical parameters to a cohort of non-MDR-TB patients using a whole genome sequencing approach. Clusters were defined based on a maximum strain-to-strain genetic distance of five single-nucleotide polymorphisms (SNPs) as surrogate marker for recent transmission, and then investigated molecular drug-resistance markers (37 genes). Results: Forty-eight (67.6%) MDR-MTBC strains were grouped in 14 different clusters, ranging in size from two to six strains; 22.5% (16/71) of all MDR-MTBC isolates were predicted to be fully resistant to all five first-line drugs, and five strains (7.0%) exhibited fluoroquinolone resistance. Moreover, we revealed the presence of 12 compensatory mutations as well as 26 non-synonymous SNPs in the rpoC gene and non-hotspot region in rpoB, respectively. Conclusion: Optimized TB molecular surveillance, diagnosis, and patient management are urgently needed to contain MDR-MTBC transmission and prevent the development of additional drug resistance. PMID- 30519062 TI - Emergence of tigecycline resistance in Escherichia coli co-producing MCR-1 and NDM-5 during tigecycline salvage treatment. AB - Objective: Here, we report a case of severe infection caused by Escherichia coli that harbored mcr-1, bla NDM-5, and acquired resistance to tigecycline during tigecycline salvage therapy. Methods: Antimicrobial susceptibility testing, Southern blot hybridization, and complete genome sequence of the strains were carried out. The genetic characteristics of the mcr-1 and bla NDM-5 plasmids were analyzed. The whole genome sequencing of mcr-1-containing plasmid was completed. Finally, putative single nucleotide polymorphisms and deletion mutations in the tigecycline-resistant strain were predicted. Results: Three E. coli isolates were obtained from ascites, pleural effusion, and stool of a patient; they were resistant to almost all the tested antibiotics. The first two strains separated from ascites (E-FQ) and hydrothorax (E-XS) were susceptible to amikacin and tigecycline; however, the third strain from stool (E-DB) was resistant to tigecycline after nearly 3 weeks' treatment with tigecycline. All three isolates possessed both mcr-1 and bla NDM-5. The bla NDM-5 gene was found on the IncX3 plasmid, whereas the mcr-1, fosA3 and blaCTX-M-14 were located on the IncHI2 plasmid. Mutations in acrB and lon were the reason for the resistance to tigecycline. Conclusion: This is the first report of a colistin-, carbapenem-, and tigecycline-resistant E. coli in China. Tigecycline resistance acquired during tigecycline therapy is of great concern for us because tigecycline is a drug of last resort to treat carbapenem-resistant Gram-negative bacterial infections. Furthermore, the transmission of such extensively drug-resistant isolates may pose a great threat to public health. PMID- 30519063 TI - Distribution and drug resistance of pathogenic bacteria in ventilator-associated pneumonia at a local hospital of North-eastern China. AB - Purpose: To study the distribution of pathogenic bacteria in ventilator associated pneumonia (VAP), and epidemiological characteristics of extended spectrum beta lactamase (ESBL)-producing bacteria. Patients and methods: Lower respiratory tract secretions from 156 patients with mechanical ventilation were collected using a protective specimen brush (PSB), with quantitative bacterial culture carried out and antibiotic sensitivity measured. ESBLs produced by Gram negative bacilli were detected using the double disk diffusion method and monitored by plasmid profiles. Results: Gram-negative bacilli accounted for 78.9% of VAP pathogens, with Acinetobacter baumannii (25%), Pseudomonas aeruginosa (19.7%), and Klebsiella pneumoniae (14.5%) as the most common strains. There were 12 Gram-positive strains detected (15.8%); mostly methicillin-resistant. Staphylococcus aureus and methicillin-resistant coagulase-negative Staphylococcus. There were also four strains of Candida albicans detected (5.26%). Most Gram-negative bacilli are sensitive to imipenem, but A. baumannii is serious resistant. ESBLs were detected in nine strains of Gram-negative bacilli; mainly produced by K. pneumoniae and Escherichia coli, to different degrees of multidrug resistance. Five strains of K. pneumoniae-producing ESBLs were from the same clonal origin, as confirmed by plasmid restriction endonuclease analysis. Conclusion: VAP was mainly caused by Gram-negative bacteria, with high antibiotic resistance rates. Plasmids played an important role in the spread of antibiotic resistance among bacteria. PMID- 30519064 TI - Cost effectiveness of ixekizumab versus secukinumab in the treatment of moderate to-severe plaque psoriasis in Spain. AB - Background: Currently, several biologic agents are available for the treatment of moderate-to-severe plaque psoriasis, including newer agents with similar mechanisms of action and efficacy; therefore, there is a need to evaluate their efficiency in terms of cost effectiveness. Objective: This study evaluates the cost effectiveness of recently approved interleukin (IL)-17A antagonists, ixekizumab and secukinumab, for the treatment of moderate-to-severe plaque psoriasis from the perspective of the Spanish National Health System (NHS). Materials and methods: A Markov model with a lifetime horizon was developed to compare the cost effectiveness of ixekizumab vs. secukinumab in a hypothetical cohort of patients with moderate-to-severe plaque psoriasis. The model used monthly cycles and included four health states: a 12-week induction period, treatment maintenance, best supportive care (BSC), and death. Patients meeting response criteria at the end of the induction period transitioned to maintenance therapy, whereas non-responders transitioned to BSC. It was assumed that, each year, 20% of patients receiving maintenance therapy would discontinue treatment. The model incorporated data from various sources, including published literature, a network meta-analysis, and expert opinion for some variables. Results: Ixekizumab was dominant over secukinumab in that it gained 0.037 more quality adjusted life years (QALYs) and saved ?1951 in total costs over the lifetime horizon. Probabilistic sensitivity analysis showed a 96.6% likelihood that ixekizumab would be cost effective at a threshold of ?30,000 per QALY gained. Conclusion: For the treatment of moderate-to-severe plaque psoriasis in Spain, ixekizumab provided additional QALYs and potential savings for the Spanish NHS compared with secukinumab. Since the magnitude of the differences in costs and QALYs was modest, other factors such as patient preferences (eg, for number of injections) and long-term safety (eg, related to time on the market) may also be important for guiding clinical decisions. PMID- 30519065 TI - Barberry in the treatment of obesity and metabolic syndrome: possible mechanisms of action. AB - Obesity is a consequence of an imbalance between energy intake and energy expenditure. It affects people of both genders and all age groups, ethnicity and socioeconomic groups, and in developed and developing countries. Obesity is often accompanied by the metabolic syndrome (MetS). MetS is characterized by a clustering of cardiovascular risk factors, including high blood pressure, adiposity, dyslipidemia and glucose intolerance, which together increase the risk of atherosclerotic cardiovascular disease, type 2 diabetes mellitus and other causes of mortality. Nowadays, there is a growing interest in the use of plant based agents instead of synthetic drugs to manage chronic diseases such as MetS; one such example is Berberis vulgaris. B. vulgaris contains isoquinonline alkaloids such as berberine, berberrubine and berbamine. Recent studies have proved that berberine exhibits pharmacological activities and positive effects on the risk factors of obesity and MetS. We have reviewed original articles related to the possible molecular mechanisms of action of berberine on obesity and MetS. Berberine suppresses adipocyte differentiation and decreases obesity. It also regulates glucose metabolism via decreasing insulin resistance and increasing insulin secretion. Other effects of berberine include antihyperlipidemic and antihypertensive activities and endothelial protection. PMID- 30519066 TI - Diabetes and depression in Lebanon and association with glycemic control: a cross sectional study. AB - Background: Diabetes mellitus is a chronic noncommunicable disease characterized by hyperglycemia and is associated with chronic complications affecting the overall quality of life. As of 2017, the prevalence of diabetes in Lebanon is estimated to be 14.6%. Depression is noted to be common among Lebanese citizens, present in around 17.3%. This study aims to investigate the prevalence of depression among the diabetic Lebanese citizens and to study its relationship with poor glycemic control and diabetes complications. Methods: In total, 436 diabetic patients participated in this cross-sectional study. Patients with diabetes mellitus attending several private clinics and health care centers were asked to fill out a well-structured questionnaire developed by an expert. Depression was assessed using Beck Depression Inventory (BDI). The study collected demographic information about the participants including their lifestyles, their last reported glycosylated hemoglobin values, and their reported microvascular and macrovascular complications. Data were collected, entered, and analyzed on SPSS software version 23.1. A descriptive analysis is carried out by calculating the mean and standard deviation for continuous variables and number and percentage for categorical ones. Association between categorical variables is evaluated using a chi-squared test. A P-value of <0.05 is considered to be significant. Results: Depression was prevalent among 28.8% of the patients with diabetes mellitus. The average age of participants was 64.08 years. In total, 280 (64.2%) of the participants were females and the average diabetes duration was 8.89 years. There was no significant relationship found between depression and glycemic control. By contrast, a significant association between retinopathy, nephropathy, and stroke and depression was found. Conclusion: Depression was found to be present among 28.8% of the patients with diabetes mellitus in Lebanon; however, no association was established between depression and glycemic control. PMID- 30519068 TI - Protective effects of a novel facial cream against environmental pollution: in vivo and in vitro assessment. AB - Background: The effects of pollution on health have received increasing attention in recent years. Extrinsic skin aging occurs via multiple processes, and pollution is now recognized as a major component, causing increased pigmentation and wrinkles via oxidative mechanisms. We tested the antipollution efficacy of a cosmetic facial cream (FC) by assessing its effects on carbon particle adhesion to skin and on oxidative and inflammatory pathways in the skin. Methods: In an in vivo study, FC was applied once to the forearms of healthy subjects. Carbon E153 powder was applied, and the skin was washed under standardized conditions. Images were taken using a dermoscope to determine the area of particle adherence. Each participant served as their own control, with the contralateral forearm being untreated with the FC but otherwise following the same protocol. In a 5-day ex vivo study, skin explants were treated with the FC daily and exposed to vaporized pollutants on day 2 and day 4 via a closed system. Explants were sampled at baseline and day 5 and culture media on day 5. The parameters evaluated were cellular viability on microscopy, Nrf2 immunostaining, malondialdehyde (MDA) levels in culture, melanin levels, and gene expression profile (TYR, IL6, and CYP1A1). Results: In the in vivo adhesion study, after standardized washing, carbon particle deposition on skin treated with the FC was significantly lower than that on untreated skin. In the ex vivo study, samples treated with the FC had reduced Nrf2 staining and MDA levels vs polluted controls. Melanin did not change significantly. The FC modulated pollution-induced increases in CYP1A1, IL 6, and TYR. Conclusion: This FC reduces particle adhesion to skin after a single application and protects against pollution-induced oxidative and inflammatory pathways in the skin. PMID- 30519067 TI - Detection of tick-borne infection in Morgellons disease patients by serological and molecular techniques. AB - Background: Morgellons disease (MD) is a skin condition associated with Lyme disease (LD) and tick-borne illness. Patients with this skin disorder experience ulcerative lesions that contain multicolored filamentous collagen and keratin inclusions. Infection with various species of Borrelia and other tick-borne pathogens has been detected in tissue and body fluid specimens from MD patients. We sought to explore this association further in a cohort of MD patients. Patients and methods: Sera from 30 patients with MD were tested for antibody reactivity to antigens from the Borrelia burgdorferi (Bb) group and the relapsing fever Borrelia (RFB) group of spirochetes. Tissue and/or body fluid specimens from these patients were also tested for the presence of Bb and RFB infection using PCR technology. In addition, tissue and body fluid specimens were tested for the presence of Bartonella henselae using PCR, and formalin-fixed skin sections from a subset of patients were tested using fluorescent in situ hybridization (FISH) with B. henselae-specific DNA probes. Results: Seroreactivity to Bb, RFB or both was detected in 63% of the cohort, while positive PCR testing for Bb, RFB or both was detected in 53% of the cohort. Overall, 90% of patients tested positive for exposure and/or infection with Borrelia spirochetes. B. henselae infection was detected by PCR in skin sections or body fluids from 20% of the subjects, and B. henselae FISH testing was positive in 30% of the dermatological specimens submitted for study. Conclusion: The study demonstrates an association between MD and positive tests for both Bb and RFB spirochetes. In conjunction with previous studies, our study provides corroborative evidence linking MD to Borrelia infection and tick-borne illness. PMID- 30519069 TI - Efficacy of a repair cream containing Rhealba oat plantlets extract l-ALA-l-GLU dipeptide, and hyaluronic acid in wound healing following dermatological acts: a meta-analysis of >2,000 patients in eight countries corroborated by a dermatopediatric clinical case. AB - Background: The frequency of dermatological acts is increasing. These procedures often cause injuries and traumatic alterations in specific skin layers, slowing down wound healing. Patients and methods: An open observational study lasting 1 month was conducted on 2,363 patients who had undergone various dermatological procedures. This study was conducted in eight European countries and an Asian country during which the tolerance and efficacy of a cosmetic cream based on Rhealba oat plantlets' extract, l-ALA-l-GLU dipeptide, and hyaluronic acid were assessed on patients' wounds. Results: Efficacy was observed 5' after the first application, which leads to an immediate relief, confirmed by the overall efficacy judged by the doctors as good or very good in 96.8% of the cases. In Germany, the efficacy of the same cream was assessed on children suffering from first- or second-degree burns. In this dermatopediatric case, the aim was to support the regeneration process and prevent scarring by using a topical cream rather than a silicon bandage or corticosteroids. A positive effect on skin regeneration and prevention of scaring could already be observed after 4 weeks of application without any undesired complication. Conclusion: This clinical focus complements the previous meta-analysis by demonstrating that the tested cream containing Rhealba oat plantlets' extracts, l-ALA-l-GLU dipeptide, and hyaluronic acid could also be used with a great efficacy in children after thermal burns to prevent scaring. PMID- 30519070 TI - Metformin ameliorated methotrexate-induced hepatorenal toxicity in rats in addition to its antitumor activity: two birds with one stone. AB - Methotrexate (MTX) is a drug used in treatment of various malignancies. Unfortunately, it leads to life-threatening complications including hepatorenal toxicity. Previous studies revealed the protective effects of metformin (MET) on hepatorenal toxicity in other models in addition to its anticancer effects. The current study investigates the effect of MET on MTX-induced hepatorenal toxicity and the possible mechanisms involved in this toxicity which can be overwhelmed by MET. Thirty male rats were divided into 3 groups: normal control, MTX treated and MET/MTX treated. After 7 days, MTX induced hepatorenal toxicity as proved by histological examinations and biochemical analysis of liver and kidney functions. Also, it led to significant increase in hepatic and renal malondialdehyde levels, significant decrease in hepatic and renal total antioxidant capacity levels and Na+/K+-ATPase activities and significant up regulation of mRNA expressions of nuclear factor kappa-light-chain-enhancer of activated B cells, cyclooxygenase-2 and caspase 3 compared with the control group. While, MET could significantly reduce hepatorenal toxicity and counteract the effects of MTX on all measured parameters. In conclusion, MET can be an effective adjuvant to MTX chemotherapy that could ameliorate its hepatorenal toxicity through antioxidant, anti inflammatory and anti-apoptotic mechanisms. PMID- 30519071 TI - Sex differences of inflammation in target organs, induced by intraperitoneal injection of lipopolysaccharide, depend on its dose. AB - Purpose: The aim of our research was to study sex differences and the severity of inflammatory changes in target organs and the peculiarities of immunological disorders when low and high doses of lipopolysaccharide (LPS) were administered to rats. Methods: Male and female 2- to 3-month-old Wistar rats (200-250 g) were injected intraperitoneally with Escherichia coli LPS in one of two doses: 1.5 or 15 mg/kg. In a day after the LPS injection, we studied endotoxin, corticosterone, sex steroids, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity levels in the serum; morphological disorders in the lung, liver, thymus, and spleen; ex vivo production of IL-2, IL-4, tumor necrosis factor (TNF), and interferon gamma (IFNgamma) by splenic cells activated by ConA; and relative amount of T- and B-lymphocytes in the peripheral blood. Results: After the injection of low-dose LPS, the serum endotoxin level increased only in males and was combined with a more pronounced inflammatory response in the lungs and thymus and an increase in ALT and AST activity levels without any changes in corticosterone level. After the injection of high-dose LPS, the inflammatory and pathological changes in the target organs manifested as severe endotoxemia and sex differences of pathological changes in the lungs and liver were not revealed. The level of production of IL-2, IL-4, IFNgamma, and TNF by splenic cells and the number of T-lymphocytes, including cytotoxic cells, in the peripheral blood, decreased in males, which is an evidence of a pronounced suppression of the immune response. Conclusion: We have shown that the morphofunctional changes in the organs of the immune system in females and males, as well as the intensity of the sex differences of inflammation, depend on the severity of systemic inflammatory response, induced by different doses of LPS. PMID- 30519072 TI - The upregulated scavenger receptor CD36 is associated with the progression of nontarget lesions after stent implantation in atherosclerotic rabbits. AB - Background: The incidence of recurrent cardiovascular events from the progression of nontarget lesions (NTLs) is high for percutaneous coronary intervention treated patients. However, the underlying mechanisms have not been thoroughly elucidated. Methods: In this study, ten atherosclerotic rabbits with multiple plaques in the upper and lower segments of abdominal aorta (group A) were randomly divided into two subgroups: group A1 underwent intravascular ultrasound examination and stent implantation in the lower segments of the abdominal aorta (n=5), whereas group A2 was without stenting (n=5). Group B was a control group without balloon injury. The serum levels of high-sensitivity CRP, interleukin-6 (IL-6), oxidized low-density lipoprotein, and CD36 were assessed via ELISA at five time points between the 10th and 18th weeks. The upper abdominal aorta was examined via the immunohistochemical stain and Western blotting of matrix metallopeptidase 9 (MMP-9), CD36, IL-6, and tumor necrosis factor alpha. Results: As a result, we found that stent implantation aggravated serum levels of CD36, oxidative stress, and inflammatory cytokines. Meanwhile, the upper abdominal arterial plaque burden significantly increased after stenting by intravascular ultrasound. Immunohistochemistry and Western blotting showed that the local NTLs' matrix metallopeptidase 9, CD36, IL-6, and tumor necrosis factor alpha expressions in group A1 were significantly higher than those in groups A2 and B (P<0.05-0.01). More importantly, a strong correlation was identified between CD36 expression and NTLs' plaque burden before the rabbits were killed. Conclusion: Taken together, stent implantation accelerated inflammation, induced oxidative stress, and increased the NTLs' progression, which were associated with the upregulated CD36 expression. PMID- 30519073 TI - Bartter syndrome: causes, diagnosis, and treatment. AB - Bartter syndrome is an inherited renal tubular disorder caused by a defective salt reabsorption in the thick ascending limb of loop of Henle, resulting in salt wasting, hypokalemia, and metabolic alkalosis. Mutations of several genes encoding the transporters and channels involved in salt reabsorption in the thick ascending limb cause different types of Bartter syndrome. A poor phenotype genotype relationship due to the interaction with other cotransporters and different degrees of compensation through alternative pathways is currently reported. However, phenotypic identification still remains the first step to guide the suspicion of Bartter syndrome. Given the rarity of the syndrome, and the lack of genetic characterization in most cases, limited clinical evidence for treatment is available and the therapy is based mainly on the comprehension of renal physiology and relies on the physician's personal experiences. A better understanding of the mutated channels and transporters could possibly generate targets for specific treatment in the future, also encompassing drugs aiming to correct deficiencies in folding or plasma membrane expression of the mutated proteins. PMID- 30519074 TI - Genetic polymorphism of the methotrexate transporter ABCG2, blood pressure and markers of arterial function in patients with rheumatoid arthritis: repeated cross-sectional study. AB - Purpose: Methotrexate (MTX) treatment is associated with lower blood pressure (BP) and arterial stiffness in rheumatoid arthritis (RA). We investigated associations between single-nucleotide polymorphism (SNP) of the ATP-binding cassette efflux transporter gene ABCG2 (rs2231142), BP, and arterial stiffness in RA patients treated with MTX. Patients and methods: Clinical and 24-hour peripheral and central BP, arterial wave reflection (Augmentation Index, AIx), arterial stiffness (Pulse Wave Velocity, PWV), and intracellular MTX polyglutamate (MTXPGs) concentrations were assessed in 56 RA patients on stable treatment with MTX using a repeated cross-sectional study design with measurements at baseline and after 8 months. Results: Majority of the RA patients were homozygotes for the normal allele (CC, n=46) whereas 10 were rs2231142 heterozygotes (AC, n=10). MTXPGs concentrations were non-significantly higher in AC when compared to CC (144.3 vs 116.3 nmol/L packed RBCs, P=0.10). At baseline, the AC group had significantly lower age-adjusted clinical systolic BP (SBP) (P=0.01), 24-hour peripheral SBP (P=0.003), and central SBP (P=0.02) when compared to the CC group. However, AIx and PWV values were not significantly different between the two groups. When data from both visits were combined in a single analysis, and additionally adjusted for visit, gender, body mass index, and Disease Activity Score 28, the trend in SBP differences between-groups persisted but was no longer significant. Conclusion: Future studies are required to test the hypothesis that this genetic polymorphism is associated with lower BP, arterial stiffness, and possibly, cardiovascular risk, in RA patients treated with MTX. PMID- 30519075 TI - Effects of a single dose of preoperative pregabalin and gabapentin for acute postoperative pain: a network meta-analysis of randomized controlled trials. AB - Background: Pregabalin (PGB) and gabapentin (GBP) are current and emerging drugs in the field of pre-emptive preoperative analgesia. However, the role of PGB or GBP in acute postoperative pain management still remains elusive. Materials and methods: We conducted a comprehensive literature search of articles published by December 3, 2017. A total of 79 randomized controlled trials with 6,201 patients receiving single-dose premedication were included. Through a network meta analysis (NMA), we validated the analgesic effect and incidence of adverse events by using various doses of PGB or GBP administration. Results: NMA results suggested that the analgesic effect may be dose related. For 24-hour opioid consumption, a consistent decrease was found with the increase in the dose of PGB or GBP. For 24-hour pain score at rest, a high dose (>=150 mg) of PGB was more effective in decreasing pain score than a dose of 75 mg, and a high dose (>=900 mg) of GBP reduced pain intensity than doses of 300 or 600 mg. Moreover, the incidence of adverse reactions varied with varying doses of PGB or GBP. Conclusion: A dose-response relationship was detected in opioid consumption and postoperative pain for a single-dose preoperative administration of PGB and GBP. Making reasonable choice of drugs and dosage may prevent the occurrence of adverse reactions. PMID- 30519076 TI - Clinical observation of the effect of prophylaxis on allodynia in patients with migraine. AB - Objective: The clinical characteristics of migraine with and without allodynia were compared to evaluate the risk factors of cutaneous allodynia in migraine. The effects of prophylactic therapy on allodynia in patients with migraine were assessed based on the change in pain threshold after therapy. Patients and methods: A total of 71 patients with migraine admitted to the Department of Neurology of Shandong Provincial Hospital were recruited in this study. The included patients were aged 18-70 years and did not present positive symptoms according to the nervous system examination. The variation in cutaneous allodynia was assessed for the role of classic prophylactic therapy in migraine-related allodynia, also termed as central sensitization (CS). Patients with migraine were randomized into two groups (topiramate and flunarizine groups), and the effect of drugs was evaluated by the change in cutaneous pain threshold between the two groups. Fifty-five patients were tested for pain threshold due to instrument failure. Pressure allodynia was measured with a force gage, and pricking was measured with Electronic von Frey Anesthesiometer. The pain threshold was measured every 3 months for 6 months. The variations in pain threshold after treatment were compared using t-test and chi 2 test. Results: Allodynia was seen in 70.4% of the patients; of these, 76.3% were females. Female gender, duration of illness, and frequency of migraine attacks per month were significantly associated with allodynia. The rate of allodynia and frequency of headache declined significantly, the number of patients with allodynia was reduced, and the pain threshold improved dramatically after treatment. The composite adverse events were low after treatment with topiramate and flunarizine. Conclusion: Allodynia was observed, especially in females who experienced frequent migraine attacks for a prolonged period. Gender, duration of illness, and number of migraine attacks per month were the major predictors of allodynia. Topiramate and flunarizine administered orally for a short duration can effectively improve the pain threshold and CS of patients with migraine, and efficiently relieve allodynia. PMID- 30519077 TI - Gender, genetics, and analgesia: understanding the differences in response to pain relief. AB - Genetic variations and gender contribute significantly to the large interpatient variations in opioid-related serious adverse effects and differences in pain relief with other analgesics. Opioids are the most commonly used analgesics to relieve moderate-to-severe postoperative pain. Narrow therapeutic index and unexplained large interpatient variations in opioid-related serious adverse effects and analgesia negatively affect optimal perioperative outcomes. In surgical, experimental, chronic, and neuropathic pain models, females have been reported to have more pain than males. This review focuses on literature evidence of differences in pain relief due to multiple genetic variations and gender of the patient. PMID- 30519078 TI - Just how much does it cost? A cost study of chronic pain following cardiac surgery. AB - Objective: The study objective was to determine use of pain-related health care resources and associated direct and indirect costs over a two-year period in cardiac surgery patients who developed chronic post-surgical pain (CPSP). Methods: This multicentric observational prospective study recruited patients prior to cardiac surgery; these patients completed research assistant administered questionnaires on pain and psychological characteristics at 6, 12 and 24 months post-operatively. Patients reporting CPSP also completed a one month pain care record (PCR) (self-report diary) at each follow-up. Data were analyzed using descriptive statistics, multivariable logistic regression models, and generalized linear models with log link and gamma family adjusting for sociodemographic and pain intensity. Results: Out of 1,247 patients, 18%, 13%, and 9% reported experiencing CPSP at 6, 12, and 24 months, respectively. Between 16% and 28% of CPSP patients reported utilizing health care resources for their pain over the follow-up period. Among all CPSP patients, mean monthly pain related costs were CAN$207 at 6 months and significantly decreased thereafter. More severe pain and greater levels of pain catastrophizing were the most consistent predictors of health care utilization and costs. Discussion: Health care costs associated with early management of CPSP after cardiac surgery seem attributable to a minority of patients and decrease over time for most of them. Results are novel in that they document for the first time the economic burden of CPSP in this population of patients. Longer follow-up time that would capture severe cases of CPSP as well as examination of costs associated with other surgical populations are warranted. Summary: Economic burden of chronic post surgical pain may be substantial but few patients utilize resources. Health utilization and costs are associated with pain and psychological characteristics. PMID- 30519079 TI - Evaluation of sexual function in Brazilian women with and without chronic pelvic pain. AB - Purpose: The aim of this study was to evaluate sexual function in women with chronic pelvic pain (CPP) compared to a control group without CPP and to investigate the factors associated with sexual dysfunction in women with CPP. Methods: This cross-sectional study included 100 women with CPP and 100 controls. Sexual function was evaluated using the Female Sexual Function Index (FSFI) and depression and anxiety using the Hospital Anxiety and Depression Scale (HADS). A generalized linear model was used to compare the groups with respect to the overall FSFI score and the scores obtained for each FSFI domain. Multiple logistic regression analysis was used to identify the factors associated with sexual dysfunction in the study group. Results: Anxiety was present in 66.0% of women with CPP in the study group compared to 49.0% of the controls (P=0.022). Depression was detected in 63.0% of women with CPP in the study group and in 38.0% of the controls (P=0.001). Sexual dysfunction was identified in 81.0% of the women with CPP in the study group compared to 58.0% of the controls (P=0.003). Following adjustment, the women with CPP had significantly lower mean scores compared to the controls in the FSFI domains of desire (3.0+/-1.3 vs 3.6+/ 1.3; P=0.038), arousal (2.6+/-1.6 vs 3.4+/-1.9; P=0.002), lubrication (3.2+/-1.9 vs 3.7+/-2.3; P=0.011), orgasm (3.0+/-1.9 vs 3.6+/-2.2; P<0.002), and pain (2.5+/ 1.7 vs 3.4+/-2.2; P<0.001). There was no difference between the groups for the satisfaction domain (P=0.337) or for the overall score (P=0.252). A positive and independent association was found between depression and sexual dysfunction in the women with CPP (P=0.012). Conclusion: In the women with CPP, sexual dysfunction was more common, and the scores in most of the sexual function domains were poorer than in the control group. Concurrently, depression was found to be positively associated with sexual dysfunction in the women with CPP. PMID- 30519080 TI - Impact of opioid dose reduction on individuals with chronic pain: results of an online survey. AB - Background: In 2016, the Centers for Disease Control and Prevention (CDC) released a guideline on opioid prescribing for primary care physicians. Patients with chronic pain receiving long-term opioid therapy were surveyed to assess the incidence and impact of opioid dose reduction following this guideline's promulgation. Methods: Members of an advocacy organization for people with chronic pain were invited to participate in a 16-item, anonymous, online survey conducted in September/October 2017. Eligibility requirements included current treatment of >=7 months' duration for chronic pain with the same extended-release (ER)/long-acting (LA) opioid. The final sample consisted of respondents who reported being on the same ER/LA opioid for >=1 year and excluded respondents whose 1) ER/LA opioid dose increased; 2) ER/LA opioid dose decreased and immediate-release (IR) opioid dose increased; and 3) ER/LA opioid dose was unchanged and IR opioid dose was changed. Survey results were analyzed using z test to ascertain differences between proportion of responses for ER/LA opioid dose decreased vs dose unchanged groups. Results: Of the 511 eligible respondents, 362 respondents were included in the final sample. In the final sample, the subgroup with decreased ER/LA opioid dose (n=149) was significantly more likely (P<= 0.05) than those who reported no dose change (n=213) to rate their condition as "worse" for level of pain (73.2 vs 33.3%), level of function (67.8 vs 31.5%), mental health (64.4 vs 32.9%), ability to work (62.9% of 97 respondents vs 33.8% of 145 respondents), and interpersonal relationships (48.3 vs 25.8%) during the previous 6 months. Conclusion: In this Internet-based survey of people with chronic pain, reduction of ER/LA opioid dose was associated with reduced pain control and diminished function. These results indicate a need for further guidance on how to apply the CDC guideline to patients with chronic pain who are stable on long-term opioid therapy. PMID- 30519081 TI - The efficacy of electromyographic biofeedback on pain, function, and maximal thickness of vastus medialis oblique muscle in patients with knee osteoarthritis: a randomized clinical trial. AB - Introduction: The aim of this survey was to examine the effect of adding electromyographic biofeedback (EMGBF) to isometric exercise, on pain, function, thickness, and maximal electrical activity in isometric contraction of the vastus medialis oblique (VMO) muscle in patients with knee osteoarthritis (OA). Methods: In this clinical trial, 46 patients with a diagnosis of knee OA were recruited and assigned to two groups. The case group consisted of 23 patients with EMGBF associated exercise, and the control group was made up of 23 patients with only isometric exercise. Data were gathered via visual analog scale (VAS) score, the Persian version of the Western Ontario and McMaster Universities Osteoarthritis Index and Lequesne questionnaires, ultrasonography of the VMO, and surface electromyography of this muscle at baseline and at the end of the study. Variables were compared before and after the exercise program in each group and between the two groups. Results: At the end of the study, there were no significant differences between the two groups regarding measured variables. Only the VAS score was significantly less in the case group. Although all assessed parameters, except for VMO muscle thickness, were found to be improved significantly in each group, the degree of change was not significantly different between the two groups, except for VAS score. VMO muscle thickness did not change significantly after exercise therapy in either of the groups. Conclusion: Isometric exercises accompanied by EMGBF and the same exercises without biofeedback for 2 months both led to significant improvements in pain and function of patients with knee OA. Real EMGBF was not superior to exercise without biofeedback in any of the measured variables, except for VAS score. PMID- 30519082 TI - ED50 of intrathecal ropivacaine for cesarean delivery with and without epidural volume extension with normal saline: a randomized controlled study. AB - Background: It was reported that epidural volume extension could decrease the ED50 of intrathecal plain bupivacaine. In this study, we investigated the ED50 of intrathecal hyperbaric ropivacaine followed by epidural normal saline bolus for cesarean section. Methods: Sixty parturients were allocated into two groups in this prospective study. About 10 mL of epidural normal saline was given after the intrathecal dose of hyperbaric ropivacaine in the Group S (normal saline group), and no epidural injection of normal saline was given after the intrathecal ropivacainve injection in the Group C (control group). The dose of intrathecal ropivacaine for each parturient was decided by up-down allocation method. The initial dose was set as 10 mg. Effective anesthesia was defined as the level of T6 or above achieved within 10 minutes after intrathecal injection and no additional epidural drug to complete operation. The Massey formula was applied to calculate the ED50 of intrathecal ropivacaine. Results: The ED50 of intrathecal ropivacaine for cesarean section determined by up-and-down method was 7.51 mg (95% CI, 7.09-7.93 mg) in the Group S and 8.29 mg (95% CI, 7.73-8.85 mg) in the Group C, and there was a significant difference in ED50 of ropivacaine between the two groups (P<0.05). Compared with the Group C, the ED50 of intrathecal ropivacaine decreased when followed by epidural normal saline bolus. Conclusion: The ED50 of intrathecal hyperbaric ropivacaine for cesarean section is 8.29 mg, and it is reduced when followed by epidural normal saline bolus (www.chictr.org.cn, registration number: ChiCTR-ROC-17013382). PMID- 30519083 TI - Penetration and efficacy of transdermal NSAIDs in a model of acute joint inflammation. AB - Purpose: Prescription and OTC non-steroidal anti-inflammatory drugs (NSAIDs) are ubiquitous treatments for pain and inflammation; however, oral administration of these drugs may produce gastrointestinal (GI) side effects. Transdermal (TD) administration of NSAIDs circumvents these adverse events by avoiding the GI tract and, presumably, achieves regional drug levels of therapeutic effect and thereby, fewer off-target complications. Methods: A drug quantification method was developed for ibuprofen and celecoxib in canine plasma and synovial fluid using liquid chromatography and mass spectrometry. This method was employed to evaluate the penetrance of ibuprofen and celecoxib topical formulations in dogs. Effectiveness of these topical NSAID formulations was compared to the equivalent oral drug concentration in a canine sodium-urate model of acute joint inflammation. In this model, pain was quantified using a modified Canine Brief Pain Inventory questionnaire and regional inflammation using joint caliper measurements; the significance of intervention was evaluated using linear mixed models for repeated measures along with Bonferroni corrections. Results: After seven days of chronic topical administration, DelivraTM (DEL) formulations of ibuprofen and celecoxib generated serum levels of 2.9ug/mL and 220ng/mL and synovial fluid levels of 1.8 ug/mL and 203 ng/mL (respectively). In the canine model of acute inflammation, the overall treatment effects as well as the treatment by time interactions were strongly significant (P<0.001) for both drugs. Oral ibuprofen proved uniquely effective at the earliest time point, while all ibuprofen formulations were effective at treating pain at 8.5 and 24.5 hours post-induction. Similarly, all celecoxib formulations (oral and topical) were equally effective at 8.5 and 24.5 hours post-induction. Conclusion: DEL formulations of ibuprofen and celecoxib successfully introduced these NSAIDs into synovial fluid at concentrations similar to those observed in circulation. Furthermore, these formulations reduced symptoms of pain associated with acute inflammation. Oral and transdermally delivered NSAIDs have similar pain relief effects; therefore, a replacement or combinatorial treatment may provide a more stable pain relief profile. In conclusion, this work supports further investigation of TD products in the treatment of regional inflammatory events. PMID- 30519084 TI - Effects of fascia iliaca compartment block combined with general laryngeal mask airway anesthesia in children undergoing femoral fracture surgery: a randomized trial. AB - Background: Postoperative agitation after general anesthesia is a common complication in children; however, pain or uncomfortable feeling is the main reason of emergence agitation. Here, we have investigated the effects of fascia iliaca compartment block (FICB) combined with general laryngeal mask airway (LMA) anesthesia in children undergoing femoral surgery. Methods: Eighty children undergoing femoral surgery were randomly divided into two groups: FICB + LMA group and control group (n=40). The FICB + LMA group received FICB combined with general LMA anesthesia, and the control group received tracheal intubation general anesthesia alone. Anesthesia was maintained with nitrous oxide and sevoflurane. Hemodynamic parameters were monitored, and pain was assessed by verbal numeric score within 24 hours postoperatively. Time to extubation, time to discharge from the postanesthesia care unit and postoperative complications were recorded. Results: Hemodynamic parameters were more stable in the FICB + LMA group than in the control group during anesthesia induction (P<0.05). Verbal numeric score values were lower in the FICB + LMA group than in the control group at 2-8 hours postoperatively (P>0.05). Compared with the control group, the time to extubation and time to discharge from postanesthesia care unit were shorter in the FICB + LMA group (P<0.05). Additionally, postoperative complications were less in the FICB + LMA group. Conclusion: The FICB combined with general LMA anesthesia may provide intra- and postoperative analgesia, shorten emergence time and reduce postoperative agitation in children undergoing femoral surgery. Trial registration: This study is registered at http://www.chictr.org.cn (registration number: ChiCTR-IOR-17012725). PMID- 30519086 TI - "But that is your opinion": the dark side of postmodern pain medicine creating a postmodern patient autonomy. PMID- 30519085 TI - Prevalence of autism traits and attention-deficit hyperactivity disorder symptoms in a clinical sample of children and adolescents with chronic pain. AB - Purpose: Recent research has suggested that autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) may be comorbid to pediatric chronic pain, but the empirical support is yet scarce. Therefore, the current study aimed to investigate the occurrence of traits and symptoms consistent with clinically significant ASD and ADHD in a group of children and adolescents with chronic debilitating pain and examine potential differences in pain and demographic variables between children with and without clinically significant traits and symptoms of ASD and ADHD. Patients and methods: This cross-sectional study included 146 parent-child dyads (102 girls, 111 mothers, children 8-17 years) consecutively referred to a tertiary pain clinic. Parents completed the Social Responsiveness Scale to assess autistic traits, and Conners-3 to measure symptoms of ADHD in their children. Children completed the Lubeck Pain Questionnaire to evaluate experienced pain. Results: Among children, 20 (13.7%) received scores consistent with clinically significant ASD and 29 (19.9%) received scores consistent with clinically significant ADHD, with a combined prevalence of clinically significant ASD/ADHD traits and symptoms of 26% of the total sample. Only 4.8% of children were previously diagnosed with either disorder. Among children with clinically significant ASD traits, girls were more prevalent, parents reported lower health, and the pain was more likely triggered by being in school. Among children with clinically significant ADHD symptoms, there were no gender differences and pain was more likely triggered by the family situation and new situations. No differences regarding pain intensity, duration, or frequency were found between children with and without clinically significant ASD traits or ADHD symptoms. Conclusion: Children with debilitating chronic pain, particularly girls, may present with an elevated risk of having a comorbid, possibly high-functioning, neurodevelopmental disorder. Results suggest that clinical assessment of pediatric chronic pain should include screening for neurodevelopmental disorders. PMID- 30519087 TI - Recovery from acute pediatric complex regional pain syndrome type I after ankle sprain by early pharmacological and physical therapies in primary care: a case report. AB - Background: Complex regional pain syndrome type I (CRPS I) in children is a serious condition disrupting the family and school life of patients with the condition after it fully develops. It has been emphasized that early diagnosis is closely associated with earlier reduction of pain leading to preferable outcomes. Objectives: To report a case of acute CRPS I in a boy who was found to develop this condition by a routine visual analog scale (VAS) pain monitoring and who recovered from CRPS I at an early phase by prompt pharmacological, physical, and educational therapies. Study design: Case report. Case report: A 12-year-old boy sprained his left ankle while playing soccer and was referred to our clinic 4 days after the injury. At the first visit, he could walk, reporting motion pain with a VAS scale of 80 mm. On day 5, pain intensity increased to 100 mm, and a diagnosis of acute CRPS I was made. On day 7, he could not move the injured ankle; therefore celecoxib and pregabalin were administered, and physical and educational therapies started. On day 35, pain intensity was 0 mm and he could walk and run normally. Conclusion: Routine monitoring of VAS for every patient in pain is useful to discover an abnormal transition of VAS, enabling the early diagnosis of CRPS I. Inflammation and peripheral or central sensitization are postulated for early development of CRPS I. The present case suggested a combination of physical therapy and pharmacological intervention with celecoxib and pregabalin reduced peripheral and central sensitization. PMID- 30519088 TI - White coat syndrome and its variations: differences and clinical impact. AB - Hypertension is closely linked to increased cardiovascular risk and development of target organ damage (TOD). Therefore, proper clinical follow-up and treatment of hypertensive subjects are mandatory. A great number of individuals present a variation on blood pressure (BP) levels when they are assessed either in the office or in the out-of-office settings. This phenomenon is defined as white coat syndrome - a change in BP levels due to the presence of a physician or other health professional. In this context, the term "white coat syndrome" may refer to three important and different clinical conditions: 1) white coat hypertension, 2) white coat effect, and 3) masked hypertension. The development of TOD and the increased cardiovascular risk play different roles in these specific subgroups of white coat syndrome. Correct diagnose and clinical guidance are essential to improve the prognosis of these patients. The aim of this review was to elucidate contemporary aspects of these types of white coat syndrome on general and hypertensive population. PMID- 30519089 TI - Prognostic significance of combined preoperative platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio in patients undergoing surgery with stage IB non small-cell lung cancer. AB - Background: Research indicates that the presence of a systemic inflammatory response plays an important role in predicting survival in patients with cancer. The aim of this study was to investigate the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index, and the combination of preoperative LMR and PLR (LMR-PLR) in predicting the survival of patients with stage IB non-small-cell lung cancer (NSCLC). Materials and methods: We retrospectively analyzed clinical data of 577 patients with stage IB NSCLC who underwent pneumonectomy from January 1999 to December 2009. Univariate and multivariate Cox survival analyses were used to evaluate the prognostic indicators, including LMR-PLR. The cutoff values for LMR and PLR were defined by the receiver operating characteristic (ROC) curve analysis. According to the ROC curve, the recommended cutoff values of LMR and PLR were 3.16 and 81.07, respectively. We divided the patients into three groups according to their LMR and PLR status and defined them with different scores. Patients with both high LMR (>3.16) and low PLR (<=81.07) were given a score of 2, whereas those with one or neither were scored 1 or 0, respectively. Survival curves were plotted using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazards analyses were used to identify the factors associated with overall survival (OS). Results: The median follow-up time was 93.77 months. The allocation of the LMR-PLR score was as follows: LMR-PLR = 0, 193 (33.4%) patients; LMR-PLR = 1, 308 (53.4%) patients; and LMR-PLR = 2, 76 (13.2%) patients. After multivariate analysis, our results showed that LMR-PLR was an independent prognostic indicator for OS (P=0.001). The 10-year OS rates were 70.0%, 60.4%, and 49.5% for LMR-PLR =2, LMR-PLR =1, and LMR-PLR =0, respectively (P<0.001). Conclusion: This study demonstrated that preoperative LMR and PLR are simple, readily available, and low-cost biomarkers. Preoperative LMR-PLR score can be used as a valuable prognostic marker for long-term survival in stage IB NSCLC patients who underwent surgery. PMID- 30519090 TI - Can contemporary trials of chemotherapy for HER2-negative metastatic breast cancer detect overall survival benefit? AB - Purpose: Although several trials have demonstrated improved progression-free survival (PFS) with first-line regimens for HER2-negative metastatic breast cancer (mBC), overall survival (OS) benefit is elusive. We calculated required sample sizes to power for OS using published data from recent mBC trials. Patients and methods: Randomized superiority trials of first-line chemotherapy/targeted therapy for HER2-negative mBC including >150 patients, meeting the primary efficacy objective, and published in 2000-2018 were identified. The sample sizes required to power for PFS and OS were calculated retrospectively for each trial using observed results and study/recruitment follow-up durations (alpha=0.05, two-sided log-rank test, 80% power), and summarized as a factor (x) relative to actual sample size. Results: Nine of 13 identified trials reported all information required for retrospective sample size calculation. Six had sample sizes larger than required to demonstrate a significant PFS benefit but all would have required larger sample sizes to demonstrate significant OS benefit with the observed results. In ten trials, the required sample size was >=5-fold larger to power for OS than PFS. Conclusion: Designing trials to test potential new treatments for HER2-negative mBC is challenging, requiring a balance of regulatory acceptability, feasibility, and realistic medical assumptions to calculate sample sizes. Powering for OS is particularly difficult in heterogeneous populations with long postprogression survival, potential crossover, heterogeneous poststudy therapy, and evolving treatment standards. Validated surrogate endpoints are critical. Ongoing trials of cancer immunotherapy (new mode of action) in triple-negative mBC (more homogeneous, shorter OS and postprogression survival, fewer treatment options) may show a new pattern. PMID- 30519091 TI - Feasibility single-arm study of a medical device containing Desmodium adscendens and Lithothamnium calcareum combined with chemotherapy in head and neck cancer patients. AB - Background: Neoplasms of the head and neck represent approximately 5% of cancers and they require complex multidisciplinary clinical management. Desmodium adscendens (Desmodium) is a plant that possesses anti-allergic, antioxidant and hepatoprotective properties. Lithothamnium calcareum (Lithothamnium) is a calcified seaweed that possesses remineralization properties and the ability to maintain homeostasis. Aim: In this single-arm study, we investigated the efficacy of a combination therapy based on Desmovit(r) which contains Desmodium and Lithothamnium, and chemotherapy in patients with head and neck cancer. Methods: Twelve patients with histological or cytological diagnosis of stage IV head and neck cancer were enrolled in this study that was approved by the ethics committee of the Unita Operativa Complessa (UOC) di Oncologia Medica Azienda Ospedaliera Ospedali Riuniti Marche Nord and followed the Declaration of Helsinki guidelines. The patients were monitored by investigation of the performance status according to the Glasgow Prognostic Score (GPS), which evaluates the plasma level of C reactive protein and albumin levels, and the Eastern Cooperative Oncology Group (ECOG) examination. Pain and fatigue were also monitored using the visual analog scale and visual analog fatigue scale, respectively. All the above parameters were assessed biweekly to week 10. Results: GPS, ECOG, and albumin remained stable throughout the study with a trend towards a decrease in GPS and albumin at week 10 post-treatment. Pain significantly improved at week 8 (P<0.05) while fatigue improved at weeks 8 and 10 (all P<0.01). Conclusion: We found that chemotherapy, combined with Desmodium and Lithothamnium, improved pain and fatigue in head and neck cancer patients, although we cannot confirm if this was due to Desmodium and Lithothamnium or chemotherapy. The improvement in pain and fatigue was supported by the ECOG performance status remaining stable with the highest score being equal to 2 throughout the study and a trend towards an improvement in GPS performance status and albumin levels. PMID- 30519092 TI - Nomogram application to predict overall and cancer-specific survival in osteosarcoma. AB - Purpose: A prognostic nomogram was applied to predict survival in osteosarcoma patients. Patients and methods: Data collected from 2,195 osteosarcoma patients in the Surveillance, Epidemiology, and End Results (SEER) database between 1983 and 2014 were analyzed. Independent prognostic factors were identified via univariate and multivariate Cox analyses. These were incorporated into a nomogram to predict 3- and 5-year overall survival (OS) and cancer-specific survival (CSS) rates. Internal and external data were used for validation. Concordance indices (C-indices) were used to estimate nomogram accuracy. Results: Patients were randomly assigned into a training cohort (n=1,098) or validation cohort (n=1,097). Age at diagnosis, tumor site, histology, tumor size, tumor stage, use of surgery, and tumor grade were identified as independent prognostic factors via univariate and multivariate Cox analyses (all P<0.05) and then included in the prognostic nomogram. C-indices for OS and CSS prediction in the training cohort were 0.763 (95% CI 0.761-0.764) and 0.764 (95% CI 0.762-0.765), respectively. C indices for OS and CSS prediction in the external validation cohort were 0.739 (95% CI 0.737-0.740) and 0.740 (95% CI, 0.738-0.741), respectively. Calibration plots revealed excellent consistency between actual survival and nomogram prediction. Conclusion: Nomograms were constructed to predict OS and CSS for osteosarcoma patients in the SEER database. They provide accurate and individualized survival prediction. PMID- 30519094 TI - Identification of potential key genes associated with ovarian clear cell carcinoma. AB - Background: Ovarian cancer is the major cause of death from cancer among females worldwide. Ovarian clear cell carcinoma (OCCC) is considered a distinct histopathologic subtype with worse prognosis and resistance to conventional chemotherapy. Materials and methods: We analyzed five microarray datasets derived from the Gene Expression Omnibus database. GEO2R tool was used to screen out differentially expressed genes (DEGs) between OCCC tumor and normal ovary tissue. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed using the g:Profiler database and Cytoscape. Based on Search Tool for the Retrieval of Interacting Genes, we performed protein-protein interaction (PPI) network analysis on the DEGs. Real-time PCR (RT-PCR) and Western blotting in frozen samples of normal ovary and OCCC were performed to verify the expression difference of hub genes in OCCC patients. Results: Thirty upregulated DEGs and 13 downregulated DEGs were identified by cross referencing. Six were chosen as hub genes with high connectivity degree via PPI network analysis, including two upregulated and four downregulated. RT-PCR and Western blotting results showed significant expression difference of the two upregulated genes, SPP1 and EPCAM, between tumor and normal tissues. Conclusion: Our research suggests that SPP1 and EPCAM are overexpressed in OCCC compared with normal ovary tissue. Clinical study of large sample is required to evaluate the value of SPP1 and EPCAM in the precision treatment and prognostic influence on OCCC in the future. PMID- 30519093 TI - Histone deacetylase 6 expression in metastatic lymph nodes is a valuable prognostic marker for resected node-positive esophageal squamous cell cancer. AB - Background: Histone deacetylase 6 (HDAC6) exerts enzymatic deacetylation activity on histones and on non-histone substrates and plays a key role in microtubule dynamics and chaperone activities. In addition, previous studies have demonstrated its role in cancer progression. However, its clinical significance in esophageal squamous cell cancer (ESCC) has not been elucidated. We investigated the correlation of HDAC6 expression and clinical outcome in a group of T3N1-3M0 surgically resected ESCCs. Methods: Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs). Immunohistochemistry was utilized to evaluate HDAC6 protein levels. The relationship between patient outcomes and HDAC6 expression was analyzed statistically. Results: The level of HDAC6 expression in ESCC MLNs was found to be significantly lower than that in PTs (P<0.001). Patients with lower MLN HDAC6 expression demonstrated improved overall survival (P=0.011) and disease-free survival (P=0.012) than those with higher HDAC6 expression. HDAC6 expression levels in PTs revealed no prognostic significance. Multivariate analysis showed that the MLN HDAC6 expression level was an independent prognostic factor for both overall survival (HR 1.456, P=0.029) and disease-free survival (HR 1.432, P=0.033). Conclusion: High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC. We should take into account the protein expression of MLNs when assessing prognosis in patients with lymph-node involvement. PMID- 30519095 TI - Osthole sensitizes with radiotherapy to suppress tumorigenesis of human nasopharyngeal carcinoma in vitro and in vivo. AB - Background: Radiotherapy is one of the most comment and useful treatment for nasopharyngeal carcinoma (NPC), but the radioresistance remains a major obstacle. Osthole, a natural coumarin derivative, has been shown to have anti-tumor and anti-inflammatory activity. However, the relationship between osthole and NPC treatment, especially for radiotherapy, is still elusive. Methods: Osthole with or without X ray radiotherapy treated with CNE2 cells, a human EC cell line. Cell viability, proliferation, migration and apoptosis were measured by MTT, colony formation, Annexin V/PI double staining, Transwell assay, respectively. NPC tumor models were established on BALB/c nude mice by subcutaneously injection of CNE2 cells and the effect of osthole and radiotherapy on tumor growth in vivo was studied. Results: We found that in a dose-dependent manner, osthole could individually, and synergistically with radiotherapy, reduce NPC cell (CNE2) viability, proliferation, migration, and invasion, and induce apoptosis, respectively. This effect of anti-tumor growth and induction of apoptosis was further confirmed in mice induced by subcutaneously injection with CNE2 cells and following treated with osthole or/and radiation. Conclusion: Osthole increases the effect of radiotherapy on anti-human nasopharyngeal cancer. PMID- 30519096 TI - miRNA expression profiles in Smad4-positive and Smad4-negative SW620 human colon cancer cells detected by next-generation small RNA sequencing. AB - Background and aims: SMAD4, as a tumor suppressive gene in human colon cancer, inhibits the metastasis of colon adenocarcinoma cells. However, the molecular mechanisms are unclear. miRNAs play an important role in the pathogenesis and progression of cancer. Methods: In this study, a deep sequencing technique was used to screen Smad4-regulated miR-NAs in human colon cancer SW620 cell line. Using a next-generation small RNA sequencing approach, we compared the miRNA expression profiles of SW620 colon cancer cells transfected with smad4 lentiviral vector with those transfected with control vector. Six samples were selected and sequenced randomly each from control group (smad4-negative cell) and Smad4 group (Smad4-positive cells). Quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB) was used to validate the results of sequencing. Results: Smad4 reexpression significantly upregulated 43 known miRNAs and downregulated 10 known miRNAs expression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis of predicted miRNAs targets showed that these genes were mainly involved in protein-binding transcription factor activity, vascular smooth muscle contraction, pathways in cancer metastasis, and phosphatidylinositol 3-kinase-Akt signal pathway. qRT-PCR and WB validated the partial results of sequencing. Reexpression of Smad4 inhibited colon cancer cell migration and invasion. Smad4 reexpression increased the expression of E-cadherin (E-cad) and decreased the Vimentin (Vim) and Matrix Metalloproteinase-9 expression. Restoration of SMAD4 results in a marked decrease of Vim by inhibiting p-AKT and p-EPHA2, but significantly increased the E-cad by AKT-EPHA2 pathways. Conclusion: Smad4 inhibits the migration and invasion ability of colon cancer cells in vitro and this is the first report of Smad4-mediated miRNA expression profiling in Smad4 positive and Smad4-negative SW620 human colon cancer cells, which may help us better understand the role of Smad4 in inhibiting the metastasis of colon cancer cells and its possible molecular mechanisms. PMID- 30519097 TI - Upregulation of centromere protein F is linked to aggressive prostate cancers. AB - Background: Centromere protein F (CENPF) is a key component of the kinetochore complex and plays a crucial role in chromosome segregation and cell cycle progression. Recent work suggests that CENPF upregulation is linked to aggressive tumor features in a variety of malignancies including prostate cancer. Materials and methods: Using a highly annotated tissue microarray, we analyzed CENPF protein expression from a cohort of 8,298 prostatectomized patients by immunohistochemistry to study its effect on prostate-specific antigen recurrence free survival. Results: CENPF overexpression was found in 53% of cancers, and was linked to higher Gleason grade, advanced pathological tumor stage, accelerated cell proliferation, and lymph node metastasis (p<0.0001, each). A comparison with other key molecular features accessible through the microarray revealed strong associations between CENPF overexpression and presence of erythroblast transformation-specific (ETS)-related gene (ERG) fusion as well as phosphatase and tensin homolog deletion (p<0.0001, each). CENPF overexpression was linked to early biochemical recurrence. A subset analysis revealed that this was driven by the ERG-negative subset (p<0.0001). This was independent of established preoperative and postoperative prognostic parameters in multivariate analyses. Conclusion: The results of our study identify CENPF overexpression as an important mechanism and a potential biomarker for prostate cancer aggressiveness. PMID- 30519098 TI - Does the use of targeted agents in advanced gastroesophageal cancer increase complete response? A meta-analysis of 18 randomized controlled trials. AB - Purpose: We aimed to investigate whether the use of targeted agents (TAs) in advanced gastroesophageal cancer (GEC) increased the complete response (CR) and to assess the surrogate endpoints for survival in the targeted treatment of GEC by using a meta-analysis of randomized controlled trials (RCTs). Methods: Eligible studies were identified using Medline, PubMed, and meeting abstracts. Searches were last updated on April 30, 2018. We calculated the incidence and Peto odds ratio (Peto OR) of CR events in patients assigned to TAs compared with controls. Simple linear regression models were fitted for median overall survival (OS) and each surrogate [median progression-free survival (PFS), CRs, objective response rate (ORR), and disease control rate (DCR), respectively]. Results: A total of 7,892 GEC patients from 18 RCTs were included for analysis. The incidence of CR in GEC patients treated with TAs was 2.0% (95% CI, 1.3%-3.0%) compared with 1.7% (95% CI, 1.0%-2.7%) in the control arms. The use of TAs in advanced GEC had a tendency to improve the possibility of archiving CR (Peto OR 1.42; 95% CI, 0.98-2.04; P=0.064) compared with controls. Subgroup analysis according to treatment TAs showed that the addition of antiepidermal growth factor receptor (EGFR) agents to chemotherapy in GEC significantly improved the CR rate in comparison with control (Peto OR 1.77; 95% CI, 1.02-3.09; P=0.044), but not for other molecular TAs (P=0.49 for angiogenesis inhibitors, P=0.66 for mesenchymal-epithelial transition inhibitors). We also found that the addition of TAs to first-line therapy (Peto OR 1.41; 95% CI, 0.94-2.11; P=0.098) had a tendency to increase the chance of obtaining a CR, but not for second-line therapy (Peto OR 1.47; 95% CI, 0.60-3.55; P=0.40). In addition, correlation analysis indicates that PFS, ORR, and DCR were strongly correlated with OS for GEC patients receiving TAs (r=0.85 for PFS; r=0.86 for ORR; r=0.81 for DCR). No marked correlation was found between OS and CRs (r=0.43; P=0.18). Conclusion: Although the CR is a rate event in advanced GEC patients, adding the TAs to therapies, especially for anti-EGFR agents, increases the chance of archiving CR in comparison with the controls. PFS, ORR, and DCR are significantly correlated with OS and could be used as surrogate endpoints in patients with GEC who have received TA therapy, but not for CR. PMID- 30519099 TI - The role of postoperative radiotherapy in pediatric patients with grade II intracranial ependymomas: a population-based, propensity score-matched study. AB - Purpose: The main objectives of this study were to clarify the efficacy of postoperative radiotherapy (PORT) for pediatric intracranial grade II ependymomas (EPNs) and to explore whether various characteristics are associated with different outcomes in patients with and without PORT. Patients and methods: Data from patients younger than 18 years diagnosed with grade II intracranial EPNs and treated by surgery, with or without PORT, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2013 data set). Propensity score-matched analysis was conducted to balance clinical variables. Patient characteristics were stratified and analyzed. Results: In total, data from 632 patients with grade II EPNs treated by cancer-directed surgery with or without PORT were obtained from the SEER database. Multivariable Cox analysis in the matched cohort suggested that undergoing PORT (overall survival [OS], P=0.020; cancer-specific survival [CSS], P=0.031), undergoing gross total resection (GTR; subtotal resection [STR] vs GTR; OS, P<0.001; CSS, P<0.001), and older age (OS, P<0.001; CSS, P<0.001) were the independent predictors of superior prognosis. Stratified analysis demonstrated that patient characteristics, including infratentorial location, younger age, and STR, were associated with benefit from PORT, while the survival advantage was not detected in patients who underwent GTR. Conclusion: Propensity score-matched analysis using SEER data indicates survival advantages of PORT. Given the strong prognostic associations with extent of resection and patient age, we recommend PORT for younger patients treated by STR. PMID- 30519100 TI - Impact of physical activity and sleep quality on quality of life of rural residents with and without a history of cancer: findings of the Day and Night Study. AB - Background: Lifestyle behaviors may impact quality of life (QoL). The relative impact of physical activity and sleep quality on QoL of individuals with and without a history of cancer living in underserved rural communities requires further study to inform health care and public health initiatives. Methods: Individuals with and without a history of cancer were recruited from rural Virginia. We collected information on physical activity level (PAL), sleep quality (Pittsburgh Sleep Quality Index), and QoL (Short Form-36). Additional dimensions of physical activity and sleep were measured including ambient light exposure and sleep duration via Actiwatch2, and serum vitamin D and urine melatonin, which are markers of outdoor activity and sleep. Results: A total of 124 cancer survivors and 48 cancer-free individuals were enrolled in the study. Mean age was 59 years, with the majority being women (89%) and Caucasian (76%). Breast cancer was the most common cancer (72%), and mean time from diagnosis to the survey was 8.1 years. Survivors were significantly less active, more likely to be inactive, and had significantly worse sleep quality and physical and mental health relative to cancer-free individuals (P<0.05). Quality of sleep and average sleep time were associated with physical (r=-0.371, P<0.001; r=-0.327, P<0.000) and mental health (r=-0.442, P=<0.001; r=-0.265, P<0.004), as was PAL (r=0.181, P=0.019; r=0.288, P=0.003). Self-reported outdoor activity was associated with mental health (r=0.233, P=0.003) and vitamin D3 (r=0.193, P=0.015). No association was found between melatonin, sleep quality, and QoL. Sleep quality, cancer status, body mass index, and sleep time were predictive of physical health, while sleep quality, sleep time, and outdoor activity were predictive of mental health. Conclusion: Quality of sleep is a significant predictor of mental and physical health, and important for cancer survivors who experience poorer QoL. Outdoor activity should be encouraged to improve mental health and vitamin D status, and interventions to improve sleep for those with poor sleep quality should be considered in cancer survivorship planning. PMID- 30519101 TI - Risk score for non-small cell lung cancer patients starting checkpoint inhibitor treatment. AB - Background: Prognosis of metastatic non-small cell lung cancer significantly improved with the availability of checkpoint inhibitors (anti-PD-1/PD-L1). Unfortunately, reliable biomarkers to predict treatment benefit are lacking. Patients and methods: We prospectively collected clinical and laboratory data of 56 non-small cell lung cancer patients treated with a checkpoint inhibitor. The aim was to identify baseline parameters correlating with worse outcome and to create a risk score that enabled to stratify patients into different risk groups. As inflammation is known to promote tumor growth, we focused on inflammation markers in the blood. Disease control (DC) was defined as complete response, partial response, and stable disease on CT scan according to RECIST 1.1. Results: Half of the patients achieved DC. Four parameters differed significantly between the DC group and the no disease control group: Eastern Cooperative Oncology Group performance status (P=0.009), number of organs with metastases (P=0.001), lactate dehydrogenase (P=0.029), and ferritin (P=0.005). A risk score defined as the number of these parameters (0= no risk factor) exceeding a threshold (Eastern Cooperative Oncology Group performance status >=2, number of organs with metastases >=4, lactate dehydrogenase >=262U/L, and ferritin >=241 ug/L) was associated with overall survival and progression-free survival. Overall survival at 6 and 12 months is as follows: Scores 0-1: 95% and 95%; Score 2: 67% and <=33%; Scores 3-4: 15% and 0%. Progression-free survival at 6 and 12 months is as follows: Scores 0-1: 81% and 50%; Score 2: 25% and <=25%; Scores 3-4: 0% and 0%. Conclusion: We propose an easy-to-apply risk score categorizing patients into different risk groups before treatment start with a PD-1/PD-L1 antibody. PMID- 30519102 TI - Transarterial chemoembolization with radiofrequency ablation versus hepatectomy in hepatocellular carcinoma beyond the Milan criteria: a retrospective study. AB - Purpose: To compare the efficacies of transarterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) with hepatectomy. Prognostic factors for the patient groups were analyzed. Patients and methods: Data of 314 newly diagnosed cases of hepatocellular carcinoma beyond the Milan criteria were studied from January 2012 to December 2013 in our hospital. Forty-four patients were excluded owing to loss to follow-up (27 cases) or missing imaging data (17 cases); finally, 270 patients were included. All patients underwent TACE combined with RFA (TR group, 136 patients) or hepatectomy (HT group, 134 patients). Efficacy evaluation and prognostic factor analysis of the groups were conducted. Overall survival (OS) rate, progression-free survival (PFS) rate, and major complications were recorded. Results: The 1-, 2-, 3-, and 5-year OS rates and median survival times were 98.5%, 83.1%, 66.2%, 37.1%, and 46 months, respectively, for the TR group and 89.6%, 69.4%, 53.7%, 30.3%, and 38 months, respectively, for the HT group. There were significant statistical differences in survival rate and median survival time between the groups. Median PFS was 21 months for the TR group and 8 months for the HT group. Difference between groups was statistically significant. Multivariate analysis showed treatment method, tumor diameter and number, Child-Pugh classification, antiviral therapy, and alpha-fetoprotein levels were the independent factors affecting OS rates. Treatment mode and tumor diameter and number were the independent factors affecting PFS. Conclusion: TACE with RFA is superior to hepatectomy in hepatocellular carcinoma treatment beyond the Milan criteria. PMID- 30519103 TI - Impact of the anterior commissure involvement on the survival of early glottic cancer treated with cricohyoidoepiglottopexy: a retrospective study. AB - Background: Laryngeal early glottic tumors can benefit from different treatment modalities, including transoral laser microsurgery, open partial horizontal laryngectomy (OPHL), and radiotherapy. However, the treatment of early glottic tumors with the involvement of the anterior commissure remains controversial. The studies about the role of anterior commissure involvement in oncologic outcomes in patients with early glottic cancer treated with supracricoid laryngectomy (SCL) are very few. For this reason, we conducted a retrospective study to evaluate local recurrence-free survival and specific survival in patients with and without involvement of the anterior commissure who underwent SCL with cricohyoidoepiglottopexy. Methods: This retrospective study has been carried out on patients with T1b-T2 glottic squamous cell carcinoma submitted to SCL with cricohyoidoepiglottopexy. The patients' demographic and clinical data were collected, and the histological findings of the surgical specimens were reviewed to identify patients who had involvement of the anterior commissure. Results: A total of 72 patients were included in the study; two of them were female and 70 were male. The mean age at diagnosis was 61.5+/-8.0 SD years. In 26 of the 72 (36.2%) patients, anterior commissure was not pathologically involved (group A), while in 46 (63.8%) patients, it was involved (group B). The 5-year local recurrence-free survival rate was 96.1% and 93.48% in groups A and B, respectively, P=0.09. The 5-year disease-specific survival rate was 92.31% and 95.65% in groups A and B, respectively, P=0.057. Conclusion: SCL with cricohyoidoepiglottopexy seems to be an adequate treatment modality, even for T1b T2 glottic tumors with anterior commissure involvement. PMID- 30519104 TI - Overexpression of RALY promotes migration and predicts poor prognosis in hepatocellular carcinoma. AB - Introduction: RALY plays a critical role in promoting invasiveness and is associated with poor prognosis in different types of cancers. However, the prognostic value of RALY and its precise role in hepatocellular carcinoma (HCC) remain unknown. Materials and methods: We detected the expression of RALY in 127 clinical HCC tissue samples and seven HCC cell lines by immunohistochemical staining and Western blotting. The prognostic value of RALY expression was assessed using the Kaplan-Meier method. The expression and prognostic value of RALY were also studied by bioinformatics analysis of data from the Gene Expression Omnibus and The Cancer Genome Atlas. The biological influence of RALY on HCC cell lines was studied using proliferation, transwell migration, and invasion assays in vitro. Results: The expression of RALY in HCC tissues was significantly higher than that in adjacent normal liver tissues. Abnormally high expression of RALY was associated with tumor size (P=0.031), TNM stage (P=0.026), presurgical serum AFP levels (P=0.025), and vascular invasion (P=0.001). Kaplan Meier analysis demonstrated that higher expression of RALY correlated with poorer overall survival and disease-free survival in HCC patients. High RALY expression was an independent adverse prognostic factor for overall survival (HR =2.559, 95% CI: 1.710-3.827, P<0.001) and disease-free survival (HR =2.053, 95% CI: 1.384 3.047, P<0.001) in HCC. Moreover, knockdown of RALY expression using a specific shRNA suppressed the proliferation, migration, and invasion capabilities of HCC cells in vitro. Knockdown of RALY expression in HCC cell lines resulted in upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and snail. Conclusion: Taken together, our results indicate that RALY represents a biomarker for the prognosis of patients with HCC and highlight the importance of RALY as an oncogene in HCC. PMID- 30519105 TI - Gene expression of hENT1, dCK, CDA, dCMPD and topoisomerase IIalpha as an indicator of chemotherapy response in AML treated with cytarabine and daunorubicin. AB - Purpose: Acute myeloid leukemia patients are commonly treated with cytarabine (Ara-C) and anthracyclines but the sustained remission rate is not very promising. We explored the role of drug-metabolizing enzymes and transporters in the therapeutic response. Patients and methods: Bone marrow and peripheral blood samples of 90 newly diagnosed acute myeloid leukemia patients treated with standard 3+7 regimen were analyzed through real-time PCR for expression of human equilibrative nucleoside transporter 1, deoxycytidine kinase, cytidine deaminase (CDA), deoxycytidine monophosphate deaminase (dCMPD) and topoisomerase IIalpha (Topo-IIa). The expression of these markers was studied in relationship with good (persistent remission) and poor therapeutic response (relapse/resistance). Results: High Topo-IIa expression in peripheral blood was associated with good response (P=0.006). Relapse was higher among low expressors of Topo-IIa in peripheral blood (OR: 26.25). Bone marrow Topo-IIa expression followed a similar trend but did not reach statistical significance. In contrast, patients with high bone marrow dCMPD expression had poor response (OR: 3; P=0.043). One-year disease free survival (DFS) was better among those with high bone marrow Topo-IIa (P=0.04) or CDA (P=0.03) expression. High bone marrow Topo-IIa expression also had better DFS at 6 months (P=0.04) and at 12 months (P=0.04). Conclusion: High expression of Topo-IIa in peripheral blood is a favorable indicator of persistent remission, good therapeutic response and DFS. High dCMPD and low CDA expression in bone marrow is associated with poor therapeutic outcome. PMID- 30519106 TI - Tumor-suppressive function of SIRT4 in neuroblastoma through mitochondrial damage. AB - Background: SIRT4 is a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent enzymes located in the mitochondria, and is involved in regulating energy metabolism, stress response, and cellular lifespan in mammalian cells. However, its function in human neuroblastoma (NB) remains unexplored. Methods: Expression of SIRT4 in 158 pairs of human NB tumor tissues and adjacent normal tissues collected from March 2009 to October 2012 was analyzed by immunohistochemistry, Western blotting, and real-time fluorescence quantitative PCR. For in vitro study, SIRT4 was overexpressed in SH-SY5Y, SK-N-BE, and IMR-32 cells to study the effects of SIRT4 expression on proliferation, invasion, and migration of human NB cells and on mitochondrial function. Results: SIRT4 gene expression in human NB tumor tissues was significantly lower than that in adjacent normal tissues (P<0.001). SIRT4 expression was lower in NB patients with higher International Neuroblastoma Staging System stage (P=0.018), with lymph node metastasis, than patients without lymph node metastasis (P<0.001). Survival times of NB patients with low expression of SIRT4 were significantly shorter than those of patients with high expression of SIRT4 (P=0.0036). Overexpression of SIRT4 significantly reduced the proliferation, invasion, and migration ability of NB cells as well as mitochondrial energy production, and caused SIRT1 upregulation and mitochondrial damage in NB cells. Conclusion: SIRT4 exhibits a tumor suppressor function in human NB and inhibits mitochondrial metabolism and SIRT1 expression in tumor cells, thereby reducing the energy metabolism of tumor cells. These results suggest that SIRT4 may be a new therapeutic target for human NB. PMID- 30519107 TI - Prognostic value of TIGAR and LC3B protein expression in nasopharyngeal carcinoma. AB - Purpose: Autophagy, the process responsible for degrading cytoplasmic organelles to sustain cellular metabolism, has been associated with cancer initiation and progression. As TP53-induced glycolysis and apoptosis regulator (TIGAR) is among the important genes that can regulate autophagy, we aimed to investigate the correlation between the expression levels of TIGAR and the autophagy-related protein microtubule-associated protein 1 light chain 3 (LC3B), as well as their association with clinical outcomes, in nasopharyngeal carcinoma (NPC) patients. Methods: We detected the expressions of TIGAR and LC3B in 182 NPC tissue samples via immunohistochemical staining. Results: A significant correlation between TIGAR and LC3B expressions was identified (P=0.045). Moreover, survival analysis showed that TIGAR- or LC3B+ expression was associated with improved overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival rates, compared with TIGAR+ or LC3B- expression, respectively. Meanwhile, when combining TIGAR with LC3B expression in terms of prognostic value, patients with TIGAR+/LC3B- expression were significantly disadvantaged with regard to overall survival, local regional failure-free survival, distant failure-free survival, and failure-free survival compared with other groups based on the log-rank test and Cox regression analyses (all P<0.05). Conclusion: TIGAR and LC3B may be novel biomarkers for predicting the prognosis of NPC patients and could be utilized as potential targets for future therapeutics aimed at treating NPC patients. PMID- 30519108 TI - Carotid blowout syndrome: modern trends in management. AB - Carotid blowout syndrome (CBS) refers to rupture of the carotid artery and is an uncommon complication of head and neck cancer that can be rapidly fatal without prompt diagnosis and intervention. CBS develops when a damaged arterial wall cannot sustain its integrity against the patient's blood pressure, mainly in patients who have undergone surgical procedures and radiotherapy due to cancer of the head and neck, or have been reirradiated for a recurrent or second primary tumor in the neck. Among patients irradiated prior to surgery, CBS is usually a result of wound breakdown, pharyngocutaneous fistula and infection. This complication has often been fatal in the past, but at the present time, early diagnosis and modern technology applied to its management have decreased morbidity and mortality rates. In addition to analysis of the causes and consequences of CBS, the purpose of this paper is to critically review methods for early diagnosis of this complication and establish individualized treatment based on endovascular procedures for each patient. PMID- 30519109 TI - Prognosis of patients with neuroendocrine tumor: a SEER database analysis. AB - Background: Neuroendocrine tumors (NETs) are a group of heterogeneous cancers arising from a variety of anatomic sites. Their incidence has increased in recent years. This study aimed to analyze the prognosis of NETs originating from different anatomic sites. Methods: We identified 73,782 patients diagnosed with NETs from the Surveillance Epidemiology and Ends Results (SEER) database from 1973 to 2014. Clinical data were compared between patients with different primary tumor sites using the chi-squared test. Differences in survival among NET patients with different tumor sites were compared by Kaplan-Meier analysis. Cox proportional hazard models were performed to identify the prognostic factors of overall survival. Results: In this cohort, the lung/bronchus was the most common site of NETs, accounting for 30.6%, followed by the small intestine (22.2%), rectum (16.2%), colon (13.4%), pancreas (10.8%), and stomach (6.8%). Totally, 73,782 patients were selected for this cohort from 1973 to 2014. The median survival duration was 41 months. The 1-, 3-, 5-, and 10-year overall survival rates for patients with NETs were 72.8%, 52.7%, 39.4%, and 18.1%, respectively. Patients with NETs located in the rectum had the best prognosis, followed by those with NETs in the small intestine (HR, 1.660, 95% CI, 1.579, 1.744), lung/bronchus (HR, 1.786, 95% CI, 1.703, 1.874), stomach (HR, 1.865, 95% CI, 1.755, 1.982), and colon (HR, 1.896, 95% CI, 1.799, 1.999). Patients with NETs in the pancreas had the highest risk of mortality (HR, 2.034, 95% CI, 1.925, 2.148). Conclusion: Significant differences in survival were found among various primary tumor sites. NETs in the rectum had the best prognosis, while those in the pancreas had the worst. Primary tumor sites might be one of the most useful outcome predictors in patients with NETs. PMID- 30519111 TI - Fall injuries, associated deaths, and 30-day readmission for subsequent falls are increasing in the elderly US population: a query of the WHO mortality database and National Readmission Database from 2010 to 2014. AB - Purpose: Clinicians anecdotally noted that elderly patients who suffered from traumatic injuries (falls or other injuries) often re-present and are readmitted with fall injuries. Herein, we hypothesized that fall injuries and fall-related deaths and readmissions are increasing over time, and assessed whether the overall rates of death, hospital admission, and 30-day readmission due to falls increased from 2010 to 2014 in the elderly population (>=65) in the US. Patients and methods: The WHO mortality database and the National Readmission Database (NRD) were queried to assess rates of deaths and hospital admissions and 30-day readmissions associated with fall injuries in the elderly population that presented with trauma. Descriptive statistics were obtained. The generalized linear mixed modeling (GLMM) framework was utilized to examine the relationship between fixed-effect predictor variables and the dichotomous outcome, indicating readmission within 30 days of previous discharge while accounting for hospital clustering with a random intercept. Results: Fall-related death increased by 1.4% from 2010 to 2014. Similarly, the hospital admission rate increased by 2% and was mainly associated with increased admission of elderly 65-74 years old. Approximately 55% of the fall patients were placed in nursing facilities in 2010, and this rate increased by 3% from 2010 to 2014. Thirty-day readmission rates for fall and trauma patients remained stable from 2010 to 2014. However, the rate of fall patients readmitted within 30 days for a subsequent fall increased from 15.6% to 17.4% between 2010 and 2014. Conclusion: Our data indicate a steady increase in deaths and admissions for fall injuries in the elderly population. Strikingly, the incidence of readmission for a subsequent fall is increasing. With the aging population, this trend is likely to continue and highlights the need for elderly social support systems and fall prevention programs. PMID- 30519110 TI - Rural and urban disparities in the care of Canadian patients with inflammatory bowel disease: a population-based study. AB - Background and aims: Canada's large geographic area and low population density pose challenges in access to specialized health care for remote and rural residents. We compared health services use, surgical rate, and specialist gastroenterologist care in rural and urban inflammatory bowel disease (IBD) patients in Canada. Methods: We used validated algorithms that were applied to population-based health administrative data to identify all people living with the following three Canadian provinces: Alberta, Manitoba, and Ontario (ON). We compared rural residents with urban residents for time to diagnosis, hospitalizations, outpatient visits, emergency department (ED) use, surgical rate, and gastroenterologist care. Multivariable regression compared the outcomes in rural/urban patients, controlling for confounders. Provincial results were meta-analyzed using random-effects models to produce overall estimates. Results: A total of 36,656 urban and 5,223 rural residents with incident IBD were included. Outpatient physician visit rate was similar in rural and urban patients. IBD-specific and IBD-related hospitalization rates were higher in rural patients (incidence rate ratio [IRR] 1.17, 95% CI 1.02-1.34, and IRR 1.27, 95% CI 1.04-1.56, respectively). The rate of ED visits in ON were similarly elevated for rural patients (IRR 1.53, 95% CI 1.42-1.65, and IRR 1.33, 95% CI 1.25-1.40). There were no differences in surgical rates or prediagnosis lag time between rural and urban patients. Rural patients had fewer IBD-specific gastroenterologist visits (IRR 0.79, 95% CI 0.73-0.84) and a smaller proportion of their IBD-specific care was provided by gastroenterologists (28.3% vs 55.2%, P<0.0001). This was less pronounced in children <10 years at diagnosis (59.3% vs 65.0%, P<0.0001), and the gap was widest in patients >65 years (33.0% vs 59.2%, P<0.0001). Conclusion: There were lower rates of gastroenterologist physician visits, more hospitalizations, and greater rates of ED visits in rural IBD patients. These disparities in health services use result in costlier care for rural patients. Innovative methods of delivering gastroenterology care to rural IBD patients (such as telehealth, online support, and remote clinics) should be explored, especially for communities lacking easy access to gastroenterologists. PMID- 30519112 TI - Factors associated with choice of intensification treatment for type 2 diabetes after metformin monotherapy: a cohort study in UK primary care. AB - Purpose: To understand the patient characteristics associated with treatment choice at the first treatment intensification for type 2 diabetes. Patients and methods: This is a noninterventional study, using UK electronic primary care records from the Clinical Practice Research Datalink. We included adults treated with metformin monotherapy between January 2000 and July 2017. The outcome of interest was the drug prescribed at first intensification between 2014 and 2017. We used multinomial logistic regression to calculate the ORs for associations between the drugs and patient characteristics. Results: In total, 14,146 people started treatment with an intensification drug. Younger people were substantially more likely to be prescribed sodium-glucose co-transporter-2 inhibitors (SGLT2is), than sulfonylureas (SUs): OR for SGLT2i prescription for those aged <30 years was 2.47 (95% CI 1.39-4.39) compared with those aged 60-70 years. Both overweight and obesity were associated with greater odds of being prescribed dipeptidyl peptidase-4 inhibitor (DPP4i) or SGLT2i. People of non-white ethnicity were less likely to be prescribed SGLT2i or DPP4i: compared with white patients, the OR of being prescribed SGLT2i among South Asians is 0.60 (95% CI 0.42-0.85), and for black people, the OR is 0.54 (95% CI 0.30-0.97). Lower socioeconomic status was also independently associated with reduced odds of being prescribed SGLT2is. Conclusion: Both clinical and demographic factors are associated with prescribing at the first stage of treatment intensification, with older and non white people less likely to receive new antidiabetic treatments. Our results suggest that the selection of treatment options used at the first stage of treatment intensification for type 2 diabetes is not driven by clinical need alone. PMID- 30519113 TI - Colonoscopy-related complications in a nationwide immunochemical fecal occult blood test-based colorectal cancer screening program. AB - Background: The Danish national screening program for colorectal cancer (CRC) consists of an immunochemical fecal occult blood test (iFOBT) followed by colonoscopy. The Danish Colorectal Cancer Screening Database (DCCSD) records data on the incidence of hospital-registered complications after colonoscopy. However, the validity of these data is unknown, and the incidence of complications is potentially underreported. Objective: To evaluate the validity of the colonoscopy complications registered in the DCCSD by using medical records as the reference. Further, to evaluate the incidence of complications leading to hospital contact. Methods: Among 14,671 individuals with a positive iFOBT result and a colonoscopy procedure performed from March 3, 2014 to December 31, 2014, we selected 295 individuals for medical record review. We calculated sensitivity as the proportion of true complications registered in the DCCSD out of all complications found in the medical records, and the positive predictive value (PPV) as the number of true complications in the DCCSD out of all DCCSD-registered complications. On the basis of the medical record data, we calculated the incidence proportion of hospital-registered complications overall and by subtype. Results: In total, we reviewed 286 records and found 102 individuals with at least one complication. The sensitivity of the DCCSD for any complication was 29.4% (95% CI: 20.8-39.3) and the PPV was 88.2% (95% CI: 72.6-96.7). On the basis of the medical record data, the incidence proportion of any complication after colonoscopy was 0.70% (95% CI: 0.57-0.84) and that of perforation or lesion was 0.10% (95% CI: 0.06-0.17); bleeding, 0.41% (95% CI: 0.31-0.53); post-polypectomy syndrome, 0.16% (95% CI: 0.10-0.24); and other medical complications, 0.04 (95% CI: 0.02-0.09). Conclusion: The DCCSD has low sensitivity for complications, and improvements in data registration are warranted. The incidence proportion of any hospital-treated post-colonoscopy complication was 0.70% in 2014, which was the first year of the Danish national CRC screening program. This is within the range of complications reported by other studies. PMID- 30519114 TI - Overuse of methylphenidate: an analysis of Swedish pharmacy dispensing data. AB - Purpose: To identify overuse of methylphenidate and to investigate patterns of overuse in relation to sociodemographic and clinical characteristics. Patients and methods: Swedish national, pharmacy dispensing data were analyzed for all 56,922 individuals aged 6-79 years, who filled a methylphenidate prescription between 2010 and 2011. Overuse was defined as having above 150% days covered by the dispensed amount during 365 days from the first prescription fill, assuming use at the maximum recommended daily dose. Results: In total, 4,304 individuals (7.6% of the methylphenidate users) were categorized as overusers. The risk of overuse increased with age (OR for 46-65 years vs 6-12 years 17.5, 95% CI 14.3 21.3), and was higher in men (OR 1.4, 95% CI 1.3-1.5) and individuals with low income (OR 1.1, 95% CI 1.0-1.2), as well as in individuals with an attention deficit hyperactivity disorder (ADHD) diagnosis (OR 1.4, 95% CI 1.3-1.6), health care visits (OR 1.3, 95% CI 1.2-1.4), previous ADHD medication use (OR 2.6, 95% CI 2.4-2.8), and previous diagnosis of mental and behavioral disorders due to psychoactive substance use (OR 2.1 95% CI 2.0-2.3). Conclusion: Among individuals using methylphenidate in Sweden, 7.6% receive amounts that are larger than what they should have a medical need for, assuming that they were using the maximum recommended daily dose 365 days per year. Notably, the prevalence of overuse was associated with previous diagnosis of alcohol and drug misuse. The prevalence was also positively associated with higher age and previous use of ADHD medication. These findings may point toward a link between exposure time and overuse. However, future studies with long-term data are needed to investigate this. PMID- 30519115 TI - Dento-skeletal characteristics of cleft patients with missing teeth. AB - Objective: The objective of this study was to compare the cephalometric skeletal and dental characteristics of unilateral complete cleft lip and palate (UCCLP) subjects with and without missing teeth. Design: A retrospective records review was conducted for patients who are being treated at the cleft lip and palate (CLP) clinics in the College of Dentistry. Methods: Ninety-six consecutive records of non-syndromic UCCLP subjects were recruited (33 subjects without missing teeth, 50 subjects with only one missing tooth, and 13 subjects with two or more missing teeth). Skeletal and dental characteristics were assessed using lateral cephalometric radiographs in UCCLP subjects with missing teeth and compared to the group with no missing teeth. A total of 25 linear and angular measurements were analyzed and compared between the sample groups. Results: Of the dental variables tested, overjet was significantly different between the three groups. The UCCLP subjects with multiple missing teeth had the smallest overjet (-3.89+/-2.75 mm; P=0.015) among the three groups. None of the skeletal characteristics reached statistical significance. Conclusion: Missing teeth influence the dental but not skeletal characteristics of UCCLP. Overjet is significantly reduced in UCCLP subjects with multiple missing teeth. Future studies with larger sample sizes are warranted. PMID- 30519116 TI - Treatment of chronic oroantral fistula with platelet-rich fibrin clot and collagen membrane: a case report. AB - An oroantral fistula is a complication of the maxillary posterior teeth that can occur after a tooth extraction that affects the maxillary sinus. Improper management may lead to a persistent fistula, which may become chronic. In this case report, platelet-rich fibrin (PRF) was used with a collagen membrane to close a chronic fistula in a single patient. A flap was raised, the oroantral fistula tract was eliminated, and the opening was closed with a resorbable membrane as a first layer and covered with a PRF clot as a second layer. The flap was closed, and the patient was followed up for suture removal and confirmation of complete soft tissue closure. The postsurgical sign and symptoms of the patient disappeared in the first week; complete tissue healing was detected within 2 weeks, and tissue hypertrophy was observed in the fourth week. The use of PRF may have advantages for soft-tissue healing and for accelerating soft tissue formation by subsequent hypertrophy. PMID- 30519117 TI - Osteoimmunology of tumor necrosis factor-alpha, IL-6, and RANTES/CCL5: a review of known and poorly understood inflammatory patterns in osteonecrosis. AB - Background: The immune and bone systems are closely linked via cytokine cross talk. This interdisciplinary field of research is referred to as osteoimmunology and pertains to inflammatory and osteoarticular diseases that feature the primary expression of tumor necrosis factor-alpha (TNF-alpha) and IL-6. Objective: Are there bone resorptive processes wherein chronic inflammatory conditions are not linked to TNF-alpha and IL-6 expression, but rather to the expression of other cytokines? Materials and methods: A comprehensive literature search was performed in PubMed Central. Discussion: Although all diseases with cytokines involved in bone resorption (TNF-alpha and IL-6) are at the forefront of destructive inflammatory processes, there is one exception in the literature: fatty oxide osteoporosis/osteolysis in the jawbone (FDOJ), which is associated with significant bone softening. However, it should be noted that TNF-alpha and IL-6 fall below the levels found in a healthy jawbone in this condition. Another conspicuous finding is that there is a nearly 35-fold overexpression of the chemokine RANTES/CCL5 (R/C) in all FDOJ cases studied thus far in the literature. Conclusion: FDOJ appears to represent a unique cytokine and inflammatory pattern from osteolysis in the body. R/C can be defined as the dominant carrier of a "maxillomandibular osteoimmunology". PMID- 30519118 TI - Shoulder dystocia: incidence, mechanisms, and management strategies. AB - Shoulder dystocia can lead to death or brain damage for the baby. Traction on the head can damage the brachial plexus. The diagnosis should be made when the mother cannot push the shoulders out with her own efforts with the next contraction after delivery of the head. There should be no traction on the head to diagnose shoulder dystocia. McRoberts' position is acceptable but it should not be accompanied by any traction on the head. If the posterior shoulder is in the sacral hollow then the best approach is to use posterior axillary traction to deliver the posterior shoulder and arm. If both shoulders are above the pelvic brim, the posterior arm should be brought down with Jacquemier's maneuver. If that fails, cephalic replacement or symphysiotomy is the next step. After shoulder dystocia is resolved, one should wait 1 minute or so to allow placental blood to return to the baby before cutting the umbilical cord. PMID- 30519119 TI - A case of ulceroglandular tularemia presenting with lymphadenopathy and an ulcer on a linear morphoea lesion surrounded by erysipelas. AB - Tularemia is a zoonosis caused by the infection of Francisella tularensis (a gram negative aerobic bacterium). Transmission to other animals or humans usually occurs through insect or tick bites, direct contact with a contaminated environment (mud or water), infected animals - mainly lagomorphs - or by ingesting undercooked meat or inhaling contaminated dust (hay or soil). This paper discusses the case of a 32-year-old man, who came to our Emergency Room presenting with persistent fever, inguinal lymphadenopathy, and an ulcer on his left lower limb on a linear morphoea lesion that had been there for some time. The lesion was surrounded by erysipelas. After hospitalization and tests, the patient was diagnosed with ulceroglandular tularemia. Antibiotic treatment with doxycycline resolved the clinical picture, but not the morphoea lesion. PMID- 30519120 TI - Pan-drug-resistant and biofilm-producing strain of Burkholderia pseudomallei: first report of melioidosis from a diabetic patient in Yogyakarta, Indonesia. AB - Melioidosis, an infectious disease caused by Burkholderia pseudomallei, has recently gained importance as an emerging infectious disease in Indonesia. Reports of this infection in Indonesia are limited, although cases have been reported in Makassar, South Sulawesi. We report a case of cutaneous melioidosis caused by pan-drug-resistant, moderate biofilm-producer strain of B. pseudomallei in a diabetic patient. To the best of our knowledge, this is the first case of melioidosis caused by multidrug resistant and biofilm-former strain of B. pseudomallei being reported from Yogyakarta Province, Indonesia. The patient was successfully treated with abscess drainage and debridement, including total contact casting and no antibiotic treatment. PMID- 30519121 TI - Clinical efficacy of transcutaneous triamcinolone acetonide injection for upper eyelid retraction and swelling in patients with thyroid eye disease. AB - Aim: To evaluate the efficacy of transcutaneous triamcinolone acetonide (TA) injection for the treatment of upper eyelid retraction and swelling in thyroid eye disease (TED) patients. Patients and methods: This is a case series. Three euthyroid TED patients with features of both upper eyelid retraction and swelling were recruited. TED signs appeared within 6 months prior to treatment. Next, 0.5 mL of TA (40 mg/mL) was transcutaneously injected targeting the orbital fat around the levator palpebrae superioris (LPS) muscle. At each visit, eyelid retraction was evaluated by palpebral fissure height and the presence of scleral show above the superior corneoscleral limbus. Eyelid swelling was judged by the appearance of upper eyelid bulging and the lack of an eyelid sulcus. In addition, the LPS muscle, orbital and retro-orbicularis oculi fat were observed using MRI before and after treatment. Results: Two patients had resolution of their upper lid retraction and swelling within 12 months. In the other patient who had proptosis, eyelid retraction resolved, while eyelid swelling remained mild. In all cases, MRI revealed that treatment resulted in thinner LPS muscle and reduced fat swelling. In addition, both high-intensity signals on T2 images and prolonged T2 relaxation time were normalized. No adverse signs were observed. Conclusion: Transcutaneous TA injection was effective as a treatment for upper eyelid retraction and swelling in euthyroid TED patients who had signs within 6 months prior to treatment. Transcutaneous TA injection induced reduction of LPS muscle enlargement and fat tissue swelling. These reductions by transcutaneous TA injection were verified using MRI. PMID- 30519122 TI - Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans. AB - Background: Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials. Materials and methods: A 10 mg/kg IV dose of KoEL-paclitaxel or nab-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model. Results: Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of nab-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by nab-paclitaxel. Conclusion: This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development. PMID- 30519123 TI - Aural foreign body removal: there is no one-size-fits-all method. AB - Background: Managing patients with aural foreign body (AFB) may pose a dilemma regarding which removal technique to use for different AFB types. The current study comprises a review of all the possible methods one could employ in removing AFB. My aim was to describe the best methods for different types of AFBs, complete with a description of the method and tool(s) required, and descriptions of the AFBs for which they are best used. Materials and methods: The medical literature published between 2000 and 2016 was reviewed using Medline, Cinahl, Embase, Cochrane, PubMed, and Scopus to compile a list of all published AFB removal methods. Results: Ten methods were identified and described, each having their own advantages for different AFBs. Patients normally permit very few attempts, so the first AFB removal attempt should ideally be the only one. Conclusion: There is no single method guaranteed to work with all AFBs, so this report also contains a flowchart to aid deciding which technique to use. PMID- 30519124 TI - Postpartum family-planning barriers and catalysts in Burkina Faso and the Democratic Republic of Congo: a multiperspective study. AB - Purpose: To address the high unmet need for postpartum family planning (PPFP) in resource-limited settings, particularly in sub-Saharan Africa, this study aimed to identify PPFP-related barriers and catalysts to inform policies and programs to increase access to postpartum contraception. Methods: Using qualitative methodology, we explored the perspectives of women, adolescent girls, men, religious and community leaders, service providers, and decision makers from three rural communities in Burkina Faso and three rural-urban communities in the Democratic Republic of Congo. Both countries have high unmet need for PPFP and are priority countries of the French Muskoka Fund for Maternal and Child Health. Results: Perceived catalysts included negative traditional views on the consequences borne by closely spaced children and their mothers; a 6-week postpartum visit dedicated to PPFP (albeit poorly attended); political will and enabling policies for FP; and support from certain religious leaders and men. Main reported barriers were the lack of male engagement; out-of-pocket copayment for contraceptives; reliance on amenorrhea for pregnancy prevention without knowing its limits; misconceptions about modern contraceptives, including prerequisites for the lactational amenorrhea method; sexual abstinence supported by religious and traditional norms for up to 3-6 months, although women reported earlier resumption of sexual activity; low prioritization of scheduled postpartum visits by women; and limited availability of readily accessible methods, PPFP counseling materials, and clinic days and scheduled visits dedicated to contraceptive services. Conclusion: Based on results found to be most actionable, the following interventions have the potential to optimize access to PPFP services: counseling women on postpartum-pregnancy risks and options at different points in time before and after childbirth through the use of appropriate information, education, and counseling materials; integrating PPFP services into existing maternal and child health visits; making contraceptives readily available and affordable; and meaningfully engaging male partners. PMID- 30519125 TI - Venous thrombosis and hormonal contraception: what's new with estradiol-based hormonal contraceptives? AB - Objective: Estradiol (E2)-based hormonal contraceptives impact less than ethinylstradiol (EE) contraceptives on venous thromboembolism (VTE) in comparison to formulations with EE. Study design: In this article, the pharamacologic data of EE and E2 were briefly reviewed, along with the induced biologic effect. These data were then related to a recent large international prospective, controlled, non-interventional cohort active surveillance study, on the cardiovascular risk of users of different types of combined estroprogestin contraceptive (CEPC). Results: The crude HR for E2-valerate (E2V)/dienogest vs other CEPCs with EE was 0.8 (95% CI, 0.4-1.6), but when the data were corrected for age, body mass index, duration of use, and family history of VTE, the corresponding adjusted HR was 0.5 (95% CI, 0.2-1.0). A comparison of the E2V/dienogest and EE/levonorgestrel groups showed that the two contraceptives induced a similar VTE risk with the crude and adjusted VTE HRs of 0.7 (95% CI, 0.3-1.8) and 0.5 (95% CI, 0.2-1.3), respectively. Similar results were obtained when the observation was prolonged to January 2017. Conclusions: The reduced impact of E2 vs EE on coagulation translates into the epidemiologic evidence of a reduced number of events in E2V vs EE users, when progestins other than levonorgestrel are used. However, E2 may continue to negatively impact on the risk of VTE, and this should not be forgotten at the time of prescription. Family history of VTE or thrombophilia, age, and obesity are risk factors for VTE too. If these risk factors are not taken into consideration and excluded, they can overcome or hide the higher safety of E2 vs CEPCs with EE. PMID- 30519126 TI - Programmatic implications of unmet need for contraception among men and young married women in northern Nigeria. AB - Purpose: The study was designed to provide programmatic recommendations for interventions to increase contraceptive prevalence in northern Nigeria. Family planning use in North-East and North-West regions of Nigeria has remained very low, despite years of domestic and donor investments. We examine respondents' perceptions of their own need for contraception and specifically focus on young women because of their higher risk for maternal mortality. Methods: In this cross sectional study, we interviewed 1,624 married women younger than 25 years and 1,627 men married to women younger than 25 years, in Kaduna and Katsina states in northern Nigeria. We classified respondents into five categories: 1) having no real need for contraception, 2) perceiving no need for contraception, despite physical or behavioral need, 3) having met need by using a modern contraceptive method, 4) perceiving met need by employing traditional practices, and 5) having unmet need for contraception. Results: Half of female respondents had no need for contraception because they were either pregnant or desiring a pregnancy at the time of the survey. A quarter of female and male respondents were not using contraception because of their religious beliefs. Less than 2% of respondents had unmet need because of lack of availability or access, or due to poor quality of care. Men had more positive views of family planning than women. Conclusion: Our findings suggest that young women in northern Nigeria would benefit from a programmatic approach that targets men, utilizes religious leaders, and addresses the prevalent religious and sociocultural norms that present barriers to contraceptive use. Such interventions have the potential to increase contraceptive prevalence more substantially, but the literature on these types of interventions in northern Nigeria is scarce. Therefore, more research is needed to identify and document what approaches work or do not work to increase contraceptive use in northern Nigeria. PMID- 30519127 TI - Contraceptive use and the risk of sexually transmitted infection: systematic review and current perspectives. AB - Purpose: Evidence on the association between contraceptive use and risk of sexually transmitted infections (STIs) and bacterial vaginosis (BV) is lacking, with few prospective studies. We systematically reviewed the last 10 years' evidence on the association between contraception and STI/BV, building on the most recent systematic reviews published in 2006 and 2009. Methods: We searched the MEDLINE and POPLINE databases for peer-reviewed articles p ublished between January 1, 2008 and January 31, 2018 reporting prospective studies that assessed the association between contraceptive use and incident STI and/or incident or recurrent BV. Results: We identified 33 articles that evaluated combined oral contraceptives (COC), depot medroxyprogesterone acetate (DMPA), the copper intrauterine device (Cu-IUD), the levonorgestrel intrauterine system (LNG-IUS) and other methods. The strength of the evidence for many specific contraceptive method/STI associations is limited by few prospective studies with comparably defined exposures and outcomes. Available data suggest no association of COCs and Neisseria gonorrhoeae, Trichomonas vaginalis, HSV-2 or syphilis, and mixed evidence on the association with HPV, Chlamydia trachomatis, and BV. For DMPA, none of the studies identified found an association with N. gonorrhoeae or syphilis, and data on C. trachomatis, T. vaginalis, HPV and BV were mixed. Two large studies showed a highly clinically significant increased risk of HSV-2 infection with DMPA use. Data on the effect of Cu-IUD and the LNG-IUS on the acquisition of C. trachomatis, N. gonorrhoeae and T. vaginalis are sparse, and data on HPV and BV are mixed. Conclusion: Few data are available from prospective studies, including randomized trials, to draw strong conclusions about the relationships between contraceptive methods and specific STIs. The overall evidence on the association between contraceptive use and STI/BV risk is limited by the lack of any randomized trials, few published prospective studies designed to analyze these associations, wide variability in exposure definitions and comparator groups, potential for confounding due to inaccurate sexual behavior data, differential confounder adjustment and differences in study populations and sizes. Despite these limitations, new evidence is supportive of a significantly increased risk of HSV-2 infection among DMPA users which warrants additional research to better understand this association. PMID- 30519129 TI - Cultivating employees' communal relationship and organizational citizenship behavior through authentic leadership: studying the influence of procedural justice. AB - Background: Leaders play vital role in organization to accomplish organizational goals and establish healthy working environment. This study addresses the effect of authentic leadership on employees' communal relationship and organizational citizenship behavior (OCB). In addition, this research also examines how procedural justice augments the effect of authentic leadership on both aforementioned employees' behavioral outcomes. Materials and methods: Using a cross-sectional design, data were collected from 425 employees working in banking sector of Pakistan. It was hypothesized that authentic leadership would positively predict employees' communal relationship and OCB. Furthermore, we also assumed that procedural justice will strengthen the relationship between authentic leadership, both behavioral outcomes, that is, employees' communal relationship and OCB. Results: Analyses reveal that authentic leadership positively predicts employees' communal relationship and OCB. In addition, procedural justice was found to positively moderate the effect of authentic leadership on employees' communal relationship and OCB. Conclusion: To our knowledge, this is the first study to investigate the relationships among authentic leadership, procedural justice, communal relationship, and OCBs in the South Asian context. This is the first study to report the moderating role of procedural justice in the relationship between authentic leadership and communal relationship and OCB. The practical implications of study findings and direction for future research are discussed. PMID- 30519128 TI - Concussion rates and effects on player performance in Major League Baseball players. AB - Background: Major League Baseball (MLB) players are throwing the ball faster and hitting harder than ever before. Although some safety measures have been implemented, by decreasing the 15 days on the disabled list (DL) to the 7 days on the DL, concussion rates remain high across positions and may impact player performance. Our hypothesis was, there would be an increase in concussion incidence following implementation of the 7 day DL, but this would not have a negative impact on player's postconcussion performance. Study design: This is a descriptive epidemiology study. Methods: The concussed players from 2005 to 2016 were identified from the MLB DL and verified using established new sources. Position-specific performance metrics from before and after injuries were gathered and compared to assess effects of the injury. Postconcussion performance metrics were compared before and after the 7-day DL rule implementation. Results: A total of 112 concussed players were placed on the DL. For all position players, the batting average (BA) and on-base percentage (OBP) showed a nonsignificant decline after injury (P=0.756). Although performance statistics for pitchers declined on average, the trend was not statistically significant. Postinjury BA and OBP did not significantly change before (0.355) and after (0.313) the 7-day DL rule change in 2011 (P=0.162). Conclusion: The incidence of reported concussion has increased with the 7-day DL rule change. Concussion incidence was highest in catchers and pitchers compared with all other players. The most common causes identified as being hit by pitch or struck by a foul ball or foul tip. While new league rules prevent collisions with catchers at home plate, injury by a foul tip was the most common cause for concussion. The shortened time spent on the DL did not negatively impact player's performance. Further research on protective helmets for catchers may reduce concussion incidence. PMID- 30519130 TI - Among substance-abusing traffic offenders, poor sleep and poor general health predict lower driving skills but not slower reaction times. AB - Background: Traffic accidents are a significant health issue in Iran. Explanations for such accidents have included single consideration of the role of poor sleep and negative psychological trait and state variables. In this study, we examined whether and to what extent sleep, general health, and aggression can concomitantly predict driving behavior. Methods: A total of 360 male traffic offenders (driving under substance use; mean age: 31 years) participated in this study. They completed the questionnaires covering sociodemographic, sleep related, and behavior-related variables. In addition, their visual and acoustic reaction times were objectively tested. Results: Poor sleep, poor general health, and higher aggression scores were associated with self-rated poor driving behavior. Poor sleep was directly associated with poor driving behavior and indirectly via poor general health and aggression. In contrast, visual and acoustic reaction times were unrelated to sleep, general health, aggression, or self-rated driving behavior. Conclusion: To our knowledge, this is the first study in Iran to assess concomitantly poor sleep, poor general health, and higher aggression scores as independent predictors of poor driving behavior among a larger sample of substance-abusing traffic offenders. Furthermore, visual and acoustic reaction times were unrelated to sleep, general health, aggression, and driving behavior. Finally, importantly, poor sleep predicted both directly and indirectly poor driving behavior. PMID- 30519131 TI - A longitudinal inquiry into directionality of effects between coping and information needs in hypertensive patients. AB - Purpose: It is well recognized that effective health communication is associated with better adherence to medical prescriptions, behavioral changes, and enhanced perception of control over the disease. However, there is limited knowledge about the variables on which to tailor health messages. This study examined whether coping strategies were related to information needs over time in a sample of patients with hypertension. Patients and methods: A three-wave longitudinal design was used to examine the potential reciprocal relationships among variables. The sample included 271 patients (43.5% women) affected by essential arterial hypertension with a mean age of 54.66 years (SD =10.74 years; range 30 78 years). Data on patients' demographic characteristics, coping strategies, and information needs were collected three times over 12 months. To test the directionality of the relationships linking coping to information needs, cross lagged path analyses were applied in a structural equation modeling approach. Results: Active coping was related to a greater need for information regarding behavioral habits; avoidance coping was negatively associated with the need for information regarding daily life activities, while passive coping showed a positive relationship with this need. Moreover, results sustained the hypothesis that the relationship between coping and information needs was bi-directional. In fact, greater need for information about the disease and its pharmacological treatment was related to greater adoption of active coping strategies. The need for information about risk and complications was associated with the coping strategy related to alcohol use. Conclusion: These results provide important suggestions for implementing more effective intervention programs aimed at fostering patients' self-care abilities. As it was possible to modify coping strategies, health care providers may consider measuring patients' strategies before the medical examination so they have time to refine the information they give to patients. PMID- 30519132 TI - Mild and severe childhood depression: differences and implications for prevention programs in the school setting. AB - Purpose: The study had two goals as follows: 1) to identify the prevalence of children with mild and severe depression (MD and SD), exploring sex differences; and 2) to determine possible significant differences in adaptive and clinical variables between children with different levels of depression (absence of depression, MD, and SD). Materials and methods: We used a sample of 420 participants aged 7-10 years (53.3% boys) enrolled in third and fourth grade of primary education, from schools in the Basque Country (Spain). The Children's Depression Scale (CDS, self-assessment) was administered as well as six more assessment instruments. Results: It was found that 84.2% of children had no depression, 10% had MD, and 5.8% had SD. Compared with children with depressive symptoms, participants without depression had significantly: 1) lower levels of maladjustment, stress, emotional symptoms, internalizing problems, and behavioral problems; and 2) higher levels of personal adjustment, resilience, social skills, and self-concept. In addition, children with MD had significantly lower levels of clinical maladjustment, emotional symptoms, and stress than children with SD. However, no differences were found in school maladjustment, internalizing problems, behavioral problems, personal adjustment, resilience, social skills, and self-concept between children with MD and SD. Conclusion: The discussion emphasizes the importance of identifying children with MD and implementing universal prevention programs from an early age. PMID- 30519133 TI - Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation. AB - ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative for clinicians to screen appropriate patients for this driver mutation with a molecular testing platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating its clinical activity against T1151K. This case illustrates the importance of performing repeat biopsy to explore mechanism(s) of resistance when patients experience disease progression on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK resistance mutation is identified. PMID- 30519134 TI - Comparing spectacle and toric contact lens prescribing trends for astigmatism. AB - Background: The purpose of this study is to investigate and compare spectacle and contact lens (CL) prescription trends, with an emphasis on astigmatic refractive error prescribing differences for patients who purchase spectacles or CLs in South Korea. Methods: A retrospective study of patient records of a major optical chain in South Korea was conducted. De-identified data of age, gender, power of prescribed spectacles and/or CLs were extracted from the practice database. Inclusion criteria were being within the first 10,000 purchasers of spectacles or CLs or both. Results: The first 10,000 purchases comprised spectacles (59%) and CLs (41%) (male:female ratio 4:6). The proportion of purchasers who were female was significantly higher for CLs (88% female, 12% male) than spectacles (43% female, 57% male) (chi 2 =4480.36, df=1, P<0.0001). There was a significant difference in the proportions of purchases by age group for spectacles and CLs (chi 2 =3246.69, df=3, P<0.0001). Spherical power distribution of prescribed lenses was similar between the groups; however, cylinder power and axis were significantly different (P<0.0001). CL astigmatic powers were more likely to be 1.00 DC or greater, whereas the majority of spectacle lenses had astigmatic power of 0.75 DC or less. In total, 90% of toric CLs were prescribed *180 and 9% other meridians, unlike spectacles where 50% were prescribed *180, 14% *90 and 40% at oblique meridians. Conclusion: There is scope for providing increased toric lens correction amongst CL wearers and increasing the proportion of wearers who are male. The estimated gap for toric lens prescription amongst CL wearers who have clinically significant astigmatism >=0.75 DC is about 59%. PMID- 30519135 TI - Radiology learning or teaching subject areas vs modalities: students' perspective and experience at Albaha University. AB - Introduction: In radiology learning, most of the integrated schools address the subject area as a theme, and several imaging modalities describe the findings. A few schools handle the imaging modalities as a separate theme wherein many subject areas are discussed. Purpose: The aim of this study was to identify the differences in student achievement in imaging course using the two learning approaches: integration within modalities under the subject area and integration within the subject area under imaging modalities. Materials and methods: This study was conducted on 60 students studying the basic imaging course. Students were divided into two main groups; group A and B. Contents were divided into two main categories: subject areas and imaging modalities. 1) Subject areas were applied according to body systems such as imaging of the central nervous system (CNS) and, cardiovascular system (CVS). 2) Modalities were addressed as plain X ray and computed tomography (CT) which were separate entities comprising the findings of the most common diseases. The two groups learned the both approaches in a sequential alternative manner for 10 days by the same radiological group experts. A 60-question final examination was adopted at the end of the module including 30 questions for each approach. The students' and peers' satisfaction was measured using Likert scale. Results: A high response from the students toward the second approach has been found. The students' grades in the second model examination reflecting the second approach were found elevated. The students' and peers' satisfaction toward the second approach was high compared with the first approach with highly significant P-value obtained. Conclusion: This experience advocated that the perception of students toward radiology teaching can be enhanced when focused on a single imaging modality for a time. Students can identify and augment more images and do multiple comparisons with the pre and post ones. The students' and peers' satisfaction was found to be high toward the imaging modality approach. PMID- 30519136 TI - Who are the right teachers for medical clinical students? Investigating stakeholders' opinions using modified Delphi approach. AB - Purpose: The purpose of this study was to realize that learning in a clinical setting, the interactions of the students with teachers, learning materials, and learning environments are essential. In clinical education, different groups may play the role of the teacher for medical students. This study was designed to determine the optimal characteristics for medical clinical teachers, their selection criteria, and their responsibilities. Methods: The modified Delphi technique was used in this study. Participants comprised vice-chancellors of education, deans of medical schools, and deputies of education in medical schools across Iran. This study was conducted in three rounds. In the first round, the participants were selected using purposive sampling, and the data were collected through focus group discussions and analyzed through content analysis. The data collection tool in the second and third rounds involved a questionnaire derived from the first round, and the consensus criterion to accept or reject the questionnaire items was frequency distribution. Results: The final number of statements in the first round was 157. The second-round questionnaire was designed in the four sections of teaching team, selection criteria, task description of the teaching team (including faculties, specialist staffs, residents, general practitioners, and health and treatment staff), and incentives separately for the specialist staff, residents, general practitioners, and health and treatment staff. The third-round questionnaire included feedback and items that were not agreed upon in the second round. Conclusion: The results of this study indicated the necessity of forming a teaching team, paying attention to the selection criteria, and planning requirements for assigning responsibilities to the teaching team in accordance with the objectives, programs, and requirements of medical schools, along with using strategies to attract participation and create motivation in the teaching team. PMID- 30519137 TI - Medical students' perception of international health electives in the undergraduate medical curriculum at the College of Medicine, King Saud University. AB - Background: International health electives prepare medical students during their student years of medical education in choosing, matching, and succeeding in the residency of their choice. They serve as a unique educational experience prior to residency training. Objective: This study was conducted to explore 4th- and 5th year medical students' perspective about international health electives and to evaluate their educational effects. Methods: An anonymous online survey with 22 items concerning perceptions about the electives with a 5-point Likert scale was administered to medical students at the College of Medicine, King Saud University. Results: For the majority of the students (81.6%) the elective course was arranged by the university and only 18.4% of students individually arranged their own. Most of the students (65.7%) agreed that the objective of the elective course was clear to them in advance. A total of 71.1% of students agreed that the program (elective) was responsive to their needs (both academically and socially). Conclusion: This is the first study looking at international electives in the context of the undergraduate medical curriculum in Saudi Arabia. The study showed that the international electives are a useful and unique experience for medical students (both academically and socially). PMID- 30519138 TI - Case-based simulation scenarios in cardiology. PMID- 30519139 TI - A response to the perception of the severity of medical error and the level of clinical seniority. PMID- 30519140 TI - Home-based neonatal care by Health Extension Worker in rural Sidama Zone southern Ethiopia: a cross-sectional study. AB - Background: Home-based neonatal care is associated with a reduction in neonatal mortality in settings with poor access to health facility-based care. The first day of a child's life is a day of unparalleled opportunity to spare lives and sets the level for a sound future. The aim of this study was to evaluate the prevalence and timing of home-based neonatal care by health extension workers (HEWs) in the rural Sidama Zone of southern Ethiopia. Subjects and methods: A community-based, cross-sectional study was conducted, and a total of 2,040 mothers who had a live birth in the last 6 months were studied from 1 to 31 January 2017. Interviewer-administered data were collected using a standard questionnaire developed by the Saving Newborn Lives Program. A descriptive analysis and logistic regression analyses were done. Results: It was found that 252/2,040 (12.4%) mothers and their neonates were visited by the HEWs during the first month of birth. Out of all households who had a history of visits, 139 (55.2%) had a single visit. Of these, only 66/252 (26.2%) of the first visit were within the first 24 hours. Mothers who received postnatal home visit by the HEWs were at 1.35 times greater odds to have good postnatal practice compared to unvisited mothers (adjusted odds ratio [AOR] 1.35, 95% CI [1, 1.71]). Mothers who gave their last birth at home were 36% less likely to have good postnatal practice compared to those who gave birth in a health institution (AOR 0.64, 95% CI [0.53, 0.79]). Conclusion: Majority of the neonates did not get the recommended number and frequency of home visits. Postnatal home visit by HEWs had a great role in mothers having good postnatal practice. Therefore, all stakeholders should give attention on strengthening supportive supervision, proper implementation of community-based maternal and neonatal care is very crucial. PMID- 30519141 TI - Biodegradability and biodegradation pathways of chlorinated cyclodiene insecticides by soil fungi. AB - An aerobic dieldrin-degrading fungus, Mucor racemosus strain DDF, and two aerobic endosulfan-degrading fungal strains, Mortierella sp. strains W8 and Cm1-45, were isolated from soil contaminated with organochlorine pesticides. Strain DDF degraded more than 90% dieldrin during 10-days of incubation at 25 degrees C and showed the production of a small amount of aldrin trans-diol. Moreover, strain DDF reduced levels of aldrin trans-diol while producing unknown metabolites that were determined to be aldrin trans-diol exo- and endo-phosphates. On the other hand, Mortierella sp. strains W8 and Cm1-45 degraded more than 70% and 50% of alpha and beta-endosulfan, respectively, over 28 days at 25 degrees C, in liquid cultures containing initial concentrations of 8.2 uM of each substance. Only a small amount of endosulfan sulfate, a persistent metabolite, was detected in the both cultures, while these strains could not degrade endosulfan sulfate when this compound was provided as the initial substrate. Both strains generate endosulfan diol as a first step in the degradation of endosulfan, then undergo further conversion to endosulfan lactone. PMID- 30519142 TI - Cytotoxic and genotoxic responses of human lung cells to combustion smoke particles of Miscanthus straw, softwood and beech wood chips. AB - Inhalation of particulate matter (PM) from residential biomass combustion is epidemiologically associated with cardiovascular and pulmonary diseases. This study investigates PM0.4-1 emissions from combustion of commercial Miscanthus straw (MS), softwood chips (SWC) and beech wood chips (BWC) in a domestic-scale boiler (40 kW). The PM0.4-1 emitted during combustion of the MS, SWC and BWC were characterized by ICP-MS/OES, XRD, SEM, TEM, and DLS. Cytotoxicity and genotoxicity in human alveolar epithelial A549 and human bronchial epithelial BEAS-2B cells were assessed by the WST-1 assay and the DNA-Alkaline Unwinding Assay (DAUA). PM0.4-1 uptake/translocation in cells was investigated with a new method developed using a confocal reflection microscope. SWC and BWC had a inherently higher residual water content than MS. The PM0.4-1 emitted during combustion of SWC and BWC exhibited higher levels of Polycyclic Aromatic Hydrocarbons (PAHs), a greater variety of mineral species and a higher heavy metal content than PM0.4-1 from MS combustion. Exposure to PM0.4-1 from combustion of SWC and BWC induced cytotoxic and genotoxic effects in human alveolar and bronchial cells, whereby the strongest effect was observed for BWC and was comparable to that caused by diesel PM (SRM 2 975), In contrast, PM0.4-1 from MS combustion did not induce cellular responses in the studied lung cells. A high PAH content in PM emissions seems to be a reliable chemical marker of both combustion efficiency and particle toxicity. Residual biomass water content strongly affects particulate emissions and their toxic potential. Therefore, to minimize the harmful effects of fine PM on health, improvement of combustion efficiency (aiming to reduce the presence of incomplete combustion products bound to PM) and application of fly ash capture technology, as well as use of novel biomass fuels like Miscanthus straw is recommended. PMID- 30519143 TI - Virtual eyes for technology and cultural heritage: toward computational strategy for new and old indigo-based dyes. AB - A cost-effective, robust, and reliable computational strategy is applied to simulate peak positions and band-shapes of UV-vis spectra together with the dye colours perceived by human eyes. The features of our virtual multifrequency spectrometer (VMS) relevant to this topic are sketched with special focus on the selection of density functional, vibronic model, and solvent description. Furthermore, the new VMS-Draw graphical user interface (GUI) is employed for user friendly pre- and post-processing of the computed data. The family of indigo dyes is used as case study in view of their continued use in the field of cultural heritage, together with new promising applications for photonics and sustainable energy. After assessment of different simplified models employed in previous studies, the role of several substituents and of dimerization in tuning the colour and spectral features are analyzed in detail by means of both accurate computations and interpretative models. The results are in remarkable agreement with experiment and allow to rationalize the behaviour of this class of dyes. PMID- 30519144 TI - Urinary schistosomiasis: report of case diagnosed in bladder biopsy. AB - Background: Urinary schistosomiasis is a common parasitic disease in endemic countries. Case presentation: We report the case of a patient who was on a working trip to Mauritania. This parasitosis, suspected in the presence of hematuria and the notion of stay in an endemic zone, was confirmed by the presence of Schistosoma heamatobium eggs during the histological examination of the bladder biopsy performed after cystoscopy, highlighting a bilharzial granuloma and of course, the diagnosis was confirmed by the presence of eggs during the direct examination of the freshly collected urine. Conclusions: It should be pointed out that the diagnosis of schistosomiasis must be evoked with the association of hematuria and the particular inflammatory aspect of the vesical mucosa and, of course, the notion of stay in an endemic zone. PMID- 30519145 TI - Nursing in an age of multimorbidity. AB - Background: A changing sociodemographic landscape has seen rising numbers of people with two or more long-term health conditions. Multimorbidity presents numerous challenges for patients and families and those who work in healthcare services. Therefore, the nursing profession needs to understand the issues involved in supporting people with multiple chronic conditions and how to prepare the future workforce to care for them. Methods: A descriptive, exploratory study was used to examine the future of nursing in an age of multimorbidity. An hour long Twitter chat was organised and run by the Florence Nightingale Foundation Chairs of Clinical Nursing Practice Research to discuss this important area of practice and identify what needs to be done to adequately upskill and prepare the nursing profession to care for individuals with more than one long-term illness. Questions were formulated in advance to provide some structure to the online discussion. Data were collected and analysed from the social media platform using NVivo and an analytics tool called Keyhole. Descriptive statistics were used to describe participants and thematic analysis aided the identification of key themes. Results: Twenty-four people, from a range of nursing backgrounds and organisations, took part in the social media discussion. Five themes encompassing coping with treatment burden, delivering holistic care, developing an evidence base, stimulating learning and redesigning health services were seen as key to ensuring nurses could care for people with multimorbidity and prevent others from developing chronic health conditions. Conclusions: Multimorbidity is a pressing health issue in today's society. Changes in nursing research, education and practice are required to help the profession work collaboratively with patients, families and multidisciplinary teams to better manage and prevent chronic illness now and in the future. PMID- 30519146 TI - Do demographic factors and a health-promoting lifestyle influence the self-rated health of college nursing students? AB - Background: To adopt a healthy lifestyle is considered an essential component of nursing education. Self-rated health is a subjective assessment of health status and is consistent with objective health status. Previous studies have shown an association between self-rated health and engagement in a healthy lifestyle. Nursing students need to feel good about their subjective health status and to be able to adopt health improvements in their lifestyle before attempting to disseminate health messages to clients. The aims of this study were to compare the difference in self-rated health and health promotion lifestyle profile between senior and junior nursing students, describe correlations between self rated health and health promotion lifestyle profile, and identify the predictors of self-rated health. Methods: A cross-sectional descriptive survey was adopted. The study sample consisted of 314 junior and senior year nursing students from a tertiary institution. The self-reported questionnaire consisted of a single-item question to examine their self-rated health. The Health Promoting Lifestyle Profile-II: Chinese version short form (HPLP-IICR) was used to investigate the health-promoting lifestyles of the students. Descriptive statistics, Mann-Whitney U test, Chi-square test, Fisher's exact test, Spearman's correlation, and ordinal logistic regression were used to analyze the data. Results: The median scores for self-rated health were 3 (Mean 3.26, IQR 3-4) and 3 (Mean 3.19, IQR 3-4) out of 5 for Year 2 and Year 5 students, respectively, with no significant difference between the two groups. The two groups of students showed no significant differences in overall score and in most subscales of the HPLP-IICR. An ordinal logistic regression showed that those students with higher health management score (OR: 1.12, 95% CI: 1.04-1.21) and who had experienced no family conflicts in the recent month than having family conflict (OR: 1.64, 95% CI: 1.01-2.66) were more likely to have higher self-rated health. Conclusion: Nursing education and clinical practice can undoubtedly increase the health knowledge of students, but may not lead to changes in actual health-promoting behaviours. Students with a higher health management score and no family conflicts are more likely to give a positive appraisal of their health status. PMID- 30519147 TI - In Vitro Study of Deuterium Effect on Biological Properties of Human Cultured Adipose-Derived Stem Cells. AB - In current in vitro study we have shown the impact of deuterium content in growth medium on proliferation rate of human cultured adipose-derived stem cells (ADSC). ADSCs have also demonstrated morphological changes when cultured in deuterated growth medium: the cell cultures did not reach confluence but acquired polygonal morphology with pronounced stress fibers. At high deuterium concentrations the ADSCs population doubling time increased which indicated the cell cycle retardation and decrease of cell proliferation rate. The deuterated and deuterium depleted growth media demonstrated acute and chronic cytotoxicity, respectively. The minimal migration ability was observed in deuterated medium whereas the highest migration activity was observed in the medium with the deuterium content close to natural. The cells in deuterated growth medium demonstrated decrease in metabolic activity after three days in culture. In contrast, in deuterium depleted medium there was an increase in ADSC metabolic activity. PMID- 30519148 TI - A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer. AB - Background: Over 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening. Methods: In the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n = 106), endometrial cancer (n = 74), benign ovarian tumors (n = 150) and healthy population controls (n = 399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n = 280), endometrial cancer (n = 228), women with benign ovarian tumors (n = 76) and healthy controls (n = 57). Results: In the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC = 0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p = 9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC = 0.89). Conclusion: The PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination. Funding: The Swedish Cancer Foundation, Vinnova (SWELIFE), The Foundation for Strategic Research (SSF), Assar Gabrielsson Foundation. PMID- 30519150 TI - Giant Left-Sided Amyand's Hernia: A Challenging Procedure in a Rural Hospital. AB - The finding of a vermiform appendix in the case of an inguinal hernia that extends below the midpoint of the inner thigh when the patient is in a standing position is defined as giant left-sided Amyand's hernia. It is a very rare case and significantly challenging in terms of preoperative diagnosis and surgical management. Here we present our experience with a case of a giant left-sided Amyand's hernia that was followed up for 2 months. PMID- 30519149 TI - The plasma peptidome. AB - Background: It may be possible to discover new diagnostic or therapeutic peptides or proteins from blood plasma using LC-ESI-MS/MS to identify, with a linear quadrupole ion trap to identify, quantify and compare the statistical distributions of peptides cleaved ex vivo from plasma samples from different clinical populations. Methods: A systematic method for the organic fractionation of plasma peptides was applied to identify and quantify the endogenous tryptic peptides from human plasma from multiple institutions by C18 HPLC followed nano electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) with a linear quadrupole ion trap. The endogenous tryptic peptides, or tryptic phospho peptides (i.e. without exogenous digestion), were extracted in a mixture of organic solvent and water, dried and collected by preparative C18. The tryptic peptides from 6 institutions with 12 different disease and normal EDTA plasma populations, alongside ice cold controls for pre-analytical variation, were characterized by mass spectrometry. Each patient plasma was precipitated in 90% acetonitrile and the endogenous tryptic peptides extracted by a stepwise gradient of increasing water and then formic acid resulting in 10 sub-fractions. The fractionated peptides were manually collected over preparative C18 and injected for 1508 LC ESI-MS/MS experiments analyzed in SQL Server R. Results: Peptides that were cleaved in human plasma by a tryptic activity ex vivo provided convenient and sensitive access to most human proteins in plasma that show differences in the frequency or intensity of proteins observed across populations that may have clinical significance. Combination of step wise organic extraction of 200 MUL of plasma with nano electrospray resulted in the confident identification and quantification ~ 14,000 gene symbols by X!TANDEM that is the largest number of blood proteins identified to date and shows that you can monitor the ex vivo proteolysis of most human proteins, including interleukins, from blood. A total of 15,968,550 MS/MS spectra >= E4 intensity counts were correlated by the SEQUEST and X!TANDEM algorithms to a federated library of 157,478 protein sequences that were filtered for best charge state (2+ or 3+) and peptide sequence in SQL Server resulting in 1,916,672 distinct best-fit peptide correlations for analysis with the R statistical system. SEQUEST identified some 140,054 protein accessions, or some ~ 26,000 gene symbols, proteins or loci, with at least 5 independent correlations. The X!TANDEM algorithm made at least 5 best fit correlations to more than 14,000 protein gene symbols with p-values and FDR corrected q-values of ~ 0.001 or less. Log10 peptide intensity values showed a Gaussian distribution from E8 to E4 arbitrary counts by quantile plot, and significant variation in average precursor intensity across the disease and controls treatments by ANOVA with means compared by the Tukey-Kramer test. STRING analysis of the top 2000 gene symbols showed a tight association of cellular proteins that were apparently present in the plasma as protein complexes with related cellular components, molecular functions and biological processes. Conclusions: The random and independent sampling of pre-fractionated blood peptides by LC-ESI-MS/MS with SQL Server-R analysis revealed the largest plasma proteome to date and was a practical method to quantify and compare the frequency or log10 intensity of individual proteins cleaved ex vivo across populations of plasma samples from multiple clinical locations to discover treatment-specific variation using classical statistics suitable for clinical science. It was possible to identify and quantify nearly all human proteins from EDTA plasma and compare the results of thousands of LC-ESI-MS/MS experiments from multiple clinical populations using standard database methods in SQL Server and classical statistical strategies in the R data analysis system. PMID- 30519151 TI - Spontaneous Pathological Complete Regression of Hepatocellular Carcinoma. AB - Several possible mechanisms for spontaneous regression of hepatocellular carcinoma (HCC) have been reported. Spontaneous complete regression of HCC is extremely rare. We herein report a case of spontaneous pathological complete regression of HCC following decrement of elevated serum alpha-fetoprotein (AFP). The serum AFP of a 74-year-old man who underwent hepatic resection for HCC twice increased up to 7,529 ng/mL and then spontaneously decreased to 404 ng/mL in 2 months. Computed tomography, magnetic resonance imaging, and angiography revealed a liver tumor in segment 7 without early enhancement. With a diagnosis of recurrent HCC, partial hepatic resection was performed. The resected specimens revealed no HCC macroscopically, and pathological examination revealed only a small area with cell dysplasia. The patient remains well with normal serum AFP and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels for 29 months after the third hepatic resection without recurrence of HCC. We describe a case of spontaneous pathological complete regression of HCC following decrement of elevated serum AFP. Further studies are needed to identify the mechanism(s) of spontaneous regression of HCC. PMID- 30519152 TI - Long-Term Cholic Acid Treatment in a Patient with Zellweger Spectrum Disorder. AB - Zellweger spectrum disorders (ZSDs) are a subgroup of peroxisomal biogenesis disorders with a generalized defect in peroxisome function. Liver disease in ZSDs has been associated with the lack of peroxisomal beta-oxidation of C27-bile acid intermediates to form primary C24-bile acids, which prevents normal physiologic feedback and leads to accumulation of hepatotoxic bile acid intermediates. Primary bile acid therapy, oral cholic acid (CA), as adjunctive treatment for ZSDs, restores physiologic feedback inhibition on bile acid synthesis and inhibits formation of hepatotoxic bile acid intermediates. Our patient is a Caucasian male diagnosed with moderately severe ZSD at age 5 months, and he received long-term CA therapy from age 16 months through 19 years old. CA treatment was well tolerated, with no reports of adverse events. His liver biopsy prior to CA therapy showed cholestasis, periportal inflammation, and bridging fibrosis. Following 5 months of CA therapy, his liver biopsy showed improvement in inflammation and no change in fibrosis. Serum liver enzymes during CA therapy improved compared to pre-therapy levels but frequently were above the upper limit of normal. At age 19 years, following several years with clinical cirrhosis with severe portal hypertension, he presented with worsening jaundice, and he was diagnosed with hepatocellular cancer (HCC). Early-onset advanced liver disease associated with ZSD and natural disease progression that is not completely suppressed with CA treatment likely caused HCC in our patient. Greater awareness is needed of the possibility of development of HCC in patients with moderately severe ZSD who survive past childhood. PMID- 30519153 TI - An Extragastrointestinal Stromal Tumor Originating from the Pancreas. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract (GIT). In fewer than 5% of cases, GIST originates primarily from outside the GIT. The occurrence of GIST originating from the pancreas is rare. Sometimes, neuroendocrine tumors should be differentiated from GISTs because of their hyperenhancing nature in radiologic images. We report a case of GIST arising in the pancreas that was confirmed by surgical resection. PMID- 30519154 TI - Comparative Transcriptomics of Rat and Axolotl After Spinal Cord Injury Dissects Differences and Similarities in Inflammatory and Matrix Remodeling Gene Expression Patterns. AB - Following spinal cord injury in mammals, maladaptive inflammation, and matrix deposition drive tissue scarring and permanent loss of function. In contrast, axolotls regenerate their spinal cord after severe injury fully and without scarring. To explore previously unappreciated molecules and pathways that drive tissue responses after spinal cord injury, we performed a 4-way intersection of rat and axolotl transcriptomics datasets and isolated shared genes with similar or differential expression at days 1, 3, and 7 after spinal cord injury in both species. Systems-wide differences and similarities between the two species are described in detail using public-domain computational tools and key differentially regulated genes are highlighted. Amongst persistent differential expression in matching neuronal genes (upregulated in axolotls but downregulated in rats) and nucleic acid metabolism genes (downregulated in axolotls but upregulated in rats), we found multiple extracellular matrix genes that were upregulated in both species after spinal cord injury and all time-points (days 1, 3, and 7), indicating the importance of extracellular matrix remodeling in wound healing. Moreover, the archetypal transcription factor SP1, which was consistently upregulated in rats but was unchanged in axolotls, was predicted as a potential transcriptional regulator of classic inflammatory response genes in rats most of which were not regulated in regenerating axolotls. This analysis offers an extensive comparative platform between a non-regenerating mammal and a regenerating urodele after spinal cord injury. To better understand regeneration vs. scarring mechanisms it is important to understand consistent molecular differences as well as similarities after experimental spinal cord injury. PMID- 30519155 TI - TPH-2 Gene Polymorphism in Major Depressive Disorder Patients With Early-Wakening Symptom. AB - Background: Sleep disturbances, such as early wakening, are frequently observed in patients with major depressive disorder (MDD). The suprachiasmatic nuclei (SCN), which controls circadian rhythm, is innervated by the raphe nucleus, a region where Tryptophan hydroxylase-2 (TPH-2) gene is primarily expressed. Although TPH-2 is often implicated in the pathophysiology of depression, few studies have applied a genetic and imaging technique to investigate the mechanism of early wakening symptom in MDD. We hypothesized that TPH-2 variants could influence the function of SCN in MDD patients with early wakening symptom. Methods: One hundred and eighty five MDD patients (62 patients without early wakening and 123 patients with early wakening) and 64 healthy controls participated in this study. Blood samples were collected and genotyping of rs4290270, rs4570625, rs11178998, rs7305115, rs41317118, and rs17110747 were performed by next-generation sequencing (NGS) technology. Logistic regression model was employed for genetic data analysis using the PLINK software. Based on the allele type, rs4290270, which was significant in the early wakening MDD group, participants were categorized into two groups (A allele and T carrier). All patients underwent whole brain resting-state functional magnetic resonance imaging (rs-fMRI) scanning and a voxel-wise functional connectivity comparison was performed between the groups. Results: rs4290270 was significantly linked to MDD patients who exhibited early wakening symptom. The functional connectivities of the right SCN with the right fusiform gyrus and right middle frontal gyrus were increased in the T carrier group compared to the A allele group. In addition, the functional connectivities of the left SCN with the right lingual gyrus and left calcarine sulcus were decreased in the T carrier group compared to the A allele group. Conclusion: These findings suggested that the TPH-2 gene variant, rs4290270, affected the circadian regulating function of SCN. The altered functional connectivities, observed between the SCN and right fusiform gyrus, right middle frontal gyrus, the right lingual gyrus and left calcarine sulcus, could highlight the neural mechanism by which SCN induces sleep-related circadian disruption in T carrier MDD patients. Hence, rs4290270 could potentially serve as a reliable biomarker to identify MDD patients with early wakening symptom. PMID- 30519156 TI - The Role of Sirt1 in Ischemic Stroke: Pathogenesis and Therapeutic Strategies. AB - Silent mating type information regulation 2 homolog 1 (Sirt1), a nicotine adenine dinucleotide (NAD+)-dependent enzyme, is well-known in playing a part in longevity. Ischemic stroke is a major neurological disorder and is a leading cause of death and adult disability worldwide. Recently, many studies have focused on the role of Sirt1 in ischemic stroke. Numerous studies consider Sirt1 as a protective factor and investigate the signaling pathways involved in the process under ischemic stress. However, the answer to whether upregulation of Sirt1 improves the outcome of stroke is still a controversy. In this review, we discuss the role and mechanisms of Sirt1 in the setting of ischemic stroke. PMID- 30519157 TI - Iron Dysregulation and Dormant Microbes as Causative Agents for Impaired Blood Rheology and Pathological Clotting in Alzheimer's Type Dementia. AB - Alzheimer's disease and other similar dementias are debilitating neurodegenerative disorders whose etiology and pathogenesis remain largely unknown, even after decades of research. With the anticipated increase in prevalence of Alzheimer's type dementias among the more susceptible aging population, the need for disease-modifying treatments is urgent. While various hypotheses have been put forward over the last few decades, we suggest that Alzheimer's type dementias are triggered by external environmental factors, co expressing in individuals with specific genetic susceptibilities. These external stressors are defined in the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis, previously put forward. This hypothesis is consistent with current literature in which serum ferritin levels of individuals diagnosed with Alzheimer's disease are significantly higher compared those of age- and gender matched controls. While iron dysregulation contributes to oxidative stress, it also causes microbial reactivation and virulence of the so-called dormant blood (and tissue) microbiome. Dysbiosis (changes in the microbiome) or previous infections can contribute to the dormant blood microbiome (atopobiosis), and also directly promotes systemic inflammation via the amyloidogenic formation and shedding of potent inflammagens such as lipopolysaccharides. The simultaneous iron dysregulation and microbial aberrations affect the hematological system, promoting fibrin amylodiogenesis, and pathological clotting. Systemic inflammation and oxidative stress can contribute to blood brain barrier permeability and the ensuing neuro-inflammation, characteristic of Alzheimer's type dementias. While large inter-individual variability exists, especially concerning disease pathogenesis, the IDDM hypothesis acknowledges primary causative factors which can be targeted for early diagnosis and/or for prevention of disease progression. PMID- 30519158 TI - Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence. AB - Myelin water imaging can be achieved using multicomponent T2 relaxation analysis to quantify in vivo measurement of myelin content, termed the myelin water fraction (MWF). Therefore, myelin water imaging can be a valuable tool to better understand the underlying white matter pathology in demyelinating diseases, such as multiple sclerosis. To apply myelin water imaging in multisite studies and clinical applications, it must be acquired in a clinically feasible scan time (less than 15 min) and be reproducible across sites and scanner vendors. Here, we assessed the reproducibility of MWF measurements in regional and global white matter in 10 healthy human brains across two sites with two different 3 T magnetic resonance imaging scanner vendors (Philips and Siemens), using a 32-echo gradient and spin echo (GRASE) sequence. A strong correlation was found between the MWF measurements in the global white matter (Pearson's r = 0.91; p < 0.001) for all participants across the two sites. The mean intersite MWF coefficient of variation across participants was 2.77% in the global white matter and ranged from 4.47% (splenium of the corpus callosum) to 17.89% (genu of the corpus callosum) in white matter regions of interest. Bland-Altman analysis showed a good agreement in MWF measurements between the two sites with small bias of 0.002. Overall, MWF estimates were in good agreement across the two sites and scanner vendors. Our findings support the use of quantitative multi-echo T2 relaxation metrics, such as the MWF, in multicenter studies and clinical trials to gain deeper understanding about the pathological processes resulting from the underlying disease progression in neurodegenerative diseases. PMID- 30519159 TI - White Matter Plasticity Keeps the Brain in Tune: Axons Conduct While Glia Wrap. AB - Precise timing of neuronal inputs is crucial for brain circuit function and development, where it contributes critically to experience-dependent plasticity. Myelination therefore provides an important adaptation mechanism for vertebrate circuits. Despite its importance to circuit activity, the interplay between neuronal activity and myelination has yet to be fully elucidated. In recent years, significant attention has been devoted to uncovering and explaining the phenomenon of white matter (WM) plasticity. Here, we summarize some of the critical evidence for modulation of the WM by neuronal activity, ranging from human diffusion tensor imaging (DTI) studies to experiments in animal models. These experiments reveal activity-dependent changes in the differentiation and proliferation of the oligodendrocyte lineage, and in the critical properties of the myelin sheaths. We discuss the implications of such changes for synaptic function and plasticity, and present the underlying mechanisms of neuron-glia communication, with a focus on glutamatergic signaling and the axomyelinic synapse. Finally, we examine evidence that myelin plasticity may be subject to critical periods. Taken together, the present review aims to provide insights into myelination in the context of brain circuit formation and function, emphasizing the bidirectional interplay between neurons and myelinating glial cells to better inform future investigations of nervous system plasticity. PMID- 30519160 TI - The Changes of Intrinsic Excitability of Pyramidal Neurons in Anterior Cingulate Cortex in Neuropathic Pain. AB - To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation. PMID- 30519161 TI - Divergent Effects of Metformin on an Inflammatory Model of Parkinson's Disease. AB - The oral antidiabetic drug metformin is known to exhibit anti-inflammatory properties through activation of AMP kinase, thus protecting various brain tissues as cortical neurons, for example. However, the effect of metformin on the substantia nigra (SN), the main structure affected in Parkinson's disease (PD), has not yet been studied in depth. Inflammation is a key feature of PD and it may play a central role in the neurodegeneration that takes place in this disorder. The aim of this work was to determine the effect of metformin on the microglial activation of the SN of rats using the animal model of PD based on the injection of the pro-inflammogen lipopolysaccharide (LPS). In vivo and in vitro experiments were conducted to study the activation of microglia at both the cellular and molecular levels. Our results indicate that metformin overall inhibits microglia activation measured by OX-6 (MHCII marker), IKKbeta (pro-inflammatory marker) and arginase (anti-inflammatory marker) immunoreactivity. In addition, qPCR experiments reveal that metformin treatment minimizes the expression levels of several pro- and anti-inflammatory cytokines. Mechanistically, the drug decreases the phosphorylated forms of mitogen-activated protein kinases (MAPKs) as well as ROS generation through the inhibition of the NADPH oxidase enzyme. However, metformin treatment fails to protect the dopaminergic neurons of SN in response to intranigral LPS. These findings suggest that metformin could have both beneficial and harmful pharmacological effects and raise the question about the potential use of metformin for the prevention and treatment of PD. PMID- 30519162 TI - Visualization of Exo- and Endocytosis of AMPA Receptors During Hippocampal Synaptic Plasticity Around Postsynaptic-Like Membrane Formed on Glass Surface. AB - Regulation of exo- and endocytosis of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA)-type glutamate receptor (AMPAR) plays a critical role in the expression of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) at excitatory central synapses. Enhanced AMPAR exocytosis or endocytosis has been suggested to contribute to LTP or LTD, respectively. However, several unsettled fundamental questions have remained about AMPAR exo- and endocytosis in the basal condition and during synaptic plasticity: (1) Does the size of each exo- or endocytosis event, and/or do the frequencies of these events change during LTP or LTD? If they change, what are the time courses of the respective changes? (2) Where does the exo- or endocytosis preferentially occur in each condition: inside or in the vicinity of postsynaptic membrane, or in the extrasynaptic membrane? (3) Do different types of AMPAR, such as GluA1 homo-tetramer, GluA1/2 hetero-tetramer and GluA2/3 hetero tetramer, show distinct exo- and endocytosis changes? To address these questions, we developed new methods to observe individual events of AMPAR exo- or endocytosis with a high signal to noise (SN) ratio in a culture preparation using total internal reflection fluorescence microscopy (TIRFM). In these studies, hippocampal neurons were cultured on a neurexin (NRX)-coated glass coverslip, which induced formation of postsynaptic-like membrane (PSLM) directly on the glass surface. Then, a super-ecliptic pHluorin (SEP)-tagged AMPAR subunit such as GluA1 (GluA1-SEP) was expressed in neurons and its fluorescence changes during LTP induced by high frequency electrical field stimulation were observed with TIRFM, which showed different time courses of exocytosis changes of GluA1-, GluA2 , or GluA3-SEP in and around PSLM. In addition, a new method to detect individual endocytosis events of AMPAR was developed by combining TIFRM observation of GluA SEP around PSLM with a rapid extracellular pH exchange method using a U-tube. Recent results on exo- and endocytosis changes of GluA-SEP during N-methyl-D aspartate (NMDA)-induced LTD suggested that suppression of AMPAR exocytosis rather than enhancement of AMPAR endocytosis primarily contributes to LTD expression, although the NMDA application transiently enhances clathrin-dependent endocytosis of GluA1-containing AMPAR. PMID- 30519163 TI - Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare. AB - Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. To our knowledge, there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare. PMID- 30519164 TI - Sugar Metabolism Regulates Flavor Preferences and Portal Glucose Sensing. AB - In most species, including humans, food preference is primarily controlled by nutrient value. In particular, glucose-containing sugars exert exquisitely strong effects on food choice via gut-generated signals. However, the identity of the visceral signals underlying glucose's rewarding effects remains uncertain. In particular, it is unknown whether sugar metabolism mediates the formation of preferences for glucose-containing sugars. Using the mouse as a model organism, we made use of a combination of conditioning schedules, gastrointestinal nutrient administration, and chromatographic/electrochemical methods to assess the behavioral and neural effects of activating the gut with either metabolizable glucose or a non-metabolizable glucose analog. We show that mice display much superior preferences for flavors associated with intra-gastric infusions of glucose compared to flavors associated with intra-gastric infusions of the non metabolizable glucose analog alpha-methyl-D-glucopyranoside ("MDG," an activator of intestinal sodium/glucose co-transporters). These effects were unaffected by surgical bypassing of the duodenum, suggesting glucose-specific post-absorptive sensing mechanisms. Consistently, intra-portal infusions of glucose, but not of MDG, induced significant rises in dopamine (DA) levels within brain reward circuits. Our data reveal that the unmatched rewarding effects of glucose containing sugars cannot be accounted for by metabolism-independent activation of sodium/glucose cotransporters; rather, they point to glucose metabolism as the physiological mechanism underlying the potent reward value of sugar-sweetened flavored beverages. In particular, no circulating "gut factors" need to be invoked to explain the reward value of ingested glucose. Thus, instead of circulating gut hormones, portal-mesenteric sensing of glucose emerges as the preferential physiological pathway for sugar reward. PMID- 30519165 TI - Empathy for Pain: Insula Inactivation and Systemic Treatment With Midazolam Reverses the Hyperalgesia Induced by Cohabitation With a Pair in Chronic Pain Condition. AB - Empathy for pain is the ability to perceive and understand the pain in the other individual. Recent studies suggested that rodents have this social ability. GABAergic system has receptors in the brain structures involved in emotional processes as well as in the insular cortex. This area has been described as an important key in modulation of pain and empathy. The present study has investigated the role of insula and its Benzodiazepine-GABAA system on social modulation of pain induced by cohabiting with a mouse submitted to sciatic nerve constriction, a neuropathic pain model. The insular cortex function was assessed by the structure inactivation (Experiments 1 and 2); the role of GABA system was evaluated by systemic treatment of midazolam (MDZ 0.5, 1, and 2 mg/kg) (Experiment 3); and the role of GABAA receptors of insula were studied by bilateral MDZ (3 and 30 nmol/0.1 MUl) microinjections in the structure (Experiment 4). Male Swiss mice were housed in groups or dyads. On dyads, after 14 days of cohabitation they were divided into two groups: cagemate nerve constriction and cagemate sham (CS). After 14 days of familiarity, cagemates were evaluated on the writhing test. For group-housed, insula inactivation did not change nociception. For dyad-housed, cohabiting with a mouse in chronic pain increased the nociceptive response and the insula inactivation has reverted this response. Systemic MDZ attenuated nociception and intra-insula MDZ did not alter it. Our results suggest that cohabitation with a pair in chronic pain induces hypernociception, insula possibly modulates this response and the GABA system is also possibly involved, but not its insular mechanisms. PMID- 30519166 TI - Neural Processing of Repeated Search Targets Depends Upon the Stimuli: Real World Stimuli Engage Semantic Processing and Recognition Memory. AB - Recent evidence has suggested that visual working memory (VWM) plays an important role in representing the target prior to initiating a visual search. The more familiar we are with the search target, the more refined the representation of the target (or "target template") becomes. This sharpening of the target template is thought to underlie the reduced response time (RT) and increased accuracy associated with repeatedly searching for the same target. Perhaps target representations transition from limited-capacity VWM to Long-Term Memory (LTM) as targets repeat. In prior work, amplitude of an event-related potential (ERP) component associated with VWM representation decreased with target repetition, broadly supporting this notion. However, previous research has focused on artificial stimuli (Landolt Cs) that are far removed from search targets in the real world. The current study extends this work by directly comparing target representations for artificial stimuli and common object images. We found VWM representation follows the same pattern for real and artificial stimuli. However, the initial selection of the real world objects follows a much different pattern than more typical artificial stimuli. Further, the morphology of nonlateralized waveforms was substantially different for the two stimulus categories. This suggests that the two types of stimuli were processed in fundamentally different ways. We conclude that object type strongly influences how we deploy attentional and mnemonic resources prior to search. Early attentional selection of familiar objects may facilitate additional LTM processes that lead to behavioral benefits not seen with more simplistic stimuli. PMID- 30519167 TI - Disruption of Multiple Distinctive Neural Networks Associated With Impulse Control Disorder in Parkinson's Disease. AB - The phenomenon of impulsivity in Parkinson's disease appears as an arduous side effect of dopaminergic therapy with potentially detrimental consequences for the life of the patients. Although conceptualized as a result of non-physiologic chronic dopaminergic stimulation, recent advances speculate on combined disruption of other networks as well. In the search for neuroanatomical correlates of this multifaceted disturbance, this study employs two distinct, well-defined tasks of close association to motor inhibition and decision-making impulsivity, Go/No Go and Delay discounting. The fMRI and functional connectivity analysis in 21 Parkinson's disease patients, including 8 patients suffering from severe impulse control disorder, and 28 healthy controls, revealed in impulsive Parkinson's disease patients not only decreased fMRI activation in the dorsolateral prefrontal cortex and bilateral striatum, but also vast functional connectivity changes of both caudate nuclei as decreased connectivity to the superior parietal cortex and increased connectivity to the insular area, clearly beyond the commonly stated areas, which indicates that orbitofronto-striatal and mesolimbic functional disruptions are not the sole mechanisms underlying impulse control disorder in Parkinson's disease. Ergo, our results present a refinement and synthesis of gradually developing ideas about the nature of impulsive control disorder in Parkinson's disease-an umbrella term encompassing various behavioral deviations related to distinct neuronal networks and presumably neurotransmitter systems, which greatly exceed the previously envisioned dopaminergic pathways as the only culprit. PMID- 30519168 TI - Anti-Centromere Antibody Positivity in a Patient with Generalized Morphea. AB - We report the case of a 45-year-old female with generalized morphea (GM), who exhibited positivity for the anti-centromere antibody (Ab). She frequently developed multiple sclerotic skin lesions, whose histological findings were compatible with morphea. She demonstrated favorable responses to topical and oral steroids. Cases of GM associated with systemic sclerosis (SSc)-specific Abs (anti Scl-70 Ab, anti-centromere Ab, and anti-RNA polymerase III Ab) have rarely been reported. The previously reported GM cases involving anti-SSc-specific Abs exhibited some skin manifestations of SSc, such as nailfold capillary changes. However, our case did not show any signs of SSc or limited cutaneous SSc. More cases are needed to clarify whether GM with SSc-specific Abs leads to SSc. PMID- 30519169 TI - Atypical Manifestation of Disseminated Sporotrichosis in an AIDS Patient. AB - Sporotrichosis is an infection caused by fungi of the Sporothrix complex. The clinical lymphocutaneous presentation corresponds to the great majority of cases. With the increased incidence of sporotrichosis in the State of Rio de Janeiro, Brazil, atypical clinical forms have been reported with increasing frequency, usually associated with immunosuppression. We report the case of a 47-year-old female, with HIV and disseminated sporotrichosis, presenting molluscum-like skin lesions, as well as lung, nasal, and oral mucosa involvement. We also report the first demonstration of culture of Sporothrix in scales of the skin lesion, a fact not identified in the consulted literature. PMID- 30519170 TI - Allergic Contact Dermatitis and Autoeczematization to Proctosedyl(r) Cream and Proctomyxin(r) Cream. AB - Proctosedyl(r) and Proctomyxin(r) are two commonly prescribed hemorrhoid therapies. Their topical application to the perianal region may be complicated by a local allergic contact dermatitis and subsequent autoeczematization reaction. We present three cases of an autoeczematization (ID) reaction to varying topical allergens found in Proctosedyl(r)/Proctomyxin(r). It is our recommendation that physician and patient education, avoidance of allergens (or cross-reactants), and appropriate choice of topical corticosteroid is important in preventing and avoiding flares. PMID- 30519171 TI - Efficacy and Safety of Intralesional Methotrexate in the Treatment of a Large Keratoacanthoma of the Dorsal Hand in a 99-Year-Old Woman. AB - Several case reports and retrospective studies have demonstrated that intralesional methotrexate (MTX) could be a very effective and safe alternative treatment of keratoacanthoma (KA). Here, we report a rapid clinical efficacy of two intralesional MTX injections (total dose 40 mg) that were performed 1 week apart in the treatment of a large KA lesion of the dorsal hand in a 99-year-old woman. The lesion, with a 3-cm major axis diameter and a thickness of 2 cm with a central ulceration had rapidly appeared on the right dorsal hand. A 3-mm punch biopsy confirmed the diagnosis of a well-differentiated KA-type spinous cellular carcinoma. Due to the presence of comorbidities (arterial hypertension and atrial fibrillation) and chronic treatment with antihypertensive and oral anticoagulant drugs, treatment with intralesional MTX was proposed to the patient. Two intralesional MTX injections of 20 mg each were performed 1 week apart. A very fast resolution of the lesion was observed after the first injection. A week after the second injection a full resolution of the skin lesion was observed, with a nearly complete resolution of the central ulceration. The treatment was very well tolerated. No local or systemic side effects were observed. This case report confirms that intralesional MTX could be considered an effective and safe treatment of KA also in very old subjects. PMID- 30519173 TI - Screening For Gestational Diabetes Mellitus Selectively in a University Maternity Hospital AB - AimsScreening for gestational diabetes mellitus (GDM) may be universal or selective based on risk factors. We audited selective screening with an Oral Glucose Tolerance Test (OGTT).MethodsClinical and laboratory details of the first 200 women who delivered a baby in 2017 were analysed.ResultsBased on national recommendations, 46.5% (n=93) had maternal risk factors (RF) and an additional 6.5% (n=13) had fetal RF. Nine women with RF, for unexplained reasons did not have their OGTT. Of the 95 who had their OGTT, the diagnosis of GDM was made in 27.4% (n=26). The diagnosis of GDM was made in an additional 8 women outside selective screening giving an overall incidence of 17.0%.DiscussionMore than half of the women needed to be screened selectively for GDM. Compliance with the national recommendations was incomplete and thus the diagnosis of GDM may be missed even in an academic setting. PMID- 30519172 TI - Phototoxic Reaction Induced by Pazopanib. AB - Multikinase inhibitors (MKIs) are a novel target therapy that offers promising long-term survival for patients with advanced-stage cancer. However, they cause a wide range of adverse reactions, skin and skin appendage being the most prevalent. Photosensitivity reactions are well-recognized effects from certain MKIs such as sunitinib and vandetanib. However, phototoxic reaction induced by pazopanib has never been reported. We present here the first case of pazopanib induced phototoxic drug reaction in a patient with renal cell carcinoma. PMID- 30519174 TI - Radiotherapy in Patients with Mycosis Fungoides and Central Nervous System Involvement. AB - Background: Involvement of the central nervous system (CNS) by mycosis fungoides (MF) is rare; however, it portends a poor prognosis. While aggressive multimodality therapy may improve outcomes, the role of radiation therapy (RT) is not well defined. Objectives: We sought to explore the efficacy of RT in the management of CNS involvement by MF. Method: We retrospectively identified five patients with MF and CNS involvement who received cranial or craniospinal RT at a single institution. Patient characteristics, disease features, radiographic findings, treatments delivered, and outcome data were extracted from the electronic medical record. Results: All 5 patients had neurologic deficits at RT initiation, and 4 experienced at least a partial improvement. Of 4 patients evaluated by MRI after RT completion, 3 had complete resolution of CNS disease within the irradiated field. At the time of last follow-up, all patients had died of MF. The median time to death was 7.4 months (range 1.0-21 months) from their diagnosis with CNS involvement and 1.2 months (range 0.4-7.1 months) from the end of RT treatment. Conclusions: We observed high rates of radiographic response and palliation of neurological symptoms. Nonetheless, all patients succumbed to their disease shortly after treatment, confirming the poor prognosis of this condition. Our findings suggest that RT may play a valuable palliative role for these patients. PMID- 30519175 TI - Cutaneous Ewing Sarcoma and Ewing Sarcoma of the Bone: Distinct Diseases. AB - Ewing sarcoma is an aggressive mesenchymal malignancy. It is the second most common bone tumor among children and adolescents and less commonly presents as a soft tissue or primary skin lesion. Cutaneous Ewing sarcoma has only been reported in case reports and case series. In this article, we describe a 12-year old Hispanic female cured of localized, cutaneous Ewing sarcoma (pT1aN0M0) at the 40-month follow-up following surgical resection and adjuvant chemotherapy according to the COG AEWS1031 protocol for Ewing sarcoma of the bone. To our knowledge, this is the first article to provide a potential biological explanation for the differences in the prognosis of Ewing sarcoma of the bone, soft tissue, and skin. PMID- 30519177 TI - Esophageal Adenocarcinoma with Extensive Metastasis to Unexpected Sites: A Case Report. AB - Background: Esophageal cancer (EC) with unexpected metastasis (UM) to unusual sites have been increasingly reported. EC with metastasis in general has a very high mortality and morbidity rate, and those with UM to unusual sites present another specific field that needs to be further studied in order to understand and manage the presentation. An extensive systematic review was recently completed regarding this field which identified characteristics and findings concerning patients with EC with UM sites. Case Presentation: We report a 61 year old Hispanic male who had an EC, adenocarcinoma subtype, with UM to an extensive number of sites such as the soft tissue of the cheek, subcutaneous forehead and scalp with penetration of the calvarium, occipital bone, base of tongue, neck muscles, paraspinal and iliopsoas musculature and, more typically, to an adrenal gland followed by a questionable new-onset finding of subcutaneous shoulder and flank nodules not initially identified by imaging. Discussion/Conclusion: The case reports a patient who not only had EC with UM to unusual sites, but also to a considerable number. The patient correlated well in terms of clinical features identified by the systematic review of this particular field, but his case also showed a new finding, another unexpected metastasis site. This case also shows an example of why the type of imaging is important when dealing with UM sites. With this, we hope to further add to the data in this particular field and provide some opinion on this matter. PMID- 30519176 TI - Thrombotic Microangiopathy with Severe Proteinuria Induced by Lenvatinib for Radioactive Iodine-Refractory Papillary Thyroid Carcinoma. AB - Standard therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is multi-targeted kinase inhibitors (m-TKIs), represented by sorafenib and lenvatinib. One of the main target molecules of m-TKIs is vascular endothelial growth factor receptor (VEGF-R). m-TKIs are known to cause adverse reactions such as hypertension and proteinuria as a class effect. In particular, proteinuria is thought to result from vascular endothelial damage and podocytopathy in glomeruli, and the development of thrombotic microangiopathy (TMA) has been reported for VEGF inhibitors. We encountered a patient with RAI refractory (RR) papillary thyroid carcinoma (PTC) who developed proteinuria and renal dysfunction due to lenvatinib. Renal biopsy demonstrated that these changes were caused by TMA. To our knowledge, this is the first reported case of TMA due to lenvatinib in a Japanese patient with RR-PTC. A 70-year-old woman developed proteinuria, renal impairment and hypertension while receiving lenvatinib for RR PTC. Her proteinuria and renal damage continued to worsen despite dose reductions and dose interruptions. Renal biopsy was consistent with the chronic type of TMA. These findings indicate that TMA is a possible cause of proteinuria due to lenvatinib, as has been reported for the VEGF inhibitors. PMID- 30519178 TI - Severe Photo Toxicity Recalled by Docetaxel. AB - Photo-recall phenomenon is a rarely recognized adverse event of chemotherapeutic agents. The physiopathology of this entity is unclear. We have reported a 56-year old breast cancer patient with severe photo toxicity recalled 5 months after the initial sunburn by one course of adjuvant docetaxel treatment. However, being given right diagnosis and proper managements the patient could be able to complete her adjuvant chemotherapy according to the planed time schedule, without any delay. Our case may be explained by the theory that long-lived memory T-cells may remember former skin damage and cross-react with cytotoxic drugs. In addition, we have proved that weekly paclitaxel can still be the drug of option after docetaxel recalled severe photo toxicity. PMID- 30519179 TI - The Wrong Turn to Tijuana: Dry Beriberi after Gastric Bypass Surgery with Incidental Spinal Stenosis. AB - Thiamine deficiency is a condition characterized by several different presentations, but one of the most devastating is dry beriberi. It is associated with polyneuropathy and muscle weakness which typically affects the lower extremities and progressively involves the upper extremities. This case outlines a case of a 41-year-old man that presented to the hospital with diffuse weakness and decreased sensation in his legs and hands over a 3-day period. The patient's medical history revealed a gastric bypass surgery 4 months previously in Tijuana, Mexico, with no follow-up, binge drinking on weekends, and emesis in the past few weeks. A physical examination revealed a significant decrease in strength in the lower extremities bilaterally as well as in the hands bilaterally. MRI showed central disc protrusion at T6-T7 that indented the spinal cord, consistent with spinal stenosis. Neurosurgery was counseled and corpectomy was recommended. While awaiting surgery, a low thiamine level resulted. Neurology was consulted, and it was recommended that high-dose IV thiamine treatment be started. An EMG study further supported the diagnosis of thiamine deficiency. The patient received high dose IV thiamine for 2 weeks and was discharged to acute rehabilitation on a high oral dose of thiamine. While at the rehabilitation facility, the patient continued to achieve functional gains and was later discharged to a skilled nursing facility, where he continues to make progress in his activities of daily living. This case serves to remind practitioners that early recognition and treatment of thiamine deficiency is imperative, especially when other clinical evidence may point to a different diagnosis. PMID- 30519180 TI - Stent-Assisted Angioplasty of Spontaneous Bilateral Extracranial Vertebral Dissections under Intravascular Ultrasound Guidance. AB - The authors here report a case of stent-assisted angioplasty under intravascular ultrasound (IVUS) guidance for the treatment of spontaneous bilateral extracranial vertebral artery (VA) dissection. A 47-year-old woman presented with spontaneous severe posterior neck pain. Examinations revealed bilateral extracranial VA dissection, which was thought to be the reason for her symptom. However, since the pain was gradually worsening even after sufficient medical treatment, she underwent stent angioplasty under IVUS guidance, following which her symptoms improved. We propose that stent placement under IVUS guidance is a safe and feasible method for treating extracranial VA dissections. Since the intravascular environment is seen in real time with IVUS, this technique is useful for confirming a true lumen and evaluating appropriate stent apposition. More clinical experience with this technique is required and mandatory, and devices with smaller diameters with improved trackability are essential for further introduction of IVUS into the field of endovascular neurosurgery. PMID- 30519181 TI - Transient Anarthria and Quadriplegia in a Patient with Basilar Artery Hypoplasia and Coincidental Intracranial Lipoma: A Case Report. AB - Cerebral ischemia may be rarely associated with a hypoplastic vertebrobasilar system. Intracranial lipoma is also a very rare congenital malformation. We report the case of a 52-year-old woman with vertebrobasilar transient ischemic attack associated with basilar artery hypoplasia and coincidental intracranial lipoma. She presented with sudden-onset dizziness, anarthria, and quadriplegia lasting for about 30 min. The patient's initial blood pressure was measured at 200/120 mm Hg. The magnetic resonance and computed tomographic images showed the absence of an acute ischemic lesion in the brain but revealed a hypoplasia of the basilar artery and bilateral V4 vertebral arteries. A lipoma of 11 mm in long diameter was also found in the quadrigeminal cistern and at the superior vermis. The electroencephalography, transthoracic echocardiogram, 24-h Holter monitoring, and transcranial Doppler ultrasonography, including patent foramen ovale study, were all noted as negative. The patient was treated with oral aspirin 100 mg, atorvastatin 10 mg, and antihypertensive medication. She had no symptom recurrence after the treatment. Our case suggests that hypoplasia of the vertebrobasilar arteries can be a predisposing factor for posterior circulation ischemia, especially when additional vascular risk factors coexist. PMID- 30519182 TI - Diagnosis, Clinical Trend, and Treatment of Diffuse Lamellar Keratitis after Femtosecond Laser-Assisted in situ Keratomileusis: A Case Report. AB - We report a severe case of diffuse lamellar keratitis (DLK) following femtosecond laser-assisted in situ keratomileusis (femto-LASIK). A 25-year-old man was submitted to 150 kHz iFS(r) IntraLase-assisted LASIK in both eyes for compound myopic astigmatism. The day after surgery, clinical examination showed a diffuse whitish granular cell reaction particularly in the right eye. High-dose dexamethasone eyedrops with topical antibiotic and artificial tears were prescribed. Five days after surgery, a central corneal opacity with convergent striae was detected at biomicroscopy. The suspicion of DLK was confirmed. Additional therapy based on hyperosmolar ophthalmological solution, oral doxycycline, and topical 10% sodium citrate was prescribed. Treatment was continued and tapered for over 3 months. Improvement in corneal transparency were obtained 2 weeks after the systemic therapy had been started. Uncorrected visual acuity improved from 20/32 to 20/20 at 1-year follow-up. DLK represents an infrequent complication after femto-LASIK. It should resolve without sequelae if promptly diagnosed and treated, without necessity of corneal flap lifting. PMID- 30519183 TI - Off-Label Use of Phakic Intraocular Lens with a "Piggyback" Technique. AB - Purpose: We report a case of a highly myopic pseudophakic patient who received off-label placement of a phakic intraocular lens (pIOL) via a "piggyback" technique, allowing the placement of an intraocular lens (IOL) in his fellow eye, resulting in improved visual acuity and emmetropia. Case Report: A 66-year-old, highly myopic, pseudophakic male with an IOL implant in his left eye was referred for second opinion for surgical options for his phakic right eye. Given the severe myopic status of both eyes, he received off-label placement of a posterior chamber pIOL with a piggyback technique for the pseudophakic left eye followed by standard cataract surgery and intraocular lens implantation in the right eye. For the left eye, uncorrected best visual acuity improved from 20/70 to 20/25. Conclusion: This case demonstrates the successful off-label use of a phakic IOL in a pseudophakic, highly myopic patient with a piggyback technique, resulting in improved visual acuity and ultimately allowing IOL placement in the fellow eye for emmetropia. This off-label use of pIOL can offer ophthalmologists an alternative option for pseudophakic patents with severe refractive error. PMID- 30519184 TI - Structural Brain Correlates of Attention Dysfunction in Lewy Body Dementias and Alzheimer's Disease. AB - Lewy body dementia (LBD) and Alzheimer's disease (AD) are common forms of dementia that have different clinical profiles but are both commonly associated with attentional deficits. The aim of this study was to investigate efficiency of different attentional systems in LBD and AD and its association with brain structural abnormalities. We studied reaction time (RT) data from 45 LBD, 31 AD patients and 22 healthy controls (HCs) using the Attention Network Test (ANT) to assess the efficiency of three different attentional systems: alerting, orienting and executive conflict. Voxel-based morphometry (VBM) was used to investigate relations between different attention components and cortical volume. Both dementia groups showed slower overall RTs than controls, with additional slowing in LBD relative to AD. There was a significant alerting effect in controls which was absent in the dementia groups, the executive conflict effect was greater in both dementia groups compared to controls, but the orienting effect did not differ between groups. Mean RT in AD was negatively correlated with occipital gray matter (GM) volume and in LBD orienting efficiency was negatively related to occipital white matter (WM) volume. Given that previous studies in less impaired patients suggest a maintenance of the alerting effect, the absent alerting effect in our study suggests a loss of alerting efficiency with dementia progression. While orienting was largely preserved, it might be related to occipital structural abnormalities in LBD. Executive function was markedly impaired in both dementia groups, however, the absence of relations to brain volume suggests that it might be more related to functional rather than macrostructural pathophysiological changes. PMID- 30519185 TI - Cognitive Profiles and Atrophy Ratings on MRI in Senior Patients With Mild Cognitive Impairment. AB - In this cross-sectional study, we sought to describe cognitive and neuroimaging profiles of Memory clinic patients with Mild Cognitive Impairment (MCI). 51 MCI patients and 51 controls, matched on age, sex, and socio-economic status (SES), were assessed with an extensive neuropsychological test battery that included a measure of intelligence (General Ability Index, "GAI," from WAIS-IV), and structural magnetic resonance imaging (MRI). MCI subtypes were determined after inclusion, and z-scores normalized to our control group were generated for each cognitive domain in each MCI participant. MR-images were scored by visual rating scales. MCI patients performed significantly worse than controls on 23 of 31 cognitive measures (Bonferroni corrected p = 0.001), and on 8 of 31 measures after covarying for intelligence (GAI). Compared to nonamnestic MCI patients, amnestic MCI patients had lower test results in 13 of 31 measures, and 5 of 31 measures after co-varying for GAI. Compared to controls, the MCI patients had greater atrophy on Schelten's Medial temporal lobe atrophy score (MTA), especially in those with amnestic MCI. The only structure-function correlation that remained significant after correction for multiple comparisons was the MTA long delay recall domain. Intelligence operationalized as GAI appears to be an important moderator of the neuropsychological outcomes. Atrophy of the medial temporal lobe, based on MTA scores, may be a sensitive biomarker for the functional episodic memory deficits associated with MCI. PMID- 30519186 TI - Targeted Delivery of Bioactive Molecules for Vascular Intervention and Tissue Engineering. AB - Cardiovascular diseases are the leading cause of death in the United States. Treatment often requires surgical interventions to re-open occluded vessels, bypass severe occlusions, or stabilize aneurysms. Despite the short-term success of such interventions, many ultimately fail due to thrombosis or restenosis (following stent placement), or incomplete healing (such as after aneurysm coil placement). Bioactive molecules capable of modulating host tissue responses and preventing these complications have been identified, but systemic delivery is often harmful or ineffective. This review discusses the use of localized bioactive molecule delivery methods to enhance the long-term success of vascular interventions, such as drug-eluting stents and aneurysm coils, as well as nanoparticles for targeted molecule delivery. Vascular grafts in particular have poor patency in small diameter, high flow applications, such as coronary artery bypass grafting (CABG). Grafts fabricated from a variety of approaches may benefit from bioactive molecule incorporation to improve patency. Tissue engineering is an especially promising approach for vascular graft fabrication that may be conducive to incorporation of drugs or growth factors. Overall, localized and targeted delivery of bioactive molecules has shown promise for improving the outcomes of vascular interventions, with technologies such as drug eluting stents showing excellent clinical success. However, many targeted vascular drug delivery systems have yet to reach the clinic. There is still a need to better optimize bioactive molecule release kinetics and identify synergistic biomolecule combinations before the clinical impact of these technologies can be realized. PMID- 30519187 TI - Eukaryotic Voltage-Gated Sodium Channels: On Their Origins, Asymmetries, Losses, Diversification and Adaptations. AB - The appearance of voltage-gated, sodium-selective channels with rapid gating kinetics was a limiting factor in the evolution of nervous systems. Two rounds of domain duplications generated a common 24 transmembrane segment (4 * 6 TM) template that is shared amongst voltage-gated sodium (Nav1 and Nav2) and calcium channels (Cav1, Cav2, and Cav3) and leak channel (NALCN) plus homologs from yeast, different single-cell protists (heterokont and unikont) and algae (green and brown). A shared architecture in 4 * 6 TM channels include an asymmetrical arrangement of extended extracellular L5/L6 turrets containing a 4-0-2-2 pattern of cysteines, glycosylated residues, a universally short III-IV cytoplasmic linker and often a recognizable, C-terminal PDZ binding motif. Six intron splice junctions are conserved in the first domain, including a rare U12-type of the minor spliceosome provides support for a shared heritage for sodium and calcium channels, and a separate lineage for NALCN. The asymmetrically arranged pores of 4x6 TM channels allows for a changeable ion selectivity by means of a single lysine residue change in the high field strength site of the ion selectivity filter in Domains II or III. Multicellularity and the appearance of systems was an impetus for Nav1 channels to adapt to sodium ion selectivity and fast ion gating. A non-selective, and slowly gating Nav2 channel homolog in single cell eukaryotes, predate the diversification of Nav1 channels from a basal homolog in a common ancestor to extant cnidarians to the nine vertebrate Nav1.x channel genes plus Nax. A close kinship between Nav2 and Nav1 homologs is evident in the sharing of most (twenty) intron splice junctions. Different metazoan groups have lost their Nav1 channel genes altogether, while vertebrates rapidly expanded their gene numbers. The expansion in vertebrate Nav1 channel genes fills unique functional niches and generates overlapping properties contributing to redundancies. Specific nervous system adaptations include cytoplasmic linkers with phosphorylation sites and tethered elements to protein assemblies in First Initial Segments and nodes of Ranvier. Analogous accessory beta subunit appeared alongside Nav1 channels within different animal sub-phyla. Nav1 channels contribute to pace-making as persistent or resurgent currents, the former which is widespread across animals, while the latter is a likely vertebrate adaptation. PMID- 30519188 TI - Improved Neural Control of Movements Manifests in Expertise-Related Differences in Force Output and Brain Network Dynamics. AB - It is well-established that expertise developed through continuous and deliberate practice has the potential to delay age-related decline in fine motor skills. However, less is known about the underlying mechanisms, that is, whether expertise leads to a higher performance level changing the initial status from which age-related decline starts or if expertise-related changes result in qualitatively different motor output and neural processing providing a resource of compensation for age-related changes. Thus, as a first step, this study aims at a better understanding of expertise-related changes in fine motor control with respect to force output and respective electrophysiological correlates. Here, using a multidimensional approach, we investigated fine motor control of experts and novices in precision mechanics during the execution of a dynamic force control task. On the level of force output, we analyzed precision, variability, and complexity. We further used dynamic mode decomposition (DMD) to analyze the electrophysiological correlates of force control to deduce brain network dynamics. Experts' force output was more precise, less variable, and more complex. Task-related DMD mean mode magnitudes within the alpha-band at electrodes over sensorimotor relevant areas were reduced in experts, and lower DMD mean mode magnitudes related to the force output in novices. Our results provide evidence for expertise dependent central adaptions with distinct and more complex organization and decentralization of sensorimotor subsystems. Results from our multidimensional approach can be seen as a step forward in understanding expertise-related changes and exploiting their potential as resources for healthy aging. PMID- 30519189 TI - Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients. AB - Sodium glucose cotransporter 2 inhibitors (SGLT2i) are the first antidiabetic compounds that effectively reduce heart failure hospitalization and cardiovascular death in type 2 diabetics. Being explicitly designed to inhibit SGLT2 in the kidney, SGLT2i have lately been investigated for their off-target cardiac actions. Here, we review the direct effects of SGLT2i Empagliflozin (Empa), Dapagliflozin (Dapa), and Canagliflozin (Cana) on various cardiac cell types and cardiac function, and how these may contribute to the cardiovascular benefits observed in large clinical trials. SGLT2i impaired the Na+/H+ exchanger 1 (NHE-1), reduced cytosolic [Ca2+] and [Na+] and increased mitochondrial [Ca2+] in healthy cardiomyocytes. Empa, one of the best studied SGLT2i, maintained cell viability and ATP content following hypoxia/reoxygenation in cardiomyocytes and endothelial cells. SGLT2i recovered vasoreactivity of hyperglycemic and TNF-alpha stimulated aortic rings and of hyperglycemic endothelial cells. Anti-inflammatory actions of Cana in IL-1beta-treated HUVEC and of Dapa in LPS-treated cardiofibroblast were mediated by AMPK activation. In isolated mouse hearts, Empa and Cana, but not Dapa, induced vasodilation. In ischemia-reperfusion studies of the isolated heart, Empa delayed contracture development during ischemia and increased mitochondrial respiration post-ischemia. Direct cardiac effects of SGLT2i target well-known drivers of diabetes and heart failure (elevated cardiac cytosolic [Ca2+] and [Na+], activated NHE-1, elevated inflammation, impaired vasorelaxation, and reduced AMPK activity). These cardiac effects may contribute to the large beneficial clinical effects of these antidiabetic drugs. PMID- 30519190 TI - Current Perspectives on Tooth Implantation, Attachment, and Replacement in Amniota. AB - Teeth and dentitions contain many morphological characters which give them a particularly important weight in comparative anatomy, systematics, physiology and ecology. As teeth are organs that contain the hardest mineralized tissues vertebrates can produce, their fossil remains are abundant and the study of their anatomy in fossil specimens is of major importance in evolutionary biology. Comparative anatomy has long favored studies of dental characters rather than features associated with tooth attachment and implantation. Here we review a large part of the historical and modern work on the attachment, implantation and replacement of teeth in Amniota. We propose synthetic definitions or redefinitions of most commonly used terms, some of which have led to confusion and conflation of terminology. In particular, there has long been much conflation between dental implantation that strictly concerns the geometrical aspects of the tooth-bone interface, and the nature of the dental attachment, which mostly concerns the histological features occurring at this interface. A second aim of this work was to evaluate the diversity of tooth attachment, implantation and replacement in extant and extinct amniotes in order to derive hypothetical evolutionary trends in these different dental traits over time. Continuous dental replacement prevails within amniotes, replacement being drastically modified only in Mammalia and when dental implantation is acrodont. By comparison, dental implantation frequently and rapidly changes at various taxonomic scales and is often homoplastic. This contrasts with the conservatism in the identity of the tooth attachment tissues (cementum, periodontal ligament, and alveolar bone), which were already present in the earliest known amniotes. Because the study of dental attachment requires invasive histological investigations, this trait is least documented and therefore its evolutionary history is currently poorly understood. Finally, it is essential to go on collecting data from all groups of amniotes in order to better understand and consequently better define dental characters. PMID- 30519191 TI - ABPS: An R Package for Calculating the Abnormal Blood Profile Score. AB - The Abnormal Blood Profile Score (ABPS) is used to identify blood doping in sport. It combines seven hematological markers, including hemoglobin level, reticulocytes percent, and haematocrit level, using two different machine learning algorithms in order to create a single score that has a better ability to identify doping than each parameter taken alone. The resulting score allows the detection of several types of doping using a single score and is part of the current Athlete Biological Passport program managed by World Anti-Doping Agency (WADA). We describe ? ABPS ?, an R package that allows the calculation of this score. This is the first software implementation calculating this score that is released publicly. The package also contains functions to calculate the OFF-score (another score used for detection of doping), as well as several test datasets. The package is useful for laboratories conducting anti-doping analyses and for researchers working on anti-doping research projects. In particular, it has been successfully used in projects estimating the prevalence of blood doping. PMID- 30519192 TI - Cerebrovascular Function in the Large Arteries Is Maintained Following Moderate Intensity Exercise. AB - Exercise has been shown to induce cerebrovascular adaptations. However, the underlying temporal dynamics are poorly understood, and regional variation in the vascular response to exercise has been observed in the large cerebral arteries. Here, we sought to measure the cerebrovascular effects of a single 20-min session of moderate-intensity exercise in the one hour period immediately following exercise cessation. We employed transcranial Doppler (TCD) ultrasonography to measure cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCAv) and posterior cerebral artery (PCAv) before, during, and following exercise. Additionally, we simultaneously measured cerebral blood flow (CBF) in the internal carotid artery (ICA) and vertebral artery (VA) before and up to one hour following exercise cessation using Duplex ultrasound. A hypercapnia challenge was used before and after exercise to examine exercise-induced changes in cerebrovascular reactivity (CVR). We found that MCAv and PCAv were significantly elevated during exercise (p = 4.81 * 10-5 and 2.40 * 10-4, respectively). A general linear model revealed that these changes were largely explained by the partial pressure of end-tidal CO2 and not a direct vascular effect of exercise. After exercise cessation, there was no effect of exercise on CBFV or CVR in the intracranial or extracranial arteries (all p > 0.05). Taken together, these data confirm that CBF is rapidly and uniformly regulated following exercise cessation in healthy young males. PMID- 30519193 TI - Emerging Roles of the Membrane Potential: Action Beyond the Action Potential. AB - Whilst the phenomenon of an electrical resting membrane potential (RMP) is a central tenet of biology, it is nearly always discussed as a phenomenon that facilitates the propagation of action potentials in excitable tissue, muscle, and nerve. However, as ion channel research shifts beyond these tissues, it became clear that the RMP is a feature of virtually all cells studied. The RMP is maintained by the cell's compliment of ion channels. Transcriptome sequencing is increasingly revealing that equally rich compliments of ion channels exist in both excitable and non-excitable tissue. In this review, we discuss a range of critical roles that the RMP has in a variety of cell types beyond the action potential. Whereas most biologists would perceive that the RMP is primarily about excitability, the data show that in fact excitability is only a small part of it. Emerging evidence show that a dynamic membrane potential is critical for many other processes including cell cycle, cell-volume control, proliferation, muscle contraction (even in the absence of an action potential), and wound healing. Modulation of the RMP is therefore a potential target for many new drugs targeting a range of diseases and biological functions from cancer through to wound healing and is likely to be key to the development of successful stem cell therapies. PMID- 30519194 TI - Associations of Insulin Levels and Insulin Resistance With Urine Glucose Excretion Independent of Blood Glucose in Chinese Adults With Prediabetes and Newly Diagnosed Diabetes. AB - Several studies have demonstrated that renal glucose reabsorption is increased in patients with type 2 diabetes. However, the increased renal glucose reabsorption may contribute to the progression of hyperglycemia. Therefore, promoting urine glucose excretion (UGE) by suppression of renal glucose reabsorption is an attractive approach for the treatment of diabetes. Insulin resistance is identified as a major characteristic in the pathogenesis of type 2 diabetes. Thus, our aim was to evaluate the association of UGE with serum insulin levels and insulin resistance in subjects with glucose abnormalities, including prediabetes and newly diagnosed diabetes (NDD). The present study included 1129 subjects, 826 individuals with prediabetes and 303 individuals with NDD. Urine samples were collected within 2 h of oral glucose loading for the measurement of glucose. Fasting serum insulin was measured. Homeostatic model assessment of insulin resistance (HOMA-IR) was assessed. Multiple linear regression analysis and multivariate logistic regression analysis were performed to determine the association of UGE with insulin levels and HOMA-IR. A negative association between serum insulin levels and UGE was observed. The relationship remained significant after adjustment for potential confounders, including age, gender, blood pressure and glucose (beta = -5.271, 95% CI: -9.775 to -0.767, p = 0.022). Furthermore, multivariable logistic regression model showed that increased insulin levels were associated with a decreased risk for high UGE after multivariable adjustment. In addition, similar correlation was also observed between HOMA-IR and UGE. HOMA-IR was negatively correlated with UGE after controlling for potential confounders. Moreover, an independent inverse relationship between HOMA-IR and the risk of high UGE was found (OR = 0.85, 95% CI: 0.78-0.93, p < 0.001). In conclusion, insulin levels and HOMA-IR were negatively correlated with UGE after adjusting for potential confounders. Subjects with increased insulin levels or IR were at a decreased risk of high UGE independent of blood glucose. The study suggests that insulin might affect UGE through other ways, in addition to the direct blood glucose-lowering effect, thereby resulting in reduced UGE. PMID- 30519195 TI - Reducing Salt Intake and Exercising Regularly: Implications From Molecular Dynamics Simulations of Endothelial Glycocalyx. AB - It is widely accepted that salt intake reduction and regular exercise is a healthy lifestyle, which can prevent cardiovascular diseases (CVD). Meanwhile, there is evidence that the endothelial glycocalyx layer (EGL) is related to CVD. However, how such a healthy lifestyle helps to prevent CVD via the function of the EGL has not been scientifically established. In this research, a series of large-scale molecular dynamics simulations have been conducted to study ion transport inside the EGL under varying flow velocities. Results show that a fast blood flow velocity favors the Na+ transport out of the EGL, which can explain the increase in the thickness of an exclusion layer between red blood cells and the EGL under fast blood flow situations, as witnessed in some previous experiments. Based on findings from this fundamental research, a theory is proposed, which can answer the open-ended question "Why do we need to reduce salt intake and exercise regularly". The findings may also have implications for other therapies to combat cardiovascular diseases. PMID- 30519196 TI - Brain Networks Reorganization During Maturation and Healthy Aging-Emphases for Resilience. AB - Maturation and aging are important life periods that are linked to drastic brain reorganization processes which are essential for mental health. However, the development of generalized theories for delimiting physiological and pathological brain remodeling through life periods linked to healthy states and resilience on one side or mental dysfunction on the other remains a challenge. Furthermore, important processes of preservation and compensation of brain function occur continuously in the cerebral brain networks and drive physiological responses to life events. Here, we review research on brain reorganization processes across the lifespan, demonstrating brain circuits remodeling at the structural and functional level that support mental health and are parallelized by physiological trajectories during maturation and healthy aging. We show evidence that aberrations leading to mental disorders result from the specific alterations of cerebral networks and their pathological dynamics leading to distinct excitability patterns. We discuss how these series of large-scale responses of brain circuits can be viewed as protective or malfunctioning mechanisms for the maintenance of mental health and resilience. PMID- 30519197 TI - A Review of Risk Factors for Methamphetamine-Related Psychiatric Symptoms. AB - The illegal use of methamphetamine (MA) is a growing public health concern globally and results in a series of negative effects. The prominent detrimental effect of MA use is MA-related psychiatric symptoms (MAP) and is observed at a much higher incidence compared to the general population. MAP often includes multiple dimensions of cognitive impairment and induces adverse consequences such as, violence and suicide. However, the assessment methods for MAP are not standardized. Hence, it is necessary to investigate factors that affect the progression of psychiatric symptoms in individuals who use MA. A review of published studies was performed by searching the following databases: PubMed, EMBASE, and PsycINFO from inception to 31 May, 2018. The search strategy included methamphetamine, dependence, psychiatric symptoms, and risk factor terms. We reviewed the different features of MAP and the various types of assessment instruments and summarized MAP risk factors from MA use-related factors, socio demographic characteristics, life events, and genetic factors. We found that MAP was consistently and causally associated with MA use, particularly as it relates to the frequency and amount of MA use. Other MAP-related risk factors like life events and genetics were relatively inconsistent in their association with MAP. Hence, causal and longitudinal studies that focus on multilateral comparisons are required. This review provides high quality evidence for MAP risk factors and would be helpful for developing early prevention and treatment strategies for MAP. PMID- 30519199 TI - Testing Claims of Crime-Related Amnesia. AB - Many violent offenders report amnesia for their crime. Although this type of memory loss is possible, there are reasons to assume that many claims of crime related amnesia are feigned. This article describes ways to evaluate the genuineness of crime-related amnesia. A recent case is described in which several of these strategies yielded evidence for feigned crime-related amnesia. PMID- 30519198 TI - Posttraumatic Stress Disorder Symptom Network Analysis in U.S. Military Veterans: Examining the Impact of Combat Exposure. AB - Recent work inspired by graph theory has begun to conceptualize mental disorders as networks of interacting symptoms. Posttraumatic stress disorder (PTSD) symptom networks have been investigated in clinical samples meeting full diagnostic criteria, including military veterans, natural disaster survivors, civilian survivors of war, and child sexual abuse survivors. Despite reliable associations across reported networks, more work is needed to compare central symptoms across trauma types. Additionally, individuals without a diagnosis who still experience symptoms, also referred to as subthreshold cases, have not been explored with network analysis in veterans. A sample of 1,050 Iraq/Afghanistan-era U.S. military veterans (851 males, mean age = 36.3, SD = 9.53) meeting current full criteria PTSD (n = 912) and subthreshold PTSD (n = 138) were assessed with the Structured Clinical Interview for DSM-IV Disorders (SCID). Combat Exposure Scale (CES) scores were used to group the sample meeting full-criteria into high (n = 639) and low (n = 273) combat exposure subgroups. Networks were estimated using regularized partial correlation models in the R-package qgraph, and robustness tests were performed with bootnet. Frequently co-occurring symptom pairs (strong network connections) emerged between two avoidance symptoms, hypervigilance and startle response, loss of interest and detachment, as well as, detachment and restricted affect. These associations replicate findings reported across PTSD trauma types. A symptom network analysis of PTSD in a veteran population found significantly greater overall connectivity in the full-criteria PTSD group as compared to the subthreshold PTSD group. Additionally, novel findings indicate that the association between intrusive thoughts and irritability is a feature of the symptom network of veterans with high levels of combat exposure. Mean node predictability is high for PTSD symptom networks, averaging 51.5% shared variance. With the tools described here and by others, researchers can help refine diagnostic criteria for PTSD, develop more accurate measures for assessing PTSD, and eventually inform therapies that target symptoms with strong network connections to interrupt interconnected symptom complexes and promote functional recovery. PMID- 30519200 TI - The How and Why of Consciousness? PMID- 30519201 TI - Exploring the Validity of the Perceived Restorativeness Soundscape Scale: A Psycholinguistic Approach. AB - Soundscapes affect people's health and well-being and contribute to the perception of environments as restorative. This paper continues the validation process of a previously developed Perceived Restorativeness Soundscape Scale (PRSS). The study takes a novel methodological approach to explore the PRSS face and construct validity by examining the qualitative reasons for participants' numerical responses to the PRSS items. The structure and framing of items are first examined, to produce 44 items which are assessed on a seven-point Likert agreement scale, followed by a free format justification. Ten English speaking participants completed the PRSS interpretation questionnaire in two cafes in Montreal, Canada. Interpretation of participant free format responses led to six themes, which related to either the individual (personal attributes, personal outcomes), the environment (physical environment attributes, soundscape design) or an interaction of the two (behavior setting, normality, and typicality). The themes are discussed in relation to each Attention Restoration Theory (ART) component, namely Fascination, Being-Away, Compatibility, and Extent. The paper concludes by discussing the face and construct validity of the PRSS, as well as the wider methodological and theoretical implications for soundscape and attention restoration research, including the terminology importance in items measuring ART components and the value of all four components in assessing perceived restorativeness. PMID- 30519202 TI - Personal Branding: Interdisciplinary Systematic Review and Research Agenda. AB - Personal branding has become an important concept in management literature in recent years. Yet, with more than 100 scholarly papers published on the concept to date, it has developed into a fragmented area of research with a diversity of definitions and conceptual boundaries. This paper posits that this heterogeneity of extant research impedes theoretical and empirical advancement. To strengthen the foundation for future work, we review the extant literature and offer an integrative model of personal branding. Through our systematic literature review we identify the key attributes of the construct, establish its clarity by comparing it with similar concepts in its nomological network, and suggest the definitions of personal branding and personal brand based on the reviewed literature. Further, we propose a theoretical model of personal branding summarizing the findings from the reviewed papers. The proposed model outlines the trends conducive to personal branding, as well as its drivers, processes, and outcomes. Finally, we discuss ethical implications of personal branding for both scholarly work and practice. In conclusion, we outline a further research agenda for studying personal branding as a critical career and organizational behavior activity in contemporary working environment. PMID- 30519203 TI - A Cross-Lagged Study of Developmental Trajectories of Video Game Engagement, Addiction, and Mental Health. AB - Objectives: Video game addiction has been associated with an array of mental health variables. There is a paucity of longitudinal studies investigating such associations, and studies differentiating addicted gaming from problem and engaged (i.e., frequent but non-problem) gaming. The current explorative study investigate the natural course of gaming behavior in three sub-studies. The aim of study 1 was to investigate antecedents and consequences of video game addiction measured as a unidimensional construct (pathological gaming). Aim of study 2 was to investigate the same associations in terms of typologies of gamers ("engaged," "problem," "addicted"). Furthermore, study 3 aimed to investigate the estimated stability and transitions occurring between the aforementioned typologies, and a non-pathological gaming group. Methods: A nationally representative sample of 3,000 adolescents aged 17.5 years was drawn from the population registry of Norway in 2012 and invited to participate in annual surveys spanning 3 years (NT1 = 2,059, NT2 = 1,334, NT3 = 1,277). The respondents completed measures of video game addiction, depression, anxiety, loneliness, aggression, and alcohol use disorder. Statistical analysis comprised cross-lagged path modeling, Satorra-Bentler chi square test (study 1), regression analyses (study 2), hidden Markov model of transition probabilities (study 3). Results: Findings in study 1 showed that depression and loneliness were reciprocally associated with pathological gaming. Physical aggression was identified as an antecedent, and anxiety was a consequence of pathological gaming. Investigation of the three typologies of gamers (study 2) identified loneliness and physical aggression as antecedents, and depression as a consequence of all typologies. Depression was found to be an antecedent of problem and engaged gamers. Loneliness was found as a consequence of problem gamers, and anxiety was a consequence of addicted gamers. High alcohol consumption was found antecedent to addicted gamers, and low alcohol consumption was found antecedent to problem gamers. The estimated stability of video game addiction was 35%. Conclusion: A reciprocal relationship between pathological gaming and measures of mental health problems seems to exist. The stability of video game addiction indicates a condition that for a substantial number of people does not resolve spontaneously over the course of 2 years. PMID- 30519204 TI - Cortisol Impacted on Explicit Learning Encoding, but Not on Storage and Retrieval, and Was Not Associated With Sleep Patterns-Results From the Trier Social Stress Test for Children (TSST-C) Among 9-Years Old Children. AB - Background: Learning is the relatively permanent change of behavior as a result of experience and tightly related to memory and cognition. Learning is particularly important for children. Further, restoring sleep is associated both with improved learning performance and lower cortisol levels as a proxy of the so called hypothalamus-pituitary-adrenocortical axis activity (HPA-AA). With the present study, we investigated, if and to what extent explicit learning performance was associated with cortisol levels at baseline and under challenge conditions and with objective sleep dimensions among 9-years old children. Methods: A total of 39 children (mean age = 9.5 years; 39% females) took part in the study. Verbal and figural working and long-term memory were tested before and after the Trier Social Stress Test for Children (TSST-C). Further, children underwent sleep-EEG assessment, and cortisol awakening response (CAR) was assessed. Results: Higher cortisol levels were associated with lower explicit learning encoding (verbal, but not figural learning). Higher verbal and figural working and long-term memory performance predicted lower cortisol secretion under the TSST-C, along with higher verbal and figural working and long-term memory performance after the TSST-C. Cognitive test performances were not mediated by cortisol secretion under the TSST-C. Cognitive performance, cortisol secretion under challenge (TSST-C) and basal conditions (morning) and sleep patterns were unrelated. Conclusions: The pattern of results suggests that among a sample of 9 years old children cortisol secretion and stages of memory processes (encoding, storage, retrieval) are associated in a complex and bi-directional way. Further, it appears that cognitive-emotional processes underlying cognitive performance and its evaluation might impact on subsequent cortisol secretion as a proxy of neuroendocrinological response to cognitive-emotional processes. Last, cognitive performance and cortisol secretion under challenge conditions were not related to objective sleep patterns and baseline cortisol secretion. PMID- 30519205 TI - What Are the Stages of the Creative Process? What Visual Art Students Are Saying. AB - Within the literature on creativity in the arts, some authors have focused on the description of the artistic process (Patrick, 1937; Getzels and Csikszentmihalyi, 1976; Mace and Ward, 2002; Yokochi and Okada, 2005) whereas others have focused on the creative process (Wallas, 1926; Osborn, 1953/1963; Runco and Dow, 1999; Howard et al., 2008). These two types of processes may be, however, somewhat distinct from each other because the creative process is not always dedicated to artistic creation, and productive work in the arts may not always involve creativity, in terms of specifically original thinking. Our goal is to identify the specific nature of the artistic creative process, to determine what are the basic stages of this kind of process. This description can then be integrated in a Creative process Report Diary (CRD; Botella et al., 2017) which allows self observations in situ when participants are creating. PMID- 30519206 TI - Are Proselfs More Deceptive and Hypocritical? Social Image Concerns in Appearing Fair. AB - Deception varies across individuals and social contexts. The present research explored how individual difference measured by social value orientations, and situations, affect deception in moral hypocrisy. In two experiments, participants made allocations between themselves and recipients with an opportunity to deceive recipients where recipients cannot reject their allocations. Experiment 1 demonstrated that proselfs were more deceptive and hypocritical than prosocials by lying to be apparently fair, especially when deception was unrevealed. Experiment 2 showed that proselfs were more concerned about social image in deception in moral hypocrisy than prosocials were. They decreased apparent fairness when deception was revealed and evaluated by a third-party reviewer and increased it when deception was evaluated but unrevealed. These results show that prosocials and proselfs differed in pursuing deception and moral hypocrisy social goals and provide implications for decreasing deception and moral hypocrisy. PMID- 30519207 TI - Weight Bias Internalization Among Adolescents Seeking Weight Loss: Implications for Eating Behaviors and Parental Communication. AB - Background: Emerging evidence has demonstrated a high prevalence of weight bias internalization (WBI) among adults, as well as consistent links between internalization and adverse psychological and physical health. However, research examining WBI in youth and its impact on their health is scarce, especially among youth seeking weight loss treatment who may be particularly vulnerable to weight stigma from peers and parents. To address this research gap, the present study assessed WBI in a weight loss treatment-seeking sample of adolescents, examining associations between internalization and adolescents' eating behaviors and parental weight-related communication. Methods: Adolescents (N = 148, M age = 15.97 years), completed online self-report measures to assess WBI (using the modified version of the WBI Scale), body weight, binge eating, eating as a coping strategy, and weight teasing from peers and family members. Adolescents also reported on the frequency of parental comments about body weight, parental dieting, and parental encouragement of adolescent dieting. Results: Adolescents expressed a high mean level of internalized weight bias (M = 5.45, SD = 0.88). Higher levels of internalization were observed across increasing body weight categories; no differences were observed for gender or history of weight teasing. WBI was significantly higher among adolescents who reported binge eating and eating to cope with distress. Regression analyses showed that weight-related comments from mothers (but not fathers) significantly predicted adolescents' WBI (including frequency of mothers' comments about adolescents' body weight, comments about their own body weight, and encouragement of their adolescent to diet), as did increased dieting frequency among mothers. Conclusion: The present study provides novel insights to the scant literature on WBI in youth. Findings indicate that WBI is high in both girls and boys engaged in weight loss, and is associated with maladaptive eating behaviors, higher frequency of maternal dieting, and mothers' comments about body weight. These findings have important clinical implications for youth and families engaged in weight loss treatment, and underscore the need for research to clarify adverse effects of internalization on weight-related health in youth and to better understand the role that parental weight communication may have on adolescents' internalization. PMID- 30519208 TI - Isolating the Effects of Word's Emotional Valence on Subsequent Morphosyntactic Processing: An Event-Related Brain Potentials Study. AB - Emotional information significantly affects cognitive processes, as proved by research in the past decades. Recently, emotional effects on language comprehension and, particularly, syntactic processing, have been reported. However, more research is needed, as this is yet very scarce. The present paper focuses on the effects of emotion-laden linguistic material (words) on subsequent morphosyntactic processing, by using Event-Related brain Potentials (ERP). The main aim of this paper is to clarify whether the effects previously reported remain when positive, negative and neutral stimuli are equated in arousal levels and whether they remain long-lasting. In addition, we aimed at testing whether these effects vary as a function of the task performed with the emotion-laden words, to assess their robustness across variations in attention and cognitive load during the processing of the emotional words. In this regard, two different tasks were performed: a reading aloud (RA) task, where participants simply read aloud the words, written in black on white background, and an Emotional Stroop (ES) task, where participants named the colors in which the emotional words were shown. After these words, neutral sentences followed, that had to be evaluated for grammaticality while recording ERPs (50% containing a morphosyntactic anomaly). ERP analyses showed main effects of valence across tasks on the two components reflecting morphosyntactic processing: The Left Anterior Negativity (LAN) is increased by previous emotional words (more by negative than positive) relative to neutral ones, while the P600 is similarly decreased. No interactions between task and valence were found. As a result, an emotion-laden word preceding a sentence can modulate the syntactic processing of the latter, independently of the arousal and processing conditions of the emotional word. PMID- 30519209 TI - Can We Infer Inter-Individual Differences in Risk-Taking From Behavioral Tasks? AB - Investigating the bases of inter-individual differences in risk-taking is necessary to refine our cognitive and neural models of decision-making and to ultimately counter risky behaviors in real-life policy settings. However, recent evidence suggests that behavioral tasks fare poorly compared to standard questionnaires to measure individual differences in risk-taking. Crucially, using model-based measures of risk taking does not seem to improve reliability. Here, we put forward two possible - not mutually exclusive - explanations for these results and suggest future avenues of research to improve the assessment of inter individual differences in risk-taking by combining repeated online testing and mechanistic computational models. PMID- 30519210 TI - Association of Stress and Musculoskeletal Pain With Poor Sleep: Cross-Sectional Study Among 3,600 Hospital Workers. AB - Background: While acute stress and pain are part of our inherent survival mechanisms, persistent stress and pain can negatively impact health and well being. This may also lead to poor sleep and thus a lack of recovery. This study investigated the influence of stress and musculoskeletal pain on sleep quality. Methods: A total of 3,593 Danish hospital workers replied to a questionnaire about work and health. Pain intensity was evaluated using subjective values as an average of 9 body parts. Stress was assessed using the full version of Cohen's Perceived Stress scale. Sleep quality was rated using 3 questions on sleep characteristics. Associations between stress and pain (mutually adjusted predictors) and sleep (outcome) were modeled using binary logistic regression controlling for gender, age, education, BMI and smoking. Results: The risk ratio of moderate stress (compared to no/low stress) on poor sleep was 1.27 (CI 1.26 1.29), whereas the risk ratio of high stress on poor sleep was 1.87 (CI 1.83 1.91). Similarly, for pain, the risk ratio of moderate pain (compared to no/low pain) on poor sleep was 1.18 (95% CI 1.16-1.19), whereas the risk ratio of a high pain score on poor sleep was 1.48 (95% CI 1.44-1.52). Conclusion: This study demonstrates that both stress and musculoskeletal pain are associated with poor sleep among hospital workers. Hospital management should consider implementing strategies for preventing stress and musculoskeletal pain to improve the overall health and workability among hospital workers. PMID- 30519211 TI - Behavioral and Resting State Functional Connectivity Effects of High Frequency rTMS on Disorders of Consciousness: A Sham-Controlled Study. AB - Objectives: A combined approach of behavioral characteristics and network properties was applied to explore the effect of repetitive transcranial magnetic stimulation (rTMS) on disorders of consciousness (DOC) and to observe changes in brain network connections before and after the stimulation. Methods: A total of 7 DOC patients and 11 healthy controls were enrolled. The study was designed as a randomized, sham-controlled study. All DOC patients were given 20 Hz rTMS real and sham stimuli to the left M1 region, with each stimulus lasting for 5 consecutive working days and the interval between two stimuli being 1 week. Coma Recovery Scale-Revised (CRS-R) and resting state functional MRI data before and after stimuli were collected. The functional connection (FC) of the default mode network and the frontoparietal network were chosen as the central target to compare differences in network connections between the DOC group and the normal control group. For DOC patients, changes in behavior and brain function before and after real and sham stimuli were also assessed as a group and individually. Results: (1). The overall analyses showed no significant changes of CRS-R scores or brain FC following real or sham rTMS stimuli in the DOC patients. However, real rTMS stimuli tended to enhance the FC of nodes in left lateral parietal cortex (LPC), left inferior temporal cortex (ITC) and right dorsolateral prefrontal cortex (DLPFC). (2). The individual analyses showed one minimally conscious state (MCS) patient presented with a obviously increased CRS-R score following real rTMS stimuli, and a visibly enhanced connectivity was observed in the nodes of left LPC, left ITC and right DLPFC of this patient. Conclusion: Our findings did not provide sufficient evidence of therapeutic effect of 20 Hz rTMS over the left M1 in DOC. However, MCS patients shortly after brain injury may possibly benefit from rTMS. Reconstruction of the left LPC, the left ITC and the right DLPFC may be the brain networking foundation of improvements in consciousness from rTMS. PMID- 30519212 TI - White Matter Changes Along the Electrode Lead in Patients Treated With Deep Brain Stimulation. AB - Introduction: Deep brain stimulation (DBS) is an established treatment for various movement disorders. There is little data available about the potential damage to brain parenchyma through DBS treatment. The objective of this study was to investigate the occurrence of signal changes on magnetic resonance imaging (MRI) in patients treated with DBS. Methods: We retrospectively analyzed MRI scans of 30 DBS patients (21 patients with Parkinson's disease, 3 patients with dystonia and 6 patients with tremor) that had undergone additional MRI scans after DBS surgery (ranging from 2 months to 8 years). Axial T2 sequences were analyzed by two raters using a standardized lesion mapping procedure. Results: 26 out of 30 analyzed patients showed hyperintense white matter changes surrounding the DBS lead (mean volume = 2.43 ml). Lesions were prominent along the upper half of the electrode lead within the subcortical white matter, with no abnormalities along the lower lead. Their volume was significantly correlated to the time from surgery to MRI and to the number of microelectrodes used in surgery, but was independent from underlying disease (Parkinson's disease, dystonia, tremor), target structure (STN, GPi, VIM), demographical data, or cardiovascular risk factors. Discussion: White matter changes along the electrode leads in DBS patients are a frequent finding. These changes seem to evolve with certain latency after surgery and might be radiologically classified as a gliosis. Our findings identify the number of intraoperatively used microelectrodes as a risk factor in the formation of gliosis. Therefore, mechanical damage at the time of surgery and an individual tissue response might contribute to their evolution. Further studies are needed to define the exact mechanisms and their clinical impact. PMID- 30519213 TI - Cerebral Microbleeds in the Patients With Acute Stroke Symptoms. AB - Background: Some patients with acute stroke symptoms do not show hyperintensities on diffusion-weighted image (DWI). A few case reports have indicated that acutely developed cerebral microbleeds (CMBs) might cause focal symptoms. This study sought to investigate the incidence and characteristics of symptomatic CMBs in the patients with acute stroke symptoms but without DWI ischemic lesions. Methods: We enrolled the patients with acute stroke symptoms who underwent magnetic resonance imaging including DWI and gradient echo (GRE) sequences within 7 days after symptom onset, at our prospective stroke registry. We then identified patients without DWI-positive ischemic lesions but with CMBs in the relevant brain regions. Results: Between January 2005 and February 2012, we identified 235 DWI-negative transient ischemic attack (n = 221) and stroke (n = 14) patients from 2129 consecutive patients at our registry. In total, 16 patients had CMBs corresponding to the focal symptoms. Among these 16 patients, 12 patients showed a hyperintense rim on DWI around a microbleed suspected to be related to focal symptoms; of the 12 patients, 7 experienced stroke symptoms for more than 24 h. However, the symptoms in the remaining patients (5 patients with the hyperintense rim and 4 patients without the hyperintense rim) improved within 24 h. Conclusion: Symptomatic microbleeds are infrequent but not rare in the patients with acute stroke symptoms. Perihematomal edema around an acute CMB can cause a hyperintense rim on DWI. Our results suggest that a combination of DWI and GRE imaging can help diagnose acute symptomatic CMBs. PMID- 30519214 TI - Corrigendum: Validation of a Questionnaire for Distinguishing X-Linked Dystonia Parkinsonism From Its Mimics. AB - [This corrects the article DOI: 10.3389/fneur.2018.00830.]. PMID- 30519215 TI - An Optimized Approach to Perform Bone Histomorphometry. AB - Bone histomorphometry allows quantitative evaluation of bone micro-architecture, bone formation, and bone remodeling by providing an insight to cellular changes. Histomorphometry plays an important role in monitoring changes in bone properties because of systemic skeletal diseases like osteoporosis and osteomalacia. Besides, quantitative evaluation plays an important role in fracture healing studies to explore the effect of biomaterial or drug treatment. However, until today, to our knowledge, bone histomorphometry remain time-consuming and expensive. This incited us to set up an open-source freely available semi automated solution to measure parameters like trabecular area, osteoid area, trabecular thickness, and osteoclast activity. Here in this study, the authors present the adaptation of Trainable Weka Segmentation plugin of ImageJ to allow fast evaluation of bone parameters (trabecular area, osteoid area) to diagnose bone related diseases. Also, ImageJ toolbox and plugins (BoneJ) were adapted to measure osteoclast activity, trabecular thickness, and trabecular separation. The optimized two different scripts are based on ImageJ, by providing simple user interface and easy accessibility for biologists and clinicians. The scripts developed for bone histomorphometry can be optimized globally for other histological samples. The showed scripts will benefit the scientific community in histological evaluation. PMID- 30519217 TI - Editorial: Habitability Beyond Earth. PMID- 30519216 TI - Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate. AB - Background: Developmental exposure to di (2-ethylhexyl) phthalate (DEHP) has been implicated in the onset of metabolic syndrome later in life. Alterations in neurobehavior and immune functions are also affected by phthalate exposure and may be linked to the metabolic changes caused by developmental exposure to DEHP. Objectives: Our goal was to study the effects of developmental exposure to DEHP in the context of metabolic syndrome by integrating different parameters to assess metabolic, neurobehavioral, and immune functions in one model. Methods: Female C57BL/6J mice were exposed to DEHP through the diet during gestation and lactation at doses ranging from 3.3 to 100,000 MUg/kg body weight/day (MUkd). During a 1-year follow-up period, a wide set of metabolic parameters was assessed in the F1 offspring, including weekly body weight measurements, food consumption, physical activity, glucose homeostasis, serum lipids, and endocrine profile. In addition, neurobehavioral and immune functions were assessed by sweet preference test, object recognition test, acute phase protein, and cytokines production. Animals were challenged with a high fat diet (HFD) in the last 9 weeks of the study. Results: Increased free fatty acids (FFA) and, high density lipoprotein (HDL-C) were observed in serum, together with a decrease in glycated hemoglobin levels in blood of 1-year old male DEHP-exposed offspring after HFD challenge. For the most sensitive endpoint measured (FFA), a lower bound of the 90% confidence interval for benchmark dose (BMD) at a critical effect size of 5% (BMDL) of 2,160 MUkd was calculated. No persistent changes in body weight or fat mass were observed. At 33,000 MUkd altered performance was found in the object recognition test in males and changes in interferon (IFN)gamma production were observed in females. Conclusions: Developmental exposure to DEHP combined with HFD in adulthood led to changes in lipid metabolism and neurobehavior in male offspring and cytokine production in female offspring. Our findings contribute to the evidence that DEHP is a developmental dyslipidemic chemical, however, more research is needed to further characterize adverse health outcomes and the mechanisms of action associated with the observed sex-specific effects. PMID- 30519218 TI - The Outer Membrane Vesicles of Aeromonas hydrophila ATCC(r) 7966TM: A Proteomic Analysis and Effect on Host Cells. AB - Gram-negative bacteria release outer membrane vesicles (OMVs) into the extracellular environment. OMVs have been studied extensively in bacterial pathogens, however, information related with the composition of Aeromonas hydrophila OMVs is missing. In this study we analyzed the composition of purified OMVs from A. hydrophila ATCC(r) 7966TM by proteomics. Also we studied the effect of OMVs on human peripheral blood mononuclear cells (PBMCs). Vesicles were grown in agar plates and then purified through ultracentrifugation steps. Purified vesicles showed an average diameter of 90-170 nm. Moreover, 211 unique proteins were found in OMVs from A. hydrophila; some of them are well-known as virulence factors such as: haemolysin Ahh1, RtxA toxin, extracellular lipase, HcpA protein, among others. OMVs from A. hydrophila ATCC(r) 7966TM induced lymphocyte activation and apoptosis in monocytes, as well as over-expression of pro inflammatory cytokines. This work contributed to the knowledge of the composition of the vesicles of A. hydrophila ATCC(r) 7966TM and their interaction with the host cell. PMID- 30519219 TI - Inhibition or Stimulation of Ochratoxin A Synthesis on Inoculated Barley Triggered by Diffuse Coplanar Surface Barrier Discharge Plasma. AB - Ochratoxin A (OTA) is one of the most abundant food-contaminating mycotoxins. Besides their high toxicity, mycotoxins are highly stable to physical, chemical or biological detoxification. Therefore, the treatment with cold atmospheric plasma could be one approach to reduce the amount of mycotoxins in different products. The aim of this study was to determine the influence of cold atmospheric plasma on the inactivation of Aspergillus niger and Penicillium verrucosum inoculated on barley and their production of OTA. Inoculated barley was treated with plasma generated by dry air, CO2 or CO2 + O2 for 1 or 3 min and stored for up to two weeks at 9, 25, or 37 degrees C. Three minutes of air plasma treatment effectively significantly reduced the total mold count of both microorganisms by 2.5-3 log cycles. The production of OTA from A. niger was only low, therefore the treatment effect was indistinguishable. The treatment of P. verrucosum on barley after an incubation of five days using a CO2 + O2 plasma resulted in a reduction of the OTA content from 49.0 (untreated) to 27.5 (1 min) and 23.8 ng/g (3 min), respectively. In contrast, CO2 plasma caused an increase of the OTA amount from 49.0 (untreated) to 55.8 (1 min) and 72.9 ng/g (3 min). Finally, the use of air plasma resulted likewise in a decrease of the OTA concentration from 56.9 (untreated) to 25.7 (1 min) and 20.2 ng/g (3 min), respectively. Reducing the incubation time before the treatment to 24 h caused in contrast an increase of the OTA content from 3.1 (untreated) to 29.1 (1 min) and 20.7 ng/g (3 min). Due to the high standard deviation, these changes were not significant, but the tendencies were clearly visible, showing the strong impact of the plasma gas on the OTA production. The results show, that even if the total mold count was reduced, under certain conditions the OTA amount was yet enhanced, probably due to a stress reaction of the mold. Concluding, the plasma gas and incubation conditions have to be considered to allow a successful inactivation of molds and in particular their toxic metabolites. PMID- 30519220 TI - Enhancement of Pneumocandin B0 Production in Glarea lozoyensis by Low-Temperature Adaptive Laboratory Evolution. AB - The production of pneumocandin B0 is limited by feedback inhibition. Here, low temperature adaptive laboratory evolution (ALE) was used to improve the production capacity of Glarea lozoyensis by enhancing its membrane permeability. After 50 cycles of ALE, the pneumocandin B0 production of the endpoint strain (ALE50) reached 2131 g/L, which was 32% higher than the starting strain (ALE0). ALE50 showed a changed fatty acid composition of the cell membrane, which-+h increased its permeability by 14%, which in turn increased the secretion ratio threefold. Furthermore, ALE50 showed increased intracellular proline and acetyl CoA concentrations, superoxide dismutase (SOD), and catalase (CAT) activity, as well as total antioxidant capacity. The slight biomass decrease in ALE50 was accompanied by decreased isocitrate dehydrogenase (ICDH) and glucose-6-phosphate dehydrogenase (G6PDH) activity. Finally, a putative model of the accumulation and secretion of pneumocandin B0 in ALE50 was established. ALE is a promising method to release intracellular feedback inhibition. PMID- 30519221 TI - Drying and Rainfall Shape the Structure and Functioning of Nitrifying Microbial Communities in Riverbed Sediments. AB - Non-flow periods in fluvial ecosystems are a global phenomenon. Streambed drying and rewetting by sporadic rainfalls could drive considerable changes in the microbial communities that govern stream nitrogen (N) availability at different temporal and spatial scales. We performed a microcosm-based experiment to investigate how dry period duration (DPD) (0, 3, 6, and 9 weeks) and magnitude of sporadic rewetting by rainfall (0, 4, and 21 mm applied at end of dry period) affected stocks of N in riverbed sediments, ammonia-oxidizing bacteria (AOB) and archaea (AOA) and rates of ammonia oxidation (AO), and emissions of nitrous oxide (N2O) to the atmosphere. While ammonium (NH4 +) pool size decreased, nitrate (NO3 -) pool size increased in sediments with progressive drying. Concomitantly, the relative and absolute abundance of AOB and, especially, AOA (assessed by 16S rRNA gene sequencing and quantitative PCR of ammonia monooxygenase genes) increased, despite an apparent decrease of AO rates with drying. An increase of N2O emissions occurred at early drying before substantially dropping until the end of the experiment. Strong rainfall of 21 mm increased AO rates and NH4 + in sediments, whereas modest rainfall of 4 mm triggered a notable increase of N2O fluxes. Interestingly, such responses were detected only after 6 and 9 weeks of drying. Our results demonstrate that progressive drying drives considerable changes in in-stream N cycling and the associated nitrifying microbial communities, and that sporadic rainfall can modulate these effects. Our findings are particularly relevant for N processing and transport in rivers with alternating dry and wet phases - a hydrological scenario expected to become more important in the future. PMID- 30519222 TI - Morbidity and Mortality Associated With Respiratory Virus Infections in Allogeneic Hematopoietic Cell Transplant: Too Little Defense or Harmful Immunity? AB - The impact on morbidity and mortality of Community Acquired Respiratory Virus (CARV) infections in patients undergoing Allogeneic Hematopoietic Cell Transplant (HCT) is widely studied. Here we give an overview of the current literature on the incidence and chance of progression to severe disease in this highly immune compromised population. We discuss the issue whether it is predominantly direct viral damage that causes clinical deterioration, or that it is in fact the allogeneic immuneresponse to the virus that is most important. This is an important question as it will guide therapeutic decision making. It asks for further collaborative studies focusing on sensitive surveillance with PCR techniques and relating clinical data with parameters of immune reconstitution. PMID- 30519223 TI - Populations of the Beet Cyst Nematode Heterodera schachtii Exhibit Strong Differences in Their Life-History Traits Across Changing Thermal Conditions. AB - It is widely accepted that climate has an essential influence on the distribution of species and that temperature is the major abiotic factor that affects their life-history traits. Species with very restricted active dispersal abilities and a wide geographical distribution are thus expected to encompass distinct populations adapted to contrasted local conditions. The beet cyst nematode Heterodera schachtii is a good biological model to study temperature adaptation in populations collected from different environments. Here, we tested the effect of temperature on H. schachtii life-history traits using seven field populations from Morocco, Spain, France, Germany, Austria, Poland and Ukraine. We tested hatching and multiplication rates of each population at different temperatures, as well as hatching rates of each population after storage at different temperatures - simulating survival conditions during the inter-cropping period. Results showed a strong temperature effect on the life-history traits explored. Temperature impact on hatching (at different temperatures and after storage at different temperatures) depended on the origin of populations, separating southern from northern ones. Surprisingly, low temperatures influenced hatching less in southern populations. However, for these populations, a storage period at low temperatures strongly reduce subsequent hatching. Conversely, nematode multiplication was not differentially affected by temperatures, as favorable conditions for the host are also favorable for the parasite. Finally, a significant correlation between the genetic diversity and the level of specialization showed that the less diverse populations were more specialized than the more diverse ones. PMID- 30519224 TI - SuperPolymyxinTM Medium for the Screening of Colistin-Resistant Gram-Negative Bacteria in Stool Samples. AB - Colistin is one of the last resort antimicrobials for the treatment of infections caused by multidrug-resistant Gram-negative bacteria. After the emergence of transferable colistin resistance genes (mcr-1-5), a reliable culture-based screening method to detect colonization with colistin-resistant Gram-negative bacteria (CRGN) is needed. The objective of this study was to test the performance of SuperPolymyxinTM medium to screen for CRGN in stool samples and to compare different methods for the confirmation of colistin resistance (e.g., Etest(r), broth microdilution [BMD], and the Rapid PolymyxinTM NP test). Colonization with CRGN was analyzed in a prospective cohort study among travelers. Stool samples (Fecal TranswabTM) taken before, during and after travel were cultured on SuperPolymyxinTM agar. Every phenotypically different colony was subcultured for species identification using MALDI-TOF mass spectrometry. Susceptibility to colistin was tested using Etest(r) and confirmed by BMD and the Rapid PolymyxinTM NP test. In total, 128 participants provided 1,495 stool samples. After culture on SuperPolymyxinTM medium (37 degrees C, 24-48 h), 1,851 phenotypically different colonies were isolated. Isolates belonging to intrinsically colistin-resistant genera (e.g., Morganella, Providencia, Proteus) or Stenotrophomonas maltophilia were excluded from further analysis (n = 421). Among the remaining 1,430 isolates, colistin resistance was confirmed in 279 by Etest(r) (19.5%) and 218 by BMD (15.3%). The Rapid PolymyxinTM NP test was compared with BMD (reference) to detect colistin resistance (specificity: 88.6%, sensitivity 71.1%). SuperPolymyxinTM medium is suitable to screen for fecal colonization with CRGN. The high proportion of colistin-susceptible isolates growing on SuperPolymyxinTM medium caused a high workload. The confirmation of CRGN with the Rapid PolymyxinTM NP Test could be a less labor-intensive alternative to BMD. PMID- 30519225 TI - Corrigendum: A Comparison of Techniques for Collecting Skin Microbiome Samples: Swabbing Versus Tape-Stripping. AB - [This corrects the article DOI: 10.3389/fmicb.2018.02362.]. PMID- 30519226 TI - Opportunistic Bacteria Dominate the Soil Microbiome Response to Phenanthrene in a Microcosm-Based Study. AB - Bioremediation offers a sustainable approach for removal of polycyclic aromatic hydrocarbons (PAHs) from the environment; however, information regarding the microbial communities involved remains limited. In this study, microbial community dynamics and the abundance of the key gene (PAH-RHDalpha) encoding a ring hydroxylating dioxygenase involved in PAH degradation were examined during degradation of phenanthrene in a podzolic soil from the site of a former timber treatment facility. The 10,000-fold greater abundance of this gene associated with Gram-positive bacteria found in phenanthrene-amended soil compared to unamended soil indicated the likely role of Gram-positive bacteria in PAH degradation. In contrast, the abundance of the Gram-negative PAHs-RHDalpha gene was very low throughout the experiment. While phenanthrene induced increases in the abundance of a small number of OTUs from the Actinomycetales and Sphingomonadale, most of the remainder of the community remained stable. A single unclassified OTU from the Micrococcaceae family increased ~20-fold in relative abundance, reaching 32% of the total sequences in amended microcosms on day 7 of the experiment. The relative abundance of this same OTU increased 4.5-fold in unamended soils, and a similar pattern was observed for the second most abundant PAH-responsive OTU, classified into the Sphingomonas genus. Furthermore, the relative abundance of both of these OTUs decreased substantially between days 7 and 17 in the phenanthrene-amended and control microcosms. This suggests that their opportunistic phenotype, in addition to likely PAH-degrading ability, was determinant in the vigorous growth of dominant PAH-responsive OTUs following phenanthrene amendment. This study provides new information on the temporal response of soil microbial communities to the presence and degradation of a significant environmental pollutant, and as such has the potential to inform the design of PAH bioremediation protocols. PMID- 30519227 TI - Antifungal Activity of the Human Uterine Cervical Stem Cells Conditioned Medium (hUCESC-CM) Against Candida albicans and Other Medically Relevant Species of Candida. AB - Background: Candidiasis is a major cause of human morbidity and mortality. Human uterine cervical stem cells conditioned medium (hUCESC-CM) is obtained from stromal stem cells of the cervical transformation zone, which are in permanent contact with a wide array of potential vaginal pathogens. In previous reports we have found that hUCESC-CM has antitumor and antibacterial potential. Since Candida is the most prevalent yeast in the human vagina, it seems plausible that hUCESC-CM might also show activity against it. Methods: In a preliminary step, to evaluate if hUCESC-CM showed any activity at all on Candida growth, in vitro activities of hUCESC-CM against fluconazole-susceptible reference strains of Candida albicans, Candida glabrata, Candida krusei, and Candida parapsilosis were studied with a microdilution method on RPMI 1640, using the BioScreen C microbiological incubator. Each measurement was repeated five times. The same methodology was used subsequently on fluconazole-susceptible and fluconazole resistant Candida isolates from blood and vagina of those species corresponding to the reference strains of Candida against which activity had been detected in the previous study. Moreover, two fluconazole-resistant clinical isolates of Candida auris from blood and urine were also included. Findings: In vitro inhibitory activity of hUCESC-CM ranged from 57.5 to 96.6% growth-reduction against fluconazole-susceptible reference strains of Candida albicans, Candida glabrata, and Candida parapsilosis. hUCESC-CM also reduced the growth of all fluconazole-susceptible tested vaginal isolates by more than 50%. For fluconazole resistant isolates, growth-reduction was higher than 67% for Candida albicans, regardless of its origin (vagina or blood). The isolate of Candida auris from urine with a MIC > 128 MU/ml for fluconazole was also significantly inhibited. However, hUCESC-CM was almost inactive against any of the fluconazole-resistant blood isolates of Candida glabrata, Candida parapsilosis, and Candida auris tested. Interpretation: This is the first report about the growth-inhibiting properties of conditioned medium from human stromal stem cells against different species of Candida. Antifungal activity of stromal stem cells depends on their site of origin, being most effective against Candida species most prevalent at that particular location. If confirmed in further studies, these findings might result in a completely new therapeutic approach against superficial and invasive candidiasis. PMID- 30519228 TI - Particle-Attached and Free-Living Archaeal Communities in the Benthic Boundary Layer of the Mariana Trench. AB - The benthic boundary layer (BBL) is the part of the water column that is situated near to the sediment surface, where active oceanic biogeochemical cycling occurs. Archaea play an important role in mediating this cycling, however, their composition and diversity in the BBL remain largely unknown. We investigated the community composition and abundance of both particle-attached (PA) and free living (FL) archaea in the BBL on the slopes of the Mariana Trench using Illumina sequencing and quantitative PCR (qPCR), at both the DNA and RNA levels. Our results showed that Thaumarchaeota (>90%) and Woesearchaeota (1-10%) dominated in all the BBL samples, and that the former was composed mainly of Marine Group I (MGI). A clear separation of PA and FL samples was observed, and they showed a high level of similarity to the subsurface sediments and the water column, respectively. No significant differences were detected in the archaeal communities located in the southern and northern slopes of the Mariana Trench, or between the levels of DNA and RNA. However, lower RNA/DNA ratios (estimated by qPCR) were found in the PA samples than in the FL samples, indicating higher transcriptional activities in the FL fractions. A distinct archaeal community structure was found in the middle of the trench when compared with samples collected at the same depth at other stations along the trench slopes. This indicates that a dynamic deep current might affect the distribution of organic matter on the slopes. Our study provides direct information regarding the archaeal communities in the BBL of the Mariana Trench. We suggest that this might promote further exploration of the ecological roles and microbial processes of such communities located in deep-sea ecosystems. PMID- 30519229 TI - Risk Assessment of Etanercept in Mice Chronically Infected With Toxoplasma gondii. AB - Toxoplasma gondii (T. gondii) is a zoonotic parasite that severely harms the health of the host. The cysts of T. gondii can reactivate from bradyzoites to tachyzoites, if the individual develops low or defective immunity, causing lethal toxoplasmosis. The host resists T. gondii infection by mediating Th1-type cellular immunity to generate pro-inflammatory cytokines. Tumor necrosis factor (TNF) is an important pro-inflammatory cytokine, which can induce lysosomal fusion of parasitophorous vacuole (PV) to kill parasites. Etanercept is a soluble TNF receptor fusion protein, which is widely used clinically to cure autoimmune diseases. The effects and specific molecular mechanisms of etanercept treatment on patients co-infected with autoimmune diseases and chronic toxoplasmosis are rarely reported. In our study, a mouse model of chronic infection with T. gondii and murine macrophages RAW264.7 cells infected with T. gondii were employed to investigate the impact of etanercept on the status of chronic infection. The cytokines levels and a series of phenotypic experiments in vivo and in vitro were measured. In the present study, the expression levels of TNF, IL-1beta, and IL-6 were decreased and the brain cysts number was increased in mice chronically infected with T. gondii after being treated with etanercept. In vivo experiments confirmed that etanercept caused a decrease in the immune levels of the mice and activated the brain cysts, which would lead to conversion from chronic infection to acute infection, causing severe clinical and pathological symptoms. Murine macrophages RAW264.7 cells were pretreated with etanercept, and then infected with T. gondii. In vitro experiments, the expression levels of cytokines were decreased, indicating that etanercept could also reduce the cells' immunity and promote the transformation of bradyzoites to tachyzoites, but did not affect the intracellular replication of tachyzoites. In summary, etanercept treatment could activate the conversion of bradyzoites to tachyzoites through reducing host immunity in vivo and in vitro. The results obtained from this study suggest that the use of etanercept in patients co-infected with autoimmune diseases and chronic toxoplasmosis may lead to the risk of activation of chronic infection, resulting in severe acute toxoplasmosis. PMID- 30519230 TI - Editorial: The Individual Microbe: Single-Cell Analysis and Agent-Based Modelling. PMID- 30519231 TI - BAC-BROWSER: The Tool for Visualization and Analysis of Prokaryotic Genomes. AB - Prokaryotes are actively studied objects in the scope of genomic regulation. Microbiologists need special tools for complex analysis of data to study and identification of regulatory mechanism in bacteria and archaea. We developed a tool BAC-BROWSER, specifically for visualization and analysis of small prokaryotic genomes. BAC-BROWSER provides tools for different types of analysis to study a wide set of regulatory mechanisms of prokaryotes: -transcriptional regulation by transcription factors (TFs), analysis of TFs, their targets, and binding sites.-other regulatory motifs, promoters, terminators and ribosome binding sites-transcriptional regulation by variation of operon structure, alternative starts or ends of transcription.-non-coding RNAs, antisense RNAs-RNA secondary structure, riboswitches-GC content, GC skew, codon usage BAC-browser incorporated free programs accelerating the verification of obtained results: primer design and oligocalculator, vector visualization, the tool for synthetic gene construction. The program is designed for Windows operating system and freely available for download in http://smdb.rcpcm.org/tools/index.html. PMID- 30519232 TI - Morin Protects Channel Catfish From Aeromonas hydrophila Infection by Blocking Aerolysin Activity. AB - Aeromonas hydrophila (A. hydrophila) is an opportunistic bacterial pathogen widely distributed in the environments, particular aquatic environment. The pathogen can cause a range of infections in both human and animals including fishes. However, the application of antibiotics in treatment of A. hydrophila infections leads to the emergence of resistant strains. Consequently, new approaches need to be developed in fighting this pathogen. Aerolysin, the chief virulence factor produced by pathogenic A. hydrophila strains has been employed as target identifying new drugs. In our present study, we found that morin, a flavonoid without anti-bacterial activity isolated from traditional Chinese medicine, could directly inhibit the hemolytic activity of aerolysin. To determine the binding sites and the action of mechanism of morin against AerA, several assays were performed. Ser36, Pro347, and Arg356 were identified as the main binding sites affecting the conformation of AerA and resulted in block of the heptameric formation. Moreover, morin could protect Vero cells from cell injury mediated by aerolysin. In vivo study showed that morin could provide a protection to channel catfish against A. hydrophila infection. These results demonstrated that morin could be developed as a promising candidate for the treatment of A. hydrophila infections by decreasing the pathogenesis of A. hydrophila. PMID- 30519233 TI - Insights Into the Redox Sensitivity of Chloroflexi Hup-Hydrogenase Derived From Studies in Escherichia coli: Merits and Pitfalls of Heterologous [NiFe] Hydrogenase Synthesis. AB - The highly oxygen-sensitive hydrogen uptake (Hup) hydrogenase from Dehalococcoides mccartyi forms part of a protein-based respiratory chain coupling hydrogen oxidation with organohalide reduction on the outside of the cell. The HupXSL proteins were previously shown to be synthesized and enzymatically active in Escherichia coli. Here we examined the growth conditions that deliver active Hup enzyme that couples H2 oxidation to benzyl viologen (BV) reduction, and identified host factors important for this process. In a genetic background lacking the three main hydrogenases of E. coli we could show that additional deletion of genes necessary for selenocysteine biosynthesis resulted in inactive Hup enzyme, suggesting requirement of a formate dehydrogenase for Hup activity. Hup activity proved to be dependent on the presence of formate dehydrogenase (Fdh H), which is typically associated with the H2-evolving formate hydrogenlyase (FHL) complex in the cytoplasm. Further analyses revealed that heterologous Hup activity could be recovered if the genes encoding the ferredoxin-like electron transfer protein HupX, as well as the related HycB small subunit of Fdh-H were also deleted. These findings indicated that the catalytic HupL and electron transferring HupS subunits were sufficient for enzyme activity with BV. The presence of the HupX or HycB proteins in the absence of Fdh-H therefore appears to cause inactivation of the HupSL enzyme. This is possibly because HupX or HycB aided transfer of electrons to the quinone pool or other oxidoreductase complexes, thus maintaining the HupSL heterodimer in a continuously oxidized state causing its inactivation. This proposal was supported by the observation that growth under either aerobic or anaerobic respiratory conditions did not yield an active HupSL. These studies thus provide a system to understand the redox sensitivity of this heterologously synthesized hydrogenase. PMID- 30519234 TI - Sinorhizobium fredii Strains HH103 and NGR234 Form Nitrogen Fixing Nodules With Diverse Wild Soybeans (Glycine soja) From Central China but Are Ineffective on Northern China Accessions. AB - Sinorhizobium fredii indigenous populations are prevalent in provinces of Central China whereas Bradyrhizobium species (Bradyrhizobium japonicum, B. diazoefficiens, B. elkanii, and others) are more abundant in northern and southern provinces. The symbiotic properties of different soybean rhizobia have been investigated with 40 different wild soybean (Glycine soja) accessions from China, Japan, Russia, and South Korea. Bradyrhizobial strains nodulated all the wild soybeans tested, albeit efficiency of nitrogen fixation varied considerably among accessions. The symbiotic capacity of S. fredii HH103 with wild soybeans from Central China was clearly better than with the accessions found elsewhere. S. fredii NGR234, the rhizobial strain showing the broadest host range ever described, also formed nitrogen-fixing nodules with different G. soja accessions from Central China. To our knowledge, this is the first report describing an effective symbiosis between S. fredii NGR234 and G. soja. Mobilization of the S. fredii HH103 symbiotic plasmid to a NGR234 pSym-cured derivative (strain NGR234C) yielded transconjugants that formed ineffective nodules with G. max cv. Williams 82 and G. soja accession CH4. By contrast, transfer of the symbiotic plasmid pNGR234a to a pSym-cured derivative of S. fredii USDA193 generated transconjugants that effectively nodulated G. soja accession CH4 but failed to nodulate with G. max cv. Williams 82. These results indicate that intra-specific transference of the S. fredii symbiotic plasmids generates new strains with unpredictable symbiotic properties, probably due to the occurrence of new combinations of symbiotic signals. PMID- 30519235 TI - Immunization of Experimental Dogs With Salivary Proteins From Lutzomyia longipalpis, Using DNA and Recombinant Canarypox Virus Induces Immune Responses Consistent With Protection Against Leishmania infantum. AB - Metacyclic Leishmania promastigotes are transmitted by sand flies that inject parasites and saliva into the host's skin. Previous studies have demonstrated that DNA plasmids encoding Lutzomyia longipalpis salivary proteins LJM17 and LJL143, when used to immunize dogs, resulted in a systemic and local Th1 cell mediated immunity that interfered in parasite survival in vitro. Here we evaluated the ability of these same salivary antigens to induce anti-Leishmania immunity and to confer protection by immunizing dogs using a novel vaccination strategy more suitable for use in the field. The strategy consisted of a single dose of plasmid followed by two doses of recombinant Canarypoxvirus (rCanarypoxvirus) expressing L. longipalpis salivary proteins (LJM17 or LJL143). Thirty days after the final immunization, dogs were intradermally challenged with 107 Leishmania infantum promastigotes in the presence of L. longipalpis saliva. We followed the experimentally infected dogs for 10 months to characterize clinical, parasitological, and immunological parameters. Upon vaccination, all immunized dogs presented strong and specific humoral responses with increased serum concentrations of IFN-gamma, TNF, IL-7, and IL-15. The serum of dogs immunized with LJM17 also exhibited high levels of IL-2, IL-6, and IL-18. L. infantum infection was established in all experimental groups as evidenced by the presence of anti-Leishmania IgG, and by parasite detection in the spleen and skin. Dogs immunized with LJM17-based vaccines presented higher circulating levels of IFN-gamma, IL-2, IL-6, IL-7, IL-15, IL-18, TNF, CXCL10, and GM-CSF post infection when compared with controls. Results demonstrated that relevant Leishmania-specific immune responses were induced following vaccination of dogs with L. longipalpis salivary antigen LJM17 administered in a single priming dose of plasmid DNA, followed by two booster doses of recombinant Canarypox vector. Importantly, a significant increase in pro-inflammatory cytokines and chemokines known to be relevant for protection against leishmaniasis was evidenced after challenging LJM17-vaccinated dogs as compared to controls. Although similar results were observed following immunization with LJL143, the pro-inflammatory response observed after immunization was attenuated following infection. Collectively, these data suggest that the LJM17-based vaccine induced an immune profile consistent with the expected protective immunity against canine leishmaniosis. These results clearly support the need for further evaluation of the LJM17 antigen, using a heterologous prime-boost vaccination strategy against canine visceral leishmaniosis (CVL). PMID- 30519236 TI - Epstein-Barr Virus-Associated T-Cell Lymphoproliferative Disorder Presenting as Chronic Diarrhea and Intestinal Bleeding: A Case Report. AB - Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease (EBV+ T-LPD) is extremely rare. Primary acute or chronic active Epstein-Barr virus infection triggers EBV+ T-LPD's onset and the disease involves clonal proliferation of infected T-cells with activated cytotoxic phenotype. The adult onset EBV+ T-LPD (ASEBV+ T-LPD) is even rarer and needs to be extensively studied. Further, according to literature review, it is a challenge to find patients who are immunocompetent and diagnosed with ASEBV+ T-LPD involving gastrointestinal tract. This case report discusses a previously healthy middle aged woman who presented with unique symptoms mimicking inflammatory bowel disease, and required a total colectomy and terminal ileum rectomy, as reveled by endoscopic examinations, due to severe gastrointestinal bleeding. Post-surgery histopathological findings were confirmatory for the diagnosis of ASEBV+ T-LPD (II: Borderline). This patient died 7 months after the diagnosis. PMID- 30519237 TI - Corrigendum: CD1d-Invariant Natural Killer T Cell-Based Cancer Immunotherapy: alpha-Galactosylceramide and Beyond. AB - [This corrects the article DOI: 10.3389/fimmu.2018.01519.]. PMID- 30519238 TI - Identification of a HIV Gp41-Specific Human Monoclonal Antibody With Potent Antibody-Dependent Cellular Cytotoxicity. AB - Antibody-Dependent Cellular Cytotoxicity (ADCC) is a major mechanism of protection against viral infections in vivo. Identification of HIV-1-specific monoclonal antibodies (mAbs) with potent ADCC activity may help develop an effective HIV-1 vaccine. In present study, we isolated such human mAb, designated E10, from an HIV-1-infected patient sample by single B cell sorting and single cell PCR. E10 bound to gp140 trimer and linear peptides derived from gp41 membrane proximal external region (MPER). E10 epitope (QEKNEQELLEL) overlapped with mAb 2F5 epitope. However, E10 differentiated from 2F5 in neutralization breadth and potency, as well as ADCC activity. E10 showed low neutralization activity and narrow spectrum of neutralization compared to 2F5, but it mediated higher ADCC activity than 2F5 at low antibody concentration. Fine mapping of E10 epitope may potentiate MPER-based subunit vaccine development. PMID- 30519239 TI - Role of Mechanotransduction and Tension in T Cell Function. AB - T cell migration from blood to, and within lymphoid organs and tissue, as well as, T cell activation rely on complex biochemical signaling events. But T cell migration and activation also take place in distinct mechanical environments and lead to drastic morphological changes and reorganization of the acto-myosin cytoskeleton. In this review we discuss how adhesion proteins and the T cell receptor act as mechanosensors to translate these mechanical contexts into signaling events. We further discuss how cell tension could bring a significant contribution to the regulation of T cell signaling and function. PMID- 30519240 TI - ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death. AB - Amyotrophic Lateral Sclerosis (ALS) is a group of neurodegenerative disorders that featured with the death of motor neurons, which leads to loss of voluntary control on muscles. The etiologies vary among different subtypes of ALS, and no effective management or medication could be provided to the patients, with the underlying mechanisms incompletely understood yet. Mutations in human Optn (Optineurin), particularly E478G, have been found in many ALS patients. In this work, we report that NF-kappaB activity was increased in Optn knockout (Optn -/-) MEF (mouse embryonic fibroblast) cells expressing OPTN of different ALS associated mutants especially E478G. Inflammation was significantly activated in mice infected with lenti-virus that allowed overexpression of OPTN E478G mutation in the motor cortex, with marked increase in the secretion of pro-inflammatory cytokines as well as neuronal cell death. Our work with both cell and animal models strongly suggested that anti-inflammation treatment could represent a powerful strategy to intervene into disease progression in ALS patients who possess the distinctive mutations in OPTN gene. PMID- 30519241 TI - Ly9 (CD229) Antibody Targeting Depletes Marginal Zone and Germinal Center B Cells in Lymphoid Tissues and Reduces Salivary Gland Inflammation in a Mouse Model of Sjogren's Syndrome. AB - Sjogren's Syndrome (SjS) is a common chronic autoimmune disease characterized by the B cell hyperactivation, lymphocyte infiltration, and tissue damage of exocrine glands. It can also present life-threatening extraglandular manifestations, such as pulmonary and hepatic involvement, renal inflammation and marginal zone (MZ) B cell lymphoma. Several biologic agents have been tested in SjS but none has shown significant efficacy. Here, we report the effects of Ly9 (CD229) antibody targeting, a cell surface molecule that belongs to the SLAM family of immunomodulatory receptors, using NOD.H-2h4 mice as a model of SjS-like disease. Female mice were treated with anti-Ly9 antibody or isotype control at week 24, when all mice present SjS related autoantibodies, salivary gland infiltrates, and marginal zone (MZ) B cell pool enlargement. Antibody injection depleted key lymphocyte subsets involved in SjS pathology such as MZ, B1, and germinal center B cells in spleen and draining lymph nodes without inducing a general immunosuppression. Importantly, mice receiving anti-Ly9 mAb showed a reduced lymphocyte infiltrate within salivary glands. This reduction may be, in part, explained by the down-regulation of L-selectin and alfa4/beta7 integrin induced by the anti-Ly9 antibody. Furthermore, levels of anti-nuclear autoantibodies were reduced after anti-Ly9 treatment. These data indicate that Ly9 is a potential therapeutic target for the treatment of SjS. PMID- 30519242 TI - Non-coding Class Switch Recombination-Related Transcription in Human Normal and Pathological Immune Responses. AB - Antibody class switch recombination (CSR) to IgG, IgA, or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor IMU and acceptor IH exons, located 5' upstream of each CH coding gene. Although, our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce. We analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA, and the Sequence Read Archive using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as, coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for IMU, Igamma3, and Igamma1 in humans in response to vaccination. We mapped IH transcription for the human IGH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called "immune privileged" tissues. However, significant Igamma4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased Idelta transcription in ileal mucosa in Crohn's disease with ulceration was found. In conclusion, CSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e., cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome. PMID- 30519243 TI - Host Adaptive Immune Status Regulates Expression of the Schistosome AMP-Activated Protein Kinase. AB - Schistosomes exhibit profound developmental adaptations in response to the immune status of their mammalian host, including significant attenuation of parasite growth, development and reproduction in response to deficits in host adaptive immunity. These observations led us to hypothesize that schistosomes regulate the utilization of energy resources in response to immunological conditions within the host. To test this hypothesis, we identified and characterized the Schistosoma mansoni AMP-activated protein kinase (AMPK), a heterotrimeric enzyme complex that is central to regulating energy metabolism at the cellular and organismal level in eukaryotes. We show that expression of the catalytic alpha subunit is developmentally regulated during the parasite life cycle, with peak expression occurring in adult worms. However, the protein is present and phosphorylated in all life cycle stages examined, suggesting a need for active regulation of energy resources throughout the life cycle. In contrast, transcription of the AMPK alpha gene is down-regulated in cercariae and schistosomula, suggesting that the protein in these life cycle stages is pre synthesized in the sporocyst and that expression must be re-initiated once inside the mammalian host. We also show that schistosome AMPK alpha activity in adult worms is sensitive to changes in the parasite's environment, suggesting a mechanism by which schistosome metabolism may be responsive to host immune factors. Finally, we show that AMPK alpha expression is significantly down regulated in parasites isolated from immunodeficient mice, suggesting that modulation of parasite energy metabolism may contribute to the attenuation of schistosome growth and reproduction in immunodeficient hosts. These findings provide insights into the molecular interactions between schistosomes and their vertebrate hosts and suggest that parasite energy metabolism may represent a novel target for anti-schistosome interventions. PMID- 30519244 TI - Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages. AB - The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression. PMID- 30519245 TI - Exosomes and miRNA-Loaded Biomimetic Nanovehicles, a Focus on Their Potentials Preventing Type-2 Diabetes Linked to Metabolic Syndrome. AB - Exosomes are small membrane vesicles of 30-150 nm, members of the extracellular vesicle family and secreted by various cell types. Different studies describe specific microRNA (miRNA) with altered expression in serum and/or plasma of patients suffering from diabetes or metabolic syndrome. Diabetic cardiomyocyte derived exosomes loaded with miRNAs like miR-320-3p (or 320a) have been shown regulating angiogenesis on endothelial cell cultures. Insufficient myocardial angiogenesis is the major manifestation of diabetes-caused ischemic cardiovascular disease. Studies on transfer of functional microRNAs between mouse dendritic cells via exosomes have shown that some miRNAs (miR-320-3p, 29b-3p, 7a 5p) are distributed in immature and mature exosomes. Among these miRNAs, miR-320 3p is better known in epigenetics for silencing polr3d gene by binding to its promoter in Human Embryonic Kidney-293 cells. Moreover, quantitative and stoichiometric analysis of the microRNA content of exosomes highlights the lack of reliable natural source of such particles loaded with miRNA opening the need for tailoring exosomes or nanoparticles delivering efficiently miRNA intimately linked to immunity, metabolism and epigenetics in target cells. However, loading of extracellular mature miRNA into recipient cells comes with a cost by at least impeding dynamic localization of miRNAs in nucleoli or inefficient miRNA delivery due to rapid recycling by exonucleases. All these works are calling for the design of new biomimetic vehicles and in vivo assessment of miRNA functionality when delivered by natural or biomimetic nanoparticles in order to control metabolic diseases from infancy to adulthood. PMID- 30519246 TI - Age-Related Changes on CD40 Promotor Methylation and Immune Gene Expressions in Thymus of Chicken. AB - One hundred and twenty one-day-old breeder cocks, included 15 cages of 8 birds each, were fed to learn the aging's effect on chicken's thymus immunity. At 2 (2 W) and 40 (40-W) weeks of age, one chicken each cage was randomly chosen and slaughtered to get the thymus sample. The results showed that thymus weight and morphology of 40-W group were far different from that of 2-W group, and exhibited a property of degeneration. Considering this phenotype variance, we analyzed the thymus' transcriptome to investigate the molecular mechanism that had been implicated in this phenotype diversity with age. Pearson correlation coefficients and principal component analysis indicated that two major populations corresponding to 40-W and 2-W group were identified, and 1949 differentially expressed genes (DEGs, 1722 up-regulated and 127 down-regulated) were obtained. Results of GO and KEGG pathway enrichment found that 4 significantly enriched KEGG pathways (Cytokine-cytokine receptor interaction, Intestinal immune network for IgA production, Toll-like receptor signaling pathway, AGE-RAGE signaling pathway in diabetic complications) related to immunoregulation were screened between 40-W and 2-W group. These results confirmed that thymus immunity of chickens had a strong age-related correlation. DEGs related to these 4 enriched KEGG pathways were suppressed in the thymus of 2-W group, this indicated that thymus immunity of 2-weeks-age chick was down-regulated. CD40 is involved in 3 of the 4 significantly enriched pathways, and it is critical for thymus immune regulation. CD40 promoter methylation level of 2-W group was higher than that of 40-W group, it is consistent with the transcriptional differences of the gene. Our study concluded that thymus immunity of chicken was varied with age. Compared to the 40-W group, thymus immunity of 2-W group was down-regulated, and in a status of hypo-activation on the whole, and these effects might be related to CD40 suppression induced by promoter hyper-methylation of the gene. PMID- 30519247 TI - Seed Germination Indicates Adaptive Transgenerational Plasticity in a Submerged Macrophyte. AB - Adaptive transgenerational plasticity is an important evolutionary strategy in plants. We investigated the resource allocation strategy in sexual reproduction and performed an in situ seed germination experiment of Potamogeton maackianus to reveal their responses to different water depths. Later, we discussed the biased adaptability to the maternal habitat in this species. We found a positive correlation between sexual and asexual reproduction in water depths from 1.0 m to 3.0 m, such a correlation failed to occur in 4.0 m water depth. These results indicate that the trade-off between sexual and asexual reproduction should only be expected in a stressful habitat, where resource acquisition is limited. For trade-off between quantity and quality of sexual units in different water depths, P. maackianus tends to produce more but lower quality sexual reproductive units in shallow water, and fewer but higher quality sexual units are found in deep water. The total germination percentage of seeds of P. maackianus was relatively poor, less than 46.65% in all of the treatments. The maximum germination percentage of seeds from 1.0 m, 2.0 m, 3.0 m, and 4.0 m water depths are 14.4%, 17.75%, 25.51%, and 46.65%, respectively. Seeds with higher germination percentage were from deeper water depths. The most interesting result was that the maximum final germination percentage occurred only when treatment water depth was the same as collection water depth. Our result showed that the variations in germination characters of the studied species appear to be based partly on the effects of maternal environmental factors. Our findings proved the adaptive transgenerational plasticity in P. maackianus, which will play an important role in evolutionary response to the selection of water depths. PMID- 30519248 TI - Metabolic Pathway of Topramezone in Multiple-Resistant Waterhemp (Amaranthus tuberculatus) Differs From Naturally Tolerant Maize. AB - Waterhemp [Amaranthus tuberculatus (Moq.) Sauer] is a problematic dicot weed in maize, soybean, and cotton production in the United States. Waterhemp has evolved resistance to several commercial herbicides that inhibit the 4 hydroxyphenylpyruvate-dioxygenase (HPPD) enzyme in sensitive dicots, and research to date has shown that HPPD-inhibitor resistance is conferred by rapid oxidative metabolism of the parent compound in resistant populations. Mesotrione and tembotrione (both triketones) have been used exclusively to study HPPD-inhibitor resistance mechanisms in waterhemp and a related species, A. palmeri (S. Wats.), but the commercial HPPD inhibitor topramezone (a pyrazolone) has not been investigated from a mechanistic standpoint despite numerous reports of cross resistance in the field and greenhouse. The first objective of our research was to determine if two multiple herbicide-resistant (MHR) waterhemp populations (named NEB and SIR) metabolize topramezone more rapidly than two HPPD inhibitor sensitive waterhemp populations (named SEN and ACR). Our second objective was to determine if initial topramezone metabolite(s) detected in MHR waterhemp are qualitatively different than those formed in maize. An excised leaf assay and whole-plant study investigated initial rates of topramezone metabolism (<24 h) and identified topramezone metabolites at 48 hours after treatment (HAT), respectively, in the four waterhemp populations and maize. Results indicated both MHR waterhemp populations metabolized more topramezone than the sensitive (SEN) population at 6 HAT, while only the SIR population metabolized more topramezone than SEN at 24 HAT. Maize metabolized more topramezone than any waterhemp population at each time point examined. LC-MS analysis of topramezone metabolites at 48 HAT showed maize primarily formed desmethyl and benzoic acid metabolites, as expected based on published reports, whereas SIR formed two putative hydroxylated metabolites. Subsequent LC-MS/MS analyses identified both hydroxytopramezone metabolites in SIR as different hydroxylation products of the isoxazole ring, which were also present in maize 48 HAT but at very low levels. These results indicate that SIR initially metabolizes and detoxifies topramezone in a different manner than tolerant maize. PMID- 30519249 TI - Inducibility of Plant Secondary Metabolites in the Stem Predicts Genetic Variation in Resistance Against a Key Insect Herbivore in Maritime Pine. AB - Resistance to herbivores and pathogens is considered a key plant trait with strong adaptive value in trees, usually involving high concentrations of a diverse array of plant secondary metabolites (PSM). Intraspecific genetic variation and plasticity of PSM are widely known. However, their ecology and evolution are unclear, and even the implication of PSM as traits that provide direct effective resistance against herbivores is currently questioned. We used control and methyl jasmonate (MJ) induced clonal copies of genotypes within families from ten populations of the main distribution range of maritime pine to exhaustively characterize the constitutive and induced profile and concentration of PSM in the stem phloem, and to measure insect herbivory damage as a proxy of resistance. Then, we explored whether genetic variation in resistance to herbivory may be predicted by the constitutive concentration of PSM, and the role of its inducibility to predict the increase in resistance once the plant is induced. We found large and structured genetic variation among populations but not between families within populations in resistance to herbivory. The MJ induction treatment strongly increased resistance to the weevil in the species, and the genetic variation in the inducibility of resistance was significantly structured among populations, with greater inducibility in the Atlantic populations. Genetic variation in resistance was largely explained by the multivariate concentration and profile of PSM at the genotypic level, rather than by bivariate correlations with individual PSM, after accounting for genetic relatedness among genotypes. While the constitutive concentration of the PSM blend did not show a clear pattern of resistance to herbivory, specific changes in the chemical profile and the increase in concentration of the PSM blend after MJ induction were related to increased resistance. To date, this is the first example of a comprehensive and rigorous approach in which inducibility of PSM in trees and its implication in resistance was analyzed excluding spurious associations due to genetic relatedness, often overlooked in intraspecific studies. Here we provide evidences that multivariate analyses of PSM, rather than bivariate correlations, provide more realistic information about the potentially causal relationships between PSM and resistance to herbivory in pine trees. PMID- 30519250 TI - Current Strategies of Polyploid Plant Genome Sequence Assembly. AB - Polyploidy or duplication of an entire genome occurs in the majority of angiosperms. The understanding of polyploid genomes is important for the improvement of those crops, which humans rely on for sustenance and basic nutrition. As climate change continues to pose a potential threat to agricultural production, there will increasingly be a demand for plant cultivars that can resist biotic and abiotic stresses and also provide needed and improved nutrition. In the past decade, Next Generation Sequencing (NGS) has fundamentally changed the genomics landscape by providing tools for the exploration of polyploid genomes. Here, we review the challenges of the assembly of polyploid plant genomes, and also present recent advances in genomic resources and functional tools in molecular genetics and breeding. As genomes of diploid and less heterozygous progenitor species are increasingly available, we discuss the lack of complexity of these currently available reference genomes as they relate to polyploid crops. Finally, we review recent approaches of haplotyping by phasing and the impact of third generation technologies on polyploid plant genome assembly. PMID- 30519251 TI - Identification, Expression, and Functional Analysis of the Group IId WRKY Subfamily in Upland Cotton (Gossypium hirsutum L.). AB - WRKY transcription factors have diverse functions in regulating stress response, leaf senescence, and plant growth and development. However, knowledge of the group IId WRKY subfamily in cotton is largely absent. This study identified 34 group IId WRKY genes in the Gossypium hirsutum genome, and their genomic loci were investigated. Members clustered together in the phylogenetic tree had similar motif compositions and gene structural features, revealing similarity and conservation within group IId WRKY genes. During the evolutionary process, 14 duplicated genes appeared to undergo purification selection. Public RNA-seq data were used to examine the expression patterns of group IId WRKY genes in various tissues and under drought and salt stress conditions. Ten highly expressed genes were identified, and the ten candidate genes revealed distinct expression patterns under drought and salt treatments by qRT-PCR analysis. Among them, Gh_A11G1801 was used for functional characterization. GUS activity was differentially induced by various stresses in Gh_A11G1801p::GUS transgenic Arabidopsis plants. The virus-induced gene silencing (VIGS) of Gh_A11G1801 resulted in drought sensitivity in cotton plants, which was accompanied by elevated malondialdehyde (MDA) content and reduced catalase (CAT) content. Taken together, these findings obtained in this study provide valuable resources for further studying group IId WRKY genes in cotton. Our results also enrich the gene resources for the genetic improvements of cotton varieties that are suitable for growth in stressful conditions. PMID- 30519252 TI - Identification of QTNs Controlling Seed Protein Content in Soybean Using Multi Locus Genome-Wide Association Studies. AB - Protein content (PC), an important trait in soybean (Glycine max) breeding, is controlled by multiple genes with relatively small effects. To identify the quantitative trait nucleotides (QTNs) controlling PC, we conducted a multi-locus genome-wide association study (GWAS) for PC in 144 four-way recombinant inbred lines (FW-RILs). All the FW-RILs were phenotyped for PC in 20 environments, including four locations over 4 years with different experimental treatments. Meanwhile, all the FW-RILs were genotyped using SoySNP660k BeadChip, producing genotype data for 109,676 non-redundant single-nucleotide polymorphisms. A total of 129 significant QTNs were identified by five multi-locus GWAS methods. Based on the 22 common QTNs detected by multiple GWAS methods or in multiple environments, pathway analysis identified 8 potential candidate genes that are likely to be involved in protein synthesis and metabolism in soybean seeds. Using superior allele information for 22 common QTNs in 22 elite and 7 inferior lines, we found higher superior allele percentages in the elite lines and lower percentages in the inferior lines. These findings will contribute to the discovery of the polygenic networks controlling PC in soybean, increase our understanding of the genetic foundation and regulation of PC, and be useful for molecular breeding of high-protein soybean varieties. PMID- 30519253 TI - Responses of Morphology, Gas Exchange, Photochemical Activity of Photosystem II, and Antioxidant Balance in Cyclocarya paliurus to Light Spectra. AB - Light quality is a critical factor regulating photosynthetic capacity which directly affects the final yield of plants. Cyclocarya paliurus is a multiple function tree species and its leaves are widely used as tea production and ingredient in functional foods in China. However, the effects of varying light quality on photosynthetic process and the photoprotective mechanisms remains unexplored in-depth. In this study, the biomass accumulation, morphology changes, photosynthetic capacity, stomata ultrastructure, pigments content, PSII activity, reactive oxygen species production, antioxidant enzymes, and phenolic content of C. paliurus plants under different light-emitting diodes (LED) light treatments were investigated to test a hypothesis that the difference in photosynthetic efficiency of C. paliurus plants under differential light quality is related to the degree of photoinhibition and the activation of photoprotection. We found that C. paliurus plants performed better under the treatments of WL (white light, 445 and 560 nm) and BL (blue light, 456 nm) than the treatment of GL (green light, 514 nm) and RL (red light, 653 nm). The better performances were characterized by higher values of photosynthetic capacity, total biomass, pigments content, specific leaf mass per area, seeding height increment, leaf thickness and palisade length. In contrast, plants under the treatments of GL and RL suffered significant photoinhibition but effectively developed photoprotective mechanisms. Results of this study provide not only some insights of the response mechanisms of plant photosynthesis to light quality but also a scientific basis for improving the cultivation of C. paliurus plantations. PMID- 30519254 TI - Plant Frataxin in Metal Metabolism. AB - Frataxin is a highly conserved protein from prokaryotes to eukaryotes. Several functions related to iron metabolism have been postulated for this protein, including Fe-S cluster and heme synthesis, response to oxidative damage and oxidative phosphorylation. In plants, the presence of one or two isoforms of this protein with dual localization in mitochondria and chloroplasts has been reported. Frataxin deficiency affects iron metabolism in both organelles, leading to an impairment of mitochondrial respiration, and chlorophyll and photosynthetic electron transport deficiency in chloroplasts. In addition, plant frataxins can react with Cu2+ ions and dimerize, which causes the reduction of free Cu ions. This could provide an additional defense mechanism against the oxidation of Fe-S groups by Cu ions. While there is a consensus on the involvement of frataxin in iron homeostasis in most organisms, the interaction of plant frataxins with Cu ions, the presence of different isoforms, and/or the localization in two plant organelles suggest that this protein might have additional functions in vegetal tissues. PMID- 30519255 TI - Dominant and Recessive Major R Genes Lead to Different Types of Host Cell Death During Resistance to Xanthomonas oryzae in Rice. AB - The bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is the most devastating bacterial disease of rice worldwide. A number of dominant major disease resistance (MR) genes and recessive MR genes against Xoo have been cloned and molecularly characterized in the last two decades. However, how these MR genes mediated-resistances occur at the cytological level is largely unknown. Here, by ultrastructural examination of xylem parenchyma cells, we show that resistances to Xoo conferred by dominant MR genes and recessive MR genes resulted in different types of programmed cell death (PCD). Three dominant MR genes Xa1, Xa4, and Xa21 and two recessive MR genes xa5 and xa13 that encode very different proteins were used in this study. We observed that Xa1-, Xa4-, and Xa21-mediated resistances to Xoo were associated mainly with autophagy-like cell death featured by the formation of autophagosome-like bodies in the xylem parenchyma cells. In contrast, the xa5- and xa13-mediated resistances to Xoo were associated mainly with vacuolar-mediated cell death characterized by tonoplast disruption of the xylem parenchyma cells. Application of autophagy inhibitor 3-methyladenine partially compromised Xa1-, Xa4-, and Xa21-mediated resistances, as did Na2HPO4 alkaline solution to xa5- and xa13-mediated resistances. These results suggest that autophagy-like cell death is a feature of the dominant MR gene-mediated resistance to Xoo and vacuolar-mediated cell death is a characteristic of the recessive MR gene-mediated resistance. PMID- 30519256 TI - Comparative Analysis of Mycoplasma gallisepticum vlhA Promoters. AB - Mycoplasma gallisepticum is an intracellular parasite affecting respiratory tract of poultry that belongs to class Mollicutes. M. gallisepticum features numerous variable lipoprotein hemagglutinin genes (vlhA) that play a role in immune escape. The vlhA promoters have a set of distinct properties in comparison to promoters of the other genes. The vlhA promoters carry a variable GAA repeats region at approximately 40 nts upstream of transcription start site. The promoters have been considered active only in the presence of exactly 12 GAA repeats. The mechanisms of vlhA expression regulation and GAA number variation are not described. Here we tried to understand these mechanisms using different computational methods. We conducted a comparative analysis among several M. gallisepticum strains. Nucleotide sequences analysis showed the presence of highly conserved regions flanking repeated trinucleotides that are not linked to GAA number variation. VlhA genes with 12 GAA repeats and their orthologs in 12 M. gallisepticum strains are more conserved than other vlhA genes and have narrower GAA number distribution. We conducted comparative analysis of physicochemical profiles of M. gallisepticum vlhA and sigma-70 promoters. Stress-induced duplex destabilization (SIDD) profiles showed that sigma-70 group is characterized by the common to prokaryotic promoters sharp maxima while vlhA promoters are hardly destabilized with the region between GAA repeats and transcription start site having zero opening probability. Electrostatic potential profiles of vlhA promoters indicate the presence of the distinct patterns that appear to govern initial stages of specific DNA-protein recognition. Open state dynamics profiles of vlhA demonstrate the pattern that might facilitate transcription bubble formation. Obtained data could be the basis for experimental identification of mechanisms of phase variation in M. gallisepticum. PMID- 30519257 TI - Second-generation pterocarpanquinones: synthesis and antileishmanial activity. AB - Background: Despite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones. Methods: The second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells. Results: In this work, we answered two pertinent questions about the structure of the first generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production. Conclusions: The data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents. PMID- 30519258 TI - Deep sequencing analysis of toad Rhinella schneideri skin glands and partial biochemical characterization of its cutaneous secretion. AB - Background: Animal poisons and venoms are sources of biomolecules naturally selected. Rhinella schneideri toads are widespread in the whole Brazilian territory and they have poison glands and mucous gland. Recently, protein from toads' secretion has gaining attention. Frog skin is widely known to present great number of host defense peptides and we hypothesize toads present them as well. In this study, we used a RNA-seq analysis from R. schneideri skin and biochemical tests with the gland secretion to unravel its protein molecules. Methods: Total RNA from the toad skin was extracted using TRizol reagent, sequenced in duplicate using Illumina Hiseq2500 in paired end analysis. The raw reads were trimmed and de novo assembled using Trinity. The resulting sequences were submitted to functional annotation against non-redundant NCBI database and Database of Anuran Defense Peptide. Furthermore, we performed caseinolytic activity test to assess the presence of serine and metalloproteases in skin secretion and it was fractionated by fast liquid protein chromatography using a reverse-phase column. The fractions were partially sequenced by Edman's degradation. Results: We were able to identify several classes of antimicrobial peptides, such as buforins, peroniins and brevinins, as well as PLA2, lectins and galectins, combining protein sequencing and RNA-seq analysis for the first time. In addition, we could isolate a PLA2 from the skin secretion and infer the presence of serine proteases in cutaneous secretion. Conclusions: We identified novel toxins and proteins from R. schneideri mucous glands. Besides, this is a pioneer study that presented the in depth characterization of protein molecules richness from this toad secretion. The results obtained herein showed evidence of novel AMP and enzymes that need to be further explored. PMID- 30519259 TI - Telemental Health in Low- and Middle-Income Countries: A Systematic Review. AB - Introduction: The rising incidence of mental illness and its impact on individuals, families, and societies is becoming a major public health concern, especially in resource-constrained countries. Consequently, there is an increasing demand for mental health services in many middle- and low-income countries (LMIC). Challenges such as inequality in access, lack of staff and hospital beds, and underfunding, often present in the LMIC, might in part be addressed by telemental health services. However, little is known about telemental health in the LMIC. Methods: A systematic review was performed, drawing on several electronic databases, including PubMed, PsycINFO, Web of Science, Springer Link, and Google Scholar. Original English language studies on the practice of telemental health in LMIC, involving patients and published between 1 January 2000 and 16 February 2017, were included. Results: Nineteen studies met the inclusion criteria. Most of the articles were recent, which may reflect an increasing focus on telemental health in the LMIC. Eight of these studies were from Asia. Eight of the studies were interventional/randomized controlled trials, and 11 examined general mental health issues. Videoconferencing was the most frequently (6) studied telemental modality. Other modalities studied were online decision support systems (3), text messaging and bibliotherapy (1), e-chatting combined with videoconferencing (1), online therapy (2), e-counseling (1), store-and-forward technology (1), telephone follow-up (1), online discussion groups (1), audiovisual therapy and bibliotherapy (1), and computerized occupational therapy (1). Although many of the studies showed that telemental services had positive outcomes, some studies reported no postintervention improvements. Conclusion: The review shows a rising trend in telemental activity in the LMIC. There is a greater need for telemental health in the LMIC, but more research is needed on empirical and theoretical aspects of telemental activity in the LMIC and on direct comparisons between telemental activity in the LMIC and the non-LMIC. PMID- 30519260 TI - PPARalpha Enhances Cancer Cell Chemotherapy Sensitivity by Autophagy Induction. AB - PPARalpha (peroxisome-proliferator-activated receptor alpha) plays a critical role in regulation of inflammation and cancer, while the regulatory mechanism of PPARalpha on cancer cell autophagy is still unclear. Here we found that PPARalpha enhanced autophagy in HEK293T, SW480, and Hela cell lines, which was independent of PPARalpha transcription activity. PPARalpha induced antiapoptotic Bcl2 protein degradation resulting in release of the Beclin-1/VPS34 complex. Consistently, silenced PPARalpha reversed this event. PPARalpha-induced autophagy significantly inhibited tumor growth and enhanced SW480 cancer cell sensitivity to chemotherapy drugs. Moreover, PPARalpha agonist increased SW480 cancer cell chemotherapy sensitivity. These findings revealed a novel mechanism of PPARalpha/Bcl2/autophagy pathway suppressed tumor progression and enhanced chemotherapy sensitivity, which is a potential drug target for cancer treatment. PMID- 30519261 TI - The Rising Era of Immune Checkpoint Inhibitors in Myelodysplastic Syndromes. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by ineffective hematopoiesis and a wide spectrum of manifestations ranging from indolent and asymptomatic cytopenias to acute myeloid leukemia (AML). MDS result from genetic and epigenetic derangements in clonal cells and their surrounding microenvironments. Studies have shown associations between MDS and other autoimmune diseases. Several immune mechanisms have been identified in MDS, suggesting that immune dysregulation might be at least partially implicated in its pathogenesis. This has led to rigorous investigations on the role of immunomodulatory drugs as potential treatment options. Epigenetic modification via immune check point inhibition, while well established as a treatment method for advanced solid tumors, is a new approach being considered in hematologic malignancies including high risk MDS. Several trials are looking at the efficacy of these agents in MDS, as frontline therapy and in relapse, both as monotherapy and in combination with other drugs. In this review, we explore the utility of immune checkpoint inhibitors in MDS and current research evaluating their efficacy. PMID- 30519262 TI - Development and Application of an UHPLC-MS/MS Method for Comparative Pharmacokinetic Study of Eight Major Bioactive Components from Yin Chen Hao Tang in Normal and Acute Liver Injured Rats. AB - Yin Chen Hao Tang (YCHT) is one of the most famous hepatoprotective herbal formulas in China, but its pharmacokinetic investigation in model rats has been rarely conducted. In this study, the hepatic injury model was caused by intraperitoneal injections of carbon tetrachloride (CCl4), and YCHT was orally administered to the model and normal rats. An ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to analyze the plasma pharmacokinetics of eight major bioactive ingredients from YCHT in both the normal and liver injured rats. The calibration curves presented good linearity (r > 0.9981) in the concentration range. The relative standard deviation (RSD%) of inter- and intraday precision was within 9.55%, and the accuracy (RE%) ranged from -10.72% to 2.46%. The extraction recovery, matrix effect, and stability were demonstrated to be within acceptable ranges. The lower limit of detection (LLOD) and lower limit of quantitation (LLOQ) were around 0.1 ng/mL and 0.5 ng/mL, respectively, which were much lower than those in other related researches. Results reveal that there are significant differences in the pharmacokinetics of scoparone, geniposide, rhein, aloe-emodin, physcion, and chrysophanol in hepatic injured rats as compared to those in control except for scopoletin and emodin. Our experimental results provide a meaningful reference for the clinical dosage of YCHT in treating liver disorders, and the improvement of LLOD and LLOQ can also broaden the range of our method's application, which is very suitable for quantitating these eight compounds with low levels. PMID- 30519263 TI - Effects of Qianlie Tongqiao Capsule on Bladder Weight and Growth Factors in Bladder Tissue of Rats with Testosterone-Induced Benign Prostatic Hyperplasia. AB - Qianlie Tongqiao Capsule (QTC) is clinically confirmed to be efficacious and safe in treating lower urinary tract syndromes and bladder dysfunction that are induced by benign prostatic hyperplasia (BPH). However, the functional mechanisms of QTC remain unclear. We aim to investigate the effects of QTC on both bladder weight and several growth factors in the bladder tissue of rats with testosterone induced BPH. BPH in the rats was established through bilateral orchiectomy and subcutaneous administration of testosterone propionate (5 mg/kg) dissolved in corn oil. At the end of the study, all bladder tissues were collected and weighed, and a histological examination was conducted using H&E staining. Immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were applied to detect the expression of nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and transformation growth factor beta1 (TGF-beta1) in the bladder tissue. The expression of Bcl-2 and Bax in the bladder tissue was tested by Western Blot and qRT-PCR. We found that QTC, especially when administered in high-dosages, had a significant inhibitory effect on bladder weight gain and overexpression of NGF, bFGF, and TGF-beta1 in rats with BPH. In addition, QTC downregulated and upregulated protein and mRNA expression of Bcl-2 and Bax in the bladder after prostatic obstruction, respectively. Furthermore, QTC balanced the Bcl-2/Bax ratio. Overall, these results reveal possible functional mechanisms of QTC in treating BPH-caused bladder dysfunction, and further studies are needed. PMID- 30519264 TI - 1-(5-Bromo-2-hydroxy-4-methoxyphenyl)ethanone [SE1] Inhibits MMP-9 Expression by Regulating NF-kappaB and MAPKs Signaling Pathways in HT1080 Human Fibrosarcoma Cells. AB - Hippocampus is a traditional medicine in China, which can be used for treating tumors, aging, fatigue, thrombosis, inflammation, hypertension, prostatic hyperplasia, and other diseases. 1-(5-Bromo-2-hydroxy-4-methoxyphenyl)ethanone [SE1] from seahorse (Hippocampus kuda Bleeler) has been shown to suppress proinflammatory responses. In the present study, SE1 potently inhibited gelatin digestion by MMP-9 induced by phorbol 12-myristate 13-acetate (PMA) and migration of human fibrosarcoma HT1080 cells in dose-dependent manner. Moreover, western blot analysis and immunofluorescence analysis have been studied on MAPKs (ERK1/2, p38 kinase and JNK) and NF-kappaB (p65 and IkappaB), which refer to the clear molecular mechanism. The results indicated that SE1 significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPK: p38 kinase and JNK) and NF-kappaB. Finally, molecular docking result showed SE1 interacts with TYR245 and HIS226 of MMP-9 by hydrogen bond and Pi-Pi bond to suppress MMP-9 activity. This data suggested that the SE1 may possess therapeutic and preventive potential for the treatment of MMP-9 related disorders. PMID- 30519265 TI - Corrigendum to "Inhibitory Effect of a French Maritime Pine Bark Extract-Based Nutritional Supplement on TNF-alpha-Induced Inflammation and Oxidative Stress in Human Coronary Artery Endothelial Cells". AB - [This corrects the article DOI: 10.1155/2015/260530.]. PMID- 30519266 TI - Zishenwan Decreases Kidney Damage in Recurrent Urinary Tract Infection through the Inhibition of Toll-Like Receptor 4 Signal. AB - Objectives: To investigate the mechanism of the protective effect of Zishenwan on pyelonephritis rats. Methods: In the rat model of pyelonephritis, protective effects of Zishenwan, the content of secretory immunoglobulin A (SIg A), and interleukins were detected by ELISA. The expressions of TLR4-NFkappaB pathway were detected by Western blot in renal and urinary tract mucosa. The protective effect and influence on TLR4-NFkappaB pathway of Zishenwan were studied. Results: Zishenwan protected rats from pyelonephritis which related to the increase of SIgA, the regulation of interleukins, and the inhibition of TLR4-NFkappaB pathway. Serum containing Zishenwan can significantly decrease LPS-induced expression of TLR4, MyD88, and NFkappaB in vitro. And the inhibition of TLR4 signal by Zishenwan related to the degradation of TRAF3 and TRAF6. Conclusions: Zishenwan protected rats from urinary tract infection by clearance of bacteria and decrease of tissue damage. 20S proteasomes mediated the degradation of TRAF3 which is important to the decrease of tissue damage from Zishenwan. PMID- 30519267 TI - Curative Anti-Inflammatory Properties of Chinese Optimized Yinxieling Formula in Models of Parkinson's Disease. AB - Parkinson's disease (PD) is marked by the progressive degeneration of dopaminergic neurons (DAN) accompanied by glial activation. Thus, inhibiting glial activation that occurs during this disease could be an effective method for treating PD. Optimized Yinxieling Formula (OYF), a Chinese medicinal formula, which is used to efficiently treat autoimmune disease psoriasis, has been proved to display potential immunomodulatory effects in inflammation-associated diseases. This study assessed the therapeutic benefits of OYF on glial-mediated neuroinflammation and neuroprotection in PD models in vitro and in vivo. First, the results showed that OYF significantly suppresses LPS-induced proinflammatory cytokine secretion and attenuates the overall inflammatory responses in BV-2 cells. Second, in vivo studies confirm that while the validity of our MPTP induced PD mouse models possesses activated glia and significant neurobehavioral dysfunction, pretreatment with OYF prevents glial activation and ameliorates movement dysfunction in the MPTP-induced PD mouse models as evaluated by the pole and rotarod tests. Third, transcriptomic analyses were carried out to reveal the underlying molecular mechanism of the OYF treatment. Sixteen pathways were significantly upregulated in the OYF-treated PD model mice, including the cytokine-cytokine receptor interaction, cell adhesion molecules, coagulation, and complement cascades. Fifteen pathways were significantly downregulated in the OYF treated PD model mice, such as the natural killer cell mediated cytotoxicity, hematopoietic cell lineage, phagosome, and others. These pathways share direct or indirect features of immunomodulation, suggesting that the physiological effects of OYF involve key roles of immune and inflammation regulations. Therefore, we prove that OYF is a useful immunomodulatory formula in developing prevention and treatment methods for neurodegenerative disease PD. PMID- 30519268 TI - 6-Gingerol Protects Heart by Suppressing Myocardial Ischemia/Reperfusion Induced Inflammation via the PI3K/Akt-Dependent Mechanism in Rats. AB - Our previous study has demonstrated that 6-Gingerol (6-G) could alleviate myocardial ischemia/reperfusion injury (MIRI). However, the molecular mechanism underlying the process of myocardial ischemia/reperfusion (I/R) injury alleviation by 6-G remains unelucidated. The objective of the present study is to further investigate the potential mechanism for 6-G to alleviate MIRI in rats. Thirty-two Sprague-Dawley rats were randomly divided into four groups: the Sham group, the I/R group, the 6-G + I/R group, and the LY294002 (LY) + 6-G + I/R group. For the rats in each of the groups, data were collected for cardiogram, cardiac function, area of myocardial infarction, myocardial pathology, myocardial enzyme, marker of inflammatory response, and PI3K/Akt signaling pathway. We found that the pretreatment of 6-G with 6 mg/kg could shrink the ST section of cardiogram, improve the cardiac function, reduce the area of myocardial infarction and the degree of cardiac pathological injury, lower the level of myocardial enzyme, and inhibit the inflammatory response. In addition, our results also indicated that 6-G could upregulate the expression of PI3K and p-Akt and that LY294002, a blocking agent of PI3K/Akt signaling pathway, could nullify the protecting role of 6-G. Our experimental results showed that 6-G could inhibit I/R-induced inflammatory response through the activation of the PI3K/Akt signaling pathway. PMID- 30519269 TI - A Network Pharmacology Approach to Uncover the Mechanisms of Shen-Qi-Di-Huang Decoction against Diabetic Nephropathy. AB - Shen-Qi-Di-Huang decoction (SQDHD), a well-known herbal formula from China, has been widely used in the treatment of diabetic nephropathy (DN). However, the pharmacological mechanisms of SQDHD have not been entirely elucidated. At first, we conducted a comprehensive literature search to identify the active constituents of SQDHD, determined their corresponding targets, and obtained known DN targets from several databases. A protein-protein interaction network was then built to explore the complex relations between SQDHD targets and those known to treat DN. Following the topological feature screening of each node in the network, 400 major targets of SQDHD were obtained. The pathway enrichment analysis results acquired from DAVID showed that the significant bioprocesses and pathways include oxidative stress, response to glucose, regulation of blood pressure, regulation of cell proliferation, cytokine-mediated signaling pathway, and the apoptotic signaling pathway. More interestingly, five key targets of SQDHD, named AKT1, AR, CTNNB1, EGFR, and ESR1, were significant in the regulation of the above bioprocesses and pathways. This study partially verified and predicted the pharmacological and molecular mechanisms of SQDHD on DN from a holistic perspective. This has laid the foundation for further experimental research and has expanded the rational application of SQDHD in clinical practice. PMID- 30519270 TI - Manilkara zapota (L.) P. Royen Leaf Water Extract Induces Apoptosis in Human Hepatocellular Carcinoma (HepG2) Cells via ERK1/2/Akt1/JNK1 Signaling Pathways. AB - Manilkara zapota (L.) P. Royen, called sapodilla, or locally known as ciku, belongs to the family Sapotaceae. We found that Manilkara zapota leaf water extract has cytotoxic effect against human hepatocellular carcinoma (HepG2) cell line in our earlier study. Therefore, this study aimed to explore the anticancer properties of Manilkara zapota leaf water extract in HepG2 cells. We also aimed to unravel yet undiscovered mechanisms and identified several expressed genes whose functions in cytotoxicity activity of Manilkara zapota leaf water extract in HepG2 cells have not been well-studied. The apoptosis and intracellular reactive oxygen species (ROS) activities were analyzed using Annexin V-propidium iodide staining and dichlorodihydrofluorescein diacetate, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were assessed using Enzyme Linked Immunosorbent Assay. The associated molecular pathways were evaluated by quantitative real-time PCR. Overall analyses revealed that Manilkara zapota leaf water extract can increase percentage of early apoptotic cells, induce the formation of ROS, upregulate c-Jun N-terminal kinase 1 (JNK1) and inducible nitric oxide synthase (iNOS), and reduce Akt1 and vascular endothelial growth factor A (VEGFA) transcriptional activities. Our data suggest that Manilkara zapota leaf water extract can suppress the growth of HepG2 cells via modulation of ERK1/2/Akt1/JNK1 transcriptional expression. PMID- 30519271 TI - Corrigendum to "Hepatoprotective Role of Ethanolic Extract of Vitex negundo in Thioacetamide-Induced Liver Fibrosis in Male Rats". AB - [This corrects the article DOI: 10.1155/2013/739850.]. PMID- 30519272 TI - The Effects of Radix Astragali Water Abstract on Energy Metabolism in Rat Yang Deficiency Cold Syndrome Model through PPAR Signaling Pathway. AB - Radix Astragali (RA) herb with warm property and significant "tonifying qi" effects is indicated for the syndrome of internal cold due to Yang deficiency. The purpose of this research was to explore effects of Radix Astragali (RA) through PPAR signaling pathway on gene expression profiles related to energy metabolism in rats with the Yang-deficiency cold (YDC) syndrome, for identifying the pathological mechanism of Yang-deficiency cold (YDC) syndrome and the effects mechanism of RA. The results indicated that RA could significantly increase body weight (BM), cold and heat tendency (CT), overall temperature (OT), rectum temperature (RT), toe temperature (TT), energy intake (EI), and V(O2)/V(CO2) ratio (which indicates basal metabolism, BM) (P<0.05), enhancing the depressed metabolic function in YDC syndrome model rat. Our data also indicated differentially expressed genes (DEGs) related to energy metabolism involving lipids, carbohydrates, and amino acids metabolic process; the expression of CPT-1 and FABP4 (ap2) was improved; PPAR, Glycolysis, Wnt, cAMP, MAPK, AMPK, and fatty acid degradation signaling pathway may be related to energy metabolism. However, the Chinese herbal medicine RA plays a certain role in promoting the metabolism of substances and energy in rats by its warming and beneficial effect. Our results suggest that the mechanism underlying the function of RA may take effect through the regulation of PPAR signaling pathway and related gene expression. Lipids, carbohydrates, and amino acids metabolic process may be affected to adjust the reduced metabolic function in the model animals. In general, results indicate that RA could promote energy metabolism in rats with the YDC syndrome via PPAR signaling pathway regulating the expression of CPT-1 and FABP4 (ap2), which reflected the warm and qi tonifying properties of RA. PMID- 30519273 TI - Aged mice display altered numbers and phenotype of basophils, and bone marrow derived basophil activation, with a limited role for aging-associated microbiota. AB - Background: The influence of age on basophils is poorly understood, as well as the effect of aging-associated microbiota on basophils. Therefore, we studied the influence of aging and aging-associated microbiota on basophil frequency and phenotype, and differentiation from basophil precursors. Results: Basophils became more abundant in bone marrow (BM) and spleens of 19-month-old mice compared with 4-month-old mice. Aged basophils tended to express less CD200R3 and more CD123, both in BM and spleen. Differences in microbiota composition with aging were confirmed by 16S sequencing. Microbiota transfers from young and old mice to germ-free recipients revealed that CD11b tended to be lowered on splenic basophils by aging-associated microbiota. Furthermore, abundance of Alistipes, Oscillibacter, Bacteroidetes RC9 gut group, and S24-7 family positively correlated and CD123 expression, whereas Akkermansia abundance negatively correlated with basophils numbers.Subsequently, we purified FcepsilonRIalpha+CD11c-CD117- BM-derived basophils and found that those from aged mice expressed lower levels of CD11b upon stimulation. Higher frequencies of IL 4+ basophils were generated from basophil precursors of aged mice, which could be reproduced in basophils derived from germ-free recipients of aging-associated microbiota. Conclusions: Collectively, these results show the influence of aging on basophils. Furthermore, this study shows that aging-associated microbiota altered activation of BM-derived basophils in a similar fashion as observed in BM derived basophils from aged mice. PMID- 30519274 TI - The effects of vitamin D supplementation on endothelial activation among patients with metabolic syndrome and related disorders: a systematic review and meta analysis of randomized controlled trials. AB - Background and objective: The current systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the effect of vitamin D supplementation on endothelial activation among patients with metabolic syndrome and related disorders. Methods: Cochrane library, Embase, PubMed, and Web of Science database were searched to identify related RCTs published before 30th April 2018. The heterogeneity among the included studies was assessed using Cochran's Q test and I-square (I2) statistic. Data were pooled by using the random-effect model and standardized mean difference (SMD) was considered as summary effect size. Results: Fourteen clinical trials that contained a total of 1253 participants were included in the current meta-analysis. Vitamin D supplementation significantly decreased von willebrand factor (vWF) (SMD -0.27; 95% CI, - 0.46, - 0.08; P = 0.006; I2:40.5%). However, we found no significant impact of vitamin D supplementation on intercellular adhesion molecule 1(ICAM-1) (SMD -1.96; 95% CI, - 4.02, 0.09; P = 0.06; I2:97.4%), vascular celladhesion molecule 1 (VCAM-1) (SMD -0.50; 95% CI, - 1.19, 0.19; P = 0.15; I2:91.2%), on E selectin (SMD -0.04; 95% CI, - 0.36, 0.28; P = 0.81; I2:78.8%) and endothelin (SMD -0.49; 95% CI, - 1.18, 0.19; P = 0.15; I2:90.5%). The pooled data from trials of vitamin D supplementation with dosage of <=4000 IU/day (- 0.37, 95% CI: -0.65, - 0.10, I2: 73.5%) significantly reduced vWF concentrations, while there was no effect of vitamin D supplementation on vWF concentrations among trials with the dosage of intervention > 4000 IU/day (- 0.17, 95% CI: -0.43, 0.10, I2: 0.0%). VWF concentrations significantly reduced in pooled data from trials with duration study <=8 weeks (- 0.37, 95% CI: -0.67, - 0.07, I2: 60.6%), but there was no effect of vitamin D supplementation on vWF concentrations among trials with > 8 weeks (- 0.20, 95% CI: -0.45, 0.05, I2: 0.0%). While there was no effect of vitamin D supplementation on vWF concentrations among trials with total sample size of <=60 patients (- 0.03, 95% CI: -0.42, 0.36, I2: 0.0%), vWF concentrations in trials with more than 60 patients decreased significantly (- 0.34, 95% CI: 0.56, - 0.12, I2: 60.9%). Conclusions: Overall, the current meta-analysis demonstrated that vitamin D supplementation to patients with metabolic syndrome and related disorders resulted in an improvement in vWF, but did not affect ICAM 1, VCAM-1, E-selectin and endothelin levels. PMID- 30519275 TI - Perception and practice of breastfeeding among HIV positive mothers receiving care for prevention of mother to child transmission in South-East, Nigeria. AB - Background: Although the risk of HIV transmission through breastfeeding is reduced considerably with the use of antiretroviral therapy, infant feeding by HIV positive mothers remains controversial. Weighing risks against benefits generates intense debate among policymakers, program managers and service providers in sub-Saharan Africa, considering that the major causes of infant death of malnutrition and infectious diseases, could be prevented if mothers breastfeed their babies. Whereas breastfeeding involves some risk of HIV transmission, not breastfeeding poses considerable risk to infant survival. This study investigated perceptions and practice of breastfeeding of HIV-exposed infants among HIV positive mothers. Methods: A cross-sectional descriptive study was conducted in Enugu metropolis among HIV positive mothers receiving care for prevention of mother-to-child transmission of HIV from two public and two private hospitals. Interviewer-administered questionnaire survey was done with 550 participants as they exited the final point of service delivery. Descriptive statistics of perception and practice variables and cross tabulation of selected variables was performed. Results: Most mothers knew that HIV could be transmitted through breast milk. The majority perceived any type of breastfeeding as beneficial to the infant: 230 (83.6%) in private facilities, and 188 (68.4%) public facilities. Over three-quarters of the mothers breastfed their infants and their reasons for breastfeeding included personal choice, cultural norms, fear of HIV status being disclosed and pressure from family members. A statistical significant association was found between; (i) practice of breastfeeding and marital status, (p < 0.01), and (ii) practice of breastfeeding and household income provider (p = 0.02). However, neither marital status (AOR 1.4; 95% CI 0.3, 6.8) nor being the household income provider (AOR 4.9; 95% CI 0.6, 12.9) is a significant predictor of breastfeeding of HIV-exposed infants. Conclusions: Breastfeeding remains a common trend among HIV positive women and it is associated with economic independence of women and social support. Fear of stigma negatively affects practice of breastfeeding. Hence, HIV positive mothers need economic independence and the support of family members to practice recommended infant feeding options. PMID- 30519276 TI - Higher likelihood of 6-months exclusive breastfeeding among HIV infected than uninfected mothers: a household survey in Kenya. AB - Background: Exclusive breastfeeding (EBF) (breast milk feeding without additional food or drink, except medicine) is associated with deceased risk of postnatal transmission of HIV from mother to child. Methods: This analysis used data from a household survey in Western Kenya in 2011. Participants were mothers with HIV and uninfected mothers, aged >=14 years who gave birth in the prior year (ever breastfed) within the Kenya Medical Research Institute/US Centers for Disease Control and Prevention (KEMRI/CDC) Health and Demographic Surveillance System. Data on breastfeeding counseling and knowledge and practices regarding breastfeeding were collected. Rates and correlates of EBF were determined using multivariable logistic regression. Results: Of 652 mothers enrolled in the study, 435 were included in this analysis. Median age was 28 years among 154 mothers with HIV and 25 years among 281 uninfected mothers. Mothers with HIV were more likely than uninfected mothers to report breastfeeding counseling at a health facility (88.9% vs. 51.6%, respectively, p < 0.001) and EBF for 6-months (64.9% versus 34.5%, p < 0.001). Premastication (pre-chewing of food by adults prior to feeding to children) was less prevalent among mothers with HIV (3.9% vs. 13.2% p = 0.001) who were also more knowledgeable about potential risk of HIV transmission through premastication (83.1% vs 71.2% p = 0.005). Mothers with HIV who EBF for six months were 3.68-fold more likely to report counseling on EBF (aOR 3.68; 95% CI: 1.00,13.70). Uninfected mothers with polygamous marriage, any antenatal care visit, unskilled delivery and delayed breastfeeding initiation (> 1 h) were less likely to practice EBF for six months 62% (aOR 0.38; 95%CI: 0.20,0.94), 72% (aOR 0.28; 95%CI: 0.10,1.00), 54% (aOR 0.46; 95% CI: 0.22,1.00) and 46% (aOR 0.54; 95%CI: 0.30,1.00) respectively. Conclusions: Mothers with HIV were more likely to report breastfeeding counseling at a health facility, EBF for six months and less likely to practice premastication than uninfected mothers. Lessons learned from breastfeeding counseling in mothers with HIV could be used to improve awareness and change breastfeeding practices for all mothers. PMID- 30519277 TI - Correction to: Simple protoplast isolation system for gene expression and protein interaction studies in pineapple (Ananas comosus L.). AB - [This corrects the article DOI: 10.1186/s13007-018-0365-9.]. PMID- 30519278 TI - Superbubbles revisited. AB - Background: Superbubbles are distinctive subgraphs in direct graphs that play an important role in assembly algorithms for high-throughput sequencing (HTS) data. Their practical importance derives from the fact they are connected to their host graph by a single entrance and a single exit vertex, thus allowing them to be handled independently. Efficient algorithms for the enumeration of superbubbles are therefore of important for the processing of HTS data. Superbubbles can be identified within the strongly connected components of the input digraph after transforming them into directed acyclic graphs. The algorithm by Sung et al. (IEEE ACM Trans Comput Biol Bioinform 12:770-777, 2015) achieves this task in Results: A re-analysis of the mathematical structure of superbubbles showed that the construction of auxiliary DAGs from the strongly connected components in the work of Sung et al. missed some details that can lead to the reporting of false positive superbubbles. We propose an alternative, even simpler auxiliary graph that solved the problem and retains the linear running time for general digraph. Furthermore, we describe a simpler, space-efficient Implementation: We present a reference implementation of the algorithm that accepts many commonly used formats for the input graph and provides convenient access to the improved algorithm. https://github.com/Fabianexe/Superbubble. PMID- 30519279 TI - First clinical experiences of concurrent bleeding control and intracranial pressure monitoring using a hybrid emergency room system in patients with multiple injuries. AB - Background: The outcomes of multiple injury patients with concomitant torso hemorrhage and traumatic brain injury (TBI) are very poor. The hybrid emergency room system (HERS) is a trauma management system designed to complete resuscitation, computed tomography (CT), surgery, angioembolization, and intracranial pressure (ICP) monitoring all in one trauma resuscitation room without patient transfer. We aimed to review the outcomes of polytrauma patients who underwent concurrent bleeding control and ICP monitoring using the HERS. Methods: In this retrospective observational study, we enrolled patients who underwent concurrent bleeding control and ICP monitoring using the HERS between August 2011 and June 2018. Initial data on vital signs, Injury Severity Score (ISS), probability of survival (Ps) calculated by the Trauma and Injury Severity Score (TRISS), intervention type, 28-day mortality, and Extended Glasgow Outcome Scale at 6 months after injury were collected. Continuous variables were expressed as the median (25th and 75th percentiles) and categorical variables as numbers (%). Results: Ten patients were included in the analysis. The injury severity of the patients was as high as an ISS of 58 (50-64) and TRISS Ps of 0.15 (0.02-0.36). Seven of the 10 (70%) patients had hemodynamic instability within 30 min from arrival. The recorded durations from arrival to events were CT examination 9 (6-16) min, bleeding control procedure 29 (22-42) min, and neurosurgical intervention 39 (31-53) min. Four of the 10 patients (40%) survived to discharge, and two of them (20%) were able to live independently at 6 months after injury. Conclusions: The concurrent performance of bleeding control procedure and ICP monitoring would be feasible in HERS settings among polytrauma patients with exsanguinating hemorrhage and TBI. PMID- 30519280 TI - Prognostic role of HPV infection in esophageal squamous cell carcinoma. AB - Background: The aims of this study were to evaluate whether HPV infection has a prognostic role in patients with esophageal squamous cell carcinoma who underwent oncological treatment and also to compare the heat shock proteins (Hsp) 90, 27 and 16.2 and growth hormone-releasing hormone receptor (GHRH-R) expression patterns of the pre-treatment tumor biopsies with the HPV status and with the oncological response. Methods: Pre-treatment tumor biopsies of 74 patients with locally advanced esophageal squamous cell carcinoma were processed retrospectively. The presence of HPV was detected by chromogenic in situ hybridization. Hsp and GHRH-R expressions were determined using immunohistochemistry. Following neoadjuvant or definitive radiochemotherapy, the patients were restaged according to the Response Evaluation Criteria in Solid Tumors. The correlation between the HPV status, response to treatment and Hsp and GHRH-R expressions were evaluated. Results: Fourteen (19%) patients were HPV positive. These patients were more likely to respond poorly to multimodal therapy (71.4% were non-responders vs. 28.6% responders) and had shorter survival compared to HPV-negative patients (mean survival of 8 months vs. 11 months), although the difference was not significant. A significantly higher number of HPV positive patients expressed Hsp 90 and 16.2 at high levels (93 and 79%, respectively) than at low levels (Chi-Square p = 0.019 and p = 0.031). Higher levels of Hsp expressions were associated with poorer response to therapy and worse overall survival. No correlation was found between GHRH-R expression and the HPV status, nor between GHRH-R expression and the treatment response of the examined samples. Conclusions: We found that HPV infection was associated with poor response to oncological treatment and decreased overall survival, and therefore proved to be a negative prognostic factor in patients with esophageal squamous cell carcinoma. There was a linear correlation between levels of Hsp 90 and 16.2 expression and HPV positivity. PMID- 30519281 TI - Living with obsessive-compulsive disorder (OCD): a South African narrative. AB - Background: Obsessive-compulsive disorder (OCD) is a highly prevalent and debilitating psychiatric disorder known to interfere with several life domains. Yet little is known about the subjective experiences of living with OCD amongst South Africans and more so, the ways in which it impacts daily functioning and quality of life (QOL). Methods: The aim of this study was to explore daily functioning and QOL among South African adults living with OCD. Qualitative semi structured interviews were conducted with 20 adults with a primary diagnosis of OCD. We used ATLAS.ti v7 to analyse the data, thematically. The study was conducted at the SU/UCT MRC Unit on Risk and Resilience in Mental Disorders in South Africa. Results: Three key themes were identified namely, (1) realisation of OCD, (2) disruptions to daily life and (3) managing the disruptions to daily life. Participants recounted their earliest recollections of OCD, the instances when they recognised something was wrong and ways in which they came to terms with their OCD. Disruptions to daily life included poor sleep quality, inability to enjoy leisure activities which impacted on socialisation and impairment in school/work performance. Perceived social support from family members, friends and colleagues were invaluable to helping participants manage these disruptions. Further, strategies such as self-talk, diary-keeping and humour helped them cope. Conclusion: While some individuals with OCD have found ways to cope with and accept having OCD, all participants perceived their QOL to be significantly reduced and their functioning impaired due to the condition, on multiple levels. The importance of acceptance in OCD ties in with research on the potential value of Acceptance and Commitment Therapy, which could form an adjunct to more conventional techniques such as Cognitive-Behavioural Therapy. The themes emanating from this study can be used to help clinicians better understand what treatment works best for patients with OCD-and whether this treatment be focused on the individual or together with close members of their microsystem, such as spouses/partners. Further these findings may potentially help to improve access, affordability and the quality of life of South Africans living with OCD from various income backgrounds. PMID- 30519282 TI - Laser MICROSAMPLING of soil microbial community. PMID- 30519283 TI - Cellulose-specific Type B carbohydrate binding modules: understanding oligomeric and non-crystalline substrate recognition mechanisms. AB - Background: Effective enzymatic degradation of crystalline polysaccharides requires a synergistic cocktail of hydrolytic enzymes tailored to the wide ranging degree of substrate crystallinity. To accomplish this type of targeted carbohydrate recognition, nature produces multi-modular enzymes, having at least one catalytic domain appended to one or more carbohydrate binding modules (CBMs). The Type B CBM categorization encompasses several families (i.e., protein folds) of CBMs that are generally thought to selectively bind oligomeric polysaccharides; however, a subset of cellulose-specific CBM families (17 and 28) appear to bind non-crystalline cellulose more tightly than oligomers and in a manner that discriminates between surface topology. Results: To provide insight into this unexplained phenomenon, we investigated the molecular-level origins of oligomeric and non-crystalline carbohydrate recognition in cellulose-specific Type B CBMs using molecular dynamics (MD) simulation and free energy calculations. Examining two CBMs from three different families (4, 17, and 28), we describe how protein-ligand dynamics contribute to observed variations in binding affinity of oligomers within the same CBM family. Comparisons across the three CBM families identified factors leading to modified functionality prohibiting competitive binding, despite similarity in sequence and specificity. Using free energy perturbation with Hamiltonian replica exchange MD, we also examined the hypothesis that the open topology of the binding grooves in families 17 and 28 necessitates tight binding of an oligomer, while the more confined family 4 binding groove does not require the same degree of tight binding. Finally, we elucidated the mechanisms of non-crystalline carbohydrate recognition by modeling CBMs complexed with a partially decrystallized cellulose substrate. Molecular simulation provided structural and dynamic data for direct comparison to oligomeric modes of carbohydrate recognition, and umbrella sampling MD was used to determine ligand binding free energy. Comparing both protein-carbohydrate interactions and ligand binding free energies, which were in good agreement with experimental values, we confirmed the hypothesis that family 17 and 28 CBMs bind non-crystalline cellulose and oligomers with different affinities (i.e., high and low). Conclusions: Our study provides an unprecedented level of insight into the complex solid and soluble carbohydrate substrate recognition mechanisms of Type B CBMs, the findings of which hold considerable promise for enhancing lignocellulosic biomass conversion technology and development of plant cell wall probes. PMID- 30519284 TI - Simultaneous consumption of cellobiose and xylose by Bacillus coagulans to circumvent glucose repression and identification of its cellobiose-assimilating operons. AB - Background: The use of inedible lignocellulosic biomasses for biomanufacturing provides important environmental and economic benefits for society. Efficient co utilization of lignocellulosic biomass-derived sugars, primarily glucose and xylose, is critical for the viability of lignocellulosic biorefineries. However, the phenomenon of glucose repression prevents co-utilization of both glucose and xylose in cellulosic hydrolysates. Results: To circumvent glucose repression, co utilization of cellobiose and xylose by Bacillus coagulans NL01 was investigated. During co-fermentation of cellobiose and xylose, B. coagulans NL01 simultaneously consumed the sugar mixtures and exhibited an improved lactic acid yield compared with co-fermentation of glucose and xylose. Moreover, the cellobiose metabolism of B. coagulans NL01 was investigated for the first time. Based on comparative genomic analysis, two gene clusters that encode two different operons of the cellobiose-specific phosphoenolpyruvate-dependent phosphotransferase system (assigned as CELO1 and CELO2) were identified. For CELO1, five genes were arranged as celA (encoding EIIAcel), celB (encoding EIIBcel), celC (encoding EIICcel), pbgl (encoding 6-phospho-beta-glucosidase), and celR (encoding a transcriptional regulator), and these genes were found to be ubiquitous in different B. coagulans strains. Based on gene knockout results, CELO1 was confirmed to be responsible for the transport and assimilation of cellobiose. For CELO2, the five genes were arranged as celR, celB, celA, celX (encoding DUF871 domain-containing protein), and celC, and these genes were only found in some B. coagulans strains. However, through a comparison of cellobiose fermentation by NL01 and DSM1 that only possess CELO1, it was observed that CELO2 might also play an important role in the utilization of cellobiose in vivo despite the fact that no pbgl gene was found. When CELO1 or CELO2 was expressed in Escherichia coli, the recombinant strain exhibited distinct cellobiose uptake and consumption. Conclusions: This study demonstrated the cellobiose-assimilating pathway of B. coagulans and provided a new co-utilization strategy of cellobiose and xylose to overcome the obstacles that result from glucose repression in a biorefinery system. PMID- 30519285 TI - Chromosomal abnormalities and copy number variations in fetal ventricular septal defects. AB - Background: This study aimed to evaluate the applicability of chromosomal microarray analysis (CMA), rather than traditional chromosome analysis, in prenatal diagnosis of ventricular septal defects (VSDs) for superior prenatal genetic counseling and to reveal a potential correlation between submicroscopic chromosomal aberrations and VSDs. Results: Among the 151 VSD cases, 79 (52.3%) had isolated defects and 72 (47.7%) had additional ultrasound anomalies. Karyotype analysis identified 16 chromosomal abnormalities. Besides the 14 cases of chromosome abnormalities consistent with karyotype analysis, CMA identified an additional 20 cases (13.2%) of abnormal copy number variations (CNVs), of which 13 were pathogenetic CNVs, 5 were variations of uncertain clinical significance (VOUS) and 2 were benign CNVs. The detection rate of pathogenic CNVs in non isolated-VSDs was significantly higher than that in isolated-VSDs (36.1% (26/72) vs. 1.3% (1/79), p = 0.001). We also found that CMA results indicating pathogenic abnormalities affected the rate of pregnancy termination. Conclusions: This study showed that CMA combined with cytogenetic analysis is particularly effective in identifying CNVs in fetuses with VSDs and can have an effect on obstetrical outcomes. The elucidation of the etiology of VSDs suggested that gene mutations or other factors may be implicated. PMID- 30519286 TI - Thyroid malignancy among patients with thyroid nodules in the United Arab Emirates: a five-year retrospective tertiary Centre analysis. AB - Objectives: Thyroid malignancy constitutes the sixth common cancer type in the United Arab Emirates (UAE). There are no epidemiological data outlining the prevalence of cancer in thyroid nodules, nor previous analysis of ultra sonographic features correlating with thyroid malignancy in the UAE. This study aimed to estimate the prevalence of thyroid malignancy in patients with thyroid nodules and to describe the ultra-sonographic characteristics of thyroid nodules harbouring malignancy. Methods: A retrospective electronic medical records review of all thyroid nodules in patients (aged 18 to 80 years) with normal thyroid stimulating hormone (TSH) levels, who underwent ultrasound guided fine needle aspiration cytology (UG-FNA) at Sheikh Khalifa Medical City (SKMC) during 2011 2015. Results: 436 patients with normal TSH underwent UG-FNA cytological examination of thyroid nodules (n = 555 nodules). The overall crude prevalence of thyroid cancer among patients was 10.1% (95% CI 7.5-13.3). The age-adjusted prevalence of thyroid cancer among UAE nationals, Arabs, Far East Asians, and Caucasians were 9.6% (3.6-15.6), 10.0% (6.2-13.8), 16.8% (4.5-29.0) and 16.3% (1.7-30.9), respectively. The crude prevalence was 14.5%(95% CI 6.2-22.8) in men, and 9.3%(95% CI 6.3-12.2) in women. The echogenicity features were significantly different between the cancerous and noncancerous nodules (p = 0.025). Cancerous nodules were relatively more hyper- and hypo-echoic, while noncancerous nodules were mostly complex. Conclusion: We report a higher prevalence of thyroid malignancy among patients with thyroid nodules relative to that reported in other parts of the world. The rate of thyroid malignancy was higher in patients of Far East Asian and Caucasian ethnic background. PMID- 30519287 TI - Microbiota profile in new-onset pediatric Crohn's disease: data from a non Western population. AB - Background: The role of microbiota in Crohn's disease (CD) is increasingly recognized. However, most of the reports are from Western populations. Considering the possible variation from other populations, the aim of this study was to describe the microbiota profile in children with CD in Saudi Arabia, a non Western developing country population. Results: Significantly more abundant genera in children with CD included Fusobacterium, Peptostreptococcus, Psychrobacter, and Acinetobacter; whereas the most significantly-depleted genera included Roseburia, Clostridium, Ruminococcus, Ruminoclostridium, Intestinibacter, Mitsuokella, Megasphaera, Streptococcus, Lactobacillus, Turicibacter, and Paludibacter. Alpha diversity was significantly reduced in stool (p = 0.03) but not in mucosa (p = 0.31). Beta diversity showed significant difference in community composition between control and CD samples (p = 0.03). Conclusion: In this developing country, we found a pattern of microbiota in children with CD similar to Western literature, suggesting a role of recent dietary lifestyle changes in this population on microbiota structure. PMID- 30519289 TI - News. AB - The latest in the ERS Satellites event series is taking place on February 21, 2019 and will focus on the popular topic of precision medicine, with a specific focus on COPD and ILD. Bringing together experts in the respective fields, this one-day event offers free attendance in London, Lisbon, Athens and Warsaw, or you can join online free of charge from anywhere in the world. PMID- 30519288 TI - Participatory Action Research: Tools for Disaster Resilience Education. AB - Purpose: Participatory action research can improve scientific knowledge and community capacity to address disaster resilience and environmental justice. Evidence from the literature suggests that resident participation enhances assessment of environmental risks, raises awareness, and empowers residents to fight for equitable distribution of hazard and climate risk adaptations. Yet, risk assessment and urban planning processes still frequently operate within expertise-driven groups without significant community engagement. Such fragmentation results in part from a lack of appreciation for community expertise in built environment adaptations and educational tools to support resident involvement in the often technical built environment planning processes. Approach: A participatory research and place-based education project was developed that enhanced co-learning between residents and researchers while collecting and analyzing local data on flood resilience in the built environment. Five research activities constitute the curriculum of resilience education on stormwater infrastructure: 1) establishment of partnership agreement/MOU, 2) participatory GIS to identify flooding issues, 3) water quality testing and health survey, 4) stormwater infrastructure assessment, and 5) urban/landscape design. Partners included high school and college students, residents, and environmental justice organizations. Findings: Outcomes include a stakeholder approved infrastructure assessment smartphone application, neighborhood maps of drainage issues, a report of water containments, and neighborhood-scaled green infrastructure provisions and growth plans. Findings indicate that participatory research positively contributed to resilience knowledge of participants. Value: This paper outlines an interdisciplinary pedagogical strategy for resilience planning that engages residents to assess and monitor the performance of stormwater infrastructure and create resilience plans. The paper also discusses challenges and opportunities for similar participatory projects. PMID- 30519290 TI - Breathe: surgical interventions in pulmonary diseases. AB - The December issue of Breathe focuses on surgical interventions in pulmonary diseases http://ow.ly/iGEa30mlZuw. PMID- 30519291 TI - Summer schools of adult and paediatric respiratory medicine: course report. AB - Participants in the 2018 ERS summer schools of adult and paediatric respiratory medicine describe their experiences http://ow.ly/MV7Q30m5SkW. PMID- 30519293 TI - Lung transplantation. AB - I was born in 1959 in Lisbon. My early years were marked by a typical family life, and we travelled a lot because of my father's work. I completed my schooling until the 12th grade and then started to work. In 1981, I completed mandatory military service at the marines' school. PMID- 30519292 TI - ERS syllabus for postgraduate training in respiratory infections: a guide for comprehensive training. AB - ERS has developed a syllabus for postgraduate training in respiratory infections to guide programme designers http://ow.ly/xJ0R30m8CYB. PMID- 30519294 TI - Controversies and emerging topics in lung transplantation. AB - : Lung transplantation provides a realistic hope of improved survival and enhanced quality of life. However, outcomes can be disappointing, meaning many decisions are highly controversial. Practice is largely based on expert opinion and there is a dearth of high-level evidence. Not surprisingly, this leads to centre-specific practices that may vary considerably in controversial areas. The aim of this review, therefore, is to explore some of those domains and present the available evidence. As the science of lung transplantation approaches its fifth decade, we are only now reaching a critical mass of clinicians and scientific researchers to enable adequately powered studies to assist in informing our approach to some of these controversies. Key points: Lung transplantation remains an art, combining experience with evidence.Clinicians need evidence to guide them on a myriad of questions, from candidate selection and listing, to organ donor acceptance, immunosuppression and chronic allograft dysfunction.Chronic lung allograft dysfunction pathogenesis deserves further detailed study. Educational aims: To illustrate the spectrum of controversial areas in lung transplantation including whom to list, which organs can be used and for whom, immune suppression and infection prophylaxis, and causes and phenotypes of chronic lung allograft dysfunction.To inspire clinicians to always ask questions and help collect the evidence we need to inform decision making. PMID- 30519295 TI - Surgery in nontuberculous mycobacteria pulmonary disease. AB - : Medical treatment of pulmonary nontuberculous mycobacteria (NTM) disease has highly variable outcomes. Despite the use of multiple antibiotics, sputum clearance is often difficult to achieve, especially in cases with macrolide resistant NTM infection. Immunocompromised patients and those with structural lung disease are at increased risk, although occurrence in immunocompetent patients without structural lung disease is well recognised. Most pulmonary NTM disease involves Mycobacterium avium complex (MAC), but with enhanced identification multiple species have now been recognised as opportunistic pathogens. The observed increase in NTM disease, especially infection with multidrug-resistant Mycobacterium abscessus complex, is probably multifactorial. Surgery has been used as adjuvant treatment in patients with 1) focal disease that can be removed or 2) bothersome symptoms despite medical treatment that can be ameliorated. Early post-surgical mortality is low, but long-term morbidity and mortality are highly dependent on the degree of lung involvement and the residual lung function, the potency of medical treatment and the type of surgical intervention. In conjunction with antibiotic therapy, reported post-surgical sputum clearance was excellent, although publication bias should be considered. Bronchopleural fistulae were problematic, especially in pneumonectomy cases. Study results support the use of minimal resection surgery, in a carefully selected subgroup of patients with focal disease or persistent symptoms. Educational aims: To critically review the literature describing the use of surgery in the treatment of pulmonary disease caused by nontuberculous mycobacteria (NTM).To assess the outcomes and complications observed with different surgical approaches used in the treatment of pulmonary NTM disease. PMID- 30519296 TI - Minimally invasive thoracic surgery for empyema. AB - The widely accepted and still increasing use of video-assisted thoracic surgery (VATS) in pleuro-pulmonary pathology imposes the need to deal with two major pitfalls: the first is to avoid its unselective use, while the second relates to inappropriate rejection of VATS on the basis of "insufficient radicality". Unlike a quite established role of VATS in lung cancer patients, in patients with pleural empyema, the role of VATS is less clearly defined. The current evidence about VATS in patients with pleural empyema could be summarised as follows: VATS is accepted as a useful treatment option for fibrinopurulent empyema, but the treatment failure rate increases with the increasing proportion of stage III empyema, necessitating further surgical options like thoracotomy and decortication. As both pulmonologists and surgeons deal with diagnosis and treatment of pleural empyema, this article is an attempt to highlight the existing evidence in a more user-friendly way in order to help practising physicians to optimise the use of VATS in these patients. In other words, in the absence of randomised studies comparing VATS and thoracotomy, the key question to be answered is: are there any pre-operative findings that can be used to select patients for initial VATS versus proceeding directly to a thoracotomy? PMID- 30519297 TI - An uncommon histopathological diagnosis. AB - Can you perform a robust histopathological diagnosis for this unusual case? ?http://ow.ly/40GB30mc5Th. PMID- 30519298 TI - Opportunities for early career members at the Lung Science Conference 2019. AB - The @ERStalk #LSC2019 in Estoril, Portugal, provides early career members with various opportunities to get actively involved in the ERS and to strengthen their network ?http://ow.ly/n0PC30lp2V3. PMID- 30519299 TI - How to write a response to the reviewers of your manuscript. AB - Organising the process of writing a response to reviewers' comments and making best use of the expertise of your co-authors increases your chances of being successful in getting your paper published http://ow.ly/WAxV30lF1g3. PMID- 30519300 TI - Will an electronic nose help at high altitude? AB - An electronic nose does not simply detect the concentrations of selected VOCs in the exhaled air, but verifies the cumulative signature, reflecting the overall VOC concentration. This technology is novel but promising. http://ow.ly/IPCt30mbIBV. PMID- 30519301 TI - A case of unexplained dyspnoea: when lung function testing matters! AB - Diverse methods are available for assessment of the respiratory muscles; the technique used should be tailored to the question posed. http://ow.ly/ChbX30m91bt. PMID- 30519302 TI - The IMPACT of triple versus dual single-inhaler therapy on exacerbations of COPD. AB - In the IMPACT trial, triple inhalation therapy resulted in a lower rate of moderate or severe COPD exacerbations compared with either dual therapy with ICS/LABA or LAMA/LABA, but pneumonia rates were increased. http://ow.ly/pYJn30mgpFp. PMID- 30519303 TI - Amazing pleiotropic effects of azithromycin. AB - The large randomised, double-blind, placebo-controlled AMAZES trial observed that azithromycin 500 mg given 3-times a week for 48 weeks in adults with persistent uncontrolled asthma decreased asthma exacerbations and improved asthma-related quality of life ?http://ow.ly/WGlz30lLL7z. PMID- 30519304 TI - Precision medicine in COPD: review of mepolizumab for eosinophilic COPD. AB - Mepolizumab can reduce exacerbation rates in those with frequently exacerbating, severe COPD and raised blood eosinophils; this represents a further advance in precision medicine for COPD and targeted therapies http://ow.ly/uklu30m4YcU. PMID- 30519305 TI - Mediastinal staging by videomediastinoscopy in clinical N1 non-small cell lung cancer. AB - VAM(LA) has adequate sensitivity to be considered as the approach of choice for preoperative mediastinal staging in the subgroup of early-stage operable NSCLC patients http://ow.ly/42Wn30m78Zw. PMID- 30519307 TI - ChILD - Children's interstitial lung disease. AB - The term 'interstitial lung disease' covers a large group of lung conditions that affect the interstitium, the tissue and space around the alveoli (air sacs) in the lungs. This is where oxygen is taken into the body and carbon dioxide is taken out of the body. PMID- 30519306 TI - Assembly 12: interstitial lung diseases. AB - Meet @ERStalk Assembly 12: interstitial lung diseases http://ow.ly/Bp0730m9zX4. PMID- 30519308 TI - Efficacy of CapeOX plus Cetuximab Treatment as a First-Line Therapy for Patients with Extended RAS/BRAF/PIK3CA Wild-Type Advanced or Metastatic Colorectal Cancer. AB - Background: Oxaliplatin and capecitabine (CapeOX) combined with cetuximab is rarely used to treat advanced and metastatic colorectal cancer (mCRC). The present study aimed to clarify the clinical benefits of this treatment regimen when used as a first-line therapy in patients with expanded RAS/BRAF/PIK3CA wild type mCRC, using the data and tumor specimens from two previously published Phase II clinical trials. Methods: The gene mutation status and clinical data of 102 patients with KRAS wild-type mCRC, who received either of CapeOX + cetuximab or FOLFOX + cetuximab, were analyzed. The primary endpoint was response rate (RR) of CapeOX + cetuximab treatment in patients with extended RAS/BRAF/PIK3CA wild-type mCRC. RR comparisons and maximum tumor size changes between different treatment regimens and gene mutation status were set as key secondary endpoints. Results: We identified 88 patients with extended RAS/BRAF/PIK3CA wild-type mCRC. Those treated with CapeOX + cetuximab (n = 52) had a 61.5% RR (95% CI, 47.0-74.7%), while those treated with FOLFOX + cetuximab (n = 36) had a 66.7% RR (95% CI, 49.0 81.4%). Patients with any mutation (n = 14) had a 42.9% RR (95% CI, 17.1-71.1%). There were no significant differences between these three groups (P = 0.298). The disease control rate was 86.5% (95% CI, 74.2-94.4%) in the CapeOX + cetuximab group, and 88.9% (95% CI, 73.9-96.9%) in the FOLFOX + cetuximab group. Maximum tumor size changes were largest in patients with wild-type mCRC treated with FOLFOX + cetuximab followed by patients with wild-type mCRC treated with CapeOX + cetuximab, and then by those with any mutation (-63.2%, -52.6%, and -27.3%, respectively; P = 0.035). Conclusions: Patients with RAS/BRAF/PIK3CA wild-type mCRC had a sufficient RR following first-line treatment with CapeOX + cetuximab. These results suggest that this combination therapy should be considered as a treatment option for patients with advanced mCRC. PMID- 30519309 TI - Immunoscore System for Predicting Clinical Outcome of Metastatic Renal Cell Carcinoma Patients Treated with Tyrosine Kinase Inhibitors. AB - We conducted this study to determine whether immunoscore system (IS) predicts survival in patients with metastatic renal cell carcinoma (mRCC). A total of 218 mRCC patients treated with sunitinib or sorafenib in Zhongshan Hospital, Fudan University were recruited during 2007-2017, retrospectively. CD8, CD4, Treg, PD-1 and PD-L1 expression were evaluated by immunohistochemical staining of paraffin embedded slide. Kaplan-Meier method and COX regression model were used in survival analyses. Multivariate analyses demonstrated that expressions of CD8, Treg, PD-1 and stromal PD-L1 (sPD-L1) expressions were independent predictive factors for OS, thus IS was established containing these four immunological factors. Subsequent analysis revealed that performance of IS provided good differentiation of OS and PFS. Besides, multivariate analysis identified IS as an independent prognostic factor for OS (p<0.001) and PFS (p=0.002). IS, compared with International mRCC Database Consortium (IMDC) risk model, and provided better prediction ability for OS. Results suggested that IS was a powerful prognostic factor for OS and PFS in patients with mRCC treated with tyrosine kinase inhibitors. And IS can be used as essential supplement to IMDC for outcome prediction in mRCC patients. PMID- 30519310 TI - Comprehensive Analysis of BAP1 Somatic Mutation in Clear Cell Renal Cell Carcinoma to Explore Potential Mechanisms in Silico. AB - Purpose: Aim of this study was to comprehensively analyze BRCA1-associated protein-1 (BAP1) somatic mutation in clear cell renal cell carcinoma (ccRCC) and explore potential therapeutic pathways and molecules. Patients and methods: In this study, we analyzed 445 ccRCC cases from The Cancer Genome Atlas (TCGA). Comprehensive analysis including survival, transcriptome and methylation between BAP1 mutated and wild-type cases was performed using bioinformatics tools in silico. Pathways and molecules related to BAP1 mutation were analyzed using Database for Annotation, Visualization and Integrated Discovery (DAVID) and protein-protein interaction (PPI) network. Results: BAP1 mutated ccRCC patients had a worse overall survival (OS) and disease free survival (DFS) than BAP1 wild type patients. We found 583 up-regulated and 1216 down-regulated different expressed genes (DEGs) in BAP1 mutated tumors. Up-regulated DEGs were enriched in molecular functions and biological processes like protein binding, protein transport and ubiquitin protein ligase binding. Down-regulated DEGs were enriched in pathways like Rap1 signaling pathway, Notch pathway and altered molecular functions like metal ion binding and ubiquitin-protein transferase activity. Furthermore, CAD, TSPO, CTNNB1 and MAPK3 were top hub genes selected using PPI network analysis. Finally, BAP1 mutation had a strong correlation with CpG island methylator phenotype (CIMP). Conclusion: Our study provides a comprehensive understanding of BAP1 functional somatic mutation in ccRCC patients. Several hub genes like CAD and TSPO may become potential therapeutic targets. PMID- 30519311 TI - Nomogram to Predict Cancer-Specific Survival in Patients with Pancreatic Acinar Cell Carcinoma: A Competing Risk Analysis. AB - Background: The objective of this study was to evaluate the probability of cancer specific death of patients with acinar cell carcinoma (ACC) and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) of these patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with ACC between 2004 and 2014 were retrospectively collected. Cancer-specific mortality and competing risk mortality were evaluated. Nomograms for estimating 1-, 2- and 3-year OS and CSS were established based on Cox regression model and Fine and Grey's model. The precision of the 1-, 2- and 3-year survival of the nomograms was evaluated and compared using the area under receiver operating characteristic (ROC) curve (AUC). Results: The study cohort included 227 patients with ACC. The established nomograms were well calibrated, and had good discriminative ability, with a concordance index (C-index) of 0.742 for OS prediction and 0.766 for CSS prediction. The nomograms displayed better discrimination power than 7th or 8th edition Tumor-Node-Metastasis (TNM) stage systems in training set and validation set for predicting both OS and CSS. The AUC values of the nomogram predicting 1-, 2-, and 3-year OS rates were 0.784, 0.797 and 0.805, respectively, which were higher than those of 7th or 8th edition TNM stage systems. Regard to the prediction of CSS rates, the AUC values of the nomogram were also higher than those of 7th or 8th edition TNM stage systems. Conclusion: We evaluated the 1-, 2 and 3-year OS and CSS in patients with ACC for the first time. Our nomograms showed relatively good performance and could be considered as convenient individualized predictive tools for prognosis. PMID- 30519312 TI - Identification of Integrin beta1 as a Novel PAG1-Interacting Protein Involved in the Inherent Radioresistance of Human Laryngeal Carcinoma. AB - Inherent radioresistance plays a crucial role in the failure of radiotherapy. Using the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines established from the parental cell line Hep-2, we previously reported that phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) overexpression in laryngeal carcinoma cells was correlated with inherent radioresistant phenotypes. However, the underlying mechanisms of this effect remain unknown. In the present study, we performed a proteomic screen to investigate the interactome of PAG1 in Hep-2max cells resulting in the identification of several interaction partners. Bioinformatic analysis and immunofluorescence experiments indicated the integrin beta1 to be a crucial interaction partner of PAG1. PAG1 was also highly expressed in laryngeal carcinoma radioresistant tissues and showed co-localization with integrin beta1. In addition, we demonstrated that integrin beta1's binding to PAG1 could be interrupted by MbetaCD, an inhibitor of lipid rafts formation. Moreover, knockdown of integrin beta1 by RNA interference sensitized radioresistant cells to irradiation. Importantly, we identified 2 potential interaction sites (Pro216 Arg232 and Asn356-Gly377) in the cytoplasmic domain of PAG1 using high throughput peptide arrays. Taken together, these results suggest that the binding of PAG1 to integrin beta1 in lipid rafts is essential for inherent radioresistance of human laryngeal carcinoma. PMID- 30519313 TI - LINC00852 Promotes Lung Adenocarcinoma Spinal Metastasis by Targeting S100A9. AB - Background: Lung adenocarcinoma has a strong tendency to develop into bone metastases, especially spinal metastases (SM). Long noncoding RNAs (lncRNAs) play critical roles in regulating several biological processes in cancer cells. However, the mechanisms underlying the roles of lncRNAs in the development of SM have not been elucidated to date. Methods: Clinical specimens were collected for analysis of differentially expressed lncRNAs. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to examine the effects of these genes on pathways. RNA pull-down was utilized to identify the targeting protein of lncRNAs. The effects of lncRNA on its target were detected in A549 and SPCA-1 cells via perturbation of the lncRNA expression. Oncological behavioral changes in transfected cells and phosphorylation of kinases in the relevant pathways, with or without inhibitors, were observed. Further, tumorigenicity was found to occur in experimental nude mice. Results: LINC00852 and the mitogen-activated protein kinase (MAPK) pathway were found to be associated with SM. Moreover, the LINC00852 target S100A9 had a positive regulatory role in the progression, migration, invasion, and metastasis of lung adenocarcinoma cells, both in vitro and in vivo. Furthermore, S100A9 strongly activated the P38 and REK1/2 kinases, and slightly activated the phosphorylation of the JNK kinase in the MAPK pathway in A549 and SPCA-1 cells. Conclusion: LINC00852 targets S100A9 to promote progression and oncogenic ability in lung adenocarcinoma SM through activation of the MAPK pathway. These findings suggest a potential novel target for early intervention against SM in lung cancer. PMID- 30519314 TI - Niclosamide Inhibits Cell Growth and Enhances Drug Sensitivity of Hepatocellular Carcinoma Cells via STAT3 Signaling Pathway. AB - Aims: Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor worldwide, with a high mortality rate at advanced stages. In this study, we investigated the effect of niclosamide on cell growth and drug sensitivity in human HCC and elucidated the underlying mechanism. Methods: Three human HCC cell lines (HepG2, QGY-7703 and SMMC-7721) were used to evaluate the effect of niclosamide. Cell proliferation was measured by MTT assay and colony formation assay. Assessment of apoptosis was evaluated by flow cytometry and Hoechst staining. The mRNA and protein levels were analyzed by real-time PCR and western blot, respectively. Results: Niclosamide suppressed cell viability, inhibited clone formation, and induced cell apoptosis in HCC cells dose- and time dependently. Furthermore, niclosamide synergized with cisplatin to promote the apoptosis of HCC cells. With niclosamide treatment, phospho-STAT3 (Y705) was inactivated and the downstream antiapoptotic proteins Mcl-1 and survivin were downregulated at both mRNA and protein levels in HCC cells. Conclusion: Niclosamide has effective function in anti-HCC and may be a single or combined drug treatment for HCC and acts via the STAT3 signaling pathway. PMID- 30519315 TI - Role of lncRNA and EZH2 Interaction/Regulatory Network in Lung Cancer. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Long non coding RNAs (lncRNAs) are non-protein-coding transcripts and longer than 200 nucleotides. LncRNAs have been demonstrated to modulate gene expression at transcriptional, post-transcriptional, as well as epigenetic levels in lung cancer. Interestingly, compelling studies have revealed that lncRNAs participated in the EZH2 oncogenic regulatory network. EZH2 plays an important role in the initiation, progression and metastasis of cancer. On one hand, lncRNAs can directly bind to EZH2, recruit EZH2 to the promoter region of genes and repress their expression. On the other hand, lncRNAs can also serve as EZH2 effectors or regulators. In this review, we summarized the types of lncRNA-EZH2 interaction and regulatory network identified till date and discussed their influence on lung cancer. Better understanding regarding the interaction and regulatory network will provide new insights on lncRNA- or EZH2-based therapeutic development in lung cancer. PMID- 30519316 TI - CASP8 rs3834129 (-652 6N insertion/deletion) Polymorphism and Colorectal Cancer Susceptibility: An Updated Meta-Analysis. AB - CASP8 rs3834129 polymorphism (-652 6N insertion/deletion) is a genetic alteration which might affect the apoptosis pathway caspase enzyme. The impaired caspase enzyme would lead to the change of cancer risk. By now, the role of CASP8 rs3834129 polymorphism has been widely investigated. However, the relationship of this genetic variant on colorectal cancer (CRC) susceptibility still remains inconsistent. Therefore, we further investigated the role of rs3834129 polymorphism on CRC risk. Eligible published studies were retrieved from EMBASE, PubMed, CNKI and WANFANG database updates to March 2018. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the relationship strengths. In general, we successfully retrieved 13 studies (8 publications) involving 13058 cases and 14418 controls. The meta-analysis results demonstrated that rs3834129 polymorphism was associated with a decreased CRC risk in heterozygous model (ID vs. II: OR = 0.94, 95% CI = 0.88-0.99), but not the homozygous and allele models. Furthermore, significantly decreased risk was also found among Asian (ID vs. II: OR = 0.86, 95% CI = 0.76-0.98), and high quality score group (ID vs. II: OR = 0.90, 95% CI = 0.81-1.00) in the stratified analyses. Taken together, we showed that CASP8 rs3834129 polymorphism influences CRC susceptibility in a weak impact manner. More case-control studies are warranted to validate such relationship. PMID- 30519317 TI - Prognostic Influence of the Time Interval between Surgery and Chemotherapy in Epithelial Ovarian Cancer. AB - The influence of time to chemotherapy (TTC) on recurrence and survival among epithelial ovarian cancer (EOC) patients still remains unknown. This single center retrospective cohort study was conducted on 489 EOC patients who underwent surgery followed by taxane- plus platinum-based chemotherapy in the Shengjing Hospital of China Medical University between 2011 and 2015. The Multivariate cox proportional regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) after adjustment for potential confounders. The median follow-up duration was 2.97 years (inter-quartile range from 2.11 to 4.13 years). The recurrence and mortality rate of the all patients was 50.9% (249/489) and 43.6% (213/489), respectively. Having comorbidity, residual disease, ascites, and advanced FIGO stage (III-IV) was associated worse PFS and OS of EOC patients. Compared to TTC less than 14 days, delayed TTC (more than 28 days) was associated with a worse PFS (HR=1.36; 95%CI: 0.96-1.92) and OS (HR=1.38; 95%CI: 0.95-2.00). Notably, in EOC patients with advanced stage, delayed TTC (more than 28 days) was associated with worse PFS (HR=1.51; 95%CI: 1.02-2.24) and OS (HR=1.53; 95%CI: 1.01-2.32) when comparing to TTC less than 14 days. In conclusion, delayed TTC was associated with higher rates of EOC recurrence and survival among these patients with advanced stage. The findings of the present study may provide evidence for gynecologist as well as these ovarian cancer patients to make further decision for the treatment. PMID- 30519318 TI - Down-Regulated microRNA-34a Expression as a Prognostic Marker for Poor Osteosarcoma in Mice: A Systematic Review and Meta-Analysis. AB - Background: In children and adolescents, osteosarcomais the most common malignant bone tumor with a high mortality rate. New therapeutic strategies are urgent to be explored. Studies have proven that microRNAs (miRNAs) in malignant tumors often appear dysregulation, this provides a direction for exploring the new therapeutic strategies for cancers. The aim of this meta-analysis is to summarize and analyze whethermicroRNA-34a(miRNA-34a) could be a prognostic marker for osteosarcoma in mice. Methods: We searched PubMed, Web of Science, Embase, Wan Fang Database, China Knowledge Resource Integrated Database, VIP Database, and SinoMed since their initiation date to January 24, 2018. After screening based on inclusion and exclusion criteria, eight articles were included for the final analysis. Results: Our results showed that tumor volume and tumor weight were inhibited by restoring the down-regulated expression of miRNA-34a in the xenograft mouse models. Conclusions: Down-regulated miRNA-34a expression is a prognostic marker for poor osteosarcoma. We should be more committed to investigate the clinical significance of miRNA-34a in osteosarcoma patients. PMID- 30519319 TI - MicroRNA-376c-3p Facilitates Human Hepatocellular Carcinoma Progression via Repressing AT-Rich Interaction Domain 2. AB - Hepatocellular carcinoma (HCC), accounting for approximately 90% of liver cancer, is the most lethal malignant tumors in the world. Large amount of evidence indicate that microRNAs (miRNAs) contribute to the tumorigenesis and progression of HCC. Among them, miR-376c-3p was recently identified as a tumor-related miRNA and is up-regulated in HBV-related HCC. But, the clinical significance of miR 376c-3p and its biological function in HCC progression are still unclear. Here, we confirmed that miR-376c-3p expression level in HCC was markedly higher than that in noncancerous tissues. Up-regulation of miR-376c-3p was detected in four different HCC cell lines. High miR-376c-3p expression correlated with poor prognostic features, such as large tumor size and venous infiltration. Follow-up data indicated that high miR-376c-3p level evidently correlated with poor clinical outcomes of HCC patients. Moreover, knockdown of miR-376c-3p repressed HCC cell growth, migration and invasion in vitro. miR-376c-3p overexpression facilitated these malignant behaviors of Bel-7402 cells. Mechanistically, miR 376c-3p posttranscriptionally repressed ARID2 expression by directly interacting with its 3'-UTR. Furthermore, an obvious negative correlation between miR-376c-3p and ARID2 mRNA expression in HCC tissues was confirmed. Notably, miR-376c-3p knockdown suppressed HCC growth and metastasis in nude mice. Gain-of-function experiments showed that ARID2 inhibited cell growth and mobility of Hep3B cells. Subsequently, ARID2 knockdown rescued miR-376c-3p silencing attenuated Hep3B cell proliferation and mobility. Our results suggest that miR-376c-3p exerts an oncogenic role in HCC progression. PMID- 30519320 TI - Management Of Synchronous Krukenberg Tumors From Gastric Cancer: a Single-center Experience. AB - Background: Whether metastasectomy improves prognosis of gastric cancer patients with ovarian metastases (Krukenberg tumors) is not clear. In this study, we examined the survival benefit of metastasectomy combined with chemotherapy for treatment of synchronous Krukenberg tumors from gastric cancer and identified the prognostic factors. Methods: The subjects of this study were patients diagnosed as synchronous Krukenberg tumors of gastric origin in the period between December 2004 and December 2015. Patients were classified in accordance with treatment modality: metastasectomy group (metastasectomy combined with chemotherapy) and non-metastasectomy group (chemotherapy alone). Clinicopathological characteristics together with treatment records were investigated in detail and their relationship with survival outcomes was examined. Results: Out of a total of 103 patients, 54 (52.4%) underwent metastasectomy of Krukenberg tumors while 49 (47.6%) patients had chemotherapy alone. Overall survival (OS) in the metastasectomy group was significantly longer than that in the non-metastasectomy group (18.9 months vs. 12.4 months, respectively; P<0.001). Metastasectomy (hazard ratio [HR] 0.486; 95% confidence interval [CI] 0.323-0.729; P<0.001), signet ring cells (HR 1.938; 95% CI 1.182-3.175; P=0.009), peritoneal carcinomatosis (HR 1.934; 95% CI 1.230-3.049; P=0.004), expression of estrogen receptor-beta (ER-beta) (HR 0.404; 95% CI 0.251-0.648; P<0.001), and progesterone receptor (PR) (HR 0.496; 95% CI 0.301-0.817; P<0.001) were independent predictors of OS. Conclusion: Metastasectomy combined with chemotherapy showed an association with survival benefit in patients with synchronous Krukenberg tumors from gastric cancer. Metastasectomy, expression of ER-beta and PR, peritoneal carcinomatosis, and signet ring cells were independent predictors of survival. Further prospective studies are warranted. PMID- 30519321 TI - Clinical Effect of Adjuvant Cytokine-Induced Killer Cells Immunotherapy in Patients with Stage II-IVB Nasopharyngeal Carcinoma after Chemoradiotherapy: A propensity score analysis. AB - As an adjuvant immunotherapy, cytokine-induced killer cells (CIKs) infusion has been demonstrated to exert potent effectiveness in several types of cancer patients who received curative treatment. However, controversy exists regarding whether nasopharyngeal carcinoma (NPC) patients can benefit from additional treatment after radical radiotherapy or chemoradiotherapy to improve their distant control and survival. In this retrospective study, we aimed to evaluate the efficacy of adjuvant CIK cells therapy in NPC patients with stage II-IVB after curative treatment. From January 1, 2005 to December 31, 2012, 85 pairs of NPC patients matching by propensity score matching (PSM) method to balance prognostic factors were included in this study: 85 cases underwent radical treatment, 85 cases received radical treatment and sequential CIKs infusion. We found that disease-free survival (DFS) and overall survival (OS) were significantly better in the CIK group than that in the control group (P = 0.009, P < 0.001, respectively). Adjuvant CIK cells immunotherapy was showed to be an independent prognostic factor for survival of the patients in further multivariate analysis. In subgroup analyses, the DFS and OS of patients with T3/4, III and IV A-B TNM (tumor-node-metastasis) stages were significantly enhanced in CIK group compared to control group. Nevertheless, both NPC patients with high and low EBV DNA benefited from adjuvant CIK cells immunotherapy. In conclusion, CIKs infusion is an effective adjuvant immunotherapy for enhancing the prognosis of NPC patients who have received the standard treatment, particularly for those with more aggressive tumor (T3/4) or advanced TNM stage. PMID- 30519322 TI - CPNE3 promotes migration and invasion in non-small cell lung cancer by interacting with RACK1 via FAK signaling activation. AB - Approximately 90% of patients diagnosed with non-small cell lung cancer (NSCLC) die due to distant metastases. However, the complicated molecular and cellular mechanisms involved in lung cancer metastasis remain poorly understood. Copine III (CPNE3), a member of a Ca2+-dependent phospholipid-binding protein family, was identified as a novel metastasis-associated protein in NSCLC in our previous study, however, its function in metastasis remains unclear. Here, we found that CPNE3 was expressed at high levels in NSCLC tissues and advanced TNM stages and was significantly associated with poor prognosis. In addition, CPNE3 interacted with phosphorylated erb-b2 receptor tyrosine kinase 2 (pErbB2) and receptor of activated protein C kinase 1 (RACK1) and activated the focal adhesion (FA) signaling pathway in NSCLC cells. Moreover, knockdown of RACK1 inhibited cell motility in the CPNE3-overexpressed NSCLC cells. These findings offer mechanistic insights into the oncogenic roles of CPNE3 and the pivotal effects of CPNE3 as a biomarker and therapeutic target for NSCLC metastasis. PMID- 30519323 TI - A Nomogram Predicting Extrahepatic Metastases for Patients with Adjuvant Transarterial Chemoembolization after Hepatectomy. AB - Background: Prognosis remains poor for hepatocellular carcinoma (HCC) patients with extrahepatic metastases (EHMs). This study aimed to develop a nomogram to predict EHMs in HCC patients who underwent adjuvant transarterial chemoembolization (TACE) following hepatectomy. Methods: Data of 578 HCC patients who underwent TACE after hepatectomy at the Eastern Hepatobiliary Surgery Hospital was retrospectively reviewed. Cox regression analyses was used to select variables to construct the nomogram. Predictive accuracy and discriminative ability of the model were performed using concordance index (C-index), calibration curve and the area under time-dependent receiver operating characteristic (ROC) curve. Results: Postoperative EHMs were detected in 89 and 31 patients in the training cohort (n = 453) and validation cohort (n = 125), respectively. Multivariate analysis showed that tumor size (HR, 1.099; 95% CI, 1.049-1.152), coarse beam type of tumor histopathological structure (HR, 2.382; 95% CI, 1.030-5.512), presence of satellite nodules (HR, 1.936; 95% CI, 1.156 3.244) and alpha-fetoprotein (AFP) (HR, 1.399; 95% CI, 1.098-1.783) were independent risk factors for EHMs (all p < 0.05). The nomogram incorporated these factors achieved good agreement between prediction and actual observation with a concordance index (C-index) of 0.73 (95% CI, 0.68 to 0.78) and 0.71 (95% CI, 0.63 to 0.79) in the training cohort and validation cohort, respectively. In addition, patients who had a nomogram score > 17 were considered to have higher risk for EHMs compared with those scored <= 12. Furthermore, the time-dependent area under the ROC curve indicated comparative stability and adequate discriminative ability of the model. Conclusions: This novel nomogram can identify those with high risk of EHMs after adjuvant TACE following hepatectomy. The validation cohort showed a good performance, suggesting it could benefit surgeons on decision-making. PMID- 30519324 TI - P53 Codon 72 Polymorphism and Risk for Squamous Cell Carcinoma of the Penis: A Caucasian Case-Control Study. AB - Squamous cell carcinoma of the penis is a rare but often aggressive disease. A large proportion of penile cancers are associated with HPV infection, mainly with HPV high-risk subtypes 16 and 18. From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented. The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant. For penile carcinoma there are only sparse data available on this topic. We therefore analyzed the distribution of this p53 codon 72 SNP in a cohort of 107 penile cancer patients and a healthy control group (n=194) using Restriction Fragment Length Polymorphism (RFLP) analysis. After DNA isolation a PCR amplicon including the variant nucleotide was generated. Based on the variant nucleotide this amplicon can be cleaved into two parts or remain unaffected by a restriction enzyme. Subsequent electrophoresis allowed the discrimination of SNP alleles in the investigated sample. Comparison of the allelic variants revealed no significant differences in the distribution of this SNP between cases and controls (p=0,622). There was also no difference in SNP distribution between cases with/without HPV infection (p=0,558) or histologic variants (p=0.339). In order to strengthen the impact of our data we performed a combined analysis of all published data on this topic with our results. This ended up in SNP distribution data from 177 cases and 1149 controls. Overall, there were also no significant differences in the allelic distribution of the p53 codon 72 SNP between either cases and controls (p=0,914) or HPV-positive and HPV negative cases (p=0,486). From this most comprehensive data available to date we conclude that there is no influence of the p53 codon 72 SNP on the risk of development of penile carcinoma in Caucasians even in the presence of HPV. PMID- 30519325 TI - Long Non-coding RNA LINC01234 Regulates Proliferation, Invasion and Apoptosis in Esophageal Cancer Cells. AB - Esophageal cancer is one of the leading malignancies globally and long non-coding RNAs (lncRNAs) have been proved to have an important role in different malignancies including esophageal cancer. However their role in disease progression is still not clear. The objective of the study was to investigate the expression and role of LINC01234 in progression of esophageal cancer cells. LncRNA LINC01234 was found to be upregulated in esophageal cancer cells by chip sequencing. The expression level of LINC01234 was detected from different esophageal cancer cell lines by qRT-PCR. After this, the LINC01234 knockdown effects on cell proliferation, migration, invasion, and apoptosis were evaluated by cell proliferation assay, wound healing assay, invasion assay, and flow cytometric analysis in vitro. Expression of lncRNA LINC01234 was found to be markedly upregulated in the CEC2 cell line. Furthermore, cell proliferation, migration and invasion were significantly (P < 0.05) suppressed as compared to negative control while apoptotic rate was also found increased as a result of the knockdown of LINC01234. Significantly upregulated expression of LINC01234 in CEC2 cells and downregulated expression after knockdown is observed. The impact of LINC01234 knockdown on cell migration, invasion, proliferation and apoptosis indicated that LINC01234 may represent a new marker and a potential therapeutic target for esophageal cancer. PMID- 30519328 TI - Distinct Changes in the Expression TAZ are Associated with Normal Cervix and Human Cervical Cancer. AB - The transcriptional coactivator with the PDZ-binding motif (TAZ) has been associated with different types of cancer. In this study, we examined the TAZ protein expression and cellular localization in 194 cases of human cervical squamous cell carcinoma (SCC). We observed that a normal cervix is characterized by higher expression levels of both nuclear and cytosolic TAZ compared to cervical SCC. Lower membranous and cytosolic TAZ expression levels are associated with lymph node involvement. We observed that TAZ expression levels are associated with beta1 integrin and Src in SCC and cell lines derived from human cervical cancers. Of note, knock down of TAZ increased the expression of beta1 integrin and Src in both normal and human cervical cancer cells. Our data indicate that the expression and cellular localization of TAZ are inversely associated with the development and progression of cervical SCC, and TAZ-mediated transcription may be involved in the activation of the integrin-Src signalling pathway. PMID- 30519327 TI - The Association of Baseline Serum Tumour Markers with Outcome of Patients with Metastatic Colorectal Cancer Treated with Anti-EGFR Monoclonal Antibodies in the First Line. AB - The measurement of serum tumour markers is a simple and non-invasive method for assessing the response to systemic therapies in metastatic colorectal cancer (mCRC) and estimation of prognosis. The aim of our retrospective study was to evaluate the association of baseline serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase (TK) and tissue polypeptide specific antigen (TPS) with outcome of patients with mCRC treated with combination of chemotherapy and monoclonal antibodies against epidermal growth factor receptor (anti-EGFR mAbs) in the first line. In our study, the cohort included 102 patients treated with therapy based on anti-EGFR mAbs between years 2011 and 2017 at Department of Oncology and Radiotherapy, Medical School and University Hospital in Pilsen, Czech Republic. Serum samples were collected within one month before the initiation of treatment. In multivariate Cox analysis that included serum tumour markers and clinical baseline parameters show that high baseline serum CA 19-9 was significantly associated with worse progression free survival (HR=1.871, p=0.0330) and also overall survival (HR=3.903, p=0.0006). We have not demonstrated association of baseline levels of CEA, TK and TPS with patients' outcome. CA 19-9 is commonly used serum tumour marker which is simple and readily available and its candidate prognostic importance in the setting of anti-EGFR therapy deserves to be studied in prospective trials. PMID- 30519326 TI - Predictors of Residual T1 High Grade on Re-Transurethral Resection in a Large Multi-Institutional Cohort of Patients with Primary T1 High-Grade/Grade 3 Bladder Cancer. AB - The aim of this multi-institutional study was to identify predictors of residual high-grade (HG) disease at re-transurethral resection (reTUR) in a large cohort of primary T1 HG/Grade 3 (G3) bladder cancer patients. A total of 1155 patients with primary T1 HG/G3 bladder cancer from 13 academic institutions that underwent a reTUR within 6 weeks after first TUR were evaluated. Logistic regression analysis was performed to assess the association of predictive factors with residual HG at reTUR. Residual HG cancer was found in 288 (24.9%) of patients at reTUR. Patients presenting residual HG cancer were more likely to have carcinoma in situ (CIS) at first resection (p<0.001), multiple tumors (p=0.02), and tumor size larger than 3 cm (p=0.02). Residual HG disease at reTUR was associated with increased preoperative neutrophil-to-lymphocytes ratio (NLR) (p=0.006) and body mass index (BMI)>=25 kg/m2. On multivariable analysis, independent predictors for HG residual disease at reTUR were tumor size >3cm (OR = 1.37; 95% CI: 1.02-1.84, p=0.03), concomitant CIS (OR 1.92; 95% CI: 1.32-2.78, p=0.001), being overweight (OR= 2.08; 95% CI: 1.44-3.01, p<0.001) and obesity (OR 2.48; 95% CI: 1.64-3.77, p<0.001). A reTUR in high grade T1 bladder cancer is mandatory as about 25% of patients, presents residual high grade disease. Independent predictors to identify patients at risk of residual high grade disease after a complete TUR include tumor size, presence of carcinoma in situ, and BMI >=25 kg/m2. PMID- 30519329 TI - Interplay of Tumor Spread, Volume and Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma: Feasibility of An Integrative Risk Stratification Scheme. AB - Purpose: To investigate the inter-correlation of tumor spread, volume and quantitative plasma Epstein-Barr virus DNA level (pEBV DNA), and to further assess the prognostic efficacy of a novel risk stratification combining anatomic, volumetric and biological features in nasopharyngeal carcinoma (NPC). Methods and Materials: One hundred and twelve patients with non-metastatic NPC were prospectively enrolled. Correlation of pEBV DNA with tumor invasiveness, lymph node (LN) metastasis, tumor volume and classification was tested by univariate and multivariate analyses. 5-year distant metastasis free survival (DMFS) was evaluated using Kaplan-Meier method and Cox proportional hazards model. Results: Tumor volume, TNM stage and pEBV DNA were strongly inter-correlated to each other. Nodal volume, skull base invasion and LN metastasis to supraclavicular fossa were determined to be independent predictors for pEBV DNA level. To exclude collinearity, a risk stratification based on combination of EBV DNA, nodal volume and anatomic features was established, offering significant distinguishing ability in 5-year DMFS. Further multivariate Cox regression analysis found the novel stratification to be independent predictor of DMFS. Conclusions: Both anatomic spread and tumor volume contribute to pEBV DNA level, leading to strong inter-correlation between NPC stage, volume and EBV DNA. The proposed risk stratification combining anatomic, volumetric and biological features showed potential in refining DMFS prediction. PMID- 30519330 TI - Prognostic Impact of TTF-1 Expression in Non-Squamous Non-Small-Cell Lung Cancer: A Meta-Analysis. AB - Thyroid transcription factor-1 (TTF-1) is overexpressed in up to 95% of primary lung adenocarcinoma while negative for almost all squamous cell carcinomas. TTF-1 expression has been investigated as a prognostic factor in non-small-cell lung cancer (NSCLC) with conflicting results. We conducted this meta-analysis to gain a better insight into the prognostic role of TTF-1 in patients only with non squamous (non-SQ) NSCLC. A systematic computerized search of the electronic databases including PubMed, PMC, EMBASE, Web of Science, and Cochrane Library was performed. From 21 studies, 6,451 patients were included in the combined analysis of hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival. Compared with patients with non-SQ NSCLC showing negative TTF-1 expression, those with tumors harboring TTF-1 overexpression had significantly better survival (HR = 0.49, 95% CI: 0.42-0.57, p < 0.00001). Subgroup analyses revealed that TTF-1 expression significantly correlated with a better prognosis in stage I (HR = 0.65, 95% CI: 0.50-0.84, p = 0.0008) as well as stage III-IV non-SQ NSCLC (HR = 0.38, 95% CI: 0.29-0.49, p < 0.00001). In conclusion, this meta-analysis demonstrates that TTF-1 overexpression is a favorable prognostic factor in patients with non-SQ NSCLC. The subgroup analyses indicate that TTF-1 is a good prognostic marker for survival not only in early-stage but also in advanced non SQ NSCLC. PMID- 30519331 TI - Prognostic Value of Lymphocyte Activation Gene-3 (LAG-3) Expression in Esophageal Squamous Cell Carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor with a high incidence in East Asia and the Middle East. The outcomes for ESCC patients are usually not optimal due to the recurrence and metastasis. This study is aim to examine the expression and the prognostic value of LAG-3 in ESCC. We applied immunohistochemistry analysis to examine the expression of LAG-3, CD4 and CD8 in 287 ESCC cohorts. Our study demonstrated that the decreased LAG-3 expression was significantly associated with CD4 tumor-infiltrated lymphocytes (TILs) (p=0.000), CD8 TILs (p=0.000), and the advanced clinical stages (p=0.041) by Chi-square analysis. Kaplan-Meier survival analysis revealed that higher LAG-3 expression were positively correlated with a better overall survival (OS) (p=0.010) and better progression free survival (PFS) (p=0.006), especially in the patients at stages T1-2 status (p=0.001, OS; p=0.001, PFS), N0 status (p=0.036, OS; p=0.050, PFS), and early stages (I-II) (p=0.006, OS; p=0.008, PFS). Both high of CD4 TIL /CD8 TIL ratio and LAG-3 expression were correlated with longer OS and PFS. Cox proportional hazards regression analysis showed that LAG-3 is an independent biomarker of survival (HR, 0.724; 95% CI 0.526-0.995; p = 0.047) (p=0.036). Taken together, we found that high expression of LAG-3 was correlated with an improved survival and LAG-3 is an independent predictor of survival, suggesting that LAG-3 may serve as a useful immune marker for the prognosis of ESCC. PMID- 30519332 TI - FABP1 Polymorphisms Contribute to Hepatocellular Carcinoma Susceptibility in Chinese Population with Liver Cirrhosis: A Case-Control Study. AB - Purpose: Single nucleotide variations in the liver fatty acid binding protein (L FABP, FABP1) gene lead to changes in cellular signaling pathways and lipid metabolism. FABP1 polymorphisms were associated with some liver diseases, like steatotic hepatocellular carcinoma. However, the association between FABP1 rs1545224 and rs2241883 polymorphisms and hepatitis B virus-related liver cirrhosis (LC) and hepatocellular carcinoma (HCC) has not been reported. We performed this study to explore their relationship. Methods: One thousand individuals (250 healthy controls, 250 chronic HBV (CHB), 250 LC, and 250 HCC patients) were recruited. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were applied to assess the difference in allele and genotype frequencies. Cochran-Armitage trend test was used to evaluate the cumulative effect. Significant difference would be defined when the P value was less than 0.05. Results: The distribution of rs1545224 GG, AG and AA genotypes in healthy controls or CHB carriers was not significant when compared to LC or HCC patients (P>0.05). LC patients carrying at least one A allele are more likely to develop HCC in contrast with those with G allele (P<0.05). After adjustment for confounders, meaningful results were only seen in the comparison between rs1545224 AG+AA genotype carriers and GG genotype carriers among the LC patients (P<0.05). Rs2241883 polymorphism did not influence the risk of developing LC or HCC in healthy and CHB individuals, nor did it influence the risk of HCC in LC patients (P>0.05). Conclusions: Taken together, FABP1 rs1545224 polymorphism might increase HCC risk in LC patients, indicating that FABP1 rs1545224 polymorphism may be related to the process of developing HCC in Chinese patients with LC. PMID- 30519333 TI - Effect of Liposomal Doxorubicin in Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). AB - Background: This ex-vivo study was performed to compare the impact of doxorubicin vs. liposomal doxorubicin on penetration depth in peritoneal tissue during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) via microcatheter (MC). Methods: Fresh post mortem swine peritoneum was cut into proportional sections. One group of samples was treated with PIPAC with Doxorubicin (D), and the other was treated with PIPAC with liposomal doxorubicin (LD). Tissue specimens were placed as follows: at the bottom of the plastic box (1), at the side wall (2), at the top cover (3) and the side of the box covered by a plastic tunnel (4). In tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Results: Medium penetration levels with D were 325 um (1), 152 um (2), 84 um (3) and 71 um (4), respectively. Medium penetration levels with LD were significantly lower with 10 um (1), 2 um (2), 0 um (3) and 0 um (4), respectively. In most samples that were treated with LD no doxorubicin could be detected at all. Conclusion: Our data indicate that liposomal coating of doxorubicin and possibly other chemotherapeutical drugs might inhibit their interaction with the peritoneal surface. This inhibition appears to be relatively strong, since doxorubicin is partially undetectable due to liposomal coating. Further studies are warranted to investigate this interaction and its potential benefit in peritoneal applications. PMID- 30519334 TI - Incidence and Survival Outcomes of Breast Cancer with Synchronous Hepatic Metastases: A Population-Based Study. AB - Background: Little is known about the clinical features of breast cancer with synchronous hepatic metastases (BCSHM). In this retrospective study, we aimed to feature the incidence and survival outcome of BCSHM. Methods: Data from the 2016 SEER*Stat database (version 8.3.2) was used. The effect of patient and tumor characteristics on the odds of developing of BCSHM was analyzed. Survival was investigated using Kaplan-Meier and Cox regression analyses. A competing risk model was also applied to further investigate cancer-specific survival. Results: Of 240911 patients with breast cancer, we identified 3468 patients (1.44%) with BCSHM. Tumor subtypes distribution of BCSHM were 45.3% HR+/HER2-, 12.2% HR+/HER2+, 7.83% HR-/HER2+ and 15.0% triple-negative subtype. The median OS of the entire cohort was 14 months, and only about 13.5% of patients survived at 3 years. Median survival was significantly shorter in triple-negative cohort (8 months) and gradually increased in HR+/HER2- (19 months), HR-/HER2+ (22 months) and HR+/HER2+ (33 months) cohorts (P<0.05). Patients BCSHM were more likely to be young age (odds ratio [OR] 1.4, 95% CI 1.0-2.0), black race (OR 1.13, 95%CI 1.11 1.37), higher tumor grade (OR 3.58, 95%CI 2.29-5.59), unmarried status (OR 3.5, 95%CI 2.1-5.7), HR-/HER2+ (OR 4.07, 95%CI 3.56-4.67), HR+/HER2+ (OR 2.5, 95%CI 2.24-2.80) and triple-negative subtypes (OR 1.64, 95%CI 1.44-1.86). Poor prognostic factors were the aged (hazard ratio 3.75, 95%CI 3.56-4.67), black race (hazard ratio 1.17, 95%CI 1.03-1.31), triple-negative subtype (hazard ratio 2.23, 95%CI 1.95-2.56) and higher grade (hazard ratio 1.32, 95%CI 1.03-1.68). Conclusion: In conclusion, patients with BCSHM had a poor survival, and only 13.5% of them were alive more than 3 years. Young patients with HER2+ tumors had higher risk for developing BCSHM, but with better prognosis. PMID- 30519335 TI - Autophagy Plays a Critical Role in Insulin Resistance- Mediated Chemoresistance in Hepatocellular Carcinoma Cells by Regulating the ER Stress. AB - The high mortality of hepatocellular carcinoma (HCC) patients is associated with several independent risk factors including type 2 diabetes mellitus (T2DM) and insulin resistance (IR), which could be caused by various pathological processes such as tumorigenesis and inflammation in the liver. In previous report, we declared that IR contributes to multidrug resistance in HCC by activation of endoplasmic reticulum (ER) stress. Here, our study revealed that the enhanced autophagy induced by IR significantly prompts the chemotherapeutic drug resistance in hepatoma cells, which was validated by stimulation and inhibition of the autophagy respectively. A potential reason is that autophagy acts as a regulator of ER stress in the IR-mediated chemoresistance in HCC. In conclusion, autophagy facilitates the HCC survival in chemotherapeutic drug treatment by maintaining the homeostasis in the ER indicating the regulatory role of autophagy in ER stress contributes to IR-mediated chemoresistance in hepatocellular carcinoma cells. Collectively, these data implied inhibition of autophagy is a potential treatment of inherent IR-mediated chemoresistance in HCC. PMID- 30519336 TI - The Clinical and Biomarker Association of Programmed Death Ligand 1 and its Spatial Heterogeneous Expression in Colorectal Cancer. AB - Background: Programmed death ligand 1 (PD-L1) expression has been shown to predict benefit from anti-PD-1 treatment in several cancers. However, its predictive value in colorectal cancer seems limited. This study was aimed to explore the clinical and biomarker association of programmed death ligand 1 and its spatial heterogeneous expression in colorectal cancer. Methods: Tissue microarrays of 422 primary colorectal cancers from our hospital were used for the interpretation of PD-L1 and programmed death 1 (PD-1) expression, cluster of differentiation 4 (CD4) and CD8 density and microsatellite instability (MSI) status by immunohistochemistry. To assess the spatial heterogeneity of PD-L1 expression, Tissue microarrays of 383 paired intra-primary-tumor tissues, and 105 paired lymph node metastatic tumors and 64 paired distant metastatic tumors were also used. Results: PD-L1 was positive in 188 (44.5%) primary colorectal cancers. PD-L1 expression was associated with less advanced N category (P<0.001), less advanced TNM stage (P<0.001) and less nervous invasion (P=0.04). Higher PD-L1 expression was associated with higher PD-1 expression (P<0.001), higher CD4 (P<0.001) and CD8 (P<0.001) density and DNA mismatch repair deficiency (P=0.01). PD-L1 expression was associated with better disease-free survival and overall survival, but it was only an independent prognostic factor for disease-free survival (hazard ratio and 95% confidence interval: 0.42 [0.25-0.72], P<0.001). The probability of inconsistent PD-L1 expression was respectively 17.8%, 31.4% and 39.1% within primary tumors, between primary tumors and lymph node metastatic tumors, and between primary tumors and distant metastatic tumors. All the three differences were statistically significant (P<0.001, P<0.001 and P=0.05, respectively). Conclusions: PD-L1 expression was a marker of pre-existing immune responses in colorectal cancer, however, it was heterogeneously expressed in colorectal cancer, especially between primary and metastatic tumors. This might partially explain the low-efficiency of its predictive value for benefit from anti-PD-1 treatment. PMID- 30519337 TI - ABO Blood Type Has No Impact on Survival in Patients with Epithelial Ovarian Cancer. AB - Evidence for an association between ABO blood type and epithelial ovarian cancer (EOC) survival has so far been limited and conflictive. This study applied a retrospective cohort and included 627 EOC patients diagnosed at Shengjing Hospital of China Medical University between 2011 and 2015. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) between the ABO blood type and progression-free survival (PFS) and overall survival (OS) of EOC patients were assessed using multivariable Cox proportional regression models. The median follow-up duration was 2.97 years (inter-quartile range from 2.11 to 4.13 years). The recurrence and mortality rates were 41.5% (260/627) and 37.0% (232/627), respectively. Possessing a comorbidity, residual disease, ascites, and advanced FIGO stage (III/IV) were associated with worse PFS and OS of EOC patients. The distribution of blood types O, A, B, and AB among patients was 27.4%, 31.3%, 33.2%, and 8.1%, respectively. Compared with blood type O, none of the blood types (A, B, and AB) were significantly associated with PFS or OS. However, in the stratified analyses, we found borderline significant results for PFS with blood type AB (HR = 0.56, 95% CI = 0.31-1.01) compared with blood type O. No significant differences were observed for blood type A when compared with all non A blood type cases. This study does not support an association between ABO blood type and EOC survival. Further prospective cohort studies are warranted to confirm our findings. PMID- 30519338 TI - Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan. AB - The most frequently reported genetic aberration among polycythemia vera (PV) patients is a gain of function mutation V617F in exon 14 of Janus kinase 2 (JAK2) gene. However in many investigations, V617F negative PV patients have been reported to harbor mutations in JAK 2 exon 12. We investigated 24 patients with PV (diagnosed following 2016 WHO guidelines) to detect V617F mutation through allele specific PCR. The frequency of which was found to be 19/24 (79.2 %). Later on JAK2 exon 12 and 14 was amplified by conventional PCR in V617F negative patients and subjected to sequence analysis. A total of 03 mutated sites in exon 12 were detected in only two V617F-negative patients 2/5 (40%). All three substitutions were heterozygous i.e. F537F/I found in both patients and R528R/T, which is a novel mutation. In addition, one patient 1/5 (10%) manifested amino acid substitution V617A in JAK2 exon 14. Hematological parameters of individuals harboring mutations do not vary significantly than rest of the PV patients. Previous history and 2.3 years of follow-up studies reveal 15-year survival of V617F positive patients (n=19) to be 76%, while it is 94% for wild type V617 patients (n=05). Mean TLC of the patient cohort was 17.6+/- 9.1 x 109/L, mean platelet count was 552+/- 253 x 109/L, mean hemoglobin was 16.9+/- 3.2 g/dl, mean corpuscular volume (MCV) was 77.2+/- 13.0 fl and mean corpuscular hemoglobin (MCH) was 25.6+/- 3.9 pg. This is the very first attempt from Pakistan to screen JAK2-exon 12 mutations in PV patients. We further aim to investigate Jak2 exon 12 mutations in larger number of PV patients to assess their clinical relevance and role in disease onset, progression and transformation. PMID- 30519339 TI - Prognostic Value of the Cycle Number of Perioperative Chemotherapy in Locoregionally Advanced Rectal Cancer: a Propensity Score Matching Analysis. AB - Background: Appropriate cycle number of perioperative chemotherapy for patients with locoregionally advanced rectal cancer (LARC) remains unknown. This study aimed to evaluate how cycle number of perioperative chemotherapy influenced the prognosis of LARC patients. Methodology / Principal Findings: In this study, a total of 388 consecutive patients were enrolled and retrospectively reviewed if they were diagnosed with untreated stage cII-III LARC and treated with neoadjuvant chemoradiotherapy plus radical surgery followed by adjuvant chemotherapy or not. After grouping by the postoperative pathologic stage (yp0-I vs. ypII-III), propensity score matching was performed in each group to balance baseline characteristics between the patients treated with chemotherapy cycle <= 7 and those treated with chemotherapy cycle >= 8. The chemotherapy cycle was analyzed for its association with the survivals of the matched patients in the 2 groups, respectively. And the incidence of treatment-related complications was also compared. Through analysis, chemotherapy cycle >= 8 appeared to predict better overall, disease-free and distant-metastasis-free survivals in the whole cohort of matched patients (P values were 0.003, 0.002 and 0.004, respectively) and the ypII-III group (P values were 0.006, 0.005 and 0.014, respectively). But in the yp0-I group, chemotherapy of 8 cycles or more brought no improvement of survivals but only more acute toxicities (83.5% vs. 57.0%, P < 0.001). Conclusions / Significance: Chemotherapy cycle >= 8 was proven associated with improved prognosis of LARC patients, especially those with ypII-III disease. But prolonged chemotherapy should be performed with caution in patients with yp0-I stage. PMID- 30519340 TI - Prognostic Values of LAPTM4B-35 in Human Cancer: A Meta-analysis. AB - Background: Lysosome-associated protein transmembrane-4beta-35(LAPTM4B-35) has been observed overexpressed in multiple malignant tumors. However, the prognostic value of LAPTM4B-35 remains controversial. Therefore, we conducted a meta analysis to evaluate the prognostic value of LAPTM4B-35 in human cancers. Methods: The relevant publications were obtained by systematically searching the PubMed, Web of Science, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the prognosis value of LAPTM4B-35 for cancer patient. Results: Our result suggest that LAPTM4B-35 overexpression is significantly associated with poor overall survival (OS) (HR = 2.49, 95% CI = 1.87-3.32, p < 0.001), disease-free survival (DFS) (HR = 2.43, 95% CI = 1.35 4.35, p = 0.003), and progression-free survival (PFS) (HR = 4.12, 95% CI = 2.30 7.37, p < 0.001). Moreover, subgroup analysis revealed significant association with poor OS in lung (HR = 2.05, 95% CI = 1.37-3.06, p < 0.001), gastric carcinoma (HR = 1.88, 95% CI = 1.01-3.50, p < 0.047) and ovarian cancer (HR = 4.94, 95% CI = 1.44-16.94, p = 0.011). Conclusion: LAPTM4B-35 may be a novel predictive biomarker and a potential target for treatment. PMID- 30519341 TI - Promotion of Cell Proliferation through Inhibition of Cell Autophagy Signalling Pathway by Rab3IP is Restrained by MicroRNA-532-3p in Gastric Cancer. AB - Background: RAB3A-interacting protein (Rab3IP) is known to be involved in cancer; however, its function during the proliferation of gastric cancer (GC) cells remains unknown. Therefore, this study aimed to explore the potential function of Rab3IP in GC. Methods: The expression of Rab3IP and its clinical pathology value were determined by quantitative real-time PCR and immunohistochemistry. Rab3IP (knockdown and overexpression) and light chain 3 (LC3) lentiviruses were transfected into GC cells, and cell proliferation was measured using cell counting kit-8, plate clone formation, flow cytometry, and tumorigenesis assays. Cell autophagy was measured using a confocal laser scanning microscope and by western blotting. Luciferase reporter assay was performed to analyse the regulation of Rab3IP by microRNA-532-3p (miR-532-3p). Results: Overexpression of Rab3IP in GC samples enhanced the cell proliferation ability, but decreased the number of autophagosomes and expression of LC3-II and sequestosome-1 (SQSTM1 or p62) markers. Furthermore, we found that miR-532-3p can bind to the 3'UTR region of RAB3IP and inhibit the proliferation ability of GC cells. Further, the expression of miR-532-3p negatively correlated with that of Rab3IP. Conclusions: Our study elucidates the central role of Rab3IP in inducing proliferation of GC cells through its involvement in autophagy. miR-532-3p directly targets Rab3IP and represses its function, thereby demonstrating a novel regulatory link in GC. PMID- 30519342 TI - PD-1 Blockade Overcomes Adaptive Immune Resistance in Treatment with Anchored-GM CSF Bladder Cancer Cells Vaccine. AB - Purpose: To investigate whether PD-L1 mediated adaptive resistance could occur in treatment with Anchored-GM-CSF vaccine and whether PD-1 blockade combined with Anchored-GM-CSF vaccine could induce a greater anti-tumor immune response than either immunotherapy alone. Materials and Methods: After establishing long established subcutaneous metastasis bladder cancer models, mice were treated with Anchored-GM-CSF vaccine and/or anti-PD-1 antibody. T-lymphocyte-cytotoxicity, flow cytometric analysis, immunohistochemical, immunofluorescence staining, CD8+ T cell apoptosis and enzyme-linked immunosorbent assays were performed to evaluate the efficacy of combination therapy with anchored-GM-CSF vaccine and PD 1 blockade and to explore the related mechanism. Results: Anchored-GM-CSF vaccine could significantly increase the number of mature DCs and up-regulate PD-L1 expression dependent on IFN-gamma released from CD8+ T cells. Anchored-GM-CSF vaccine combined with anti-PD-1 antibody could effectively inhibit tumor growth and even cause regression of the established tumor. More CD4+ and CD8+ T cells appeared at tumor sites and in peripheral blood in the combination therapy group than in the control groups. Splenocytes from mice of the combination therapy group exhibited the most potent cytotoxicity to MB49 cells. Apoptotic assays showed that PD-1 blockade could significantly reduce CD8+ T cells apoptosis. Conclusions: Anchored-GM-CSF vaccines and anti-PD-1 antibodies have synergistic effects in metastatic bladder cancer treatment. PD-1 blockade can overcome immune resistance in treatment with the Anchored-GM-CSF vaccine, while Anchored-GM-CSF vaccine can enhance the efficacy of PD-1 blockade therapy. PMID- 30519343 TI - A Nomogram Based on a TRUS Five-Grade Scoring System for the Prediction of Prostate Cancer and High Grade Prostate Cancer at Initial TRUS-Guided Biopsy. AB - Purpose: To evaluate the efficacy of transrectal ultrasound five-grade scoring system (TRUS-5) in predicting prostate cancer (PCa) and high grade PCa (HGPCa), compared with TRUS two-grade scoring system (TRUS-2), and establish a TRUS-5 based nomogram for the prediction of PCa and HGPCa at initial biopsy (IPBx). Methods: Data were collected from 862 men who underwent initial TRUS-guided 12 core prostate biopsy. Age, prostate-specific antigen (PSA), percent free PSA, digital rectal examination (DRE), prostate volume (PV), PSA density (PSAD) and TRUS findings were included in the analysis. For TRUS-5, the probability of PCa was quantified on a scale from 1 (benign) to 5 (malignant). TRUS-2 used the grades "normal" and "suspicious". After univariate and multivariate logistic regression analyses, nomogram models were developed and internally validated based on independent predictors to predict the probability of PCa and HGPCa. Results: Overall PCa was detected in 42% (362/862) with 26.22% (226/862) showing HGPCa. TRUS-5 significantly outperformed TRUS-2 for the risk prediction of PCa and HGPCa (area under the receiver operating characteristic curve [AUC]: 0.787 vs. 0.694 for PCa, 0.841 vs. 0.713 for HGPCa, P<0.05). The TRUS-5 based nomogram showed higher AUCs (0.905 for PCa, 0.903 for HGPCa) than PSA alone, clinical base model, the TRUS-2 based model, and other predictive models (P<0.05). Conclusions: TRUS-5 represents a better imaging predictor than TRUS-2 for PCa and HGPCa. Our TRUS-5 based nomogram models performed well for the prediction of PCa and HGPCa at IPBx, which may help to make the decision to biopsy. PMID- 30519344 TI - Oncolytic Adenovirus Harboring Interleukin-24 Improves Chemotherapy for Advanced Prostate Cancer. AB - PURPOSE: Oncolytic adenoviruses emerge as new agents for cancer therapy. This study aimed to investigate the synergistic anti-tumor activity of oncolytic adenovirus armed with IL-24 (ZD55-IL-24) and docetaxel (DTX) on advanced prostate cancer in vitro and in vivo. METHODS: DU145 prostate cancer cells or nude mice xenografted with DU145 prostate cancer cells were treated by ZD55-IL-24 and DTX alone or in combination. RESULTS: DTX did not affect ZD55-IL-24 replication and IL-24 expression in DU145 cells. In vitro, the combination of ZD55-IL-24 and DTX showed synergistic inhibitory effects on prostate cancer cell viability and invasion. In vivo, ZD55-IL-24 and DTX synergistically inhibited the growth and activated the apoptosis of DU145 xenografts, accompanied by significantly decreased PARP-1 levels and increased caspase-3 and caspase-8 levels as well as decreased CD31 expression. CONCLUSION: We reported the synergistic anti-tumor efficacy of ZD55-IL-24 and DTX on prostate cancer. Our results suggest that chemotherapy combined with oncolytic adenovirus mediated gene therapy is a promising strategy for the treatment of advanced prostate cancer. PMID- 30519345 TI - Outcomes of Laparoscopic Total Gastrectomy for Elderly Gastric Cancer Patients. AB - Purpose: The purpose of this study was to compare the short- and long-term outcomes after laparoscopic total gastrectomy (LTG) between elderly and non elderly patients with gastric cancer. Methods: A retrospective analysis was performed using clinical and follow-up data from 168 patients treated with LTG for gastric cancer at our institution from January 2010 to December 2017. For this study, the short- and long-term outcomes (including tumor recurrence rate, disease-free survival rate, and overall survival rate) were compared between the elderly group (>=70 years) and non-elderly group (<70 years). Results: The preoperative American Society of Anesthesiologists score and Charlson Comorbidity Index were higher in the elderly group than in the non-elderly group, while there was no significant difference between the two groups in terms of operation duration, intraoperative blood loss, and rate of conversion to laparotomy. The incidence of postoperative 30-day complications in the elderly group was higher than that in the non-elderly group due to a higher incidence of pulmonary infection, while the incidence of major complications was similar in both groups. The tumor recurrence rate was also similar in both groups. There was no statistically significant difference between the two groups in terms of 5-year disease-free survival and 5-year overall survival rate. Conclusions: LTG is safe and feasible for elderly patients with gastric cancer and is associated with relatively good long-term outcomes. PMID- 30519346 TI - The prognostic value of Cyclin-Dependent Kinase 5 and Protein Phosphatase 2A in Gastric Cancer. AB - Purpose To discuss the relationship between the clinicopathological data, long term survival of gastric cancer patients and different expression levels of Cyclin-Dependent Kinase 5 (CDK5) and Protein Phosphatase 2A (PP2A). Method The expression levels of CDK5 and PP2A were detected by immunohistochemistry in specimens from 124 patients with primary gastric cancer. The correlation among the expression of CDK5 and PP2A, clinicopathological factors and prognosis was investigated. Result The expression level of CDK5 was correlated with the TNM stage (p=0.030) and N stage (p=0.001), while the expression level of PP2A was correlated with the TNM stage and N stage (p=0.001 and p=0.004) as well as the degree of differentiation (p=0.046). The expression of CDK5 was positively correlated with the expression of PP2A in gastric cancer. Co-expression of CDK5 and PP2A is an independent prognostic factor that affected overall survival, and provided more accurate prognostic value for the overall survival of gastric cancer patients. Conclusion The expression of CDK5 and PP2A is positively correlated in gastric cancer. Co-expression of CDK5 and PP2A was an independent prognostic factor in patients with gastric cancer. PMID- 30519347 TI - Myotilin, a New Topotecan Resistant Protein in Ovarian Cancer Cell Lines. AB - Background: Low effectiveness of chemotherapy in ovarian cancer results from development of drug resistance during treatment. Topotecan (TOP) is a chemotherapeutic drug used in second-line chemotherapy of this cancer. Unfortunately, during treatment cancer can develop diverse cellular and tissue specific mechanisms of resistance to cytotoxic drugs. Methods: We analyzed development of TOP resistance in ovarian cancer cell lines (A2780 and W1). On the base of our previous results where a set of "new genes" with different functions that can be related to TOP-resistance was described hereby we performed detailed analysis of MYOT expression. MYOT mRNA level (real time PCR analysis), protein expression in cell lysates and cell culture medium (western blot analysis) and protein expression in cancer cells (immunofluorescence analysis) were determined in this study. Results: We observed increased expression of MYOT in TOP resistant cell lines at both mRNA and protein level. MYOT, together with extracellular matrix molecules like COL1A2 and COL15A1 were also secreted to corresponding cell culture media. Conclusion: Our results suggest that upregulation of MYOT can be related to TOP resistance in ovarian cancer cell lines. PMID- 30519348 TI - Age at First Birth and the Risk of Endometrial Cancer Incidence: A Pooled Analysis of Two Prospective Cohort Studies among Japanese Women. AB - Background: Age at first birth has been increasing among women in developed countries. Meanwhile, endometrial cancer has also been increasing worldwide, being one of the most common female hormone-related cancers. The purpose of this study was to examine the association between age at first birth and the risk of endometrial cancer among Japanese women, and to examine the hypothesis that the recent increase in endometrial cancer incidence can be partly explained by the trend for increasing age at first birth. Methods: We conducted a pooled analysis of two prospective studies among residents in Miyagi Prefecture in rural northern in Japan. The Miyagi Cohort Study started in 1990 and included 21,455 parous women. The Ohsaki Cohort Study started in 1994 and included 17,287 parous women. The subjects responded to a self-administrated questionnaire including reproductive factors such as age at first birth. Incident cases of cancer were identified through linkage to the Miyagi Prefectural Cancer Registry, which covers the study area. Results: In a consortium of two prospective studies with 598,933 person-years, we identified 105 incident case of endometrial cancer. Compared with women aged 22 years or less at first birth, multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of endometrial cancer were 0.79 (0.49-1.26) for women aged 23 to 25 years at first birth, and 0.53 (0.28-1.00) for those aged 26 years and older (p-trend<0.05). Conclusion: This pooled analysis of two prospective studies does not support the hypothesis that the recent increase in the incidence of endometrial cancer can be partly explained by the increase in the age at first birth. PMID- 30519349 TI - TFF3 Contributes to Epithelial-Mesenchymal Transition (EMT) in Papillary Thyroid Carcinoma Cells via the MAPK/ERK Signaling Pathway. AB - Trefoil factor 3 (TFF3) was found to be overexpressed in many types of tumours. Evidence has shown that TFF3 plays an important role in tumour proliferation, migration and invasion metastasis. However, the impact of TFF3 on patients' clinicopathological characteristics and underlying mechanisms remain unknown in papillary thyroid carcinoma (PTC). In this study, the expression of TFF3 and the epithelial-mesenchymal transition (EMT) transcriptional factor Snail in PTC and para-carcinoma specimens was evaluated by immunohistochemistry (IHC) and Western blot, and the possible associations with lymph node (LN) metastasis and other clinicopathological parameters were analysed. In vitro, the effect of TFF3 on the malignant behaviour of TPC-1 cells was evaluated by cell proliferation assays, cell adhesion assays, colony formation assays, wound-healing assays and transwell chamber invasion assays. EMT markers and regulatory molecules were detected by quantitative RT-PCR (qRT-PCR) and Western blot analysis in the TFF3-knockdown groups and shRNA control group. The results showed that TFF3 was upregulated in PTC tissue and was associated with lymph node metastasis (P=0.0001), pathological grade (P=0.0002) and Snail expression (P=0.0001). The knockdown of TFF3 markedly inhibited the abilities of TPC-1 cell proliferation, adhesion, colony formation, migration and invasion. Mechanically, the results demonstrated that TFF3 might activate the MAPK/ERK signalling pathways, affect the expression of the transcription factors snail and slug in addition to affecting EMT associated markers E-cadherin and N-cadherin, and accelerate the progression of EMT in TPC-1 cells. These findings indicate that TFF3 might promote the metastatic potential of PTC by promoting the EMT process through cascades of MAPK/ERK pathways. PMID- 30519350 TI - Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor. AB - MPHOSPH1, which is one of the kinesin superfamily proteins, has been reported to play an essential role in the carcinogenesis and progression of several kinds of cancers. MPHOSPH1 has also been suggested to be involved in STAT3 phosphorylation in hepatocellular carcinoma. However, the biological behavior of MPHOSPH1 in testicular germ cell tumors (TGCTs) is unclear at present. The purposes of this study were to investigate the correlation between the expression of MPHOSPH1 and clinicopathological factors and to examine the efficacy of MPHOSPH1 target therapy in TGCTs. We investigated 75 formalin-fixed paraffin-embedded TGCT samples, containing a total of 86 germ cell tumor components, by immunohistochemistry and 12 frozen samples by Western blotting. Moreover, we carried out in vitro studies to clarify the antitumor effect of MPHOSPH1 knockdown in embryonal carcinoma cell lines, NEC8 and NEC14, using small interference RNA (siRNA). A significantly high expression of MPHOSPH1 was recognized in embryonal carcinoma and yolk sac tumor components compared to the seminoma component (p<0.001, respectively). Clinically, non-seminoma cases are known to have worse prognosis than pure-seminoma cases. Interestingly, high MPHOSPH1 expression was associated with distant metastasis (p=0.001), and thus with advanced-stage disease in this study. High expression of MPHOSPH1 interacted with high expression of phosphorylated STAT3 (p=0.01). The in vitro experiments demonstrated that MPHOSPH1 interruption by siRNA resulted in a significant reduction of cell migration, invasion, proliferation and colony formation in both embryonal carcinoma cell lines (p<0.001, respectively). In conclusion, MPHOSPH1 may be a potential treatment option for TGCTs, and its expression may be a novel biomarker of poor prognosis. PMID- 30519351 TI - Tenascin-C Modulates Cell Cycle Progression to Enhance Tumour Cell Proliferation through AKT/FOXO1 Signalling in Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a disease with an extremely poor prognosis that is characterized by a rich extracellular matrix (ECM). Tenascin-C (TNC) is a component of the ECM and plays a role in tumour progression. In this study, we reported that TNC is overexpressed in PDAC tissues and is correlated with tumour stage and cyclin D1 expression. Cyclin D1 is key regulator of the cell cycle G1/S transition. Further experiments revealed that TNC promotes G1/S transition through AKT signalling. TNC/AKT increases the expression of cyclin D1 by enhancing the transcriptional activity of beta-catenin, whereas the translocation of FOXO1 from the nucleus results in the downregulation of p27Kip1. Cyclin D1 and p27Kip1 regulate the activity of cyclin D1-CDK4 complexes and retinoblastoma (Rb), and then they stimulate the progression of G1/S transition and tumour cell proliferation. In conclusion, TNC exerts its activating effect on the proliferation of pancreatic cancer cells in vitro and in vivo through its functional target AKT/FOXO1/beta-catenin. The molecular mechanisms that drive PDAC progression will be useful for the development of molecular markers and the evaluation of patient prognosis. PMID- 30519352 TI - Identification of Grade-associated MicroRNAs in Brainstem Gliomas Based on Microarray Data. AB - Gliomas arising in the brainstem are rare tumours that are difficult to surgically resect, and the microRNAs (miRNAs) and signalling pathways associated with brainstem gliomas (BSGs) are largely unknown. To identify grade-associated miRNAs in BSGs, a microarray analysis of 10 low-grade and 15 high-grade BSGs was performed in this study. Differentially expressed miRNAs (DE-miRNAs) were identified, and the functional DE-miRNAs were selected. The potential target genes and enriched pathways were analysed, and a target gene-associated protein protein interaction (PPI) network was generated. Grade-associated functional DE miRNAs were confirmed by real-time quantitative PCR. First, 28 functional DE miRNAs, including 13 upregulated miRNAs and 15 downregulated miRNAs, were identified. Second, 2546 target genes that were involved in BSG-related pathways, such as signalling pathways regulating the pluripotency of stem cells, the AMPK signalling pathway, the HIF-1 signalling pathway, the PI3K-Akt signalling pathway, the Wnt signalling pathway and the Hippo signalling pathway, were screened. Third, PHLPP2 and VEGFA were identified as hub genes in the PPI network. Last, we found that hsa-miR-34a-5p inhibits BSG cell invasion in vitro. In summary, using integrated bioinformatics analysis, we have identified the potential target genes and pathways of grade-associated functional DE-miRNAs in BSGs, which could improve the accuracy of prognostic evaluation. Furthermore, these hub genes and pathways could be therapeutic targets for the treatment of BSGs. PMID- 30519353 TI - Feasibility and Efficacy of Simultaneous Integrated Boost Intensity-modulated Radiation Therapy based on MRI-CT fusion in Patients with Brain Metastases of Non small Cell Lung Cancer. AB - Purpose: To assess the feasibility and therapeutic effects of simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) based on the fusion imaging of magnetic resonance imaging (MRI) and computed tomography (CT) as a dose-intensive technique in patients with brain metastases (BM) of non-small cell lung cancer (NSCLC). Methods and materials: Forty-six NSCLC patients with 1 to 7 brain metastases were enrolled in this retrospective study between November, 2011 and February, 2017. Thirty-one patients (67.4%) had 1-3 metastases (oligometastases), otherwise, more than 3 metastases were seen in only 15 patients (32.6%). GTV (Gross tumor volume) contouring was based on the fusion imaging of MRI-CT, WBRT was prescribed in 37.5 Gy/15 fractions with a simultaneous boost in the metastatic lesions of 52.5 Gy/15 fractions. Results: The median overall survival (OS) and intracranial progression free survival (PFS) for all the patients were 20.0 months and 11.0 months, respectively. The 6-month and 1-year OS were 87.0% and 69.6% respectively, while the 6-month and 1-year PFS were 78.3% and 43.5% respectively. Until the end of the follow-up, 16 patients (34.8%) were alive. No evidence of intracranial progress or recurrence was found in 6 patients (13.0%) during the follow-up. Conclusion: SIB-IMRT with the dose/fractionation based on the fusion imaging of MRI-CT is feasible and safe. It is beneficial to the NSCLC patients with BM and can reduce the overall costs of treatment. PMID- 30519354 TI - Identification of Five Genes as a Potential Biomarker for Predicting Progress and Prognosis in Adrenocortical Carcinoma. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a limited endocrine fatality with a minor diagnosis and rare remedial options. The progressive and predictive meaning of message RNA (mRNA) expression oddity in ACC has been studied extensively in recent years. However, differences in measurement platforms and lab protocols as well as small sample sizes can render gene expression levels incomparable. METHODS: An extensive study of GEO datasets was conducted to define potential mRNA biomarkers for ACC. The study compared the mRNA expression profiles of ACC tissues and neighboring noncancerous adrenal tissues in the pair. The study covered a sum of 165 tumors and 36 benign control samples. Hub genes were identified through a protein-protein interaction (PPI) network and Robust Rank Aggregation method. Then the Cancer Genome Atlas (TCGA) and Oncomine database were used to perform the validation of hub genes. 4 ACC tissues and 4 normal tissues were collected and then Polymerase Chain Reaction (PCR), Western-blot and immunofluorescence were conducted to validate the expression of five hub genes. RESULTS: We identified five statistically significant genes (TOP2A, NDC80, CEP55, CDKN3, CDK1) corrected with clinical features. The expression of five hub genes in TCGA and Oncomine database were significantly overexpressed in ACC compared with normal ones. Among all the TCGA ACC cases, the strong expression of TOP2A (logrank p=1.4e-04, HR=4.7), NDC80 (logrank p=8.8e-05, HR=4.9), CEP55 (logrank p=5.2e-07, HR=8.6), CDKN3 (log rank p=2.3e-06, HR=7.6) and CDK1 (logrank p=7e-08, HR=11) were correlated with low comprehensive survival, disease free survival (logrank p < 0.001), pathology stage and pathology T stage (FDR < 0.001). PCR results showed that the transcriptional levels of these five genes were significantly higher in ACC tissues than in normal tissues. The western blotting results also showed that the translational level of TOP2A was significantly higher in tumor tissues than in normal tissues. The results of immunofluorescence showed that TOP2A was abundantly observed in the adrenal cortical cell membrane and nucleus and its expression in ACC tissues was significantly higher than that in normal tissues. CONCLUSIONS: The distinguished five genes may be utilized to form a board of progressive and predictive biomarkers for ACC for clinical purpose. PMID- 30519355 TI - GFAP expression is influenced by astrocytoma grade and rs2070935 polymorphism. AB - Glial fibrillary acidic protein (GFAP) is an intermediate filament that provides mechanical support to astrocytes. Rs2070935 is a single nucleotide polymorphism (SNP) located in the promoter region of the GFAP gene. The aim of this pilot study is to investigate GFAP expression at mRNA, protein levels and rs2070935 polymorphism in 50 different grade human astrocytoma samples. GFAP expression at mRNA level was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) with SYBR Green dye, whereas the translational activity of the following gene was detected using western blot assay. Furthermore, genotypes of rs2070935 were identified using qPCR with TaqMan probes. As a result, GFAP mRNA and protein expression was found to be declining with increasing astrocytoma grade (p < 0.05). A tendency was observed between increased GFAP mRNA expression and shorter grade IV astrocytoma patient survival (p = 0.2117). The rs2070935 CC genotype was found to be associated with increased GFAP translational activity in grade II astrocytoma (p = 0.0238). Possible links between rs2070935 genotypes and alternative splicing of GFAP were also observed. The rs2070935 AA genotype was found to be associated with poor clinical outcome for grade IV astrocytoma patients (p = 0.0007), although the following data should be checked in a larger sample size of astrocytoma patients. PMID- 30519356 TI - Ribonucleotide Reductase Inhibitor 3-AP Induces Oncogenic Virus Infected Cell Death and Represses Tumor Growth. AB - Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human malignancies, particularly Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation while still lacking of effective therapeutic options. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic HGF/c-MET pathway in KSHV-related lymphoma cells. One of RR inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively induced apoptosis of KSHV+ lymphomas and suppressed tumor progression in vivo. In the current study, we found that 3-AP treatment selectively inhibited the proliferation of KSHV-infected endothelial cells, the major cellular components of KS, through inducing DNA damage, reducing the levels of intracellular iron and reactive oxygen species (ROS) and increasing viral lytic gene expression. By using a KS-like nude mouse model, we found that 3-AP treatment significantly suppressed KSHV induced tumorigenesis in vivo. Taken together, our data demonstrate targeting RR by 3-AP may represent a promising strategy for improving the treatment of KS in future. PMID- 30519357 TI - The Efficacy and Safety of Anti-epidermal Growth Factor Receptor Monoclonal Antibodies in Nasopharyngeal Carcinoma: Literature-based Meta-analyses. AB - Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti EGFR mAbs), such as cetuximab and nimotuzumab have been used in the treatment of nasopharyngeal carcinoma (NPC), yet their efficacy and safety are undetermined. Materials and Methods: We performed two meta-analyses based on systematic searches of PubMed, EMBASE, the Cochrane Library and SinoMed: comparison 1 (standard therapy plus mAbs vs. standard therapy) and comparison 2 (radiotherapy plus concurrent mAbs vs. concurrent chemoradiotherapy) to explore the treatment value of anti-EGFR mAbs in NPC. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcomes, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and grade 3 and above acute adverse events. Results: Four randomized controlled trials and thirteen observational studies were eligible. Comparison 1 (twelve studies): adding mAbs to standard therapy (radiotherapy or chemoradiotherapy) significantly improved OS (HR, 0.51; 95% CI, 0.39-0.66) and DFS (HR, 0.68; 95% CI, 0.54-0.86), but increased the frequency of skin rashes and mucositis. Comparison 2 (six studies): OS (HR, 1.17; 95% CI, 0.81-1.70) and DFS (HR, 1.16; 95% CI, 0.86-1.57) were not significantly different when mAbs replaced conventional cytotoxic chemotherapy concurrently with radiotherapy, with fewer hematological, gastrointestinal and renal toxicities and more skin rashes in the mAb group. Conclusion: We recommend anti-EGFR mAbs enhance-but should not replace-current treatment paradigms for locoregionally advanced NPC. Further evidence from phase III clinical trials is required. PMID- 30519358 TI - Functional Polymorphisms in hOGG1 Gene and Neuroblastoma Risk in Chinese Children. AB - Neuroblastoma is a lethal tumor of the sympathetic nervous system. 8 Hydroxydeoxyguanine (8-OH-dG) formation is a common seen type of oxidative DNA damage, which could be repaired by human oxoguanine glycosylase 1 (hOGG1). To explore the contributing role of hOGG1 gene single nucleotide polymorphisms (SNPs) in neuroblastoma risk, we performed a case-control study by genotyping three SNPs (rs1052133 G>C, rs159153 T>C, rs293795 A>G) in hOGG1 gene. A total of 512 neuroblastoma cases and 1076 cancer-free controls were enrolled from three medical centers in China. The hOGG1 gene polymorphisms were determined using TaqMan real-time PCR. The results showed that only the rs1052133 G>C polymorphism was associated with neuroblastoma risk [GC vs. GG: adjusted odds ratio (OR)=0.64, 95% confidence interval (CI)=0.51-0.81, P=0.0002; dominant model: adjusted OR=0.71, 95% CI=0.57-0.88, P=0.002]. Moreover, subjects carrying 1, 2, or 1-3 protective genotypes have less opportunity to develop neuroblastoma, in comparison to those without protective genotypes. Stratified analysis revealed that rs1052133 GC/CC carriers were less likely to develop neuroblastoma in subgroups of age >18 months, males, tumor that develops from retroperitoneal, mediastinum and clinical stage I+II+4s. Our results indicate that hOGG1 rs1052133 G>C polymorphism is associated with decreased risk of neuroblastoma. However, the exact biological mechanism awaits further research. PMID- 30519359 TI - Oxymatrine Synergistically Potentiates the Antitumor Effects of Cisplatin in Human Gastric Cancer Cells. AB - Cisplatin (CDDP) has been extensively used for gastric cancer (GC) treatment but limited by drug resistance and severe toxicity. The chemo-sensitizers that enhance its efficiency and overcome its limitation are urgently needed. Oxymatrine (OMT), a primary active ingredient from the dry roots of Sophora favescens, has shown powerful anti-cancer property with little side-effect. In this study, we explored the chemo-sensitization of OMT to potentiate the anti tumor effect of CDDP. GC cell lines were dealt with OMT and/or CDDP and then subjected to different experimental methods. We found that OMT could significantly potentiate the CDDP-caused BGC-823 and SGC7901 cells viability loss, and OMT acts synergistically with CDDP. The combinative treatment could arrest cell cycle in G0/G1 phase by increasing p21, p27 and decreasing cyclin D1, and induced apoptosis by ROS generation and AKT/ERK inactivation. Inhibition of ROS respectively reversed the cell death induced by OMT and/or CDDP, suggesting the pivotal roles of ROS in the process. Moreover, OMT enhanced the antitumor effects of CDDP in nude mice bearing BGC823 tumor xenografts in vivo. Taken together, this study highlights that the co-treatment with OMT and CDDP exerted synergistic antitumor effects in GC cells, and that these effects may be mediated by ROS generation and inactivation of the AKT/ERK pathways. PMID- 30519360 TI - The Combination of Omega-3 Stearidonic Acid and Docetaxel Enhances Cell Death over Docetaxel Alone in Human Prostate Cancer Cells. AB - Background: Docetaxel (DOC), or Taxotere, is an anthracycline antibiotic used to treat multiple types of cancer. It is a first-line chemotherapy treatment for patients with metastasized, hormone-resistant prostate cancer (PCa) or for patients with high-risk, localized PCa that could benefit from early chemotherapy treatment. Previously, we showed that stearidonic acid (SDA), an omega-3 fatty acid, enhances the cytotoxicity of doxorubicin (DOX) in human PCa cells. This observation suggests that PCa therapies using SDA and chemotherapeutic drugs in combination offer attractive possibilities for developing treatments that ameliorate toxic side effects of some commonly used chemotherapy drugs. Objectives: We used androgen-resistant PC3 and DU 145 cells derived from human prostate cancer to quantify the effects of combined SDA and DOC on proliferation/viability and on the production of pro-apoptotic caspases 9 and 3. We also compared the effects of SDA with those of BAY, a pharmacological inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF KB), in androgen-sensitive LNCaP cells. Finally, we qualitatively and quantitatively assessed the drug combination on androgen receptor (AR) and peroxisome proliferator-activated receptor gamma (PPARgamma) expression in LNCaP and PC3 cells, respectively. Methods: The half maximal inhibitory concentration (IC50) and combination indices of SDA and DOC in PC3 and DU 145 cells were determined using the MTT cell viability assay. To quantify the effects of SDA and BAY on NF-KB activity, we used luciferase reporter assays in LNCaP cells that were stably transduced with lentiviral vectors carrying NF-KB response element sequence upstream of the luciferase gene sequence. AR and PPARgamma expression were assessed by western blotting and immunocytochemistry. We considered caspase 9 and 3 cleavage to be apoptosis markers and determined the drug combination effect on the extent of that cleavage by western blot analysis. Results: The cytotoxic effects of DOC were synergistically enhanced by SDA when the two were added to DU145 and PC3 cell cultures. Combination index (CI) analyses based on the Chou-Talalay method and mass action law showed synergistic interaction with CI <1. SDA suppressed TNFalpha-induced NF-kappaB activity similarly to BAY. The SDA/DOC combination down regulated testosterone (T)-induced AR and troglitazone induced PPARgamma protein expression when compared to using the drugs singly. Similarly, the SDA/DOC combination induced caspase 9 and 3 production and cleavage suggesting apoptosis induction. Like our DOX studies, this work provides proof-of-concept for using SDA and DOC in combination to reduce the dose, and therefore the toxicity, of DOC and possibly increasing the survival benefit in DOC clinical translation studies. PMID- 30519361 TI - Prognosis Analysis of Histone Deacetylases mRNA Expression in Ovarian Cancer Patients. AB - Histone deacetylases modulate the dynamic balance of histone acetylation and deacetylation in cells, which participate in epigenetic regulations. Accumulated evidence has demonstrated that histone deacetylases are associated with angiogenesis, cell proliferation and survival in a variety of human cancers. However, the expression and distinct prognostic value of histone deacetylases in ovarian cancer have not been well elucidated. In the present study, we collected the overall survival (OS), progress free survival (PFS), and histone deacetylases (HDAC1-11) mRNA expression in ovarian cancer from the Kaplan-Meier plotter online database. We investigated the relationship between histone deacetylases mRNA level and the clinicopathological parameters of the ovarian cancer patients, such as histology subtypes, clinical stages, grades and TP53 mutation. Our analysis data showed that over-expression of HDAC1, HDAC2, HDAC4, HDAC5 and HDAC11 were correlated to poor overall survival and unfavorable progress free survival in all ovarian cancer patients. Notably, the higher level of HDAC11 was associated with the worse OS and PFS for serous/ stage III+IV/ grade III/ TP53 mutation ovarian cancer patients. In conclusion, HDACs may play a crucial role in the prognosis of ovarian cancer, but it is worth noting that HDAC11 may be a biomarker for poor prognosis in ovarian cancer patients. PMID- 30519362 TI - Efficacy and Safety of Ipilimumab plus Chemotherapy for Advanced Lung Cancer: A Systematic Review and Meta-Analysis. AB - Lung cancer is the leading cause of cancer-related deaths worldwide, with poor prognosis in advanced lung cancer patients. Platinum-based chemotherapy has always been a first-line treatment for the majority of advanced lung cancer patients, but its long-term survival benefit is limited. Ipilimumab is an immune drug that targets the CTLA-4 protein in T cells. Therefore, we evaluated the efficacy and safety of adding ipilimumab to simple chemotherapy for patients with advanced lung cancer. We searched literatures in PubMed, Web of Science, EMBASE, the Cochrane Library and cliniclatrials.gov. The primary end points of this assessment were overall survival (OS), progression-free survival (PFS) and immune related PFS(irPFS) of lung cancer patients. Other end points were objective response rate (ORR), disease control rate (DCR) and safety. The results of this study will be presented by the risk ratio (RR) of the endpoints and the 95% confidence interval (CI) of the various effect sizes. And when the p value is less than 0.05, we think there is a statistical difference. Finally, 6 RCTs and 2,037 patients including 953 with advanced or recurrent non-small cell lung cancer (NSCLC) and 1084 with extensive-disease small-cell lung cancer (ED-SCLC) were identified. Among them, 1089 received immunochemotherapy, and 948 patients received chemotherapy alone. Immunochemotherapy can't improve OS (6months: risk ratio (RR)=0.97 P=0.11; 1year: RR=1.05 P=0.36), ORR (RR=1.00 P=0.95) and DCR (RR=0.92, 95%CI 0.85-1.00, P=0.04) of patients with lung cancer compared to pure chemotherapy, but it can improve the PFS (6months: RR=1.16 P=0.02; 1year: RR=1.39 P=0.02) and 6months-irPFS(RR=1.60 P=0.004). However, due to the addition of ipilimumab, the immune-related toxicities are more apparent in immunochemotherapy group. PMID- 30519363 TI - Masters or pawns? Examining injury and chronic disease in male Masters Athletes and chess players compared to population norms from the Canadian Community Health Survey. AB - Background: Identifying the optimal type and amount of activity for the maintenance of function in older adults has proved challenging. On the one hand, Masters Athletes have been proposed as the ideal model of successful aging but most of this research has focused on physical functioning. On the other hand, the importance of cognitive engagement has been emphasized, which may be more strongly related to activities such as playing chess. The current study aimed to compare physical health outcomes (i.e., prevalence of physical injury and chronic disease) among older athletes and chess players. Masters Athletes and chess players were recruited from track and field and chess competitions within the province of Ontario. In addition to these primary groups, moderately active and inactive older adults from Canadian Community Health Survey were also included for comparison. Results: Masters Athletes had significantly higher rates of injury with the lowest rates of chronic disease, compared to all other activity groups. In contrast, chess players reported lower rates of injury compared to Masters Athletes as well as lower prevalence of chronic diseases compared to the moderately active and inactive groups. The normative groups reported the lowest rate of injury, but increased prevalence of chronic diseases compared to Masters Athletes and chess players. Conclusions: Findings from this study indicate that both athletic and cognitive engagement may be positively related to the physical health of older adults, since Masters Athletes and chess players reported a lower prevalence of chronic disease. Importantly, the results expand our current understanding of health by providing evidence for physical health outcomes associated with an activity that is primarily associated with cognitive health. PMID- 30519365 TI - Food intake biomarkers for apple, pear, and stone fruit. AB - Fruit is a key component of a healthy diet. However, it is still not clear whether some classes of fruit may be more beneficial than others and whether all individuals whatever their age, gender, health status, genotype, or gut microbiota composition respond in the same way to fruit consumption. Such questions require further observational and intervention studies in which the intake of a specific fruit can be precisely assessed at the population and individual levels. Within the Food Biomarker Alliance Project (FoodBAll Project) under the Joint Programming Initiative "A Healthy Diet for a Healthy Life", an ambitious action was undertaken aiming at reviewing existent literature in a systematic way to identify validated and promising biomarkers of intake for all major food groups, including fruits. This paper belongs to a series of reviews following the same BFIRev protocol and is focusing on biomarkers of pome and stone fruit intake. Selected candidate biomarkers extracted from the literature search went through a validation process specifically developed for food intake biomarkers. PMID- 30519364 TI - SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice. AB - Background: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1 antichymotrypsin (alpha1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFalpha, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFkappaB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1 -/- ) mice. Conclusions: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation. PMID- 30519366 TI - Targeting myomiRs by tocotrienol-rich fraction to promote myoblast differentiation. AB - Background: Several muscle-specific microRNAs (myomiRs) are differentially expressed during cellular senescence. However, the role of dietary compounds on myomiRs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on myomiRs and myogenic genes during differentiation of human myoblasts. Young and senescent human skeletal muscle myoblasts (HSMM) were treated with 50 MUg/mL TRF for 24 h before and after inducing differentiation. Results: The fusion index and myotube surface area were higher (p < 0.05) on days 3 and 5 than that on day 1 of differentiation. Ageing reduced the differentiation rate, as observed by a decrease in both fusion index and myotube surface area in senescent cells (p < 0.05). Treatment with TRF significantly increased differentiation at days 1, 3 and 5 of young and senescent myoblasts. In senescent myoblasts, TRF increased the expression of miR-206 and miR-486 and decreased PTEN and PAX7 expression. However, the expression of IGF1R was upregulated during early differentiation and decreased at late differentiation when treated with TRF. In young myoblasts, TRF promoted differentiation by modulating the expression of miR-206, which resulted in the reduction of PAX7 expression and upregulation of IGF1R. Conclusion: TRF can potentially promote myoblast differentiation by modulating the expression of myomiRs, which regulate the expression of myogenic genes. PMID- 30519367 TI - Bootstrapped Biocatalysis: Biofilm-Derived Materials as Reversibly Functionalizable Multienzyme Surfaces. AB - Cell-free biocatalysis systems offer many benefits for chemical manufacturing, but their widespread applicability is hindered by high costs associated with enzyme purification, modification, and immobilization on solid substrates, in addition to the cost of the material substrates themselves. Herein, we report a "bootstrapped" biocatalysis substrate material that is produced directly in bacterial culture and is derived from biofilm matrix proteins, which self assemble into a nanofibrous mesh. We demonstrate that this material can simultaneously purify and immobilize multiple enzymes site specifically and directly from crude cell lysates by using a panel of genetically programmed, mutually orthogonal conjugation domains. We further demonstrate the utility of the technique in a bienzymatic stereoselective reduction coupled with a cofactor recycling scheme. The domains allow for several cycles of selective removal and replacement of enzymes under mild conditions to regenerate the catalyst system. PMID- 30519368 TI - Change over time of the mutagenicity in the lungs of gpt delta transgenic mice by extract of airborne particles collected from ambient air in the Tokyo metropolitan area. AB - Background: Previously we found that DNA adducts were accumulated in the lungs of the rats exposed to ambient air in the Tokyo metropolitan area. To examine chronological change in in vivo mutagenicity of airborne particles, extracts produced from samples of total suspended particulates (TSP) collected from urban air in 1980, 1990, and 2010 in the Tokyo metropolitan area were intratracheally administered into the lungs of gpt delta mice, and differences in mutation and mutant frequency were determined by using the gpt assay. In vivo mutations induced by the extracts were characterized and mutation hotspots were identified by DNA sequencing of the mutated gpt gene. Results: Administration of the 1990 extract at a dose of 0.3 mg/animal significantly elevated total mutant frequency to 3.3-times that in vehicle control, and the in vivo mutagenicity of the extract (induced mutation frequency per milligram extract) was estimated to be 2.0- and 2.4-times higher than that of the 2010 and 1980 extract, respectively. G-to-A transition was the most common base substitution in the vehicle control mice. However, administration of the 1990 extract increased the frequency of G-to-T transversion, which is a landmark base substitution induced by oxidative stress; furthermore, when the extract was administered at a dose of 0.15 mg, the mutant and mutation frequencies of G-to-T transversion were significantly increased to frequencies comparable with those of G-to-A transition. Similar increases in the mutant and mutation frequencies of G-to-T transversion were observed after administration of the 2010 extract. Hotspots (mutation foci identified in three or more mice) of G-to-A transition mutations at nucleotides 64 and 110 were induced by the 1980, 1990, and 2010 extracts; a hotspot of G-to-T transversions at nucleotide 406 was also induced by the 2010 extract. Previously, we showed that diesel exhaust particles or their extract, as well as 1,6-dinitropyrene, administered to mice induced these hotspots of G-to-A transitions. Conclusions: The results of the present study suggested that mutagenesis induced by extracts produced from TSP collected in the Tokyo metropolitan area induced in vivo mutagenicity via the same mechanism underlying the induction of in vivo mutagenicity by components of diesel exhaust. PMID- 30519369 TI - German National Case Collection for familial pancreatic Cancer (FaPaCa) - acceptance and psychological aspects of a pancreatic cancer screening program. AB - Background: Pancreatic cancer screening is recommended to individuals at risk (IAR) of familial pancreatic cancer (FPC) families, but little is known about the acceptance of such screening programs. Thus, the acceptance and psychological aspects of a controlled FPC screening program was evaluated. Methods: IAR of FPC families underwent comprehensive counseling by a geneticist and pancreatologist prior to the proposed screening. Participating IAR, IAR who discontinued screening and IAR who never participated in the screening program were invited to complete questionnaires to assess the motivation for participating in surveillance, cancer worries, structural distress and experiences with participation. Questionnaires were completed anonymously to receive most accurate answers. Results: Of 286 IAR to whom pancreatic ductal adenocarcinoma (PDAC) screening was recommended, 139 (48.6%) IAR regularly participated (group 1), 49 (17.1%) IAR (group 2) discontinued screening after median 1 (1-10) screening visits and 98 (34.2%) IAR (group 3) never underwent screening. The overall response rate of questionnaires was 67% (189/286) with rates of 100% (139 of 139 IAR), 49% (29 of 49 IAR) and 23.4% (23 of 98 IAR) for groups 1, 2 and 3, respectively. At least 93% of IAR felt adequately informed about the screening program after initial counseling. However, only 38.8% received knowledge of or the recommendation for PDAC screening by physicians. The reported cancer-related distress and the fear of investigations were highest in group 1, but acceptably low in all three groups. The main reasons to discontinue or not to participate in screening were the time efforts and travel costs (groups 2 and 3 48,7%). Conclusion: Less than 50% of IAR regularly participate in a proposed PDAC screening program, although the associated psychological burden is quite low. Physicians should be educated about high risk PDAC groups and screening recommendations. Time and travel efforts must be reduced to encourage more IAR to participate in a recommended screening. PMID- 30519370 TI - Achieving the optimal vaginal state: using vaginal products and study gels in Uganda, Zimbabwe, and South Africa. AB - Preferences and practices related to the vaginal condition have implications for the use of vaginal HIV prevention products. We used qualitative methods to explore narratives relating to the vaginal state amongst women in South Africa, Uganda and Zimbabwe who had previously participated in a biomedical HIV prevention trial. We investigated women's behaviours related to optimising the vaginal state, experiences and perceptions of the gel's effect on the vaginal state and on penile-vaginal intercourse, women's narratives on male partner perceptions, and how preferences relating to the vaginal state may have interfered with gel use. PMID- 30519371 TI - Paper-based immunosensor utilizing dielectrophoretic trapping of microprobes for quantitative and label free detection using electrochemical impedance spectroscopy. AB - In this study, we have developed a novel paper based immunoassay for the quantitative detection of immunoreactions using electrochemical impedance spectroscopy. Paper provides an attractive platform for fabrication of simple, low cost, and portable diagnostic devices as it allows passive liquid transport, is biocompatible, and has tunable properties such as hydrophilicity, flexibility, permeability, and reactivity. We have used screen-printing to fabricate interdigitated electrodes (finger width and gap of 200 MUm) on the paper substrate, while UV-lithography enables patterning of the paper into hydrophobic/hydrophilic regions. As a proof of concept, we have used this immunosensor to detect the immune response of Human Serum Albumin (HSA) antibody antigen complex formation. To enable efficient immobilization of HSA antibodies, we have utilized dielectrophoresis to trap microprobes (MPs) on the electrode surface. The microprobes consist of an alumina nanoparticle core with a well adhered polyaniline outer coating to which the HSA antibodies are conjugated in an oriented manner via covalent chemistry. The efficacy of the impedance-based immunosensor is compared when MPs are immobilized specifically on the electrode surface using dielectrophoresis (DEP) as opposed to being dropped and immobilized via physical absorption on the entire sensing area. Results show that a more reproducible and sensitive response is observed when DEP is utilized to trap the microprobes. Furthermore, the normalized impedance variation during immunosensing shows a linear dependence on the concentration of HSA with an observed limit of detection of 50 MUg/ml, which is lower than conventionally used paper based urine dipsticks used for urinary protein detection. Thus, we have developed a low cost paper based immunoassay platform that can be used for the quantitative point of care detection of a wide range of immunoreactions. PMID- 30519372 TI - A nanofilter for fluidic devices by pillar-assisted self-assembly microparticles. AB - We present a nanofilter based on pillar-assisted self-assembly microparticles for efficient capture of bacteria. Under an optimized condition, we simply fill the arrays of microscale pillars with submicron scale polystyrene particles to create a filter with nanoscale pore diameter in the range of 308 nm. The design parameters such as the pillar diameter and the inter-pillar spacing in the range of 5 MUm-40 MUm are optimized using a multi-physics finite element analysis and computational study based on bi-directionally coupled laminar flow and particle tracking solvers. The underlying dynamics of microparticles accumulation in the pillar array region are thoroughly investigated by studying the pillar wall shear stress and the filter pore diameter. The impact of design parameters on the device characteristics such as microparticles entrapment efficiency, pressure drop, and inter-pillar flow velocity is studied. We confirm a bell-curve trend in the capture efficiency versus inter-pillar spacing. Accordingly, the 10 MUm inter pillar spacing offers the highest capture capability (58.8%), with a decreasing entrapping trend for devices with larger inter-pillar spacing. This is the case that the 5 MUm inter-pillar spacing demonstrates the highest pillar wall shear stress limiting its entrapping efficiency. As a proof of concept, fluorescently labeled Escherichia coli bacteria (E. coli) were captured using the proposed device. This device provides a simple design, robust operation, and ease of use. All of which are essential attributes for point of care devices. PMID- 30519374 TI - Erratum. PMID- 30519373 TI - Wash-Line Dermatitis: A Diagnostic Clue. PMID- 30519375 TI - Hidradenitis Suppurativa: Causes, Features, and Current Treatments. AB - Hidradenitis suppurativa (HS), a relatively common and chronic inflammatory skin disorder. HS can have debilitating consequences if not diagnosed and treated appropriately. Clinically defined by recurrent, inflamed nodules in intertriginous regions (i.e., axillary, inguinal, and perianal areas), HS can cause intense pain and, in severe disease stages, lead to the formation of fistulas, sinus tracts, and extensive scarring. Postpubertal onset and female preponderance further characterize HS. Numerous pathogenic mechanisms have been proposed in HS, including immune dysregulation, genetics, smoking, and obesity; however, the exact etiology remains to be elucidated. The association of HS with inflammatory bowel disease, cardiovascular disease risk factors, and psychiatric disorders suggests HS is a systemic disease. HS significantly impairs quality of life in patients in excess versus other skin diseases. Unfortunately, experiences indicate long diagnostic delays, which in many cases might be due to disease unawareness among physicians. Increased knowledge of HS is therefore important in order to optimize disease management and ultimately improve the quality of life of patients. PMID- 30519376 TI - Split-face Evaluation of a Multi-ingredient Brightening Foam Versus a Reference Control in Women with Photodamaged Facial Skin. AB - Background: The gold standard for the treatment of hyperpigmentation is hydroquinone (HQ), which has been available as a skin lightener for more than 50 years. Numerous clinical studies have proven its efficacy in various topical formulations. In the United States, HQ is available as a nonprescription product in 2% formulations and as a 4% prescription product. Objective: This study compared the safety and efficacy of a 2% hydroquinone multi-ingredient foam with a standard 4% hydroquinone cream on photodamaged facial skin. Methods: A 12-week, investigator-blinded, randomized trial with a split-face design was conducted in women with moderate photodamaged facial skin. Results: Both products improved the appearance of photodamaged facial skin and were well-tolerated. No statistically significant changes were seen between treatments during the efficacy or tolerability evaluations. Conclusion: Both treatments (2% HQ Brighten and 4% HQ) improved the appearance of photodamaged facial skin and were well-tolerated and results well-perceived by subjects over the 12-week treatment period, compared with baseline grading scores. PMID- 30519377 TI - Effectiveness of Topical Onion Extract Gel in the Cosmetic Appearance of Blepharoplasty Scar. AB - Objectives: Topical onion extract gel is commonly used in commercial anti-scar medications. The purpose of this study was to evaluate the effectiveness of topical onion extract gel on the appearance of blepharoplasty scars and to compare the results of its use to those of petroleum jelly. Design: The participants enrolled in this prospective, double-blind study were randomly treated with either topical onion extract gel or petroleum jelly. The products were applied twice daily for two months following suture removal. Patients were evaluated objectively using the Manchester Scar Scale at the end of treatment. Six months after surgery, a follow-up phone interview was conducted. Setting: The study was carried out in the Khalili and Dastghaib Hospitals in Shiraz, Iran. Participants: Out of 43 participants who had upper blepharoplasty, 26 patients completed the follow up. Measurements: The Manchester Scar Scale evaluates five different characteristics of scar: color (score: 1-4), distortion (score: 1-4), contour (score: 1-4), texture (score: 1-4), and transparency (score: 1-2). A visual analogue scale (VAS) was also used to quantify the overall scar appearance on a range of 0 to 10 (with the highest number indicating the worst appearance). The scores for the five different parameters and the VAS were calculated and compared. Results: There was no statistically significant difference in overall cosmetic appearance objectively and/or subjectively between the two sides (p value: 0.25). Conclusion: Topical onion extract gel was ineffective in improving overall blepharoplasty scar appearance when compared with a petroleum-based ointment. PMID- 30519378 TI - Detection of Angiotensin II and AT1 Receptor Concentrations in Keloid and Hypertrophic Scar. AB - Background: Keloid and hypertrophic scars (HTS) are formed by excessive collagen formation. Angiotensin II, through the AT1 receptor, plays an important role in extracellular matrix production. However, less is known about angiotensin II and AT1 receptor concentrations in HTS and keloid tissues. Objective: The purpose of this study was to determine the angiotensin II and AT1 receptor concentrations in keloid, HTS, and normal skin tissues. Methods: Skin biopsy samples from patients with HTS (n=26), keloid (n=20), and normal (n=30) skin tissues were evaluated for angiotensin II and AT1 receptor concentrations by use of the enzyme-linked immunosorbent assay technique. Results: The angiotensin II concentration in patients with HTS was higher than that in the normal (P<0.0067) and keloid (P>0.9553) groups, while the AT1 receptor concentration in patients with keloid was higher than that in the HTS (P<0.0001) and normal (P<0.0048) groups. Conclusion: Angiotensin II and AT1 receptor concentrations could stimulate the formation of HTS and keloid. Angiotensin II receptor blockers and angiotensin converting enzyme inhibitors may be suitable compounds for the treatment of scar tissue. PMID- 30519379 TI - The Association of Various Metabolic Parameters with Multiple Skin Tags. AB - Background: Skin tags (STs) are benign skin lesions. Their definite etiology remains unknown. We aim to examine the association of obesity, diabetes mellitus, hyperlipidemia, thyroid abnormalities, acanthosis nigricans, and multiple STs in a Greek primary population. Methods: Phototype and body weight were recorded. Fasting serum blood samples were analyzed for cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, and thyroid stimulating hormone. Univariate ordinal logistic regression multivariate analysis was performed. Results: The univariate analysis showed that patients who were overweight with Fitzpatrick Skin Type III, acanthosis nigricans, and hypothyroidism were more likely to present with multiple skin tags as compared with patients at a normal weight with Skin Type I. Statistically significant associations were also found with the presence of cholesterol and triglycerides. In the multivariate analysis, a significant association between hypercholesterolemia and STs was demonstrated. Those with skin tags were more likely to have hypothyroidism. Conclusion: STs are often associated with obesity. An association between lipid profile and STs has been reported. Multiple STs have been independently associated with acanthosis nigricans. Although a possible relationship between STs and thyroid disease has not yet been proved, our review reveals a possible trend. Future investigations with larger sample sizes might clarify the association between skin tags and hypothyroidism. PMID- 30519381 TI - Automatic Seizure Detection Based on Nonlinear Dynamical Analysis of EEG Signals and Mutual Information. AB - Introduction: In this paper, nonlinear dynamical analysis based on Recurrence Quantification Analysis (RQA) is employed to characterize the nonlinear EEG dynamics. RQA can provide useful quantitative information on the regular, chaotic, or stochastic property of the underlying dynamics. Methods: We use the RQA-based measures as the quantitative features of the nonlinear EEG dynamics. Mutual Information (MI) was used to find the most relevant feature subset out of RQA-based features. The selected features were fed into an artificial neural network for grouping of EEG recordings to detect ictal, interictal, and healthy states. The performance of the proposed procedure was evaluated using a database for different classification cases. Results: The combination of five selected features based on MI achieved 100% accuracy, which demonstrates the superiority of the proposed method. Conclusion: The results showed that the nonlinear dynamical analysis based on Rcurrence Quantification Analysis (RQA) can be employed as a suitable approach for characterizing the nonlinear EEG dynamics and detecting the seizure. PMID- 30519380 TI - Draft genomes of Cronobacter sakazakii strains isolated from dried spices bring unique insights into the diversity of plant-associated strains. AB - Cronobacter sakazakii is a Gram-negative opportunistic pathogen that causes life- threatening infantile infections, such as meningitis, septicemia, and necrotizing enterocolitis, as well as pneumonia, septicemia, and urinary tract and wound infections in adults. Here, we report 26 draft genome sequences of C. sakazakii, which were obtained from dried spices from the USA, the Middle East, China, and the Republic of Korea. The average genome size of the C. sakazakii genomes was 4393 kb, with an average of 4055 protein coding genes, and an average genome G + C content of 56.9%. The genomes contained genes related to carbohydrate transport and metabolism, amino acid transport and metabolism, and cell wall/membrane biogenesis. In addition, we identified genes encoding proteins involved in osmotic responses such as DnaJ, Aquaproin Z, ProQ, and TreF, as well as virulence related and heat shock-related proteins. Interestingly, a metabolic island comprised of a variably-sized xylose utilization operon was found within the spice-associated C. sakazakii genomes, which supports the hypothesis that plants may serve as transmission vectors or alternative hosts for Cronobacter species. The presence of the genes identified in this study can support the remarkable phenotypic traits of C. sakazakii such as the organism's capabilities of adaptation and survival in response to adverse growth environmental conditions (e.g. osmotic and desiccative stresses). Accordingly, the genome analyses provided insights into many aspects of physiology and evolutionary history of this important foodborne pathogen. PMID- 30519382 TI - Environmental Enrichment Attenuates Morphine-Induced Conditioned Place Preference and Locomotor Sensitization in Maternally Separated Rat Pups. AB - Introduction: This study investigated the effect of the environmental enrichment during adolescence on morphine-induced Conditioned Place Preference (CPP) and locomotor sensitization in maternally separated male and female rat pups. Methods: Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups were separated from them 3 hours per day during 2-14 days postnatal. All pups were weaned at 21 Postnatal Day (PND) and reared in standard environment or enriched environment from 21 to 50 PND with litter-mates of the same sex. The CPP and behavioral sensitization to morphine were assessed by an unbiased place conditioning paradigm and open filed method. Results: The results showed that the maternal separation enhanced morphine-induced CPP in both sexes, locomotor sensitization in male pups and tolerance to morphine-induced motor activity in female pups during adolescence. While, male and female pups reared in an EE exhibited a decrease in morphine-induced CPP, locomotor sensitization and tolerance induced by maternal separation compared to their control pups. Conclusion: Access to enriched environment during adolescence may have a protective effect against morphine-induced reward, locomotor sensitization and tolerance in adolescent male and female rats following maternal separation. PMID- 30519383 TI - The Antinociceptive Effects of Rosuvastatin in Chronic Constriction Injury Model of Male Rats. AB - Introduction: According to studies, statins possess analgesics and anti inflammatory properties. In the present study, we examined the antinociceptive, anti-inflammatory and antioxidative effects of rosuvastatin in an experimental model of Chronic Constriction Injury (CCI). Methods: Our study was conducted on four groups; sham, CCI (the control group), CCI+rosuvastatin (i.p. 5 mg/kg), and CCI+rosuvastatin (i.p. 10 mg/kg). We performed heat hyperalgesia, cold and mechanical allodynia tests on the 3rd, 7th, 14th, and 21st after inducing CCI. Blood samples were collected to measure the serum levels of Tumor Necrosis Factor (TNF)-alpha, and Interleukin (IL)-6. Rats' spinal cords were also examined to measure tissue concentration of Malondialdehyde (MDA), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) enzymes. Results: Our findings showed that CCI resulted in significant increase in heat hyperalgesia, cold and mechanical allodynia on the 7th, 14th and 21st day. Rosuvastatin use attenuated the CCI-induced hyperalgesia and allodynia. Rosuvastatin use also resulted in reduction of TNF-alpha, IL-6, and MDA levels. However, rosuvastatin therapy increased the concentration of SOD and GPx in the CCI+Ros (5 mg/kg) and the CCI+Ros (10 mg/kg) groups compared to the CCI group. Conclusion: Rosuvastatin attenuated the CCI-induced neuropathic pain and inflammation. Thus, antinociceptive effects of rosuvastatin might be channeled through inhibition of inflammatory biomarkers and antioxidant properties. PMID- 30519384 TI - Assessment of Behavioral Approach and Behavioral Inhibition Systems in Mood Disorders. AB - Introduction: Psychiatric disorders could be evaluated in terms of behavioral activation and inhibition systems. Dysregulation of these systems may lead to development of manic or depressive episodes in patients with mood disorders. This study aimed to identify Behavioral Approach System (BAS) and Behavioral Inhibition System (BIS) hypersensitivity as the functional brain system behaviors in patients with major depressive disorder and bipolar mood disorder I, compared to healthy individuals. Methods: This case-control study was conducted in Razi Psychiatric Hospital, a mental health referral center in Northwest of Iran. The study consisted of two groups of patients, one with major depressive and the other with bipolar mood disorders and one healthy group. Each group had 40 patients (20 men and 20 women). The study data were collected through BIS and BAS questionnaire, Beck Depression Inventory (BDI-II), Young Mania Rating Scale (YMRS). The obtained data were analyzed by SPSS version 18. Results: The findings showed a significant negative correlation between BIS, BAS and BAS subscales with the severity of depression and positive correlation with mania symptoms (P<0.05). Conclusion: BAS and BIS dysregulations may predispose people to mood disorder symptoms. BAS is hyperactive during manic phase and may predict the symptom severity of bipolar mood disorder. PMID- 30519385 TI - Comparison of Effects of Light Anesthetics, Diethyl Ether and Carbon Dioxide, on Hypothalamic Paraventricular Nucleus D1 and D2 Dopamine Receptors- and Glucosensitive Neurons-Induced Food Intake in Fasted Conscious Rats. AB - Introduction: Carbon Dioxide (CO2) and diethyl ether are used as light anesthetics. However, experimental data about their side effects are scarce. In addition, in all our previous works on regulatory mechanisms of hypothalamus during food intake, including the effect of Paraventricular Nucleus (PVN) D1 and D2 dopamine receptors and glucosensitive neurons, the drug injections were performed under brief diethyl ether anesthesia. In the current study, we tested the hypothesis which postulates that CO2 and diethyl ether as light anesthetic agents affect the stimulatory effect of PVN dopamine receptors and glucosensitive neurons in feeding behavior. Methods: Male Wistar rats were implanted with guide cannula directed to their PVN. Glucose (0.8 MUg), SKF38393 (D1 agonist, 0.5 MUg), quinpirole (D2 agonist, 0.3 MUg) and saline (0.3 MUL) were microinjected into the PVN and food intake was measured over 1 hour. Results: Our results showed that CO2 but not diethyl ether decreased food intake compared to intact animals. The PVN injections of glucose, SKF38393, and quinpirole increased food intake under brief diethyl ether anesthesia. In contrast, the PVN microinjected glucose induced and dopamine receptor agonists-induced food intake were inhibited under light CO2 anesthesia. Conclusion: Our results suggest that brief exposure to CO2 and diethyl ether as light anesthetic agents may affect PVN glucosensing neurons induced and dopamine receptors-induced food intake in fasted rats. PMID- 30519386 TI - Assessing the Effects of Opioids on Pathological Memory by a Computational Model. AB - Introduction: Opioids hijack learning and memory formation mechanisms of brain and induce a pathological memory in the hippocampus. This effect is mainly mediated by modifications in glutamatergic system. Speaking more precisely, Opioids presence in a synapse inhibits blockage of N-Methyl-D-Aspartate Receptor (NMDAR) by Mg2+, enhances conductance of NMDAR and thus, induces false Long-Term Potentiation (LTP). Methods: Based on experimental observations of different researchers, we developed a mathematical model for a pyramidal neuron of the hippocampus to study this false LTP. The model contains a spine of the pyramidal neuron with NMDAR, alpha-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic Acid Receptors (AMPARs), and Voltage-Gated Calcium Channels (VGCCs). The model also describes Calmodulin-dependent protein Kinase II (CaMKII) and AMPAR phosphorylation processes which are assumed to be the indicators of LTP induction in the synapse. Results: Simulation results indicate that the effect of inhibition of blockage of NMDARs by Mg2+ on the false LTP is not as crucial as the effect of NMDAR's conductance modification by opioids. We also observed that activation of VGCCs has a dominant role in inducing pathological LTP. Conclusion: Our results confirm that preventing this pathological LTP is possible by three different mechanisms: 1. By decreasing NMDAR's conductance; and 2. By attenuating VGCC's mediated current; and 3. By enhancing glutamate clearance rate from the synapse. PMID- 30519387 TI - Effects of Clavulanic Acid on the Acquisition and Reinstatement Following Morphine-induced Conditioned Place Preference in Mice. AB - Introduction: beta-Lactam antibiotics like Clavulanic Acid (CA) enhances cellular glutamate uptake through activation of Glutamate Transporter subtype 1 (GLT-1) and decreases the level of glutamate in the nervous system. Based on studies, blocking the glutamate activity inhibits morphine-induced Conditioned Place Preference (CPP) in animals. Therefore, the effects of CA on the acquisition of morphine craving were evaluated using the CPP model in the current study. Methods: CA (1, 50 and 150 mg/kg, ip) was co-administered with morphine (40 mg/kg) for 4 days in the conditioning phase. On day 8, the effects of CA on morphine preference was assessed. In another experiment, the effect of CA on reinstatement of morphine preference by a single morphine injection (10 mg/kg) was evaluated after an extinction period. Results: In the first method, the morphine-induced place preference was markedly reduced following administration of CA (50 and 150 mg/kg). In the second experiment, a single administration of CA (50 and 150 mg/kg) markedly inhibited the reinstatement of morphine preference on day 16. The results indicated that CA (50, 150 mg/kg) can block both morphine induced CPP and the reinstatement of place preference following priming dose of morphine. Also memantine (as a positive control) (10 mg/kg) significantly inhibited both acquisition and reinstatement of morphine CPP. Conclusion: Considering the important role of glutamate neurotransmission in morphine dependence, the effects of CA may be partly due to decrease in glutamate level in synaptic space and blockade of N-Methyl-D-aspartate Acid (NMDA) receptors. Although, we need further studies to determine exact cellular mechanism. PMID- 30519388 TI - The Conference of the Birds: An Old Artistic Concept Making Sense in Modern Sciences. AB - In this article, we will discuss scientific aspects of an old Persian story, Simorgh, in the book of The Conference of the Birds. The story is fulfilled with artistic and philosophical metaphors that make sense in two hot topics of the contemporary modern sciences i.e. cognitive science and complexity science. The poet addresses some humanity's bygone concerns and fundamental questions about self, the quality that shapes a person's uniqueness, and essential existence. The sophisticated language used in the poem contains allusions, symbols, and implications that are interpreted in five main topics. We think that the story deserves to be the touchstone for questions on the nature of the mind, including the profound question of humanity's search for self and meaning of life. PMID- 30519389 TI - Maternal mRNA input of growth and stress-response-related genes in cichlids in relation to egg size and trophic specialization. AB - Background: Egg size represents an important form of maternal effect determined by a complex interplay of long-term adaptation and short-term plasticity balancing egg size with brood size. Haplochromine cichlids are maternal mouthbrooders showing differential parental investment in different species, manifested in great variation in egg size, brood size and duration of maternal care. Little is known about maternally determined molecular characters of eggs in fishes and their relation to egg size and trophic specialization. Here we investigate maternal mRNA inputs of selected growth- and stress-related genes in eggs of mouthbrooding cichlid fishes adapted to different trophic niches from Lake Tanganyika, Lake Malawi, Lake Victoria and compare them to their riverine allies. Results: We first identified two reference genes, atf7ip and mid1ip1, to be suitable for cross-species quantification of mRNA abundance via qRT-PCR in the cichlid eggs. Using these reference genes, we found substantial variation in maternal mRNA input for a set of candidate genes related to growth and stress response across species and lakes. We observed negative correlation of mRNA abundance between two of growth hormone receptor paralogs (ghr1 and ghr2) across all haplochromine cichlid species which also differentiate the species in the two younger lakes, Malawi and Lake Victoria, from those in Lake Tanganyika and ancestral riverine species. Furthermore, we found correlations between egg size and maternal mRNA abundance of two growth-related genes igf2 and ghr2 across the haplochromine cichlids as well as distinct clustering of the species based on their trophic specialization using maternal mRNA abundance of five genes (ghr1, ghr2, igf2, gr and sgk1). Conclusions: These findings indicate that variations in egg size in closely related cichlid species can be linked to differences in maternal RNA deposition of key growth-related genes. In addition, the cichlid species with contrasting trophic specialization deposit different levels of maternal mRNAs in their eggs for particular growth-related genes; however, it is unclear whether such differences contribute to differential morphogenesis at later stages of development. Our results provide first insights into this aspect of gene activation, as a basis for future studies targeting their role during ecomorphological specialization and adaptive radiation. PMID- 30519390 TI - Eosinophil Counts in Mucosal Biopsies of the Ileum and Colon: Interobserver Variance Affects Diagnostic Accuracy. AB - Primary eosinophilic gastroenteritis and colitis (EGE) is a rare entity with unspecific clinical and endoscopic findings. Validated histopathologic criteria for confirming the diagnosis are lacking, because numeric values for normal or elevated concentrations of eosinophils in mucosal biopsies are varying between observers. To quantify this interobserver variance, we had the same set of 30 slides of eosinophilic-rich mucosal biopsies from the ileum and colon systematically reviewed by a panel of six independent pathologists, each with more than a ten-year experience in the field. Using a highly standardized biopsy and slide preparation protocol, we ruled out any influence by the preparation, the patient, the endoscopist, the endoscopes and calipers used, the sampling site, the fixation and staining method, and the microscopic field sizes. Still, all numeric results differed between pathologists up to a factor greater than 30. Calculated positive or negative diagnosis of EGE differed up to a factor greater than 8. A theoretical incidence for EGE calculated from these numbers differed by a factor greater than 1500. We conclude that eosinophil counts in mucosal biopsies from the lower gastrointestinal tract are subject to a very high interobserver variance. Until further research provides objective and validated methods for standardization, all epidemiologic numbers derived from histopathologic findings may have to be questioned. When diagnosing individual patients with EGE, overall morphologic picture together with clinical and endoscopic findings is more important than numeric eosinophil count. PMID- 30519391 TI - Study of Endothelio- and Osteoprotective Effects of Combination of Rosuvastatin with L-Norvaline in Experiment. AB - The experiment was carried out on 120 female white Wistar rats, to study the endothelio- and osteoprotective action of the combination of rosuvastatin with L norvaline in the model of experimental osteoporosis. It was found that, after ovariectomy in rats, endothelial dysfunction of the vessels of the microcirculatory bed of bone tissue develops, leading to the appearance of osteoporosis, but the combination of the studied drugs prevents the decrease in the level of microcirculation in the bone tissue, thereby preventing the thinning of bone trabeculae and preventing the occurrence of microfractures in them. PMID- 30519392 TI - TUG1 confers cisplatin resistance in esophageal squamous cell carcinoma by epigenetically suppressing PDCD4 expression via EZH2. AB - Background: Increasing evidence has suggested the involvement of long non-coding RNA taurine upregulated gene 1 (TUG1) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in esophageal squamous cell carcinoma (ESCC) chemoresistance are still not well elucidated. In the present study, we investigate the functional role of TUG1 in cisplatin (DDP) resistance of ESCC and discover the underlying molecular mechanism. Results: Our study revealed that TUG1 was up-regulated in DDP-resistant ESCC tissues and cells. High TUG1 expression was correlated with poor prognosis of ESCC patients. TUG1 knockdown improved the sensitivity of ECA109/DDP and EC9706/DDP cells to DDP. Moreover, TUG1 could epigenetically suppress PDCD4 expression via recruiting enhancer of zeste homolog 2. PDCD4 overexpression could mimic the functional role of down-regulated TUG1 in DDP resistance. PDCD4 knockdown counteracted the inductive effect of TUG1 inhibition on DDP sensitivity of ECA109/DDP and EC9706/DDP cells. Furthermore, TUG1 knockdown facilitated DDP sensitivity of DDP resistant ESCC cells in vivo. Conclusion: TUG1 knockdown overcame DDP resistance of ESCC by epigenetically silencing PDCD4, providing a novel therapeutic target for ESCC. PMID- 30519393 TI - Elevated expression of IL-17RB and ST2 on myeloid dendritic cells is associated with a Th2-skewed eosinophilic inflammation in nasal polyps. AB - Background: Interleukin(IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) underlie the crosstalk between epithelial cells and dendritic cells (DCs) during the development of Th2 responses. This study aimed to measure the expressions of IL-17RB, ST2 and TSLPR, receptor of IL-25, IL-33, and TSLP respectively, on myeloid DCs in nasal polyps (NP) and evaluate their association with local Th2 inflammation and disease severity in patients with NP. Methods: Samples were collected from 30 NP patients and 16 control subjects recruited prospectively. The mRNA expression of cytokines, including TSLP, IL-25 and IL-33, as well as interferon (IFN)-gamma, IL-4, IL-5, IL-13 and IL-17A in NP and control tissues was examined by qualitative polymerase chain reaction (qPCR). The expression of IL-17RB, ST2 and TSLPR as well as other surface markers on myeloid DCs (mDCs) was examined by flow cytometry. Results: Increased numbers of total and activated mDCs were found in NP patients. mDCs demonstrated significantly higher expression of IL-17RB, ST2 and TSLPR than those in control tissues. The activated mDCs exhibited up-regulations of OX40L and ICOSL, but down-regulation of PDL1 in NP. Moreover, the IL-17RB, ST2 and TSLPR levels on mDCs were positively correlated with IL-25, IL-33 and TSLP mRNA levels, respectively, in NP. Furthermore, IL-17RB and ST2 expressions on mDCs were correlated with the IL-5 mRNA level as well as eosinophil number in NP. Importantly, the IL-17RB expression on mDCs and the OX40L expression on activated mDCs in NP were positively correlated with CT score and total nasal symptom score. Conclusions: Increased expressions of IL-17RB and ST2 on mDCs are associated with enhanced local Th2 inflammation in NP, suggesting that mDCs might play a role in IL-25- and IL-33-induced type 2 responses and eosinophilic inflammation in NP. PMID- 30519394 TI - Pooled whole-genome sequencing of interspecific chestnut (Castanea) hybrids reveals loci associated with differences in caching behavior of fox squirrels (Sciurus niger L.). AB - Dispersal of seeds by scatter-hoarding rodents is common among tropical and temperate tree species, including chestnuts in the genus Castanea. Backcrossed (BC) interspecific hybrid chestnuts exhibit wide variation in seed traits: as the parent species (Castanea dentata and C. mollissima) have distinct seed phenotypes and tend to be handled differently by seed dispersers, phenotypic variation in BC trees is likely due to inheritance of genes that have undergone divergent evolution in the parent species. To identify candidate genomic regions for interspecific differences in seed dispersal, we used tagged seeds to measure average dispersal distance for seeds of third-generation BC chestnuts and sequenced pooled whole genomes of mother trees with contrasting seed dispersal: high caching rate/long distance; low caching rate/short distance; no caching. Candidate regions affecting seed dispersal were identified as loci with more C. mollissima alleles in the high caching rate/ long-distance pool than expected by chance and observed in the other two pools. Functional annotations of candidate regions included predicted lipid metabolism, dormancy regulation, seed development, and carbohydrate metabolism genes. The results support the hypothesis that perception of seed dormancy is a predominant factor in squirrel caching decisions, and also indicate profitable directions for future work on the evolutionary genomics of trees and coevolved seed dispersers. PMID- 30519395 TI - The importance of competition for light depends on productivity and disturbance. AB - Eutrophication is a major cause of biodiversity loss. In grasslands, this appears to occur due to asymmetric competition for light following the increases in aboveground biomass production. Here, we report the results of an experiment with five grass species that tests how well-competitive outcomes can be predicted under a factorial combination of fertilized and disturbed (frequent cutting) conditions. Under fertile conditions, our results confirm earlier success in predicting short-term competitive outcomes based on light interception in monocultures. This effect was maintained but weakened under less fertile conditions with competition becoming more symmetric. However, under disturbed conditions, competitive outcomes could not be predicted from differences in light interception in monocultures regardless of fertility. Our results support the idea that competition in grasslands shifts from symmetric to asymmetric as fertility increases but that disturbance destroys this relationship, presumably by preventing the development of differences in canopy structure and reducing competition for light. PMID- 30519396 TI - Migratory connectivity in the Loggerhead Shrike (Lanius ludovicianus). AB - Aim: We combine genetic and stable isotope data to quantify migration patterns in Loggerhead Shrike (Lanius ludovicianus), a species of conservation concern in North America, to assess how connectivity differs and impacts population evolution, ecology, and conservation. Location: We sampled shrikes across the majority of their nonbreeding range, from the Atlantic Coast to the western United States east of the Rocky Mountains and throughout Mexico. Methods: Our study used a Bayesian framework using delta2Hf from a breeding season origin feather and nuclear genetic microsatellite markers to distinguish between co occurring migratory and nonmigratory individuals on the wintering grounds and, for migrants, to assign individuals to a breeding ground origin and genetic group. Results: Migratory shrikes were present throughout the nonbreeding range but the proportion differed among sample areas. Four main wintering areas were identified. Connectivity ranged from weakly negative in birds wintering on the Atlantic Coast to strongly positive between wintering grounds in the southwestern United States and Mexico and northwestern breeding populations. Connectivity was weakest in L. l. migrans, and strongest in L. l. mexicanus and L. l. excubitorides. Although believed to be nonmigratory, long-distance movements of individuals were observed in L. ludovicianus and L. l. mexicanus. Our data support a pattern of chain migration, again most notable in the western half of the species nonbreeding range, and differential migration based on age. Main conclusions: Our study provides of one such of the first quantitative measures of migratory connectivity and is among the first studies of a short-distance migratory passerine in North America. The higher migratory connectivity among western, versus eastern populations, and less severe population declines attributable to habitat loss or reproductive success, may result in more localized and/or less severe limiting factors for western populations and more severe on the Atlantic coast and Mississippi Alluvial Valley wintering grounds. PMID- 30519397 TI - The first complete mitochondrial genome of the Mariana Trench Freyastera benthophila (Asteroidea: Brisingida: Brisingidae) allows insights into the deep sea adaptive evolution of Brisingida. AB - Starfish (phylum Echinodermata) are ecologically important and diverse members of marine ecosystems in all of the world's oceans, from the shallow water to the hadal zone. The deep sea is recognized as an extremely harsh environment on earth. In this study, we present the mitochondrial genome sequence of Mariana Trench starfish Freyastera benthophila, and this study is the first to explore in detail the mitochondrial genome of a deep-sea member of the order Brisingida. Similar to other starfish, it contained 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes (duplication of two tRNAs: trnL and trnS). Twenty-two of these genes are encoded on the positive strand, while the other 15 are encoded on the negative strand. The gene arrangement was identical to those of sequenced starfish. Phylogenetic analysis showed the deep-sea Brisingida as a sister taxon to the traditional members of the Asteriidae. Positive selection analysis indicated that five residues (8 N and 16 I in atp8, 47 D and 196 V in nad2, 599 N in nad5) were positively selected sites with high posterior probabilities. Compared these features with shallow sea starfish, we predict that variation specifically in atp8, nad2, and nad5 may play an important role in F. benthophila's adaptation to deep-sea environment. PMID- 30519398 TI - Plant phenological asynchrony and community structure of gall-inducing insects associated with a tropical tree species. AB - The dynamics of occurrence of target organs in plant populations produces windows of opportunity that directly and indirectly affect the structure of herbivore communities. However, mechanisms that drive herbivore specialization between resource patches are still poorly known. In this study, we tested three hypotheses related to variation in host plant phenology and community structure (i.e., composition, richness, and abundance) of gall-forming species: (a) plants with early leaf-flushing in the season will have greater vegetative growth and high contents of secondary chemical compounds; (b) gall-inducing insect community structure changes among temporary resource patches of the host; and (c) interspecific competition is a probable mechanism that drives gall-inducing insect community structure on Copaifera langsdorffii. We monitored daily a total of 102 individuals of the super-host C. langsdorffii from August 2012 to May 2013, to characterize the leaf flushing time of each host plant. The leaf flushing time had a positive relationship with the number of folioles per branch and a negative relationship with branch growth. We sampled a total of 4,906 galls belonging to 24 gall-inducing insect species from 102 individuals of C. langsdorffii. In spite of some gall-inducing species presented high abundance on early leaf-flushing plants, direct and indirect effects of plant phenology on galling insect abundance was species dependent. At the community level, our study revealed that the quality and quantity of plant resources did not affect the richness and abundance of gall-inducing insects associated with C. langsdorffii. However, the richness and composition of gall-inducing species varied according to the variation in leaf flushing time of the host plant. The results of null model analysis showed that galls co-occurrence on C. langsdorffii trees differ more than expected by chance and that interspecific competition can be one potential mechanism structuring this gall-inducing insect community. PMID- 30519399 TI - Noninvasive western lowland gorilla's health monitoring: A decade of simian immunodeficiency virus surveillance in southern Cameroon. AB - Simian immunodeficiency virus (SIVgor) causes persistent infection in critically endangered western lowland gorillas (Gorilla gorilla gorilla) from west central Africa. SIVgor is closely related to chimpanzee and human immunodeficiency viruses (SIVcpz and HIV-1, respectively). We established a noninvasive method that does not interfere with gorillas' natural behaviour to provide wildlife pathogen surveillance and health monitoring for conservation. A total of 1,665 geo-referenced fecal samples were collected at regular intervals from February 2006 to December 2014 (123 sampling days) in the Campo-Ma'an National Park (southwest Cameroon). Host genotyping was performed using microsatellite markers, SIVgor infection was identified by serology and genetic amplification was attempted on seropositive individuals. We identified at least 125 distinct gorillas, 50 were resampled (observed 3.5 times in average) and 38 were SIVgor+ (seven individuals were seroconverters). Six groups of gorillas were identified based on the overlapping occurrence of individuals with apparent high rates of gene flow. We obtained SIVgor genetic sequences from 25 of 38 seropositive genotyped gorillas and showed that the virus follows exponential growth dynamics under a strict molecular clock. Different groups shared SIVgor lineages demonstrating intergroup viral spread and recapture of positive individuals illustrated intra-host viral evolution. Relatedness and relationship genetic analysis of gorillas together with Bayesian phylogenetic inference of SIVgor provided evidence suggestive of vertical transmission. In conclusion, we provided insights into gorilla social dynamics and SIVgor evolution and emphasized the utility of noninvasive sampling to study wildlife health populations. These findings contribute to prospective planning for better monitoring and conservation. PMID- 30519400 TI - Evolutionary effects of fishing gear on foraging behavior and life-history traits. AB - Fishing gears are designed to exploit the natural behaviors of fish, and the concern that fishing may cause evolution of behavioral traits has been receiving increasing attention. The first intuitive expectation is that fishing causes evolution toward reduced boldness because it selectively removes actively foraging individuals due to their higher encounter rate and vulnerability to typical gear. However, life-history theory predicts that fishing, through shortened life span, favors accelerated life histories, potentially leading to increased foraging and its frequent correlate, boldness. Additionally, individuals with accelerated life histories mature younger and at a smaller size and therefore spend more of their life at a smaller size where mortality is higher. This life-history evolution may prohibit increases in risk-taking behavior and boldness, thus selecting for reduced risk-taking and boldness. Here, we aim to clarify which of these three selective patterns ends up being dominant. We study how behavior-selective fishing affects the optimal behavioral and life history traits using a state-dependent dynamic programming model. Different gear types were modeled as being selective for foraging or hiding/resting individuals along a continuous axis, including unselective fishing. Compared with unselective harvesting, gears targeting hiding/resting individuals led toward evolution of increased foraging rates and elevated natural mortality rate, while targeting foraging individuals led to evolution of decreased foraging rates and lower natural mortality rate. Interestingly, changes were predicted for traits difficult to observe in the wild (natural mortality and behavior) whereas the more regularly observed traits (length-at-age, age at maturity, and reproductive investment) showed only little sensitivity to the behavioral selectivity. PMID- 30519401 TI - Maternal age effects on fecundity and offspring egg-to-adult viability are not affected by mitochondrial haplotype. AB - While numerous studies have demonstrated that mitochondrial genetic variation can shape organismal phenotype, the level of contribution the mitochondrial genotype makes to life-history phenotype across the life course remains unknown. Furthermore, a clear technical bias has emerged in studies of mitochondrial effects on reproduction, with many studies conducted on males, but few on females. Here, we apply a classic prediction of the evolutionary theory of aging to the mitochondrial genome, predicting the declining force of natural selection with age will have facilitated the accumulation of mtDNA mutations that confer late-life effects on female reproductive performance. This should lead to increased levels of mitochondrial genetic variation on reproduction at later-life stages. We tested this hypothesis using thirteen strains of Drosophila melanogaster that each possessed a different mitochondrial haplotype in an otherwise standard nuclear genetic background. We measured fecundity and egg-to adult viability of females over five different age classes ranging from early to late life and quantified the survival of females throughout this time period. We found no significant variation across mitochondrial haplotypes for the reproductive traits, and no mitochondrial effect on the slope of decline in these traits with increasing age. However, we observed that flies that died earlier in the experiment experienced steeper declines in the reproductive traits prior to death, and we also identified maternal and grandparental age effects on the measured traits. These results suggest the mitochondrial variation does not make a key contribution to shaping the reproductive performance of females. PMID- 30519402 TI - Hidden cost of disease in a free-ranging ungulate: brucellosis reduces mid-winter pregnancy in elk. AB - Demonstrating disease impacts on the vital rates of free-ranging mammalian hosts typically requires intensive, long-term study. Evidence for chronic pathogens affecting reproduction but not survival is rare, but has the potential for wide ranging effects. Accurately quantifying disease-associated reductions in fecundity is important for advancing theory, generating accurate predictive models, and achieving effective management. We investigated the impacts of brucellosis (Brucella abortus) on elk (Cervus canadensis) productivity using serological data from over 6,000 captures since 1990 in the Greater Yellowstone Ecosystem, USA. Over 1,000 of these records included known age and pregnancy status. Using Bayesian multilevel models, we estimated the age-specific pregnancy probabilities of exposed and naive elk. We then used repeat-capture data to investigate the full effects of the disease on life history. Brucellosis exposure reduced pregnancy rates of elk captured in mid- and late-winter. In an average year, we found 60% of exposed 2-year-old elk were pregnant compared to 91% of their naive counterparts (a 31 percentage point reduction, 89% HPDI = 20%-42%), whereas exposed 3- to 9-year-olds were 7 percentage points less likely to be pregnant than naive elk of their same age (89% HPDI = 2%-11%). We found these reduced rates of pregnancy to be independent from disease-induced abortions, which afflict a portion of exposed elk. We estimate that the combination of reduced pregnancy by mid-winter and the abortions following mid-winter reduces the reproductive output of exposed female elk by 24%, which affects population dynamics to a similar extent as severe winters or droughts. Exposing hidden reproductive costs of disease is essential to avoid conflating them with the effects of climate and predation. Such reproductive costs cause complex population dynamics, and the magnitude of the effect we found should drive a strong selection gradient if there is heritable resistance. PMID- 30519403 TI - Mycorrhizal interactions do not influence plant-herbivore interactions in populations of Clarkia xantiana ssp. xantiana spanning from center to margin of the geographic range. AB - Multispecies interactions can be important to the expression of phenotypes and in determining patterns of individual fitness in nature. Many plants engage in symbiosis with arbuscular mycorrhizal fungi (AMF), but the extent to which AMF modulate other species interactions remains poorly understood. We examined multispecies interactions among plants, AMF, and insect herbivores under drought stress using a greenhouse experiment and herbivore choice assays. The experiment included six populations of Clarkia xantiana (Onagraceae), which span a complex environmental gradient in the Southern Sierra Nevada of California. Clarkia xantiana's developing fruits are commonly attacked by grasshoppers at the end of the growing season, and the frequency of attack is more common in populations from the range center than range margin. We found that AMF negatively influenced all metrics of plant growth and reproduction across all populations, presumably because plants supplied carbon to AMF but did not benefit substantially from resources potentially supplied by the AMF. The fruits of plants infected with AMF did not differ from those without AMF in their resistance to grasshoppers. There was significant variation among populations in damage from herbivores but did not reflect the center-to-margin pattern of herbivory observed in the field. In sum, our results do not support the view that AMF interactions modulate plant herbivore interactions in this system. PMID- 30519404 TI - Size-dependent movement explains why bigger is better in fragmented landscapes. AB - Body size is a fundamental trait known to allometrically scale with metabolic rate and therefore a key determinant of individual development, life history, and consequently fitness. In spatially structured environments, movement is an equally important driver of fitness. Because movement is tightly coupled with body size, we expect habitat fragmentation to induce a strong selection pressure on size variation across and within species. Changes in body size distributions are then, in turn, expected to alter food web dynamics. However, no consensus has been reached on how spatial isolation and resource growth affect consumer body size distributions. Our aim was to investigate how these two factors shape the body size distribution of consumers under scenarios of size-dependent and size independent consumer movement by applying a mechanistic, individual-based resource-consumer model. We also assessed the consequences of altered body size distributions for important ecosystem traits such as resource abundance and consumer stability. Finally, we determined those factors that explain most variation in size distributions. We demonstrate that decreasing connectivity and resource growth select for communities (or populations) consisting of larger species (or individuals) due to strong selection for the ability to move over longer distances if the movement is size-dependent. When including size-dependent movement, intermediate levels of connectivity result in increases in local size diversity. Due to this elevated functional diversity, resource uptake is maximized at the metapopulation or metacommunity level. At these intermediate levels of connectivity, size-dependent movement explains most of the observed variation in size distributions. Interestingly, local and spatial stability of consumer biomass is lowest when isolation and resource growth are high. Finally, we highlight that size-dependent movement is of vital importance for the survival of populations or communities within highly fragmented landscapes. Our results demonstrate that considering size-dependent movement is essential to understand how habitat fragmentation and resource growth shape body size distributions-and the resulting metapopulation or metacommunity dynamics-of consumers. PMID- 30519405 TI - Evaluation of modeling strategies for assessing self-thinning behavior and carrying capacity. AB - Self-thinning and site maximum carrying capacity are key concepts for understanding and predicting ecosystem dynamics as they represent the outcome of several fundamental ecological processes (e.g., mortality and growth). Relationships are often derived using alternative modeling strategies, depending on the statistical approach, model formulation, and underlying data with unclear implications of these various assumptions. In this analysis, the influence of contrasting modeling strategies for estimating the self-thinning relationship and maximum carrying capacity in long-term, permanent plot data (n = 130) from the mixed Nothofagus forests in southern Chile was assessed and compared. Seven contrasting modeling strategies were used including ordinary least squares, quantile, and nonlinear regression that were formulated based on static (no remeasurements) or dynamic data (with remeasurements). Statistically distinct differences among these seven approaches were identified with mean maximum carrying capacity ranging from 1,050 to 1,912 stems/ha depending on the approach. The population-level static approach based on quantile regression produced an estimate closest to the overall mean with site-level carrying capacity depending on tree species diversity and climate. Synthesis and applications. Overall, the findings highlight strong variability within and between contrasting methods of determining self-thinning and site maximum carry capacity, which may influence ecological inferences. PMID- 30519406 TI - Plasticity in nesting adaptations of a tidal marsh endemic bird. AB - If individuals can perceive and manage risks, they may alter their behaviors based on prior experience. This expectation may apply to nest site selection of breeding birds, for which adaptive behavioral responses may enhance fitness. Birds that nest in tidal marshes have adapted to the challenges posed primarily by periodic, monthly tidal flooding and secondarily by predation. We investigated adaptive responses in nesting behavior of the saltmarsh sparrow (Ammospiza caudacutus), an obligate tidal-marsh-breeding bird, using 536 nests monitored across 5 years. Using linear mixed effects models, we tested whether nest characteristics differed among nests that were successful, depredated, or flooded, and we investigated whether females made changes in nest structure and placement according to outcome of their previous nesting attempt. Nest characteristics differed among females with different nest fates. Fledged and depredated nests were built higher in the vegetation and in higher elevation areas of the marsh than those that flooded. Successful nests had more canopy cover and were comprised of a lower proportion of high marsh vegetation (Spartina patens) than those that were flooded or depredated. Females with nests that failed due to flooding constructed subsequent nests higher in the vegetation and at higher elevation than those that were successful in their prior attempt, consistent with a response to previous experience. Eighty-five percent of females renested within the average home range core area distance (77 m), indicating a high degree of nest placement fidelity. Females for which nests were depredated in their prior nesting attempt renested at a greater distance than females for which the previous nesting attempts were successful. Our findings suggest saltmarsh sparrows exhibit plasticity in nesting behavior, which may be important for balancing selective pressures in a dynamic environment. This plasticity, however, is insufficient to enable them to adapt to the increased flooding predicted with sea-level rise. PMID- 30519407 TI - Effects of model choice, network structure, and interaction strengths on knockout extinction models of ecological robustness. AB - Analysis of ecological networks is a valuable approach to understanding the vulnerability of systems to disturbance. The tolerance of ecological networks to coextinctions, resulting from sequences of primary extinctions (here termed "knockout extinction models", in contrast with other dynamic approaches), is a widely used tool for modeling network "robustness". Currently, there is an emphasis to increase biological realism in these models, but less attention has been given to the effect of model choices and network structure on robustness measures. Here, we present a suite of knockout extinction models for bipartite ecological networks (specifically plant-pollinator networks) that can all be analyzed on the same terms, enabling us to test the effects of extinction rules, interaction weights, and network structure on robustness. We include two simple ecologically plausible models of propagating extinctions, one new and one adapted from existing models. All models can be used with weighted or binary interaction data. We found that the choice of extinction rules impacts robustness; our two propagating models produce opposing effects in all tests on observed plant pollinator networks. Adding weights to the interactions tends to amplify the opposing effects and increase the variation in robustness. Variation in robustness is a key feature of these extinction models and is driven by the structural heterogeneity of nodes (specifically, the skewness of the plant degree distribution) in the network. Our analysis therefore reveals the mechanisms and fundamental network properties that drive observed trends in robustness. PMID- 30519408 TI - The impact of autotrophic versus heterotrophic nutritional pathways on colony health and wound recovery in corals. AB - For animals that harbor photosynthetic symbionts within their tissues, such as corals, the different relative contributions of autotrophy versus heterotrophy to organismal energetic requirements have direct impacts on fitness. This is especially true for facultatively symbiotic corals, where the balance between host-caught and symbiont-produced energy can be altered substantially to meet the variable demands of a shifting environment. In this study, we utilized a temperate coral-algal system (the northern star coral, Astrangia poculata, and its photosynthetic endosymbiont, Symbiodinium psygmophilum) to explore the impacts of nutritional sourcing on the host's health and ability to regenerate experimentally excised polyps. For fed and starved colonies, wound healing and total colony tissue cover were differentially impacted by heterotrophy versus autotrophy. There was an additive impact of positive nutritional and symbiotic states on a coral's ability to initiate healing, but a greater influence of symbiont state on the recovery of lost tissue at the lesion site and complete polyp regeneration. On the other hand, regardless of symbiont state, fed corals maintained a higher overall colony tissue cover, which also enabled more active host behavior (polyp extension) and endosymbiont behavior (photosynthetic ability of Symbiondinium). Overall, we determined that the impact of nutritional state and symbiotic state varied between biological functions, suggesting a diversity in energetic sourcing for each of these processes. PMID- 30519409 TI - SSR-seq: Genotyping of microsatellites using next-generation sequencing reveals higher level of polymorphism as compared to traditional fragment size scoring. AB - Microsatellites (or simple sequence repeats, SSR) are widely used markers in population genetics. Traditionally, genotyping was and still is carried out through recording fragment length. Now, next-generation sequencing (NGS) makes it easy to obtain also sequence information for the loci of interest. This avoids misinterpretations that otherwise could arise due to size homoplasy. Here, an NGS strategy is described that allows to genotype hundreds of individuals at many custom-designed SSR loci simultaneously, combining multiplex PCR, barcoding, and Illumina sequencing. We created three different datasets for which alleles were coded according to (a) length of the repetitive region, (b) total fragment length, and (c) sequence identity, in order to evaluate the eventual benefits from having sequence data at hand, not only fragment length data. For each dataset, genetic diversity statistics, as well as F ST and R ST values, were calculated. The number of alleles per locus, as well as observed and expected heterozygosity, was highest in the sequence identity dataset, because of single nucleotide polymorphisms and insertions/deletions in the flanking regions of the SSR motif. Size homoplasy was found to be very common, amounting to 44.7%-63.5% (mean over all loci) in the three study species. Thus, the information obtained by next-generation sequencing offers a better resolution than the traditional way of SSR genotyping and allows for more accurate evolutionary interpretations. PMID- 30519410 TI - The effect of plant identity and mixed feeding on the detection of seed DNA in regurgitates of carabid beetles. AB - Carabids are abundant in temperate agroecosystems and play a pivotal role as biocontrol agents for weed seed and pest regulation. While there is good knowledge regarding their effects on invertebrate pests, direct evidence for seed predation in the field is missing. Molecular approaches are ideally suited to investigate these feeding interactions; however, the effects of an omnivorous diet, which is characteristic for many carabid species, and seed identity on the detection success of seed DNA has not yet been investigated. In a series of feeding experiments, seeds of six different Central European weed species were fed to beetles of the species Pseudoophonus rufipes, to determine post-feeding seed DNA detection rates and how these are affected by plant identity, meal size, and chemical seed composition. Moreover, we investigated the effect of a mixed diet of seeds and mealworm on prey DNA detection. Four out of six seed species were detectable for up to five days after consumption, and seed species identity significantly affected post-feeding detection rates. Detectability was negatively influenced by protein content and seed mass, whereas oil content and meal size had a positive effect. The mixed diet led to both increased detection rates and post-feeding detection intervals of seed DNA. This suggests that mixed feeding leads to an enhancement of food detection intervals in carabid beetles and that seed identity, their chemical composition, and meal size can affect DNA detection of consumed seeds. These aspects and potential implications of this non-invasive approach are discussed as they can become highly relevant for interpreting field derived data. PMID- 30519411 TI - Trade-off between reproductive and anti-competitor abilities in an insect parasitic nematode-bacteria symbiosis. AB - Mutualistic symbionts can provide diverse benefits to their hosts and often supply key trait variation for host adaptation. The bacterial symbionts of entomopathogenic nematodes play a crucial role in successful colonization of and reproduction in the insect host. Additionally, these symbionts can produce a diverse array of antimicrobial compounds to deter within-host competitors. Natural isolates of the symbiont, Xenorhabdus bovienii, show considerable variation in their ability to target sympatric competitors via bacteriocins, which can inhibit the growth of sensitive Xenorhabdus strains. Both the bacteria and its nematode partner have been shown to benefit from bacteriocin production when within-host competition with a sensitive competitor occurs. Despite this benefit, several isolates of Xenorhabdus do not inhibit sympatric strains. To understand how this variation in allelopathy could be maintained, we tested the hypothesis that inhibiting isolates face a reproductive cost in the absence of competition. We tested this hypothesis by examining the reproductive success of inhibiting and non-inhibiting isolates coupled with their natural nematode host in a non-competitive context. We found that nematodes carrying non-inhibitors killed the insect host more rapidly and were more likely to successfully reproduce than nematodes carrying inhibitors. Lower reproductive success of inhibiting isolates was repeatable across nematode generations and across insect host species. However, no difference in insect mortality was observed between inhibiting and non-inhibiting isolates when bacteria were injected into insects without their nematode partners. Our results indicate a trade-off between the competitive and reproductive roles of symbionts, such that inhibiting isolates, which are better in the face of within-host competition, pay a reproductive cost in the absence of competition. Furthermore, our results support the hypothesis that symbiont variation within populations can be maintained through context dependent fitness benefits conferred to their hosts. As such, our study offers novel insights into the selective forces maintaining variation within a single host-symbiont population and highlights the role of competition in mutualism evolution. PMID- 30519412 TI - A mechanistic assessment of the relationship between gut morphology and endozoochorous seed dispersal by waterfowl. AB - Many plants and invertebrates rely on internal transport by animals for long distance dispersal. Their dispersal capacity is greatly influenced by interactions with the animal's digestive tract. Omnivorous birds adjust their digestive tract morphology to seasonally variable diets. We performed feeding trials in waterfowl to unravel how changing organ size, in combination with seed size, affects dispersal potential. We subjected captive mallards to mimics of summer (animal-based), winter (plant-based), and intermediate diets, and analyzed gut passage of seeds before and after the treatment (trials 1 and 2). To test the effect of gut morphology on seed digestion, we measured digestive organ size after euthanasia. Three hours before euthanasia, differently sized seeds were fed to test how seed size affects gut passage by determining their relative position in the digestive tract (trial 3). Trials 1 and 2 showed that intact seed passage was lower in the plant-based than in the animal-based diet group. Retention time changed only within groups, decreasing in the animal-based, and increasing in the plant-based diet group. No post-diet differences in organ size were detected, probably due to large between-individual variation within groups. Digestive tract measures did not explain variation in seed survival or retention time. Trial 3 revealed that small seeds pass the digestive tract rapidly, while large seeds are retained longer, particularly in the gizzard. Differential retention in the gizzard, the section where seeds can be destroyed, is likely why larger seeds have a lower probability to pass the digestive tract intact. Our results confirm that rapid, flexible adaptation to diet shifts affects seed digestion in waterfowl, although we could not conclusively relate this to organ size. Large interindividual variation in digestive efficiency between mallards feeding on the same diet may provide opportunities for seed dispersal in the field throughout the annual cycle. PMID- 30519413 TI - Small copepods could channel missing carbon through metazoan predation. AB - Global ecosystem models are essential tools for predicting climate change impacts on marine systems. Modeled biogenic carbon fluxes in the ocean often match measured data poorly and part of this could be because small copepods (<2 mm) are modeled as unicellular feeders grazing on phytoplankton and microzooplankton. The most abundant copepods from a seasonal upwelling region of the Eastern North Atlantic were sorted, and a molecular method was applied to copepod gut contents to evaluate the extent of metazoan predation under two oceanographic conditions, a trophic pathway not accounted for in global models. Scaling up the results obtained herein, based on published field and laboratory estimates, suggests that small copepods could ingest 1.79-27.20 gigatons C/year globally. This ignored metazoan-copepod link could increase current estimates of biogeochemical fluxes (remineralization, respiration, and the biological pump) and export to higher trophic levels by 15.6%-24.4%. It could also account for global discrepancies between measured daily ingestion and copepod metabolic demand/growth. The inclusion of metazoan predation into global models could provide a more realistic role of the copepods in the ocean and if these preliminary data hold true at larger sample sizes and scales, the implications would be substantial at the global scale. PMID- 30519414 TI - Accounting for observation processes across multiple levels of uncertainty improves inference of species distributions and guides adaptive sampling of environmental DNA. AB - Understanding factors that influence observation processes is critical for accurate assessment of underlying ecological processes. When indirect methods of detection, such as environmental DNA, are used to determine species presence, additional levels of uncertainty from observation processes need to be accounted for. We conducted a field trial to evaluate observation processes of a terrestrial invasive species (wild pigs- Sus scrofa) from DNA in water bodies. We used a multi-scale occupancy analysis to estimate different levels of observation processes (detection, p): the probability DNA is available per sample (theta), the probability of capturing DNA per extraction (gamma), and the probability of amplification per qPCR run (delta). We selected four sites for each of three water body types and collected 10 samples per water body during two months (September and October 2016) in central Texas. Our methodology can be used to guide sampling adaptively to minimize costs while improving inference of species distributions. Using a removal sampling approach was more efficient than pooling samples and was unbiased. Availability of DNA varied by month, was considerably higher when water pH was near neutral, and was higher in ephemeral streams relative to wildlife guzzlers and ponds. To achieve a cumulative detection probability >90% (including availability, capture, and amplification), future studies should collect 20 water samples per site, conduct at least two extractions per sample, and conduct five qPCR replicates per extraction. Accounting for multiple levels of uncertainty of observation processes improved estimation of the ecological processes and provided guidance for future sampling designs. PMID- 30519415 TI - Evaluating the individuality of animal-habitat relationships. AB - Examining the ways in which animals use habitat and select resources to satisfy their life history requirements has important implications for ecology, evolution, and conservation. The advent of radio-tracking in the mid-20th century greatly expanded the scope of animal-habitat modeling. Thereafter, it became common practice to aggregate telemetry data collected on a number of tagged individuals and fit one model describing resource selection at the population level. This convention, however, runs the risk of masking important individuality in the nature of associations between animals and their environment. Here, we investigated the importance of individual variation in animal-habitat relationships via the study of a highly gregarious species. We modeled elk (Cervus elaphus) location data, collected from Global Positioning System (GPS) collars, using Bayesian discrete choice resource selection function (RSF) models. Using a high-performance computing cluster, we batch-processed these models at the level of each individual elk (n = 88) and evaluated the output with respect to: (a) the composition of parameters in the most supported models, (b) the estimates of the parameters featured in the global models, and (c) spatial maps of the predicted relative probabilities of use. We detected considerable individual variation across all three metrics. For instance, the most supported models varied with respect to parameter composition with a range of seven to 17 and an average of 14.4 parameters per individual elk. The estimates of the parameters featured in the global models also varied greatly across individual elk with little conformity detected across age or sex classes. Finally, spatial mapping illustrated stark differences in the predicted relative probabilities of use across individual elk. Our analysis identifies that animal-habitat relationships, even among the most gregarious of species, can be highly variable. We discuss the implications of our results for ecology and present some guiding principles for the development of RSF models at the individual-animal level. PMID- 30519416 TI - Habitat effects on intra-species variation in functional morphology: Evidence from freshwater fish. AB - Biotic-environment interactions have long been considered an important factor in functional phenotype differentiation in organisms. The differentiation processes determining functional phenotypes can reveal important mechanisms yielding differences in specific functions of animal traits in the ecosystem. In the present study, we examined functional morphological variations in relation to increasing geographic altitude. Six fish species were examined for how environment factors affect intra-specific functional morphology in the subtropical Pearl River in southern China. Functional morphology traits revealed variable effects due to geographic elevation, although spatial autocorrelation existed among the species tested. The results showed that high-elevation individuals had a more narrow-bodied morphology, with more flexible maneuvrability when swimming, and more evenly distributed musculature than low elevation individuals. Low-elevation individuals preyed upon larger food sources than high-elevation individuals in some species. Fish functional morphology was strongly affected by regional environmental factors (such as elevation and water temperature) and physical characteristics of local rivers (such as flow velocity, river fractals, and coefficients of fluvial facies). In addition, the effects of the regional factors were stronger than those of the local factors in the Pearl River. Furthermore, it was found that morphological traits associated with locomotion were primarily effected by the river's physical characteristics. While morphological traits associated with food acquisition were primarily affected by water chemical factors (such as DO, water clarity, NH 4-N concentration, and TDS). These results demonstrated that habitat has an influence on the biological morphology of fish species, which further affects the functioning of the organism within the ecosystem. PMID- 30519417 TI - Table for five, please: Dietary partitioning in boreal bats. AB - Differences in diet can explain resource partitioning in apparently similar, sympatric species. Here, we analyzed 1,252 fecal droppings from five species (Eptesicus nilssonii, Myotis brandtii, M. daubentonii, M. mystacinus, and Plecotus auritus) to reveal their dietary niches using fecal DNA metabarcoding. We identified nearly 550 prey species in 13 arthropod orders. Two main orders (Diptera and Lepidoptera) formed the majority of the diet for all species, constituting roughly 80%-90% of the diet. All five species had different dietary assemblages. We also found significant differences in the size of prey species between the bat species. Our results on diet composition remain mostly unchanged when using either read counts as a proxy for quantitative diet or presence absence data, indicating a strong biological pattern. We conclude that although bats share major components in their ecology (nocturnal life style, insectivory, and echolocation), species differ in feeding behavior, suggesting bats may have distinctive evolutionary strategies. Diet analysis helps illuminate life history traits of various species, adding to sparse ecological knowledge, which can be utilized in conservation planning. PMID- 30519418 TI - Pronounced genetic differentiation in Fokienia hodginsii revealed by simple sequence repeat markers. AB - Fokienia hodginsii is a Tertiary relict conifer of the monotypic genus Fokienia (Cupressaceae s.l.). Currently, the species is distributed in southern China, northern Vietnam, and northern Laos and listed as a "near threatened" species by the IUCN. In this study, a total of 427 individuals of F. hodginsii were sampled from China and Vietnam to characterize its genetic diversity and population differentiation. Based on the profiles of 12 simple sequence repeat (SSR) markers, we observed a high level of genetic diversity in F. hodginsii at the species level (H e =0.635), albeit slightly lower than that of its sister species Chamaecyparis obtusa. Signals of bottleneck events were detected in the populations GXDMS, GXHJ, V-PXB, and V-HB, probably due to Pleistocene glaciations or overexploitation in recent years. Pronounced genetic differentiation (F st = 0.157) was found in this species. The inbreeding index (F is = 0.176 +/- 0.024) indicated that F. hodginsii has a mixed mating system. Significant correlation was found between the pairwise genetic differentiation and geographic distance (r = 0.882, p = 0.01), suggesting that genetic differentiation among the populations follows the model of isolation by distance (IBD). STRUCTURE analysis and principal coordinate analysis revealed that these populations were divided into four groups: the western China group located mainly in the Yunnan-Guizhou Plateau, the central China group located mostly in the Luoxiao Mountains and Nanling Mountains, the eastern China group located in the Wuyi Mountains and the Vietnam group containing two populations in Vietnam. The different terrains and elevations of populations may be the most likely factors leading to the differentiation between the western China group and the central China group, while the geographic isolation caused by the lack of appropriate habitats may greatly contribute to the differentiation between the central China group and the eastern China group. Based on the results, some conservation suggestions for this species are provided, such as establishing seed orchards and multiple nature reserves. PMID- 30519419 TI - The disproportionate importance of long-unburned forests and woodlands for reptiles. AB - Our understanding of the impacts of time since fire on reptiles remains limited, partly because there are relatively few locations where long-term, spatially explicit fire histories are available. Such information is important given the large proportion of some landscapes that are managed with frequent prescribed fire to meet fuel management objectives. We conducted a space-for-time study across a landscape in southeastern Australia where the known fire history spanned 6 months to at least 96 years. Four methods were used to survey reptiles in 81 forest and woodland sites to investigate how time since fire (TSF), habitat, and environmental variables affect reptile richness, abundance, and composition. We used generalized linear models, generalized linear mixed-effects models, PERMANOVA, and SIMPER to identify relationships between the reptile assemblage (richness, abundance, and composition, respectively) and TSF, habitat, and environmental variables. All three reptile metrics were associated with TSF. Reptile richness and abundance were significantly higher in sites >96 years postfire than younger fire ages (0.5-12 years). Reptile composition at long unburned sites was dissimilar to sites burned more recently but was similar between sites burned 0.5-2 and 6-12 years prior to sampling. Synthesis and applications. Long-unburned forests and woodlands were disproportionately more important for reptile richness and abundance than areas burned 6 months to 12 years prior to sampling. This is important given that long-unburned areas represent <8% of our study area. Our results therefore suggest that reptiles would benefit from protecting remaining long-unburned areas from fire and transitioning a greater proportion of the study area to long-unburned. However, some compositional differences between the long-unburned sites and sites 0.5-12 years postfire indicate that maintaining a diversity in fire ages is important for conserving reptile diversity. PMID- 30519420 TI - Genetic evidence of female kin clusters in a continuous population of a solitary carnivore, the Eurasian lynx. AB - Large terrestrial carnivores can sometimes display strong family bonds affecting the spatial distribution of related individuals. We studied the spatial genetic relatedness and family structure of female Eurasian lynx, continuously distributed in southern Finland. We hypothesized that closely related females form matrilineal assemblages, clustering together with relatives living in the neighboring areas. We evaluated this hypothesis using tissue samples of 133 legally harvested female lynx (from year 2007 to 2015), genotyped with 23 microsatellite markers, and tested for possible spatial genetic family structure using a combination of Bayesian clustering, spatial autocorrelation, and forensic genetic parentage analysis. The study population had three potential family genetic clusters, with a high degree of admixture and geographic overlap, and showed a weak but significant negative relationship between pairwise genetic and geographic distance. Moreover, parentage analysis indicated that 64% of the females had one or more close relatives (sister, mother, or daughter) within the study population. Individuals identified as close kin consistently assigned to the same putative family genetic cluster. They also were sampled closer geographically than females on average, although variation was large. Our results support the possibility that Eurasian lynx forms matrilineal assemblages, and comparisons with males are now required to further assess this hypothesis. PMID- 30519421 TI - Managing birds of conservation concern on sandy shores: How much room for future conservation actions is there? AB - Resource limitations often prevent the active management required to maintain habitat quality in protected areas. Because restrictions in access or allowable public activities are the sole conservation measure in these locations, an important question to consider is whether species of conservation concern truly benefit from parcels that are shielded from human disturbance. Here, we assess the conservation benefit of protecting birds from human recreation on over 204 km of sandy beaches by (a) estimating the total area of beach-nesting bird habitat that has been created by conservation protections; (b) quantifying the change in nesting habitat extent should further conservation protections be implemented; and (c) providing data to inform future protected area expansion. We use a maximum entropy species distribution modeling approach to estimate the extent and quality of suitable habitat for four beach-nesting bird species of conservation concern under the existing management regime and compare it to scenarios in which the entire study area is either unprotected of fully protected from human disturbance. Managing humans has dramatic conservation returns for least terns and piping plovers, creating extensive nesting habitat that otherwise would not exist. There is considerable scope for conservation gains, potentially tripling the extent of nesting areas. Expanding conservation footprints for American oystercatchers and black skimmers is predicted to enhance the quality of existing nesting areas. The work demonstrates the utility of modeling changes in habitat suitability to inform protected area expansion on ocean beaches and coastal dunes. PMID- 30519422 TI - Ice ages and butterflyfishes: Phylogenomics elucidates the ecological and evolutionary history of reef fishes in an endemism hotspot. AB - For tropical marine species, hotspots of endemism occur in peripheral areas furthest from the center of diversity, but the evolutionary processes that lead to their origin remain elusive. We test several hypotheses related to the evolution of peripheral endemics by sequencing ultraconserved element (UCE) loci to produce a genome-scale phylogeny of 47 butterflyfish species (family Chaetodontidae) that includes all shallow water butterflyfish from the coastal waters of the Arabian Peninsula (i.e., Red Sea to Arabian Gulf) and their close relatives. Bayesian tree building methods produced a well-resolved phylogeny that elucidated the origins of butterflyfishes in this hotspots of endemism. We show that UCEs, often used to resolve deep evolutionary relationships, represent an important tool to assess the mechanisms underlying recently diverged taxa. Our analyses indicate that unique environmental conditions in the coastal waters of the Arabian Peninsula probably contributed to the formation of endemic butterflyfishes. Older endemic species are also associated with narrow versus broad depth ranges, suggesting that adaptation to deeper coral reefs in this region occurred only recently (<1.75 Ma). Even though deep reef environments were drastically reduced during the extreme low sea level stands of glacial ages, shallow reefs persisted, and as such there was no evidence supporting mass extirpation of fauna in this region. PMID- 30519423 TI - Measuring agreement among experts in classifying camera images of similar species. AB - Camera trapping and solicitation of wildlife images through citizen science have become common tools in ecological research. Such studies collect many wildlife images for which correct species classification is crucial; even low misclassification rates can result in erroneous estimation of the geographic range or habitat use of a species, potentially hindering conservation or management efforts. However, some species are difficult to tell apart, making species classification challenging-but the literature on classification agreement rates among experts remains sparse. Here, we measure agreement among experts in distinguishing between images of two similar congeneric species, bobcats (Lynx rufus) and Canada lynx (Lynx canadensis). We asked experts to classify the species in selected images to test whether the season, background habitat, time of day, and the visible features of each animal (e.g., face, legs, tail) affected agreement among experts about the species in each image. Overall, experts had moderate agreement (Fleiss' kappa = 0.64), but experts had varying levels of agreement depending on these image characteristics. Most images (71%) had >=1 expert classification of "unknown," and many images (39%) had some experts classify the image as "bobcat" while others classified it as "lynx." Further, experts were inconsistent even with themselves, changing their classifications of numerous images when they were asked to reclassify the same images months later. These results suggest that classification of images by a single expert is unreliable for similar-looking species. Most of the images did obtain a clear majority classification from the experts, although we emphasize that even majority classifications may be incorrect. We recommend that researchers using wildlife images consult multiple species experts to increase confidence in their image classifications of similar sympatric species. Still, when the presence of a species with similar sympatrics must be conclusive, physical or genetic evidence should be required. PMID- 30519424 TI - Complex gene expansion of the CYP2D gene subfamily. AB - Cytochrome P450 (CYP) superfamily genes encode enzymes that play a role in metabolizing endogenous compounds and in detoxifying exogenous chemicals. The CYP2D subfamily is a member of the CYP2 family, and its gene expansion in herbivores is presumably linked with the need to detoxify abundant plant toxins in the diet, which indicates that CYP2D gene expansion is associated with dietary preferences. To test this hypothesis, the dietary information and CYP2D gene number for 73 vertebrates from different taxonomic groups including 22 mammals, 49 birds, 1 reptile, and 1 amphibian were collected, and correlation analysis and ANOVA were conducted. The results showed that most species (45/73) had only one CYP2D gene, despite their different diets, and dietary preferences were not correlated with CYP2D gene numbers. Specifically, the majority of birds and 7 mammals had only 1 CYP2D gene, and the CYP2D gene number of mammals ranged from 1 to 11, irrespective of their feeding habits. Species with a CYP2D gene number >=5 included carnivores, herbivores, and omnivores. Furthermore, statistical analyses revealed that no significant correlation existed between dietary preferences and CYP2D gene number, and there was no significant CYP2D gene number variation among species with different dietary preferences, regardless of whether all vertebrates or specific lineages were considered. Furthermore, gene dynamics which indicated by gene duplication events and loss events showed that CYP2D gene number variation had no relationship with diet, suggesting that diet was not a driving force of CYP2D gene expansion and that CYP2D gene expansion was more complex than previously recognized. PMID- 30519425 TI - Social environment affects the transcriptomic response to bacteria in ant queens. AB - Social insects have evolved enormous capacities to collectively build nests and defend their colonies against both predators and pathogens. The latter is achieved by a combination of individual immune responses and sophisticated collective behavioral and organizational disease defenses, that is, social immunity. We investigated how the presence or absence of these social defense lines affects individual-level immunity in ant queens after bacterial infection. To this end, we injected queens of the ant Linepithema humile with a mix of gram+ and gram- bacteria or a control solution, reared them either with workers or alone and analyzed their gene expression patterns at 2, 4, 8, and 12 hr post injection, using RNA-seq. This allowed us to test for the effect of bacterial infection, social context, as well as the interaction between the two over the course of infection and raising of an immune response. We found that social isolation per se affected queen gene expression for metabolism genes, but not for immune genes. When infected, queens reared with and without workers up-regulated similar numbers of innate immune genes revealing activation of Toll and Imd signaling pathways and melanization. Interestingly, however, they mostly regulated different genes along the pathways and showed a different pattern of overall gene up-regulation or down-regulation. Hence, we can conclude that the absence of workers does not compromise the onset of an individual immune response by the queens, but that the social environment impacts the route of the individual innate immune responses. PMID- 30519426 TI - Transcriptomic responses to predator kairomones in embryos of the aquatic snail Radix balthica. AB - The ability of organisms to respond to predation threat by exhibiting induced defenses is well documented, but studies on the potential mechanistic basis for such responses are scarce. Here, we examine the transcriptomic response to predator kairomones of two functionally distinct developmental stages in embryos of the aquatic snail Radix balthica: E8-the stage at which a range-finding trial indicated that kairomone-induced accelerated growth and development first occurred; and E9-the stage at which embryos switched from ciliary- to crawling driven locomotion. We tested whether expression profiles were influenced by kairomones and whether this influence varied between stages. We also identified potential candidate genes for investigating mechanisms underpinning induced responses. There were 6,741 differentially expressed transcripts between developmental stages, compared to just five in response to predator kairomones. However, on examination of functional enrichment in the transcripts responding to predator kairomones and adopting a less stringent significance threshold, 206 transcripts were identified relating to muscle function, growth, and development, with this response being greater at the later E9 stage. Furthermore, these transcripts included putative annotations for genes identified as responding to predator kairomones in other taxa, including C1q, lectin, and actin domains. Globally, transcript expression appeared reduced in response to predator kairomones and we hypothesize that this might be a result of metabolic suppression, as has been reported in other taxa in response to predation threat. PMID- 30519427 TI - Short-distance barriers affect genetic variability of Rhizophora mangle L. in the Yucatan Peninsula. AB - The environmental variability at local scale results in different physiognomic types of mangrove forest. However, this variability has never been considered in studies of mangrove genetic variability. This study analyzed the genetic and morphological variability and structure of Rhizophora mangle at regional and local scales in the Yucatan Peninsula. Thirteen mangrove populations (eight scrub and five tall), located in seven sites, were sampled, and their morphological variability and relationship with the availability of phosphorus and salinity were analyzed. The diversity and genetic structure were estimated at different hierarchical levels with nine microsatellites, also Bayesian inference and Principal Coordinates Analysis were used. We found a great morphological variability of R. mangle that responded to local environmental variability and not to the precipitation gradient of the peninsula. The genetic diversity found in the peninsula was greater than that reported for other populations in Mexico and was grouped into two regions: the Gulf of Mexico and the Caribbean Sea. At a local scale, tall and scrub mangroves had significant genetic differentiation suggesting that ecological barriers promote genetic differentiation within sites. These results need to be considered in future population genetic studies and for mangrove management and conservation. PMID- 30519428 TI - Regional differences in winter diets of bobcats in their northern range. AB - When generalist predators have wide geographic ranges, diets may differ dramatically, largely as a result of differing prey communities. Bobcats (Lynx rufus) are widely distributed across southern North America, with their northern range edge occurring in southern Canada and in the northern US states. Within this northern range, bobcats are exposed to cold and snowy winters and a limited number of prey species, conditions that are atypical for most of the range of bobcats. We examined winter diets of bobcats in high elevation and very snowy forests in northwest Montana to determine how these generalist predators managed in these harsh conditions in comparison with elsewhere in the northern range. Bobcats consumed five major prey types: Red squirrels (Tamiasciurus hudsonicus) and Cricetid rodents comprised >78% of the dietary biomass, whereas the larger snowshoe hares (Lepus americanus), deer (Odocoileus spp.), and grouse were consumed much less often. The standardized niche breadth of bobcat diets was 0.29; bobcats from across the northern range also routinely ate multiple prey species, although Eastern bobcats appear to consume more lagomorphs than do Western bobcats. These results indicate that bobcats remain generalists in difficult winter conditions while preying primarily on small-bodied prey, although bobcats have highly variable diets across their northern range. PMID- 30519429 TI - Human paths have positive impacts on plant richness and diversity: A meta analysis. AB - We assess the impacts of human paths, trails, and roads on plant species richness and Shannon diversity. Most reviews of this topic have not considered community level measures and have focused on excessive tourism impacts. We found significant positive effects of paths on plant richness and diversity. The effect size for richness was highest when studies included roads (paved) or trails (unpaved). The effect size found for diversity was highest when studies were in grasslands. We also found experimental designs comparing high levels of path use to low levels of path use, near-to-path versus far-from-path and path-presence versus path-absence comparisons obtained the largest effect sizes. There was no evidence that non-native species explained most increases in species richness or diversity. The effect sizes of human paths on plant communities are comparable in magnitude to those reported for other mammals' disturbance and ecosystem engineering activities. PMID- 30519430 TI - Competition alters seasonal resource selection and promotes use of invasive shrubs by an imperiled native cottontail. AB - Many ecosystems face multiple invaders, and interactions among invasive and native species may complicate conservation efforts for imperiled species. Examination of fine-scale resource selection can be used to detect patterns in habitat selection resulting from species interactions and assess the value of specific resources, including invasive plants, to wildlife. We used animal location data with mixed-effects resource selection models to examine seasonal competitive interactions and species-specific selection for forage and cover resources by an imperiled native lagomorph, the New England cottontail Sylvilagus transitionalis and its nonnative competitor, the eastern cottontail S. floridanus in the eastern Hudson Valley, NY. We found evidence that resource selection by New England cottontails depended on the relative prevalence of eastern cottontails to New England cottontails. Where eastern cottontails were less prevalent New England cottontail selected for resources characteristic of early successional shrublands. Where eastern cottontails were more prevalent, New England cottontails selected for resources characteristic of later successional shrublands. New England cottontail use of certain invasive shrubs depended on the prevalence of eastern cottontails relative to New England cottontails, suggesting response to invasive plants is confounded by interactions with a nonnative competitor. Our results further emphasize the need for conservation efforts to consider invasive management within the ecosystem context. We demonstrate the utility of resource selection studies to assist in this regard by exploring competitive interactions in the absence of removal studies, while simultaneously assessing the impact of habitat components such as invasive vegetation on species of conservation concern. Synthesis and applications Resource selection studies can be directly applied to inform ongoing species conservation where multiple invaders are present or where species interactions influence resource selection. Fine-scale assessments of resource selection, similar to those presented here, can be used to selectively manage habitat to benefit desired species within the ecosystem context. PMID- 30519431 TI - The metric matters when assessing diversity: Assessing lepidopteran species richness and diversity in two habitats under different disturbance regimes. AB - How we measure diversity can have important implications for understanding the impacts of anthropogenic pressure on ecosystem processes and functioning. Functional diversity quantifies the range and relative abundance of functional traits within a given community and, as such, may provide a more mechanistic understanding of ecosystems. Here, we use a novel approach to examine how lepidopteran richness and diversity, weighted by species abundance, differ between habitats under different disturbance regimes (highly disturbed non-native plantations and less disturbed broadleaf woodlands), both with and without constraining by similarity due to shared taxonomy or functional traits. Comparisons of diversity between the two habitats differed according to which metric was being used; while species richness was 58% greater in broadleaf woodlands, after accounting for species similarity due to shared functional traits, there was little difference between woodland types under two different disturbance regimes. Functional diversity varied within the landscape but was similar in paired broadleaf and plantation sites, suggesting that landscape rather than local factors drive biotic homogenization in plantation dominated landscapes. The higher richness in broadleaf sites appears to be driven by rare species, which share functional traits with more common species. Moth populations in disturbed, plantation sites represent a reduced subset of moth species compared to broadleaf sites, and may be more vulnerable to disturbance pressures such as clear-felling operations due to low community resilience. PMID- 30519432 TI - Paternity analysis, pollen flow, and spatial genetic structure of a natural population of Euterpe precatoria in the Brazilian Amazon. AB - Euterpe precatoria, known as acai do Amazonas, is a regionally important palm of the Amazon rainforest for the fruit production through extractive agriculture. Little information is available with regard to genetic diversity, gene flow, and spatial genetic structure (SGS) of acai populations, which are essential for the use, management, and conservation of genetic resources of the species. This research aimed to assess the genetic diversity, inbreeding level, SGS, and gene flow in four ontogenetic stages of a natural E. precatoria population in the Brazilian Amazon, based on 18 microsatellite loci. The study was carried out in a natural population dispersed in an area of about 10 ha. Leaf tissues of 248 plants were mapped and sampled and classified into four ontogenetic stages: reproductive (59), immature (70), young (60), and seedling (59). Genetic diversity indices were high for all ontogenetic stages. The fixation index (F) for all ontogenetic stages was not significantly different from zero, indicating the absence of inbreeding. A significant SGS was found for all ontogenetic stages (68-110 m), indicating seed dispersal over short distances. Paternity analysis detected pollen immigration of 39.1%, a selfing rate of 4.2%, and a mean pollen dispersal distance within the population of 531 m. The results indicate substantial allele input in the population via pollen immigration, contributing to the maintenance of the genetic diversity of the population. However, within a population, the renewal with new progenies selected from seed plants spaced at least 110 m apart is important to avoid collecting seeds from related plants. PMID- 30519433 TI - Population responses of common ravens to reintroduced gray wolves. AB - Top predators have cascading effects throughout the food web, but their impacts on scavenger abundance are largely unknown. Gray wolves (Canis lupus) provide carrion to a suite of scavenger species, including the common raven (Corvus corax). Ravens are wide-ranging and intelligent omnivores that commonly take advantage of anthropogenic food resources. In areas where they overlap with wolves, however, ravens are numerous and ubiquitous scavengers of wolf-acquired carrion. We aimed to determine whether subsidies provided through wolves are a limiting factor for raven populations in general and how the wolf reintroduction to Yellowstone National Park in 1995-1997 affected raven population abundance and distribution on the Yellowstone's Northern Range specifically. We counted ravens throughout Yellowstone's Northern Range in March from 2009 to 2017 in both human use areas and wolf habitat. We then used statistics related to the local wolf population and the winter weather conditions to model raven abundance during our study period and predict raven abundance on the Northern Range both before and after the wolf reintroduction. In relatively severe winters with greater snowpack, raven abundance increased in areas of human use and decreased in wolf habitat. When wolves were able to acquire more carrion, however, ravens increased in wolf habitat and decreased in areas with anthropogenic resources. Raven populations prior to the wolf reintroduction were likely more variable and heavily dependent on ungulate winter-kill and hunter-provided carcasses. The wolf recovery in Yellowstone helped stabilize raven populations by providing a regular food supply, regardless of winter severity. This stabilization has important implications for effective land management as wolves recolonize the west and global climate patterns change. PMID- 30519434 TI - Soil organic carbon dynamics matching ecological equilibrium theory. AB - The persistence of soil organic carbon (SOC) has traditionally been explained as a combination of recalcitrance properties and stabilization processes, which lead to the formation of complex organic compounds. However, recent conceptual advances and experimental evidence challenge this view. Here, we test these conceptual advances using a dynamic equilibrium theory of SOC founded on classic ecological theory. We postulate that the persistence of SOC is an equilibrium point where SOC losses resulting from continuous decomposition and SOC gains due to SOC protection are balanced. We show that we can describe the temporal dynamics of SOC remarkably well (average and median R 2 = 0.75) in publicly available SOC time series from experiments that investigated the effects of agricultural practices in arable soils. The predictive power of our simplistic model is not meant to compete with that of current multi-pool SOC models or recent developments that include microbial loops. The simplicity of our analysis can, however, show how the conceptual distinction between the forces that control SOC loss and gain, and their equilibrium, can shed light on SOC dynamics. Specifically, our analysis shows that, regardless of specific mechanisms, the persistence of SOC will depend on the ultimate equilibrium between SOC gains and losses, which may depend on environmental (e.g. temperature) and ecological (e.g. spatially structured microbial activities) factors and the relative roles of these factors. Future experimental studies should quantify these roles to formulate a new generation of SOC dynamics model. PMID- 30519435 TI - Rainfall pulse response of carbon fluxes in a temperate grass ecosystem in the semiarid Loess Plateau. AB - Rainfall pulses can significantly influence carbon cycling in water-limited ecosystems. The magnitude of carbon flux component responses to precipitation may vary depending on precipitation amount and antecedent soil moisture, associated with nonlinear responses of plants and soil microbes. The present study was carried out in a temperate grass ecosystem during 2013-2015 in the semiarid Loess Plateau of China, to examine the response of carbon fluxes to precipitation using the "threshold-delay" model. The unique contribution of environmental variables such as precipitation amount and antecedent soil moisture before rainfall (SWC_antecedent) to carbon fluxes in response to rainfall was also investigated. The lower threshold of effective rainfall was 6.6 mm for gross ecosystem production (GEP), 8.5 mm for net ecosystem production (NEP), and 4.5 mm for ecosystem respiration (RE); and the upper threshold of effective rainfall was 21.4 mm for GEP and NEP, and 16.8 mm for RE. Rainfall amount was positively affected the relative rainfall responses of GEP, NEP, and RE. However, SWC_antecedent at 20 cm soil depth offset the response of GEP to rainfall pulses, and SWC_antecedent at 5 cm soil depth offset the response of NEP and RE to rainfall pulses, with corresponding partial slopes of linear regressions of 0.50, -0.40, and -0.52. These results indicated that NEP was more sensitive to rainfall pulses and RE was more sensitive to SWC_antecedent. These results demonstrate the importance of rainfall events of <10 mm and that the negative effect of SWC_antecedent should also be considered when estimating ecosystem carbon fluxes in this semiarid region. PMID- 30519436 TI - Invasive species denialism: Sorting out facts, beliefs, and definitions. AB - In the last decades, thousands of investigations confirmed the detrimental effects of species translocated by man outside of their native ranges (nonindigenous species, or NIS). However, results concluding that many NIS have null, neutral, or positive impacts on the biota and on human interests are as common in the scientific literature as those that point at baneful impacts. Recently, several scholars confronted the stand that origin per se is not a reliable indicator of negative effects, suggesting that such conclusions are the expression of scientific denialism, often led by spurious purposes, and that their numbers are increasing. When assessed in the context of the growing interest in introduced species, the proportion of academic publications claiming that NIS pose no threats to the environment and to social and economic interests is extremely low, and has not increased since 1990. The widely prevailing notion that many NIS are effectively or potentially harmful does not conflict with the fact that most have mixed (negative, neutral, and positive) impacts. When based on solid grounds, reports of positive or neutral impacts should not be labeled as manipulative or misleading unless proven otherwise, even if they may hamper interest in- and funding of research and control bioinvasion programs. PMID- 30519437 TI - Stand dynamics and competition in a mixed forest at the northern distribution limit of evergreen hardwood species. AB - Tree species of three growth forms (evergreen conifers, deciduous hardwoods, and evergreen hardwoods) codominate at the northern distribution limit of evergreen hardwoods in central Japan. This study examined the stand dynamics and competition during 13 years at a single plot to reveal how three growth forms codominate at the ecotone. Species were characterized as large DBH and low tree density for evergreen conifers, and conversely for evergreen hardwoods. Total basal area increased during the examined period, accompanied with the reduction in tree density (i.e., mortality exceeded the recruitment rate). Mortality increased with time especially for small trees of deciduous hardwoods. The effect of competition among the three growth forms on tree growth was not detected. Species were classified into two axes. Ingrowth and recruitment rates of large evergreen conifers were lower than those of small evergreen hardwoods. The population growth rate was lower in species with greater mortality within each growth form. Deciduous hardwoods showed the highest mortality and lowest population growth rates among the three growth forms. Although the tree-ring analysis revealed that disturbances occurred to some extent, the current disturbance regime would not trigger the regeneration of deciduous hardwoods. This study suggests that negative relations of maximum DBH with ingrowth and recruitment rates contribute to codominance of evergreen conifers and evergreen hardwoods, and more frequent or larger disturbances than at present are necessary for regeneration of deciduous hardwoods. PMID- 30519438 TI - Short-term, low-level nitrogen deposition dampens a trophic cascade between bears and plants. AB - Human activities have substantially increased atmospheric nitrogen (N) deposition in ecosystems worldwide, often leading to higher plant quality for herbivores and greater herbivory. Predators frequently suppress herbivores and indirectly benefit plants via "trophic cascades", and the strength of these interactions can also depend on N availability. However, the evidence for N deposition effects on cascades primarily comes from studies of high-level N deposition. Most terrestrial ecosystems currently receive elevated, but low-level N deposition, and it is unclear whether this subtle N enrichment has any effect on cascades. Here, I asked whether low-level N deposition alters a trophic cascade from black bears to plants in Colorado. In this ecological network, bears indirectly benefit plants by consuming ants and suppressing positive effects of ants on herbivores. Using a three year N enrichment experiment, I assessed changes in this cascade by measuring plant and arthropod responses to simulated N deposition, bear damage to ant nests, and the presence of mutualist herbivores and ants. I found that low level N enrichment and bears had interacting effects on plant reproduction. In ambient N conditions, bears indirectly increased plant reproduction by causing ant nests to become inactive and suppressing positive ant effects on herbivores that were detrimental for plants. Yet, bear-induced ant nest inactivity had no effect on plant reproduction in N-enriched conditions. When N was added, ants had greater positive effects on herbivores, but herbivores had weak effects on plants, potentially because plants were more resistant to herbivores. Ultimately, the results indicate that N enrichment strengthened resource control of the community and weakened plant-herbivore interactions and the cascade from bears to plants. This study suggests that common rates of low-level N deposition are changing the strength of trophic cascades and may have already altered resource versus consumer control of ecological community structure in many ecosystems. PMID- 30519439 TI - Combining Bayesian genetic clustering and ecological niche modeling: Insights into wolf intraspecific genetic structure. AB - The distribution of intraspecific genetic variation and how it relates to environmental factors is of increasing interest to researchers in macroecology and biogeography. Recent studies investigated the relationships between the environment and patterns of intraspecific genetic variation across species ranges but only few rigorously tested the relation between genetic groups and their ecological niches. We quantified the relationship of genetic differentiation (F ST) and the overlap of ecological niches (as measured by n-dimensional hypervolumes) among genetic groups resulting from spatial Bayesian genetic clustering in the wolf (Canis lupus) in the Italian peninsula. Within the Italian wolf population, four genetic clusters were detected, and these clusters showed different ecological niches. Moreover, different wolf clusters were significantly related to differences in land cover and human disturbance features. Such differences in the ecological niches of genetic clusters should be interpreted in light of neutral processes that hinder movement, dispersal, and gene flow among the genetic clusters, in order to not prematurely assume any selective or adaptive processes. In the present study, we found that both the plasticity of wolves-a habitat generalist-to cope with different environmental conditions and the occurrence of barriers that limit gene flow lead to the formation of genetic intraspecific genetic clusters and their distinct ecological niches. PMID- 30519440 TI - Orchid diversity: Spatial and climatic patterns from herbarium records. AB - Aim: We test for spatial and climatic patterns of diversification in the Orchidaceae, an angiosperm family characterized by high levels of species diversity and rarity. Globally, does orchid diversity correlate with land area? In Australia, does diversity correlate with herbarium collecting effort, range size, or climate niche breadth? Where are Australia's orchids distributed spatially, in protected areas, and in climate space? Location: Global, then Australia. Methods: We compared orchid diversity with land area for continents and recognized orchid diversity hotspots. Then, we used cleaned herbarium records to compare collecting effort (for Australian Orchidaceae vs. all other plant families, and also among orchid genera). Spatial and climate distributions were mapped to determine orchids' coverage in the protected area network, range sizes, and niche breadths. Results: Globally, orchid diversity does not correlate with land area (depauperate regions are the subantarctic: 10 species, and northern North America: 394 species). Australian herbarium records and collecting effort generally reflect orchid species diversity (1,583 spp.), range sizes, and niche breadths. Orchids are restricted to 13% of Australia's landmass with 211 species absent from any protected areas. Species richness is the greatest in three biomes with high general biodiversity: Temperate (especially southwest and southeast Australia), Tropical, and Subtropical (coastal northern Queensland). Absence from the Desert is consistent with our realized climate niche-orchids avoid high temperature/low rainfall environments. Orchids have narrower range sizes than nonorchid species. Highly diverse orchid genera have narrower rainfall breadths than less diverse genera. Main conclusions: Herbarium data are adequate for testing hypotheses about Australian orchids. Distribution is likely driven by environmental factors. In contrast, diversification did not correlate with increases in range size, rainfall, or temperature breadths, suggesting speciation does not occur via invasion and local adaptation to new habitats. Instead, diversification may rely on access to extensive obligate symbioses with mycorrhizae and/or pollinators. PMID- 30519441 TI - Embryonal life histories: Desiccation plasticity and diapause in the Argentinean pearlfish Austrolebias bellottii. AB - Embryos of annual killifish diapause in soil egg banks while ponds are dry. Their rates of development and survival in different developmental stages determine the numbers and stages of embryos at rewetting. In the Argentinean pearlfish Austrolebias bellottii, we investigated plasticity for desiccation in such embryonal life history components across phases of mild desiccation and rewetting and also effects of life history on hatching. In comparison with nonannuals, our data suggest that incidences of diapause have become relatively independent of the occurrence of desiccation, as if they have become genetically assimilated. We found limited survival effects of desiccation, limited developmental delays, and an acceleration of development into the prehatching stage. This response can be adaptive when desiccation informs that an opportunity to hatch approaches. Embryos arrest development in the prehatching stage (diapause DIII) or in the dispersed-cell phase (diapause DI). Parental pair variation in rates of development and survival in the earliest developmental stages affects the fraction of embryos that are in DI at rewetting and the number surviving. Given such effects on life history fitness components, rates during embryonal development seem "visible" to selection and the developmental system can thus adapt when pair variation contains a heritable component. In agreement with expectations for the presence of diversified bet-hedging, some embryos hatched and others not in over half of the clutches with several developed embryos at the moment of rewetting. Hatching probabilities increased for eggs produced later in the experiment, and they increased when embryos were rewetted a second time after two months. This response is opposite of what is expected when age-dependent hatching would be adapted to exploit opportunities for completing another generation before the dry season. PMID- 30519442 TI - Leaf phenology of thirteen African origins of baobab (Adansonia digitata (L.)) as influenced by daylength and water availability. AB - Water availability is often described as one of the main drivers of phenology of tropical dry forests but experimental studies to identify the cues triggering phenological changes are few. In a greenhouse trial, we exposed seedlings of thirteen origins, seven from West and six from East Africa, respectively, of Adansonia digitata L.(baobab) to a well-watered control treatment and a water withholding treatment in combination with exposure to three different daylengths (11.5, 12.0, and 12.5 hr). Responses were measured in terms of meristematic activity, number of leaves, and height growth followed over 6.5 months. Multi level mixed-effects statistical models were used to analyze how environmental and inter-population variables affected phenological behavior. Flushing was influenced by the daylength with the lowest degree of meristematic activity observed in the short daylength treatment. Daylength also influenced the number of leaves through an interaction with the water regime. The water regime influenced all variables through interactions with the origins. Seedlings subjected to water stress had higher meristematic activity, but initially lower numbers of leaves than continuously watered plants. Height growth in continuously watered plants was fastest or at par with water-stressed plants, depending on the origin. Origins from West Africa tended to have higher meristematic activity and their phenology was found to be less influenced by water withholding than East African origins. There were no signs of significant differences between origins in their response to photoperiod. In conclusion, baobab seedlings show opportunistic behavior, setting leaves when water is available, but larger activity is found when days are long. We discuss the results in terms of triggering factors for baobab phenology and adaptation to specific environmental conditions at the site of origins. PMID- 30519443 TI - Preliminary insights into the genetics of bank vole tolerance to Puumala hantavirus in Sweden. AB - Natural reservoirs of zoonotic pathogens generally seem to be capable of tolerating infections. Tolerance and its underlying mechanisms remain difficult to assess using experiments or wildlife surveys. High-throughput sequencing technologies give the opportunity to investigate the genetic bases of tolerance, and the variability of its mechanisms in natural populations. In particular, population genomics may provide preliminary insights into the genes shaping tolerance and potentially influencing epidemiological dynamics. Here, we addressed these questions in the bank vole Myodes glareolus, the specific asymptomatic reservoir host of Puumala hantavirus (PUUV), which causes nephropathia epidemica (NE) in humans. Despite the continuous spatial distribution of M. glareolus in Sweden, NE is endemic to the northern part of the country. Northern bank vole populations in Sweden might exhibit tolerance strategies as a result of coadaptation with PUUV. This may favor the circulation and maintenance of PUUV and lead to high spatial risk of NE in northern Sweden. We performed a genome-scan study to detect signatures of selection potentially correlated with spatial variations in tolerance to PUUV. We analyzed six bank vole populations from Sweden, sampled from northern NE-endemic to southern NE free areas. We combined candidate gene analyses (Tlr4, Tlr7, and Mx2 genes) and high-throughput sequencing of restriction site-associated DNA (RAD) markers. Outlier loci showed high levels of genetic differentiation and significant associations with environmental data including variations in the regional number of NE human cases. Among the 108 outliers that matched to mouse protein-coding genes, 14 corresponded to immune-related genes. The main biological pathways found to be significantly enriched corresponded to immune processes and responses to hantavirus, including the regulation of cytokine productions, TLR cascades, and IL-7, VEGF, and JAK-STAT signaling. In the future, genome-scan replicates and functional experimentations should enable to assess the role of these biological pathways in M. glareolus tolerance to PUUV. PMID- 30519444 TI - Navigating fragmented landscapes: Canada lynx brave poor quality habitats while traveling. AB - Anthropogenic and natural habitat fragmentation inhibit movement of animals through landscapes. An important challenge for connectivity conservation is determining which conditions facilitate or limit movements, so that these areas can be prioritized for protection or restoration. We examine Canada lynx Lynx canadensis habitat connectivity in the fragmented North Cascade Mountains of Washington, as an example of a highly mobile species that is specialized both on prey and in habitat needs. We identify lynx Habitat Concentration Areas based on Core Habitat Models, parameterize resistance surfaces from our Matrix Habitat Model, and develop linkages of habitat lynx use to move between patches of high quality habitat. We identify a number of linkages for lynx comprised of habitat conditions that differed from high quality core patches identified from our habitat modeling. Radio-locations from lynx confirm lower-quality habitats of low resistance to movement were used by traveling lynx. Our results thus suggest traveling lynx do indeed use a much broader range of habitats than do lynx moving within core areas. For lynx in the North Cascades, our results show that maintaining connectivity will require preserving habitats and linkages that would previously have been deemed unsuitable for lynx. Maintaining connectivity for lynx is particularly important given the many recent large wildfires in this region that have reduced the number of mature forest stands that form prime habitat for lynx. Policy implications. Our results strongly suggest that habitat connectivity models should be based on empirical information of animal location data and focused on matrix habitat analysis. Traveling predators use a wide suite of habitats, resulting in more and broader linkage zones that should inform conservation efforts. Failure to identify these areas of functional connectivity could result in the oversight of usable linkage zones, leaving them without protection and vulnerable to degradation. PMID- 30519445 TI - Genetic diversity and differentiation among Prosopis alba (Leguminosae) populations from dry valleys of Bolivia with different levels of human disturbance and altitude. AB - The fast expansion of human population around La Paz, Bolivia (3,200-4,100 m.a.s.l.) triggered new suburban settlements in nearby areas in valleys and mountain feet. The white mesquite, Prosopis alba Griseb. (Leguminosae), is a resource (originally used by native communities) that is strongly affected by changes in land use. A gradient in the level of disturbance is found moving away from the La Paz city toward less altitude areas. The main objective of this study was to characterize genetically three P. alba populations with different levels of human disturbance located at different altitudes in Bolivia, in order to provide some guidelines for management and conservation of these species. Based on 10 SSR loci, the populations showed high level of genetic diversity in comparison with other forest species. The population less disturbed and situated at the lowest altitude was the most variable (H e = 0.51-0.42), whereas the less variable was the most disturbed and situated at the highest altitude. Heterozygote excess was observed in all populations. Most of genetic diversity (99%) is contained within populations. Genetic differentiation among populations is low (1%), suggesting low gene flow among populations. No evidence of recent bottlenecks events was detected. The estimates of the effective population size were low in all populations. The results are in agreement with the hypothesis that genetic diversity is reduced by the impact of anthropic disturbance in the population located at higher altitude in comparison with the lightly disturbed situated at lower altitude and farther from urban settlements. PMID- 30519446 TI - Realized niche and microhabitat selection of the eastern green lizard (Lacerta viridis) at the core and periphery of its distribution range. AB - The available range of habitats and suitable abiotic conditions like temperature and radiation tends to be narrower toward the periphery of the distribution range of species. Peripheral populations of generalist species could then be more specialized and have a smaller and differentiated realized niche (habitat niche in our study) compared to populations at the core. Likewise, patterns of microhabitat selection can differ between periphery and core. In our study, we compared niche size and microhabitat selection among core (Bulgaria) and northern peripheral (Germany, Czech Republic) populations of Lacerta viridis and estimated niche differentiation among regions. We collected data on vegetation structure and abiotic parameters at the microhabitat scale in each region. In order to compare niche size among regions and estimate niche differentiation, we built multidimensional niche hypervolumes. We applied generalized linear mixed models and model averaging, accounting for spatial autocorrelation when necessary, to analyze microhabitat differences among regions and microhabitat selection in each region. Peripheral populations were more specialized, having a smaller niche than core ones, and their niche differed from that in the core (Sorensen overlap in all comparisons <0.3). Microhabitats at the periphery had lower radiation and soil compaction and less structured vegetation. Microhabitat selection at the core depended solely on abiotic parameters, while at the periphery it was defined by only vegetation structure (Czech Republic) or a combination of both, vegetation structure, and abiotic factors (Germany). Thus, peripheral populations seem to compensate for overall harsher climatic conditions by responding to different parameters of the microhabitat compared to core populations. We suggest specific conservation measures for L. virids in each studied region and point out the general implications of a higher specialization degree of peripheral populations in relation to climate change and habitat fragmentation. PMID- 30519447 TI - The impact of artificial light at night on nocturnal insects: A review and synthesis. AB - In recent decades, advances in lighting technology have precipitated exponential increases in night sky brightness worldwide, raising concerns in the scientific community about the impact of artificial light at night (ALAN) on crepuscular and nocturnal biodiversity. Long-term records show that insect abundance has declined significantly over this time, with worrying implications for terrestrial ecosystems. The majority of investigations into the vulnerability of nocturnal insects to artificial light have focused on the flight-to-light behavior exhibited by select insect families. However, ALAN can affect insects in other ways as well. This review proposes five categories of ALAN impact on nocturnal insects, highlighting past research and identifying key knowledge gaps. We conclude with a summary of relevant literature on bioluminescent fireflies, which emphasizes the unique vulnerability of terrestrial light-based communication systems to artificial illumination. Comprehensive understanding of the ecological impacts of ALAN on diverse nocturnal insect taxa will enable researchers to seek out methods whereby fireflies, moths, and other essential members of the nocturnal ecosystem can coexist with humans on an increasingly urbanized planet. PMID- 30519449 TI - Phylogenetic signal in tooth wear dietary niche proxies: What it means for those in the field. AB - In response to DeSantis et al., we describe that the presence of phylogenetic signal in tooth wear dietary niche proxies is likely a result of the evolutionary process. We also address their concerns regarding enforcement of the use of phylogenetic comparative methods by editors of ecology and evolution journals. PMID- 30519448 TI - The phylogenetic signal in tooth wear: What does it mean? AB - A new study by Fraser et al (2018) urges the use of phylogenetic comparative methods, whenever possible, in analyses of mammalian tooth wear. We are concerned about this for two reasons. First, this recommendation may mislead the research community into thinking that phylogenetic signal is an artifact of some sort rather than a fundamental outcome of the evolutionary process. Secondly, this recommendation may set a precedent for editors and reviewers to enforce phylogenetic adjustment where it may unnecessarily weaken or even directionally alter the results, shifting the emphasis of analysis from common patterns manifested by large clades to rare cases. PMID- 30519450 TI - Breaking point: the genesis and impact of structural variation in tumours. AB - Somatic structural variants undoubtedly play important roles in driving tumourigenesis. This is evident despite the substantial technical challenges that remain in accurately detecting structural variants and their breakpoints in tumours and in spite of our incomplete understanding of the impact of structural variants on cellular function. Developments in these areas of research contribute to the ongoing discovery of structural variation with a clear impact on the evolution of the tumour and on the clinical importance to the patient. Recent large whole genome sequencing studies have reinforced our impression of each tumour as a unique combination of mutations but paradoxically have also discovered similar genome-wide patterns of single-nucleotide and structural variation between tumours. Statistical methods have been developed to deconvolute mutation patterns, or signatures, that recur across samples, providing information about the mutagens and repair processes that may be active in a given tumour. These signatures can guide treatment by, for example, highlighting vulnerabilities in a particular tumour to a particular chemotherapy. Thus, although the complete reconstruction of the full evolutionary trajectory of a tumour genome remains currently out of reach, valuable data are already emerging to improve the treatment of cancer. PMID- 30519451 TI - Transcripts and tumors: regulatory and metabolic programming during biotrophic phytopathogenesis. AB - Biotrophic fungal pathogens of plants must sense and adapt to the host environment to complete their life cycles. Recent transcriptome studies of the infection of maize by the biotrophic pathogen Ustilago maydis are providing molecular insights into an ordered program of changes in gene expression and the deployment of effectors as well as key features of nutrient acquisition. In particular, the transcriptome data provide a deeper appreciation of the complexity of the transcription factor network that controls the biotrophic program of invasion, proliferation, and sporulation. Additionally, transcriptome analysis during tumor formation, a key late stage in the life cycle, revealed features of the remodeling of host and pathogen metabolism that may support the formation of tremendous numbers of spores. Transcriptome studies are also appearing for other smut species during interactions with their hosts, thereby providing opportunities for comparative approaches to understand biotrophic adaptation. PMID- 30519452 TI - Chondrosarcoma: biology, genetics, and epigenetics. AB - Chondrosarcomas constitute a heterogeneous group of primary bone cancers characterized by hyaline cartilaginous neoplastic tissue. They are the second most common primary bone malignancy. The vast majority of chondrosarcomas are conventional chondrosarcomas, and most conventional chondrosarcomas are low- to intermediate-grade tumors (grade 1 or 2) which have indolent clinical behavior and low metastatic potential. Recurrence augurs a poor prognosis, as conventional chondrosarcomas are both radiation and chemotherapy resistant. Recent discoveries in the biology, genetics, and epigenetics of conventional chondrosarcomas have significantly advanced our understanding of the pathobiology of these tumors and offer insight into potential therapeutic targets. PMID- 30519453 TI - RNA interactomics: recent advances and remaining challenges. AB - Tight regulation of cellular processes is key to the development of complex organisms but also vital for simpler ones. During evolution, different regulatory systems have emerged, among them RNA-based regulation that is carried out mainly by intramolecular and intermolecular RNA-RNA interactions. However, methods for the transcriptome-wide detection of these interactions were long unavailable. Recently, three publications described high-throughput methods to directly detect RNA duplexes in living cells. This promises to enable in-depth studies of RNA based regulation and will narrow the gaps in our understanding of RNA structure and function. In this review, we highlight the benefits of these methods and their commonalities and differences and, in particular, point to methodological shortcomings that hamper their wider application. We conclude by presenting ideas for how to overcome these problems and commenting on the prospects we see in this area of research. PMID- 30519454 TI - Recent advances in the management of nasopharyngeal carcinoma. AB - Over the last few years, certain areas in the management nasopharyngeal carcinoma (NPC) that have an impact on the care of these patients have evolved, particularly with regard to liquid biopsies, minimally invasive surgery, and advances in chemotherapy and immunotherapy. Beyond its proven role in the diagnostics, surveillance, and treatment of NPC, liquid biopsy with plasma Epstein-Barr virus DNA in the screening of high-risk populations for NPC is strongly supported by recent evidence. Surgery of the nasopharynx is reserved for locally recurrent NPC, and in recent years there have been great strides in minimally invasive techniques with survival rates similar to those of open techniques in treating NPC. Induction chemotherapy in a recent pooled analysis was shown to be superior to concurrent chemotherapy alone for locoregionally advanced NPC. Finally, immunotherapy with a PD-1 inhibitor in NPC has been shown to have 1-year overall survival rates comparable to those of other patients with heavily pre-treated metastatic or recurrent NPC. In this commentary, we discuss these recent advances and their potential in the clinical management of patients with NPC. PMID- 30519455 TI - Voltage-gated calcium channel alpha 2delta subunits: an assessment of proposed novel roles. AB - Voltage-gated calcium (CaV) channels are associated with beta and alpha2delta auxiliary subunits. This review will concentrate on the function of the alpha2delta protein family, which has four members. The canonical role for alpha2delta subunits is to convey a variety of properties on the CaV1 and CaV2 channels, increasing the density of these channels in the plasma membrane and also enhancing their function. More recently, a diverse spectrum of non-canonical interactions for alpha2delta proteins has been proposed, some of which involve competition with calcium channels for alpha2delta or increase alpha2delta trafficking and others which mediate roles completely unrelated to their calcium channel function. The novel roles for alpha2delta proteins which will be discussed here include association with low-density lipoprotein receptor-related protein 1 (LRP1), thrombospondins, alpha-neurexins, prion proteins, large conductance (big) potassium (BK) channels, and N-methyl-d-aspartate (NMDA) receptors. PMID- 30519456 TI - Needle lost in the haystack: multiple reaction monitoring fails to detect Treponema pallidum candidate protein biomarkers in plasma and urine samples from individuals with syphilis. AB - Background: Current syphilis diagnostic strategies are lacking a sensitive manner of directly detecting Treponema pallidum antigens. A diagnostic test that could directly detect T. pallidum antigens in individuals with syphilis would be of considerable clinical utility, especially for the diagnosis of reinfections and for post-treatment serological follow-up. Methods: In this study, 11 candidate T. pallidum biomarker proteins were chosen according to their physiochemical characteristics, T. pallidum specificity and predicted abundance. Thirty isotopically labelled proteotypic surrogate peptides (hPTPs) were synthesized and incorporated into a scheduled multiple reaction monitoring assay. Protein extracts from undepleted/unenriched plasma (N = 18) and urine (N = 4) samples from 18 individuals with syphilis in various clinical stages were tryptically digested, spiked with the hPTP mixture and analysed with a triple quadruple mass spectrometer. Results: No endogenous PTPs corresponding to the eleven candidate biomarkers were detected in any samples analysed. To estimate the Limit of Detection (LOD) of a comparably sensitive mass spectrometer (LTQ-Orbitrap), two dilution series of rabbit cultured purified T. pallidum were prepared in PBS. Polyclonal anti- T. pallidum antibodies coupled to magnetic Dynabeads were used to enrich one sample series; no LOD improvement was found compared to the unenriched series. The estimated LOD of MS instruments is 300 T. pallidum/ml in PBS. Conclusions: Biomarker protein detection likely failed due to the low (femtomoles/liter) predicted concentration of T. pallidum proteins. Alternative sample preparation strategies may improve the detectability of T. pallidum proteins in biofluids. PMID- 30519457 TI - Effectiveness of implementation of "mental health nursing students' clinical competency model" on academic performance of nursing students. AB - Background: Clinical nursing competence in mental health is one of the most important topics in theoretical and practical nursing training with many factors affecting it. The purpose of this study is to determine the impact of the implementation of the "mental health nursing students' clinical competence model" on nursing students' academic performance. Methods: This study is a semi experimental following one group of student nurses. "mental health nursing students' clinical competence model" for undergraduate nursing student's education was applied. The study population included 50 nursing students, who were studying from fifth semester to seventh semester and selected through census sampling. During the seventh semester after the completion of theoretical and practical courses in mental health nursing, re-evaluation was conducted and the scores before and after the implementation of the clinical competence model were compared. Results: Rate of clinical competency before the intervention, was estimated at the level of non-mastered; and after intervention was at the level of mastered, demonstrating a significant difference (p<0.001). Areas of clinical competency scores before and after the intervention were compared which showed significant difference in all the areas except the mental competency areas (p<0.05). Conclusions: The implementation of the "mental health nursing students' clinical competence model" and appropriate planning for achievement of mental health nursing specialized competency can ensure the achievement of clinical competency by nursing students. PMID- 30519458 TI - Young key affected population in Myanmar: are there any challenges in seeking information and care for HIV/sexually transmitted infections and reproductive health? AB - Background: Unmet needs and barriers in seeking HIV/STI and RH information and care are present especially among young key affected population (YKAP). Therefore, the study was conducted to determine the health seeking behaviors of YKAP regarding HIV/STI and RH, and challenges in seeking health information and care. Methods: A cross-sectional, mixed-methods study was conducted at two large cities in Myanmar. Face-to-face interviews were conducted with YKAP aged 15-24 years. In-depth interviews and key informant interviews were done with YKAP and health care providers. Descriptive statistics and bivariate analyses were done for quantitative data and thematic analysis was applied for qualitative data. Results: A total of 119 young men who have sex with men (YMSM) and 123 young female sex workers (YFSW) included in the study. Mean age of YMSM and YFSW were 20.9+/-2.4 and 21.7+/-2.2 years. Over 30% of YMSM and 49.3% of YFSW had experience of any STI symptom. Particularly, 17% of YMSM and 10% of YFSW had genital ulcer, and majority sought health care at NGO clinics. About 37% of YMSM and 40% of YFSW visited Drop-in-center (DIC) within one to six months. Over 13% of YMSM and 14.6% of YFSW had challenges in seeking HIV/STI and RH information. YMSM/YFSW type and age of YMSM were associated with visit to DIC. Lesser proportions of Tha-nge (43.5%), younger age YMSM (66.7%), brothel-based YFSW (47.9%) visited DIC than others (p<0.05). Challenges and unmet needs expressed by YKAP were reluctance in asking health information, worry for future fertility, consequences of anal sex and contraception. Challenges expressed by providers were limited time during outreach service and difficulty in reaching entertainment-based sex workers. Conclusions: Special attention in provision of health information should be paid to YKAP since there is a considerable proportion of YKAP with unmet need in seeking HIV/STI/RH information and care. PMID- 30519459 TI - Improve your Galaxy text life: The Query Tabular Tool. AB - Galaxy provides an accessible platform where multi-step data analysis workflows integrating disparate software can be run, even by researchers with limited programming expertise. Applications of such sophisticated workflows are many, including those which integrate software from different 'omic domains (e.g. genomics, proteomics, metabolomics). In these complex workflows, intermediate outputs are often generated as tabular text files, which must be transformed into customized formats which are compatible with the next software tools in the pipeline. Consequently, many text manipulation steps are added to an already complex workflow, overly complicating the process and decreasing usability, especially for non-expert bench researchers focused on obtaining results. In some cases, limitations to existing text manipulation are such that desired analyses can only be carried out using highly sophisticated processing steps beyond the reach of most users. As a solution, we have developed the Query Tabular Galaxy tool, which leverages a SQLite database generated from tabular input data. This database can be queried and manipulated to produce transformed and customized tabular outputs compatible with downstream processing steps. Regular expressions can also be utilized for even more sophisticated manipulations, such as find and replace and other filtering actions. Using several Galaxy-based multi-omic workflows as an example, we demonstrate how the Query Tabular tool dramatically streamlines and simplifies the creation of multi step analyses, efficiently enabling complicated textual manipulations and processing. This tool should find broad utility for users of the Galaxy platform seeking to develop and use sophisticated workflows involving text manipulation on tabular outputs. PMID- 30519460 TI - A discontinuous Galerkin model for fluorescence loss in photobleaching of intracellular polyglutamine protein aggregates. AB - Background: Intracellular phase separation and aggregation of proteins with extended poly-glutamine (polyQ) stretches are hallmarks of various age-associated neurodegenerative diseases. Progress in our understanding of such processes heavily relies on quantitative fluorescence imaging of suitably tagged proteins. Fluorescence loss in photobleaching (FLIP) is particularly well-suited to study the dynamics of protein aggregation in cellular models of Chorea Huntington and other polyQ diseases, as FLIP gives access to the full spatio-temporal profile of intensity changes in the cell geometry. In contrast to other methods, also dim aggregates become visible during time evolution of fluorescence loss in cellular compartments. However, methods for computational analysis of FLIP data are sparse, and transport models for estimation of transport and diffusion parameters from experimental FLIP sequences are missing. Results: In this paper, we present a computational method for analysis of FLIP imaging experiments of intracellular polyglutamine protein aggregates also called inclusion bodies (IBs). By this method, we can determine the diffusion constant and nuclear membrane transport coefficients of polyQ proteins as well as the exchange rates between aggregates and the cytoplasm. Our method is based on a reaction-diffusion multi-compartment model defined on a mesh obtained by segmentation of the cell images from the FLIP sequence. The discontinuous Galerkin (DG) method is used for numerical implementation of our model in FEniCS, which greatly reduces the computing time. The method is applied to representative experimental FLIP sequences, and consistent estimates of all transport parameters are obtained. Conclusions: By directly estimating the transport parameters from live-cell image sequences using our new computational FLIP approach surprisingly fast exchange dynamics of mutant Huntingtin between cytoplasm and dim IBs could be revealed. This is likely relevant also for other polyQ diseases. Thus, our method allows for quantifying protein dynamics at different stages of the protein aggregation process in cellular models of neurodegeneration. PMID- 30519461 TI - Costs of outpatient and inpatient MRSA screening and treatment strategies for patients at elective hospital admission - a decision tree analysis. AB - Background: Nosocomial infections are among the most common complications in hospitals. A major part is caused by multidrug-resistant organisms (MDRO). MRSA is still the most prominent and frequent MDRO. The early detection of carriers of multidrug-resistant bacteria is an effective measure to reduce nosocomial infections caused by MDRO. For patients who are planning to go to the hospital, an outpatient screening for MDRO and pre-hospital decolonization is recommended. However, the effectiveness of such pre-admission MDRO management in preparation for a planned hospital stay has not yet been sufficiently scientifically examined from an economic perspective. Methods: A decision tree will be used to develop scenarios for MDRO screening and treatment in the context of the outpatient and inpatient sectors using MRSA-positive patients as an example. Subsequently, the expected costs for the respective strategy are presented. Results: The decision tree analysis shows that the expected costs of outpatient MRSA management are ?8.24 and that of inpatient MRSA management are ?672.51. Conclusion: The forward displacement of the MRSA screening to the ambulatory sector and any subsequent outpatient decolonization for patients with a planned hospitalization is the most cost-effective strategy and should become a standard benefit. Excluding opportunity costs, the expected costs of inpatient MRSA management are ?54.94. PMID- 30519462 TI - Large variations in the practice patterns of surgical antiseptic preparation solutions in patients with open and closed extremity fractures: a cross-sectional survey. AB - Background: Surgically-managed fractures, particularly open fractures, are associated with high rates of surgical site infections (SSIs). To reduce the risk of an SSI, orthopaedic surgeons routinely clean open fracture wounds in the emergency department (ED) and then apply a bandage to the open wound. Prior to the surgical incision, it is standard practice to prepare the fracture region with an antiseptic skin solution as an additional SSI prevention strategy. Multiple antiseptic solutions are available. Objectives: To explore the variation in practice patterns among orthopaedic surgeons regarding antiseptic solution use in the ED and antiseptic preparatory techniques for fracture surgery. Methods: We developed a 27-item survey and surveyed members of several orthopaedic associations. Results: Two hundred and-ten surveys were completed. 71.0% of respondents irrigate the open wound and skin in the ED, primarily with saline alone (59.7%) or iodine-based solutions (32.9%). 90.5% of responders indicated that they dress the open wound in the ED, with 41.0% applying a saline-soaked bandage and 33.7% applying an iodine-soaked dressing (33.7%). In their surgical preparation of open fractures, 41.0% of respondents used an iodine-based solution, 26.7% used a chlorhexidine gluconate (CHG)-based solution, and 31.4% used a combination of the two. In closed fractures, 43.8% of respondents used a CHG-based solution, 28.1% used an iodine-based solution, and 27.1% used a combination. Despite theoretical concerns about the use of alcohol in open wounds, 51.4% used alcohol-based solutions or alcohol alone during skin preparation of open fractures. Conclusions: A lack of consensus exists regarding use of antiseptic surgical preparation solutions for fractures. High-quality clinical research is needed to assess the effectiveness of different surgical antiseptic preparation solutions on patient outcomes in fracture populations. PMID- 30519463 TI - The use of distortion product otoacoustic emissions (DPOAE) records to estimate effect of vitamin B complex on changing severity of tinnitus. AB - Introduction: Patients that are complaining from tinnitus but have normal hearing comprise an uncommon group and there is rare literature about them. Deficiency in B-complex vitamins has been shown to result in tinnitus and supplementation may improve the symptom which means manipulation of cochlear status. Distortion Product Otoacoustic emissions (DPOAEs) used frequently to assess cochlear status. Objectives: The uses of DPOAE changing amplitude as a parameter to estimate effect of vitamin B complex on changing the severity of tinnitus in patients with tinnitus only in comparison to patients have tinnitus with Sensory Neural Hearing Loss (SNHL) and a control group. Methods: Prospective observational cohort study was performed in AL-Karama Teaching Hospital as a secondary medical care center, from 01/01/2012 to 31/12/2016. A three groups had been evaluated clinically and by OAE device (ECHOLAB) to study the DPOAE changing amplitude before and after one month of supplementation of B-complex vitamins to 25 patients in study group (1) have (tinnitus only) and also to 25 patients in study group (2) have (Tinnitus + SNHL) but leaving control group who were a 25 medical staff (No Tinnitus and nor SNHL) without treatment. Results: It has been found that among Study group 1 (patients had Tinnitus only), Study group 2 (patients had Tinnitus + SNHL) and the control group: 16 patients (44%), P-value = 0.000 HS; 28 patients (78%) P-value = 0.000 HS; and 0% respectively, they had low Amplitude of DPOAE recorded by OAE device (ECHOLAB). After one month from treatment with Neurobine ampules for study group 1& 2 but not control group (whom receive no treatment), those who got clinical improvement + increase Amplitude of DPOAE (i.e. subjective + objective changes) after treatment were 10 patients (28%) P-value = 0.000 HS in study group1, and two patients (5%) P-value 0.321 NS in study group 2, and there was no changes (zero) among control group. Conclusions: The uses of DPOAE changing amplitude could be used as a parameter to estimate effect of vitamin B complex on changing the severity of Tinnitus in patients with tinnitus only or those have Tinnitus with SNHL. The supplementation of vitamin B complex could improve the tinnitus severity especially in patients with tinnitus without SNHL. PMID- 30519464 TI - Diagnostic laparoscopy to investigate unexplained lactic acidosis in critically ill patients - A descriptive single centre cohort study. AB - Introduction: Unexplained lactic acidosis (LA) in a critically ill patient often prompts investigations to rule out any reversible intra-abdominal cause. Equivocal results can lead to an emergency laparotomy (EL) with subsequent high morbidity and mortality rates. Our objective was to determine the clinical impact of urgent diagnostic laparoscopy (UDL) in such patients. Methods: This was a descriptive single-centre cohort study. UDL on 28 consecutive critically ill patients with unexplained LA who were referred to a single surgeon over 16 years period were analysed. UDL was proformed either at bedside or in theatre without prior computerised tomography (CT) scan. Patient's demographics, ASA grade, referral route and intraoperative findings were analysed. Results: Eighteen patients underwent bedside UDL in the critical care setting and further 10 had UDL in theatre. Fourteen patients had normal UDL, out of these 10 had LA secondary to low cardiac output states. Fourteen patients had positive UDL findings. Seven patients had features of mesenteric ischaemia, two had gangrenous gallbladder, two had hepatic ischaemia, one patient had acute pancreatitis, one had gangrenous uterus and one had gastric volvulus. Five of the 14 patients with positive UDL were converted to laparotomy for definitive management. In total, of the 28 patients in the cohort, 23 patients avoided EL. Conclusion: UDL is useful and feasible investigation for unexplained LA in the critically ill patients and it can avoid unnecessary EL in many patients. We would recommend the use of UDL as a safe and feasible investigation in such patients. PMID- 30519465 TI - Isolated antro-pyloric metastatic mass from colonic carcinoma: A rare case presentation. AB - Metastatic tumors to stomach are extremely rare with very few cases being described so far in the surgical literature. Colonic tumors metastatic to stomach represent a rarer entity and present a surgical challenge for diagnosis and management to the clinician. We, hereby present a case of adenocarcinoma of transverse colon metastatic to stomach more than 6 years after the index malignancy, presenting clinically with features of gastric outlet obstruction. It was treated with open subtotal gastrectomy, with diagnosis being made on histopathologic examination using special immunochemical stains. Adjuvant treatment in the form of chemotherapy was given and follow up cross sectional imaging showed no evidence of residual disease so far. PMID- 30519466 TI - Assessment of survival in patients with idiopathic pulmonary fibrosis using quantitative HRCT indexes. AB - Background: The assessment of Idiopathic Pulmonary Fibrosis (IPF) using HRCT requires great experience and is limited by a significant inter-observer variability, even between trained radiologists. The evaluation of HRCT through automated quantitative analysis may hopefully solve this problem. The accuracy of CT-histogram derived indexes in the assessment of survival in IPF patients has been poorly studied. Methods: Forty-two patients with a diagnosis of IPF and a follow up time of 3 years were retrospectively collected; HRCT and Pulmonary Function Tests (PFTs) performed at diagnosis time were analysed; the extent of fibrotic disease was quantified on HRCT using kurtosis, skewness, Mean Lung Density (MLD), High attenuation areas (HAA%) and Fibrotic Areas (FA%). Univariate Cox regression was performed to assess hazard ratios for the explored variables and a multivariate model considering skewness, FVC, DLCO and age was created to test their prognostic value in assessing survival. Through ROC analysis, threshold values demonstrating the best sensitivity and specificity in predicting mortality were identified. They were used as cut-off points to graph Kaplan-Meier curves specific for the CT-indexes. Results: Kurtosis, skewness, MLD, HAA% and FA% were good predictors of mortality (HR 0.44, 0.74, 1.01, 1.12, 1.06; p = 0.03, p = 0.01, p = 0.02, p = 0.02 and p = 0.017 respectively). Skewness demonstrated the lowest Akaike's information criterion value (55.52), proving to be the best CT variable for prediction of mortality. Significant survival differences considering proposed cut-off points were also demonstrated according to kurtosis (p = 0.02), skewness (p = 0.005), MLD (p = 0.003), HAA% (p = 0.009) and FA% (p = 0.02) - obtained from quantitative HRCT analysis at diagnosis time. Conclusions: CT-histogram derived indexes may provide an accurate estimation of survival in IPF patients. They demonstrate a correlation with PFTs, highlighting their possible use in clinical practice. PMID- 30519467 TI - Focused ultrasound for the treatment of bone metastases: effectiveness and feasibility. AB - Background: To evaluate the effectiveness and feasibility of high-intensity focused ultrasound (HIFU) for the treatment of bone metastases. Methods: A single center prospective study was made involving 17 consecutive patients with symptomatic bone metastases. Patients were treated by Focused Ultrasound (FUs) performed with magnetic resonance (MR) guidance. Surgical treatment or radiotherapy treatment was not indicated for patients who underwent FUs. Lesions were located in the appendicular and axial skeleton and consisted of secondary symptomatic lesions. The clinical course of pain was evaluated using the Visual Analog Scale (VAS) before treatment, at 1 week, and at 1 month after treatment and the Oral Morphine Equivalent Daily Dose (OMEDD) was also recorded. We used Wilcoxon signed rank test to assess change in patient pain (R CRAN software V 3.1.1). Results: We observed a significant decrease in the pain felt by patients between pre- procedure and 1 week post-procedure (p = 2.9.10-4), and pre procedure and 1 month post-procedure (p = 3.10-4). The proportion of responders according to the International Bone Metastases Consensus Working Party was: Partial Response 50% (8/16) and Complete Response 37.5% (6/16). Conclusions: HIFU under MR-guidance seems to be an effective and safe procedure in the treatment of symptomatic bone lesions for patients suffering from metastatic disease. A significant decrease of patient pain was observed. Trial registration: NCT01091883. Registered 24 March 2010. Level of evidence: Level 3. PMID- 30519468 TI - Coexistent sarcoidosis and lymphangioleiomyomatosis in a patient with cystic lung disease. AB - A 45-year-old lady presented acutely with pleuritic chest pain, haemoptysis, and dyspnoea. Her background was significant for a 1.4 cm renal angiomyolipoma, and she was an ex-smoker without any relevant family history. A computed tomography (CT) pulmonary angiogram was negative for a pulmonary embolism but demonstrated diffuse cystic change throughout both lungs. A bronchoscopy confirmed a normal endobronchial tree, and pulmonary function tests demonstrated moderate airways obstruction, with reversibility and a normal diffusion capacity for carbon monoxide (DLCO). A video-assisted thoracoscopic surgery (VATS) lung biopsy showed non-caseating granulomas, and serum angiotensin converting enzyme (ACE) was elevated consistent with a diagnosis of pulmonary sarcoidosis. Further sectioning indicated focal areas that stained positive for Human Melanoma Black 45 (HMB-45), confirming lymphangioleiomyomatosis (LAM). A diagnosis of cystic lung disease secondary to coexistent sarcoidosis and LAM was made. PMID- 30519469 TI - Pleural anthracosis presenting with massive effusion: a rare entity. AB - Pleural anthracosis is rare and, in most cases, is diagnosed incidentally or at autopsy. We report a 67-year-old man with pleural anthracosis. He was initially referred for possible tuberculous pleural effusion and had recurrent admissions for symptomatic pleural effusion, which increased with each subsequent episode. A thoracoscopic examination demonstrated diffuse hyperpigmentation in both parietal and visceral pleura. Parietal pleural biopsy indicated granuloma with foreign body giant cell. A contrast-enhanced computed tomography (CECT) thorax showed focal plaques in parietal pleura with calcifications in the ipsilateral lung. Investigations for tuberculosis, fungal, and malignancy proved to be negative. With these results, a diagnosis of pleural anthracosis was made. This case highlights the unusual presentation of pleural anthracosis with pleural effusion. PMID- 30519470 TI - Porous diaphragm syndrome with recurrent thymoma. AB - Porous diaphragm syndrome describes a defect in the diaphragm in which substances pass from the peritoneal cavity to the pleural space. Defects may be congenital or acquired. Acquired defects are caused by the thinning and eventual splitting of collagen fibres in the tendinous part of the diaphragm. We report a case of porous diaphragm syndrome with recurrent thymoma that presented with massive ascites. Increasing intra-abdominal pressure by ascites and diaphragmatic thinning due to malnutrition by malignancies resulted in the formation of an artificial hole. Thoracentesis changed the balance of hydrostatic pressure, which initiated the influx of a large volume of ascites to the pleural cavity through a hole in the diaphragm. PMID- 30519471 TI - A case of Aspergillus and Nocardia infections after bronchial thermoplasty. AB - Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. A 35 year-old woman with uncontrolled severe asthma despite maximal pharmacological treatment underwent BT and started coughing after the first procedure. One month later, during the second BT procedure, there were white ulcerous lesions on the right B9 bronchus. Culture of the bronchial brushing specimen showed Aspergillus fumigatus, for which voriconazole was started for treatment. On the third BT procedure, endobronchial mucus sampling demonstrated Nocardia spp., for which trimethoprim-sulfamethoxazole was given for three months. Seven months after the third BT procedure, no particular endobronchial lesions were found, and no abnormal pathogens were obtained by culture. The resulting bronchial infection in this case may be attributed to the use of systemic steroids, which rendered the patient immunocompromised, and to tissue fragility that was caused by the thermal energy from the BT procedure. Culture of endobronchial mucus should be considered during BT. PMID- 30519472 TI - A 17-year-old woman with a solitary, mixed squamous cell and glandular papilloma of the bronchus. AB - A 17-year-old woman was referred to our hospital due to cough on exertion and right chest pain over the previous two months, together with bloody sputum over the previous week. Chest X-ray demonstrated a nodule measuring 3 cm in diameter in the right middle lung field. On repeated bronchoscopy, the tumour was recognized as a rapidly growing intra-bronchial protruded tumour at the orifice of the right B8. Based on a tentative diagnosis of lung cancer, right lower lobectomy was performed. She was diagnosed with mixed squamous cell and glandular papilloma of the bronchus without smoking history and human papillomavirus infection. Solitary endobronchial papillomas are rare but should be considered a differential diagnosis for solitary lung nodule with the potential to develop into carcinoma. PMID- 30519473 TI - Physicochemical properties of air discharge-generated manganese oxide nanoparticles: Comparison to welding fumes. AB - Exposures to high doses of manganese (Mn) via inhalation, dermal contact or direct consumption can cause adverse health effects. Welding fumes are a major source of manganese containing nanoparticles in occupational settings. Understanding the physicochemical properties of manganese-containing nanoparticles can be a first step in understanding their toxic potential following exposure. In particular, here we compare the size, morphology and Mn oxidation states of Mn oxide nanoparticles generated in the laboratory by arc discharge to those from welding collected in heavy vehicle manufacturing. Fresh nanoparticles collected at the exit of the spark discharge generation chamber consisted of individual or small aggregates of primary particles. These nanoparticles were allowed to age in a chamber to form chain-like aggregates of primary particles with morphologies very similar to welding fumes. The primary particles were a mixture of hausmannite (Mn3O4), bixbyite (Mn2O3) and manganosite (MnO) phases, whereas aged samples revealed a more amorphous structure. Both Mn2+ and Mn3+, as in double valence stoichiometry present in Mn3O4, and Mn3+, as in Mn2O3 and MnOOH, were detected by X-ray photoelectron spectroscopy on the surface of the nanoparticles in the laboratory nanoparticles and welding fumes. Dissolution studies conducted for these two Mn samples (aged and fresh fume) reveal different release kinetics of Mn ions in artificial lysosomal fluid (pH 4.5) and very limited dissolution in Gamble's solution (pH 7.4). Taken together, these data suggest several important considerations for understanding the health effects of welding fumes. First, the method of particle generation affects the crystallinity and phase of the oxide. Second, welding fumes consist of multiple oxidation states whether they are amorphous or crystalline or occur as isolated nanoparticles or agglomerates. Third, although the dissolution behavior depends on conditions used for nanoparticle generation, the dissolution of Mn oxide nanoparticles in the lysosome may promote Mn ions translocation into various organs causing toxic effects. PMID- 30519474 TI - Synergistic interaction between the agonism of cebranopadol at nociceptin/orphanin FQ and classical opioid receptors in the rat spinal nerve ligation model. AB - Cebranopadol (trans-6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenyl spiro[cyclohexane-1,1'(3'H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ opioid peptide (NOP) and classical opioid receptor (MOP, DOP, and KOP) agonist with highly efficacious and potent activity in a broad range of rodent models of nociceptive, inflammatory, and neuropathic pain as well as limited opioid-type side effects such as respiratory depression. This study was designed to explore contribution and interaction of NOP and classical opioid receptor agonist components to cebranopadol analgesia in the rat spinal nerve ligation (SNL) model. Assessing antihypersensitive activity in SNL rats intraperitoneal (IP) administration of cebranopadol resulted in ED 50 values of 3.3 and 3.58 MUg/kg in two independent experiments. Pretreatment (IP) with J 113397 (4.64 mg/kg) a selective antagonist for the NOP receptor or naloxone (1 mg/kg), naltrindole (10 mg/kg), or nor-BNI (10 mg/kg), selective antagonists for MOP, DOP, and KOP receptors, yielded ED 50 values of 14.1, 16.9, 17.3, and 15 MUg/kg, respectively. This 4-5 fold rightward shift of the dose-response curves suggested agonistic contribution of all four receptors to the analgesic activity of cebranopadol. Combined pretreatment with a mixture of the antagonists for the three classical opioid receptors resulted in an 18-fold potency shift with an ED 50 of 65.5 MUg/kg. The concept of dose equivalence was used to calculate the expected additive effects of the parent compound for NOP and opioid receptor contribution and to compare them with the observed effects, respectively. This analysis revealed a statistically significant difference between the expected additive and the observed effects suggesting intrinsic synergistic analgesic interaction of the NOP and the classical opioid receptor components of cebranopadol. Together with the observation of limited respiratory depression in rats and humans the synergistic interaction of NOP and classical opioid receptor components in analgesia described in the current study may contribute to the favorable therapeutic index of cebranopadol observed in clinical trials. PMID- 30519475 TI - A comparison of biological activity of commercially available purified native botulinum neurotoxin serotypes A1 to F1 in vitro, ex vivo, and in vivo. AB - Botulinum neurotoxin (BoNT) is a major therapeutic agent. Of seven native BoNT serotypes (A to G), only A and B are currently used in the clinic. Here we compared the potency of commercially available purified native serotypes A1 to F1 across in vitro, ex vivo, and in vivo assays. BoNT potency in vitro was assessed in rat primary cells (target protein cleavage and neurotransmitter release assays) in supraspinal, spinal, and sensory systems. BoNT potency ex vivo was measured in the mouse phrenic nerve hemidiaphragm (PNHD) assay, measuring muscle contractility. In vivo, BoNT-induced muscle relaxation in mice and rats was assessed in the Digit Abduction Score (DAS) test, while effects on body weight (BW) gain were used to assess tolerability. In all assays, all BoNT serotypes were potent toxins, except serotype D1 in vivo which failed to produce significant muscle flaccidity in mice and rats. In rats, all serotypes were well tolerated, whereas in mice, reductions in BW were detected at high doses. Serotype A1 was the most potent serotype across in vitro, ex vivo, and in vivo assays. The rank order of potency of the serotypes revealed differences among assays. For example, species-specificity was seen for serotype B1, and to a lesser extent for serotype C1. Serotypes F1 and C1, not currently in the clinic, showed preference for sensory over motor models and therefore could be considered for development in conditions involving the somatosensory system. PMID- 30519476 TI - Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. AB - Spinal muscular atrophy (SMA) is a rare, inherited neuromuscular disease caused by deletion and/or mutation of the Survival of Motor Neuron 1 (SMN1) gene. A second gene, SMN2, produces low levels of functional SMN protein that are insufficient to fully compensate for the lack of SMN1. Risdiplam (RG7916; RO7034067) is an orally administered, small-molecule SMN2 pre-mRNA splicing modifier that distributes into the central nervous system (CNS) and peripheral tissues. To further explore risdiplam distribution, we assessed in vitro characteristics and in vivo drug levels and effect of risdiplam on SMN protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n = 90), rats (n = 148), and monkeys (n = 24). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam CSF levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39 weeks. A parallel dose-dependent increase in SMN protein levels was seen in CNS and peripheral tissues in two SMA mouse models dosed with risdiplam. These in vitro and in vivo preclinical data strongly suggest that functional SMN protein increases seen in patients' blood following risdiplam treatment should reflect similar increases in functional SMN protein in the CNS, muscle, and other peripheral tissues. PMID- 30519477 TI - West Nile virus in Algeria: a comprehensive overview. AB - West Nile virus (WNV) is a mosquito-borne virus belonging to the genus Flavivirus, related to the Japanese encephalitis antigenic complex of Flaviviridae family. It is transmitted by the bite of infected mosquitoes. The virus is maintained in a mosquito-bird-mosquito transmission cycle. WNV has recently dramatically expanded its geographical range and is now considered the most widespread arbovirus in the world, including the Americas, Europe and countries facing the Mediterranean Basin. In Algeria, West Nile disease (WND) infections with human meningoencephalitis cases have been reported in 1994 in Tinerkouk (southwest Sahara. In autumn 2012, one fatal clinical case of WNV neuroinvasive infection was reported in Jijel (coastal east). During the same year, a retrospective serosurvey performed in Algiers and bordering areas highlighted specific anti-WNV IgG in local population. Between 2013 and 2014 two clinical cases were reported, in Timimoune (south) and Guelma (northeast) respectively. Although no case was reported in equids, serosurveys demonstrated its presence: an animal serosurvey was conducted in Djanet (south) in 1975, and in 2014 a seroprevalence of equids in the northeast part of Algeria highlighted a virus circulation. This review aims to evaluate the global epidemiologic situation of West Nile disease in Algeria, with an updated situation based on human cases, equine reports and entomologic investigations. Our study reinforces the need for building the capacity for surveillance in this region to prevent future emergence of WNV and other arboviruses. PMID- 30519478 TI - Investigation of tolerability and quality of life for carboplatin-based chemotherapy in an elderly urothelial carcinoma patient undergoing hemodialysis: a case report. AB - Background: To our knowledge, no studies have evaluated the safety of carboplatin (CBDCA)-based chemotherapy in hemodialysis patients > 80 years-old. In addition, the impact of CBDCA-based chemotherapy on such elderly patients' quality of life (QOL) is unknown. We report a case of gemcitabine plus CBDCA chemotherapy treatment in an 81-year-old man with metastatic urothelial carcinoma undergoing hemodialysis. Case presentation: The optimal CBDCA dose and hemodialysis timing were determined by monitoring the measured area under the concentration-time curve (AUC) of CBDCA. This was used because the AUC of CBDCA is correlated with hematologic toxicities, especially nadir thrombocytopenia, and CBDCA is easily dialyzed during hemodialysis. In the first cycle, a 160 mg CBDCA dose, calculated using Calvert's formula (target-AUC: 5), was administered on day 1. Hemodialysis was performed for 3 h, starting 2 h after the end of the CBDCA infusion. The measured-AUC was 5.96 mg/mL min in the first cycle, after which the patient developed grade 3/4 hematologic toxicities. Thus, in the second cycle, the CBDCA dose was reduced to 135 mg and the time interval between CBDCA infusion and hemodialysis was shortened to 1 h, according to the results of a pharmacokinetic study performed using parameters from the first cycle. The measured-AUC in the second cycle was 4.97 mg/mL min, and hematologic toxic effects decreased to grade 2. Stable disease according to the Response Evaluation Criteria in Solid Tumors was demonstrated after the second and third cycles. QOL scores determined using a short-form questionnaire (SF-36) after 2 cycles were not significantly lower than pretreatment values. Conclusions: CBDCA-based chemotherapy is clinically acceptable in hemodialysis patients aged > 80 years, and this systemic chemotherapy can be a treatment option in such elderly patients undergoing hemodialysis. However, the measured-AUC should be monitored, as the actual AUC is unpredictable in hemodialysis patients. This is due to the influence of various factors that may be different for each patient, such as the patient's residual renal function and hemodialysis duration and conditions, especially in elderly patients, who have a higher risk of chemotherapy-induced neutropenia. PMID- 30519479 TI - A prospective cohort study of game-based learning by digital simulation of a pig farm to train agriculture students to reduce piglet mortality. AB - Background: Acquisition of knowledge and skills by agriculture students prior to real-life experience is a well-known educational challenge. Game-based learning has the advantage of being active, experiential, and problem-based, and provides immediate feedback. Simulation games are widely used in other fields to support traditional teaching methodology and actively engage students. This study investigates whether a digital pig farm game can assist agriculture students in acquiring knowledge and skills in farrowing management to reduce mortality in piglets prior to weaning. Results: Overall the simulation group tended to score higher; however, at 5% confidence level, the difference was not significant. The simulation group had the lowest standard deviation which to some extent was due to reduced number of low-scoring students. Nevertheless, students requested more digital simulation for learning and practicing skills. Conclusion: The use of game-based learning in agricultural education has a huge potential for building skills needed on a real pig farm. However, an increase in knowledge related to farrowing management was not documented.The integration of game-based learning into an educational setting needs further evaluation. PMID- 30519480 TI - A study protocol "saving futures: developing an integrated model of rehabilitation and paediatric HIV care to foster success at school". AB - Background: A significant number of children experience disabilities as a result of living with HIV, including those on antiretroviral therapy (ART). Current paediatric HIV care does not prioritise rehabilitation. Furthermore, little attention is paid to cognitive development and educational needs, thereby placing the future of these children at risk. This can be mitigated by providing rehabilitation services to help overcome these disabilities. Methods: The study will assess the feasibility (acceptability, practicality, preliminary efficacy) of an integrated model of rehabilitation and paediatric HIV care in order to improve diagnosis and interventions for disability amongst children living with HIV between the ages of 5 and 10 years. The model will integrate data entry and management tools, improving identification, referral, and linkage to care, with an intervention approach that can be used by trained lay health professionals. The study targets both physical and cognitive impairments that lead to disabilities to improve school readiness and success. Phase 1 will inform the design of an optimal integrated model of rehabilitation and paediatric HIV care in a public healthcare setting in South Africa. The study will first undertake a formative investigation of the factors impacting integration of rehabilitation with paediatric HIV care from the perspective of caregivers and health professionals. It will use qualitative methods, including in-depth interviews and focus group discussions. The knowledge from this phase will inform the design of the model in phase 2, and phase 3 will pilot the integrated rehabilitation and paediatric HIV model with the aim to improve school readiness for the participants at the study site. The pilot intervention will be formally evaluated. Discussion: The results from this study will determine whether the model has potential for widespread application in South African paediatric HIV care and recommend further possible modifications. This will inform the development of a proposal to support the current government initiative to strengthen disability and rehabilitation services. The study results will also inform South Africa's current efforts to strengthen early interventions for children with disabilities and will be an important and critically needed step in the use of rehabilitation to strengthen paediatric HIV care in the region. PMID- 30519481 TI - Safety and feasibility of an interactive workshop and facilitated outdoor walking group compared to a workshop alone in increasing outdoor walking activity among older adults: a pilot randomized controlled trial. AB - Background: Limited outdoor walking is a marker of frailty and a risk factor for decline in mobility and self-care functioning, social isolation, and reduced health-related quality of life (HRQL). Objectives were to evaluate the safety, feasibility, and preliminary effect of a supervised outdoor walking group and interactive workshop compared to the workshop alone in increasing outdoor walking activity and identify an optimal method for estimating outdoor walking activity among older adults who infrequently walk outdoors. Methods: A pilot 2-parallel group randomized controlled trial was conducted. Adults aged >= 65 years who reported walking <= 20 min/week outdoors were randomized in a 2:1 ratio to receive the GO-OUT program (1-day workshop and 9-week outdoor walking group), or the workshop alone. An external site conducted the randomization after workshop completion. The eight workshop activity stations aimed to build knowledge and skills to safely walk outdoors. The group-based outdoor walking program consisted of repetitive practice of mobility tasks at local parks. The primary outcome of outdoor walking activity used an activity monitor and GPS; secondary outcomes included aerobic, balance, and walking capacity; physical activity; participation; mood; and HRQL. Blinded outcome assessors evaluated participants at 0, 3, and 6 months. Qualitative interviews occurred after 3 months; data were analyzed with qualitative description. Quantitative data were summarized using descriptive statistics. Results: Forty-eight individuals were screened; 9 were eligible and randomized to the GO-OUT (n = 6) or workshop (n = 3) group. Data from 9 participants were analyzed. Mean age was 77 and 74 years in the GO-OUT and workshop groups, respectively. No falls occurred during the workshop and outdoor walking program. Average attendance of the walking group was 61%. All participants attended the evaluations and workshop. An analysis method combining data from activity monitors and GPS was developed to estimate outdoor walking. Themes from the qualitative analysis included the barriers to outdoor walking, impact of the workshop and GO-OUT walking group, and feasibility and acceptance of the assessment and intervention strategies. Conclusions: The trial protocol was deemed safe and feasible. Results were used to inform changes to the protocol to conduct a full-scale study. Trial registration: Clinical Trials.gov: NCT02339467. PMID- 30519482 TI - Peer-led intervention to prevent and reduce STI transmission and improve sexual health in secondary schools (STASH): protocol for a feasibility study. AB - Background: Young people in the UK are at highest risk of sexually transmitted infections and report higher levels of unsafe sex than any other age group. Involving peer supporters in intervention delivery is acceptable to students and effective in reducing risk behaviours via 'diffusion of innovation', particularly where peer supporters are influential in their networks. Informal peer-led interventions offer a useful alternative to peer-led didactic teaching, which has shown limited effects. Building on the successful ASSIST anti-smoking intervention, the 'STis And Sexual Health' (STASH) intervention involves identification and recruitment of the most influential students as peer supporters, training and support to these students by specialist trainers, positive sex and relationships messages, spread by peer supporters to their friendship groups in person and via social media. Methods/design: This protocol describes a feasibility trial of the STASH intervention in six schools. It builds on an earlier study phase of intervention co-development using patient and public involvement (PPI) activities, followed by a pilot of intervention components and evaluation tools in one school. Participants are fourth year (S4) students (aged 14-16) in state-funded Scottish secondary schools who have received some level of teacher-led sex education. The previous cohort of S4 students (those completing S4 in the year prior to the intervention) will serve as controls. Data will be collected from controls (month 16), baseline (month 20-21) and follow-up (month 27-30) via a web-based questionnaire, which will measure (and test the reliability of) primary outcome measures for a phase III trial (delayed initiation of/abstinence from sex and consistent condom use), secondary outcomes and mediators of sexual behaviour (including school climate and social networks). The main feasibility outcome is whether the study meets pre-set progression criteria regarding feasibility and acceptability, measured largely via a process evaluation (basic measures in all 6 schools and in-depth in 2-4 schools). An economic evaluation reporting costs alongside consequences will be conducted. Discussion: This study will inform decisions on the feasibility, design and sample size for a phase III effectiveness trial to assess whether the STASH intervention is effective in reducing the risk of sexually transmitted infections in young people. Trial registration: ISRCTN97369178. PMID- 30519484 TI - Level of adherence to dietary recommendations and barriers among type 2 diabetic patients: a cross-sectional study in an Ethiopian hospital. AB - Background: Limited data are available regarding the level of adherence and barriers to dietary recommendations in individuals with type 2 diabetes in Africa including Ethiopia. Therefore, this study aimed at assessing the level of dietary adherence and its barriers among patients with type 2 diabetes in northwest Ethiopia. Methods: A prospective hospital-based cross-sectional study was conducted from August to October 2017 at Debre Tabor General Hospital, Northwest Ethiopia. The Perceived Dietary Adherence Questionnaire (PDAQ) was used for dietary adherence measurement. Multivariate logistic regression was done to identify the barriers influencing dietary adherence. Result: A significant percentage (74.3%) of the study participants had poor adherence to dietary recommendations. The highest mean score was obtained for the question regarding consuming foods high in sugar with a mean 5.49 +/- 1.20 times a week. On the other hand, our participants had a low consumption of fruits and vegetables and foods high in omega-3 fats with a mean of 1.84 +/- 1.96 and 0.1 +/- 0.62 times a week respectively. According to the survey of participants, lack of knowledge, lack of diet education, inability to afford the cost of healthy diet and poor awareness about the benefit of dietary recommendations were the most cited reasons for poor dietary adherence. In multivariate logistics regression, low level of educational status, the presence of co-morbidities, lack of previous exposure to dietary education and low monthly income were statistically significant factors associated with non-adherence. Conclusion: The rate of non adherence to dietary recommendation among patients with T2DM was found to be high in northwest Ethiopia. Hence, providing customized health education about the potential benefit of proper dietary recommendations in controlling blood glucose is recommended. Health care providers should be proactive in promoting adherence to dietary recommendations in patients with T2DM. PMID- 30519483 TI - Multimorbidity rehabilitation versus disease-specific rehabilitation in people with chronic diseases: a pilot randomized controlled trial. AB - Background: Multimorbidity (the co-existence of two or more chronic conditions in an individual) is a growing healthcare burden internationally; however, healthcare and disease management, including rehabilitation, is often delivered in single-disease siloes. The aims of this study were to (1) evaluate the safety and feasibility of multimorbidity rehabilitation compared to a disease-specific rehabilitation program in people with multimorbidity and (2) gather preliminary data regarding clinical outcomes and resource utilization to inform the design of future trials. Methods: A pilot feasibility randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis. Seventeen individuals with a chronic disease eligible for disease-specific rehabilitation (pulmonary, cardiac, heart failure rehabilitation) and at least one other chronic condition were recruited. The intervention group attended multimorbidity exercise rehabilitation and the control group attended disease specific exercise rehabilitation. Participants attended twice-weekly exercise training and weekly education for 8 weeks. Feasibility measures included numbers screened, recruited, and completed. Other outcome measures were change in functional exercise capacity (6-minute walk test (6MWT)), health-related quality of life (HRQoL), activities of daily living (ADL), and resource utilization. Results: Sixty-one people were screened to recruit seventeen participants (nine intervention, eight control); one withdrew prior to rehabilitation. Participants were mostly male (63%) with a mean (SD) age of 69 (9) years and body mass index of 29 (6). The intervention group attended a mean (SD) of 12 (6) sessions, and the control group attended 11 (4) sessions. One participant (6%) withdrew after commencing; two (12%) were lost to follow-up. The intervention group 6MWT distance increased by mean (SD) of 22 (45) meters (95% confidence interval - 16 to 60) compared to 22 (57) meters (95% confidence interval - 69 to 114) (control). Conclusions: It was feasible to recruit people with multimorbidity to a randomized controlled trial of rehabilitation. A large RCT with the power to make significant conclusions about the impact on the primary and secondary outcomes is now required. Trial registration: The trial was registered with the Australian and New Zealand Clinical Trials Registry available at http://www.anzctr.org.au ACTRN12614001186640. Registered 12/11/2014. PMID- 30519485 TI - Arterial stiffness and hypertension. AB - Measures of the functional and structural properties of blood vessels can be used to assess preclinical stage of vascular disorders. Recent experimental and population studies show that arterial stiffening precedes development of high blood pressure, and can be used to predict future cardiovascular events. Arterial stiffness was also shown to be reversible in several experimental models of various conditions. Since reversing arterial stiffness could prevent development of hypertension and other clinical conditions, understanding the biological mechanisms of arterial stiffening and investigating potential therapeutic interventions to modulate arterial stiffness are important research topics. For research and application in general clinical settings, it is an important step to develop reliable devices and a standardized arterial stiffness measurement protocol. PMID- 30519486 TI - Assessing community (peer) researcher's experiences with conducting spirometry and being engaged in the 'Participatory Research in Ottawa: Management and Point of-care for Tobacco-dependence' (PROMPT) project. AB - Plain summary: This article examines the overall experiences of community researchers in their involvement with the 'PROMPT' project for smoking cessation, which targeted community members who were homeless or at-risk for homelessness. More specifically, four community members, representing the study population were involved in the project as researchers. They were asked to complete surveys at both the beginning and end of each research training session to better understand their learning as it related to using a key instrument for this project, a spirometer, to measure project participants' lung function. Spirometry is typically performed by trained healthcare providers. Community researchers were also interviewed to explore what their experiences were like working as a researcher with their own at-risk community. Although the researchers felt that the training was sufficient, more research is needed to evaluate training effectiveness among community researchers in delivering acceptable quality lung function testing using a spirometer. Upon analyzing the small group discussion and survey results, we found that the community researchers had an overall positive experience with both the project, and the training that was provided to equip them with the knowledge, tools, and resources they needed to successfully work in a research project of this kind. They also faced challenges that are common in such community-based projects, such as the power differential between the researchers with a healthcare background and themselves who have lived experience with the issue at hand. Abstract: Background The Ottawa Citizen Engagement and Action Model (OCEAM) used a Community Based Participatory Action Research (CBPAR) approach by involving the most at-risk urban population. Community (peer) researchers participated in every step of the study despite the multiple challenges. Objective To assess the community researchers' training and experiences in a CBPAR project, PROMPT: Participatory Research in Ottawa: Management and Point-of-care for Tobacco Dependence. Method Four community researchers were recruited, representative of the PROMPT project's target population with current or past poly-substance use; smoking tobacco; and/or being homeless or at-risk for homelessness. The community researchers participated in all phases of PROMPT, including study design, development of questionnaires, participant recruitment, administering consent forms and questionnaires, as well as hand-held spirometry after rigorous training. To assess their knowledge and comfort level with spirometry testing after standardized training, questionnaires were administered pre- and post-training. In turn, to assess their overall experience, interviews were conducted at the end of study completion. Results All community researchers underwent small-group training sessions including presentations, discussions and hands-on practice adapted from standardized training material prepared for health care professionals. Spirometry training was included in all sessions. Self-perceived knowledge and confidence in administering spirometry, as well as skill-testing score averages improved between the pre- and post-training questionnaires. Overall, all the community researchers had a fulfilling experience participating in the project. Conclusion Despite challenges, involving community researchers with lived experience is feasible, satisfying and productive even in the most marginalized populations. Standardized spirometry training of community researchers' representative of the PROMPT target population, with no healthcare educational background, was feasible and effective in improving knowledge, confidence and readiness to administer spirometry. PMID- 30519487 TI - Multimodal imaging in a patient with Prader-Willi syndrome. AB - Background: Prader-Willi syndrome (PWS) is a genetic disease caused by loss of expression of the paternally inherited copy of several genes on the long arm of chromosome 15. Ophthalmic manifestations of PWS include strabismus, amblyopia, nystagmus, hypopigmentation of the iris and choroid, diabetic retinopathy, cataract and congenital ectropion uvea. An overlap between PWS and oculocutaneous albinism (OCA) has long been recognized and attributed to deletion of OCA2 gene located in PWS critical region (PWCR). Case report: A 30-year-old male patient with PWS presented with vision loss in his left eye. His right eye had normal visual acuity. Multimodal imaging revealed absence of a foveal depression and extremely reduced diameter of the foveal avascular zone in the right eye and an inactive type 2 macular neovascular lesion in the left eye. Conclusions: We report a presumed association of fovea plana and choroidal neovascularization with PWS. The use of multimodal imaging revealed novel findings in a PWS patient that might enrich our current understanding of the overlap between PWS and OCA. PMID- 30519489 TI - Assessing the Prevalence of Incidental Findings Identified by CTPA in Women of Reproductive Age. AB - Background and Objective: Though multiple studies have evaluated the prevalence of incidental findings identified by CTPA, none have done so with a focus on reproductive-age females with normal chest X-ray (CXR). Due to a comparatively lower breast radiation dose, the oft-recommended alternative to CTPA in this patient group is a V/Q scan. However, these are limited in their assessment of these alternate findings; therefore, it is of particular importance to evaluate the likelihood of these findings on CT in this patient group, which is the goal of this study. Methods: Through a review of our PACS system, female patients aged 18-50 years who underwent diagnostic CTPA prior to April 1, 2017, were identified. The 100 most recent cases which had a normal CXR within 48 hours of CTPA were included. Incidental/non-PE findings were then divided into PE-positive (PE+) and PE-negative (PE-), and subcategorized into types I, II, III, and nil non-PE finding groups. Type I findings required immediate follow-up or intervention, type II findings required outpatient follow-up, and type III findings required no follow-up or were previously known. Results: PE was detected in 15% of scans. Type I findings were found in 8% of patients (0% of PE+, 9.4% of PE-), type II findings in 10% of patients (13.3% of PE+, 9.4% of PE-), type III findings in 34% of patients (40% of PE+, 32.9% of PE-), and nil non-PE finding in 48% of patients (46.7% PE+, 48.2% of PE-). Conclusion: While CTPA identifies incidental findings in the majority of patients, a small minority of these findings are likely to alter immediate management. In the context in increased radiation risk, this strengthens the argument that alternate imaging modalities such as V/Q should be strongly considered for the investigation of potential PE in women of reproductive age with normal CXR. PMID- 30519488 TI - Renal Dysfunction among Ghanaians Living with Clinically Diagnosed Hypertension in the Asutifi-South District: A Cross-Sectional Descriptive Study at the St. Elizabeth Hospital, Hwidiem. AB - Background: This study aimed at evaluating the burden of renal dysfunction among people living with hypertension in the Asutifi-South District of the Brong Ahafo Region, who were attending clinic at the St. Elizabeth Hospital in Hwidiem. Methodology: A hospital-based, cross-sectional study was conducted among two hundred (200) hypertensive clients aged between 27 and 88 years who reported for clinical management from January to March, 2018. Data on sociodemography, comorbid disease status, antihypertensive medication, and their duration was obtained using a semistructured questionnaire and patient folders. Blood pressure, weight, and creatinine were measured using standard methods. Kidney function was assessed using Cockcroft Gault (CG), Four-Variable Modification of Diet in Renal Disease (4v-MDRD) and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations. The 2012 Kidney Disease Improvement Global Outcome (KDIGO) Criteria were used to categorize renal function among study participants. Results: Renal impairment was observed among 25.00%, 9.50%, and 10.50% of study participants using CG, 4v-MDRD, and CKD-EPI equations, respectively. With the exception of CKD-EPI equation, females significantly recorded higher scores compared to their male counterparts (28.95% vs 12.5%, 11.84%, vs 2.08%) using CG and 4v-MDRD, respectively. Participants aged 50 years or more recorded the highest renal impairment. Conclusion: Renal dysfunction is common among people living with hypertension in the Asutifi-South District of the Brong Ahafo Region. Femininity, older age, disease comorbidity with diabetes, Thiazide diuretic and AR Blocker usage, and increasing duration of medication accounted for higher kidney dysfunction. Regular screening and management are therefore recommended to avert progression to end-stage renal failure (ESRD). PMID- 30519490 TI - Mirror and Vibration Therapies Effects on the Upper Limbs of Hemiparetic Patients after Stroke: A Pilot Study. AB - Background/Aim: To evaluate, in this pilot study, the effects of the mirror (MT) and vibration therapies (VT) on the functionality of hemiparesis patients after stroke. Materials and Methods: Twenty-one individuals after stroke with upper limb hemiparesis were randomized into control group (CG), Mirror Therapy Group (MTG), and Vibration Therapy Group (VTG). The functionality was evaluated before and after 12 sessions with three tests (i) Mobility Index Rivermead, (ii) Motor Function Wolf Test (time, functional ability), and (iii) Jebsen Taylor Test. Results: Significant findings were observed for MTG or VTG when compared to the CG, obtaining improvements in the three functional tests: Mobility Index Rivermead, Motor Function Test Wolf (time) and Motor Function Test Wolf (functional ability), and Jebsen Test Taylor. Conclusions: MT or VT showed enhancements on the functionality of subjects with poststroke hemiparesis. In consequence, these interventions may be used in the rehabilitation of these individuals in order to promote improvements of the affected upper limb functionality. Probably, neuromuscular responses of the used therapies would be related to these desirable effects. However, it is necessary conducting further controlled studies with more subjects. PMID- 30519491 TI - Lack of Association between Variant rs7916697 in ATOH7 and Primary Open Angle Glaucoma in a Saudi Cohort. AB - A case-control genetic association study was performed to investigate whether variant rs7916697 in atonal bHLH transcription factor 7 (ATOH7), which has been previously reported to be associated with optic disc parameters and primary open angle glaucoma (POAG) in different ethnic groups, is a risk factor for POAG or any of its clinical phenotypes in a Saudi cohort. Genotyping of rs7916697 (G>A) variant was performed in 186 unrelated POAG cases and 171 unrelated nonglaucomatous controls of Saudi origin using real-time Taq-Man(r) assay. Genotypic and allelic association with POAG and its related clinical indices were evaluated. Demographic and systemic disease status did not differ significantly between POAG cases and controls. Association analysis between POAG cases and controls showed no significant genotype effect under additive (p=0.707), dominant (p=0.458), and recessive (p=0.554) models. Besides, the minor 'A' allele frequency was 0.39 in POAG cases and 0.36 in controls with no significant distribution (p=0.406). In addition, there was no significant difference between genotypes and clinical phenotypes such as intraocular pressure and cup/disc ratio within the POAG group, or any age and sex adjusted genotype effect on the disease outcome in regression analysis. Variant rs7916697 in ATOH7 is not associated with POAG or its clinical indices such as IOP and cup/disc ratio in a Saudi cohort. PMID- 30519492 TI - Meningococcemia Masquerading as a Nonspecific Flu-Like Syndrome. AB - Neisseria meningitidis is a cause of bacterial meningitis and meningococcemia worldwide. Rarely, it causes invasive disease with significant lifelong sequela if survived. Early clinical recognition is key as meningococcemia is an easily treatable disease, yet mortality is 50% if it is left untreated. In this case review, we present a classic case of meningococcemia, with an atypical presentation. PMID- 30519493 TI - Denosumab-Induced Severe Hypocalcaemia in Chronic Kidney Disease. AB - Background: Hypocalcaemia is increasingly recognized as a complication of denosumab use in Chronic Kidney Disease (CKD) patients with osteoporosis. Despite Therapeutic Goods Administration (TGA) notifications in 2013, we have subsequently encountered several cases of denosumab-induced hypocalcaemia, raising concern about lack of widespread awareness among prescribing practitioners. Aims: We reviewed the morbidity and healthcare intervention needs of CKD patients with hypocalcaemia attributed to denosumab. Methods: A retrospective case series of CKD patients with clinically significant hypocalcaemia after exposure to denosumab, encountered at the tertiary care referral hospital from December 2013 to February 2017, was undertaken. Results: Eight patients (52-85 years of age) with stage 4-5 CKD developed clinically significant hypocalcaemia (corrected calcium 1.45+/-0.21mmol/L) following denosumab therapy for osteoporosis. Seven of the eight patients required inpatient management with three patients requiring intravenous calcium replacement and cardiac monitoring in a high dependency unit. Our study also identified additional factors that could potentially contribute to hypocalcaemia such as lack of calcium supplementation, use of noncalcium based phosphate binders, absence of or use of lower doses of calcitriol supplementation, low vitamin D levels, concomitant treatment with loop diuretics, history of parathyroidectomy, or presence of acute medical illness. Conclusion: Multiple cases of severe hypocalcaemia in CKD patients following denosumab exposure were encountered after TGA warnings, resulting in considerable morbidity and intensive healthcare interventions in CKD patients. We advocate greater awareness amongst the medical profession, careful consideration before using denosumab in CKD patients, and close follow-up after administration to prevent morbidity. PMID- 30519494 TI - Creutzfeldt-Jakob Disease Presenting as Nonconvulsive Status Epilepticus. AB - Creutzfeldt-Jakob disease is a rare, rapidly progressive spongiform encephalopathy in humans. EEG plays an important role in diagnosing this disease. In some patients, epileptic activity and encephalopathy from various aetiologies may share morphological features on EEG. This similarity could create difficulties in EEG interpretation, especially if the patient presents with disturbed consciousness. In this case report, a 74-year-old female with Creutzfeldt-Jakob disease presented initially with rapidly progressive impairment of consciousness and focal epileptiform activity on EEG. An EEG performed 25 days later showed periodic sharp-wave complexes with triphasic morphology at a rate of 0.5 Hz, compatible with a diagnosis of Creutzfeldt-Jakob disease. Based on these results, we recommend that a diagnosis of Creutzfeldt-Jakob disease be considered in patients presenting with a rapid deterioration of consciousness and a clinical presentation of nonconvulsive status epilepticus. Monitoring these patients with serial EEGs could be useful to establish an accurate diagnosis. PMID- 30519495 TI - Life-Threatening Hypertriglyceridemia in a Patient on Ruxolitinib and Sirolimus for Chronic Graft-versus-Host Disease. AB - Ruxolitinib is an oral selective Janus-associated kinase 1 (JAK1) and JAK2 inhibitor that was initially approved by the FDA in 2014 for treatment of myelofibrosis. In preclinical and retrospective clinical studies, use of ruxolitinib was shown to reduce graft-versus-host-disease (GVHD) in allograft recipients with moderate/severe corticosteroid-dependent or refractory chronic GVHD. While the exact mechanism for action in GVHD is not yet fully understood, prospective studies are ongoing and some patients are receiving ruxolitinib in the setting of steroid refractory GVHD. Although ruxolitinib is generally well tolerated, here we describe a case involving a 50-year-old man with acute myeloid leukemia and chronic GVHD who experienced life-threatening hypertriglyceridemia associated with concomitant use of sirolimus and ruxolitinib for GVHD. This case report highlights the importance of vigilance for severe side effects in novel immunosuppressive drug combinations. PMID- 30519496 TI - A Case of Urethral Diverticulum with Surgical Repair Using Cadaveric Pericardial Tissue. AB - A urethral diverticulum is a relatively uncommon finding. The estimated prevalence is approximately 1-5% in the general population. While the definitive treatment is surgical correction, there are limited studies guiding the best approach to repair. This is the case of a 48-year-old female who initially presented with vaginal discharge, dysuria, and dyspareunia. MRI revealed the diagnosis of suspected urethral diverticulum. The patient was treated with surgical correction with the aid of needle localization prior to the procedure. After the diverticulum was excised, the resulting defect in the urethra was successfully closed with cadaveric pericardial tissue. A urethral diverticulum should be considered in the differential diagnosis when a patient presents with symptoms such as recurrent urinary tract infections (UTIs) vaginal mass, dysuria, dyspareunia, or vaginal discharge. The use of cadaveric tissue augments the surgical technique for repair. PMID- 30519497 TI - Evaluation of fiber optic methane sensor using a smoke chamber. AB - This report presents the results of experiments to evaluate a prototype fiber optic methane monitor exposed to smoke using a smoke chamber to simulate atmospheric conditions in an underground coal mine after a fire or explosion. The experiments were conducted using test fires of different combustible sources commonly found in mines -douglas-fir wood, SBR belt, and Pittsburgh seam coal. The experiments were designed to assess the response of the fiber optic methane sensor to different contaminants, different contaminant levels and different contaminant durations produced from the test fires. Since the prototype methane monitor detects methane by measuring absorption at a specific wavelength, optical power at the absorption wavelength (1650 nm) was measured as a function of smoke concentration and duration. The other sensor response parameter-methane response times-were measured between smoke tests to assess the impact of soot accumulation on the sensor. Results indicate that the sensor screen effectively prevented smoke from obscuring the optical beam within the sensor head, with minimal impact on the system optical power budget. Methane response times increased with smoke exposure duration, attributed to soot loading on the protective screen. PMID- 30519498 TI - Evaluation of RETICs Glaucoma Diagnostic Calculators in Preperimetric Glaucoma. AB - Purpose: To evaluate two glaucoma diagnostic calculators (GDC) in a group of eyes with preperimetric glaucoma (PPG). Methods: All eyes (n = 265) included in this study had ocular hypertension with normal visual fields (VFs) on repeated VF tests. PPG was defined as progression in the Guided Progression Analysis software from Cirrus-optical coherence tomography (GPA-OCT). Three PPG types were defined according to the GPA-OCT software as follows: (1) GPA-OCT with one or more red boxes in two or more columns; (2) GPA-OCT with two or more red boxes in two or more columns; and (3) GPA-OCT with two or more red boxes in two or more columns (definition 2), and in the last scan one or more red box in the RNFL average or quadrants. Nonparametric tests, areas under the receiver operating characteristic curve (AUC), and Bland-Altman tests were assessed. Results: Definitions one, two, and three were met by 44 (16.6%), 29 (10.9%), and 11 (4.2%) eyes, respectively. The GDC indices (means +/- standard deviations) were, respectively, 14.49 +/- 21.55% and 26.06 +/- 22.50% using the combined and quantitative GDC (P < 0.001) in all eyes. Both GDC showed higher glaucoma probability in the PPG group (P < 0.04; combined GDC AUCs, 0.720-0.833; quantitative GDC AUCs, 0.700-0.839). GDC values were higher (P < 0.01) with greater GPA progression. Conclusions: The values of both GDC were higher in the PPG group than the ocular hypertension group. The GDC were higher when more columns in the GPA software indicated progression. Both GDC showed a similar ability to detect PPG. Translational Relevance: These calculators facilitate diagnosis of PPG in ocular hypertensive eyes. PMID- 30519499 TI - A Method to Measure the Rate of Glaucomatous Visual Field Change. AB - Purpose: To develop a method to measure the rate of glaucomatous visual field (VF) deterioration and to identify fast progressors. Methods: Retrospective, longitudinal, observational study of 8486 eyes of 4610 glaucomatous patients with >=6 VFs and >=3 years of follow-up. A Glaucoma Rate Index (GRI) was calculated. VF locations were partitioned into exponential decay or exponential improvement models. A pointwise rate of change (PRC) was estimated with an exponential fit and expressed as the percent/year change of the age- and location-matched normal perimetric range, presented as a spatially conserved VF map. PRCs were summed and normalized with boundary rates set by simulated decaying and improving VF series on a scale of -100 to +100, respectively. Results: A total of 89,704 VF examinations with 425,039 test location series was used. Median follow-up and number of VFs/eye were 9.7 years and 9 VFs, respectively. Initial and final mean deviations (+/-SD) were -4.2 (+/-5.2) and -5.7 (+/-6.4) dB. The proportions of test locations designated as decayed, improved, and unchanged were 13%, 4%, and 83%, respectively. Mean PRCs for decay, improvement, and no change were -3.7 (+/ 4.7)%/y, 2.5 (+/-2.6)%/y, and -0.5 (+/-2.1)%/y, respectively. The number of eyes with negative and positive GRIs was 5802 (68%) and 2390 eyes (28%), respectively. The proportion of eyes defined as fast progressors was 6.8%. Conclusions: GRI provides a robust measure of glaucomatous VF change, operates without discontinuity over the entire perimetric range, and can be used to identify fast progressors. Translational Relevance: This study describes a novel method that can help the clinician to determine VF progression. PMID- 30519500 TI - Functional Connectivity of Paired Default Mode Network Subregions in Retinal Detachment. AB - Purpose: To explore the difference of the default mode network (DMN) in patients with retinal detachment (RD) by the study of the resting state functional connectivity (rs-FC). Methods: A total of 30 patients with RD (16 men, 14 women) and 30 similarly matched normal controls (NCs) were examined and recorded with rs fMRI. The DMN was divided into eight core regions, and each rs-FC map of each subregion was obtained. The receiver operating characteristic (ROC) curve was performed to classify the mean FC values of RD patients from NCs, and the interrelationships between the FC and each region were evaluated with Pearson's correlation analysis. Results: Compared with NCs, there were significantly increased FC in the left medial temporal lobe (MTL.L) and posterior cingulate cortex (PCC), MTL.L and left hippocampus formation (HF.L), MTL.L and HF.R, MTL.L and left inferior parietal cortices (IPC.L), MTL.L and IPC.R in the RD group (P < 0.05). Nevertheless, no correlation between the FC values of each paired region and the manifestations was found in the RD group. ROC curve analysis showed that the accuracy of the area under the curve was excellent in MTL.L-HF.R and MTL.L IPC.R and less reliable in MTL.L-PCC, MTL.L-HF.L, and MTL.L-IPC.L. Conclusions: The visual function impairments of RD patients were closely related to the DMN functional connections, which provided insight into the neural variation in RD patients and assisted in revealing the potential mechanisms of RD. Translational Relevance: This study provided insight into the neural variation in RD patients and assisted in revealing the potential mechanisms of RD. PMID- 30519501 TI - Composition and Comparison of the Ocular Surface Microbiome in Infants and Older Children. AB - Purpose: Unlike other microbiomes of the body, the composition of the ocular surface microbiome (OSM) in children has yet to be thoroughly explored. Our goal was to evaluate the OSM in young infants and compare its composition to older children using both culture dependent and independent methodologies to assess for differences with age. Methods: Prospective, observational, cross-sectional study of children <18 years of age at a university-based institution. The mucosal surfaces of both eyes, nose and throat were swabbed with a forensic-quality swab. Half of the swab was plated for culture and the other half underwent 16S sequencing. Culture results and microbiome diversity were analyzed. Results: Fifty patients (mean age 37 months, range 1-168 months) were enrolled. Forty seven eyes of 30 patients had positive cultures; four eyes grew >1 species. Culture positive patients were older (43 vs. 29 months, P = 0.19). Additionally, older children had greater diversity than children under 6 months of age by 16S sequencing (P = 0.05). Staphylococcus species were predominant by culture (35/52 isolates) and by 16S sequencing. The OSM was fairly similar to the nose microbiome, whereas the throat microbiome differed significantly and had a higher abundance of Streptococcaceae (P = 0.001). Conclusions: The OSM is predominantly composed of Staphylococcus species in children, as demonstrated by both culture dependent and culture independent methods. Older children were more likely to have growth on culture and have more a complex bacterial milieu with 16S sequencing. Translational Relevance: 16S sequencing provides more robust information regarding the composition of the microbiomes than culture dependent methods. PMID- 30519502 TI - Correlation of Optical Coherence Tomography and Retinal Histology in Normal and Pro23His Retinal Degeneration Pig. AB - Purpose: We correlate optical coherence tomography (OCT) retinal layer thickness measurements with histology in wild-type and retinal degenerative pigs. Methods: OCT scans were obtained using the Bioptigen Envisu R2200. In normal pigs, three eyes were imaged in vivo, and three eyes were imaged after enucleation. In the Pro23His retinal degeneration pigs (P23H), one eye was imaged in vivo and four eyes were imaged after enucleation. All eyes were fixed in 4% paraformaldehyde and processed for histology. Corresponding retinal locations on OCT and histology were identified using anatomic landmarks (optic nerve, retinal vessels, visual streak). Individual retinal layer thicknesses were measured by two independent, masked graders, and intraclass correlation coefficients were used to determine agreement. OCT and histologic retinal thickness measurements were averaged and compared. Results: OCT and histologic measurements correlated highly in normal and diseased eyes (R 2 = 0.91 and 0.92, respectively), and scans performed in vivo and ex vivo did not differ significantly. Despite good overall correlation, certain individual retinal layers (e.g., retinal nerve fiber layer [NFL], inner [INL] and outer [ONL] nuclear layers) appeared thicker on OCT compared to histology, while other layers (e.g., retinal pigment epithelium) appeared thinner. No statistically significant difference was found between OCT and histology for any retinal layer thickness measurement. Conclusions: Retinal layer thickness measurements correlate well with histology in pig eyes, but differences in individual retinal layers may be seen. Translational Relevance: OCT may be used in pigs to measure retinal thicknesses with good overall correlation to histologic measurements. PMID- 30519503 TI - Correction: Reinvestigating an enigmatic Late Cretaceous monocot: morphology, taxonomy, and biogeography of Viracarpon. AB - [This corrects the article DOI: 10.7717/peerj.4580.]. PMID- 30519504 TI - Disinfection effect of povidone-iodine in aquaculture water of swamp eel (Monopterus albus). AB - The swamp eel (Monopterus albus) is an important commercial farmed fish species in China. However, it is susceptible to Aeromonas hydrophila infections, resulting in high mortality and considerable economic loss. Povidone-iodine (PVP I) is a widely used chemical disinfectant in aquaculture, which can decrease the occurrence of diseases and improve the survival. However, environmental organic matter could affect the bactericidal effectiveness of PVP-I, and the efficacy of PVP-I in aquaculture water is still unknown. In this paper, disinfection assays were conducted to evaluate the effectiveness of PVP-I against the A. hydrophila in different types of water. We found that the effective germicidal concentration of PVP-I in outdoor aquaculture water was 25 ppm for 12 h. In indoor aquaculture water with 105 CFU/mL bacteria, 10 ppm and 20 ppm of PVP-I could kill 99% and 100% of the bacteria, respectively. The minimal germicidal concentration of PVP-I in Luria-Bertani broth was 4,000 ppm. Available iodine content assay in LB solutions confirmed that the organic substance had negative impact on the effectiveness of PVP-I, which was consistent with the different efficacy of PVP-I in different water samples. Acute toxicity tests showed that the 24 h-LC50 of PVP I to swamp eel was 173.82 ppm, which was much higher than the germicidal concentrations in outdoor and indoor aquaculture water, indicating its safety and effectivity to control the A. hydrophila. The results indicated PVP-I can be helpful for preventing the transmission of A. hydrophila in swamp eel aquaculture. PMID- 30519505 TI - ShapeGTB: the role of local DNA shape in prioritization of functional variants in human promoters with machine learning. AB - Motivation: The identification of functional sequence variations in regulatory DNA regions is one of the major challenges of modern genetics. Here, we report results of a combined multifactor analysis of properties characterizing functional sequence variants located in promoter regions of genes. Results: We demonstrate that GC-content of the local sequence fragments and local DNA shape features play significant role in prioritization of functional variants and outscore features related to histone modifications, transcription factors binding sites, or evolutionary conservation descriptors. Those observations allowed us to build specialized machine learning classifier identifying functional single nucleotide polymorphisms within promoter regions-ShapeGTB. We compared our method with more general tools predicting pathogenicity of all non-coding variants. ShapeGTB outperformed them by a wide margin (average precision 0.93 vs. 0.47 0.55). On the external validation set based on ClinVar database it displayed worse performance but was still competitive with other methods (average precision 0.47 vs. 0.23-0.42). Such results suggest unique characteristics of mutations located within promoter regions and are a promising signal for the development of more accurate variant prioritization tools in the future. PMID- 30519506 TI - A wavelet-based decomposition method for a robust extraction of pulse rate from video recordings. AB - Background: Remote photoplethysmography (rPPG) is a promising optical method for non-contact assessment of pulse rate (PR) from video recordings. In order to implement the method in real-time applications, it is necessary for the rPPG algorithms to be capable of eliminating as many distortions from the pulse signal as possible. Methods: In order to increase the degrees-of-freedom of the distortion elimination, the dimensionality of the RGB video signals is increased by the wavelet transform decomposition using the generalized Morse wavelet. The proposed Continuous-Wavelet-Transform-based Sub-Band rPPG method (SB-CWT) is evaluated on the 101 publicly available RGB facial video recordings and corresponding reference blood volume pulse (BVP) signals taken from the MMSE-HR database. The performance of the SB-CWT is compared with the performance of the state-of-the-art Sub-band rPPG (SB). Results: Median signal-to-noise ratio (SNR) for the proposed SB-CWT ranges from 6.63 to 10.39 dB and for the SB from 4.23 to 6.24 dB. The agreement between the estimated PRs from rPPG pulse signals and the reference signals in terms of the coefficients of determination ranges from 0.81 to 0.91 for SB-CWT and from 0.41 to 0.47 for SB. All the correlation coefficients are statistically significant (p < 0.001). The Bland-Altman plots show that mean difference range from 5.37 to 1.82 BPM for SB-CWT and from 22.18 to 18.80 BPM for SB. Discussion: The results show that the proposed SB-CWT outperforms SB in terms of SNR and the agreement between the estimated PRs from RGB video signals and PRs from the reference BVP signals. PMID- 30519507 TI - Effects of waste stream combinations from brewing industry on performance of Black Soldier Fly, Hermetia illucens (Diptera: Stratiomyidae). AB - Background: In recent years, there has been a rapidly growing demand for readily accessible substrates for mass production of Black Soldier Fly, Hermetia illucens Linnaeus. Beer production results in various by-products that typically end up in uncontrolled dumpsites constituting pollution problems, which merits urgent attention. The present study investigated whether the 12 formulated diets composed of brewers' spent grains (BSGs), brewers' yeast and cane molasses can serve as substrate for H. illucens production. Methods: Four different BSGs were selected and formulated into 12 diets, aiming at varying protein and net energy levels. The diets were offered to newly hatched (~1 h old) H. illucens larvae and the influence on developmental duration, survival, wet weight, pre-oviposition time, fecundity, and longevity were compared. Results: Developmental duration of the larvae (16-21 days) and pre-pupae (8-11 days) differed significantly across the different diets. The developmental duration of the pupae (8.7-9.1 days) was not affected by diet. The larval (86-99.2%), pre-pupal (71-95%), and pupal (65 91%) survival rates varied significantly between flies reared on the different diets. The pre-oviposition time was similar for flies provided with water (7-11 days) and 10% sugar solution (8-14 days) or across the different diets. The mean fecundity per female ranged from 324-787 eggs and did not differ between females provided with water or sugar solution. However, the number of eggs laid per female varied significantly across the different diets when provided with water. The longevity of starved H. illucens adults was significantly lower (5 days) compared to those provided with water (11-14 days) or sugar solution (14-15 days). Discussion: The implications of these findings as part of a quality control procedure for commercial production of high-quality H. illucens larvae as an alternative protein ingredient in livestock and aquaculture feed are discussed. PMID- 30519508 TI - The effect of insulin on equine lamellar basal epithelial cells mediated by the insulin-like growth factor-1 receptor. AB - Background: In horses and ponies, insulin dysregulation leading to hyperinsulinemia may be associated with increased risk of laminitis, and prolonged infusion of insulin can induce the condition. It is unclear whether insulin may have a direct or indirect effect on the lamellar tissues. Insulin is structurally related to insulin-like growth factor (IGF-1), and can bind the IGF 1 receptor, albeit at a lower affinity than IGF-1. Methods: Immunohistochemistry was performed on formalin-fixed lamellar tissue sections from six normal horses, euthanised for non-research purposes, using an anti-IGF-1 receptor antibody. In further studies, lamellar epithelial cells were obtained by collagenase digestion from the hooves of 18 normal horses, also euthanised for non-research purposes, and incubated for 48 h in the presence of insulin (0-2,000 m IU/ml). The increase in cell numbers was determined using a cell proliferation assay, and compared to the effect of zero insulin using one-way ANOVA. Results: Immunohistochemistry demonstrated IGF-1 receptors on lamellar epidermal epithelial cells. With cultured cells, insulin caused a concentration-dependent increase in cell proliferation compared to untreated cells (maximal effect 63.3 +/- 12.8% more cells after 48 h with 1,000 m IU/ml insulin; P < 0.01). Co-incubation with a blocking antibody against the IGF-1 receptor significantly inhibited the proliferative effect of insulin (P < 0.01). Discussion: These results demonstrate that IGF-1 receptors are present on lamellar epithelial cells. At high physiological concentrations, insulin may activate these cells, by a mechanism involving IGF-1 receptors, resulting in a proliferative effect. This mechanism could help to explain the link between hyperinsulinemia and laminitis. PMID- 30519509 TI - Taxonomic patterns in the zoonotic potential of mammalian viruses. AB - Predicting and simplifying which pathogens may spill over from animals to humans is a major priority in infectious disease biology. Many efforts to determine which viruses are at risk of spillover use a subset of viral traits to find trait based associations with spillover. We adapt a new method-phylofactorization-to identify not traits but lineages of viruses at risk of spilling over. Phylofactorization is used to partition the International Committee on Taxonomy of Viruses viral taxonomy based on non-human host range of viruses and whether there exists evidence the viruses have infected humans. We identify clades on a range of taxonomic levels with high or low propensities to spillover, thereby simplifying the classification of zoonotic potential of mammalian viruses. Phylofactorization by whether a virus is zoonotic yields many disjoint clades of viruses containing few to no representatives that have spilled over to humans. Phylofactorization by non-human host breadth yields several clades with significantly higher host breadth. We connect the phylogenetic factors above with life-histories of clades, revisit trait-based analyses, and illustrate how cladistic coarse-graining of zoonotic potential can refine trait-based analyses by illuminating clade-specific determinants of spillover risk. PMID- 30519510 TI - Chemical analysis and evaluation of antioxidant and antimicrobial activities of fruit fractions of Mauritia flexuosa L. f. (Arecaceae). AB - Background: Fruit consumption is currently considered beyond the nutritional aspects because of the important roles in disease prevention and benefits to health. The objective of this study was to characterize the chemical profile and evaluate the antioxidant and antimicrobial properties of different fractions obtained from fruit pulps of Mauritia flexuosa (MFFs). Methods: Initially, chloroform, ethyl acetate and ethanol fractions were obtained from the pulps. Quantifications of total phenols and flavonoids were performed using the methods of Folin-Ciocalteu and complexation with aluminum chloride, respectively. Standard samples were used to identify and quantify phenolic acids and flavonoids using high-performance liquid chromatography with a diode-array detector (HPLC DAD). The antioxidant capacity of the fractions was verified by sequestration of the free radical 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and iron chelating activity. The antimicrobial activity was determined using the microdilution method and the modulating activity was determined using sub inhibitory concentrations of the fractions in association with antibiotics. Results: The chemical analyzes revealed the presence of catechin, caffeic acid, rutin, orientin, quercetin, apigenin, luteolin and kaempferol, where all are present in the ethyl acetate fraction. The fractions exhibited moderate antioxidant and antimicrobial activities against Gram-positive and Candida strains in addition to modulating the activity of conventional antibiotics. The most expressive result was obtained from the association of the chloroform fraction with cefotaxime, which produced a synergistic effect, reducing the minimum inhibitory concentration (MIC) of the antibiotic from 1,024 to 256 MUg/mL. Discussion: The fractions presented a constitution rich in phenolic compounds, especially flavonoids. The data obtained demonstrated that the fractions presented moderate antioxidant activity by acting both as primary and secondary antioxidants. The fractions presented antimicrobial and antibiotic potentiating activities, being the first record of modulating effect of fractions of this species against the studied microbial strains, but failed in modulating the activity of antifungal drugs, indicating that this plant has the potential to be used in the development of therapeutic alternatives against resistant bacteria. The constitution phenolic the fractions may be responsible for their pharmacological properties in vitro. PMID- 30519511 TI - Decline in coral cover and flattening of the reefs around Mauritius (1998-2010). AB - Coral reefs are degrading through the impacts of multiple anthropogenic stressors. How are coral reef communities going to change and how to protect them for future generations are important conservation questions. Using coral reef data from Mauritius, we examined changes in cover in 23 benthic groups for a 13 yr period and at 15 sites. Moreover, we determined which land-based stressor out of four (human population, agriculture, tourism, rainfall) correlated the most with the observed changes in coral reef cover. Among the stony corals, Acropora corals appeared to be the most impacted, decreasing in cover at many sites. However, the non-Acropora encrusting group increased in cover at several sites. The increase in abundance of dead corals and rubble at some sites also supported the observations of stony coral decline during the study period. Additionally, the decline in stony corals appeared to be more pronounced in second half of the study period for all sites suggesting that a global factor rather than a local factor was responsible for this decline. There was little change in cover for the other benthic groups, some of which were quite rare. Human population was significantly correlated with changes in coral reef cover for 11 sites, followed by tourism and agriculture. Rainfall, a proxy for runoff, did not appear to affect coral reef cover. Overall, our results showed that there has been a decline of stony coral cover especially the ones with complex morphologies, which in turn suggest that coral reefs around Mauritius have experienced a decline in habitat complexity during the study period. Our study also suggests that humans are an important factor contributing to the demise of coral reefs around the island. PMID- 30519512 TI - Molecular serotyping of Haemophilus parasuis isolated from diseased pigs and the relationship between serovars and pathological patterns in Taiwan. AB - Background: Haemophilus parasuis is the etiological agent of Glasser's disease, and causes severe economic losses in the swine industry. Serovar classification is intended as an indicator of virulence and pathotype and is also crucial for vaccination programs and vaccine development. According to a polysaccharide biosynthesis locus analysis, H. parasuis isolates could be classified by a molecular serotyping assay except serovars 5 and 12 detected by the same primer pair. The aim of this study was to identify H. parasuis isolates from diseased pigs in Taiwan by using a molecular serotyping assay and to analyze the relationship between serovars and pathological patterns. Methods: From August 2013 to February 2017, a total of 133 isolates from 277 lesions on 155 diseased animals from 124 infected herds serotyped by multiplex PCR and analyzed with pathological data. Results: The dominant serovars of H. parasuis in Taiwan were serovars 5/12 (37.6%), 4 (27.8%) and 13 (15%) followed by molecular serotyping non-typable (MSNT) isolates (13.5%). Nevertheless, the serovar-specific amplicons were not precisely the same sizes as previously indicated in the original publication, and MSNT isolates appeared with unexpected amplicons or lacked serovar-specific amplicons. Most H. parasuis isolates were isolated from nursery pigs infected with porcine reproductive and respiratory syndrome virus. The percentage of lung lesions (30.4%) showing H. parasuis infection was significantly higher than that of serosal lesions. Discussion: Collectively, the distribution of serovars in Taiwan is similar to that found in other countries, but MSNT isolates remain due to genetic variations. Furthermore, pulmonary lesions may be optimum sites for H. parasuis isolation, the diagnosis of Glasser's disease, and may also serve as points of origin for systemic H. parasuis infections in hosts. PMID- 30519513 TI - Nitrogen input by bamboos in neotropical forest: a new perspective. AB - Background: Nitrogen (N) is an important macronutrient that controls the productivity of ecosystems and biological nitrogen fixation (BNF) is a major source of N in terrestrial systems, particularly tropical forests. Bamboo dominates theses forests, but our knowledge regarding the role of bamboo in ecosystem functioning remains in its infancy. We investigated the importance of a native bamboo species to the N cycle of a Neotropical forest. Methods: We selected 100 sample units (100 m2 each) in a pristine montane Atlantic Forest, in Brazil. We counted all the clumps and live culms of Merostachys neesii bamboo and calculated the specific and total leaf area, as well as litter production and respective N content. Potential N input was estimated based on available data on BNF rates for the same bamboo species, whose N input was then contextualized using information on N cycling components in the study area. Results: With 4,000 live culms ha-1, the native bamboo may contribute up to 11.7 kg N ha-1 during summer (January to March) and 19.6 kg N ha-1 in winter (July to September). When extrapolated for annual values, M. neesii could contribute more than 60 kg N ha 1y-1. Discussion: The bamboo species' contribution to N input may be due to its abundance (habitat availability for microbial colonization) and the composition of the free-living N fixer community on its leaves (demonstrated in previous studies). Although some N is lost during decomposition, this input could mitigate the N deficit in the Atlantic Forest studied by at least 27%. Our findings suggest that M. neesii closely regulates N input and may better explain the high diversity and carbon stocks in the area. This is the first time that a study has investigated BNF using free-living N fixers on the phyllosphere of bamboo. PMID- 30519514 TI - Ecology and life history of Meta bourneti (Araneae: Tetragnathidae) from Monte Albo (Sardinia, Italy). AB - The orb-weaver spider Meta bourneti Simon 1922 (Araneae: Tetragnathidae) is one of the most common cave predators occurring in the Mediterranean basin. Although the congeneric M. menardi represented the model species in several studies, our knowledge of M. bourneti is only founded on observations performed on a handful of populations. In this study M. bourneti spiders were studied in caves of Monte Albo (Sardinia, Italy) over a year. Generalized Linear Mixed Models were used to analyze spider occupancy inside cave environments, as well as spider abundance. Analyses on M. bourneti occupancy and abundance were also repeated for adults and juveniles separately. Generalized Linear Models, were used to weight species absence based on its detection probability. Linear Mixed Models were used to detect possible divergences in subterranean spatial use between adult and juvenile spiders. Although widespread on the mountain, M. bourneti generally showed low density and low detection probability. Most of the individuals observed were juveniles. The spiders generally occupied cave sectors with high ceilings that were deep enough to show particular microclimatic features. Adults tended to occupy less illuminated areas than juveniles, while the latter were more frequently found in sectors showing high humidity. The abundance of M. bourneti was strongly related to high humidity and the presence of two troglophile species, Hydromantes flavus Wake, Salvador & Alonso-Zarazaga, 2005 (Amphibia: Caudata) and Oxychilus oppressus (Shuttleworth, 1877) (Gastropoda: Panpulmonata). The abundance of juveniles was related to sector temperature and humidity, the presence of H. flavus and O. oppressus and to morphological sector features. However, when only adults were considered, no significant relationships were found. Adult and juvenile spiders did not differ in their spatial distribution inside the caves studied, but a seasonal distribution of the species along cave walls was observed. Microclimate was one of the most important features affecting both the presence and abundance of M. bourneti in subterranean environments. Individuals tended to occupy lower heights during hot seasons. PMID- 30519515 TI - Stroke Patients' Acceptance of a Smart Garment for Supporting Upper Extremity Rehabilitation. AB - The objective is to evaluate to which extent that Zishi a garment equipped with sensors that can support posture monitoring can be used in upper extremity rehabilitation training of stroke patients. Seventeen stroke survivors (mean age: 55 years old, SD =13.5) were recruited in three hospitals in Shanghai. Patients performed 4 tasks (analytical shoulder flexion, functional shoulder flexion placing a cooking pot, analytical flexion in the scapular plane, and functional flexion in the scapular plane placing a bottle of water) with guided feedback on a tablet that was provided through inertial sensors embedded in the Zishi system at the scapula and the thoracic spine region. After performing the training tasks, patients completed four questionnaires for assessing their motivation, their acceptance of the system, its credibility, and usability. The study participants were highly motivated to train with Zishi and the system was rated high usability, while the subjects had moderate confidence with technology supported training in comparison with the training with therapists. The patients respond positively to using Zishi to support rehabilitation training in a clinical setting. Further developments need to address more on engaging and adaptive feedback. This paper paves the way for larger scale effectiveness studies. PMID- 30519516 TI - Closed-Loop Intravenous Drug Administration Using Photoplethysmography. AB - An optically-based injection control system has been developed for preclinical use for an intravenous drug delivery application. Current clinical drug delivery for oncology typically provides for intravenous administration without an awareness of achieved plasma concentration, yet interpatient variability produces consequences ranging from toxicity to ineffectual treatments. We report a closed loop injection system integrating a pulse-photoplethysmograph to measure the concentration of an injected agent in the circulating blood system using a previously described technique. A proportional-derivative (PD) controller manages the injection rate in real-time. The target function for the controller is the population estimate of the pharmacokinetic model developed using Bayesian statistics describing the injection phase of a calibration set of 22 injections in mice. The controlled set of eight injections showed a reduction in variance from the target injection phase concentration profile of 74.8%. PMID- 30519517 TI - Pernicious Anemia Presented with Isolated Nominal Dysphasia in Type Ill Polyglandular Failure Female Patient. AB - Pernicious anemia (also known as Biermer's disease) is an autoimmune atrophic gastritis which predominantly affects the fundus of the stomach. It results in a deficiency of vitamin B12 (cobalamin) as it affects the normal process of absorption in the ileum. The pernicious anemia is characterized by a wide range of hematological and neurological features. Neurological features can present without hematological manifestations. One of the early neurological features of this anemia is nominal dysphasia (word-finding difficulties), which was usually not reported before as an isolated finding. We present a case of pernicious anemia with isolated nominal dysphasia responding dramatically to parenteral vitamin B12 therapy. PMID- 30519518 TI - Comprehensive Review of Spinal Neurenteric Cysts with a Focus on Histopathological Findings. AB - Among the occult spinal dysraphisms, neurenteric cysts (NECs) are rare and are thought to arise due to a failure of the separation of the primitive endoderm and ectoderm. Patients experience various neurological symptoms depending on the location of the lesion. As the epithelial morphology of NECs share similarities with other intracranial and intraspinal cystic growths, the definitive diagnosis of NEC can be made after a histochemical analysis with endodermal markers. Complete resection is associated with the lowest disease recurrence rate. PMID- 30519519 TI - Spontaneous Arrest of Sporadic Spinal Hemangioblastoma Growth after Postoperative Nodular Recurrence: Case Report. AB - Hemangioblastomas are rare, slow-growing, highly vascularized tumors of the central nervous system which often occur in the spinal cord. When presenting as sporadic, isolated tumors without Von-Hippel Lindau disease, they are curable through surgery with a low rate of recurrence. Tumor recurrence in these cases is usually associated with prior subtotal resection. However, to the best of our knowledge, cases of recurrent, sporadic spinal hemangioblastoma have not been reported to spontaneously arrest without intervention or symptoms. We report a patient who underwent an initial complete resection of a cervical spinal hemangioblastoma, a subtotal resection of tumor recurrence four and a half years later, and nine years of neurologic and radiographic stability with no additional interventions. PMID- 30519520 TI - Clival Chondroid Chordoma: A Case Report and Review of the Literature. AB - Chordomas are rare, slow-growing, and locally aggressive malignant neoplasms derived from primitive notochord remnants. The chondroid variety represents 14% of all chordomas mainly developing in the spheno-occipital region and presenting between the third and fifth decades of life. When developing intracranially, symptoms can range from headaches and neck pain to cranial nerve neuropathies and facial numbness. We illustrate a case of an adolescent woman who presented with excruciating facial pain, otalgia, decreased visual acuity, quadriparesis, headache, nausea, and dysphagia. Radiological studies revealed a large heterogeneous mass in the spheno-occipital region with clivus destruction. Biopsy and histopathology confirmed the diagnosis. Proper identification with prompt surgical resection and adjuvant radiotherapy remains critical to prevent complications. PMID- 30519521 TI - Horner Syndrome Due to Spontaneous Internal Carotid Artery Dissection. AB - Horner syndrome is a constellation of neurological findings consisting of ipsilateral ptosis, miosis, and anhidrosis. Partial Horner syndrome, comprising ipsilateral ptosis and miosis in the absence of anhidrosis, is a well-documented but uncommon manifestation of internal carotid artery dissection. We report the case of a 42-year-old male patient who presented with ipsilateral ptosis and miosis and was subsequently diagnosed with internal carotid artery dissection. In this case report, we discuss the anatomy of the oculosympathetic pathway and the pharmacological diagnosis for a better understanding of the localization of the lesions causing Horner syndrome. PMID- 30519522 TI - Spontaneous Acute Subdural Hematoma Associated with Arachnoid Cyst and Intra cystic Hemorrhage. AB - Arachnoid cysts (ACs) are congenital, extra-axial lesions containing fluid similar to the composition of cerebrospinal fluid. Usually found incidentally, these lesions are observed with serial imaging to document their growth patterns and stability, and are then followed conservatively until clinical symptoms develop. Surgical options for symptomatic arachnoid cysts include cyst aspiration, cyst evacuation with fenestration into the subarachnoid space, and shunt procedures including cysto-peritoneal and cysto-ventricular shunts. Intra cystic hemorrhage and subdural hematoma are rare and more emergent sequelae of ACs that may require an emergent craniotomy. This case report further documents a rare cause of spontaneous subdural hematoma, as well as serves as a pivot point for further discussion into whether continued neuroimaging surveillance in patients with ACs would prove to be beneficial. PMID- 30519523 TI - Novel Method of Non-contact Remote Measurement of Neuronal Electrical Activity. AB - Measuring the electrical potential of a neuron cell currently requires direct contact with the cell surface. This method requires invasive probing and is limited by the deflection of electricity from baseline. From a clinical perspective, the electrical potential of the brain's surface can only be measured to a depth of one centimeter using an electroencephalogram (EEG), however, it cannot measure much deeper structures. In this trial, we attempt a novel method to remotely record the electromagnetic field (EMF) of action potential provoked from hippocampal neurons without contact. A bipolar stimulating electrode was placed in contact with the CA1 region of viable hippocampal slice from donor mice. The specimen was bathed in artifical cerebrospinal fluid (aCSF) to simulate in vivo conditions. This setup was then placed into a magnetic shielded tube. Very low-frequency EMF sensors were used to obtain recordings. The impedance of the aCSF and hippocampal slice were measured after each stimulation individually and in combination. An electromagnetic signal was detected in three out of four scenarios: (a) aCSF alone with electrical stimulus without a hippocampal slice, (b) Hippocampal slice in aCSF without electrical stimulus and, (c) Hippocampal slice in aCSF with an electric stimulus applied. Therefore, our trial suggests that EMFs from neuronal tissue can be recorded through non-invasive non-contact sensors. PMID- 30519524 TI - Belief and Counterfactuality: A Teleological Theory of Belief Attribution. AB - The development and relation of counterfactual reasoning and false belief understanding were examined in 3- to 7-year-old children (N = 75) and adult controls (N = 14). The key question was whether false belief understanding engages counterfactual reasoning to infer what somebody else falsely believes. Findings revealed a strong correlation between false belief and counterfactual questions even in conditions in which children could commit errors other than the reality bias (r p = .51). The data suggest that mastery of belief attribution and counterfactual reasoning is not limited to one point in development but rather develops over a longer period. Moreover, the rare occurrence of reality errors calls into question whether young children's errors in the classic false belief task are indeed the result of a failure to inhibit what they know to be actually the case. The data speak in favor of a teleological theory of belief attribution and challenges established theories of belief attribution. PMID- 30519525 TI - Deep cutaneous Trichosporon asahii infection in a patient recovering from toxic epidermal necrolysis. AB - Patients with toxic epidermal necrolysis, a condition that causes full thickness epidermal necrosis that affects over 30% of the skin surface and mucosal membranes, often develop comorbid infections throughout the recovery of the disease [1]. While most commonly these are related to a bacterial source, infections due to viral, mycobacterial, and rarely fungal organisms occur. We present a case of a patient who developed a deep cutaneous fungal infection caused by Trichosporon asahii and discuss the management. PMID- 30519526 TI - Life threatening polyserositis post oesophagectomy. AB - A 46 year old lady presented three weeks after an oesophagectomy for oesophageal carcinoma with increasing breathlessness and a large left-sided pleural effusion. Computed tomography (CT) scan of her thorax, abdomen and pelvis revealed a large left-sided and small right-sided pleural effusions, a pericardial effusion, ascites and intra-abdominal lymphadenopathy. The patient underwent both pericardial and pleural fluid drainage, however, unfortunately, deteriorated despite these interventions with increasing oxygen requirements requiring nasal high flow oxygen on the Intensive Care Unit. Her pleural and pericardial collections resolved with colchicine and later introduction of prednisolone over a period of 5 weeks. Polyserositis is well recognised after cardiac surgery, but such a dramatic complication after thoracotomy for non-cardiac surgery has as not previously been reported. The polyserositis may relate to the induction chemotherapy combined with surgery. PMID- 30519527 TI - Efficacy of mace (Arils of Myristica fragrans Houtt) plus PFMT on symptoms in mixed urinary incontinence: a randomized placebo-controlled trial. AB - Background: It is not only to evaluate the efficacy and safety of mace (Arils of Myristica fragrans Houtt) but also to compare pelvic floor muscle training vs. pelvic floor muscle training (PFMT) for improving symptoms and health-related quality of life (HRQoL) of woman with mixed urinary incontinence (MUI). Methods: A prospective, single-blind randomized controlled study was conducted. Patients (n = 60) were randomly allocated (1:1) to receive either mace powder or placebo (1.5 g) orally twice daily along with pelvic floor muscle training in both groups for three consecutive months. The primary outcomes included symptom evaluation with Patient Global Impression Index of Improvement (PGI-I) and the Patient Global Impression Index of Severity (PGI-S) for MUI. For safety, clinical examination and biochemical parameters were assessed. Secondary outcomes included Short form of Urogenital Distress Inventory Questionnaire-6 (UDI-6) and quality of life assessment with questionnaire tools such as Short form of Incontinence Impact Questionnaire-7 (IIQ-7), Short form of the Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12) and ICIQ-SF. The data were statistically interpreted with 5% level of significance. Results: After treatment (at third month), the patient reported cure for PGI-I and PGI-S was 46.66% and 90% for the mace group, whereas 0% and 16.66% for the control group, respectively (P < 0.001), statistically significant. No side effects were reported in the mace group. The mean difference noted in terms of scores, at the third month from baseline for UDI-6 (51.09 vs. 24.78), IIQ-7 (45.48 vs. 23.49), PISQ (11.33 vs. 5.40), and ICIQ-SF (8.10 vs. 2.43) scores were higher in the mace than that in the control group (P < 0.001). Conclusion: Mace is effective and safe for the subjective improvement of mixed urinary incontinence symptoms and for the improvement of women's HRQoL than the placebo.Clinical Trial Registry No.: CTRI/2017/04/008342. PMID- 30519528 TI - A conjugated-polymer-based ratiometric nanoprobe for evaluating in-vivo hepatotoxicity induced by herbal medicine via MSOT imaging. AB - Herbal medicines are widely used around the world, while some of them are associated with adverse effects like herb-induced liver injury due to oxidative/nitrosative stress resulted from hepatically-generated ROS/RNS. It is of significance to accurately evaluate herbal-medicine-induced hepatotoxicity, since it would help provide effective monitoring method of the safety of herbal remedies. Herein we designed a ratiometric nanoprobe for in vivo imaging hepatic injury induced by herbal medicine (polygonum multiflorum, PM) via specifically responding to NO generated in liver by PM, and with MSOT imaging the precise location of liver injury can be identified. The liposomal nanoprobe consists of a responsive dye (IX-2NH2) which could specifically respond to NO and the diketopyrrolopyrrole-based conjugated polymer (DPP-TT) as the internal reference. Thus we can realize ratiometric optoacoustic detection of herbal-medicine-induced liver injury with 3D information in mouse model in a noninvasive way. PMID- 30519530 TI - Influence of smoking on levels of urinary 8-iso Prostaglandin F2alpha. AB - Background: To evaluate the reduced-risk potential of alternative tobacco products, biomarkers that are involved in the biological pathways affected by cigarette smoking and smoking cessation are needed. Isoprostanes, a measure of oxidative stress, appear to be influenced by smoking and reversible upon smoking cessation and therefore could be a good biomarker. This review aims at quantifying the effect of smoking and smoking cessation on levels of urinary 8 iso prostaglandin F2alpha (8-epi-PGF2alpha), an isoprostane. Methods: PubMed and Scopus databases were searched for publications that reported 8-epi-PGF2alpha levels in smokers and nonsmokers as well as articles reporting the effect of smoking cessation on 8-epi-PGF2alpha levels. Results: Eighteen studies assessing 8-epi-PGF2alpha levels by smoking status were identified. Five of the papers reported the results as quantity excreted in 24-hour urine (MUg/24 h), and 15 reported creatinine adjusted values. The meta-analyses show increased levels of 8 epi-PGF2alpha in current smokers compared with nonsmokers (mean difference = 0.16, 95% confidence interval [95%CI]: 0.14-0.19 MUg/24 h with inconsistency statistic [I2] = 98%; mean difference = 172.38, 95%CI: 152.75-192.01 pg/mg creatinine with I2 = 89%, respectively). There were too few publications to perform a meta-analysis assessing the effects of smoking cessation on 8-epi PGF2alpha levels. Conclusions: Due to the high heterogeneity among the studies included in these meta-analyses, it is difficult to generalize the results; however, our study indicates increased levels of 8-epi-PGF2alpha and therefore increased oxidative stress in smokers compared with nonsmokers. More studies are still needed to assess if 8-epi-PGF2alpha levels are reversible after cessation. PMID- 30519529 TI - Allogeneic stem cell transplantation with reduced intensity conditioning for patients with adrenoleukodystrophy. AB - Objective: The prognosis of adrenoleukodystrophy (ALD)with neurological involvement is generally dismal; however, allogeneic stem cell transplantation (SCT) is recognized as effective to stabilize or improve the clinical symptoms of ALD. Herein, we report the clinical outcomes of patients with ALD who consecutively underwent allogeneic stem cell transplantation with reduced intensity conditioning at our institution. Patients: Sixteen patients with ALD, who were symptomatic (n = 14) or presymptomatic (n = 2), received SCT from 2010 to 2016. The stem cell source was cord blood (n = 14), or bone marrow from a human leukocyte antigen identical sibling (n = 2). The conditioning regimen prior to transplantation was reduced intensity and consisted of fludarabine (125 mg/m2), melphalan (140 mg/m2) and low dose total body irradiation (TBI) of 4Gy (n = 15) or 3Gy (n = 1). Results: Primary engraftment was obtained in 11 patients, and 4 of the 5 patients who lost the primary graft received a second cord blood transplantation and were engrafted. Five years overall and event-free survival were 90.9% and 61.1% respectively, with a median of 45 months (range 16-91). Loes score stabilized or improved by 18 months after transplantation except for patients with internal capsule involvement. Conclusion: Allogeneic SCT with reduced intensity conditioning for patients with ALD was safely performed without major transplant-related complications even in symptomatic patients and neurological symptoms were stabilized after SCT in patients without internal capsule involvement. PMID- 30519531 TI - The role of knowledge in internet-based cognitive behavioural therapy for adolescent depression: Results from a randomised controlled study. AB - Background and objectives: Clients' knowledge about their condition and treatment is considered crucial for general health improvement, and knowledge acquisition is an essential part in internet-based cognitive behavioural therapy (ICBT). Yet, little is known about the role of knowledge and how it influences treatment outcome. This study aimed to examine if explicit knowledge increased following ICBT for adolescent depression, if knowledge gain would be associated with symptom reduction, and if pre-existing knowledge predicted changes in depressive symptoms. Methods: Seventy-one adolescents were randomised to a therapist supported ICBT or a attention control condition. A measure of depression (BDI-II) and a knowledge test dealing with depression, comorbid anxiety, and its CBT treatment were administered before and after treatment. Results: Significant improvements in knowledge were observed following ICBT compared to the attention control (between-group Cohen's d = 1.25, 95% CI [0.67-1.79]). On average, participants in the treatment group answered 1.4 more questions correctly at post treatment compared to the control group. No relation between change in knowledge and change in depressive symptoms could be observed. Knowledge scores at baseline were high for both groups, with participants answering approximately 75% of the questions correct. A higher level of initial knowledge level predicted poorer treatment response (Parson's r = -0.38, p = .048). Conclusions: The findings indicate that knowledge about basic concepts and principles about depression, anxiety, and CBT increases following ICBT. This increase in knowledge was not related to change in depressive symptoms, indicating that knowledge is a different construct. The results also suggest that clients who are more knowledgeable prior to treatment might benefit less from ICBT. In sum, the results highlight the need to further examine the role of knowledge in ICBT. PMID- 30519532 TI - A quick and simple method for the determination of ivermectin in dog plasma by LC MS/MS. AB - Ivermectin is an endectocide belonging to the macrocyclic lactone class, commonly used in dogs as a heartworm preventative and for the treatment of several external and internal parasite infections. Among the analytical methods for ivermectin determination in plasma available in literature, many require a laborious clean-up step on SPE cartridge, and use fluorescence detection instead of the more reliable mass spectrometry. In the context of a project aimed at its pharmacokinetic evaluation in this species, a liquid chromatography-tandem mass spectrometry method for the determination of ivermectin in dog plasma was developed and validated, using blank plasma provided by a local canine blood transfusion service. Samples underwent a quick liquid-liquid extraction before analysis in the LC-MS/MS system, operating in selected reaction monitoring (SRM) mode. The method provided satisfactory linearity (R2 >0.99), accuracy (bias <3%) and precision (CV <10%) over the 0.5-20.0 ng/mL range. *This is to our knowledge the first validated LC-MS/MS method for ivermectin determination in dog plasma.*Sample preparation is simple, rapid and inexpensive, without compromising sensitivity.*The modest amount of plasma required makes the proposed technique suitable for pharmacokinetic studies also in small dogs. PMID- 30519533 TI - An in vitro method to survey DNA methylation in peripheral blood mononuclear cells (PBMCs) treated by airborne particulate matter (PM10). AB - The International Agency for Research on Cancer (IARC) has defined outdoor air pollution and PM as the human carcinogen (Group 1), which mainly cause an increased risk of lung cancer. Scientists have considered epigenetic modifications as a possible mechanism to deal with adverse effects of air pollution. This study aimed to compare the effect of airborne PM10 (PM with aerodynamic diameter <=10 MUm) on in vitro global methylation in human peripheral blood mononuclear cells (PBMCs). PM10 was sampled in metropolitan Tehran, the capital of Iran. PBMCs were extracted from whole blood of healthy males and treated with PM10 suspension at concentrations of 50-300 MUg/mL for 4 h. Untreated cells were used as the negative control. Genomic DNA was extracted from each sample using the DNA blood mini kit according to the manufacturer's instruction. Moreover, 5-methylsytosine (%5-mC) and 5-hydroxymethylcytosine (%5 hmC) were measured by the enzyme-linked immunosorbent assay (ELISA) method. %5-mC and %5-hmC in each sample was compared with negative control and reported as difference %5-mC and %5-hmC. PMID- 30519534 TI - Chemical methods for determining the electron storage capacity of black carbon. AB - Electron storage capacity (ESC) is a new and important property that determines the capacity of a black carbon to mediate abiotic and microbial electron transfer reactions in natural and engineered systems. It is necessary to develop accurate and reproducible methods to measure black carbon's ESC in order to understand its redox behavior and to predict its capacity to support redox transformation of contaminants in subsurface environments. In this study, we developed chemical methods that employed combinations of reductants and oxidants of different redox potentials - Ti(III) citrate or dithionite as reductant, and ferricyanide or dissolved O2 as oxidant - to measure the ESC of a wood-derived biochar. Pore diffusion within biochar particles was rate-limiting and controlled the timescale for redox equilibrium and ESC measurements. *The new methods can handle sample mass on the order of a gram*Sample pretreatment (e.g., oxidation via aeration) is necessary to produce consistent results*For a given reductant-oxidant pair, colorimetric (or potentiometric) measurements gave constant and reproducible ESC. PMID- 30519536 TI - Precision medicine allergy immunoassay methods for assessing immunoglobulin E sensitization to aeroallergen molecules. AB - Molecular-based allergy diagnosis for the in vitro assessment of a patient immunoglobulin E (IgE) sensitization profile at the molecular level uses allergen molecules (also referred to as allergen components), which may be well-defined, highly purified, natural allergen components or recombinant allergens. Modern immunoassay methods used for the detection of specific IgE against aeroallergen components are either singleplex (such as the fluorescence enzyme immunoassay with capsulated cellulose polymer solid-phase coupled allergens, the enzyme enhanced chemiluminescence immunoassay and the reversed enzyme allergosorbent test, with liquid-phase allergens), multiparameter (such as the line blot immunoassay for defined partial allergen diagnostics with allergen components coating membrane strips) or multiplex (such as the microarray-based immunoassay on immuno solid-phase allergen chip, and the two new multiplex nanotechnology based immunoassays: the patient-friendly allergen nano-bead array, and the macroarray nanotechnology-based immunoassay used as a molecular allergy explorer). The precision medicine diagnostic work-up may be organized as an integrated "U-shape" approach, with a "top-down" approach (from symptoms to molecules) and a "bottom-up" approach (from molecules to clinical implications), as needed in selected patients. The comprehensive and accurate IgE sensitization molecular profiling, with identification of the relevant allergens, is indicated within the framework of a detailed patient's clinical history to distinguish genuine IgE sensitization from sensitization due to cross-reactivity (especially in polysensitized patients), to assess unclear symptoms and unsatisfactory response to treatment, to reveal unexpected sensitizations, and to improve assessment of severity and risk aspects in some patients. Practical approaches, such as anamnesis molecular thinking, laboratory molecular thinking and postmolecular anamnesis, are sometimes applied. The component-resolved diagnosis of the specific IgE repertoire has a key impact on optimal decisions making for prophylactic and specific immunotherapeutic strategies tailored for the individual patient. PMID- 30519535 TI - A methodology for detecting the wound state sensing in terms of its colonization of pathogenic bacteria. AB - A methodology for wound state sensing in terms of its colonization with pathogenic bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa has been developed. Here we report polydiacetylene (PDA) liposomes containing self quenched carboxyfluorescein dye are only sensitive to toxins/enzymes secreted by Pathogenic bacteria but not by non-pathogenic species of Escherichia coli (DH5alpha). The basis of the detection assay is that at high concentration, carboxyfluorescein is non-fluorescent. Following breakdown of the bilayer of liposome containers by bacterial toxins, the dye becomes diluted and "switches on". The methodology can be easily adapted to evaluate the release of payloads from PDA liposomes in terms of fluorescence intensity and in addition to detect the potential interaction mechanism of biomimetic bilayer and pathogenic bacteria. *Self-quenched when encapsulated at high concentration, while fluorescence when diluted in solution*Easy quantification by measuring fluorescence intensity*Simple measurement procedure required (plate reading fluorimeter). PMID- 30519537 TI - Can extracorporeal shock-wave therapy be used for the management of lateral elbow tendinopathy? AB - Lateral elbow tendinopathy (LET) is one of the two most common tendinopathies of the upper limb. The most effective treatment in the management of LET is the exercise program. Clinicians combine exercise program with other physiotherapy, electrotherapeutic and no, techniques. Extracorporeal shock wave therapy (ESWT) is one of the most common recommended electrotherapeutic modalities for the management of LET. Further research is needed to find out the optimal treatment protocol of ESWT in the management of LET. PMID- 30519538 TI - Microembolic signal detection by transcranial Doppler: Old method with a new indication. AB - Transcranial Doppler (TCD) is useful for investigation of intracranial arterial blood flow and can be used to detect a real-time embolic signal. Unfortunately, artefacts can mimic the embolic signal, complicating interpretation and necessitating expert-level opinion to distinguish the two. Resolving this situation is critical to achieve improved accuracy and utility of TCD for patients with disrupted intracranial arterial blood flow, such as stroke victims. A common type of stroke encountered in the clinic is cryptogenic stroke (or stroke with undetermined etiology), and patent foramen ovale (PFO) has been associated with the condition. An early clinical trial of PFO closure effect on secondary stroke prevention failed to demonstrate any benefit for the therapy, and research into the PFO therapy generally diminished. However, the recent publication of large randomized control trials with demonstrated benefit of PFO closure for recurrent stroke prevention has rekindled the interest in PFO in patients with cryptogenic stroke. To confirm that emboli across the PFO can reach the brain, TCD should be applied to detect the air embolic signal after injection of agitated saline bubbles at the antecubital vein. In addition, the automated embolic signal detection method should further facilitate use of TCD for air embolic signal detection after the agitated saline bubbles injection in patients with cryptogenic stroke and PFO. PMID- 30519539 TI - Assessment of quality control system by sigma metrics and quality goal index ratio: A roadmap towards preparation for NABL. AB - AIM: To study sigma metrics and quality goal index ratio (QGI). METHODS: The retrospective study was conducted at the Clinical Biochemistry Laboratory, PGIMS, Rohtak, which recently became a National Accreditation Board for Testing and Calibration of Laboratories accredited lab as per the International Organization for Standardization 15189:2012 and provides service to a > 1700-bed tertiary care hospital. Data of 16 analytes was extracted over a period of one year from January 2017 to December 2017 for calculation of precision, accuracy, sigma metrics, total error, and QGI. RESULTS: The average coefficient of variation ranged from 2.12% (albumin) to 5.42% (creatinine) for level 2 internal quality control and 2% (albumin) to 3.62% (high density lipoprotein-cholesterol) for level 3 internal quality control. Average coefficient of variation of all the parameters was below 5%, reflecting very good precision. The sigma metrics for level 2 indicated that 11 (68.5%) of the 16 parameters fall short of meeting Six Sigma quality performance. Of these, five failed to meet minimum sigma quality performance with metrics less than 3, and another six just met minimal acceptable performance with sigma metrics between 3 and 6. For level 3, the data collected indicated eight (50%) of the parameters did not achieve Six Sigma quality performance, out of which three had metrics less than 3, and five had metrics between 3 and 6. QGI ratio indicated that the main problem was inaccuracy in the case of total cholesterol, aspartate transaminase, and alanine transaminase (QGI > 1.2), imprecision in the case of urea (QGI < 0.8), and both imprecision and inaccuracy for glucose. CONCLUSION: On the basis of sigma metrics and QGI, it may be concluded that the Clinical Biochemistry Laboratory, PGIMS, Rohtak was able to achieve satisfactory results with world class performance for many analytes one year preceding the accreditation by the National Accreditation Board for Testing and Calibration of Laboratories. Aspartate transaminase and alanine transaminase required strict external quality assurance scheme monitoring and modification in quality control procedure as their QGI ratio showed inaccuracy. PMID- 30519540 TI - Spotlight on risankizumab and its potential in the treatment of plaque psoriasis: evidence to date. AB - Psoriasis is a common chronic immune-mediated skin disease, with systemic involvement and significant impact in patients' quality of life. Several highly specific treatments have been developed over the years, such as tumor necrosis factor-alpha inhibitors, a nonselective IL-23 inhibitor (ustekinumab), and most recently IL-17 inhibitors. Risankizumab is a monoclonal antibody which targets IL 23p19 without binding IL-12. This novel therapeutic approach is expected to have advantages over the recently approved anti-IL-17 agents, such as the avoidance of Candida infections and neutropenia. In addition, unlike ustekinumab, the selective inhibition of IL-23 may preserve IL-12-dependent functions such as protection against infections and tumor immune surveillance. Risankizumab showed an excellent efficacy when compared to placebo and ustekinumab, with higher Psoriasis Area Severity Index (PASI) 75, PASI 90, and PASI 100 rates, along with a convenient every 12-week maintenance dosing regimen. Overall, risankizumab was well tolerated and the most common adverse event was upper respiratory tract infection. In the near future, further data will be available not only in psoriasis but also in Crohn's disease and psoriatic arthritis fields. Head-to head trials comparing risankizumab with other IL-23 inhibitors and with IL-17 inhibitors will be crucial to reveal the role of risankizumab in the treatment of psoriasis. PMID- 30519541 TI - Crosstalk Between PD-1/PD-L1 Blockade and Its Combinatorial Therapies in Tumor Immune Microenvironment: A Focus on HNSCC. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide with a poor prognosis and high mortality. More than two-thirds of HNSCC patients still have no effective control of clinical progression, and the five year survival rate is < 50%. Moreover, patients with platinum-refractory HNSCC have a median survival of < 6 months. The significant toxicity and low survival rates of current treatment strategies highlight the necessity for new treatment modalities. Recently, a large number of studies have demonstrated that programmed cell death protein-1 (PD-1) and its ligand, programmed cell death protein ligand 1 (PD-L1) play an essential role in tumor initiation and progression. PD-1/PD-L1 blockade has shown a desired and long-lasting therapeutic effect in the treatment of HNSCC and other malignancies. However, only a small number of patients with HNSCC can benefit from PD-1/PD-L1 blockade monotherapy, while the majority of patients do not respond. To overcome the unsatisfactory therapeutic effect of PD 1/PD-L1 blockade monotherapy, combining other treatment options for HNSCC (including chemotherapy, radiotherapy, targeted therapy, and immunotherapy) in the treatment scheme has become a commonly used strategy. Herein, the potential mechanisms underlying the crosstalk between PD-1/PD-L1 blockade and its combinatorial therapies for HNSCC were reviewed, and it is hoped that the improved understanding of the crosstalk process would provide further ideas for the design of a combinatorial regimen with a higher efficiency and response rate for the treatment of HNSCC and other malignancies. PMID- 30519542 TI - Patient Preferences Regarding Chemotherapy in Metastatic Breast Cancer-A Conjoint Analysis for Common Taxanes. AB - Background: The purpose of this investigation was to explore patient perception regarding the importance of efficacy, toxicity, and logistics in the choice of regimen of taxane-based chemotherapy (CHT) for patients with metastatic breast cancer (MBC). Methods: This dual-center study analyzed data of 100 women diagnosed with MBC, who were asked for their preferences regarding chemotherapy by means of conjoint analysis. Included attributes were progression free survival (PFS), application form, time and frequency, need of premedication, risk of alopecia, fatigue, febrile neutropenia, and neuropathy. Furthermore, participants completed a questionnaire about their personal and medical history. Regression analyses were performed to identify factors that influence patient preference in terms of specific treatment choice. Results: Of 8 attributes, severe neutropenia was top priority for the majority of patients, followed by alopecia, neuropathy and PFS. When combining these patient preferences and the results of the questionnaire, patients' age as, well as, relationship status had significant impact on the importance of PFS. Moreover, longer travel time to the treatment center was significantly associated with preferences regarding PFS. Ranking by combination of respective part-worth values demonstrated nab-paclitaxel to be favored over paclitaxel and docetaxel. Conclusion: Side effects of CHT and PFS prove to be critical factors for patients affecting choice of treatment in MBC with severe neutropenia being top priority, followed by alopecia, neuropathy, and PFS. Age, commute time, and relationship status were identified as significant determinants of patient preference. Total utility calculation by combination of part-worth values ranked nab-paclitaxel as the most preferable taxane. PMID- 30519543 TI - Zinc Blockade of SOS Response Inhibits Horizontal Transfer of Antibiotic Resistance Genes in Enteric Bacteria. AB - The SOS response is a conserved response to DNA damage that is found in Gram negative and Gram-positive bacteria. When DNA damage is sustained and severe, activation of error-prone DNA polymerases can induce a higher mutation rate than is normally observed, which is called the SOS mutator phenotype or hypermutation. We previously showed that zinc blocked the hypermutation response induced by quinolone antibiotics and mitomycin C in Escherichia coli and Klebsiella pneumoniae. In this study, we demonstrate that zinc blocks the SOS-induced development of chloramphenicol resistance in Enterobacter cloacae. Zinc also blocked the transfer of an extended spectrum beta-lactamase (ESBL) gene from Enterobacter to a susceptible E. coli strain. A zinc ionophore, zinc pyrithione, was ~100-fold more potent than zinc salts in inhibition of ciprofloxacin-induced hypermutation in E. cloacae. Other divalent metals, such as iron and manganese, failed to inhibit these responses. Electrophoretic mobility shift assays (EMSAs) revealed that zinc, but not iron or manganese, blocked the ability of the E. coli RecA protein to bind to single-stranded DNA, an important early step in the recognition of DNA damage in enteric bacteria. This suggests a mechanism for zinc's inhibitory effects on bacterial SOS responses, including hypermutation. PMID- 30519544 TI - Archaea Symbiont of T. cruzi Infection May Explain Heart Failure in Chagas Disease. AB - Background: Archaeal genes present in Trypanosoma cruzi may represent symbionts that would explain development of heart failure in 30% of Chagas disease patients. Extracellular vesicles in peripheral blood, called exosomes (< 0.1 MUm) or microvesicles (>0.1 MUm), present in larger numbers in heart failure, were analyzed to determine whether they are derived from archaea in heart failure Chagas disease. Methods: Exosomes and microvesicles in serum supernatant from 3 groups were analyzed: heart failure Chagas disease (N = 26), asymptomatic indeterminate form (N = 21) and healthy non-chagasic control (N = 16). Samples were quantified with transmission electron microscopy, flow cytometer immunolabeled with anti-archaemetzincin-1 antibody (AMZ 1, archaea collagenase) and probe anti-archaeal DNA and zymography to determine AMZ1 (Archaeal metalloproteinase) activity. Results: Indeterminate form patients had higher median numbers of exosomes/case vs. heart failure patients (58.5 vs. 25.5, P < 0.001), higher exosome content of AMZ1 antigens (2.0 vs. 0.0; P < 0.001), and lower archaeal DNA content (0.2 vs. 1.5, P = 0.02). A positive correlation between exosomes and AMZ1 content was seen in indeterminate form (r = 0.5, P < 0.001), but not in heart failure patients (r = 0.002, P = 0.98). Higher free archaeal DNA (63.0 vs. 11.1, P < 0.001) in correlation with exosome numbers (r = 0.66, P = 0.01) was seen in heart failure but not in indeterminate form (r = 0.29, P = 0.10). Flow cytometer showed higher numbers of AMZ1 microvesicles in indeterminate form (64 vs. 36, P = 0.02) and higher archaeal DNA microvesicles in heart failure (8.1 vs. 0.9, P < 0.001). Zymography showed strong% collagenase activity in HF group, mild activity in IF compared to non-chagasic healthy group (121 +/- 14, 106 +/- 13 and 100; P < 0.001). Conclusions: Numerous exosomes, possibly removing and degrading abnormal AMZ1 collagenase, are associated with indeterminate form. Archaeal microvesicles and their exosomes, possibly associated with release of archaeal AMZ1 in heart failure, are future candidates of heart failure biomarkers if confirmed in larger series, and the therapeutic focus in the treatment of Chagas disease. PMID- 30519545 TI - Flank bulge following subcostal percutaneous nephrolithotomy. AB - Loss of tone of the anterolateral abdominal wall muscles due to denervation injury is quite common after open renal surgery by lumbotomy incision. Although rare, flank bulge following percutaneous nephrolithotomy (PCNL) after supracostal approach has been reported in literature. But pseudohernia after PCNL with subcostal access has not been reported yet. In this case report, we present the rare complication of an abdominal wall bulge that occurred after PCNL with a subcostal access. The index case had been operated for a partial staghorn calculus with lower calyceal extension. PCNL with subcostal approach was used. Complete stone-free status was achieved with an uneventful recovery. During the first follow-up after 1 week, an unsightly, painless flank bulge was noticed, which continued to persist till 9 months of periodic follow-up. PMID- 30519546 TI - Hepatocellular carcinoma: a review of diagnostic challenges for the pathologist. AB - Histopathologists retain a critical role in the diagnosis and management of hepatocellular carcinoma (HCC). HCC arises usually but not exclusively in a background of advanced-stage chronic liver disease. The histological diagnosis of HCC poses many challenges particularly when dealing with liver biopsy specimens due to the heterogeneity of HCC and the difficulty to confirm hepatocellular differentiation in some instances. Primary liver tumors should be considered as a continuum with typical hepatocellular and cholangiocarcinoma at the two ends and a whole range of tumors showing both hepatocellular and cholangiocellular differentiation with or without an associated progenitor/stem cell component in the middle. Characterization of combined (or mixed) hepatocellular cholangiocarcinoma can be very challenging. In advanced-stage chronic liver disease, the main challenge for the histopathologist is still to differentiate between HCC and its precursors, although this is rarely critical in the clinical setting at present. HCC originating in non-cirrhotic livers needs to be differentiated from other primary and extrahepatic tumors and from hepatocellular adenoma, bearing in mind that progression to malignancy is more through a continuum that watertight histological categories. PMID- 30519547 TI - Portal Hypertension. PMID- 30519548 TI - Chronic Viral Hepatitis and Metabolic Syndrome/Cardiovascular Risk. PMID- 30519549 TI - Metastatic Colorectal Cancer in the Era of Personalized Medicine: A More Tailored Approach to Systemic Therapy. AB - Colorectal cancer is the second most common malignancy diagnosed in Canada. Despite declining incidence and mortality rates in recent years, there is still a significant number of cases that are metastatic at presentation. Fluoropyrimidine based chemotherapy was the backbone of colorectal cancer treatment, but the addition of irinotecan and oxaliplatin to form combination regimens has significantly improved overall survival. In the past decade, the development of novel biologic agents including therapies directed against vascular endothelial growth factor and epidermal growth factor receptor has further altered the landscape of metastatic colorectal cancer treatment. However, clinical trials have demonstrated that not all patients respond to these therapies similarly and consideration must be given to individual patient- and tumor-related factors. A more tailored and biomarker driven approach to treatment selection can optimize outcomes and avoid unnecessary adverse effects. In this review article, we offer a comprehensive overview of the panel of clinical- and tumor-associated characteristics that influence treatment decisions in metastatic colorectal cancer and how this sets the foundation for a more personalized treatment strategy in oncology. PMID- 30519550 TI - New Achievements in High-Pressure Processing to Preserve Human Milk Bioactivity. AB - High-pressure processing (HPP) is a non-thermal technology that is being increasingly applied in food industries worldwide. It was proposed that this method could be used as an alternative to holder pasteurization (HoP; 62.5 degrees C, 30 min) in milk banks but its impact on the immunologic, enzymatic and hormonal components of human milk has not yet been evaluated in detail. The aim of our study was to compare the effects of HPP in variants: (1) 600 MPa, 10 min (2) 100 MPa, 10 min, interval 10 min, 600 MPa, 10 min (3) 200 MPa, 10 min, interval 10 min, 400 MPa, 10 min (4) 200 MPa, 10 min, interval 10 min, 600 MPa, 10 min in temperature range 19-21 degrees C and HoP on the leptin, adiponectin, insulin, hepatocyte growth factor (HGF), lactoferrin and IgG contents in human milk. HoP was done at the Regional Human Milk Bank in Warsaw at the Holy Family Hospital on S90 Eco pasteurizer (Sterifeed, Medicare Colgate Ltd). Apparatus U4000/65 (Unipress Equipment, Poland) was used for pascalization. Milk samples were obtained from women during 2-6 weeks of lactation. Post-treatment culture showed no endogenous bacterial contamination in any tested option. Concentrations of selected components were determined using ELISA tests. The level of all analyzed components were significantly decreased by HoP: leptin 77.86%, adiponectin 32.79%, insulin 32.40%, HGF 88.72%, lactoferrin 60.31@.%, IgG 49.04%. All HPP variants caused an increase in leptin concentration, respectively (1) 81.79% (2) 90.01% (3) 86.12% (4) 47.96%. Retention of insulin after HPP was (1) 88.20% (2) 81.98% (3) 94.76% (4) 90.31% HGF (1) 36.15% (2) 38.81% 97.15% (3) 97.15% (4) 43.02%, lactoferrin (1) 55.78% (2) 57.63% (3) 78.77% (4) 64.75%. Moreover, HPP variant as 200 + 400 MPa preserved IgG (82.24%) better than HoP and resulted not statistically significant change of adiponectin level (38.55%) compare to raw milk. Our results showed that HPP leads to preservation of adipokines, growth factor, and lactoferrin, IgG much better or comparable with HoP. PMID- 30519551 TI - How to Best Convey Information About Intensive/Comfort Care to the Family Members of Premature Infants to Enable Unbiased Perinatal Decisions. AB - Background: As the infant's best interests are determined through the perinatal decisions of family members and physicians, it is important to understand the factors that affect such decisions. This paper investigated the separate and combined effects of various factors related to perinatal decision making and sought to determine the best way to convey information in an unbiased manner to family members. Methods: In total, 613 participants were consecutively recruited. Each participant completed a series of surveys. All responses to four items were examined via a latent class analysis (LCA) to identify subgroups of participants with similar preferences for intensive care (IC) and comfort care (CC) regarding their potentially premature infant. Multiple logistic regression analyses were applied to identify the sociodemographic predictors for the classification of participants into different subgroups. Results: chi2-tests indicated that perinatal decision making for Item 2 was influenced by framing information, whereas decision making wasn't affected by presentation modes. Furthermore, the endorsement rates of IC significantly decreased with the information increased from brief to detailed, regardless of framing or presentation mode. The LCA indicated that a 3-subgroup model, which included the IC, CC, and variation subgroups, was optimal. Logistic regression analyses demonstrated that, compared with the IC subgroup, negative framing, higher education, parenthood, and poor numeracy predicted participants' preferences for CC. Meanwhile, worrying about physical or mental disabilities predicted preferences for CC and sensitivity to the amount of information provided regarding treatment options (variation subgroup). Conclusions: Perinatal decision making is affected by many factors, suggesting that more detailed information, improved understandability of numerical data, and a neutral tone of voice regarding therapeutic outcomes would be helpful for the families of premature infants to make unbiased decisions. Our findings should be replicated in future research. PMID- 30519552 TI - Celiac Disease: A Review of Current Concepts in Pathogenesis, Prevention, and Novel Therapies. AB - Our understanding of celiac disease and how it develops has evolved significantly over the last half century. Although traditionally viewed as a pediatric illness characterized by malabsorption, it is now better seen as an immune illness with systemic manifestations affecting all ages. Population studies reveal this global disease is common and, in many countries, increasing in prevalence. These studies underscore the importance of specific HLA susceptibility genes and gluten consumption in disease development and suggest that other genetic and environmental factors could also play a role. The emerging data on viral and bacterial microbe-host interactions and their alterations in celiac disease provides a plausible mechanism linking environmental risk and disease development. Although the inflammatory lesion of celiac disease is complex, the strong HLA association highlights a central role for pathogenic T cells responding to select gluten peptides that have now been defined for the most common genetic form of celiac disease. What remains less understood is how loss of tolerance to gluten occurs. New insights into celiac disease are now providing opportunities to intervene in its development, course, diagnosis, and treatment. PMID- 30519553 TI - A Comparative Cost Analysis of Antibiotic Treatment for Community Acquired Pneumonia (CAP) in Adult Inpatients at Piggs Peak Government Hospital in Swaziland. AB - Background: Of the different types of pneumonia, community acquired pneumonia (CAP), has been identified as the leading cause of infectious morbidity and mortality in the western and developing countries. To eradicate the bacterial cause of CAP, medical doctors) often tend to prescribe a differing cocktail of medicine which may be costly for the health care system. Aim: To analyze the cost of oral and/or intravenous antibiotic medicine use in different treatment approaches for treating CAP in adult inpatients from the health care system perspective. Settings: This study was undertaken at Piggs Peak Government Hospital, a 220 bed tertiary hospital located in the rural northern Hhohho region of Swaziland. Method: Seventy-one (n = 71) medical records of adult patients, hospitalized and diagnosed with CAP at Piggs Peak Government Hospital from July 2014 to June 2015, were retrieved and entered into the database once confirmed as having met the selection criteria. Only direct antibiotic medicine(s) costs were considered. The total cost per treatment option was calculated by multipling the unit cost of the medicine by the administration frequency and the length of hospital stay. The Kruskal-Wallis test was used to compare the cost difference between more than two treatment options. Results: Medical doctors at Piggs Peak Government Hosptial use a range of antibiotics to treat community acquire pneumonia. Furthermore, doctors prefer using dual antibiotics combination as first line treatment of CAP in adult inpatients. The cost of treating community acquire pneumonia at the hospital ranged from ZAR 70.98 to ZAR 467.60 per adult inpatient admitted into care. A statistically significant difference in the cost of the different treatment approaches used for treating CAP was noted. Conclusion: This cost-exploratory study has highlighted a significant difference in the monetary cost of the differing approaches used for treating CAP at the hospital. It is evident therefore that the use of different treatment approaches in treating CAP significantly influences the cost of CAP treatment. There is therefore need for cost minimization measure to be put in place at the facility. PMID- 30519554 TI - Push-Pull Zinc Porphyrins as Light-Harvesters for Efficient Dye-Sensitized Solar Cells. AB - Dye-sensitized solar cell (DSSC) has been attractive to scientific community due to its eco-friendliness, ease of fabrication, and vivid colorful property etc. Among various kinds of sensitizers, such as metal-free organic molecules, metal complex, natural dyes etc., porphyrin is one of the most promising sensitizers for DSSC. The first application of porphyrin for sensitization of nanocrystaline TiO2 can be traced back to 1993 by using [tetrakis(4-carboxyphenyl) porphyrinato] zinc(II) with an overall conversion efficiency of 2.6%. After 10 years efforts, Officer and Gratzel improved this value to 7.1%. Later in 2009, by constructing porphyrin sensitizer with an arylamine as donor and a benzoic acid as acceptor, Diau and Yeh demonstrated that this donor-acceptor framwork porphyrins could attain remarkable photovoltaic performance. Now the highest efficiencies of DSSC are dominated by donor-acceptor porphyrins, reaching remarkable values around 13.0% with cobalt-based electrolytes. This achievement is largely contributed by the structural development of donor and acceptor groups within push-pull framwork. In this review, we summarized and discussed the developement of donor acceptor porphyrin sensitizers and their applications in DSSC. A dicussion of the correlation between molecular structure and the spectral and photovoltaic properties is the major target of this review. Deeply dicussion of the substitution group, especially on porphyrin's meso-position were presented. Furthermore, the limitations of DSSC for commercialization, such as the long-term stability, sophisticated synthesis procedures for high efficiency dye etc., have also been discussed. PMID- 30519555 TI - Imidazolium Based Ionic Liquids: A Promising Green Solvent for Water Hyacinth Biomass Deconstruction. AB - Water hyacinth (WH) is a troublesome aquatic weed of natural and artificial water bodies of India and other tropical countries and causing severe ecological problems. The WH biomass is low in lignin content and contains high amount of cellulose and hemicellulose, making it suitable material for conversion into liquid fuels for energy production. This study highlighted that, how different imidazolium based ionic liquids (ILs) [1-alkyl-3-methylimidazolium bromide, [Cnmim]Br (n = 2, 4, 6, 8, and 10)] with tunable properties can be employed for the degradation of WH biomass. Different characterizations techniques, such as XRD, FT-IR, SEM, and DSC are used to unravel the interplay between ILs and the biomass. In this study, it is observed that [Emim][Br] pretreated samples have maximum crystalline value (Crl = 26.38%) as compared to other ionic liquids pretreatments. FTIR data showed the removal of lignin from WH biomass by 12.77% for [Emim][Br] and 10.74% for [Edmim][Br]. SEM images have proven that [Emim][Br] pretreatment have altered the structure of biomass the most. Our results proved that IL pretreatment is a promising approach for effective treatment of WH biomass and causes high levels disruption of cellulose structure. PMID- 30519556 TI - A Porous and Conductive Graphite Nanonetwork Forming on the Surface of KCu7S4 for Energy Storage. AB - A flexible all-solid-state supercapacitor is fabricated by building a layer of porous and conductive nanonetwork on the surface of KCu7S4 nanowires supported on the carbon fiber fabric, where the porous and conductive nanonetwork is assembled by graphite nanoparticles. This porous graphite layer plays a key role in providing ion diffusion channels to access the KCu7S4 through the pores for electrochemical reactions and forming electron transport pathways from the graphite network to the electronic collector of the carbon fiber fabric. This flexible supercapacitor exhibits excellent electrochemical performance with high specific capacitance of 408 F g-1 at a current density of 0.5 A g-1 and high energy density of 36 Wh kg-1 at a power density of 201 W kg-1. Moreover, it is cost-effective, easy to scale up and environmentally friendly with high flexibility. Our investigation demonstrates that such a porous and conductive nanonetwork could be used to improve the charge storage efficiency for a wide range of electrode materials. PMID- 30519557 TI - Corrigendum: Microwave-Assisted Knoevenagel-Doebner Reaction: An Efficient Method for Naturally Occurring Phenolic Acids Synthesis. AB - [This corrects the article DOI: 10.3389/fchem.2018.00426.]. PMID- 30519558 TI - Pyrite-Type CoS2 Nanoparticles Supported on Nitrogen-Doped Graphene for Enhanced Water Splitting. AB - It is extremely meaningful to develop cheap, highly efficient, and stable bifunctional electrocatalysts for both hydrogen and oxygen evolution reactions (HER and OER) to promote large-scale application of water splitting technology. Herein, we reported the preparation of CoS2 nanoparticles supported on nitrogen doped graphene (CoS2@N-GN) by one-step hydrothermal method and the enhanced electrochemical efficacy for catalyzing hydrogen and oxygen in water electrolysis. The CoS2@N-GN composites are composed of nitrogen-doped graphene and CoS2 nanocrystals with the average size of 73.5 nm. Benefitting from the improved electronic transfer and synergistic effect, the as-prepared CoS2@N-GN exhibits remarkable OER and HER performance in 1.0 M KOH, with overpotentials of 243 mV for OER and 204 mV for HER at 10 mA cm-2, and the corresponding Tafel slopes of 51.8 and 108 mV dec-1, respectively. Otherwise, the CoS2@N-GN hybrid also presents superior long-term catalytic durability. Moreover, an alkaline water splitting device assembled by CoS2@N-GN as both anode and cathode can achieve a low cell voltage of 1.53 V at 60 degrees C with a high faraday efficiency of 100% for overall water splitting. The tremendously enhanced electrochemical behaviors arise from favorable factors including small sized, homogenously dispersed novel CoS2 nanocrystals and coupling interaction with the underlying conductive nitrogen-doped graphene, which would provide insight into the rational design of transition metal chalcogenides for highly efficient and durable hydrogen and oxygen-involved electrocatalysis. PMID- 30519559 TI - Chemometric Methods for Spectroscopy-Based Pharmaceutical Analysis. AB - Spectroscopy is widely used to characterize pharmaceutical products or processes, especially due to its desirable characteristics of being rapid, cheap, non invasive/non-destructive and applicable both off-line and in-/at-/on-line. Spectroscopic techniques produce profiles containing a high amount of information, which can profitably be exploited through the use of multivariate mathematic and statistic (chemometric) techniques. The present paper aims at providing a brief overview of the different chemometric approaches applicable in the context of spectroscopy-based pharmaceutical analysis, discussing both the unsupervised exploration of the collected data and the possibility of building predictive models for both quantitative (calibration) and qualitative (classification) responses. PMID- 30519560 TI - Nanoscale Imaging of Kidney Glomeruli Using Expansion Pathology. AB - Kidney glomerular diseases, such as the minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), and other nephrotic syndromes, are typically diagnosed or confirmed via electron microscopy. Although optical microscopy has been a vital tool to examine clinical specimens for diagnoses in pathology for decades, the optical resolution is constricted by the physical diffraction limit of the optical microscope, which prevents high-resolution investigation of subcellular anatomy, such as of the podocyte tertiary foot processes. Here, we describe a simple, fast, and inexpensive protocol for nanoscale optical imaging of kidney glomeruli. The protocol is based on Expansion Pathology (ExPath), a new principle of microscopy that overcomes optical diffraction limit by chemically embedding specimens into a swellable polymer and physically expanding it homogenously prior to imaging. Our method uses only commercially available reagents, a conventional fluorescence microscope and it can be applied to both fixed-frozen or formalin-fixed paraffin embedded (FFPE) tissue sections. It requires minimal operative experience in a wet lab, optical microscopy and imaging processing. Finally, we also discuss challenges, limitations and prospective applications for ExPath-based imaging of glomeruli. PMID- 30519561 TI - Forced-Air Warming and Resistive Heating Devices. Updated Perspectives on Safety and Surgical Site Infections. AB - Introduction: Perioperative hypothermia is one of the most common phenomena seen among surgical patients, leading to numerous adverse outcomes such as intraoperative blood loss, cardiac events, coagulopathy, increased hospital stay and associated costs. Forced air warming (FAW) and resistive heating (RH) are the two most commonly used and widely studied devices to prevent perioperative hypothermia. The effect of FAW on operating room laminar flow and surgical site infection is unclear and we initiated an extensive literature search in order to get a scientific insight of this aspect. Material and Methods: The literature search was conducted using the Medline search engine, PubMed, Cochrane review, google scholar, and OSU library. Results: Out of 92 Articles considered initially for review we selected a total of 73 relevant references. Currently there is no robust evidence to support that FAW can increase SSIs. In addition, both of the two warming devices present safety problems. Conclusion: As unbiased independent reviewers, we advise clinicians to weigh the risks and benefits when using either one of these devices; no change in the current practice is necessary until further data emerges. PMID- 30519562 TI - Stress Coping Strategies in the Heart: An Integrated View. AB - The heart is made up of an ordered amalgam of cardiac cell types that work together to coordinate four major processes, namely energy production, electrical conductance, mechanical work, and tissue remodeling. Over the last decade, a large body of information has been amassed regarding how different cardiac cell types respond to cellular stress that affect the functionality of their elaborate intracellular membrane networks, the cellular reticular network. In the context of the heart, the manifestations of stress coping strategies likely differ depending on the coping strategy outcomes of the different cardiac cell types, and thus may underlie the development of distinct cardiac disorders. It is not clear whether all cardiac cell types have similar sensitivity to cellular stress, how specific coping response strategies modify their unique roles, and how their metabolic status is communicated to other cells within the heart. Here we discuss our understanding of the roles of specialized cardiac cells that together make the heart function as an organ with the ability to pump blood continuously and follow a regular rhythm. PMID- 30519563 TI - Assessing the Efficacy of Ventilation of Anesthetized Neonatal Calves Using a Laryngeal Mask Airway or Mask Resuscitator. AB - Calves that have undergone a dystocia are often hypoxic and acidemic, which can result in reduced vigor and subsequent mortality. Methods of field resuscitation of apneic newborn calves are often ineffective and therefore underutilized. This proof-of-concept study aimed to determine the efficacy of the laryngeal mask airway (LMA) as well as the current industry standard method of ventilation, the McCulloch Calf Aspirator/ Resuscitator (MMR) for positive pressure ventilation of neonatal calves. Five LMA models of various sizes were first tested in cadaver heads to assess anatomical fit. Three LMA models in two sizes each were then tested in two anesthetized calves to determine the model best suited to ventilate calves. Next, the selected LMA and the MMR were both assessed for efficacy of ventilation. Six anesthetized calves had hypoventilation induced by administering alfaxalone intravenously. Calves were ventilated for 3 min with the LMA, allowed a brief washout period, then given a second administration of alfaxalone prior to ventilation with the MMR. Serial arterial blood gas analyses were performed prior to ventilation (baseline), at 1, 2, and 3 min during ventilation, and 1 min after ventilation had ceased. Success of ventilation was assessed by monitoring partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), bicarbonate ( HCO3- ), pH, L-lactate, and hemoglobin saturation (SaO2) in arterial blood. A one-way ANOVA for repeated measures with Bonferroni correction was used to assess the efficacy of ventilation of each device compared to baseline. For the LMA, PaO2, SaO2, and pH were significantly higher than baseline throughout ventilation and PaCO2 was significantly lower than baseline at 1 min of ventilation. For the MMR, PaO2 and SaO2 were significantly higher and PaCO2 and HCO3- were significantly lower than baseline for 1 to 2 min of ventilation. This proof-of-concept study showed the LMA is an effective means of ventilating neonatal calves, as was the MMR. PMID- 30519564 TI - Patients' perspective on pulmonary rehabilitation: experiences of European and American individuals with chronic respiratory diseases. AB - Pulmonary rehabilitation benefits people with chronic respiratory diseases, yet few eligible patients enrol. People with chronic lung diseases are often unaware of or lack access to PR. This is an important healthcare disparity that should be addressed. http://ow.ly/2HER30mxLLj. PMID- 30519565 TI - Nasal microbiota and symptom persistence in acute respiratory tract infections in infants. AB - Acute respiratory tract infections (ARI) in infancy have been implicated in the development of chronic respiratory disease, but the complex interplay between viruses, bacteria and host is not completely understood. We aimed to prospectively determine whether nasal microbiota changes occur between the onset of the first symptomatic ARI in the first year of life and 3 weeks later, and to explore possible associations with the duration of respiratory symptoms, as well as with host, environmental and viral factors. Nasal microbiota of 167 infants were determined at both time-points by 16S ribosomal RNA-encoding gene PCR amplification and subsequent pyrosequencing. Infants were clustered based on their nasal microbiota using hierarchical clustering methods at both time-points. We identified five dominant infant clusters with distinct microbiota at the onset of ARI but only three clusters after 3 weeks. In these three clusters, symptom persistence was overrepresented in the Streptococcaceae-dominated cluster and underrepresented in the cluster dominated by "Others" (p<0.001). Duration of symptoms was not associated with the type of respiratory virus. Infants with prolonged respiratory symptoms after their first ARI tend to exhibit distinct microbial compositions, indicating close microbiota-host interactions that seem to be of importance for symptom persistence and recovery. PMID- 30519566 TI - Evaluating the Longitudinal Item and Category Stability of the SF-36 Full and Summary Scales Using Rasch Analysis. AB - Introduction: The Medical Outcome Study Short Form 36 (SF-36) is widely used for measuring Health-Related Quality of Life (HRQoL) and has undergone rigorous psychometric evaluation using Classic Test Theory (CTT). However, Item Response Theory-based evaluation of the SF-36 has been limited with an overwhelming focus on individual scales and cross-sectional data. Purpose: This study aimed to examine the longitudinal item and category stability of the SF-36 using Rasch analysis. Method: Using data from the 1921-1926 cohort of the Australian Longitudinal Study on Women's Health, responses of the SF-36 from six waves of data collection were analysed. Rasch analysis using Winsteps version 3.92.0 was performed on all 36 items of the SF-36 and items that constitute the physical health and mental health scales. Results: Rasch analysis revealed issues with the SF-36 not detected using classical methods. Redundancy was seen for items on the total measure and both scales across all waves of data. Person separation indexes indicate that the measure lacks sensitivity to discriminate between high and low performances in this sample. The presence of Differential Item Functioning suggests that responses to items were influenced by locality and marital status. Conclusion: Previous evaluations of the SF-36 have relied on cross-sectional data; however, the findings of the current study demonstrate the longitudinal efficacy of the measure. Application of the Rasch Measurement Model indicated issues with internal consistency, generalisability, and sensitivity when the measure was evaluated as a whole and as both physical and mental health summary scales. Implications for future research are discussed. PMID- 30519567 TI - Effect of Comorbidity on Lung Cancer Diagnosis Timing and Mortality: A Nationwide Population-Based Cohort Study in Taiwan. AB - The effect of comorbidity on lung cancer patients' survival has been widely reported. The aim of this study was to investigate the effects of comorbidity on the establishment of the diagnosis of lung cancer and survival in lung cancer patients in Taiwan by using a nationwide population-based study design. This study collected various comorbidity patients and analyzed data regarding the lung cancer diagnosis and survival during a 16-year follow-up period (1995-2010). In total, 101,776 lung cancer patients were included, comprising 44,770 with and 57,006 without comorbidity. The Kaplan-Meier analyses were used to compare overall survival between lung cancer patients with and without comorbidity. In our cohort, chronic bronchitis patients who developed lung cancer had the lowest overall survival in one (45%), five (28.6%), and ten years (26.2%) since lung cancer diagnosis. Among lung cancer patients with nonpulmonary comorbidities, patients with hypertension had the lowest overall survival in one (47.9%), five (30.5%), and ten (28.2%) years since lung cancer diagnosis. In 2010, patients with and without comorbidity had 14.86 and 9.31 clinical visits, respectively. Lung cancer patients with preexisting comorbidity had higher frequency of physician visits. The presence of comorbid conditions was associated with early diagnosis of lung cancer. PMID- 30519568 TI - Endophytic Actinomycetes from Tea Plants (Camellia sinensis): Isolation, Abundance, Antimicrobial, and Plant-Growth-Promoting Activities. AB - Endophytic actinomycetes are a promising source of novel metabolites with diverse biological activities. Tea plants (Camellia sinensis) produce arsenals of phytochemicals, which are linked to a number of medicinal and nutritional properties. However, a systematic investigation into the abundance and diversity of cultivated actinomycetes residing in tea plants has not been performed. In this study, a total of 46 actinobacteria were recovered from leaf, stem, and root samples of 15 tea cultivars collected in Fujian province, China. Their abundance and diversity were shown to be influenced by both the genotypes and tissue types of tea plants. Based on 16S RNA sequence analysis, these isolates were taxonomically grouped into 11 families and 13 genera, including Streptomyces, Actinomadura, Kribbella, Nocardia, Kytococcus, Leifsonia, Microbacterium, Micromonospora, Mobilicoccus, Mycobacterium, Nocardiopsis, Piscicoccus, and Pseudonocardia. The genus Streptomyces was most prevalent whereas rare genera, Mobilicoccus and Piscicoccus, were reported for the first time to occur as plant endophytes. PCR screening of polyketide synthase genes (PKS-I and PKS-II) and nonribosomal peptide synthetase genes (NRPS), along with antimicrobial assays against a set of bacterial and fungal pathogens, showed that endophytic actinomycetes associated with tea plants have a high potential for producing antimicrobial metabolites. Furthermore, indole acetic acid (IAA) production and 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase activities were recorded in 93.5% and 21.7% of all isolates, respectively. Overall, these results indicate that endophytic actinomycetes from tea plants represent a valuable source of bioactive metabolites with antibacterial, antifungal, and plant-growth-promoting properties. PMID- 30519569 TI - Should We Always Use Antibiotics after Urodynamic Studies in High-Risk Patients? AB - Aim: The aim of this observational study was to evaluate the effectiveness of a phytotherapic drug (Canephron N) in preventing urinary tract infection (UTI) in high-risk women undergoing urodynamic studies (UDS). Methods: The study protocol was approved by the local institutional ethical committee. Adult women with at least one risk factor for acquiring UTI (defined as: age over 70, elevated postvoid residual urine>100 ml, recurrent UTI, pelvic organ prolapse (POP) >=II in POP-Q scale, and neurogenic bladder) had received after UDS either a single oral dose of fosfomycin trometamol (FT) (3 grams) or a phytodrug containing centaury herb, lovage root, and rosemary leaves (5 ml taken orally three times daily for one week). All patients included in the study had no pyuria according to urine dipstick (nitrite and/or blood and/or leukocyte esterase) and negative urine culture (CFU < 103/ml) before UDS. Urine samples were also tested 7 days after UDS. Results: Seventy-two high-risk participants completed the study. Seven days after urodynamic studies UTI symptoms, pyuria (nitrite and/or blood and/or leukocyte esterase) and bacteriuria with E. coli occurred in two patients (one (2.8%) in the FT and one (2.7%) in the phytodrug group, respectively). No statistical differences in UTI incidence were found between both treatment groups. We did not observe any additional adverse events in both groups. The major disadvantage of prophylaxis with the phytodrug as compared to FT was the necessity of continuing therapy for 7 days. Conclusion: Prophylaxis of UTI with a phytodrug (Canephron N) may be considered a good alternative to antibiotic prophylaxis use after UDS in high-risk female patients. PMID- 30519570 TI - Cyclic Stretch Enhances Osteogenic Differentiation of Human Periodontal Ligament Cells via YAP Activation. AB - Periodontal remodeling and alveolar bone resorption and formation play essential roles during orthodontic tooth movement (OTM). In the process, human periodontal ligament cells (HPDLCs) sense and respond to orthodontic forces, contributing to the alveolar bone formation. However, the underlying mechanism in this process is not fully elucidated. In the present study, cyclic stress stimulus was applied on HPDLCs to mimic the orthodontic forces during OTM. Our results demonstrated that cyclic stretch promoted the osteogenic differentiation of HPDLCs. Moreover, our data suggested that yes-associated protein (YAP), the Hippo pathway effector, which also involved in mechanical signaling transduction, was activated as we found that the nuclear translocation of YAP was significantly increased in the cyclic stress treated HPDLCs. The mRNA expression of CTGF and CYR61, the target genes of YAP, was also remarkably increased. Furthermore, knockdown of YAP suppressed the cyclic stretch induced osteogenesis in HPDLCs, while overexpression of YAP in HPDLCs enhanced osteogenesis. We also noticed that YAP activities could be suppressed by the ROCK and nonmuscle myosin II inhibitors, Y 27632 and Blebbistatin. The inhibitors also significantly inhibited the cyclic stretch induced osteogenesis in HPDLCs. Finally, in the murine OTM model, our results revealed that YAP was upregulated and nuclearly translocated in the PDLCs at the tension side. In summary, our present study demonstrated that cytoskeleton remodeling induced activation of YAP signaling pathway was crucial for the cyclic stretch-induced osteogenesis of HPDLCs, which might play important roles during OTM. PMID- 30519571 TI - A Comparative Study of Smartphone Game with Spirometry for Pulmonary Function Assessment in Stroke Patients. AB - Background: The monitoring and rehabilitation of pulmonary function can be immensely important for long-term performance of daily life activities in stroke patients. In recent times, smartphone game-based assessment (SGA) has been gaining in popularity as an alternative to laboratory assessments. Hence, the aims of this study were (1) to quantify the reliability and validity of SGA for pulmonary function and (2) to assess the validity of SGA in comparison to spirometry. Materials/Methods: Thirty-four stroke subjects (age = 49.24 +/- 8.25 years) performed spirometry and the smartphone game on different days. Spirometric values were obtained using a spirometer (SP-1, Schiller, USA). A breathing game application (Breathing+ package, Breathing Labs, Slovenia) was used to obtain the values for the SGA of pulmonary function. The concurrent validity was determined by comparing data collected from the 2 systems, and the reliability was determined by comparing data collected from 3 sessions of using the breathing game on a smartphone. Results: All parameters demonstrated excellent agreement with intraclass correlation coefficients (ICC (2.1)) values for reliability and concurrent validity. Conclusion: We compared the relationship between the SGA and the spirometry as certified pulmonary function test. The SGA data were statistically significant and reliable for pulmonary function assessment in stroke patients. It will therefore be useful during rehabilitation to improve pulmonary function and clinical monitoring in stroke patients. PMID- 30519572 TI - Antagonism of Bacteria from Dog Dental Plaque against Human Cariogenic Bacteria. AB - Dental caries are a process of demineralization and destruction of human teeth. They originate through many factors and are associated with biofilm formation, which consists of bacteria adhered to the teeth that form a structurally and functionally organized mass called dental plaque. Both the presence of Streptococcus mutans and the frequent consumption of sucrose correlate with a higher prevalence of caries in humans. In dogs, however, the incidence of this disease is low, due to factors such as differences in dental microbiota and/or their low consumption of sucrose. This work evaluated the antagonism of bacteria from dog's dental plaque against S. mutans, for the identification of producing strains of biotechnological products for use in preventing caries. This study used 95 bacterial isolates of canine dental plaque from the Veterinary Department at the Federal University of Vicosa, Minas Gerais, Brazil. A spot-on-the-lawn method was performed using Brain Heart Infusion agar with catalase for an initial identification of the antagonistic activity. Additional tests were conducted on the isolates classified as antagonists for confirmation of the activity, using modified Mann-Rogosa-Sharpe medium containing low dextrose concentration. These isolates were incubated at 37 degrees C for 24 hours in anaerobiosis. The peptide nature of inhibition was evaluated using the following proteinases: proteinase K from Tritirachium album, bovine pancreatic trypsin, and type XII-A alpha-amylase from Bacillus licheniformis. In the initial identification of those strains exhibiting antimicrobial activity, 14 were classified as antagonists. One of the isolates (Bacillus sp.) indicated bacteriocinogenic activity, with a deformed inhibition halo on S. mutans by the addition of trypsin. These results suggest that this bacterial isolate may be applicable to biotechnological use to combat the main etiological agent of caries in humans. Further studies are needed to evaluate the bacteriocinogenic nature of the antimicrobial activities of the other 13 antagonistic bacterial isolates. PMID- 30519573 TI - A Simple Guideline to Assess the Characteristics of RNA-Seq Data. AB - Next-generation sequencing (NGS) techniques have been used to generate various molecular maps including genomes, epigenomes, and transcriptomes. Transcriptomes from a given cell population can be profiled via RNA-seq. However, there is no simple way to assess the characteristics of RNA-seq data systematically. In this study, we provide a simple method that can intuitively evaluate RNA-seq data using two different principal component analysis (PCA) plots. The gene expression PCA plot provides insights into the association between samples, while the transcript integrity number (TIN) score plot provides a quality map of given RNA seq data. With this approach, we found that RNA-seq datasets deposited in public repositories often contain a few low-quality RNA-seq data that can lead to misinterpretations. The effect of sampling errors for differentially expressed gene (DEG) analysis was evaluated with ten RNA-seq data from invasive ductal carcinoma tissues and three RNA-seq data from adjacent normal tissues taken from a Korean breast cancer patient. The evaluation demonstrated that sampling errors, which select samples that do not represent a given population, can lead to different interpretations when conducting the DEG analysis. Therefore, the proposed approach can be used to avoid sampling errors prior to RNA-seq data analysis. PMID- 30519574 TI - Clinical Course of Dual-Chamber Implantable Cardioverter-Defibrillator Recipients followed by Cardiac Remote Monitoring: Insights from the LION Registry. AB - Patients receiving dual-chamber implantable cardioverter-defibrillator (DR-ICD) therapy are at risk of developing atrial arrhythmia because of the increased rate of ventricular pacing and the progression of heart failure. Remote monitoring (RM) may identify the patients at highest risk of adverse events such as atrial arrhythmias. A total of 283 patients with 91,632 remote transmissions during a 15 month follow-up (FU) period enrolled in the LION registry were analysed. The parameters retrieved included the pacing mode, lower rate limit, percentage of atrial (%AP) and ventricular pacing (%VP), and percentage of atrial arrhythmia burden (%AB). In 92.7% of patients, the devices were initially programmed in DDD(R) or DDI(R), with changes of the pacing mode in 19.3% only. The lower rate limit remained stable in 80.4% of patients. At the first transmission, 8.7% of patients suffered from RM-detected atrial arrhythmia, which reached 36% during FU. The %AP was not associated with increased AB (p = 0.67), but the %VP was different in patients developing RM-detected atrial arrhythmia (26.9% vs. 13.7%, p < 0.00001). The %VP increased in 105 patients (significance level of alpha = 0.05), and 11 patients crossed the border of 50% VP. The LION substudy supports the concept of using RM in a real-world DR-ICD population. Remote monitoring of DR-ICDs allows for the quantification of the course of the pacing parameters and AB. Based on these observations, device parameters can be adjusted and optimized. PMID- 30519575 TI - Local Tensile Stress in the Development of Posttraumatic Osteoarthritis. AB - The pathogenesis of posttraumatic osteoarthritis (PTOA) remains unrevealed. We speculate that cartilage crack caused by joint trauma will induce local abnormal tensile stress, leading to change in extracellular matrix (ECM) expression of chondrocytes, cartilage degeneration, and initiation of osteoarthritis. Finite element model was used to examine whether the local tensile stress could be produced around the crack. Cell experiments were conducted to test the effect of tensile strain on chondrocyte ECM expression. Animal tests in rabbits were carried out to examine the change around the cartilage crack. The results indicated that the local tensile stress was generated around the crack and varied with the crack angles. The maximum principal tensile stress was 0.59 MPa around the 45 degrees crack, and no tensile stress was found at 90 degrees . 10% tensile strain could significantly promote type I collagen mRNA expression and inhibit type II collagen and aggrecan (the proteoglycan core protein) mRNA expression. Type I collagen was detected around the 45 degrees crack region in the cartilage with no change in type II collagen and proteoglycan. We conclude that the local tensile stress produced around the cartilage crack can cause the change in cartilage matrix expression which might lead to cartilage degeneration and initiation of osteoarthritis. This study provides biomechanical-based insight into the pathogenesis of PTOA and potentially new intervention in prevention and treatment of PTOA. PMID- 30519576 TI - Derivation and Validation of the Potential Core Genes in Pancreatic Cancer for Tumor-Stroma Crosstalk. AB - Background: Pancreatic cancer is a fatal malignancy with a poor prognosis. The interactions between tumor cells and stromal cells contribute to cancer progression. Pancreatic stellate cells (PSCs) play a key role in tumor-stroma crosstalk of pancreatic cancer. The in-depth exploration for tumor-stroma crosstalk is helpful to develop novel therapeutic strategies. Our aim was to identify the potential core genes and pathways in tumor-stroma crosstalk. Methods: 3 microarray datasets were from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were screened through bioinformatics analysis. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network were used to obtain the biological roles of DEGs. The top 15 DEGs were explored by principal component analysis. We validated the top 15 DEGs expression in the tumor-stroma crosstalk model in which PSCs were treated with the mixture of Aspc-1 and Panc-1 supernatant. Results: A total of 221 genes were filtered as DEGs for tumor-stroma crosstalk. The results of principal component analysis for the top 15 DEGs can distinguish three groups. According to the KEGG enrichment, there were 8, 7, and 7 DEGs enriched in cancer related pathway, PI3K-Akt signaling pathway, and microRNAs, respectively. In the tumor-stroma crosstalk model, significant differences can be validated in the AKAP12, CLDN1, CP, FKBP1A, LAMB3, LSM4, MTMR3, PRKARIA, YWHAZ, and JUND expressions. Conclusions: These results identified the potential core genes and pathways in pancreatic cancer for tumor stroma crosstalk, which could provide potential targets for the treatment of pancreatic cancer. PMID- 30519577 TI - Carbon Dioxide Laser Microsurgery versus Low-Temperature Plasma Radiofrequency Ablation for T1a Glottic Cancer: A Single-Blind Randomized Clinical Trial. AB - Background: Very few studies have been conducted to compare carbon dioxide laser microsurgery (CO2-LS) with low-temperature plasma radiofrequency ablation (LTP RFA) in treating T1a glottic cancer. Therefore, we conducted this study to compare the efficacy of CO2-LS and LTP-RFA to define a superior therapeutic modality for T1a glottic cancer. Methods: Patients (n=131) with T1a glottic cancer were recruited between January 2010 and September 2014. The included patients were randomly assigned to either receive CO2-LS (n=65) or LTP-RFA (n=66). We conducted the following multidimensional vocal assessments: (i) videostroboscopic evaluation; (ii) auditory-perceptual evaluation; (iii) aerodynamics/ efficiency; (iv) acoustics; and (v) self-assessment questionnaires. Meanwhile, the surgery time and three-year overall survival rates in two groups were recorded. The predefined primary endpoint was overall survival, and the minimum follow-up time was set to six months. Results: After treatment, we found that the structure and vibration of vocal cord might recover more quickly in patients receiving LTP-RFA than in patients receiving CO2-LS, and moreover, the patients in the LTP-RFA group had the better vocal functions. Meanwhile, the surgery time was significantly less in the LTP-RFA group (8.83+/-1.59 minutes) than in the CO2-LS group (12.49+/-1.40 minutes) (p<0.00001). In addition, the two intervention methods had the similar three-year overall survival rates (94% versus 96%, p=0.58). Conclusion: These results indicated that both LTP-RFA and CO2-LS could effectively treat T1a glottic cancer, and LTP-RFA might have some advantages in voice function. Limited by the relatively small sample size, future studies were needed to validate our conclusion. PMID- 30519578 TI - The Association between Deliberate Self-Harm and School Bullying Victimization and the Mediating Effect of Depressive Symptoms and Self-Stigma: A Systematic Review. AB - Background: Identifying deliberate self-harm in the young and its relationship with bullying victimization is an important public health issue. Methods: A systematic review was performed to explore evidence of the association between deliberate self-harm and school bullying victimization in young people, as well as the mediating effect of depressive symptoms and self-stigma on this association. An advanced search in the following electronic databases was conducted in January 2018: PubMed/Medline; CINAHL; PsycINFO; PsycARTICLES; Science Direct; Scopus, and Cochrane Library. Studies that fulfilled the inclusion criteria were further assessed for their methodological integrity. The Norwegian Knowledge Centre for Health Services tool was applied for cross sectional studies and the Critical Appraisal Skills Programme instrument for the cohort studies. Only empirical quantitative studies published in the English language in peer reviewed journals during the last decade (2007-2018) aimed at exploring the association between deliberate self-harm and school bullying victimization in community-based schoolchildren with a mean age of under 20 years were included. Results: The reviewed cross-sectional and cohort studies (22) revealed a positive association between school bullying victimization and deliberate self-harm, including nonsuicidal self-injury, which remained statistically significant when controlled for the main confounders. The mediating role of depressive symptoms in the association between deliberate self-harm and school bullying victimization was confirmed. A dose-response effect was shown in the association between nonsuicidal self-injury and school bullying victimization, whilst the mediating effect of depressive symptoms needs to be further explored. No studies were found directly exploring the mediating effect of self-stigma in the association between deliberate self-harm and bullying victimization. Conclusion: Targeted interventions aimed at eliminating victimization behaviours within the school context are therefore proposed, as well as interventions to promote healthy parenting styles for the parents of schoolchildren. Moreover, school healthcare professionals should screen students involved in bullying for self-injury, and vice versa. PMID- 30519579 TI - Is Vibration Training Good for Your Bones? An Overview of Systematic Reviews. AB - Whole-body vibration (WBV) intervention studies and reviews have been increasing lately. However, the results regarding its effects on bone tissue in different populations are still inconclusive. The goal of this overview was to summarize systematic reviews assessing the effects of WBV training on bone parameters. Three electronic databases were scanned for systematic reviews and meta-analyses evaluating the effects of WBV on bone tissue. The search had no time restrictions and was limited to articles written in English. Vibration protocols and the main bone parameters included in each review were extracted. Methodological quality was assessed and analyses were conducted stratifying by age. 17 reviews and meta analyses fulfilled the inclusion criteria. No increase or small improvements in bone mineral density (BMD) after WBV interventions were observed in reviews regarding postmenopausal women. One intervention study regarding young adults was included and reported no bone-related benefits from WBV. Most reviews including children and adolescents with compromised bone mass showed an improvement of BMD at lower limbs, lumbar spine, and whole body. In conclusion, WBV interventions seem to help children and adolescents with compromised bone mass to increase their BMD, but these improvements are limited in postmenopausal women and there is insufficient evidence for young adults. Further research is also needed to identify the ideal parameters of WBV training focused on bone health. PMID- 30519580 TI - Anti-IL-5 and IL-5Ra: Efficacy and Safety of New Therapeutic Strategies in Severe Uncontrolled Asthma. AB - The current developments of the new biological drugs targeting interleukin 5 (IL 5) and IL-5 receptor allowed to expand the treatment options for severe hypereosinophilic asthma. Clinicians will then be able to choose between antibodies targeting either circulating IL-5 or its receptor expressed on eosinophils and basophils. The available clinical trials consistently reported favorable results about the reduction of exacerbations rate, improvement in quality of life, and sparing of the systemic steroid use, with a favorable safety profile. Two of these new drugs are administered subcutaneously, mepolizumab every 4 weeks and benralizumab every 8 weeks, whereas reslizumab is given intravenously monthly on a weigh-based dose. In the future, the research actions will be involved in the identification of a single biomarker or multiple biomarkers for the optimal choice of biological agents to be properly prescribed. PMID- 30519581 TI - Pain Management during Rehabilitation after Distal Radius Fracture Stabilized with Volar Locking Plate: A Prospective Cohort Study. AB - Introduction: Internal fixation with volar locking plate (VLP) was widely adopted as a first-line choice in treatment of distal radius fracture (DRF). Methods: Total 315 patients with distal radius fracture receiving VLP fixation were included for analysis in this study. The rehabilitation protocol was started immediately after surgery for all patients. During the initial two weeks after surgery, 149 patients received 200 mg celecoxib twice per day, 89 received buprenorphine transdermal patch at 5 MUg/h, and 77 received 13 mg codeine plus 200 mg ibuprofen twice per day for pain management. Visual analog scale (VAS) scores of pain at rest, daily activity, and rehabilitative exercise were measured, respectively, every week according to the experiences of the past week in the initial six weeks after surgery. Functional outcomes including range of motion (ROM) for extension, flexion, pronation, supination, ulnar and radial abduction, the disabilities of arm, shoulder, and hand (DASH) score and the validated patient rated wrist evaluation (PRWE), and grip strength were collected at one, three, and six months after surgery. Results: We showed that patients receiving transdermal buprenorphine and codeine/ibuprofen had decreased VAS scores during rehabilitative exercise, better compliance to the rehabilitation program, and thus faster functional recovery. Conclusions: We recommend transdermal buprenorphine or codeine/ibuprofen for pain management during rehabilitation after distal radius fracture stabilized with VLP. PMID- 30519582 TI - Trends and Drivers of Inpatient Antibiotic Consumption among 89 China Tertiary General Hospitals from 2011Q1 to 2015Q4. AB - Antibacterial surveillance is an essential measure for strengthening the management of clinical antibiotic use. This study aimed to determine the trends and drivers of inpatient antibiotic consumption in China. A sample of 89 hospitals with complete data from 2011Q1 to 2015Q4 was included. Accumulative defined daily doses (DDDs), antibiotic use density (AUD), and drug variety were calculated to evaluate antibiotic consumption. From 2011Q1 to 2015Q4, the median values of DDDs, AUD, and drug variety dropped by 10.49%, 39.19%, and 27.96%, respectively. Panel regression results showed, for each additional quarter, DDDs reduced by 6.714 DDDs, AUD reduced by 0.013 DDDs per 100 inpatients per day, and drug variety reduced by 0.012 types (p < 0.001). National hospitals were more likely to use antibiotics, with the highest number of DDDs (106 709 DDDs) and AUD (60 DDDs per 100 inpatients per day) and a large number of drug variety (71 types of drug) all reported from national hospitals. Overall, a downward trend of inpatient antibiotic consumption was observed in competitive tertiary general hospitals in China. However, antibiotic use in China, especially in national hospitals, continues to exceed the guidelines set forth by the nationwide antibiotic stewardship program. China must continue to improve surveillance of antibiotic consumption by constructing a more comprehensive, continuous, and targeted stewardship program. Policy interventions in China should be made in consideration of unbalanced regional development and the consequences this may have on antibiotic consumption. PMID- 30519583 TI - Simvastatin Impairs the Inflammatory and Repair Phases of the Postinjury Skeletal Muscle Regeneration. AB - Background: Recent clinical data have suggested that the chronic use of high lipophilic statins impairs the regenerative capacity of skeletal muscle. Because this activity of statins is poorly understood, we aimed to investigate the effect of simvastatin (SIM) on postinjury myofibre regeneration. Methods: The porcine model was used in this study. The animals were divided into two groups: nontreated (control; n=24) and SIM-treated (40 mg/day; n=24). On the 15th day (day 0) of the experiment, a bupivacaine hydrochloride- (BPVC-) induced muscle injury was established, and the animals were sacrificed in the following days after muscle injury. The degree of regeneration was assessed based on histopathological and immunohistochemical examinations. The presence and degree of extravasation, necrosis, and inflammation in the inflammatory phase were assessed, whereas the repair phase was evaluated based on the numbers of muscle precursor cells (MPCs), myotube and young myofibres. Results: In the inflammatory phase, SIM increased the distribution and prolonged the period of extravasation, prolonged the duration of necrosis, and prolonged and enhanced the infiltration of inflammatory cells. In the repair phase, SIM delayed and prolonged the activity of MPCs, delayed myotube formation, and delayed and decreased the formation of young myofibres. Our results indicated that SIM did not improve blood vessel stabilization at the site of the injury, did not exert an anti inflammatory effect, prolonged and enhanced the inflammatory response, and impaired MPC activity, differentiation, and fusion. Moreover, SIM appeared to reduce M1 macrophage activity, resulting in slower removal of necrotic debris and sustained necrosis. Conclusion: This study shows that SIM negatively affects the inflammatory and repair phases of the postinjury muscle regeneration. These findings are unique, strengthen the available knowledge on the side effects of SIM, and provide evidence showing that statin therapy is associated with an increased risk of impairment of the regenerative capacity of muscle. PMID- 30519584 TI - Chloroquine Protects Human Corneal Epithelial Cells from Desiccation Stress Induced Inflammation without Altering the Autophagy Flux. AB - Dry eye disease (DED) is a multifactorial ocular surface disorder affecting millions of individuals worldwide. Inflammation has been associated with dry eye and anti-inflammatory drugs are now being targeted as the alternate therapeutic approach for dry eye condition. In this study, we have explored the anti inflammatory and autophagy modulating effect of chloroquine (CQ) in human corneal epithelial and human corneal fibroblasts cells exposed to desiccation stress, (an in-vitro model for DED). Gene and protein expression profiling of inflammatory and autophagy related molecular factors were analyzed in HCE-T and primary HCF cells exposed to desiccation stress with and without CQ treatment. HCE-T and HCF cells exposed to desiccation stress exhibited increased levels of activated p65, TNF-alpha, MCP-1, MMP-9, and IL-6. Further, treatment with CQ decreased the levels of active p65, TNF-alpha, MCP-1, and MMP-9 in cells underdesiccation stress. Increased levels of LC3B and LAMP1 markers in HCE-T cells exposed to desiccation stress suggest activation of autophagy and the addition of CQ did not alter these levels. Changes in the phosphorylation levels of MAPKinase and mTOR pathway proteins were found in HCE-T cells under desiccation stress with or without CQ treatment. Taken together, the data suggests that HCE-T cells under desiccation stress showed NFkappaB mediated inflammation, which was rescued through the anti-inflammatory effect of CQ without altering the autophagy flux. Therefore, CQ may be used as an alternate therapeutic management for dry eye condition. PMID- 30519585 TI - The Effect of Vitamin E and Metallothionein on the Antioxidant Capacities of Cadmium-Damaged Liver in Grass Carp Ctenopharyngodon idellus. AB - Cadmium (Cd) causes a broad spectrum of toxicological effects to animals. Aquatic animals were more likely to accumulate Cd than terrestrial animals because of the living environment. Clearance of Cd in aquatic animals has become an important part of aquatic food safety. The present study was focused on the oxidative damage induced by Cd in the liver of grass carp Ctenopharyngodon idellus and the protective effect of vitamin E (VE) and metallothionein (MT). Grass carp were divided into four groups: the control group, Cd+phosphate-buffered saline (PBS) group, Cd+VE group, and Cd+MT group. All fish were injected with CdCl2 on the first day and then VE, MT, and PBS were given 4 days after injection, respectively. The liver function and antioxidant capacity of grass carp were evaluated. Cd administration resulted in damage of liver function and morphology in liver, which was expressed as the increased content of AST and ALT, rupture of organelles, and decrease of CAT, SOD, and GSH-Px activity. However, VE and MT treatments protected against Cd-induced damage of liver in grass carp by decreasing AST and ALT content, repairing organelles, and maintained the antioxidant system by elevating CAT, SOD, and GSH-Px activity and regulating related mRNA transcript expression. The results revealed that VE and MT might play an important role in the treatment of heavy metal poisoning through their antioxidative effects. PMID- 30519586 TI - RNA Sequencing Reveals the Suitability of Cardiac Death Livers for Transplantation. AB - Background: Organ transplantation is considered the best treatment for end-stage organ failure. However, the lack of available organs for transplantation and the increasing number of patients waiting for transplants are primary issues facing the transplant community. Thus, developing strategies to increase the number of donors, especially for liver transplantation, has become a priority. The use of organs acquired from donors who suffered cardiac related deaths has increased the pool of potential liver donors. However, donation after cardiac death (DCD) livers increases the risk of primary graft dysfunction. Methods: In the current study, we conducted transcriptome sequencing using livers from a DCD rat to assess the short-term feasibility and functional efficacy of DCD livers. RNA sequencing (RNAseq) data showed that the liver transcriptome varied greatly in rat livers subjected to 15 minutes of cardiac arrest. Results: The livers used in the current study had a significant loss of normal function before transplantation. Functional and network analyses consistently indicated that transcription and translation processes were inhibited after approximately 15 minutes of cardiac arrest. Moreover, the transcriptomic sequencing data provides significant insight for identifying functional genes and testing additional biological questions in DCD liver transplantation in future studies. PMID- 30519587 TI - Corrigendum to "Effective Treatment of Chronic Proliferative Cholangitis by Local Gentamicin Infusion in Rabbits". AB - [This corrects the article DOI: 10.1155/2018/6751952.]. PMID- 30519588 TI - Preliminary Results of Bone Regeneration in Oromaxillomandibular Surgery Using Synthetic Granular Graft. AB - Traumatic, neoplastic, inflammatory, or infective dental removal promotes a gradual resorption process of bone which leads to a "nonuse" atrophy of the alveolar ridges. Many techniques allows restoring an appropriate bone thickness, but nowadays the attention is focused on the use of natural or synthetic grafts. Numerous studies have been conducted to develop and test new synthetic materials. In this article, the authors report their experience using a synthetic bone substitute in combination with Platelet Rich Fibrin (PRF). This technique was applied in different zones of the maxillomandibular district. The procedure showed a very satisfying bone regeneration without important complications. PMID- 30519589 TI - Phosphoprotein Contributes to the Thermostability of Newcastle Disease Virus. AB - Newcastle disease (ND), caused by Newcastle disease virus (NDV), is highly contagious and represents a major threat to the poultry industry. The thermostable vaccines are not insensitive to heat and ease of storage and transportation, but the mechanism of NDV thermostability remains unknown. The phosphoprotein (P), fusion protein (F), hemagglutinin-neuraminidase protein (HN), and large polymerase protein (L) are associated with NDV virulence. The association between F, HN, or L and viral thermostability has been, respectively, studied in different reports. However, the effects of P on NDV thermostability have not been demonstrated. Here, we utilized an existing reverse genetics system in our laboratory, to generate chimeric viruses by exchanging the P protein between the thermostable NDV4-C strain and the thermolabile LaSota strain. Chimeric viruses were found to possess similar growth properties, passage stability, and virulence, as compared to those of these parental strains. Interestingly, the thermostability of the chimera with P derived from the thermolabile LaSota strain was reduced compared to that of the parental virus, and P of the thermostable NDV4-C strain enhanced chimeric virus thermostability. Our data demonstrate that P is an important factor for the thermostability of NDV and provides information regarding the molecular mechanism of NDV thermostability; moreover, these results suggest a theoretical basis for using the NDV4-C strain as a thermostable vaccine. PMID- 30519590 TI - Impact of Intravenous Fluid Challenge Infusion Time on Macrocirculation and Endothelial Glycocalyx in Surgical and Critically Ill Patients. AB - (i) Purpose. The fluid challenge (FC) is a well-established test of preload reserve. Only limited data exist in regard to the FC efficacy based on infusion time. Slow administration may be associated with lack of effect based on fluid redistribution and external conditions changes. On the contrary, fast administration may lead to brisk fluid overload and damage to the endothelium and endothelial glycocalyx (EG). The aim of this trial was to compare the FC infusion time on its hemodynamic effects and EG. (ii) Methods. Prospective randomized single-center trial of fast (5-10 minutes) versus slow (20-30 minutes) administration of 500ml balanced crystalloid FC in spinal surgery (cohort OR) and septic shock (cohort SEP) patients. Hemodynamic response was assessed using standard monitoring and blood flow measurements; damage to EG was assessed using the perfused boundary region (PBR) via intravital microscopy monitoring in the sublingual region within relevant time points ranging up to 120 minutes. (iii) Results. Overall, 66 FCs in 50 surgical and 16 septic patients were assessed. Fluid administration was associated with increase of PBR in general (1.9 (1.8 2.1) vs. 2.0 (1.8-2.2); p= 0.008). These changes were transient in OR cohort whereas they were long-lasting in septic fluid responders. The rate of fluid responsiveness after fast versus slow administration was comparable in global population (15 (47%) vs. 17 (50%); p=0.801) as well as in both cohorts. (iv) Conclusions. Fluid challenge administration was associated with increased PBR (and presumable EG volume changes) which normalized within the next 60 minutes in surgical patients but remained impeded in septic fluid responders. The fluid responsiveness rate after fast and slow FC was comparable, but fast administration tended to induce higher, though transient, response in blood pressure. PMID- 30519591 TI - Uncontrolled Diabetes Mellitus Has No Major Influence on the Platelet Transcriptome. AB - Background: Diabetes mellitus (DM) has been associated with increased platelet reactivity as well as increased levels of platelet RNAs in plasma. Here, we sought to evaluate whether the platelet transcriptome is altered in the presence of uncontrolled DM. Methods: Next-generation sequencing (NGS) was performed on platelet RNA for 5 patients with uncontrolled DM (HbA1c 9.0%) and 5 control patients (HbA1c 5.5%) with otherwise similar clinical characteristics. RNA was isolated from leucocyte-depleted platelet-rich plasma. Libraries of platelet RNAs were created separately for long RNAs after ribosomal depletion and for small RNAs from total RNA, followed by next-generation sequencing. Results: Platelets in both groups demonstrated RNA expression profiles characterized by absence of leukocyte-specific transcripts, high expression of well-known platelet transcripts, and in total 6,343 consistently detectable transcripts. Extensive statistical bioinformatic analysis yielded 12 genes with consistently differential expression at a lenient FDR < 0.1, thereof 8 protein-coding genes and 2 genes with known expression in platelets (MACF1 and ITGB3BP). Three of the four differentially expressed noncoding genes were YRNAs (RNY1, RNY3, and RNY4) which were all downregulated in DM. 23 miRNAs were differentially expressed between the two groups. Of the 13 miRNAs with decreased expression in the diabetic group, 8 belonged to the DLK1-DIO3 gene region on chromosome 14q32.2. Conclusions: In this study, uncontrolled DM had a remote impact on different components of the platelet transcriptome. Increased expression of MACF1, together with supporting predicted mRNA-miRNA interactions as well as reduced expression of RNYs in platelets, may reflect subclinical platelet activation in uncontrolled DM. PMID- 30519592 TI - Efficacy of Alveolar Ridge Preservation after Maxillary Molar Extraction in Reducing Crestal Bone Resorption and Sinus Pneumatization: A Multicenter Prospective Case-Control Study. AB - Aim: To evaluate, with three-dimensional analysis, the effectiveness of alveolar ridge preservation (ARP) after maxillary molar extraction in reducing alveolar bone resorption and maxillary sinus pneumatization when compared to unassisted socket healing. Methods: Patients were included in the study following inclusion criteria and underwent minimally traumatic maxillary molar extraction followed by ARP using synthetic nanohydroxyapatite (Fisiograft Bone, Ghimas, Italy) (test group) or unassisted socket healing (control group). Cone-beam computerized tomographies (CBCT) were performed immediately after tooth extraction (T0) and 6 months postoperatively (T1). CBCTs were superimposed by using a specific software (Amira, Thermo Fisher Scientific, USA) and the following items were analyzed in both groups: (i) postextractive maxillary sinus floor expansion in coronal direction and (ii) postextractive alveolar bone dimensional changes (both vertical and horizontal). All data were tested for normality and equality of variance and subsequently analyzed by independent samples T-test and Mann-Whitney test. Results: Thirty patients were treated by three centers and twenty-six (test n=13; control n=13) were included in the final analysis. Mean sinus pneumatization at T1 was 0.69+/-0.48 mm in the test group and 1.04+/-0.67 mm in the control group (p=0.15). Mean vertical reduction of the alveolar bone at T1 was 1.62+/-0.49 mm in the test group and 2.01+/-0.84 mm in the control group (p=0.08). Mean horizontal resorption of crestal bone at T1 was 2.73+/-1.68 mm in test group and 3.63+/-2.24 mm in control group (p=0.24). Conclusions: It could be suggested that ARP performed after maxillary molar extraction may reduce the entity of sinus pneumatization and alveolar bone resorption, compared to unassisted socket healing. This technique could decrease the necessity of advanced regenerative procedures prior to dental implant placement in posterior maxilla. PMID- 30519593 TI - CX-3543 Promotes Cell Apoptosis through Downregulation of CCAT1 in Colon Cancer Cells. AB - Aim: Colon cancer-associated transcript-1 (CCAT1), located in the vicinity of transcription factor c-Myc, was first identified in colon cancer. A small molecule compound CX3543 (Quarfloxin) selectively targeting Myc G-quadruplexes has entered phase II clinical trials for neuroendocrine carcinomas. The aim of the study was to explore the relationship between CX3543, CCAT1, and cell apoptosis in colon cancer cells. Methods: Semiquantitative PCR was used to detect the relative expression of CCAT1 in colon cancer (CC) tissues and HT29 cell lines. Real-time PCR (RT-PCR) was also used to investigate the expression of CCAT1 and c-Myc after HT29 cells being treated by CX3543 for 24 h. Cell apoptosis assay and cell proliferation assay were conducted in HT29 cells after being treated by CX3543. Results: The results showed that the expression of CCAT1 was remarkably increased in CC tissues and HT29 cells compared to controls. CX3543 treatment reduced the expression of c-Myc and CCAT1 and promoted cell apoptosis and inhibited cell proliferation. After the expression of CCAT1 was inhibited by sh-CCAT1 transfection, the cell apoptosis rate was higher than that of control group. After the cells were treated by CCAT1 overexpression plasmid transfection and CX3543, the cell apoptosis rate was lower than that of control group. In vivo results showed that CX3543 inhibited the xenograft tumor growth of rats through downregulation of CCAT1. Conclusion: Our study demonstrated that CX3543 could inhibit the progression of colon cancer by downregulating CCAT1 expression and might be a potential drug for the treatment of colon cancer. PMID- 30519594 TI - The Influence of Suspension Containing Nanodiamonds on the Morphology of the Tooth Tissue Surface in Atomic Force Microscope Observations. AB - Reduced friction and wear of materials after the use of the carbon nanomaterials including nanodiamonds (NDs) have been confirmed by several studies in material engineering. Mechanical cleaning of the tooth surface by brush bristles should leave as little tissue roughened as possible. Higher surface roughness increases the tissue's wear and encourages the redeposition of the bacteria and the colouring agents present in the diet. Therefore, we evaluated the tooth tissues' surface's morphological changes after brushing them with the NDs suspension. Ten human teeth were brushed with the NDs aqueous suspension. The surfaces were observed using an Atomic Force Microscope (AFM). We found that the nature of the tissue surface became milder and smoother. A number of selected profilometric parameters were compared before and after brushing. We observed that brushing with the suspension of NDs resulted in a significant reduction in the enamel and dentine's surface roughness both in the range of the average parameters (Ra; p 0,0019) and in the detailed parameters (Rsk; p-0,048 and Rku; p-0,036). We concluded that the NDs used in the oral hygiene applications have a potentially protective effect on the enamel and the dentine's surfaces. PMID- 30519595 TI - Prospective randomised controlled trial of AlgisiteTM M, CuticerinTM, and Sorbact(r) as donor site dressings in paediatric split-thickness skin grafts. AB - Background: This is a parallel three-arm prospective randomised controlled trial (RCT) comparing AlgisiteTM M, CuticerinTM, and Sorbact(r) as donor site dressings in paediatric split-thickness skin grafts (STSG). All three were in current use within the Pegg Leditschke Children's Burn centre (PLCBC), the largest paediatric burns centre in Queensland, Australia. Our objective was to find the best performing dressing, following on from previous trials designed to rationalise dressings for the burn wound itself. Methods: All children for STSG, with thigh donor sites, were considered for enrolment in the trial. Primary outcome measures were days to re-epithelialisation, and pain. Secondary measures were cost, itch, and scarring at 3 and 6 months. Patients and parents were blinded to group assignment. Blinding of assessors was possible with the dressing in situ, with partial blinding following first dressing change. Blinded photographic assessments of re-epithelialisation were used. Scar assessment was blinded. Covariates for analysis were sex, age, and graft thickness (as measured from a central biopsy). Results: There were 101 patients randomised to the AlgisiteTM M (33), CuticerinTM (32), and Sorbact(r) (36) arms between April 2015 and July 2016. All were analysed for time to re-epithelialisation. Pain scores were not available for all time points in all patients. There were no significant differences between the three arms regarding pain, or time to re epithelialisation. There were no significant differences for the secondary outcomes of itch, scarring, or cost. Regression analyses demonstrated faster re epithelialisation in younger patients and decreased donor site scarring at 3 and 6 months with thinner STSG. There were no adverse effects noted. Conclusions: There are no data supporting a preference for one trial dressing over the others, in donor site wounds (DSW) in children. Thinner skin grafts lead to less donor site scarring in children. Younger patients have faster donor site wound healing. Trial registration: Australia and New Zealand Clinical Trials Register (ACTRN12614000380695).Royal Children's Hospital Human Research Ethics Committee (HREC/14/QRCH/36).University of Queensland Medical Research Ethics Committee (#2014000447). PMID- 30519596 TI - Astrocyte HIF-2alpha supports learning in a passive avoidance paradigm under hypoxic stress. AB - Background: The brain is extensively vascularized, uses20% of the body's oxygen, and is highly sensitive to changes in oxygen. While synaptic plasticity and memory are impaired in healthy individuals by exposure to mild hypoxia, aged individuals appear to be even more sensitive. Aging is associated with progressive failure in pulmonary and cardiovascular systems, exposing the aged to both chronic and superimposed acute hypoxia. The HIF proteins, the "master regulators" of the cellular response to hypoxia, are robustly expressed in neurons and astrocytes. Astrocytes support neurons and synaptic plasticity via complex metabolic and trophic mechanisms. The activity of HIF proteins in the brain is diminished with aging, and the increased exposure to chronic and acute hypoxia with aging combined with diminished HIF activity may impair synaptic plasticity. Purpose: Herein, we test the hypothesis that astrocyte HIF supports synaptic plasticity and learning upon hypoxia. Materials and Methods: An Astrocyte-specific HIF loss-of-function model was employed, where knock-out of HIF-1alpha or HIF-2alpha in GFAP expressing cells was accomplished by cre mediated recombination. Animals were tested for behavioral (open field and rotarod), learning (passive avoidance paradigm), and electrophysiological (long term potentiation) responses to mild hypoxic challenge. Results: In an astrocyte specific HIF loss-of-function model followed by mild hypoxia, we identified that the depletion of HIF-2alpha resulted in an impaired passive avoidance learning performance. This was accompanied by an attenuated response to induction in long term potentiation (LTP), suggesting that the hippocampal circuitry was perturbed upon hypoxic exposure following HIF-2alpha loss in astrocytes, and not due to hippocampal cell death. We investigated HIF-regulated trophic and metabolic target genes and found that they were not regulated by HIF-2alpha, suggesting that these specific targets may not be involved in mediating the phenotypes observed. Conclusion: Together, these results point to a role for HIF-2alpha in the astrocyte's regulatory role in synaptic plasticity and learning under hypoxia and suggest that even mild, acute hypoxic challenges can impair cognitive performance in the aged population who harbor impaired HIF function. PMID- 30519597 TI - Born to sense: biophysical analyses of the oxygen sensing prolyl hydroxylase from the simplest animal Trichoplax adhaerens. AB - Background: In humans and other animals, the chronic hypoxic response is mediated by hypoxia inducible transcription factors (HIFs) which regulate the expression of genes that counteract the effects of limiting oxygen. Prolyl hydroxylases (PHDs) act as hypoxia sensors for the HIF system in organisms ranging from humans to the simplest animal Trichoplax adhaerens. Methods: We report structural and biochemical studies on the T. adhaerens HIF prolyl hydroxylase (TaPHD) that inform about the evolution of hypoxia sensing in animals. Results: High resolution crystal structures (<=1.3 A) of TaPHD, with and without its HIFalpha substrate, reveal remarkable conservation of key active site elements between T. adhaerens and human PHDs, which also manifest in kinetic comparisons. Conclusion: Conserved structural features of TaPHD and human PHDs include those apparently enabling the slow binding/reaction of oxygen with the active site Fe(II), the formation of a stable 2-oxoglutarate complex, and a stereoelectronically promoted change in conformation of the hydroxylated proline-residue. Comparison of substrate selectivity between the human PHDs and TaPHD provides insights into the selectivity determinants of HIF binding by the PHDs, and into the evolution of the multiple HIFs and PHDs present in higher animals. PMID- 30519598 TI - Tri-culture system for pro-hapten sensitizer identification and potency classification. AB - Allergic contact dermatitis (ACD) is an inflammatory disease that impacts 15-20% of the general population and accurate screening methods for chemical risk assessment are needed. However, most approaches poorly predict pre- and pro hapten sensitizers, which require abiotic or metabolic conversion prior to inducing sensitization. We developed a tri-culture system comprised of MUTZ-3 derived Langerhans cells, HaCaT keratinocytes, and primary dermal fibroblasts to mimic the cellular and metabolic environments of skin sensitization. A panel of non-sensitizers and sensitizers was tested and the secretome was evaluated. A support vector machine (SVM) was used to identify the most predictive sensitization signature and classification trees identified statistical thresholds to predict sensitizer potency. The SVM computed 91% tri-culture prediction accuracy using the top 3 ranking biomarkers (IL-8, MIP-1beta, and GM CSF) and improved the detection of pre- and pro-haptens. This in vitro assay combined with in silico data analysis presents a promising approach and offers the possibility of multi-metric analysis for enhanced ACD sensitizer screening. PMID- 30519599 TI - Data on the working population in Spain related to training, workplace conditions and accident rates. AB - Obtaining data on worker accident rates is necessary in order to analyze the causes and variables involved in the occurrence of said accidents. The majority of these data, collected after the accident occurs, do not consider the employee's working conditions. Here are presented the data on workplace accidents and the conditions of the workers by analyzing the generic data supplied as part of the 7th National Survey of Workplace Conditions (EWCS) in Spain, conducted in 2011. These data will yield the variables needed to determine if the information on workplace risks provided by the survey respondents has an appreciable effect on the occurrence of occupational accidents in the working population, and will also be used to explore other variables. PMID- 30519600 TI - Measurement and monitoring of anions, cations and metals in landfill leachate in Iranian metropolises. AB - Leachate generation is a major problem for municipal solid waste (MSW) landfills and causes significant threat to surface and groundwater. Samples were collected from the landfills of Iranian metropolises (Ahwaz, Mashhad, Tehran (before and after treatment plant), Isfahan, Tabriz, Hamedan, Rasht, Sanandaj and Qazvin) based on the standard sampling methods and transferred to the laboratory. Cr, Cd, Hg, Pb, Ni, As, Ca, Mg, Fe, Mn, Na, K, Zn, Al, Ba, Li, Sr, Ti and V were analyzed. The pH values for the ten leachate samples obtained from 4.57 to 8.95. The results showed the amount of some metals in Iranian landfill sites higher than the DOE standards for agricultural irrigation and surface water. PMID- 30519601 TI - Dataset of relationships among social media marketing activities, brand loyalty, revisit intention. Evidence from the hospitality industry in Northern Cyprus. AB - The central purpose of this data article is to empirically investigate the relationships among social media marketing (SMM) activities, brand loyalty and revisit intention in five-star hotels in Northern Cyprus. Few researchers have investigated SMM activities, while none has looked at how SMM activities can be used toward improving brand loyalty and revisit intention in the tourism service industry. Hence, data gathered for the purposes of this research add to our understanding of today's social media marketing as a new generation marketing tool. This data was generated via a structured questionnaire, a total of 389 customers were surveyed who used five (5) hotels Facebook profiles, the hotels were all five-star ranked and located in Kyrenia city (Northern Cyprus). The data were examined by Structural Equation Modelling (SEM). Several analysis techniques have been used, the result showed a significant influence of SMM activities on brand loyalty and revisit intention, also the mediation outcome of brand trust is partially supported. Thus, consequential recommendations have been put forward. PMID- 30519602 TI - Data on chemical compositions and fermentation quality of silages made from low market-value vegetables supplemented with potato protein concentrate, a byproduct of starch production. AB - This data article reports the chemical compositions (protein, fat, fiber, ash, lactic acid, acetic acid, propionic acid, butyric acid and valeric acid) and fermentation quality, represented by V-value determined from the proportion of ammonia nitrogen in total nitrogen and volatile fatty acid contents, in silages prepared from low-market-value vegetables (carrot roots, cabbage leaves, and radish leaves). Potato protein concentrate, a byproduct of starch production from potato tuber, was used to supplement the protein contents in the silages. The first type of silage was produced by fermentation of a mixture of wheat bran and either carrot, cabbage, or radish without supplemental potato protein. The second type of silage was produced by fermentation of a mixture of wheat bran and either carrot, cabbage, or radish with supplemental potato protein. The third type of silage was produced by mixing the first silage type with unfermented potato protein. Chemical compositions and fermentation quality of the three silage types are provided in table formats. PMID- 30519603 TI - A dataset of synthetic hexagonal close packed 3D polycrystalline microstructures, grain-wise microstructural descriptors and grain averaged stress fields under uniaxial tensile deformation for two sets of constitutive parameters. AB - This data article presents a data set comprised of 54 synthetic 3D equiaxed polycrystalline microstructures, the microstructural descriptors for each grain and the stress fields resulting from two sets of crystal plasticity simulations mimicking uniaxial tensile deformation to a total strain of 2%. This is related to the research article entitled "Applied Machine Learning to predict stress hotspots II: Hexagonal Close Packed Materials" (Mangal and Holm, 2018). The microstructures were created using an open source Dream.3D software tool and the crystal plasticity simulations were carried out using elasto-viscoplastic fast Fourier transform (EVPFFT) method. Eight different kinds of HCP textures are represented with stochastically different microstructures with varying texture intensity for each texture kind. For each texture kind, between six and nine stochastically different microstructures with varying texture intensity (measured by multiples of random density (MRD)) are created. This dataset is freely available in two Mendeley Data archives "Synthetic HCP 3D polycrystalline microstructures with grain-wise microstructural descriptors and stress fields under uniaxial tensile deformation: Part One" and "Synthetic HCP 3D polycrystalline microstructures with grain-wise microstructural descriptors and stress fields under uniaxial tensile deformation: Part Two" located at http://dx.doi.org/10.17632/kt8hfg4t2p.1 and http://dx.doi.org/10.17632/nsfn6tw295.1 respectively for any academic, educational, or research purposes. PMID- 30519604 TI - Data on concentrations of polycyclic aromatic hydrocarbons (PAHs) in roasted and fried chicken - A case study: Bushehr, Iran. AB - In the present data article, the presence and amount of 16 polycyclic aromatic hydrocarbons (PAHs) were surveyed in Iranian roasted and fried chicken in Bushehr restaurants. For data collection, 73 samples (including 36 Roasted chicken and 37 Fried chicken samples) were collected from local restaurants and various retail outlets of Bushehr, Iran. The concentrations of 16 PAHs were determined by gas chromatography-mass spectrometry (GC-MS). Results indicated that the total PAHs level was ranged from 4.20 to 32.29 mg/kg and 2.06-19.65 ug/kg in Roasted and Fried chicken, respectively. The differences in PAHs levels were observed among charcoal and gas-roasted samples as well as between chicken fried with different oil types. benzo[a] pyrene(BaP), an appropriate marker for occurrence and potential toxicity of PAHs food matrixes was found in all roasted samples ranged from 1.41-5.71 mg/kg and all fried samples in range of 0.9-3.32 ug/kg. Moreover, unsaturated fatty acid (UFA) and saturated fatty acid (SFA) ratios in the in the used vegetable oils had an important role in the generation of PAHs in fried chicken. PMID- 30519605 TI - Dataset on the numbers and proportion of mortality attributable to hunting, trapping, and powerlines in wild and captive-bred migratory Asian houbara Chlamydotis macqueenii. AB - The data shown in this article are the number and proportion of deaths attributable to hunting/trapping, powerline collisions and natural causes in migratory Asian houbara Chlamydotis macqueenii originating from a breeding population in Uzbekistan. For wild adult and juvenile Asian houbara wintering in Central Asia during the period 2011-2018, 53.9% and 52.9%, respectively, of mortality was due to hunting/trapping, while in contrast most mortality in captive-bred released birds was natural with only 23.3% attributable to hunting/trapping. In winter, only one instance of powerline mortality was confirmed (6.0%). For wild adults, 23.0% of mortality during the summer was due to hunting/trapping, while 30.7% was due to powerline collisions. This data article is related to the publication "Captive breeding cannot sustain migratory Asian houbara Chlamydotis macqueenii without hunting controls" (Dolman et al., 2018) where further interpretation of the population-level consequences of these mortality causes can be found. PMID- 30519606 TI - Dataset on the relation of synthetic super para magnetic nanoparticles coated with various electric charges and fibrillation of albumin protein. AB - The data provided in this article are related to the research article entitled "Effect of Super Magnetic Nanoparticles Coated with Various Electric Charges on alpha-Synuclein Protein Fibrillation Process" (Javdani et al.). This article describes how electrically different charged and concentrated iron oxide nanoparticles synthesized using reverse co-precipitation method affects the fibrillation of albumin protein. PMID- 30519607 TI - DNA insecticides: Data on the trial in the field. AB - This data article is related to the research articles entitled "The RING for gypsy moth control: topical application of fragment of its nuclear polyhedrosis virus anti-apoptosis gene as insecticide" (Oberemok et al., 2016), "Molecular alliance of Lymantria dispar multiple nucleopolyhedrovirus and a short unmodified antisense oligonucleotide of its anti-apoptotic IAP-3 gene: a novel approach for gypsy moth control" (Oberemok et al., 2017), and "Topical treatment of LdMNPV infected gypsy moth caterpillars with 18 nucleotides long antisense fragment from LdMNPV IAP-3 gene triggers higher levels of apoptosis in infected cells and mortality of the pest" (Oberemok et al., 2017). This data article reports on the significant decrease of survival of L. dispar larvae after contact application of 18 nucleotides long antisense oligoRING fragment in the field experiment and supports perspective of use of DNA insecticides in forests. PMID- 30519608 TI - FTIR and Py-GC-MS data of wood from various living oak species and Iberian shipwrecks. AB - Data in this article are related to the chemical characterization of various oak wood samples. Data have been obtained by the application of Fourier Transform Infrared (FTIR) spectroscopy and pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) to living tree species and shipwreck wood fragments. Measurements were performed on individual rings in order to facilitate the understanding of the variability in wood chemical composition along the radial cores, i.e. the same kind of material traditionally used for dendrochronological analysis. The data in this article is labelled according to the anatomical sections of the wood (sapwood, transition wood and heartwood) where the samples were taken. The experimental background and the results can be found in the related research article, "Chemometric tools for identification of wood from different oak species and their potential for provenancing of Iberian shipwrecks (16th-18th centuries CE)" (Traore et al., 2018). PMID- 30519609 TI - An exploration of research information security data affecting organizational compliance. AB - In this article, data collected from onsite assessments of federal healthcare research programs were reviewed and analyzed. 103 research programs were evaluated for adherence to federal and organizational information security requirements and the data clustered into three primary compliance groupings, technological, procedural, and behavioral. Frequency and cross-tabulation statistics were conducted and chi-square statistics used to test for associations. PMID- 30519610 TI - Effects of Cimicifuga racemosa extract Ze450 on mitochondria in models of oxidative stress in neuronal cells. AB - This data article describes the influence of Cimicifuga racemosa extract Ze 450 on neuronal cells in models of glutamate-induced excitotoxicity and cell death induced by oxidative stress. Effects of Ze 450 on glutamate-mediated excitotoxicity were assessed in primary cortical rat and mouse neurons and, further, glutamate-mediated oxidative stress was analyzed in HT22 cells lacking ionotropic glutamate receptors. This study especially focusses on mitochondrial parameters like mitochondrial ROS formation, mitochondrial membrane potential, ATP production and mitochondrial integrity. Further the effects of Ze 450 on lipid-peroxidation, metabolic activity, cell proliferation and cell death were assessed under control conditions and oxidative challenge evoked by millimolar concentrations of glutamate in HT22 cells. These data support the findings in HT22, mHypo and HepG2 liver cells (Rabenau et al., 2018) [1]. PMID- 30519611 TI - Survey dataset on Muslim's religiosity, Muslim personality and work behavior. AB - Data were collected from administration officers ranging from middle-management to top management of the five universities of Malaysia. The data was collected through a standardized and structured questionnaire. The variables of the study were religiosity, personality and work behavior of Muslims. Muslim work behavior construct formulated on the basis on collected data. PMID- 30519612 TI - Diatoms and pollen data from modern surface sediment samples collected from the Merang wetlands, Kuala Terengganu, Malaysia. AB - The data presented here are related to the research paper entitled "A below-the present late Holocene relative sea level and the glacial isostatic adjustment during the Holocene in the Malay Peninsula" (Tam et al., 2018) [1]. The diatoms and pollen data are collected from surface sediments of the Merang wetlands, Kuala Terengganu, Malaysia, and are presented as percentages of total diatoms or total land pollen respectively. Ground elevations of the sampling sites are levelled to the national datum and expressed as elevations above or below mean sea level. These diatom and pollen data can be used for indicative meaning calibration of sea-level index points and for the development of diatom-based or pollen-based tidal level transfer functions. These data have been used for calibrating the indicative meanings for sea-level index points in the reconstruction of Holocene sea-level history of the Peninsular Malaysia. PMID- 30519613 TI - Data on heavy metal concentration in common carp fish consumed in Shiraz, Iran. AB - Food contamination by heavy metals can lead to the accumulation of these elements in the body of consumers and the contraction of diseases. Accordingly, heavy metal concentration in common carp fishes consumed in Shiraz, Iran was determined in the present study. The mean concentrations of Pb, Cd, Zn, and Cu were 0.23, 0.07, 0.47, and 0.59 mg/kg (dry weight), respectively. The average concentration of heavy metals in the muscle of common carps consumed in Shiraz was less than the permissible standard of the WHO and FAO. The estimated weekly intake (EWI) of the studied metals was below the provisional tolerable weekly intake (PTWI). The maximum and minimum relative risk (RR) equaled 48.93 and 0.55% of the total risk for Cd and Zn, respectively. PMID- 30519614 TI - Data on European seafood biomass production by country, sectors, and species in 2004-2014 and on ecological characteristics of the main species produced. AB - In this data article, we present the 2004-2014 average European seafood production volume by production sector, country, and species. The production data originates from the Food and Agriculture Organisation of the United Nations (FAO) and covers three production sectors: Marine fisheries, marine aquaculture, and freshwater production. We present the main ecological characteristics of each species produced or harvested. These species characteristics were retrieved from various published sources and include biological sensitivity to harvesting and temperature ranges for the most important species. These indices were weighted by each species production volume in order to produce maps of European country's color-coded by their overall temperature range, maximum temperature, and biological sensitivity within each production sector. PMID- 30519615 TI - Sustainability indicators for bioenergy generation from Amazon's non-woody native biomass sources. AB - This data article focuses on sustainability indicators for bioenergy generation from Brazilian Amazon's non-woody native biomass sources, considered to be modern forms of biomass. In the construction of the indicators, the Indicator-based Framework for Evaluation of Natural Resource Management Systems (MESMIS, from the original Spanish) method was used, with the application of the seven sustainability attributes to identify critical points and limiting and favorable factors for sustainability. The data yielded a list of 29 indicators distributed across 27 critical points, selected from three system evaluation areas: 11 environmental indicators, 11 social indicators, and 7 economic indicators. PMID- 30519616 TI - Petrology and geochemistry data of the precambrian granitoids from the Hyderabad area, part of Eastern Dharwar Craton, Telangana state India. AB - The data presented in this article are related to research to the research article entitled 'Petrology and Geochemistry Data of the Precambrian granitoids from the Hyderabad part of Eastern Dharwar Craton, Telangana state, India'. The granitoids from the Hyderabad area of the Telangana State are confined to the Precambrian gneissic complex of the northern-eastern part of Eastern Dharwar Craton. They cover 7760 Sq. km of the study area and fall between latitudes 16 degrees 52'-17 degrees 42' N and between East longitudes 77 degrees 21'-77 degrees 51' E. The granitoids are mainly classified into grey and pink granites, granodiorites and aplites. The field studies are understood they occasionally contain older mafic enclaves in the form of lensoid bodies and thin bands and cut by younger dolerite dykes, pegmatite and quartz veins and laboratory investigations resolved the classification of the granitods and their chemical histories. PMID- 30519617 TI - Data on health risk assessment to the nitrate in drinking water of rural areas in the Khash city, Iran. AB - The main objective of this data was determination of the nitrate concentration and its health risk assessment in the drinking water resources. In the aim of this data article a number of 30 samples of nitrate concentration in drinking water resources were collected from villages of the Khash city, Sistan and Baluchistan province, Iran. The nitrate concentration was measured using a Spectrophotometer accordance standard methods for examination of water and wastewater. Data indicated that nitrate concentration in drinking water ranged from 6 to 35 mg/L (average 16.083 mg/L). The mean EDI values for nitrate in different groups of infants, children, teenagers and adults were 0.1287, 0.9114, 0.6433 and 0.5155 mg/Kg, respectively. The findings of data showed that HQ value was less than 1 in 96% of samples in age groups of infants, children, teenagers and adults. PMID- 30519618 TI - Dataset of ptychographic X-ray computed tomography of inverse opal photonic crystals produced by atomic layer deposition. AB - This data article describes the detailed parameters for synthesizing mullite inverse opal photonic crystals via Atomic Layer Deposition (ALD), as well as the detailed image analysis routine used to interpret the data obtained by the measurement of such photonic crystals, before and after the heat treatment, via Ptychographic X-ray Computed Tomography (PXCT). The data presented in this article are related to the research article by Furlan and co-authors entitled "Photonic materials for high-temperature applications: Synthesis and characterization by X-ray ptychographic tomography" (Furlan et al., 2018). The data include detailed information about the ALD super-cycle process to generate the ternary oxides inside a photonic crystal template, the raw data from supporting characterization techniques, as well as the full dataset obtained from PXCT. All the data herein described is publicly available in a Mendeley Data archive "Dataset of synthesis and characterization by PXCT of ALD-based mullite inverse opal photonic crystals" located at https://data.mendeley.com/datasets/zn49dsk7x6/1 for any academic, educational, or research purposes. PMID- 30519619 TI - Simultaneous EEG, eye-tracking, behavioral, and screen-capture data during online German language learning. AB - This article presents concurrent multimodal data, including EEG, eye-tracking, and behavioral data (cursor movements and clicks), acquired from individuals (N = 22) while engaging in several German language lessons using the web-based Duolingo interface. Lessons were restricted to visual learning only (excluding audio and speech components), including reading and writing vocabulary words and sentences, and matching vocabulary to images. EEG data was collected using the open-source OpenBCI device utilizing dry Ag-AgCl electrodes, while eye-tracking data was recorded using the Gazepoint GP3 system. Timestamped screen captures associated with mouse click and keypress events and user behavior (cursor movements) were acquired using AutoHotKey macro scripts. These data provide neural (EEG), gaze (eye-tracking), and behavioral (mouse movements, clicks, and keypresses) data, with respect to presented language-learning media (Duolingo screen captures) for a wide range of possible scientific analyses and methods development. PMID- 30519620 TI - Data concerning secondary structure and alpha-glucans-binding capacity of the LaCBM26. AB - Carbohydrate-binding modules (CBMs) are auxiliary domains into glycoside hydrolases that allow the interaction between the insoluble substrate and the solubilized enzyme, through hydrophobic, CH-pi interactions and hydrogen bonds. Here, we present the data article related to the interaction of one LaCBM26 and some mutated proteins with soluble alpha-glucans determined by enzyme-linked carbohydrate-binding assay, isothermal titration calorimetry (ITC), and affinity gel electrophoresis (AGE). The data of the behavior of proteins in presence and absence of substrate analyzed by circular dichroism CD and thermofluor are also presented. These results are complementary to the research article "The role of conserved non-aromatic residues in the Lactobacillus amylovorus alpha-amylase CBM26-starch interaction" (Armenta et al., 2019). PMID- 30519621 TI - Comparison of the novel ARCHITECT procalcitonin assay with established procalcitonin assay systems. AB - Aims: This study assessed the performance of a new fully automated immunoassay, ARCHITECT B.R.A.H.M.S procalcitonin (PCT), comparing the results with other commercial assays on routine clinical specimens. Methods: At nine sites from eight countries, precision analysis was carried out on controls by ANOVA. Threshold and linearity were verified according to standard procedures. Comparison of ARCHITECT B.R.A.H.M.S PCT with the Cobas(r), LIAISON(r), VIDAS(r) and Kryptor(r) PCT assays was evaluated using Passing-Bablok and Deming regression analyses. Results: The within-laboratory standard deviation and %CV across all sites ranged from 0.005 to 0.008 and 2.7 to 4.1; 0.040 to 0.212 and 2.1 to 11.7; 1.628 to 4.191 and 2.5-6.3 for the three control levels, respectively. The mean slope (linearity analysis) across all sites ranged from 0.85 to 1.03, with a mean y-intercept ranging from -6.15 to + 1.71 and a correlation coefficient ranging from 0.94 to 1.00. The LoB, LoD, and LoQ claims were verified. Deming regression analysis of 1116 plasma or serum samples with PCT results detected across a dynamic assay range of 0.02-100 MUg/l using the ARCHITECT B.R.A.H.M.S PCT assay yielded results of r = 0.989 vs. Roche Cobas(r), r = 0.986 vs Kryptor(r) B.R.A.H.M.S, r = 0.987 vs BioMerieux VIDAS(r) and r = 0.972 vs. Diasorin LIAISON(r), respectively. Concordance at cut-offs of 0.25 MUg/l and 0.50 MUg/l were 96.9% and 98.1% with Roche Cobas(r), 95.4% and 96.1% with B.R.A.H.M.S Kryptor(r), 93.8% and 98.4% with BioMerieux VIDAS(r), and 92.7% and 93.9% with Diasorin LIAISON(r). Conclusions: Compared with other assays, ARCHITECT B.R.A.H.M.S PCT offers excellent precision and low-end sensitivity. PMID- 30519623 TI - Surgical management of cervical cancer by laparoscopy or laparotomy? PMID- 30519622 TI - A randomized phase II study of letrozole vs. observation in patients with newly diagnosed uterine leiomyosarcoma (uLMS). AB - Objective: Up to 87% of uterine leiomyosarcomas have estrogen receptor positivity. There are no effective adjuvant therapies for LMS. The objective of this study was to determine the efficacy of letrozole in patients with newly diagnosed uterine leiomyosarcoma (uLMS). The primary endpoint of this study was a reduction in the recurrence rate for patients with this disease. Methods: We performed a randomized, open-label, phase II study of letrozole (experimental arm) administered orally on a daily basis vs. observation (control) in patients with newly diagnosed early stage uLMS. Patient enrollment was to be open to any individual with newly diagnosed uLMS seen in the Gynecologic Oncology Center at M. D. Anderson Cancer Center. Hormone receptor positivity using CLIA approved lab testing was an eligibility requirement. No prior therapy was allowed. Results: Nine patients were randomized. Four patients were in the experimental arm and five patients were in the observation arm. No patients had prior therapy. The median duration of protocol treatment was 43.9 months (range, 6.5-70.2). The median PFS for the experimental arm was not reached (NR) compared to 17.3 months. The percent progression free at 12 and 24 months was 100% for patients receiving letrozole compared to 80% at 12 months and 40% at 24 months for patients in the observation arm. Conclusions: While no definitive conclusions can be made due to early study closure, these early observations warrant further investigation. We desperately need an effective adjuvant therapy for women with early stage uLMS. PMID- 30519624 TI - Response to "surgical management of cervical cancer by laparoscopy or laparotomy". PMID- 30519625 TI - Delayed presentation of complete arterial transection treated with interposition graft: A case report. AB - Introduction: Traumatic arterial injuries have a high degree of morbidity if left untreated. Frequently, arterial injuries are found soon after injury due to either subjective complaints or objective findings. Opportunity for delayed repair of vascular injury is a rare event as irreversible ischemia occurs at such early time points. Case report: We report a case of delayed presentation of complete arterial transection of the brachial artery due to penetrating trauma, but without classical hard signs of vascular injury. Trajectory, symptoms, and pulse exam prompted further evaluation. Successful reverse saphenous vein interposition grafting of the transected artery returned normal blood flow to the affected extremity with preserved function. Conclusion: This case of delayed presentation of arterial transection is significant as delayed identification of arterial injury is rare. Furthermore, it demonstrates the need for clinicians to have a high index of suspicion in patients with traumatic limb injuries who present in a subacute or delayed fashion with increasing pain and worsening of initial physical exam findings. PMID- 30519626 TI - Subjective assessments of income and social class on health and survival: An enigma. AB - We examined the association between various measures of subjective social class identification (SSCI) and self-rated health as well as survival using the 2014 General Social Survey-National Death Index dataset (n = 21,108). We used multinomial logistic regression models to assess the association between SSCI and self-rated health and used Cox proportional hazards to assess the association between SSCI and survival. All analyses were adjusted for age, year at interview, race, gender, family income, and educational attainment level. The measures of SSCI that we had available were strongly correlated with self-rated health after controlling for objective measures of social status. For example, those who saw themselves as lower class were nine times as likely to self-report poor rather than excellent health status (odds ratio = 8.69; 95% confidence interval = 5.04 14.98) compared with those saw themselves as upper class. However, no such associations were observed for survival. While our alternative measures of SSCI were important predictors of self-rated health, they were not predictive of survival. This suggests that there may be potential confounding between two perceptions: SSCI and self-rated health. PMID- 30519627 TI - Cerebrospinal fluid neurogranin/beta-site APP-cleaving enzyme 1 predicts cognitive decline in preclinical Alzheimer's disease. AB - Introduction: The cerebrospinal fluid neurogranin (Ng)/beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Abeta) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease. Methods: We compared Ng/BACE1 levels between cases with subjective cognitive decline (n = 18) and mild cognitive impairment (n = 20) both with amyloid plaques and healthy controls (APOE-epsilon4+, n = 16; APOE-epsilon4-, n = 20). We performed regression analyses between cerebrospinal fluid levels, baseline hippocampal and amygdala volumes, and pertinent cognitive measures (memory, attention, Mini Mental State Examination [MMSE]) at baseline and after 2 years. Results: Ng/BACE1 levels were elevated in both subjective cognitive decline and mild cognitive impairment compared to healthy controls. Higher Ng/BACE1 ratio was associated with lower hippocampal and amygdala volumes; lower baseline memory functions, attention, and MMSE; and significant decline in MMSE and memory function at 2-year follow-up. Discussion: High Ng/BACE1 ratio predicts cognitive decline also in preclinical cases with amyloid plaques. PMID- 30519628 TI - The hidden variables problem in Alzheimer's disease clinical trial design. AB - As the leading cause of dementia worldwide, Alzheimer's disease has garnered intense academic and clinical interest. Yet, trials in search of a disease modifying therapy have failed overwhelmingly. We suggest that, in part, this may be attributable to the influence of disruptive variables inherent to the framework of a clinical trial. Specifically, we observe that everyday factors such as diet, education, mental exertion, leisure participation, multilingualism, sleep, trauma, and physical activity, as well as clinical/study parameters including environment, family coaching, concurrent medications, and illnesses may serve as potent confounders, disruptors, or sources of bias to an otherwise significant drug-disease interaction. This perspective briefly summarizes the potential influence of these hidden variables on the outcomes of clinical trials and suggests strategies to abate their impact. PMID- 30519629 TI - User experience and clinical effectiveness with two wearable global positioning system devices in home dementia care. AB - Introduction: The user experience and clinical effectiveness with wearable global positioning system (GPS) devices for persons with dementia (PwDs) and caregivers (CGs) remain unclear although many are available. Methods: Using a crossover design, 20 dyads tested two similar commercial GPS watches (products A and B) at home for 4 weeks each. Usability, product functions, design features and product satisfaction at home and the clinic were investigated. Caregiver burden and quality of life assessed clinical effectiveness. Results: The final 17 dyads rated the usability, telephone function, overall design features, font, buttons, and battery life of B significantly better than A. PwDs rated the overall design features and buttons of A significantly better than CGs. Product satisfaction with both products was significantly lower at home. Clinical effectiveness was not found. Discussion: User experience can be improved by optimizing specific product details. This might translate to clinical effectiveness. Social desirability bias may explain different product satisfaction ratings. PMID- 30519630 TI - Factors Associated with Asthma ED Visit Rates among Medicaid-enrolled Children: A Structural Equation Modeling Approach. AB - Background: Asthma is one of the leading causes of emergency department visits and school absenteeism among school-aged children in the United States, but there is significant local-area variation in emergency department visit rates, as well as significant differences across racial-ethnic groups. Analysis: We first calculated emergency department (ED) visit rates among Medicaid-enrolled children age 5-12 with asthma using a multi-state dataset. We then performed exploratory factor analysis using over 226 variables to assess whether they clustered around three county-level conceptual factors (socioeconomic status, healthcare capacity, and air quality) thought to be associated with variation in asthma ED visit rates. Measured variables (including ED visit rate as the outcome of interest) were then standardized and tested in a simple conceptual model through confirmatory factor analysis. Results: County-level (contextual) variables did cluster around factors declared a priori in the conceptual model. Structural equation models connecting the ED visit rates to socioeconomic status, air quality, and healthcare system professional capacity factors (consistent with our conceptual framework) converged on a solution and achieved a reasonable goodness of fit on confirmatory factor analysis. Conclusion: Confirmatory factor analysis offers an approach for quantitatively testing conceptual models of local-area variation and racial disparities in asthma-related emergency department use. PMID- 30519631 TI - Is Awareness Enough to Bring Patients to Colorectal Screening? AB - Background: The aim of the study was to assess the awareness of colorectal cancer (CRC) patients about CRC screening methods and to investigate the relationship between awareness, socio-demographic characteristics and the stage in which patients with CRC are diagnosed. Methods: The observational cross-sectional study included 275 CRC patients admitted between 2014 and 2016 to two surgical clinics from Tirgu Mures, Romania. Study variables were collected via face-to-face interview and from patients' observation sheets. Results: Only 41.5% of the patients heard about cancer screening and 6.5% about specific CRC screening methods. Mass-media was the major source of information (85.1%) followed to a much lesser extent (14.9%) by family, friends, and colleagues. Health professionals did not contribute at all to informing patients about screening methods. Awareness about screening methods was statistically associated with the patients' residence, age, and educational achievement, but not with the stage of CRC. Conclusion: The level of awareness of CRC screening methods was very low among the CRC patients included in the study but it could not predict the stage in which malignancy was diagnosed, suggesting that awareness alone is not enough to bring patients to undergo early CDC screening procedures. PMID- 30519632 TI - Thromboembolic Complications Following Tissue Plasminogen Activator Therapy in Patients of Acute Ischemic Stroke - Case Report and Possibility for Detection of Cardiac Thrombi. AB - Many reports focus on the probability of intracranial hemorrhage as a complication after recombinant tissue plasminogen activator (rt-PA) therapy. However, thromboembolic complications are not well discussed. We experienced a case in which severe thromboembolic complications occurred in the right radial and right ulnar artery. Arterial fibrillation was observed in this case. If multiple thrombi exist in the atrium or ventricle, multiple small embolic particles may appear following thrombolytic therapy, and that may be a potential risk of secondary thromboembolic complications due to incomplete dissolution of thrombi. Transesophageal echocardiography is a standard method to detect intracardiac sources of emboli in the case of arterial fibrillation. Transesophageal echocardiography is, however, an invasive method for patients with ischemic stroke during rt-PA therapy. High resolution enhanced CT could be a useful tool and may be a reliable alternative to transthoracic echocardiography. Careful assessment of thromboembolic complications following rt-PA therapy in patients with arterial fibrillation is needed. In this case report and mini review, we would like to discuss about the accurate diagnostic methods to detect cardiac or undetermined embolic sources and provide expedited stroke care. These embolic sources may be more readily discovered during rt-PA therapy within the limited therapeutic time window. PMID- 30519633 TI - A Report of Chronic Intestinal Pseudo-obstruction Related to Systemic Lupus Erythematosus. AB - Chronic intestinal pseudo-obstruction (CIPO) is a functional gastrointestinal disorder with symptoms of ileus. CIPO can either be idiopathic or secondary to other diseases such as systemic lupus erythematosus (SLE). SLE is involved in many parts of the gastrointestinal system with variable clinical presentations. Reports about reduplicated CIPO as a complication of SLE is infrequent. A 49-year old female suffering from clinical symptoms of ileus has been hospitalized 3 times over 1 year. Her examination results showed no observation of mechanical obstruction. In August 2017, she came to the nephrology department due to edema in both lower limbs along with symptoms of ileus. After thorough examination, she was diagnosed with secondary CIPO related to SLE. Results of renal biopsy confirmed to be lupus nephritis (Class III-(A) + V). The symptoms of ileus are gradually improved after treatment of full-dose intravenous corticosteroid for 5 days. PMID- 30519634 TI - Risk Model in Women with Ovarian Cancer Without Mutations. AB - Ovarian cancer is characterised by the greatest mortality among all tumors of the reproductive tract. This study included 246 patients which consisted of 136 women with ovarian cancer without genetic mutation and 110 women with benign ovarian cysts. We created two mathematical logic models containing positive and negative risk factors of ovarian cancer such as: age at last menstruation cycle, patient age, OC, HRT, smoking, education status, and alcohol consumption. The calculated cut-off point for the first model was 0.5117. Classification determined on the basis of that cut-off point yielded 87.19% of correctly classified cases, of which 91.38% are "case" and 81.61% - "noncase". For the second model the designated cut-off point was set at 0.5149 and the percentage of correctly classified patients was 88.12%, with 92.24% correctly rated as cancer patients and 82.56% of the cases rightly recognised as having no ovarian cancer. Logit is a simple mathematical model that can be a useful tool for identification of patients with increased risk of ovarian cancer. PMID- 30519635 TI - Direct Oral Anticoagulants and Travel-related Venous Thromboembolism. AB - Travel- related thromboembolism reflects the relationship between venous thromboembolism (VTE) and long-haul flights. Although this condition is rare, it may cause significant morbidity and mortality. Therefore, travelers should be evaluated for the risks for thrombosis. Travel physicians should employ a clinical risk score and select in vestigations, prophylaxis, and treatment that are appropriate for each individual. This review summarizes current VTE clinical risk scores and patient management from various reliable guidelines. We summarized 16 reliable publications for reviewing data. Direct oral anticoagulants (DOACs) are currently the standard treatment for VTE and a prophylactic measure for VTE in orthopedic surgery. Compared with a vitamin K antagonist (VKA), DOACs show better safety and similar efficacy without the need for monitoring, and have fewer food/drug interactions. Inferred from the data on general VTE, DOACs may be used to treat travel-related VTE. Although the data are lacking, DOACs may be used off-label as VTE prophylax is. Before using DOACs, physicians must know the pharmacology of the drugs well and should realize that the availability of antidotes for bleeding complications is limited. PMID- 30519636 TI - How Bispectral Index Compares to Spectral Entropy of the EEG and A-line ARX Index in the Same Patient. AB - Background: Bispectral index (BIS) monitoring of depth of anesthesia has pioneered the field for more recent monitoring devices like the A-line ARX Index (AAI) or the state (SE) and response entropy (RE) monitoring devices. Following an observational design the present study aimed to simultaneously compare in the same patient recorded BIS, AAI and entropy values. Methods: Data from patients (n = 32) undergoing minor gynecological operations were analyzed. For all patients, standardized anesthesia was used. Before induction of anesthesia AEP electrodes, BIS and entropy sensors were simultaneously placed on the forehead and recordings were started at 3 minutes before induction and continued until patient transfer to the postanesthesia care unit. Markers were set at defined landmarks. Results: Anesthesia reduced mean BIS, AAI and entropy values. During uneventful, and even more pronounced, during eventful anesthesia BIS/ entropy and BIS/ AAI values showed better correlation than did AAI and entropy values. The prediction probability (Pk) of AAI (0.824 +/- 0.036) and RE (0.786 +/- 0.040) or SE (0.781 +/- 0.040) for preanesthesia awake, postanesthesia awake or anesthesia was comparable and significantly greater than that of BIS (0.705 +/- 0.047). However, only 20% of BIS, AAI and entropy values simultaneously categorized the state of the patient as awake, inadequate anesthesia, optimal anesthesia or deep anesthesia. Conclusion: The prediction probability (Pk) of entropy and AAI was comparable and better than that of BIS. However, agreement between BIS, AAI and entropy measurements on patient state was poor. PMID- 30519637 TI - Henoch-schonlein Purpura Nephritis with Renal Interstitial Lesions. AB - Objective: To investigate the clinical pathology and prognosis & outcome of Henoch-Schonlein purpura nephritis (HSPN) with renal interstitial lesions. Methods: All 148 patients were analyzed for clinical, renal pathological, and prognostic features. Patients with no, mild, and moderate- severe renal tubulo interstitial lesions were included in group A, B and C, respectively. Results: The estimated glomerular filtration rate (eGFR) of group B was significantly lower than that of group A. The levels of serum creatinine and blood urea nitrogen in group C were significantly higher than those in groups A and B. Clinical type II was correlated with pathological types II and IIIa; pathological type IV and IIIb were correlated with clinical type VI and IV. There were significant differences in the level of red blood cells in urinary sediment, levels of urine occult blood and in the prognosis among the 3 groups. Conclusion: Clinically, Type II is the most common cause; pathologically, Type IIIa is more common. The severity of renal tubulo-interstitial lesions is positively correlated with a decline in renal function and GFR. There is a correlation between the severity of renal tubulo-interstitial lesions and the severity of hematuria. Most patients with HSPN have a good prognosis. PMID- 30519638 TI - CD5 and CD43 Expression are Associate with Poor Prognosis in DLBCL Patients. AB - Objective: To investigate the expression and clinical significance of CD5 and CD43 in diffuse large B cell lymphoma (DLBCL) (unspecified). Methods: Sixty - five patients with diagnosed DLBCL were enrolled. The expressions of CD5, CD43, CD10, Bcl-6 and Mun-1 were detected by immuno histochemistry. The relationship between CD5 and CD43 and clinicopathological features and prognosis of DLBCL was analyzed. Results: In sixty - five adult DLBCL patients , 6 cases of DLBCL (9.2%) were CD5 positive, 24 cases of DLBCL (36.9%) were CD43 positive, 5 cases of DLBCL (7.7%) were both CD5 and CD43 positive. 40 cases of DLBCL (61.5%) were CD5 and CD43 negative. CD5 expression was not related to age, sex, clinical stage, type of immunophenotype (Hans typing), location, and whether infected with hepatitis B virus (HBV); CD43 expression was correlated with immunophenotyping and HBV i nfection, but was not correlated with the age, sex, clinical stage, and site. Median survival time was significantly lower in CD5- and CD43- positive DLBCL patients than CD5- and CD43-negative patien ts. Conclusion: The prognosis of DLBCL patients may be worse with positive CD5 and CD43 expression. PMID- 30519639 TI - Migration and cognitive function: a conceptual framework for Global Health Research. AB - Background: Migration is a fundamental demographic process that has been observed globally. It is suggested that migration is an issue of global health importance that can have an immediate and lasting impact on an individual's health and well being. There is now an increasing body of evidence linking migration with cognitive function in older adults. In this paper, we synthesized the current evidence to develop a general conceptual framework to understand the factors contributing to the association between migration and cognitive function. Methods: A comprehensive review of the literature was conducted on the associations between migration and cognition among middle-aged and older adults. Results: Five potential mechanisms were identified from the literature: 1) socioeconomic status-including education, occupation, and income; 2) psychosocial factors-including social networks, social support, social stressors, and discrimination; 3) behavioral factors-including smoking, drinking, and health service utilization; 4) physical and psychological health status-including chronic conditions, physical function, and depression; and 5) environmental factors-including both physical and social environment. Several underlying factors were also identified-including early-life conditions, gender, and genetic factors. Conclusions: The factors linking migration and cognitive function are multidimensional and complex. This conceptual framework highlights potential implications for global health policies and planning on healthy aging and migrant health. Additional studies are needed to further examine these mechanisms to extend and refine our general conceptual framework. PMID- 30519640 TI - Prospective pilot study comparing deep sclerectomy outcomes with a long-term and intense corticosteroid treatment versus a standard one. AB - Objective: To compare prospectively intraocular pressure (IOP) results after deep sclerectomy (DS) using a topical short-term corticosteroid treatment (STCT, 1 month) versus a topical long-term and intense corticosteroid treatment (LTCT, 6 months) in a two2 year-follow-up. Methods: Patients with medically uncontrolled open angle glaucoma were prospectively recruited and underwent a DS. Results: We operated 45 eyes of 45 patients, 22 in STCT group and 23 in LTCT group. Median preoperative IOP was 27 (22-36.75) mm Hg for STCT and for 25 (22-28) mm Hg for LTCT group without significant difference (p=0.195). Median postoperative IOP was 4 (3-6.25) mm Hg in STCT group versus 2 (0-5) mm Hg in LTCT at day 1 (p=0.003); 8.5 (5.75-11.25) mm Hg (STCT) vs 6 (4-9) mm Hg (LTCT) at week 1 (p=0.079); 17.5 (14.75-22.25) mm Hg (STCT) vs 13 (10-14) mm Hg (LTCT) at month 1 (p=0.001); 16 (12-20) mm Hg (STCT) vs 12 (10-15) mm Hg (LTCT) at month 3 (p=0.008); 17 (14-20) mm Hg (STCT) vs 12 (10-14) mm Hg (LTCT) at month 6 (p=0.000); 16 (14-20) mm Hg (STCT) vs 14 (10-16) mm Hg (LTCT) at year 1 (p=0.002) and 17.5 (15-19) mm Hg (STCT) vs 14 (12-16) mm Hg (LTCT) at year 2 (p=0.001). The complete success rate was 54.5 % in STCT and 87 % in LTCT (p=0.018). Conclusions: A long-term and intensive postoperative treatment enhances success rate in DS compared with a standard protocol. PMID- 30519641 TI - Increased sensitivity of microbiological testing of cornea organ culture medium by additional resin treatment. AB - Objective: This validation study investigates the treatment of cornea organ culture medium (Modified Eagle Medium, Biochrom GmbH, Berlin, Germany) with RESEP, a new medical device for antibiotics removal, before microbiological testing with BACTEC TM blood culture bottles. Methods and analysis: 10-100 colony forming units of Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Bacillus subtillis, Aspergillus brasiliensis, Clostridium sporogenes, Enterobacter cloacae and Staphylococcus epidermidis were inoculated in 9mL of cornea organ culture medium. In group A, the medium was withdrawn with RESEP and treated for 20 min at room temperature, and then inoculated in BACTEC Plus Aerobic/F/Anaerobic/F blood culture bottles. In group B, the medium, spiked by the inoculation of microorganism, was injected directly. For each strain, a growth control was performed, by direct inoculation of the microorganisms in BACTECTMvials (positive control). All samples were incubated in the automated BACTECTMblood culture system at 36 degrees C +/-1 degrees C for maximum of 14 days or until a positive reading. The elimination of antibiotics from the medium by RESEP was determined by high-performance liqiud chromatography. Results: After 20 min of RESEP treatment, 100% (n=9) of streptomycin, 100% (n=9) of amphotericin B and 99.7% (n=9) of penicillin G were eliminated. In group A, all microorganisms were detected within 3 days of incubation with a sensitivity of 100% (n=99) and showed no significant delay compared with the positive controls. In group B, the overall sensitivity was 67.9% (n=96) with a significant delay until detection of microbial growth for all tested microorganisms except for A. brasiliensis. Conlclusion: The use of RESEP to eliminate the antibiotics from cornea organ culture medium increases the sensitivity of the microbiological testing with BACTECTMPlus blood culture bottles significantly and fulfils the requirements of the European Pharmacopoeia method suitability test. PMID- 30519642 TI - Loss of horizontal macular ganglion cell complex asymmetry: an optical coherence tomography indicator of chiasmal compression. AB - Objective: To estimate the macular ganglion cell complex (GCC) asymmetry in patients with suprasellar tumours, to compare its diagnostic performance to the nasal GCC thickness and visual field (VF) and to investigate how the parameters correlate with magnetic resonance imaging (MRI) findings. Methods and analysis: Cross-sectional study of patients with suprasellar tumours affecting the optic chiasm. Macular optical coherence tomography (OCT) scans were evaluated for nasal GCC sector thinning and loss of normal GCC asymmetry between corresponding nasal temporal sectors. Equivalently, VFs were analysed for defects compatible with chiasm dysfunction. The relationship between optic chiasm and tumour was measured on MRI. Results: Thirty-three eyes of 33 patients were included. There were OCT findings in 14 eyes. Nasal GCC thinning was found in 9 eyes and loss of GCC asymmetry in 12 eyes; the two parameters were not significantly different with respect to number of positive findings (p=0.45). Loss of GCC asymmetry, however, occurred in 5 eyes among 24 without GCC thinning (proportion 0.21; 95% confidence interval 0.071 to 0.42). In 8 eyes, VF indicated pathology; of these, 7 had concurring OCT findings. The prevalence of OCT and VF findings increased significantly with suprasellar tumour extension on MRI. Conclusion: The diagnostic capabilities of nasal GCC thinning and loss of GCC asymmetry were comparable, whilst their complementary performances increased the proportion of eyes in which OCT suggested compression. The prevalence of both OCT and VF findings grew with suprasellar tumour extension. In several cases, however, structural findings on OCT preceded detectable VF deficits. PMID- 30519643 TI - Stroke: The past, present and future. AB - Since the inception of the British Neuroscience Association, there have been major advances in our knowledge of the mechanistic basis for stroke-induced brain damage. Identification of the ischaemic cascade led to the development of hundreds of new drugs, many showing efficacy in preclinical (animal-based) studies. None of these drugs has yet translated to a successful stroke treatment, current therapy being limited to thrombolysis/thrombectomy. However, this translational failure has led to significant improvements in the quality of animal-based stroke research, with the refinement of rodent models, introduction of new technologies (e.g. transgenics, in vivo brain imaging) and improvements in study design (e.g. STAIR, ARRIVE and IMPROVE guidelines). This has run in parallel with advances in clinical diagnostic imaging for detection of ischaemic versus haemorrhagic stroke, differentiating penumbra from ischaemic core, and improved clinical trial design. These preclinical and clinical advances represent the foundation for successful translation from the bench to the bedside in the near future. PMID- 30519644 TI - Promoter methylation cooperates with SNPs to modulate RAGE transcription and alter UC risk. AB - Single-nucleotide polymorphisms (SNPs) located in the promoter region of the receptor for advanced glycation end products (RAGE) gene have been linked to the activity of RAGE. However, contrary to our expectation, we previously detected no correlation between SNPs within the RAGE promoter and ulcerative colitis (UC) risk in a case-control study. Here, we investigated the methylation of the RAGE promoter and analyzed the collective contribution of methylation and SNPs to UC risk. We found that RAGE promoter hypomethylation was more common in UC patients compared to controls (70% vs. 30%, respectively), as determined via bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP). Furthermore, we investigated the cooperativity of promoter methylation and SNPs and found that either of two SNPs (rs1800624 or rs1800625) and promoter methylation jointly contributed to UC risk (30 UC patients vs. 30 controls, P < 0.05). There was no correlation between UC risk and either methylation or SNPs when analyzed separately. This lack of correlation is likely due to promoter methylation repressing gene transcription, whereas SNPs in the RAGE promoter region activate RAGE transcription. We found that variant allele carriers with promoter hypomethylation were at an increased risk for UC (rs1800624, OR = 10, 95% CI: 1.641-60.21, P = 0.009; rs1800625, OR = 4.8, 95% CI: 1.074-21.447, P = 0.039). Furthermore, our data revealed that the RAGE mRNA levels in variant allele carriers with promoter hypomethylation were significantly higher compared to those with promoter hypermethylation (P < 0.05) as well as to those in wild-type allele individuals exhibiting promoter hypomethylation (P < 0.05). We therefore speculate that the methylation status and SNPs present in the RAGE promoter region alter RAGE transcription, thereby impacting UC risk. We also propose that the methylation status and RAGE promoter genotype could jointly serve as clinical biomarkers to assist in UC risk assessment. PMID- 30519645 TI - The mouse-canine chimeric anti-dog podoplanin antibody P38B exerts antitumor activity in mouse xenograft models. AB - Podoplanin (PDPN) is a type I transmembrane heavily glycosylated sialoglycoprotein that is expressed in normal tissues such as pulmonary type I alveolar cells, renal podocytes, and lymphatic endothelial cells. PDPN overexpression in cancerous tissue is associated with hematogenous metastasis through interactions with the C-type lectin-like receptor 2 (CLEC-2). Previously, we have reported the development of a mouse monoclonal antibody (mAb), PMab-38 (IgG1, kappa) against dog PDPN (dPDPN). PMab-38 was found to strongly react with canine squamous cell carcinomas (SCCs) and melanomas; however, it showed no reaction with lymphatic endothelial cells. Recently, we have developed and produced the mouse-canine mAb of subclass B, P38B that showed antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against Chinese hamster ovary (CHO)/dPDPN cells. In the present study, we investigated the antitumor activity using mouse xenograft model. To induce ADCC activity by P38B, canine mononuclear cells were injected surrounding the tumors in a xenograft model. It was demonstrated that P38B exerted antitumor activity against the mouse xenograft model using CHO/dPDPN. These results suggest that P38B is useful for antibody therapy against dPDPN-expressing canine SCCs and melanomas. PMID- 30519646 TI - A LEA model peptide protects the function of a red fluorescent protein in the dry state. AB - We tested whether a short model peptide derived from a group 3 late embryogenesis abundant (G3LEA) protein is able to maintain the fluorescence activity of a red fluorescent protein, mKate2, in the dry state. The fluorescence intensity of mKate2 alone decreased gradually through repeated dehydration-rehydration treatments. However, in the presence of the LEA model peptide, the peak intensity was maintained almost perfectly during such stress treatments, which implies that the three dimensional structure of the active site of mKate2 was protected even under severe desiccation conditions. For comparison, similar experiments were performed with other additives such as a native G3LEA protein, trehalose and BSA, all of whose protective abilities were lower than that of the LEA model peptide. PMID- 30519647 TI - Gross tumour delineation on computed tomography and positron emission tomography computed tomography in oesophageal cancer: A nationwide study. AB - Background and purpose: Accurate delineation of the primary tumour is vital to the success of radiotherapy and even more important for successful boost strategies, aiming for improved local control in oesophageal cancer patients. Therefore, the aim was to assess delineation variability of the gross tumour volume (GTV) between CT and combined PET-CT in oesophageal cancer patients in a multi-institutional study. Materials and methods: Twenty observers from 14 institutes delineated the primary tumour of 6 cases on CT and PET-CT fusion. The delineated volumes, generalized conformity index (CIgen) and standard deviation (SD) in position of the most cranial/caudal slice over the observers were evaluated. For the central delineated region, perpendicular distance between median surface GTV and each individual GTV was evaluated as in-slice SD. Results: After addition of PET, mean GTVs were significantly smaller in 3 cases and larger in 1 case. No difference in CIgen was observed (average 0.67 on CT, 0.69 on PET CT). On CT cranial-caudal delineation variation ranged between 0.2 and 1.5 cm SD versus 0.2 and 1.3 cm SD on PET-CT. After addition of PET, the cranial and caudal variation was significantly reduced in 1 and 2 cases, respectively. The in-slice SD was on average 0.16 cm in both phases. Conclusion: In some cases considerable GTV delineation variability was observed at the cranial-caudal border. PET significantly influenced the delineated volume in four out of six cases, however its impact on observer variation was limited. PMID- 30519648 TI - Two cases of late-onset neuromyelitis optica spectrum disorder initially presenting with isolated cerebral white matter lesions. PMID- 30519649 TI - Foam Sclerotherapy Augmented Phlebectomy (SAP) Procedure for Varicose Veins: Report of a Novel Technique. AB - Introduction: While traditional ambulatory phlebectomy (AP) is a safe and effective procedure, few adverse effects such as hematoma, bleeding, bruising and nerve injury have been reported. To improve AP and to reduce some of these adverse events, herein we report a novel technique - Foam Sclerotherapy Assisted Phlebectomy (SAP). Report: The details of the above technique, along with the potential advantages and limitations will be discussed. Discussion: Foam sclerotherapy and DUS act as valuable adjuncts to traditional AP. SAP increases precision and creates additional venospasm leading to reduced bruising, reduced nerve injury and sclerosis of residual vein segments. PMID- 30519650 TI - Initiating patient discussions about oocyte cryopreservation: Attitudes of obstetrics and gynaecology resident physicians. AB - This study examined the attitudes of obstetrics and gynaecology (OB/GYN) resident physicians to initiating patient discussions regarding medical and elective oocyte cryopreservation (OC). The study used a cross-sectional online survey of OB/GYN medical residents in the USA, sampled from residency programmes approved by the American Council for Graduate Medical Education. In total, 208 medical residents, distributed evenly between postgraduate years 1-4, participated in the study. Residents' fertility knowledge and attitudes to initiating discussions about OC were gathered. Forty percent (n = 83) believed that OB/GYN residents should initiate discussions about OC with patients (initiators), while 60% (n = 125) did not (non-initiators). Initiators were less likely to overestimate the age at which a woman's fertility begins to decline, and were more likely to believe that discussions about OC and age-related fertility decline should take place during a well-woman annual examination. Initiators and non-initiators did not differ in their attitudes towards discussing OC with patients undergoing cancer treatments; however, initiators were significantly more likely to discuss elective OC with patients who were currently unpartnered or who wished to delay childbearing to pursue a career. Given the increasing age of childbearing among women, and the fact that women prefer to receive reproductive information from their healthcare providers, it is critical that such topics are discussed in consultations to assist patients in making more informed reproductive decisions. Further research is needed to assess the existing barriers to these discussions from both physician and patient perspectives. PMID- 30519651 TI - Possibility of numt co-amplification from gigantic genome of Orthoptera: testing efficiency of standard PCR protocol in producing orthologous COI sequences. AB - Mitochondrial DNA has been the preferential genome biodiversity studies. However, several factors contribute to its inadequacy. Numts constitute one of the main complications that prevent obtaining orthologous mitochondrial sequences. Orthoptera have been a model group in numt studies because of their huge genome size. In this study we aimed to; (i) test efficiency of standard PCR protocol in producing orthologous sequences of cytochrome C oxidase, (ii) study presence/absence of numts in several unstudied Orthoptera species, (iii) test if there is a threshold between the length of mtDNA targeted for amplification and possibility of encountering numts, and (iv) estimate reliability of the sequences in databases in light of these findings. For these aims we studied 38 species of Orthoptera representing different sublineages and genome sizes. DNA extracted from each sample was used to amplify five different fragments of COI region by standard PCR protocol. Sequenced PCR amplicons were checked for numt possibility by several different numt criteria. No sequences without numt signs were obtained for the first fragment. The number of samples with numt signs for the other four fragments differed between the suborders Ensifera and Caelifera. The percentage of samples with numt signs was higher in Caelifera than Ensifera for all fragments. The numt percentage considerably decreased for the longest two fragments. Numts are more prevalent in families with larger genome size. We arrived at the following conclusions: (i) numts are common in all members of Orthoptera, but, their prevalence differs among intra-lineages, especially more prevalent in Caelifera, (ii) there seems a correlation between numt rate and genome size, (iii) there is no threshold to avoid numt co-amplification, but, a 1,000 bp length may be a threshold for Ensifera, (iv) Folmer region of COI doesn't seem an appropriate marker for animal barcoding. Additionally, a phylogenetic tree produced from the numt sequences of fragment four detected in genus Anterastes suggested a paleonumt gained in generic ancestor a 3.5-4 times slower divergence rate for numt sequences. PMID- 30519652 TI - Effect of the strigolactone analogs methyl phenlactonoates on spore germination and root colonization of arbuscular mycorrhizal fungi. AB - Strigolactones (SLs), a novel class of plant hormones, are key regulator of plant architecture and mediator of biotic interactions in the rhizosphere. Root released SLs initiate the establishment of arbuscular mycorrhizal (AM) symbiosis by inducing spore germination and hyphal branching in AM fungi (AMF). However, these compounds also trigger the germination of root parasitic weeds, paving the way for deleterious infestation. Availability of SLs is required for investigating of their functions and also for application in agriculture. However, natural SLs are difficult to synthesize due to their complex structure and cannot be isolated at large scale, as they are released at very low concentrations. Therefore, there is a need for synthetic SL analogs. Recently, we reported on the development of simple SL analogs, methyl phenlactonoates (MPs), which show high SL activity in plants. Here, we investigate the effect of MP1, MP3 and the widely used SL-analog GR24 on AMF spore germination and host root colonization. Our results show that MP1 and MP3 inhibit AMF spore germination, but promote the intra-radical root colonization, both more efficiently than GR24. These results indicate that field application of MP1 and MP3 does not have negative impact on mycorrhizal fungi. In conclusion, our data together with the previously reported simple synthesis, high activity in regulating plant architecture and inducing Striga seed germination, demonstrate the utility of MP1 and MP3 as for field application in combating root parasitic weeds by inducing germination in host's absence. PMID- 30519654 TI - Evaluating the replicability of the uncanny valley effect. AB - The uncanny valley (UV) effect refers to an eerie feeling of unfamiliarity people get while observing or interacting with robots that resemble humans almost but not quite perfectly. The effect is not well understood, and it is also unclear how well results from previous research on the UV can be replicated. In six studies, both in the laboratory and online (N = 1343), we attempted to replicate the UV effect with various stimuli used in previous research. In Studies 1 and 2 we failed to replicate the UV effect with CGI stimuli created using the so-called morphing technique (a robot image morphed into a human image, resulting in a supposedly creepy robot-human image). In Studies 3a and 3b we found a prominent UV effect using pre-evaluated, non-morphed and photorealistic robot pictures. Finally, in exploratory Studies 4a and 4b we found the UV effect using morphed and photorealistic human and robot pictures. Our results suggest that the UV effect is more robust when elicited by pre-validated or prima facie uncanny robot pictures than by non-photorealistic images generated using the morphing technique. We argue that photorealistic pictures are more suitable than less realistic CGI pictures as stimuli for research attempting to elicit the UV effect - however, our results do not invalidate any previous research on the UV effect using morphing techniques, but point to their domain of applicability and context sensitivity. PMID- 30519655 TI - An extended Levinson-Durbin algorithm and its application in mixed excitation linear prediction. AB - Ten order all-pole model is used in the 2400 bit/second mixed excitation linear prediction to describe human vocal tract. Traditional Levinson-Durbin algorithm is one of the methods to solve the Yule-Walker equations conducted by the ten order linear prediction model. Taking the iteration step of traditional Levinson Durbin algorithm as 1, an extended algorithm with any positive integer iteration step which is no larger than the order of Teoplitz matrix is proposed. The extended algorithm considers interaction between the adjacent subtracts. A hybrid algorithm of the extended algorithm and traditional algorithm has been applied to solve the 2400 bit/second mixed excitation linear prediction under some conditions. The perceptual evaluation of speech quality mean opinion score of nasal syllable is improved in some degree. PMID- 30519653 TI - State-of-the-art in artificial neural network applications: A survey. AB - This is a survey of neural network applications in the real-world scenario. It provides a taxonomy of artificial neural networks (ANNs) and furnish the reader with knowledge of current and emerging trends in ANN applications research and area of focus for researchers. Additionally, the study presents ANN application challenges, contributions, compare performances and critiques methods. The study covers many applications of ANN techniques in various disciplines which include computing, science, engineering, medicine, environmental, agriculture, mining, technology, climate, business, arts, and nanotechnology, etc. The study assesses ANN contributions, compare performances and critiques methods. The study found that neural-network models such as feedforward and feedback propagation artificial neural networks are performing better in its application to human problems. Therefore, we proposed feedforward and feedback propagation ANN models for research focus based on data analysis factors like accuracy, processing speed, latency, fault tolerance, volume, scalability, convergence, and performance. Moreover, we recommend that instead of applying a single method, future research can focus on combining ANN models into one network-wide application. PMID- 30519656 TI - Isolation of halophilic bacteria associated with saline and alkaline-sodic soils by culture dependent approach. AB - Cultivable halophilic microorganisms were isolated and identified from saline and alkaline-sodic soils: Cuatro Cienegas, Sayula and San Marcos lakes. Physicochemical characteristics of soils were determined to understand the relationship between those and the microorganisms isolated. The Cuatro Cienegas soils had a neutral pH, EC of 2.3-8 dS cm-1, classified as moderately saline. Whereas, the soils from Sayula and San Marcos lakes, had an alkaline pH, EC 15 to 65 dS m-1, typical of saline-sodic. We identified 23 cultivable halophilic bacteria using 16s rDNA, being Halobacillus sp., Marinococcus sp., and Alkalibacillus sp. the predominant genus by culture dependent approach. We found a correlation between the soils anion and cation content with the occurrence of different genus of halophilic bacteria in each studied site. Alkalibacillus sp. was predominant in Sayula and San Marcos lakes and was related to the high Na+ content; while Bacillus sp. and Halobacillus sp. were predominant in Cuatro Cienegas, their occurrence was related to a high content of Ca2+, Mg2+, and SO4 2 . PMID- 30519657 TI - The effectiveness of a Japanese style health program: comparison between Minowa, Japan and Rayong, Thailand. AB - Aim: This study aimed to appropriately establish a Japanese style healthcare program under the ISO9001:2008 (ISO: International Organization for Standardization) in Minowa, Japan and Rayong, Thailand to improve problem areas and inspect its effectiveness. Furthermore, we want to make this health promotion through ISO widely available in Asian countries and to make an international contribution. Method: We implemented a 6-month health program in the c Rayong city, Thailand, and a 12 month health program in the Minowa town, Japan. This study assessed findings from pedometry, anthropometry and blood pressure measurements, physical fitness, blood chemistry, and brain function tests. Results: The comparisons were made using interaction effects between the participants in Rayong and Minowa. They showed significant differences in the 10 m obstacle walk, the 6-minute walk, HDL, the reverse and reverse differentiation time, the total number of forgets, the total number of mistakes, and the total number of brain function errors. Conclusions: To improve the brain function in participants from Rayong through this health education program, measures such as increasing the number of steps, adding muscular strength/stretching exercises, and home training every day is suggested. PMID- 30519658 TI - The influence of teaching methodologies in the assimilation of density concept in primary teacher trainees. AB - Density is one of the most misunderstood concepts amongst the most basic scientific ones, although it is studied even from the earlier academic stages. This is the reason teachers must know its implications as well as possible, including not only the classical definition or what students called "formula" (density is equal to mass divided by volume) but also the concept itself (that is, an intensive matter property). According to this concern, the current research focuses its interest in studying how different teaching methodologies have different outputs in the learning process of pre-service primary teachers. The main aim of this research is to compare the learning results of a control group (n = 84), where mainly oral-based expositions were used as the teaching instrument, with an experimental group (n = 109), where the main educative tool were laboratory activities. The results show statistically significant differences (p < 0.05) between both methodologies and reveal the existence of difficulties in the conceptual and experimental understanding of the concept of density. Although those students that were submitted to hands-on activities presented a significant better comprehension of the density idea, the persistence of misconceptions regarding this scientific relevant concept is also confirmed at university level. PMID- 30519659 TI - Predicting posttraumatic stress and depression symptoms among adolescents in the extended postpartum period. AB - Background: Adolescent childbirth continues as a public health concern, and investigation of postpartum posttraumatic stress symptoms (PTSS) and depression is important to inform future research and practice. Longitudinal studies exploring PTSS alone or in combination with depression are non-existent for postpartum adolescent populations. This study aimed to identify stress/PTSS and depression symptoms at 72 hours and three, six, and nine months postpartum, and determine if symptoms at each time point predicted later symptoms. Methods: A convenience sample of 303 adolescents 13-19 years of age were recruited from two postpartum units of one, large, public hospital. The Impact of Event Scale and the Edinburgh Postpartum Depression Inventory provided a screen of symptoms for stress/PTSS and depression at all time points. A lagged autoregressive model was developed to assess the predictive power of symptoms at each time point to the next across the extended postpartum period. Results: About 30% of adolescents displayed early symptoms; 20% showed symptoms at the final time point. Early symptoms did not predict symptoms at 3 months; yet, symptoms at 3 months predicted symptoms at 6-9 months. Limitations: Attrition at final time points necessitated pooled data. Adolescents were primarily older, Hispanics, and recruited from one public hospital decreasing demographic representation. Use of screening tools prevented diagnostic outcomes. Unknown stressors occurring before and after pregnancy or birth may have influenced final outcomes. Conclusions: Early symptoms were common and 3 month symptoms predicted later symptoms. For at risk adolescents, a plan for follow-up beyond hospital discharge is recommended. PMID- 30519660 TI - WeChat use is significantly correlated with college students' quality of friendships but not with perceived well-being. AB - Although WeChat is currently one of the fastest growing social media in mainland China, many scholars and researchers are yet to systematically investigate the potential social and psychological consequences of the newly emerging online social network. Based on theory and previous studies, the principal purpose of this present study is to probe and understand whether and how the use of WeChat is related to individuals' friendship quality and psychological well-being. Research participants were a total of 508 college students who completed anonymous questionnaires gauging their WeChat usage behaviors, self-disclosure, friendship quality, and well-being. Using structural equation modeling, results demonstrate that the intensity of WeChat use is significantly correlated with college students' quality of friendships but not with perceived well-being. Moreover, the outcomes also reveal that students' friendship quality is a significant predictor of well-being. However, there is no relationship between online self-disclosure and friendship quality or well-being. Overall, these obtained findings of the empirical study could cast a much-needed light on the nuanced understanding of the certain social and technological affordances of WeChat and how it may ultimately impact individual's quality of life in the new media context. PMID- 30519661 TI - Differential expression of MicroRNA let-7e and 296-5p in plasma of Egyptian patients with essential hypertension. AB - Essential hypertension is a chronic medical condition affecting thousands of people worldwide. Hypertension results from interplay of genetic and environmental factors. MicroRNAs regulate gene expression and can be biomarkers for disease. MicroRNA let-7e and microRNA 296-5p have been linked to different cardiovascular diseases. This study aimed to determine association of serum miRNA let-7e and miRNA 296-5p with essential hypertension in Egyptian patients. MicroRNA let-7e and miRNA-296-5p expression was determined in sera of 25 hypertensive patients and 25 normotensive controls by quantitative real-time polymerase chain reaction. Hypertensive patients showed significantly higher expression of miRNA let-7e (3.23-fold increase, p = 0.036) in comparison with normotensive controls. In hypertensive patients, miRNA let-7e expression was positively correlated with increased systolic and diastolic blood pressure. Furthermore, miRNA 296-5p expression was negatively correlated with serum total cholesterol and low-density lipoprotein. Results from this study indicate that miRNA let-7e can potentially be a biomarker for essential hypertension. PMID- 30519662 TI - Influenza vaccination discourse in major Canadian news media, 2017-2018. AB - Influenza vaccine uptake is less-than-ideal in many jurisdictions, including Canada. In this study we sought to assess news articles relating to influenza vaccination by major Canadian newspapers during a six-month period relatively congruent to the seasonal influenza outbreak for 2017-2018. We identified 116 unique articles published between August 16, 2017 and February 15, 2018, then developed and applied a coding frame to them. Influenza vaccination was portrayed primarily positively (74.14%), sometimes negatively (14.66%), and occasionally neutrally (11.21%). Articles were most commonly focused on news about the prevalence, or amount of harm/death caused by, the influenza virus (31.03%), or on public announcements primarily concerning influenza vaccination (17.24%). Benefits of influenza vaccination were often stated (59.48%), most commonly including reduction in disease (47.41%) and protection of vulnerable individuals (26.72%). Issues or problems with influenza vaccination were also often stated (55.17%), most commonly relating to low or non-effectiveness of the vaccine (43.10%). Most articles stated that people should get vaccinated (65.52%). Canadian newspaper articles generally support the scientific consensus that influenza vaccination is a highly positive intervention. Nonetheless, a clear picture of the true value of influenza vaccination may sometimes be missing in articles focusing on low effectiveness and lacking any mention of vaccination's positive value. Overall, we can reasonably conclude that, in Canada, misinformation and antivaccination rhetoric are coming primarily from sources other than newspapers. PMID- 30519664 TI - Fungal metabolite (+)-terrein suppresses IL-6/sIL-6R-induced CSF1 secretion by inhibiting JAK1 phosphorylation in human gingival fibroblasts. AB - Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor 1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL 6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP 2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling. PMID- 30519663 TI - Modeling the output power of heterogeneous photovoltaic panels based on artificial neural networks using low cost microcontrollers. AB - Many implementations of artificial neural networks have been reported in scientific papers. However, few of these implementations allow the direct use of off-line trained networks. Moreover, no implementation reported the use of relatively small network adequate to run on low cost microcontroller. Hence, this work, which presents a small artificial neural network, which models the output power of heterogeneous photovoltaic panel. In addition, the work discuss the hardware implementation that allows such network to run on low cost microcontroller. The hardware implementation has the ability to model heterogeneous photovoltaic panel's output power with very high accuracy and fast response time. Feedforward back propagation has been used because of its high resolution and accurate activation function. Real-time measured parameters can be used as inputs for the developed system. The resulting hardware data is tested with data from real photovoltaic panels; to confirm that it can efficiently implement the models prepared off-line with Matlab. The comparison revealed the robustness of the proposed heterogeneous photovoltaic model system at different conditions. The proposed heterogeneous photovoltaic model system offer a proper and efficient tool that can be used in monitoring photovoltaic panels, such as the ones used in smart-house applications. PMID- 30519665 TI - Critical success factors for mobile health implementation in Indonesia. AB - Purpose: Mobile-based technology health services in Indonesia are experiencing significant growth. However, the implementation of m-health in Indonesia is at a stand-still because the numbers of users or medical personnel who use m-health applications are still low. Given this fact, this study aims to identify critical success factors (CSFs) in the implementation of a mobile health applications in Indonesia. This research covers the following four dimensions: system quality, information quality, service quality, and organizational. Method: This study uses a quantitative research approach with the entropy method to analyze system quality, information quality, and service quality, and it uses a qualitative approach for the organizational dimension. A total of 127 respondents completed the questionnaire (quantitative approach) and interviews were performed with three personnel from the Social Security Agency for Health (BPJS-K) (qualitative approach). Results: The highest weights for each dimension were as follows: ease of access for the system quality dimension; adequate and relevant information for the information quality dimension; user service convenience for the service quality dimension; and top management support for the organizational dimension. Conclusions: Based on the results of this study, the regulator, health facilities management, and mobile health provider should ensure a long-term commitment to support the implementation of mobile health applications. In order to reach a wider market, all mobile health applications should be as user friendly as possible for the patients. PMID- 30519666 TI - Possible sexual dimorphism in Pankowskichthys libanicus (Neopterygii, Pycnodontiformes) from the Cenomanian of Lebanon. AB - Sexual dimorphism is a commonly observed phenomenon in the natural world today but it is far more difficult to determine how common it was in extinct taxa. Here, we describe a new specimen of Pankowskichthys libanicus (Pycnodontiformes, Gladiopycnodontidae) from Haqel, Lebanon (MNHN HAK 1950), which has distinct morphological differences from the holotype of this taxon (IRSNB P9278) which occurs in Hjoula, Lebanon but has also been found at Haqel. Since most of the cranial and pectoral girdle morphologies as well as other postcranial characters are similar to that seen in IRSNB P9278, the distinctive characters seen in MNHN HAK 1950 are unlikely to define a second species but rather represent sexual dimorphic traits. PMID- 30519668 TI - Hypertensive crisis with massive retinal and choroidal infarction: A case update. AB - Purpose: We report an update on a recently published case of uncontrolled hypertension secondary to immunoglobulin A (IgA) nephropathy resulting in massive bilateral retinal and choroidal infarction. Observations: In our previous report, we presented a 30-year old female with end-stage renal disease who complained of painless vision loss after many missed hemodialysis. The patient was found to be in hypertensive crisis resulting in massive retinal and choroidal infarction with severe vision loss in both eyes. The patient was treated with pan-retinal photocoagulation (PRP) with intravitreal Bevacizumab and was subsequently lost to follow-up. In this update, we report the complications that followed. After many months, she presented to clinic with a blind painful right eye. She was found to have a further decrease in vision with neovascular glaucoma in the right eye and a tractional retinal detachment in the left eye. The patient ultimately elected for enucleation of her right eye. Immunohistopathology revealed IgA deposition, confirming the presumed diagnosis of IgA nephropathy, previously unconfirmable through renal biopsy. Conclusions and Importance: There is a strong association between severity of retinopathy and level of kidney function. Although a rare presentation, hypertensive retinopathy is a common complication of end-stage renal disease and can be a devastating process as emphasized by this report. Those with auto-immune renal disease, such as IgA nephropathy, are at higher risk for retino-choroidal complications. It should remind all ophthalmologists and clinicians on the necessity of closer eye examinations for these patients, particularly for those with auto-immune renal disease. PMID- 30519667 TI - Mild heat stress induces hormetic effects in protecting the primary culture of mouse prefrontal cerebrocortical neurons from neuropathological alterations. AB - Hormesis is a dose response phenomenon of cells and organisms to various types of stressors. Mild stress stimulates prosurvival pathways and makes the cells adaptive to stressful conditions. It is a widely used fundamental dose-response phenomenon in many biomedical and toxicological sciences, radiation biology, health science etc. Mild heat stress is an easily applicable hormetic agent that exerts consistent results. In the present investigations mouse cerebrocortical prefrontal neurons from E17 mouse embryos were grown in the laboratory on poly-L lysine coated glass cover slips. The cells from the mild heat stressed group were subjected to a hyperthermic stress of 38 degrees C for 30 min every alternate day (i.e. mild heat stress was repeated after 48 h) up to the sixth day. After completion of twenty four hours of the final i.e. third exposure of the mild heat stress, the neurons were fixed for the cytochemical studies of neurofibrillary tangles, senile plaques, lipofuscin granules and Nissl substance. There was highly significant decrease in the neuropathological alterations (viz. deposition of Neurofibrillary tangles, deposition of senile plaques, accumulation of Lipofuscin granules) in the neurons from the mild heat stressed group as compared to control. Moreover, the Nissl substance was significantly preserved in the mild heat stressed group as compared to control. The results indicate that the applied mild heat stress (38 degrees C for 30 min) exerts beneficial effects on the prefrontal cerebrocortical neurons by slowing down the neuropathological alterations, suggesting the hormetic effect of the mild heat stress. PMID- 30519669 TI - Epithelial ingrowth through venting incision into laser-assisted in situ keratomileusis flap interface after descemet stripping automated endothelial keratoplasty. AB - Purpose: To present a case of epithelial ingrowth into the laser-assisted in situ keratomileusis (LASIK) flap interface after a patient underwent descemet stripping automated endothelial keratoplasty (DSAEK) surgery with venting incisions. Observations: We present a case of a 48-year-old man with previous history of LASIK that underwent DSAEK for pseudophakic bullous keratopathy after complicated cataract surgery requiring an intraocular lens (IOL) exchange. The patient developed epithelial ingrowth into the LASIK flap interface from one of the venting incisions. The epithelial ingrowth was observed as it was a small peripheral area that did not affect his visual acuity. Conclusions and Importance: Epithelial ingrowth is a well-described complication following LASIK but has rarely been described to occur after endothelial keratoplasty (EK). Even rarer, are reports of epithelial ingrowth after EK cases that have been found to result from venting incisions. To the authors' knowledge, this is the first case of the ingrowth into a LASIK flap interface occurring after EK through a venting incision. Although it may be an uncommon occurrence in which a patient with a history of LASIK requires EK, surgeons should take extra precautions to avoid this complication. PMID- 30519670 TI - Profound bilateral post-partum retinal circulation ischemia in two diabetic mothers with pre-eclampsia. AB - Purpose: We report 2 cases of young diabetic mothers with pre-eclampsia and no previously documented visual deficits prior to pregnancy who were found to have profound retinal circulation loss during the postpartum period. Observations: Fluorescein angiogram in both cases documented profound ischemia of retinal and macular circulation with resulting severe vision loss, leading to legal blindness. Conclusions and Importance: While Pre-eclampsia and Eclampsia are well known clinical entities with potentially grave effects on both the mother and child, there is little information about the possible combined effects of diabetes and Pre-eclampsia/Eclampsia on the retinal circulation. We aim to raise awareness about this devastating association with a need for aggressive monitoring and prompt treatment of similar patients to potentially avoid poor visual outcomes. PMID- 30519671 TI - Embryonic Inversion in Volvox carteri: The Flipping and Peeling of Elastic Lips. AB - The embryos of the green alga Volvox carteri are spherical sheets of cells that turn themselves inside out at the close of their development through a programme of cell shape changes. This process of inversion is a model for morphogenetic cell sheet deformations; it starts with four lips opening up at the anterior pole of the cell sheet, flipping over and peeling back to invert the embryo. Experimental studies have revealed that inversion is arrested if some of these cell shape changes are inhibited, but the mechanical basis for these observations has remained unclear. Here, we analyse the mechanics of this inversion by deriving an averaged elastic theory for these lips and we interpret the experimental observations in terms of the mechanics and evolution of inversion. PMID- 30519672 TI - Recombinant Human FSH Treatment Outcomes in Five Boys With Severe Congenital Hypogonadotropic Hypogonadism. AB - Context: Recombinant human FSH (r-hFSH), given to prepubertal boys with hypogonadotropic hypogonadism (HH), may induce Sertoli cell proliferation and thereby increase sperm-producing capacity later in life. Objective: To evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients. Design and Setting: Retrospective review in three tertiary centers in Finland between 2006 and 2016. Patients: Five boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1 mutation in one, and homozygous GNRHR mutation in one. Prepubertal testicular volume (TV) varied between 0.3 and 2.3 mL; three boys had micropenis, three had undergone orchidopexy. Interventions: Two boys received r-hFSH (6 to 7 months) followed by r-hFSH plus hCG (33 to 34 months); one received T (6 months), then r-hFSH plus T (29 months) followed by hCG (25 months); two received T (3 months) followed by r-hFSH (7 months) or r-hFSH plus T (8 months). Main Outcome Measures: TV, inhibin B, anti Mullerian hormone, T, puberty, sperm count. Results: r-hFSH doubled TV (from a mean +/- SD of 0.9 +/- 0.9 mL to 1.9 +/- 1.7 mL; P < 0.05) and increased serum inhibin B (from 15 +/- 5 ng/L to 85 +/- 40 ng/L; P < 0.05). hCG further increased TV (from 2.1 +/- 2.3 mL to 8.6 +/- 1.7 mL). Two boys with initially extremely small testis size (0.3 mL) developed sperm (maximal sperm count range, 2.8 to 13.8 million/mL), which was cryopreserved. Conclusions: Spermatogenesis can be induced with gonadotropins even in boys with HH who have extremely small testes, and despite low-dose T treatment given in early puberty. Induction of puberty with gonadotropins allows preservation of fertility. PMID- 30519673 TI - Severe Familial Hypertriglyceridemia: Successful Treatment With Insulin and a Modified Meal Plan. AB - Context: Mutations in genes encoding the lipoprotein lipase enzyme, its cofactor, or transport proteins can cause severe familial hypertriglyceridemia, resulting in serious complications, such as severe pancreatitis, hepatosplenomegaly, lipid encephalopathy, and failure to thrive. Current treatment includes a low-saturated fat formula enriched with high medium-chain triglyceride (TGs), oral fibrates, omega-3 fatty acids, or plasmapheresis. Case Description: A 71-day-old infant with very severe hypertriglyceridemia and recurrent pancreatitis associated with a likely pathogenic variant in the LPL gene was treated successfully with insulin infusion and a locally prepared low-fat formula feed after stopping breast milk. Subcutaneous insulin was administered daily from 9 to 30 months of age. His serum TG level was markedly lower, although higher than normal. No episodes of hypoglycemia were noted. Fenofibrate and omega-3 fatty acids were ineffective in this infant. At the last follow-up visit, he was 36 months old and growing normally. He was consuming a special meal plan and receiving insulin injections during high-fat meals. Two other young infants with severe hypertriglyceridemia were growing normally after a short course of insulin infusion and the same modified reduced long chain fat diet. Conclusions: Insulin is an unusual and affordable therapeutic option for some patients with severe hypertriglyceridemia and can be helpful in the prevention of acute and chronic complications. Locally available cereals and millets with high crude fiber and a low glycemic index, along with medium chain TGs, was used to prepare an economical special formula at home to maintain TG concentrations in the acceptable limits. PMID- 30519674 TI - RISK EFFECTS OF NEAR-ROADWAY POLLUTANTS AND ASTHMA STATUS ON BRONCHITIC SYMPTOMS IN CHILDREN. AB - Background: Bronchitic symptoms in children pose a significant clinical and public health burden. Exposures to criteria air pollutants affect bronchitic symptoms, especially in children with asthma. Less is known about near-roadway exposures. Methods: Bronchitic symptoms (bronchitis, chronic cough, or phlegm) in the past 12 months were assessed annually with 8 to 9 years of follow-up on 6757 children from the southern California Children's Health Study. Residential exposure to freeway and non-freeway near-roadway air pollution was estimated using a line-source dispersion model. Mixed-effects logistic regression models were used to relate near-roadway air pollutant exposures to bronchitic symptoms among children with and without asthma. Results: Among children with asthma, a two standard deviation increase in non-freeway exposures (odds ratio [OR]: 1.44; 95% confidence interval [CI]: 1.17-1.78) and freeway exposures (OR: 1.31; 95% CI: 1.06-1.60) were significantly associated with increased risk of bronchitic symptoms. Among children without asthma, only non-freeway exposures had a significant association (OR: 1.14; 95% CI: 1.00-1.29). Associations were strongest among children living in communities with lower regional particulate matter. Conclusions: Near-roadway air pollution was associated with bronchitic symptoms, especially among children with asthma and those living in communities with lower regional particulate matter. Better characterization of traffic pollutants from non-freeway roads is needed since many children live in close proximity to this source. PMID- 30519675 TI - Peroxisome biogenesis deficiency attenuates the BDNF-TrkB pathway-mediated development of the cerebellum. AB - Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the central nervous system, including neuronal migration defects and abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. Here, to investigate how peroxisome deficiency causes neurological defects of PBDs, we established a new PBD model mouse defective in peroxisome assembly factor Pex14p, termed Pex14 DeltaC/DeltaC mouse. Pex14 DeltaC/DeltaC mouse manifests a severe symptom such as disorganization of cortical laminar structure and dies shortly after birth, although peroxisomal biogenesis and metabolism are partially defective. The Pex14 DeltaC/DeltaC mouse also shows malformation of the cerebellum including the impaired dendritic development of Purkinje cells. Moreover, extracellular signal-regulated kinase and AKT signaling are attenuated in this mutant mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. Our results suggest that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of the cerebellum in PBDs. PMID- 30519676 TI - Extracellular vesicles from mature dendritic cells (DC) differentiate monocytes into immature DC. AB - During inflammation, murine and human monocytes can develop into dendritic cells (DC), but this process is not entirely understood. Here, we demonstrate that extracellular vesicles (EV) secreted by mature human DC (maDC) differentiate peripheral monocytes into immature DC, expressing a unique marker pattern, including 6-sulfo LacNAc (slan), Zbtb46, CD64, and CD14. While EV from both maDC and immature DC differentiated monocytes similar to GM-CSF/IL-4 stimulation, only maDC-EV produced precursors, which upon maturation stimulus developed into T-cell activating and IL-12p70-secreting maDC. Mechanistically, maDC-EV induced cell signaling through GM-CSF, which was abundant in EV as were IL-4 and other cytokines and chemokines. When injected into the mouse skin, murine maDC-EV attracted immune cells including monocytes that developed activation markers typical for inflammatory cells. Skin-injected EV also reached lymph nodes, causing a similar immune cell infiltration. We conclude that DC-derived EV likely serve to perpetuate an immune reaction and may contribute to chronic inflammation. PMID- 30519677 TI - A carnivorous plant genetic map: pitcher/insect-capture QTL on a genetic linkage map of Sarracenia. AB - The study of carnivorous plants can afford insight into their unique evolutionary adaptations and their interactions with prokaryotic and eukaryotic species. For Sarracenia (pitcher plants), we identified 64 quantitative trait loci (QTL) for insect-capture traits of the pitchers, providing the genetic basis for differences between the pitfall and lobster-trap strategies of insect capture. The linkage map developed here is based upon the F2 of a cross between Sarracenia rosea and Sarracenia psittacina; we mapped 437 single nucleotide polymorphism and simple sequence repeat markers. We measured pitcher traits which differ between S. rosea and S. psittacina, mapping 64 QTL for 17 pitcher traits; there are hot spot locations where multiple QTL map near each other. There are epistatic interactions in many cases where there are multiple loci for a trait. The QTL map uncovered the genetic basis for the differences between pitfall- and lobster traps, and the changes that occurred during the divergence of these species. The longevity and clonability of Sarracenia plants make the F2 mapping population a resource for mapping more traits and for phenotype-to-genotype studies. PMID- 30519678 TI - High-Fidelity Modeling of Detector Lag and Gantry Motion in CT Reconstruction. AB - Detector lag and gantry motion during x-ray exposure and integration both result in azimuthal blurring in CT reconstructions. These effects can degrade image quality both for high-resolution features as well as low-contrast details. In this work we consider a forward model for model-based iterative reconstruction (MBIR) that is sufficiently general to accommodate both of these physical effects. We integrate this forward model in a penalized, weighted, nonlinear least-square style objective function for joint reconstruction and correction of these blur effects. We show that modeling detector lag can reduce/remove the characteristic lag artifacts in head imaging in both a simulation study and physical experiments. Similarly, we show that azimuthal blur ordinarily introduced by gantry motion can be mitigated with proper reconstruction models. In particular, we find the largest image quality improvement at the periphery of the field-of-view where gantry motion artifacts are most pronounced. These experiments illustrate the generality of the underlying forward model, suggesting the potential application in modeling a number of physical effects that are traditionally ignored or mitigated through pre-corrections to measurement data. PMID- 30519679 TI - Efficient Clustering-based Noise Covariance Estimation for Maximum Noise Fraction. AB - Most hyperspectral images (HSI) have important spectral features in specific combination of wave numbers or channels. Noise in these specific channels or bands can easily overwhelm these relevant spectral features. Maximum Noise Fraction (MNF) by Green et al. [1] has been extensively studied for noise removal in HSI data. The MNF transform maximizes the Signal to Noise Ratio (SNR) in feature space, thereby explicitly requiring an estimation of the HSI noise. We present two simple and efficient Noise Covariance Matrix (NCM) estimation methods as required for the MNF transform. Our NCM estimations improve the performance of HSI classification, even when ground objects are mixed. Both techniques rely on a superpixel based clustering of HSI data in the spatial domain. The novelty of our NCM's comes from their reduced sensitivity to HSI noise distributions and interference patterns. Experiments with both simulated and real HSI data show that our methods significantly outperforms the NCM estimation in the classical MNF transform, as well as against more recent state of the art NCM estimation methods. We quantify this improvement in terms of HSI classification accuracy and superior recovery of spectral features. PMID- 30519680 TI - A single light spot GC detector employing localized surface plasmon resonance of porous Au@SiO2 nanoparticle multilayer. AB - This paper describes the synthesis of a nano-porous multilayered film consisting of Au@SiO2 nanoparticles. This film was used to miniaturize the size of a localized surface plasmon resonance (LSPR)-based capillary gas chromatograph (GC) detector. A layer-by-layer (LbL) approach with proper surface reaction sequences was used to create a multilayer structure that consisted of as many as five layers of Au@SiO2 nanoparticles. The center wavelength of LSPR was shifted from 520 to 634 nm due to the approximation of additional layers of nanoparticles. The vapor response time for this Au@SiO2 multilayer LSPR sensor was identical to that of an Au nanoparticle monolayer, which confirmed that this multilayer structure has a high level of gas permeability. The multilayer was synthesized inside a glass capillary for use as a GC detector. Due to the enhancement of absorbance, the gas chromatographic signal was obtained via a single spotlight that penetrated one side of the glass capillary and was then reflected by a silver mirror coated on the opposite side. The detection limits were <=20 ng for cyclohexanone and m-xylene. PMID- 30519681 TI - Polypeptide-affined interpenetrating hydrogels with tunable physical and mechanical properties. AB - Novel hydrogels with tunable mechanical properties similar to human soft tissue have increasing applications in biomedicine, soft robotics, and biocompatible electronics. However, most of these materials require multiple-step fabrication, are not robust, and compromise bioactivity. Thus, aiming to address these shortfalls, herein, we report a versatile hydrogel system with tunable properties and a facile one-pot fabrication process. The hydrogel system is comprised of a hydrogen-bonded hydrophilic polyurethane (HPU) network and a loosely crosslinked copolymer crosslinked with long chain crosslinkers and decorated with succinimide groups. The active succinimide sites conjugate to proteins, such as bovine serum albumin as a model protein, providing additional biocompatibility and controlled release of growth factors and peptides. The interpenetrating nature of this hydrogel system provides a high degree of freedom over mechanical and physical properties by adjusting the ratio of networks and the composition of the second network. Through this process, a library of biocompatible hydrogels with stiffness ranging from 1 to more than 200 kPa was developed. Moreover, it was found that the succinimide groups impact the degree of crosslinking and contribute to the controlled release of peptides. PMID- 30519682 TI - 2D planar penta-MN2 (M = Pd, Pt) sheets identified through structure search. AB - Two-dimensional (2D) metal dinitrides have attracted increasing attention because of their diverse geometry configurations and extraordinary properties. Using the particle swarm optimization (PSO)-based global structure search method combined with first principles calculations, we have identified 2D metal dinitride MN2 (M = Pd, Pt) sheets containing N2 dimers, penta-MN2, which are planar and composed entirely of pentagons. These pentagonal sheets are not only dynamically, thermally and mechanically stable, but also energetically more favorable over the experimentally synthesized pyrite MN2 monolayers. In particular, penta-PtN2 can withstand a temperature as high as 2000 K, showing its potential as a refractory material. In addition, due to its unique atomic configuration, penta-MN2 exhibits intriguing electronic properties. Penta-PdN2 is metallic, while penta-PtN2 is semiconducting with a direct band gap of 75 meV and an ultrahigh carrier mobility. This study expands the family of 2D metal nitrides, and provides new insight into finding new materials using a reliable structure search algorithm rather than chemical and physical intuition. PMID- 30519683 TI - Observation of electrochemically active Fe3+/Fe4+ in LiCo0.8Fe0.2MnO4 by in situ Mossbauer spectroscopy and X-ray absorption spectroscopy. AB - LiCo0.8Fe0.2MnO4 has been investigated as an active material for the positive electrode in lithium-ion batteries (LIBs) with a discharge potential of around 5 V (vs. Li+|Li). After synthesis by a Pechini based sol-gel route, the structural and morphological properties have been investigated by X-ray diffraction, scanning electron microscopy, 7Li MAS NMR spectroscopy, and 57Fe Mossbauer spectroscopy. With galvanostatic cycling, it was possible to obtain a specific discharge capacity of 117 mA h g-1, which is more than 80% of the theoretical capacity. The lithium extraction/insertion mechanism has been characterized by in situ synchrotron powder diffraction. The reversible oxidation process of Fe3+ to Fe4+ has been observed by in situ Mossbauer spectroscopy and in situ XAS measurements. PMID- 30519684 TI - Thermo-orientation in fluids of arbitrarily shaped particles. AB - Recent nonequilibrium Molecular Dynamics (NEMD) simulations revealed preferential orientation, induced by a temperature gradient, in fluids of uncharged dumbbell like particles. The magnitude of this phenomenon, called thermo-orientation, was found to be linear in the applied temperature gradient and to increase with the difference in shape or mass between the two beads of the particles. The underlying mechanism and the microscopic determinants of the phenomenon are not obvious. Here, after examination of the general symmetry requirements for thermo orientation, we have extended the NEMD simulations to uncharged particles of various shapes and mass distribution, including chiral cases. The numerical results are rationalized by a microscopic model, based on the assumption of local equilibrium. This allows us to correlate the thermo-orientation response of arbitrarily shaped particles to quantities that characterize their shape and mass distribution. PMID- 30519685 TI - The nature of interactions of benzene with CF3I and CF3CH2I. AB - In situ grown crystals of CF3I and CF3CH2I are dominated by II and FF interactions. Their co-crystals with benzene, (CF3I)2.C6H6 and CF3CH2I.C6H6, contain two completely different sets of intermolecular interactions. (CF3I)2.C6H6 shows a unique halogen-bond type: above-the-bond C-IpiC6H6 interactions. CF3CH2I.C6H6 shows above-the-centre C-HpiC6H6 interactions. These interactions are electrostatically dominated type II halogen bonds between single halogenoalkane molecules and weaker dispersion dominated interactions between the co-crystal components. The observed preferences for benzene for the two binding partners match with calculated molecular electrostatic potentials. PMID- 30519686 TI - Rapid identification of specific DNA aptamers precisely targeting CD33 positive leukemia cells through a paired cell-based approach. AB - Aptamers are short single-stranded DNA or RNA molecules, which have recently been developed for potential broad applications such as clinical therapeutics, diagnosis and tumor-targeted drug delivery. However, the selection of specific aptamers is often unsatisfactory using the classical protein or cell-based SELEX. Herein, we modified the paired cell line approach to identify aptamers targeting leukemia cells expressing the CD33 antigen. Our strategy artfully used the same cells for negative (HEK293T cells) and positive (CD33 transfected-HEK293T cells) aptamer selections, and the negative selections were performed adequately before the positive selection to remove unspecific sequences. The advantages of this strategy are that it is fast and accurate, where only a few rounds of selection together with PCR amplifications are sufficient to obtain high binding affinity antigen-targeted aptamers. By using our modified approach, we successfully obtained the CD33-targeting aptamer S30, which could highly recognize the C2 domain of the CD33 antigen in vitro and in vivo. Moreover, the optimized aptamer S30-T1 (i.e., core region of S30) was conjugated with doxorubicin (Dox) to synthesize S30-T1-Dox conjugates, which could specifically inhibit CD33 positive acute myeloid leukemia HL-60 cell proliferation by arresting the cell cycle at the G2 phase. Thus, our modified approach can rapidly screen reliable, stable and high binding affinity aptamers for precise cancer treatment. PMID- 30519687 TI - Interplay of orbital hopping and perpendicular magnetic field in anisotropic phase transitions for Bernal bilayer graphene and hexagonal boron-nitride. AB - We theoretically address the perpendicular magnetic field effects on the electronic phase of Bernal bilayer graphene and hexagonal boron-nitride (h-BN) taking into account the total and orbital-projected electronic bands using the tight-binding parameters in the Harrison model, followed by the Green's function method. First, we confirm that our model is computationally efficient and accurate for calculating the magneto-orbital electronic phase transition by reproducing the semimetallic and insulating treatments of pristine Bernal bilayer graphene and h-BN, respectively. In our model, the magnetic field couples only to the electron spin degrees of freedom (with the same contributions for spin-up and spin-down) due to the low dimension of the systems. Here, the main features of the phase transitions are characterized by the electronic density of states (DOS). We found that sp2-hybridization is destroyed when the systems are immersed in the magnetic field, leading to a phase transition to metal for both systems at strong magnetic fields. While there is no phase transition for bilayer graphene at weak magnetic fields, for the case of bilayer h-BN, an insulator to semiconductor phase transition can be viewed, making h-BN more applicable in industry. In bilayer graphene, the anisotropic phase transition appears as insulator-semiconductor, insulator-metal, and semimetal-metal for s-, {px + py}-, and pz-orbitals, respectively, whereas in the case of bilayer h-BN, one observes the same transitions for {s,pz}-orbitals but insulator-semiconductor for {px + py} orbitals. Generically, our findings highlight that the applied magnetic field manipulates the band structure of bilayer graphene and h-BN, and gives ideas to experimentalists for tuning the electro-optical properties of these materials. PMID- 30519688 TI - Synthesis and biochemical characterization of quasi-stable trimer models of full length amyloid beta40 with a toxic conformation. AB - Here, we report the first synthesis of quasi-stable trimer models of full-length Abeta40 with a toxic conformation using a 1,3,5-phenyltris-l-alanyl linker at position 34, 36, or 38. The only trimer to exhibit weak neurotoxicity against SH SY5Y cells was the one which was linked at position 38. This suggests that such a propeller-type trimer model is not prone to forming oligomers with potent neurotoxicity, which is in contrast with its corresponding dimer model. PMID- 30519689 TI - Versatile approach to activation of alkoxyamine homolysis by 1,3-dipolar cycloaddition for efficient and safe nitroxide mediated polymerization. AB - An alkoxyamine was prepared from a cyclic aldonitrone nitroxide. The resulting alkoxyamine containing an aldonitrone functional substituent is relatively stable but can react readily with vinyl monomers to form a cycloadduct that has a much higher C-ON homolysis rate. This type of in situ activation converts the aldonitrone alkoxyamine into an efficient controlling agent for nitroxide mediated polymerization. Here we present a study on this reaction of C-ON bond homolysis and application of such an alkoxyamine as an in situ-activated initiator. PMID- 30519690 TI - Special features of monolayer characteristics of N-alkanoyl substituted threonine amphiphiles. AB - The monolayers of N-alkanoyl substituted threonine amphiphiles, similar to those of other N-alkanoyl-substituted amino acid amphiphiles, point to substantial differences in the main characteristics compared to usual amphiphilic monolayers. pi-A measurements of the enantiomeric and racemic forms of N-alkanoyl-substituted threonine monolayers with C16 and C18 chain lengths reveal that, independent of the alkyl chain length, all compression curves are located above the corresponding decompression curves. A theoretical model developed for the kinetics of two-dimensional condensation of Langmuir monolayers can describe this behavior concluding the attachment of monomers to large aggregates. The linear fit of the entropy changes versus temperature (DeltaS = f(T)) at the LE/LC phase transition and extrapolation to zero DeltaS specifies the critical temperature Tc, above which the monolayer cannot be compressed into the condensed state. The relatively small DeltaTc difference between the enantiomeric and the racemic forms is consistent with the increased strength of van der Waals interactions between the longer alkyl chains reducing the influence of chirality on the thermodynamic parameters. The BAM experiments reveal clearly the absence of inner anisotropy as a specific feature of the domain topology of N-palmitoyl-threonine monolayers. Furthermore, the growth kinetics of the racemic N-palmitoyl-dl threonine domains reveals a transition from homochiral discrimination and chiral separation within the domain to a state with heterochiral preference. GIXD studies show that at all pressures the enantiomers exhibit three Bragg peaks indicating an oblique lattice structure, whereas the racemates show only two Bragg peaks indicating a NNN tilted orthorhombic structure. Characteristic for the structure of all condensed monolayer phases is the large tilt angle of ~49 degrees , nearly independent of the lateral pressure. The transition from the oblique lattice structures, as detected for enantiomeric monolayers, to orthorhombic structures of racemic monolayers is clear evidence that the dominant heterochiral interaction in the racemic mixtures leads to the formation of a compound with congruent transition pressure having with ~20.0 A2 an essentially smaller alkyl chain cross-sectional area than the enantiomers with ~20.7 A2. PMID- 30519691 TI - High-performance solar-blind SnO2 nanowire photodetectors assembled using optical tweezers. AB - One-dimensional semiconducting SnO2 nanowires with wide bandgaps are promising candidates to build many important optoelectronic devices. Because building these devices involves the assembly of nanowires into complex structures, manipulation of the active materials needs to be done with high spatial precision. In this paper, an optical tweezer system, comprising a spatial light-modulator, a microscope, and optical elements, is used to individually trap, transfer, and assemble SnO2 nanowires into two-terminal photodetectors in a liquid environment. After the assembly using optical trapping, the two ends of the SnO2 nanowire photodetectors, which are connected with the electrodes, were further stabilized using a focused laser. During exposure to 275 nm deep-ultraviolet light, the as assembled photodetectors show a high Iph/Idark ratio of 2.99 * 105, a large responsivity of 4.3 * 104 A W-1, an excellent external quantum efficiency of 1.94 * 105, and a high detectivity of 2.32 * 1013 Jones. The photoresponse-speed of the devices could be improved further using passivation with a polymer. The rise and decay times are about 60 ms and 100 ms, respectively. As a result of this study, we can confirm that non-contact optical trapping can enable the construction of nanowire architectures for optoelectronic, bioelectronic, and other devices. PMID- 30519692 TI - The viscoelastic signature underpinning polymer deformation under shear flow. AB - Entangled polymers are deformed by a strong shear flow. The shape of the polymer, called the form factor, is measured by small angle neutron scattering. However, the real-space molecular structure is not directly available from the reciprocal space data, due to the phase problem. Instead, the data has to be fitted with a theoretical model of the molecule. We approximate the unknown structure using piecewise straight segments, from which we derive an analytical form factor. We fit it to our data on a semi-dilute entangled polystyrene solution under in situ shear flow. The character of the deformation is shown to lie between that of a single ideal chain (viscous) and a cross-linked network (elastic rubber). Furthermore, we use the fitted structure to estimate the mechanical stress, and find a fairly good agreement with rheology literature. PMID- 30519693 TI - Uncertainty quantification of a DNA origami mechanism using a coarse-grained model and kinematic variance analysis. AB - Significant advances have been made towards the design, fabrication, and actuation of dynamic DNA nanorobots including the development of DNA origami mechanisms. These DNA origami mechanisms integrate relatively stiff links made of bundles of double-stranded DNA and relatively flexible joints made of single stranded DNA to mimic the design of macroscopic machines and robots. Despite reproducing the complex configurations of macroscopic machines, these DNA origami mechanisms exhibit significant deviations from their intended motion behavior since nanoscale mechanisms are subject to significant thermal fluctuations that lead to variations in the geometry of the underlying DNA origami components. Understanding these fluctuations is critical to assess and improve the performance of DNA origami mechanisms and to enable precise nanoscale robotic functions. Here, we report a hybrid computational framework combining coarse grained modeling with kinematic variance analysis to predict uncertainties in the motion pathway of a multi-component DNA origami mechanism. Coarse-grained modeling was used to evaluate the variation in geometry of individual components due to thermal fluctuations. This variation was incorporated in kinematic analyses to predict the motion pathway uncertainty of the entire mechanism, which agreed well with experimental characterization of motion. We further demonstrated the ability to predict the probability density of DNA origami mechanism conformations based on analysis of mechanical properties of individual joints. This integration of computational analysis, modeling tools, and experimental methods establish the foundation to predict and manage motion uncertainties of general DNA origami mechanisms to guide the design of DNA-based nanoscale machines and robots. PMID- 30519694 TI - Probing shear-induced rearrangements in Fourier space. I. Dynamic light scattering. AB - Understanding the microscopic origin of the rheological behavior of soft matter is a long-lasting endeavour. While early efforts concentrated mainly on the relationship between rheology and structure, current research focuses on the role of microscopic dynamics. We present in two companion papers a thorough discussion of how Fourier space-based methods may be coupled to rheology to shed light on the relationship between the microscopic dynamics and the mechanical response of soft systems. In this first companion paper, we report a theoretical, numerical and experimental investigation of dynamic light scattering coupled to rheology. While in ideal solids and simple viscous fluids the displacement field under a shear deformation is purely affine, additional non-affine displacements arise in many situations of great interest, for example in elastically heterogeneous materials or due to plastic rearrangements. We show how affine and non-affine displacements can be separately resolved by dynamic light scattering, and discuss in detail the effect of several non-idealities in typical experiments. PMID- 30519695 TI - Resolving X-ray photoelectron spectra of ionic liquids with difference spectroscopy. AB - X-ray photoelectron spectroscopy (XPS) is a powerful element-specific technique to determine the composition and chemical state of all elements in an involatile sample. However, for elements such as carbon, the wide variety of chemical states produce complex spectra that are difficult to interpret, consequently concealing important information due to the uncertainty in signal identity. Here we report a process whereby chemical modification of carbon structures with electron withdrawing groups can reveal this information, providing accurate, highly refined fitting models far more complex than previously possible. This method is demonstrated with functionalised ionic liquids bearing chlorine or trifluoromethane groups that shift electron density from targeted locations. By comparing the C 1s spectra of non-functional ionic liquids to their functional analogues, a series of difference spectra can be produced to identify exact binding energies of carbon photoemissions, which can be used to improve the C 1s peak fitting of both samples. Importantly, ionic liquids possess ideal chemical and physical properties, which enhance this methodology to enable significant progress in XPS peak fitting and data interpretation. PMID- 30519696 TI - Introduction of Fe2+ in Fe0.8Ti1.2O40.8- nanosheets via photo reduction and their enhanced electrochemical performance as a lithium ion battery anode. AB - Fe2+ doped Fe0.8Ti1.2O40.8- nanosheets were firstly utilized as a lithium ion battery anode. The Fe2+ was introduced into the Fe0.8Ti1.2O40.8- nanosheets using a photoreduction method. The introduction of Fe2+ enhanced the electrical conductivity of the material, as well as the specific capacity. PMID- 30519697 TI - Aromaticity, Coulomb repulsion, pi delocalization or strain: who is who in endohedral metallofullerene stability? AB - Endohedral metallofullerenes (EMFs) synthetized in the laboratory are known to often violate the isolated pentagon and pentagon adjacency penalty rules that successfully describe the relative stability of pristine fullerene isomers. To explain these anomalies, several models have been proposed. In this work, we have systematically investigated the performance of the widely used IPSI (inverse pentagon separation index), ALA (additive local aromaticity) and CSI (charge stabilization index) models in predicting the relative stability of a large number of EMF isomers with cages ranging from C28 to C104 and charge states of 4- and 6-. By explicitly comparing with existing experiments and quantum chemistry calculations, we show that the predictive power of the ALA and CSI models is similarly good, with CSI being slightly superior though computationally much less involved. IPSI's performance is generally worse though still acceptable in a wide range of cage sizes, except for the higher charge states in the C62 to C82 size interval. From our analysis, we conclude that neither Coulomb electronic repulsion (IPSI) nor aromaticity (ALA) are the sole parameters governing the relative stability of EMF isomers. Electron delocalization in the pi shell in combination with minimum strain (CSI) provides a more realistic description of the relative stabilities observed experimentally, as the former can compensate an unfavorable Coulomb repulsion and account for stabilizing binding effects that do not necessarily translate into aromaticity. PMID- 30519698 TI - Mutual energy transfer luminescent properties in novel CsGd(MoO4)2:Yb3+,Er3+/Ho3+ phosphors for solid-state lighting and solar cells. AB - In this work, we prepared a novel kind of Yb3+,Er3+/Ho3+ co-doped CsGd(MoO4)2 phosphors with a different structure from the reported ALn(MoO4)2 (A = Li, Na or K; Ln = La, Gd or Y) compounds using a high-temperature solid-state reaction method. X-ray diffraction showed that the as-prepared samples had a pure phase. Based on the efficient energy transfer from Yb3+ to Er3+/Ho3+, the up-conversion (UC) luminescence of the optimal CsGd(MoO4)2:0.30Yb3+,0.02Er3+ sample showed intensely green light with dominant emission peaks at 528 and 550 nm corresponding to Er3+ transitions 2H11/2 -> 4I15/2 and 4S3/2 -> 4I15/2, respectively, as well as a weak emission peak originating from 4F9/2 -> 4I15/2 at 671 nm, under 975 nm laser excitation. The CsGd(MoO4)2:Yb3+,Ho3+ samples mainly displayed two emission bands around 540 and 660 nm together with a negligible one at 755 nm, which corresponded to Ho3+ transitions 4F4,5F2 -> 5I8, 5F5 -> 5I8 and 4F4,5F2 -> 5I7, respectively, under 975 nm laser excitation. With increasing Yb3+ concentration in CsGd(MoO4)2:Yb3+,Ho3+ phosphors, the emission color could be tuned from orange red to light yellow due to the large energy gap between levels 4F4,5F2 and 5F5. In addition, the CsGd(MoO4)2:Yb3+,Er3+ showed green light under 376 nm UV irradiation similar to that upon 975 nm laser excitation. However, the emissions for CsGd(MoO4)2:Yb3+,Ho3+ samples under 358 nm UV or 449 nm blue excitation showed dominant emission peaks at 540 nm and weak 660 nm and 752 nm peaks, which were a bit different from those under 975 nm excitation. Interestingly, we observed efficient energy transfer phenomena (possible quantum cutting) from Er3+/Ho3+ to Yb3+ and a Yb3+-O2- charge transfer (CT) transition in the molybdates, which was deduced from the visible and near-infrared emission spectra and the decrease of the Er3+/Ho3+ luminescent lifetimes with increasing Yb3+ concentration in the CsGd(MoO4)2:Yb3+,Er3+/Ho3+ samples. The luminescence properties of these phosphors suggest their potential possibility for applications in solid-state lighting and displays as well as in c-Si solar energy conversion systems. PMID- 30519699 TI - External temperature control of lymphatic drainage of thermo-sensitive nanomaterials. AB - Nano-carrier-facilitated delivery of bioactive molecules into lymph nodes (LNs) has found application in the treatment and diagnosis of numerous immune-related diseases. Much work has focused on optimization of physicochemical properties of the nano-carrier to enhance lymphatic drainage passively, whereas active modulation of the quantity and timing of lymphatic delivery remains a significant challenge. Here, inspired by the success of thermo-modulation of tumor targeting, we have developed a simple external temperature control strategy to regulate the distribution of thermo-sensitive nanomaterials between the injection site and draining LNs. To demonstrate feasibility of this strategy, we injected Rhodamine B-labeled poly(N-isopropylacrylamide) (RhB-PNIPAm) (2.5 kDa) into the footpad of mice at different initial temperatures - either below or above the lower critical solution temperature (LCST), followed by physical cooling of the injection site. We show that RhB-PNIPAm drained efficiently into the popliteal and inguinal nodes (pLNs, iLNs, respectively) with low levels of accumulation in major internal organs. Within the first two hours post-injection the rate of drainage was primarily dependent on the initial temperature of RhB-PNIPAm. However, over the course of 24 h, temperature gradient due to local cooling affected significantly the draining of the injection site, resulting in differential accumulation of RhB PNIPAm in the proximal (pLNs) versus the distal (iLNs) nodes. This study provides a new methodology and insights for modulating in vivo lymphatic distribution of thermo-sensitive nanomaterials with implications in immune regulation and immunotherapy. PMID- 30519700 TI - Spin glass like transition and the exchange bias effect in Co3O4 nanoparticles anchored onto graphene sheets. AB - We have synthesized Co3O4 nanoparticles having 40 nm average size, which are anchored on reduced graphene oxide. X-ray diffraction, FESEM, TEM and Raman spectroscopy are performed for the characterization. The temperature dependence of field cooled (FC) and zero field cooled (ZFC) magnetization curves exhibits antiferromagnetic (AFM) transition around ~30 K, as observed for bulk Co3O4. The exchange bias effect is observed below ~30 K. A significant change in the exchange bias effect is noted around ~8 K, which is close to a spin-glass-like transition. The spin-glass-like phase has been confirmed by the memory effects observed by different experimental protocols. The possible origin of exchange bias is discussed in the manuscript. PMID- 30519701 TI - Tailoring Fano lineshapes using plasmonic nanobars for highly sensitive sensing and directional emission. AB - Plasmonic oligomers are one class of the most promising nanoclusters for generating Fano resonances. This study reveals that a nanobar-based heptamer concurrently sustains triple polarization-dependent Fano resonances, in sharp contrast to traditional nanodisk or nanosphere-based counterparts. Benefiting from the enhanced near field and reduced spectral linewidth, the gold heptamer exhibits a high refractive index sensitivity (940 nm per RIU) together with a figure of merit (FoM) value as large as 20.9, which outperforms that of most other gold oligomers. On the other hand, it is found that the spectral positions of hybridized eigenmodes depend strongly on the spatial configurations of the constituent nanobars. As a proof of concept, we design a simple heterodimer comprising a nanocross and a nanobar, where plasmonic modes with opposite radiative decay characteristics are excellently overlapped both spectrally and spatially by elaborate tailoring. Double strong Fano resonances appear on opposite sides of the spectrum as expected. More interestingly, the radiation main lobes all point to one direction at these two Fano resonances due to the spatial charge distributions and mode interferences with the maximal directivity ratio (DR) as high as 22.4, in a similar manner to the radio frequency (RF) Yagi Uda antenna. Furthermore, the emission directions can also be easily switched by adjusting the orientations of the individual nanobar in the heterodimer. Our study demonstrates that the nanobar-based oligomers with tailored Fano lineshapes could serve as versatile and delicate platforms for the label-free biochemical sensing and directional transmission of optical information at the nanometre scale. PMID- 30519702 TI - A spin crossover porous hybrid architecture for potential sensing applications. AB - Spin crossover cations have been successfully synthesized in the pores of a mesoporous robust Metal-Organic Framework (MOF) MIL-100(Al) through sequential introduction of Fe(iii) cations and a sal2trien ligand. The MIL 100(Al)@Fe(sal2trien) hybrid material retains its crystallinity and partial porosity compared to the parent MOF. The spin state of the Fe(sal2trien)+ cations can be modulated at room temperature through sorption of guest molecules, paving the way to the design of a new generation of sensors based on MOF@spin crossover complex solids. PMID- 30519703 TI - High-performance stretchable conductive nanocomposites: materials, processes, and device applications. AB - Highly conductive and intrinsically stretchable electrodes are vital components of soft electronics such as stretchable transistors and circuits, sensors and actuators, light-emitting diode arrays, and energy harvesting devices. Many kinds of conducting nanomaterials with outstanding electrical and mechanical properties have been integrated with elastomers to produce stretchable conductive nanocomposites. Understanding the characteristics of these nanocomposites and assessing the feasibility of their fabrication are therefore critical for the development of high-performance stretchable conductors and electronic devices. We herein summarise the recent advances in stretchable conductors based on the percolation networks of nanoscale conductive fillers in elastomeric media. After discussing the material-, dimension-, and size-dependent properties of conductive fillers and their implications, we highlight various techniques that are used to reduce the contact resistance between the conductive filler materials. Furthermore, we categorize elastomer matrices with different stretchabilities and mechanical properties based on their polymeric chain structures. Then, we discuss the fabrication techniques of stretchable conductive nanocomposites toward their use in soft electronics. Finally, we provide representative examples of stretchable device applications and conclude the review with a brief outlook for future research. PMID- 30519704 TI - Effectiveness of a no-cost-to-workers, slip-resistant footwear program for reducing slipping-related injuries in food service workers: a cluster randomized trial. AB - Objective This study evaluated the effectiveness of a no-cost-to-workers, slip resistant footwear (SRF) program in preventing workers' compensation injury claims caused by slipping on wet or greasy floors. Methods The study population was a dynamic cohort of food service workers from 226 school districts' kindergarten through 12th grade food service operations. A two-arm cluster randomized controlled study design was implemented, with school districts randomized to the intervention group receiving SRF. Data were analyzed according to the intent-to-treat principle. Logistic regression was used to analyze dichotomous response data (injured based on workers' compensation injury claims data, or not injured, for each month worked). Changes in slipping injury rates from baseline to post-intervention follow-up periods were compared between treatment groups. Results The probability of a slipping injury was reduced significantly in the intervention group, from a baseline measure of 3.54 slipping injuries per 10 000 worker-months to 1.18 slipping injuries per 10 000 worker months in the follow-up period [adjusted odds ratio (OR adj) 0.33, 95% confidence interval (CI) 0.17-0.63]. In the control group, slipping injuries were 2.01 per 10 000 worker-months in the baseline, and 2.30 per 10 000 worker-months in the follow-up. The interaction between treatment group and time period (baseline or follow-up) indicated that the decline seen in the intervention group was significantly different than the increase seen in the control group (OR adj0.29, 95% CI 0.11-0.74, adjusted for age >55 years). Conclusions This study provides evidence for the effectiveness of a no-cost-to-workers SRF program in reducing slipping-related workers' compensation injury claims in food service workers. PMID- 30519705 TI - Predictors of dropout in interdisciplinary chronic pain management programmes: A systematic review. AB - OBJECTIVE: Systematic review to identify predictors for dropout during interdisciplinary pain management programmes. DATA SOURCES: PubMed, PsycINFO, CINAHL, Embase, and SPORTDiscus were searched from inception to 22 June 2017. STUDY SELECTION: Screening, data-extraction and quality assessment was carried out independently by 2 researchers. DATA SYNTHESIS: Eight studies with low methodological quality were included in this review. Out of 63 potential predictors identified in univariate analyses, significant results were found for 18 predictors of dropout in multiple logistic regression analyses in 4 domains, as described by Meichenbaum and Turk: (i) sociodemographic domain (2); (ii) patient domain (8); (iii) disease domain (6); and (iv) treatment domain (2). CONCLUSION: This systematic review presents an overview of predictors of dropout. The literature with regard to the prediction of dropout has focused mainly on patient characteristics and is still in the stage of model development. Future research should focus on therapist/therapy-related predictors and the interaction between these predictors. This review suggests future research on this topic, in order to generate better outcomes in interdisciplinary pain management programmes. PMID- 30519706 TI - Decreased platelet-to-lymphocyte ratio as predictor of thrombogenesis in nonvalvular atrial fibrillation. AB - BACKGROUND: Inflammation plays a key role in the progression of atrial fibrillation and its related prothrombotic state. The platelet-to-lymphocyte ratio (PLR) is an easily obtainable biomarker of inflammatory burden. Decreased left atrial appendage flow velocity (LAA-FV) reflects blood stasis, and left atrial strain is a manifestation of atrial remodeling. This study examined the role of PLR in reflecting decreased LAA-FV and its correlation with impaired left atrial strain. METHODS: In 54 patients with nonvalvular atrial fibrillation, LAA FV and left atrial strain were measured by echocardiography. The PLR was calculated from a complete blood count. RESULTS: The PLR was lower in the group of patients with decreased LAA-FV (84.22 [IQR, 69.87-98.17 cm/s] vs. 103.27 [IQR, 90.37-127.16 cm/s]; p = 0.018). PLR was predictive of decreased LAA-FV with a sensitivity of 66.7% and a specificity of 83.3%. In a receiver operator characteristic curve analysis, using a cut-off value of 88.16, the area under the curve for PLR as a predictor of decreased LAA-FV was 0.726 (p = 0.018). Furthermore, the patients with a PLR of < 88.16 had a lower left atrial strain than those with a PLR of > 88.16 (0.38 vs. 0.77, p = 0.02). CONCLUSION: The PLR was lower in patients with nonvalvular atrial fibrillation and with a decreased LAA-FV. Its correlation with left atrial strain might indicate the role of inflammation in the progression of atrial remodeling and in the prothrombotic state. PMID- 30519707 TI - Inhibition by general anesthetic propofol of compound action potentials in the frog sciatic nerve and its chemical structure. AB - Although the intravenous general anesthetic propofol (2,6-diisopropylphenol) has an ability to inhibit nerve conduction, this has not been fully examined. Various agents inhibit compound action potentials (CAPs) in a manner dependent on their chemical structures. To determine propofol's chemical structure that is important in nerve conduction inhibition, we examined the effects of propofol and its related compounds on fast-conducting CAPs recorded from the frog sciatic nerve by using the air-gap method. Propofol concentration-dependently reduced the peak amplitude of the CAP with a half-maximal inhibitory concentration (IC50) value of 0.14 mM. A similar inhibition was produced by other phenols, 4-sec-butylphenol and 4-amylphenol (IC50 values: 0.33 and 0.20 mM, respectively). IC50 values for these and more phenols (4-isopropylphenol, 4-tert-butylphenol, and 4-ter amylphenol; data published previously) were correlated with the logarithm of their octanol-water partition coefficients. A phenol having ketone group (raspberry ketone) and alcohols (3-phenyl-1-propanol and 2-phenylethylalcohol) inhibited CAPs less effectively than the above-mentioned phenols. The local anesthetic (LA) benzocaine reduced CAP peak amplitudes with an IC50 of 0.80 mM, a value larger than that of propofol. When compared with other LAs, propofol activity was close to those of ropivacaine, levobupivacaine, and pramoxine, while benzocaine activity was similar to those of cocaine and lidocaine. It is concluded that propofol inhibits nerve conduction, possibly owing to isopropyl and hydroxyl groups bound to the benzene ring of propofol and to its lipophilicity; propofol's efficacy is comparable to those of some LAs. These results could serve to develop propofol-related agents exhibiting analgesia when applied topically. PMID- 30519708 TI - Phenotypical characterisation of a putative omega-amino acid transaminase in the yeast Scheffersomyces stipitis. AB - Phylogenetic analysis of class III transaminases in the budding yeasts Lachancea kluyveri, Saccharomyces cerevisiae and Scheffersomyces stipitis identified a hitherto uncharacterised Sch. stipitis transaminase encoded by the PICST_54153 gene, which clustered with previously described gamma-amino butyric acid (GABA) and beta-alanine transaminases. Deletion of the PICST_54153 gene in Sch. stipitis resulted in a complete loss in the utilisation of beta-alanine and beta ureidopropionic acid as nitrogen sources, while growth on 1,3-diaminopropane displayed a significant lag phase compared to the wild-type control. It was therefore concluded that the Sch. stipitis PICST_54153 gene likely encodes a beta alanine transaminase. However, minor growth defects when 1,4-diaminobutane or 1,5 diaminopentane was provided as the nitrogen source suggested that the Picst_54153 transaminase may also participate in the catabolism of other diamine-derived omega-amino acids. Unexpectedly, the ?picst_54153 deletion mutant failed to grow on solid minimal medium in the presence of 5 mM beta-alanine even if a preferred nitrogen source was provided. PMID- 30519709 TI - Safety of statin drugs in patients with dyslipidemia and stable systemic autoimmune myopathies. AB - Recent studies have shown a high prevalence of dyslipidemia in patients with systemic autoimmune myopathies (SAM). However, little is known about the safety of the use of statins in these patients, and this gap in research motivated the accomplishment of the present study. In a retrospective cohort study conducted from 2004 to 2018, 250 patients with SAM were evaluated, and 24 patients had stable forms of SAM (16 dermatomyositis, 1 polymyositis and 7 antisynthetase syndrome) but had dyslipidemia and had received statins. Patients with clinically amyopathic dermatomyositis, immune-mediated necrotizing myopathy, dermatomyositis, or polymyositis induced by statins were excluded. The mean age of the patients was 50.6 years, and they were predominantly women. The median duration of the disease was 5.0 years. Twelve patients received simvastatin (10 60 mg/day), and 11 patients received atorvastatin (20-40 mg/day), and 1 patient received atorvastatin (10 mg/day) which was later replaced by simvastatin (20 mg/day). The median time of exposure to the statin was 22.5 months. The follow-up appointments showed that the patients' lipid profiles had improved and that there had been no recurrences of disease activity or clinical intercurrences. Despite the small sampling, the data showed that the use of statins in patients with SAM was safe. New studies with a larger sample and patients with different degrees of disease activity are necessary to corroborate the results of the present study. PMID- 30519710 TI - Targeted disruption of PI3K/Akt/mTOR signaling pathway, via PI3K inhibitors, promotes growth inhibitory effects in oral cancer cells. AB - PURPOSE: The phosphoinositide-3-kinase (PI3K) pathway is the frequently altered in human cancer. This has led to the development and study of novel PI3K inhibitors for targeted therapy and also to overcome resistance to radiotherapy. METHOD: The anti-tumour effects of PI3K inhibitors (PI-828, PI-103 and PX-866) in terms of cell proliferation, colony formation, induction of apoptosis, cell cycle arrest, invasion, autophagy, and pNF-kappaB/p65 translocation in SCC-4, SCC-9 and SCC-25 cells were studied by performing MTT, clonogenic, DAPI staining, propidium iodide staining, annexin-V binding, matrigel invasion, acridine orange staining and immuno-fluorescence assay. Western blot assay was performed to assess the alteration in the expression of various proteins. RESULT: PI-828 and PI-103 treatment exhibited dose-dependent inhibition of growth and proliferation of OSCC cells with a concomitant induction of apoptosis, altered cell cycle regulation and decreased invasiveness (p < 0.01). PX-866 induced apoptosis, cell cycle arrest, autophagy and a significant decrease in the invasiveness of oral cancer cells as compared to untreated cells (p < 0.01). These compounds significantly reduced expression of COX-2, cyclin-D1 and VEGF in the treated cells besides cytoplasmic accumulation of pNF-kappaB/p65 protein. In addition to PI3Kalpha, inactivation of downstream components, i.e. Akt and mTOR was seen. CONCLUSION: PI3K inhibitors such as PI-103, PI-828 and PX-866 may be developed as potential therapeutic agents for effective treatment of oral squamous cell carcinoma (OSCC) patients, associated with activated PI3K/Akt pathway. PMID- 30519711 TI - A wheat protein kinase gene TaSnRK2.9-5A associated with yield contributing traits. AB - KEY MESSAGE: We developed breeder-friendly high-throughput and cost-effective KASP marker for marker-assisted selection for grain yield related traits in wheat. Plant-specific protein kinase, SnRK2s, is a major family of signaling genes associated with metabolic regulations, nutrient utilization and response to external stimuli. In the present study, three copies of TaSnRK2.9 were isolated from chromosomes 5A, 5B and 5D of wheat (Triticum aestivum L.). The coding regions of TaSnRK2.9-5A, TaSnRK2.9-5B and promoter region of TaSnRK2.9-5D were investigated for sequence polymorphism. Single nucleotide polymorphisms (SNPs) were identified for TaSnRK2.9-5A, while no polymorphism was identified in TaSnRK2.9-5B and TaSnRK2.9-5D. The nucleotide sequence of TaSnRK2.9-5A consisted of 2180 bp having eight introns and nine exons. Three SNPs were identified at 308 nt, 698 nt and 1700 nt. For high-throughput genotyping, two kompetitive allele specific PCR (KASP) markers were developed. Four haplotypes Hap-5A-1, Hap-5A-2, Hap-5A-3 and Hap-5A-4 were detected in wheat populations collected from China, Europe and Pakistan. Association analysis was performed with mixed linear model in TASSEL (v 5.0). The results indicated that Hap-5A-1/2 of TaSnRK2.9-5A were significantly associated with high thousand kernel weight, while Hap-5A-4 with high grains per spike. Overexpressing transgenic rice also showed higher grains per spike which is in accordance with association analysis results. Geographic distribution and allelic frequency indicted that the favored haplotypes were positively selected in Chinese (Hap-5A-1/2), Pakistani (Hap-5A-1), east European (Hap-5A-1) and west European (Hap-5A-4) wheat breeding. The results suggest that the developed KASP markers can be utilized in yield improvement by marker assisted selection in wheat breeding. PMID- 30519713 TI - Novel insights into molecular chaperone regulation of ribonucleotide reductase. AB - The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many disease-related proteins including those in cancer. Substantial effort has been devoted to developing a range of chaperone inhibitors for clinical use. Recent studies have identified the oncogenic ribonucleotide reductase (RNR) complex as an interactor of chaperones. While several generations of RNR inhibitor have been developed for use in cancer patients, many of these produce severe side effects such as nausea, vomiting and hair loss. Development of more potent, less patient toxic anti-RNR strategies would be highly desirable. Inhibition of chaperones and associated co-chaperone molecules in both cancer and model organisms such as budding yeast result in the destabilization of RNR subunits and a corresponding sensitization to RNR inhibitors. Going forward, this may form part of a novel strategy to target cancer cells that are resistant to standard RNR inhibitors. PMID- 30519712 TI - Vascular density and inflammatory infiltrate in primary oral squamous cell carcinoma and after allogeneic hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) recipients have been reported to have an increased risk of chronic graft versus host disease (cGVHD) and hematological and solid cancers. Oral manifestations are the first signs of cGVHD observed in the majority of patients, and oropharyngeal cancer is the most frequent secondary malignancy occurred after HSCT. In this study, we have evaluated the inflammatory infiltrate cell content and correlated with the vascular density in patients affected by primary oral squamous cell carcinoma (OSCC) from previous healthy controls and OSCC after cGVHD. Results have demonstrated that patients with OSCC after GVHD show a more consistent inflammatory infiltrate as compared with the OSCC ones. In detail, the inflammatory background composed of CD3-positive T cells, tryptase-positive mast cells, CD31-positive endothelial cells, and CD68-positive macrophages may be more pronounced in the setting of GVHD + OSCC than in the control group. By contrast, CD20-positive B cells and CD1a-positive dendritic cells were more abundant in the latter population. Finally, a positive correlation was found as between vascular density and inflammatory cell infiltration in both GVHD + OSCC and OSCC groups. Overall, these results confirm the role played by immune cells in enhancing tumor progression and angiogenesis and suggest a potential therapeutic strategy involving inhibition of recruitment of immune cells to the tumor microenvironment and blockade of pro-tumoral effects and pro-angiogenic functions. PMID- 30519715 TI - [Sexually transmitted infections-current since ancient times]. PMID- 30519714 TI - [The adaptive Freiburg monosyllabic test in noise : Development of a procedure and comparison of the results with the Oldenburg sentence test]. AB - BACKGROUND: Whereas sentence tests are commonly performed using an adaptive procedure, this method has not yet been transferred to the Freiburg monosyllabic speech test, the most important word test. When using different procedures, a comparison of results between sentence and word tests is not possible. Therefore, an adaptive procedure which has proven itself in sentence tests was transferred to the Freiburg monosyllabic test in noise. The results of the new procedure were compared to the standard of sentence tests, i.e., the Oldenburg sentence test. METHODS: The adaptive Freiburg monosyllabic speech test and the Oldenburg sentence test were applied in 40 otologically normal subjects in a randomized order. Results were analyzed with respect to time requirements, possible gender differences, the influence of test order, and correlation of test results. RESULTS: The time required for the adaptive Freiburg monosyllabic speech test was significantly higher than for the Oldenburg sentence test. No significant impact of gender or test order could be shown. The mean signal-to-noise ratio for 50% speech discrimination of the Oldenburg sentence test was significantly smaller than for the adaptive Freiburg monosyllabic speech test. No correlation could be shown between the results of the two tests CONCLUSION: The Freiburg monosyllabic test can not only be used for quantifying discrimination loss in percentage terms, but also to measure the 50% speech recognition threshold with an adaptive algorithm. However, the procedure of the adaptive Freiburg monosyllabic test is more time consuming than that of the Oldenburg sentence test. Concerning a possible missing correlation between the results for 50% speech discrimination, further studies with hearing-impaired persons are needed. PMID- 30519716 TI - ? PMID- 30519717 TI - ? PMID- 30519718 TI - ? PMID- 30519724 TI - Effects of Varicocele Treatment on Sperm Conventional Parameters: Surgical Varicocelectomy Versus Sclerotherapy. AB - INTRODUCTION: Varicocele is often associated with impaired sperm parameters. Different procedures have been developed for varicocele treatment. The aim of this study was to evaluate the effects of varicocele treatment on conventional sperm parameters. MATERIALS AND METHODS: We compared two different techniques of intervention: surgical varicocelectomy and sclerotherapy. We also evaluated the number of varicocele recurrences and the pregnancy rate. We included 102 patients (mean age 29.8 +/- 0.8 years) with ultrasound diagnosis of varicocele. We excluded patients whose ultrasound evaluation and/or sperm parameters were not known before and after varicocele correction. We divided the patients (excluding 8 with azoospermia) into two subgroups: surgical varicocelectomy (n = 44) and sclerotherapy (n = 50). For each patient, we compared conventional sperm parameters before and after varicocele correction. RESULTS: After varicocele correction, we found a significant improvement in sperm concentration, total count and total motility. Considering the two subgroups, baseline sperm parameters did not differ significantly. Sperm concentration and total count increased significantly after varicocele correction by varicocelectomy. Varicocele correction by sclerotherapy resulted in a significant increase in sperm concentration, progressive and total motility. We found varicocele recurrence in 32% of patients who underwent varicocelectomy and in 19.7% of patients undergoing sclerotherapy. The pregnancy rate was higher after sclerotherapy (28%) than after surgical varicocelectomy (13%). CONCLUSION: Varicocele treatment must be recommended when other causes of infertility have been treated. Our results suggest the use of sclerotherapy for varicocele repair. LEVEL OF EVIDENCE: 2 b. PMID- 30519725 TI - Advantages of Intraprocedural Unenhanced CT During Adrenal Venous Sampling to Confirm Accurate Catheterization of the Right Adrenal Vein. AB - PURPOSE: To evaluate the advantages of intraprocedural CT during adrenal venous sampling (AVS) to confirm accurate catheterization of the right adrenal vein (RAV). MATERIALS AND METHODS: This single-institution study included 106 patients (mean age 52.4 years; range 28-74 years) with primary aldosteronism who performed contrast-enhanced CT (CECT) before AVS following AVS between January 2011 and March 2018. After catheterization of the RAV under fluoroscopic guidance, unenhanced CT images were obtained to confirm catheter position on unified CT angiography system. Catheter repositioning was performed when the catheter was inaccurately positioned. Venography findings were classified into two groups: (1) presumably cannulated in the RAV (presumed RAV group) and (2) obscured visualization of the RAV because of collateral vessels (obscured RAV group). Success rates of AVS were compared using Fisher's exact test. RESULTS: The overall success of AVS was achieved in 104 patients (98.1%). Catheter was deviated into the IVC during intraprocedural CT in four patients. Fourteen patients (14.0%) required catheter repositioning by intraprocedural CT images, and accurate catheterization in the RAV was eventually accomplished. The success rate of AVS was significantly higher in the presumed RAV group (90.1% [73/81]) than that in the obscured RAV group (68.4% [13/19]) (p = 0.024). If intraprocedural CT was not acquired during AVS, the success rate of AVS would have been significantly lower (84.9% [90/106]) compared with that use of intraprocedural CT (98.1% [104/106]) (p < 0.001). CONCLUSIONS: Intraprocedural unenhanced CT by referring to the preprocedural CECT before AVS enables the confirmation of accurate catheterization of the RAV. LEVEL OF EVIDENCE: Level 4, case series. PMID- 30519726 TI - Endovascular Embolization of Post-tonsillectomy Pseudoaneurysm: A Single-Center Case Series. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of endovascular embolization of post-tonsillectomy pseudoaneurysm with the usage of monomeric n-butyl-2-cyanoacrylate (NBCA) glue as a first intention. METHODS: We retrospectively analyzed the technical details and clinical outcome of ten consecutive children presented with delayed post-tonsillectomy bleeding, caused by lingual or facial artery pseudoaneurysm, which was treated by endovascular embolization. RESULTS: Seven patients had lingual artery pseudoaneurysm, and three patients had injury of a common linguo-facial trunk. Eight patients were treated by endovascular embolization using NBCA glue, and two patients had to be embolized using microcoils. All patients were successfully embolized with no clinical complications. One patient suffered from bleeding during the interventional procedure that was controlled by NBCA which infiltrated normal branches with no clinical sequelae. CONCLUSION: NBCA glue can be used as an effective appropriate embolizing material in endovascular embolization of post tonsillectomy pseudoaneurysm. However, certain precautions are mandatory to avoid distal infiltration of normal arteries or proximal reflux that may endanger the internal carotid artery. LEVEL OF EVIDENCE: Level 4, case series. PMID- 30519728 TI - [Toxic metabolic alterations of the central nervous system]. PMID- 30519727 TI - Catheter-Directed Fenestration for Branch Vessel Reconnection in Aortic Dissection Using a Novel Diamond-Tipped Chronic Total Occlusion Drilling Device: A Technical Report. AB - PURPOSE: Aortic dissection is a complex condition with high morbidity and mortality. Endovascular treatments including percutaneous fenestration can be used to manage branch vessel ischaemia or risk of aortic rupture. A variety of techniques for aortic fenestration have been described. We describe the novel use of the TruePath Chronic Total Occlusion (CTO) device for aortic intimal fenestration to achieve side branch reconnection. MATERIALS AND METHODS: We present three cases of aortic dissection presenting with symptoms of aortic side branch occlusion and end organ malperfusion, treated with aortic fenestration using the TruePath CTO device via trans-brachial and trans-femoral approaches. RESULTS: Technical success was achieved in all three cases. No complications were encountered. Flow was restored in compromised visceral branches. Branches remained patent on follow-up CT angiography over a minimum 2.5-year follow-up period. CONCLUSION: Percutaneous aortic fenestration techniques enable a minimally invasive approach to treat visceral branch malperfusion associated with aortic dissection. The TruePath CTO device improves the control of the fenestration procedure with the potential to improve efficacy and safety. PMID- 30519729 TI - ? PMID- 30519730 TI - Institutional patient accrual volume and the treatment quality of I-125 prostate seed implantation in a Japanese nationwide prospective cohort study. AB - PURPOSE: It is unclear whether experience at high-volume institute improves the treatment quality of prostate seed implantation. The aim of this study was to evaluate the effect of institutional experience on postimplant dosimetric parameters in a nationwide prospective cohort study. METHODS: From July 2005 to June 2007, 2354 patients were registered in the Japanese Prostate Cancer Outcome Study of Permanent I-125 Seed Implantation (J-POPS), and 1126 patients treated with seed implantation alone were evaluated. As a surrogate for institutional experience, we classified the J-POPS institutions as high-volume (patient accrual volume was >=120 patients per institution) or low-volume institutions (patient accrual volume was <120 patients per institution). To compare treatment quality between institutions, we evaluated the postimplant dosimetric parameters including D90, V100/150 (prostatic dose parameters), UD5/90, U200 (urethral dose parameters), and rectum R100/150 (rectal dose parameters). RESULTS: In the 5 high volume institutions (n = 601 patients), most of the patients were treated with >144 Gy of D90, whereas in the 20 low-volume institutions (n = 525) some of the patients were treated with <144 Gy. The V100 of most of the high-volume institution patients were >90%, whereas in the low-volume institutions a considerable percentage of patients showed lower V100. Although there was no correlation between D90 and rectal dose parameters, UD90 had a moderate positive correlation with D90 in both the high- and low-volume institutions. U200 varied more widely in the low-volume institutions. CONCLUSIONS: Our findings indicate that the institutional patient accrual volume is associated with the treatment quality of I-125 prostate seed implantation. PMID- 30519731 TI - The QIAGEN 140-locus single-nucleotide polymorphism (SNP) panel for forensic identification using massively parallel sequencing (MPS): an evaluation and a direct-to-PCR trial. AB - Massively parallel sequencing (MPS) of identity informative single-nucleotide polymorphisms (IISNPs) enables hundreds of forensically relevant markers to be analysed simultaneously. Generating DNA sequence data enables more detailed analysis including identification of sequence variations between individuals. The GeneRead DNAseq 140 IISNP MPS panel (QIAGEN) has been evaluated on both the MiSeq (Illumina) and Ion PGMTM (Applied Biosystems) MPS platforms using the GeneRead DNAseq Targeted Panels V2 library preparation workflow (QIAGEN). The aims of this study were to (1) determine if the GeneRead DNAseq panel is effective for identity testing by assessing deviation from Hardy-Weinberg (HWE) and pairwise linkage equilibrium (LE); (2) sequence samples with the GeneRead DNAseq panel on the Ion PGMTM using the QIAGEN workflow and assess specificity, sensitivity and accuracy; (3) assess the efficacy of adding biological samples directly to the GeneRead DNAseq PCR, without prior DNA extraction; and (4) assess the effect of varying coverage and allele frequency thresholds on genotype concordance. Analyses of the 140 SNPs for HWE and LE using Fisher's exact tests and the sequential Bonferroni correction revealed that one SNP was out of HWE in the Japanese population and five SNP combinations were commonly out of LE in 13 of 14 populations. The panel was sensitive down to 0.3125 ng of DNA input. A direct-to PCR approach (without DNA extraction) produced highly concordant genotypes. The setting of appropriate allele frequency thresholds is more effective for reducing erroneous genotypes than coverage thresholds. PMID- 30519732 TI - Microsurgical reconstruction with vascularized fibula and massive bone allograft for bone tumors. AB - INTRODUCTION: Combining massive bone allograft and vascularized fibula in intercalary reconstruction following resection of bone tumors represents a complex reconstructive procedure that requires specialists in microvascular surgery as well as orthopedic surgery. The purpose of our study was to examine the outcomes using this surgical technique in patients with bone tumors in terms of oncologic results, complications related to surgery, Musculoskeletal Tumor Society (MSTS) scores and duration of surgery. MATERIALS AND METHODS: We analyzed 81 patients with femoral or tibial sarcomas who underwent intercalary resection and microsurgical reconstruction with massive bone allograft and vascularized fibula. There were 56 boys and 25 girls with a mean age of 13.4 years at the time of surgery. The patients' medical records were reviewed for clinical and functional outcomes as well as postoperative complications. The study group was comprised of 33 patients who underwent reconstruction of the femur with massive bone allograft and free vascularized fibula and 48 patients who underwent reconstruction of the tibia with massive bone allograft and free or pedicle vascularized fibula. The mean length of resection was 15.9 cm (8-31 cm). The functional evaluation of the patients was done at the end of the follow-up using MSTS score for the lower limb. All patients had at least a 2-year follow-up. RESULTS: The overall limb salvage rate was 94%, although many patients required re-operation after the procedure. Complications occurred in 24 patients, 18 of which underwent additional surgical procedures. They included fractures of the massive bone allograft-vascularized fibula construct with or without implant failure (19) and deep infection (5). After surgical or conservative treatment, all the fractures successfully healed. The overall MSTS functional score was good to excellent in 91% of patients. CONCLUSIONS: The combination of massive bone allograft and vascularized fibula seems to be a reasonable option for reconstruction of diaphyseal defects following intercalary resection of bone tumors. Although there was a high rate of complications and therefore re operations, the biology of vascularized fibula was able to save the reconstruction in most of the cases that had complications. PMID- 30519733 TI - In reply: Use of low-molecular weight dextran as an LA adjuvant to extend LA action. PMID- 30519734 TI - Needs-focused interventions for family caregivers of older adults with cancer: a descriptive interpretive study. AB - PURPOSE: Although family caregivers (FCs) of older adults with cancer (OACs) provide invaluable assistance by fulfilling multiple tasks along the cancer trajectory, evidence suggests that their needs are poorly assessed, and there is a scarcity of supportive interventions that influence their well-being. Viewing these issues as opportunities for improvement, we conducted this qualitative study to understand FCs' needs and identify promising needs-focused interventions. METHODS: This descriptive interpretive qualitative study was conducted in Quebec, Canada, in a French Canadian Oncology Clinic. Participants were FCs who were spouses or adult children (n = 25) of OACs aged 70 years or older. Data were collected via focus groups and were analyzed using an ongoing analytic process following each interview. RESULTS: Three types of needs were of particular importance: information, relationships between FC and others, and care for oneself. The need for information was described in terms of the content, timeliness, and modalities in which information should be verbalized and delivered. The need for relationships specifically targeted health care providers (HCPs), family members, and OACs. The need to care for oneself was recognized as important throughout the cancer trajectory but also represented a challenge. Participants proposed innovative ideas for interventions, resources, and strategies for each type of need. CONCLUSIONS: According to our results, HCPs should systematically include FCs into OACs' care plan through the use of concrete actions such as the "family systems approach" suggested by Duhamel, and integrate a systematic FC's needs assessment. PMID- 30519735 TI - Continuous improvement process: ortho-geriatric co-management of proximal femoral fractures. AB - OBJECTIVE: The objective of the current study was to evaluate the effect of a quality management system on treatment and care delivery of proximal femoral fractures. Specifically, our hypothesis was that the "plan-do-check-act (PDCA)" philosophy of the ISO 9001 quality management system results in a continuous improvement process. METHODS: 1015 proximal femoral fractures were prospectively included into a hip fracture database over a 5-year period, after a restructuring process with implementation of clinical pathways and standard operation procedures. A close and structured ortho-geriatric co-management (certified ortho geriatric center) was the basis for treatment. ISO 9001 certification was granted for the first time in 2012. Procedural and patient outcome parameters were analyzed by year and evaluated statistically using SPSS 25.0. RESULTS: In both categories (procedural and outcome) significant changes could be detected during the 5-year period, e.g., significant reduction of time to surgery for the first 2 years, improvement in discharge management, and reduction of surgical complications. However, no significant changes could be demonstrated for mortality or internal complications such as pneumonia, urinary tract infections, or postoperative delirium. However, the incidence of the latter was already on a very low level at the onset of the quality improvement process. CONCLUSION: We could show a relevant and continuous improvement of several quality indicators during a 5-year period after implementation of a quality management system based on the PDCA philosophy for the treatment of proximal femoral fractures in elderly patients. However, other parameters (internal complications, cost-effectiveness, etc.) need our close attention in the future. PMID- 30519736 TI - Clinical and biological characteristics of myeloma patients influence response to elotuzumab combination therapy. AB - Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted. PMID- 30519738 TI - Three types of a high-carbohydrate diet are differently associated with cardiometabolic risk factors in Korean adults. AB - PURPOSE: Although a high-carbohydrate diet typically shows low-fat intake, the prevalence of metabolic abnormalities in Asian countries has increased. We evaluated three types of a high-carbohydrate diet and its association with cardiometabolic risk factors in the Korean adult population. METHODS: A total of 14,438 adults (5813 men and 8625 women) who participated in the 2008-2012 Korea National Health and Nutrition Examination Surveys were selected. Dietary data were obtained by a single 24-h recall method. High-carbohydrate diets were defined using three carbohydrate variables, including total carbohydrate intake, proportion of energy from carbohydrate, and white rice consumption as dietary exposures. Cardiometabolic risk factors included obesity, abdominal obesity, hypercholesterolemia, atherogenic dyslipidemia, impaired fasting glucose, and elevated blood pressure. A multivariate-adjusted logistic regression was performed to examine the associations between high-carbohydrate diets and cardiometabolic risk factors by sex. RESULTS: Three types of high-carbohydrate diets showed different energy intakes and food group consumption when individuals in the highest quintile of each type were compared. In men, intakes of total carbohydrate and white rice were inversely associated with obesity, impaired fasting glucose, and elevated blood pressure and proportion of energy from carbohydrate and white rice consumption were inversely related to hypercholesterolemia. In women, a high consumption of white rice was positively associated with impaired fasting glucose. All three types of high-carbohydrate diets were positively associated with the prevalence of atherogenic dyslipidemia in both sexes. CONCLUSIONS: Three types of high-carbohydrate diets show different associations with cardiometabolic risk factors except for unfavorable effects on atherogenic dyslipidemia. PMID- 30519737 TI - Comparison of native myocardial T1 and T2 mapping at 1.5T and 3T in healthy volunteers : Reference values and clinical implications. AB - BACKGROUND: Myocardial native T1 and T2 mapping are promising techniques for quantitative assessment of diffuse myocardial pathologies; however, due to conflicting data regarding normal values, routine clinical implementation of this method is still challenging. METHODS: To evaluate this situation during daily clinical practice the characteristics of normal values obtained in 60 healthy volunteers who underwent magnetic resonance imaging (MRI) scans on 1.5T and 3T scanners were studied. The T1 modified look-locker inversion recovery (MOLLI; 5(3)3; modified for higher heart rates) and T2 navigator gated black-blood prepared gradient-spin-echo (GraSE) sequences were used. RESULTS: While age and body mass index did not affect relaxation times, a gender and heart rate dependency was found showing higher T1 and T2 values in females, whereas at higher heart rates a prolongation of T1 and a shortening of T2 relaxation times was found. Particularly prone to artifacts were T2 measurements at 3T and the inferolateral wall. In the individual setting mean relaxation times for T1 were 995.8 +/- 30.9 ms at 1.5T and 1183.8 +/- 37.5 ms at 3T and 55.8 +/- 2.8 ms at 1.5T and 51.6 +/- 3 ms at 3T for T2 indicating a high dependency of reference values on MRI protocol when compared to the literature. Furthermore, as presumed mean T1 and T2 values correlated in the same individual. CONCLUSIONS: The T1 and T2 relaxation times depend on physiological factors and especially on MRI protocols. Therefore, reference values should be validated individually in every radiological institution before implementing mapping protocols in daily clinical practice. Correlation of mean T1 and T2 values in the same proband at both field strengths indicates intraindividual reproducibility. PMID- 30519739 TI - [Cheek-midface lift for revision following failed excessive lower eyelid blepharoplasty]. AB - Iatrogenic ectropion with sagging of the lower eyelid after failed excessive lower eyelid blepharoplasty is a severe complication in aesthetic surgery. Traditionally, free skin grafting is the method of choice for correction. This overview presents the cheek-midface lift as a useful and powerful method for the correction of ectropion following excessive lower eyelid blepharoplasty. This technique, which can be performed with the patient under local anesthesia, enables good functional as well as aesthetic outcomes. PMID- 30519740 TI - [Combined XEN and Baerveldt implant-principles and management of complications]. AB - The treatment of congenital glaucoma requires special expertise and often novel surgical approaches. The combined use of a XEN and a Baerveldt implant is an alternative to conventional tube implants and may be less harmful for long-term corneal endothelial damage. If this technique does not provide sufficient long term control of intraorbital pressure (IOP), a direct implantation of the Baerveldt tube can be easily performed in a second intervention. PMID- 30519741 TI - Habitat selection and prediction of the spatial distribution of the Chinese horseshoe bat (R. sinicus) in the Wuling Mountains. AB - Habitat selection by the Chinese horseshoe bat (Rhinolophus sinicus) in the Wuling Mountains was studied in this paper. Global positioning system (GPS), remote sensing (RS) and geographic information system (GIS) technologies were used to obtain ground survey data and analyse the habitat factors driving the distribution of R. sinicus. Based on these basic data, a binary logistic regression method was used to establish habitat selection models of R. sinicus. Then, the corrected Akaike information criterion (AICC) was used to screen an optimal model, and the Hosmer-Lemeshow test indicated that the optimal model has suitable goodness of fit. Finally, the optimal model was used to predict the spatial distribution of R. sinicus in the Wuling Mountains. Verification analysis showed that the overall accuracy of the model was 72.7% and that the area under the curve (AUC) value was 0.947, which indicated that the model was effective for predicting suitable habitat for R. sinicus. The model results also showed that the main factors that influenced habitat selection were slope, annual mean temperature and distances from roads, rivers and residential land. R. sinicus preferred areas far from roads and residential land and areas near rivers. Generally, higher values of slope and annual mean temperature were associated with a greater likelihood of R. sinicus presence. Therefore, the protection of the water bodies surrounding R. sinicus habitats and fully addressing the impacts of human activities on R. sinicus habitats are recommended to protect the survival and reproduction of the population. PMID- 30519742 TI - Incidence of fatigue and low-dose corticosteroid use in prostate cancer patients receiving systemic treatment: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Cancer-related fatigue (CRF) is a complex condition that is reported in > 50% of cancer patients. In men with castration-resistant prostate cancer (CRPC), CRF was reported in 12-21% of patients. Approved systemic therapy against CRPC is commonly administered in combination with androgen-deprivation treatment (ADT) and, in some cases, with daily, low-dose corticosteroids. Importantly, the use of low-dose corticosteroids is associated with multiple negative effects, including reduced muscle mass. On these grounds, we hypothesized that the chronic use of corticosteroids may increase the incidence of fatigue in patients with prostate cancer. METHODS: We reviewed all randomized trials published during the last 15 years conducted in patients with prostate cancer receiving systemic treatment and we performed a sub-group analysis to gather insights regarding the potential differences in the incidence of fatigue in patients receiving vs. not receiving daily corticosteroids as part of their systemic anti-neoplastic regimen. RESULTS: Overall, 22,734 men enrolled in prospective randomized phase II and III trials were evaluable for fatigue. Estimated pooled incidence of grade 1 2 fatigue was 30.89% (95% CI = 25.34-36.74), while estimated pooled incidence of grade 3-4 fatigue was reported in 3.90% (95% CI = 2.91-5.02). Sub-group analysis showed that grade 3-4 fatigue was approximately double in patients who received daily corticosteroids as part of their anti-neoplastic treatment (5.58; 95% CI = 4.33-6.98) vs. those who did not (2.67%; 95% CI = 1.53-4.11). CONCLUSION: Our findings highlight the need for ad hoc-designed prospective clinical trials to investigate whether the benefits associated with low-dose, daily corticosteroids outweigh the risks associated with corticosteroid-related adverse events such as fatigue. PMID- 30519743 TI - Factors influencing intraoperative conversion from planned orthotopic to non orthotopic urinary diversion during radical cystectomy. AB - OBJECTIVES: To determine and investigate the intraoperative factors that contribute to a change in plan from continent orthotopic neobladder to ileal conduit or continent cutaneous diversion at the time of radical cystectomy. SUBJECTS AND METHODS: A retrospective review of our prospectively maintained bladder cancer database was performed. Of the 711 patients who underwent radical cystectomy from 2012 to 2016, 387 (54.4%) had given consent to have a NB. Of these 387 patients, 348 (89.9%) ultimately received a neobladder while 34 (8.8%) received an ileal conduit and 5 (1.3%) continent cutaneous diversion. The factors involved in the intraoperative change of plan were examined in this study. RESULTS: Patients who ultimately received a neobladder were significantly more likely to have clinical node-negative disease (p = 0.045), negative soft tissue margins (p = 0.001), lower body mass index (p = 0.045) and higher volume surgeons (p < 0.001). Oncologic reasons for intraoperative conversions were more common than technical reasons (58.3% vs 35.9%), in both robotic and open surgical techniques. The choice of surgical approach (open vs robotic) did not influence the rate of intraoperative conversion. CONCLUSION: The factors influencing intraoperative decision not to perform neobladder are predominantly oncologic rather than technical. A clear understanding of the factors involved in influencing the intraoperative change in the urinary diversion plan may improve shared decision making in patients undergoing radical cystectomy in the future. PMID- 30519744 TI - Prognostic value of unifocal and multifocal positive surgical margins in a large series of robot-assisted radical prostatectomy for prostate cancer. AB - PURPOSE: To evaluate the prognostic value of positive surgical margins (PSM) focality for the prediction of biochemical recurrence (BCR) in patients undergoing robotic-assisted radical prostatectomy (RARP) for prostate cancer. METHODS: All men with clinically localized prostate cancer undergoing RARP in our tertiary referral centre between May 2005 and August 2016 were retrospectively identified. Patients with neoadjuvant therapy were excluded. Comparisons were made between cases with negative surgical margins (NSM), unifocal PSM (uPSM), and multifocal PSM (mPSM). RESULTS: From a total of 973 patients available for analysis, 315 (32%) had a PSM. In these patients, 190 had uPSM and 125 had mPSM. Focality of PSM was significantly associated with tumour stage and grade, preoperative PSA, and postoperative PSA persistence (all p < 0.001), but not with nerve sparing (NS) (p = 0.15). PSA persistence was found in 120 (12%) patients, resulting in 853 patients available for survival analyses with a median follow-up of 52 months. Both uPSM and mPSM were found to be independent predictors of BCR, conferring a hazard ratio of 1.9 (95% CI 1.3-3.0; p = 0.002) and 3.4 (95% CI 2.1 5.6; p < 0.001), respectively, when compared to NSM. In subgroup analyses, PSM was particularly predictive for BCR when patients underwent unilateral or bilateral NS (p <= 0.003). CONCLUSIONS: Based on a large case series of RARP, we found PSM focality to be an independent predictor of BCR, with a 1.9- and 3.4 fold risk increase for BCR in case of uPSM and mPSM, respectively. PSM seems to be of particular prognostic relevance when NS has been performed. PMID- 30519745 TI - Laparoscopic and robotic-assisted repair of retrocaval ureter in children: a multi-institutional comparative study with open repair. AB - PURPOSE: This retrospective study aimed to report a multi-institutional experience with laparoscopic and robotic-assisted repair of retrocaval ureter in children and to compare outcome of minimally invasive surgery (MIS) with open repair. METHODS: The records of all children, who underwent MIS and open repair of retrocaval ureters in six international pediatric urology units over a 5-year period, were retrospectively collected. Data were grouped according to the operative approach: a laparoscopic group (G1) included five patients, a robotic assisted group (G2) included four patients, and an open group (G3) included three patients. The groups were compared in regard to operative and postoperative outcomes. RESULTS: At follow-up, all patients (one G1 patient after redo-surgery) reported complete resolution of symptoms and radiologic improvement of hydronephrosis and obstruction. In regard to postoperative complications, one G1 patient developed stenosis of anastomosis and needed re-operation with no further recurrence (IIIb Clavien). G2 reported the lowest average operative time (135 min) compared to G1 (178.3 min) and G3 (210 min). MIS (G1-G2) reported a significantly better postoperative outcome compared to open repair (G3) in terms of analgesic requirements, hospitalization, and cosmetic results. CONCLUSIONS: The study outcomes suggest that MIS should be the first choice for retrocaval ureter because of the minimal invasiveness and the better cosmetic outcome compared to open surgery. Furthermore, our results showed that robotic-assisted reconstruction was technically easier, safer, and quicker compared to laparoscopic repair, and for these reasons, it should be preferentially adopted, when available. PMID- 30519746 TI - Impact of neoadjuvant chemotherapy on short-term complications and survival following radical cystectomy. AB - OBJECTIVES: To compare perioperative and short-term postoperative complication rates between patients receiving radical cystectomy (RC) after neoadjuvant chemotherapy (NAC) and patients undergoing RC alone. Secondary objectives were to compare overall survival (OS) and cancer-specific survival (CSS). MATERIALS AND METHODS: Clinico-pathological data of all patients who received RC between 1996 and 2015 were retrospectively collected. Only patients with RC for muscle invasive bladder cancer were included in the final analysis. Short-term (30-day) postoperative complications were assessed by registering the Clavien-Dindo classification (CDC) and dividing into sub-groups: low-grade (LGC) CDC 1-2 and high-grade (HGC) CDC 3-5. To compare populations with similar age, comorbidities and preoperative creatinine, we used a propensity score-adjusted statistical model. Pre- and perioperative predictors of short-term complications were identified using uni- and multivariable models. Survival was assessed using Kaplan-Meier analysis. RESULTS: A total of 491 patients undergoing RC were included, of whom 102 (20.8%) received NAC. After propensity score covariate adjustment, there was no significant difference in postoperative complications between patients undergoing NAC plus RC and RC alone with an overall complication rate of 69% and 66%, respectively. No significant differences in the 30-day HGC rates (11.76% and 11.83%, respectively) were observed. NAC plus RC patients had worse prognostic factors at baseline; nevertheless, after correction for group differences OS and CSS did not differ from RC only group (5-year OS 61.3% vs. 50.2%, and 5-year CSS 61.8% vs. 57.9% respectively, p > 0.05 for all). CONCLUSION: In appropriately selected patients, exposure to NAC is not associated with increased short-term complications. PMID- 30519747 TI - Usefulness of transabdominal ultrasonography for assessing ulcerative colitis: a prospective, multicenter study. AB - BACKGROUND: Transabdominal ultrasonography (US) has been reported to be a useful tool for evaluating ulcerative colitis (UC) although with less well-established data than for Crohn's disease. This prospective multicenter study aimed to establish the usefulness of US compared with colonoscopy (CS) for assessing disease extent and activity of UC. METHODS: Altogether, 173 patients with UC were prospectively enrolled, among whom 156 were eligible for this study. All patients underwent US and CS within 2 days at five facilities. We divided the colon into six segments and examined each segment and the rectum using US and CS. US severity was graded 1-4 regarding bowel wall thickness, stratification, and ulceration. CS severity was also graded 1-4 according to Matts' endoscopic classification. Concordance between US and CS grades for all colonic segments was analyzed using kappa statistics. US and CS findings were also compared with the clinical disease activity index (CAI) and histological grade using Spearman's correlation coefficient. RESULTS: There was moderate concordance between US and CS grades in all colonic segments (weighted kappa = 0.55, p < 0.001). Concordance was rated moderate for each colonic segment but only slight for the rectum. The US grade was significantly correlated with the CAI score (r = 0.40, p < 0.001) and histological grade (r = 0.35, p < 0.001). CONCLUSIONS: This prospective multicenter study showed moderate concordance between US and CS for assessing the disease activity of UC. Hence, US may be used more generally for evaluating UC in daily clinical practice. PMID- 30519748 TI - Gut microbiota dysbiosis worsens the severity of acute pancreatitis in patients and mice. AB - BACKGROUND: The gut is implicated in the pathogenesis of acute pancreatitis (AP) and the infectious complications of AP are commonly associated with enteric bacteria, yet whether gut microbiota dysbiosis participants in AP severity remains largely unknown. METHODS: We collected clinical information and fecal samples from 165 adult participants, including 41 with mild AP (MAP), 59 with moderately severe AP (MSAP), 30 with severe AP (SAP) and 35 healthy controls (HC). The serum inflammatory cytokines and gut barrier indexes were detected. Male C57BL/6 mice with AP were established and injuries of pancreas were evaluated in antibiotic-treated mice, germ-free mice as well as those transplanted with fecal microbiota. The gut microbiota was analyzed by 16S rRNA gene sequencing. RESULTS: The structure of gut microbiota was significantly different between AP and HC, and the disturbed microbiota was closely correlated with systematic inflammation and gut barrier dysfunction. Notably, the microbial composition changed further with the worsening of AP and the abundance of beneficial bacteria such as Blautia was decreased in SAP compared with MAP and MSAP. The increased capacity for the inferred pathway, bacterial invasion of epithelial cells in AP, highly correlated with the abundance of Escherichia Shigella. Furthermore, the antibiotic-treated mice and germ-free mice exhibited alleviated pancreatic injury after AP induction and subsequent fecal microbiota transplantation in turn exacerbated the disease. CONCLUSIONS: This study identifies the gut microbiota as an important mediator during AP and its dysbiosis is associated with AP severity, which suggests its role as potential therapeutic target. PMID- 30519749 TI - [Immunoadsorption in dermatology]. AB - Autoimmmune bullous diseases are mediated by pathogenetically relevant autoantibodies against components of the epidermis and/or superficial mucous membranes (in pemphigus) and structural proteins of the dermal-epidermal junction (in pemphigoid diseases). Using immunoadsorption (IA), an already well established procedure in cardiac and rheumatic disorders, antibodies can be removed from the plasma. At present, most data on the adjuvant use of IA in dermatology are derived from patients with severe and/or refractory pemphigus vulgaris or pemphigus foliaceus and also from patients with pemphigoid diseases. Additionally, in the last few years different protocols for IA in patients with severe atopic dermatitis and elevated total serum IgE levels have been published. While panimmunoglobulin adsorbers are mainly used in dermatology, an IgE-specific adsorber has been used in some patients with atopic dermatitis and in the future, antigen-specific adsorbers are to be expected that will enable the specific reduction of autoantibodies. PMID- 30519750 TI - Cesarean section scar in 3 T magnetic resonance imaging and ultrasound: image characteristics and comparison of the methods. AB - PURPOSE: Uterine rupture during labor is a rare but life-threatening complication after previous cesarean section (CS). Prenatal risk is assessed using ultrasound thickness measurement of the lower uterine segment (LUS). Due to inhomogeneous study results, however, clinical obstetrics still lacks for standard protocols and reliable reference values. As 3 T magnetic resonance imaging (MRI) has not yet been sufficiently studied regarding LUS diagnostics after previous CS, we sought to evaluate its feasibility focusing on thickness measurements and typical characteristics of the CS-scar region in comparison to ultrasound and the intraoperative status. METHODS: In this prospective study, 25 asymptomatic patients with one previous CS and inconspicuous ultrasound findings were included. An additional 3 T MRI with either a T2-weighted Turbo-Spin-Echo or a Half Fourier-Acquired-Single-shot-Turbo-spin-Echo sequence in a sagittal orientation was performed. We analyzed categorical image quality, inter- and intra-rater reliability as well as anatomy, morphology and thickness of the LUS. Results were compared to ultrasound and intraoperative findings. RESULTS: MRI provided good to excellent image quality in all patients. The imaged structures presented with a high variability in anatomy and morphology. Image characteristics indicating the uterine scar were only found in 11/25 (44%) patients. LUS thickness measurements with MRI showed good inter- and intra-rater reliability but poor agreement with ultrasound. CONCLUSIONS: MRI is appropriate for additional LUS diagnostics in patients with previous CS. The strong individual variability of LUS-anatomy and morphology might explain the difficulties in establishing uniform diagnostic standards after CS. PMID- 30519751 TI - False-positive rates in screening for trisomies 18 and 13: a comparison between first-trimester combined screening and a cfDNA-based approach. AB - PURPOSE: To determine the false-positive rates (FPR) associated with screening for trisomy 18/13 using first-trimester combined screening (FTCS) and an ultrasound plus cfDNA-based approach (US-cfDNA), which includes a detailed ultrasound examination, a cfDNA analysis and a FTCS reflex backup test for cases with uninformative results. METHODS: This is a sub-analysis of a randomized controlled trial, which was performed between 2015 and 2016. Pregnant women with a normal first-trimester ultrasound examination at 11-13 weeks' gestation (NT < 3.5 mm, no anomalies) were randomized into two groups: FTCS and US-cfDNA screening. The overall FPR in screening for trisomies 18/13 and 21 was compared with the FPR in screening for trisomy 21 alone. Pregnancies were considered screen positive if the risk for trisomy 21 was 1:100 and for trisomy 18 and 13, 1:20 each. RESULTS: The study population consisted of 688 pregnancies in each study arm. In the FCTS group, median delta NT was 0.0 mm, free beta-hCG and PAPP A 0.96 and 1.11 MoM. In the US-cfDNA group, median delta NT was 0.0 mm. In 10 pregnancies, the cfDNA analysis was uninformative. In the FTCS and in the US cfDNA group, the FPR in screening for trisomy 21 was 2.5% and 0%. In both groups, the overall FPR was not increased by adding screening algorithms for trisomies 18 and 13. CONCLUSION: In conclusion, the addition of screening for trisomies 18 and 13 to screening for trisomy 21 does not significantly change FPR. This is true for both the FTCS and the US-cfDNA-based approach. PMID- 30519752 TI - The incidence and predictors of gynecologic malignancies among postmenopausal patients with endometrial fluid collection. AB - OBJECTIVE: To investigate the incidence and predictors of gynecologic malignancies among postmenopausal patients with endometrial fluid collection (EFC). METHODS: All patients with EFC diagnosed by transvaginal sonography (TVS) were retrospectively reviewed if they had undergone biopsy of the endometrium from January 2008 to January 2016 in a tertiary teaching hospital. Follow-up ended in June 2017. The incidence of gynecologic malignancies was described, and predictive factors were determined by comparing the epidemiological and clinico pathological characteristics of the patients. RESULTS: During the study period, 273 women with EFC (3.4%) were enrolled. Biopsy pathology and the following hysterectomy revealed 29 (10.6%) cases of gynecological cancer. In the multivariable analysis, patient-reported genital symptoms [odds ratio (OR) 16.2, 95% confidence interval (CI) 1.9-139.3], abnormal serum CA125 (OR 14.5, 95% CI 4.5-46.5), lesions in the uterine cavity (OR 18.8, 95% CI 6.0-59.1) and endometrial thickness (OR 1.1, 95% CI 1.0-1.2) determined by TVS were independent factors associated with malignancy. Only 1.1% (1/90) of the asymptomatic patients had gynecologic cancer. During the follow-up, gynecologic cancer was diagnosed in nine patients, six of whom had vaginal bleeding at the time of initial enrollment. The prognosis of patients with cancer was worse than that of patients with benign results. CONCLUSION: The risk of gynecologic malignancies in postmenopausal patients with EFC is related to genital symptoms, TVS findings and CA 125 levels. Asymptomatic EFC is associated with an extremely low risk of malignancy. PMID- 30519753 TI - Malignant transformation of adenomyosis: literature review and meta-analysis. AB - PURPOSE: To review and analyze risk factors and the pathology of malignant transformation of adenomyosis. METHODS: In this paper, the relevant research on current risks factors and the pathology of malignant transformation of adenomyosis was reviewed and analyzed by metaanalysis. All studies included were retrieved from the PUBMED. RESULTS: Analysis of existing studies revealed that most malignant transformation of adenomyosis occurs in elderly or postmenopausal patients. Adenomyosis with uterine leiomyoma or benign endometrial hyperplasia and other benign diseases appears to be more prone to malignancy, but there is currently no strong evidence to confirm this finding. CONCLUSIONS: At present, the malignant transformation of adenomyosis is thought to be due to its endometrial epithelium transition to monolayer tumor cells before malignant transformation, which eventually develops to varying degrees of cancer. However, the specific molecular mechanism of adenomyosis is not yet clear. Because of its low incidence of malignant transformation, lack of large-sample, multi-center clinical trials, and large heterogeneity of the existing research, the evidence based on the high-risk factors of malignant transformation of adenomyosis is weak. PMID- 30519754 TI - Theoretical study of the mechanism of the manganese catalase KatB. AB - The mechanism of the H2O2 disproportionation catalyzed by the manganese catalase (MnCat) KatB was studied using the hybrid density functional theory B3LYP and the quantum chemical cluster approach. Compared to the previous mechanistic study at the molecular level for the Thermus thermophilus MnCat (TTC), more modern methodology was used and larger models of increasing sizes were employed with the help of the high-resolution X-ray structure. In the reaction pathway suggested for KatB using the Large chemical model, the O-O homolysis of the first substrate H2O2 occurs through a MU-eta1:eta1 coordination mode and requires a barrier of 10.9 kcal/mol. In the intermediate state of the bond cleavage, two hydroxides form as terminal ligands of the dimanganese cluster at the Mn2(III,III) oxidation state. One of the two Mn(III)-OH- moieties and a second-sphere tyrosine stabilize the second substrate H2O2 in the second-sphere of the active site via hydrogen bonding interactions. The H2O2, unbound to the metals, is first oxidized into HO2. through a proton-coupled electron transfer (PCET) step with a barrier of 9.5 kcal/mol. After the system switches to the triplet surface, the uncoordinated HO2. replaces the product water terminally bound to the Mn(II) and is then oxidized into O2 spontaneously. Transition states with structural similarities to those obtained for TTC, where MU-eta2-OH-/O2- groups play important roles, were found to be higher in energy. PMID- 30519755 TI - Cost-effectiveness of continuity of midwifery care for women with complex pregnancy: a structured review of the literature. AB - BACKGROUND: Critical evaluation of the cost-effectiveness and clinical effectiveness of continuity of midwifery care models for women experiencing complex pregnancy is an important consideration in the review and reform of maternity services. Most studies either focus on women who experience healthy pregnancy or mixed risk samples. These results may not be generalised across the childbearing continuum to women with risk factors. This review critically evaluates studies that measure the cost of care for women with complex pregnancies, with a focus on method and quality. AIMS / OBJECTIVES: To critically appraise and summarise the evidence relating to the combined cost-effectiveness, resource use and clinical effectiveness of midwifery continuity models for women who experience complex pregnancies and their babies in developed countries. DESIGN: Structured review of the literature utilising a matrix method to critique the methods and quality of studies. METHOD: A search of Medline, CINAHL, MIDIRS, DARE, EMBASE, OVID, PubMed, ProQuest, Informit, Science Direct, Cochrane Library, NHS Economic Evaluation Database (NHSEED) for the years 1994 - 2018 was conducted. RESULTS: Nine articles met the inclusion criteria. The review identified four areas of economic evaluation that related to women who experienced complex pregnancy and continuity of midwifery care. (1) cost and clinical effectiveness comparisons between continuity of midwifery care versus obstetric-led units; (2) cost of continuity of midwifery care and/or team midwifery compared to Standard Care; (3) cost-effectiveness of continuity of midwifery care for Australian Aboriginal women versus standard care; (4) patterns of antenatal care for women of high obstetric risk and comparative provider cost. Cost savings specific to women from high risk samples who received continuity of midwifery care compared with obstetric-led standard care was stated for only one study in the review. Kenny et al. 1994 identified cost savings of AUS $29 in the antenatal period for women who received the midwifery team model from a stratified sub-set of high-risk pregnant woman within a mixed risk sample of 446 women. One systematic review relevant to the UK context, Ryan et al. (2013), applied sensitivity analysis to include women of all risk categories. Where risk ratio for overall fetal/neonatal death was systematically varied based on the 95% confidence interval of 0.79 to 1.09 from pooled studies, the aggregate annual net monetary benefit for continuity of midwifery care ranged extremely widely from an estimated gain of L472 million to a loss of L202 million. Net health benefit ranged from an annual gain of 15 723 QALYs to a loss of 6 738 QALYs. All other studies in this review reported cost savings narratively or within mixed risk samples where risk stratification was not clearly stated or related to the midwifery team model only. CONCLUSIONS: Studies that measure the cost of continuity of midwifery care for women with complex pregnancy across the childbearing continuum are limited and apply inconsistent methods of economic evaluation. The cost and outcomes of implementing continuity of midwifery care for women with complex pregnancy is an important issue that requires further investigation. Robust cost-effectiveness evidence is essential to inform decision makers, to implement sustainable systems change in comparative maternity models for pregnant women at risk and to address health inequity. PMID- 30519756 TI - Vertebral fractures cascade: potential causes and risk factors. AB - : We performed a study to identify potential causes and risk factors of vertebral fracture cascade. Vertebral fracture cascade is a severe clinical event in patients with bone fragility. Only half of patients have an identified cause of secondary osteoporosis. INTRODUCTION: Vertebral fracture (VF) is the most common osteoporotic fracture, and a strong risk factor of subsequent VFs leading to VF cascade (VFC). We prompted a study to identify potential causes and risk factors of VFC. METHODS: VFC observations were collected retrospectively between January 2016 and April 2017. VFC was defined as an occurrence of at least three VFs within 1 year. RESULTS: We included in 10 centers a total of 113 patients with VFC (79.6% of women, median age 73, median number of VFs in the cascade, 5). We observed 40.5% and 30.9% of patients with previous major fractures and a previous VF, respectively, and 68.6% with densitometric osteoporosis; 18.9% of patients were currently receiving oral glucocorticoids and 37.1% in the past. VFC was attributed by the physician to postmenopausal osteoporosis in 54% of patients. A secondary osteoporosis associated with the VFC was diagnosed in 52 patients: glucocorticoid-induced osteoporosis (25.7%), non-malignant hemopathies (6.2%), alcoholism (4.4%), use of aromatase inhibitors (3.6%), primary hyperparathyroidism (2.7%), hypercorticism (2.7%), anorexia nervosa (2.7%), and pregnancy and lactation-associated osteoporosis (1.8%). A total of 11.8% of cases were reported following a vertebroplasty procedure. A total of 31.5% patients previously received an anti-osteoporotic treatment. In six patients, VFC occurred early after discontinuation of an anti-osteoporotic treatment, in the year after the last dose effect was depleted: five after denosumab and one after odanacatib. CONCLUSION: The results of this retrospective study showed that only half of VFC occurred in patients with a secondary cause of osteoporosis. Prospective studies are needed to further explore the determinants of this severe complication of osteoporosis. PMID- 30519758 TI - Risk factors for potential pulmonary embolism in the patients with deep venous thrombosis: a retrospective study. AB - INTRODUCTION: The risk factors for the detachment of big thrombi from the vessel wall in patients with deep venous thrombosis (DVT) are still not clear, which are potential risks for pulmonary embolism (PE). This study was aimed to identify the risk factors for big thrombi detaching from the vessel wall in the patients with lower extremity DVT and to identify the role of the lower limb immobilization. METHODS: We retrospectively reviewed the patients whose inferior vena cava (IVC) filter were removed in our hospital. Baseline data and clinical characteristics of all patients were reviewed, including hypertension, diabetes, D-dimer, the onset site of the thrombus, major surgery and lower limb immobilization. The size of the thrombus in the removed IVC filter was assessed by digital subtraction angiography. The thrombus above 1 cm in diameter was defined as potential thrombus of PE and the thrombus below 1 cm as non-potential thrombus of PE. The characteristics and potential risk factors of the patients with potential thrombus of PE were compared with those with non-potential thrombus of PE. Independent risk factors were further analyzed using multivariable regression analyses. RESULTS: Three hundred and forty-nine patients were included in the study. There is no significant difference in age, gender, hypertension, diabetes, D-dimer, or the thrombus site between the two groups. Major surgery and mobile lower limb were independent risk factors for potential thrombus of PE. CONCLUSION: The results suggested that major surgery and mobile lower limb were independent risk factors for potential thrombus of PE in patients with DVT. Immobilization of lower limb might play a protective role in preventing big thrombi from detaching from the vessel wall in patients with DVT. PMID- 30519757 TI - The first comprehensive description of the expression profile of genes involved in differential body growth and the immune system of the Jeju Native Pig and miniature pig. AB - Sus scrofa provides a major source of animal protein for humans as well as being an excellent biomedical model. This study was carried out to understand, in detail, the genetic and functional variants of Jeju Native Pigs and miniature pigs through differential expression profiling of the genes controlling their immune response, growth performance, and meat quality. The Illumina HiSeq 2000 platform was used for generating 1.3 billion 90 bp paired-end reads, which were mapped to the S. scrofa genome using TopHat2. A total of 2481 and 2768 genes were differentially expressed with 8-log changes in muscle and liver samples, respectively. Five hundred forty-eight genes in muscle and 642 genes in liver samples had BLAST matches within the non-redundant database. GO process and pathway analyses showed enhanced biological processes related to the extracellular structural organization and skeletal muscle cell differentiation in muscle tissue, whereas the liver tissue shares functions related to the inflammatory response. Herein, we identify inflammatory regulatory genes in miniature pigs and growth response genes in Jeju Native Pigs, information which can provide a stronger base for the selection of breeding stock and facilitate further in vitro and in vivo studies for therapeutic purposes. PMID- 30519759 TI - Embedded Finite Elements for Modeling Axonal Injury. AB - The purpose of this paper is to propose and develop a large strain embedded finite element formulation that can be used to explicitly model axonal fiber bundle tractography from diffusion tensor imaging of the brain. Once incorporated, the fibers offer the capability to monitor tract-level strains that give insight into the biomechanics of brain injury. We show that one commercial software has a volume and mass redundancy issue when including embedded axonal fiber and that a newly developed algorithm is able to correct this discrepancy. We provide a validation analysis for stress and energy to demonstrate the method. PMID- 30519760 TI - ASO Author Reflections: Pancreatic Neuroendocrine Tumor Recurrence and Survival Predicted by Ki67. PMID- 30519761 TI - ASO Author Reflections: PTTG1 Protein Expression in Adrenocortical Carcinoma. PMID- 30519762 TI - ASO Author Reflections: Annexin A3 as a Potential Biomarker for Hepatocellular Carcinoma. PMID- 30519763 TI - Promising Long-Term Outcomes After Pelvic Exenteration. AB - BACKGROUND: Pelvic exenteration (PE) is a complex and challenging surgical procedure. The reported results of this procedure for primary and recurrent disease are limited and conflicting. METHODS: This study analyzed patient outcomes after all PEs performed in the authors' department between October 2001 and December 2016. Relevant patient data were obtained from a prospective database. Morbidity and mortality were reported for all patients. For patients with malignant disease, differences in perioperative outcomes, prognostic indicators for overall survival, and local and systemic disease recurrence were analyzed using uni- and multivariate analyses. RESULTS: The study enrolled 187 patients. Of the 183 patients with malignant disease, 63 (38.2%) had primary locally advanced tumors and 115 (62.5%) had recurrent tumors. The 10-year overall survival rate was 63.5% for the patients with primary tumors that were curatively resected and 20.9% for the patients with recurrent disease (p = 0.02). The 10 year survival rate for the patients with extrapelvic disease who underwent curative resection was 37%. Multivariable analysis identified margin positivity (p < 0.01), surgery lasting longer than 7 h (p = 0.02), and recurrent disease (p < 0.01) as predictors of poor survival. Multivariate analysis of local and systemic disease recurrence showed recurrent disease (p < 0.01) as the only significant prognostic factor. CONCLUSIONS: Pelvic exenteration has good long term results, even for patients with extrapelvic disease. The oncologic outcome for patients with recurrent disease is worse than for patients with primary disease. However, even for these patients, long-time survival is possible. PMID- 30519764 TI - The Role of the Neo-Bioscore Staging System in Guiding the Optimal Strategies for Regional Nodal Irradiation Following Neoadjuvant Treatment in Breast Cancer Patients with cN1 and ypN0-1. AB - BACKGROUND: The role of regional nodal irradiation (RNI) in patients with cN1 breast cancer following neoadjuvant treatment (NAT) is still controversial. The Neo-Bioscore staging system has shown promising prospect in assessing individual prognosis after NAT, and we sought to evaluate the role of Neo-Bioscore in guiding RNI following NAT. METHODS: Medical records of 163 women with cN1 and ypN0-1 disease treated with NAT between 2009 and 2014 were retrospectively reviewed and a Neo-Bioscore was assigned to each patient. Survivals were calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate analysis was used to identify independent predictors by using Cox proportional hazards models. RESULTS: The median follow-up after surgery was 59.4 months. Of all 163 patients, 119 received RNI. At surgery, 36 patients (22.1%) had pathological complete response (pCR), while 89 patients (54.6%) achieved ypN0. In the whole cohort, RNI significantly improved distant metastasis-free survival (DMFS) on multivariable analysis. In the subgroup of patients with a Neo Bioscore of 1-3, RNI significantly improved the 5-year DMFS rate of 97.0% versus 76.9% (p = 0.002), 5-year regional node recurrence-free survival rate of 95.5% versus 76.9% (p = 0.007), and 5-year overall survival rate of 100% versus 89.2% (p = 0.005). No significant difference in outcomes was found between the RNI and non-RNI groups in patients with a score of 4-6. CONCLUSIONS: In patients with cN1 and ypN0-1, RNI was found to significantly improve DMFS following NAT. Patients with a Neo-Bioscore of 1-3 are more likely to benefit from RNI, however a large prospective study is needed to confirm this finding. PMID- 30519765 TI - [Acute Pelvic pain in women-gynecological causes]. AB - BACKGROUND: Acute pelvic pain in women may be due to gynecological, gastrointestinal, and urinary tract disorders. Ectopic pregnancy (EP), pelvic inflammatory disease (PID), and ruptured ovarian cysts are the most common gynecological causes for acute pelvic pain and their diagnosis can be challenging. METHODS: Patient history, clinical examination, and blood tests as well as patient age and potential pregnancy status help to establish the correct diagnosis. While sonography (US) remains the primary imaging modality of choice, computed tomography (CT) plays an important role in patients with indeterminate US evaluation and for treatment planning. CONCLUSION: Diagnostic imaging is pivotal to differentiate potentially life- and fertility-threatening conditions from those that can be treated conservatively. Profound knowledge of the most common gynecological pathologies allows prompt and correct radiological diagnosis and assists in proper treatment planning. PMID- 30519766 TI - Effects of omega-3 fatty acids on metabolic syndrome in patients with schizophrenia: a 12-week randomized placebo-controlled trial. AB - RATIONALE: Individuals with schizophrenia are at increased risk of developing metabolic syndrome (MetS) due to their lifestyle and antipsychotic treatment. Our previous study showed that patients with both schizophrenia and MetS present an increased expression and production of tumor necrosis factor-alpha (TNF-alpha). Omega-3 fatty acids have a documented role in suppressing TNF-alpha; therefore, we hypothesized that they may be of value in relieving inflammation and improving metabolic disturbance in patients with both schizophrenia and MetS. OBJECTIVES: This study employed a randomized placebo-controlled trial to investigate the effects of omega-3 fatty acids on MetS in patients with schizophrenia. METHODS: We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). RESULTS: Patients with both schizophrenia and MetS had significantly higher levels of TNF-alpha than the control subjects (Z = - 4.37, P < 0.01). There was a significant correlation between omega-3 fatty acid treatment and reduced triglyceride (TG) levels (Fgroup * time = 13.42; df = 1, 66; P < 0.01) when the patients completed this study. Along with metabolic improvement, omega-3 fatty acids decreased TNF-alpha levels after 12 weeks of treatment (Fgroup * time = 6.71; df = 1, 66; P = 0.012). We also found that the extent of TNF-alpha decrease was significantly correlated with that of TG decrease (r = 0.38, P = 0.001). CONCLUSIONS: Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on TG metabolism in patients with both schizophrenia and MetS that parallel decreased inflammation levels. PMID- 30519767 TI - Response to the Letter from Dr. Jacob Peedicayil. PMID- 30519769 TI - Application of a linear stapler to the laparoscopic treatment of gastrocolic fistula in patients with Crohn's disease. PMID- 30519768 TI - [Care of parents with dementia: comparison of caregiving sons and daughters]. AB - BACKGROUND: In view of the demographic changes and the associated increasing need for care, the role of caregiving sons will also become more important; however, little is known about the caregiving experiences of sons. OBJECTIVE: Potential differences between caregiving sons and daughters were investigated with respect to the style of caregiving, the feeling of stress and burden and the utilization of support offers. MATERIAL AND METHODS: Baseline survey data from the interventional study Tele.TAnDem conducted from September 2012 to January 2014 were analyzed. From the total sample of 322 caregiving relatives of people suffering from dementia the participating sons (n = 17) were selected. For comparison 17 participants from the subsample of daughters (n = 111) were selected by propensity score matching. The analyses were conducted using t-tests, Mann-Whitney tests and chi2-tests. RESULTS: The analyses regarding the style of caregiving, the feeling of stress and burden and the utilization of professional and informal assistance did not reach statistical significance. Daughters scored on average higher than sons only with respect to the acceptance of the caregiving situation (p < 0.05). CONCLUSION: Overall caregiving daughters and sons did not differ with respect to caregiving experiences as strongly as previously assumed. Perhaps earlier studies found more gender differences because caregiving sons compared to daughters already have different initial situations, which however remained uncontrolled. PMID- 30519770 TI - The application of fluorescence techniques in meningioma surgery-a review. AB - Surgical resections of meningiomas, the most common intracranial tumor in adults, can only be curative if radical resection is achieved. Potentially, the extent of resection could be improved, especially in complex and/or high-grade meningiomas by fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA), indocyanine green (ICG), or fluorescein. This review aims to summarize and evaluate these fluorescence-guided meningioma surgery techniques. PubMed and Embase were searched for relevant articles. Additionally, we checked reference lists for further studies. Forty-eight articles were included in the final analysis. 5-ALA fluoresced with varying sensitivity and selectivity in meningiomas and in invaded bone and dura mater. Although ICG was mainly applied for video angiography, one report shows tumor fluorescence 18-28 h post-ICG injection. Lastly, the use of fluorescein could aid in the identification of tumor remnants; however, detection of dural tail is highly questionable. Fluorescence-guided meningioma surgery should be a reliable, highly specific, and sensitive technique. Despite numerous studies reporting the use of fluorescent dyes, currently, there is no evidence that these tools improve the radical resection rate and long-term recurrence-free outcome in meningioma surgery without neurological deficits. Evidence regarding the effectiveness and increased safety of resection after the application of these fluorophores is currently lacking. Future research should focus on the development of a meningioma-targeted, highly sensitive, and specific fluorophore. PMID- 30519771 TI - A literature review concerning contralateral approaches to paraclinoid internal carotid artery aneurysms. AB - Ipsilateral approaches remain the standard technique for clipping paraclinoid aneurysms. Surgeons must however be prepared to deal with bony and neural structures restricting accessibility. The application of a contralateral approach has been proposed claiming that some structures in the region can be better exposed from this side. Yet, only few case series have been published evaluating this approach, and there is a lack of systematic reviews assessing its specific advantages and disadvantages. We performed a structured literature search and identified 19 relevant publications summarizing 138 paraclinoid aneurysms operated via a contralateral approach. Patient's age ranged from 19 to 79 years. Aneurysm size mainly varied between 2 and 10 mm and only three articles reported larger aneurysms. Most aneurysms were located at the origin of the ophthalmic artery, followed by the superior hypophyseal artery and carotid cave. All aneurysm protruded from the medial aspect of the carotid artery. Interestingly, minimal or even no optic nerve mobilization was required during exposure from the contralateral side. Strategies to achieve proximal control of the carotid artery were balloon occlusion and clinoid segment or cervical carotid exposure. Successful aneurysm occlusion was achieved in 135 cases, while 3 ophthalmic aneurysms had to be wrapped only. Complications including visual deterioration, CSF fistula, wound infection, vasospasm, artery dissection, infarction, and anosmia occurred in a low percentage of cases. We conclude that a contralateral approach can be effective and should be considered for clipping carefully selected cases of unruptured aneurysms arising from medial aspects of the above listed vessels. PMID- 30519772 TI - Metal Substrate-Induced Line Width Compression in the Magnetic Dipole Resonance of a Silicon Nanosphere Illuminated by a Focused Azimuthally Polarized Beam. AB - We investigate the modification of the magnetic dipole resonance of a silicon nanosphere, which is illuminated by a focused azimuthally polarized beam, induced by a metal substrate. It is found that the magnetic dipole of the silicon nanosphere excited by the focused azimuthally polarized beam and its image dipole induced by the metal substrate are out of phase. The interference of these two anti-parallel dipoles leads to a dramatic line width compression in the magnetic dipole resonance, manifested directly in the scattering spectrum of the silicon nanosphere. The quality factor of the modified magnetic dipole resonance is enhanced by a factor of ~ 2.5 from ~ 14.62 to ~ 37.25 as compared with that of the silicon nanosphere in free space. Our findings are helpful for understanding the mode hybridization in the silicon nanosphere placed on a metal substrate and illuminated by a focused azimuthally polarized beam and useful for designing photonic functional devices such as nanoscale sensors and color displayers. PMID- 30519773 TI - Iftikhar and Colleagues Reply: Methodology Clarified. PMID- 30519774 TI - HIV-associated cancers: the role of a unique multidisciplinary board to optimize patient's care behalf the CANCERVIH Group. AB - Since 1996, the life expectancy of people living with HIV (PLWHIV) has improved, while their risk of cancer is 2-3 times higher than in the general population. HIV-associated cancers remain a critical issue in this population and represent a particular care challenge due to the high risk of drug interactions and additive toxicity. The new standards of care with immunotherapy will also become a major issue for PLWHIV because of the potential impact on immunology and virology. Thus, the National Cancer Institute created the CANCERVIH national network in 2014 in France, enabling the establishment of a multidisciplinary national board of experts. This is an important first step that will help patients and health professionals provide optimal treatment to PLWHIV and prevent disparities. We hope that such a multidisciplinary council will make its voice heard in other countries and that this could be useful for patients with HIV-related cancers. PMID- 30519775 TI - Dendritic cells in the pathogenesis of ankylosing spondylitis and axial spondyloarthritis. AB - The interaction of dendritic cells (DCs) with the human microbiome, with distorted handling of the microbiota or its products via the direct effect of HLA B27, probably represents the initial element in the chain of events leading to the development of clinical axial spondyloarthritis. The mechanism of disease extension onto the skeleton and other tissues involved, such as uvea, may also involve migratory DCs. Finally, the role of DCs in the initiation of the inflammatory tissue response with activation of the IL-17 axis has been demonstrated. Further, some initial data suggests the possible connection of DCs with disease-related new bone formation. PMID- 30519776 TI - Vibrotactile feedback improves balance and mobility in patients with severe bilateral vestibular loss. AB - The impact of vibrotactile feedback of the gravity vector, provided by a "balance" belt worn around the waist, was evaluated in 39 patients with a severe bilateral vestibular loss, confirmed by extensive laboratory testing and suffering from a low quality of life, mainly due to imbalance. The mobility and balance score (MBS) of all patients prior to the use of the belt was equal or less than 5 out of a scale of 10. Thirty-one out of the 39 patients experienced the effect of the belt on their balance and mobility as positive in a preselection trial of 2 h in the hospital. The 31 positive responders then used the belt for 1 month in daily life. The average MBS increased significantly from 4.2 to 7.9 (paired T test, T = 9.82, p < 0.00001). Twenty-three out of 31 patients reported a benefit ranging from an improvement of 60-200% in their MBS. Eight patients did not experience any benefit. In summary, 23 out of 39 patients with a severe imbalance due to a bilateral vestibular loss experienced a clear benefit of vibrotactile feed = back in daily life. We conclude that vibrotactile feedback via the waist can serve as an effective prothesis for patients with severe bilateral vestibular loss to improve the quality of life. PMID- 30519777 TI - Diastereoselective synthesis of cyclohexadienes via tandem cyclization strategies. AB - A new protocol has been developed for the diastereoselective synthesis of 1,3 cyclohexadienes using vinyl malononitriles, dibenzalacetones and NaH as reagents in THF. This transformation is comprised of interesting steps like Michael addition, cyclization and ring-opening reactions. PMID- 30519778 TI - 1,1-Diaryl compounds as important bioactive module in pesticides. AB - 1,1-Diaryl compounds are a series of compounds which possess two aryl groups attached to a central carbon atom. This special structure made it as a very important module in bioactive molecules, and compounds of this type are numerous. 1,1-Diaryl derivatives can be used as catalysts in chemical synthesis, chemical probes and biologically active molecules for medicines and pesticides. In this review, we focus on the application of these compounds in pesticides, such as insecticides and fungicides. The generic structure of the 1,1-diaryl compounds is discussed in this review. PMID- 30519779 TI - Perfluorinated compounds binding to estrogen receptor of different species: a molecular dynamic modeling. AB - Perfluorinated compounds (PFCs) were widely utilized in commercial and industrial applications, which could interfere with the endocrine systems of experimental animals and humans by interacting with estrogen receptors (ERs). Considering the possible differential binding preferences and relative binding affinities of PFCs to ERs of humans and other species, a cross-species comparison is necessary to effectively assess the health risk of PFCs to humans. In the present work, the species-specific binding characterizations between two PFCs, including perfluorooctane sulfonate (PFOS) and PFOS(4m, 5m), and the different ERalphas from Rattus norvegicus, rainbow trout, and humans were explored based on a molecular dynamic modeling. The results proved that linear perfluorinated compound PFOS could make a much stronger binding to ERalphas than the branched perfluorinated compounds PFOS(4m, 5m). In addition, PFOS and PFOS(4m, 5m) presented species-difference among human, Rattus norvegicus, and rainbow trout. The binding affinity with ERalpha presented an order of human >Rattus norvegicus > rainbow trout. This suggested that PFOS and PFOS(4m, 5m) have the strongest effects on human ERalpha over the other two species. As a consequence, the PFCs were more sensitive to human ERalpha than to those of Rattus norvegicus and rainbow trout. This resulted in greater susceptibility to adverse effects, which suggested a possible underestimation of the endocrine-disrupting effects of PFCs in humans. The cross-species comparison represents the first and necessary step to identify species-specific binding mechanisms and to accurately evaluate the potential health risks of PFCs in humans. PMID- 30519780 TI - MicroRNA-214 promotes the calcification of human aortic valve interstitial cells through the acceleration of inflammatory reactions with activated MyD88/NF-kappaB signaling. AB - Calcific aortic valve disease (CAVD) is a complex active process involving in endothelial injury, lipid infiltration, chronic inflammation, matrix remodeling, cell differentiation, progressive bone formation, and new angiogenesis. The excess inflammatory responses induced by aortic valve interstitial cells (AVICs) are one of the common pathogeneses of this disease. Although many microRNAs (miRs) have been identified to play crucial roles in the calcification process of the aortic valve, numerous miRs are still waiting to be explored. In this study, we explored the functional role of miR-214 in the inflammatory reaction and calcification of human AVICs and its underlying molecular mechanism. Alizarin red staining was used to determine the number of calcified nodules. The protein levels of ICAM-1, IL-6, IL-8, and MCP-1 detected by enzyme-linked immunosorbent assay (ELISA) were used to assess the inflammatory reaction of AVICs; expression levels of RUNX2, Msx2, and BMP2 were used to evaluate AVICs osteoblast differentiation. Results showed that the expression levels of TLR4, MyD88, NF kappaB, and miR-214 were up-regulated in the blood and aortic valve tissue samples of patients with CAVD when compared with normal individuals. Knockdown of miR-214 in AVICs inhibited the secretion of IL-6, IL-8, ICAM-1, and MCP-1, while this effect was repressed when lipopolysaccharide (LPS) was added to AVICs. LPS also enhanced the effects of miR-214 in promoting the secretion of pro inflammatory factors. Besides, up-regulation of miR-214 promoted the protein expression of MyD88 and NF-kappaB but had no influence on TLR4, and miR-214 could directly combine with MyD88 protein. Up-regulation of MyD88 facilitated the secretion of pro-inflammatory factors and increased calcified nodules number and accelerated the expression of RUNX2, Msx2, and BMP2. Moreover, promotion of the expressions of pro-inflammatory factors and "osteoblast-like" cell markers induced by miR-214 overexpression was abolished when MyD88 was down-regulated in AVICs. In conclusion, this study revealed that miR-214 promoted calcification by facilitating inflammatory reaction through MyD88/NF-kappaB signaling pathway in AVICs. PMID- 30519781 TI - Catheter ablation in ASymptomatic PEDiatric patients with ventricular preexcitation: results from the multicenter "CASPED" study. AB - BACKGROUND: As there are limited data about the clinical practice of catheter ablation in asymptomatic children and adolescents with ventricular preexcitation on ECG, we performed the multicenter "CASPED" (Catheter ablation in ASymptomatic PEDiatric patients with Ventricular Preexcitation) study. METHODS AND RESULTS: In 182 consecutive children and adolescents aged between 8 and 18 years (mean age 12.9 +/- 2.6 years; 65% male) with asymptomatic ventricular preexcitation, a total of 196 accessory pathways (APs) were targeted. APs were right sided (62%) or left sided (38%). The most common right-sided AP location was the posteroseptal region (38%). Ablation was performed using radiofrequency (RF) energy (93%), cryoablation (4%) or both (3%). Mean procedure time was 137.6 +/- 62.0 min with a mean fluoroscopy time of 15.6 +/- 13.8 min. A 3D mapping or catheter localization system was used in 32% of patients. Catheter ablation was acutely successful in 166/182 patients (91.2%). Mortality was 0% and there were no major periprocedural complications. AP recurrence was observed in 14/166 patients (8.4%) during a mean follow-up time of 19.7 +/- 8.5 months. A second ablation attempt was performed in 20 patients and was successful in 16/20 patients (80%). Overall, long-term success rate was 92.3%. CONCLUSION: In this retrospective multicenter study, the outcome of catheter ablation for asymptomatic preexcitation in children and adolescents irrespective of antegrade AP conduction properties is summarized. The complication rate was low and success rate was high, the latter mainly depending on pathway location. The promising results of the study may have future impact on the ongoing risk-benefit discussion regarding catheter ablation in the setting of asymptomatic preexcitation in children and adolescents. PMID- 30519782 TI - Involvement of natriuretic peptide system in C2C12 myocytes. AB - The natriuretic peptide system, a key regulator of cGMP signaling, comprises three types of natriuretic peptides, osteocrin/musclin (OSTN), and their natriuretic peptide receptors. Although this system plays important roles in many organs, its physiological roles in skeletal muscle have not been clearly described. In the present study, we investigated the role of the natriuretic peptide system in C2C12 myocytes. All three natriuretic peptide receptors were expressed by cells differentiating from myoblasts to myotubes, and natriuretic peptide receptor B (NPR-B) transcripts were detected at the highest levels. Further, higher levels of cGMP were generated in response to stimulation with C type natriuretic peptide (CNP) versus atrial natriuretic peptide (ANP), which reflected receptor expression levels. A cGMP analog downregulated the expression of a few ER stress-related genes. Furthermore, OSTN gene expression was strongly upregulated after 20 days of differentiation. Augmented gene expression was found to correlate closely with endoplasmic reticulum (ER) stress, and C/EBP [CCAAT enhancer-binding protein] homologous protein (CHOP), which is known to be activated by ER stress, affected the expression of OSTN. Together, these results suggest a role for natriuretic peptide signaling in the ER stress response of myocytes. PMID- 30519783 TI - Sodium fluoride induces apoptosis and autophagy via the endoplasmic reticulum stress pathway in MC3T3-E1 osteoblastic cells. AB - Fluorosis and bone pathologies can be caused by chronic and/or excessive fluoride intake. Despite this, few studies have been conducted on the cellular mechanisms underlying osteoblast toxicity in the presence of NaF. Here, we investigated the effects of fluoride on MC3T3-E1 cells. We showed that the proliferation of MC3T3 E1 cells was inhibited by exposure to NaF. In addition, apoptosis was induced by NaF, as caspase-associated proteins showed a higher level of expression and apoptotic bodies were formed. Furthermore, endoplasmic reticulum (ER) stress induced by NaF activated the unfolded protein response (UPR) and upregulated the expression of the glucose-regulated proteins 94 (GRP94) and 78 (BiP). Therefore, ER stress plays a vital role in NaF-induced autophagy and apoptosis. Furthermore, apoptosis is promoted following the inhibition of NaF-induced autophagy. In conclusion, under NaF treatment, the ER stress-signaling pathway is activated, leading to apoptosis and autophagy and affecting the proliferation and survival of MC3T3-E1 cells. PMID- 30519784 TI - Quality and Stability of Cross-Ethnic Friendships: Effects of Classroom Diversity and Out-of-School Contact. AB - Cross-ethnic friendships are linked to a range of positive outcomes in adolescence, but have been shown to be lower quality and less stable than same ethnic friendships. The current study examined how classroom diversity and out-of school contact contribute to these relational differences between cross-and same ethnic friendships. Multilevel analyses were conducted on a sample of 9,171 classroom-based friends nested within 4,333 ethnically diverse sixth grade students (54% female; 32% Latino, 20% White, 14% East/Southeast Asian, 12% African American, 14% Multiethnic, 8% Other ethnic). Consistent with the hypotheses, lower ethnic diversity in classes shared by friends and lack of home contact (as opposed to electronic) contributed to relational differences between cross- and same-ethnic friendships. The findings suggest that while diverse classrooms enable youth to bond across ethnic groups, connecting outside of school is critical for the relational quality and longevity of cross-ethnic friendships. PMID- 30519785 TI - Winogradskyella algae sp. nov., a marine bacterium isolated from the brown alga. AB - An aerobic, Gram-negative, yellow-pigmented non-motile rod-shaped bacterium Kr9 9T was isolated from a brown alga specimen collected near the Kuril Islands. Based on the 16S rRNA gene sequence analysis strain Kr9-9T was assigned to the genus Winogradskyella, and its close phylogenetic neighbors were found to be Winogradskyella damuponensis KCTC 23552T, Winogradskyella sediminis LMG 28075T, and Winogradskyella rapida CCUG 59098T showing high similarities of 98.1%, 97.5%, and 97.1%, respectively. It contained MK-6 as the predominant menaquinone and iso C15:0, anteiso-C15:0, iso-C16:0 3-OH followed by iso-C15:1 as the major fatty acids. Polar lipids included phosphatidylethanolamine, three unidentified aminolipids and an unidentified lipid. The DNA C+C content was 32.3 mol%. Based on the phylogenetic analysis and distinctive phenotypic characteristics, strain Kr9-9T is concluded to represent a novel species of the genus Winogradskyella, for which the name Winogradskyella algae sp. nov. is proposed. The type strain of the species is strain Kr9-9T (= KMM 8180T = KACC 19709T). PMID- 30519786 TI - Learning climate positively influences residents' work-related well-being. AB - An optimal learning climate is crucial for the quality of residency training and may also improve residents' well-being and empathy. We investigated the associations of learning climate with residents' work-related well-being. A multicenter questionnaire study was performed among 271 surgery and gynaecology residents in 21 training programs from September 2012 to February 2013. Residents were asked to complete work-related well-being measurements: work engagement (Utrecht Work Engagement Scale), job and specialty satisfaction (measures from Physician Worklife Study), and physician empathy (Jefferson Scale of Physician Empathy). The Dutch Residency Educational Climate Test was used to evaluate learning climate. Multivariate adjusted linear regression analyses were used to estimate associations of learning climate with work-related well-being measures. Well-being measures were completed by 144 residents (53.1%). Learning climate was evaluated by 193 residents, yielding 9.2 evaluations per training program on average. Overall learning climate score was positively associated with work engagement [regression coefficient b = 0.58; 95% confidence interval (CI) 0.18 0.98; p = 0.004] and job satisfaction (b = 0.80; 95% CI 0.48-1.13; p < 0.001). No associations were found between learning climate and empathy and specialty satisfaction. Residents' work engagement and job satisfaction are positively related to the learning climate and may be further enhanced by improved learning climates of training programs. PMID- 30519787 TI - Autism Spectrum Disorder: Incidence and Time Trends Over Two Decades in a Population-Based Birth Cohort. AB - We retrospectively identified autism spectrum disorder (ASD) incident cases among 31,220 individuals in a population-based birth cohort based on signs and symptoms uniformly abstracted from medical and educational records. Inclusive and narrow research definitions of ASD (ASD-RI and ASD-RN, respectively) were explored, along with clinical diagnoses of ASD (ASD-C) obtained from the records. The incidence of ASD-RI, ASD-RN, and ASD-C increased significantly from 1985 to 1998, then ASD-RI and ASD-RN plateaued while the rate of ASD-C continued to increase during 1998-2004. The rising incidence of research-defined ASD may reflect improved recognition and documentation of ASD signs and symptoms. Although the frequency of threshold ASD symptoms stabilized, the rate of ASD-C continued to increase, narrowing the gap between clinical ascertainment and symptom documentation. PMID- 30519788 TI - Studies on cellulase-ultrasonic assisted extraction technology for flavonoids from Illicium verum residues. AB - BACKGROUND: Illicium verum is widely cultivated in southern China especially in Guangxi province. Its fruits has been traditionally used in Chinese medicine. In recent years, it has been the industrial source of shikimic acid. Usually the residues after extracting shikimic acid are treated as waste. Thus, the aim of this study was to optimize the extraction conditions of cellulase-ultrasonic assisted extraction technology for flavonoids from I. verum residues. RESULTS: The optimum extraction conditions with a maximum flavonoids yield of 14.76 % are as follows: the concentration of ethanol is 51.14 %, the liquid-solid ratio is 20.52 mL/g, the enzymatic hydrolysis pH is 5.303, the sonication time is 60 min, the enzyme solution temperature is kept at 45 degrees C, the amount of added enzyme is 70 mg/g, the enzymatic hydrolysis time is 2 h and the crushed mesh size is 0.355-0.85 mm. CONCLUSIONS: The data indicate that the cellulase-ultrasonic assisted extraction technology has the potential be used for the industrial production of flavonoids from I. verum. PMID- 30519789 TI - Determination of the activity of T4 polynucleotide kinase phosphatase by exploiting the sequence-dependent fluorescence of DNA-templated copper nanoclusters. AB - A fluorometric method is described for the determination of the activity of the enzyme T4 polynucleotide kinase phosphatase (T4 PNKP). A short 3'-terminus phosphorylated DNA strand is hybridized with a long DNA strand to produce a partially double-stranded DNA (dsDNA) substrate. On addition of T4 PNKP, the substrate is dephosphorylated to generate the long dsDNA, and then the long dsDNA acted as a template for synthesizing copper nanoclusters (CuNCs). The dsDNA templated CuNCs display fluorescence with excitation/emission peak wavelengths of 340/570 nm. The fluorescence is DNA sequence-dependent. A DNA substrate was designed to enhance fluorescence and to reduce the background in order to improve the sensitivity of the assay. The assay has an analytical range that extends from 0.07 U mL-1 to 15 U mL-1 and a detection limit of 0.06 U mL-1. Graphical abstract The sequence-dependent fluorescence of DNA-templated copper nanoclusters, which are in-situ synthesized through the reduction of CuSO4 by ascorbate (Vc) in the presence of dsDNA template, is utilized to obtain the method for sensitive detection of T4 PNKP activity with near-zero background. PMID- 30519790 TI - Cell laden alginate-keratin based composite microcapsules containing bioactive glass for tissue engineering applications. AB - Microcapsules based on alginate-keratin, alginate dialdehyde (ADA)-keratin and ADA-keratin-45S5 bioactive glass (BG) were successfully prepared. The samples were characterized by light microscopy, scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The results showed that ADA-based materials possess higher degradation rate compared to alginate-based materials. The incorporation of BG particles (mean particle size: 2.0 um) improved the bioactivity of the materials. Moreover, the biological properties of the samples were evaluated by encapsulating MG-63 osteosarcoma cells into the microcapsules. The cell viability in all samples increased during 21 days of cultivation. However, the presence of 0.5% BG particle seemed to have initial negative effect on cell growth compared to other samples without BG. On the other hand, the positive effect of CaP formation was visible after 3 weeks in the BG containing samples. The results are relevant to consider the development of cell laden bioinks incorporating inorganic bioactive particles for biofabrication approaches. PMID- 30519791 TI - Centiloid scaling for quantification of brain amyloid with [18F]flutemetamol using multiple processing methods. AB - INTRODUCTION: A standardised method for quantifying beta-amyloid PET tracers would allow comparison across different tracers and different sites. The development of the Centiloid scale has aimed to achieve this, applying a common scale to better aid the diagnosis and prognosis of Alzheimer's disease (AD) and to monitor anti-amyloid therapeutic interventions. Here, we apply the Centiloid method to [18F]flutemetamol and [11C]PiB (PiB, Pittsburgh compound B) PET images and derive the scaling factor to express their binding in Centiloids. METHODS: Paired PiB and [18F]flutemetamol scans for 74 subjects, including 24 young healthy controls (37 +/- 5 years), were analysed using the standard Centiloid method. The same subjects were also analysed using PMOD- and FSL-based pipelines as well as SPM8. Test-retest analysis of 10 AD subjects was also performed with each pipeline. RESULTS: The standard uptake value ratios (SUVR), determined using the standard SPM8 Centiloid process, showed a strong correlation between [18F]flutemetamol (Flute) and PiB binding (SUVR-Flute = 0.77 * SUVR-PiB + 0.22, R2 = 0.96). Application of the standard Centiloid process allowed the calculation of a direct conversion equation for SUVR-Flute to Centiloid units (CL) (CL = (121.42*SUVR-Flute) - 121.16). Analysis of the data via the two alternate Centiloid pipelines allowed us to derive standardised, SPM8-equivalent equations for both PMOD (CL = (115.24*SUVR-Flute) - 107.86) and FSL (CL = (120.32*SUVR Flute) - 112.75) respectively. Test-retest analysis of 10 AD subjects showed an approximate 2% difference for each pipeline. CONCLUSIONS: [18F]flutemetamol data can now be expressed in Centiloid units, enhancing its utility in clinical and research applications for beta-amyloid imaging. The standard Centiloid method also demonstrates that [18F]flutemetamol has favourable performance compared with PiB and other beta-amyloid tracers. Test-retest difference averaged 2%, with no difference between image processing pipelines. Centiloid scaling is robust and can be implemented on a number of platforms. PMID- 30519792 TI - Organochlorine pesticides exposure in female adolescents: potential impact on sexual hormones and interleukin-1 levels. AB - The objective of this study was to assess the potential impact of organochlorine pesticides (OCPs) on IL-1 axis in exposed female adolescents through an observational cross-sectional study. The study was conducted in Sary-Agach District (OCPs exposed girls) and Sairam District (OCPs unexposed controls), South Kazakhstan. The study included 524 female adolescents aged 10-17 years (OCPs exposed, n = 253; OCPs unexposed, n = 271). The main outcome was assessment of OCPs blood levels (correlating to pubertal development and sexual hormonal status) and IL-1 levels. The delayed sexual development and the hormonal profile in OCPs exposed female adolescents correlated to the blood levels of OCPs. Interestingly, serum IL-1alpha and IL-1beta in girls living in contaminated areas correlated to OCPs blood levels as well. Both OCPs and IL-1 blood levels in exposed female adolescents resulted to be increased, but further research is required to establish if that might represent an additional factor contributing to puberty disorders and/or reproductive health issues. PMID- 30519793 TI - Testing the keepin' it REAL Substance Use Prevention Curriculum Among Early Adolescents in Guatemala City. AB - This article describes a test in Guatemala City of Mantente REAL, a linguistically adapted version of the keepin' it REAL universal substance use prevention curriculum for early adolescents that teaches culturally grounded drug resistance, risk assessment, and decision making skills. Academic researchers collaborated with a local non-profit to recruit and randomize 12 elementary schools in Guatemala City to intervention and comparison conditions. Regular classroom teachers were trained to deliver the ten-lesson Mantente REAL (MR) manualized curriculum to sixth-grade students. Parents provided passive consent and students gave active assent for data collection, which occurred between February 2013 and September 2014. Two academic year cohorts of students participated (n = 676; 53% male; M age = 12.2). All students completed a pretest questionnaire before the curriculum lessons began in intervention schools and a posttest (87% matched) 4 months later, 1 month after the final lesson. We assessed the MR intervention with paired t tests, effect sizes (Cohen's d), and general linear models adjusted for baseline, attrition, non-linear distributions, and school-level clustering. Results indicated that MR can be an effective school based prevention approach in Guatemala. The MR participants reported pretest-to posttest changes in desirable directions on substance use behaviors, attitudinal antecedents of substance use, and acquisition of drug resistance skills. The comparison group generally changed in undesirable directions. In linear models, the MR participants, relative to the comparison group, reported less cigarette and marijuana use, less positive drug use expectancies, and greater use of drug resistance skills. Intervention effect sizes were between .2 and .3. PMID- 30519794 TI - MRI Presentation of Infectious Intracranial Aneurysms in Infective Endocarditis. AB - BACKGROUND: The radiographic appearance of infectious intracranial aneurysms (IIAs) of infective endocarditis (IE) on magnetic resonance imaging (MRI) of brain is varied. We aimed to describe the IIA-specific MRI features in a series of patients with IIAs. METHODS: Records of patients with active IE who had digital subtraction angiography (DSA) at a tertiary medical center from January 2011 to December 2016 were reviewed. MRIs performed prior to IIA treatment were reviewed for findings on susceptibility-weighted imaging (SWI), diffusion weighted imaging, and T1 with and without contrast. RESULTS: Of the 732 patients with IE, 53 (7%) had IIAs. Of these, 28 patients had an evaluable pre-treatment MRI, in whom 33 IIAs were imaged. MRI to DSA median time was 1 day (interquartile range = 1-5). On MRI, 12 (36%) IIAs had SWI lesion with contrast enhancement, 7 (21%) had cerebral microbleeds, 3 (11%) had sulcal SWI lesion, 2 (6%) IIAs had abscesses, 3 (9%) had intraparenchymal hemorrhage, 3 (9%) had subarachnoid hemorrhage, and 6 (18%) had ischemic stroke at the anatomical locations of IIAs. Four IIAs (12%) had no correlating MRI findings, though those patients had MRI without contrast. CONCLUSION: The MRI features such as SWI lesion and contrast enhancement were the commonest MRI presentations associated with the presence of IIA. PMID- 30519795 TI - Surveillance Ultrasound in the Neuro Intensive Care Unit: Time to Deep Vein Thrombosis Diagnosis. AB - BACKGROUND/OBJECTIVES: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are complications of hospitalization leading to increased morbidity and mortality. Routine surveillance ultrasound has become common practice in some intensive care units (ICU) to detect DVT early and initiate anticoagulation, preventing complications. However, initiating anticoagulants for asymptomatic DVT treatment may increase risk of hemorrhage. The objective of this study was to investigate the value of routine surveillance ultrasound in early DVT diagnosis in Neuro ICU patients. METHODS: This is a retrospective review of patients diagnosed with DVT during admission to the Neuro ICU at University Hospital from January 1, 2012, through December 31, 2017. Patients were identified through International Classification of Diseases 9th and 10th Revision codes for DVT and PE, screened for inclusion criteria, and then classified as surveillance group or symptom driven group based on intervention received. Primary outcome was time to DVT diagnosis. Secondary outcome included clinically significant hemorrhage identified by anticoagulation treatment discontinuation for suspected hemorrhage or new or expanding hemorrhage on head computerized tomography (CT). RESULTS: A total of 116 patients were identified, with 50 included: 27 were classified as surveillance and 23 as symptom-driven. Seven patients (surveillance = 3 and symptom-driven = 4) were diagnosed with only PE and were excluded from primary outcome. Median time to DVT diagnosis was similar at 148 h for surveillance versus 172 h for symptom driven (p = 0.2). There was no difference in treatment discontinuation rates (surveillance 21% vs symptom 31%; p = 0.4). Of the 27 patients with follow-up head CT, two in the surveillance group and two in the symptom-driven group showed a new or expanding hemorrhage. CONCLUSION: Routine surveillance ultrasound did not lead to significantly earlier DVT diagnosis. Hemorrhagic events were not different between groups. Utility of surveillance ultrasound in this population should be evaluated in large, prospective trials before routine use can be recommended. PMID- 30519796 TI - Comparative features between recombinant lipases CALA-like from U. maydis and CALA from C. antarctica in thermal stability and selectivity. AB - OBJECTIVES: Ustilago maydis lipase A (UMLA) expressed in Pichia pastoris was compared with Candida antarctica lipase A (CALA) to study its biochemical properties such as thermostability and selectivity. RESULTS: UMLA had similar behavior to its homologue CALA regarding the effect of pH and temperature on enzymatic activity, substrate preference and selectivity. Both lipases were active on insoluble triglycerides as well as natural oils and hydrolyzed preferably esters with short and medium acyl and alkyl chains. Both enzymes were slightly selective for the (S)-glycidyl butyrate enantiomer and had a remarkable preference for the sn-2 position of triglycerides. The optimal activity was 40 and 50 degrees C for UMLA and CALA, respectively. However, temperature had a greater effect on the stability of UMLA compared to CALA, observing a half-life at 50 degrees C of 2.07 h and 12.83 h, respectively. CONCLUSIONS: UMLA shares some biochemical properties with CALA such as the sn-2 preference on triglyceride hydrolysis and transesterification. However, the high thermostability attributed to CALA was not observed in UMLA; this can be due to the lack of stabilization via AXXXA motifs in helices and fewer proline residues at the surface. PMID- 30519797 TI - Alpinia calcarata: potential source for the fabrication of bioactive silver nanoparticles. AB - In the present study silver nanoparticles fabricated by using leaf extract of Alpinia calcarata. We have also studied the effect of various experimental parameters viz., metal ion concentration, pH and incubation period on nanoparticle biosynthesis. Results of optimization showed that metal ion concentration of 1.5 mM, alkaline pH and incubation period of 12 h were the optimum conditions for metal nanoparticle biosynthesis. Synthesized silver nanoparticles were characterized by UV-Visible spectroscopy, Dynamic light scattering (DLS), Zeta potential analysis, Fourier transform infrared spectroscopy (FTIR), Inductively coupled plasma-optical emission spectrometry (ICP-OES), Transmission electron microscopy (TEM) and X-ray diffraction analysis (XRD). The UV-visible spectrum shows a sharp peak at 420 nm which was due to the surface plasmon resonance of the silver nanoparticles. Effect of several phytochemicals present in A. calcarata, on synthesis of silver nanoparticles was studied by Fourier transform infrared spectroscopy. The results indicate that the flavonoids, phytosterol, quinones and phenolic compounds present in the plant extract plays a major role in formation of silver nanoparticles in their respective ions in solution. Results of TEM and XRD analysis showed that synthesized silver nanoparticles were mostly spherical in shape with an average diameter of 27.2 +/- 0.2.5 nm and highly crystalline in nature. Moreover the synthesized silver nanoparticles were also evaluated for their potential antibacterial and antioxidant activities. It showed good antibacterial activity as well as antioxidant activity. Thus the obtained result provides a scientific support that leaf extract of A. calcarata can be used efficiently in the production of potential bioactive silver nanoparticles with several pharmaceutical applications. PMID- 30519798 TI - M-Current Expands the Range of Gamma Frequency Inputs to Which a Neuronal Target Entrains. AB - Theta (4-8 Hz) and gamma (30-80 Hz) rhythms in the brain are commonly associated with memory and learning (Kahana in J Neurosci 26:1669-1672, 2006; Quilichini et al. in J Neurosci 30:11128-11142, 2010). The precision of co-firing between neurons and incoming inputs is critical in these cognitive functions. We consider an inhibitory neuron model with M-current under forcing from gamma pulses and a sinusoidal current of theta frequency. The M-current has a long time constant (~90 ms) and it has been shown to generate resonance at theta frequencies (Hutcheon and Yarom in Trends Neurosci 23:216-222, 2000; Hu et al. in J Physiol 545:783-805, 2002). We have found that this slow M-current contributes to the precise co-firing between the network and fast gamma pulses in the presence of a slow sinusoidal forcing. The M-current expands the phase-locking frequency range of the network, counteracts the slow theta forcing, and admits bistability in some parameter range. The effects of the M-current balancing the theta forcing are reduced if the sinusoidal current is faster than the theta frequency band. We characterize the dynamical mechanisms underlying the role of the M-current in enabling a network to be entrained to gamma frequency inputs using averaging methods, geometric singular perturbation theory, and bifurcation analysis. PMID- 30519799 TI - Metvan, bis(4,7-Dimethyl-1,10-phenanthroline)sulfatooxidovanadium(IV): DFT and Spectroscopic Study-Antitumor Action on Human Bone and Colorectal Cancer Cell Lines. AB - The complex bis(4,7-dimethyl-1,10-phenantroline)sulfatooxidovanadium(IV), commonly known as Metvan, was prepared using a known synthetic procedure. Its optimized molecular structure was obtained by DFT calculations, as it was impossible to grow single crystals adequate for a crystallographic study. The complex was also characterized by a detailed analysis of its infrared spectrum, supported by the theoretical calculations, and also by some data derived from its Raman spectrum. In addition, cytotoxicity studies were performed using human osteosarcoma (MG-63) and human colorectal adenocarcinoma (HT-29) cell lines. The results show that Metvan impaired cell viability of both cancer cell lines in a low concentration range (0.25-5.0 MUM). PMID- 30519800 TI - Effect of Long-term Administration of Oral Magnesium Sulfate and Insulin to Reduce Streptozotocin-Induced Hyperglycemia in Rats: the Role of Akt2 and IRS1 Gene Expressions. AB - The effects of long-term oral administration of magnesium sulfate and insulin on hyperglycemia were investigated using Akt2 and IRS1 gene expression methods in streptozotocin-induced diabetic rats. Fifty rats were randomly divided into five experimental groups: 1, non-diabetic control (NDC); 2, Mg2+-treated non-diabetic control (Mg-NDC); 3, chronic diabetic (CD); 4, Mg2+-treated chronic diabetic (Mg CD); and 5, insulin-treated chronic diabetic (Ins-CD). Streptozotocin was used to induce diabetes. The Mg-CD and Mg-NDC groups received 10 g/l of MgSO4 added to drinking water. The Ins-CD group received 2.5 U/kg of insulin twice a day. Blood glucose level and body weight were measured every week. The intraperitoneal glucose tolerance test (IPGTT) was performed after 16 weeks. MgSO4 administration improved the blood glucose level and IPGTT. It also increased Akt2 and IRS1 genes as well as protein expression. Insulin lowered the blood glucose level and increased IRS1 gene and protein expression, but did not affect Akt2 gene and protein expression. Glucose reduction after Mg therapy may be mediated, at least partially, via IRS1 and Akt2 genes and protein stimulation. In insulin-treated rats, insulin resistance was not significant due to the absence of Akt2 gene expression. PMID- 30519801 TI - A modified method of separating Tl(I) and Tl(III) in aqueous samples using solid phase extraction. AB - In spite of the development of new measurement techniques in recent years, the rapid and accurate speciation of thallium in environmental aqueous samples remains a challenge. In this context, a novel method of solid phase extraction (SPE), involving the anion exchange resin AG1-X8, is proposed to separate Tl(I) and Tl(III). In the presence of diethylene triamine pentacetate acid (DTPA), Tl(III) and Tl(I) can be separated by selective adsorption of Tl(III)-DTPA onto the resin, Tl(III) is then eluted by a solution of HCl with SO2. The validity of this method was confirmed by assays of standard solutions of Tl(I) and Tl(III). The proposed method is shown to have an outstanding performance even in solutions with a high ratio of Tl(I)/Tl(III), and can be applied to aqueous samples with a high concentration of other electrolytes, which could interfere with the measurement. Portable equipment and reagents make it possible to use the proposed method routinely in the field. PMID- 30519803 TI - Predictors of Mental Health Recovery in Homeless Adults with Mental Illness. AB - For people with mental illness, experiences of homelessness can complicate mental health recovery processes. This study used longitudinal data from a randomized controlled trial of housing first (HF) to examine predictors of recovery among homeless people with mental illness. Findings showed that health and community predictors were most strongly associated with mental health recovery. Receipt of HF did not have any effect on changes in recovery scores at follow-up. Overall, the findings suggest that interventions aimed at preventing chronic homelessness, strengthening social networks and community involvement, and providing case management services will facilitate mental health recovery. PMID- 30519802 TI - Neuroprotective Autophagic Flux Induced by Hyperbaric Oxygen Preconditioning is Mediated by Cystatin C. AB - We have previously reported that Cystatin C (CysC) is a pivotal mediator in the neuroprotection induced by hyperbaric oxygen (HBO) preconditioning; however, the underlying mechanism and how CysC changes after stroke are not clear. In the present study, we demonstrated that CysC expression was elevated as early as 3 h after reperfusion, and this was further enhanced by HBO preconditioning. Concurrently, LC3-II and Beclin-1, two positive-markers for autophagy induction, exhibited increases similar to CysC, while knockdown of CysC blocked these elevations. As a marker of autophagy inhibition, p62 was downregulated by HBO preconditioning and this was blocked by CysC knockdown. Besides, the beneficial effects of preserving lysosomal membrane integrity and enhancing autolysosome formation induced by HBO preconditioning were abolished in CysC-/- rats. Furthermore, we demonstrated that exogenous CysC reduced the neurological deficits and infarct volume after brain ischemic injury, while 3-methyladenine partially reversed this neuroprotection. In the present study, we showed that CysC is biochemically and morphologically essential for promoting autophagic flux, and highlighted the translational potential of HBO preconditioning and CysC for stroke treatment. PMID- 30519805 TI - A note of thanks and an invitation. PMID- 30519804 TI - Sedentary Behavior and Quality of Life in People with Psychotic Disorders from a Low Income Country: A Study from Uganda. AB - The current study examined the impact of sedentary behaviour (SB) on quality of life (QoL) in people with psychotic disorders. Thirty-six Ugandan women (mean age = 33.9 +/- 8.0 years) and 23 men (37.4 +/- 11.8 years) with a DSM 5 diagnosis of psychosis completed the World Health Organization Quality of Life-Brief version and Simple Physical Activity Questionnaire (SIMPAQ). Medication use, physical co morbidities, weight, height, blood pressure and smoking habits were recorded. Multiple regression analyses were undertaken. Variability in SIMPAQ sedentary and walking scores explained 56% of the variability in psychological QoL, while variability in SIMPAQ walking explained 46% of the variability in physical QoL. Health care professionals should not only consider increasing physical activity but also reducing SB to improve QoL in their patients. PMID- 30519806 TI - Sympathetic nervous system as a target for aging and obesity-related cardiovascular diseases. AB - Chronic sympathetic nervous system overactivity is a hallmark of aging and obesity and contributes to the development of cardiovascular diseases including hypertension and heart failure. The cause of this chronic sympathoexcitation in aging and obesity is multifactorial and centrally mediated. In this mini-review, we have provided an overview of the key and emerging central mechanisms contributing to the pathogenesis of sympathoexcitation in obesity and healthy aging, specifically focusing on hypertension. A clear understanding of these mechanisms will pave way for targeting the sympathetic nervous system for the treatment of cardiovascular diseases in obesity and aging. PMID- 30519807 TI - The clinical impact of sex differences on ischemic postconditioning during primary percutaneous coronary intervention: a POST (the effects of postconditioning on myocardial reperfusion in patients with ST-segment elevation myocardial infarction) substudy. AB - The POST (the effects of postconditioning on myocardial reperfusion in patients with ST-Segment elevation myocardial infarction) study showed that ischemic postconditioning did not improve myocardial reperfusion in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, it has not been determined whether postconditioning is effective in women. This study sought to evaluate the impact of sex differences on ischemic postconditioning during the primary PCI. We analyzed clinical outcomes at 1 year in the 537 men and 163 women with STEMI, who were randomized to the postconditioning or to the conventional PCI group. Women were older, had higher rates of hypertension, were less likely to be current smokers, and had longer symptom-to-reperfusion time. The rate of major adverse cardiac events (MACE: a composite of death, myocardial infarction, severe heart failure, stent thrombosis, or target vessel revascularization) at 1 year was higher in women compared to men (9.8% vs. 5.4%, p = 0.044). MACE was significantly higher in women compared to men in the postconditioning group (12.2% vs. 5.4%, p = 0.042), but not in the conventional PCI group (7.9% vs. 5.4%, p = 0.391). However, women was not an independent predictor after adjusting baseline risk factors, angiographic and procedural parameters (HR 2.67, 95% CI 0.68-10.5, p = 0.158). Despite women having more adverse clinical characteristics, their prognosis was similar to men in the conventional group. Although women showed a higher rate of the MACE compared to men, women were not an independent predictor in the postconditioning group. PMID- 30519808 TI - Diastolic wall strain as a predictor of age-related cardiovascular events in patients with preserved left ventricular ejection fraction. AB - Diastolic wall strain (DWS) was reported as a simple and feasible echocardiographic index in assessing left ventricular (LV) diastolic stiffness. We sought to evaluate whether DWS predicts age-related cardiovascular events. Patients referred for transthoracic echocardiogram, those with preserved LV ejection fraction and no clinical heart failure were studied. Cardiovascular events were ascertained using Framingham criteria (myocardial infarction, coronary insufficiency, stroke, transient ischemic attack, congestive heart failure, or cardiovascular death). DWS was calculated with a validated formula. Cox proportional hazards modeling was used to assess the risk of cardiovascular events. Of a total number of 962 patients (mean age 60.9 +/- 14.9 years, 48.0% men), 69 (7.2%) developed at least 1 cardiovascular event during a mean follow-up of 43 +/- 32 months. After adjusting for cardiovascular comorbidities in a multivariable model, low DWS (? 0.33) was a significant independent predictor of cardiovascular events [hazard ratio (HR): 1.87, 95% confidential interval (CI) 1.04-3.36, P = 0.04]. Echocardiographic assessment of DWS may help in identifying the patients at increased risk for future age-related cardiovascular events. PMID- 30519809 TI - Impact of decreased insulin resistance by ezetimibe on postprandial lipid profiles and endothelial functions in obese, non-diabetic-metabolic syndrome patients with coronary artery disease. AB - The association between insulin resistance and lipid dysmetabolism after consuming a meal is unclear. We aimed at assessing the effects of ezetimibe on postprandial hyperlipidemia and hyperinsulinemia and to find out whether the medication improves endothelial function in obese metabolic syndrome (MetS) patients with coronary artery disease (CAD). We obtained oral fat loading test results (4 and 6 h after load) and brachial flow-mediated vasodilation (FMD) measurements before and 24 weeks after ezetimibe treatment initiation from 27 MetS patients with CAD and from 68 control patients with CAD alone. Serum triglyceride (TG) and insulin levels (2 h after the loading dose) were significantly higher in MetS patients than in control patients. The incremental areas under the curve (iAUCs) for these levels decreased significantly after ezetimibe treatment in MetS patients but not in control patients. Treatment with ezetimibe resulted in significant FMD changes in MetS patients (from 3.4 to 4.9%, P = 0.002), but not in control patients (from 5.1 to 5.4%, P = 0.216). When MetS patients were divided into two groups based on the median insulin iAUC reduction rate (higher group >= 34%, n = 14; lower group < 34%, n = 13), those in the higher group showed a significantly higher rate of change in the iAUCs of TG and FMD than those in the lower group (TG, 31.0% vs. 10.8%; P = 0.033; FMD, 39.2% vs. 9.8%; P = 0.037). These results suggest that ezetimibe may reverse insulin resistance, reducing lipid dysmetabolism after a meal and endothelial dysfunction in MetS patients with CAD. PMID- 30519810 TI - APOLO-Teens, a web-based intervention for treatment-seeking adolescents with overweight or obesity: study protocol and baseline characterization of a Portuguese sample. AB - PURPOSE: APOLO-Teens is an ongoing web-based program combining a manualized intervention delivered by Facebook(r), a self-monitoring web application and monthly chat sessions to optimize treatment as usual for adolescents with overweight and obesity. The aims of this paper are twofold: (1) to describe the study protocol of the APOLO-Teens randomized controlled effectiveness trial and (2) to present baseline descriptive information of the Portuguese sample. METHODS: APOLO-Teens includes adolescents aged between 13 and 18 years with BMI percentile >= 85 (N = 210; 60.00% girls, BMI z-score 2.40 +/- 0.75) undergoing hospital ambulatory treatment for overweight/obesity. Participants completed a set of self-report measures regarding eating behaviors and habits, psychological functioning (depression, anxiety, stress, and impulsivity), physical activity, and quality of life. RESULTS: Depression, anxiety, stress, impulsivity, and percentage body fat were inversely associated with health-related quality of life (rs = - 0.39 to - 0.62), while physical activity out-of-school was positively correlated with health-related quality of life (rs = 0.22). When compared to boys, girls demonstrated statistically significant higher scores on psychological distress, disturbed eating behaviors, impulsivity, were less active at school and had lower scores on the health-related quality of life (p < 0.05). CONCLUSION: The results showed that there were gender differences in key psychological constructs that are likely to determine success with the treatment and that, therefore, need to be considered in future interventions. The results of APOLO Teens randomized controlled trial will determine the impact of these constructs on the efficacy and adherence to a web-based intervention for weight loss in the Portuguese population. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 30519811 TI - Insulin action on protein synthesis and its association with eIF5A expression and hypusination. AB - The hormone insulin plays a central role in the metabolism of carbohydrates, lipids, and proteins. In relation to protein metabolism, insulin stimulates amino acid uptake and activates protein synthesis in responsive cells by modulation of signal transduction pathways, such as associated to Akt/PkB, mTOR, S6Ks, 4E-BP1, and several translation initiation/elongation factors. In this context, there is no information on direct cellular treatment with insulin and effects on eukaryotic translation initiation factor 5A (eIF5A) regulation. The eIF5A protein contains an exclusive amino acid residue denominated hypusine, which is essential for its activity and synthesized by posttranslational modification of a specific lysine residue using spermidine as substrate. The eIF5A protein is involved in cellular proliferation and differentiation processes, as observed for satellite cells derived from rat muscles, revealing that eIF5A has an important role in muscle regeneration. The aim of this study was to determine whether eIF5A expression and hypusination are influenced by direct treatment of insulin on L6 myoblast cells. We observed that insulin increased the content of eIF5A transcripts. This effect occurred in cells treated or depleted of fetal bovine serum, revealing a positive insulin effect independent of other serum components. In addition, it was observed that hypusination follows the maintenance of eIF5A protein content in the serum depleted cells and treated with insulin. These results demonstrate that eIF5A is modulated by insulin, contributing the protein synthesis machinery control, as observed by puromycin incorporation in nascent proteins. PMID- 30519812 TI - Evaluation of an extract of the Punica granatum flower as a biological stain of rat tissues: a preliminary study. AB - Natural dyes and especially hematoxylin, which is herbal, are widely used in staining tissues. The aim of this study is to evaluate the staining status of different tissues taken from rats with pomegranate flower extract. For this reason, 2 Wistar albino rats, one male and one female, were used as stain biomaterial. A histological follow up procedure was applied to the lung, kidney, liver, and heart tissue samples taken from the rats and the unstained preparates of these tissues were prepared. As the source of the dye, the dry flowers of Punica granatum (PG) obtained from local markets of Kayseri were used. Each tissue sample underwent the same staining procedure with the same temperature, duration, and dye solution. Before and after the staining procedure, * 40 images of the tissue preparates were taken using a light microscope. Generally, different tones of staining were observed in the nuclei and cytoplasms of all cells and epithelium cells. Staining in parts specific to each tissue occurred. For example, there were light stains on the glomerular cells and the Bowman capsule in the kidney tissue Differences in staining can only be explained by molecular diversity differences in tissue. However, in order to improve the initial staining results obtained in this study, it is possible that working with different temperatures, pH values, mordant substances, and dye that the dye molecules in the extract will provide more vivid colors with different molecules in the tissues. PMID- 30519813 TI - The comparative analysis of phenotypic and whole transcriptome gene expression data of ascites susceptible versus ascites resistant chickens. AB - Ascites syndrome (AS) is a metabolic disorder that mainly occurs at later ages of meat-type chickens. Despite many research, there is no consensus about the origin of this syndrome. Our main purpose were to investigate the syndrome using both phenotypic and RNA-Seq data to elucidate the most causative factors predisposing the birds to AS. Phenotypic data analysis showed that AS indicator traits (AITs) were moderate to high heritable. Inexistence of consistent direct genetic correlation between AITs and growth related traits, indicated that neither faster growth rate nor heavier body weight is the most causative factor affecting the susceptibility of broilers to AS. However, respiratory capacity was revealed to be the most probable factor predisposing the birds to AS, as both lung weight and lung percentage were negatively correlated with AITs. Transcriptomic data analysis revealed 125 differentially expressed genes (DEGs) between the ascitic and healthy groups. Up-regulated genes in ascitic group enriched mainly in gas transport biological process, while down-regulated genes involved in defense response to bacteria, biological adhesion, cell adhesion, killing of cells of another organism and cell division. Genetic association of the DEGs with human cardiovascular diseases suggested excessive heart problems of the ascitic chicks. Heart is, probably, the first tissue suffering from the incompetence of small respiratory system of the AS-susceptible chickens. In other word, tissue hypoxia, that causes free radicals to concentrate in heart cells, may be the commencement of events that finally result to heart failure, suffocation and death of chicks due to the AS. PMID- 30519814 TI - Function-specific Tractography of Language Pathways Based on nTMS Mapping in Patients with Supratentorial Lesions. AB - PURPOSE: In patients with supratentorial lesions diffusion tensor imaging fiber tracking (DTI-FT) is increasingly used to visualize subcortical fiber courses. Navigated transcranial magnetic stimulation (nTMS) was applied in this study to reveal specific cortical functions by investigating the particular language errors elicited by stimulation. To make DTI-FT more function-specific, the identified language-positive nTMS spots were used as regions of interest (ROIs). METHODS: In this study 40 patients (mean age 53.8 +/- 16.0 years) harboring language-eloquent left hemispheric lesions underwent preoperative nTMS language mapping. All induced error categories were separately defined as a ROI and used for function-specific nTMS-based DTI-FT. The fractions of patients showing various subcortical language-related pathways and the fibers-per-tract ratio (number of visualized fibers divided by the number of visualized tracts) were evaluated and compared for tractography with the single error types against less specific tractography including all identified cortical language sites (all errors except hesitations). RESULTS: The nTMS-based DTI-FT using all errors except hesitations led to high fractions of visualized tracts (81.1% of patients), with a fibers-per-tract ratio of 538.4 +/- 340.5. When only using performance errors, a predominant visualization of the superior longitudinal fascicle (SLF) occurred, which is known to be involved in articulatory processes. Fibers-per-tract ratios were comparatively stable for all single error categories when compared to all errors except hesitations (p > 0.05). CONCLUSION: This is one of the first studies aiming on function-specific tractography. The results demonstrated that when using different error categories as ROIs, more detailed nTMS-based DTI-FT and, therefore, potentially superior intraoperative guidance becomes possible. PMID- 30519815 TI - PD-1 and PD-L1 Expression in Male Breast Cancer in Comparison with Female Breast Cancer. AB - BACKGROUND: Male breast cancer is rare, as it represents less than 1% of all breast cancer cases. In addition, male breast cancer appears to have a different biology than female breast cancer. Programmed death-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), seem to have prognostic and predictive values in a variety of cancers, including female breast cancer. However, the role of PD 1 and PD-L1 expression in male breast cancer has not yet been studied. OBJECTIVES: To compare PD-1 and PD-L1 expression in male breast cancer to female breast cancer and to evaluate prognostic values in both groups. PATIENTS AND METHODS: Tissue microarrays from formalin-fixed paraffin-embedded resection material of 247 female and 164 male breast cancer patients were stained for PD-1 and PD-L1 by immunohistochemistry. RESULTS: PD-1 expression on tumor-infiltrating lymphocytes was significantly less frequent in male than in female cancers (48.9 vs. 65.3%, p = 0.002). In contrast, PD-L1 expression on tumor and immune cells did not differ between the two groups. In male breast cancer, PD-1 and tumor PD L1 were associated with grade 3 tumors. In female breast cancer, PD-1 and PD-L1 were associated with comparably worse clinicopathological variables. In a survival analysis, no prognostic value was observed for PD-1 and PD-L1 in either male and female breast cancer. In a subgroup analysis, female patients with grade 3/tumor PD-L1-negative or ER-negative/immune PD-L1-negative tumors had worse overall survival. CONCLUSIONS: PD-1 seems to be less often expressed in male breast cancer compared to female breast cancer. Although PD-1 and PD-L1 are not definite indicators for good or bad responses, male breast cancer patients may therefore respond differently to checkpoint immunotherapy with PD-1 inhibitors than female patients. PMID- 30519818 TI - Effect of metoclopramide administration to mothers on neonatal bilirubin and maternal prolactin: a randomized, controlled, clinical trial. AB - BACKGROUND: Jaundice is a common neonatal problem. This study was conducted to determine the effect of metoclopramide on neonatal bilirubin and maternal prolactin (primary outcomes) and milk volume (secondary outcome). METHODS: This triple-blind, randomized, controlled, clinical trial was conducted on 112 mothers. The participants were assigned to the intervention (metoclopramide) and control groups (placebo) using block randomization. Ten-mg metoclopramide and placebo tablets were taken by the participants three times a day. The intervention began in the first 2-10 hours after childbirth and continued until the fifth day. The mothers' prolactin level was measured on the first morning after the intervention and on the sixth day (1 day after the intervention was over). Neonatal total bilirubin was also measured before the intervention and on the sixth day. RESULTS: After the intervention, the two groups did not differ significantly in terms of the mean neonatal indirect bilirubin (P = 0.565) and milk volume (P = 0.261), but the mean serum prolactin was significantly higher in the metoclopramide group compared to the placebo group (adjusted mean difference 37; 95% confidence interval 58.1-16.5; P = 0.001). CONCLUSIONS: Metoclopramide increased maternal serum prolactin but had no effects on neonatal jaundice. The insufficient numbers of studies on this subject mandate further research. PMID- 30519816 TI - Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa. AB - In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from - 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN. PMID- 30519817 TI - Conditional Haploinsufficiency of beta-Catenin Aggravates Neuronal Damage in a Paraquat-Based Mouse Model of Parkinson Disease. AB - The canonical Wnt pathway is critical for both the development and adulthood survival and homeostatic maintenance of the midbrain dopaminergic (DA) neurons. Expanding evidence has demonstrated that genetic factors associated with familial Parkinson disease (PD) deregulate this important pathway, suggesting that a disturbed canonical Wnt pathway is likely involved in PD pathogenesis; yet, the specific role of this pathway in sporadic PD remains unclear. In this study, we aimed to determine the effects of specific inhibition of the canonical pathway by hemizygous knockout of beta-catenin, the obligatory component of the canonical Wnt pathway, on paraquat (PQ)-induced DA neuronal degeneration in the substantia nigra in vivo. We found that while hemizygous conditional knockout of beta catenin in DA neurons did not cause any significant TH+ neuronal loss in the substantia nigra at basal level, it triggered elevated oxidative stress at basal level and further enhanced PQ-induced oxidative damage and loss of TH+ neurons in the substantia nigra and axonal termini in the striatum that manifested as exacerbated motor deficits. These data support the notion that reduced Wnt/beta catenin signaling in sporadic PD likely contributes to DA neuronal loss through an enhanced oxidative stress-response pathway. PMID- 30519819 TI - Structured versus narrative reporting of pelvic MRI in perianal fistulizing disease: impact on clarity, completeness, and surgical planning. AB - OBJECTIVE: To evaluate clarity, completeness, and impact on surgical planning of MRI reporting of perianal fistulizing disease using a structured disease-specific template versus narrative reporting for planning of disease treatment by colorectal surgeons. MATERIALS AND METHODS: In this HIPAA-compliant, IRB-approved study with waiver of informed consent, a structured reporting template for perianal fistulizing disease MRIs was developed based on collaboration between colorectal surgeons and abdominal radiologists. The study population included 45 consecutive patients who underwent pelvic MRI for perianal fistulizing disease prior to implementation of structured reporting, and 60 consecutive patients who underwent pelvic MRI for perianal fistulizing disease after implementation of structured reporting. Objective evaluation of the reports for the presence of 12 key features was performed, as also subjective evaluation regarding the clarity and completeness of reports, and impact on surgical planning. RESULTS: Significantly more key features were absent in narrative reports [mean: 6.3 +/- 1.8 (range 3-11)] than in structured reports [mean: 0.3 +/- 0.9 (range 1-5)] (p <= 0.001). The use of structured reporting also increased the percentage of completeness (72.5-88.3% for surgeon 1, and 61.2-81.3% for surgeon 2; p = 0.05 and 0.03, respectively), helpfulness in surgical planning (7.1 +/- 1.5-7.6 +/- 1.5 for surgeon 1, and 5.8 +/- 1.4-7.1 +/- 1.1 for surgeon 2; p = 0.05 and p < 0.001, respectively), and clarity (7.6 +/- 1.3-8.3 +/- 1.1 for surgeon 1, and 5.2 +/- 1.4-7.1 +/- 1.3 for surgeon 2; p = 0.006 and p < 0.001, respectively) of the reports. CONCLUSION: Structured MRI reports in patients with perianal fistulizing disease miss fewer key features than narrative reports. Moreover, structured reports were described as more complete and clear, and more helpful for treatment planning. PMID- 30519820 TI - One-Step Mask-Based Diffraction Lithography for the Fabrication of 3D Suspended Structures. AB - We propose a novel one-step exposure method for fabricating three-dimensional (3D) suspended structures, utilizing the diffraction of mask patterns with small line width. An optical model of the exposure process is built, and the 3D light intensity distribution in the photoresist is calculated based on Fresnel Kirchhoff diffraction formulation. Several 3D suspended photoresist structures have been achieved, such as beams, meshes, word patterns, and multilayer structures. After the pyrolysis of SU-8 structures, suspended and free-standing 3D carbon structures are further obtained, which show great potential in the application of transparent electrode, semitransparent solar cells, and energy storage devices. PMID- 30519821 TI - Current status of esophageal endoscopy including the evaluation of smoking and alcohol consumption in Japan: an analysis based on the Japan endoscopy database. AB - PURPOSE: The aim was to investigate the current status of esophageal endoscopy, including the evaluation of smoking and alcohol consumption, in Japan. METHODS: A total of 47,441 patients who underwent 69,748 sessions of esophageal endoscopy were registered in the Japan Endoscopy Database between January 2015 and March 2017. The study variables were as follows: (1) methods for monitoring the esophagus and the time required for monitoring and (2) the status of smoking and alcohol consumption in patients with esophageal cancer and head and neck cancer. RESULTS: Image-enhanced endoscopy was performed in 10.6%, Lugol chromoendoscopy in 4.1%, and magnifying endoscopy in 3.2%. The mean time required for gastrointestinal endoscopy was 10 min 58 s. The mean examination times in patients with or without monitoring of the head and neck were 10 min 51 s and 11 min 13 s, respectively. In 57.0% of the patients with esophageal cancer, the head and neck were monitored at the time of gastrointestinal endoscopy. The proportion of current smokers (esophageal cancer: 16.8-4.7%; head and neck cancer: 24.3 9.3%) and addicted drinkers (esophageal cancer: 52.3-40.8%; head and neck cancer: 50.2-47.3%) were lower at the second or subsequent endoscopy than at the initial endoscopy. CONCLUSIONS: The new strategy for esophageal endoscopy has led to an evolutionary change in Japan. The patients with esophageal cancer and head and neck cancer who underwent a second or subsequent endoscopy had lower incidences of smoking and alcohol consumption, although the incidences remained high. PMID- 30519822 TI - Adsorption of Tetracycline with Reduced Graphene Oxide Decorated with MnFe2O4 Nanoparticles. AB - Nanomaterials were widely used as efficient adsorbents for environmental remediation of tetracycline pollution. However, the separation of the adsorbents posed the challenge to their practical applications. In this study, we grew magnetic MnFe2O4 nanoparticles on the reduced graphene oxide (rGO) to form MnFe2O4/rGO nanocomposite with a one-step method. When used as the absorbent of Tetracycline, it exhibited an adsorption capacity of 41 mg/g. The adsorption kinetics and isotherm were fitted well with the pseudo-second order model and Freundlich model, respectively. The MnFe2O4/rGO nanocomposite could be easily extracted from the solution with the external magnetic field and regenerated with acid washing. PMID- 30519823 TI - The fate of root canals obturated with Thermafil: 10-year data for patients treated in a master's program. AB - OBJECTIVES: Retrospective description of the 10-year success rate of endodontic treatments with Thermafil (TF). MATERIALS AND METHODS: Patients treated by postgraduate students in an Endodontics Master's Program (2006-2008) were enrolled. All treated root canals were filled with TF and AH Plus. Teeth satisfying the inclusion criteria (206 teeth in 89 patients) were reexamined clinically and radiographically to estimate a 10-year survival and periapical health. Demographic and medical data were registered; collected information included pre-, intra-, and postoperative variables. Teeth were classified as "healthy" (PAI <= 2 in absence of signs/symptoms), "endodontically diseased" (presenting at least one of the following: PAI >= 3, signs/symptoms, retreated in the course of the follow-up, or extracted for endodontic reasons), or "non endodontically diseased" (extracted for non-restorable fractures or periodontal disease). For teeth lost during the 10-year follow-up, details and reason of extraction were analyzed. Two PAI-calibrated examiners assessed outcomes blinded to preoperative status. Bivariate and multilevel analyses were performed (alpha level set at 0.05). RESULTS: At 10 years, 179 (87%) teeth survived and 27 were extracted: 20 for non-endodontic reasons (excluded from success analysis) and 7 for endodontic reasons (considered "endodontically diseased"). Multilevel analysis revealed that the probability of extraction was increased by the presence of preoperative pain (odds ratio = 6.720; 95% confidence interval, 1.483 30.448) and by maxillary location (odds ratio = 2.950; 95% confidence interval, 1.043-8.347). Concerning periapical status, 159/186 teeth (85%) were assessed as "healthy." Multilevel analysis confirmed that maxillary location (odds ratio = 3.908; 95% confidence interval, 1.370-11.146), presence of flare up (odds ratio = 9.914; 95% confidence interval, 2.388-41.163), and fracture occurrence (odds ratio = 35.412; 95% confidence interval, 3.366-372.555) decreased the odds of healing, respectively. CONCLUSIONS: After 10 years, teeth filled with Thermafil in a specialist master's program presented a survival and a periapical health comparable to cohorts where root canals were filled with other obturation techniques. CLINICAL RELEVANCE: Carrier-based techniques provide time savings for clinicians while satisfying clinical quality criteria for the root filling and consequently the clinical outcome. PMID- 30519824 TI - Correlation analysis of the transcriptome and metabolome reveals the regulatory network for lipid synthesis in developing Brassica napus embryos. AB - KEY MESSAGE: In this manuscript, we explored the key molecular networks for oil biosynthesis with the transcriptome and metabolome of B. napus embryo at different developmental stages. Brassica napus (B. napus) is an important oil crop worldwide, yet the molecular pathways involved in oil biosynthesis in seeds are not fully understood. In this study, we performed a combined investigation of the gene expression profiles and metabolite content in B. napus seeds at 21, 28 and 35 days after flowering (DAF), when seed oil biosynthesis takes place. The total triacylglycerol (TAG) content in seed embryos increased over the course of seed maturation, and was accompanied by changes in the fatty acid profile, an increase in lipid droplets, and a reduction in starch grains. Metabolome analysis showed that the total amino acid, free fatty acid and organic acid contents in seed embryos decreased during seed maturation. In total, the abundance of 76 metabolites was significantly different between 21 and 28 DAF, and 68 metabolites changed in abundance between 28 and 35 DAF. Transcriptome analysis showed that the set of genes differentially expressed between stages was significantly enriched in those related to lipid metabolism, transport, protein and RNA metabolism, development and signaling, covering most steps of plant lipid biosynthesis and metabolism. Importantly, the metabolite and gene expression profiles were closely correlated during seed development, especially those associated with TAG and fatty acid biosynthesis. Further, the expression of major carbohydrate metabolism-regulating genes was closely correlated with carbohydrate content during seed maturation. Our results provide novel insights into the regulation of oil biosynthesis in B. napus seeds and highlights the coordination of gene expression and metabolism in this process. PMID- 30519825 TI - Transcription profiles reveal the regulatory mechanisms of spur bud changes and flower induction in response to shoot bending in apple (Malus domestica Borkh.). AB - KEY MESSAGE: Shoot bending, as an effective agronomic measure, has been widely used to promote flowering in 'Fuji' apple trees. Here, we examined the transcriptional responses of genes in 'Fuji' apple buds at different flowering stages under a shoot-bending treatment using RNA sequencing. A complex genetic crosstalk-regulated network, involving abscisic acid-related genes, starch metabolism and circadian rhythm-related genes, as well as stress response-related genes, was up-regulated by shoot bending, in which were contrbuted to apple flower bud formation in response to shoot-bending conditions. Flower induction plays an important role in the apple tree life cycle, but young trees produce fewer and inferior flower buds. Shoot bending, as an effective agronomic measure, has been widely used to promote flowering in 'Fuji' apple trees. However, little is known about the gene expression network patterns and molecular regulatory mechanisms caused by shoot bending during the induced flowering. Here, we examined the transcriptional responses of genes in 'Fuji' apple buds at different flowering stages under a shoot-bending treatment using RNA sequencing. A steady up-regulation of carbon metabolism-related genes led to relatively high levels of sucrose in early induced flowering stages and starch accumulation during shoot bending. Additionally, global gene expression profiling determined that cytokinin, indole-3-acetic acid, gibberellin synthesis and signalling-related genes were significantly regulated by shoot bending, contributing to cell division and differentiation, bud growth and flower induction. A complex genetic crosstalk-regulated network, involving abscisic acid-related genes, starch metabolism- and circadian rhythm-related genes, as well as stress response related genes, was up-regulated by shoot bending. Additionally, some transcription factor family genes that were involved in sugar, abscisic acid and stress response signalling were significantly induced by shoot bending. These important flowering genes, which were mainly involved in photoperiod, age and autonomous pathways, were up-regulated by shoot bending. Thus, a complex genetic network of regulatory mechanisms involved in sugar, hormone and stress response signalling pathways may mediate the induction of apple tree flowering in response to shoot-bending conditions. PMID- 30519827 TI - [Role of surgical endoscopy in management of complications]. PMID- 30519826 TI - Genome-wide association study of maize plant architecture using F1 populations. AB - KEY MESSAGE: Genome-wide association study of maize plant architecture using F1 populations can better dissect various genetic effects that can provide precise guidance for genetic improvement in maize breeding. Maize grain yield has increased at least eightfold during the past decades. Plant architecture, including plant height, leaf angle, leaf length, and leaf width, has been changed significantly to adapt to higher planting density. Although the genetic architecture of these traits has been dissected using different populations, the genetic basis remains unclear in the F1 population. In this work, we perform a genome-wide association study of the four traits using 573 F1 hybrids with a mixed linear model approach and QTXNetwork mapping software. A total of 36 highly significant associated quantitative trait SNPs were identified for these traits, which explained 51.86-79.92% of the phenotypic variation and were contributed mainly by additive, dominance, and environment-specific effects. Heritability as a result of environmental interaction was more important for leaf angle and leaf length, while major effects (a, aa, and d) were more important for leaf width and plant height. The potential breeding values of the superior lines and superior hybrids were also predicted, and these values can be applied in maize breeding by direct selection of superior genotypes for the associated quantitative trait SNPs. A total of 108 candidate genes were identified for the four traits, and further analysis was performed to screen the potential genes involved in the development of maize plant architecture. Our results provide new insights into the genetic architecture of the four traits, and will be helpful in marker assisted breeding for maize plant architecture. PMID- 30519828 TI - ? PMID- 30519829 TI - Structural insights into the species preference of the influenza B virus NS1 protein in ISG15 binding. PMID- 30519830 TI - Symptoms and Impacts in Metastatic Castration-Resistant Prostate Cancer: Qualitative Findings from Patient and Physician Interviews. AB - BACKGROUND: There is little information available on health-related quality of life in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. This study aimed to develop a conceptual model that describes patients' experiences of living with this condition. METHODS: This was a cross-sectional, non-interventional qualitative research study. Sixty-minute semi-structured interviews were conducted with physicians experienced in treating metastatic castration-resistant prostate cancer and with chemotherapy-naive patients with metastatic castration-resistant prostate cancer. Interviews were audio-recorded and transcripts were analysed to identify the key symptoms and impacts on quality of life. Results were used to expand a previously published conceptual model for non-metastatic castration-resistant prostate cancer. RESULTS: Three physicians and 19 patients with metastatic castration-resistant prostate cancer were interviewed. Physicians identified several symptoms frequently mentioned by their patients: fatigue, bone pain, anxiety, stress, depression and interference with daily activities. The most salient symptoms emerging from the patient interviews were urinary frequency and urgency, fatigue, pain/stiffness and sexual dysfunction. The most salient impacts were interference with daily activities, frustration, anxiety and sleep problems. Compared with non-metastatic castration resistant prostate cancer, some symptoms and impacts in metastatic castration resistant prostate cancer were more common and rated as more disturbing (e.g. fatigue, pain, urinary frequency, interference with daily activities and frustration). New concepts that were added to the non-metastatic castration resistant prostate cancer model, to more accurately reflect the experiences of patients with metastatic disease, were enlarged breasts, muscle loss/deconditioning, inability to focus/mental slowing, body image perception, interference with work and lack of ambition/motivation. CONCLUSIONS: Chemotherapy naive patients with metastatic castration-resistant prostate cancer experience a substantial burden from their condition. Furthermore, as castration-resistant prostate cancer progresses from the non-metastatic stage to the early metastatic (pre-chemotherapy) stage, certain symptoms become more common and disturb patients' lives to a greater extent. The resulting conceptual model for metastatic castration-resistant prostate cancer highlights areas that are not adequately assessed with current patient-reported outcome instruments. PMID- 30519831 TI - The past decade in type 2 diabetes and future challenges. AB - There is today an exponential increase in prevalence of type 2 diabetes mellitus (T2DM), especially in young people. This downward shift in age of onset of T2DM has been shown by abundant evidence to be due to an increase in obesity among the young, the latter mainly attributable to unhealthy dietary habits and a sedentary lifestyle. It is therefore obvious that the prevention of diabetes rather its treatment is of is paramount importance. In the past decade, because concerns about the safety of antidiabetic agents took precedence over the issue of efficacy, almost all studies have been diabetes CVOTs and not traditional CVOTs. Until 2015, the evidence showed that antidiabetic agents are effective in terms of reduction of microvascular, as opposed to macrovascular, complications. However, following publication of the results of some new studies, it became clear that the new class of antidiabetic drugs, e.g., SGLT 2 inhibitors and GLP-1 agonists, are also effective in reducing cardiovascular disease (CVD). In the coming decade, numerous health challenges are expected to arise, the most important being the greater expansion of the therapeutic armamentarium for T2DM and the adoption of strategies for prevention of CVDs. In parallel, the new generation of antidiabetic agents will target the recently investigated pathophysiologic disorders of diabetes, while, ideally, treatments should include smart drugs without side effects. PMID- 30519832 TI - The Influence of Endogenous Opioids on the Relationship between Testosterone and Romantic Bonding. AB - The endogenous opioid system has received attention and extensive research for its effects on reward, pleasure, and pain. However, relative to other neurochemicals, such as oxytocin, vasopressin and dopamine, the function of opioids in regulating human attachment, sociosexuality, and other aspects of human sociality has not received much consideration. For example, nonapeptides (oxytocin and vasopressin) have been extensively studied in animals and humans for their possible roles in mother-offspring attachment, romantic attachment, fatherhood, and social cognition. Likewise, others have proposed models wherein oxytocin and vasopressin are moderators of the relationship between steroid hormones and human social behaviors. Recently, opioids have generated renewed interest in relation to social pain, and importantly, the brain opioid hypothesis of social attachment (BOTSA), which suggests that endogenous opioids are a key implementer in primate and human bonding, has received some support. Here we focus on romantic bonds by proposing that endogenous opioids are an important mechanism mediating reproductive trade-offs through their inhibitory effects on testosterone production. PMID- 30519833 TI - Sodium dichloroisocyanurate delays ripening and senescence of banana fruit during storage. AB - Banana as a typical climacteric fruit soften rapidly, resulting in a very short shelf life after harvest. Sodium dichloroisocyanurate (NaDCC) is reported to be an effectively antibacterial compound. Here, we investigated the effects of NaDCC on ripening and senescence of harvested banana fruit at physiological and molecular levels. Application of 200 mg L-1 NaDCC solution effectively inhibited the ripening and senescence of banana fruit after harvest. NaDCC treatment reduced greatly ethylene production rate and expressions of genes encoding 1 aminocyclopropane-1-carboxylate synthetase, 1-aminocyclopropane-1-carboxylate oxidase, ethylene-responsive transcription factor and EIN3-binding F-box protein. Meanwhile, NaDCC treatment down-regulated markedly the expressions of xyloglucan endotransglucosylase/hydrolase and pectinesterase genes. Furthermore, NaDCC treatment affected significantly the accumulation of ripening-related primary metabolites such as sugars and organic acids. Additionally, NaDCC treatment decreased the production of hydroxyl radical and increased 1,1-diphenyl-2 picrylhydrazyl (DPPH) scavenging activity, reducing power and hydroxyl radical scavenging activity. In conclusion, NaDCC delayed effectively the ripening and senescence of harvested banana fruit via the reduced ethylene effect and enhanced antioxidant activity. PMID- 30519834 TI - A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-kappaB mediated apoptosis-to-pyroptosis switch. AB - Pyroptosis is a novel manner of cell death that can be mediated by chemotherapy drugs. The awareness of pyroptosis is significantly increasing in the fields of anti-tumor research and chemotherapy drugs. Invoking the occurrence of pyroptosis is an attractive prospect for the treatment of lung cancer. Here, the compound L61H10 was obtained as a thiopyran derivative to compare its activity with curcumin. It was indicated that L61H10 exhibited good anti-tumor activity both in vitro and in vivo via the switch of apoptosis-to-pyroptosis, which was associated with the NF-kappaB signaling pathway. In addition, L61H10 had no obvious side effects both in vitro and in vivo. In brief, L61H10 is shown to be a potential anti-lung cancer agent and research on its anti-tumor mechanism provides new information for chemotherapy drug research. PMID- 30519835 TI - Fatty acids and selected endocannabinoids content in cerebrospinal fluids from patients with neuroinfections. AB - Neuroinfections are a significant medical problem and can have serious health consequences for patients. Their outcome, if not fatal, can be associated with permanent residual deficits. Cerebrospinal fluid (CSF) examination is commonly used for meningitis confirmation. Fatty acids (FA) are precursors of lipid mediators with pharmacological activity. They actively modulate inflammation as well as contribute to its resolution. Therefore the aim of this study was to determine the FA and selected endocannabinoids (ECB) content in the CSF obtained from patients with bacterial (BM) and viral meningitis (VM) using chromatographic techniques. A significantly lower level of saturated FA was found in patients with BM and VM as compared to controls. There was a significantly higher concentration of long-chain monounsaturated FA and polyunsaturated n-6 FA in the CSF obtained from patients with neuroinfection. Moreover, a significant reduction of n-3 FA in CSF obtained from patients with BM and VM was demonstrated. The highest amount of ECB was detected in the CSF of patients with VM: eicosapentaenoyl ethanolamide (1.65 pg/mL), docosahexaenoyl ethanolamide (655.5 pg/mL) and nervonoyl ethanolamide (3.09 ng/mL). Results indicate the participation of long-chain monounsaturated and polyunsaturated FA and their derivatives in the inflammatory process and likely in the process of resolution of inflammation during neuroinfection. It seems that the determination of the FA and ECB profile in CSF may be a valuable biomarker of health and may allow the development of new pharmacological strategies, therapeutic goals and fatty acids supplementation necessary in the fight against inflammation of the central nervous system. PMID- 30519836 TI - Adolescent social isolation affects parvalbumin expression in the medial prefrontal cortex in the MAM-E17 model of schizophrenia. AB - Altered parvalbumin (PV) expression is observed in the prefrontal cortex of subjects with schizophrenia. Environmental context, particularly during adolescence, might regulate PV expression. In the present study, we investigated the effect of adolescent social isolation (SI) on PV expression in the medial prefrontal cortex in a neurodevelopmental model (MAM-E17) of schizophrenia. SI exposure occurred from postnatal day 30 to 40, followed by resocialization until late adolescence or early adulthood. PV mRNA and protein levels, as well as the number of PV cells, were analysed at these ages. Moreover, epigenetic regulation of PV expression by histone methylation was examined by measuring the total and PV gene-bound H3K4me3 levels. MAM only decreased levels of the PV mRNA and protein in adulthood. Decreases in total H3K4me3 levels and its level at the PV gene were also observed at this age. In contrast, in late adolescence, SI induced a decrease in the expression of the PV mRNA in the MAM group that was related to the reduction in total and PV gene-bound H3K4me3 levels. However, at this age, SI increased the levels of the PV protein in both the control and MAM groups. In adulthood, SI did not affect PV mRNA or H3K4me3 levels but decreased levels of the PV protein in both groups. Both MAM and SI failed to change the number of PV cells at any age. The results indicate that adolescent SI accelerated epigenetic impairments of PV expression in MAM-E17 rats; however, subsequent resocialization abolished this dysfunction, but failed to prevent alterations in PV protein. PMID- 30519837 TI - Two ancient neuropeptides, PACAP and AVP, modulate motivated behavior at synapses in the extrahypothalamic brain: a study in contrast. AB - We examine evolutionary aspects of two primordial neuropeptides, arginine vasopressin (AVP) and pituitary adenylate cyclase-activating polypeptide (PACAP); the distribution of AVP and PACAP and their receptors in mammals; AVP and PACAP release patterns relevant to their roles in neuroendocrine control in brain and periphery; and finally the intricate interlocking of homeostatic and allostatic regulation created by extrahypothalamic AVP and PACAP projections to brain circuit nodes important in controlling appetitive, avoidance and aggressive motor responses. A cardinal feature of peptide neurotransmission important in regulatory control of organismic responses and emphasized in this review, is that neuropeptides are released from large dense-core vesicles docked not only within axonal varicosities and dendrites but also at presynaptic nerve terminal sites, along with small clear synaptic vesicles, at active zones. Peptide transmitter nerve terminals, from hypothalamic and other projections, are distributed widely to multiple brain areas important in integrative control of behavior. They converge with heterologous inputs that release other transmitters, including other peptides, in the same areas. The concept of a quasi-hormonal effect of peptide neurotransmission through coordinated release at multiple synapses throughout the brain echoes earlier conceptualizations of "action-at-a-distance" by diffusion following peptide release at non-synaptic sites. Yet, it recognizes that peptide delivery occurs with neuroanatomical precision, from discrete peptide-containing brain nuclei, via highly distributed projections to multiple extrahypothalamic nodes, registering multiple homeostatic, hedonistic, aversive and reproductive drives that modulate real-time motor decisions. There is paradigmatic value in the discussion of these two particular ancient neuropeptides, for peptide-centric translational neuroendocrinology and peptide GPCR-based neurotherapeutics. PMID- 30519838 TI - The Longitudinal Associations Between Outness and Health Outcomes Among Gay/Lesbian Versus Bisexual Emerging Adults. AB - Sexual minorities are at increased risk for substance use and mental health problems. Although previous studies have examined the associations between outness and health outcomes, few have used longitudinal designs or examined differences across subgroups of sexual minorities. To address these gaps, the current study examined sexual orientation and gender as moderators of the longitudinal associations between outness and substance use (cigarettes, marijuana, illicit drugs, and alcohol) and mental health (depression and anxiety). Data were from a sample of 169 sexual minority emerging adults (98 women and 71 men) who provided self-report data at four times over 3.5 years. Results indicated that sexual orientation moderated the within-person associations between outness and changes in health. For bisexual individuals, being more out was associated with increases in marijuana use, illicit drug use, and depression. In contrast, for gay/lesbian individuals, being more out was associated with decreases in illicit drug use and it was not significantly associated with changes in marijuana use or depression. Additionally, outness was not significantly associated with changes in cigarette use, alcohol use, or anxiety for gay/lesbian or bisexual individuals, and gender did not moderate any of the associations. In sum, being more open about one's sexual orientation had negative consequences for bisexual individuals but not for gay/lesbian individuals. Professionals who work with sexual minorities need to be aware of the potential risks of being open about one's sexual orientation for bisexual individuals. Interventions are needed to facilitate disclosure decisions and to promote the health of sexual minorities. PMID- 30519839 TI - Changes in Health and Ability to Work Among Medicaid Expansion Enrollees: a Mixed Methods Study. AB - BACKGROUND: Michigan expanded Medicaid under the Affordable Care Act (Healthy Michigan Plan [HMP]) to improve the health of low-income residents and the state's economy. OBJECTIVE: To understand HMP's impact on enrollees' health, ability to work, and ability to seek employment DESIGN: Mixed methods study, including 67 qualitative interviews and 4090 computer-assisted telephone surveys (response rate 53.7%) PARTICIPANTS: Non-elderly adult HMP enrollees MAIN MEASURES: Changes in health status, ability to work, and ability to seek employment KEY RESULTS: Half (47.8%) of respondents reported better physical health, 38.2% better mental health, and 39.5% better dental health since HMP enrollment. Among employed respondents, 69.4% reported HMP helped them do a better job at work. Among out-of-work respondents, 54.5% agreed HMP made them better able to look for a job. Among respondents who changed jobs, 36.9% agreed HMP helped them get a better job. In adjusted analyses, improved health was associated with the ability to do a better job at work (aOR 4.08, 95% CI 3.11 5.35, p < 0.001), seek a job (aOR 2.82, 95% CI 1.93-4.10, p < 0.001), and get a better job (aOR 3.20, 95% CI 1.69-6.09, p < 0.001), but not with employment status (aOR 1.08, 95% CI 0.89-1.30, p = 0.44). In interviews, several HMP enrollees attributed their ability to get or maintain employment to improved physical, mental, and dental health because of services covered by HMP. Remaining barriers to work cited by enrollees included older age, disability, illness, and caregiving responsibilities. CONCLUSIONS: Many low-income HMP enrollees reported improved health, ability to work, and job seeking after obtaining health insurance through Medicaid expansion. PMID- 30519840 TI - Fabrication of Poly(acrylic acid)/Boron Nitride Composite Hydrogels with Excellent Mechanical Properties and Rapid Self-Healing Through Hierarchically Physical Interactions. AB - Many living tissues possess excellent mechanical properties and self-healing ability. To mimic these living tissues, a series of novel composite hydrogels, poly(acrylic acid)/surface-modified boron nitride nanosheets (PAA/BNNS-NH2) were fabricated simply through hierarchically physical interactions: molecular-scale metal coordination interaction between -COOH of PAA and Fe3+ and nanoscale H-bond between -COOH of PAA and -NH2 of BNNS-NH2. The composite hydrogels exhibit both excellent mechanical properties (including enhanced fracture stress, elongation, toughness, Young's modulus, and dissipated energy) and rapid healing ability without any external stimulus. Especially, the B0.5P70 (the hydrogel with BNNS concentration of 0.5 mg mL- 1, the water content of 70 wt%) exhibits a fracture stress of ~ 1311 kPa and toughness of ~ 4.7 MJ m- 3, almost ~ 3 times and ~ 8 times to B0P70, respectively. The excellent properties, combined with the simple preparation method, endow these composite hydrogels with potential applications. PMID- 30519841 TI - Divergent evolution of rice blast resistance Pi54 locus in the genus Oryza. AB - BACKGROUND: The rice blast resistance gene Pi54 was cloned from Oryza sativa ssp. indica cv. Tetep, which conferred broad-spectrum resistance against Magnaporthe oryzae. Pi54 allelic variants have been identified in not only domesticates but also wild rice species, but the majority of japonica and some indica cultivars lost the function. RESULTS: We here found that Pi54 (Os11g0639100) and its homolog Os11g0640600 (named as #11) were closely located on a 25 kbp region in japonica cv. Sasanishiki compared to a 99 kbp region in japonica cv. Nipponbare. Sasanishiki lost at least six genes containing one other R-gene cluster (Os11g0639600, Os11g0640000, and Os11g0640300). Eight AA-genome species including five wild rice species were classified into either Nipponbare or Sasanishiki type. The BB-genome wild rice species O. punctata was Sasanishiki type. The FF genome wild rice species O. brachyantha (the basal lineage of Oryza) was neither, because Pi54 was absent and the orientation of the R-gene cluster was reversed in comparison with Nipponbare-type species. The phylogenetic analysis showed that #11gene of O. brachyantha was on the root of both Pi54 and #11 alleles. All Nipponbare-type Pi54 alleles were specifically disrupted by 143 and 37/44 bp insertions compared to Tetep and Sasanishiki type. In addition, Pi54 of japonica cv. Sasanishiki lost nucleotide-binding site and leucine-rich repeat (NBS-LRR) domains owing to additional mutations. CONCLUSIONS: These results suggest that Pi54 might be derived from a tandem duplication of the ancestor #11 gene in progenitor FF-genome species. Two divergent structures of Pi54 locus caused by a mobile unit containing the nearby R-gene cluster could be developed before domestication. This study provides a potential genetic resource of rice breeding for blast resistance in modern cultivars sustainability. PMID- 30519842 TI - Effect of transcutaneous vagus nerve stimulation on muscle activity in the gastrointestinal tract (transVaGa): a prospective clinical trial. AB - PURPOSE: Postoperative ileus (POI) is a common complication after abdominal surgery. Invasive stimulation of the cervical vagus nerve is known to reduce inflammatory response and ameliorated POI after surgery in a mouse model. However, the transcutaneous vagus nerve stimulation (tVNS) is a possible non invasive approach. In this clinical study, we aimed to investigate the effect of tVNS on the activation of the stomach muscle in humans. METHODS: Patients requiring open laparotomy were screened for this prospective proof of concept clinical study. After open laparotomy, muscle activity of the stomach was measured by a free running electromyography (EMG) before and during tVNS on the ear. Frequency and amplitude of compound gastric action potentials were the electrophysiological parameters we assessed to reveal the changes in electro motor gastric activity. Gastrin levels as a surrogate marker for vagus nerve activation was analyzed before, 1 and 3 h after tVNS. RESULTS: Fourteen patients were included, no severe adverse events and no medical device related adverse events occurred. tVNS led to significant reduction of action potential frequency and significant elevation of action potential amplitude in the stomach compared to control. Gastrin levels were significantly elevated 3 h after tVNS compared to levels before tVNS. CONCLUSION: Application of tVNS is a safe and feasible procedure during surgical intervention. Our results provide evidence that tVNS activates efferent visceral vagal fibers. Therefore, this low risk and easy to perform method could be useful to prevent postoperative ileus. CLINICAL TRIAL REGISTER NUMBER: DRKS00013340. PMID- 30519843 TI - Thoracic epidural analgesia (TEA) versus patient-controlled analgesia (PCA) in laparoscopic colectomy: a systematic review and meta-analysis. AB - PURPOSE: A meta-analysis of RCTs was designed to provide an up-to-date comparison of thoracic epidural analgesia (TEA) and patient-controlled analgesia (PCA) in laparoscopic colectomy. METHODS: Our study was completed following the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. A systematic literature screening was performed in MEDLINE and Web of Science. Fixed effects (FE) or random effects (RE) models were estimated based on the Cochran Q test result. RESULTS: Totally, 8 studies were introduced in the present meta-analysis. Superiority of PCA in terms of length of hospital stay (LOS) (WMD 0.73, p = 0.004) and total complication rate (OR 1.57, p = 0.02) was found. TEA had a lower resting pain visual analogue scale (VAS) score at Day 1 (WMD - 2.23, p = 0.005) and Day 2 (WMD - 2.17, p = 0.01). TEA group had also a systematically lower walking VAS. Moreover, first bowel opened time (first defecation) (WMD - 0.88, p < 0.00001) was higher when PCA was applied. CONCLUSIONS: TEA was related to a lower first bowel opened time, walking, and resting pain levels at the first postoperative days. However, the overall complication rate and LOS were higher in the epidural analgesia group. Thus, for a safe conclusion to be drawn, further randomized controlled trials (RCTs) of a higher methodological and quality level are required. PMID- 30519844 TI - Lifespan Dispersion in Times of Life Expectancy Fluctuation: The Case of Central and Eastern Europe. AB - Central and Eastern Europe (CEE) have experienced considerable instability in mortality since the 1960s. Long periods of stagnating life expectancy were followed by rapid increases in life expectancy and, in some cases, even more rapid declines, before more recent periods of improvement. These trends have been well documented, but to date, no study has comprehensively explored trends in lifespan variation. We improved such analyses by incorporating life disparity as a health indicator alongside life expectancy, examining trends since the 1960s for 12 countries from the region. Generally, life disparity was high and fluctuated strongly over the period. For nearly 30 of these years, life expectancy and life disparity varied independently of each other, largely because mortality trends ran in opposite directions over different ages. Furthermore, we quantified the impact of large classes of diseases on life disparity trends since 1994 using a newly harmonized cause-of-death time series for eight countries in the region. Mortality patterns in CEE countries were heterogeneous and ran counter to the common patterns observed in most developed countries. They contribute to the discussion about life expectancy disparity by showing that expansion/compression levels do not necessarily mean lower/higher life expectancy or mortality deterioration/improvements. PMID- 30519845 TI - Prevalence and Risk Factors for Early Motherhood Among Low-Income, Maltreated, and Foster Youth. AB - Early childbearing is associated with a host of educational and economic disruptions for teenage girls and increased risk of adverse outcomes for their children. Low-income, maltreated, and foster youth have a higher risk of teen motherhood than the general population of youth. In this study, we assessed differences in the risk of early motherhood among these groups and investigated whether differences likely reflect selection factors versus effects of involvement with Child Protective Services (CPS) or foster care. Using a statewide linked administrative data system for Wisconsin, we employed survival analysis to estimate the hazard of early birth (child conceived prior to age 18) among females. We found that both the youth involved in CPS and youth in foster care were at significantly higher risk of early motherhood than low-income youth, and these differences were not explained by a range of sociodemographic and family composition characteristics. Moreover, our findings indicate that CPS and foster care are unlikely to be causal agents in the risk of early motherhood: among foster youth, risk was lower during foster care compared with before; among CPS-involved girls, risk was the same or lower after CPS investigation compared with before. Subsequent analysis showed that after girls exited foster care, those who were reunified with their birth families were at higher risk than those placed in adoption or guardianship. Overall, our findings suggest that whereas CPS and foster youth are high-risk populations for early motherhood, CPS involvement and foster care placement do not exacerbate, and may instead reduce, risk. PMID- 30519846 TI - Immigrant Legal Status and Health: Legal Status Disparities in Chronic Conditions and Musculoskeletal Pain Among Mexican-Born Farm Workers in the United States. AB - Immigrant legal status determines access to the rights and privileges of U.S. society. Legal status may be conceived of as a fundamental cause of health, producing a health disparity whereby unauthorized immigrants are disadvantaged relative to authorized immigrants, a perspective that is supported by research on legal status disparities in self-rated health and mental health. We conducted a systematic review of the literature on legal status disparities in physical health and examined whether a legal status disparity exists in chronic conditions and musculoskeletal pain among 17,462 Mexican-born immigrants employed as farm workers in the United States and surveyed in the National Agricultural Workers Survey between 2000 and 2015. We found that unauthorized, Mexican-born farm workers have a lower incidence of chronic conditions and lower prevalence of pain compared with authorized farm workers. Furthermore, we found a legal status gradient in health whereby naturalized U.S. citizens report the worst health, followed by legal permanent residents and unauthorized immigrants. Although inconsistent with fundamental cause theory, our results were robust to alternative specifications and consistent with a small body of existing research on legal status disparities in physical health. Although it is well known that Mexican immigrants have better-than-expected health outcomes given their social disadvantage, we suggest that an epidemiologic paradox may also apply to within immigrant disparities by legal status. We offer several explanations for the counterintuitive result. PMID- 30519847 TI - Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose. AB - BACKGROUND: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium. difficile infection (rCDI). FMT capsules have emerged, and it is unknown if delivery location and dose impact efficacy. METHODS: We compared two cohorts of patients receiving two capsule formulations: gastric release (FMTgr) and targeted colonic release (FMTcr) at two different sites. Cohort A received FMTgr at (1) high dose: 60 capsules and low dose: 30 capsules. Patients in Cohort B received FMTcr at (1) high dose: 30 capsules (2) low dose: 10 capsules. Clinical cure rates and adverse events were monitored through week 8. Paired t-tests were used to compare diversity pre- and post-FMT. RESULTS: 51 rCDI patients were enrolled. Cohort A contained n = 20 and Cohort B contained n = 31. Overall cure at week 8 for FMTgr was 75% (15/20) compared to 80.6% for FMTcr, (25/31), p = 0.63. Both formulations were safe with no serious adverse events. FMTcr was superior at increasing gut microbial diversity. DISCUSSION: To our knowledge, this is the first study to compare targeted delivery of FMT capsules. While both capsules were safe and efficacious, microbial engraftment patterns were superior in FMTcr. PMID- 30519848 TI - Patient Satisfaction and Healthcare Utilization Using Telemedicine in Liver Transplant Recipients. AB - BACKGROUND: Post-liver transplantation care is limited to tertiary care centers. Concentration at expert centers leads to high-volume clinics with long wait times and decreased accessibility. AIM: To assess whether telemedicine can be utilized to overcome barriers to care while sustaining strong patient-physician relationships. METHODS: The Patient Satisfaction Questionnaire-18, Telemedicine Satisfaction Questionnaire, and Health Utilization Questionnaire were used to assess patient satisfaction and healthcare utilization among patients who received care via video connection (telemedicine group) and in clinic (control group). Propensity matching was performed. Scores for questionnaires were reported as mean and standard deviations (SD) and were compared by one-way multivariate analysis of variance and one-way analysis of variance. RESULTS: There were 21 matched telemedicine patients in our study. Overall mean age (+/- SD) was 51 (+/- 5.62) years and 52 (+/- 6.12) years for telemedicine group and control group, respectively. General patient satisfaction was similar between the two groups (p = 0.89). While telemedicine patients were just as satisfied with communication and interpersonal approach compared to clinic patients, they experienced significantly less commute (p < 0.0001) and waiting (p < 0.0001) times. Given ease of using telemedicine without compromising patient-physician interaction, 90% (19/21) of the telemedicine patients opted to use the service again. CONCLUSION: Telemedicine appeared to be both a time and cost-saving alternative to clinic follow-up without compromise of the valuable patient physician relationship. Telemedicine has the potential to improve clinic flow, reduce wait times, and decrease costs for liver transplant recipients. PMID- 30519849 TI - Presumed Consent: A Potential Tool for Countries Experiencing an Organ Donation Crisis. AB - BACKGROUND: There is currently an inadequate supply of allografts to meet the number of transplant candidates worldwide. A number of controversial policies, including implementation of a presumed consent organ donation system, have been considered to rectify the organ donation crisis. AIMS: A secondary retrospective data analysis aimed to assess the impact of switching to a presumed consent organ donation model on organ donation rates. METHODS: Deceased organ donation rates were compared before and after countries adopted presumed consent. RESULTS: Six countries met entry criteria. All six countries had an increase in liver donation rates, while 4 out of the six countries had an increase in kidney donation rates. The overall mean (+/- SD) liver donation rate was 3.23 (+/- 0.97) per million population (pmp) before the transition and 6.46 (+/- 1.81) pmp after the transition (p < 0.0001). The overall mean (+/- SD) kidney donation rate was 17.94 (+/- 3.34) pmp before the transition and 26.58 (+/- 4.23) pmp after the transition (p < 0.0001). The percentage increase in liver and kidney donation rates varied among countries, ranging from 28 to 1186%. CONCLUSION: The transition from explicit to presumed consent was associated with a significant increase in liver donation rates in all countries that met our criteria, while the effect on kidney donation rates was partially realized. Although presumed consent alone is unlikely to explain the increase in donation rates, the adoption of such a policy may prove to be a worthwhile risk for countries experiencing consistently low organ donation rates. PMID- 30519851 TI - Prevalence of Small Intestine Carcinoid Tumors: A US Population-Based Study 2012 2017. AB - BACKGROUND AND AIMS: Most carcinoid tumors of the gastrointestinal tract are located in the small bowel (SB). Epidemiological studies of these tumors have been limited by small sample sizes. Our aim was to evaluate the epidemiology of SB carcinoids (SBCs) using a large database. METHODS: We queried a commercial database (Explorys), an aggregate of electronic health data from 26 US healthcare systems. We identified patients with SBCs between 2012 and 2017. We evaluated the epidemiology of SBC and identified possible risk factors. RESULTS: Of the 35,798,290 individuals in the database between 2012 and 2017, we identified 3280 patients with SBCs, with a prevalence of 9.2/100,000. Prevalence was higher in men [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.153-1.322, p < 0.0001], whites [OR 2.031, 95% CI 1.872-2.203, p < 0.0001], and elderly (aged > 65) [OR 4.856, 95% CI 4.533-5.203, p < 0.0001]. Patients with SBCs were more likely to have a history of smoking [OR 2.749, 95% CI 2.549-2.970, p < 0.0001], alcohol use [OR 2.031, 95% CI 1.864-2.21, p < 0.0001], obesity (BMI > 30) [OR 3.476, 95% CI 3.213-3.761, p < 0.0001], diabetes mellitus [OR 4.198, 95% CI 3.900-4.519, p < 0.0001], and a family history of cancer [OR 5.902, 95% CI 5.396-6.456, p < 0.0001]. CONCLUSIONS: This is one of the largest studies done on the prevalence of SBC. The prevalence of 9.2/100,000 individuals is higher than previously reported. Further genetic and environmental studies are needed to understand the potential mechanisms for the risk factors identified in this study. PMID- 30519850 TI - Nonalcoholic Fatty Liver Disease Demonstrates a Pre-fibrotic and Premalignant Molecular Signature. AB - BACKGROUND: Metabolic syndrome contributing to nonalcoholic fatty liver disease (NAFLD) can lead to hepatic dysfunction, steatohepatitis, cirrhosis, and hepatocellular carcinoma. AIMS: In this study, we tested whether diet-induced fatty liver in a mouse model physiologically mimicked human NAFLD, and whether transcriptional alterations in mouse fatty liver signified risk for the development of hepatitis, cirrhosis, and/or hepatocellular carcinoma. METHODS: SAMP6 strain mice were fed a low-fat diet or high-fat diet (HFD) for 6 months. Mouse livers were isolated and subjected to histology, immunohistochemistry, and whole transcriptome RNA sequencing. Sequences were aligned to the mouse reference genome, and gene expression signatures were analyzed using bioinformatics tools including Cufflinks, Pathview, Cytoscape, ClueGO, and GOstats. RESULTS: Consistent with NAFLD, livers from HFD-fed mice demonstrated steatosis, high levels of inflammation, an up-regulation of genes encoding proteins associated with the complement pathway and immune responses, and down-regulation of those associated with metabolic processes. These livers also showed an up-regulation of genes associated with fibrosis and malignant transformation but no histological evidence of either pathobiology or DNA damage. CONCLUSIONS: HFD-fed mice exhibited NAFLD that had incompletely transitioned from fatty liver to NASH. Importantly, bioinformatics approaches identified pre-fibrotic and premalignant signatures, suggesting that the pathogenesis of both fibrosis and cancer may initiate in fatty livers well before associated histological changes are evident. PMID- 30519852 TI - Circ-TTC17 Promotes Proliferation and Migration of Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: Circular RNAs (circRNAs), a special class of noncoding RNAs with the characteristic of covalent closed-loop structure, have been widely found in various organisms. Growing evidence has shown that circRNAs play a crucial role in regulating biological functions of cancers. However, the specific role of circRNAs in esophageal squamous cell carcinoma (ESCC) remains largely unknown. AIM: The present study aims to investigate the effects of circ-TTC17 in ESCC clinical samples as well as cells. METHODS: Sanger sequencing and agarose gel electrophoresis were used to verify the specificity of circ-TTC17. Expression levels of circ-TTC17 in ESCC cells, plasma, and tissues were measured by quantitative real-time polymerase chain reaction. A colony formation experiment, CCK-8 assay, and wound-healing assay were applied to detect the functions of circ TTC17 in KYSE30 and KYSE450 cells. A nucleus-cytoplasm fractionation experiment was used to probe the location of circ-TTC17 in ESCC cells. Finally, a network of circ-TTC17 with its targeted miRNAs interactions and corresponding mRNAs was analyzed and framed by bioinformatics. RESULTS: The expression level of circ TTC17 was found to be significantly higher in ESCC cells, plasma, and tissues compared with normal cases. In vitro experiments indicated that circ-TTC17 promoted proliferation and migration of ESCC cells. Bioinformatics predictions showed that circ-TTC17 might regulate progress of ESCC by acting as a sponge for microRNAs (miRNAs). CONCLUSIONS: The results of this study demonstrate that upregulated circ-TTC17 plays a key role in promoting proliferation and migration of ESCC cells and has potential to become a novel biomarker for diagnosis, treatment, and prognosis of ESCC in the future. PMID- 30519853 TI - Endoscopy Is Relatively Safe in Patients with Acute Ischemic Stroke and Gastrointestinal Hemorrhage. AB - BACKGROUND: Gastrointestinal hemorrhage (GIH) is reported to occur in 1-8% of patients admitted with acute ischemic stroke (AIS). AIS is considered to be a relative contraindication to GIE. AIMS: Evaluate the outcomes of gastrointestinal endoscopy (GIE) in patients hospitalized with AIS and GIH. METHODS: Patients hospitalized with AIS and GIH were included from the National Inpatient Sample 2005-2014. Primary outcome measure was in-hospital mortality in patients with AIS and GIH who underwent gastrointestinal endoscopy. Secondary outcomes were (1) resource utilization as measured by length of stay (LOS) and total hospitalization costs and (2) to identify independent predictors of undergoing GIE in patients with AIS and GIH. Confounders were adjusted for by using multivariable regression analysis. RESULTS: A total of 75,756 hospitalizations were included in the analysis. Using a multivariate analysis, the in-hospital mortality was significantly lower in patients who underwent GIE as compared to those who did not [aOR: 0.4, P < 0.001]. Patients who underwent GIE also had significantly shorter adjusted mean LOS [adjusted mean difference in LOS: 0.587 days, P < 0.001]. Patients with AIS and GIH who did not undergo GIE had significantly higher adjusted total hospitalization costs. [Mean adjusted difference in total hospitalization costs was $5801 (P < 0.001).] Independent predictors of undergoing GIE in this population were male gender, age > 65 years, Asian or Pacific race, hypovolemic shock, need for blood transfusion and admission to urban non-teaching hospital. CONCLUSIONS: Gastrointestinal endoscopy can be safely performed in a substantial number of patients with AIS and GIH. PMID- 30519854 TI - Opioid Use is Associated with Higher Severity-Adjusted Episode Costs in Patients with Conservatively Managed Degenerative Joint Disease of the Back and Neck. AB - BACKGROUND: Opioid use and misuse are urgent health issues. Previous studies suggest that opioid use increases healthcare resource use but severity adjustment is lacking. OBJECTIVE: The objective of this study was to evaluate the severity adjusted cost difference between opioid users and non-users among patients with conservatively managed degenerative joint disease of the spine within a large commercial health plan population in the United States. METHODS: A retrospective observational study was performed using a national commercial database covering 531,819 patients aged 18-64 years with non-surgically managed cervical or lumbar degenerative spine disease during 2015-6. Patients were grouped based on whether there was evidence for an opioid prescription. Costs for the opioids themselves were excluded. Severity adjustment, on an ascending integer scale from 1 to 4, was performed based on member demographics, clinical comorbidities, disease progression indicators, and complications. RESULTS: Median episode costs for patients given opioids were approximately twice that for patients not given opioids after severity adjustment. For patients with episodes in both years and stable severity, patients with new prescriptions for opioids in 2016 doubled their median 2015 costs, and patients who had opioids discontinued in 2016 had a 60% cost reduction. Episode costs showed a nearly linear increase based on the length of time taking opioids, as well as with a higher average daily dose. Cost increases with opioids were broad across service categories even when comparing within the same severity-adjusted episodes of care. CONCLUSIONS: The data suggest a clinically and statistically significant increase in episode costs associated with opioid use for degenerative joint disease of the spine, both within and between patients, and higher costs with a longer duration of opioid use as well as with higher daily dosages. Given the health consequences surrounding the overuse of opioids, concerted efforts to move towards a non-opioid pain control strategy are needed. PMID- 30519855 TI - Development of a reverse genetics system for a feline panleukopenia virus. AB - Feline panleukopenia virus (FPV) infects cats and can be fatal to kittens. There is evidence that canine parvovirus originated from FPV, which makes FPV important in studies of the family Parvoviridae. In the present study, the entire genome of FPV strain HH-1/86 was converted into a full-length infectious clone (pFPV). The FPV strain HH-1/86 has a 5123-nt single stranded DNA genome with a Y-shaped inverted 3' terminal repeat (ITR) and a U-shaped inverted 5' ITR. Feline kidney cells (F81) were transfected with the pFPV clone which contained a genetic marker, and a rescued virus was obtained (rFPV). The rFPV was identified by its cytopathic effects, indirect immunofluorescence, growth curve analysis, western blot assay and hemagglutination, and was indistinguishable from the parent virus. The FPV infectious clone will facilitate the study of pathogenicity and viral replication of FPV and the inter-species transmission of parvoviruses. PMID- 30519856 TI - The Nine Habits of successful comprehensive cancer control coalitions. AB - The nine habits of successful comprehensive cancer control coalitions (Nine Habits) is a guide that outlines the key elements of successful comprehensive cancer control (CCC) coalitions. The guide was developed under the auspices of the Comprehensive Cancer Control National Partnership (CCCNP) and is based on evaluation including a literature review, qualitative and quantitative data collection from high-performing comprehensive cancer control coalitions. Comprehensive cancer control coalitions are made up of key stakeholders who come together to create a shared vision and shared plans to fight cancer, improve health outcomes, and reduce the burden from cancer. The CCCNP produced this guide to help coalitions maintain the health of their coalition efforts by providing tools to examine the key elements of successful coalitions, including leadership, membership, organizational structure, shared resources, and efforts in planning and communications. This paper provides information on how the guide was used by two states to rebuild their coalition and ultimately improve their efforts in improving health outcomes and reducing cancer burden. Lastly, the paper outlines future efforts to continue to support CCC coalitions in their work. PMID- 30519857 TI - Evolution of comprehensive cancer control plans and partnerships. AB - This article explores how comprehensive cancer control plans and partnerships have evolved, over the past 20 years, to meet the ever-changing environment of cancer prevention and control. This evolution has resulted in plans that take a more focused approach in identifying cancer-related priorities and coalitions with structures that have been redesigned to better engage a more wide-ranging group of partners to help address the priorities. Presented in this paper are examples from three states that describe how recognizing the need for change has led to improved processes in updating a cancer plan; strengthened and more diverse partnerships; and coalition sustainment by leveraging and maximizing resources. PMID- 30519858 TI - Correction to: Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase 4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons. AB - The authors have updated Fig. 3 which was incorrectly published in the original publication. PMID- 30519859 TI - Announcement of the resignation of Holger Eltzschig as an Associate Editor. PMID- 30519860 TI - L-Carnitine inhibits the senescence-associated secretory phenotype of aging adipose tissue by JNK/p53 pathway. AB - Senescence-associated secretory phenotype (SASP) plays a role in aging adipose tissue dysfunction by directly promoting chronic inflammation. The JNK/p53 pathway was reported as a potential mechanism that mediates SASP. In this study, we investigated the effects of L-carnitine, an inhibitor of the JNK/p53 pathway in adipose tissue SASP and dysfunction. Young and aging rat were given L carnitine by gavage. Next, we detected the senescence, cytokines expression, chronic inflammation and insulin resistance of adipose tissue. Additionally, JNK/p53 pathway was estimated. Our results show a significant increase expression of SASP components in the adipose tissue of aging rats compared to young rats. Further, we found that infiltration of immune cells and the expression of pro inflammatory cytokines were enhanced in aging adipose tissue while insulin signaling activity was reduced in aging adipose tissue. Interestingly, L carnitine markedly reduced the expression of SASP factors. L-Carnitine could significantly reduce chronic inflammation, improving insulin resistance. Further, L-carnitine inhibited SASP by inhibiting JNK/p53 pathway. L-Carnitine inhibited SASP by JNK/p53 pathway and attenuated adipose tissue dysfunction of aging. PMID- 30519861 TI - Late-onset administration of GDF11 extends life span and delays development of age-related markers in the annual fish Nothobranchius guentheri. AB - Current studies have generated disputes on the age-related change in the concentration of growth differentiation factor 11 (GDF11) and its role in the genesis of rejuvenation conditions. In this study we showed for the first time that both GDF11 gene expression and its protein abundance decreased with age in the fish Nothobranchius guentheri. We also showed that rGDF11 fed was indeed absorbed by the fish. Importantly, we demonstrated that dietary intake of recombinant GDF11 had little influences on the body weight and length of aging N. guentheri, but it delayed the development of age-related biomarkers and extended both the median and maximum life span of the fish. Our results clearly demonstrate that piscine GDF11 has rejuvenation and anti-aging capacity, the first data as such in non-mammalian vertebrates. PMID- 30519862 TI - Policy Impacts of the Australian National Perinatal Depression Initiative: Psychiatric Admission in the First Postnatal Year. AB - This paper helps to quantify the impact of the Australian National Perinatal Depression Initiative (NPDI) on postnatal inpatient psychiatric hospitalisation. Based on individual hospital admissions data from New South Wales and Western Australia, we found that the NPDI reduced inpatient psychiatric hospital admission by up to 50% [0.9% point reduction (95% CI 0.70-1.22)] in the first postnatal year. The greatest reduction was observed for adjustment disorders. The NPDI appears to be associated with fewer post-birth psychiatric disorders hospital admissions; this suggests earlier detection of psychiatric disorders resulting in early care of women at risk during their perinatal period. PMID- 30519863 TI - Do emotional difficulties and peer problems occur together from childhood to adolescence? The case of children with a history of developmental language disorder (DLD). AB - Children and adolescents with developmental language disorder (DLD) are, overall, vulnerable to difficulties in emotional adjustment and in peer relations. However, previous research has shown that different subgroups follow different trajectories in respect to the quality of peer relations. Less is known about the trajectories of emotional development. We consider here the possibility that development in these two domains is interrelated: that is, the trajectories of emotional and peer problems will proceed in parallel. We conducted longitudinal joint trajectories analyses of emotional and peer relations in a sample of young people identified as having DLD at the age of 7 years and seen at intervals up to 16 years. Potential influences on joint trajectory group membership were examined. Findings revealed five distinct joint trajectories. Emotional and peer difficulties do occur together from childhood to adolescence for just over half of the sample, but not all. The variables most clearly associated with group membership were pragmatic language ability, prosociality and parental mental health. This is the first study to examine joint longitudinal trajectories of emotional and peer difficulties in individuals with DLD. We demonstrate that development in individuals with DLD is heterogeneous and identify three key variables associated with personal and social adjustment from childhood to adolescence. Theoretical and clinical implications of these findings are discussed. PMID- 30519864 TI - Altered Global mRNA Expressions of Pain and Aggression Related Genes in the Blood of Children with Autism Spectrum Disorders. AB - Autism spectrum disorder (ASD) is characterized by repetitive stereotypic behaviors, restricted interests, social withdrawal, and communication deficits. Aggression and insensitivity to pain are largely unexplained in these cases. We analyzed nine mRNA expressions of the candidate genes related to aggression and insensitivity to pain in the peripheral blood of patients with ASD. Whole blood samples were obtained from 40 autistic patients (33 boys, 7 girls) and 50 age- and sex-matched controls (37 boys and 13 girls) to isolate RNA. Gene expression was assessed by quantitative Real-Time PCR (qRT-PCR) in the Erciyes University Genome and Stem Cell Center (GENKOK). All of the gene expressions except CRHR1 and SLC6A4 were found to be statistically different between the ASD patients and controls. Gene expression also differed according to gender. Alterations in the mRNA expression patterns of the HTR1E, OPRL1, OPRM1, TACR1, PRKG1, SCN9A and DRD4 genes provide further evidence for a relevant effect of the respective candidate genes on the pathophysiology of ASD. Future studies may determine the sensitivity of these candidate markers in larger samples including further neuropsychiatric diagnosis. PMID- 30519865 TI - Mitochondrial Electron Transport Chain Complex Dysfunction in MeCP2 Knock-Down Astrocytes: Protective Effects of Quercetin Hydrate. AB - Astrocytes play the central role in CNS metabolism to support neuronal functions. Mehyl-CpG-binding protein 2 (MeCP2) is the global transcription factor with differential expression in neuronal and non-neuronal cells. MeCP2 mutation and downstream detrimental effects have been reported in astrocytes also in MeCP2 associated neurodevelopmental disorder-Rett syndrome. Several studies have shown mitochondrial impairment linked to ROS production and reduced ATP synthesis in Rett patients and models, but consequences of MeCP2 deficiency on mitochondrial electron transport chain complexes in astrocytes and effect of known antioxidant quercetin aglycone has not yet been reported. The present study aimed to investigate effect of quercetin on mitochondrial functioning in MeCP2-deficient astrocytes. Our data show onefold upregulated Uqcrc1 and Ndufv2 gene expression, subtle change in protein expression, and significantly reduced mitochondrial respiratory chain complex-II and complex-III enzyme activities in MeCP2 knock down astrocytes. Intracellular calcium robustly increased and mitochondrial membrane potential decreased, while no change in ROS was observed in MeCP2 knock down astrocytes. Quercetin increased MeCP2 and normalized Uqcrc1 and Ndufv2 gene expression but did not modulate MeCP2 and Ndufv2 proteins expression. Interestingly, quercetin upregulated significantly the mitochondrial respiratory complex-II, complex-III, and complex-IV activities in dose-dependent manner. It also restored intracellular calcium level and mitochondrial membrane potential. In vitro observations suggest the beneficial effect of quercetin in mitochondrial functioning in MeCP2-deficient condition. There are no reports focusing on role of quercetin in mitochondrial function in MeCP2-deficient astrocytes, and these observations serve as preliminary data to evaluate quercetin's effects in vivo. PMID- 30519866 TI - Role of Macrophage Dopamine Receptors in Mediating Cytokine Production: Implications for Neuroinflammation in the Context of HIV-Associated Neurocognitive Disorders. AB - Despite the success of combination anti-retroviral therapy (cART), around 50% of HIV-infected individuals still display a variety of neuropathological and neurocognitive sequelae known as NeuroHIV. Current research suggests these effects are mediated by long-term changes in CNS function in response to chronic infection and inflammation, and not solely due to active viral replication. In the post-cART era, drug abuse is a major risk-factor for the development of NeuroHIV, and increases extracellular dopamine in the CNS. Our lab has previously shown that dopamine can increase HIV infection of primary human macrophages and increase the production of inflammatory cytokines, suggesting that elevated dopamine could enhance the development of HIV-associated neuropathology. However, the precise mechanism(s) by which elevated dopamine could exacerbate NeuroHIV, particularly in chronically-infected, virally suppressed individuals remain unclear. To determine the connection between dopaminergic alterations and HIV associated neuroinflammation, we have examined the impact of dopamine exposure on macrophages from healthy and virally suppressed, chronically infected HIV patients. Our data show that dopamine treatment of human macrophages isolated from healthy and cART-treated donors promotes production of inflammatory mediators including IL-1beta, IL-6, IL-18, CCL2, CXCL8, CXCL9, and CXCL10. Furthermore, in healthy individuals, dopamine-mediated modulation of specific cytokines is correlated with macrophage expression of dopamine-receptor transcripts, particularly DRD5, the most highly-expressed dopamine-receptor subtype. Overall, these data will provide more understanding of the role of dopamine in the development of NeuroHIV, and may suggest new molecules or pathways that can be useful as therapeutic targets during HIV infection. PMID- 30519868 TI - Ectopic corticotropin-releasing hormone syndrome caused by pancreatic neuroendocrine tumor localized by 68Ga-DOTATATE PET/CT. PMID- 30519867 TI - Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for imaging of gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0. AB - These joint practice guidelines, or procedure standards, were developed collaboratively by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO). Brain PET imaging is being increasingly used to supplement MRI in the clinical management of glioma. The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with glioma to achieve a high-quality imaging standard for PET using FDG and the radiolabelled amino acids MET, FET and FDOPA. This will help promote the appropriate use of PET imaging and contribute to evidence-based medicine that may improve the diagnostic impact of this technique in neurooncological practice. The present document replaces a former version of the guidelines published in 2006 (Vander Borght et al. Eur J Nucl Med Mol Imaging. 33:1374-80, 2006), and supplements a recent evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in patients with glioma (Albert et al. Neuro Oncol. 18:1199-208, 2016). The information provided should be taken in the context of local conditions and regulations. PMID- 30519869 TI - Cervical disc arthroplasty: tips and tricks. AB - Cervical disc arthroplasty (CDA) is a powerful, motion-sparing treatment option for managing cervical radiculopathy or myelopathy. While CDA can be an excellent surgery for properly indicated patients, it is also less forgiving than cervical fusion. Optimally resolving patient symptoms while maintaining range of motion relies on near perfection in the surgical technique. Different CDA options exist on the market, with some having long-term proven success and others in early stages of clinical trials. We discuss the different options available for use, as well as strategies of positioning, approach, disc space preparation, implantation, and fusion prevention that we believe can help improve performance and outcomes of CDA. PMID- 30519870 TI - Automatic detection of perforator vessels using infrared thermography in reconstructive surgery. AB - PURPOSE: Knowing the location of the blood vessels supplying the skin and subcutaneous tissue is a requirement during the planning of tissue transfer in reconstructive surgery. Commonly used imaging techniques such as computed tomography angiography and indocyanine green angiography expose the patient to radiation or a contrast agent, respectively. Infrared thermal imaging was evaluated with success as a non-invasive alternative. To support the interpretation of thermograms, a method to automatically detect the perforators was developed and evaluated. METHODS: A system consisting of a thermal camera, a PC and custom software was developed. The temperature variations of the skin surface were analysed to extract the perforator locations. A study was conducted to assess the performance of the algorithm by comparing the detection results of the algorithm with manually labelled thermal images by two clinicians of the deep inferior epigastric perforator flap of 20 healthy volunteers. RESULTS: The F measure, precision and recall were used to evaluate the system performance. The median F measure is 0.833, the median precision is 0.80, and the median recall is 0.907. CONCLUSION: The results of this study showed that it is possible to automatically and reliably detect the skin perforators in thermograms despite their weak temperature signature. Infrared thermal imaging is a non-invasive and contactless approach suitable for intraoperative use. Combined with a computer assisted tool for the automatic detection of perforator vessels, it is a relevant alternative intraoperative imaging method to the standard indocyanine green angiography. PMID- 30519871 TI - Reconstruction and positional accuracy of 3D ultrasound on vertebral phantoms for adolescent idiopathic scoliosis spinal surgery. AB - PURPOSE: Determine the positional, rotational and reconstruction accuracy of a 3D ultrasound system to be used for image registration in navigation surgery. METHODS: A custom 3D ultrasound for spinal surgery image registration was developed using Optitrack Prime 13-W motion capture cameras and a SonixTablet Ultrasound System. Temporal and spatial calibration was completed to account for time latencies between the two systems and to ensure accurate motion tracking of the ultrasound transducer. A mock operating room capture volume with a pegboard grid was set up to allow phantoms to be placed at a variety of predetermined positions to validate accuracy measurements. Five custom-designed ultrasound phantoms were 3D printed to allow for a range of linear and angular dimensions to be measured when placed on the pegboard. RESULTS: Temporal and spatial calibration was completed with measurement repeatabilities of 0.2 mm and 0.5 degrees after calibration. The mean positional accuracy was within 0.4 mm, with all values within 0.5 mm within the critical surgical regions and 96% of values within 1 mm within the full capture volume. All orientation values were within 1.5 degrees . Reconstruction accuracy was within 0.6 mm and 0.9 degrees for geometrically shaped phantoms and 0.5 and 1.9 degrees for vertebrae-mimicking phantoms. CONCLUSIONS: The accuracy of the developed 3D ultrasound system meets the 1 mm and 5 degrees requirements of spinal surgery from this study. Further repeatability studies and evaluation on vertebrae are needed to validate the system for surgical use. PMID- 30519872 TI - Effect of Tai Chi on Cardiac and Static Pulmonary Function in Older Community Dwelling Adults at Risk of Ischemic Stroke: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect of tai chi exercise on cardiac and static lung function for older community-dwelling adults at risk of ischemic stroke. METHODS: A total of 170 older community-dwelling adults (aged 55-75 years old) at risk of ischemic stroke were allocated to either tai chi training group (85 cases, five 60-min sessions of tai chi training per week for 12 weeks) or control group (85 cases, usual pbysical activity for 12 weeks) using a computer-generated randomization. The echocardiographic parameters of cardiac structure, cardiac function and static lung function were measured at baseline, after 12 weeks of intervention and additional 12-week follow-up period by a blinded professional staffmember using a color Doppler ultrasound imaging device or a cardiopulmonary function instrument. The t test and linear mixed model based on the intentionto treat analysis principle was used to calculate the effect. The adverse effect was observed. RESULTS: Most of echocardiographic parameters on the cardiac structure, cardiac function and static lung function between the tai chi group and control group did not have a significant difference either post 12-week intervention or additional 12-week follow-up period. Only three parameters involving in right ventricular diameter (P=0.024), main pulmonary artery diameter (P=0.002) and vital capacity maximum (P=0.036) were beneficial to be improved in the tai chi group compared to the control group by the analysis of mixed linear model. No adverse effects were found during the intervention period. CONCLUSION: The 12 week tai chi exercise did not have an obvious beneficial effect on cardiac structure, cardiac function and static lung function in older community-dwelling adults at risk of ischemic stroke. The study with a longer duration of intervention should be necessary. (Trial registration No. ChiCTR-TRC-13003601). PMID- 30519873 TI - Acupuncture Regulates the Balance of CD4+ T Cell Subtypes in Experimental Asthma Mice. AB - OBJECTIVE: To evaluate the involvement of different CD4+ T cell subtypes in the anti-asthmatic effects of acupuncture in asthmatic mice. METHODS: BALB/c mice were challenged by ovalbumin (OVA) for the establishment of experimental asthma model. Mice were divided into 4 groups by a random number table including the normal control, asthma model, acupuncture and sham acupuncture groups (14 per group). Acupoints Dazhui (GV 14), bilateral Fengmen (BL 12) and Feishu (BL 13) were selected for manual acupuncture treatment every other day for 4 weeks and Huantiao (GB 30) was selected for sham acupuncture. Airway hyperresponsiveness was examined by Buxco Pulmonary System. Pulmonary histopathology analysis was performed for inflammatory cell infiltration and mucus hypersecretion by haematoxylin eosin staining and periodic acid-Schiffstaining. Inflammatory mediators assays of serum were investigated by enzyme-linked immunosorbent assay and Bio-Plex. CD4+ T cell subpopulations including the expression levels of important factors in T lymphocyte polarization in lung tissue were examined by flow cytometric and Western blot analyses. Related pathways were detected by Western blot assay. RESULTS: Compared with the OVA-induced asthma model group, acupuncture could attenuate airway hyperresponsiveness, inhibit inflammatory cell infiltration and mucus hypersecretion (P<0.05 or P<0.01). Furthermore, acupuncture increased the expressions of T-bet and Foxp3+, the cell numbers of CD4+ interferon gamma (IFN-gamma)+ and CD4+ Foxp3+ in lung tissue and the level of Treg type cytokine interleukin (IL)-10 in serum (P<0.05 or P<0.01). Meanwhile, acupuncture reduced the RAR-related orphan receptor gamma t (RORgammat) level, the cell numbers of CD4+ IL-17A+ as well as the levels of IL-5, IL-13 and IL-17A in serum (P<0.05 or P<0.01). In addition, both acupuncture and sham acupuncture could inhibit the phosphorylation of p38 and p44/42 (P<0.01). CONCLUSION: Acupuncture could alleviate allergic airway inflammation by strengthening the activities of Th1 and Treg, thus regulating the balance of CD4+ T cell subtypes in experimental asthmatic mice. PMID- 30519874 TI - Hawthorn Extract Alleviates Atherosclerosis through Regulating Inflammation and Apoptosis Related Factors: An Experimental Study. AB - OBJECTIVE: To determine the effects of hawthorn extract on serum lipid levels, pathological changes in aortic atherosclerosis plaque, inflammatory factors, and apoptosis-related protein and mRNA expression in apolipoprotein E gene knockout (ApoE-/-) mice. METHODS: Thirty-six ApoE-/- mice were fed with a high-fat diet starting at the age of 8 weeks. Mice were randomly divided into 3 groups by a random number table including model group, hawthorn extract group, and simvastatin group, 12 mice in each group. Twelve 8-week-old C57BL/6 mice were fed a basic diet and served as control. The mice in the control and model groups were administered 0.2 mL saline daily, the mice in the hawthorn extract and simvastatin groups were administered with 50 mg/kg hawthorn extract or 5 mg/kg simvastatin daily for 16 weeks. After 16 weeks, plasma lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined by an enzymatic assay. Aortic atherosclerotic lesions were observed by light microscopy, scanning and transmission electron microscopy, respectively. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-1beta (IL-1beta), adiponectin (APN), and hypersensitive C-reactive protein (hs-CRP) were measured by enzyme linked immunosorbent assay (ELISA). Protein and mRNA expressions of Bax and Bcl-2 in the aorta were assessed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RESULTS: Compared to the control group, the plasma levels of TC, TG and LDL-C were significantly increased and HDL-C were significantly decreased in the model group (P<0.01). Compared to the model group, treatment with hawthorn extract significantly decreased the plasma levels of TC, TG, and LDL-C and increased the plasma level of HDL-C in ApoE-/- mice (P<0.01). The levels of MCP-1, IL-1beta, and hs-CRP in the model group were significantly increased and APN was significantly decreased compared with the control group (P<0.01). Compared to the model group, treatment with hawthorn extract decreased the levels of MCP-1, IL-1beta, and hs-CRP and increased the APN level (P<0.01). Compared to the control group, the protein and mRNA expression of Bax in the model group were significantly increased and the expression of Bcl-2 was significantly decreased (P<0.01). Hawthorn extract also reduced the protein and mRNA expression of Bax and increased the Bcl-2 expression in the aorta (P<0.01). CONCLUSION: Hawthorn extract has anti-atherosclerosis and stabilizing unstable plaque effects. The mechanism may be related to the inflammation and apoptosis signaling pathways. PMID- 30519875 TI - Bilateral trigeminal root entry zone enhancement in MOG-IgG-associated brainstem encephalitis. PMID- 30519876 TI - Significance of Cholesterol-Binding Motifs in ABCA1, ABCG1, and SR-B1 Structure. AB - ABCA1, ABCG1 transporters, and SR-B1 receptor are the major proteins involved in cholesterol efflux from cells. We superposed in silico the location of putative cholesterol (Chol)-binding motifs CRAC/CARC and CCM in human ABCA1, ABCG1, and SR B1 with (1) transmembrane protein topology, (2) a profile of structural order of protein, and (3) with an influence of single amino acid substitutions on protein structure and function. ABCA1, ABCG1, and SR-B1 molecules contain 50, 19, and 13 Chol-binding motifs, respectively, that are localized either in membrane helices, or at membrane-water interface, or in water-exposed protein regions. Arginine residues in motifs that coincide with molecular recognition features within intrinsically disordered regions of the transporters are suggested to be important in cholesterol binding; cholesterol-arginine interaction may result in the induction of local order in protein structure. Chol-binding motifs in membrane helices may immobilize cholesterol, while motifs at membrane-water interface may be involved into the efflux of "active" cholesterol. Cholesterol may interfere with ATP binding in both nucleotide-binding domains of ABCA1 structure. For ABCA1 and ABCG1, but not for SR-B1, the presence of mirror code as a CARC-CRAC vector couple in the C-terminal helices controlling protein cholesterol interactions in the outer and inner membrane leaflets was evidenced. We propose the role of Chol-binding motifs with different immersion in membrane in transport of different cholesterol pools by ABCA1 and ABCG1. PMID- 30519878 TI - Development of an innovative one-step nested PCR strategy for virus detection using the LNA technique. PMID- 30519879 TI - Inevitability or contingency: how many chromosomes do we really need? PMID- 30519877 TI - Chinese society of cardiology expert consensus statement on the diagnosis and treatment of adult fulminant myocarditis. AB - Fulminant myocarditis is primarily caused by infection with any number of a variety of viruses. It arises quickly, progresses rapidly, and may lead to severe heart failure or circulatory failure presenting as rapid-onset hypotension and cardiogenic shock, with mortality rates as high as 50%-70%. Most importantly, there are no treatment options, guidelines or an expert consensus statement. Here, we provide the first expert consensus, the Chinese Society of Cardiology Expert Consensus Statement on the Diagnosis and Treatment of Fulminant Myocarditis, based on data from our recent clinical trial (NCT03268642). In this statement, we describe the clinical features and diagnostic criteria of fulminant myocarditis, and importantly, for the first time, we describe a new treatment regimen termed life support-based comprehensive treatment regimen. The core content of this treatment regimen includes (i) mechanical life support (applications of mechanical respirators and circulatory support systems, including intraaortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO)), (ii) immunological modulation by using sufficient doses of glucocorticoid, immunoglobulin and (iii) antiviral reagents using neuraminidase inhibitor. The proper application of this treatment regimen may and has helped to save the lives of many patients with fulminant myocarditis. PMID- 30519880 TI - A lumbrokinase isozyme targets hepatitis B e-antigen. PMID- 30519881 TI - Hindbrain induction and patterning during early vertebrate development. AB - The hindbrain is a key relay hub of the central nervous system (CNS), linking the bilaterally symmetric half-sides of lower and upper CNS centers via an extensive network of neural pathways. Dedicated neural assemblies within the hindbrain control many physiological processes, including respiration, blood pressure, motor coordination and different sensations. During early development, the hindbrain forms metameric segmented units known as rhombomeres along the antero posterior (AP) axis of the nervous system. These compartmentalized units are highly conserved during vertebrate evolution and act as the template for adult brainstem structure and function. TALE and HOX homeodomain family transcription factors play a key role in the initial induction of the hindbrain and its specification into rhombomeric cell fate identities along the AP axis. Signaling pathways, such as canonical-Wnt, FGF and retinoic acid, play multiple roles to initially induce the hindbrain and regulate Hox gene-family expression to control rhombomeric identity. Additional transcription factors including Krox20, Kreisler and others act both upstream and downstream to Hox genes, modulating their expression and protein activity. In this review, we will examine the earliest embryonic signaling pathways that induce the hindbrain and subsequent rhombomeric segmentation via Hox and other gene expression. We will examine how these signaling pathways and transcription factors interact to activate downstream targets that organize the segmented AP pattern of the embryonic vertebrate hindbrain. PMID- 30519882 TI - Plasmonic ELISA for Sensitive Detection of Disease Biomarkers with a Smart Phone Based Reader. AB - Serum myoglobin is one of the earliest markers for the diagnosis of acute myocardial infarction. It is, therefore, critical to develop a point-of-care testing technology for myoglobin detection. In this work, we reported a sensitive plasmonic immunoassay-based on enzyme-mediated localized surface plasmon resonance change of gold nanorods for the point-of-care testing detection of myoglobin. In addition, we developed a novel plasmonic immunoassay reader using the ambient light sensor of smart phone to increase the accessibility and utility of the plasmonic immunoassay. The linear detection range of gold nanorods-based plasmonic immunoassay for myoglobin detection was 0.1-1000 ng mL-1 and the limit of detection was 0.057 ng mL-1. Myoglobin in serum samples was also analyzed by the plasmonic immunoassay. The results were significantly correlated with those of conventional enzyme-linked immunosorbent assay. The plasmonic immunoassay, coupled with smart phone-based reader, could be widely used for point-of-care testing application of acute myocardial infarction, especially in the regions with limited technological resources. PMID- 30519883 TI - 6,7-Dehydroroyleanone diterpene derived from Tetradenia riparia essential oil modulates IL-4/IL-12 release by macrophages that are infected with Leishmania amazonensis. AB - The treatment of cutaneous leishmaniasis in associated with several adverse effects and therapeutic failure, resulting in patients' abandonment of treatment. Research on new drugs with leishmanicidal potential from medicinal plants is essential. The anti-Leishmania activity of Tetradenia riparia essential oil (TrEO) and its derivatives, such as the diterpene 6,7-dehydroroyleanone (TrROY), and the immunomodulatory effects of TrEO have been reported. However, few studies have investigated the effects of TrROY. The present study evaluated the modulation of cytokine production by murine macrophages that were infected with Leishmania amazonensis (6 parasites/macrophage) and treated with TrROY (0.1, 1, and 100 MUg/ml). Cytokine levels were measured by flow cytometry. The results were analyzed using Student's t test at a 95% confidence interval. Microscopic counting was performed to evaluate the inhibitory effects of TrROY on intracellular infection. TrROY modulated the production of cytokines that are essential for the immune defense response to Leishmania, with a decrease in interleukin-4 (IL-4) levels and an increase in IL-12 levels. A TrROY concentration of 0.1 MUg/ml was chosen for the subsequent experiments. This dose was chosen because it modulated IL-4/IL-12 release by murine macrophages that were infected with Leishmania and because it presented no cytotoxic effects. TrROY (0.1 MUg/ml) induced a 31% reduction of the rate of infection in murine macrophages compared with untreated cells. TrROY may be a promising leishmanicidal agent. Further in vitro and in vivo studies should be conducted to evaluate the anti-Leishmania and immunomodulatory activity of TrROY. PMID- 30519884 TI - Correction to: Validation of a virtual intracorporeal suturing simulator. AB - The surname of Sreekanth Arikatla incorrectly appeared as Sreekanth Artikala. PMID- 30519885 TI - How radical is total parathyroidectomy in patients with renal hyperparathyroidism? AB - PURPOSE: Total parathyroidectomy (tPTX) in patients with renal hyperparathyroidism (RHPT) aims at the complete removal of all hyperfunctioning parathyroid tissue. Whenever parathyroidectomy is termed "total," undetectable postoperative parathyroid hormone (PTH) levels within the first postoperative week are expected. The aim of this study was to evaluate if tPTX is technically possible using a radical surgical procedure. METHODS: In 109 consecutive patients with RHPT (on hemodialysis: n = 50; after kidney grafting n = 59), removal of all visible parathyroid tissue, bilateral thymectomy, bilateral central neck dissection (level VI), and immediate autotransplantation (AT) was performed. Intact PTH (iPTH) levels were measured in the first postoperative week. PTX was classified "total" when iPTH dropped below 10 pg/ml, "subtotal" between 10 and 65 pg/ml, and "insufficient" where levels stayed above 65 pg/ml. RESULTS: According to the postoperative PTH value, tPTX was achieved in 80 of 109 (73.4%) patients (hemodialysis n = 27, normal kidney function: n = 43, restricted: n = 10). PTX was "subtotal" in 25 patients (22.9%), 19 on hemodialysis, 2 had normal, and 4 had restricted kidney graft function. PTX turned out to be insufficient in four patients (3.7%); all of them were on hemodialysis. Insufficient PTX was not observed in kidney-grafted patients. Postoperative temporary laryngeal nerve morbidity was 1.8% (no permanent paresis). CONCLUSIONS: Although applying a very radical concept in patients with RHPT, PTX was "total" in only 73.4%. Persistence of disease was avoided in 91.7%, and low morbidity was documented. In conclusion, it seems difficult to remove all parathyroid tissue from the neck which has to be considered when choosing the surgical procedure. PMID- 30519887 TI - ? PMID- 30519888 TI - Correction to: Abstract 2018. AB - The following corrections have been made to the Abstract Supplement. PMID- 30519886 TI - Contemporary practice and short-term outcomes after liver resections in a complete national cohort. AB - BACKGROUND: Improved outcome after liver resections have been reported in several series, but outcomes from national cohorts are scarce. Our aim was to evaluate nationwide practice and short-term outcomes after liver surgery in a universal healthcare system. METHODS: A complete 5-year cohort of all liver resections from the Norwegian Patient Registry (NPR). Short-term outcomes were aggregated length of stay (a-LoS), reoperation and 90-day mortality. RESULTS: Of 2118 liver resections, 605 (28.6%) were major, median age was 65 years and 1184 (55%) were male. Most common indication was metastatic disease (n = 1554; 73.4%) and primary malignancy (n = 328; 15.3%). Laparoscopy was performed in 513 (33.9%) of minor and 37 (6.1%) of major liver resections and increased over time to 39.1% of minor resections in 2016. Median a-LoS was 12 days for major resections, 8 days for open minor and 3 days for laparoscopic minor resections. Reoperation was reported for 159 (7.4%) and 90-day mortality for 44 (2.1%). Primary malignancy, male gender, elderly patients and major resections were associated with poorer outcome. CONCLUSIONS: In a national cohort, laparoscopy is used for a substantial proportion of minor resections and was associated with reduced a-LoS. Risk factors for reoperation and mortality were male gender, increased age and major resection for primary malignancy. PMID- 30519889 TI - Correlations between cervical spinal cord magnetic resonance diffusion tensor and diffusion kurtosis imaging metrics and motor performance in patients with chronic ischemic brain lesions of the corticospinal tract. AB - PURPOSE: To investigate modifications of Magnetic Resonance Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) metrics in lateral white matter (WM) bundles of the cervical spinal cord in patients with previous stroke in the vascular territory of the middle cerebral artery (MCA). METHODS: Twenty consecutive patients with a previous ischemic stroke of the MCA territory and a varying degree of upper motor impairment were enrolled. DKI was centered at the C3C4 and C5C6 intervertebral level. RESULTS: The fractional anisotropy (FA) values in C3C4 and C5C6 were found to be significantly lower in the lateral WM bundles contralateral to the ischemic lesion and thus, in the WM bundle including the affected corticospinal tract (CST) (p = 0.005 and p = 0.008, respectively), as well as mean kurtosis (MK) and axonal water fraction (AWF) values (p = 0.004 and p = 0.04. respectively). FA values correlated significantly with the Global Motor Index (GMI) both for C3C4 (rho = 0.61, p = 0.004) and C5C6 (rho = 0.69, p = 0.002). At C3C4, AWF correlated significantly with GMI (rho = 0.54, p = 0.03). No correlations were found between lateral WM bundle volumes and GMI. CONCLUSION: A reduction of anisotropy and microstructural complexity in the affected lateral WM bundle of the cervical spinal cord was observed in patients with previous ischemic stroke involving the CST. The correlations between these metrics and motor performance were statistically significant. PMID- 30519890 TI - Transition to parenthood and mental health at 30 years: a prospective comparison of mothers and fathers in a large Brazilian birth cohort. AB - Parenthood represents a major biological, social and environmental life change. Mental health disorders are common in parents and impact both the parent and their offspring. However, the relationship between parenthood and mental health and the direction of these effects are poorly understood. Longitudinal data from the Pelotas 1982 birth cohort, Southern Brazil, on 3701 individuals was used to investigate the association between number of children by age 30 years and mental health disorders using DSM-IV diagnoses at age 30 years, suicidal risk and the change in symptoms using repeated measures (using the SRQ-20) from age 19 to 30 years. Mothers, but not fathers, with higher number of children by age 30 years, were at a substantially increased risk of a wide range of mental health disorders compared to women with no children. There was evidence that motherhood was associated with an increase in symptoms over time rather than higher symptoms at baseline. Younger age at first child was also a risk factor for mental health disorders. Mothers, particularly those with multiple children, are at risk of a wide range of mental health disorders. The mechanisms to explain these risks are yet to be elucidated; however, the risk of mental health disorders was not replicated in fathers, which would be expected if residual confounding explained observed associations. Thus, multiparous mothers represent a high-risk group and should be prioritised for supportive interventions. PMID- 30519891 TI - Spray Dried Smectite Clay Particles as a Novel Treatment against Obesity. AB - PURPOSE: To explore the feasibility of spray dried smectite clay particles fabricated from montmorillonite or laponite materials for adsorbing dietary lipids and reducing rodent weight gain in vivo. METHODS: Spray dried montmorillonite (SD-MMT) and spray dried laponite (SD-LAP) particles were prepared via spray drying. Particle morphology, surface area and redispersion/aggregation properties in aqueous media were characterized. The ability of SD-MMT and SD-LAP particles to inhibit lipid digestion kinetics and adsorb lipid species from solution was assessed during in vitro lipolysis using proton nuclear magnetic resonance analysis. SD-MMT and SD-LAP particles were dosed to rodents fed a high-fat diet and their effect on body weight gain was evaluated. RESULTS: Both SD-MMT and SD-LAP particles adsorbed significant quantities of medium chain triglycerides and lipolytic products from solution during in vitro lipolysis. At a concentration of 50% w/w relative to lipid content, SD-MMT and SD-LAP particles adsorbed 42% and 94% of all lipid species, respectively. SD-MMT and SD-LAP particles also reduced the extent of rodent weight gain relative to the negative control treatment group and performed similarly to orlistat via an alternate mechanism of action. CONCLUSIONS: Spray dried smectite clay particles (SD-MMT and SD-LAP) with significant adsorptive capacities for dietary lipids and digestion products were successfully fabricated. These particles may be developed as novel anti-obesity treatments with fewer adverse effects than currently marketed treatment options. PMID- 30519892 TI - eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data. AB - The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer's disease in which brain shrinkage is a key biomarker. PMID- 30519893 TI - Colo-Pro: a pilot randomised controlled trial to compare standard bolus-dosed cefuroxime prophylaxis to bolus-continuous infusion-dosed cefuroxime prophylaxis for the prevention of infections after colorectal surgery. AB - Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus infusion (intervention arm) targeting free serum cefuroxime concentrations of 64 mg/L, or 1.5 g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500 mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2 h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64 mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30 days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). These infection rates can be used to power future clinical trials. This study demonstrates the feasibility of cefuroxime bolus-continuous infusion of antibiotic prophylaxis trials, and provides safety data for infusions targeting free serum cefuroxime concentrations of 64 mg/L. Trial registration: NCT02445859 . PMID- 30519894 TI - The clinicopathological analysis of receptor tyrosine kinases in meningiomas: the expression of VEGFR-2 in meningioma was associated with a higher WHO grade and shorter progression-free survival. AB - WHO grade II/III meningiomas recur frequently and there is currently no established molecular target therapy for meningioma. No previous studies have revealed the association between receptor tyrosine kinases (RTKs) and the recurrence of meningiomas. This study aims to elucidate the association between RTKs and the clinicopathological characteristics and recurrence of meningioma. We investigated the immunohistochemical expression of RTKs (VEGFR-1/2/3, PDGFR alpha/beta and c-Kit) in 81 meningiomas (WHO grade I, n = 64, WHO grade II/III, n = 17) in 74 patients. Immunohistochemistry revealed that 29 WHO grade I (45%), 10 WHO grade II (77%), and 4 WHO grade III (100%) tumors were VEGFR-2-positive, and that the VEGFR-2 expression was significantly correlated with the WHO grade. In univariate analyses to investigate the clinicopathological factors associated with recurrence, Simpson grade IV/V resection, a larger tumor size, a high VEGFR 2 expression level, WHO grade II/III, a high Ki-67 expression level, and the non expression of PgR were identified as significant factors. Furthermore, patients with VEGFR-2-positive meningiomas showed significantly shorter progression-free survival. In the multivariate analysis, WHO grade II/III and the location were significantly associated with recurrence. In conclusion, our study suggests that VEGFR-2 inhibitors might be one of the best candidates for molecular therapy against recurrent meningiomas. PMID- 30519895 TI - Mindray 3-directional NMT Module (a new generation "Tri-axial" neuromuscular monitor) versus the Relaxometer mechanomyograph and versus the TOF-Watch SX acceleromyograph. AB - Recently introduced Mindray "3-directional" neuromuscular transmission transducer (NMT, Shenzhen, China) acceleromyograph) claim to monitor thumb movement in 3 different directions. We compared NMT with the gold standard Relaxometer(r) mechanomyograph (MMG, Groningen University, Netherlands) in Study-1 and with TOF Watch SXTM (WTCH) acceleromyograph from which it was developed in Study-2. We used first twitch (T1%) and train-of-four (TOF) ratio rocuronium 0.6 mg kg-1 neuromuscular block to evaluate NMT diagnostic accuracy in indicating 3 clinically relevant time points namely; MMG T1 5% (95% twitch depression) for tracheal intubation, MMG T1 25% for repeat neuromuscular blocking agents (NMBAs) administration, and MMG 0.9 TOF ratio full neuromuscular block recovery. We compared onset time (time from beginning of rocuronium administration until maximal depression), Dur25 (time until T1 25% recovery) and Dur0.9 (time until 0.9 TOF ratio recovery). In Study-1, NMT showed low sensitivity in indicating MMG time for tracheal intubation, repeat NMBAs administration and full neuromuscular block recovery (6.25%, 38.9% and 38.9% respectively). NMT onset time, Dur25 and Dur0.9 (2:51 +/- 00:57, 36:50 +/- 24:25, 70:08 +/- 25:27 min:s) were significantly longer than MMG (1:56 +/- 00:46, 30:26 +/- 20:24, 62:03 +/- 20:01). In Study-2, NMT onset time, Dur25 and Dur0.9 (02:37 +/- 00:53, 35:38 +/- 11:54, 53:40 +/- 13:49) were not significantly different than WTCH (02:23 +/- 00:45, 33:27 +/- 12:51, 53:57 +/- 12:47). NMT could not efficaciously detect MMG time for tracheal intubation; NMBAs repeat dose administration or full neuromuscular block recovery. Data from NMT cannot be used interchangeably with MMG. Our study revealed that NMT Tri-axial acceleromyography seems to offer no advantage over the MMG gold standard or the classic Mono-axial TOF-Watch SX monitor. PMID- 30519896 TI - Oxygen reserve index (ORiTM) contributes to prediction of hypoxemia and patient safety during tracheal stent insertion using rigid bronchoscopy: a case report. AB - The oxygen reserve index (ORiTM) is a new noninvasive and continuous variable, which represents a moderate hyperoxygenation status, with a unitless scale between 0.00 and 1.00. When percutaneous oxygen saturation (SpO2) exceeds 100%, arterial blood oxygen partial pressure cannot be evaluated without performing arterial blood gas analysis. Because of significant air leakage during rigid bronchoscopy, it is difficult to monitor respiration using capnography, which does not measure end-tidal carbon dioxide (ETCO2) accurately. A 66-year-old man (175 cm, 76.8 kg) with a chief complaint of difficulty in breathing was diagnosed with a thyroid tumor. Computed tomography revealed tracheal stenosis due to direct invasion of the thyroid tumor; therefore, tracheal stenting was planned immediately. After supplying 6 L/min oxygen with a face mask and administering 180 mg of propofol intravenously, the supraglottic airway was intubated. General anesthesia (total intravenous anesthesia) through continuous administration of 6 10 mg/kg/h of propofol and intermittent administration of 50 ug of fentanyl (total 200 ug) preserved spontaneous breathing. During tracheal stent insertion, disconnection between the oxygen supply system and rigid bronchoscopy, and tracheal stent expansion, the ORi tended to decrease before SpO2 decreased. Thus, measuring ORi could prevent hypoxemia during tracheal stent insertion using rigid bronchoscopy. PMID- 30519897 TI - Impact of extremely low-frequency magnetic fields on human postural control. AB - Studies have found that extremely low-frequency (ELF, < 300 Hz) magnetic fields (MF) can modulate standing balance; however, the acute balance effects of high flux densities in this frequency range have not been systematically investigated yet. This study explores acute human standing balance responses of 22 participants exposed to magnetic induction at 50 and 100 mTrms (MF), and to 1.5 mA alternating currents (AC). The center of pressure displacement (COP) was collected and analyzed to investigate postural modulation. The path length, the area, the velocity, the power spectrum in low (< 0.5 Hz) and medium (0.5-2 Hz) bands have computed and showed the expected effect of the positive control direct current (DC) electric stimulation but failed to show any significant effect of the time-varying stimulations (AC and MF). However, we showed a significant biased stabilization effect on postural data from the custom experimental apparatus employed in this work, which might have neutralized the hypothesized results. PMID- 30519898 TI - Transdermal versus oral estrogen: clinical outcomes in patients undergoing frozen thawed single blastocyst transfer cycles without GnRHa suppression, a prospective randomized clinical trial. AB - PURPOSE: To conduct a non-inferiority study to compare the clinical outcomes of transdermal estrogen patch and oral estrogen in patients undergoing frozen-thawed single blastocyst transfer non-donor cycles without GnRHagonist (GnRHa) suppression. METHODS: A total of 317 women with irregular menses or anovulatory cycle undergoing frozen-thawed embryo transfer (FET) non-donor cycles without GnRHa suppression were involved in a prospective randomized clinical trial between May 2017 and October 2017. The trial was conducted in an ART and Reproductive Genetics Centre within a private hospital. The unit is designated as a teaching center by the Turkish Ministry of Health. Oral or transdermal estrogen was administered in patients undergoing frozen-thawed single blastocyst transfer. The outcomes of the study were the following: endometrial thickness on the day of progesterone administration, implantation rate, and clinical and viable ongoing pregnancy rates. RESULTS: Endometrial thickness and clinical outcomes of oral and transdermal estrogen administration were equally successful (p > 0.05). CONCLUSION: No significant difference was found in endometrial thickness on the day of progesterone administration nor in clinical outcomes between transdermal estrogen and oral estrogen in patients undergoing frozen-thawed single blastocyst stage transfer cycles without GnRHa suppression. PMID- 30519899 TI - Discrepancy Between Equations Estimating Kidney Function in Geriatric Care: A Study of Implications for Drug Prescription. AB - BACKGROUND: In older patients, the agreement is low between creatinine clearance estimated with the Cockcroft-Gault equation (eCrCl) and glomerular filtration rate estimated with the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI). The implications of these discrepancies for drug prescription have so far been assessed only for a few selected molecules. OBJECTIVE: The aim of this study was to investigate the proportion of geriatric patients receiving drugs with a different recommended dose or indication (i.e. an adjustment discrepancy) depending on eCrCl versus eGFRCKD-EPI estimates of kidney function. METHODS: Patients admitted to acute geriatric care units in our university hospital were eligible for inclusion. All drug classes were studied. We retrospectively determined recommended prescriptions according to eCrCl and eGFRCKD-EPI. RESULTS: Sixty percent of patients received at least one drug requiring dose adjustment and/or received a drug with a relative contraindication based on their estimated kidney function. Thirty-one percent of patients received at least one drug with an adjustment discrepancy: 20% received at least one drug for which the recommended dose differed depending on eCrCl versus eGFRCKD-EPI estimates of kidney function, 4% received a drug with a relative contraindication according to eCrCl but not eGFRCKD-EPI, and 7% received both. Factors independently associated with an adjustment discrepancy were older age and lower weight. Main drug classes involved were benzodiazepines, anticoagulants, and anti microbial drugs. CONCLUSION: In acute geriatric care units, recommended drug dose adjustments are frequently discordant according to the equations used to estimate kidney function, notably for benzodiazepines, anticoagulants, and anti-microbial drugs. The consequences for treatment efficacy and safety should be investigated. PMID- 30519901 TI - What's new in management and clearing of airway secretions in ICU patients? It is time to focus on cough augmentation. PMID- 30519900 TI - Distinctive role of ACVR1 in dentin formation: requirement for dentin thickness in molars and prevention of osteodentin formation in incisors of mice. AB - Dentin is a major component of teeth that protects dental pulp and maintains tooth health. Bone morphogenetic protein (BMP) signaling is required for the formation of dentin. Mice lacking a BMP type I receptor, activin A receptor type 1 (ACVR1), in the neural crest display a deformed mandible. Acvr1 is known to be expressed in the dental mesenchyme. However, little is known about how BMP signaling mediated by ACVR1 regulates dentinogenesis. To explore the role of ACVR1 in dentin formation in molars and incisors in mice, Acvr1 was conditionally disrupted in Osterix-expressing cells (designated as cKO). We found that loss of Acvr1 in the dental mesenchyme led to dentin dysplasia in molars and osteodentin formation in incisors. Specifically, the cKO mice exhibited remarkable tooth phenotypes characterized by thinner dentin and thicker predentin, as well as compromised differentiation of odontoblasts in molars. We also found osteodentin formation in the coronal part of the cKO mandibular incisors, which was associated with a reduction in the expression of odontogenic gene Dsp and an increase in the expression of osteogenic gene Bsp, leading to an alteration of cell fate from odontoblasts to osteoblasts. In addition, the expressions of WNT antagonists, Dkk1 and Sost, were downregulated and B-catenin was up-regulated in the cKO incisors, while the expression levels were not changed in the cKO molars, compared with the corresponding controls. Our results indicate the distinct and critical roles of ACVR1 between incisors and molars, which is associated with alterations in the WNT signaling related molecules. This study demonstrates for the first time the physiological roles of ACVR1 during dentinogenesis. PMID- 30519902 TI - Acute respiratory distress syndrome (ARDS) phenotyping. PMID- 30519903 TI - Older African Americans and the HIV Care Continuum: A Systematic Review of the Literature, 2003-2018. AB - Evidence suggests that racial disparities in the HIV care continuum persist in older age groups, particularly among African Americans. The objective of this systematic review was to identify factors that facilitate or hinder older African Americans' engagement in the HIV care continuum. For studies published between 2003 and 2018, we: (1) searched databases using keywords, (2) excluded non-peer reviewed studies, (3) limited findings to older African Americans and the HIV care continuum, and (4) retrieved and summarized data focused on barriers and facilitators of the HIV care continuum. Among the 1023 studies extracted, 13 were included: diagnosis/testing (n = 1), engagement in care (n = 7), and antiretroviral adherence (n = 5). Barriers included lack of HIV risk awareness, routine testing, and healthcare access, stigma, and multimorbidities. Social support, health/medication literacy, and increased self-efficacy facilitated engagement. A targeted focus on older African Americans is needed to achieve national goals of improving HIV care and treatment outcomes. PMID- 30519904 TI - HIV Physicians and Chronic Opioid Therapy: It's Time to Raise the Bar. AB - Clinical practice that utilizes chronic opioid therapy has been recognized as one major cause of the opioid crisis. Among patients living with HIV, the risks associated with chronic opioid therapy may be complicated by factors such as co occurring mental health diagnoses, substance use, and economic marginalization. Improving opioid prescribing practices in HIV clinics requires attention to these and other characteristics common to HIV care. In the context of a randomized controlled trial testing an intervention to improve opioid prescribing practices in HIV outpatient clinics, we interviewed physicians about their perspectives on chronic opioid therapy. Overwhelmingly, physicians voiced ambivalence about their own knowledge and comfort with prescription opioids. They raised concerns about the impact of opioid prescribing on patient-provider relationships and the increasing workload associated with prescribing and monitoring patients. In this report, we explore these concerns and propose several strategies for improving clinical care in which chronic opioid therapy is addressed. PMID- 30519905 TI - The weight-specific adolescent instrument for economic evaluation (WAItE): psychometric evaluation using a Rasch model approach. AB - PURPOSE: The Weight-specific Adolescent Instrument for Economic evaluation (WAItE) is a 7-item condition-specific tool assessing the impact of weight status on seven dimensions of quality of life. The content of the WAItE was developed with both treatment-seeking and non-treatment-seeking adolescents aged 11-18 years. The aim of this study was to assess the psychometric properties of the WAItE in adolescent and adult populations. METHODS: Treatment-seeking adolescents with obesity (females n = 155; males n = 123; mean age = 13.3; 13.1 years, respectively) completed the WAItE twice. An adult general population sample completed the WAItE via an online survey (females n = 236; males n = 231; mean age = 41.2; 44.3 years, respectively). The Partial Credit Model was applied to the data and item fit evaluated against published criteria. RESULTS: The WAItE had a unidimensional structure both for adolescents and adults. There was no item misfit observed for either participant samples and no differential item functioning (DIF) was present by age or gender for the adolescents. Some DIF was observed across age groups for the adult sample. For the adolescent sample, stable item locations were observed over time. CONCLUSIONS: The aim of the WAItE is to assess the impact of weight status on the lives of adolescents in cost effectiveness evaluation of weight management programmes. The results of this study demonstrated that the WAItE has reliable psychometric properties. The instrument may therefore be used to aid informed decision around the identification of cost-effective weight management programmes in both adolescent and adult populations. PMID- 30519906 TI - Exploration of a cultural-adaptation of the EQ-5D for Thai population: A "bolt on" experiment. AB - PURPOSE: As the EQ-5D was developed in western countries with only five dimensions, it might be insensitive to non-western populations including Thai. This study examined the impact of adding two candidate dimensions, "interpersonal relationships (IR)" and "activities related to bending knees (AK)," to the EQ-5D questionnaire, and evaluated their psychometric properties in a Thai population sample. METHODS: Face-to-face interviews were conducted with 600 Thai. Ceiling effect for the EQ-5D and the EQ-5D-5L+AK+IR were compared. Spearman's rho correlation was used to determine whether the two new dimensions were redundant with the existing EQ-5D dimensions. Correlations between the two dimensions and similar dimensions of the SF-36v2 were also assessed. Hierarchical multiple regression was performed to evaluate the incremental value of the EQ-5D-5L+AK+IR over the EQ-5D in predicting VAS scores. RESULTS: The two new dimensions were not redundant with the existing five dimensions of the EQ-5D. The highest correlation (0.371) was found between MO and AK. The overall ceiling effect decreased by 5% (50.5-45.5%) when using the EQ-5D-5L+AK+IR. Moderate correlations were found between the candidate dimensions and similar dimensions of the SF-36v2. Multiple regression indicated that adding AK (adjusted r2 0.329 vs. 0.306) but not IR (adjusted r2 0.307 vs. 0.306) significantly increased ability to predict VAS scores. CONCLUSIONS: Our preliminary results suggested that AK holds promise for making the EQ-5D more relevant to Thai while it is premature to conclude on the impact of IR. Nevertheless, more work is required to carefully assess the value of the new dimensions as well as the trade-off for the modification. PMID- 30519907 TI - Force-velocity profiling of sprinting athletes: single-run vs. multiple-run methods. AB - PURPOSE: This study explored the agreement between a single-run and a multiple run method for force-velocity (Fv) profiling of sprinting athletes; we evaluated both absolute values and changes over time caused by sprint training. METHODS: Seventeen female handball players (23 +/- 3 years, 177 +/- 7 cm, 73 +/- 6 kg) performed 30 m un-resisted and resisted sprints (50, 80 and 110 N resistance) before and after an 8-week sprint training intervention. Two approaches were used to calculate theoretical maximal velocity (v0), horizontal force (F0), power (Pmax), and the force-velocity slope (SFv): (1) the single-run method, based on inverse dynamics applied to the centre-of-mass movement, was calculated from anthropometric and sprint split time data; and (2) the multiple-run method, where peak velocity from un-resisted and resisted sprints were plotted against the horizontal resistances. RESULTS: Trivial differences in v0 (0.7%) were observed between the two calculation methods. Corresponding differences for F0, Pmax and SFv were 16.4, 15.6 and 17.6%, respectively (most likely; very large effect size). F0 showed poor agreement between the methods (r = 0.26 and 0.16 before and after the intervention). No substantial correlation between the changes (from pre to post-training tests) in SFV calculated with the single-run and the multiple run methods were observed (r = 0.02). CONCLUSIONS: This study revealed poor agreement between the Fv relationships of the investigated calculation methods. In practice, both methods may have a purpose, but the single-run and the multiple run methods appear to measure somewhat different sprint properties and cannot be used interchangeably. PMID- 30519908 TI - Italian consensus for the classification and reporting of thyroid cytology: the risk of malignancy between indeterminate lesions at low or high risk. A systematic review and meta-analysis. AB - BACKGROUND: Italian consensus for the classification and reporting of thyroid cytology has proposed to discriminate the cancer prevalence of high (Tir 3B) vs. low (Tir 3A) risk indeterminate nodules. To obtain more robust evidence on this topic, we performed a meta-analysis of the Odds Ratio (OR) of malignancy of Tir 3B vs. Tir 3A nodules. METHODS: A comprehensive literature exploration of online databases was conducted until May 2018. Original articles reporting histology of nodules cytologically classified as Tir 3A and Tir 3B were eligible. Pooled cancer prevalence in Tir 3A and Tir 3B, and OR of Tir 3B vs. Tir 3A were calculated. RESULTS: The search revealed 95 articles, and 10 were included for the meta-analysis. Overall, 1168 indeterminate lesions were reported (441 Tir 3A and 727 Tir 3B), of which 391 were cancers. The pooled cancer prevalence was 17% in Tir 3A and 47% in Tir 3B. The OR of Tir 3B vs. Tir 3A was 4.24 (95% CI 2.75 to 6.53) with mild heterogeneity and without publication bias. When we considered non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) as non-malignant, cancer rate was lower, and OR of Tir 3B against Tir 3A was 2.93 (95% CI 1.60 to 5.37), with no heterogeneity but with publication bias. CONCLUSIONS: The Italian system for thyroid cytology is reliable to assess indeterminate lesions at low and high risk, being Tir 3B associated with a cancer risk significantly higher than Tir 3A, also when considering NIFTP as non malignant entity. PMID- 30519909 TI - Causes of recurrences after open inguinal herniorrhaphy. AB - PURPOSE: One of the most important measures of success of open inguinal herniorrhaphy is the incidence of recurrence. Reports suggest that up to 13% of all inguinal hernia repairs worldwide, irrespective of the approach, are repaired for recurrence. The reason as to why inguinal hernias recur is most likely multifactorial. The aim of this review is to evaluate the risk factors responsible for these recurrences in open suture and mesh techniques. METHODS: A search of the Medline, Embase, Science Citation Index, Current Contents and PubMed databases identified English language, peer-reviewed articles on the causes of recurrence following open inguinal herniorrhaphy published between 1990 and 2018. The search terms included 'Inguinal hernia'; 'Open methods'; 'Suture repair'; 'Mesh repair', 'Recurrence', 'Causes', 'Humans'. RESULTS: The literature revealed several contributing modifiable and non-modifiable risk factors that were responsible for recurrence following open suture and mesh inguinal herniorrhaphy. These included perioperative, patient and hernia factors. CONCLUSIONS: Despite the advent of laparoscopic techniques, open inguinal herniorrhaphy remains one of the most common surgical operations. With open inguinal hernia repairs, risk factors for recurrence can be broadly classified into perioperative, patient and hernia factors. Certain patient and technical risk factors are modifiable and could reduce the recurrence rate. However, many others factors are non-modifiable. It is therefore imperative that the outcome of open inguinal herniorrhaphy must be optimised by careful planning and education for both surgeons and patients to achieve the lowest possible risk of subsequent surgery for recurrence. PMID- 30519910 TI - Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle. AB - This study investigated vildagliptin-induced vasodilation and its related mechanisms using phenylephrine induced precontracted rabbit aortic rings. Vildagliptin induced vasodilation in a concentration-dependent manner. Pretreatment with the large-conductance Ca2+-activated K+ channel blocker paxilline, ATP-sensitive K+ channel blocker glibenclamide, and inwardly rectifying K+ channel blocker Ba2+ did not affect the vasodilatory effects of vildagliptin. However, application of the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine significantly reduced the vasodilatory effects of vildagliptin. In addition, application of either of two sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors, thapsigargin or cyclopiazonic acid, effectively inhibited the vasodilatory effects of vildagliptin. These vasodilatory effects were not affected by pretreatment with adenylyl cyclase, protein kinase A (PKA), guanylyl cyclase, or protein kinase G (PKG) inhibitors, or by removal of the endothelium. From these results, we concluded that vildagliptin induced vasodilation via activation of Kv channels and the SERCA pump. However, other K+ channels, PKA/PKG-related signaling cascades associated with vascular dilation, and the endothelium were not involved in vildagliptin induced vasodilation. PMID- 30519911 TI - Assessment of sediment capping with zirconium-modified bentonite to intercept phosphorus release from sediments. AB - Three different types of zirconium-modified bentonites (ZrMBs) including zirconium-modified original bentonite (ZrMOB), zirconium-modified magnesium pretreated bentonite (ZrMMgB), and zirconium-modified calcium-pretreated bentonite (ZrMCaB) were synthesized and used as active covering materials to suppress the release of phosphorus (P) from sediments. To assess the covering efficiency of ZrMBs to inhibit P release from sediments, we examined the impact of ZrMB covering layer on P mobilization in sediments at different depths as well as the release of P through the interface between sediment and overlying water (SWI) by use of simulating P release control experiments and diffusive gradients in thin films (DGT) technology. The results showed that the amount of soluble reactive P (SRP) in the overlying water greatly decreased after covering with ZrMBs. Moreover, both pore water SRP and DGT-liable P (DGT-P) in the top sediments decreased after capping with ZrMBs. An obvious stratification of DGT-P was observed along the vertical direction after covering with ZrMBs, and static and active layers were found in the top sediment and in the lower sediment directly below the static layer, respectively. Furthermore, ZrMB covering led to the change of P species from easily released P to relatively or very stable P, making P in the top sediment more stable compared to that without ZrMB covering. Besides, an overwhelming majority of P immobilized by ZrMBs is hard to be re released into the water column in a common environment. Overall, the above results demonstrate that sediment covering with ZrMBs could effectively prevent the transport of SRP from sediments into the overlying water through the SWI, and the control of P transport into the overlying water by ZrMB covering could be mostly due to the immobilization of pore water SRP, DGT-P, and mobile P in the top sediment by ZrMBs. PMID- 30519912 TI - Genotoxicity of inhalational anesthetics and its relationship with the polymorphisms of GSTT1, GSTM1, and GSTP1 genes. AB - Due to their wide applications, concern exists regarding possible genotoxic effects of inhalational anesthetics (IAs) among operating room personnel. This study was undertaken to examine genotoxic properties of co-exposure to nitrous oxide, sevoflurane, and isoflurane on induction of micronucleus (MN) and chromosomal aberrations (CAs) and to determine whether any associations exist between polymorphisms of GST genes and the level of genomic damage measured by MN and CAs assays. Sixty operating room personnel and 60 unexposed referent nurses were studied. The workers' exposure to the IAs was determined. DNA damage was evaluated by MN and CAs assays. Additionally, the GSTM1, GSTT1, and GSTP1 polymorphisms were detected. The mean concentrations of nitrous oxide, isoflurane, and sevoflurane were found to be 850.92 +/- 919.78, 2.40 +/- 0.86, and 0.18 +/- 0.14 ppm, respectively. The frequency of MN and CAs in the exposed group was significantly higher than that of the non-exposed group. The frequency of MN was significantly higher in referent nurses with null GSTT1, compared to referent nurses with positive GSTT1. The frequency of MN was significantly higher in exposed individuals carrying the combined genotype of GSTT1 (-), GSTM1 (-), and GSTP1 AG as compared with subjects carrying a combination of GSTT1 (+), GSTM1 (+), and GSTP1 AA. Statistically significant associations were noted between exposure to the IAs, gender, and the combination of the three GSTs genotypes with MN frequency. These findings indicate that inhalation exposure to IAs induces genotoxic response and the polymorphisms of GSTs genes might modulate the effect of exposure to IAs on MN. PMID- 30519913 TI - Continuous degradation of Direct Red 23 by calcium pectate-bound Ziziphus mauritiana peroxidase: identification of metabolites and degradation routes. AB - In the present study, oxido-reductive degradation of diazo dye, Direct Red 23, has been carried out by Ziziphus mauritiana peroxidases (specific activity 17.6 U mg-1). Peroxidases have been immobilized via simple adsorption and cross-linking by glutaraldehyde; adsorbed and cross-linked enzyme retained 94.28% and 91.23% of original activity, respectively. The stability of peroxidases was enhanced significantly upon immobilization; a marked widening in both pH and temperature activity profiles were observed. Adsorbed peroxidases exhibited similar pH and temperature optima as reported for the free enzyme. Thermal stability was significantly enhanced in case of cross-linked enzyme which showed 80.52% activity even after 2 h of incubation at 60 degrees C. Packed bed reactors containing adsorbed and cross-linked peroxidases were run over a period of 4 weeks; adsorbed peroxidases retained 52.86% activity whereas cross-linked peroxidases maintained over 77% dye decolorization ability at the end of the fourth week of its continuous operation. Gas chromatography coupled with mass spectrometry was used to analyze the degradation products; it showed the presence of four major metabolites. Degradation of dye starts with the 1 Hydroxybenzotriazole radical attack on the carbon atom of the phenolic ring bearing azo linkage, converting it into cation radical which underwent nucleophilic attack by a water molecule and results in cleavage of chromophore via symmetric and asymmetric cleavage pathways. Intermediates undergo spontaneous removal of nitrogen, deamination, and oxidation reactions to produce maleic acid as the final degradation product. Graphical abstract. PMID- 30519914 TI - The enhanced lipid productivity of Chlorella minutissima and Chlorella pyrenoidosa by carbon coupling nitrogen manipulation for biodiesel production. AB - Biodiesel production from microalgae has been researched extensively and attempted to commercialize on a large scale, but there are major hurdles in the production process like harvesting and low lipid content, which should be studied to enhance the process and make it economical. Present study aimed to improve the lipid productivity of Chlorella minutissima and Chlorella pyrenoidosa by modifying the carbon and nitrogen content of the medium. Both organisms were grown in BG11 medium for the first 6 days and thereafter grown in a modified BG11 medium completely deprived of nitrogen for 2 to 10 days. Nitrogen deprivation increased the lipid productivity of Chlorella minutissima to 20% and that of Chlorella pyrenoidosa to 17.6% by day 6. This was further coupled with carbon addition in the form of citric acid (5 g/L), sodium acetate (5 g/L), sodium carbonate (5 g/L), and sodium potassium tartarate (5 g/L), which increased the total lipid productivity of Chlorella minutissima up to 24% and that of Chlorella pyrenoidosa up to 23%. The highest lipid productivity of up to 24% for Chlorella minutissima and up to 23% for Chlorella pyrenoidosa was observed with nitrogen deprivation coupled with sodium acetate. Acidic transesterification revealed the presence of fatty acid methyl esters, majority of which consisted of hexadecanoic acid methyl ester and octadecanoic acid methyl ester. Maximum of 3% fatty acid methyl esters for Chlorella minutissima and 4% for Chlorella pyrenoidosa were obtained under nitrogen deprivation and sodium acetate as a carbon source. Thus, nitrogen deprivation coupled with sodium acetate as an increased carbon source in BG11 medium helps to increase the lipid productivity of Chlorella minutissima and Chlorella pyrenoidosa, and produces long-chain fatty acid methyl esters of C17 and C19 along with C21, C25, and C29. PMID- 30519915 TI - Chronic mercury exposure and blood pressure in children and adolescents: a systematic review. AB - The aim of this paper is to systematically review the scientific literature on the possible relation of chronic mercury exposure and blood pressure among children and adolescents. We searched for observational studies in 6 electronic databases and grey literature for English, French or Spanish language studies published up to 30th November 2017. We performed a quality assessment of primary studies. We identified 8 articles involving 5 cohorts, 1 cross-sectional study and 1 case-control study. The participants had mean ages of between 3 and 17 years. Mercury was analysed in different matrices and periods of exposure. Four articles evaluated prenatal exposure, 2 evaluated both prenatal and postnatal exposures and 2 postnatal exposure. Blood pressure was measured according to different protocols. The association between mercury and blood pressure was adjusted by different covariates in each study. Four articles found a positive significant association between chronic mercury exposure and blood pressure in children or adolescents. Among these 4 articles, three of them evaluated prenatal exposure. There are still few studies assessing chronic mercury exposure and blood pressure in children and adolescents with inconsistency in results. Designs are very heterogeneous, which hampers their comparability. Evidence of this association is scarce and further research is needed. PMID- 30519916 TI - Spatial identification of environmental health hazards potentially associated with adverse birth outcomes. AB - Reduced birth weight (RBW) and reduced head circumference (RHC) are adverse birth outcomes (ABOs), often linked to environmental exposures. However, spatial identification of specific health hazards, associated with these ABOs, is not always straightforward due to presence of multiple health hazards and sources of air pollution in urban areas. In this study, we test a novel empirical approach to the spatial identification of environmental health hazards potentially associated with the observed RHC and RBW patterns. The proposed approach is implemented as a systematic search, according to which alternative candidate locations are ranked based on the strength of association with the observed birth outcome patterns. For empirical validation, we apply this approach to the Haifa Bay Area (HBA) in Israel, which is characterized by multiple health hazards and numerous sources of air pollution. We identified a spot in the local industrial zone as the main risk source associated with the observed RHC and RBW patterns. Multivariate regressions, controlling for personal, neighborhood, and geographic factors, revealed that the relative risks of RHC and RBW tend to decline, other things being equal, as a function of distance from the identified industrial spot. We recommend the proposed identification approach as a preliminary risk assessment tool for environmental health studies, in which detailed information on specific sources of air pollution and air pollution dispersion patterns is unavailable due to limited reporting or insufficient monitoring. PMID- 30519917 TI - A possible still role for colchicine in children with idiopathic recurrent acute pericarditis? PMID- 30519918 TI - Central PRES (posterior reversible encephalopathy syndrome) in HELLP syndrome. PMID- 30519919 TI - Correction to: Clinical impact of hospital malnutrition. AB - In the original publication, article was published with a wrong title as 'Risk, prevalence, and impact of hospital malnutrition in a Tertiary Care Referral University Hospital: a cross-sectional study' and also one of the references has been omitted in the reference list. The correct article title should be read as 'Clinical impact of hospital malnutrition'. PMID- 30519920 TI - Retroperitoneal dedifferentiated liposarcoma. PMID- 30519921 TI - Soft tissue reactions following cochlear implantation. AB - INTRODUCTION: Cochlear implantation is a boon to children with hearing loss. Rarely, it can be associated with complications. Soft tissue reaction can be a particularly distressing complication. MATERIALS AND METHODS: The study was conducted on all patients presenting with soft tissue reaction post-cochlear implant in a tertiary care referral institute from March 2011 to June 2018. We graded the severity of soft tissue reaction as per the severity and then managed these patients accordingly. RESULTS: Thirty-five patients were included in this study. Grade 1 had 12 patients, grade 2 had 9, grade 3 had 4 and grade 4 had 9 patients. Grade 1, 2 and 3 reactions were managed conservatively, while grade 4 required surgery. The incidence of explantations increased with the grade severity. CONCLUSION: Soft tissue reaction post-cochlear implant is a rare, but distressing complication. Grading and analyzing them can help us manage them in a better way. PMID- 30519922 TI - An original procedure for orbitonasal cutaneous infiltrative tumor repair, using combined forehead and melolabial propeller flaps. AB - INTRODUCTION: Resections of cutaneous tumors in the medial orbitonasal region can be transfixing. Repairs using a single local flap run the risk of failure and that of secondary sinonasal fistula, especially in cases of surgery on a radiated field. We propose an original and reliable repair procedure using two pedicled regional flaps vascularized by two distinct arterial systems clinched together to reconstruct the mucosal and cutaneous planes. MATERIALS AND METHODS: A first melolabial propeller flap (MPF) with a superior perforating pedicle was elevated and the cutaneous side was sutured to the deep plane of the loss of substance (mucosal lining). A second homolateral or contralateral paramedian forehead flap (PFF) was then lifted and sutured over the first flap (superficial plane). The forehead pedicle flap was divided at 1 month. RESULTS: No trophic complication or failure was recorded on two patients. The 7-year carcinologic, aesthetic, and functional results were satisfying. CONCLUSION: This technique involving the superimposition of two local flaps, vascularized by two different arterial systems, appears to offer a simple and reliable repair technique for transfixing cutaneous losses of substance in the medial orbitonasal region. It could be used in the first-line treatment, particularly if an additional radiotherapy is to be performed. PMID- 30519923 TI - Apocrine papillary lesion: comparison of pathological findings from 22 years previously and the present. AB - Apocrine papillary lesion (APL) is difficult to diagnose as benign or malignant. We experienced an APL remaining in the body for 22 years. We present a case of a 71-year-old woman who had undergone excisional biopsy 22 years previously at the first hospital that she visited. 1 year previously, she had undergone fine-needle aspiration cytology at a second hospital, and the lesion was diagnosed as potentially malignant. She underwent core-needle biopsy at a third hospital, but whether the lesion was benign or malignant could not be definitively diagnosed. We performed right mastectomy and sentinel lymph-node biopsy, because her tumor was suspected to be malignant based on imaging means, and malignancy could not be ruled out on either biopsy or cytology. The histopathological diagnosis was tiny foci of apocrine proliferative lesion with massive hemorrhagic necrosis and no tumor metastasis in two sentinel lymph nodes. Retrospectively, we compared all of the patient's previous specimens with the present ones, and applied the recent pathological diagnostic criteria. Although the biopsy specimen excised 22 years ago suggested an encapsulated apocrine papillary carcinoma or a papilloma with apocrine ductal carcinoma in situ, neither infiltration nor metastasis has occurred. Furthermore, neither the pathological findings nor the clinical behavior has changed over time. PMID- 30519924 TI - The Ocular Status of Cystinosis Patients Receiving a Hospital Pharmacy-Made Preparation of Cysteamine Eye Drops: A Case Series. AB - INTRODUCTION: Infantile nephropathic cystinosis (INC) is an autosomal recessive lysosomal disorder in which patients develop deposits of cystine crystals in their kidneys and corneas from a young age. METHODS: We conducted a retrospective analysis of children with INC seen by ophthalmologists at the Manchester Royal Eye Hospital between 2002 and 2018, to evaluate clinical findings, symptoms and treatment. RESULTS: Twenty-two children diagnosed with INC from age 0 (prenatally) to 11 years were assessed. All evaluable patients had corneal cystine crystal deposits, and 15 had mild to moderate photophobia. Ten patients had other ocular conditions including blepharitis/chalzion (n = 6), swollen optic nerve (n = 3), punctate epitheliopathy (n = 3), corneal scarring (n = 1),and elevated intraocular pressure (n = 2). Confocal imaging identified nerve abnormalities in two patients (enlarged corneal nerve + abnormal-looking tortuous nerves in one patient and beaded nerves in the sub-basal plexus in the other), both of whom had significant crystal deposition in the anterior stroma. Visual acuity was relatively unaffected. All 22 patients were receiving oral cysteamine, and 21 were applying cysteamine eye drops (galenic preparation of 0.55% concentration, compounded by a hospital pharmacy). Recommended application frequency was at least eight times per day in all patients with dosing information available. CONCLUSIONS: This case series of patients with INC highlights the consistent pattern of corneal cystine crystal deposition, which is universally present from a young age in this condition, and the high incidence of photophobia even in young children. Corneal manifestations of INC persisted despite frequent administration of the hospital pharmacy-made eye drop preparation. Reasons for this lack of efficacy may include the lag period between diagnosis and first prescription of cysteamine eye drops and the difficulty in maintaining rigorous compliance with this treatment. In addition, the challenge for patients of maintaining optimal storage conditions may adversely affect the stability and efficacy of cysteamine within this preparation. FUNDING: Editorial assistance was funded by Orphan Europe Ltd. PMID- 30519925 TI - Aspherical and Spherical InvA497-Functionalized Nanocarriers for Intracellular Delivery of Anti-Infective Agents. AB - PURPOSE: The objective of this work was to evaluate the potential of polymeric spherical and aspherical invasive nanocarriers, loaded with antibiotic, to access and treat intracellular bacterial infections. METHODS: Aspherical nanocarriers were prepared by stretching of spherical precursors, and both aspherical and spherical nanocarriers were surface-functionalized with the invasive protein InvA497. The relative uptake of nanocarriers into HEp-2 epithelial cells was then assessed. Nanocarriers were subsequently loaded with a preparation of the non permeable antibiotic gentamicin, and tested for their ability to treat HEp-2 cells infected with the enteroinvasive bacterium Shigella flexneri. RESULTS: InvA497-functionalized nanocarriers of both spherical and aspherical shape showed a significantly improved rate and extent of uptake into HEp-2 cells in comparison to non-functionalized nanocarriers. Functionalized and antibiotic-loaded nanocarriers demonstrated a dose dependent killing of intracellular S. flexneri. A slight but significant enhancement of intracellular bacterial killing was also observed with aspherical as compared to spherical functionalized nanocarriers at the highest tested concentration. CONCLUSIONS: InvA497-functionalized, polymer based nanocarriers were able to efficiently deliver a non-permeable antibiotic across host cell membranes to affect killing of intracellular bacteria. Functionalized nanocarriers with an aspherical shape showed an interesting future potential for intracellular infection therapy. PMID- 30519926 TI - Schisandrin B Improves the Renal Function of IgA Nephropathy Rats Through Inhibition of the NF-kappaB Signalling Pathway. AB - Schisandrin B (SchB) is an active compound extracted from the Chinese herb Schisandra chinensis and shows excellent anti-inflammatory activity. This study was performed to examine the effects of SchB in a rat model of IgA nephropathy (IgAN). IgAN was established in Sprague-Dawley rats by immunization with lipopolysaccharide (LPS), bovine serum albumin, and carbon tetrachloride. Renal function was evaluated by determining the levels of urinary red blood cells, proteinuria, blood urea nitrogen (BUN), and creatinine (Cr). Renal tissue and protein samples were collected for further analysis. Pre-treatment and treatment with SchB significantly ameliorated renal function of IgAN rats, which was evidenced by decreased levels of proteinuria, hematuria, BUN, and Cr. IgAN rats exhibited increased serum IgA, renal IgA deposition, mesangial cell proliferation, and inflammatory cell infiltration, which were significantly attenuated by intervention with SchB. Moreover, SchB inhibited infiltration of CD3+ and CD11b+ cells, decreased levels of tumour necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1 in the kidney, and decreased the numbers of CD3+CD69+ cells in the spleen. Of note, SchB therapy significantly increased cytoplasmic p65 and IkappaB expression and decreased nuclear p65 levels both in the damaged renal tissue and LPS-stimulated HK-2 cells, indicating a direct inhibitory effect on the NF-kappaB pathway in IgAN rats. Taken together, our data provide insight into a new application of SchB for the treatment of IgAN and represent a novel mechanism behind these effects. PMID- 30519927 TI - Bioassay Method for Toxicity Studies of Toxic Bait Formulations to Ceratitis capitata (Diptera: Tephritidae). AB - The development of appropriate methodologies for bioassays is of paramount importance to study the methodological factors that may interfere in the experimental design. Thus, laboratory bioassays have become increasingly important for the determination of data that are realistic and replicable. The objective of the study was to develop a bioassay methodology with the ready-to use toxic bait SuccessTM 0.02CB, 96 mg L-1 of spinosad, in adults of Ceratitis capitata (Wiedemann) as a study model. The insect origin (laboratory population, LT50 = 11.16 h), time of toxic bait supply (4 h, LT50 = 16.85 h), food deprivation (12 h, LT50 = 15.55 h), and the adult age (5 days, LT50 = 35.31 h) of C. capitata showed higher susceptibility and a shorter LT50 lethal time to the SuccessTM 0.02CB toxic bait. However, the absence or presence of a food source (LT50 ~ 31.17 h) during the bioassay did not affect the susceptibility of C. capitata. Further, adults of C. capitata who were deprived and in the absence of a food source (artificial diet) had higher consumption of toxic baits (mg) during treatment exposure. The use of a 12-h deprivation period, toxic baits offered for 4 h, and absence of an artificial diet for adults of C. capitata at 5 days of age during the bioassay are considered adequate for evaluating formulations of toxic baits under laboratory conditions. PMID- 30519928 TI - Passalidae (Coleoptera: Scarabaeoidea) from the West-Most Brazilian Amazon Region: Checklist, New Records, and Identification Key. AB - We present a list of Passalidae species found in the westmost Brazilian Amazon region, which is considered to be a diversity-rich area due to being a tectonic and geographic transition zone in relation to Brazilian Amazon lowlands and the Andean range. The specimens acquired in field collections and museums were analyzed. Their geographical distributions were estimated based on data from labeled specimens and the literature. Twenty-nine species belonging to two subfamilies, six genera, and four subgenera were listed. Among them, 20, 1, and 2 showed to be new records for the region, Brazilian Amazon, and Brazil, respectively. An identification key is provided for the species being listed. PMID- 30519929 TI - Magnetic resonance imaging of the time course of hyperpolarized 129Xe gas exchange in the human lungs and heart. AB - PURPOSE: To perform magnetic resonance imaging (MRI), human lung imaging, and quantification of the gas-transfer dynamics of hyperpolarized xenon-129 (HPX) from the alveoli into the blood plasma. MATERIALS AND METHODS: HPX MRI with iterative decomposition of water and fat with echo asymmetry and least-square estimation (IDEAL) approach were used with multi-interleaved spiral k-space sampling to obtain HPX gas and dissolved phase images. IDEAL time-series images were then obtained from ten subjects including six normal subjects and four patients with pulmonary emphysema to test the feasibility of the proposed technique for capturing xenon-129 gas-transfer dynamics (XGTD). The dynamics of xenon gas diffusion over the entire lung was also investigated by measuring the signal intensity variations between three regions of interest, including the left and right lungs and the heart using Welch's t test. RESULTS: The technique enabled the acquisition of HPX gas and dissolved phase compartment images in a single breath-hold interval of 8 s. The y-intersect of the XGTD curves were also found to be statistically lower in the patients with lung emphysema than in the healthy group (p < 0.05). CONCLUSION: This time-series IDEAL technique enables the visualization and quantification of inhaled xenon from the alveoli to the left ventricle with a clinical gradient strength magnet during a single breath hold, in healthy and diseased lungs. KEY POINTS: * The proposed hyperpolarized xenon-129 gas and dissolved magnetic resonance imaging technique can provide regional and temporal measurements of xenon-129 gas-transfer dynamics. * Quantitative measurement of xenon-129 gas-transfer dynamics from the alveolar to the heart was demonstrated in normal subjects and pulmonary emphysema. * Comparison of gas-transfer dynamics in normal subjects and pulmonary emphysema showed that the proposed technique appears sensitive to changes affecting the alveoli, pulmonary interstitium, and capillaries. PMID- 30519930 TI - CT imaging comparison between intraductal papillary neoplasms of the bile duct and papillary cholangiocarcinomas. AB - OBJECTIVES: To identify imaging features that assist in discriminating intraductal papillary neoplasms of the bile duct (IPNBs) from papillary cholangiocarcinomas (PCCs). METHODS: This study was approved by the institutional review board. Using the recently proposed histological diagnostic criteria for biliary papillary neoplasms, IPNBs and PCCs were selected from 537 biliary neoplasms consecutively resected in a 12.5-year period. Clinical and imaging features were compared between the two groups. RESULTS: The histology review identified 19 IPNBs and 48 PCCs, representing an estimated prevalence of IPNBs among biliary neoplasms of 4%. Approximately one half of IPNBs were incidentally found on imaging conducted for other purposes. In terms of tumor location, 15/19 IPNBs (79%) developed in intrahepatic bile ducts, and 41/48 PCCs (85%) in the distal bile duct. Cystic appearance was highly suggestive for IPNBs (p < 0.001). Using these two parameters, 78% of papillary bile duct neoplasms could be classified into IPNBs or PCCs. Other imaging findings favoring IPNBs included frond-like mural nodule, downstream bile duct dilatation, and the lack of abnormal enhancement in the adjacent bile duct. Interestingly, two patients with non-invasive or microinvasive IPNB had undergone abdominal imaging studies > 3 years before, and a retrospective review of the previous images identified small nodular or cystic lesions, suggesting a less progressive nature of IPNBs than currently thought. CONCLUSIONS: Imaging findings useful for discriminating IPNBs from PCCs appear to be tumor location, shape of tumor, appearance of mural nodules, duct dilatation at unaffected duct, and abnormal enhancement of the adjacent bile duct. KEY POINTS: * Intrahepatic location and cystic dilatation of the affected bile duct are the strong discriminators between IPNBs and PCCs. * The shape of the mural nodule and appearance of the neighboring bile duct are helpful for distinguishing IPNBs and PCCs. * The less aggressive behavior of IPNBs compared with PCCs may facilitate less invasive management in patients with IPNB. PMID- 30519931 TI - Prognostic value of computed tomography radiomics features in patients with gastric cancer following curative resection. AB - OBJECTIVES: The present study aimed to investigate the clinical prognostic significance of radiomics signature (R-signature) in patients with gastric cancer who had undergone radical resection. METHODS: A total of 181 patients with gastric cancer who had undergone radical resection were enrolled in this retrospective study. The association between the R-signature and overall survival (OS) was assessed in the primary cohort and verified in the validation cohort. Furthermore, the performance of a radiomics nomogram integrating the R-signature and significant clinicopathological risk factors was evaluated. RESULTS: The R signature, which consisted of six imaging features, stratified patients with gastric cancer who had undergone radical resection into two prognostic risk groups in both cohorts. The radiomics nomogram incorporating R-signature and significant clinicopathological risk factors (T stage, N stage, and differentiation) exhibited significant prognostic superiority over clinical nomogram and R-signature alone (Harrell concordance index, 0.82 vs 0.71 and 0.82 vs 0.74, respectively, p < 0.001 in both analyses). All calibration curves showed remarkable consistency between predicted and actual survival, and decision curve analysis verified the usefulness of the radiomics nomogram for clinical practice. CONCLUSIONS: The R-signature could be used to stratify patients with gastric cancer following radical resection into high- and low-risk groups. Furthermore, the radiomics nomogram provided better predictive accuracy than other predictive models and might aid clinicians with therapeutic decision-making and patient counseling. KEY POINTS: * Radiomics can stratify the gastric cancer patients following radical resection into high- and low-risk groups. * Radiomics can improve the prognostic value of TNM staging system. * Radiomics may facilitate personalized treatment of gastric cancer patients. PMID- 30519932 TI - Technical challenges of quantitative chest MRI data analysis in a large cohort pediatric study. AB - OBJECTIVES: This study was conducted in order to evaluate the effect of geometric distortion (GD) on MRI lung volume quantification and evaluate available manual, semi-automated, and fully automated methods for lung segmentation. METHODS: A phantom was scanned with MRI and CT. GD was quantified as the difference in phantom's volume between MRI and CT, with CT as gold standard. Dice scores were used to measure overlap in shapes. Furthermore, 11 subjects from a prospective population-based cohort study each underwent four chest MRI acquisitions. The resulting 44 MRI scans with 2D and 3D Gradwarp were used to test five segmentation methods. Intraclass correlation coefficient, Bland-Altman plots, Wilcoxon, Mann-Whitney U, and paired t tests were used for statistics. RESULTS: Using phantoms, volume differences between CT and MRI varied according to MRI positions and 2D and 3D Gradwarp correction. With the phantom located at the isocenter, MRI overestimated the volume relative to CT by 5.56 +/- 1.16 to 6.99 +/- 0.22% with body and torso coils, respectively. Higher Dice scores and smaller intraobject differences were found for 3D Gradwarp MR images. In subjects, semi automated and fully automated segmentation tools showed high agreement with manual segmentations (ICC = 0.971-0.993 for end-inspiratory scans; ICC = 0.992 0.995 for end-expiratory scans). Manual segmentation time per scan was approximately 3-4 h and 2-3 min for fully automated methods. CONCLUSIONS: Volume overestimation of MRI due to GD can be quantified. Semi-automated and fully automated segmentation methods allow accurate, reproducible, and fast lung volume quantification. Chest MRI can be a valid radiation-free imaging modality for lung segmentation and volume quantification in large cohort studies. KEY POINTS: * Geometric distortion varies according to MRI setting and patient positioning. * Automated segmentation methods allow fast and accurate lung volume quantification. * MRI is a valid radiation-free alternative to CT for quantitative data analysis. PMID- 30519933 TI - Multiparametric whole-body 3.0-T MRI in newly diagnosed intermediate- and high risk prostate cancer: diagnostic accuracy and interobserver agreement for nodal and metastatic staging. AB - OBJECTIVES: To determine the diagnostic accuracy and interobserver concordance of whole-body (WB)-MRI, vs. 99mTc bone scintigraphy (BS) and 18fluoro-ethyl-choline (18F-choline) PET/CT for the primary staging of intermediate/high-risk prostate cancer. METHODS: An institutional review board approved prospective cohort study carried out between July 2012 and November 2015, whereby 56 men prospectively underwent 3.0-T multiparametric (mp)-WB-MRI in addition to BS (all patients) +/- 18F-choline PET/CT (33 patients). MRI comprised pre- and post-contrast modified Dixon (mDixon), T2-weighted (T2W) imaging, and diffusion-weighted imaging (DWI). Patients underwent follow-up mp-WB-MRI at 1 year to derive the reference standard. WB-MRIs were reviewed by two radiologists applying a 6-point scale and a locked sequential read (LSR) paradigm for the suspicion of nodal (N) and metastatic disease (M1a and M1b). RESULTS: The mean sensitivity/specificity of WB MRI for N1 disease was 1.00/0.96 respectively, compared with 1.00/0.82 for 18F choline PET/CT. The mean sensitivity and specificity of WB-MRI, 18F-choline PET/CT, and BS were 0.90/0.88, 0.80/0.92, and 0.60/1.00 for M1b disease. ROC-AUC did not show statistically significant improvement for each component of the LSR; mean ROC-AUC 0.92, 0.94, and 0.93 (p < 0.05) for mDixon + DWI, + T2WI, and + contrast respectively. WB-MRI had an interobserver concordance (kappa) of 0.79, 0.68, and 0.58 for N1, M1a, and M1b diseases respectively. CONCLUSIONS: WB-MRI provides high levels of diagnostic accuracy for both nodal and metastatic bone disease, with higher levels of sensitivity than BS for metastatic disease, and similar performance to 18F-choline PET/CT. T2 and post-contrast mDixon had no significant additive value above a protocol comprising mDixon and DWI alone. KEY POINTS: * A whole-body MRI protocol comprising unenhanced mDixon and diffusion weighted imaging provides high levels of diagnostic accuracy for the primary staging of intermediate- and high-risk prostate cancer. * The diagnostic accuracy of whole-body MRI is much higher than that of bone scintigraphy, as currently recommended for clinical use. * Staging using WB-MRI, rather than bone scintigraphy, could result in better patient stratification and treatment delivery than is currently provided to patients worldwide. PMID- 30519934 TI - Vertebral body insufficiency fractures: detection of vertebrae at risk on standard CT images using texture analysis and machine learning. AB - PURPOSE: To evaluate the diagnostic performance of bone texture analysis (TA) combined with machine learning (ML) algorithms in standard CT scans to identify patients with vertebrae at risk for insufficiency fractures. MATERIALS AND METHODS: Standard CT scans of 58 patients with insufficiency fractures of the spine, performed between 2006 and 2013, were analyzed retrospectively. Every included patient had at least two CT scans. Intact vertebrae in a first scan that either fractured ("unstable") or remained intact ("stable") in the consecutive scan were manually segmented on mid-sagittal reformations. TA features for all vertebrae were extracted using open-source software (MaZda). In a paired control study, all vertebrae of the study cohort "cases" and matched controls were classified using ROC analysis of Hounsfield unit (HU) measurements and supervised ML techniques. In a within-subject vertebra comparison, vertebrae of the cases were classified into "unstable" and "stable" using identical techniques. RESULTS: One hundred twenty vertebrae were included. Classification of cases/controls using ROC analysis of HU measurements showed an AUC of 0.83 (95% confidence interval [CI], 0.77-0.88), and ML-based classification showed an AUC of 0.97 (CI, 0.97-0.98). Classification of unstable/stable vertebrae using ROC analysis showed an AUC of 0.52 (CI, 0.42-0.63), and ML-based classification showed an AUC of 0.64 (CI, 0.61-0.67). CONCLUSION: TA combined with ML allows to identifying patients who will suffer from vertebral insufficiency fractures in standard CT scans with high accuracy. However, identification of single vertebra at risk remains challenging. KEY POINTS: * Bone texture analysis combined with machine learning allows to identify patients at risk for vertebral body insufficiency fractures on standard CT scans with high accuracy. * Compared to mere Hounsfield unit measurements on CT scans, application of bone texture analysis combined with machine learning improve fracture risk prediction. * This analysis has the potential to identify vertebrae at risk for insufficiency fracture and may thus increase diagnostic value of standard CT scans. PMID- 30519935 TI - Incidence and endovascular treatment of severe spontaneous non-cerebral bleeding: a single-institution experience. AB - OBJECTIVES: To investigate the incidence and endovascular treatment of severe spontaneous non-cerebral hemorrhage (SSNCH) in a high-volume, tertiary university hospital. METHODS: All patients diagnosed with SSNCH between January 2016 and June 2017 were retrospectively analyzed. Endovascular treatment (group EVT) was offered only in patients demonstrating active bleeding at CT angiography (CTA). In cases without active bleeding at CTA, conservative management was decided (group CM). Outcome measures included the incidence of SSNCH, 6-month rebleeding, and survival rates in the two groups as well as EVT technical success and related complications. RESULTS: Within the 18-month period, 44 SSNCH cases were identified, resulting in an annual incidence of 29.3 cases. In 37/44 cases (84.1%), bleeding was attributed to the antithrombotic therapy. In total, 19/44 patients underwent EVT (43.2%), and 25/44 patients (56.8%) were managed conservatively. Two patients who were initially treated conservatively finally underwent EVT due to rebleeding (7.4%). The technical success of EVT was 100%, while rebleeding occurred in 1 case (5.2%) following lumbar artery embolization and was successfully re-embolized. According to the Kaplan-Meier analysis, the 1 , 3-, and 6-month survival rates were 68.4%, 63.2%, and 42.1% for group EVT and 87.5%, 75.0%, and 58.3% for group CM, respectively. There were no EVT-related complications. CONCLUSIONS: The annual incidence of SSNCH in our institution is substantial. EVT resulted in uncomplicated, high bleeding control rates. The mortality rate was similarly high following either EVT or conservative treatment and was mainly attributed to severe comorbidities. KEY POINTS: * This study demonstrates that the incidence of severe spontaneous non-cerebral hemorrhage (SSNCH) in our institution is substantial. * Endovascular treatment was offered only in patients with clinical signs of ongoing hemorrhage and active bleeding at CT angiography and resulted in effective and uncomplicated, minimal invasive hemostasis, in a population with severe comorbidities. * This is the first study to evaluate the outcomes of both endovascular hemostasis and conservative management. Rebleeding following either conservative or endovascular treatment was minimal. PMID- 30519936 TI - Better understanding of acute gouty attack using CT perfusion in a rabbit model. AB - OBJECTIVE: To assess hemodynamic changes related to acute gouty knee arthritis in a rabbit with CT perfusion (CTP) METHODS: Forty-two rabbits were randomly separated into two groups: the treated group of 30 and the control group of 12. The right knee was injected with monosodium urate solution and polymyxin in the treated group and saline and polymyxin in the control group. At 2, 16, 32, 48, 60, and 72 h after injection, five rabbits from the treated group and two rabbits from the control group were selected for CTP. At each time point, blood flow (BF), blood volume (BV), and clearance rate (CL) were measured, and microvessel density (MVD) was evaluated with a microscope. RESULTS: In the treated group, BF, BV, CL, and MVD were significantly higher than in the control group (p < 0.001). Differences within paired comparison of BV, BF, CL, and MVD were all significant (all p < 0.001). Peak time of BV, BF, and MVD was 32 h and 48 h for CL. After multivariate stepwise linear regression analysis, BV was linearly associated with MVD and vice versa, which also applied to BF with MVD and BF with CL, separately. The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL. CONCLUSION: CTP in this rabbit knee model accurately detected hemodynamic changes during a gouty attack. KEY POINTS: * Acute gouty arthritis can be evaluated with CTP in a rabbit knee model. * Following injection of MSU crystals, producing an acute gouty attack, CTP successfully assessed hemodynamic changes. * The ascending rate of MVD was the highest among that of all parameters; so was the descending rate of CL. PMID- 30519937 TI - pH-responsive calcium alginate hydrogel laden with protamine nanoparticles and hyaluronan oligosaccharide promotes diabetic wound healing by enhancing angiogenesis and antibacterial activity. AB - Diabetic wounds as chronic wounds represent a severe, persistent complication of diabetes and, in the most extreme cases, can lead to amputation. Two critical and unfavorable factors affecting diabetic wound healing are sustained bacterial induced chronic inflammation and disrupted vascularization. In this paper, we presented a novel, pH-responsive calcium alginate hydrogel laden with protamine nanoparticles and hyaluronan oligosaccharides, and explored its potential for accelerating diabetic wound healing. A thorough investigation indicated that the drug- and nanoparticle-loaded hydrogel demonstrated strong bactericidal behavior mediated by protamine nanoparticles and reduced bacterial-induced chronic inflammation at the wound site. Furthermore, it accelerated the wound-healing process by promoting angiogenesis in skin wounds with the hyaluronan oligosaccharide-mediated enhanced expression of vascular endothelial growth factor. PMID- 30519938 TI - PREDECT Protocols for Complex 2D/3D Cultures. AB - PREDECT, a European IMI consortium, has assumed the task to generate robust 2D and 3D culture platforms. Protocols established for 2D and 3D monoculture and stromal coculture models of increasing complexity (spheroid, stirred-tank bioreactor, Matrigel- and collagen-embedded cultures) have been established between six laboratories within academia, biotech, and pharma. These models were tested using three tumor cell lines (MCF7, LNCaP, and NCI-H1437), covering three pathologies (breast, prostate, and lung), but should be readily transferable to other model systems. Fluorescent protein tagged cell lines were used for all platforms, allowing for online measurement of growth curves and drug responses to treatments. All methods, from culture setup to phenotypic characterization and gene expression profiling are described in this chapter.The adaptable methodologies and detailed protocols described here should help to include these models more readily to the drug discovery pipeline. PMID- 30519939 TI - Phenotypic Screening Using Mouse and Human Stem Cell-Based Models of Neuroinflammation and Gene Expression Analysis to Study Drug Responses. AB - High-throughput phenotypic screening enables the identification of new therapeutic targets even when the molecular mechanism underlying the disease is unknown. In the case of neurodegenerative disease, there is a dire need to identify new targets that can ameliorate, halt, or reverse degeneration. Stem cell-based disease models are particularly powerful tools for phenotypic screening because they use the same cell type affected in patients. Here, we describe the expansion of mouse stem cells and human induced pluripotent stem cells as well as the differentiation of these cells into neural lineages that, when exposed to neuroinflammatory stress, can be used for compound screening followed by hit identification, validation, and target deconvolution. PMID- 30519940 TI - Quantitative, Real-Time Measurements of Intracellular Target Engagement Using Energy Transfer. AB - Intracellular target affinity and residence time are fundamental aspects of pharmacological mechanism (Lu and Tonge, Curr Opin Chem Biol 14:467-474, 2010). Although various robust biochemical approaches exist to measure these binding characteristics, analysis of compound binding with isolated targets may not accurately reflect engagement in the milieu of living cells. To realize the influence of cellular context, methods are needed that are capable of quantifying affinity and residence time in the presence of the intracellular factors that may impact target engagement. Bioluminescence resonance energy transfer (BRET) offers a solution for intracellular target engagement when quantitative metrics or kinetic analyses are required. PMID- 30519941 TI - Target Engagement of Small Molecules: Thermal Profiling Approaches on Different Levels. AB - The identification of protein targets and the elucidation of the molecular mechanism of action (MMoA) of bioactive small molecules are central goals of chemical biology. Many different techniques for target identification and engagement are developed, but none of them is generic. Here we describe one of these techniques-the cellular thermal shift assay (CETSA). The assay works without any labeling of proteins or small molecules, which allows the investigation of the unaltered interaction between the interaction partners. Briefly, the influence of small molecules on the thermal stability of proteins within whole cell lysates is investigated. We describe this approach in two variants: the conventional immunoblot-based approach (CETSA), as well as an unbiased approach based on a proteome-wide mass spectrometric analysis (thermal proteome profiling, TPP). The CETSA approach requires preknowledge about possible target proteins and can only detect a few proteins at once. Although TPP is technically more demanding, it allows for the identification of multiple (off)targets without any preknowledge. PMID- 30519942 TI - Visualizing Bioactive Small Molecules by Alkyne Tagging and Slit-Scanning Raman Microscopy. AB - An understanding of the intracellular distribution of bioactive small molecules provides insight into their target organelles and biomolecules, and throws light on their molecular mechanisms of action and specificity. Many studies in this area have employed fluorescence imaging, using molecules of interest labeled with fluorescent dyes. However, modification with a bulky fluorophore may significantly alter the properties, including bioactivity, of small molecules. To address this issue, we have recently developed Raman scattering microscopy of alkyne tags to visualize small molecules in biological systems. The tiny alkyne tag should have a minimal effect on the properties of the tagged molecule, and the unique alkyne vibrational properties allow observation of the Raman signals of the tagged molecules in a wavelength region where there is little interference from Raman signals of endogenous biomolecules. Here we summarize the methodology for Raman imaging of alkyne-tagged bioactive small molecules in living biological systems including the development of slit-scanning Raman microscope, which is useful for fast imaging of alkyne-tagged molecules. PMID- 30519943 TI - The Cell Painting Assay as a Screening Tool for the Discovery of Bioactivities in New Chemical Matter. AB - Multiparametric phenotypic screening based on cellular morphology interrogates many biological pathways simultaneously and is therefore a valuable screening tool for the discovery of new biological activities. The cell painting assay stains various cellular features using six different dyes in one well. By automated image analysis, hundreds of parameters are calculated from the images which deliver a phenotypic profile of the cell. It has been shown that compounds with similar modes of action deliver similar phenotypic profiles. Using a reference set of compounds with known modes of action, it is possible to assign probable modes of action to new compounds and to discover compounds with potentially new modes of action.Here we describe the cell painting assay as a screening tool using a hit identification workflow which has been implemented using open-source software. PMID- 30519944 TI - Proteomic Profiling for Target Identification of Biologically Active Small Molecules Using 2D DIGE. AB - Recent improvements in technologies such as omics analysis have enabled us to acquire a large amount of data regarding the biological changes in cells treated with bioactive small molecules. Using such data, a variety of profiling methods have been established for target identification of such bioactive compounds. In this chapter, we describe a proteomic profiling system, ChemProteoBase, based on proteome analysis using two-dimensional difference gel electrophoresis. This system compares the similarities in protein expression of 296 spots detected in the gel among the test compounds. PMID- 30519945 TI - Examining Cellular Responses to Kinase Drug Inhibition Through Phosphoproteome Mapping of Substrates. AB - This chapter provides a detailed description for mass spectrometry-based phosphoproteomics analysis. We describe sample preparation, phosphopeptide enrichment, mass spectrometry acquisition, label-free data analysis and statistical analysis. This technique can be employed to characterize cell signaling networks, and is particularly useful to monitor cellular responses to kinase drug inhibitors. PMID- 30519946 TI - CRISPR/Cas9-Based Chemogenomic Profiling in Mammalian Cells. AB - Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. It is based on identifying cellular hypersensitivity and resistance caused by individual gene modulations with genome-wide coverage. Due to the requirement of bar-coded, genome-wide deletion collections, high-resolution experiments of this nature have historically been limited to fungal systems. Pooled RNAi reagents have enabled similar attempts in mammalian cells but efforts have been hampered by significant off-target effects and experimental noise. The CRISPR/Cas9 system for the first time enables precise DNA editing at defined loci in a genome-wide fashion. Here we present the detailed protocol that leverages the CRISPR/Cas9 system for chemogenomic profiling and target identification of diverse chemical probes. PMID- 30519947 TI - Exome Sequencing of Drug-Resistant Clones for Target Identification. AB - Many small molecule compounds with anticancer activities are discovered through phenotype-based screens. However, discovering the targets of these small molecules has been challenging. The gold standard for target identification requires the discovery of mutations in the target protein that block the effects of small molecules in vitro as well as in vivo. Here we describe the procedures for isolating drug resistant clones using the colorectal cancer cell line HCT-116 followed by whole-exome sequencing to identify recurrent mutations associated with compound resistance. Together with downstream in vitro and in vivo validation experiments, this strategy enables rapid target discovery for cytotoxic compounds. PMID- 30519948 TI - The Use of Large-Scale Chemically-Induced Transcriptome Data Acquired from LINCS to Study Small Molecules. AB - Identification of the modes of action of bioactive compounds is an important issue in chemical systems biology. In this chapter we review a recently developed data-driven approach using large-scale chemically induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures to elucidate the modes of action of bioactive compounds. First, we present a method for pathway enrichment analyses of regulated genes to reveal biological pathways activated by compounds. Next, we present a method using the pre-knowledge on chemical-protein interactome for predicting potential target proteins, including primary targets and off-targets, with transcriptional similarity. Finally, we present a method based on the target proteins for predicting new therapeutic indications for a variety of diseases. These approaches are expected to be useful for mode-of-action analysis, drug discovery, and drug repositioning. PMID- 30519949 TI - Integrated Analysis of Drug Sensitivity and Selectivity to Predict Synergistic Drug Combinations and Target Coaddictions in Cancer. AB - High-throughput drug sensitivity testing provides a powerful phenotypic profiling approach to identify effective drug candidates for individual cell lines or patient-derived samples. Here, we describe an experimental-computational pipeline, named target addiction scoring (TAS), which mathematically transforms the drug response profiles into target addiction signatures, and thereby provides a ranking of potential therapeutic targets according to their functional importance in a particular cancer sample. The TAS pipeline makes use of drug polypharmacology to integrate the drug sensitivity and selectivity profiles through systems-wide interconnection networks between drugs and their targets, including both primary protein targets as well as secondary off-targets. We show how the TAS pipeline enables one to identify not only single-target addictions but also combinatorial coaddictions among targets that often underlie synergistic drug combinations. PMID- 30519950 TI - Predicting Drug Interactions From Chemogenomics Using INDIGO. AB - Designing effective antibiotic combination regimens is critical for countering drug resistance in pathogens. Yet the large combinatorial search-space makes the identification of effective combinations a significant challenge. There is a great need for computational approaches that can rapidly prioritize potential combination regimens based on the antagonistic and synergistic interactions among the constituent antibiotics. This protocol outlines the steps to predict antibiotic interactions from chemogenomics data using the INDIGO algorithm. INDIGO predicted novel drug-drug interaction outcomes quantitatively with high accuracy based on experimental evaluation of predictions in E. coli and S. aureus, and it overcomes several limitations of existing drug-interaction prediction algorithms. The INDIGO approach also expands the applicability of chemogenomic data from model organisms to a broader set of less-studied pathogens. INDIGO can predict drug-interaction outcomes in the bacterial pathogens S. aureus and M. tuberculosis, using chemogenomics data from E. coli by quantifying the degree of conservation of the drug-gene interaction network between different species. The INDIGO approach, which is demonstrated for E. coli and S. aureus in this protocol, can be applied easily to other organisms including pathogens. PMID- 30519951 TI - Computational Analyses Connect Small-Molecule Sensitivity to Cellular Features Using Large Panels of Cancer Cell Lines. AB - We recently pioneered several analyses of small-molecule sensitivity data collected from large-scale perturbation of hundreds of cancer cell lines with hundreds of small molecules, with cell viability measured as a readout of compound sensitivity. We performed these studies using cancer cell lines previously annotated with cellular, genomic, and basal gene-expression features. By combining small-molecule sensitivity data with these other datasets, we identified new candidate biomarkers of sensitivity, gained insights into small molecule mechanisms of action, and proposed candidate hypotheses for cancer dependencies (including candidate combination therapies). Nevertheless, given the size of these datasets, we expect that many connections between cellular features and small-molecule sensitivity remain underexplored. In this chapter, we provide a step-by-step account of foundational data-analysis methods underlying our published studies, including working MATLAB code applied to our own public datasets. These procedures will allow others to repeat analyses of our data with new parameters, in additional contexts, and to adapt our procedures to their own datasets. PMID- 30519952 TI - Web-Based Tools for Polypharmacology Prediction. AB - Drug promiscuity or polypharmacology is the ability of small molecules to interact with multiple protein targets simultaneously. In drug discovery, understanding the polypharmacology of potential drug molecules is crucial to improve their efficacy and safety, and to discover the new therapeutic potentials of existing drugs. Over the past decade, several computational methods have been developed to study the polypharmacology of small molecules, many of which are available as Web services. In this chapter, we review some of these Web tools focusing on ligand based approaches. We highlight in particular our recently developed polypharmacology browser (PPB) and its application for finding the side targets of a new inhibitor of the TRPV6 calcium channel. PMID- 30519953 TI - In Silico Target Prediction for Small Molecules. AB - Drugs modulate disease states through their actions on targets in the body. Determining these targets aids the focused development of new treatments, and helps to better characterize those already employed. One means of accomplishing this is through the deployment of in silico methodologies, harnessing computational analytical and predictive power to produce educated hypotheses for experimental verification. Here, we provide an overview of the current state of the art, describe some of the well-established methods in detail, and reflect on how they, and emerging technologies promoting the incorporation of complex and heterogeneous data-sets, can be employed to improve our understanding of (poly)pharmacology. PMID- 30519954 TI - BDNF rs6265 (Val66Met) Polymorphism as a Risk Factor for Blepharospasm. AB - A few genetic variants are implicated in the development of blepharospasm (BSP). The precise role of the rs6265 on the brain-derived neurotrophic factor (BDNF) gene on BSP remains controversial. The effect of rs6265 on BSP was evaluated. 206 patients with BSP and 206 healthy controls were recruited and genotyped for the rs6265. We also performed a meta-analysis, by pooling our results with those from previous studies. A significant effect of rs6265 on the risk of BSP was found in the dominant model of inheritance [odds ratio (OR) (95% confidence interval (CI) 1.52 (1.01-2.29), p = 0.044]. Mutational load analysis of rs6265 in the risk of BSP using the ORG revealed that higher load of the "A" allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.48; 95% CI 1.00-2.19). Finally, pooled results from the meta-analysis revealed that the rs6265 is associated with an increased risk of BSP in the dominant model [OR 1.26; 95% CI 1.02-1.55, pz = 0.03]. Also, higher load of the "A" allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.26; 95% CI 1.04-1.53). The present study provides additional evidence to the existing knowledge concerning the contribution of the rs6265 BDNF on the risk of developing BSP. While the pathophysiology and genetic susceptibility in BSP and focal dystonia are only partially understood, it seems that BDNF and rs6265 may constitute one essential risk factor that is heavily involved. PMID- 30519955 TI - Efficacy of external cold and a vibrating device in reducing discomfort of dental injections in children: A split mouth randomised crossover study. AB - AIM: To study the discomfort and fear associated with maxillary infiltration injections when using a combination of external cold and a commercially available vibrating device. METHODOLOGY: A total of 60 children aged 7 years old participated in this split mouth randomised crossover study. The control intervention comprised of the administration of 1.8 ml of 2% lidocaine with 1:100,000 adrenaline using a 24 mm 30 gauge needle, while the test intervention used external cold and a commercially available vibrating device in addition to the control protocol. The heart rate of the child at the time of injection was used as an objective measure and the Wong-Baker pain scale was used as a subjective measure of the child's discomfort. The face, limbs, arms, cry and consolability (FLACC) scale was used to record the child's pain as perceived by the dentist. RESULTS: Children reported a significantly lower Wong-Baker score and the operators observed a significantly lower heart rate and FLACC scores in the test visit than the control visit. CONCLUSIONS: Combining external cold with vibrating devices might be effective in reducing discomfort and fear in children undergoing infiltration dental analgesia. CLINICAL TRIALS IDENTIFIER: NCT02675387. PMID- 30519956 TI - Coupling of urban energy balance model with 3-D radiation model to derive human thermal (dis)comfort. AB - While capabilities in urban climate modeling have substantially increased in recent decades, the interdependency of changes in environmental surface properties and human (dis)comfort have only recently received attention. The open source solar long-wave environmental irradiance geometry (SOLWEIG) model is one of the state-of-the-art models frequently used for urban (micro-)climatic studies. Here, we present updated calculation schemes for SOLWEIG allowing the improved prediction of surface temperatures (wall and ground). We illustrate that parameterizations based on measurements of global radiation on a south-facing vertical plane obtain better results compared to those based on solar elevation. Due to the limited number of ground surface temperature parameterizations in SOLWEIG, we implement the two-layer force-restore method for calculating ground temperature for various soil conditions. To characterize changes in urban canyon air temperature (Tcan), we couple the calculation method as used in the Town Energy Balance (TEB) model. Comparison of model results and observations (obtained during field campaigns) indicates a good agreement between modeled and measured Tcan, with an explained variance of R2 = 0.99. Finally, we implement an energy balance model for vertically mounted PV modules to contrast different urban surface properties. Specifically, we consider (i) an environment comprising dark asphalt and a glass facade and (ii) an environment comprising bright concrete and a PV facade. The model results show a substantially decreased Tcan (by up to - 1.65 degrees C) for the latter case, indicating the potential of partially reducing/mitigating urban heat island effects. PMID- 30519957 TI - The significant role of health surveillance in the occupational heat stress assessment. AB - In order to address the heat stress hazard, the worker health surveillance makes a difference by providing information about individual factor, feedback, and evidence about efficacy of preventive measures and activities carried out through the risk assessment process, at individual and group levels. Every technical, procedural, or organizational measures could be ineffective without taking into account the results provided by health surveillance. PMID- 30519958 TI - Bone turnover markers, BMD and TBS after short-term, high-dose glucocorticoid therapy in patients with Graves' orbitopathy: a small prospective pilot study. AB - PURPOSE: Chronic GC administration has numerous side effects, but little is known about the side effects of their short-term use (< 3 months)-particularly, when high doses are involved, as in the treatment of Graves' orbitopathy (GO). We investigated the effects of short-term, high-dose GC on bone turnover markers, bone mineral density (BMD), and trabecular bone scores (TBS). METHODS: Eleven patients (10 females and 1 male; median age 56 years) with active GO who were candidates for treatment with intravenous (iv) methylprednisone were consecutively enrolled. All patients were pretreated with a loading dose of 300,000 units of cholecalciferol, then given a median cumulative dose of 4.5 g (range 1.5-5.25 g) iv methylprednisone. Biochemical parameters of bone metabolism (25OHD3, PTH, P1NP, CTX and bALP) were measured at the baseline, and then 1 week and 1, 3, 6 and 12 months. BMD and TBS were obtained by X-ray absorptiometry (DXA) at the baseline and at 6 and 12 months. On DXA image, morphometric vertebral fracture assessment (VFA) was done. RESULTS: There were no significant changes in PTH, bALP or P1NP. A significant drop in CTX was seen at 1 month (down Delta49.31% from the baseline, p = 0.02), with a return to the baseline at the 3 month measurement. There was a moderate (not significant), but persistent reduction in P1NP. No changes in BMD or TBS came to light. No vertebral fractures were documented. CONCLUSIONS: Short-term, high-dose GC treatment caused a rapid, transient suppression of bone resorption, with no effects on BMD or bone micro architecture (TBS). PMID- 30519959 TI - A validated workflow for drug detection in oral fluid by non-targeted liquid chromatography-tandem mass spectrometry. AB - Oral fluid is recognized as an important specimen for drug testing. Common applications are monitoring in substance abuse treatment programs, therapeutic drug monitoring, pain management, workplace drug testing, clinical toxicology, and driving under the influence of drugs (DRUID). In this study, we demonstrate that non-targeted LC-MS/MS with subsequent compound identification by tandem mass spectral library search is a valuable tool for comprehensive detection and confirmation of drugs in oral fluid samples. The workflow developed involves solid-phase extraction and chromatographic separation on reversed phase materials. Mass spectrometric detection is accomplished on a quadrupole quadrupole-time-of-flight instrument operated with data-dependent acquisition control. The workflow was optimized for 500 MUl of neat oral fluid collected with the Greiner Bio-One saliva collection system. The fitness of the developed method was tested and proven by analyzing blank and spiked samples as well as 59 authentic patient samples. We could demonstrate that compounds with logP values in the range 0.5-5.5 are efficiently detected at low nanograms per milliliter concentrations. The true positive and true negative rates of automated library search were equal or close to 100%. The beauty of the non-targeted LC-MS/MS approach is the ability to detect compounds hardly included in routinely applied targeted assays, and this was demonstrated by detecting the synthetic opioid U 47700 in two patient samples. Graphical abstract ?. PMID- 30519960 TI - A bi-end injection capillary electrophoresis method for simultaneous determination of 37 cations and anions in beers. AB - Capillary electrophoresis (CE) is excellent at separating all the ions in a sample but is rarely used as a result of its detection issue and easy loss of very fast ions by common one-end injection methods. Herein we propose a newly developed method aimed at simultaneous determination of positive and negative ions with a home-made CE device, featuring bi-end injection and contactless conductivity detection at the middle. By simply using 2.5 M acetic acid as a running buffer, the method can separate 37 ions (3 inorganic anions, 8 inorganic cations, 10 biogenic amines, and 16 amino acids) per run, with linearity between 10 and 2000 MUM (R2 > 0.99), limit of detection of 1.0-16.6 MUM, and limit of quantification of 2.3-31.7 MUM. The recovery measured by spiking standards into samples at high, middle, and low levels was between 73% and 110%. The intra- and interday repeatability of the 37 analytes ranged from 0.69% to 8.97% and from 0.68% to 11.04%, respectively. The proposed method was evaluated by analysis of 21 beers and, in addition to acquiring the concentration information, the brands of the tested beers were distinguished. This method is of high throughput, fast, and cost-effective. It could be a promising tool for ionomic analysis. Graphical abstract ?. PMID- 30519961 TI - EPA's non-targeted analysis collaborative trial (ENTACT): genesis, design, and initial findings. AB - In August 2015, the US Environmental Protection Agency (EPA) convened a workshop entitled "Advancing non-targeted analyses of xenobiotic chemicals in environmental and biological media." The purpose of the workshop was to bring together the foremost experts in non-targeted analysis (NTA) to discuss the state of-the-science for generating, interpreting, and exchanging NTA measurement data. During the workshop, participants discussed potential designs for a collaborative project that would use EPA resources, including the ToxCast library of chemical substances, the DSSTox database, and the CompTox Chemicals Dashboard, to evaluate cutting-edge NTA methods. That discussion was the genesis of EPA's Non-Targeted Analysis Collaborative Trial (ENTACT). Nearly 30 laboratories have enrolled in ENTACT and used a variety of chromatography, mass spectrometry, and data processing approaches to characterize ten synthetic chemical mixtures, three standardized media (human serum, house dust, and silicone band) extracts, and thousands of individual substances. Initial results show that nearly all participants have detected and reported more compounds in the mixtures than were intentionally added, with large inter-lab variability in the number of reported compounds. A comparison of gas and liquid chromatography results shows that the majority (45.3%) of correctly identified compounds were detected by only one method and 15.4% of compounds were not identified. Finally, a limited set of true positive identifications indicates substantial differences in observable chemical space when employing disparate separation and ionization techniques as part of NTA workflows. This article describes the genesis of ENTACT, all study methods and materials, and an analysis of results submitted to date. Graphical abstract ?. PMID- 30519962 TI - Hypertrophic obstructive cardiomyopathy and mitral regurgitation in Libman-Sacks endocarditis. AB - Hypertrophic obstructive cardiomyopathy in Libman-Sacks endocarditis is quite rare and the correct etiological relationship between them is unknown. Some changes may cause a secondary disorganization of the ordinary muscle structure, making a disarray pattern with irregular interwoven myocyte fibers. This case report describes one of the first cases of ventricular septal myectomy and mitral valve replacement for hypertrophic obstructive cardiomyopathy and mitral valve regurgitation associated with Libman-Sacks endocarditis. PMID- 30519963 TI - A case of duodenal hemorrhage due to arteriovenous malformation around a serous cystic neoplasm. AB - BACKGROUND: No reports have so far described arteriovenous malformation (AVM) in the pancreas caused by a tumor. We herein report a case of pancreatoduodenectomy for a patient who developed duodenal hemorrhage due to AVM developed around serous cystic neoplasm (SCN) of the pancreas. CASE PRESENTATION: A 79-year-old man was referred to our hospital because of anemia (Hb 7.4 g/dl) and pancreatic head tumor. Computed tomography showed microcystic-type SCN, 87 mm in size, in the pancreatic head. Vascular hyperplasia had developed around the cystic lesion. Upper gastrointestinal endoscopy and colonoscopy did not reveal the cause of anemia, so the patient was followed closely without hemostatic therapy. Iron preparations had improved the anemia. Three months later, the patient developed anemia (Hb 5.8 g/dl) again. Gastrointestinal endoscopy showed oozing from the mucosa in the duodenum via the swollen vascular hyperplasia. He was diagnosed as duodenal hemorrhage from the blood vessels around SCN. Pancreatoduodenectomy was performed to control repeated duodenal bleeding. A histopathological examination revealed that the cystic lesion in the pancreatic head was SCN, and the AVM developed around SCN and duodenum, causing repeated duodenal hemorrhage. The patient was discharged on postoperative day 22. Nine months after surgery, the patient had no recurrence of anemia. CONCLUSIONS: There have been no reports of duodenal hemorrhage due to acquired pancreatic AVM around pancreatic tumor, including SCN. We successfully treated a case of duodenal hemorrhage due to pancreatic AVM around SCN by pancreatoduodenectomy. PMID- 30519964 TI - Osteomyelitis of a sacral neurocentral synchondrosis: a case report of another metaphyseal equivalent. AB - Pelvic osteomyelitis may occur in a metaphyseal equivalent, defined as a portion of flat or irregular bone that is adjacent to cartilage. The pelvic bone is known to have several metaphyseal equivalents and of these, the sacroiliac joint is the most frequent site of involvement. However, a sacral neurocentral synchondrosis has not been recognized as a metaphyseal equivalent, and there have been no previous reports describing this as the site of origin of sacral osteomyelitis. We here report two cases of sacral osteomyelitis originating in a neurocentral synchondrosis, another metaphyseal equivalent. We, as pediatric radiologists, should recognize a sacral neurocentral synchondrosis as another metaphyseal equivalent, especially in infants and younger patients. PMID- 30519965 TI - A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue? AB - Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD. PMID- 30519966 TI - Suboptimal performance of APRI and FIB-4 in ruling out significant fibrosis and confirming cirrhosis in HIV/HCV co-infected and HCV mono-infected patients. AB - PURPOSE: We aimed to assess the diagnostic reliability of two indirect biomarkers, APRI and FIB-4, for the staging of liver fibrosis using transient elastography (TE) as reference standard, among HIV/HCV co-infected and HCV mono infected patients. METHODS: This is an observational, retrospective study on subjects who had access to the RESIST HCV from October 2013 to December 2016, a regional network encompassing 22 hospitals and academic centers throughout Sicily. Sensitivity, specificity and diagnostic accuracy of indirect biomarkers for liver stiffness measurement (LSM) < 9.5 kPa (significant fibrosis) and LSM >= 12.5 kPa (cirrhosis) were determined by receiver operator characteristics (ROC) curves. RESULTS: 238 HIV/HCV co-infected and 1937 HCV mono-infected patients were included. Performances of FIB-4 and APRI for the detection of significant fibrosis and cirrhosis proved to be unsatisfactory, with very high false negative and false positive rates among both cohorts. No significant differences were found after stratification of HIV/HCV co-infected patients for BMI < or >= 25, ALT < or >= 40 IU/L, ALT < or >= 80 IU/L, and presence/absence of a bright liver echo pattern on ultrasonography. CONCLUSIONS: Differently from other studies, we detected the unreliability of APRI and FIB-4 for the assessment of liver fibrosis in both HCV mono-infected and HIV/HCV co-infected patients. PMID- 30519967 TI - Sick leave before and after a work-place targeted terror attack. AB - OBJECTIVES: To estimate the rate of sick leave and sick leave diagnosis among employees before and after a work-place targeted terror attack, and to compare sick leave in subgroups of employees based on gender and trauma exposure. METHODS: Data on sick leave and diagnosis in ministerial employees from the period 3 years before to 3 years after the 2011 bombing in the governmental district of Oslo was retrieved from the Norwegian Social Insurance Administration Registries. RESULTS: Prior to the attack, sick leave was twice as high in women as in men. Compared to the period prior to the attack, sick leave increased the first year after the attack, for both women and men that were directly exposed to the event. Sick leave stabilized to the initial level 3 years after the incident. For indirectly exposed employees, i.e., those who were not present at the site of the attack, there was no significant increase in sick leave from before to after the attack. There were no statistical significant changes in diagnoses applied before and after the terrorist attack. However, there was a tendency towards an increase in sick leave due to psychological diagnoses among the directly exposed women. CONCLUSIONS: After a work-place terrorist attack a transient increase in sick leave may occur among employees who were present at the site of the attack. The increase may seem relatively modest and last for 1-3 years. PMID- 30519968 TI - Empiric neurocognitive performance profile discovery and interpretation in HIV infection. AB - The measurement and determinants of HIV-associated neurocognitive disorders (HAND) are under intense debate. We used latent profile analysis (LPA) and machine learning to define neurocognitive performance profiles and identify their associated risk factors in HIV patients receiving antiretroviral therapy (ART). Neurocognitive performance was assessed by a multidomain neuropsychological test battery. LPA was used to define individual neurocognitive profiles. Random forest analyses (RFA) identified the most important factors distinguishing each profile. Three profiles emerged from the LPA: profile 1 (P1, n = 159) achieved the highest performance, while profile 2 (P2, n = 163) had lowered executive functions and verbal memory, and profile 3 (P3, n = 59) was globally impaired. RFA achieved good prediction (area under the curve >= 0.80) only for global impairment (P3). Non-North American descent was the dominant predictor of P3, followed by factors coinciding with non-North American descent (female sex and toxoplasma seropositivity). Additional predictors included unemployment, current depressive symptoms, lower nadir CD4, and longstanding HIV. Restricting analyses to North Americans pointed to the additional importance of ART achieving high CSF levels and older age in prediction of P3. HAND diagnoses were most common in the globally impaired profile (P3 = 89.8%), followed by the group with reduced higher order neurocognitive performance (P2 = 16.6%). Thus, implementation of LPA and RFA empirically distinguished three distinct neurocognitive performance profiles in this HIV-infected cohort while also highlighting potential risk factors and their relative importance to neurocognitive impairment. These data-driven analytical methods pointed to discernible demographic, HIV- and treatment-related risk factor constellations in patients born outside and within North America that might influence diagnostic and therapeutic decisions. PMID- 30519969 TI - Are We Justified in Introducing Carbon Monoxide Testing to Encourage Smoking Cessation in Pregnant Women? AB - Smoking is frequently presented as being particularly problematic when the smoker is a pregnant woman because of the potential harm to the future child. This premise is used to justify targeting pregnant women with a unique approach to smoking cessation including policies such as the routine testing of all pregnant women for carbon monoxide at every antenatal appointment. This paper examines the evidence that such policies are justified by the aim of harm prevention and argues that targeting pregnant women in this way is likely to do more harm than good. Routine carbon monoxide testing is particularly problematic as it sends a message to pregnant women that they cannot be trusted either to truthfully answer questions as to whether or not they smoke, or to make decisions in the best interests of themselves and their future children in the way that non-pregnant individuals are. Further, if the aim is to reduce rates of prenatal harm, the evidence suggests that adopting a supportive and empowering approach to prenatal care is the most effective way to achieve this, something that the current policies aimed at pregnant women are in conflict with. PMID- 30519970 TI - Growth of children with biliary atresia living with native livers: impact of corticoid therapy after portoenterostomy. AB - We addressed growth of biliary atresia (BA) patients living with native livers between ages 0-6 and effects of post-surgical corticosteroid treatment on growth. Growth charts of 28 BA patients born in Finland between 1987 and 2017 were retrospectively evaluated. Dosage and length of corticosteroid treatment and hydrocortisone substitution were reviewed. At birth, BA patients were shorter (median height - 0.6 (interquartile range (IQR) - 1.3 to - 0.1) SDS, n = 28, P < 0.001) than general population. Height remained stable during early childhood (median height - 0.6 (IQR - 1.4 to 0.1) SDS for girls and - 0.4 (IQR - 1.6 to 0.2) SDS for boys at 6 years of age). Patients were of normal height adjusted weight at 6 years with a median age and sex-adjusted body mass index (ISO-BMI) of 20.9 (IQR 19.3 to 25.0) for girls and 22.1 (IQR 20.7 to 25.6) for boys. Higher (>= 50 mg/kg) cumulative post-portoenterostomy prednisolone dosage resulted in 0.18 SDS lower height per treatment week (beta - 0.18, SE 0.04, P < 0.001) compared to lower dosage (< 50 mg/kg).Conclusion: BA patients grow normally during early childhood. As high postoperative corticosteroid dosage has a short term negative effect on height, very high dosages should be avoided. What Is Known: * Growth of biliary atresia patients has mostly been shown to be within normal limits * Corticosteroids may decrease growth rate What Is New: * Biliary atresia patients surviving with their native livers are shorter than general population and their mid-parental target height at birth * A high (> 50 mg/kg) cumulative prednisolone dosage has a negative transitory impact on height gain after portoenterostomy. PMID- 30519971 TI - Association between serum 25(OH)D and hematological markers of erythropoiesis: the curse of large numbers, the treachery of p value. PMID- 30519972 TI - IoT-Based Services and Applications for Mental Health in the Literature. AB - Internet of Things (IoT) has emerged as a new paradigm today, connecting a variety of physical and virtual elements integrated with electronic components, sensors, actuators and software to collect and exchange data. IoT is gaining increasing attention as a priority research topic in the Health sector in general and in specific areas such as Mental Health. The main objective of this paper is to show a review of the existing research works in the literature, referring to the main IoT services and applications in Mental Health diseases. The scientific databases used to carry out the review are Google Scholar, IEEE Xplore, PubMed, Science Direct, and Web of Science, taking into account as date of publication the last 10 years, from 2008 to the present. Several search criteria were established such as "IoT OR Internet of Things AND (Application OR Service) AND Mental Health" selecting the most interesting articles. A total of 51 articles were found on IoT-based services and applications in Mental Health, of which 14 have been identified as relevant works in mental health. Many of the publications (more than 60%) found show the applications developed for monitoring patients with mental disorders through sensors and networked devices. The inclusion of the new IoT technology in Health brings many benefits in terms of monitoring, welfare interventions and providing alert and information services. In pathologies such as Mental Health is a vital factor to improve the patient life quality and effectiveness of the medical service. PMID- 30519973 TI - Mouse models of Alzheimer's disease cause rarefaction of pial collaterals and increased severity of ischemic stroke. AB - Vascular dysfunction contributes to the progression and severity of Alzheimer's disease (AD). Patients with AD also sustain larger infarctions after ischemic stroke; however, the responsible mechanisms are unknown. Pial collaterals are the primary source of protection in stroke. Unfortunately, natural aging and other vascular risk factors cause a decline in collateral number and diameter (rarefaction) and an increase in stroke severity. Herein, we tested the hypothesis that AD accelerates age-induced collateral rarefaction and examined potential underlying mechanisms. Triple and double transgenic mouse models of AD both sustained collateral rarefaction by 8 months of age, well before the onset of rarefaction caused by aging alone (16 months of age). Rarefaction, which did not progress further at 18 months of age, was accompanied by a twofold increase in infarct volume after MCA occlusion. AD did not induce rarefaction of similarly sized pial arterioles or penetrating arterioles. Rarefaction was minimal and occurred only at 18 months of age in a parenchymal vascular amyloid-beta model of AD. Rarefaction was not associated with amyloid-beta deposition on collaterals or pial arteries, nor was plaque burden or CD11b+ cell density greater in brain underlying the collateral zones versus elsewhere. However, rarefaction was accompanied by increased markers of oxidative stress, inflammation, and aging of collateral endothelial and mural cells. Moreover, rarefaction was lessened by deletion of CX3CR1 and prevented by overexpression of eNOS. These findings demonstrate that mouse models of AD promote rarefaction of pial collaterals and implicate inflammation-induced accelerated aging of collateral wall cells. Strategies that reduce vascular inflammation and/or increase nitric oxide may preserve collateral function. PMID- 30519974 TI - Validation of the physiological background correction method for the suppression of the spill-in effect near highly radioactive regions in positron emission tomography. AB - BACKGROUND: Positron emission tomography (PET) imaging has a wide applicability in oncology, cardiology and neurology. However, a major drawback when imaging very active regions such as the bladder is the spill-in effect, leading to inaccurate quantification and obscured visualisation of nearby lesions. Therefore, this study aims at investigating and correcting for the spill-in effect from high-activity regions to the surroundings as a function of activity in the hot region, lesion size and location, system resolution and application of post-filtering using a recently proposed background correction technique. This study involves analytical simulations for the digital XCAT2 phantom and validation acquiring NEMA phantom and patient data with the GE Signa PET/MR scanner. Reconstructions were done using the ordered subset expectation maximisation (OSEM) algorithm. Dedicated point-spread function (OSEM+PSF) and a recently proposed background correction (OSEM+PSF+BC) were incorporated into the reconstruction for spill-in correction. The standardised uptake values (SUV) were compared for all reconstruction algorithms. RESULTS: The simulation study revealed that lesions within 15-20 mm from the hot region were predominantly affected by the spill-in effect, leading to an increased bias and impaired lesion visualisation within the region. For OSEM, lesion SUVmax converged to the true value at low bladder activity, but as activity increased, there was an overestimation as much as 19% for proximal lesions (distance around 15-20 mm from the bladder edge) and 2-4% for distant lesions (distance larger than 20 mm from the bladder edge). As bladder SUV increases, the % SUV change for proximal lesions is about 31% and 6% for SUVmax and SUVmean, respectively, showing that the spill-in effect is more evident for the SUVmax than the SUVmean. Also, the application of post-filtering resulted in up to 65% increment in the spill-in effect around the bladder edges. For proximal lesions, PSF has no major improvement over OSEM because of the spill-in effect, coupled with the blurring effect by post-filtering. Within two voxels around the bladder, the spill-in effect in OSEM is 42% (32%), while for OSEM+PSF, it is 31% (19%), with (and without) post-filtering, respectively. But with OSEM+PSF+BC, the spill-in contribution from the bladder was relatively low (below 5%, either with or without post-filtering). These results were further validated using the NEMA phantom and patient data for which OSEM+PSF+BC showed about 70-80% spill-in reduction around the bladder edges and increased contrast-to-noise ratio up to 36% compared to OSEM and OSEM+PSF reconstructions without post-filtering. CONCLUSION: The spill-in effect is dependent on the activity in the hot region, lesion size and location, as well as post-filtering; and this is more evident in SUVmax than SUVmean. However, the recently proposed background correction method facilitates stability in quantification and enhances the contrast in lesions with low uptake. PMID- 30519975 TI - Quenching of Luminol Fluorescence at Nano-Bio Interface: Towards the Development of an Efficient Energy Transfer System. AB - Surface modified colloidal gold (Au) and silver (Ag) nanoparticles (NPs) were used as efficient quenchers of luminol (LH2) fluorescence either in homogeneous aqueous medium or its noncovalent assembly with bovine serum albumin (BSA). The mechanism as well as the extent of fluorescence quenching was found to be strongly dependent on the nature of the nanoparticles. While simple static type fluorescence quenching mechanism was perceived with AuNP, a more complex protocol involving quenching sphere model was envisaged for AgNP quenching. Nevertheless, the magnitude of Stern-Volmer (SV) quenching constant (KSV ~ 108-1010 M-1) was calculated to be ca. 104 times more for surface quoted NPs in comparison with BSA NP bioconjugates system. On the other hand, a highly efficient (E ~ 95%) energy transfer (ET) process was predicted for LH2 captured in the hydrophobic assembly with BSA in presence of AgNP as an acceptor. The ET efficiency is critically dependent on the concentration of BSA and nicely correlated with the extent of NP surface coverage. However, fluorescence quenching on AuNP surface is relatively less responsive towards protein concentration, primarily due to the difference in surface activity as well as the mode of interaction of the protein with NPs. Graphical Abstract Energy transfer from excited luminol to metal nanoparticles is strongly modulated in presence of serum albumins. PMID- 30519976 TI - The Finnish Interprofessional Medication Assessment (FIMA): baseline findings from home care setting. AB - PURPOSE: Medication-related problems and declined functional capacity are closely associated factors among older people. The purpose of this study is to describe the procedure of interprofessional medication assessment in home care context and the baseline characteristics of the study population. METHODS: The FIMA study was a randomized, controlled intervention study comparing general practitioner-led interprofessional medication assessment and usual care. Patients' chronic diagnoses and medication use as well as physical and cognitive functions were investigated. Performance in daily activities, use of care services and help from family and relatives, self-rated health and health-related quality of life, and adverse effects commonly related to medication were assessed. RESULTS: The home care patients (n = 512) had significant disease burden and functional limitations. The mean number of all medicines was 15 and that of regularly taken medicines 10. The majority of patients (87%) had excessive polypharmacy. The most commonly used (97%) ATC medicine class was nervous system medicines. Clinically relevant (class C or D SFINX record) drug-drug interactions were seen in 74% of the patients. The most frequent risks of adverse effects were risk of bleeding (66%), constipation (58%) and orthostatism (54%) occurring in over half of the patients. Medicines affecting renal function were used by 85% of the patients. CONCLUSIONS: There is an evident need and justification for medication assessments in home care. In most cases, home care patients fulfill the criteria for regular medication assessments. PMID- 30519977 TI - Daily and per-meal animal and plant protein intake in relation to muscle mass in healthy older adults without functional limitations: an enable study. AB - OBJECTIVE: Animal protein sources are considered to be of higher quality than plant protein sources in terms of stimulating muscle metabolism. Our objective was to investigate whether protein intake from animal and plant sources on a daily and per-meal basis differs between healthy older adults with normal and with low muscle mass. METHODS: In this cross-sectional study including 100 healthy, community-dwelling adults (51 women) aged 75-85 years without functional limitations dietary intake was assessed using 7-day food records. Protein intake was classified by six animal and six plant protein sources. Skeletal muscle index (SMI) was determined based on bioelectrical impedance analysis and categorized into 'normal' or 'low' (men <= 8.50, women <= 5.75 kg/m2). The absolute animal and plant protein intake and their proportion of total protein intake were compared between these groups using Mann-Whitney U test. RESULTS: Daily protein intake was 0.96 +/- 0.27 g/kg body weight (BW), 61 +/- 10% hereof were from animal origin with no difference between men and women. SMI was low in 39% of men and 35% of women. No differences in absolute daily animal and plant protein intake between participants with normal vs. low SMI were observed. The proportion of animal protein was not different on neither a daily nor a per-meal basis between those with normal and those with low SMI. Women with low SMI consumed less animal protein (in g) for breakfast (4.8 +/- 4.1 g vs. 8.5 +/- 6.9 g, p = 0.031) and fewer meals per day with at least 50% animal protein (2.2 +/- 0.9 vs. 2.7 +/- 1.0, p = 0.046) compared to those with normal SMI. CONCLUSION: On a daily basis, the absolute and relative animal protein intake does not differ between healthy older adults without functional limitations with normal vs. low SMI. However, our results indicate that in women animal protein intake on a per-meal basis might be of relevance for the maintenance of muscle mass. PMID- 30519978 TI - CME INSTRUCTIONS: The role of nuclear medicine in assessments of cardiac dyssynchrony. PMID- 30519979 TI - A modification with threading cannula needle-assisted 4-point suspension fixation for retroperitoneal laparoscopic pyeloplasty in children with ureteropelvic junction obstruction: a cohort study in single center. AB - PURPOSE: To evaluate the effect and safety of modifying a threading cannula needle-assisted suspension fixation in retroperitoneal laparoscopic dismembered pyeloplasty (LDP) for children with congenital ureteropelvic junction obstruction (UPJO). METHODS: Between December 2012 and December 2017, 45 children (< 14 years of age) with congenital UPJO were divided into two groups. In Group A, children underwent conventional "no-suspension fixation" LDP; and in Group B, "4-point suspension fixation" LDP was performed to lower difficulties and shorten operative time. The perioperative clinical data were recorded and analyzed. RESULTS: No statistical difference was found between two groups in preoperative characteristics. The duration of surgery, operative time for completion of anastomosis and the length of postoperative hospital stay in Group B was remarkably shortened than that in Group A, respectively (P < 0.05 for all). There was no significant difference between two groups in terms of postoperative renal pelvic diameter (RPD) decreasing, extubation time and success rates of surgery (P > 0.05 for all). In addition, no recurrent stenosis and urine leakage in both groups, and the postoperative RPD remained at the low level in both groups during the period of follow-up. CONCLUSIONS: Our modification of the 4-point suspension fixation for retroperitoneal LDP is an effective and safe method for children with UPJO. It can simplify the surgical procedures, lower difficulties (especially in precise anastomotic suturing) and shorten the learning curve. This modification might be of particular interest to urologists for improving treatment of children with UPJO. PMID- 30519980 TI - The effect of chronic kidney disease on lipid metabolism. AB - The major cause of death among chronic kidney disease patients is cardiovascular diseases. Cardiovascular and kidney disease are interrelated and increase the severity of each other. Dyslipidemia is one the major causes of cardiovascular disease among chronic kidney disease patients along with diabetes and hypertension. The relationship between dyslipidemia and chronic kidney disease is reciprocal. Dyslipidemia is known to be a risk factor for chronic kidney disease and chronic kidney disease causes major alterations on lipoprotein profile, defined as the "dyslipidemic profile" of chronic kidney disease patients. Increased triglyceride, very low density lipoprotein and oxidized low density lipoprotein as well as decreased high density lipoprotein and changes in the composition of lipoproteins contribute to the "dyslipidemic profile." Treatment strategies targeting the "dyslipidemic profile" of chronic kidney disease could contribute to prevent cardiovascular diseases. Current therapy is based on the patient kidney function and consist mainly of statins. This review focuses on the effects of chronic kidney disease on the lipoprotein profile and how this may impact novel therapeutic approaches to cardiovascular risk. PMID- 30519981 TI - Urine proteomic profiling in patients with nephrolithiasis and cystinuria. AB - PURPOSE: The purpose of the study was to assess the differences in the concentration and function of urinary proteins between patients with cystine stones (CYS) and healthy controls (HC). We postulated that CYS and HC groups would demonstrate different proteomic profiles. METHODS: A pilot study was performed comparing urinary proteomes of 10 patients with CYS and 10 age- and gender-matched HC, using liquid chromatography-mass spectrometry. Proteins which met the selection criteria (i) >= 2 unique peptide identifications; (ii) >= twofold difference in protein abundance; and (iii) <= 0.05 p value for the Fisher's Exact Test were analyzed using Gene Ontology classifications. RESULTS: Of the 2097 proteins identified by proteomic analysis, 398 proteins were significantly different between CYS and HC. Of those, 191 were involved in transport processes and 61 in inflammatory responses. The majority were vesicle mediated transport proteins (78.5%), and 1/3 of them were down-regulated; of those, 12 proteins were involved in endosomal transport (including 6 charged multivesicular body proteins (CHMP) and 3 vacuolar sorting-associated proteins) and 9 in transmembrane transport. Myosin-2 and two actin-related proteins were significantly up-regulated in the vesicle-mediated transport group. CONCLUSION: We provide proteomic evidence of impaired endocytosis, dysregulation of actin and myosin cytoskeleton, and inflammation in CYS. Endosomal transport proteins were down-regulated mainly through defective CHMP. These findings may contribute to further understanding of the pathogenesis of CYS, potentially affecting its management. PMID- 30519982 TI - The Prognostic and Predictive Value of Dihydropyrimidine Dehydrogenase-Related Indicators in Clinical Outcomes of Chemotherapy in Colorectal Cancer Patients: a Systematic Review and Meta-Analysis. AB - Colorectal cancer (CRC) is the third most common cancer worldwide. Predictive biomarkers are needed to predict patients' outcomes and to select a chemotherapy regimen. We assessed whether dihydropyrimidine dehydrogenase (DPD)-related indicators can predict CRC patients' outcomes. We searched the studies in PubMed, EmBase, and the Cochrane Library up to March 4, 2018. We mainly analyzed different CRC patients' outcomes according to specific DPD-related indicators. Twenty-five articles were included in the meta-analysis. The results showed that for disease-free survival (DFS), low DPD expression was significantly superior to high expression (I2 = 72%; HR: 1.59; 95%CI: 1.21-2.09; p = 0.001). However, this result had a potential publication bias (Begg's test: p = 0.007; Egger's test: p = 0.004). Among patients treated with chemotherapy, a high thymidylate phosphorylase (TP)/DPD ratio was advantageous for DFS (I2 = 63.7%; HR: 0.65; 95%CI: 0.46-0.92; p = 0.015), and this result did not have a publication bias. For overall survival (OS), low DPD expression was superior to high expression (I2 = 74.4%; HR: 2.11; 95%CI: 1.48-3.00; p < 0.001), although this result had a publication bias (Egger's test: p = 0.003; Begg's test: p = 0.010). There was no difference in OS according to the TP/DPD ratio (I2 = 0%; HR: 0.92; 95%CI: 0.75 1.13; p = 0.420). DFS and OS were better in CRC patients with low DPD expression than in those with high DPD expression. However, because of publication bias, more DPD indicator-related studies, especially with negative results, are still needed. Patients with a high TP/DPD ratio have better DFS but not OS. PMID- 30519984 TI - The role of Rhodotorula mucilaginosa in selected biological process of wild fish. AB - Defense mechanisms of fish are investigated in many aspects. One of the most interesting systems is that based on non-specific immune factors whose mechanisms of biocontrol have evolved in complex processes of microbiological co-existence. The wild fish devoid of probiotic stimulation have developed their own system to control the biosynthesis of immunostimulating compounds based on commensal microflora. Results of this study demonstrated the gastrointestinal tract (GI) of wild fish (Abramis brama, Rutilus rutilus, Perca fluviatilis) was colonized by permanently residing strains of Rhodotorula mucilaginosa. The genetic profile of the tested strains (PCR-random amplification of polymorphic DNA) indicated their affinity only to the GI of the analyzed fish. The capability for biosynthesis of beta-carotene, torulene, torularhodin, and exopolysaccharides (EPS) under conditions of fish gastrointestinal tract was found to be a strain-specific trait. Rhodotorula spp. interactions with fish should be considered as a mechanism of symbiotic relations based on the stimulation of non-specific mechanisms of fish immunoprotection and antioxidative properties of yeast. PMID- 30519983 TI - Effect of Silk Fibroin on Neuroregeneration After Traumatic Brain Injury. AB - Traumatic brain injury is one of the leading causes of disability among the working-age population worldwide. Despite attempts to develop neuroprotective therapeutic approaches, including pharmacological or cellular technologies, significant advances in brain regeneration have not yet been achieved. Development of silk fibroin-based biomaterials represents a new frontier in neuroregenerative therapies after brain injury. In this study, we estimated the short and long-term effects of silk fibroin scaffold transplantation on traumatic brain injury and biocompatibility of this biomaterial within rat neuro-vascular cells. Silk fibroin microparticles were injected into a brain damage area 1 day after the injury. Silk fibroin affords neuroprotection as judged by diminished brain damage and recovery of long-term neurological functions. We did not detect considerable toxicity to neuro-vascular cells cultured on fibroin/fibroin-gelatin microparticles in vitro. Cultivation of primary cell cultures of neurons and astrocytes on silk fibroin matrices demonstrated their higher viability under oxygen-glucose deprivation compared to 2D conditions on plastic plates. Thus, we conclude that scaffolds based on silk fibroin can become the basis for the creation of constructs aimed to treat brain regeneration after injury. PMID- 30519985 TI - Characteristic "neck collar" injuries in Australian sea lions (Neophoca cinerea) caused by marine debris. AB - An adult male Australian sea lion (Neophoca cinerea) presented with a deep, almost circumferential, incised wound around the neck caused by a noose formed by a single strand of green nylon rope. The wound extended 4-5 cm deeply through the skin and blubber into skeletal muscle, predominantly on the dorsal surface and left side, but had not involved the airway or major vessels. The edges of the wound were sharply incised and oozing blood with a granulating infected base. The rope was removed and the wound debrided of necrotic tissues and irrigated with disinfectant. Antibiotic and rehydration therapy were successful and the seal was released after 2 weeks of treatment. Entanglement injuries such as "neck collars" have characteristic features, are increasing in incidence and often have lethal outcomes. This type of injury may significantly impact upon populations of pinnipeds in the wild. PMID- 30519986 TI - An interdisciplinary review of the thanatomicrobiome in human decomposition. AB - Death does not occur instantaneously and organs do not decompose at the same rate or in the same way. Nulligravid human uteri and prostate glands are the last internal organs to deteriorate during decomposition; however, the reason for this very important observation is still enigmatic. Recent studies have elucidated that the composition and abundance of microbes in the human thanatomicrobiome (microbiome of death) varies by organ and changes as a function of time and temperature. The ileocecal area has the largest absolute postmortem burden that spreads to the liver and spleen and continues to the heart and brain depending on the cause of death. To truly understand the mechanisms of microbial assembly during decomposition, a thorough examination of different strategies utilized by the trillions of microbes that colonize decaying tissues is needed from a multi organ and multidisciplinary approach. In this review, we highlight interdisciplinary research and provide an overview of human decomposition investigations of thanatomicrobiomic changes in internal organs. PMID- 30519987 TI - Applying virtual reality in forensics - a virtual scene walkthrough. AB - A major task of forensic investigations is the documentation and interpretation of evidence to reconstruct a forensically relevant incident. To accomplish this task, a scene is documented not only with photographs but also with 3D documentation technologies. The resulting 3D data are used for 3D visualization and to perform 3D reconstructions. In this article, we present an approach for using forensic 3D data in conjunction with virtual reality to perform scene walkthroughs in the context of witness or suspect interrogations. The aim is to provide a method for scene visits showing the original scene even years after the incident. These scene walkthroughs in VR can be reproduced and allow to see through the eyes of a witness by recording their behavior and actions. These recordings allow subsequent examinations and reconstruction to support the investigation and scene understanding and can be used as evidence in court. PMID- 30519989 TI - Expression of Concern: Emphysematous pyelonephritis due to Aspergillus fumigatus a case report. PMID- 30519988 TI - Minimally invasive plate osteosynthesis (MIPO) in AO/OTA type B displaced clavicle fractures. AB - INTRODUCTION: Open reduction and plate fixation is known to reduce chances of malunion and symptomatic nonunion in displaced middle-third clavicle fractures. However, this treatment modality is also associated with several complications, such as hardware irritation, numbness around the surgical scar, infection, nonunion and implant failure. The minimally invasive plate osteosynthesis (MIPO) technique may reduce these complications. OBJECTIVE: To study clinical, radiological and functional outcomes of MIPO in AO/OTA type B displaced clavicle fractures and report any complications. MATERIALS AND METHODS: A total of 22 patients underwent internal fixation of acute displaced AO/OTA type B clavicle fractures from Jan 2014 to Dec 2015 by MIPO using locking compression plates. Patients were followed up at a regular interval and assessed clinically and radiologically. The clavicle length difference was measured. Functional assessment was done at the end of 2 year using constant shoulder score (CSS) and disability of the arm, shoulder and hand score (Quick DASH) and complications if any were noted. RESULTS: All fractures united at a mean of 12.5 weeks. One (4.5%) patient had numbness around the surgical scar. None of the patients had wound related complications. In four patients, hardware irritation was noted. The difference in clavicle length was not significant. All patients had excellent CSS and Quick DASH score at the final follow-up. CONCLUSION: Internal fixation of displaced AO/OTA type B clavicle fractures by MIPO showed high fracture union rates and good functional outcomes. PMID- 30519990 TI - MER: a shell script and annotation server for minimal named entity recognition and linking. AB - Named-entity recognition aims at identifying the fragments of text that mention entities of interest, that afterwards could be linked to a knowledge base where those entities are described. This manuscript presents our minimal named-entity recognition and linking tool (MER), designed with flexibility, autonomy and efficiency in mind. To annotate a given text, MER only requires: (1) a lexicon (text file) with the list of terms representing the entities of interest; (2) optionally a tab-separated values file with a link for each term; (3) and a Unix shell. Alternatively, the user can provide an ontology from where MER will automatically generate the lexicon and links files. The efficiency of MER derives from exploring the high performance and reliability of the text processing command-line tools grep and awk, and a novel inverted recognition technique. MER was deployed in a cloud infrastructure using multiple Virtual Machines to work as an annotation server and participate in the Technical Interoperability and Performance of annotation Servers task of BioCreative V.5. The results show that our solution processed each document (text retrieval and annotation) in less than 3 s on average without using any type of cache. MER was also compared to a state of-the-art dictionary lookup solution obtaining competitive results not only in computational performance but also in precision and recall. MER is publicly available in a GitHub repository ( https://github.com/lasigeBioTM/MER ) and through a RESTful Web service ( http://labs.fc.ul.pt/mer/ ). PMID- 30519991 TI - Ultrasound-guided selective nerve root block versus fluoroscopy-guided interlaminar epidural block for the treatment of radicular pain in the lower cervical spine: a retrospective comparative study. AB - PURPOSE: Recent studies have compared the therapeutic efficacy and safety of the procedure using ultrasound and fluoroscopy. However, there are no published studies comparing the therapeutic efficacy and safety of fluoroscopy (FL)-guided cervical interlaminar epidural steroid injection (CIESI) with that of ultrasound (US)-guided selective nerve root block (SNRB). This study aimed to compare the mid-term effects and advantages of US-guided SNRB with FL-guided CIESI for radicular pain in the lower cervical spine through assessment of pain relief and functional improvement. METHODS: Patients with radicular pain in the lower cervical spine who received US-guided SNRB (n = 51) or FL-guided CIESI (n = 61) were included in this retrospective study. All procedures were performed using FL or US. The complication frequencies during the procedures, adverse events, treatment effects, and functional improvement were compared at intervals of 1, 3, and 6 months after the last injection. RESULTS: Both the neck disability index and verbal numeric scale showed improvements at 1, 3, and 6 months after the last injection in both groups, with no significant differences between groups (p < 0.05). Furthermore, the treatment success rate at all time points was not significantly different between groups. Logistic regression analysis revealed that the injection method (US- or FL-guided), sex, analgesic use, pain duration, number of injections, and age were not independent predictors of treatment success. Blood was aspirated before injection in 8% (n = 5) and 0% of patients in the FL-guided and US-guided groups, respectively. In seven patients of the FL guided group, intravascular contrast spread was noted during injection. CONCLUSIONS: Our results suggest that, compared with FL-guided CIESI, US-guided SNRB requires a shorter administration duration while providing similar pain relief and functional improvements. PMID- 30519992 TI - Villous lymphocytes in splenic large B-cell lymphoma with diffuse red pulp infiltration. PMID- 30519993 TI - What Is the Good of It-Ethical Controls of Human Subject Health Research? : Curtin University Annual Ethics Lecture. AB - The term "ethics" covers a multitude of virtues and possibly some sins where ethical perspectives differ. Given the diversity of ethical philosophies there is a question about what common ground can, or should, inform health research ethics. At a minimum it must be consistent with the law. Beyond that, ethics embraces a variety of possible approaches. This raises the question-what criteria are applied in determining the appropriate approach and what standards by way of quality control are applied to its decisional application by ethics committees or other authorities exercising responsibility in this difficult area. The particular issue of ethical perspectives on the use of "big data" in medical research also raises complex issues for consideration. PMID- 30519994 TI - Medium-Range Narratives as a Complementary Tool to Principle-Based Prioritization in Sweden: Test Case "ADHD". AB - In this paper, for the benefit of reflection processes in clinical and in local, regional, and national priority-setting, we aim to develop an ethical theoretical framework that includes both ethical principles and medium-range narratives. We present our suggestion in the particular case of having to choose between treatment interventions for attention deficit hyperactivity disorder (ADHD) and treatment interventions for other conditions or diseases, under circumstances of scarcity. In order to arrive at our model, we compare two distinct ethical approaches: a generalist (principles) approach and a particularist (narratives) approach. Our focus is on Sweden, because in Sweden prioritization in healthcare is uniquely governmentally regulated by the "ethics platform." We will present a (fictional) scenario to analyse the strengths and weaknesses of the generalist principled perspective of the ethics platform and the particularist perspective of narrative ethics. We will suggest an alternative (moderately particularist) approach to prioritization, which we dub a "principles plus medium-range narratives" approach. Notwithstanding the undeniably central role of principles in distributive justice, we claim that medium-range narratives concerning individuals or groups who stand to benefit or lose from ADHD prioritization practices should also be read or listened to and taken into account at all levels of priority-setting. These narratives are expected to ethically optimize clinical priority-setting, as well as that undertaken at local, regional, and national levels. PMID- 30519995 TI - Opposite subgenual cingulate cortical functional connectivity and metabolic activity patterns in refractory melancholic major depression. AB - Although in treatment-resistant depression (TRD) subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) is frequently used to examine deregulated brain networks, neurobiological data from other sources may be required to interpret these FC findings. In 16 melancholic TRD patients with a high level of treatment resistance and 16 closely matched healthy never-depressed individuals we verified whether sgACC FC patterns were related to regional metabolic activity (CMRglc) with 18FDG PET imaging. Notwithstanding that TRD patients displayed stronger sgACC FC with the right lateral frontotemporal cortex, metabolically they exhibited the opposite pattern. Our results indicate that the sgACC seed and its functionally connected regions not automatically follow a similar metabolic pattern in TRD, possibly reflecting the refractory state of the sample. Multimodal brain imaging may help to increase our insight into the pathophysiology of TRD. PMID- 30519996 TI - White matter microstructure varies with post-traumatic stress severity following medical trauma. AB - The prefrontal cortex, amygdala, hippocampus, and hypothalamus are important components of the neural network that mediates the healthy learning, expression, and regulation of emotion. These brain regions are connected by white matter pathways that include the cingulum bundle, uncinate fasciculus, and fornix/stria terminalis. Individuals with trauma and stress-related disorders show dysfunction of the cognitive-affective processes supported by the brain regions these white matter tracts connect. Therefore, variability in the microstructure of these white matter pathways may play an important role in the cognitive-affective dysfunction related to post-traumatic stress disorder. Thus, the current study used diffusion weighted imaging to assess the white matter microstructure of the cingulum bundle, uncinate fasciculus, and fornix/stria terminalis acutely (< 1 month) following trauma. Further, we assessed both acute (i.e., < 1 month) and subacute (i.e., 3 months post-trauma) post-traumatic stress symptom severity. White matter microstructure (assessed < 1 month post-trauma) of the uncinate fasciculus and fornix/stria terminalis varied with acute post-traumatic stress severity (assessed < 1 month post-trauma). Further, white matter microstructure (assessed < 1 month post-trauma) of the cingulum bundle and fornix/stria terminalis varied with subacute post-traumatic stress severity (assessed 3 months post-trauma). The current results suggest white matter architecture of the prefrontal cortex - amygdala network plays an important role in the development of trauma and stress-related disorders. PMID- 30519997 TI - Effect of blast-related mTBI on the working memory system: a resting state fMRI study. AB - Reduced working memory is frequently reported by Veterans with a history of blast related mild traumatic brain injury (mTBI), but can be difficult to quantify on neuropsychological measures. This study aimed to improve our understanding of the impact of blast-related mTBI on the working memory system by using resting state functional magnetic resonance imaging (fMRI) to explore differences in functional connectivity between OEF/OIF/OND Veterans with and without a history of mTBI. Participants were twenty-four Veterans with a history of blast-related mTBI and 17 Veterans who were deployed but had no lifetime history of TBI. Working memory ability was evaluated with the Auditory Consonants Trigrams (ACT) task. Resting state fMRI was used to evaluate intrinsic functional connectivity from frontal seed regions that are known components of the working memory network. No significant group differences were found on the ACT, but the imaging analyses revealed widespread hyper-connectivity from the frontal seed regions in the Veterans with a history of mTBI relative to the deployed control group. Further, within the mTBI group, but not the control group, better performance on the ACT was associated with increased functional connectivity to multiple brain regions, including cerebellar components of the working memory network. These results were present after controlling for age, PTSD symptoms, and estimated premorbid IQ, and suggest that long-term alterations in the functional connectivity of the working memory network following blast-related mTBI may reflect a compensatory change that contributes to intact performance on an objective measure of working memory. PMID- 30519998 TI - Morphological changes in subregions of hippocampus and amygdala in major depressive disorder patients. AB - Despite many neuroimaging studies in the past years, the neuroanatomical substrates of major depressive disorder (MDD) subcortical structures are still not well understood. Since hippocampus and amygdala are the two vital subcortical structures that most susceptible to MDD, finding the evidence of morphological changes in their subregions may bring some new insights for MDD research. Combining structural magnetic resonance imaging (MRI) with novel morphometry analysis methods, we recruited 25 MDD patients and 28 healthy controls (HC), and investigated their volume and morphological differences in hippocampus and amygdala. Relative to volumetric method, our methods detected more significant global morphological atrophies (p<0.05). More precisely, subiculum and cornu ammonis (CA) 1 subregions of bilateral hippocampus, lateral (LA) and basolateral ventromedial (BLVM) of left amygdala and LA, BLVM, central (CE), amygdalostriatal transition area (ASTR), anterior cortical (ACO) and anterior amygdaloid area (AAA) of right amygdala were demonstrated prone to atrophy. Correlation analyses between each subject's surface eigenvalues and Hamilton Depression Scale (HAMD) were then performed. Correlation results showed that atrophy areas in hippocampus and amygdala have slight tendencies of expanding into other subregions with the development of MDD. Finally, we performed group morphometric analysis and drew the atrophy and expansion areas between MDD-Medicated group (only 19 medicated subjects in MDD group were included) and HC group, found some preliminary evidence about subregional morphological resilience of hippocampus and amygdala. These findings revealed new pathophysiologic patterns in the subregions of hippocampus and amygdala, which can help with subsequent smaller-scale MDD research. PMID- 30519999 TI - Multilevel diffusion tensor imaging classification technique for characterizing neurobehavioral disorders. AB - This proposed novel method consists of three levels of analyses of diffusion tensor imaging data: 1) voxel level analysis of fractional anisotropy of white matter tracks, 2) connection level analysis, based on fiber tracks between specific brain regions, and 3) network level analysis, based connections among multiple brain regions. Machine-learning techniques of (Fisher score) feature selection, (Support Vector Machine) pattern classification, and (Leave-one-out) cross-validation are performed, for recognition of the neural connectivity patterns for diagnostic purposes. For validation proposes, this multilevel approach achieved an average classification accuracy of 90% between Alzheimer's disease and healthy controls, 83% between Alzheimer's disease and mild cognitive impairment, and 83% between mild cognitive impairment and healthy controls. The results indicate that the multilevel diffusion tensor imaging approach used in this analysis is a potential diagnostic tool for clinical evaluations of brain disorders. The presented pipeline is now available as a tool for scientifically applications in a broad range of studies from both clinical and behavioral spectrum, which includes studies about autism, dyslexia, schizophrenia, dementia, motor body performance, among others. PMID- 30520000 TI - Reducing Drug Wastage in Pharmaceuticals Dosed by Weight or Body Surface Areas by Optimising Vial Sizes. AB - BACKGROUND: When pharmaceuticals are administered based on patient characteristics (for example weight or body surface area), an amount of product will be unused and must be disposed of. This wastage represents inefficiency and can distort decision making. METHODS: We present a method for the analysis of optimum fill volumes of pharmaceuticals to minimise wastage across a patient population, using publicly available data. Wastage for patients at each 'step' e.g. by kg of bodyweight is calculated, the frequency of each of these steps in the structure of the population is then estimated using the method of moments, with wastage then estimated for each 'step' multiplied by its prevalence. Illustrative examples of pembrolizumab and cabazitaxel show how wastage could be reduced using UK population data, whilst simultaneously reducing administrative burden. RESULTS: Changing the available vial sizes for pembrolizumab (available as 50 mg/100 mg vials) to 70 mg/100 mg, wastage could be cut from 13.3% to 8.7%. For cabazitaxel (only 60 mg vials available), increasing the fill to 70 mg could reduce wastage from 19.4% to 18.8%, or alternatively, adding a 12.5 mg vial reduce this to 6.5%. A secondary finding is that wastage is higher when the larger vial size is perfectly divisible by the smaller vial size. CONCLUSIONS: Reductions in wastage have the potential to reduce the cost of manufacturing medicines, which is not necessarily low for novel products. These cost reductions could lead to increased profit (at the same prices), constant profit with a better return rate (at lower prices), or a combination of the two. Most importantly, they would improve the efficiency of the health-care sector, increasing funding available to treat patients. PMID- 30520001 TI - Population Pharmacokinetics, Safety and Tolerability of Extended-Release Bupropion and Its Three Metabolites in Chinese Healthy Volunteers. AB - BACKGROUND AND OBJECTIVE: Bupropion is used for the treatment of major depressive disorder. We determined the pharmacokinetics, safety, and tolerability of extended-release bupropion XL in healthy Chinese volunteers. METHODS: This open label, single-center pharmacokinetic study was conducted between May 2016 and June 2016. Eligible volunteers received bupropion XL 150 mg once daily for 5 days, then 300 mg once daily from days 6 to 14. Pharmacokinetic parameters were evaluated after first and repeated doses by non-compartmental and population pharmacokinetic analyses. RESULTS: Fifteen out of 16 enrolled volunteers completed the study. The geometric mean of the bupropion area under the concentration-time curve from 0 to 24 h (AUC0-24) was 498.2 and 1,165.7 h.ng/mL on days 1 and 14, respectively; maximum plasma concentration (Cmax) was 49.9 ng/mL on day 1 and steady-state maximum observed plasma concentration (Css_max) was 111.9 ng/mL on day 14. Among the three metabolites, hydroxybupropion showed the highest AUC0-24 and Cmax. The population pharmacokinetic model findings indicated an apparent oral clearance of 221 L/h for bupropion in a typical healthy 60.9-kg Chinese volunteer. CONCLUSIONS: This was the first pharmacokinetic study for bupropion XL and its active metabolites in the Chinese population. The AUC and Cmax of bupropion XL and its three metabolites increased approximately in a dose-proportional manner with an increase from 150 mg to 300 mg. Adverse events were similar to those reported in studies outside China. A population pharmacokinetic model was developed for bupropion XL, with pharmacokinetics of bupropion adequately described by a two-compartment model with first-order absorption and linear elimination plus lag time. TRIAL REGISTRATION NUMBER: NCT02698553. PMID- 30520002 TI - Racial and Ethnic Trends in Prostate Cancer Incidence and Mortality in Philadelphia, PA: an Observational Study. AB - BACKGROUND: To learn more about local prostate cancer (PCa) disparities, we conducted descriptive analyses of the role of race and age in PCa using the Pennsylvania Cancer Registry data for Philadelphia (2005-2014). METHODS: We focused on the most prevalent race/ethnic groups: white (33%), black (44%), and Hispanic (9%). Outcomes included PCa rates, tumor stage, and tumor grade. Percent change was used to describe changes in age-adjusted incidence and mortality rates. Frequency tables and logistic regression models were used to describe trends in proportions of advanced PCa by race and time. Race-by-time interaction terms were retained in the models if statistically significant. RESULTS: PCa incidence was highest for black men over time. Incidence rates declined over time for all race groups (- 28% for white men to - 38% for Hispanic men). PCa mortality rates declined in a less universal manner (- 5% for blacks to - 32% for whites). Each year, odds increased across all race groups for advanced tumor stage (4% each year among white and Hispanic men and 9% each year among black men) and for advanced tumor grade (4% each year among white and black men and 23% each year among Hispanic men). Among younger men, black men experienced significantly increased odds of advanced tumor stage each year (8%) and Hispanics experienced significantly increased odds of advanced tumor grade each year (30%). CONCLUSIONS: Black men remain at highest PCa risk relative to other racial/ethnic groups in Philadelphia. Younger black and Hispanic men are at particular risk for advanced PCa at diagnosis. PMID- 30520003 TI - Optimizing Trajectories for Cranial Laser Interstitial Thermal Therapy Using Computer-Assisted Planning: A Machine Learning Approach. AB - Laser interstitial thermal therapy (LITT) is an alternative to open surgery for drug-resistant focal mesial temporal lobe epilepsy (MTLE). Studies suggest maximal ablation of the mesial hippocampal head and amygdalohippocampal complex (AHC) improves seizure freedom rates while better neuropsychological outcomes are associated with sparing of the parahippocampal gyrus (PHG). Optimal trajectories avoid sulci and CSF cavities and maximize distance from vasculature. Computer assisted planning (CAP) improves these metrics, but the combination of entry and target zones has yet to be determined to maximize ablation of the AHC while sparing the PHG. We apply a machine learning approach to predict entry and target parameters and utilize these for CAP. Ten patients with hippocampal sclerosis were identified from a prospectively managed database. CAP LITT trajectories were generated using entry regions that include the inferior occipital, middle occipital, inferior temporal, and middle temporal gyri. Target points were varied by sequential AHC erosions and transformations of the centroid of the amygdala. A total of 7600 trajectories were generated, and ablation volumes of the AHC and PHG were calculated. Two machine learning approaches (random forest and linear regression) were investigated to predict composite ablation scores and determine entry and target point combinations that maximize ablation of the AHC while sparing the PHG. Random forest and linear regression predictions had a high correlation with the calculated values in the test set (rho = 0.7) for both methods. Maximal composite ablation scores were associated with entry points around the junction of the inferior occipital, middle occipital, and middle temporal gyri. The optimal target point was the anteromesial amygdala. These parameters were then used with CAP to generate clinically feasible trajectories that optimize safety metrics. Machine learning techniques accurately predict composite ablation score. Prospective studies are required to determine if this improves seizure-free outcome while reducing neuropsychological morbidity following LITT for MTLE. PMID- 30520004 TI - The effects of five types of tea solutions on epiboly process, neural and cardiovascular development, and locomotor capacity of zebrafish. AB - The effects of teas on embryonic development are still known little. The objective of this study was to compare and analyze developmental effects of green tea, delicate flavor oolong tea, strong flavor oolong tea, black tea, and pu'er tea using zebrafish embryos. Embryos were exposed in tea solutions from one-cell stage; the morphology, locomotor capacity, and gene expression of embryos or larvae were analyzed. The results showed that either tea could decrease the length of body and the size of head and eyes. The effect of green tea had the most significant effects on morphology. Only green tea disturbed cell movement, epiboly, and nervous system development. All five tea solutions caused heart structure alternations and lowered heart rates, and effects caused by green tea were severe. Green tea inhibited the formation of dorsal aorta and segmental arteries and decreased the velocity and total movement distance of larvae. In conclusion, the toxicity of green tea to epiboly, neural and cardiovascular development, and locomotor capacity is more severe than that of other teas. Our study played a warning role for safety consumption of teas and provided references for further study of tea's physiological and pharmacological effects and biological activity. PMID- 30520005 TI - Berberis lycium Royle fruit extract mitigates oxi-inflammatory stress by suppressing NF-kappaB/MAPK signalling cascade in activated macrophages and Treg proliferation in splenic lymphocytes. AB - Although Berberis plant species have been advocated as immune modulators, information regarding their mechanism(s) of action is limited. Therefore, in the present study we assessed the efficacy of Berberis lycium Royle fruit extract (BLFE) in the attenuation of lipopolysaccharide (LPS)-induced oxi-inflammatory aggravation and concanavalin A (Con-A)-induced proliferation in murine peritoneal macrophages and lymphocytes, respectively. BLFE strongly suppressed production of the oxidative and inflammatory effector molecules nitric oxide (NO), reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), inflammatory cytokines (TNF-alpha/IL-6/IL-1beta/IFN-gamma) as well as chemokines (MCP-1 and RANTES), with a concomitant enhancement in heme oxygenase-1 (HO-1) and IL-10 levels. Subsequent mechanistic analysis revealed that BLFE strongly inhibited the phosphorylation of IkappaBalpha as well as MAPKs such as extracellular signal regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal kinase (JNK), thereby directly resulting in the suppression of nuclear factor-kappaB (NF-KB) and c-Jun activation, ultimately culminating in the observed attenuation of inflammatory molecules. Additionally, BLFE appeared to mitigate Con-A-induced proliferation of Tregs (CD3+ CD4+ CD25+) thereby suggesting its modulatory effects on adaptive immune cells. UPLC-DAD-ESI-QTOF-MS/MS of BLFE revealed the presence of major bioactive phenolics and alkaloids including chlorogenic acid, rutin, catechin and quercetin 3-D-galactoside, berberine and magnoflorine, which could have synergistically contributed to the above findings. Overall, this work provides evidence that BLFE may be effective in the mitigation of inflammatory disorders, especially those associated with NF-kappaB/MAPK activation. PMID- 30520006 TI - Automated segmentation of trabecular and cortical bone from proton density weighted MRI of the knee. AB - Patient-specific implant design and pre- and intra-operative planning is becoming increasingly important in the orthopaedic field. For clinical feasibility of these techniques, fast and accurate segmentation of bone structures from MRI is essential. However, manual segmentation is time intensive and subject to inter- and intra-observer variation. The challenge in developing automatic segmentation algorithms for MRI data mainly exists in the inhomogeneity problem and the low contrast among cortical bone and adjacent tissues. In this paper, we proposed a method for automatic segmentation of knee bone structures for MRI data with a 3D local intensity clustering-based level set and a novel approach to determine the cortical boundary utilizing the normal vector of the trabecular surface. Application to clinical imaging data shows that our method is robust to MRI inhomogeneity. In comparing our method to manual segmentation in 18 femurs and tibiae, we found a dice similarity coefficient (DSC) of 0.9611 +/- 0.0052 for the femurs and 0.9591 +/- 0.0173 for tibiae. The average surface distance error was 0.4649 +/- 0.1430 mm for the femurs and 0.4712 +/- 0.2113 mm for the tibiae. The results of the automatic technique thus strongly corresponded to the manual segmentation using less than 3% of the time and with virtually no workload. Graphical abstract ?. PMID- 30520007 TI - Improving Soluble Expression of Tyrosine Decarboxylase from Lactobacillus brevis for Tyramine Synthesis with High Total Turnover Number. AB - The soluble expression of tyrosine decarboxylase (TDC) in heterologous host is often challenging. Here, acidic condition was found to be favorable for improving the soluble expression of TDC from Lactobacillus brevis in Escherichia coli, while addition of carbohydrates (such as glucose, arabinose, and fructose) was vital for decreasing the insoluble fraction. By simple pH control and addition of glucose, the specific activity of TDC in crude extract was enhanced to 46.3 U mg 1, 3.67-fold of that produced from LB medium. Optimization of the reaction conditions revealed that Tween-80 was effective in improving the tyramine production catalyzed by TDC, especially at high tyrosine loadings. As much as 400 mM tyrosine could be completely converted into tyramine with a substrate to catalyst ratio of 29.0 g g-1 and total turnover number of 23,300. This study provides efficient strategies for the highly soluble expression of TDC and biocatalytic production of tyramine. PMID- 30520008 TI - Examining HPV Vaccination Practices and Differences Among Providers in Virginia. AB - Virginia has some of the lowest HPV vaccination rates, despite being one of the few states in the USA requiring adolescent girls receive the vaccine. Provider characteristics may be an important factor in HPV vaccination. Thus, the present study assessed provider vaccination, practices, knowledge about the vaccine, and confidence in performing behaviors related to the vaccine. We conducted a cross sectional electronic survey in a large health care system in Northern Virginia. A total of 53 responses were received. Only respondents who reported seeing adolescent patients were included in analyses (N = 42). Differences in responses were examined by provider age, gender, and type. Respondents reported recommending the vaccine a high percent of the time to eligible patients and had overall high levels of knowledge and confidence. Male providers recommended the vaccine to boys ages 11-12, less frequently than female providers. Providers age 50 and over recommended the vaccine to boys ages 11-12 less frequently than younger providers. This study shows that there are some gaps in HPV vaccine recommendation practices among providers. These gaps may be one reason for the low uptake of the HPV vaccine among adolescents. Thus, educational and training interventions of providers could be considered. PMID- 30520009 TI - Dynamic distractor environments reveal classic visual field anisotropies for judgments of temporal order. AB - Numerous studies have shown that visual performance critically depends on the stimulus' projected retinal location. For example, performance tends to be better along the horizontal relative to the vertical meridian (lateral anisotropy). Another case is the so-called upper-lower anisotropy, whereby performance is better in the upper relative to the lower hemifield. This study investigates whether temporal order judgments (TOJs) are subject to these visual field constraints. In Experiments 1 and 2, subjects reported the temporal order of two disks located along the horizontal or vertical meridians. Each target disk was surrounded by 10 black and white distractor disks, whose polarity remained unchanged (static condition) or reversed throughout the trial (dynamic condition). Results indicate that the mere presence of dynamic distractors elevated thresholds by more than a factor of four and that this elevation was particularly pronounced along the vertical meridian, evidencing the lateral anisotropy. In Experiment 3, thresholds were compared in upper, lower, left, and right visual hemifields. Results show that the threshold elevation caused by dynamic distractors was greatest in the upper visual field, demonstrating an upper-lower anisotropy. Critically, these anisotropies were evident exclusively in dynamic distractor conditions suggesting that distinct processes govern TOJ performance under these different contextual conditions. We propose that whereas standard TOJs are processed by fast low-order motion mechanisms, the presence of dynamic distractors mask these low-order motion signals, forcing observers to rely more heavily on more sluggish higher order motion processes. PMID- 30520010 TI - Modified Hinderer's Technique for Serious Proximal Hypospadias with Ventral Curvature: Outcomes and Our Experience. AB - PURPOSE: Hypospadias is a congenital anomaly that includes defi-cient ventral structure of the penis. Proximal hypospadias cases make up 20% of all hypospadias cases. The choice of operative technique for hypospadias repair depends on the severity, and it is influenced by the surgeon's experience and perception of where priorities should lie. Several other factors interact to determine the type of repair, such as meatal site, presence of chordee, availability of the prepuce, and quality of the urethral plate and in addition surgeon's experience effects the type of repair. MATERIALS AND METHODS: The treatment records of 42 penoscrotal and perineal hypospadias cases that were treated in our clinic from 1998 to 2017 were reviewed retrospectively. Cases with penoscrotal, and prineal meatus were included in the study at the beginning of the urethroplasty. All cases had surgical intervention via Hinderer's technique. RESULTS: Acceptable cosmetic results were obtained in 37 (85%) patients with an objective scoring system (HOSE) for evaluating the results of hypospadias surgery score. The mean score after surgery was 14.8. Fistula and wound breakdown occurred in 7 out of the 42 cases. CONCLUSION: In conclusion, the modified Hinderer's technique is a safe and reliable technique for both proximal and perineal hypospadias. Low complication rates and application in a single surgical session increase the comfort of both the patient and the surgeon. PMID- 30520011 TI - Adaptation, chance, and history in experimental evolutionary reversals to unicellularity. AB - Evolution is often deemed irreversible. The evolution of complex traits that require many mutations makes their reversal unlikely. Even in simpler traits, reversals might become less likely as neutral or beneficial mutations, with deleterious effects in the ancestral context, become fixed in the novel background. This is especially true in changes that involve large re organizations of the organism and its interactions with the environment. The evolution of multicellularity involves the reorganization of previously autonomous cells into a more complex organism; despite the complexity of this change, single cells have repeatedly evolved from multicellular ancestors. These repeated reversals to unicellularity undermine the generality of Dollo's law. In this paper we evaluated the dynamics of reversals to unicellularity from recently evolved multicellular phenotypes of the brewers yeast Saccharomyces cerevisae. Even though multicellularity in this system evolved recently, it involves the evolution of new levels of selection. Strong selective pressures against multicellularity lead to rapid reversibility to single cells in all of our replicate lines, whereas counterselection favoring multicellularity led to minimal reductions to the rates of reversal. History and chance played an important role in the tempo and mode of reversibility, highlighting the interplay of deterministic and stochastic events in evolutionary reversals. This article is protected by copyright. All rights reserved. PMID- 30520012 TI - Lipid Lowering and Incidence of Cataract, a Role for Fibrates. AB - Cataract is a pathological eye condition with loss of lens transparency. Age related cataract is the most common type in adults, and opacity is believed to result from oxidative stress. According to estimates by the World Health Organization, cataract affects ~100 million people worldwide. There has been discussion on the role of lipid-lowering drugs in inducing cataract. Herein, we comment on an article suggesting a role for fibrates. PMID- 30520013 TI - Doubling rituximab in high-risk patients with aggressive B-cell lymphoma -results of the DENSE-R-MegaCHOEP trial. AB - To further improve outcome in young high-risk patients with diffuse large B-cell lymphoma (DLBCL) the number of rituximab (R) infusions was doubled in combination with standard CHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) chemotherapy. Seventy-seven patients (aged 18-60 years) with an age adjusted International Prognostic Index of 2-3 received 12 * R (375 mg/m2 ) on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85 and 99 together with eight cycles of CHOEP-14. Results were retrospectively compared to those of patients receiving 6 * R and 8 * CHOEP-14 in the standard arm of the randomized R-MegaCHOEP trial. Two year overall survival (OS) was 82% [95% confidence interval (CI) 73%-92%]; 2-year event-free (EFS) and progression-free survival (PFS) was 69% (95% CI 59-80%) and 76% (95% CI 66%--6%), respectively. Comparing 12 to six doses of R revealed no differences (univariate/multivariate) in EFS (at 2 years: 69% vs. 71%), PFS (76% vs. 75%) and OS (82% vs. 85%), with P = 0.766, P = 0.871 and P = 0.843, respectively. Doubling the number of R infusions concomitant to CHOEP did not improve treatment outcomes. Nonetheless, OS and PFS of young high-risk patients who received only six infusions of R combined with CHOEP remain excellent and were confirmed in an independent cohort of patients. PMID- 30520014 TI - Supplemental oxygen and hyperoxemia in trauma patients: A prospective, observational study. AB - BACKGROUND: Supplemental oxygen is recommended during the initial treatment of trauma patients according to several guidelines, but the supporting evidence is sparse. We aimed to describe the use of supplemental oxygen and occurrence of hyperoxemia in the initial phase of trauma management at two level 1 trauma centers, TC1 and TC2. METHODS: In this prospective, observational study we included trauma patients >=16 years of age. Data on pre- and in-hospital supplemental oxygen, arterial oxygen tension (PaO2 ), and outcomes (in-hospital mortality, hospital- and intensive care unit length of stay) were collected. RESULTS: We included 56 patients. There were 22 (39%) females with a mean age of 49 years (SD: 18) and a median Injury Severity Score of 9 (IQR: 4-14, n = 49). A total of 23 (45%) out of 51 spontaneously breathing patients received pre hospital supplemental oxygen, but did not differ significantly from the patients that did not receive supplemental oxygen. In-hospital, 29 (59%) out of 49 spontaneously breathing patients received supplemental oxygen. The median PaO2 was 26.5 kPa [IQR: 22.2-34.1] in four intubated patients and 12.3 kPa [IQR: 9.7 25.7] in eight patients with spontaneous respiration on supplemental oxygen. At TC1 a significantly greater proportion of spontaneously breathing patients received both pre-hospital (TC1: 18 [64%]; TC2: 5 [21%], P = 0.002) and in hospital (TC1: 24 [92%]; TC2: 7 [30%], P < 0.001) supplemental oxygen. CONCLUSION: Approximately 50% of trauma patients received supplemental oxygen during the initial treatment. Hyperoxemia was a common finding for patients treated with supplemental oxygen, and it was more pronounced in intubated patients. PMID- 30520015 TI - Revisiting CLEC12A as leukaemic stem cell marker in AML: highlighting the necessity of precision diagnostics in patients eligible for targeted therapy. AB - Targeted therapy directed against rare disease-propagating leukaemic stem cells (LSCs) is a promising prospect for improving the outcome of acute myeloid leukaemia (AML) patients. Thus, distinguishing LSCs from normal haematopoietic stem and progenitor cells (HSPCs) is essential. The CLEC12A receptor has been proposed as a specific marker of LSCs, and consequently as an appealing treatment target. To explore the role of CLEC12A in further detail, we investigated whether a sorting strategy based on the activity of aldehyde dehydrogenase and CLEC12A expression could separate residual normal HSPCs from LSCs in bone marrow from 5 AML patients. We demonstrate that this distinction was possible in 2/5 cases, however with evidence of pre-leukaemic mutations in the CLEC12A- stem cells in one case. In contrast, cytogenetic and/or molecular aberrations were detected in both the CLEC12A+/- cell subsets in 3/5 AML cases studied. Furthermore, targeted next generation sequencing (NGS) of the sorted cell subsets revealed a pronounced clonal heterogeneity in the CLEC12A- cells suggestive of the leukaemia often originating in this immature cell subset. In conclusion, we provide proof-of concept that precision diagnostics employing targeted cytogenetic/NGS-based analyses on highly purified cell subsets could be a powerful tool for selecting patients eligible for LSC-directed therapy. PMID- 30520016 TI - Impact of systemic and tumor lipid metabolism on everolimus efficacy in advanced pancreatic neuroendocrine tumors (pNETs). AB - The mTOR inhibitor everolimus is effective against advanced pancreatic neuroendocrine tumors (pNETs). However, it can cause metabolic adverse events, such as hyperglycemia, hypertriglyceridemia and hypercholesterolemia. In this work we aimed at evaluating the impact of systemic and tumor lipid metabolism on everolimus efficacy. We carried out a monocentric, retrospective study to correlate plasma triglyceride and cholesterol levels with the progression free survival (PFS) of advanced pNET patients treated with everolimus. In formalin fixed, paraffin embedded (FFPE) tumor specimens, we also assessed by mRNA quantification and immunohistochemistry the expression of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), two enzymes crucially involved in fatty acid biosynthesis, and we analyzed their impact on PFS. We evaluated 58 consecutive pNET patients who started everolimus between December 2006 and January 2015. Patients with higher plasma triglycerides during the first three months of treatment had an increased risk of disease progression (aHR 3.08, 95% CIs 1.15-8.21; p = 0.025). In 23 FFPE tumor specimens amenable for IHC evaluations, we found a positive correlation between ACC1 and FASN at both mRNA (r = 0.87, p = 0.00045) and protein (r = 0.68, p = 0.0004) level. Patients with higher ACC1 protein expression in metastatic lesions had significantly lower PFS when compared to patients with lower ACC1 levels (5.5 vs 36 months; aHR 4.49, 95% CIs 1.08-18.72; p = 0.039). In conclusion, systemic and tumor lipid metabolism are associated with the PFS of everolimus-treated patients with advanced pNETs; based on these findings, dietary and pharmacological interventions targeting lipid metabolism could improve everolimus efficacy in this patient population. Pancreatic neuroendocrine tumors (pNETs) are highly heterogeneous, so to improve treatment, it's critical to learn more about how different tumor types respond to therapy. The mTOR inhibitor everolimus is a standard therapy for pNETs. Here, the authors conducted a retrospective study to evaluate how circulating triglyceride and cholesterol levels affect the efficacy of everolimus. Patients with higher plasma triglyceride levels at the start of treatment, they found, had worse outcomes. In addition, they noted a correlation between disease progression and higher intratumoral levels of ACC1, a key enzyme in fatty acid biosynthesis. This article is protected by copyright. All rights reserved. PMID- 30520017 TI - Adductor canal block with a suture-method catheter - A parallel or perpendicular approach? AB - BACKGROUND: We performed a randomised blinded pilot study in 16 healthy volunteers to assess whether placing a suture-method catheter in the adductor canal is feasible with two different insertion techniques. METHODS: Each volunteer had a suture-method catheter placed approximately halfway between the superior anterior iliac spine and base of the patella in both legs. Catheters were placed using a parallel technique in one leg and a perpendicular technique in the other leg, according to randomisation. 15 mL lidocaine 1% was injected in each catheter. Successful placement was defined as loss of cold sensation in the saphenous area 30 min after injection. Volunteers were sent home and returned the following day and another dose of lidocaine (15 mL, 1%) was injected through the catheters. Catheter displacement distance was assessed by ultrasound and cold sensation was assessed. In case of preserved cold sensation, we attempted to reposition the catheter with a subsequent injection of lidocaine and reassessment of cold sensation. RESULTS: All primary placements were successful using the perpendicular approach (100%; 95% CI 81%-100%) whereas one placement failed using the parallel approach (94%; 95% CI 72%-99%). Three catheters placed using the perpendicular approach were displaced on day 2, compared to one catheter placed with the parallel approach. Displacement distance was highly variable. All catheters, except one, could be repositioned. Three volunteers reported transient sensory deficits lasting approximately 6-8 weeks. CONCLUSION: The suture-method catheter can be placed in the adductor canal with high success rates for initial placement with both techniques. PMID- 30520018 TI - Induction response criteria in acute myeloid leukaemia: implications of a flow cytometric measurable residual disease negative test in refractory adults. PMID- 30520019 TI - Efficacy of inpatient psychotherapy for major depressive disorder: A meta analysis of controlled trials. AB - OBJECTIVE: This meta-analysis investigates the efficacy of inpatient psychotherapy in major depressive disorders compared to control conditions. METHODS: In total, 14 studies were entered into the meta-analysis with a total of 1.080 patients. Primary outcome were the standardized mean differences in self rated depression outcomes. A priori planned subgroup analyses included the influence of different control conditions (a) no psychiatric inpatient treatment (e.g., wait-list control), b) treatment as usual (TAU; e.g., non-manualized clinical management), c) TAU determined by study design (manualized/'placebo' control condition), as well as number of sessions and influence of self vs. clinician ratings. RESULTS: The meta-analysis of19 available comparisons resulted in a moderate pooled effect size showing a small and statistically significant benefit of the psychotherapeutic intervention over control conditions(g = 0.24, p< 0.001, I2 = 0%). This corresponds to a number-needed-to-treat of 7.4. The effects of the interventions were stable over 12-month follow-up (g = 0.21, p< 0.01, I2 = 30%). Comparisons with waitlist or non-standardized control treatments tended to be associated with larger effect sizes than standardized control treatments. CONCLUSIONS: Despite some limitations (small number of studies), this meta-analysis provides evidence for a small but sustained effect of inpatient psychotherapy in patients with MDD. This article is protected by copyright. All rights reserved. PMID- 30520021 TI - Abortion by telemedicine in the European Union. AB - This paper analyses an important set of legal issues raised by the telemedical provision of abortion pills. Focusing on the case of European Union (EU) law, it suggests that a properly accredited doctor seeking to treat a patient with abortion pills is entitled, in principle, to rely on EU rules of free movement to protect their access to patients in other member states, and women facing unwanted pregnancies likewise have legal rights to access the services thus offered. EU countries seeking to claim an exception to those rules on the basis of public health or the protection of a fundamental public policy interest (here, the protection of fetal life) will face significant barriers. This article is protected by copyright. All rights reserved. PMID- 30520020 TI - Genetic profiling of basal cell carcinomas detects postzygotic mosaicism in basal cell naevus syndrome. AB - Basal cell naevus syndrome (BCNS) is associated with germline mutations in the PTCH1 gene. Postzygotic mosaicism can also cause BCNS. Here we describe two patients, one with multiple basal cell carcinomas (BCCs) and one with clinical BCNS, who had no PTCH1 mutation in DNA extracted from blood. In both patients, we performed genetic analysis on different BCCs, revealing the presence of a shared PTCH1 mutation in all tumours. Our findings show that in patients with symptoms of BCNS and initial absence of a PTCH1 mutation in blood, genetic profiling of BCCs can detect postzygotic mosaicism. PMID- 30520022 TI - Nanoparticle-biomolecular corona: A new approach for the early detection of non small-cell lung cancer. AB - Lung cancer (LC) is the most common type of cancer and the second cause of death worldwide in men and women after cardiovascular diseases. Non-small-cell lung cancer (NSCLC) is the most frequent type of LC occurring in 85% of cases. Developing new methods for early detection of NSCLC could substantially increase the chances of survival and, therefore, is an urgent task for current research. Nowadays, explosion in nanotechnology offers unprecedented opportunities for therapeutics and diagnosis applications. In this context, exploiting the bio-nano interactions between nanoparticles (NPs) and biological fluids is an emerging field of research. Upon contact with biofluids, NPs are covered by a biomolecular coating referred to as "biomolecular corona" (BC). In this study, we exploited BC for discriminating between NSCLC patients and healthy volunteers. Blood samples from 10 NSCLC patients and 5 subjects without malignancy were allowed to interact with negatively charged lipid NPs, leading to the formation of a BC at the NP surface. After isolation, BCs were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). We found that the BCs of NSCLC patients was significantly different from that of healthy individuals. Statistical analysis of SDS-PAGE results allowed discriminating between NSCLC cancer patients and healthy subjects with 80% specificity, 80% sensitivity and a total discriminate correctness rate of 80%. While the results of the present investigation cannot be conclusive due to the small size of the data set, we have shown that exploitation of the BC is a promising approach for the early diagnosis of NSCLC. PMID- 30520024 TI - IJGO: Committed to research capacity strengthening. PMID- 30520023 TI - Alive or dead: Validity of the Social Security Administration Death Master File after 2011. AB - OBJECTIVE: To determine the reliability of the Social Security Death Master File (DMF) after the November 2011 changes limiting the inclusion of state records. DATA SOURCES: Secondary data from the DMF, New York State (NYS) and New Jersey (NJ) Vital Statistics (VS), and institutional data warehouse. STUDY DESIGN: Retrospective study. Two cohorts: discharge date before November 1, 2011, (pre 2011) or after (post-2011). Death in-hospital used as gold standard. NYS VS used for out-of-hospital death. Sensitivity, specificity, Cohen's Kappa, and 1-year survival calculated. DATA COLLECTION METHODS: Patients matched to DMF using Social Security Number, or date of birth and Soundex algorithm. Patients matched to NY and NJ VS using probabilistic linking. PRINCIPAL FINDINGS: 97 069 patients January 2007-March 2016: 39 075 pre-2011; 57 994 post-2011. 3777 (3.9 percent) died in-hospital. DMF sensitivity for in-hospital death 88.9 percent (kappa = 0.93) pre-2011 vs 14.8 percent (kappa = 0.25) post-2011. DMF sensitivity for NY deaths 74.6 percent (kappa = 0.71) pre-2011 vs 26.6 percent (kappa = 0.33) post 2011. DMF sensitivity for NJ deaths 62.6 percent (kappa = 0.64) pre-2011 vs 10.8 percent (kappa = 0.15) post-2011. DMF sensitivity for out-of-hospital death 71.4 percent pre-2011 (kappa = 0.58) vs 28.9 percent post-2011 (kappa = 0.34). Post 2011, 1-year survival using DMF data was overestimated at 95.8 percent, vs 86.1 percent using NYS VS. CONCLUSIONS: The DMF is no longer a reliable source of death data. Researchers using the DMF may underestimate mortality. PMID- 30520025 TI - Cochrane crisis: secrecy, intolerance, and evidence-based values. AB - The Cochrane Collaboration was launched in 1993 with great enthusiasm. It aimed to offer a volunteer-based, community-strong, independent, and critical effort for materializing the goals of evidence-based medicine worldwide through the production of high-quality, rigorous systematic reviews (1). In the next quarter of a century, the effort did accomplish an enormous amount and its members should be proud of their achievements. The quality, depth, and breadth of expertise of the people involved in this collaborative endeavor is unmatched. Cochrane systematic reviews gained a well-deserved reputation of excellence (2). This article is protected by copyright. All rights reserved. PMID- 30520027 TI - Quality-based ratings in Medicare and trends in kidney transplantation. AB - OBJECTIVE: To assess the relationship between the 2007 Medicare regulation enforcing quality standards for transplant centers and trends in kidney transplantation. DATA SOURCES: Transplant centers' biannual reports and the national registry for kidney transplantation from 2003 to 2010. STUDY DESIGN: Non compliant (low-performing) centers were compared with centers in compliance with quality standards according to: number of transplants, waiting-list registrations, and rates of graft failures, transfers, and deaths. Multivariate regressions were estimated to evaluate the association between the regulation and transplantation outcomes. DATA EXTRACTION METHODS: Patient characteristics and outcomes were aggregated to six-month periods and linked to centers' reports. PRINCIPAL FINDINGS: Relative to average-performing centers, 12 percent of transplants shifted away from low-performing centers and high-performing centers captured 6 percent of this decline. Low-performing centers experienced a 2 percentage point per period decline in 1-year graft failure rates and a 15 percent decrease in registrations post-regulation, whereas high-performing centers incurred a 5-percent decrease in registrations relative to average performing centers. CONCLUSIONS: Government oversight in kidney transplantation was associated with a small downward shift in overall kidney transplants. Reductions in graft failure rates at low-performing centers may imply an increase in quality or a decline in transplantation of either marginal organs or riskier patients; whereas reductions in registrations may indicate risk aversion toward high-risk patients. Policy makers should consider making less punitive requirements for programs, which employ new transplantation techniques to expand access. PMID- 30520026 TI - Phase I/II study of dasatinib and exploratory genomic analysis in relapsed or refractory non-Hodgkin lymphoma. AB - Relapsed or refractory non-Hodgkin lymphomas (NHLs) often carry poor prognosis and pose management challenges. We evaluated the safety and efficacy of dasatinib, a broad-spectrum multi-kinase inhibitor in relapsed/refractory NHL with correlative genomic analysis in a Phase I/II trial. The study included 33 patients with various sub-types of NHL who had received at least one prior therapy. The most common sub-types were diffuse large B-cell lymphoma (24%), follicular lymphoma, grade 1/2 (21%) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; 21%). Most patients were heavily pre-treated, including 42% with more than four prior therapies, 67% with rituximab exposure and 24% with prior autologous transplant. In this cohort, dasatinib showed modest activity in evaluable patients with an objective response rate of 29% (7/24) and clinical benefit rate of 71% (17/24). In 32 patients with outcome data, median progression free survival was 3 months and median overall survival was 22.4 months. There were two patients with sustained complete responses, both with PTCL-NOS histology. The side effect profile was consistent with prior studies, with pleural effusion being the most common non-haematological toxicity. Exploratory genomic analysis showed two cases of PTCL-NOS with sustained response had a common mutation in LRRK2 and high prevalence of FOXO1 mutation in relapsed/refractory follicular lymphoma. PMID- 30520028 TI - Anaphylaxis to intravenous gelatin-based solutions: a case series examining clinical features and severity. AB - The proportion of patients receiving intravenous gelatin-based colloids has increased in the last decade due to safety concerns about starch-based products. Recent research suggests hypersensitivity reactions to intravenous gelatin-based solutions occur at similar rates per administration as non-depolarising neuromuscular blocking agents such as rocuronium (6.2/100,000 administrations). There are scant published data on clinical features, diagnosis and time course of these reactions. We undertook a review of cases reported and tested at one of the UK's largest drug allergy clinics. All patients seen in the drug allergy clinic at Imperial College Healthcare NHS Trust (London, UK) with a confirmed diagnosis of anaphylaxis to gelatin-based solutions between May 2013 and May 2018 were included. We retrospectively reviewed clinical histories, skin test results and severity of reactions in this cohort of patients. Twelve patients with anaphylaxis to gelatin-based solutions were identified (eight women, mean (SD) age 58 (17) years). Eleven reactions were severe or life-threatening with three progressing to cardiac arrest. Presentation was commonly delayed; only three patients suffered reactions within 5 min of the solution being administered with a further six presenting 10-70 min later. Where measured, tryptase was elevated in all patients (median (IQR [range]) 14.7 (8.2-23.8 [6.5-83.4]) ng.ml-1 ). Reactions to gelatin-based solutions are usually severe and can present with latency uncommon with other intravenous anaesthetic triggers. The use of gelatin based solutions in the peri-operative setting should be re-assessed given the risk of severe allergy. PMID- 30520029 TI - CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. AB - CD8+ cytotoxic T lymphocytes (CTLs) are preferred immune cells for targeting cancer. During cancer progression, CTLs encounter dysfunction and exhaustion due to immunerelated tolerance and immunosuppression within the tumor microenvironment (TME), with all favor adaptive immune-resistance. Cancer associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and regulatory T cells (Tregs) could make immunologic barriers against CD8 + T cell-mediated antitumor immune responses. Thus, CD8 + T cells are needed to be primed and activated toward effector CTLs in a process called tumor immunity cycle for making durable and efficient antitumor immune responses. The CD8 + T cell priming is directed essentially as a corroboration work between cells of innate immunity including dendritic cells (DCs) and natural killer (NK) cells with CD4 + T cells in adoptive immunity. Upon activation, effector CTLs infiltrate to the core or invading site of the tumor (so-called infiltrated-inflamed [I-I] TME) and take essential roles for killing cancer cells. Exogenous reactivation and/or priming of CD8 + T cells can be possible using rational immunotherapy strategies. The increase of the ratio for costimulatory to coinhibitory mediators using immune checkpoint blockade (ICB) approach. Programmed death-1 receptor (PD-1)-ligand (PD L1) and CTL-associated antigen 4 (CTLA-4) are checkpoint receptors that can be targeted for relieving exhaustion of CD8 + T cells and renewing their priming, respectively, and thereby eliminating antigen-expressing cancer cells. Due to a diverse relation between CTLs with Tregs, the Treg activity could be dampened for increasing the number and rescuing the functional potential of CTLs to induce immunosensitivity of cancer cells. PMID- 30520030 TI - PACE Forward-Making Pharmacogenomics Testing Available for Real-Life Clinical Utility. AB - Although pharmacogenomics (PGx) offers the promise of ensuring the right patient receives the right medication at the right dose the first time, gene-drug interaction data have yet to be seamlessly integrated into patients' health records. PGx testing that is preemptive, adaptable, current, and executable (PACE) overcomes the human and technological barriers to successful implementation, thus capitalizing on the affordable cost of such testing and clinical practice guidelines at the point of prescription ordering. PMID- 30520031 TI - Seroprevalence and geographical distribution of sero-positive blood donors to Trypanosoma cruzi at the central blood bank of the National Medical Center "La Raza". AB - BACKGROUND: Trypanosoma cruzi is a protozoan parasite that causes Chagas disease endemic to Latin-America. It is estimated that 1.0 to 1.5% of Mexicans are infected with T. cruzi, which constitutes a potential risk of disease transmission via contaminated blood. New cases are being reported worldwide due to the migration of infected people from endemic areas. STUDY DESIGN AND METHODS: Serum samples were collected from donors at the Central Blood Bank of the National Medical Center "La Raza" from July 2008 to December 2015 and analyzed for T. cruzi antibodies using Enzyme-linked Immunosorbent Assays. Blood donors were classified serologically as either negative or positive for Chagas disease based on the Official Mexican Standard NOM-032-SSA2-2014. The geographical distribution of sero-positive donors for Chagas disease was then determined based on the donor's areas of residence. RESULTS: Of the 510, 047 donors, 595 tested positive for Chagas disease. We found a prevalence of 0.12%, was higher in males (0.13%) than females (0.08%) In both genders, there were more sero-positive donors aged 51-65 years as compared to other age groups. Overall there were more positive donors from the State of Mexico, northern area of Mexico City, and southern area of Hidalgo State, with rates of 67.4%, 20.6%, and 5.9%, respectively. CONCLUSIONS: The seroprevalence of Chagas disease in blood donors attending to La Raza BB is low. Chagas disease is more prevalent in the older age groups; most sero-positive donors are from areas considered non-endemic to Chagas disease. PMID- 30520032 TI - Human paleoneurology: shaping cortical evolution in fossil hominids. AB - Evolutionary neuroanatomy must integrate two different sources of information, namely from fossil and from living species. Fossils supply information concerning the process of evolution, while living species supply information on the product of evolution. Unfortunately, the fossil record is partial and fragmented, and often cannot support validations for specific evolutionary hypotheses. Living species can provide more comprehensive indications, but they do not represent ancestral groups or primitive forms. Macaques or chimpanzees are frequently used as proxy for human ancestral conditions, despite the fact they are divergent and specialized lineages, with their own biological features. Similarly, in paleoanthropology independent lineages (such as Neanderthals) should not be confused with ancestral modern human stages. In this comparative framework, paleoneurology deals with the analysis of the endocranial cavity in extinct species, in order to make inferences on brain evolution. A main target of this field is to distinguish the endocranial variations due to brain changes, from those due to cranial constraints. Digital anatomy and computed morphometrics have provided major advances in this field. However, brains and endocasts can be hard to analyze with geometrical models, because of uncertainties due to the localization of cortical landmarks and boundaries. The study of the evolution of the parietal cortex supplies an interesting case-study in which paleontological and neontological data can integrate and test evolutionary hypotheses based on multiple sources of evidence. The relationships with visuospatial functions and brain-body-tool integration stress further that the analysis of the cognitive system should go beyond the neural boundaries of the brain. This article is protected by copyright. All rights reserved. PMID- 30520035 TI - MRI measurement of blood-brain barrier leakage: filling the gaps. PMID- 30520033 TI - Lack of Sphenoid Pneumatization Does Not Affect Endoscopic Endonasal Pediatric Skull Base Surgery Outcomes. AB - OBJECTIVES/HYPOTHESIS: Currently, due to the rarity of pathology, there are limited data surrounding outcomes of pediatric skull base surgery. Traditionally, surgeons have proceeded with caution when electing endonasal endoscopic transsellar/transplanum approaches to the skull base in pediatric patients due to poor sphenoid pneumatization. In this study, we review outcomes of endoscopic pediatric skull base surgery based on sphenoid pneumatization patterns. STUDY DESIGN: Retrospective chart review. METHODS: A review of all cases of pediatric (age < 18 years) craniopharyngioma managed via an endoscopic endonasal approach at a tertiary academic medical center. RESULTS: A total of 27 patients were included in the analysis. The median age was 8 years. Nineteen (70%) patients were male. Presellar, sellar/postsellar, and conchal sphenoid pneumatizations were found in 6, 11, and 10 patients, respectively. There was no significant association between sphenoid pneumatization pattern and extent of resection (gross vs. subtotal, P = .414), postoperative cerebrospinal fluid (CSF) leak (P = .450), intraoperative estimated blood loss (P = .098), total operative time (P = .540), and length of stay (P = .336). On multivariate analysis, after accounting for age, sex, preoperative cranial nerve involvement, and cavernous sinus invasion, there remained no significant association between sphenoid pneumatization pattern and extent of resection (P = .999) and postoperative CSF leak (P = .959). CONCLUSIONS: Sphenoid pneumatization pattern does not appear to affect outcomes in endoscopic skull base surgery in the pediatric population. Importantly, lack of sphenoid pneumatization does not impede gross total resection or increase complications. Thorough knowledge of the anatomy during the endoscopic approach is critical to optimize outcomes. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30520034 TI - Ultra high field Imaging of Myelin Disease Models: Towards Specific Markers of Myelin Integrity? AB - Specific Magnetic Resonance Imaging (MRI) markers of myelin are critical for the evaluation and development of regenerative therapies for demyelinating diseases. Several MRI methods have been developed for myelin imaging, based either on acquisition schemes or on mathematical modeling of the signal. They generally showed good sensitivity but validation for specificity towards myelin is still warranted to allow a reliable interpretation in an in vivo complex pathological environment. Experimental models of dys-/demyelination are characterized by various levels of myelin disorders, axonal damage, gliosis and inflammation, and offer the opportunity for powerful correlative studies between imaging metrics and histology. Here, we review how ultra-high field MRI markers have been correlated with histology in these models and provide insights into the trends for future developments of MRI tools in human myelin diseases. To this end, we present the biophysical basis of the main MRI methods for myelin imaging based on T1 , T2 , water diffusion and magnetization transfer signal, the characteristics of animal models used and the outcomes of histological validations. To date such studies are limited, and demonstrate partial correlations with immunohistochemical and electron microscopy measures of myelin. These MRI metrics also often correlate with axons, glial or inflammatory cells in models where axonal degeneration or inflammation occur as potential confounding factors. Therefore, the MRI markers' specificity for myelin is still perfectible and future developments should improve mathematical modeling of the MR signal based on more complex systems or provide multimodal approaches to better disentangle the biological processes underlying the MRI metrics. This article is protected by copyright. All rights reserved. PMID- 30520036 TI - Does interindividual variability of saliva affect the release and metabolisation of aroma compounds ex-vivo? The particular case of elderly suffering or not from hyposalivation. AB - The aim of this work was to study the effects of interindividual variability of human elderly saliva on aroma release and metabolisation by ex vivo approaches. Thirty individuals suffering or not from hyposalivation were selected from a panel formed by 110 elderly people (aged >65 years old) that were matched by age and sex. Then, their stimulated saliva samples were independently incubated in presence of three aroma compounds (ethyl hexanoate, octanal, 2-nonanone) to perform headspace-gas chromatography (HS-GC) and liquid/liquid extraction-gas chromatography mass spectrometry (LLE-GC/MS) analyses. These assays revealed that the extent of saliva effect on the release and metabolisation of aroma compounds was highly dependent on the chemical family of the compounds (octanal>ethyl hexanoate>2-nonanone). Moreover, salivas from the hyposalivator (HPS) group exerted a significant lower release and/or higher metabolisation than those of the control group for the three assayed compounds. Regarding the biochemical characterization of the saliva samples, no significant differences were found in the total protein content between the two groups. This does not preclude the involvement of specific proteins on the observed results that need to be clarified in further experiments. Saliva from the HPS group presented a significantly higher total antioxidant capacity than that of the control group, which suggests that this parameter could be related to the metabolisation of aroma compounds by saliva. Such effects might alter aroma perception in individuals suffering from hyposalivation. This article is protected by copyright. All rights reserved. PMID- 30520037 TI - Structure and function of dual-source cholinergic modulation in early vision. AB - Behavioral states such as arousal and attention have profound effects on sensory processing, determining how - even whether - a stimulus is perceived. This state dependence is believed to arise, at least in part, in response to inputs from subcortical structures that release neuromodulators such as acetylcholine, often non-synaptically. The mechanisms that underlie the interaction between these non synaptic signals and the more point-to-point synaptic cortical circuitry are not well understood. This review highlights the state of the field, with a focus on cholinergic action in early visual processing. Key anatomical and physiological features of both the cholinergic and the visual systems are discussed. Furthermore, presenting evidence of cholinergic modulation in visual thalamus and primary visual cortex, we explore potential functional roles of acetylcholine and its effects on the processing of visual input over the sleep-wake cycle, sensory gain control during wakefulness, and consider evidence for cholinergic support of visual attention. This article is protected by copyright. All rights reserved. PMID- 30520038 TI - Effects of cannabinoids in Amyotrophic Lateral Sclerosis (ALS) murine models: A systematic review and meta-analysis. AB - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that results from motor neuron damage. Cannabinoids have been proposed as treatments for ALS due to their anti-excitotoxicity, anti-oxidant, and anti-inflammatory effects. Pre-clinical studies in mice models of ALS have been published using a range of cannabinoid formulations and doses. To date, there has been no rigorous evaluation of these trials to assess a potential cannabinoid treatment effect. This review and meta-analysis was undertaken to provide evidence for or against a treatment effect of cannabinoids in murine ALS models. Evidence of a treatment effect in mice may provide motivation for trials in human ALS. We identified a total of 10 studies; 9 studies using cannabinoid treatment in transgenic SOD1 G93A ALS-model mice and 1 study in TDP-43 transgenic mice. 8 of the 9 studies that used SOD1-G93A mice expressed similarly high copy numbers of the transgene whilst one study used a low-copy number line. Outcomes evaluated were survival time and disease progression. The latter was measured by motor function and bodyweight decline. Meta-analysis of the mean difference in survival time across the 7 studies showed an increase in survival of 3.84 days (95% CI 0.35 to 7.32 days; P =0.031) for cannabinoid treated compared to control SOD1-G93A mice. It was not possible to conduct meta-analyses for motor function decline or weight loss. However, 8 of 9 studies reported significant improvements in measures of motor function decline and 1 reported non-significant improvements. Weight loss was significantly attenuated in 4 of 5 studies reporting this measure whilst the other study reported a non-significant attenuation. This review provides some evidence for the efficacy of cannabinoids in prolonging survival time in an ALS mouse model. A delay in disease progression is also suggested following cannabinoid treatment though it was not possible to consolidate the results from reviewed studies. However, studies have moderate to high risk of bias and are highly heterogeneous. Although this review provides some evidence to support the conduct of a cannabinoid trial in human ALS, more standardized studies on specific cannabinoids are necessary before supporting therapeutic potential of cannabinoids in treating patients with ALS. This article is protected by copyright. All rights reserved. PMID- 30520039 TI - Long-range projections from sparse populations of GABAergic neurons in murine subplate. AB - The murine subplate contains some of the earliest generated populations of neurons in the cerebral cortex, which play an important role in the maturation of cortical inhibition. Here we present multiple lines of evidence, that the subplate itself is only very sparsely populated with GABAergic neurons at postnatal day (P)8. We used three different transgenic mouse lines, each of which labels a subset of GABAergic, ganglionic eminence derived neurons. Dlx5/6-eGFP labels the most neurons in cortex (on average 11% of NEUN+ cells across all layers at P8) whereas CGE-derived Lhx6-Cre::Dlx1-Venusfl cells are the sparsest (2% of NEUN+ cells across all layers at P8). There is significant variability in the layer distribution of labelled interneurons, with Dlx5/6-eGFP and Lhx6 Cre::R26R-YFP being expressed most abundantly in layer 5, whereas CGE-derived Lhx6-Cre::Dlx1-Venusfl cells are least abundant in that layer. All three lines label at most 3% of NEUN+ neurons in the subplate, in contrast to L5, in which up to 30% of neurons are GFP+ in Dlx5/6-eGFP. We assessed all three GABAergic populations for expression of the subplate neuron marker connective tissue growth factor (CTGF). CTGF labels up to two thirds of NeuN+ cells in the subplate, but was never found to co-localise with labelled GABAergic neurons in any of the three transgenic strains. Despite the GABAergic neuronal population in the subplate being sparse, long-distance axonal connection tracing with carbocyanine dyes revealed that some Gad65-GFP+ subplate cells form long-range axonal projections to the internal capsule or callosum. PMID- 30520040 TI - Validation of the Targeted Metabolomic Pathway in the Hippocampus and Comparative Analysis with the Prefrontal Cortex of Social Defeat Model Mice. AB - The proportion of major depressive disorder (MDD) patients around the world has increased remarkably. Although many studies of MDD have been conducted based on classic hypotheses, like alteration of the hypothalamic-pituitary-adrenal axis or monoamine neurotransmitters, the mechanisms underlying MDD remain unclear. Aiming to further investigate the mechanisms of MDD, liquid-chromatography tandem mass spectrometry was employed to measure target metabolites in the hippocampus (HIPPO) of chronic social defeat stress (CSDS) model mice. Compared with control mice, stress-susceptible mice showed a reduction of 5-hydroxyindoleacetic acid and kynurenic acid in the tryptophan pathway, and an increased level of dopamine in the catecholamine pathway, while stress-resilient mice displayed a reduction of 5-hydroxytryptamine in the tryptophan pathway. The altered levels of key molecules related to the tryptophan or dopamine metabolic pathways were validated by real-time quantitative polymerase chain reaction or western blotting. Comparative analysis with previous targeted metabolomics results in the prefrontal cortex (PFC) of CSDS mice revealed that the altered metabolites manifested in specific brain areas, and only the dopamine metabolic pathway was perturbed in both the HIPPO and PFC after stress. Additionally, correlation analysis validated that levels of kynurenic acid in the HIPPO, along with glutamic acid, L-3, 4-dihydroxyphenylalanine and vanillylmandelic acid in the PFC, were correlated with depression-like behaviors. This study provides a unique perspective on the potential molecular mechanisms of stress susceptibility and stress resilience. This article is protected by copyright. All rights reserved. PMID- 30520041 TI - Hematological evaluation of free-living golden-headed lion tamarins (Leontopithecus chrysomelas) from an Urban Atlantic Forest. AB - BACKGROUND: The Atlantic Forest where the animals were captured is surrounded by residences, so this close contact could favor the presence of disease transmitting pathogens, putting the local population at risk. For these and other factors, it is important to perform laboratory tests enabling the performance of important diagnoses. METHODS: Blood samples of 268 golden-headed lion tamarins (Leontopithecus chrysomelas) inhabiting an Atlantic Forest area in Rio de Janeiro, Brazil, were processed for accessing age and sex influence in hematological parameters and to establish normative hematology values. RESULTS: Mean values of red blood cells, hematocrit, hemoglobin, and platelet count were significantly higher in adult males than in adult females. Adult animals had significantly higher mean neutrophil count, and young animals had higher averages than adults in lymphocyte values. Anisocytosis and platelet indices parameters were also provided for the first time. CONCLUSIONS: Averages presented can be used as hematological parameters for golden-headed lion tamarins. PMID- 30520042 TI - Expression of class III Semaphorins and their receptors in the developing chicken (Gallus gallus) inner ear. AB - Class III Semaphorin (Sema) secreted ligands are known to repel neurites expressing Neuropilin (Nrp) and/or Plexin (Plxn) receptors. There is, however, a growing body of literature supporting that Sema signaling also has alternative roles in development such as synaptogenesis, boundary formation and vasculogenesis. To evaluate these options during inner ear development, we used in situ hybridization or immunohistochemistry to map the expression of Sema3D, Sema3F, Nrp1, Nrp2, and PlxnA1 in the chicken (Gallus gallus) inner ear from embryonic day (E)5 to E10. The resulting expression patterns in either the otic epithelium or its surrounding mesenchyme suggest that Sema signaling could be involved in each of the varied functions reported for other tissues. Sema3D expression flanking the sensory tissue in vestibular organs suggests that it may repel Nrp2- and PlxnA1-expressing neurites of the vestibular ganglion away from nonsensory epithelia, thus channeling them into the sensory domains at E5-E8. Expression of Sema signaling genes in the sensory hair cells of both the auditory and vestibular organs on E8-E10 may implicate Sema signaling in synaptogenesis. In the nonsensory regions of the cochlea, Sema3D in the future tegmentum vasculosum opposes Nrp1 and PlxnA1 in the future cuboidal cells; the abutment of ligand and receptors in adjacent domains may enforce or maintain the boundary between them. In the mesenchyme, Nrp1 colocalized with capillary-rich tissue. Sema3D immediately flanks this Nrp1-expressing tissue, suggesting a role in endothelial cell migration towards the inner ear. In summary, Sema signaling may play multiple roles in the developing inner ear. This article is protected by copyright. All rights reserved. PMID- 30520043 TI - HIV gp120-induced neuroinflammation potentiates NMDA receptors to overcome basal suppression of inhibitory synapses by p38 MAPK. AB - HIV-associated neurocognitive disorder (HAND) affects about half of HIV-infected patients. HIV impairs neuronal function through indirect mechanisms mainly mediated by inflammatory cytokines and neurotoxic viral proteins, such as the envelope protein gp120. HIV gp120 elicits a neuroinflammatory response that potentiates NMDA receptor function and induces the loss of excitatory synapses. How gp120 influences neuronal inhibition is not known. In this study, we expressed a green fluorescent protein (GFP)-tagged recombinant antibody-like protein that binds to the post-synaptic scaffolding protein gephyrin to label inhibitory synapses in living neurons. Treatment with 600 pM gp120 for 24 h increased the number of labelled inhibitory synapses. HIV gp120 evoked the release of interleukin-1beta (IL-1beta) from microglia to activate IL-1 receptors on neurons. Subsequent activation of the tyrosine kinase Src and GluN2A containing NMDA receptors increased the number of inhibitory synapses via a process that required protein synthesis. In naive cultures, inhibition of neuronal p38 mitogen-activated protein kinase (p38 MAPK) increased the number of inhibitory synapses suggesting that p38 MAPK produces a basal suppression of inhibitory synapses that is overcome in the presence of gp120. Direct activation of a mutant form of p38 MAPK expressed in neurons mimicked basal suppression of inhibitory synapses. This study shows for the first time that gp120-induced neuroinflammation increases the number of inhibitory synapses and that this increase overcomes a basal suppression of synaptic inhibition. Increased inhibition may be an adaptive mechanism enabling neurons to counteract excess excitatory input in order to maintain network homeostasis. This article is protected by copyright. All rights reserved. PMID- 30520044 TI - Nervous system characterization during the development of a basal echinoderm, the feather star Antedon mediterranea. AB - Neural development of echinoderms has always been difficult to interpret, as larval neurons degenerate at metamorphosis and a tripartite nervous system differentiates in the adult. Despite their key phylogenetic position as basal echinoderms, crinoids have been scarcely studied in developmental research. However, since they are the only extant echinoderms retaining the ancestral body plan of the group, crinoids are extremely valuable models to clarify neural evolution in deuterostomes. Antedon mediterranea is a feather star, endemic to the Mediterranean Sea. Its development includes a swimming lecithotrophic larva, the doliolaria, with basiepithelial nerve plexus, and a sessile filter-feeding juvenile, the pentacrinoid, whose nervous system has never been described in detail. Thus, we characterized the nervous system of both these developmental stages by means of immunohistochemistry and, for the first time, in situ hybridization techniques. The results confirmed previous descriptions of doliolaria morphology and revealed that the larval apical organ contains two bilateral clusters of serotonergic cells while GABAergic neurons are localized under the adhesive pit. This suggested that different larval activities (e.g. attachment and metamorphosis) are under the control of different neural populations. In pentacrinoids, the analysis showed the presence of a cholinergic entoneural system while the ectoneural plexus appeared more composite, displaying different neural populations. The expression of three neural-related microRNAs was described for the first time, suggesting that these are evolutionarily conserved also in basal echinoderms. Overall, our results set the stage for future investigations that will reveal new information on echinoderm evo-devo neurobiology. This article is protected by copyright. All rights reserved. PMID- 30520045 TI - Platelet transfusion practices in immune thrombocytopenia related hospitalizations. AB - BACKGROUND: The role of platelet transfusions in management of Immune Thrombocytopenia (ITP) remains controversial. Current guidelines recommend that platelet transfusions in ITP be reserved for catastrophic hemorrhage or invasive surgical procedures. This study assesses the nationwide platelet transfusion practices in hospitalized children and adults with ITP. STUDY DESIGN AND METHODS: We studied hospitalizations with ITP as the primary admitting diagnosis from 2010 2014 in National Inpatient Sample (NIS), the largest all-payer inpatient database. Univariate and multivariable logistic regression analyses were used to determine factors predicting platelet transfusions. Sampling weights were applied to generate nationally representative estimates. Propensity score matching was used to perform sensitivity analyses. RESULTS: From 2010 to 2014, there were 78,376 admissions with ITP as the primary admission diagnosis (mean +/- SD age: 45 +/- 27 years; females 56%, children [age < 18 years] 22%) and 282,285 with ITP as one of all the admission diagnoses. Overall, 27% admissions were with ITP as primary (children 4%) and 15% admissions with ITP as one of all the diagnoses documented with at least one platelet transfusion. On multivariable adjustment the following factors were associated with worsening disease severity and a higher odds of platelet transfusion, adult age (adjOR = 9.03, 95% CI = 7.40 11.02), male gender (adjOR = 1.21, 95% CI = 1.11-1.31), bleeding occurrence (intracranial/gastrointestinal/genitourinary/epistaxis) (adjOR = 1.78, 95% CI = 1.61-1.96), admission to rural non-teaching hospital (adjOR = 1.85, 95% CI = 1.52 2.22), and small bed-size hospital (adjOR = 1.23, 95% CI = 1.05-1.45).. Of admissions reporting platelet transfusions, only 26% reported a bleeding complication, and 11% had a major operating-room surgery/procedure. Overall, 65% of transfused patients had neither bleeding nor a major operative procedure during the hospitalization. Admissions with platelet transfusions had a significantly longer mean length of hospitalization 2.2 days (95% CI = 1.96-2.41, p < 0.001), and accrued higher mean total hospital charges; $31,150 USD (95% CI = 27,644-34,656, p < 0.001). However, platelet transfusions were not associated with in-hospital mortality (adjOR = 1.02, 95% CI = 0.73-1.45, p = 0.892). CONCLUSION: Platelets are administered to a small fraction of the hospitalized ITP patients. In a majority of these cases however, platelet usage does not appear to be concordant with the current guidelines or associated with improvement in clinical outcomes. PMID- 30520046 TI - Frequent blood donation and offspring birth weight-a next-generation association? AB - BACKGROUND: The prevalence of iron depletion is high among premenopausal women who donate blood frequently. Studies in nondonor populations indicate that iron deficiency anemia is associated with an increased risk of low birth weight. This prompts concerns that iron deficiency induced by frequent blood donation might impair subsequent fetal development. STUDY DESIGN AND METHODS: The aim of this study was to assess whether prepregnancy donation intensity affects the birth weight of singletons born at term (gestational week 38 or later) to nulliparous female donors in Denmark. We identified 293,897 first live singleton births to Danish women between 1997 and 2012 with complete information on gestational age, birth weight, child sex, parental age, maternal smoking status during pregnancy, and parental education length and annual income. Linear regression analysis was applied, with birth weight as outcome, number of donations within the 3 years before pregnancy as the explanatory variable, and confounding variables as described. RESULTS: Birth weight among children of low-intensity donors (n = 22,120) was 12.6 g (95% confidence interval, 6.7-18.6) higher than nondonors (n = 268,253) after controlling for the above-mentioned factors. The higher birth weight among low-intensity donors can be explained by the healthy donor effect. In fully adjusted analyses, birth weight among children of high-intensity donors (n = 3,524) was 20.2 g (95% confidence interval, 5.1-35.3 g) lower compared with low-intensity donors. This reduced birth weight among high-intensity donors compared to low-intensity donors may reflect blood donation-induced iron deficiency. CONCLUSIONS: Our results show that high prepregnancy donation intensity is inversely associated with birth weight of singletons born at term to nulliparous women. PMID- 30520047 TI - Endoplasmic reticulum stress is transmissible in vitro between cells of the central nervous system. AB - Improper protein folding and trafficking are common pathological events in neurodegenerative diseases that result in the toxic accumulation of misfolded proteins within the lumen of the endoplasmic reticulum (ER). While low-level stimulation of the unfolded protein response (UPR) is protective, sustained UPR activation resulting from prolonged ER stress can promote neurotoxicity. The cell autonomous mechanisms of the UPR have been extensively characterized. However, the cell-extrinsic role of the UPR under physiological and pathological states in the central nervous system (CNS) remains to be elucidated. To begin to address this, we evaluated if transferring conditioned media between ER stressed astrocytes and neurons could modulate their functional characteristics. Our results indicate that ER stressed astrocytes and neurons secrete a molecule(s) with lipid characteristics which regulates both inflammatory and ER stress responses in other astrocytes, neurons, and microglia in vitro. Initial exposure to this stress factor(s) confers resistance against subsequent ER stress to neurons. However, persistent exposure to this unidentified mediator(s) suppresses the initial protective effect and becomes cytotoxic. Overall, these findings provide insight into the cell-nonautonomous influence of ER stress on cells of the central nervous system. This article is protected by copyright. All rights reserved. PMID- 30520048 TI - Distribution, projections and association with calbindin baskets of motor neurons, interneurons and sensory neurons in guinea-pig distal colon. AB - Normal gut function relies on the activity of the enteric nervous system (ENS) found within the wall of the gastrointestinal tract. The structural and functional organisation of the ENS has been extensively studied in the guinea pig small intestine, but less is known about colonic circuitry. Given that there are significant differences between these regions in function, observed motor patterns and pathology, it would be valuable to have a better understanding of the colonic ENS. Furthermore, disorders of colonic motor function, such as irritable bowel syndrome, are much more common. We have recently reported specialised basket-like structures, immunoreactive for calbindin, that likely underlie synaptic inputs to specific types of calretinin-immunoreactive neurons in the guinea-pig colon. Based on detailed immunohistochemical analysis, we postulated the recipient neurons may be excitatory motor neurons and ascending interneurons. In the present study, we combined retrograde tracing and immunohistochemistry to examine the projections of circular muscle motor neurons, myenteric interneurons and putative sensory neurons. We focused on neurons with immunoreactivity for calbindin, calretinin and nitric oxide synthase and their relationship with calbindin baskets. Retrograde tracing using indocarbocyanine dye (DiI) revealed that many of the nerve cell bodies surrounded by calbindin baskets belong to motor neurons and ascending interneurons. Unique functional classes of myenteric neurons were identified based on morphology, neuronal markers and polarity of projection. We provide evidence for three groups of ascending motor neurons based on immunoreactivity and association with calbindin baskets, a finding that may have significant functional implications. This article is protected by copyright. All rights reserved. PMID- 30520049 TI - Mediolateral and dorsoventral projection patterns of cutaneous afferents within transverse planes of the mouse spinal dorsal horn. AB - The central projection patterns of cutaneous afferents from the forelimb and shoulder of mice were studied in the spinal dorsal horn after intracutaneous injection of AlexaFluor 488-conjugated and/or 594-conjugated cholera toxin subunit B (CTB). Based on their dermatomes, the following eight skin regions are thought to be innervated by spinal nerves from the sixth to eighth cervical spinal nerve roots: the dorsal surface of the shoulder, brachium, proximal forearm, distal forearm, hand, palmar surface of the second and third digits, and palm. The termination areas of afferents from the dorsal surface of the shoulder and forearm were narrow, distributed in a dorsoventral direction, and aligned in order from lateral to medial within the sixth to eighth cervical dorsal horns. By contrast, the termination areas of the palmar surface of the second and third digits largely overlapped. We also injected CTB into the dorsal surface of the hindlimb and pelvic regions. Skin regions there are thought to be innervated by nerves from the third to fifth lumbar spinal nerve roots. The observed projection patterns in the lumbar dorsal horn were similar to the cervical patterns. Injection of a mixture of CTB and wheat-germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), which are thought to label Abeta and Adelta/C fibers, respectively, showed segregated termination areas of CTB- and WGA-HRP-labeled afferents. Moreover, alignment of the termination areas was in the dorsoventral direction. These results suggest there is fine somatotopic (mediolateral axis) and modality-specific (dorsoventral axis) organization within the spinal dorsal horn. This article is protected by copyright. All rights reserved. PMID- 30520050 TI - Extensive branching of radially-migrating neurons in the mammalian cerebral cortex. AB - Excitatory neurons of the cerebral cortex migrate radially from their place of birth to their final position in the cortical plate during development. Radially migrating neurons display a single leading process that establishes the direction of movement. This leading process has been described as being unbranched, and the occurrence of branches proposed to impair radial migration. Here we have analyzed the detailed morphology of leading process in radially-migrating pyramidal neurons and its impact on radial migration. We have compared ferret and mouse to identify differences between cortices that undergo folding or not. In mouse, we find that half of radially-migrating neurons exhibit a branched leading process, this being even more frequent in ferret. Branched leading processes are less parallel to radial glia fibers than those unbranched, suggesting some independence from radial glia fibers. Two-photon videomicroscopy revealed that a vast majority of neurons branch their leading process at some point during radial migration, but this does not reduce their migration speed. We have tested the functional impact of exuberant leading process branching by expressing a dominant negative Cdk5. We confirm that loss of Cdk5 function significantly impairs radial migration, but this is independent from increased branching of the leading process. We propose that excitatory neurons may branch their leading process as an evolutionary mechanism to allow cells changing their trajectory of migration to disperse laterally, such that increased branching in gyrencephalic species favors the tangential dispersion of radially-migrating neurons, and cortical folding. This article is protected by copyright. All rights reserved. PMID- 30520051 TI - Hepatic neuroendocrine carcinoma in a Japanese macaque (Macaca fuscata). AB - Primary neuroendocrine neoplasm of the liver is extremely rare in both humans and non-human primates. The present report describes the clinical and pathological findings of an aged Japanese macaque (Macaca fuscata) with hepatic neuroendocrine carcinoma. To our knowledge, this is the first report of hepatic neuroendocrine neoplasm in macaques. PMID- 30520052 TI - Hepatic Autophagy Deficiency Compromises FXR Functionality and Causes Cholestatic Injury. AB - Autophagy is important for hepatic homeostasis, nutrient regeneration and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy due to the lack of Atg7 or Atg5, key autophagy-related genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of TMCA/TCA in the bile, increased hepatic bile acid load, abnormal bile canaliculi and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and upregulated expression of Fxr in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly Bsep, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, co-deletion of Nrf2 in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. CONCLUSIONS: Together with earlier reports that FXR can suppress autophagy our new findings indicate that autophagy and FXR form a novel regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury. This article is protected by copyright. All rights reserved. PMID- 30520053 TI - Development and validation of a rapid and sensitive UPLC-MS/MS assay for the quantification of tofacitinib in human plasma. AB - A highly sensitive, selective and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method has been developed for the quantification of a Janus kinase (JAK) inhibitor, tofacitinib (TOF). The assay employed liquid-liquid extraction with methyl-tert butyl ether to extract tofacitinib and tofacitinib-13C3 15N (as internal standard) from human plasma. The samples were analyzed on UPLC BEH C18 (50 * 2.1 mm, 1.7 MUm) column using acetonitrile and 10.0 mM ammonium acetate, pH 4.5 (75:25, v/v) as the mobile phase within 1.4 min. The precursor/product ion transitions were monitored at m/z 313.3/149.2 and 317.4/149.2 for tofacitinib and tofacitinib-13C3 15N, respectively in the positive electrospray ionization mode. The calibration curves were linear (r2 >= 0.9978) across the concentration range of 0.05-100 ng/mL. The mean extraction recovery of tofacitinib across quality controls was 98.6 %. The intra-batch and inter-batch precision (% CV) and accuracy ranged from 2.1-5.1 and 96.2-103.1 %, respectively. All validation results complied well with the current guidelines. The method is amenable to high sample throughput and was applied to determine TOF plasma concentration in a pharmacokinetic study with 12 healthy Indian subjects after oral administration of 5 mg tablets. PMID- 30520054 TI - Metformin inhibits pro-inflammatory responses via targeting nuclear factor-kappaB in HaCaT cells. AB - Psoriasis is a prevalent, chronic inflammatory skin disease that arises from rapid and excessive growth of keratinocytes induced by abnormal inflammatory responses. Metformin is the first-line drug in type 2 diabetes and has been proven to possess significant anti-inflammatory effects in various diseases. In the present study, we examined the role of metformin in nuclear factor kappa B (NF-kappaB)-mediated inflammatory responses in HaCaT cells, a cell line for the keratinocyte. Our results demonstrated that metformin significantly decreased the mRNA and protein levels of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-8, and IL-1beta induced by TNFalpha. Immunofluorescence staining and western blot analysis showed that metformin inhibited the nuclear localization of p65, a subunit of nuclear factor NF-kappaB. In addition, metformin suppressed the transcription activity of NF-kappaB by inhibiting the degradation of IkappaBalpha. The inhibitory effect of metformin on NF-kappaB signalling is comparable with a specific IKKbeta inhibitor BI605906. Collectively, our data suggest that metformin may be a potential therapeutic agent in inflammatory skin diseases like psoriasis. PMID- 30520055 TI - Deep-Learning Convolutional Neural Network: Inner and Outer Bladder Wall Segmentation in CT Urography. AB - PURPOSE: We are developing a computerized segmentation tool for the inner and outer bladder wall as a part of an image analysis pipeline for CT urography (CTU). MATERIALS AND METHODS: A data set of 172 CTU cases was collected retrospectively with IRB approval. The data set was randomly split into two independent sets of training (81 cases) and testing (92 cases) which were manually outlined for both the inner and outer wall. We trained a deep-learning convolutional neural network (DL-CNN) to distinguish the bladder wall from the inside and outside of the bladder using neighborhood information. Approximately 240,000 regions of interest (ROIs) of 16 x 16 pixels in size were extracted from regions in the training cases identified by the manually outlined inner and outer bladder walls to form a training set for the DL-CNN; half of the ROIs were selected to include the bladder wall and the other half were selected to exclude the bladder wall with some of these ROIs being inside the bladder and the rest outside the bladder entirely. The DL-CNN trained on these ROIs was applied to the cases in the test set slice by slice to generate a bladder wall likelihood map where the gray level of a given pixel represents the likelihood that a given pixel would belong to the bladder wall. We then used the DL-CNN likelihood map as an energy term in the energy equation of a cascaded level sets method to segment the inner and outer bladder wall. The DL-CNN segmentation with level sets was compared to the 3D hand-segmented contours as a reference standard. RESULTS: For the inner wall contour, the training set achieved the average volume intersection, average volume error, average absolute volume error, and average distance of 90.0+/-8.7%, -4.2+/- 18.4%, 12.9+/-13.9%, and 3.0+/-1.6mm, respectively. The corresponding values for the test set were 86.9+/-9.6%, -8.3+/ 37.7%, 18.4+/-33.8%, and 3.4+/-1.8mm, respectively. For the outer wall contour, the training set achieved the values of 93.7+/-3.9%, -7.8+/-11.4%, 10.3+/-9.3%, and 3.0+/-1.2mm, respectively. The corresponding values for the test set were 87.5+/-9.9%, -1.2+/-20.8%, 11.9+/-17.0%, and 3.5+/-2.3mm, respectively. CONCLUSIONS: Our study demonstrates that DL-CNN assisted level sets can effectively segment bladder walls from the inner bladder and outer structures despite a lack of consistent distinctions along the inner wall. However, even with the addition of level sets, the inner and outer walls may still be over segmented and the DL-CNN assisted level sets may incorrectly segment parts of the prostate that overlap with the outer bladder wall. The outer wall segmentation was improved compared to our previous method and the DL-CNN assisted level sets was also able to segment the inner bladder wall with similar performance. This study shows the DL-CNN assisted level set segmentation tool can effectively segment the inner and outer wall of the bladder. This article is protected by copyright. All rights reserved. PMID- 30520056 TI - Advanced Paternal Age, Infertility, and Reproductive Risks: A Review of the Literature. AB - Advanced paternal age (APA) is associated with infertility and other reproductive risks. Studies looking at APA and outcomes have used different paternal age cut offs, which has complicated systematic evaluations of reproductive risk associated with paternal aging. This review of the literature suggests that the impact of paternal aging on adverse reproductive outcomes is small, but significant. Studies suggest the incidence of paternal age effect disorders attributed to de novo autosomal dominant mutations is less than 0.5%. Other risks associated with APA include infertility, miscarriage, birth defects, poor neurodevelopmental outcomes, and childhood cancer. Although the increasing prevalence of APA has mirrored the rise in maternal age, this topic has not received similar attention. In this review, we summarize the available literature on the reproductive risks associated with APA to provide a framework for comprehensive genetic counseling and evidence-based management of APA pregnancies. PMID- 30520057 TI - Use of Generally Recognized as Safe or Dietary Compounds to Inhibit Buprenorphine Metabolism: Potential to Improve Buprenorphine Oral Bioavailability. AB - The present study evaluated the potential of five generally recognized as safe (GRAS) or dietary compounds (alpha-mangostin, chrysin, ginger extract, pterostilbene and silybin) to inhibit oxidative (CYP) and conjugative (UGT) metabolism using pooled human intestinal and liver microsomes. Buprenorphine was chosen as the model substrate as it is extensively metabolized by CYPs to norbuprenorphine and by UGTs to buprenorphine glucuronide. Chrysin, ginger extract, alpha-mangostin, pterostilbene and silybin were tested for their inhibition of formation of norbuprenorphine or buprenorphine glucuronide in both intestinal and liver microsomes. Pterostilbene was the most potent inhibitor of norbuprenorphine formation in both intestinal and liver microsomes, with IC50 values of 1.3 and 0.8 MUM, respectively, while alpha-mangostin and silybin most potently inhibited buprenorphine glucuronide formation. The equipotent combination of pterostilbene and ginger extract additively inhibited both pathways in intestinal microsomes. Since pterostilbene and ginger extract showed potent CYP and/or UGT inhibition of BUP metabolism, their equipotent combination was tested to assess presence of synergistic inhibition. However, because the combination showed additive inhibition, it was not used while performing IVIVE analysis. Based on quantitative in-vitro-in-vivo extrapolation, pterostilbene (21 mg oral dose) appeared to be most effective in improving the mean predicted Foral and AUCinfinity PO of buprenorphine from 3+/-2% and 340+/-330 ng*min/ml to 75+/ 8% and 36,000+/-25,000 ng*min/ml, respectively. At a 10-fold lower dose of pterostilbene, predicted buprenorphine Foral approximated sublingual bioavailability (~35%) and showed a 2-4 fold reduction in the variability around predicted AUCinfinity PO of buprenorphine. These results demonstrate the feasibility of using various GRAS/dietary compounds to substantially inhibit the metabolism by CYP and UGT enzymes to achieve higher and less variable oral bioavailability. This inhibitor strategy may be useful for drugs suffering from low and variable oral bioavailability due to extensive presystemic oxidative and/or conjugative metabolism. PMID- 30520058 TI - European Surveillance System on Contact Allergies (ESSCA): contact allergies in relation to body sites in patients with allergic contact dermatitis. AB - BACKGROUND: Analyses of the European Surveillance System on Contact Allergies (ESSCA) database have focused primarily on prevalence of contact allergies to the European baseline series; overall and in subgroups of patients. However, affected body sites have hitherto not been addressed. OBJECTIVE: To determine prevalence of contact allergies for distinct body sites in patients with allergic contact dermatitis (ACD). METHODS: Analysis of data collected by ESSCA (www.essca-dc.org) in consecutively patch tested patients, 2009-2014, in 8 European countries. Cases were selected based on the presence of minimally one positive patch test to the baseline series, and a final diagnosis of ACD attributed to only one single body site. RESULTS: N=6,255 cases were analyzed. The head and hand were the most common single sites ACD was attributed to. Differences between countries were seen for several body sites. Nickel, fragrance mix I, cobalt and methylchloroisothiazolinone/methylisothiazolinone were the most frequent allergens reported for various body sites. CONCLUSION: Distinct allergen patterns per body site were observed. However, contact allergies were probably not always relevant for the dermatitis that patients presented themselves with. Adding possibility to link positive patch test reactions to relevance, along with affected body sites should be a useful addition to data capturing systems. PMID- 30520059 TI - Impact of left atrial box surface ratio on the recurrence after ablation for persistent atrial fibrillation. AB - BACKGROUND: The posterior wall of the left atrium (LA) is a well-known substrate for atrial fibrillation (AF) maintenance. Isolation of the posterior wall between the pulmonary veins (box lesion) may improve ablation success. Box lesion surface area size varies depending on the individual anatomy. This retrospective study evaluates the influence of box lesion surface area as a ratio of total LA surface area (box surface ratio) on arrhythmia recurrence. METHODS: Seventy consecutive patients with persistent AF (63+/-11 years, 53 men) undergoing CT imaging and ablation procedure consisting of a first box lesion were included in this study. Box lesion surface area was measured on electroanatomical maps and total LA surface area was derived from CT. Patients were followed with 24-hour electrocardiography and exercise tests at 3, 6 and 12 months after AF ablation. Arrhythmia recurrence was defined as any AF/atrial tachycardia (AT) beyond 3 months without anti-arrhythmic drugs. RESULTS: During a median follow-up of 13 (IQR 10-17) months, 42 (60%) patients had AF/AT recurrence. Multivariate Cox proportional regression analysis showed that a larger box surface ratio protected against recurrence (Hazard Ratio (HR) 0.81; 95% confidence interval (CI) (0.690 0.955); p = 0.012). Left atrial volume index (HR 1.01 (0.990-1.024, p = 0.427) and a history of mitral valve surgery (HR 2.90; 95% CI 0.970-8.693; p = 0.057) were not associated with AF recurrence in multivariate analysis. CONCLUSION: A larger box lesion surface area as a ratio of total LA surface area is protective for AF/AT recurrence after ablation for persistent AF. This article is protected by copyright. All rights reserved. PMID- 30520060 TI - The Interplay Between Nonalcoholic Fatty Liver Disease and Atherosclerotic Heart Disease. AB - Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, exists in two predominant histological subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NASH is the clinically aggressive variant with higher risk of fibrosis progression and mortality. The leading cause of mortality in patients with NAFLD is cardiovascular disease (CVD), and is linked to diagnosis of NASH and severity of hepatic fibrosis. This article is protected by copyright. All rights reserved. PMID- 30520061 TI - Effects of Danhong injection, a traditional Chinese medicine, on nine cytochrome P450 isoforms in vitro. AB - Danhong injection (DHI) is made from Salvia miltiorrhiza Bunge. and Carthamus tinctorius L. extract and is widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. This study was aimed to evaluate the effect of DHI on cytochrome P450 (CYP450) enzymes in vitro to predict drug-drug interactions based on CYP450 as combination therapy. To assess the inhibitory effect of DHI on CYP450, we detected the IC50 value of DHI on CYP450 in vitro by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Simultaneously, the induction effect of DHI on CYP450s was also evaluated. The relative induction ratio of DHI on CYP1A2, CYP2B6 and CYP3A4 activity were calculated by LC-MS/MS. The expression level of CYP3A4 mRNA was determined by reverse transcription PCR (RT-PCR). The data of LC-MS/MS showed DHI intensively inhibit CYP2A6 activity and the intensity of inhibition was followed by CYP2C8, CYP3A4, CYP2C19, CYP2B6, CYP2D6, CYP1A2, CYP2E1 and CYP2C9 in vitro. The results of RT-PCR showed that there is a certain induction of DHI on CYP3A4 mRNA in human primary hepatocytes in vitro. The study suggested that drug-drug interactions might occur in clinical co-administration of drugs due to the CYP2A6 inhibition and CYP3A4 induction. PMID- 30520062 TI - Hepatocyte Nuclear Factor 4 alpha (HNF4alpha) Activation is Essential for Termination of Liver Regeneration. AB - Hepatocyte Nuclear Factor 4 alpha (HNF4alpha) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4alpha in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4alpha activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4alpha protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4alpha protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4alpha (HNF4alpha-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4alpha target gene expression throughout regeneration indicated HNF4alpha-KO mice were unable to compensate for loss of HNF4alpha transcriptional activity. Deletion of HNF4alpha resulted in sustained proliferation accompanied by c-Myc and Cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4alpha in hepatocytes delayed but did not prevent initiation of regeneration after PH. Finally, AAV8 mediated reexpression of HNF4alpha in hepatocytes of HNF4alpha-KO mice post-PH restored HNF4alpha protein levels, induced target gene expression and improved survival of HNF4alpha-KO mice post-PH. In conclusion, these data indicate that HNF4alpha reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4alpha in liver regeneration and have implications for therapy of liver failure. This article is protected by copyright. All rights reserved. PMID- 30520063 TI - Stereotactic radiofrequency ablation of hepatocellular carcinoma - A histopathological study in explanted livers. AB - BACKGROUND AND RATIONALE FOR THE STUDY: This retrospective study was performed to evaluate the efficacy of 3D-navigated multi-probe radiofrequency ablation (RFA) with intraprocedural image fusion for the treatment of hepatocellular carcinoma (HCC) by histopathologic examination. MAIN RESULTS: From 2009 to 2018, 97 patients (84 men, 13 women; median age 60 years, range 1 -71) were transplanted after bridging therapy of 195 HCCs by stereotactic RFA (SRFA). The median interval between the first SRFA and transplantation was 6.8 months (range: 0 - 71). The rate of residual vital tissue (RVT) could be assessed in 188/195 lesions in 96/97 patients by histological examination of the explanted livers using Hematoxylin & Eosin (H&E) and TUNEL stains. The histopathologic results were compared with the findings of the last CT imaging prior to LT. The median number and size of the treated tumors were 1 (range: 1-8) and 2.5 cm (range: 1-8 cm). Complete radiological response was achieved in 186/188 nodules (98.9%) and 94/96 patients (97.9%) and complete pathological response in the explanted liver specimen in 183/188 nodules (97.3%) and 91/96 patients (94.8%), respectively. In lesions >=3 cm complete tumor cell death was achieved in 50/52 nodules (96.2%). Residual tumor did not correlate with tumor size (p = 0.5). CONCLUSIONS: Multi probe SRFA with intraprocedural image fusion represents an efficient minimal invasive therapy for HCC, even with tumor sizes larger than 3cm, and without the need of a combination with additional treatments. The results seem to justify the additional efforts related to the stereotactic approach. This article is protected by copyright. All rights reserved. PMID- 30520064 TI - Metabolomics study on promoting blood circulation and ameliorating blood stasis: investigating the mechanism of Angelica sinensis and its processed products. AB - Angelica sinensis (Danggui, DG) parched with alcohol (Jiu Danggui, JDG) and charred DG (CDG) were main processed products of DG, which were used to treat blood stasis syndrome (BSS). However, their therapeutic effect and mechanisms are still unclear. Based on a rats acute BSS model, the intervention effects of DG and its processed products (DGPPs) were evaluated by the hemorheology and coagulation function parameters. Meanwhile, plasma and urine metabolites were detected and analyzed by liquid chromatography coupled to quadrupole time-of flight mass spectrometry and multivariate statistical analysis method. The results of hemorheology, coagulation function parameters and metabolomics all showed that the BSS model was successfully established, DGPPs intervention could significantly relieve rats BSS, and the therapeutic effect of JDG was best. Moreover, 23 differential metabolites (14 in plasma and 9 in urine) were identified closely related to the BSS, involving 7 potential target metabolic pathways. DGPPs intervention had different degrees of reverse effect on these metabolites. JDG was the most effective due to its extensive regulation effect on differential metabolites. This study provides a reference to understanding the pathological mechanism of BSS and the mechanism of DGPPs, which lays a theoretical foundation for the rational use of DGPPs in clinical practice. PMID- 30520065 TI - Postural orthostatic tachycardia syndrome (POTS) in teens: A guide for behavior change to manage symptoms. PMID- 30520066 TI - Late cutaneous B-Cell pseudolymphoma after an upper-lid gold weight implant. AB - Upper eyelid gold weight implants are an established tool in the symptomatic treatment of lagophthalmos, the inability to close your eyes completely. Complications associated to this procedure are infrequent. When noted, non infectious inflammatory reactions corresponding to type IV hypersensitivity reactions are resolved with the removal of the implant. Here, we report a case of a late B-cell cutaneous pseudolymphoma in a patient, four years after the removal of the weight that showed strongly positive patch tests to gold sodium thiosulfate. PMID- 30520068 TI - Referees. PMID- 30520067 TI - Orderly authors and author order. PMID- 30520069 TI - Connections. PMID- 30520070 TI - Efficiency of autocoding programs for converting job descriptors into standard occupational classification (SOC) codes. AB - BACKGROUND: Existing datasets often lack job exposure data. Standard Occupational Classification (SOC) codes can link work exposure data to health outcomes via a Job Exposure Matrix, but manually assigning SOC codes is laborious. We explored the utility of two SOC autocoding programs. METHODS: We entered industry and occupation descriptions from two existing cohorts into two publicly available SOC autocoding programs. SOC codes were also assigned manually by experienced coders. These SOC codes were then linked to exposures from the Occupational Information Network (O*NET). RESULTS: Agreement between the SOC codes produced by autocoding programs and those produced manually was modest at the 6-digit level, and strong at the 2-digit level. Importantly, O*NET exposure values based on SOC code assignment showed strong agreement between manual and autocoded methods. CONCLUSION: Both available autocoding programs can be useful tools for assigning SOC codes, allowing linkage of occupational exposures to data containing free text occupation descriptors. PMID- 30520071 TI - Assessment of the long-acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions. AB - The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long-acting (LA) formulation to sheep and its impact on potential drug-drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 MUg/kg) and as LA formulation at 630 MUg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long-lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated Cmax and AUC0-t values of the IVM-LA formulation were 1.47- and 3.35-fold higher compared with IVM 1% formulation, respectively. The T1/2ab and Tmax collected after administration of the LA formulation were 2- and 3.5-fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7-fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post-administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug-drug interactions is a further contribution to the field. PMID- 30520072 TI - Downregulation of long noncoding RNA SNHG1 inhibits cell proliferation, metastasis, and invasion by suppressing the Notch-1 signaling pathway in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer (PC) has become the fourth most lethal among human cancers. Long noncoding RNAs (lncRNAs) have been reported to play a role in the progression of a variety of cancers. However, the role of lncRNA SNHG1 in PC is not clear. METHODS: Real-time Quantitative PCR Detection System (qPCR) was used to detect the expression of SNHG1 in PC cells. Then, the SNHG1 knockdown cell was constructed with si-SNHG1. AsPC-1 and PANC1 cells were used to analyze the ability of cell proliferation, invasion, and migration. MTT assay was used to analyze the proliferation ability. Transwell experiments and wound healing experiments were used to detect the capacity of invasion and migration. Finally, Western blot analysis was used to explore the mechanism of SNHG1 in PC. RESULTS: SNHG1 was significantly upregulated in PC cells. Knockdown of SNHG1 could obviously suppress cell proliferation, invasion, and migration. Furthermore, SNHG1 knockdown inhibited the activation of the Notch-1 signaling pathway and inhibited the expression of N-cadherin, Hes1, Vimentin, Notch-1. The inhabitation was reversed when Notch-1 was overexpressed in si-SNHG1 cells. CONCLUSION: The lncRNA SNHG1 promotes cell growth and metastasis in PC through activation of the Notch-1 signaling pathway in PC. PMID- 30520073 TI - LncRNA SNHG20 contributes to cell proliferation and invasion by upregulating ZFX expression sponging miR-495-3p in gastric cancer. AB - Long noncoding RNAs (lncRNAs) exert key regulators in cancer development and progression. The functional significance of lncRNA small nucleolar RNA host gene 20 (SNHG20) was reported in gastric cancer (GC); however, the underlying molecular mechanism in GC development is largely unknown. Here, our results showed that the lncRNA SNHG20 expression was significantly higher in GC tissues compared with adjacent normal tissues by quantitative real-time PCR (qRT-PCR) analysis. Higher lncRNA SNHG20 expression was highly associated with tumor size and lymphatic metastasis of patients. Patients with higher lncRNA SNHG20 expression predicted a short disease-free survival (DFS) and overall survival (OS). Furthermore, lncRNA SNHG20 expression negatively associated with miR-495-3p expression and regulated miR-495-3p expression. Function assays confirmed that lncRNA SNHG20 knockdown using RNA interference suppressed cell proliferation and invasion of GC by negatively regulating miR-495-3p expression. Moreover, we demonstrated that lncRNA SNHG20 inhibited zinc finger protein X-linked (ZFX) expression by negatively miR-495-3p expression in GC cells. In vivo, the current study also indicated that lncRNA SNHG20 knockdown reduced the tumor growth by downregulating ZFX expression. Thus, our results implied that inhibition of SNHG20/miR-495-3p/ZFX axis may provide valuable target for GC treatment. PMID- 30520074 TI - III. THE ORGANIZATION OF ATTACHMENT BEHAVIOR IN EARLY CHILDHOOD: LINKS WITH MATERNAL SENSITIVITY AND CHILD ATTACHMENT REPRESENTATIONS. AB - This article investigated two central questions about mother-child attachment relationships during early childhood: (1) the association between maternal sensitivity and child attachment behavior (Study 1) and (2) the link between child attachment behavior and representations (Study 2). In Study 1, maternal sensitivity and child security were assessed in naturalistic contexts among 74 middle-class dyads, when children were about 3.5 and again 5.5 years of age, using the Maternal Behavior with Preschoolers Q-set (MBPQS) and the Attachment Q set (AQS), respectively. Sensitivity and security were significantly related at each point in time and stable from 3.5 to 5.5 years of age. Furthermore, changes in sensitivity predicted changes in child security. In Study 2, the relationship between the organization of preschoolers' attachment behavior and the structure of attachment representations (secure base script knowledge) was assessed. Participants were 158 preschoolers between 3 and 5.5 years. Children's secure base behavior was described with the AQS, whereas their attachment script knowledge was assessed with the MacArthur Attachment Story Completion Task. The organization of children's secure base behavior was significantly, if modestly, associated with their knowledge of the secure base script. PMID- 30520075 TI - VII. MATERNAL SECURE BASE SCRIPT KNOWLEDGE AND JUDGMENTS OF MOTHER-CHILD INTERACTIONS. AB - Previous studies have shown that mothers with high script scores are better at providing secure base support in naturalistic settings. In the current study, we examine whether maternal script knowledge guides mothers' expectations and judgments of mother-child interactions, providing a bridge between their knowledge and behavior. Forty mothers were asked to use a new Parental Secure Base Q-set designed to characterize a typical mother-child play day at a park. Furthermore, video clips from mother-child joint storytelling sessions, already scored for maternal co-construction skills (from Chapter IV), were presented. The mothers rated the videotaped mothers' interaction skills on several quality of interaction scales (sensitivity to signals, cooperation vs. inference, affect regulation). Results indicated that mothers with high script scores showed greater understanding of secure base support (Q-sort data) and an observant "eye" for skillful mother-child interaction, particularly with respect to noting less effective mother-child interactions. These findings support the hypothesis that secure base script knowledge is linked to broad-based understanding of secure base support across contexts. PMID- 30520076 TI - THE MOTHER-CHILD ATTACHMENT PARTNERSHIP IN EARLY CHILDHOOD: SECURE BASE BEHAVIORAL AND REPRESENTATIONAL PROCESSES. AB - The chapters in this monograph describe the transition of attachment representations from a predominantly sensorimotor, in the moment, experience for the infant/toddler to internalized, mental representations of attachment that are transportable to new social contexts, in which attachment figures may not be present. The chapters focus on means that parents use to help their child effect this transition in terms of both behavioral support for the child's secure base behavior and for cognitive skills that underlie the child's construction of mental models of attachment. The results cohere across studies and make a compelling case for Bowlby's notion that internal models of how attachment "works" are co-constructed through social processes during early childhood. Taken together, the results reported here constitute a milestone achievement for the attachment enterprise in terms of their theoretical and methodological rigor. These findings also justify Bowlby's confidence that cognitive psychology would become a critical disciplinary ally of attachment theory. PMID- 30520077 TI - VI. INTERGENERATIONAL TRANSMISSION OF SECURE BASE SCRIPT KNOWLEDGE: THE ROLE OF MATERNAL CO-CONSTRUCTION SKILLS. AB - This study examined the link between mothers' and children's script-like representations of attachment and the role of maternal co-construction skills in facilitating script knowledge in their children. Fifty-nine children recruited from preschools in Bucharest, Romania (age range 4 to 5 years) completed a shortened version of the Attachment Story Completion Task (ASCT) to assess their secure base script knowledge whereas their mother's script knowledge was assessed with the Attachment Script Assessment (ASA). In addition, the mother-child pairs completed the Affect Discussion Task (see Chapter II) to assess mothers' co construction skills. Mother and child secure base script knowledge was significantly related, as were maternal co-construction skills and child script knowledge. Regression analyses indicated that maternal co-construction skills impacted children's script knowledge above and beyond the effects of maternal script scores. PMID- 30520078 TI - ACKNOWLEDGMENTS. PMID- 30520079 TI - V. MATERNAL SENSITIVITY AND CO-CONSTRUCTION SKILLS: CONCURRENT AND LONGITUDINAL ASSOCIATIONS WITH PRESCHOOLERS' SECURE BASE BEHAVIOR. AB - This study investigated the associations among maternal sensitivity, maternal secure base script co-construction skills, and children's secure base behavior during early childhood. Maternal sensitivity and children's secure base behavior were assessed in naturalistic settings among 81 mother-child dyads when the children were approximately 3.5 years old. Maternal co-construction skills were also assessed at that age via a joint mother-child storytelling task. Maternal sensitivity and secure base behavior were assessed again when children (N = 74) were about 5.5 years old. Results indicated that mother sensitivity assessed at the early age was significantly related to maternal co-construction skills. Maternal co-constructive skills in turn were also significantly associated with children's secure base behavior both concurrently and longitudinally. Finally, regression analyses indicated both maternal sensitivity, concurrently at each point in time, and co-construction skills contributed unique and significant information to the prediction of child secure base behavior. PMID- 30520080 TI - APPENDICES. PMID- 30520081 TI - II. MEASURES: SECURE BASE BEHAVIOR, CO-CONSTRUCTION, AND ATTACHMENT SCRIPTS. AB - In order to examine the interplay between behavioral and cognitive representations of attachment during early childhood, we compiled both behavior based and more cognitive-based attachment measures for this age range. The behavior-based measures were observational Q-set methodologies already established in the literature. Measures of attachment representations for the children and mothers were narrative-based procedures, that is, established storytelling tasks for obtaining attachment narratives from children and adults. For assessing maternal co-construction processes, we developed two new co construction tasks that required joint storytelling of attachment relevant storylines in one case, and joint conversations about emotion-laden situations in the other. All of these measures are based on the central secure base construct of attachment theory. Behavioral measures assess secure base use and support. Attachment narratives collected from both children and parents are scored for secure base script knowledge. Maternal co-construction is assessed in terms of cognitive processes that enhance and promote attachment script knowledge. PMID- 30520082 TI - IV. CO-CONSTRUCTION OF ATTACHMENT REPRESENTATIONS AND AFFECT-REGULATING COGNITIONS: THE ROLE OF MATERNAL ATTACHMENT SECURITY. AB - This study focused on the role of maternal co-construction skills in building attachment relevant representations in early childhood. Thirty-four mothers and their 4- to 5-year-old children were presented with two co-construction tasks, one an attachment storytelling task, the other an affect discussion task about emotion-laden situations. Maternal co-construction skills were assessed with several scales that scored the quality of the co-construction partnership, the mother's skill in prompting elaboration, and helping build an explanatory framework. Mothers completed the Attachment Script Assessment (ASA) and the Adult Attachment Interview (AAI) as well. Results indicated that mothers' secure base script knowledge (ASA) was significantly related to communication effectiveness, encouraging elaboration of storylines, and using open-ended and why questions. Maternal AAI coherence showed similar relations to co-construction support. PMID- 30520083 TI - VIII. CONCLUSION: CO-CONSTRUCTING A SECURE BASE PARTNERSHIP: MOTHER-CHILD INTERACTIONS, COMMUNICATION, AND SCRIPT REPRESENTATIONS. AB - Using the secure base construct, the evidence presented indicates that interactional experience continues to be a central factor in the organization of mother-child attachment relationships. The parent-child codetermination process that establishes their relationship in infancy expands during the preschool years. Furthermore, with the increasingly relevant role of language, parent-child verbal communication during this time plays an important part in structuring children's attachment behavior and knowledge. Parents help their children construe attachment-related information, control and regulate emotional experience, and guide behavior during attachment-related experiences. That is, during early childhood, parent and child continue the process of constructing a secure base partnership through their gradually more complex interactions that take advantage of children's behavioral, emotional, representational, and language advances. Although the studies are interrelated and contribute to a coherent understanding of attachment relationships during this time period, they represent small-scale studies. Further, some of the effect sizes presented are small. Thus, future research should include tests of replication as well as explorations of links to early and later development and parallel findings in more diverse samples. PMID- 30520084 TI - I. INTRODUCTION: THE CO-CONSTRUCTION OF MOTHER-CHILD ATTACHMENT RELATIONSHIPS IN EARLY CHILDHOOD. AB - Attachment relationships are formed, organized, and elaborated through interactions between an attachment figure and her/his child. The parent-child codetermination process that establishes their relationship in infancy extends and expands during the preschool years. A child's developing ability to use her/his mother as a secure base requires support, time, and practice during early childhood. Moreover, experiences with attachment figures provide information that children use to build internal representations of their relationship. Thus, the organization of attachment behavior is expected to be related to the structure of a child's attachment representations. Yet, questions about how the structure of those representations develop remain unanswered. In moving into the preschool years, we anticipate that building of mental representations of secure base support and use will be guided by parent-child co-construction processes. The child's improving language and advancing information processing skills increase the opportunities for verbally based interactions between caregiver and child. The mother-child co-construction process of secure base relationships includes now a verbal-representational component, but the nonverbal, behavioral building blocks remain in play as well. PMID- 30520085 TI - ATTACHMENT AND MEMORY RESEARCH: REFLECTING ON A SHARED PAST AND A COLLABORATIVE FUTURE. AB - This commentary applauds the authors of the monograph, The Mother-Child Attachment Partnership in Early Childhood: Secure Base Behavioral and Representational Processes, for their thorough and elegant exploration of the development of attachment working models in the preschool years in relation to maternal sensitivity and attachment representations, mother-child co constructions of attachment-relevant stories, and children's own secure base behavior. These findings are set against a backdrop of children's memory development, with the recommendation that future research delves even younger to explore the development of attachment working models in children under 3 years. A second recommendation is to continue the work with older children, with a particular focus on the conversations they are having with caregivers about actual attachment-related experiences. This new research poses challenges, especially with at-risk samples. Fortunately, the stage is now set for attachment and memory researchers to come together to continue to map the development of attachment working models. PMID- 30520086 TI - Mutilating genital aphthous ulceration causing perforation in two women. PMID- 30520087 TI - Phenotypes of atopic dermatitis identified by cluster analysis in early childhood. AB - Atopic dermatitis is a chronic, relapsing, inflammatory skin disease that usually appears in early childhood and develops into a heterogeneous disease during childhood. The clinical course and treatment for atopic dermatitis can differ according to its phenotype and/or endotype. This study aimed to identify clinical phenotypes of atopic dermatitis in early childhood. Data were obtained from 572 children under 3 years of age with atopic dermatitis. Cluster analysis applied to 11 variables, and we identified four clusters of atopic dermatitis. Children in cluster A (n = 141) had early-onset atopic dermatitis with high blood eosinophil counts, serum total immunoglobulin E and rates of sensitization to food allergens. Children in cluster B (n = 218) had early-onset atopic dermatitis with low blood eosinophil counts, serum total immunoglobulin E and rates of sensitization to both food and inhalant allergens. Children in cluster C (n = 53) had early-onset atopic dermatitis with high C-reactive protein levels and white blood cell counts. Children in cluster D (n = 160) had middle-onset atopic dermatitis with high serum total immunoglobulin E and rates of sensitization to inhalant allergens. Cluster A had the highest Scoring for Atopic Dermatitis and transepidermal water loss values. Age at onset, age at diagnosis, white blood cell count, eosinophil count, C-reactive protein and serum total immunoglobulin E level were the strongest predictors of cluster assignment. Analysis of these six variables alone resulted in correct classification of 95.5% of the subjects. These results support the heterogeneity of atopic dermatitis, even in early childhood. PMID- 30520088 TI - Zosteriform lymphangitis carcinomatosis in the cervical area arising from pyriform fossa adenocarcinoma. PMID- 30520090 TI - Continuing Medical Education Program in Transfusion. PMID- 30520089 TI - Heparin-induced thrombocytopenia suggested by microscopic examination of a below knee amputation. PMID- 30520091 TI - Can anti-A1 cause hemolysis? PMID- 30520092 TI - Evacuation, resuscitation, and transfusion near "The Front," First World War, 1918. PMID- 30520093 TI - Reviewer Thank You. PMID- 30520094 TI - Downregulation of fibroblast growth factor 5 inhibits cell growth and invasion of human nonsmall-cell lung cancer cells. AB - The morbidity and mortality rates of nonsmall-cell lung cancer (NSCLC) have increased in recent years. We aimed to explore the biological role of fibroblast growth factor 5 (FGF5) in NSCLC. We first established that the expression of FGF5 was increased in NSCLC tissues compared with the normal adjacent tissues. The expression of FGF5 was also increased in NSCLC cell lines. The effect of FGF5 silencing on cell proliferation, cell cycle, apoptosis, migration, and invasion of H661 and CALU1 cells was then examined. Downregulation of FGF5 significantly inhibited cell proliferation and induced G1 phase cell cycle arrest compared with the negative control small interfering (siNC) groups. Cell apoptosis was promoted by siFGF5 treatment. Cell migration and invasion of H661 and CALU1 cells with siFGF5 transfection were markedly diminished compared with the siNC groups. In addition, migration and invasion-associated proteins (E-cadherin, matrix metalloproteinase-2 [MMP-2], and MMP-9) and epithelial mesenchymal transition markers (N-cadherin, vimentin, snail, and slug) were also regulated by FGF5 siRNA treatment. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that the Kyoto Encyclopedia of Genes and Genomes (KEGG) cell cycle and vascular endothelial growth factor (VEGF) pathways were correlated with FGF5 expression, which was further confirmed in NSCLC cells by Western blot analysis. Our results indicated that FGF5 silencing suppressed cell growth and invasion via regulation of the cell cycle and VEGF pathways. Therefore, FGF5 may serve as a promising therapeutic strategy for NSCLC. PMID- 30520095 TI - Molecular detection of Bifidobacterium spp. in faeces of black howler monkeys (Alouatta pigra). AB - BACKGROUND: Bifidobacterium genus are considered to be beneficial bacteria for their hosts; however, knowledge about the specific species that are part of the gut microbiome of howler monkeys is scarce. Polymerase chain reaction (PCR) is a useful technique for the identification of non-cultivable or difficult to grow bacterial species. With the goal of detecting species of the genus Bifidobacterium in black howler monkeys, we used PCR on DNA derived from faecal samples. METHODS: We collected and extracted DNA from 40 faecal samples. Using specific primers, we performed PCR and nested PCR to detect members of the Bifidobacterium genus and a subset of species: Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium infantis, Bifidobacterium longum and Bifidobacterium animalis subsp. animalis. RESULTS: 97.5% (39/40) of the samples were positive for Bifidobacterium spp. We found B longum in 100% of the analysed samples. CONCLUSIONS: This is the first report of B longum in black howler monkey faeces. PMID- 30520096 TI - A four-gene signature predicts the efficacy of paclitaxel-based neoadjuvant therapy in human epidermal growth factor receptor 2-negative breast cancer. AB - Neoadjuvant chemotherapy (NAC) is the major preoperative treatment of breast cancer (BC) with negative human epidermal growth factor receptor 2 (HER2), and the efficacy of NAC and the optimization of regimen are under intensive research. The current study aimed to define the predictive biomarkers for paclitaxel (PTX) response in NAC of HER2-negative BC. Data from GSE25065, GSE26065, GSE41998, as well as drug sensitivity data of breast and ovarian cancer cell line from NCI60, were used. Through logistic regression, COX regression, and correlation analysis with bootstrapping, we found that four genes (CDK8, FAM64A, MARC2, and OCEL1) were associated with drug sensitivity of PTX. The four gene ">=3" model had the best classification accuracy. Subgroup analysis found that the model performed well in the hormone receptor positive, HER2-negative subgroup and did not perform well in the triple-negative subgroup. Decision curve analysis showed that the model could enhance the predictive effect of clinical features. Subsequent gene set enrichment analysis, network analysis showed that these genes may be related to the cell cycle, mitosis and other pathways. The current study demonstrated the promising potential of the novel four-gene signature as a predictive biomarker for pathological complete response of HER2-negative BC patients and indicated the drug sensitivity of PTX. PMID- 30520097 TI - Hsa-miRNA-29a protects against high glucose-induced damage in human umbilical vein endothelial cells. AB - Sustained exposure to high glucose (HG) results in dysfunction of vascular endothelial cells. Hence, diabetic patients often suffer from secondary vascular damages, such as vascular sclerosis and thrombogenesis, which may eventually cause cardiovascular problems. Thus, elucidating how HG results in vascular endothelial cell damage and finding an approach for prevention are important to prevent and treat vascular damages in diabetic patients. In the current study, we first showed that 72-hour exposure to HG-decreased hsa-miRNA-29a and increased the expression of Bcl-2 associated X protein (Bax), which subsequently inhibited Bcl-2 and promoted the expression of apoptotic protease activating factor-1 and activation of caspase-3, thus directly triggering the mitochondrial apoptotic pathway in human umbilical vein endothelial cells (HUVECs). Study of the underlying mechanism showed that hsa-miRNA-29a/Bax plays an essential role in the decreased proliferation and increased apoptosis of HUVECs induced by HG, and overexpression of hsa-miRNA-29a effectively inhibits HG-induced apoptosis and restores the proliferation and tube formation of HUVECs exposed to HG by inhibiting its target gene Bax. In short, our study demonstrates that hsa-miRNA 29a is a promising target for the prevention and treatment of vascular injury in diabetic patients. PMID- 30520098 TI - miR-202 modulates the progression of neuropathic pain through targeting RAP1A. AB - Neuropathic pain is a somatosensory disorder which is caused by disease or nerve injury that affects the nervous system. microRNAs (miRNAs) are proved to play crucial roles in the development of neuropathic pain. However, the role of miR 202 in neuropathic pain is still unknown. Sprague-Dawley rats were used for constructing the neuropathic pain model. The expression of miR-202 was determined by quantitative real-time polymerase chain reaction. Potential target gene for miR-202 was measured using bioinformatics methods and Western blot analysis. In this study, we used rats to establish a neuropathic pain model and measured the effect of miR-202 in neuropathic pain. We demonstrated that miR-202 expression was downregulated in the spinal dorsal horn of bilateral sciatic nerve chronic constriction injury (bCCI) rat. However, miR-202 expression was not changed in the dorsal root ganglion, hippocampus, and anterior cingulated cortex of bCCI rat. We identified that RAP1A was a direct target gene of miR-202 in the PC12 cell. RAP1A expression was upregulated in the spinal dorsal horn of bCCI rat. Overexpression of miR-202 could improve the pain threshold for bCCI rats in both hindpaws, indicating that miR-202 overexpression could lighten the pain threshold for model rats. Moreover, RAP1A overexpression increased the pain threshold effect of miR-202 overexpression treated bCCI rats, indicating that miR-202 could lighten the pain threshold through inhibiting RAP1A expression. These data suggested that miR-202 acted pivotal roles in the development of neuropathic pain partly through targeting RAP1A gene. PMID- 30520099 TI - MicroRNA-590-3P suppresses cell survival and triggers breast cancer cell apoptosis via targeting sirtuin-1 and deacetylation of p53. AB - Downregulation of microRNA-590-3p (miR-590-3p) is a frequently occurring, nonphysiological event which is observed in several human cancers, especially breast cancer. However, the significance of miR-590-3p still remain unclear in the progression of this disease. This study explored the role of miR-590-3p in apoptosis of breast cancer cells. Gene expression of miR-590-3p, Sirtuin-1 (SIRT1), Bcl-2 associated X protein (BAX), and p21 was evaluated with real-time polymerase chain reaction (PCR) and SIRT1 protein expression was assessed by Western blot analysis in breast cancer cell lines. Bioinformatics analysis and luciferase reporter assay were used to evaluate targeting of SIRT1 messenger RNA (mRNA) by miR-590-3p. Cells were transfected with miR-590-3p mimic and inhibitor and their effects on the expression and activity of SIRT1 were evaluated. The effects of miR-590-3p upregulation on the acetylation of p53 as well as cell viability and apoptosis were assessed by Western blot analysis, WST-1 assay, and flow cytometry, respectively. miR-590-3p expression was considerably downregulated in breast cancer cells which was accompanied by upregulation of SIRT1 expression. SIRT1 was recognized as a direct target for miR-590-3p in breast cancer cells and its protein expression and activity was dramatically inhibited by the miR-590-3p. In addition, there was an increase in p53 and its acetylated form that ultimately led to upregulation of BAX and p21 expression, suppression of cell survival, and considerable induction of apoptosis in breast cancer cells. These findings suggest that miR-590-3p exerts tumor-suppressing effects through targeting SIRT1 in breast cancer cells, which makes it a potential therapeutic target for developing more efficient treatments for breast cancer. PMID- 30520100 TI - Has_circ_0055625 from circRNA profile increases colon cancer cell growth by sponging miR-106b-5p. AB - Circular RNAs (circRNA) are endogenous noncoding RNAs and play important roles in cancer; however, the roles of circRNAs in colon cancer are far from clear. The circRNA expression profile in colon cancer tissues was analyzed by microarray. The data from microarray showed that there were 198 upregulated and 136 downregulated circRNAs in colon cancer tissues. Among the top 10 upregulated circRNAs, hsa_circ_0055625 (circ_0055625) was confirmed to be significantly upregulated in colon cancer tissues. Further analysis demonstrated that circ_0055625 might get involved in the pathogenesis of colon cancer by functioning as miRNA sponges and performed bioinformatics analysis of the predicted circ_0055625/miR-106b-5p (miR-106b)/ITGB8 network. Moreover, we found that circ_0055625 expression was associated with pathological TNM stage and metastasis. These data indicated that circ_0055625/miR-106b/ITGB8 played a role in promoting tumor growth and metastasis, which suggested that circ_0055625 was a potential biomarker of colon cancer. PMID- 30520101 TI - Passive sampling of pesticides and polychlorinated biphenyls (PCBs) along the Quequen Grande River watershed (Argentina). AB - Water monitoring is of great importance, especially for waterbodies in agricultural or industrial areas. Grab sampling is a widely used technique for aquatic monitoring but represents only a snapshot of the contaminant levels at a specific point in time. Passive sampling, on the other hand, is an integrative technique which provides an average concentration of contaminants representative for its deployment period. Thus, the current contamination by organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and some currently used pesticides (CUPs) was assessed along the Quequen Grande River watershed using the integrative silicone rubber (SR) passive sampling technique in a year-long study. SR samplers were deployed at six sampling sites selected according to different land uses (agricultural-livestock production, agricultural and urban activities) during three periods in 2014 and 2015. OCPs were dominated by endosulfan (sum of alpha-, beta-endosulfan, endosulfan sulfate = 0.15-23.4 ng/L). The highest endosulfan levels were registered during the pesticide application period (December-March), exceeding the international water quality guidelines for protecting freshwater biota (3 ng/L). Comparing with previous reports, no reduction in endosulfan levels were observed at the Quequen Grande River watershed. These results would suggest the illegal use of remaining stocks since water sampling was carried out after endosulfan ban in Argentina. Chlorpyrifos was the second major pesticide found in water (0.02-4.3 ng/L), associated with its widespread usage on soybean crops. A reduction in levels of legacy pesticides (heptachlors, DDTs, dieldrin and chlordanes) was evident when compared with previous reports from 2007. PCBs levels were very low indicating that probably only minor diffuse sources were still available along the Quequen Grande River watershed. This article is protected by copyright. All rights reserved. PMID- 30520102 TI - Hepatic Resection Compared to Chemoembolization in Intermediate to Advanced-Stage HCC: a comment for moving forward. AB - Treatment of hepatocellular carcinoma (HCC) depends on disease staging, which is usually performed according to the Barcelona Clinic Liver Cancer (BCLC) system. Although the BCLC system is recommended in the guidelines from the European Association for the Study of the Liver,1 the American Association for the Study of Liver Diseases,2 and the European Society for Medical Oncology3 , its treatment recommendations for intermediate and advanced HCC are inconsistent with the literature. This article is protected by copyright. All rights reserved. PMID- 30520103 TI - Mitochondrial DNA plays an important role in lung injury induced by sepsis. AB - The effects and mechanisms of mitochondrial DNA (mtDNA) in the development of sepsis-induced lung injury is not well understood. In our present study, we studied the mtDNA effects in sepsis-induced lung injury model, in vitro and in vivo. Compared with the Normal group, the lung histopathological score, the number of positive apoptosis cell, wet/dry (W/D) ratio and TNF-alpha, IL-1beta, and IL-6 concentrations of lipopolysaccharides (LPSs) and mtDNA groups were significantly increased (P < 0.001, respectively). Meanwhile, the lung histopathological score, positive W/D ratio, number of apoptosis cell and tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 concentrations of LPS + mtDNA and small interfering RNA (siRNA)-NC + LPS + mtDNA groups were significantly upregulated compared with those of LPS group (P < 0.05, respectively). However, the lung histopathological score, the number of positive apoptosis cell, W/D ratio and TNF-alpha, IL-1beta, and IL-6 concentrations were significantly improved within the toll-like receptor (TLR9)siRNA + LPS + mtDNA group compared with the LPS group (P < 0.01, respectively). The TLR9, MyD88, and NF-kappaB proteins or gene expressions of the LPS group and mtDNA group were significantly upregulated compared with those of Normal group by Western blot analysis or immunohistochemistry assay (P < 0.01, respectively), and the TLR9, MyD88, and NF-kappaB proteins or gene expressions of LPS + mtDNA and siRNA-NC + LPS + mtDNA groups were significantly enhanced compared with those of LPS group (P < 0.05, respectively). However, the TLR9, MyD88, and NF-kappaB proteins or gene expressions of TLR9siRNA + LPS + mtDNA group were significantly suppressed compared with those of the LPS group (P < 0.01, respectively). In conclusion, mtDNA could provoke lung injury induced by sepsis via regulation of TLR9/MyD88/NF kappaB pathway in vitro and in vivo. PMID- 30520104 TI - A seed change in our understanding of legume biology from genomics to the efficient cooperation between nodulation and arbuscular mycorrhizal fungi. AB - Grain legumes play a significant role in global food security. They have an advantage over cereals in that they can form symbiotic associations with nitrogen fixing bacteria, making them self-sufficient in terms of nitrogen acquisition. In addition to this superior agronomic trait, grain legumes have excellent nutritional properties and are thus widely used as animal feed as well as in human nutrition. Current global trends towards increased legume consumption and availability of value-added products, as well as legume production in developing countries require the provision of improved cultivars with better productivity and adaptability. Intensive efforts are thus underway to elaborate genomic resources and gain an improved knowledge base in a number of legume crops. There is also an emerging understanding of the beneficial interactions between legume associated organisms, particularly rhizobia and arbuscular mycorrhizal fungi, which result in improved nodulation and nutrient acquisition. The emerging focus on legume breeding for high sustainable yields as well as improved biotic and abiotic stress tolerance traits will serve to close the current gap between grain legume production and demand. With the support from policymakers, this increase in knowledge can be readily translated into increased crop production to meet the demands of an increasing global population. PMID- 30520105 TI - Comprehensive analysis of presurgical factors predicting psychiatric disorders in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis underwent cortico-amygdalohippocampectomy. AB - BACKGROUND: This study aimed to evaluate the predictive value of presurgical factors for psychiatric disorders (PD) in refractory temporal lobe epilepsy and mesial temporal sclerosis (TLE-MTS) patients underwent cortico amygdalohippocampectomy (CAH). METHODS: A total of 98 refractory TLE-MTS patients underwent CAH were consecutively enrolled in this cohort study. Several presurgical factors were recorded, such as married status, employment status, highest education, disease duration, family history of epilepsy, and disorganized VEEG background activity. RESULTS: There were 17 (17.3%) refractory TLE-MTS patients occurring PD after CAH, including 8 (8.2%) mood disorders, 7 (7.1%) anxiety disorders, 8 (8.2%) psychoses, and 1 (1.0%) interictal dysphoric disorder. Employed status correlated with low PD occurrence, while disease duration and asymmetric VEEG background activity positively correlated with PD occurrence. Multivariate logistic analysis revealed employed status (P = 0.009) could independently predict lower PD occurrence, while highest education (P = 0.027), disease duration (P = 0.028), seizure frequencies (P = 0.015), and asymmetric VEEG background activity (P = 0.034) could independently predict higher PD occurrence. Receiver operating characteristic curve showed combination of these five factors (area under curve (AUC) = 0.871, 95%CI: 0.783-0.960) disclosed a great predictive value of PD occurrence. The sensitivity and specificity were 70.6% and 92.6% at the best cutoff point. In addition, the percentage of PD was increased with higher Engel classification (P = 0.003). CONCLUSION: Employed status, highest education, disease duration, seizure frequencies, and asymmetric VEEG background activity correlate with PD occurrence independently in epileptic patients. PMID- 30520106 TI - Editor-in-Chief thanks the Associate Editors, Editorial Board and Referees. PMID- 30520107 TI - Multimodal imaging of foveal neovascularisation in diabetic retinopathy. PMID- 30520108 TI - Theoretical investigation on the optical and EPR spectra for Cu2+ doped ZnO-CdS nanocomposites. AB - The three optical absorption bands and EPR parameters of the [CuO6 ]10- center in the ZnO-CdS composite nanopowders are theoretically studied from the perturbation formulas based on the cluster approach. In the formulas, the contributions to EPR parameters arising from the ligand orbital and spin-orbit coupling interactions via covalence effect are considered. For the studied [CuO6 ]10- cluster, the Cu-O bond lengthes are suggested to show a relative elongation ratio rho (~ 4.1%) along the z-axis due to Jahn-Teller effect. The defect models suggested in this work is different from the previous assumption that the impurity Cu2+ can replace the host Zn2+ site when it enters the lattices of the ZetanO and ZetanS nanocrystals, forming the tetrahedral [CuChi4 ]6- clusters (Chi = O, S). The validity of the proposed model is discussed. The differences between the present calculations and the previous ones for the interstitial Cu2+ center in ZnO nanocrystals are analyzed in view of the dissimilar impurity behaviors due to the new composition CdS and distinct preparation conditions. PMID- 30520109 TI - Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response. AB - BACKGROUND: In vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments. METHODS: Three PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA). RESULTS: We compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors. CONCLUSIONS: Ex vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals. PMID- 30520110 TI - Presystolic wave is associated with carotid intima media thickness. AB - INTRODUCTION: Carotid intima media thickness (CIMT), a direct marker of atherosclerosis, has emerged as a promising means for cardiovascular risk evaluation. Presystolic wave (PSW) is commonly detected by the Doppler interrogation of the left ventricular outflow tract (LVOT). It is thought to be a result of a stiff left ventricle and impaired LV compliance. Herein, we aimed to investigate a possible association between carotid intima media thickness, an atherosclerotic marker, and PSW. METHOD: We prospectively enrolled 282 patients divided into two groups based on the presence of PSW: 221 (89F; mean age: 49.3 +/ 11.5 years) had PSW on Doppler examination while 61 patients (32F; mean age: 46.4 +/- 10.3 years) did not. Both groups were compared with respect to demographic, clinical properties, and CIMT. RESULTS: Both groups had comparable age, body mass index, and diabetes mellitus, hypertension, dyslipidemia, smoking, and family history for coronary heart disease. PSW-positive group had significantly higher CIMT (PSW-positive: 0.59 +/- 0.22 mm vs PSW-negative: 0.42 +/- 0.11 mm; P < 0.001) than PSW-negative group. Multivariate analysis showed that the independent predictors of increased CIMT were age (95% CI; 1.044-1.101, P < 0.001), dyslipidemia (95% CI; 0.147-0.664, P = 0.002), and the presence of PSW (95% CI; 2.168-7.836, P < 0.001).Correlation analysis showed that PSW velocity is correlated with increased CIMT in PSW-positive group (r: 0.418, P < 0.001). CONCLUSION: Assessment of PSW on TTE is easy and feasible method. Presence of PSW and increased PSW velocity on TTE might provide information that we should be careful in terms of subclinical atherosclerosis. PMID- 30520111 TI - The effectiveness of topical therapy combined with 308-nm excimer laser on vitiligo compared to excimer laser monotherapy in pediatric patients. AB - We evaluated the efficiency of using a 308-nm excimer laser with either tacrolimus, pimecrolimus, or halometasone for the treatment of childhood vitiligo. Patients who received combined treatments had significantly higher rates of repigmentation in comparison with individuals who underwent excimer laser alone therapy. Moreover, patients who received treatment with excimer laser and halometasone had significantly higher rates of repigmentation, even higher than individuals who were treated with tacrolimus combined or pimecrolimus combined. This regimen was more effective on the face, neck, and limbs. We conclude that the use of a combined excimer laser and halometasone cream has a greater therapeutic effect than laser alone. PMID- 30520112 TI - Knockdown of sal-like 4 expression by small interfering RNA induces apoptosis in breast cancer cells. AB - Breast cancer is the most prevalent cancers worldwide and causes a significant amount of deaths annually. Spalt-like transcription factor 4 is known as a transcription factor, which has an important role in the proliferation of cancerous cells. Small interfering RNA (siRNA) is a short-chain molecule of 20 to 25 nucleotides that protrude on two sides of the 3', two nucleotides. In this study, using a specific sequence of siRNA against the sequence of this gene, its activity is investigated in the cell line of breast cancer. The breast cancer cells (MCF-7) were cultured and then, using a specific anti-sal-like 4 (SALL4) siRNA, their toxic doses were determined. Then, the gene is transfected into the cell. Proliferation and expression of the SALL4 and BCL-2 gene were measured using the real-time polymerase chain reaction method. The specific concentration of siRNA IC50 of the SALL4 gene was 40.35 nmole. Gene expression results indicated that the expression of the Bcl-2 gene in the siRNA group was significantly reduced ( P < 0.05). SiRNA can increase the apoptosis of breast cancer cells by reducing the gene expression of SALL4 gene and Bcl-2; it can be used as a novel targeted therapy. This strategy, in addition to increasing the specificity of the drug, also reduces the side effects when compared with conventional chemotherapy. PMID- 30520114 TI - Foreword. PMID- 30520113 TI - Improvements in Lipid Suppression for 1H NMR-based Metabolomics: Applications to Solution-state and HR-MAS NMR-natural and in vivo samples. AB - Proton NMR spectra of intact biological samples often show strong contributions from lipids which overlap with signals of interest from small metabolites. Pioneering work by Diserens et al. demonstrated that the relative differences in diffusivity and relaxation of lipids verses small metabolites could be exploited to suppress lipid signals, in HR-MAS NMR spectroscopy. In solution state NMR, suspended samples can exhibit very broad water signals which are challenging to supress. Here, improved water suppression is incorporated into the sequence and the CPMG train is replaced with a low power adiabatic spinlock that reduces heating and spectral artefacts seen with longer CPMG filters. The result is a robust sequence that works well in both HR-MAS as well as static solution-state samples. Applications are also extended to include in vivo organisms. For solution-state NMR, samples containing significant amount of fats such as milk and hemp hearts seeds are used to demonstrate the technique. For HR-MAS, living earthworms (Eisenia fetida) and freshwater shrimp (Hyalella azteca) are used for in vivo applications. Lipid suppression techniques are essential for non-invasive NMR-based analysis of biological samples with a high lipid content and adds to the suite of experiments advantageous for in vivo environmental metabolomics. PMID- 30520115 TI - Extending spin-symmetry projected coupled-cluster to large model spaces using an iterative null-space projection technique. AB - Recently, we introduced an orbital-invariant approximate coupled-cluster (CC) method in the spin-projection manifold. The multi-determinantal property of spin projection means that the parametrization in the spin-extended CC (ECC) ansatz is nonorthogonal and overcomplete. Therefore, the linear dependencies must be removed by an orthogonalization procedure to obtain meaningful solutions. Multi reference methods often achieve this by diagonalizing a metric of the equation system, but this is not feasible with ECC because of the enormous size of the metric, a consequence of the incomplete active space of the spin-projected Hartree-Fock reference. As a result, the applicability of ECC has been limited to small benchmark systems, for which the ansatz was shown to be superior to the configuration interaction and linearized approximations. In this article, we provide a solution to this problem that completely avoids the metric diagonalization by iteratively projecting out its null-space from the working equations. As the additional computational cost required for this iterative projection is only marginal, it greatly expands the application range of ECC. We demonstrate the potential of approximate ECC by studying the complete basis set limit of F2 and transition metal complexes such as NiO, Mn2 , and [Cu2 O2 ]2+ , which have all been hindered by the prohibitively large metric size. We also identify the potential inadequacy of the molecular orbitals given by spin projected Hartree-Fock in some cases, and propose possible solutions. (c) 2018 Wiley Periodicals, Inc. PMID- 30520116 TI - Electronic and nuclear flux analysis on nonadiabatic electron transfer reaction: A view from single-configuration adiabatic born-huang representation. AB - A detailed flux analysis on nonadiabatically coupled electronic and nuclear dynamics in the intramolecular electron transfer of LiF is presented. Full quantum dynamics both of electrons and nuclei within two-state model has uncovered interesting features of the individual fluxes (current of probability density) and correlation between them. In particular, a spatiotemporal oscillatory pattern of electronic flux has been revealed, which reflects the coherence coming from spatiotemporal differential overlap between nuclear wavepackets running on covalent and ionic potential curves. In this regard, a theoretical analogy between the nonadiabatic transitions and the Rabi oscillation is surveyed. We also present a flux-flux correlation between the nuclear and electronic motions, which quantifies the extent of deviation of the actual electronic and nuclear coupled dynamics from the Born-Oppenheimer adiabatic limit, which is composed only of a single product of the adiabatic electronic and nuclear wavefunctions. (c) 2018 Wiley Periodicals, Inc. PMID- 30520117 TI - ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma. AB - Cancer stem cells (CSCs) are well contributing to high rate of recurrence and chemotherapeutic resistance in many types of cancer including intrahepatic cholangiocarcinoma (ICC). Inhibitor of differentiation 3 (ID3) has been reported to promote cancer stem cells, but its role in ICC is obscure. In this study, we identified that ID3 is highly expressed in human ICC tissues compared with matched normal tissues and correlates with poor prognosis. Functional studies demonstrate that ID3 is required for stemness maintenance in cholangiocarcinoma both in vitro and in vivo. Consistent with the regulation of CSC features by ID3, transgenic expression of ID3 enhances chemo-resistance of cholangiocarcinoma cells. Moreover, we found that ICC patients with low ID3 levels benefited from postoperative transarterial chemoembolization (TACE), while patients with high ID3 levels did not, indicating the significance of ID3 in individualized ICC therapy. Mechanistically, ID3 could interact with E47 and block E47 recruitment to the promoter of beta-catenin, which leads to activation of Wnt/beta-catenin signaling. Therefore, our results show that ID3 could promote the stemness of ICC by increasing the transcriptional activity of beta-catenin and could serve as a novel biomarker in predicting ICC patient's response to adjuvant chemotherapeutics. This article is protected by copyright. All rights reserved. PMID- 30520118 TI - Airflow obstruction among ever-employed U.S. adults aged 18-79 years by industry and occupation: NHANES 2007-2008 to 2011-2012. AB - INTRODUCTION: This study estimated the prevalence of spirometry-defined airflow obstruction by industry and occupation and chronic obstructive pulmonary disease (COPD) among ever-employed U.S. adults. METHODS: Data came from the National Health and Nutrition Examination Survey (NHANES) 2007-2008 to 2011-2012, a nationally representative study of the non-institutionalized civilian U.S. POPULATION: Data on respondent's current and/or longest held job were used to create prevalence estimates and adjusted prevalence odds ratios (PORs) for airflow obstruction and COPD. RESULTS: Among ever-employed U.S. adults, airflow obstruction prevalence was 12.40% and COPD was 3.47%. High airflow obstruction prevalence and significant PORs were reported in mining; manufacturing; construction; and services to buildings industries as well as extraction; bookbinders, prepress, and printing; installers and repairers; and construction occupations. CONCLUSION: Prevalence of airflow obstruction varies by industry and occupation. Industries and occupations with increased risk were identified using the most current NHANES data including detailed occupations and spirometry. PMID- 30520119 TI - The use of heart rate variability analysis to detect arrhythmias in horses undergoing a standard treadmill exercise test. AB - BACKGROUND: Little is known about normal heart rate variability (HRV) in horses during exercise. It can be difficult to separate premature beats from normal beat to-beat variation at higher heart rates. OBJECTIVES: The aim was to quantify HRV in healthy horses during a high-speed treadmill-standardized exercise test (HSET) and to compare with the HRV in horses observed to have arrhythmias during exercise. ANIMALS: Thirteen healthy horses (Group H), 30 horses with arrhythmias (Group A), and 11 horses with poor performance but no observed arrhythmias (Group O). METHODS: Prospective, observational study. All horses performed a HSET with simultaneous electrocardiograph (ECG) recorded. The ECGs were corrected for artifacts, and arrhythmias noted. Percent instantaneous beat-to-beat cycle length variation (% R-R variation) was calculated, and HRV analyses were performed on trot, canter, and recovery segments. RESULTS: Group H showed between -4.4 and +3.8% R-R variation during trot and between -6.1 and +5.4% R-R variation during the canter phase of the HSET. Group A had significantly larger maximum and 1st percentile R-R shortening and lengthening compared with Group H and Group O during the recovery phase where most arrhythmias were observed. During recovery, a cutoff of 6% maximum % R-R shortening predicted the presence of arrhythmia with 88% sensitivity and 97% specificity and likelihood ratio of 26. CONCLUSIONS AND CLINICAL IMPORTANCE: Healthy horses have little instantaneous R-R variation during exercise. If a cardiac cycle shortens more than 6% from the previous cycle during the recovery phase, this R-R interval is likely to represent an arrhythmic event. PMID- 30520121 TI - Looking back to move forward. PMID- 30520120 TI - Deep integrative analysis of microRNA-mRNA regulatory networks for biomarker and target discovery in chondrosarcoma. AB - Chondrosarcoma (CHS) is a common malignant bone sarcoma and its occurrence increases with age. microRNAs (miRNAs) are a class of noncoding RNAs that participate in various biological processes and disease pathogenesis by targeting functional messenger RNA (mRNA). However, the modulation of miRNAs in CHS remains largely unknown. In this study, we performed integrative analysis to explore the expression profiles of miRNAs and mRNAs, together with their interaction networks in human CHS tissues and cell lines by RNA-seq (miRNA and mRNA). A total of 133 and 796 differentially expressed miRNAs and mRNAs were identified (|Fold change| >= 2 and P-value <= 0.5). miRNA-mRNA regulatory interactions between 55 miRNAs and 242 mRNAs were screened by the Pearson correlation analysis and target prediction. mRNAs in the network were enriched to 145 Gene Ontology terms and 35 Kyoto Encyclopedia of Genes and Genomes pathways. Specifically, some key regulators (hub-miRNAs) in the network (miR-622, miR-4539, miR-145, miR-25, and miR-96) were suggested to play important regulatory roles in the pathogenesis of CHS. In addition, functional experiments validated that miR-622 regulated CHS cell proliferation by targeting bone morphogenetic protein 1 (BMP1). PMID- 30520122 TI - Extracts of Coleus forskohlii relieves cough and asthma symptoms via modulating inflammation and the extracellular matrix. AB - Asthma is characterized by airway inflammatory infiltration, which leads to airway remodeling and airway hyperreactivity. Coleus forskohlii (CFK) has been used to treat asthma, however, the mechanism involved is not clear. To explore the antiasthma mechanism of extracts of Coleus forskohlii (ECFK), guinea pigs were administered with a spray of phosphoric acid histamine, and rats were sensitized with ovalbumin (OVA). Hematoxylin and eosin staining (H&E) were used to evaluate pathological changes in lung tissue. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels in serum and bronchoalveolar lavage fluid (BALF). Immunohistochemistry and Western blot analysis were used to assess the expression of intercellular cell adhesion molecule-1 (ICAM-1), phosphorylation of p65 (p-p65), matrix metallopeptidase 9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1). After ECFK treatment, the asthma incubation period of guinea pigs was significantly prolonged. The H&E results showed that the number of eosinophils in the 12.8 g/kg ECFK group was significantly lower when compared with the control group. Moreover, ELISA results demonstrated that interleukin (IL)-4, IL-5, and IL-17 in serum and BALF were significantly decreased, and interferon-gamma (IFN-gamma) and IL-10 were increased after ECFK treatment. In addition, ECFK treatment resulted in downregulation of ICAM-1, p-p65, MMP-9, and TIMP-1 in lung tissue after being sensitized by OVA. In conclusion, our findings indicated that ECFK significantly alleviated OVA-induced inflammatory infiltration and airway remodeling in asthma. This study laid a theoretical foundation for the clinical use of ECFK. PMID- 30520123 TI - Gene ontology improves template selection in comparative protein docking. AB - Structural characterization of protein-protein interactions is essential for our ability to study life processes at the molecular level. Computational modeling of protein complexes (protein docking) is important as the source of their structure, and as a way to understand the principles of protein interaction. Rapidly evolving comparative docking approaches utilize target/template similarity metrics, which are often based on the protein structure. Although the structural similarity, generally, yields good performance, other characteristics of the interacting proteins (eg, function, biological process, localization, and such) may improve the prediction quality, especially in the case of weak target/template structural similarity. For the ranking of a pool of models for each target, we tested scoring functions that quantify similarity of Gene Ontology (GO) terms assigned to target and template proteins in three ontology domains - biological process, molecular function and cellular component (GO score). The scoring functions were tested in docking of bound, unbound and modeled proteins. The results indicate that the combined structural and GO-terms functions improve the scoring, especially in the twilight zone of structural similarity, typical for protein models of limited accuracy. This article is protected by copyright. All rights reserved. PMID- 30520124 TI - Impact of image averaging on wide-field choroidal thickness measurements using enhanced-depth imaging optical coherence tomography. AB - BACKGROUND: The aim of this study was to examine the influence of B-scan averaging on choroidal thickness using wide-field enhanced-depth imaging optical coherence tomography. METHODS: Six high-resolution trans-foveal horizontal enhanced-depth imaging line scans (spanning a 60 degrees field) were acquired consecutively from the right eye of 10 healthy adults (mean age 30 +/- 5 years), with each line scan an average of 10, 20, 30, 40, 50 or 100 B-scans, using the automated real-time image averaging and follow-up features of a Spectralis device. The impact of B-scan averaging on regional measures of wide-field choroidal thickness (across macular and peripheral regions) and their accuracy was investigated, assuming that averaging 100 B-scans would provide the most accurate estimate of choroidal thickness. RESULTS: Regional estimates of wide field choroidal thickness did not vary across the different B-scan averaging conditions (all p > 0.05). The mean choroidal thickness averaged across the full wide-field area exhibited the closest agreement to measures obtained with 100 averaged B-scans, when frame averaging exceeded 30 B-scans (95 per cent limits of agreement +10 to -7, +7 to -7 and +6 to -3 MUm for 30, 40 and 50 averaged B scans, respectively), compared to 10 and 20 averaged B-scans (95 per cent limits of agreement +13 to -8 and +13 to -6 MUm, respectively; p < 0.01 and p < 0.02 compared to the accuracy of 50 averaged B-scans). CONCLUSION: Averaging 30 B scans for an individual enhanced-depth imaging optical coherence tomography line scan provided accurate measures of choroidal thickness across a wide-field (60 degrees ) area in young healthy eyes. This information can assist in designing the volumetric scan protocols required for detailed examination of the macular and peripheral choroid. PMID- 30520125 TI - Investigating skin age analysis to reduce tanning intentions among adolescents: A pilot study. AB - As skin cancer rates continue to rise, targeted efforts to reduce excessive exposure to ultraviolet radiation are crucial. Adolescents are a high-risk population for intentional tanning; thus, we sought to determine whether the novel use of skin age analysis with ultraviolet (UV) photography would be an effective tool for reducing intentions to tan in adolescents with a calculated skin age (measured by complexion analysis software) that exceeds their actual age. Surveying 85 students in this study, skin age difference above zero was associated with reduced intentions to tan (P = 0.006) and high-risk sun exposure behaviors were identified. This provides rationale for skin age analysis as a potentially effective intervention in decreasing intentions to tan in this high risk young population. PMID- 30520126 TI - Rapid and Accurate Structure-Based Therapeutic Peptide Design using GPU Accelerated Thermodynamic Integration. AB - Peptide-based therapeutics are an alternative to small molecule drugs as they offer superior specificity, lower toxicity and easy synthesis. Here we present an approach that leverages the dramatic performance increase afforded by the recent arrival of GPU accelerated thermodynamic integration (TI). GPU TI facilitates very fast, highly accurate binding affinity optimization of peptides against therapeutic targets. We benchmarked TI predictions using published peptide binding optimization studies. Prediction of mutations involving charged side chains was found to be less accurate than for non-charged, and use of a more complex 3-step TI protocol was found to boost accuracy in these cases. Using the 3-step protocol for non-charged side-chains either had no effect or was detrimental. We use the benchmarked pipeline to optimize a peptide binding to our recently discovered cancer target: EME1. TI calculations predict beneficial mutations using both canonical and non-canonical amino acids. We validate these predictions using fluorescence polarization and confirm that binding affinity is increased. We further demonstrate that this increase translates to a significant reduction in pancreatic cancer cell viability. This article is protected by copyright. All rights reserved. PMID- 30520127 TI - Enantioselective vinylation of aldehydes with the vinyl Grignard reagent catalyzed by magnesium complex of chiral BINOLs. AB - Enantioselective vinylation of aldehydes via direct catalytic asymmetric Grignard reaction of aldehdyes and the vinyl Grinard reagent is a long-standing challenge. This work demonstrated that the magnesium (S)-3,3'-dimethyl BINOLate enantioselectively catalyze the direct vinylation of aldehydes with the deactivated vinylmagnesium bromide by bis(2-[N,N'-dimethylamino]ethyl) ether (BDMAEE) in the addition of n-butylmagnesium chloride. The highest ee of 63% was achieved up to date. PMID- 30520128 TI - Quantitative proteomics using SILAC-MS identifies N-acetylcysteine-solution triggered reversal response of renal cell carcinoma cell lines. AB - N-acetylcysteine (NAC), a precursor for glutathione (GSH), causes permeable antioxidation protecting normal cells and disrupting cancer cells. In the present study, we found that a NAC-based medium can trigger a reversal response of human clear cell renal cell carcinoma (ccRCC). To further investigate the action of a NAC-based solution in ccRCC cell lines, 786-O and SN12C were incubated in a serum free acid medium (low pH) in the presence of 2 mM NAC for 24 hours or in a serum free medium (normal pH) as the control, and then a phenotypic and proteomic analyses were performed. To determine the reversal occurrence, we tested the phenotypic features associated with cancer cells. Under this premise, a systematic and in-depth analysis of NAC-solution-triggered protein alterations was carried out by quantitative proteomics in both cell lines. Among the paramount protein signature, we identified a large number of proteins associated with cancer features were downregulated, but other proteins in the KEGG pathways associated with recovery of the missing tumorigenicity, such as the p53 pathway and repair pathway, were significantly upregulated. Quantification of notable proteins was validated by messenger RNA (mRNA) and protein levels in the ccRCC cell line. Collectively, our data indicate that the NAC-based solution inhibits human ccRCC cell growth by decreasing cell proliferation and inducing apoptosis, limiting their migration by limiting cell motility and completely changing their metabolic mode. Thus, NAC-based solutions could be used for the prevention or treatment of ccRCC. PMID- 30520129 TI - Microbial keratitis complicated by acute hydrops following corneal collagen cross linking for keratoconus. PMID- 30520130 TI - Yak OXGR1 promotes fibroblast proliferation via the PI3K/AKT pathways. AB - Oxoglutarate receptor 1 (OXGR1), as one of the intermediates in G protein-coupled receptors (GPCRs), plays a crucial role in the citric acid cycle receptor of alpha-ketoglutarate and metabolism. GPCR can control the cell proliferation by regulating the downstream signaling of G protein signaling pathways. The PI3K/AKT pathway transmits the downstream signals of GPCRs and receptor tyrosine kinases. However, the specific role of OXGR1 promoting cell proliferation and differentiation are still unknown. In current study, the over-expression vector and knockdown sequence of yak OXGR1 were transfected into yak fibroblasts, and the effects were detected by a series of assays. The results revealed that OXGR1 expression in yak lung parenchyma tissue was significantly higher than that of other tissues. In yak fibroblasts, the upregulated expression of OXGR1 resulted in activating the PIK3CG (downstream signal) of the PI3K/AKT1 pathway that can upregulated the expression of proliferation genes ( CDK1, PCNA, and CyclinD1) and promote cell proliferation. Conversely, the downregulated expression of OXGR1 inhibited cell proliferation via PI3K/AKT1 pathway. Cell cycle and cell proliferation assays demonstrated that over-expression of OXGR1 can enhanced the DNA synthesis and promoted yak fibroblasts proliferation. While the conversely, knockdown of OXGR1 can decreased DNA synthesis and inhibited cell proliferation. These results illustrated that changes of OXGR1 expression can trigger the fibroblasts proliferation via PI3K/AKT signaling pathway, which indicating that OXGR1 is a novel regulator for cell proliferation and differentiation. Furthermore, these results provide evidence supporting the functional role of GPCRs-PI3K-AKT1 and OXGR1 in cell proliferation. PMID- 30520131 TI - Long noncoding RNA HAND2-AS1 inhibits cancer cell proliferation, migration, and invasion in esophagus squamous cell carcinoma by regulating microRNA-21. AB - Long noncoding RNA (lncRNA) HAND2-AS1 is a well-characterized tumor suppressor in several types of malignancies, while its role in esophagus squamous cell carcinoma (ESCC) is unknown. In this study, we found that lncRNA HAND2-AS1 was downregulated, while microRNA-21 ( miRNA-21) was upregulated in tumor tissues than in adjacent healthy tissues of ESCC patients. Expression levels of lncRNA HAND2-AS1 and miRNA-21 were significantly and inversely correlated in tumor tissues but not in healthy tissues. Plasma levels of lncRNA HAND2-AS1 were lower in ESCC patients than in healthy controls, and downregulation of plasma lncRNA HAND2-AS1 distinguished early stage ESCC patients from healthy controls. lncRNA HAND2-AS1 overexpression resulted in downregulation of miRNA-21 in cells of ESCC cell lines and inhibited cell proliferation, migration, and invasion. miRNA-21 overexpression failed to affect lncRNA HAND2-AS1 expression but significantly attenuated the inhibitory effect of lncRNA HAND2-AS1 overexpression on cancer cell proliferation, migration, and invasion. Therefore, lncRNA HAND2-AS1 may inhibit cancer cell proliferation, migration, and invasion in ESCC by regulating miRNA-21. PMID- 30520133 TI - Astrocyte elevated gene-1 induces autophagy in diabetic cardiomyopathy through upregulation of KLF4. AB - BACKGROUND: Astrocyte elevated gene-1 (AEG-1), also known as metadherin, 3D3, and lysine-rich carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) coisolated, has emerged as an important oncogene that is overexpressed in a variety of cancers. Previous studies revealed that AEG-1 is also involved in multiple physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine, and Huntington's disease. However, the function of AEG-1 in diabetic cardiomyopathy (DCM) has not been reported yet. Therefore, we conducted this study to characterize the potential role and mechanism of AEG-1 in DCM rats. METHODS: DCM was induced by injections of streptozocin (STZ) in Wistar rats. Rats were randomized to be injected with lentivirus carrying AEG-1 small interfering RNA. Haemodynamic changes of Wistar rats, assessment of cardiac weight index, and the expression of AEG-1 and KLF4 were detected and compared among these three groups. RESULTS: The expressions of AEG-1 and KLF4 in the STZ group were significantly elevated in cardiac tissues compared with the control group. Knockdown of AEG-1 significantly increased the values of left ventricular ejection fraction, +/-dp/dt max , repressed autophagy, as well as upregulated the expression of KLF4. CONCLUSIONS: Knockdown of AEG-1 suppresses autophagy in DCM by downregulating the expression of KLF4. This study provide first-notion evidence for the potential value of AEG-1 as a therapeutic target for the treatment of the patients with DCM. PMID- 30520132 TI - Viral testing of 10 cases of Theiler's disease and 37 in-contact horses in the absence of equine biologic product administration: A prospective study (2014 2018). AB - BACKGROUND: A novel equine parvovirus (EqPV-H) was recently discovered in the equine liver with Theiler's disease. OBJECTIVES: To determine the prevalence of EqPV-H infection in naturally occurring Theiler's disease cases and in-contact horses in the absence of historical equine biologic product administration. ANIMALS: Ten cases of Theiler's disease from 6 separate properties were included in the study, based on the criteria of acute onset of clinical signs of liver failure with laboratory or histopathologic findings characteristic of Theiler's disease and no history of receiving an equine biologic product within the preceding 4 months. In addition, 37 in-contact horses from 4 of the 6 properties were screened for EqPV-H infection and hepatitis. METHODS: In prospective case series, cases were diagnosed with Theiler's disease by the attending veterinarian and were tested for EqPV-H by PCR of liver or serum. In-contact horses were assessed via serum chemistry and PCR at the attending veterinarian's discretion. Hepatitis was defined as serum gamma-glutamyltransferase activity above reference interval. The association of EqPV-H with hepatitis was determined by Fisher's exact test. RESULTS: Nine of 10 (90%) Theiler's disease cases and 54% of tested in-contact horses were EqPV-H positive. Hepatitis was significantly associated with EqPV-H infection (P = .036). CONCLUSIONS AND CLINICAL IMPORTANCE: Although further study is required to identify EqPV-H as the causative agent of Theiler's disease, EqPV-H appears strongly associated with cases of fatal Theiler's disease and subclinical hepatitis in horses in contact with those cases. The prevalence of EqPV-H infection on affected properties can be high. PMID- 30520134 TI - Re: Does the temperature of an artificial tear affect its comfort? PMID- 30520135 TI - Reply to a correspondence addressing the European guideline for treatment of atopic eczema, functional textiles and the CLOTHES trial. AB - We have read with interest the respectfully written correspondence by Wuthrich et al. regarding antimicrobial silk textiles for atopic dermatitis (AD) (1). Though it was submitted as a comment to the European consensus-based S2k guidelines on treatment of atopic eczema (2,3), it is discussing in 70% of its length the CLOTHES trial - published in two non-JEADV-publications which we have neither designed nor authored (4,5). This article is protected by copyright. All rights reserved. PMID- 30520137 TI - Brentuximab induced CD30+ cutaneous lymphoma responded to anti-PD1 treatment. AB - Over the last decade major efforts have been made for the optimization of immune directed therapies against cancer. Regarding cutaneous lymphomas (CTCLs), brentuximab (BV) has been recently approved by FDA and EMA for the treatment of primary cutaneous anaplastic large cell lymphoma as well as CD30-expressing mycosis fungoides, based on the ALCANZA trial favorable results. Concurrently, immune checkpoint inhibition has been shown to be of great value in the treatment of solid tumors and with promising results in a range of hematologic malignancies, however relevant data concerning CTCLs' treatment remain inconclusive. This article is protected by copyright. All rights reserved. PMID- 30520136 TI - High renal DC-SIGN+ cell density is associated with severe renal lesions and poor prognosis in patients with Immunoglobulin A Nephropathy. AB - BACKGROUND AND OBJECTIVES: In this observational cohort study, we assessed the prognostic value of DC-SIGN+ cells in pathogenesis and progression of IgA nephropathy (IgAN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 139 adult IgAN patients were enrolled in this study from June 2009 to June 2010. We characterized DC-SIGN+ cells by immunohistochemistry or immunofluorescence in renal biopsy tissue. Correlations between the DC-SIGN, ICAM-3, CD4, and CD8 were evaluated. Patients were classified into the DC-SIGNhigh and DC-SIGNlow group. Depending on a 100-month follow-up, the predictive value of DC-SIGN+ cells in IgAN progression was analyzed. RESULTS: DC-SIGN+ cells were found popular in IgAN kidneys while rarely observed in normal kidneys and almost all of DC-SIGN+ cells expressed MHCII. We also found DC-SIGN+ cells were adjacent to ICAM-3 positive CD4+ and CD8+ lymphocytes. The density of DC-SIGN+ cells was positively and linearly correlated with the density of ICAM-3+ cells, CD4+ cells, CD8+ cells in renal biopsy tissues. In DC-SIGNhigh group, the degree of renal lesion and inflammatory cells infiltration were severer compared to DC-SIGNlow group. Patients in DC-SIGNhigh group also had increased incidences of descending renal function over a 100-month follow-up compared to patients in DC-SIGNlow group. CONCLUSIONS: DC-SIGN+ cells probably served as a potential contributor to exacerbate local inflammatory response. The density of DC-SIGN+ cells was associated with severity of renal lesions of the patients. High renal DC-SIGN+ cell density DC-SIGN+ cells might be used as a predictor factor of poor prognosis in patients with IgAN. This article is protected by copyright. All rights reserved. PMID- 30520138 TI - Endothelial cell autophagy in chronic intermittent hypoxia is impaired by miRNA 30a-mediated translational control of Beclin-1. AB - Chronic intermittent hypoxia (CIH) in obstructive sleep apnea causes damage of aortic endothelial cells, which predisposes the development of many cardiovascular diseases. Recently, both altered expression of microRNAs (miRNAs) and impaired autophagy were found to be associated with endothelial cell dysfunction in CIH. However, the exact molecular regulatory pathway has not been determined. Here, we address this question. In a mouse model of CIH, we detected significant upregulation of miR-30a, a miRNA that targets 3'-untranslated region of autophagy-associated protein 6 (Beclin-1) messenger RNA (mRNA) for suppressing the protein translation, which subsequently attenuated the endothelial cell autophagy against cell death. Indeed, unlike Beclin-1 mRNA, the Beclin-1 protein in endothelial cells did not increase after CIH. Suppression of miR-30a by expression of antisense of miR-30a significantly increased Beclin-1 levels to enhance endothelial cell autophagy in vitro and in vivo, which improved endothelial cell survival against CIH. Together, these data suggest that endothelial cell autophagy in CIH may be attenuated by miR-30a-mediated translational control of Beclin-1 as an important cause of endothelial cell dysfunction and damage. PMID- 30520139 TI - Effects of red light on inflammation and skin barrier recovery following acute perturbation. Pilot study results in healthy human subjects. AB - In an original article recently published in Photodermatology, Photoimmunology and Photomedicine (1), we aimed to prove therapeutic effects of photobiomodulation (PBM) based on clinical outcomes by investigating the impact of UV-free blue light at 453 nm on the recovery of the skin barrier and on the cutaneous inflammatory response elicited by acute perturbation of the skin of healthy human volunteers. In this Letter we describe a study of same design and scope in which we investigated the impact of LED red light at 656 nm. Briefly, tape stripping and histamine iontophoresis were performed on the forearm of 22 healthy volunteers in two consecutive weeks: in one week, challenges were followed by irradiation with red light at 656 nm, in the other week (control), no light was administered. This article is protected by copyright. All rights reserved. PMID- 30520140 TI - Effect of sex hormone-binding globulin polymorphisms on the outcome of in vitro fertilization-embryo transfer for polycystic ovary syndrome patients: A case control study. AB - Polycystic ovary syndrome (PCOS), known as a common endocrine disorder among females, plagues many PCOS patients. The current study aimed to explore the correlations of sex hormone-binding globulin (SHBG) polymorphisms with the outcome of in vitro fertilization-embryo transfer (IVF-ET) in PCOS patients. PCOS patients who underwent IVF-ET and patients with non-PCOS-related infertility were selected in the study. Correlations of SHBG rs6259 and rs727428 with the risk factors in PCOS were analyzed, followed by the evaluation of the effect of SHBG polymorphisms on the outcome of IVF-ET in PCOS patients. At last, unconditional logistic regression analysis was performed to study the risk factors for IVF-ET treatment outcome. Compared with SHBG rs6259 GG carriers, the incidence of PCOS was found to be elevated in SHBG rs6259 GA+AA carriers which indicated that the A allele was a risk factor for PCOS. Compared with SHBG rs6259 TT carriers, the number of retrieved oocytes and embryo as well as the fertility rate in SHBG rs6259 GA+AA carriers was found to be decreased, while the abortion rate, incidence of ovarian hyperstimulation syndrome, transplant rejection rate, estradiol, and testosterone in serum, as well as testosterone in follicular fluid were elevated. The luteal hormone, serum testosterone, and progesterone and GA+AA genotype of rs6259 were the risk factors for IVF-ET treatment outcome. Taken together, the study showed that SHBG rs6259 polymorphisms might be correlated with the risk of PCOS and the outcome of IVF-ET treatment. PMID- 30520141 TI - Long noncoding RNA FOXD2-AS1 promotes glioma malignancy and tumorigenesis via targeting miR-185-5p/CCND2 axis. AB - Glioma is the most aggressive malignant tumor in the adult central nervous system. Abnormal long noncoding RNA (lncRNA) FOXD2-AS1 expression was associated with tumor development. However, the possible role of FOXD2-AS1 in the progression of glioma is not known. In the present study, we used in vitro and in vivo assays to investigate the effect of abnormal expression of FOXD2-AS1 on glioma progression and to explore the mechanisms. FOXD2-AS1 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of FOXD2-AS1 was correlated with poor prognosis of glioma. Downregulation of FOXD2-AS1 decreased cell proliferation, migration, invasion, stemness, and epithelial-mesenchymal transition (EMT) in glioma cells and inhibited tumor growth in transplanted tumor. We also revealed that FOXD2-AS1 was mainly located in cytoplasm and microRNA (miR)-185-5p both targeted FOXD2-AS1 and CCND2 messenger RNA (mRNA) 3' untranslated region (3'-UTR). miR-185-5p was downregulated in glioma tissue, cells, and sphere subpopulation. Downregulation of miR-185-5p was closely correlated with poor prognosis of glioma patients. In addition, miR-185-5p mimics decreased cell proliferation, migration, invasion, stemness, and EMT in glioma cells. CCND2 was upregulated in glioma tissue, cells, and sphere subpopulation. Upregulation of CCND2 was closely correlated with poor prognosis of glioma patients. CCND2 knockdown decreased cell proliferation, migration, invasion, and EMT in glioma cells. In glioma tissues, CCND2 expression was negatively associated with miR-185-5p, but positively correlated with FOXD2-AS1. FOXD2-AS1 knockdown and miR-185-5p mimics decreased CCND2 expression. Inhibition of miR-185 5p suppressed FOXD2-AS1 knockdown-induced decrease of CCND2 expression. Overexpression of CCND2 suppressed FOXD2-AS1 knockdown-induced inhibition of glioma malignancy. Taken together, our findings highlight the FOXD2-AS1/miR-185 5p/CCND2 axis in the glioma development. PMID- 30520142 TI - Methotrexate in atopic eczema. Comments to: Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. AB - The recent European guidelines for the treatment of atopic eczema (AE) are a thorough overview of therapeutic opportunities for AE.1 Among the systemic treatments, we propose to bring further insights on methotrexate (MTX) use in adult AE patients. This article is protected by copyright. All rights reserved. PMID- 30520143 TI - Alantolactone sensitizes human pancreatic cancer cells to EGFR inhibitors through the inhibition of STAT3 signaling. AB - Several studies have implicated the feedback activation of signal transducer and activator of transcription 3 (STAT3) as a new cancer drug-resistance mechanism and linked it to the failure of epidermal growth factor receptor (EGFR)-targeted therapies. In this study we discovered that Alantolactone, a natural sesquiterpene lactone, potently inhibited human pancreatic cancer cells and suppressed constitutively activated STAT3. In contrast, Alantolactone had little effect on the EGFR pathway. Moreover, combination of Alantolactone and an EGFR inhibitor, Erlotinib or Afatinib, demonstrated a remarkable synergistic anti cancer effect against pancreatic cancer cells both in vitro and in vivo. Our results suggested that Alantolactone could sensitize human pancreatic cancer cells to EGFR inhibitors possibly through down-regulating the STAT3 signaling. Alantolactone, when combined with other EGFR targeted agents, could be further developed as a potential therapy for pancreatic cancer. This article is protected by copyright. All rights reserved. PMID- 30520144 TI - alpha1A-adrenoceptor is involved in norepinephrine-induced proliferation of pulmonary artery smooth muscle cells via CaMKII signaling. AB - Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Some studies have demonstrated the sympathetic nervous system is activated in PAH and norepinephrine (NE) released is closely linked with its activation. However, the subtypes of adrenoreceptor (AR) and the downstream molecular cascades which are involved in the proliferation of PASMCs are still unclear. In this study, adult male Wistar rats were exposed to chronic hypoxia and PASMCs were cultured in hypoxic condition. Significant upregulation of alpha1A -AR was identified by Western blot analysis or immunofluorescence in all of the pulmonary arteries, lung tissues, and cell hypoxic models. Western blot analysis, flow cytometry, and immunofluorescence were applied to detect the roles of alpha1A -AR in NE mediated proliferation of PASMCs. We revealed 5 methylurapidil (5-MU) reversed NE-induced upregulation of PCNA, CyclinA and CyclinE, more cells from G0 /G1 phase to G2 /M+S phase, enhancement of the microtubule formation. In addition, we found calcium/calmodulin(CaM)-dependent protein kinase type II (CaMKII) pathway was involved in alpha1A -AR-mediated cell proliferation. [Ca2+ ]i measurements showed that an increase of [Ca2+ ]i caused by NE or/and hypoxia could be blocked by 5-MU in PASMCs. Western blot analysis results demonstrated the augmentation of CaMKII phosphorylation level was caused by hypoxia or NE in pulmonary arteries, lung tissues, and PASMCs. KN62 attenuated NE-induced proliferation of PASMCs under normoxia and hypoxia. In conclusion, those results suggested NE which stimulated alpha1A -AR-mediated the proliferation of PASMCs, which may be via the CaMKII pathway, and it could be used as a novel treatment strategy in PAH. PMID- 30520145 TI - Rebound effect associated with JAK inhibitor use in the treatment of alopecia areata. AB - Alopecia areata (AA) is a common autoimmune disease driven by Th1 cytokines characterized by non-scarring hair loss.1,2 Mouse models have demonstrated that IFN-gamma-producing NKG2D+ CD8+ cytotoxic T lymphocytes (CTLs) are essential for disease pathogenesis, along with JAK-STAT dependent cytokines IFN-gamma and IL 15, which induce autoreactive T cell activation.1,3 This article is protected by copyright. All rights reserved. PMID- 30520146 TI - Optimization strategies for HIV, hepatitis and syphilis testing in Infectious Disease Clinic and Dermatology Unit of Modena: seven-years results of collaboration experience. AB - BACKGROUND: Screening tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis infections performed in at-risk population show a higher number of positive tests compared to those carried out in the general population. "Test & Counselling" Ambulatory of Infectious Disease Clinic (T&C-IDC) and Sexually Transmitted Diseases Ambulatory of Dermatology Unit (STDs-DU) of Modena began collaboration in 2010 and adopted a common diagnostic serological profile since 2013. OBJECTIVES: The main objective was to analyse the number of screening tests performed in the T&C-IDC and STDs-DU, comparing the results obtained after the adoption of the shared protocol with the previous period. The secondary aim was to evaluate the linkage to care of newly diagnosed patients. METHODS: Consecutive patients referred to the T&C-IDC and STDs-DU from January 2010 to December 2016, with at least one performed screening test for HIV, HBV, HCV and syphilis were enrolled. Referral of patients with a new infection was obtained by capture-recapture methods in hospital databases. RESULTS: During the seven-years observation we collected 13117 admittances for 9154 patients. A significant increase in the number of screening tests (p<0.001) and ratio between tests and admissions (p=0.002) was observed. 644 (7.0%) people with at least one infection were diagnosed. Among these, the most common was syphilis (41.9%), followed by HBV (25.7%), HCV (21.4%) and HIV (10.9%). Syphilis occurred predominantly in Italians (72.5%) and males (75.7%), as like as HCV, while foreign-born (85.5%) mainly harboured HBV infection. HIV diagnosis was detected more frequently among males (67.1%) with a similar proportion between Italians and foreign-born. 543 out of 644 (84.3%) patients were linked to care. CONCLUSION: The collaboration between T&C-IDC and STDs-DU has proven to work well increasing the diagnosis over the time and obtaining good results in linkage to care. This article is protected by copyright. All rights reserved. PMID- 30520147 TI - Letter to the Editor: Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. JEADV 2018, 32, 850 878. doi.org/10.1111/jdv.14888. AB - We read with interest and with full consent the new consensus-based European guidelines for the treatment of atopic eczema, Part II1 . However, we would like to comment on the section on microbial textiles where the recommendation to use silk garments with permanent antimicrobial in the management of children with moderate to severe eczema is raised. On the basis of an UK multicenter clinical trial2 which seemed to show that silk garments with permanent antimicrobial were ineffective in the treatment of children with atopic eczema, the guidelines deny now any clinical benefit of AEGIS-coated silk textiles in children with atopic eczema and this contrary to the previous two guidelines3,4 . This article is protected by copyright. All rights reserved. PMID- 30520148 TI - Immune Associated LncRNAs Identify Novel Prognostic Subtypes of Renal Clear Cell Carcinoma. AB - Kidney Renal Clear Cell Carcinoma (KIRC) is a significant cause of cancer-related deaths. Here, we aim to identify the LncRNAs associated with the immune system and characterise their clinical utility in KIRC. A total of 504 patients' data was used from TCGA-GDC. In-silico correlation analysis identified 143 LncRNAs associated with immune-related genes (r > 0.7, p-value < 0.05). K-means consensus method clustered KIRC samples in three immune clusters, namely cluster C1, C2, and C3 based on the expression of 143 immune-related LncRNAs. Kaplan-Meier analysis showed that C3 patients survived significantly worse than the other two clusters (p-value < 0.0001). A comparison of TCGA miRNA, mRNA cluster with immune cluster showed the independence and robustness of immune clusters (HR = 2.02 and p-value = 2.12 * 10-8 ). The GSEA and CIBERSORT analysis showed high enrichment of poorly activated T-cells in C3 patients. To define LncRNA immune prognostic signature, we randomly divided the TCGA sample into discovery and validation sets. By utilising multivariate Cox regression analysis, we identified and validated a seven LncRNA immune prognostic signature score (LIPS score) (HR = 1.43 and p-value = 2.73 * 10-6 ) in KIRC. Comparison of LIPS score with all the clinical factors validated its independence and superiority in KIRC prognosis. In summary, we identified LncRNAs associated with the immune system and showed the presence of prognostic subtypes of KIRC patients based on immune-related LncRNA expression. We also identified a novel immune LncRNA based gene-signature for KIRC patients' prognostication. This article is protected by copyright. All rights reserved. PMID- 30520149 TI - Left ventricular mass regression after aortic valve replacement: Sex differences or effect of different methods of indexation? AB - BACKGROUND: The influence of sex on regression of left ventricular (LV) hypertrophy (LVH) after aortic valve replacement (AVR) for aortic stenosis (AS) remains elusive. The lack of consensus on how to correct LV mass (LVM) for body size, and different normalcy values, contribute to inconclusive results. METHODS: In 164 consecutive patients (mean age 80 +/- 4 years, 59% females) with AS, we analyzed LVM (Devereux formula) before and 1 year after AVR (St.Jude Trifecta bio prosthesis). LVM was indexed to BSA (Du Bois and Gehan formulas), to height1.7 and height2.7 . Limits of normalcy were (women and men, respectively): <95 and <115 g/m2, BSA-indexed LVM; <60 and <81 g/m, LVM/height1.7 ; <44 and <48 g/m, LVM/height2.7 . RESULTS: Women had smaller BSA, but not body mass index, than men. AS severity and incidence of hypertension did not differ. LVM indexed to height2.7 was greater in women. LVH incidence was similar in males and females. Independently of the indexation method, LVH reduced significantly (P < 0.0001). LVM reduction was greater in women (P < 0.05 for all methods). At follow-up, nearly half the patients, irrespective of sex, showed residual LVH, and diastolic dysfunction. CONCLUSIONS: We tested different methods of LVM indexation in AS patients. LVM was similar between men and women. Indexation to height2.7 gives higher LVM in women because of their shorter stature. LVH prevalence is independent of sex. Irrespective of the indexation method, LVM reduction is greater in females, whereas LVM normalization occurs in equal proportion. Persistent LVH and diastolic dysfunction suggest earlier AVR in elderly. PMID- 30520150 TI - Methotrexate in atopic eczema - Reply to a letter. AB - Goujon et al. submit a letter-type manuscript to JEADV (1), as a comment to the recently published European consensus-based S2k guidelines or treatment of atopic eczema (2,3). The assigned writing subgroups for each topic were encouraged to include the 'best available evidence' for all chapters of the guideline (2). Data were included only if a reference had been published as a full paper in a peer reviewed journal by March 2017 (see page 661 of the guideline), but not based on an abstract or a conference presentation only (2). This article is protected by copyright. All rights reserved. PMID- 30520151 TI - hsa_circRNA_0006528 as a competing endogenous RNA promotes human breast cancer progression by sponging miR-7-5p and activating the MAPK/ERK signalling pathway. AB - Emerging research has indicated that circular RNAs (circRNAs), a novel class of non-coding RNAs, play a vital role in human tumourigenesis and progression. Our previous results suggested that hsa_circ_0006528 (circ_0006528), a circRNA with an unknown function, mediates adriamycin resistance in human breast cancer cells. However, the role of circ_0006528 in breast cancer progression remains unknown. Here, we investigated the probable involvement of circ_0006528 in breast cancer. We analysed a cohort of 97 patients and found that circ_0006528 expression was significantly upregulated in human breast cancer tissues compared with that in adjacent non-tumourous tissues and was significantly associated with advanced tumour-node-metastasis (TNM) stage and poor prognosis. In addition, we found that in breast cancer cells, circ_0006528 could promote DNA synthesis and cell proliferation, invasion and migration. Downregulating circ_0006528 induced G2 phase arrest and cell apoptosis. Further mechanistic studies revealed that circ_0006528 could sponge endogenous miR-7-5p and inhibit its activity. We also identified Raf1, which activates the MAPK/ERK signalling pathway, as a target of miR-7-5p and determined that circ_0006528 promotes breast cancer growth, invasion and migration by promoting the expression of Raf1 and activates the MAPK/ERK pathway. Thus, this study provides the first evidence of the circ_0006528/miR-7 5p/Raf1/MEK/ERK regulatory network in the development of breast cancer and suggests that circ_0006528 is a potential therapeutic target and prognostic predictor for breast cancer. This article is protected by copyright. All rights reserved. PMID- 30520152 TI - A potential contribution of trappin-2 to the development of vasculopathy in systemic sclerosis. AB - BACKGROUND: Trappin-2/pre-elafin is an endogenous inhibitor of human neutrophil elastase involved in inflammation, innate immunity and vascular remodeling, which consist of the complex pathological process of systemic sclerosis (SSc). OBJECTIVES: To clarify the potential role of trappin-2 in SSc. METHODS: Serum trappin-2 levels were determined by enzyme-linked immunosorbent assay in 51 SSc and 18 healthy subjects. Trappin-2 expression was evaluated in SSc lesional skin and cultured endothelial cells treated with FLI1 siRNA by immunohistochemistry, reverse transcript-real time PCR and/or immunoblotting. Fli1 binding to the PI3 promoter was assessed by chromatin immunoprecipitation. RESULTS: Since serum trappin-2 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction, SSc patients with normal renal function were analyzed. Although serum trappin-2 levels were comparable between diffuse cutaneous SSc, limited cutaneous SSc and control subjects, the prevalence of digital ulcers or elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum trappin-2 levels than in those with normal levels. Furthermore, serum trappin-2 levels were significantly increased in SSc patients with digital ulcers or elevated RVSP compared to those without. Moreover, serum trappin-2 levels positively correlated with RVSP values in SSc patients. Importantly, trappin-2 expression was enhanced in small vessels of SSc lesional skin. In cultured endothelial cells, trappin-2 expression was elevated by gene silencing of FLI1 at mRNA and protein levels and Fli1 occupied the PI3 promoter. CONCLUSIONS: Endothelial trappin-2 up-regulation partially due to Fli1 deficiency can be associated with the development of SSc vasculopathy. This article is protected by copyright. All rights reserved. PMID- 30520153 TI - The dilemma of pest suppression in the conservation of endangered species. AB - In the conservation of endangered species, active suppression of a population of one native species to benefit another native species poses challenges. Examples include predator control and nest parasite reduction. Less obvious is the control of blood-feeding arthropods. We present a case study on the effect of blood feeding black flies (Simulium spp.) on reintroduced Whooping Cranes (Grus americana). Our intent is to provide a transferrable, science-driven approach for determining the effects of blood-feeding arthropods on endangered vertebrates, and demonstrate an approach for guiding management actions for managers faced with competing objectives. A multi-year experiment demonstrated that black flies reduce nest success in reintroduced cranes by driving the birds off their nests during incubation. Deciding how to respond is complicated because the target black flies are native species that serve important ecological functions. A decision-analytic approach can inspire creative management alternatives and facilitate a transparent process that evaluates trade-offs among competing objectives. Recognizing that these decisions involve trade-offs, which must be weighed in the context of each case, is crucial to identifying alternatives that best balance multiple management objectives. Given the uncertainty about the population dynamics of blood-feeding arthropods, an adaptive management approach will offer substantial benefits. This article is protected by copyright. All rights reserved. PMID- 30520154 TI - Casticin inhibits growth and enhances ionizing radiation-induced apoptosis through the suppression of STAT3 signaling cascade. AB - Casticin (CTC), one of the major components of Vitex rotundifolia L., has been reported to exert significant beneficial pharmacological activities and can function as an antiprolactin, anticancer, anti-inflammatory, neuroprotective, analgesic, and immunomodulatory agent. This study aimed at investigating whether the proapoptotic effects of CTC may be mediated through the abrogation of signal transducers and activators of transcription-3 (STAT3) signaling pathway in a variety of human tumor cells. We found that CTC significantly decreased cell viability in a concentration-dependent manner and suppressed cell proliferation in 786-O, YD-8, and HN-9 cells. CTC also induced programmed cell death that was found to be mediated via caspase-3 activation and induction of poly(ADP-ribose) polymerase cleavage. Interestingly, CTC repressed both constitutive and interleukin-6-induced STAT3 activation in 786-O and YD-8 cells but only affected constitutive STAT3 phosphorylation in HN-9 cells. Moreover, CTC could potentiate ionizing radiation-induced apoptotic effects leading to the downregulation of STAT3 activation and thus may be used in combination with radiation against diverse malignancies. PMID- 30520155 TI - Perceptions and experiences of patients following treatment with single-implant mandibular overdentures: a qualitative study. AB - OBJECTIVE: This study aimed to explore the perceptions and long-term experiences of edentulous patients rehabilitated with single-implant mandibular overdentures (SIMO). METHODS: Thirteen participants, mean age 65.7 years, 69.2% women, who had had their treatment completed for at least 1 year, were invited and included in the study. Focus groups including four to five participants each, were conducted, audio and video recorded and transcribed verbatim. Subsequently, the transcripts were analysed according to the principles of thematic analysis. RESULTS: Four major themes emerged: before decision to undergo treatment with SIMO, implant surgery experience, perception of treatment outcomes, and impressions about the care received. Lack of information, cost, comorbidities, older age and fear were initial barriers to the decision for treatment. Dissatisfaction with previous treatment and a sense of opportunity motivated the decision. There were ambivalent reports of absence of pain during surgery and discomfort during anaesthesia. Post-surgical recovery exceeded the pre-surgical negative expectations in most cases. There was a tendency for a positive impact of SIMO on the patients' quality of life, comprising improved ability to chew and communicate, dietary diversification, greater comfort and safety, increased self confidence and social interaction. Few minor inconveniences were reported: insecurity after an episode of denture fracture, and the need to use adhesive paste. Satisfaction with the care received and the trust in the dentist and dental team were evident. CONCLUSION: In general, participants presented positive perceptions and rewarding experiences after rehabilitation with SIMO. This article is protected by copyright. All rights reserved. PMID- 30520156 TI - A two-tier standard method to test the toxicity of microplastics in marine water using Paracentrotus lividus and Acartia clausi larvae. AB - A two-tier standardized protocol was designed in order to test the toxicity of microplastics to planktonic organisms. The protocol uses sea-urchin (Paracentrotus lividus) and copepod (Acartia clausi) larvae since they are common biological models in marine research, and standard methods for toxicity testing with regulatory applications are available. In Tier I, leachates obtained at a 100:1 liquid to solid ratio are tested, and toxic units (TU) are calculated using a probit dose:response model in order to quantify the toxicity of the plastics. In Tier II, conducted only if significant toxicity (>1 TU) is found in the first tier, particles below 20 um size are tested at concentrations between 0.1 and 10 mg L-1 , and a toxicity threshold suitable for ranking materials according to their toxicity is obtained from the EC10 values. Results obtained point at chemical additives as responsible for the toxicity found in certain plastic materials. The method is suitable for both a priori identification of the hazard posed by plastic objects in the aquatic environment, and a posteriori assessment of environmental risk caused by microplastic pollution. This method provides also a quantitative procedure suitable to rank plastic materials according to their toxicity to aquatic organisms. This article is protected by copyright. All rights reserved. PMID- 30520157 TI - Reduced capacity for empathy in corticobasal syndrome and its impact on carer burden. AB - Corticobasal syndrome (CBS) is clinically characterised by a wide range of motor, cognitive, and behavioural features but remains challenging to diagnose accurately. Despite recent evidence supporting the presence of social cognition and emotion processing disturbances, few studies have explored the nature of empathic ability in CBS. This study aimed to: (i) investigate the extent to which cognitive and affective dimensions of empathy are affected in CBS, and (ii) to determine the impact of such changes on carer burden. Empathic capacity was assessed in 29 CBS patients and 28 matched healthy controls. We employed the Interpersonal Reactivity Index (IRI), an instrument measuring: (i) perspective taking, (ii) fantasy (iii) empathic concern, and (iv) personal distress. A significant change in both perspective taking and empathic concern was observed in CBS following disease onset. Furthermore, affective empathy deficits in CBS patients predicted higher levels of carer burden. Disturbances in both cognitive and affective empathy are present in CBS and lead to increased levels of carer burden. PMID- 30520158 TI - Response to Re: Does the temperature of an artificial tear affect its comfort? PMID- 30520159 TI - Therapeutic strategies for skin regeneration based on biomedical substitutes. AB - Regenerative medicine and tissue engineering (TE) have experienced significant advances in the development of in vitro engineered skin substitutes, either for replacement of lost tissue in skin injuries or for the generation of in vitro human skin models to research. However, currently available skin substitutes present different limitations such as expensive costs, abnormal skin microstructure and engraftment failure. Given these limitations, new technologies, based on advanced therapies and regenerative medicine, have been applied to develop skin substitutes with several pharmaceutical applications that include injectable cell suspensions, cell-spray devices, sheets or 3D-scaffolds for skin tissue regeneration and others. Clinical practice for skin injuries has evolved to incorporate these innovative applications to facilitate wound healing, improve the barrier function of the skin, prevent infections, manage pain and even to ameliorate long-term aesthetic results. In this article we review current commercially available skin substitutes for clinical use, as well as the latest advances in biomedical and pharmaceutical applications used to design advanced therapies and medical products for wound healing and skin regeneration. We highlight the current progress in clinical trials for wound healing as well as the new technologies that are being developed and hold the potential to generate skin substitutes such as 3D bioprinting-based strategies. This article is protected by copyright. All rights reserved. PMID- 30520160 TI - Value of tissue-tracking tricuspid annular plane by speckle-tracking echocardiography for the assessment of right ventricular systolic dysfunction. AB - BACKGROUND: Assessment of right ventricular (RV) function remains challenging because of its complex geometry. Application of speckle-tracking echocardiography (STE) to the tricuspid annulus provides rapid and automated assessment of the midpoint of the tricuspid annular plane displacement (TAD). The aim of this study was to investigate the value of tissue-tracking TAD for the assessment of RV systolic dysfunction. METHODS: We retrospectively studied 61 patients in whom RV ejection fraction (EF) measured by 3-dimensional echocardiography was performed. STE-derived displacement of the midpoint between the septal and lateral tricuspid annulus and its percentage of RV length at end-diastole (MTAD) were automatically assessed. We performed comparative analyses between the RVEF >=45% group and the RVEF <45% group in each parameter for the assessment of RV systolic function. RESULTS: MTAD was successfully assessed in 56 (91.2%). According to receiver operating characteristics analysis, RVEF <45% was best detected by MTAD <14.7% with area under curve (AUC) 0.97, sensitivity 93%, specificity 95%, followed by RV free wall longitudinal strain (AUC 0.86), RV fractional area change (AUC 0.84), tricuspid annular plane systolic excursion (AUC 0.79), and systolic peak velocity of tricuspid annulus (AUC 0.70), although there was no significant difference between MTAD and RV free wall strain (P = 0.14). CONCLUSION: The present study showed that MTAD was simple index and useful for the assessment of RV systolic dysfunction. PMID- 30520161 TI - Disulfide bridge formation influences ligand recognition by the ATAD2 bromodomain. AB - The ATPase Family, AAA domain-containing protein 2 (ATAD2) contains a C-terminal bromodomain, which functions as a chromatin reader domain recognizing acetylated lysine on the histone tails within the nucleosome. ATAD2 is overexpressed in many cancers and its expression is correlated with poor patient outcomes, making it an attractive therapeutic target and potential biomarker. We solved the crystal structure of the ATAD2 bromodomain and found that it contains a disulfide bridge near the base of the acetyllysine binding pocket (Cys1057-Cys1079). Site-directed mutagenesis revealed that removal of a free C-terminal cysteine (C1101) residue greatly improved the solubility of the ATAD2 bromodomain in vitro. Isothermal titration calorimetry experiments in combination with the Ellman's assay demonstrated that formation of an intramolecular disulfide bridge negatively impacts the ligand binding affinities and alters the thermodynamic parameters of the ATAD2 bromodomain interaction with a histone H4K5ac peptide as well as a small molecule bromodomain ligand. Molecular dynamics simulations indicate that the formation of the disulfide bridge in the ATAD2 bromodomain does not alter the structure of the folded state or flexibility of the acetyllysine binding pocket. However, consideration of this unique structural feature should be taken into account when examining ligand-binding affinity, or in the design of new bromodomain inhibitor compounds that interact with this acetyllysine reader module. This article is protected by copyright. All rights reserved. PMID- 30520163 TI - Printable Fabrication of a Fully Integrated and Self-Powered Sensor System on Plastic Substrates. AB - Wearable and portable devices with desirable flexibility, operational safety, and long cruising time, are in urgent demand for applications in wireless communications, multifunctional entertainments, personal healthcare monitoring, etc. Herein, a monolithically integrated self-powered smart sensor system with printed interconnects, printed gas sensor for ethanol and acetone detection, and printable supercapacitors and embedded solar cells as energy sources, is successfully demonstrated in a wearable wristband fashion by utilizing inkjet printing as a proof-of-concept. In such a "wearable wristband", the harvested solar energy can either directly drive the sensor and power up a light-emitting diode as a warning signal, or can be stored in the supercapacitors in a standby mode, and the energy released from supercapacitors can compensate the intermittency of light illumination. To the best of our knowledge, the demonstration of such a self-powered sensor system integrated onto a single piece of flexible substrate in a printable and additive manner has not previously been reported. Particularly, the printable supercapacitors deliver an areal capacitance of 12.9 mF cm-2 and the printed SnO2 gas sensor shows remarkable detection sensitivity under room temperature. The printable strategies for device fabrication and system integration developed here show great potency for scalable and facile fabrication of a variety of wearable devices. PMID- 30520162 TI - Viral testing of 18 consecutive cases of equine serum hepatitis: A prospective study (2014-2018). AB - BACKGROUND: Three flaviviruses (equine pegivirus [EPgV]; Theiler's disease associated virus [TDAV]; non-primate hepacivirus [NPHV]) and equine parvovirus (EqPV-H) are present in equine blood products; the TDAV, NPHV, and EqPV-H have been suggested as potential causes of serum hepatitis. OBJECTIVE: To determine the prevalence of these viruses in horses with equine serum hepatitis. ANIMALS: Eighteen horses diagnosed with serum hepatitis, enrolled from US referral hospitals. METHODS: In the prospective case study, liver, serum, or both samples were tested for EPgV, TDAV, NPHV, and EqPV-H by PCR. RESULTS: Both liver tissue and serum were tested for 6 cases, serum only for 8 cases, and liver only for 4 cases. Twelve horses received tetanus antitoxin (TAT) 4-12.7 weeks (median = 8 weeks), 3 horses received commercial equine plasma 6-8.6 weeks, and 3 horses received allogenic stem cells 6.4-7.6 weeks before the onset of hepatic failure. All samples were TDAV negative. Two of 14 serum samples were NPHV-positive. Six of 14 serum samples were EPgV-positive. All liver samples were NPHV-negative and EPgV-negative. EqPV-H was detected in the serum (N = 8), liver (N = 4), or both samples (N = 6) of all 18 cases. The TAT of the same lot number was available for virologic testing in 10 of 12 TAT-associated cases, and all 10 samples were EqPV H positive. CONCLUSIONS AND CLINICAL IMPORTANCE: We demonstrated EqPV-H in 18 consecutive cases of serum hepatitis. EPgV, TDAV, and NPHV were not consistently present. This information should encourage blood product manufacturers to test for EqPV-H and eliminate EqPV-H-infected horses from their donor herds. PMID- 30520164 TI - Influence of dietary restriction and low-intensity exercise on weight loss and insulin sensitivity in obese equids. AB - BACKGROUND: The importance of including exercise with dietary modification for the management of obese equids is not clearly understood. OBJECTIVES: To evaluate the effect of a practical low-intensity exercise regimen, in addition to dietary restriction, on indices of insulin sensitivity (SI) and plasma adipokine concentrations in obese equids. ANIMALS: Twenty-four obese (body condition score [BCS] >= 7/9) horses and ponies. METHODS: Over a 12-week period, animals received either dietary restriction only (DIET) or dietary restriction plus low-intensity exercise (DIET+EX). All animals were provided with a restricted ration of grass hay at 1.25% body weight (BW) on a dry matter basis, providing 82.5% estimated digestible energy requirements. The DIET+EX group undertook low-intensity exercise 5 days per week on an automated horse walker. Before and after weight loss, total body fat mass (TBFM) was determined, indices of SI were calculated using minimal model analysis of a frequently sampled IV glucose tolerance test, and adipokines plus inflammatory biomarkers were measured using validated assays. RESULTS: Decreases in BCS, BW, and TBFM were similar between groups (all P > .05). After weight loss, animals in both groups had decreased basal insulin and leptin concentrations, and increased adiponectin concentrations (all P < .001). Furthermore, animals in the DIET+EX group had significantly improved SI and decreased serum amyloid A concentrations relative to animals in the DIET group (both P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Regular low-intensity exercise provided additional health benefits compared with dietary restriction alone in this population of obese equids. PMID- 30520165 TI - Functionalized Silver Ion Mediated alpha-dC-beta-dC Hybrid Base Pairs with Exceptional Stability: alpha-d 5-Iodo-2'-Deoxycytidine and Its Octadiynyl Derivative in Metal DNA. AB - Silver-mediated alpha-dC-Ag+-beta-dC hybrid base pairs decorated with 5-iodo- or 5-octadiynyl residues are well accommodated in duplex DNA. A strong Tm increase and favorable thermodynamic data for duplex DNA were observed after addition of silver ions. The phenomenon is particularly obvious when both nucleobases of the base pairs are functionalized. Neither the position of the base pair, nor the type of 5-substituent had a negative influence. On the contrary, functionalization of conventional silver-mediated beta-dC-Ag+-beta-dC homo base pairs showed a negative impact induced by the bulky substituents. To this end, cytosine modified 12-mer oligodeoxynucleotides were prepared by solid-phase synthesis employing new alpha-anomeric 2'-deoxycytidine phosphoramidites. A multigram scale synthesis was developed for 5-iodo-alpha-D-2'-deoxycytidine (1) employing the direct glycosylation of cytosine with Hoffer's alpha-D-halogenose followed by separation of anomeric DMT nucleosides. Regarding base pair stability and functionalization silver-mediated alpha/beta-dC hybrid base pairs were found to be superior to beta/beta-dC homo pairs. According to their extraordinary properties they might find applications in DNA diagnostics, material science or nanotechnology. PMID- 30520166 TI - Biomaterial-Based "Structured Opals" with Programmable Combination of Diffractive Optical Elements and Photonic Bandgap Effects. AB - Naturally occurring iridescent systems produce brilliant color displays through multiscale, hierarchical assembly of structures that combine reflective, diffractive, diffusive, or absorbing domains. The fabrication of biopolymer based, hierarchical 3D photonic crystals through the use of a topographical templating strategy that allows combined optical effects derived from the interplay of predesigned 2D and 3D geometries is reported here. This biomaterials based approach generates 2D diffractive optics composed of 3D nanophotonic lattices that allow simultaneous control over the reflection (through the 3D photonic bandgap) and the transmission (through 2D diffractive structuring) of light with the additional utility of being constituted by a biocompatible, implantable, edible commodity textile material. The use of biopolymers allows additional degrees of freedom in photonic bandgap design through directed protein conformation modulation. Demonstrator structures are presented to illustrate the lattice multifunctionality, including tunable diffractive properties, increased angle of view of photonic crystals, color-mixing, and sensing applications. PMID- 30520167 TI - A revolutionary tool: CRISPR technology plays an important role in construction of intelligentized gene circuits. AB - With the development of synthetic biology, synthetic gene circuits have shown great applied potential in medicine, biology, and as commodity chemicals. An ultimate challenge in the construction of gene circuits is the lack of effective, programmable, secure and sequence-specific gene editing tools. The clustered regularly interspaced short palindromic repeat (CRISPR) system, a CRISPR associated RNA-guided endonuclease Cas9 (CRISPR-associated protein 9)-targeted genome editing tool, has recently been applied in engineering gene circuits for its unique properties-operability, high efficiency and programmability. The traditional single-targeted therapy cannot effectively distinguish tumour cells from normal cells, and gene therapy for single targets has poor anti-tumour effects, which severely limits the application of gene therapy. Currently, the design of gene circuits using tumour-specific targets based on CRISPR/Cas systems provides a new way for precision cancer therapy. Hence, the application of intelligentized gene circuits based on CRISPR technology effectively guarantees the safety, efficiency and specificity of cancer therapy. Here, we assessed the use of synthetic gene circuits and if the CRISPR system could be used, especially artificial switch-inducible Cas9, to more effectively target and treat tumour cells. Moreover, we also discussed recent advances, prospectives and underlying challenges in CRISPR-based gene circuit development. PMID- 30520168 TI - Itch relief in patients with psoriasis: effectiveness of calcipotriol plus betamethasone dipropionate foam. AB - BACKGROUND: Itch is common in psoriasis, adversely affecting health-related quality of life (HRQoL) and sleep. OBJECTIVE: We evaluated the efficacy of topical fixed-dose combination calcipotriol 50 MUg/g plus betamethasone dipropionate 0.5 mg/g cutaneous foam (Cal/BD foam) on itch, itch-related sleep loss and HRQoL versus foam vehicle. METHODS: We pooled data from three Phase II/III trials (NCT01536886/NCT01866163/NCT02132936) of Cal/BD foam versus foam vehicle in adults with mild-severe psoriasis. For itch-related analyses, patients with baseline itch VAS >40 (range 1-100) were analysed. Outcomes included: itch VAS reduction >40, >=70% improvement in itch (Itch70) or itch-related sleep loss, 75% improvement in modified PASI (excluding head) (mPASI75), and Dermatology Life Quality Index (DLQI) scores 0/1 through 4 weeks. RESULTS: Of 837 patients, 800 had baseline itch VAS >0 (Cal/BD foam, n=610; foam vehicle, n=190); 484 had baseline itch VAS >40. There was no correlation between itch VAS score and mPASI at baseline (R2 = 0.021). In patients with baseline itch VAS >40, more patients achieved itch VAS reduction >40 in the active versus vehicle group from Day 5 onwards (Day 5: 57.5 vs 40.2% [P<0.05]; Week 4: 83.0 vs 45.8% [P<0.001]). More Cal/BD foam4-treated patients achieved Itch70 at Day 3 (34.2 vs 22.5%; P<0.05) through to Week 4 (79.3 vs 38.1%; P<0.001). In patients with baseline itch VAS >40 and sleep loss >20, improvements in itch-related sleep loss occurred at Week 1 and continued through 4 weeks. Itch-related improvements occurred before improvements in mPASI75. There were significant differences in the proportion of Cal/BD-foam- versus foam-vehicle-treated patients with baseline DLQI >10 (N=172 vs N=50) achieving DLQI <=1 (25.0% vs 4.0%; P=0.001) and DLQI 0 (17.4% vs 2.0%; P=0.006) at Week 4. CONCLUSION: Compared with foam vehicle, Cal/BD foam offers more rapid and effective itch relief, with associated significant improvements in sleep and DLQI. This article is protected by copyright. All rights reserved. PMID- 30520169 TI - Solar Angioedema: A report of a patient and a review of literature. AB - Solar angioedema is a rare photodermatosis, with only 11 reported patients worldwide. Patients develop facial (predominately eyelids, lips) and/or acral swelling hours after sun exposure, especially while on vacation to tropical areas. Management includes photoprotection and sun avoidance; preemptive antihistamines have been tried with minimal effect. Short courses of oral corticosteroids may be needed when these measures fail. Recognition of solar angioedema is important for dermatologists, allergists, emergency physicians, and primary care physicians as this condition can significantly affect the quality of life. This article is protected by copyright. All rights reserved. PMID- 30520171 TI - Regrets after tattooing and tattoo removal in the general population of France. AB - The market of tattoo removal is constantly rising [1]. Recent American polls showed a growing proportion of tattooed individuals that regretted getting tattooed: nearly one fourth (23%) in 2016 against 14% in 2012 [2]. In France, a recent poll in 2016 in France showed that 7% of the tattooed individuals had a tattoo removed [3]. In 2017, we performed a national survey on 5000 French individuals that were representative from the general population to evaluate the prevalence and the characteristics of the tattooed population [4]. We report here about regrets and tattoo removal among the participants. This article is protected by copyright. All rights reserved. PMID- 30520170 TI - A core outcome set for the evaluation of treatments for twin-twin transfusion syndrome. AB - BACKGROUND: A minimum data set, known as a core outcome set, should standardise outcome selection, collection, and reporting across future twin-to-twin transfusion syndrome research. METHODS: An international steering group including healthcare professionals, researchers, and patients, guided the development of this core outcome set. Potential core outcomes, identified through a comprehensive literature review, were entered into a three round Delphi survey. Healthcare professionals, researchers, and patients were invited to participate. Consensus outcomes were entered into a modified nominal group technique to identify the final core outcome set. RESULTS: One hundred and three participants, from 29 countries, participated in a three-round Delphi survey. Of those 88 completed the three rounds. Twenty-two consensus outcomes were identified and entered into a modified nominal group technique. Eleven healthcare professionals, two researchers, and three patients prioritised 12 core outcomes. Fetal core outcomes included live birth, fetal loss (including miscarriage, stillbirth, and termination of pregnancy), recurrence of twin-twin transfusion syndrome, twin anaemia polycythaemia syndrome and amniotic band syndrome. Neonatal core outcomes included gestational age at delivery, birthweight, neonatal mortality, brain injury syndromes, and ischaemic limb injury. Maternal core outcomes included maternal mortality and admission to level two or three care. CONCLUSIONS: Embedding the core outcome set within future twin-to-twin transfusion syndrome research could make a substantial contribution to advancing the usefulness of research. Standardised definitions and measurement instruments are now required for individual core outcomes. This article is protected by copyright. All rights reserved. PMID- 30520172 TI - Physical response of dogs supplemented with fish oil during a treadmill training programme. AB - The rise in popularity of dog sports competitions has led to the evaluation of improvements in dog physical performance. The potential benefit of dietary supplementation with fish oil (FO) on the physical performance of human beings and horses has been reported. However, such effect has not been studied in dogs. We therefore evaluated the effect of FO dietary supplementation on heart rate (HR), rectal temperature (RT) and thigh circumference (TC) in dogs during aerobic treadmill training, and further determined HR response and blood lactate (BL) concentration during an incremental exercise test. Using a cross-over design, eight male dogs were randomly assigned to two groups and received a standard balanced commercial diet (control, CG, n = 7) and the same diet supplemented with 54 mg FO/kg metabolic weight per day (FOG, n = 8). All dogs had 30-min treadmill sessions at 8 km/hr and 7.5% slope twice a week for 12 weeks. Assessment of HR and RT was performed before and immediately after each session; HR was also assessed 5 min after the end of each session. Thigh circumference was evaluated before each session. All dogs performed an incremental exercise test on the treadmill at 0, 6 and 12 weeks to evaluate HR response and BL concentration. Data were analysed using the mixed procedure (SAS 9.4). In FOG, pre-HR (-4.9%) and post-HR (-2.4%) values and post-RT (-0.3%) values were lower during treadmill training, whereas TC (+2.2%) values were higher as compared with CG (p < 0.01). Through the incremental exercise test, mean HR (week 6, -5.3%; week 12, -6.0%) values in FOG were lower than in CG (p < 0.05). In conclusion, FO supplementation slightly improved the physiological response of dogs to exercise during training. PMID- 30520173 TI - Radical carbofluorination of alkenes with arylhydrazines and Selectfluor: Additives, mechanistic pathways and polar effects. AB - Radical carbofluorination reactions starting from arylhydrazines and non activated alkenes, in which the C-F bond is formed through the use of Selectfluor, can be improved through the addition of anisole. Since direct trapping products could be detected only in trace amounts, anisole does primarily act as a reversible scavenger for the highly reactive ammonium radical dication released from Selectfluor in the C-F bond forming step. As shown for three diverse substitution patterns, the main role of anisole is to prevent, or at least reduce, the undesired addition of the ammonium radical dication to the alkene, which in turn leads to an unfavorable consumption of the arylhydrazine derived precursors required for carbofluorination. Besides the observation of remarkable polar effects in radical trapping, this study moreover shows that the Selectfluor-derived nitrogen-centered radical dication may add directly to alkenes, which has not been described so far. PMID- 30520174 TI - Quantitative High-Dynamic-Range Electron Diffraction of Polar Nanodomains in Pb2 ScTaO6. AB - Highly B-site ordered Pb2 ScTaO6 crystals are studied as a function of temperature via dielectric spectroscopy and in situ high-dynamic-range electron diffraction. The degree of ordering is examined on the local and macroscopic scale and is determined to be 76%. Novel analysis of the electron diffraction patterns provides structural information with two types of antiferroelectric displacements determined to be present in the polar structure. It is then found that a low-temperature transition occurs on cooling at ~210 K that is not present on heating. This phenomenon is discussed in terms of the freezing of dynamic polar nanodomains where a high density of domain walls creates a metastable state. PMID- 30520175 TI - The voice of patients in system redesign: A case study of redesigning a centralized system for intake of referrals from primary care to rheumatologists for patients with suspected rheumatoid arthritis. AB - BACKGROUND: The published literature demands examples of health-care systems designed with the active engagement of patients to explore the application of this complex phenomenon in practice. METHODS: This case study explored how the voice of patients was incorporated into the process of redesigning an element of the health-care system, a centralized system for intake of referrals from primary care to rheumatologists for patients with suspected rheumatoid arthritis (RA) centralized intake. The phenomenon of patient engagement using "patient and community engagement researchers" (PaCERs) in research and the process of redesigning centralized intake were selected as the case. In-depth evaluation of the case was undertaken through the triangulation of findings from the document review and participants' reflection on the case. RESULTS: In this case, patients and PaCERs participated in multiple activities including an initial meeting of key stakeholders to develop the project vision; a patient-to-patient PaCERs study to gather perspectives of patients with RA on the challenges they face in accessing and navigating the health-care system, and what they see as key elements of an effective system that would be responsive to their needs; the development of an evaluation framework for future centralized intake; and the choice of candidate centralized intake strategies to be evaluated. CONCLUSIONS: The described feasible multistep approach to active patient engagement in health care system redesign contributes to an understanding of the application of this complex phenomenon in practice. Therefore, the manuscript serves as one more step towards a patient-centred health-care system that is redesigned with active patient engagement. PMID- 30520176 TI - Effect of microbial inoculants on the fermentation characteristics, nutritive value, and in vitro digestibility of various forages. AB - This study was aimed to examine the characteristics of three isolated lactic acid bacteria (LAB) strains (HG24, M1, and TG1), and to evaluate their effects on fermentation characteristics, nutritive value, and in vitro digestibility in a variety of substrates. The experiments were conducted with Italian ryegrass (Lolium multiflorum Lam.), tall fescue (Festuca arundinacea Schred.), and oat (Avena sativa L.) in laboratory silo (1 L) for ensiling 30 days. All the treated silages had significantly (p < 0.05) higher in vitro dry matter digestibility (IVDMD), and lower undesirable microorganism populations compared with controls. In Italian ryegrass and oat silages, all the inoculants improved the fermentation quality, evidenced by distinctly (p < 0.05) higher LA contents and ratios of LA to acetic acid, and lower pH, butyric acid and ammonia nitrogen contents. Strains HG24 and commercial inoculant G (Lactobacillus plantarum MTD-1) performed better than strains M1 and TG1, indicated by obviously (p < 0.05) higher LA contents, LAB numbers, and IVDMD. In tall fescue silage, all the isolated LAB strains (HG24, M1 and TG1) markedly (p < 0.05) increased IVDMD compared with strain G. Strain HG24 is recommended as a good LAB inoculant for ensiling in various forages. PMID- 30520177 TI - Prevalence and persistence of oral HPV infection in Italy. AB - Oral human papillomavirus (HPV) persistent infection may cause numerous tumors1,2 but little is known about the HPV clearance time and the variables that may influence the HPV persistence3 . We aimed to assess the prevalence of the oral HPV infection, the HPV persistence rate and the variables influencing the persistence. This article is protected by copyright. All rights reserved. PMID- 30520178 TI - Unexpected photosensitivity - a patient with dermatomyositis and concomitant solar urticaria. AB - Dermatomyositis (DM) is a connective tissue disease with rare incidence, characterized by progressive muscle weakness and typical cutaneous manifestations. Its pathogenesis is still incompletely understood, but next to genetic predisposition environmental factors seem to be implicated in the development of DM (1). Photosensitivity is one important factor for the onset and exacerbation of DM, which is corroborated by the distribution of the cutaneous features on sun-exposed areas and disease photoaggravation (2,3). This article is protected by copyright. All rights reserved. PMID- 30520179 TI - Critical review of emergency department management of chemotherapy complications in cancer patients. AB - INTRODUCTION: Recent worldwide advances in cancer therapies have resulted in an increased number of people receiving chemotherapy in ambulatory care settings. In Spain, emergency departments are the single point of entry to acute inpatient services and they play a pivotal role in the management of chemotherapy complications. Little research exists in patterns of emergency department utilisation by oncology patients with chemotherapy-related complications. However, it is important for the oncology patients and the healthcare system to gain understanding in the disease pathway and the organisational factors influencing the quality of care. METHODS: This critical review's main aims were to describe the clinical characteristics of patients who presented to an emergency department after chemotherapy treatment as reported in international literature; to map reported patterns of care in emergency department access; and quality of care exploring the management of febrile neutropenic patients described in the literature, against best practice guidelines. RESULTS: The search strategy yield 701 articles from MEDLINE, TROVE and SCOPUS and 26 were included. The review combines systematic reviews, observational, cross-sectional case-control studies and randomised control trials. CONCLUSION: All articles showed areas and opportunities for improvement in the management of this population, especially with regard to time from triage to antibiotic administration in febrile neutropenic patients. PMID- 30520180 TI - Paracrine Factors Released by Osteoblasts Provide Strong Platelet Engraftment Properties. AB - Ex vivo expansion of hematopoietic stem cells (HSC) and progenitors may one day overcome the slow platelet engraftment kinetics associated with umbilical cord blood (UCB) transplantation. Serum-free medium conditioned with osteoblasts (i.e., OCM) derived from mesenchymal stromal cells (MSC) was previously shown to increase cell growth and raise the levels of human platelets (hPLT) in mice transplanted with OCM-expanded progenitors. Herein, we characterized the cellular and molecular mechanisms responsible for these osteoblast-derived properties. Limiting dilution transplantation assays revealed that osteoblasts secrete soluble factors that synergize with exogenously-added cytokines to promote the production of progenitors with short term (ST) platelet engraftment activities, and to a lesser extent with long term (LT) platelet engraftment activities. OCM also modulated the expression repertoire of cell-surface receptors implicated in the trafficking of HSC and progenitors to the bone marrow. Furthermore, OCM contains growth factors with prosurvival and proliferation activities that synergized with stem cell factor (SCF). Insulin-like growth factor (IGF)-2 was found to be present at higher levels in OCM than in control medium conditioned with MSC. Inhibition of the IGF-1 receptor, which conveys IGF-2' intracellular signaling, largely abolished the growth-promoting activity of OCM on immature CD34+ subsets and progenitors in OCM cultures. Finally, IGF-1R effects appear to be mediated in part by the coactivator beta-catenin. In summary, these results provide new insights into the paracrine regulatory activities of osteoblasts on HSC, and how these can be used to modulate the engraftment properties of human HSC and progenitors expanded in culture. SIGNIFICANCE STATEMENT: Osteoblasts are one of many different cell type implicated in the regulation of hematopoiesis through various mechanism including the release of paracrine factors such as growth factors, chemokines and extracellular matrix proteins. We show that these factors strongly modulate the growth of umbilical cord blood stem and progenitor cells through activation of insulin-like growth factor-1 receptor and subsequent activation of the transcriptional activation complex? -catenin/TCF. Osteoblasts also modulated the expression repertoire of cell-surface receptors implicated in the homing of progenitors to the bone marrow. Altogether, these properties significantly enhanced the platelet engrafting activity of progenitors produced in cultures. (c) AlphaMed Press 2018. PMID- 30520181 TI - Preliminary experience of the use of high-resolution skin ultrasound for the evaluation of extrathyroideal manifestations of Graves' disease and response to UVA-1 phototherapy. AB - Graves' orbitopathy (GO) and pre-tibial mixedema (PTM) are autoimmune manifestation sharing the same etiology and histopathology, a chronic course and a frustrating treatment. Current management include topical and systemic corticosteroid as first line therapy, whereas cyclosporine, surgery and orbital radiotherapy are indicated for severe GO with variable results and mostly temporary remissions. In particular, keratopath and photophobia, due to exophthalmos and eyelid retraction, impaired eye mobility and diplopia due to the compression of optic nerve and extra-ocular muscles are usually minimally modified, as well as leg plaques/nodules and lymphoedema. This article is protected by copyright. All rights reserved. PMID- 30520182 TI - Commentary on Madah-Amiri et al. (2019): Beyond saturation. PMID- 30520183 TI - Anti-Parasitic Activity of Auranofin Against Pathogenic Naegleria fowleri. AB - We report that the gold containing anti-rheumatoid drug auranofin is amoebicidal against human pathogenic Naegleria fowleri. Treatment of N. fowleri cultures at biologically relevant concentrations of 0.75 MUg/ml to 3.0 MUg/ml auranofin reduced amoeba counts, metabolic activity and increased cell permeability. These results suggest that the addition of auranofin may benefit the treatment of N. fowleri infected patients afflicted by the rapidly fatal disease primary amoebic meningoencephalitis. This article is protected by copyright. All rights reserved. PMID- 30520185 TI - Work-related skin diseases of Santa Claus. AB - The health of Santa Claus (SC) and work-related risks have been discussed on very few occasions in the medical literature [1,2]. We believe that due to his unique line of work, the skin of SC is peculiarly at risk and SC may be exposed to various work-related cutaneous hazards (table 1). According to Finnish folklore, SC currently lives and mainly work during the year in Korvatunturi (literally "Ear fell") in Finnish Lapland [3]. This article is protected by copyright. All rights reserved. PMID- 30520184 TI - ERBB2 mutation frequency in lobular breast cancer with pleomorphic histology or high-risk characteristics by molecular expression profiling. AB - HER2-positive breast cancer is defined by amplification or overexpression of the HER2/ERBB2 oncogene and accounts for about 15% of breast cancer (BC) cases. Somatic mutation of ERBB2 is an alternative mechanism, by which activation of HER2 signaling can occur. ERBB2 mutation has been associated with invasive lobular breast cancer (ILBC). This study investigates the frequency and phenotype of ILBC harboring mutated ERBB2. The ERBB2 mutation status was determined by next generation sequencing and/or pyrosequencing in n = 106 ILBCs, including n = 86 primary or locally recurrent tumors and n = 20 metastases from visceral organs, soft tissue or skin. Immunohistochemical characteristics were determined using tissue microarrays. This series was enriched for ILBCs with pleomorphic histology and/or high-risk expression profiles (Oncotype DX, recurrence score RS > 25). Nearly all specimens were E-cadherin-negative (99%), estrogen receptor (ER) positive (92%), and lacked ERBB2 overexpression (96%). ERBB2 mutations (p.V777 L, p.L755S, p.S310F) were identified in 5/106 (5%) cases. ERBB2-mutated cases included 2/86 (2%) primary tumors and 3/20 (15%) metastases (P = 0.045). ERBB2 mutated cases were associated with loss of ER (2/7, 29%, P = 0.035) and histological grade 3 (4/34, 12%, P = 0.023), but not with solid growth (3/31, 10%, P = 0.148) or pleomorphic histology (2/27, 7%, P = 0.599). No ERBB2 mutation was detected in ILBCs with RS > 25 (0/22, 0%). In ten patients with multiple matched specimens (n = 25), the ERBB2 mutational status was always concordant. In summary, a small subset of ILBCs harbors potentially actionable ERBB2 mutations. In ERBB2-mutated ILBCs, no association with pleomorphic histology was found. This article is protected by copyright. All rights reserved. PMID- 30520186 TI - Dermoscopic evaluation of melanocytic nevi changes after photoepilation techniques: a prospective study. AB - BACKGROUND: The clinical and dermoscopic changes of melanocytic nevi under the effects of photo-epilation are poorly known. OBJECTIVE: Prospective study on clinical and dermatoscopic effects of photoepilation on melanocytic nevi. METHODS: Eighteen patients exposed to photo-epilation gave consent to a follow-up program from 2008 to 2017 at the Videodermatoscopic Office of the Dermatology Clinic of Cagliari (Italy), with clinical and dermoscopic assessment. RESULTS: A mean 2-year follow-up was recorded for 73 lesions. The most frequent clinical change was nevi colour, clearer than basal pictures, sometimes with increased pigmentation at the periphery, or residual islands of pigmentation, with vanishing borders. Acute burn with crusting was noted in few cases. Only one case showed progressive growth. Corresponding dermoscopic findings were bleaching of nevi, followed by pigment network disruption, appearance of white structureless areas and grey-blue globules. Complete regression occurred in 32.8% of the lesions. The growing nevus was characterized by peripheral globules. Excision for histopathological examination showed a compound nevus with mild atypia. CONCLUSIONS: Although malignant modifications of nevi after photo-epilation have not been described, the clinical and dermoscopic changes we observed suggest to extend the follow for more than 24 months, as the potential long term adverse effects of photo-epilation on melanocytic nevi are unknown. This article is protected by copyright. All rights reserved. PMID- 30520187 TI - Transition to practice experiences of first and second career nurses: A mixed methods study. AB - AIMS AND OBJECTIVES: To explore the transition to nursing practice experiences of first and second career nursing students. BACKGROUND: To address the nursing shortage, alternative educational programs have been increasingly developed and implemented with to help individuals with prior career experiences transition into a career in nursing (second career nurses). However, we know little about the transition to practice experiences of second career nurses. DESIGN: This mixed methods study utilized qualitative interviews with nurses who had completed a year of practice and a longitudinal survey of nurses' perceptions of stress, coping and burnout throughout their first year of nursing practice. METHODS: Qualitative data (n=15) was analyzed using latent thematic analysis and following COREQ guidelines. Descriptive and effect size analysis of quantitative data (n=122) was conducted in order to assess for significant differences across time points. RESULTS: The thematic analysis identified three themes: Stressors and Coping, Prevalence of Burnout and Presenteeism, and Difficulty Describing Nursing's Role. The quantitative findings showed that participants' self compassion decreased over their first year of practice. Levels of stress, presenteeism and burnout increased by the year mark. These increases were meaningfully significant between time points. CONCLUSIONS: Differences in the stressors and coping of first and second career nurses should be considered in developing transition to practice programs for new nurses. Increasing rates of stress, burnout, and presenteeism, highlight the ongoing need to address these issues. Improving the nurse work environment may aid in the transition to nursing practice of both first and second career nurses. RELEVANCE TO CLINICAL PRACTICE: First and second career nurses have increasing rates of stress, burnout and presenteeism that need to be addressed. However, there are differences in stressors and coping between first and second career nurses. This article is protected by copyright. All rights reserved. PMID- 30520188 TI - Non-genetic and genetic predictors of a superficial first basal cell carcinoma. AB - BACKGROUND: several observational studies have suggested differences in the risk factor profile between patients with superficial basal cell carcinomas (BCCs) and non-superficial BCCs. OBJECTIVE: to test the reproducibility of previous study findings and to find new genetic and non-genetic predictors for patients with a superficial first BCC. METHODS: 14.628 participants of northwestern European descent aged 45 years or older from a prospective population-based cohort study (Rotterdam Study) were linked with the Dutch Pathology Registry (PALGA) of whom 1,528 were identified as BCC patients. After exclusion, 948 eligible BCC patients remained for further non-genetic analyses and 1,014 for genetic analyses. We included 11 phenotypic, environmental and tumor-specific characteristics, and 20 candidate single nucleotide polymorphisms (SNP) as potential predictors for patients with a superficial first BCC. We performed binary logistic multivariable regression analyses. RESULTS: we found that patients with a superficial first BCC were significantly younger, almost two times more often female and 12-18 times more likely to have their BCC on the trunk or extremities than patients with a non-superficial first BCC. One SNP (rs12203592), mapped to IRF4, looked promising (OR 1.83, 95% CI 1.13-2.97, p-value <0.05), but after adjustment for multiple testing, no significant differences in genetic make-up between superficial BCC and non-superficial BCC patients were found. CONCLUSION: we conclude that patients with a superficial BCC differ from non-superficial BCC patients with respect to environmental factors (tumor localization as a proxy for UVR exposure) and phenotypic characteristics (age and sex), but we found no difference in genotype. As superficial BCC patients develop their first BCCs at a younger age, they could be at higher life-time risk for subsequent skin cancers and therefore be an important group for secondary prevention. This article is protected by copyright. All rights reserved. PMID- 30520189 TI - Effect of fermentation system on the physicochemical and microbial community dynamics during enset (Ensete ventricosum) fermentation. AB - AIMS: The present study was conducted to assess the effect of three different fermentation systems on fermentation of enset into kocho. METHODS AND RESULTS: Nine enset plants were processed, mixed and fermented in either a pit, a bamboo basket or a Sauerkraut jar. Samples were taken on days 1, 7, 15, 31, 60 and 90. Moisture content and pH generally decreased and titratable acidity increased during fermentation. Total viable aerobic counts were generally high for all samples and Enterobacteriaceae counts were reduced to below the detectable level after day 1 for the pits and jars and after day 7 for the baskets. Illumina MiSeq sequencing of 16S ribosomal RNA genes revealed that Leuconostoc and Lactococcus spp. were the most abundant lactic acid bacteria in the initial phases of the fermentation. Later on, Lactobacillus, Weissella and Bifidobacterium dominated. CONCLUSIONS: The type of fermentation system used had an effect on the microbial dynamics and the effect increased towards the end of fermentation. SIGNIFICANCE AND IMPACT OF STUDY: Millions of people in Ethiopia daily consume kocho prepared in either a pit or a basket. These systems show practical problems, but this study shows that fermentation is also possible in a Sauerkraut jar. This article is protected by copyright. All rights reserved. PMID- 30520190 TI - Hydration practices in residential and nursing care homes for older people. AB - AIM: The aim of the study was to scope and explore hydration practices in care homes. BACKGROUND: Older residents do not regularly consume adequate fluids to support health. Achieving this is difficult with residents who have coexisting health, sensory and functional problems, as well as challenging hydration habits. DESIGN: This project used a sequential exploratory mixed method design to scope and explore existing hydration practices. METHODS: Data were collected via two stages. First was a survey of hydration practices. Twenty-nine responses were received from 81 care homes (response rate: 35.8%). Second was the exploration of practitioners' experiences and perceptions of hydration practice via semi structured interviews (54 staff: 43 interviews). Descriptive statistics summarised the survey findings. Open coding and thematic analysis were applied to the qualitative data and details of the methods are reported in adherence to COREQ criteria. RESULTS: It is important to provide hydration support in addition to regularly offering drinks to residents. Hydration practices include: use of social interaction to encourage drinking; verbal and non-verbal prompts to drink; giving fluids with routine practices and social activities; providing drinks related activity, use of aids and equipment to support drinking, and creating a drink-friendly environment. Practices are implemented in care homes, however no one care home implements all these hydration strategies at any one time. CONCLUSIONS: Older care home residents need support and encouragement to drink adequate fluids which can be difficult to achieve with residents who have complex needs and challenging drinking habits. In addition to the routine offer of drinks, hydration support should be used to facilitate residents to drink sufficient amounts of fluid. RELEVANCE TO CLINICAL PRACTICE: Staff working in care homes have an important role in assessing the hydration needs of residents and using multiple hydration practices to support residents to achieve their hydration requirements. This article is protected by copyright. All rights reserved. PMID- 30520191 TI - Patulin removal from synbiotic apple juice using Lactobacillus plantarum ATCC 8014. AB - AIMS: The aim of this study was to evaluate the elimination of patulin by Lactobacillus plantarum ATCC 8014 from artificially contaminated apple juice and its dependence on prebiotic, citric acid, and ascorbic acid content. METHODS AND RESULTS: A central composite design was used for studying each of the three factors at five levels to find the optimum concentrations. The results showed that inserting 2.3% (w v-1 ) fructooligosaccharide, 213 mg l-1 ascorbic acid, and 1.4 g l-1 citric acid to apple juice with inoculating 3.6 * 1011 CFU ml-1 Lactobacillus plantarum improved the efficiency of patulin removal to 95.91% during 6 weeks cold storage. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of cell surface proteins of probiotics revealed that surface layer proteins have an important role in patulin removal from apple juice. No significant difference was observed in the flavor and color of the optimized synbiotic apple juice and the control sample until 3 weeks of cold storage. CONCLUSION: Lactobacillus plantarum ATCC 8014 is capable of patulin removal from artificially contaminated synbiotic apple juice. SIGNIFICANCE AND IMPACT OF THE STUDY: Synbiotic apple juice artificially contaminated with patulin will be safe for consumers after the first day of probiotic inoculation and surface layer proteins of probiotic cells are responsible for patulin removal. This article is protected by copyright. All rights reserved. PMID- 30520192 TI - A novel model for predicting non-responsiveness to intravenous immunoglobulins in Kawasaki disease: The Singapore experience. AB - AIM: We aimed to assess the utility of four published risk-scoring methods in predicting intravenous immunoglobulins (IVIG) non-responsiveness in Kawasaki disease (KD) patients from Singapore and develop a new predictive model. METHODS: We reviewed the medical records of 215 KD children. The performance of existing scoring methods in identifying non-responsive cases based on sensitivities (SN) and specificities (SP) was evaluated in 122 Singaporean Chinese. From our dataset, a model involving six predictors was built. RESULTS: The following respective SN (%) and SP (%) were obtained: Egami: 26%, 68%; Kobayashi: 21%, 62%; Sano: 13%, 86% and Fukunishi: 46%, 71%. These results indicated that the existing scoring methods performed poorly compared to those reported in their respective original publications, which ranged between 68 and 87%. The new predictive model was derived with an improved SN (80%) and SP (80%). CONCLUSIONS: Currently available risk-scoring methods have less applicability in the Singaporean Chinese population. The proposed new risk-scoring predictive model derived based on data from Chinese cohort demonstrated much better SN and SP. PMID- 30520193 TI - Response shift effects of quality of life assessments in breast cancer survivors. AB - Measurements of quality of life (QoL) can be distorted by respondents adapting to new situations between measurement points and consequently having a changed frame of reference. To investigate this bias in breast cancer survivors, we compare their QoL with that of the general population and use two complementary methods for detecting this bias. Breast cancer survivors (n = 308, response rate: 91%) were tested with the QoL questionnaire European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Response shift was examined with the thentest (retrospective judgements) and with the structural equation modelling (SEM) approach. Compared with the general population, breast cancer survivors showed impaired QoL in all functioning scales (Hedges' g: -0.56 to -0.93) and symptom scales (Hedges' g: 0.28-0.74).The thentest method indicated recalibration effects in several dimensions including social functioning. The SEM method detected a non-uniform recalibration effect for social functioning from pretest to posttest and from pretest to thentest, but no effect between thentest and posttest. Breast cancer survivors' QoL is clearly diminished. Comparing the two approaches for detecting response shift showed that it is also useful to apply SEM to retrospective judgements and that this can reveal response shift effects that would otherwise be overlooked. PMID- 30520194 TI - Effect of instrumentation systems on endotoxin reduction from root canal systems: A systematic review of clinical studies and meta-analysis. AB - This systematic review assessed the effect of different root canal instrumentation systems on endotoxin reduction from the root canal system. The literature search was conducted in two electronic databases (PubMed and Scopus) using specific key words. The search strategy followed the PRISMA guidelines. Qualitative synthesis and quantitative synthesis of the data were performed and data interpretation was done based on the guidelines in the Cochrane Handbook. The risk of bias was assessed using Cochrane criteria. The initial search yielded 600 citations, of which three papers met the criteria for inclusion in this review. Studies showed a significant reduction in endotoxin following rotary and reciprocating instrumentation, with no significant differences between them. The meta-analysis showed no statistical significant difference between reciprocation and rotary files (P > 0.05). In conclusion, the instrumentation techniques compared in this review decrease endotoxin content from root canals, with no significant difference between them. PMID- 30520196 TI - Caring for the older person with cognitive impairment in hospital: qualitative analysis of nursing personnel reflections on fall events. AB - AIMS AND OBJECTIVES: To explore nurse and nursing assistant reflections on the care of older patients with cognitive impairment who have experienced a fall. BACKGROUND: While there are evidence-based clinical guidelines for the prevention and management of falls and for the care of older people with cognitive impairment, the falls rates for older people with cognitive impairment is three times as high as those without. DESIGN: Critical incident technique. METHODS: Eleven registered and two enrolled nurses and four assistants in nursing working in one subacute and two acute wards within two hospitals of a tertiary level health service in south-east Queensland. Individual semi-structured interviews focused on two past events when a patient with cognitive impairment had fallen in hospital: one when there was minimal harm and the second when there was significant harm. Thematic analysis was undertaken. The COREQ checklist was followed. RESULTS: Three themes emerged from 23 reflective accounts of fall events: 'direct observation is confounded by multiple observers' and 'knowing the person has cognitive impairment is not enough', and 'want to rely on the guideline but unsure how to enact it'. While participants were aware of the falls prevention policy and techniques available to prevent falls, the implementation of these was challenging due to the complexity of care required by the older person with cognitive impairment. CONCLUSIONS: Falls prevention for older people with cognitive impairment is complex and belies the simple application of policy. RELEVANCE TO CLINICAL PRACTICE: To reduce falls, nurses can involve the family to support 'knowing the patient' to enable prediction of impulsive actions; shift the focus of in-service from lectures to specific case presentations, with collaborative analysis on person-focused strategies to prevent falls in older people with cognitive impairment; and reconsider the sitter role from simple observer to assistant, focused on ambulation and supporting independence in activities of daily living. This article is protected by copyright. All rights reserved. PMID- 30520197 TI - Irritative potency of selected wound antiseptics in the hen's egg test on chorioallantoic membrane to predict their compatibility to wounds. AB - Antiseptics are being used for prevention of infections in acute wounds and for treatment of infections in acute and chronic wounds. However, some antiseptics' high tissue toxicity might delay the healing process. The aim of this study was to investigate the tissue toxicity of preferentially used wound antiseptics and the influence of antiphlogistic additives via the hen's egg test on the chorioallantoic membrane (HET-CAM). The HET-CAM is a semi-in-vivo method testing the tissue tolerability of wound antiseptics by evaluating the blood vessel reaction of the chorioallantoic membrane in terms of hemorrhage, vessel lysis, and coagulation. For each test day, selected test substances were applied on the membranes of two to three eggs according to the test protocol. The overall irritation was then evaluated by referring to a calculated score. Normal distribution of the resulting scores was confirmed by D'Agostino-Pearson omnibus K2 test. Significant differences between the antiseptics were calculated by Tukey's multiple comparisons test. Severe CAM reactions were observed after short term application of octenidine based wound gel (0.05%) and chlorhexidine digluconate (0.5% solution), moderate reactions for octenidine (0.05%) in aqueous solution combined with dexpanthenol (1.34%) and allantoin (0.2%) or for hydrogen peroxide (1.5% and 0.5%) in aqueous solution, slight reactions were observed for hydrogen peroxide (1.5%) in aqueous solution in combination with sodium thiocyanate (0.698%) and for the combination of NaOCl/HOCl (each 0.004%). Polyhexanide (0.04%) in Ringer solution and polyhexanide (0.05%) in Lipofundin, the hemoglobin spray (10%), dexpanthenol, and allantoin showed no irritation. The HET-CAM qualifies as a primary screening test for tissue tolerance of wound antiseptics. Regarding local tolerability, polyhexanide and hypochlorite are superior to other antiseptics. PMID- 30520195 TI - Real Life Management of Chronic Urticaria: multicenter and cross sectional study on patients and dermatologists in Iran. AB - Recently, advances in understanding the etiology of urticaria and updates of diagnostic and therapeutic management guidelines have drawn attention to chronic urticaria (CU) morbidity. This study aimed to evaluate Iranian dermatologists' practice and real life management of CU patients. A total of 35 dermatologists and 443 patients were included in the study. Number of female patients was 321 (72.5%). Mean (Standard Deviation) age of the study patients was 38 (13) years and the median (Inter Quartile Range) of disease duration was 12 (6- 48) months. Severity of patients' symptoms was mild for 32.1%, moderate for 38.7%, severe for18.8% and 10.4% of them had no evident signs or symptoms. The most common diagnostic methods were physical examination (96.6%), differential blood count (83.5%), erythrocyte sedimentation rate (77.4%), and C-reactive protein (62.8%). The number of dermatologists prescribed non-sedating antihistamines (nsAH) in regular dose and high dose mono therapy were 26 (74%) and 6 (17%), respectively. About 66% of dermatologists were familiar with British Association of Dermatologists (BAD) guideline. The most common first-line treatment for CU by Iranian dermatologists was non-sedating antihistamines in regular or high doses. The real-life management of patients with CU in Iran was in accordance with the available practice guidelines. This article is protected by copyright. All rights reserved. PMID- 30520198 TI - Genome-wide patterns of transposon proliferation in an evolutionary young hybrid fish. AB - Hybridization can induce transposons to jump into new genomic positions, which may result in their accumulation across the genome. Alternatively, transposon copy numbers may increase through non-allelic (ectopic) homologous recombination in highly repetitive regions of the genome. The relative contribution of transposition bursts versus recombination-based mechanisms to evolutionary processes remains unclear because studies on transposon dynamics in natural systems are rare. We assessed the genome-wide distribution of transposon insertions in a young hybrid lineage ("invasive Cottus", n=11) and its parental species Cottus rhenanus (n=17) and Cottus perifretum (n=9) using a reference genome assembled from long single molecule PacBio reads. An inventory of transposable elements was reconstructed from the same data and annotated. Transposon copy numbers in the hybrid lineage increased in 120 (15.9%) out of 757 transposons studied here. The copy number increased on average by 69% (range: 10 197%). Given the age of the hybrid lineage, this suggests that they have proliferated within a few hundred generations since admixture began. However, frequency spectra of transposon insertions revealed no increase of novel and rare insertions across assembled parts of the genome. This implies that transposons were added to repetitive regions of the genome that remain difficult to assemble. Future studies will need to evaluate whether recombination-based mechanisms rather than genome-wide transposition may explain the majority of the recent transposon proliferation in the hybrid lineage. Irrespectively of the underlying mechanism, the observed over-abundance in repetitive parts of the genome suggests that gene-rich regions are unlikely to be directly affected. This article is protected by copyright. All rights reserved. PMID- 30520199 TI - Scalable Enantioselective Total Synthesis of (-)-Goniomitine. AB - A scalable enantioselective total synthesis of (-)-goniomitine has been developed by using an iridium-catalyzed asymmetric hydrogenation of exocyclic enone ester to control the configuration of molecule. The synthesis begins from commercially available starting materials, and integrated asymmetric ketone hydrogenation, Johnson-Claisen rearrangement, and one-pot oxidation/deprotection/cyclization process. With this highly efficient and scalable strategy (-)-goniomitine was synthesized in eleven steps with 27% overall yield, and the formal enantioselective synthesis of (+)-1,2-dehydroaspidospermidine, (+) aspidospermidine and (+)-vincadifformine were also achieved. PMID- 30520200 TI - The antibiotic action of methylarsenite is an emergent property of microbial communities. AB - Arsenic is the most ubiquitous environmental toxin. Here, we demonstrate that bacteria have evolved the ability to use arsenic to gain a competitive advantage over other bacteria at least twice. Microbes generate toxic methylarsenite (MAs(III)) by methylation of arsenite (As(III)) or reduction of methylarsenate (MAs(V)). MAs(III) is oxidized aerobically to MAs(V), making methylation a detoxification process. MAs(V) is continually re-reduced to MAs(III) by other community members, giving them a competitive advantage over sensitive bacteria. Because generation of a sustained pool of MAs(III) requires microbial communities, these complex interactions are an emergent property. We show that reduction of MAs(V) by Burkholderia sp. MR1 produces toxic MAs(III) that inhibits growth of Escherichia coli in mixed culture. There are three microbial mechanisms for resistance to MAs(III). ArsH oxidizes MAs(III) to MAs(V). ArsI degrades MAs(III) to As(III). ArsP confers resistance by efflux. Cells of E. coli expressing arsI, arsH or arsP grow in mixed culture with Burkholderia sp. MR1 in the presence of MAs(V). Thus MAs(III) has antibiotic properties: a toxic organic compound produced by one microbe to kill off competitors. Our results demonstrate that life has adapted to use environmental arsenic as a weapon in the continuing battle for dominance. PMID- 30520201 TI - 2-hr vs. 1-hr Glucose Tolerance Testing: Predicting prediabetes in adolescent girls with obesity. AB - BACKGROUND: During an oral glucose tolerance test (OGTT), morphological features of the glucose curve (monophasic curve, glucose peak >30mins and 1-hr glucose >=155mg/dL) maybe associated with higher prediabetes risk, but their reproducibility and predictive ability in adolescents with obesity are unknown. DESIGN/METHODS: Nondiabetic adolescent girls with obesity underwent a multiple sample OGTT at baseline (n=93), 6-weeks (n=83), and 1-year (n=72). Short-term reproducibility (baseline to 6-weeks) and the predictive ability for prediabetes (baseline to 1-year) for each feature were compared to standard fasting and 2-hr OGTT diagnostic criteria. RESULTS: There was fair/moderate short-term reproducibility (kappa<0.5) for all morphological features. At 1-year, compared to standard OGTT criteria, the ROC-AUCs for glucose peak >30 mins, 1-hr >=155mg/dL or a combination of the 2 criteria were comparable (all P>0.05), but the monophasic curve had the lowest ROC-AUC (P<0.001). CONCLUSION: In adolescent girls with obesity, glucose peak > glucose >=155mg/dL had similar reproducibility and 1-year predictive ability for prediabetes compared to standard OGTT criteria. The shortened 1-hr OGTT may provide diagnostic equivalence for prediabetes risk with the additional advantage of a less time-consuming risk assessment. This article is protected by copyright. All rights reserved. PMID- 30520202 TI - Dramatically Enhanced Li-Ion Storage of ZnO@C Anodes through TiO2 Homogeneous Hybridization. AB - Amorphous nanoparticles of ZnO and TiO2 embedded in carbon nanocages (AZT?CNCs) were successfully synthesized through a simple annealing process of TiO2 -coated zeolitic imidazolate framework-8 (ZIF-8). In the current anode of AZT?CNCs, tiny ZnO and TiO2 nanoparticles were uniformly distributed in the carbon matrix (carbon nanocages), which could effectively buffer the volume expansion of electroactive ZnO and provide excellent electric conductivity. After fully investigating the electrochemical performance of the AZT?CNCs samples obtained with different additive amounts of tetrabutyl orthotitanate (TBOT) for TiO2 coating, it has been found that AZT-30 (0.1 g ZIF-8 with 30 mL TBOT) shows the best cycle stability (510 mA h g-1 after 350 cycles at 200 mA g-1 ) and a superior rate capability (610 mA h g-1 after 3500 cycles at 2 A g-1 ). The greatly enhanced Li-ion storage performance could be ascribed to the fact that the introduction of amorphous TiO2 could activate the reversible lithiation/delithiation reaction of ZnO during the charge/discharge process. PMID- 30520203 TI - Perinatal changes in fetal cardiac geometry and function in gestational diabetic pregnancies at term. AB - OBJECTIVE: To evaluate the effect of gestational diabetes mellitus (GDM) on fetal and neonatal cardiac geometry and function around the time of birth. METHODS: A prospective study of 75 pregnant women delivering at term, comprising of 54 normal pregnancies and 21 with a diagnosis GDM. Fetal and neonatal conventional cardiac indices, spectral tissue Doppler and 2D speckle tracking imaging were performed a few days before and within hours of birth. RESULTS: Compared to normal pregnancy, GDM fetuses demonstrated significant impairment in ventricular geometry, myocardial deformation and cardiac function (right ventricular [RV] sphericity index: 0.56 vs 0.65, LV torsion: 2.1deg/cm vs 5.6deg/cm, LV isovolumetric relaxation time': 101ms vs 115ms, and RV isovolumetric contraction time': 107ms vs 119ms, p<0.001 for all). When compared to normal newborns, GDM neonates revealed persistent alteration in cardiac parameters (RV sphericity index 0.43 vs 0.55, LV torsion 1.3deg/cm vs 2.8deg/cm, LV myocardial performance index [MPI'] 0.39 vs 0.51, RV MPI' 0.34 vs 0.40, p<0.001 for all). Paired comparison of fetal and neonatal cardiac indices in GDM demonstrated that birth resulted in significant improvement in some, but not all cardiac indices (RV sphericity index: 0.65 vs 0.55, LV torsion 5.6cm/deg vs 2.8cm/deg, RV MPI': fetus 0.50 vs neonate 0.40, p<0.001 for all). CONCLUSIONS: Compared to normal pregnancy, GDM term fetuses and neonates exhibit cardiac indices indicative of myocardial impairment reflecting a response to a relatively hyperglycaemic intrauterine environment with alteration in fetal loading conditions (LV preload deprivation and increased RV afterload) and adaptation to subsequent acute changes in haemodynamic load at birth. Elucidating mechanisms that contribute to the alterations in perinatal cardiac function in GDM could help in refining management and evolve better therapeutic strategies to reduce the risk of adverse pregnancy outcome. This article is protected by copyright. All rights reserved. PMID- 30520204 TI - Neurodevelopmental outcome in children with spina bifida aperta repaired prenatally versus postnatally: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the neurodevelopmental outcome of children with spina bifida aperta (SBA) who were treated prenatally as compared to those treated postnatally. METHODS: We performed a systematic review of the literature comparing neurological outcomes of prenatally and postnatally repaired spina bifida in Pubmed/MEDLINE, Embase, Web of Science and Cochrane Library. We retrieved all randomized and non-randomized prospective controlled studies. The primary outcome assessed was neurodevelopmental impairment at the age of one year or later. The secondary outcomes were prematurity, the need for cerebrospinal fluid (CSF) shunting from 12 months of age, absence of signs of hindbrain herniation at the first postnatal MRI evaluation, independent ambulation evaluated at 30 months. RESULTS: Six studies out of 11,359 met the inclusion criteria and were assessed as full-text articles. Two studies, one randomized controlled trial (RCT) and one prospective cohort study, were included. Sensitivity analysis did not show a difference between the outcomes in the RCT and the prospective cohort study when pooled. This allowed neurodevelopmental assessment of 213 children between 14 and 53 months of age. Neurodevelopment was assessed by the Bayley Scales of Infant Development (BSIDII) mental development index (MDI) corrected for chronological age with a cut-off >70 (representing no more than 2 standard deviations below the mean). Neurodevelopmental impairment was present in 25/105 (23.8%) and in 30/108 (27.7%) children who underwent prenatal and postnatal repair, respectively (OR 0.82, 95% Confidence Interval [CI] 0.43-1.56, p=0.54), although the prematurity risk was higher in the prenatal group (OR 17.6, 95% CI 7.60-40.87, p<0.0001). For every two fetuses operated before birth, there was, compared to those operated after birth, one additional premature birth (number needed to harm [NNH]=2, CI 1-3). 45/109 (41.2%) children in the prenatal group needed CSF shunting by 12 months of age compared to 93/112 (83%) in the postnatal group (OR 0.14, 95% CI 0.08-0.26, p<0.0001). Data on neurodevelopmental impairment in shunted children was only available in patients from the prenatal surgery group of the RCT. The likelihood for impairment when having a shunt was not higher (7/39 [18%] with a shunt and 4/48 [8%] without a shunt, p=0.21). The first postnatal MRI evaluation detected no signs of hindbrain herniation in 28/88 (31.8%) children in the prenatal group compared to 4/89 (4.5%) in the postnatal group (OR 9.45, 95% CI 3.12-28.6, p<0.0001). Independent ambulation at 30 months was achieved by 41/109 (37.6%) children in the prenatal group compared to 21/111 (18.9%) in the postnatal repair group (OR 2.62, 95% CI 1.39-4.86, p=0.003). CONCLUSIONS: The risk for neurodevelopmental impairment is similar in the prenatally operated group compared to the postnatal repair group, despite an increased prematurity risk. This article is protected by copyright. All rights reserved. PMID- 30520205 TI - Carbon-Supported Divacancy-Anchored Platinum Single-Atom Electrocatalysts with Superhigh Pt Utilization for Oxygen Reduction Reaction. AB - Maximizing the platinum utilization in electrocatalysts toward oxygen reduction reaction (ORR) is very desirable for large-scale sustainable application of Pt in energy systems. Here, we report a cost-effective carbon-supported carbon-defect anchored platinum single-atom electrocatalysts (Pt1/C) with remarkable ORR performance. Impressively, the acidic H2/O2 single cell with Pt1/C as the cathode delivers a maximum power density of 520 mW cm-2 at 80 degrees C, corresponding to a superhigh platinum utilization of 0.09 gPt kW-1. Further physical characterization and density functional theory (DFT) computations reveal that the single platinum atoms anchored stably by four carbon atoms neighbouring carbon divacancies (Pt-C4) are the main active centers for the observed high ORR performance. PMID- 30520206 TI - Orientation of Amphiphilic Copolymer to Lamellar Structure on Hydrophobic Surface and Implications for CO2 Capture Membranes. AB - We first report the structural orientation of an amphiphilic crystalline polymer to a highly ordered microphase-separated lamellar structure on a hydrophobic surface. It is formed by the surface graft polymerization of poly(ethylene glycol)behenyl ether methacrylate onto poly(trimethylsilyl) propyne in the presence of allylamine. In particular, allylamine plays a pivotal role in controlling the crystalline phase, configuration and permeation property. The resulting materials are effectively used to improve the CO2 capture property of membranes. Upon the optimization of the reaction conditions, a high CO2 permeability of 501 Barrer and a CO2/N2 selectivity of 77.2 are obtained, which exceed the Robeson upper bound limit. It is inspiring to surpass the upper bound limit in such a remarkable fashion via a simple surface modification method. PMID- 30520207 TI - Pull-down of metallated carbonic anhydrase using desthiobiotin-based probes. AB - One-third of all proteins are estimated to require metals for structural stability and/or catalytic activity. Desthiobiotin probes containing metal binding groups can be used to capture metalloproteins with exposed active-site metals under mild conditions to prevent changes in metallation state. The proof of-concept was demonstrated with carbonic anhydrase (CA), an open active site, Zn containing protein. CA was targeted using sulfonamide derivatives. Linkers of various lengths and structures were screened to determine the optimal structure for capture of the native protein. The optimized probes could selectively pull down CA from red blood cell (RBC) lysate and other protein mixtures. Pull-down of differently metallated CAs was also investigated. PMID- 30520208 TI - Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomised controlled trial. AB - BACKGROUND: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). AIM: To determine in a multi-centre, double-blinded placebo controlled randomised trial, whether testosterone treatment combined with lifestyle intervention (Weight Watchers(r)) relative to lifestyle intervention alone, reduces T2DM incidence and improves glucose tolerance at 2 years. STUDY POPULATION: Overweight or obese men aged 50-74 years with a serum testosterone of <=14nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). SETTING, DRUG AND PROTOCOL: Six Australian capital city based tertiary care centres. Participants were randomised 1:1 and injected with testosterone undecanoate (Reandron, Bayer) (1000mg/4ml) or vehicle (4ml castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (1) Proportion of participants with 2-hour OGTT >= 11.1 mmol/L at 2 years. (2) A difference at 2 years >= 0.6mmol/L in the mean 2-hour OGTT glucose between treatments. SECONDARY ENDPOINTS: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilisation and costs. SAFETY: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids, and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (i) Changes in bone density and micro architecture; (ii) motivation and behaviour; (iii) telomere length; (iv) extended treatment up to 4 years, and (v) hypothalamo-pituitary testicular axis recovery at treatment end. This article is protected by copyright. All rights reserved. PMID- 30520209 TI - Shift work, sleep disturbances and social jetlag in healthcare workers. AB - The aim of this study was to compare chronotype- and age-dependent sleep disturbances and social jetlag between rotating shift workers and non-shift workers, and between different types of shifts. In the Klokwerk+ cohort study, we included 120 rotating shift workers and 74 non-shift workers who were recruited from six Dutch hospitals. Participants wore Actigraph GT3X accelerometers for 24 hr for 7 days. From the Actigraph data, we predicted the sleep duration and social jetlag (measure of circadian misalignment). Mixed models and generalized estimation equations were used to compare the sleep parameters between shift and non-shift workers. Within shift workers, sleep on different shifts was compared with sleep on work-free days. Differences by chronotype and age were investigated using interaction terms. On workdays, shift workers had 3.5 times (95% confidence interval: 2.2-5.4) more often a short (< 7 hr per day) and 4.1 times (95% confidence interval: 2.5-6.8) more often a long (>= 9 hr per day) sleep duration compared with non-shift workers. This increased odds ratio was present in morning chronotypes, but not in evening chronotypes (interaction p-value < .05). Older shift workers (>= 50 years) had 7.3 times (95% confidence interval: 2.5-21.8) more often shorter sleep duration between night shifts compared with work-free days, while this was not the case in younger shift workers (< 50 years). Social jetlag due to night shifts increased with increasing age (interaction p-value < .05), but did not differ by chronotype (interaction p-value >= .05). In conclusion, shift workers, in particular older workers and morning chronotypes, experienced more sleep disturbances than non-shift workers. Future research should elucidate whether these sleep disturbances contribute to shift work related health problems. PMID- 30520210 TI - Flavanols protect the yeast Saccharomyces cerevisiae against heating and freezing/thawing injury. AB - AIMS: The aim of the study was to check whether two flavanols [(-) epigallocatechin gallate and (+)-catechin] can ameliorate oxidative stress accompanying and contributing to the lethal effects of heating (50 degrees C) and freezing-thawing on the yeast Saccharomyces cerevisiae. METHODS AND RESULTS: The flavanols studied increased yeast survival during heating and freezing-thawing, estimated by the colony forming assay. They improved also such indices of oxidative stress as increased production of reactive oxygen species, decrease of total antioxidant activity of yeast cell extracts and increase in the level of protein carbonyls. CONCLUSIONS: Amelioration of oxidative stress by flavanols increases the survival of the yeast subjected to high temperature and freezing thawing. SIGNIFICANCE AND IMPACT OF THE STUDY: Flavanols may be considered as means of enhancing yeast survival under extreme temperature conditions and probably in other conditions involving oxidative stress. This article is protected by copyright. All rights reserved. PMID- 30520211 TI - Reproducibility of the PIROP ultrasonic biometer for gingival thickness measurements. AB - OBJECTIVES: Gingival thickness (GT) has a great importance in periodontal flap design, gingival recession, and soft tissue esthetic. The aim of this study was to determine the reproducibility of PIROP ultrasonic biometer, which is specially designed for human GT measurements and to compare with the invasive transgingival probing technique. MATERIALS AND METHODS: GT was measured in 25 periodontally healthy volunteers both by PIROP and an endodontic spreader on the attached gingiva. Reproducibility was assessed by calculating standrad deviaton (SD) in five repeated measurements and Pearson correlation coefficient (r). Agreement between the two methods was evaluated based on Bland-Altman limits of agreement (LoA). RESULTS: No systemic bias in GT was observed between the two methods. The repeatability of the PIROP was better than the spreader method (SD = 0.14 mm vs 0.20 mm, P < 0.001). With five repetitions, the measurement error of the PIROP was halved. The correlation among the repeated observations were strong (r = 0.86) for the ultrasonic, weak (r = 0.34) for the invasive method. The LoA between the two methods was -0.58 to +0.75 mm. CONCLUSION: PIROP is a reliable device for GT measurements, but it is recommended to repeat the measurement a few times to improve the precision in individual case. CLINICAL SIGNIFICANCE: PIROP ultrasonic biometer could be used in routine practice to reliably measure the GT in noninvasive way. After short learning curve the measurement can be done quickly and conveniently. PMID- 30520213 TI - Abstracts, RCOG National Trainees Conference (NTC), Birmingham, UK, 6-7 December 2018. PMID- 30520212 TI - Temperature- and Pressure-induced Structural Transition of Binary (C4H8O + CH4) Clathrate Hydrates. AB - We discover new structure II (sII) hydrate forming agents of two C4H8O molecules (2-methyl-2-propen-1-ol and 2-butanone) and report the abnormal structural transition of binary C4H8O + CH4 hydrates between structure I (sI) and sII with varying temperature and pressure conditions. In both (2-methyl-2-propen-1-ol + CH4) and (2-butanone + CH4) system, the phase boundary of the two different hydrate phases (sI and sII) exists at the slope change of the phase-equilibrium curve in the semi-logarithmic plots. We confirm the crystal structures of two hydrates synthesized at low (278 K and 6 MPa) and high (286 K and 15 MPa) temperature and pressure conditions by using high resolution powder diffraction and Raman spectroscopy. 2-methyl-2-propen-1-ol and 2-butanone can occupy the large cages of sII hydrate at low temperature and pressure conditions; however, they are excluded from the hydrate phase at high temperature and pressure conditions, resulting in the formation of sI pure CH4 hydrate. PMID- 30520214 TI - Improvements in the perception of facial attractiveness following surgical aesthetic treatment; study based on online before and after photos. AB - BACKGROUND: Aesthetic surgery procedures such as lip augmentation, eyelid correction, face-lifting, or Botox treatment for lines and wrinkles are an important part of cosmetic surgery. OBJECTIVES: The aim of the study was to estimate improvement in appearance following plastic surgery using modern collective intelligence methods of validation. METHODS: A total of 108 photographs showing 54 patients prior to and following cosmetic surgery were downloaded from Internet web presentations of several unnamed plastic surgeons. The same number of photographs depicted each of the four investigated areas of treatment-26 lip enhancement, 26 blepharoplasty, 26 face-lift, 26 botulinum toxin injection. Attractiveness of depicted individuals was assessed by 167 observers. Each photograph was judged separately. RESULTS: Blepharoplasty produced the most remarkable improvement in attractiveness amounting to 32.79 (SD +/- 26.35). Improvement following Botox treatment stood at 30.29 (SD +/- 24.55), whereas face lifting produces improvement of 28.70 (SD +/- 22.76). Improvement following lip augmentation was estimated at 12.70 (SD +/- 29.8). Highest Spearman's rank correlation coefficient was obtained for face-lift and Botox (0.24 and 0.22, respectively). CONCLUSIONS: Blepharoplasty, face-lifting, and Botox deliver a significant improvement in facial attractiveness. Additionally, face-lifting and Botox are distinguished by a high level of reproducibility. Our results indicate that lip augmentation is a treatment with a statistically significant, but less marked improvement in attractiveness. PMID- 30520215 TI - Nuclear compartmentalization, dynamics and function of regulatory DNA sequences. AB - Transcription regulatory elements (TREs) have been extensively studied on the biochemical level with respect to their interactions with transcription factors, other DNA segments and larger protein complexes. In this review we describe concepts and preliminary experimental evidence for positional changes of TREs within a dynamic, functional nuclear architecture. We suggest a multi-layered shell-like chromatin organization of chromatin domain clusters with increasing chromatin compaction levels from the periphery toward the interior with a decondensed transcriptionally active peripheral layer and compact repressed chromatin typically located in the interior. This model organization of nuclear architecture implies a differential accessibility of transcription factors to targets located in co-aligned active and inactive nuclear compartments. It is based on evidence that active, easily accessible chromatin (perichromatin, PR) lines a network of channels (interchromatin compartment, IC) involved in nuclear import-export functions. The IC and PR constitute the active nuclear compartment (ANC), whereas transcriptionally non-competent chromatin with higher compactness is part of the likely less accessible inactive nuclear compartment (INC). Preliminary experimental evidence shows an enrichment of active TREs in the ANC and of inactive TREs in the INC suggesting positional changes of TREs between the ANC and INC depending on changes in their functional state. This article is protected by copyright. All rights reserved. PMID- 30520216 TI - A whey/guar "preload" improves postprandial glycaemia and HbA1c in type 2 diabetes - a 12-week, single-blind, randomized, placebo-controlled trial. AB - AIMS: To evaluate the effects of 12 weeks' treatment with a whey/guar preload on gastric emptying, postprandial glycaemia, and glycated haemoglobin (HbA1c), in type 2 diabetes (T2DM). MATERIALS AND METHODS: 79 patients with T2DM managed on diet or metformin (HbA1c 6.6+/-0.1% (49+/-0.7mmol/mol), were randomized, in single-blind fashion, to receive 150mL flavoured preloads, containing either 17g whey protein plus 5g guar (n=37), or flavoured placebo (n=42), 15 min before two meals each day for 12 weeks. Blood glucose and gastric emptying (breath test) were measured before and after a mashed potato meal at baseline (without preload), and after the preload at the beginning (week 1) and end (week 12) of treatment. HbA1c, energy intake, weight, and body composition were also evaluated. RESULTS: Gastric emptying was slower (P<0.01) and postprandial blood glucose lower (P<0.05) with the whey/guar preload compared to placebo, and the magnitude of reduction in glycaemia was related to the rate of gastric emptying at both week 1 (r= -0.54, P<0.001) and week 12 (r=-0.54, P<0.0001). At the end of treatment, there was a 0.1% reduction in HbA1c in the whey/guar group compared to placebo (6.6+/-0.05% [49+/-1.0mmol/mol] versus 6.7+/-0.05% [50+/-0.8mmol/mol], P<0.05). There were no differences in energy intake, body weight, or lean or fat mass between the groups. CONCLUSIONS: In patients with well-controlled T2DM, 12 weeks' treatment with a low-dose whey/guar preload, taken twice daily before meals, has sustained effects to slow gastric emptying and reduce postprandial blood glucose, associated with a modest reduction in HbA1c, without causing weight gain. This article is protected by copyright. All rights reserved. PMID- 30520217 TI - Commencing insulin glargine 100 U/mL therapy in people with type 2 diabetes: Determinants of achievement of HbA1c goal <7.0. AB - AIMS: To identify factors associated with achievement of glycated haemoglobin A1c (HbA1c) target at 24 weeks after commencing basal insulin therapy in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Post-hoc pooled analysis of 16 randomised, treat-to-target trials involving people with T2DM inadequately controlled on oral anti-hyperglycaemic drugs (n=3415) initiated on once-daily insulin glargine 100 U/mL (Gla-100). Clinical outcomes were assessed by HbA1c response at 24 weeks and people classified as "good responders" by reaching HbA1c <7.0% (<53 mmol/mol) and "poor responders" with HbA1c >=7.0% (>=53 mmol/mol). Univariable and multivariable stepwise logistic regression analyses were performed to identify predictive factors for attaining an HbA1c of <7.0%. RESULTS: Lower levels of baseline HbA1c, fasting plasma glucose (FPG), and post prandial plasma glucose (PPG), higher body mass index (BMI), shorter diabetes duration, and male sex were associated with a good glycaemic response, not age or baseline C-peptide levels. Gla-100 dose (U/kg) was highest in the poor-responder group, which had the fewest hypoglycaemia episodes. Univariable analysis for achievement of a HbA1c of <7.0% confirmed these observations. Multivariable analysis retained baseline HbA1c, body weight, BMI, sex, 2-h PPG, and diabetes duration as predictors of a good response. Continued use of sulfonylureas, hypoglycaemia, and body weight change were indicative of poor response. CONCLUSIONS: Baseline HbA1c was the strongest determinant for achieving target HbA1c <7.0% by supplementary Gla-100 therapy while sex and BMI were also useful indicators. However, age and C-peptide levels at baseline did not predict glycaemic response to the introduction of basal insulin. This article is protected by copyright. All rights reserved. PMID- 30520218 TI - Rapid tool for identification of bacterial strains using Fourier-transform infrared spectroscopy on genomic DNA. AB - AIMS: We developed a new rapid and reliable method for identifying bacteria using a combination of Fourier transform infrared (FT-IR) spectroscopy of bacterial genomic DNA and multivariate analysis. METHODS AND RESULTS: FT-IR spectra of genomic DNA from four type strains of Pseudomonas spp., three Escherichia spp., and two Bacillus spp. were analyzed in the region 4,000-400 cm-1 . Spectral differences were found in the frequency regions of N-H stretching (amide I), C=O stretching vibrations (amide II), and PO2 - ionized asymmetric and symmetric stretching. Partial least squares discriminant analysis of the FT-IR spectra showed that the microbial strains could be discriminated by hierarchical clustering analysis. CONCLUSIONS: FT-IR spectral analysis of bacterial genomic DNA has potential for the rapid identification of bacteria at the genus and species levels. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports a new bacterial identification method using multivariate analysis of FT-IR spectra of bacterial genomic DNA. This article is protected by copyright. All rights reserved. PMID- 30520219 TI - Quantification of three triterpenic acids in dried rosemary using HPLC fluorescence detection and 4-(4,5-diphenyl-1H-imidazole-2-yl)benzoyl chloride derivatization. AB - Functional triterpenic acids such as ursolic acid (UA), oleanolic acid (OA) and betulinic acid (BA) are representative ingredients in rosemary that may have health benefits. UA, OA and BA in rosemary extracts were derivatized with 4-(4,5 diphenyl-1H-imidazole-2-yl)benzoyl chloride (DIB-Cl) and detected using HPLC fluorescence (FL). Dried rosemary (50 mg) was ground, added to 3 ml of ethanol, sonicated for 40 min, then the sample solution was added to a mixture of 1% trimethylamine and 1 mM DIB-Cl in acetonitrile. The mixture was settled for 5 min at room temperature, then the DIB-triterpenic acid derivatives were separated using a Wakopak Handy ODS column (250 * 4.6 mm, 6 MUm) eluted with 25 mM acetate buffer (pH 4.5)/methanol/acetonitrile (= 8:10:82 v/v/v%). The fluorescence intensity of the eluent was monitored at 365 (lambdaex ) and 490 nm (lambdaem ) and the maximum retention time of the derivatives was 30 min. Calibration curves constructed using rosemary extract spiked with standards showed good linearity (r >= 0.997) in the range 2.5-100 ng/ml. The detection limits at 3sigma for internal BA, UA and OA peaks in rosemary extract were 0.2, 0.4 and 0.5 ng/ml, respectively. This method was used to quantify BA, UA and OA in commercially available dried rosemary products. PMID- 30520220 TI - The first example of fluorescence of the solid individual compounds of Eu2+ ion: EuCl2 , EuI2 , EuBr2. AB - Fluorescence (FL) from Eu2+ ion solid individual compounds was observed for the first time using the examples EuCl2 , EuI2 and EuBr2 . Fluorescence was detected at excitation by ultraviolet (UV) light from powdered samples of Eu (II) halides at room temperature (RT) in an argon atmosphere. In air, FL of all Eu2+ compounds studied was stable, and intensity persisted for weeks. Depending on the nature of the halide anion and due to a nephelauxetic effect, the position of the maxima in the FL spectra underwent a red shift in the series: EuCl2 (409 nm) < EuBr2 (428 mm) < EuI2 (432 nm). The lifetimes of the excited states of the Eu2+ * ions for EuI2 , EuCl2 and EuBr2 were 355, 76 and 54 ns, respectively. PMID- 30520222 TI - Mindfulness and burnout among beside registered nurses: A cross-sectional study. AB - Nursing is a high stress job, and burnout of nurses is of particular concern. The aim of this cross-sectional survey study was to examine the relationship between mindfulness and burnout, and how the mindfulness facets vary in their associations with the different domains of burnout for Chinese nurses. A sample of registered bedside nurses working in a tertiary Chinese hospital (n = 763) was surveyed from February to June 2017 regarding mindfulness (i.e. acting with awareness, describing, and non-judging of experiences), burnout (i.e. emotional exhaustion, depersonalization, and personal accomplishment), and sociodemographic and job-related characteristics. Higher scores on the three facets of mindfulness were associated with less emotional exhaustion and depersonalization, and acting with awareness showed the highest regression coefficients. Personal accomplishment was positively associated with acting with awareness and describing, whereas it was negatively related to non-judging of experiences. Describing was the strongest facet associated with personal accomplishment. In conclusion, there were clearly correlations between mindfulness as a personal trait and burnout among Chinese bedside nurses. These findings suggest the potential benefits of tailored mindfulness-based interventions in reducing nurse burnout in China. PMID- 30520221 TI - The comparative effect of saxagliptin and glimepiride with a composite endpoint of adequate glycaemic control without hypoglycaemia and no weight gain in patients uncontrolled with metformin therapy: results from the SPECIFY study, a 48-week, multi-centre, randomized, controlled trial. AB - AIMS: To compare the efficacy and safety of saxagliptin and glimepiride in type 2 diabetes (T2D) patients inadequately controlled with metformin monotherapy. MATERIALS AND METHODS: In this 48-week, multi-centre, open-label, randomized, parallel trial, a total of 388 T2D patients were 1:1 randomized to saxagliptin or glimepiride group. The primary endpoint was the achievement of HbA1c<7.0%, without hypoglycaemia (defined as blood glucose < 3.9 mmol/L) and no weight (weight gain < 3.0%) after 48 weeks of treatment. RESULTS: Over 48 weeks, a greater proportion of patients achieved the primary endpoint with saxagliptin compared with glimepiride (43.3% vs. 31.3%; odds ratio 1.38, 95%CI: 1.05-1.82; p=0.019), especially among the patients with baseline HbA1c<8.0%, duration<5 years or baseline BMI >=25 kg/m2 . The mean reduction in HbA1c was similar in the two treatment groups at week 48 (-0.94% in saxagliptin vs. -0.98% in glimepiride, p=0.439). The bodyweight decreased with saxagliptin, but increased with glimepiride over the treatment period, and the treatment difference was -1.6 kg (p<0.001) at week 48. The proportion of patients experiencing hypoglycaemia was much lower with saxagliptin vs. glimepiride (3.1% vs. 12.8%, p<0.001). CONCLUSIONS: This study provides evidence that compared to glimepiride, saxagliptin more effectively achieves a composite endpoint of adequate glycaemic control without hypoglycaemia and no weight gain in T2D patients inadequately controlled with metformin monotherapy, especially in overweight patients with moderate hyperglycaemia and a relatively shorter diabetes duration. This article is protected by copyright. All rights reserved. PMID- 30520223 TI - Identification of Saliva Proteins of Spider Mite Tetranychus evansi by Transcriptome and LC-MS/MS Analyses. AB - The spider mite Tetranychus evansi has a remarkable ability to suppress and manipulate plant defenses, which makes it an ideal model to investigate plant herbivores interactions. In this study, we performed a de novo assembly of the transcriptome of T. evansi, and characterized the proteins in its secreted saliva by Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS). A total of 29,365 unigenes were assembled and 136 saliva proteins were identified. Comparative analysis of the saliva proteins in T. evansi, T. truncatus, and T. urticae showed that 64 protein groups were shared by at least two Tetranychus species, and 52 protein groups were specifically identified in T. evansi. In addition, some saliva proteins were common in arthropod species, while others were species-specific. These results will help to elucidate the molecular mechanisms by which T. evansi modulates plant defenses. This article is protected by copyright. All rights reserved. PMID- 30520224 TI - Synthesis, insecticidal activity and phytotoxicity of novel chiral amides. AB - BACKGROUND: The lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrychidae) is an important pest of stored grains worldwide. Chemical control is the main method used to manage this pest, but the continuous use of insecticides can lead to the selection of resistant R. dominica strains. Thus, there is a constant demand for the development of new insecticide molecules. This study describes the synthesis of 14 chiral amides and evaluation of their insecticidal activity against R. dominica. Their phytotoxicity to wheat (Triticum sativum) seeds was also evaluated. RESULTS: In the screening assay, compounds 8i and 8j caused 100 and 87% mortality of R. dominica. These values did not differ from the mortality caused by Bifenthrin(r) (75%). Amide 8i presented similar toxicity (LD50 = 27.98 MUmol g-1 , CI95 = 25.14 - 30.71) and speed of action (LT50 = 22 hours, CI95 = 19.34 - 24.66) to amide 8j (LD50 = 29.37 MUmol g-1 , CI95 = 27.43 - 31.09 and LT50 = 19 hours, CI95 = 17.05 - 20.95) against the pest. Both amides inhibited less than 44% of wheat growth. CONCLUSION: Among the tested amides, only 8i and 8j were effective in R. dominica control and presented no considerable phytotoxicity towards wheat seeds. Therefore, these amides are promising as insecticides for the management of R. dominica. This article is protected by copyright. All rights reserved. PMID- 30520225 TI - The relation between androgenetic thin hair diagnosed by trichoscope and benign prostatic hyperplasia. AB - BACKGROUND: Androgenetic alopecia carries a major cosmetic disfigurement and benign prostatic hyperplasia is associated with many urinary tract symptoms and both diseases are mediated by dihydrotestosterone. OBJECTIVES: The study aimed to determine the relationship between hair diameter in androgenetic alopecia diagnosed, by trichoscope, to benign prostatic hyperplasia symptoms and signs. METHODS: Fifty androgenetic alopecia males and 50 normal males as control were included. We used trichoscope for hair examination, transrectal ultrasound for prostate volume, and urodynamic inspectoscope for urinary symptoms, serum total testosterone, dihydrotestosterone, and total prostatic specific antigen were measured in blood samples. All participants answered the International prostate symptom score questionnaire and the International Index of Erectile Function score questionnaire. RESULTS: A significant difference between patient and control groups was detected as regards hair thickness (P = 0.001), prostatic volume (P = 0.013), urinary symptoms, prostatic specific antigen level (P = 0.015). A significant difference was detected between thin (<0.03 mm, n = 26) and medium to thick hair (>0.03, n = 24) subgroups of patients as regards age (P = 0.001), dihydrotestosterone level (P = 0.001), testosterone level (P = 0.001), and urinary symptoms (P = 0.001). CONCLUSION: Androgenetic alopecia patients with thin hair diagnosed by trichoscopy are more prone to prostatic enlargement and its related symptoms. Androgenetic alopecia severity can be diagnosed by trichoscopy in addition to Hamilton-Norwood scale. PMID- 30520226 TI - Mediating effects of fatigue on the relationships among sociodemographic characteristics, depression, and quality of life in patients receiving hemodialysis. AB - The aim of this study was to explore how hemodialysis patients' quality of life is related to sociodemographic data and depression as predicting variables, and how it is affected by fatigue as a mediating variable. Participants were 405 patients who has been receiving hemodialysis treatment regularly. SPSS Amos path analysis was used to explore the causal relationship and the mediating effect of fatigue among the variables of sociodemographic characteristics, depression, and quality of life. Unstandardized estimates determined that while sociodemographic characteristics were a significant predictor of fatigue, they were not directly related to quality of life. The results showed that depression and fatigue in patients receiving hemodialysis are important factors that affect patients' quality of life to a greater (fatigue) or lesser (depression) extent. Depression can affect patients' quality of life either directly or indirectly via fatigue. In this study, we demonstrated that fatigue plays an important role in the relationships among sociodemographic characteristics, depression, and quality of life in patients receiving hemodialysis. The results of the study further suggest that comprehensive management programs should be applied with patients to reduce their fatigue, and ultimately to improve their quality of life. PMID- 30520227 TI - Dermoscopic follow-up of therapeutic response in mantle cell lymphoma with secondary involvement of the scalp. AB - The scalp is a potential location for both benign and malignant tumors. Lymphoproliferative diseases can involve the skin as a primary or secondary manifestation. Dermoscopy is a noninvasive diagnostic tool for rapid diagnosis, screening, and follow-up of the majority of skin tumors. Mantle cell lymphoma (MCL), a rare type of aggressive systemic lymphoma, usually occurs as a generalized lymphadenopathy, commonly with infiltration of the bone marrow, spleen, gastrointestinal tract, and Waldeyer's ring. In rare cases, it can also involve other structures, such as the lungs, central nervous system, liver, or skin. We report the case of a 74-year-old male patient suffering from MCL since 2015. Complete remission was obtained after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment. During maintenance therapy with rituximab, a solitary tumor occurred on the scalp. Dermoscopy of the lesion suggested relapse because of the presence of multiple chaotically distributed short linear vessels with multiple red dots within the hair follicles. Histological examination confirmed the diagnosis of MCL. After second-line therapy with rituximab and bendamustine (R-B), the tumor of the scalp completely disappeared and dermoscopy showed no abnormalities. PMID- 30520228 TI - Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes by a 1,2 Metalate Rearrangement/anti-SN2' Elimination/Rearomatizing Allylic Suzuki-Miyaura Reaction Sequence. AB - The one-pot sequential coupling of benzylamines, boronic esters and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-SN2' elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing gamma-selective allylic Suzuki-Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched alpha substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity. PMID- 30520230 TI - Meetings of Interest. PMID- 30520229 TI - A new approach to lower eyelid-cheek junction rejuvenation. AB - BACKGROUND: Anti-aging in lower eyelid-cheek junction area has always been the upmost widely sought of cosmetic surgery. Removal of orbital fat from inside or outside, removal of part of the skin or even the orbicularis muscle, superficial pull and deep fill and a series of surgical procedures like these have been or are becoming the mainstream of clinical practice. However, aging involves a variety of tissues and causes, which is a dynamic and continuous process. Conventional or a single method cannot fundamentally solve all of the problems of the aging in lower eyelid-cheek junction area. Therefore, we propose a better organized surgical approach based on the whole anatomy of lower eyelid-cheek junction area. METHODS: A total of 103 patients received lower eyelid-cheek junction rejuvenation surgery from September 2014 to September 2017 in our department. Efficacy of surgeries was delineated and scored by both patients and surgeons. RESULTS: All patients of different ages, genders were relatively satisfied with the lower eyelid-cheek junction rejuvenation surgery in our department. Patients with different past histories of cosmetic surgeries could all benefit from the lower eyelid-cheek junction rejuvenation surgery. CONCLUSION: Rejuvenation of lower eyelid-cheek junction area should be based on a thorough understanding of periorbital anatomy, age-related changes of the lid cheek junction, and the variables controlling lower lid tone and position. The surgical strategies are best used in a graded fashion. PMID- 30520231 TI - Disruption of sex-specific doublesex exons results in male- and female-specific defects in the black cutworm, Agrotis ipsilon. AB - BACKGROUND: Doublesex (dsx), the downstream gene in the insect sex determination pathway, is a key regulator of sexually dimorphic development and behavior across a variety of insects. Manipulating the expression of dsx could be a useful method in genetic control of insects. However, information on the sex-specific function of dsx in non-model insects is lacking. RESULTS: In this work, we isolated a dsx homolog, which is alternatively spliced into six female-specific and one male specific isoforms, from an important agricultural pest, the black cutworm, Agrotis ipsilon. Studies on the expression of sex-specific Aidsx mRNA during embryonic development showed that the 6th hour post oviposition is the key stage for sex determination in A. ipsilon. Functional analysis of Aidsx was conducted using CRISPR/Cas9 system targeting female-specific and male-specific Aidsx exons. Disruptions of sex-specific exons of Aidsx resulted in corresponding sex specific, sexually dimorphic defects in external genitals, gonads and antennae, and expression of sex-specific genes as well as production of offspring in both sexes. CONCLUSION: Our results not only demonstrate that dsx is a key player determining A. ipsilon sexually dimorphic traits, but also provide a potential method for genetic control of this pest. This article is protected by copyright. All rights reserved. PMID- 30520232 TI - Changes in the Distal Esophageal Microbiota in Chinese Patients with Reflux Esophagitis. AB - OBJECTIVE: Changes in microbiota structure in the distal esophagus may be associated with the pathogenesis of gastroesophageal reflux disease. The composition of the distal esophageal microbiota between Chinese patients and healthy volunteers was compared through metagenomic high-throughput DNA sequencing and bioinformatic analyses. METHODS: Healthy volunteers (HV) and patients with reflux esophagitis (RE) were enrolled. Distal esophageal (2 cm above the gastroesophageal junction) biopsy specimens were obtained under the endoscopy. Microbial DNA was extracted from the specimens, followed by 16S rDNA gene amplification and Illumina sequencing. Bioinformatic tools were applied to dissect the community structure and statistical methods were used to compare the differences. RESULTS: No dramatic differences in microbiota were found in RE patients compared to the healthy controls. At the phylum level, only Bacteroidetes differed between the groups, being less abundant in the RE group. The overall number and diversity of species tended to be lower in RE patients, but there were no significant differences between the groups. Three genera, Prevotella, Helicobacter, and Moraxella, were obviously depleted in RE patients as revealed by linear discriminant analysis (LDA) effect size (LEfSe) analyses. CONCLUSIONS: The structure of distal esophageal microbiota in Chinese RE patients showed moderate changes compared to healthy volunteers. To what extent these changes are associated with the pathogenesis of reflux esophagitis needs further investigation. PMID- 30520233 TI - Positive endoscopic and ultrasonographic findings in symptom-diagnosed functional gastrointestinal disorder patients: Data from a Chinese cross-sectional study. AB - OBJECTIVE: Few studies have systematically assessed symptom-based diagnosis of functional gastrointestinal disorders (FGIDs) in China. This study aimed to evaluate the positive endoscopic and ultrasonographic findings in symptom-based FGID patients. METHODS: Adult patients with gastrointestinal symptoms but not red flag symptoms who were empirically diagnosed with FGIDs underwent upper and/or lower gastrointestinal endoscopy based on their symptoms. Abdominal ultrasonography was also performed to screen for potential organic diseases. Demographic data were collected, and the Rome III questionnaire was used for symptom-based assessment. RESULTS: Positive endoscopic and ultrasonographic findings were detected in 31.8%, 26.2% and 9.9% of patients with esophageal, gastroduodenal and intestinal disorders, respectively. Among patients diagnosed with FGIDs by the questionnaire, the rates of positive endoscopic and ultrasonographic findings were higher in patients with upper gastrointestinal symptoms than in those with lower gastrointestinal symptoms. Moreover, patients with upper gastrointestinal symptoms older than 34.5 years and those with lower gastrointestinal symptoms older than 47.5 years were more likely to have positive findings. CONCLUSIONS: TheRome III questionnaire is a valuable diagnostic tool for the screening of FGIDs in China. However, the rates of positive endoscopic and ultrasonographic findings varied depending on the location of symptoms. Endoscopy and ultrasonography have irreplaceable value, especially for investigating upper gastrointestinal symptoms. PMID- 30520234 TI - The effectiveness of scoring systems in the prediction of diagnosis-based mortality. AB - Scoring systems are used for mortality and morbidity rating in intensive care conditions, prognosis prediction, standardization of scientific data and the monitoring of clinical quality. The aim of this study was to retrospectively analyze the efficacy of APACHE II (Acute Physiology and Chronic Health Evaluation), APACHE IV and SAPS (Simplified Acute Physiology Score) III prognostic scorings in the prediction of mortality and disease severity of patients admitted to the Anesthesia and Reanimation Clinic Intensive Care Unit (ICU) in Bakirkoy Dr. Sadi Konuk Training and Research Hospital according to general and specific diagnoses. A total of 1896 patient files were included in the study. With the exception of single system or head trauma patient groups, a statistically significant difference was found in the mortality prediction rates in all other diagnosis groups (p<0.05). The discrimination calculated with AUROC fields was sufficient in all groups, and calibration was evaluated as good except for the Neurological and Neurosurgical patient group. In respect of standard mortality prediction, APACHE II and IV were good in cases of sepsis, and SAPS III made almost exact predictions for cardiovascular diseases, APACHE II for neurological diseases, and APACHE IV for gastrointestinal system diseases. From the results of this study, it was seen that different scoring systems vary in predictions according to the diagnoses, therefore, it can be recommended that the diagnosis should be taken into account more when applying scoring systems. PMID- 30520235 TI - Oxidative Addition to Palladium(0) Made Easy through Photoexcited-State Metal Catalysis: Experiment and Computation. AB - Visible-light induced, palladium catalyzed alkylations of alpha,beta-unsaturated acids with unactivated alkyl bromides are described. A variety of primary, secondary, and tertiary alkyl bromides are activated by the photoexcited palladium metal catalyst to provide a series of olefins at room temperature under mild reaction conditions. Mechanistic investigations and density functional theory (DFT) studies suggest that a photoinduced inner-sphere mechanism is operative in which a barrierless, single electron oxidative addition of the alkyl halide to Pd(0) is key for the efficient transformation. PMID- 30520236 TI - Inflammation, edema, hematoma and etiology - a rectangular relationship? PMID- 30520237 TI - The role of skin biopsy in differentiating small-fiber neuropathy from ganglionopathy. PMID- 30520238 TI - Abstracts for ESCCA 2018 Conference: At the Shore of Future Cytometry September 13-15, 2018, Valencia, Spain. AB - We are pleased to present abstracts from ESCCA 2018: At the Shore of Future Cytometry. This year, the European Society for Clinical Cell Analysis (ESCCA) organised its annual Conference over 3 days in Valencia, Spain. Four workshops for a limited number of participants - dedicated to Cytometry Analysis Tools, Cytometry of Microparticles, Cytometry in Veterinary and Animal Sciences and CLL MRD - as well as ESCCA certification exams took place before the Conference. The Conference itself included four Education Programmes from which the participants had to choose in advance: (i) Good Cytometry Practices; (ii) Advanced Hemato Oncology; (iii) Clinical Diagnostic Cytometry and (v) Advanced Immunology. A group of experts in these fields coordinated, presented, and discussed these topics with the attendees. The Education Programme sessions were alternated with plenary keynote lectures and other sessions, such as an interactive voting session on interesting cases, a Round Table discussion and a session jointly organised with the Iberian Cytometry Society (SIC) on The future of flow cytometry in Europe. Finally, 125 accepted abstracts were scheduled as poster presentation. Three abstracts that have received the highest ranking from the abstract reviewer committee have been nominated for the ESCCA Best Oral Award, and were presented in one of the plenary sessions. In addition the next best 18 best abstracts were presented during 3 poster walks. The abstracts of the keynote lectures and the poster abstracts are published in this issue of Clinical Cytometry. The abstracts are available as Online Supporting Information. PMID- 30520239 TI - Transforming Growth Factor Beta-1 Promotes Smooth Muscle Cell Proliferation and Migration in an Arteriovenous Fistulae, the Role of Wall Shear Stress. AB - BACKGROUND: The wall shear stress (WSS) as a mechanical stimuli to venous wall has a significant role in neointimal hyperplasia of arteriovenous fistulae (AVF), which is often related to the proliferation and migration of vascular smooth muscle cells(VSMCs). Transforming growth factor beta-1 (TGF-beta1) has the function of promoting VSMCs proliferation and migration. Our study is to detect that the correlation between WSS, TGF-beta1, VSMCs proliferation and neointimal hyperplasia. METHODS: An 'end-to-side' AVF canine model was created. We choose four typical vein regions containing arteriovenous anastomosis segment (A-V), juxta-anastomotic segment (J-V), juxta-ligation segment (L-V), and proximal vein (P-V). The expression of TGF-beta1 and alpha-SMA of different positions was then measured and the transwell assay was used to measure the VSMC migration with different concentrations of rhTGF-beta1 or for different time points in vitro study. RESULTS: Neointimal hyperplasia and higher expression of TGF-beta1and alpha-SMA in the inner wall of sites J-V and L-V(low and disturbed WSS) was more obvious compared to the P-V, A-V sites and outer wall of L-V and J-V segment (high and laminar WSS) (p<0.01). Transwell assay reveals that the migration of VSMCs was up-regulated following the increase of rhTGF-beta1 or for a longer time. CONCLUSIONS: The WSS levels have a strong inverse correlation with neointimal hyperplasia. VSMCs do not only proliferate but also migrate from the media to the intima. rhTGF-beta1 can stimulate migration of VSMCs in a time dependent and dose-dependent fashion. The neointimal formation of AVF might be a local proliferative process through WSS-TGF-beta1 regulating. PMID- 30520241 TI - Water-Soluble Pillar[n]arene Mediated Supramolecular Self-Assembly: Multi Dimensional Morphology Controlled by Host Size. AB - We report tunable supramolecular self-assemblies formed by water-soluble pillar[n]arenes (WPns, n = 5-7) and bipyridinium-azobenzene guests. Nanoscale or microscale morphology of self-assemblies in water was controlled by host size of WPn. Supramolecular self-assemblies could undergo morphology conversion under UV irradiation. PMID- 30520240 TI - Targeted Feature Extraction in MALDI Mass Spectrometry Imaging to Discriminate Proteomic Profiles of Breast and Ovarian Cancer. AB - PURPOSE: To develop a mass spectrometry imaging (MSI) based workflow for extracting m/z values related to putative protein biomarkers and using these for reliable tumor classification. EXPERIMENTAL DESIGN: Given a list of putative breast and ovarian cancer biomarker proteins, we extracted a set of related m/z values from heterogeneous MSI datasets derived from formalin-fixed paraffin embedded tissue material. Based on these features, a linear discriminant analysis classification model was trained to discriminate the two tumor types. RESULTS: We show that the discriminative power of classification models based on the extracted features is increased compared to the automatic training approach, especially when classifiers are applied to spectral data acquired under different conditions (instrument, preparation, laboratory). CONCLUSIONS AND CLINICAL RELEVANCE: We obtained robust classification models not confounded by technical variation between MSI measurements. This supports the assumption that the classification of the respective tumor types is based on biological rather than technical differences, and that the selected features are related to the proteomic profiles of the tumor types under consideration. This article is protected by copyright. All rights reserved. PMID- 30520242 TI - Outcomes following neonatal portal vein thrombosis: A descriptive, single-center study and review of anticoagulant therapy. AB - BACKGROUND: Neonatal portal vein thrombosis (PVT) is uncommon with potentially serious complications that may manifest in infancy and childhood. OBJECTIVE: The primary aim of our study was to describe the short-term and long-term outcomes of neonatal PVT. METHODS: A retrospective chart review was conducted from 2008 to 2016 of neonates diagnosed with PVT. A systematic review was also performed from 2000 to 2018 to evaluate anticoagulant therapy (ACT) in neonatal PVT. RESULTS: Forty-four premature and 30 term infants (mean gestational age 30.7 vs 39.1 weeks, respectively) had PVT. Sixty-eight involved the left portal vein, one involved only the main portal vein, and 5 involved >=1 vein. PVT was catheter associated in 46 (62%); none of the 7 neonates tested had thrombophilia. Of 74 neonates, 19 (26%) received ACT and 55 (74%) were untreated. The mean follow-up duration was 16.6 months (SD = 17.62; range, 0-89.6); 59.5% were followed for >=6 months. On last ultrasound examination, thrombus resolution was documented in treated (ACT; n = 19) and nontreated (n = 55) neonates: 12 (63%) versus 32 (58%) with complete resolution, 1 (5%) versus 6 (11%) partial, 0 versus 1 (2%) extension, and 6 (32%) versus 16 (29%) had nonprogressive lesions, respectively. Seventy-one (96%) had no complications. Seventy-one articles met inclusion criteria for the systematic review and 19 were retained for analysis after assessment. CONCLUSIONS: PVT resolution rate was similar to previous reports. Although a low complication rate was detected, longer follow-up is necessary to determine the need for early treatment and the precise incidence of outcomes such as portal hypertension. PMID- 30520243 TI - Impact of Baseline BMI on Glycemic Control and Weight Change with Exenatide Monotherapy in Chinese Drug-naive Type 2 Diabetic Patients. AB - BACKGROUND: The weight reduction effect of exenatide has been well proved, which may concern physicians about too much weight loss in patients with normal weight. This study evaluated the effects of exenatide monotherapy on glycemic control and weight change among normal-weight, overweight, and obese patients with newly diagnosed type 2 diabetes (T2D). METHODS: In this multicenter, prospective study, 29 normal-weight, 54 overweight, and 27 obese newly diagnosed and drug-naive patients with T2D were treated with exenatide for 48 weeks. The primary efficacy endpoint was the effect of baseline body mass index (BMI) on glycemic control, measured as the change from baseline in glycosylated hemoglobin A1c (HbA1c) at week 48 compared among different BMI groups. Other endpoints included comparisons of exenatide's effects on fasting plasma glucose, postprandial plasma glucose, body weight, and other metabolic indices. RESULTS: After 48-week treatment, the estimated mean HbA1c changes were -1.9%, -1.8% and -1.5% in normal-weight, overweight and obese patients (P=0.290 among groups after adjusted for baseline values). Fasting, 0.5h and 2h postprandial plasma glucose decreased similarly among groups. The weight reductions (decreased by 2.2 kg, 3.9 kg and 4.0 kg, respectively, P=0.104) as well as the waist circumference changes (decreased by 2.2cm, 3.2cm, and 5.6cm, respectively, P=0.078) presented non-significantly increasing trends from normal-weight, overweight to obese patients. CONCLUSIONS: Baseline BMI had no impact on glycemic control, weight change, or other metabolic indices with exenatide monotherapy. Normal-weight patients with T2D would benefit from exenatide as much as the overweight or obese patients on glucose control, without increased risk of excess weight loss. This article is protected by copyright. All rights reserved. PMID- 30520244 TI - Assessing the population relevance of endocrine disrupting effects for non-target vertebrates exposed to plant protection products. AB - The European Commission intends to protect vertebrate wildlife populations by regulating Plant Protection Product (PPP) active substances that have endocrine disrupting properties with a hazard-based approach. In this paper we consider how the Commission's hazard-based Regulation and accompanying Guidance can be operationalised to ensure that a technically robust process is used to distinguish between substances with adverse population level effects and those for which it can be demonstrated that adverse effects observed (typically in the laboratory) do not translate into adverse effects at the population level. Our approach is to use population models within the adverse outcome pathway framework to link the non-linear relationship between adverse effects at the individual and population levels in the following way: (1) Use Specific Protection Goals for focal wildlife populations within an ecosystem services framework; (2) Model the effects of changes in population-related inputs on focal species populations using individual-based population models to determine thresholds between negligible and non-negligible (i.e. adverse) population level effects; (3) Compare these thresholds with the relevant endpoints from laboratory toxicity tests to determine whether they are likely to be exceeded at hazard-based limits or the Maximum Tolerated Dose/Concentration from the experimental studies. If the population threshold is not exceeded then the substance should not be classified as an endocrine disruptor with population-relevant adversity unless there are other lines of evidence within a weight of evidence approach to challenge this. We believe this approach is scientifically robust whilst still addressing the political and legal requirement for a hazard-based assessment. This article is protected by copyright. All rights reserved. PMID- 30520245 TI - PCSK9 inhibitors and diabetes: translational biology to clinical practice. AB - Improving patient care incorporates well done translational science with excellent clinical trials. The development of new medications beyond statins to reduce low-density lipoprotein (LDL) in patients who are at high risk for cardiovascular (CV) events has ushered in new concerns by physicians from recent clinical trials. This article is protected by copyright. All rights reserved. PMID- 30520246 TI - P(III)-Chelation-Assisted Indole C7-Arylation, Olefination, Methylation, and Acylation with Carboxylic Acids/Anhydrides via Rhodium Catalysis. AB - Rhodium-catalyzed C7-selective decarbonylative arylation, olefination and methylation of indoles with carboxylic acids or anhydrides via C-H and C-C bond activation have been developed. Furthermore, C7-acylation products can also be generated selectively at a lower reaction temperature in our system. The key to the high reactivity and regioselectivity of this transformation is the appropriate choice of an indole N-PtBu2 chelation-assisted group. This method has many advantages, including easy access and removal of the directing group, the use of cheap and widely available coupling agents, no requirement of an external ligand or oxidant, a broader substrate scope, high efficiency and the sole regioisomer. PMID- 30520247 TI - Combined effect of GABA and GLP-1 receptor agonist on cytokine-induced apoptosis in pancreatic beta-cell lines and isolated human islets. AB - BACKGROUND: Gamma-aminobutyric acid (GABA) or glucagon-like peptide-1 (GLP-1) treatment can preserve pancreatic beta-cell mass and prevent diabetes. Recently, we reported that the combination of GABA and sitagliptin (a dipeptidyl peptidase 4 inhibitor that increases endogenous GLP-1) was more effective than either agent alone in reducing drug-induced beta-cell damage and promoting beta-cell regeneration in mice. However, in human islets, it remains unclear whether GABA and GLP-1 exert similar effects. METHODS: To investigate GABA and GLP-1 interactions, human islets or INS-1 cells were treated with GABA and/or exendin 4, a GLP-1 receptor (GLP-1R) agonist in clinical use, and incubated with a cytokine mixture. Cleaved caspase-3 and Annexin V binding were measured by western blot and flow cytometry analysis respectively, to address the effect on cytokine-induced apoptosis. RESULTS: Cytokine-induced apoptosis was reduced by either GABA or exendin-4 alone. This was markedly improved by combining GABA and exendin-4, resulting in a reversal of apoptosis. Akt pathway signaling was notably increased by the combination. Furthermore, sirtuin-1 (SIRT1) and alpha Klotho, both reported to have protective effects on beta-cells, were increased. Importantly, the combination ameliorated insulin secretion by human beta-cells. CONCLUSIONS: GABA and a GLP-1R agonist exert additive effects on beta-cell survival and function, suggesting that this combination may be superior to either drug alone in the treatment of diabetes. This article is protected by copyright. All rights reserved. PMID- 30520248 TI - Adherence, Persistence, Glycemic Control and Costs Among Patients with Type 2 Diabetes Initiating Dulaglutide Compared with Liraglutide or Exenatide QW at 12 Months Follow-Up in a US Real-World Setting. AB - AIMS: This study evaluated adherence, persistence, glycemic control, and costs at 12 months follow-up for patients initiating dulaglutide vs liraglutide or exenatide QW. MATERIALS AND METHODS: This retrospective observational claims study included patients with type 2 diabetes (T2D) and >=1 pharmacy claims for dulaglutide, liraglutide, or exenatide QW from HIRD(r). Adherence was defined as proportion of days covered (PDC) >=80%; persistence by time to discontinuation of index therapy. HbA1c change from baseline was assessed in a subset with pre- and post-index HbA1c results. Propensity scores were used to match the cohorts. RESULTS: The baseline characteristics were balanced for the matched cohorts, dulaglutide vs liraglutide (n=2,471) and dulaglutide vs exenatide QW (n=1,891). Patients initiating dulaglutide had significantly higher proportion of adherent patients compared with liraglutide (51.2% vs 38.2%, p<0.001) and exenatide QW (50.7% vs 31.9%, p<0.001). At 12 months, 55% dulaglutide vs 43.8% liraglutide (p<.001); 54.9% dulaglutide vs 34.4% exenatide QW (p<.001) were persistent. Dulaglutide patients had significantly greater reduction in HbA1c than liraglutide (-0.98% vs -0.77%, p=0.032), and greater but nonsignificant reduction in HbA1c than exenatide QW (-1.00% vs -0.77%, p=0.056). The diabetes-related total costs were not significantly different between dulaglutide vs liraglutide ($16,174 vs $16,694; p=0.184), and were significantly higher for dulaglutide vs exenatide QW ($15,768 vs $14,615; p=0.005). CONCLUSIONS: Adherence and persistence are important considerations in patient-centric treatment selection for patients with T2D. Higher adherence and persistence for dulaglutide compared to liraglutide or exenatide QW are relevant criteria when choosing GLP-1 RA treatment for patients with T2D. This article is protected by copyright. All rights reserved. PMID- 30520249 TI - The role of metabolic syndrome and its components as mediators of the genetic effect on type 2 diabetes: a family-based study in China. AB - BACKGROUND: Metabolic syndrome (MetS) and its components share genetic basis with type 2 diabetes (T2D). However, whether MetS and its components play a role in mediating the T2D genetic susceptibility is not completely understood. METHODS: We assessed the mediation effects of MetS and its components on the genetic susceptibility for 18 GWAS-identified T2D-associated variants using a two-stage strategy based on parametric models involving 7110 Chinese participants (of which, 2,436 T2D patients) across 2,885 families. For all the analyses, both an unweighted genetic risk score and individual variant were fitted. Multilevel logistic regression was used to account for the intra-familial correlation. RESULTS: We found that MetS significantly mediated the effect of MTNR1B polymorphism on T2D risk (OR of average causal mediation effect [ORACME ]: 1.004; 95% CI: 1.001-1.008; p-value: 0.018). In addition, low level of high-density lipoprotein cholesterol (HDL-c) mediated the genetic effects of MTNR1B (1.012; 1.007-1.015; <0.001), SLC30A8 (1.001; 1.000-1.007; 0.040), BCL11A (1.009; 1.007 1.016; <0.001), PROX1 (1.005; 1.003-1.011; <0.001) and ADAMTS9 (1.006; 1.001 1.009; 0.022), whereas increased fasting blood glucose (FBG) significantly mediated the genetic effect of BCL11A (1.017; 1.003-1.021, 0.012). CONCLUSIONS: Our findings provide evidence on that MetS and its two components (HDL-c, and FBG), might be involved in mediating the genetic predisposition to T2D. Our results emphasize the importance of maintaining normal HDL-c and FBG levels in the prevention of T2D. This article is protected by copyright. All rights reserved. PMID- 30520250 TI - Phytol ameliorated benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice via inhibition of oxidative stress and apoptosis. AB - In the present study, the modulatory effect of phytol against benzo(a)pyrene [B(a)P] induced lung carcinogenesis was investigated in Swiss albino mice. During the experimental period, phytol treatment showed no adverse toxic effect and mortality to the experimental animals. Lung tumor was observed in B(a)P treated group and also in animals post-treated with low concentration (50 mg/kg) of phytol. No neoplastic changes were observed in the lung tissue of the animals treated with the maximum dose of phytol (100 mg/kg). An elevated level of antioxidant enzymes combined with macromolecular damage (lipid peroxidation, protein carbonyl content) was observed upon B(a)P treatment whereas, phytol restored the level of antioxidant enzymes which were comparable to the vehicle control group. Moreover, administration of B(a)P induced apoptosis, as observed by the highest expression of Bax, caspase-3, and caspase-9 proteins in lung tissue of B(a)P alone treated animals. However, phytol treatment reduced the expression of Bax, caspase-3, and caspase-9 protein and maintained the constant expression of anti-apoptotic protein Bcl-2. These observations positively reveal that phytol regulates the antioxidant enzymes and thereby protects the cells against B(a)P induced carcinogenesis without showing any adverse toxic effect to the animals. PMID- 30520251 TI - The role of BRCA1-associated protein 1 in the diagnosis of malignant mesothelioma in effusion and fine-needle aspiration cytology. AB - BACKGROUND: Malignant mesothelioma (MM) is a diagnostically challenging entity in cytology specimens due to the lack of architectural context and a cytomorphologic overlap between malignant and reactive mesothelial cells (RMCs). A diagnostic marker with excellent specificity is not currently available in clinical practice. The newly appreciated BRCA1-associated protein 1 (BAP1) antibody may help distinguish MM from RMC based on its immunohistochemical (IHC) staining pattern but its role in cytopathology is controversial. METHODS: Immunohistochemistry with BAP1 antibody was performed on cell blocks from 39 cytology specimens including 13 cases of RMC and 26 cases of effusion and fine needle aspiration specimens (FNAC) with tissue-specimen-proven MM. Cases were dichotomised into positive and negative cohorts. Positivity was defined as >50% loss of nuclear BAP1 IHC staining. RESULTS: Of the 26 MM cases, a slight majority (14/26, 54%) showed loss of BAP1 nuclear IHC staining, while all 13 RMC controls showed strong nuclear BAP1 IHC staining. MM was more likely to show loss of BAP1 than RMC (P < .001); and peritoneal MM was more likely to demonstrate loss of BAP1 than pleural MM (P = .04). There was perfect specificity at 1.0 and positive predictive value of 1.0 for loss of nuclear BAP1 IHC staining. However, only modest sensitivity at 0.52 and negative predictive value of 0.50 was seen. CONCLUSION: These data confirm that absence of BAP1 nuclear staining identifies malignant mesothelial cells. On the other hand, positive BAP1 nuclear staining can occur in both benign and malignant pleural effusions. PMID- 30520252 TI - Predictive factors associated with 3 years of response to HbA1c goal with exenatide QW or insulin glargine: Post hoc analysis of DURATION-3. AB - This DURATION-3 study post hoc analysis aimed to identify factors associated with sustained glycaemic response with exenatide once weekly (QW) or insulin glargine (IG) among patients with type 2 diabetes. Response was defined as achieving treatment target of HbA1c <7.0% (<53 mmol/mol) at week 26; sustained responders maintained treatment target for >=80% of remaining visits, including 1 during the final 6 months. Of 467 patients, 287 (61.5%) completed 156 weeks of treatment. At week 26, 175 patients (61.0%; exenatide QW, n=95; IG, n=80) achieved an HbA1c response. At week 156, 84 of 175 responders (48.0%) had sustained response, with more sustained responders with exenatide QW (22.7% vs 13.9% with IG; P<.03). Logistic regression identified 3 predictors of sustained response: exenatide QW versus IG treatment (odds ratio, 2.584 [95% confidence interval, 1.288-5.187]; P=.0075), lower HbA1c at week 26 (0.139 [0.053-0.366]; P<.0001) and lower fasting serum glucose at week 26 (0.693 [0.541-0.888]; P=.0037). A regression model estimated likelihood of sustained response with either treatment. This analysis provides a helpful tool for predicting sustained response with exenatide QW or IG. This article is protected by copyright. All rights reserved. PMID- 30520253 TI - 2018 Reviewer List. PMID- 30520254 TI - Continuing Professional Development. PMID- 30520255 TI - Effect of simulation education and case management on glycemic control in type 2 diabetes patients. AB - BACKGROUND: The aim of the study was to investigate whether simulation education (SE) and case management had any effect on glycemic control in type 2 diabetes (T2DM) patients. METHODS: In this single center pilot trial, 100 T2DM patients who received medication and basic diabetes self-management education (DSME) were randomly divided into a control group (n=50) and an experimental group (n=50), who received SE and a case management program. Evaluation of biochemical indices was conducted at baseline and after 6 months. DSME consisted of 2-hour group trainings weekly for 2 consecutive weeks followed by 2 * 30 minute education sessions after 3 and 6 months. The SE program comprised additional 50-minute video sessions 3 times in the first week and twice in the second week. The experimental group was supervised by a nurse case manager, who followed up participants at least once a month, and who conducted group sessions once every 3 months, focusing on realistic aspects of physical activity and nutrition, with open discussions about setting goals and strategies to overcome barriers. RESULTS: After 6 months, HbA1c, fasting plasma glucose and postprandial blood glucose level improvements were superior in the experimental group compared to the control group (P<0.05). Self-care behavior adherence scores of healthy diet (P= 0.001), physical activity (P=0.043), self-monitoring of blood glucose (P<0.001) and reducing risks (P<0.001) were significantly increased in the experimental group compared to the control group. CONCLUSIONS: SE and case management added to routine DSME effectively improved glycemic control in T2DM patients. PMID- 30520256 TI - Co-occurrence of V1016I and F1534C mutations in the voltage-gated sodium channel and resistance to pyrethroids in Aedes aegypti (L.) from the Colombian Caribbean region. AB - BACKGROUND: Knockdown resistance is conferred primarily by non-synonymous mutations that reduce pyrethroids binding to voltage-gated sodium channels. In 2014, kdr mutation V1016I in Aedes aegypti populations resistant to pyrethroids was reported for the first time in Colombialpha, in 2016 another kdr mutation, F1534C and in 2018 the mutation V419L. Nine populations of A. aegypti, previously characterized as being resistant to lambda-cyhalothrin, deltamethrin, cyfluthrin, and permethrin, were used for this study. Genomic DNA was used to determine genotypes by allele-specific PCR for mutations V1016I and F1534C and to determine their association with pyrethroid resistance. RESULTS: All the populations analyzed showed both mutations, with allelic frequencies of 0.07-0.35 for I1016 and 0.47-0.88 for C1534. A percentage of co-occurrence of mutant homozygotes I1016/C1534 of 5.3% was detected. A significant positive correlation was found between the frequency of the genotype I1016 and the resistance to permethrin, lambda-cyhalothrin and cyfluthrin, but not to deltamethrin; on the other hand, the correlation was not significant for the C1534 genotype and the four pyrethroids evaluated. No significant correlation was found between the frequencies of the mutations V1016I and F1534C. CONCLUSIONS: Both mutations V1016I and F1534C are present in A. aegypti populations of the Colombian Caribbean, and although the frequency of F1534C exceeds V1016I, the latter was correlated to resistance to pyrethroid insecticides. This article is protected by copyright. All rights reserved. PMID- 30520257 TI - Metyltetraprole, a novel putative complex III inhibitor, targets known QoI resistant strains of Zymoseptoria tritici and Pyrenophora teres. AB - BACKGROUND: Metyltetraprole is a new fungicide with unique tetrazolinone-moiety and similar side chain to a known QoI, pyraclostrobin. In this study, we describe a unique bioactivity of metyltetraprole especially on QoI-resistant strains of Zymoseptoria tritici and Pyrenophora teres. RESULTS: Metyltetraprole exhibited potent antifungal activity against Ascomycetes; it was especially effective against Z. tritici and P. teres in seedling pot tests. Metyltetraprole was also effective in field tests with QoI-resistant mutants. Antifungal activity tests using field strains of Z. tritici and P. teres showed that the performance of metyltetraprole was unaltered by QoI, SDHI, and DMI resistance. However, the mitochondrial activity test indicated that the compound inhibits the respiratory chain via complex III. CONCLUSION: Metyltetraprole is a novel fungicide that is highly effective against a wide range of fungal diseases including important cereal diseases. Although metyltetraprole most likely inhibits the respiratory chain via complex III, it remains effective against QoI resistant strains. Therefore, metyltetraprole is considered as a novel fungicidal agent for controlling diseases affecting cereal crops and overcoming pathogen resistance to existing fungicides. This article is protected by copyright. All rights reserved. PMID- 30520258 TI - Puffing up Energetic Metal-organic Frameworks to Large Carbon Networks with Hierarchical Porosity and Atomically Dispersed Metal Sites. AB - Large carbon networks featuring hierarchical pores and atomically dispersed metal sites (ADMSs) are ideal materials for energy storage and conversion due to the spatial-continuous conductive networks and highly active ADMSs. However, it is a challenge to synthesize such ADMS-decorated carbon networks. Here, we innovatively present a fusion-foaming methodology to puff up energetic metal organic framework (EMOF) nanoparticles to submillimetric ADMS-decorated carbon networks via one-step pyrolysis. Their extraordinary catalytic performance towards oxygen reduction reaction verifies the practicability of this synthetic approach. Moreover, this approach can be readily applicable to a wide range of unexplored EMOFs, expanding scopes for future materials design. PMID- 30520259 TI - Response to "Preserved" glucagon secretion in fulminant type 1 diabetes. AB - We compared the glucagon responses to arginine stimulation in five patients with fulminant type 1 diabetes and five age- and diabetes duration-matched acute-onset type 1 diabetes, and the curves of the glucagon responses were similar. In our study, we measured the glucagon levels by not only radioimmunoassay, but also novel enzyme-linked immunosorbent assay. PMID- 30520260 TI - Operando CatalysisReveals the Superior Cracking Activity and Stability of Hierarchical ZSM-5 for the Cracking of LDPE. AB - In this communication, a new theoretical and practical framework through Operando Catalysis to study the zeolite catalytic cracking of the low-density polyethylene as model reaction, under reaction conditions is provided. Results show that a microporous ZSM-5 gives rise to less cracking products. Hierarchical ZSM-5 zeolites are more cracking active, rendering more C2-C5 hydrocarbons, with a delayed deactivation due to the secondary porosity. This tool in combination with thermogravimetric analysis provides complementary and valuable information for the study, and design of advanced catalysts. PMID- 30520261 TI - Highly Efficient Hydrogen Production via a Reformed Electrolysis System Driven by One Single Perovskite Solar Cell. AB - Highly efficient hydrogen production by photovoltaic-driven electrolysis system requires low overpotential of electrolyzer and high couple efficiency of both components. Herein, we firstly propose Ni5P4 as cost-effective bifunctional electrocatalyst for hydrogen evolution and hydrazine oxidation in a reformed electrolyzer and experimentally validated that the electrolytic overpotential can be significantly reduced via replacing oxygen evolution reaction with hydrazine oxidation reaction at the anode. Furthermore, we conceive a novel scenario for hydrogen production by utilization of a low-cost and stable perovskite solar cell featuring with carbon back electrode to drive a reformed electrolyzer. More importantly, one single perovskite solar cell can drive three reformed electrolyzers in series for hydrogen production by careful matching the operating point of electrolyzer with the maximum power point of photovoltaic device, yielding an H2 evolution rate of 1.77 mg h-1 for the whole PV-EC system. This would be a new starting point for hydrogen production via single perovskite solar cell-driven electrolysis system. PMID- 30520262 TI - Proteomics Analysis of Thermoplasma Quinone Droplets. AB - A novel type of lipid droplet/lipoprotein (LD/LP) particle from Thermoplasma acidophilum has been identified recently, and based on biochemical evidences it was named Thermoplasma Quinone Droplet (TaQD). The major components of TaQDs are menaquinones, and to some extent polar lipids, and the 153 amino acid long Ta0547 vitellogenin-N domain protein. In this paper we aimed to identify TaQD proteome components with 1D-SDS-PAGE/Lc-MS/MS and cross reference them with Edman degradation. TaQD samples isolated with three different purification methods - column chromatography, immunoprecipitation, and LD ultracentrifugation - were analyzed. Proteins Ta0093, Ta0182, Ta0337, Ta0437, Ta0438, Ta0547 and Ta1223a were identified as constituents of the TaQD proteome. The majority of these proteins are uncharacterized and have low molecular weight, and none of them is predicted to take part in lipid metabolism. Bioinformatics analyses did not predict any interaction between these proteins, however, there were indications of interactions with proteins taking part in lipid metabolism. Whether if TaQDs provide platform for lipid metabolism and the interactions between TaQD proteins and lipid metabolism proteins occur in the reality remains for further studies. This article is protected by copyright. All rights reserved. PMID- 30520263 TI - Differences in blood pressure among ethnicities presenting for catecholamine secreting tumor evaluation. PMID- 30520264 TI - Functional study of Carboxylesterase 1 protein isoforms. AB - Carboxylesterase1 (CES1) is a primary human hepatic hydrolase involved in hydrolytic biotransformation of numerous medications. Considerable interindividual variability in CES1 expression and activity has been consistently reported. Four isoforms of the CES1 protein are produced by alternative splicing (AS). In the current study, we examined the activity and expression of each CES1 isoform using transfected cell lines and determined CES1 isoform composition and its impact on CES1 activity in human livers. In transfected cells, isoforms 3 and 4 showed mRNA and protein expressions comparable to isoforms 1 and 2, but had significantly impaired activity when hydrolyzing enalapril and clopidogrel. In individual human liver samples, isoforms 1 and 2 were the major forms, contributing 73%-90% of total CES1 protein expression. In addition, the protein expression ratios of isoforms 1 and 2 to isoforms 3 and 4 were positively associated with CES1 activity in the livers, suggesting that CES1 isoform composition is a factor contributing to the variability in hepatic CES1 function. Further investigations of the regulation of CES1 AS would improve our understanding of CES1 variability and help develop a strategy to optimize the pharmacotherapy of many CES1 substrate medications. This article is protected by copyright. All rights reserved. PMID- 30520265 TI - Identifying Lysophosphatidic Acid Acyltransferase beta (LPAAT-beta) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2. AB - By screening a focused library of kinase inhibitor analogues in a phenotypic co culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole-kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (http://ppb2.gdb.tools), which suggested lysophosphatidic acid acyltransferase beta (LPAAT-beta) as a possible target for this aminotriazine as well as several analogues identified by structure-activity relationship profiling. LPAAT-beta inhibition (IC50 ~15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT-beta inhibitor. These experiments illustrate the value of target-prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT-beta inhibitors. PMID- 30520267 TI - Implementation of clinical proteomics: A step closer to personalised medicine? AB - The success of clinical proteomics, per definition, is ultimately defined by the clinical implementation of proteomics findings. Extensive research activity in the field, targeting especially biomarker discovery, has been conducted the past decades, with several studies suggesting a benefit from proteome based application in patient management. This viewpoint article discusses the current status in clinical proteomics with respect to implementation, (as evidenced by use of protein findings in drug labeling and patient stratification), and proposes specific action points for accelerating the biomarker validation process, placing special emphasis on the importance of data and resource sharing. This article is protected by copyright. All rights reserved. PMID- 30520266 TI - Proteomic Landscape of Cholangiocarcinomas Reveals 3 Different Subgroups According to their Localization and the Aspect of Non-Tumor Liver. AB - PURPOSE: Cholangiocarcinomas (CC), tumors derived from epithelial biliary cells, define a heterogeneous entity based upon their anatomic localization (intra- versus extrahepatic) and, for those developing in the liver, depending on the aspect of non-tumor liver (normal versus cirrhosis). The aim of the study was to characterize the molecular heterogeneity of the different types of CC by a global proteomic approach. EXPERIMENTAL DESIGN: Thirty-three tumor samples from 17 intrahepatic CC (iCC) including 9 and 8 developed on normal (iCCN ) and cirrhotic liver (iCCC ), respectively; 5 hilar CC (CCH ), 5 CC developed in the pancreatic portion of the bile duct (CCP ) and 6 hepatocellular carcinoma (HCC), were submitted to label-free quantitative proteomic analysis. Differentially expressed proteins were further analyzed by immunohistochemistry in a validation set of 30 CC. RESULTS: In the overall series, 4590 proteins were quantified. Unsupervised analysis revealed two main clusters: cluster 1 contained most the iCCC while cluster 2 was divided in 2 subgroups, one containing most of the iCCN and the other regrouping CCH and CCP . Compared to iCCN , iCCC displayed upregulation of molecules involved in cell adhesion and motility and in angiogenesis. Epithelial markers associated with secretory pathway (mucins and AGR2) as well as fibroblast markers (S100A4) were overexpressed in CCH compared to iCCN . CONCLUSION AND CLINICAL RELEVANCE: This study demonstrated that among iCC, iCCC is a specific entity, suggesting a major impact of the underlying liver condition on the tumor biology, and confirmed that extrahepatic CCs, including CCP and CCH, define an homogeneous subgroup. This article is protected by copyright. All rights reserved. PMID- 30520269 TI - Letter to the Editor concerning "Serological and clinical evaluation of the Yugoslavian RM65 sheep pox strain vaccine use in cattle against lumpy skin disease" by Abutarbush and Tuppurainen (Transbound Emerg Dis; 2018: DOI: 10.1111/tbed.12923). AB - The aim of the manuscript entitled "Serological and clinical evaluation of the Yugoslavian RM65 sheep pox strain vaccine use in cattle against lumpy skin disease" was to compare the humoral response of three different dosages of the RM65 sheep pox (SPP) vaccine to assess the use of ten times sheep dose of the RM65 vaccine against lumpy skin disease, and to explore the possible causes of, and characterize This article is protected by copyright. All rights reserved. PMID- 30520268 TI - Cardiotoxicity and myocardial infarction-associated DNA damage induced by thiamethoxam in vitro and in vivo: Protective role of Trigonella foenum-graecum seed-derived polysaccharide. AB - The risk of pesticides on the human health and environment has drawn increasing attention. Today, new tools are developed to reduce pesticide adverse effects. This study aimed to evaluate the toxicity induced by, thiamethoxam (TMX), and the cytoprotective effect of a novel polysaccharide, named fenugreek seed water polysaccharide (FWEP) in vitro using H9c2 cardiomyoblastes and in vivo using Wistar rat model. Animals were assigned into four groups per eight rats each: group 1 served as a control group, group 2 received TMX, group 3, and group 4 received both FWEP and TMX tested at two doses (100 and 200 mg/kg, respectively). Regarding the in vitro study, our results demonstrated that TMX induced a decrease in H9c2 cell viability up to 70% with the highest concentration. In vivo, TMX injection induced marked heart damage noted by a significant increase in plasma lactate dehydrogenase, creatine phosphokinase, troponin-T, aspartate amino transferase activities, cholesterol, and triglyceride levels. Concomitant alterations in cardiac antioxidant defense system revealed depletion in the levels of glutathione and non-protein thiol and an increase in the activity of superoxide dismutase, catalase, and glutathione peroxidase. Similarly, a significant increase in heart lipid, malondialdehyde, advanced oxidation protein product and in protein carbonyls levels was also noted. In addition, heart tissues histo-architecture displayed major presence of apoptosis and necrosis as confirmed by DNA degradation. However, supplementation with FWEP alleviated heart oxidative damage and genotoxicity. In this manner, ABTS radical-scavenging activity, linoleic acid oxidation tests and heart genomic and DNA nicking assay had proved FWEP strong antioxidant potential. In conclusion, FWEP provided significant protection against TMX-induced heart injury, and could be a useful and efficient agent against cardiotoxicity and atherosclerosis. PMID- 30520270 TI - Individual optimal attentional strategy during implicit motor learning boosts frontoparietal neural processing efficiency: A functional near-infrared spectroscopy study. AB - INTRODUCTION: Optimal focus of attention is a crucial factor for improving motor learning. Most previous studies have shown that directing attention to movement outcome (external focus; EF) is more effective than directing attention to body movement itself (internal focus; IF). However, our recent studies demonstrated that the optimal attentional strategy in healthy and clinical populations varies depending on individual motor imagery ability. To explore the neurological basis underlying individual optimal attentional strategy during motor learning tasks, in the present study, we measured frontoparietal activities using functional near infrared spectroscopy (fNIRS). METHODS: Twenty-eight participants performed a visuomotor learning task requiring circular tracking. During the task, the participants were required to direct their attention internally or externally. The individual optimal attentional strategy was determined by comparing the after effect sizes between the IF and EF conditions. RESULTS: Fifteen participants showed larger after-effects under the EF condition (External-dominant), whereas the others showed larger after-effects under the IF condition (Internal dominant). Based on the differences in neural activities between Internal- and External-dominant groups, we identified the right dorsolateral prefrontal cortex (Brodmann area 46) and right somatosensory association cortex (Brodmann area 7) as the neural bases associated with individual optimal attentional strategy during motor learning. Furthermore, we observed a significant negative correlation, that is, lower activity in these areas was associated with a larger after-effect size under the optimal attentional strategy. CONCLUSION: Our findings demonstrated that more efficient neural processing in the frontoparietal area under the individual optimal attentional strategy can accelerate motor learning. PMID- 30520271 TI - Neural correlates of the effect of implementation intention on prospective memory. AB - Prospective memory (PM) refers to the ability to remember to do something in the future. Implementation intention refers to a self-regulatory strategy in the form of "If ..., then ..." planning that can improve PM performance. However, the neural basis of the effect of implementation intention on PM remains unclear, as do the phases of PM that are affected by implementation intention. This study aimed to address these issues. Healthy participants were randomly assigned to the implementation intention (n = 18) and typical instruction (n = 20) conditions. All of them underwent functional magnetic resonance imaging (fMRI) scanning when performing a PM task, which differentiated encoding, maintenance, and execution phases. Results demonstrated that participants in the implementation intention group showed different brain activations compared to participants in the typical instruction group. During the encoding phase, the implementation intention group showed increased activations in the inferior frontal gyrus (BA 10) and supramarginal gyrus (BA 40) compared to the typical instruction group; during the maintenance phase, the typical instruction group showed stronger activations in the inferior frontal gyrus (BA 46) than the implementation intention group; during the execution phase, the typical instruction group showed increased activations in the precentral gyrus (BA 6) and middle frontal gyrus (BA 8) than the implementation intention group. These results demonstrated the neural correlates of implementation intention on PM in different phases, and support the conclusion of our previous review based on fMRI evidence that implementation intention's improvement of PM performance is not fully automatic. PMID- 30520272 TI - Manipulating nutritional conditions and salinity-gradient stress for enhanced lutein production in marine microalga Chlamydomonas sp. AB - Marine microalgae has great potential for lutein production with the advantage of saving fresh water resource. Thus, marine microalga Chlamydomonas sp. JSC4 was investigated as a potential lutein producer in this study. The medium types, nitrate-N and sea salt concentration were individually investigated to promote the cell growth rate and lutein production of JSC4. In Modified Bold Basal 3N medium, cell growth and lutein content were optimal at the nitrate-N concentration of 1000 mg/L and sea salt concentration of 2%. In addition, an innovative salinity-gradient strategy was operated to dramatically enhance biomass productivity (560 mg/L/d) and lutein content (3.42 mg/g), resulting in the optimal lutein productivity (1.92 mg/L/d). Overall, this study clearly demonstrates that salinity is a significant inducer of lutein accumulation by strain JSC4 and that lutein production can be successfully optimized using the salinity-gradient strategy, which is beneficial for the outdoor large-scale lutein production in the future. PMID- 30520273 TI - Assessing CYP2C19 Ontogeny in Neonates and Infants Using Physiologically Based Pharmacokinetic Models: Impact of Enzyme Maturation Versus Inhibition. AB - The objective of this study was to develop pediatric physiologically based pharmacokinetic (PBPK) models for pantoprazole and esomeprazole. Pediatric PBPK models were developed by Simcyp version 15 by incorporating cytochrome P450 (CYP)2C19 maturation and auto-inhibition. The predicted-to-observed pantoprazole clearance (CL) ratio ranged from 0.96-1.35 in children 1-17 years of age and 0.43 0.70 in term infants. The predicted-to-observed esomeprazole CL ratio ranged from 1.08-1.50 for children 6-17 years of age, and 0.15-0.33 for infants. The prediction was markedly improved by assuming no auto-inhibition of esomeprazole in infants in the PBPK model. Our results suggested that the CYP2C19 auto inhibition model was appropriate for esomeprazole in adults and older children but could not be directly extended to infants. A better understanding of the complex interplay of enzyme maturation, inhibition, and compensatory mechanisms for CYP2C19 is necessary for PBPK modeling in infants. PMID- 30520274 TI - Portable, low-cost multispectral imaging system: design, development, validation, and utilization. AB - Optical spectral images can be used to estimate the amount of bulk absorbers in tissues, specifically oxy- and deoxyhemoglobin, as well as scattering parameters. Most systems that capture spectral image data are large, heavy, and expensive. This paper presents a full end-to-end analysis of a low-cost reflectance-mode multispectral imaging system operating in the visible and near-infrared spectra. The system consists of 13 LEDs mounted on a printed circuit board, a monochrome machine vision camera, and a tablet computer to control the hardware. The bill of materials for the system is less than $1000. Hardware design and implementation are detailed. Calibration, image capture, and preprocessing are also discussed. In validation experiments, excellent agreement is observed in diffuse reflectance measurements between the spectral camera setup and a spectrometer. To demonstrate that such spectral image data can yield meaningful optical measurements in vivo, the forearms of eight volunteers are imaged in the system. Their data are then analyzed to estimate the tissue optical properties of different skin layers using a Monte Carlo lookup table. In three volunteers, spectral images are captured before and after inducing erythema using a warm wet towel. Across the three subjects, a clear increase in the blood content of the superficial plexus layer was observed as a result of the erythema. Collectively, these findings suggest that a low-cost system can capture accurate spectral data and that clinically meaningful information can be derived from it. PMID- 30520277 TI - Extramammary Paget 's disease Of Glans Penis: A Rare Case Report AB - We present the case of an 83-year-old man with Extramammary Paget's disease (EMPD) of the penis. He underwent a total penectomy and histopathology confirms the association of underlying invasive high grade urothelial carcinoma. Penile EMPD is rare and can be misinterpreted for benign skin conditions. A high index of suspicion is required for correct diagnosis and appropriate treatment. PMID- 30520275 TI - In vivo characterization of connective tissue remodeling using infrared photoacoustic spectra. AB - Premature cervical remodeling is a critical precursor of spontaneous preterm birth, and the remodeling process is characterized by an increase in tissue hydration. Nevertheless, current clinical measurements of cervical remodeling are subjective and detect only late events, such as cervical effacement and dilation. Here, we present a photoacoustic endoscope that can quantify tissue hydration by measuring near-infrared cervical spectra. We quantify the water contents of tissue-mimicking hydrogel phantoms as an analog of cervical connective tissue. Applying this method to pregnant women in vivo, we observed an increase in the water content of the cervix throughout pregnancy. The application of this technique in maternal healthcare may advance our understanding of cervical remodeling and provide a sensitive method for predicting preterm birth. PMID- 30520278 TI - Scombrotoxic Fish Poisoning Secondary to Tuna Ingestion AB - Scombrotoxic poisoning results from the improper handling and refrigeration of fish containing naturally occurring histidine. Scombroid fish species such as tuna, mackerel and swordfish contain histidine, which is converted to histamine when inadequately chilled. European legislation states that scombroid fish species should be tested for the presence of histamine and mean values should be <100mg/kg1. The authors report an outbreak of scombrotoxic fish poisoning in 12 individuals following ingestion of tuna. Symptoms occurred rapidly and included flushing, headache, palpitations and diarrhoea. Fortunately, symptoms were short lived and self-limiting except in one individual, who required anti-histamine medication. Adequate refrigeration practices are crucial in preventing scombrotoxic food poisoning. PMID- 30520279 TI - A Combination of Surgery and Methotrexate for Successful Treatment of a Caesarean Scar Pregnancy. AB - Caesarean scar ectopic pregnancy (CSEP) is one of the rarest forms of ectopic pregnancies. With rising caesarean delivery (CD) rates worldwide, there is an increase in the incidence of CSEP. Patients usually present with painless vaginal bleeding and often misdiagnosed as spontaneous miscarriage. The use of ultrasonography with colour flow Doppler helps in the differential diagnosis. Different treatment options are described in the literature, although there is insufficient evidence regarding the best approach. We report the diagnosis and management of a case of CSEP in a woman with four previous CD who presented with vaginal bleeding and lower abdominal cramps at six weeks of gestation. She was treated with laparoscopic and ultrasound guided aspiration of the gestational sac and local injection of methotrexate supplemented by intramuscular methotrexate injection. PMID- 30520276 TI - Transvaginal fast-scanning optical-resolution photoacoustic endoscopy. AB - Photoacoustic endoscopy offers in vivo examination of the visceral tissue using endogenous contrast, but its typical B-scan rate is ~10 Hz, restricted by the speed of the scanning unit and the laser pulse repetition rate. Here, we present a transvaginal fast-scanning optical-resolution photoacoustic endoscope with a 250-Hz B-scan rate over a 3-mm scanning range. Using this modality, we not only illustrated the morphological differences of vasculatures among the human ectocervix, uterine body, and sublingual mucosa but also showed the longitudinal and cross-sectional differences of cervical vasculatures in pregnant women. This technology is promising for screening the visceral pathological changes associated with angiogenesis. PMID- 30520280 TI - Introduction of an Oral Fluid Challenge Protocol in the Management of Children with Acute Gastroenteritis: A Regional Hospital Experience. AB - Oral rehydration therapy (ORT) remains the ideal first line therapy for acute gastroenteritis (AGE). Our aim was to assess the impact of introducing an Oral Fluid Challenge (OFC) protocol on outcomes such as intravenous fluid use and documentation in our institution. A single centre study with data collected retrospectively pre-implementation (April 2015) of the OFC protocol and post implementation (April 2016). Consecutive sampling of the first 55 patients presenting with GE like symptoms and underwent OFC were recruited. One hundred and ten patients were included in this study with 55 patients per cycle. The rates of IVF use decreased from 22% (12) in cycle one to 18% (10) in cycle two. There was an improvement in documentation by 26% (14) for level of dehydration and 52% (31) for OFC volume from cycle one to two. Overall, the addition of the OFC protocol to the management of patients with uncomplicated AGE would help streamline and improve care. PMID- 30520281 TI - The Opportunities for Medical Education Internationalisation in the Republic of Ireland PMID- 30520282 TI - The Light at the End of the Tunnel: A Case of Dysautonomia Associated With Melkersson-Rosenthal Syndrome PMID- 30520283 TI - Peripheral White Blood Cell Differential Counts In Children With UTI, Is There A Link? PMID- 30520284 TI - Influenza Vaccine Attitudes in Amateur GAA Club Footballers. PMID- 30520285 TI - Wilm's tumor-1 (WT1) rs16754 polymorphism PMID- 30520286 TI - Medical Negligence Costs are Unsustainable PMID- 30520287 TI - Advances in Management of Neonatal Abstinence Syndrome: What's the score? PMID- 30520288 TI - Emergency Admissions of Children and Young People with Mental Health Needs to the Paediatric Ward PMID- 30520289 TI - An Assessment of the Paediatric Internship at University Hospital Limerick over a 30 Month Period PMID- 30520290 TI - Large-Scale Alignment of Polymer Semiconductor Nanowires for Efficient Charge Transport via Controlled Evaporation of Confined Fluids. AB - Long-range alignment of conjugated polymers is as critical as polymer chain packing for achieving efficient charge transport in polymer thin films used in electronic and optoelectronic devices. Here, the present study reports a facile, scalable strategy that enables the deposition of macroscopically aligned polymer semiconductor nanowire (NW)-array films with highly enhanced charge carrier mobility, using a modified controlled evaporative self-assembly (MCESA) technique. The organic field-effect transistors (OFETs) based on highly oriented poly(3-hexylthiophene) (P3HT)-NW films exhibit a more than 10-fold enhancement in the carrier mobility, with the highest mobility of 0.13 cm2 V-1 s-1, compared to the OFETs based on pristine P3HT films. Significantly, the large-area aligned P3HT NW-films, which are deposited over 12 arrays of transistors on a 4-in wafer by the MCESA coating, result in a lower device performance variation (i.e., standard deviation ~ +/-?0.0172 (16 %) cm2 V-1 s-1) as well as an excellent average device performance (i.e., average charge mobility ~ 0.11 cm2 V-1 s-1), compared to those obtained using the conventional CESA coating, overcoming a critical challenge in the field of OFETs. PMID- 30520291 TI - Nitrogen-doped carbon materials for the metal-free reduction of nitro compounds. AB - In this study, nitrogen-doped carbon materials (labeled as NC-T) were easily prepared by the thermal treatment of the melamine-chitosan composite. NC-T catalysts demonstrated a good activity towards the reduction of nitro compounds by the use of hydrazine hydrate (N2H4*H2O) as the reductant. The activity of NC-T enhanced with the rise of the pyrolysis temperature because of the enhanced ratio of graphitic-type nitrogen, which should be the active sites for reduction of nitro compounds. NC-950 showed high activity for the selective reduction of nitro compounds in hexane to produce amines in yields from 87.5 to 100% at 90 oC by the use of 2 equiv. N2H4*H2O. The NC-950 catalyst demonstrated comparable or even higher catalytic activity in comparison with the reported metal catalysts. The hydrogenation of nitro compounds with N2H4*H2O proceeded via the direct way involving hydroxylamine as the reaction intermediate. PMID- 30520292 TI - Direct Selection Strategy for Isolating Aptamers with pH-Sensitive Binding Activity. AB - An aptamer reagent that can switch its binding affinity in a pH-responsive manner would be highly valuable for many biomedical applications including imaging and drug delivery. Unfortunately, the discovery of such aptamers is difficult and only a few have been reported to date. Here we report the first experimental strategy for generating pH-responsive aptamers through direct selection. As an exemplar, we report streptavidin-binding aptamers that retain nanomolar affinity at pH 7.4 but exhibit a ~100-fold decrease in affinity at pH 5.2. These aptamers were generated by incorporating a known streptavidin-binding DNA motif into an aptamer library and performing FACS-based screening at multiple pH conditions. Upon structural analysis, we found that one aptamer's affinity-switching behavior is driven by a noncanonical G-A base-pair that controls its folding in a highly pH-dependent manner. We believe our strategy could be readily extended to other aptamer-target systems because it does not require a priori structural knowledge of the aptamer or the target. PMID- 30520293 TI - Logic Sensing of MicroRNA in Living Cells Using DNA-Programmed Nanoparticle Network with High Signal Gain. AB - Molecular circuits capable of implementing Boolean logic in cellular environments have emerged as an important tool for in situ sensing, elucidating, and modulating cell functions. The performance of existing molecular computation devices in living cells is limited because of the low level of biomolecular inputs and moderate signal gain. Herein, we devised a new class of DNA-programmed nanoparticle network with integrated molecular computation and signal amplification functions for logic operation of dual microRNA (miRNA) molecules in living cells. The nanoparticle network, which is composed of DNA-bridged gold nanoparticles and quantum dots (QDs), could simultaneously interface with two miRNA molecules, amplify the molecular inputs, perform a calculation through AND logic gate, and generate QD photoluminescence (PL) as an output signal. Significant improvement in imaging sensitivity is achieved by integrating the signal amplifier into the molecular computation device. It allows discrimination of specific cancer cell type via intelligent sensing of miRNA patterns in living cells. PMID- 30520294 TI - Graphene interdigital electrodes for improving sensitivity in Ga2O3:Zn deep ultraviolet photoconductive detector. AB - Graphene (Gr) has been widely used as a transparent electrode material for photodetectors due to its high conductivity and high transmittance, in recent years. However, the currently low-efficiency manipulation of Gr has hindered the arraying and practical use of such detectors. We invented a multi-step method of accurately tailoring graphene into interdigital electrodes, for fabricating a sensitive, stable deep-ultraviolet photodetector based on Zn-doped Ga2O3 films. The fabricated photodetector exhibits a series of excellent performance, including extremely low dark current (~10-11 A), ultra-high photo-to-dark ratio (>105), satisfactory responsivity (1.05 A/W) and excellent selectivity for DUV band, compared to those with ordinary metal electrodes. The raising of photocurrent and responsivity is attributed to the increase of incident photons through Gr, and separated carriers caused by the built-in electric field formed at the interface of Gr and Ga2O3:Zn films. The proposed ideas and methods of tailoring Gr can not only improve the performance of devices, but more importantly, it contributes to the practical development of graphene. PMID- 30520295 TI - Interfacing a Potential Purely Organic Molecular Quantum Bit with a Real-Life Surface. AB - By using a multidisciplinary and multi-technique approach, we have addressed the issue of attaching a molecular quantum bit to a real surface. First, we demonstrate that an organic derivative of the pyrene-Blatter radical is a potential molecular quantum bit. Our study of the interface of the pyrene-Blatter radical with a copper-based surface reveals that the spin of the interface layer is not cancelled by the interaction with the surface and that the Blatter-radical is resistant in presence of molecular water. Although the measured pyrene-Blatter derivative quantum coherence time is not the highest value known, this molecule is known as a "super stable" radical. Conversely, other potential qubits show poor thin film stability upon air exposure. Therefore, we discuss strategies to make molecular systems candidates as qubits competitive, bridging the gap between potential and real applications. PMID- 30520296 TI - Novel insight into the role of chlorobenzene anti-solvent engineering for high efficient perovskite solar cells: gradient diluted chlorine doping. AB - Chlorobenzene and diethyl ether were chosen as anti-solvent to control the crystallization of CH3NH3PbI3. Under the condition of similar crystallization for both perovskite films, the obvious larger short circuit current density for CH3NH3PbI3 film treated by chlorobenzene prompted us to unveil the roles of chlorobenzene in the perovskite films via adjusting the dipping amount of chlorobenzene. A novel insight of chlorobenzene function was revealed, i.e. gradient diluted chlorine doping in the CH3NH3PbI3 film, which forms a gradient bandgap in the perovskite films, prompts photogenerated carriers accumulating at the interface, makes the electron transport faster and effectively enhances the power conversion efficiency (PCE) of solar cells. The maximum PCE of 20.58% has been achieved under standard AM1.5 conditions. Moreover, this technique exhibits very high reproducibility and 20 devices fabricated in one batch can yield an average PCE of 20.31%. PMID- 30520297 TI - The folding and aggregation energy landscapes of tethered RRM domains of human TDP-43 are coupled via a metastable molten globule-like oligomer. AB - Stress-induced misfolding and intraneuronal aggregation of the highly conserved nucleic acid binding protein TDP-43 (transactive response DNA binding protein 43 kDa) and its fragments have been implicated in amyotrophic lateral sclerosis and multiple other neurodegenerative diseases. However, the physico-chemical mechanism of its misfolding from the functional folded state is poorly understood. TDP-43 is a four domain protein and it performs the essential nucleic acid binding function with the help of its two tandem RNA recognition motif domains naturally tethered by a linker (called here tethered RRM domain of TDP-43 or TDP-43tRRM). Here, we show that the monomeric native form of TDP-43tRRM remains in a pH-dependent and reversible thermodynamic equilibrium with a protonated, nanosized, 40-meric form (the A form). Under the stress-like low-pH condition, the A form becomes predominantly populated. In the A form, protein molecules have restricted dynamics of surface side-chain residues but native-like secondary structure. This self-assembled form possesses a loosely packed core where the intrinsically disordered and aggregation prone regions are in proximity. The A form is metastable and swiftly aggregates into a highly stable amyloid-like protofibrillar form (beta form) mediated by the disorder-to-order transition of intrinsically disordered regions, on small environmental perturbations. Interestingly, the A form and the beta form are not formed when TDP-43tRRM is bound to DNA, indicating that the nucleic acid binding regions of the protein participate in their formation. Our results reveal how the energy landscapes of folding and aggregation of TDP-43tRRM are coupled by a metastable molten-globule like oligomeric form, and modulated by stress-like conditions. PMID- 30520298 TI - Correction to "Magnetic Printing of a Biosensor: Inexpensive Rapid Sensing To Detect Picomolar Amounts of Antigen with Antibody-Functionalized Carbon Nanotubes". PMID- 30520299 TI - Simultaneous Sensitive Determination of Selenium, Silver, Antimony, Lead and Bismuth in Microsamples Based on Liquid Spray Dielectric Barrier Discharge Plasma Induced Vapor Generation. AB - A high-efficient liquid spray dielectric barrier discharge (LSDBD) plasma induced vapor generation technique is developed for the simultaneous determination of selenium, silver, antimony, lead, and bismuth in liquid microsamples (20 MUL) by inductively coupled plasma mass spectrometry (ICP-MS). It is demonstrated that the dissolved Se, Ag, Sb, Pb, and Bi ions in solution samples are readily simultaneously converted to volatile species efficiently by LSDBD plasma induced chemical processes under similar conditions. It eliminates the use of unstable and expensive reducing reagents, and only formic acid is required in the proposed LSDBD chemical vapor generation technique. It is also worth to note that this is the first report of using plasma induced chemical processes for the vapor generation of Ag and Bi. The simultaneous sensitive determination of Se, Ag, Sb, Pb, and Bi is realized with sample volume of only 20 MUL and the sample throughput could be as high as 180 samples h-1. The limits of detection (LODs) for simultaneous determination of Se, Ag, Sb, Pb, and Bi, are 10 ng L-1 (200 fg), 2 ng L-1 (40 fg), 5 ng L-1 (100 fg), 4 ng L-1 (80 fg), and 3 ng L-1 (60 fg), respectively. The precision of Se, Ag, Sb, Pb, and Bi in the present method are evaluated to be better than 4 %. The utility of the proposed technique is demonstrated by the analysis of ultratrace Se, Ag, Sb, Pb, and Bi in archaea cell and single conodont samples. PMID- 30520300 TI - Next-generation PNA chimeras exhibit high affinity and potent gene silencing. AB - We present a new design of mixed-backbone antisense oligonucleotides (ASOs) containing both DNA and peptide nucleic acid (PNA). Previous generations of PNA DNA chimeras showed low binding affinity, reducing their potential as therapeutics. The addition of a 5'-wing of locked nucleic acid as well as the combination of modified nucleotide and PNA monomer at the junction between PNA and DNA gave high affinity to the chimeras. The resulting ASOs demonstrated high serum stability and elicited robust RNase H-mediated cleavage of complementary RNA. These properties allowed the chimeric ASOs to demonstrate high gene silencing efficacy and potency in cells, comparable with LNA gapmer ASOs, both by lipid transfection and gymnosis. PMID- 30520301 TI - A Photon-Responsive Antibacterial Nanoplatform for Synergistic Photothermal /Pharmaco- Therapy of Skin Infection. AB - Abuse of antibiotics and their residues in the environment result in the emergence and prevalence of drug-resistant bacteria and lead to serious health problems. Herein, a photon-controlled antibacterial platform that can efficiently kill drug-resistant bacteria and avoid the generation of new bacterial resistance was designed by encapsulating black phosphorus quantum dots (BPQDs) and pharmaceutical inside a thermal-sensitive liposome. The antibacterial platform can release pharmaceutical in a spatial-, temporal- and dosage-controlled fashion since the BPQDs can delicately generate heat under near-infrared (NIR) light stimulation to disrupt the liposome. This user-defined delivery of drug can greatly reduce the antibiotic dosage, thus avoiding the indiscriminate use of antibiotics and preventing the generation of superbugs. Moreover, by coupling the photothermal effect with antibiotics, this antibacterial platform achieved a synergistic photothermal-/pharmaco- therapy with significantly improved antibacterial efficiency towards drug-resistant bacteria. The antibacterial platform was further employed to treat antibiotic-resistant bacteria-caused skin abscess and it displayed excellent antibacterial activity in vivo, promising its potential clinical applications. Additionally, the antibacterial mechanism was further investigated. The developed photon-controlled antibacterial platform can open new possibilities for avoiding bacterial resistance and efficiently killing antibiotic-resistant bacteria, making it valuable in fields ranging from anti infective therapy to precision medicine. PMID- 30520302 TI - On the Intrinsic Reactivity of Diatomic 3d Transition-Metal Carbides in the Thermal Activation of Methane: Striking Electronic Structure Effects. AB - Mechanistic aspects of the C-H bond activation of methane by metal-carbide cations MC+ of the 3d transition-metals Sc - Zn were elucidated by NEVPT2//CASSCF quantum-chemical calculations, and verified experimentally for M = Ti, V, Fe and Cu by using Fourier transform ion-cyclotron resonance mass spectrometry. While MC+ species with M = Sc, Ti, V, Cr, Cu, and Zn activate CH4 at ambient temperature, this is prevented with carbide cations of M = Mn, Fe, and Co by high apparent barriers; NiC+ has a small apparent barrier. Hydrogen-atom transfers from methane to metal-carbide cations were found to proceed via a proton-coupled electron transfer mechanism for M = Sc - Co; wherein the doubly-occupied pixz/yz orbitals between metal and carbon at the carbon site serve as electron donors and the corresponding metal-centered vacant pi*xz/yz-orbitals as electron acceptors. Classical hydrogen-atom transfer transpires only in case of NiC+, while ZnC+ follows a mechanistic scenario, in which a formally hydridic hydrogen is transferred. CuC+ reacts by a synchronous activation of two C-H bonds. While spin density is often so crucial for the reactions of numerous MO+/CH4 couples, it is much less important for the C-H bond activation by carbide cations of the 3d transition-metals, in which one notes large changes in bond dissociation energies, spin states, number of d-electrons, and charge distributions. All these factors jointly affect both the reactivity of the metal carbides and their mechanisms of C-H bond activation. PMID- 30520303 TI - A Chemical Chaperone Decouples TDP-43 Disordered Domain Phase Separation from Fibrillation. AB - Ribonucleoprotein (RNP) condensations through liquid-liquid phase separation play vital roles in the dynamic formation-dissolution of stress granules (SGs). These condensations are, however, usually assumed to be linked to pathologic fibrillation. Here, we show that physiologic condensation and pathologic fibrillation of RNPs are independent processes that can be unlinked with the chemical chaperone trimethylamine N-oxide (TMAO). Using the low complexity disordered domain of the archetypical SG-protein TDP-43 as model system, we show that TMAO enhances RNP liquid condensation yet inhibits protein fibrillation. Our results demonstrate effective decoupling of physiologic condensation from pathologic aggregation and suggests that selective targeting of protein fibrillation (without altering condensation) can be employed as therapeutic strategy for RNP aggregation-associated degenerative disorders. PMID- 30520304 TI - Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation. AB - A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans and six-membered analogues. The general applicability and functional group tolerance of this method was exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process. PMID- 30520305 TI - Characterization of the Blister Fluid Proteome for Pediatric Burn Classification. AB - Blister fluid (BF) is a novel and viable research matrix for burn injury study, which can reflect both systemic and local micro-environmental responses. The protein abundance in BF from different burn severities were initially observed using a 2D SDS-PAGE approach. Subsequently, a quantitative data independent acquisition (DIA) method - SWATHTM was employed to characterize the proteome of pediatric burn blister fluid. More than 600 proteins were quantitatively profiled in 87 BF samples from different pediatric burn patients. These data were correlated with clinically assessed burn depth and time until complete wound re epithelialization through several different statistical analyses. Several proteins from these analyses exhibited significant abundance change between different burn depth or re-epithelialization groups, and can be considered as potential biomarker candidates. Further gene ontology (GO) enrichment analysis of the significant proteins revealed the most significant burn related biological processes (BP) that are altered with burn depth including homeostasis and oxygen transport. However, for wounds with re-epithelialization times more or less than 21 days, the significant GO annotations were related to enzyme activity. This quantitative proteomics investigation of burn BF may enable objective classification of burn wound severity and assist with clinical decision-making. Data are available via ProteomeXchange with identifier PXD011102. PMID- 30520306 TI - Synthesis of Amides by Mild Palladium-Catalyzed Aminocarbonylation of Arylsilanes with Amines Enabled by Copper(II) Fluoride. AB - A general Pd-catalyzed synthesis of amides by oxidative aminocarbonylation of arylsilanes under mild conditions has been accomplished for the first time. The reaction is promoted by a commercially available copper(II) fluoride, which acts as a dual silane activator and mild oxidant, enabling highly efficient aminocarbonylation of versatile arylsilanes at atmospheric CO pressure. The reaction is tolerant of a wide range of arylsilanes and various sensitive halide functional groups, as well as a broad scope of amines are compatible with this oxidative process using cheap CO. A significant aspect involves the increased efficiency by the catalyst system. The reaction represents a segue into the powerful Pd-catalyzed oxidative transformations of organosilanes. PMID- 30520307 TI - Emerging Design and Characterization Guidelines for Polymer-Based Infrared Photodetectors. AB - Infrared photodetectors are essential to many applications, including surveillance, communications, process monitoring, and biological imaging. The short-wave infrared (SWIR) spectral region (lambda = 1-3 MUm) is particularly powerful for health monitoring and medical diagnostics because biological tissues show low absorbance and minimal SWIR autofluorescence, enabling greater penetration depth and improved resolution in comparison with visible light. However, current SWIR photodetection technologies are largely based on epitaxially grown inorganic semiconductors, which are costly, require complex processing, and impose cooling requirements incompatible with wearable electronics. Solution-processable semiconductors are being developed for infrared detectors to enable low-cost direct deposition and facilitate monolithic integration and resolution not achievable using current technologies. In particular, organic semiconductors offer numerous advantages, including large area and conformal coverage, temperature insensitivity, and biocompatibility, for enabling ubiquitous SWIR optoelectronics. This Account introduces recent efforts to advance the spectral response of organic photodetectors into the SWIR. High performance visible to near-infrared (NIR) organic photodetectors have been demonstrated by leveraging the wealth of knowledge from organic solar cell research in the past decade. On the other hand, organic semiconductors that absorb in the SWIR are just emerging, and only a few organic materials have been reported that exhibit photocurrent past 1 MUm. In this Account, we survey novel SWIR molecules and polymers and discuss the main bottlenecks associated with charge recombination and trapping, which are more challenging to address in narrow-band-gap photodetectors in comparison with devices operating in the visible to NIR. As we call attention to discrepancies in the literature regarding performance metrics, we share our perspective on potential pitfalls that may lead to overestimated values, with particular attention to the detectivity (signal-to noise ratio) and temporal characteristics, in order to ensure a fair comparison of device performance. As progress is made toward overcoming challenges associated with losses due to recombination and increasing noise at progressively narrower band gaps, the performance of organic SWIR photodetectors is steadily rising, with detectivity exceeding 1011 Jones, comparable to that of commercial germanium photodiodes. Organic SWIR photodetectors can be incorporated into wearable physiological monitors and SWIR spectroscopic imagers that enable compositional analysis. A wide range of potential applications include food and water quality monitoring, medical and biological studies, industrial process inspection, and environmental surveillance. There are exciting opportunities for low-cost organic SWIR technologies to be as widely deployable and affordable as today's ubiquitous cell phone cameras operating in the visible, which will serve as an empowering tool for users to discover information in the SWIR and inspire new use cases and applications. PMID- 30520308 TI - Phenanthroline- tBuOK Promoted Intramolecular C-H Arylation of Indoles with ArI under Transition-Metal-Free Conditions. AB - The first example of phenanthroline- tBuOK promoted intramolecular radical C-H arylation of N-(2-iodobenzyl)indoles without involvement of transition metals has been developed. A variety of substituted 6 H-isoindolo [2, 1-a] indoles were prepared by a simple and efficient intramolecular cyclization using 1,10 phenanthroline in the presence of potassium tert-butoxide and chlorobenzene. This strategy provides a fast and versatile access to isoindolo[2,1- a]indole derivatives for the synthesis of pharmaceuticals and organic electroluminescent (EL) materials. PMID- 30520309 TI - The interaction of HIV set-point viral load and subtype on disease progression. AB - HIV-1 subtype and viral load set-point have been implicated as strong predictors of HIV-1 disease progression; however the relationship between these two variables has not been investigated. We used data from the Rakai Community Cohort Study to investigate whether the association between viral load set-point and disease progression is modified by HIV subtype. Time to AIDS or AIDS-related death was investigated through Cox proportional hazards regression with an interaction term between viral load set point and HIV subtype. The interaction term did not indicate effect measure modification between viral load set-point and progression to AIDS by HIV-1 subtype (adjusted hazard ratio aHR, 0.99; 95% CI, 0.61 - 1.61; p = 0.968). Stratifed analysis by subtype was also not indicative of a difference in relationship between viral load set-point and time to AIDS with overlapping 95% confidence intervals between subtypes A and D (subtype A aHR: 2.40, 95% CI: 1.45 - 3.99, p = 0.001; subtype D aHR: 1.96, 95% CI 1.60 - 2.40, p < 0.001). These results indicate that there is no significant excess risk with having a subtype D HIV-1 infection and a high set-point viral load in progression to AIDS. The higher mortality rate observed in subtype D infected individuals is independent of viral load set-point. PMID- 30520310 TI - ADDENDUM. PMID- 30520311 TI - CORRIGENDUM. PMID- 30520313 TI - Circulation: Arrhythmia and Electrophysiology. PMID- 30520314 TI - Circulation: Genomic and Precision Medicine Editors and Editorial Board. PMID- 30520312 TI - The impact of the implementation of the Dutch combined Meeting Centres Support Programme for family caregivers of people with dementia in Italy, Poland and UK. AB - OBJECTIVES: The MEETINGDEM research project aimed to implement the combined Dutch Meeting Centre Support Programme (MCSP) for community-dwelling people with dementia and caregivers within Italy, Poland and UK and to assess whether comparable benefits were found in these countries as in the Netherlands. METHOD: Nine pilot Meeting Centres (MCs) participated (Italy-5, Poland-2, UK-2). Effectiveness of MCSP was compared to usual care (UC) on caregiver outcomes measuring competence (SSCQ), mental health (GHQ-12), emotional distress (NPI-Q) and loneliness (UCLA) analysed by ANCOVAs in a 6-month pre-test/post-test controlled trial. Interviews using standardised measures were completed with caregivers. RESULTS: Pre/post data were collected for 93 caregivers receiving MCSP and 74 receiving UC. No statistically significant differences on the outcome measures were found overall. At a country level MC caregivers in Italy showed significant better general mental health (p = 0.04, d = 0.55) and less caregiver distress (p = 0.02, d = 0.62) at post-test than the UC group. Caregiver satisfaction was rated on a sample at 3 months (n = 81) and 6 months (n = 84). The majority of caregivers reported feeling less burdened and more supported by participating in MCSP. CONCLUSION: The moderate positive effect on sense of competence and the greater mental health benefit for lonely caregivers using the MCSP compared to UC as found in the original Dutch studies were not replicated. However, subject to study limitations, caregivers in Italy using MCSP benefitted more regarding their mental health and emotional distress than caregivers using UC. Further evaluation of the benefits of MCSP within these countries in larger study samples is recommended. PMID- 30520315 TI - Branched-Chain Amino Acids: The Metabolic Link Between Type 2 Diabetes Mellitus and Cardiovascular Disease? PMID- 30520316 TI - Revealing Pathways of Cardiac Regeneration. PMID- 30520317 TI - Fingerprint pattern of bone mineralisation on cemented and uncemented femoral stems: analysis by [18F]-fluoride-PET in a randomised clinical trial. AB - PURPOSE:: We present a randomised clinical study using 18F-fluoride positron emission tomography/computed tomography (F-PET/CT) to analyse the osteoblastic part of bone metabolism (new bone mineralisation) in periprosthetic bone adjacent to femoral stems following total hip arthoplasty (THA) surgery. Patients with hip osteoarthritis were randomly assigned to THA surgery with cemented or uncemented femoral components. PATIENTS AND METHODS:: THA was performed on 26 patients (26 cases) with hip osteoarthritis. The patients received either an uncemented HA coated femoral stem or a cemented one. The contralateral healthy femur was used as referent for normal bone metabolism. The patients were analysed with clinical score, radiography and F-PET/CT preoperatively, and postoperatively at 6 weeks and 6 months. After 2 years, clinical score and radiography was analysed again. We used the Polar Map system for analysing and presenting the PET results in 13 regions of interest adjacent to the whole stem. RESULTS:: The clinical results were good in all patients; there were no major complications. Radiographically, all stems were stable. PET analyses after 6 weeks showed that bone mineralising activity was significantly higher around the uncemented stems, both compared to the cemented group and to the contralateral healthy reference femur group. The cemented group also had elevated activity but only at a barely significant level. INTERPRETATION:: Mineralising activity analysed with F-PET/CT was significantly higher for the uncemented group and also decreased at a slower rate. F-PET/CT is a useful new tool for analysing secondary stabilisation of femoral stems after THA. The study was registered at ClinicalTrials.gov (identifier NCT01623687). PMID- 30520318 TI - Circulation: Clinical Summaries. PMID- 30520319 TI - Circulation: Clinical Summaries. PMID- 30520320 TI - ECG Challenge: January 6, 2015. PMID- 30520321 TI - Validation of a New North American Islet Donor Score for Donor Pancreas Selection and Successful Islet Isolation in a Medium-Volume Islet Transplant Center. AB - The selection of optimal pancreas donors is one of the key factors in determining the ultimate outcome of clinical islet isolation. North American Islet Donor Score (NAIDS) allows for estimating the chance of the success of islet isolation. It was developed based on the data from over 1000 donors from 11 islet isolation centers and validated in the University of Alberta, Edmonton, on the cohort from the most active islet transplant center. Now we aimed to also validate it in our much less active program. Areas under the receiver operating characteristic curves (AUROCs) and logistic regression analyses were obtained to test if NAIDS would better predict successful islet isolation (defined as post-purification islet yield >400,000 islet equivalents (IEQ)) than previously described Edmonton islet donor score (IDS) and our modified version of IDS. We analyzed the donor scores with reference to 82 of our islet isolation outcomes. The success rate increased proportionally as NAIDS increased, from 0% success in NAIDS < 50 points to 40% success in NAIDS >= 80 points. AUROCs were 0.67 (95% confidence interval (CI) 0.55-0.79) for NAIDS, 0.58 (95% CI 0.44-0.71) for modified IDS, and 0.51 (95% CI 0.37-0.65) for IDS and did not differ significantly. However, based on logistic regression analyses, NAIDS was the only statistically significant predictor of successful isolation (p = 0.01). The main advantage of NAIDS is an enhanced ability to discriminate poor-quality donors than previously used scoring systems at University of Chicago, with 0% chance for success when NAIDS was <50 as compared with 40% success rate for IDS <50. NAIDS was found to be the most useful available tool for donor pancreas selection in clinical and research practice in our center, allowing for identification and rejection of poor-quality donors, saving time and resources. PMID- 30520323 TI - Late-Breaking Clinical Trial and Clinical Science Special Reports Abstracts From the American Heart Association's Scientific Sessions 2016; Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2016. PMID- 30520322 TI - Potential of Exosomes for the Treatment of Stroke. AB - Stroke is the result of blockage or rupture of blood vessels in the brain and is the leading cause of death and disability in the world. Currently only a very limited number of therapeutic approaches are available for treatment of stroke patients, and the vast majority of neuroprotective agents that tested positively in pre-clinical studies failed in clinical trials. In recent years, the clinical value of the use of exosomes for stroke treatment has received widespread attention due their unique characteristics such as low immunogenicity, low toxicity and biodegradability, ability to cross the blood-brain barrier (BBB), and their important role in communication between cells. More and more evidence suggests that the secretion of exosomes is the mechanism underlying the protection induced by mesenchymal stromal cells (MSCs) after stroke. Exosomes are thought to support brain restoration and induce repairing effects, including neurovascular remodeling, and anti-apoptosis and anti-inflammatory effects. Recent reports have focused on the clinical application of exosomes as a potential drug delivery approach. This review focuses on the ability of exosomes to interrupt the stroke-induced pathologic processes of stroke, and on publications describing how to achieve more effective treatment of stroke with exosomes. PMID- 30520324 TI - A computational and experimental study to develop E-selectin targeted peptides for molecular imaging applications. AB - AIM: E-selectin is overexpressed on angiogenic and inflamed endothelium. Molecules binding to E-selectin with high affinity and specificity enable its use as a molecular imaging biomarker. MATERIAL & METHODS: The interactions of four different peptides (i.e., Ac-P1 [Acetyl-IELLQAR-CONH2], H2N-P2 [H2N-DITWDQLWDLMK CONH2], H2N-P3A5 [H2N-YRNWAGRW-CONH2], and Ac-P4 [Acetyl-YRNWDGRW-CONH2]) with E selectin were analyzed by computational methodologies, surface plasmon resonance and in vitro using activated human umbilical vein endothelial cells. Poly(butyl cyanoacrylate) microbubbles were functionalized with the best candidates and evaluated as molecular ultrasound probes in cultured cells and explanted carotid arteries. RESULTS: H2N-P3A5 and Ac-P4 peptides bound stronger to E-selectin than Ac-P1 and H2N-P2, but with lower specificity. H2N-P2 bound with higher specificity and affinity than Ac-P1. CONCLUSION: H2N-P2 is a good candidate for designing E-selectin-targeted molecular imaging agents. PMID- 30520325 TI - KLF2 Inhibits the Migration and Invasion of Prostate Cancer Cells by Downregulating MMP2. AB - KLF2, a member of the Kruppel-like factor (KLF) family, is thought to be a tumor suppressor in many kinds of malignant tumors. Its functions in prostate cancer (PCa) are unknown. This study aimed to explore the role of KLF2 in the migration and invasion of PCa cells. The expression of KLF2 was measured by immunohistochemistry in PCa tissues and in paired non-tumor tissues. KLF2 and MMP2 expression in cells was measured by Western blot and RT-qPCR. Adenoviruses and siRNAs were used in cell function tests to investigate the role of KLF2 in regulating MMP2. Interactions between KLF2 and MMP2 were analyzed by a luciferase activity assay. The present study, for the first time, identified that KLF2 was downregulated both in PCa clinical tissue samples and in cancer cell lines. The overexpression of KLF2 inhibited the migration and invasion of PCa cells via the suppression of MMP2.This study demonstrates that KLF2 might act as a tumor suppressor gene in PCa and that the pharmaceutical upregulation of KLF2 may be a potential approach for treatment. PMID- 30520326 TI - Luteinized Fibrothecoma. PMID- 30520327 TI - The impact of functioning hemodialysis arteriovenous accesses on renal graft perfusion: Results of a pilot study. AB - INTRODUCTION:: After a kidney transplant, it is unknown whether the maintenance of a functioning hemodialysis arteriovenous access could have deleterious effects on renal grafts. We hypothesize that maintaining an arteriovenous access can deviate a significant proportion of the cardiac output from the renal graft. The aim of this study was to investigate whether a temporary closure of the arteriovenous access could lead to an increase in graft perfusion. METHODS:: We conducted a study in 17 kidney-transplanted patients with a functioning arteriovenous access. We evaluated, at baseline and 30 s after compression of the arteriovenous access (access flow occlusion), the hemodynamic parameters and the renal resistive index of the graft by Doppler ultrasound. RESULTS:: After arteriovenous access occlusion 82.4% (n = 14) of the patients had a decrease in resistive index. All patients had a decrease in heart rate (67 vs 58 bpm, p < 0.001) and 14 (82.4%) had an increase in mean blood pressure (98.3 vs 101.7 mm Hg, p = 0.044). There was a significant decrease in the resistive index (DeltaRI) after the access occlusion (0.68 vs 0.64, p = 0.030). We found a negative correlation in Qa (r2 = -0.55, p = 0.022) with the DeltaRI, and Qa was an independent predictor of DeltaRI in a model adjusted to pre-occlusion resistive index. CONCLUSION:: Our results showed that temporary occlusion of an arteriovenous access causes a significant decline in renal graft resistive index and this decline is higher with the occlusion of accesses with higher Qa. These results suggest that the maintenance of arteriovenous accesses, mainly those with higher Qa, can decrease renal graft perfusion. PMID- 30520329 TI - Clinical Implications. PMID- 30520328 TI - Development of exercise-related values in heart failure patients supported with a left ventricular assist device. AB - Following implantation of a left ventricular assist device, the build-up and long term maintenance of adequate exercise capacity and functional performance become crucial. The aim of this study was to observe the development of exercise-related values at different times, as well as to detect possible influencing factors. We performed a prospective single-centre study: 10 patients (63 years, 100% male, body mass index = 27.5, 100% HeartWare) underwent the following diagnostic tests during cardiac rehabilitation and during two subsequent ambulatory visits: 6-min walking test, handgrip strength test, cardiopulmonary exercise test and Minnesota Living with Heart Failure questionnaire. Mean follow-up was 482 days after left ventricular assist device implantation. Significant improvements could be observed between the end of cardiac rehabilitation and ambulatory visit 1; 6-min walking distance increased from 367 to 449 m (p < 0.01), peak VO2 from 10.0 to 11.9 mL/kg/min (p < 0.05) and peak load from 62.4 to 83.0 W (p < 0.01). However, there were no further improvements between ambulatory visit 1 and ambulatory visit 2. In the long term, a significant mean weight gain of more than 10 kg could be observed (p < 0.01). A negative linear correlation between weight gain and absolute improvement in peak load (r = -0.77, p < 0.01) and peak VO2 (r = 0.75, p < 0.05) could be demonstrated. In conclusion, exercise-related values following left ventricular assist device implantation initially improve significantly. Later, however, no further improvements can be observed. In the long term, pronounced weight gain is conspicuous, concomitant with a significantly lower increase in exercise values of the patients. In the future, both dietary and structured physical activity follow-up interventions should be integrated in patient routines. PMID- 30520330 TI - Mortality and Disability According to Baseline Blood Pressure in Acute Ischemic Stroke Patients Treated by Thrombectomy: A Collaborative Pooled Analysis. PMID- 30520331 TI - Impact of Diabetes Mellitus on the Evaluation of Stable Chest Pain Patients: Insights From the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) Trial. PMID- 30520333 TI - 2016 AHA Late-Breaking Basic Science Abstracts. PMID- 30520332 TI - Plasma Nitrate and Incidence of Cardiovascular Disease and All-Cause Mortality in the Community: The Framingham Offspring Study. PMID- 30520335 TI - Calorie Restriction Curbs Proinflammation That Accompanies Arterial Aging, Preserving a Youthful Phenotype. PMID- 30520334 TI - Transjugular percutaneous endovascular treatment of dysfunctional hemodialysis access. AB - PURPOSE:: To evaluate the feasibility and the outcomes of transjugular percutaneous endovascular treatment of dysfunctional hemodialysis access in patients with chronic kidney disease. METHODS:: A total of 50 transjugular treatments in 38 patients with arteriovenous fistulas or arteriovenous grafts from September 2011 to May 2015 were included in this study. Medical records and angiographies were retrospectively reviewed. Success rate, patency rate, procedure time, and complications including internal jugular vein stenosis were evaluated. RESULTS:: A total of 50 sessions of transjugular treatments were performed in 38 patients. There were 31 native arteriovenous fistulas including 10 immature cases and 19 arteriovenous grafts. Among the 50 cases, technical success was achieved in 45 and clinical success was achieved in 44; 37 cases (74%) with multiple stenotic sites were treated by the transjugular approach without placement of cross-sheaths. The mean time from puncture of the internal jugular vein to first fistulography was 10 min, and the mean total procedure time was 64 min. The primary patency rate at 6 months was 77%, while the secondary patency rate at 6 months was 97%. Perforation occurred in two cases during conventional percutaneous transluminal angioplasty after failure of the transjugular approach. One dissection occurred during the transjugular approach. There was no newly developed internal jugular vein stenosis during a mean follow up period of 19.3 months. CONCLUSION:: For the treatment of dysfunctional or immature hemodialysis access, the transjugular approach is a feasible and effective option that avoids injury to the graft or draining vein, especially in immature fistulas. PMID- 30520337 TI - Circulation: Cardiovascular Interventions. PMID- 30520336 TI - The emerging role of liquid biopsy in diagnosis, prognosis and treatment monitoring of pancreatic cancer. AB - Circulating tumor DNA, circulating tumor cells and tumor-related exosomes may offer new opportunities to provide insights into the biological and clinical characteristics of a neoplastic disease. They represent alternative routes for diagnostic and prognostic purposes, and for predicting and longitudinally monitoring response to treatment and disease progression. Hence, circulating biomarkers represent promising noninvasive tools in the scenario of pancreatic cancer, where neither molecular nor clinical predictors of treatment benefit have been identified yet. This review aims to provide an overview of the current status of circulating biomarker research in pancreatic cancer, and discusses their potential clinical utility to facilitate clinical decision-making. PMID- 30520338 TI - Prolonged clonazepam-induced withdrawal symptoms in an NAT2 ultraslow acetylator. AB - Clonazepam undergoes nitroreduction to 7-amino-clonazepam via CYP3A4/5, followed by acetylation to 7-acetamido-clonazepam via N-acetyltransferase-2 (NAT2) enzyme. While no pharmacological activity is attributed to the metabolites of clonazepam, 7-amino-clonazepam has some affinity for the benzodiazepine receptor as a partial agonist for the gamma aminobutyric acid-A receptor and can compete with clonazepam. Interindividual variability in the incidence of adverse events in patients may, in part, be attributable to differences in clonazepam metabolism. Here, we report on a case of a 70-year-old Caucasian female with insomnia and difficulty weaning off long-term use of clonazepam suggesting that a slow acetylator phenotype contributing to patient's presentation. This hypothesis was confirmed by NAT2 gene sequencing. NAT2 genotyping may play a role in guiding clonazepam therapy. PMID- 30520339 TI - Doxorubicin effects on leukemia and breast cancer cells in culture on the TK1 protein levels using AroCell TK 210 ELISA: a tool for drug development. AB - In this study changes in thymidine kinase 1 (TK1) levels after 24 hours of Doxorubicin (Dox) exposure of CEM and MDA MB-231 cells were determined using the commercially available AroCell TK 210 ELISA test. In cell extracts, TK1 levels increased twofold with 1 uM Dox in both cell lines, while the TK1 levels in the culture media increased with 5 and 10 uM of Dox only in case of CEM cells. In conclusion, this study reveals that the TK 210 ELISA can measure changes in intra and extracellular TK1 levels apparently related to the mechanism of cytotoxicity of anti-cancer agents. PMID- 30520340 TI - Reducing Social Judgment Biases May Require Identifying the Potential Source of Bias. AB - Social judgment is shaped by multiple biases operating simultaneously, but most bias-reduction interventions target only a single social category. In seven preregistered studies (total N > 7,000), we investigated whether asking participants to avoid one social bias affected that and other social biases. Participants selected honor society applicants based on academic credentials. Applicants also differed on social categories irrelevant for selection: attractiveness and ingroup status. Participants asked to avoid potential bias in one social category showed small but reliable reductions in bias for that category ( r = .095), but showed near-zero bias reduction on the unmentioned social category ( r = .006). Asking participants to avoid many possible social biases or alerting them to bias without specifically identifying a category did not consistently reduce bias. The effectiveness of interventions for reducing social biases may be highly specific, perhaps even contingent on explicitly and narrowly identifying the potential source of bias. PMID- 30520342 TI - In This Issue. PMID- 30520341 TI - Patients carrying CYP2C8*3 have shorter systemic paclitaxel exposure. AB - AIM: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 MUM [Tc >0.05]). Second, screen additional pharmacogenes for associations with Tc >0.05. Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with Tc >0.05 (n = 58). RESULTS: Patients with predicted low-activity CYP2C8 had shorter Tc >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, beta = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer Tc >0.05 (12.12 vs 10.15 hrs, beta = 0.85, p = 0.012). CONCLUSION: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability. PMID- 30520343 TI - Risky sexual behavior among adolescents: The role of decision-making, problems from cannabis use and externalizing disorder symptoms. AB - INTRODUCTION: Previous research has demonstrated that externalizing symptoms, cannabis use problems, and poor decision-making abilities are each independently related to risky sexual behavior (RSB). However, few studies have examined the joint effect of these factors on RSB among a sample of adolescents. METHODS: The current study addresses this gap in the literature by examining how externalizing disorder symptoms, cannabis use, and decision-making abilities interact to predict RSB among a sample of adolescents (n = 204; Mage = 15.5) at-risk for escalation in cannabis use. Poisson regression was used for all analyses, and simple slope difference tests were used for all post-hoc analyses. RESULTS: A greater number of externalizing symptoms, more problems from cannabis use, and more risk disadvantageous choices on the Cups Task (CT) total trials and more risk disadvantageous choices on the CT-gain trials predicted greater RSB endorsement. Findings also highlight significant interactions between cannabis use problems and CT-total and -gain trial performance, as well as between cannabis use problems and externalizing symptoms in predicting RSB. CONCLUSION: Current treatment and prevention approaches to reduce RSB among adolescents may benefit from incorporating techniques that improve decision-making skills. PMID- 30520344 TI - Prevalence of pharmacogenomic variants affecting the efficacy of clopidogrel therapy in the Hispanic Community Health Study/Study of Latinos cohort. AB - PURPOSE: Although clopidogrel is the most widely used oral P2Y12 receptor antagonist, up to 10% of acute coronary syndrome patients treated with clopidogrel will experience a recurrent myocardial infarction and 2-3% will experience stent thrombosis within 1 year. The purpose of this research is to describe the prevalence of pharmacogene variants associated with clopidogrel responsiveness (CYP2C19, B4GALT2, ABCB1, PON1, CES1 and P2RY12) in Hispanic/Latino patients of diverse backgrounds. METHODS: Minor allele frequencies of nine variants from participants of Hispanic Community Health Study/Study of Latinos were compared between subpopulations as well as to continental ancestry references using z-test for independent proportions. RESULTS: MAFs for six out of nine variants differed between Caribbean and Mainland subpopulations (p < 0.05). Compared with European reference group, MAFs of ABCB1, CES1 and PON1 were higher in Hispanic Community Health Study/Study of Latinos, whereas B4GALT2 and CYP2C19*2 and *17 were lower. CONCLUSION: Significant differences in the prevalence of most pharmacogenomic variants related to clopidogrel response provide a foundation to better inform ongoing and future clinical studies of clopidogrel pharmacogenetics in the US Hispanic/Latino populations. PMID- 30520346 TI - 2018: the knee of the rejuvenation curve. AB - n/a. PMID- 30520345 TI - More Than Words: The Use of Video in Ethnographic Research With People With Intellectual Disabilities. AB - There is a tendency to exclude people with intellectual disabilities from participating in research about their own lives. While the use of participatory research approaches is increasing, the methods used for engaging people with intellectual disabilities in research are generally limited to interviews and focus groups. Yet a focus on the spoken or written word can present a challenge for those who may prefer to use alternative forms of communication. The purpose of this article is to share the methodological insights gained from a visual ethnographic study that sought to explore the experiences of people with intellectual disabilities engaged in nature based (or "green care") therapeutic interventions for health and well-being. If used within carefully negotiated relationships, we suggest that video can be an empowering visual medium for doing research that can help to elicit the experiences of people with intellectual disabilities firsthand, without having to rely on the views and perspectives of other people. PMID- 30520347 TI - Biosynthetic Vascular Graft: A Valuable Alternative to Traditional Replacement Materials for Treatment of Prosthetic Aortic Graft Infection? AB - BACKGROUND AND AIMS:: To report the experience of a tertiary vascular surgery center using Omniflow II(r) biosynthetic vascular grafts for treatment of prosthetic aortic graft infection. MATERIALS AND METHODS:: Retrospective analysis of all patients with prosthetic graft infections who underwent in situ aortic reconstruction using Omniflow II(r) grafts or other conduits between March 2015 and May 2017. Early and late mortality, perioperative complications, and reinfection rate were analyzed. RESULTS:: Sixteen patients (14 males, median age 68.5, range 57-89) with prosthetic aortic graft infection were treated at our center. Eight patients received an Omniflow II(r) biosynthetic graft, two patients silver-triclosan coated grafts, three patients bovine pericardial tube grafts, and three patients composite bovine pericardial tube grafts with Omniflow II(r) graft extensions. Perioperative complications occurred in seven patients (43.8%). Early mortality rate was 18.7% (n = 3). In addition, four patients died during follow-up after a median of 11 months (range 0-34 months). We did not observe any reinfections. Bypass grafts were patent in all patients. No major limb amputations were performed during follow-up. CONCLUSION:: Treatment of prosthetic aortic graft infection with Omniflow II(r) vascular grafts is feasible. Graft material seems to have an excellent resistance to infection and might be a valuable alternative to traditional replacement materials. Especially long-term durability has to be continuously monitored and documented. PMID- 30520348 TI - Novel Insights in the Activation Patterns at the Pulmonary Vein Area. AB - BACKGROUND: Extensiveness of conduction delay and block at the pulmonary vein area (PVA) was quantified in a previous study. We hypothesized that the combination of lines of conduction block with multiple concomitantly entering sinus rhythm wavefronts at the PVA may result in increased arrhythmogenicity and susceptibility to atrial fibrillation (AF). METHODS: Intraoperative high-density epicardial mapping of PVA (N~450 sites, interelectrode distances: 2 mm) was performed during sinus rhythm in 327 patients (241 male [74%], 67+/-10 [21-84] years) with and without preoperative AF. For each patient, activation patterns at the PVA were quantified, including the location of entry sites of wavefronts, direction of propagation, and their relative activation times. The association between activation patterns and the presence of AF was examined. RESULTS: Excitation of the PVA occurred via multiple consecutive wavefronts in the vast majority of patient (N=216, 81%). In total, 561 wavefronts were observed, which mostly propagated through the septal or paraseptal regions towards the PVA (N=461, 82%). A substantial dissociation of consecutive wavefronts was observed with Deltaactivation times of 10.6+/-8.8 (0-46) ms. No difference was observed in Deltaactivation times of consecutive wavefronts during sinus rhythm between patients without and with AF. An excitation-based risk factor model, including conduction delay >=6 mm, conduction block >=6 mm, and conduction delay and block >=16 mm, wavefronts via the posteroinferior to posterosuperior regions and multiple opposing wavefronts, demonstrated a 5-fold risk of AF when multiple risk factors were present. CONCLUSIONS: In contrast to previous findings, quantification of activation patterns at the PVA on high-resolution scale demonstrated complex patterns with often multiple entry sites and high interindividual variability. Altered patterns of activation, consisting of multiple opposing wavefronts combined with long lines of conduction slowing, were associated with the presence of AF. PMID- 30520350 TI - Displaced and segregated: The socio-economic status of the second generation of internally displaced Palestinians in Israel. AB - This study investigates the effects of displacement on the socio-economic status of second-generation Palestinian internally displaced persons (IDPs) in Israel. The results show that members of this group do not differ from non-displaced Palestinians in their educational or occupational attainment, but that displaced households experience higher rates of poverty and poorer housing conditions than non-displaced households. I find that the relationship between displacement and the prime indicators of social mobility-education and jobs-was weakened by three factors: extreme spatial segregation between Palestinians and Jews, the concentration of disadvantage among Palestinian IDPs within the host communities, which were Palestinian spaces, and a high level of dependence on resources concentrated in Jewish spaces among all Palestinians, not just IDPs. These three conditions, however, do not eliminate gaps in assets and land ownership between IDPs and non-displaced Palestinians, which, I argue, contribute to higher poverty rates among displaced households. PMID- 30520349 TI - Safety of Sports for Young Patients With Implantable Cardioverter-Defibrillators. AB - BACKGROUND: Despite safety concerns, many young patients with implantable cardioverter-defibrillators (ICDs) participate in sports. We undertook a prospective, multinational registry to determine the incidence of serious adverse events because of sports participation. The primary end points were death or resuscitated arrest during sports or injury during sports because of arrhythmia or shock. Secondary end points included system malfunction and incidence of ventricular arrhythmias requiring multiple shocks for termination. METHODS: Athletes with ICDs aged <=21 years were included in this post hoc subanalysis of the ICD Sports Registry. Data on sports and clinical outcomes were obtained by phone interview and medical records review. ICD shocks and clinical details of lead malfunction were classified by 2 electrophysiologists. RESULTS: A total of 129 young athletes participating in competitive (n=117) or dangerous (n=12) sports were enrolled. The mean age was 16 years (range, 10-21; 40% female; 92% white). The most common diagnoses were long QT syndrome (n=49), hypertrophic cardiomyopathy (n=30), and congenital heart disease (n=16). The most common sports were basketball and soccer, including 79 varsity/junior varsity high school and college athletes. During a median follow-up of 42 months, 35 athletes (27%) received 38 shocks. There were no occurrences of death, arrest, or injury related to arrhythmia, during sports. There was 1 ventricular tachycardia/ventricular fibrillation storm during competition. Freedom from lead malfunction was 92.3% at 5 years and 79.6% at 10 years. CONCLUSIONS: Although shocks related to competition/practice are not uncommon, there were no serious adverse sequelae. Lead malfunction rates were similar to previously reported in unselected pediatric ICD populations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00637754. PMID- 30520351 TI - Incidental Hepatic Tissue Obtained via Routine Cholecystectomy. AB - BACKGROUND: The hepatic tissue that may occupy specimens from routine cholecystectomies has yet to be studied. Our objectives were to determine the prevalence of hepatic tissue obtained at routine cholecystectomy, to determine whether such hepatic tissue can histologically withstand technical artifacts commonly associated with cholecystectomy, and to determine whether examining such hepatic tissue has diagnostic utility. MATERIALS AND METHODS: We retrospectively reviewed 50 specimens from routine cholecystectomies that were performed by surgeons who lacked knowledge of our study. All 50 specimens were grossed according to standard protocol, with only limited, nontargeted sampling of the rough nonperitonealized margin, and were received without fixative. RESULTS: Twelve specimens (24.0%) contained hepatic tissue. The hepatic tissue measured up to 44.5-mm long and 1.8-mm wide and contained up to 11 complete portal tracts. Hepatic tissue in 3 specimens satisfied criteria for adequacy established for core biopsies based on number of portal tracts or size. Despite cautery and delayed fixation, all hepatic tissue had surprisingly well-preserved histology. Pathologic findings included nonalcoholic fatty liver disease, von Meyenburg complex, chronic cholestasis, and senescence. CONCLUSIONS: The hepatic tissue that accompanies specimens from routine cholecystectomies may be relatively common, can be large, is well preserved, and can harbor diagnostically useful information. PMID- 30520352 TI - Abstract 4: Safety of Intravenous Thrombolysis Among Patients Taking Direct Oral Anticoagulants: A Systematic Review and Meta-analysis. AB - INTRODUCTION: Direct oral anticoagulants (DOACs) are increasingly being administered for atrial fibrillation and stroke prevention. The risk of symptomatic hemorrhagic transformation (sHT) following intravenous thrombolysis (IVT) among stroke patients who take DOACs is not clear. METHODS: We conducted a systematic review of literature through six different resources-PubMed, Scopus, Embase, Clinicaltrial.gov, ICTRP and Cochrane library. The control groups included patients who took warfarin with INR<1.7 and patients without prior anticoagulation use. The heterogeneity between studies was assessed by chi2 test for heterogeneity. Meta-analysis was conducted by assuming the random-effect models. RESULTS: A total of 12606 search results were retrieved. After reduction of the duplication, screening the title and abstracts and review of the candidate manuscripts, 44877 stroke patients were enrolled in this study-DOACs: 369 patients, warfarin: 1997 patients and 42511 patients without prior anticoagulation use. Pretreatment use of DOACs was not associated with increased risk of sHT compared to those who received warfarin (OR: 0.62; 95% CI: 0.23-1.71; P=0.74) or patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.31- 2.56; P=0.98). Similarly, by restricting the results to last DOACs-IVT interval of 48 hours, DOACs was not associated with increased risk of sICH; neither in comparison with warfarin (OR: 0.63; 95% CI: 0.39- 1.02; P=0.82), nor with patients without prior anticoagulation use (OR: 0.89; 95% CI: 0.53- 1.48; P=0.36). CONCLUSION: Pretreatment use of DOACs appears not to be associated with increased risk of sHT among patients who presented with stroke symptoms and treated with IVT. PMID- 30520353 TI - Abstract 79: Chronic and Acute Hypertension in Ischemic Stroke Are Distinct Markers of Impaired Collateral Circulation. AB - BACKGROUND: Acute blood pressure (BP) elevation in acute ischemic stroke (AIS) is common, yet the link with collateral circulation remains elusive due to lack of longitudinal data on premorbid hypertension (HTN) and serial BP changes within an individual. Precision medicine for AIS and management of HTN requires an understanding of collateral circulation. METHODS: The Interventional Management of Stroke III angiography core lab prospectively evaluated collateral circulation utilizing the ASITN scale prior to endovascular therapy. We used these data to discern the relationship of clinical and imaging markers of premorbid HTN with acute, serial BP measures and collaterals. RESULTS: Collaterals at angiography were graded in 276/331 (83%) subjects. Higher initial BP was associated with impaired collateral status, driven by diastolic BP (ASITN 0-1: mean 88.9 +/- 23.5 mmHg (n=70); 2: 82.7 +/- 18.5 mmHg (n=106); 3-4: 79.4 +/- 15.0 mmHg (n=95); p=0.002) but not systolic BP (ASITN 0-1: mean 153.7 +/- 31.5 mmHg (n=71); 2: 147.8 +/- 29.0 mmHg (n=107); 3-4: 146.8 +/- 28.3 mmHg (n=95); p=0.153). Premorbid HTN was linked with worse collaterals (ASITN 0-1: 88.9% (64/72); 2: 78.7% (85/108); 3-4: 64.2% (61/95); p=0.001). Admission anti-hypertensive medications were tied to worse collaterals (ASITN 0-1: 76.4% (55/72); 2: 64.8% (70/108); 3-4: 57.3% (55/96); p=0.036). Prior infarction on baseline imaging was also a marker of worse collaterals (ASITN 0-1: 33.3% (24/72); 2: 24.3% (26/107); 3-4: 19.1% (18/94); p=0.039). Serial BP from pre-randomization to post-tPA, however, was unrelated to collateral status. Multivariate modeling to predict collateral grade revealed that history of HTN (OR 0.29 95%CI (0.13, 0.64); p=0.002) and diastolic BP measured post-stroke but pre-randomization (per 10 mm Hg) (OR 0.80 95%CI (0.69, 0.93); p=0.004) were both distinct markers of impaired collaterals. The poorest collaterals were seen in those with both history of HTN and acutely elevated BP. CONCLUSIONS: Chronic and acute HTN are both potent predictors of impaired collaterals in AIS. Understanding how HTN affects the structure and function of collaterals and response to acute BP changes is critical for future hypertensive management and collateral augmentation. PMID- 30520354 TI - Morphology and Habitats of the Hermit-Crab-Associated Calyptraeid Gastropod Ergaea walshi. AB - Ergaea walshi, a gastropod with a markedly flat shell, often lives inside empty snail shells occupied by hermit crabs. We investigated its lifestyle, shell growth pattern, and habitat preference for host hermit crabs and host snail shells. Four hundred sixteen snail shells, including 363 shells with hermit crabs and 53 empty shells, were collected from intertidal zones of sandy and muddy flats around Kii Peninsula, Japan. The specimens comprised seven hermit crab species occupying 24 shell species; E. walshi was harbored in 13.2% of snail shells with hermit crabs and 17.0% of those without hermit crabs. Although no preference was detected for particular species of hermit crab or snail shell, E. walshi preferred to live inside of snail shells with wider apertures used by comparatively bigger hermit crabs. This suggests that the occurrence of E. walshi was influenced by host size rather than host species. When looking at growth patterns, we found that the attached shell portion of E. walshi continued to be enlarged horizontally, while growth in shell height slowed at approximately 5.0 mm. The conspicuously flattened shell of E. walshi is considered as a growth pattern for adapting to the narrow space within the snail shell occupied by hermit crabs. Consistent with this idea, our comparison of shell growth patterns in 23 calyptraeid species showed that shell of E. walshi is the flattest in this family. PMID- 30520355 TI - Microclimate and Physiological Effects in the Roosts of Cave Dwelling Bats: Implications in Roost Selection and Conservation in Sarawak, Malaysian Borneo. AB - Bats play crucial ecological and economic roles. However, this group of mammals is largely threatened due to anthropogenic activities inside or around their caves. In the present study, we investigate the effects of cave microclimate and physiological parameters on bat roost preference in Fairy Cave Nature Reserve (Fairy Cave NR). The microclimate and physiological parameters including temperature ( degrees C), relative humidity (RH), light intensity (lux), air flow, passage dimension (m), roost height (m) and distance of roost from nearest entrance (m) were measured. Results showed that Emballonura monticola, Hipposideros diadema, Hipposideros larvatus and Penthetor lucasi roost in Fairy Cave NR. These bats can be distinguished by their colony size, roost posture, spatial arrangement and position of their roost. Penthetor lucasi makes up the largest colony in the bright zone, whereas E. monticola has the smallest colony, occupying the twilight zone throughout the cave. Members from the family Hipposideridae roost in the dark portion of the cave with zero light intensity. Emballonura monticola utilizes the hottest roost in the cave compared to the other microbats, whereas H. diadema inhabits the coolest roost. Physiological parameters such as light intensity, passage dimension, and distance from nearest entrance are significant parameters in roosting preferences. These parameters should be monitored to ensure the sustainability of not only the aforementioned species, but also other species that roost in nearby caves of Bau limestone (Wind Cave Nature Reserve: with 13 recorded species). PMID- 30520356 TI - Rhabdostylid Ciliates (Ciliophora, Peritrichia, Epistylididae) as Epibionts on Chironomid Larvae: Evidence of High Specificity and Association with Organic Pollution. AB - Although epibiont ciliates make up a significant part of the biomass in aquatic ecosystems and may cause perceptible alterations in the population dynamics of their hosts, studies on the extrinsic and intrinsic factors that control the abundance of these microorganisms are scarce in literature. In the present study, we investigated the colonization site and intensity of rhabdostylid epibiont upon chironomid larvae and assessed the influence of organic pollution and chironomid communities on the prevalence and abundance of epibiont ciliates at five sampling stations (two in rural areas and three in urban areas) along a neotropical urban stream over a period of 12 months. Among the 24 genera of chironomids found and the 31,976 larvae analyzed, 96.12% belonged to the Chironomus genus, of which 16.95% (5212) were colonized by Rhabdostyla aff. chironomi. The infestation intensity varied from one to 67 individuals per host with an average intensity of 4.86 (+/- 33.45). Ciliates were only found colonizing the chironomids' ventral tubules. The high number of chironomid larvae, high host- and site-specificity, low infestation intensity, and absence of apparent structural damage to hosts evidence an intimate relationship between epibiont and basibiont as well as a possibly long coevolutionary history. Both prevalence and abundance of epibiont ciliates were correlated to the pollution rate of the studied stream. There was an alteration in the composition and structure of the chironomid community along the sampling stations. Numeric dominance of Chironomus-tolerant chironomids and its direct correlation to infestation prevalence and to ciliates abundance highlights the predilection of both peritrich ciliates and Chironomus larvae for organically-enriched environments. PMID- 30520357 TI - How Snakes Find Prey Underwater: Sea Snakes Use Visual and Chemical Cues for Foraging. AB - Fully aquatic adaptation generally leads amniotes to change sensory modalities drastically. Terrestrial snakes rely heavily on chemical cues to locate and recognize prey, but little is known about how sea snakes find prey fishes underwater. Sea snakes of the genus Hydrophis are fish-eating marine elapids which adapted from land to water approximately 5-10 million years ago. Here, using two species of captive Hydrophis snakes, we show that they can recognize and discriminate their preferred fish species solely by using olfactory cues. However, they locate places where their preferred fishes may hide without relying on chemical cues. These findings indicate that Hydrophis snakes find prey in water as follows: they use visual cues to locate a place where their prey fishes are likely to hide, and then use chemical cues to find and attack prey. As is the case for other aquatic amniotes, snakes also modified their sensory modalities upon becoming aquatic. PMID- 30520358 TI - Males with More Pheomelanin Have a Lower Oxidative Balance in Asian Barn Swallows (Hirundo rustica gutturalis). AB - Pheomelanin-based plumage pigmentation has been suggested to be an honest signal of individual quality to conspecifics. It has been hypothesized that oxidative stress is an important agent linking pheomelanic pigmentation to individual quality. Using the Asian barn swallow Hirundo rustica gutturalis, a wild passerine, we tested whether the pheomelanin pigmentation in the red throat patch of adult males, a sexually selected trait, is associated with the ratio between reduced and oxidized glutathione (RGSH/GSSG) as an indicator of current oxidative balance during the early breeding season. We found that males with a higher pheomelanin concentration in their throat feathers had a significantly lower RGSH/GSSG ratio (i.e., higher oxidative stress), but exhibited a better body condition, measured as residual body mass on body size, compared to males with a lower pheomelanin concentration. The total GSH level was not significantly related to the pheomelanin concentration. These findings suggest a negative association between the red pheomelanin pigmentation and oxidative balance during mating and reproductive efforts, which might be mitigated by high-quality males. Further research is needed to understand its actual damage and mitigation mechanism. PMID- 30520359 TI - Total Non-Consumptive Effects of Fish on Pelobates fuscus and Hyla orientalis Tadpoles in Pond Enclosure Experiments. AB - Most research on non-consumptive predator effects on amphibian larvae has been conducted in laboratory or mesocosm designs. Here, Pelobates fuscus and Hyla orientalis tadpoles were separately exposed to non-lethal (free-moving, but with tied mouthparts) common carp Cyprinus carpio for one week in enclosures placed in a pond densely stocked with fish. Tadpoles exposed to nonlethal fish did not differ in mortality, body mass, or, except for deeper tail fin depth in P. fuscus, morphological plasticity from controls kept in a fishless pond. Hyla orientalis tadpoles recovered from the fish treatment were subsequently enclosed until metamorphosis in either the pond with fish or the fishless pond. Metamorphs from the pond containing fish were heavier, and did not differ in survivorship or development time from their counterparts initially kept in the fish treatment and then transferred to the fishless pond or from controls kept the entire time under fish-free conditions. The lack of apparent metamorphic costs is consistent with previous experiments on anuran larvae, but the morphological defenses induced (or their absence) are not. In the fish-dominated pond, carp indirectly affected tadpole developmental responses by generating turbidity, through adverse impacts on submerged vegetation and predatory insects, and by increasing food resource (unicellular algae) levels. While the present study does not question the validity of laboratory and mesocosm experiments on the costs of non-consumptive predator effects on amphibian larvae, their outcomes cannot easily be extrapolated to ecologically complex natural habitats. PMID- 30520360 TI - Structural and Mass Spectrometric Imaging Analyses of Adhered Tunic and Adhesive Projections of Solitary Ascidians. AB - Most ascidian species settle on underwater substrates during a short free swimming tadpole larval period. During this process, "rapid adhesion" occurs on adhesive papillae located at the anterior region of the cephalenteron. Settled and transformed ascidians subsequently expand the attachment area by "slow adhesion" with ampullae. In the present study, we attempted to identify the ultrastructures related to the adhesion process and adhesive materials in the ascidian tunic and to elucidate the biological function of vanadium in adhesion. We focused on an adhesive organ named the adhesive projection, which is newly generated by the adhered tunic to enlarge the bonding area between ascidian and substrate. Based on its structure and the presence of vanadiumcontaining blood cells, the adhesive projection was considered to be a large tunic vessel. At the adhered tunic, eosinophilic regions and migrated tunic cells were observed, but metal deposition was not detected. We speculate that the eosinophilic materials were components of the adhesive glue, and these are likey produced in epithelial cells, tunic cells, or both. Furthermore, using imaging mass spectrometry, we identified eight tunic-specific molecules as glue candidates. PMID- 30520361 TI - Measurement of Tunic Hardness in an Edible Ascidian, Halocynthia roretzi, with Remarks on Soft Tunic Syndrome. AB - The infection caused by a kinetoplastid flagellate, Azumiobodo hoyamushi, in an ascidian, Halocynthia roretzi, results in softening of the tunic, and finally death. This disease is usually recognized using palpation of the softening tunic, and A. hoyamushi infection is detectable using microscopy or PCR amplification of specific gene fragments. The present study is the first quantitative evaluation of the symptoms of soft tunic syndrome by measuring the amount of bending (bending) and the peak force required to pierce the tunic (force). There was a strong correlation between bending and force. Correlation analyses among other parameters (ascidian total weight, tunic thickness, and tunic water content) indicated that larger ascidians had harder and thicker tunics with a higher water content. As compared to the tunic of healthy individuals, softened tunic was thinner and had lower water content. Infected tunics thus possibly lose water and become softer and thinner. Mechanisms for maintaining the appropriate water level content may be crucial for preventing tunic softening. PMID- 30520362 TI - Molecular Characterization and Tissue Distribution of Mitochondrial Ca2+ Dependent Solute Carrier Protein during Prevention of Diapause by HCl Treatment in the Silkworm, Bombyx mori. AB - To clarify the molecular mechanism of prevention of entry into diapause in Bombyx mori by HCl treatment, we biochemically analyzed mitochondrial Ca2+ -dependent solute carrier protein (MCSC) in diapause eggs treated with HCl solution. Our previous studies revealed that HCl treatment causes Ca2+ to efflux from diapause eggs. Therefore, we attempted to analyze MCSC, which is known to associate with Ca2+ . The isolated cDNA of B. mori MCSC (BmMCSC) had an open reading flame (ORF) of 667 amino acid residues, and the ORF contained two EF-hand calcium-binding domains and three characteristic features of the mitochondrial solute carrier superfamily. The gene expression level of BmMCSC increased by HCl treatment. A Ca2+ binding assay indicated that recombinant BmMCSC (rBmMCSC) shows an affinity with Ca2 + . The distribution of BmMCSC was investigated with an immunohistochemical technique using antisera against BmMCSC in diapause eggs and HCl-treated diapause eggs. BmMCSC was localized in serosa cells in both eggs. These data may suggest that BmMCSC is activated by intracellular Ca2+ or efflux Ca2+ by HCl treatment, and that it plays a role in the molecular mechanisms of artificial diapause prevention or the breaking of diapause in the silkworm. PMID- 30520363 TI - Follicular Development and Reproductive Characteristics in Four Species of Brazilian Tropidurus Lizards. AB - The follicular development and reproductive characteristics of four species of oviparous lizards in the Tropidurus torquatus group were anatomically and histologically evaluated. We measured specimens, recorded the number of follicles and eggs, and removed the right ovary of each individual, which we processed according to histological routine and photo-documented. For all species, ovaries were divided into a cortical germinal bed, where oogonia and stage I oocytes are located, and a medullar stroma, where the remaining follicular developmental stages occur. Microscopic analysis did not show differences in ovarian follicle development for the four species of the T. torquatus group. The only measurement that presented significant variation throughout follicular development was the thickness of the granulosa layer in stage VII follicles. Regarding snout-tovent length at sexual maturity, few variations were observed among the species, with the smallest length recorded for T. oreadicus. Clutch size was higher for T. itambere and T. torquatus species, with a maximum of five and six eggs in the oviducts, respectively. Tropidurus oreadicus and T. hispidus had a maximum of five and six follicles, respectively, but neither species presented eggs in the oviducts. In addition, the reproductive activity varied among the four lizard species of the T. torquatus group. Finally, besides the morphological characteristics observed among these species, this is the first study to report data on the germinal bed, number of ovarian follicles, corpus luteum, and follicular atresia in relation to reproductive activity. PMID- 30520364 TI - Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. AB - AIM: To conducted a systematic review and meta-analysis of prospective, randomized controlled trials (RCTs) that examined pharmacogenetic-guided decision support tools (DSTs) relevant to depressive symptom remission in major depressive disorder (MDD). PATIENTS & METHODS: Random-effects meta-analysis was performed on RCTs that examined the effect of DSTs on remission rates in MDD. RCT quality was assessed using the Cochrane Collaboration Criteria. RESULTS & CONCLUSION: A total of 1737 eligible subjects from five RCTs were examined. Individuals receiving pharmacogenetic-guided DST therapy (n = 887) were 1.71 (95% CI: 1.17-2.48; p = 0.005) times more likely to achieve symptom remission relative to individuals who received treatment as usual (n = 850). Pharmacogenetic-guided DSTs might improve symptom remission among those with MDD. PMID- 30520365 TI - Preoperative Myocardial Troponin T Elevation is Associated with the Fracture Type in Patients with Proximal Femoral Fracture. AB - BACKGROUND AND AIMS:: Cardiovascular complications are common in hip fracture patients but the role of fracture type and operative method in these is unclear. This prospective cohort study aimed to evaluate the impact of fracture- and operative characteristics on perioperative cardiovascular complications and prognosis in unselected hip fracture patients. MATERIAL AND METHODS:: During a 7 month trial registration period, a population of 197 consecutive hip fracture patients (median age 84 years) diagnosed with femoral neck or pertrochanteric fracture was formed. The exclusion criteria were patient refusal, subtrochanteric fracture, or death preoperatively. Pre- and postoperative troponin T (TnT) elevation, perioperative N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP) level, perioperative cardiovascular adverse events, and all-cause 30 day and 2- and 5-year mortalities were studied. RESULTS:: Femoral neck fracture was independently associated with preoperative myocardial injury witnessed by TnT elevation (HR 2.95, 95% confidence interval 1.21-7.19, p = 0.018). The fracture type, surgery delay, or operative method were not significantly associated with NT-proBNP levels, cardiovascular adverse event diagnoses, or prognosis. Cardiovascular adverse events were clinically diagnosed in 28 (14%) participants, and these had a higher mortality compared to participants without such diagnosis (at 30 days, 32% vs 5%; 2 years, 71% vs 31%; and 5 years, 86% vs 59%; p < 0.001). CONCLUSION:: While the femoral neck fracture independently predicts preoperative cardiovascular morbidity, the operative method does not affect perioperative cardiovascular complications or the prognosis, and it may be selected by the treating clinician based on other criteria. PMID- 30520366 TI - The Association Between Concussions and Suicidal Behaviors. AB - While there is increasing evidence on the long-term risks associated with concussions, the association between hopelessness, suicidal ideation, suicidal planning and suicidal attempts in high school aged adolescents has not yet been explored. The current study aims to estimate the association between concussions and suicidal behaviors in Utah high school students. We analyzed the 2013 Utah Youth Risk Behavior Survey (YRBS), a state, representative survey of 2,195 9th through 12th grade high school students. Bivariate and multivariable logistic regressions controlling for race/ethnicity, sex, grade, and alcohol use were conducted to evaluate the adjusted odds ratio and 95% confidence interval (CI) of suicidal behaviors comparing students exposed to one or more concussions to those unexposed. Students with self-reported concussion exposure had significantly greater odds of reporting feeling sad or hopeless (OR=1.7; 95% CI 1.4, 2.2), suicidal ideations (AOR=2.0; 95% CI 1.4, 2.7), suicidal planning (AOR=2.0; 95% CI 1.4, 2.8) and suicidal attempts (OR=2.3; 95% CI 1.4, 3.7) after controlling for grade, sex, race and alcohol-use. Results from this study suggest that high school students who have suffered from a concussion are more likely to report suicidal behaviors, compared to high school students who did not report a concussion. Given the results, concussion prevention education efforts in high schools are warranted. In addition, it's imperative to educate parents, teachers, and health professionals how to recognize a concussion and any possible mental health outcomes as a result. Future longitudinal research is needed to better understand temporality of this association. PMID- 30520367 TI - 3D Printing Methods for Pharmaceutical Manufacturing: Opportunity and Challenges. AB - BACKGROUND: A recently FDA approved 3D printed drug is paving a path for new pharmaceutical manufacturing era. The 3D printing is a novel approach of producing 3D pharmaceuticals from digital designs, in a layer-by-layer fashion. However, traditional manufacturing of drug products are being carried out from decades with well-established manufacturing processes and with well approved regulatory guidelines but these processes are too obsolete in concern of process aptitude and manufacturing flexibility. On the other hand, 3D printing provides a competitive flexibility in terms of personalized drug dosage forms with complex geometries that will be made on-demand with desired drug release kinetics, hence providing the formulator a substantial provision of improvising the safety and efficacy of the drugs. Furthermore, this novel 3D technology allows tailoring of composite tissue scaffolds and sample models for characterization that closely mimic in-vivo simulations. Nevertheless, certain limitations are there in terms of regulatory aspects hindering the launch of 3DP products in the market. METHODS: Exhaustive search were made on Google Scholar and PubMed databases concerning 3-D printing methods, drug delivery applications, and past to present evolution of personalized medicine. RESULTS: Although a high magnitude of progress have been made on 3-D printing techniques in a short span of time, still inkjet, nozzle-based deposition, stereolithography and selective laser sintering techniques are the most popular one. Their application is adapted in the fabrication of tablets, implants, polypills and nanoparticles. CONCLUSION: 3D printing is revolutionizing the pharma expectations towards customized medicines but still there is a need to explore the aspects of cost, flexibility and bioequivalence. The present review provides a comprehensive account of various 3D printing technologies and highlights the opportunities and key challenges of 3D printing relevant to pharmaceuticals. PMID- 30520368 TI - 3D printing Technology in drug delivery: Recent progress and Application. AB - BACKGROUND: 3D printing technology is a new chapter in pharmaceutical manufacturing and has gained vast interest in the recent past as it offers significant advantages over traditional pharmaceutical processes. Advances in technologies can lead to design of suitable 3D printing device capable of producing formulations with intended drug release. METHODS: This review summarizes the applications of 3D printing technology in various drug delivery systems. The applications are well arranged in different sections like uses in personalized drug dosing, complex drug-release profiles, personalized topical treatment devices, novel dosage forms and drug delivery devices and 3D printed polypills. RESULTS: This niche technology seems to be a transformative tool with more flexibility in pharmaceutical manufacturing. Typically, 3D printing is a layer-by layer process having the ability of fabricating 3D formulations by depositing the product components by digital control. This additive manufacturing process can provide tailored and individualized dosing for treatment of patients different backgrounds with varied customs and metabolism pattern. In addition, this printing technology has the capacity for dispensing low volumes with accuracy along with accurate spatial control for customized drug delivery. After the FDA approval of first 3D printed tablet Spritam, the 3D printing technology is extensively explored in the arena of drug delivery. CONCLUSION: There is enormous scope for this promising technology in designing various delivery systems and provide customized patient compatible formulations with polypills. The future of this technology will rely on its prospective to provide 3D printing systems capable of manufacturing personalized doses. In nutshell, the 3D approach is likely to revolutionize drug delivery systems to a new level, though need time to evolve. PMID- 30520369 TI - A critical review on 3D-printed dosage forms. AB - BACKGROUND: In the last decades, 3D-printing has been investigated and used intensively in the field of tissue engineering, automotive and aerospace. With the first FDA approved printed medicinal product in 2015, the research on 3D printing for pharmaceutical application has attracted attention of pharmaceutical scientists. Due to its potential of fabricating complex structures and geometrics, it is a highly promising technology for manufacturing individualized dosage forms. In addition, it enables the fabrication of dosage forms with tailored drug release profiles. OBJECTIVE: The aim of this review article is to give a comprehensive overview of the used 3D-printing techniques for pharmaceutical applications, including information about the required material, advantages and disadvantages of the respective technique. METHODS: For the literature research, relevant key words were identified and the literature was then thoroughly researched. CONCLUSION: The current status of 3D-printing as a manufacturing process for pharmaceutical dosage forms was highlighted in this review article. Moreover, this article presents a critical evaluation of 3D printing to control the dose and drug release of printed dosage forms. PMID- 30520370 TI - The Applications of 3d Printing in Pulmonary Drug Delivery and Treatment of Respiratory Disorders. AB - BACKGROUND: Pulmonary diseases are the third leading cause of morbidity worldwide, however treatment and diagnosis of these diseases continues to be challenging due to the complex anatomical structure as well as physiological processes in the lungs. METHODS: 3D printing is progressively finding new avenues in the medical field and this technology is constantly being used for diseases where diagnosis and treatment heavily rely on the thorough understanding of complex structural-physiology relationships. The structural and functional complexity of the pulmonary system makes it well suited to 3D printing technology. RESULTS: 3D printing can be used to deconstruct the complex anatomy of the lungs and improve our understanding of its physiological mechanisms, cell interactions and disease pathophysiology. Thus, this technology can be quite helpful in the discovery of novel therapeutic targets, new drugs and devices for the treatment of lung diseases. CONCLUSION: The intension of this review is to detail our current understanding of the applications of 3D printing in the design and evaluation of inhalable medicines and to provide an overview on its application in the diagnosis and treatment of pulmonary diseases. This review also discusses other technical and regulatory challenges associated with the progression of 3D printing into clinical practice. PMID- 30520371 TI - A network integration method for deciphering the types of metabolic pathway of chemicals with heterogeneous information. AB - AIM AND OBJECTIVE: A metabolic pathway is an important type of biological pathway, which is composed of a series of chemical reactions. It provides essential molecules and energies for living organisms. To date, several metabolic pathways have been uncovered. However, their completeness is still on the way. A number of prediction methods have been built to assign chemicals into certain metabolic pathway, which can further be used to predict novel latent chemicals for a given metabolic pathway. However, they did not make use of chemical properties in a system level to construct prediction models. METHOD: In this study, we applied a network integration method, which can extract topological features from different chemical networks, representing chemical associations from their different properties, and fused several high-dimension vector representations into a low-dimension vector representation for each chemical. The compact vector representations were fed into the support vector machine (SVM) to construct the prediction model. To tackle the problem that one chemical can participate in more than one pathway type, we construct an SVM-based binary prediction model for each pathway type to determine whether a given chemical can participate in the pathway type. Furthermore, the Synthetic Minority Over sampling Technique (SMOTE) was adopted to weaken the influence of imbalanced dataset. RESULTS AND CONCLUSION: Each binary model gave a quite good performance and was superior to the classic prediction model, indicating that the proposed models can be useful tools for integrating heterogeneous information to assign chemicals into correct metabolic pathways. PMID- 30520372 TI - Cranberry consumption against urinary tract infections: Clinical state-of-the-art and future perspectives. AB - INTRODUCTION: Urinary tract infections (UTIs) represent a common and costly public health issue. The bacterium Escherichia coli is mainly responsible for most uncomplicated UTIs. Cranberry antibacterial effects have extensively been studied in order to understand the molecular mechanisms of action of its bioactive components and their clinical benefits against UTIs. In this aspect, the present review aims to critically analyze the current clinical studies that have evaluated the efficacy of supplementing cranberry products against UTIs in different subpopulations. METHODS: PubMed database was comprehensively searched, using relative keywords in order to identify clinical trials exploring the efficacy of cranberry supplementation against UTIs. RESULTS: Current clinical evidence clearly indicates a possible benefit overall from the use of cranberries against UTIs. Cranberry consumption may prevent bacterial adherence to uroepithelial cells, reducing UTI related symptoms. Cranberry consumption could also decrease UTI related symptoms by suppressing inflammatory cascades as an immunologic response to bacteria invasion. The existing clinical trials have supported substantial evidence that the beneficial effects of cranberry against UTIs seem to be prophylactic by preventing infections recurrence; however, they exert low effectiveness in populations at increased risk for contracting UTIs. Moreover, a lack of cost-effectiveness for cranberry supplementation has been highlighted. CONCLUSIONS: Additional well-designed, double-blind, placebo controlled clinical trials that use standardized cranberry products for long study periods are strongly recommended in order to determine the efficiency of cranberry on the prevention of UTIs in susceptible populations. At present, cranberry supplementation can safely be suggested as complementary therapy in women with recurrent UTIs. . PMID- 30520373 TI - Mesoporous silica nanoparticles as a prospective and promising approach for drug delivery and biomedical applications. AB - BACKGROUND: With the development of nanotechnology, nanocarrier has widely applied in such fields as drug delivery, diagnostic and medical imaging and engineering in recent years. Among all of the available nanocarrier, mesoporous silica nanoparticles (MSNs) have become a hot issue because of their unique properties, such as large surface area and voidage, tunable drug loading capacity and release kinetics, good biosafety and easily modified surface. OBJECTIVES: We described the most recent progress in silica-assisted drug delivery and biomedical applications according to different types of Cargo in order to allow researchers to quickly learn about of the advance in this field. METHODS: Information has been collected from the recently published literature available mainly through Title or Abstract search in SpringerLink and PubMed database. Special emphasis on the literature available during 2008-2017. RESULT: In this review, the major research advances of MSNs on the drug delivery and biomedical applications were summarized. The significant advantages of MSNs have aslo been listed. It was found that the several significant challenges need to be addressed and investigated to further advance the applications of these structurally defined nanomaterials. CONCLUSION: Through approaching to this review, the researchers can be aware of many new synthetic methods, smart designs proposed in recent year and remained question of MSNs at present. PMID- 30520374 TI - Application of the Co-Agonist Concerted Transition Model to Analysis of GABAA Receptor Properties. AB - The co-agonist concerted transition model is a simple and practical solution to analyzing various aspects of GABAA receptor function. Several model-based predictions have been verified experimentally in previous reports. We review here the practical implications of the model and demonstrate how it enables simplification of the experimental procedure and data analysis to characterize the effects of mutations or properties of novel ligands. Specifically, we show that the value of EC50 and the magnitude of current response are directly affected by basal activity, and that coapplication of a background agonist acting at a distinct site or use of a gain-of-function mutation can be employed to enable studies of weak activators or mutated receptors with impaired gating. We also show that the ability of one GABAergic agent to potentiate the activity elicited by another is a computable value that depends on the level of constitutive activity of the ion channel and the ability of each agonist to directly activate the receptor. Significantly, the model accurately accounts for situations where the paired agonists interact with the same site compared to distinct sites on the receptor. PMID- 30520375 TI - Neuroprotective role of hypothermia in hypoxic-ischemic brain injury: combined therapies using estrogen. AB - Hypoxic-ischemic brain injury is a complex network of factors, which is mainly characterized by a decrease in levels of oxygen concentration and blood flow, which lead to an inefficient supply of nutrients to the brain. Hypoxic-ischemic brain injury can be found in perinatal asphyxia and ischemic-stroke, which represent one of the main causes of mortality and morbidity in children and adults worldwide. Therefore, knowledge on underlying mechanisms triggering these insults may help establish neuroprotective treatments. Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators exert several neuroprotective effects, including decrease of reactive oxygen species, maintenance of cell viability, mitochondrial survival, among others. However, these strategies represent a traditional approach of targeting a single factor of pathology without satisfactory results. Hence, combined therapies, such as the administration of therapeutic hypothermia with a complementary neuroprotective agent, constitute a promising alternative. In this sense, the present review summarizes the underlying mechanisms of hypoxic-ischemic brain injury and compiles several neuroprotective strategies, including Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators, which represent putative agents for combined therapies with therapeutic hypothermia. PMID- 30520376 TI - Sense of Smell: Structural, Functional, Mechanistic Advancements and Challenges in Human Olfactory Research. AB - Olfaction, the sense of smell detects and discriminate odors as well as social cues which influence our innate responses. The olfactory system in human beings is found to be weak as compare to other animals; however, it seems to be very precise. It can detect and discriminate millions of chemical moieties (odorants) even in minuscule quantities. The process initiates with the binding of odorants to specialized olfactory receptors, encoded by a large family of Olfactory Receptor (OR) genes belonging to the G-protein-coupled receptor superfamily. Stimulation of ORs converts the chemical information encoded in the odorants, into respective neuronal action-potentials which causes depolarization of olfactory sensory neurons. The olfactory bulb relays this signal to different parts of the brain for processing. Odors are encrypted using a combinatorial approach to detect a variety of chemicals and encode their unique identity. The discovery of functional OR genes and proteins provided an important information to decipher the genomic, structural and functional basis of olfaction. ORs constitute of 17 gene families, out of which 4 families were reported to contain more than hundred members each. The olfactory machinery is not limited to GPCRs; a number of non-GPCRs is also employed to detect chemosensory stimuli. The article provides detailed information about such olfaction machinery, structures, transduction mechanism, theories of odor perception, and challenges in the olfaction research. It covers the structural, functional and computational studies carried out in the olfaction research in the recent past. PMID- 30520377 TI - M918: A novel cell penetrating peptide for effective delivery of HIV-1 Nef and Hsp20-Nef proteins into eukaryotic cell lines. AB - BACKGROUND: HIV-1 Nef protein is a possible attractive target in development of therapeutic HIV vaccines including protein-based vaccines. The most important disadvantage of protein-based vaccines is their low immunogenicity which can be improved by heat shock proteins (Hsps) as an immunomodulator, and cell penetrating peptides (CPPs) as a carrier. METHODS: In this study, the HIV-1 Nef and Hsp20-Nef proteins were generated in E.coli expression system for delivery into the HEK-293T mammalian cell line using a novel cell penetrating peptide, M918, in a non-covalent fashion. The size, zeta potential and morphology of the peptide/protein complexes were studied by scanning electron microscopy (SEM) and Zeta sizer. The efficiency of Nef and Hsp20-Nef transfection using M918 was evaluated by western blotting in HEK-293T cell line. RESULTS: The SEM data confirmed the formation of discrete nanoparticles with a diameter of approximately 200-250 nm and 50-80 nm for M918/Nef and M918/Hsp20-Nef, respectively. The dominant band of ~ 27 kDa and ~ 47 kDa was detected in the transfected cells with the Nef/ M918 and Hsp20-Nef/ M918 nanoparticles at molar ratio of 1:20 using anti-HIV-1 Nef monoclonal antibody. These bands were not detected in the un-transfected and transfected cells with Nef or Hsp20-Nef protein alone indicating that M918 could increase the penetration of Nef and Hsp20-Nef proteins into the cells. CONCLUSION: These data suggest that M918 CPP can be used to enter HIV-1 Nef and Hsp20-Nef proteins inside mammalian cells efficiently as a promising approach in HIV-1 vaccine development. PMID- 30520378 TI - The Effect of MSM and CD4+ Count on the Development of Cancer AIDS (AIDS-defining Cancer) and Non-cancer AIDS in the HAART Era. AB - BACKGROUND: The HIV epidemic is increasing among Men who have Sex with Men (MSM) and the risk for AIDSdefining cancer (ADC) is higher among them. OBJECTIVE: To examine the effect of MSM and CD4+ count on time to cancer AIDS (ADC) and non cancer AIDS in competing risks setting in the HAART era. METHOD: Using Ontario HIV Treatment Network Cohort Study data, HIV-positive adults diagnosed between January 1997 and October 2012 having baseline CD4+ counts <= 500 cells/mm3 were evaluated. Two survival outcomes, cancer AIDS and non-cancer AIDS, were treated as competing risks. Kaplan-Meier analysis, Cox cause-specific hazards (CSH) model and joint modeling of longitudinal and survival outcomes were used. RESULTS: Among 822 participants, 657 (79.9%) were males; 686 (83.5%) received anti retroviral (ARV) ever. Regarding risk category, the majority (58.5%) were men who have Sex with men (MSM). Mean age was 37.4 years (SD = 10.3). In the multivariate Cox CSH models, MSM were not associated with cancer AIDS but with non-cancer AIDS [HR = 2.92; P = 0.055, HR = 0.54; P = 0.0009, respectively]. However, in joint models of longitudinal and survival outcomes, MSM were associated with cancer AIDS but not with non-cancer AIDS [HR = 3.86; P = 0.013, HR = 0.73; P = 0.10]. CD4+ count, age, ARV ever were associated with both events in the joint models. CONCLUSION: This study demonstrates the importance of considering competing risks, and time-dependent biomarker in the survival model. MSM have higher hazard for cancer AIDS. CD4+ count is associated with both survival outcomes. PMID- 30520379 TI - Capitate and Lunate Morphology in Normal Wrist Radiographs-A Pilot study. AB - Morphology may provide the basis for the understanding of wrist mechanics. We used classification systems based on cadaver dissection of lunate and capitate types to evaluate a normal database of 70 wrist radiographs in 35 subjects looking for associations between bone shapes. Kappa statistics and a log-linear mixed -effects model with a random intercept were used. There were 39 type-1, 31 type- 2 lunates, 50 spherical, 10 flat and 10 V- shaped capitates. There was a significant difference in lunate and capitate shape between the hands of the same individual p <0.001. This may be due to different loads on the dominant vs. nondominant hands in the same individual. Further study to better understand the development of radiographic parameters of the midcarpal joint may aid in our understanding of the morphology and mechanics of the wrist. PMID- 30520380 TI - Extensively thrombosed ectatic circumflex coronary artery fistula presenting as acute coronary syndrome. AB - BACKGROUND: Coronary artery fistula (CAF) is an abnormal communication between the termination of a coronary artery or its branches and a cardiac chamber, a great vessel or other vascular structure. Symptomatic patients with large CAF should undergo surgical or percutanous closure of the fistula at the drainage site while still the debate on closing asymptomatic CAF and re-openening symptomatic occluded CAF is ongoing. CASE SUMMARY: We are reporting a 30-year-old male patient with no previous medical history presented as non-ST segment elevation myocardial Infarction. Coronary angiography showed an entirely thrombosed ectatic circumflex artery with a suspicion of thrombosed coronary arterial fistula. In view of ongoing ischemia in the setting of acute coronary syndrome; we tried to open percutaneously but all efforts were to no avail. DISCUSSION: In this case report, we are sharing our experience in management of this challenging case in view of the rarity of such peculiar clinical condition and the unfavourable presentation along with the lack of clear-cut Guideline and Consensus whether to/not to open such huge and immensely thrombosed symptomatic coronary artery fistula as well as the dilemma of choosing the best long-term medical treatment between antiplatelets vs anticoagulants in such young patient. PMID- 30520381 TI - Synthesis, Characterization, Antibacterial and Antioxidant Potency of N Substituted-2-Sulfanylidene-1,3-Thiazolidin-4-one Derivatives and QSAR Study. AB - BACKGROUND: Rhodanine is known for its potential and important role in the medicinal chemistry since its derivatives exhibit a wide range of pharmacological activities such as antibacterial, antifungal, antidiabetic, antitubercular, anti HIV, antiparasitic, antioxidant, anticancer, anti-proliferative and anthelmintic agents. OBJECTIVES: Since N-substituted rhodanine synthons are rarely commercially available, it is desirable to develop a straight forward synthetic approach for the synthesis of these key building blocks. The objective was to synthesize a series of rhodanine derivatives and to investigate their antimicrobial and antioxidant activity. Also, in order to obtain an insight into their structure-activity relationship QSAR studies on the antioxidant activity were performed. METHODS: 1H and 13C FTNMR spectra were recorded on Bruker Avance 600 MHz NMR Spectrometer, mass analysis were carried out on ESI+ mode by LC-MS/MS API 2000. 2,2-Diphenyl-1-picrylhydrazyl radical scavenging activity (% DPPH) was determined in dimethylsulfoxide (DMSO) as a solvent. The antibacterial activity was assessed against Bacillus subtilis, Staphylococcus aureus (Gram positive) and Escherichia coli, Pseudomonas aeruginosa (Gram negative) bacteria in terms of the minimum inhibitory concentrations (MICs) by a modified broth microdilution method. RESULTS: A series of N-substituted-2-sulfanylidene-1,3-thiazolidin-4-ones were synthesized and characterized by 1H NMR, 13C NMR, FTIR, GC MS, LCMS/MS and C,H,N,S elemental analysis. Most of the synthesized compounds showed moderate to excellent antibacterial activity (MIC values from 125 ug/ml to 15.62 ug/mL) and DPPH scavenging activity (from 3.60% to 94.40%). Compound 2-thioxo-3-(4 (trifluoromethyl)phenyl)thiazolidin-4-one showed the most potent activity against Escherichia coli (3.125 ug/mL), equivalent to antibiotic Amikacin sulphate and against Staphylococcus aureus (0.097 ug/ml), 100 times superior then antibiotic Amikacin sulphate. It has also shown a potent antioxidant activity (95% DPPH scavenging). Two best QSAR models, obtained by GETAWAY descriptor R7p+, Balabans molecular connectivity topological index and Narumi harmonic topological index (HNar), suggest that the enhanced antioxidant activity is related to the presence of pairs of atoms higher polarizability at the topological distance 7, substituted benzene ring and longer saturated aliphatic chain in N-substituents. CONCLUSION: A series of novel N-substituted-2-thioxothiazolidin-4-one derivatives were designed, synthesized, characterized and evaluated for their antibacterial and antioxidant activity in vitro. Majority of the compounds showed excellent antibacterial activity compared to ampicillin and few of them have an excellent activity as compared to Chloramphenicol standard antibacterial drug. The QSAR study has clarified the importance of presence a pairs of atoms higher polarizability, such as Cl and S at the specific distance, as well as the substituted benzene ring and a long saturated aliphatic chain in N-substituents for the enhanced antioxidant activity of 2-sulfanylidene-1,3-thiazolidin-4-one derivatives. PMID- 30520382 TI - Evaluation of Cytotoxic Potentials of Some Isoindole-1,3-Dione Derivatives on HeLa, C6 and A549 Cancer Cell Lines. AB - BACKGROUND: Norcantharimides are known as norcantharidine derivatives and contain an isoindole skeleton structure. Isoindole derivatives have positively effect on inflammatory pathologies including cancers. OBJECTIVE: Considering this information, firstly, isoindole derivatives containing different functional groups 4-13 have been synthesized from 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1H isoindole-1,3(2H)-dione. METHODS: For the synthesis of all compounds, 2 alkyl/aryl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione was used as the starting compound. The syntheses were based on two main reactions: Ene-reaction of singlet oxygen and epoxidation. Second, their anticancer activities were evaluated against HeLa, C6 and A549 cancer cell lines by the BrdU assay. RESULTS: Anticancer activities of synthesized compounds (4-13) and 5-FU (5-Florouracil) against HeLa, C6 and A549 cells were investigated at four concentrations (100, 50, 25 and 5 uM). IC50 values of compounds 4-13 were calculated for all cancer cell lines. The investigated compounds showed an anticancer activity against the cancer cell lines depending on doses. Compound 7 containing azide and silyl ether exhibited higher inhibitory activity than the other compounds and 5-FU against A549 cancer cell lines (IC50 =19.41+/- 0.01 uM). Compounds 9 and 11 were determined to exhibit cell-selective activity against HeLa cancer cell lines. Compound 11 had higher activity than the positive control at 100 uM concentration against the C6 cancer cell lines. CONCLUSION: According to the results found, isoindole derivatives 7, 9, and 11 might be good potential anticancer agents for the treatment of cervical and glioma cancer due to their antiproliferative properties, having less cytotoxic effects on healthy cells. In addition, compound 7 could be used in in vivo studies of all three cancer cell lines (C6, HeLa, and A549). PMID- 30520383 TI - Advanced Non Small Cell Lung Cancer with activating Epidermal Growth Factor Receptor mutation: First line treatment and beyond. AB - BACKGROUND: Lung cancer is the leading cause of cancer mortality, being responsible for more than 1.6 million deaths each year worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers; moreover, 10 to 15% of all NSCLCs harbors EGFR (epidermal growth factor receptor) activating mutations, being suitable for EGFR-Tyrosine Kinase Inhibitors (TKI) molecular targeted therapy. However, EGFR+ NSCLCs gain acquired resistance to these agents, representing one of the key challenges for modern precision oncology. OBJECTIVE: Therefore, this paper aims to provide an extensive state of the art review, alongside with hints about future perspectives. CONCLUSION: To date, in the light of the data from the FLAURA study, osimertinib represents the best first line option in NSCLC patients with EGFR activating mutations; EGFR-TKI plus chemotherapy combination therapies, even though interesting, must still be considered investigational. PMID- 30520384 TI - Target discovery for new antitubercular drugs using a large dataset of growth inhibitors from PubChem. AB - The number of drugs available for treatment of active tuberculosis are diminishing due to increased multidrug resistance selection in Mycobacterium tuberculosis leading to multiple (MDR) and extensively (XDR) resistant strains. Also, TB is treated with multiple drugs to minimize further resistance development, mandating a sustained effort to identify new lead compounds for treating drug resistant TB, and shortening time to cure for all TB infections. High throughput screening, a well-known approach to discovery of new leads, is conducted in two basic modes 1) using whole cells and screening for inhibition of growth, or whole cell reporter cells that signals when a specific pathway is perturbed, and 2) in vitro non-cell based enzyme or other functional assays for direct ligand-target binding. Combining high throughput screening for inhibitors of growth (to identify and chemically assess inhibitors active on whole cells), followed by target identification abrogates the problem of discovering new leads in non-cell based systems that are inactive on whole cells due to issues with target access (e.g., uptake). High throughput screening of 341,778 compounds by the National Institutes of Health identified 8,950 primary hit, growth inhibitors of M. tuberculosis. Final evaluation based on reproducibility, potency, medicinal chemistry inspection, and cytotoxicity on tissue culture cells identified 1,113 priority compounds. These data were deposited in PubChem, making data available to TB research labs for follow up studies on target identification. This effort led to identification of compounds targeting Pks13, MmpL3, DprE1, AspS, EthA, GuaB2, nonreplicating cells, and VKOR (Vitamin K epoxide reductase). PMID- 30520385 TI - Diagnostic Value of HLA Typing in Pathogenesis of Cardiomyopathy. AB - Development of cardiomyopathy (CM) is dependent upon several factors. However, reaction of immune response against myocardial tissue due to microbial and viral infections plays an important role in this disease. Therefore, the purpose of this study is to investigate the relationship between HLAs and their pathogenic mechanisms in the incidence of CM. Relevant literature was identified by a PubMed search (1989-2017) of English-language papers using the terms "Cardiomyopathy", "Human leukocyte antigen or HLA", "immune response", and "polymorphism". If CM patients are afflicted with viral and microbial infections, HLA class II molecules, which are not expressed on myocardial tissue in normal conditions, are mainly expressed on it. As a result, these HLAs present self- antigens and provoke autoimmune responses against myocardial tissue. On the other hand, the occurrence of polymorphism as well as disrupted expression of miRNAs can affect HLA expression, leading to hypertrophy and fibrosis of cardiac muscle. Finally, it is inferred that the expression evaluation of HLAs as well as identification of polymorphisms in their coding genes can be effective diagnostic factors in the detection of people susceptible to CM. PMID- 30520386 TI - Prolactin induces IL-2 associated TRAIL expression on natural killer cells from chronic hepatitis C patients in vivo and in vitro. AB - BACKGROUND: Natural killer cells (NKC) are a major component of innate immune response to HCV, mediating their effects through TRAIL and IFN-gamma. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC. OBJECTIVE: To explore if hyperprolactinemia can activate NKC in HCVp. METHOD: We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-gamma levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls. RESULTS: Treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-gamma. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls. CONCLUSION: Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1 type cytokine profile. Also, increase in TRAIL and IL-2 were associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp. PMID- 30520387 TI - A Rare Diagnosis After the Fall of a 96-Year-Old Woman: Doege-Potter Syndrome. AB - INTRODUCTION: Doege-Potter syndrome (DPS) is a rare but life-threatening paraneoplastic syndrome, characterized by non-islet cell tumor-induced hypoglycemia (NICTH) secondary to a solitary fibrous tumor (SFT), which secretes an incompletely processed form of insulin-like growth factor 2 (IGF-2). RESULTS: A 96-year-old woman was admitted with head trauma due to an accidental fall. During her hospital stay she experienced frequent hypoglycemic episodes. Multiple injections of 33% dextrose and continuous infusion with 10% dextrose were required to maintain normal blood glucose levels. Biochemical analyses revealed hypoinsulinemic hypoglycemia, low C-peptide levels, suppressed insulin-like growth factor-1, normal insulin-like growth factor-2, and an elevated IGF-2:IGF-1 ratio, all consistent with IGF-2 secretion by a non-islet cell tumor. A contrast enhanced chest and abdominal CT scans showed a single large pleural mass in the left lower hemithorax measuring 15x14 cm without secondary lesions. Histological analysis of biopsied specimens suggested a solitary fibrous pleural tumor; accordingly, a diagnosis of Doege-Potter syndrome was considered. Due to extensive tumor burden and the advanced age of the patient, supportive and non invasive management was chosen. Dexamethasone therapy was started, and while receiving this therapy she was able to discontinue glucose infusion and successfully maintain euglycemia. DISCUSSION: In the elderly, a sudden and unexplained fall can be the expression of severe hypoglycemia, usually as a complication of insulin therapy or of oral hypoglycemic agents administered to patients with diabetes. However, in patients without diabetes, other causes should be investigated, and the hypothesis of neoplastic diseases should be considered. CONCLUSION: In this case report we describe an uncommon cause of paraneoplastic hypoglycemia occurring in the oldest patient with a non-islet cell tumor reported thus far. PMID- 30520388 TI - miR-342-5p as a potential regulator of HER2 breast cancer cell growth. AB - HER2 positive breast cancers (BC) have aggressive behavior and poor prognosis. Previously, we have identified miR-342-5p as an upstream regulator of HER2 signaling, as well as inhibitor of HER2 positive BC cell line growth. Here, we aimed to further investigate the molecular mechanisms behind miR-342-5p-induced HER2 pathway deregulation. Two HER2 amplified breast cancer cell lines were transiently transfected with miR-342-5p mimic or negative control, and gene expression was analyzed by Agilent microarrays. Three clinical datasets with BC patients were used to identify correlations between candidate genes and miR-342 5p, and associations with survival. Pathway analyses of all deregulated genes revealed a significant suppression of the HER2 downstream pathways ERK/MAPK and SAPK/JNK, whereas the miR-342-5p predicted target genes were enriched for pathways associated with cell motility. Biological functions linked to mitochondrial stability were ranked among the top toxicological functions in both gene lists. Among the most deregulated genes, Cytochrome B5 Reductase 3 (CYB5R3) and Rap Guanine Nucleotide Exchange Factor 6 (RAPGEF6) significantly anticorrelated and correlated, respectively, with miR-342-5p in all three clinical BC datasets. Low CYB5R3 levels and high RAPGEF6 levels were significantly associated with survival, although this was not directly associated with HER2 expression. Our data suggest that miR-342-5p overexpression in HER2 positive BC cell lines elicits broad effects on HER2 downstream signaling, cell motility and mitochondrial stability. Together these effects may render cells less proliferative and more sensitive to cellular stress. PMID- 30520389 TI - Links Between Strokes and Hereditary Hemorrhagic Telangiectasia: A Population Based Study. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a disease of abnormal vasculature where patients are predisposed to strokes of multiple etiologies. We assessed yearly stroke incidence among Albertans with HHT and compared with the general population. Given the tendency for stroke in HHT patients, we expected HHT patients to have higher stroke incidence, in particular at younger ages. METHODS: Population-based administrative health data on inpatient and ambulatory admissions were extracted over a 16-year period using International Classification of Diseases (ICD)-9 and ICD-10, Canada codes. We analyzed overall occurrence of strokes in Alberta by age, gender, stroke subtype, and diagnosis of HHT. RESULTS: The age-standardized incidence rate of stroke in HHT was 450 per 100,000 compared with 260 per 100,000 in the general population with a rate ratio of 1.73 (95% confidence interval (CI) [1.046-2.842]). This study found a higher HHT prevalence in Alberta (1 in 3800) compared to the world average of 1 in 5000. Women were also more likely to be diagnosed with HHT, with a 3.25:1 female gender preponderance in the yearly incidence.InterpretationThis study not only shows that HHT patients are at higher risk of having a stroke but also quantifies that risk using an age-adjusted metric in Alberta. This province has a higher than expected disease burden of HHT, with the majority of cases affecting women. Our study found that acute ischemic strokes and transient ischemic attacks are far more common than hemorrhage in HHT. As HHT is a rare, multi-system, chronic disease, these patients should be referred to an HHT Centre of Excellence. PMID- 30520390 TI - Developing a risk management framework to improve public health outcomes by enumerating Salmonella in ground turkey. AB - Salmonella spp. continue to be a leading cause of foodborne morbidity worldwide. To assess the risk of foodborne disease, current national regulatory schemes focus on prevalence estimates of Salmonella and other pathogens. The role of pathogen quantification as a risk management measure and its impact on public health is not well understood. To address this information gap, a quantitative risk assessment model was developed to evaluate the impact of pathogen enumeration strategies on public health after consumption of contaminated ground turkey in the USA. Public health impact was evaluated by using several dose response models for high- and low-virulent strains to account for potential under or overestimation of human health impacts. The model predicted 2705-21 099 illnesses that would result in 93-727 reported cases of salmonellosis. Sensitivity analysis predicted cooking an unthawed product at home as the riskiest consumption scenario and microbial concentration the most influential input on the incidence of human illnesses. Model results indicated that removing ground turkey lots exceeding contamination levels of 1 MPN/g and 1 MPN in 25 g would decrease the median number of illnesses by 86-94% and 99%, respectively. For a single production lot, contamination levels higher than 1 MPN/g would be needed to result in a reported case to public health officials. At contamination levels of 10 MPN/g, there would be a 13% chance of detecting an outbreak, and at 100 MPN/g, the likelihood of detecting an outbreak increases to 41%. Based on these model prediction results, risk management strategies should incorporate pathogen enumeration. This would have a direct impact on illness incidence linking public health outcomes with measurable food safety objectives. PMID- 30520391 TI - Thermal effects on IgM-milk fat globule-mediated agglutination. AB - The process of agglutination causes firm cream layers in bovine milk, and a functioning agglutination mechanism is paramount to the quality of non homogenized milks. The phenomenon is not well-described, but it is believed to occur due to interactions between immunoglobulins (Ig) and milk fat globules. For the first time, this paper demonstrates how the process of agglutination can be visualized using confocal laser scanning microscopy, rhodamine red and a fluoresceinisothiocynat-conjugated immunoglobulin M antibody. The method was used to illustrate the effect on agglutination of storage temperature and pasteurization temperature. Storage at 5 degrees C resulted in clearly visible agglutination which, however, was markedly reduced at 15 degrees C. Increasing storage temperature to 20 or 37 degrees C cancelled any detectable interaction between IgM and milk fat globules, whereby the occurrence of cold agglutination was documented. Increasing 20 s pasteurization temperatures from 69 degrees C to 71 degrees C and further to 73 degrees C lead to progressively higher inactivation of IgM and, hence, reduction of agglutination. Furthermore, 2 dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that changes in storage temperature caused a redistribution of Ig-related proteins in milk fat globule membrane isolates. Poly-immunoglobulin G receptor was present in milk fat globule preparations stored at cold (4 degrees C) conditions, but absent at storage at higher temperature (25 degrees C). The findings provide valuable knowledge to dairy producers of non-homogenized milk in deciding the right pasteurization temperature to retain the crucial agglutination mechanism. PMID- 30520392 TI - The dynamics of individual whey protein concentrations in cows' mammary secretions during the colostral and early lactation periods. AB - The bovine whey consists of more than 200 different types of proteins, of which beta-lactoglobulin, alpha-lactalbumin, serum albumin, immunoglobulins and lactoferrin predominate. However, their concentrations are not stable due to the existence of protein dynamics during a transition from colostrum secretion to mature milk. To evaluate the dynamics of whey proteins of Jersey cows during a colostral phase and first month of lactation and an influence of the number of lactations, 268 milk samples from 135 Jersey cows were selected through a clinical evaluation. Whey was obtained by rennet coagulation of the mammary secretion. The concentration of total proteins was determined by the biuret method and their fractions were identified by 12% dodecyl sulfate-polyacrylamide gel electrophoresis (12% SDS-PAGE). Maximum concentrations of all protein fractions were observed in the first 12 h of lactation, reducing over the course of the study. Modification of the protein predominance was also observed. The transition from colostrum secretion to milk occurred between 24 and 72 h postpartum. There was an influence of the number of lactations on the dynamics of whey proteins, indicating that multiparous cows had better immunological and nutritional quality when compared to primiparous cows. PMID- 30520393 TI - An amended description of two Gyrodactylus species (Platyhelminthes: Monogenea) parasitizing Antarctic Notothenioid fish. AB - Species identification based on the morphometry of opisthaptoral hard parts, in combination with internal transcribed spacer ribosomal DNA (ITS rDNA) region sequences, confirmed the presence of four viviparous Gyrodactylus von Nordman, 1832 (Plathyhelminthes, Monogenea) species on Nototheniid fish from the Prince Gustav Channel (Weddell Sea, Antarctica). Gyrodactylus antarcticus Gusev, 1967 was found mostly on Trematomus newnesi Boulenger (93 specimens) but also on T. bernacchii Boulenger (one specimen), the latter representing a new host record for this species. Gyrodactylus byrdi Hargis & Dillon, 1968 and G. coriicepsi Rokicka, Lumme & Zietara, 2009 were recorded on their type hosts, T. newnesi and Notothenia coriiceps Richardson, respectively. Gyrodactylus wilkesi Hargis & Dillon, 1968 was found mostly on the fins of T. bernacchii (29 specimens), but also on T. hansoni Boulenger (one specimen) and T. newnesi (three specimens). The finding of G. wilkesi on T. newnesi represents a new host record. The low number of Gyrodactylus specimens may indicate an accidental infection. The occurence of all four Gyrodactylus species in the Prince Gustav Channel represents a new locality record. According to phylogentic methods, the newly redescribed monogeneans belong to the Antarctic lineage, forming a sister group to North American and European marine Gyrodactylus species, and consist of two species groups, one comprising G. coriicepsi and G. nudifronsi Rokicka, Lumme & Zietara, 2009, and the other G. anarcticus and G. wilkesi. PMID- 30520394 TI - Involving people with dementia and their carers in dementia education for undergraduate healthcare professionals: a qualitative study of motivation to participate and experience. AB - : ABSTRACTBackground:There is a need to improve dementia education to prepare future generations of healthcare professionals to deal with the increasing challenges they will face. Time for Dementia is an innovative undergraduate education program for medical, nursing, and paramedic students in the south of England. Success of the program is dependent upon the participation of families (people with dementia and their carers). This qualitative study seeks to explore the motivation and experiences of the families taking part in the program. METHODS: A topic guide was developed to understand factors influencing motivation and retention. A purposeful sample of participant families, who had at least 12 months of involvement in the program, were selected from a cohort of 282 families and were invited to take part in an in-depth qualitative interview. Interviews were audio recorded, transcribed verbatim, and analyzed using thematic analysis. This was subsequently refined in an on-going process of analysis aided by the use of Nvivo 11. Interviewing stopped when thematic saturation was reached. RESULTS: Eighteen families took part in an in-depth qualitative interviews. Four themes were identified from the analysis. These themes were motivators, value to family, value to the person with dementia, and student factors. CONCLUSIONS: This study identifies underpinning factors that motivate families to join dementia education programs and the impact of such programs upon them. We found that engagement in such programs can have therapeutic benefits to participants, and do not cause harm. These findings can be used to strengthen recruitment and enhance family involvement in similar programs. PMID- 30520395 TI - Evaluation of macrolinguistic aspects of the oral discourse in patients with Alzheimer's disease. AB - : ABSTRACTIntroduction:Alzheimer's disease (AD) is a degenerative syndrome that impairs cognitive functioning, including speech and language. Discourse can be used to analyze language processing, which is organized into microlinguistic and macrolinguistic dimensions. OBJECTIVES: To identify the occurrence of changes in the macrolinguistic dimension of oral discourse in AD patients. DESIGN: This was developed as a cross-sectional study. SETTING: Outpatient clinic of the Behavioural Neurology Division of Sao Paulo Federal University. PARTICIPANTS: 121 elderly patients, with >= 4 years of education, divided into AD and comparison groups. MEASUREMENTS: The subjects were asked to create a narrative based on seven figures that made up a story. The macrolinguistic aspects of the narratives were analyzed. RESULTS: The performance of the AD group was inferior to that of the comparison group on content-related, no-content-related complete and incomplete propositions as well as macropropositions, main information units, appropriated local and global coherence, cohesive devices and all subtypes, cohesive errors and some of their subtypes. Global coherence, macropropositions and ellipsis subtype of cohesive devices were the variables that best differentiated the groups. CONCLUSIONS: Changes were observed in most aspects of the macrolinguistic dimension of oral discourse in patients with AD. PMID- 30520396 TI - Predictors of caregiver burden and care costs for older persons with dementia in Taiwan. AB - : ABSTRACTObjectives:As a degenerative disease, the progression of dementia needs continued care provision and poses both psychological and financial burden for family caregivers of persons with dementia (PWD). This study seeks to compare predictors of care costs and caregiver burden, and to identify modifiable factors that could alleviate the burden faced by dementia caregivers. METHODS: This study interviewed 231 PWD-caregiver dyads in a dementia clinic at a teaching hospital in southern Taiwan in 2013. A follow-up study was conducted a year later, and 167 dyads completed the second interview. Data collected included PWD characteristics, caregiver characteristics, relationship to PWD, and social support to caregivers. Caregiver burden was measured with the Zarit Burden Interview instrument. The association between each predictor variable and cost of care and caregiver burden scores was examined using linear mixed models. RESULTS: Predictors of care costs were found to be different from predictors of caregiver burden: functional declines measured by Katz's activities of daily living (ADL) scale were associated with total cost as compared to behavioral disturbance measured by Neuropsychiatric Inventory (NPI), which showed no impact on care costs. However, NPI was a significant predictor of caregiver burden. Caregivers who were better-off financially also reported significantly lower caregiver burden. CONCLUSIONS: Since predictors of care costs were different from the predictors of caregiver burden, providing training to caregivers in addressing PWD's behavioral disturbance and proving financial assistance to low income caregivers could be effective in reducing caregiver burden. PMID- 30520397 TI - A Case of a Cardiac Cephalgia. PMID- 30520398 TI - Appropriate selection indices for functional traits in dairy cattle breeding schemes. AB - The objective of this study was to establish different single or multiple trait selection indices to calculate genetic and economic gains by combining some production, reproduction and udder health traits in a population similar to the overall practical situation in Iran, with and without imposing restrictions on genetic change for some traits. The SelAction software was used to perform the analyses based on selection index theory through a deterministic model. Results indicated that among established indices, the index that showed the highest genetic gain for milk yield did not maximize the total genetic and economic gains. Rather, the index that included all production, reproduction and udder health traits yielded the highest genetic and economic gains. When we placed restriction on the selection indices, the economic gain decreased and the amount of reduction depended on the heritability and the correlation of restricted trait(s) with other traits. Generally, regarding the economic genetic gain per generation, the indices based on records of 200 offspring were 4.819% more efficient than those that used information of 100 offspring. PMID- 30520399 TI - Role of adolescent exposure to rockets in the links between personality vulnerability and psychopathology. AB - The aim of this study is to examine the role of repeated exposure to rocket attacks in the links between personality vulnerability (dependency and self criticism) and internalizing/externalizing psychopathology. A main-effect vulnerability model (personality leads to psychopathology) was compared with a main-effect scarring model (psychopathology leads to personality vulnerability). Also, a stress-diathesis pattern (personality vulnerability is activated under stress) was compared to a dual-vulnerability pattern (either personality vulnerability or stress, but not both, lead to psychopathology). Israeli adolescents (N = 362) repeatedly exposed to rocket attacks were assessed annually over 3 years. In 2008 and 2010, personality and psychopathology were assessed. Cumulative exposure was measured as the sums of exposure across the three assessment waves. Theoretical models were tested via Autoregressive Cross-Lagged Structural Equation Modeling analyses. Baseline dependency and self-criticism were associated with an increase in anxiety, whereas baseline depression was associated with an increase in dependency. Under low, not high, levels of rocket exposure, self-criticism and depression were longitudinally associated. Violence commission was associated with an increase in dependency under high, not low, cumulative exposure. Results are consistent with both scarring and vulnerability models, and with both stress-diathesis and dual-vulnerability patterns of adolescent risk and resilience. PMID- 30520400 TI - Role of FGF signalling in neural crest cell migration during early chick embryo development. AB - SummaryFibroblast growth factor (FGF) signalling acts as one of modulators that control neural crest cell (NCC) migration, but how this is achieved is still unclear. In this study, we investigated the effects of FGF signalling on NCC migration by blocking this process. Constructs that were capable of inducing Sprouty2 (Spry2) or dominant-negative FGFR1 (Dn-FGFR1) expression were transfected into the cells making up the neural tubes. Our results revealed that blocking FGF signalling at stage HH10 (neurulation stage) could enhance NCC migration at both the cranial and trunk levels in the developing embryos. It was established that FGF-mediated NCC migration was not due to altering the expression of N-cadherin in the neural tube. Instead, we determined that cyclin D1 was overexpressed in the cranial and trunk levels when Sprouty2 was upregulated in the dorsal neural tube. These results imply that the cell cycle was a target of FGF signalling through which it regulates NCC migration at the neurulation stage. PMID- 30520401 TI - Are medical doctors in Latin America prepared to deal with the dementia epidemic? PMID- 30520402 TI - The clinical course and interrelations of dementia related symptoms - CORRIGENDUM. PMID- 30520403 TI - Agency in dementia care: systematic review and meta-ethnography. AB - : ABSTRACTObjectives:Dementia often limits the agency of the person to such an extent that there is need for external support in making daily life decisions. This support is usually provided by family members who are sometimes legally empowered to engage in decision-making on behalf of the person for whom they care. However, such family carers receive little or no information on how to best provide support when there is a lack of capacity. This may have an impact on the agency of the person with dementia. This review explores the experience of agency in people living with dementia. DESIGN: A systematic search was conducted on IBSS, MedLine, PsychINFO, EMBASE, and CINAHL. Two independent researchers screened the studies and conducted the quality appraisal. We used meta ethnography for data analysis. As part of the synthesis, we identified behavioral mechanisms underlying the process of decision-making and looked at how the support of carers comes into play in making deliberate choices. RESULTS: The meta ethnography involved 20 studies. Three levels of third-order constructs were identified, each describing a decision-making pathway and reflecting the degree of autonomy of the person with dementia: autonomous decision-making, shared decision-making, and pseudo decision-making. Findings highlight those inter relational processes that promote or negatively impact on the agency of people with dementia. CONCLUSIONS: Our review will provide health and social care personnel with an understanding of the role of the carer in the decision-making process, and therefore which mechanisms need to be promoted or discouraged through training. PMID- 30520404 TI - Gait parameters and characteristics associated with increased risk of falls in people with dementia: a systematic review. AB - : ABSTRACTBackground:People with dementia fall twice as often and have more serious fall-related injuries than healthy older adults. While gait impairment as a generic term is understood as a fall risk factor in this population, a clear elaboration of the specific components of gait that are associated with falls risk is needed for knowledge translation to clinical practice and the development of fall prevention strategies for people with dementia. OBJECTIVE: To review gait parameters and characteristics associated with falls in people with dementia. METHODS: Electronic databases CINAHL, EMBASE, MedLine, PsycINFO, and PubMed were searched (from inception to April 2017) to identify prospective cohort studies evaluating the association between gait and falls in people with dementia. RESULTS: Increased double support time variability, use of mobility aids, walking outdoors, higher scores on the Unified Parkinson's Disease Rating Scale, and lower average walking bouts were associated with elevated risk of any fall. Increased double support time and step length variability were associated with recurrent falls. The reviewed articles do not support using the Performance Oriented Mobility Assessment and the Timed Up-and-Go tests to predict any fall in this population. There is limited research on the use of dual-task gait assessments for predicting falls in people with dementia. CONCLUSION: This systematic review shows the specific spatiotemporal gait parameters and features that are associated with falls in people with dementia. Future research is recommended to focus on developing specialized treatment methods for these specific gait impairments in this patient population. PMID- 30520405 TI - Evidence of palliative care stigma: The role of negative stereotypes in preventing willingness to use palliative care. AB - OBJECTIVE: Although palliative care is critical to managing symptoms, pain, and transitions to end-of-life care among those facing serious or chronic illness, it is often underused, which may be due to stigma associated with palliative care representing giving up fighting one's illness. The goal of the present studies was to test the theoretical framework of stigma within the context of palliative care to inform future work on intervention development that addresses potential barriers to palliative care utilization. METHOD: In study 1, participants (n = 152) had an oncologist describe two treatment options to a terminally ill cancer patient: (1) palliative care and (2) chemotherapy. Participants were then randomly assigned to read that the patient chose palliative care or chemotherapy. In study 2, these stereotypes about those receiving palliative care were examined as a potential mediator between perceived palliative care stigma and prospective palliative care use. Participants (n = 199) completed self-report measures of palliative care stigma, negative stereotypes about palliative care users, and prospective use of palliative care. Mediation analysis tested the mediational effects of stereotypes on the relationship between palliative care stigma and prospective usage of palliative care.ResultIn study 1, those in the palliative care condition endorsed significantly higher levels of negative stereotypes about the patient, viewed the decision more negatively, and saw the patient as less afraid of death. In study 2, palliative care stigma was associated with less prospective usage of palliative care for self and for one's family member. This relationship was mediated by negative stereotypes about individuals receiving palliative care.Significance of resultsResults suggest that palliative care stigma exists (study 1) and that this stigma may be a barrier to the utilization of palliative care (study 2). Future research should examine stigma reduction as a potential intervention target to improve palliative care utilization. PMID- 30520406 TI - Evaluating interventions to improve child nutrition in Eastern Democratic Republic of Congo. AB - OBJECTIVE: The prevention of malnutrition in children under two approach (PM2A), women's empowerment and agricultural interventions have not been widely evaluated in relation to child diet and nutrition outcomes. The present study evaluated the effectiveness of PM2A, women's empowerment groups (WEG), farmer field schools (FFS) and farmer-to-farmer training (F2F). DESIGN: Community-matched quasi experimental design; outcome measures included children's dietary diversity, stunting and underweight. SETTING: Communities in South Kivu, Democratic Republic of the Congo.ParticipantsA total of 1312 children from 1113 households. RESULTS: Achievement of minimum dietary diversity ranged from 22.9 to 39.7 % and was significantly greater in the PM2A and FFS groups (P<0.05 for both comparisons). Fewer than 7.6 and 5.8 % of children in any group met minimum meal frequency and acceptable diet targets; only the PM2A group differed significantly from controls (P<0.05 for both comparisons). The endline stunting prevalence ranged from 54.7 % (PM2A) to 69.1 % (F2F) and underweight prevalence from 22.3 % (FFS) to 34.4 % (F2F). No significant differences were found between intervention groups and controls for nutrition measures; however, lower prevalences of stunting (PM2A, -4 %) and underweight (PM2A and FFS, -7 %) suggest potential impact on nutrition outcomes. CONCLUSIONS: Children in the PM2A and FFS groups had better child diet measures and nutrition outcomes with the best results among PM2A beneficiaries. Interventions that address multiple aspects nutrition education, health, ration provision and income generation may be more effective in improving child diet and nutrition in resource-poor settings than stand-alone approaches. PMID- 30520407 TI - A meta-analysis of neuropsychological, social cognitive, and olfactory functioning in the behavioral and language variants of frontotemporal dementia. AB - BACKGROUND: Though meta-analyses of neuropsychological and social cognitive deficits in behavioral variant frontotemporal dementia (bvFTD) have been conducted, no study has comprehensively characterized and compared the neuropsychological, social cognitive, and olfactory profiles in the behavioral and language variants of FTD. METHODS: Our search yielded 470 publications meeting inclusion criteria representing 11 782 FTD patients and 19 451 controls. For each domain, we calculated Hedges' g effect sizes, which represent the mean difference between the patient and control group divided by the pooled standard deviation. The heterogeneity of these effects was assessed with Cochran's Q statistic using a random-effects model. Meta-regressions were employed to analyze the influence of demographic and disease characteristics. RESULTS: Though semantic variant primary progressive aphasia patients showed the greatest impairment across all task types, the three groups showed similar cognitive effect sizes once contributions from the language subdomain were excluded from analysis. Contrary to expectation, the magnitude of deficits in executive functioning, social cognition and olfaction were comparable between the three subgroups. Among indices, a metric of executive errors distinguished the behavioral variant of FTD from the language phenotypes. CONCLUSIONS: These data indicate that social cognitive and traditional executive functioning measures may not capture differences between FTD syndromes. These results have important implications for the interpretation of neuropsychological assessments, particularly when applied to the differential diagnosis of FTD. It is hoped that these findings will guide clinical and research assessments and spur new studies focused on improving the measurement of FTD syndromes. PMID- 30520408 TI - Variable sialic acid content in milk of Indian cattle and buffalo across different stages of lactation. AB - The aim of this Research Communication was to contribute to the knowledge of milk sialic acid concentration of bovines with specific focus on India. Sialic acids (SA) are important constituents of mammalian milks. Buffaloes are the main milk producing species in India, therefore, our research focused on both cow and buffalo. Two Indian cattle (Bos indicus) breeds (Sahiwal, Tharparkar), one cross bred cattle - Karan Fries (Tharparkar * Holstein Friesian) and a buffalo breed (Murrah) were selected. Systematic comparisons of the total, free and bound form of SA and also its distribution over the course of lactation- colostrums and mature milk (120-140 d) was generated. Animal management, sample collection and methodology of SA estimation were identical for the different groups. Colostrum had the highest concentration of SA, which declined with the progress of lactation in all the groups. Majority of the SA existed in bound form. No significant (P < 0.05) difference was recorded in the total, bound or free SA across all the groups. However, differences were obvious in the total and bound SA level in the mature milk. Indian cattle, Sahiwal and Tharparkar were equivalent, but had higher concentration of total and bound SA than crossbred cattle. Milk of buffalo had SA equivalent to that of crossbred cattle. The mean (se) levels of total SA was 23.4 (0.8), 25.8 (2.4), 20.3 (0.6) and 20.2 (1.2) in Sahiwal, Tharparkar, cross bred and Murrah buffalo, respectively. The findings suggested that milk of indigenous cattle may be a potential source of SA, a bioactive compound with beneficial effect on human health and a potential functional ingredient in foods. Results add value to the currently declining indigenous cattle of India. PMID- 30520409 TI - Effect of selective serotonin reuptake inhibitor on prefrontal-striatal connectivity is dependent on the level of TNF-alpha in patients with major depressive disorder. AB - BACKGROUND: We hypothesize that the tumor necrosis factor-alpha (TNF-alpha) may play a role in disturbing the effect of selective serotonin reuptake inhibitor (SSRI) on the striatal connectivity in patients with major depressive disorder (MDD). METHODS: We performed a longitudinal observation by combining resting state functional magnetic resonance imaging (rs-fMRI) and biochemical analyses to identify the abnormal striatal connectivity in MDD patients, and to evaluate the effect of TNF-alpha level on these abnormal connectivities during SSRI treatment. Eighty-five rs-fMRI scans were collected from 25 MDD patients and 35 healthy controls, and the scans were repeated for all the patients before and after a 6 week SSRI treatment. Whole-brain voxel-wise functional connectivity (FC) was calculated by correlating the rs-fMRI time courses between each voxel and the striatal seeds (i.e. spherical regions placed at the striatums). The level of TNF alpha in serum was evaluated by Milliplex assay. Factorial analysis was performed to assess the interaction effects of 'TNF-alpha * treatment' in the regions with between-group FC difference. RESULTS: Compared with controls, MDD patients showed significantly higher striatal FC in the medial prefrontal cortex (MPFC) and bilateral middle/superior temporal cortices before SSRI treatment (p < 0.001, uncorrected). Moreover, a significant interaction effect of 'TNF-alpha * treatment' was found in MPFC-striatum FC in MDD patients (p = 0.002), and the significance remained after adjusted for age, gender, head motion, and episode of disease. CONCLUSION: These findings provide evidence that treatment-related brain connectivity change is dependent on the TNF-alpha level in MDD patients, and the MPFC-striatum connectivities possibly serve as an important target in the brain. PMID- 30520410 TI - Patient with Parkinson's disease presenting with impulse control disorders following treatment with selegiline. PMID- 30520411 TI - Visceral adiposity index is a better predictor of unhealthy metabolic phenotype than traditional adiposity measures: results from a population-based study. AB - OBJECTIVE: The present study aimed to investigate whether the visceral adiposity index (VAI) is an effective predictor to identify unhealthy metabolic phenotype by comparing normal-weight and overweight individuals. DESIGN: A population-based cross-sectional study. Data were collected by interviews, anthropometric evaluation, dietetic, clinical and laboratory tests. The area under the receiver operating characteristic curve (AUC) and prevalence ratio (PR), obtained from Poisson regression, were used to compare the predictive capacity of the obesity indicators evaluated (VAI, BMI, waist and neck circumference, waist-to-height and waist-to-hip ratios) and their association with the unhealthy metabolic phenotype. All analyses were stratified by sex and by nutritional status. SETTING: Vicosa, Minas Gerais, Brazil.ParticipantsA total of 854 Brazilian adults (20-59 years old) of both sexes. RESULTS: VAI was the best predictor for unhealthy metabolic phenotype among men (AUC = 0.865) and women (AUC = 0.843) at normal weight. VAI also had the best predictive capacity among overweight women (AUC = 0.903). Among overweight men, its accuracy (AUC = 0.830) was higher than that of waist-to-hip ratio. In the adjusted regression models, VAI was the indicator most strongly associated with the unhealthy metabolic phenotype, especially among those with normal weight (PR = 6.74; 95 % CI 3.15, 14.42 for men; PR = 7.14; 95 % CI 3.79, 13.44 for women). CONCLUSIONS: VAI has better predictive capacity in detecting unhealthy metabolic phenotype than conventional anthropometric indicators, regardless of nutritional status and sex. PMID- 30520412 TI - Case Reports: Late Emergence of Cutaneous Leishmaniasis in an Immunocompromised Patient in a Non-Endemic Setting. AB - We report a case of reactivation of cutaneous leishmaniasis caused by Leishmania major in a 40-year-old man from Afghanistan, in the context of immune suppression. His last potential exposure was 7 years before the clinical presentation. To our knowledge, this is the most temporally distant reactivation of cutaneous leishmaniasis reported in a non-endemic country. PMID- 30520413 TI - Temporarily quadrupling the dose of inhaled steroid to prevent asthma exacerbations: FAST. AB - BACKGROUND: Asthma exacerbations affect the quality of life of patients with asthma and have a major effect on the overall costs of asthma care. An asthma self-management plan that advises the temporary quadrupling of inhaled corticosteroid dose may prevent asthma exacerbations, but this needs to be confirmed before being adopted widely. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of an asthma self-management plan that advises patients to temporarily quadruple the dose of inhaled corticosteroid when asthma control starts to deteriorate with a standard self-management plan. DESIGN: A multicentre, parallel-group, pragmatic randomised trial, with follow-up for 12 months. SETTING: Primary and secondary care across 207 sites in the UK. PARTICIPANTS: Asthma patients aged >= 16 years treated with an inhaled corticosteroid who had experienced at least one exacerbation in the previous 12 months. INTERVENTIONS: Participants were randomised (1 : 1) to a usual-care self management plan or to a modified self-management plan that advised a temporary quadrupling of the inhaled corticosteroid at the point of asthma deterioration, both of which were actively implemented and supported by local research staff. PRIMARY OUTCOME: The primary outcome of 'time to first asthma exacerbation' was defined as the need for systemic corticosteroids (for at least 3 consecutive days) and/or unscheduled health-care consultations for asthma (i.e. reaching zone 3 or 4 of the Asthma UK self-management plan). RESULTS: A total of 1922 participants were randomised: the primary analysis included 938 participants (97%) in the usual-care group and 933 participants (97%) in the modified self management group. The number of participants having at least one exacerbation of asthma in the year after randomisation was 484 (51.6%) in the usual-care group and 420 (45.0%) in the modified self-management group [adjusted hazard ratio 0.81, 95% confidence interval (CI) 0.71 to 0.92; p = 0.002]. There were fewer serious adverse events reported in the modified self-management group than in the usual-care group (11 vs. 32, respectively). Eight and six events of pneumonia, lower respiratory tract infections or influenza were reported in the usual-care group and the modified self-management group, respectively. Health-care-related costs were lower in the modified self-management group. The modified self management group was L24 (bootstrapped 95% CI -L122 to L71) less costly than usual care, with a greater quality-adjusted life-year gain of 0.02 (bootstrapped 95% CI -0.005 to 0.04). Therefore, the modified self-management group was 'dominant', with a 94-95% probability of being cost-effective at the L20,000 30,000 threshold. LIMITATIONS: As the Fourfold Asthma STudy (FAST) was an open label pragmatic trial, the possibility of treatment bias that may have affected the participants in the modified self-management group cannot be ruled out. Poorer than expected completion of participant diary cards, particularly within the usual-care self-management group, could have led to a null bias, underestimating the true effect of the intervention. CONCLUSIONS: An asthma self management plan that advises patients to temporarily quadruple their dose of inhaled corticosteroid at the point of asthma symptoms worsening does reduce clinically important asthma exacerbations. In addition, the plan is cost effective compared with the usual-care self-management plan. FUTURE WORK: To effectively implement asthma self-management plans that advise a temporary quadrupling of inhaled steroid at asthma deterioration into routine practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15441965. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 70. See the NIHR Journals Library website for further project information. PMID- 30520414 TI - Association of serum total cholesterol with pegylated interferon-alpha treatment in HBeAg-positive chronic hepatitis B patients. AB - BACKGROUND: Recent studies suggest that serum lipids are associated with pegylated interferon-alpha (PegIFNalpha) treatment response in chronic hepatitis C patients. However, the role of serum lipids in influencing the outcome of HBV treatment is not well understood. This study aims to investigate the association of serum lipids with the response to interferon-alpha treatment for chronic hepatitis B (CHB) patients. METHODS: We dynamically measured 11 clinical serum lipid parameters of 119 HBeAg-positive CHB patients, including 53 patients who achieved sustained response (SR) and 66 patients who achieved nonresponse (NR) induced by PegIFNalpha treatment for 48 weeks. RESULTS: The dynamic analysis showed that the baseline serum total cholesterol (TCHO) level was higher in the NR group than that in the SR group (P = 0.004). Moreover, the correlation analysis demonstrated a significant positive correlation between TCHO and HBsAg at baseline (P = 0.009). In addition, CHB patients with the high baseline TCHO levels exhibited higher HBV DNA, HBsAg, HBeAg and HBeAb levels during early treatment periods (weeks 0, 4, 12 and 24) than those with the low TCHO levels. Furthermore, the logistic regression analysis identified that baseline serum TCHO was a risk factor of NR achievement (OR = 4.94, P = 0.047). CONCLUSIONS: Our results indicated that serum TCHO was associated with PegIFNalpha therapeutic response in HBeAg-positive CHB patients which suggested that serum TCHO could be useful as an auxiliary clinical factor to predict poor efficacy of PegIFNalpha therapy. PMID- 30520415 TI - Dose response and stability of water equivalent PRESAGE(r) dosimeters for synchrotron radiation therapy dosimetry. AB - This research investigated the dose response and post-irradiation stability of water-equivalent PRESAGE(r) dosimeters exposed to synchrotron radiation. Water equivalent PRESAGE(r) dosimeters were irradiated up to 1000 Gy in a synchrotron x ray beam with a mean energy of 95.3 keV. The change in optical density was measured using UV/visible spectrophotometry pre- and post-irradiation using a wavelength of 630 nm. Dose response was found to be approximately linear from 0 200 Gy with saturation occurring above 300 Gy. The post-irradiation stability was determined by measuring the change in optical density at 10, 30, 60, 180, 420 min and 7, 21 and 33 d post-irradiation for three groups of dosimeters stored at different temperatures. Each group had two dosimeters irradiated at 50, 100, 200 and 300 Gy and each group was stored at a different temperature following irradiation: room temperature (22 degrees C), 4 degrees C and -18 degrees C. The optimal time for readout of the dosimeters varied with the post-irradiation storage temperature. The room temperature group had an optimal time-to-readout of 10 min for maximum signal before fading, while the 4 degrees C group was reasonably stable from 90 min to 1 week. The -18 degrees C group showed the least amount of ongoing post-irradiation development and fading with an optimal readout window from 30 min to 21 d. The intra-batch variation between the mean of each temperature control group was 4.2% at 10 min post-irradiation. PMID- 30520416 TI - Feasibility of closed-MLC tracking using high sensitivity and multi-layer electronic portal imagers. AB - In radiation therapy, improvements in treatment conformality are often limited by movement of target tissue. To better treat the target, tumor tracking strategies involving beam's-eye-view (BEV) have been explored. However, localization surrogates like implanted fiducial markers may sometimes leave the field-of-view (FOV), as defined by the linear accelerator (LINAC) multi-leaf collimator (MLC). Radiation leakage through the MLC has been measured previously at approximately 1%-2%. High sensitivity prototype detectors imagers may improve the ability to visualize objects outside of the MLC FOV during treatment. The present study presents a proof-of-concept for tracking fiducial markers outside the MLC FOV by employing high sensitivity detectors using a high-efficiency, prototype scintillating glass called LKH-5 and also investigates the impact of multi-layer imager (MLI) architecture. It was found that by improving the detector efficiency, using either of these methods results in a reduction of dose required for fiducial marker visibility. Further, image correction by a rectangular median filter will improve fiducial marker representation in the MLC blocked images. Quantified by measuring the peak-to-sidelobe ratio (PSR) of the normalized cross correlation (NCC) between a template of the fiducial marker with the blocked MLC acquisition, visibility has been found at a threshold of roughly 5 for all configurations with a 3 * 3 cm2 ROI. For typical gadolinium oxysulfide (GOS) detectors in single and simulated 4-layer configurations, the minimum dose required for visualization was 20 and 10 MU, respectively. For LKH-5 detectors in single and simulated 4-layer configurations, this minimum dose was reduced to 4 and 2 MU, respectively. With a 6 MV flattening filter free (FFF) beam dose rate of 1400 MU min-1, the maximum detector frame rate while maintaining fiducial visibility is approximately 12 fps for a 4-layer LKH-5 configuration. PMID- 30520417 TI - A gold nanorod-based plasmonic platform for multi-logic operation and detection. AB - A multi-logic gate platform was designed based on morphological changes of gold nanorods (AuNRs) resulted from the iodine-mediated etching. By utilizing the anti etching effects of mercapto compounds and Au-Hg amalgams as well as the etch promoting effect of Cu2+, we successfully built five logic gates, namely, AND, NOR, XNOR, YES and IMPLY, along with a three-input combinational logic gate XNOR IMPLY. The platform was versatile and easy to use, did not require complex surface modification or separation/purification steps as the conventional AuNR based logic gates did. The logic operations, accompanied by distinct color changes, enabled multi-task detection by naked-eye for 'have' or 'none' discrimination or highly sensitive and selective analysis by spectroscopy with wide linear ranges. PMID- 30520418 TI - Dual SPECT imaging of 111In and 67Ga to simultaneously determine in vivo the pharmacokinetics of different radiopharmaceuticals: a quantitative tool in pre clinical research. AB - Dual-isotope (DI) studies offer a number of advantages in pre-clinical imaging. These include: reducing study times when compared with sequential scans, reducing the number of animals required for any given study, and most importantly, producing images perfectly registered in space and time that provide simultaneous information about two distinct body functions. The ability of single photon emission computed tomography (SPECT) to measure and differentiate energies of the emitted photons makes it well suited for DI imaging. However, since scattered photons originating from one radioisotope may be detected in the energy window of the other and thus degrade image quality and quantitative accuracy, scatter and crosstalk corrections must be applied. The decay characteristics of 111In and 67Ga, which are suitable for quantitative DI imaging for up to 2 weeks post injection, led us to investigate the performance of simultaneous 111In/67Ga SPECT imaging using a small-animal pre-clinical scanner. A series of phantom experiments were performed to investigate image quality and accuracy of activity quantification in 111In/67Ga images acquired with three different collimators and reconstructed from different photopeak combinations. The triple energy window (TEW) method was used to correct for scatter and crosstalk. Based on these phantom studies, the optimal selection of collimator and energy window settings was determined. When using these optimal settings, submillimeter-size structures were distinguishable in the reconstructed images and quantification errors below 20% were achieved for both isotopes. The optimal parameters were subsequently applied to an in vivo animal study. The determination of the distinct pharmacokinetic profiles of two polymer radiopharmaceuticals injected simultaneously, but by different administration routes (intravenously and intraperitoneally) into a single animal demonstrated the feasibility of simultaneous 111In/67Ga SPECT. PMID- 30520419 TI - 2D and 3D real-time passive cavitation imaging of pulsed cavitation ultrasound therapy in moving tissues. AB - Pulsed cavitation ultrasound therapy (PCUT) is an effective non-invasive therapeutic approach in various medical indications that relies on the mechanical effects generated by cavitation bubbles. Even though limited by the poor contrast, conventional ultrasound B-Mode imaging has been widely used for the guidance and monitoring of the therapeutic procedure, allowing the visualization of the cavitation bubble cloud. However, the visualization of the bubble cloud is often limited in deep organs such as the liver and the heart and remains moreover completely subjective for the operator. Our goal is to develop a new imaging mode to better identify the cavitation cloud. Active and passive cavitation imaging methods have been developed but none of them has been able to locate the cavitation bubble created by PCUT in real-time and in moving organs. In this paper we propose a passive ultrasound imaging approach combined with a spatiotemporal singular value decomposition filter to detect and map the bubble cloud with high sensitivity and high contrast. In moving applications at a maximal motion speed of 10 mm s-1, the contrast-to-noise ratio for passive cavitation imaging is up to 10 times higher than for active cavitation imaging, with a temporal resolution of about 100 ms. The mapping of the bubble cloud can be overlaid in real-time to the conventional B-Mode, which permits to locate the cavitation phenomena in relation to the anatomic image. Finally, we extend the technique to volumetric imaging and show its feasibility on moving phantoms. PMID- 30520420 TI - Optimization of a depth of interaction encoding PET block detector for a PET/MRI insert. AB - Preclinical positron emission tomography, combined with magnetic resonance imaging (PET/MRI), is increasingly used as a tool to simultaneously characterize functional processes in vivo. Many emerging preclinical applications, however, are limited by PET detection sensitivity, especially when generating short imaging frames for quantitative studies. One such application is dynamic multifunctional imaging, which probes multiple aspects of a biological process, using relationships between the datasets to quantify interactions. These studies have limited accuracy due to the relatively low sensitivity of modern preclinical PET/MRI systems. The goal of this project is to develop a preclinical PET/MRI insert with detection sensitivity above 15% (250-750 keV) to improve quantitation in dynamic PET imaging. To achieve this sensitivity, we have developed a detector module incorporating a 2 cm thick crystal block, which will be arranged into a system with 8 cm axial FOV, targeting mice and rats. To maintain homogenous spatial resolution, the detector will incorporate dual-ended depth-of-interaction (DOI) encoding with silicon photomultiplier (SiPM) based photodetector arrays. The specific aim of this work is to identify a detector configuration with adequate performance for the proposed system. We have optimized the SiPM array geometry and tested two crystal array materials with pitch ranging from 0.8 to 1.2 mm and various surface treatments and reflectors. From these configurations, we have identified the best balance between crystal separation, energy resolution, and DOI resolution. The final detector module uses two rectangular SiPM arrays with 5 * 6 and 5 * 4 elements. The photodetector arrays are coupled to a 19 * 19 array of 1 mm pitch LYSO crystals with polished surfaces and a diffuse reflector. The prototype design has 14.3% +/- 2.9% energy resolution, 3.57 +/- 0.88 mm DOI resolution, and resolves all elements in the crystal array, giving it sufficient performance to serve as the basis for the proposed high sensitivity PET/MRI insert. PMID- 30520421 TI - Fabrication of step-by-step drug release system both sensitive to magnetic field and temperature based on layered double hydroxides and PNIPAM. AB - Fabrication of environmental sensitive and controllable drug release systems is urgently needed. In this paper, thermosensitive and magnetic response drug release systems were fabricated via layer-by-layer technique using acetylsalicylic acid (AA) intercalated ZnAl-LDH as core, poly (N isopropylacrylamide) (PNIPAM) and AA micelles as well as small size ZnAl-LDH sheets as building blocks of the shell. By forming anionic micelles, cationic PNIPAM macromolecules were sandwiched in the LDH sheets with cationic charges which provided a novel way of fabrication of drug release systems. The characteristics of the building blocks, the fabrication process and the release behaviors of the as-prepared drug release systems were characterized in detail. Due to the micro-environmental difference of AA in the core and shell of the systems, step-by-step release behaviors were observed. Also the drug release systems showed obvious temperature and magnetic field dependent responsibility. The obtained assembly is a potential drug release system. PMID- 30520422 TI - Vapreotide-mediated hierarchical mineralized Ag/Au nanoshells for photothermal anti-tumor therapy. AB - A new type of vapreotide-templated Ag/Au bimetallic nanoshells (Vap@Ag/AuNSs) were successfully designed and fabricated based on polypeptide-directed mineralization and hierarchical self-assembly mechanisms under mild synthetic conditions. The nanoparticles with polypeptides serving as a core and coated Ag/Au bimetallic nanoshells exhibit diverse advantages, such as excellent biocompatibility, tumor targeting and low-cost. The Vap@Ag/AuNSs share excellent dispersibility, uniform size (120 nm) and a positive zeta potential (36.74 +/- 4.49 mV), hence they easily accumulate in negatively charged tumor tissue. The results of thermal imaging, temperature variation assays and photothermal conversion efficiency (41.6%) indicated that Vap@Ag/AuNSs have excellent photothermal conversion capability. Based on their photothermal response, as well as biocompatibility determined by MTT assay, the prominent anti-tumor effects of Vap@Ag/AuNSs have been verified by fluorescein diacetate staining. Therefore, Vap@Ag/AuNSs are novel and promising candidates for photothermal tumor therapy. PMID- 30520423 TI - Self-ordering promoted by the nanoconfinement of poly(3-hexylthiophene) and its nanocomposite with single-walled carbon nanotubes. AB - Nanostructuration and self-ordering of semiconducting organic materials are required to fabricate highly efficient photovoltaic and photoemissive devices. In this work, we investigated the combined effect of melt-assisted template processing and self-ordering of high purity regio-regular poly (3-hexylthiophene) (P3HT) to obtain nanofibers of P3HT and of P3HT-single-walled carbon nanotubes (SWNT) nanocomposites. An original ordering of the polymer and the carbon nanotubes within the nanofibers, as well as their surprising anisotropic photoluminescent properties were determined by vibrational and optical spectroscopy. It was attributed to the combined effect of the melt-assisted wetting confined within alumina nanopores, altogether with the self-organization of both P3HT chains on the one hand, and of the P3HT charged with SWNT on the other hand. It is proposed that the well-ordered regio-regular P3HT matrix orientation is promoted by the interaction with the alumina pore surface and the 1D confinement. For the composite case, the P3HT matrix imposes additionally a preferential orientation of the SWNT transversal to the nanofiber axis. This original organization is responsible for the unexpected polarization of the composite nanofibers photoluminescence. This work opens the way to alternative methods for tackling challenges of nanofabrication to obtain more efficient optoelectronic nanodevices. PMID- 30520424 TI - Simplifying the ShangRing technique for circumcision in boys and men: use of the no-flip technique with randomization to removal at 7 days versus spontaneous detachment. AB - To assess safety of the no-flip ShangRing male circumcision technique and to determine clinical course and safety of spontaneous detachment (i.e., allowing the device to fall off), we conducted a case series of no-flip ShangRing circumcision combined with a randomized controlled trial of removal 7 days postcircumcision versus spontaneous detachment at two health facilities in Kenya. The primary outcome was the safety of the no-flip technique based on moderate and severe adverse events (AEs) during the procedure and through 42-day follow-up. A main secondary outcome was clinical course and safety of spontaneous detachment. Two hundred and thirty males 10 years and older underwent no-flip circumcision; 114 randomized to 7-day removal and 116 to spontaneous detachment. All circumcisions were successfully completed. Overall 5.3% (6/114) of participants in the 7-day group and 1.7% (2/116) in the spontaneous group had an AE; with no differences when compared to the 3% AE rate in historical data from African studies using the original flip technique (P = 0.07 and P = 0.79, respectively). Overall 72.4% (84/116) of participants in the spontaneous group wore the ShangRing until it detached. Among the remaining (27.6%; 32/116), the ring was removed, primarily at the participants' request, due to pain or discomfort. There was no difference in AE rates (P = 0.169), visit day declared healed (P = 0.324), or satisfaction (P = 0.371) between randomization groups. The median time to detachment was 14.0 (IQR: 7-21, range: 5-35) days. The no-flip technique and spontaneous detachment are safe, effective, and acceptable to boys and men 10 years and older. Phimosis and penile adhesions do not limit successful ShangRing circumcision with the no-flip technique. PMID- 30520425 TI - Predictive significance of serum inhibin B on testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men. AB - The purpose of this study was to determine the diagnostic accuracy of serum inhibin B (INHB) as a predictor of the retrieval outcome of testicular haploid gametes (spermatids and testicular spermatozoa) in nonobstructive azoospermic men. Serum hormone levels, testicular volume, and histological evaluation were performed in 403 Chinese nonobstructive azoospermic men. Testicular haploid gamete was successfully retrieved in 213 of 403 patients (52.85%). The haploid gamete group always had higher INHB levels than the non-haploid gamete group. According to the receiver operating characteristic (ROC) curve analysis, INHB was a good predictor of testicular haploid gamete retrieval outcome in all patients (sensitivity: 77.93% and specificity: 91.58%) and patients with normal follicle stimulating hormone (FSH; sensitivity: 88.52% and specificity: 70.83%). The area under the ROC curve (AUC) of INHB was similar to that of FSH in all patients or patients with normal FSH. In patients with elevated FSH, INHB was superior to FSH in predicting the presence of haploid gamete (AUC: 0.73 vs 0.55, P < 0.05), with a sensitivity of 60.00% and a specificity of 80.28%. It concluded that serum INHB as an effective marker for spermatogenesis was a significant predictor of testicular haploid gamete retrieval outcomes in nonobstructive azoospermic men. Especially, INHB is superior to FSH in predicting the presence of haploid gamete in the patients with elevated FSH. PMID- 30520426 TI - The impact of heart rate on patients diagnosed with heart failure with mid-range ejection fraction. AB - OBJECTIVE: The relationship between prognosis and heart rate remains unclear among patients diagnosed with heart failure with mid-range ejection fraction (HFmrEF). The aim of the present study was to assess the effect of heart rate in this group of patients. METHODS: Of the 197 patients diagnosed with HFmrEF, 92 had a heart rate <70 beats/min (bpm), and 105 had a heart rate >=70 bpm. We analyzed the outcomes including all-cause death and HF-related hospitalization and evaluated the quality of life. RESULTS: The outcome demonstrated a lower incidence in patients with heart rate <70 bpm. The outcome-free survival illustrated significant difference in survival rate (p=0.045). The Minnesota Living with Heart Failure Questionnaire total scores and physical subscale in the lower heart rate group decreased compared with the heart rate >=70 bpm group (p=0.048 and p=0.03, respectively). In the following analysis of patients with sinus rhythm, beta blockers showed great positive effects on patients with heart rate <70 bpm (p=0.046), as for the quality of life in patients with beta blocker, heart rate <70 bpm showed lower total and physical scores (p=0.025 and p=0.017, respectively). CONCLUSION: Our results showed that heart rate is an important prognostic factor in patients with HFmrEF. Patients with heart rate <70 bpm was related with a lower risk of outcomes and better quality of life. Beta blockers reduced the outcome rate in patients with sinus rhythm. PMID- 30520427 TI - Retrospective analysis of 11 cases of primary cardiac valve tumors. AB - OBJECTIVE: To explore the clinical features and surgical treatment experience of primary cardiac valve tumor. METHODS: The present study retrospectively analyzed the clinical data of 11 patients with primary valvular tumors who underwent surgical treatment in our department from 1980 to 2016. Echocardiography of preoperative patients was indicated as a heart valve tumor. All patients underwent cardiopulmonary bypass surgery after endocardial angiography and positron emission tomography-computed tomography diagnosis, including four tumor resections-valvuloplasty and seven tumor resections-heart valve replacement. Pathological analysis was performed on all tumors. Postoperative cardiac ultrasound was followed up. Pathological analysis was performed on all tumors. All patients underwent postoperative ultrasound follow-up examination. RESULTS: Primary valvular tumors are rare, accounting for only 0.034% (11/32.728) of extracorporeal circulation surgery in our center. It accounts for 2.8% (11/399) of primary cardiac tumors in the same period. Pathological study indicated that there were 10 cases of benign tumor and 1 case of low-grade sarcoma. After 0.6-16 years of follow-up, the operation effect was satisfactory. CONCLUSION: Most of these tumors are papillary fibroelastoma located on the mitral valve, and surgical operation is the best strategy for cardiac primary valve tumors. PMID- 30520428 TI - Type I Brugada pattern associated with diabetic ketoacidosis in a patient with type II diabetes mellitus. PMID- 30520429 TI - The real-life data of hospitalized patients with heart failure: On behalf of the Journey HF-TR study investigators. AB - OBJECTIVE: Acute heart failure (AHF) is a life-threatening clinical syndrome characterized by rapid onset of heart failure (HF) symptoms and signs and requires urgent therapy. The aim of the present study was to evaluate the overall clinical characteristics, management, and in-hospital outcomes of hospitalized patients with AHF in a large sample of Turkish population. METHODS: The Journey HF-TR study is a cross-sectional, multicenter, non-invasive and observational trial. Patients who were hospitalized with a diagnosis of AHF in the intensive care unit (ICU)/coronary care unit and cardiology wards between September 2015 and September 2016 were included in our study. RESULTS: A total of 1606 (male: 57.2%, mean age: 67.8+/-13 years) patients who were diagnosed with AHF were enrolled in the study. Seventeen percent of the patients were admitted to the hospital with a diagnosis of new onset AHF. Hypertension (67%) and coronary artery disease (CAD) (59.6%) were the most frequent underlying diseases. Acute coronary syndrome accompanying HF (14.7%), infection (29.3%), arrhythmia (25.1%), renal dysfunction (23%), and non-compliance with medication (23.8%) were the precipitating factors. The median length of stay in the ICU was 3 days (interquartile range, IQR 1-72) and 7 days (IQR 1-72) for in-hospital journey. The guideline recommended medications were less likely used in our patient population (<73%) before admission and were similar to European and US registers at discharge. The in-hospital mortality rate was 7.6%. Hypertension and CAD were the most frequent underlying diseases in our population similar to other European surveys. Although our study population was younger than other registers, in hospital mortality was high. CONCLUSION: Analyses of such real-world data will help to prepare a national database and distinctive diagnosis and treatment algorithms and to provide observing compliance with the current European Society of Cardiology guidelines for more effective management of HF. PMID- 30520430 TI - Heart rate in heart failure with mid-range ejection fraction. PMID- 30520431 TI - Non-ergot dopamine agonists and heart failure. PMID- 30520432 TI - A rare complication of balloon pulmonary angioplasty: Aortopulmonary window and its treatment. PMID- 30520433 TI - Circular RNA expression profiles of persistent atrial fibrillation in patients with rheumatic heart disease. AB - OBJECTIVE: To investigate the expression profile of circular RNAs (circRNAs) and proposed circRNA-microRNA (miRNA) regulatory network in atrial fibrillation (AF). METHODS: Atrial tissues from patients with persistent AF with rheumatic heart disease and non-AF myocardium with normal hearts were collected for circRNA differential expression analyses by high-throughput sequencing. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the potential functions of the differentially expressed genes and AF-related pathways. Co-expression networks of circRNA-miRNA were constructed based on the correlation analyses between the differentially expressed RNAs. Quantitative reverse transcription polymerase chain reaction (PCR) was performed to validate the results. RESULTS: A total of 108 circRNAs were found to be differentially expressed in AF. Among them, 51 were up regulated, and 57 were down-regulated. Dysregulated circRNAs were validated by quantitative real-time PCR. The GO and KEGG pathway enrichment analyses were executed to determine the principal functions of the significantly deregulated genes. Furthermore, we constructed correlated expression networks between circRNAs and miRNAs. circRNA19591, circRNA19596, and circRNA16175 interacted with 36, 28, and 18 miRNAs, respectively; miR-29b-1-5p and miR-29b-2-5p were related to 12 down-regulated circRNAs, respectively. CONCLUSION: Our findings provide a novel perspective on circRNAs involved in AF due to rheumatic heart disease and establish the foundation for future research of the potential roles of circRNAs in AF. PMID- 30520434 TI - Diffusion Kurtosis Imaging Reflects Glial Fibrillary Acidic Protein (GFAP), Topo IIalpha, and O6-Methylguanine-DNA Methyltransferase (MGMT) Expression in Astrocytomas. AB - BACKGROUND Astrocytomas are the most common primary brain neoplasms. Biological indicators of astrocytomas can reflect its biological characteristics. The aim of this study was to assess the expression of the pathological glial fibrillary acidic protein (GFAP) Topo IIalpha and O6-methylguanine-DNA methyltransferase (MGMT) in astrocytomas using magnetic resonance (MR) diffusion kurtosis imaging (DKI) to evaluate the biological characteristics of astrocytomas. MATERIAL AND METHODS Sixty-six patients with pathologically proven astrocytomas were enrolled in this study. All patients underwent conventional MRI head scanning, DKI scanning, and enhanced scanning under the same conditions. Spearman's rank correlation analysis and Bonferroni correction were used to compare the values of DKI and the expression levels of GFAP, Topo IIalpha, and MGMT between the 2 groups. RESULTS Mean kurtosis (MK) values were negatively correlated with the expression of GFAP (r=-0.836; P=0.03). However, these were positively correlated with the expression of Topo IIalpha (r=0.896; P=0.01). Moreover, fractional anisotropy (FA) values were not correlated with the expression of GFAP (r=0.366; P=0.05), Topo IIalpha (r=-0.562; P=0.05), or MGMT (r=-0.153; P=0.10). CONCLUSIONS MK was significantly associated with the expression of GFAP and Topo IIalpha. To a certain extent, applying DKI may show the biological behavior of tumor cell differentiation, proliferation activity, invasion, and metastasis, and guide individual treatment. PMID- 30520435 TI - Evaluation of the safety of users of active implantable medical devices (AIMD) in the working environment in terms of exposure to electromagnetic fields - practical approach to the requirements of European Directive 2013/35/EU. AB - OBJECTIVES: Electromagnetic fields (EMF) may cause malfunctions in electronic devices, in particular in active implantable medical devices (AIMD), along with discomfort or health hazards to users. The use of AIMD by workers is increasing (especially cardiac pacemakers, implantable cardioverter defibrillators and wearable insulin infusion pumps). Electromagnetic fields may be much stronger in the working environment than applied in basic immunity tests of AIMD (based on EN 60601- 1-2:2015 and EN 50527-1:2016). European Directive 2013/35/EU regarding the safety of workers exposed to EMF considered the AIMD users to be "workers at particular risk" who need an individual evaluation of EMF hazards. The study aimed at evaluating the safety of users of AIMD in medical and industrial working environments exposed to EMF. MATERIAL AND METHODS: Near the common sources of strong EMF applied in medical and industrial use, the "standard safety distances" (SSD) for AIMD users were evaluated (i.e., distances from the EMF source, where exposure drops below limits from Recommendation 1999/519/EC and AIMD safety may be expected). The analysis is based on the results of measurements of magnetic and electric field strengths near 127 typical devices, in their normal use. RESULTS: The longest electric field related SSD was identified near dielectric sealers (up to 180 cm), and the longest magnetic field related SSD - near induction heaters (up to 450 cm). CONCLUSIONS: Electromagnetic fields related AIMD malfunctions need to be considered up to several meters from EMF sources. The "individual safety distance," that is sufficient to ensure the safety of a particular AIMD user may be significantly different (usually shorter) from the presented SSD, but needs to be considered in the context of detailed safety data from the AIMD manufacturer (if available). The labelling indicating the location of the area of a strong EMF increases safety of AIMD users in the work environment. PMID- 30520436 TI - Knitted silk mesh-like scaffold incorporated with sponge-like regenerated silk fibroin/collagen I and seeded with mesenchymal stem cells for repairing Achilles tendon in rabbits. AB - A scaffold knit with natural sericin-free silk fibroin fiber possesses desirable mechanical properties, biocompatibility, ease of fabrication, and slow degradability. However, regenerated silk fibroin degrades faster than natural silk. In this study, natural silk fibroin fiber mesh-like scaffolds were prepared by a weft-knitting method and the pores were filled with sponge-like regenerated silk fibroin-collagen I. The microporous sponge and mesh-like scaffolds were fused to achieve gradient degradation of the scaffolds, and rabbit bone marrow mesenchymal stem cells (BMSCs) were seeded onto the scaffolds to form scaffold BMSCs composites. The composites were implanted into gap defects made in the rabbit Achilles tendon. Twenty weeks after implantation, histological observation showed that tendon-like tissue had formed, collagen I mRNA was expressed, abundant collagen was generated, and that there was no obvious degradation of silk. The maximum load of the neo-Achilles tendon was 62.14% that of the natural Achilles tendon. These outcomes were superior to those obtained in the group implanted with a scaffold without BMSCs. These findings suggest the feasibility of constructing tissue-engineered tendons using weft-knitted silk scaffolds incorporated with sponge-like regenerated silk fibroin/collagen I and seeded with BMSCs, and show potential of the scaffold-BMSCs composites to repair Achilles tendon defects. PMID- 30520437 TI - The influence of minimalist and conventional sports shoes and lower limbs dominance on running gait. AB - PURPOSE: The aim of this study was to determine how minimalist running shoes (MRS), conventional running shoes (CRS) and the dominance of lower limbs influence the running gait. METHODS: Trained recreational runners (N = 13) who have been engaged in regulary running for more than one year were participants in this study. They were experienced with using MRS and CRS for more than half year and they used both types of shoes. An in-shoe pressure measuring system (Pedar X(r), Novel, Munich, Germany) was used to monitor plantar pressure and vertical force and the temporal parameters when running in MRS and CRS during the stance phase, the swing phase and over one stride. RESULTS: Running in CRS significantly prolonged stance, swing and stride phases by 2-11%, compared to MRS. In contrast, when running in MRS significantly larger values of maximum pressure (9-14%) and maximum vertical force (3-7%) than in CRS were found. CONCLUSIONS: For this reason, running in MRS could be recommended to recreational runners only with care. The effect of limb dominance on temporal characteristics was detected when running in CRS. Significantly longer stance phase for dominant limb is associated with a shorter swing. The kinematics variables were significantly higher for dominant limb than for non-dominat limb when running in MRS and CRS (by 12-23%). PMID- 30520438 TI - The influence of different composite mixtures (PLA/HA) manufactured with additive laser technology on the ability of S. aureus and P. aeruginosa to form biofilms. AB - PURPOSE: Staphylococcus aureus (Gram-positive coccus) and Pseudomonas aeruginosa (Gram-negative bacterium) are the leading etiologic agents of biofilm-related, life-threatening infections in patients after orthopaedic implantations. The aim of the present paper is to estimate the ability of these two bacterial strains to form a biofilm on bioresorbable composites manufactured from polylactide (PLA) and hydroxyapatite (HA) with the use of Selective Laser Sintering (SLS) method. METHODS: Microbiological tests were conducted on two variants of a solid specimen made with additive laser technology. Samples with different content of hydroxyapatite were made, with appropriate manufacturing parameters to ensure stability of both composite ingredients. The geometry of samples was obtained by tech- nical computed tomography. Microbiological tests determined the number of bacterial cells after incubation. RESULTS: The results indicate significantly decreased ability of S. aureus and P. aeruginosa to form biofilms on the surface of materials with higher content of hy- droxyapatite ceramics. CONCLUSIONS: The data may be useful for future applications of SLS technology in the production of bioresorbable PLA/HA medical implants. PMID- 30520439 TI - The effect of aging and gender on plantar pressure distribution during the gait in elderly. AB - PURPOSE: The effect of age on structural foot characteristics as well as on the plantar pressure distribution has been shown previously. However, the number of studies focused also on gender gait differences of elderly is lacking. The purpose of this study was to compare dynamic gait characteristic in younger and older elderly and to investigate the gender differences as the life-long load and footwear choice differ in males and females. METHODS: 61 healthy elderly participants were divided by age and gender into four groups: males 60-69, males 70-79, females 60-69 and females 70-79 years old. Plantar pressures were recorded during barefoot walking at naturally chosen speed using Emed-at (Novel GmbH, Germany). Three steps of the left foot of each participant were used for further analysis, furthermore, hallux angle, foot progression angle, and arch index were calculated by the Emed software from obtained foot- prints. To compare the differences between the analyzed groups, effect size obtained by Cohen's d was used. RESULTS: Comparing the two age male groups, higher mean pressure was found in the 70-79 age group in region MH4, MH5 and mid-foot, suggesting a greater lateral load and decreased longitudinal arch of the foot. Comparing female groups, the higher mean pressure was found in the older age group in region MH1. In all other regions, the mean pressures were reduced in the older groups. CONCLUSIONS: The results suggest that the effect of aging on plantar pressure distribution during the gait is affected by gender and should be considered when evaluating the gait of elderly. PMID- 30520440 TI - Human cancellous bone mechanical properties and penetrator geometry in nanoindentation tests. AB - PURPOSE: The goal of the study was to determine the influence of the penetrator geometry on the human cancellous bone mechanical properties in indentation tests. The aim of this research was also the assessment of the material properties of bone structures, having in mind the energy aspects of the curve obtained in the cycle: inelastic loading and elastic unloading. METHODS: The samples were resected from a femoral heads of patients qualified for a hip replacement surgery. During the Depth Sensing Indentation tests, hardness and elastic modulus of the cancellous bone tissue were measured using the spherical and Vickers penetrators. Measurements were made in a node and in a trabecula for each sample. RESULTS: The analysis of the measurement results and the calculations of total energy, i.e., elastic and inelastic, and those of the parameters of hardness and elasticity made it possible to assess the influence of the penetrator geometry on the mechanical properties of bone structures at a microscopic level. CONCLUSIONS: It was found, with respect to the methodology of indenta- tion, that without determining the shape of the penetrator and the site of the indentation, an objective assessment of the micro mechanical properties of the tested material is not possible. PMID- 30520441 TI - Concurrent validity and reliability of proprietary and open-source jump mat systems for the assessment of vertical jumps in sport sciences. AB - PURPOSE: Vertical jump tests are used to assess lower-limb power of athletes in sport sciences. Flight time measurement with jump-mat systems is the most common procedure for this purpose. The aim of this study was to analyze the concurrent validity and reliability of two proprietary systems (Globus and Axon) and an open source system (Chronojump). METHODS: A conditioning electric circuit governed by a controlled wave generator is designed to substitute athletes jumping on a physical mat. In order to look for possible differences associated to timekeeping by each microcontroller device, all three systems are fed by the circuit simultaneously. RESULTS: Concurrent validity was high for the three systems. Standarized typical error of estimate (TEE) was trivial, according to MBI interpretation as well as perfect Pearson correlation coefficient. Reliability was assessed based on the coefficient of variation of flight time measure, resulting in 0.17-0.63% (0.05-0.12 cm) for Globus, 0.01% (0.09 cm) for Chronojump and 5.65-9.38% (2.15-3.53 cm) for Axon. These results show that all jump-mat system produced nearly identical measures of flight time so they can be considered valid and reliable for practical purposes. In comparison, Chronojump showed the best performance whereas Axon showed enough variability and disagreement to pose a problem in testing elite athletes. CONCLUSIONS: These experiments show that open-source jump mats are as valid and reliable as their proprietary counterparts at a lower cost. Therefore, practitioners can be confident in using Globus or Chronojump systems to test athletes' jump height because of their negligible errors and Axon system to monitor general population. PMID- 30520442 TI - Artificial neural network simulation of lower limb joint angles in normal and impaired human gait. AB - PURPOSE: Simulating the complexities of lower limb motion can be useful for orthosis or rehabilitation planning. The aim of this study was to develop an artificial neural network (ANN) able to accurately simulate the changes in the angle of the ankle, knee and hip joints during the gait cycle, then to use it to simulate the impact of a restricted range of ankle and hip joint angle changes on the progres- sion of the knee joint angle. METHODS: Thirty four young healthy students participated in the study. Gait kinematics data were collected using the Vicon system, then analyzed with an ANN. RESULTS: We developed an ANN able to accurately simulate the progression of joint angles of lower-limb motion; its simulation of the impact of restricted ankle and hip joint angular ranges in the on the knee joint indicate that the braking phase is critical. CONCLUSIONS: ANNs offer a useful research method in clinical biomechanics. Further research in this vein should expand our understanding of compensatory functions in the lower limbs. PMID- 30520443 TI - Effects of physical exercise in winter training conditions on the thermographic temperature distribution of the horse rider's skin. AB - PURPOSE: The purpose of this work was to assess the impact of a specific equestrian training, conducted in winter weather conditions, on the thermovision temperature distribution of a rider's body surface. The study included a riding pair with 12 years of experience (female rider, aged 25, sports active and 16 year-old horse, Trakehner breed). METHODS: The study included the temperature distribution of selected parts of the rider's body (the area of the right and left shoulder blade, chest and lumbar section, and the region of the left and right cross) was carried out before and after recreational, jumping and dressage training. Each winter training has been repeated, at dif- ferent times, 10 times, giving a total of 30 workouts. The thermovision measurements were made in a separate room, always under the same conditions. RESULTS: Research has shown that, along with the increase in the level and intensity of the training, the body surface temperature of the rider increased. After recreational driving, this temperature increased, compared to the pre-workout measurement, by 3.15 degrees C, after jumping through obstacles to 4.39 degrees C, and in dressage to 5.82 degrees C. CONCLUSIONS: The highest increase in body surface temperature (on the example of dressage training) was recorded in the thoracic and lumbar part of the spine region, then in the area of the left and right scapula, while the smallest in the left and right sacral region of the rider. PMID- 30520444 TI - Changes in electromyographic signals and skin temperature during standardised effort in volleyball players. AB - PURPOSE: The state of athletes' muscles is not constant, but it differs depending on the stage of sports training, which is associated with different degrees of muscle fatigue. There is thus a need to find a non-invasive and simple method to assess muscle fatigue. The aim of the study was to determine the relationship between muscle fatigue due to physical effort and changes in skin temperature, measured using a thermographic camera. METHODS: The study involved 12 volleyball players. The participants were to maintain 70% of peak torque in the joint for as long as possible. We measured peak torque and the time of maintaining 70% of its value (tlim) as well as continuously recording skin temperature and electromyographic (EMG) signals in the region of the belly of the rectus femoris. The measurements were taken twice: before and after a series of squats. RESULTS: The study found that tlim decreased when isometric contraction was per- formed after physical effort. Pre- and post-exercise skin temperature did not differ significantly, however, the increase rates of tempera- ture and the root mean square (RMS) of the EMG signals grew significantly. In most of the players, skin temperature also correlated with the RMS, median frequency (MDF), and mean frequency (MF) of the EMG signals. CONCLUSIONS: Measuring the time of maintaining submaximal torque during isometric contraction and the slope coefficient for the increase in temperature recorded using a thermographic camera can be a simple, cost-effective, and non-invasive method of assessing fatigue and efficiency decreases in the muscles in volley- ball players. PMID- 30520445 TI - Influence of number of records on reliability of myotonometric measurements of muscle stiffness at rest and contraction. AB - PURPOSE: The aim of this study was to determine an effect of myotonometric records' number on stiffness measurements' reliability in muscles at rest and contraction. METHODS: Muscle stiffness was measured using Myoton-3 device. Twenty records were taken for: (i) biceps (BB) and triceps brachii (TB) at rest and for BB at 10% of maximal voluntary contraction (MVC) in healthy elderlies (HE) and in Parkinson's disease patients (PD); and (ii) brachioradialis (BR) at rest and at 25, 50 and 80% MVC in healthy young (HY) subjects. Also, in HY group, the 3 records mode was used for BR's measurements at maximal contraction. Each measurement taken with 20-records was classed into five records groups: the whole 20- and the first 15-, 10-, 5- and 3-records. Test-retest reliability for these records groups was analyzed. RESULTS: In HE and PD group measurements' reliability was excellent for all groups of records (20-3 rec- ords). In HY group, for the five groups of records taken at rest and submaximal levels of contraction (25, 50 and 80% MVC) the meas- urements reliability: (i) was mostly excellent or rarely average; and (ii) only in one per three 50% MVC conditions was unacceptable, i.e., for the 3-records group. The reliability of 3-records mode measurements at maximal contraction were unacceptable. CONCLUSIONS: Reliable myotonometric stiffness measurements in muscles at rest and during submaximal contractions can be achieved with less than 20 records (15, 10, 5 records) and even for the most of measurements with 3 records in HY and HE as well as in the PD patients. Myotonometric stiffness measurements with 3-records mode during maximal contraction were not reliable. PMID- 30520446 TI - Are the knee extensor and flexor muscles isokinetic parameters affected by the duration of postoperative physiotherapy supervision in patients eight months after ACL reconstruction with the use of semitendinosus and gracilis tendons autograft? AB - PURPOSE: The observational study evaluated isokinetic parameters in patients at eight months after anterior cruciate ligament reconstruction (ACLR) utilizing semitendinosus and gracilis tendons autograft, with two different modes of physiotherapy, and investigated whether analysed parameters were affected by the postoperative physiotherapy supervision duration. METHODS: Strict exclusion criteria were employed on a group of 259 ACL-reconstructed patients to identify two groups of males preoperatively well trained and frequently participating in sports, with different durations of postoperative physiotherapy supervision: Group I (n = 18; x = 27.67 weeks) and Group II (n = 20; x = 10.75 weeks). The patients underwent knee extensor and flexor muscles torques measurements with the 180 degrees /s and 60 degrees /s. The torque, position and time parameters were analysed. Limb Symmetry Index (LSI) was calculated. The parametric tests for dependent samples, parametric tests for independent samples, and linear Pearson's correlation coefficient calculations were performed. RESULTS: There were significant between-limb differences in the Group II in the knee extensor and flexor muscles torque parameters, with LSI ranging from x = 75.72 to x = 78.75 and from x = 78.69 to x = 87.82, respectively. The knee extensor muscles torque parameters and LSI values were positively correlated with the physiotherapy supervision duration. The inter-limb differences in the Group I and II in knee flexor muscles PT angle amounted to x = 10.94 degrees (180 degrees /s), x = 9.39 degrees (60 degrees /s), and x = 12.00 degrees (180 degrees /s), x = 9.75 degrees (60 degrees /s), respectively. CONCLUSIONS: The longer postoperative physiotherapy supervision was more effective for improving knee muscles torque parameters. The knee flexor muscles PT angle was shifted towards extension in the ACL-reconstructed limb, regardless of the time of postoperative physiotherapy supervision duration. PMID- 30520447 TI - A simple method of incorporating the effect of the Uniform Stress Hypothesis in arterial wall stress computations. AB - PURPOSE: Residual stress has a great influence on the mechanical behaviour of arterial wall. Numerous research groups used the Uniform Stress Hypothesis to allow the inclusion of the effects of residual stress when computing stress distributions in the arterial wall. Nevertheless, the available methods used for this purpose are very computationally expensive, due to their iterative nature. In this paper we present a new method for including the effects of residual stress on the computed stress distribution in the arterial wall. METHODS: The new method, by using the Uniform Stress Hypothesis, enables computing the effect of residual stress by averaging stresses across the thickness of the arterial wall. RESULTS: Being a post-processing method for the computed stress distributions, the proposed method is computationally inexpensive, and thus, better suited for clinical applications than the previously used ones. CONCLUSIONS: The resulting stress distributions and values obtained using the proposed method based on the Uniform Stress Hypothesis are very close to the ones returned by an existing iterative method. PMID- 30520448 TI - Acute effects of core stability exercises on balance control. AB - PURPOSE: The aim of this study was to investigate whether a single bout of core stability exercises improves body balance immediately after the bout of exercise and during a retention test. METHODS: The study involved 16 women (age 22-25 years, body weight 60.5 +/- 5.2 kg, height 166 +/- 5.4 cm). Postural stability was assessed in the mediolateral (ML) and anteroposterior (AP) planes separately on a force plate (Kistler 9286 AA) during quiet standing on a soft support surface with the eyes closed. Subjects were measured 4 times: just before (T0), 1 minutes after (T1 m), 30 minutes after (T30 m), and 24 hours after the workout (T24 h). Postural balance was evaluated by five parameters based on the center of pressure (COP) signal: variability (VAR), mean velocity (VEL), sample entropy (ENT), frequency (FRE), and fractal dimension (FRA). RESULTS: We observed a decrease in VAR and VEL in the ML plane at T30 m and T24 h, compared to T0. The COP entropy significantly increased in the ML plane at T24 h, compared to T0. CONCLUSIONS: A single bout of core stability exercises improved the control of the mediolateral body balance. This effect was evident within 30 minutes after exercise, and remained for at least 24 hours. In addition, 24 hours after exercise we observed an increased automaticity in the strategy to maintain a stable upright stance. PMID- 30520449 TI - Effect of preservation methods on tensile properties of human femur-ACL-tibial complex (FATC) - a cadaveric study on male subjects. AB - PURPOSE: Deep freezing and storing in formalin are some of the common techniques of human tissue preservation. However, the preservation modes affect the biomechanical properties of the tissues. In this work, the effects of the above stated preservation tech- niques are compared with that of fresh cadaveric samples. METHODS: FATC samples from male cadavers of age between 60 and 70 years were tested under tensile loading at a strain rate of 0.8 s-1. Fourteen FATC samples from soft embalmed cadavers were preserved for 3 weeks by two methods: (a) 10% formalin and (b) deep freezing at -20 degrees C followed by thawing. Seven FATC samples from fresh ca- davers were experimented as control samples. The results were evaluated by a two-stage statistical process of Kruskal-Wallis H test and Mann-Whitney U-test. RESULTS: It was observed that the failure force of fresh cadavers was the highest while that of preserved samples were approximately half the value. Failure elongation of frozen samples exceeded fresh samples while formalin samples failed at lesser elongations. Higher incidence of tibial insertion point or mid-section failures were observed in fresh samples while the higher incidence of ruptures at femoral insertion point was observed in the two preservation methods. CONCLUSION: Tensile properties of fresh tissues vary significantly from that of formalin preserved or frozen preserved samples. PMID- 30520450 TI - Impact of modification with cetylpyridinium chloride - a potential cariogenic microbiota inhibitor, on selected physical-mechanical properties of the water activated glass-ionomer. AB - PURPOSE: Teeth caries is one of predominant civilization diseases. Dental fillings with antimicrobial addition might allow prevention of secondary caries. The purpose of this study was to evaluate hardness and tensile strength of cetylpyridinium chloride modified water activated glass-ionomer cement. METHODS: Samples with diameter of 6 mm and height of 3 mm made of water-activated glass ionomer cement were control group (0.0%). Test groups were series of samples of the same dimensions, with addition of cetylpyridinium chloride antimicrobial in concentrations of 0.5, 1.0, 1.5 and 2.0%. Two subgroups were prepared in each group to determine Vickers Hardness and Diametral Tensile Strength after 1 and 24 hours of sample storage in distilled water. RESULTS: During hardness studies, no strong effect of antimicrobial concentration on hardness of samples was observed. Higher hardness values after 24 hours were demonstrated for all groups, compared to the samples tested after 1 hour. The exception was the group with the addition of 1% cetylpyridinium chloride, in which no statistically significant differences were observed. Diametral Tensile Strength values for samples tested after 1 hour decreased with increasing antibacterial concentration. A similar relationship was noticed for samples tested after 24 hours. No statistically signifi- cant differences were found between test samples after 1 or 24 hours. CONCLUSIONS: There was no significant effect of cetylpyridinium chloride concentration on the hardness of the samples that significantly increased during the study. With the increase in antimicrobial concentration a decrease in diametral tensile strength value was observed, but these values did not change over time. PMID- 30520451 TI - The influence of different intensity treadmill efforts on the sense of rhythm of non-professional runners - pilot study. AB - PURPOSE: The purpose of this study was to determine how global effort affects the rhythm of multi-joint coordination in the global task. We wanted to examine how this specific kind of fatigue impacts sense of rhythm. METHODS: In this study, fourteen non-professsional runners performed two effort trials of different intensity, where speed was set individually according to the speed of running when par- ticipants reached lactate threshold. Before and after each effort trial they had to perform the rhythm test. RESULTS: Two-way analysis of variance ANOVA did not reveal significant differences among the variables of pre- and post effort rhythm test. It is suggested that these results are supported by the application of different movement strategies to compensate for fatigue, and possible motor learning effect of simple timing performance. CONCLUSIONS: In our opinion the training workout routine should include cyclic technical exercises after fatigue. Not only to develop and improve energetics of movement, but also to learn and perfect different movement patterns and develop novel movement strategies. PMID- 30520452 TI - The change of volume of the lumbar vertebrae along with aging in asymptomatic population: a preliminary analysis. AB - INTRODUCTION: Previous studies have demonstrated that the length of the lumbar spine is decreasing with age. Despite considerable research based on sagittal measurements, little is known about the changes in the volume of vertebrae. The objective of this study was to evaluate the changes in the volume of either column of the spine with age. MATERIALS AND METHODS: Computed tomography scans of 62 asymptomatic subjects, performed for thoracolumbar trauma evaluation were used to create virtual 3D models. At least 10 patients were assigned to every decade of life from third to eight. We used a novel technique to measure the volume of anterior column (AC) and posterior column (PC) per each segment (a total of 310 segments). Midline sagittal images were used to measure disc height (DH) and vertebral body height (VH). RESULTS: With age, both DH increases, whereas the VH decreases. The overall length of lumbar segment of the spine decreases with age. The volumetric measurements performed on same subjects showed that volume of both AC and PC does not change with age in females. In males, there is a weak but statistically significant correlation between AC volume and age and no change in the volume of PC. The ratio of PC:AC volume does not change with age in women, although it decreases slightly but significantly (in favor of AC) with age in males. CONCLUSIONS: The overall length of lumbar spine decreases with age. This process is not a result of mere changes in the volume of either AC or PC. PMID- 30520453 TI - Force analysis of shoulder joint muscles in the early phase of brain stroke. AB - PURPOSE: Upper limb impairment in the early phase of brain stroke is one of the key problems in rehabilitation. An estimation of muscle force can be a helpful factor for functional improvement after a stroke. The primary goals of this study were to determine the muscles with the lowest force in the affected (A) and non affected (non-A) upper limb. Moreover, the differences between men and women were compared and these values were correlated with age. METHODS: One hundred (n = 35 female, n = 65 male) post-stroke pa- tients met the inclusion criteria. The mean age of the study participants was 66.1 years. Muscle force for external and internal rotators of shoulder was measured with handheld dynamometer. Moreover, the correlation coefficients for differences in muscular force with the patient's age were estimated. RESULTS: Our study reports that the force of the (A) side in relation to the (non-A) was by 37% weaker. We observed about a 40% decrease in the force of the shoulder's external rotation (female - 42%; male - 41%) and shoulder's flexion (by 38% - female; 40% - male). Significant correlations between the muscle force and the age of post-stroke patients were also found. It was concluded that about 4 weeks after the first stroke in the patient's life, the external rotators are the most affected group of shoulder muscles. CONCLUSIONS: Neither sex nor the side of the ischemic brain injury influence the muscle force, whereas age determines both muscle force and muscle force deficits. Older post-stroke patients demonstrate fewer deficits in muscle strength than younger ones. PMID- 30520454 TI - Center of plantar pressure during gait in pregnancy-related pelvic girdle pain and the effect of pelvic belts. AB - PURPOSE: Many pregnant women suffer from pelvic girdle pain (PGP) during pregnancy. Etiologies are multifactorial and affect the joint stability of the sacroiliac joint. Pelvic belts could restore stability and reduce pain during gait. The center of pressure (COP) is a reliable parameter to assess gait and balance. The objectives of this study were to analyze the COP during gait in pregnant women with PGP, to evaluate the effect of pelvic belts and to compare two types of belts on COP parameters. MATERIALS AND METHODS: 46 pregnant women with PGP, 58 healthy pregnant women and 23 non-pregnant women participated in the study. The motor task consisted of three gait trials at different velocities on an electronic walkway. Two pelvic belts for pregnant women were used. An analysis of variance was performed to determine the effects of the progression of the pregnancy, gait speed, presence of pregnancy and occurrence of pain on the COP parameters. RESULTS: Compared to the control group, pregnant women with PGP had a higher stance time, but COP displacement and velocity were lower. The COP parameters varied between pregnant women with and without pelvic girdle pain, the use of a belt during pregnancy decreased the walking velocity. No difference was found according to the type of belt. CONCLUSIONS: Differences in COP parameters during gait between pregnant women with or without PGP were minimal. Pelvic girdle pain did not affect the center of pres- sure. Wearing a belt during pregnancy modified the center of pressure velocity during gait in pregnant women with PGP. PMID- 30520456 TI - [Presentation]. PMID- 30520455 TI - [2018 ESC/ESH Guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH)]. PMID- 30520457 TI - [What's new in the 2018 ESC/EACTS guidelines on myocardial revascularization?] AB - A revised version of the European Society of Cardiology (ESC) and European Association for Cardio-Thoracic Surgery (EACTS) guidelines on myocardial revascularization has recently been published. These guidelines represent the third time that the ESC and EACTS have brought together cardiologists and cardiac surgeons in a joint Task Force to review the available evidence, with the mission of drafting balanced, patient-oriented, clinical practice guidelines on myocardial revascularization. During the last 4 years, a large body of evidence has become available and brought substantial changes to the guidelines. This paper aims to summarize what is new in the 2018 ESC/EACTS guidelines on myocardial revascularization. PMID- 30520458 TI - [Revascularization in stable coronary artery disease: what does the future hold after the ORBITA trial?] PMID- 30520459 TI - [Is angioplasty in patients with stable coronary artery disease only a placebo? Absolutely not]. PMID- 30520460 TI - [Coronary artery disease: when to withhold a decision and call in the Heart Team? Almost every time]. AB - The multidisciplinary discussion is a well-established method, highly widespread in different medical disciplines, with documented optimal results. This practice, despite mandate by international guidelines, is not universally applied to guide treatment in coronary artery disease (CAD) patients. The literature provides data both on overtreatment or undertreatment in different patient subsets, clearly suggesting its strong need. Randomized trials, meta-analyses and registries provide evidence-based treatment options for different patient subsets suffering from different conditions, although results are applicable only to highly selected populations enrolled in clinical trials, making generalizability of results to routine practice limited. CAD patients are usually elderly and with a comorbidity burden that does not allow for the simple application of clinical trial results to obtain the best clinical practice. Thus, multidisciplinary discussion within the Heart Team, through different professional expertise sharing, allows to select the best treatment option for the individual patient. PMID- 30520461 TI - [Coronary artery disease: when to withhold a decision and call in the Heart Team? Almost never]. AB - The expansion of the options for the treatment of patients with stable multivessel coronary artery disease (CAD), including medical therapy or myocardial revascularization by a surgical or a percutaneous strategy, has raised the need to set the decision-making process to select the optimal therapy on a multidisciplinary approach. Indeed, this latter would potentially lead to identify the most appropriate strategy for a given patient in the most transparent, shared and comprehensive way as possible. The multidisciplinary approach has been widely encouraged in the cardiovascular field, where it has been defined as "Heart Team" (HT), a collegial system essentially including a cardiac surgeon, a clinical cardiologist and an interventionalist. However, due to the unavailability of on-site surgery in many centers, along with the increasing use of sophisticated materials and advanced technologies, the growing confidence of interventionalists with more meticulous and complex techniques, in addition to sharper guideline indications, the HT approach may currently lead to an anachronistic and unjustified slowdown of the decision-making process, sometimes until impasse, with subsequent increase in social and health costs. Therefore, the present article will examine the possibilities to judiciously restrict the actual HT use for choosing the treatment of patients with stable multivessel CAD at higher complexity. PMID- 30520462 TI - [Tips and tricks: how to do a good coronary angioplasty? Instructions for use]. AB - Percutaneous coronary angioplasty celebrated its 40th anniversary and gained an established role thanks to its remarkable results. The progressive development of techniques and materials together with a better understanding about the pharmacological treatment of patients with coronary artery disease contributed to this success. Nowadays percutaneous treatments have become a valid alternative to coronary artery bypass graft surgery in many patients. In this article we will highlight practical "tips and tricks" to improve the performance and the results of percutaneous coronary interventions. PMID- 30520464 TI - Retraction of: Optimization of Suzhou Creek Rehabilitation Project Stage 1: Based on Water Quality Model, by Zuxin Xu and Zhenliang Liao. Environ Eng Sci 2006; 23(2):253-262. DOI: 10.1089/ees.2006.23.253. AB - [This retracts the article DOI: 10.1089/ees.2006.23.253.]. PMID- 30520463 TI - [The hybrid strategy for complete myocardial revascularization in the frail elderly patient]. AB - The hybrid strategy allows for a complete myocardial revascularization in patients with multivessel coronary artery disease and a high frailty index. These patients, due to their old age and multi-comorbidities, are evaluated with inadequate tools for their clinical complexity and destined to an incomplete revascularization for increased surgical or procedural risk. Hybrid revascularization enables to use the best techniques resulting from the surgical and percutaneous approach defining a tailored strategy for the patient. In the frail patient, this strategy is associated with favorable outcomes and a lower exposure to periprocedural complications. PMID- 30520465 TI - Visual detection of cancer cells by using in situ grown functional Cu2 xSe/reduced graphene oxide hybrids acting as an efficient nanozyme. AB - A simple protocol for in situ growth of Cu2-xSe nanoparticles on graphene oxide hybrids (Cu2-xSe/rGO) acting as an efficient nanozyme is developed and thus a sensitive visual detection method of cancer cells is proposed. The Cu2-xSe/rGO heterogeneous nanomaterials have been proven to exhibit high peroxidase-like activity to catalyze the reaction of the peroxidase substrate in the presence of hydrogen peroxide. Herein, we used Cu2-xSe/rGO as a signal transducer to develop a colorimetric assay for the direct detection of cancer cells and a total of 63 cancer cells (MCF-7) can be distinguished by naked-eye observation. The results showed that the Cu2-xSe/rGO hybrids could be the promising nanozyme mimetics for potential applications in bioanalytical fields. PMID- 30520466 TI - Bacterial detection and identification from human synovial fluids on an integrated microfluidic system. AB - Periprosthetic joint infections (PJIs) are among the most severe complications emerging from prosthetic joint replacement surgeries. In order to possess a rapid means of diagnosing PJIs, an integrated microfluidic system was developed herein for detecting and identifying bacteria in human synovial fluid (HSF). The entire molecular diagnostic process, including (1) sample treatment, (2) bacterial isolation, (3) bacterial lysis, (4) nucleic acid amplification (via polymerase chain reaction (PCR)), and (5) optical detection, could be automated on a single chip. First, N-acetyl-l-cysteine was used to decrease the viscosity of HSF samples and consequently enhance bacterial isolation with vancomycin-coated nano magnetic beads. Then, a universal 16S ribosomal ribonucleic acid PCR primer set and four species-specific primer sets were used for PCR-based detection and identification of four common bacteria previously associated with PJIs, including Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, and Acinetobacter baumannii. With this approach, the limit of detection was as low as 100 colony forming units (CFUs) per milliliter (or 20 CFUs per reaction), which is suitable for clinical diagnostics and for making informed decisions regarding post-operative antibiotic administration. More importantly, bacterial detection and identification data could be acquired within 90 minutes, representing a significant improvement over traditional culture-based methods (3-7 days). The developed microfluidic system may therefore serve as a promising tool for rapid diagnosis of PJIs. PMID- 30520467 TI - Digital versatile discs as platforms for multiplexed genotyping based on selective ligation and universal microarray detection. AB - The development of a high-performance assay readout using integrated detectors is a current challenge in the implementation of DNA tests in diagnostic laboratories, particularly for supporting pharmacogenetic tests. A method for allelic discrimination, associated with single nucleotide polymorphisms (SNPs), is presented. Genomic DNA is extracted from blood and buccal swab samples. The procedure comprises fast multiplex ligation-dependent probe amplification, PCR amplification using universal primers and subsequent barcode hybridization. In this last step, each product is recognized by the specific probes immobilized on the surface of an optical disc. Assay results can be obtained with a disc reader. The optical sensing method in a DNA microarray format was optimized and evaluated for the simultaneous identification of 28 polymorphisms associated with psychiatric pharmacogenomics. The target biomarkers were located in the genes related to drug-metabolizing enzymes and drug transporters. The multiplexing capability and assay selectivity strongly depended on correct design (ligation probes, tails and barcodes). The discriminant analysis of reader outputs (spot intensities) led to patients being classified into different allelic populations. The obtained assignations correlated properly with the results provided by the reference technique (bead arrays), and the assay ended in an 8-fold shorter time using affordable equipment. The combination of a highly selective genotyping reaction as array-MLPA and the compact disc technology provides a reliable point of-care approach. This genotyping tool is useful for the selection of personalized drug therapies in decentralized clinical laboratories. PMID- 30520468 TI - Remarkable photoluminescence of europium(ii)-doped phosphate cyan@red-emitting phosphors with highly dispersed luminescence centers. AB - Europium(ii)-doped phosphate cyan@red-emitting phosphors with highly dispersed luminescence centers were developed for the first time by using the deposition precipitation method. Amazingly, when excited by near-ultraviolet light, the single phosphor generated warm white light with an adjustable correlated colour temperature (4000-2500 K) and high colour-rendering index (Ra ~ 90). PMID- 30520469 TI - Front cover. PMID- 30520470 TI - Inside front cover. PMID- 30520471 TI - Contents list. PMID- 30520472 TI - Inside back cover. PMID- 30520473 TI - Back cover. PMID- 30520474 TI - Inside front cover. PMID- 30520476 TI - Back cover. PMID- 30520475 TI - Front cover. PMID- 30520477 TI - Inside back cover. PMID- 30520478 TI - Reduced graphene oxide wrap buffering volume expansion of Mn2SnO4 anodes for enhanced stability in lithium-ion batteries. AB - MSnO4 (M = Mn, Zn, Co, Mg, etc.) has been widely investigated as an anode material for lithium-ion batteries in recent years, but its practical applications are limited by serious capacity loss caused by severe volume expansion during Li+ insertion/extraction. So far, hollow structures, carbon coating, and encapsulation by reduced graphene oxide have been introduced to improve the electrochemical properties of MSnO4. In this study, Mn2SnO4 nanoparticles@reduced graphene oxide (Mn2SnO4@rGO) composites were prepared using simple steps and applied as anode materials for lithium-ion batteries. The rGO sheet encapsulated Mn2SnO4 nanoparticles show improved electrochemical properties. The first discharge capacity of Mn2SnO4@rGO reaches 1223.5 mAh g-1 and remains at 542.0 mAh g-1 after 100 cycles at a current density of 0.1 A g-1. The electrochemical properties were significantly improved compared to those of pure Mn2SnO4 nanoparticles. PMID- 30520479 TI - Development of bismuth-functionalized graphene oxide to remove radioactive iodine. AB - Bismuth-functionalized graphene oxide (Bi-GO) was successfully synthesized and showed both high iodide and iodate removal efficiencies from radioactive wastewater. Batch experiments for kinetic and selectivity tests were performed, respectively. Additional SEM, XRD, FT-IR, and XPS analyses were performed for characterization of a sorbent and bismuth on the GO surface and this confirmed that bismuth on the GO surface reacted with iodine species by surface complexation (or precipitation). Dominant surface species are BiOI and Bi(IO3)3 for iodide and iodate removal, respectively. After the selectivity test using a KCl background solution with varying concentrations, Bi-GO still showed higher removal efficiencies (>=95%) for both iodide and iodate than the commercial silver-exchanged zeolite (>=95% for iodide and <=25% for iodate). Our study suggests the potential application of Bi on graphene-based materials for selective removal of both iodide and iodate from radioactive wastewater. PMID- 30520480 TI - Contents list. PMID- 30520481 TI - Elucidating the multiple structures of pipecolic acid by rotational spectroscopy. AB - The complex conformational space of the non-proteinogenic cyclic amino acid pipecolic acid has been explored in the gas phase for the first time. Solid pipecolic acid samples were vaporized by laser ablation and expanded in a supersonic jet where the rotational spectral signatures owing to nine different conformers were observed by Fourier transform microwave spectroscopy. All species were identified by comparison of the experimental rotational and nuclear quadrupole coupling constants with those predicted theoretically. Observation of type-III conformers, leading to a difference when compared against the conformational behavior of the analog amino acid proline, has been interpreted by an increment in steric hindrance when increasing the number of carbons present in the ring. PMID- 30520482 TI - A revolution of photovoltaics: persistent electricity generation beyond solar irradiation. AB - Renewable energy utilization by energy conversion devices is regarded as a promising solution to resolve energy crisis and environmental pollution problems. Solar energy occupies 99% of the total energy of the Earth; therefore, the development of photovoltaic technology to convert solar energy into electricity is attracting considerable interests. The state-of-the-art research in this field mainly focuses on the improvement of power conversion efficiency under the sunlight irradiation by new materials development, device structure optimization, technique innovation, etc. In real natural environments, there is no or negligible sunlight for at least half of the time, particularly during rainy, foggy days or at night. Therefore, it is a challenging but promising strategy to develop new-type solar cells that can persistently harvest waste energies from nature without sacrificing the solar-to-electric conversion ability. In theory, these photovoltaics may break through the theoretical efficiency limitation and maximize the total power output. In this frontier article, the status quo of these physical proof-of-concept hybrid solar cells as well as the preparation methods of the solar cell architectures, and why harvesting waste energies are discussed. According to the working principles, the possible strategies of improving waste energy conversion efficiency are also envisaged. PMID- 30520483 TI - Magnetic, thermal, and neutron diffraction studies of a coordination polymer: bis(glycolato)cobalt(ii). AB - The two-dimensional quadratic lattice magnet, bis(glycolato)cobalt(ii) ([Co(HOCH2CO2)2]), showed antiferromagnetic ordering at 15.0 K and an abrupt increase in magnetisation at H = 22 600 Oe and 2 K, thereby acting as a metamagnet. Heat capacity measurements revealed that the associated entropy change DeltaS around the transition temperature was evaluated to be 6.20 J K-1 mol-1 and that the Co(ii) ion had the total angular momentum of J = 1/2 at low temperatures. Neutron diffraction studies suggested that the magnetic moment vectors of the Co(ii) ions had an amplitude of 3.59MUB and were not aligned in a fully antiparallel fashion to those of their neighbours, which caused canting between the magnetic moment vectors in the sheet. The canting angle was determined to be 7.1 degrees . Canting induced net magnetisation in the sheet, but this magnetisation was cancelled between sheets. The magnetisations in the sheets were oriented parallel to the magnetic field at the critical magnetic field. PMID- 30520484 TI - Transmembrane domain dimerization induces cholesterol rafts in curved lipid bilayers. AB - Are the dimerization of transmembrane (TM) domains and the reorganization of the lipid bilayer two independent events? Does one event induce or interfere with the other? In this work, we have performed well-tempered metadynamics simulations to calculate the free energy cost to bend a model ternary lipid bilayer in the presence of a TM peptide in its dimer form. We have compared this result with the free energy cost needed to bend a bilayer-only system. Additionally, we have calculated the free energy cost to form a model TM peptide dimer quantitatively describing how lipids reorganize themselves in response to the increase of the membrane curvature and to the lipid-peptide interactions. Our results indicate that the formation of the peptide dimer inside the bilayer increases the cost of the membrane bending due to the spontaneous clustering of cholesterol molecules. PMID- 30520485 TI - Reversible complexation of ammonia by breaking a manganese-manganese bond in a manganese carbonyl ethylenedithiolate complex: a theoretical study of an unusual type of Lewis acid. AB - The reaction of Mn(CO)5Br with sodium ethylenedithiolate was reported in 1968 to give a dark red binuclear H2C2S2Mn2(CO)6 complex possessing the unusual property of complexing reversibly with ammonia to give a yellow H2C2S2Mn2(CO)6.NH3 adduct. In order to provide some insight into the nature of this adduct, density functional studies were performed on the H2C2S2Mn2(CO)n (n = 4 to 8) systems as well as their relevant ammonia and trimethylphosphine adducts. These theoretical studies support the structure of H2C2S2Mn2(CO)6 originally suggested 50 years ago involving the binding of the ethylenedithiolate C[double bond, length as m-dash]C double bond as well as the sulfur atoms to the Mn2 unit with a bonding Mn-Mn distance of ~2.8 A. Complexation of H2C2S2Mn2(CO)6 with NH3 or Me3P preserves the complexed C[double bond, length as m-dash]C double bond of the ethylenedithiolate ligand but lengthens the MnMn distance to a non-bonding ~3.6 A. Thus H2C2S2Mn2(CO)6 represents a novel type of Lewis acid where reversible complexation with Lewis bases involves the rupture of a metal-metal bond. Carbonyl dissociation energies in the H2C2S2Mn2(CO)n series account for the formation of the hexacarbonyl H2C2S2Mn2(CO)6 as the stable product from the Mn(CO)5Br/ethylenedithiolate reaction. PMID- 30520486 TI - Synthesis of modified beta-methoxyphenylalanines via diazonium chemistry and their incorporation in desoxycyclomarin analogues. AB - The marine natural products cyclomarins have remarkable anti-mycobacterial and antiplasmodial activities. The heptapeptic structure of this compound class comprisis four highly interesting non-canonical amino acids, including a rather unusual syn beta-methoxyphenylalanine. To get a deeper insight into the structure activity realtionship of cyclomarines, a straightforward protocol for the stereoselective synthesis of this building block was developed, based on diazonium chemistry. PMID- 30520487 TI - Enhanced intrinsic CYP3A4 activity in human hepatic C3A cells with optically controlled CRISPR/dCas9 activator complex. AB - Human hepatic C3A cells have been applied in bioartificial liver development, although these cells display low intrinsic cytochrome P450 3A4 (CYP3A4) enzyme activity. We aimed to enhance CYP3A4 enzyme activity of C3A cells utilizing CRISPR gene editing technology. We designed two CYP3A4 expression enhanced systems applying clustered regularly interspaced short palindromic repeats (CRISPR) gene technology: a CRISPR-on activation system including dCas9-VP64-GFP and two U6-sgRNA-mCherry elements, and a light-controlled CRISPR-on activation system combining our CRISPR-on activation system with an optical control system to facilitate regulation of CYP3A4 expression for various applications. Results of enzymatic activity assays displayed increased CYP3A4 activity in C3A cells expressing the CRISPR-on activation system compared with C3A cells. In addition, CYP3A4 activity increased in C3A cells expressing the light-controlled CRISPR-on activation system under blue light radiation compared with C3A cells. Notably, there was no statistical difference in the increase of CYP3A4 protein amounts induced by these two methods. After expansion in culture, C3A cells with the light-controlled CRISPR-on activation system exhibited no statistical difference in CYP3A4 mRNA levels between generations. Our findings provide a method to stably enhance functional gene expression in bioartificial liver cells with the potential for large-scale cell expansion. PMID- 30520488 TI - Flowback verses first-flush: new information on the geochemistry of produced water from mandatory reporting. AB - Unconventional oil and gas development uses the subsurface injection of large amounts of a variety of industrial chemicals, and there are concerns about the return of these chemical to the surface with water produced with oil and gas from stimulated wells. Produced water, including any flowback of injected fluids, must be managed so as to protect human health and the environment, and understanding the chemistry of produced water from stimulated wells is necessary to ensure the safe management of produced water. In 2014, California instituted mandatory reporting for all well stimulations, including sampling produced water two times and comprehensive chemical characterization of fluids injected and fluids recovered from stimulated wells. In this study, we analyzed data from mandatory reporting with the objective of closing previously identified data gaps concerning oil-field chemical practices and the nature of flowback and produced water from stimulated wells. It was found that the plug-flow conceptual model of flowback developed in shale formations, where salinity increases over time as produced water is extracted, was not appropriate for characterizing produced water from unconventional wells in these oil reservoirs, which are predominately diatomite and sandstones. In these formations stimulation caused a "first-flush" phenomena, where salts and metals were initially high and then decreased in concentration over time, as more produced water was extracted. Although widely applied to meet regulatory requirements, total carbohydrate measurement was not found to be a good chemical indicator of hydraulic fracturing flowback. Mandatory reporting closed data-gaps concerning chemical use, provided new information on acid treatments, and allowed more detailed analysis of hydraulic fracturing practices, including comparison of water use by geological formation. PMID- 30520489 TI - Electronic versus steric control in palladium complexes of carboranyl phosphine iminophosphorane ligands. AB - A new family of carboranyl phosphine-iminophosphorane ligands was prepared and characterized. The new ligands present a carboranyl group directly attached to the iminophosphorane nitrogen atom through a cage carbon atom (C-carboranyl derivatives L1-L3) or through the B3 boron atom (B-carboranyl derivatives L4 and L5), and the phosphine group on a side chain derived from the diphosphine dppm, i.e. with a two-atom spacer between the P and N donor atoms. The non-carboranyl analogue L6, with a biphenyl group on the nitrogen atom, was also synthesized for comparison. These potential (P, N) ligands were used to obtain palladium complexes (Pd1-Pd6) and, thus, study how the different inductive effect of the carboranyl substituents can modify the coordinating ability of the nitrogen atom. The structural analysis of the complexes revealed two different coordination modes for the ligands: the (P, N) chelate coordination and the unexpected P terminal coordination, which is not observed for non-carboranyl phosphine iminophosphoranes. These unexpected structural differences led us to perform DFT calculations on the ligands and metal complexes. The calculations show that the final coordination modes depend on the balance between the electronic and steric properties of the particular carboranyl group. PMID- 30520490 TI - Copper(i)-polymers and their photoluminescence thermochromism properties. AB - Under hydro(solvo)thermal conditions, four organic bidentate bridging N,N'-donor ligands 1,3-bis(2-methylimidazol-1-yl)propane (L1), 4,4'-di(1H-imidazol-1-yl) 1,1'-biphenyl (L2), 1,2-bis(2-methyl-1H-imidazol-1-ylmethyl)benzene (L3) and 5,6,7,8-tetrahydroquinoxaline (L4) were employed to react with CuBr/CuI, generating four 2-D layered copper(i)-polymer coordination polymer materials [Cu2Br2(L1)] 1, [CuI(L2)] 2, [CuI(L3)] 3 and [CuI(L4)0.5] 4. In 1-4, different Cu X motifs are found: a cubic Cu4Br4 core in 1; a castellated Cu-I single chain in 2; a rhombic Cu2I2 core in 3; and a staircase-like Cu-I double chain in 4. The 2 D layer networks of 1-3 can all be simplified into a simple 44 topology (planar for 1 and 3; wave-like for 2), while the 2-D layer network of 4 has a 63 topology. The photoluminescence behaviors of 1-4 under a UV lamp suggest that 1 and 2 possess fluorescence thermochromism properties. Under the UV lamp, with the decrease in temperature, (i) 1 exhibits a yellow-to-red emission; (ii) 2 exhibits a yellow-to-green emission; (iii) 3 always emits green light; and (iv) 4 never emits light. These are further confirmed by their emission spectra. From 297 K to 77 K, the emission of 1 exhibits a large red shift from 561 nm to 623 nm; the emission of 2 exhibits a large blue shift from 571 nm to 515 nm; only a minor red shift is observed for the emission of 3; and no peaks appear in the emission spectra of 4. The crystal data of 1 and 2 at different temperatures have been collected for revealing the origination of their fluorescence thermochromism properties. Based on the above investigations, the effect of the rigidity/flexibility of the organic ligand on the fluorescence thermochromism properties of copper(i)-polymer coordination polymer materials is discussed. The quantum yields at 297 K and the photoluminescence lifetimes at 297 K and 77 K for 1-3 were also measured for better understanding their photoluminescence properties. PMID- 30520491 TI - Access and unprecedented reaction pathways of Li/Cl phosphinidenoid iron(0) complexes. AB - Complexes [Fe(CO)4(RPCl2)] (2) (a: R = CPh3, b: R = tBu) were used to generate the first examples of phosphinidenoid iron(0) complexes [Li(12-crown 4)(solv)n][Fe(CO)4(RPCl] (3a,b), characterized by NMR spectroscopy. The bonding situation of 3 was analyzed for a P-Me model complex using DFT calculations. Complex 3a (R = CPh3) reacted with H2O and MeOH to give selectively O-H bond insertion products 5 and 7; for the case of H2O, a multistep electrophilic reaction is supported by detailed DFT calculations. Clear-cut evidence for an unprecedented electrophilic reactivity of 3a was obtained as a reaction with MeLi led to P-chloro substitution. The intermediately formed phosphanido complex [Fe(CO)4(Ph3CPMe)] (8) was quenched with HCl or MeOTf to furnish neutral iron(0) complexes 9 and 10. PMID- 30520492 TI - Anthracene-rhodium complexes with metal coordination at the central ring - a new class of catalysts for reductive amination. AB - A new class of anthracene complexes with a metal coordinated at the central ring was applied in catalysis for the first time. As a result, a simple and efficient protocol for reductive amination that involves CO as a reducing agent has been developed. The rhodium complex [(cyclooctadiene)Rh(C10H4Me2(OMe)4)]+ (1 mol%) catalyses such reactions under mild conditions (40-130 degrees C) and produces a variety of amines in good yields (74-95%) without affecting the functional groups. The protocol is acceptable for all combinations of aldehydes (aromatic and aliphatic), ketones (aromatic and aliphatic) and amines (aromatic and aliphatic; primary and secondary). PMID- 30520493 TI - Enhanced release of palladium and platinum from catalytic converter materials exposed to ammonia and chloride bearing solutions. AB - The environmental levels of platinum group elements (PGEs) are steadily rising, primarily due to exhaust emissions of vehicle catalytic converter (VCC) materials containing solid PGEs. Once these VCC materials reach soil and water, the PGEs may be transported in the form of nanoparticles (dimensions 1-100 nm) or they may be mobilized by forming coordination complexes with ligands in the environment. Chloride (Cl-) and ammonia (NH3) are two ligands of particular concern due to their ubiquity as well as their potential to form the chemotherapy drug cisplatin (Pt(NH3)2Cl2) or other potentially bioactive complexes. This initial study examines the release of Pd and Pt into solutions exposed to VCC materials at pH 8 and 25 degrees C, using elemental analysis of metal content in post-exposure extracts. The solutions had total ammonia nitrogen concentrations (TAN, [NH4+] + [NH3]) of 0 MUM, 5.56 MUM, 55.6 MUM and 1.13 * 105 MUM (0 ppm, 0.1 ppm, 1 ppm, and 2147 ppm). The former three represent background environmental levels had a minimal effect on release. However, when combined with 1.13 * 105 MUM Cl- (4000 ppm Cl-), 55.6 MUM TAN induced a marked increase in metal release (~41* for Pd). High TAN solutions induced more Pd and Pt release than equimolar NaCl solutions. Materials characterization revealed that ~4 nm palladium-containing nanoparticles were present, spatially associated with nanoparticles of gamma-Al2O3; ceria zirconia nanoparticles were also present but did not have any metal associated with them. Platinum-containing nanoparticles were not observed. PMID- 30520494 TI - Cholesterol in phospholipid bilayers: positions and orientations inside membranes with different unsaturation degrees. AB - Cholesterol is an essential component of all animal cell membranes and plays an important role in maintaining the membrane structure and physical-chemical properties necessary for correct cell functioning. The presence of cholesterol is believed to be responsible for domain formation (lipid rafts) due to different interactions of cholesterol with saturated and unsaturated lipids. In order to get detailed atomistic insight into the behaviour of cholesterol in bilayers composed of lipids with varying degrees of unsaturation, we have carried out a series of molecular dynamics simulations of saturated and polyunsaturated lipid bilayers with different contents of cholesterol, as well as well-tempered metadynamics simulations with a single cholesterol molecule in these bilayers. From these simulations we have determined distributions of cholesterol across the bilayer, its orientational properties, free energy profiles, and specific interactions of molecular groups able to form hydrogen bonds. Both molecular dynamics and metadynamics simulations showed that the most unsaturated bilayer with 22:6 fatty acid chains shows behaviour which is most different from other lipids. In this bilayer, cholesterol is relatively often found in a "flipped" configuration with the hydroxyl group oriented towards the membrane middle plane. This bilayer has also the highest (least negative) binding free energy among liquid phase bilayers, and the lowest reorientation barrier. Furthermore, cholesterol molecules in this bilayer are often found to form head-to-tail contacts which may lead to specific clustering behaviour. Overall, our simulations support ideas that there can be a subtle interconnection between the contents of highly unsaturated fatty acids and cholesterol, deficiency or excess of each of them is related to many human afflictions and diseases. PMID- 30520495 TI - The interplay between activity and filament flexibility determines the emergent properties of active nematics. AB - Active nematics are microscopically driven liquid crystals that exhibit dynamical steady states characterized by the creation and annihilation of topological defects. Motivated by differences between previous simulations of active nematics based on rigid rods and experimental realizations based on semiflexible biopolymer filaments, we describe a large-scale simulation study of a particle based computational model that explicitly incorporates filament semiflexibility. We find that energy injected into the system at the particle scale preferentially excites bend deformations, reducing the apparent filament bend modulus. The emergent characteristics of the active nematic depend on activity and flexibility only through this activity-renormalized bend 'modulus', demonstrating that apparent values of material parameters, such as the Frank 'constants', depend on activity. Thus, phenomenological parameters within continuum hydrodynamic descriptions of active nematics must account for this dependence. Further, we present a systematic way to estimate these parameters from observations of deformation fields and defect shapes in experimental or simulation data. PMID- 30520496 TI - Deciphering crystal packing effects in the spin crossover of six [FeII(2 pic)3]Cl2 solvatomorphs. AB - In this work we investigate how the crystal packing affects the spin crossover (SCO) of [FeII(2-pic)3]Cl2. Four alcohol solvatomorphs of this compound have been reported to present a transition from a singlet low spin (LS, S = 0) to a quintet high spin (HS, S = 5) state at different temperatures, whereas two other solvatomorphs remain in the HS state along the entire range of temperatures explored. Given that all these solvatomorphs are isostructural, this behavior hints at crystal packing effects playing an important role in the spin transition. With the aim of deciphering their origin, we performed periodic DFT+U+D2 computations on the crystal lattices of the six solvatomorphs to quantify the importance of all possible molecular and intermolecular contributions to their spin-state energetics. We demonstrate that the spin crossover of the alcohol solvatomorphs of [FeII(2-pic)3]Cl2 (1) is strongly influenced by the change of intermolecular interactions. We prove that isolated molecules of 1 would not undergo SCO, whereas intermolecular interactions are crucial to allow the spin transition in the solid state. The key interactions are those between (i) different SCO molecules (stabilizing the LS) and (ii) between SCO molecules and counterions (stabilizing the HS). Moreover, we show that these contributions are proportional to the crystal expansion associated with the phase change, in a way that larger volume expansions imply larger changes in these contributions, with the overall effect of stabilizing the LS state of the material. Finally, we discuss how our results challenge the common perspective that associates the cooperativity of a spin transition with the number- and strength- of intermolecular contacts in the crystal. PMID- 30520497 TI - Construction and efficient dye adsorption of supramolecular hydrogels by cyclodextrin pseudorotaxane and clay. AB - Supramolecular hydrogels, which are usually used to develop excellent smart soft materials, are widely applied in miscellaneous fields due to their inherent reversible properties, unique functions and mechanical properties. Compared with covalently linked hydrogels, supramolecular hydrogels have advantages of easy preparation, stimulus responsiveness and good biocompatibility. Herein, after threading amino-modified beta-cyclodextrins onto poly(propyleneglycol)bis(2 amionopropylether) (PPG-NH2) chains, the resultant pseudorotaxanes non-covalently interacted with a clay nanosheet (CNS) matrix to construct supramolecular hydrogels bearing negative charges, and the mechanical properties of these hydrogels were positively correlated with the number of amino groups on the pseudorotaxane. Significantly, these hydrogels presented good adsorption properties for cationic dyes. The adsorption capacity (Qe) of the hydrogels towards rhodamine B (RhB), crystal violet (CV), and methylene blue (MB) could reach 181-228 mg g-1, and most of the dyes were adsorbed within 5 min. Thus, these hydrogels may have potential applications in the field of waste water treatment. PMID- 30520498 TI - Premarital hepatitis screening. Attitude towards screening and the risk factors for transmission. AB - OBJECTIVE: To explore all research articles investigating hepatitis premarital screening programs (PSPs) worldwide, considering all different outcomes of such programs, including efficacy, possible limitations to screening, and participants' knowledge and satisfaction regarding the program. Methods: The present systematic review used the databases of PubMed, Ovid Medline, and Google Scholar to search for articles related to both PSPs and the hepatitis viruses. Research articles were identified between October and December 2017, and articles were selected and extracted based on predefined inclusion and exclusion criteria from the year 1957 up to 2017. The review included all full-length original articles related to premarital hepatitis screening in both indexed and non indexed journals, but reviews, mini-reviews, and letters were excluded. Ultimately, 4 research papers were included. While conducting the search, the project was registered on PROSPERO database. Results: In all these papers, the participants' attitude toward premarital screening was good, but their level of knowledge about the program and the diseases being screened was low. Pre- and post-test counseling were provided to only a limited number of participants in each of the studies. This emphasizes the need for effective counseling sessions, which may help in decreasing the hepatitis burden in Saudi Arabia and worldwide. Conclusions: The role of the practicing physician in any screening program is to provide effective pre and post-test counseling and correct any misinformation about the transmission of the hepatitis viruses. PMID- 30520499 TI - Risk factors and molecular features of extended-spectrum beta-lactamase producing bacteria at southwest of Saudi Arabia. AB - OBJECTIVES: To explore the risk factors, the prevalence rate, and gene types of extended-spectrum beta-lactamase (ESBL)-producing bacteria as the causative agents of infection at King Abdulaziz Specialist Hospital (KAASH), Taif, Kingdom of Saudi Arabia. Methods: This was a retrospective study conducted during the period between February 2017 and January 2018. All samples obtained from the KAASH were analyzed. The MicroScan Walkaway System, bacteriological examination and double disk synergy tests were used to detect ESBL-producing bacteria. To identify ESBL genes, the polymerase chain reaction (PCR) technique was used. Results: The ESBL phenotype was detected in 351 of 1151 isolates (30.5%); Escherichia coli (E. coli) (62.7%) and Klebsiella pneumoniae (K. pneumoniae) (23.6%) were the most prevalent. The highest proportion of ESBL specimens was found in urine (62%.5), and these organisms were mainly isolated from the female medical ward (20.2%). Based on the statistical analysis, lung diseases, renal diseases, diabetes and heart diseases contributed to the spread of ESBL infections. Amikacin, imipenem, meropenem and tigecycline were found to be effective in overcoming ESBL infections; however, these antibiotics may be inappropriate for new strains of K.pneumoniae. The distribution of the blaCTX-M gene was high (87%), compared with blaTEM (74.9%) and blaSHV (29.4%). Conclusion: These data provide new epidemiological information about the prevalence of ESBL-producing organisms among patients in KAASH, Taif, Saudi Arabia. In addition, this study identified the clonal nature of isolated E.coli and K.pneumoniae. PMID- 30520500 TI - Screening for Q fever. A tertiary care hospital-based experience in central Saudi Arabia. AB - OBJECTIVES: To evaluate the presence of Coxiella burnetii (C. brunetii) infection among patients presenting with fever of unknown origin (FUO). METHODS: A cross-sectional study of 100 patients (54 men and 46 women; mean age: 34.3 +/- 19.2 years) with FUO was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia between March 2015 and June 2016. Phase 1 and phase 2 C. burnetii specific antibodies in serum samples were detected by enzyme-linked immunosorbent assay. RESULTS: Coxiella burnetii phase 1 and phase 2 antibodies were detected in 16% of the patients. Phase 2 IgM was present in 2% of the patients, whereas phase 2 IgG antibodies were detected in 11% of the patients. Coxiella burnetii specific phase 1 IgG was found in 2% of the patients, and 8% of the patients harbored phase 1 IgA antibodies in their serum. CONCLUSION: The presence of C. burnetii-specific antibodies in many patients suffering from FUO highlights the importance of Q fever screening among patients presenting with febrile illness. PMID- 30520501 TI - War against respiratory syncytial virus. An 8-year experience at a tertiary hospital. AB - OBJECTIVES: To assess the respiratory syncytial virus (RSV) infection incidence rate through the analysis of data collected before and after implementation of a new palivizumab dosing regimen customized for a high-risk Saudi population. Methods: This was a retrospective cohort study performed at Prince Sultan Military Medical City, Riyadh, Saudi Arabia between November 2009 and April 2017 on 1704 high risk Saudi young children and comparing 3 palivizumab regimens: a 4 week interval dosing regimen starting in either November or mid-September and a 3 week interval dosing regimen starting in mid-September. Results: Despite a decrease in the incidence rate of RSV infection with the three-week interval regimen (3.9% versus 5.9% in seasons 1 and 9.1% in seasons 2), we did not find significant differences among the 3 groups. Conclusion: Expanded use of palivizumab in newborn children could improve outcomes, but further investigation and a careful cost analysis are required. PMID- 30520502 TI - Risk of potential drug-drug interactions in the cardiac intensive care units. A comparative analysis between 2 tertiary care hospitals. AB - OBJECTIVES: To identify and compare the prevalence of drug-drug interactions (DDIs) in the intensive cardiac care units (CCUs) of 2 tertiary care hospitals and analyze their association with various predictors. Methods: This one-year prospective cross-sectional study was conducted in 2 tertiary care hospitals of Peshawar, Khyber Teaching Hospital (KTH) and Hayatabad Medical Complex (HMC), Peshawar, Pakistan, between January 2014 to Janury 2015. The patient medication profiles from the respective CCUs were evaluated for potential DDIs (PDDIs) using Micromedex DrugReax and Drug interaction facts. Results: The prevalence of PDDIs was 96.5% and 95.7% in the 2 hospitals, with over 1200 PDDIs in total. A significant association was found between the number of prescribed drugs and PDDIs in both hospitals. Conclusion: The knowledge of PDDIs is either lacking among the clinicians or is not taken into consideration. Monitoring PDDIs and timely interventions are required to minimize the adverse outcomes. PMID- 30520503 TI - Recent-onset of rheumatoid arthritis leads to increase in wall thickness of left anterior descending coronary artery. An evidence of subclinical coronary artery disease. AB - OBJECTIVES: To explore the atherosclerotic changes of the left anterior descending coronary artery (LADCA) in patients with early onset of rheumatoid arthritis (RA). METHODS: Transthoracic echocardiographic scans were performed on 15 early RA patients and 20 control subjects, free of rheumatological diseases, diabetes mellitus (DM), and cardiovascular disease (CVD). Out of 15 RA patients, 10 were matched for age and gender with control. Left anterior descending coronary artery wall thickness was compared between RA subjects and their matched control. Among early RA patients, correlation was assessed between LADCA wall thickness and the demographic features, RA activity features, and cardiovascular risk factors. Results: Left anterior descending coronary artery wall thickness was significantly increased (p=0.001) in early RA compared to controls, as it was reported to be 0.61+/-0.04 mm (CI: 0.52-0.7); and 0.48+/-0.08 mm (CI: 0.44-0.51) respectively. Within early RA, LADCA wall thickness was related to the disease activity score (p=0.025, beta-coefficient 0.066, CI: 0.01-0.122) as well as to the patient global assessment of disease activity (PGADA) at RA onset (p=0.006, beta-coefficient 0.003, CI: 0.001-0.005), in a positive linear relationship. Left anterior descending coronary artery wall thickness was found to be thicker among RA patients with rheumatoid factor (RF) positive (p=0.015, CI: 0.53-0.66). Conclusion: Early RA patients have increased coronary arteries atherosclerotic burden compared to healthy subjects matched for age, and gender. Rheumatoid factor positivity, high disease activity score and PGADA were found to be associated with coronary artery wall thickness. PMID- 30520504 TI - Knowledge and practice in the management of asymptomatic hyperuricemia among primary health care physicians in Jeddah, Western Region of Saudi Arabia. AB - OBJECTIVES: To assess knowledge and practice levels in asymptomatic hyperuricemia (AH) and investigate predictors of urate-lowering therapy (ULT) misprescribing among primary health care (PHC) physicians. METHODS: A cross-sectional study was conducted among 201 PHC physicians from December 2017 to May 2018. A based clinical guidelines for hyperuricemia management from American Professional Organizations, a semi-structured questionnaire was administered to collect demographic and professional data; knowledge and practice levels in management of AH; and barriers to the management of hyperuricemia and gout, with focus of the misprescribing of ULT in AH. A 2-stage stratified sampling technique was used to select 4 PHC centers were from each of the 5 advisory sectors in Jeddah, Kingdom of Saudi Arabia; and to recruit a minimum of 10 eligible participants per primary health care center (PHCC). Binary logistic regression was used to analyze predictors of ULT misuse in AH. Results: Only 32.8% participating physicians had adequate knowledge about AH. Regarding practice, while majority (88.1%) correctly recommended a low-purine diet and lifestyle changes to patients, almost half misprescribed ULT and 10.9% misprescribed non-steroid anti-inflammatory drugs. Lack of knowledge and awareness about guidelines were the most frequently self reported barriers to adequate practice. Predictors of ULT misuse included the percentage of patients having gout (1-10%: OR=5.40, p=0.047) or receiving ULT (greater than 10-20%: OR=20.02, p=0.001)among patients seen in clinic, attendance of rheumatology conferences (OR=2.55, p=0.017), and having a close relative with hyperuricemia or gout (OR=2.45, p=0.026). Conclusion: There are inadequate levels of knowledge regarding AH among Saudi PHC physicians increasing risk of malpractice including misprescription of ULT and anti-inflammatory medications. PMID- 30520505 TI - Knowledge and attitude toward hemoglobinopathies premarital screening program among unmarried population in western Saudi Arabia. AB - OBJECTIVES: To assess the knowledge and attitude toward hemoglobinopathies premarital screening (PMS) program among unmarried population in Jeddah, Kingdom of Saudi Arabia. METHODS: A cross-sectional study was conducted among 1039 unmarried males and females from the general population who fulfilled the eligibility criteria. Data was collected from July-December 2017, using an electronic questionnaire to assess the socio-demographic data, knowledge and attitudes of the participants regarding PMS. Results: Approximately half of the participants had poor knowledge scores (51.1%), while 28.4% of them had fair and 20.5% had good scores. Individuals with an educational level of "university degree and above" had significantly higher knowledge than those with lower educational levels. Furthermore, 60.4% of the participants had a positive attitude toward PMS. The data was analyzed using the Statistical Package for the Social Sciences (SPSS) Version 21 (IBM Corp., Armonk, NY, USA); and a Chi-squared test was used for comparisons between proportions and a p-value <=0.05 was considered significant. Conclusion: Participants showed a lack of knowledge regarding PMS but they had a positive attitude towards the program. More efforts are required to raise awareness in the public regarding PMS, via social media and educational lectures in schools and universities. Additionally, early genetic screening may help improve test acceptance and higher impact. PMID- 30520506 TI - Surgical practice among pediatric surgeons and pediatric urologists in the Kingdom of Saudi Arabia for the management of suspected testicular torsion. AB - OBJECTIVES: To review and compare clinical practice and experience among pediatric surgeons (PS) and pediatric urologists (PU) for the management of testicular torsion (TT) in the Kingdom of Saudi Arabia (KSA). METHODS: This was a cross-sectional study conducted between August 2016 and November 2017, among all PU and PS involved in the management of suspected TT in KSA. A questionnaire was distributed to participants through the Survs.com platform, and direct email when requested by participant. Results: Most PU (12/20, 60%) utilized ultrasound with Doppler before exploration, while 29 (74.4%) PS performed immediate exploration without imaging, representing a statistically significant difference (p=0.03). When the explored testis was dusky (not frank gangrenous), 27 PS (69.2%) performed fixation, 6 (15.4%) followed the second look policy, and 6 (15.4%) performed orchiectomy. With respect to PU, 6 (30%) performed fixation, 8 (40%) followed the second look policy, and 6 (30%) performed orchiectomy. The differences between the 2 specialties were statistically significant (p=0.02). Most consultants in both specialties performed fixation of the contralateral testis during the same operation. Also, there is a variation in practice when there is other pathology than TT. Conclusion: There were significant variations between the 2 specialties in the management of TT. National guidelines are needed to provide homogenous clinical practice and training of trainees. PMID- 30520507 TI - Does skin thickness affect satisfaction post rhinoplasty? Middle Eastern population as an example. AB - OBJECTIVES: To determine the mean nasal skin thickness in the Middle Eastern population and to assess the effect of skin thickness on patients' satisfaction following rhinoplasty surgeries. Methods: Radiological measurements of skin thickness at the 3 vertical thirds of the nasal dorsum were taken. A total of 154 patients (80 females and 74 males) who were scheduled for computed tomography scan for the paranasal sinuses were included in the study. The patients were then categorized into 3 groups: thick, medium, and thin nasal skin. A scale from 10% to 100% was used to assess patient satisfaction following rhinoplasty. Satisfaction and skin thickness were analyzed using the Kruskal-Wallis test. Results: Nasal skin thickness for males was 6.13, 2.76 millimeter (mm) from the upper and 3.70 mm to the lower third. For females, it was 5.34, 2.13 mm from the upper and 3.21 mm to the lower third. There was no statistically significant difference in patient satisfaction among the 3 skin thickness groups (p=0.089). Conclusion: This study provides baseline results of nasal skin thickness in the Middle Eastern population. The results also show that nasal skin thickness may not be a strong factor affecting patient satisfaction. PMID- 30520508 TI - Development of an oral anticoagulant-use attitude scale, and assessment of its validity and reliability. AB - OBJECTIVES: To develop a reliable scale that can measure the attitudes of individuals using oral anticoagulant drugs (OACs). Methods: This methodological study was conducted with 296 followed-up individuals using OACs for at least 6 months and visiting the cardiology and neurology clinics of a hospital in Turkey during 2017. A 20-item pool was used to construct the scale and all items were found suitable after content validity analysis and preliminary testing. Construct validity was examined using confirmatory factor analysis (CFA) and exploratory factor analysis (EFA). Results: The Kaiser-Meyer-Olkin (KMO) value of the scale (0.79) and results of Bartlett's test showed that the sample size was suitable for factor analysis (p less than 0.001). The total Cronbach alpha coefficient of the scale was 0.83. Factor analysis to assess construct-content validity of the scale identified 4 factors (variance, 54%). Using a path diagram in CFA, Chi square/df ratio values was calculated at 2.807, standardized root mean square residual (SRMR) at 0.093, comparative fit index (CFI) at 0.879, and root mean square error of approximation (RMSEA) at 0.078. Conclusions: We found that the OACAs we developed had high reliability and validity. PMID- 30520509 TI - Emergent surgical treatment of lethal valve dysfunction during pregnancy in a last-trimester patient. AB - A mechanical heart valve thrombosis during pregnancy is one of the most lethal conditions to experience due to its detrimental effects on both mother and fetus. Cardiac surgery during pregnancy is reserved for cases where medical treatment fails due to harmful maternal and fetal effects. A 24-year-old female in the 38th week of pregnancy was admitted to the emergency room with aggravated dyspnea, tachypnea, and palpitations. She had 2 previous cardiac operations in her medical history. A stuck mechanical valve was diagnosed in the mitral position via transthoracic echocardiography, which had resulted from her decision to cease taking warfarin when planning to become pregnant. In pregnant patients who have prosthetic mechanical valve thrombosis, surgical approach should be considered depending on the conditions of the mother and the baby. When emergency delivery of the baby is feasible, emergent surgical treatment should be utilized for patients who are in critical condition. PMID- 30520510 TI - New variants in beta globin gene among the Palestinian refugees with sickle cell disease in Lebanon. AB - OBJECTIVES: To examine the association between beta-globin sequence variations and phenotypes of sickle-cell disease (SCD) complications among Palestinian refugees in Lebanon correlating them with chromatographic readings and co inheritance with beta-thalassemia traits. Methods: This cross-sectional study included 47 Palestinian refugees aged 4 to 54 living in different regions in Lebanon during the year 2015. Participant filled a well-designed questionnaire. Deoxyribonucleic acid (DNA) was purified from the blood collected from all participants, followed by polymerase chain reaction (PCR) amplification of exon 1, exon 2, and IVS 1 of hemoglobin beta. Multiple sequence alignment for comparative analysis was performed against normal hemoglobin sequences. Results: In addition to well-known SCD mutations, rare beta globin variations were identified. Participants with these variations have phenotypic thalassemia despite the absence of known beta-thalassemia mutations. Conclusion: The genetic variation seen among our study population is correlated with reduced beta globin transcription, and phenotypic beta-thalassemia complications among SCD patients under study. PMID- 30520512 TI - Comment on: Factors affecting quality of life in children and adolescents with thalassemia in Iraqi Kurdistan. AB - [No Abstract Available]. PMID- 30520511 TI - Trends in the incidence and mortality of cancer in Saudi Arabia. AB - OBJECTIVES: To analyze the overall trends in cancer incidence and mortality in Saudi Arabia between 1990 and 2016. Methods: Data were retrieved through a Global Burden of Disease (GBD, 2016) database (Viz Hub) that is developed by the Institute for Health Metrics and Evaluation at the University of Washington. Results: The incidence of cancer increased around 26-fold for thyroid cancer; approximately 10-fold in breast, colon, bladder and uterine cancers; 8-fold for prostate cancer; 5-fold for renal cancer; 4-fold for pancreatic and ovarian cancer; 3.5-fold for lung cancer; 3-fold for liver cancer, and 2 folds for lymphoma, leukemia and gastric cancer. There was also an increase in the percentage of mortality due to cancer during this period. However, we noticed that the percentage of deaths due to cancer decreased after 70 years of age in Saudi Arabia population. Conclusion: The increases in the incidence of different types of cancer in the past decade could be due to the revolutionary change in socioeconomic status that has occurred in Saudi Arabia; therefore, a national plan should be established for cancer prevention, screening and therapy. Concerning mortality, the decrease in its percentage among elderly people could be due to biological factors that should be investigated in the future. PMID- 30520513 TI - TDP-43 accelerates deadenylation of target mRNAs by recruiting Caf1 deadenylase. AB - TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein, whose loss-of function mutation causes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Recent studies demonstrated that TDP-43 binds to the 3' UTR of target mRNAs to promote mRNA instability. Here, we show that TDP-43 recruits Caf1 deadenylase to mRNA targets and accelerates their deadenylation. Tethering TDP-43 to the mRNA 3'UTR recapitulates destabilization of the mRNA, and TDP-43 accelerates their deadenylation. This accelerated deadenylation is inhibited by a dominant negative mutant of Caf1. We find that TDP-43 physically interacts with Caf1. In addition, we provide evidence that TDP-43 regulates poly(A) tail length of endogenous Progranulin (GRN) mRNA. These results may shed light on the link between dysregulation of TDP-43-mediated mRNA deadenylation and pathogenesis of neurodegenerative diseases. This article is protected by copyright. All rights reserved. PMID- 30520514 TI - Traditional Chinese herbal medicine for vascular dementia. AB - BACKGROUND: Traditional Chinese herbal medicine (TCHM) is widely used for treating vascular dementia (VaD) in China. Recent studies of a number of TCHMs have demonstrated in vitro biological activity and therapeutic effects in animals, but the published clinical evidence has not been systematically appraised. OBJECTIVES: To evaluate the efficacy and safety of TCHMs listed in either the Chinese Pharmacopoeia (CP) or the Chinese National Essential Drug List (NEDL) that are used to treat VaD. A secondary aim was to identify promising TCHMs for further clinical research. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialised Register (on 14 March 2018) and also several Chinese biomedical databases: the Chinese Biological Medicine Database (January 1979 to May 2015), Wanfang database (January 1998 to May 2015), Chongqing VIP Information Co. Ltd or Weipu (January 1998 to May 2015) and the Chinese National Knowledge Infrastructure (January 1979 to May 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of TCHMs compared to placebo, to Western medicine (WM) or to routine therapy for VaD risk factors. Eligible participants were men and women aged 18 years and above, diagnosed with VaD by any of the following four criteria: (1) Diagnostic and Statistical Manual of Mental Disorders (DSM) versions III, III-R, IV, IV-TR; (2) National Institute of Neurological Disorders and Stroke (NINDS-AIREN); (3) International Classification of Diseases 9 or 10; (4) the Hachinski or the Modified Hachinski Ischaemic Score. We required the use of an imaging technique to differentiate VaD from other dementias. We excluded (1) trials with participants diagnosed with mixed dementia or those that did not use an imaging technique to ascertain VaD; (2) trials of NEDL-listed Gingko biloba or Huperzine A as experimental interventions, to avoid duplication of existing Cochrane Reviews; (3) trials using acupuncture alone as the experimental intervention; (4) trials using another CP- or NEDL-listed TCHM (except for Huperzine A and Gingko which are popular in Western practice) as the control intervention; and (5) trials using purely non-pharmacological interventions as the control intervention unless explicitly described as 'routine therapy for VaD risk factors'. DATA COLLECTION AND ANALYSIS: We assessed the risks of bias using the Cochrane 'Risk of bias' tool and adapted the Outcome Reporting Bias in Trials (ORBIT) classification system for outcome reporting bias. We assessed TCHM effects on five clinically important outcomes: cognition, global performance, safety, activities of daily living and behaviour and summarised the effects using mean differences for continuous outcomes and risk ratios or risk differences for binary outcomes. We stratified the studies into those that estimated the TCHM versus 'no treatment' effect and those that estimated the TCHM versus the WM effect, with further stratification by the specific TCHM tested or by one of the four modes of action. We pooled using a random-effects model. Due to substantial clinical and design heterogeneity, we did not estimate an 'overall TCHM effect'. MAIN RESULTS: We only found studies (47 studies, 3581 participants) for 18 of the 29 eligible TCHMs as defined by our inclusion criteria. All were superiority trials conducted in China between 1997 and 2013, with most employing a two-arm parallel design with sample sizes ranging from 26 to 240 and a median treatment duration of 12 weeks (range: 2 to 24 weeks).We found that reporting and trial methodology were generally poor; in particular, there was a lack of information on randomisation, an absence of blinding of participants and outcome assessors and incomplete reporting of adverse events (AEs). None of the 30 trials published from 2007 onwards adopted the CONSORT recommendations for reporting RCTs of herbal interventions.We found seven TCHMs which each had potentially large benefits in studies estimating the TCHM versus 'no treatment' effect and in studies estimating the TCHM versus the WM effect. Two TCHMs (NaoXinTong and TongXinLuo) were common to both groups. Three of these TCHMs - Nao XinTong, NaoMaiTai and TongXinLuo - had the strongest evidence to justify further research. Two TCHMs (NaoMaiTai and TongXinLuo) had a 5% or more increased risk of AEs compared to the 'no Treatment' control, but the quality of this evidence was poor. AUTHORS' CONCLUSIONS: We found moderate- to very low-quality evidence of benefit and harm of TCHMs for VaD. Methodological inadequacies need to be addressed by better conducted and reported trials. We identified NaoMaiTai, NaoXinTong and TongXinLuo as warranting special research priority. PMID- 30520515 TI - High-resolution crystal structure of peptidyl-tRNA hydrolase from Thermus thermophilus. AB - Peptidyl-tRNA hydrolase (Pth) cleaves the ester bond between the peptide and the tRNA of peptidyl-tRNA molecules, which are the products of defective translation, to recycle the tRNA for further rounds of protein synthesis. Pth is ubiquitous in nature, and its activity is essential for bacterial viability. Here, we have determined the crystal structure of Pth from Thermus thermophilus (TtPth) at 1.00 A resolution. This is the first structure of a Pth from a thermophilic bacterium and the highest resolution Pth structure reported so far. The present atomic resolution data enabled the calculation of anisotropic displacement parameters for all atoms, which revealed the directionality of the fluctuations of key regions for the substrate recognition. Comparisons between TtPth and mesophilic bacterial Pths revealed that their structures are similar overall. However, the structures of the N- and C-terminal, loop-helix alpha4, and helix alpha6 regions are different. In addition, the helix alpha1 to strand beta4 region of TtPth is remarkably different from those of the mesophilic bacterial Pths, because this region is 9 or 10 amino acid residues shorter than those of the mesophilic bacterial Pths. This shortening seems to contribute to the thermostability of TtPth. To further understand the determinants for the thermostability of TtPth, we compared various structural factors of TtPth with those of mesophilic bacterial Pths. The data suggest that the decreases in accessible surface area and thermolabile amino acid residues, and the increases in ion pairs, hydrogen bonds, and proline residues cooperatively contribute to the thermostability of TtPth. This article is protected by copyright. All rights reserved. PMID- 30520516 TI - Dermoscopy of cutaneous smooth muscle neoplasms: a morphological study of 136 cases. AB - BACKGROUND: A variety of cutaneous smooth muscle neoplasms may arise in the skin and are frequently unrecognized by clinicians. There is sparse data relating to the dermoscopy of piloleiomyiomas (PL) and nothing has been published about the dermoscopy of angioleiomyomas (AL) and leiomyosarcomas (LS). OBJECTIVES: To evaluate the morphological findings of a large series of cutaneous PL, AL and LS under dermoscopic observation, comparing these findings among them. METHODS: Digital dermoscopic images of 136 histopathologically confirmed cases of cutaneous smooth muscle neoplasms (114 PL, 13 AL and 9 LS) collected from 10 Hospitals in Spain, Austria and Italy were evaluated for the presence of dermoscopic structures and patterns. RESULTS: The pattern composed of a symmetric, total delicate pigment network with the variable presence of multiple hypopigmented areas in a painful lesion is the most common dermoscopic pattern associated with PL. This pattern was found in 69.3% of PL and in no cases of AL and LS. The most common and characteristic pattern associated with AL was the one composed of symmetric pink-reddish tumor with vessels, white structures and the absence of ulceration, which was found in 46.2% of AL, but also in 3.5% of PL, and in 22.2% of LS. Finally, the most common pattern associated with LS was the one composed of an asymmetric, multilobulated tumor with linear-irregular or polymorphic-atypical vessels and white structures, which was found in 44.4% of cases, but also in 0.9% of PL and in 15.4% of AL. CONCLUSION: Dermoscopy is helpful in improving the diagnostic accuracy of PL. The dermoscopic patterns associated with AL and LS were more variable and less specific. This article is protected by copyright. All rights reserved. PMID- 30520518 TI - Cochrane's plans to update its COI policy: truth and fiction. PMID- 30520517 TI - Updating guidance for preventing and treating cryptococcal disease: how evidence and decisions interface. PMID- 30520519 TI - Residue-level determinants of Angiopoietin-2 interactions with its receptor Tie2. AB - We combined computational and experimental methods to interrogate the binding determinants of Angiopoietin-2 (Ang2) to its receptor tyrosine kinase (RTK) Tie2 a central signaling system in angiogenesis, inflammation, and tumorigenesis. We employed physics-based electrostatic and surface-area calculations to identify the subset of interfacial Ang2 and Tie2 residues that can affect binding directly. Using random and site-directed mutagenesis and yeast surface display (YSD), we validated these predictions and identified additional Ang2 positions that affected receptor binding. We then used burial-based calculations to classify the larger set of Ang2 residues that are buried in the Ang2 core, whose mutations can perturb the Ang2 structure and thereby affect interactions with Tie2 indirectly. Our analysis showed that the Ang2-Tie2 interface is dominated by non-polar contributions, with only three Ang2 and two Tie2 residues that contribute electrostatically to intermolecular interactions. Individual interfacial residues contributed only moderately to binding, suggesting that engineering of this interface will require multiple mutations to reach major effects. On the other hand, substitutions in substantially buried Ang2 residues were more prevalent in our experimental screen, reduced binding substantially, and are therefore more likely to have a deleterious effect that might contribute to oncogenesis. Computational analysis of additional RTK-ligand complexes, c-Kit SCF and M-CSF-c-FMS, and comparison to previous YSD results, further show the utility of our combined methodology. This article is protected by copyright. All rights reserved. PMID- 30520520 TI - A minimally-invasive hybrid approach for cardiac resynchronization of the systemic right ventricle. AB - BACKGROUND: Patients with systemic right ventricles (RV) often develop progressive heart failure and may benefit from cardiac resynchronization therapy (CRT), however the optimal strategy for CRT has not been defined. METHODS: A retrospective review of all patients with systemic RV failure undergoing a hybrid transcatheter-surgical approach was performed. Procedural technique and outcomes are reported. RESULTS: Six patients underwent detailed EAM of the systemic RV followed by a new hybrid approach targeting latest endocardial activation followed by focused epicardial mapping. The exact site of latest endocardial activation was variable but localized to the basolateral RV in all cases. Sites of latest activation tended to be more superior during contralateral ventricular pacing versus intact AV conduction (p = 0.06). Latest endocardial activation at the targeted site occurred at 157 ms (IQR 120-181 ms) and corresponding epicardial activation 174 ms (IQR 140-198 ms), after the onset of the QRS complex. Following hybrid CRT, the QRS duration decreased from a median of 193 to 147 ms and the FAC increased from a median of 15.5 to 30% (p < 0.001). Patients were discharged to home after a median of 4 days. Of 3 patients initially referred for transplant evaluation, 2 (66%) no longer met criteria following CRT. CONCLUSIONS: Whereas latest endocardial activation for the systemic RV appears to localize to the basolateral region, the optimal lead position may be variable. An approach utilizing endocardial mapping followed by a limited surgical incision and confirmation of latest activation may result in minimally invasive surgery and a favorable acute CRT response. This article is protected by copyright. All rights reserved. PMID- 30520521 TI - Strangles, convalescent Streptococcus equi subspecies equi M antibody titers, and presence of complications. AB - BACKGROUND: Streptococcus equi subspecies equi infection elicits M protein antibody titers in equids. Interpretation of titers is not generally accepted. HYPOTHESIS: The magnitude of S. equi M protein (SeM) antibody titer after infection (titer >= 1:12 800) will be useful to monitor for the presence of complications or the risk of development of complications. ANIMALS: Forty-eight horses on 1 farm involved in strangles outbreak. METHODS: Clinical and observational study. S. equi M protein antibody titers were measured on all horses 8 weeks after infection and select horses 12 and 28 weeks after infection. Horses were categorized: no disease, uncomplicated case, persistent guttural pouch (GP) infection, or complicated cases (metastatic abscesses, purpura hemorrhagica, secondary infections, and dysphagia). Category was compared to titer. RESULTS: Twenty-eight of 48 (58%) developed clinical signs of S. equi infection. Of those, 11 (39%) had uncomplicated strangles, 9 (21%) had persistent GP infection, 5 (18%) were complicated cases, and 3 (11%) had both persistent GP infection and complications. Thirty-three percent of horses (16 of 48) had SeM antibody titers >=1:12 800 eight weeks after infection. Of horses with titers >=1:12 800, 6 of 16 had evidence of complications. Of complicated cases, 6 of 8 had titers >=1:12 800. In this outbreak, the sensitivity (75%; 95% CI [confidence interval] 45-105) for a SeM antibody titer >=1:12 800 detecting complications was higher than the specificity (43%; 95% CI 23-64). CONCLUSIONS AND CLINICAL IMPORTANCE: This outbreak demonstrates that SeM antibody titers can be increased after infection (>=1:12 800) in the absence of complications of strangles. PMID- 30520522 TI - The QTc interval and risk of cardiac events in bulimia nervosa: A long-term follow-up study. AB - OBJECTIVE: An association between bulimia nervosa (BN) and prolonged corrected QT interval (QTc) in the electrocardiogram has been suggested, but results of previous studies are conflicting, and the risk of cardiac events in patients with BN has yet to be investigated. METHOD: We estimated mean QTc interval and relative risk of borderline (QTc >440 ms) and prolonged QTc (QTc >460 ms) between adult women with BN (N = 531) and healthy controls (N = 123). In follow-up analyses, we investigated the risk of a primary endpoint (syncope, ventricular tachycardia, and cardiac arrest) and all-cause mortality in patients with BN (N = 702) compared with a population-based cohort derived from the Danish Civil Register (N = 7,020). RESULTS: Mean QTc did not differ between patients with BN and controls. Relative risk of borderline prolonged QTc was 2.3 (p = 0.28). The number of patients and controls with prolonged QTc was small, and the risk did not differ between patients with BN and controls. Median follow-up was 10.6 years. Although there appeared to be increased risks after 5 years of follow-up, long-term risks of the primary endpoint (Hazard ratio [HR] = 1.4, p = 0.37) and all-cause mortality (HR = 1.7, p = .28), respectively, were not increased in patients with BN compared to a population-based cohort. DISCUSSION: Mean QTc did not differ between patients with BN and healthy controls, and the risk of prolonged QTc was not increased in patients with BN. There was no difference in the long-term risk of cardiac events, and long-term all-cause mortality did not differ significantly between patients with BN and a population-based cohort. PMID- 30520523 TI - Allergen-specific immunoglobulin E in sera of horses affected with insect bite hypersensitivity, severe equine asthma or both conditions. AB - BACKGROUND: Genetic, epidemiologic, and clinical evidence suggests that, in horses, there are manifestations of hypersensitivity that can occur together. OBJECTIVES: To investigate whether concurrent insect bite hypersensitivity (IBH) and severe equine asthma (EA) is associated with higher allergen-specific and total serum immunoglobulin E (IgE) concentrations than only EA or IBH. ANIMALS: Healthy control horses (C, n = 40), horses with IBH (IBH, n = 24), severe EA (EA, n = 18), and both conditions (IBH/EA, n = 23) were included. METHODS: In our retrospective comparative study, sera from horses with signs of severe EA, IBH, and control animals were used. IgE specific for 15 recombinant (r) allergens as well as total serum IgE concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: Group IBH (median sum r-Culicoides IgE: optical density at 405 nm [OD405 ] = 3.54 [0.48-15.07]) and group IBH/EA (OD405 = 4.55 [0.46-17.15]) had significantly (P < .001) higher IgE against Culicoides r allergens than groups C (OD405 = 0.44 [0.21-2.05]) and EA (OD405 = 0.6 [0.2 2.9]). There were no significant (P > .05) differences between group IBH and group IBH/EA. No significant differences among the groups were found for the other r-allergens or total serum IgE concentration. Compared to controls, horses with severe IBH had significantly increased IgE concentration to 5 Culicoides r allergens (P < .05), whereas horses with moderate IBH had significantly increased IgE concentration to only 3 Culicoides r-allergens (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Susceptibility of IBH-affected horses to develop EA is likely not associated with IgE-mediated immune reactions but with other immunopathological mechanisms. PMID- 30520524 TI - Synthesis of novel derivatives of 7,8-dihydro-6H-imidazo[2,1-b][1,3]benzothiazol 5-one and their virus-inhibiting activity against influenza A virus. AB - Influenza remains a highly pathogenic and hardly controlled human infection. The ability of selecting drug-resistant variants necessitates the search and development of novel anti-influenza drugs. Herein, we describe the synthesis and evaluation of a series of novel 2-substituted 7,8-dihydro-6H-imidazo[2,1 b][1,3]benzothiazol-5-ones 3a-k for their virus-inhibiting activity against influenza A virus. The new analogues 3a-k prepared in two steps from commercially available cyclohexane-1,3-diones were fully characterized by their NMR and mass spectral data. Among the new derivatives screened for cytotoxicity and in vitro antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells, three analogues 3i-k containing a thiophene unit were found to exhibit high virus-inhibiting activity (high SI values) and a favorable toxicity profile. The compound 3j (CC50 : >1000 MUM, SI = 77) with higher potency is the best anti influenza hit analogue for further structural optimization and drug development. The most active compounds did not inhibit viral neuraminidase and possess therefore other targets and mechanisms of activity than the currently used neuraminidase inhibitors. PMID- 30520525 TI - Comprehensive blood group antigen profile predictions for Western Desert Indigenous Australians from whole exome sequence data. AB - BACKGROUND: The distribution of RBC antigens, which define blood group types, differs among populations. In contrast to many world populations, blood group profiles for Indigenous Australians have not been well studied. As it is now possible to predict comprehensive blood group antigen profiles from genomic data sets, we aimed to apply this for Indigenous Australians and to provide a comparison to other major world populations. STUDY DESIGN AND METHODS: Whole exome sequence data for 72 Western Desert Indigenous Australians was provided by the Telethon Kids Institute. Variants (against hg19) were annotated using computer software (ANNOVAR, Qiagen Bioinformatics) and filtered to include only variants in genes for 36 blood group systems, and the transcription factors KLF1 and GATA1. The RHCE*C allele and RHD zygosity were identified by copy number variant analysis of sequence alignments. The impact of missense variants was investigated in silico using a meta-predictor of disease-causing variants (Meta SNP). RESULTS: For 21 blood group systems the predicted blood group antigen frequencies were comparable to those for other major world populations. For 13 systems, interesting points of contrast were identified. Furthermore, we identified 12 novel variants, one novel D allele, and four rare variants with potential clinical significance. CONCLUSION: This is the first systematic assessment of genomic data to elucidate blood group antigen profiles for Indigenous Australians who are linguistically and culturally diverse. Our study paves the way to understanding the geographic distribution of blood group variants in different Indigenous groups and the associated RBC phenotypes. This in turn is expected to guide transfusion practice for Indigenous individuals. PMID- 30520526 TI - CD8-positive lymphomatoid papulosis (type D): Some lesions may lack CD30 expression and overlap histologically with mycosis fungoides. AB - BACKGROUND: CD8+ lymphomatoid papulosis is frequently indistinguishable histopathologically from primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma except for the expression of CD30. However, absent or weak expression of CD30 has been rarely reported in cases of CD8+ LyP. OBJECTIVE: We aim to study the clinical and pathologic features of cases of CD8+ LyP with no or minimal expression of CD30. MATERIAL AND METHODS: We identified all cases of CD8+ LyP diagnosed in our institution over a period of 10 years. Blinded comparison of clinical and histopathologic features of cases with and without CD30 expression was performed. RESULTS: Among seven cases (four patients) with definitive clinical and histopathologic diagnosis of CD8+ LyP, two cases (29%) had no expression of CD30. These two cases had more prominent epidermotropism, less epidermal ulceration, and less vascular damage relative to cases with CD30 expression and therefore resembled mycosis fungoides and type B LyP. CD5 and CD7 were frequently lost regardless of the CD30 status. Expression of cytotoxic markers was not different between the two groups. In the two cases with lack of CD30 expression, subsequent biopsies showed classic features of CD8+ LyP with strong expression of CD30. CONCLUSION: CD8+ LyP with lack of expression of CD30 may have distinct histopathologic features that resemble mycosis fungoides and LyP type B. Clinically, they are indistinguishable from their CD30+ counterparts, signifying the importance of clinical correlation to avoid the erroneous diagnosis of lymphoma. Interval biopsies may be needed to establish a definitive diagnosis. PMID- 30520527 TI - Eating pathology and associations with long-term changes in weight and quality of life in the longitudinal assessment of bariatric surgery study. AB - OBJECTIVE: This study examines the course of eating pathology and its associations with change in weight and health-related quality of life following bariatric surgery. METHOD: Participants (N = 184) completed the eating disorder examination-bariatric surgery version (EDE-BSV) and the medical outcomes study 36 Item short form health survey (SF-36) prior to and annually following Roux-en-Y gastric bypass (RYGB) or laparoscopic adjustable gastric banding (LAGB) for up to 7 years. RESULTS: The prevalence of >= weekly loss of control (LOC) eating, picking/nibbling, and cravings declined post-RYGB and remained lower through 7 years (LOC: 5.4% at Year-7 vs. 16.2% pre-RYGB, p = .03; picking/nibbling: 7.0% vs. 32.4%, p < .001; and cravings: 19.4% vs. 33.6%, p = .02). The prevalence of picking/nibbling was significantly lower 7 years following LAGB vs. pre-LAGB (29.4% vs 45.8%, p = .049), while cravings (p = .13) and LOC eating (p = .95) were not. EDE-BSV global score and ratings of hunger and enjoyment of eating were lower 7 years following both RYGB and LAGB versus pre-surgery (p's for all <.05). LOC eating following RYGB was associated with less long-term weight loss from surgery (p < .01) and greater weight regain from weight nadir (p < .001). Higher post-surgery EDE-BSV global score was associated with less weight loss/greater regain (both p < .001) and worsening/less improvement from surgery in the SF-36 mental component summary scores (p < .01). DISCUSSION: Initial improvements in eating pathology following RYGB and LAGB were sustained across 7 years of follow up. Individuals with eating pathology post-RYGB, reflected by LOC eating and/or higher EDE-BSV global score, may be at risk for suboptimal long-term outcomes. PMID- 30520528 TI - The influence of intrinsic folding mechanism of an unfolded protein on the coupled folding-binding process during target recognition. AB - Intrinsically disordered proteins (IDPs) are extensively involved in dynamic signaling processes which require a high association rate and a high dissociation rate for rapid binding/unbinding events and at the same time a sufficient high affinity for specific recognition. Although the coupled folding-binding processes of IDPs have been extensively studied, it is still impossible to predict whether an unfolded protein is suitable for molecular signaling via coupled folding binding. In this work, we studied the interplay between intrinsic folding mechanism and coupled folding-binding process for unfolded proteins through molecular dynamics simulations. We first studied the folding process of three representative IDPs with different folded structures, that is, c-Myb, AF9, and E3 rRNase. We found the folding free energy landscapes of IDPs are downhill or show low barriers. To further study the influence of intrinsic folding mechanism on the binding process, we modulated the folding mechanism of barnase via circular permutation and simulated the coupled folding-binding process between unfolded barnase permutant and folded barstar. Although folding of barnase was coupled to target binding, the binding kinetics was significantly affected by the intrinsic folding free energy barrier, where reducing the folding free energy barrier enhances binding rate up to two orders of magnitude. This accelerating effect is different from previous results which reflect the effect of structure flexibility on binding kinetics. Our results suggest that coupling the folding of an unfolded protein with no/low folding free energy barrier with its target binding may provide a way to achieve high specificity and rapid binding/unbinding kinetics simultaneously. This article is protected by copyright. All rights reserved. PMID- 30520529 TI - Posttraumatic Stress Disorder and Cancer Risk: A Nested Case-Control Study. AB - Data regarding cancer risk for individuals who were exposed to traumatic and stressful life events are conflicting. We sought to evaluate the association between posttraumatic stress disorder (PTSD) and the risk of the four most common solid tumors: lung, breast, prostate, and colorectal cancers. We conducted four nested case-control studies using a large UK population-based database. Cases were defined as individuals with any medical code for the specific malignancy. For every case, we used incidence-density sampling to match four controls by age, sex, practice site, and both duration and calendar time of follow-up. Exposure of interest was any diagnosis of PTSD prior to cancer diagnosis. The odds ratios (ORs) and 95% confidence intervals (CIs) for cancer risk associated with PTSD were estimated using multivariable conditional logistic regression and were adjusted for smoking status, obesity, and antidepressant use. The study population included four case groups according to cancer type. There were 19,143 cases with lung cancer (74,473 matched controls), 22,163 cases with colorectal cancer (86,538 matched controls), 31,352 cases with breast cancer (123,285 matched controls), and 27,212 cases with prostate cancer (105,940 matched controls). There was no statistically significant association between PTSD and cancer risk among any of the cancer types: lung, OR = 0.73, 95% CI [0.43, 1.23]; breast, OR = 0.73, 95% CI [0.52, 1.01]; prostate, OR = 1.24, 95% CI [0.87, 1.77]; and colorectal, OR = 1.05, 95% CI [0.68, 1.62]. Our findings indicated that participants in our study with PTSD were not at increased risk of lung, breast, prostate, and colorectal cancers. PMID- 30520530 TI - Prediction of folding mechanisms for Ig-like beta sandwich proteins based on inter-residue average distance statistics methods. AB - To understand the folding mechanism of a protein is one of the goals in bioinformatics study. Nowadays, it is enigmatic and difficult to extract folding information from amino acid sequence by using standard bioinformatics techniques or even experimental protocols which can be time consuming. To overcome these problems, we aim to extract the initial folding unit for titin protein (Ig and fnIII domains) by means of inter-residue average distance statistics, Average Distance Map (ADM) and contact frequency analysis (F-value). TI I27 and TNfn3 domains are used to represent the Ig-domain and fnIII-domain, respectively. Beta strands 2, 3, 5 and 6 are significant for the initial folding processes of TI I27. The central strands of TNfn3 were predicted as a primary folding segment. Known 3D structure and unknown 3D structure domains were investigated by structure or non-structure based multiple sequence alignment, respectively, to learn the conserved hydrophobic residues and predicted compact region relevant to evolution. Our results show good correspondence to experimental data, phi-value and protection factor from H-D exchange experiments. The significance of conserved hydrophobic residues near F-value peaks for structural stability by using hydrophobic packing is confirmed. Our prediction methods once again could extract a folding mechanism only knowing the amino acid sequence. This article is protected by copyright. All rights reserved. PMID- 30520531 TI - Structure and function insights garnered from in silico modeling of the thrombospondin type-1 domain-containing 7A antigen. AB - The thrombospondin type-1 domain containing 7A (THSD7A) protein is known to be one of the antigens responsible for the autoimmune disorder idiopathic membranous nephropathy. The structure of this antigen is currently unsolved experimentally. Here we present a homology model of the extracellular portion of the THSD7A antigen. The structure was evaluated for folding patterns, epitope site prediction, and function was predicted. Results show that this protein contains 21 extracellular domains and with the exception of the first two domains, has a regular repeating pattern of TSP-1-like followed by F-spondin-like domains. Our results indicate the presence of a novel Trp-ladder sequence of WxxxxW in the TSP 1-like domains. Of the 21 domains, 18 were shown to have epitope binding sites as predicted by epitopia. Several of the F-spondin-like domains have insertions in the canonical TSP-fold, most notably the coiled coil region in domain 4, which may be utilized in protein-protein binding interactions, suggesting that this protein functions as a heparan sulfate binding site. This article is protected by copyright. All rights reserved. PMID- 30520532 TI - Family-based treatment: Where are we and where should we be going to improve recovery in child and adolescent eating disorders. AB - OBJECTIVE: Family therapy has long been advocated as an effective intervention for eating disorders. A specific form of family therapy, one that utilizes family resources, has proven especially effective for adolescents with anorexia or bulimia nervosa (AN and BN). First developed in London, a behaviorally focused adaptation, called family-based treatment (FBT), has been manualized and systematically studied in six randomized clinical trials for adolescent AN and two for adolescent BN. METHOD: This Commentary focuses on manualized FBT; what we know, what we do not know (yet), and what we hope for. RESULTS: We do know that efficacy data for FBT, especially adolescent AN, are quite robust, even though remission rates remain elusive for more than half of all cases. While preliminary, moderators of FBT for adolescent AN have been identified and could aid us in determining the most (or least) responsive patient groups. And weight gain (~2.5kg) by week four has been confirmed as an early predictor of remission at end-of-treatment. What we do not know, yet, is whether specific adaptations to manualized FBT will confer improved remission rates. DISCUSSION: Finally, and in terms of what is hoped for, we highlight the promise of improved access, dissemination, and implementation of FBT. PMID- 30520533 TI - Hemolytic disease of the fetus and newborn due to alloanti-M: three Chinese case reports and a review of the literature. AB - BACKGROUND: Alloanti-M was once regarded as not clinically significant, with a few exceptions in extremely rare cases. However, an increasing number of cases of severe hemolytic disease of the fetus and newborn (HDFN), resulting in fetal hydrops and recurrent abortion caused by alloanti-M, have been reported mainly in the Asian population. STUDY DESIGN AND METHODS: Three pregnant Chinese women with a history of abnormal pregnancy with hydrops fetalis were encountered. During this pregnancy, a series of clinical examinations and an alloantibody identification against RBCs and platelets were conducted. Intrauterine transfusion and postnatal transfusion were then performed in the fetuses. In addition, the HDFN cases caused by alloanti-M reported in different ethnic groups as well as their clinical and serologic features are also summarized. RESULTS: Three pregnant women were identified with an M-N+ phenotype and IgM mixed with IgG alloanti-M in serum. Their fetuses were found by ultrasound examination and cord blood testing to have severe anemia. Additionally, an M+N+ phenotype and IgG alloanti-M were detected in the cord blood of the three fetuses with titers ranging from 1:1 to 1:128. Moreover, low reticulocyte counts and negative direct antiglobulin tests were also shown in two of the fetuses. After receiving intrauterine transfusions and postnatal transfusions several times, these three fetuses eventually survived and then healthfully developed in the follow-up tracking. CONCLUSION: Alloanti-M immunization can cause severe HDFN with hyporegenerative anemia, often seen in the Asian population, and suppression of erythropoiesis might account for it. PMID- 30520535 TI - Management of adverse reactions to high-dose moxifloxacin used in multidrug resistant tuberculosis treatment programmes. PMID- 30520534 TI - Test-retest properties of the Patient Reported Outcomes, Burdens and Experiences (PROBE) questionnaire and its constituent domains. AB - BACKGROUND: The Patient Reported Outcomes, Burdens and Experiences (PROBE) study aims to develop and validate questionnaire for assessing health status in patients with haemophilia and participants without bleeding disorders. OBJECTIVE: To investigate the test-retest properties of the PROBE questionnaire. METHODS: The PROBE questionnaire covers four domains and is comprised of 29 questions. People with haemophilia (PWH) and participants without bleeding disorder were invited to participate in this study. All participants were asked to complete the PROBE questionnaire three times (paper-based survey on two consecutive days: T1 and T2 and then a web-based version: T3). Test-retest properties and percentage agreement were analysed. RESULTS: A total of 63 participants were enrolled in this study with a median age of 50 (range: 17-76) years. Of these, 30 (47.6%) were PWH. On the questions common to PWH and participants without bleeding disorder, Kappa coefficients ranged from 0.69 to 1.00, indicating substantial to almost perfect agreement (T1 vs T2). For haemophilia-related questions (T1 vs T2), Kappa coefficients ranged from 0.5 to 1.0. Of these, 5 of 11 items were in perfect agreement (Kappa = 1.0). The web-based questionnaire (T3) showed substantial to almost perfect agreement with the paper version (T1 test-retest properties were comparable between PWH and individuals without a bleeding disorder). CONCLUSIONS: The results suggest that PROBE is a reliable tool to assess patient-reported outcomes for PWH and benchmark data in participants without bleeding disorder. The web-based questionnaire and the standard paper based version can be used interchangeably. PMID- 30520536 TI - Relation between post-myocardial infarct remodelling and gelatinase activity in patients enrolled in the TIPTOP trial. PMID- 30520538 TI - Near-home heart failure care. PMID- 30520537 TI - Assembly of a miRNA-modified QCM sensor for miRNA recognition through response patterns. AB - In this paper, a miRNA-based quartz crystal microbalance (QCM) biosensor was fabricated and used to the rapid and effective sensing of miRNA. The specific hybridization between probe miRNA and different selected miRNAs (miR-27a, miR 27b, and Let-7a) cause a different interaction mode, thus display different frequency change and response patterns in the QCM sensor, which were used to detect miR-27a and miR-27b. The selective sensing of miR-27a in mixed miRNA solution was also achieved. This miRNA-based QCM biosensor has the advantages of real-time, label-free, and short cycle detection. PMID- 30520539 TI - circLARP4 induces cellular senescence through regulating miR-761/RUNX3/p53/p21 signaling in hepatocellular carcinoma. AB - circular RNAs (circRNAs), a novel class of non-coding RNAs, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various cancers. The association of circRNAs with cellular senescence in tumor is still a virgin soil to be upturned. Here we investigated the role of circLARP4 in cellular senescence and cell proliferation in hepatocellular carcinoma (HCC). Downregulated circLARP4 level was observed in HCC tissues and cell lines. Low expression level of circLARP4 independently predicted poor survival outcome. Gain-of-function and loss-of-function assays demonstrated that circLARP4 suppressed HCC cell proliferation, mediated cell cycle, and induced senescence in vitro. Levels of p53 and p21, two key regulatory molecules in cellular senescence, were increased in circLARP4-overexpressed HCC cells and decreased in circLARP4-silenced HCC cells. In vivo experiments further confirmed the tumor-suppressing activities of circLARP4. Further mechanistic studies showed that circLARP4 dampened HCC progression via sponging miR-761, thereby promoting the expression level of RUNX3 and activating the downstream p53/p21 signaling. Our study revealed the role of circLARP4/miR-761/RUNX3/p53/p21 signaling in HCC progression, providing a potential survival predictor and therapeutic candidate in HCC. This article is protected by copyright. All rights reserved. PMID- 30520540 TI - Norcantharidin inhibits proliferation and promotes apoptosis via c-Met/Akt/mTOR pathway in human osteosarcoma cells. AB - Osteosarcoma (OS) is the most common malignant bone tumor that frequently affects adolescents. Norcantharidin (NCTD), a demethylated derivative of cantharidin, has been reported exhibits anticancer activity against various types of tumors except human OS. The aims of this study were to evaluate the effects of NCTD on OS cell lines (MG63 and HOS) and to explore the underlying mechanisms. In the present study, the proliferation of OS cells decreased significantly, while the apoptosis was accelerated significantly after exposure to NCTD. Meanwhile, our results also indicated that NCTD could suppresses the migration and invasion, decrease the colony forming ability and induce S phase cell cycle arrest of OS cells in a dose dependent manner. Moreover, our results revealed that the anticancer effects induced by NCTD on OS cells involved autophagy, mitophagy, endoplasmic reticulum (ER) stress and c-Met pathway. Furthermore, the results of animal experiments showed that NCTD inhibited tumor growth in a xenograft model of human OS. These evidences provide important new insight into the possible molecular mechanisms of NCTD and highlight its potential use as an antitumor drug for human OS. This article is protected by copyright. All rights reserved. PMID- 30520541 TI - Posturographic and ankle muscle activation characteristics in patients with haemophilia. AB - INTRODUCTION: The objective of this work was to examine the interrelations of posturographic and surface EMG (SEMG) characteristics of ankle muscles in patients with haemophilia while standing naturally. METHODS: Surface EMG of five bilaterally recorded ankle muscles was conducted in 24 patients with haemophilia (PwH, age: 42 [11] years, mean [SD], 22 A, 2 B, 21 severe, 3 moderate) with median (quartiles) WFH orthopaedic joint score of 30 (20/39) points and 24 non haemophilic controls (Con, age: 42 [12]). Force plate (IBS) signals were captured simultaneously during bipedal stance with eyes open. Load proportion of the left and right sides as well as heel and forefoot were calculated via four independent pressure transducers. Overall, weight distribution (WD) indices are reported with higher results representing a poorer WD. RESULTS: Analyses of WD showed large differences between groups (PwH: 10.2 [5.4], Con: 5.2 [2.9], P < 0.001, d = 1.15). After clustering PwH, large effects (P = 0.02, etap 2 > 0.16) were found for amplitude ratios of the lateral gastrocnemius (LG) muscle. In PwH, the degree of joint alteration of the right lower limb was associated with load proportion of the left side (rho > 0.64, P = 0.001). CONCLUSION: Patients with greater dysbalance showed higher forefoot loads and appeared to compensate their altered joint situations with considerably higher amplitude ratios of LG. Further studies should investigate whether therapeutic interventions could alter postural alignment and muscle activation and how these can influence patients' joint function and symptoms. PMID- 30520542 TI - Chronic tubal pregnancy manifesting as a heterogeneous adnexal mass with prominent neovascularization in a woman with a negative serum beta-human chorionic gonadotropin level. AB - A 41-year-old woman (gravida 2, para 1) underwent elective termination of pregnancy at approximately 7 weeks of gestation. At 1 month after the elective abortion, she was referred due to abnormal results in a cervical cytological examination. Transvaginal ultrasonography showed a heterogeneous mass of 16 mm in diameter in the left adnexal region. At 3 months after her referral, the asymptomatic left adnexal mass had increased to 55 mm in diameter. Prominent vascular flow was detected in the solid portion by color Doppler ultrasonography. Magnetic resonance imaging showed suspected hemorrhage in the left adnexal cystic mass. Three-dimensional computerized tomographic angiography showed the prominent development of tortuous blood vessels in the left adnexal region, which originated from the left ovarian artery. The patient had a negative beta-human chorionic gonadotropin (hCG) level. Left salpingectomy was performed by a single port laparoscopic approach. A pathological examination revealed degenerated villous tissue with beta-hCG-positive syncytiotrophoblasts. PMID- 30520543 TI - Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet. AB - Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in the prevention for NASH related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenDeltahep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenDeltahep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenDeltahep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis, and tumor growth in PtenDeltahep mice on the HF diet. Tumor cells were highly proliferative by HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenDeltahep mice with hypercholesterolemia. This article is protected by copyright. All rights reserved. PMID- 30520544 TI - Prognostic value of multiple repeated biomarkers in pulmonary arterial hypertension associated with congenital heart disease. PMID- 30520546 TI - Idarucizumab for the reversal of dabigatran in patients undergoing heart transplantation. PMID- 30520545 TI - Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. AB - AIM: This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. METHODS AND RESULTS: We enrolled 73 chronic HF patients who were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose-dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ~4-fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT-proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). CONCLUSION: Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides. PMID- 30520548 TI - Co-localization of Middle East respiratory syndrome coronavirus (MERS-CoV) and dipeptidyl peptidase-4 in the respiratory tract and lymphoid tissues of pigs and llamas. AB - The present study investigated the co-localization of the Middle East respiratory syndrome coronavirus (MERS-CoV) and its receptor dipeptidyl peptidase-4 (DPP4) across respiratory and lymphoid organs of experimentally MERS-CoV infected pigs and llamas by immunohistochemistry (IHC). Also, scanning electron microscopy (SEM) was performed to assess the ciliary integrity of respiratory epithelial cells in both species. In pigs, on day 2 post-inoculation (p.i.), DPP4-MERS-CoV co-localization was detected in medial turbinate epithelium. On day 4 p.i., the virus/receptor co-localized in frontal and medial turbinate epithelial cells in pigs, and epithelial cells distributed unevenly through the whole nasal cavity and in the cervical lymph node in llamas. MERS-CoV viral nucleocapsid was mainly detected in upper respiratory tract sites on days 2 and 4 p.i. in pigs and day 4 p.i. in llamas. No MERS-CoV was detected on day 24 p.i. in any tissue by IHC. While pigs showed severe ciliary loss in the nasal mucosa both on days 2 and 4 p.i. and moderate loss in the trachea on days 4 and 24 p.i., ciliation of respiratory organs in llamas was not significantly affected. Obtained data confirm the role of DPP4 for MERS-CoV entry in respiratory epithelial cells of llamas. Notably, several nasal epithelial cells in pigs were found to express viral antigen but not DPP4, suggesting the possible existence of other molecule/s facilitating virus entry or down regulation of DPP4 upon infection. This article is protected by copyright. All rights reserved. PMID- 30520547 TI - Potential limits of AAV-based gene therapy with the use of new transgenes expressing factor IX fusion proteins. AB - INTRODUCTION: The variety of treatment for haemophilia B (HB) has recently improved with the emergence of both AAV-based gene therapy and bioengineered human factor IX (hFIX) molecules with prolonged half-life due to fusion to either albumin (Alb) or immunoglobulin Fc fragment (Fc). AIM: Adeno-associated viral vectors (AAV) mediating expression of hFIX-Alb and hFIX-Fc fusion proteins was investigated for gene therapy of HB to explore if their extended half-life translates to higher plasma levels of FIX. METHODS: Single-stranded cross packaged AAV2/8 vectors expressing hFIX-Alb, hFIX-Fc and hFIX were evaluated in vitro, and in mice. RESULTS: Both hFIX-Alb and hFIX-Fc fusion proteins were synthesized and expressed as single chains of expected size following AAV mediated gene transfer in vitro and in vivo. The procoagulant properties of these hFIX-fusion proteins were comparable to wild-type hFIX. However, their expression levels were threefold lower than wild-type hFIX in vivo most likely due to inefficient secretion. CONCLUSION: This, the first, evaluation of hFIX-fusion proteins in the context of AAV gene transfer suggests that the hFIX-fusion proteins are secreted inefficiently from the liver, thus preventing their optimal use in gene therapy approaches. PMID- 30520549 TI - Ischemic optic neuropathy in robotic-assisted gynaecologic surgery: A case report. AB - The study was aimed to present a rare case of who developed non arteritic anterior ischemic optic neuropathy (NAION) following robotic-assisted gynaecologic surgery. A 58-year-old female patient presented with vision loss in right eye after non-complicated robotic-assisted total hysterectomy and bilateral salpingo-oopherectomy. We observed on fundoscopy optic disc edema and splinter hemorrhages at the optic disc edges. Fluorescein angiography showed hypofluorescence of the optic disc in the early phases due to filling delay followed by hyperfluorescence with leakage from disc capillaries in the late phases of the angiogram. From these findings, we diagnosed NAION in the right eye. When NAION was diagnosed, the patient received intravenous methylprednisolone. Topical brimonidin and coenzyme-Q were given. On 1-month follow-up, recovery of visual loss was observed. Here, we present a case of NAION that is an uncommon cause of perioperative visual loss after robotic-assisted gyneacologic surgery. PMID- 30520550 TI - Spatial analysis of lumpy skin disease (LSD) in Eurasia - Predicting areas at risk for further spread within the region. AB - Data from affected lumpy skin disease (LSD) locations between July 2012 and September 2018 in the Balkans, Caucasus and Middle East were retrieved from FAO's Global Animal Disease Information System (EMPRES-i) from the European Commission's Animal Disease Notification System (ADNS) and completed with data from the official veterinary services of some countries. During this period, a total of 7,593 locations from twenty-two countries were affected. Within this period, over 46,000 cattle were clinically affected by LSD, 3,700 animals died and 17,500 were slaughtered due to culling policies to stop the spread of the disease. Most outbreaks occurred in 2016, between the months of May and November. The affected region was divided in a grid of 10 x 10 km cells and we fit a spatial regression model to analyse the association between the reported LSD outbreaks and climatic variables, land cover and cattle density. The results showed big differences in the odds of being LSD positive due to the type of land cover: the odds of a cell being LSD positive was increased in areas mostly covered with croplands, grassland or shrubland. The odds was also increased for higher cattle density, as well as areas with higher annual mean temperature and higher temperature diurnal range. The resulting model was utilized to predict the LSD risk in neighboring unaffected areas in Europe, the Caucasus and Central Asia, identifying several areas with high risk of spread. Results from this study provide useful information for the design of surveillance and awareness systems, and preventive measures, e.g. vaccination programs. This article is protected by copyright. All rights reserved. PMID- 30520551 TI - Epidermolytic ichthyosis due to a de novo missense mutation c.1307T> C; p.Leu436Pro in KRT10. PMID- 30520552 TI - Why pesticides with mutagenic, carcinogenic and reproductive risks are registered in Brazil. AB - Brazil is the biggest market for pesticides in the world. In the registration process, a pesticide must be authorized by the Institute of the Environment, Health Surveillance Agency and Ministry of Agriculture. Evaluations follow a package of toxicological studies submitted by the companies and also based on the Brazilian law regarding pesticides. We confronted data produced by private laboratories, submitted to the Institute of the Environment for registration, with data obtained from scientific databases, corresponding to mutagenicity, carcinogenicity and teratogenicity of pesticides. All studies submitted by the companies were carried out by private laboratories. From 247 pesticide formulations analyzed, none showed positive results for mutagenicity, carcinogenicity or teratogenicity. From 574 articles in the scientific literature, 84% published by public laboratories showed positive results, while 79% of those showing negative results came from private laboratories. There is an ethical concern about a conflict of interest between public/independent laboratories and private laboratories that produce data for registering pesticides. We demonstrated that there is a clear contradiction between public and private laboratories. Brazilian regulatory authorities have approved the registration of pesticides based almost exclusively on the monographs provided by the pesticide industry, because the use of scientific articles or information from the independent literature is strongly belittled by the industry. Pesticide companies argue that scientific articles cannot be trusted. Also, according to the industry, pesticide registration cannot be refused based on results from scientific articles. Thus, the registration of pesticides with mutagenic, carcinogenic and teratogenic risks has been approved in Brazil. PMID- 30520553 TI - Directed Evolution Empowered Redesign of Natural Proteins for the Sustainable Production of Chemicals and Pharmaceuticals. AB - Directed evolution has advanced into a standard industrial "tool" to tailor naturally occurring proteins for a variety of biotechnological applications, thus enabling product valorization and bringing societal benefits across industrial sectors. Examples are sustainable enzymatic production processes for chemicals, pharmaceuticals, or applications in the food, feed, and laundry industries. In essence, directed evolution has contributed to sustainable industrial processes that fuel the transition from a fossil-based economy to a biobased economy utilizing renewable resources. Phage display technologies represent a comparable breakthrough that allow for the directed evolution of binding proteins by physical coupling between a phenotype and the respective genotype, thus enabling the identification of highly selective antibodies for a broad variety of applications in diagnostics and therapy. PMID- 30520555 TI - Nagoya Medal of Organic Chemistry / KCS-Wiley Young Chemist Award. PMID- 30520554 TI - Emergence and adaptation of H3N2 canine influenza virus from avian influenza virus: An overlooked role of dogs in interspecies transmission. AB - H3N2 CIV originated from avian species and emerged in dogs in Asia around 2005 where it became enzootic before reaching the USA in 2015. To investigate the key aspects of the evolution of H3N2 CIV regarding its emergence and adaptation in the canine host, we conducted an extensive analysis of all publicly available H3N2 CIV sequences spanning a 10-year period. We believe that H3N2 AIVs transferred to canines around 2002-2004. Furthermore, H3N2 CIVs could be divided into seven major clades with strong geographic clustering and some changed sites evidence of adaptive evolution. Most notably, the dN/dS of each H3N2 CIVs segment was higher than the correspondent of H3N2 AIV and the U content of HA and NA was increasing over time, suggesting the idea that this avian-origin virus may be gradually adapting to the host. Our results provide a framework to elucidate a general mechanism for emergence of novel influenza viruses. This article is protected by copyright. All rights reserved. PMID- 30520556 TI - Overview of non-coding mutations in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most frequent leukemia type in which the genetic alterations influencing the clinico-biological course are not entirely understood. CLL has a heterogeneous course, with some patients showing an indolent course, and others experiencing an aggressive course. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) studies identified recurrently mutated genes in CLL, and profiled its clonal evolution patterns. However, more recent WGS studies also identified variants in non-coding sequences of the CLL genome, revealing important lesions outside the protein-coding regions. Here we describe the most representative non-coding lesion of the CLL genome, including lesions in the 3'-UTR region of NOTCH1 which result in the truncation of the NOTCH1 protein PEST domain, and non-coding mutations in an enhancer region on chromosome 9p13 which result in reduced expression of the PAX5 transcription factor. In addition, we describe the role of microRNAs in CLL, in particular the miR15A/miR16-1 microRNAs recurrently affected by deletions of chromosome 13q14. Together, new findings in non-coding genome genetic lesions provide a more complete portrait of the genomic landscape of CLL with clinical implications. PMID- 30520557 TI - Systemic therapies of pityriasis rubra pilaris: a systematic review. AB - Pityriasis rubra pilaris (PRP) is a rare papulosquamous disorder. Treatment is challenging; the armamentarium consists of topical corticosteroids, phototherapy, classic systemic treatments such as retinoids or immunosuppressive drugs, and most recently biologicals. However, the relative effectiveness of therapies is unclear. Our objective was to review the published literature on systemic treatment of PRP. A systematic review was conducted on PubMed and the Cochrane Library up to 5 September 2017. Studies evaluating any systemic treatments of PRP (except for historical treatments) were included. Overall, 182 studies met the predefined inclusion criteria, and reported on 475 patients and 652 courses of treatment. 42.0 % (225/514) of all patients treated with retinoids achieved an excellent response (isotretinoin: 61.1 % [102/167], etretinate: 47 % [54/115], and acitretin: 24.7 % [43/174]) compared to an excellent response rate of 33.1 % (53/160) with methotrexate. Therapy with biologicals was successful in 51.0 % of patients (71/133) (ustekinumab: 62.5 % [10/16], infliximab: 57.1 % [28/49], etanercept: 53.3 % [16/30], and adalimumab: 46.4 % [13/28]). This review balances effectiveness, side effects, experience, and drug costs in order to suggest a treatment regimen starting with isotretinoin as first-line, methotrexate as second-line and biologicals as third-line treatment for this difficult-to-treat dermatosis. PMID- 30520558 TI - Solving for X: Evidence for sex-specific autism biomarkers across multiple transcriptomic studies. AB - Autism spectrum disorder (ASD) is a markedly heterogeneous condition with a varied phenotypic presentation. Its high concordance among siblings, as well as its clear association with specific genetic disorders, both point to a strong genetic etiology. However, the molecular basis of ASD is still poorly understood, although recent studies point to the existence of sex-specific ASD pathophysiologies and biomarkers. Despite this, little is known about how exactly sex influences the gene expression signatures of ASD probands. In an effort to identify sex-dependent biomarkers and characterize their function, we present an analysis of a single paired-end postmortem brain RNA-Seq data set and a meta analysis of six blood-based microarray data sets. Here, we identify several genes with sex-dependent dysregulation, and many more with sex-independent dysregulation. Moreover, through pathway analysis, we find that these sex independent biomarkers have substantially different biological roles than the sex dependent biomarkers, and that some of these pathways are ubiquitously dysregulated in both postmortem brain and blood. We conclude by synthesizing the discovered biomarker profiles with the extant literature, by highlighting the advantage of studying sex-specific dysregulation directly, and by making a call for new transcriptomic data that comprise large female cohorts. PMID- 30520559 TI - Cytomine: towards an open and collaborative software platform for digital pathology bridged to molecular investigations. AB - PURPOSE: Digital histology is being increasingly used in research and clinical applications. In parallel new tissue imaging methods (e.g. imaging mass spectrometry) are currently regarded as very promising approaches for better molecular diagnosis in pathology. However, these new data sources are still often underexploited because of the lack of collaborative software to share and correlate information for multimodal analysis. EXPERIMENTAL DESIGN: We followed the open science paradigm to develop new features in our web-based Cytomine software to support next-generation digital pathology bridged to molecular investigations. RESULTS: Our new open-source developments allow to explore whole slide classical histology with MALDI imaging and to support preprocessing for biomarker discovery using laser microdissection-based microproteomics. CONCLUSIONS AND CLINICAL RELEVANCE: Our updated version of Cytomine is the first open and web-based tool to enable sharing data from classical histology, molecular imaging and cell counting for proteomics preprocessing. It holds good promise to fulfill imminent needs in molecular histopathology. This article is protected by copyright. All rights reserved. PMID- 30520560 TI - Epithelioid angiosarcoma arising from a frontoparietal arteriovenous malformation. PMID- 30520561 TI - Dermatologic manifestations in end stage renal disease. AB - Skin manifestations are commonly seen in end stage renal disease (ESRD). Skin involvement in this population can be extensive and dramatically worsen quality of life. Close observation of the skin and nails of ESRD patients by clinicians allows for timely diagnosis and treatment, which ultimately improves quality of life and reduces mortality. In this article we focus on the cutaneous changes most commonly seen in ESRD patients. PubMed/Medline database search was done for published literature on skin manifestations in ESRD patients. All the available literature was reviewed and relevant articles were used to discuss about clinical features, pathogenesis, histology and treatment of each skin disorder in ESRD patients. Most commonly encountered skin manifestations in patients with ESRD are pruritus, xerosis, pigmentation changes, nail changes, perforating disorders, calcifying disorders, bullous dermatoses and nephrogenic systemic fibrosis. Skin manifestations in ESRD can be difficult to treat and multiple comorbidities in this patient population can exacerbate these disorders. Many of the treatment options are experimental with evidence largely derived from the case reports and small clinical trials. More large-scale trials are needed to firmly establish evidence based treatment guidelines. Prompt evaluation and management of these disorders improve morbidity and quality of life in ESRD patients. PMID- 30520562 TI - Early-onset colorectal cancer in young individuals. AB - Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC incidence in individuals younger than 50 years has been increasing by 2% per year. The surge of CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early-onset CRCs are characterized by more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left-colon sided location of the primary tumor. Among EO-CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have CRC familiarity. Most notably, the remaining 50% of EO-CRC have neither hereditary syndromes nor family history of CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, hereditariness and outcome to treatments of EO-CRC, finally providing considerations for future perspectives. PMID- 30520563 TI - BCG Vaccination for bovine tuberculosis; conclusions from the jersusalem one health workshop. AB - The global burden of bovine tuberculosis (bTB) remains poorly characterized, with spill-over impacts on multiple species. The "One Health" concept is especially relevant given the bidirectional risk of cattle infecting humans with Mycobacterium bovis and humans infecting cattle with M. tuberculosis. "Test and cull" is the traditional bTB control method, but the strategy may not be economically feasible or culturally acceptable where cattle are highly prized or their killing is a religious taboo; it is also less effective when there are wildlife reservoirs of infection. Vaccination with M. bovis bacille Calmette Guerin (BCG) provides protection against bTB, but its use in animals has been limited. The Jerusalem One Health workshop considered key bTB knowledge gaps and innovative solutions. Knowledge gaps identified included 1) the poorly quantified prevalence of M. bovis infection and disease in cattle, domestic camelids and human populations in developing countries, 2) the absence of alternatives to a "test and cull" strategy in settings where the killing of infected animals is culturally or economically unacceptable, or where affected species are protected, and 3) an understanding of the induction of mucosal immunity against bTB. We summarize discussions on the use of BCG vaccination in domestic animals and wildlife and list potential projects to address the knowledge gaps identified. This article is protected by copyright. All rights reserved. PMID- 30520564 TI - Basal insulin therapy: unmet medical needs in Asia and the new insulin glargine in diabetes treatment. AB - Diabetes remains a global epidemic problem and a tremendous health challenge especially in Asian population. Dramatic increases in the prevalence of diabetes across different countries or areas in Asia have been reported in recent epidemiological studies. While clinical guidelines have strengthen appropriate anti-hyperglycaemic medications and lifestyle modifications for optimal diabetes management, inadequate glycaemic control still occurs in many patients with an increased risk of developing microvascular and macrovascular complications. Insulin administration is the main therapy for diabetes in response to the inability of insulin secretion, and is recommended in current guidelines to treat patients with type 2 diabetes (T2D) after failure on oral anti-diabetic drugs (OADs). Clinical studies have revealed that long-acting insulin analogues improve basal glyacemic control with reduced risk of hypoglyacemia. In this review, we discuss previous challenges with basal insulin therapy in Asia, the pharmacological development of insulin analogues to overcome the unmet medical needs, and recent clinical studies of the new ultra-long acting insulin analogue, insulin glargine U300 (Gla-300). Moreover, relevant findings of current real world evidence are also included for the comparison of efficacy and safety of different insulin formulations. Based on the accumulating evidence showing low incidence of hypoglyacemia and technical benefits of dose titration, treatment of Gla-300 can be a promising strategy for Asian diabetic patients to achieve glyacemic target with favorable safety. This article is protected by copyright. All rights reserved. PMID- 30520565 TI - Proteins regulating microvesicle biogenesis and multidrug resistance in cancer. AB - Microvesicles (MV) are emerging as important mediators of intercellular communication. These signalling vectors are implicated in physiological processes ranging from vascular homeostasis to inflammation. They also play an important role in the cancer pathology and progression. MVs can be formed in response to stimuli, or in the case of cancer, spontaneously and constitutively. Cellular activation is perhaps the most widely reported initiator of MV biogenesis, however, the precise mechanism remains undefined. What is clear, is cellular activation causes an increase in intracellular calcium and this modulates a number of membrane bound and cytosolic proteins that untether the membrane from the underlying cytoskeleton. This results in outward budding and ultimately in the vesiculation of the plasma membrane. Uncovering the proteins involved in regulating MV biogenesis is of interest given their role in the dissemination of deleterious cancer traits. Our laboratory was the first to report that MVs shed from drug-resistant cancer cells transfer multidrug resistance (MDR) proteins to drug-sensitive cells, conferring the MDR phenotype in a matter of hours. MDR is attributed to the overexpression of ABC transporters, primarily P-glycoprotein and MRP1. These ATP-dependent efflux transporters can efflux a broad range of substrates out of the cytoplasm. Their expression and functionality is dependent on a number of proteins that are involved in their translation, trafficking from the Golgi, as well as their subcellular localisation. In particular, FERM domains proteins have been implicated in supporting the functionality of these proteins in drug-resistant cells and in recipient cells during intercellular transfer by vesicles. Herein, we have compiled the most recent research on the proteins involved in MV biogenesis and in the dissemination of MV-mediated MDR. We also draw attention to unanswered questions in the literature that may prove to be of benefit in ongoing efforts to improve clinical response to chemotherapy and circumventing MDR. This article is protected by copyright. All rights reserved. PMID- 30520566 TI - Pegbelfermin (BMS-986036), PEGylated FGF21, in Patients with Obesity and Type 2 Diabetes: Results from a Randomized Phase 2 Study. AB - OBJECTIVE: Obesity and type 2 diabetes mellitus (T2DM) are risk factors for nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. This study assessed pegbelfermin (BMS-986036), recombinant PEGylated human fibroblast growth factor 21 (FGF21), in patients with obesity and T2DM predisposed to fatty liver. METHODS: In this randomized, double-blind, placebo-controlled study, patients with T2DM and BMI of 30 to 50 kg/m2 received subcutaneous pegbelfermin (1, 5, or 20 mg daily or 20 mg weekly; n = 96) or placebo (n = 24) for 12 weeks. Primary end points were safety, tolerability, and change in HbA1c. Additional end points included insulin sensitivity, lipids, adiponectin, and disease progression biomarkers. RESULTS: There were no significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high-density lipoprotein cholesterol (P = 0.015) and triglycerides (P = 0.037). All pegbelfermin regimens significantly increased adiponectin levels; 20-mg daily and weekly regimens decreased serum PRO-C3. Most adverse events were mild; the most frequent adverse events were injection-site bruising and diarrhea. CONCLUSIONS: Twelve-week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity-related metabolic diseases (e.g., nonalcoholic steatohepatitis). PMID- 30520567 TI - High probability areas for ASF infection in china along the russian and korean borders. AB - African swine fever (ASF) is a transcontinental, contagious, fatal virus disease of pig with devastating socioeconomic impacts. Interaction between infected wild boar and domestic pig may spread the virus. The disease is spreading fast from the west of Eurasia towards ASF-free China. Consequently, prediction of the distribution of ASF along the Sino-Russian-Korean borders is urgent. Our area of interest is Northeast China. The reported ASF-locations in eleven contiguous countries from the Baltic to the Russian Federation were extracted from the archive of the World Organization for Animal Health from July 19, 2007 to March 27, 2017. The locational records of the wild boar were obtained from literature. The environmental predictor variables were downloaded from the WorldClim website. Spatial rarefication and pair-wise geographic distance comparison were applied to minimize spatial autocorrelation of presence points. Principal component analysis (PCA) was used to minimize multi-collinearity among predictor variables. We selected the maximum entropy algorithm for spatial modelling of ASF and wild boar separately, combined the wild boar prediction with the domestic pig census in a single map of suids and overlaid the ASF with the suids map. The accuracy of the models was assessed by the AUC. PCA delivered five components accounting for 95.7% of the variance. Spatial autocorrelation was shown to be insignificant for both ASF and wild boar records. The spatial models showed high mean AUC (0.92 and 0.97) combined with low standard deviations (0.003 and 0.006) for ASF and wild boar respectively. The overlay of the ASF and suids maps suggest that a relatively short sector of the Sino-Russian border has been a high probability entry point of ASF at current conditions. Two sectors of the Sino-Korean border present an elevated risk. This article is protected by copyright. All rights reserved. PMID- 30520568 TI - Hollow Fiber Countercurrent Dialysis for Continuous Buffer Exchange of High Value Biotherapeutics. AB - Buffer exchange, desalting, and formulation of high value biotherapeutics are currently performed using batch diafiltration; however, this type of tangential flow filtration process may be difficult to implement as part of a fully continuous biomanufacturing process. The objective of this study was to explore the potential of using countercurrent dialysis for continuous protein formulation and buffer exchange. Experiments were performed using concentrated solutions of Immunoglobuin G (IgG) with commercially available hollow fiber dialyzers having 1.5 and 1.8 m2 membrane surface area. More than 99.9% buffer exchange was obtained over a range of conditions, as determined from the removal of a model impurity (vitamin B12 ). The dialyzers were able to process more than 0.5 kg of IgG per day in an easily scalable low-cost process. In addition, buffer requirements were less than 0.02 L of buffer per g IgG, which is several times less than that used in current batch diafiltration processes. These results clearly demonstrate the potential of using low-cost hollow fiber dialyzers for buffer exchange and product formulation in continuous bioprocessing. This article is protected by copyright. All rights reserved. PMID- 30520569 TI - Same day implant bridge for full-arch implant fixed rehabilitation. AB - OBJECTIVE: To report an alternative clinical and laboratory protocol for same-day implant fixed full-arch provisional rehabilitation that may overcome limitations associated with traditional immediate provisional denture conversion rehabilitation protocols. CLINICAL CONSIDERATIONS: The traditional denture conversion fabrication method of an immediate full-arch fixed provisional involves the conversion of a complete denture into a provisional fixed implant support prosthesis. The conversion technique has several shortcomings which compromise structural integrity, longevity, ease of modification, and the need for a silicone impression. CONCLUSIONS: The "Same day" implant bridge (SDIB) concept provides clinical and laboratory advantages which overcome the limitations of the traditional denture conversion technique. This article reviews the rationale, clinical stages, and conventional fabrication sequence of the SDIB concept. CLINICAL SIGNIFICANCE: Compared to the traditional denture conversion method for immediate implant bridge fabrication, the SDIB technique offers the following advantages for implant-supported fixed rehabilitation: rapid fabrication, improved structural integrity and rigidity, elimination of all silicone impressions, ease of modification to promote comfort, function and adaptability, and favorable esthetics. PMID- 30520570 TI - Factors affecting Porcine Reproductive and Respiratory Syndrome virus time-to stability in breeding herds in the Midwestern United States. AB - The time needed to wean porcine reproductive and respiratory syndrome (PRRS) virus negative pigs consistently from a breeding herd after an outbreak is referred to as time-to-stability (TTS). TTS is an important measure to plan herd closure as well as to manage economic expectations. Weekly PRRS incidence data from 82 sow farms in six production systems located in the Midwestern United States were used for the analysis. The objective of this study was to evaluate the effect of recorded predictors on TTS in participant sow farms. The median TTS was 41.0 weeks (1st quartile 31.0 weeks-3rd quartile 55.0 weeks). In the final multivariable mixed-effects Cox model, farms that experienced winter (hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.37-4.43) and autumn (HR 1.73, 95% CI 1.00-2.99) PRRS outbreaks achieved stability sooner than farms that experienced PRRS outbreaks during summer. No statistically significant difference (p=0.76) was observed between the TTS of farms that had a PRRS outbreak during spring and summer (HR 1.09, 95% CI 0.59-1.88). Additionally, farms that had a PRRS outbreak associated with a 1-7-4 restriction fragment length polymorphism (RFLP) cut pattern took significantly longer to achieve stability (HR 0.4, 95% CI 0.3-0.7) compared to farms which had a non-1-7-4 PRRS outbreak. Finally, farms that had a previous PRRS outbreak within a year achieved stability sooner (HR 2.18, 95% CI 1.23-3.86) than farms that did not have a previous PRRS outbreak within a year. This study provides information that may result useful for planning herd closure and managing expectations about the time needed to wean PRRS virus negative pigs in breading herds according to the season of the year when the outbreak occurred and the RFLP cut pattern associated with the outbreak virus. This article is protected by copyright. All rights reserved. PMID- 30520572 TI - Colloidal FeIII, MnIII, CoIII and CuII hydroxides stabilized by starch as catalysts of water oxidation reaction with one electron oxidant Ru(bpy)33. AB - Colloidal catalysts for water oxidation to dioxygen, which are stable on storage and under the reaction conditions, are synthesized based on CoIII, MnIII, FeIII and CuII hydroxides. Stabilization of the colloids with dextrated starch allows the process of hydroxide ageing to be stopped at the stage of the formation of primary nuclei (ca. 2-3 nm from TEM data). Molecular mechanics and DLS studies indicate the core-shell type structure of the catalysts, where the hydroxide core is stabilized by the molecular starch network (ca. 5-7 nm). The colloidal catalysts are highly effective to oxidation of water with one electron oxidant Ru(bpy)33+ at pH 7 to 10. The influence of pH, catalyst concentration and buffer nature on the oxygen yield is studied. The maximal yields are 72, 53 and 78 % over Fe-, Mn- and Co-containing catalysts, respectively, and TON are 7.8; 54 and 360, respectively. The Cu-containing catalyst is poorly effective to water oxidation (the maximal yield is 28 % O2). The developed catalysts are of interest for kinetic studies of the mechanism of water oxidation using stopped-flow technique and as precursors for anchoring nanosize hydroxides onto various supports in order to develop biomimetic systems for artificial photosynthesis. PMID- 30520571 TI - Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function. AB - Next-generation sequencing has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome and whole genome sequencing in 4 independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter and thinning of the corpus callosum, we identified 4 previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co-Immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin-488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by bi-allelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway. This article is protected by copyright. All rights reserved. PMID- 30520573 TI - Spasmolytic Action of Preparations and Compounds from Hofmeisteria schaffneri. AB - Hofmeisteria schaffneri is used in Mexican folk medicine for treating painful gastric complaints. Therefore, in this paper the smooth muscle relaxant effect of the essential oil, and an infusion of the whole plant were evaluated using the gastrointestinal transit test in mice. The results revealed that both preparations at 316 mg/kg inhibited gastrointestinal transit by 47.5 and 52.1%, respectively. The common component of the infusion and essential oil was 8.9 epoxy-10-acetoxythymol angelate (2), which inhibited the gastrointestinal transit by 53.4% at a dose of 31.6 mg/kg. An HPLC-UV method was developed and validated to quantify 2. The chromatographic conditions were: A LiChrospher(r) 100 RP-18 column (250 x 4 mm i.d., 5MUm) with a mobile phase composed of CH3CN-H2O, in a gradient run at a flow rate of 0.6 mL/min, using a wavelength of 215 nm. The method was linear, precise, accurate, and showed excellent recovery. According to the results, compound 2 can be used as a marker for the quality control procedures of the crude drug of H. schaffneri. PMID- 30520574 TI - Sesquiterpene Quinones and Diterpenes from Smenospongia cerebriformis and Their Cytotoxic Activity. AB - Using various chromatographic methods, one new sesquiterpene quinone named smenohaimien F (1) and five known, neodactyloquinone (2), dactyloquinone C (3), dactyloquinone D (4), isoamijiol (5), and amijiol (6), were isolated from the marine sponge Smenospongia cerebriformis Duchassaing & Michelotti, 1864. Their structures were elucidated by ID-, 2D-NMR spectroscopic analysis, HR-ESI-MS, and by comparing with the NMR data reported in the literature. The cytotoxic activities of the all compounds were evaluated on five human cancer cell lines, LU-1, HL-60, SK-Mel-2, HepG-2, and MCF-7. Compound 4 was found to exhibit significant cytotoxic activities on all tested human cancer cell lines with IC50 values ranging from 0.7 to 1.6 MUg/mL. PMID- 30520575 TI - Comparison of Different Strains of Agrobacterium rhizogenes for Hairy Root Induction and Betulin and Betulinic Acid Production in Morus alba. AB - Three Agrobacterium rhizogenes strains were tested for their ability to transform the plant Mois alba L. and to induce production of the secondary metabolites betulin and betulinic acid. All the tested strains of A. rhizogenes (R1601, LBA9402 and R1000) were able to induce hairy root formation in leaf tissue explants. Strain LBA9402 had the highest rate of infection (92.7% +/- 8.8%), whereas strain R1601 had the lowest rate (87.4% +/- 9.3%). The highest number of hairy roots per explant (5.6 +/-0.5) and the greatest root length (2.4 +/- 0.2 mm) were obtained with strain LBA9402. We also evaluated dry weight (a measure of growth) and betulin and betulinic acid production in hairy roots and found that the highest growth (167.8 +/- 14.5 mg/flask) occurred after infection with strain LBA9402. Furthermore the highest production of betulin (5.4 +/- 0.4 mg/g dry weight) and betulinic acid (2.3 +/- 0.2 mg/g dry weight) was noted using strain LBA9402. Among three elicitors, yeast extract showed the highest induction of betulin production (8.7 +/- 0.4 mg/g) and silver nitrate induced the highest yield of betulinic acid (4.1 +/- 0.2 mg/g). Our study showed that A. rhizogenes strain LBA9402 was the most effective of the three tested strains for production of transformed root cultures and betulin and betulinic acid. PMID- 30520576 TI - Two New Triterpenes and Other Compounds from Mentha aquatica (Lamiaceae). AB - Two new triterpenoids, maquatic acid (1), a 2,3-seco-triterpene having an acetal in its A-ring, and 3-Omicron-benzoyltormentic acid (2), were isolated from underground parts of Mentha aquatica, in addition to twelve known compounds, tormentic acid (3), 1-Omicron-benzoylhyptadienic acid (4), 3-epi-ursolic acid (5), hyptadienic acid (6), 3-epi-maslinic acid (7), 3-epi-tormentic acid (8), ursolic acid (9), beta-sitosterol (10), oleanolic acid (11), pomolic acid (12), micromeric acid (13) and 21alpha-hydroxyursolic acid (14) from aerial and underground parts of the plant. Compounds 4-6, 8, 13 and 14 have been isolated from the genus Mentha for the first time. PMID- 30520577 TI - Chemical Composition and Antioxidant Activity of Lawsonia inermis Seed Extracts from Morocco. AB - The aim of the present study was to investigate the composition of Lawsonia inermis (henna) seed oil from Morocco and to evaluate some of its activities in order to use it in cosmetics. Phytosterols are valuable henna-oil constituents, but henna oil does not present any interesting antioxidant activity. PMID- 30520578 TI - Talarofuranone, a New Talaroconvolutin Analog from the Endophytic Fungus Talaromyces purpurogenus from Pouteria campechiana Seeds. AB - An endophytic fungus Talaronyces pinpurogenus was isolated from the seeds of the popular edible fruit Pouteria campechiana. The fungus was fermented in potato dextrose agar and the fungal media were extracted with EtOAc. Chromatographic separation of the EtOAc extracts over silica gel, Sephadex LH-20 and preparative thin layer chromatography furnished a furanone analogue of talaroconvolutin A, named talarofuranone (1), along with talaroconvolutin A (2), 4 hydroxyactophenone, tyrosol and ergosterol. The structure of 1 was determined by comparing the NMR data with that of 2 and by HRFABMS. PMID- 30520579 TI - Ochroborbone, A New Cytotoxic Indole Alkaloid from Ochrosia borbonica. AB - A new monoterpenoid indole alkaloid, ochroborbone (1), along with five known alkaloids (2-6), were isolated from the stems and leaves of Ochrosia borbonica. Among them, ochroborbone (1) is a rare C17-nor monoterpenoid indole alkaloid, and the known compounds (2-6) were isolated from Ochrosia for the first time-These structures were established on the basis of extensive spectroscopic methods. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1 and 2 exhibited inhibitory effects with IC50 values comparable with those of cisplatin. PMID- 30520580 TI - A New Ajmaline-type Alkaloid from the Roots of Rauvolfia serpentina. AB - A new ajmaline-type alkaloid, 21-Omicron-methylisoajmaline (1), together with twenty-one known compounds, a mixture of beta-sitosterol (2) and stigmasterol (3), reserpinine (4); tetrahydroalstonine (5), reserpine (6), venoterpine (7), yohimbine (8), 6'-O-(3,4,5-trimethoxybenzoyl)glomeratose A (9), isoajmaline (10), 3-epi-alpha-yohimbine (11), methyl 3,4,5-trimethoxy-trans-cinnamate (12), a mixture of beta-sitosterol 3-Omicron-beta-D-glucopyranoside (13) and stigmasterol 3-Omicron-beta-D- glucopyranoside (14), rescidine (15), 7-deoxyloganic acid (16), ajmaline (17), suaveoline (18), (+)-tetraphyllicine (19), loganic acid (20), 3 hydroxysarpagine (21), and sarpagine (22), were isolated from the roots of Rauvolla serpentina. Their structures were elucidated by spectroscopic data analysis and comparison with literature data. Compounds 11, 12 and 15 were for the first time identified from the genus Rauvolfla and 5, 7, 11, 12, 15, 18 and 22 were found from R. sepentina for the first time. Compound 11 showed moderate anticholinesterase activity with IC50 value of 15.58 MUM, whereas 6 exhibited strong vasorelaxant activity with the EC50 value of 0.05 MUM. PMID- 30520581 TI - Positions of Hydroxyl Groups in Chrysin are Critical for Inhibiting Plasminogen Activator Inhibitor-1 Release from Human Umbilical Vein Endothelial Cells. AB - Chrysin suppresses the TNFalpha-induced increase in the secretion of plasma plasminogen activator inhibitor 1 (PAl-1), a risk factor for thrombotic diseases, from human umbilical vein endothelial cells (HUVECs). The present study aimed to determine the association between the location of the hydroxyl groups in chrysin.to levels of-PAI-1. in the medium of HUVEC stimulated with TNFalpha. We cultured HUVEC for 3 h in medium containing chrysin or various flavonoids and then stimulated them with TNFalpha (10 ng/mL) for 12 h. Levels of PAI-1 antigen measured using ELISA showed that chrysin significantly inhibited the PAl- I increase with an IC50 of 15.6 MUM. The flavones, galangin, baicalein, 5 hydroxyflavone, 6-hydroxyflavone, 7-hydroxyflavone and quercetin did not significantly inhibit the PAI- increase. Apigenin and luteolin were cytotoxic and thus their ability to inhibit PAI production could not be evaluated. Chrysin also inhibited PAI- mRNA expression whereas the other compounds did not. Hydroxyl groups located in the A-5 and A-7 positions were essential for the inhibitoryactivity, which along with cytotoxicity, was significantly influenced by adding a third hydroxyl group. PMID- 30520582 TI - Constituents of Flourensia blakeana (Asteraceae). AB - Chemical study of the aerial parts of Flourensia blakeana Dillon allowed the isolation and identification of two novel compounds, 3, 5, 5'-trihydroxy-7, 3'- dimethoxyflavanone (1), and 2alpha-angeloyloxycostic acid (2) together with several known compounds. The structures were elucidated using spectroscopic data from.ID, 2D NMR and HRDEIMS experiments. PMID- 30520583 TI - Monoamine Oxidase Inhibitory Activity of Biflavonoids from Branches of Garcinia gardneriana (Clusiaceae). AB - Garcinia gardneriana is chemically characterized by the presence of biflavonoids. Taking into account that flavonoids are able to inhibit monoamine oxidase (MAO) activity, in the present study, the chemical composition of the branches' extract of the plant is described for the first time and the MAO inhibitory . activity of the isolated biflavonoids was evaluated. Based on spectroscopic and spectrometric data, it was possible to identify volkesiflavone, morelloflavone (1), Gb-2a (2) and Gb-2a-7-Omicron-glucoside (3) in the ethyl acetate fraction from ethanol extract of the branches. Compounds 1-3 were evaluated in vitro and demonstrated the capacity to inhibit MAO-A activity with an IC50 ranging from 5.05 to 10.7 MUM, and from 20.7 to 66.2 MUM for MAO-B. These inhibitions corroborate with previous IC50 obtained for monomeric flavonoids, with a higher selectivity for MAO-A isoform. The obtained results indicate that biflavonoids might be promising structures for the identification of new MAO inhibitory compounds. PMID- 30520584 TI - Effects of Intestinal Microecology on Metabolism and Pharmacokinetics of Oral Wogonoside and Baicalin. AB - Baicalin and wogonoside are two of the most abundant flavonoid glycosides in the root of Scutellaria baicalensis Georgi, which is a widely used peroral herbal medicine with anticancer, antiviral, antibacterial and anti-inflammatory properties. In the present study, the effects of intestinal microecology on the metabolism and pharmacokinetics of orally administered baicalin and wogonoside were investigated by UPLC-QTOF/MS measurement of the difference in metabolites between normal and antibiotic-pretreated rats. In the antibiotic-pretreated rats, the plasma concentration-time profile and pharmacokinetic parameters of the two flavonoid glycosides and their relevant aglycone forms were significantly changed compared with those in normal rats. Further, hydrolysis and glucuronidated metabolites were not detected in the cecum contents and urine samples from antibiotic-pretreated rats. These results suggested that intestinal microbiota may play a key role in the pharmacokinetics and metabolism of peroral baicalin and wogonoside. According to our findings, it is recommended that the root of S. baicalensis should not be co-administered with antibiotics in clinical use. PMID- 30520585 TI - Protoflavanones from the Wood Stem of Salvertia convallariodora. AB - Phytochemical-analysis of the ethyl acetate extract of stem wood of Salvertia convallariodora A. St.-Hil. (Vochysiaceae), a Brazilian Cerrado species, led to the isolation and full characterization of three new non-aromatic B-ring flavanones (1-3) as well as the terpene mixture of sericic acid (4), 24 hydroxytormentic acid (5); 24-hydroxytormentic acid glucosyl ester (6), and sericoside (7), all identified for the first time from S. convallariodora. The structures of the new flavanones (1-3) were established from IR, LC-PDA-qTOF-MS, and NMR spectral data, including 2D NMR experiments. PMID- 30520586 TI - Chemical Composition and Antioxidant Activity of Cirsium vulgare Inflorescences. AB - The chemical composition of Cirsium vulgare flower heads was examined. Petrol and chloroform extracts of this plant material were analyzed by GC-MS for the presence of fatty acids, phytosterols, and triterpenes. Diethyl ether, ethyl acetate, and butanol fractions of the methanolic extract were subjected to multistep - chromatographic separations, and as a result, fourteen flavonoids were obtained (1-14). All compounds were isolated from this morphological part for the first time and eleven from the plant. Among the identified components were four aglycones, eight glycosides, and two glycoside esters, derivatives of apigenin, luteolin, kaemferol, and quercetin. One of them was a rarely occurring compound apigenin 7-0-p-(6"-butyl)-glucuronide) (14). Total flavonoid content and antioxidant activity were determined in the various fractions of methanolic extract. PMID- 30520587 TI - Glycosylation and Methylation of Quercetin and Myricetin by Cultured Cells of Phytolacca americana. AB - The glycosylation and methylation of quercetin by cultured plant cells of Phytolacca americana gave quercetin 3-Omicron-beta-D-glucoside and isorharnnetin 3-Omicron-beta-D- glucoside. Myricetin was glycosylated and methylated to syringetin 3-Omicron-beta-D-glucoside by cultured P. americana cells. PMID- 30520588 TI - Buxusoside, a Flavonoid Disaccharide from Buxus sinica. AB - A new flavonoid diglycoside named buxusoside (1), together with its aglycone chrysosplenol-D (2), as well as 4', 5-dihydroxy-3,6,7-trimethoxyflavone (3) and 3',4',5-tiihydroxy-3,6,7-trimethoxyflavone (4), were isolated from the 70% EtOH extract of the air-dried plant of Buxus sinica. Its structure was elucidated mainly by iD and 2D NMR spectra. PMID- 30520589 TI - Isoflavone Composition, Total Phenolic Content and Antioxidant Capacity of Soybeans with Colored Seed Coat. AB - The influence of soybean seed coat color and genotype on antioxidant capacity, phenolic content and isoflavone profile was investigated. Isoflavone content and compositiontof 21 seed samples - yellow, green, brown, black and rarely mentioned ocher and reddish, were determined by high-performance liquid chromatographic analysis Antioxidant capacity and total phenolic content (TPC) were evaluated spectrophotometrically. Significant correlation between total isoflavone content and total genisteins was established in all colored groups. Total isoflavone content was in the range from 2.11 mg/g in a green wrinkled sample to -5.24 fig/g in yellow seed. It was found that black genotypes had the highest TPC and antioxidant capacity, which were significantly different (p<0.05) from other colored soybeans. The obtained interconnections among analyzed isoflavones can be used as a model for estimation of their specific content. PMID- 30520590 TI - Main Constituents and Antidiabetic Properties of Otholobium mexicanum. AB - Two phenols, bakuchiol (1) and 3-hydroxybakuchiol (2), and two isoflavone glycosides, daidzin (3) and genistin (4) were isolated from Otholobium mexicanum J. W. Grimes (Fabaceae). Moreover, the ability of the raw extract and isolated metabolites to inhibit the enzymes alpha-amylase and alpha-glucosidase was evaluated in vitro. In the alpha-amylase assay, the methanolic extract exhibited a moderate inhibitory activity with an IC50 of 470 MUg/mL, while inhibition percentages of bakuchiol (1), 3-hydroxybakuchiol (2), and daidzin (3) were less than 25% at the maximum dose tested (1 MUM). Genistin (4) exhibited a poor activity with an IC50 of 805 MUM. In the alpha-glucosidase assay, the methanolic extract exhibited a strong inhibitory activity with an IC50 value of 32 MUg/mL, while 3-hydroxybakuchiol (2) exhibited a moderate inhibitory activity with an IC50 of 345 MUM. Daidzin (3) and genistin (4) exhibited lower inhibitory activity with IC50 values of 564 MUM and 913 MUM, respectively. Bakuchiol (1) exhibited a poor inhibitory activity with an inhibition percentage less than 10% at the maximum dose tested (1 mM). PMID- 30520591 TI - Syntheses of Benzo[c]Chromen-6-ones by Palladium Catalyzed C-H Bond Activation using Diazonium Salts. AB - An efficient palladium catalyzed C-H bond activation for the synthesis of benzo[c]chromen-6-ones using diazonium salts is described. In the presence of Pd(OAc)2, dppp, PivOH and K2CO3, the diazonium salt can be transformed into the product through a denitrogenation/C-H bond activation/cyclization sequence in acetonitrile. Altogether, nine structurally diverse substituted benzoLc]chromen-6 ones were prepared in excellent yields through two different methods. PMID- 30520592 TI - Antioxidant Activity and Phenolic Composition of a Red Bean (Phasoelus vulgaris) Extract and its Fractions. AB - - The activities of the crude acetonic extract of red bean and its two fractions were determined using a 0-carotene-linoleate model system as well as the total antioxidant activity (TAA), the total phenolics content (TPC), the DPPH radical scavenging activity, and the reducing power assays. Results from the in vitro assays showed the highest values when tannins (fraction II) were tested. Specifically, the TAA of the tannins fraction was 4.37 mmol Trolox eq./g fraction; whereas, the crude extract and fraction I were 0.481 and 0.093 MUmol Trolox eqi/mg extract or fraction, respectively. The content of total phenolics in fraction II was the utmost (612 mg/g); the tannins content, assayed by the vanillin method and expressed as absorbance units at 500 nm per I g, was 938. RP HPLC- PAD-MS profiling revealed the presence of 33 compounds: quercetin arabinoglucoside, quercetin rutinoside, quercetin, p-hydroxybenzoic acid, and kaempferol rutinoside were the most abundant phenolics in the extract. PMID- 30520593 TI - Variation in Phenolic Composition of Knautia arvensis in Correlation with Geographic Area and Plant Organ. AB - Knautia arvensis (family Dipsacaceae) is usually found in grasslands of Europe, but can also be found in some parts of Africa and Asia, usually in dry meadows, pastures, dry hills, and open woods. The chemical composition of this species is relatively unknown. The aim of this study was to give a phenolic profile of this plant, and to show how its phenolic composition varies depending upon plant organ and geographic origin. The chemical analysis included quantification of free phenolics soluble in methanol, esters and glycosides, and phenolics that are insoluble in methanol. Fourteen different phenolic acids and eight flavonoids were quantified in total. According to this study, the chemical composition of individual plant parts can differ tremendously within one - population, which does not have to be in correspondence with chemical variability between populations. As shown in this study, the variation in chemical composition between plant parts can exceed that between different populations (from different climates, altitudes, with different environmental factors), which implies that microhabitat conditions can greatly affect the composition of some plant parts, which was shown also after PCA and HCA analysis. PMID- 30520594 TI - Arbutin Content and Tyrosinase Activity of Bergenia Extracts. AB - The total arbutin content in the leaves of all the studied Bergenia plants (B. crassifolia, B. ciliata and B. x ornata) was determined. The highest values of the arbutin content have been established for B. crassifolia (58.9 +/- 0.7 mg.g-1 DW) and B. x ornata (51.0 +/- 1.21 mg.g-1 DW), and the lowest for B. ciliata (5.9 +/- 0.6 mg.g-1 DW). Arbutin concentration in the Bergenia leaves was the lowest in spring, in the autumn, on the contrary it increased. All the tested aqueous extracts caused a dose-dependent increase in diphenolase activity of fungal tyrosinase in a similar way as arbutin. On the other hand, all the ethanol extracts inhibited the diphenolase activity of tyrosinase. PMID- 30520595 TI - GC-MS-based Metabolomic Profiling of Thymoquinone in Streptozotocin-induced Diabetic Nephropathy in Rats. AB - *Diabetic nephropathy is a common complication of diabetes mellitus and one of the major etiologies of end-stage renal disease. Specific therapeutic interventions are necessary to treat such complications. The present study was designed to investigate the metabolomic changes induced by thymoquinone for the treatment of diabetic nephropathy, using a rodent model. Rats were divided into three different groups (n = 6 each): control, diabetic, and thymoquinone- treated diabetic groups. Metabolites in serum samples were analyzed via gas chromatography-mass spectrometry. Multiple changes were observed, including those related to the metabolism of amino acids and fatty acids. The correlation analysis suggested that treatment with thymoquinone led to the reversal of diabetic nephropathy that was associated with modulations in the metabolism and proteolysis of amino acids, fatty acids, glycerol phospholipids, and organic acids. In addition, we explored the mechanisms linking the metabolic profiling of diabetic nephropathy, with a particular emphasis on the potential roles of increased reactive oxygen species production and mitochondrial dysfunctions. Our findings demonstrated that metabolomic profiling provided significant insights into the basic mechanisms of diabetic nephropathy and the therapeutic effects of thymoquinone. PMID- 30520596 TI - Synthesis and Bioconversion of Curcumin Analogs. AB - Hydrogdnation of curcumin (1), a chemopreventive agent from Turmeric (Curcuma longa L.) yielded three major compounds: 1,7-bis(4-hydroxy-3- methoxyphenyl)heptane-3,5-dione (2), 5-hydroxy-1,7-bis(4-hydroxy-3 methoxyphenyl)heptan-3-one (3), and 1,7-bis(4-hydroxy-3-methoxyphenyl)heptane- 3,5-diol (4). Incubation of compound (2) with Beauveria bassiana ATCC 7159 afforded the hexahydrocurcumin (3) as the sole metabolite while biotransformation.of curcumin (1) with B. bassiana gave metabolites 2-4 along with the curcumin-4'-0-4"'-O-methyl-beta-D-glucopyranoside (5) and octahydrocurcumih-4'-O-4"'-O-methyl--beta-D-glucopyranoside (6). The bioconversion of curcumin (1) with Rhizopus oryzae ATCC 11145 yielded analogs 2-4 while no transformation of curcumin (1) was observed with Aspergillus niger ATCC 16888. The preparation, structural elucidation and biological activities of these metabolites are reported herein. PMID- 30520597 TI - Chemical Constituents of Chirita drakei. AB - Chirita drakei Burtt (now accepted as Primzina drakei (B.L.Burtt) Mich.M61ler & A.Weber) is growing on limestone mountain slopes of Ha Long Bay islands in Vietnam. The chemical investigation of the aerial parts of C. drakei led to the isolation and structural elucidation of two new compounds named chiridrakoside A (1) and chiridrakoside B (2) besides twelve known compounds comprising five phenylethanoid glycosides (3-7), two lignans (8, 9), a phenyl propanoid (10), an anthraquinone (11), a furan derivative (12) and two triterpenes (13, 14). All described compounds, except 4, 5 and 11, were obtained for the first time from the genera Chirita or Primulina. The cytotoxic activity of the isolated compounds was evaluated against the four human cancer cell lines KB (mouth epidermal carcinoma), HepG2 (hepatocellular carcinoma), Lu (lung carcinoma) and MCF7 (breast carcinoma). Epoxyconiferyl alcohol (10) exhibited cytotoxic activity against the tested cell lines (IC50 from 46 to 128 MUM). PMID- 30520598 TI - Antibacterial Activity of 2-(3',5'-Dibromo-2'-methoxyphenoxy)-3,5- dibromophenol Isolated from Phyllospongia papyracea. AB - A principal active antimicrobial compound, 2-(3',5'-dibromo-2'-methoxyphenoxy) 3,5-dibromophenol, was isolated from the methanol extract of Phyllospongiapapyracea via bioassay-guided fractionation and isolation. The crude extract and the purified compound were assayed to determine the minimal - inhibitory concentration and minimal bactericidal concentration (MBC) using the broth. microdilution method. The purified compound was found to be highly active against Bacillus subtilis and Staphylococcus aureus at MIC=1 MUg/mL, Campylobacter jejuni at MIC=2 gg/mL, Pseudomonas aeruginosa at MIC=4 MUg/mL; and Streptococcus pneumoniae and Listeria monocytogenes at MIC = 8 MUg/mL. The activity of this compound was found to be comparable with antibiotics commonly used to control these species of bacteria. The results establish 2-(3',5'-dibromo 2'-methoxyphenoxy)-3,5-dibromopheno as a potential lead molecule for the development of antibacterial agents. PMID- 30520599 TI - The Antitumor Antibiotics Complex of Aureolic Acids from the Marine Sediment associated Strain of Streptomyces sp. KNIM 9048. AB - A new antibiotic complex of six aureolic acids was isolated from the marine sediment-associated strain Streptomyces sp. KMM 9048. Four of the compounds (3-6) were found to be similar but not identical to the known chromomycins A2, A3, demethyl chromomycin A3 and A4. The two remaining.compounds; A2-1 (1) and A3-1 (2), were established as novel chromomycin analogs, which did not contain sugar B. Spectroscopic methods including ID and 2D NMR, and HRMS and MS/MS were applied for structure elucidation. Compounds 1-5 showed strong antimicrobial activity against Gram-positive indicatory bacteria Enterococcusfaecium, Staphylococcus aureus, S. epidernzidis, and Bacillus subtilis. Antitumor assay indicated that all tested compounds, in different manners, inhibited colony formation of RPMI 7951 and SK-Mel-28 cancer cells. This is the first study reporting the inhibitory effects of chromomycin analogs 1-5 on the colony formation of the investigated cancer cell lines. Compound 3, in a concentration of 5 nM, inhibited colony formation of RPMI-7951 and SK-Mel-28 cells by 82 % and 72 %, respectively. Our finding indicated that, of the compounds tested, 3 and 4 are promising anticancer and antimicrobial agents. PMID- 30520600 TI - Anti-dormant Mycobacterial Activity of Viomellein and Xanthomegnin, Naphthoquinone Dimers Produced by Marine- derived Aspergillus sp. AB - In the course of a search for anti-dormant mycobacterial substances from marine derived microorganisms, viomellein (1) and xanthomegnin (2) were re- discovered from the active fraction of the culture of a marine-derived Aspergillus sp. together with rubrosulphin (3) and asteltoxin (4) on the guidance of bioassay guided separation. In particular, compound 1 showed higher activity against the dormant than against actively growing Mycobacterium bovis BCG and weak activity against M smegmatis. Furthermore, evidence that compound 1 did not directly bind to plasmid DNA suggests its anti-mycobacterial activity differs from its direct chelating effect on the mycobacterial genome. PMID- 30520601 TI - Two New Sulfonoglycolipids from the Green Alga Codium dwarkense. AB - Two new sulfonoglycosides named Codioside E (1) and Codioside F (2) have been isolated from the MeOH extract of the marine green alga Codium darkense.collected:from the coastal areas of the Gulf of Oman. The structures of these secondary metabolites were elucidated by combined analysis of lD (1H- and 13C-) and 2D (H-C correlations; HSQC and HMBC) NMR spectroscopic and MS data. PMID- 30520602 TI - A Convergent Total Synthesis of Balticolid. AB - A convergent total synthesis of the 12 membered macrolide, Balticolid (1) is described, starting from readily available homoallylic alcohol and 1,3 propane diol The synthetic strategy involves the construction of the 12-membered lactone. PMID- 30520603 TI - Improvement Effects of Wasabi (Wasabiajaponica) Leaves and Allyl Isothiocyanate on Stomach Lesions of Mongolian Gerbils Infected with Helicobacter pylori. AB - The relationship between Helicobacter pylori infection and gastric cancer associated with stomach lesions has been reported. Improvement of the adverse effects induced by H. pylori is required for human health. It has been reported that wasabi (Wasabiajaponica Matsum) leaves have various effects on bacteria and mammals. In this study, the effect was examined of wasabi leaf extract and allyl isothiocyanate (AIT), which is a main functional component of wasabi, on stomach lesions in Mongolian gerbils infected with H. pylori. After the gerbils infected with H. pylori were orally administrated with wasabi leaf extract and AIT for two weeks, colony forming units (CFU) of H. pylori, the degree of gastric mucosal erosion, and petechial hemorrhage in the stomachs of the gerbils were evaluated. Wasabi leaf extract and AIT exhibited a decreasing tendency of CFU in the stomachs. The degree of gastric mucosal erosion and petechial hemorrhage were significantly decreased by the intake of wasabi leaf extract and AIT. Wasabi leaf extract and AIT did not affect body weight, dietary intake, water intake, and the pH of the stomach. From these results, wasabi leaves and AIT may provide a natural remedy for stomach lesions induced by H. pylori. PMID- 30520604 TI - Antiviral Activity of Aspalathus linearis against Human Influenza Virus. AB - Influenza A viruses are responsible for annual epidemics and occasional pandemics, which cause significant morbidity and mortality. The limited protection offered by influenza vaccination, and the emergence of drug-resistant influenza strains, highlight the urgent need for the development of novel anti influenza drugs. However, the search for antiviral substances from the library of low molecular weight chemical compounds is limited. Thus, because of their natural diversity and accessibility, plants or plant-derived materials are rapidly becoming valuable sources for the discovery and development of new antiviral drugs. In this study, crude extracts of Aspalathus linearis, a plant reported to have anti-HIV activity, were evaluated in vitro for their activity against the influenza A virus Of the extracts tested, an alkaline extract of Aspalathus linearis demonstrated the strongest inhibition against influenza A virus and could also inhibit different.types of influenza viruses, including Oseltamivir-resistant influenza viruses A and B. Our time course of addition studies indicated that the alkaline extract of Aspalathus linearis exerts its antiviral effect predominantly during the late stages of the influenza virus replication process. PMID- 30520605 TI - Methyl 3-(5-(prop-1-yn-1-yl)thiophen-2-yl)propanoate: A Rare Acetylene Derivative from Artemisia absinthium Root Essential Oil. AB - Methyl 3-(5-(prop-l-yn-l-yl)thiophen-2-yl)propanoate (1), biosynthetically and structurally related to dehydromatricaria ester, was isolated from the root essential oil of Artemisia absinthium L. (0.7% of the total oil). This is the second record of this compound and the very first one regarding it as an essential-oil constituent. In this paper, we give details regarding its isolation, structural elucidation and gas chromatographic properties (RI on DB-5 MS column: 1694). The NMR-based identification of the compound was corroborated by simulation of its 'H- and "C-NMR spectra using a GIAO method (DFT level of theory). A tentative biosynthetic pathway, possibly leading to this compound, is also proposed. PMID- 30520606 TI - Chemical Investigation on Leaf, Flower and Fruit Oils of Lantana camara from Cote d'Ivoire. AB - The compositions of essential oil obtained from leaves, flowers and fruits of Lantana camara L. growing in wild at Cte d'Ivoire, were investigated by GC and 13C NMR. Thirty-seven compounds accounting for 88.3-94.5% of the oils have been identified. The leaf, flower and fruits of L. camara produced sesquitetpene-rich essential oils predominated by (E)-beta-caryophyllene and a-humulene, in addition to the important content of sabinene, Pbetaphellandrene and thymol as monoterpenes. It was found the new chemical profiles of L. camara. PMID- 30520607 TI - Chemical Composition and Anti-inflammatory Activity of Algerian Thymus vulgaris Essential Oil. AB - This work aims to elucidate the chemical composition of two essential oil (EO) samples obtained from the leaves of Thymus vulgaris L. (Lamiaceae) collected in two regions of Northwestern Algeria (Tlemcen and Mostaganem) and to assess their in vivo acute toxicity and anti-inflammatory activity. Sixty-six compounds could be identified by means of simultaneous GC-FID and GC-MS, accounting for 99.3% of total thyme oil of Mostaganem (EO.TM) and 99.0% of Tlemcen (EO.TT). In both samples, thymol was the major component, amounting to 59.5% (EO.TM) and 67.3% (EO.TT) of the total oil. EO.TT proved to be acutely toxic to mice at a dose of 4500 mg/kg p.o., whereas EO.TM did not show signs of acute toxicity, even at the highest dose tested (5000 mg/kg p.o.). Both EO samples were proven to possess anti-inflammatory activities, significantly reducing carrageenan-induced paw edema in mice (after 6 hours at a dose -of 400 mg/kg p.o) at 58.4% for EO.TT and 50.4% for EO.TM, respectively. In conclusion, it could be demonstrated that EOs of T. vulgaris exhibit a considerable in vivo anti-inflammatory activity at non toxic doses. PMID- 30520608 TI - Elionurus tristis Essential Oil: GC-MS Analysis and Antioxidant and Antituberculosis Activities. AB - Essential oil was obtained in a yield 1.1%, w/w, by steam distillation of Elionurus tristis leaves from Madagascar. The chemical composition was analyzed qualitatively and quantitatively by GC-MS and GC-FID, respectively. To the best of our knowledge, this is the first chemical analysis of this essential oil. Seventy-three compounds were identified, corresponding to 94.9% of the total essential oil. The principal compounds were sesquiterpenes and the more represented were beta-gudjunene (18.4%), neoclovene (15.8%) and nootkatone (10.4%). Through a comparative study, we observed a large variability between the components of E. tristis essential oil and those from others species of the same genus. Evaluation of the antioxidant (ABTS and DPPH assays) and anti- tuberculosis activities of the essential oil showed weak antioxidant potency but an interesting anti-tuberculosis activity with a MIC of 32 mg/L. This activity prompted us to evaluate individually the major components for the treatment of tuberculosis. PMID- 30520609 TI - Chemical Composition and Bactericidal Activity of the Essential Oils of Four Species of Annonaceae Growing in Brazilian Amazon. AB - A study was conducted to determine the chemical composition and the antibacterial activity of essential oils from Bocageopsis multiflora (Mart.) R.E. Fr., Ephedranthus amazonicus R.E. Fr., Guatteria blepharophylla Mart. and Xylopia aromatica (Lam.) Mart . The essential oils were obtained from the leaves by hydrodistillation and analyzed by GC-FID and GC-MS. The chromatograms showed the predominance of sesquiterpenoids. Spathulenol was the major constituent of oils of B. inultiflora (20.3%), X aromatica (21.5%) and E. amazonicus (16.9%); followed by caryophyllene oxide of G. blepharophylla (55.7%). Other constituents with significant percentages were the sesquiterpenes P-bisabolene (11.9%) in the samples oil of B. multiflora, humulene epoxide 11 (16.3%) -of E. amazonicus, the monoterpenes trans-pinocarveol (10.2%) and dihydrocarveol (11.6%) of X aromatica. The essential oils of X. aromatica and G. blepharophylla showed strong activity against Gram-positive bacteria Streptococcus sanguinis by microdilution method. The antimicrobial activity against Staphylococcus aureus also was detected by G. blepharophylla essential oil. PMID- 30520610 TI - Coriander (Coriandrum sativum) Essential Oil: Effect on Multidrug Resistant Uropathogenic Escherichia coli. AB - Coriander (Coriandruim sativum L., Apiaceae) is known for its antimicrobial activity and the aim of this study was to investigate the effect of its essential oil (CDO) against multidrug resistant uropathogenic Escherichia coli (UPEC). CDO was able to inhibit the growth of UPEC strains and propidium iodide uptake, - and electron microscopy examination suggested that bacterial structural modifications occurred. The presence of CDO reduced the MIC of gentamicin. E.coli adhesion efficiency on cell monolayers and abiotic surfaces was not affected by subMIC oil concentrations; furthermore, CDO showed cytotoxic activity towards the HEp-2 tumor cell line. These findings contribute to the knowledge about essential oils as sources of potential antimicrobial agents against uropathogenic E. coli and encourage further investigations. PMID- 30520611 TI - Dietary Soy Isoflavone: A Mechanistic Insight. AB - Soy, a major component of the diet for centuries contains the largest concentration of isoflavones, a class of phytoestrogens. A variety of health benefits are associated with the consumption of soy primarily because of the isoflavones genistein, daidzein, and glycitein with a potential protective effect against a number of chronic diseases. Owing to the pharmaceutical and nutraceutical properties allied with isoflavonoids and their use in functional foods, there is a growing interest in these compounds. This review throws light on the chemistry, and significant pharmacological and biopharmaceutical aspects of soy isoflavones. This article critically describes the mechanisms of action, infers conclusions and shows opportunity for future research. PMID- 30520612 TI - Distribution and Diversity of Usage of the Amaryllidaceae in the Traditional Remediation of Infectious Diseases. AB - Globalization and multidrug resistance are amongst the factors implicated in the resurgence of infectious diseases in recent years. This has fostered a compelling need in drug discovery to replace (or supplement) existing schedules. The floral biodiversity has been identified as a viable resource platform due to its inimitable chemical characteristics as well as the presence of numerous of its members in traditional medicinal approaches towards these diseases. Whilst the plant family Amaryllidaceae is conventionally associated with cancer and motor neuron disease therapies, this survey shows that it has a significant presence in the remediation of infections and infection-related ailments. This verifiable indigenous knowledge could amplify efforts towards the identification of the active chemical constituents. PMID- 30520613 TI - The Perceptions of Patients, their Parents and Healthcare Providers on the Transition of Young Adults with Type 1 Diabetes to Adult Services in the West of Ireland. AB - Aim This study aims to describe the perceptions of young adults', parents of young adults' and health care professionals' (HCPs) of the transition process for young adults with Type 1 Diabetes in the West of Ireland.MethodsThematic analysis of semi-structured interviews conducted with the three stakeholder groups was performed.ResultsYoung adults hardly noticed the transition, with many of them seeing it as a physical move, whereas parents were more anxious and felt their involvement was still needed but not accommodated. Both groups perceived the young adults' ability to manage their diabetes as a facilitator, as well as the continuity of care provided by the diabetes nurse. Resource limitations and an inability of a young adult to self-manage were identified as barriers to smooth transition by parents, whilst HCPs were experiencing problems with non-attendance and a lack of a psychology service.ConclusionThis study highlights the importance of encouraging adolescents' autonomy in the years leading to transition. A key healthcare professional link between both services appears to facilitate smooth transition. Being flexible and supportive of both parents and adolescents including the provision of mental health services are other important considerations. PMID- 30520615 TI - Emergency Department Overcrowding And The Full Capacity Protocol Cross Over Study: What Patients Who Have Experienced Both Think About Being An Extra Patient In The Emergency Department Or On A Ward. AB - Hospital overcrowding is evidenced by Emergency Department (ED) overcrowding. The Full Capacity Protocol (FCP) is activated to move patients to temporary extra beds placed in the inpatient wards. This research aims to establish patient preferences when waiting for a ward bed in an Irish Hospital.The FCP in Beaumont Hospital was updated in the context of national guidelines. Patients' attitudes towards boarding in the ED as opposed to being in extra beds on the wards were assessed using a questionnaire based structured interview.Ninety nine patients took part in the study. Eighty three patients (83.83%) preferred being an additional patient on the ward, 12 (12.12%) had no preference and four (4.04%) preferred being boarded in the ED.Moving patients from the ED into extra beds on the wards creates space, facilitating safer care delivery. The vast majority of patients who have experienced both, prefer being boarded in the ward rather than in the ED. PMID- 30520614 TI - Management of Paediatric Buckle (Torus) Wrist Fractures in Irish Emergency Departments: A National Survey AB - Buckle fractures are the most common wrist fractures reported in the paediatric age group. National Institute for Clinical Excellence (NICE) recommends using a non-rigid immobilisation with no follow up for these patients and appropriate discharge advice. A telephone survey was conducted to assess the variation in practice in Irish hospitals regarding the mpediatrianagement of buckle fractures. Twenty eight centres that manage paediatric patients with trauma were contacted. This survey demonstrates that over 70% (>20) of centres in Ireland are managing buckle fractures using the traditional approach of backslab cast and follow-up in fracture clinic. Despite relevant research and NICE guideline recommendations, there is a slow adoption of current evidence among Irish hospitals which points to a need for a national consensus on management of buckle fractures. PMID- 30520616 TI - Sweat Testing in Ireland AB - IntroductionQuick, painless, cheap and reliable, the sweat test remains the gold standard diagnostic test for cystic fibrosis. We aimed to describe the pattern of testing in Ireland over a calendar year.MethodsInformation on sweat test practices was requested from each centre between 1st January 2011 and 31st December 2011, and the number of positive, negative, equivocal, and insufficient samples was recorded.ResultsIn 2011 there were 2555 sweat tests performed in 15 centres, ranging from 35 to over 450 tests per centre. 35 (1.4%) were in the diagnostic range. The overall quantity not sufficient (QNS) rate was 10.3% (range 0-28.3%). Testing was performed across a wide age range (2.5 weeks to 75 years). The mean sweat chloride value was 16.5 mmol/L (SD 16.1 mmol/L).DiscussionOur study demonstrates a high number of sweat tests performed in Ireland with significant variation in sweat testing practices across 15 different sites. PMID- 30520617 TI - The Predictive Ability of Pre-Operative Magnetic Resonance Imaging to Detect Pathological Outcomes in Prostate Cancer AB - AimsAccurate preoperative knowledge of tumour stage is important in preoperative planning at radical prostatectomy (RP). The aim of this study was to assess the predictive ability of multiparametric MRI for detecting pathological outcomes.MethodsA retrospective review was performed of all patients who underwent RP over a 4 year period.ResultsPreoperative MRI was reported as showing T3 or T4 disease in 26(17.9%) out of 145 patients undergoing RP. Of these, 10(6.9%) had ECE (extra-capsular extension) and 1(0.7%) had SVI (seminal vesicle invasion) on final histology. The sensitivity and specificity of MRI for detecting ECE were 27.3% and 87.6%, respectively. The sensitivity and specificity of MRI for detecting SVI were 11.1% and 97.8%, respectively. The positive predictive values for determining ECE and SVI were 45.5% and 25%, respectively and negative predictive values were 75.9% and 94.4%.ConclusionMRI has good specificity but poor and heterogeneous sensitivity for predicting T3 disease in RP specimen. PMID- 30520618 TI - Giant Cell Arteritis Presenting as an Ischaemic Upper Limb AB - AimTo present an interesting case of giant cell arteritis presenting as ischaemic upper limb. MethodsData was collected from the patient's chart and from radiology and laboratory systems in our institution.ResultsThe patient had a temporal artery biopsy confirming the diagnosis of temporal arteritis. This was successfully treated with high dose steroids leading to resolution of symptoms in the arm.ConclusionArteritis is an important consideration to consider in patients who present with limb ischaemia as it is a reversible cause which can be treated effectively. PMID- 30520619 TI - Apixaban-Associated Spontaneous Splenic Rupture-A Case Report. AB - IntroductionA 62-year-old lady presented to The Emergency Department (ED) with one-day history of dizziness, vomiting and feeling weak. ECG showed new onset Atrial Fibrillation. Four days ago, she was referred to the Cardiology team where she underwent PCI and was discharged on Apixaban and Plavix. Two days later she represented to the ED pale and hypotensive with BP 70/50. CT-Abdomen showed a large splenic hematoma and thickening of the inferior wall of the stomach.TreatmentShe was then taken for an emergency laparotomy with splenectomy and partial gastrectomy. She became septic post-operative, responded well to antibiotics and was discharged after 18 days on lifelong prophylactic oral antibiotics.ConclusionSpontaneous splenic rupture in a patient on Direct Oral Anticoagulants (DOAC) presented with abdominal pain could be even with no history of trauma. PMID- 30520620 TI - Magnetic Tunnel Junctions with a Nearly Zero Moment Manganese Nanolayer with Perpendicular Magnetic Anisotropy. AB - A magnetic nanolayer with a perpendicular magnetic easy axis and negligible magnetization is demonstrated. Even though a manganese metal is antiferromagnetic in bulk form, a few manganese monolayers grown on a paramagnetic ordered alloy template and capped by an oxide layer exhibit a strong perpendicular magnetic anisotropy field exceeding 19 T as well as a negligible magnetization of 25 kA/m. The nanolayer shows tunnel magnetoresistance. Moreover, the perpendicular magnetic anisotropy for the nanolayer can be reduced by applying an electric voltage. These findings will provide new insight into a creation of new nanolayer magnets. PMID- 30520621 TI - Robustly Superhydrophobic Conductive Textile for Efficient Electromagnetic Interference Shielding. AB - Superhydrophobic electromagnetic interference (EMI) shielding textile (EMIST) is of great significance to the safety and long-term service of all-weather outdoor equipment. However, it is still challenging to achieve long-term durability and stability under external mechanical deformations or other harsh service conditions. Herein, by designing and implementing silver nanowire (AgNW) networks and a superhydrophobic coating onto a commercial textile, we demonstrate a highly robust superhydrophobic EMIST. The resultant EMIST shows a synergy of high water contact angle (160.8 degrees ), low sliding angle (2.9 degrees ), and superior EMI shielding effectiveness (51.5 dB). Remarkably, the EMIST still maintains its superhydrophobic feature and high EMI shielding level (42.6 dB) even after 5000 stretching-releasing cycles. Moreover, the EMIST exhibits strong resistance to ultrasonic treatment up to 60 min, peeling test up to 100 cycles, strong acidic/alkaline solutions and different organic solvents, indicating its outstanding mechanical robustness and chemical durability. These attractive features of the EMIST are mainly a result of the joint action of AgNWs, carbon nanotubes, polytetrafluoroethylene nanoparticles and fluoroacrylic polymer. This work offers a promising approach for the design of future durable, superhydrophobic EMISTs, which are capable of remaining fully functional against long-time exposure to extreme conditions, e.g. wet and corrosive environments. PMID- 30520622 TI - Cytometric Micro-Bead Magnetic Suspension Array for High-Throughput Ultra Sensitive Detection of Aflatoxin B1. AB - High-throughput and low-cost detection of mycotoxins in complex matrices is becoming increasingly urgent but still challenged for ultra-sensitive analyses. Here we reported a green and practical cytometric micro-bead magnetic suspension array (CBMSA) strategy for rapid and economical detection of aflatoxin B1 (AFB1) in multiple batches of lotus seeds samples. The protocol included the fabrication of the suspension array chips by immobilizing the biotin-modified bovine serum albumin-AFB1 (antigen) onto the surface of streptavidin-coated magnetic micro beads in a multi-wells array, the indirect immuno-competition of antigen and target of AFB1 in lotus seed samples with the specific antibodies, the rapid magnetic separation regardless complex pretreatment steps, and the ultra sensitive fluorescence detection of fluorescein isothiocyanate labeled goat anti mouse immunoglobulin G (FITC-IgG) probes. After systematical optimization regarding some crucial parameters, the developed CBMSA assay allowed for ultra sensitive detection of AFB1 with limit of detection as low as 7.8125 pg kg-1. For high-throughput analysis, the CBMSA technique was capable of on-site coinstantaneous detection of 50-100 samples in one operation within 30 s only needing a small amount (50 MUL) of solution, which is much cheaper, greener and more user-friendly than conventional techniques. Moreover, CBMSA with magnetic separation are free of multi-times' centrifugation and clean-up steps to avoid unpredictable loss of targets. Since various capture and fluorescent probes can be randomly constructed and bound onto the surface of magnetic micro-beads to establish the ultra-sensitive detection system, the CBMSA technique is very promising for more trace-analytes in complex matrices and for broad point-of-need applications, such as drug screening and real-time high-throughput analysis. PMID- 30520623 TI - Correction to "Tumor Targeting and Lipid Rafts Disrupting Hyaluronic Acid Cyclodextrin-Based Nanoassembled Structure for Cancer Therapy". PMID- 30520624 TI - A Biomimetic Approach Towards Enterocin and Deoxyenterocin. AB - Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2 oxabicyclo[3.3.1]nonane core of the natural product. PMID- 30520625 TI - Facile Synthesis of Amorphous Ternary Metal Borides - Reduced Graphene Oxide Hybrid with Superior Oxygen Evolution Activity. AB - Metal borides represent an emerging family of advanced electrocatalyst for oxygen evolution reaction (OER). Herein, we present a fast and simple method of synthesizing iron-doped amorphous nickel boride on reduced graphene oxide (rGO) sheets. The hybrid exhibits outstanding OER performance and stability in prolonged OER operation. In 1.0 M KOH, only 230 mV is required to afford a current density of 15 mA cm-2 with a small Tafel slope of 50 mV dec-1. The superior OER activity of the as-prepared catalyst is attributed to (i) unique amorphous structure to allow abundant active sites, (ii) synergistic effect of constituents and, (iii) strong coupling of active material and highly conductive rGO. This work not only provides new perspectives to design highly effective material for OER, but also opens a promising avenue to tailor the electrochemical properties of metal borides which could be extended to other materials for energy storage and conversion technologies. PMID- 30520626 TI - Fragmentation of Valence and Carbon Core Excited and Ionized CH2FCF3 Molecule. AB - The photofragmentation dynamics of 1,1,1,2-tetrafluoroethane (R134a) with photon energies from 12 eV up to 320 eV, surrounding the C 1s edge is discussed. The ionic moieties were measured according to their mass to charge ratio, in coincidence with the photoelectrons (PEPICO mode), and collected as a function of the incident photon energy. In the C K core region, the fragmentation patterns are examined in terms of site specific excitation of the CH2FCF3 molecule. In the present case, site-selectivity is favored by the distinct chemical environments surrounding both C atoms. Our observations indicate that the C(H2F) 1s excitation to a highly repulsive potential expels a fluorine atom leaving the heavier radical fragment C2F3H2* which relaxes via Auger process to the fundamental state of the ion C2F3H2+ giving rise to the observed site specific fragmentation. On the other hand, the excitation from the C(F3) 1s carbon to a repulsive statein the C-C bond. The preferred cleavage for the C-C bond can be given as a possible explanation to the observed site specific fragmentation. PMID- 30520627 TI - High-Pressure Synthesis, Crystal Chemistry, and Ionic Conductivity of a Structural Polymorph of Li3BP2O8. AB - A new structural polymorph of Li3BP2O8 has been successfully synthesized via a solid-state reaction between Li3PO4 and BPO4 at 4 GPa and 600 degrees C. The high-pressure phase of Li3BP2O8 (HP-Li3BP2O8) was found to crystallize in monoclinic symmetry with the cell parameters of a = 8.57010(4) A, b = 11.11812(5) A, c = 5.55380(3) A, and beta = 97.7269(3) degrees [space group P21/ a (No. 14)]. HP-Li3BP2O8 has a new crystal structure that has not been reported so far. The total ionic conductivities measured for the polycrystalline sample by alternating-currrent impedance were 3.4 * 10-7 and 2.1 * 10-6 S/cm at 399 and 456 K, respectively. The lithium ionic conductivity of HP-Li3BP2O8 was higher than that of the low-pressure phase Li3BP2O8 in the temperature range of 375-456 K. This is caused by the difference in the dimensions of the lithium arrangements between LP- and HP-Li3BP2O8. PMID- 30520628 TI - In vitro DNA Adduction Resulting from Metabolic Activation of Diosbulbin B and 8 Epidiosbulbin E Acetate. AB - Diosbulbin B (DBB) and 8-epidiosbulbin E acetate (EEA), belonging to furan containing diterpenoid lactones, are the primary components of Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Our earlier studies indicated that consumption of DBB or EEA induced acute hepatotoxicities. Both DBB and EEA were bioactivated by P450 3A4 to generate the corresponding cis-enedial reactive metabolites which are associated with the hepatotoxicities. It has been proposed that the electrophilic intermediates attack cellular nucleophiles such as protein or DNA, thought to be a mechanism of triggering toxicities. The purpose of our present study were to define the interaction of the electrophilic reactive metabolites originating from DBB and EEA with 2'-deoxyguanosine (dGuo), 2'-deoxycytidine (dCyd), and 2'-deoxyadenosine (dAdo) and to characterize DNA adducts arising from the reactive metabolites of DBB and EEA. The reactive metabolites of DBB and EEA were found to covalently bind to the exocyclic and endocyclic nitrogens of dCyd, dGuo, and dAdo to generate oxadiazabicyclo[3.3.0]octaimine adducts. The reactive metabolites of DBB and EEA also attacked dGuo, dAdo, and dCyd of calf thymus DNA. The DNA adducts possibly contribute to the toxicologies of DBB and EEA. PMID- 30520629 TI - Bio-statistical options for Quantitative diet analysis. AB - Sufficient statistics knowledge is crucial for right scheming of a research plan. The elucidations of results are interpretive only if appropriate statistical methods are applied. Statistical strategies are a particular approach to demonstrate complicated information in broad and explicable conclusions. The emergence of bio-statistical approaches for diet evaluation has improved the accuracy of diet estimation, and different methodologies of data integration promise to magnify our understanding of ecological communities. The present study aimed to compile multiple statistical methods used for diet analysis. More specifically, the significant analysis used in diet assessment, central expectations, and preferences related to each measure was conceptualized. In addition, the ability of each test to evaluate diversity, richness, differentiation, fluctuation, similarity, and quantification of multiple diet items was summarized. Moreover, different options were proposed for researchers to select the appropriate statistical tests. This study covers a framework, aim, and understanding of the statistical test methods of diet analysis. PMID- 30520630 TI - Toughening Nanoparticle Films via Polymer Infiltration and Confinement. AB - Disordered nanoparticle films have significant technological applications as coatings and membranes. Unfortunately, their use to date has been limited by poor mechanical properties, notably low fracture toughness, which often results in brittle failure and cracking. We demonstrate that the fracture toughness of TiO2 nanoparticle films can be increased by nearly an order of magnitude through infiltration of polystyrene into the film. The fracture properties of films with various polymer volume fractions were characterized via nanoindentation pillar splitting tests. Significant toughening is observed even at low volume fractions of polymer, which allows the nanoparticle packing to be toughened while retaining porosity. Moreover, higher-molecular-weight polymers lead to greater toughening at low polymer volume fractions. The toughness enhancement observed in polymer infiltrated nanoparticle films may be attributed to multiple factors, including an increase in the area and strength of interparticle contacts, deflection and blunting of cracks during failure, and confinement-induced polymer bridging of nanoparticles. Our findings demonstrate that polymer infiltration is a highly effective route for reinforcing nanoparticle packings while retaining porosity. PMID- 30520631 TI - Large magnetoelectric effects in electrodeposited nanoporous micro-disks driven by effective surface charging and magneto-ionics. AB - A synergetic approach to enhance magnetoelectric effects (i.e., control of magnetism with voltage) and improve energy efficiency in magnetically actuated devices is presented. The investigated material consists of an ordered array of Co-Pt micro-disks, in which nanoporosity and partial oxidation are introduced during the synthetic procedure to synergetically boost the effects of electric field. The micro-disks are grown by electrodeposition from an electrolyte containing an amphiphilic polymeric surfactant. The bath formulation is designed to favor the incorporation of oxygen in the form of cobalt oxide. A pronounced reduction of coercivity (88%) and a remarkable increase of Kerr signal amplitude (60%) are observed at room temperature upon subjecting the micro-disks to negative voltages through an electrical double layer. These large voltage-induced changes in the magnetic properties of the micro-disks are due to: (i) the high surface area-to-volume ratio with ultra-narrow pore walls (sub-10 nm) that promote enhanced electric charge accumulation and (ii) magneto-ionic effects, where voltage-driven O2- migration promotes a partial reduction of CoO to Co at room temperature. This simple and versatile procedure to fabricate patterned 'nano-in-micro' magnetic motifs with adjustable voltage-driven magnetic properties is very appealing for energy-efficient magnetic recording systems and other magnetoelectronic devices. PMID- 30520632 TI - Cardiovascular effects and molecular mechanisms of bisphenol A and its metabolite MBP in zebrafish. AB - The plastic monomer bisphenol A (BPA) is one of the highest production volume chemicals in the world and is frequently detected in wildlife and humans, particularly children. BPA has been associated with numerous adverse health outcomes relating to its estrogenic and other hormonal properties, but direct causal links are unclear in humans and animal models. Here we simulated measured (1*) and predicted worst-case (10*) maximum foetal exposures for BPA, or equivalent concentrations of its metabolite MBP, using fluorescent reporter embryo-larval zebrafish capable of quantifying Estrogen Response Element (ERE) activation throughout the body. Heart valves were primary sites for ERE activation by BPA and MBP, and transcriptomic analysis of micro-dissected heart tissues showed that both chemicals perturbed similar downstream molecular pathways and biological processes, including down-regulation of cartilage morphogenesis and filamentous protein synthesis. Collagen/keratin deficiency and impact on heart valve structural integrity were confirmed by histopathology for high-level MBP exposure, and structural defects (abnormal curvature) of the atrio ventricular valves corresponded with impaired cardiovascular function (reduced ventricular beat rate and blood flow). Our results are the first to demonstrate plausible mechanistic links between ERE activation in the heart valves by BPA's reactive metabolite MBP and the development of valvular- cardiovascular disease states. PMID- 30520633 TI - Hybrid Nanomaterials of Conjugated Polymers and Albumin for Precise Photothermal Therapy. AB - Heretofore, conjugated polymers (CPs) attract considerable attention in photothermal therapy (PTT). Although various CPs with different structures have been reported, the suboptimal circulation persistence and biodistribution limit their efficacy in tumor treatment. Human serum albumin (HSA), an endogenous plasm protein, has been widely functioned as a carrier for therapeutic agents. Herein, we construct nanocomplexs C16 pBDP@HSA NPs from hydrophobic 4, 4-difluoro-4-bora 3a, 4adiaza-s-indacene (BODIPY)-containing CPs and HSA, which exhibit robust stability in physiological conditions and excellent photothermal activity upon irradiation. The high photothermal conversion efficiency of 37.5 %, higher than that of other reported PTT agents such as gold nanorods, phosphorus quantum dots and 2D materials, results in the potent photocytotoxicity towards cancer cells. Simultaneously, C16 pBDP@HSA NPs' capabilities of near infrared fluorescence and photoacoustic imaging can provide guidance to the PTT. The outstanding inhibition of tumor growth results from great photothermal activity, the benefited accumulation in tumor and optimal timing of treatment. To the best of our knowledge, this is the first study which combines the BODIPY-based CPs and HSA in one nanostructure and finds application in cancer treatment. Moreover, this article also offers a new strategy for other insoluble macromolecules to explore more biomedical applications. PMID- 30520634 TI - Synthesis of urban CO2 emission estimates from multiple methods from the Indianapolis Flux Project (INFLUX). AB - Urban areas contribute approximately three-quarters of fossil fuel derived CO2 emissions, and many cities have enacted emissions mitigation plans. Evaluation of the effectiveness of mitigation efforts will require measurement of both the emission rate and its change over space and time. The relative performance of different emission estimation methods is a critical requirement to support mitigation efforts. Here we compare results of CO2 emissions estimation methods including an inventory-based method and two different top-down atmospheric measurement approaches implemented for the Indianapolis, Indiana, USA urban area in winter. By accounting for differences in spatial and temporal coverage, as well as trace gas species measured, we find agreement among the wintertime whole city fossil fuel CO2 emission rate estimates to within 7 %. This finding represents a major improvement over previous comparisons of urban-scale emissions, making urban CO2 flux estimates from this study consistent with local and global emission mitigation strategy needs. The complementary application of multiple scientifically-driven emissions quantification methods enables and establishes this high level of confidence and demonstrates the strength of the joint implementation of rigorous inventory and atmospheric emissions monitoring approaches. PMID- 30520635 TI - Melanogenesis-Inhibitory and Cytotoxic Activities of Triterpene Glycoside Constituents from the Bark of Albizia procera. AB - Five oleanane-type triterpene glycosides including three new ones, proceraosides E-G (1-3), were isolated from a MeOH-soluble extract of Albizia procera bark. The structures of 1-3 were determined by use of NMR spectra, HRESIMS, and chemical methods. Compounds 1-5 exhibited inhibitory activities against the proliferation of the A549, SKBR3, AZ521, and HL60 human cancer cell lines (IC50 0.28-1.8 MUM). Additionally, the apoptosis-inducing activity of compound 2 was evaluated by Hoechst 33342 staining and flow cytometry, while the effects of 2 on the activation of caspases-9, -8, and -3 in HL60 cells were revealed by Western blot analysis. PMID- 30520636 TI - Linkages between epithelial microbiota and host transcriptome in the ileum during high grain challenges: implications for gut homeostasis in goats. AB - A high-grain diet (HG) can result in ruminal subacute acidosis, which is detrimental to gut health and can lead to decreased productivity. This study investigated the ileal epithelial microbiota and its relationship with host epithelial function in goats fed an HG diet (concentrate: hay, 90: 10) and a Control diet (concentrate: hay, 55: 45) aiming to elucidate the mechanisms involved in ileal adaptation to subacute acidosis. The HG challenge increased ileal volatile fatty acid concentration (P = 0.030), altered the ileal epithelial microbiota by increasing (FDR < 0.05) relative abundances of active carbohydrate and protein degraders Synergistetes, Prevotella, Fibrobacter, Clostridium, Treponema and unclassified Ruminococcaceae by 20.1-fold, 6.3-fold, 16.8-fold, 8.5 fold, 19.9-fold and 7.1-fold, respectively. However, the HG diet tended to reduce (FDR < 0.10) relative abundance of Candidatus_Arthromitus (38.8+/-36.1 vs. 2.1+/ 3.1). Microbial functional potentials inferred using PICRUSt indicated that HG challenge elevated abundances of pathways associated with metabolism of amino acid, glycan, cofactors and vitamins, whereras decreased pathways associated with signal transduction, xenobiotics biodegradation and metabolism. Additionally, in the ileal epithelium of HG goats, transcriptome analysis identified increment (FDR < 0.10) of candidate genes involved in metabolism of carbohydrates, lipids, proteins, vitamins and pro-inflammatory cytokine pathway, whist down-regulation of genes encoding antimicrobials and complements (FDR < 0.05). Collectively, high grain challenge shifted the structure and functional potentials of ileal microbial community, and affected the host responses in the ileum of goats toward increased metabolic activities of macronutrients and micronutrients, together with an increased risk of gut inflammation. PMID- 30520637 TI - One Pot Synthesis of 2-Styrylindoles from Ortho-Substituted Chloroenynes. AB - A facile one pot synthesis of 2-styrylindoles, through Suzuki-arylation of ortho substituted chloroenynes followed by N-cyclization and N-demethylation has been developed. A variety of 2-styrylindoles were obtained in good to excellent yields and were evaluated for their anticancer properties. PMID- 30520638 TI - Highly Potent and Selective Plasmin Inhibitors Based on the Sunflower Trypsin Inhibitor-1 Scaffold Attenuate Fibrinolysis in Plasma. AB - Antifibrinolytic drugs provide important pharmacological interventions to reduce morbidity and mortality from excessive bleeding during surgery and after trauma. Current drugs used for inhibiting the dissolution of fibrin, the main structural component of blood clots, are associated with adverse events due to lack of potency, high doses and non-selective inhibition mechanisms. These deficiencies warrant the development of a new generation highly potent and selective fibrinolysis inhibitors. Here we use the 14-amino acid backbone-cyclic sunflower trypsin inhibitor-1 scaffold to design a highly potent (Ki = 0.05 nM) inhibitor of the primary serine protease in fibrinolysis, plasmin. This compound displays a million-fold selectivity over other serine proteases in blood, inhibits fibrinolysis in plasma more effectively than the gold-standard therapeutic inhibitor aprotinin and is a promising candidate for development of highly specific fibrinolysis inhibitors with reduced side effects. PMID- 30520639 TI - Enantioselective Synthesis of Isocarbostyril Alkaloids and Analogs Using Catalytic Dearomative Functionalization of Benzene. AB - Enantioselective total syntheses of the anticancer isocarbostyril alkaloids (+)-7 deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, and (+)-narciclasine are described. Our strategy for accessing this unique class of natural products is based on the development of a Ni-catalyzed dearomative trans-1,2 carboamination of benzene. The effectiveness of this dearomatization approach is notable, as only two additional olefin functionalizations are needed to construct the fully decorated aminocyclitol cores of these alkaloids. Installation of the lactam ring has been achieved through several pathways and a direct interconversion between natural products was established via a late-stage C-7 cupration. Using this synthetic blueprint, we were able to produce natural products on a gram scale and provide tailored analogs with improved activity, solubility, and metabolic stability. PMID- 30520640 TI - Diphosphination of 1,3-Dienes with Diphosphines under Visible-Light-Promoted Photoredox Catalysis. AB - A diphosphination of 1,3-dienes with tetraaryldiphosphines proceeds under Ir(ppy)3-promoted photoredox catalysis to form the corresponding 1,4-diphosphino 2-butenes in good yields with good regioselectivity. The key to success is the addition of a Br+ additive. Subsequent double bond hydrogenation successfully delivers the 1,4-bis(diphenylphosphino)butane (DPPB) derivatives with uniquely large bite angles. Thus, the present method can provide a facile access to DPPB type ligands, which are of great importance in transition metal catalysis, from readily available diene substrates. PMID- 30520641 TI - Regioselective Synthesis of 2- or 2,7-Functionalized Pyrenes via Migration. AB - A simple method for the preparation of 2- or 2,7-functional pyrenes from 1- or 1,6-substituted derivatives is reported. The synthesis involves the unexpected 1,2-phosphinyl migration in an AlCl3/NaCl melt. The structure of the product has been unambiguously confirmed by X-ray crystallography. We also demonstrated that further functionalization of pyrene through C-P bond activation is possible. These 2,7-positions are difficult to derivatize otherwise. PMID- 30520642 TI - Tools for 3D Interactome Visualization. AB - In cells, intra- and inter-molecular interactions of proteins confer function and the dynamic modulation of this interactome is critical to meet changing needs required to support life. Cross-linking and mass spectrometry (XL-MS) enable detection of both intra- and inter-molecular protein interactions in organelles, cells, tissues and organs. Quantitative XL-MS enables detection of interactome changes in cells due to environmental, phenotypic, pharmacological, or genetic perturbations. We have developed new informatics capabilities, the first to enable three-dimensional visualization of multiple quantitative interactome datasets, acquired over time or with varied perturbation levels, to reveal relevant dynamic interactome changes. These new tools are integrated within release 3.0 of our online cross-linked peptide database and analysis tool suite XLinkDB. With the recent rapid expansion in XL-MS for protein structural studies and the extension to quantitative XL-MS measurements, 3D interactome visualization tools are of critical need. PMID- 30520643 TI - Fabrication of Opaline ZnO Photonic Crystal Film and its Slow Photon Effect on Photoreduction of Carbon Dioxide. AB - Monodisperse ZnO particles with adjustable size have been produced on a large scale by two-step seeding-growth polyol reactions. Through spin coating of supersaturated ZnO/DEG solution and evaporation of solvent, opaline ZnO photonic crystal (PC) film with good crystallinity and uniform photonic structures can be prepared from these ZnO particles. Compared with a disorderly stacked ZnO film, the ZnO PC film shows higher activity in photocatalytic reduction of CO2 because of the generated slow photons at the edge of photonic bandgap and their promotion to the light absorption. When the electronic bandgap of ZnO matches the red-edge of photonic bandgap of ZnO PC, the enhancement factor of photocatalytic activity represented by CO evolution can be maximized to 2.64 fold in current experiment. Compared to the traditional inverse opal photocatalysts, the opaline ZnO photocatalysts are prepared by simplified and scalable procedures and they still possess the same enhancement in activity compared to ZnO without photonic structure, which might be broadly used in solar energy utilization, environment protection and many other green chemical processes in the future. PMID- 30520644 TI - Phosphite Esters: Reagents for Exploring S-Nitrosothiol Chemistry. AB - The reactions between S-nitrosothiols and phosphite esters, including P(OPh)3, P(OBn)3, and P(OEt)3, were studied. Two different conjugated adducts, thiophosphoramidates and phosphorothioates, were formed, depending on the structures of the S-nitrosothiol substrate (e.g., primary vs tertiary). These reactions proceeded under mild conditions, and the reaction mechanisms were studied using experiments and calculations. PMID- 30520645 TI - Tackling the Spiro Tetracyclic Skeleton of Cyanogramide: Incorporation of a Hydantoin Moiety. AB - Wang's enantioselective thiourea-catalyzed spiro-annulation paved the way to the first tetracyclic analog of the marine natural product cyanogramide from the actinobacterium Actinoalloteichus cyanogriseus. The synthesis comprises seven steps starting from an alkylidene indolinone. Installation of the ( E)-styryl side chain faced a regiochemistry problem, circumvented by prior conversion to the hydantoin and employing Batey's conditions. Comparison of the ECD spectra of the spiro indoline pyrrolo[1,2- c]imidazole and cyanogramide confirmed the absolute configuration of the natural product. PMID- 30520646 TI - Regioselective Transition-Metal-Free Oxidative Cyclobutanol Ring Expansion to 4 Tetralones. AB - A facile and transition-metal-free ring expansion of the cyclobutanol moiety to 4 tetralones fused to heteroaromatic systems is described. The oxidative ring expansion proceeds rapidly and regioselectively through mediation by N bromosuccinimide and acetonitrile in satisfactory to good yields. The preparation of precursors and the ring expansion have proven to be scalable and are straightforward to carry out. PMID- 30520647 TI - Catalytic Asymmetric Ring-Opening/Cyclopropanation of Cyclic Sulfur Ylides: Construction of Sulfur-Containing Spirocyclopropyloxindoles with Three Vicinal Stereocenters. AB - A highly efficient asymmetric ring-opening/cyclopropanation reaction of ( E)-3 (oxyethylidene)-2-oxoindolines with 1-alkyl-3-oxotetrahydro-1 H-thiophen-1-ium salts as cyclic sulfur ylides was realized by using a chiral N, N' dioxide/Mg(OTf)2 complex as catalyst. A range of sulfur-containing syn, anti spirocyclopropyloxindoles with three contiguous stereocenters were obtained in excellent yields with excellent dr and good ee values under mild reaction conditions. The origin of stereoselectivity was discussed. PMID- 30520648 TI - Noninterleaved Metasurface for (26-1) Spin- and Wavelength-Encoded Holograms. AB - Nanostructured metasurfaces demonstrate extraordinary capabilities to control light at the subwavelength scale, emerging as key optical components to physical realization of multitasked devices. Progress in multitasked metasurfaces has been witnessed in making a single metasurface multitasked by mainly resorting to extra spatial freedom, for example, interleaved subarrays, different angles. However, it imposes a challenge of suppressing the cross-talk among multiwavelength without the help of extra spatial freedom. Here, we introduce an entirely novel strategy of multitasked metasurfaces with noninterleaved single-size Si nanobrick arrays and minimalist spatial freedom demonstrating massive information on 6-bit encoded color holograms. The interference between electric dipole and magnetic dipole in individual Si nanobricks with in-plane orientation enables manipulating six bases of incident photons simultaneously to reconstructed 6-bit wavelength- and spin-dependent multicolor images. Those massively reconstructed images can be distinguished by pattern recognition. It opens an alternative route for integrated optics, data encoding, security encryption, and information engineering. PMID- 30520649 TI - Meta-analysis to derive an empirically based set of personality facet criteria for the alternative DSM-5 model for personality disorders. AB - The alternative model for personality disorders (AMPD) is outlined in Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This model includes 25 dimensional trait facets that are used as criteria for six personality disorders in addition to impairment in functioning. Numerous previous studies have examined the degree to which the proposed trait facets converge with the Section II personality disorders (PDs) they are meant to capture, but the results from these various studies have been inconsistent. The current investigation sought to provide a meta-analysis of published and unpublished data, and in particular, to develop empirically derived trait criterion profiles for each of the six AMPD PDs. A total of 25 independent data sets utilizing diverse samples and methods that included measurement of AMPD traits and at least one Section II PD derived from both published and unpublished work were considered for this review. The findings indicated general support for the traits proposed for each of the six PDs within the AMPD, with obsessive-compulsive PD the notable exception. The discriminant validity, however, was questionable for several of the PDs; several nonproposed traits also correlated with the Section II PD counterparts at moderate to large degrees. Intraclass correlations used to model the agreement across the empirically derived trait profiles for each of the six PDs, however, revealed that most of the disorders were relatively distinct from one another. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520650 TI - Difficulties regulating emotions mediates the associations of parental psychological control and emotion invalidation with borderline personality features. AB - Extant research has supported a connection between socialization in childhood and difficulties regulating emotions. The biosocial theory of borderline personality disorder (BPD; Crowell, Beauchaine, & Linehan, 2009; Linehan, 1993) suggests that emotion dysregulation is a core mechanism underlying the extreme behaviors, mood instability, identity disturbance, and relationship instability observed in BPD. The present study investigated the impact of socialization factors related to emotions, parental autonomy support, parental psychological control, and childhood trauma on BPD features in a nonclinical young adult sample (N = 357). Relationships between socialization factors and BPD features were evaluated using structural equation modeling, to test integrative hypotheses informed by biosocial theory and self-determination theory. We found that recalled experiences of childhood trauma, emotional magnification of negative emotions, neglect of negative emotions, and parental psychological control were positively associated with BPD features. Difficulties regulating emotions mediated the relationships of childhood emotion socialization factors and psychological control with BPD features. Implications for future research, resiliency, and intervention are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520651 TI - Spiteful and contemptuous: A new look at the emotional experiences related to psychopathy. AB - Psychopathy has long been conceptualized in terms of an absence of emotion. Yet, recent studies have suggested that the experience of other-directed negative emotions may be more intimately linked to psychopathy than previously acknowledged, although there is limited knowledge concerning the experience of such emotions. The present study examined the disposition to experience two other directed emotions, spitefulness and contempt, that are conceptually linked with psychopathy but currently are limited in empirical support. Across 2 studies with 3 nonclinical samples (Ns = 1,237, 239, 521), we found evidence that psychopathic traits-as assessed via the Self-Report Psychopathy Scale (SRP; Paulhus, Neumann, & Hare, 2016; Study 1 and Study 2) and the Triarchic Psychopathy Measure (TriPM; Patrick, 2010; Study 2)-were positively associated with spitefulness (Study 1) and contempt (Study 2). These associations were consistent across psychopathy instruments (SRP and TriPM) and dimensions (i.e., the SRP Interpersonal, Affective, Lifestyle, and Antisocial facets, and the TriPM Meanness and Disinhibition dimensions), were stronger for the interpersonal and affective traits of psychopathy, and held when accounting for several theoretically relevant covariates. The only exception concerned the TriPM Boldness scale, which had less consistent associations with contempt. The present findings further our understanding of the emotional experiences related to psychopathy, highlighting the relevance of focusing on other-directed negative emotions, especially those that are interpersonal in nature and share an antagonistic component. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520652 TI - Getting help for others: An examination of indirect helping in young children. AB - When young children recruit others to help a person in need, media reports often treat it as a remarkable event. Yet it is unclear how commonly children perform this type of pro-social behavior and what forms of social understanding, cognitive abilities, and motivational factors promote or discourage it. In this study, 48 three- to four-year-old children could choose between two actors to retrieve an out-of-reach object for a third person; during this event, one actor was physically unable to provide help. Nearly all of children's responses appropriately incorporated the actors' action capacities, indicating that rational prosocial reasoning-the cognitive basis for effective indirect helping is common at this young age. However, only half of children actually directed an actor to help, suggesting that additional motivational factors constrained their prosocial actions. A behavioral measure of social inhibition and within-task scaffolding that increased children's personal involvement were both strongly associated with children's initiation of indirect helping behavior. These results highlight social inhibition and recognizing one's own potential agency as key motivational challenges that children must overcome to recruit help for others. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520653 TI - Examination of differential validity of MMPI-2-RF scores by gender and ethnicity in predicting future suicidal and violent behaviors in a forensic sample. AB - Given the diversity of individuals who undergo psychological assessment, examining whether cultural bias exists in psychological assessment instruments (i.e., differential validity) is crucial. This issue occurs when a measure systematically over- or underpredicts a criterion across demographic groups or is associated with the criterion unequally across the groups. We tested the differential validity of a widely used psychological test, the Minnesota Multiphasic Personality Inventory (MMPI)-2-Restructured Form (MMPI-2-RF), as a function of gender (male, female) and ethnicity (Caucasian, African American, and Hispanic/Latino American) in large samples of forensic psychiatric inpatients. Regression models were estimated in a multigroup framework. The analyses yielded negligible to small statistical evidence of differential validity in MMPI-2-RF scores predicting the number of future suicidal behaviors and violent behaviors in the samples. This evidence supports use of the MMPI-2-RF as a generally unbiased instrument for predicting key criteria across genders and ethnicities in a forensic psychiatric population. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520654 TI - The development and validation of a measure of eating disorder-specific interpersonal problems: The Interpersonal Relationships in Eating Disorders (IR ED) Scale. AB - Clinical reports suggest that interpersonal problems are associated with the onset and maintenance of eating pathology, but existing measures of such problems have limited links to eating pathology. Therefore, the aim of this study was to develop an eating-specific measure of interpersonal problems. The new measure, the Interpersonal Relationships in Eating Disorders scale (IR-ED), was administered to a large community sample, a nonclinical replication sample, and a clinical group of eating disorder patients. In Study 1, the psychometric properties of the IR-ED were established, and they were tested using confirmatory analyses in Study 2. Study 3 determined the validity of the test score interpretations in a clinical sample. The final 15-item version of the IR-ED demonstrated 3 distinct factors with reliability of test scores-Food-Related Isolation; Avoidance of Body Evaluation; and Food-Related Interpersonal Tension. Study 2 demonstrated that the IR-ED comprises a common Interpersonal Problems factor and a specific group factor-Avoidance of Body Evaluation. Study 3 showed that the clinical group had higher IR-ED scores than a nonclinical group. Across the studies, Avoidance of Body Evaluation was the strongest correlate of eating pathology in this group. The IR-ED has strong psychometric properties and its test scores appear to be more valid than those of a generic measure of interpersonal problems. Avoidance of Body Evaluation is the strongest facet of such interpersonal problems, and has meaningful links to models of eating psychopathology. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520655 TI - Development and validation of the Adult Interpersonal Acceptance-Rejection Scale: Measuring mother, best friend, and romantic partner acceptance. AB - Acceptance-rejection studies and inventories commonly examine children's relationships with parents, but no measurement scale is available in the literature to assess interpersonal acceptance across adulthood close relationships. The Adult Interpersonal Acceptance-Rejection Scale (AIARS) was developed, validated, and psychometrically scrutinized across three studies using independent samples of adult participants. In Study 1 (N = 342), the created items were administered to participants and data were subjected to exploratory factor analysis. The correlated three-factor structure of Mother Acceptance, Best Friend Acceptance, and Romantic Partner Acceptance was preliminarily supported. In Study 2 (N = 420), confirmatory factor analysis successfully cross-validated the three-factor measurement model after the deletion of items possessing the poorest loadings. In Study 3 (N = 315), convergent, discriminant, and criterion validities were scrutinized with tests of correlations and multiple regression. Higher acceptance subscale scores uniquely contributed to higher positive emotions, lower negative emotions, and higher life satisfaction. The current research confers measurement and assessment insights to capture the construct of interpersonal acceptance and yields applied implications for future research using the scale. Administration of the scale is anticipated to encourage novel primary investigations that examine acceptance across pivotal close relationships in adulthood. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520656 TI - Mindfulness is positively related to socioeconomic job status and income and independently predicts mental distress in a long-term perspective: Danish validation studies of the Five-Factor Mindfulness Questionnaire. AB - The Five Factor Mindfulness Questionnaire (FFMQ) measures 5 factor-analytically derived mindfulness aspects (Observe, Describe, Non-Judgment, Non-Reactivity, and Acting with Awareness) and is commonly used as an indicator of mindfulness in population surveys and studies of mindfulness-based interventions (MBI). Outside MBI, FFMQ scores are hypothesized to reflect relatively stable human dispositions of importance to psychological health. However, the long-term test-retest reliability of FFMQ scores is virtually untested and it remains unknown whether FFMQ scores predict psychological health after controlling for standardized socioeconomic status classifications. First, we focused on psychometric validation of the FFMQ translated to Danish in a randomly invited healthy and nonmeditating adult community sample (N = 490). Confirmatory factor analyses primarily supported a four-factor construct excluding the Observe facet. The four factor model showed adequate composite reliability, convergent validity and satisfactory-excellent internal consistency, Cronbach alphas = .72-.91. Structural equation modeling revealed that FFMQ Total scores were positively related to income and socioeconomic status but independently predicted psychological distress and mental health scores, respectively, after controlling for age, gender, body mass index, socioeconomic job classification, stressful life events, and social desirability, beta = -.24-.29, ps < .001. Second, FFMQ scores showed adequate short-term (two weeks) test-retest reliability among 99 healthy university students, Spearman's rhos >= .82. Finally, all FFMQ mean scores showed satisfactory test-retest reliability across a long-term (six months) interval (N = 407), intraclass correlation coefficients >=.74. We recommend the Danish FFMQ for further use. The Observe facet should be interpreted with caution. Remaining FFMQ facet scores comprise an internally consistent four-dimensional construct reflecting long-term-reliable human dispositions of independent significance for predicting mental health. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30520658 TI - The usefulness of selected biomarkers in patients with valve disease. AB - AIM: The aim of the study was to investigate the prognostic value of selected biomarkers in patients undergoing valve surgery. MATERIALS & METHODS: A prospective study was conducted on a group of consecutive patients with hemodynamically significant valve defects that underwent elective valve repair or replacement surgery. The primary end point was any major adverse event including death within 30 days. RESULTS: The study group included 416 patients. The composite end point occurred in 81 patients. At multivariate analysis high sensitivity C-reactive protein (p = 0.03), red cell distribution width (p = 0.0001) and red blood cell count (p = 0.005) remained independent predictors of the primary end point. CONCLUSION: Elevated high-sensitivity C-reactive protein, red cell distribution width and red blood cell count were associated with a poorer outcome following valve surgery. PMID- 30520657 TI - Cloning, function, and localization of human, canine and Drosophila Zip10 (Slc39a10), a Zn2+ transporter. AB - Zinc (Zn2+) is the second most abundant trace element, but is considered a micronutrient as it is a cofactor for many enzymes and transcription factors. While Zn2+ deficiency can cause cognitive immune or metabolic dysfunction and infertility, excess Zn2+ is nephrotoxic. As for other ions and solutes, Zn2+ is moved into and out of cells by specific membrane transporters: ZnT, Zip, and NRAMP/DMT proteins. ZIP10 is reported to be localized at the apical membrane of renal proximal tubules in rats, where it is believed to play a role in Zn2+ import. Renal regulation of Zn2+ is of particular interest in light of growing evidence that Zn2+ may play a role in kidney stone formation. The objective of this study was to show ZIP10 homologs transport Zn2+, as well as ZIP10 kidney localization across species.. We cloned ZIP10 from dog, human, and Drosophila ( CG10006), tested clones for Zn2+ uptake in Xenopus oocytes, and localized the protein in renal structures. CG10006, rather than foi (fear-of-intimacy, CG6817) is the primary ZIP10 homolog found in Drosophila Malpighian tubules. The ZIP10 antibody recognizes recombinant dog, human and Drosophila ZIP10 proteins. Immunohistochemistry reveals that ZIP10 in higher mammals is found not only in the proximal tubule but also the collecting duct system. These ZIP10 proteins show Zn2+ transport. Together, these studies reveal ZIP10 kidney localization, a role in renal Zn2+ transport, and indicates that CG10006 is a Drosophila homolog of ZIP10. PMID- 30520659 TI - Levels of 17beta-hydroxysteroid dehydrogenase type 10 in CSF are not a valuable biomarker for multiple sclerosis. AB - AIM: We aimed to characterize the role of mitochondrial 17beta-hydroxysteroid dehydrogenase type 10 (17beta-HSD10) overexpression in multiple sclerosis (MS) and to evaluate its use as a biomarker. Materials & methods: We estimated levels of 17beta-HSD10, amyloid beta 1-42, cyclophilin D, 17beta-HSD10-cyclophilin D complexes or 17beta-HSD10-parkin complexes in cerebrospinal fluid (CSF) samples. RESULTS: The increase in 17beta-HSD10 levels or in 17beta-HSD10-parkin complexes and links to leukocytes were found only in relapsing-remitting MS. The sensitivity of the biomarker was 64%, the specificity equaled 60-63% compared with controls. CONCLUSION: Increased CSF levels of 17beta-HSD10 in later stages of MS could be interpreted via its upregulation in demyelinated neuronal axons. CSF levels of 17beta-HSD10 are not the valuable biomarker for the early diagnosis or for the progression of MS. PMID- 30520660 TI - High-sensitivity troponin T is a prognostic marker of hemodynamic instability in patients undergoing valve surgery. AB - AIM: The usefulness of high-sensitivity troponin T (hs-TnT) as a predictor of perioperative hemodynamic instability is currently unknown. METHODS: A prospective study was conducted on a group of 708 consecutive patients with significant valvular heart disease that underwent elective valve surgery. The primary end point was postoperative hemodynamic instability. The secondary end point was death from all causes in patients with perioperative hemodynamic instability. RESULTS: The postoperative hemodynamic instability occurred in 131 patients. At multivariate analysis hs-TnT measured immediately after surgery and New York Heart Association classes remained independent predictors of the primary end point. Age and hs-TnT measured immediately after surgery were associated with an increased risk of death. CONCLUSION: Elevated postoperative hs-TnT was associated with a higher risk of postoperative hemodynamic instability and death. PMID- 30520661 TI - The brain network in a model of thalamo-cortical dysrhythmia. AB - Sensory information processing and higher cognitive functions rely on the interactions between thalamus and cortex. Many types of neurological and psychiatric disorders are accompanied or driven by alterations in the brain connectivity. In the present study putative changes in functional and effective cortico-cortical (CC), thalamo-cortical (TC) and cortico-thalamic (CT) connectivity during wakefulness and slow-wave sleep in a model of thalamo cortical dysrhythmia (TCD), TRIP8b-/- mice and in control (WT) mice are described. Coherence and nonlinear Granger Causality (GC) were calculated for twenty 10 s length epochs of slow-wave sleep and active-wakefulness of each animal. Coherence was reduced between 4 and ca 20 Hz in the cortex and between cortex and thalamus during slow-wave sleep compared to active-wakefulness in WT, but not in TRIP8b-/- mice. Moreover, TRIP8b-/- mice showed lower CT coherence during active-wakefulness compared to WT mice; these differences were no longer present during slow-wave sleep. Unconditional GC analysis also showed sleep related reductions in TC and CT couplings in WT mice, while TRIP8b-/- mice showed diminished wake and enhanced sleep CC coupling and rather strong CT directed coupling during wake and sleep, albeit smaller during sleep. Conditional GC coupling analysis confirmed the diminished CC and enhanced CT coupling in TRIP8b /- mice. Our findings indicate that altered properties of HCN channels, characterizing TRIP8b-/- mice, have clear effects on CC, TC and CT networks. A more complete understanding of the function of the altered communication within these networks awaits detailed phenotyping of TRIP8b-/- mice aimed at specifics of sensory and attentional processes. PMID- 30520662 TI - Psychological benefits of attending the theatre associated with positive affect and well-being for subscribers over age 60. AB - OBJECTIVES: Although late adulthood may be a time of greater well-being, optimal aging still characterizes a minority of older adults. Understanding how individuals achieve well-being across adulthood is important for intervention and social policy. We focused on how attending live theatre might enhance the well being of a sample of 53 season ticket holders aged 60 and older. Based on a previously tested conceptual framework, we hypothesized that post-performance reports of social-cognitive experience while at the play would predict post performance positive affect, which in turn would predict well-being. METHOD: The sample was a subset of volunteers from a large survey study of theatre ticket purchasers. They completed baseline and two-year follow-up measures of well being, and questionnaires immediately after attending seven plays across two seasons: measures of social engagement, belonging, flow, positive affect, and their reactions to the plays. RESULTS: We found that sense of belonging, social engagement, and flow were associated with positive affect after performances, as hypothesized. We also found that the cumulative positive affect experienced after plays in the two seasons predicted change in well-being between baseline and follow-up. CONCLUSION: Our findings suggest that attending performances is a combined social, cognitive, and affective experience that transcends entertainment. Future research might investigate whether the psychological benefit model we assessed will generalize to other leisure activities that create similar engagement. The findings have implications for individuals seeking to promote their own well-being, and, possibly more importantly, for policies that support enriching cultural opportunities, particularly in the arts. PMID- 30520664 TI - Circulation: Heart Failure. PMID- 30520663 TI - Issue Information. PMID- 30520665 TI - Assessing ADHD Through the Multi-Informant Approach: The Contribution of the Conners' 3 Scales. AB - OBJECTIVE: Symptoms of ADHD need to be present in at least two different settings to suggest a diagnosis, so multi-informant assessment approaches are usually adopted. The Conners' Rating Scales offer three versions, completed by parents (Conners 3-P), teachers (Conners 3-T), and youth (Conners 3-SR). Nonetheless, there is a lack of studies examining the psychometric properties of the Parent and Teacher versions and the relation between each version of the Conners 3 scales. METHOD: The present work examined the psychometric properties of the Parent and Teacher scales in terms of the structural validity and reliability of their Content scales in an Italian sample. Moreover, to support the need to administer all Conners 3 scales together and to exclude their potential redundancy, cross-informant agreement between parents, teachers, and children was assessed. RESULTS: Results supported the Conners 3 scales as reliable and valid tools to assess ADHD and provided evidence for their non-redundancy. CONCLUSION: The non-redundancy of the Conners 3 may promote clinicians to adopt a multi informant perspective. PMID- 30520667 TI - Serum Cholesterol Concentration and Prevalence, Awareness, Treatment, and Control of High Low-Density Lipoprotein Cholesterol in the Korea National Health and Nutrition Examination Surveys 2008-2010: Beyond the Tip of the Iceberg. PMID- 30520666 TI - Decision-Making Deficits in ADHD Are Not Related to Risk Seeking But to Suboptimal Decision-Making: Meta-Analytical and Novel Experimental Evidence. AB - OBJECTIVE: ADHD is related to decision-making deficits in real-life (e.g., substance abuse) and on experimental tasks (increased preference for risky options). In most tasks, risk and expected value are confounded (risky options have lowest expected value), making it impossible to disentangle risky from suboptimal (i.e., not choosing highest expected value) decision-making. We differentiated between risky and suboptimal decision-making in ADHD in two studies. METHOD AND RESULTS: First, on a multilevel meta-regression analysis ( k = 48, n_ADHD = 1,144, n_Control = 1,108), ADHD and controls differed if the risky option was suboptimal (ADHD choosing more risky/suboptimal), whereas groups performed similar if the risky option was not suboptimal. Second, an empirical study showed that adults with ADHD ( n = 40) made more suboptimal, but not more risky choices than controls ( n = 40). CONCLUSION: These results contribute to a growing body of evidence that decision-making deficits in ADHD are driven by suboptimal decision-making and not by risk seeking. PMID- 30520668 TI - Issue Information. PMID- 30520669 TI - Issue Information. PMID- 30520670 TI - Impulsivity as an Endophenotype in ADHD: Negative Findings. AB - : Impulsivity has a strong genetic component and is considered an endophenotype in many psychiatric disorders. Impulsivity in adult ADHD has become a focus of interest more recently because of its suggested prominence in this age. OBJECTIVE: This study aimed to access self-reported impulsivity levels in biological parents of ADHD offspring, according to their status: non-ADHD (controls), remitted, nonremitted. METHOD: Impulsivity levels of 155 parents of ADHD children were compared according to their status using the Barratt Impulsiveness Scale (BIS-11). RESULTS: The ADHD group presented the highest levels of impulsivity compared with all other groups. The remitted ADHD and control groups showed no significant differences in impulsivity levels. CONCLUSION: Impulsivity tended to remit alongside ADHD symptoms in remitters and to persist in those presenting with the residual form of adult ADHD suggesting it should not be considered as an endophenotype. Only the attentional dimension was impaired, cautioning against Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5) impulsivity proposed criteria. PMID- 30520671 TI - Investigation of the contribution of an underlying platelet defect in women with unexplained heavy menstrual bleeding. AB - Heavy menstrual bleeding (HMB) is often undiagnosed in women and can cause discomfort and distress. A haemostatic cause for excessive bleeding is often not routinely investigated and can lead to hysterectomy at an early age. A prospective cohort study was carried out to determine whether certain patients with unexplained HMB have an underlying platelet function defect (PFD). The Genotyping and Phenotyping of Platelets (GAPP) study recruited 175 women with HMB and 44 unrelated volunteers from 25 Haemophilia Centres across the UK, and a tertiary gynaecology service. Bleeding history was assessed using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT). Platelet count, platelet size, haemoglobin and mean corpuscular volume were measured in whole blood using the Sysmex XN-1000 Haematology Analyzer. Platelet function testing using lumiaggregometry and flow cytometry was performed in patients included in this study. A PFD was identified in 47% (82/175) of patients with HMB. Cutaneous bleeding was the most frequent additional bleeding symptom (89% in PFD and 83% with no PFD). Whole blood platelet count was significantly lower (P < 0.0001) between the PFD group and no PFD group. The prevalence of anaemia did not differ between patients and healthy volunteers. Clinical evaluation alone is insufficient to determine presence of an underlying PFD in patients with HMB. Platelet function tests may be considered and clinical guidelines may include them in their algorithms. An appropriate diagnosis and subsequent tailored management of HMB may prevent unnecessary surgery and help manage future haemostatic challenges. PMID- 30520672 TI - Cardiovascular Risk Factors and Brain Health: Impact on Long-Range Cortical Connections and Cognitive Performance. AB - Background Cardiovascular risk factor burden in the absence of clinical or radiological "events" is associated with mild cognitive impairment. Magnetic resonance imaging techniques exploring the integrity of neuronal fiber connectivity within white matter networks supporting cognitive processing could be used to measure the impact of cardiovascular disease on brain health and be used beyond bedside neuropsychological tests to detect subclinical changes and select or stratify participants for entry into clinical trials. Methods and Results We assessed the relationship between verbal IQ and brain network integrity and the effect of cardiovascular risk factors on network integrity by constructing whole-brain structural connectomes from magnetic resonance imaging diffusion images (N=60) from people with various degrees of cardiovascular risk factor burden. We measured axonal integrity by calculating network density and determined the effect of fiber loss on network topology and efficiency, using graph theory. Multivariate analyses were used to evaluate the relationship between cardiovascular risk factor burden, physical activity, age, education, white matter integrity, and verbal IQ . Reduced network density, resulting from a disproportionate loss of long-range white matter fibers, was associated with white matter network fragmentation ( r=-0.52, P<10-4), lower global efficiency ( r=0.91, P<10-20), and decreased verbal IQ (adjusted R2=0.23, P<10-4). Conclusions Cardiovascular risk factors may mediate negative effects on brain health via loss of energy-dependent long-range white matter fibers, which in turn leads to disruption of the topological organization of the white matter networks, lowered efficiency, and reduced cognitive function. PMID- 30520673 TI - Increased Vulnerability to Atrial Fibrillation Is Associated With Increased Susceptibility to Alternans in Old Sheep. AB - Background Atrial fibrillation ( AF ) is common in the elderly, but rare in the young; however, the changes that occur with age that promote AF are not fully understood. Action potential ( AP ) alternans may be involved in the initiation of AF . Using a translationally relevant model, we investigated whether age associated atrial vulnerability to AF was associated with susceptibility to AP alternans. Methods and Results AF was induced in conscious young and old sheep using 50 Hz burst pacing. Old sheep were more vulnerable to AF . Monophasic and cellular AP s were recorded from the right atrium in vivo and from myocytes isolated from the left and right atrial appendages. AP alternans occurred at lower stimulation frequencies in old sheep than young in vivo (old, 3.0+/-0.1 Hz; young, 3.3+/-0.1 Hz; P<0.05) and in isolated myocytes (old, 1.6+/-0.1 Hz; young, 2.0+/-0.1 Hz; P<0.05). Simultaneous recordings of [Ca2+]i and membrane potential in myocytes showed that alternans of AP s and [Ca2+]i often occurred together. However, at low stimulation rates [Ca2+]i alternans could occur without AP alternans, whereas at high stimulation rates AP alternans could still be observed despite disabling Ca2+ cycling using thapsigargin. Conclusions We have shown, for the first time in a large mammalian model, that aging is associated with increased duration of AF and susceptibility to AP alternans. We suggest that instabilities in Ca2+ handling initiate alternans at low stimulation rates, but that AP restitution alone can sustain alternans at higher rates. PMID- 30520675 TI - Peripheral inflammation accelerates the onset of mechanical hypersensitivity after spinal cord injury and engages TNFalpha signaling mechanisms. AB - Previously, we showed that noxious stimulation of the tail produces numerous detrimental effects after spinal cord injury (SCI), including an earlier onset and increased magnitude of mechanical hypersensitivity. Expanding on these observations, this study sought to determine whether localized peripheral inflammation similarly impacts the expression of mechanical hypersensitivity after SCI. Adult rats received a moderate contusion injury at thoracic level (Tl0) or sham surgery, and were administered complete Freund's adjuvant (CFA) or vehicle in one hind paw 24 hours later. Examination of locomotor recovery (Basso, Beattie, and Bresnahan [BBB] score) showed no adverse effect of CFA. Mechanical testing with von Frey hairs was done at time-points ranging from 1 hour to 28 days after CFA or vehicle treatment, and rats were sacrificed at 1, 7 or 28 days for cellular assessment. Unlike vehicle-treated SCI rats where mechanical hypersensitivity emerged at 14 days, CFA-treated SCI rats showed mechanical hypersensitivity as early as 1 hour after CFA administration which lasted at least 28 days. CFA-treated sham subjects also showed an early onset of mechanical hypersensitivity, but this was maintained up to 7 days after treatment. Cellular assessments revealed congruent findings. Expression levels of c-fos, tumor necrosis factor (TNF)alpha, TNF receptors, and members of TNFalpha signaling pathway such as caspase 8 and phosphorylated extracellular related kinase (pERK) were preferentially upregulated in the lumbar spinal cord of SCI-CFA rats. Meanwhile, c-jun was significantly increased in both CFA treated groups. Overall, these results together with our previous reports, suggest that peripheral noxious input after SCI facilitates the development of pain by mechanisms that may require TNFalpha signaling. PMID- 30520674 TI - Interhemispheric anatomical disconnection in disorders of consciousness patients. AB - In disorder of consciousness (DOC) patients, corpus callosum (CC) and subcortical white matter (SWM) integrity were showed to discriminate between diagnostic categories. The aims of the study were: 1) to clarify the link between the integrity of CC and of SWM and the clinical status in DOC patients, disentangling the role played by the different brain injuries (traumatic or hemorrhagic brain injury); 2) to investigate the relationship between the CC integrity and the brain metabolism. We assessed the diagnostic accuracy of the CC and SWM integrity, using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (sMRI), in a sample of DOC individuals, well-balanced for diagnosis and etiology. CC DTI-derived measures were correlated with the brain metabolism, computed with FDG-PET. Our results showed that the CC macrostructural DTI-derived measures discriminate between diagnosis and correlate with the clinical status of DOC patients irrespective of the etiology. Moreover, the CC DTI-derived measures strongly correlate with the metabolism of the right hemisphere. No significant diagnostic accuracy emerged for the CC sMRI evaluation and the SWM measures. Our results indicate that: 1) the degree of the interhemispheric anatomical disconnection is a marker of the level of consciousness independently from the type of brain injury; 2) CC alterations might be the consequence of the reduced brain metabolism. Remarkably, our results suggest that the functional interplay between the two hemispheres is tightly linked to the level of consciousness. PMID- 30520676 TI - Issue Information. PMID- 30520677 TI - Heritable phytohormone profiles of poplar genotypes vary in resistance to a galling aphid. AB - Insect galls are highly specialized structures arising from atypical development of plant tissue induced by insects. Galls provide the insect enhanced nutrition and protection against natural enemies and environmental stresses. Galls are essentially plant organs formed by an intimate biochemical interaction between the gall-inducing insect and its host-plant. Because galls are plant organs, their development is likely to be governed by phytohormones involved in normal organogenesis. We characterized concentrations of both growth and defensive phytohormones in ungalled control leaves and galls induced by the aphid, Pemphigus betae, on narrowleaf cottonwood, Populus angustifolia, that differ genotypically in resistance to this insect. We found that susceptible trees differed from resistant trees in constitutive concentrations of both growth and defense phytohormones. Susceptible trees were characterized by significantly higher constitutive cytokinin concentrations in leaves, significantly greater ability of aphids to elicit cytokinin increases, and significantly lower constitutive defense phytohormone concentrations than observed in resistant trees. Phytohormone concentrations in both constitutive and induced responses in galled leaves exhibited high broad-sense heritability (H2B), that respectively ranged from 0.39 to 0.93 and from 0.28 to 0.66, suggesting that selection can act upon these traits and that they might vary across the landscape. Increased cytokinin concentrations may facilitate forming strong photosynthate sinks in the galls, a requirement for galling insect success. By characterizing for the first time the changes in 15 phytohormones, belonging to five different classes, this study offers a better overview of the signaling alteration occurring in galls that has likely been important for their ecology and evolution. PMID- 30520678 TI - Disruption and overexpression of the gene encoding ACC (1-aminocyclopropane-1 carboxylic acid) deaminase in soil-borne fungal pathogen Verticillium dahliae revealed the role of ACC as a potential regulator of virulence and plant defense. AB - It has been suggested that some microorganisms, including plant growth promoting rhizobacteria (PGPR), manipulate the level of ethylene in plants by degrading 1 aminocyclopropane-1-carboxylic acid (ACC), an ethylene precursor, into alpha ketobutyrate and ammonia using ACC deaminase. Here, we investigated whether ACC deaminase of Verticillium dahliae, a soil-borne fungal pathogen of many important crops, is involved in causing vascular wilt disease. Overexpression of the V. dahliae gene encoding this enzyme, labeled as ACCd, significantly increased virulence in both tomato and eggplant, while disruption of ACCd reduced virulence. Both types of mutant produced more ethylene than wild type (70V-WT) strain although they significantly differed in ACC content. Overexpression strains lowered ACC levels in the roots of infected plants while the amount of ACC in the roots of plants infected with deletion mutants increased. To test the hypothesis that ACC acts as a signal for controlling defense, roots of WT and Never ripe (Nr) tomato plants were treated with ACC before V. dahliae inoculation. Plants pre-treated with ACC displayed less severe symptoms than untreated controls. Collectively, our results suggest a novel role of ACC as a regulator of both plant defense and pathogen virulence. PMID- 30520679 TI - Peer Victimization in Preadolescent Children With ADHD in Turkey. AB - The present study aims to investigate peer victimization and its relationship with comorbid psychiatric diagnoses and quality of life (QoL) among children with attention deficit hyperactivity disorder (ADHD). Study sample consisted of 66 children with ADHD (mean age = 8.6 +/- 1.1 years) and age- and gender-matched 66 controls (mean age = 8.5 +/- 1.3 years). In self-reports, the ADHD group reported significantly higher rates of victimization and bullying than the non-ADHD group. Verbal and physical forms of victimization and bullying were the most prevalent forms in both groups; however, exclusion from peer groups, which is named as relational bullying, was the most significantly differing type between two groups. QoL parameters did not significantly differ between the children involved in bullying and those not involved, except for the lower physical QoL in victimized children in the control group. In conclusion, peer victimization was significantly more prevalent in the ADHD group than the non-ADHD group. Preventive measures are needed for peer victimization, especially for children with ADHD. PMID- 30520680 TI - Response to Elliot and Crew (DOI: 10.1089/neu.2018.5697) Response to Christison et al. (DOI: 10.1089/neu.2017.5413): Intermittent Catheterization: The Devil Is in the Details. AB - N/a. PMID- 30520682 TI - Anti-Remodeling and Anti-Fibrotic Effects of the Neuregulin-1beta Glial Growth Factor 2 in a Large Animal Model of Heart Failure. PMID- 30520683 TI - Soluble Urokinase Plasminogen Activator Receptor Level Is an Independent Predictor of the Presence and Severity of Coronary Artery Disease and of Future Adverse Events. PMID- 30520684 TI - Issue Information. PMID- 30520681 TI - Paths to successful translation of new therapies for severe TBI in the golden age of traumatic brain injury research: A Pittsburgh vision. AB - New neuroprotective therapies for severe traumatic brain injury (TBI) have not translated from pre-clinical to clinical success. Numerous explanations have been suggested in both the pre-clinical and clinical arenas. Coverage of TBI in the lay press has reinvigorated interest creating a golden age of TBI research with innovative strategies to circumvent roadblocks. We discuss the need for more robust therapies. We present concepts for traditional and novel approaches to defining therapeutic targets. We review lessons learned from the ongoing work of the pre-clinical drug and biomarker screening consortium Operation Brain Trauma Therapy and suggest ways to further enhance pre-clinical consortia. Biomarkers have emerged that empower choice and assessment of target engagement by candidate therapies. Drug combinations may be needed and it may require moving beyond conventional drug therapies. Precision medicine may also link the right therapy to the right patient including new approaches to TBI classification beyond the Glasgow coma scale or anatomical phenotyping-incorporating new genetic and physiologic approaches. Therapeutic breakthroughs may also come from alternative approaches in clinical investigation (comparative effectiveness, adaptive trial design, use of the electronic medical record, big data). The full continuum of care must also be represented in translational studies, given the important clinical role of pre-hospital events, extra-cerebral insults in the ICU, and rehabilitation. TBI research from concussion to coma can cross-pollinate and further advancement of new therapies. Misconceptions can stifle/misdirect TBI research and deserve special attention. Finally, we synthesize an approach to deliver therapeutic breakthroughs in this golden age of TBI research. PMID- 30520685 TI - Cryptococcus neoformans and Cryptococcus gattii clinical isolates from Thailand display diverse phenotypic interactions with macrophages. AB - Cryptococcus-macrophage interaction is crucial in the development of cryptococcocal diseases. C. neoformans and C. gattii are major pathogenic species that occupy different niches and cause different clinical manifestations. However, the differences of macrophage interaction among these species in affecting different disease outcomes and immune responses have not been clearly addressed. Here, we examined the macrophage uptake rates, intracellular loads and intracellular proliferation rates of C. neoformans and C. gattii clinical isolates from Thailand and analyzed the effect of those interactions on fungal burdens and host immune responses. C. neoformans isolates showed a higher phagocytosis rate but lower intracellular proliferation rate than C. gattii. Indeed, the high intracellular proliferation rate of C. gattii isolates did not influence the fungal burdens in lungs and brains of infected mice, whereas infection with high-uptake C. neoformans isolates resulted in significantly higher brain burdens that associated with reduced survival rate. Interestingly, alveolar macrophages of mice infected with high-uptake C. neoformans isolates showed distinct patterns of alternatively activated macrophage (M2) gene expressions with higher Arg1, Fizz1, Il13 and lower Nos2, Ifng, Il6, Tnfa, Mcp1, csf2 and Ip10 transcripts. Corresponding to this finding, infection with high uptake C. neoformans resulted in enhanced arginase enzyme activity, elevated IL-4 and IL-13 and lowered IL-17 in the bronchoalveolar lavage. Thus, our data suggested that the macrophage interaction with C. neoformans and C. gattii may affect different disease outcomes and the high phagocytosis rates of C. neoformans may influence the induction of type-2 immune responses that support fungal dissemination and disease progression. PMID- 30520686 TI - Group Psychological Abuse and Psychopathological Symptoms: The Mediating Role of Psychological Stress. AB - In the context of the long-term effects of psychological abuse, this study examined psychological stress and psychopathological symptoms in survivors of groups with cultic dynamics where abusive behaviors take place on an ongoing basis. We specifically tested the mediating role of psychological stress suffered after the departure from the group between the group psychological abuse experienced and current psychopathology. An online questionnaire was administered to 608 Spanish-speaking former members of different groups. We distributed participants into a sample of victims ( N = 365) and a sample of nonvictims ( N = 243), according to whether or not they reported having experienced group psychological abuse. Moderate associations were found among group psychological abuse, psychological stress, and psychopathological symptoms. Greater differences in psychological stress intensity between samples were related to personal conflicts ([Formula: see text] = .30) and social relations ([Formula: see text] = .29). Greater differences in psychopathological symptoms were related to paranoid ideation ([Formula: see text] = .17), psychoticism ([Formula: see text] = .15), depression ([Formula: see text] = .15), and interpersonal sensitivity ([Formula: see text] = .13). Moreover, mediation testing demonstrated that psychological stress partially mediated the impact of group psychological abuse on psychopathological symptoms. These findings contribute to a better understanding of the long-term effects of group psychological abuse. Survivors of abusive groups not only need help in dealing with psychopathological symptoms, but also need resources to cope with stressful environmental demands. Interventions should address both psychological stress and clinical symptoms to promote survivors' health and well-being during their integration process into the outgroup society. PMID- 30520687 TI - Oxidative stress and macrophages: driving forces behind exacerbations of asthma and COPD? AB - Oxidative stress is a common feature of obstructive airway diseases like asthma and chronic obstructive pulmonary disease (COPD). Lung macrophages are key innate immune cells that can generate oxidants and are known to display aberrant polarization patterns and defective phagocytic responses in these diseases. Whether these characteristics are linked in one way or another and whether they contribute to the onset and severity of exacerbations in asthma and COPD remains poorly understood. Insight into oxidative stress, macrophages and their interactions may be important in fully understanding acute worsening of lung disease. This review therefore highlights the current state of the art regarding the role of oxidative stress and macrophages in exacerbations of asthma and COPD. It shows that oxidative stress can attenuate macrophage function, which may result in impaired responses towards exacerbating triggers and may contribute to exaggerated inflammation in the airways. PMID- 30520688 TI - Impaired Hypoxic Pulmonary Vasoconstriction in a Mouse Model of Leigh Syndrome. AB - Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 (Ndufs4-/-) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4-/- mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen (PaO2) during LMBO was lower in Ndufs4-/- and in piericidin A-treated mice than in matched controls. Impairment of HPV in air breathing Ndufs4-/- mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4 deficient mice, three weeks of breathing 11% O2 restored HPV in response to LMBO. Compared to Ndufs4-/- mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically-inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV. PMID- 30520689 TI - A Functional Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphism is Associated with Reduced Diffusing Capacity. AB - Cigarette smoke exposure is the leading modifiable risk factor for COPD, however the clinical and pathologic consequences of chronic cigarette smoke exposure are variable amongst smokers. MIF (Macrophage Migration Inhibitory Factor) is a pleiotropic cytokine implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Within the promoter of the MIF gene is a functional polymorphism that regulates MIF expression (-794 CATT5-8 microsatellite repeat) ( rs5844572). The role of this polymorphim in mediating disease susceptibility to COPD-related traits remains unknown. We performed a cross-sectional analysis of DNA samples from 641 subjects to analyze MIF-794 CATT5-8 (rs5844572) polymorphism by standard methods. We generated multivariable logistic regression models to determine the risk of low expressing MIF alleles for airflow obstruction (defined by FEV1/FVC ratio < 0.70) and an abnormal diffusion capacity (defined by a DLCO percent predicted < 80%). We then used generalized linear models to determine the association of MIF genotypes with FEV1 percent predicted and DLCO percent predicted. The MIF-794 CATT5 allele was associated with an abnormal diffusion capacity in two cohorts of (OR; 9.31;95% CI:1.97-4.06 and OR:2.21; 95% CI:1.03 4.75). Similarly, the MIF-794 CATT5 allele was associated with a reduced DLCO in these two cohorts: (63.5 vs. 70.0, p=0.0023) and (60.1 vs. 65.4, p=0.059). This study suggests an association between a common genetic polymorphism of an endogenous innate immune gene, MIF, with reduced diffusing capacity for carbon monoxide, an important measurement of COPD severity. PMID- 30520690 TI - Does lifestyle matter? Individual lifestyle factors and their additive effects associated with cognitive function in older men and women. AB - OBJECTIVES: This study investigated the association between healthy lifestyle comprised of multiple domains, gender, and cognitive function in older Chinese people in Hong Kong. METHODS: We conducted a cross-sectional analysis with data from 1,831 community-dwellers aged 65 years and above. Participants' basic demographics, comorbidity, and six lifestyle factors: diet; smoking; alcohol drinking; and physical, mental, and social activities were surveyed. Cognitive function was assessed using the Cantonese Chinese Montreal Cognitive Assessment (CC-MoCA). Linear regressions were performed to examine the associations between lifestyle, gender, and cognitive performance. RESULTS: There were gender differences in lifestyle: men smoked (chi2(1) = 159.4) and drank more (chi2(1) = 85.9) and were more active in mentally stimulating activities (chi2(1) = 14.3, all p<.001); while women were more socially active (chi2(1) = 28.0). Age, gender and education explained the greatest variance in cognition (R2=.32). Being active/healthy in more domains further contributed to better cognitive function, although the effect was small (DeltaR2=0.03 in women; DeltaR2=0.01 in men, both p<.05). Among the lifestyle domains, physical activity showed the strongest effects on cognitive function (DeltaR2=0.004 in men and DeltaR2=0.02 in women, both p<.05). CONCLUSIONS: Naturalistically, a physically active lifestyle and being active/healthy in more domains is associated with better cognitive function in older people after controlling for non-modifiable and early-life factors. The effects are however small. There are gender differences in lifestyle and the impact of lifestyle on cognitive function. Preventive strategies targeting lifestyle domains for cognitive health in older people may consider these naturalistic associations. PMID- 30520691 TI - Energy intake, gastrointestinal transit and gut hormone release in response to oral triglycerides and fatty acids in severely obese and non-obese men. AB - Dietary fat, and particularly fatty acids from hydrolyzed triglycerides, reduce appetite, whereas, paradoxically, a high-fat diet leads to excess calorie intake and weight gain. We therefore hypothesized that the appetite-regulating effects of dietary fat is perturbed in obesity. Ten men with severe obesity (median BMI 51.0 kg/m2 [range 47.9 to 69.0]) and 10 non-obese men (BMI 24.6 kg/m2 [21.7 to 26.8]) were recruited for a double-blind randomized crossover study. On two occasions separated by at least one week, participants were given isocaloric (2660 kJ) and isovolemic (80 ml) loads of either oleic acid (long-chain fatty acid) or olive oil (triglyceride) containing radiolabeled lipid and water markers. Post-load scintigraphy, blood sampling and assessment of appetite were performed for 10 hours after which an ad libitum meal was served. Gastric mean emptying time (GMET) and oro-coecal transit time (OCTT) was slower in severely obese than non-obese men (GMETlipid p=0.046, GMETwater p=0.003, OCTT p=0.001). GMETlipid was slower for oleic acid than olive oil (p<0.001). Secretion of glucagon-like peptide-1 (GLP-1) was attenuated in severely obese compared to non obese men both in basal (p=0.045) and post-load state (p=0.048), while no difference was found for cholecystokinin (CCK) and peptide YY. In both groups, post-load CCK secretion was elevated in response to oleic acid (p<0.001). Ad libitum energy intake was equally suppressed in both groups. We conclude that long-chain fatty acids more efficiently suppress appetite than triglycerides also in men with severe obesity, although overall obesity was associated with delayed gut transit and attenuated hormone secretion. PMID- 30520692 TI - RNA regulons are essential in intestinal homeostasis. AB - Intestinal epithelial cells are among the most rapidly proliferating cell types in the human body. There are several different sub-types of epithelial cells, each with unique functional roles in responding to the ever-changing environment. The epithelium's ability for rapid and customized responses to environmental changes requires multi-tiered levels of gene regulation. An emerging paradigm in gastrointestinal epithelial cells is the regulation of functionally-related mRNA families, or regulons, via RNA binding proteins (RBPs). RBPs represent a rapid and efficient mechanism to regulate gene expression and cell function. In this review, we will provide an overview of intestinal epithelial RBPs and how they contribute specifically to intestinal epithelial stem cell dynamics. In addition, we will highlight key gaps in knowledge in the global understanding of RBPs in gastrointestinal physiology as an opportunity for future studies. PMID- 30520693 TI - Overexpression of IL-11 promotes premalignant gastric epithelial hyperplasia in isolation from germline gp130-JAK-STAT3 driver mutations. AB - Expression of the cytokine IL-11 is elevated in human Helicobacter pylori infection and progressively increases with worsening gastric pathology. Additionally, IL-11 is required for tumour development in STAT3 dependent murine models of gastric cancer (GC) and, when administered acutely, causes resolving atrophic gastritis. However, it is unclear whether locally elevated IL-11 ligand expression can, in isolation from oncogenic gp130-JAK-STAT pathway mutations, initiate GC pathogenesis. Here we developed a transgenic mouse model of stomach specific (keratin 19 promoter) IL-11 ligand overexpression. Keratin 19 promoter IL-11 transgenic ( K19-IL11Tg) mice showed specific IL-11 overexpression in gastric corpus and antrum, but not elsewhere in the gastrointestinal tract, or in other tissues. K19-IL11Tg mice developed spontaneous premalignant disease of the gastric epithelium, progressing from atrophic gastritis to TFF2-positive metaplasia and severe epithelial hyperplasia, including adenoma-like lesions in a subset of older (1-year-old) animals. Though locally advanced, the hyperplastic lesions remained non-invasive. Helicobacter ( H.) pylori infection in K19-IL11Tg mice accelerated some aspects of the premalignant phenotype. Finally, K19-IL11Tg mice had splenomegaly in association with elevated serum IL-11, with spleens showing an expanded myeloid compartment. Our results provide direct in vivo functional evidence that stomach-specific overexpression of IL-11, in isolation from germline gp130-JAK-STAT3 genetic drivers, is sufficient for premalignant progression. These findings have important functional implications for human GC, in which frequent IL-11 overexpression occurs in the reported absence of somatic mutations in gp130 signalling components. PMID- 30520694 TI - Cyclic AMP-dependent protein kinase A and EPAC mediate VIP and Secretin stimulation of PAK4 and activation of Na+, K+-ATPase in pancreatic acinar cells. AB - Rat pancreatic acinar cells possess only the p21-activated kinase (PAKs), PAK4 of the Group-II p21-activated kinase (PAK) and it is activated by gastrointestinal hormones/neurotransmitters stimulating PLC and by a number of growth factors. However, little is known generally of cAMP-agents causing PAK4 activation and there are no studies with gastrointestinal hormones/neurotransmitters activating cAMP cascades. In the present study, we examined the ability of VIP and secretin, which stimulate cAMP generation in pancreatic acini, to stimulate PAK4 activation, the signaling cascades involved and its possible role in activating Na+,K+ATPase. PAK4 activation was compared to activation of the well-established cAMP-target, CREB. Secretin-stimulated PAK4-activation was inhibited by KT-5720 and PKI, PKA-inhibitors, whereas VIP activation was inhibited by ESI-09 and HJC0197, EPAC-inhibitors. In contrast, both VIP/secretin-stimulated pCREB via EPAC activation, however it was inhibited by the p44/42 inhibitor, PD98059, and the p38 inhibitor, SB202190. The specific EPAC-agonist, 8-CPT-2-O-Me-cAMP, as well 8-Br-cAMP and Forskolin, stimulated PAK4 activation. Secretin/VIP activation of Na+,K+ ATPase, was inhibited by PAK4 inhibitors (PF-3758309, LCH-7749944). These results demonstrate PAK4 is activated in pancreatic acini by stimulation of both VIP-/secretin-preferring receptors, as is CREB. However, they differ in their signaling cascades. Furthermore, PAK4 activation is needed for Na+,K+ATPase activation, which mediates pancreatic fluid secretion. These results, coupled with recent studies reporting PAKs are involved in both pancreatitis/pancreatic cancer growth/enzyme secretion, show that PAK4, similar to PAK2, likely plays an important role in both pancreatic physiological/pathological responses. PMID- 30520695 TI - Evaluation of the Risk of Development of Fluopicolide Resistance in Phytophthora erythroseptica. AB - Fluopicolide has shown effective pink rot (Phytophthora erythroseptica) control in potato disease management. To efficiently utilize this chemical, the risk of fluopicolide resistance in P. erythroseptica needs to be assessed. In this study, 34 isolates of P. erythroseptica were obtained from symptomatic potato tubers with pink rot in Maine. The sensitivity of these wild-type isolates to fluopicolide was assessed by culturing them on agar medium amended with fluopicolide at various concentrations. The 50% effective concentration (EC50) of fluopicolide for the inhibition of mycelial growth was determined and used to establish a baseline sensitivity of these P. erythroseptica isolates to fluopicolide. The wild-type isolates were sensitive to fluopicolide, with EC50 values ranging from 0.08 to 0.35 MUg/ml. By exposing P. erythroseptica zoospores to agar medium containing 100 MUg/ml fluopicolide, 6 out of the 34 wild-type isolates produced fluopicolide-resistant mutants. The mutants were transferred to fungicide-free V8 medium consecutively for 10 times, and the 10th transfer of mutants was examined for resistance stability and biological fitness. In general, the mutants had similar or slower growth rates compared with their wild-type parents, and the virulence of some mutants was significantly reduced. The results indicated a low to moderate risk of P. erythroseptica developing resistance to fluopicolide, and suggested a trade-off between fluopicolide resistance and biological fitness in P. erythroseptica. PMID- 30520696 TI - High Humidity and Age-Dependent Fruit Susceptibility Promote Development of Trichothecium Black Spot on Apple. AB - Fruit bagging is a widely used orchard practice in China. Trichothecium black spot (TBS) is a disease highly associated with the fruit bagging. In this study, we characterized in vitro factors affecting the causal agent, Trichothecium roseum, and TBS development and infection histology on field-bagged apple fruit in situ. Under in vitro conditions, conidial germination required exogenous nutrients, and the germination rate was significantly promoted by high humidity, a condition mimicking the bag microenvironment. Germ tubes penetrated fruit via natural openings including stomata, lenticels, and surface cracks. To determine the chronology of infection by T. roseum, 'Fuji' fruit were inoculated in the field at different developmental stages. The earliest infection occurred 60 days after full bloom (dafb), and disease incidence increased as fruit maturity advanced. At harvest time (165 dafb), lesions on more recently inoculated fruit (105 dafb, 150 dafb) were larger than lesions from fruit inoculated on earlier dates. Histological observation showed that infection of younger fruit elicited stronger host lignification responses restricting lesion development. Taken together, our results support the hypothesis that high humidity in sealed bags and increased susceptibility associated with advancing fruit maturity are key factors promoting T. roseum infection and TBS symptom development on bagged apple fruit. PMID- 30520698 TI - Case Report in Clinical Pediatric Dentistry: How to Review, Organize and Prepare a Manuscript. AB - A case report is a useful type of publication to describe information on unusual clinical diseases or syndromes, new management techniques, potential risk factors/oral disease associations, and uncommon side effects or responses to traditional dental treatments. In the practice of Dentistry and Medicine, the publication of case reports has the purpose of sharing new clinical experiences and knowledge with interested colleagues. Case reports in the field of Evidence Based Pediatric Dentistry convey unique contributions to the clinical practice and help improve the process of clinical decision making in the form of a brief written communication. Additionally, case reports are potential resources of new hypotheses for more complex methodological designs in clinical research studies and are one of the best ways to get started in scholarly writing. The purposes of the present report were to comment on the role, relevance, and main limitations of case reports in Clinical Pediatric Dentistry, to describe the reasons for writing a case report and some recommendations for critically reviewing a published case report, and finally, to provide the fundamentals of preparing a case report manuscript in a structured manner. PMID- 30520697 TI - Exploring the Brain Lateralization in ADHD Based on Variability of Resting-State fMRI Signal. AB - OBJECTIVE: In this study, we investigate the brain lateralization in ADHD patients. Furthermore, we also explore the difference between male and female patients, and the difference among distinct ADHD subtypes, that is, ADHD inattentive (ADHD-IA) and ADHD-combined (ADHD-C). METHOD: We employed the standard deviation to quantify the variability of resting-state functional magnetic resonance imaging (fMRI) signal and measure the lateralization index (LI). RESULTS: ADHD patients showed significantly increased rightward lateralization in the inferior frontal gyrus (opercular), precuneus, and paracentral lobule, and decreased rightward lateralization in the insula. Compared with male patients, female patients showed significantly rightward lateralization in the putamen and lobule VII of cerebellar hemisphere. ADHD-C patients exhibited increased rightward lateralization in the inferior frontal gyrus (opercular), and decreased rightward lateralization in the inferior temporal gyrus, as compared with ADHD-IA. The LI was also found to be related to inattentive and hyper/impulsive scores. CONCLUSION: These key findings may aid in understanding the pathology of ADHD. PMID- 30520699 TI - In Vivo Evaluation of Customized Pulse Oximeter and Sensitivity Pulp Tests for Assessment Of Pulp Vitality. AB - OBJECTIVE: The purpose of this study was to test a customized pulse oximeter (CPO) for evaluation of pulp vitality in primary and permanent teeth against clinical diagnosis (vital and untreated non-vital) in order to expand its clinical use for pulp preservation. STUDY DESIGN: CPO was evaluated on intact primary and permanent central or lateral incisor (CI, LI) teeth- vital (group 1, 20n each); untreated non-vital (group 2, 10n each) and; root filled non-vital (group 3, 10n each) of children 4-12 years according to inclusion/exclusion criteria. For each patient CPO was first applied on finger followed by vitality tests in following sequence-electrical, pulse oximetry and thermal tests. RESULTS: Mean oxygen saturation (%SpO2) in permanent and primary-vital teeth was 88.78% & 87.77% respectively; non-vital teeth was 74.67% & 75.00% respectively; and in all root filled teeth was 0%. Tooth and finger oxygen saturation values showed strong positive relationship in vital primary or permanent teeth and; no correlation in untreated non-vital primary or permanent teeth. The accuracy rate of thermal pulp test and pulse oximetry was 100% and for electrical pulp test it was 90% for permanent and 86.67% for primary teeth. CONCLUSION: The CPO tested in this study proved to be a valuable adjunct for diagnosing pulp vitality by objective means. PMID- 30520700 TI - A Survey of Pediatric Dentists on the Treatment Timing and Modalities for White Spot Lesions in the United States. AB - PURPOSE: The purpose of this study was to estimate the prevalence of white spot lesions (WSLs) in various practice settings and patient populations, and to gather information about the treatment timing and modalities used by pediatric dentists in the United States. STUDY DESIGN: A fourteen question, multiple choice, electronic survey was developed and distributed to 6,092 active American Academy of Pediatric Dentistry (AAPD) members. RESULTS: A total of 625 active members responded, garnering a 9.7% response rate. Before treatment, there were significantly more WSLs reported in Corporate practice than Multi-Doctor Practice (P=0.002), and significantly more WSLs in Academics/Hospital-Based Practices than in Multi-Doctor Practices (P=0.002). For WSLs after treatment, there were significantly more WSLs in Academic/Hospital-Based practices than in single practitioner settings (P=0.003). Approximately 38% of pediatric dentists preferred to treat WSLs before, during or after orthodontic treatment, while 23% treat only before and 20% treat only after treatment. The three most common treatment modalities for WSLs, were prescription fluoride toothpaste (5000 ppm), fluoride varnish, and fluoride rinse. Approximately 47% of respondents reported they were "very comfortable" treating WSLs and 31.0% felt "comfortable." CONCLUSIONS: The prevalence of WSLs differed across types of practice. There is no agreement among pediatric dentist as to timing and treatment modalities for WSLs. PMID- 30520701 TI - Are Increased Masticatory Forces Risk for Primary 2nd Molars without Successors? A 3D FEA Study. AB - OBJECTIVE: Persistent primary teeth with healthy crown-root structures and acceptable functional and esthetic properties may be preserved over a long-term period if needed. However, they may experience root resorption, ankylosis or infraocclusion especially in the second or third decades of life. Despite a lack of sufficient detailed data, increases in occlusal forces by age are known to cause destructive stresses on root surfaces and periodontal tissue. The aim of this study was to evaluate the effect of increasing occlusal forces on mandibular persistent primary molars by using 3D finite element analysis. STUDY DESIGN: The impact of increased masticatory forces on compressive and tensile stresses in tooth and surrounding tissue was simulated in two different models (simulating child and adult mouths) by using 3D finite element analysis. RESULTS: In both models, the stress values increased by age and compressive stresses were seen on internal root surfaces, while the tensile stresses focused on the furcation area and external root surfaces. CONCLUSION: It was concluded that practices such as reducing occlusal surface width may be used to diminish the occlusal forces for long-term tooth survival in persistent primary molars. PMID- 30520702 TI - The reliability of evaluating conversations between people with traumatic brain injury and their communication partners via videoconferencing. AB - There is growing interest in using telehealth to work with people with traumatic brain injury (TBI). This study investigated whether established rating scales for evaluating conversations of people with TBI are reliable for use over videoconferencing. Nineteen participants with TBI and their communication partners completed two conversation samples during both in-person (IP) and videoconferencing-based (VC) assessment, with randomised order of assessment. Independent clinicians evaluated the conversations using the Adapted Measure of Participation in Conversation (MPC), the Adapted Measure of Support in Conversation (MSC) and the Global Impression scales. Comparisons between IP and VC ratings identified no significant differences on the MPC, MSC, and four out of five of the Global Impression scales. There was a significant difference between IP and VC recordings for "Task Completion" (p = .047), with participants performing significantly better in VC ratings. Inter-rater reliability was fair to excellent for the MPC and Global Impression scales for both IP and VC recordings. For the MSC scale, inter-rater reliability was poor to excellent. This study confirms the potential for using videoconferencing for evaluating conversations of people with TBI. Further development of training and rating procedures for these scales could facilitate more frequent and reliable use of these measures. PMID- 30520703 TI - Regulating Osteogenic Differentiation by Suppression of Exosomal microRNAs. AB - Exosomes are membranous nanovesicles that naturally transport bio-molecules, including miRNAs, and play critical roles in intercellular communication. We found that the growth condition milieu of pre-osteoblast exosomes contains a high level of the let-7 miRNAs. After blocking exosome secretion, we found that osteogenic differentiation of pre-osteoblasts (MC3T3-E1 cells) decreased significantly whereas addition of exosomes from growth condition recovered osteogenic ability. The expression levels of osteogenic markers in MC3T3-E1 cells were changed through the ectopic expression of the let-7 mimics or inhibitors. These findings suggest that this occurred due to the let-7 in the exosomes. Furthermore, exosomes whose let-7 was inactivated by inhibitors via electroporation efficiently lost their osteogenic differentiation capacity. Genetically modified exosomes may thus serve as highly effective biomaterials for developmental control, including osteogenesis regulation. PMID- 30520704 TI - Effects of High- and Low-LET Radiation on Human Hematopoietic System Reconstituted in Immunodeficient Mice. AB - Over the last 50 years, a number of important physiological changes in humans who have traveled on spaceflights have been catalogued. Of major concern are the short- and long-term radiation-induced injuries to the hematopoietic system that may be induced by high-energy galactic cosmic rays encountered on interplanetary space missions. To collect data on the effects of space radiation on the human hematopoietic system in vivo, we used a humanized mouse model. In this study, we irradiated humanized mice with 0.4 Gy of 350 MeV/n 28Si ions, a dose that has been shown to induce tumors in tumor-prone mice and a reference dose that has a relative biological effectiveness of 1 (1 Gy of 250-kVp X rays). Cell counts, cell subset frequency and cytogenetic data were collected from bone marrow spleen and blood of irradiated and control mice at short-term (7, 30 and 60 days) and long-term (6-7 months) time points postirradiation. The data show a significant short-term effect on the human hematopoietic stem cell counts imparted by both high- and low-LET radiation exposure. The radiation effects on bone marrow, spleen and blood human cell counts and human cell subset frequency were complex but did not alter the functions of the hematopoietic system. The long-term data acquired from high-LET irradiated mice showed complete recovery of the human hematopoietic system in all hematopoietic compartments. The combined results demonstrate that, in spite of early perturbation, the longer term effects of high LET radiation are not detrimental to human hematopoiesis in our system of study. PMID- 30520705 TI - Engineered Heart Slice Model of Arrhythmogenic Cardiomyopathy using Plakophilin-2 Mutant Myocytes. AB - Arrhythmogenic cardiomyopathy (AC), a cause of sudden cardiac death among young and otherwise healthy individuals, is a heritable disease that can be modeled in vitro using patient-specific cardiac myocytes (CMs) from induced pluripotent stem cells. An understanding of underlying disease mechanisms, particularly in the early concealed stages, could lead to new diagnosis and treatment strategies. However, multicellular syncytial models are needed to understand how genetically encoded mutations of the desmosomes that interconnect cells lead to aberrant electrical conduction and arrhythmias. Here, engineered heart slices (EHS) were created by seeding human induced pluripotent stem cell-derived CMs from an AC patient with a plakophilin-2 (PKP2) mutation onto intact slices of decellularized myocardium and then compared to age-matched AC CMs cultured as monolayers. After 2 weeks of culture, EHS developed into a confluent, multilayered syncytia that exhibited spontaneous, coordinated beating and could be electrically paced at cycle lengths ranging from 2000ms to 500ms. AC CMs cultured as EHS displayed highly aligned, dense, and ordered sarcomeric structures, with gene expression analyses revealing increased maturation. Additionally, AC-relevant genes were affected by CM culture in EHS, with a substantial increase in PPARG and a decrease in SCN5A when compared to monolayers. Functionally, AC EHS exhibited similar conduction velocities, shorter action potentials, and a slower and steadier spontaneous beat rate compared with monolayers. Reentrant arrhythmias could also be induced in AC EHS by S1-S2 pacing. Our findings suggest that the EHS microenvironment enhances the phenotype of AC CMs in culture while allowing for functional studies of an appropriately aligned syncytium of AC-CMs. Results reported here demonstrate the benefits of studying AC using EHS, a tissue construct that allows syncytial culture and the incorporation of matrix cues. PMID- 30520706 TI - Diminished Risk-Aversion After Right DLPFC Stimulation: Effects of rTMS on a Risky Ball Throwing Task. AB - OBJECTIVES: Several studies on human risk taking and risk aversion have reported the involvement of the dorsolateral prefrontal cortex (DLPFC). Yet, current knowledge of the neural mechanisms of risk-related decision making is not conclusive, mainly relying on studies using non-motor tasks. Here we examine how modulation of DLPFC activity by repetitive transcranial magnetic stimulation (rTMS) affects risk-taking behavior during a motor response task. METHODS: One Hertz rTMS to the right DLPFC was applied to monitor risk-taking and risk aversion performance during a goal-directed risky task with motor response. Healthy participants were instructed to aim for a high score by throwing a ball as close to the ceiling as possible, while avoiding touching the ceiling with the ball. RESULTS: One-Hertz rTMS stimulation to the right DLPFC significantly increased the frequency of ceiling hits, compared to Sham-stimulation. CONCLUSIONS: Our results suggest that the right DLPFC is a valid target for manipulating risky behavior in tasks with a motor-response. Following rTMS stimulation participants' preference shifts toward immediate awards, while becoming significantly less sensitive to potential negative consequences. The results confirm that the right DLPFC is involved in impulse control in goal directed executive tasks. (JINS, 2018, 00, 1-7). PMID- 30520707 TI - Transient Q-waves in an infant with asymptomatic myocardial infarction due to Kawasaki disease. AB - Giant coronary artery aneurysms are a complication of Kawasaki disease and can be fatal if associated with thrombosis. We describe the clinical outcome of a boy with Kawasaki disease who exhibited "supergiant" coronary artery aneurysms at the age of 14 months and, despite treatment with anticoagulant and antiplatelet medication, developed a left coronary artery thrombosis and presented following a myocardial infarction at 2 years old. Although his symptoms were minimal, the myocardial infarction was identified by abnormal Q-waves and giant negative T waves in precordial leads of routine electrocardiography. Intensive anticoagulant therapy combining heparin injections and high-dose warfarin was successful. The abnormal Q-waves and negative T-waves had completely disappeared 2 weeks later, likely in association with confirmed reperfusion. On the basis of prompt identification of abnormal Q-waves by electrocardiography, the patient could avoid thrombolytic therapy and catheter or surgical intervention. PMID- 30520708 TI - Human factors-based risk analysis to improve the safety of doffing enhanced personal protective equipment. AB - OBJECTIVE: To systematically assess enhanced personal protective equipment (PPE) doffing safety risks. DESIGN: We employed a 3-part approach to this study: (1) hierarchical task analysis (HTA) of the PPE doffing process; (2) human factors informed failure modes and effects analysis (FMEA); and (3) focus group sessions with a convenience sample of infection prevention (IP) subject matter experts. SETTING: A large academic US hospital with a regional Special Pathogens Treatment Center and enhanced PPE doffing protocol experience.ParticipantsEight IP experts. METHODS: The HTA was conducted jointly by 2 human-factors experts based on the Centers for Disease Control and Prevention PPE guidelines. The findings were used as a guide in 7 focus group sessions with IP experts to assess PPE doffing safety risks. For each HTA task step, IP experts identified failure mode(s), assigned priority risk scores, identified contributing factors and potential consequences, and identified potential risk mitigation strategies. Data were recorded in a tabular format during the sessions. RESULTS: Of 103 identified failure modes, the highest priority scores were associated with team members moving between clean and contaminated areas, glove removal, apron removal, and self-inspection while preparing to doff. Contributing factors related to the individual (eg, technical/ teamwork competency), task (eg, undetected PPE contamination), tools/technology (eg, PPE design characteristics), environment (eg, inadequate space), and organizational aspects (eg, training) were identified. Participants identified 86 types of risk mitigation strategies targeting the failure modes. CONCLUSIONS: Despite detailed guidelines, our study revealed 103 enhanced PPE doffing failure modes. Analysis of the failure modes suggests potential mitigation strategies to decrease self-contamination risk during enhanced PPE doffing. PMID- 30520710 TI - Desikacharya gen. nov., a phylogenetically distinct genus of Cyanobacteria along with the description of two new species, Desikacharya nostocoides sp. nov. and Desikacharya soli sp. nov., and reclassification of Nostoc thermotolerans to Desikacharya thermotolerans comb. nov. AB - Two Nostoc-like strains have been isolated, purified, cultured and identified on the basis of the polyphasic approach using morphological, ecological, molecular and phylogenetic methods. Both strains were found to have morphology similar to the genus Nostoc, but clustered strongly in a group distant from the Nostocsensu stricto clade. Further analysis, using the folded structures of the 16S-23S ITS region revealed strong differences from closely related members of the genus Nostoc. Distinct phylogenetic clustering and strong tree topologies using Bayesian inference, maximum-likelihood and maximum-parsimony methods indicated the need to revisit the taxonomy of the members of this particular clade with a clear need for giving a generic status distinct from the genus Nostoc. In accordance with the International Code of Nomenclature for Algae, Fungi and Plants, the name Desikacharya gen. nov. is proposed for the new genus along with the description of two new species, Desikacharya nostocoides sp. nov. and Desikacharya soli sp. nov., and reclassification of Nostoc thermotolerans to Desikacharya thermotolerans comb. nov. PMID- 30520711 TI - Social behaviour and making attachments: a report from the fifth 'Young Microbiologists Symposium on Microbe Signalling, Organisation and Pathogenesis'. AB - The fifth Young Microbiologists Symposium was held in Queen's University Belfast, Northern Ireland, in late August 2018. The symposium, focused on 'Microbe signalling, organization and pathogenesis', attracted 121 microbiologists from 15 countries. The meeting allowed junior scientists to present their work to a broad audience, and was supported by the European Molecular Biology Organization, the Federation of European Microbiological Societies, the Society of Applied Microbiology, the Biochemical Society and the Microbiology Society. Sessions covered recent advances in areas of microbiology including gene regulation and signalling, secretion and transport across membranes, infection and immunity, and antibiotics and resistance mechanisms. In this Meeting Report, we highlight some of the most significant advances and exciting developments communicated during talks and poster presentations. PMID- 30520709 TI - Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. AB - BACKGROUND: Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi therapy-resistant bipolar depression (MTRBD).AimsTo reach consensus regarding threshold definitions criteria for TRBD and MTRBD. METHOD: Based on the evidence of standard treatments available in the latest bipolar disorder treatment guidelines, TRBD and MTRBD criteria were agreed by a representative panel of bipolar disorder experts using a modified Delphi method. RESULTS: TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy. CONCLUSIONS: The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.Declaration of interestIn the past 3 years, M.B. has received grant/research support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Meat and Livestock Board, Organon, Novartis, Mayne Pharma, Servier, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Eli Lilly, Grunbiotics, Glaxo SmithKline, Janssen Cilag, LivaNova, Lundbeck, Merck, Mylan, Otsuka, Pfizer and Servier. A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. A.J.C. has in the past 3 years received honoraria for speaking from Astra Zeneca and Lundbeck, honoraria for consulting from Allergan, Janssen, Lundbeck and LivaNova and research grant support from Lundbeck. G.M.G. holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, MSD, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire and Sun Pharma. J.G. has received research funding from National Institute for Health Research, Medical Research Council, Stanley Medical Research Institute and Wellcome. H.G. received grants/research support, consulting fees or honoraria from Gedeon Richter, Genericon, Janssen Cilag, Lundbeck, Otsuka, Pfizer and Servier. R.H.M.-W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. R.M. has received research support from Big White Wall, Electromedical Products, Johnson and Johnson, Magstim and P1Vital. S.N. received honoraria from Lundbeck, Jensen and Otsuka. J.C.S. has received funds for research from Alkermes, Pfizer, Allergan, J&J, BMS and been a speaker or consultant for Astellas, Abbott, Sunovion, Sanofi. S.W has, within the past 3 years, attended advisory boards for Sunovion and LivaNova and has undertaken paid lectures for Lundbeck. D.J.S. has received honoraria from Lundbeck. T.S. has reported grants from Pathway Genomics, Stanley Medical Research Institute and Palo Alto Health Sciences; consulting fees from Sunovion Pharamaceuticals Inc.; honoraria from Medscape Education, Global Medical Education and CMEology; and royalties from Jones and Bartlett, UpToDate and Hogrefe Publishing. S.P. has served as a consultant or speaker for Janssen, and Sunovion. P.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. E.V. received grants/ research support, consulting fees or honoraria from Abbott, AB-Biotics, Allergan, Angelini, Dainippon Sumitomo, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka and Sunovion. L.N.Y. has received grants/research support, consulting fees or honoraria from Allergan, Alkermes, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Servier, Sunovion, Teva and Valeant. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has also previously received funding for investigator-initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth. P.R.A.S. has received research funding support from Corcept Therapeutics Inc. Corcept Therapeutics Inc fully funded attendance at their internal conference in California USA and all related expenses. He has received grant funding from the Medical Research Council UK for a collaborative study with Janssen Research and Development LLC. Janssen Research and Development LLC are providing non-financial contributions to support this study. P.R.A.S. has received a presentation fee from Indivior and an advisory board fee from LivaNova. PMID- 30520712 TI - How actively should we screen for chlamydia and gonorrhoea in MSM and other high ST-prevalence populations as we enter the era of increasingly untreatable infections? A viewpoint. AB - A number of national and international organizations are advocating more intensive screening for Chlamydia trachomatis and Neisseria gonorrhoeae in high prevalence populations as a way to reduce the prevalence of these infections. In this article, we review the available evidence and conclude that there is a paucity of evidence to support this approach. We further hypothesize that increasing screening intensity in high-prevalence populations will result in a considerable risk for the emergence of antimicrobial resistance in Neisseria gonorrhoeae and other pathobionts. PMID- 30520713 TI - Request for revision of the Statutes of the International Committee on Systematics of Prokaryotes. AB - At the Valencia Plenary meeting on 7-9 July, 2017, the Working Group on the organization and structure of the ICSP recommended amendment of the Statutes of the ICSP (Dijkshoorn L. Int J Syst Evol Microbiol 2018; 68: 2104-2110). In October 2017, our Executive-Secretary, Lenie Dijkshoorn, sent out a call for participation in this working group, which began work in December, 2017. The members included William B. Whitman, Carolee Bull, Hans-Jurgen Busse, Pierre Edouard Fournier, Aharon Oren, and Stefano Ventura. During the Winter and Spring, 2018, a large number of revisions were discussed by the working group. In addition, comments were solicited from Dan Brown [Secretary for Subcommittees on Taxonomy], Iain Sutcliffe [Chair ICSP], Fanus Venter [Member at Large, EB-ICSP], and Martha Trujillo [Editor-in-Chief of IJSEM]. The draft Statutes were then presented to the Executive Board [EB] at its online meeting on May 31, 2018. The EB asked that the working group circulate the draft to the members of the ICSP for comments for 45 days and that comments be returned by July 27, 2018. After that time, the working group incorporated additional suggestions before the final submission to IJSEM for publication. According to our current statutes, there will then be a period of 90 days following publication for further deliberation before a vote by the ICSP members. PMID- 30520714 TI - Temperature-sensitive origin-binding protein as a tool for investigations of herpes simplex virus activities in vivo. AB - While it is fairly clear that herpes simplex virus (HSV) DNA replication requires at least seven virus-encoded proteins in concert with various host cell factors, the mode of this process in infected cells is still poorly understood. Using HSV 1 mutants bearing temperature-sensitive (ts) lesions in the UL9 gene, we previously found that the origin-binding protein (OBP), a product of the UL9 gene, is only needed in the first 6 hours post-infection. As this finding was just a simple support for the hypothesis of a biphasic replication mode, we became convinced through these earlier studies that the mutants tsR and tsS might represent suitable tools for more accurate investigations in vivo. However, prior to engaging in highly sophisticated research projects, knowledge of the biochemical features of the mutated versions of OBP appeared to be essential. The results of our present study demonstrate that (i) tsR is most appropriate for cell biological studies, where only immediate early and early HSV gene products are being expressed without the concomital viral DNA replication, and (ii) tsS is a prime candidate for the analysis of HSV DNA replication processes because of its reversibly thermosensitive OBP-ATPase, which allows one to switch on the initiation of DNA synthesis precisely. PMID- 30520715 TI - Prevalence of macrolide resistance in Treponema pallidum is associated with macrolide consumption. AB - We hypothesized that the large global variations in the prevalence of macrolide resistance in Treponema pallidum are related to differences in population-level macrolide consumption. The hypothesis was tested by, at a country-level, regressing the peak prevalence of macrolide resistance against the national macrolide consumption in the year prior to this, controlling for the year of the resistance prevalence estimate. A strong association was found between the per capita consumption of macrolides and macrolide resistance (coefficient 0.7, 95 % confidence interval 0.2-0.12, P=0.009). PMID- 30520716 TI - ? PMID- 30520717 TI - [Individualised treatment of patients with bronchoectasis]. AB - Bronchiectasis is characterised by chronic cough, airway inflammation, infection and bronchial dilatation. The disease may lead to impaired lung function and premature death. An underlying inflammatory disease or immunodeficiency may be present, but 40% of the cases are idiopathic. The diagnosis is based on high resolution CT scan. Treatment is aimed at reducing symptoms and risk of exacerbations, and includes antibiotics, bronchodilators and pulmonary rehabilitation. Assessment of disease severity and individual phenotypes may help to modify treatment strategies in the future. PMID- 30520718 TI - [Indications for orogastric emptying in poisonings are rarely present]. AB - Orogastric aspiration (OA) without orogastric lavage has been the traditional gastric emptying method of choice in Denmark; this being based on national historic studies on poisoned patients. The treatment is still observed to be initiated prior to consultations with the Danish poisons information centre. In this review, we present relevant knowledge in the field of OA. The procedure should only be considered in very limited cases and never routinely. Also, an algorithm is presented for its rare use in relation to other more effective gastrointestinal decontamination methods. PMID- 30520719 TI - [Phytoestrogens as a dietary supplement]. AB - Phytoestrogens (PE) are widely used as a dietary supplement. PE affect oestrogen receptors. PE have been investigated regarding menopausal hot flushes, bone mineral density and prostate hyperplasia/cancer. It seems consistent, that PE increase bone mineral density, whereas the effect on hot flushes is controversial. Due to the effect on oestrogen receptors, concerns exist on the risk of cancer and venous thromboembolism related to the intake of PE. To date, no studies with PE have been large enough to clarify their safety. Widespread use of PE should therefore be discouraged. PMID- 30520720 TI - [Traumatic rectal lesions]. AB - Traumatic rectal lesions can be seen in both blunt and penetrating traumas and are associated with a high morbidity and high mortality. This is a review of the literature on diagnosis and treatment of intra- and extraperitoneal rectal lesions. There is a consensus, that intraperitoneal rectal lesions should be treated with primary repair alone. There is more debate concerning the extraperitoneal lesions, and the level of evidence is generally low. We suggest, that extraperitoneal rectal lesions should be treated with colostomy. PMID- 30520721 TI - [Antibodies in patients with chronic inflammatory demyelinating polyneuropathy]. AB - Recent studies have identified specific immunoglobulin (Ig) G4 antibodies against the paranodal proteins neurofascin 155 and contactin 1 in subgroups of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These patients present with distinct clinical phenotypes and poor response to first-line therapy with intravenous Ig. Detection of these antibodies in patients with CIDP has diagnostic, prognostic, and therapeutic implications. This review summarises the current knowledge on clinical characteristics, pathogenesis and treatment of these patients. PMID- 30520722 TI - [Acromegaly]. AB - Acromegaly is a rare and disabling disease with a plethora of symptoms and signs attributed to sustained elevations and actions of growth hormone and insulin-like growth factor 1. Acromegaly is characterised by excessive somatic growth and multiple comorbidities in addition to occasional compression of the optic nerve and hypopituitarism due to the underlying adenoma. The course of the disease is insidious, and a diagnostic delay of 5-10 years is typical, and this pre diagnostic period is also associated with increased morbidity. Effective treatment is available, once the diagnosis is established. PMID- 30520723 TI - Sputum induction for assessment of biomarkers in early respiratory drug development?. AB - OBJECTIVE: To study the success rate and reproducibility of sputum induction (SI) in healthy subjects (HS) and asthma patients (AP). MATERIALS AND METHODS: 130 HSs/APs were recruited for early-phase studies to evaluate sputum biomarkers. SI and sample processing were performed according to standard protocols. RESULTS: Adequate samples were obtained from 46% of HSs and 80% of APs. There was no difference between the groups with adequate and nonadequate samples. Differences between HS and AP groups were minor. Reproducibility was 56.0% in HSs and 90.6% in APs. CONCLUSION: Sputum induction for biomarker assessment in early drug development is feasible in HSs and APs, but only modestly reproducible in HSs. The technique is complex and time consuming.?. PMID- 30520724 TI - General decapping activators target different subsets of inefficiently translated mRNAs. AB - The Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deleting PAT1, LSM1, or DHH1, or the DCP2 C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and Dhh1 exhibit only partial overlap, are generally translated inefficiently, and, as expected, are targeted to decapping-dependent decay. Our results define the roles of Pat1, Lsm1, and Dhh1 in decapping of general mRNAs and suggest that these factors may monitor mRNA translation and target unique features of individual mRNAs. PMID- 30520725 TI - A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV. AB - : Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced HIV restriction factors, we assembled a CRISPR sgRNA library of Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. A small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain the inhibitory effects of IFN on the CXCR4-tropic HIV-1 strain, HIV-1LAI, in THP-1 cells. A second screen with a CCR5-tropic primary strain, HIV-1Q23.BG505, described an overlapping, but non-identical, panel of restriction factors. Further, this screen also identifies HIV dependency factors. The ability of IFN-induced restriction factors to inhibit HIV strains to replicate in human cells suggests that these human restriction factors are incompletely antagonized. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30520726 TI - Stem cells repurpose proliferation to contain a breach in their niche barrier. AB - Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity. PMID- 30520727 TI - Drought adaptation in Arabidopsis thaliana by extensive genetic loss-of-function. AB - Interdisciplinary syntheses are needed to scale up discovery of the environmental drivers and molecular basis of adaptation in nature. Here we integrated novel approaches using whole genome sequences, satellite remote sensing, and transgenic experiments to study natural loss-of-function alleles associated with drought histories in wild Arabidopsis thaliana. The genes we identified exhibit population genetic signatures of parallel molecular evolution, selection for loss of-function, and shared associations with flowering time phenotypes in directions consistent with longstanding adaptive hypotheses 7 times more often than expected by chance. We then confirmed predicted phenotypes experimentally in transgenic knockout lines. These findings reveal the importance of drought timing to explain the evolution of alternative drought tolerance strategies and further challenge popular assumptions about the adaptive value of genetic loss-of-function in nature. These results also motivate improved species-wide sequencing efforts to better identify loss-of-function variants and inspire new opportunities for engineering climate resilience in crops. PMID- 30520728 TI - The transcription factors TFE3 and TFEB amplify p53 dependent transcriptional programs in response to DNA damage. AB - The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress. PMID- 30520729 TI - Protein gradients on the nucleoid position the carbon-fixing organelles of cyanobacteria. AB - Carboxysomes are protein-based bacterial organelles encapsulating key enzymes of the Calvin-Benson-Bassham cycle. Previous work has implicated a ParA-like protein (hereafter McdA) as important for spatially organizing carboxysomes along the longitudinal axis of the model cyanobacterium Synechococcus elongatus PCC 7942. Yet, how self-organization of McdA emerges and contributes to carboxysome positioning is unknown. Here, we identify a small protein, termed McdB that localizes to carboxysomes and drives emergent oscillatory patterning of McdA on the nucleoid. Our results demonstrate that McdB directly stimulates McdA ATPase activity and its release from DNA, driving carboxysome-dependent depletion of McdA locally on the nucleoid and promoting directed motion of carboxysomes towards increased concentrations of McdA. We propose that McdA and McdB are a previously unknown class of self-organizing proteins that utilize a Brownian ratchet mechanism to position carboxysomes in cyanobacteria, rather than a cytoskeletal system. These results have broader implications for understanding spatial organization of protein mega-complexes and organelles in bacteria. PMID- 30520730 TI - Auxiliary subunits keep AMPA receptors compact during activation and desensitization. AB - Signal transduction at vertebrate excitatory synapses involves the rapid activation of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors, glutamate-gated ion channels whose four subunits assemble as a dimer-of-dimers. Technical advances in cryo-electron microscopy brought a slew of full-length structures of AMPA receptors, on their own and in combination with auxiliary subunits. These structures indicate that dimers might undergo substantial lateral motions during gating, opening up the extracellular layer along the central 2 fold symmetry axis. We used bifunctional methanethiosulfonate cross-linkers to calibrate the conformations found in functional AMPA receptors in the presence and absence of the auxiliary subunit Stargazin. Our data indicate that extracellular layer of AMPA receptors can get trapped in stable, opened-up conformations, especially upon long exposures to glutamate. In contrast, Stargazin limits this conformational flexibility. Thus, under synaptic conditions, where brief glutamate exposures and the presence of auxiliary proteins dominate, extracellular domains of AMPA receptors likely stay compact during gating. PMID- 30520731 TI - A secretory pathway kinase regulates sarcoplasmic reticulum Ca2+ homeostasis and protects against heart failure. AB - Ca2+ signaling is important for many cellular and physiological processes, including cardiac function. Although sarcoplasmic reticulum (SR) proteins involved in Ca2+ signaling have been shown to be phosphorylated, the biochemical and physiological roles of protein phosphorylation within the lumen of the SR remain essentially uncharacterized. Our laboratory recently identified an atypical protein kinase, Fam20C, which is uniquely localized to the secretory pathway lumen. Here we show that Fam20C phosphorylates several SR proteins involved in Ca2+ signaling, including calsequestrin2 and Stim1, whose biochemical activities are dramatically regulated by Fam20C mediated phosphorylation. Notably, phosphorylation of Stim1 by Fam20C enhances Stim1 activation and store operated Ca2+ entry. Physiologically, mice with Fam20c ablated in cardiomyocytes develop heart failure following either aging or induced pressure overload. We extended these observations to show that non-muscle cells lacking Fam20C display altered ER Ca2+ signaling. Overall, we show that Fam20C plays an overarching role in ER/SR Ca2+ homeostasis and cardiac pathophysiology. PMID- 30520732 TI - Promoting subjective preferences in simple economic choices during nap. AB - Sleep is known to benefit consolidation of memories, especially those of motivational relevance. Yet it remains largely unknown the extent to which sleep influences reward-associated behavior, in particular, whether and how sleep modulates reward evaluation that critically underlies value-based decisions. Here, we show that neural processing during sleep can selectively bias preferences in simple economic choices when the sleeper is stimulated by covert, reward-associated cues. Specifically, presenting the spoken name of a familiar, valued snack item during midday nap significantly improves the preference for that item relative to items not externally cued. The cueing-specific preference enhancement is sleep-dependent and can be predicted by cue-induced neurophysiological signals at the subject and item level. Computational modeling further suggests that sleep cueing accelerates evidence accumulation for cued options during the post-sleep choice process in a manner consistent with the preference shift. These findings suggest that neurocognitive processing during sleep contributes to the fine-tuning of subjective preferences in a flexible, selective manner. PMID- 30520733 TI - Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists. AB - Pathways modulating glucose homeostasis independently of insulin would open new avenues to combat insulin resistance and diabetes. Here, we report the establishment, characterization and use of a vertebrate 'insulin-free' model to identify insulin-independent modulators of glucose metabolism. insulin knockout zebrafish recapitulate core characteristics of diabetes and survive only up to larval stages. Utilizing a highly efficient endoderm transplant technique, we generated viable chimeric adults that provide the large numbers of insulin mutant larvae required for our screening platform. Using glucose as a disease-relevant readout, we screened 2233 molecules and identified 3 that consistently reduced glucose levels in insulin mutants. Most significantly, we uncovered an insulin independent beneficial role for androgen receptor antagonism in hyperglycemia, mostly by reducing fasting glucose levels. Our study proposes therapeutic roles for androgen signaling in diabetes and, more broadly, offers a novel in vivo model for rapid screening and decoupling of insulin-dependent and -independent mechanisms. PMID- 30520734 TI - Control of neural crest multipotency by Wnt signaling and the Lin28/let-7 axis. AB - A crucial step in cell differentiation is the silencing of developmental programs underlying multipotency. While much is known about how lineage-specific genes are activated to generate distinct cell types, the mechanisms driving suppression of stemness are far less understood. To address this, we examined the regulation of the transcriptional network that maintains progenitor identity in avian neural crest cells. Our results show that a regulatory circuit formed by Wnt, Lin28a and let-7 miRNAs controls the deployment and the subsequent silencing of the multipotency program in a position-dependent manner. Transition from multipotency to differentiation is determined by the topological relationship between the migratory cells and the dorsal neural tube, which acts as a Wnt-producing stem cell niche. Our findings highlight a mechanism that rapidly silences complex regulatory programs, and elucidate how transcriptional networks respond to positional information during cell differentiation. PMID- 30520735 TI - DNA translocation mechanism of an XPD family helicase. AB - The XPD family of helicases, that includes human disease-related FANCJ, DDX11 and RTEL1, are Superfamily 2 helicases that contain an iron-sulphur cluster domain, translocate on ssDNA in a 5'-3' direction and play important roles in genome stability. Consequently, mutations in several of these family members in eukaryotes cause human diseases. Family members in bacteria, such as the DinG helicase from Escherichia coli, are also involved in DNA repair. Here we present crystal structures of complexes of DinG bound to single-stranded DNA (ssDNA) in the presence and absence of an ATP analogue (ADP*BeF3), that suggest a mechanism for 5'-3' translocation along the ssDNA substrate. This proposed mechanism has implications for how those enzymes of the XPD family that recognise bulky DNA lesionsmight stall at these as the first step in initiating DNA repair. Biochemical data reveal roles for conserved residues that are mutated in human diseases. PMID- 30520736 TI - Bayesian analysis of retinotopic maps. AB - Human visual cortex is organized into multiple retinotopic maps. Characterizing the arrangement of these maps on the cortical surface is essential to many visual neuroscience studies. Typically, maps are obtained by voxel-wise analysis of fMRI data. This method, while useful, maps only a portion of the visual field and is limited by measurement noise and subjective assessment of boundaries. We developed a novel Bayesian mapping approach which combines observation-a subject's retinotopic measurements from small amounts of fMRI time-with a prior-a learned retinotopic atlas. This process automatically draws areal boundaries, corrects discontinuities in the measured maps, and predicts validation data more accurately than an atlas alone or independent datasets alone. This new method can be used to improve the accuracy of retinotopic mapping, to analyze large fMRI datasets automatically, and to quantify differences in map properties as a function of health, development and natural variation between individuals. PMID- 30520737 TI - Managing Acinetobacter baumannii infections. AB - PURPOSE OF REVIEW: We reviewed recent data about epidemiology of Acinetobacter baumannii, resistance mechanisms, and therapeutic options for severe infections caused by multidrug-resistant strains. RECENT FINDINGS: A. baumannii is a major cause of nosocomial infections affecting mainly to debilitating patients in the ICU, although the spread to regular wards and to long-term care facilities is increasing. It is characterized by its great persistence in the environment and to have an extraordinary capability to develop resistance to all antimicrobials.Carbapenems may not be considered the treatment of choice in areas with high rates of carbapenem-resistant A. baumannii. Nowadays, polymyxins are the antimicrobials with the greatest level of in-vitro activity against A. baumannii. Colistin is the most widely used in clinical practice although polymyxin B seems to be associated with less renal toxicity. Colistin is administered intravenously as its inactive prodrug colistimethate. A loading dose of 9 million IU and subsequently high, extended-interval maintenance doses (4.5 million IU/12 h) are recommended. Combination therapy instead of monotherapy increases the rates of microbiological eradication although no clinical study has demonstrated a reduction in clinical outcomes (mortality or length of stay). SUMMARY: The optimal treatment for multidrug-resistant A. baumannii nosocomial infections has not been established. There are no compelling data to recommend combination therapy for severe A. baumannii infections. PMID- 30520738 TI - Left Atrial Appendage Occlusion in the Management of Stroke in Patients With Atrial Fibrillation. AB - Atrial fibrillation (AF) is associated with a substantially higher risk of thromboembolism, particularly stroke events, resulting in significant morbidity and mortality. Oral anticoagulation (OAC), while effective in reducing embolic events in AF patients, is associated with an increased bleeding risk. Thus, not all patients with AF are candidates for OAC and some are only candidates for OAC in the short term. Of the available non-pharmacologic strategies for the management of AF, left atrial appendage occlusion (LAAO) has emerged as a potential approach for reducing the risk of systemic thromboembolism in AF patients eligible for OAC. LAAO can be achieved either surgically or percutaneously utilizing an epicardial, endocardial, or a combined approach. Although available data are limited, currently available LAAO devices, and those being developed, have shown promise in reducing bleeding risk in AF patients due to the reduced overall need for anticoagulation, while maintaining efficacy in preventing thromboembolism. The optimal device will reduce both embolic and hemorrhagic strokes, and other bleeds, with a high implant success rate and a low complication rate. Until that time, anticoagulation remains the gold standard that these devices strive to surpass, and thus LAAO devices are currently indicated in patients with relative contraindication to OAC therapy. PMID- 30520739 TI - Modifiable risk factors for young onset dementia. AB - PURPOSE OF REVIEW: Although young onset dementia (YOD) causes high levels of burden and distress, factors that contribute to its onset are not well understood. Identifying relevant modifiable risk and protective factors for YOD can inform efforts to prevent or delay onset of symptoms to later in life. RECENT FINDINGS: Studies of modifiable factors for YOD have increased in frequency in recent years. Poor educational attainment and low socioeconomic status, a history of heavy alcohol use, and poor cardiovascular health may be key targets for YOD prevention or delay. Traumatic brain injury has attracted significant attention but evidence of its importance is limited except in cases occurring secondarily to the injury. SUMMARY: A growing body of evidence suggests that modifiable risk factors have a role in modulating the age of dementia onset. Clinicians should be aware that many people with YOD will present with complex histories of multifactorial (including modifiable and nonmodifiable) risk exposure. Exploring trajectories of risk and gene-environment interactions is an important future research direction and will inform targeted prevention efforts. PMID- 30520740 TI - Psychosis in neurodegenerative disorders: recent developments. AB - PURPOSE OF REVIEW: This review presents the latest developments covered in the literature regarding psychosis in neurodegenerative disorders and discusses possible future research directions. RECENT FINDINGS: Recent findings in the field of psychosis and neurodegenerative disorders revolve around four main themes. The first theme is the impact of sex on the expression of psychosis in neurodegenerative disorders. The second theme focuses on the relationship between psychosis and neurodegenerative disease biomarkers. The third concerns how psychotic symptoms in neurodegenerative disorders may share common mechanisms with other primary psychotic disorders such as schizophrenia. Finally, there have been some promising developments in the area of therapeutics to treat dementia related psychosis involving both established and novel treatments. SUMMARY: New findings in the field of neurodegeneration and psychosis parallel new directions in the field of neurodegeneration in general. More specifically, we have seen a shift in focus to issues highlighting the role of sex, biomarkers, translation to other disorders, and therapeutics. PMID- 30520741 TI - Pain therapy for the elderly patient: is opioid-free an option? AB - PURPOSE OF REVIEW: Chronic noncancer pain is an increasing problem in elderly because of rising life expectancy together with an increase of potentially painful medical conditions. Concomitantly, adequate treatment of elderly is often limited by coexisting diseases and polypharmacy.This review summarizes the most important specifics presented by elderly patients and discusses the pharmacological and nonpharmacological options of pain management. RECENT FINDINGS: A comprehensive pain assessment is a prerequisite for effective pain management. However, this can be a major challenge in patients who are unable to communicate adequately, that is, in patients with dementia. A recently developed electronic tool assessing automated facial expression and clinical behavioral indicators may help to solve this problem. The discussion about benefits and harms of opioids in elderly goes on. Although some authors underline the lack of efficacy together with the potential problems, such as, abuse, others report a beneficial effect in terms of pain relief, functional activities and disability. In addition, opioids have become an important treatment option in patients with restless legs syndrome. Various topical treatment options (i.e. capsaicin patch) and nonpharmacological interventions have been proven to be beneficial in elderly. SUMMARY: Adequate pain management of elderly patients constitutes numerous pharmacological options including nonopioids, opioids, coanalgesics and topical agents. Due to age-related characteristics, all systemic analgesics have to be given very cautiously ('start low, go slow'). Whenever possible, treatment should be performed as a multimodal approach based on the biopsychosocial model of chronic pain. PMID- 30520742 TI - Low Bladder Compliance in Women: A Clinical Overview. AB - Bladder compliance refers to the ability of the bladder to accommodate large volumes of urine. Patients with low bladder compliance may present with persistent urinary incontinence and/or evidence of upper tract damage. Clinicians often may not consider low bladder compliance in their differential for patients complaining of bothersome lower urinary tract symptoms. In this article, we aim to provide further guidance in the management of women with low bladder compliance given the lack of information on this topic in the medical literature. PMID- 30520743 TI - Biomarkers for chronic obstructive pulmonary disease diagnosis and progression: insights, disappointments and promise. AB - PURPOSE OF REVIEW: This article reviews the status of biomarkers useful in the diagnosis and progression of chronic obstructive pulmonary disease (COPD). Biomarkers have been the focus of a great deal of COPD-related research in recent years, although useful markers in these specific arenas remain elusive. RECENT FINDINGS: No biomarker other than lung function has been shown to be useful, to date, for the diagnosis of COPD. The best blood-based biomarkers for the progression of COPD may involve combinations of individual markers, such as CC16, fibrinogen and sRAGE. New imaging metrics, such as central airway collapse, pulmonary vascular changes and central airway branch variation, may be able to provide valuable prognostic and information, although these remain confined to research applications. SUMMARY: Blood-based biomarkers for diagnosing and determining the progression of COPD remain disappointingly elusive. Although there have been some advances in nonblood-based markers, such as those from imaging, exhaled breath or physiologic assessment, these remain limited, for the most part, to research applications. Moving toward better markers that could be used in clinical application in the screening and diagnosis of COPD that could also provide prognostic information remains an important goal of research. PMID- 30520744 TI - Everything in its right place: resident memory CD8+ T cell immunosurveillance of HIV infection. AB - PURPOSE OF REVIEW: To introduce emerging concepts in tissue resident CD8 T cell immunosurveillance and their relevance to control HIV infection. RECENT FINDINGS: It is well appreciated that HIV preferentially infects and persists in CD4 T cells located in gut and in lymphoid tissue, yet the majority of known immunological correlates of HIV control are derived from peripheral blood. Instead, tissue-based immunological surveillance likely dictates the course of infection. Recent studies have established that nonrecirculating resident memory CD4 and CD8 T cells can be found in virtually every human tissue. These cells bear a transcriptional profile of tissue retention and immediate effector function, suggesting a pivotal role in protective immunity. Resident memory CD8 T cells specific for HIV have been found in higher numbers in sites of HIV persistence (gut and lymph nodes), and are inversely associated with HIV viral titers. These findings, along with previous studies on tissue-derived cells now known to include resident memory cells, shed new light on the compartmentalization of the immune response against HIV and its correlates of protection. SUMMARY: Resident memory CD8 T cells represent a critical unexplored component of immune surveillance in the setting of HIV infection. Understanding the induction, dynamics, and functional properties of HIV-specific resident memory T cells in relevant tissues will better inform efforts in the treatment, control, and potential cure of HIV infection. PMID- 30520745 TI - Scaling Perioperative Services Across Health Care Systems. PMID- 30520746 TI - Surgical Overlap: An Ethical Approach to Empirical Ambiguity. PMID- 30520747 TI - The Perioperative Surgical Home: High-reliability or Ultra-safe Organization? PMID- 30520748 TI - IT-driven Clinical Improvement Processes: The SkunkwORks. PMID- 30520749 TI - Value-based Health Care: Lessons for the Anesthesiologist. PMID- 30520750 TI - Nontechnical Skills in a Technical World. PMID- 30520751 TI - Physician Wellness and Practice Sustainability. PMID- 30520752 TI - Revisiting Mission-based Productivity. PMID- 30520753 TI - Anesthesia Quality Improvement on Both Sides of the Atlantic. PMID- 30520755 TI - Index. PMID- 30520754 TI - Lessons Learned: From a C-130 to the C-Suite in Health Care. PMID- 30520756 TI - Cyclin-dependent kinase 4/6 inhibitors: what have we learnt across studies, therapy situations and substances. AB - PURPOSE OF REVIEW: Cyclin-dependent kinases (CDK) are key regulatory enzymes that control cell cycle and cell division. In the recent years, new therapeutic options selectively targeting CDK 4 and 6 have shown promising clinical activity in several solid tumors. Since 2015, three CDK 4/6 inhibitors have been approved for treatment of hormone receptor-positive HER2-negative metastatic breast cancer: palbociclib, ribociclib and abemaciclib. These drugs share a common mechanism of action and have been evaluated in studies with a similar design. The following review gives a clinical overview of the CDK 4/6 inhibitors in breast cancer therapy and highlight current study data with regard to their antitumor efficacy and toxicities. RECENT FINDINGS: In clinical trials in the first-line and later-line setting, palbociclib, ribociclib and abemaciclib in combination with endocrine therapy significantly prolonged progression-free survival. The most common adverse events during treatment with CDK 4/6 inhibitors are neutropenia, fatigue and gastrointestinal symptoms. SUMMARY: CDK 4/6 inhibitors represent a valuable treatment option for patients with metastatic hormone receptor-positive HER2-negative breast cancer. Although the clinical efficacy of the three agents seems similar, their toxicity profiles differ. Therefore, the choice of a CKD 4/6 inhibitor depends on patient's characteristics and individual preferences. VIDEO ABSTRACT: In the video, the author describe the content of the review and present the main topics discussed in the article (http://links.lww.com/COOG/A44). PMID- 30520757 TI - Translational highlights in breast cancer research and treatment: recent developments with clinical impact. AB - PURPOSE OF REVIEW: Over the last decades the time which is needed to translate a preclinical finding or idea in the clinic has reduced continuously. Especially but not only for breast cancer the number of tested drugs and targeted pathways have increased immensely. In addition, the introduction of immune-oncological treatments has further advanced the possibilities for future treatments. This review focuses on recent developments in the prevention and treatment of breast cancer including results from major clinical trials and recent conferences. RECENT FINDINGS: Many pathways involved in the progression or treatment of breast cancer have been also identified in the cause and pathogenesis of breast cancer. Therefore, breast cancer risk can be described in much more detail, possibly leading to new prevention strategies. In breast cancer treatment the introduction of PARP inhibitors has begun. Recent trials will lead to a better understanding whether PI3K inhibitors can be developed for application in the clinic and first large randomized trials show the superiority of anti PD-1/PD-L1 treatments. SUMMARY: Treatment strategies which were developed over the last decade are moving rapidly into the clinical use. The understanding of treatment targets and involved side effects will be important for the safe implementation of these treatments into routine practice. PMID- 30520758 TI - Single-Dose Pharmacokinetics and Pharmacodynamics of IPX203 in Patients With Advanced Parkinson Disease: A Comparison With Immediate-Release Carbidopa Levodopa and With Extended-Release Carbidopa-Levodopa Capsules. AB - OBJECTIVE: IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). METHODS: This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. RESULTS: Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD (P < 0.0001) and Rytary (P <= 0.0290). IPX203 had a 2.7 hour advantage over IR CD-LD (P < 0.0001) and a 0.9-hour advantage over Rytary in "off" time (P = 0.023) and in "good on" time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. CONCLUSIONS: Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30520759 TI - Association Study Between Serotonin Transporter Gene and Fluoxetine Response in Mexican Patients With Major Depressive Disorder. AB - OBJECTIVE: Pharmacogenetic studies have identified genetic variants associated with fluoxetine response in patients with major depression disorder (MDD). The serotonin transporter gene is the principal site of action of selective serotonin reuptake inhibitors. Previous studies analyzing SLC6A4 gene variants are inconsistent and differ among populations. The aim of the present study was to analyze the association between 5-HTTLPR/rs24531 triallelic polymorphism and fluoxetine response in Mexican patients with MDD. METHODS: We analyzed a sample of 150 patients with MDD. Fluoxetine response was assessed according to a reduction in the Hamilton Depression Rating Scale and Montgomery Depression Rating Scale scores of 50% or more at 8 weeks from baseline. In addition, we analyzed the genotype and allele distribution between responder and nonresponder patients in a subgroup of very severe depression patients. RESULTS: We did not find association between fluoxetine responders and 5-HTTLPR/rs25531 variants (P = 0.0637). However, in the analysis of severe depression at baseline (Hamilton Depression Rating Scale >= 25), we observed a high frequency of low activity alleles (S/LG) in nonresponders patients (P = 0.0102). CONCLUSIONS: Our findings showed an association between low activity alleles of SLC6A4 gene and fluoxetine nonresponse in patients with severe depression. PMID- 30520760 TI - Thrombospondin-1 and Vitamin D in Children With Sickle Cell Anemia. AB - BACKGROUND: Thrombospondin-1 (TSP-1) and 25-hydroxyvitamin D (25-OHD) play significant roles in the pathogenesis of sickle cell anemia (SCA). TSP-1 enhances cellular adhesion/inflammation, hence contributing to vaso-occlusive crisis (VOC); vitamin D, in contrast, retards inflammation and may lower rate of pain episodes. We determined serum levels of TSP-1 and 25-OHD in Nigerian children with SCA and their matched hemoglobin AA controls; and assess the relationship between the 2 biomarkers. METHODS: In total 90 children (32 SCA in steady state, 30 SCA in VOC, and 28 HbAA controls) were studied. Serum TSP-1 and 25-OHD levels were measured with ELISA and HPLC, respectively. RESULTS: The mean TSP-1 of children with VOC was significantly higher than those in steady state (P=0.022) and HbAA controls (P<0.001). Similarly, the mean TSP-1 of those in steady state was higher than the controls (P=0.007). However, mean serum 25-OHD of the children with VOC was significantly lower than those in steady state (28.9+/-8.2 ng/mL vs. 37.1+/-12.3 ng/mL, P =0.004). There was a significant inverse correlation between TSP-1 and 25-OHD among the VOC subgroup, r=-0.57, P=0.001. The mean TSP-1 of the 28 children with SCA who had suboptimal vitamin D (213.5+/ 118.6 ng/mL) was higher than 144.2+/-58.7 ng/mL of the 34 SCA who had normal serum vitamin D, P=0.008. CONCLUSIONS: Children with SCA, especially those with VOC, had high serum TSP-1 and low 25-OHD. Also, an inverse relationship exist between serum 25-OHD and TSP-1 in children with VOC. These findings provide basis for further studies into the regulation of TSP-1 by vitamin D. PMID- 30520761 TI - Childhood Hearing Loss in Patients With Sickle Cell Disease in the United States. AB - This study sought to examine if modern medical evaluations including newborn screening and early diagnosis along with better methods of disease control have improved rates of hearing loss in children with sickle cell disease (SCD). Audiometric and medical data for patients with SCD was obtained from the AudGen Database and analyzed for the presence of hearing loss, type of hearing loss, severity of hearing loss, and correlation with comorbid conditions. Children with sickle cell trait (SCT) were used as a comparison group. A total of 189 patients with SCD and 244 patients with SCT had sufficient audiologic data available. Hearing loss was present in 62% of children with SCD and 50% of children with SCT in the study population. Patients with SCD were significantly more likely than those with SCT to have a sensorineural component to their hearing loss (P<0.001, odds ratio: 2.41 [1.53 to 3.79]) and to have severe or profound hearing loss (P=0.02, odds ratio: 4.00 [1.14 to 14.04]). The true prevalence of hearing loss in children with SCD has not been established as routine screening is not being performed. Routine auditory testing should be done for these children to detect this loss before it impacts development. PMID- 30520762 TI - Delaying Induction Therapy in Children With Newly Diagnosed Lymphoblastic Leukemia: Is that a Viable Strategy to Decrease Early Mortality? PMID- 30520763 TI - Impact of nurse champion on quality of care and outcomes in type 2 diabetes patients. AB - Over 29 million people in the United States have diabetes, with an additional 86 million living with prediabetes. On inpatient hospital units it is estimated that 50% of admitted patients have diabetes as a primary or secondary diagnosis. Nurse champions have improved outcomes and quality of life for patients across different clinical settings. The purposes of this evidence literature review are to evaluate and synthesize evidence regarding the impact of a nurse champion model on nurses' performances and diabetic patient health outcomes. Nurse champions in this review also refer to clinical nurse specialists, certified diabetes educators, and clinical mentors. Search of evidence-based literature was conducted using PubMed, CINAHL, Ovid, Cochrane Library, and Google Scholar databases. Keywords included Nurse Champion and Diabetes, Clinical Mentor and Diabetes, and Diabetes Educator. Search limits included date of publication within last 15 years, English language, and peer-reviewed journals. A total of 14 articles were included in the synthesis of literature with level of evidence ranging from I to V. The study designs of selected evidence fluctuate from randomized controlled trials (3), case studies (6), qualitative studies (2), systematic review (1), and quasi-experimental study (1). The synthesis of evidence indicated that implementation of a nurse champion model did not only significantly improve nurses' diabetic knowledge and skills, but also improved the health outcomes of diabetic patients including reduction in hemoglobin A1c levels, reduction in perceived Diabetes Distress Scale, quality of life improvement, reduction of number of near misses, decreased readmission rates, improved hypoglycemic outcomes, and greater weight loss in patients with type 2 diabetes. Improving diabetic patient outcomes could save the hospital a significant amount of money and create a higher standard of care across the healthcare field. Bettering patient outcomes are good not only for the patient but also the hospital and nurses. Implementation of nurse champion models into nursing practice could significantly improve patient outcomes and quality of life as well as nursing performance. Nurse champion models also can create new leadership roles in nursing. PMID- 30520764 TI - Reasons why the diagnosis of serrated polyposis syndrome is missed. AB - OBJECTIVES: Serrated polyposis syndrome (SPS) is a relatively new and under recognized colorectal cancer (CRC) predisposition syndrome. Previous studies have reported miss-rates of SPS diagnosis varying from 40 to 82%. As SPS patients and their first-degree relatives have an increased risk of CRC, early recognition is important. We aimed to determine the miss-rate of SPS and to determine the reasons for missed diagnosis. PATIENTS AND METHODS: We retrospectively identified all patients diagnosed with at least one colorectal polyp or carcinoma detected at our tertiary referral center between January 1986 and July 2013 using the nationwide pathology registry. On the basis of cumulative polyp count with size and location, SPS patients were identified. We checked whether the SPS diagnosis was made in the medical files and, if not, what might have been the reason for missing the diagnosis. RESULTS: We randomly assessed 5000 patients, of whom 25 patients fulfilled the WHO criteria for SPS. In six patients, no previous SPS diagnosis had been made, leading to a miss-rate of 24.0% (95% confidence interval: 7.3-40.7). The reasons for missed diagnosis were polyps removed before establishment of the WHO criteria, unavailable pathology reports, and failure to apply the criteria by the clinician. CONCLUSION: The miss-rate for the diagnosis of SPS is considerable, even during longer follow-up with repeated colonoscopies. A preventable reason for missing SPS cases is failure to apply the WHO criteria. Awareness of this CRC predisposition syndrome needs to be raised to decrease the miss-rate of SPS. PMID- 30520765 TI - Partial Deletion of Tie2 Affects Microvascular Endothelial Responses to Critical Illness in a Vascular Bed and Organ-Specific Way. AB - Tie2 is a tyrosine kinase receptor that is mainly expressed by endothelial cells. In animal models mimicking critical illness, Tie2 levels in organs are temporarily reduced. Functional consequences of these reduced Tie2 levels on microvascular endothelial behaviour are unknown. We investigated the effect of partial deletion of Tie2 on the inflammatory status of endothelial cells in different organs. Newly-generated heterozygous Tie2 knockout mice (exon 9 deletion, DeltaE9/Tie2) exhibiting 50% reduction in Tie2 mRNA and protein, and wild type littermate controls (Tie2), were subjected to hemorrhagic shock and resuscitation (HS + R), or challenged with i.p. lipopolysaccharide (LPS). Kidney, liver, lung, heart, brain, and intestine were analyzed for mRNA levels of adhesion molecules E-selectin, VCAM-1, and ICAM-1, and CD45. Exposure to HS + R did not result in different expression responses of these molecules between organs from Tie2 or Tie2 mice and sham-operated mice. In contrast, the LPS induced mRNA expression levels of E-selectin, VCAM-1, and ICAM-1, and CD45 in organs were attenuated in Tie2 mice when compared to Tie2 mice in kidney and liver, but not in the other organs studied. Furthermore, reduced expression of E selectin and VCAM-1 protein, and reduced influx of CD45 cells upon LPS exposure, was visible in a microvascular bed-specific pattern in kidney and liver of Tie2 mice compared to controls. In contrast to the hypothesis that a dysbalance in the Ang/Tie2 system leads to increased microvascular inflammation, heterozygous deletion of Tie2 is associated with an organ-restricted, microvascular bed specific attenuation of endothelial inflammatory response to LPS. PMID- 30520766 TI - An embodied neurocomputational framework for organically integrating biopsychosocial processes: An application to the role of social support in health and disease. AB - OBJECTIVE: Two distinct perspectives - typically referred to as the biopsychosocial and biomedical models - currently guide clinical practice. While the role of psychosocial factors in contributing to physical and mental health outcomes is widely recognized, the biomedical model remains dominant. This is due in part to 1) the largely non-mechanistic focus of biopsychosocial research, and 2) the lack of specificity it currently offers in guiding clinicians to focus on social, psychological, and/or biological factors in individual cases. In this article, our objective is to provide an evidence-based and theoretically sophisticated mechanistic model capable of organically integrating biopsychosocial processes. METHODS: To construct this model, we provide a narrative review of recent advances in embodied cognition and predictive processing within computational neuroscience, which offer mechanisms for understanding individual differences in social perceptions, visceral responses, health-related behaviors, and their interactions. We also review current evidence for bidirectional influences between social support and health as a detailed illustration of the novel conceptual resources offered by our model. RESULTS: When integrated, these advances highlight multiple mechanistic causal pathways between psychosocial and biological variables. CONCLUSIONS: By highlighting these pathways, the resulting model has important implications motivating a more psychologically sophisticated, person-specific approach to future research and clinical application in the biopsychosocial domain. It also highlights the potential for quantitative computational modeling and the design of novel interventions. Finally, it should aid in guiding future research in a manner capable of addressing the current criticisms/limitations of the biopsychosocial model, and may therefore represent an important step in bridging the gap between it and the biomedical perspective. PMID- 30520768 TI - S1 Pedicle Subtraction Osteotomy for Fixed Sagittal Imbalance and Lumbosacral Kyphosis. AB - S1 pedicle subtraction osteotomies (PSOs) are indicated in patients with fixed, high-grade L5-S1 spondylolisthesis or kyphosis secondary to a sacral fracture, who present with severe sagittal imbalance. Unlike lumbar PSOs, sacral osteotomies are rare, and there is a paucity of literature outlining techniques. Here, we present the indications, planning, technique, and outcomes for S1 PSOs. PMID- 30520767 TI - Anatomic Considerations in the Lateral Transpsoas Interbody Fusion: The Impact of Age, Sex, BMI, and Scoliosis. AB - STUDY DESIGN: This is a retrospective case series. OBJECTIVE: Define the anatomic variations and the risk factors for such within the operative corridor of the transpsoas lateral interbody fusion. SUMMARY OF BACKGROUND DATA: The lateral interbody fusion approach has recently been associated with devastating complications such as injury to the lumbosacral plexus, surrounding vasculature, and bowel. A more comprehensive understanding of anatomic structures in relation to this approach using preoperative imaging would help surgeons identify high risk patients potentially minimizing these complications. MATERIALS AND METHODS: Age-sex distributed, naive lumbar spine magnetic resonance imagings (n=180) were used to identify the corridor for the lateral lumbar interbody approach using axial images. Bilateral measurements were taken from L1-S1 to determine the locations of critical vascular, intraperitoneal, and muscular structures. In addition, a subcohort of scoliosis patients (n=39) with a Cobb angle >10 degrees were identified and compared. RESULTS: Right-sided vascular anatomy was significantly more variant than left (9.9% vs. 5.7%; P=0.001). There were 9 instances of "at-risk" vasculature on the right side compared with 0 on the left (P=0.004). Age increased vascular anatomy variance bilaterally, particularly in the more caudal levels (P<=0.001). A "rising-psoas sign" was observed in 26.1% of patients. Bowel was identified within the corridor in 30.5% of patients and correlated positively with body mass index (P<0.001). Scoliosis increased variant anatomy of left-sided vasculature at L2-3/L3-4. Nearly all variant anatomy in this group was found on the convex side of the curvature (94.2%). CONCLUSIONS: Given the risks and complications associated with this approach, careful planning must be taken with an understanding of vulnerable anatomic structures. Our analysis suggests that approaching the intervertebral space from the patient's left may reduce the risk of encountering critical vascular structures. Similarly, in the setting of scoliosis, an approach toward the concave side may have a more predictable course for surrounding anatomy. LEVEL OF EVIDENCE: Level 3-study. PMID- 30520769 TI - CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele): implications for CYP2D6 genotyping panels. AB - INTRODUCTION: CYP2D6 metabolizes ~25% of all clinically used drugs, with numerous genetic polymorphisms affecting enzyme activity and drug response. Clinical utility of current CYP2D6 genotyping is partially compromised the unresolved complex haplotype structure of the CYP2D6 locus. We have identified a distal enhancer single-nucleotide polymorphism rs5758550 that robustly increases CYP2D6 expression, whereas rs16947 (CYP2D6*2), previously considered inert, reduces correct mRNA splicing and expression, thereby affecting presumed activity of other alleles on the *2 haplotype. OBJECTIVE: This study aims to determine the structure and frequency of haplotypes containing either rs5758550 or rs16947, or both, together with other relevant CYP2D6 alleles, assigning predictive enzyme activity scores to each, and addressing ambiguities in estimating diplotypes in different populations. METHODS: The structure and frequency of haplotypes containing rs5758550 and/or rs16947 in different populations were determined by using phased genotype data from 'The 1000 Genomes Project'. The assigned haplotype-phenotype relationship was tested by associating assigned CYP2D6 activity score with CYP2D6 enzyme activity in a cohort of 122 human liver microsomes. RESULTS: Addition of enhancer single-nucleotide polymorphism rs5758550 and *2 to a CYP2D6 panel improves prediction of CYP2D6 activity. Moreover, the haplotype containing rs5758550 and rs16947 predict extensive CYP2D6 activity more accurately than CYP2D6*2A, a surrogate marker for extensive activity. CONCLUSION: With further studies, the results support possible incorporation of rs5758550 and rs16947 into CYP2D6 biomarker panels for more accurate prediction of CYP2D6 metabolizer status. PMID- 30520770 TI - Evaluation of triage quality in the emergency department: a scoping review protocol. AB - REVIEW QUESTIONS: The objective of this scoping review is to explore the existing literature on the evaluation of the quality of triage for patients of all ages and medical conditions in emergency departments (ED).The question for this review is: How is triage in ED evaluated? More specifically, we are interested in answering the following sub-questions. PMID- 30520771 TI - Diagnostic accuracy of computed tomography coronary angiography utilising recent advances in technology in patients with high heart rates: a systematic review protocol. AB - REVIEW QUESTION: The primary question to be considered in this review is: what is the diagnostic accuracy of a computed tomography coronary angiography scan utilising recent advances in technology compared to invasive coronary angiography for adult patients with high heart rates in the diagnosis of coronary artery disease?A secondary question will also be considered: what is the diagnostic accuracy of a computed tomography coronary angiography scan utilising individual technologies compared with invasive coronary angiography for adult patients with high heart rates in the diagnosis of coronary artery disease? PMID- 30520772 TI - Barriers and facilitators to type 2 diabetes management in the Caribbean region: a systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this systematic review is to summarize the barriers and facilitators to type 2 diabetes management in the Caribbean region. PMID- 30520773 TI - Nurse leaders' experiences of upwards violence in the workplace: a systematic review protocol. AB - REVIEW QUESTION: This qualitative, systematic review will address the question: what are nurse leaders' experiences of upwards violence in nursing workplaces? PMID- 30520774 TI - Comparative effectiveness of vitamin D supplementation via buccal spray versus oral supplements on serum 25-hydroxyvitamin D concentrations in humans: a systematic review protocol. AB - REVIEW QUESTION:: the questions of this review are. PMID- 30520776 TI - Activation of GPR120 promotes the metastasis of breast cancer through the PI3K/Akt/NF-kappaB signaling pathway. AB - G-protein-coupled receptor 120 (GPR120) plays an important role in regulating lipid and glucose metabolism as a long-chain unsaturated fatty acid receptor. However, it has been widely accepted that omega-3 polyunsaturated fatty acids are not dependent on the activation of GPR120 to exert anti-tumor activity. Therefore, the role of GPR120 in tumor development has not yet been elucidated. Here we show that activation of GPR120 promotes angiogenesis and metastasis in human breast cancer. We show that activation of GPR120 in human breast cancer cells can promote vascular endothelial growth factor, interleukin-8 secretion, cell migration, and epithelial mesenchymal transition. Similarly, phosphatidylinositide 3-kinases/RAC-alpha serine/threonine-protein kinase/nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway is involved in GPR120 activation-induced cell migration and epithelial mesenchymal transition in breast cancer cells. In conclusion, our findings indicate that GPR120 acts as a cancer-promoting receptor in the development of breast cancer. Therefore, GPR120 is expected to be a potential new target for cancer therapy. PMID- 30520775 TI - Paclitaxel, 5-fluorouracil, and leucovorin combination chemotherapy as first-line treatment in patients with advanced gastric cancer. AB - The aim of this retrospective analysis was to evaluate the efficacy and toxicity of combination chemotherapy with paclitaxel, 5-fluorouracil, and leucovorin (TFL) as first-line treatment in patients with advanced gastric cancer (AGC). One hundred and thirteen patients were enrolled in the study who were confirmed to have AGC by histopathology. These patients were treated with TFL: paclitaxel at a dose of 135 mg/m as a 3-h intravenous infusion on day 1, LV 400 mg/m as an intravenous infusion over 2 h on day 1, followed by 5-fluorouracil 2400 mg/m as an infusion over a 46-h period on 3 consecutive days. Cycles were repeated every 2 weeks. A total of 113 patients were assessed for their response to therapy. A total of three patients achieved complete responses and 46 patients achieved partial responses, yielding an overall objective response rate of 43.4% [95% confidence interval (CI): 34.3-52.5%]. Fifty-four cases of stable disease and 10 cases of progressive disease were observed in the remaining patients. The median time to progression and overall survival were 5.2 months (95% CI: 4.7-5.8 months) and 14.1 months (95% CI: 12.5-15.8 months), respectively. Toxicities were tolerable and moderate. The most common grade 3-4 toxicities included leukopenia (16.8%), neutropenia (17.7%), anemia (8.0%), thrombocytopenia (5.3%), and fatigue (6.2%). Combination chemotherapy with TFL offers an active and safe therapeutic approach for patients with AGC. PMID- 30520777 TI - Widened QRS-T Angle May Be a Measure of Poor Ventricular Stretch During Exercise Among On-duty Firefighters. AB - BACKGROUND: The spatial QRS-T angle is a measure of repolarization heterogeneity and may be a predictor of poor ventricular health. It is unknown whether a relationship exists between QRS-T angle and blood pressure (BP) during exercise. OBJECTIVE: The purpose of this study was to evaluate the potential relationship between QRS-T angle and BP during exercise, which may be indicative of ventricular stretch. METHODS: Ambulatory 12-lead 24-hour Holter electrocardiographic monitoring for QRS-T angle measurement was followed by exercise testing with BP (mm Hg) recordings taken preexercise, maximum achieved BP during exercise, and 2 minutes postexercise. Blood pressure recovery was calculated by subtracting the maximal and 2-minute postexercise BPs. Means (+/- standard deviation) and percentages are presented. Pearson correlations (r) among all QRS-T angles and all BP measures were performed. One-way analysis of variance was conducted on classification of QRS-T angle and all BP measures. RESULTS: One hundred eleven firefighters (95.5% male; mean age, 44 years) were included in this analysis. Twenty-seven percent of the firefighters had either a borderline (100 degrees -139 degrees ) or widened (>=140 degrees ) QRS-T angle. Although the analysis of variance was not statistically significant, a near-statistically significant negative correlation existed between QRS-T angle and maximum diastolic BP (r = -0.190, P = .05), and a statistically significant relationship existed between QRS-T angle and postexercise diastolic BP (r = -0.261, P = .008). CONCLUSIONS: A negative correlation existed between QRS-T angle and maximal diastolic BP and postexercise diastolic BP. Lower maximum diastolic BP during and after exercise may be a sign of poor ventricular stretch. A widened spatial QRS-T angle may represent poor ventricular stretch. PMID- 30520778 TI - Gastrointestinal Bleeding During Continuous-Flow Left Ventricular Assist Device Support: State of the Field. AB - Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly used for the management of advanced heart failure refractory to optimal medical therapy. Despite the encouraging outcomes with CF-LVADs, gastrointestinal bleeding (GIB) continues to be a rather concerning complication resulting in increased rates of readmission and increased morbidity. The exact pathophysiology of CF-LVAD-associated GIB remains poorly understood, and this lack of knowledge limits our ability to control this morbid complication. What is clear, however, is that the majority of GIB episodes in LVAD patients are due to fragile GI arteriovenous malformations or angiodysplasias, in the setting of CF-LVAD associated acquired von Willebrand syndrome. We will, herein, appraise the proposed interactions between different pathophysiological processes thought to be causing angiodysplasias and GIB in patients on CF-LVAD support. PMID- 30520779 TI - Racial Disparities in the Cardiac Computed Tomography Assessment of Coronary Artery Disease: Does Gender Matter. AB - Coronary heart disease (CHD) represents a significant healthcare burden in terms of hospital resources, morbidity, and mortality. Primary prevention and early detection of risk factors for the development of CHD are pivotal to successful intervention programs and prognostication. Yet, there remains a paucity of evidence regarding differences in the assessment of these risk factors and the tools of assessment among different ethnicities. We conducted a narrative review to assess the utility of cardiac computed tomography, particularly coronary artery calcification (CAC), in different ethnicities. We also looked to see whether age, sex, comorbidities, and genetic background have peculiar influences on CAC. In this review, we highlight some of the pivotal studies regarding the question of CAC in relation to the development of CHD among different ethnicities. We identify several key trends in the literature showing that although African Americans have high rates of CHD, their risk of CAC may be relatively lower compared with other ethnicities. Similarly, South Asian patients may be at a high risk for adverse cardiac events due to elevated CAC. We also note that several studies are limited by small sample size and were based on 1 large cohort study. Future studies should include a large international prospective cohort to truly evaluate the effects of ethnicity on CAC and CHD risk. To appropriately apply CAC in the clinical practice, the variations in its scoring based on a subject's age, sex, comorbidity, and ethnicity should be addressed and interpreted beforehand. PMID- 30520780 TI - "How Many Recipes for Chocolate Cake Do We Need?" or When Does Similarity Become Self-plagiarism? PMID- 30520781 TI - The Post-Master's Doctor of Nursing Practice as a Critical Strategy to Reduce the Time Lag to Implement Research in Clinical Care. PMID- 30520782 TI - CYP1B1 Gene and Phenotypic Correlation in Patients from Northeastern Brazil with Primary Congenital Glaucoma. AB - PURPOSE: To identify variants in the CYP1B1 gene in northeastern Brazilian patients with PCG and possible genotype-phenotype correlations. MATERIALS AND METHODS: This is a cross-sectional observational study of 17 non-related patients with PCG, performed at the Altino Ventura Foundation, Recife, Brazil, between December 2017 and February 2018. All patients underwent an examination, including gathering information from their medical records, slit lamp examination, fundoscopy, tonography, and measuring corneal diameter and thickness. RESULTS: The mean age at the time of the examination was 27.7 years; 52.9% (n = 9) were male, 29.4% (n = 5) had history of parental consanguinity. The mean age when the diagnosis was confirmed was 0.53+/-2.18 years. Horizontal corneal diameter ranged from 12 to 16?mm (mean 14.05+/-1.42?mm) and the IOP mean value was 17.31+/ 9.84?mm Hg. Predicted pathogenic variants of the CYP1B1 gene were identified in four patients (23.5%). The differences among all clinical parameters did not reach statistical significance between individuals with and without CYP1B1 variants (P values > 0.05). CONCLUSION: Two variants which had not been previously related to PCG in Brazil (c.182G>A, c.241T>A) were identified. No statistically significant genotype-phenotype correlations were found.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30520783 TI - Ketamine stakes in 2018: Right doses, good choices. PMID- 30520784 TI - Targeting the affective component of pain with ketamine: A tool to improve the postoperative experience? PMID- 30520785 TI - Uterine tilt for caesarean section. PMID- 30520786 TI - Ketamine-induced anaphylactic shock during elective parotidectomy: A case report. PMID- 30520787 TI - Continuous haemodynamic effects of left tilting and supine positions during Caesarean section under spinal anaesthesia with a noninvasive cardiac output monitor system. PMID- 30520788 TI - Assessing the effect of dexmedetomidine in patients with pre-eclampsia. PMID- 30520789 TI - The effect of pectoral block type II on persistent pain: Follow up of a randomised trial and hypotheses for further analyses. PMID- 30520790 TI - Fluid therapy for critical haemorrhage during elective noncardiac surgery. PMID- 30520791 TI - Reply to: fluid therapy for critical haemorrhage during elective noncardiac surgery. PMID- 30520792 TI - Reply to: fluid therapy for critical haemorrhage during elective noncardiac surgery. PMID- 30520793 TI - Prediction of bilateral cerebral oxygen desaturation from a single sensor in adult cardiac surgery. PMID- 30520794 TI - Reply to: prediction of bilateral cerebral oxygen desaturation from a single sensor in adult cardiac surgery. PMID- 30520795 TI - Cerebral oximetry monitoring. To guide physiology, avert catastrophe or both? PMID- 30520796 TI - Reply to: cerebral oximetry monitoring. To guide physiology, avert catastrophe or both? PMID- 30520797 TI - Retraction: Visual evaluation of train-of-four and double burst stimulation, fade at various currents, using a rubber band. Saitoh Y, Nakazawa K, Makita K, et al. PMID- 30520798 TI - Outcomes Analysis of Children Diagnosed With Hemophagocytic Lymphohistiocytosis in the PICU. AB - OBJECTIVES: Describe a single center experience of hemophagocytic lymphohistiocytosis in a PICU over a 10-year period, to identify clinical features that may be associated with worse outcomes, including mortality, hospital and ICU length of stay, and functional and cognitive impairments on discharge. DESIGN: Retrospective electronic medical record review, 2007-2017. SETTING: PICU located in a large urban academic quaternary care children's hospital. PATIENTS: All children admitted with hemophagocytic lymphohistiocytosis to our PICU from 2007 to 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patients were identified utilizing International Classification of Diseases, 9th Revision and International Classification of Diseases, 10th Revision codes. Each chart was reviewed for demographic information, hemophagocytic lymphohistiocytosis diagnostic criteria, laboratory data, Pediatric Risk of Mortality Score III, clinical features and events of ICU stay, and PICU and hospital (length of stay). Mortality at 1 year and change in Functional Status Scale from admission to discharge were recorded. There were 42 admissions with 33 unique patients. Median Pediatric Risk of Mortality score at admission was 9 (interquartile range, 7-16). Median PICU length of stay was 7 days (interquartile range, 2-21 d) and hospital length of stay was 24 days (interquartile range, 14-37 d). During their ICU stay, 56% of patients received mechanical ventilation, 43% required vasoactives, 18% required continuous renal replacement therapy, and 5% received extracorporeal life support. Clinical factors related to increased PICU length of stay included Pediatric Risk of Mortality III score (p = 0.019), maximum lactate dehydrogenase (p = 0.017), maximum total bilirubin (p = 0.042), need for mechanical ventilation (p = 0.002), vasoactive use (p = 0.02), and secondary infection (p = 0.007). The most common therapies for hemophagocytic lymphohistiocytosis included steroids (93%), etoposide (55%), and anakinra (48%). Of the 26 patients who survived to hospital discharge, 19% had newly acquired morbidities. Overall 1-year mortality was 42%. CONCLUSIONS: Hemophagocytic lymphohistiocytosis diagnosed in the PICU is a disease with high mortality. Patients who survive to discharge had relatively little morbidity, however, the mortality risk in the year following discharge continued to remain high. PMID- 30520799 TI - Pembrolizumab in the treatment of advanced/metastatic melanoma: a single-center institution experience. AB - Pembrolizumab is an anti-programmed cell death-1 monoclonal antibody, currently representing the first-line treatment for advanced melanoma. Apart from registration trials, there is a paucity of data on its effectiveness and safety in a real-world setting. We retrospectively analyzed patients with metastatic melanoma treated at our institution in the context of an Expanded Access Program. Survival outcomes were assessed using Kaplan-Meier and Cox hazard models. Overall, 42 melanoma patients were treated. BRAF status was wild type in 30 (71%) patients and mutated in 12 (29%). Twelve (29%) patients received pembrolizumab as the II line treatment, the other 30 (71%) as at least III line treatment. One (2%) patient experienced complete response, six (14%) partial response, and seven (17%) stable disease; 39 (93%) patients had disease progression. Median progression-free survival and overall survival were 2.4 (range: 0.2-46.5) and 5.5 months (range: 0.2-47.1), respectively. Results of the multivariate analysis showed that performance status [hazard ratio (HR): 7.10; 95% confidence interval (CI): 2.73-18.4; P<0.001] and the number of previous therapeutic lines (HR: 1.84; 95% CI: 1.08-3.13; P=0.025) influenced progression-free survival. Similarly, performance status (HR: 6.14; 95% CI: 2.44-15.4; P<0.001) and the number of previous lines (HR: 2.04; 95% CI: 1.17-3.56; P=0.012) influenced overall survival. Fourteen (33%) patients reported immune-related adverse events. Three (7%) patients discontinued treatment due to immune-related adverse events onset. At present eight (19%) patients are still alive and one patient is still on treatment. Despite the limitations related to the size and characteristics of this report, our experience confirms the use of pembrolizumab for advanced melanoma in a real-life setting. PMID- 30520800 TI - A pilot clinical trial testing topical resiquimod and a xenopeptide as immune adjuvants for a melanoma vaccine targeting MART-1. AB - A vaccine that could expand melanoma-specific T cells might reduce the risk of recurrence of resected melanoma and could provide an alternative or adjunct to standard immunotherapy options. We tested the safety and immunogenicity of a vaccine coupling a melanoma-associated peptide with a xenogenic peptide (to promote epitope spreading) and/or resiquimod (to activate antigen-presenting cells). HLA-A2-positive patients with resected stage II, III, and IV melanoma were assigned to treatment on one of three schedules. All patients received three subcutaneous doses of the peptide MART-1a mixed with Montanide. In addition, patients on schedule 1 received the xenoantigen peptide Gag267-274, patients on schedule 2 received topical resiquimod, and patients on schedule 3 received both Gag267-274 and resiquimod. Blood samples were tested for the frequency of antigen specific T cells by tetramer assay, as well as immune cell subtypes and plasma cytokine levels. Patients enrolled from October 2012 to December 2014, with 10 patients enrolling to each schedule. The most common adverse events were injection site reaction (26 patients) and fatigue (15 patients). Tetramer analysis revealed antigen-specific responses (defined as doubling of MART-1a specific T cells from pretreatment to post-treatment) in 20, 60, and 40% of patients treated on schedules 1, 2, and 3, respectively. Vaccine treatment consisting of MART-1a peptide, Gag267-274, Montanide, and topical resiquimod was well-tolerated. The addition of the Gag267-274 xenoantigen was not associated with an increase in the response to MART-1a, whereas use of topical resiquimod was associated with a higher frequency of MART-1a-specific T-cell responses that did not meet statistical significance. PMID- 30520801 TI - Cutibacterium acnes in Spine Pathology: Pathophysiology, Diagnosis, and Management. AB - Cutibacterium acnes, long thought to be skin flora of pathological insignificance, has seen a surge in interest for its role in spine pathology. C acnes has been identified as a pathogen in native spine infection and osteomyelitis, which has implications in the management compared with more commonly recognized pathogens. In addition, It has also been recognized as a pathogen in postoperative and implant-associated infections. Some evidence exists pointing to C acnes as an unrecognized source of otherwise aseptic pseudarthrosis. Recently, it is hypothesized that low virulent organisms, in particular C acnes, may play a role in degenerative disk disease and the development of Modic end plate changes found in MRI. To this end, controversial implications exist in terms of the use of antibiotics to treat certain patients in the setting of degenerative disk disease. C acnes continues to remain an expanding area of interest in spine pathology, with important implications for the treating spine surgeon. PMID- 30520802 TI - Septic Arthritis of the Hip-Risk Factors Associated With Secondary Surgery. AB - INTRODUCTION: Septic arthritis of the hip (SAH) is a common condition encountered by pediatric orthopaedic surgeons and is treated with arthrotomy and irrigation. Depending on the response to initial treatment, some patients require surgical treatment beyond the index procedure. The purpose of this study was to investigate risk factors for repeat surgical intervention after initial arthrotomy for presumed SAH. METHODS: A multicenter retrospective review of all children who underwent surgical arthrotomy for presumed SAH over a ten-year period was conducted. Variables queried included demographics, clinical presentation, laboratory parameters, imaging, infecting organism, presence of osteomyelitis, and surgical interventions performed. Logistic regression was used to predict the risk of a second procedure. Chi-square was used to compare patients who required further surgery and those who did not. RESULTS: One hundred and thirty-eight patients (139 hips) qualified for inclusion. The average age at initial surgery was 6.1 years (range, zero to 17 years), and 57% of the patients were male. Concomitant osteomyelitis was diagnosed in 55 cases (40%). An infecting organism was identified from 70 (50%) index intraoperative cultures, with Staphylococcus aureus infections (methicillin-resistant Staphylococcus aureus [MRSA], 27; methicillin-sensitive Staphylococcus aureus, 25) being the most frequent. Fifty-six patients (41%) underwent subsequent surgical intervention, at an average of 5.5 days (range, 2 to 95) from the index procedure. Independent risk factors for repeat surgical procedures included presenting C-reactive protein >10 mg/dL (P = 0.002) and presenting erythrocyte sedimentation rate >40 (P = 0.011). The odds of repeat surgical intervention were significantly increased by the presence of concomitant osteomyelitis (odds ratio, 3.4; P = 0.001) and positive index intraoperative cultures for MRSA (odds ratio, 1.19; P = 0.001). Preoperative MRI before the index procedure was not universal (73/138; 53%), and acquisition of preoperative MRI was not associated with secondary surgical intervention (P = 0.389). DISCUSSION: Forty-one percent of children in this multicenter cohort underwent at least one repeat surgical procedure after the index arthrotomy for management of presumed SAH. Risk factors for return to the operating room include elevated initial erythrocyte sedimentation rate and C-reactive protein, infection with MRSA, and presence of osteomyelitis. LEVEL OF EVIDENCE: Level 3, case-cohort series. Type of evidence, therapeutic. PMID- 30520803 TI - Obstructive Sleep Apnea and Arthroscopic Rotator Cuff Repair-Are Complication Rates Really Increased? AB - BACKGROUND: A few investigations exist which evaluate the influence of obstructive sleep apnea (OSA) on complications after arthroscopic rotator cuff repair. METHODS: A database was queried for patients undergoing rotator cuff repair with and without OSA and further subdivided into those with and without a billing code for a continuous positive airway pressure (CPAP) device. Thirty-day and 6-month adverse events were assessed. RESULTS: After regression analysis, patients with OSA had markedly increased emergency department visits and hospital admission (P < 0.05). This risk was mitigated by CPAP orders compared with control subjects. Patients without CPAP use had markedly increased risks of emergency department visits, hospital admission, and respiratory complications compared with control subjects (P < 0.05). CONCLUSIONS: Patients with OSA have higher risks of emergency department visits and hospital admissions postoperatively; however, a CPAP order appears to mitigate this risk. The independent risk imparted by OSA for the studied complications was markedly lower than other comorbidities. PMID- 30520805 TI - Using Simulation to Teach Echocardiography: A Systematic Review. AB - STATEMENT: We identified 24 studies of high-fidelity simulation being used to teach echocardiography. A variety of study designs were used with outcomes ranging from reports of learner self-confidence up to improvement in organizational practice. Most studies were carried out in graduate medical populations, specifically in anesthesia trainees. The substantial majority of studies (91.6%) concluded that simulation has positive outcomes for teaching echocardiography. Future investigations would benefit from application of educational theory and should focus on demonstrating whether simulation can improve care delivery and patient outcomes. PMID- 30520804 TI - Diagnosis and Management of Fungal Periprosthetic Joint Infections. AB - Fungal periprosthetic joint infection (PJI) is a devastating complication because it can be difficult to diagnose, manage, and eradicate. Fungal PJI treatment requires a systematic approach. Increased awareness is essential when patients with painful arthroplasties present with immunosuppression, significant comorbidities, multiple surgeries, and history of drug use. Every suspected fungal PJI should be promptly diagnosed using readily available serum and synovial fluid markers. Surgical management involves debridement, antibiotics, and implant retention, one-stage exchange arthroplasty, prosthetic articulating spacers, and two-stage exchange arthroplasty. Because mycotic infections develop robust biofilms, the utility of debridement, antibiotics, and implant retention and one-stage revisions seem limited. A thorough irrigation and debridement is essential to decrease infection burden. Adjunctive local and systemic antifungal therapy is critical, although the agent choice and duration should be tailored appropriately. Future high-quality studies are needed to develop standardized guidelines for the management of fungal PJI. PMID- 30520806 TI - The Impact of Individual Mentored Career Development (K) Awards on the Research Trajectories of Early-Career Scientists. AB - PURPOSE: This analysis examined the role of a National Institutes of Health (NIH) individual Mentored Career Development Award (K01, K08, K23) on launching and sustaining independent research careers for early-career scientists and investigated the effects of these awards during and after the doubling of the NIH budget. METHOD: The authors used grants data from the NIH covering the period 1990 through 2016 and compared success in receipt of R01 equivalent awards (R01 Eq.) and Research Project Grants (RPGs) for K awardees and K applicants who did not receive funding. The analysis combined regression discontinuity design with coarsened exact matching and regression. RESULTS: Overall, receipt of K award was associated with a 24.1% increase in likelihood of first independent NIH award (P < .01) and a larger number of R01 Eq. and RPG awards. After accounting for first major independent awards, K awards were uncorrelated with receiving second major independent research awards. Comparing different funding periods, K01 awards were predictive of subsequent R01 Eq. and RPG awards after but not during the NIH doubling, K08 awards were predictive only during the NIH doubling, and K23 awards were predictive during both periods. CONCLUSIONS: Receipt of Mentored Career Development Awards was linked to increased likelihood that early-career scientists successfully transitioned to an independent research career. These findings indicate that extending funding to additional K award applicants with meritorious scores could significantly strengthen the pipeline of biomedical researchers. In addition, enhancing K awards may be relevant to sustaining research careers for clinician scientists.Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. PMID- 30520807 TI - The Yale Center for Biomedical Innovation and Technology (CBIT): One Model to Accelerate Impact From Academic Health Care Innovation. AB - The process of translating academic biomedical advances into clinical care improvements is difficult, risky, expensive, and poorly understood. Notably, many clinicians who identify health care problems do not have the time or expertise to solve the problems, and many academic researchers are unaware of important gaps in clinical care to which their expertise may apply.Recognizing an opportunity to connect people who can identify health care problems with those who can solve them, the Yale Center for Biomedical Innovation and Technology (CBIT) was established in 2014 to educate and enhance the impact of health care innovators. The authors review other health care innovation centers (HICs), and describe best practices borrowed by Yale CBIT, which tailored its activities and approach to its unique ecosystem.In four years, Yale CBIT has affected over 3,000 people and established a health care innovation cycle as an efficient strategy to guide translational research. Yale CBIT has created or supported graduate and undergraduate courses, clinical immersion programs for industry partners, and large health care hackathon events. Over 200 projects have been submitted to CBIT for mentorship, and some of those projects have been commercialized and raised millions of dollars of follow-on funding.The authors present Yale CBIT as one model of accelerating the impact of academic medicine on clinical practice and outcomes. The project advising strategy is intended to be a template to maximize the efficiency of biomedical innovation and ultimately improve the outcomes and experiences of future patients. PMID- 30520808 TI - High-Value Interviewing: A Call for Quality Improvement in the Match Process. AB - Within the Match process, current residency interview practices are inefficient for both applicants and programs. Problems include disorganized interview offers and scheduling, excessive numbers of applicant interviews, unclear postinterview communication policies, and the significant expenses entailed. To address these issues, the authors propose applying a quality improvement approach to create a high-value interview process that would decrease investments of time, money, and energy and improve the quality of the Match experience for both applicants and programs. They propose establishing an interview offer week to streamline and systematize the interview offer and scheduling process; placing an evidence-based cap on the number of interviews that applicants are allowed to schedule; and enforcing a moratorium on postinterview communication that would apply to both applicants and programs. Implementing these proposals would decrease expenses, improve the efficiency of this process for all involved, and demonstrate that quality improvement methods used to improve patient care can also be applied to improving medical student and physician experiences. PMID- 30520809 TI - Do Mindfulness and Self-Compassion Predict Burnout in Pediatric Residents? AB - PURPOSE: Burnout symptoms are common among health professionals. Gaps remain in understanding both the stability of burnout and compassion over time and relationships among burnout, self-compassion, stress, and mindfulness in pediatric residents. METHOD: The authors conducted a prospective cohort study of residents at 31 U.S. residency programs affiliated with the Pediatric Resident Burnout - Resilience Study Consortium. Residents completed online cross-sectional surveys in spring 2016 and 2017. The authors assessed demographic characteristics and standardized measures of mindfulness, self-compassion, stress, burnout, and confidence in providing compassionate care. RESULTS: Of 1,108 eligible residents, 872 (79%) completed both surveys. Of these, 72% were women. The prevalence of burnout was 58% and the level of mindfulness was 2.8 in both years; levels of stress (16.4 and 16.2), and self-compassion (37.2 and 37.6) were also nearly identical in both years. After controlling for baseline burnout levels in linear mixed model regression analyses, mindfulness in 2016 was protective for levels of stress and confidence in providing compassionate care in 2017. Self-compassion in 2016 was protective for burnout, stress, and confidence in providing compassionate care in 2017; one standard deviation increase in self-compassion score was associated with a decrease in the probability of burnout from 58% to 48%. CONCLUSIONS: Burnout and stress were prevalent and stable over at least 12 months among pediatric residents; mindfulness and self-compassion were longitudinally associated with lower stress and greater confidence in providing compassionate care. Future studies are needed to evaluate the effectiveness of training that promotes mindfulness and self-compassion in pediatric residents. PMID- 30520810 TI - New Educator Roles for Health Systems Science: Implications of New Physician Competencies for U.S. Medical School Faculty. AB - To address gaps in U.S. health care outcomes, medical education is evolving to incorporate new competencies, as well as to align with care delivery transformation and prepare systems-ready providers. These new health systems science (HSS) competencies-including value-based care, quality improvement, social determinants of health, population health, informatics, and systems thinking-require formal education and role modeling in both classroom and clinical settings. This is challenging because few faculty had formal training in how to practice or teach these concepts. Thus, these new competencies require both expanding current educators' skills and a new cohort of educators, especially interprofessional clinicians. Additionally, since interprofessional teams are the foundation of many clinical learning environments, medical schools are developing innovative experiential activities that include interprofessional clinicians as teachers. This combination of a relative "expertise vacuum" within the current cohort of medical educators and expanding need for workplace-learning opportunities requires a reimagining of medical school teachers. Based on experiences with implementing HSS curricula at two U.S. medical schools (Penn State College of Medicine and University of California, San Francisco, School of Medicine, starting in 2013), this Perspective explores the need for new educator competencies and the implications for medical education, including the need to identify and integrate "new" educators into the education mission, develop faculty educators' knowledge and skills in HSS, and acknowledge and reward new and emerging educators. These efforts have the potential to better align the clinical and education missions of academic health centers and cultivate the next generation of physician leaders. PMID- 30520811 TI - Is it Necessary to Send the Sleeve Gastrectomy Specimens to Pathology? AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become more popular among other bariatric procedures. The histopathologic changes in the sleeve gastrectomy specimens have not been widely investigated among the Turkish population. OBJECTIVE: The purpose of this study was to delineate these histopathologic findings of the LSG specimens of morbidly obese patients from a single center. MATERIALS AND METHODS: A prospective database of all patients who have undergone LSG at a single center was reviewed. Demographic parameters, that is, sex, age, and body mass index were examined. The incidence of Helicobacter pylori, and other pathologic findings in the specimens were studied. RESULTS: In total, 253 patients who had undergone LSG between the period spanning from April 2012 to January 2017 were included in the study. The 183 patients were female individuals and 70 patients were male individuals. The mean age at the time of operation was 38.5 years (range, 18 to 65 y). The mean body mass index was 47.7 kg/m. The pathologic findings were H. pylori positivity in 69 patients (27%), chronic active gastritis in 52 patients (20.5%), chronic gastritis in 135 patients (53.4%), and intestinal metaplasia in 5 patients (2%), whereas normal histopathologic findings were observed in 65 patients (25.7%). As regards surgical complications, the mortality rate was 0%, the staple-line leak was observed in 2 patients (0.8%), and intra-abdominal hemorrhage occurred in 2 patients (0.8%). CONCLUSIONS: The majority of patients who underwent LSG had pathologic findings in the resected specimens. With regard to the high incidence of pathologic findings in this study, we conclude that it is essential to send the gastrectomy materials for pathologic investigation after sleeve gastrectomy. PMID- 30520812 TI - Why Does Postoperative Pancreatic Fistula Occur After Hand-sewn Parenchymal Closure and Staple Closure in Distal Pancreatectomy? AB - Hand-sewing (HS) and stapling are common parenchymal closure techniques after distal pancreatectomy. However, these methods cannot completely prevent postoperative pancreatic fistula (POPF). The mechanisms of POPF formation after closure are unknown. We performed distal pancreatectomy in mongrel dogs to identify the mechanisms of POPF formation after HS and staple closure. We measured the closed pancreatic duct burst pressures and examined the histology of the remnant pancreas. The after staple-closure burst pressures depended on stapler height; lower pressures were associated with greater stapler heights. Post-HS closure burst pressures were significantly higher than those at each stapler height (P<0.01). Post-HS closure pathologic findings showed extensive necrosis (day 3), and some regenerated pancreatic duct stumps (day 5). Necrosis was not observed around the stapled tissues. Although HS completely closes the pancreatic ducts, stump necrosis and blood flow disturbances may cause POPF. With stapler closure, pancreatic fluid leakage may occur even with appropriate stapler heights. PMID- 30520813 TI - Accuracy of Right Upper Quadrant Ultrasound in Estimating Gallbladder Wall Thickness. AB - OBJECTIVE: Ultrasound (US) evaluation of biliary pathology can be influenced by a variety of factors. This study examines the effect of patient specific factors on the accuracy of sonographic evaluation of gallbladder wall thickness (GBW). METHODS: We performed a retrospective review of all patients who underwent cholecystectomy at a single institution from November 2012 to October 2015. GBW measured on US was compared with pathology results. Results were analyzed in relation to patient specific factors to include BMI, age, presence of diabetes, sex, and urgent versus elective cases. RESULTS: In total 601 patients underwent cholecystectomy, 484 of which had paired preoperative US GBW measurement and postoperative pathologic specimen measurement. No significant difference in accuracy or precision of US measurement of the GBW based on BMI was found. Accuracy was not related to age, sex, urgency, or diabetes. Precision decreased with pathologic thickening, age, male sex, and urgent case performance. CONCLUSIONS: US is accurate in measuring GB wall thickness regardless of patient specific factors. A nonsignificant trend exists with decreased precision with pathologic thickening, age, male sex, and urgently performed cases. PMID- 30520814 TI - Index Admission Emergency Laparoscopic Cholecystectomy and Common Bile Duct Exploration: Results From a Specialist Center in the United Kingdom. AB - BACKGROUND: The incidence of common bile duct (CBD) stones is between 10% to 18% in people undergoing cholecystectomy for gallstones. Laparoscopic exploration of the CBD is now becoming routine practice in the elective setting, however its safety and efficacy in emergencies is poorly understood. METHODS: We analyzed our results for index emergency admission laparoscopic cholecystectomy within a specialist center in the United Kingdom. Data from all emergency cholecystectomies in our unit, between 2011 to 2016 were collected and analyzed retrospectively. RESULTS: In total, 494 patients underwent emergency laparoscopic cholecystectomy; 53 (10.7%) patients underwent common bile duct exploration (CBDE), with 1 conversion and 1 bile leak. Indications for CBDE were based on preoperative imaging (41 cases, 81%) or intra-operative cholangiogram (44 cases, 83%) findings. CONCLUSIONS: Index admission laparoscopic cholecystectomy and concomitant CBDE is safe and should be the gold standard treatment for patients presenting with acute biliary complications, reducing readmissions and the need for a 2-stage procedure. PMID- 30520815 TI - Laparoscopic Multiple Parenchyma-sparing Concomitant Liver Resections for Colorectal Liver Metastases. AB - BACKGROUND: Parenchyma-sparing concept in liver surgery has received a new incitement with the introduction of laparoscopic techniques. Multiple concomitant liver resections are a major component in the parenchyma-sparing concept. MATERIALS AND METHODS: In total, 689 patients underwent laparoscopic liver resection for colorectal liver metastases from August 1998 to 2017, and 171 patients were eligible for this study. Patients were divided into 3 groups: group I with single liver resection (36 patients); group II with multiple concomitant liver resections (104 patients); group III with liver resection(s) combined with concomitant liver ablation (31 patients). Perioperative outcomes and survival were compared between the groups I and II, whereas variables of group III were presented as complementary information, avoiding statistically exigent multiple comparisons. RESULTS: There were 6 conversions, 0, 3 (2.9%), and 2 (6.5%), respectively in the groups I, II, and III. Median operative time was 161, 186, and 224 minute in the groups I, II, and III, respectively. Median blood loss was 300 mL in groups I and II, and 200 mL in group III. It was a tendency to higher rate of postoperative complications in the group of single resections with morbidity rate of 31%, 19%, and 23% in group I, II, and III, respectively. Median postoperative stay was 3 days in all groups. Tumor-free margin resection was achieved in 92%, 86%, and 93%, respectively in the groups I, II, III. The median weight of resected specimen was significantly lower in group II (90 vs. 257 g; P<0.001). There were no significant differences in survival between the groups. The 5-year overall survival was 31%, 42%, and 43% for groups I, II, and III, respectively. CONCLUSIONS: Laparoscopic multiple concomitant parenchyma-sparing liver resections provide surgical and oncologic outcomes comparable with single greater resections for multiple lesions. This approach could be recommended for a wide application in specialized hepatopancreatobiliary centers. PMID- 30520816 TI - Fluoroscopy Dose and Time Characteristics During Endoscopic Retrograde Cholangiopancreatography (ERCP). AB - Radiation exposure during endoscopic retrograde cholangiopancreatography is known, however, data in relation to radiation usage is unclear. We evaluate radiation exposure using fluoroscopy dose (FD) and time (FT). A prospective analysis of 197 patients undergoing endoscopic retrograde cholangiopancreatography was completed. Univariate and multivariate analyses were performed to determine characteristics associated with higher FD and FT. The mean FT was 307 seconds; the mean FD was 16.5 centigray. On univariate and multivariate analysis, indication of common bile duct stricture and pancreatic stricture, interventions including dilation and the use of plastic stents placement, procedures that were moderately or very difficult, and procedures that used magnification and high-resolution images were associated with higher FD+/- and longer FT. Indications of common bile duct stricture and pancreatic stricture as well as interventions of dilation, plastic stents placement, and procedures that are moderately or very difficult, involve high-resolution image leading to a higher radiation exposure. Special care should be considered in these settings. PMID- 30520817 TI - The HTN3-MSANTD3 Fusion Gene Defines a Subset of Acinic Cell Carcinoma of the Salivary Gland. AB - The spectrum of tumors arising in the salivary glands is wide and has recently been shown to harbor a network of tumor-specific fusion genes. Acinic cell carcinoma (AciCC) is one of the more frequently encountered types of salivary gland carcinoma, but it has remained a genetic orphan until recently when a fusion between the HTN3 and MSANTD3 genes was described in one case. Neither of these 2 genes is known to be implicated in any other malignancy. This study was undertaken to investigate whether the HTN3-MSANTD3 fusion is a recurrent genetic event in AciCC and whether it is a characteristic of one of its histological variants. Of the 273 AciCCs screened, 9 cases showed rearrangement of MSANTD3 by break-apart fluorescence in situ hybridization, 2 had 1 to 2 extra signals, and 1 had gain, giving a total of 4.4% with MSANTD3 aberrations. In 6 of 7 available cases with MSANTD3 rearrangement, the HTN3-MSANTD3 fusion transcript was demonstrated with real-time polymerase chain reaction . Histologically, all fusion-positive cases were predominantly composed of serous tumor cells growing in solid sheets, with serous tumor cells expressing DOG-1 and the intercalated duct-like cell component being CK7 positive and S-100 positive in 6/9 cases. All but one case arose in the parotid gland, and none of the patients experienced a recurrence during follow-up. In contrast, the case with MSANTD3 gain metastasized to the cervical lymph nodes and lungs. In conclusion, we find the HTN3-MSANTD3 gene fusion to be a recurrent event in AciCC with prominent serous differentiation and an indolent clinical course. PMID- 30520818 TI - Novel NTRK3 Fusions in Fibrosarcomas of Adults. AB - NTRK fusions in malignant tumors are therapeutic targets of tyrosine kinase inhibitors. Because they occur only in a small subset of mesenchymal tumors, knowledge regarding the corresponding histology is important to effectively identify patients who could benefit from targeted therapy. In this study, using RNA sequencing, we identified novel NTRK3 fusions involving related partner genes in 2 adult bone and soft tissue tumors that met the current histologic criteria of fibrosarcoma. Case 1 involved the left radius of a 38-year-old woman, whereas in case 2, the right thigh of a 26-year-old man was affected. Histologically, both tumors consisted of the long fascicular growth of long spindle cells. The tumor in case 1 additionally showed focal myxoid changes. Tumor cells had nonpleomorphic, atypical nuclei, and lacked evidence of a specific line of differentiation. Both tumors showed widespread CD34 immunoreactivity and very limited expression of actin. RNA sequencing detected in-frame fusion transcripts of STRN (exon 3)-NTRK3 (exon 14) in case 1 and STRN3 (exon 3)-NTRK3 (exon 14) in case 2, which were confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. Pan-TRK immunostaining was diffusely positive in both cases. Fluorescence in situ hybridization showed signal patterns compatible with NTRK3 rearrangements in both cases, with case 2 additionally harboring a CDKN2A homozygous deletion. This study expands the clinicopathologic and genetic spectrum of sarcomas associated with NTRK fusions, and suggests that CD34 positive fibrosarcoma of bone and soft tissue could be a good candidate for NTRK testing. PMID- 30520819 TI - MDM2 RNA In Situ Hybridization for the Diagnosis of Atypical Lipomatous Tumor: A Study Evaluating DNA, RNA, and Protein Expression. AB - The distinction of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) from its benign counterpart, lipoma, may represent a challenge. MDM2 DNA amplification is used as the gold standard as MDM2 immunohistochemistry lacks specificity and sensitivity. Herein, we investigate the diagnostic utility of MDM2 RNA in situ hybridization (RNA-ISH) and compare the test with MDM2 immunohistochemistry and MDM2 DNA fluorescence in situ hybridization (FISH) in benign and malignant lipomatous neoplasms. We evaluated 109 neoplasms including 27 lipomas, 25 spindle cell lipomas, 32 ALTs/WDLs, and 25 dedifferentiated liposarcomas (DDL). The validation cohort included 14 lipoma-like neoplasms that lacked unequivocal features of ALT/WDL and in which MDM2 immunohistochemistry was either equivocal, negative or falsely positive. Immunohistochemistry, automated RNA-ISH and DNA-FISH for MDM2 were performed. Tumors with diffuse nuclear staining or >50 dots per cell on RNA-ISH were considered positive. All lipomas and lipoma variants were negative for RNA-ISH while all ALTs/WDLs and DDLs were positive. Eighty percent (24/30) and 92% (22/24) of ALTs/WDLs and DDLs were positive for MDM2 immunohistochemistry. Lipomas and its variants were negative for MDM2 amplification; 92% and 100% of ALTs/WDLs and DDLs showed MDM2 DNA amplification. The mean percentage of ALT/WDL tumor cells showing MDM2 RNA-ISH positivity was 73% compared with 24% on MDM2 immunohistochemistry. RNA-ISH correctly classified all 10 ALTs/WDLs and all 4 lipomas in the validation cohort. The performance of MDM2 RNA-ISH and MDM2 DNA-FISH are equivalent. MDM2 RNA-ISH can be of diagnostic value in histologically challenging lipomatous neoplasms. The automated MDM2 RNA-ISH assay should allow for more widespread use of MDM2 testing and for a more sensitive and specific diagnosis of ALT/WDL. PMID- 30520820 TI - Cholangiolocellular Carcinoma With "Ductal Plate Malformation" Pattern may be Characterized by ARID1A Genetic Alterations. AB - Cholangiolocellular carcinoma (CLC) is a unique subtype of primary liver carcinoma, which sometimes coexists with hepatocellular carcinoma (HCC), cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). "Ductal plate malformation" (DPM)-pattern of primary liver carcinoma, which resembles biliary lesions in Caroli disease and von Meyenburg complex, is sometimes associated with CLC. We examined genetic alterations of hTERT promoter (hTERT), IDH1 or 2 (IDH1/2), KRAS, ARID1A, PBRM1, ARID2, BAP1, p53 and their association with histologic features such as proportion of CLC and DPM-pattern in 77 patients with primary liver carcinoma diagnosed as cHCC-CCA or CLC. Primary liver carcinomas were histologically subdivided into 29 CLC-predominant (CLC component >80%), 31 with CLC (5% to 80%) and 17 without CLC (<5%). CLC predominant group was characterized by older age, male-predominant and smaller tumor size. Genetic alterations were detected in hTERT (25%), ARID1A (21%), PBRM1 (20%), ARID2 (3%), BAP1 (1%), p53 (46%), KRAS (5%), and IDH1/2 (8%). ARID1A alteration was more frequent in CLC-predominant group, compared with other groups (P<0.05) and was correlated with the degree of DPM-pattern (P<0.01). Alterations of hTERT and p53 were less frequent in CLC-predominant group compared with "with CLC group" (P<0.05). hTERT mutation was less frequent in carcinomas with DPM pattern (P<0.01). PBRM1 alteration was more frequent in CLC with focal HCC subgroup and without CLC group compared with other groups (P<0.05). CLC may be a distinct subgroup of primary liver carcinoma, which is different from cHCC-CCA, based on clinicopathologic and genetic alterations. ARID1A alterations may characterize CLC with DPM-pattern and could be a diagnostic immunohistochemical marker for small CLCs with DPM-pattern. PMID- 30520821 TI - Rheumatoid Arthritis and Mortality in End Stage Renal Disease. AB - OBJECTIVE: To determine whether rheumatoid arthritis (RA) is a risk factor for cardiovascular disease (CVD) events, all-cause mortality and cardiovascular mortality in End Stage Renal Disease (ESRD). METHODS: Cohort study of adult patients with ESRD in the United States Renal Data System (USRDS) with RA and a 5% random sample of those without RA. CVD events, all-cause mortality and cardiovascular mortality were determined in those with RA compared to those without RA using Cox Proportional Hazards modeling. RESULTS: 2,824 subjects, 407 with RA and 2,417 without RA, were included in the analyses. The duration of the study was up to 5 years, depending on mortality and initiation of dialysis. There were no significant differences in CVD events by RA status (n = 311 [76.4% RA] vs. n = 1936 [80.1% without RA], p = 0.09). Subjects with RA had a significantly shorter mean time in months from start of dialysis to an incident CVD event (20.1 +/- 12.2 vs. 21.2 +/- 14.1, p < 0.01) than those without RA. In multivariable adjusted models, RA was not associated with an increased risk for all-cause mortality (aHR = 1.09, 95%CI 0.94-1.27) or cardiovascular mortality (aHR = 0.95, 95% CI 0.74-1.22) within 5 years. Risk factors for all-cause mortality and cardiovascular mortality in RA included older age and a higher Charlson comorbidity index (CCI). CONCLUSIONS: Clinicians should be aware that persons with RA who develop ESRD incur cardiac events sooner ESRD than the general population. However, RA is not an independent risk factor for all-cause or cardiovascular mortality in ESRD. PMID- 30520822 TI - Unilateral Eyelid Plaque Leading to Diagnosis of Systemic Lupus Erythematosus. PMID- 30520823 TI - Gout in the Gilded Age: The Case of Richard Morris Hunt. AB - Richard Morris Hunt, a distinguished American architect of the late 19th century (the Gilded Age), had onset of gout at age 41 years. His attacks became more frequent and severe, eventually leading to chronic pain and disability. His medical care by highly regarded physicians resulted in very limited benefit, but through his dedication and work ethic, he remained productive until his death at age 67 years. PMID- 30520824 TI - Successful Methotrexate Treatment of Chronic Chikungunya Arthritis. PMID- 30520826 TI - Making our voices heard in 2 019 and beyond. PMID- 30520825 TI - A Practical Roadmap for Writing of Medical Scientific Publications. AB - In this article, we are providing a general description of the process of moving a research project from completion to publication; we are describing the process of assigning authors, the drafting of the manuscript, the review process, and how to respond to comments received from reviewers and editors. This roadmap is meant to stimulate the scientific productivity of junior researchers across the continent. PMID- 30520827 TI - Short communication: switching immunosuppression from cyclosporine to tacrolimus in kidney transplant recipients based on CYP3A5 genotyping. AB - BACKGROUND: Kidney transplant recipients on long-term cyclosporine (CsA) therapy may develop multiple adverse drug events, and immunosuppression conversion from CsA to tacrolimus (Tac) is an option. Genetic variations, especially cytochrome P450 (CYP) 3A5*3 affects Tac dosing. However, little information is available to guide the conversion with regards to patients' pharmacogenomics. We aimed to investigate whether CYP3A5, CYP3A4 and ABCB1 genotyping could contribute to a more precise and individualized initial dosing of Tac at the time of immunosuppressant conversion. METHODS: Genotypes of 5 candidate genes (CYP3A5*3, CYP3A4*1G, ABCB1C1236T, ABCB1C3435T, ABCB1G2677T/A) were investigated by polymerase chain reaction and restriction fragment-length polymorphism methods in 46 adult kidney transplant recipients requiring immunosuppressant conversion from CsA to TAC. Associations between these functional genetic polymorphisms and the dose-adjusted trough concentrations of CsA and Tac were evaluated, retrospectively. RESULTS: Based on the linear regression analysis, CYP3A5 expressers (*1/*1 and *1/*3) had lower Tac dose-adjusted trough concentrations on days 7, 14, 21 and 28, and they required 1.40- to 1.75-fold higher daily dose to reach the target concentration compared to non-expressers (*3/*3) on day 28 [0.07 (0.06-0.09) mg/kg/day vs 0.05 (0.02-0.06) mg/kg/day, P=0.001]. CYP3A4*1G or ABCB1 genetic polymorphisms had no effect on the Tac dose-adjusted trough concentrations. CONCLUSION: Our preliminary study supports the use of CYP3A5 genotyping to guide the initial dosing of Tac when converting the immunosuppression therapy from CsA to Tac. PMID- 30520828 TI - Simultaneous quantification of thirteen cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients. AB - BACKGROUND: A sensitive, robust method was developed and validated to quantitate thirteen major natural cannabinoid parent and metabolite compounds in human plasma at or below 0.5 ng/mL. METHODS: A liquid chromatography-tandem mass spectrometry method was developed and validated to measure thirteen cannabinoid compounds: cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), Delta-tetrahydocannabinol (THC), Delta-tetrahydrocannabinolic acid A (THCA), Delta-tetrahydrocannabivarin (THCV), 11-hydroxy-Delta-tetrahydrocannbinol (11-OH-THC), 11-nor-9-carboxy-Delta-tetrahydrocannbinol (THC-COOH), and 11-nor-9 carboxy-Delta-tetrahydrocannabinol-glucuronide (THC-COOH-glu). Samples (200 uL) were extracted via protein precipitation and separated with a Kinetex-EVO C18 column and a 65%-95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy receiving cannabis for the treatment of seizures. RESULTS: The extracted lower limit of quantification was 0.05 ng/mL for CBD, CBDV, CBN, and 11-OH-THC; 0.10 ng/mL for CBDA, CBG, CBC, CBGA, THC, THCA, and THCV; 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean QC intra-day accuracy and precision for all analytes ranged 96.5-104% and 2.7-4.9% respectively while inter-day accuracy and precision ranged 98-103.3% and 0.2-3.6%, respectively. An absolute matrix effect was observed for some analytes, however, with minimal relative matrix effect. Lack of nonspecific drug binding to extraction glass and plasticware was verified. Patient CBD levels ranged from 0.135-11.13 ng/mL. CONCLUSIONS: The validated method met FDA guidelines for Bioanalytical Assays precision and accuracy criteria. The assay reliably confirmed the use of particular medical cannabis formulations in patient samples as well as reliably measured low CBD concentrations from single dose CBD exposure. PMID- 30520829 TI - Low serum trough concentrations and high vancomycin MIC in methicillin-sensitive Staphylococcus aureus from hemodialysis patients in Brazil. AB - BACKGROUND: The empiric antimicrobial therapy for bacteremia of long-term hemodialysis (HD) outpatients is currently based on the combination of vancomycin and gentamicin because of the high frequency of isolated Staphylococcus species. The vancomycin trough level range from 15 to 20 ug/mL is expected for therapeutic success against methicillin-resistant S. aureus with vancomycin MIC >= 1.0 ug/mL. Despite the availability of clinical practice guidelines for vancomycin therapeutic drug monitoring (TDM), these target serum concentrations are not reached in many patients. METHODS: In this study the authors investigated the vancomycin trough levels in 20 HD-patients with S. aureus bacteremia, as well as the antimicrobial susceptibility pattern of 45 S. aureus strains isolated from 45 HD-patients. The vancomycin serum concentration was determined by chemiluminescent assay. The MIC was determined by broth microdilution method. RESULTS: None of the HD-patients included in this study had vancomycin trough concentrations within the therapeutic range. Also, the vancomycin MIC for most methicillin-sensitive S. aureus (MSSA) isolated from bacteremia was >= 1.0 ug/mL. CONCLUSIONS: The therapeutic range of vancomycin was not achieved, and vancomycin MIC was surprisingly high in MSSA. PMID- 30520830 TI - Therapeutic drug monitoring of second-generation antipsychotics for the estimation of early drug effect in first-episode psychosis. PMID- 30520831 TI - Short communication: rapid quantitation of flecainide in human plasma for therapeutic drug monitoring using liquid chromatography and time-of-flight mass spectrometry. AB - BACKGROUND: Measurement of flecainide is useful to optimize dosage and minimize risks of toxicity. Further, there is a need for urgent sample analysis when flecainide is used in transplacental therapy for fetal tachycardia. To this end, we have developed and validated a rapid assay for the measurement of flecainide in human plasma or serum, using a small sample volume (50 uL). METHOD: Following a simple deproteination with zinc sulfate and methanol, prepared samples were injected onto a short (30 mm) analytical column and eluted using a rapid gradient elution. Detection was carried out using time-of-flight mass-spectrometry. Flecainide was quantified using flecainide-D4 as internal standard, with both compounds extracted from the total-ion chromatogram using a +/-5 ppm extraction window based on the theoretical m/z values for the protonated ions. RESULTS: The assay was linear over a putative therapeutic range (100-1,500 ug/L). Between- and within-assay imprecision and accuracy were <4.6 % and 94.8-110.0 %, respectively. Matrix effects were minimal and were compensated for by flecainide-D4. There were no effects due to hemolysis or lipemia, and no carryover was apparent. Total analysis time was just 1.2 minutes (72 s). CONCLUSIONS: We have developed and validated a rapid method for the analysis of flecainide. The method is particularly suited for flecainide TDM, when analyzing samples from mothers receiving flecainide for the treatment of fetal tachycardia. PMID- 30520832 TI - p53-Family Proteins in Odontogenic Cysts: An Immunohistochemical Study. AB - The present study investigated the immunohistochemical expression of p53, p63, and p73 in different types of odontogenic cysts (OC), a group of common intraosseous jaw lesions, to provide a better understanding of p53-family functions in odontogenic lesions. We carried out immunohistochemical analysis to evaluate the expression of p53, p63, and p73 in 60 samples of OC, including dentigerous cysts, radicular cysts, orthokeratinized OC, and odontogenic keratocysts (OKC). The epithelial expression of p53-family members was evaluated both in the basal-parabasal and in the superficial layers, measuring the percentage of positive cells and the value of expression intensity. The expression of p53-family members showed a significant difference between the "OKC" and "non-OKC" groups. In particular, p53 positivity in the basal-parabasal layers, as well as p63 positivity in the superficial layers, were more common in OKC (P<0.0001; P=0.0237). p73 expression in the superficial layers was significantly more expressed in the "non-OKC" group (P<0.0001). No significant differences of staining intensity scores were reported between the groups. The Spearman test showed a positive correlation between p53 and p73 expression at the basal-parabasal level in all cysts (r=0.6626; P<0.0001). These results showed a significantly different expression of p53-family members in OC groups, in particular between the "OKC" and "non-OKC" groups, suggesting the existence of a p53-family pathway in the epithelial lining of OC. PMID- 30520833 TI - Characteristics of State Policies Impact Health Care Delivery, Medical Care, September 2018. PMID- 30520834 TI - Inpatients Sign On: An Opportunity to Engage Hospitalized Patients and Caregivers Using Inpatient Portals. AB - BACKGROUND: Inpatient portals are online patient portals linked to electronic health records that provide hospitalized patients and caregivers secure access to real-time clinical information and tools to enhance their communication with providers and hospital experience. OBJECTIVE: The main objective of this commentary was to provide a perspective that inpatient portals are innovative tools poised to engage patients and caregivers during hospitalization and, thus, enhance patient-centered care. RESULTS: Inpatient portals are desired by patients and caregivers and may contribute to improved recognition of their inpatient care team, knowledge of their treatment plan and overall inpatient experience. A sociotechnical systems approach is recommended to mitigate potential unintended consequences of inpatient portal use and support effective portal design, implementation and evaluation. CONCLUSIONS: This article highlights the potential of using inpatient portals to engage hospitalized patients and caregivers and proposes next steps to evaluate this emerging technology. PMID- 30520835 TI - Falsification Tests for Instrumental Variable Designs With an Application to Tendency to Operate. AB - BACKGROUND: Instrumental variable (IV) methods are becoming an increasingly important tool in health services research as they can provide consistent estimates of causal effects in the presence of unobserved confounding. However, investigators must provide justifications that the IV is independent with any unmeasured confounder and its effect on the outcome occurs only through receipt of the exposure. These assumptions, while plausible in some contexts, cannot be verified from the data. METHODS: Falsification tests can be applied to provide evidence for the key IV assumptions. A falsification test cannot prove the assumptions hold, but can provide decisive evidence when the assumption fails. We provide a general overview of falsification tests for IV designs. We highlight a falsification test that utilizes a subpopulation of the data where an overwhelming proportion of units are treated or untreated. If the IV assumptions hold, we should find the intention-to-treat effect is zero within these subpopulations. RESULTS: We demonstrate the usage of falsification tests for IV designs using an IV known as tendency to operate from health services research. We show that the falsification test provides no evidence against the IV assumptions in this application. PMID- 30520836 TI - Role of Prices, Utilization, and Health in Explaining Texas Medicaid Newborn Care Spending Variation. AB - BACKGROUND: Newborn care is one of the most frequent types of hospitalization and Medicaid covers over 50% of all births nationwide. However, little is known about regional variation in Medicaid newborn care spending and its drivers. OBJECTIVES: To measure the contribution of market-level prices, utilization, and health risk on regional variation in spending among newborn Medicaid population in Texas. RESEARCH DESIGN AND METHODS: The study used 2014 Texas Medicaid newborn claims and encounters linked to birth and death certificate data. Newborn care spending was defined as Medicaid payments per newborn hospital stay, including hospital transfers, from birth through discharge home or death. Spending was further categorized into inpatient facility and related professional spending. Variation in spending across neonatal intensive care regions was decomposed into price and utilization, accounting for input price and health risk differences. RESULTS: Newborn care spending across Texas regions varied significantly (coefficient of variation, 0.31), with most of the variation attributed to spending on inpatient facility services (91%). Both price (41%) and utilization (27%) played a role in explaining this variation, after adjusting for health status (29%) and input price (4%). Though most regions with the highest spending indexes had high price and utilization indexes, some had high spending driven mostly by high prices and others by high utilization. CONCLUSIONS: Significant regional variations in price, utilization, and health status exist in Medicaid newborn care across Texas in 2014. Disentangling the effect of each driver is important to address spending variation and improve efficiency in newborn care. PMID- 30520837 TI - The Methodological Challenges of Using Veterans Benefits Administration Disability Codes to Ascertain Agent Orange Exposure Among Vietnam Theater Veterans With Service-connected Disabilities. PMID- 30520838 TI - Indirect Estimation of Race/Ethnicity for Survey Respondents Who Do Not Report Race/Ethnicity. AB - BACKGROUND: Researchers are increasingly interested in measuring race/ethnicity, but some survey respondents skip race/ethnicity items. OBJECTIVES: The main objectives of this study were to investigate the extent to which racial/ethnic groups differ in skipping race/ethnicity survey items, the degree to which this reflects reluctance to disclose race/ethnicity, and the utility of imputing missing race/ethnicity. RESEARCH DESIGN: We applied a previously developed method for imputing race/ethnicity from administrative data (Medicare Bayesian Improved Surname and Geocoding 2.0) to data from a national survey where race/ethnicity was usually self-reported, but was sometimes missing. A linear mixed-effects regression model predicted the probability of self-reporting race/ethnicity from imputed racial/ethnic probabilities. SUBJECTS: In total, 508,497 Medicare beneficiaries responding to the 2013-2014 Medicare Consumer Assessment of Healthcare Providers and Systems surveys were included in this study. MEASURES: Self-reported race/ethnicity and estimated racial/ethnic probabilities. RESULTS: Black beneficiaries were most likely to not self-report their race/ethnicity (6.6%), followed by Hispanic (4.7%) and Asian/Pacific Islander (4.7%) beneficiaries. Non-Hispanic whites were the least likely to skip these items (3.2%). The 3.7% overall rate of missingness is similar to adjacent demographic items. General patterns of item missingness rather than a specific reluctance to disclose race/ethnicity appears to explain the elevated rate of missing race/ethnicity among Asian/Pacific Islander and Hispanic beneficiaries and most but not all among Black beneficiaries. Adding imputed cases to the data set did not substantially alter the estimated overall racial/ethnic distribution, but it did modestly increase sample size and statistical power. CONCLUSIONS: It may be worthwhile to impute race/ethnicity when this information is unavailable in survey data sets due to item nonresponse, especially when missingness is high. PMID- 30520839 TI - Comparing Vasoactive-Inotropic Score Reporting Strategies in the PICU Relative to Mortality Risk. AB - OBJECTIVES: High Vasoactive-Inotropic Scores have demonstrated association with poor outcomes in pediatric cardiac ICUs and are being calculated more frequently in studies of critically ill noncardiac patients. Available studies differ in their approach to assigning Vasoactive-Inotropic Scores, making direct comparisons difficult. The goal of this investigation is to compare multiple approaches to Vasoactive-Inotropic Score assignment to determine their strength of association with mortality in a general pediatric intensive care population. In doing so, we aim to help validate the use of the Vasoactive-Inotropic Score in noncardiac patients and to help inform future studies of the relative strength of available approaches in assigning this score. DESIGN: Retrospective chart review. SETTING: PICU at an academic freestanding children's hospital. PATIENTS: Two thousand seven-hundred fifty-two consecutive patients admitted over a 17-month time period were screened for receiving inotrope or vasopressor therapies regardless of disease process. Four-hundred seventy-four patients met inclusion criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For each patient treated with continuous infusions of vasoactive medications, a Vasoactive Inotropic Score was calculated (and then recalculated) every time they had a documented dose change. Multiple strategies were evaluated to generate receiver operating characteristic curves in relation to mortality. Area under the curve was greatest when evaluating the maximum Vasoactive-Inotropic Score (Max Any) during the initial treatment course (0.788) with an increasing relative risk as the score increased. The Vasoactive-Inotropic Score at 48 hours after treatment initiation had next highest area under the curve (0.736). Primary diagnosis categories were also analyzed, and area under the curve was greatest for the cardiovascular group (0.879). CONCLUSIONS: Increasing Vasoactive-Inotropic Scores for patients in the PICU are associated with mortality risk. The scoring strategy used can influence the strength of the association, as can the primary diagnosis category. PMID- 30520840 TI - To PICC or Not to PICC, That Is the Question! PMID- 30520841 TI - Evaluating the Impact of Delaying Parenteral Nutrition in Critically Ill Children. PMID- 30520842 TI - Why Is the Vasoactive-Inotrope Score Like an IV Pole? PMID- 30520843 TI - PICU Autopsies: Every One Is Important. PMID- 30520844 TI - Dear Mommy and Daddy, I Wish to Go Home at the Right Date, Not Too Early But Not Too Late.... PMID- 30520845 TI - Tranexamic Acid and Seizures in Pediatric Trauma. PMID- 30520846 TI - Weighing in on Ventilator Strategies. PMID- 30520847 TI - One More Chasm to Cross for Telemedicine in the ICU? PMID- 30520848 TI - Outcomes of minority patients with very severe hypertension (>220/>120 mmHg). AB - OBJECTIVES: Acute severe hypertension is a common problem among inner-city ethnic minority populations. Nevertheless, the effects of currently employed treatment regimens on blood pressure have not been determined in a clinical practice setting. We determined the SBP responses to acute antihypertensive drug protocols and the 2-year natural history of patients presenting with severe hypertension. METHODS: Retrospective cohort investigation in consecutive patients with SBP at least 220 mmHg and/or DBP at least 120 mmHg during 3-month enrollment in 2014 with 2-year follow-up. Primary outcomes were SBP versus time for the first 5 h of emergency treatment and 2-year follow-up including repeat visits, target organ events, and hospitalizations. RESULTS: One hundred and fifty-six unique patients met criteria with 69% Black; 34% Hispanic; 56% had previous visits for severe hypertension; 31% had preexisting target injury. Acute management: Acute antihypertensive regimens resulted in grossly unpredictable and often exaggerated effects on SBP. Treatment acutely reduced SBP to less than 140 mmHg in 30 of 159 patients. Clonidine reduced SBP to less than 140 mmHg in 19/61. Two-year follow up: We observed 389 repeat visits for severe hypertension, 99 new target events, and 76 hospitalizations accounting for 620 hospital days. CONCLUSION: Acute treatment of severe hypertension produced unpredictable and potentially dangerous responses in SBP. Two-year follow-up demonstrated extraordinary rates of recurrent visits, target organ events, and hospitalizations. Our findings indicate a need to develop effective management strategies to lower blood pressure safely and to prevent long-term consequences. Our findings may apply to other hospitals caring for ethnic minority populations. PMID- 30520850 TI - PCNA News. PMID- 30520849 TI - T-cell Activating Tribodies as a Novel Approach for Efficient Killing of ErbB2 positive Cancer Cells. AB - The Tyrosine Kinase Receptor ErbB2 (HER2) when overexpressed in breast cancer (BC) is associated with poor prognosis. The monoclonal antibody Trastuzumab has become a standard treatment of ErbB2+BC. The antibody treatment has limited efficacy, often meets resistance and induces cardiotoxicity. T-cell recruiting bispecific antibody derivatives (TRBA) offer a more effective alternative to standard antibody therapy. We evaluated a panel of TRBAs targeting 3 different epitopes on the ErbB2 receptor either in a bivalent targeting tribody structure or as a monovalent scFv-fusion (BiTE format) for binding, cytotoxicity on Trastuzumab-resistant cell lines, and induction of cardiotoxicity. All three TRBAs bind with high affinity to the ErbB2 extracellular domain and a large panel of ErbB2-positive tumor cells. Tribodies had an increased in vitro cytotoxic potency as compared to BiTEs. It is interesting to note that, Tribodies targeting the epitopes on ErbB2 receptor domains I and II bind and activate lysis of mammary and gastric tumor cells more efficiently than a Tribody targeting the Trastuzumab epitope on domain IV. The first 2 are also active on Trastuzumab resistant cancer cells lacking or masking the epitope recognized by Trastuzumab. None of the Tribodies studied showed significant toxicity on human cardiomyocytes. Altogether these results make these novel anti-ErbB2 bispecific Tribodies candidates for therapeutic development for treating ErbB2-positive Trastuzumab-resistant cancer patients. PMID- 30520851 TI - Protecting the Evidence Base in a Predatory Environment. PMID- 30520852 TI - Nurses Are Key in Preventing Deadly Diagnostic Errors in Cardiovascular Diseases. PMID- 30520853 TI - Council on Cardiovascular and Stroke Nursing Liaison Report. PMID- 30520854 TI - Effect of Postablation Statin Treatment on Arrhythmia Recurrence in Patients With Paroxysmal Atrial Fibrillation. AB - BACKGROUND: Statins have been proposed as a means to prevent postablation atrial fibrillation (AF) recurrences, mainly on the basis of their pleiotropic effects. The objective of this subanalysis of a prospectively randomized controlled study population of patients undergoing radiofrequency ablation for paroxysmal AF was to test the hypothesis that statin treatment is associated with longer time to recurrence. METHODS AND RESULTS: This is a subanalysis over an extended follow-up period of a prospective randomized study (ClinicalTrials.gov Identifier NCT01791699). Among 291 patients, 2 propensity score-matched subgroups of patients who received or did not receive statins after pulmonary vein isolation were created. In the unmatched cohort, there was no difference in the rate of recurrence between statin-treated and not treated patients, with a 1-year recurrence estimate of 19% and 23%, respectively (Gehan statistic 0.59, P = 0.443). In the propensity-matched cohort (N = 166, 83 per group), recurrence-free survival did not differ significantly between groups (839 days, 95% confidence interval 755-922 days, in the no statin group vs. 904 days, 95% confidence interval 826-983 in the statin group; P = 0.301). The 1-year recurrence rate estimate was 30% in the no statin group versus 27% in the statin group (Gehan statistic 0.56, P = 0.455). CONCLUSION: Statin treatment does not seem to affect AF recurrence in following radiofrequency ablation for paroxysmal AF, over a follow-up time of about 2.5 years. PMID- 30520856 TI - RNA epigenetics spurs investor interest, but uncertainties linger. PMID- 30520855 TI - Taming preeclampsia at its source. PMID- 30520857 TI - Recent patents in neuroengineering. PMID- 30520858 TI - Roche's cell squeeze provokes killers. PMID- 30520859 TI - Building a career planning course for STEM PhDs. PMID- 30520860 TI - RNAi biotechs flush with pharma dollars. PMID- 30520861 TI - Around the world in a month. PMID- 30520862 TI - T cells fingered as culprits for narcolepsy. PMID- 30520863 TI - The myriad targets of a T cell. PMID- 30520864 TI - Correction. PMID- 30520865 TI - Mouse development hits the big screen. PMID- 30520867 TI - Drug pipeline 3Q18. PMID- 30520866 TI - Was the Myriad decision a 'surgical strike' on isolated DNA patents, or does it have wider impacts? PMID- 30520868 TI - People. PMID- 30520870 TI - First edible cottonseed go-ahead. PMID- 30520869 TI - Biopharmaceutical benchmarks 2018. PMID- 30520871 TI - A reference standard for genome biology. PMID- 30520872 TI - Research Highlights. PMID- 30520873 TI - Radioactive drugs emerge from the shadows to storm the market. PMID- 30520874 TI - The European Open Science Cloud and commercialization. PMID- 30520875 TI - To hear a whisper: biotechs chase new thinking to restore hearing. PMID- 30520876 TI - ? PMID- 30520877 TI - [Giornale Italiano di Cardiologia Supplements and the Editor's role]. PMID- 30520878 TI - [Journey around the heart in the movies of the last century: from Charlie Chaplin to the present day]. AB - Imagine a journey through the cinema's history to recover the figure of the doctor in the last century. At the same time, we have found that the progress of medicine has conditioned the stories told on the big screen. Cardiology has achieved a leading role at the cinema when technological innovations have begun to emerge, from the '60s onwards. Indeed, the success of acute myocardial infarction network stimulated the idea of using a movie - Questione di cuore - to tell the course of coronary artery disease in parallel to the life of the two movie's characters, as well as to become a project for a scientific meeting shared with our patients. PMID- 30520879 TI - [What's new in the 2018 ESC guidelines for the diagnosis and management of syncope?] PMID- 30520880 TI - [The CULPRIT-SHOCK trial]. PMID- 30520881 TI - [Do not prescribe or defer treatment: when doing less could be better for the patient]. PMID- 30520882 TI - [Clinical applications of cardiac magnetic resonance imaging: heart failure and cardiomyopathies]. AB - Cardiac magnetic resonance (CMR) has proved to be a powerful tool in the assessment of several cardiac diseases, thanks to its capability to offer multiparametric morphologic and functional evaluation of the heart and great vessels, using neither ionizing radiations nor nephrotoxic contrast medium. The accuracy in quantification of cardiac volumes and ejection fraction (gold standard) together with native and post-contrast myocardial tissue characterization have made CMR an invaluable tool for the diagnosis, prognosis and therapeutic planning in patients with heart failure and cardiomyopathy. PMID- 30520883 TI - [Usefulness, timing and modality of ECG stress testing after myocardial revascularization]. AB - Myocardial revascularization in patients with stable ischemic heart disease aims at eliminating myocardial ischemia, in order to (i) relieve anginal symptoms; (ii) improve functional capacity; and, possibly, (iii) improve prognosis. Given that ischemic recurrences are relatively common in patients undergoing myocardial revascularization, an appropriate follow-up is needed as part of a secondary prevention program. Stress testing can be here useful to: (i) detect residual or recurrent ischemia/angina; (ii) define functional capacity in order to establish physical aerobic training individualized programs; (iii) stratify prognosis. These goals can in large part be achieved by the ECG stress test, by far the cheapest, the easiest to perform and the most accessible test among those proposed so far, particularly compared with other imaging stress test modalities. There is, however, considerable discrepancy among scientific society recommendations on the use, timing and methods of ECG stress testing and of stress testing in general after revascularization. In addition to the diversity of recommendations, the use of stress tests in general is extremely variable in current clinical practice.This review aims therefore at revisiting principles, advantages and limitations of the ECG stress test and of stress tests in general in revascularized patients, highlighting recent developments of the ECG stress technique. This should also aim at issuing new recommendations to avoid the inappropriate prescription of expensive and more cumbersome techniques, to be reserved only to a second-tier diagnostic level and in a minority of cases. PMID- 30520884 TI - ? PMID- 30520885 TI - [The coronary sinus Reducer: a new opportunity for refractory angina. Comparison between Italian experiences]. AB - Refractory angina is a disabling condition that afflicts patients in whom we have no more strategy to improve their quality of life. This phenomenon has been increasing over the last years due to longer life expectancy, also resulting in a significant impact upon healthcare resources. The coronary sinus Reducer is a novel technology designed to improve the quality of life of these patients. The aim of this paper is to provide an overview of the available data regarding this new technology, along with the experience of the three centers that have performed the highest number of implants in Italy, focusing our attention on the clinical presentation of these complex patients and their follow-up. PMID- 30520886 TI - [The second multicenter observational registry on the management of acute ST elevation myocardial infarction in the Veneto Region (VENERE 2)]. AB - BACKGROUND: We sought to evaluate the epidemiology and the management of ST elevation acute myocardial infarction (STEMI) in the Veneto Region (VENERE 2) in 2014, 10 years after a similar survey conducted in the early 2000s. METHODS: Between October 2014 and March 2015, all consecutive patients admitted to the Cardiology Divisions of the Veneto Region with STEMI were enrolled in an observational, prospective, multicenter register, called VENERE 2. The main diagnostic and therapeutic efficiency indicators were analyzed and compared with data from the previous VENERE study performed 10 years earlier. RESULTS: Overall, 1165 patients were enrolled, 902 (77%) with an interval <12 h between symptom onset and diagnosis. The incidence of STEMI was 657/million inhabitants per year (vs 697/million inhabitants in VENERE). For 883 (99%) patients, the chosen reperfusion strategy was primary percutaneous coronary intervention (pPCI) (vs 52.3% in VENERE); among these, 503 (55.8%) alerted the 118 (vs 29.7% in VENERE) and pre-hospital ECG was performed in 319 (35.4%) (vs 0% in VENERE). The proportion of patients who underwent recanalization within 90 min of diagnosis was 76.6% in patients treated in hospitals and 50% in transferred patients (vs 70% and 32% in VENERE, respectively). The median delay between symptom onset and recanalization was 60 min (vs 81 min in VENERE). In-hospital mortality was 5.4% (vs 7.3% in VENERE). The cumulative in-hospital incidence of urgent stroke, reinfarction, urgent revascularization was 5.1% (vs 7.1% in VENERE). CONCLUSIONS: The current reperfusion treatment of STEMI in the Veneto Region is pPCI. Compared to the data of the VENERE registry, an improvement of all diagnostic and therapeutic efficiency indicators was observed. PMID- 30520887 TI - [Regional network for ST-elevation myocardial infarction in Italy: from development to management]. PMID- 30520888 TI - [Intravascular ultrasound-guided antegrade recanalization of a complex chronic total occlusion of the left anterior descending coronary artery: a case report]. AB - Patients with coronary chronic total occlusion (CTO) if symptomatic for angina or with extensive inducible ischemia at provocative tests may be revascularized percutaneously or surgically. Percutaneous revascularization can be performed by antegrade or retrograde approach. In our case, in the presence of a long CTO of the left anterior descending coronary artery, the antegrade approach was chosen using an intravascular ultrasound (IVUS) catheter positioned in a secondary branch, to accurately identify the proximal lesion cap. IVUS is useful for selecting the appropriate stent size and length to ensure lesion coverage and stent optimization and to detect related complications. PMID- 30520889 TI - [When a purely observational approach does not provide reliable evidence]. PMID- 30520890 TI - Direct sampling mass spectrometry for clinical analysis. AB - Direct sampling mass spectrometry (MS) has been advancing aggressively, showing immense potential in translating MS into the clinical field. Unlike traditional MS analysis involving extensive sample preparation and chromatographic separation, quick and simple procedures with minimal sample pretreatment or purification became available with direct sampling. An overview of the development in this field is provided, including some representative ambient ionization and fast extraction methods. Quantitative applications of these methods are emphasized and their efficacy are highlighted from a clinical aspect; non-quantitative applications in clinical analysis are also discussed. This review also discusses the integration of direct sampling MS with miniature mass spectrometers and its future outlook as an emerging clinical tool for point-of care analysis. PMID- 30520891 TI - Water as a structure-driving agent between the UiO-66 and MIL-140A metal-organic frameworks. AB - We report a careful investigation of a selective phase formation in the zirconium terephthalic acid system during solvothermal synthesis, which could result in the UiO-66 (Zr6O6(OH)4(BDC)6) or MIL-140A (ZrO(BDC)) metal-organic frameworks (MOFs). The introduction of water varies the phase from MIL-140A to UiO-66 by producing at the nucleation stage tetragonal ZrO2 nanoparticles, where the local arrangement of Zr and O atoms is similar to that in the UiO-66 SBU. PMID- 30520892 TI - Highly efficient and stable air-processed hole-transport-material free carbon based perovskite solar cells with caesium incorporation. AB - An inorganic caesium cation was incorporated into perovskite to improve the performance and stability of solar cells with a hole-transport-material free structure in ambient air. A triple cation device with a champion power conversion efficiency of over 15% was achieved, exhibiting superior thermal, long-term and operational stabilities. PMID- 30520893 TI - Understanding the role of co-surfactants in microemulsions on the growth of copper oxalate using SAXS. AB - This study is an effort to understand the mechanism of the effect of the chain length of co-surfactants on the growth of copper oxalate inside the core of reverse micelles using small angle X-ray scattering (SAXS). In this study, we have used two different kinds of co-surfactants viz. 1-butanol (C4) and 1-octanol (C8) for the formation of the microemulsions. Time-dependent SAXS studies were carried out for these two systems. The data were analyzed using both the model independent approach and model-dependent approach. For microemulsions containing only water inside the core of reverse micelles (no ions), the shape of the reverse micelles was observed to be ellipsoid and spherical in nature for 1 butanol and 1-octanol respectively. For a system containing copper oxalate nanostructures, the fitting was carried out using the ellipsoidal core-shell model for reverse micelles and spheres, ellipsoids and cylinders for copper oxalate nanostructures with 1-butanol as the co-surfactant. With 1-octanol as the co-surfactant, the two contributions that were used were the spherical core-shell model for reverse micelles and spheres for copper oxalate nanostructures. Based on the analysis of SAXS data, a growth mechanism has been proposed. The study discussed here could open the field of understanding the growth mechanism of complex nanostructures formed using the microemulsion route. PMID- 30520894 TI - SecScan: a general approach for mapping disulfide bonds in synthetic and recombinant peptides and proteins. AB - Selenocysteine scanning (SecScan) is a novel technique to map disulfide networks in proteins independent of structure-based distance information and mass spectrometry. SecScan applies systematic substitution of single Cys by Sec in combination with NMR spectroscopy for reliable and unambiguous determination of disulfide bond networks. PMID- 30520895 TI - Fluorogenic probes for disease-relevant enzymes. AB - Traditional biochemical methods for enzyme detection are mainly based on antibody based immunoassays, which lack the ability to monitor the spatiotemporal distribution and, in particular, the in situ activity of enzymes in live cells and in vivo. In this review, we comprehensively summarize recent progress that has been made in the development of small-molecule as well as material-based fluorogenic probes for sensitive detection of the activities of enzymes that are related to a number of human diseases. The principles utilized to design these probes as well as their applications are reviewed. Specific attention is given to fluorogenic probes that have been developed for analysis of the activities of enzymes including oxidases and reductases, those that act on biomacromolecules including DNAs, proteins/peptides/amino acids, carbohydrates and lipids, and those that are responsible for translational modifications. We envision that this review will serve as an ideal reference for practitioners as well as beginners in relevant research fields. PMID- 30520896 TI - Shell model extension to the valence force field: application to single-layer black phosphorus. AB - We propose an extension of the traditional valence force field model to allow for the effect of electronic polarization to be included in the inter-atomic potential. Using density functional theory as a reference, this model is parameterized for the specific case of single-layer black phosphorus by fitting the phonon dispersion relation over the entire Brillouin zone. The model is designed to account for the effect of induced dipole interaction on the long wavelength (|q[combining right harpoon above]| -> 0) modes for the case of homopolar covalent crystals. We demonstrate that the near Gamma-point frequencies of the IR-active modes are substantially damped by the inclusion of the induced dipole interaction, in agreement with experiment. The fitting procedure outlined here allows for this model to be adapted to other materials, including but not limited to two-dimensional crystals. PMID- 30520897 TI - The effect of nanoconfinement on the glass transition temperature of ionic liquids. AB - This work is concerned with investigating the glass transition behavior of ionic liquids as a function of nanoconfinement. The glass transition temperature was found to increase with a decrease in confinement length, below a critical confinement of 40-50 nm and 80-90 nm for 1-butyl-3-methylimidazolium tetrafluoro borate and 1-methyl-3-octylimidazolium tetrafluoro-borate between alumina surfaces, respectively. PMID- 30520899 TI - Front cover. PMID- 30520898 TI - Organocatalytic [10+4] cycloadditions for the synthesis of functionalised benzo[a]azulenes. AB - A direct and mild strategy for the synthesis of benzo[a]azulenes based on an organocatalytic [10+4] cycloaddition reaction is described. The strategy enables a diversity-oriented approach for the synthesis of various poly-functionalised azulenes from easily accessible starting materials. PMID- 30520900 TI - Inside front cover. PMID- 30520901 TI - Contents list. PMID- 30520902 TI - Inside back cover. PMID- 30520903 TI - Back cover. PMID- 30520904 TI - Contents list. PMID- 30520905 TI - Rational design and observation of the tight interface between graphene and ligand protected nanocrystals. AB - Heterostructures constructed of graphene and colloidal nanocrystals provide a unique way to exploit the coupled physical properties of the two functional building blocks. Studying the interface structure between the two constituent materials is important to understand the formation mechanism and the resulting physical and chemical properties. Along with ab initio calculations, we elucidate that the bending rigidity and the strong van der Waals interaction of graphene to the metal surface guide the formation of a tight and conformal interface. Using theoretical foundations, we construct colloidal nanocrystal-graphene heterostructures with controlled interfacial structures and directly investigate the cross-sectional structures of them at high resolution by using aberration corrected transmission electron microscopy. The experimental method and observations we present here will link the empirical methods for the formation of nanocrystal-graphene heterostructures to the mechanistic understanding of their properties. PMID- 30520906 TI - Excellent benzocoumarin-based ratiometric two-photon fluorescent probe for H2O2 detection. AB - The level of hydrogen peroxide (H2O2) plays an essential role in regulating biological processes. The in vivo or in vitro detection of H2O2 in deep tissues by utilizing two-photon (TP) fluorescent probes can significantly alleviate the detection damage inflicted onto living organisms as well as facilitate high resolution imaging when compared with one-photon (OP) fluorescent probes. However, few TP fluorescent probes possess both high fluorescence efficiency and easily distinguishable spectra for measuring H2O2. Therefore, an in-depth understanding of the relationship between the electronic structure and TP fluorescent properties and fabricating probes with excellent performance are still challenging. Consequently, we designed a series of benzocoumarin-based ratiometric TP fluorescent probes and corresponding product molecules for H2O2 detection. Thereafter, we theoretically evaluated the TP recognition performance of these compounds and studied the relationship between their molecular structure and TP performance by means of time-dependent density functional theory and quadratic response theory. Moreover, we determined their spectral properties and fluorescence efficiencies. Fortunately, in this study, we were able to propose an excellent TP probe BC-3 and the corresponding product molecule DCCA-3, which exhibit large TPA cross-sections in the NIR region (3420 GM/988 nm; 316 GM/939 nm) and large Stokes (116 nm; 60 nm) and emission (225 nm) shifts. Therefore, this probe enables the simultaneous NIR and TP imaging of H2O2, which is a unique ability and has never been previously reported. Moreover, we comprehensively investigated the effect of the benzene-fused position in the coumarin backbone on the transition dipole moment and nonradiative decay channels, explaining the fluorescence near-quenching mechanism of benzo[f]coumarin derivative DCCA-4 for the first time. PMID- 30520907 TI - 14N NQR spectroscopy reveals the proton position in N-HN bonds: a case study with proton sponges. AB - The position of protons in hydrogen bonds is often uncertain to some degree, as the technique most often used for structure determination, X-ray diffraction, is sensitive to electron density, which is not particularly abundant around protons. In hydrogen bonds, protons introduce an additional problem: the potential for proton motion is inherently anharmonic and thus requires the consideration of nuclear quantum effects (NQEs). Here, we demonstrate that 14N NQR spectroscopy is able to rather accurately determine proton positions in N-HN bonds, in certain cases with an accuracy comparable to that of X-ray and neutron diffraction at room temperature. We first derive, using ab initio calculations considering also the NQEs, a relation between the proton distance from the bond midpoint and the difference between the quadrupole coupling constants for the two nitrogen sites. The found relation is linear with a proportionality constant of 0.108 A MHz-1 for tertiary amine nitrogens. Then, we validate our theoretical calculations experimentally, using several 1,8-bis(dimethylamino)naphthalene (DMAN) complexes. PMID- 30520908 TI - A single AT-GC exchange can modulate charge transfer-induced p53-DNA dissociation. AB - Using molecular dynamics simulations and electronic structure theory, we shed light on the charge dynamics that causes the differential interaction of tumor suppressor protein p53 with the p21 and Gadd45 genes in response to oxidative stress. We show that the sequence dependence of this selectivity results from competing charge transfer to the protein and through the DNA, with implications on the use of genome editing tools to influence the p53 regulatory function. PMID- 30520909 TI - Iridium-induced regioselective B-H and C-H activations at azo-substituted m carboranes: facile access to polynuclear complexes. AB - Iridium(iii)-induced selective B(2,3)-H and C-H bond activations at mono- and bi p-methoxybenzeneazo-substituted m-carboranes have been investigated. A powerful methodology is introduced for the preparation of unique polynuclear complexes featuring m-carboranyl ligands in a single step. The experimental results highlight that the base employed in the reaction plays a key role in the formation and the structures of the complexes. PMID- 30520910 TI - Single molecule magnet behaviors of Zn4Ln2 (Ln = DyIII, TbIII) complexes with multidentate organic ligands formed by absorption of CO2 in air through in situ reactions. AB - In this work, we report the syntheses, crystal structures and magnetic properties of three novel Zn-Ln mixed metal complexes, namely [Zn4Dy2(L1)2(L2)2(N3)2]Cl2.2H2O (1), [Zn4Tb2(L1)2(L2)2(Cl)2][ZnN3Cl3].2H2O (2), and [Zn4Gd2(L1)2(L2)2(Cl)2][ZnN3Cl3].2H2O (3), in which L12- and L23- were formed from the ligand L [L = N1,N3-bis(3-methoxysalicylidene)diethylenetriamine] through in situ reactions. Interestingly, carbon dioxide in air was absorbed in the process of forming carbamate ligand L23-; this can be ascribed to the insertion of CO2 into M-N amide bonds. Moreover, 1 and 2 represent the first series of 3d-4f SMMs containing carbamate ligands by fixation of CO2 in air. Single-crystal X-ray diffraction analyses reveal that the crystal structures of 1 and 2 are anion-dependent, i.e., the apical positions of the two ZnII ions in 1 and 2 are occupied by an N atom of N3- and by Cl-, respectively. However, the topologies of 2 and 3 are similar. Two ZnII ions and one LnIII (Ln = Dy (1), Tb (2) and Gd (3)) form nearly linear trinuclear [Zn2Ln] units which are double bridged by two L23- ligands. Magnetic studies reveal that two complexes show single molecule magnet behavior under a direct current (dc) field, with effective energy barriers (Ueff) of 30.66(5) K for 1 and 8.87(3) K for 2. Ab initio calculations reveal that the DyIII ions in 1 and the TbIII ions in 2 are axial in nature; however, a difference in the tunnel splitting of 1 and 2 leads to variation in the magnetization blockades of the two complexes. Theoretical calculations also indicate that the directions of the main magnetic axes severely deviate from the coordination atoms of the first spheres of DyIII and TbIII in 1 and 2; thus further results in poor SMM behavior of the two complexes. PMID- 30520911 TI - Enantioselective synthesis and absolute configuration determination of hydroxywilfordic acid in sesquiterpene pyridine alkaloids. AB - An enantioselective synthetic route to hydroxywilfordic acid, a key subunit of sesquiterpene pyridine alkaloids such as wilfortrine, was developed. Asymmetric cyanation using Jacobsen's (R,R)-amino-thiourea and hydrolysis were performed to afford chiral alpha-hydroxy-alpha-methyl acid as the (S)-isomer. Naturally derived hydroxywilfordate prepared by methanolysis of wilfortrine was found to be the (R)-isomer upon comparison with the synthetic compound. PMID- 30520912 TI - CuO-Coated and Cu2+-doped Co-modified P2-type Na2/3[Ni1/3Mn2/3]O2 for sodium-ion batteries. AB - Layered P2-type CuO-coated Na2/3[Ni1/3Mn2/3]O2 (NNMO@CuO) with excellent rate capability and cycling performance was investigated as a sodium-ion battery cathode material for the first time. The NNMO@CuO cathode material combines the advantages of CuO coating and Cu2+ doping. Transmission electron microscopy (TEM) images, TEM elemental line scan analysis and ex situ scanning electron microscopy (SEM) images show that CuO has been successfully coated on the particle surface uniformly, and that this CuO layer effectively suppresses the exfoliation of the metal oxide layers and unfavorable side reactions. Furthermore, Cu2+ is also partially incorporated into the host structure, according to the X-ray diffraction (XRD) patterns and refinement results. Although incorporated Cu2+ does not take part in the redox reactions of the battery cell, the refinement results indicate that the d-spacing of the Na+-ion diffusion layer is enlarged due to Cu2+ doping in the crystal structure, which results in better Na+ kinetics. Thus, the CuO-coated cathode material shows prominent cycling performance and rate capability. We believe that this CuO-coating and Cu2+-doping co-modification strategy provides a promising approach to designing advanced cathode materials for sodium-ion batteries. PMID- 30520913 TI - Visible-light induced decarboxylative C2-alkylation of benzothiazoles with carboxylic acids under metal-free conditions. AB - An effective protocol of photoredox catalyzed C2-alkylation of benzothiazoles with aliphatic carboxylic acids was disclosed. In the presence of an acridinium salt as a photocatalyst and air as an oxidant, a wide range of secondary or tertiary aliphatic carboxylic acids were employed as alkylation reagents, providing the desired products in good to excellent yields under mild reaction conditions with a broad substrate scope. PMID- 30520914 TI - Extremely selective detection of ppb levels of indoor xylene using CoCr2O4 hollow spheres activated by Pt doping. AB - Ultrahigh gas selectivity and response for ppb levels of xylene are achieved by doping Pt in CoCr2O4 hollow spheres, whereas the addition of Au or Pd is less effective or even deteriorated the performance. PMID- 30520915 TI - Scalable preparation and property investigation of a cis-cyclobutane-1,2 dicarboxylic acid from beta-trans-cinnamic acid. AB - Scalable synthesis of beta-truxinic acid (CBDA-4) was accomplished by capturing and photodimerizing a metastable crystalline solid of trans-cinnamic acid. This synthetic approach builds a foundation for investigating the properties and applications of the useful diacid. The X-ray crystal structure of CBDA-4 was determined for the first time. The cyclobutane ring in CBDA-4 was cleaved upon heating, making it a promising building block for thermally recyclable/degradable materials. PMID- 30520916 TI - Posttranscriptional spin labeling of RNA by tetrazine-based cycloaddition. AB - The site-specific introduction of spin labels into RNA for distance measurements by EPR gives insight into its solution structure. We here present a method for spin labeling of in vitro transcribed RNA. Distance distributions between two nitroxide spin labels are determined by PELDOR in a self-complementary RNA duplex. PMID- 30520917 TI - Contents list. PMID- 30520918 TI - Shear flow simulations of smectic liquid crystals based on the Gay-Berne fluid and the soft sphere string-fluid. AB - We have studied the shear flow of the smectic A phase of three coarse grained liquid crystal model systems, namely two versions of the Gay-Berne fluid and the soft sphere string-fluid. At low shear rates, the orientation where the smectic layers are parallel to the shear plane and the orientation parallel to the vorticity plane are both stable in all the systems. In one of the Gay-Berne fluids, there is a transition from the orientation parallel to the shear plane to the orientation parallel to the vorticity plane. At higher shear rates, a nonequilibrium nematic phase is obtained in all the systems in the same way as in linear alkanes under shear. If the initial configuration is an equilibrium smectic A phase or a nematic phase with the molecules parallel to the streamlines, the orientation parallel to the shear plane is attained at low shear rates in the Gay-Berne fluids. In order to analyze the stability of the different orientations, the torque acting on the liquid crystal is calculated. It consists of an elastic torque caused by deformations due to the shape of the simulation cell and the periodic boundary conditions and a shear-induced torque. The elastic torque stabilizes both the orientation parallel to the shear plane and the orientation parallel to the vorticity plane because the liquid crystal is deformed if it is turned away from these orientations. The shear-induced torque, on the other hand, always turns the liquid crystal to the orientation parallel to the vorticity plane where the viscosity and the irreversible energy dissipation rate are minimal. Since the latter torque is proportional to the square of the shear rate, rather high shear rates are required for it to overwhelm the elastic torque. However, the elastic torque decreases with the system size so that it is likely that the shear-induced torque will dominate in large systems and that the orientation parallel to the vorticity plane will be attained at low or even zero shear rate. PMID- 30520919 TI - Back cover. PMID- 30520920 TI - Controlling the dominant magnetic relaxation mechanisms for magnetic hyperthermia in bimagnetic core-shell nanoparticles. AB - We report a simple and effective way to control the heat generation of a magnetic colloid under alternate magnetic fields by changing the shell composition of bimagnetic core-shell Fe3O4/ZnxCo1-xFe2O4 nanoparticles. The core-shell structure constitutes a magnetically-coupled biphase system, with an effective anisotropy that can be tuned by the substitution of Co2+ by Zn2+ ions in the shell. Magnetic hyperthermia experiments of nanoparticles dispersed in hexane and butter oil showed that the magnetic relaxation is dominated by Brown relaxation mechanism in samples with higher anisotropy (i.e., larger concentration of Co within the shell) yielding high specific power absorption values in low viscosity media as hexane. Increasing the Zn concentration of the shell, diminishes the magnetic anisotropy, which results in a change to a Neel relaxation that dominates the process when the nanoparticles are dispersed in a high-viscosity medium. We demonstrate that tuning the Zn contents at the shell of these exchange-coupled core/shell nanoparticles provides a way to control the magnetic anisotropy without loss of saturation magnetization. This ability is an essential prerequisite for most biomedical applications, where high viscosities and capturing mechanisms are present. PMID- 30520921 TI - Palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole to diastereoselectively access spirooxindoles. AB - A novel palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole with alpha,beta-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in high yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient pathway for the assembly of spirooxindoles. PMID- 30520922 TI - Inside front cover. PMID- 30520923 TI - Correction: Synthesis and application of a highly branched, mechanism-based 2 deoxy-2-fluoro-oligosaccharide inhibitor of endo-xyloglucanases. AB - Correction for 'Synthesis and application of a highly branched, mechanism-based 2 deoxy-2-fluoro-oligosaccharide inhibitor of endo-xyloglucanases' by Namrata Jain et al., Org. Biomol. Chem., 2018, 16, 8732-8741. PMID- 30520924 TI - Correction: A synthetic study toward the core structure of (-)-apicularen A. AB - Correction for 'A synthetic study toward the core structure of (-)-apicularen A' by Tapas R. Pradhan et al., Org. Biomol. Chem., 2018, 16, 8810-8818. PMID- 30520925 TI - Molecules in confinement in clusters, quantum solvents and matrices: general discussion. PMID- 30520927 TI - Inside back cover. PMID- 30520926 TI - Even-odd oscillation of bandgaps in GeP3 nanoribbons and a tunable 1D lateral homogenous heterojunction. AB - GeP3 is a new kind of IV-V two dimensional material that has been predicted very recently. Here, we have theoretically explored the electronic properties of GeP3 nanoribbons (NRs) by employing first-principles calculations within density functional theory. We find that, unlike other monolayer materials, the bandgaps of armchair GeP3 NRs exhibit a strong even-odd oscillation as a function of nanoribbon width and such oscillations can remain intensive even when the width reaches up to 9 nm. The underlying physics of such oscillation originates from both the parity-dependent geometric symmetry and quantum size effects. Furthermore, we also find that suitable chemical decoration at the nanoribbon edge, e.g., by passivating hydrogen atoms, effectively tunes the indirect band gap into a direct one, making these nanoribbons potentially important for photovoltaic applications. Based on the strong bandgap oscillating nature of GeP3 NRs, we have conceptually designed a lateral homogenous heterojunction, constructed by GeP3 nanoribbons with different widths, which has shown a type-II band alignment beneficial for photo-detector applications. PMID- 30520928 TI - A mitochondria-targeted near-infrared fluorescent probe with a large Stokes shift for real-time detection of hypochlorous acid. AB - Hypochlorous acid (HOCl) has been known to be intertwined with various pathophysiological processes. In this paper, a novel mitochondria-targeted near infrared (NIR) fluorescent probe L based on a chromenylium-phenothiazine conjugate has been designed and synthesized for the detection of hypochlorous acid. Due to the HOCl-promoted intramolecular charge transfer processes, the probe L shows near-infrared fluorescence emission at 672 nm, large Stokes shifts of 97 nm, fast response, and high selectivity and sensitivity. Furthermore, the probe L is biocompatible, cell-membrane permeable and mitochondria-targetable, and can be used for endogenous HOCl imaging in living cells. PMID- 30520929 TI - Revisiting the strong stretching theory for pH-responsive polyelectrolyte brushes: effects of consideration of excluded volume interactions and an expanded form of the mass action law. AB - In this paper, we develop a theory to account for the effect of excluded volume (EV) interactions in the strong stretching theory (SST) based description of pH responsive polyelectrolyte (PE) brushes. The existing studies have considered the PE brushes to be present in a theta-solvent and hence have neglected the EV interactions; however, such a consideration cannot describe the situations where the pH-responsive brushes are in a "good" solvent. Secondly, we consider a more expanded form of the mass action law, governing the pH-dependent ionization of the PE molecules, in the SST description of the PE brushes. This expanded form of the mass action law considers different values of gammaa3 (gamma is the density of chargeable sites on the PE molecule and a is the PE Kuhn length) and therefore is an improvement over the existing SST models of PE brushes as well as other theories involving pH-responsive PE molecules that always consider gammaa3 = 1. Our results demonstrate that the EV effects enhance the brush height by inducing additional PE inter-segmental repulsion. Similarly, the consideration of the expanded form of the mass action law would lead to a reduced (enhanced) brush height for gammaa3 < 1 (gammaa3 > 1). We also quantify variables such as the monomer density distribution, the distribution of the ends of the PE brush, and the EDL electrostatic potential and explain their differences with respect to those obtained with no EV interactions or gammaa3 = 1. PMID- 30520930 TI - Spin-echo small-angle neutron scattering (SESANS) studies of diblock copolymer nanoparticles. AB - Poly(glycerol monomethacrylate)-poly(benzyl methacrylate) (PGMA-PBzMA) diblock copolymer nanoparticles were synthesized via polymerization-induced self-assembly (PISA) using reversible addition-fragmentation chain-transfer (RAFT) aqueous emulsion polymerization in D2O. Such PISA syntheses produce sterically-stabilized nanoparticles in situ and can be performed at relatively high copolymer concentrations (up to 50 wt%). This PGMA-PBzMA formulation is known to form only spherical nanoparticles in water using aqueous emulsion polymerization (Macromolecules, 2014, 47, 5613-5623), which makes it an ideal model system for exploring new characterization methods. The polymer micelles were characterized using small-angle X-ray scattering (SAXS) and a recently developed form of neutron scattering, spin-echo small-angle neutron scattering (SESANS). As far as we are aware, this is the first report of a study of polymer micelles by SESANS, and the data agree well with reciprocal-space scattering. Using this technique enables characterization of the concentrated, as synthesized dispersions directly without dilution, and this will provide a method to study self-assembled polymer systems that have concentration dependent morphologies, while still maintaining the advantages of scattering techniques. PMID- 30520932 TI - Front cover. PMID- 30520931 TI - Alkoxyallene-based syntheses of preussin and its analogs and their cytotoxicity. AB - Short syntheses of oxa-preussin, racemic preussin and (-)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (-)-preussin with an enantiomeric ratio of >95 : 5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (-) preussin, were identified as highly cytotoxic with IC50 values in the range of 3 6 MUM. PMID- 30520933 TI - Radical SAM-dependent adenosylation catalyzed by l-tyrosine lyases. AB - The radical S-adenosylmethionine (SAM) superfamily is currently the largest known enzyme family. These enzymes reductively cleave SAM to produce a highly reactive 5'-deoxyadenosyl (dAdo) radical, which abstracts a hydrogen from the substrate and initiates diverse reactions. The canonic dAdo radical-mediated hydrogen abstraction can be changed to radical addition reactions by using olefin containing substrate analogues, which result in adenosylation reactions. Here we report investigation of the adenosylation reactions catalyzed by four radical SAM l-Tyr lyases (RSTLs), including HydG, FbiC, and two ThiH enzymes from different organisms. We show RSTLs have diverse substrate specificity, and ThiH from E. coli exhibits the highest substrate tolerance toward the tested substrates. We also show ThiH from Clostridium berjerinckii does not act on 4-amino-l phenylalanine, but catalyzes adenosylation of the corresponding olefin-containing analogue, suggesting adenosylation may occur more easily than the canonic radical SAM reactions. Our study highlights the remarkable catalytic promiscuity of radical SAM enzyme and the potential in using these enzymes for the synthesis of nucleotide-containing compounds. PMID- 30520934 TI - A Woman With Fluctuating Left Eye Swelling and Redness. PMID- 30520935 TI - Moving Beyond Limited and Extensive Staging of Small Cell Lung Cancer. PMID- 30520937 TI - Whatever Happened to Local Otolaryngology Societies? PMID- 30520936 TI - Assessment of Frequency and Reporting of Changes in Cancer Trial Design After Initiation of Patient Accrual. PMID- 30520938 TI - Incorrect Treatment Group in Results and Error in Legend of Figure 2. PMID- 30520939 TI - Health as a Way of Doing Business. PMID- 30520940 TI - ARGDIT: A Validation and Integration Toolkit for Antimicrobial Resistance Gene Databases. AB - Motivation: Antimicrobial resistance is currently one of the main challenges in public health due to the excessive use of antimicrobials in medical treatments and agriculture. The advancements in high throughput next-generation sequencing and development of bioinformatics tools allow simultaneous detection and identification of antimicrobial resistance genes (ARGs) from clinical, food and environment samples, to monitor the prevalence and track the dissemination of these ARGs. Such analyses are however reliant on a comprehensive database of ARGs with accurate sequence content and annotation. Most of the current ARG databases are therefore manually curated, but this is a time-consuming process and the resulting curation errors could be hard to detect. Several secondary ARG databases consolidate contents from different source ARG databases, and hence modifications in the primary databases might not be propagated and updated promptly in the secondary ARG databases. Results: To address these problems, a validation and integration toolkit called ARGDIT was developed to validate ARG database fidelity, and merge multiple primary ARG databases into a single consolidated secondary ARG database with optional automated sequence re annotation. Experimental results demonstrated the effectiveness of this toolkit in identifying errors such as sequence annotation typos in current ARG databases and generating an integrated non-redundant ARG database with structured annotation. A toolkit-oriented workflow is also proposed to minimize the efforts in validating, curating, and merging multiple ARG protein or coding sequence databases. Database developers therefore benefit from faster update cycles and lower costs for database maintenance, while ARG pipeline users can easily evaluate the reference ARG database quality. Availability: ARGDIT is available at https://github.com/phglab/ARGDIT. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30520942 TI - Pretreatment Hearing Level-Another Prognostic Factor in Sudden Sensorineural Hearing Loss. PMID- 30520943 TI - Association Between Noninfectious Uveitis and Psychological Stress and the Importance of Holistic Management: Treating the Patient With Uveitis as an Individual-Not a Disease. PMID- 30520941 TI - Loss of CXCR4 on non-classical monocytes in participants of the Women's Interagency HIV Study (WIHS) with subclinical atherosclerosis. AB - Aims: To test whether human immunodeficiency virus (HIV) infection and subclinical cardiovascular disease (sCVD) are associated with expression of CXCR4 and other surface markers on classical, intermediate, and non-classical monocytes in women. Methods and Results: sCVD was defined as presence of atherosclerotic lesions in the carotid artery in 92 participants of the Women's Interagency HIV Study (WIHS). Participants were stratified into 4 sets (n = 23 each) by HIV and sCVD status (HIV-/sCVD-, HIV-/sCVD+, HIV+/sCVD-, HIV+/sCVD+) matched by age, race/ethnicity, and smoking status. Three subsets of monocytes were determined from archived peripheral blood mononuclear cells. Flow cytometery was used to count and phenotype surface markers. We tested for differences by HIV and sCVD status accounting for multiple comparisons. We found no differences in monocyte subset size among the 4 groups. Expression of seven surface markers differed significantly across the three monocyte subsets. CXCR4 expression (median fluorescence intensity, MFI) in non-classical monocytes was highest among HIV /CVD- (628, IQR (295-1389)), followed by HIV+/CVD- (486, IQR (248-699)), HIV-/CVD + (398, IQR (89-901)), and lowest in HIV+/CVD+ women (226, IQR (73-519)), P = 0.006 in ANOVA. After accounting for multiple comparison (Tukey) the difference between HIV-CVD- vs HIV+CVD+ remained significant with P = 0.005 (HIV-CVD- vs HIV+CVD- P = 0.04, HIV-CVD- vs HIV-CVD+ P = 0.06, HIV+CVD+ vs HIV+CVD- P = 0.88, HIV+CVD+ vs HIV-CVD+ P = 0.81, HIV+CVD- vs HIV-CVD+, P = 0.99). All pairwise comparisons with HIV-CVD- were individually significant (P = 0.050 vs HIV-CVD+, P = 0.028 vs HIV+CVD-, P = 0.009 vs HIV+CVD+). CXCR4 expression on non-classical monocytes was significantly higher in CVD- (501.5, IQR (249.5-887.3)) vs CVD + (297, IQR (81.75-626.8) individuals (P = 0.028, n = 46 per group). CXCR4 expression on non-classical monocytes significantly correlated with cardiovascular and HIV-related risk factors including systolic blood pressure, platelet and T cell counts along with duration of antiretroviral therapy (P < 0.05). In regression analyses, adjusted for education level, study site, and injection drug use, presence of HIV infection and sCVD remained significantly associated with lower CXCR4 expression on non-classical monocytes (P = 0.003), but did not differ in classical or intermediate monocytes. Conclusion: CXCR4 expression in non-classical monocytes was significantly lower among women with both HIV infection and sCVD, suggesting a potential atheroprotective role of CXCR4 in non-classical monocytes. PMID- 30520944 TI - Pretest probability for patients with suspected obstructive coronary artery disease: re-evaluating Diamond-Forrester for the contemporary era and clinical implications: insights from the PROMISE trial. AB - Aims: To update pretest probabilities (PTP) for obstructive coronary artery disease (CAD >= 50%) across age, sex, and clinical symptom strata, using coronary computed tomography angiography (CTA) in a large contemporary population of patients with stable chest pain referred to non-invasive testing. Methods and results: We included patients enrolled in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial and randomized to CTA. Exclusively level III-certified readers, blinded to demographic and clinical data, assessed the prevalence of CAD >= 50% in a central core lab. After comparing the recent European Society of Cardiology-Diamond and Forrester PTP (ESC-DF) with the actual observed prevalence of CAD >= 50%, we created a new PTP set by replacing the ESC-DF PTP with the observed prevalence of CAD >= 50% across strata of age, sex, and type of angina. In 4415 patients (48.3% men; 60.5 +/- 8.2 years; 78% atypical angina; 11% typical angina; 11% non-anginal chest pain), the observed prevalence of CAD >= 50% was 13.9%, only one-third of the average ESC-DF PTP (40.6; P < 0.001 for difference). The PTP in the new set ranged 2-48% and were consistently lower than the ESC-DF PTP across all age, sex, and angina type categories. Initially, 4284/4415 (97%) patients were classified as intermediate probability by the ESC-DF (PTP 15-85%); using the PROMISE-PTP, 50.2% of these patients were reclassified to the low PTP category (PTP < 15%). Conclusion: The ESC-DF PTP overestimate vastly the actual prevalence of CAD >= 50%. A new set of PTP, derived from results of non-invasive testing, may substantially reduce the need for non-invasive tests in stable chest pain. PMID- 30520945 TI - Alfred: Interactive multi-sample BAM alignment statistics, feature counting and feature annotation for long- and short-read sequencing. AB - Summary/Motivation: Harmonizing quality control of large-scale second and third generation sequencing datasets is key for enabling downstream computational and biological analyses. We present Alfred, an efficient and versatile command-line application that computes multi-sample quality control metrics in a read-group aware manner, across a wide variety of sequencing assays and technologies. In addition to standard quality control metrics such as GC bias, base composition, insert size and sequencing coverage distributions it supports haplotype-aware and allele-specific feature counting and feature annotation. The versatility of Alfred allows for easy pipeline integration in high-throughput settings, including DNA sequencing facilities and large-scale research initiatives, enabling continuous monitoring of sequence data quality and characteristics across samples. Alfred supports haplo-tagging of BAM/CRAM files to conduct haplotype-resolved analyses in conjunction with a variety of next-generation sequencing based assays. Alfred's companion web application enables interactive exploration of results and comparison to public data sets. Availability: Alfred is open-source and freely available at https://tobiasrausch.com/alfred/. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30520946 TI - Sources of Variation in the Adult Flight of Walnut Husk Fly (Diptera: Tephritidae): A Phenology Model for California Walnut Orchards. AB - A phenology model of the walnut husk fly, Rhagoletis completa Cresson, was developed to more accurately predict the timing of the flight period and optimize management decisions. A data set of 153 orchard years in which adults were trapped throughout the season was used for the development and validation of this model. Data from California Irrigation Management Information System (CIMIS) weather stations were used to match orchard-year datasets with historical climatic data on degree-day (DD) accumulation, winter chill, and winter rainfall. A cumulative Weibull distribution was used to model the relationship between cumulative trap catch and DD accumulation for R. completa in California. The model was used to predict thermal requirements for the start (5% cumulative trap catch) and mid-point (50% cumulative trap catch) of the flight period, which were 1,670 and 2,179 DDs, respectively. The prediction for 50% cumulative trap catch of R. completa in California was much higher than the thermal requirement estimated in Oregon previously (1,751 DDs). Linear mixed effects models were used to evaluate other environmental and orchard-specific factors which could explain the large variation between predicted and observed thermal requirements for both the start and mid-point of the flight period. Latitude, walnut cultivar leaf-out time, orchard age and year, as a continuous variable, all contributed significantly to explain deviations from the predictions of the DD model for individual orchard years. Such factors can be used both to adjust predicted thermal requirements for these two specific and informative stages of the flight period, and to provide a basis for ecological and evolutionary hypotheses. PMID- 30520947 TI - Assessment of ERBB2/HER2 Status in HER2-Equivocal Breast Cancers by FISH and 2013/2014 ASCO-CAP Guidelines. AB - Importance: The 2013/2014 American Society of Clinical Oncology and College of American Pathologists (ASCO-CAP) guidelines for HER2 testing by fluorescence in situ hybridization (FISH) designated an "equivocal" category (average HER2 copies per tumor cell >=4-6 with HER2/CEP17 ratio <2.0) to be resolved as negative or positive by assessments with alternative control probes. Approximately 4% to 12% of all invasive breast cancers are characterized as HER2-equivocal based on FISH. Objective: To evaluate the following hypotheses: (1) genetic loci used as alternative controls are heterozygously deleted in a substantial proportion of breast cancers; (2) use of these loci for assessment of HER2 by FISH leads to false-positive assessments; and (3) these HER2 false-positive breast cancer patients have outcomes that do not differ from clinical outcomes for patients with HER2-negative breast cancer. Design, Setting, and Participants: We retrospectively assessed the use of chromosome 17 p-arm and q-arm alternative control genomic sites (TP53, D17S122, SMS, RARA, TOP2A), as recommended by the 2013/2014 ASCO-CAP guidelines for HER2 testing, in patients whose data were available through Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and whose tissues were available through the Breast Cancer International Research Group clinical trials. We used data from an international cohort database of invasive breast cancers (1980 participants) and international clinical trial of adjuvant chemotherapy in invasive, node-positive breast cancer patients. Main Outcomes and Measures: The primary objectives were to (1) assess frequency of heterozygous deletions in chromosome 17 genomic sites used as FISH internal controls for evaluation of HER2 status among HER2-equivocal cancers; (2) characterize impact of using deleted sites for determination of HER2-to-internal control-gene ratios; (3) assess HER2 protein expression in each subgroup; and (4) compare clinical outcomes for each subgroup. Results: Of the 1980 patients in METABRIC,1915 patients were fully evaluated. In addition, 100 HER2-equivocal breast cancers by FISH and 100 comparator FISH-negative breast cancers from the BCIRG-005 trial were analyzed. Heterozygous deletions, particularly in specific p arm sites, were common in both HER2-amplified and HER2-not-amplified breast cancers. Use of alternative control probes from these regions to assess HER2 by FISH in HER2-equivocal as well as HER2-not-amplified breast cancers resulted in high rates of false-positive ratios (HER2-to-alternative control ratio >=2.0) owing to heterozygous deletions of control p-arm genomic sites used in ratio denominators. Misclassification of HER2 status was observed not only in breast cancers with ASCO-CAP equivocal status but also in breast cancers with an average of fewer than 4.0 HER2 copies per tumor cell when using alternative control probes. Conclusions and Relevance: The indiscriminate use of alternative control probes to calculate HER2 FISH ratios in HER2-equivocal breast cancers may lead to false-positive interpretations of HER2 status resulting from unrecognized heterozygous deletions in 1 or more of these alternative control genomic sites and incorrect HER2 ratio determinations. PMID- 30520948 TI - Whole-genome sequence of the oriental lung fluke Paragonimus westermani. AB - Background: Foodborne infections caused by lung flukes of the genus Paragonimus are a significant and widespread public health problem in tropical areas. Around 50 Paragonimus species have been reported to infect animals and humans, but Paragonimus westermani is responsible for the bulk of human disease. Despite their medical and economic importance, no genome sequence for any Paragonimus species is available. Results: We sequenced and assembled the genome of P. westermani, which is among the largest of the known pathogen genomes with an estimated size of 1.1 Gb. A 922.8 Mb genome assembly was generated from Illumina and PacBio sequence data, covering 84% of the estimated genome size. The genome has a high proportion (45%) of repeat-derived DNA, particularly of the LINE and LTR subtypes, and the expansion of these elements may explain some of the large size. We predicted 12,852 protein coding genes, showing a high level of conservation with related trematode species. The majority of proteins (80%) had homologs in the human liver fluke Opisthorchis viverrini with an average sequence identity of 64.1%. Assembly of the P. westermani mitochondrial genome from long PacBio reads resulted in a single high-quality circularized 20.6 kb contig. The contig harboured a 6.9 kb region of non-coding repetitive DNA comprised of three distinct repeat units. Our results suggest that the region is highly polymorphic in P. westermani, possibly even within single worm isolates. Conclusions: The generated assembly represents the first Paragonimus genome sequence and will facilitate future molecular studies of this important, but neglected, parasite group. PMID- 30520949 TI - Eye and Vision Health for Tomorrow: From Recommendations to Coordinated Action. AB - In 2016, the report Making Eye Health a Population Health Imperative: Vision for Tomorrow was published by the National Academies of Sciences, Engineering, and Medicine. Conference presentations and key stakeholder discussions have continued the dialogue initiated by this report. In 2018, a stakeholder meeting assessed the feasibility of establishing a backbone organization, a national center that can provide technical and resource assistance regarding eye and vision health. This meeting also resulted in a consensus to translate the report recommendations into action through 7 core functions: (1) supporting ongoing surveillance efforts, (2) establishing and strengthening a national multisector network of partner organizations, (3) creating an online vision and population health toolkit, (4) integrating and expanding early-detection initiatives across diverse clinical and nonclinical settings, (5) expanding eye and vision health education, (6) identifying and disseminating evidence-based interventions, and (7) exploring the integration of eye and vision health interventions into broader chronic care models. The report's recommendations aim to improve vision and health equity in the United States and should be implemented through an ongoing centrally coordinated campaign. PMID- 30520950 TI - Corrigendum to 'Simulating the ideal geometrical and biomechanical parameters of the pulmonary autograft to prevent failure in the Ross operation' [Interactive CardioVascular and Thoracic Surgery 2018;27:269-276]. PMID- 30520951 TI - Role of epithelial-to-mesenchymal transition in inflammatory bowel disease. AB - Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease (IBD), occurring in its two major clinical manifestations: ulcerative colitis and Crohn's disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to mesenchymal transition (EMT) represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in inflammatory bowel disease-associated intestinal fibrosis and fistulae formation. In addition, we briefly review the knowledge acquired on the cognate process of endothelial-to mesenchymal transition (EndMT). Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal program will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine. PMID- 30520952 TI - Let me out-of the Synthes fixation system. PMID- 30520954 TI - Trastuzumab Therapy for 9 Weeks vs 1 Year for Human Epidermal Growth Factor 2 Positive Breast Cancer-Reply. PMID- 30520953 TI - Assessment of Hedgehog Signaling Pathway Activation for Craniofacial Bone Regeneration in a Critical-Sized Rat Mandibular Defect. AB - Importance: Osseous craniofacial defects are currently reconstructed with bone grafting, rigid fixation, free tissue transfer, and/or recombinant human bone morphogenetic protein 2. Although these treatment options often have good outcomes, they are associated with substantial morbidity, and many patients are not candidates for free tissue transfer. Objective: To assess whether polysaccharide-based scaffold (PS) constructs that are cross-linked with smoothened agonist (SAG), vascular endothelial growth factor (VEGF), and bone morphogenetic protein 6 (BMP-6) would substantially increase bone regeneration. Design, Setting, and Participants: This animal model study was conducted at the University of Virginia School of Medicine Cui Laboratory from March 1, 2017, to June 30, 2017. Thirty-three 10-week-old female Lewis rats were acquired for the study. Bilateral nonsegmental critical-sized defects were created in the angle of rat mandibles. The defects were either left untreated or filled with 1 of the 9 PSs. The rats were killed after 8 weeks, and bone regeneration was evaluated using microcomputed tomographic imaging and mechanical testing. Analysis of variance testing was used to compare the treatment groups. Main Outcomes and Measures: Blinded analysis and computer analysis of the microcomputed tomographic images were used to assess bone regeneration. Results: In the 33 female Lewis rats, minimal healing was observed in the untreated mandibles. Addition of SAG was associated with increases in bone regeneration and bone density in all treatment groups, and maximum bone healing was seen in the group with BMP-6, VEGF, and SAG cross-linked to PS. For each of the 5 no scaffold group vs BMP-6, VEGF, and SAG cross-linked to PS group comparisons, mean defect bone regeneration was 4.14% (95% CI, 0.94%-7.33%) vs 66.19% (95% CI, 54.47%-77.90%); mean bone volume, 14.52 mm3 (95% CI, 13.07-15.97 mm3) vs 20.87 mm3 (95% CI, 14.73- 27.01 mm3); mean bone surface, 68.97 mm2 (95% CI, 60.08-77.85 mm2) vs 96.77 mm2 (95% CI, 76.11-117.43 mm2); mean ratio of bone volume to total volume, 0.11 (95% CI, 0.10-0.11) vs 0.15 (95% CI, 0.10-0.19); and mean connectivity density 0.03 (95% CI, 0.02-0.05) vs 0.32 (95% CI, 0.25-0.38). On mechanical testing, mandibles with untreated defects broke with less force than control mandibles in which no defect was made, although this force did not reach statistical significance. No significant difference in force to fracture was observed among the treatment groups. Conclusions and Relevance: In this rat model study, activation of the hedgehog signaling pathway using smoothened agonist was associated with increased craniofacial bone regeneration compared with growth factors alone, including US Food and Drug Administration-approved recombinant human bone morphogenetic protein 2. Pharmaceuticals that target this pathway may offer a new reconstructive option for bony craniofacial defects as well as nonunion and delayed healing fractures. Level of Evidence: NA. PMID- 30520955 TI - Association of Audiometric Age-Related Hearing Loss With Depressive Symptoms Among Hispanic Individuals. AB - Importance: Age-related hearing loss is highly prevalent and has recently been associated with numerous morbid conditions of aging. Late-life depression is also prevalent and can be resistant to available treatments. Preliminary studies examining the association between hearing loss and late-life depression have been limited by subjective hearing measures, small sample sizes, and primarily white populations. Objective: To assess whether a cross-sectional association exists between objective audiometric hearing loss and depressive symptoms in older Hispanic adults. Design, Setting, and Participants: This cross-sectional study uses 2008-2011 Hispanic Community Health Study/Study of Latinos data collected in Miami, Florida, San Diego, California, Chicago, Illinois, or the Bronx, New York, from 5328 Hispanic adults 50 years or older who had exposure, outcome, and covariate data. Data analyses were conducted from March 2018 to September 2018. Exposure: Audiometric hearing loss (pure-tone average). Main Outcomes and Measures: Center for Epidemiologic Studies Depression Scale, 10-item version (CESD-10) score of 10 or higher, which indicates clinically significant depressive symptoms. Results: The median age (interquartile range) of the 5328 participants was 58 (53-63) years, and 3283 participants (61.6%) were female. The mean (SD) CESD-10 score was 7.7 (6.4). Of the 5328 included participants, 1751 (32.9%) had clinically significant depressive symptoms. The odds of having these symptoms increased 1.44 (95% CI, 1.27-1.63) times for every 20 dB of hearing loss, adjusting for hearing aid use, age, sex, educational level, study site, geographic background, cardiovascular disease, and antidepressant use. Compared with those for individuals with normal hearing (0 dB), the odds of having clinically significant depressive symptoms was 1.81 (95% CI, 1.48-2.22) times as high in individuals with mild hearing loss (median threshold, 32.5 dB), 2.38 (95% CI, 1.77-3.20) times as high in individuals with moderate hearing loss (median threshold, 47.5 dB), and 4.30 (95% CI, 2.61-7.09) times as high in individuals with severe hearing loss (median threshold, 80 dB). Conclusions and Relevance: Objective hearing loss appears to be associated with clinically significant depressive symptoms in older Hispanic people, with greater hearing loss seemingly associated with greater odds of having depressive symptoms. Given the high prevalence of untreated hearing loss in older adults, hearing loss may be a potentially modifiable risk factor for late-life depression. PMID- 30520956 TI - In silico error correction improves cfDNA mutation calling. AB - Motivation: Circulating-free DNA (cfDNA) profiling by sequencing is an important minimally invasive protocol for monitoring the mutation profile of solid tumours in cancer patients. Since the concentration of available cfDNA is limited, sample library generation relies on multiple rounds of PCR amplification, during which the accumulation of errors results in reduced sensitivity and lower accuracy. Results: We present PCR Error Correction (PEC), an algorithm to identify and correct errors in short read sequencing data. It exploits the redundancy that arises from multiple rounds of PCR amplification. PEC is particularly well suited to applications such as single-cell sequencing and circulating tumour DNA (ctDNA) analysis, in which many cycles of PCR are used to generate sufficient DNA for sequencing from small amounts of starting material. When applied to ctDNA analysis, PEC significantly improves mutation calling accuracy, achieving similar levels of performance to more complex strategies that require additional protocol steps and access to calibration DNA datasets. Availability and implementation: PEC is available under the GPL-v3 Open Source licence, and is freely available from: https://github.com/CRUKMI-ComputationalBiology/PCR_Error_Correction.git. Supplementary information: Supplementary figures are available at Bioinformatics online. PMID- 30520957 TI - Association Between Noninfectious Uveitis and Psychological Stress. AB - Importance: Uveitis involves dysregulation of the ocular immune system. Stress has been shown to affect immune function, but it is unclear whether there is an association between stress and uveitis. Objective: To determine whether having uveitis is associated with psychological stress. Design, Setting, and Participants: A cross-sectional, case-control study including a self-administered survey, medical records review, and diurnal salivary cortisol test was conducted at a university-based uveitis clinic and comprehensive eye clinic. Participants included 146 consecutive adults with noninfectious uveitis and age-matched controls with no eye disease. The study was conducted from December 1, 2017, to March 14, 2018. Main Outcomes and Measures: Participants completed the self administered, Cohen 10-item Perceived Stress Scale (PSS-10), a demographics questionnaire. Responses to each question were categorized on a 5-point Likert scale, with total scores ranging from 0 (no stress) to 40 (high stress). In addition, participants submitted 3 salivary cortisol samples. Those with uveitis were classified as having recently active or controlled disease through medical records review. The prespecified primary analysis was a linear regression of PSS 10 score and uveitis correcting for age, sex, educational level, employment, and median income. Secondary analyses included comparing PSS-10 scores in patients with recently active and controlled uveitis, determining predictors of stress, and comparing diurnal salivary cortisol between uveitis and control groups. Results: Of 146 eligible patients, 17 declined participation and 9 consented but were excluded because they did not complete both questionnaires, resulting in 120 patients (80 uveitis; 40 controls) in the final analysis. Eighty participants (66.7%) were women, and 70 (58.3%) were white. Median age was 40 years (interquartile range, 29-59 years). Having uveitis was associated with a 4.3 point increase in PSS-10 score (95% CI, 1.8 to 6.9; P = .002). There was no significant difference in PSS-10 scores between patients with recently active and controlled uveitis (1.0 point greater for patients with active uveitis; 95% CI, 2.0 to 3.9; P = .52). Factors associated with increased PSS-10 score in patients with uveitis included female sex (coefficient, 4.0; 95% CI, 1.6 to 6.5; P = .002), current immunomodulatory therapy (coefficient, 2.5; 95% CI, -0.3 to 5.2; P = .08), history of depression (coefficient, 3.8; 95% CI, 0.8 to 6.8; P = .02), and having posterior or panuveitis (coefficient, 2.6; 95% CI, 0.8 to 4.4; P = .006). Of the 70 participants (58.3%) who had testable samples for cortisol analysis, diurnal salivary cortisol levels did not significantly differ between uveitis and nonuveitis groups. Conclusions and Relevance: These findings suggest that patients with uveitis have higher levels of psychological stress compared with controls, yet no significant difference was identified in the stress of patients with active vs controlled uveitis. Consequently, comprehensive treatment for noninfectious uveitis may be able to address the psychological results of this disease. PMID- 30520958 TI - Deriving an Adolescent Executive Behavior Screener from the Behavior Assessment System for Children-2. AB - Objective: Typical executive functioning (EF) measurements do not reflect the complexity of daily life. We derived an executive behavior screener from the BASC 2-PRS-A using a previously derived four-component model of EF and provided support for the use of the screener in adolescent populations. Methods: A total of 2,722 census-matched American adolescents were sampled. We assigned 25 items a priori to four executive factors (problem solving, attentional control, behavioral control, and emotional control) and evaluated via confirmatory factor analysis, invariance testing and differential item functioning (DIF) models. Results: We found acceptable-to-good reliability and that the four-factor model had the best fit. We showed DIF for age and socioeconomic status (SES). While groups were invariant based on sex, latent mean comparisons showed significant differences. Conclusions: Construct validity of the adolescent four-factor model as measured through the screener was supported. Females demonstrated fewer executive behavior problems. Standardized norms are available and split by age and sex. SES may influence the interpretation of T-scores. Continued exploration and development of the screener is suggested. PMID- 30520959 TI - Assessment of Publication Bias and Systematic Review Findings in Top-Ranked Otolaryngology Journals. PMID- 30520960 TI - Impact of HLA allele-KIR pairs on HIV clinical outcome in South Africa. AB - Background: HLA class I contributes to HIV immune control through antigen presentation to both cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. However, by contrast with investigations of CTL, studies of NK cells in HIV control through HLA-killer immunoglobulin-like receptor (KIR) interactions remain sparse in African cohorts. Methods: 312 treatment naive, chronically HIV infected adults were recruited from South Africa, and the effects of HLA-KIR pairs on clinical outcome were statistically analyzed. Results: There was no significant difference in viral load among all subjects with HLA alleles from the HLA-C1 group (p=0.1). However, differences in HLA-C type significantly influenced viremia among 247 KIR2DL3 positives (p=0.04), suggesting that specific HLA-KIR interactions contribute to immune control. Higher viral load (p=0.02) and lower CD4+ T cell counts (p=0.008) were observed in subjects with HLA-C*16:01+KIR2DL3+. Longitudinal analysis showed more rapid progression to AIDS among HLA C*16:01+KIR2DL3+ positives (aHR 1.9, p=0.03) than in subjects without this genotype, independent of CD4+ T cell count and viral load. Conclusions: These highlight the existence of unique anti-HIV innate immunity within distinct populations and the contribution of KIR on NK cells and some CTLs to the well described HLA-mediated impact on HIV disease progression. PMID- 30520961 TI - Protein-protein interaction sites prediction by ensemble random forests with synthetic minority oversampling technique. AB - Motivation: The prediction of protein-protein interaction (PPI) sites is a key to mutation design, catalytic reaction, and the reconstruction of PPI networks. It is a challenging task considering the significant abundant sequences and the imbalance issue in samples. Results: A new ensemble learning based method, EL SMURF, was proposed for PPI sites prediction in this study. The sequence profile feature and the residue evolution rates were combined for feature extraction of neighboring residues using a sliding window, and the synthetic minority oversampling technique was applied to oversample interface residues in the feature space for the imbalance problem. The multidimensional scaling feature selection method was implemented to reduce feature redundancy and subset selection. Finally, the Random Forest classifiers were applied to build the ensemble learning model, and the best feature vectors were inserted into EL-SMURF to predict PPI sites. The performance validation of EL-SMURF on two PPI datasets showed 77.1% and 77.7% accuracy, which were 6.2%-15.7% and 6.1%-18.9% higher than the other existing tools, respectively. Availability: The source codes and data used in this study are publicly available at http://github.com/QUST-AIBBDRC/EL SMURF/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30520962 TI - Novel Paranannizziopsis species in a Wagler's viper (Tropidolaemus wagleri), tentacled snakes (Erpeton tentaculatum), and a rhinoceros snake (Rhynchophis boulengeri) in a zoological collection. AB - We report several cases of fungal infections in snakes associated with a new species within the genus Paranannizziopsis. Three juvenile Wagler's vipers (Tropidolaemus wagleri) presented with skin abnormalities or ulcerative dermatitis, and two snakes died. Histologic examination of skin from the living viper revealed hyperplastic, hyperkeratotic, and crusting epidermitis with intralesional fungal elements. The terrestrial Wagler's vipers were housed in a room with fully aquatic tentacled snakes (Erpeton tentaculatum), among which there had been a history of intermittent skin lesions. Approximately 2 months after the biopsy of the viper, a skin sample was collected from one tentacled snake (TS1) with skin abnormalities and revealed a fungal infection with a similar histologic appearance. Fungal isolates were obtained via culture from the Wagler's viper and TS1 and revealed a novel species, Paranannizziopsis tardicrescens, based on phenotypic characterization and molecular analysis. P. tardicrescens was cultured and identified by DNA sequence analysis 8 months later from a dead tentacled snake in an exhibit in an adjacent hallway and 13 months later from a living rhinoceros snake (Rhynchophis boulengeri) with two focal skin lesions. Antifungal susceptibility testing on three of four cultured isolates demonstrated potent in vitro activity for terbinafine and voriconazole. PMID- 30520963 TI - Trastuzumab Therapy for 9 Weeks vs 1 Year for Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer. PMID- 30520964 TI - Cost-effectiveness analysis of medical management versus conservative surgery for early tubal pregnancy. AB - STUDY QUESTION: Is conservative surgery (laparoscopic salpingotomy) cost effective, using fertility as the endpoint compared with medical management (Methotrexate) in women with an early tubal pregnancy? SUMMARY ANSWER: Conservative surgery appeared slightly, but not statistically significantly, more effective than medical management but also more costly. WHAT IS KNOWN ALREADY: Women with an early tubal pregnancy treated with medical therapy (Methotrexate) or conservative surgery (laparoscopic salpingotomy) have comparable future intrauterine pregnancy rates by natural conception. Also, cost-minimisation studies have shown that medical therapy was less expensive than conservative surgery, but there is no cost-effectiveness study comparing these two treatments with fertility as the endpoint. STUDY DESIGN, SIZE, DURATION: A multicentre randomised controlled trial-based (DEMETER study) cost-effectiveness analysis of conservative surgery compared with medical therapy in women with an early tubal pregnancy was performed. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Included women had an ultrasound that confirmed an early tubal pregnancy. They were randomly allocated to conservative surgery or to medical therapy. The study clinical outcome was the intrauterine pregnancy rate. The payer's perspective was considered. Costs of conservative surgery and medical therapy were compared. The analysis was performed according to the intention-to-treat principle. Missing variables were imputed using the fully conditional method. To characterise uncertainty and to provide a summary of it, a non-parametric bootstrap resampling was executed and cost-effectiveness accessibility curves were constructed. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, costs per woman in the conservative surgery group and in the medical therapy group were 2627? and 2463?, respectively, with a statistically significant difference of +164?. Conservative surgery resulted in a marginally, but non-significant (P = 0.46), higher future intrauterine pregnancy rate compared to medical therapy (0.700 vs. 0.649); leading, after bootstrap, to an incremental cost-effectiveness ratio of 1299? (95% CI = -29 252; +29 919). Acceptability curves showed that conservative surgery could be considered a cost-effective treatment at a threshold of 3201? for one additional future intrauterine pregnancy. LIMITATIONS, REASONS FOR CAUTION: A limitation was that monetary valuation was carried out using 2016 euros while the DEMETER study took place from 2005 to 2009. Anyway, the results would not have been very different given the marginal changes in the health insurance reimbursement tariffs during this period. WIDER IMPLICATIONS OF THE FINDINGS: Conservative surgery can be considered a cost-effective treatment, if the additional cost of 3201? per additional future intrauterine pregnancy is an acceptable financial effort for the payer. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT 00137982. PMID- 30520965 TI - Global Biobank Engine: enabling genotype-phenotype browsing for biobank summary statistics. AB - Summary: Large biobanks linking phenotype to genotype have led to an explosion of genetic association studies across a wide range of phenotypes. Sharing the knowledge generated by these resources with the scientific community remains a challenge due to patient privacy and the vast amount of data. Here we present Global Biobank Engine (GBE), a web-based tool that enables exploration of the relationship between genotype and phenotype in biobank cohorts, such as the UK Biobank. GBE supports browsing for results from genome-wide association studies, phenome-wide association studies, gene-based tests, and genetic correlation between phenotypes. We envision GBE as a platform that facilitates the dissemination of summary statistics from biobanks to the scientific and clinical communities. Availability and implementation: GBE currently hosts data from the UK Biobank and can be found freely available at biobankengine.stanford.edu. PMID- 30520966 TI - Gender Alters the MHC Class I HLA-A Association with Polyglandular Autoimmunity. AB - Context: The Major Histocompatibility Complex (MHC) strongly contributes to the development of polyglandular autoimmunity (PGA). Objective: To evaluate the impact of gender on human leukocyte antigen (HLA) association with PGA for the first time. Design: Cross-sectional immunogenetic study. Setting: Academic, tertiary referral, orphan disease center for PGA (ORPHA 282196) and immunogenetics laboratory. Subjects: 158 patients with coexistent type 1 diabetes and autoimmune thyroid disease (adult type three PGA, ORPHA 227982) and 479 unrelated healthy controls. Methods: All 637 Caucasian subjects were typed for HLA-A, -B, DRB1, -DQA1, and -DQB1 alleles at a two-field level. Main outcome measure: Modification of the gene-disease association by gender. Results: MHC class I HLA-A association was gender-related to both the total Caucasian adult type three PGA collective (n=158, p=0.0065) as well as in PGA patients with autoimmune Hashimoto's thyroiditis (n=91, p=0.010). Compared to HLA-A*02:01, A*11:01 was overrepresented in male patients, yet underrepresented in females (OR 1.49, 95% CI 0.55-3.88 vs. 0.42, 0.12-1.17). A*24:02 was underrepresented in males but not in female patients (OR 0.37, 95% CI 0.111.04 vs. 1.19, 0.65-2.15). Excluding the five most frequent alleles (A*01:01, A*02:01, A*03:01, A*11:01, and A*24:02), the sum of all other identified alleles was underrepresented in male patients (OR 0.37, 0.18-0.72, p=0.0046). The strong MHC HLA-B association with PGA (p<0.0001) was not gender-related (p=0.55). Further, no interaction with gender was observed for the MHC class II HLA-DRB1, DQA1, and DQB1 alleles. Conclusion: MHC class I HLA-A association with type three PGA is significantly affected by gender. PMID- 30520967 TI - Cervical Discs as a Source of Neck Pain. An Analysis of the Evidence. AB - Objectives.: To determine the extent and strength of evidence that supports the belief that cervical intervertebral discs are a source of neck pain. The evidence from anatomical, laboratory, experimental, diagnostic, and treatment studies was summarized and analyzed for concept validity, face validity, content validity, and construct validity. Evidence from basic sciences shows that cervical discs have a nociceptive innervation, and experimental studies show that they are capable of producing neck pain. Disc stimulation has been developed as a diagnostic test but has rarely been used in a disciplined fashion. The prevalence of cervical disc pain has not been properly established but appears to be low. No treatment has been established that reliably achieves complete relief of neck pain in substantial proportions of patients. Basic science evidence supports the concept of cervical disc pain, but epidemiologic and clinical evidence to vindicate the clinical application of the concept is poor or lacking. PMID- 30520968 TI - Waldenstrom's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 30520969 TI - Histones Predate the Split Between Bacteria and Archaea. AB - Motivation: Histones form octameric complexes called nucleosomes, which organize the genomic DNA of eukaryotes into chromatin. Each nucleosome comprises two copies each of the histones H2A, H2B, H3, and H4, which share a common ancestry. Although histones were initially thought to be a eukaryotic innovation, the subsequent identification of archaeal homologs led to the notion that histones emerged before the divergence of archaea and eukaryotes. Results: Here, we report the detection and classification of two new groups of histone homologs, which are present in both archaea and bacteria. Proteins in one group consist of two histone subunits welded into single-chain pseudodimers, whereas in the other they resemble eukaryotic core histone subunits and show sequence patterns characteristic of DNA binding. The sequences come from a broad spectrum of deeply branching lineages, excluding their genesis by horizontal gene transfer. Our results extend the origin of histones to the Last Universal Common Ancestor. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30520971 TI - Prevalence of Human Papillomavirus, HIV and other sexually transmitted infections among men having sex with men in Togo: a national cross-sectional survey. AB - Background: Sub-Saharan Africa is a region of both high HIV and anal cancer incidence. We conducted the first national study in Togo to assess HPV, HIV and other Sexually Transmitted Infections (STIs) prevalence among Men having Sex with Men (MSM). Methods: A multicentric cross-sectional study was conducted among MSM recruited in four Togolese cities based on the respondent-driven sampling method. Socio-demographic characteristics and sexual behaviors were recorded using a standardized questionnaire. Anal swabs were collected to test HPV, HSV-1/2 and seven anal STIs. HIV, Syphilis and HBV were screened with rapid tests. Results: 207 MSM were recruited, showing HIVand high-risk HPV (hrHPV) overall prevalence of 26.1% and 44.9%, respectively. Most common hrHPV types were HPV35 (15.0%) and HPV16 (13.0%). Prevalence of hrHPV and multiple HPV infections were higher among HIV-positive than among HIV-negative MSM (85.2% versus 30.7%, p<10-5 and 85.2% versus 28.7%, p<10-5, respectively). Other STIs, except HBV, were also more prevalent among HIV-positive MSM (N.gonorrhoeae, p=0.03; M.genitalium, p=0.04; HSV-2, p=0.001 and a trend for C.trachomatis, p=0.06). In multivariate analysis, HIV infection (aOR: 10.1, 95%CI: 4.0-25.6), living in Lome (2.8, 1.1-7.1), HSV-2 anal excretion (26.7, 2.9-244.3), anal C.trachomatis (11.7, 2.3-58.9) and M.genitalium infection (9.6, 3.1-29.9) were associated with increased risk of anal hrHPV infection. All participants with anal N.gonorrhoeae infection were infected with at least one hrHPV. Conclusions: We report a high-burden of anal STIs with an unusual hrHPV types distribution among MSM, highlighting the critical need of implementation of a national strategy regarding prevention of STIs and vaccination against Papillomavirus. PMID- 30520972 TI - Capsule Network for Protein Post-Translational Modification Site Prediction. AB - Motivation: Computational methods for protein post-translational modification (PTM) site prediction provide a useful approach for studying protein functions. The prediction accuracy of the existing methods has significant room for improvement. A recent deep-learning architecture, Capsule Network (CapsNet), which can characterize the internal hierarchical representation of input data, presents a great opportunity to solve this problem, especially using small training data. Results: We proposed a CapsNet for predicting protein PTM sites, including phosphorylation, N-linked glycosylation, N6-acetyllysine, methyl arginine, S-palmitoyl-cysteine, pyrrolidone-carboxylic-acid, and SUMOylation sites. The CapsNet outperformed the baseline CNN architecture MusiteDeep and other well-known tools in most cases and provided promising results for practical use, especially in learning from small training data. The capsule length also gives an accurate estimate for the confidence of the PTM prediction. We further demonstrated that the internal capsule features could be trained as a motif detector of phosphorylation sites when no kinase-specific phosphorylation labels were provided. In addition, CapsNet generates robust representations that have strong discriminant power in distinguishing kinase substrates from different kinase families. Our study sheds some light on the recognition mechanism of PTMs and applications of CapsNet on other bioinformatic problems. Availability: The codes are free to download from https://github.com/duolinwang/CapsNet_PTM. PMID- 30520970 TI - Benzene Exposure Response and Risk of Myeloid Neoplasms in Chinese Workers: A Multicenter Case-Cohort Study. AB - Background: There is international consensus that benzene exposure is causally related to acute myeloid leukemia (AML), and more recent evidence of association with myelodysplastic syndromes (MDS). However, there are uncertainties about the exposure response, particularly risks by time since exposure and age at exposure. Methods: In a case-cohort study in 110 631 Chinese workers followed up during 1972-1999 we evaluated combined MDS/AML (n = 44) and chronic myeloid leukemia (n = 18). We estimated benzene exposures using hierarchical modeling of occupational factors calibrated with historical routine measurements, and evaluated exposure response for cumulative exposure and average intensity using Cox regression; P values were two-sided. Results: Increased MDS/AML risk with increasing cumulative exposure in our a priori defined time window (2 to <10 years) before the time at risk was suggested (Ptrend = 08). For first exposure (within the 2 to <10-year window) before age 30 years, the exposure response was stronger (P = .004) with rate ratios of 1.12 (95% confidence interval [CI] = 0.27 to 4.29), 5.58 (95% CI = 1.65 to 19.68), and 4.50 (95% CI = 1.22 to 16.68) for cumulative exposures of more than 0 to less than 40, 40 to less than 100, and at least 100 ppm-years, respectively, compared with no exposure. There was little evidence of exposure response after at least 10 years (Ptrend = .94), regardless of age at first exposure. Average intensity results were generally similar. The risk for chronic myeloid leukemia was increased in exposed vs unexposed workers, but appeared to increase and then decrease with increasing exposure. Conclusion: For myeloid neoplasms, the strongest effects were apparent for MDS/AML arising within 10 years of benzene exposure and for first exposure in the 2 to less than 10-year window before age 30 years. PMID- 30520973 TI - Associations Between Drosophila suzukii (Diptera: Drosophilidae) and Fungi in Raspberries. AB - The invasive vinegar fly, Drosophila suzukii Matsumura, has emerged as one of the most serious arthropod pests of primocane red raspberries (Rubus ideaus L.) in the United States. In raspberries, D. suzukii encounter a diverse community of microbes, including fruit rot pathogens such as Botrytis cinerea Pers and Cladosporium cladosporioides de Vries. In this study, our primary objectives were to evaluate D. suzukii-fungal associations and determine D. suzukii's influence on fungal communities in raspberry fruit. Through culture-based surveys of larval gut microbes, we isolated several yeast fungi (primarily Hanseniaspora spp.), as well as Cladosporium, Botrytis, and several other non-yeast fungi from larval frass, suggesting that D. suzukii larvae encounter and feed on these fungi. Subsequent field surveys confirmed that D. suzukii larvae occurred in berries affected by Botrytis fruit rot and Cladosporium fruit rot. Under laboratory conditions, D. suzukii may facilitate C. cladosporioides infections, likely through the introduction of epiphytic propagules on the fruit surface. We could not detect impacts on B. cinerea infections or establish a clear vectoring relationship for either fruit rot. These studies provide evidence for an association between D. suzukii and fungal fruit rot pathogens. Understanding interactions between raspberry fruit, D. suzukii, and fungal microbes-especially whether D. suzukii facilitates the development of fruit rots or conversely, if fruit rots influence D. suzukii infestation patterns-may improve pest and pathogen management programs. PMID- 30520974 TI - New Onset of Blurred Vision and Floaters. PMID- 30520975 TI - Computer vision-based phenotyping for improvement of plant productivity: A machine learning perspective. AB - Employing computer vision to extract useful information from images and videos is becoming a key technique for identifying phenotypic changes in plants. In this report, we review the emerging aspects of computer vision for automated plant phenotyping. Recent advances in image analysis empowered by machine learning based techniques, including convolutional neural network-based modeling, have expanded their application to assist high-throughput plant phenotyping. Combinatorial use of multiple sensors to acquire various spectra has allowed us to noninvasively obtain a series of datasets, including those related to the development and physiological responses of plants throughout their life. Automated phenotyping platforms accelerate the elucidation of gene functions associated with traits in model plants under controlled conditions. Remote sensing techniques with image collection platforms, such as unmanned vehicles and tractors, are also emerging for large-scale field phenotyping for crop breeding and precision agriculture. Computer vision-based phenotyping will play significant roles in both the nowcasting and forecasting of plant traits through modeling of genotype/phenotype relationships. PMID- 30520976 TI - Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational Study. AB - Importance: Obesity is associated with an increased risk of breast cancer, including the estrogen receptor (ER)-positive subtype in postmenopausal women. Whether excess adiposity is associated with increased risk in women with a normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown. Objective: To investigate the association between body fat and breast cancer risk in women with normal BMI. Design, Setting, and Participants: This ad hoc secondary analysis of the Women's Health Initiative (WHI) clinical trial and observational study cohorts was restricted to postmenopausal participants with a BMI ranging from 18.5 to 24.9. Women aged 50 to 79 years were enrolled from October 1, 1993, through December 31, 1998. Of these, 3460 participants underwent body fat measurement with dual-energy x-ray absorptiometry (DXA) at 3 US designated centers with follow-up. At a median follow-up of 16 years (range, 9-20 years), 182 incident breast cancers had been ascertained, and 146 were ER positive. Follow-up was complete on September 30, 2016, and data from October 1, 1993, through September 30, 2016, was analyzed August 2, 2017, through August 21, 2018. Main Outcomes and Measures: Body fat levels were measured at baseline and years 1, 3, 6, and 9 using DXA. Information on demographic data, medical history, and lifestyle factors was collected at baseline. Invasive breast cancers were confirmed via central review of medical records by physician adjudicators. Blood analyte levels were measured in subsets of participants. Results: Among the 3460 women included in the analysis (mean [SD] age, 63.6 [7.6] years), multivariable-adjusted hazard ratios for the risk of invasive breast cancer were 1.89 (95% CI, 1.21-2.95) for the highest quartile of whole-body fat and 1.88 (95% CI, 1.18-2.98) for the highest quartile of trunk fat mass. The corresponding adjusted hazard ratios for ER-positive breast cancer were 2.21 (95% CI, 1.23-3.67) and 1.98 (95% CI, 1.18-3.31), respectively. Similar positive associations were observed for serial DXA measurements in time-dependent covariate analyses. Circulating levels of insulin, C-reactive protein, interleukin 6, leptin, and triglycerides were higher, whereas levels of high density lipoprotein cholesterol and sex hormone-binding globulin were lower in those in the uppermost vs lowest quartiles of trunk fat mass. Conclusions and Relevance: In postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer and altered levels of circulating metabolic and inflammatory factors. Normal BMI categorization may be an inadequate proxy for the risk of breast cancer in postmenopausal women. Trial Registration: ClinicalTrials.gov identifier: NCT00000611. PMID- 30520977 TI - Association of Chemoradiotherapy With Outcomes Among Patients With Stage I to II vs Stage III Small Cell Lung Cancer: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: There is limited evidence to guide stage I to II small cell lung cancer (SCLC) treatment. Objective: To examine the characteristics and outcomes among patients with stage I to II SCLC treated with modern chemoradiotherapy. Design, Setting, and Participants: In this post hoc secondary analysis of the Concurrent Once-Daily vs Twice-Daily Radiotherapy Trial (CONVERT), a multicenter phase 3 trial conducted in patients with limited-stage SCLC from April 7, 2008, to November 29, 2013, patients with TNM stage I to II SCLC were compared with those with stage III disease. Data analysis was performed from November 1, 2017, to February 28, 2018. Interventions: In CONVERT, patients were randomized to receive twice-daily (45 Gy in 30 fractions) or once-daily (66 Gy in 33 fractions) chemoradiotherapy. Prophylactic cranial irradiation (PCI) was offered, if indicated. Main Outcomes and Measures: The primary trial end point was overall survival (OS). TNM staging information was collected prospectively; this was an unplanned analysis because stratification was not performed according to TNM stage. Results: A total of 509 (277 [54.4%] men; mean [SD] age, 61.5 [8.3] years) of 543 patients (93.7%) with TNM staging information were eligible for this subgroup analysis, and 86 of the 509 (16.9%) had TNM stage I to II disease. The median gross tumor volume was smaller in patients with stage I to II disease (38.4 cm3; range, 2.2-593.0 cm3) compared with patients with stage III disease (93 cm3; range, 0.5-513.4 cm3) (P < .001). No other significant differences were found in baseline and treatment characteristics and chemoradiotherapy adherence between the 2 groups or the number of patients with stage I to II disease (78 [90.7%]) and stage III disease (346 [81.8%]) who received PCI (P = .10). Patients with stage I to II disease achieved longer OS (median, 50 months [95% CI, 38 to not reached months] vs 25 months [95% CI, 21-29 months]; hazard ratio, 0.60 [95% CI, 0.44-0.83]; P = .001) compared with patients with stage III disease. In patients with stage I to II disease, no significant survival difference was found between the trial arms (median, 39 months in the once-daily arm vs 72 months in the twice-daily arm; P = .38). Apart from lower incidence of acute esophagitis in patients with stage I to II disease compared with patients with stage III disease (grade >=3, 9 [11.3%] vs 82 [21.1%]; P < .001), the incidences of acute and late toxic effects were not significantly different. Conclusions and Relevance: Patients with stage I to II SCLC in CONVERT achieved long-term survival with acceptable toxic effects after chemoradiotherapy and PCI. This study suggests that patients with stage I to II small cell lung cancer treated with modern chemoradiotherapy have better outcomes compared with patients with stage III disease, providing information that practitioners can potentially give their patients to aid clinical decisions. Trial Registration: ClinicalTrials.gov identifier: NCT00433563. PMID- 30520978 TI - New models of atherosclerosis and multi-drug therapeutic interventions. AB - Motivation: Atherosclerosis is amongst the leading causes of death globally. However, it is challenging to study in vivo or in vitro and no detailed, openly available computational models exist. Clinical studies hint that pharmaceutical therapy may be possible. Here we develop the first detailed, computational model of atherosclerosis and use it to develop multi-drug therapeutic hypotheses. Results: We assembled a network describing atheroma development from the literature. Maps and mathematical models were produced using the Systems Biology Graphical Notation (SBGN) and Systems Biology Markup Language (SBML), respectively. The model was constrained against clinical and laboratory data. We identified five drugs that together potentially reverse advanced atheroma formation. Availability and Implementation: The map is available in the supplementary information in SBGN-ML format. The model is available in the supplementary material and from BioModels, a repository of SBML models, containing CellDesigner markup. Supplementary Information: Available from Bioinformatics online. PMID- 30520979 TI - Luteal granulosa cells from natural cycles are more capable of maintaining their viability, steroidogenic activity and LH receptor expression than those of stimulated IVF cycles. AB - STUDY QUESTION: Are there any differences in the molecular characteristics of the luteal granulosa cells (GC) obtained from stimulated versus non-stimulated (natural) IVF cycles that may help explain the defective luteal phase in the former? SUMMARY ANSWER: Luteal GC of stimulated IVF cycles, particularly those of agonist-triggered antagonist cycles, are less viable ex vivo, express LH receptor and anti-apoptotic genes at lower levels, undergo apoptosis earlier and fail to maintain their estradiol (E2) and progesterone (P4) production in comparison to natural cycle GC. WHAT IS KNOWN ALREADY: Luteal function is defective in stimulated IVF cycles, which necessitates P4 and/or hCG administration (known as luteal phase support) in order to improve clinical pregnancy rates and prevent miscarriage. The luteal phase becomes shorter and menstruation begins earlier than a natural cycle if a pregnancy cannot be achieved, indicative of early demise of corpus luteum (premature luteolysis). Supra-physiological levels of steroids produced by multiple corpora luteae in the stimulated IVF cycles are believed to inhibit LH release directly via negative feedback actions on the hypothalamic-pituitary-ovarian axis resulting in low circulating levels of LH and a defective luteal phase. We hypothesized that some defects in the viability and steroidogenic activity of the luteal GC of the stimulated IVF cycles might contribute to this defective luteal phase in comparison to natural cycle GC. This issue has not been studied in human before. STUDY DESIGN, SIZE, DURATION: A comparative translational research study of ex vivo and in vitro models of luteal GC recovered from IVF patients undergoing natural versus stimulated IVF cycles was carried out. Luteinized GC were obtained from 154 IVF patients undergoing either natural (n = 22) or stimulated IVF cycles with recombinant FSH and GnRH agonist (long) (n = 44), or antagonist protocol triggered conventionally either with recombinant hCG (n = 46) or with a GnRH agonist (n = 42). GC were maintained in vitro for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cellular viability (YO-PRO-1 staining), the expression of the steroidogenic enzymes, pro apoptotic genes [Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX) and Caspase-3 (CASP3)], anti-apoptotic genes [RAC-alpha serine/threonine-protein kinase (AKT-1) and Bcl-2-like protein 2 (BCL2-L2)], LH receptor, vascular endothelial growth factor (VEGF) (using real-time quantitative PCR at mRNA level and western blot immunoprecipitation assay at protein level) and in vitro E2 and P4 production (electrochemiluminescence immunoassay) were compared in GC among the groups. MAIN RESULTS AND THE ROLE OF CHANCE: Natural cycle GC were significantly more viable ex vivo (88%) compared to their counterparts of the stimulated IVF cycles (66, 64 and 37% for agonist and antagonist cycles triggered with hCG and GnRH agonist respectively, P < 0.01). They were also more capable of maintaining their vitality in culture compared to their counterparts from the stimulated IVF cycles: at the end of the 6-day culture period, 74% of the cells were still viable whereas only 48, 43 and 22% of the cells from the agonist and antagonist cycles triggered with hCG and agonist respectively, were viable (P < 0.01). The mRNA expression of anti-apoptotic genes (AKT-1 and BCL2-L2) was significantly lower, while that of pro-apoptotic genes (BAD, BAX and CASP3) was significantly higher in the stimulated cycles, particularly in the agonist-triggered antagonist cycles, compared to natural cycle GC (P < 0.01 for long protocol and antagonist hCG trigger, P < 0.001 for agonist trigger). The expression of steroidogenic enzymes (stAR, SCC, 3beta-HSD and aromatase) and VEGF was significantly higher in the agonist and hCG-triggered antagonist cycles compared to natural cycle GC. Therefore, in vitro E2 and P4 production in cells from the stimulated IVF cycles was significantly higher than their counterparts obtained from the natural cycles in the first 2 days of culture. However, after Day 2, their viability and hormone production began to decline very rapidly with the most drastic decrease being observed in the agonist triggered cycles. By contrast, natural cycle GC maintained their viability and produced E2 and P4 in increasing amounts in culture up to 6 days. In vitro P production and the mRNA and protein expression of LH receptor, VEGF and 3beta-HSD were most defective in the agonist-triggered antagonist cycles compared to natural and agonist and hCG-triggered antagonist cycles. In vitro hCG treatment of a subset of the cells from the agonist-triggered cycles improved their viability, increased E2 and P4 production in vitro and up-regulated the mRNA expression of anti-apoptotic gene BCL-L2 together with steroidogenic enzymes stAR, SCC, 3B-HSD, LH receptor and VEGF. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: The limitations include analysis of luteinized GC only might not reflect the in vivo mechanisms involved in survival and function of the whole corpus luteum; GC recovered during oocyte retrieval belong to a very early stage of the luteal phase and might not be representative; effects of ovulation triggered with hCG may not equate to the endogenous LH trigger; the clinical characteristics of the patients may vary among the different groups and it was not possible to correlate stimulation-related molecular alterations in luteal GC with the clinical outcome, as no oocytes have been utilized yet. Therefore, our findings do not conclusively rule out the possibility that some other mechanisms in vivo may also account for defective luteal function observed in stimulated IVF cycles. WIDER IMPLICATIONS OF THE FINDINGS: Ovarian stimulation is associated with significant alterations in the viability and steroidogenic activity of luteal GC depending on the stimulation protocol and mode of ovulation trigger. Reduced survival and down-regulated expression of 3B-HSD, LH receptor and VEGF leading to compromised steroid production in stimulated cycles, and particularly in the agonist-triggered cycles, may at least in part help explain why the luteal phase is defective and requires exogenous support in these cycles. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koc University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. PMID- 30520981 TI - Pretreatment Hearing Level-Another Prognostic Factor in Sudden Sensorineural Hearing Loss-Reply. PMID- 30520980 TI - Prospective, randomized trial of bioresorbable scaffolds vs. everolimus-eluting stents in patients undergoing coronary stenting for myocardial infarction: the Intracoronary Scaffold Assessment a Randomized evaluation of Absorb in Myocardial Infarction (ISAR-Absorb MI) trial. AB - Aims: Bioresorbable scaffolds (BRS) provide short-term coronary artery scaffolding and drug delivery. Although prior trials showed a higher rate of device failure compared with conventional drug-eluting stents (DES), only a single trial investigated patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI). We aimed to compare outcomes with BRS vs. DES in patients undergoing PCI for MI. Methods and results: We did a prospective, randomized, multicentre, non-inferiority, clinical trial of everolimus-eluting BRS vs. durable polymer everolimus-eluting stents (EES) in patients with acute MI. Patients were eligible for enrolment if they presented with ST-elevation MI, or non-ST-elevation MI with thrombosis visual at angiography and were randomly allocated to treatment with BRS or EES in 2:1 proportion. Angiographic follow-up was scheduled at 6-8 months and clinical follow-up was done at 12 months. The primary endpoint was percentage diameter stenosis in-segment at follow-up. A total of 262 patients were enrolled and were allocated to BRS (n = 173) or EES (n = 89). Angiographic follow-up was available for 213 (81.3%) patients. Mean diameter stenosis was 24.6 +/- 12.2% with BRS vs. 27.3 +/- 11.7% with EES (mean difference -2.7%, upper limit of one-sided 97.5% confidence limit 0.7%, pre-specified margin of non-inferiority 5%, Pnon inferiority <0.001). The rate of the device-oriented composite of cardiac death/target vessel MI/target lesion revascularization [BRS: 12 (7.0%) vs. EES: 6 (6.7%), hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.39-2.78] and definite/probable stent thrombosis [3 (1.7%) vs. 2 (2.3%), HR 0.76, 95% CI 0.13 4.56] were comparable in both groups. Conclusion: In patients undergoing PCI for acute MI BRS were non-inferior to EES for percentage diameter stenosis at angiographic follow-up. Rates of clinical events were comparable between the treatment groups, although the study was not powered to detect differences in clinical outcomes. Clinical trial registration: The trial was registered at www.clinicaltrials.gov (NCT01942070). PMID- 30520982 TI - LONG-TERM HEALTH RISK AFTER BREAST-CANCER RADIOTHERAPY: OVERVIEW OF PASSOS METHODOLOGY AND SOFTWARE. AB - Breast-cancer radiotherapy reduces the recurrence rates and improves patient survival. However, it also increases the incidence of second cancers and of heart disease. These radiation-induced long-term health risks become increasingly important with improved cure rates and prolonged patient survival. Radiation doses to nearby as well as distant organs strongly vary between different irradiation techniques and among individual patients. To provide personalized lifetime risk estimates, the German national project PASSOS combines individual anatomy, dosimetric estimates, organ-specific low- and high-dose risk models and personal risk factors such as smoking. A dedicated software tool is under development to assist clinical decision-making processes. PMID- 30520984 TI - MODELLING gamma-H2AX FOCI INDUCTION TO MIMIC LIMITATIONS IN THE SCORING TECHNIQUE. AB - An approach based on track-structure calculations has been developed to take account of artefacts occurring during gamma-H2AX foci detection in 2D images of samples analyzed through immunocytochemistry. The need of this works stems from the observed saturation in foci yields measured after X-ray doses higher than few grays, hindering an unambiguous quantification of DNA damage and of radiation effectiveness. The proposed modelling approach allows to simulate the observer's point of view for foci scoring, mimicking the selection of a slice Deltaz of the cell nucleus due to the microscope depth of field, and applying a clustering algorithm to group together damages within a resolution parameter r. Calculation results were benchmarked with experimental measurements at an early time-point for mouse breast cancer cells, irradiated with X-ray doses in the range 0-5 Gy. The model is able to reproduce the saturation in experimental data. PMID- 30520983 TI - Comparative genome analysis of Aspergillus flavus clinically isolated in Japan. AB - Aspergillus flavus is an important zoonotic pathogen and a well-known aflatoxin producer. Aspergillus flavus strains that are prevalent in Japanese environments are reported to be non-aflatoxigenic, although their aflatoxin productivity, especially among clinical isolates, has not been thoroughly investigated to date. In this study, we sequenced the genomes of ten strains of A. flavus isolated in Japan and compared their sequences with each other as well as with those of Aspergillus oryzae RIB40 and A. flavus NRRL3357. The phylogenetic analysis based on identified SNPs indicated that five strains were closer to A. oryzae RIB40 than to A. flavus NRRL3357. In contrast, of those isolates that were closer to A. flavus NRRL3357 than to A. oryzae RIB40, three were found to possess either the entire or partial aflatoxin biosynthesis gene cluster of NRRL3357-type. Furthermore, two of the three actually produced either aflatoxin B1 or an intermediate of the reaction leading to aflatoxin formation. Three of the ten strains we isolated were identified to possess part of the aflatoxin gene cluster, while five others retained the A. oryzae RIB40-type cluster. The genome data thus obtained may be further explored and utilized for comparative analysis of aflatoxin production in environmental and clinical isolates of A. flavus. PMID- 30520985 TI - New CRISPR-Cas9 vectors for genetic modifications of Bacillus species. AB - Genetic manipulation is a fundamental procedure for the study of gene and operon functions and new characteristics acquisition. Modern CRISPR-Cas technology allows genome editing more precise and increases the efficiency of transferring mutations in a variety of hard to manipulate organisms. Here, we describe new CRISPR-Cas vectors for genetic modifications in bacillary species. Our plasmids are single CRISPR-Cas plasmids comprising all components for genome editing and should be functional in a broad host range. They are highly efficient (up to 97%) and precise. The employment and delivery of these plasmids to bacillary strains can be easily achieved by conjugation from E. coli. During our research we also demonstrated the absence of compatibility between CRISPR-Cas system and NHEJ in B. subtilis. PMID- 30520986 TI - Glomerular filtration rate: when to measure and in which patients? AB - Of the glomerular, tubular and endocrine functions of the kidney, nephrologists have mostly focused their attention on the glomerular functions-albuminuria and glomerular filtration rate (GFR)-to grade the severity of chronic kidney disease (CKD). Although both albuminuria and GFR are associated with renal and cardiovascular morbidity and mortality, the utility of measured GFR (mGFR) has been questioned. GFR when measured adequately is the most precise measure of glomerular function and can be useful to individualize therapy among patients with CKD. In situations where estimated GFR is known to provide imprecise estimates of glomerular function, for example, sarcopenia and advanced cirrhosis, the measurement of GFR may be especially important. We discuss several clinical situations where mGFR can potentially influence the quality of life or complications of therapy because of interventions based on imperfect knowledge of GFR. We reason that although large databases may not detect the benefits of mGFR at the population level, precision medicine requires that therapy be individualized based on the best estimate of GFR that can be obtained particularly when the risk of harm is increased. The recent standardization of mGFRs is a step in the right direction and may help in treating the individual patient with CKD with a lower risk of complications and a better quality of life. We call for research in these subgroups of patients where it is clinically felt that mGFR is useful for clinical decision-making. PMID- 30520987 TI - Inflammatory and Infectious Syndromes Associated with Cancer Immunotherapies. AB - Immunotherapy using antibodies to immune checkpoint molecules or targeted chimeric antigen receptor-modified T (CAR-T) cells represent dramatic advances in cancer treatment. These therapies mediate immune-related adverse events (irAEs) which may mimic or amplify infectious presentations. Checkpoint inhibitor therapy may be associated with diverse irAEs including mild skin, endocrine and autoimmune manifestations or severe inflammatory processes including colitis, pneumonitis, myocarditis, and shock. CAR-T-cell therapies may induce toxicities including Cytokine-Release Syndrome (CRS) with fevers and multiorgan dysfunction, CAR-T-cell-related encephalopathy syndrome (CRES) with altered mental status and neurologic dysfunction, or Hemophagocytic Lymphohistiocytosis-Macrophage Activation Syndrome (HLH/MAS). Infectious risks may relate to prior cancer therapies or to treatments of inflammatory dysregulation including corticosteroids and inhibitors of tumor necrosis factor-alpha and interleukin-6. Immune activation may unmask subclinical infections. Clinical approaches must attempt to identify infections in the face of immunotherapy-associated inflammatory processes. Empirical antimicrobial therapies should not be delayed based on the presumption of noninfectious syndromes. PMID- 30520988 TI - Mechanistic insights into the slow peptide bond formation with D-amino acids in the ribosomal active site. AB - During protein synthesis, ribosomes discriminate chirality of amino acids and prevent incorporation of D-amino acids into nascent proteins by slowing down the rate of peptide bond formation. Despite this phenomenon being known for nearly forty years, no structures have ever been reported that would explain the poor reactivity of D-amino acids. Here we report a 3.7A-resolution crystal structure of a bacterial ribosome in complex with a D-aminoacyl-tRNA analog bound to the A site. Although at this resolution we could not observe individual chemical groups, we could unambiguously define the positions of the D-amino acid side chain and the amino group based on chemical restraints. The structure reveals that similarly to L-amino acids, the D-amino acid binds the ribosome by inserting its side chain into the ribosomal A-site cleft. This binding mode does not allow optimal nucleophilic attack of the peptidyl-tRNA by the reactive alpha-amino group of a D-amino acid. Also, our structure suggests that the D-amino acid cannot participate in hydrogen-bonding with the P-site tRNA that is required for the efficient proton transfer during peptide bond formation. Overall, our work provides the first mechanistic insight into the ancient mechanism that helps living cells ensure the stereochemistry of protein synthesis. PMID- 30520989 TI - DAG-informed regression modelling, agent-based modelling and microsimulation modelling: a critical comparison of methods for causal inference. AB - The current paradigm for causal inference in epidemiology relies primarily on the evaluation of counterfactual contrasts via statistical regression models informed by graphical causal models (often in the form of directed acyclic graphs, or DAGs) and their underlying mathematical theory. However, there have been growing calls for supplementary methods, and one such method that has been proposed is agent-based modelling due to its potential for simulating counterfactuals. However, within the epidemiological literature, there currently exists a general lack of clarity regarding what exactly agent-based modelling is (and is not) and, importantly, how it differs from microsimulation modelling-perhaps its closest methodological comparator. We clarify this distinction by briefly reviewing the history of each method, which provides a context for their similarities and differences, and casts light on the types of research questions that they have evolved (and thus are well suited) to answering; we do the same for DAG-informed regression methods. The distinct historical evolutions of DAG-informed regression modelling, microsimulation modelling and agent-based modelling have given rise to distinct features of the methods themselves, and provide a foundation for critical comparison. Not only are the three methods well suited to addressing different types of causal questions, but, in doing so, they place differing levels of emphasis on fixed and random effects, and also tend to operate on different timescales and in different timeframes. PMID- 30520990 TI - Annotation of the Giardia proteome through structure-based homology and machine learning. AB - Background: Large-scale computational prediction of protein structures represents a cost-effective alternative to empirical structure determination with particular promise for non-model organisms and neglected pathogens. Conventional sequence based tools are insufficient to annotate the genomes of such divergent biological systems. Conversely, protein structure tolerates substantial variation in primary amino acid sequence, and is thus a robust indicator of biochemical function. Structural proteomics is poised to become a standard part of pathogen genomics research, however informatic methods are now required to assign confidence in large volumes of predicted structures. Aims: To predict the proteome of a neglected human pathogen, Giardia duodenalis, and stratify predicted structures into high- and lower-confidence categories using a variety of metrics in isolation and combination. Methods: We used the I-TASSER suite to predict structural models for ~5000 proteins encoded in Giardia duodenalis and identify their closest empirically determined structural homologues in the Protein Data Bank. Models were assigned to high or lower-confidence categories depending on the presence of matching PFAM domains in query and reference peptides. Metrics output from the suite and derived metrics were assessed for their ability to predict the high confidence category individually, and in combination through development of a random forest classifier. Results: We identified 1095 high confidence models including 212 hypothetical proteins. Amino acid identity between query and reference peptides was the greatest individual predictor of high confidence status, however the random forest classifier out-performed any metric in isolation (AUC = 0.977), and identified a subset of 305 high confidence like models, corresponding to false positive predictions. High confidence models exhibited higher transcriptional abundance, and the classifier generalized across species, indicating the broad utility of this approach for automatically stratifying predicted structures. Additional structure-based clustering was used to cross-check confidence predictions in an expanded family of Nek kinases. Several high confidence-like proteins yielded substantial new insight into mechanisms of redox balance in Giardia duodenalis-a system central to the efficacy of limited anti-giardial drugs. Conclusion: Structural proteomics combined with machine learning can aid genome annotation for genetically divergent organisms including human pathogens, and stratify predicted structures to promote efficient allocation of limited resources for experimental investigatio. PMID- 30520991 TI - The Buckwheat Effect: A Biopesticide for Wireworm? AB - Growing buckwheat (Fagopyrum esculentum Moench. Caryophyllales: Polygonaceae) in rotation with potato and other vegetable crops has been reported to decrease the density of an invasive wireworm species (Agriotes sputator Linnaeus. Coleoptera: Elateridae) in Nova Scotia, Canada. It was predicted that the negative effects on wireworm populations result from phytochemicals by buckwheat that act as deterrents, anti-feedants, or toxins in the roots or when released into the soil. Choice assays were conducted to test the attractiveness of germinating, branching, and flowering buckwheat, red spring wheat (Triticum aestivum Linnaeus. Poales: Poaceae) and island barley (Hordeum vulgare Linnaeus. Poales: Poaceae) to the larvae. Twenty-one day, no choice feeding assays were conducted to determine change in mass and mortality of A. sputator larvae when fed buckwheat or barley. There was no evidence that the wireworms were deterred by buckwheat and the germinating stage of all three crops was the most attractive based on the 24-h choice assays. After the 21-d no choice feeding assays, no differences between hosts were observed; however, wireworm herbivory significantly reduced the growth of barley but not buckwheat. The findings from the no choice feeding assays suggest that buckwheat may produce anti-feedants, but longer term feeding assays and field trials are required to confirm this possibility. PMID- 30520992 TI - Education and mortality in three Eastern European populations: findings from the PrivMort retrospective cohort study. AB - Background: The aim of the study is 2-fold. Firstly, it attempts to investigate the potential impact of major political and economic changes on inequalities in all-cause mortality among men and women with different levels of education in three Eastern European countries. Secondly, to identify changes in contribution of smoking and drinking to educational differences in all-cause mortality. Study covers the period from 1982 to 2013. Methods: Data were collected in 2013-14 as a part of the PrivMort retrospective cohort study. Participants in Russia, Belarus and Hungary provided information on their educational attainment, health-related behaviors and vital statistics of their close relatives (N = 179 691). Odds ratios for mortality and relative indices of inequality (RII) were estimated for individuals aged 20-65 years, stratifying by three levels of educational attainment: higher, secondary and less than secondary education. Results: Those in lower educational groups were significantly more likely to die, through most time periods and sub-groups. The RII increased over time in all countries and both genders, except for Hungarian men. Alcohol consumption and smoking have increasingly contributed to educational inequalities in mortality during this period. Conclusion: Educational inequalities in mortality in these Eastern European countries have increased during recent decades. Smoking and alcohol consumption, two major health-related behaviors, made a significant contribution to these increases in inequality. PMID- 30520993 TI - Resistance testing for integrase-strand-transfer inhibitors in naive HIV infected individuals. PMID- 30520994 TI - BIOINFORMATIC ANALYSIS OF DOSE- AND TIME-DEPENDENT miRNome RESPONSES. AB - The advent of new 'omics' techniques determined a massive boost in the measurement of the whole spectra of molecules within cells, favoring promising new radiobiological studies at low doses. The main aim of this work was to assess the radiation-induced perturbations of miRNA profiles and their temporal dynamics. Human Umbilical Vein Endothelial Cells were irradiated with low doses of gamma-rays. At different time points post-irradiation, cells were harvested and miRNAs isolated. A full mapping of the miRNA sequences via Next-Generation Sequencing analysis was performed followed by bioinformatic analyses. Pathway enrichment analyses on the differentially expressed miRNAs focused both on the averaged effects of different doses over the 24-h experiment and on the altered temporal dynamics of the miRNA profiles. These complementary analyses provided a picture of the dose- and time-dependent miRNAs responses, allowing to better explore the candidate biomarkers linked to radiation exposures and their corresponding pathways and functions. PMID- 30520995 TI - Normal Weight Adiposity and Postmenopausal Breast Cancer Risk. PMID- 30520996 TI - Hereditary Spastic Paraplegia: gain-of-function mechanisms revealed by new transgenic mouse. AB - Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of Hereditary Spastic Paraplegia. Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of Hereditary Spastic Paraplegia (not observed in spastin knockout mice) were adult-onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying-back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying Hereditary Spastic Paraplegia, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone. PMID- 30520997 TI - Reply to Ambrosioni et al. PMID- 30520998 TI - A novel transnational fresh oocyte donation (TOD) program based on transport of frozen sperm and embryos. AB - STUDY QUESTION: What is the clinical efficacy of an oocyte donation program based on the transportation of frozen semen and embryos between two countries? SUMMARY ANSWER: The transnational oocyte donation program is efficient and reliable and it could provide a first-line strategy to overcome the lack of donors in some countries. WHAT IS KNOWN ALREADY: While there is increasing need for donated oocytes, in many countries the availability of donors is still insufficient to cover the therapeutic demands, and patients are referred abroad for treatment. Since embryo cryopreservation is reliable and efficient, we propose a strategy based on frozen embryos instead of frozen oocytes to satisfy the increasing demand for cross border oocyte donation. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study including 630 patients treated from December 2015 to July 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women were treated with elective vitrified-thawed embryo shipping and embryo transfer (ET) between two IVF clinics, one in Spain and one in Italy. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2617 embryos were created for the 630 patients and the survival rate after warming was 98.5%. After the first ET the live birth rate (LBR) was 30.6%. In 476 patients (75.5%), embryos were transferred at the cleavage stage (Day 2 or 3) and the LBR was 29.2%. Vitrified blastocysts were available for 154 patients (24.5%) and the LBR was 35%. Among patients who did not achieve a pregnancy after the first frozen ET (FET), 92.5% had at least one frozen embryo for successive procedures. 213 patients underwent a second FET. The LBR at the second FET was 30%. The cumulative LBR at the end of the observation period was 39.3%. LIMITATIONS, REASONS FOR CAUTION: The study design was retrospective. A direct comparison with vitrified oocyte donors cycle and subsequent fresh ET would have permitted to compare this strategy versus the current standard based on vitrified gametes. WIDER IMPLICATIONS OF THE FINDINGS: The LBR found in our study is more than acceptable and seems to be higher than what reported with vitrified oocytes. The transnational fresh oocyte donation program may have several advantages over the shipment of vitrified oocytes: similarly to the fresh oocyte donation program it allows for personalized care in oocyte recipient, which is provided by assigning a flexible number of oocytes, and at the same time it maintains the benefit of a frozen ART program permitting scheduling flexibility. The TOD program is efficient and may be proposed as a first-line strategy for distance and inter-countries oocyte donation programs. STUDY FUNDING, COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NA. PMID- 30520999 TI - Letter to the editor: Protective Role of Skeletal Muscle Mass against Progression from Metabolically Healthy to Unhealthy Phenotype. PMID- 30521000 TI - miRDeep-P2: accurate and fast analysis of the microRNA transcriptome in plants. AB - Motivation: Two major challenges arise when employing next generation sequencing (NGS) methods to comprehensively identify microRNAs (miRNAs) in plants: 1) how to minimize the false-positive inheritable to computational predictions; 2) how to minimize the computational time required for analyzing the miRNA transcriptome in plants with complex and large genomes. Results: We updated miRDeep-P to miRDeep P2 (miRDP2) by employing a new filtering strategy and overhauling the algorithm. miRDP2 has been tested against miRNA transcriptomes in plants with increasing genome sizes that included Arabidopsis, rice, tomato, maize and wheat. Compared with miRDeep-P and several other computational tools, miRDP2 processes NGS data with superior speed. By incorporating newly updated plant miRNA annotation criteria and developing a new scoring system, the accuracy of miRDP2 outperformed other programs. Taken together, our results demonstrate miRDP2 as a fast and accurate tool for analyzing the miRNA transcriptome in plants. Availability: The miRDP2 are freely available from https://sourceforge.net/projects/mirdp2/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30521001 TI - Venezuela's migration crisis: a growing health threat to the region requiring immediate attention. PMID- 30521002 TI - Differences in peripheral and tissue immune cell populations following hematopoietic stem cell transplantation in Crohn's disease patients. AB - Background and Aims: Recent studies show the efficacy of autologous hematopoietic stem cell transplantation (HSCT) in severely refractory Crohn's disease (CD) patients. HSCT is thought to eliminate auto-reactive cells; however, no specific studies of immune reconstitution in CD patients are available. Methods: We followed a group of CD patients (n=18) receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanisms driving efficacy, we monitored changes after HSCT in blood and intestine immune cell composition. CD patients (n=22) receiving anti-tumor necrosis factor (TNF)- were included for comparisons. Results: Severe immune ablation followed by HSCT induced dramatic changes in both peripheral blood T and B cells in all patients regardless of the efficacy of the treatment. Endoscopic remission at week 52 following HSCT was associated with significant intestinal transcriptional changes. A comparison of the remission signature with that of anti-TNF identified both common and unique genes in the HSCT-induced response. Based on deconvolution analysis of intestinal biopsies transcriptome data, we show that response to HSCT, but not to anti-TNF, is associated with an expansion of naive B-cells, as seen in blood, and a decrease in the memory resting T-cell content. As expected, endoscopic remission, both in response to HSCT or anti-TNF, led to a significant reduction in intestinal neutrophil and M1 macrophage content. Conclusions: Peripheral blood immune remodeling after HSCT does not predict efficacy. In contrast, a profound intestinal T cell depletion that is maintained long after transplant is associated with mucosal healing following HSCT, but not anti-TNF. PMID- 30521003 TI - Evolution of DNA methylation in Papio baboons. AB - Changes in gene regulation have long been thought to play an important role in primate evolution. However, although a number of studies have compared genome wide gene expression patterns across primate species, fewer have investigated the gene regulatory mechanisms that underlie such patterns, or the relative contribution of drift versus selection. Here, we profiled genome-scale DNA methylation levels in blood samples from five of the six extant species of the baboon genus Papio (4-14 individuals per species). This radiation presents the opportunity to investigate DNA methylation divergence at both shallow and deeper time scales (380,000 - 1.4 million years). In contrast to studies in human populations, but similar to studies in great apes, DNA methylation profiles clearly mirror genetic and geographic structure. Divergence in DNA methylation proceeds fastest in unannotated regions of the genome and slowest in regions of the genome that are likely more constrained at the sequence level (e.g., gene exons). Both heuristic approaches and Ornstein-Uhlenbeck models suggest that DNA methylation levels at a small set of sites have been affected by positive selection, and that this class is enriched in functionally relevant contexts, including promoters, enhancers, and CpG islands. Our results thus indicate that the rate and distribution of DNA methylation changes across the genome largely mirror genetic structure. However, at some CpG sites, DNA methylation levels themselves may have been a target of positive selection, pointing to loci that could be important in connecting sequence variation to fitness-related traits. PMID- 30521004 TI - Structural adjustment, state capacity and child health: evidence from IMF programmes. AB - Background: Consensus is growing that policy reform programmes by the International Monetary Fund (IMF)-an international organization mandated with upholding global financial stability and assisting countries in economic turmoil produce adverse effects on public health. However, this consensus is unclear about which policies of these programmes underlie these effects. This article fills parts of this gap by examining the impact of four kinds of IMF policies (fiscal policy, public-sector employment, privatization of state-owned enterprises and price liberalization) on public-health expenditure, child vaccination and child mortality. Methods: We conducted time-series cross-section analyses for up to 128 developing countries over the 1980-2014 period using observational data on health outcomes and IMF conditionality for different policy areas. IMF effectiveness research faces two types of potential biases: self selection into IMF programmes and IMF policy conditions. We deployed instrumental variables in a seemingly unrelated regression framework to address both types of endogeneity, besides traditional remedies such as the use of fixed effects on countries and years. Results: IMF policy conditions on public-sector employment are negatively related to child health. A change from the minimum to the maximum number of such policy conditions decreases vaccination (which ranges from 0 to 100) by 10.97% [95% confidence interval (CI): 1.16 to 20.79]. This effect is robust against different sets of control variables. In addition, IMF programmes increase the share of government expenditure devoted to public health in developing countries by 0.91 percentage points (95% CI: 0.15 to 1.68). Conclusions: These findings suggest that IMF policies-particularly those that require public-sector reforms-undermine health by weakening the capacity of states to deliver vaccination. Therefore, international financial institutions need to increase their awareness of the public-health impact of their policy prescriptions. Strengthening state capacity in times of economic crisis would ensure that increased health spending also delivers quality healthcare. PMID- 30521005 TI - Longitudinal Associations of Sensory and Cognitive Functioning: A Structural Equation Modelling approach. AB - Objectives: although visual and hearing impairments have been found to be associated with cognitive decline in the old age, the mechanism underlying this relationship remains unclear. This study aims at assessing the predictive role of visual and hearing difficulties on subsequent cognitive functioning. Method: 3,508 individuals aged 60 and over from the cohort of the first (2002) and fifth waves (2010) of the English Longitudinal Study of Ageing (ELSA). Five self reported visual and hearing functioning items were used to assess sensory functioning at baseline. Cognition was assessed eight years later by means of four measured tests covering immediate and delayed recall, verbal fluency, and processing speed. A Multiple Indicators Multiple Causes approach was used to assess the longitudinal associations of visual and hearing functioning with cognitive difficulties. A multi-group longitudinal measurement invariance was used to estimate latent change in cognitive difficulties across groups of participants presenting either visual, hearing, or dual sensory impairment (i.e., those reporting difficulties in both visual and hearing functioning items). Results: visual (beta=0.140, p<0.001) and hearing (beta=0.115, p<0.001) difficulties predicted cognitive difficulties eight years later. The latent increase in cognitive difficulties was steeper in people with visual impairment (d= 0.52, p<0.001), hearing impairment (d=0.50, p<0.001), and dual-sensory impairment (d=0.68, p<0.001) than those non-impaired (d=0.12, p<0.001). Discussion: visual and hearing difficulties were identified as predictors of subsequent cognitive decline in the old age. Interventions to prevent visual and hearing difficulties may have a substantial impact to slow down subsequent age related cognitive decline. PMID- 30521006 TI - Risk-Reducing Mastectomy in BRCA1 and BRCA2 Mutation Carriers: A Complex Discussion. PMID- 30521007 TI - Yeast-like filamentous fungi: Molecular identification and in vitro susceptibility study. AB - Yeast-like filamentous fungi, collected in Italy from 1985 to 2018, were submitted to molecular identification and antifungal susceptibility testings. Clinical isolates were identified as Magnusiomyces capitatus (28), M. clavatus (18), and Geotrichum candidum (2). M. clavatus was prevalent among blood isolates (18/24), M. capitatus among isolates from other biological materials. The intrinsic echinocandin resistance was confirmed. Both species had low minimum inhibitory concentrations (MICs) of itraconazole, posaconazole, and voriconazole, while M. clavatus had lower MIC of flucytosine and higher MIC of isavuconazole than M. capitatus. The intrinsic resistance of these species to echinocandins could be the reason of the recent increase of M. clavatus bloodstream infections. PMID- 30521008 TI - INFLUENCE OF NEW MASS ENERGY-ABSORPTION COEFFICIENTS FROM ICRU REPORT NO. 90 ON AIR KERMA TO DOSE EQUIVALENT CONVERSION COEFFICIENTS. AB - In Report No. 90 of the International Commission on Radiation Units and Measurements (ICRU), new mass energy-absorption coefficients are listed which are based on renormalized Scofield photoeffect cross-sections. The mass energy absorption coefficients are the basis for the conversion coefficients from air kerma to the operational quantities listed in ISO 4037-3. Although ICRU does not give a recommendation if these new mass energy-absorption coefficients should be applied instead of the values used so far, an examination of the possible consequences for radiation protection quantities is necessary. We calculated the conversion coefficients for the X-ray qualities specified in ISO 4037-1 with the new mass energy-absorption coefficients and with the mass energy-absorption coefficients used so far to determine the deviations. Our calculations show that the change of the conversion coefficients due to the new values from ICRU Report No. 90 is negligible. PMID- 30521009 TI - BaiHui: Cross-species Brain-specific Network Built with Hundreds of Hand-curated Datasets. AB - Motivation: Functional gene networks, representing how likely two genes work in the same biological process, are important models for studying gene interactions in complex tissues. However, a limitation of the current network-building scheme is the lack of leveraging evidence from multiple model organisms as well as the lack of expert curation and quality control of the input genomic data. Results: Here, we present BaiHui, a brain-specific functional gene network built by probabilistically integrating expertly-hand-curated (by reading original publications) heterogeneous and multi-species genomic data in human, mouse and rat brains. To facilitate the use of this network, we deployed a web server through which users can query their genes of interest, visualize the network, gain functional insight from enrichment analysis and download network data. We also illustrated how this network could be used to generate testable hypotheses on disease gene prioritization of brain disorders. Availabilityand implementation: BaiHui is freely available at: http://guanlab.ccmb.med.umich.edu/BaiHui/. Supplementary information: Supplementary data is available at Bioinformatics online. PMID- 30521010 TI - CG258 Klebsiella pneumoniae isolates without beta-lactam resistance at the onset of the carbapenem-resistant Enterobacteriaceae epidemic in New York City-author response. PMID- 30521011 TI - Strongyloides stercoralis infection in a migrant on dialysis. PMID- 30521012 TI - BIOLITMAP: a web-based geolocated, temporal and thematic visualization of the evolution of bioinformatics publications. AB - Motivation: The fast growth of bioinformatics adds a significant difficulty to assess the contribution, geographical and thematic distribution of the research publications. Results: To help researchers, grant agencies and general public to assess the progress in bioinformatics, we have developed BIOLITMAP, a web-based geolocation system that allows an easy and sensible exploration of the publications by institution, year and topic. Availability: BIOLITMAP is available at http://socialanalytics.bsc.es/biolitmap and the sources have been deposited at https://github.com/inab/BIOLITMAP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30521013 TI - Reproductive homeostasis and senescence in Drosophila melanogaster. AB - The homeostatic properties of reproduction in aging female Drosophila melanogaster are investigated. Classic studies based on cohort analysis suggest that homeostatic capacity declines gradually as daily oviposition rates decline in aging flies. Analysis at the level of individuals gives a very different picture: reproductive homeostasis remains relatively constant for most of adult life until a critical point when oviposition either ceases entirely or continues in dysregulated fashion. The collapse of homeostatic capacity is abrupt. Enhanced homeostasis is associated with increased lifetime fecundity and improved prospects for survival. The fractal concept of lacunarity can be used to parameterize the "roughness" of individual fecundity trajectories and is inversely related to homeostatic capacity. PMID- 30521014 TI - Increased urinary miR-196a level predicts the progression of renal injury in patients with diabetic nephropathy. AB - Background: Recent data suggest that miR-196a is predominantly expressed in the kidney and plays an inhibitory role in the progress of renal interstitial fibrosis (IF). However, the predictive value of miR-196a in diabetic nephropathy (DN) remains unknown. We validated the role of urinary miR-196a in the progression of renal injury in a cohort of patients with type 2 diabetes mellitus. Methods: Our study included 209 patients with biopsy-proven DN. The mean follow-up time was 54.03 +/- 32.94 months. Histological lesions were assessed using the pathological classification established by the Renal Pathology Society. Percentages of IF and tubular atrophy were assessed using the Aperio ScanScope system. We measured the correlation of urinary miR-196a with clinical and pathological parameters using the Spearman's correlation test. The influence of urinary miR-196a on renal outcomes was assessed using Cox regression analysis. Results: Urinary miR-196a levels correlated positively with proteinuria (rho = 0.385, P < 0.001), duration of diabetes mellitus (rho = 0.255, P < 0.001) and systolic blood pressure (rho = 0.267, P < 0.001). The baseline estimated glomerular filtration rate (eGFR) and hemoglobin level showed a negative correlation with urinary miR-196a (rho = -0.247, P < 0.001 and rho = -0.236, P = 0.001, respectively). Pathologically, urinary miR-196a levels correlated with glomerular sclerosis and IF in patients with DN. Urinary miR-196a was significantly associated with progression to end-stage renal disease [hazard ratio (HR) 2.03, P < 0.001] and a 40% reduction of baseline eGFR (HR 1.75, P = 0.001), independent of age, gender, body mass index, mean arterial pressure and hemoglobinA1c level. However, urinary miR-196a did not improve predictive power to proteinuria and eGFR in DN patients. Conclusions: Increased urinary miR-196a was significantly associated with the progression of renal injury and might be a noninvasive prognostic marker of renal fibrosis in DN patients. PMID- 30521015 TI - Possible cold-adaptation for the fungal kinesin in compensation for thermal stability acquired by single amino acid substitution. AB - The amino acid sequence of the motor domain of AnKinA, kinesin-1 from Aspergillus nidulans, growing optimally at 37 degrees C, was compared with that of SbKin1, kinesin-1 from the snow mold Sclerotinia borealis. For cold-adaptation, some enzymes are thought to exhibit augmented protein structure flexibility, acquired most effectively by substituting a glycine residue for another amino acid residue. By the comparison described above, two glycine residues proximal to tightly-bound ADP were identified in the SbKin1 motor domain, of which the corresponding residues of AnKinA were non-glycine ones (P60 and S323). We made AnKinA recombinant kinesin (AnKinA-WT; abbreviated as WT) along with P60G and S323G mutants. From the basal ATPase activity (without microtubules), these kinesins showed similar characteristics in activation energies, while deviation from the linearity of the ATPase activity time-course was detected at 34 degrees C for WT and P60G but at 24 degrees C for S323G. The microtubule translocation velocity of WT, P60G, or S323G exhibited an activation energy of 60, 58, or 53 kJ/mol, respectively; for S323G, the activation energy was lower and the velocity at low temperatures was higher than those for the other two. These results suggest that the point mutation S323G would offer possible cold-adaptation in compensation for thermal stability. PMID- 30521016 TI - Emerging evidence of an effect of salt on innate and adaptive immunity. AB - Salt intake as part of a western diet currently exceeds recommended limits, and the small amount found in the natural diet enjoyed by our Paleolithic ancestors. Excess salt is associated with the development of hypertension and cardiovascular disease, but other adverse effects of excess salt intake are beginning to be recognized, including the development of autoimmune and inflammatory disease. Over the last decade there has been an increasing body of evidence demonstrating that salt affects multiple components of both the innate and adaptive immune systems. In this review we outline the recent laboratory, animal and human data, highlighting the effect of salt on immunity, with a particular focus on the relevance to inflammatory kidney disease. PMID- 30521017 TI - Reducing Disparities in Pediatric Vision Care Utilization by Strategically Addressing Access. PMID- 30521018 TI - APOE-epsilon4 Genotype is Associated with Elevated Post-Concussion Symptoms in Military Veterans with a Remote History of Mild Traumatic Brain Injury. AB - Objective: We evaluated the influence of the APOE-epsilon4 allele on post concussive symptoms in military Veterans with a remote history of mild traumatic brain injury (mTBI). Method: Participants (N = 77) were administered neuropsychiatric measures, on average, approximately 5 years following their most recent mTBI and provided a DNA sample for APOE genotyping. Veterans were divided into two groups based on their epsilon4 status (n = 14 epsilon4+, n = 63 epsilon4 ). The Neurobehavioral Symptom Inventory (NSI) was the primary outcome measure, from which a total score was derived, as well as three symptom clusters (somatic, cognitive, and affective). Results: ANCOVAs showed a significant main effect of epsilon4 genotype on the NSI total score and somatic symptom cluster after adjusting for posttraumatic stress symptoms and mTBI history (p = .019-.028, etap2 = .064-.073), such that epsilon4+ Veterans endorsed significantly greater symptoms than epsilon4- Veterans. Conclusions: Our findings suggest that genetic risk may help to explain the poorer long-term outcomes often observed in this population. PMID- 30521019 TI - Antiphospholipid score is a novel risk factor for idiopathic osteonecrosis of the femoral head in patients with systemic lupus erythematosus. AB - Objectives: Idiopathic osteonecrosis of the femoral head (ION) is a common complication of SLE associated with CS therapy. Although the pathogenesis of ION involves local bone ischaemia favoured by thrombophilia, the involvement of aPL in lupus ION remains to be elucidated. We have previously reported the aPL score (aPL-S) as a quantitative marker of aPL and the development of thrombotic events in autoimmune diseases. The aim of this study was to identify the impact of aPL on the development of ION using aPL-S. Methods: This was a single-centre retrospective study comprising 88 consecutive SLE patients who underwent MRI of the hip joints from January 2000 to March 2017. Baseline characteristics, pharmacotherapy and total hip arthroplasty performed during follow-up were evaluated. Results: The presence of ION was confirmed by MRI scan in 38 patients (43.1%). Male gender, positivity of any aPL, aPL-S, high aPL-S (>=30) and high dose of CS were identified as risk factors for ION by univariate analysis. Multivariate analysis revealed high aPL-S (odds ratio 5.12, 95% CI 1.18-29.79) and use of high-dose CS (odds ratio 10.25, 95% CI 3.00-48.38) as independent variables. Kaplan-Meier analysis showed that patients with high aPL-S received total hip arthroplasty more frequently than those without aPL (P = 0.010). Conclusion: We newly identified high aPL-S as an important risk factor for ION development in SLE, suggesting the involvement of aPL-induced coagulopathy in the pathophysiology of lupus ION. PMID- 30521020 TI - A databank for intracellular electrophysiological mapping of the adult somatosensory cortex. AB - Background: Neurons in the supragranular layers of the somatosensory cortex integrate sensory (bottom-up) and cognitive/perceptual (top-down) information as they orchestrate communication across cortical columns. It has been inferred, based on intracellular recordings from juvenile animals, that supragranular neurons are electrically mature by the fourth postnatal week. However, the dynamics of the neuronal integration in the adulthood is largely unknown. Electrophysiological characterization of the active properties of these neurons throughout adulthood will help to address the biophysical and computational principles of the neuronal integration. Findings: Here we provide a database of whole-cell intracellular recordings from 315 neurons located in the supragranular layers (L2/3) of the primary somatosensory cortex in adult mice (9-45 weeks old) from both sexes (females, N = 195; males, N = 120). Data include 361 somatic current-clamp (CC) and 476 voltage-clamp (VC) experiments, recorded using a step and-hold protocol (CC, N = 257; VC, N = 46), frozen noise injections (CC, N = 104) and triangular voltage sweeps (VC, 10 (N = 132), 50 (N = 146) and 100 ms (N = 152)), from regular spiking (N = 169) and fast-spiking neurons (N = 66). Conclusions: The data can be used to systematically study the properties of somatic integration, and the principles of action potential generation across sexes and across electrically characterized neuronal classes in adulthood. Understanding the principles of the somatic transformation of postsynaptic potentials into action potentials will shed light onto the computational principles of intracellular information transfer in single neurons and information processing in neuronal networks, helping to recreate neuronal functions in artificial systems. PMID- 30521021 TI - Anterior Nasal Cavity Mass in a Neonate. PMID- 30521022 TI - Concurrent Developmental Course of Sleep Problems and Emotional/behavioral Problems in Childhood and Adolescence as Reflected by the Dysregulation Profile. AB - Objectives: Longitudinal data on the course and relationship of concurrent psychopathology in youth are scarce but are of need for better practical patient care and prevention. This study explores the course of (and relationships over time) between sleep problems and concurrent dimensional difficulties relating to anxiety/depression, attention deficiency and aggressive behaviors in childhood and adolescence. The latter three may jointly form a broad syndrome, the dysregulation profile. Methods: Young people from the Raine Study, a large community cohort-sample (N = 1625) were followed from age 5 to 17 years. Developmental courses of sleep problems and its concurrent regulatory difficulties were estimated separately and jointly. Results: The majority of adolescents reported low levels of problems and which appeared to be stable over time, while a small group (rates between 7.8%-10.1%) reported enduring problematic developmental courses. Sleep problems and regulatory difficulties shared a strong association in their development over time (individual's probabilities of having the same courses, i.e., low-low and high-high, were between 89.8%-92.3%). Furthermore, having persistent sleep problems over time was associated with an increased risk of having regulatory difficulties by approximately 10 times, and vice versa. Conclusion: Findings from this study provide empirical evidence for a strong mutual association in the development of sleep problems and difficulties of dysregulation with emotion, cognition and aggression. It may be suggested that a positive screening of one such psychopathological dimension should lead to a carful assessment, not only to reduce the problem in question but also to prevent the youth from further problems. PMID- 30521023 TI - Advances in Genomic Hepatocellular Carcinoma Research. AB - Background: Hepatocellular carcinoma (HCC) is the cancer with the second highest mortality in the world due to its late presentation and limited treatment options. As such, there is an urgent need to identify novel biomarkers for early diagnosis and develop novel therapies. The availability of Next Generation Sequencing (NGS) data from tumors of liver cancer patients has provided us with invaluable resources to better understand HCC through the integration of data from different sources to facilitate the identification of promising biomarkers or therapeutic targets. Main findings: Here, we review key insights gleaned from over 20 NGS studies of HCC tumor samples, comprising approximately 582 whole genomes and 1211 whole exomes mainly from the East Asian population. Through consolidation of reported somatic mutations from multiple studies, we identified genes with different types of somatic mutations including single nucleotide variations, insertion/deletions, structural variations and copy number alterations as well as genes with multiple frequent viral integration. Pathway analysis showed that this curated list of somatic mutations is critically involved in cancer-related pathways, viral carcinogenesis and signalling pathways. Lastly, we addressed the future directions of HCC research as more NGS datasets become available. Conclusion: Our review is a comprehensive resource for the current NGS research in HCC consolidating published articles, potential gene candidates and their related biological pathways. PMID- 30521024 TI - Resolving Deep Nodes in an Ancient Radiation of Neotropical Fishes in the Presence of Conflicting Signals from Incomplete Lineage Sorting. AB - Resolving patterns of ancient and rapid diversifications is one of the most challenging tasks in evolutionary biology. These difficulties arise from confusing phylogenetic signals that are associated with the interplay of incomplete lineage sorting and homoplasy. Phylogenomic analyses of hundreds, or even thousands, of loci offer the potential to resolve such contentious relationships. Yet, how much useful phylogenetic information these large data sets contain remains uncertain and often goes untested. Here, we assess the utility of different data filtering approaches to maximize phylogenetic information and minimize noise when reconstructing an ancient radiation of Neotropical electric knifefishes (Order Gymnotiformes) using ultraconserved elements. We found two contrasting hypotheses of gymnotiform evolutionary relationships depending on whether phylogenetic inferences were based on concatenation or coalescent methods. In the first case, all analyses inferred a previously-and commonly-proposed hypothesis, where the family Apteronotidae was found as the sister group to all other gymnotiform families. In contrast, coalescent-based analyses suggested a novel hypothesis where families producing pulse-type (viz., Gymnotidae, Hypopomidae and Rhamphichthyidae) and wave-type electric signals (viz., Apteronotidae, Sternopygidae) were reciprocally monophyletic. Nodal support for this second hypothesis increased when analyzing loci with the highest phylogenetic information content and further increased when data were pruned using targeted filtering methods that maximized phylogenetic informativeness at the deepest nodes of the Gymnotiformes. Bayesian concordance analyses and topology tests of individual gene genealogies demonstrated that the difficulty of resolving this radiation was likely due to high gene-tree incongruences that resulted from incomplete lineage sorting. We show that data filtering reduces gene tree heterogeneity and increases nodal support and consistency of species trees using coalescent methods; however, we failed to observe the same effect when using concatenation methods. Furthermore, the targeted filtering strategies applied here support the use of "gene data interrogation" rather than "gene genealogy interrogation" approaches in phylogenomic analyses, to extract phylogenetic signal from intractable portions of the Tree of Life. PMID- 30521025 TI - Gestational Age at Arrest of Development: An Alternative Approach for Assigning Time at Risk in Studies of Time-Varying Exposures and Miscarriage. AB - Time between arrest of pregnancy development and miscarriage represents a window in which pregnancy is nonviable and not developing. In effect, the loss has happened and exposures cannot influence its fate. However, epidemiologic studies of miscarriage traditionally use gestational age at miscarriage to assign time in survival analyses, which overestimates duration of exposure and time at risk. In the Right from the Start pregnancy cohort (2000-2012), we characterized the gap between estimated gestational age at arrest of development (GAAD) and miscarriage using transvaginal ultrasound in 500 women recruited from 3 states (North Carolina, Tennessee, and Texas). We compare effect estimates from models using GAAD versus gestational age at miscarriage to assign time at risk through a simulation study of 4 exposure patterns with varying effect sizes. The median gap between GAAD and miscarriage was 23 days (inter-quartile range 15-32 days). Use of GAAD decreased bias and variance of the estimated association for time-varying exposures, whereas half the time using gestational age at miscarriage led to estimates that differed from the true effect by more than 20%. Using GAAD to assign time at risk should result in more accurate and consistent characterization of miscarriage risk associated with time-varying exposures. PMID- 30521026 TI - An RK/ST C-terminal Motif is Required for Targeting of OEP7.2 and a Subset of Other Arabidopsis Tail-Anchored Proteins to the Plastid Outer Envelope Membrane. AB - Tail-anchored (TA) proteins are a unique class of integral membrane proteins that possess a single C-terminal transmembrane domain and target post-translationally to the specific organelles at which they function. While significant advances have been made in recent years in elucidating the mechanisms and molecular targeting signals involved in the proper sorting of TA proteins, particularly to the endoplasmic reticulum and mitochondria, relatively little is known about the targeting of TA proteins to the plastid outer envelope. Here we show that several known or predicted plastid TA outer envelope proteins (OEPs) in Arabidopsis possess a C-terminal RK/ST sequence motif that serves as a conserved element of their plastid targeting signal. Evidence for this conclusion comes primarily from experiments with OEP7.2, which is a member of the Arabidopsis 7-kDa OEP family. We confirmed that OEP7.2 is localized to the plastid outer envelope and possesses a TA topology, and its C-terminal sequence (CTS), which includes the RK/ST motif, is essential for proper targeting to plastids. The CTS of OEP7.2 is functionally interchangeable with the CTSs of other TA OEPs that possess similar RK/ST motifs, but not with those that lack the motif. Further, a bioinformatics search based on a consensus sequence led to the identification of several new OEP TA proteins. Collectively, this study provides new insight to the mechanisms of TA protein sorting in plant cells, defines a new targeting signal element for a subset of TA OEPs, and expands the number and repertoire of TA proteins at the plastid outer envelope. PMID- 30521027 TI - Detection and prioritization of developmentally neurotoxic and/or neurotoxic compounds using zebrafish. AB - The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive and cost effective alternate models to reliably predict toxicity. As part of Tox21 Phase III's effort, a 90-compound library was created and made available to researchers to screen for neurotoxicants using novel technology and models. The chemical library was evaluated in zebrafish in a dose range finding test for embryo toxicity (i.e., mortality or morphological alterations induced by each chemical). In addition, embryos exposed to the LEL (lowest effect level) and non-observable effect level were used to measure the internal concentration of the chemicals within the embryos by bioanalysis. Finally, considering the LEL as the highest testing concentration, a functional assay was performed based on locomotor activity alteration in response to light-dark changes. The quality control chemicals included in the library, i.e. negative controls and replicated chemicals, indicate that the assays performed were reliable. The use of analytical chemistry pointed out the importance of measuring chemical concentration inside embryos, and in particular, in the case of negative chemicals to avoid false negative classification. Overall, the proposed approach presented a good sensitivity and supports the inclusion of zebrafish assays as a reliable, relevant and efficient screening tool to identify, prioritize and evaluate chemical toxicity. PMID- 30521028 TI - Heart Rate Variability Predicts Older Adults' Avoidance of Negativity. AB - Objectives: The ability to produce situation-appropriate cognitive and emotional responses is dependent on autonomic nervous system (ANS) functionality. Heart rate variability (HRV) is an index of ANS functionality, and resting HRV levels have been associated with cognitive control and inhibitory capacity in young adults, particularly when faced with emotional information. As older adults' greater preference for positive and avoidance of negative stimuli (positivity effect) is thought to be dependent on cognitive control, we hypothesized that HRV could predict positivity-effect magnitude in older adults. Method: We measured resting-level HRV and gaze preference for happy and angry (relative to neutral) faces in 63 young and 62 older adults. Results: Whereas young adults showed no consistent preference for happy or angry faces, older adults showed the expected positivity effect, which predominantly manifested as negativity avoidance rather than positivity preference. Crucially, older but not young adults showed an association between HRV and gaze preference, with higher levels of HRV being specifically associated with stronger negativity avoidance. Discussion: This is the first study to demonstrate a link between older adults' ANS functionality and their avoidance of negative information. Increasing the efficiency of the cardiovascular system might selectively improve older adults' ability to disregard negative influences. PMID- 30521029 TI - Inhibition of PTEN activates bovine non-growing follicles in vitro but increases DNA damage and reduces DNA repair response. AB - STUDY QUESTION: Does ovarian follicle activation by phosphatase homologue of chromosome-10 (PTEN) inhibition affect DNA damage and repair in bovine oocytes and granulosa cells? SUMMARY ANSWER: PTEN inhibition promotes bovine non-growing follicle activation but results in increased DNA damage and impaired DNA repair capacity in ovarian follicles in vitro. WHAT IS KNOWN ALREADY: Inhibition of PTEN is known to activate primordial follicles but may compromise further developmental potential. In breast cancer cells, PTEN inhibition represses nuclear translocation of breast cancer susceptibility 1 (BRCA1) and Rad51; this impairs DNA repair resulting in an accumulation of damaged DNA, which contributes to cell senescence. STUDY DESIGN, SIZE, DURATION: Bovine ovarian tissue fragments were exposed to control medium alone or containing either 1 or 10 MUM bpv(HOpic), a pharmacological inhibitor of PTEN, in vitro for 24 h. A sub-group of tissue fragments were collected for Western blot analysis after bpv(HOpic) exposure. The remainder were incubated in control medium for a further 5 days and then analysed histologically and by immunohistochemistry to detect DNA damage and repair pathways. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bovine ovaries were obtained from abattoir-slaughtered heifers. Tissue fragments were exposed to either control medium alone or medium containing either 1 MUM or 10 MUM bpv(HOpic) for 24 h. Tissue fragments collected after 24 h were subjected to Akt quantification by Western blotting (six to nine fragments per group per experiment). Follicle stage and morphology were classified in remaining fragments. Immunohistochemical analysis included nuclear exclusion of FOXO3 as a marker of follicle activation, gammaH2AX as a marker of DNA damage, meiotic recombination 11 (MRE11), ataxia telangiectasia mutated (ATM), Rad51, breast cancer susceptibility 1 (BRCA1) and breast cancer susceptibility 2 (BRCA2) as DNA repair factors. A total of 29 550 follicles from three independent experiments were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Tissue fragments exposed to bpv(HOpic) had increased Akt phosphorylation at serine 473 (pAkt/Akt ratio, 2.25- and 6.23-fold higher in 1 and 10 MUM bpv(HOpic) respectively compared to control, P < 0.05). These tissue fragments contained a significantly higher proportion of growing follicles compared to control (78.6% in 1 MUM and 88.7% in 10 MUM versus 70.5% in control; P < 0.001). The proportion of morphologically healthy follicles did not differ significantly between 1 MUM bpv(HOpic) and control (P < 0.001) but follicle health was lower in 10 MUM compared to 1 MUM and control in all follicle types (P < 0.05). DNA damage in oocytes, indicated by expression of gammaH2AX, increased following exposure to 1 MUM bpv(HOpic) (non-growing, 83%; primary follicles, 76%) and 10 MUM (non-growing, 77%; primary, 84%) compared to control (non-growing, 30% and primary, 59%) (P < 0.05 for all groups). A significant reduction in expression of DNA repair proteins MRE11, ATM and Rad51 was observed in oocytes of non-growing and primary follicles of treatment groups (primary follicles in controls versus 10 MUM bpv(HOpic): MRE, 68% versus 47%; ATM, 47% versus 18%; Rad51, 48% versus 24%), P < 0.05 for all groups. Higher dose bpv(HOpic) also resulted in lower expression of BRCA1 compared to control and 1 MUM bpv(HOpic) (P < 0.001) in non-growing and primary follicles. BRCA2 expression was increased in oocytes of primary follicles in 1 MUM bpv(HOpic) (36%) compared to control (20%, P = 0.010) with a marked decrease in 10 MUM (1%, P <= 0.001). Granulosa cells of primary and secondary follicles in bpv(HOpic) groups showed more DNA damage compared to control (P < 0.05). However, bpv(HOpic) did not impact granulosa cell DNA repair capacity in secondary follicles, but BRCA1 declined significantly in higher dose bpv(HOpic). LARGE-SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This study focuses on non-growing follicle activation after 6 days culture and may not reflect DNA damage and repair capacity in later stages of oocyte and follicle growth. WIDER IMPLICATIONS OF THE FINDINGS: In vitro activation of follicle growth may compromise the bidirectional signalling between oocyte and granulosa cells necessary for optimal oocyte and follicle health. This large animal model may be useful in optimising follicle activation protocols with a view to transfer for clinical application. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Indonesia endowment fund for education. No competing interest. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30521030 TI - Accurate and efficient estimation of small p-values with the cross-entropy method: applications in genomic data analysis. AB - Motivation: Small p-values are often required to be accurately estimated in large scale genomic studies for the adjustment of multiple hypothesis tests and the ranking of genomic features based on their statistical significance. For those complicated test statistics whose cumulative distribution functions are analytically intractable, existing methods usually do not work well with small p values due to lack of accuracy or computational restrictions. We propose a general approach for accurately and efficiently estimating small p-values for a broad range of complicated test statistics based on the principle of the cross entropy method and Markov chain Monte Carlo sampling techniques. Results: We evaluate the performance of the proposed algorithm through simulations and demonstrate its application to three real-world examples in genomic studies. The results show that our approach can accurately evaluate small to extremely small p values (e.g. 10-6 to 10-100). The proposed algorithm is helpful for the improvement of some existing test procedures and the development of new test procedures in genomic studies. Availability: R programs for implementing the algorithm and reproducing the results are available at: https://github.com/shilab2017/MCMC-CE-codes. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30521031 TI - Predictors associated with an increased prevalence of postimplantation syndrome after thoracic endovascular aortic repair for type B aortic dissection. AB - OBJECTIVES: The aim of this study was to identify patients who are at high risk of developing postimplantation syndrome (PIS) after thoracic endovascular aortic repair (TEVAR) for type B aortic dissection. METHODS: This retrospective study included 646 patients who underwent TEVAR for type B aortic dissection between January 2010 and December 2015 at the Guangdong General Hospital. PIS was defined as fever (>38 degrees C) and leucocytosis (>12 000 MUl-1) without evidence of infection. The PIS rate was calculated, and a multivariable logistic regression model was used to investigate the factors related to PIS. RESULTS: A total of 646 patients (58.8 +/- 11.0 years, 87.9% men) were included in the analysis. PIS was diagnosed in 204 (31.6%) patients. Age <60 years [odds ratio (OR) 1.828, 95% confidence interval (CI) 1.277-2.619; P < 0.001), hypertension (OR 12.125, 95% CI 4.310-34.111; P < 0.001), >1 stent graft placed (OR 1.862, 95% CI 1.109-3.124; P = 0.011), arch vessel bypass (OR 2.107, 95% CI 1.397-3.176; P = 0.001) and Ankura stent graft placement (OR 1.951, 95% CI 1.298-2.933; P = 0.001) were positively associated with PIS, whereas statin use (OR 0.659, 95% CI 0.460-0.944; P = 0.023) was negatively associated with PIS in the multivariable logistic regression analysis based on a stepwise regression model. CONCLUSIONS: Age <60 years, comorbid hypertension, >1 stent graft placed, arch vessel bypass and Ankura stent graft placement emerged as independent predictors of PIS. Stepwise increases in the prevalence of PIS were found to depend on the number of independent predictors. PMID- 30521032 TI - INNOVATIVE SOLUTIONS FOR PERSONAL RADIATION SHIELDING IN SPACE. AB - Personal radiation shielding is likely to play an important role in the strategy for radiation protection of future manned interplanetary missions. There is potential for the successful adoption of wearable shielding devices, readily available in case of accidental exposures or used for emergency operations in low shielded areas of the habitat, particularly in case of solar particle events (SPEs). Based on optimization of available resources, conceptual models for radiation protection spacesuits have been proposed, with elements made of different materials, and the first prototype of a water-fillable garment was designed and manufactured in the framework of the PERSEO project, funded by the Italian Space Agency, leading to the successful test of such prototype for ease of use and wearability on-board the International Space Station. We present results of Monte Carlo calculations offering a proof-of-principle validation of the shielding efficacy of such prototype in different SPE environments and shielding conditions. PMID- 30521033 TI - Effects of immune suppression in murine models of disseminated Candida glabrata and Candida tropicalis infection and utility of a synthetic peptide vaccine. AB - Candida species are the second most frequent cause of fungal infections worldwide. Current knowledge of immunity to Candida has been gleaned almost exclusively from studies on Candida albicans, the most common disease-causing species. Knowledge of immunity to non-albicans Candida (NAC) species is still at an early stage due to the lack of tractable animal models with which to study these important pathogens. This is partly because many NAC species are not usually pathogenic in mouse models of candidiasis. In this study, we established an immunosuppressed mouse model of disseminated candidiasis by the two clinically important NAC species, C. glabrata and C. tropicalis. The inbred mouse strains, A/J and BALB/c, show distinct susceptibilities to disseminated Candida infection. A/J mice, deficient for complement C5, are more susceptible to disseminated infection with both C. glabrata and C. tropicalis compared to BALB/c mice, the latter having functional C5. Here we show that peptide-pulsed dendritic cell (DC) vaccination with a peptide derived from a C. tropicalis cell surface protein, significantly improved survival and reduced the fungal burdens of disseminated candidiasis in these immunocompromised mice. Importantly, this study is the first report of protective efficacy conferred by a peptide vaccine against medically important NAC species in immunosuppressed hosts. Establishing this experimental mouse model provides an important tool to further understand pathogenesis and host resistance in Candida infection. Significantly, our findings also demonstrate how this model can be used to evaluate new control strategies against candidiasis, such as vaccines. PMID- 30521035 TI - Determinants of medication adherence among chronic patients from an urban area: a cross-sectional study. AB - Background: Medication adherence is a complex area of behaviour. Little is known about what influences chronic patients to take their medicines. This study has aimed to compare and contrast the health-related beliefs, experiences and types of behaviour typical among patients who have at least one chronic condition and are following a pharmacological treatment in accordance with their level of medication adherence. Methods: A questionnaire-based cross-sectional study, consisting of socio-demographic data, the 4-item Morisky-Green scale and 37 statements about health beliefs, perceptions and experiences, was conducted at different levels of healthcare (primary and tertiary settings). Results: A total of 577 questionnaires were analyzed. Respondents had a mean age of 64 and took an average of 4.6 drugs. Optimal adherence was reported by 58.6% of respondents. Bivariate analysis showed adherent subjects were older, took more medications, were in better spirits and had greater confidence and information regarding their treatment. Multivariate analysis found older age and the statements 'My doctor periodically reviews my treatment' and 'I am motivated to continue with the treatment' to be significantly related to medication adherence, while 'I make variations when taking medication depending on how I feel' was significant for medication non-adherence. Conclusion: Medication non-adherence is common among chronic patients. Patient-centred approaches should be implemented in daily clinical practice as patient health beliefs, experiences and conduct influence medication-taking. Motivational interviewing might improve medication adherence in permitting emotional state managing and increasing educational skills, patient motivation and confidence between patients and healthcare providers. PMID- 30521034 TI - Erratum to: The sponge microbiome project. PMID- 30521036 TI - Population Genetics Based Phylogenetics Under Stabilizing Selection for an Optimal Amino Acid Sequence: A Nested Modeling Approach. AB - We present a new phylogenetic approach SelAC (Selection on Amino acids and Codons), whose substitution rates are based on a nested model linking protein expression to population genetics. Unlike simpler codon models which assume a single substitution matrix for all sites, our model more realistically represents the evolution of protein coding DNA under the assumption of consistent, stabilizing selection using cost-benefit approach. This cost-benefit approach allows us generate a set of 20 optimal amino acid specific matrix families using just a handful of parameters and naturally links the strength of stabilizing selection to protein synthesis levels, which we can estimate. Using a yeast dataset of 100 orthologs for 6 taxa, we find SelAC fits the data much better than popular models by 104-105 AICc units. Our results also indicated that nested, mechanistic models better predict observed data patterns highlighting the improvement in biological realism in amino acid sequence evolution that our model provides. Additional parameters estimated by SelAC indicate that a large amount of non-phylogenetic, but biologically meaningful, information can be inferred from exisiting data. For example, SelAC prediction of gene specific protein synthesis rates correlates well with both empirical (r = 0.33-0.48) and other theoretical predictions (r=0.45-0.64) for multiple yeast species. SelAC also provides estimates of the optimal amino acid at each site. Finally, because SelAC is a nested approach based on clearly stated biological assumptions, future modifications, such as including shifts in the optimal amino acid sequence within or across lineages, are possible. PMID- 30521037 TI - Practice patterns of surgery for advanced ovarian cancer: analysis from international surveys. AB - Background: We investigated the practice patterns of surgery for advanced ovarian cancer (AOC) through relevant international surveys. Methods: After searching for 878 studies on surgery for AOC till 2017, we extracted 18 questions with similar query and answer formats from eight studies. Among them, 5 and 13 were classified as comprehensive and procedure information. Results: In comprehensive information, there was a higher preference for optimal cytoreduction defined as no visible tumor (44%) compared with residual tumors <1 cm (38%) or <2 cm (2%) and omental disease involving the spleen or pancreas was more important as an intraoperative finding precluding optimal cytoreduction (35%) since 2010. The preference for neoadjuvant chemotherapy was the highest at its use for 1-10% (36%), which was preferred in Europe over USA. The positive expectation of preoperative determination of optimal cytoreduction was higher in Europe than in USA (44 vs. 27%; P < 0.05). In procedure information, conventional gynecological surgery was mainly performed by gynecological oncologists, whereas more than 50% of upper abdominal or urological surgeries were conducted by other surgeons. European clinicians showed a higher response rate of diaphragmatic stripping and resection than those from USA (88 vs. 60%; 69 vs. 24%; P < 0.05). Conclusion: No visible tumor as the criterion for optimal cytoreduction was preferred in AOC, and aggressive surgery beyond conventional gynecological surgery tended to be performed by other surgeons. Moreover, the preference of neoadjuvant chemotherapy and the positive expectation of preoperative determination of optimal cytoreduction were higher in Europe than in USA. PMID- 30521038 TI - Analysis of a lectin microarray identifies altered sialylation of mouse serum glycoproteins induced by whole-body radiation exposure. AB - Microarrays containing 45 different lectins were analyzed to identify global changes in the glycosylation of serum glycoproteins from mice exposed to whole body gamma-radiation. The results showed that radiation exposure increased and decreased the relative amounts of alpha-2,3- and alpha-2,6-sialic acids, respectively. The expression of alpha-2,3- and alpha-2,6-sialyltransferase genes in the liver was analyzed to determine whether changes in their expression were responsible for the sialic acid changes. The increase in alpha-2,3-sialic acid correlated with St3gal5 upregulation after radiation exposure; however, a decrease in St6gal1 expression was not observed. Analysis of a PCR array of genes expressed in irradiated mouse livers revealed that irradiation did not alter the expression of most of the included genes. These results suggest that glycomic screening of serum glycoproteins using lectin microarrays can be a powerful tool for identifying radiation-induced changes in the post-translational addition of sugar moieties to proteins. In addition, the results indicate that altered sialylation of glycoproteins may be an initial response to acute radiation exposure. PMID- 30521039 TI - Erratum. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. PMID- 30521040 TI - Pediatric Office Delivery of Smoking Cessation Assistance for Breast-Feeding Mothers. AB - Introduction: National and international organizations have done an excellent job of advocating and promoting breast feeding for all mothers. This study assessed to what extent an intervention increased delivery of cessation assistance to breast-feeding mothers who smoke. Methods: Data were collected between April and October 2015 in five US states as part of a cluster randomized controlled trial in 10 pediatric practices. Practices were randomized to the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention or usual care control arms. Mothers were asked about their smoking status and breast-feeding history during a screening interview upon exiting the practice and eligible mothers who agreed to participate in an enrollment interview were asked if they received smoking cessation assistance during their child's visit. Mothers with a child 1 year old and younger were included in the analyses. Results: Current breast feeding was associated with a reduced likelihood of current smoking (adjusted odds ratio [aOR] = 0.38, 95% confidence interval [95% CI] = 0.25 to 0.57) and a greater likelihood of quitting smoking (aOR = 2.33, 95% CI = 1.29 to 4.21) after controlling for known confounders. Mothers who concurrently smoked and breast-fed were more likely to be asked about smoking (66.7% vs. 28.6%, p = .01), advised to quit (61.1% vs. 21.4%, p < .01), prescribed nicotine replacement therapy (50.0% vs. 0%, p < .001), and enrolled into the quitline (27.8% vs. 0%, p < .01) at CEASE practices compared to control practices. Conclusion: Breast-feeding mothers were less likely to be current smokers and more likely to have recently quit smoking. Among mothers who continue to smoke and breast feed, the CEASE intervention enhances delivery of smoking cessation assistance. Implications: Breast feeding and eliminating infants' exposure to tobacco smoke are important protective factors for serious pediatric health risks including sudden infant death. This study shows that breast feeding was positively associated with desirable tobacco control outcomes, specifically that breast feeding was associated with a lower likelihood of smoking among ever smokers and a greater likelihood of recently quitting smoking. This is also the first study to look specifically at delivery of smoking cessation assistance to breast-feeding mothers seen at pediatric offices and demonstrates the effectiveness of delivering evidence-based smoking cessation assistance to them in this context. Trial Registration: www.ClinicalTrials.gov (identifier NCT01882348). PMID- 30521041 TI - Insomnia in breast cancer: a prospective observational study. AB - STUDY OBJECTIVES: Insomnia in cancer patients is prevalent, persistent and confers risk for physical and psychological disorder. We must better understand how insomnia develops in cancer patients and explore the main contributors to its chronicity so that insomnia management protocols can be integrated more effectively within cancer care. This study monitors the etiology of insomnia in breast cancer patients and identifies risk factors for its persistence. METHODS: 173 females with newly diagnosed, non-metastatic breast cancer were tracked from diagnosis for 12-months. Participants completed monthly sleep assessments using the Insomnia Severity Index (ISI) and 3-monthly health-related quality-of-life assessments using the European Organisation for Research and Treatment of Cancer Breast (EORTC QLQ-C30-BR23) scale. Clinical data on disease status and treatment regimens were also assessed. RESULTS: Prior to diagnosis, 25% of participants reported sleep disturbance, including 8% with insomnia syndrome (IS). Prevalence increased at cancer diagnosis to 46% (18% IS) and remained stable thereafter at around 50% (21% IS). We also explored sleep status transitions. The most common pattern was to remain a good sleeper (34%-49%) or to persist with insomnia (23% 46%). 77% of good sleepers developed insomnia during the 12-month period and 54% went into insomnia remission. Chemotherapy (odds ratio=0.08, 95% ci 0.02-0.29, p<.001) and pre-diagnosis ISI scores (odds ratio=1.13/unit increase in pre diagnosis sleep score, 95% ci 1.05-1.21, p=.001) were identified as the main risk factors for persistent insomnia. CONCLUSIONS: These data advance our understanding of insomnia etiology in cancer patients and help identify those who should be prioritised for insomnia management protocols. PMID- 30521043 TI - Pseudoephedrine at international borders: advising the unwary traveller. PMID- 30521042 TI - Hexameric assembly of the AAA+ protein McrB is necessary for GTPase activity. AB - McrBC is one of the three modification-dependent restriction enzymes encoded by the Escherichia coli K12 chromosome. Amongst restriction enzymes, McrBC and its close homologues are unique in employing the AAA+ domain for GTP hydrolysis dependent activation of DNA cleavage. The GTPase activity of McrB is stimulated by the endonuclease subunit McrC. It had been reported previously that McrB and McrC subunits oligomerise together into a high molecular weight species. Here we conclusively demonstrate using size exclusion chromatography coupled multi-angle light scattering (SEC-MALS) and images obtained by electron cryomicroscopy that McrB exists as a hexamer in solution. Furthermore, based on SEC-MALS and SAXS analyses of McrBC and the structure of McrB, we propose that McrBC is a complex of two McrB hexamers bridged by two subunits of McrC, and that the complete assembly of this complex is integral to its enzymatic activity. We show that the nucleotide-dependent oligomerisation of McrB precedes GTP hydrolysis. Mutational studies show that, unlike other AAA+ proteins, the catalytic Walker B aspartate is required for oligomerisation. PMID- 30521044 TI - Effects of Zinc Combined with Probiotics on Antibiotic-associated Diarrhea Secondary to Childhood Pneumonia. AB - Aim: The aim of this study was to evaluate the impact of zinc combined with probiotics (Bifico) on antibiotic-associated diarrhea (AAD) secondary to pneumonia. Methods: A total of 50 patients with AAD secondary to pneumonia were randomly divided into a probiotics group (Bifico) and a combined group (zinc combined with Bifico) and 25 pneumonia patients without AAD as the control group. Serum levels of zinc, diamine oxidase (DAO) activity, D-lactate and intestinal flora [Bifidobacterium, Escherichia coli and Bifidobacterium/E. coli (B/E) ratio] were detected before and after intervention. Results: The results showed that zinc combined with Bifico had significantly higher overall efficiency than Bifico alone for treatment of AAD secondary to pneumonia. Notably, the combined treatment increased the population of Bifidobacterium, while the number of E. coli was reduced, the B/E value was improved and DAO activity and D-lactate levels were markedly reduced. Conclusion: Patients with AAD secondary to pneumonia benefit from zinc supplementation of probiotic treatment. PMID- 30521045 TI - IMAGING URANIUM DISTRIBUTION ON RAT KIDNEY SECTIONS THROUGH DETECTION OF ALPHA TRACKS USING CR-39 PLASTIC NUCLEAR TRACK DETECTOR. AB - Uranium is renowned as a global contaminant, and attracts major concern with regards to the health risks involved because its nephrotoxicity. This paper discusses the development of a simple method to identify accumulated regions or localized sites of uranium within kidneys using the CR-39 plastic nuclear track detector. To demonstrate the proposed method, renal cryo-sections (5 MUm-t) from Wistar male rats, subcutaneously administered with uranyl acetate (2 mg/kg), were prepared on day one after administration. Concerned sections were subsequently placed on CR-39, stored for 1.25 years, and then etched in a 7 M NaOH solution at 70 degrees C for 3 h. alpha-tracks were then detected in the form of etch pits, corresponding to uranium, and also the tissue shape and structure were transferred as a roughness on the surface of CR-39. As observed, the proposed method served to facilitate simultaneous detection and identification of localized regions of uranium accumulation within kidneys. PMID- 30521046 TI - Exposure to gestational diabetes is a stronger predictor of dysmetabolic traits in children than size at birth. AB - Context and Objective: Being born small or large for gestational age and intrauterine exposure to gestational diabetes (GDM) increase the risk of type 2 diabetes (T2D) in the offspring, however, the potential combined deleterious effects of size at birth and GDM exposure remains unknown. We aimed to examine the independent effect of size at birth as well as the influence of GDM exposure in utero on cardio-metabolic traits, body composition, and puberty status in children. Design, Participants and Methods: This study is a longitudinal birth cohort study. We used clinical data from 490 offspring of mothers with GDM and 527 control offspring aged 9-16 years, born singleton at term from the Danish National Birth Cohort with available birth weight data. Results: We found no evidence of a U-shaped association between size at birth (expressed as birth weight, sex and gestational age adjusted z-score) and cardio-metabolic traits. Body size in childhood and adolescence reflected size at birth, but was not reflected in any metabolic outcome. No synergistic adverse effect of being born small or large for gestational age and being exposed to GDM was shown. However, GDM was associated with an adverse metabolic profile and earlier onset of female puberty in childhood and adolescence independently of size at birth. Conclusion: In childhood and adolescence, GDM is a stronger predictor of dysmetabolic traits than size at birth. The combination of being born small or large and being exposed to GDM does not exacerbate the metabolic profile in the offspring. PMID- 30521047 TI - Recent developments in endovascular interventions to sustain vascular access patency in haemodialysis patients. AB - There is amassed evidence regarding the use of endovascular procedures for the treatment of vascular access stenosis and thrombosis. A review was conducted based on available randomized trials, cohort studies and retrospective analyses published after 2000 on endovascular treatment of dysfunctional and thrombosed vascular access, with an aim to illustrate the available device and procedural options. The use of paclitaxel-coated balloons, cutting balloons and covered stents is described in the field of vascular access stenosis. The broad spectrum of available devices and endovascular declotting procedures ranging from thrombolysis to thrombectomy is also discussed. Overall, in this review we demonstrate the increasing role of endovascular procedures in vascular access treatment and the improved patency outcomes provided by the implementation of novel endovascular devices. Moreover, the improvement of post-intervention primary patency rates after endovascular declotting procedures and the shift to more thrombectomy-dependent procedures over time is also highlighted. In conclusion, endovascular treatment of dialysis access stenosis and thrombosis has an established role, owing to the implementation of sophisticated devices, allowing, when needed, the simultaneous treatment of thrombosis and the underlying stenosis. PMID- 30521048 TI - A QJM legacy: medical research during both world wars. PMID- 30521049 TI - Polygenic risk score identifies associations between sleep duration and diseases determined from an electronic medical record biobank. AB - Study Objectives: We aimed to detect cross-sectional phenotype and polygenic risk score (PRS) associations between sleep duration and prevalent diseases using the Partners Biobank, a hospital-based cohort study linking electronic medical record (EMR) with genetic information. Methods: Disease prevalence was determined from EMR, and sleep duration was self-reported. A PRS for sleep duration was derived using 78 previously associated SNPs from GWAS for self-reported sleep duration. We tested for associations between 1) self-reported sleep duration and 22 prevalent diseases (n=30,251), 2) the PRS and self-reported sleep duration (n=6,903), and 3) the PRS and the 22 prevalent diseases (n=16,033). For observed PRS-disease associations, we tested causality using two-sample Mendelian randomization (MR). Results: In the age-, sex-, and race-adjusted model, u-shaped associations were observed for sleep duration and asthma, depression, hypertension, insomnia, obesity, obstructive sleep apnea, and type 2 diabetes, where both short and long sleepers had higher odds for these diseases than normal sleepers (P<2.27x10-3). Next, we confirmed associations between the PRS and longer sleep duration (0.65 +/- 0.19 SD minutes per effect allele; P=7.32*10-04). The PRS collectively explained 1.4% of the phenotypic variance in sleep duration. After adjusting for age, sex, genotyping array, and principal components of ancestry, we observed that the PRS was also associated with congestive heart failure (P=0.015), obesity (P=0.019), hypertension (P=0.039), restless legs syndrome (RLS; P=0.041), and insomnia (P=0.049). Associations were maintained following additional adjustment for obesity status, except for hypertension and insomnia. For all diseases, except RLS, carrying a higher genetic burden of the 78 sleep duration-increasing alleles (i.e. higher sleep duration PRS) associated with lower odds for prevalent disease. In MR, we estimated causal associations between genetically defined longer sleep duration with decreased risk of CHF [IVW OR per minute of sleep (95% CI) =0.978 (0.961-0.996); P =0.019] and hypertension [IVW OR (95% CI) =0.993 (0.986-1.000); P =0.049], and increased risk of RLS [IVW OR (95% CI) =1.018 (1.000-1.036); P =0.045]. Conclusion: By validating the PRS for sleep duration and identifying cross-phenotype associations, we lay the groundwork for future investigations on the intersection between sleep, genetics, clinical measures, and diseases using large EMR datasets. PMID- 30521050 TI - RAD-seq data reveal a cryptic Viburnum species on the North American Coastal Plain. AB - Species are the starting point for most studies of ecology and evolution, but the proper circumscription of species can be extremely difficult in morphologically variable lineages, and there are still few convincing examples of molecularly informed species delimitation in plants. We focus here on the Viburnum nudum complex, a highly variable clade that is widely distributed in eastern North America. Taxonomic treatments have mostly divided this complex into northern (V. nudum var. cassinoides) and southern (V. nudum var. nudum) entities, but additional names have been proposed. We used multiple lines of evidence, including RADseq, morphological, and geographic data, to test how many independently evolving lineages exist within the V. nudum complex. Genetic clustering and phylogenetic methods revealed three distinct groups-one lineage that is highly divergent, and two others that are recently diverged and morphologically similar. A combination of evidence that includes reciprocal monophyly, lack of introgression, and discrete rather than continuous patterns of variation supports the recognition of all three lineages as separate species. These results identify a surprising case of cryptic diversity in which two broadly sympatric species have consistently been lumped in taxonomic treatments. The clarity of our findings is directly related to the dense sampling and high quality genetic data in this study. We argue that there is a critical need for carefully sampled and integrative species delimitation studies to clarify species boundaries even in well-known plant lineages. Studies following the model that we have developed here are likely to identify many more cryptic lineages and will fundamentally improve our understanding of plant speciation and patterns of species richness. PMID- 30521051 TI - Coexistence of systemic lupus erythematosus with Kikuchi-Fujimoto disease involving the salivary gland, initially disguised as lymphoma. PMID- 30521052 TI - Insights into the evolution of the suppressors of cytokine signalling (SOCS) gene family in vertebrates. AB - The SOCS family are key negative regulators of cytokine and growth factor signalling. Typically 8-17 SOCS genes are present in vertebrate species and eight known in mammals, classified as type I (SOCS4-7) and type II (CISH and SOCS1-3) SOCS. It was believed that the type II SOCS were expanded through the two rounds of whole genome duplication (1R and 2R WGDs) from a single CISH/SOCS1-3 precursor. Previously 12 genes were identified in rainbow trout but here we report additional 15 loci are present, and confirm 26 of the genes are expressed, giving rainbow trout the largest SOCS gene repertoire identified to date. The discovery of the additional SOCS genes in trout has led to a novel model of SOCS family evolution, whereby the vertebrate SOCS gene family was derived from CISH/SOCS2, SOCS1/SOCS3, SOCS4/5, SOCS6 and SOCS7 ancestors likely present before the two round WGD events. It is also apparent that teleost SOCS2b, SOCS4 and SOCS5b molecules are not true orthologues of mammalian SOCS2, SOCS4 and SOCS5, respectively. The rate of SOCS gene structural changes increased from 2R vertebrates, to 4R rainbow trout, and the genes with structural changes show large differences and low correlation coefficient of expression levels relative to their paralogues, suggesting a role of structural changes in expression and functional diversification. This study has important impacts in the functional prediction and understanding of the SOCS gene family in different vertebrates, and provides a framework for determining how many SOCS genes could be expected in a particular vertebrate species/lineage. PMID- 30521054 TI - Painless Horny Keratotic Spines on the Palms: A Quiz. PMID- 30521053 TI - Global Health Journal Club: The Use of Rapid Diagnostic Test (RDT) in the Diagnosis of Congenital Malaria. PMID- 30521055 TI - Massive Localized Lymphedema, an Emerging Problem and a Challenging Pseudosarcomatous Condition Mimicking Liposarcoma. PMID- 30521056 TI - Use of Systemic Treatment in Patients with Chronic Pruritus: A Survey of Dermatologists in the Netherlands. AB - Treatment of chronic pruritus can be a challenge for clinicians. Several systemic treatments have been suggested to reduce itch, such as gabapentinoids and antidepressants. The aim of this study was to assess the current practice of dermatologists regarding systemic treatment in patients with chronic pruritus, and to identify possible barriers in the prescription of these treatments. An online survey was sent to all dermatologists and dermatology residents in the Netherlands between July 2017 and April 2018. A total of 193 physi-cians completed the questionnaire (response rate 27.0%). Overall, 61.7% prescribed gabapentinoids or antidepressants in patients with chronic pruritus. Amitriptyline was prescribed most frequently, followed by gabapentin, doxepin and mirtazapine. Reasons not to prescribe systemic treatment included lack of knowledge or experience, risk of side-effects, and lack of available evidence. As only a minority of respondents felt comfortable prescribing these drugs, more education on effective and safe dosing is needed. PMID- 30521057 TI - Nail Psoriasis: An Updated Review and Expert Opinion on Available Treatments, Including Biologics. AB - Nail psoriasis affects 50-79% of patients with skin psoriasis and up to 80% of patients with psoriatic arthritis, and can also represent a negative prognostic factor in individuals with plaque psoriasis. Treatments for nail psoriasis are limited, as nails are often difficult to treat with topical therapies alone, and relapse is common. Among different systemic agents, secukinumab, a fully human monoclonal antibody targeting interleukin (IL)-17A, is the only antibody supported by a trial specifically conducted in patients with nail psoriasis (the TRANSFIGURE trial) and has the longest follow-up available to date. In this setting, secukinumab is characterized by the highest efficacy at week 16. This review analysed the different therapeutic options for nail psoriasis, focusing on new treatments that have shown promising results in this field. PMID- 30521058 TI - Association of Vulvar Melanoma with Lichen Sclerosus. PMID- 30521059 TI - Anetoderma and Systemic Lupus Erythematosus: Case Report and Literature Review. PMID- 30521060 TI - Out-of-pocket Costs for Individuals with Atopic Eczema: A Cross-sectional Study in Nine European Countries. AB - Atopic eczema (AE) is one of the most common non-communicable inflammatory skin diseases, and has a huge socioeconomic impact. Studies on the everyday economic impact of AE on patients, however, are limited. To estimate the annual extra out of-pocket spending due to AE among patients in Europe, a cross-sectional study using computer-assisted phone interviewing of patients with AE was performed in 9 European countries. A total of 1,189 patients (56% women) with AE, who were either eligible for, or on, systemic treatment, participated in the study between October 2017 and March 2018. Mean extra spending on everyday necessities was ?927 per patient per year for healthcare expenses, and this figure was slightly, but not statistically significantly, influenced by the severity of AE. Emollients and moisturizers accounted for the highest monthly costs, followed by medication that was not reimbursed, doctors' and hospital costs. AE-related out-of-pocket costs pose a substantial burden for affected individuals, are higher than in other chronic diseases, and should always be included in economic assessments of the impact of this disease. PMID- 30521061 TI - The Prevalence of Atopic Dermatitis and Chronic Spontaneous Urticaria are Associated with Parental Socioeconomic Status in Adolescents in China. AB - The association of atopic dermatitis and chronic spontaneous urticaria with socioeconomic status has been little studied. The aim of this study was to investigate the prevalence of skin diseases and their association with socioeconomic status in adolescents in China. A cross-sectional study was conducted at a comprehensive university. All newly enrolled students underwent dermatological examination and completed a survey. Socioeconomic status was measured in terms of parental education level and income. Two-level logistic regression models were used. A total of 8,226 students consented to participate. On dermatological examination, moderate to severe acne (10.2%) had the highest prevalence, followed by chronic spontaneous urticaria (2.7%), atopic dermatitis (2.5%), and tinea (1.7%). Socioeconomic status was positively associated with the prevalence of chronic spontaneous urticaria (ptrend = 0.001) and atopic dermatitis (ptrend = 0.0094). Tinea was inversely associated with socioeconomic status (ptrend = 0.025). Higher parental socioeconomic status was associated with higher risk of atopic dermatitis and chronic spontaneous urticaria, but lower risk of tinea. PMID- 30521062 TI - Minimal residual disease-based long-term efficacy of reduced-intensity conditioning versus myeloablative conditioning for adult Philadelphia-positive acute lymphoblastic leukemia. AB - BACKGROUND: The sensitivity of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) to reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) versus myeloablative conditioning (MAC) allogeneic HCT by minimal residual disease (MRD) kinetics is not well established. METHODS: This study compared long-term outcomes based on MRD kinetics for 79 patients with RIC transplants and 116 patients with MAC transplants in first complete remission (CR1) after tyrosine kinase inhibitor based chemotherapy (median follow-up, 67.1 months). MRD monitoring was centrally evaluated by real-time quantitative polymerase chain reaction for all patients. RESULTS: RIC showed a cumulative incidence of relapse (CIR; 30.6% vs 31.7%), nonrelapse mortality (17.5% vs 14.9%), disease-free survival (DFS; 51.9% vs 53.4%), and overall survival (61.1% vs 61.4%) comparable to those associated with MAC. In all MRD kinetics-based subgroups, no differences in CIR (early complete molecular response [CMR], 19.3% vs 4.8%; early major molecular response [MMR], 17.0% vs 26.8%; late CMR, 20.0% vs 14.3%; late MMR, 28.3% vs 31.0%; poor molecular response [PMR], 57.9% vs 62.4%) or DFS (early CMR, 71.6% vs 76.2%; early MMR, 66.9% vs 52.1%; late CMR, 50.0% vs 64.3%; late MMR, 50.7% vs 53.7%; PMR, 31.6% vs 34.1%) were observed between RIC and MAC. In a multivariate analysis, the conditioning intensity had no significant impact on transplantation outcomes. CONCLUSIONS: RIC is a valid alternative choice for long-term disease control and is worthy of further investigation in prospective trials for adult Ph positive ALL in CR1. PMID- 30521063 TI - Medical resource utilization of abiraterone acetate plus prednisone added to androgen deprivation therapy in metastatic castration-naive prostate cancer: Results from LATITUDE. AB - BACKGROUND: Abiraterone acetate plus prednisone (AA+P), when added to androgen deprivation therapy (ADT), demonstrated significant improvements in overall survival and disease progression over dual placebos added to ADT in the LATITUDE clinical trial (NCT01715285). The objective of this study was to assess event driven medical resource utilization (MRU) of ADT plus AA+P (ADT+AA+P) versus ADT plus dual placebos (ADT+placebos) in LATITUDE. METHODS: Event-driven MRU data from LATITUDE while patients were on treatment were used for analyses. Types of MRU included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person-years) and rate ratios comparing ADT+AA+P with ADT+placebos were estimated with zero-inflated Poisson regression. The difference in the average hospital LOS between arms was assessed with repeated measures regression analyses. Reasons for hospitalization were explored. Sensitivity analyses were conducted to assess the robustness of the results. RESULTS: A total of 1199 patients were enrolled in LATITUDE. Significantly lower rates of hospitalization (a 24% reduction), imaging (a 36% reduction), and radiotherapy (a 50% reduction) were observed with ADT+AA+P versus ADT+placebos. There was a nonsignificant trend of lower rates of specialist visits and surgery. The rates of ER and GP visits and the average LOS per hospitalization episode were similar across arms. The most common hospitalization reasons were genitourinary, musculoskeletal, and respiratory tract symptoms/disorders. The results remained consistent in a sensitivity analysis. CONCLUSIONS: Adding AA+P to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with ADT+AA+P therapy. PMID- 30521065 TI - Efficacy of a polyvalent injectable vaccine against Flavobacterium psychrophilum administered to rainbow trout (Oncorhynchus mykiss L.). AB - Flavobacterium psychrophilum is one of the most important pathogens affecting cultured rainbow trout (Oncorhynchus mykiss). Recent information from UK salmonid farms showed country-wide distribution of genetically and serologically divergent clones, which has hampered the development of a vaccine for rainbow trout fry syndrome. The current study assessed the efficacy of an injectable polyvalent vaccine containing formalin-inactivated F. psychrophilum in rainbow trout. The vaccine was formulated with an oil adjuvant (Montanide ISA 760VG) or formalin killed cells alone. Duplicate groups of trout (60 +/- 13 g) were given phosphate buffered saline or vaccine formulated with Montanide by intra-peritoneal (i.p.) injection and challenged by intra-muscular (i.m.) injection with a homologous and a heterologous isolate of F. psychrophilum at 525 degree days post-vaccination (dd pv). Significant protection was achieved in vaccinated fish (p = 0.0001, RPS 76% homologous, 88% heterologous). Efficacy of the adjuvanted vaccine was also demonstrated by heterologous challenge at 1155 dd pv resulting in 100% protection, whereas survival in the un-adjuvanted group was not significantly different from control fish. Levels of specific antibody at 1155 dd pv, as measured by ELISA, were significantly higher in the fish vaccinated with adjuvant when compared with unvaccinated fish. PMID- 30521064 TI - Universal screening for Lynch Syndrome in a large consecutive cohort of Chinese colorectal cancer patients: high prevalence and unique molecular features. AB - The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population. This article is protected by copyright. All rights reserved. PMID- 30521066 TI - Mediation of Associations Between Adiposity and Colorectal Cancer Risk by Inflammatory and Metabolic Biomarkers. AB - Inflammation and hyperinsulinemia may drive associations between adiposity and colorectal cancer (CRC) risk, but few studies have examined this hypothesis using mediation analysis. We used inverse odds ratio weighting and logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for estimated total effects (ORTE ) of body mass index, waist circumference, and adult weight gain on CRC risk, and estimated effects operating through seven inflammatory and metabolic biomarkers (natural indirect effect; ORNIE ) or through paths independent of these biomarkers (natural direct effect; ORNDE ) among 209 CRC cases and 382 matched controls nested within the Health Professionals Follow-up Study, a prospective cohort of male health professionals. A one-interquartile range (IQR) increase in body mass index (3.6 kg/m2 ) was associated with an ORTE of 1.40 (95% CI: 1.13, 1.73), which decomposed into an ORNIE of 1.26 (95% CI: 0.97, 1.52) and an ORNDE of 1.11 (0.87, 1.42), with possibly stronger mediation by these biomarkers for adult weight gain (IQR = 10.4kg; ORTE = 1.32 [95% CI: 1.06, 1.64]; ORNIE = 1.47 [95% CI: 1.01, 1.81]; ORNDE = 0.89 [95% CI: 0.72, 1.11]), but no mediation for waist circumference. Mediation appeared to be stronger for the metabolic biomarkers than the inflammatory biomarkers. Inflammatory and metabolic mechanisms may mediate associations between both body mass index and adult weight gain with CRC risk. This article is protected by copyright. All rights reserved. PMID- 30521067 TI - Oligometastatic prostate cancer: Reality or figment of imagination. AB - The term "oligometastatic prostate cancer" refers to a heterogeneous group of disease states currently defined solely on the basis of clinical features. Oligorecurrent disease, de novo oligometastases, and oligoprogressive disease likely have unique biologic underpinnings and natural histories. Evidence suggesting the existence of a subset of patients who harbor prostate cancer with limited metastatic potential currently includes disparate and overwhelmingly retrospective reports. Nevertheless, emerging prospective data have corroborated the "better-than-expected," retrospectively observed outcomes, particularly in the setting of oligorecurrent prostate cancer. Improved functional imaging with prostate-specific membrane antigen-targeted strategies may enhance the identification of patients with oligometastatic prostate cancer in the short term. In the long term, refinement of the oligometastatic case definition likely will require biologic risk-stratification schemes. To determine optimal treatment strategies and identify patients most likely to benefit from metastasis-directed therapy, future efforts should focus on conducting high-quality, prospective trials with much-needed molecular correlative studies. PMID- 30521068 TI - Diffuse Tibiofemoral Cartilage Change Prior to the Development of Accelerated Knee Osteoarthritis: Data from the Osteoarthritis Initiative. AB - INTRODUCTION: We compared the spatial distribution of tibiofemoral cartilage change between individuals who will develop accelerated knee osteoarthritis (KOA) versus typical onset of KOA prior to the development of radiographic KOA. MATERIALS AND METHODS: We conducted a longitudinal case-control analysis of 129 individuals from the Osteoarthritis Initiative. We assessed the percent change in tibiofemoral cartilage on magnetic resonance images at 36 informative locations from two to one year prior to the development of accelerated (n=44) versus typical KOA (n=40). We defined cartilage change in the accelerated and typical KOA groups at 36 informative locations based on thresholds of cartilage percent change in a no KOA group (n=45). We described the spatial patterns of cartilage change in the accelerated KOA and typical KOA groups and performed a logistic regression to determine if diffuse cartilage change (predictor; at least half of the tibiofemoral regions demonstrating change in multiple informative locations) was associated with KOA group (outcome). RESULTS: There was a non-significant trend that individuals with diffuse tibiofemoral cartilage change were 2.2 times more likely to develop accelerated knee OA when compared to individuals who develop typical knee OA (OR [95% CI] = 2.2 [0.90,5.14]. Adults with accelerated or typical KOA demonstrate heterogeneity in spatial distribution of cartilage thinning and thickening. CONCLUSIONS: These results provide preliminary evidence of a different spatial pattern of cartilage change between individuals that will develop accelerated versus typical KOA. These data suggest there may be different mechanisms driving the early structural disease progression between accelerated versus typical KOA. This article is protected by copyright. All rights reserved. PMID- 30521069 TI - Intracerebroventricular administration of sulfated CCK octapeptide induces anxiety-like behavior in goldfish. AB - Sulfated cholecystokinin octapeptide (CCK-8s) is involved in feeding regulation as an anorexigenic neuropeptide in vertebrates. In rodents, intracerebroventricular (ICV) administration of CCK-8s has been shown to affect not only feeding behavior, but also psychomotor activity. However, there is still no information regarding the psychophysiological effects of CCK-8s in goldfish. Therefore, we examined the effect of synthetic goldfish (gf) CCK-8s on psychomotor activity in this species. ICV administration of gfCCK-8s at 0.1, 0.5 and 2.5 pmol/g body weight (BW) did not affect swimming distance (locomotor activity). Since intact goldfish prefer the lower to the upper area of a tank, we used this as a preference test (upper/lower test) for assessing anxiety-like behavior. ICV administration of gfCCK-8s at 2.5 pmol/g BW shortened the time spent in the upper area. The action of gfCCK-8s mimicked that of FG-7142 (the central-type benzodiazepine receptor inverse agonist, an anxiogenic agent) at 5 and 10 pmol/g BW. The anxiogenic-like effect of gfCCK-8s was abolished by treatment with the CCK receptor antagonist proglumide at 50 pmol/g BW. We also investigated the localization of CCK/gastrin-like immunoreactivity in the goldfish brain. CCK/gastrin-like immunoreactivity was observed in the anxiety related regions (the nucleus habenularis and the interpeduncular nucleus). These data indicate that gfCCK-8s potently affects psychomotor activity in goldfish, and exerts an anxiogenic-like effect via the CCK receptor-signaling pathway. This article is protected by copyright. All rights reserved. PMID- 30521070 TI - Mechanical Behavior of Posterior All-Ceramic Hybrid-Abutment-Crowns Versus Hybrid Abutments with Separate Crowns - A Laboratory Study. AB - OBJECTIVE: The purpose of this laboratory study was to evaluate the fatigue resistance, fracture resistance and mode of failure of posterior hybrid-abutment crown versus hybrid-abutment with separate crown, both bonded to short titanium bases. MATERIALS AND METHODS: Thirty-two titanium implants were embedded perpendicularly in auto-polymerizing resin. Implant-supported restorations simulating a maxillary first premolar were designed and milled using a CAD/CAM system and divided into 2 groups according to material (n=16): zirconia (Z) and lithium disilicate (L). Each group was subdivided into 2 subgroups according to design (n=8): hybrid-abutment-crown (ZS, LS) and hybrid-abutment with separate crown (ZC, LC). Each group was subjected to 1.2 million cycles of thermo mechanical fatigue loading in a dual-axis chewing simulator at 120 N load. Surviving specimens were subjected to quasi-static loading in a universal testing machine. Mode of failure was determined under a low magnification optical microscope. RESULTS: During chewing simulation, 18.8% of zirconia and 43.8% of lithium disilicate restorations failed. The fracture resistance median values ranged from 3730 N for group ZC, 3400 N for group ZS, 1295 N for group LS to 849 N for group LC. Group ZC had a statistically significant higher fracture resistance than groups LC and LS, however it did not differ significantly from group ZS (P <= 0.05). Failures were seen in both titanium bases and ceramic superstructure. CONCLUSIONS: Zirconia and lithium disilicate hybrid implant supported restorations with short (3 mm) titanium bases failed in a considerable number already during chewing simulation. Therefore, despite their high fracture strength the use in the posterior region should be considered critically. This article is protected by copyright. All rights reserved. PMID- 30521071 TI - Docosahexaenoic acid promotes cell cycle arrest and decreases proliferation through WNT/beta-catenin modulation in colorectal cancer cells exposed to gamma radiation. AB - The effects of radiation are known to be potentiated by N-3 polyunsaturated fatty acids, which modulate several signaling pathways, but the molecular mechanisms through which these fatty acids enhance the anticancer effects of irradiation in colorectal cancer (CRC) treatment remain poorly elucidated. Here, we aimed to ascertain whether the fatty acid docosahexaenoic acid (DHA) exerts a modulating effect on the response elicited by radiation treatment (RT). Two CRC cell lines, Caco-2 and HT-29, were exposed to RT, DHA, or both (DHA + RT) for various times, and then cell viability, proliferation, and clonogenicity were assessed. Moreover, cell cycle, apoptosis, and necrosis were analyzed using flow cytometry, and the involvement of WNT/beta-catenin signaling was investigated by immunofluorescence to determine nuclear beta-catenin, GSK3beta phosphorylation status, and TCF/LEF-activity reporter. DHA and RT applied separately diminished the viability of both HT-29 and Caco-2 cells, and DHA + RT caused a further reduction in proliferation mainly in HT-29 cells, particularly in terms of colony formation. Concomitantly, our results verified cell cycle arrest in G0/G1 phase, a reduction of cyclin D1 expression, and a decrease in GSK3beta phosphorylation after the combined treatment. Furthermore, immunofluorescence quantification revealed that nuclear beta-catenin was increased in RT-exposed cells, but this effect was abrogated in cells exposed to DHA + RT, and the results of TCF/LEF activity assays confirmed that DHA attenuated the increase in nuclear beta catenin activity induced by irradiation. Our finding shows that DHA applied in combination with RT enhanced the antitumor effects of irradiation on CRC cells, and that the underlying mechanism involved the WNT/beta-catenin pathway. (c) 2018 BioFactors, 9999(9999):1-11, 2018. PMID- 30521072 TI - Children's Facial Emotion Recognition Skills: Longitudinal Associations With Lateralization for Emotion Processing. AB - This is the first longitudinal study to evaluate the relations between hemispheric laterality for emotion processing and the development of facial emotion recognition (FER) skills, both of which show similar developmental trajectories. Five to 12-year-old children (N = 160) completed an emotion discrimination task, emotion matching task, identity matching task, and behavioral lateralization for emotion processing task at baseline and 1 year later. Lateralization at baseline predicted later emotion discrimination, whereas change in strength of lateralization across the year predicted emotion matching ability. Lateralization was not a significant predictor of identity matching. These findings provide evidence that it is changes in laterality for emotion processing that contribute to improvements in FER skills between 5 and 12 years of age. PMID- 30521074 TI - Population structure leads to male-biased population sex ratios under environmental sex determination. AB - Spatial structure has been shown to favor female-biased sex allocation, but current theory fails to explain male biases seen in many taxa, particularly those with environmental sex determination (ESD). We present a theory and accompanying individual-based simulation model that demonstrates how population structure leads to male-biased population sex ratios under ESD. Our simulations agree with earlier work showing that the high productivity of female-producing habitats creates a net influx of sex-determining alleles into male-producing habitats, causing larger sex ratio biases and lower productivity in male-producing environments (Harts et al. 2014). In contrast to previous findings, we show that male-biasing habitats disproportionately impact the global sex ratio, resulting in stable male-biased population sex ratios under ESD. The failure to detect a male bias in earlier work can be attributed to small subpopulation sizes leading to local mate competition, a condition unlikely to be met in most ESD systems. Simulations revealed that consistent male biases are expected over a wide range of population structures, environmental conditions, and genetic architectures of sex determination, with male excesses as large as 30 percent under some conditions. Given the ubiquity of genetic structure in natural populations, we predict that modest, enduring male biased allocation should be common in ESD species, a pattern consistent with reviews of ESD sex ratios. This article is protected by copyright. All rights reserved. PMID- 30521076 TI - Cognitive Health and Incarceration among Older Adults. PMID- 30521073 TI - A novel method for the determination of field output factors and output correction factors for small static fields for six diodes and a microdiamond detector in megavoltage photon beams. AB - PURPOSE: The goal of this work is to provide a large and consistent set of data for detector specific output correction factors, METHODS: null RESULTS: Field output factors and detector specific CONCLUSIONS: Selection of two reference detectors, EBT3 films and W1 plastic scintillator, and use of an analytical function, is a novel approach for the determination of PMID- 30521075 TI - Self-management intervention for head and neck cancer couples: Results of a randomized pilot trial. AB - BACKGROUND: Patients with head and neck cancer (HNC) experience significant physical and psychological morbidity during radiotherapy (RT) that contributes to treatment interruptions and a poor quality of life. Although spouses/partners can help by encouraging patient self-management (eg, self-care) during RT, they often experience high psychological distress rates, lack basic health care knowledge and skills, and report increased marital conflict regarding patient self management. The current pilot study examined the feasibility and acceptability of a 6-session telephone-based intervention called Spouses coping with the Head And neck Radiation Experience (SHARE), which teaches self-management, communication, and coping skills to patients with HNC and their spouses. The treatment effects of SHARE compared with usual medical care (UMC) in controlling patient physical symptoms and improving patient/spouse psychological and marital functioning also were examined. METHODS: Thirty patients who initiated RT and their spouses (60 participants; 40% of whom were racial/ethnic minorities) were randomized to SHARE or UMC, and preintervention and postintervention assessments were completed. RESULTS: Solid recruitment (70%) and low attrition rates (7%) demonstrated feasibility. Strong program evaluations and homework completion rates (72%) supported acceptability. Significant treatment effects (medium in magnitude) were observed for SHARE compared with UMC with regard to HNC-specific physical symptom burden (Cohen's d, -0.89) and symptom interference (Cohen's d, -0.86). Medium to large effects favoring SHARE also were found for patient and spouse depressive symptoms (Cohen's d, -0.84) and cancer-specific distress (Cohen's d, -1.05). CONCLUSIONS: The findings of the current study support the feasibility, acceptability, and preliminary efficacy of SHARE. They also suggest that programs that empower HNC couples with the necessary skills to coordinate care and manage the challenges of RT together hold great promise for controlling a patient's physical symptoms and improving the psychological functioning of both partners. PMID- 30521077 TI - Differential associations of depression-related phenotypes with cardiometabolic risks: Polygenic analyses and exploring shared genetic variants and pathways. AB - BACKGROUND: Numerous studies have suggested associations between depression and cardiometabolic (CM) diseases. However, little is known about the mechanism underlying this comorbidity, and whether the relationship differs by depression subtypes. METHODS: Using polygenic risk scores (PRS) and linkage disequilibrium (LD) score regression, we investigated the genetic overlap of various depression related phenotypes with a comprehensive panel of 20 CM traits. GWAS results for major depressive disorder (MDD) were taken from the PGC and CONVERGE studies, with the latter focusing on severe melancholic depression. GWAS results on general depressive symptoms (DS) and neuroticism were also included. We identified the shared genetic variants and inferred enriched pathways. We also looked for drugs over-represented among the top-shared genes, with an aim to finding repositioning opportunities for comorbidities. RESULTS: We found significant genetic overlap between MDD, DS, and neuroticism with cardiometabolic traits. In general, positive polygenic associations with CM abnormalities were observed except for MDD-CONVERGE. Counterintuitively, PRS representing severe melancholic depression was associated with reduced CM risks. Enrichment analyses of shared SNPs revealed many interesting pathways such as those related to inflammation that underlie the comorbidity of depressive and CM traits. Using a gene-set analysis approach, we also revealed several repositioning candidates with literature support (e.g., bupropion). CONCLUSIONS: Our study highlights shared genetic bases of depression with CM traits, and suggests the associations vary by depression subtypes, which may have implications in targeted prevention of cardiovascular events for patients. Identification of shared genetic factors may also guide drug discovery for the comorbidities. PMID- 30521079 TI - C-reactive protein and its association with depression in patients receiving treatment for metastatic lung cancer. AB - BACKGROUND: Depression is highly prevalent in lung cancer. Although there is a known association between inflammation and depression, this relationship has not been examined in patients with lung cancer who undergo treatment with immune and other targeted drug therapies. Peripheral blood C-reactive protein (CRP), a marker of systemic inflammation, may help identify metastatic lung cancer patients with inflammation-associated depression. METHOD: Patients with metastatic lung cancer undergoing treatment were evaluated for depression using the Hospital Anxiety and Depression Scale (HADS). Inflammation (CRP and CRP cutoffs >=1 and >=3 mg/mL) and demographic and treatment variables were analyzed for association with depression. RESULTS: One hundred nine consecutive participants exhibited an average plasma CRP concentration of 1.79 mg/mL (median, 0.75 mg/mL [standard deviation, 2.5 mg/mL), and 20.7% had a CRP concentration of >=3.0 mg/mL; 23.9% met depression screening criteria (HADS >=8). A log transformation of CRP was significantly correlated with depression severity (r = 0.47, P < .001). CRP was the only covariate to predict depression severity (P = .008) in a multivariate model including lung cancer disease subtype and type of systemic treatment. Receiver operating characteristic analysis indicated that CRP had moderate predictive accuracy in identifying elevated depression (area under the curve = 0.74). A cutoff of CRP >=3.0 generated high specificity (88%) but identified only 50% of those with elevated depression. CONCLUSION: Elevated CRP is associated with depression in patients with metastatic lung cancer. Thus, CRP may identify a subset of lung cancer patients with inflammation-induced depression and may be useful in predicting response to treatments that target inflammation or its downstream mediators on the brain. PMID- 30521078 TI - Incidence of adverse events attributable to bupivacaine liposome injectable suspension or plain bupivacaine for postoperative pain in pediatric surgical patients: a retrospective matched cohort analysis. AB - BACKGROUND: Surgical wound infiltration with local anesthetics is common as part of multimodal analgesia and enhanced recovery pathways in pediatric surgical patients. Liposomal bupivacaine can provide up to 92 hours of pain relief, and was approved by the U.S Food and Drug Administration for local infiltration in adults. It is also commonly used by pediatric surgeons, but its safety profile in this age group has not been described. AIM: To describe the incidence of local anesthetic systemic toxicity (LAST) syndrome in pediatric surgical patients receiving liposomal bupivacaine compared to plain bupivacaine for surgical wound infiltration. METHODS: We conducted a retrospective, single center, assessor blinded cohort study of pediatric surgical inpatients having open or laparoscopic surgery in the Cleveland Clinic between 2013 and 2017 and receiving wound infiltration with local anesthetics. We compared the incidence of LAST among those who received any dose of liposomal bupivacaine and those who received plain bupivacaine. Groups were matched 1:2 according to procedure type, age, and physical status score. LAST was primarily defined as at least 2 signs or symptoms possibly related to anesthetic toxicity, as judged by 2 independent adjudicators blinded to the type of local anesthetic. A sensitivity analysis compared the incidence of a single sign/symptom possibly related to anesthetic toxicity. RESULTS: A total of 924 surgical cases were included in the final analysis (356 liposomal bupivacaine and 568 plain bupivacaine cases). The primary outcome did not occur in any patient (P>0.99). The sensitivity analysis found 3 cases in the liposomal bupivacaine group and 2 cases in the plain bupivacaine group having a single sign/symptom possibly related to local anesthetic administration (relative risk 2.4, 95% CI 0.4-14.0, P=0.38). CONCLUSIONS: In a cohort of pediatric surgical patients receiving wound infiltration with either plain or liposomal bupivacaine, we identified no cases of LAST syndrome, and only few patients with any sign or symptom that could potentially be related to local anesthetic toxicity. This article is protected by copyright. All rights reserved. PMID- 30521081 TI - Introduction of D-Amino Acids in Minimalistic Peptide Substrates by an S-Adenosyl L-Methionine Radical Epimerase. AB - Post-translational modifying enzymes from the S-adenosyl-L-methionine (AdoMet) radical superfamily garner attention due to their ability to accomplish challenging biochemical reactions. Among them, a family of AdoMet radical epimerases catalyze irreversible L- to D-amino acid transformations of diverse residues, including 18 sites in the complex sponge-derived polytheonamide toxins. These enzymes are from the proteusin family of ribosomally synthesized and post translationally modified peptide natural products and act on precursor proteins with relatively large N-terminal leaders and highly variable core sequences. Here we report the in vitro activity of the model epimerase OspD and provide a closer look at its catalytic mechanism and substrate flexibility. The wild-type enzyme was capable of leader-independent epimerization toward not only the stand-alone core peptide, but also truncated and cyclic core variants. Introduction of D amino acids can drastically alter the stability, structure, and activity of peptides; thus, epimerases offer opportunities in peptide bioengineering. PMID- 30521080 TI - Early surveillance is associated with less incidence and severity of breast cancer-related lymphedema compared with a traditional referral model of care. AB - BACKGROUND: Bioimpedance spectroscopy (BIS) has enabled the early identification of breast cancer-related lymphedema. In this study, differences in health service metrics and in the incidence of breast cancer-related lymphedema are evaluated in an early surveillance model of care compared with a traditional referral model of care. METHODS: In a retrospective analysis of data from 753 women who underwent BIS measures between January 1, 2007 and December 31, 2016, 188 women were assigned to the "early surveillance" group if they began lymphedema monitoring presurgery (n = 121) or within 90 days postsurgery (n = 67), and 285 women were assigned to the "traditional referral" group if they began monitoring after 90 days postsurgery. Health service metrics were calculated as the time to the first BIS measure after 90 days postsurgery, the median follow-up, and the number of health care visits. Lymphedema was diagnosed based on BIS measures. RESULTS: Women in the early surveillance group received lymphedema care significantly earlier than those in the traditional referral group. However, there was no difference in the number of visits per year to the clinic between groups. Significantly more women in the traditional referral group were diagnosed with clinical lymphedema (stage I-III, 39 % vs 14%; P < .001) and with greater severity (stage II-III, 24%) compared with those in the early surveillance group (4%). CONCLUSIONS: The current findings support the adoption of an early prospective surveillance model of care using BIS for the early detection and management of breast cancer-related lymphedema. PMID- 30521083 TI - Challenges of Differential Placebo Effects in Contemporary Medicine: The Example of Brain Stimulation. AB - 'Differential placebo effects' is the concept that different types of placebos (e.g. inert pill versus sham device) may yield different magnitudes of placebo effects. This issue has been pushed into the spotlight by recent clinical trials of new technologies reporting unexpectedly large placebo effects from sham devices/procedures needed to maintain blinding integrity. In this Neurology Grand Rounds, we use transcranial magnetic stimulation as a model to explore the principles and implications of differential placebo effects. We highlight emerging research on the neurobiology of placebo effects and analyze fundamental questions of measuring efficacy in contemporary medicine. This article is protected by copyright. All rights reserved. PMID- 30521082 TI - Living Messages from Chemistry Icons: Legacies with Contemporary Relevance. AB - Beyond individual scientific virtuosity and creativity that leading figures in chemistry have displayed, they have sometimes conveyed wider messages of significance beyond their own professional specialization. They include insights into broader aspects of science, society or the ways of the world. On the other hand, the words, attitudes and actions of eminent chemists from former times have not always presented good models for others to follow, whether judged by their own contemporary or our present standards. Both positive and negative lessons may convey to us something about humanity in general or the nature of our current predicaments and challenges. In an era when science is more necessary than ever to help meet oncoming global challenges, yet the principles and results of science are irrationally questioned, it is particularly relevant to re-connect with the broad insights and messages that can be derived from examining the thoughts and deeds of chemistry icons from the past. PMID- 30521084 TI - Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy. AB - BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had >=1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials. PMID- 30521085 TI - Effect of high fat diet on NF-kB microRNA146a negative feedback loop in ovalbumin sensitized rats. AB - The present study aimed to investigate the role of microRNA-146a and its adapter proteins [interleukin-1 receptor-associated kinase 1 (IRAK1) and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6)] in the pathogenesis of ovalbumin (OVA)-sensitized rats in association with the diet-induced obesity condition. Twenty male Wistar rats were divided into four groups: control with normal diet (ND), OVA-sensitized with normal diet (S + ND), high-fat diet (HFD), and OVA-sensitized with high-fat diet (S + HFD). All the animals were fed for 8 weeks with standard pelts or high-fat diet, and were then sensitized and challenged with OVA or saline for another 4 weeks. The tracheal responsiveness to methacholine, serum protein levels, and lipid profile levels was measured by the ELISA method. Moreover, the gene expression level of microRNA-146a (miR-146a) was measured in the lung tissue of the rats using the real-time PCR method. Maximum response to methacholin increased in the S + HFD group in compared with ND, S + ND, and HFD groups (P < 0.05 to P < 0.001). Moreover, in the S + HFD group the mRNA expression levels of miRNA-146a increased in the lung tissue (P < 0.001). In addition, the protein analysis results showed that IRAK1, TRAF6, NF-kB, and IL 1beta protein levels were high in the S + HFD group compared to the ND and HFD groups; however, in compared with the S + ND group, only the IL-1beta protein level was higher in the S + HFD group (P < 0.05). These results suggest that a defect in the NF-kB-miR-146a negative feedback loop may be involved in the pathogenesis of obesity associated with OVA-sensitized condition. (c) 2018 BioFactors, 2018. PMID- 30521087 TI - Energetic investment associated with vitellogenesis induces an oxidative cost of reproduction. AB - 1.Oxidative stress is a potential cost of reproduction, but conclusive evidence for this relationship is lacking. The goal of this study was to serially assess across a seasonal gradient the relationship between reproduction, circulating plasma energy metabolites, and oxidative state. 2.Here we examine a study animal ideally suited to test for the oxidative costs of reproduction: The Allen Cays Rock Iguana. Female rock iguanas reproduce at varying frequencies, often skipping years, allowing for a comparison between reproductive and non-reproductive females during the same narrow, annual breeding season. This feature of iguana life-history enabled us to address not just sex and seasonal differences in physiology, but also potential oxidative costs of reproduction in females. 3.Male and female iguanas were sampled during the early (vitellogenic), late (gravid), and post-reproductive seasons. Ultrasound examinations were performed on females to quantify reproductive investment, and blood samples were collected for physiology assays, which included reactive oxygen metabolites (d-ROMs), antioxidants, triglycerides, free glycerol, and glucose. 4.The early reproductive season was characterized by significant increases in reproductive female's triglycerides, free glycerol, and oxidative stress compared to late and post reproductive periods and non-reproductive females and males during all sampling periods. Antioxidants were significantly elevated during the early reproductive season for reproductive females, non-reproductive females, and males when compared to late and post-season. Follicle number in early reproductive females was positively related to d-ROMs, triglycerides, and free glycerol, negatively related to antioxidants, and showed no relationship with glucose. Measures of oxidative stress, d-ROMs and oxidative index were positively correlated with circulating levels of the lipid metabolite free glycerol during the early reproductive period, but this relationship weakened in the late season and disappeared in the post-season. 5.Broadly, this study supports the hypothesis that the relationship between reproduction and oxidative stress is driven by energy investment, being greatest during early reproduction when vitellogenesis is occurring. This article is protected by copyright. All rights reserved. PMID- 30521086 TI - Predicting Progression to Mild Cognitive Impairment. AB - Despite much attention to the use of biomarkers for predicting Alzheimer's disease, little information is available at the individual level. We used the population-based Mayo Clinic Study of Aging to estimate absolute risk of cognitive impairment by biomarker group. Risk increased with age and any biomarker abnormality. For example, a 75-year-old with abnormal amyloid and cortical thinning biomarkers has ~20% chance of cognitive impairment by age 80 whereas with normal biomarkers the chance is <10%. Persons with only one abnormal biomarker had similar intermediate risks. This article is protected by copyright. All rights reserved. PMID- 30521089 TI - Methane production and emissions in trees and forests. AB - Forest ecosystem methane (CH4 ) research has focused on soils, but trees are also important sources and sinks in forest CH4 budgets. Living and dead trees transport and emit CH4 produced in soils; living trees and deadwood emit CH4 produced inside trees by microorganisms; and trees produce CH4 through an abiotic photochemical process. Here, we review the state of the science on the production, consumption, transport, and emission of CH4 by living and dead trees, and the spatial and temporal dynamics of these processes across hydrologic gradients inclusive of wetland and upland ecosystems. Emerging research demonstrates that tree CH4 emissions can significantly increase the source strength of wetland forests, and modestly decrease the sink strength of upland forests. Scaling from stem or leaf measurements to trees or forests is limited by knowledge of the mechanisms by which trees transport soil-produced CH4 , microbial processes produce and oxidize CH4 inside trees, a lack of mechanistic models, the diffuse nature of forest CH4 fluxes, complex overlap between sources and sinks, and extreme variation across individuals. Understanding the complex processes that regulate CH4 source-sink dynamics in trees and forests requires cross-disciplinary research and new conceptual models that transcend the traditional binary classification of wetland versus upland forest. This article is protected by copyright. All rights reserved. PMID- 30521088 TI - Antibiotic allergy labels in hospitalised and critically ill adults: a review of current impacts of inaccurate labelling. AB - Antibiotic Allergy Labels (AAL) are reported by approximately 20% of hospitalised patients, yet over 85% will be negative on formal allergy testing. Hospitalised patients with an AAL have inferior patient outcomes, increased colonization with multidrug resistant organisms and frequently receive inappropriate antimicrobials. Hospitalised populations have been well studied, yet to date the impact of AALs on patients with critical illness remain less well defined. We review the prevalence and impact of AALs on hospitalised patients, including those in in critical care. PMID- 30521090 TI - Computerized anatomy of the distal radius and its relevance to volar plating, research, and teaching. AB - Distal radius fractures are common and fracture patterns and fixation can be complex. Computerized anatomy evaluation (CAE) might offer non-invasive and enhanced anatomy assessment that might help with implant selection and placement and screw length determination. Our goal was to test the accuracy of two CAE methods for anatomical volar plate positioning and screw lengths measurement of the distal radius. We included 56 high-resolution peripheral quantitative computed tomography scans of intact, human distal radii. Plates were placed manually onto 3D printed models (method 1), which was compared to automated computerized plate placement onto the 3D computer models (method 2). Subsequently, screw lengths were determined digitally for both methods. Screw lengths evaluations were compared via Bland-Altman plots. Both CAE methods resulted in identical volar plate selection and in anatomical plate positioning. For screw length the concordance correlation coefficient was >=0.91, the location shift <=0.22 mm and the scale shift <=0.16. The differences were smaller than +/ 1 mm in all samples. Both CAE methods allow for comparable plate positioning and subsequent screw length measurement in distal radius volar plating. Both can be used as a non-invasive teaching environment for volar plate fixation. Method 2 even offers fully computerized assessments. Future studies could compare our models to other anatomical areas, post-operative volar plate positioning, and model performance in actual distal radius fracture instead of intact radii. This article is protected by copyright. All rights reserved. PMID- 30521091 TI - The inner ear proteome of fish. AB - The mechanisms that underpin the formation, growth and composition of otoliths, the biomineralized stones in the inner ear of fish, are largely unknown, as only a few fish inner ear proteins have been reported. Using a partial transcriptome for the inner ear of black bream (Acanthopagrus butcheri), in conjunction with proteomic data, we discovered hundreds of previously unknown proteins in the otolith. This allowed us to develop hypotheses to explain the mechanisms of inorganic material supply and daily formation of growth bands. We further identified a likely protein mediator of crystal nucleation and an explanation for the apparent metabolic inertness of the otolith. Due to the formation of both daily and annual increments, otoliths are routinely employed as natural chronometers, being used for age and growth estimation, fisheries stock assessments, and the reconstruction of habitat use, movement, diet, and the impacts of climate change. Our findings provide an unprecedented view of otolith molecular machinery, aiding in the interpretation of these essential archived data. This article is protected by copyright. All rights reserved. PMID- 30521093 TI - Reply to "Cognitive Health and Incarceration among Older Adults". PMID- 30521092 TI - The prevalence of human papillomavirus in oropharyngeal cancer is increasing regardless of sex or race, and the influence of sex and race on survival is modified by human papillomavirus tumor status. AB - BACKGROUND: The purpose of this study was to evaluate the influence of sex and race/ethnicity upon prevalence trends of human papillomavirus (HPV) in oropharyngeal cancer (OPC) and survival after OPC. METHOD: This was a cohort study of patients included in the United States National Cancer Database who had been diagnosed with OPC between 2010 and 2015. Outcomes were HPV status of tumor specimens and overall survival. Sex- and race-stratified trends in HPV prevalence were estimated using generalized linear modeling. The influence of sex, race, and HPV tumor status on overall survival was compared by Kaplan-Meier method and Cox Proportional Hazards models. RESULTS: This analysis included 20,886 HPV-positive and 10,364 HPV-negative OPC patients. The prevalence of HPV-positive tumors was higher among men (70.6%) than women (56.3%) and increased significantly over time at a rate of 3.5% and 3.2% per year among men and women, respectively. The prevalence of HPV-positive tumors was highest among whites (70.2%), followed by Hispanics (61.3%), Asians (55.8%), and blacks (46.3%). Blacks and Hispanics experienced significantly more rapid increases in prevalence of HPV-positive tumors over time compared with whites (6.5% vs 5.6% vs 3.2% per year, respectively). In HPV-positive OPC, neither sex nor race/ethnicity was associated with survival among patients with HPV-positive OPC. In contrast, for HPV-negative OPC, risk of death was significantly higher for women versus men (adjusted hazard ratio [aHR], 1.17; 95% confidence interval [CI], 1.08-1.26) and blacks versus whites (aHR, 1.21; 95% CI, 1.10-1.33). CONCLUSION: The prevalence of HPV-positive tumors is increasing for all sex and race/ethnicity groups in the United States. Sex and race are independently associated with survival for HPV-negative but not HPV-positive OPC. PMID- 30521094 TI - Diagnostic methods for identifying different Aeromonas species and examining their pathogenicity factors, their correlation to cytotoxicity and adherence to fish mucus. AB - Aeromonas spp. are ubiquitous in the aquatic environment, acting as facultative or obligate pathogens for fish. Identifying Aeromonas spp. is important for pathogenesis and prognosis in diagnostic cases but can be difficult because of their close relationship. Forty-four already characterized isolates of Aeromonas spp. were analysed by 16S rRNA gene sequencing, by gyrase B sequencing, by analysing their fatty acid profiles, by biochemical reactions and by MALDI-TOF MS. To determine their pathogenicity, cytotoxicity, adhesion to mucus and the expression of 12 virulence factors were tested. The susceptibility of the isolates towards 13 different antibiotics was determined. MALDI-TOF MS was found to be an acceptable identification method for Aeromonas spp. Although the method does not detect all species correctly, it is time-effective and entails relatively low costs and no other methods achieved better results. A high prevalence of virulence-related gene fragments was detected in almost all examined Aeromonas spp., especially in A. hydrophila and A. salmonicida, and most isolates exhibited a cytotoxic effect. Single isolates of A. hydrophila and A. salmonicida showed multiple resistance to antibiotics. These results might indicate the potentially pathogenic capacity of Aeromonas spp., suggesting a risk for aquatic animals and even humans, given their ubiquitous nature. PMID- 30521096 TI - A city-scale assessment reveals that native forest types and overstory species dominate New York City forests. AB - Cities are increasingly focused on expanding tree canopy cover as a means to improve the urban environment by, for example, reducing heat island effects, promoting better air quality, and protecting local habitat. The majority of efforts to expand canopy cover focus on planting street trees or on planting native tree species and removing nonnatives in natural areas through reforestation. Yet many urban canopy assessments conducted at the city-scale reveal co-dominance by nonnative trees, fueling debates about the value of urban forests and native-specific management targets. In contrast, assessments within cities at site or park scales find that some urban forest stands harbor predominantly native biodiversity. To resolve this apparent dichotomy in findings, about the extent to which urban forests are native dominated, between the city-scale canopy and site-level assessments, we measure forest structure and composition in 1,124 plots across 53 parks in New York City's 2,497 ha of natural area forest. That is, we assess urban forests at the city-scale and deliberately omit sampling trees existing outside of forest stands but which are enumerated in citywide canopy assessments. We find that on average forest stand canopy is comprised of 82% native species in New York City forests, suggesting that conclusions that the urban canopy is co-dominated by nonnatives likely results from predominantly sampling street trees in prior city-scale assessments. However, native tree species' proportion declines to 75% and 53% in the midstory and understory, respectively, suggesting potential threats to the future native dominance of urban forest canopies. Furthermore, we find that out of 57 unique forest types in New York City, the majority of stands (81%) are a native type. We find that stand structure in urban forest stands is more similar to rural forests in New York State than to stand structure reported for prior assessments of the urban canopy at the city scale. Our results suggest the need to measure urban forest stands apart from the entire urban canopy. Doing so will ensure that city scale assessments return data that align with conservation policy and management strategies that focus on maintaining and growing native urban forests rather than individual trees. PMID- 30521095 TI - Citrus fruit intake and gastric cancer: the Stomach cancer Pooling (StoP) project consortium. AB - Diets rich in vegetables and fruit have been associated with reduced risk of gastric cancer, and there is suggestive evidence that citrus fruits have a protective role. This study aimed at evaluating and quantifying the association between citrus fruit consumption and gastric cancer risk. We conducted a one stage pooled analysis including 6340 cases and 14,490 controls from 15 case control studies from the Stomach cancer Pooling (StoP) Project consortium. Odds ratio (OR) and the corresponding 95% confidence intervals (CI) of gastric cancer across study-specific tertiles of citrus fruit intake (grams/week) were estimated by generalized linear mixed effect models, with logistic link function and random intercept for each study. The models were adjusted for sex, age, and the main recognized risk factors for gastric cancer. Compared to the first third of the distribution, the adjusted pooled ORs (95% CI) for the highest third was 0.80 (0.73-0.87). The protective effect of citrus fruits increased progressively until three servings/week and levelled off thereafter. The magnitude of the association was similar between cancer sub-sites and histotype. The analysis by geographic area showed no association in studies from the Americas. Our data confirm an inverse association between citrus fruit intake and gastric cancer and provide precise estimates of the magnitude of the association. However, the null association found in studies from America and in some previous cohort studies prevent to draw definite conclusions on a protective effect of citrus fruit consumption. This article is protected by copyright. All rights reserved. PMID- 30521098 TI - Photofunctionalizing effects of hydroxyapatite combined with TiO2 on bone regeneration in rabbit calvarial defects. AB - The hydrophilicity of bone graft material generally used as a carrier can play an important role in regulating bone morphogenetic protein (BMP) expression at the bone graft site. The hydrophilicity, altering physicochemical properties, and enhancing biological capabilities, can be increased via surface modification through ultraviolet (UV) photofunctionalization and the effect on de novo osteogenesis could be further improved. Therefore, this study aimed to assess the effects of UV-irradiated TiO2 -coated hydroxyapatite (HA) in combination with rhBMP-2 on bone regeneration in rabbit calvarial defects. The hydrophilicity of HA and TiO2 -coated HA pellets was evaluated by measuring the contact angle of water droplets with UV irradiation. To compare de novo osteogenesis in rabbit calvarial defects, the rabbits were segregated into four different groups: negative control, HA, TiO2 -coated HA, and TiO2 -coated HA with UV; histomorphometric analysis and micro-computed tomography (MUCT) imaging were performed after 4 and 8 weeks. In vivo analysis revealed that de novo osteogenesis occurred on the critical size defects in all groups and was significantly increased in the TiO2 -coated HA with UV group than in other groups (p < 0.05). The present results indicate that UV photofunctionalization promotes de novo osteogenesis. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2018. PMID- 30521097 TI - Orchestration of Tryptophan-Kynurenine pathway, acute decompensation and acute-on chronic liver failure in cirrhosis. AB - Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation via the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers), were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. CONCLUSION: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course and mortality. This article is protected by copyright. All rights reserved. PMID- 30521099 TI - Extreme cold consistently reduces seedling growth but has species-specific effects on browse tolerance in summer. AB - PREMISE OF THE STUDY: Extreme weather events can injure plants, causing decreased survival. However, we may underestimate the ecological importance of extreme events if they have strong sublethal effects that manifest after several months. We tested the hypothesis that late-winter extreme-cold events decrease the ability of woody plants to grow and tolerate stem removal in summer. METHODS: Seedlings from four temperate tree species (Abies balsamea, Pinus resinosa, P. strobus, Quercus rubra) were acclimated to winter conditions in growth chambers, and experienced 1 week of warm temperatures before being exposed to one of three 24-h extreme-cold events (minimum temperature: 8 degrees C control, -8 degrees C, or -16 degrees C). Seedlings were then transferred to a greenhouse where we monitored survival and growth. Three months after the extreme-cold event, we mimicked an herbivore attack by removing either 25% or 75% of new stem growth from seedlings of two species (P. resinosa, Q. rubra). KEY RESULTS: While extreme cold had no immediate effect on seedling survival, the coldest temperature treatment reduced stem growth 51% relative to controls. Stem removal decreased P. resinosa survival in the -16 degrees C treatment, but stem removal treatment had no effect on P. resinosa survival in the intermediate -8 degrees C treatment or 8 degrees C control. Stem removal did not alter Q. rubra survival. CONCLUSIONS: Ephemeral late-winter cold temperatures can have unappreciated effects on growing season seedling dynamics, including growth and herbivory. For predicting how extreme-cold events might alter large-scale patterns of tree distribution, seedlings should be monitored throughout the growing season following extreme late-winter frosts. PMID- 30521101 TI - Surface modification of ultrafine-grained titanium: influence on mechanical properties, cytocompatibility and osseointegration potential. AB - OBJECTIVE: The main objective of this study was to demonstrate that dental implants made from ultrafine-grain titanium (UFG-Ti) can be created that replicate state of the art surfaces of standard coarse-grain titanium (Ti), showing excellent cytocompatibility and osseointegration potential while also providing improved mechanical properties. MATERIAL AND METHODS: UFG-Ti was prepared by continuous equal channel angular processing (ECAP) and surfaces were treated by sand-blasting and acid-etching. Mechanical properties (tensile and fatigue strength), wettability and roughness parameters were evaluated. Human trabecular bone-derived osteoblast precursor cells (HBCs) were cultured on all samples to examine cytocompatibility and mineralization after 4 and 28 days, respectively. Biomechanical pull-out measurements were performed in a rabbit in vivo model 4 weeks after implantation. RESULTS: Both yield and tensile strength as well as fatigue endurance were higher for UFG-Ti compared to Ti by 40%, 45% and 34%, respectively. Fatigue endurance was slightly reduced following surface treatment. Existing surface treatment protocols could be applied to UFG-Ti and resulted in similar roughness and wettability as for standard Ti. Cell attachment and spreading was comparable on all samples, but mineralization was higher for the surfaces with hydrophilic treatment with no significant difference between UFG-Ti and Ti. Pull-out tests revealed that osseointegration of surface treated UFG-Ti was found to be similar to that of surface treated Ti. CONCLUSION: It could be demonstrated that existing surface treatments for Ti can be translated to UFG-Ti and furthermore, that dental implants made from surface-treated UFG-Ti exhibit superior mechanical properties while maintaining cytocompatibility and osseointegration potential. This article is protected by copyright. All rights reserved. PMID- 30521100 TI - A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis. AB - BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% +/- 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH. PMID- 30521102 TI - Second infield re-irradiation with a resulting cumulative equivalent dose (EQD2max ) of >180 Gy for patients with recurrent head and neck cancer. AB - BACKGROUND: For locally recurrent head and neck cancer, re-irradiation with modern techniques like stereotactic body radiotherapy is a promising, possibly curative alternative to palliative systemic therapy. METHODS: We report on 1 patient with nasopharyngeal carcinoma (NPC) and 1 patient with cutaneous squamous cell carcinoma (SCC). Both patients received full dose primary treatment (>66 Gy, EQD2), full dose re-irradiation (>50 Gy, EQD2), and a second course of re irradiation via robotic radiosurgery (CyberKnife) for a second local recurrence. RESULTS: Both treatments resulted in adequate tumor response. No grade III-IV acute or late toxicities occurred. Follow-up at 6 months after third irradiation showed partial remission for the patient with NPC. In the second case (SCC), no toxicities occurred and the tumor was in remission 18 months after last treatment. CONCLUSION: These cases show that a second course of re-irradiation utilizing modern techniques like robotic radiosurgery might be feasible for carefully selected patients with head and neck cancer. PMID- 30521103 TI - Chondroitin sulfate inhibits secretion of TNF and CXCL8 from human mast cells stimulated by IL-33. AB - Glycosaminoglycans (GAGs) are linear, highly negatively charged carbohydrate chains present in connective tissues. Chondroitin sulfate (CS) and heparin (Hep) are also found in the numerous secretory granules of mast cells (MC), tissue immune cells involved in allergic and inflammatory reactions. CS and Hep may inhibit secretion of histamine from rat connective tissue MC, but their effect on human MC remains unknown. Human LAD2 MC were pre-incubated with CS, Hep, or dermatan sulfate (DS) before being stimulated by either the peptide substance P (SP, 2 MUM) or the cytokine IL-33 (10 ng/mL). Preincubation with CS had no effect on MC degranulation stimulated by SP, but inhibited TNF (60%) and CXCL8 (45%) secretion from LAD2 cells stimulated by IL-33. Fluorescein-conjugated CS (CS-F) was internalized by LAD2 cells only at 37 degrees C, but not 4 degrees C, indicating it occurred by endocytosis. DS and Hep inhibited IL-33-stimulated secretion of TNF and CXCL8 to a similar extent as CS. None of the GAGs tested inhibited IL-33-stimulated gene expression of either TNF or CXCL8. There was no effect of CS on ionomycin-stimulated calcium influx. There was also no effect of CS on surface expression of the IL-33 receptor, ST2. Neutralization of the hyaluronan receptor CD44 did not affect the internalization of CS-F. The findings in this article show that CS inhibits secretion of TNF and CXCL8 from human cultured MC stimulated by IL-33. CS could be formulated for systemic or topical treatment of allergic or inflammatory diseases, such as atopic dermatitis, cutaneous mastocytosis, and psoriasis. (c) 2018 BioFactors, 2018. PMID- 30521104 TI - Electrophysiological Properties of Identified Oxytocin and Vasopressin Neurons. AB - To understand the contribution of intrinsic membrane properties to the different firing patterns of oxytocin (OT) and vasopressin (VP) neurons in vivo, in vitro studies are needed, where stable intracellular recordings can be made. Combining immunochemistry for OT and VP and intracellular dye injections allows characterization of identified OT and VP neurons, and several differences between the two cell types have emerged. These include a greater transient K+ current that delays spiking to stimulus onset, and a higher Na+ current density leading to greater spike amplitude and a more stable spike threshold, in VP neurons. VP neurons also show a greater incidence of both fast and slow Ca2+ -dependent depolarizing afterpotentials, the latter of which summate to plateau potentials and contribute to phasic bursting. In contrast, OT neurons exhibit a sustained outwardly rectifying potential (SOR), and a consequent depolarizing rebound potential, not found in VP neurons. The SOR makes OT neurons more susceptible to spontaneous inhibitory synaptic inputs and correlates with a longer period of spike frequency adaptation in these neurons. While both types exhibit prominent Ca2+ -dependent afterhyperpolarizing potentials (AHPs) that limit firing rate and contribute to bursting patterns, Ca2+ -dependent AHPs in OT neurons selectively show significant increases during pregnancy and lactation. In OT, but not VP neurons, AHPs are highly dependent on the constitutive presence of the second messenger, phosphatidylinositol 4,5-bisphosphate, which permissively gates N-type channels that contribute the Ca2+ during spike trains that activates the AHP. In contrast to the intrinsic properties supporting phasic bursting in VP neurons, the synchronous bursting of OT neurons has only been demonstrated in vitro in cultured hypothalamic explants and is completely dependent on synaptic transmission. Additional differences in Ca2+ channel expression between the two neurosecretory terminal types suggests these channels are also critical players in the differential release of OT and VP during repetitive spiking, in addition to their importance to the potentials controlling firing patterns. This article is protected by copyright. All rights reserved. PMID- 30521105 TI - A randomized, double-blind, placebo-controlled trial of probiotics to reduce the severity of oral mucositis induced by chemoradiotherapy for patients with nasopharyngeal carcinoma. AB - BACKGROUND: The objective of this study was to evaluate the effect of a probiotic combination on the severity of oral mucositis (OM), which is a common, unpreventable complication induced by radiochemotherapy in patients with nasopharyngeal carcinoma who undergo concurrent radiochemotherapy (CCRT). METHODS: Eligible patients (n = 99) with locally advanced nasopharyngeal carcinoma who were undergoing CCRT were randomly assigned (2:1) to receive a probiotic combination or placebo during radiochemotherapy, and the incidence of severe OM (grade 3 or higher) was the primary endpoint. RESULTS: Patients taking the probiotic combination showed a significant reduction in the severity of OM. The incidences of grade 0, 1, 2, and 3 OM in the placebo group and the probiotic combination group were 0% and 12.07%, 0% and 55.17%, 54.29% and 17.24%, and 45.71% and 15.52%, respectively. Furthermore, CCRT greatly lowered the number of immune cells, whereas the probiotic combination markedly lowered the reduction rates of CD4+ T cells (76.59% vs 52.85%; P < .05), CD8+ T cells (62.94% vs 29.76%; P < .05), and CD3+ T cells (69.72% vs 45.49%; P < .05) in an A-CCRT-P (after treatment with radiotherapy plus chemotherapy plus the probiotic combination) group. High-throughput sequencing results indicated that CCRT had obviously disturbed the intestinal diversity of patients in an A-CCRT (after treatment with radiotherapy plus chemotherapy plus a placebo) group, whereas the probiotic combination distinctly restored the microbial diversity in the A-CCRT-P group toward that of healthy people and a B-CCRT-P (before the treatment of radiotherapy plus chemotherapy plus the probiotic combination) group. CONCLUSIONS: A probiotic combination significantly enhances the immune response of patients and reduces the severity of OM through modification of gut microbiota. PMID- 30521106 TI - Full-arch implant supported rehabilitations: A prospective study comparing porcelain-veneered zirconia frameworks to monolithic zirconia. AB - OBJECTIVES: To evaluate the performance of two types of zirconia frameworks. MATERIAL AND METHODS: From 2014 to 2016, in a prospective clinical trial 150 patients were rehabilitated with 83 and 110 implant-supported, screw-retained, full-arch ceramic-veneered zirconia (PVZ) rehabilitations and monolithic zirconia with porcelain veneering limited to buccal (MZ) rehabilitations, respectively. Patients were consecutively enlisted according to pre-defined inclusion criteria and evaluated on 4 months intervals. A Kaplan Meier estimator was adopted, and the log-rank test and Wilcoxon test used to test differences in survival and successful function in the two different groups. RESULTS: The average follow up time (+/- SD) and implant success rate was 608.80 +/- 172.52 days with 99.53% implant success for the PVZ group and 552.63 +/- 197.57 days with 99.83% success for the MZ group. According to the Kaplan Meier estimator, the mean cumulative survival rate at the 2 year follow up for framework fracture, major chipping, minor chipping, or any of the former combined to occur was 0.99, 0.95, 0.93 and 0.85 for the PVZ group (n=18) and 0.99, 0.95, 0.95 and 0.89 for the MZ group (n=15). No significant differences were found between the two groups. CONCLUSIONS: Results suggest zirconia as a suitable material for frameworks in full-arch implant-supported rehabilitations. Both groups presented a low incidence of technical complications. When comparing the two different designs the MZ group presented a lower technical complication rate, thus presenting itself as a viable alternative for full arch implant-supported rehabilitations. Further clinical studies with longer follow-ups (5 years) should be performed to evaluate the long-term stability of such rehabilitations. This article is protected by copyright. All rights reserved. PMID- 30521108 TI - The need for complete population-based studies on the etiology of liver disease. AB - I read Kim et al.'s "Changing Trends in Etiology- and Ethnicity-Based Annual Mortality Rates of Cirrhosis and Hepatocellular Carcinoma in the US"(1) with great interest. Patterns for hepatocellular carcinoma (HCC) are complex, with disparities likely rooted in etiological differences. Addressing the increasing burden of HCC is urgent. Precisely for this reason, I feel compelled to respectfully share three concerns with Kim et al.'s research. This article is protected by copyright. All rights reserved. PMID- 30521107 TI - Gallic Acid Suppresses Cardiac Hypertrophic Remodeling and Heart Failure. AB - SCOPE: Gallic acid (GA) is a dietary phenolic acid found in tea, red wine, and some plants. It exhibits antioxidative and anti-inflammatory activities. Recent studies have revealed that GA has beneficial effects against several cardiovascular diseases; however, whether GA attenuates pressure overload-induced cardiac hypertrophy and the underlying mechanism remain unclear. METHODS AND RESULTS: Primary cardiomyocyte hypertrophy was stimulated with angiotensin II (Ang II). Cardiac hypertrophic remodeling was induced in mice by transverse aortic constriction (TAC). Myocardial function was evaluated by echocardiographic and hemodynamic analyses, while cardiac tissues were analyzed by histological staining. We observed that GA significantly decreased Ang II-induced increases in cardiomyocyte size in vitro. Administration of GA in mice markedly improved TAC induced cardiac dysfunction and attenuated pathological changes, including cardiac myocyte hypertrophy, fibrosis, inflammation, and oxidative stress. Mechanistically, GA inhibited ULK1 and activated autophagy, which induced the degradation of EGFR, gp130, and calcineurin A, thereby inhibiting the downstream signaling cascades (AKT, ERK1/2, JAK2/STAT3, and NFATc1). CONCLUSIONS: Our results demonstrate for the first time that GA prevents myocardial hypertrophy and dysfunction via an autophagy-dependent mechanism. Thus, GA represents a promising therapeutic candidate for treating cardiac hypertrophy and heart failure. This article is protected by copyright. All rights reserved. PMID- 30521109 TI - Loop assembly: a simple and open system for recursive fabrication of DNA circuits. AB - High efficiency methods for DNA assembly have enabled routine assembly of synthetic DNAs of increased size and complexity. However, these techniques require customisation, elaborate vector sets or serial manipulations for the different stages of assembly. We have developed Loop assembly based on a recursive approach to DNA fabrication. The system makes use of two Type IIS restriction endonucleases and corresponding vector sets for efficient and parallel assembly of large DNA circuits. Standardised level 0 parts can be assembled into circuits containing 1, 4, 16 or more genes by looping between the two vector sets. The vectors also contain modular sites for hybrid assembly using sequence overlap methods. Loop assembly enables efficient and versatile DNA fabrication for plant transformation. We show construction of plasmids up to 16 genes and 38 Kb with high efficiency (>80%). We have characterized Loop assembly on over 200 different DNA constructs and validated the fidelity of the method by high-throughput Illumina plasmid sequencing. Our method provides a simple generalised solution for DNA construction with standardised parts. The cloning system is provided under an OpenMTA license for unrestricted sharing and open access. This article is protected by copyright. All rights reserved. PMID- 30521110 TI - Synthesis of C-C bonded Two-dimensional Conjugated Covalent Organic Framework Films via Suzuki Polymerization on Liquid/liquid Interface. AB - Synthesis of free standing two-dimensional (2D) conjugated covalent organic framework (COF) films linked by C-C bonds can be considered as a holy grail of synthetic chemistry. However, reactions for their synthesis are quite rare. Herein we developed a very simple and mild strategy to synthesize them via the Nobel Prize reaction (Suzuki polymerization) on water/toluene interface in a fridge. The versatility of this strategy was proved by the successful synthesis of two different 2D-COF films: a porous graphene and a porphyrin-contained 2D COF. Both 2D-COF films have large lateral size and their crystalline domains were visualized by high resolution TEM. Based on the wide compatibility of Suzuki reaction, our breakthrough work opened a door for the synthesis of various 2D conjugated COF films. For application studies, the porous graphene exhibits a good carrier mobility which is much higher than -C=N- linked 2D COF films and a good catalytic activity for hydrogen evolution reaction which is comparable with nitrogen or phosphorus doped graphene. PMID- 30521111 TI - Dietary Prevention of Colitis by Aronia Berry is Mediated Through Increased Th17 and Treg. AB - SCOPE: Increased fruit consumption is associated with reduced risk of colitis. We investigated whether the anti-colitic effects of the polyphenol-rich aronia berry (Aronia mitschurinii 'Viking') were mediated through Th17 and Treg. METHODS AND RESULTS: Colitis was induced in recombinase activating gene-1 deficient mice injected with syngeneic CD4+ CD62L+ naive T cells. Mice consumed either 4.5% w/w aronia berry-supplemented or a control diet concurrent with T cell transfer. The extent of colitis and immunocyte populations were evaluated at weeks 3 to 7 after transfer. Aronia consumption prevented colitic wasting and reduced colon weight/length ratios relative to the control diet at weeks 5 and 7. Compared to the control diet, aronia feeding increased Treg in mesenteric lymph node at all colitis stages. Treg and regulatory Th17 subpopulations (IL-17A+ IL-10+ and IL 17A+ IL-22+ ) were increased in lamina propria and spleen at week 5 in aronia-fed mice. Aronia feeding also decreased total CD4+ cells but increased colonic Tregs. The ability of aronia to modulate colonic cytokines was associated with functional T cell IL-10 and increased diversity of microbiota. CONCLUSIONS: Aronia berry consumption inhibits adoptive transfer colitis by increasing Treg and regulatory Th17 cells. Dietary modulation of T cells is dynamic and precede colitic wasting. This article is protected by copyright. All rights reserved. PMID- 30521112 TI - Human Embryonic Stem Cells: Distinct Molecular Personalities and Applications in Regenerative Medicine. AB - The field of stem cell biology is exciting because it provides researchers and clinicians with seemingly unlimited applications for treating many human diseases. Stem cells are a renewable source of pluripotent cells that can differentiate into nearly all human cell types. In this article we focus particularly on human embryonic stem (hES) cells, derived from the inner cell mass of the blastocyst and cultured for expansion while remaining undifferentiated, to explore their unique molecular personalities and clinical applications. The aim of this literature review is to reflect the interest in hES cells and to provide a resource for researchers and clinicians interested in the molecular characteristics of such cells. This article is protected by copyright. All rights reserved. PMID- 30521113 TI - Overcoming T790M mutant small cell lung cancer with the third-generation EGFR-TKI osimertinib. AB - A large number of EGFR mutant non-small cell lung cancer patients primordially benefit from first-line treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. However, multiple acquired resistance mechanisms have been described that limit the clinical efficacy of first-generation EGFR-TKIs. Herein, we report a rare case of lung adenocarcinoma harboring an EGFR exon 19-deletion mutation before the administration of target therapy. This patient acquired resistance to first-generation EGFR-TKIs through small cell lung cancer (SCLC) transformation accompanied by the T790M mutation. Unexpectedly, this SCLC patient maintained a sensitive response to the third generation EGFR-TKI osimertinib. This special case may indicate that osimertinib represents an effective target drug for SCLC patients who harbor an EGFR T790M mutation. PMID- 30521115 TI - Single-scan diffusion-ordered NMR spectroscopy of SABRE-hyperpolarized mixtures. AB - The analysis of complex mixtures of dissolved molecules is a major challenge, especially for systems that gradually evolve, e.g., in the course of a chemical reaction or in the case of chemical instability. 1D NMR is a fast and non invasive method suitable for detailed molecular analysis, though of low sensitivity. Moreover, the spectral resolution of proton, the most commonly used and most sensitive stable isotope in NMR, is also quite limited. Spatially encoded (SPEN) experiments aim at creating in one acquisition a 2D data set by simultaneously performing different 1D sub-experiments on different slices of the NMR tube, at the price of an extra loss of sensitivity. Choosing translational diffusion coefficients as the additional dimension (the so-called DOSY approach) helps to recover proton spectra of each molecule in a mixture. The sensitivity limitation of SPEN NMR can, on the other hand, be addressed with hyperpolarization methods. Within hyperpolarization methods, signal amplification by reversible exchange (SABRE), based on parahydrogen, is the cheapest and the easiest one to set up, and allows multi-shot experiments. Here we show that the spectra of a mixture's components at millimolar concentration are resolved in few seconds by combining the SABRE, SPEN and DOSY concepts. PMID- 30521114 TI - Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3-internal tandem duplication genotypes. AB - BACKGROUND: The revised 2017 European LeukemiaNet (ELN) classification (ELN-2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN-2017 in comparison with ELN-2010 in younger patients with AML has not been validated to date. METHODS: The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)-based induction chemotherapy for newly diagnosed AML. RESULTS: According to ELN-2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5-year overall survival probabilities in the Fav (169 patients), intermediate (IR)-1 (80 patients), IR-2 (306 patients), and Adv (160 patients) ELN-2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN-2010 historically distinguishes prognosis into IR-1 and IR-2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3-ITD AR with those with a high FLT3-ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)-mutated AML (P = .28) or wild-type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10). CONCLUSIONS: The ELN-2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3-ITD AR needs further evaluation in different treatment settings. PMID- 30521116 TI - Metal-Organic Framework Derived Hierarchical Co/C@V2O3 Hollow Spheres as a Thin, Lightweight and High-Efficiency Electromagnetic Wave Absorber. AB - Developing high-efficiency electromagnetic (EM) wave absorbing materials with light weight, thin thickness and wide absorption bandwidth is highly desirable for ever-developing electronic and telecommunication devices. Herein, hierarchical metal-organic framework (MOF)-derived Co/C@V2O3 hollow spheres were designed and synthesized through a facile hydrothermal, precipitation and pyrolysis method. The composite exhibits both excellent impedance matching and light weight due to the rational combination of hollow V2O3 spheres and porous Co/C. Additionally, multiple components enable a large dielectric and magnetic loss of the composite, giving rise to enhanced EM wave absorption performance with a maximum reflection loss (RL) of -40.1 dB and a broad effective absorption bandwidth (RL < -10 dB) of 4.64 GHz at a small thickness of 1.5 mm. This work provides insights into the design of hierarchical hollow and porous composites as a thin and lightweight EM wave absorbers with efficient absorption, which can also be extended to energy storage, catalysis and sensing. PMID- 30521117 TI - Cyclin-Dependent Kinase Inhibitor-1-Deficient Mice Are Susceptible to Osteoarthritis Associated With Enhanced Inflammation. PMID- 30521118 TI - Endogenous Parathyroid Hormone-Related Protein Compensates for the Absence of Parathyroid Hormone in Promoting Bone Accrual In Vivo in a Model of Bone Marrow Ablation. PMID- 30521120 TI - JBMR Reviewer List 2018. PMID- 30521119 TI - Periarticular Bone Loss in Arthritis Is Induced by Autoantibodies Against Citrullinated Vimentin. PMID- 30521121 TI - Issue Information-Declaration of Helsinki. PMID- 30521122 TI - Memoriam. PMID- 30521123 TI - The role of post-mastectomy radiotherapy in elderly patients with 1-3 positive lymph nodes breast cancer: An International Retrospective Double-Center Study. AB - This study evaluated the role of post-mastectomy radiotherapy (PMRT) in 111 patients with 1-3 positive nodes, aged 65 years or above between 2007 and 2013. In total, 64 received PMRT. The PMRT group had more aggressive tumor. Three patients suffered locoregional recurrences in each group at median follow-up of 50 months. PMRT has no significant impact on distant disease-free survival (DDRFS), recurrence-free survival (RFS) and overall survival (OS). In patients with tumors >5 cm, PMRT significantly improved DDRFS, RFS, and marginally prolonged OS. These results supported that PMRT should not be compromised in all elderly patients, especially in those with tumor >5 cm. PMID- 30521124 TI - Immunomodulatory response of layered small intestinal submucosa in a rat bladder regeneration model. AB - Based on the hypothesis that bioscaffold permeability is a major factor in determining the outcome of histologically complete and functional bladder regeneration, we evaluated regeneration processes of four-layer porcine small intestinal submucosa (SIS) construct; and compared results between rat bladders augmented with single-layer SIS bioscaffolds. Sprague-Dawley female rats were subjected to hemi-cystectomy followed by anastomosis of a patch of either single- or four-layer porcine SIS. Permeability was analyzed in situ using magnetic resonance imaging (MRI) at post-operative days 7 and 14. Bladder sections excised at days 7, 14, 28, and 56 post-operation Samples were assessed by H&E and Masson's trichrome stains. Urothelial differentiation was analyzed using cytokeratin AE1/AE3, and uroplakin III (UPIII). In addition, quantitative and qualitative evaluations of neutrophils, mast cells, eosinophils, and macrophages were performed using anti-myeloperoxidase, Alcian blue, Giemsa stain, and anti CD68 staining methods, respectively. Four-layer SIS was consistently impermeable as evidenced by the absence of intravesical administered gadolinium with diethylenetriaminepentacetate (Gd-DTPA) contrast signal in peripheral regions of augmented bladders compared with single-layer SIS bioscaffold. Elevated and sustained eosinophil and neutrophil infiltrations were prominent in four-layered SIS-augmented bladders compared with single-layer SIS with comparable impermeability. Delayed but consistent urothelial regeneration and differentiation were observed in four-layer SIS-augmented bladders; and urothelial differentiation was observed at day 56 post-augmentation. In conclusion, four-layer SIS enacts an elevated inflammatory response along with extended urothelial regeneration. Four-layer SIS may activate a different but yet to be identified mechanism for inflammatory responses. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B, 2018. PMID- 30521126 TI - Evaluation of magnesium alloys for use as an intraluminal tracheal for pediatric applications in a rat tracheal bypass model. AB - Tracheal stenting currently using non-degradable stents is commonplace for treatment of trauma, prolonged intubation related adult airway obstructions, and pediatric patients-associated tracheal stenosis conditions. Degradable tracheal stent placement will avoid complications of stent removal and restenosis. Widespread reports exist on degradable magnesium alloys success for orthopedic and cardiovascular applications but none to date for intra tracheal use. This research explores the use of pure Mg, AZ31, and Mg-3Y alloys for degradable tracheal stent assessment. In vitro evaluation of magnesium, prototype stents in a bioreactor simulate the airway environment and corrosion. Micro-CT imaging and biocompatibility evaluation helped assess the 24-week degradation of intraluminal alloy stents following implantation in a rat tracheal in vivo bypass model. Histological analysis indicate tissue response of the harvested stented trachea segments after each time point. Corrosion studies for each alloy indicate significant differences between the simulated and control in vitro conditions. AZ31 exhibited the lowest volume loss of 6.8% in saline, while pure Mg displayed the lowest volume loss of 4.6% in simulated airway fluid (SAF), both at 1-week time points. Significant differences in percentage of total volume lost after 6 months were determined between the alloys over time. MgY alloy displayed the slowest corrosion losing only 15.1% volume after 24 weeks of immersion. Additionally, in vitro magnesium alloy corrosion was not significantly different from the percentage of total volume lost in vivo at 1-week time point. The study demonstrates promise of magnesium alloys for intraluminal tracheal stent application albeit viability of a clinically translatable model warrants further studies. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30521127 TI - The Development of a Core Syllabus for Teaching Musculoskeletal Anatomy of the Vertebral Column and Limbs to Medical Students. AB - INTRODUCTION: The study of human anatomy is fundamental to medical education globally. Knowledge of musculoskeletal anatomy is essential for safe and effective clinical practice, yet this topic often receives insufficient medical programme time and perceptions differ regarding which knowledge is core. Given the lack of syllabuses specific to musculoskeletal anatomy, this paper aims to provide a detailed syllabus for the vertebral column and limbs relevant to medical students. MATERIALS AND METHODS: A Delphi panel comprising anatomists and clinicians rated 2260 anatomical structures and concepts as "essential", "important", "acceptable" or "not required", with evaluations based around the core knowledge deemed acceptable for a competent medical student. Based on the percentage of panellist agreement for an item to be considered "essential", each item was then classified as core (>=60%), recommended (30%-59%), not recommended (20%-29%) or not core (<20%). Items not classified as core or recommended but rated important by >50% of the panel were highlighted for future consideration. RESULTS: A total of 252/389 musculoskeletal concept items were categorised as core or recommended. The number of core or recommended items for the vertebral column, upper limb and lower limb were 220/438, 322/663 and 318/770, respectively. Ninety-six items were recommended for future consideration. CONCLUSIONS: The results of this Delphi panel will be published on the International Federation of Associations of Anatomists website for continuing international consideration and deliberation by relevant stakeholders. The aim is to set an internationally recognized syllabus, that covers the minimum musculoskeletal content that is academically and clinically relevant. This article is protected by copyright. All rights reserved. PMID- 30521128 TI - Reproducibility of measuring QRS duration and implications for optimization of interventricular pacing delay in cardiac resynchronization therapy. AB - BACKGROUND: QRS narrowing after CRT is a predictor of patient outcome. Further narrowing can be obtained by interventricular pacing delay (VVd) optimization, raising interest to inter and intraobserver variation in manual measurements of QRS duration. METHODS: (a) Variation in intrinsic rhythm QRS duration in CRT patients with LBBB: In 40 intrinsic 12-lead ECGs, six observers measured QRS duration defined as widest QRS in any lead. In 20 of these ECGs, two observers repeated the measurements. (b) Variation in paced QRS duration at different VVd settings and agreement in selecting the narrowest QRS: In 20 CRT patients, five paced ECGs were recorded at different VVds. The most frequently selected VVd(s) estimated to cause the narrowest QRS in each patient defined the optimal VVd. Two observers repeated the measurements and VVd selections. RESULTS: Absolute interobserver difference in measured QRS duration in intrinsic rhythm ECGs was mean 2 ms, range (-40; 40 ms), mean limits of agreement (LoA): -21; 25 ms. Absolute interobserver difference in measured QRS duration in paced ECGs was mean 3 ms, range (-50; 60 ms), mean LoA: -20; 27 ms. There was no difference in LoA between intrinsic and paced QRS duration (lower limit p = 0.68; upper limit p = 0.44). The optimal VVd was included in 17/20 (85%) of the VVd selections by six observers. Interobserver variation was comparable with the intraobserver variation. CONCLUSIONS: Interobserver variation and intraobserver variation in manually measured paced and intrinsic rhythm QRS duration are clinically acceptable and comparable in a cohort of CRT patients. Inter and intraobserver reproducibility for selecting the optimal VVd is good and warrants manual VVd optimization for QRS narrowing in CRT. PMID- 30521129 TI - Particle Size and Gastrointestinal Absorption Influence Tiotropium Pharmacokinetics: A Pilot Bioequivalence Study of PUR0200 and Spiriva HandiHaler. AB - AIMS: Plasma pharmacokinetics permits the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva(r) HandiHaler(r) (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block. METHODS: A seven-period, single-dose, cross-over study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in 5 periods and Spiriva HH in 2 periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8h after inhalation. RESULTS: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3MUg tiotropium) lung deposition was similar to Spiriva HH (18MUg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The Cmax and AUC0-0.5h of Spiriva HH with and without charcoal block were bioequivalent, however Spiriva HH AUC0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration. CONCLUSIONS: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC0 t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract. PMID- 30521130 TI - The association between markers of tumor cell metabolism, the tumor microenvironment and outcomes in patients with colorectal cancer. AB - Tumor cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumor microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I-III CRC were utilised to assess tumor cell expression of MCT-1, MCT-2, LDH-1 and LDH5 by immunohistochemistry. Expression levels were dichotomised and associations with tumor factors, the tumor microenvironment and survival analysed. Nuclear LDH-5 associates with poor prognosis (HR 1.68 95% CI 0.99-2.84, p=0.050) and trends towards increased tumor stroma percentage (TSP, p=0.125). Cytoplasmic MCT-2 also trends towards increased TSP (p=0.081). When combined into a single score; nuclear LDH-5+TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27 5.35, p=0.009), increased tumor budding (p=0.002) and decreased stromal T lymphocytes (p=0.014). Similarly, cytoplasmic MCT-2+TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31-4.11, p=0.003), decreased necrosis (p=0.039), and increased tumor budding (p=0.004). The present study reports that the combination of TSP and nuclear LDH-5 was significantly associated with survival, increased tumor budding, and decreased stromal T-lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumor progression via modulation of tumor metabolism. Moreover, MCT-2 and LDH-5 may provide promising therapeutic targets for patients with stromal-rich CRC. This article is protected by copyright. All rights reserved. PMID- 30521131 TI - Utility of first positron emission tomography-computed tomography scan as a prognostic tool following treatment of sinonasal and skull base malignancies. AB - BACKGROUND: The prognostic value of the first posttreatment whole body integrated positron emission tomography-computed tomography (PET/CT) scanning in patients with sinonasal/skull base malignancies is undetermined. METHODS: We retrospectively reviewed the data of all patients that underwent surgery for sinonasal/skull base malignancies in 2000-2015. The results of the pretreatment and posttreatment PET/CT findings and the clinical course were retrieved. RESULTS: Thirty-eight patients (average age 60.6 years, 20 males) were included. Sensitivity and specificity, positive predictive value, and negative predictive value of the first PET/CT scan for predicting persistent/recurrent disease were 85.7%, 87.5%, 80%, and 91.3%, respectively. Overall 5-year survival was significantly lower in the first posttreatment PET/CT-positive group (35%) compared to the PET/CT-negative group (93%) (P = .0008). CONCLUSION: Posttreatment PET/CT findings are highly prognostic in patients with sinonasal/skull base malignancies. Negative findings on the first posttreatment PET/CT scan predict a significantly better overall survival. PMID- 30521132 TI - Synthesis and structure determination of SCM-15: a 3D large pore zeolite with interconnected straight 12*12*10-ring channels. AB - A new germanosilicate zeolite named SCM-15 (Sinopec Composite Material No. 15), the first zeolite containing a 3-dimensional (3D) channel system with interconnected 12-, 12-, and 10-ring channels (pore sizes: 6.1*7.2, 6.1*7.4, and 5.2*5.9 A), has been synthesized using neutral 4-pyrrolidinopyridine as organic structure-directing agents (OSDAs). Its structure has been determined by combining single-crystal electron diffraction (SCED) and synchrotron powder X-ray diffraction (SPXD) data. The unique open framework structure of SCM-15 is related to that of FOS-5 (BEC), ITQ-7 (ISV), PKU-16 (POS), ITQ-26 (IWS), ITQ-21, Beta polymorph B, and SU-78B, since all these framework structures can be constructed from similar chains which are connected through shared 4-ring or double 4-ring (d4r) units. Based on this relation, six topologically reasonable 3D large or extra-large pore hypothetical zeolites are predicted. PMID- 30521125 TI - Development and validation of a haematuria cancer risk score to identify patients at risk of harbouring cancer. AB - BACKGROUND: A lack of consensus exists among national guidelines regarding who should be investigated for haematuria. Type of haematuria and age specific thresholds are frequently used to guide referral for investigation of haematuria. OBJECTIVES: To develop and externally validate the haematuria cancer risk score (HCRS) to improve patient selection for investigation of haematuria. METHODS: Development cohort comprise of 3,539 prospectively recruited patients recruited at 40 UK hospitals (DETECT 1; ClinicalTrials. gov: NCT02676180) and validation cohort comprise of 656 Swiss patients. All patients were aged >18 years and referred to hospital for the evaluation of visible (VH) and non-visible haematuria (NVH). Sensitivity and specificity of the HCRS in the validation cohort was derived from a cut-off identified from the discovery cohort. RESULTS: Patient age, gender, type of haematuria and smoking history were used to develop the HCRS. HCRS validation achieves good discrimination (AUC 0.835; 95% CI: 0.789 0.880) and calibration (calibration slope=1.215) with no significant overfitting (p=0.151). The HCRS detected 11.4% (n=8) more cancers which would be missed by UK National Institute for Health and Clinical Excellence guidelines. The American Urological Association guidelines would identify all cancers with a specificity of 12.6% compared to 30.5% achieved by the HCRS. All patients with upper tract cancers would have been identified. CONCLUSION: The HCRS offers good discriminatory accuracy which is superior to existing guidelines. The simplicity of the model would facilitate adoption and improve patient and physician decision making. This article is protected by copyright. All rights reserved. PMID- 30521133 TI - Influence of miR-520e-mediated MAPK signaling pathway on HBV replication and regulation of hepatocellular carcinoma cells via targeting EphA2. AB - We determined the role of miR-520e in the replication of hepatitis B virus (HBV) and the growth of hepatocellular carcinoma (HCC) cells. MiR-520e and EPH receptor A2 (EphA2) in HBV-positive HCC tissues and cells were detected and we studied the impact of miR-520e and the EphA2 receptor in cellular and murine HBV replication models. We find that MiR-520e was up-regulated and EphA2 was down-regulated in HBV-positive HCC tissues and cells. MiR-520e was decreased in Huh7-X and HepG2-X cells in which HBx was stably expressed, but was dose-dependently elevated after interfering with HBx. Additionally, miR-520e mimic and si-EphA2 groups were reduced in association with increases in HBV-DNA content, HBsAg and HBeAg levels, cell proliferation, and were enhanced in the expressions of EphA2, p p38MAPK/p38MAPK, phosphorylated extracellular signal-regulated kinase 1/2 (p ERK1/2)/ERK1/2 and cell apoptosis. Furthermore, si-EphA2 reversed the promotion effect of miR-520e inhibitor on HBV replication and tumor cell growth. Up regulating miR-520e in rAAV8-1.3HBV infected-mouse resulted in reduced EphA2 in liver tissues and HBV-DNA content in serum. We find that MiR-520e was decreased in HBV-positive HCC, while over-expression of miR-520e blocked p38MAPK and ERK1/2 signalling pathways by an inhibitory effect on EphA2 and ultimately reduced HBV replication and inhibited tumor cell growth.These data indicate a role for miR 520e in the regulation of HBV replication. This article is protected by copyright. All rights reserved. PMID- 30521134 TI - Chlorogenic acid-mediated chemical defense of plants against insect herbivores. AB - Chlorogenic acid is one of the most abundant beneficial polyphenols in plants and is well known as nutritional anti-oxidant in plant based foods. Apart from its dietary antioxidant activity, it has been proven to be an efficient defense molecule against a broad range of insect herbivores. In the last two decades, several reports have shown the effectiveness of chlorogenic acid for insect's growth deterrence. Biosynthetic pathway for chlorogenic acid biosynthesis in plants was previously elucidated and metabolic engineering of the principal pathway showed high chlorogenic acid production in tomato plants. Herbivore mediated induction of chlorogenic acid biosynthesis was also demonstrated both at metabolite and transcript level, though herbivore-mediated molecular regulation of chlorogenic acid biosynthesis is not fully elucidated yet. In this communication, we present our views on the efficacy of chlorogenic acid as anti herbivore defense molecule in plants and also discuss its future outlook. This article is protected by copyright. All rights reserved. PMID- 30521135 TI - Is Sexting Associated with Sexual Behaviors During Adolescence? A Systematic Literature Review and Meta-Analysis. AB - INTRODUCTION: A growing body of research has addressed adolescent use of mobile devices to exchange sexually explicit images and messages (sexting). Although there are legal consequences in some states for sexting among adolescents, research findings have also demonstrated associations between sexting and sexual activity. The purpose of this systematic review was to synthesize research examining the association between adolescent sexting and sexual activity. METHODS: Five databases (CINAHL, Embase, Ovid MEDLINE, PsycINFO, and Scopus) were searched for studies measuring adolescent sexting and sexual behaviors. Studies were appraised for quality using a modified Downs and Black scale. Studies reporting frequencies or odds ratios were eligible for inclusion in random effects meta-analytic models. RESULTS: Of 669 articles retrieved, 9 studies met inclusion criteria for systematic review; of these, 6 were included in meta analysis. After pooling data from 9676 adolescents, the odds of reporting sexual activity were found to be 6.3 times higher (95% CI, 4.9-8.1; Q = 14.3; I2 = 65.1) for adolescents who sent sexts compared with those who did not. DISCUSSION: These data suggest that adolescents who send sexually explicit text messages are more likely to report sexual activity than adolescents who do not. Midwives are well poised to integrate a discussion of sexting into sexual and reproductive health counseling with adolescent and young adult patients. PMID- 30521137 TI - Evaluation of the Serum Levels of Galectin-3 in Patients with Oral Lichen Planus Disease. AB - OBJECTIVES: Galectin-3, a member of beta-galactoside-binding proteins, can be found in cytoplasm and nucleus as well as extracellularly in various tissues and involved in many physiological and pathological processes. We aimed to measure the serum levels of galectin-3 in oral lichen planus (OLP) disease and compare the result with that observed in healthy ones. MATERIALS AND METHODS: In this cross-sectional study, the serum levels of galectin-3 were measured in 56 healthy individuals and 53 pathologically proven OLP patients including those with atrophic/erosive (33 cases) or reticular (20 cases) lesions, using enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with healthy individuals (1.1+/ 0.4 ng/ml), galectin-3 serum levels in patients with OLP (3.1+/-1.1 ng/ml) were significantly elevated (p < 0.0001). Serum galectin-3 levels were elevated significantly in patients with atrophic/erosive lesions compared to those of reticular (3.9+/-2.1 ng/ml vs. 1.9+/-1.4 ng/ml, p = 0.001), but it has not associated with age and gender. CONCLUSIONS: The elevation of galectin-3 in OLP is a future tool to increase the knowledge about the possible etiology of the disease and may be helpful to differentiate atrophic/erosive lesions from reticular ones. To the best of our knowledge, this is the first study evaluated the serum galectin-3 levels in OLP. This article is protected by copyright. All rights reserved. PMID- 30521136 TI - Prediction of major depressive disorder onset in college students. AB - BACKGROUND: Major depressive disorder (MDD) in college students is associated with substantial burden. AIMS: To assess 1-year incidence of MDD among incoming freshmen and predictors of MDD-incidence in a representative sample of students. METHOD: Prospective cohort study of first-year college students (baseline: n = 2,519, 1-year follow-up: n = 958) RESULTS: The incidence of MDD within the first year of college was 6.9% (SE = 0.8). The most important individual-level predictors of onset were prior suicide plans and/or attempts (OR = 9.5). The strongest population-level baseline predictors were history of childhood adolescent trauma, stressful experience in the past 12 months, parental psychopathology, and other 12-month mental disorder. Multivariate cross-validated prediction (cross-validated AUC = 0.73) suggest that 36.1% of incident MDD cases in a replication sample would occur among the 10% of students at highest predicted risk (24.5% predicted incidence in this highest-risk subgroup). CONCLUSIONS: Screening at college entrance is a promising strategy to identify students at risk of MDD onset, which may improve the development and deployment of targeted preventive interventions. PMID- 30521138 TI - Mapping Aldehyde Dehydrogenase 1A1 Activity using an [18F]Substrate-based Approach. AB - Aldehyde dehydrogenases (ALDHs) catalyze the oxidation of aldehydes to carboxylic acids, with elevated ALDH expression in human cancers linked to metastases and poor overall survival. Despite ALDH being a poor prognostic factor, the non invasive assessment of ALDH activity in vivo has not been possible due to a lack of sensitive and translational imaging agents. In this report, we present the synthesis and biological evaluation of ALDH1A1-selective chemical probes composed of an aromatic aldehyde derived from N,N-diethylamino benzaldehyde (DEAB) linked to a fluorinated pyridine ring either via an amide or amine linkage. Of the focused library of compounds evaluated, N-ethyl-6-(fluoro)-N-(4 formylbenzyl)nicotinamide 4b was found to have excellent affinity and isozyme selectivity for ALDH1A1 in vitro. Following 18F-fluorination, [18F]4b was taken up by colorectal tumor cells and trapped through the conversion to its 18F labelled carboxylate product under the action of ALDH. In vivo positron emission tomography revealed high uptake of [18F]4b in the lungs and liver, with radioactivity cleared through the urinary tract. Oxidation of [18F]4b, however, was observed in vivo which may limit the tissue penetration of this first-in class radiotracer. PMID- 30521139 TI - Medial elbow anatomy: A paradigm shift for UCL injury prevention and management. AB - INTRODUCTION: To improve the management outcomes and diagnostic accuracy of the ulnar collateral ligament (UCL) injury, the anatomy of the medial side of the elbow joint is necessary to be understood in terms of the periarticular surroundings rather than the specific ligaments. The aim of this study was to anatomically clarify the medial side of the elbow joint in terms of the tendinous structures and joint capsule. MATERIALS AND METHODS: We conducted a descriptive anatomical study of 23 embalmed cadaveric elbows. We macroscopically analyzed the relationship between the flexor pronator muscles (FPMs) and the joint capsule in ten elbows, histologically analyzed in six elbows, and observed the bone morphology through micro computed tomography in seven elbows. RESULTS: The two tendinous septa (TS) were found: between the pronator teres (PT) and flexor digitorum superficial (FDS) muscles, and between the FDS and flexor carpi ulnaris (FCU) muscles. These two TS are connected to the medial part of the brachialis tendon, deep aponeurosis of the FDS, and FCU to form the tendinous complex, which linked the humeroulnar joint and could not be histologically separated from each other. Moreover, the capsule of the humeroulnar joint under the tendinous complex had attachment on the ST of 7 mm width. CONCLUSIONS: The two TS, the brachialis tendon, the deep FDS and FCU aponeuroses, and the joint capsule linked the humeroulnar joint. These anatomical findings could lead to a paradigm shift in the prevention, diagnosis, and treatment of UCL injuries in baseball players. This article is protected by copyright. All rights reserved. PMID- 30521140 TI - Isolation and identification of endogenous RFRP1 and RFRP3 in the mouse hypothalamus. AB - Although RFamide-related peptide (RFRP) preproprotein sequence is known in mice, until now the molecular structure of the mature, functional peptides processed from the target precursor molecule has not been determined. In the present study we purified endogenous RFRP1 and RFRP3 peptides from mouse hypothalamic tissue extracts using immunoaffinity column conjugated with specific antibodies against the mouse C-terminus of RFRP-1 and RFRP-3. Employing liquid chromatography coupled with mass spectrometry (LC-MS) we demonstrated, that RFRP1 consists of 15 and RFRP3 of 10 amino acid residues (ANKVPHSAANLPLRF-NH2 and SHFPSLPQRF-NH2 , respectively). To investigate the distribution of RFRPs in the mouse central nervous system (CNS), we performed immunohistochemical (IHC) staining of the brain sections collected from wild-type (WT) and Rfrp knock-out (Rfrp KO) animals. This data together with gene expression in multiple tissues provides strong confidence that RFRP-immunoreactive (RFRP-ir) neuronal cells are localized in the dorsomedial (DMH) and between DMH and the ventromedial (VMH) hypothalamic nuclei. The identification of RFRP1 and RFRP3 peptides and the IHC visualization of targeting RFRPs neurons in the mice brain provide the basis for the investigations into a functional biology of RFRPs. This article is protected by copyright. All rights reserved. PMID- 30521141 TI - Interplay of Cysteine Exposure and Global Protein Dynamics in Small-molecule Recognition by a Regulator of G-protein Signaling Protein. AB - Regulator of G protein signaling (RGS) proteins play a pivotal role in regulation of G protein-coupled receptor (GPCR) signaling and are therefore becoming an increasingly important therapeutic target. Recently discovered thiadiazolidinone (TDZD) compounds that target cysteine residues have shown different levels of specificities and potencies for the RGS4 protein, thereby suggesting intrinsic differences in dynamics of this protein upon binding of these compounds. In this work, we investigated using atomistic molecular dynamics (MD) simulations the effect of binding of several small-molecule inhibitors on perturbations and dynamical motions in RGS4. Specifically, we studied two conformational models of RGS4 in which a buried cysteine residue is solvent-exposed due to side-chain motions or due to flexibility in neighboring helices. We found that TDZD compounds with aromatic functional groups perturb the RGS4 structure more than compounds with aliphatic functional groups. Moreover, small-molecules with aromatic functional groups but lacking sulfur atoms only transiently reside within the protein and spontaneously dissociate to the solvent. We further measured inhibitory effects of TDZD compounds using a protein-protein interaction assay on a single-cysteine RGS4 protein showing trends in potencies of compounds consistent with our simulation studies. Thermodynamic analyses of RGS4 conformations in the apo-state and on binding to TDZD compounds revealed links between both conformational models of RGS4. The exposure of cysteine side-chains appears to facilitate initial binding of TDZD compounds followed by migration of the compound into a bundle of four helices, thereby causing allosteric perturbations of the RGS/Galpha protein-protein interface. This article is protected by copyright. All rights reserved. PMID- 30521142 TI - Interleukin-32epsilon induces caspase-independent apoptosis mediated by N-Myc interactor in macrophages infected with Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) is the pathogen responsible for tuberculosis, a leading cause of illness and death worldwide. Growing evidence suggests that the proinflammatory cytokine IL-32 plays a major role in host defenses against pathogens such as Mtb. IL-32 exists in six alternatively spliced isoforms, but anti-tuberculosis effects have been reported only for some of them. In this study, we examined the effect of all six IL-32 isoforms on Mtb replication in the murine macrophage cell line RAW 264.7. Compared with cells transfected with the other isoforms, IL-32epsilon-transfected cells exhibited the strongest anti tuberculosis effect and the highest rate of Mtb-induced apoptosis. Of note, this apoptosis pathway was independent of caspase-3 activation. Instead, N-Myc interactor (NMI), an inhibitor of Wnt signaling, was a key player in IL-32epsilon mediated apoptosis by inhibiting Wnt/beta-catenin signaling and thereby activating c-Myc-mediated apoptosis. Moreover, we identified two cis-acting elements that are binding sites for the transcriptional regulators paired box 6 (PAX6) and transcription factor CP2 (TFCP2) in the promoter of NMI and these elements proved essential for IL-32epsilon-induced upregulation of Nmi expression. Furthermore, IL-32epsilon-mediated activation of the mitogen activated protein kinase p38 also contributed to NMI upregulation. In conclusion, our results demonstrate that Mtb infection-induced IL-32epsilon-mediated apoptosis in macrophages plays a key role in host defenses against Mtb. This article is protected by copyright. All rights reserved. PMID- 30521143 TI - PPICurator: a tool for extracting comprehensive protein-protein interaction information. AB - PPI extraction through biological literature curation has been widely employed for proteome analysis. There is a strong need for a tool that can assist researchers in extracting comprehensive PPI information through literature curation, which is critical in research on protein, e.g., construction of protein interaction network, identification of protein signaling pathway and discovery of meaningful protein interaction. However, most of current tools can only extract PPI relations. None of them are capable of extracting other important PPI information, such as interaction directions, effects and functional annotations. To address these issues, this paper proposes PPICurator, a novel tool for extracting comprehensive PPI information with a variety of logic and syntax features based on a new support vector machine (SVM) classifier. PPICurator provides a friendly web-based user interface. It is a platform that automates the extraction of comprehensive PPI information through literature, including PPI relations, as well as their confidential scores, interaction directions, effects and functional annotations. Thus, PPICurator is more comprehensive than state-of the-art tools. Moreover, it outperforms state-of-the-art tools in the accuracy of PPI relation extraction measured by F-score and recall on the widely-used open datasets. PPICurator is available at https://ppicurator.hupo.org.cn. This article is protected by copyright. All rights reserved. PMID- 30521144 TI - Chinese Expert Consensus Workshop Report: Guideline for permanent iodine-125 seed implantation of primary and metastatic lung tumors. AB - Surgery remains the first choice of cure for early stage lung cancer. However, many patients are diagnosed at advanced stage, and thus miss the opportunity to undergo surgery. As such patients derive limited benefits from chemotherapy or radiotherapy, alternatives focusing on local control have emerged, including iodine-125 seed implantation. The Interstitial Brachytherapy Society, Committee of Minimally Invasive Therapy in Oncology, Chinese Anti-Cancer Association organized a group of multidisciplinary experts to develop guidelines for this treatment modality. These guidelines aim to standardize iodine-125 seed implantation procedures, inclusion criteria, and outcome assessment to prevent and manage procedure-related complications. PMID- 30521145 TI - Efficient production of antifungal proteins in plants using a new transient expression vector derived from tobacco mosaic virus. AB - Fungi that infect plants, animals or humans pose a serious threat to human health and food security. Antifungal proteins (AFPs) secreted by filamentous fungi are promising biomolecules that could be used to develop new antifungal therapies in medicine and agriculture. They are small highly stable proteins with specific potent activity against fungal pathogens. However, their exploitation requires efficient, sustainable and safe production systems. Here, we report the development of an easy-to-use, open access viral vector based on Tobacco mosaic virus (TMV). This new system allows the fast and efficient assembly of the open reading frames of interest in small intermediate entry plasmids using the Gibson reaction. The manipulated TMV fragments are then transferred to the infectious clone by a second Gibson assembly reaction. Recombinant proteins are produced by agroinoculating plant leaves with the resulting infectious clones. Using this simple viral vector, we have efficiently produced two different AFPs in Nicotiana benthamiana leaves, namely the Aspergillus giganteus AFP and the Penicillium digitatum AfpB. We obtained high protein yields by targeting these bioactive small proteins to the apoplastic space of plant cells. However, when AFPs were targeted to intracellular compartments, we observed toxic effects in the host plants and undetectable levels of protein. We also demonstrate that this production system renders AFPs fully active against target pathogens, and that crude plant extracellular fluids containing the AfpB can protect tomato plants from Botrytis cinerea infection, thus supporting the idea that plants are suitable biofactories to bring these antifungal proteins to the market. PMID- 30521146 TI - Interconnection of sulfides and sulfoxides in medicinal chemistry. AB - Aromatic heterocycles with basic nitrogen atoms as well as carboxylic acid derivatives are the dominating chemical space in the universe of drug-like molecules. These established and exceedingly evaluated structural motifs have to be combined with elements of diversity in order to chart less well-explored galaxies of chemical space and to be able to tackle seemingly undruggable targets. Flat scaffolds should be replaced by shapely molecular cores. In this context, it has been unheeded that phenyl rings in diaryl sulfides are less co planar than in ethers and that the metabolic interconnection of sulfides and sulfoxides offers advantages that are unalike from the chemistry of amines and N oxides in the CHN-O world. Moreover, sigma-hole potentials increase with the polarizability of the atom N < P < O < S and do not only play a role in long-time overlooked halogen bonds. Examples for lambda2 , lambda4 , and lambda6 S-based functionalities related to improved solubility, reduced drug resistance, linkers in drug conjugates, drug-targeting to parasites, and as basis for drug monitoring in sports are given and discussed. PMID- 30521147 TI - Appearance of di- and Tripeptides in Human Plasma after a Protein Meal does not Correlate with PEPT1 Substrate Selectivity. AB - SCOPE: PEPT1 function is well understood, yet little is known about its contribution towards the absorption of dietary amino acids in the form of di- and tripeptides. In the present human study, we investigated changes in plasma concentrations of a representative oligopeptide panel after meat intake. METHODS AND RESULTS: Based on an LC-MS/MS method for quantitative analysis of a panel of selected di- and tripeptides in biological samples, we describe the kinetics of plasma changes of peptides derived from a widely accessible dietary protein source. Our findings demonstrate postprandial changes of a whole spectrum of dipeptides of different size, charge, and polarity in peripheral blood in a dose dependent manner after consumption of chicken breast in healthy human volunteers. Although the substrate specificity of PEPT1 is well known, the spectrum of peptides appearing in blood cannot be matched to the affinity to PEPT1. Stability against hydrolysis by exo- and endopeptidases appears to be another factor influencing their presence in blood. In addition, our study shows that dipeptides, including gamma-glutamyl-peptides, as well as tripeptides are common components present in human plasma. CONCLUSION: Besides amino acids, human peripheral blood contains numerous di- and tripeptides. The dietary source determines their abundance and composition. This article is protected by copyright. All rights reserved. PMID- 30521148 TI - Fresh/frozen Tubingen technique (Margin strip method) for head and neck basal cell carcinoma: A retrospective study of 298 cases. PMID- 30521149 TI - Breast implant-associated anaplastic large cell lymphoma: Clinical and imaging findings at a large US cancer center. AB - PURPOSE: Evaluate the clinical presentation and imaging findings of breast implant-associated anaplastic large cell lymphoma (BIA ALCL) at a large US cancer center. MATERIALS AND METHODS: HIPAA-compliant IRB approved retrospective study, for which informed consent was waived. The Hospital Information System was screened for women who underwent implant reconstruction and were diagnosed with BIA ALCL between 2010 and 2016. Two radiologists reviewed images in consensus. Clinical and imaging characteristics were summarized using means and ranges for continuous variables and percentages for categorical variables. RESULTS: Patient cohort included 11 women with BIA ALCL (mean age at diagnosis = 54 years, range: 35-77), including women with (9/11) and without (2/11) history of breast cancer. Mean time from breast implant placement to diagnosis was 10 years (range: 6-14). BIA ALCL was identified in patients with saline (4/11) and silicone (5/11) implants. Implants were textured in 7/11 (63%) and unknown in 4/11 (36%) cases. All patients presented with a peri-implant seroma, (9/11 documented on imaging). Two of 11 patients had a mass within this seroma. Ten of 11 patients (91%) presented with symptoms. CONCLUSIONS: Saline and silicone breast implants may predispose patients to a rare lymphoma subtype, BIA ALCL, which presents on imaging as a peri-implant fluid collection +/- mass. PMID- 30521150 TI - Tripyridine-Derivatives-Derived Semiconducting Iodo-argentate/cuprate Hybrids with Excellent Visible-light Induced Photocatalytic Performance. AB - Through regulating the pH values, a series of iodo-argentate/cuprate hybrids, [Me3(4-TPT)]4[Ag6I18] (1, Me3(4-TPT) = N,N',N''-trimethyl-2,4,6-tris(4-pyridyl) 1,3,5-triazine), [Me3(4-TPT)][M5I8] (M=Ag/2, Cu/2a), [Me3(3-TPT)][M5I8] (Me3(3 TPT) = N,N',N''-trimethyl-2,4,6-tris(3-pyridyl)-1,3,5-triazine, M=Ag/3, Cu/4), exhibit adjustable structural variations with different dimensional structures, have been obtained under solvothermal conditions. They are directed by two types of in situ N-alkylation TPT-derivatives (Me3(4-TPT) for 1/2/2a and Me3(3-TPT) for 3/4) and represent the isolated units (1), 1-D polymeric chain (4), 2-D layered structures (2/2a, 3) based on diverse metal iodide clusters. These compounds possess reducing band gaps comparing with the bulk beta-AgI and CuI and belong to potential semiconductor materials. Iodocuprates feature highly efficient photocatalytic activity in sunlight-induced degradation of organic dyes. The detailed study on the possible photocatalytic mechanism, including the radical trapping tests and theoretical calculations, reveals that the N-alkylation TPT moieties contribute to the narrow semiconducting behavior and effectively inhibit the recombination of photogenerated electron-hole pairs, which result in an excellent visible-light induced photocatalytic performance. PMID- 30521151 TI - Structural basis for neutralization of cytotoxic abrin by monoclonal antibody D6F10. AB - Abrin, an extremely cytotoxic Type-II ribosome inactivating protein (RIP), is a potential bio-warfare agent. Abrin A-chain (ABA) depurinates an adenosine of sarcin-ricin loop (SRL) from eukaryotic 28S rRNA thereby arresting protein synthesis and leading to cell death. Monoclonal antibody (mAb) D6F10 is the only known antibody that neutralizes ABA's activity in cell-free systems as well as abrin's toxicity in vitro and in vivo. However, how binding of mAb D6F10 to abrin interferes with abrin's catalytic activity at ribosome is still poorly understood. To provide structural basis for mAb D6F10-mediated rescue of ribosome inactivation by abrin, we determined crystal structures of ABA with and without substrate analogs. The structures of ABA-substrate analogs and ribosome were used in an experiment-guided computational protocol, to construct the ABA-Ribosome complex. A homology model of the variable region (Fv ) of mAb D6F10 was generated and docked with the apo-ABA structure to construct the ABA-D6F10 Fv complex. Structural superposition of ABA common to ABA-D6F10 Fv and ABA-Ribosome complexes reveals steric hindrance as the primary mechanism by which mAb D6F10 neutralizes abrin. In contrast to ABA alone, ABA bound to mAb D6F10 is unable to access the SRL on the ribosome owing to steric clashes of mAb D6F10 with the ribosome. Crystal structures of ABA also reveal a catalytic water molecule implicated in hydrolyzing N-glycosidic bond of the susceptible adenosine by RIPs. Furthermore, our strategy can be used to provide structural details of steric hindrance important for neutralization of ricin, another RIP, by mAb 6C2 and hence is of wide applicability. This article is protected by copyright. All rights reserved. PMID- 30521152 TI - Prophylaxis of osteonecrosis in the case of patients treated with bisphosphonates: A review paper. AB - Bisphosphonates are a group of medicines used in the treatment of oncological osteoporosis, Paget disease and osteogenesis imperfecta. They significantly interfere with the regeneration processes of bone tissue and have a tendency to accumulate in the areas of increased bone remodeling, i.e., the maxilla and the mandible. One of their most serious and problematic side effects is the induction of bisphosphonaterelated osteonecrosis of the jaw (BRONJ), characterized by an exposed, necrotic bone in the maxillofacial area, which lasts longer than 8 weeks, in the case of a patient who is using or was using bisphosphonates and who did not undergo radiotherapy in this anatomical area. Dentistry manipulations are one of the factors which may increase the risk of BRONJ occurrence. The existing recommendations for preventing osteonecrosis are ambiguous. Some authors recommend that the bisphosphonate therapy be discontinued prior to dental procedures, while others say that there is no evidence for the effectiveness of interrupting the therapy. There is also no unequivocal attitude toward antibiotic prophylaxis. According to this research, each case should be considered individually, primarily having regard to the good of a patient. PMID- 30521153 TI - The orthogeriatric units in Mexico are a priority AB - Hip fracture is a public health problem, 85% of cases occur in people older than 65 years of age. The Orthogeriatric Unit is a multidisciplinary model that helps to reduce the average hospital stay, mortality and postoperative complications; it allows the recovery of previous functionality, decreases the dependence degree and associated costs. PMID- 30521154 TI - Extracorporeal membrane oxygenation as a bridge for heart transplantation by Chagas cardiomyopathy AB - Background: Extracorporeal membrane oxygenation is a technique indicated in cases of severe respiratory failure or in situations where pump failure or heart failure is refractory to conventional medical treatment. Our goal was to describe the results of a patient with chronic Chagas dilated cardiomyopathy treated with extracorporeal membrane oxygenation as bridging therapy for heart transplantation. Case report: A 62-year old male with a history of Chagas disease and severe ventricular failure who underwent veno-arterial extracorporeal membrane oxygenation as bridging therapy for heart transplantation, with good clinical evolution. Conclusion: Extracorporeal membrane oxygenation is a temporary, viable, safe and effective alternative for patients with severe heart failure refractory to treatment who will undergo transplantation. PMID- 30521155 TI - An update and systematic review on the treatment of primary dysmenorrhea. AB - OBJECTIVES: Primary dysmenorrhea is a painful uterine contraction caused by endometrial laceration. Drug therapies and complementary medicine have been used to treat dysmenorrhea. The aim of this study was to investigate and offer an updated perspective on the treatments for dysmenorrhea. METHODS: The present study was conducted in accordance with the PRISMA checklist for systematic reviews and meta-analyses. The required information was collected based on searches for the following keywords: treatment, primary dysmenorrhea, medicinal plants, chemical drugs, and herbs. Searches were performed on databases Pubmed, Web of Sciences, Scopus, Iran medex, and SID by March 2018 to find literature in the English and Persian languages on this subject without a time limit. RESULTS: This review included 17 papers, 10 of which on complementary medicine, three on drug therapies, and four on acupuncture and acupressure. The largest and smallest samples had 303 and 24 patients, respectively. Length of treatment ranged from one to six months and the measures most commonly used in the studies were the visual analogue scale and clinical efficacy. Reported complications included gastrointestinal events, nausea, vomiting, diarrhea, abdominal pain, and liver and kidney disorders. CONCLUSION: Medicinal plants, drugs, and acupressure seem to suppress pain by reducing the level of prostaglandins, mediating nitric oxide, increasing beta-endorphin levels, blocking the calcium channel, and enhancing circulatory flow through the uterine pathway. Further trials are required to confirm the benefits of the procedures described and ensure the absence of complications. PMID- 30521156 TI - In memory of Dr. Arturo Zarate Trevino, pioneer in the study of gynecological endocrinology in Mexico AB - No abstract PMID- 30521157 TI - Breast cancer in males, case presentation and literature review AB - Background: Male breast cancer is a rare entity, with an approximate rate of 1.1 / 100 000 in the US, with an average age of 67 years. In all cases a genetic study must be performed, in order to find mutations in known genes, and after the resolution of the disease, based on the results, a contralateral prophylactic mastectomy should be considered. Clinical case: 53 -year-old male diagnosed with right breast cancer, infiltrating ductal adenocarcinoma type, clinical stage IIB, breast cancer on 2 immediate family history, mutations of the BRCA1 gene and positive hormone receptors and Her2/Neu. He was treated with modified radical mastectomy in diseased side with subsequent neoadjuvant chemotherapy/radiotherapy. After a year of follow-up and a free behavior of disease, contralateral prophylactic mastectomy was performed. The patient progressed satisfactorily, following up to 18 months since the beginning, with no tumor activity data. Conclusions: Breast cancer in male patient has a worse prognosis than female patients, due to lower amount of tissue in breast exposed to an earlier chest spread and a different biological behavior, also a higher risk of prostate and pancreatic cancer is associated. Studies of adequate methodological quality are scarce, so that decisions are based on guidelines for breast cancer in women. PMID- 30521158 TI - Bladder hematoma: a complication from an oocyte retrieval procedure. AB - INTRODUCTION: More than one million fertilization cycles are performed every year. The incidence of serious complications associated with transvaginal oocyte pick-up is low, but the procedure is not risk-free. Risks are inherent to procedures in which thin needles and sharp instruments are introduced into the vaginal wall and ovarian capsule to access the ovaries. CASE DESCRIPTION: A 45 year-old patient reported urinary discomfort and difficulty urinating after her second cycle, 12 hours after oocyte pick-up. She had visible hematuria with small blood clots. Transvaginal ultrasound examination performed 24 hours after pick-up showed a heterogeneous intravesical image suggestive of a clot; her bladder measured 23x19mm. She was afebrile and in good condition. The patient was managed conservatively and offered fluids. The clot was expelled within a matter of hours. This case of a bladder hematoma was the first in the 21 years of a clinic where all procedures are guided by ultrasonography with clear visualization of the tip of the needle throughout the 15-20 minutes of the procedure. Patients submitted to ultrasound-guided transvaginal oocyte pick-up procedures in IVF protocols must be informed of this rare potential complication. PMID- 30521159 TI - Comment on article "Professionalism in physicians in a second-level hospital" AB - The definition and measurement of complex variables, such as medical professionalism, demand the revision of concepts and adherence to a methodology that allows the foundation of results, based on which some observations and suggestions are pointed out in this letter. PMID- 30521160 TI - Pulmonary embolectomy in a case of subacute pulmonary embolism, with previous unsuccessful fibrinolysis AB - Background: Pulmonary embolism is a potentially fatal heart condition that requires prompt restoration of blood flow in the pulmonary vascular bed and prevention of recurrent events. Mortality is associated to the degree of hemodynamic repercussion, complications and opportunity in the treatment. Case report: Male 33 years of age who began with sudden dyspnea, chest pain of moderate intensity, sweating and syncope. His admission vitals signs: blood pressure 100/70 mm Hg, heart rate 125 beats per minute, respiratory rate 24; peripheral saturation 85 %. Physical examination: grade I jugular engorgement at 45 degrees, rhythmic heart sounds, with auscultation of systolic murmur I/IV in tricuspid focus and second reinforced heart sound. Rest of exploration without relevant data. The echocardiogram showed data of right ventricular failure and systolic pulmonary artery pressure of 60 mm Hg; the angiotomography showed thrombosis of both branches of the pulmonary artery. The patient received fibrinolytic therapy with tecneteplase 50 mg single bolus and antithrombotic therapy. Due to persistence of residual thrombus, the patient underwent surgical bilateral embolectomy. Conclusion: Surgical pulmonary embolectomy rescue is an alternative management with highly satisfactory results. PMID- 30521161 TI - Small cell bladder cancer: should we consider prophylactic cranial irradiation? AB - PURPOSE: To describe the clinical characteristics, treatment patterns, and outcomes in patients with small cell bladder cancer at our institution, including those who received prophylactic cranial irradiation (PCI) for the prevention of intracranial recurrence. MATERIALS AND METHODS: Patients with small cell bladder cancer treated at a single institution between January 1990 and August 2015 were identified and analyzed retrospectively for demographics, tumor stage, treatment, and overall survival. RESULTS: Of 44 patients diagnosed with small cell bladder cancer, 11 (25%) had metastatic disease at the time of presentation. Treatment included systemic chemotherapy (70%), radical surgery (59%), and local radiation (39%). Six patients (14%) received PCI. Median overall survival was 10 months (IQR 4 - 41). Patients with extensive disease had worse overall survival than those with organ confined disease (8 months vs. 36 months, respectively, p = 0.04). Among those who received PCI, 33% achieved 5 - year survival. CONCLUSION: Outcomes for patients with small cell bladder cancer remain poor. Further research is indicated to determine if PCI increases overall survival in small call bladder cancer patients, especially those with extensive disease who respond to chemotherapy. PMID- 30521162 TI - Laparoscopic approach for intravesical surgery using pneumovesicum in the management of anterior colporrhaphy mesh erosion and stones around the bladder neck. AB - INTRODUCTION AND OBJECTIVE: Perforation of the bladder or urethra and erosion of the mesh after cystocele repair surgery are not uncommon and have potentially serious complications. Traditionally, surgical management of such complications has involved excision of the mesh using either a transurethral approach or open surgery. In this video, we present our experience of laparoscopic transvesical surgery for exposed mesh and stone. MATERIALS AND METHODS: Patient was placed in the lithotomy position under general anesthesia and a 30 degrees operating cystoscope was inserted under direct vision. After filling the bladder with 300 mL normal saline, a 5 - mm VersaStepTM bladeless trocar was placed 2 cm above the pubic symphysis. Two more 5 mm trocars were placed bilaterally at 3 cm intervals from the initial trocar site. The pneumovesicum state was maintained at 8 - 12 mmHg and a 5 mm telescope was introduced. Using a curved dissector and curved Mayo scissors, the exposed mesh was mobilized and removed. Interrupted 4 - 0 Vicryl sutures were used to close the defect. To localize the ureteral orifice, intravenous Indigo Carmine was used. The bladder stones were removed through the urethra using a stone basket, guided using a ureteral stent pusher. RESULTS: Total operation time was 55 min and the Foley catheter was removed at post - operative day 5 after postoperative cystography. CONCLUSIONS: Excellent visualization of mesh exposure and ureteral orifice was possible under aparoscopic transvesical surgery, and reconstruction including the mucosa and muscle layer was able to be achieved. This method is useful and feasible, with minimal invasiveness and an early post - operative recovery. PMID- 30521163 TI - The iranian model as a potential solution for the current kidney shortage crisis. PMID- 30521164 TI - Does the experience of the bedside assistant effect the results of robotic surgeons in the learning curve of robot assisted radical prostatectomy? AB - INTRODUCTION: The success of the robot assisted radical prostatectomy (RARP) procedures depend on a successful team, however the literature focuses on the performance of a console surgeon. The aim of this study was to evaluate surgical outcomes of the surgeons during the learning curve in relation to the bedside assistant's experience level during RARP. MATERIALS AND METHODS: We retrospectively reviewed two non - laparoscopic, beginner robotic surgeon's cases, and we divided the patients into two groups. The first surgeon completed the operations on 20 patients with a beginner bedside assistant in February - May 2009 (Group-1). The second surgeon completed operations on 16 patients with an experienced (at least 150 cases) bedside assistant in February 2015 - December 2015 (Group-2). The collected data included age, prostate volume, prostate specific antigen (PSA), estimated blood loss, complications and percent of positive surgical margins. In addition, the elapsed time for trocar insertion, robot docking, console surgery, specimen extraction and total anesthesia time were measured separately. RESULTS: There were no significant differences between the groups in terms of age, co-morbidity, prostate volume, PSA value, preoperative Gleason score, number of positive cores, postoperative Gleason score, pathological grade, protection rate of neurovascular bundles, surgical margin positivity, postoperative complications, length of hospital stay, or estimated blood loss. The robot docking, trocar placement, console surgery, anesthesia and specimen extraction times were significantly shorter in group 2 than they were in group 1 (17.75 +/- 3.53 min vs. 30.20 +/- 7.54 min, p <= 0.001; 9.63 +/- 2.71 min vs. 14.40 +/- 4.52 min , p = 0.001; 189.06 +/- 27.70 min vs. 244.95 +/- 80.58 min, p = 0.01; 230.94 +/- 30.83 min vs. 306.75 +/- 87.96 min, p = 0.002; 10.19 +/- 2.54 min vs. 17.55 +/- 8.79 min, p = 0.002; respectively). CONCLUSION: Although the bedside assistant's experience in RARP does not appear to influence the robotic surgeon's oncological outcomes during the learning curve, it may reduce the potential complications by shortening the total operation time. PMID- 30521165 TI - Re: Incidence and treatment of malignant tumors of the genitourinary tract in renal transplant recipients. PMID- 30521166 TI - The effect of urethroplasty surgery on erectile and orgasmic functions: a prospective study. AB - OBJECTIVES: to examine the effects of urethroplasty surgery on sexual functions by taking into account age, location of stenosis, length of stenosis and surgical technique parameters. MATERIALS AND METHODS: The prospective study was conducted between January 2015 and August 2017 with 60 cases. Patients were categorized according to age groups (19-65 / 65-75 years), surgery technique and stricture localization and length. Before the urethroplasty operation and postoperative 6th month follow-up, the international index of erectile function (IIEF) form (15 questions), was filled, the relevant domains of sexual function; erectile function (Q1,2,3,4,5,15), orgasmic function (Q9,10) and overall satisfaction (Q13,14) were assessed. RESULTS: The mean age of the cases is 54 +/- 13. However, preoperative IIEF, sexual satisfaction and orgasmic function averages of patients with a stenosis segment length of 1-3 cm was found to be significantly higher than that of patients with a stenosis segment length of 4-7 cm. Between stenosis segment length groups, there was no statistical difference in terms of preoperative and postoperative sexual functions. And also, there was no statistically significant change in patients' preoperative and postoperative sexual function scores in terms of localization of stricture and surgery techniques. However, there were statistically significant change in the postoperative IIEF and sexual satisfaction averages according to preoperative averages. CONCLUSION: Our study suggests that urethroplasty surgery itself does not significantly affect erectile function, orgasmic function, and general sexual satisfaction regardless of the type of surgery, localization and length of stenosis. Besides, there was a significant decrease in erectile function in senior adults. PMID- 30521167 TI - Dramatic polarization in genitourinary expert opinions regarding the clinical utility of positron emission tomography (PET) imaging in prostate cancer. AB - OBJECTIVES: To ascertain the opinions of North American genitourinary (GU) experts regarding inclusion of technologies such as prostate - specific membrane antigen (PSMA) and C - 11 choline positron emission tomography (PET) into routine practice. MATERIALS AND METHODS: A survey was distributed to North American GU experts. Questions pertained to the role of PSMA and C - 11 PET in PCa management. Participants were categorized as "supporters" or "opponents" of incorporation of novel imaging techniques. Opinions were correlated with practice patterns. RESULTS: Response rate was 54% and we analyzed 42 radiation oncologist respondents. 17 participants (40%) have been in practice for > 20 years and 38 (90%) practice at an academic center. 24 (57%) were supporters of PSMA and 29 (69%) were supporters of C - 11. Supporters were more likely to treat pelvic nodes (88% vs. 56%, p < 01) and trended to be more likely to treat patients with moderate or extreme hypofractionation (58% vs. 28%, p = 065). Supporters trended to be more likely to offer brachytherapy boost (55% vs. 23%, p = 09), favor initial observation and early salvage over adjuvant radiation (77% vs. 55%, p = 09), and to consider themselves expert brachytherapists (69% vs. 39%, p = 09). CONCLUSIONS: There is a polarization among GU radiation oncology experts regarding novel imaging techniques. A correlation emerged between support of novel imaging and adoption of treatment approaches that are clinically superior or less expensive. Pre - existing biases among GU experts on national treatment - decision panels and leaders of cooperative group studies may affect the design of future studies and influence the adoption of these technologies in clinical practice. PMID- 30521168 TI - Comparative study of percutaneous nephrolithotomy performed in the traditional prone position and in three different supine positions. AB - PURPOSE: To compare the outcomes of percutaneous nephrolithotomy (PCNL) performed in the prone position (PRON) and in three variations of the supine position. MATERIALS AND METHODS: We performed a retrospective analysis of patients that underwent PCNL at our institution from June 2011 to October 2016 in PRON and in three variations of the supine position: complete supine (COMPSUP), original Valdivia (VALD), and Galdakao - modified Valdivia (GALD). All patients had a complete pre - operative evaluation, including computed tomography (CT). Success was defined as the absence of residual fragments larger than 4 mm on the first post - operative day CT. RESULTS: We analyzed 393 PCNLs: 100 in COMPSUP, 94 in VALD, 100 in GALD, and 99 in PRON. The overall success rate was 50.9% and was similar among groups (p = 0.428). There were no differences between groups in the number of punctures, stone - free rate, frequency of blood transfusions, drop in hemoglobin level, length of hospital stay, and severe complications (Clavien >= 3). COMPSUP had a significantly lower operative time than the other positions. COMPSUP had lower fluoroscopy time than VALD. CONCLUSION: Patient positioning in PCNL does not seem to impact the rates of success or severe complications. However, COMPSUP is associated with a shorter surgical time than the other positions. PMID- 30521169 TI - Robotic surgery in the management of complex pelvic endometriosis. AB - INTRODUCTION: Endometriosis consists in the proliferation of endometrial tissue outside of the uterine cavity, predominantly in the ovaries but also in the urinary bladder or bowel. About 10% of fertile women are affected and the main symptoms are pain, menstrual disorders and infertility. Surgery is the treatment option for those symptomatic patients in which medical treatment had no success. MATERIAL AND METHODS: We report on a case of a 43 - years - old patient without urologic personal history submitted to our office because of a grade - III right hydronephrosis. The patient, with an endometriosis diagnosis since years, presents chronic pelvic pain with the daily necessity of strong opioids intake. CT scan revealed several endometriosis implants in the uterine wall and rectum that caused right ureteral entrapment. Renography revealed a 24% function in the right kidney. After right nephrostomy a multidisciplinary committee decided surgical intervention. With robotic approach, we performed an hysterectomy with right salpingo - oophorectomy; release, resection and right ureteral reimplantation; anterior resection of the rectum and protective ileostomy. Vaginal extraction of the specimen. In this video we show the key steps of the procedure. RESULTS: Total operative time: 330 minutes. Total bleeding: 250 cc. Nephrostomy removal: 4 th day. Urethral catheter removal: 5 th day. Patient was discharged in the 7 th day. Ureteral JJ - stent removal: 30 th day. CT urography reveals a permeable ureteral tract with no urine leakage. Renography shows a progressive improvement of the kidney function. CONCLUSIONS: Robotic surgery allows a correct handling of endometriosis, mainly in complex cases. It is a safe and reproducible technique with correct outcomes in selected patients. A multidisciplinary team is required. PMID- 30521170 TI - Micro-ureteroscopy for treatment of pelvic ureteral stone in pediatric patient. AB - INTRODUCTION: During the last years there has been an effort in miniaturizing the endoscopic devices. The video presents an alternative for the management of distal ureteral stone, using a ureteral access of 4.85 Fr and 27 cm of length, previously described as micro-ureteroscopy. MATERIAL AND METHODS: This procedure was performed through a 3-part all-seeing needle, consisting of micro-optics 0.9 mm in diameter with a 120-degree angle of view, an irrigation channel and an integrated light. CLINICAL CASE: Seven year-old boy, with history of preterm birth (29 weeks) was referred to our consultation complaining of left back pain and an elevation of serum creatinine. The renal ultrasound revealed a left ureterohydronephrosis, caused by a 10 mm stone located 13 mm from the ureterovesical junction. The patient underwent a micro-ureteroscopy with laser lithotripsy. The stone was fragmented with an average energy of 0.5 J with 12 Hz of frequency. The total energy spent was 12514 J. At the end of the procedure, a double J stent was placed. The procedure lasted 45 minutes and was uneventful. The patient was discharged 24h after the procedure without complaints and remained stone free. CONCLUSION: Micro-ureteroscopy is a safe and effective technique in distal ureteral lithiasis treatment in children. The small dimensions of the equipment increase the safety of the procedure making this a good option for the treatment of ureteral stones in children. PMID- 30521171 TI - A rare case of prostato - symphyseal fistula after GreenLight photovaporization of the prostate. PMID- 30521172 TI - The importance of histopathologic review of biopsies in patients with prostate cancer referred to a tertiary uro-oncology center. AB - INTRODUCTION: In view of the detailed histologic evaluation of prostate cancer (PC), it is usually advisable to provide a "second opinion" to confirm diagnosis. This study aimed to compare the Gleason score (GS) of initial diagnosis versus that of histopathologic review of patients with PC. The secondary objective was to compare initial GS versus histopathologic review versus post - surgical histopathology. MATERIAL AND METHODS: Retrospective study based on chart review of patients with PC that attended the Uro - oncology Department of Hospital das Clinicas - UNICAMP - Campinas, Brazil, from April, 2002, to April, 2012. Data were divided in groups: patients with biopsies performed elsewhere, biopsies after pathological review and histopathological results following retropubic radical prostatectomy (RRP). These were evaluated in relation to GS difference using Fleis's Kappa concordance coefficient. RESULTS: 402 PC patients, with a median age of 66 years, were evaluated. Reviewed GS showed worsening, with accuracy of 61.2%, and Kappa concordance value = 0.466. Among 143 patients submitted to surgery, GS varied widely, regarding initial evaluation, review and post - surgical RRP. Joint concordance of evaluations was weak (Kappa = 0.216), mainly due to almost no existence concordance between initial evaluation and following RRP (Kappa = 0.041). CONCLUSION: There is a great histopathological variation of initial GS versus reviewed GS. There is also a better correlation of reviewed GS and post - surgical GS than with initial GS. The second opinion by an uropathologist improves diagnosis and should be advised for better therapeutic decision. PMID- 30521173 TI - Prognosis of patients with prostate cancer and middle range prostate - specific antigen levels of 20 - 100 ng / mL. AB - INTRODUCTION: Prostate - specific antigen (PSA) is a useful biomarker for detection of prostate cancer (PCa) and for risk classification in addition to TNM classification and Gleason score (GS). We reported the role of PSA in patients with low (< 20 ng / mL) and extremely high (>= 100 ng / mL) PSA levels. However, it is unclear whether a correlation exists between middle range PSA levels (20 - 100 ng / mL) at diagnosis and prognosis. MATERIALS AND METHODS: Between January 2000 and December 2014, 1873 patients underwent prostate biopsy at Kanazawa University Hospital. Of 802 patients who were diagnosed with PCa, 148 patients with middle range PSA levels (20 - 100 ng / mL) were retrospectively analyzed. RESULTS: The percentage of patients with T3 - 4 consistently increased as PSA levels increased from 20 to 100 ng / mL. Although the percentage of patients with GS >= 8 or metastases increased as PSA levels increased up to approximately 70 ng / mL, there was no significant increase between 70 and 100 ng / mL. PCa - specific and castration - resistant PCa - free survivals were adversely associated with PSA levels up to 70 ng / mL, but not between 70 and 100 ng / mL. CONCLUSION: PSA is a useful biomarker for predicting prognosis at levels between 20 and 70 ng / mL. However, PSA cannot be used as a prognostic factor in patients with PCa and PSA levels >= 70 ng / mL. When the PSA level reaches approximately 70 ng / mL, prognosis might bottom and reach a plateau. PMID- 30521174 TI - Predictors of surgical complications of nephrectomy for urolithiasis. AB - OBJECTIVES: Nephrectomy due to stone disease may be a challenging procedure owing to the presence of significant inflammation and infection, involving high complication rate. The objective of our study was to identify predictors for complications of nephrectomy for urolithiasis. PATIENTS AND METHODS: A retrospective review of 149 consecutive patients > 18y submitted to simple nephrectomy for urolithiasis from January 2006 to July 2012 was performed. Clinical data, computed tomography findings and pathology report were analyzed. Postoperative complications were categorized based on Clavien - Dindo classification. Logistic multivariate regression models assessed the predictors for surgical complications of nephrectomy for urolithiasis. RESULTS: Eighty-three (55.7%) patients were submitted to laparoscopic nephrectomy and 66 (44.2%) to open procedure. Conversion to open surgery was necessary in 19.2% (16 / 83). On univariable analysis, higher preoperative chronic kidney stage (p = 0.02), Charlson comorbidity index >= 2 (p = 0.04), higher ASA score (p = 0.001), urgency due to sepsis (p = 0.01), kidney size >= 12 cm (p = 0.006), renal and perirenal abscess (p = 0.004 and 0.002 respectively) and visceral adhesion (p = 0.04) were associated with Clavien - Dindo score > 1. On multivariate analysis, higher ASA score (p = 0.01), urgency due to sepsis (p = 0.03), kidney size >= 12 cm (p = 0.04) and preoperative abscess (p = 0.04) remained significantly associated with complications. End - stage renal disease with dialysis was needed post - operatively in 3.4% (5 / 144) of patients. CONCLUSIONS: We identified that higher ASA score, urgency due to sepsis, kidney size >= 12 cm and preoperative abscess were associated with Clavien - Dindo score > 1. PMID- 30521175 TI - Implant of ATOMS(r) system for the treatment of postoperative male stress urinary incontinence: results of a single centre. AB - PURPOSE: The aim of our study is to evaluate the efficacy and safety of ATOMS(r) system for the treatment of postoperative male stress urinary incontinence (SUI). MATERIALS AND METHODS: We retrospectively evaluated all patients treated at our institution for postoperative male SUI with ATOMS(r) implant. We excluded patients with low bladder compliance (< 20 mL / cmH2O), uncontrolled detrusor overactivity, detrusor underactivity (BCI < 100), urethral or bladder neck stricture and low cystometric capacity (< 200 mL). RESULTS: From October 2014 to July 2017 we treated 52 patients, mean age 73.6 years. Most of them (92.3%) had undergone radical prostatectomy, 3.85% simple open prostatectomy, 3.85% TURP; 28.8% of patients had undergone urethral surgery, 11.5% adjuvant radiotherapy; 57.7% had already undergone surgical treatment for urinary incontinence. The average24 hours pad test was 411.6 g (180 - 1100). The mean follow-up was 20.1 months (8.1 - 41.5) 30.8% of patients were dry, 59.6% improved >= 50%, 7.7% improved < 50% and 1.9% unchanged. In total 73.1% reached social continence. There was a significant reduction of the 24 hours pad test and ICIQ - UI SF scores (p < 0.01). In the postoperative follow-up we detected complications in 8 patients (19%): 5 cases of displacement of the scrotal port, in 2 cases catheterization difficulties, one case of epididimitis and concomitant superficial wound infection; no prosthesis infection, nor explants. Radiotherapy, previous urethral surgery,previous incontinence surgery were not statistically related to social continence rates (p 0.65;p 0.11;p 0.11). CONCLUSIONS: The ATOMS(r) system is an effective and safe surgical treatment of mild and moderate male postoperative SUI with durable results in the short term. PMID- 30521176 TI - Immunohistochemical expressionof sodium-dependent glucose transporter - 2 (SGLT 2) in clear cell renal carcinoma: possible prognostic implications. AB - PURPOSE: Glucose is a major energy resource for tumor cell survival and growth, and its influx into cells is mainly carried out by facilitative glucose transporters (GLUTs). Sodium - dependent glucose transporters (SGLTs) have been highlighted as playing important roles in diabetic treatment. However, their potential roles in cancer remain unclear. We examined expression patterns of SGLTs in tumor tissues together with conventional pathological variables to determine prognostic significance in patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: Nephrectomy specimens were obtained from 68 patients. GLUT - 1, - 2 and SGLT - 1, - 2 expression in tumor and adjacent normal tissues were analyzed by immunohistochemical staining, and intensity was quantified using an image analyzer. RESULTS: The four glucose transporters evaluated were broadly distributed in tumor tissues as well as throughout the normal parenchyma. There was no significant correlation between transporter expression and conventional pathological variables. However, increased SGLT - 2 expression was significantly associated with shorter overall survival (p < 0.01), regardless of metastatic status. CONCLUSIONS: We propose possible prognostic significance of SGLT - 2 expression in human RCC. Given that glucose is a major energy resource for tumor cells and that glucose transport is largely mediated by SGLT, SGLT - 2 may serve as a possible therapeutic target in RCC. PMID- 30521177 TI - Answer to Comment on article "Professionalism in physicians in a second-level hospital" AB - In relation to the letter to the editor on the article "Professionalism in physicians in a second-level hospital" this reply is issued. PMID- 30521178 TI - Abdominal tuberculosis in renal transplant recipient. Presentation of a case and literature review AB - Background: Kidney transplantation presents a susceptible point, and is related to infections; tuberculosis is a common and endemic etiology in a country like Mexico, where the most frequent presentation is the respiratory condition, the extrapulmonary is extremely rare and it is derived from immunosuppression conditions. Case report: 33-year-old man with kidney disease of undetermined etiology, kidney transplant in 2003 (donor mother) with adequate evolution; presented with chronic graft nephropathy, with baseline creatinine of 1.8 mg / dL, immunosuppression with prednisone 10 mg every 24 hours, mycophenolate mofetil 500 mg every 8 hours and ciclosporin 100 mg every 12 hours; surgical intervention was performed due to acute abdomen, appendectomy and omentectomy with histopathological finding of tuberculosis, Dotbal, antiproliferative in suspension was started and decrease of calcineurin inhibitor. Adequate kidney function was recovered and maintained as well as control of the infectious disease during the maintenance period. Conclusions: The management of immunosuppression is vital to find the right dose to avoid rejection and allow an immune response to infection, together with antimicrobial treatment. PMID- 30521179 TI - Variability of arterial and peripheral venous blood gases parameters in subjects with stable obstructive pulmonary disease AB - Background: Peripheral venous blood gases may be useful in subjects with exacerbation of chronic obstructive pulmonary disease to evaluate their gas exchange. Objective: To describe the variability of parameters of arterial and peripheral venous blood gases in subjects with stable obstructive pulmonary disease. Methods: Cross-sectional design, consecutive subjects were studied in a blinded manner, while arterial and peripheral venous blood was obtained for analysis. Variability was established with Bland-Altman statistical method and its magnitude with the intraclass correlation coefficient (95 % confidence interval). Results: Three hundred blood samples from 150 patients were studied, 89 (59.3%) women, age 66 +/- 10 years old, body mass index 28.44 +/- 4.81 Kg/m2. Mean difference (bias) [intraclass correlation coeficient] pH 0.012 (-0.009, 0.032) [0.927], Carbon dioxide pressure -6.5 (-14.1, 1.1) [ 0.643], serum bicarbonate -1.3 (-3.3, 0.7) [0.929], base excess -1 (-4, 2.1) [0.904], hemoglobin -0.1 (-1.9, 1.8) [0.947]. Conclusions: The variability of pH, serum bicarbonate, and hemoglobin are similar in both blood samples. These arterial or peripheral venous blood gas parameters could be used interchangeably. PMID- 30521301 TI - Comorbidities and antimicrobial resistance in urological outpatients with positive urine culture AB - Background: The urinary tract infections are the third cause of infections in Mexico. The inappropriate use of antibiotic has generated the presence of multidrugresistant bacteria. Objective: To identify the bacterial resistance patterns of the hospital and to detect the present comorbidities that can modify the evolution of urinary tract infection for proper empirical management. Methods: Non-comparative cross-sectional study, positive urine cultures were reviewed in the period from December 2015 to May 2016, in outpatients of urology in the hospital. The obtained growth, bacterial resistance and the comorbidities of each patient were analyzed. Results: 190 urine cultures were included. The most frequent bacterium was Escherichia coli. Greater general antibiotic resistance was detected to ceftazidime (91.5%), quinolones (> 65%) and trimethoprim / sulfamethoxazole (58%). The general multiresistance was 66.3%. The antibiotics that showed greater sensitivity were: amikacin, imipenem, nitrofurantoin, meropenem and piperacillin / tazobactam. The most frequent comorbidities were diabetes mellitus, previous use of antibiotics for urinary tract infection and prostatic hyperplasia. Conclusion: In patients with urinary tract infection in the hospital, the empirical use of nitrofurantoin and amikacin is recommended. Quinolones and trimethoprim / sulfamethoxazole have a high resistance index. PMID- 30521302 TI - Updates in the correlation of electroneuromyographic findings in diabetic polyneuropathy AB - Background: The diabetic neuropathy is the most common microvascular complication of diabetes mellitus. The reported prevalence ranges from 10-90%. Electrophysiological alterations can be demonstrated in nearly 100% of diabetics. Objective: To know the current profile of the patient with diabetic polyneuropathy. Methods: Retrospective and descriptive study from 2015 to 2016. Reports of electroneuromyography with diabetic polyneuropathy result were analyzed, evaluating neuroconduction parameters of motor and sensory nerves, late F responses and myography. Descriptive statistics, Student's t-test and Pearson's correlation coefficient were used. Results: The sample included 72 men (65.5%) and 38 women (34.5%), mean age 61.2 years, mean duration of diabetes of 9.9 years. The most affected nerve was superficial peroneus, absent in 70% of the population.A positive correlation was found (p < 0.001) for the affection of all the nerves symmetrically and predominantly in neuroconduction velocities of the lower and upper limbs. Conclusion: The most frequent electrophysiological finding in diabetic polyneuropathy was sensory affection, being more severe in lower limbs. A finding in patients with recent diagnosis is the prolongation of proximal latencies in the lower extremities. PMID- 30521303 TI - Brachial and uterine arteries Doppler in healthy women and with preeclampsia AB - Objective: To compare the Doppler ultrasound parameters of the uterine and brachial arteries, between healthy pregnant women and pregnant women with preeclampsia. Methods: 102 pregnant women were studied in the third trimester, group I 83 healthy women and group II 19 patients with severe preeclampsia. All of them underwent Doppler ultrasound of the uterine arteries, measuring the pulsatility index (PI) and determining the presence of proto-diastolic notch. The PI and the arterial diameter were measured in the brachial artery before and after the hyperemic stimulus. Comparisons between the groups were performed with Student's t-test for independent samples and Mann-Whitney U and the comparison within each group with Student's t-test for related samples. Results: Gestational age was 35 +/- 3 and 35 +/- 2 weeks for group I and II, respectively. The proto diastolic notch was present in 6 of 19 patients in group II (p < 0.001), the PI of uterine arteries was 0.68 +/- 0.1 and 0.93 +/- 0.3 for group I and II, respectively (p < 0.006). In the brachial artery, the arterial diameter after the hyperemic stimulus was significantly higher in women in group I (3.7 +/- 0.5 mm and 3.5 +/- 0.6 mm, p < 0.006). Conclusion: Preeclamptic women had higher PI of the uterine artery than the healthy ones; healthy women had greater arterial diameter after hyperemic stimulus than preeclamptic ones. PMID- 30521304 TI - Phosphorene as a Catalyst for Highly Efficient Nonaqueous Li-Air Batteries. AB - Li-Air batteries can yield exceptionally high predicted energy densities. However, for this technology to become realizable, round trip efficiency issues and slow kinetics at the cathode require implementation of a catalyst. With design parameters not well understood, and limitations on material selection, choosing an ideal catalyst is complex. In Li-Air batteries energy storage is achieved by reactions between Li and O (Oxygen Reduction Reaction for discharge, Oxygen Evolution Reaction for charge). Here, Phosphorene is proposed as a solution through simulations of its catalytic behaviour towards discharge initiated via either O2 dissociation or Li adsorption. After obtaining intermediate geometries for both nucleation paths leading to either Li2O2 or 2(Li2O), free-energy diagrams are generated to predict the promoted discharge product of Li2O2. Furthermore, considering a final product of Li2O2, the overpotentials are predicted to be 1.44 V for discharge and 2.63 V for charge. Activation barriers for the catalytic decomposition of Li2O2 (during charge) are found to be 1.01 eV for Phosphorene versus 2.06 eV for Graphene. This leads to a major difference in reaction rate up to 1017 times in favour of Phosphorene. These results, complemented by electronic analysis, establish Phosphorene as a promising catalyst for Li-Air batteries. PMID- 30521305 TI - Abnormal Stranski-Krastanov Mode Growth of Green InGaN Quantum Dots: Morphology, Optical Properties, and Applications in Light-Emitting Devices. AB - Stranski-Krastanov (SK) growth mode is widely adopted for the self-assembled growth of semiconductor quantum dots (QDs), wherein a relatively large critical thickness is essential and a thick wetting layer (WL) is formed beneath the QD layer. In this paper, we report the metal organic vapor phase epitaxy (MOVPE) of green InGaN QDs, employing a growth interruption method to decrease the critical thickness and improve the morphology of QDs. The QDs exhibit similar photoluminescence properties with those grown by conventional SK mode, implying the existence of a WL. We experimentally verify that the formation of QDs, whether based on the SK mode or the growth interruption method, conforms to the phase separation theory. However, the density of QDs grown by the interruption method exhibits abnormal dependence on the strain when a quantum well (QW) is inserted beneath the QD layer. Furthermore, the underlying QW not only influences the morphology of the QDs but also plays as a reservoir of electrons, which helps enhance the photoluminescence and the electroluminescence of the QDs. The method of QD growth with improved morphology and luminescence by introducing the QW-QD coupled nanostructure is universally applicable to similar material systems. Furthermore, a 550-nm green light-emitting diode (LED) and a 526-nm superluminescent light-emitting diode (SLED) based on the nanostructure are demonstrated. PMID- 30521306 TI - High Energy Density Micro-Supercapacitor based on Three-Dimensional Bicontinuous Porous Carbon with Interconnected Hierarchical Pore. AB - On-chip micro-supercapacitors (MSCs) are attracting great attentions recently. However, the performance of MSC is usually unsatisfactory due to the unreasonable pore structure. The construction of three-dimensional (3D) interconnected porous carbon based MSC by controllable activation is proposed. The porous monolithic carbon microelectrode activated by ZnO nanowires provides electron/ion bicontinuous conduction path. The fabricated MSC with this microelectrode rendered a high areal specific capacitance of 10.01 mF cm-2, 6 times higher than that of pure pyrolyzed carbon based MSC, 1.6-5 times higher than that of the MSC with porous carbon activated by ZnO nanoparticles due to its cross-linking macropore-mesopore-micropore structure and considerable areal atomic ratio. The optimization mechanism of hierarchical channel pore for electrochemical performance of MSC is investigated in details. Four kinds of electrolytes, including H2SO4, redox additive KI/H2SO4, LiCl and LiTFSi, are employed for constructing MSCs. The voltage window of water in salt electrolyte assembled LiTFSi-MSC is expanded to 2.5 V. The energy density of LiTFSi-MSC is 6 times higher than that of H2SO4-MSC, which can drive LEDs without serial or parallel connection. This high-performance 3D interconnected porous carbon based MSC shows a great potential in applications for large-scale integration of micro/nano devices. PMID- 30521307 TI - Spray-Printed and Self-Assembled Honeycomb Electrodes of Silicon-Decorated Carbon Nanofibers for Li-Ion Batteries. AB - Directional, micron-scale honeycomb pores in Li-ion battery electrodes were fabricated using a layer-by-layer, self-assembly approach based on spray printing of carbon nanofibers. By controlling the drying behavior of each printed electrode layer through optimization of (i) the volume ratio of fugitive bi solvent carriers in the suspension, and (ii) the substrate temperature during printing, self-assembled, honeycomb pore channels through the electrode were created spontaneously and reliably on current collector areas larger than 20 cm * 15 cm. The honeycomb pore structure promoted efficient Li-ion dynamics at high charge/discharge current densities. Incorporating an optimum fraction (2.5 wt%) of high energy density Si particulate into the honeycomb electrodes provided a four-fold increase in deliverable discharge capacity at 8000 mA/g. The spray printed, honeycomb pore electrodes were then investigated as negative electrodes coupled with similar spray printed LiFePO4 positive electrodes in a full Li-ion cell configuration, providing an approximately 50 % improvement in rate capacity retention over half-cell configurations of identical electrodes at 4000 mA/g. PMID- 30521308 TI - Pt-C Interfaces Based on Electronegativity-Functionalized Hollow Carbon Spheres for Highly Efficient Hydrogen Evolution. AB - The hydrogen evolution reaction activity of carbon-supported Pt catalyst is highly dependent on Pt-C interfaces. Herein, we focus on the relationships between Pt activity and N/O-functionalized hollow carbon sphere (HCS) substrate in acidic media. The electrochemical dissolution of Pt counter electrode is performed to prepare Pt nanoparticles in low loading. The N groups are beneficial for homogeneously sized Pt nanoparticles, whereas the O groups lead to aggregated nanoparticles. Moreover, the proper electronegativity of the N groups may enable capturing of protons to create proton-rich Pt-C interfaces and transfer them onto the Pt sites. The O groups may also capture protons by hydrogen bonding, but the subsequent release of protons is more difficult due to a stronger electronegativity and result in an inferior Pt activity. Consequently, the N doped HCS with a low Pt loading (1.7 MUg cm-2 and 0.05 wt %) possesses a higher intrinsic activity compared with Pt on O-doped HCS. Moreover, it outperforms the commercial 20% Pt/C with a stable operation for 12 h. This work may provide suggestions for constructing the advantageous Pt-C interfaces by proper functional groups for high catalytic efficiencies. PMID- 30521309 TI - Oxide vs. Non-oxide Cathode Materials for Aqueous Zn Batteries: An Insight into the Charge Storage Mechanism and Consequences Thereof. AB - Aqueous Zn-ion batteries, which are being proposed as large scale energy storage solutions due to their unparalleled safety and cost advantage, are comprised of a positive host (cathode) material, a metallic zinc anode, and a mildly acidic aqueous electrolyte (pH ~ 3 - 7). Typically, the charge storage mechanism is believed to be reversible Zn2+ (de)intercalation in the cathode host, with the exception of alpha-MnO2, for which multiple vastly different and contradicting mechanisms have been proposed. However, our present study, combining electrochemical, operando X-ray diffraction (XRD), electron microscopy in conjunction with energy dispersive X-ray spectroscopy (EDX), and in situ pH evolution analyses on two oxide hosts - tunneled alpha-MnO2 and layered V3O7.H2O vis-a-vis two non-oxide hosts - layered VS2 and tunneled Zn3[Fe(CN)6]2, suggests that oxides and non-oxides follow two dissimilar charge storage mechanisms. While the oxides behave as dominant proton intercalation materials, the non-oxides undergo exclusive zinc intercalation. Stabilization of the H+ on the hydroxyl terminated oxide surface is revealed to facilitate the proton intercalation by a preliminary molecular dynamics simulation study. Proton intercalation for both oxides leads to the precipitation of layered double hydroxide (LDH) - Zn4SO4(OH)6.5H2O with ZnSO4/H2O electrolyte and a triflate anion (CF3SO3-) based LDH with Zn(SO3CF3)2/H2O electrolyte - on the electrode surface. The LDH precipitation buffers the pH of the electrolytes to a mildly acidic value, sustaining the proton intercalation to deliver large specific capacities for the oxides. Moreover, we also show that the stability of the LDH precipitate is crucial for the rechargeability of the oxide cathodes, revealing a critical link between the charge storage mechanism and the performance of the oxide hosts in aqueous zinc batteries. PMID- 30521310 TI - Direct Imaging of Photo-Switching Molecular Conformations Using Individual Metal Atom Markers. AB - Photo-switching behavior of individual organic molecules was imaged by annular dark-field scanning transmission electron microscopy (ADF-STEM) using a highly electron beam transparent graphene support. Photo-switching azobenzene derivatives with ligands at each ends containing single transition metal atoms (Pt) were designed (Pt-complex), and the distance between the strong ADF-STEM contrast from the two Pt atoms in each Pt-complex is used to track molecular length changes. UV irradiation was used to induce photo-switching of the Pt complex on graphene, and we show that the measured Pt-Pt distances within isolated molecules decreases from ~2.1 nm to ~1.4 nm, indicative of a trans-to cis isomerization. Light illumination of the Pt-complex on the graphene support also caused their diffusion out from initial clusters to the surrounding area of graphene, indicating that the light-activated mobilization overcomes the inter molecular van der Waals interactions. This approach shows how individual isolated heavy metal atoms can be included as markers into complex molecules to track their structural changes using ADF-STEM on graphene supports, providing an effective method to study a diverse range of complex organic materials at the single molecule level. PMID- 30521311 TI - Determination of Handedness in a Single Chiral Nanocrystal via Circularly Polarized Luminescence. AB - The occurrence of biological homochirality is attributed to symmetry breaking mechanisms which are still debatable. Studies of symmetry breaking require tools for monitoring the population ratios of individual chiral nano-objects, such as molecules, polymers or nanocrystals. Moreover, mapping their spatial distributions may elucidate on their symmetry breaking mechanism. While luminescence is preferred for detecting single particle chirality due to its high signal to noise ratio, the typical low optical activity of chromophores limits its applicability. Here, we report on handedness determination of single chiral lanthanide based luminescent nanocrystals with a total photon count of 2*104. Due to the large emission dissymmetry we could determine the handedness of individual particles using only a single circular polarization component of the emission spectrum, without polarization modulation. A machine learning algorithm, trained to several spectral lineshape features, enabled us to determine and spatially map the handedness of individual nanocrystals with high accuracy and speed. This technique may become invaluable in studies of symmetry breaking in chiral materials. PMID- 30521312 TI - The Cationic Alkynyl Heck Reaction Towards Substituted Allenes Using BobCat: A New Hybrid Pd(0)-Catalyst Incorporating a Water-Soluble dba Ligand. AB - The cationic alkynyl Heck reaction between aryl triflates and alkynes to give substituted allenes is described. Key to the success of this method was the discovery and development of a new hybrid Pd(0)-catalyst, BobCat, that incorporates a water-soluble dba-ligand and biaryl phosphine ligand to provide substituted allenes in good yields under mild reaction conditions. PMID- 30521313 TI - Aromatic Nitrogen Mustard-Based Autofluorescent Amphiphilic Brush Copolymer as pH Responsive Drug Delivery Vehicle. AB - Delivery of clinically approved nonfluorescent drugs is facing challenges because it is difficult to monitor the intracellular drug delivery without incorporating any integrated fluorescence moiety into the drug carrier. The present investigation reports the synthesis of a pH-responsive autofluorescent polymeric nano-scaffold for the administration of nonfluorescent aromatic nitrogen mustard chlorambucil (CBL) drug into the cancer cells. Copolymerization of poly(ethylene glycol) (PEG) appended styrene and CBL conjugated N-substituted maleimide monomers enables the formation of well-defined luminescent alternating copolymer. These amphiphilic brush copolymers self-organized in aqueous medium into 25-68 nm nanoparticles, where the CBL drug is enclosed into the core of the self-assembled nanoparticles. In vitro studies revealed ~70% drug was retained under physiological conditions at pH 7.4 and 37 oC. At endolysosomal pH 5.0, 90% of the CBL was released by the pH-induced cleavage of the aliphatic ester linkages connecting CBL to the maleimide unit. Although the nascent nanoparticle (without drug conjugation) is nontoxic, the drug conjugated nanoparticle showed higher toxicity and superior cell killing capability in cervical cancer (HeLa) cells rather than in normal cells. Interestingly, the copolymer without any conventional chromophore exhibited photoluminescence under UV light irradiation due to the presence of "through-space" pi-pi interaction between the C=O group of maleimide unit and the adjacent benzene ring of the styrenic monomer. This property helped us intracellular tracking of CBL conjugated autofluorescent nanocarriers through fluorescence microscope imaging. Finally, the 4-(4 nitrobenzyl)pyridine (NBP) colorimetric assay was executed to examine the ability of CBL-based polymeric nanomaterials towards alkylation of DNA. PMID- 30521314 TI - Improving the Electrochemical Properties of the Manganese-Based P3 Phase by Multiphasic Intergrowth. AB - Layered transition-metal oxides are one kind of the most promising cathode materials for sodium-ion batteries. In this study, we propose a strategy to enhance the electrochemical properties of P3-type manganese-based layered oxide cathode by introducing a small amount of layered P2 and Li-O'3 phases. Powder X ray diffraction (PXRD) structural refinement and aberration-corrected scanning transmission electron microscopy (STEM) are performed to confirm the microstructures of different samples. PXRD refinement results show that the elevated annealing temperature leads to a partial conversion of the P3 phase to the P2 phase and the addition of lithium results in the formation of a new O'3 phase in the P3/P2-layered matrix. STEM results identify the intergrowth of P3/P2 and P3/P2/O'3 in biphasic and triphasic materials, respectively. Electron energy loss spectroscopy verifies that the alkali metal layer in the O'3 phase is occupied by the lithium ion. The intergrowth of biphasic and triphasic materials in these layered P3/P2 and P3/P2/O'3 hybrid structures brings forth a positive effect on the electrochemical properties. In particular, the formation of P3/P2/O'3-intergrown hybrid structures greatly improves the cycling stability of the P3 phase that the capacity retention of P3/P2/O'3 hybrid structures remains 78%, while capacity retention of the pure P3 phase is only 54.1% after 50 cycles at a rate of 0.2 C, and the rate performance of the P3 phase has also been enhanced. PMID- 30521315 TI - Imaging mass spectrometry analysis of flavonoids in blue viola petals and their enclosure effects on violanin during color expression. AB - The color expression of anthocyanin pigments in blue flowers is precisely controlled by the pigments' chemical and physical environmental properties such as pH, metal ions, and the presence of colorless copigments. Despite the large number of known blue flowers, the coloration mechanisms of these have rarely been resolved. Herein, we showed that the blue coloration of Viola cornuta petals is expressed via the copigmentation of various flavonol 3-O-glycosides that are localized in considerable amounts in the blue regions together with violanin, an anthocyanin. By employing quantitative imaging mass spectrometry, we identified the structures and amounts of the flavonols co-localized with violanin in discrete blue-colored regions in the petal. The obtained data allowed an in vitro reconstruction of the color expression that agreed with the raw viola petal visible spectrum. Visible spectral analysis indicated that neither pH elevation in the vacuoles nor coexisting metal ions affected the color development. Eventually, we experimentally revealed that the excess amounts of flavonol 3-O glycosides enclosed and destructed the levorotatory helical self-assembly of violanin when blue coloration was expressed via copigmentation. PMID- 30521316 TI - Combinatorial Peptide Array Synthesis Based on Microfluidic Impact Printing. AB - In this paper, a novel inkjet printing technique, micro impact printing (MI printing), is applied for the first time to combinatorial peptide array synthesis on amine functionalized micro disc arrays through standard Fmoc chemistry. MI printing shows great advantages in combinatorial peptide array synthesis compared with other printing techniques, including 1) a disposable cartridge; 2) a small spot size (80 MUm) increases array density; 3) minimal loading volume (0.6 MUL) and dead volume (<0.1 MUL) reduce chemical waste; and 4) multiplexability for up to 5 channels. Using this synthesis approach, a tetrapeptide library with 625 permutations was constructed and then applied for the screening of ligands targeting alpha4beta1 integrin on Jurkat cells. PMID- 30521317 TI - [2, 2'-Bipyridin]-6(1H)-one, a Truly Cooperating Ligand in the Palladium-Mediated C-H Activation Step: Experimental Evidence in the Direct C-3 Arylation of Pyridine. AB - The ligand [2, 2'-bipyridin]-6(1H)-one (bipy-6-OH) has a strong accelerating effect in the Pd-catalyzed direct arylation of pyridine or arenes. The isolation of relevant intermediates and the study of their decomposition unequivocally show that the deprotonated coordinated ligand acts as a base and assists the cleavage of the C-H bond. Mechanistic work indicates that the direct arylation of pyridine with this ligand occurs through a Pd(0)/Pd(II) cycle. Because of this dual ligand intramolecular base role, there is no need of an available coordination site on the metal for an external base, a difficulty encountered when chelating ligands are used in coupling reactions that involve a C-H cleavage step. PMID- 30521318 TI - Selective Catalytic Formation of Cross-Tetramers from Tetrafluoroethylene, Ethylene, Alkynes, and Aldehydes via Nickelacycles as Key Reaction Intermediates. AB - In the presence of a catalytic amount of Ni(cod)2 (cod = 1,5-cyclooctadiene) and PCy3 (Cy = cyclohexyl), the cross-tetramerization of tetrafluoroethylene (TFE), ethylene, alkynes, and aldehydes leads to a variety of fluorine-containing enone derivatives. This reaction is the first example of a highly selective cross tetramerization between four different unsaturated compounds. Stoichiometric reactions revealed that the present reaction involves partially fluorinated five- and seven-membered nickelacycles as key reaction intermediates. PMID- 30521319 TI - Key Characteristics Approach to Carcinogenic Hazard Identification. AB - Evaluating carcinogenic mechanisms is a challenging part of hazard identification, as mechanistic data are both voluminous and diverse. An evaluation approach based on 10 key characteristics of human carcinogens provides a holistic and unbiased way to tackle this challenge. PMID- 30521320 TI - Characterization of Caenorhabditis elegans Nucleosome Assembly Protein 1 Uncovers the Role of Acidic Tails in Histone Binding. AB - Nucleosome assembly proteins (Naps) influence chromatin dynamics by directly binding to histones. Here we provide a comprehensive structural and biochemical analysis of a Nap protein from Caenorhabditis elegans (CeNap1). CeNap1 naturally lacks the acidic N-terminal tail and has a short C-terminal tail compared to many other Nap proteins. Comparison with full length and a tail-less constructs of Saccharomyces cerevisiae Nap1 (ScNap1) uncovers the role of these tails in self association, histone-binding, and competing H2A-H2B from DNA. We find that the presence of tails influences the stoichiometry of H2A-H2B-binding and is required to compete interactions between H2A-H2B and DNA. The absolute stoichiometry of the Nap protein and H2A-H2B complex is 2:1 or 2:2, with only a very small population of higher-order oligomers occurring at 150 mM NaCl. We also show that H3-H4 binds differently than H2A-H2B, and that a (H3-H4)2 tetramer can simultaneously bind two Nap2 protein homodimers. PMID- 30521321 TI - Chromatin Modifications in Toxicology. AB - Histone modifications regulate chromatin structure and function. Primary and secondary metabolites stemming from environmental and chemical exposures may play a critical role in the underlying epigenomic state of a cell through covalent histone modifications. Future investigations should be focused on characterizing the "Histone Code" when performing toxicogenomic analyses. PMID- 30521322 TI - Cation exchange reactions in layered double hydroxides intercalated with sulfate and alkaline cations (A(H2O)6)[M+26Al3(OH)18(SO4)2].6H2O (M+2= Mn, Mg, Zn; A+= Li, Na, K). AB - Layered double hydroxides (LDHs) with similar compositions to the minerals Shigaite, Natroglaucocerinite and Motukoreaite were synthesized by coprecipitation with increasing pH and characterized by several instrumental techniques. These minerals have previously been described to occur only with sodium and sulfate (Na(H2O)6)[M+26Al3(OH)18(SO4)2].6H2O (M+2= Mn, Mg and Zn). These phases were synthesized successfully along with others containing lithium and potassium. Cation exchange reactions were performed in the presence of alkaline metal sulfates and for the first time several instrumental techniques were employed to show that the cations can be totally exchanged without removing the intercalated sulfate anions. This class of compounds, traditionally considered to be anion exchangers, can also be considered cation exchangers, which opens new avenues for future scientific and industrial applications. PMID- 30521323 TI - Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer's Disease. AB - Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression. PMID- 30521324 TI - Chemoenzymatic synthesis of substituted azepanes by sequential biocatalytic reduction and organolithium-mediated rearrangement. AB - Enantioenriched 2-aryl azepanes and 2-arylbenzazepines were generated biocatalytically by asymmetric reductive amination using imine reductases or by deracemisation using monoamine oxidases. The amines were converted to the corresponding N'-aryl ureas, which rearranged on treatment with base with stereospecific transfer of the aryl substituent to the 2-position of the heterocycle via a configurationally stable benzyllithium intermediate. The products are previously inaccessible enanti-oenriched 2,2-disubstituted azepanes and benzazepines. PMID- 30521325 TI - Target engagement and binding mode of an anti-tuberculosis drug to its bacterial target deciphered in whole living cells by NMR. AB - Detailed information on hit-target interaction is very valuable for drug discovery efforts and indispensable for rational hit to lead optimization. We developed a new approach combining NMR in whole-cells (in-cell NMR) and docking to characterize hit-target interaction at the atomic level. By using in-cell NMR, we validated target engagement of the anti-tuberculosis imidazopyridine amide (IPA) series with the subunit b of the cytochrome bc1:aa3, the major respiratory terminal oxidase in mycobacteria. The most advanced IPA called Q203 is currently in clinical trial. Using its derivative IPA317, we identified the atoms of the drug interacting with the cytochrome b in whole cells. NMR data and the Self Organising Map algorithm were used to cluster a large set of drug-target complex models. The selected ensemble revealed IPA317 in a transient cavity of the cytochrome b, interacting directly with the residue T313, which is the site of spontaneous mutation conferring resistance to the IPA series. Our approach constitutes a pipeline to obtain atomic information on hit-target interactions in the cellular context. PMID- 30521326 TI - Phytic Acid-Assisted Formation of Hierarchical Porous CoP/C Nanoboxes for Enhanced Lithium Storage and Hydrogen Generation. AB - Application of transition metal phosphides (TMPs) for electrochemical energy conversion and storage has great potential to alleviate the energy crisis. Although there are various methods to obtain TMPs, it is still immensely challenging to fabricate hierarchical porous TMPs with superior electrochemical performances by a simple, green and secure method. We herein describe a facile approach for fabricating CoP/C nanoboxes by pyrolyzing phytic acid (PA) cross linked Co complexes that acquired from reaction of PA and ZIF-67. The PA can not only slowly etch ZIF-67 and gain a hollow structure, but also act as a source of phosphorus to prepare CoP/C nanoboxes. As an anode for lithium-ion batteries the CoP/C nanoboxes deliver a high specific capacity (868 mA h g-1 at 100 mA g-1) and excellent cycle stability (523 mA h g-1 after 1000 cycles at 500 mA h g-1). Moreover, when used as an electrocatalyst for hydrogen evolution reaction, the CoP/C nanoboxes exhibit low onset overpotential and small Tafel slope as well as particularly outstanding durability in acidic media. The method to produce CoP/C nanoboxes is easy and environmentally friendly, and can be readily extended to design other TMPs/C nanocomposites. PMID- 30521327 TI - Supramolecular Polymer Cross-Linked by Discrete Tris-[2]pseudorotaxane Metallacycles and Its Redox-Responsive Behavior. AB - A new discrete hexagonal metallacycle M containing tris-[2]pseudorotaxane moiety has been successfully designed and synthesized via coordination-driven self assembly. The newly designed tris-[2]pseudorotaxane metallacycle was well characterized with nuclear magnetic resonance and mass spectra analysis. Such tris-[2]pseudorotaxane metallacycle M and pillar[5]arene dimer (PD) could further form a new family of cross-linked redox-responsive supramolecular polymer M?(PD)3 through a host-guest interaction. Interestingly, the polymer M?(PD)3 displayed redox-responsive behavior and showed tuned weight-average diffusion coefficients D upon redox stimuli, which is attributed to the changed coordination geometries of [Cu(phen)2]+ and [Cu(phen)2]2+ in such system. PMID- 30521328 TI - A Radical Approach to Enzymatic beta-Thioether Bond Formation. AB - Ribosomally-synthesized and post-translationally-modified peptides (RiPPs) are an emerging class of natural products that harbor diverse chemical functionalities, usually introduced via the action of a small number of tailoring enzymes. We have been interested in RiPP biosynthetic gene clusters that encode unusual metalloenzymes, as these may install yet unknown alterations. Using a new bioinformatic search strategy, we recently identified an array of unexplored RiPP gene clusters that are quorum sensing-regulated and contain one or more uncharacterized radical S-adenosylmethionine (RaS) metalloenzymes. Herein, we investigate the reaction of one of these RaS enzymes and find that it installs an intramolecular beta-thioether bond onto its substrate peptide by connecting a Cys thiol group to the beta-carbon of an upstream Asn residue. The enzyme responsible, NxxcB, accepts several amino acids in place of Asn and introduces unnatural beta-thioether linkages at unactivated positions. This new transformation adds to the growing list of Nature's peptide macrocyclization strategies and expands the already impressive catalytic repertoire of the RaS enzyme superfamily. PMID- 30521329 TI - Arsenic concentrations, speciation, and localization in 141 cultivated market mushrooms: implications for arsenic exposure to humans. AB - Mushrooms accumulate arsenic (As), yet As concentrations, speciation, and localization in cultivated mushrooms across a large geographic distribution are unknown. We characterized 141 samples of 9 species from markets in 9 capital cities in China, with samples of Lentinula edodes, Pleurotus ostreatus, and Agaricus bisporus being analyzed for As speciation and localization. Total As concentrations ranged 0.01-8.31 mg kg-1 dw, with A. bisporus (0.27-2.79 mg kg-1) containing the highest As followed by P. ostreatus and L. edodes (0.04-8.31 and 0.12-2.58 mg kg-1). However, As in A. bisporus was mostly organic including non toxic arsenobetaine, while P. ostreatus and L. edodes contained mainly inorganic As (iAs). Based on in situ imaging using LA-ICP-MS, As in L. edodes was localized to the surface coat of the cap, while As in P. ostreatus was localized to the junction of the pileus and stipe. When As speciation and daily mushroom consumption (1.37 g d-1 dw) were considered, daily mushroom consumption may result in elevated iAs exposure, with bladder and lung cancer rates being up to 387 cases per 100,000. Our study showed market mushrooms could be a health risk to the general public and its production should be regulated. PMID- 30521330 TI - Occurrence and human exposure assessment of short- and medium-chain chlorinated paraffins in dusts from plastic sports courts and synthetic turf in Beijing, China. AB - This study presents the first investigation of concentrations and congener group patterns of short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) in 159 dust samples from plastic sports courts and synthetic turf in Beijing, China. The geometric mean concentration of SCCPs and MCCPs in dusts from plastic tracks (5429 and 15157 MUg g-1) and basketball courts (5139 and 11878 MUg g-1) were significantly higher than those from plastic tennis courts, badminton courts, and synthetic turf, meanwhile they were 1-3 orders of magnitude higher than those in dusts from other indoor environments. The friction between sneaker soles and plastic track materials may lead to the wear and decomposition of rubber, which may be an important source of chlorinated paraffins (CPs) in the dust from plastic tracks. The mean estimated daily intakes of CPs from plastic tracks and basketball courts are generally higher than those estimated from dietary, breast milk, or other indoor dust sources. The margin of exposure for adults and children was greater than 1000 both at mean and high exposure scenarios, indicating that no significant health risks were posed by CPs in the dust from plastic sports courts and synthetic turf. PMID- 30521331 TI - In Vitro Synthesis and Crystallization of beta-1,4-Mannan. AB - In vitro polymerization of beta-mannans is a challenging reaction due to the steric hindrance confered by the configuration of mannosyl residues and the thermodynamic instability of the beta-anomer. Whatever the approach used to date whether chemical, or enzymatic with glycosynthases and mannosyltransferases - pure beta-1,4-mannans have never been synthesized in vitro. This has limited attempts to investigate their role in the production of plant and algal cell walls, in which they are highly abundant. It has also impeded the exploitation of their properties as biosourced materials. In this paper, we demonstrate that TM1225, a thermoactive glycoside phosphorylase from the hyperthermophile species Thermotoga maritima, is a powerful biocatalytic tool for the ecofriendly synthesis of pure beta-1,4-mannan. The recombinant production of this enzyme and its biochemical characterization allowed us to prove that it catalyses the reversible phosphorolysis of beta-1,4-mannosides, and determine its role in the metabolism of the algal mannans on which T. maritima feeds in submarine sediments. Furthermore, after optimizing the reaction conditions, we exploited the synthetic ability of TM1225 to produce beta-1,4-mannan in vitro. At 60 degrees C and from alpha-D-mannose 1-phosphate and mannohexaose, the enzyme synthesized mannoside chains with a degree of polymerisation up to 16, which precipitated into lamellar single crystals. The X-ray powder diffraction and base plane electron diffraction patterns of the lamellar crystals unambiguously show that the synthesized product belongs to the mannan I family previously observed in planta in pure linear mannans, such as those of the ivory nut. The in vitro formation of these mannan I crystals is likely determined by the high reaction temperature and the narrow chain length distribution of the insoluble chains. PMID- 30521332 TI - Legacy and Emerging Persistent Organic Pollutants (POPs) in Terrestrial Compartments in the High Arctic: Sorption and Secondary Sources. AB - Legacy persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and emerging perfluoroalkyl substances (PFASs) were measured in vegetation and soil samples collected at remote lakes in the Canadian High Arctic. Field studies were carried out in 2015 and 2016 to assess concentrations of POPs, study the relevant sorbing phases, and determine whether Arctic soils were sinks or sources of legacy POPs to the atmosphere and to neighboring lakes. The patterns of legacy POPs in vegetation and soils were dominated by low molecular weight PCB congeners along with OCPs, confirming the importance of long-range atmospheric transport. Lipid and non-lipid organic matter was a key determinant of legacy POPs in Arctic vegetation. Soil organic matter was the main descriptor of hydrophobic PCBs and OCPs in soils, while soil inorganic carbon content, was an important driver of the sorption of PFASs in soils. While contaminant concentrations were low in soil and vegetation, higher PCBs and PFOS organic and inorganic carbon-normalized concentrations were found at Resolute Lake indicating the presence of local sources of contamination. Comparison of fugacities of PCBs in soil and air from Resolute Lake indicated soils as net sources of PCBs to the atmosphere. PMID- 30521333 TI - A Finite-field Approach for GW Calculations Beyond the Random Phase Approximation. AB - We describe a finite-field approach to compute density response functions, which allows for efficient G0 W0 and G0 W0Gamma0 calculations beyond the random phase approximation. The method is easily applicable to density functional calculations performed with hybrid functionals. We present results for the electronic properties of molecules and solids and we discuss a general scheme to overcome slow convergence of quasiparticle energies obtained from G0 W0Gamma0 calculations, as a function of the basis set used to represent the dielectric matrix. PMID- 30521334 TI - Assessing the Performance of the Nonbonded Mg2+ Models in a Two-metal-dependent Ribonuclease. AB - Magnesium ions (Mg2+), abundant in living cells, are essential for biomolecular structure, dynamics, and function. The biological importance of Mg2+ has motivated continuous development and improvement of various Mg2+ models for molecular dynamics (MD) simulations during the last decades. There are four types of nonbonded Mg2+ models: the point charge models based on a 12-6 or 12-6-4 type Lennard-Jones (LJ) potential, and the multisite models based on a 12-6 or 12-6-4 LJ potential. Here, we systematically assessed the performance of these four types of nonbonded Mg2+ models (21 models in total) in terms of maintaining a challenging intermediate state configuration captured in the structure of a prototypical two-metal-ion RNase H complex with an RNA/DNA hybrid. Our data demonstrate that the 12-6-4 multisite models, which account for charge-induced dipole interactions, perform the best in reproducing all the unique coordination modes in this intermediate state and maintaining the correct carboxylate denticity. Our benchmark work provides a useful guideline for MD simulations and structural refinement of Mg2+-containing biomolecular systems. PMID- 30521335 TI - Towards Automated Tools for Characterization of Molecular Porosity. AB - The emerging advanced porous materials, e.g. extended framework materials and porous molecular materials, offer an unprecedented level of control of their structure and function. The enormous possibilities for tuning these materials by changing their building blocks mean that, in principle, optimally performing materials for a variety of applications can be systematically designed. However, the process of finding a set of optimal structures for a given application requires computational high-throughput tools to analyze and sieve through many candidate materials. In particular, in the case of porous molecular materials, the analysis and selection of a molecule is one of key aspects as the structure of the molecule determines the structure of the resulting material, and very often the porosity of the molecule significantly contributes to the porous properties of the resulting material. In this work, we introduce definitions and algorithms to characterize porosity at the molecular level, along with a software implementation of these algorithms. We demonstrate applications of the software tool in the discovery and characterization of porous molecules among ca. 94 million molecules currently enlisted in PubChem database. PMID- 30521336 TI - Iridium(III)-Catalyzed Tandem Annulation Synthesis of Pyrazolo [1,2-alpha] Cinnolines from Pyrazolones and Sulfoxonium Ylides. AB - A highly efficient iridium-catalyzed cascade annulation of pyrazolones and sulfoxonium ylides to access various pyrazolo [1,2-alpha] cinnoline derivatives has been achieved. This novel approach expanded the application scope of coupling partners to ylides. The control experiments were performed to give insight to the mechanism of this reaction. PMID- 30521337 TI - Improved on-the-fly MCTDH simulations with many-body-potential tensor decomposition and projection diabatisation. AB - We have recently demonstrated how potential energy surface (PES) interpolation methods such as kernel ridge regression (KRR), can be combined with accurate wavefunction time-propagation methods, specifically the multi-configuration time dependent Hartree (MCTDH) method, to generate a new "on-the-fly" MCTDH scheme (DD MCTDH) which does not require the pre-fitting of the PES which is normally required by MCTDH. Specifically, we have shown how our DD-MCTDH strategy can be used to model non-adiabatic dynamics in a 4-mode/2-state model of pyrazine, with ab initio electronic structure calculations performed directly during propagation, requiring around 100 hours of computer wall-time. In this Article, we show how the efficiency and accuracy of DD-MCTDH can be dramatically improved further still by: (i) using systematic tensor decompositions of the KRR PES, and (ii) using a novel scheme for diabatisation within the framework of configuration interaction (CI) methods which only requires local adiabatic electronic states, rather than non-adiabatic coupling matrix elements. The result of these improvements is that our latest version of DD-MCTDH can perform a 12-mode/2-state simulation of pyrazine, with PES evaluations at CAS level, in just 29-90 hours on a standard desktop computer; this work therefore represents an enormous step towards direct quantum dynamics with MCTDH. PMID- 30521338 TI - GHB614 x T304-40 x GHB119 x COT102 Cotton: Protein Expression Analyses of Field Grown Samples. AB - Food and feed safety assessment is not enhanced by performing protein expression analysis on stacked trait products. The expression levels of six proteins in cotton matrices from four single cotton events and three conventionally stacked trait cotton products are reported. Three proteins were for insect control, two proteins confer herbicide tolerance, and one protein was a transformation selectable marker. The cotton matrices were produced at three US, five Brazil and two Argentina field trials. Similar protein expression was observed for all six proteins in the stacked trait products and the single events. However, when two copies of the bar gene were present in the stacked trait products, the expression level of PAT herbicide tolerance was additive. Conventional breeding of genetically engineered traits does not alter the level or pattern of expression of the newly introduced proteins except when multiple copies of the same transgene are present. PMID- 30521339 TI - Understanding the Nanoscale Structure of Inverted Hexagonal Phase Lyotropic Liquid Crystal Polymer Membranes. AB - Periodic, nanostructured porous polymer membranes made from the cross-linked inverted hexagonal phase of self-assembled lyotropic liquid crystals (LLCs) are a promising class of materials for selective separations. In this work, we investigate an experimentally characterized LLC polymer membrane using atomistic molecular modeling. In particular, we compare simulated X-ray diffraction (XRD) patterns with experimental XRD data to quantify and understand the differences between simulation and experiment. We find that the nanopores are likely composed of 5 columns of stacked LLC monomers which surround each hydrophilic core. Evidence suggests that these columns likely move independently of each other over longer time scales than accessible via atomistic simulation. We also find that WAXS structural features previously attributed to monomer tail tilt is likely instead due to ordered tail packing. Although this system has been reported as dry, we show that small amounts of water are necessary to reproduce all features from the experimental XRD pattern due to asymmetries introduced by hydrogen bonds between the monomer head groups and water molecules. Finally, we explore the composition and structure of the nanopores and reveal that there exists a composition gradient rather than an abrupt partition between the hydrophilic and hydrophobic regions. A caveat is that the time scales of the dynamics are extremely long for this system, resulting in simulated structures that appear too ordered, thus requiring careful examination of the metastable states observed in order to draw any conclusions. The clearer picture of the nanoscopic structure of these membranes provided in this study will enable a better understanding of the mechanisms of small molecule transport within these nanopores. PMID- 30521340 TI - Superbound Excitons in 2D Phosphorene Oxides. AB - The optical excitations in layered phosphorene oxides are studied via ab inito calculation together with GW approximation for the self-energy and solving the Bethe-Salpeter equation (BSE) for the excitations. It is found that the electronic structure of phosphorene oxides closely depend on the oxygen concentration, for the high oxygen coverage structure P4O10, it shows a strong localized molecular like electronic structure with exciton binding (Eb) energy up to 3.0 eV, which is several times larger than the ordinary Eb value in various low dimensional materials. This study may provide an alternative way to design functional layered materials with large exciton binding energy by controlling the oxidation level in phosphorene oxides. PMID- 30521341 TI - Selectivity map for molecular beam epitaxy of advanced III-V quantum nanowire networks. AB - Selective area growth is a promising technique to enable fabrication of scalable III-V nanowire networks required to test proposals for Majorana-based quantum computing devices. However, the contours of the growth parameter window resulting in selective growth remain undefined. Herein, we present a set of experimental techniques which unambiguously establish the parameter space window resulting in selective III-V nanowire networks growth by molecular beam epitaxy. Selectivity maps are constructed for both GaAs and InAs compounds based on in situ characterization of growth kinetics on GaAs(001) substrates, where the difference in group III adatom desorption rates between the III-V surface and the amorphous mask area is identified as the primary mechanism governing selectivity. The broad applicability of this method is demonstrated by successful realization of high quality InAs and GaAs nanowire networks on GaAs, InP, and InAs substrates of both (001) and (111)B orientations as well as homoepitaxial InSb nanowire networks. Finally, phase coherence in Aharonov-Bohm ring experiments validates the potential of these crystals for nanoelectronics and quantum transport applications. This work should enable faster and better nanoscale crystal engineering over a range of compound semiconductors for improved device performance. PMID- 30521342 TI - Formulation and structural study of a biocompatible water-in-oil microemulsion as an appropriate enzyme carrier: The model case of Horseradish peroxidase. AB - A novel biocompatible water-in-oil microemulsion was developed using non-ionic surfactants and was investigated as a potential enzyme delivery system for pharmaceutical applications. The system composed of isopropyl myristate/polysorbate 80 (Tween 80TM)/distilled monoglycerides/water/propylene glycol (PG), had a low total surfactant concentration (8.3% w/w) and was able to incorporate approximately 3% w/w aqueous phase containing Horseradish peroxidase (HRP). Structural and activity aspects of the system were studied using a variety of techniques such as Dynamic Light Scattering (DLS), Electron Paramagnetic Resonance (EPR) and Dynamic Interfacial Tension. Apparent hydrodynamic diameter of the empty droplets was calculated at about 37 nm. Different enzyme concentrations, ranging from 0.01-1.39 uM, were used for both DLS and EPR studies in order to effectively determine the localization of the macromolecule in the microemulsion. According to the results, for high enzyme concentrations a participation of HRP in the surfactant monolayer of the microemulsion is evident. The number of reverse micelles in the microemulsion was defined by a theoretical model and was used to clarify how the enzyme concentration affects the number of empty and loaded reverse micelles. In order to assure that the system allows the enzyme to retain its catalytic activity, an omicronxidative reaction catalyzed by HRP was successfully carried out with the use of the model substrate 2,2?-azino bis[3-ethylbenzo-thiazoline-6-sulfonic acid] (ABTS). The influence of several parameters such as temperature, pH and PG concentration were examined in order to optimize the reaction conditions and a kinetic study was conducted revealing an ordered-bi-bi mechanism. Values of all kinetic parameters were determined. The release of the encapsulated enzyme was studied using an adequate receiver phase, revealing the effectiveness of the proposed microemulsion not only as a microreactor but also as carrier for therapeutic biomolecules. PMID- 30521343 TI - Performance of DFT for C60 Isomerization Energies: A Noticeable Exception to Jacob's Ladder. AB - The ability to accurately calculate relative energies of fullerenes is important in many areas of computational nanotechnology. Due to the large size of fullerenes, their relative energies cannot normally be calculated by means of high-level ab initio procedures, and therefore density functional theory (DFT) represents a cost-effective alternative. In an extensive benchmark study, we calculate the electronic energies of eight C60 isomers by means of the high-level G4(MP2) composite procedure. G4(MP2) isomerization energies span a wide range between 307.5-1074.0 kJ mol-1. We use this benchmark data to assess the performance of DFT, double-hybrid DFT (DHDFT), and MP2-based ab initio methods. Surprisingly, functionals from the second and third rungs of Jacob's Ladder (i.e., GGA and meta-GGA functionals) significantly and systematically outperform hybrid and hybrid-meta-GGA functionals, which occupy higher rungs of Jacob's Ladder. In addition, DHDFT functionals do not offer a substantial improvement over meta-GGA functionals, with respect to isomerization energies. Overall, the best performing functionals with mean absolute deviations (MADs) below 15.0 kJ mol-1 are (MADs given in parenthesis) the GGA N12 (14.7); meta-GGAs M06-L (10.6), M11-L (10.8), MN15-L (11.9), and TPSS-D3BJ (12.8); and the DHDFT functionals B2T PLYP (9.3), mPW2-PLYP (9.8), B2K-PLYP (12.1), and B2GP-PLYP (12.3 kJ mol-1). In light of these results, we recommend the use of meta-GGA functionals for the calculation of fullerene isomerization energies. Finally, we show that inclusion of very small percentages of exact Hartree-Fock exchange (3-5%) slightly improves the performance of the GGA and meta-GGA functionals. However, their performance rapidly deteriorates with the inclusion of larger percentages of exact Hartree Fock exchange. PMID- 30521344 TI - Metal-ligand interface in the chemical reactions of ligand protected noble metal clusters. AB - We discuss the role of the metal-ligand (M-L) interfaces in the chemistry of ligand protected, atomically precise noble metal clusters, a new and expanding family of nanosystems, in solution as well as in gas phase. A few possible mechanisms in which the structure and dynamics of M-L interfaces could trigger intercluster exchange reactions are presented first. How interparticle chemistry can be a potential mechanism of Ostwald ripening, a well-known particle coarsening process, is also discussed. Reaction of Ag59(2,5-DCBT)32 (DCBT = dichlorobenzenethiol) with 2,4-DCBT leading to the formation of Ag44(2,4-DCBT)30 is presented, demonstrating the influence of the ligand structure in ligand induced chemical transformations of clusters. We also discuss structural isomerism of clusters such as Ag44(SR)30 (-SR = alkyl/aryl thiolate) in gas phase wherein the occurrence of isomerism is attributed to the structural rearrangements in the M-L bonding network. Interfacial bonding between Au25(SR)18 clusters leading to the formation of cluster dimers and trimers is also discussed. Finally, we show that desorption of phosphine and hydride ligands on a silver cluster, [Ag18(TPP)10H16]2+ (TPP = triphenylphosphine) in gas phase, lead to the formation of a naked silver cluster of precise nuclearity, such as Ag17+. We demonstrate that the nature of the M-L interfaces, i.e., the oxidation state of metal atoms, structure of the ligand, M-L bonding network, etc., play key roles in the chemical reactivity of clusters. The structure, dynamics and chemical reactivity of nanosystems in general are to be explored together to obtain new insights into their emerging science. PMID- 30521345 TI - Expressway to Rheumatoid Arthritis by Macrophage-derived Microvesicle-Coated Nanoparticles. AB - The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. Poly (lactic-co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of red blood cell membrane coated-nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material with which to mimic macrophages and that MNP is an efficient biomimetic vehicle for RA targeting and treatment. PMID- 30521346 TI - Graphene Quantum Dots-Mediated Theranostic Penetrative Delivery of Drug and Photolytics in Deep Tumors by Targeted Biomimetic Nanosponges. AB - Dual targeted delivery of drugs and energy by nanohybrids can potentially alleviate side effects and improve the unique features required for precision medicine. To realize this aim, however, the hybrids which are often rapidly removal from circulation and piled up tumors periphery near the blood vessels must address the difficulties in low blood half-lives and tumor penetration. In this study, a sponge-inspired carbon composites-supported red blood cell (RBC) membrane that doubles as a stealth agent and photolytic carrier that transports tumor-penetrative agents (graphene quantum dots and docetaxel (GQD-D)) and heat with irradiation was developed. The RBC-membrane enveloped nanosponge (RBC@NS) integrated to a targeted protein that accumulates in tumor spheroids via high lateral bilayer fluidity exhibits an 8-fold increase in accumulation compared to the NS. Penetrative delivery of GQDs to tumor sites is actuated by near-infrared irradiation through a one-atom-thick structure, facilitating penetration and drug delivery deep into the tumor tissue. The synergy of chemotherapy and photolytic effects was delivered by the theranostic GQDs deep into tumors, which effectively damaged and inhibited the tumor in 21 days when treated with a single irradiation. This targeted RBC@GQD-D/NS with the capabilities of enhanced tumor targeting, NIR-induced drug penetration into tumors, and thermal ablation for photolytic therapy promotes tumor suppression and exhibits potential for other biomedical applications. PMID- 30521347 TI - Antibody-assisted delivery of a peptide-drug conjugate for targeted cancer therapy. AB - A number of cancer-targeting peptide-drug conjugates (PDCs) have been explored as alternatives to antibody-drug conjugates (ADCs) for targeted cancer therapy. However, the much shorter circulation half-life of PDCs compared with ADCs in vivo has limited their therapeutic value and thus their translation into the clinic, highlighting the need to develop new approaches for extending the half life of PDCs. Here, we report a new strategy for targeted cancer therapy of a PDC based on a molecular hybrid between an anti-hapten antibody and a hapten-labeled PDC. An anti-cotinine antibody (Abcot) was used as a model anti-hapten antibody. The anticancer drug SN38 was linked to a cotinine-labeled aptide specific to extra domain B of fibronectin (cot-APTEDB), yielding the model PDC, cot-APTEDB SN38. The cotinine-labeled PDC showed specific binding to and cytotoxicity toward an EDB-overexpressing human glioblastoma cell line (U87MG) and also formed a hybrid complex (HC) with Abcot in situ, designated HC[cot-APTEDB-SN38/Abcot]. In glioblastoma-bearing mice, in situ HC[cot-APTEDB-SN38/Abcot] significantly extended the circulation half-life of cot-APTEDB-SN38 in blood, and enhanced accumulation and penetration within the tumor and, ultimately, inhibition of tumor growth. These findings suggest that the present platform holds promise as a new, targeted delivery strategy for PDCs in anticancer therapy. PMID- 30521348 TI - Catalyst-Free Aromatic Radiofluorination via Oxidized Iodoarene Precursors. AB - Oxidized iodoarenes (OIAs), prepared via mCPBA-mediated oxidation, have been demonstrated as versatile precursors for the synthesis of [18F]fluoroarenes in the absence of catalysts. OIAs have been identified as intermediates in single pot syntheses of iodonium salts and ylides but have never been recognized as radiofluorination precursors. Here, the isolated OIAs were used without any catalysts to produce functionalized [18F]fluoroarenes, regardless of the electronic nature of the arenes. This method was also applied to the production of radiolabeling synthons for use as aromatic 18F-labeled building blocks. PMID- 30521349 TI - Self-assembly of hybrid nanorods for enhanced volumetric performance of nanoparticles in Li-ion batteries. AB - The benefits of nanosized active particles in Li-ion batteries are currently ambiguous. They are acclaimed for enhancing the cyclability of certain electrode materials and for improving rate performance. However, at the same time, nanoparticles are criticized for causing side reactions as well as for their low packing density and therefore poor volumetric battery performance. This paper demonstrates for the first time that self-assembly can be used to pack nanoparticles into dense battery electrodes with up to four-fold higher volumetric capacities. Further, despite the dense packing of the self-assembled electrodes, they retain a higher volumetric capacity than randomly dispersed nanoparticles up to rates of 5C. Finally, we did not observe any degradation in capacity after 1000 cycles and post-mortem analysis indicates that the self assembled structures are maintained during cycling. Therefore, the proposed self assembled electrodes profit from the advantages of nanostructured battery materials without compromising the volumetric performance. PMID- 30521350 TI - Insight into Amorphous Solid Dispersion Performance by Coupled Dissolution and Membrane Mass Transfer Measurements. AB - The tendency of highly supersaturated solutions of poorly water soluble drugs to undergo liquid-liquid phase separation (LLPS) into drug-rich and water-rich phases when the concentration exceeds the amorphous solubility, for example, during dissolution of some amorphous solid dispersions, is thought to be advantageous from a bioavailability enhancement perspective. Recently, we have developed a high surface area, flow-through absorptive dissolution testing apparatus that enables fast mass transfer providing more in vivo relevant conditions and time frames for formulation testing. Using this apparatus, the absorption behaviors of solutions with different extents of supersaturation below and above the amorphous solubility were evaluated. In addition, simultaneous dissolution-absorption testing of amorphous solid dispersions (ASDs) with varying drug loadings and polymer types was carried out to study and distinguish the absorption behavior of ASDs that do or do not undergo LLPS. When compared with closed-compartment dissolution testing, a significant influence of the absorptive compartment on the dissolution rate of ASDs, particularly at high drug loadings, was observed. The formation of drug-rich nanodroplets, generated by both solvent addition and ASD dissolution, resulted in a higher amount of drug transferred across the membrane. Moreover, the mass transfer was further enhanced with increasing concentration above the amorphous solubility, thereby showing correlation with an increase in the number of drug-rich particles. The importance of including an absorptive compartment in dissolution testing is highlighted in this study, enabling coupling of dissolution to membrane transport, and providing a more meaningful comparison between different formulations and insight into dissolution mechanisms. PMID- 30521351 TI - On the Electrochemical Degradation of Pt-Ni Nanocatalysts: An Identical Location Aberration-Corrected STEM Study. AB - The evolution of PtNi nanopartiles supported on amorphous carbon is investigated before and after electrochemical potential cycling (0.6-1.1V), using aberration corrected STEM and EDS. During voltage cycling and due to the dissolution of the nanoparticles, single ions/atoms and ionic/atomic clusters emerge and diffuse across the carbon support towards larger nanoparticles, where they re-deposit. We observe that the preferred locations for the dissolution are the steps and corners of the nanoparticles. On the other hand, the re-deposition process happens often on {111} type planes. In addition, contrary to the conventional view, where larger particles grow isotropically from smaller ones, this research work shows that anisotropic growth of smaller particles, occurs during potential cycling. The reason for this behavior seems to be related with the fact that smaller particles with thicker Pt-rich shells trigger the nucleation and deposition of Pt. PMID- 30521352 TI - DHA supplementation during prenatal ethanol exposure alters the expression of fetal rat liver genes involved in oxidative stress regulation. AB - Prenatal ethanol (EtOH) exposure is known to induce adverse effects on fetal brain development. Docosahexaenoic acid (DHA) has been shown to alleviate these effects by upregulating antioxidant mechanisms in the brain. The liver is the first organ to receive enriched blood after placental transport; therefore, it could be negatively affected by EtOH, but no studies have assessed the effects of DHA on fetal liver. This study examined the effects of maternal DHA intake on DHA status and gene expression of key enzymes of the glutathione antioxidant system in the fetal liver after prenatal EtOH exposure. Pregnant Sprague-Dawley dams were intubated with EtOH for the first 10 days of pregnancy, while being fed a control or DHA-supplemented diet. Fetal livers were collected at gestational day 20, and free fatty acids and phospholipid profile, as well as the glutathione reductase (GR) and glutathione peroxidase-1 (Gpx1) gene expressions were assessed. Prenatal EtOH exposure increased fetal liver weight, whereas the maternal DHA-supplementation decreased the fetal liver weight. DHA supplementation increased fetal liver free fatty acid and phospholipid DHA independently of EtOH. GR and Gpx1 mRNA expressions were significantly increased and decreased, respectively, in the EtOH-exposed group compared to all other groups. Providing DHA normalized GR and GPx1 mRNA expression to control levels. This study shows maternal DHA-supplementation alters the expression of fetal liver genes involved in the glutathione antioxidative system during prenatal EtOH exposure. Fetal liver may play an important role in mitigating the signs and symptoms of fetal alcohol spectrum disorders in affected offspring. PMID- 30521353 TI - Hemodynamic Responses to an Exercise Stress Test in Parkinson's Disease Patients without Orthostatic Hypotension. AB - The presence of postganglionic sympathetic denervation is well established in Parkinson's disease (PD). Denervation at cardiac and blood vessel sites may lead to abnormal cardiovascular and hemodynamic responses to exercise. The aim of the present investigation was to examine how heart rate (HR) and hemodynamics are affected by an exercise test in PD patients without orthostatic hypotension. Fourteen individuals with PD and sixteen age-matched healthy controls performed an exercise test on a cycle ergometer. HR, blood pressure, and other hemodynamic variables were measured in a fasted state during supine rest, active standing, exercise, and supine recovery. Peak HR and percent of age-predicted maximum HR (HRmax) achieved were significantly blunted in PD (p<.05, p<.01). HR remained significantly elevated in PD during recovery compared to controls (p=.03, p<.05). Systolic, diastolic, and mean arterial pressures were significantly lower at multiple time-points during active standing in PD compared to controls. Systemic vascular resistance (SVR) decreased significantly at the onset of exercise in PD, and remained significantly lower during exercise and the first minute of supine recovery. End diastolic volume (EDV) was significantly lower in PD during supine rest and recovery. Our results indicate for the first time that normal hemodynamics are disrupted during orthostatic stress and exercise in PD. Despite significant differences in EDV at rest and during recovery, and SVR during exercise, cardiac index was not affected. Our finding of significantly blunted HRmax and HR recovery in PD patients has substantial implications for exercise prescription and recovery guidelines. PMID- 30521354 TI - Asthma Information Seeking via Wikipedia Between 2015 and 2018: Implications for Awareness Promotion. PMID- 30521355 TI - Wound care in older adults. AB - Wound care in older adults is complex. A logical, structured approach should be taken, using a nursing process such as assessing, planning, implementing and evaluating. This clinical focus paper outlines the nursing process to support wound care in this patient group. It recommends considering dressing selection as a cost-effective, prescribing decision because of the risks and comorbidities associated with these patients. PMID- 30521356 TI - Dressing wounds. PMID- 30521357 TI - Social prescribing and the Lindsay Leg Club model of care. PMID- 30521358 TI - Pressure ulcer definitions and core curricula-how does this affect wound care and the older patient? AB - Chronic wounds are associated with a significant patient, healthcare and financial burden and can have extensive implications for healthcare. Age is a significant risk factor for developing chronic wounds, due to physical changes in skin integrity and several age-related complex comorbidities, including poor nutrition and mobility. Pressure ulcers (PU) are a common type of chronic wound that can have a substantial impact on health-related quality of life and patient outcomes. Understanding the extent of PU harm is problematic, due to discrepancies in the definition, recording and reporting of PUs on both a local and national level. Education and training are central to ensuring the risk factors associated with PU development are recognised, and a consistent and coherent structure to the definition, measurement and reporting of PUs across the NHS is developed. PMID- 30521359 TI - The value of the Lindsay Leg Club Foundation. PMID- 30521360 TI - Monitoring service quality: Lindsay Leg Club member satisfaction survey. AB - The Lindsay Leg Club network is a research-based initiative that provides treatment, health guidance, education and ongoing care for people of all age groups who are experiencing lower limb-related problems. Leg Club clinicians work in a unique partnership with patients (known as 'members') and the local community. Working to current best-practice guidelines, they provide a high standard of care in a social and friendly setting that promotes understanding, peer support and informed choice. This article presents the findings of a member satisfaction survey, through which we aimed to identify additional services we could provide or areas of improvement. PMID- 30521361 TI - Addressing social isolation in lower-limb management. PMID- 30521362 TI - Wound Exudate. AB - Tina Chambers, Independent Tissue Viability Consultant. PMID- 30521363 TI - Can early detection prevent venous leg ulceration? AB - Venous leg ulceration is the most common form of leg ulceration, affecting 1.5% of the UK adult population. This was reviewed within the latest best practice statement (2016) which set out to create clear guidance on the assessment, management and preventing the reoccurrence of venous leg ulceration. With a growing elderly population at risk of venous insufficiency, early identification of those at risk is vital in the fight to reduce the number of people suffering with chronic venous ulceration. This article looks at the need for early assessment and commencement of appropriate treatment in order to reduce the occurrence of venous ulceration and improve clinical processes across the UK. PMID- 30521364 TI - Nurse's knitted poppies blossom into annual fundraiser for Woundcare4Heroes. PMID- 30521365 TI - Wound Expo 2018 highlights. PMID- 30521366 TI - Separate and interacting effects of the endogenous circadian system and behaviors on plasma aldosterone in humans. AB - INTRODUCTION: Measurements of aldosterone for diagnosis of primary aldosteronism are usually made from blood sampled in the morning when aldosterone typically peaks. We tested the relative contributions and interacting influences of the circadian system, ongoing behaviors and prior sleep to this morning peak in aldosterone. METHODS: To determine circadian rhythmicity and separate effect of behaviors on aldosterone, 16 healthy participants completed a 5-day protocol in dim-light while all behaviors ranging from sleep to exercise were standardized and scheduled evenly across the 24-h circadian period. In another experiment, to test the separate effects of prior nocturnal sleep or the inactivity that accompanies sleep on aldosterone, 10 healthy participants were studied across two nights: one with sleep and one with maintained wakefulness (randomized order). Plasma aldosterone was measured repeatedly in each experiment. RESULTS: Aldosterone had a significant endogenous rhythm (p<0.001), rising across the circadian night and peaking in the morning (~8 AM). Activity, including exercise, increased aldosterone, and different behaviors modulated aldosterone differently across the circadian cycle (circadian/behavioral interaction; p<0.001). In the second experiment, prior nocturnal sleep and prior rested wakefulness both increased plasma aldosterone (p<0.001) in the morning--to the same extent as the change in circadian phases between evening and morning. CONCLUSIONS: The morning increase in aldosterone is due to effects of the circadian system plus increased morning activities, and not prior sleep or the inactivity accompanying sleep. These findings have implications for the time of and behaviors preceding measurement of aldosterone, especially under conditions of shift work and jet lag. PMID- 30521367 TI - Application of resilience theories in the transition to parenthood: a scoping review. AB - OBJECTIVE: Investigate the use of resilience theories in the transition to parenthood literature. BACKGROUND: The transition to parenthood is a key developmental experience for many adults. Resilience is a unifying theoretical concept which incorporates many of the skills and resources linked with the transition to parenthood, but the uptake of resilience theory in this literature is unknown. METHODS: We used a scoping review to examine the use of resilience theory in published transition to parenthood research. This included a systematic search of the literature, descriptive analysis of theories and methods used and an assessment of theoretical integration. RESULTS: We identified 17 studies which met inclusion criteria. Explicit use of theory occurred in six studies and quality of theoretical integration was high for all of these. Resilience was seen as a desirable concept for mapping complex data, taking a holistic approach to psychological health and acknowledging environmental and systemic influences. We also identified 29 resilience supporting factors including positive self-concept, optimism, social support, family relationships, community services and social connectedness. CONCLUSION: Resilience is a useful concept for synthesising information about the transition to parenthood. PMID- 30521368 TI - Intra-articular injection of hydrogen sulfide decreased the progression of gonarthrosis. AB - Hydrogen sulfide (H2S) is found in both the plasma and synovial fluid of patients with gonarthrosis. In the present study, we investigated whether intra-articular injection of sodium hydrosulfide (NaSH) (1 mM, 30 MUL), a H2S donor, might affect gonarthrosis in rats. Gonarthrosis was induced surgically in the left knees of rats and left for 6 weeks for the development of disease. Then, intra-articular injections of NaSH or methylprednisolone (1 mg/kg, 30 MUL) were administered to rats. Half of each group was sacrificed at the end of the first day and the other half was sacrificed at the end of 4 weeks to evaluate early and later effects of injections on gonarthrosis. The injury induced by anterior cruciate ligament resection and medial meniscectomy in rats caused the development of gonarthrosis. As the duration lengthened after gonarthrosis induction, the progression of the disease continued. According to the modified Mankin Scoring System, intra articular injection of NaSH histopathologically slowed the progression of gonarthrosis, whereas methylprednisolone was ineffective. In addition, NaSH decreased apoptosis in rat knees with gonarthrosis. Each treatment did not cause injury to healthy knees. Our results lead to the consideration that intra articular NaSH administration may be effective in the progression of gonarthrosis. PMID- 30521369 TI - Hatching success and survival of fish early life stages in a chronic exposure to nevirapine: a case study of the Mozambique tilapia. AB - The anti-retroviral nevirapine has been detected in surface waters throughout South Africa and its effects on non-target aquatic animals are still unknown. The aim was to investigate the potential effects of nevirapine on the hatching success and survival of Oreochromis mossambicus early life stages through a chronic exposure. The exposer started with newly fertilized O. mossambicus eggs and concluded 30 days after hatching. Environmental relevant concentration of nevirapine (1.48 ug/l) was used in a static renewal system and a controlled environment (27 +/- 1 degrees C; 14:10 day/night cycle). The main endpoints assessed included hatching success and survival; a morphological assessment was also done on whole individual on day 1 and 30 post-hatching to identify any physical abnormality. Nevirapine had no noticeable effects on the hatching success and survival of O. mossambicus larvae; no statistically significant differences were observed between the control and the nevirapine exposed fish (p > 0.05). PMID- 30521370 TI - Social support, social participation, & depression among caregivers and non caregivers in Canada: a population health perspective. AB - OBJECTIVES: The study used data from the Canadian Longitudinal Study on Aging to investigate the relationships among social support (measured as affectionate support, emotional/informational support, positive social interaction, tangible support), social participation and depression in caregivers and non-caregivers. METHOD: Hierarchical multiple regression was used to investigate relationships among social support, social participation, and depression. Analyses of variance were used to examine differences in the means of social support, social participation, and depression between the two participant groups. RESULTS: Higher levels of affectionate support, positive social interaction, and social participation were associated with lower depression scores. Social participation was a significant mediator of the relationship between caregiver status and depression. Caregivers reported significantly higher levels of affectionate support, emotional/informational support, positive social interaction, and social participation than non-caregivers. There were no between-group difference in depression scores. DISCUSSION: The study provides support for the beneficial role of social participation in preserving caregiver mental health. Results are discussed in the context of policy and practice implications for caregivers in Canada. PMID- 30521371 TI - The nature of decision-making in people living with dementia: a systematic review. AB - OBJECTIVE: The objectives of this systematic review were to: 1) understand how people living with dementia are involved in making decisions; 2) explore the different decisional styles and domains of decision-making that people living with dementia experience and 3) identify what influences the level of decisional involvement of people living with dementia. METHODS: A systematic review of literature identified studies from Medline, PsycINFO, HAPI and CINAHL databases. Search terms related to decision-making and dementia. Qualitative and quantitative research designs were included. Appraisal of included studies was done using quality ratings. All studies focused on how decision-making took place. Extracted findings were synthesised narratively with concept mapping, conceptualisation and an exploration of connections between studies to develop an overall model of decision-making involvement Results: Fifteen studies fully met the eligibility criteria (thirteen qualitative and two quantitative). All studies had moderate (n = 10) to high (n = 5) quality ratings. Participants were predominantly people living with dementia (n = 13), Parkinson's disease and stroke. The model of decision-making encompasses four decisional styles (managed autonomy, mutual, reductive and delegated) determined by different degrees of involvement from the person living with dementia and their supporter. The decisional style implemented was influenced by the presence or absence of background (the Freedom of Choice framework) and contextual factors (risk, relationships and resources). CONCLUSION: Decision-making in dementia is complex and influenced by many factors beyond cognitive impairment alone. This review indicates that decision-making in dementia takes place through decisional styles, determined by unique levels of involvement from people living with dementia and their carers. PMID- 30521372 TI - Recommended housing densities for research mice: filling the gap in data-driven alternatives. AB - Space recommendations for mice made in the Guide for Care and Use of Laboratory Animals have not changed since 1972, despite important improvements in husbandry and caging practices. The 1996 version of the Guide put forth a challenge to investigators to produce new data evaluating the effects of space allocation on the well-being of mice. In this review, we summarize many studies published in response to this challenge. We distinguish between studies using ventilated or nonventilated caging systems and those evaluating reproductive performance or general well-being of adult mice. We discuss how these studies might affect current housing density considerations in both production and research settings and consider gaps in mouse housing density research. Additionally, we discuss reliable methods used to monitor and quantify general well-being of research mice. Collectively, this large body of new data suggests that husbandry practices dictating optimal breeding schemes and space allocation per mouse can be reconsidered. Specifically, these data demonstrate that prewean culling of litters has no benefit, trio breeding is an effective production strategy without adversely affecting pup survival and well-being, and housing of adult mice at densities of up to twice current Guide recommendations does not compromise well being for most strains.-Svenson, K. L., Paigen, B. Recommended housing densities for research mice: filling the gap in data-driven alternatives. PMID- 30521373 TI - microRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex. AB - Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self renewal is controlled by choline via the expression of a microRNA (miR-129-5p), whose role in the developing brain has not been examined, and which, in turn, inhibits synthesis of the epidermal growth factor receptor (EGFR) protein. Specifically, we found that low choline (LC) availability led to the upregulation of miR-129-5p expression in cortical NPCs in vitro and in vivo, causing the downregulation of EGFR and thereby disrupting NPC self-renewal and cortical neurogenesis. Furthermore, in response to LC availability, methylation potential (the S-adenosylmethionine: S-adenosylhomocysteine ratio) in the developing brain was reduced. Restoring methylation potential in LC cortical NPCs led to the re establishment of normal miR-129-5p expression. We concluded that inhibiting miR 129-5p function and restoring EGFR protein levels in vivo is sufficient to reverse LC-induced defects in cortical NPC self-renewal. For the first time, to our knowledge, we have identified the molecular links that explain how a change in the availability of the diet metabolite choline impacts the essential cellular processes underlying brain development.-Trujillo-Gonzalez, I., Wang, Y., Friday, W. B., Vickers, K. C., Toth, C. L., Molina-Torres, L., Surzenko, N., Zeisel, S. H. microRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex. PMID- 30521374 TI - Elevated truncated oxidized phospholipids as a factor exacerbating ALI in the aging lungs. AB - As mechanisms controlling redox homeostasis become impaired with aging, exaggerated oxidant stress may cause disproportional oxidation of cell membranes and circulating phospholipids (PLs), leading to the formation of truncated oxidized PL products (Tr-OxPLs), which exhibit deleterious effects. This study investigated the role of elevated Tr-OxPLs as a factor exacerbating inflammation and lung barrier dysfunction in an animal model of aging. Mass spectrometry analysis of Tr-OxPL species in young (2-4 mo) and aging (18-24 mo) mice revealed elevated basal levels of several products [1-palmitoyl-2-(5-oxovaleroyl)- sn glycero-phosphocholine (POVPC), 1-palmitoyl-2-glutaroyl- sn-glycero phosphocholine, lysophosphocholine, 1-palmitoyl-2-(9-oxo-nonanoyl)- sn-glycero-3 phosphocholine, 1-palmitoyl-2-azelaoyl- sn-glycero-3-phosphocholine, O-1-O palmitoyl-2-O-(5,8-dioxo-8-hydroxy-6-octenoyl)-l-glycero-3-phosphocholine, and others] in the aged lungs. An intratracheal (i.t.) injection of bacterial LPS caused increased generation of Tr-OxPLs in the lungs but not in the liver, with higher levels detected in the aged group. In addition, OxPLs clearance from the lung tissue after LPS challenge was delayed in the aged group. The impact of Tr OxPLs on endothelial cell (EC) barrier compromise under inflammatory conditions was further evaluated in the 2-hit cell culture model of acute lung injury (ALI). EC barrier dysfunction caused by cell treatment with a cytokine mixture (CM) was augmented by cotreatment with low-dose Tr-OxPLs, which did not significantly affect endothelial function when added alone. Deleterious effects of Tr-OxPLs on inflamed ECs stimulated with CM were associated with further weakening of cell junctions and more robust EC hyperpermeability. Aged mice injected intratracheally with TNF-alpha exhibited a more pronounced elevation of cell counts and protein content in bronchoalveolar lavage (BAL) samples. Interestingly, intravenous administration of low POVPC doses-which did not affect BAL parameters alone in young mice exposed to i.t. TNF-alpha challenge-augmented lung injury to the levels observed in aged mice stimulated with TNF-alpha alone. Inhibition of Tr-OxPL generation by ectopic expression of PL-specific platelet activating factor acetylhydrolase 2 (PAFAH2) markedly reduced EC dysfunction induced by CM, whereas PAFAH2 pharmacologic inhibition augmented deleterious effects of cytokines on EC barrier function. Moreover, exacerbating effects of PAFAH2 inhibition on TNF-alpha-induced lung injury were observed in vivo. These results demonstrate an age-dependent increase in Tr-OxPL production under basal conditions and augmented Tr-OxPL generation upon inflammatory stimulation, suggesting a major role for elevated Tr-OxPLs in more severe ALI and delayed resolution in aging lungs.-Ke, Y., Karki, P., Kim, J., Son, S., Berdyshev, E., Bochkov, V. N., Birukova, A. A., Birukov, K. G. Elevated truncated oxidized phospholipids as a factor exacerbating ALI in the aging lungs. PMID- 30521375 TI - Low-value care: antipsychotic medication use among community-dwelling medicare beneficiaries with Alzheimer's disease and related dementias and without severe mental illness. AB - BACKGROUND: Antipsychotic medication use among elderly with Alzheimer's disease and related dementias (ADRD) and without severe mental illness is considered as low-value care. Our objective was to assess the factors associated with this inappropriate use of antipsychotic medications among community-dwelling Medicare beneficiaries with ADRD and without severe mental illness. METHODS: This study used a retrospective cross-sectional design. Data for this study were derived from the nationally representative Medicare Current Beneficiary Survey (MCBS) and linked Medicare claims. Logistic regression models were used to examine factors associated with low-value care. RESULTS: Overall 8.5% had low-value care. In the final adjusted logistic regression model, race other than Hispanic or Non Hispanic White (AOR =0.54, 95% CI = [0.30,0.98]), individuals over 80 years of age (AOR =0.53, 95% CI = [0.36,0.76]), and obese individuals (AOR =0.55, 95% CI = [0.35,0.85]) had significantly lower odds of receiving low-value care. Those with depression (AOR =1.71, 95% CI = [1.21, 2.43]), who lived in the Midwest (AOR =1.7, 95% CI = [1.08,2.68]), and with a higher number of ADL limitations (AOR =1.28, 95% CI = [1.19,1.38]) had significantly higher odds of low-value care. CONCLUSIONS: There were subgroup differences in low-value care. Interventions may target these subgroups to reduce low-value care. PMID- 30521376 TI - Obstetric Racism: The Racial Politics of Pregnancy, Labor, and Birthing. AB - In this article, I analyze the birth stories of Black women living in the United States. Their birth stories describe various forms of racism during medical encounters while they were pregnant or during labor and delivery. In the global women's health arena, the issues raised are viewed as obstetric violence. However, obstetric racism-as both an occurrence and analytic-best captures the particularities of Black women's reproductive care during the pre- and post-natal period. Obstetric racism is a threat to positive birth outcomes. I argue that birth workers including midwives and doulas, mediate obstetric racism and stratified reproductive outcomes. PMID- 30521377 TI - Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1. AB - Equilibrative nucleoside transporters (ENTs) translocate nucleosides and nucleobases across plasma membranes, as well as a variety of anti-cancer, -viral, and -parasite nucleoside analogs. They are also key members of the purinome complex and regulate the protective and anti-inflammatory effects of adenosine. Despite their important role, little is known about the mechanisms involved in their regulation. We conducted membrane yeast 2-hybrid and coimmunoprecipitation studies and identified, for the first time to our knowledge, the existence of protein-protein interactions between human ENT1 and ENT2 (hENT1 and hENT2) proteins in human cells and the formation of hetero- and homo-oligomers at the plasma membrane and the submembrane region. The use of NanoLuc Binary Technology allowed us to analyze changes in the oligomeric status of hENT1 and hENT2 and how they rapidly modify the uptake profile for nucleosides and nucleobases and allow cells to respond promptly to external signals or changes in the extracellular environment. These changes in hENTs oligomerization are triggered by PKC activation and subsequent action of protein phosphatase 1.-Grane-Boladeras, N., Williams, D., Tarmakova, Z., Stevanovic, K., Villani, L. A., Mehrabi, P., Siu, K. W. M., Pastor-Anglada, M., Coe, I. R. Oligomerization of equilibrative nucleoside transporters: a novel regulatory and functional mechanism involving PKC and PP1. PMID- 30521378 TI - Global Tudor-SN transgenic mice are protected from obesity-induced hepatic steatosis and insulin resistance. AB - In the current study, we explored the impact of Tudor-staphylococcal nuclease (SN) on obesity induced by a high-fat diet (HFD) in mice, because the functional involvement of Tudor-SN in lipid metabolism in vivo is unknown. HFD-transgenic (Tg) mice exhibited reductions in hepatic steatosis and systemic insulin resistance. There was no difference in hepatic lipid accumulation between chow fed wild-type (WT) and chow-fed Tg mice; consistently, no difference in activation of the lipogenic pathway was detected. Overactivation of hepatic nuclear sterol regulatory element-binding protein (nSrebp2)-2, the central regulator of cholesterol metabolic proteins, was observed in HFD-Tg livers along with improved cholesterol homeostasis, but no such changes were observed in HFD WT livers. Consistent results were observed in vitro in alpha-mouse liver 12 cells treated with palmitate mimicking the HFD state. In addition, global gene analysis indicated that various downstream targets of nSrebp2, were up-regulated in HFD-Tg livers. Moreover, HFD-WT mice displayed islet hypertrophy and suppression of glucose-induced insulin secretion from islets, whereas HFD-Tg mice had normal pancreatic islets. This finding suggests that the improved pancreatic metabolism of HFD-Tg mice is related to the systemic effect of insulin resistance, not to the autonomous influence of pancreatic cells. Tudor-SN is likely to be a key regulator for ameliorating HFD-induced hepatic steatosis and systemic insulin resistance in vivo.-Wang, X., Xin, L., Duan, Z., Zuo, Z., Wang, Y., Ren, Y., Zhang, W., Sun, X., Liu, X., Ge, L., Yang, X., Yao, Z., Yang, J. Global Tudor-SN transgenic mice are protected from obesity-induced hepatic steatosis and insulin resistance. PMID- 30521379 TI - Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress induced endothelial dysfunction in renal microvessels. AB - Protein tyrosine (Tyr) nitration, the covalent addition of a nitro group (*NO2) to Tyr residues, is emerging as a candidate mechanism of endothelial dysfunction. Previous studies have shown that Tyr nitration is primarily induced by nitrosative stress, a process characterized by the production of reactive nitrogen species, especially peroxynitrite anion (ONOO-), which is considered a secondary product of NO in the presence of superoxide radicals (O2*-). However, the impact of nitrosative stress-induced Tyr nitration on endothelial dysfunction has not been thoroughly elucidated to date. We developed an endothelial dysfunction model, a process called "endothelial-to-mesenchymal transition (EndMT)," and evaluated the production of NO, O2*-, and protein nitration during EndMT. The results showed that TGF-beta1 stimulation induced EndMT and elevated endothelial NO and O2*- production as well as nitration of the catalytic subunit of protein phosphatase (PP)2A. Mass spectrometry analysis showed that Tyr265 was the nitration site in the catalytic subunit of protein phosphatase (PP)2A, and this Tyr nitration increased PP2A activity and disrupted endothelial integrity. To devise an endothelial-targeted anti-PP2Ac nitration strategy, a mimic peptide, tyrosine 265 wild type (Y265WT), conjugated with the cell-penetrating peptide HIV 1 TAT protein (TAT) was synthesized. PP2Ac nitration and PP2A activity were significantly inhibited by pretreatment with TAT-265WT, and the integrity of endothelial cells was maintained. Furthermore, injection of TAT-265WT attenuated renal nitration formation and caused anticapillary rarefaction in a unilateral urethral obstructive nephropathy model. Taken together, these results offer preclinical proof of concept for TAT-265WT as a tractable agent to protect against nitrosative stress-induced endothelial dysfunction in renal microvessels. Deng,Y., Cai, Y., Liu, L., Lin, X., Lu, P., Guo, Y., Han, M., Xu, G. Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. PMID- 30521380 TI - Development of a host-microbiome model of the small intestine. AB - The intestinal epithelium plays an essential role in the balance between tolerant and protective immune responses to infectious agents. In vitro models do not typically consider the innate immune response and gut microbiome in detail, so these models do not fully mimic the physiologic aspects of the small intestine. We developed and characterized a long-term in vitro model containing enterocyte, goblet, and immune-like cells exposed to a synthetic microbial community representative of commensal inhabitants of the small intestine. This model showed differential responses toward a synthetic microbial community of commensal bacterial inhabitants of the small intestine in the absence or presence of LPS from Escherichia coli O111:B4. Simultaneous exposure to LPS and microbiota induced impaired epithelial barrier function; increased production of IL-8, IL-6, TNF-alpha, and C-X-C motif chemokine ligand 16; and augmented differentiation and adhesion of macrophage-like cells and the overexpression of dual oxidase 2 and TLR-2 and -4 mRNA. In addition, the model demonstrated the ability to assess the adhesion of specific bacterial strains from the synthetic microbial community more specifically, Veillonella parvula-to the simulated epithelium. This novel in vitro model may assist in overcoming sampling and retrieval difficulties when studying host-microbiome interactions in the small intestine.-Calatayud, M., Dezutter, O., Hernandez-Sanabria, E., Hidalgo-Martinez, S., Meysman, F. J. R., Van de Wiele, T. Development of a host-microbiome model of the small intestine. PMID- 30521381 TI - Evidence for functional interactions between the placenta and brain in pregnant mice. AB - The placenta plays a pivotal role in the development of the fetal brain and also influences maternal brain function, but our understanding of communication between the placenta and brain remains limited. Using a gene expression and network analysis approach, we provide evidence that the placenta transcriptome is tightly interconnected with the maternal brain and fetal brain in d 15 pregnant C57BL/6J mice. Activation of serotonergic synapse signaling and inhibition of neurotrophin signaling were identified as potential mediators of crosstalk between the placenta and maternal brain and fetal brain, respectively. Genes encoding specific receptors and ligands were predicted to affect functional interactions between the placenta and brain. Paralogous genes, such as sex comb on midleg homolog 1/scm-like with 4 mbt domains 2 and polycomb group ring finger (Pcgf) 2/ Pcgf5, displayed antagonistic regulation between the placenta and brain. Additionally, conditional ablation of forkhead box a2 ( Foxa2) in the glands of the uterus altered the transcriptome of the d 15 placenta, which provides novel evidence of crosstalk between the uterine glands and placenta. Furthermore, expression of cathepsin 6 and monocyte to macrophage differentiation associated 2 was significantly different in the fetal brain of Foxa2 conditional knockout mice compared with control mice. These findings provide a better understanding of the intricacies of uterus-placenta-brain interactions during pregnancy and provide a foundation and model system for their exploration. Behura, S. K., Kelleher, A. M., Spencer, T. E. Evidence for functional interactions between the placenta and brain in pregnant mice. PMID- 30521382 TI - MMP14 empowers tumor-initiating breast cancer cells under hypoxic nutrient depleted conditions. AB - Tumor-initiating cells (TICs) existing in breast cancer are thought to be involved in initiation, progression, and relapse of tumors. In these processes, the epithelial-to-mesenchymal transition (EMT) and proteases are crucial factors that also dependent on the tumor milieu, including hypoxic nutrient-deprived, as well as normoxic nutrient-rich, environments. Therefore, we investigated EMT and proteases in TICs and their response to different environments by means of a newly generated immortalized TIC (iTIC) line. With the use of primary CD24+CD90+CD45- TICs from the mouse mammary tumor virus-polyoma middle T mouse breast cancer model, iTICs were generated by single cell-initiated sphere and subsequent 2-dimensional monolayer culture. Our data demonstrate the possibility to generate iTICs that are highly tumorigenic in culture and in mouse mammary fat pad. Contrasting environmental conditions provide these cells with a phenotypic and molecular plasticity that has a growth-promoting character in nutrient-rich normoxia and a motile character in nutrient-deprived hypoxia. Expression profiling revealed partial and dynamically changing EMT states, as well as a significantly up-regulated proteolytic signature, including many metalloproteinases, such as matrix metalloproteinase 14 ( Mmp14). Inhibitor treatment of metalloproteinases, as well as short hairpin RNA-mediated knockdown of Mmp14 strongly impacted TIC characteristics, including tumor initiation, cell growth, migration, and invasion, especially in starved environments. We conclude that metalloproteinases empower TICs to adapt to changing environments. Hillebrand, L. E., Wickberg, S. M., Gomez-Auli, A., Follo, M., Maurer, J., Busch, H., Boerries, M., Reinheckel, T. MMP14 empowers tumor-initiating breast cancer cells under hypoxic nutrient-depleted conditions. PMID- 30521383 TI - Roles of CD133 in microvesicle formation and oncoprotein trafficking in colon cancer. AB - Extracellular vesicles contain various cellular components that are involved in tumor growth, metastasis, and immune escape. Extracellular vesicles are classified into 2 groups, namely, exosomes and microvesicles (MV). Although the formation and roles of exosomes have been studied, the exact functions of MVs and mechanisms underlying MV release are not fully understood. We found that epidermal growth factor accelerates the release of MVs from the plasma membrane by inducing NF-kappaB activation and CD133 expression. The amount and sizes of budding MVs were found to be dependent on the expression level of CD133, which regulates the activities of the small guanosine 5'-triphosphatases RhoA and Rac1. CD133-containing MVs released from KRAS mutant colon cancer cells delivered KRAS mutant to adjacent nontumorigenic cells and activated KRAS downstream signaling. CD133-containing MVs were found to promote the migration and invasion of adjacent cells. CD133-containing MVs induced the development of chemoresistance by abolishing the inhibitory effects of anti-epidermal growth factor receptor (EGFR) drugs on cell proliferation and motility in colon cancer. These results suggest that CD133 acts as a novel modulator in MV release and in oncoprotein trafficking. CD133 can serve as a therapeutic target for treatment of anti-EGFR drug-resistant colon cancer.-Kang, M., Kim, S., Ko, J. Roles of CD133 in microvesicle formation and oncoprotein trafficking in colon cancer. PMID- 30521384 TI - Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation. AB - Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-kappaB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-gamma plus TNF-alpha restimulation induced iNOS expression as a model of MSC activation, because IFN-gamma and TNF alpha play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-alpha, IL 1beta, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation. PMID- 30521385 TI - Microgravity-induced hepatogenic differentiation of rBMSCs on board the SJ-10 satellite. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are able to differentiate into functional hepatocytelike cells, which are expected to serve as a potential cell source in regenerative medicine, tissue engineering, and clinical treatment of liver injury. Little is known about whether and how space microgravity is able to direct the hepatogenic differentiation of BMSCs in the actual space microenvironment. In this study, we examined the effects of space microgravity on BMSC hepatogenic differentiation on board the SJ-10 Recoverable Scientific Satellite. Rat BMSCs were cultured and induced in hepatogenic induction medium for 3 and 10 d in custom-made space cell culture hardware. Cell growth was monitored periodically in orbit, and the fixed cells and collected supernatants were retrieved back to the Earth for further analyses. Data indicated that space microgravity improves the differentiating capability of the cells by up regulating hepatocyte-specific albumin and cytokeratin 18. The resulting cells tended to be maturated, with an in-orbit period of up to 10 d. In space, mechanosensitive molecules of beta1-integrin, beta-actin, alpha-tubulin, and Ras homolog gene family member A presented enhanced expression, whereas those of cell surface glycoprotein CD44, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, vinculin, cell division control protein 42 homolog, and Rho associated coiled-coil kinase yielded reduced expression. Also observed in space were the depolymerization of actin filaments and the accumulation of microtubules and vimentin through the altered expression and location of focal adhesion complexes, Rho guanosine 5'-triphosphatases, as well as the enhanced exosome mediated mRNA transfer. This work furthers the understanding of the underlying mechanisms of space microgravity in directing hepatogenic differentiation of BMSCs.-Lu, D., Sun, S., Zhang, F., Luo, C., Zheng, L., Wu, Y., Li, N., Zhang, C., Wang, C., Chen, Q., Long, M. Microgravity-induced hepatogenic differentiation of rBMSCs on board the SJ-10 satellite. PMID- 30521386 TI - Nordic homecare nursing from the perspective of homecare nurses-a meta ethnography. AB - The pressure on homecare nursing in the Nordic countries has increased in recent years because of a reorganisation of healthcare systems that has put a focus on very early discharge from hospital as well as demographic changes. This article details an analysis of the findings of 13 published qualitative research reports about Nordic homecare nurses' experiences of their work. Using a process of meta ethnography, the authors identify five themes within the primary research: home care as a professional practice on foreign ground; home care as a massive time constraint; home care as fair rationing; home care as relationships with relatives as fellow players or opponents; and home care as latent paternalism. These have two main implications for practice: homecare nurses should continuously be taught how to cooperate with partners who are emotionally involved; and also homecare nurses may benefit from training that focuses on the challenges of carrying out professional work in private settings. PMID- 30521387 TI - A closer look at the social prescribing phenomenon. PMID- 30521388 TI - Self-management of chronic skin conditions. PMID- 30521389 TI - Lymphoedema: a new year and new opportunities! PMID- 30521390 TI - A life like yours: dedicated to nursing. PMID- 30521391 TI - Planning for more palliative care. PMID- 30521392 TI - Letters to the editor. PMID- 30521394 TI - Infection control in the community. PMID- 30521393 TI - Seeking an order to withdraw treatment from the Court of Protection. AB - The Court of Protection is the specialist court that makes decisions in relation to people who lack decision-making capacity. In this article, Richard Griffith considers the powers of the Court of Protection and discusses when it might be necessary for a district nurse to seek an order from the court in relation to the care or treatment of a patient. PMID- 30521396 TI - The blueprint for palliative care provision. PMID- 30521395 TI - Influences on clinical decision-making during a community placement: reflections of a student nurse. AB - High quality care is dependent on good clinical judgement and often-complex decision making. Nurses need to be able to justify and defend their clinical decisions. In this article, a third-year nursing student reflects on an incident from a community placement involving a collaborative clinical decision. Carper's (1978) four fundamental patterns of knowing are used to analyse the decision making process. It is shown that influences on decision-making include prior knowledge and expertise, law and accountability, and ethical principles such as respect for autonomy and beneficence. Good communication, interpersonal skills and a person-centred approach have a bearing on decision-making. It is argued that intuition also has a place and may be increasingly used with experience. PMID- 30521397 TI - Faecal incontinence: investigation, treatment and management. AB - Faecal incontinence (FI) is a hidden problem that is under-diagnosed, under investigated and under treated. Up to 10% of adults can experience an episode of FI. The prevalence of FI in the adult population has been estimated at 0.8-6.2%. Recent North American research indicates a prevalence of 8.3% in adults living in the community. This article explores the reasons why adults can develop FI, the importance of assessment, what treatments are available and how intractable FI can best be managed. PMID- 30521398 TI - Residual Normality Assumption and the Estimation of Multiple Membership Random Effects Models. AB - While conventional hierarchical linear modeling is applicable to purely hierarchical data, a multiple membership random effects model (MMrem) is appropriate for nonpurely nested data wherein some lower-level units manifest mobility across higher-level units. Although a few recent studies have investigated the influence of cluster-level residual nonnormality on hierarchical linear modeling estimation for purely hierarchical data, no research has examined the statistical performance of an MMrem given residual non-normality. The purpose of the present study was to extend prior research on the influence of residual non-normality from purely nested data structures to multiple membership data structures. Employing a Monte Carlo simulation study, this research inquiry examined two-level MMrem parameter estimate biases and inferential errors. Simulation factors included the level-two residual distribution, sample sizes, intracluster correlation coefficient, and mobility rate. Results showed that estimates of fixed effect parameters and the level-one variance component were robust to level-two residual non-normality. The level-two variance component, however, was sensitive to level-two residual non-normality and sample size. Coverage rates of the 95% credible intervals deviated from the nominal value assumed when level-two residuals were non-normal. These findings can be useful in the application of an MMrem to account for the contextual effects of multiple higher-level units. PMID- 30521399 TI - National Health Care Spending In 2017: Growth Slows To Post-Great Recession Rates; Share Of GDP Stabilizes. AB - Total nominal US health care spending increased 3.9 percent to $3.5 trillion in 2017, slowing from growth of 4.8 percent in 2016. The rate of growth in 2017 was similar to the increases between 2008 and 2013, which preceded the faster growth experienced during 2014-15-a period that was marked by insurance coverage expansion and large increases in prescription drug spending. Slower growth in health care spending in 2017 was mainly attributable to the use and intensity of goods and services, particularly for hospital care, physician and clinical services, and retail prescription drugs. Nearly all major sources of insurance and sponsors of health care experienced slower growth in 2017. On a per capita basis, spending on health care increased 3.2 percent and reached $10,739 in 2017. The share of gross domestic product devoted to health care spending was 17.9 percent in 2017, similar to the share in 2016. PMID- 30521400 TI - Workload and Performance: Associations, Insensitivities, and Dissociations. AB - OBJECTIVE:: The aim of this study was to distill and define those influences under which change in objective performance level and the linked cognitive workload reflections of subjective experience and physiological variation either associate, dissociate, or are insensitive, one to another. BACKGROUND:: Human factors/ergonomics frequently employs users' self-reports of their own conscious experience, as well as their physiological reactivity, to augment the understanding of changing performance capacity. Under some circumstances, these latter workload responses are the only available assessment information to hand. How such perceptions and physiological responses match, fail to match, or are insensitive to the change in primary-task performance can prove critical to operational success. The reasons underlying these associations, dissociations, and insensitivities are central to the success of future effective human-machine interaction. METHOD:: Using extant research on the relations between differing methods of workload assessment, factors influencing their association, dissociation, and insensitivity are identified. RESULTS:: Dissociations and insensitivities occur more frequently than extant explanatory theories imply. Methodological and conceptual reasons for these patterns of incongruity are identified and evaluated. APPLICATION:: We often seek convergence of results in order to provide coherent explanations as bases for future prediction and practical design implementation. Identifying and understanding the causes as to why different reflections of workload diverge can help practitioners toward operational success. PMID- 30521401 TI - Urine Catecholamines in Children with Severe Enterovirus A71 infection: Comparison with Paediatric Septic Shock. AB - PURPOSE: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine catecholamine concentrations in severe EV-A71 infected children. METHODS: A total of 35 children, aged 2.5 +/- 2.1 years, were divided into three groups. Group 1: 15 septic shock patients, group 2: 17 EV-A71 stage-2 patients, and group 3: 3 EV-A71-stage-4 patients. The laboratory results, cardiac biomarkers and urine catecholamine concentrations were statistically analyzed. RESULTS: Group 1 had the highest C-reactive protein levels and group 2 had the lowest B-type natriuretic peptide and its N-terminal prohormone among the groups (p = 0.039, <0.01 and <0.01, respectively). Group 3 patients had significantly higher urine catecholamine and troponin-I values among the groups. If urine epinephrine >134 ug/gCr, norepinephrine >176 ug/gCr, and vanillylmandelic acid >11.7 mg/gCr were used as the cut-off points to differentiate group 2 and 3, the sensitivities and specificity were all 100%. CONCLUSIONS: The significantly elevated urine catecholamine concentrations in EV A71-stage-4 patients support the hypothesis that hypercatecholaminemia-related heart failure is involved in severe EV-A71 infection. Urine catecholamines could be used as reliable biomarkers for differentiation of severe EV-A71 infection with or without heart failure and septic shock. PMID- 30521402 TI - Asymmetric Synthesis of Chiral Flavan-3-Ols. AB - Flavan-3-ols are a series of natural products widely present in plants and show versatile biological activities. The structures of such compounds are characterized by owing two adjacent chiral centers and three rings. Their interesting structures and promising biological activities have driven increasing research developments toward the preparation of enantioenriched flavan-3-ols. This review summarizes the recent approaches for the asymmetric synthesis of chiral flavan-3-ols from two strategies in the construction of chiral centers. The key steps in the synthetic protocol involve Sharpless asymmetric dihydroxylation, Shi asymmetric epoxidation and Sharpless asymmetric epoxidation. PMID- 30521403 TI - The Effects of Load Stability and Visual Access During Asymmetric Lifting Tasks on Back and Upper Extremity Biomechanical Responses. AB - OBJECTIVE:: To explore the change of muscular and biomechanical responses in different load stability and visual access conditions during an asymmetric lifting task. BACKGROUND:: Previous studies found that lifting unstable loads resulted in changes to the biomechanical loads experienced by the spine and upper extremities. However, researchers have not extensively investigated behaviors when people lift potentially unstable loads. It was hypothesized that lifting a potentially unstable load can lead to changes in lifting behavior, which may be mitigated by visual access to the load. METHOD:: Fourteen volunteers lifted either a stable load or a potentially unstable load that could move within the container during the lifting task. In half of the lifting conditions, the box was covered to restrict visual access when lifting. Spine kinematic and kinetic measures and surface electromyographic (EMG) signals from back, shoulder, and arm muscles were obtained. RESULTS:: Lifts of the stable load were faster and generally had higher peak muscle activations than lifts of the potentially unstable load. Participants had less spine flexion when handling the potentially unstable load without visual access. CONCLUSION:: When lifting and moving a potentially unstable load that could lead to a perturbation, people tended to lift the container more slowly comparing with lifting a stable load, which in turn reduced the peak muscle activities. APPLICATION:: In industry, there are many work situations where workers need to lift or carry unstable loads that can shift during transport. Providing visual access to the load may help mitigate some of these effects. PMID- 30521404 TI - Techniques for improving ophthalmic studies performed on administrative databases. PMID- 30521405 TI - Towards a regulation of HTA in Europe: the proposal from the European Commission. PMID- 30521406 TI - Choosing an ideal pharmacotherapeutic strategy for dyslipidemia in children. PMID- 30521407 TI - An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders. AB - INTRODUCTION: Neuroinflammation has a critical role in brain disorders. Cyclooxygenase (COX) is one of the principal drug targets for the reduction of neuroinflammation; however, studies have yielded mixed results for COX-inhibitors in the treatment of diverse acute and chronic models of epilepsy. Areas covered: The article covers the effects of COX-inhibitors in epilepsy disorders. A considerable emphasis has been placed on the antiepileptic and "disease modifying" properties of COX-1 and COX-2 inhibitors in various preclinical epilepsy models. Expert opinion: The effect of COX-inhibitors on epilepsy is inconclusive. Studies have indicated beneficial effects in preclinical models; however, proconvulsant or no effect have also been observed. These molecules may have a bidirectional role with early neuroprotective and delayed neurotoxic effects. Further systematic preclinical studies to establish the use of COX inhibitors in epilepsy are necessary. PMID- 30521408 TI - Building the evidence base for dengue vector control: searching for certainty in an uncertain world. AB - This review discusses biological and chemical methods for dengue vector control, using recently emerging summary evidence, meta-analyses and systematic reviews to conclude on practical public health recommendations for Aedes control, which is increasingly relevant in an era of widespread Chikungunya, yellow feer and Zika outbreaks. The analysis follows an a priori framework of systematic reviews by the authors on vector control methods, distinguishing vector control methods into biological, chemical and environmental methods. Findings of each published systematic review by the authors, following each individual vector control method, are summarised and compared in the discussion against the findings of existing meta-analyses covering all vector control methods. Analysing nine systematic reviews and comparing to two existing meta-analyses provided low-to moderate evidence that the control of Aedes mosquitoes can be achieved using 1) chemical methods, particularly indoor residual spraying and insecticide treated materials, and 2) biological methods, where appropriate. The level of efficacy and community effectiveness of the methods in most studies analysed is low, as was the overall assessment of study quality. Furthermore, the results show that too optimise results, larvae and adults should be targeted simultaneously. The quality of service delivery is probably one of the most important features of this analysis - and including high coverage. The analysis also highlights the urgent need for standards to guide the design and reporting of vector control studies, ensuring the validity and comparability of results. These studies should aim to include measurements of human transmission data - where and when possible. PMID- 30521409 TI - Application of amniotic membrane in reconstructive urology; the promising biomaterial worth further investigation. AB - INTRODUCTION: In reconstructive urology, autologous tissues such as intestinal segments, skin, and oral mucosa are used. Due to their limitations, reconstructive urologists are waiting for a novel material, which would be suitable for urinary tract wall replacement. Human amniotic membrane (AM) is a naturally derived biomaterial with a capacity to support reepithelization and inhibit scar formation. AM has a potential to become a considerable asset for reconstructive urology, i.e., reconstruction of ureters, urinary bladder and urethrae. Area covered: This review aims to discuss the potential application of human AM in reconstructive urology. The environment for urinary tract healing is particularly unfavorable due to the presence of urine and the tendency for extensive scarring. Due to its fetal origin, the bioactivity of AM is orientated to induce intrinsic regeneration mechanisms and inhibit scarring. This review introduces the concept of applying human AM in reconstructive urology procedures to improve their outcomes and future tissue engineering based strategies. Expert opinion: Many fields of medicine that have accomplished translational research have proven the usefulness of AM in clinical practice. There is an urgent need for studies to be conducted on large animal models that might convincingly demonstrate the underestimated potential of AM to urologists around the world. PMID- 30521410 TI - In vivo monitoring of intracellular Ca2+ dynamics in the pancreatic beta-cells of zebrafish embryos. AB - Assessing the response of pancreatic islet cells to glucose stimulation is important for understanding beta-cell function. Zebrafish are a promising model for studies of metabolism in general, including stimulus-secretion coupling in the pancreas. We used transgenic zebrafish embryos expressing a genetically encoded Ca2+ sensor in pancreatic beta-cells to monitor a key step in glucose induced insulin secretion; the elevations of intracellular [Ca2+]i. In vivo and ex vivo analyses of [Ca2+]i demonstrate that beta-cell responsiveness to glucose is well established in late embryogenesis and that embryonic beta-cells also respond to free fatty acid and amino acid challenges. In vivo imaging of whole embryos further shows that indirect glucose administration, for example by yolk injection, results in a slow and asynchronous induction of beta-cell [Ca2+]i responses, while intravenous glucose injections cause immediate and islet-wide synchronized [Ca2+]i fluctuations. Finally, we demonstrate that embryos with disrupted mutation of the CaV1.2 channel gene cacna1c are hyperglycemic and that this phenotype is associated with glucose-independent [Ca2+]i fluctuation in beta cells. The data reveal a novel central role of cacna1c in beta-cell specific stimulus-secretion coupling in zebrafish and demonstrate that the novel approach we propose - to monitor the [Ca2+]i dynamics in embryonic beta-cells in vivo - will help to expand the understanding of beta-cell physiological functions in healthy and diseased states. PMID- 30521411 TI - Insight into the perioperative management of direct oral anticoagulants: concerns and considerations. AB - INTRODUCTION: Direct oral anticoagulants (DOACs) have gained momentum in recent years in patients requiring anticoagulation for the prevention and management of venous thromboembolism and thromboembolic events caused by atrial fibrillation. The use of these agents involves potential bleeding complications, particularly during invasive procedures. With increasing use of DOACs, adequate knowledge regarding the perioperative management of patients on DOACs has become indispensable. Areas covered: This review covers the indications, mechanism of action, and pharmacokinetics of DOACs and their management in different perioperative settings based on various current guidelines and practices. The role of bridging therapy with heparin and the recently developed reversal agents are also discussed. Expert opinion: The perioperative management of DOACs is influenced by drug pharmacokinetics, potential comorbidities of the patient and perioperative thrombotic and bleeding risk. In low bleeding risk and minor procedures, continuing DOACs seems to be safe. Interrupting DOACs in high-risk procedures might be necessary and should be based on the elimination half-life of the drug and renal function of the patient. Further research is needed to better clarify the role of recently developed reversal agents in the perioperative setting and to identify specific laboratory tests to guide the perioperative management of DOACs. PMID- 30521412 TI - Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers. AB - Advances in genetic sequencing and other diagnostic technologies have enabled the use of precision medicine in clinical cancer care, as well as the development of novel therapies that are targeted to specific molecular drivers of cancer. Developing these new agents and making them accessible to patients requires global clinical studies and regulatory review and approval by different national regulatory agencies. Whereas these global trials present challenges for drug developers who conduct them and regulatory agencies who oversee them, they also raise practical issues about patients with low-frequency cancers who need these therapies. A lack of uniform standards in both regulatory approval for marketing and reimbursement for approved agents across countries may make the newly developed agent either unavailable or inaccessible to patients in certain countries or regions, even if patients from those countries or regions participated in the clinical research that established the safety and efficacy of the agent. In an effort to further understand and address this need, we convened an international workshop in 2017 in North Bethesda, MD. After presentations of the individual regulatory pathways for marketing approval and reimbursement for individual nations, participants discussed expedited pathways and specific challenges for uncommon cancers. As a matter of justice, agents being developed for rare cancers, pediatric cancers, or uncommon molecular subsets of common cancers need a pragmatic, science-based regulatory policy framework to clearly specify the type and quantity of evidence needed to demonstrate efficacy from these trials and evidence to support accessibility. PMID- 30521413 TI - Review of Haploidentical Hematopoietic Cell Transplantation. AB - Use of haploidentical (haplo) donors for hematopoietic cell transplantation (HCT) has significantly increased in the last decade. The major advantage with this strategy is universal availability and faster acquisition of the donor, along with affordability and provision of immunotherapy in post-transplantation period. Historically, haplo-HCT was associated with compromised outcomes because of high rates of graft-versus-host disease and graft failure, but after the development of a post-transplantation high-dose cyclophosphamide strategy, which results in selective T-cell depletion, these issues have been addressed to a large extent. Nevertheless, graft failure, high treatment-related mortality due to graft-versus host disease, infections, delayed immune reconstitution, and disease relapse remain significant concerns. As the experience with haplo-HCTs grows, the clinical outcomes are becoming more at par with those seen with fully matched unrelated donor allogeneic HCTs. PMID- 30521414 TI - Follow-up and adherence to glaucoma care by newly diagnosed glaucoma patients in enugu, nigeria. AB - PURPOSE: To determine uptake, adherence and influencing factors to follow-up care by newly diagnosed glaucoma patients from free eye screening exercise. METHODS: The study was a cross-sectional survey of newly diagnosed glaucoma patients during free eye screenings carried out in March and October, 2016 in Enugu, Nigeria. Data on participants were analyzed after a minimum of 6 months from the screening for uptake and adherence to follow-up care. Qualifying patients had questionnaires administered to them by phone interview. Information requested regards awareness, knowledge on diagnosis as well as reasons for non-uptake and non-adherence. RESULTS: In total, 182 newly diagnosed glaucoma patients were included of which 121(66.5%) were males, with median age of 50 years. About 164 (90.1%) had at least a primary education. There were more self-employed persons 59(32.4%) compared to other occupations. Uptake of follow-up care was 17.6% (32/182). Adherence rate was 25% (8/32). Major reasons for non-uptake were lack of funds 54.9% (n = 50/91), unprofessional staff attitude 13.2% (n = 12/91) and distance 11% (n = 10/91). Similarly, major reasons for non-adherence were lack of funds 32% (n = 8/25) and distance 16% (4/25). Knowledge and prior awareness of glaucoma were found to be significantly associated with uptake of follow-up care (p = 0.020). CONCLUSION: Uptake and adherence to follow-up was found to be low in this study population which was mainly attributed to financial challenge, unprofessional staff attitude and distance. Reviewing cost, adequate education of staff and patients and providing care closer to patients may significantly improve uptake of care after initial diagnosis. PMID- 30521415 TI - Nonwoven flax fibres geotextiles effects on solute heavy metals transport in porous media. AB - Filtration tests were carried out in laboratory columns filled with crushed sand with and without flax geotextiles to study the transfer and retention of soluble heavy metals. Divalent cations of copper, zinc and lead were simultaneously and continuously injected in filtration columns. Results show that, when geotextiles discs are present the retention of metals in sand is favoured and retention profiles are modified. In addition, and unlike synthetic geotextiles, flax fibres geotextiles contribute to the retention of a significant fraction of the cationic metal pollutants in their own structure. The overall metals retention efficiency of the filter is improved. Competition between cationic metals for adsorption on retention sites occurs in the column in the order Pb > Cu > Zn. Most of the lead is retained in the inlet of the column while copper and even more zinc migrate deeper in the column. PMID- 30521416 TI - Diet and prevention of type 2 diabetes mellitus: beyond weight loss and exercise. AB - INTRODUCTION: Insulin resistance (IR) and pancreatic beta-cell dysfunction are core pathophysiologic features of type 2 diabetes mellitus (T2DM). Select lifestyle and pharmacologic interventions, including weight loss, physical activity, a Mediterranean diet intervention, and hypoglycemic agents, have been shown to prevent or delay T2DM. However, dietary factors other than weight loss may also impact risk, mainly through effects to enhance insulin sensitivity, although some may also directly or indirectly impact pancreatic beta-cell function. Areas covered: A literature review of observational studies and randomized controlled trials (RCTs) was conducted, and the research indicates dietary factors showing promise for reducing T2DM risk include higher intakes of cereal fibers, unsaturated fatty acids, magnesium, and polyphenols (e.g. anthocyanins), while reducing dietary glycemic load, added sugars, and high-sugar beverages. Expert commentary: While these dietary factors are mainly supported by evidence from observational studies and RCTs of surrogate markers for T2DM, they are consistent with current recommendations to emphasize consumption of whole grains, nuts, seeds, legumes, seafood, fruits, and vegetables, while limiting intakes of saturated fatty acids, refined carbohydrates, and processed meats. Additional dietary intervention RCTs are needed to assess the efficacy of these promising dietary interventions for delaying or preventing the onset of T2DM. PMID- 30521417 TI - Circlular RNA BARD1 (Hsa_circ_0001098) overexpression in breast cancer cells with TCDD treatment could promote cell apoptosis via miR-3942/BARD1 axis. AB - Breast cancer threatened the health of millions of people around the world. Here we explored the influence of TCDD on the expression of circRNA_BARD1 (circ_0001098) in breast cancer and studied the potential molecular mechanism of circRNA_BARD1. The data from GSE76608 was applied to analyze differentially expressed circRNAs and mRNAs. The expressions of circRNA_BARD1, BARD1, miR-3942 3p, miR-4760-3p and apoptosis-related protein p53 were detected by qRT-PCR or western blot. Circinteractome, TargetScan, CIRCNET and dual luciferase reporter assay were employed to uncover the target relationship between circRNA_BARD1/BARD1 and miR-3942-3p/miR-4760-3p. Flow cytometric analysis was used to reveal cell cycle and cell apoptosis. Immunofluorescence was applied to determinate gamma-H2AX level. Xenograft assay and in vivo 3-D imaging was implemented to further verify the conclusions in vitro. CircRNA_BARD1 (circ_0001098) was up-regulated in breast cancer with the treatment of TCDD and the up-regulation of circRNA_BARD1 could restrain cell proliferation, block cell cycle and promote cell apoptosis. Moreover, the target relationship between circRNA_BARD1/BARD1 and miR-3942-3p was confirmed. In addition, miR-3942-3p overexpression promoted the disease progression and BARD1 up-regulation inhibited the disease progression in the breast cancer. Similarly, circRNA_BARD1 overexpression induced by TCDD suppressed the growth and metastasis of tumor in vivo. In conclusion, TCDD induced circ_0001098 overexpression and then suppressed breast cancer tumorigenesis via miR-3942-3p/BARD1 axis. The finding of TCDD circRNA-miRNA-mRNA axis might bring a new perspective for cure strategy of breast cancer. PMID- 30521418 TI - Initial Diagnostic Workup of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement Summary of the CAP and ASH Guideline. PMID- 30521419 TI - Cannabinoid exposure and altered DNA methylation in rat and human sperm. AB - Little is known about the reproductive effects of paternal cannabis exposure. We evaluated associations between cannabis or tetrahydrocannabinol (THC) exposure and altered DNA methylation in sperm from humans and rats, respectively. DNA methylation, measured by reduced representation bisulfite sequencing, differed in the sperm of human users from non-users by at least 10% at 3,979 CpG sites. Pathway analyses indicated Hippo Signaling and Pathways in Cancer as enriched with altered genes (Bonferroni p<0.02). These same two pathways were also enriched with genes having altered methylation in sperm from THC-exposed versus vehicle-exposed rats (p<0.01). Data validity is supported by significant correlations between THC exposure levels in humans and methylation for 177 genes, and substantial overlap in THC target genes in rat sperm (this study) and genes previously reported as having altered methylation in the brain of rat offspring born to parents both exposed to THC during adolescence. In humans, cannabis use was also associated with significantly lower sperm concentration. Findings point to possible pre-conception paternal reproductive risks associated with cannabis use. PMID- 30521420 TI - Iron oxide nanoparticles as heterogeneous electro-Fenton catalysts for the removal of AR18 azo-dye. AB - Heterogeneous electro-Fenton mineralization of Acid Red 18 (AR18) in aqueous solution was studied with magnetite Fe3O4 (MNPs) and hematite Fe2O3 (HNPs) nanoparticles as catalysts. High mineralization yields of AR18 were obtained with magnetite, 81% TOC removal after 180 min of electrolysis in 40 mg.L-1 Fe3O4, pH 3.0, at 50 mA of current intensity and in 50 mM Na2SO4. In order to explain the obtained mineralization yield achieved with MNPs, the quantification of hydrogen peroxide (H2O2), hydroxyl radical (*OH) and iron leaching were performed at 50 and 100 mA. From the high iron concentration found in the bulk solution and the slight impact of the catalyst mass concentration on TOC removal, the formation of hydroxyl radicals occurs mainly through homogeneous process. In the presence of hydroxyl radical scavenger, degradation remained total after 15 min showing the involvement of a direct electrochemical oxidation of the dye at the electrode surface. The hydroxyl radical oxidation is responsible for at least 50% of mineralization. PMID- 30521421 TI - EEG of patients in coma after traumatic brain injury reflects physical parameters of auditory stimulation but not its emotional content. AB - PRIMARY OBJECTIVE: We aimed to investigate the origin of EEG response of patients in coma and after moderate TBI to emotional stimulation, whether they distinguish emotional content or only react to the physical features of an audio signal. RESEARCH DESIGN: We registered EEG during continuous pleasant and unpleasant non verbal stimulation and in rest. A total of 69 subjects participated in our study: healthy adults, conscious patients after moderate TBI and patients in coma after severe TBI. We analysed the distances between the stimuli according to EEG data and applied correlation analysis to the distances, acoustic parameters of stimuli, subjects' emotional assessment of the stimuli, GCS score and Doppler ultrasound data. MAIN OUTCOMES AND RESULTS: The EEG response to the stimulation in patients in coma mostly reflects the physical parameters of the stimuli, and correlated with Doppler ultrasound data. The EEG of healthy adults reflects their psychological assessment of the stimuli. Patients after moderate TBI differentiate unpleasant stimuli well and pleasant stimuli poorly, they mainly consider pitch to cope with this task like healthy adults do. CONCLUSIONS: The reactivity to the acoustic features of emotional stimulation in patients in coma should be investigated further as a marker of patients' recovery. ABBREVIATIONS: TBI: traumatic brain injurym; TBI: moderate TBI; MCA: middle cerebral artery; GCS: Glasgow Coma Scale; M: mean; SD: standard deviation. PMID- 30521422 TI - Correction. PMID- 30521423 TI - Ventilatory responses to acute hypoxia and hypercapnia in humans with a patent foramen ovale. AB - Subjects with a patent foramen ovale (PFO) have blunted ventilatory acclimatization to high altitude, compared to subjects without PFO. The blunted response observed could be due to differences in central and/or peripheral respiratory chemoreflexes. We hypothesized that compared to subjects without a PFO (PFO-), subjects with a PFO (PFO+) would have blunted ventilatory responses to acute hypoxia and hypercapnia. Sixteen PFO+ subjects (9 female) and fifteen PFO- subjects (8 female) completed four 20-minute trials on the same day: 1) normoxic hypercapnia (NH), 2) hyperoxic hypercapnia (HH), 3) isocapnic hypoxia (IH), and 4) poikilocapnic hypoxia (PH). Hypercapnic trials were completed prior to the hypoxic trials, the order of the hypercapnic (NH & HH) and hypoxic (IH & PH) trials were randomized, and trials were separated by >=40 minutes. During the NH trials, but not the HH trials, PFO+ subjects had a blunted hypercapnic ventilatory response compared to PFO- subjects (1.41 +/- 0.46 L min-1 mmHg-1 vs. 1.98 +/- 0.71 L min-1 mmHg-1, p = 0.02). There were no differences between the PFO+ and PFO- subjects with respect to the acute hypoxic ventilatory response during IH and PH trials. Hypoxic ventilatory depression was similar between PFO+ and PFO- subjects during IH. These data suggest that compared to PFO- subjects, PFO+ subjects have normal ventilatory chemosensitivity to acute hypoxia but blunted ventilatory chemosensitivity to carbon dioxide, possibly due to reduced carbon dioxide sensitivity of either the central and/or the peripheral chemoreceptors. PMID- 30521424 TI - The effect of net gas volume changes on alveolar and arterial gas partial pressures in the presence of ventilation-perfusion mismatch. AB - The second gas effect (SGE) occurs when nitrous oxide enhances the uptake of volatile anesthetics administered simultaneously. Recent work shows that the SGE is greater in blood than in the gas phase, that this is due to ventilation perfusion mismatch, that as mismatch increases, the SGE increases in blood but is diminished in the gas phase, and that these effects persist well into the period of nitrous oxide maintenance anesthesia. These modifications of the SGE are most pronounced with the low soluble agents in current use. We investigate further the effect of net gas volume loss during nitrous oxide uptake on low concentrations of other gases present using partial pressure solubility diagrams. The steady state equations of gas exchange were solved assuming a log normal distribution of ventilation-perfusion ratios using Lebesgue-Stieltjes integration. It was shown that under these conditions, the classical partial pressure-solubility diagram must be modified, that for currently used volatile anesthetic agents the alveolar arterial partial pressure difference is less than that predicted in the past, and that the alveolar-arterial partial pressure difference may even be reversed during uptake in the case of highly insoluble gases such as sulfur hexafluoride. Comparing this with the situation described previously for nitrogen in steady state air breathing, we show that for nitrogen, the direction of the alveolar arterial gradient is opposite to the direction of net gas volume movement. Although gas uptake with ventilation-perfusion inequality exceeding that when matching is optimal, is shown to be possible, it is less likely than alveolar arterial partial pressure reversal. PMID- 30521425 TI - Titin as a force generating muscle protein under regulatory control. AB - Titin has long been recognized as a mechanical protein in muscle cells that has a main function as a molecular spring in the contractile units, the sarcomeres. Recent work suggests that the titin spring contributes to muscle contraction in a more active manner than previously thought. In this review, we highlight this property, specifically the ability of the immunoglobulin-like (Ig) domains of titin to undergo unfolding-refolding transitions when isolated titin molecules or skeletal myofibrils are held at physiological force levels. Folding of titin Ig domains under force is a hitherto unappreciated, putative source of work production in muscle cells, which could work in synergy with the actomyosin system to maximize the energy delivered by a stretched, actively contracting muscle. This review also focusses on the mechanisms shown to modulate titin-based viscoelastic forces in skeletal muscle cells, including chaperone binding, titin oxidation, phosphorylation, Ca2+-binding, and interaction with actin filaments. Along the way, we discuss which of these modulatory mechanisms might contribute to the phenomenon of residual force enhancement relevant for eccentric muscle contractions. Finally, a brief perspective is added on the potential for the alterations in titin-based force to dynamically alter mechano-chemical signaling pathways in the muscle cell. We conclude that titin from skeletal muscle is a determinant of both passive and active tension and a bona fide mechanosensor, whose stiffness is tuned by various independent mechanisms. PMID- 30521426 TI - Reflex response to airway occlusion in human inspiratory muscles when recruited for breathing and posture. AB - Briefly occluding the airway during inspiration produces a short-latency reflex inhibition in human inspiratory muscles. This occlusion reflex seems specific to respiratory muscles; however, it is not known whether the reflex inhibition has a uniform effect across a motoneurone pool when a muscle is recruited concurrently for breathing and posture. In this study, participants were seated and breathed through a mouthpiece that occluded inspiratory airflow for 250 ms at a volume threshold of 0.2 l. The reflex response was measured in the scalene and sternocleidomastoid muscles during (i) a control condition with the head supported in space and the muscles recruited for breathing only, (ii) a postural condition with the head unsupported and the neck flexors recruited for both breathing and to maintain head posture, and (iii) a large-breath condition with the head supported and the volume threshold raised to between 0.8-1.0 l to increase inspiratory muscle activity. When normalized to its pre-occlusion mean, the reflex response in the scalene muscles was not significantly different between the large-breath and control conditions, whereas concomitant recruitment of these muscles for posture control reduced the reflex response by half compared to the control condition. A reflex response occurred in sternocleidomastoid when it contracted phasically as an accessory muscle for inspiration during the large breath condition. These results indicate that the occlusion reflex does not produce a uniform effect across the motoneurone pool, and that afferent inputs for this reflex most likely act via intersegmental networks of pre-motoneurones rather than at a motoneuronal level. PMID- 30521427 TI - An integrated method for quantitative morphometry and oxygen transport modelling in striated muscle. AB - Identifying structural limitations in O2 transport is primarily restricted by current methods employed to characterise the nature of physiological remodelling. Inadequate resolution or breadth of available data has impaired development of routine diagnostic protocols and effective therapeutic strategies. Understanding O2 transport within striated muscle faces major challenges, most notably in quantifying how well individual fibres are supplied by the microcirculation, which has necessitated exploring tissue O2 supply using theoretical modelling of diffusive exchange. Having identified capillary domains as a suitable model for the description of local O2 supply, and requiring less computation than numerically calculating the trapping regions that are supplied by each capillary via biophysical transport models, we sought to design a high throughput method for histological analysis. We present an integrated package that identifies optimal protocols for identification of important input elements, processing of digitised images with semi-automated routines, and incorporation of these data into a mathematical modelling framework with computed output visualised as the tissue partial pressure of O2 (PO2) distribution across a biopsy sample. Worked examples are provided using muscle samples from experiments involving rats and humans. PMID- 30521428 TI - Effects of weight loss on dynamic hyperinflation in women obese asthmatics. AB - : Obese adults with asthma are more likely to develop dynamic hyperinflation (DH) and expiratory flow limitation (EFL) than non-obese asthmatics, and weight-loss seems to improve the breathing mechanics during exercise. However, studies evaluating the effect of weight-loss on DH in obese adults with asthma have not been performed. OBJECTIVE: To evaluate the effect of a weight-loss program on DH in obese adults with asthma. METHODS: Forty-two asthma patients were enrolled in a weight-loss program (diet, psychological support and exercise) and were subsequently divided into two groups according to the percentage of weight-loss: the >=5%group (n=19) and the <5%group (n=23). Before and after the intervention, DH and EFL (constant load exercise), health-related quality of life (HRQoL), asthma control, quadriceps muscle strength and endurance, body composition and lung function were assessed. RESULTS: Both groups exhibited a decrease of >=10% in inspiratory capacity (DH) before intervention, and only the >=5%group showed clinical improvement in DH compared to <5%group post-intervention (-9.1+/-14.5% vs. -12.5+/-13.5%, respectively). In addition, the >=5%group displayed a significant delay in the onset of both DH and EFL and a clinically significant improvement in HRQoL and asthma control. Furthermore, a correlation was observed between reduced waist circumference and increased inspiratory capacity (r=-0.45, p=0.05) in the >=5%group. CONCLUSION: A weight-loss >=5% of the body weight improves DH, which is associated with waist circumference in obese adults with asthma. In addition, the group with greater weight-loss showed a delayed onset of DH and EFL during exercise and improved asthma clinical control and HRQoL. PMID- 30521430 TI - Forty years of "Waltzing Matilda": the history of the multichannel cochlear implant. PMID- 30521429 TI - The MJA-Lancet Countdown on health and climate change: Australian policy inaction threatens lives. AB - Climate plays an important role in human health and it is well established that climate change can have very significant impacts in this regard. In partnership with The Lancet and the MJA, we present the inaugural Australian Countdown assessment of progress on climate change and health. This comprehensive assessment examines 41 indicators across five broad sections: climate change impacts, exposures and vulnerability; adaptation, planning and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. These indicators and the methods used for each are largely consistent with those of the Lancet Countdown global assessment published in October 2017, but with an Australian focus. Significant developments include the addition of a new indicator on mental health. Overall, we find that Australia is vulnerable to the impacts of climate change on health, and that policy inaction in this regard threatens Australian lives. In a number of respects, Australia has gone backwards and now lags behind other high income countries such as Germany and the United Kingdom. Examples include the persistence of a very high carbon-intensive energy system in Australia, and its slow transition to renewables and low carbon electricity generation. However, we also find some examples of good progress, such as heatwave response planning. Given the overall poor state of progress on climate change and health in Australia, this country now has an enormous opportunity to take action and protect human health and lives. Australia has the technical knowhow and intellect to do this, and our annual updates of this assessment will track Australia's engagement with and progress on this vitally important issue. PMID- 30521431 TI - News briefs. PMID- 30521432 TI - From the curious case of Patient K to TOP GEAR and Bond. PMID- 30521433 TI - Correction. PMID- 30521434 TI - Ignaz Philipp Semmelweis (1818-1865): herald of hygienic medicine. PMID- 30521435 TI - Adding kindness at handover to improve our collegiality: the K-ISBAR tool. PMID- 30521436 TI - Morbus diei Lunae. PMID- 30521437 TI - The guilty pleasure of Christmas cookies. PMID- 30521438 TI - Physician burnout: a recipe for disaster. PMID- 30521439 TI - A comprehensive review of significant issues in health law. PMID- 30521440 TI - Everything you need to know in one short book. PMID- 30521441 TI - Understanding the use of simulation in medical teaching. PMID- 30521442 TI - Challenges in community-based participatory research. PMID- 30521443 TI - The emergence and characteristics of the Australian Mamil. AB - BACKGROUND: The Mamil (middle-aged man in Lycra) appears to be an emergent cycling-focused species. OBJECTIVES: To explore the nature and distribution of the Mamilian species; to determine whether rates of cycling by middle-aged men in Australia have changed since the pre-Mamilian era. SETTING: Secondary analysis of representative population-based datasets. National sport participation data from the Exercise, Recreation and Sport (2002-2004, 2008-2010) and Ausplay surveys (2016) were analysed to assess trends in recreational and exercise-related cycling, including by middle-aged men (45-64 years of age). Data from New South Wales Population Health Surveys (2006, 2010, 2014) and Australian censuses (2006, 2011, 2014) were analysed to assess trends in cycling to work. MAIN OUTCOME MEASURES: Cycling participation rates (at least once or at least once a week in the past 12 months); rates of cycling to work. RESULTS: The proportion of middle aged men who cycled for exercise or recreational purposes at least once a week during the previous year increased from 6.2% (95% CI, 5.5-7.0%) during 2002-2004 to 13.2% (95% CI, 11.9-14.6%) in 2016. The prevalence of Mamils in the most affluent residential areas has more than doubled since 2002-2004, and is twice as high as in the least advantaged locations. Media reports of "Mamils" corroborate these temporal trends. DISCUSSION: Mamils in Australia are socially graded, and also grade themselves according to bicycle-related expenditure and hill gradients overcome. They often form cohesive and supportive groups, but may not reflect a population-wide social movement to increase physical activity among adult Australians. PMID- 30521444 TI - Licence to swill: James Bond's drinking over six decades. AB - OBJECTIVES: To describe the patterns of alcohol use in James Bond movies over six decades. DESIGN: Film content analysis. SETTING: Wide range of international locations in 24 James Bond movies (Eon Productions series, 1962-2015). MAIN OUTCOME MEASURES: Drinking episodes for Bond and major female characters; alcohol product placement in films; peak estimated blood alcohol concentrations; features relevant to DSM-5 criteria for alcohol use disorder. RESULTS: Bond has drunk heavily and consistently across six decades (109 drinking events; mean, 4.5 events per movie). His peak blood alcohol level was estimated to have been 0.36 g/dL, sufficient to kill some people. We classified him as having severe alcohol use disorder, as he satisfied six of 11 DSM-5 criteria for this condition. Chronic risks for Bond include frequently drinking prior to fights, driving vehicles (including in chases), high stakes gambling, operating complex machinery or devices, contact with dangerous animals, extreme athletic performance, and sex with enemies, sometimes with guns or knives in the bed. Notable trends during the study period included a decline in using alcohol as a weapon (P = 0.023) and an increase in the number of alcohol products in his environment (for alcohol related product placement: P < 0.001), but his martini consumption has been steady. Drinking by lead female characters and a random selection of 30 of his sexual partners was fairly stable over time, but also occasionally involved binges. CONCLUSIONS: James Bond has a severe chronic alcohol problem. He should consider seeking professional help and find other strategies for managing on-the job stress. PMID- 30521445 TI - The curious case of Patient K. PMID- 30521446 TI - The Observational Physician and surGEon Automobile Response (TOP GEAR) survey. AB - OBJECTIVE: To determine whether surgeons and junior doctors intending to pursue careers in surgery are more likely to purchase more expensive vehicles and to replace them sooner than colleagues of similar seniority pursuing non-surgical careers. DESIGN AND SETTING: Survey of practising medical officers at an Australian tertiary referral hospital. MAIN OUTCOME MEASURES: Car value; proportion of doctors who bought their car new; median time to replacement of vehicle. RESULTS: 154 doctors participated in the survey (17% response rate). 49% were interns, residents or unaccredited registrars, 18% were accredited registrars or fellows, and 31% were consultants; 40% of respondents were surgical trainees or consultants. 59% of surgical trainees and consultants purchased their car new, compared with 38% of non-surgical doctors (P = 0.013); 52% of doctors in the junior surgeon group purchased their car new, compared with 28% of non surgeon junior doctors (P = 0.019). Median car value was $16 500 (IQR, $9350-37 000) for surgeons and $8500 (IQR, $4400-14 100) for non-surgeons (P < 0.001); 30% of surgeons owned cars valued at more than $50 000, compared with 6% of non surgeons (P = 0.025). The median time to replacement was 5-7 years for surgeons and 7-10 years for non-surgeons (P < 0.001). CONCLUSIONS: Surgeons more frequently purchase their cars new and replace their cars earlier than non surgeons, and the median value of their vehicles is higher. These findings were consistent across all levels of seniority. PMID- 30521447 TI - Carols by glow sticks: a retrospective analysis of Poisons Information Centre data. AB - OBJECTIVE: To win a Christmas hamper. We also devised a study of our most festive seasonal poisoning, to demonstrate how hard we are working while everyone else is partying. DESIGN: Retrospective analysis of the New South Wales Poisons Information Centre database, which we searched for exposures to the substance code "Cyalume light sticks/glow toys" from 1 July 2013 to 30 June 2017. SETTING: A dimly lit basement with a constantly ringing phone. At the other end of the phone was a highly anxious parent and a luminescent child. MAIN OUTCOME MEASURES: Number of glow stick exposures, route of exposures, patient demographics and seasonal trends in exposures. RESULTS: There were 2918 glow stick exposures over the 4-year study period. The vast majority of exposures (94%) were in children aged 14 years and younger. Medical complications were very rare. Glow stick exposures were 4.38 times more likely in December (95% CI, 3.02-6.35; P < 0.001). Statistically significant increases were also observed in October, November, January, February and March. Glow stick exposures were 4.20 times more likely during the holiday period of 1 December to 7 January (95% CI, 3.42-5.15; P < 0.001), 2.52 times more likely over summer (95% CI, 2.12-3.00; P < 0.001), and 1.77 times more likely during school holidays (95% CI, 1.47-2.13; P < 0.001). CONCLUSIONS: This epidemic of poisoning is perhaps due to mass seasonal synaesthesia. The lack of any significant adverse consequences highlights the contribution that 50 years of injury prevention has made to everyone having a Merry Christmas and a Happy New Year. PMID- 30521448 TI - C-ABC: cash before care in a private emergency department? PMID- 30521449 TI - The Christmas e-list (an ode to big data). PMID- 30521450 TI - The MJA-Lancet Countdown on health and climate change: Australian policy inaction threatens lives(Summary). PMID- 30521451 TI - Is There a Surplus of Non-Specialist Physicians in Portugal or Just Poor Human Resources Planning? PMID- 30521452 TI - What Do You Do With a Doctor that Does Not Make It into Specialist Training? PMID- 30521453 TI - The Added Value of a Vasculitis Clinic in a Tertiary Referral Hospital. PMID- 30521454 TI - Reasons for Declining Venom Immunotherapy. AB - INTRODUCTION: Hymenoptera venom allergy is associated with significant morbidity and deterioration in health-related quality of life, and risk of fatal systemic reactions. Although venom immunotherapy is safe and the only effective treatment in allergic individuals, some patients prefer not to pursue this treatment. Since 2011, when the 50% reimbursement was stopped, patients must fully support the cost of immunotherapy. This study aimed to ascertain the reasons why patients decline immunotherapy. MATERIAL AND METHODS: A medical records review of all patients proposed to receive venom immunotherapy at an Allergy and Clinical Immunology Department in Porto, Portugal, between 2006 and 2015, followed by a phone interview to patients refusing treatment. RESULTS: A total of 83 subjects were enrolled, with a mean (+/- SD) age of 44.4 (14.7) years and 55 (66%) males; 27 refused venom immunotherapy between 2006 and 2015. Nineteen were interviewed and 14 of those stated price as the main reason for declining treatment. The only identified risk factor associated with immunotherapy refusal was being proposed after 2011 (OR: 3.29; 95% CI: 1.12 - 9.68; p = 0.03). DISCUSSION: The number of patients refusing venom immunotherapy doubled since reimbursement was withdrawn. Price was identified as the major obstacle to treatment completion. Immunotherapy proposal after reimbursement was stopped was associated with a 3-fold increase in the risk of refusing treatment. CONCLUSION: These findings show how economic decisions may have a detrimental effect on patient care, as immunotherapy refusal left them exposed to an avoidable life-threatening risk. PMID- 30521455 TI - [Chronic Pain After Outpatient Inguinal Hernioplasty: Retrospective Cohort Study]. AB - INTRODUCTION: Chronic postoperative pain is the most frequent late complication of inguinal hernia repair surgery. The aim of this study is to evaluate the incidence of chronic post-hernioplasty pain in outpatient care at Centro Hospitalar do Porto, describe it, analyse its relation with other variables defined in the literature and study its functional interference. MATERIAL AND METHODS: We performed a retrospective cohort study between February and May 2016, using a structured telephone interview composed of questions from the authors and sections of published questionnaires, two of which are validated for the Portuguese language and culture. We included men who underwent ambulatory inguinal hernioplasty, by laparotomy or laparoscopy, at Centro Hospitalar do Porto, between January 2011 and October 2015. RESULTS: In a final sample of 829 surgeries, the incidence of chronic post-hernioplasty pain was 24.0% [confidence interval: 21.2 - 27.1]. The development of chronic post-hernioplasty pain was higher in patients with pre-surgical pain and younger age and was related with the presence of pain during the first month after surgery. No relationship was found between surgical technique and the development of chronic post-hernioplasty pain. Of the individuals with chronic pain, 65.0% mentioned moderate-severe 'pain on the average' and 37.7% presented descriptors suggestive of neuropathic pain. The only parameter evaluated with which chronic post-hernioplasty pain 'did not interfere completely' was sleep. DISCUSSION: The prevalence found for chronic posthernioplasty pain with significant functional interference is in line with data retrieved from literature. The predictive potential of pre-surgical pain and young age for the development of chronic posthernioplasty pain is also in agreement with previous studies. Limitations were found to this study given its retrospective nature. CONCLUSION: The high prevalence of chronic post hernioplasty pain raises the urgent need for raising awareness regarding this issue among health care professionals. The main areas for improvement are diagnosis, follow-up and treatment of pain. PMID- 30521456 TI - [Problematic Eating Behaviors after Bariatric Surgery: A National Study with a Portuguese Sample]. AB - INTRODUCTION: Bariatric surgery is the most effective method for the treatment of morbid obesity. However, the development of eating psychopathology and the emergence of problematic eating behaviours have been reported in the literature. The aim of this crosssectional study was to characterize the post-bariatric population in terms of the frequency of problematic eating behaviours over time and to understand the related psychological features. MATERIAL AND METHODS: This sample was composed of 155 bariatric patients that responded to several self reported instruments assessing eating psychopathology, problematic eating behaviours, anxiety, depression and stress and impulsive behaviour. RESULTS: Results showed that grazing, binge eating, concerns about body weight and shape, and negative urgency are significantly more frequent at 24 months after bariatric surgery (when compared to earlier postoperative assessments). Correlational analyses showed that eating psychopathology and problematic eating behaviours were significantly and positively associated with levels of anxiety, depression, stress and negative urgency. This study also reinforces the mediating role of negative urgency in the relationship between time elapsed since surgery and psychological distress, and problematic eating behaviours, accounting for a total of 32.3% and 27.2% of its variance, respectively. DISCUSSION: The results suggest a growing trend of problematic eating behaviours and levels of impulsivity being reported by bariatric patients over time. CONCLUSION: Given the established evidence that supports its impact on weight variability, early identification of problematic eating behaviours and of patients with a tendency to act impulsively in situations of negative emotionality should be a central concern in the follow up of the bariatric population. PMID- 30521457 TI - Histological Subtypes and Clinical Behavior Evaluation of Salivary Gland Tumors. AB - INTRODUCTION: Salivary gland tumors include a wide spectrum of histological subtypes and clinical behavior, which we aim to evaluate. MATERIAL AND METHODS: We performed a retrospective study of all salivary gland tumors diagnosed and treated at the Centro Hospitalar Sao Joao, Porto, between 2005 and 2015. Histological re- evaluation was performed in all cases and patient files were reviewed and both clinical and follow-up data were collected. Disease-free survival and overall survival were evaluated using Kaplan-Meier survival curves and compared using the Mantel-Cox log-rank test. The significance threshold was set at 0.05. RESULTS: We selected 295 cases, 150 males with a mean age at diagnosis of 50.4 (+/- 16.4) years. Primary benign epithelial tumors [n = 228 (77.3%)] were mostly pleomorphic adenomas [n = 148 (64.9%)] and Warthin tumors [n = 61 (26.8%)]. Primary malignant epithelial tumors [n = 43 (14.8%)] included mucoepidermoid [n = 16 (37.2%)], adenoid cystic [n = 6 (14.0%)] and acinic cell [n = 5 (11.6%)] carcinomas; 32 (74.4%) in parotid, 2 (4.6%) in submandibular and 9 (21%) in minor salivary glands. Primary epithelial tumors were more frequently malignant in minor (33.3%) than in major (13.9%) salivary glands. Local recurrence occurred in 30.2% and distant metastases in 25.6% tumors. The mean disease-free interval was 26 (+/- 37.5) months; most metastases were in lung and central nervous system. The 5 and 10 year disease-free survival rates were 63.4% and 50.1%, respectively; the 5 and 10 year disease-specific survival rates were 76.9% and 57.9%, respectively. Primary salivary tumors included also lymphomas [n = 8 (2.7%)] and soft tissue tumors [n = 5 (1.7%)]. Secondary tumors included metastases of carcinomas [n = 7 (2.4%)] and involvement by lymphoma [n = 1 (0.3%)]. DISCUSSION: Our results concerning age, gender, histological subtype, frequency and clinical behavior of salivary tumors concur with European studies. Divergence with Portuguese studies might be related with the inclusion criteria, clinical referral and time lag variations. CONCLUSION: Although uncommon, salivary gland tumors occur in a wide age range and include histological subtypes with diverse prognosis. PMID- 30521458 TI - [Morbidity in Prematurity Associated with Fetal Growth Restriction: Experience of a Tertiary Care Center]. AB - INTRODUCTION: Prematurity and low birth weight have been associated with increased neonatal morbidity and mortality. This study aimed to evaluate possible risk factors for prematurity associated with fetal growth restriction and being small for gestational age and to determine the incidence of morbidity in these two groups of infants. MATERIAL AND METHODS: Retrospective case-control study of newborns with gestational age of less than 32 weeks, with obstetric diagnosis of fetal growth restriction and with the clinical diagnosis of small for gestational age, admitted to the Neonatal Intensive Care Unit of a tertiary hospital for a period of six years. RESULTS: A total of 356 newborns were studied, with an incidence of 11% of fetal growth restriction and 18% of small for gestational age. Pre-eclampsia was the risk factor for gestation with higher statistical significance (47% vs 16%, p < 0.001) in small for gestational age newborns. There was also a higher incidence of mild bronchopulmonary dysplasia (66% vs 38%, p = 0.005), late sepsis (59% vs 37%, p = 0.003), retinopathy of prematurity (58% vs 26%, p = 0.003) and necrotizing enterocolitis (20% vs 9%, p = 0.005). Mortality was similar in all three groups. DISCUSSION: There were fewer newborn males diagnosed with fetal growth restriction during pregnancy compared to women. Significant differences were observed in the group of these infants regarding the occurrence of chorioamnionitis and pre-eclampsia in comparison to the control group. Newborns with fetal growth restriction and small for age had higher scores on clinical risk indices compared to the control group. In general, small for gestational age newborns had a higher incidence of morbidity than infants with fetal growth restriction and the control group. CONCLUSION: Advances in neonatal intensive care decreased mortality in preterm infants. However, there are still significant differences in the incidence of morbidity in newborns with growth compromise. The collaboration between obstetricians and neonatologists provides the basis for a correct clinical evaluation, early signaling and global intervention on these newborns, with a significant impact on short and long-term prognosis. PMID- 30521459 TI - Supportive Care Network: Evaluation of Its Impact on the Performance of a Urology Department. AB - INTRODUCTION: Hospitals are dealing with patients who may have clinical discharge but cannot return to their home due to non-medical issues. MATERIAL AND METHODS: Cross-sectional analysis of all the cases referred to the Integrated Care Network during the year 2016. Evaluation of waiting times, typology, reason for referral and clinical parameters. IBM SPSS 24.0 software was used for all statisticalanalyses. RESULTS: In the evaluated period, 2294 patients were discharged from our department. Of these, 55 were referred to Integrated Care Network. The mean length of hospitalization of the patients referred to the network was 20.6 +/- 11.4 days, and the mean overall length of hospital stay in the period analyzed was 4.8 +/- 0.9 days. The mean time between hospitalization and referral for continuing care was 10.7 +/- 7.2 days. The time between referral and discharge of the hospital was 10.0 +/- 8.7 days. Thirty-nine (70.9%) patients were hospitalized for oncological diseases. The most common referral was to Palliative Care units (n = 16; 29.1%). Patients referred to Palliative Care units showed the largest waiting times between the referral for the network and the hospital discharge, 12.2 +/- 10.51 days. We observed 289 hospitalization days with patients who had no need of specialized urological care. DISCUSSION: In order to reduce time between referral to the network and hospital discharge, there is a need for enhanced cooperation and coordination among doctors, nurses and social workers. CONCLUSION: Early identification by physicians and nurses of patients who will require care after discharge will provide a better response from social workers and increased hospital performance. PMID- 30521460 TI - Molecular Staging of Patients with Colon Cancer. The C-Closer-II Study: A Multicentre Study in Portugal. AB - INTRODUCTION: Approximately 20% - 30% of histological lymph node-negative patients with colorectal cancer relapse at five years after surgical treatment. This recurrence is likely due to occult nodal disease undetected by standard histopathological practice which has implications in terms of the clinical management of patients. MATERIAL AND METHODS: Lymph nodes were collected from colectomy specimens. A central section from each lymph node was histologically examined following haematoxylin-eosin staining and the remaining tissue was subjected to OSNA - one step nucleic acid amplification analysis. RESULTS: A total of 1046 lymph nodes from 59 pN0 patients were assessed. Of these, 753 lymph nodes were examined by both methods. The median number of lymph nodes assessed with OSNA - one step nucleic acid amplification was 12 (IQR: 7;16). Among pN0 patients, 17 had OSNA - one step nucleic acid amplification-positive lymph nodes, resulting in a positive molecular staging rate of 28.8% (95% CI: 17.8 - 42.1). Among these patients, 12 (70.59%) were molecular-staged as pN1 and 5 (29.41%) were molecular staged as pN2. The tumour burden of lymph nodes assessed with OSNA - one step nucleic acid amplification ranged from 270 to 17 000 cytokeratin 19 mRNA copies/MUL. Most of these patients (88.2%) were found to have lymph nodes with micrometastases only (250 - 4999 copies/MUL). DISCUSSION: We provide the results from the first study of the use of the OSNA - one step nucleic acid amplification assay in colorectal cancer patients in Portugal. Our results are in line with other international studies, showing the improvement on patients' staging by molecular examination of lymph nodes. CONCLUSION: In our study, 28.8% of patients with histologically negative lymph nodes were found to have metastatic lymph nodes using OSNA - one step nucleic acid molecular assessment. OSNA - one step nucleic acid assay allows a more accurate staging of patients with colorectal cancer and standardizes lymph node assessment. PMID- 30521461 TI - [Evaluation of The Medical Board Exam in Portugal]. AB - INTRODUCTION: There is a high heterogeneity in the structure of postgraduate medical training evaluation worldwide. However, in contrast to other countries, there have been no scientific studies of the final medical board examination, in Portugal. The present study aimed to evaluate the adequacy of the medical board examination including its validity as measured by its association with medical school grade average and national seriation examination. MATERIAL AND METHODS: Cross-sectional, observational study. We analyzed the final results on the medical board examination of 2439 physicians, across 47 specialties, who completed their training in 2016 and 2017, using measures of central tendency and variability. We assessed the association between these grades and the national exam to initiate residency, and the grade average in Medical School. RESULTS: Measures of central tendency and variability, and consequent shape measures, revealed that the distribution of the scores of the final medical board exam is extremely negatively asymmetric and leptokurtic. A positive association was also found between the results in this exam and the score on national exam to initiate residency, and the grade average in Medical School. CONCLUSION: Although the medical board examination was, in general, positively associated with scores on the national exam to initiate residency, and the mean final Medical School grades, thus indicating its potential validity, our results demonstrate that this exam presents no satisfactory discriminative capacity. Therefore, there is room to improve the actual postgraduate medical examination model, including changes in its classification system and potentially consider other assessment models. PMID- 30521462 TI - [The Role of Testosterone in The Improvement of Sexual Desire in Postmenopausal Women: An Evidence-Based Clinical Review]. AB - INTRODUCTION: Female sexual dysfunction is a common problem, affecting more than 1/3 of women during their lives. The aim of this review is to review the evidence for the effectiveness of testosterone in sexual dysfunction in postmenopausal women, particularly in the improvement of sexual desire. MATERIAL AND METHODS: The authors searched in international databases National Guidelines Clearinghouse, Guidelines Finder, Cochrane Library and MEDLINE/PubMed, for guidelines, systematic reviews, meta-analysis and randomized controlled trials, published between January 2005 and February 2017, using the MeSH terms 'testosterone', 'androgens', 'libido', 'sexual dysfunctions' and 'menopause'. RESULTS: From a pool of 506 articles, 11 were selected: three guidelines, one systematic review with meta-analysis and seven randomized controlled trials. The selected articles showed testosterone's efficacy on global sexual function and improvement of sexual desire in postmenopausal women, when both are used in monotherapy or in association with other hormones. No study showed changes in hepatic enzymes or serious adverse effects. DISCUSSION: The small sample size and short follow-up used in the included studies limits the ability to assess testosterone's long-term benefits and effects. CONCLUSION: At short-term, testosterone seems to improve sexual function in postmenopausal women, particularly sexual desire. Nevertheless, more studies with larger sample size and longer follow-up are needed to understand its long-term safety and effectiveness. PMID- 30521463 TI - [Foodbourne Botulism: A Forgotten Disease]. AB - Botulism is a serious illness caused by exposure to botulinum toxin. It is manifested by flaccid, paralysis, symmetric and in descending pattern affecting cranial and peripheral nerves. Given the frequent need for invasive mechanical ventilation, these patients should be approached in an intensive care setting. Treatment with anti-botulinum toxin is the only effective treatment. The authors present the case of a 64-year-old patient, with vomiting and vertigo, evolution to diplopia, dysphagia and flaccid, muscle paralysis, installation after ingestion of canning homemade. From the etiologica, we highlight the electroneuromyogram study with a pre-synaptic lesion compatible with the botulism hypothesis. Progressive improvement of the deficits after administration of anti botulinum toxin. A brief theoretical review is made of a serious, potentially fatal and infrequent pathology in our country. PMID- 30521464 TI - Aggressive Angiomyxoma: A Rare Tumor of Male Pelvic Cavity. AB - Aggressive angiomyxoma is an uncommon, benign, slow-growing, and locally infiltrative soft tissue neoplasm which is located primarily in the genital region and pelviperineal interstitial tissue of female patient in the fourth decade of life. Its occurrence in male patients is even more unusual and commonly appears at a later age. The mainstay of treatment typically involves surgical excision with tumor-free margins, and despite complete resection, local recurrences are common. Here, an unusual case of aggressive angiomyxoma occurring in the pelvic region of a 55-year-old man and its treatment is discussed due to its rarity. PMID- 30521465 TI - African Kaposi's Sarcoma. PMID- 30521466 TI - Letter to The Editor: Access to Opioids, A Global Challenge - Impressions of The Brazilian Scenario. PMID- 30521467 TI - Letter to the Editor: The Opioid Prescribing Scenario in Portugal from a Primary Care Perspective. PMID- 30521468 TI - [The New Medical Licensing Examination in Portugal: It Is Just the Beginning but We Are on The Right Path]. PMID- 30521469 TI - [Letter to the Editor: Choosing Wisely Portugal]. PMID- 30521470 TI - Erratum to "Letter to the Editor about the Article: "Still Regarding Anxiety, Depression and Academic Performance: A Study Amongst Portuguese Medical Students Versus Non-Medical Students", by Joao Moreira de Sousa, Catia A. Moreira, Diogo Telles-Correia. Acta Med Port. 2018;31:454-62. ". PMID- 30521471 TI - LncRNA TINCR / microRNA-107 / CD36 regulates cell proliferation and apoptosis in colorectal cancer via PPAR signaling pathway based on bioinformatics analysis. AB - Present study aims to determine the potential biomarkers and uncover the regulatory mechanisms of lncRNA TINCR / miR-107 / CD36 axis in CRC. Aberrantly expressed lncRNAs and differential-expressed genes were identified by analyzing the dataset GSE40967. Gene set enrichment analysis were employed, and Cytoscape software helps establishing the co-expression network between lncRNAs and genes. Quantitative RT-PCR analysis contributes to examining the expression levels of lncRNA TINCR, miR-107 and CD36. Dual luciferase assay was used to validate the association between miR-107 and lncRNA TINCR or CD36. EdU incorporation assay was employed, and flow cytometry was employed to detect cell apoptosis with Tumor Xenograft model utilized. Significantly dysregulated lncRNAs and mRNAs were identified. Peroxisome proliferators-activated receptor signaling pathway in CRC tissues was down-regulated. Loss of TINCR expression was associated with CRC progression. The expression levels of the TINCR and CD36 were down-regulated. We identified miR-107 as an inhibitory target of TINCR and CD36. Overexpression of TINCR could inhibit cell proliferation and promote apoptosis. MiR-107 overexpression in CRC cells induced proliferation and impeded apoptosis. Regulatory function of lncRNA TINCR/miR-107/CD36 axis in CRC was revealed. LncRNA TINCR overexpression exerted suppressive influence on CRC progression through modulating PPAR signaling pathway via miR-107 / CD36 axis. PMID- 30521472 TI - Directed evolution of the 3C protease from Coxsackievirus using a novel fluorescence-assisted intracellular method. AB - Proteases are crucial for regulating biological processes in organisms through hydrolysis of peptide bonds. Recombinant proteases have moreover become important tools in biotechnological, and biomedical research and as therapeutics. We have developed a labelfree high-throughput method for quantitative assessment of proteolytic activity in Escherichia coli. The screening method is based on co expression of a protease of interest and a reporter complex. This reporter consists of an aggregation-prone peptide fused to a fluorescent protein via a linker that contains the corresponding substrate sequence. Cleavage of the substrate rescues the fluorescent protein from aggregation, resulting in increased fluorescence that correlates to proteolytic activity, which can be monitored using flow cytometry. In one round of flow-cytometric cell sorting, we isolated an efficiently cleaved TEV substrate from a 1:100,000 background of non cleavable sequences, with around 6000- fold enrichment. We then engineered the 3C protease from Coxsackievirus B3 (CVB3 3Cpro) towards improved proteolytic activity on the substrate LEVLFQ?GP. We isolated highly proteolytic active variants from a randomly mutated CVB3 3Cpro library with up to 4-fold increase in activity. The method enables simultaneous measurement of proteolytic activity and protease expression levels and can therefore be applied for protease substrate profiling, as well as directed evolution of proteases. PMID- 30521473 TI - Kinetically selective and potent inhibitors of HDAC8. AB - HDAC8 is an established and validated target for T-cell lymphoma and childhood neuroblastoma. The active site binding pocket of HDAC8 is highly conserved among all zinccontaining representatives of the histone deacetylase family. This explains that most HDACs are unselectively recognized by similar inhibitors featuring a zinc binding group (ZBG), a hydrophobic linker and a head group. In the light of this difficulty, the creation of isoenzymeselectivity is one of the major challenges in the development of HDAC inhibitors. In a series of trifluoromethylketone inhibitors of HDAC8 compound 10 shows a distinct binding mechnism and a dramatically increased residence time providing kinetic selectivity against HDAC4. Combining the binding kinetics results with computational docking and binding site flexibility analysis suggests that 10 occupies the conserved catalytic site as well as an adjacent transient sub-pocket of HDAC8. PMID- 30521474 TI - Platelet to lymphocyte ratio predicts all-cause mortality in patients with carotid arterial disease. AB - BACKGROUND: Platelet to lymphocyte ratio (PLR) has been demonstrated as an risk and prognostic marker in many of cardiovascular diseases. Relationship between PLR and severity of carotid stenosis has been shown. The aim of our study was to investigate the relationship between PLR and all cause mortality in patients with carotid arterial disease. METODS: This retrospective study included 146 patients who had been performed selective carotid angiography. Carotid stenosis were graded by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Platelet to lymphocyte ratio was calculated as the ratio of plateletes to lymphocytes. The end point of the study was all-cause mortality. RESULTS: During median follow-up of 16 months (0-65 months) 15 (10.3%) patients suffered all-cause mortality. 50 patients(34.2%) underwent carotid endarterectomy and 69 patients (47.3%) had non-carotid cardiac surgery. 38 patients (26.02%) had cerebrovascular events (stroke/transient ischemic attack) at admission. NASCET grades were not different between survivors and non-survivors. Non-survivors had significantly lower hemoglobin (Hb) levels (12.7+/-1.6 g/dl vs. 13.7+/-1.7 g/dl , p= 0.031) and they were older than survivors (74.2+/-8.4 years vs. 68.6+/-8.5 years, p=0.029). Non-survivors had significantly higher PLR values compared with survivors (190.3+/-85.6 and 126.8+/-53.8, p=0.017). In multivariate analysis, only PLR predicted all-cause mortality in patients with carotid artery stenosis. CONCLUSION: In our study, higher PLR was associated with increased all-cause mortality. PMID- 30521475 TI - Multiple acute ischemic strokes as the onset manifestation of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia often manifests with hemorrhagic diathesis, thrombotic events being much rarer. This is the case of a 59-year-old patient with thrombotic cerebro-vascular complications as the onset manifestation of acute promyelocytic leukemia. PMID- 30521476 TI - Beneficial effects of combined therapy with lacidipine and candesartan in obese hypertensive patients. AB - INTRODUCTION: Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro inflammatory cytokines and oxidative stress. AIMS: To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity. METHODS: A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 +/- 5.8 years), who previously have not been receiving regular antihypertensive therapy. RESULTS: During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-alpha to its type I soluble receptor ratio (TNF- alpha/sTNF-alphaRI), and oxidative stress marker - 8-iso-PgF2alpha has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period. CONCLUSION: The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan. PMID- 30521477 TI - Pancreas divisum: a reemerging risk factor for pancreatic diseases. AB - Pancreas divisum (PD) is the most common developmental anatomic variant of pancreatic duct. The attention towards the PD has grown significantly since there are reports that this condition may cause acute relapsing pancreatitis, chronic pancreatitis and chronic abdominal pain syndrome. Furthermore, over the years, there have been multiple reports of PD associated with different types of tumors. There is evidence that PD can be associated with pancreatic tumors (up to 12.5% of cases). The golden standard for diagnosing PD is endoscopic retrograde cholangiopancreatography, but since it is an invasive procedure magnetic resonance cholangiopancreatography with secretin is a good alternative. In case the patient is symptomatic, endoscopic or surgical treatment should be performed. This review describes the key points of the pathophysiology, diagnostic modalities, risks of pancreatitis and tumors, as well as treatment options of PD. PMID- 30521478 TI - Laparoscopic sleeve gastrectomy and gastroesophageal reflux. AB - The prevalence of obesity is rising, becoming a medical problem worldwide. Also GERD incidence is higher in obese patients compared with normal weight, with an increased risk of 2.5 of developing symptoms and erosive esophagitis. Different treatment modalities have been proposed to treat obese patients, but bariatric surgery due to its complex interactions via anatomic, physiologic and neurohormonal changes achieved the best long-term results, with sustained weight loss and decrease of complications and mortality caused by obesity. The bariatric surgical procedures can be restrictive: laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG), or malabsorptive-restrictive such as Roux-en-Y gastric bypass (RYGB). These surgical procedures may influence esophageal motility and lead to esophageal complications like gastroesophageal reflux disease (GERD) and erosive esophagitis. From the literature we know that the RYGB can ameliorate GERD symptoms, and some bariatric procedures were finally converted to RYGB because of refractory reflux symptoms. For LAGB the results are good at the beginning, but some patients experienced new reflux symptoms in the follow-up period. Recently LSG has become more popular than other complex bariatric procedures, but some follow-up studies report a high risk of GERD after it. This article reviews the results published after LSG regarding gastroesophageal reflux and the mechanisms responsible for GERD in morbidly obese subjects. PMID- 30521479 TI - ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling. AB - We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer. PMID- 30521480 TI - GLUT3 expression in cystic change induced by hypoxia in pituitary adenomas. AB - Tumor cells require large amounts of energy to sustain growth. Through the mediated transport of glucose transporters, the uptake and utilization of glucose by tumor cells are significantly enhanced in the hypoxic microenvironment. Pituitary adenomas are benign tumors with high energy metabolisms. We aimed to investigate the role of expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1) in pituitary adenomas, including effects on size, cystic change, and hormone type. Pituitary adenomas from 203 patients were collected from January 2013 to April 2017, and immunohistochemical analysis was used to detect the expression of GLUT3 and GLUT1 in tumor specimens. GLUT3-positive expression in the cystic change group was higher than that in the non-cystic change group (P = 0.018). Proportions of GLUT3-positive staining of microadenomas, macroadenomas, and giant adenomas were 22.7% (5/22), 50.4% (66/131), and 54.0% (27/50), respectively (P = 0.022). In cases of prolactin adenoma, GLUT3-positive staining was predominant in cell membranes (P =0.000006), while in cases of follicle-stimulating hormone or luteotropic hormone adenoma, we found mainly paranuclear dot-like GLUT3 staining (P = 0.025). In other hormonal adenomas, GLUT3 was only partially expressed, and the intensity of cell membrane or paranuclear punctate staining was weak. In contrast to GLUT3, GLUT1 expression was not associated with pituitary adenomas. Thus, our results indicate that the expression of GLUT3 in pituitary adenomas is closely related to cystic change and hormonal type. This study is the first to report a unique paranuclear dot-like GLUT3 staining pattern in pituitary adenomas. PMID- 30521482 TI - My Womban's Life: Understanding Human Endometrial Function. AB - The focus of my life in science, has been to improve reproductive health for women, with an emphasis on the endometrium, the most dynamic tissue in the human body: its remarkable cyclical remodelling is essential for establishment of pregnancy. The most notable events in a woman's endometrial cycle are menstruation and endometrial repair, regeneration of the endometrium during the proliferative phase, attainment of receptivity by the mid-secretory phase of the cycle and the embryo-maternal interactions that initiate peri-implantation events within the microenvironment of the uterine cavity. I have contributed to understanding the molecular and cellular changes underpinning these events, and how disturbance of them leads to menstrual disorders, infertility and endometrial diseases including abnormal uterine bleeding, endometriosis and endometrial cancer. My team have contributed to changes in clinical IVF practice, to a new diagnostic for endometrial receptivity in infertile women, and to enhancing endometrial repair. I have shared my world with many amazing younger scientists: it has indeed been a privileged journey. PMID- 30521481 TI - Not performing an OGTT results in underdiagnosis, inadequate risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years: a population based prospective cohort study. AB - Screening for (pre)diabetes is recommended in China using fasting blood glucose as routine strategy currently but not oral glucose tolerance test (OGTT) in high risk population. We aimed to explore the impact by not performing an OGTT in Han Chinese over 40 years. 6682 participants were included in the prospective cohort study followed up for 3 years. Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2h-PG), FPG and 2h-PG (in OGTT), and HbA1c testing using WHO or ADA Criteria were employed for strategy analysis. The prevalence of diabetes is 12.4% (95% CI: 11.6-13.3), while the prevalence of prediabetes is 34.1% (95% CI: 32.9 35.3) and 56.5% (95% CI: 55.2-57.8) using WHO and ADA Criteria respectively. 2h PG determined more diabetes individuals than FPG and HbA1c. The testing cost per true positive case of OGTT is close to FPG and less than 2h-PG or HbA1c. FPG, 2h PG and HbA1c strategies would increase costs from complications for FP or FN results compared with OGTT. Moreover, the least individuals identified as normal by OGTT at baseline developed (pre)diabetes, and the most prediabetes individuals identified by HbA1c or FPG using ADA criteria developed diabetes. We concluded that the prevalence of isolated IGT and isolated 2h post-load diabetes were high and the majority of individuals with (pre)diabetes were undetected in Chinese Han population. Additionally, not performing an OGTT results in underdiagnosis, inadequate developing risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years and great consideration should be given to OGTT in detecting (pre)diabetes in this population. Further population based prospective cohort study of longer-term effects is necessary to investigate the risk assessment and cost of (pre)diabetes. PMID- 30521483 TI - Aging, inhibition and GABA. PMID- 30521484 TI - Molecular insights into vascular aging. PMID- 30521485 TI - Transverse and longitudinal spin-fluctuations in INVAR Fe0.65Ni0.35. AB - The presence of spin-fluctuations deep within the ordered state of ferromagnetic [Formula: see text] alloy [Formula: see text] has long been suspected but seldom directly observed. Inhomogeneities of one type or another have been cited as important in stabilizing [Formula: see text] behaviour-either longitudinal spin fluctuations associated with the [Formula: see text]-state (local environment) model or transverse magnetisation arising from non-collinear spin structures. In this study we employ small-angle neutron scattering with neutron polarization analysis to distinguish between the two possibilities. Surprisingly we in fact find evidence of dominant but uncorrelated longitudinal spin-fluctuations coexisting with transverse magnetisation which exists in short-range clusters of size ~[Formula: see text]. This finding supports recent first principles calculations of [Formula: see text] in which both longitudinal spin-fluctuations and magnetic short-range order are identified as important ingredients in reproducing the equilibrium [Formula: see text] lattice. PMID- 30521486 TI - Ginzburg-Landau theory for the magnetic and structural transitions in La1-y (Ca1 x Sr x ) y MnO3. AB - We present a phenomenological theory for the ferromagnetic transition temperature, the magnetic susceptibility at high temperatures, and the structural distortion in the La[Formula: see text](Ca[Formula: see text]Sr[Formula: see text])[Formula: see text]MnO[Formula: see text] system. We construct a Ginzburg Landau free energy that describes the magnetic and the structural transitions, and a competition between them. The parameters of the magnetic part of the free energy are derived from a mean-field solution of the magnetic interaction for arbitrary angular momentum. The theory provides a qualitative description of the observed magnetic and structural phase transitions as functions of Sr-doping level ([Formula: see text]) for [Formula: see text]. PMID- 30521487 TI - On the role of magnesium in a LiF:Mg,Ti thermoluminescent dosimeter. AB - LiF doped with Mg and Ti is the most widely used thermoluminescent (TL) dosimeter for a large variety of applications. It has been argued that the Mg dopant is the most important defect in the TL process. Besides the common F-centre defects in LiF, optical absorption measurements have suggested the presence of Mg-related absorption bands at 380 nm (3.26 eV), and 310 nm (4.0 eV) when LiF:Mg is exposed to ionizing radiation, whose origin is not yet well understood. This work presents an investigation of the role of defects induced by Mg interstitials in LiF through electronic structure calculations. The calculations show that Mg interstitials induce a local lattice distortion characterized by the displacement of two opposite fluorine atoms, adjacent to the magnesium, away from their original sites by an average distance of 0.6 A each, while the closest Li atoms are displaced by 0.1 A. This defect introduces electronic states in the band-gap that can trap excess electrons produced during irradiation, thus enhancing the efficiency of the detector. Holes, on the other hand, are created and trapped in orbitals of mainly Mg-3s character. Additionally, the results suggest that irradiation can simultaneously remove a Li atom nearby a Mg interstitial; substitute a Li by a Mg atom or create a Li vacancy plus a Mg substitutional, giving rise to defects within the LiF gap that are more stable thermodynamically than the Mg interstitial itself. Interestingly, under irradiation the energy levels obtained for LiF:Mg-Lisub + e - (3.486 eV) and LiF:Mg + e - (4.224 eV) defects are very close to the experimental absorption bands. PMID- 30521488 TI - 3D surface condensation of large atomic shear strain in nanoscale metallic glasses under low uniaxial stress. AB - Nanoscale metallic glasses (MGs) are frequently used in experimental and computational studies to probe the deformation mechanisms in amorphous metals. Potential consequences of the significant surface to volume ratio in these extremely small materials, nevertheless, are not well understood. Here, using molecular dynamics simulations and novel selective 3D visualization, we show that significant irreversible atomic shear strain condenses on the 3D surface of these materials under low uniaxial stress, while the interior atoms are bearing much lower, mostly reversible shear strain. This is observed for various sample geometries, dimensions, strain rates and temperatures, and attributable to the correlations of atomic shear strain with atomic potential energy and coordination number. The results reveal the profound influence of the surface on the strain partitioning in nanoscale MGs across the 3D volume, critical to the initiation and continuation of plasticity. PMID- 30521489 TI - Quasi-degenerate magnetic states in alpha-RuCl3. AB - Exploring quantum spin liquid (QSL) state has both fundamental scientific value and realistic application potential. Recently, alpha-RuCl3 was experimentally observed to hold in-plane zigzag antiferromagnetic (AFM) order at low temperature, which was further proposed to be proximate to a Kitaev QSL ground state. We have studied the magnetic properties of alpha-RuCl3 in the framework of electronic structure calculation based on density functional theory (DFT) with Hubbard U correction (DFT+U) and spin-orbit coupling. When the intra-orbital Hubbard interaction U and the inter-orbital Hund's coupling J adopt the commonly accepted values of U = 2.0 eV and J = 0.4 eV, the zigzag AFM order indeed owns the minimum energy, consistent with the experimental observation. More importantly, we find that compared with the ferromagnetic order in the previous theoretical studies, there exist a series of magnetic configurations energetically even closer to the zigzag AFM ground state. The further calculations and analysis indicate that these low-energy magnetic states are closely related to the electronic correlation effect of Ru 4d orbitals. By decreasing U and increasing J with just about 0.2 eV, they become energetically degenerate with the zigzag AFM order, inducing strong magnetic frustration and then yielding a state without long-range magnetic order but with nonzero local moments. Considering the facts that theoretically the pressure usually reduces the intra-orbital Hubbard interaction and meanwhile enhances the inter-orbital Hund's coupling, while experimentally the pressure drives alpha-RuCl3 into a quantum disordered phase, our results provide a perspective to understand the exotic magnetic behaviors of alpha-RuCl3. PMID- 30521490 TI - Nanocone-based plasmonic metamaterials. AB - Metamaterials and metasurfaces provide unprecedented opportunities for designing light-matter interactions. Optical properties of hyperbolic metamaterials with meta-atoms based on plasmonic nanorods, important in nonlinear optics, sensing and spontaneous emission control, can be tuned by varying geometrical sizes and arrangement of the meta-atoms. At the same time the role of the shape of the meta atoms forming the array has not been studied. We present the fabrication and optical characterization of metamaterials based on arrays of plasmonic nanocones closely packed at the subwavelength scale. The plasmonic mode structure of the individual nanocones and pronounced coupling effects between them provide multiple degrees of freedom to engineer both the field enhancement and the optical properties of the resulting metamaterials. The metamaterials are fabricated using a scalable manufacturing procedure, allowing mass-production at the centimeter scale. The ultra-sharp cone apex ([Formula: see text]2 nm) and the associated field enhancement provide an extremely high density of electromagnetic hot-spots (~1010 cm-2). These properties of nanocone-based metamaterials are important for the development of gradient-index metamaterials and in numerous applications in fluorescence enhancement, surface enhanced Raman spectroscopy as well as hot-carrier plasmonics and photocatalysis. PMID- 30521491 TI - Experimental and theoretical evidences for the ice regime in planar artificial spin ices. AB - In this work, we explore a kind of geometrical effect in the thermodynamics of artificial spin ices (ASI). In general, such artificial materials are athermal. Here, We demonstrate that geometrically driven dynamics in ASI can open up the panorama of exploring distinct ground states and thermally magnetic monopole excitations. It is shown that a particular ASI lattice will provide a richer thermodynamics with nanomagnet spins experiencing less restriction to flip precisely in a kind of rhombic lattice. This can be observed by analysis of only three types of rectangular artificial spin ices (RASI). Denoting the horizontal and vertical lattice spacings by [Formula: see text] and [Formula: see text], respectively, then, a RASI material can be described by its aspect ratio [Formula: see text]. The rhombic lattice emerges when [Formula: see text]. So, by comparing the impact of thermal effects on the spin flips in these three appropriate different RASI arrays, it is possible to find a system very close to the ice regime. PMID- 30521492 TI - Two Double-hit Lymphomas Cases: A Molecular Cytogenetic Approach. AB - OBJECTIVES: Double-hit lymphomas represent 5% of cases of diffuse large B-cell lymphomas (DLBCL). They are currently recognized as highgrade B-cell lymphomas (HGBCL) with rearrangements of MYC and BCL2 and/or BCL6 by the 2016 WHO classification. One of these rearrangements is the translocation of the BCL2 gene (18q21.33), which codes for an apoptotic inhibitor, to the immunoglobulin heavy chain gene (14q32). In rarer instances, a translocation of the BCL2 gene to the immunoglobulin light chain gene on 2p11 also occurs. Both of these rearrangements result in consistent expression of the BCL2 protein. Another rearrangement is the translocation of the MYC proto-oncogene (8q24.21) to the IGH gene (14q32), which results in the overactivation of MYC. A t(14;18) can drive a low-grade malignant lymphoma, which is commonly a follicular or DLBCL. However, the presence of a t(8;14) abnormality may result in a highgrade malignant lymphoma, such as Burkitt's lymphoma. Both translocations affecting MYC and BCL2 rarely occur in an identical cell, and this lymphoid malignancy is known as BCL2 and MYC double-hit lymphoma. The incidence of aggressive B-cell lymphomas other than Burkitt's with a MYC breakpoint is difficult to assess, mainly because the published cytogenetics data may be biased toward specific categories of lymphomas and not consider the BCL2 involvement. BCL6/MYC double-hit lymphomas are less common, and most of these cases represent triple-hit lymphomas with involvement of BCL2 as well. In this review, we summarize and discuss the significance of cytogenetic abnormalities found in HGBCL and discuss possible directions for future research. We present two patients with double-hit lymphomas as well as our molecular cytogenetic approach to check the presence of MYC and BCL6 rearrangements as well as a BCL2/ IGH fusion. PMID- 30521493 TI - Unexplained cytopenias in an adolescent? You GATA think about it. AB - OBJECTIVES: The GATA family of DNA binding proteins consists of six different transcription factors (GATA1-6), each with a diverse biologic function. The transcription factors GATA1-3 function primarily to orchestrate hematopoiesis; however, they have roles in non-hematopoietic cells as well. Much of our current knowledge of the GATA transcription factors has come through observation of disease states with known GATA mutations. The GATA2 protein has been shown to be vital for proliferation and maintenance of hematopoietic stem cells; mutations result in variable phenotypes including myelodysplastic syndrome. We present a case of a 19-year-old male with a history of pancytopenia and hypocellular bone marrow with dysplastic morphologic changes who underwent an extensive workup to determine an etiology. Molecular testing identified a germline GATA2 c.1081 C>T heterozygous mutation, allowing his case to be classified as the World Health Organization (WHO) entity: myeloid neoplasm with germline GATA2 mutation. PMID- 30521494 TI - Tissue Specificity in Trisomy 22 Mosaicism: A Tale of Caution for Interpretation of Chromosomal Microarray Results. AB - OBJECTIVES: While the complete form of trisomy 22 is seemingly incompatible with life, the mosaic form is a rare syndrome associated with developmental delays, intellectual disability, and dysmorphic features. Due in part to the difficulty of analyzing chromosomal mosaicism, many instances either go undiagnosed or have their diagnosis delayed. We report a case of mosaic trisomy 22 in a diamnionic dichorionic twin with marked growth discordance and intra-uterine growth restriction, diagnosed in a 2-year-old with developmental delays, sensorineural hearing loss, cardiac and gastrointestinal abnormalities, and osteopenia of prematurity. Evaluation with a chromosomal oligonucleotide microarray with SNP analysis did not detect any copy number variants. Fibroblast metaphase karyotype analysis from a skin biopsy, however, showed trisomy 22 which was confirmed by FISH. Follow-up peripheral blood karyotype analysis and FISH studies revealed a normal male karyotype. This case highlights an instance where classical cytogenetics from two separate tissue types can provide a diagnosis that is more cost-effective than microarray analysis in assessing pediatric developmental delay. Trisomy 22 is the second most common aneuploidy in spontaneous miscarriages and has a nondescript and variable phenotype, especially in cases of mosaicism. As such, this condition may be underdiagnosed using the current recommended testing algorithm. Chromosomal microarray is considered first tier testing in an unrecognized phenotype with whole exome or whole genome sequencing, often performed on peripheral blood, as second tier testing. Diagnoses such as mosaic trisomy 22 suggest the second tier of testing in undiagnosed cases should also include a recommendation to look at alternative tissue types. PMID- 30521495 TI - Loss of ARHGEF1 causes a human primary antibody deficiency. AB - ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in two primary-antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centres and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target ROCK, the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signalling, and confining B lymphocytes and myelocytes within their dedicated functional environment. PMID- 30521496 TI - Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA-stem. AB - Both natural influenza infection and current seasonal influenza vaccines primarily induce neutralising antibody responses against highly diverse epitopes within the "head" of the viral hemagglutinin (HA) protein. There is increasing interest on redirecting immunity towards the more conserved HA-stem or stalk as a means to broaden protective antibody responses. Here we examined HA-stem-specific B cell and T-follicular helper (Tfh) cell responses in the context of influenza infection and immunisation in mouse and monkey models. We found that during infection the stem domain was immunologically subdominant to the head in terms of serum antibody production and antigen-specific B and Tfh responses. Similarly, we found HA-stem immunogens were poorly immunogenic compared to the full-length HA with abolished sialic acid binding activity, with limiting Tfh elicitation a potential constraint to the induction or boosting of anti-stem immunity by vaccination. Finally, we confirm that currently licensed seasonal influenza vaccines can boost pre-existing memory responses against the HA-stem in humans. An increased understanding of the immune dynamics surrounding the HA-stem is essential to inform the design of next-generation influenza vaccines for broad and durable protection. PMID- 30521497 TI - The appropriate whole body metric for calculating standardised uptake value and the influence of sex. AB - AIM: To compare weight, lean body mass and body surface area for calculation of standardised uptake value (SUV) in fluorine-18-fluorodeoxyglucose PET/computed tomography, taking sex into account. PATIENTS AND METHODS: This was a retrospective study of 161 (97 men) patients. Maximum standardised uptake value (SUVmax) and mean standardised uptake value (SUVmean) were obtained from a 3-cm region of interest over the right lobe of the liver and scaled to weight, scaled to lean body mass (SUL) and scaled to body surface area (SUA). Mean hepatic computed tomography density was used to adjust SUVmean for hepatic fat (SUVFA). Hepatic SUV indices were divided by SUV from left ventricular cavity, thereby, eliminating whole body metric, to obtain a surrogate of blood fluorine-18 fluorodeoxyglucose clearance into liver, and multiplied by blood glucose to give a surrogate of hepatic glucose uptake rate (mSUV). RESULTS: SULmax, SUAmax and all scaled to weight indices correlated strongly with weight. SULmean, SULFA, SUAmean and SUAFA, however, correlated weakly or not at all with weight, nor with their corresponding whole body metric in men or women, but correlated strongly when the sexes were combined into one group. This was the result of sex differences in SUL (greater in men) and SUA (greater in women). There was, however, no sex difference in mSUV. CONCLUSION: Weight is unsuitable for calculating SUV. SUL and SUA are also inappropriate as maxima but appropriate as mean and fat-adjusted values. However, SUL is recommended for both sexes because SUA is influenced by both body fat and weight. Sex differences in SUL and SUA give rise to misleading correlations when sexes are combined into one group. PMID- 30521498 TI - Effect of positive carbon-11-choline PET/CT results in the therapeutic management of prostate cancer biochemical relapse. AB - OBJECTIVE: Carbon-11-(C)-choline PET/computed tomography (CT) has shown good results in re-staging of prostate cancer (PCa) with raised serum levels of prostate-specific antigen. Our aim was to evaluate the effect of positive C choline PET/CT results in the therapeutic management of patients with PCa with biochemical relapse (BR) after curative intention treatment. PATIENTS AND METHODS: A total of 112 patients with PCa BR and positive C-choline PET/CT were retrospectively evaluated. PET/CT was acquired 20 min after intravenous administration of 555-740 MBq of C-choline. The therapeutic management after C choline PET/CT was obtained from the clinical records. The minimum follow-up time was 18 months. RESULTS: In 80 (71.4%) of 112 patients, C-choline PET/CT showed local recurrence of PCa; in 17 (15.2%) patients, distant recurrence; and in 15 (13.4%) patients, local plus distant recurrence. A second malignancy was detected in five (4.5%) patients. The planned therapeutic management was changed as per positive C-choline PET/CT result in 74 (66.1%) patients and were treated as follows: 31 (27.7%) patients with HT, combined with other treatments in eight (7.1%), 17 (15.2%) with BT, 13 (11.6%) with external beam radiotherapy, one (0.9%) with RP, and four (3.6%) with chemotherapy. Treatment approach was not modified in 37 (33%) patients. No data was available from one (0.9%) patient. CONCLUSION: Positive C-choline PET/CT result had an important effect in the therapeutic management of patients with PCa and BR, leading to a change in the planned approach in two (66.1%) out of three patients. In addition, in 4.5% of the patients, the C-choline PET/CT allowed the detection of a second malignancy. PMID- 30521499 TI - Short communication: Targeted proteomic analysis detects acute T cell-mediated kidney allograft rejection in belatacept-treated patients. AB - BACKGROUND: There is an unmet need for reliable minimally invasive diagnostic biomarkers for immunological allograft monitoring and for the detection of acute kidney transplant rejection. Here, targeted proteomic analysis was applied to compare 92 proteins in sera of belatacept-treated patients who had biopsy-proven, acute T cell-mediated rejection (aTCMR) with patients without aTCMR. METHODS: Proximity extension immunoassay (PEA) was used to measure 92 inflammation-related protein concentrations in the pre-rejection and rejection sera of 11 patients with aTCMR and 9 patients without aTCMR. This assay uses two matched oligonucleotide-labelled antibody probes for each protein and PCR to measure normalized protein expression values. RESULTS: Five proteins (CD5, CD8A, NCR1, TNFRSF4 and TNFRSF9) were expressed significantly higher in samples with aTCMR compared with samples without aTCMR (adjusted p-value<0.014) and had a good predictive capacity for aTCMR (area under the curve in a receiver operator curve ranged from 0.83 to 0.91 [p<0.014]). These proteins are associated with CD8 cytotoxic T cell and NK cell functions. Non-hierarchical clustering analysis showed distinct clustering of samples with aTCMR and samples without aTCMR. This clustering was not found in pre-rejection samples (one month after transplantation). In pre-rejection samples, IFN-gamma was expressed at a significantly lower level (NPX value median -0.15, IQR: -0.27-0.04) than in samples of patients without rejection (median 0.13, IQR: -0.07-0.15, adjusted p value=0.00367). CONCLUSIONS: Targeted proteomic analysis with PEA is a promising minimally invasive technique to diagnose aTCMR in kidney transplant recipients. PMID- 30521500 TI - LINC01118 Modulates Paclitaxel Resistance of Epithelial Ovarian Cancer by Regulating miR-134/ABCC1. AB - BACKGROUND Epithelial ovarian cancer (EOC) has a high mortality rate and is a common malignant tumor of women, seriously impairing health. Chemoresistance is one of the major causes of poor prognosis. Therefore, analyzing the molecular mechanism of paclitaxel resistance has great significance. MATERIAL AND METHODS We analyzed aberrantly expressed lncRNAs in chemoresistant EOC cells by microarray and confirmed LINC01118 expression by real-time PCR. The paclitaxel sensitivity alternation was analyzed by MTS, flow cytometry, and Transwell assay, while wound healing assays were performed to assess apoptosis, migration, and invasion in vitro. The interaction between LINC01118 and miR-134 was confirmed by luciferase assay. RESULTS LINC01118 was highly expressed in EOC tissues and chemoresistant cells. Biological function experiments showed LINC01118 could facilitate paclitaxel resistance and promote migration and invasion while inhibiting apoptosis of EOC cells. Moreover, LINC01118 targets miR-134 and then affects ABCC1 expression. CONCLUSIONS LINC01118 acted as an oncogene and modulated EOC paclitaxel sensitivity by regulating miR-134/ABCC1. PMID- 30521501 TI - Outbreak of Epidemic Keratoconjunctivitis Caused by Human Adenovirus Type D53 in an Eye Care Clinic - Los Angeles County, 2017. AB - On June 22, 2017, the Los Angeles County Department of Public Health (LAC DPH) was notified of seven patients who were seen at an eye care clinic on June 8, 2017, and later developed symptoms of epidemic keratoconjunctivitis (EKC). EKC is a contagious, severe form of viral conjunctivitis that can cause pain and blurred vision for up to 4 weeks (1). LAC DPH conducted an investigation, which identified 17 patients with EKC, including 15 who had visited the optometry clinic and two who were household contacts of clinic patients. Observations in the clinic found deficiencies in disinfection of tonometers (an instrument connected to a slit lamp and used to test for glaucoma by measuring intraocular pressure) and multiuse eye drop administration. Staff member education and revision of disinfection practices interrupted further transmission. Patient specimens tested positive for human adenovirus (HAdV) type D53 (HAdV-53). As the first documented EKC outbreak associated with HAdV-D53 in the United States, this outbreak highlights the need for rigorous implementation of recommended infection prevention practices in eye care settings. PMID- 30521502 TI - Exposure to Secondhand Smoke Among Nonsmokers - United States, 1988-2014. AB - Exposure to secondhand smoke from burning tobacco products can cause sudden infant death syndrome, respiratory infections, ear infections, and asthma attacks in infants and children, and coronary heart disease, stroke, and lung cancer in adult nonsmokers (1). There is no risk-free level of secondhand smoke exposure (2). CDC analyzed questionnaire and laboratory data from the National Health and Nutrition Examination Survey (NHANES) to assess patterns of secondhand smoke exposure among U.S. nonsmokers. The prevalence of secondhand smoke exposure among U.S. nonsmokers declined substantially during 1988-2014, from 87.5% to 25.2%. However, no change in exposure occurred between 2011-2012 and 2013-2014, and an estimated one in four nonsmokers, or approximately 58 million persons, were still exposed to secondhand smoke during 2013-2014. Moreover, marked disparities persisted across population groups. Exposure prevalence was highest among nonsmokers aged 3-11 years (37.9%), non-Hispanic blacks (50.3%), and those who were living in poverty (47.9%), in rental housing (38.6%), or with someone who smoked inside the home (73.0%), or among persons who had less than a high school education (30.7%). Comprehensive smoke-free laws and policies for workplaces and public places and smoke-free rules for homes and vehicles can further reduce secondhand smoke exposure among all nonsmokers. PMID- 30521503 TI - Public Health Response to an Avian Influenza A(H7N8) Virus Outbreak in Commercial Turkey Flocks - Indiana, 2016. AB - In January 2016, highly pathogenic avian influenza (HPAI) A(H7N8) virus and low pathogenicity avian influenza (LPAI) A(H7N8) virus were detected in commercial turkey flocks in Dubois County, Indiana. The Indiana State Department of Health (ISDH) and the Dubois County Health Department (DCHD) coordinated the public health response to this outbreak, which was the first detection of HPAI A(H7N8) in any species (1). This response was the first to fully implement unpublished public health monitoring procedures for HPAI responders that were developed by the U.S. Department of Agriculture (USDA) and CDC in 2015 (Sonja Olsen, CDC, personal communication, October 2017). No cases of zoonotic avian influenza infection in humans were detected during the outbreak. PMID- 30521504 TI - QuickStats: Percentage* of Adults Aged 20-64 Years with a Blood Cholesterol Check by a Health Professional? During the Past 12 Months, by Poverty StatusS - National Health Interview Survey, 2012 and 2017 . PMID- 30521505 TI - Uterine Cancer Incidence and Mortality - United States, 1999-2016. AB - Uterine cancer is one of the few cancers with increasing incidence and mortality in the United States, reflecting, in part, increases in the prevalence of overweight and obesity since the 1980s (1). It is the fourth most common cancer diagnosed and the seventh most common cause of cancer death among U.S. women (1). To assess recent trends in uterine cancer incidence and mortality by race and ethnicity, CDC analyzed incidence data from CDC's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and mortality data from the National Vital Statistics System (2). Most recent data available are through 2015 for incidence and through 2016 for mortality. Uterine cancer incidence rates increased 0.7% per year during 1999-2015, and death rates increased 1.1% per year during 1999-2016, with smaller increases observed among non-Hispanic white (white) women than among women in other racial/ethnic groups. In 2015, a total of 53,911 new uterine cancer cases, corresponding to 27 cases per 100,000 women, were reported in the United States, and 10,733 uterine cancer deaths (five deaths per 100,000 women) were reported in 2016. Uterine cancer incidence was higher among non-Hispanic black (black) and white women (27 cases per 100,000) than among other racial/ethnic groups (19-23 per 100,000). Uterine cancer deaths among black women (nine per 100,000) were higher than those among other racial/ethnic groups (four to five per 100,000). Public health efforts to help women achieve and maintain a healthy weight and obtain sufficient physical activity can reduce the risk for developing cancer of the endometrium (the lining of the uterus), the most common uterine cancer. Abnormal vaginal bleeding, including bleeding between periods or after sex or any unexpected bleeding after menopause, is an important symptom of uterine cancer (3). Through programs such as CDC's Inside Knowledge* campaign, promoting awareness among women and health care providers of the need for timely evaluation of abnormal vaginal bleeding can increase the chance that uterine cancer is detected early and treated appropriately. PMID- 30521506 TI - Notes from the Field: An Outbreak of Salmonella Agbeni Infections Linked to Turtle Exposure - United States, 2017. PMID- 30521507 TI - Rediscovered identity of the scaphocephalic skull housed in the museum of the Department of Anatomy of the Medical College of the Jagiellonian University. AB - A personal data referring to the scaphoid skull housed in the Department of Anatomy of the Jagiellonian University, Medical College was established thanks to reviewing 19th century literature performed by Dr. Soficaru. We received information that the skull had belonged to an adult man who was a carpenter, born at Cracow. The original anthropometrical study of this skull was performed by prof. Kopernicki 19th century. PMID- 30521508 TI - Risk factors for recoarctation of aorta after Norwood procedure in patients with hypoplastic left heart syndrome. AB - BACKGROUND: Recoarctation (reCoA) of the aorta is a common complication afer the Norwood procedure. Untreated, it can lead to failure of the systemic ventricle and death. The main goal of the study is to define risk factors of reCoA after the Norwood procedure in hypoplastic left heart syndrome (HLHS). METHODS: We retrospectively analyzed the pre-, intra- and postoperative data of 96 successive patients who underwent the Norwood procedure between 2007 and 2011. In case of reCoA balloon angioplasty was performed. We analyzed and compared the data of the patients with reCoA and without reCoA using the StatSo STATISTICA TM 10 software. RESULTS: ReCoA was noted in 23 patients (33.3%). This complication was diagnosed 95.1 days (49-156 days) on the average a er the Norwood procedure. Balloon angioplasty successfully allowed for decreasing the mean gradient across the site of the narrowing from the average 27.5 mmHg to the average 9.7 mmHg (p = 0.008) and enlarged the neo-isthmus by the average of 2 mm (p <0.05). The risks factors seemed to be the diameter of the ascending aorta OR = 7.82 (p = 0.001), atresia of the mitral valve OR = 7.00 (p = 0.003) and atresia of the aortic valve - OR = 6.22 (p = 0.002). CONCLUSION: Balloon angioplasty seems to be an effective intervention in case of reCoA. A low diameter of the native ascending aorta (<=3mm) and the presence of atresia of the mitral and/or aortic valve should intensify the vigilance of a cardiologist in the search for signs of reCoA of the aorta. PMID- 30521509 TI - Evaluation of the effectiveness of laser photoselective vaporization of the prostate in the treatment of patients with benign prostatic hyperplasia. AB - INTRODUCTION: The prolongation of the life of men results in the growing number of people suffering from benign prostatic hyperplasia (BPH). In 2010, BPH concerned more than 200 million men in the whole world, which at that time made up 6% of the population of men at large. Currently, the population of men in the world amounts about three billion six hundred million. The modern surgical treatment of BPH consists of minimally invasive techniques, including laser systems. AIM: Evaluation of the effectiveness of photoselective vaporization of the prostate (PVP) on the basis of subjective parameters assessed by patients using IPSS and QoL questionnaires as well as objective parameters obtained from results of urodynamic tests. MATERIAL AND METHODS: Between 2012 and 2015, 120 patients with benign prostatic hyperplasia were included in the study and underwent PVP. Finally, 77 patients were included in the study. In all patients, IPSS and QoL sheets were carried out 1, 6 and 12 months, and urodynamic tests 12 months a er the surgical treatment. RESULTS: The statistically significant change in the value of each parameter assessed: decrease in the IPSS, QoL, PVR, Pmax, Pop, the degree of obstruction according to Schafer and ICS nomogram, and an increase in the values of Qmax and Qave. CONCLUSIONS: Photoselective vaporization of the prostate is an effective method of therapy in patients with benign prostatic hyperplasia. PMID- 30521510 TI - Doping in sport - attitude and professional experience among physicians in Poland. AB - INTRODUCTION: The history of using performance-enhancing substances (PES) is long and it goes back to ancient times. At present, PES are employed at all levels of sport competition, starting from Olympic level contestants to individuals recreationally involved in various sports disciplines. PURPOSE: e objective of the study was examining the views on doping in sports in a group of physicians, together with evaluating the frequency of their contacts with this phenomenon, in their professional activities. METHODS: e investigation was carried out using a validated questionnaire developed by the authors. Questionnaire included 34 questions divided into 6 sections. In total, 257 individuals participated in the study. e percentage of answers was 75.81%. RESULTS: Among the responders, 96.50% believed that using PES by sports competitors represented unethical behavior. 42% participants declared that they met doping problem during their professional career. Almost one-third of the physicians (28.79%) declared that during their work, they consulted patient suffering from adverse side effects resulting from using PES. CONCLUSIONS: In Poland, physicians regard using PES as unethical behavior. They believe that a health care system professional should participate in counteracting doping in sports. Physicians - regardless of their specialty - are also exposed to PES-related problems in their professional work. In view of the above facts and the consistently increasing popularity of PES, extending the knowledge in this field among physicians seems to be of importance to allow for their offering better medical services to their patients. PMID- 30521511 TI - Treatment outcomes of pancreatic cancer in the elderly - literature review. AB - BACKGROUND: The older population is very heterogeneous with regard to the co morbidityand the physical reserve. This can result in unacceptably high postoperative complications rates. Therefore, the aim of the study was to review the literature regarding the outcomes of older patients treated for pancreatic cancer, including the usage of minimal invasive techniques. METHODOLOGY: A review of the literature was carried out including studies on pancreatic cancer in older patients published between 2011 and 2016. RESULTS: Seventeen retrospective studies were included. The total number of patients was 9981 with the age range of 65 years and more. Studies on surgical treatment alone (1.4%), neoadjuvant/adjuvant treatment with or without surgery (89.4%) and palliative therapy (9.2%) were assessed separately. Appropriate comparison was diffcult due to the retrospective character and heterogeneity of the study population. Mortality was low, yet there was a great difference in morbidity ranging from some percent to even 100% of the study population. Long-term results were poor. CONCLUSIONS: The functional status, not the chronological age alone, is the factor limiting therapeutic options in older patients with pancreatic cancer. PMID- 30521512 TI - The total number of septa and antra in the sphenoid sinuses - evaluation before the FESS. AB - PURPOSE: The purpose of this research is to define the total number of septa and the total number of antra in the sphenoid sinuses (created as a result of the presence of additional septa), as well as the relation between the number of the septa and their location in the adult population. MATERIALS AND METHODS: e study was conducted as a retrospective analysis of the computed tomography (CT) scans of the paranasal sinuses of 296 patients (147 females and 149 males), who did not present any pathology in the sphenoid sinuses. The CT scans of the paranasal sinuses were done with the spiral CT scanner (Siemens Somatom Sensation 16) by using a standard procedure, in the option Siemens CARE Dose 4D, without using any contrast medium. A er obtaining the transverse planes, the frontal and sagittal planes were created using secondary reconstruction tool (multiplans reconstruction - MPR). RESULTS: The analysis of the obtained images in the transverse plane and secondary CT reconstructions has shown the presence of only one sphenoid septum (main septum - MS) in 21.96% of the patients, which divided the sphenoid sinus into two sphenoid antra. In 78.04% of the patients, there were more than one sphenoid septa present in the posterior part of the sphenoid sinuses, hence there were additional septa (AS) present. One AS was present in 22.97% of the patients. The most common variant - two AS - was found in 32.09% of the cases. The presence of more than two AS was found in the following number of patients: three AS in 9.8%, four AS in 7.09%, five AS in 1.69%, six AS in 3.04% and seven AS in 1.01%. The rarest variant was the presence of more than seven AS: eight AS in 0.34% and nine AS also in 0.34%. There were no sphenoid sinuses that would have more than nine AS in the researched material. CONCLUSIONS: Due to the high incidence of the anatomical variants of the paranasal sinuses, a CT scan is recommended in all patients before a planned surgery in order to avoid the potential complications that might arise as a result of the complicated structure of the paranasal sinuses. PMID- 30521513 TI - Covered perforation of Meckel's diverticulum ulcer to transverse colon: highlighting the urgent intervention and the avoidance of a dramatic evolution (case report and literature review). AB - Meckel's diverticulum represents a remnant of the proximal end of the omphalomesenteric duct, which constitutes a connection between the middle intestine and the vitelline vesicle. It is the most common congenital anomaly of the gastrointestinal tract and is found in approximately 0.3-2% of the general population. Complications such as hemorrhage, bowel obstruction, inflammation, perforation, intussusception, volvulus and malignant transformation develop in only 4-4.8% of all patients, with most cases presenting in childhood, while relative risk decreases during life. The aim of the present study is to present our experience in managing a 15-year old male patient with Meckel's diverticulum covered perforation. It was a case of disguised perforation of the Meckel's diverticulum, with development of adhesions to the anterior surface of the right third of the transverse colon, which was successfully treated on the basis of emergency. Diagnosis was made intraoperatively and was documented by histological examination of the excised diverticulum. PMID- 30521514 TI - Identification of uterine telocytes and their architecture in leiomyoma. AB - INTRODUCTION: Uterine leiomyoma is the most widespread benign tumor affecting women of childbearing age. ere are still gaps in the understanding of its pathogenesiss. Telocytes are unique cells described in greater than 50 different locations inside the human body. The functional relationship of cells could clarify the pathogenesis of leiomyomata. In the current study, we focused on the identification of telocytes in all regions of the human uterus to explain their involvement in leiomyoma development. MATERIALS AND METHODS: Tissue samples from a healthy and myomatous uterus were stained for c-kit, tryptase, CD34 and PDGFRalpha to identify telocytes. Routine histology was performed to analyze tissue morphology and collagen deposits. RESULTS: Telocytes were detected in the cervix, corpus of the uterus and leiomyoma. The density of telocytes in fibroid foci was reduced compared with normal myometrium. CONCLUSIONS: Our results demonstrated the existence of telocytes in all parts of the human body affected and unaffected by leiomyoma of the uterus. In addition, telocytes were also present in leiomyoma foci. Our results suggest that the reduced density of telocytes is important for the pathomechanisms of myometrial growth, demonstrating its value as a main component of the myomatous architecture. PMID- 30521515 TI - Current treatment of the inguinal hernia - the role of the totally extraperitoneal (TEP) hernia repair. AB - Inguinal hernia repairs are one of the most common procedures performed in general surgical departments. Approximately 20 million hernia repairs are performed annually all over the world. According to the EHS guidelines, the recommended treatment methods of the inguinal hernia are tension-free techniques: the Lichtenstein open hernia repair and the laparoscopic transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) methods. The TEP hernia repair, first performed by Duluq in 1992, is one of the three current leading techniques in the inguinal hernia repair. The most important advantage of this technique is minimal invasive access without the need to open the peritoneum, which carries a lower risk of abdominal organs injury. Additionally, the TEP method facilitates shorter recovery time, less postoperative pain and an earlier discharge form hospital. The aim of the article is to present the TEP method by comparing it with the other inguinal hernia repair techniques, on the basis of the available literature. PMID- 30521516 TI - Aberrations in the female reproductive organs and a role of telocytes in a rat model of anorexia nervosa. AB - BACKGROUND: Anorexia nervosa is a widely prevalent eating disorder that o en leads to life-threatening complications. Since it mostly concerns females, many authors have focused on studying the reproductive system in anorexic women. Recently discovered telocytes may give a new insight into the pathophysiology of gynecological complications in these patients. MATERIAL AND METHODS: We adopted an animal model of anorexia nervosa induced by voluntary physical activity. Sixteen female Wistar rats were divided into two groups: control and activity based anorexia. When the weight loss of activity-based anorexia (ABA) rats reached 25% animals were euthanized. Size and weight measurements as well as histopathological analysis of the reproductive organs were performed. Additionally, we used immunohistochemical staining for detection of telocytes. RESULTS: Telocytes were identified in uteri of anorectic rats but no differences were observed when compared to the control group. Nevertheless, in the ABA group the weight of the uteri and the number of follicles in the ovaries decreased significantly. CONCLUSIONS: Our rat model of anorexia nervosa mimics the effects of this eating disorder that occur in the female reproductive system since we reported ovarian dysfunction and uterine involution in the experimental animals. It supports its potential role in the further studies of anorexia pathophysiology and treatment possibilities. PMID- 30521517 TI - Correction: Association analysis using somatic mutations. AB - [This corrects the article DOI: 10.1371/journal.pgen.1007746.]. PMID- 30521518 TI - Reinvestigating the status of malaria parasite (Plasmodium sp.) in Indian non human primates. AB - Many human parasites and pathogens have closely related counterparts among non human primates. For example, non-human primates harbour several species of malaria causing parasites of the genus Plasmodium. Studies suggest that for a better understanding of the origin and evolution of human malaria parasites it is important to know the diversity and evolutionary relationships of these parasites in non-human primates. Much work has been undertaken on malaria parasites in wild great Apes of Africa as well as wild monkeys of Southeast Asia however studies are lacking from South Asia, particularly India. India is one of the major malaria prone regions in the world and exhibits high primate diversity which in turn provides ideal setting for both zoonoses and anthropozoonoses. In this study we report the molecular data for malaria parasites from wild populations of Indian non-human primates. We surveyed 349 fecal samples from five different Indian non-human primates, while 94 blood and tissue samples from one of the Indian non-human primate species (Macaca radiata) and one blood sample from M. mulatta. Our results confirm the presence of P. fragile, P. inui and P. cynomolgi in Macaca radiata. Additionally, we report for the first time the presence of human malarial parasite, P. falciparum, in M. mulatta and M. radiata. Thus, Indian primates might serve both as source and sink for recurrent malaria infection in humans. Additionally, our results indicate that M. radiata does not exhibit population structure probably due to human mediated translocation of problem monkeys. Human mediated transport of macaques adds an additional level of complexity to tacking malaria in human. This issue has implications for both the spread of primate as well as human specific malarias. PMID- 30521519 TI - Bayesian adaptive dual control of deep brain stimulation in a computational model of Parkinson's disease. AB - In this paper, we present a novel Bayesian adaptive dual controller (ADC) for autonomously programming deep brain stimulation devices. We evaluated the Bayesian ADC's performance in the context of reducing beta power in a computational model of Parkinson's disease, in which it was tasked with finding the set of stimulation parameters which optimally reduced beta power as fast as possible. Here, the Bayesian ADC has dual goals: (a) to minimize beta power by exploiting the best parameters found so far, and (b) to explore the space to find better parameters, thus allowing for better control in the future. The Bayesian ADC is composed of two parts: an inner parameterized feedback stimulator and an outer parameter adjustment loop. The inner loop operates on a short time scale, delivering stimulus based upon the phase and power of the beta oscillation. The outer loop operates on a long time scale, observing the effects of the stimulation parameters and using Bayesian optimization to intelligently select new parameters to minimize the beta power. We show that the Bayesian ADC can efficiently optimize stimulation parameters, and is superior to other optimization algorithms. The Bayesian ADC provides a robust and general framework for tuning stimulation parameters, can be adapted to use any feedback signal, and is applicable across diseases and stimulator designs. PMID- 30521520 TI - Molecular basis for the increased affinity of an RNA recognition motif with re engineered specificity: A molecular dynamics and enhanced sampling simulations study. AB - The RNA recognition motif (RRM) is the most common RNA binding domain across eukaryotic proteins. It is therefore of great value to engineer its specificity to target RNAs of arbitrary sequence. This was recently achieved for the RRM in Rbfox protein, where four mutations R118D, E147R, N151S, and E152T were designed to target the precursor to the oncogenic miRNA 21. Here, we used a variety of molecular dynamics-based approaches to predict specific interactions at the binding interface. Overall, we have run approximately 50 microseconds of enhanced sampling and plain molecular dynamics simulations on the engineered complex as well as on the wild-type Rbfox.pre-miRNA 20b from which the mutated systems were designed. Comparison with the available NMR data on the wild type molecules (protein, RNA, and their complex) served to establish the accuracy of the calculations. Free energy calculations suggest that further improvements in affinity and selectivity are achieved by the S151T replacement. PMID- 30521522 TI - The elimination of human African trypanosomiasis is in sight: Report from the third WHO stakeholders meeting on elimination of gambiense human African trypanosomiasis. PMID- 30521521 TI - A pragmatic cluster randomised controlled trial of a tailored intervention to improve the initial management of suspected encephalitis. AB - OBJECTIVE: To determine whether a tailored multifaceted implementation strategy improves the initial management of patients with suspected encephalitis. DESIGN: Pragmatic two arm cluster randomised controlled trial. SETTING: Hospitals within the United Kingdom. PARTICIPANTS: Twenty-four hospitals nested within 12 postgraduate deaneries. Patients were identified retrospectively by searching discharge, microbiology, radiology and pharmacy records and included if they met clinical criteria or had a recorded suspicion of encephalitis. INTERVENTION: An implementation strategy designed to overcome barriers to change, comprising local action planning, education and training, feedback on performance, a lumbar puncture pack and a range of optional components. OUTCOMES: The primary outcome was the proportion of patients with suspected encephalitis undergoing diagnostic lumbar puncture within 12 hours of admission and starting aciclovir treatment within six hours. Secondary outcomes included the proportions of adults and children who had a lumbar puncture, who had appropriate cerebrospinal fluid investigations, and who had appropriate radiological imaging within 24 hours of admission. Data were collected from patient records for 12 months before and 12 months during the intervention period, and analysed blind to allocation. RESULTS: 13 hospitals were randomised to intervention and 11 to control (no intervention), with 266 and 223 patients with suspected encephalitis identified respectively. There was no significant difference in primary outcome between intervention and control hospitals (13.5% and 14.8% respectively, p = 0.619; treatment effect 0.188, 95% confidence interval -0.927 to 0.552), but both had improved compared to pre-intervention (8.5%). CONCLUSION: The improvement in both intervention and control arms may reflect overall progress in management of encephalitis through wider awareness and education. TRIAL REGISTRATION: Controlled Trials: ISRCTN06886935. PMID- 30521523 TI - Statistical modeling of the effect of rainfall flushing on dengue transmission in Singapore. AB - BACKGROUND: Rainfall patterns are one of the main drivers of dengue transmission as mosquitoes require standing water to reproduce. However, excess rainfall can be disruptive to the Aedes reproductive cycle by "flushing out" aquatic stages from breeding sites. We developed models to predict the occurrence of such "flushing" events from rainfall data and to evaluate the effect of flushing on dengue outbreak risk in Singapore between 2000 and 2016. METHODS: We used machine learning and regression models to predict days with "flushing" in the dataset based on entomological and corresponding rainfall observations collected in Singapore. We used a distributed lag nonlinear logistic regression model to estimate the association between the number of flushing events per week and the risk of a dengue outbreak. RESULTS: Days with flushing were identified through the developed logistic regression model based on entomological data (test set accuracy = 92%). Predictions were based upon the aggregate number of thresholds indicating unusually rainy conditions over multiple weeks. We observed a statistically significant reduction in dengue outbreak risk one to six weeks after flushing events occurred. For weeks with five or more flushing events, compared with weeks with no flushing events, the risk of a dengue outbreak in the subsequent weeks was reduced by 16% to 70%. CONCLUSIONS: We have developed a high accuracy predictive model associating temporal rainfall patterns with flushing conditions. Using predicted flushing events, we have demonstrated a statistically significant reduction in dengue outbreak risk following flushing, with the time lag well aligned with time of mosquito development from larvae and infection transmission. Vector control programs should consider the effects of hydrological conditions in endemic areas on dengue transmission. PMID- 30521524 TI - Integrated Aedes management for the control of Aedes-borne diseases. AB - BACKGROUND: Diseases caused by Aedes-borne viruses, such as dengue, Zika, chikungunya, and yellow fever, are emerging and reemerging globally. The causes are multifactorial and include global trade, international travel, urbanisation, water storage practices, lack of resources for intervention, and an inadequate evidence base for the public health impact of Aedes control tools. National authorities need comprehensive evidence-based guidance on how and when to implement Aedes control measures tailored to local entomological and epidemiological conditions. METHODS AND FINDINGS: This review is one of a series being conducted by the Worldwide Insecticide resistance Network (WIN). It describes a framework for implementing Integrated Aedes Management (IAM) to improve control of diseases caused by Aedes-borne viruses based on available evidence. IAM consists of a portfolio of operational actions and priorities for the control of Aedes-borne viruses that are tailored to different epidemiological and entomological risk scenarios. The framework has 4 activity pillars: (i) integrated vector and disease surveillance, (ii) vector control, (iii) community mobilisation, and (iv) intra- and intersectoral collaboration as well as 4 supporting activities: (i) capacity building, (ii) research, (iii) advocacy, and (iv) policies and laws. CONCLUSIONS: IAM supports implementation of the World Health Organisation Global Vector Control Response (WHO GVCR) and provides a comprehensive framework for health authorities to devise and deliver sustainable, effective, integrated, community-based, locally adapted vector control strategies in order to reduce the burden of Aedes-transmitted arboviruses. The success of IAM requires strong commitment and leadership from governments to maintain proactive disease prevention programs and preparedness for rapid responses to outbreaks. PMID- 30521525 TI - Monitoring the elimination of human African trypanosomiasis: Update to 2016. AB - BACKGROUND: Human African trypanosomiasis (HAT) is a neglected tropical disease targeted for elimination 'as a public health problem' by 2020. The indicators to monitor progress towards the target are based on the number of reported cases, the related areas and populations exposed at various levels of risk, and the coverage of surveillance activities. Based on data provided by the National Sleeping Sickness Control Programmes (NSSCP), Non-Governmental Organizations (NGOs) and research institutions-and assembled in the Atlas of HAT-the World Health Organization (WHO) provides here an update to 2016 for these indicators, as well as an analysis of the epidemiological situation. RESULTS: Trends for the two primary indicators of elimination are on track for the 2020 goal: 2,164 cases of HAT were reported in 2016 (as compared to the milestone of 4,000 cases), and for the period 2012-2016 280,000 km2 are estimated to be at moderate risk or higher (i.e. >= 1 case/10,000 people/year), as compared to the milestone of 230,000 km2. These figures correspond to reductions of 92% and 61% as compared to the respective baselines (i.e. 26,550 HAT cases in the year 2000, and 709,000 km2 exposed at various levels of risk for the period 2000-2004). Among the secondary indicators, an overall improvement in the coverage of at risk populations by surveillance activities was observed. Regarding passive surveillance, the number of fixed health facilities providing gambiense HAT diagnosis or treatment expanded, with 1,338 enumerated in endemic countries in 2017 (+52% as compared to the survey completed only sixteen months earlier). Concerning rhodesiense HAT, 124 health facilities currently provide diagnosis or treatment. The broadening of passive surveillance is occurring in a context of fairly stable intensity of active case finding, with between 1.8 million and 2.4 million people screened per year over the period 2012-2016. DISCUSSION: Elimination of HAT as a public health problem by 2020 seems within reach, as the epidemiological trends observed in previous years are confirmed in this latest 2016 monitoring update. However, looking beyond 2020, and in particular to the 2030 goal of elimination of transmission as zero cases for the gambiense form of the disease only, there is no room for complacency. Challenges still abound, including ensuring the effective integration of HAT control activities in the health system, sustaining the commitment of donors and HAT endemic countries, and clarifying the extent of the threat posed by cryptic reservoirs (e.g. human asymptomatic carriers and the possible animal reservoirs in gambiense HAT epidemiology). WHO provides through the network for HAT elimination the essential coordination of the wide range of stakeholders to ensure synergy of efforts. PMID- 30521526 TI - Age trends in asymptomatic and symptomatic Leishmania donovani infection in the Indian subcontinent: A review and analysis of data from diagnostic and epidemiological studies. AB - BACKGROUND: Age patterns in asymptomatic and symptomatic infection with Leishmania donovani, the causative agent of visceral leishmaniasis (VL) in the Indian subcontinent (ISC), are currently poorly understood. Age-stratified serology and infection incidence have been used to assess transmission levels of other diseases, which suggests that they may also be of use for monitoring and targeting control programmes to achieve elimination of VL and should be included in VL transmission dynamic models. We therefore analysed available age-stratified data on both disease incidence and prevalence of immune markers with the aim of collating the currently available data, estimating rates of infection, and informing modelling and future data collection. METHODOLOGY/PRINCIPAL FINDINGS: A systematic literature search yielded 13 infection prevalence and 7 VL incidence studies meeting the inclusion criteria. Statistical tests were performed to identify trends by age, and according to diagnostic cut-off. Simple reversible catalytic models with age-independent and age-dependent infection rates were fitted to the prevalence data to estimate infection and reversion rates, and to test different hypotheses about the origin of variation in these rates. Most of the studies showed an increase in infection prevalence with age: from ?10% seroprevalence (<20% Leishmanin skin test (LST) positivity) for 0-10-year-olds to >10% seroprevalence (>20% LST-positivity) for 30-40-year-olds, but overall prevalence varied considerably between studies. VL incidence was lower amongst 0 5-year-olds than older age groups in most studies; most showing a peak in incidence between ages 5 and 20. The age-independent catalytic model provided the best overall fit to the infection prevalence data, but the estimated rates for the less parsimonious age-dependent model were much closer to estimates from longitudinal studies, suggesting that infection rates may increase with age. CONCLUSIONS/SIGNIFICANCE: Age patterns in asymptomatic infection prevalence and VL incidence in the ISC vary considerably with geographical location and time period. The increase in infection prevalence with age and peaked age-VL-incidence distribution may be due to lower exposure to infectious sandfly bites in young children, but also suggest that acquired immunity to the parasite increases with age. However, poor standardisation of serological tests makes it difficult to compare data from different studies and draw firm conclusions about drivers of variation in observed age patterns. PMID- 30521527 TI - 2'-Hydroxyflavanone activity in vitro and in vivo against wild-type and antimony resistant Leishmania amazonensis. AB - BACKGROUND: To overcome the current problems in leishmaniasis chemotherapy, natural products have become an interesting alternative over the past few decades. Flavonoids have been studied as promising family of compounds for leishmaniasis treatment. 2'-Hydroxyflavanone (2HF) is a flavanone, a class of flavonoid that has shown promising results in cancer studies. In this study, we demonstrated the effects of 2HF in vitro and in vivo against wild-type and antimony-resistant Leishmania amazonensis promastigotes. METHODOLOGY/PRINCIPAL FINDINGS: 2HF was effective against promastigotes and the intracellular amastigote form, decreasing the infection index in macrophages infected with wild type and antimony-resistant promastigotes, but it was not toxic to macrophages. In silico analysis indicated 2HF as a good oral candidate for leishmaniasis treatment. In vivo, 2HF was able to reduce the lesion size and parasite load in a murine model of cutaneous leishmaniasis using wild-type and antimony-resistant promastigotes, demonstrating no cross-resistance with antimonials. CONCLUSIONS/SIGNIFICANCE: Taken together, these results suggest 2HF as a potential candidate for leishmaniasis chemotherapy for cutaneous leishmaniasis caused by both wild-type and antimony-resistant Leishmania species by oral administration. Furthermore, studies should be conducted to determine the ideal dose and therapeutic regimen. PMID- 30521528 TI - Function and energy consumption constrain neuronal biophysics in a canonical computation: Coincidence detection. AB - Neural morphology and membrane properties vary greatly between cell types in the nervous system. The computations and local circuit connectivity that neurons support are thought to be the key factors constraining the cells' biophysical properties. Nevertheless, additional constraints can be expected to further shape neuronal design. Here, we focus on a particularly energy-intense system (as indicated by metabolic markers): principal neurons in the medial superior olive (MSO) nucleus of the auditory brainstem. Based on a modeling approach, we show that a trade-off between the level of performance of a functionally relevant computation and energy consumption predicts optimal ranges for cell morphology and membrane properties. The biophysical parameters appear most strongly constrained by functional needs, while energy use is minimized as long as function can be maintained. The key factors that determine model performance and energy consumption are 1) the saturation of the synaptic conductance input and 2) the temporal resolution of the postsynaptic signals as they reach the soma, which is largely determined by active membrane properties. MSO cells seem to operate close to pareto optimality, i.e., the trade-off boundary between performance and energy consumption that is formed by the set of optimal models. Good performance for drastically lower costs could in theory be achieved by small neurons without dendrites, as seen in the avian auditory system, pointing to additional constraints for mammalian MSO cells, including their circuit connectivity. PMID- 30521529 TI - Visceral leishmaniasis: Spatiotemporal heterogeneity and drivers underlying the hotspots in Muzaffarpur, Bihar, India. AB - BACKGROUND: Despite the overall decrease in visceral leishmaniasis (VL) incidence on the Indian subcontinent, there remain spatiotemporal clusters or 'hotspots' of new cases. The characteristics of these hotspots, underlying transmission dynamics, and their importance for shaping control strategies are not yet fully understood and are investigated in this study for a VL endemic area of ~100,000 inhabitants in Bihar, India between 2007-2015. METHODOLOGY/PRINCIPAL FINDINGS: VL incidence (cases/10,000/year) dropped from 12.3 in 2007 to 0.9 in 2015, which is just below the World Health Organizations' threshold for elimination as a public health problem. Clustering of VL was assessed between subvillages (hamlets), using multiple geospatial and (spatio)temporal autocorrelation and hotspot analyses. One to three hotspots were identified each year, often persisting for 1 5 successive years with a modal radius of ~500m. The relative risk of having VL was 5-86 times higher for inhabitants of hotspots, compared to those living outside hotspots. Hotspots harbour significantly more households from the two lowest asset quintiles (as proxy for socio-economic status). Overall, children and young adelescents (5-14 years) have the highest risk for VL, but within hotspots and at the start of outbreaks, older age groups (35+ years) show a comparable high risk. CONCLUSIONS/SIGNIFICANCE: This study demonstrates significant spatiotemporal heterogeneity in VL incidence at subdistrict level. The association between poverty and hotspots confirms that VL is a disease of 'the poorest of the poor' and age patterns suggest a potential role of waning immunity as underlying driver of hotspots. The recommended insecticide spraying radius of 500m around detected VL cases corresponds to the modal hotspot radius found in this study. Additional data on immunity and asymptomatic infection, and the development of spatiotemporally explicit transmission models that simulate hotspot dynamics and predict the impact of interventions at the smaller geographical scale will be crucial tools in sustaining elimination. PMID- 30521530 TI - Cluster randomized trial of comprehensive gender-based violence programming delivered through the HIV/AIDS program platform in Mbeya Region, Tanzania: Tathmini GBV study. AB - The Tathmini GBV study was a cluster randomized trial to assess the impact of a comprehensive health facility- and community-based program delivered through the HIV/AIDS program platform on reduction in gender-based violence and improved care for survivors. Twelve health facilities and surrounding communities in the Mbeya Region of Tanzania were randomly assigned to intervention or control arms. Population-level effects were measured through two cross-sectional household surveys of women ages 15-49, at baseline (n = 1,299) and at 28 months following program scale-out (n = 1,250). Delivery of gender-based violence services was assessed through routine recording in health facility registers. Generalized linear mixed effects models and analysis of variance were used to test intervention effects on population and facility outcomes, respectively. At baseline, 52 percent of women reported experience of recent intimate partner violence. The odds of reporting experience of this violence decreased by 29 percent from baseline to follow-up in the absence of the intervention (time effect OR = 0.71, 95% CI: 0.57-0.89). While the intervention contributed an additional 15 percent reduction, the effect was not statistically significant. The program, however, was found to contribute to positive, community-wide changes including less tolerance for certain forms of violence, more gender equitable norms, better knowledge about gender-based violence, and increased community actions to address violence. The program also led to increased utilization of gender-based violence services at health facilities. Nearly three times as many client visits for gender-based violence were recorded at intervention (N = 1,427) compared to control (N = 489) facilities over a 16-month period. These visits were more likely to include provision of an HIV test (55.3% vs. 19.6%, p = .002). The study demonstrated the feasibility and impact of integrating gender-based violence and HIV programming to combat both of these major public health problems. Further opportunities to scale out GBV prevention and response strategies within HIV/AIDS service delivery platforms should be pursued. Trial Registration: Pan African Clinical Trials Registry No. PACTR201802003124149. PMID- 30521531 TI - Uterine contractility changes in a perfused swine uterus model induced by local anesthetics procaine, lidocaine, and ropivacaine. AB - BACKGROUND: Local anesthetics (LAs) are increasingly used as therapeutics due to their multiple molecular effects. They may be potential agents also in gynecology and reproductive medicine. The objective of this study was to investigate the contractility response of the perfused swine uterus to different concentrations of the LAs procaine, lidocaine, and ropivacaine. METHODS AND FINDINGS: In an extracorporeal perfusion model with fresh swine uteri, effects of administered boli of these three LAs in concentrations of 0.1 mg/mL, 0.5 mg/mL and 1.0 mg/mL on uterine contractility and peristalsis were assessed using an intrauterine double-chip micro-catheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus and corpus uteri was observed after the administration of the ester-LA procaine 0.1, 0.5, and 1.0%, which was not seen with lower concentrations, or buffer solution. An increase-decrease curve was found after increasing concentrations of the amide-LA lidocaine and ropivacaine, with an IUP plateau with 0.1 and 0.5%, and a decrease with 1% (p<0.01). All reactions were seen in both the isthmus and corpus uteri. The difference of the contractility pattern between ester- and amide-LA at 1% concentration was significant. CONCLUSION: LAs dose-dependently modulate contractility in non-pregnant swine uteri. The amid-LAs lidocaine and ropivacaine reduce contractility in higher concentrations and may be used as therapeutics in disorders with increased uterine contractility, as dysmenorrhoea, endometriosis, and infertility. The multiple molecular effects of LAs may explain these effects. This in-vitro pilot study in vitro provides initial data for designing further studies to transfer the results onto humans. PMID- 30521532 TI - Non-professional caregiver burden is associated with the severity of patients' cognitive impairment. AB - BACKGROUND/OBJECTIVES: To analyse the relationship between caregiver burden and severity of patients' cognitive impairment. DESIGN: Data were drawn from the cross-sectional 2015/2016 Adelphi Real World Dementia Disease-Specific Programme. SETTING: This research was multi-national and studied physicians and their consulting patients with cognitive impairment. PARTICIPANTS: 1,201 caregivers completed self-assessment forms. MEASUREMENTS: Validated instruments of caregiver wellbeing and burden (EQ-5D-3L questionnaire, EQ-VAS, Zarit Burden Interview, and Work Productivity and Activity Impairment questionnaire) and number of caregiver hours were analysed by severity of patients' cognitive impairment, categorised according to the Mini-Mental State Examination. Data were analysed using Spearman's rank correlation coefficients and ordinary least squares regression models, to compare outcomes between caregivers of patients with prodromal, mild, moderate, and severe dementia. RESULTS: The majority of caregivers were female (69.1%), lived with the patient they cared for (75.8%), and only approximately one third (28.3%) were in part- or full-time employment. There were statistically significant (p<0.001) increases in caregiver time (36.9 versus 108.6 hours per week for prodromal versus severe dementia, respectively) and measures of caregiver burden and health status (EQ-5D-3L, EQ-VAS, and Zarit Burden Interview) and increases in measures of work productivity and activity impairment with increasing severity of patients' disease. CONCLUSION: This study of real-world data confirmed an association between increased caregiver burden and severity of patients' cognitive impairment by analysis of a wide range of validated measures of caregiver burden. These findings suggest that maintaining patients in the earliest stages of their disease for as long as possible may potentially help to protect caregiver wellbeing, although further research is required to confirm this hypothesis. PMID- 30521533 TI - Using time series analysis approaches for improved prediction of pain outcomes in subgroups of patients with painful diabetic peripheral neuropathy. AB - Prior work applied hierarchical clustering, coarsened exact matching (CEM), time series regressions with lagged variables as inputs, and microsimulation to data from three randomized clinical trials (RCTs) and a large German observational study (OS) to predict pregabalin pain reduction outcomes for patients with painful diabetic peripheral neuropathy. Here, data were added from six RCTs to reduce covariate bias of the same OS and improve accuracy and/or increase the variety of patients for pain response prediction. Using hierarchical cluster analysis and CEM, a matched dataset was created from the OS (N = 2642) and nine total RCTs (N = 1320). Using a maximum likelihood method, we estimated weekly pain scores for pregabalin-treated patients for each cluster (matched dataset); the models were validated with RCT data that did not match with OS data. We predicted novel 'virtual' patient pain scores over time using simulations including instance-based machine learning techniques to assign novel patients to a cluster, then applying cluster-specific regressions to predict pain response trajectories. Six clusters were identified according to baseline variables (gender, age, insulin use, body mass index, depression history, pregabalin monotherapy, prior gabapentin, pain score, and pain-related sleep interference score). CEM yielded 1766 patients (matched dataset) having lower covariate imbalances. Regression models for pain performed well (adjusted R-squared 0.90 0.93; root mean square errors 0.41-0.48). Simulations showed positive predictive values for achieving >50% and >30% change-from-baseline pain score improvements (range 68.6-83.8% and 86.5-93.9%, respectively). Using more RCTs (nine vs. the earlier three) enabled matching of 46.7% more patients in the OS dataset, with substantially reduced global imbalance vs. not matching. This larger RCT pool covered 66.8% of possible patient characteristic combinations (vs. 25.0% with three original RCTs) and made prediction possible for a broader spectrum of patients. Trial Registration: www.clinicaltrials.gov (as applicable): NCT00156078, NCT00159679, NCT00143156, NCT00553475. PMID- 30521534 TI - Molecular epidemiology of HIV-1 infection among men who have sex with men in Taiwan from 2013 to 2015. AB - Men who have sex with men (MSM) is the major risk population of HIV-1 infection in Taiwan, and its surveillance has become critical in HIV-1 prevention. We recruited MSM subjects from 17 high-risk venues and 4 community centers in northern and southern Taiwan for anonymous HIV-1 screening during 2013-2015. Blood samples were obtained for genotyping and phylogenetic analysis, and a questionnaire survey covering demographic variables and social behavior was conducted. In total, 4,675 subjects were enrolled, yielding a HIV-1 prevalence rate of 4.3% (201/4675). Eight risk factors including subjects who did not always use condoms (OR = 1.509, p = 0.0123), those who used oil-based lubricants (OR = 1.413, p = 0.0409), and those who used recreational drugs (OR = 2.182, p = < .0001) had a higher risk of HIV-1 infection. The annual prevalence and incidence of HIV-1 showed a downward trend from 2013 to 2015 (6.56%, 5.97 per 100 person years in 2013; 4.53%, 3.97 per 100 person-years in 2014; 1.84%, 2.08 per 100 person-years in 2015). Factors such as always using condoms, water-based lubricant use, correct knowledge of lubricating substitutes, and recreational drug use were significantly associated with the trend of incidence. Phylogenetic tree analysis showed that the cross-regional and international interaction of the local MSM population may have facilitated transmission of HIV. This survey of high-risk venues showed decreased prevalence and incidence of HIV-1 infection in Taiwan from 2013 to 2015, and this may be related to changes in behavioral patterns. Moreover, cross-regional interaction and recreational drug use need to be considered in future surveillance. PMID- 30521535 TI - Temporal changes in the viromes of Swedish Varroa-resistant and Varroa susceptible honeybee populations. AB - The parasitic mite, Varroa destructor, in combination with the viruses it vectors, is the main cause for global colony losses of the European honeybee, Apis mellifera. However, an isolated honeybee population established in 1999 on the Island of Gotland, Sweden has naturally acquired resistance to the mite, and has survived without mite control treatment for more than 18 years. A recent study has shown that this mite resistant (MR) population also appears to be resistant to Black queen cell virus (BQCV) and Sacbrood virus (SBV) and tolerant to Deformed wing virus (DWV), relative to nearby mite susceptible (MS) honeybee populations. In this study, RNA sequencing was employed to corroborate these previous findings and identify other viral factors that may play a role in the enhanced survival of this mite resistant honeybee population. Two additional honeybee-infecting viruses, Apis rhabdovirus-1 (ARV-1) and Lake Sinai virus (LSV), were identified and near-complete genomes of these two viruses were obtained. Phylogenetic analyses of the assembled virus sequences revealed consistent separation between the MR and MS honeybee populations, although it is unclear whether this is due to pre-existing differences between the viruses in the two populations when they were established, and isolated, or due to virus genetic adaptation towards reduced virulence in the MR population, to promote colony survival. Reverse transcription quantitative polymerase chain reaction(RT qPCR) analyses show higher ARV and LSV titres in MS colonies compared to MR colonies, gradually increasing from summer to autumn 2009, and reaching maximum titres in the following spring 2010. While the DWV and BQCV titres in MR colonies increased between autumn 2009 and spring 2010, the SBV practically disappeared entirely by spring 2010. Possible explanations for the apparent virus tolerance or resistance in the Gotland mite-resistant honeybee population are discussed. PMID- 30521536 TI - Comparison of efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy analyzing multi-factor mediated disease-causing modules. AB - Atherosclerosis-predominant vasculopathy is a common complication of diabetes with high morbidity and high mortality, which is ruining the patient's daily life. As is known to all, traditional Chinese medicine (TCM) SHENQI compound and western medicine rosiglitazone play an important role in the treatment of diabetes. In particular, SHENQI compound has a significant inhibitory effect on vascular lesions. Here, to explore and compare the therapeutic mechanism of SHENQI compound and rosiglitazone on diabetic vasculopathy, we first built 7 groups of mouse models. The behavioral, physiological and pathological morphological characteristics of these mice showed that SHENQI compound has a more comprehensive curative effect than rosiglitazone and has a stronger inhibitory effect on vascular lesions. While rosiglitazone has a more effective but no significant effect on hypoglycemic. Further, based on the gene expression of mice in each group, we performed differential expression analysis. The functional enrichment analysis of these differentially expressed genes (DEGs) revealed the potential pathogenesis and treatment mechanisms of diabetic angiopathy. In addition, we found that SHENQI compound mainly exerts comprehensive effects by regulating MCM8, IRF7, CDK7, NEDD4L by pivot regulator analysis, while rosiglitazone can rapidly lower blood glucose levels by targeting PSMD3, UBA52. Except that, we also identified some pivot TFs and ncRNAs for these potential disease-causing DEG modules, which may the mediators bridging drugs and modules. Finally, similar to pivot regulator analysis, we also identified the regulation of some drugs (e.g. bumetanide, disopyramide and glyburide etc.) which have been shown to have a certain effect on diabetes or diabetic angiopathy, proofing the scientific and objectivity of this study. Overall, this study not only provides an in-depth comparison of the efficacy of SHENQI compound and rosiglitazone in the treatment of diabetic vasculopathy, but also provides clinicians and drug designers with valuable theoretical guidance. PMID- 30521537 TI - Effects of turbulent aggregation on clay floc breakup and implications for the oceanic environment. AB - Understanding how turbulence impacts marine floc formation and breakup is key to predicting particulate carbon transport in the ocean. While floc formation and sinking rate has been studied in the laboratory and in-situ, the breakup response to turbulence has attracted less attention. To address this problem, the breakup response of bentonite clay particles flocculated in salt water was studied experimentally. Flocs were grown in a large aggregation tank under unmixed and mixed aggregation conditions and then subjected to turbulent pipe flow. Particle size was quantified using microscope imaging and in-situ measurements obtained from standard optical oceanographic instruments; a Sequoia Scientific LISST-100X and two WET Labs ac-9 spectrophotometers. The LISST instrument was found to capture the breakup response of flocs to turbulent energy, though the resulting particle size spectra appear to have underestimated the largest floc lengthscales in the flow while overestimating the abundance of primary particles. Floc breakup and the resulting shift towards smaller particles caused an increase in spectral slope of attenuation as measured by the ac-9 instruments. The Kolmogorov lengthscale was not found to have a limiting effect on floc size in these experiments. While the flocs were found to decrease in overall strength over the course of the two-month experimental time period, repeatable breakup responses to turbulence exposure were observed. Hydrodynamic conditions during floc formation were found to have a large influence on floc strength and breakup response. A non constant strength exponent was observed for flocs formed with more energetic mixing. Increased turbulence from mixing during aggregation was found to increase floc fractal dimension and apparent density, resulting in a shift in the breakup relationships to higher turbulence dissipation rates. The results suggest that marine particle aggregation and vertical carbon transport concepts should include the turbulence energy responsible for aggregate formation and the resulting impact on floc strength, density, and the disruption potential. PMID- 30521538 TI - Pain characterization and response to palliative care in dogs with naturally occurring appendicular osteosarcoma: An open label clinical trial. AB - This study aimed to characterize bone cancer pain (quantitative sensory testing (QST), stance asymmetry index, actimetry, scores of pain and quality of life (QoL)) in dogs with appendicular osteosarcoma (OSA), and to evaluate a stepwise palliative analgesic treatment. The pain profile of thirteen client-owned dogs with OSA was compared with seven healthy dogs. Dogs with OSA were then enrolled in a prospective, open-label, clinical trial. Outcome measures included: primary and secondary mechanical thresholds (MT), conditioned pain modulation (CPM), stance asymmetry index, actimetry (most and least active periods), visual analog scales and QoL. After baseline assessments, stepwise treatment comprised orally administered cimicoxib (2 mg/kg q 24h), amitriptyline (1-1.5 mg/kg q 24h) and gabapentin (10 mg/kg q 8h); re-evaluations were performed after 14 (D14), 21 (D21) and 28 (D28) days, respectively. Statistics used mixed linear models (alpha = 5%; one-sided). Centralized nociceptive sensitivity (primary and secondary MT, and dynamic allodynia) was recorded in OSA dogs. Healthy dogs had responsive CPM, but CPM was deficient in OSA dogs. Construct validity was observed for the QST protocol. Asymmetry index was significantly present in OSA dogs. The CPM improved significantly at D14. When compared with baseline (log mean +/- SD: 4.1 +/- 0.04), most active actimetry significantly improved at D14 (4.3 +/- 0.04), D21 and D28 (4.2 +/- 0.04 for both). When compared with baseline, least active actimetry significantly decreased after treatment at all time-points indicating improvement in night-time restlessness. No other significant treatment effect was observed. Except for tactile threshold and actimetry, all outcomes worsened when gabapentin was added to cimicoxib-amitriptyline. Dogs with bone cancer are affected by widespread somatosensory sensitivity characterized by peripheral and central sensitization and have a deficient inhibitory system. This severe pain is mostly refractory to palliative analgesic treatment, and the latter was only detected by specific and sensitive outcomes. PMID- 30521539 TI - Association between metabolic parameters and glomerular hyperfiltration in a representative Korean population without chronic kidney disease. AB - AIMS: To investigate associations of glomerular hyperfiltration with other metabolic factors in a nationally representative dataset. METHODS: We analyzed cross-sectional data from 15,918 subjects with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 and urine albumin creation ratio (ACR) <30 mg/g, who participated in the 5th and 6th Korea National Health and Nutrition Examination Surveys. Hyperfiltration was defined as eGFR (CKD-EPI equation) exceeding the age- and sex-specific 95th percentile for healthy control subjects. RESULTS: Prevalence of hyperfiltration was 5.2% and that among normal, prediabetic, and diabetic subjects was 4.9%, 5.6%, and 7.3%, respectively, after adjusting for age, sex, and body weight (p for trend = 0.008). In a multiple logistic regression analysis, hyperfiltration was associated with a body mass index >=30 kg/m2 [odds ratio (OR) = 3.461, p<0.001], waist circumference 85 cm (men) or 80 cm (women) (OR = 1.425, p = 0.015), systolic blood pressure 120-129 mmHg (OR = 1.644, p = 0.022), fasting plasma glucose 140 mg/dL (OR = 1.695, p = 0.033) and t serum triglyceride level 500 mg/dL (OR = 2.988, p = 0.001), and was independently associated with the ACR (B = 0.053, p<0.001). CONCLUSIONS: In a general Korean population, both hyperfiltration and ACR were associated with similar metabolic parameters, and hyperfiltration correlated independently with a high ACR. Longitudinal studies are needed to further explore risks of hyperfiltration and microalbuminuria. PMID- 30521540 TI - Identification of midgut membrane proteins from different instars of Helicoverpa armigera (Lepidoptera: Noctuidae) that bind to Cry1Ac toxin. AB - Helicoverpa armigera is a polyphagous pest sensitive to Cry1Ac protein from Bacillus thuringiensis (Bt). The susceptibility of the different larval instars of H. armigera to Cry1Ac protoxin showed a significant 45-fold reduction in late instars compared to early instars. A possible hypothesis is that gut surface proteins that bind to Cry1Ac differ in both instars, although higher Cry toxin degradation in late instars could also explain the observed differences in susceptibility. Here we compared the Cry1Ac-binding proteins from second and fifth instars by pull-down assays and liquid chromatography coupled to mass spectrometry analysis (LC-MS/MS). The data show differential protein interaction patterns of Cry1Ac in the two instars analyzed. Alkaline phosphatase, and other membrane proteins, such as prohibitin and an anion selective channel protein were identified only in the second instar, suggesting that these proteins may be involved in the higher toxicity of Cry1Ac in early instars of H. armigera. Eleven Cry1Ac binindg proteins were identified exclusively in late instar larvae, like different proteases such as trypsin-like protease, azurocidin-like proteinase, and carboxypeptidase. Different aminopeptidase N isofroms were identified in both instar larvae. We compared the Cry1Ac protoxin degradation using midgut juice from late and early instars, showing that the midgut juice from late instars is more efficient to degrade Cry1Ac protoxin than that of early instars, suggesting that increased proteolytic activity on the toxin could also explain the low Cry1Ac toxicity in late instars. PMID- 30521541 TI - The impact of a fine-scale population stratification on rare variant association test results. AB - Population stratification is a well-known confounding factor in both common and rare variant association analyses. Rare variants tend to be more geographically clustered than common variants, because of their more recent origin. However, it is not yet clear if population stratification at a very fine scale (neighboring administrative regions within a country) would lead to statistical bias in rare variant analyses. As the inclusion of convenience controls from external studies is indeed a common procedure, in order to increase the power to detect genetic associations, this problem is important. We studied through simulation the impact of a fine scale population structure on different rare variant association strategies, assessing type I error and power. We showed that principal component analysis (PCA) based methods of adjustment for population stratification adequately corrected type I error inflation at the largest geographical scales, but not at finest scales. We also showed in our simulations that adding controls obviously increased power, but at a considerably lower level when controls were drawn from another population. PMID- 30521542 TI - Association of pre-eclampsia risk with maternal levels of folate, homocysteine and vitamin B12 in Colombia: A case-control study. AB - BACKGROUND: Maternal serum concentrations of folate, homocysteine, and vitamin B12 have been associated with pre-eclampsia. Nevertheless, reported studies involve limited number of cases to reliably assess the nature of these associations. Our aim was to examine the relation of these three biomarkers with pre-eclampsia risk in a large Colombian population. MATERIALS AND METHODS: Design: A case-control study. Setting: Cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight different Colombian cities between 2000 and 2012. Population or Sample: 2978 cases and 4096 controls were studied. Maternal serum concentrations of folate, homocysteine, and vitamin B12 were determined in 1148 (43.6%) cases and 1300 (31.7%) controls. Also, self-reported folic acid supplementation was recorded for 2563 (84%) cases and 3155 (84%) controls. Analysis: Adjusted odds ratios (OR) for pre-eclampsia were estimated for one standard deviation (1SD) increase in log-transformed biomarkers. Furthermore, we conducted analyses to compare women that reported taking folic acid supplementation for different periods during pregnancy. Main Outcomes Measures: Odds ratio for pre-eclampsia. RESULTS: After adjusting for potential confounders in logistic regression models, the OR for pre-eclampsia was 0.80 (95% CI: 0.72, 0.90) for 1SD increase in log-folate, 1.16 (95%CI: 1.05, 1.27) for 1SD increase in log-homocysteine, and 1.10 (95%CI: 0.99, 1.22) for 1SD increase in log-vitamin B12. No interactions among the biomarkers were identified. Women who self-reported consumption of folic acid (1 mg/day) throughout their pregnancy had an adjusted OR for pre-eclampsia of 0.86 (95%CI: 0.67, 1.09) compared to women that reported no consumption of folic acid at any point during pregnancy. CONCLUSIONS: Maternal serum concentrations of folate were associated as a protective factor for pre-eclampsia while concentrations of homocysteine were associated as a risk factor. No association between maternal vitamin B12 concentrations and preeclampsia was found. PMID- 30521543 TI - Human bone marrow contains high levels of extracellular vesicles with a tissue specific subtype distribution. AB - INTRODUCTION: Extracellular vesicles (EV) are shed from a broad variety of cells and play an important role in activation of coagulation, cell to cell interaction and transport of membrane components. They are usually measured as circulating EV in peripheral blood (PB) and other body fluids. However, little is known about the distribution, presence and impact of EV and their subpopulations in bone marrow (BM). In our study, we focused on the analysis of different EV subtypes in human BM as compared to EV subsets in PB. METHODS: EV in BM and PB from 12 healthy stem cell donors were measured by flow-cytometry using Annexin V and cell specific antibodies for hematopoietic stem cells, leucocytes, platelets, red blood cells, and endothelial cells. Additionally, concentrations of tissue factor bearing EV were evaluated. RESULTS: High numbers of total EV were present in BM (median value [25-75 percentile]: 14.8 x109/l [8.5-19.3]). Non-significantly lower numbers of total EV were measured in PB (9.2 x109/l [3.8-14.5]). However, distribuation of EV subtypes showed substantial differences between BM and PB: In PB, distribution of EV fractions was similar as previously described. Most EV originated from platelets (93.9%), and only few EV were derived from leucocytes (4.5%), erythrocytes (1.8%), endothelial cells (1.0%), and hematopoietic stem cells (0.7%). In contrast, major fractions of BM-EV were derived from red blood cells or erythropoietic cells (43.2%), followed by megacaryocytes / platelets (27.6%), and by leucocytes as well as their progenitor cells (25,7%); only low EV proportions originated from endothelial cells and hematopoietic stem cells (2.0% and 1.5%, respectively). Similar fractions of tissue factor-bearing EV were found in BM and PB (1.3% and 0.9%). CONCULSION: Taken together, we describe EV numbers and their subtype distribution in the BM compartment for the first time. The tissue specific EV distribution reflects BM cell composition and favours the idea of a BM-PB barrier existing not only for cells, but also for EV. PMID- 30521544 TI - Prospective patterns of modifiable health risk behaviors and the utilization of healthcare services in the "Health Workers Cohort Study" in Mexico. AB - INTRODUCTION: We still lack information about how changes in modifiable health risk behaviors influence the utilization of healthcare services. This study assesses the relationships between prospective patterns of modifiable health risk behaviors and the utilization of healthcare services. MATERIAL AND METHODS: This was a prospective study among men and women participants in the Health Workers Cohort Study, aged 18 years and older. The following data about modifiable health risk behaviors was collected in two waves of the study (2004-2006 and 2010-2012): 1) physical activity, b) consumption of fruit and vegetables, 3) alcohol, and 4) tobacco consumption, to determine the association between the utilization of healthcare services after 6 years of follow-up (period 2010-2012). Information was collected through self-administered questionnaires; clinical and anthropometric variables were measured following standard procedures. Analyses were conducted using zero-inflated negative binomial regression models. RESULTS: Participants with a pattern of consumption of < 3 portions of fruits and vegetables per day (p = 0.035) and did not meet recommended levels of PA (p = 0.013) during the two waves of the study had fewer preventative consultations; those who quit smoking reported a higher frequency of preventative consultations (p = 0.021) and more visits with a medical specialist (p = 0.048). Participants who reduced alcohol consumption to low or completely stopped its consumption reported fewer visits to the general physician (p = 0.031), p < 0.05. CONCLUSIONS: Changes in prospective patterns of modifiable health risk behaviors influenced the use of healthcare services after 6 years of follow-up. Findings in this study could be useful to determine possible demands of healthcare services among populations with specific modifiable health risk behaviors. PMID- 30521545 TI - Baroreflex function, haemodynamic responses to an orthostatic challenge, and falls in haemodialysis patients. AB - BACKGROUND: Stage 5 chronic kidney disease patients on haemodialysis (HD) often present with dizziness and pre-syncopal events as a result of the combined effect of HD therapy and cardiovascular disease. The dysregulation of blood pressure (BP) during orthostasis may be implicated in the aetiology of falls in these patients. Therefore, we explored the relationship between baroreflex function, the haemodynamic responses to a passive orthostatic challenge, and falls in HD patients. METHODS: Seventy-six HD patients were enrolled in this cross-sectional study. Participants were classified as "fallers" and "non-fallers" and completed a passive head up tilting to 60o (HUT-60 degrees ) test on an automated tilt table. ECG signals, continuous and oscillometric BP measurements and impedance cardiography were recorded. The following variables were derived from these measurements: heart rate (HR) stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), number of baroreceptor events, and baroreceptor effectiveness index (BEI). RESULTS: The forty-four participants who were classified as fallers (57.9%) had a lower number of baroreceptor events (6.5+/ 8.5 vs 14+/-16.7, p = .027) and BEI (20.8+/-24.2% vs 33.4+/-23.3%, p = .025). In addition, fallers experienced a significantly larger drop in systolic (-6.4+/ 10.9 vs -0.4+/-7.7 mmHg, p = .011) and diastolic (-2.7+/-7.3 vs 1.8+/-6 mmHg, p = .027) oscillometric BP from supine to HUT-60 degrees compared with non-fallers. None of the variables taken for the analysis were significantly associated with falls in multivariate logistic regression analysis. CONCLUSIONS: This cross sectional comparison indicates that, at rest, HD patients with a positive history of falls present with a lower count of baroreceptor sequences and BEI. Short-term BP regulation warrants further investigation as BP drops during a passive orthostatic challenge may be implicated in the aetiology of falls in HD. PMID- 30521546 TI - Polyphenol enriched ethanolic extract of Cajanus scarabaeoides (L.) Thouars exerts potential antifilarial activity by inducing oxidative stress and programmed cell death. AB - Development of antifilarial drug from the natural sources is considered as one of the most efficacious, safe, and affordable approaches. In this study, we report the antifilarial activity of a leguminous plant Cajanus scarabaeoides (L.) Thouars. The polyphenol-rich ethanolic extract obtained from the stem part of the plant C. scarabaeoides (EECs) was found to be efficient in killing the filarial nematode Setaria cervi in all the three developmental stages viz. oocytes, microfilariae (Mf) and adults with LD50 values of 2.5, 10 and 35 MUg/ml, respectively. While studying the molecular mechanism of action, we found that induction of oxidative stress plays the key role in inducing the mortality in S. cervi. The redox imbalance finally results in activation of the nematode CED pathway that executes the death of the parasite. Intriguingly, EECs was found to be selectively active against the worm and absolutely non-toxic to the mammalian cells and tissues. Taken together, our experimental data demonstrate that C. scarabaeoides can be chosen as an affordable natural therapeutic for treating filarial infection in the future with high efficacy and less toxicity. PMID- 30521548 TI - 'I should not feed such a weak woman'. Intimate partner violence among women living with podoconiosis: A qualitative study in northern Ethiopia. AB - BACKGROUND: Intimate Partner Violence (IPV) is a serious, preventable public health problem that affects millions of people worldwide. Research indicates that adults suffering from long term, disabling conditions are more likely to be victims of IPV due to the intersection of disease-associated stigma and discrimination. IPV in turn is known to worsen the overall health and wellbeing of those affected by it. Little research however explores the relationship between neglected tropical diseases such as podoconiosis and IPV. This study explores the relationship between IPV and podoconiosis in northern Ethiopia with the aim of identifying new avenues for limiting disability and promoting the wellbeing of people affected by this neglected tropical disease. METHODS: The study was conducted in East and West Gojjam zones, located in the Amhara Regional State of Ethiopia. Research participants were first screened using the domestic violence screening tool Hurt-Insult-Threaten-Scream (HITS). Data were collected by native speakers of the local language (Amharic) in the form of semi-structured interviews during January and February 2016. Thematic and content data analysis was carried out, using the Open Code 3.4 qualitative data analysis software for coding. RESULTS: A total of 15 women living with podoconiosis and experiencing IPV were interviewed (aged 31 to 75). Women experienced different forms of IPV, including beatings (with or without an object), insults, name calling, undermining, denial of equal rights over common assets, movement monitoring, cheating, abandonment, forced divorce, obstruction of health care access, inhibition of decision-making and sexual coercion. Podoconiosis increases the frequency and severity of IPV and in occasions shapes a change from physical to psychological and financial violence. In turn, frequent episodes of IPV worsen disease outcomes and contribute to disease persistence in the region, in that these impede women's ability to manage the disease and help perpetuate the conditions of poverty that influence disease onset. CONCLUSIONS: Women living with podoconiosis are victims of various, overlapping forms of IPV that negatively impact their health and wellbeing. Poverty, scarce IPV prevention services in the area together with a social acceptance of IPV and these women's decreased ability to work due to the debilitating effects of podoconiosis and childcare responsibilities frequently prompt these women to tolerate IPV and remain in abusive relationships. Tackling disease-associated taboo and stigma, developing accessible IPV interventions, working towards greater gender equality at the household and societal levels and developing sustainable strategies for improving the socio-economic assets of women affected by podoconiosis are all necessary to both prevent IPV and to improve disease outcome. PMID- 30521547 TI - Gender differences in the relationship between alcohol consumption and insomnia in the northern Chinese population. AB - BACKGROUND: Insomnia is one of the main symptoms of sleep disorders. Previous studies have suggested that alcohol intake is associated with several adverse health outcomes. The association between alcohol consumption and insomnia has been addressed in several studies with different results. However, whether gender may modify the association between alcohol consumption and insomnia is not clear. This study will focus on gender differences in the relationship between alcohol consumption and insomnia. METHODS: The final study includes 8081 subjects aged between 18 and 65 years from the Jidong cohort. The data on alcohol consumption is collected by questionnaires, and insomnia problems are assessed using the entire 8-item Athens Insomnia Scale (AIS-8). Logistic analysis is used to evaluate the association between alcohol consumption and insomnia. RESULTS: Among the 8081 participants in this study, 2618 (32.4%) are alcohol drinkers, including 2424 males and 194 females. The prevalence of insomnia is 9.6% in the male and 10.6% in the female. The adjusted odds ratios (ORs) with 95% confidence interval (CI) of mild-to-moderate drinkers and heavy drinkers for insomnia are 1.27 (1.02 1.58) and 1.02 (0.79-1.32), respectively. Heavy alcohol consumption is significantly correlated with insomnia in the female, after controlling for potential confounding factors (OR: 2.11, 95% CI: 1.28-3.49, p for interaction = 0.002). CONCLUSION: A significant association between alcohol consumption and insomnia is found in females, but not in males from the northern Chinese population. PMID- 30521549 TI - Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay. AB - BACKGROUND: After transplantation, cell-free DNA derived from the donor organ (ddcfDNA) can be detected in the recipient's circulation. We aimed to quantify ddcfDNA levels in plasma of kidney transplant recipients thereby investigating the kinetics of this biomarker after transplantation and determining biological variables that influence ddcfDNA kinetics in stable and non-stable patients. MATERIALS AND METHODS: From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (day 1-3 months) within a multicenter set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex PCR-based method for the analysis of single nucleotide polymorphisms. A subgroup of stable renal transplant recipients was identified to determine a ddcfDNA threshold value. RESULTS: In stable transplant recipients, plasma ddcfDNA% decreased to a mean (SD) ddcfDNA% of 0.46% (+/- 0.21%) which was reached 9.85 (+/- 5.6) days after transplantation. A ddcfDNA threshold value of 0.88% (mean + 2SD) was determined in kidney transplant recipients. Recipients that did not reach this threshold ddcfDNA value within 10 days after transplantation showed a higher ddcfDNA% on the first day after transplantation and demonstrated a higher individual baseline ddcfDNA%. CONCLUSION: In conclusion, plasma ddcfDNA fractions decreased exponentially within 10 days after transplantation to a ddcfDNA threshold value of 0.88% or less. To investigate the role of ddcfDNA for rejection monitoring of the graft, future research is needed to determine causes of ddcfDNA% increases above this threshold value. PMID- 30521550 TI - Risk prediction system for dengue transmission based on high resolution weather data. AB - BACKGROUND: Dengue is the fastest spreading vector-borne viral disease, resulting in an estimated 390 million infections annually. Precise prediction of many attributes related to dengue is still a challenge due to the complex dynamics of the disease. Important attributes to predict include: the risk of and risk factors for an infection; infection severity; and the timing and magnitude of outbreaks. In this work, we build a model for predicting the risk of dengue transmission using high-resolution weather data. The level of dengue transmission risk depends on the vector density, hence we predict risk via vector prediction. METHODS AND FINDINGS: We make use of surveillance data on Aedes aegypti larvae collected by the Taiwan Centers for Disease Control as part of the national routine entomological surveillance of dengue, and weather data simulated using the IBM's Containerized Forecasting Workflow, a high spatial- and temporal resolution forecasting system. We propose a two stage risk prediction system for assessing dengue transmission via Aedes aegypti mosquitoes. In stage one, we perform a logistic regression to determine whether larvae are present or absent at the locations of interest using weather attributes as the explanatory variables. The results are then aggregated to an administrative division, with presence in the division determined by a threshold percentage of larvae positive locations resulting from a bootstrap approach. In stage two, larvae counts are estimated for the predicted larvae positive divisions from stage one, using a zero-inflated negative binomial model. This model identifies the larvae positive locations with 71% accuracy and predicts the larvae numbers producing a coverage probability of 98% over 95% nominal prediction intervals. This two-stage model improves the overall accuracy of identifying larvae positive locations by 29%, and the mean squared error of predicted larvae numbers by 9.6%, against a single stage approach which uses a zero-inflated binomial regression approach. CONCLUSIONS: We demonstrate a risk prediction system using high resolution weather data can provide valuable insight to the distribution of risk over a geographical region. The work also shows that a two-stage approach is beneficial in predicting risk in non-homogeneous regions, where the risk is localised. PMID- 30521551 TI - Gut microbiota signatures in cystic fibrosis: Loss of host CFTR function drives the microbiota enterophenotype. AB - BACKGROUND: Cystic fibrosis (CF) is a disorder affecting the respiratory, digestive, reproductive systems and sweat glands. This lethal hereditary disease has known or suspected links to the dysbiosis gut microbiota. High-throughput meta-omics-based approaches may assist in unveiling this complex network of symbiosis modifications. OBJECTIVES: The aim of this study was to provide a predictive and functional model of the gut microbiota enterophenotype of pediatric patients affected by CF under clinical stability. METHODS: Thirty-one fecal samples were collected from CF patients and healthy children (HC) (age range, 1-6 years) and analysed using targeted-metagenomics and metabolomics to characterize the ecology and metabolism of CF-linked gut microbiota. The multidimensional data were low fused and processed by chemometric classification analysis. RESULTS: The fused metagenomics and metabolomics based gut microbiota profile was characterized by a high abundance of Propionibacterium, Staphylococcus and Clostridiaceae, including Clostridium difficile, and a low abundance of Eggerthella, Eubacterium, Ruminococcus, Dorea, Faecalibacterium prausnitzii, and Lachnospiraceae, associated with overexpression of 4 aminobutyrate (GABA), choline, ethanol, propylbutyrate, and pyridine and low levels of sarcosine, 4-methylphenol, uracil, glucose, acetate, phenol, benzaldehyde, and methylacetate. The CF gut microbiota pattern revealed an enterophenotype intrinsically linked to disease, regardless of age, and with dysbiosis uninduced by reduced pancreatic function and only partially related to oral antibiotic administration or lung colonization/infection. CONCLUSIONS: All together, the results obtained suggest that the gut microbiota enterophenotypes of CF, together with endogenous and bacterial CF biomarkers, are direct expression of functional alterations at the intestinal level. Hence, it's possible to infer that CFTR impairment causes the gut ecosystem imbalance.This new understanding of CF host-gut microbiota interactions may be helpful to rationalize novel clinical interventions to improve the affected children's nutritional status and intestinal function. PMID- 30521552 TI - Validity and measurement invariance across sex, age, and education level of the French short versions of the European Health Literacy Survey Questionnaire. AB - BACKGROUND: Short versions of the European Health Literacy Survey (HLS-EU) questionnaire are increasingly used to measure and compare health literacy (HL) in populations worldwide. As no validated versions of these questionnaires have thus far appeared in French, this study aimed to study the psychometric properties of the French translation of the 16- and 6-item short versions (HLS-EU Q16 and HLS-EU-Q6), including their measurement invariance across sex, age, and education level. METHODS: A consensual French version of the HLS-EU-Q16 and HLS EU-Q6 was developed by following the current recommendations for transcultural questionnaire adaptation. It was then completed by 317 patients recruited in waiting rooms of general practitioners in the Paris area (France). Structural validity was studied with the Rasch model for the HLS-EU-Q16 and confirmatory factorial analysis (CFA) for the HLS-EU-Q6. Concurrent and convergent validity, respectively, were assessed by scores on the Functional Communicative Critical Health Literacy (FCCHL) questionnaire and the physicians' evaluations of their patient's HL. RESULTS: The 16 items of the HLS-EU-Q16 were Rasch homogenous but meaningful differential item functioning (DIF) was found across sex, age, and/or education level for eight items. The CFA model fit for the HLS-EU-Q6 was poor. The overall scores for both HLS-EU short versions correlated poorly with the FCCHL scores. Similarly, HL levels defined using either short-version score did not agree with physicians' HL assessments. CONCLUSION: The French version of the HLS-EU-Q16 has acceptable psychometric properties, despite meaningful DIF for age, sex and education level and a poor discriminative power among subjects with average to high HL level. We recommend its use to measure HL in populations with sufficient reading skills to discriminate between subjects with low to average HL. Also, sensitivity analyses should be performed to evaluate the potential measurement bias due to DIF. Our results did not demonstrate the validity of the HLS-EU-Q6. PMID- 30521553 TI - Effectiveness of influenza and pneumococcal polysaccharide vaccines against influenza-related outcomes including pneumonia and acute exacerbation of cardiopulmonary diseases: Analysis by dominant viral subtype and vaccine matching. AB - BACKGROUND: Influenza and pneumonia are leading causes of morbidity and mortality among the elderly. Although vaccination is a main strategy to prevent these infectious diseases, concerns remain with respect to vaccine effectiveness. METHODS: During three influenza seasons (2014-2015, 2015-2016 and 2016-2017), we evaluated the effectiveness of the influenza and pneumococcal vaccines against pneumonia and acute exacerbation of cardiopulmonary diseases among the elderly aged >=65 years with influenza-like illness (ILI). Demographic and clinical data were collected prospectively. RESULTS: Among 2,119 enrolled cases, 1,302 (61.4%) and 871 (41.1%) received the influenza vaccine and 23-valent pneumococcal polysaccharide vaccine (PPV23), respectively. During an A/H3N2-dominant season with poor influenza vaccine effectiveness (2014-2015 season), neither the influenza vaccine nor PPV23 showed significant effectiveness against pneumonia or acute exacerbation of cardiopulmonary diseases. During seasons with good influenza vaccine effectiveness (2015-2016 and 2016-2017 seasons), the influenza vaccine was effective in preventing pneumonia, but PPV23 was not. In particular, the influenza vaccine was effective in preventing acute exacerbation of heart diseases (75.0%) during the A/H1N1-dominant 2015-2016 season. CONCLUSION: The influenza vaccine was effective in preventing pneumonia only during vaccine matched seasons with good effectiveness against circulating influenza viruses. In addition, the influenza vaccine was cardio-protective during a vaccine-matched A/H1N1-dominant season. PMID- 30521554 TI - Determination of the minimum protective dose of a glycoprotein-G-deficient infectious laryngotracheitis virus vaccine delivered via eye-drop to week-old chickens. AB - Infectious laryngotracheitis (ILT) is an upper respiratory tract disease of chickens that is caused by infectious laryngotracheitis virus (ILTV), an alphaherpesvirus. This disease causes significant economic loses in poultry industries worldwide. Despite widespread use of commercial live attenuated vaccines, many poultry industries continue to experience outbreaks of disease caused by ILTV. Efforts to improve the control of this disease have resulted in the generation of new vaccine candidates, including ILTV mutants deficient in virulence factors. A glycoprotein G deletion mutant vaccine strain of ILTV (DeltagG ILTV), recently licenced as Vaxsafe ILT (Bioproperties Pty Ltd), has been extensively characterised in vitro and in vivo, but the minimum effective dose required to protect inoculated animals has not been determined. This study performed a vaccination and challenge experiment to determine the minimum dose of DeltagG ILTV that, when delivered by eye-drop to seven-day-old specific pathogen free chickens, would protect the birds from a robust challenge with a virulent field strain of virus (class 9 ILTV). A dose of 103.8 plaque forming units was the lowest dose capable of providing a high level of protection against challenge, as measured by clinical signs of disease, tracheal pathology and virus replication after challenge. This study has shown that the DeltagG ILTV vaccine strain is capable of inducing a high level of protection against a virulent field virus at a commercially feasible dose. These results lay the foundations upon which a commercial vaccine can be developed, thereby offering the potential to provide producers with another important tool to help control ILTV. PMID- 30521555 TI - Atypical and severe manifestations of chikungunya virus infection in French Guiana: A hospital-based study. AB - BACKGROUND: French Guiana (FG) was the first country in South America to declare chikungunya virus infection (CHIKV). The outbreak affected about 16,000 persons between February 2014 and October 2015, with several atypical cases, but only two fatal cases. We aimed to describe the clinical presentation of patients hospitalized for CHIKV infection, to estimate and identify risk factors of unusual and severe forms in adult patients. MATERIALS AND METHODS: A monocentric retrospective study was conducted in Cayenne hospital, the main city and the main hospital in FG, from March 1st 2014 to August 31st 2015. All patients admitted for at least one night with a biological diagnosis of CHIKV infection during the 2014/2015 outbreak were included, except pregnant women and children under 15 years. RESULTS: During the study period, 285 patients with a diagnosis of CHIKV infection were hospitalized in Cayenne hospital, among whom 96 nonpregnant adults were studied. Five were classified as severe forms (5.2%) and 23 as unusual forms (23.9%). The most frequent atypical and/or severe form was neurological (n = 20), followed by cardio-respiratory failure (acute respiratory failure n = 4, acute heart failure n = 2), digestive and hepatic disorders (acute hepatitis n = 3, acute pancreatitis n = 2), renal disorders (acute renal failure n = 5) and muscular impairment (rhabdomyolysis n = 3). CONCLUSION: During the outbreak, hospitalizations were frequent, particularly for common forms, driven by algic clinical presentations and concerns due to the novelty of this infection. Despite atypical neurological and liver forms of CHIKV infection, case-fatality was low in French Guiana. No specific risk factor of atypical and/or severe forms was found in our study. PMID- 30521556 TI - Screening for osteoporosis: A systematic assessment of the quality and content of clinical practice guidelines, using the AGREE II instrument and the IOM Standards for Trustworthy Guidelines. AB - BACKGROUND: Numerous clinical practice guidelines (CPGs) are published to guide management of osteoporosis. Little is known about their quality or how recommendations have changed over time. OBJECTIVE: To systematically assess the quality and content of the guidelines on screening for osteoporosis, using the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool, and the Institute of Medicine (IOM) standards for trustworthy guidelines. METHODS: We conducted a systematic search for osteoporosis CPGs published between 2002-2016, using multiple databases and guideline websites. Two reviewers appraised the quality of eligible CPGs using the AGREE II. High quality CPGs were considered if they scored >= 60 in four or more domains including the domain for rigor of development. Non-parametric tests were used to test for the change of quality over time. One reviewer assessed the guidelines with IOM standards. We summarized the different evidence grading systems and extracted and compared the recommendations. RESULTS: A total of 33 CPGs were identified. The mean scores for AGREE II differed by domain (range: 42% to 71%). CPGs scored higher on domains for clarity of presentation, scope and purpose, and rigor of development. CPGs scored lower on domains for stakeholder involvement, editorial independence and applicability. Assessment of CPGs by IOM standards showed that CPGs scored better on standards for systematic review, establishing evidence foundation and rating strength of recommendation, articulation of recommendation, and establishing transparency. While scored lower on standards for updating, external review, and the development group composition. There was no difference in AGREE II and IOM defined guidelines' quality before and after the introduction of the two tools (P values >0.05). The IOM identified four more guidelines as high quality compared to the AGREE II. Examining these additional guidelines indicated that the two tools may give conflicting results especially for the rigor of development domain. Recommendations in certain areas showed substantial differences between guidelines. CONCLUSION: Osteoporosis screening CPGs are of variable quality, and their recommendations often differ. Guideline quality as measured by AGREE II and IOM standards has not improved overtime. Guideline developers should work together to improve the quality and consistency of recommendations to improve the likelihood that their guidelines will be used in practice. PMID- 30521557 TI - An improved power loss model of full-bridge converter under light load condition. AB - When the full-bridge converter works under the light load condition, the power efficiency obtained by the theoretical model is much different from that of the actual converter. Facing with this situation, an improved power loss model based on the typical power loss model is proposed. In this paper, the typical power loss model is called typical model for short and the improved power loss model is called proposed model for short. Firstly, the antiparallel freewheeling diodes at the arms of full-bridge circuit are taken into account. Every barrier junction capacitance of Schottky diode in the rectifier circuit is neglected. Then, the turning-off loss of full-bridge and the core loss of inductive components (the transformer and the filter inductor) in the typical model are compensated and modified by combining the theoretical values with the measured input current under the minimum and the maximum output current. In addition, it also corrects the equivalent resistance related to the conduction loss of converter. Eventually, the proposed model is established. The rise time and fall time of the midpoint voltage of two arms, and the fluctuation degree of the reverse bias voltage related to the Schottky rectifier diodes are regarded as the local indexes. The conduction time of the metal oxide semiconductor field effect transistor (MOSFET) in each switching period, and the power efficiency of converter are regarded as the global indexes. Based on the analyses, the local indexes are compared qualitatively, while the global indexes are compared quantitatively. It is found that the differences of the local indexes between the proposed model and the experiment are smaller than those between the typical model and the experiment. Meanwhile, the global indexes of the proposed model are closer to the experimental results. Therefore, it can be further demonstrated that the proposed model is more approximate to the actual converter than the typical model. PMID- 30521558 TI - Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer. AB - The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05 4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23-0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05-3.96, p = 0.036). Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer. PMID- 30521559 TI - Location of water in fresh sugarcane bagasse observed by synchrotron X-ray microtomography. AB - Sugarcane bagasse is a vast lignocellulosic byproduct generated in the industry with ~50% humidity (1 kg dry matter associated with 1 kg water). Although the presence of water brings deleterious consequences for combustion, storage and sugar extraction, the location of water in fresh bagasse remains unknown. In this work, we use synchrotron X-ray microtomography for non-invasive 3D imaging of fresh bagasse particles, which allows the visualization of intraparticle water. The sclerified fiber cells in the sheaths surrounding xylem vessels are often found full of water. We suggest this can be juice preserved from the native stalks as many sclerified fibers seem to keep their structural integrity despite the mechanical action during sugarcane crushing. The microtomograms of fresh bagasse also shows mineral particles adhered to biomass surfaces, with adhesion presumably favored by the presence of water. In summary, this work unveils the location of water in fresh bagasse, solving an old mystery of sugarcane technology. PMID- 30521560 TI - A gradient-based, GPU-accelerated, high-precision contour-segmentation algorithm with application to cell membrane fluctuation spectroscopy. AB - We present a novel intensity-gradient based algorithm specifically designed for nanometer-segmentation of cell membrane contours obtained with high-resolution optical microscopy combined with high-velocity digital imaging. The algorithm relies on the image oversampling performance and computational power of graphical processing units (GPUs). Both, synthetic and experimental data are used to quantify the sub-pixel precision of the algorithm, whose analytic performance results comparatively higher than in previous methods. Results from the synthetic data indicate that the spatial precision of the presented algorithm is only limited by the signal-to-noise ratio (SNR) of the contour image. We emphasize on the application of the new algorithm to membrane fluctuations (flickering) in eukaryotic cells, bacteria and giant vesicle models. The method shows promising applicability in several fields of cellular biology and medical imaging for nanometer-precise boundary-determination and mechanical fingerprinting of cellular membranes in optical microscopy images. Our implementation of this high precision flicker spectroscopy contour tracking algorithm (HiPFSTA) is provided as open-source at www.github.com/michaelmell/hipfsta. PMID- 30521561 TI - Bacterial microbiome of the chigger mite Leptotrombidium imphalum varies by life stage and infection with the scrub typhus pathogen Orientia tsutsugamushi. AB - Scrub typhus is a mites-borne rickettsiosis caused by the obligate intracellular Gram-negative bacterium Orientia tsutsugamushi. The disease is potentially life threatening and is prevalent in tropical Asia, islands of the western Pacific Ocean and northern Australia where an estimated one million cases occur annually. Orientia tsutsugamushi is transmitted by the bite of larval mites in the genus Leptotrombidium. In the present study, the composition of the microbiome in larvae, deutonymphs and adult males and females from laboratory colonies of L. imphalum that were infected as well as uninfected with O. tsutsugamushi were investigated by high-throughput sequencing of the bacterial 16S rRNA gene. Notably, the bacterial microbiomes of infected adult females were dominated by sequences of O. tsutsugamushi and an unidentified species of Amoebophilaceae, which together comprised 98.2% of bacterial sequences. To improve the taxonomic resolution of the Amoebophilaceae OTU a nearly full length sequence of the 16S rRNA gene was amplified, cloned, and Sanger sequenced. Infected female mites had 89 to 92% nucleotide identity with the Amoebophilaceae family, indicating that the bacterium was likely to be a species of a novel genus. The species composition of bacterial communities varied between mite life stages regardless of their infection status. Uninfected adults exhibited greater species diversity than adults infected with O. tsutsugamushi. In the infected colony, the rate of filial infection with Orientia was less than 100%. Larval and male mites that were PCR-negative for Orientia contained low numbers of sequences of Amoebophilaceae (0.01 and 0.06%, respectively) in their taxonomic profiles, suggesting that a mutualistic relationship exists between the novel species of Amoebophilaceae and O. tsutsugamushi. Our study findings provide the basis for further research to determine the influence of the novel Amoebophilaceae species on the bacterial microbiome and on vector susceptibility to and transovarial transmission of O. tsutsugamushi. PMID- 30521563 TI - Pseudomonas coronafaciens sp. nov., a new phytobacterial species diverse from Pseudomonas syringae. AB - We propose Pseudomonas coronafaciens sp. nov. as a new species in genus Pseudomonas, which is diverse from P. syringae. We also classified strains from onions which are responsible for yellow bud (YB) disease as P. coronafaciens. Sequencing of 16S rRNA gene and multi-locus sequence analysis (MLSA) of housekeeping genes (gyrB, rpoD, gltA and gap1 genes) for the P. syringae pv. coronafaciens strains along with other strains of P. syringae pathovars resulted in a distinct cluster separate from other P. syringae pathovars. Based on DNA-DNA relatedness, pathotype strain of P. syringae pv. coronafaciens (CFBP 2216PT) exhibited <=35.5% similarity with the pathotype strains of P. syringae pv. syringae (CFBP 1392PT, 4702T) but exhibited >=90.6% with the YB strains (YB 12-1, YB 12-4, YB 09-1). Also, the YB strains (YB 12-1, YB 12-4, YB 09-1) were able to infect only onion but not oat, rye and Italian ryegrass (common hosts for P. syrinage pv. coronafaciens). Contrastingly, P. syringae pv. coronafaciens strains (NCPPB 600PT, ATCC 19608, Pcf 83-300) produced typical halo blight symptoms on oat, rye and Italian rye grass but did not produce any symptoms on onion. These results provide evidence that P. syringae pv. coronafaciens should be elevated to a species level and the new YB strains may potentially be a novel pathovar of hereto proposed P. coronafaciens species. PMID- 30521562 TI - The multiple maternal legacy of the Late Iron Age group of Urville-Nacqueville (France, Normandy) documents a long-standing genetic contact zone in northwestern France. AB - The compilation of archaeological and genetic data for ancient European human groups has provided persuasive evidence for a complex series of migrations, population replacements and admixture until the Bronze Age. If the Bronze-to-Iron Age transition has been well documented archaeologically, ancient DNA (aDNA) remains rare for the latter period and does not precisely reflect the genetic diversity of European Celtic groups. In order to document the evolution of European communities, we analysed 45 individuals from the Late Iron Age (La Tene) Urville-Nacqueville necropolis in northwestern France, a region recognized as a major cultural contact zone between groups from both sides of the Channel. The characterization of 37 HVS-I mitochondrial sequences and 40 haplogroups provided the largest maternal gene pool yet recovered for the European Iron Age. First, descriptive analyses allowed us to demonstrate the presence of substantial amounts of steppe-related mitochondrial ancestry in the community, which is consistent with the expansion of Bell Beaker groups bearing an important steppe legacy in northwestern Europe at approximately 2500 BC. Second, maternal genetic affinities highlighted with Bronze Age groups from Great Britain and the Iberian Peninsula regions tends to support the idea that the continuous cultural exchanges documented archaeologically across the Channel and along the Atlantic coast (during and after the Bronze Age period) were accompanied by significant gene flow. Lastly, our results suggest a maternal genetic continuity between Bronze Age and Iron Age groups that would argue in favour of a cultural transition linked to progressive local economic changes rather than to a massive influx of allochthone groups. The palaeogenetic data gathered for the Urville Nacqueville group constitute an important step in the biological characterization of European Iron age groups. Clearly, more numerous and diachronic aDNA data are needed to fully understand the complex relationship between the cultural and biological evolution of groups from the period. PMID- 30521564 TI - Effect of crop residues on interception and activity of prosulfocarb, pyroxasulfone, and trifluralin. AB - Crop residue retention on the soil surface in no-tillage system can intercept pre emergent herbicides and reduce their efficacy. Three experiments were conducted to investigate the effect of crop residue amount (0, 1, 2 and 4 t ha-1), moisture (wet versus dry), type (wheat, barley, canola, chickpea and lupin) and age (fresh or aged for one year) on the interception and subsequent leaching of prosulfocarb, pyroxasulfone, and trifluralin from the residue into soil. Bioassays, using cucumber and annual ryegrass as indicator plants, were used to assess herbicide activity/availability in the soil and on the residue. Herbicide interception increased considerably as residue quantity increased from 2 to 4 t ha-1. After simulated rainfall, which washed herbicide into the soil, complete control of ryegrass occurred for trifluralin with 0 t ha-1 residue, for prosulfocarb with 0 and 1 t ha-1 residue, and for pyroxasulfone with all residue rates. Therefore, with rain or irrigation, pyroxasulfone was the herbicide least affected by high residue loads. Less chemical leached from the crop residue into the soil after rainfall, when prosulfocarb and trifluralin were applied to wet residue compared with dry residue, but the initial moisture condition had no effect on the leaching of pyroxasulfone from residue. If practically possible, farmers should minimise spraying prosulfocarb and trifluralin onto wet crop residue. Barley and wheat residues intercepted more herbicide than an equivalent mass of canola, chickpea or lupin residue, which was largely due to the increased ground cover with cereal residues. The effect of residue age on herbicide interception and leaching was relatively small and variable. Overall, more herbicide reached the soil when sprayed on one-year old residue than new residue, which was largely due to reduced ground cover with aged residue. A strong positive linear relationship existed between ground cover percentage and growth of bioassay species (r2 = 0.75). This means that there was little difference in the ability of residue to adsorb and retain herbicide between crop residue types and ages, such that farmers can simply use the ground cover of the crop residue to assess interception. PMID- 30521565 TI - An efficient proteome-wide strategy for discovery and characterization of cellular nucleotide-protein interactions. AB - Metabolite-protein interactions define the output of metabolic pathways and regulate many cellular processes. Although diseases are often characterized by distortions in metabolic processes, efficient means to discover and study such interactions directly in cells have been lacking. A stringent implementation of proteome-wide Cellular Thermal Shift Assay (CETSA) was developed and applied to key cellular nucleotides, where previously experimentally confirmed protein nucleotide interactions were well recaptured. Many predicted, but never experimentally confirmed, as well as novel protein-nucleotide interactions were discovered. Interactions included a range of different protein families where nucleotides serve as substrates, products, co-factors or regulators. In cells exposed to thymidine, a limiting precursor for DNA synthesis, both dose- and time dependence of the intracellular binding events for sequentially generated thymidine metabolites were revealed. Interactions included known cancer targets in deoxyribonucleotide metabolism as well as novel interacting proteins. This stringent CETSA based strategy will be applicable for a wide range of metabolites and will therefore greatly facilitate the discovery and studies of interactions and specificities of the many metabolites in human cells that remain uncharacterized. PMID- 30521566 TI - Citizen Social Lab: A digital platform for human behavior experimentation within a citizen science framework. AB - Cooperation is one of the behavioral traits that define human beings, however we are still trying to understand why humans cooperate. Behavioral experiments have been largely conducted to shed light into the mechanisms behind cooperation-and other behavioral traits. However, most of these experiments have been conducted in laboratories with highly controlled experimental protocols but with limitations in terms of subject pool or decisions' context, which limits the reproducibility and the generalization of the results obtained. In an attempt to overcome these limitations, some experimental approaches have moved human behavior experimentation from laboratories to public spaces, where behaviors occur naturally, and have opened the participation to the general public within the citizen science framework. Given the open nature of these environments, it is critical to establish the appropriate data collection protocols to maintain the same data quality that one can obtain in the laboratories. In this article we introduce Citizen Social Lab, a software platform designed to be used in the wild using citizen science practices. The platform allows researchers to collect data in a more realistic context while maintaining the scientific rigor, and it is structured in a modular and scalable way so it can also be easily adapted for online or brick-and-mortar experimental laboratories. Following citizen science guidelines, the platform is designed to motivate a more general population into participation, but also to promote engaging and learning of the scientific research process. We also review the main results of the experiments performed using the platform up to now, and the set of games that each experiment includes. Finally, we evaluate some properties of the platform, such as the heterogeneity of the samples of the experiments, the satisfaction level of participants, or the technical parameters that demonstrate the robustness of the platform and the quality of the data collected. PMID- 30521567 TI - The DFR locus: A smart landing pad for targeted transgene insertion in tomato. AB - Targeted insertion of transgenes in plants is still challenging and requires further technical innovation. In the present study, we chose the tomato DFR gene involved in anthocyanin biosynthesis as a landing pad for targeted transgene insertion using CRISPR-Cas9 in a two-step strategy. First, a 1013 bp was deleted in the endogenous DFR gene. Hypocotyls and callus of in vitro regenerated plantlets homozygous for the deletion were green instead of the usual anthocyanin produced purple colour. Next, standard Agrobacterium-mediated transformation was used to target transgene insertion at the DFR landing pad in the dfr deletion line. The single binary vector carried two sgRNAs, a donor template containing two homology arms of 400 bp, the previously deleted DFR sequence, and a NptII expression cassette. Regenerating plantlets were screened for a purple-colour phenotype indicating that DFR function had been restored. Targeted insertions were identified in 1.29% of the transformed explants. Thus, we established an efficient method for selecting HDR-mediated transgene insertion using the CRISPR Cas9 system in tomato. The visual screen used here facilitates selection of these rare gene targeting events, does not necessitate the systematic PCR screening of all the regenerating material and can be potentially applied to other crops. PMID- 30521568 TI - Effect estimate comparison between the prescription sequence symmetry analysis (PSSA) and parallel group study designs: A systematic review. AB - Prescription sequence symmetry analysis (PSSA), a case-only design introduced in 1996, has been increasingly used to identify unintentional drug effects, and has potential applications as a hypothesis-testing and a hypothesis-generating method, due to its easy application and effective control of time-invariant confounders. The aim of this study is to systematically compare effect estimates from the PSSA to effect estimates from conventional observational parallel group study designs, to assess the validity and constraints of the PSSA study design. We reviewed the MEDLINE, EMBASE, and Web of Science databases until February 2016 to identify studies that compared PSSA to a parallel group design. Data from the eligible articles was extracted and analyzed, including making a Bland-Altman plot and calculating the number of discrepancies between the designs. 63 comparisons (from two studies) were included in the review. There was a significant correlation (p < 0.001) between the effect estimates of the PSSA and the parallel group designs, but the bias indicated by the Bland-Altman plot (0.20) and the percentage of discrepancies (70-80%) showed that this correlation was not accompanied by a considerable similarity of the effect estimates. Overall, the effect estimates of the parallel group designs were higher than those of the PSSA, not necessarily further away from 1, and the parallel group designs also generated more significant signals. However, these results should be approached with caution, as the effect estimates were only retrieved from two separate studies. This review indicates that, even though PSSA has a lot of potential, the effect estimates generated by the PSSA are usually lower than the effect estimates generated by parallel group designs, and PSSA mostly has a lower power than the conventional study designs, but this is based on limited comparisons, and more comparisons are needed to make a proper conclusion. PMID- 30521569 TI - Performance of GPS units for deployment on semiaquatic animals. AB - Global Positioning System (GPS) technology is widely used in wildlife research to study animal movement and habitat use. In order to evaluate the quality and reliability of GPS data, the factors influencing the performance of these devices must be known, especially for semiaquatic species, because terrestrial and aquatic habitat might affect GPS performance differently. We evaluated the location error and fix success rate of three GPS receiver models in stationary tests and on a semi-aquatic mammal, the Eurasian beaver (Castor fiber). The location error during stationary tests was on average 15.7 m, and increased with increasing canopy closure, slope, and horizontal dilution of precision, potentially leading to the erroneous classification of GPS positions when studying habitat use in animals. In addition, the position of the GPS antenna (flat versus 90 degrees tilted) affected the location error, suggesting that animal behavior affects GPS performance. The fix success rate was significantly higher during stationary tests compared to when GPS units were deployed on beavers (94% versus 86%). Further, GPS receivers did not obtain any positions underwater and underground, the latter potentially allowing the estimation of activity periods in animals that use lodges or burrows as shelter. We discuss the possibilities for data screening, the use of buffer zones along the shoreline, and combination with other data loggers to avoid the erroneous classification of GPS positions when studying habitat use. PMID- 30521570 TI - Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. AB - Domestic dog breeds exhibit remarkable morphological variations that result from centuries of artificial selection and breeding. Identifying the genetic changes that contribute to these variations could provide critical insights into the molecular basis of tissue and organismal morphogenesis. Bulldogs, French Bulldogs and Boston Terriers share many morphological and disease-predisposition traits, including brachycephalic skull morphology, widely set eyes and short stature. Unlike other brachycephalic dogs, these breeds also exhibit vertebral malformations that result in a truncated, kinked tail (screw tail). Whole genome sequencing of 100 dogs from 21 breeds identified 12.4 million bi-allelic variants that met inclusion criteria. Whole Genome Association of these variants with the breed defining phenotype of screw tail was performed using 10 cases and 84 controls and identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) (Chr5: 32195043_32195044del, p = 4.37 X 10-37) as the most strongly associated variant in the canine genome. This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers. The DVL2 variant segregated with thoracic and caudal vertebral column malformations in a recessive manner with incomplete and variable penetrance for thoracic vertebral malformations between different breeds. Importantly, analogous frameshift mutations in the human DVL1 and DVL3 genes cause Robinow syndrome, a congenital disorder characterized by similar craniofacial, limb and vertebral malformations. Analysis of the canine DVL2 variant protein showed that its ability to undergo WNT-induced phosphorylation is reduced, suggesting that altered WNT signaling may contribute to the Robinow-like syndrome in the screwtail breeds. PMID- 30521571 TI - Evaluation of the prognostic value of all four HER family receptors in patients with metastatic breast cancer treated with trastuzumab: A Hellenic Cooperative Oncology Group (HeCOG) study. AB - In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2 negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21 0.88, Wald's p = 0.022 and HR = 0.43, 95% CI 0.21-0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19-10.50, p = 0.023 and HR = 3.37, 95% CI 1.12-10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22-0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29-12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2 positive subgroup (HR = 0.47, 95% CI 0.23-0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. PMID- 30521572 TI - Showup identification decisions for multiple perpetrator crimes: Testing for sequential dependencies. AB - Research in perception and recognition demonstrates that a current decision (i) can be influenced by previous ones (i-j), meaning that subsequent responses are not always independent. Experiments 1 and 2 tested whether initial showup identification decisions impact choosing behavior for subsequent showup identification responses. Participants watched a mock crime film involving three perpetrators and later made three showup identification decisions, one showup for each perpetrator. Across both experiments, evidence for sequential dependencies for choosing behavior was not consistently predictable. In Experiment 1, responses on the third, target-present showup assimilated towards previous choosing. In Experiment 2, responses on the second showup contrasted previous choosing regardless of target-presence. Experiment 3 examined whether differences in number of test trials in the eyewitness (vs. basic recognition) paradigm could account for the absence of hypothesized ability to predict patterns of sequential dependencies in Experiments 1 and 2. Sequential dependencies were detected in recognition decisions over many trials, including recognition for faces: the probability of a yes response on the current trial increased if the previous response was also yes (vs. no). However, choosing behavior on previous trials did not predict individual recognition decisions on the current trial. Thus, while sequential dependencies did arise to some extent, results suggest that the integrity of identification and recognition decisions are not likely to be impacted by making multiple decisions in a row. PMID- 30521573 TI - The accumulation of metals, PAHs and alkyl PAHs in the roots of Echinacea purpurea. AB - We examined the accumulation of polycyclic aromatic hydrocarbons (PAHs), alkyl PAHs, and toxic metals in soils by the roots of Echinacea purpurea (L.) Moench, in a 20-week greenhouse study and a 2-year field study. In the greenhouse study, inoculation by arbuscular mycorrhizal fungus (AMF), Rhizoglomus intraradices (N.C. Schenck & G.S. Sm.). increased the first order accumulation rates (k1) for PAHs by 10-fold, though had no effect on the bioaccumulation rates of toxic metals. In the greenhouse study, PAHs concentrations in soil increased over time with AMF inoculation, suggesting AMF promote 'solvent depletion' in soils by enhancing absorption of minerals and carbon by roots, concentrating the more hydrophobic PAHs in the residual soil. Under field conditions, contaminant concentrations in soils remained unchanged over the 2-year duration of the study. Despite this, all contaminants in E. purpurea roots increased significantly, as a result of a long term extraction of contaminants by plants from soil and a reduction in soil volume as a result of plant growth. First order accumulation rates by roots were inversely correlated to log Kow for the PAHs and alkyl PAHs, indicating that accumulation is inversely related to the compound's hydrophobicity. This study is the first to our knowledge to assess the accumulation of alkyl PAHs by roots, with implications for soil bioremediation by plants because alkyl PAHs are a major source of petrogenic contamination in soils. PMID- 30521574 TI - Unexpected discrepancies in hospital administrative databases can impact the accuracy of monitoring thyroid surgery outcomes in France. AB - OBJECTIVE: To determine the validity of hospital administrative databases compared to prospective collection of medical data assessing thyroid surgery complications. BACKGROUND: Administrative data are increasingly used to track surgical outcomes. METHODS: All patients undergoing thyroid surgery at three French university hospitals between April 2008 and April 2009 were prospectively included. Using diagnosis and procedural codes from hospital administrative database, we designed three indicators for measuring complications of thyroid surgery: recurrent laryngeal nerve palsy, postoperative hypoparathyroidism, and postoperative hemorrhage. Gold standard was obtained from a prospective collection of medical data after systematically screening each patient for the above-mentioned complications. Their ability to monitor surgical outcomes over time within individual hospitals was estimated using control charts. Spatial comparison between hospitals was performed by funnel plots. RESULTS: A total of 1909 patients were included. Complication rates extracted from administrative data were significantly lower compared to medical data (nerve palsy 2.4% vs. 6.7%, hypoparathyroidism 10.6% vs. 22.3%, p<0.0001). Indicator sensitivity was 30.4% for nerve palsy, 45.4% for hypoparathyroidism and 71.4% for postoperative hemorrhage. Corresponding positive predictive values were 84.4%, 95.1% and 68.2%. In two of the three hospitals, administrative data were not able to track temporal variations in complications rates. Regarding inter-hospital comparisons, 2 out of 3 hospitals were considered outliers according to administrative data despite having an average performance based on medical data. CONCLUSIONS: The ability of indicators extracted from administrative databases to measure thyroid surgery outcomes depends on the quality of underlying data coding. Validation in every center should be a prerequisite before implementing such metrics for tracking performance. PMID- 30521575 TI - A comparison of maternal and newborn health services costs in Sindh Pakistan. AB - Pakistani women suffer the highest rate of maternal mortality in South Asia. A lack of comprehensive knowledge about maternal and newborn health (MNH) services costs impedes policy decisions to maximize the benefit from existing, as well as emerging, MNH interventions in Pakistan. We compared MNH service costs at different levels of care. A cross-sectional survey was conducted during January to March 2016 as part of a large economic evaluation in Sindh, Pakistan. Health providers and facilities were selected from a sampling frame, inclusive of public and private sectors. This study utilized a broad perspective (i.e. costs to the health system and patients/families). The unit costs of MNH services were determined through a simultaneous allocation method in the public facilities; and patient billing department in the private facilities. Descriptive analysis was performed, and an analysis of variance (ANOVA) test was applied to compare overall mean costs both within and between health facilities. A total of 31 eligible health providers and facilities (n = 25 in private; n = 7 in public) were included in the final analysis. An ambulatory visit (AV) for routine antenatal care (ANC) costs $3.6 and $0.9 at secondary- and tertiary-level public facilities, respectively. In the private sector, the costs of an AV for ANC were slightly less ($2.8) at secondary-level and much higher ($6) at tertiary-level facilities compared to the public sector. Diagnostic test costs were much higher in private facilities. The average costs of inpatient admissions were $30.5 at general ward (GW), and $151 at the intensive care unit (ICU) in public facilities. In-patient admissions costs were lower such as $9.3 at GW and $36.5 at ICU in private facilities. Understanding cost is critical to guide decisions of resource allocation within the public sector; and risk mitigation for excessive OOP costs through third party payer for services in the private sector. PMID- 30521576 TI - The effect of water-based plyometric training on vertical stiffness and athletic performance. AB - Since higher vertical stiffness is related to superior athletic performance, training has traditionally been aimed at augmenting this variable to enhance neuromuscular output. However, research has linked elevated stiffness with increased injury risk, therefore, this study examined the effect of a novel training intervention on vertical stiffness and athletic performance. Vertical stiffness, jump performance and athletic performance were assessed in two randomly allocated groups, prior to, and following, an eight-week period. One group was exposed to a training intervention involving aqua-based plyometrics (n = 11) over the 8 weeks while the other acted as a control group (n = 9). The training intervention involved hopping, jumping and bounding in water at a depth of 1.2m whilst control participants performed their normal training. There were no significant changes in vertical stiffness in either group. Countermovement jump height and peak power significantly increased within the aqua plyometric group (p < 0.05). Athletic performance markers improved in the aqua plyometric group as measured using an agility and a 5-bound test exhibiting superior values at the post-test (p < 0.05). The results suggest that an aqua plyometric training program can enhance athletic performance without elevating stiffness. The increase in athletic performance is likely due to a reduction in ground reaction forces created by the buoyancy of the water, causing a shorter amortization phase and a more rapid application of concentric force. The findings from this study can inform exercise professionals and medical staff regarding the ability to enhance neuromuscular performance without elevating vertical stiffness. This has implications for improving athletic performance while concurrently minimising injury risk. PMID- 30521577 TI - Patient-reported outcomes associated with different restorative techniques in pediatric dentistry: A systematic review and MTC meta-analysis. AB - BACKGROUND: Despite the increasing number of studies evaluating patient reported outcome measures (PROs), there is no clearness regarding which restorative treatment offers major benefits based on the pediatric patient perspective. AIM: To compare different restorative techniques in pediatric dentistry regarding patient-reported outcomes. DESIGN: Literature searching was carried out on prospective studies indexed in PubMed, Scopus and OpenGrey. A Mixed Treatment Comparisons (MTC) meta-analysis was undertaken considering the results from reviewed studies. Anxiety, pain and quality of life were extracted as mean with standard deviation, percentage of pain, and mean difference of scores with standard deviation, respectively. For direct comparisons, data were combined using a random-effect model. Heterogeneity was assessed with the I2 statistic. For indirect comparisons, fixed and random effects were chosen through comparison of competing models based on the Deviance Information Criteria (DIC). The expected efficacy ranking based on the posterior probabilities of all treatment rankings was also calculated. RESULTS: An initial search resulted in 4,322 articles, of which 17 were finally selected. Due to unavailability of data, only pain, anxiety and oral health related quality of life (OHRQoL) were statistically analyzed. The difference in means (95% CI) of anxiety between treatments using only hand instruments with or without chemomechanical agents were -5.35 (-6.42 to -4.20) and -5.79 (-7.77 to -3.79) respectively when compared to conventional treatment using rotary instruments and/or local anesthesia. Regarding pain, there was a trend for treatments without rotary instruments and local anesthesia to be less frequently reported as painful. No statistical difference was found intragroup nor among treatments for OHRQoL. CONCLUSIONS: Anxiety and pain are directly related with more invasive restorative treatments. On the other hand, quality of life is not improved regardless of the restorative technique used. Further well-designed prospective studies regarding PROs in children are still necessary. PMID- 30521578 TI - A study for multiscale information transfer measures based on conditional mutual information. AB - As the big data science develops, efficient methods are demanded for various data analysis. Granger causality provides the prime model for quantifying causal interactions. However, this theoretic model does not meet the requirement for real-world data analysis, because real-world time series are diverse whose models are usually unknown. Therefore, model-free measures such as information transfer measures are strongly desired. Here, we propose the multi-scale extension of conditional mutual information measures using MORLET wavelet, which are named the WM and WPM. The proposed measures are computational efficient and interpret information transfer by multi-scales. We use both synthetic data and real-world examples to demonstrate the efficiency of the new methods. The results of the new methods are robust and reliable. Via the simulation studies, we found the new methods outperform the wavelet extension of transfer entropy (WTE) in both computational efficiency and accuracy. The features and properties of the proposed measures are also discussed. PMID- 30521579 TI - Alpha7 acetylcholine receptor autoantibodies are rare in sera of patients diagnosed with schizophrenia or bipolar disorder. AB - The alpha7 acetylcholine receptor (AChR) has been linked with the onset of psychotic symptoms and we hypothesized therefore that it might also be an autoimmune target. Here, we describe a new radioimmunoassay (RIA) using iodine 125-labelled alpha-bungarotoxin and membrane extract from transfected HEK293 cells expressing human alpha7 AChR. This RIA was used to analyze sera pertaining to a cohort of 711 subjects, comprising 368 patients diagnosed with schizophrenia spectrum disorders, 140 with bipolar disorder, 58 individuals diagnosed of other mental disorders, and 118 healthy comparison subjects. We identified one patient whose serum tested positive although with very low levels (0.2 nM) for alpha7 AChR-specific antibodies by RIA. Three out of 711 sera contained antibodies against iodine 125-labelled alpha-bungarotoxin, because they precipitated with it in the absence of alpha7 AChR. This first evidence suggests that autoantibodies against alpha7 AChR are absent or very rare in these clinical groups. PMID- 30521580 TI - E4orf1: A protein for enhancing glucose uptake despite impaired proximal insulin signaling. AB - BACKGROUND: Type 2 diabetes is often linked with impaired proximal insulin signaling. Hence, a therapeutic agent that enhances cellular glucose uptake without requiring proximal insulin signaling would be desirable for improving glycemic control. The E4orf1 peptide (E4) derived from human adenovirus 36 (Ad36) promotes cellular glucose uptake in vitro and in vivo, independent of insulin. E4 bypasses a part of insulin signaling to upregulate cellular glucose uptake. We tested the hypothesis that E4 requires the distal but not proximal insulin signaling to enhance cellular glucose disposal. METHODS: 3T3-L1 preadipocytes inducibly expressing E4 or a null vector (NV) were treated with inhibitor of insulin receptor (S961), inhibitor of insulin like growth factor-1receptor (IGF 1R) (Picropodophyllin, PPP), PPP+S961, or phosphatidyl inositol-3 kinase (PI3K) inhibitor (Wortmannin, WM). We used PPP and S961 to block the proximal insulin signaling, or WM to block the distal insulin signaling. Cells were exposed to 0 or 100nM insulin. RESULTS: As expected, when the proximal or distal insulin signaling was blocked in NV cells, insulin could not enhance pAKT protein abundance, Glut4 translocation, or glucose uptake. Whereas, E4 cells significantly increased pAKT abundance, Glut4 translocation and glucose uptake independent of the presence of insulin or proximal insulin signaling. Enhanced glucose disposal in E4 cells was completely abrogated when the distal insulin signaling was blocked. CONCLUSIONS: E4 bypasses the proximal insulin signaling but uses the distal insulin signaling to activate pAkt and in turn Glut4 translocation to improve cellular glucose uptake. E4 offers a promising template to improve glycemic control when the proximal insulin signaling is impaired. PMID- 30521581 TI - An evaluation roadmap for critical quality attributes from tier 1 in analytical similarity assessment. AB - Analytical similarity assessment of critical quality attributes (CQAs) serves as a foundation for the development of biosimilar products and facilitates an abbreviated subsequent clinical evaluation. In this study, we establish a statistical evaluation roadmap with statistical approaches for some selected CQAs from Tier 1, because they are most relevant to clinical outcomes and require the most rigorous statistical methods. In the roadmap, we incorporate 3 methods ranking and tier assignment of quality attributes, the equivalence test, and the Mann-Whitney test for equivalence-that are important to determine analytical similarity between the reference and biosimilar products. For the equivalence test, we develop a power calculation formula based on the two one-sided tests procedure. Exact sample sizes can be numerically calculated. Then, we propose a flexible idea for selecting the number of reference lots (nR) and the number of biosimilar lots (nT) to adjust for serious unbalanced sample sizes. From results of extensive simulations under various parameter settings, we obtain a workable strategy to determine the optimum sample size combination (nT, nR) for the equivalence test of CQAs from Tier 1. R codes are provided to facilitate implementation of the roadmap and corresponding methods in practice. PMID- 30521582 TI - Identifying missed clinical opportunities for the earlier diagnosis of HIV in Australia, a retrospective cohort data linkage study. AB - BACKGROUND: Treatment as prevention approaches for HIV require optimal HIV testing strategies to reduce undiagnosed HIV infections. In most settings, HIV testing strategies still result in unacceptably high rates of missed and late diagnoses. This study aimed to identify clinical opportunities for targeted HIV testing in persons at risk to facilitate earlier HIV diagnosis in New South Wales, Australia; and to assess the duration between the diagnosis of specific conditions and HIV diagnosis. METHODS: The Australian National HIV registry was linked to cancer diagnoses, notifiable condition diagnoses, emergency department presentations and hospital admissions for all HIV diagnoses between 1993 and 2012 in NSW. Date of HIV acquisition was estimated from back-projection models and people with a likely duration from infection to diagnosis of less than 180 days were excluded. Risk factors associated with clinical opportunities for the earlier diagnosis of HIV were identified. RESULTS: Sexually transmitted infection diagnoses (particularly gonorrhoea and syphilis) and some hospital admissions (mental health and drug-related diagnoses, and non-infective digestive disorder diagnoses) were prominent among people estimated to be living with undiagnosed HIV. The length of time between a clinical opportunity for the earlier HIV diagnosis and actual HIV diagnosis was 13.3 months for notifiable conditions, and 15.2 months for hospital admissions. People with lower CD4+ cell count at diagnosis, and older people were significantly less likely to have a missed opportunity for earlier HIV diagnosis. CONCLUSIONS: Additional targeted clinical HIV testing strategies are warranted for people with gonorrhoea and syphilis; and hospital presentations or admissions for mental health, drug-related and gastrointestinal diagnoses. PMID- 30521583 TI - The burden of stroke in China: Results from a nationwide population-based epidemiological survey. AB - Stroke is a serious threat to human health that often leads to severe complications, and currently ranks first as leading cause of death in China. However, reliable data on stroke burden in China in the 21st century are lacking. We used the data from NESS-China (National Epidemiological Survey of Stroke in China) for assessing the adverse health effects of stroke in Chinese population. We carried out inter-regional comparative study in order to obtain regular burden related characteristics of stroke in China, as measured by YLLs (years of life lost due to premature mortality), YLDs (years lived with disability) and DALYs (disability adjusted life years). Amongst the nationwide population of 596,536 individuals of all ages in 2013, the YLLs for stroke was 1748, the YLDs was 262, and the DALYs was 2010(per 100,000). The gender subtype analysis of DALYs was 2171(male) and 1848(female). The YLLs, YLDs and DALYs in rural areas were higher compared to urban areas. Among the 18 age groups, the highest YLLs was observed in >= 80 years old group. The impact of stroke on Chinese population is more severe compared to the global average levels. Stroke results as the main cause of YLLs in China, while there is no significant difference for the YLDs. Nevertheless, DALYs caused by stroke rank 3th in global epidemiologic study territories, 1st in China. PMID- 30521584 TI - Does perceived ostracism contribute to mental health concerns among veterans who have been deployed? AB - Posttraumatic stress-negative psychological experiences as a result of traumatic stressors-can hinder military veterans' reintegration into society and cause various mental health problems. Veterans need quality social relationships to facilitate reintegration and to cope with posttraumatic stress and related mental health problems; discrimination or other forms of interpersonal rejection can exacerbate these veterans' problems. Ostracism (i.e., being ignored and excluded) is a painful and psychologically distressing experience that may be one factor that contributes to the problems of veterans who are dealing with posttraumatic stress. To our knowledge, this connection has yet to be tested empirically. Thus, we investigated the correlation between posttraumatic stress, perceived ostracism, and other theoretically relevant variables (i.e., mental health problems, perceived social support, psychological need satisfaction) in a sample of veterans who have had at least one deployment. Our results provide preliminary empirical evidence suggesting that perceived ostracism may contribute to veteran' deployment-related psychological problems. Veterans' perceived ostracism correlated with psychological problems (i.e., posttraumatic stress symptoms, anxiety and psychological distress), and it explained additional variance in posttraumatic stress symptoms above and beyond common predictors of these symptoms (i.e., deployment stress, perceived military and civilian-based social support). Finally, perceived ostracism emerged as the most important predictor of posttraumatic stress symptoms in a relative weights analysis. PMID- 30521585 TI - Microbiota control acute arterial inflammation and neointimal hyperplasia development after arterial injury. AB - BACKGROUND: The microbiome has a functional role in a number of inflammatory processes and disease states. While neointimal hyperplasia development has been linked to inflammation, a direct role of the microbiota in neointimal hyperplasia has not yet been established. Germ-free (GF) mice are an invaluable model for studying causative links between commensal organisms and the host. We hypothesized that GF mice would exhibit altered neointimal hyperplasia following carotid ligation compared to conventionally raised (CONV-R) mice. METHODS: Twenty week-old male C57BL/6 GF mice underwent left carotid ligation under sterile conditions. Maintenance of sterility was assessed by cultivation and 16S rRNA qPCR of stool. Neointimal hyperplasia was assessed by morphometric and histologic analysis of arterial sections after 28 days. Local arterial cell proliferation and inflammation was assessed by immunofluorescence for Ki67 and inflammatory cell markers at five days. Systemic inflammation was assessed by multiplex immunoassays of serum. CONV-R mice treated in the same manner served as the control cohort. GF and CONV-R mice were compared using standard statistical methods. RESULTS: All GF mice remained sterile during the entire study period. Twenty-eight days after carotid ligation, CONV-R mice had significantly more neointimal hyperplasia development compared to GF mice, as assessed by intima area, media area, intima+media area, and intima area/(intima+media) area. The collagen content of the neointimal lesions appeared qualitatively similar on Masson's trichrome staining. There was significantly reduced Ki67 immunoreactivity in the media and adventitia of GF carotid arteries 5 days after ligation. GF mice also had increased arterial infiltration of anti-inflammatory M2 macrophages compared to CONV-R mouse arteries and a reduced proportion of mature neutrophils. GF mice had significantly reduced serum IFN-gamma-inducible protein (IP)-10 and MIP-2 5 days after carotid ligation, suggesting a reduced systemic inflammatory response. CONCLUSIONS: GF mice have attenuated neointimal hyperplasia development compared to CONV-R mice, which is likely related to altered kinetics of wound healing and acute inflammation. Recognizing the role of commensals in the regulation of arterial remodeling will provide a deeper understanding of the pathophysiology of restenosis and support strategies to treat or reduce restenosis risk by manipulating microbiota. PMID- 30521586 TI - Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation. AB - Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-a-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders. PMID- 30521587 TI - A randomized controlled trial to evaluate performance of pigs raised in antibiotic-free or conventional production systems following challenge with porcine reproductive and respiratory syndrome virus. AB - The trial objective was to compare the performance and animal health parameters of pigs raised according to one of 3 antibiotic (AB) protocols: standard AB medication consisting of mass treatment on days 4 and 21 and judicious AB therapy given therapeutically thereafter as group medication in water and feed or by individual injection (group T1, N = 702); modified AB medication identical to group T1 but with mass treatment only on day 4 and without subsequent therapeutic feed medication (group T2, N = 675); or an antibiotic-free (ABF) regimen (group T3, N = 702). All pigs were vaccinated with a modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine 3 days after weaning. Using a seeder pig model to mimic endemic field infection dynamics, pigs were contact challenged with virulent PRRSV lineage 1 strain 174 four weeks after vaccination. At finishing, average daily gain (ADG) and mean feed conversion ratio (FCR) were significantly better (p <= 0.05) for the T1 and T2 groups compared to the T3 group. There were no significant differences in post-weaning ADG and FCR between the T1 and T2 groups. Mortality and removals significantly favored (p <=0.05) the T1 and T2 groups (20.94% and 24.89%, respectively) versus the T3 group (57.98%). Net revenue per pig was $105.43, $98.79, and $33.81 for the T1, T2 and T3 groups, respectively. Under the conditions of this study, these results indicate that in a PRRSV-endemic setting involving bacterial co-infections, an ABF production strategy may leave pigs at considerable risk of exposure to severe clinical disease and that judicious use of antibiotics can significantly improve animal health. PMID- 30521588 TI - Health literacy in men and women with cardiovascular diseases and its association with the use of health care services - Results from the population-based GEDA2014/2015-EHIS survey in Germany. AB - BACKGROUND: Health literacy (HL), defined as the ability to access, understand, appraise and apply health information, offers a promising approach to reduce the development of cardiovascular diseases (CVD) and to improve the management of CVD in populations. DESIGN: We used data from nationwide cross-sectional German Health Update (GEDA2014/2015-EHIS) survey. 13,577 adults >= 40 years completed a comprehensive standardized paper or online questionnaire including the short form of the European Health Literacy Survey Questionnaire (HLS-EU-Q16). METHODS: We compared participants with and without CVD with regard to their HL. We also analyzed the association between HL level and health care outcomes among individuals with CVD, i.e. frequency of general practitioner or specialist consultations, hospitalization and treatment delay. RESULTS: The percentage of "problematic" or "inadequate" HL, defined as "not sufficient" HL, was significantly higher in individuals with CVD compared to without CVD (men 41.8% vs. 33.6%, women 46.7% vs. 33.4%). Having CVD was independently associated with "not sufficient" HL after adjusting for age, education, income, health consciousness and social support (adjusted OR: men 1.36, women 1.64). Among participants with CVD, individuals with "inadequate" HL were more likely to have more than 6 general practitioner consultations (49.3% vs. 28.7%), hospitalization (46.6% vs. 36.0%) in the last 12 months and to experience delay in getting health care because of long waiting lists for an appointment (30.7% vs. 18.5%) compared to participants with "sufficient" HL. CONCLUSION: "Problematic" or "inadequate" HL is independently associated with CVD and health care use. This is a challenge and an opportunity for both CVD prevention and treatment. PMID- 30521589 TI - Extracellular polymeric substances (EPS) producing and oil degrading bacteria isolated from the northern Gulf of Mexico. AB - Sinking marine oil snow was found to be a major mechanism in the transport of spilled oil from the surface to the deep sea following the Deepwater Horizon (DwH) oil spill. Marine snow formation is primarily facilitated by extracellular polymeric substances (EPS), which are mainly composed of proteins and carbohydrates secreted by microorganisms. While numerous bacteria have been identified to degrade oil, there is a paucity of knowledge on bacteria that produce EPS in response to oil and Corexit exposure in the northern Gulf of Mexico (nGoM). In this study, we isolated bacteria from surface water of the nGoM that grow on oil or Corexit dispersant. Among the 100 strains isolated, nine were identified to produce remarkable amounts of EPS. 16S rRNA gene analysis revealed that six isolates (strains C1, C5, W10, W11, W14, W20) belong to the genus Alteromonas; the others were related to Thalassospira (C8), Aestuariibacter (C12), and Escherichia (W13a). The isolates preferably degraded alkanes (17-77%), over polycyclic aromatic hydrocarbons (0.90-23%). The EPS production was determined in the presence of a water accommodated fraction (WAF) of oil, a chemical enhanced WAF (CEWAF), Corexit, and control. The highest production of visible aggregates was found in Corexit followed by CEWAF, WAF, and control; indicating that Corexit generally enhanced EPS production. The addition of WAF and Corexit did not affect the carbohydrate content, but significantly increased the protein content of the EPS. On the average, WAF and CEWAF treatments had nine to ten times more proteins, and Corexit had five times higher than the control. Our results reveal that Alteromonas and Thalassospira, among the commonly reported bacteria following the DwH spill, produce protein rich EPS that could have crucial roles in oil degradation and marine snow formation. This study highlights the link between EPS production and bacterial oil-degrading capacity that should not be overlooked during spilled oil clearance. PMID- 30521590 TI - Structural insight into substrate and product binding in an archaeal mevalonate kinase. AB - Mevalonate kinase (MK) is a key enzyme of the mevalonate pathway, which produces the biosynthetic precursors for steroids, including cholesterol, and isoprenoids, the largest class of natural products. Currently available crystal structures of MK from different organisms depict the enzyme in its unbound, substrate-bound, and inhibitor-bound forms; however, until now no structure has yet been determined of MK bound to its product, 5-phosphomevalonate. Here, we present crystal structures of mevalonate-bound and 5-phosphomevalonate-bound MK from Methanosarcina mazei (MmMK), a methanogenic archaeon. In contrast to the prior structure of a eukaryotic MK bound with mevalonate, we find a striking lack of direct interactions between this archaeal MK and its substrate. Further, these two MmMK structures join the prior structure of the apoenzyme to complete the first suite of structural snapshots that depict unbound, substrate-bound, and product-bound forms of the same MK. With this collection of structures, we now provide additional insight into the catalytic mechanism of this biologically essential enzyme. PMID- 30521591 TI - Pain could negatively affect school grades - Swedish middle school students with low school grades most affected. AB - Recurrent headache, abdominal and musculoskeletal pain are common in adolescents and it is therefore important to understand their impact on the transitional period from childhood to adulthood. However, studies of the prevalence over time and implications on educational outcomes are still limited, especially regarding multiple pain symptoms. The present study material consists of questionnaire surveys, completed in 2000 and 2008, including two study populations of 9th grade adolescents aged 15 living in West Sweden (n = 20 877). Pain symptoms and demographic variables were based on self-reports from the questionnaires, and school grades were obtained from Statistics Sweden after the student had finished their 9th grade. Between 2000 and 2008, the prevalence of abdominal pain increased among Swedish adolescents (largest increase in girls); the prevalence of headache increased only in girls; the prevalence of pain in upper body decreased only in boys. School grades were significantly lower among those with headache or abdominal pain. Among students with low school grades (10th percentile) the estimated difference between those having any of the symptoms or none were -27 school grade units (95% confidence interval for girls (-27.8; 26.0), for boys (-27.6; -25.5). Both symptoms being present pronounced the association. Low parental education increased the negative effect of symptoms on school grades, most pronounced in the group with the lowest grades. In conclusion, identification of pain symptoms may improve academic achievements, especially in students with multiple symptoms and with parents having low education. Further intervention studies are need. PMID- 30521592 TI - Effects of acute exposures of 2,4,6-trinitrotoluene and inorganic lead on the fecal microbiome of the green anole (Anolis carolinensis). AB - Microbiome studies focused on ecologically relevant vertebrate models like reptiles have been limited. Because of their relatively small home range, fast maturation, and high fecundity, lizards are an excellent reptilian terrestrial indicator species. For this study we used the green anole, Anolis carolinensis, to assess the impact of military relevant contaminants on fecal microbiome composition. Fourteen day sub-acute exposures were conducted via oral gavage with 2,4,6-Trinitrotoluene (TNT) and inorganic lead at doses of 60 mg/kg and 20 mg/kg of body weight, respectively. Body weights and food consumption were monitored and fecal samples were collected for high-throughput 16S rRNA gene amplicon sequencing and analytical chemistry at days 0 and 15. At the end of the study, liver and gut were harvested for body burden data. Chemical analysis confirmed accumulation of TNT, TNT transformation products, and lead in liver tissue and fecal samples. Bacterial community analysis of fecal material revealed significant differences between day 0 and day 15 of TNT exposed anoles with an operational taxonomic unit (OTU) within the genus Erwinia representing 32% of the microbial community in TNT exposed anoles. Predictable changes in gut microbiome composition could offer an easily assayed, noninvasive biomarker for specific chemical exposure providing enhanced scientific support to risk assessments on military installations. PMID- 30521593 TI - The eyes know it: Toddlers' visual scanning of sad faces is predicted by their theory of mind skills. AB - The current research explored toddlers' gaze fixation during a scene showing a person expressing sadness after a ball is stolen from her. The relation between the duration of gaze fixation on different parts of the person's sad face (e.g., eyes, mouth) and theory of mind skills was examined. Eye tracking data indicated that before the actor experienced the negative event, toddlers divided their fixation equally between the actor's happy face and other distracting objects, but looked longer at the face after the ball was stolen and she expressed sadness. The strongest predictor of increased focus on the sad face versus other elements of the scene was toddlers' ability to predict others' emotional reactions when outcomes fulfilled (happiness) or failed to fulfill (sadness) desires, whereas toddlers' visual perspective-taking skills predicted their more specific focusing on the actor's eyes and, for boys only, mouth. Furthermore, gender differences emerged in toddlers' fixation on parts of the scene. Taken together, these findings suggest that top-down processes are involved in the scanning of emotional facial expressions in toddlers. PMID- 30521594 TI - Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga Y5. AB - Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer's disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation in a mouse model of tauopathy, rTg4510. The rTg4510 mouse is a bitransgenic mouse model that uses a system of responder and activator transgenes to express human four-repeat tau with the P301L mutation. This strain is obtained by crossing tetO-MAPT*P301L mouse line (on a FVB/NJ background) with CaMKII-tTA mouse line (on a C57BL/6J background). Male rTg4510 mice and wild-type mice were fed with a standard chow diet with or without Shiga Y5 (500 ppm) for 4 months. Behavioral tests were conducted from 5.5 months of age, and the mice were sacrificed at 6 months of age. There were no significant changes in behavioral performance in rTg4510 mice fed with SY5-containing chow diet compared with rTg4510 mice fed with control chow diet. Histological and biochemical analyses also showed no significant alterations in tau accumulation by the treatment with SY5. One of noticeable finding in this study was that rTg4510 mice on a F1 female FVB/NJ x male C57BL/6J background showed more severe tau accumulation than rTg4510 mice on a F1 female C57BL/6J x male FVB/NJ background. Further studies to clarify the mechanisms underlying tau aggregation may help to develop therapeutic approaches aimed at preventing this pathological feature. PMID- 30521595 TI - Secular trend in interobserver agreement of VIA diagnosis for cervical cancer screening in Nigeria. AB - OBJECTIVE: In low resource settings, visual inspection with acetic acid (VIA) by allied health workers, has been suggested as an alternative for cervical cancer screening. However, there are concerns about the objectivity and time to diagnostic concordance with specialists. We evaluated the secular trend in interobserver agreement between nurse providers and a gynecologist/colposcopist over a five-year period. METHODS: Nurses provided VIA screening with digital cervivography to 4,961 participants in five screening clinics from October 2010 to May 2014 in Nigeria in this observational study. Cervigraphs were reviewed at meetings where a gynaecologist/colposcopist made an assessment from the cervigraphs. We used weighted kappa statistics to calculate agreement in diagnosis between nurse providers and the gynecologist/colposcopist; linear regression models to examine overall trend and investigate potential clinic characteristics that may influence agreement; and time series models to characterize month to month variations. RESULTS: Mean age of participants was 37+/-8 years. Overall agreement was 0.89 at Site D, 0.78 and 0.73 at Sites A and C respectively, 0.50 for Site E and 0.34 for Site C. The number of trainings attended by nurse providers(beta = 0.47,95%CI:0.02-0.93, p = 0.04), high level of engagement by site gynecologists(beta = 0.11,95%CI:0.01-0.21,p = 0.04) were associated with increased agreement; while increasing distance from the coordinating site(beta = -0.47,95%CI:-0.92-0.02,p = 0.04) was associated with decreased agreement. There were no associations between number of years screening clinics were operational(beta = 0.01,95%CI: -0.01-0.03,p = 0.29), cumulative experience of nurse providers(beta = 0.04,95%CI:-0.03-0.12,p = 0.19) and agreement. There were no significant increases in weighted kappa statistics over time for all sites considered. Monthly variations were significant for only one of two sites considered in time series models (AR1 term = -0.40, 95%CI:-0.71 0.09,p = 0.01). CONCLUSION: Our results showed a lack of objectivity, persistent variation and lack of convergence of diagnostic capabilities of nurse led VIA cervical cancer screening with the diagnostic capabilities of a specialist in a cervical cancer screening program in Nigeria. PMID- 30521596 TI - Effects of cold on murine brain mitochondrial function. AB - Therapeutic hypothermia is a strategy that reduces metabolic rate and brain damage during clinically-relevant hypoxic events. Mitochondrial respiration is compromised by hypoxia, with deleterious consequences for the mammalian brain; however, little is known about the effects of reduced temperature on mitochondrial metabolism. Therefore, we examined how mitochondrial function is impacted by temperature using high resolution respirometry to assess electron transport system (ETS) function in saponin-permeabilized mouse brain at 28 and 37 degrees C. Respirometric analysis revealed that, at the colder temperature, ETS respiratory flux was ~ 40-75% lower relative to the physiological temperature in all respiratory states and for all fuel substrates tested. In whole brain tissue, the enzyme maximum respiratory rates for complexes I-V were similarly reduced by between 37-88%. Complexes II and V were particularly temperature-sensitive; a temperature-mediated decrease in complex II activity may support a switch to complex I mediated ATP-production, which is considerably more oxygen-efficient. Finally, the mitochondrial H+-gradient was more tightly coupled, indicating that mitochondrial respiration is more efficient at the colder temperature. Taken together, our results suggest that improvements in mitochondrial function with colder temperatures may contribute to energy conservation and enhance cellular viability in hypoxic brain. PMID- 30521597 TI - Gene landscape and correlation between B-cell infiltration and programmed death ligand 1 expression in lung adenocarcinoma patients from The Cancer Genome Atlas data set. AB - Tumor-infiltrating lymphocytes are related to positive clinical prognoses in numerous cancer types. Programmed death ligand 1 (PD-L1), a mediator of the PD-1 receptor, plays an inhibitory role in cancer immune responses. PD-L1 upregulation can impede infiltrating T-cell functions in lung adenocarcinoma (LUAD), a lung cancer subtype. However, associations between the expression of PD-L1 and infiltration of B cells (a major immunoregulatory cell) remain unknown. Therefore, we investigated the role of infiltrating B cells in LUAD progression and its correlation with PD-L1 expression. The Cancer Genome Atlas (TCGA) LUAD data set was used to explore associations among B-cell infiltration, PD-L1 expression, clinical outcome, and gene landscape. Gene set enrichment analysis was used to explore putative signaling pathways and candidate genes. The drug enrichment analysis was used to identify candidate genes and the related drugs. We found that high B-cell infiltration was correlated with better prognoses; however, PD-L1 may interfere with the survival advantage in patients with high B cell infiltration. The gene landscape was characterized comprehensively, with distinct PD-L1 levels in cell populations with high B-cell infiltration. We obtained five upregulated signaling pathways from the gene landscape: apoptosis, tumor necrosis factor (TNF)-alpha signaling via nuclear factor (NF)-kappaB, apical surface, interferon-alpha response, and KRAS signaling. Moreover, four candidate genes and their related target drugs were also identified, namely interleukin-2beta receptor (IL2RB), IL-2gamma receptor (IL2RG), Toll-like receptor 8 (TLR8), and TNF. These findings suggest that tumor-infiltrating B cells could act as a clinical factor in anti-PD-L1 immunotherapy for LUAD. PMID- 30521598 TI - Climatic factors shaping intraspecific leaf trait variation of a neotropical tree along a rainfall gradient. AB - Intraspecific trait variation has been singled out as an important mechanism by which individuals can cope with environmental variations and avoid local extinctions. Here we evaluate variation in metamer traits (i.e., traits associated with internodes, petioles and their corresponding leaves) and parameters of chlorophyll fluorescence within and among populations of a neotropical tree, Copaifera langsdorffii. We also evaluated phenotypic plasticity in natural settings comparing traits between shade and sun-exposed metamers. We selected six populations along a climatic gradient ranging from semi-arid to humid and representing three different biomes (Caatinga, Cerrado, and Atlantic Forest). Local climatic conditions significantly affected the morphological and physiological traits of populations. Trait variation among populations was explained mainly by aridity index and evapotranspiration. Individuals from drier regions had lower specific leaf area (SLA), lower investment in leaf area per total dry mass of metamer (LARm), lower specific petiole length (SPL) and lower potential quantum yield (Fv/Fm, only for sun-exposed metamers). Populations from locations with greater environmental heterogeneity (interannual variation) had greater plasticity in response to light for Fv/Fm and electron transport rate (ETR) and morphological traits related to the hydraulic and biomechanical aspects of the leaves (petiole length, internode length and SPL). High intraspecific variation in metamer traits in C. langsdorffii coupled with its ability to modify these traits in response to different climate conditions can explain the success of the species over a range of different habitats and represent important factors for the persistence of this species in the face of climate change. PMID- 30521599 TI - Global analysis of erythroid cells redox status reveals the involvement of Prdx1 and Prdx2 in the severity of beta thalassemia. AB - beta-thalassemia is a worldwide distributed monogenic red cell disorder, characterized by an absent or reduced beta globin chain synthesis. The unbalance of alpha-gamma chain and the presence of pathological free iron promote severe oxidative damage, playing crucial a role in erythrocyte hemolysis, exacerbating ineffective erythropoiesis and decreasing the lifespan of red blood cells (RBC). Catalase, glutathione peroxidase and peroxiredoxins act together to protect RBCs from hydrogen peroxide insult. Among them, peroxiredoxins stand out for their overall abundance and reactivity. In RBCs, Prdx2 is the third most abundant protein, although Prdxs 1 and 6 isoforms are also found in lower amounts. Despite the importance of these enzymes, Prdx1 and Prdx2 may have their peroxidase activity inactivated by hyperoxidation at high hydroperoxide concentrations, which also promotes the molecular chaperone activity of these proteins. Some studies have demonstrated the importance of Prdx1 and Prdx2 for the development and maintenance of erythrocytes in hemolytic anemia. Now, we performed a global analysis comparatively evaluating the expression profile of several antioxidant enzymes and their physiological reducing agents in patients with beta thalassemia intermedia (BTI) and healthy individuals. Furthermore, increased levels of ROS were observed not only in RBC, but also in neutrophils and mononuclear cells of BTI patients. The level of transcripts and the protein content of Prx1 were increased in reticulocyte and RBCs of BTI patients and the protein content was also found to be higher when compared to beta thalassemia major (BTM), suggesting that this peroxidase could cooperate with Prx2 in the removal of H2O2. Furthermore, Prdx2 production is highly increased in RBCs of BTM patients that present high amounts of hyperoxidized species. A significant increase in the content of Trx1, Srx1 and Sod1 in RBCs of BTI patients suggested protective roles for these enzymes in BTI patients. Finally, the upregulation of Nrf2 and Keap1 transcription factors found in BTI patients may be involved in the regulation of the antioxidant enzymes analyzed in this work. PMID- 30521600 TI - Evaluating risk factors of radiation pneumonitis after stereotactic body radiation therapy in lung tumor: Meta-analysis of 9 observational studies. AB - BACKGROUND: In this study, we assessed the association of SBRT (stereotactic body radiotherapy) dose and volume with radiation pneumonitis (RP) risk in lung tumor. METHODS: Relevant articles were identified up to April 2018, using following databases; Medline, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI). The pooled OR (odds ratio) with 95% CI (confidence interval) data [mean +/- SD (standard deviation)] obtained from different studies was analyzed by statistical analysis using a fixed-effects model or a random effects model when appropriate. RESULTS: The analysis was based on nine observational studies, which were identified based on the study selection criteria. Between RP and non-RP patients, no difference was observed based on age, but significant differences were observed based on planning target volume (PTV), mean ipsilateral lung dose (MLD), total MLD, and V5, V10, V20 and V40 (the percentage of lung volume exceeding 5, 10, 20 and 40 Gy). In addition, PTV >145 cm3, total MLD >=4.7 Gy, V5 >=26.8%, V10 >12% and V20 >=5.8 were associated with RP risk. Overall, the grade assessments of V5 and V20 revealed moderate quality evidence. CONCLUSION: The present study indicated V5 and V20 as major risk factors for RP after SBRT treatment in lung tumor. In addition, it was observed that lung DVH (Dose Volume Histogram) patterns should be assessed more carefully, while predicting RP incidence after SBRT. PMID- 30521601 TI - Phosphate effect on filipin production and morphological differentiation in Streptomyces filipinensis and the role of the PhoP transcription factor. AB - The biosynthesis of the antifungal filipin in Streptomyces filipinensis is very sensitive to phosphate regulation. Concentrations as low as 2.5 mM block filipin production. This effect is, at least in part, produced by repression of the transcription of most filipin biosynthetic genes. The role of the two-component PhoRP system in this process was investigated. The phoRP system of S. filipinensis was cloned and transcriptionally characterised. PhoP binds to two PHO boxes present in one of its two promoters. Filipin production was greatly increased in DeltaphoP and DeltaphoRP mutants, in agreement with a higher transcription of the fil genes, and the effect of phosphate repression on the antibiotic production of these strains was significantly reduced. No PhoP binding was observed by electrophoretic mobility gel shift assays (EMSAs) with the promoter regions of the fil gene cluster thus suggesting an indirect effect of mutations. Binding assays with cell-free extracts from the wild-type and mutant strains on fil genes promoters revealed retardation bands in the parental strain that were absent in the mutants, thus suggesting that binding of the putative transcriptional regulator or regulators controlled by PhoP was PhoP dependent. Noteworthy, PhoP or PhoRP deletion also produced a dramatic decrease in sporulation ability, thus indicating a clear relationship between the phosphate starvation response mediated by PhoP and the sporulation process in S. filipinensis. This effect was overcome upon gene complementation, but also by phosphate addition, thus suggesting that alternative pathways take control in the absence of PhoRP. PMID- 30521602 TI - The relationship between perceptions and self-paid hepatitis B vaccination: A structural equation modeling approach. AB - BACKGROUND: Malaysia has a comprehensive, publicly-funded immunization program for hepatitis B (HepB) among infants, but adults must pay for the vaccine. The number of HepB carriers among adults is expected to increase in the future; therefore, we examined the impact of five constructs (cues to action, perceived barriers, perceived benefit, perceived severity, and perceived susceptibility) on adults' willingness to pay (WTP) for HepB vaccine; secondarily, we examined the association between perceived barriers and perceived benefits. METHODS: Adults were selected through a stratified, two-stage cluster community sample in Selangor, Malaysia. The reliability, convergent validity, and discriminant validity of the measurement model were assessed before implementing a partial least squares structural equation model (PLS-SEM) to evaluate the significance of the structural paths. RESULTS: A total of 728 participants were enrolled. The five constructs all showed adequate internal reliability, convergent validity, and discriminant validity. There was a significant, positive relationship to WTP from constructs (perceived barriers [Path coefficient (beta) = 0.082, P = 0.036], perceived susceptibility [beta = 0.214, P<0.001], and cues to action [beta = 0.166, P<0.001]), and the model all together accounted for 8.8% of the variation in WTP. There was a significant, negative relationship between perceived barriers and perceived benefit [beta = -0.261, P<0.001], which accounted for 6.8% of variation in perceived benefit. CONCLUSIONS: Policy and programs should be targeted that can modify individuals' thoughts about disease risk, their obstacles in obtaining the preventive action, and their readiness to obtain a vaccine. Such programs include educational materials about disease risk and clinic visits that can pair HepB screening and vaccination. PMID- 30521603 TI - Extended cleavage specificities of mast cell proteases 1 and 2 from golden hamster: Classical chymase and an elastolytic protease comparable to rat and mouse MCP-5. AB - Serine proteases constitute the major protein content of mast cell secretory granules. Here we present the extended cleavage specificity of two such proteases from the golden hamster, Mesocricetus auratus. Analysis by phage display technique showed that one of them (HAM1) is a classical chymase with a specificity similar to the human mast cell chymase. However, in contrast to the human chymase, it does not seem to have a particular preference for any of the three aromatic amino acids, Phe, Tyr and Trp, in the P1 position of substrates. HAM1 also efficiently cleaved after Leu similarly to human and many other mast cell chymases. We observed only a 3-fold lower cleavage activity on Leu compared to substrates with P1 aromatic amino acids. Chymotryptic enzymes seem to be characteristic for connective tissue mast cells in mammalian species from opossums to humans, which indicates a very central role of these enzymes in mast cell biology. HAM1 also seems to have the strongest preference for negatively charged amino acids in the P2'position of all mast cell chymases so far characterized. The second hamster chymase, HAM2, is an elastolytic in its activity, similarly to the alpha-chymases in rats and mice (rMCP-5 and mMCP-5, respectively). The presence of an alpha-chymase that developed elastase activity thereby seems to be a relatively early modification of the alpha-chymase within the rodent branch of the mammalian evolutionary tree. PMID- 30521604 TI - Two jatropha karyotypes constructed from meiotic pachytene chromosomes: Pericentric distribution of heterochromatin and variation in repetitive DNAs. AB - Jatropha (Jatropha curcas) is an oil-bearing plant used for biodiesel production. Construction of its standard karyotype and identification of the euchromatin/heterochromatin distribution associated with gene expression and meiotic recombination are essential to fully characterize its genome. Here, we developed a J. curcas karyotype based on meiotic pachytene chromosomes. In addition, a karyotype of J. integerrima, a useful species for jatropha breeding, was also constructed. Five out of eleven J. curcas chromosomes were metacentric, but only two were metacentric in J. integerrima. Almost all of the heterochromatin was distributed around the pericentric regions. The interstitial and distal regions were euchromatic without heterochromatic knobs, except for small heterochromatin regions associated with the subtelomeric repeat sequence JcSat1. These pericentric heterochromatin distribution patterns, together with chromosome structure data and the results of FISH probing with rDNA and JcSat1, allowed us to classify all chromosomes of both species. The two species had two 35S rDNA loci and one 5S rDNA locus; one 35S rDNA locus in J. integerrima was located on the interstitial region of the short arms. In addition, JcSat1 was found at only the heterochromatic ends of the J. curcas chromosome, not the J. integerrima chromosome. Despite the same chromosome number, the two pachytene chromosome-based karyotypes suggest variation in chromosome structure and distribution of repetitive DNAs in these two species. PMID- 30521605 TI - Anthocyanins from Cornus kousa ethanolic extract attenuate obesity in association with anti-angiogenic activities in 3T3-L1 cells by down-regulating adipogeneses and lipogenesis. AB - Cornus kousa the Korean dogwood has been traditionally used in East Asia as therapeutic traditional medicine however biological activities of Cornus kousa have not been investigated previously. The aim of the present study was to evaluate anti-obesity activities coupled with anti-angiogenic activities of anthocyanins rich fraction of ethanolic leaf extract of Cornus kousa (ELECk) in HUVECs and 3T3- L1 cells. Dried plants leaves were extracted with 70% ethanol and anthocyanin fraction (AnT Fr) was obtained by eluting the ethanolic extract through non-polar macroporous resin and further purification by HPLC. Antiangiogenic activities were determined by antiproliferative effect of AnT Fr on HUVECs. In the presence of various concentrations of AnT Fr, 3T3-L1 preadipocytes were induced to differentiate. Lipid accumulation in differentiated adipocytes were quantified by Oil-Red O staining. AnT Fr significantly suppressed angiogenesis by inhibiting proliferation and tube formation of HUVECs via downregulating VEGRF 2, PI3K, beta-catenin, NF-kB, and Akt1 in a dose dependent manner. AnT Fr inhibited lipid accumulation by down-regulating adipogenesis and lipogenesis promoting signaling proteins, PPARgamma, CCAAT, C/EBPalpha, aP2, FAS, and LPL, however enhanced AMPK activation to p-AMPK in 3T3 cells quantified and expressed by western blotting. AnT Fr inhibit lipid accumulation by regulating adipogenesis and lipogenesis related genes and signaling proteins. The anti obesity activities exerted by Cornus kousa are associated with antiangiogenic activities of anthocyanins rich fraction of Cornus kousa. Hence the presence of bioactive anthocyanins, Cornus kosa, is a good candidate for nutraceutical and pharmaceutical formulation for treating or controlling obesity. PMID- 30521606 TI - Assessing the role of the T-box transcription factor Eomes in B cell differentiation during either Th1 or Th2 cell-biased responses. AB - Successful T-dependent humoral responses require the production of antibody secreting plasmablasts, as well as the formation of germinal centers which eventually form high-affinity B cell memory. The ability of B cells to differentiate into germinal center and plasma cells, as well as the ability to tailor responses to different pathogens, is driven by transcription factors. In T cells, the T-box transcription factors T-bet and Eomesodermin (Eomes) regulate effector and memory T cell differentiation, respectively. While T-bet has a critical role in regulating anti-viral B cell responses, a role for Eomes in B cells has yet to be described. We therefore investigated whether Eomes was required for B cell differentiation during either Th1 or Th2 cell-biased immune responses. Here, we demonstrate that deletion of Eomes specifically in B cells did not affect B cell differentiation in response to vaccination, as well as following viral or helminth infection. In contrast to its established role in CD8+ T cells, Eomes did not influence memory B cell differentiation. Finally, the use of an Eomes reporter mouse confirmed the lack of Eomes expression during immune responses. Thus, germinal center and plasma cell differentiation and the formation of isotype-switched memory B cells in response to infection are independent of Eomes expression. PMID- 30521607 TI - Modelling Toxoplasma gondii infection in a 3D cell culture system In Vitro: Comparison with infection in 2D cell monolayers. AB - Three-dimensional (3D) cell culture models bridge the gap between two-dimensional (2D) monolayer cultures and animal models. Physiologically relevant, 3D culture models have significantly advanced basic cell science and provide unique insights into host-pathogen interactions intrinsically linked to cell morphology. Toxoplasma gondii is an obligate intravacuolar parasite that chronically infects a large portion of the global human population. Our current understanding of Toxoplasma infection is largely based on 2D cell cultures, in which mammalian cells are grown on flat surfaces. However, 2D cell cultures may not recapitulate key conditions of in vivo infections as they introduce artificial pressures and tensions, which may subsequently alter infectious processes that are dependent on spatiality, e.g., invasion, replication and egress. In this study, we adapted a collagen-based 3D cell culture system to reproduce the 3D environment of T. gondii natural infections for investigation of the replication and egress of the parasite from the parasitophorous vacuole. Suspended in the 3D matrix, Toxoplasma infected VERO cells have round morphology, as opposed to infected VERO cells in 2D monolayers. The doubling time of Toxoplasma in VERO cells within the matrix is comparable to that of parasites cultivated in VERO cell monolayers. In the absence of the pressure of flattened host cells grown in 2D cultures, the parasitophorous vacuole of T. gondii has a globular shape, with intravacuolar parasites distributed radially, forming 3D spherical 'rosette' structures. Parasites egress radially away from the ruptured host cell in 3D matrices, in contrast to Toxoplasma cultivated in 2D monolayer cultures, where the parasites escape perpendicularly from the flat surface below the host cells. These observations demonstrate the utility of collagen matrices for studying parasite modes of infection as these 3D assays more closely mimic in vivo conditions. PMID- 30521608 TI - CRISPR/Cas9 mediated knockout of the abdominal-A homeotic gene in fall armyworm moth (Spodoptera frugiperda). AB - The fall armyworm (FAW), Spodoptera frugiperda (J.E. Smith), is an important pest of maize in the Americas and has recently been introduced into Africa. Fall armyworm populations have developed resistance to control strategies that depend on insecticides and transgenic plants expressing Bacillus thuringiensis toxins. The study of various resistance mechanisms at the molecular level and the development novel control strategies have been hampered by a lack of functional genomic tools such as gene editing in this pest. In the current study, we explored the possibility of using the CRISPR/Cas9 system to modify the genome of FAW. We first identified and characterized the abdominal-A (Sfabd-A) gene of FAW. Sfabd-A single guide RNA (sgRNA) and Cas9 protein were then injected into 244 embryos of FAW. Sixty-two embryos injected with Sfabd-A sgRNA hatched. Of these hatched embryos, twelve developed into larvae that displayed typical aba-A mutant phenotypes such as fused segments. Of the twelve mutant larvae, three and five eventually developed into female and male moths, respectively. Most mutant moths were sterile, and one female produced a few unviable eggs when it was outcrossed to a wild-type male. Genotyping of 20 unhatched Sfabd-A sgRNA-injected embryos and 42 moths that developed from Sfabd-A sgRNA-injected embryos showed that 100% of the unhatched embryos and 50% of the moths contained indel mutations at the Sfabd-A genomic locus near the guide RNA target site. These results suggest that the CRISPR/Cas9 system is highly efficient in editing FAW genome. Importantly, this gene editing technology can be used to validate gene function to facilitate an understanding of the resistance mechanism and lead to the development of novel pest management approaches. PMID- 30521609 TI - Porcine circovirus 2 (PCV-2) genotype update and proposal of a new genotyping methodology. AB - Porcine circovirus 2 (PCV-2) is one of the most widespread viral infections of swine, causing a remarkable economic impact because of direct losses and indirect costs for its control. As other ssDNA viruses, PCV-2 is characterized by a high evolutionary rate, leading to the emergence of a plethora of variants with different biological and epidemiological features. Over time, several attempts have been made to organize PCV-2 genetic heterogeneity in recognized genotypes. This categorization has clearly simplified the epidemiological investigations, allowing to identify different spatial and temporal patterns among genotypes. Additionally, variable virulence and vaccine effectiveness have also been hypothesized. However, the rapid increase in sequencing activity, coupled with the per se high viral variability, has challenged the previously established nomenclature, leading to the definition of several study-specific genotypes and hindering the capability of performing comparable epidemiological studies. Based on these premises, an updated classification scheme is herein reported. Recognizing the impossibility of defining a clear inter-cluster p-distance cut off, the present study proposes a phylogeny-grounded genotype definition based on three criteria: maximum intra-genotype p-distance of 13% (calculated on the ORF2 gene), bootstrap support at the corresponding internal node higher than 70% and at least 15 available sequences. This scheme allowed defining 8 genotypes (PCV-2a to PCV-2h), which six of those had been previously proposed. To minimize the inconvenience of implementing a new classification, the most common names already adopted have been maintained when possible. The analysis of sequence-associated metadata highlighted a highly unbalanced sequencing activity in terms of geographical, host and temporal distribution. The PCV-2 molecular epidemiology scenario appears therefore characterized by a severe bias that could lead to spurious associations between genetic and epidemiological/biological viral features. While the suggested classification can establish a "common language" for future studies, further efforts should be paid to achieve a more homogeneous and informative representation of the PCV-2 global scenario. PMID- 30521610 TI - Comparison of brain magnetic resonance imaging between myotonic dystrophy type 1 and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. AB - BACKGROUND: Anterior temporal lobe hyperintensities detected by brain MRI are a recognized imaging hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Because similar findings may be present in patients with myotonic dystrophy type 1 (DM1), the brain MRI in these two diseases is often misinterpreted. We compared the MRI findings between the two entities to examine whether they display distinctive characteristics. METHODS: This retrospective, cross-sectional study reviewed medical records of patients with DM1 or CADASIL admitted to Asan Medical Center between September 1999 and September 2017. We compared the frequency and grades of white matter changes in specific spatial regions between the groups according to age-related white matter change scores. We also evaluated the presence of cerebral microbleeds. RESULTS: A total of 29 patients with DM1 and 68 with CADASIL who had undergone MRI were included in the analysis. The overall prevalence of white matter hyperintensities was 20 (69%) and 66 (97%) in DM1 and CADASIL, respectively (p < 0.001), whereas the frequency of anterior temporal lobe hyperintensities was comparable between the groups (10 [34.5%] in DM1 vs. 35 [51.5%] in CADASIL, p = 0.125). The brain MRI of patients with DM1 revealed more limited involvement of the frontal, parieto-occipital, external capsule and basal ganglia regions compared with imaging in patients with CADASIL. Cerebral microbleeds were not observed in any case of DM1 but were present in 31 of 45 (68.9%) cases of CADASIL. CONCLUSIONS: Anterior temporal lobe involvement in DM1 is not infrequent compared with CADASIL. However, because brain MRI in patients with DM1 lacks other distinctive features seen in CADASIL, imaging might assist in differentiating these two conditions. PMID- 30521611 TI - Spectral clustering with distinction and consensus learning on multiple views data. AB - Since multi-view data are available in many real-world clustering problems, multi view clustering has received considerable attention in recent years. Most existing multi-view clustering methods learn consensus clustering results but do not make full use of the distinct knowledge in each view so that they cannot well guarantee the complementarity across different views. In this paper, we propose a Distinction based Consensus Spectral Clustering (DCSC), which not only learns a consensus result of clustering, but also explicitly captures the distinct variance of each view. It is by using the distinct variance of each view that DCSC can learn a clearer consensus clustering result. In order to optimize the introduced optimization problem effectively, we develop a block coordinate descent algorithm which is theoretically guaranteed to converge. Experimental results on real-world data sets demonstrate the effectiveness of our method. PMID- 30521612 TI - Accuracy of Calcium Scoring calculated from contrast-enhanced Coronary Computed Tomography Angiography using a dual-layer spectral CT: A comparison of Calcium Scoring from real and virtual non-contrast data. AB - PURPOSE: Modern non-invasive evaluation of Coronary Artery Disease (CAD) requires non-contrast low dose Computed Tomography (CT) imaging for determination of Calcium Scoring (CACS) and contrast-enhanced imaging for evaluation of vascular stenosis. Several methods for calculation of CACS from contrast-enhanced images have been proposed before. The main principle for that is generation of virtual non-contrast images by iodine subtraction from a contrast-enhanced spectral CT dataset. However, those techniques have some limitations: Dual-Source CT imaging can lead to increased radiation exposure, and switching of the tube voltage (rapid kVp switching) can be associated with slower rotation speed of the gantry and is thus prone to motion artefacts that are especially critical in cardiac imaging. Both techniques cannot simultaneously acquire spectral data. A novel technique to overcome these difficulties is spectral imaging with a dual-layer detector. After absorption of the lower energetic photons in the first layer, the second layer detects a hardened spectrum of the emitted radiation resulting in registration of two different energy spectra at the same time. The objective of the present investigation was to evaluate the accuracy of virtual non-contrast CACS computed from spectral data in comparison to standard non-contrast imaging. METHODS: We consecutively investigated 20 patients referred to Coronary Computed Tomography Angiography (CCTA) with suspicion of CAD using a Dual-Layer spectral CT system (IQon; Philips Healthcare, The Netherlands). CACS was calculated from both, real- and virtual non-contrast images by certified software for medical use. Correlation analyses for real- and virtual non-contrast images and agreement evaluation with Bland-Altman-Plots were performed. RESULTS: Mean patient age was 57.7 +/- 14 years (n = 20). 13 patients (65%) were male. Inter-quartile-range of clinical CACS was 0-448, the mean was 334. Correlation of CACS from real- and virtual non-contrast images was very high (0.94); p < 0.0001. The slope was 2.3 indicating that values from virtual non-contrast images are approximately half of the results obtained from real non-contrast data. Visual analysis of Bland-Altman Plot shows good accordance of both methods when results from virtual non-contrast data are multiplied by the slope of the logistic regression model (2.3). The acquired power of this results is 0.99. CONCLUSION: Determination of Calcium Score from contrast enhanced CCTA using spectral imaging with a dual-layer detector is feasible and shows good agreement with the conventional technique when a proportionality factor is applied. The observed difference between both methods is due to an underestimation of plaque volume, and-to an even greater extend -an underestimation of plaque density with the virtual non-contrast approach. Our data suggest that radiation exposure can be reduced through omitting additional native scans for patients referred to CCTA when using a dual layer spectral system without the usual limitations of dual energy analysis. PMID- 30521613 TI - A novel approach to stabilize fetal cell-free DNA fraction in maternal blood samples for extended period of time. AB - This study was undertaken to evaluate a novel method for stabilizing and preserving the original proportion of cell-free fetal DNA (cffDNA) in maternal blood for extended periods of time without using crosslinking agents, such as formaldehyde, which compromise DNA integrity and extraction efficiency. Blood was drawn from pregnant donors into K3EDTA and Blood Exo DNA ProTeck(r) (ProTeck) tubes. Blood drawn into both tubes were aliquoted and stored at three different temperatures. At indicated times sample aliquots were processed for cell-free DNA (cfDNA) extraction. Plasma cfDNA and cffDNA quantified by droplet digital PCR (ddPCR) assay which amplify RASSF1A gene promoter region. ProTeck reagent is formaldehyde free and inhibits blood cell metabolism in blood samples during storage. Cell-free DNA concentration increased over time in blood plasma stored in K3EDTA tubes at 4, 22 and 30 degrees C. Blood stored in ProTeck tubes, cfDNA concentration was stable at 4, 22 and 30 degrees C for 21, 28 and 7 days, respectively. In K3EDTA tubes cffDNA proportion decreases steadily over time whereas in ProTeck tubes cffDNA proportion remained stable. This novel technology stabilizes cffDNA proportion in maternal blood samples at 4, 22 and 30 degrees C for 21, 28 and 7 days, respectively. PMID- 30521614 TI - The relationship between iron deficiency anemia and sexual function and satisfaction among reproductive-aged Iranian women. AB - Iron deficiency anemia (IDA) is a common micronutrient deficiency worldwide, and an important health problem especially in women of reproductive age. This study aimed to determine the relationship between IDA and sexual satisfaction and function among reproductive-aged Iranian women. In this study, 129 women (52 with IDA and 77 non-IDA) with age 18-45 in Mahshahr, Iran were recruited. Data was gathered by a demographic questionnaire, Female Sexual Function Index (FSFI) and Larson Sexual Satisfaction Questionnaire. Data were analyzed using an independent t-test, Mann-Whitney test, Chi-square, and correlation coefficient test. The results of this study showed that the means of hemoglobin (Hb), hematocrit (HCT), serum iron and ferritin were significantly lower in the IDA group than those in the non-IDA group (p<0.01). All dimensions of sexual function and satisfaction were significantly lower in women with IDA compared to the healthy women (p<0.001). Also, all blood indices for IDA had a significant relationship with all sexual function components and sexual satisfaction (p = 0.01) except for pain with Hb and ferritin. Health care providers should provide screening, education, and counseling about anemia and sexual function in reproductive age women. PMID- 30521615 TI - Identification of factors during bronchoscopy that affect patient reluctance to undergo repeat examination: Questionnaire analysis after initial bronchoscopy. AB - BACKGROUND: Re-biopsy by bronchoscopy is an important part of treatment for patients with relapsed lung cancer; however, some patients refuse to undergo a re examination due to discomfort during their first bronchoscopy. The aim of the present study was to determine factors causing discomfort during bronchoscopy and to identify the factors that affect patients' reluctance to undergo repeat examinations via a questionnaire administered immediately after the initial bronchoscopy. METHODS AND FINDINGS: We evaluated 283 patients who underwent bronchoscopy at Chiba University Hospital between September 2015 and March 2017. Following bronchoscopy, the patients answered a questionnaire regarding the procedure. We identified patient characteristics and factors related to bronchoscopy that were associated with patients' reluctance to undergo re examination. Two hundred nine patients were ultimately enrolled in the study. The factors affecting patient tolerance for re-examination were female sex (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.43-5.53), discomfort during the examination (OR, 1.70; 95% CI, 1.13-2.56), and unexpectedness of discomfort during the examination (OR, 1.83; 95% CI, 1.19-2.81). Patients experienced discomfort most frequently owing to throat anesthesia (n = 50 [24%]). CONCLUSIONS: Comfort during bronchoscopy is an important factor influencing patient tolerance for re-examination. Expectations of discomfort during bronchoscopy, as indicated by instructions provided before examination, and throat anesthesia are also important factors. Detailed explanations about bronchoscopy and improvement of the methods of throat anesthesia could decrease patient discomfort and may help decrease patients' reluctance to undergo re examinations. PMID- 30521616 TI - Chinese adolescents' power distance value and prosocial behavior toward powerful people: A longitudinal study. AB - We were interested in how specific cultural value and adolescent social behavior would influence each other over time. Thus the present study explored the longitudinal and bidirectional relations between adolescents' power distance value and prosocial behavior toward powerful people over a year. A sample of 434 Chinese adolescents participated in the investigation (initial mean age = 11.27; 54.15% females). The results based on cross-lagged models showed that, earlier prosocial behavior toward powerful people was positively correlated to subsequent power distance value, but not vice versa. The findings point toward an understanding of the important role of adolescent social behavior on his/her cultural value development, and also shed light on future research in terms of the interplay between cultural values and individual's social behaviors in other cultures. PMID- 30521617 TI - Stepping into a dangerous quagmire: Macroecological determinants of Bothrops envenomings, Brazilian Amazon. AB - Despite significant and successful efforts in Brazil regarding snakebites in the areas of research, antivenom manufacture and quality control, training of health professionals in the diagnosis and clinical management of bites, little is known about determinants of snakebites incidence in order to further plan interventions to reduce the impact of this medical condition. Understanding the complexity of ecological interactions in a geographical region is important for prediction, prevention and control measures of snakebites. This investigation aims to describe spatial distribution and identify environmental determinants of human envenoming by lancehead pit vipers (Bothrops genus), in the Brazilian Amazon. Aggregated data by the municipality was used to analyze the spatial distribution of Bothrops bites cases and its relationship with geographic and environmental factors. Eight geo-environmental factors were included in the analysis as independent variables: (1) tree canopy loss increase; (2) area with vegetation cover; (3) area covered by water bodies; (4) altitude; (5) precipitation; (6) air relative humidity; (7) soil moisture; and (8) air temperature. Human envenoming by lancehead pit vipers (Bothrops genus) in the Amazon region is more incident in lowlands [Adjusted regression coefficient [ARC] -0.0007 (IC95%: -0.001; -0.0006), p<0.0001], with high preserved original vegetation cover [ARC 0.0065 (IC95%: 0.0071; 0.0060), p<0.0001], with heaviest rainfall [ARC 0.0001 (IC95%: 0.00009; 0.0001), p<0.0001] and higher air relative humidity [ARC 0.0082 (IC95%: 0.0108; 0.0056), p<0.0001]. This association is interpreted as the result of the higher prey availability and further abundance of pit vipers in such landscapes. PMID- 30521618 TI - Sex differences in intrusive memories following trauma. AB - BACKGROUND: A key mechanism thought to underlie Posttraumatic Stress Disorder (PTSD) is enhanced emotional memory consolidation. Recent evidence in healthy controls revealed that women have greater negative memory consolidation following stress relative to men. This study examined emotional memory consolidation in women and men with PTSD, and in trauma-exposed and non-trauma controls to test the hypothesis that emotionally negative memory consolidation would be greater in women with PTSD. METHOD: One hundred and forty-seven men and women (47 with PTSD, 49 trauma-exposed controls, and 51 non-trauma controls) completed an emotional memory task where they looked at negative, neutral and positive images from the International Affective Picture System (IAPS). Delayed recall and an intrusive memory diary were completed two days later. RESULTS: Women displayed greater recall, and reported more negative intrusive memories than men. A gender x group interaction effect showed that both women with PTSD and trauma-exposed women reported more intrusive memories than women without trauma exposure or men. CONCLUSION: This study provided preliminary evidence of sex differences in intrusive memories in those with PTSD as well as those with a history of trauma exposure. Future research should include measures of sex hormones to further examine sex differences on memory consolidation in the context of trauma exposure and PTSD. PMID- 30521619 TI - Estimating lake ice thickness in Central Ontario. AB - Lakes are a key geographical feature in Canada and have an impact on the regional climate. In the winter, they are important for recreational activities such as snowmobiling and ice fishing and act as part of an important supply route for northern communities. The ability to accurately report lake ice characteristics such as thickness is vital, however, it is underreported in Canada and there is a lack of lake ice thickness records for temperate latitude areas such as Central Ontario. Here, we evaluate the application of previously developed temperature models and RADARSAT-2 for estimating lake ice thickness in Central Ontario and provide insight into the regions long term ice thickness variability. The ALS Environmental Science Shallow Water Ice Profiler (SWIP) was used for validation of both temperature and radar-based models. Results indicate that the traditional approach that uses temperatures to predict ice thickness during ice growth has low RMSE values of 2.3 cm and correlations of greater than 0.9. For ice decay, similar low RMSE values of 2.1 cm and high correlations of 0.97 were found. Using RADARSAT-2 to estimate ice thickness results in R2 values of 0.6 (p < 0.01) but high RMSE values of 11.7 cm. Uncertainty in the RADARSAT-2 approach may be linked to unexplored questions about scattering mechanisms and the interaction of radar signal with mid-latitude lake ice. The application of optimized temperature models to a long-term temperature record revealed a thinning of ice cover by 0.81 cm per decade. PMID- 30521620 TI - Prevalence of functional constipation among Palestinian preschool children and the relation to stressful life events. AB - AIM: Increasing evidence exists with respect to the relation between stressful life events and functional constipation (FC). We aimed to investigate the prevalence of FC in Palestinian refugee preschool children and to determine if stress and trauma exposure are risk factors of FC in these children. METHODS: From November 2013 until May 2014, a cross-sectional survey was conducted in West Bank, Gaza and Jordan. Mothers of 862 Palestinian refugee children aged 7-48 months were interviewed on defecation pattern, socio-economic factors and the child's exposure to traumatic events. RESULTS: Twelve percent of the Palestinian refugee children fulfilled the criteria for FC. The prevalence of constipation was significantly lower in Gaza compared to Jordan (2% vs. 17%, p <0,001). Living in Gaza was associated with lower odds of FC (OR 0,08, 95% CI 0,03-0,20). Trauma exposure was associated with higher odds of FC (OR 1,19, 95% CI 1,06-1,35), however only a small number of children had been exposed to traumatic events. CONCLUSION: The overall prevalence of FC in Palestinian preschool children is comparable to prevalence rates among older children worldwide. In this age group stressful life events and trauma exposure seem not to play an important role in the development of FC. PMID- 30521621 TI - Comparison of GnRH agonist and hCG for priming in vitro maturation cycles in cancer patients undergoing urgent fertility preservation. AB - In vitro maturation (IVM) of oocytes retrieved at germinal vesicle or Metaphase I stage, followed by vitrification of Metaphase II (MII) oocytes, has recently emerged as an option for urgent fertility preservation (FP). Priming is usually achieved with an injection of hCG, 10,000 IU, 36 hours before retrieval. This study aimed to assess a new method of priming, using GnRH agonists, and compare it to hCG, in cancer patients undergoing urgent FP. From 2009 to 2015, 373 cancer patients underwent MII oocyte cryopreservation after IVM cycles primed either with GnRHa (triptorelin 0.2 mg) (n = 138) or hCG (10,000 IU) (n = 235). Patients' characteristics were comparable between the two groups. The number of COC retrieved was significantly higher in the GnRHa group (9.1 +/- 6.8 versus 7.7 +/- 5.5 oocytes, p = 0.04). However, the maturation rates (59 +/-25% versus 64 +/ 26%, p = 0.07, respectively), and the total number of MII oocytes frozen (5.2 +/ 4.2 versus 4.9 +/-4.0, p = 0.6, respectively) were similar between the GnRha and hCG groups. We did not find any difference between GnRHa and hCG priming for IVM. GnRHa priming is more physiological since it stimulates endogenous FSH and LH activity, and is well suited for FP in hormone-sensitive cancers and urgent cases. PMID- 30521622 TI - The genetic diversity and relationships of cauliflower (Brassica oleracea var. botrytis) inbred lines assessed by using SSR markers. AB - Inbred lines are important germplasm in cauliflower breeding programs. To understand the genetic diversity and relationships of cauliflower inbred lines, the use of simple sequence repeat (SSR) markers will be of great value for parental line selection and breeding strategy design. In this study, the genetic diversity and relationships of 165 cauliflower inbred lines primarily derived from southeast China were assessed using SSR markers. Forty-three SSR markers were polymorphic across these inbred lines and generated a total of 111 alleles. The mean values of the number of alleles (Na), effective number of alleles (Ne), Shannon's Information index (I), and polymorphism information content (PIC) per locus were 2.581, 1.599, 0.517 and 0.316, respectively. Genetic distance values among all pairs of the inbred lines varied from 0 to 0.67 with an average of 0.30. On the basis of genetic distance data estimated with the SSR markers, the 165 cauliflower inbred lines were classified into four main clusters (from group I to group IV) by cluster analysis and four subpopulations (from POP 1 to POP 4) by structure analysis. The classification patterns of most cauliflower inbred lines were not consistent with their curd maturity, curd solidity or geographic origins. These results based on estimates by the SSR markers, suggested the genetic diversity of the 165 cauliflower inbred lines was relatively narrow. Therefore, pyramiding the valuable genes among different types of the cauliflower inbred lines is important to increase the genetic diversity to obtain desirable hybridization combinations. The information generated in this report will be useful for assessing germplasm and breeding in cauliflower. PMID- 30521623 TI - Acquisition and transfer of antibiotic resistance genes in association with conjugative plasmid or class 1 integrons of Acinetobacter baumannii. AB - Conjugation is a type of horizontal gene transfer (HGT) that serves as the primary mechanism responsible for accelerating the spread of antibiotic resistance genes in Gram-negative bacteria. The present study aimed to elucidate the mechanisms underlying the conjugation-mediated gene transfer from the extensively drug-resistant Acinetobacter baumannii (XDR-AB) and New Delhi Metallo beta-lactamase-1-producing Acinetobacter baumannii (NDM-AB) to environmental isolates of Acinetobacter spp. Conjugation experiments demonstrated that resistance to ticarcillin and kanamycin could be transferred from four donors to two sodium azide-resistant A. baumannii strains, namely, NU013R and NU015R. No transconjugants were detected on Mueller-Hinton Agar (MHA) plates containing tetracycline. Plasmids obtained from donors as well as successful transconjugants were characterized by PCR-based replicon typing and S1-nuclease pulsed-field gel electrophoresis (S1-PFGE). Detection of antibiotic resistance genes and integrase genes (int) was performed using PCR. Results revealed that the donor AB364 strain can transfer the blaOXA-23 and blaPER-1 genes to both recipients in association with int1. A 240-kb plasmid was successfully transferred from the donor AB364 to recipients. In addition, the aphA6 and blaPER-1 genes were co-transferred with the int1 gene from the donor strains AB352 and AB405. The transfer of a 220-kb plasmid from the donors to recipient was detected. The GR6 plasmid containing the kanamycin resistance gene (aphA6) was successfully transferred from the donor strain AB140 to both recipient strains. However, the blaNDM-1 and tet(B) genes were not detected in all transconjugants. Our study is the first to demonstrate successful in vitro conjugation, which indicated that XDR-AB contained combination mechanisms of the co-transfer of antimicrobial resistance elements with integron cassettes or with the plasmid group GR6. Thus, conjugation could be responsible for the emergence of new types of antibiotic-resistant strains. PMID- 30521624 TI - Transgenerational effects in asexually reproduced offspring of Populus. AB - The response of trees to a changing climate can be affected by transgenerational phenotypic plasticity, i.e. phenotypic variation that is conserved and transferred to the offspring. Transgenerational plasticity that is influenced by epigenetics (heritable changes in gene function that do not result from changes in DNA sequence) during both sexual and asexual reproduction are of major relevance for adaptation of plants to climate change. To understand the transgenerational effects on the responses of vegetatively propagated poplar (Populus deltoides and P. trichocarpa) ramets (cuttings) to a changing environment, we tested whether the temperature and photoperiod experienced by the mother trees (genets) persistently affects the phenology of the cuttings grown in a common environment. We weekly monitored the bud phenology of the cuttings collected from the parent trees that have been growing across Europe along a >2100 km latitudinal gradient for at least 18 years. In addition, we asked whether there was variation in DNA methylation as measured by Methylation Sensitive Amplified Fragment Length Polymorphism (MSAPs) in the clones due to the different environmental conditions experienced by the parent trees. Our results indicate a transgenerational effect on bud phenology in the asexually reproduced offspring (vegetative cuttings). The temperatures experienced by the parent tree clones (from different geographic regions) altered the bud flush of the cuttings in the common garden. However, no significant epigenetic variation was detected in the cuttings of the parent trees within single genotypes growing under different climates. In sum, our results show that trees have the potential to respond to rapid climate change but the mechanism behind these changes needs to be further investigated by more powerful molecular methods like whole-genome bisulphite sequencing techniques. PMID- 30521626 TI - The self-care dilemma of type 2 diabetic patients: The mechanism of self regulation resource depletion. AB - Self-care is important for type 2 diabetes mellitus (T2DM) patients' disease prognosis, but there is a common phenomenon of self-regulation failure in T2DMs. In order to figure this problem out, the current study explored the interaction between self-regulation resource depletion and diabetes self-care based on the limited resource model of self-regulation. 104 patients were surveyed using the Self-Regulatory Fatigue Scale (SRF-S) and the Diabetes Self-care Scale (DSCS) in study 1. Study 2 recruited 30 T2DM patients and 30 healthy controls, and used a sequential-task paradigm to test the effect of self-regulation resource depletion on them. Participants in study 3 were 60 T2DM patients under different levels of self-regulation resource depletion manipulation, and their self-regulation performance was recorded and compared. Study 1 indicated that the correlation between self-regulation resource depletion and exercise and diet was significant and negative, suggesting that patients with greater self-regulation resource depletion performed poorly in exercise and diet. In Study 2, T2DM patients exhibited a poorer performance on the Spatial Incompatibility Task than the participants in the control group, suggesting that their self-regulation resource was insufficient. Study 3 indicated that there was no difference in Spatial Incompatibility Task performance, reaction time or error number among patients who were requested to complete a dietary record for one week and patients who were only requested to record eating times. This research demonstrated that low levels of diabetes self-care execution was associated with patients' deficiency in self-regulatory resource, and self-care as a series of goal-directed behaviors consumed patients' self-regulatory resources before these behaviors became a habit. PMID- 30521625 TI - Lack of NWC protein (c11orf74 homolog) in murine spermatogenesis results in reduced sperm competitiveness and impaired ability to fertilize egg cells in vitro. AB - NWC is an uncharacterised protein containing three strongly conserved domains not found in any other known protein. Previously, we reported that the NWC protein is detected in cells in the germinal layer in murine testes (strain: C57BL/6), and its knockout results in no obvious phenotype. We determined the NWC expression pattern during spermatogenesis, and found this protein in spermatocytes and round spermatids, but not in epididymal sperm. Although NWC knockout males are fertile, we further characterised their reproductive potential employing non-standard mating that better simulates the natural conditions by including sperm competition. Such an approach revealed that the sperm of knockout males fail to successfully compete with control sperm. After analysing selected characteristics of the male reproductive system, we found that NWC knockout sperm had a reduced ability to fertilize cumulus-intact eggs during IVF. This is the first report describing a subtle phenotype of NWC knockout mice that could be detected under non-standard mating conditions. Our results indicate that NWC plays an important role in spermatogenesis and its deficiency results in the production of functionally impaired sperm. PMID- 30521627 TI - An association between multiculturalism and psychological distress. AB - Amidst increasing focus on rising rates of substance abuse and suicide among white Americans and extending prior research on intergroup attitudes and health, this study examines a novel factor associated with psychological distress: disagreement with multiculturalism. Using the Portraits of American Life Study (N = 2,292), logistic regressions indicate that for Whites and Hispanics, increased likelihood of psychological distress (depression, hopelessness and worthlessness) is associated with stronger disagreement with multiculturalism, measured as "If we want to create a society where people get along, we must recognize that each ethnic group has the right to maintain its own unique traditions." For Blacks, however, attitudes toward multiculturalism are not associated with psychological distress. Future research might determine if these results can be replicated, and if so, identify the causal mechanism(s) at work. PMID- 30521628 TI - Correction: The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow. AB - [This corrects the article DOI: 10.1371/journal.pone.0190525.]. PMID- 30521630 TI - Staphylococcus aureus from ocular and otolaryngology infections are frequently resistant to clinically important antibiotics and are associated with lineages of community and hospital origins. AB - Staphylococcus aureus is an important human pathogen that causes serious antibiotic-resistant infections. Its population structure is marked by the appearance and dissemination of successful lineages across different settings. To begin understanding the population structure of S. aureus causing ocular and otolaryngology infections, we characterized 262 isolates by antimicrobial sensitivity testing and multilocus sequence typing (MLST). Methicillin-resistant S. aureus were subjected to SCCmec typing and Panton-Valentine leukocidin (PVL) screening. Although we detected a high level of genetic diversity among methicillin-sensitive (MSSA) isolates, (63 sequence types-STs), the population was dominated by five lineages: ST30, ST5, ST8, ST15 and ST97. Resistance to penicillin, erythromycin and clindamycin was common among the major MSSA lineages, with fluctuations markedly impacted by genetic background. Isolates belonging to the predominant lineage, ST30, displayed high rates of resistance to penicillin (100%), erythromycin (71%), and clindamycin (63%). Overall, 21% of the isolates were methicillin-resistant (MRSA), with an apparent enrichment among otitis and orbital cellulitis isolates (>40%). MRSA isolates belonged to 14 STs grouped in 5 clonal complexes (CC), however, CC5 (56.1%) and CC8 (38.6%) dominated the population. Most CC5 strains were SCCmec type II, and resembled the hospital-adapted USA100 clone. CC8 strains were SCCmec type IV, and 86% were positive for the PVL toxin, common features of the community-acquired clone USA300. CC5 strains harboring a SCCmec type IV, typical for the USA800 clone, comprised 15.5% of the population. USA100 strains were highly resistant to clindamycin, erythromycin and levofloxacin (100%), while USA300 strains were frequently resistant to erythromycin (89%) but displayed lower rates of resistance to levofloxacin (39%) and clindamycin (17%). Our data demonstrate that the ocular and otolaryngology S. aureus populations are composed of strains that are commonly resistant to clinically relevant antibiotics, and are associated with the major epidemic clonal complexes of both community and hospital origins. PMID- 30521629 TI - CCR5 structural plasticity shapes HIV-1 phenotypic properties. AB - CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs. PMID- 30521631 TI - Association of colorectal polyps and cancer with low-dose persistent organic pollutants: A case-control study. AB - BACKGROUND: Low-dose persistent organic pollutants (POPs) have recently been linked to immunosenescence, a key mechanism in carcinogenesis, as well as many aging-related chronic diseases. Since feces are the main excretion route of POPs, the large intestine is a potential target organ for these pollutants. We performed a case-control study to evaluate whether exposure to low-dose POPs is related to the risk of colorectal polyps and cancer. METHODS: A total of 277 participants were recruited from one hospital: 99 cancer patients, 102 polyp patients, and 76 control subjects. As typical examples of POPs, we measured the serum concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). RESULTS: Across the tertiles of the summary measure of POPs, the adjusted odds ratios (ORs) of colorectal polyps and cancer were 2.8 (1.2-6.8) (Ptrend = 0.01) and 3.0 (1.0-8.8) (Ptrend = 0.02), respectively, for subjects in the highest tertile. When OCPs and PCBs were analyzed separately, OCPs were linked to an increased risk of both polyps and cancer; the adjusted ORs were 2.3 (0.9-5.7) (Ptrend = 0.05) for polyps and 3.6 (1.1-11.8) (Ptrend< 0.01) for cancer. However, PCBs were only significantly associated with a high risk of polyps but not cancer; the adjusted OR was 2.8 (1.2-6.6) (Ptrend = 0.01). CONCLUSION: Chronic exposure to low-dose POPs may be associated with an increased risk of colorectal polyps and cancer. Our findings suggest the carcinogenic potential of strong lipophilic chemical mixtures such as POPs which are accumulated in adipose tissue, released to circulation, and eliminated through feces. PMID- 30521632 TI - Agentic appeals increase charitable giving in an affluent sample of donors. AB - Recent research suggests that affluent individuals adopt agentic self-concepts, striving to stand out from others and to master the environment on their own. The present study provides a road test of this idea, showing that this theorizing can be utilized to increase charitable giving among the affluent, when individuals do not realize that their behavior is being studied. In a naturalistic field experiment conducted as part of an annual fundraising campaign (N = 12,316), we randomly assigned individuals from an affluent sample to view messages focused on agency (vs. communion). Messages that focused on personal agency (vs. communion) increased the total amount of money that individuals in the sample donated by approximately 82%. These findings provide evidence for a simple, theoretically grounded method of encouraging donations among those with the greatest capacity to give. PMID- 30521633 TI - Feasibility of the annulus fibrosus repair with in situ gelating hydrogels - A biomechanical study. AB - The surgical standard of care for lumbar discectomy leaves the annulus fibrosus (AF) defect unrepaired, despite considerable risk for a recurrent herniation. Identification of a viable defect repair strategy has until now been elusive. The scope of this ex vivo biomechanical study was to evaluate crosslinking hydrogels as potentially promising AF defect sealants, and provide a baseline for their use in combination with collagen scaffolds that restore disc volume. This study directly compared genipin crosslinked fibrin hydrogel (FibGen) as a promising preclinical candidate against a clinically available adhesive composed of glutaraldehyde and albumin (BioGlue). Forty-two bovine coccygeal functional spine units (FSU) were randomly allocated into four groups, namely untreated (control, n = 12), repaired with either one of the tested hydrogels (BioGlue, n = 12; FibGen, n = 12), or FibGen used in combination with a collagen hydrogel scaffold (FibGen+Scaffold, n = 6). All specimens underwent a moderate mechanical testing protocol in intact, injured and repaired states. After completion of the moderate testing protocol, the samples underwent a ramp-to-failure test. Lumbar discectomy destabilized the FSU as quantified by increased torsional range of motion (28.0 degrees (19.1, 45.1) vs. 41.39 degrees (27.3, 84.9), p<0.001), torsional neutral zone (3.1 degrees (1.2, 7.7) vs. 4.8 degrees (2.1, 12.1), Z = -3.49, p < 0.001), hysteresis(24.4 J (12.8, 76.0) vs. 27.6 J (16.4, 54.4), Z = -2.61, p = 0.009), with loss of both disc height (7.0 mm (5.0, 10.5) vs 6.1 mm (4.0, 9.3), Z = -5.16, p < 0.001) and torsional stiffness (0.76 Nmdeg-1 (0.38, 1.07) vs. 0.66 Nmdeg-1 (0.38, 0.97), Z = -3.98, p < 0.001). Most FibGen repaired AF endured the entire testing procedure whereas only a minority of BioGlue repaired AF and all FibGen+Scaffold repaired AF failed (6/10 vs. 3/12 vs. 0/6 respectively, p = 0.041). Both BioGlue and FibGen+Scaffold repaired AF partially restored disc height (0.47 mm (0.07, 2.41), p = 0.048 and 1.52 mm (0.41, 2.57), p = 0.021 respectively) compared to sham treatment (0.08 mm (-0.63, 0.88)) whereas FibGen only repaired AF had no such effect (0.04 mm (-0.73, 1.13), U = 48.0, p = 1). The AF injury model demonstrated considerable change of FSU mechanics that could be partially restored by use of an AF sealant. While inclusion of a volumetric collagen scaffold led to repair failure, use of FibGen alone demonstrated clinically relevant promise for prevention of mechanical reherniation, outperforming an FDA approved sealant in this ex vivo test series. PMID- 30521634 TI - Optimizing beat synchronized running to music. AB - The use of music and specifically tempo-matched music has been shown to affect running performance. But can we maximize the synchronization of movements to music and does maximum synchronization influence kinematics and motivation? In this study, we explore the effect of different types of music-to-movement alignment strategies on phase coherence, cadence and motivation. These strategies were compared to a control condition where the music tempo was deliberately not aligned to the running cadence. Results show that without relative phase alignment, a negative mean asynchrony (NMA) of footfall timings with respect to the beats is obtained. This means that footfalls occurred slightly before the beat and that beats were anticipated. Convergence towards this NMA or preferred relative phase angle was facilitated when the first music beat of a new song started close to the step, which means that entrainment occurred. The results also show that using tempo and phase alignment, the relative phase can be manipulated or forced in a certain angle with a high degree of accuracy. Ensuring negative angles larger than NMA (step before beat) results in increased motivation and decreasing cadence. Running in NMA or preferred relative phase angles results in a null effect on cadence. Ensuring a positive phase angle with respect to NMA results in higher motivation and higher cadence. None of the manipulations resulted in change in perceived exhaustion or a change in velocity. Results also indicate that gender plays an important role when using forced phase algorithms: effects were more pronounced for the female population than for the male population. The implementation of the proposed alignment strategies and control of beat timing while running opens possibilities optimizing the individual running cadence and motivation. PMID- 30521636 TI - Correction: Awareness, prevalence, treatment, and control of type 2 diabetes in a semi-urban area of Nepal: Findings from a cross-sectional study conducted as a part of COBIN-D trial. AB - [This corrects the article DOI: 10.1371/journal.pone.0206491.]. PMID- 30521635 TI - Correction: Disparities in the Burden of HIV/AIDS in Canada. AB - [This corrects the article DOI: 10.1371/journal.pone.0047260.]. PMID- 30521637 TI - Correction: Type V Collagen Induced Tolerance Suppresses Collagen Deposition, TGF beta and Associated Transcripts in Pulmonary Fibrosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0076451.]. PMID- 30521638 TI - Objectively measured physical activity levels and sedentary time in children and adolescents with sickle cell anemia. AB - The aim of this study was to identify the levels of physical activity and sedentary behaviour of children and adolescents with sickle cell disease (SCA) compared to healthy individuals. A cross-sectional study with a quantitative approach was performed at a reference center for the treatment of patients with hemoglobinopathies in northeastern Brazil. Patients were recruited between October 2015 and January 2017. Eligible participants answered a Physical Activity Questionnaire for Older Children and Adolescents (PAQ-C) and were instructed to use an ActiGraph wGT3X-BT triaxial accelerometer for seven consecutive days. Fifty patients (and their 50 controls matched for age and sex) were then evaluated. We observed lower moderate (19.2 +/- 11.9 and 27.1 +/- 13.8 min/d; p<0.01) and vigorous PA (3.6 +/- 4.1 and 7.8 +/- 7.4 min/d; p<0.01) in cases than controls, respectively. There was also a significant difference among cases and controls in the following variables: total of steps (51010 +/- 19600 and 59105 +/ 22650; p = 0.04) and "total caloric expenditure" (1015 +/- 516 and 2404 +/- 1308; p<0.01), with the lowest values for the patients with SCA for all variables. Children and adolescents with SCA presented lower levels of physical activity than healthy children and adolescents, either when evaluated by PAQs or by accelerometer. PMID- 30521639 TI - Rapid and substantial increases in anticoagulant use and expenditure in Australia following the introduction of new types of oral anticoagulants. AB - OBJECTIVES: To quantify changes in anticoagulant use in Australia since the introduction of Non-vitamin K antagonist anticoagulants (NOACs) and to estimate government expenditure. DESIGN: Interrupted-time-series analysis quantifying anticoagulant dispensing, before and after first Pharmaceutical Benefits Scheme (PBS) NOAC listing in August 2009 for venous thromboembolism prevention; and expanded listing for stroke prevention in non-valvular atrial fibrillation (AF) in August 2013, up to June 2016. Estimated government expenditure on PBS-listed anticoagulants. SETTING AND PARTICIPANTS: PBS dispensing in 10% random sample of Australians, restricted to continuous concessional beneficiaries dispensed oral anticoagulants from July 2005 to June 2016. Total PBS anticoagulant expenditure was calculated using Medicare Australia statistics. MAIN OUTCOME MEASURES: Monthly dispensing and initiation of oral anticoagulants (warfarin, rivaroxaban, dabigatran or apixaban). Annual PBS anticoagulant expenditure. RESULTS: An estimated 149,180 concessional beneficiaries were dispensed anticoagulants (100% warfarin) during July 2005. This increased to 292,550 during June 2016, of whom 47.0%, 27.1%, 18.7% and 7.2% were dispensed warfarin, rivaroxaban, apixaban and dabigatran, respectively. Of 16,500 initiated on anticoagulants in June 2016, 24.3%, 38.2%, 30.0% and 7.5% were initiated on warfarin, rivaroxaban, apixaban, and dabigatran, respectively. Compared to July 2005-July 2013, from August 2013 June 2016, dispensings for all anticoagulants increased by 2,303 dispensings/month (p<0.001, 95%CI = [1,229 3,376]); warfarin dispensing decreased by 1,803 dispensings/month (p<0.001, 95%CI = [-2,606, -1,000]). Total PBS anticoagulant expenditure was $19.5 million (97.0% concessional) in 2008/09, of which 100% was warfarin and $203.3 million (86.2% concessional) in 2015/16, of which 11.2% was warfarin. CONCLUSIONS: The introduction of the NOACs led to substantial increases in anticoagulant use and expenditure in Australia. PMID- 30521640 TI - Application of the Andersen-Newman model of health care utilization to understand antenatal care use in Kersa District, Eastern Ethiopia. AB - BACKGROUND: In Ethiopia, the uptake of antenatal care services has been low. Moreover, there is less frequent and late attendance of antenatal care among women who attend. Using the Anderson-Newman model of health care utilization, this study identified factors that either facilitate or impede antenatal care utilization in Kersa district, Eastern Ethiopia. METHOD: A community-based cross sectional study was conducted. A total of 1294 eligible women participated in the study. Data were collected using face to face interviews with a pre-tested structured questionnaire administered with a digital survey tool. Data were collected in a house to house survey of eligible women in the community. Bivariate and multivariate logistic regression analyses were used to examine the predisposing, enabling and need factors associated with antenatal care utilization. RESULT: Out of the 1294 respondents, 53.6% (95% CI: 50.8%, 56.3%) attended antenatal care at least once during their last pregnancy. Only 15.3% attended four or more antenatal care visits and just 32.6% attended prior to the 12th week of gestation. Educational status, previous use of antenatal care and best friend's use of maternal care were significant predisposing factors associated with at least one antenatal care visit. Type of kebele, wealth index and husband's attitude towards antenatal care were significant enabling factors associated with at least one antenatal care consultation. Health Extension Workers providing home visits, perceived importance of ANC and awareness of pregnancy complications were significant need factor associated with at least one antenatal care consultation. Husband's attitude towards ANC, head of the household, awareness of pregnancy complications, and history of abortion were predictors of attending four or more antenatal care visits. CONCLUSION: More than half of the women attended at least one antenatal care visit. A sizable proportion of women had infrequent and delayed antenatal care. Intervention efforts to improve antenatal care utilization should involve the following: improving women's educational achievement, peer education programs to mobilize and support women, programs to change husbands' attitudes, ameliorate the quality of antenatal care, increasing the Health Extension Worker's home visits program, and increasing the awareness of pregnancy complications. PMID- 30521641 TI - Transmission dynamics of re-emerging rabies in domestic dogs of rural China. AB - Despite ongoing efforts to control transmission, rabies prevention remains a challenge in many developing countries, especially in rural areas of China where re-emerging rabies is under-reported due to a lack of sustained animal surveillance. By taking advantage of detailed genomic and epidemiological data for the re-emerging rabies outbreak in Yunnan Province, China, collected between 1999 and 2015, we reconstruct the demographic and dispersal history of domestic dog rabies virus (RABV) as well as the dynamics of dog-to-dog and dog-to-human transmission. Phylogeographic analyses reveal a lower diffusion coefficient than previously estimated for dog RABV dissemination in northern Africa. Furthermore, epidemiological analyses reveal transmission rates between dogs, as well as between dogs and humans, lower than estimates for Africa. Finally, we show that reconstructed epidemic history of RABV among dogs and the dynamics of rabid dogs are consistent with the recorded human rabies cases. This work illustrates the benefits of combining phylogeographic and epidemic modelling approaches for uncovering the spatiotemporal dynamics of zoonotic diseases, with both approaches providing estimates of key epidemiological parameters. PMID- 30521642 TI - Magnetic resonance imaging quantification of dehydration and rehydration in vocal fold tissue layers. AB - Clinicians commonly recommend increased hydration to patients with voice disorders. However, effects on clinical voice outcome measures have been inconsistent. Hydration-induced change within different layers of vocal fold tissue is currently unknown. Magnetic Resonance Imaging (MRI) is a promising method of noninvasively measuring water content in vocal folds. We sought to image and quantify changes in water content within vocal fold mucosa and thyroarytenoid muscle after dehydration and rehydration. Excised porcine larynges were imaged using proton density (PD) weighted MRI (1) at baseline and (2) after immersion in one of five hypertonic, isotonic, or hypotonic solutions or in dry air. Larynges dehydrated in hypertonic solutions or dry air were rehydrated and imaged a third time. Scans revealed fluid-rich vocal fold mucosa that was distinct from muscle at baseline. Baseline normalized signal intensity in mucosa and muscle varied by left vs. right vocal fold (p < 0.01) and by anterior, middle, or posterior location (p < 0.0001). Intensity changes in the middle third of vocal fold mucosa differed by solution after immersion (p < 0.01). Hypertonic solutions dehydrated the middle third of mucosa by over 30% (p < 0.001). No difference from baseline was found in anterior or posterior mucosa or in muscle after immersion. No association was found between intensity change in mucosa and muscle after immersion. After rehydration, intensity did not differ by solution in any tissue, and was not different from baseline, but post-rehydration intensity was correlated with post-immersion intensity in both mucosa and muscle (p < 0.05), suggesting that degree of change in vocal fold water content induced by hypertonic solutions ex vivo persists after rehydration. These results indicate that PD-MRI can be used to visualize large mammalian vocal fold tissue layers and to quantify changes in water content within vocal fold mucosa and thyroarytenoid muscle independently. PMID- 30521643 TI - Correction: Automated phenotyping for early vigour of field pea seedlings in controlled environment by colour imaging technology. AB - [This corrects the article DOI: 10.1371/journal.pone.0207788.]. PMID- 30521644 TI - Immunogenic particles with a broad antigenic spectrum stimulate cytolytic T cells and offer increased protection against EBV infection ex vivo and in mice. AB - The ubiquitous Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is etiologically linked to the development of several malignancies and autoimmune diseases. EBV has a multifaceted life cycle that comprises virus lytic replication and latency programs. Considering EBV infection holistically, we rationalized that prophylactic EBV vaccines should ideally prime the immune system against lytic and latent proteins. To this end, we generated highly immunogenic particles that contain antigens from both these cycles. In addition to stimulating EBV-specific T cells that recognize lytic or latent proteins, we show that the immunogenic particles enable the ex vivo expansion of cytolytic EBV-specific T cells that efficiently control EBV-infected B cells, preventing their outgrowth. Lastly, we show that immunogenic particles containing the latent protein EBNA1 afford significant protection against wild-type EBV in a humanized mouse model. Vaccines that include antigens which predominate throughout the EBV life cycle are likely to enhance their ability to protect against EBV infection. PMID- 30521645 TI - Diagnosing the double burden of malnutrition using estimated deviation values in low- and lower-middle-income countries. AB - OBJECTIVE: To examine the possibility of diagnosing the double burden of malnutrition using estimated deviation values in low- and lower-middle-income countries. METHODS: A modified version of the Japanese Diagnostic Tool was used. Data on 194 countries were analyzed, including data from the United Nations International Children's Fund, World Health Organization and World Bank. After conducting a Box-Cox transformation, deviation values were calculated. The degree to which the values deviated relative to a deviation cutoff value of 50 was assessed. Focusing on countries with low- and middle-income economic levels, we examined the utility of this tool to show characteristic nutritional problems in each country. RESULTS: The deviation values had normal, distorted, bimodal, or trimodal distributions. In the lower-middle-income countries, almost all countries had values ranging from 40 to 60 for education and water environments (urban and rural), and the differences were minimal. However, different causes of noncommunicable disease-related deaths were considered, and the primary cause appeared to be related to lifestyle factors, particularly alcohol consumption and tobacco smoking. In comparison, the deviation values related to death among low income countries also appeared to be related to differences in education and sanitation in urban and rural areas. CONCLUSION: The study results can help to determine the status of nutritional inequalities and plan country-specific strategies to reduce the double burden of malnutrition. PMID- 30521646 TI - Is sex necessary for the proliferation and transmission of Pneumocystis? PMID- 30521647 TI - The promises and risks of probiotic Bacillus species. AB - Supplementing the human microbiome with probiotic microorganisms is a proposed solution for civilization syndromes such as dysbiosis and gastrointestinal tract (GIT) disorders. Bimodal probiotic strains of the Bacillus genus constitute the microbiota of the human environment, and are typically found in soil, water, a number of non-dairy fermented foods, as well as in human and animal GIT. Probiotic Bacillus sp. are Gram positive rods, with the ability of sporulation to survive environmental stress and preparation conditions. In vitro models of the human stomach and human studies with probiotic Bacillus reveal the mechanisms of its life cycle and sporulation. The Bacillus sp. probiotic biofilm introduces biochemical effects such as antimicrobial and enzymatic activity, thus contributing to protection from GIT and other infections. Despite the beneficial activity of Bacillus strains belonging to the safety group 1, a number of strains can pose a substantial health risk, carrying genes for various toxins or antibiotic resistance. Commercially available Bacillus probiotic preparations include strains from the subtilis and other closely related phylogenetic clades. Those intended for oral administration in humans, often encapsulated with appropriate supporting materials, still tend to be mislabeled or poorly characterized. Bacillus sp. MALDI-TOF analysis, combined with sequencing of characteristic 16S rRNA or enzyme coding genes, may provide accurate identification. A promising future application of the probiotic Bacillus sp. might be the microflora biocontrol in the human body and the closest human environment. Environmental probiotic Bacillus species display the potential to support human microflora, however controversies regarding the safety of certain strains is a key factor in their still limited application. PMID- 30521648 TI - Long-term results of endosseous implants as retention elements of orbital epitheses, reconstruction techniques, and aftercare after radical tumor resection. AB - PURPOSE: The aim of this study was to examine the long-term results of implants in orbital reconstruction after exenteration. MATERIALS AND METHODS: From 1998 to 2012, patients undergoing implant-supported rehabilitation after subtotal or total exenteration due to a tumor were included in a retrospective study. All the patients were evaluated for soft tissue reconstruction, irradiation, complications, abutments, hygiene index, implant mobility, and long-term success. RESULTS: Forty-eight patients (aged between 27 and 81 years) were selected. A total of 187 implants were inserted. All the patients were supplied with epitheses after implantation in the long term. Of the 187 implants, nine implants placed on five patients were lost. The mean follow-up period was 34 months (ranging from 6 to 144 months). The 5-year survival rate was 88%. CONCLUSION: On the basis of this retrospective study of 48 patients with 187 implants, the following observations were made: (1) The 5-year survival of implants in nonradiated bone was 92%, and (2) the 5-year survival of implants in radiated bone was 86%. Extraoral implants should be presented as an option in orbital rehabilitation after exenteration. PMID- 30521649 TI - Instrument Selection and Application Used to Probe Dental Implants. AB - PURPOSE: The purpose of this study is to survey clinicians' choice of peri implant instrument selection and the application used to probe dental implants as well as to evaluate peri-implant probing force and pressure applied as compared to that reported in current literature. MATERIALS AND METHODS: 48 clinicians (16 periodontists/periodontal residents, 16 restorative dentists and 16 hygienists) participated in the study. A questionnaire to determine the frequency and method of probing dental implants was provided and subject to the Chi-square test. Each participant was given a choice of three periodontal probes (Marquis, UNC15, Plastic) to use on the typodont and probing force was recorded blindly. Probing force and pressure data were analyzed with ANOVA among subject groups as well as probe types per site; where statistical differences (p < .05) were detected, Tukey's posthoc test was applied. RESULTS: The questionnaire resulted in a variety of answers although the majority demonstrated an agreement on probing implants in everyday practice. There was no significant difference among provider groups in regard to instrument selection, probing forces and pressure in both maxilla and mandible although the mean probing forces and pressures in all provider groups were higher than the suggested value reported in the literature. CONCLUSION: This study indicates that there are variations among clinical provider groups with regard to peri-implant probe instrument type used and forces applied, though these are not statistically significant. Probe tip diameter should be considered to avoid BOP false positives when probing dental implants especially as the forces generally used by the clinicians may be higher than advised. PMID- 30521650 TI - Quantification of image artifacts from navigation markers in dynamic guided implant surgery and the effect on registration performance in different clinical scenarios. AB - PURPOSE: Different navigation markers in dynamic guided implant surgery could cause different degrees of artifacts, which would affect the accuracy and efficiency of the implant navigation system. This study aimed to quantify artifacts caused by navigation markers made of different materials and to evaluate their effects on registration accuracy under various oral conditions. MATERIALS AND METHODS: Four U-shaped tubes with different navigation markers (440c stainless steel, silicon nitride, zirconium oxide, and aluminium oxide) were produced by three-dimensional printing. Four kinds of maxillary plaster models were prepared to stimulate four tooth crown conditions. U-shaped tubes combined with different tooth models were scanned using cone beam computed tomography (CBCT). The size of artifacts from different navigation markers and registration rate were measured. Abrasion performance of navigation markers was evaluated by scanning electron microscopy (SEM) images. RESULTS: Aluminium oxide navigation markers showed the fewest artifacts. Silicon nitride markers caused fewer artifacts than zirconium oxide and 440c stainless steel ones (P < .05) and had the best registration performance under all tooth crown conditions with the lowest volume of abrasion. Registration data suggested aluminium oxide worked badly under artificial crown and natural tooth conditions for its lower radiopacity, and zirconium oxide worked undesirably in edentulous conditions. 440c stainless steel was worst in all dental conditions. CONCLUSION: Navigation markers made of silicon nitride have the best overall performance and perform the best in registration under all circumstances owing to less artifact generation, better radiopacity, and desirable abrasion resistance. Silicon nitride can be regarded as an ideal material, including but not limited to oral implant navigator-guided surgery. PMID- 30521651 TI - The effect of the configurations of fiducial markers on accuracy of surgical navigation in zygomatic implant placement: An in vitro study. AB - PURPOSE: Real-time surgical navigation has been increasingly applied in implant placement. The initial registration procedures were found to substantially affect the overall accuracy of the system for zygomatic implant placement, but the exact number and distribution of fiducial markers was yet undetermined. This study aimed to determine the minimal numbers and optimal distributions of fiducial markers to achieve clinically acceptable accuracy in surgical navigation, through systematically analyzing the effects of different setups of fiducial markers on target registration errors (TRE). MATERIALS AND METHODS: A maxillary phantom with bone-anchored fiducial markers was scanned using cone beam computed tomography, followed by data processing on Brainlab, a commercially available navigation system. A total of 10 mini-screws were inserted in the edentulous maxilla for configuration of fiducial markers, with another two mini-screws as implant targets to assess TRE in zygomatic bone. Data were then collected in nine configurations with distinct fiducial numbers and positions. Statistical analyses were performed with SPSS. RESULTS: Accuracy of the surgical navigation system was found to depend on both the numbers and positions of fiducial markers. No significant difference was observed in accuracy among groups with eight fiducials and with polygon span distribution (P > .05). When the fiducial numbers decreased to less than six, the markers inserted in a regular triangle area were more precise than in an inverse triangle configuration. When the number of fiducials was five with a polygonal distribution, a low TRE value of 0.59 mm was detected, which was comparable to the accuracy with more than eight fiducials in the study. CONCLUSION: A scattered distribution with a polygon span with at least five fiducial markers in the edentulous maxilla for registration seems to achieve an acceptable TRE value with a high accuracy for navigation in zygomatic implant placement. PMID- 30521652 TI - Regenerated Bone Pattern Around Exposed Implants with Various Designs. AB - PURPOSE: The design and surface features of dental implants substantially affect the healing and remodeling of adjacent bones. This study aimed to investigate the impact of design and surface on bone regeneration using implants of two different pitches, each with three different surface features. MATERIALS AND METHODS: Custom-manufactured titanium implants (length, 10 mm; diameter, 3.5 mm) were divided along the major axis into two sections: one with 0.6-mm pitch and the other with 0.4-mm pitch. They were processed by turned, blasting and etching, and anodic oxidation surface treatments and implanted into rabbit tibia. The upper 4 mm of the inserted implants was exposed, and bone regeneration was induced around the exposed area using a titanium chamber (height: 4 mm) containing particulate autogenous and bovine bone. After a 12-week healing period, the quantity and quality of bone regeneration around the implants were evaluated. Thirty specimens 10 specimens each from the turned, blasting and etching, and anodic oxidation surface groups with 0.6- and 0.4-mm pitch sizes- were evaluated by histomophometric analysis. RESULTS: The vertical height and width of regenerated bone around blasting and etching and anodic oxidation surfaces were significantly greater than those around turned implants (P < .05); the vertical heights of regenerated bone around the 0.4-mm-pitch sections of blasting and etching and anodic oxidation surfaces were significantly greater than those around the 0.6-mm pitch sections (P < .05). Both blasting and etching and anodic oxidation surfaces exhibited significantly greater bone-to-implant contact and bone volume at the implant thread than turned implants (P < .05). However, there was no significant difference between the 0.6- and 0.4-mm-pitch sections. CONCLUSION: The findings of this study indicate that blasting and etching and anodic oxidation surfaces with a 0.4-mm-pitch design result in greater vertical ingrowth of regenerated bone than those with a 0.6-mm-pitch design. PMID- 30521653 TI - Influence of the height of the antrostomy in sinus floor elevation assessed by cone beam computed tomography- a randomized clinical trial. AB - PURPOSE: To evaluate the influence of the height of the antrostomy on dimensional variations of the elevated space after sinus floor elevation. MATERIALS AND METHODS: Twenty-four healthy volunteers planned for sinus floor elevation were included in the study. An antrostomy of either 4 mm (Group A) or 8 mm (Group B) in height was prepared in the lateral wall of the sinus. Cone beam computed tomography (CBCT) scans were taken before surgery (T0) and after 1 week (T1) and 9 months (T2). Dimensional variation analyses were performed. RESULTS: The CBCT scans of 10 patients per group were evaluated. After 1 week (T1), the sinus floor was found elevated in the middle region by 12.0 +/- 2.3 mm in Group A, while in Group B, the height was 11.8 +/- 2.1 mm. After 9 months (T2), the respective heights were 9.9 +/- 2.4 mm and 8.9 +/- 2.7 mm, with a reduction of -2.1 +/- 2.2 mm in Group A and -3.0 +/- 2.6 mm in Group B. The area in a central position was reduced by 25.5% to 34.2%, showing a slightly higher shrinkage in Group B compared with Group A. However, no statistically significant differences were found between the two groups. DISCUSSION: In maxillary sinus floor elevations performed by the lateral approach, the size of the antrostomy did not affect the clinical and radiographic outcomes. PMID- 30521654 TI - A laminin-derived functional peptide, PPFEGCIWN, promotes bone formation on sandblasted, large-grit, acid-etched titanium implant surfaces. AB - PURPOSE: This study aimed to investigate the in vitro and in vivo bone-forming potential of a sandblasted, large-grit, acid-etched (SLA) titanium (Ti) surface treated with a laminin-derived functional peptide, PPFEGCIWN (DN3). MATERIALS AND METHODS: Human osteoblast-like MG63 cells were cultured with SLA Ti discs untreated or treated with DN3 or a control scrambled peptide (SP). Cell adhesion, spreading, and viability on the discs were tested. Alkaline phosphatase gene expression and enzyme activity were also evaluated. Four DN3-coated SLA Ti implants and four untreated implants were placed into the tibiae of two rabbits (two implants/tibia). Ten days later, the bone-implant interfaces were subjected to histomorphometry to measure the bone response. The surface properties of the discs and implants were determined using scanning electron, widefield confocal, and confocal laser microscopy and x-ray photoelectron spectroscopy. RESULTS: The peptide-treated and untreated discs and implants were similar in terms of physical surface properties, but the peptide-treated surfaces had significantly higher nitrogen levels (P < .05). The DN3 peptide promoted cell adhesion, spreading, and alkaline phosphatase expression and enzyme activity (P < .05). Histomorphometry of the harvested implants showed rapid bone formation and affinity of the motif. CONCLUSION: This study suggests that treatment with the cell adhesion peptide DN3 promotes bone healing at the SLA Ti surface. PMID- 30521655 TI - Micro-ATR FTIR, SEM-EDS and X-ray micro-CT: an innovative multi-technique approach to investigate bone affected by peri-implantitis. AB - PURPOSE: The aim of this work was to prove the synergic complementarity of attenuated total reflection Fourier transform infrared microspectroscopy (micro ATR FTIR), scanning electron microscopy (SEM) coupled with energy-dispersive x ray spectroscopy (EDS) and x-ray computed microtomography (micro-CT) by studying implant samples with bone affected by peri-implantitis. MATERIALS AND METHODS: Six samples of implanted bone affected by peri-implantitis and one control healthy bone were analyzed. Thick bone sections included in epoxy-resin and removed implants were analyzed by micro-ATR FTIR, SEM-EDS, and micro-CT. RESULTS: Micro-ATR FTIR revealed the complex nature of the bone composition. Vibrational bands characteristic of both mineral bone phase (acidic phosphates, CO32- groups) and organic bone phase (mostly collagen) could be recognized, and their proportion could be seen to change accordingly with the bone degradation. Similarly, SEM-EDS clearly revealed the cortical nature of the control mandible and its homogenous mineral composition. On the contrary, EDS analyses performed over relevant portions of pathologic samples revealed that defective areas were almost Ca and P free. Micro-CT data showed that the morphology of the interface was smooth and linear in the physiologic periimplant bone, while in the pathologic samples, an altered morphology was evident. CONCLUSION: This study demonstrated that morphologic, elemental, and biochemical modifications of periimplant bone can be studied using micro-ATR FTIR, SEM-EDS, and micro-CT. The complement of these techniques can be considered a new multipurpose approach to investigate bone affected by peri-implantitis. PMID- 30521656 TI - A Comparative Study with Biphasic Calcium Phosphate to Deproteinized Bovine Bone in Maxillary Sinus Augmentation: A Prospective Randomized and Controlled Clinical Trial. AB - PURPOSE: The purpose of this study was to evaluate a new graft material, biphasic calcium phosphate, composed of 60% hydroxyapatite and 40% beta-Tricalcium phosphate and deproteinized bovine bone mineral, which is established as a predictable graft material for maxillary sinus augmentation. MATERIALS AND METHODS: Maxillary sinus augmentation was performed with different bone materials. Bone biopsies were performed on tissue harvested from the future implant bed using a trephine bur at 6 months after maxillary sinus augmentation. Resonance frequency analysis was performed immediately and at 6 months after the implant placement. Microcomputed tomography and histomorphometric analysis were performed in all patients. RESULTS: Fifty-six patients (60 sinuses) were included in the study. At 6 months postoperative, 31 biopsies were performed on tissues harvested from the calcium phosphate, and 29 biopsies on tissues from the bovine bone grafts. There was no implant failure during the 21-month mean follow-up period. The overall implant stability quotient values were higher than 60, and gradually increased for 6 months. Higher new bone volume fraction and new bone surface density were observed in the calcium phosphate group compared with the bovine bone group. In contrast, residual bone graft volume in the bovine bone group was higher than that in the calcium phosphate group. Nevertheless, there was no significant difference between groups in the microcomputed tomography and histomorphometric parameters. CONCLUSION: Within the study's limitations, both graft materials demonstrated similar biocompatibility and osteoconductivity in the maxillary sinus augmentation. PMID- 30521657 TI - Bone Graft Displacement After Maxillary Sinus Floor Augmentation With or Without Covering Barrier Membrane: A Retrospective Computed Tomographic Image Evaluation. AB - PURPOSE: Scientific publications have recently found that bone graft quality and implant survival rates were not influenced by antrostomy membrane coverage during maxillary sinus floor augmentation with a lateral approach. The aim of this study was to evaluate the stability of the bone substitute after a maxillary sinus floor augmentation procedure with or without using a covering membrane. MATERIALS AND METHODS: This retrospective study evaluated all patients who were enrolled between April 2016 and January 2017. The stability of the bone graft inside the sinus cavity as well at the level of the lateral bone window was assessed through preoperative and postoperative cone beam computed tomography images up to 6-month follow-up. The clinical postoperative morbidity was evaluated following a visual analog scale (VAS) protocol. RESULTS: Maxillary sinus floor augmentation with a lateral approach was performed in 41 patients. In 17 cases (10 women/7 men, mean age: 55.4 years), a barrier membrane was used to cover the lateral bone window (control group), and in 24 cases (13 women/11 men, mean age: 56.2 years), no membrane was used (test group). The bone graft dislodgement within the buccal mucosa at 6 months postoperative ranged from 0 to 2.2 mm (mean value: 3.8 +/- 3.1 [standard deviation] mm) in the test group and from 0 to 2.3 mm (mean value: 0.5 +/- 0.4 mm) in the control group. The postoperative pain and swelling complications were significantly more important for the test group (3.3 +/- 1.4/4.3 +/- 4.5, respectively) than for the control group (2.1 +/- 0.9/2.7 +/- 0.9). CONCLUSION: On the basis of this preliminary study, it appears that the use of a barrier membrane to cover the lateral bone window during maxillary sinus floor augmentation surgery with a lateral approach reduces the postoperative dislodgement of the bone graft throughout the sinus antrostomy and prevents the bone substitute particles penetrating within the buccal mucosa, which is related to postoperative morbidity. PMID- 30521658 TI - Mandible reconstruction with patient-specific implants: Case report of five consecutive patients. AB - The purpose of this case report was to assess whether patient-specific implants (PSI: Xillocs) and soft tissue flaps contribute in reconstructing large mandibular defects. Five patients with a medical situation and history not suitable for free microvascular bone flaps were operated with PSI and evaluated. The mean follow-up time was 12 months. The excellent fit, convenient surgery, and esthetic outcome were seen as the major advantages. The PSI can, in the authors' experience, be considered as a useful alternative provided they are well embedded by viable tissue and attached to vital resection margins of the recipient bone. PMID- 30521659 TI - Influence of UV irradiation and cold atmospheric pressure plasma on zirconia surfaces: an in vitro study. AB - PURPOSE: To compare the influence of ultraviolet (UV) irradiation and cold atmospheric pressure plasma (CAP) treatment on surface structure, surface chemistry, cytocompatibility, and cell behavior on zirconia in vitro. MATERIALS AND METHODS: Zirconia samples (TZ-3YSBE) were treated by UV irradiation, oxygen plasma, or argon plasma for 12 minutes each and compared with the nontreated samples. Surface analysis was conducted using scanning electron microscopy, roughness analysis, and x-ray photoelectron spectroscopy. Cell proliferation, viability, and cell attachment as well as cytotoxicity were evaluated using MC3T3 E1 murine osteoblasts cultivated directly on the zirconia samples. RESULTS: Surface structure and roughness were not affected by the surface treatments. CAP and UV irradiation significantly reduced organic material and increased the surface oxidation on the zirconia samples. Furthermore, CAP and UV treatment significantly decreased the contact angle on the zirconia samples, indicating superhydrophilicity. Cell attachment was significantly increased on oxygen plasma treated zirconia samples compared with the nontreated samples at all times (P < .001). After 24 and 48 hours, cell proliferation and viability (P < .001) were significantly increased on oxygen plasma-treated samples in comparison with the nontreated, UV-treated, and argon plasma-treated samples. Neither UV nor CAP treatment led to cytotoxicity. CONCLUSION: In vitro, surface treatment by UV irradiation or CAP causes a significant reduction of organic material, increases the hydrophilicity of zirconia, and improves the conditions for osteoblasts. Results stipulate that treatment of zirconia surfaces with oxygen plasma may favor cell proliferation. PMID- 30521660 TI - Accuracy of a Dynamic Dental Implant Navigation System in a Private Practice. AB - PURPOSE: To evaluate the in vivo accuracy of dental implants placed using a dynamic computer-aided dental implant (CAI) navigation system. The impact of various factors on accuracy was also analyzed. MATERIALS AND METHODS: A retrospective, in vivo study was performed during the period of October 2015 to December 2017. Data were obtained on all implants placed during this time frame. A chart review was conducted to identify the type of flap, number of implants placed, number of patients treated, and factors related to the description of edentulism (partial or complete). To evaluate accuracy outcomes, the preoperative cone beam computed tomography (CBCT) plan was volumetrically registered to a postimplant placement CBCT scan. Deviations between the planned and placed implant positions were analyzed. Data were statistically analyzed to factors that may affect the accuracy during usage. RESULTS: Data were obtained on 231 implants placed in healed ridges using a flapless or minimal flap approach under dynamic guidance by a single surgeon. In the 89 arches operated on, 28 (125 implants) were fully edentulous. For all implants, the mean (SD) discrepancies were: 0.71 (0.40) mm for entry point (lateral) and 1.00 (0.49) mm at the apex (3D). The mean angle discrepancy was 2.26 degrees (1.62 degrees) from actual vs planned implant positions. The accuracy measurements for partially edentulous patients using a thermoplastic stent attachment and for fully edentulous patients using a mini implant-based attachment were nearly identical. No significant accuracy differences were found between implant position within the different sextants. Guided insertion of the implant itself reduced angular and apex location deviations. The accuracy of implant placement improved during the study period, with the mean entry point and apex deviation as well as overall angle discrepancy measured for the last 50 implants being better (0.59 mm, 0.85 mm, and 1.98 degrees, respectively) when compared with the first 50 implants (0.94 mm, 1.19 mm, and 3.48 degrees, respectively). CONCLUSION: Dynamic surgical navigation is an accurate method for executing CBCT-based computer-aided implant surgery. In addition, an increased experience level of the surgeon with dynamic navigation appears to improve accuracy outcomes. PMID- 30521661 TI - Comparison of Three-Dimensional Accuracy of Digital and Conventional Implant Impressions: Effect of Interimplant Distance in an Edentulous Arch. AB - PURPOSE: This study compared the three-dimensional (3D) accuracy of conventional impressions with digital impression systems (intraoral scanners and dental laboratory scanners) for two different interimplant distances in maxillary edentulous arches. MATERIALS AND METHODS: Six impression systems comprising one conventional impression material(Impregum), two intraoral scanners (TRIOS and True Definition), and three dental laboratory scanners (Ceramill Map400, inEos X5, and D900) were evaluated on two completely edentulous maxillary arch master models (A and B) with six and eight implants, respectively. Centroid positions at the implant platform level were derived using either physical or virtual probe hits with a coordinate measuring machine. Comparison of centroid positions between master and test models (n = 5) defined linear distortions (dx, dy, dz), global linear distortions (dR), and 3D reference distance distortions between implants (DeltaR). The two-dimensional (2D) angles between the central axis of each implant to the x- or y-axes were compared to derive absolute angular distortions (Absdthetax, Absdthetay). RESULTS: Model A mean dR ranged from 8.7 +/ 8.3 MUm to 731.7 +/- 62.3 MUm. Model B mean dR ranged from 16.3 +/- 9 MUm to 620.2 +/- 63.2 MUm. Model A mean Absdthetax ranged from 0.021 +/- 0.205 degrees to -2.349 +/- 0.166 degrees, and mean Absdthetay ranged from -0.002 +/- 0.160 degrees to -0.932 +/- 0.290 degrees. Model B mean Absdthetax ranged from -0.007 +/- 0.076 degrees to -0.688 +/- 0.574 degrees, and mean Absdthetay ranged from 0.018 +/- 0.048 degrees to -1.052 +/- 0.297 degrees. One-way analysis of variance (ANOVA) by Impression system revealed significant differences among test groups for dR and DeltaR in both models, with True Definition exhibiting the poorest accuracy. Independent samples t tests for dR, between homologous implant location pairs in Model A versus B, revealed the presence of two to four significant pairings (out of seven possible) for the intraoral scanner systems, in which instances dR was larger in Model A by 110 to 150 MUm. CONCLUSION: Reducing interimplant distance may decrease global linear distortions (dR) for intraoral scanner systems, but had no effect on Impregum and the dental laboratory scanner systems. Impregum consistently exhibited the best or second-best accuracy at all implant locations, while True Definition exhibited the poorest accuracy for all linear distortions in both Models A and B. Impression systems could not be consistently ranked for absolute angular distortions. PMID- 30521662 TI - Comparative study of immediate loading on short dental implants and conventional dental implants in the posterior mandible: A randomized clinical trial. AB - PURPOSE: Immediate dental implant loading has been investigated with favorable results. However, short implants have not been investigated in this treatment option. This study compared the clinical outcomes and survival rates of immediately loaded short and conventional length dental implants in replacing mandibular molar teeth. MATERIALS AND METHODS: Forty-six implants (23 short dental implants and 23 conventional dental implants) in 46 patients were included in the study. Provisional computer-aided design/computer-aided manufacturing (CAD/CAM) ceramic crowns were cemented to the abutments and immediately loaded. Several clinical parameters were recorded and statistically analyzed at 4-month- and 1-year-follow-up. RESULTS: Two short implants lost integration, and one conventional implant failed. No statistically significant difference between the two implant types was found (P = 1.00). Minor complications were recorded; three provisional crown fractures were found in the short implant group and two provisional crown fractures in the conventional implant group. There was no significant difference in implant stability quotient values for short or conventional implants between baseline (short: 73.86 +/- 2.38, conventional: 75.05 +/- 3.26, P = .088), 4 months after loading (short: 72.37 +/- 1.35, conventional: 72.89 +/- 1.87, P = .165), and 1 year after loading (short: 74.60 +/- 2.03, conventional: 75.35 +/- 2.66, P = .296). The mean marginal bone level loss 4 months after loading was 0.28 +/- 0.29 mm for short implants and 0.25 +/- 0.25 mm for conventional implants (P = .73), and at 1 year after loading was 0.33 +/- 0.47 mm for short implants and 0.26 +/- 0.27 mm for conventional implants (P = .554); there was no statistical difference between the two implant types. CONCLUSION: The immediate loading of short implants is comparable to conventional length implants in terms of implant survival, marginal bone level change, and implant stability quotient value. PMID- 30521663 TI - Application of the Communication Complexity Scale in Peer and Adult Assessment Contexts for Preschoolers With Autism Spectrum Disorders. AB - Purpose: The purpose of this study was to measure changes in communication of preschoolers with autism using the Communication Complexity Scale (CCS; Brady et al., 2012) and to examine the utility of the CCS in measuring pretreatment and posttreatment changes within peer and adult assessment contexts. Method: The CCS was used to code preassessment and postassessment for 23 children with autism randomly assigned to a treatment that incorporated a peer-mediated approach and a speech-generating device and 22 assigned to a business-as-usual condition with untrained peers. Children were assessed in 2 structured 30-min contexts-1 with an adult examiner and 1 with a peer partner coached by an adult. Results: Children in both groups showed significant changes in communication complexity CCS scores from pretreatment to posttreatment in the adult and peer contexts. At both occasions, CCS scores were higher with adult partners yet showed greater improvements over time with peer partners. Conclusions: Results showed that the CCS was sensitive to change over time but did not discriminate changes in communication complexity associated with maturation versus treatment. It did show some differences based on interactions with peer versus adult partners. Outcomes provide preliminary support for using this scale to measure communication changes in different contexts. Supplemental Material: https://doi.org/10.23641/asha.7408856. PMID- 30521664 TI - The Development of American Sign Language-Based Analogical Reasoning in Signing Deaf Children. AB - Purpose: This article examines whether syntactic and vocabulary abilities in American Sign Language (ASL) facilitate 6 categories of language-based analogical reasoning. Method: Data for this study were collected from 267 deaf participants, aged 7;6 (years;months) to 18;5. The data were collected from an ongoing study initially funded by the U.S. Institute of Education Sciences in 2010. The participants were given assessments of ASL vocabulary and syntax knowledge and a task of language-based analogies presented in ASL. The data were analyzed using mixed-effects linear modeling to first see how language-based analogical reasoning developed in deaf children and then to see how ASL knowledge influenced this developmental trajectory. Results: Signing deaf children were shown to demonstrate language-based reasoning abilities in ASL consistent with both chronological age and home language environment. Notably, when ASL vocabulary and syntax abilities were statistically taken into account, these were more important in fostering the development of language-based analogical reasoning abilities than were chronological age and home language. We further showed that ASL vocabulary ability and ASL syntactic knowledge made different contributions to different analogical reasoning subconstructs. Conclusions: ASL is a viable language that supports the development of language-based analogical reasoning abilities in deaf children. PMID- 30521665 TI - Identifiers of Language Impairment for Spanish-English Dual Language Learners. AB - Purpose: The purpose of this study was to determine if a standardized assessment developed for Spanish-English dual language learners (SEDLLs) differentiates SEDLLs with language impairment (LI) from children with typical language better than the translated/adapted Spanish and/or English version of a standardized assessment and to determine if adding informal measure/s to the standardized assessment increases the classification accuracy. Method: Standardized and informal language assessment measures were administered to 30 Mexican American 4- to 5-year-old SEDLLs to determine the predictive value of each measure and the group of measures that best identified children with LI and typical language. Discriminant analyses were performed on the data set. Results: The Morphosyntax and Semantics subtests of the Bilingual English-Spanish Assessment (Pena, Gutierrez-Clellen, Iglesias, Golstein, & Bedore, 2014) resulted in the largest effect size of the individual assessments with a sensitivity of 93.3% and a specificity of 86.7%. Combining these subtests with mean length of utterance in words from the child's better language sample (English or Spanish) was most accurate in identifying LI and can be used with above 90% confidence. Conclusion: The Bilingual English-Spanish Assessment Morphosyntax and Semantics subtests were shown to comprise an effective measure for identifying LI; however, including a language sample is suggested to identify LI with greater accuracy. PMID- 30521666 TI - Regional Gene Expression Profile Comparison Reveals the Unique Transcriptome of the Optic Fissure. AB - Purpose: The optic fissure (OF) is a transient opening in the ventral optic cup (OC) that acts as a passage for blood vessels and retinal ganglion cell axons during early eye development. Failure to close the OF is the developmental basis for uveal coloboma, a congenital blinding eye disease that significantly contributes to childhood blindness. Genes specifically expressed in the OF region may play important roles in OF development and function. The aim of this study was to characterize the transcriptome of OC cells in the OF region and investigate the function of OF-specific genes during OF closure. Methods: Laser assisted microdissection was used to collect different regions of OC tissues. Microarray analysis was used to obtain and compare gene expression profiles of different OC regions. RNA in situ hybridization (ISH) was used to further characterize OF-specific gene expression patterns. Morpholino knockdown in zebrafish was used to study the function of a newly discovered OF-specific gene during OF closure. Results: Microarray comparison revealed that the OC at the OF region exhibited a unique gene expression profile. OC expression patterns of a number of newly discovered OF-specific genes were confirmed by ISH. Morpholino knockdown and downstream target expression and function analysis demonstrated that afap1l2, a newly discovered OF-specific gene, controls OF closure by regulating pax2a expression. Conclusions: Our study characterized the unique transcriptome of the OF region of the OC and demonstrated the essential role of a newly discovered OF-specific gene in OF closure. This study provides a valuable foundation for future mechanism dissection in OF development and physiology, and for human coloboma etiology exploration. PMID- 30521667 TI - Epithelial-Mesenchymal Transdifferentiation in Pediatric Lens Epithelial Cells. AB - Purpose: Posterior capsule opacification (PCO) is a complication after cataract surgery, particularly in children. Epithelial-mesenchymal transition (EMT) of lens epithelial cells, mediated by transforming growth factor beta (TGFbeta), contributes to PCO. However, its pathogenesis in children is poorly understood. We correlated cell growth in culture with patient characteristics, studied gene expression of pediatric lens epithelial cells (pLEC), and examined the effects of TGFbeta-2 on these cells in vitro. Methods: Clinical characteristics of children with cataracts correlated with growth behavior of pLEC in vitro. mRNA expression of epithelial (alphaB-crystallin, connexin-43) and mesenchymal (alphaV-integrin, alpha-smooth muscle actin, collagen-Ialpha2, fibronectin-1) markers was quantified in pLEC and in cell line HLE-B3 in the presence and absence of TGFbeta 2. Results: Fifty-four anterior lens capsules from 40 children aged 1 to 180 months were obtained. Cell outgrowth occurred in 44% of the capsules from patients <= 12 months and in 33% of capsules from children aged 13 to 60 months, but in only 6% of capsules from children over 60 months. TGFbeta-2 significantly upregulated expression of alphaB-crystallin (HLE-B3), alphaV-integrin (HLE-B3), collagen-Ialpha2, and fibronectin-1 (in pLEC and HLE-B3 cells). Conclusions: Patient characteristics correlated with growth behavior of pLEC in vitro, paralleling a higher clinical incidence of PCO in younger children. Gene expression profiles of pLEC and HLE-B3 suggest that upregulation of alphaV integrin, collagen-Ialpha2, and fibronectin-1 are involved in EMT. PMID- 30521668 TI - Opposing Effects of PPARalpha Agonism and Antagonism on Refractive Development and Form Deprivation Myopia in Guinea Pigs. AB - Purpose: To determine if drug-induced peroxisome proliferator-activated receptor alpha (PPARalpha) signal pathway modulation affects refractive development and myopia in guinea pigs. Methods: Pigmented guinea pigs were randomly divided into normal vision (unoccluded) and form deprivation myopia (FDM) groups. Each group received daily peribulbar injections of either a vehicle or (1) PPARalpha agonist, GW7647, clofibrate, or bezafibrate or (2) PPARalpha antagonist, GW6471, for 4 weeks. Baseline and posttreatment refraction and ocular biometric parameters were measured. Immunofluorescent staining of PPARalpha and two of its downstream readouts, cytosolic malic enzyme 1 (ME1) and apolipoproteinA II (apoA II), was undertaken in selected scleral sections. Western blot analysis determined collagen type I expression levels. Results: GW6471 induced a myopic shift in unoccluded eyes, but had no effect on form-deprived eyes. Conversely, GW7647 inhibited FDM progression without altering unoccluded eyes. Bezafibrate and clofibrate had effects on refraction similar to those of GW7647 in unoccluded and form-deprived eyes. GW6471 downregulated collagen type I expression in unoccluded eyes whereas bezafibrate inhibited collagen type I decreases in form deprived eyes. GW6471 also reduced the density of ME1- and apoA-II-stained cells in unoccluded eyes whereas bezafibrate increased apoA-II-positive cell numbers in form-deprived eyes. Conclusions: As GW7647 and GW6471 had opposing effects on myopia development, PPARalpha signaling modulation may be involved in this condition in guinea pigs. Fibrates are potential candidates for treating myopia since they reduced both FDM and the associated axial elongation. Bezafibrate also inhibited form deprivation-induced decreases in scleral collagen type I expression and the density of apoA-II expressing cells. PMID- 30521669 TI - Binocular Summation for Reflexive Eye Movements: A Potential Diagnostic Tool for Stereodeficiencies. AB - Purpose: Stereoscopic vision, by detecting interocular correlations, enhances depth perception. Stereodeficiencies often emerge during the first months of life, and left untreated can lead to severe loss of visual acuity in one eye and/or strabismus. Early treatment results in much better outcomes, yet diagnostic tests for infants are cumbersome and not widely available. We asked whether reflexive eye movements, which in principle can be recorded even in infants, can be used to identify stereodeficiencies. Methods: Reflexive ocular following eye movements induced by fast drifting noise stimuli were recorded in 10 adult human participants (5 with normal stereoacuity, 5 stereodeficient). To manipulate interocular correlation, the stimuli shown to the two eyes were either identical, different, or had opposite contrast. Monocular presentations were also interleaved. The participants were asked to passively fixate the screen. Results: In the participants with normal stereoacuity, the responses to binocular identical stimuli were significantly larger than those induced by binocular opposite stimuli. In the stereodeficient participants the responses were indistinguishable. Despite the small size of ocular following responses, 40 trials, corresponding to less than 2 minutes of testing, were sufficient to reliably differentiate normal from stereodeficient participants. Conclusions: Ocular-following eye movements, because of their reliance on cortical neurons sensitive to interocular correlations, are affected by stereodeficiencies. Because these eye movements can be recorded noninvasively and with minimal participant cooperation, they can potentially be measured even in infants and might thus provide an useful screening tool for this currently underserved population. PMID- 30521670 TI - Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. AB - BACKGROUND: Researchers have suggested that omega-3 polyunsaturated fatty acids from oily fish (long-chain omega-3 (LCn3), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), as well as from plants (alpha-linolenic acid (ALA)) benefit cardiovascular health. Guidelines recommend increasing omega-3 rich foods, and sometimes supplementation, but recent trials have not confirmed this. OBJECTIVES: To assess effects of increased intake of fish- and plant-based omega-3 for all-cause mortality, cardiovascular (CVD) events, adiposity and lipids. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to April 2017, plus ClinicalTrials.gov and World Health Organization International Clinical Trials Registry to September 2016, with no language restrictions. We handsearched systematic review references and bibliographies and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase LCn3 or ALA intake versus usual or lower intake. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data and assessed validity. We performed separate random-effects meta-analysis for ALA and LCn3 interventions, and assessed dose-response relationships through meta-regression. MAIN RESULTS: We included 79 RCTs (112,059 participants) in this review update and found that 25 were at low summary risk of bias. Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet. LCn3 doses ranged from 0.5g/d LCn3 to > 5 g/d (16 RCTs gave at least 3g/d LCn3).Meta-analysis and sensitivity analyses suggested little or no effect of increasing LCn3 on all-cause mortality (RR 0.98, 95% CI 0.90 to 1.03, 92,653 participants; 8189 deaths in 39 trials, high-quality evidence), cardiovascular mortality (RR 0.95, 95% CI 0.87 to 1.03, 67,772 participants; 4544 CVD deaths in 25 RCTs), cardiovascular events (RR 0.99, 95% CI 0.94 to 1.04, 90,378 participants; 14,737 people experienced events in 38 trials, high-quality evidence), coronary heart disease (CHD) mortality (RR 0.93, 95% CI 0.79 to 1.09, 73,491 participants; 1596 CHD deaths in 21 RCTs), stroke (RR 1.06, 95% CI 0.96 to 1.16, 89,358 participants; 1822 strokes in 28 trials) or arrhythmia (RR 0.97, 95% CI 0.90 to 1.05, 53,796 participants; 3788 people experienced arrhythmia in 28 RCTs). There was a suggestion that LCn3 reduced CHD events (RR 0.93, 95% CI 0.88 to 0.97, 84,301 participants; 5469 people experienced CHD events in 28 RCTs); however, this was not maintained in sensitivity analyses - LCn3 probably makes little or no difference to CHD event risk. All evidence was of moderate GRADE quality, except as noted.Increasing ALA intake probably makes little or no difference to all-cause mortality (RR 1.01, 95% CI 0.84 to 1.20, 19,327 participants; 459 deaths, 5 RCTs),cardiovascular mortality (RR 0.96, 95% CI 0.74 to 1.25, 18,619 participants; 219 cardiovascular deaths, 4 RCTs), and CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants; 193 CHD deaths, 3 RCTs) and ALA may make little or no difference to CHD events (RR 1.00, 95% CI 0.80 to 1.22, 19,061 participants, 397 CHD events, 4 RCTs, low quality evidence). However, increased ALA may slightly reduce risk of cardiovascular events (from 4.8% to 4.7%, RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence with greater effects in trials at low summary risk of bias), and probably reduces risk of arrhythmia (3.3% to 2.6%, RR 0.79, 95% CI 0.57 to 1.10, 4,837 participants; 141 events, 1 RCT). Effects on stroke are unclear.Sensitivity analysis retaining only trials at low summary risk of bias moved effect sizes towards the null (RR 1.0) for all LCn3 primary outcomes except arrhythmias, but for most ALA outcomes, effect sizes moved to suggest protection. LCn3 funnel plots suggested that adding in missing studies/results would move effect sizes towards null for most primary outcomes. There were no dose or duration effects in subgrouping or meta-regression.There was no evidence that increasing LCn3 or ALA altered serious adverse events, adiposity or lipids, except LCn3 reduced triglycerides by ~15% in a dose dependant way (high-quality evidence). AUTHORS' CONCLUSIONS: This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event and arrhythmia risk. PMID- 30521671 TI - Oral and intrauterine progestogens for atypical endometrial hyperplasia. AB - BACKGROUND: Endometrial carcinoma is the most common gynaecologic malignancy in the world and develops through preliminary stages of endometrial hyperplasia. Atypical endometrial hyperplasia suggests a significant pre-malignant state with frank progression to endometrial carcinoma, and tends to occur at a young age. Oral progestins have been used as conservative treatment in young women with atypical endometrial hyperplasia, but they are associated with poor tolerability and side effects that may limit their overall efficacy. So it has become increasingly important and necessary to find a safe and effective fertility sparing treatment with better tolerability and fewer side effects than the options currently available. The levonorgestrel-releasing intrauterine system (LNG-IUS) has been used to provide endometrial protection in women with breast cancer who are on adjuvant tamoxifen. The antiproliferative function of levonorgestrel is thought to reduce the risk of endometrial hyperplasia. OBJECTIVES: To determine the efficacy and safety of oral and intrauterine progestogens in treating atypical endometrial hyperplasia. SEARCH METHODS: In July 2018 we searched CENTRAL; MEDLINE; Embase; CINAHL, PsycINFO and the China National Knowledge Infrastructure for relevant trials. Cochrane Gynaecology and Fertility (CGF) Specialised Register and Embase were searched in November 2018. We attempted to identify trials from references in published studies. We also searched for ongoing trials in five major clinical trials registries. SELECTION CRITERIA: Randomised controlled trials (RCTs) of oral and intrauterine progestogens (LNG-IUS) versus each other or placebo in women with a confirmed histological diagnosis of simple or complex endometrial hyperplasia with atypia. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and extracted the data. The primary outcomes of the review were rate of regression and adverse effects. Secondary outcomes included rate of recurrence and proportion of women undergoing hysterectomy. We have used GRADE methodology to judge the quality of the evidence. MAIN RESULTS: We included one RCT (153 women) comparing the LNG-IUS administering 20 micrograms (MUu) levonorgestrel per day versus 10 milligrams of continuous or cyclical oral medroxyprogesterone (MPA) for treating any type of endometrial hyperplasia. Only 19 women in this study were histologically confirmed with atypical complex hyperplasia before treatment. The evidence was of low or very low quality. The included study was at low risk of bias, but the quality of the evidence was very seriously limited by imprecision and indirectness. We did not find any RCTS comparing the LNG-IUS or oral progestogens versus placebo in women with atypical endometrial hyperplasia.Among the 19 women with atypical complex hyperplasia, after six months of treatment there was insufficient evidence to determine whether there was a difference in regression rates between the LNG-IUS group and the progesterone group (odds ratio (OR) 2.76, 95% confidence interval (CI) 0.26 to 29.73; 1 RCT subgroup, 19 women, very low-quality evidence). The rate of regression was 100% in the LNG-IUS group (n = 6/6) and 77% in the progesterone group (n = 10/13).Among the total study population (N = 153), over the six months' treatment the main adverse effects were nausea and vaginal bleeding. There was no evidence of a difference between the groups in rates of nausea (OR 0.58, 95% CI 0.28 to 1.18; 1 RCT, 153 women, very low-quality evidence). Vaginal bleeding was more common in the LNG-IUS group (OR 2.89, 95% CI 1.11 to 7.52; 1 RCT, 153 women, low-quality evidence). Except for nausea and vaginal bleeding, no other adverse effects were reported. AUTHORS' CONCLUSIONS: We did not find any RCTS of women with atypical endometrial hyperplasia, and our findings derive from a subgroup of 19 women in a larger RCT. All six women who used the LNG-IUS system achieved regression of atypical hyperplasia, but there was insufficient evidence to draw any conclusions regarding the relative efficacy of LNG-IUS versus oral progesterone (MPA) in this group of women. When assessed in a population of women with any type of endometrial hyperplasia, there was no clear evidence of a difference between LNG-IUS and oral progesterone (MPA) in risk of nausea, but vaginal bleeding was more likely to occur in women using the LNG-IUS. Larger studies are necessary to assess the efficacy and safety of oral and intrauterine progestogens in treating atypical endometrial hyperplasia. PMID- 30521672 TI - Multi-light responsive quantum dot sensitized hybrid micromotors with dual-mode propulsion. AB - CdS quantum dots/C60 tubular micromotors with chemical/multi-light-controlled propulsion and "on-the-fly" acceleration capabilities are described. "In-situ" growth of CdS quantum dots on the outer fullerene layer impart them with light responsive properties in connection to inner Pt, Pd or MnO2 layers. This is the first time that visible-light is used to drive bubble propelled tubular micromotors. The micromotors exhibit broad absorption range from 320 to 670 nm and can be wirelessly-controlled by modulating light intensity and peroxide concentration. The built-in accelerating optical system allows for the control of the velocity over the entire UV and VIS light spectra by modulating the catalyst surface chemistry. The light responsive properties have been also exploited to accelerate the chemical dealloying and propulsion of micromotors containing a Cu/Pd layer. Such dual operated hybrid micromotors hold considerable promise for designing smart micromachines for on-demand operations, motion-based sensing and enhanced cargo transportation. PMID- 30521673 TI - Inhaled steroids with and without regular salmeterol for asthma: serious adverse events. AB - BACKGROUND: Epidemiological evidence has suggested a link between use of beta2 agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta2 agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018. SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration. DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations. MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I2 = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I2 = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I2 = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I2 = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I2 = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice. PMID- 30521674 TI - Early experience of transoral thyroidectomy: Comparison of robotic and endoscopic procedures. AB - BACKGROUND: The aim of this study was to evaluate the feasibility, safety, and early surgical outcomes of transoral thyroidectomy and to compare robotic and endoscopic procedures. METHODS: A total of 37 patients underwent robotic (23 cases) or endoscopic (14 cases) transoral thyroidectomy. We compared the outcomes of the two procedures. RESULTS: Of the 37 patients, 2 were converted to the robotic facelift approach as a result of an intraoperative CO2 embolism and inability to remove the tumor. The mean operative time was 172.8 +/- 37.5 minutes. Transient recurrent laryngeal nerve palsy occurred in one case, and transient hypoparathyroidism in two cases. Most of patients were satisfied with the postoperative cosmesis. There were no significant differences between the robotic and endoscopic procedures, except for operative time, which was significantly longer in the robotic group. CONCLUSION: Robotic and endoscopic transoral thyroidectomies are both feasible and safe in appropriate patients. PMID- 30521675 TI - Socioeconomic disparities in a population of patients undergoing total thyroidectomy for benign disease. AB - BACKGROUND: This study examines the effect of insurance status (as a measure of socioeconomic status) on patient with benign thyroid disease. METHODS: A retrospective review was performed among 60 patients undergoing total thyroidectomy for benign thyroid disease. Univariate and multivariable analyses examined the relationship between insurance status and thyroid volume (sum of the left and right lobe volumes). RESULTS: Twenty-eight (47%) patients were considered of underinsured/uninsured status, and 32 (53%) patients were considered of private/government/military insurance status. Median pathologic whole thyroid volume was 66 mL (range, 2-855). After multivariable linear regression, underinsured/uninsured status was the only significant predictor of larger volume (correlation coefficient [r] = 118; 95% CI, 42 to 194; P = .003), after adjusting for age, sex, body mass index, and presence of concomitant thyroid disease and compressive symptoms. CONCLUSION: Patients of underinsured/uninsured status suffered more severe disease presentations at time of thyroidectomy, as measured by larger thyroid volumes. PMID- 30521676 TI - Factors of local recurrence and organ preservation with transoral laser microsurgery in laryngeal carcinomas; CHAID decision-tree analysis. AB - BACKGROUND: Indications of transoral laser microsurgery (TLM) are conditioned by the risk of local relapse. OBJECTIVE: To evaluate prognostic factors of local relapse and local control with TLM (LC-TLM). METHODS: Local relapse and LC-TLM were evaluated in 1119 patients. Logistic regression and CHAID decision tree analysis were performed. RESULTS: Local relapse correlated to previous radiotherapy failure (8.45, CI 95%: 2.64-27.03; P < .001), paraglottic involvement (2.42, CI: 1.41-4.15; P = .001), anterior commissure involvement (2.12, CI: 1.43-3.14; P < .001), grade of differentiation (1.74, CI: 1.18-2.57; P = .005), and alcohol consumption (1.4, CI: 0.99-1.98; P = .057). Local relapse tended to inversely correlate with experience (0.73, CI: 0.51-1.03; P = .078). The most important factors for local relapse were previous radiotherapy failure and anterior commissure involvement. LC-TLM inversely correlated with previous radiotherapy failure (0.09, CI: 0.03-0.28; P < .001), paraglottic involvement (0.25, CI: 0.14-0.43; P < .001), anterior commissure involvement (0.49, CI: 0.32 0.77; P = .007), margins (0.56, CI: 0.30-1.04; P = .068), and differentiation (0.68, CI: 0.44-1.05; P = .087). LC-TLM correlated with experience (1.71, CI: 1.13-2.55; P = .010). The most important factors for LC-TLM were previous radiotherapy failure and paraglottic involvement. CONCLUSION: Previous radiotherapy failure is the most important factor for local relapse and LC-TLM. In primary treatments, anterior commissure involvement and paraglottic involvement are the most important factors for local relapse and LC-TLM, respectively. PMID- 30521677 TI - Acute effects of zinc and insulin on arcuate anorexigenic Proopiomelanocortin (POMC) neurons. AB - BACKGROUND AND PURPOSE: Acute insulin administration results in a hyperpolarization and concomitant decrease of firing rate in a subpopulation of arcuate Proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) cells. This rapid effect on cellular activity has been implicated as a cellular correlate of insulin effects on energy balance and glucose homeostasis. Recent evidence suggests that zinc in mammalian insulin formulations is required for the insulin-induced inhibition of arcuate POMC neurons, while guinea-pig insulin, which fails to bind zinc, activates POMC neurons in mice. Here, we tested the effects of zinc and insulin formations on arcuate POMC neurons. EXPERIMENTAL APPROACH: The effects of zinc and insulin formulations were assessed through whole-cell patch clamp recordings on transgenic mice in vitro. KEY RESULTS: Insulin formulations containing zinc hyperpolarized POMC neurons. Zinc also hyperpolarized arcuate POMC neurons, albeit at much higher concentration than found in various insulin formulations. Chelation of zinc caused a rightward shift in the dose response of the zinc-induced hyperpolarization of POMC neurons, while the insulin effects on POMC cellular activity remained intact after chelation. Zinc-free insulin also hyperpolarized arcuate POMC neurons. Moreover, insulin failed to hyperpolarize POMC neurons deficient for insulin receptors, suggesting that insulin receptors are required for these effects. Notably, the activation of POMC neurons by guinea pig insulin was independent of insulin receptors while abrogated with PDGF receptor antagonism or loss of TRPC5 subunits. CONCLUSIONS & IMPLICATIONS: Together, these findings suggest insulin inhibits arcuate POMC neurons independent of zinc, and highlights a possible role of putative PDGF receptors in the acute effects of guinea pig insulin. PMID- 30521678 TI - A simple DNAzyme-based fluorescent assay for Klebsiella pneumoniae. AB - Pathogenic bacteria pose a serious public health threat. Rapid and cost effective detection of such bacteria remains a major challenge. Here, we present a DNAzyme based fluorescent paper sensor for Klebsiella pneumoniae. The DNAzyme was generated by an in vitro selection technique to cleave a fluorogenic DNA-RNA chimeric substrate in the presence of K. pneumoniae. The DNAzyme was printed on a paper substrate in a 96 well format to serve as mix-and-read fluorescent assay which exhibited a limit of detection (LOD) 105 CFUs/mL. It was evaluated with 20 strains of clinical bacterial isolates and the DNAzyme produced the desired fluorescence signal with the samples of K. pneumoniae, regardless of their source or drug resistance. The assay is simple to use, rapid, inexpensive, avoids complex procedures of sample preparation and equipment. We believe, this DNAzyme based fluorescent assay has potential for practical applications to identify K. pneumoniae. PMID- 30521679 TI - Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. AB - BACKGROUND: Observational studies suggest higher pregnancy rates after the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions, which are present in 10% to 15% of women seeking treatment for subfertility. OBJECTIVES: To assess the effects of the hysteroscopic removal of endometrial polyps, submucous fibroids, uterine septum or intrauterine adhesions suspected on ultrasound, hysterosalpingography, diagnostic hysteroscopy or any combination of these methods in women with otherwise unexplained subfertility or prior to intrauterine insemination (IUI), in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the following databases from their inception to 16 April 2018; The Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies Online, ; MEDLINE, Embase , CINAHL , and other electronic sources of trials including trial registers, sources of unpublished literature, and reference lists. We handsearched the American Society for Reproductive Medicine (ASRM) conference abstracts and proceedings (from 1 January 2014 to 12 May 2018) and we contacted experts in the field. SELECTION CRITERIA: Randomised comparison between operative hysteroscopy versus control for unexplained subfertility associated with suspected major uterine cavity abnormalities.Randomised comparison between operative hysteroscopy versus control for suspected major uterine cavity abnormalities prior to medically assisted reproduction.Primary outcomes were live birth and hysteroscopy complications. Secondary outcomes were pregnancy and miscarriage. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, and extracted data. We contacted study authors for additional information. MAIN RESULTS: Two studies met the inclusion criteria.1. Randomised comparison between operative hysteroscopy versus control for unexplained subfertility associated with suspected major uterine cavity abnormalities.In women with otherwise unexplained subfertility and submucous fibroids, we were uncertain whether hysteroscopic myomectomy improved the clinical pregnancy rate compared to expectant management (odds ratio (OR) 2.44, 95% confidence interval (CI) 0.97 to 6.17; P = 0.06, 94 women; very low-quality evidence). We are uncertain whether hysteroscopic myomectomy improves the miscarriage rate compared to expectant management (OR 1.54, 95% CI 0.47 to 5.00; P = 0.47, 94 women; very low-quality evidence). We found no data on live birth or hysteroscopy complication rates. We found no studies in women with endometrial polyps, intrauterine adhesions or uterine septum for this randomised comparison.2. Randomised comparison between operative hysteroscopy versus control for suspected major uterine cavity abnormalities prior to medically assisted reproduction.The hysteroscopic removal of polyps prior to IUI may have improved the clinical pregnancy rate compared to diagnostic hysteroscopy only: if 28% of women achieved a clinical pregnancy without polyp removal, the evidence suggested that 63% of women (95% CI 45% to 89%) achieved a clinical pregnancy after the hysteroscopic removal of the endometrial polyps (OR 4.41, 95% CI 2.45 to 7.96; P < 0.00001, 204 women; low quality evidence). We found no data on live birth, hysteroscopy complication or miscarriage rates in women with endometrial polyps prior to IUI. We found no studies in women with submucous fibroids, intrauterine adhesions or uterine septum prior to IUI or in women with all types of suspected uterine cavity abnormalities prior to IVF/ICSI. AUTHORS' CONCLUSIONS: Uncertainty remains concerning an important benefit with the hysteroscopic removal of submucous fibroids for improving the clinical pregnancy rates in women with otherwise unexplained subfertility. The available low-quality evidence suggests that the hysteroscopic removal of endometrial polyps suspected on ultrasound in women prior to IUI may improve the clinical pregnancy rate compared to simple diagnostic hysteroscopy. More research is needed to measure the effectiveness of the hysteroscopic treatment of suspected major uterine cavity abnormalities in women with unexplained subfertility or prior to IUI, IVF or ICSI. PMID- 30521680 TI - Acupuncture and related interventions for the treatment of symptoms associated with carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is a compressive neuropathic disorder at the level of the wrist. Acupuncture and other methods that stimulate acupuncture points, such as electroacupuncture, auricular acupuncture, laser acupuncture, moxibustion, and acupressure, are used in treating CTS. Acupuncture has been recommended as a potentially useful treatment for CTS, but its effectiveness remains uncertain. We used Cochrane methodology to assess the evidence from randomised and quasi-randomised trials of acupuncture for symptoms in people with CTS. OBJECTIVES: To assess the benefits and harms of acupuncture and acupuncture related interventions compared to sham or active treatments for the management of pain and other symptoms of CTS in adults. SEARCH METHODS: On 13 November 2017, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL Plus, DARE, HTA, and NHS EED. In addition, we searched six Korean medical databases, and three Chinese medical databases from inception to 30 April 2018. We also searched clinical trials registries for ongoing trials. SELECTION CRITERIA: We included randomised and quasi-randomised trials examining the effects of acupuncture and related interventions on the symptoms of CTS in adults. Eligible studies specified diagnostic criteria for CTS. We included outcomes measured at least three weeks after randomisation. The included studies compared acupuncture and related interventions to placebo/sham treatments, or to active interventions, such as steroid nerve blocks, oral steroid, splints, non steroidal anti-inflammatory drugs (NSAIDs), surgery and physical therapy. DATA COLLECTION AND ANALYSIS: The review authors followed standard Cochrane methods. MAIN RESULTS: We included 12 studies with 869 participants. Ten studies reported the primary outcome of overall clinical improvement at short-term follow-up (3 months or less) after randomisation. Most studies could not be combined in a meta analysis due to heterogeneity, and all had an unclear or high overall risk of bias.Seven studies provided information on adverse events. Non-serious adverse events included skin bruising with electroacupuncture and local pain after needle insertion. No serious adverse events were reported.One study (N = 41) comparing acupuncture to sham/placebo reported change on the Boston Carpal Tunnel Questionnaire (BCTQ) Symptom Severity Scale (SSS) at three months after treatment (mean difference (MD) -0.23, 95% confidence interval (CI) -0.79 to 0.33) and the BCTQ Functional Status Scale (FSS) (MD -0.03, 95% CI -0.69 to 0.63), with no clear difference between interventions; the evidence was of low certainty. The only dropout was due to painful acupuncture. Another study of acupuncture versus placebo/sham acupuncture (N = 111) provided no usable data.Two studies assessed laser acupuncture versus sham laser acupuncture. One study (N = 60), which was at low risk of bias, provided low-certainty evidence of a better Global Symptom Scale (GSS) score with active treatment at four weeks after treatment (MD 7.46, 95% CI 4.71 to 10.22; range of possible GSS scores is 0 to 50) and a higher response rate (risk ratio (RR) 1.59, 95% CI 1.14 to 2.22). No serious adverse events were reported in either group. The other study (N = 25) did not assess overall symptom improvement.One trial (N = 77) of conventional acupuncture versus oral corticosteroids provided very low-certainty evidence of greater improvement in GSS score (scale 0 to 50) at 13 months after treatment with acupuncture (MD 8.25, 95% CI 4.12 to 12.38) and a higher responder rate (RR 1.73, 95% CI 1.22 to 2.45). Change in GSS at two weeks or four weeks after treatment showed no clear difference between groups. Adverse events occurred in 18% of the oral corticosteroid group and 5% of the acupuncture group (RR 0.29, 95% CI 0.06 to 1.32). One study comparing electroacupuncture and oral corticosteroids reported a clinically insignificant difference in change in BCTQ score at four weeks after treatment (MD -0.30, 95% CI -0.71 to 0.10; N = 52).Combined data from two studies comparing the responder rate with acupuncture versus vitamin B12, produced a RR of 1.16 (95% CI 0.99 to 1.36; N = 100, very low-certainty evidence). No serious adverse events occurred in either group.One study of conventional acupuncture versus ibuprofen in which all participants wore night splints found very low certainty evidence of a lower symptom score on the SSS of the BCTQ with acupuncture (MD -5.80, 95% CI -7.95 to -3.65; N = 50) at one month after treatment. Five people had adverse events with ibuprofen and none with acupuncture.One study of electroacupuncture versus night splints found no clear difference between the groups on the SSS of the BCTQ (MD 0.14, 95% CI -0.15 to 0.43; N = 60; very low-certainty evidence). Six people had adverse events with electroacupuncture and none with splints. One study of electroacupuncture plus night splints versus night splints alone presented no difference between the groups on the SSS of the BCTQ at 17 weeks (MD -0.16, 95% CI -0.36 to 0.04; N = 181, low-certainty evidence). No serious adverse events occurred in either group.One study comparing acupuncture plus NSAIDs and vitamins versus NSAIDs and vitamins alone showed no clear difference on the BCTQ SSS at four weeks (MD 0.20, 95% CI -0.86 to 0.46; very low-certainty evidence). There was no reporting on adverse events. AUTHORS' CONCLUSIONS: Acupuncture and laser acupuncture may have little or no effect in the short term on symptoms of CTS in comparison with placebo or sham acupuncture. It is uncertain whether acupuncture and related interventions are more or less effective in relieving symptoms of CTS than corticosteroid nerve blocks, oral corticosteroids, vitamin B12, ibuprofen, splints, or when added to NSAIDs plus vitamins, as the certainty of any conclusions from the evidence is low or very low and most evidence is short term. The included studies covered diverse interventions, had diverse designs, limited ethnic diversity, and clinical heterogeneity. High-quality randomised controlled trials (RCTs) are necessary to rigorously assess the effects of acupuncture and related interventions upon symptoms of CTS. Based on moderate to very-low certainty evidence, acupuncture was associated with no serious adverse events, or reported discomfort, pain, local paraesthesia and temporary skin bruises, but not all studies provided adverse event data. PMID- 30521681 TI - Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults. AB - BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Early detection and treatment is key to improving survival; however, anxiety around missing early cases needs to be balanced against appropriate levels of referral and excision of benign lesions. Used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may reduce unnecessary excisions without missing melanoma cases. OBJECTIVES: To determine the diagnostic accuracy of reflectance confocal microscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with any lesion suspicious for melanoma and lesions that are difficult to diagnose, and to compare its accuracy with that of dermoscopy. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; and seven other databases. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated RCM alone, or RCM in comparison to dermoscopy, in adults with lesions suspicious for melanoma or atypical intraepidermal melanocytic variants, compared with a reference standard of either histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. To compare RCM with dermoscopy, we grouped studies by population (defined by difficulty of lesion diagnosis) and combined data using hierarchical summary receiver operating characteristic (SROC) methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of specificity at the point on the SROC curve with 90% sensitivity as this value lies within the estimates for the majority of analyses. We investigated the impact of using a purposely developed RCM algorithm and in-person test interpretation. MAIN RESULTS: The search identified 18 publications reporting on 19 study cohorts with 2838 lesions (including 658 with melanoma), which provided 67 datasets for RCM and seven for dermoscopy. Studies were generally at high or unclear risk of bias across almost all domains and of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, lack of blinding of the reference test to the RCM result, and differential verification were particularly problematic. Studies may not be representative of populations eligible for RCM, and test interpretation was often undertaken remotely from the patient and blinded to clinical information.Meta-analysis found RCM to be more accurate than dermoscopy in studies of participants with any lesion suspicious for melanoma and in participants with lesions that were more difficult to diagnose (equivocal lesion populations). Assuming a fixed sensitivity of 90% for both tests, specificities were 82% for RCM and 42% for dermoscopy for any lesion suspicious for melanoma (9 RCM datasets; 1452 lesions and 370 melanomas). For a hypothetical population of 1000 lesions at the median observed melanoma prevalence of 30%, this equated to a reduction in unnecessary excisions with RCM of 280 compared to dermoscopy, with 30 melanomas missed by both tests. For studies in equivocal lesions, specificities of 86% would be observed for RCM and 49% for dermoscopy (7 RCM datasets; 1177 lesions and 180 melanomas). At the median observed melanoma prevalence of 20%, this reduced unnecessary excisions by 296 with RCM compared with dermoscopy, with 20 melanomas missed by both tests. Across all populations, algorithms and thresholds assessed, the sensitivity and specificity of the Pellacani RCM score at a threshold of three or greater were estimated at 92% (95% confidence interval (CI) 87 to 95) for RCM and 72% (95% CI 62 to 81) for dermoscopy. AUTHORS' CONCLUSIONS: RCM may have a potential role in clinical practice, particularly for the assessment of lesions that are difficult to diagnose using visual inspection and dermoscopy alone, where the evidence suggests that RCM may be both more sensitive and specific in comparison to dermoscopy. Given the paucity of data to allow comparison with dermoscopy, the results presented require further confirmation in prospective studies comparing RCM with dermoscopy in a real-world setting in a representative population. PMID- 30521682 TI - Dermoscopy, with and without visual inspection, for diagnosing melanoma in adults. AB - BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of 'tests' to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other high resolution image analysis techniques. OBJECTIVES: To determine the diagnostic accuracy of dermoscopy alone, or when added to visual inspection of a skin lesion, for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in-person), or based on remote (image-based), assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary receiver operating characteristic (SROC),methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. MAIN RESULTS: We included a total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases), providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as 'high' concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in person (dermoscopy added to visual inspection), and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) 4.6, 95% confidence interval (CI) 2.4 to 9.0; P < 0.001).We compared accuracy for (a), in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas),versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas), and for (b), image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas),versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a), 4.7 (95% CI 3.0 to 7.5; P < 0.001), and (b), 5.6 (95% CI 3.7 to 8.5; P < 0.001). For a), the predicted difference in sensitivity at a fixed specificity of 80% was 16% (95% CI 8% to 23%; 92% for dermoscopy + visual inspection versus 76% for visual inspection), and predicted difference in specificity at a fixed sensitivity of 80% was 20% (95% CI 7% to 33%; 95% for dermoscopy + visual inspection versus 75% for visual inspection). For b) the predicted differences in sensitivity was 34% (95% CI 24% to 46%; 81% for dermoscopy versus 47% for visual inspection), at a fixed specificity of 80%, and predicted difference in specificity was 40% (95% CI 27% to 57%; 82% for dermoscopy versus 42% for visual inspection), at a fixed sensitivity of 80%.Using the median prevalence of disease in each set of studies ((a), 12% for in-person and (b), 24% for image-based), for a hypothetical population of 1000 lesions, an increase in sensitivity of (a), 16% (in-person), and (b), 34% (image-based), from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a), 19 and (b), 81 with (a), 176 and (b), 152 false positive results. An increase in specificity of (a), 20% (in-person), and (b), 40% (image-based), at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a), 176 and (b), 304 with (a), 24 and (b), 48 melanomas missed.The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis), had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34 to 5.6; P = 0.17), or image-based (RDOR 1.4, 95% CI 0.60 to 3.3; P = 0.22), evaluations. This result was supported by subgroup analysis according to algorithm used. We observed higher accuracy for observers reported as having high experience and for those classed as 'expert consultants' in comparison to those considered to have less experience in dermoscopy, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. AUTHORS' CONCLUSIONS: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care are limited, however, it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in person are lacking. PMID- 30521683 TI - High-frequency ultrasound for diagnosing skin cancer in adults. AB - BACKGROUND: Early, accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers with the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised, with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique that relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high frequency ultrasound (HFUS) with transducer frequencies of 20 MHz or more has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical and/or dermoscopic examination of suspected skin cancer, HFUS may offer additional diagnostic information compared to other technologies. OBJECTIVES: To assess the diagnostic accuracy of HFUS to assist in the diagnosis of a) cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, b) cutaneous squamous cell carcinoma (cSCC), and c) basal cell carcinoma (BCC) in adults. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists as well as published systematic review articles. SELECTION CRITERIA: Studies evaluating HFUS (20 MHz or more) in adults with lesions suspicious for melanoma, cSCC or BCC versus a reference standard of histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS 2). Due to scarcity of data and the poor quality of studies, we did not undertake a meta-analysis for this review. For illustrative purposes, we plot estimates of sensitivity and specificity on coupled forest plots. MAIN RESULTS: We included six studies, providing 29 datasets: 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). We did not identify any data relating to the diagnosis of cSCC.Studies were generally poorly reported, limiting judgements of methodological quality. Half the studies did not set out to establish test accuracy, and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data-driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to lack of visualisation in the test.Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies (lower limits of the 95% CIs were 94% and 82%), with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%), respectively. Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities. AUTHORS' CONCLUSIONS: Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between-study heterogeneity, unclear to low methodological quality and limited volume of evidence, we cannot draw any implications for practice. The main value of the preliminary studies included may be in providing guidance on the possible components of new diagnostic rules for diagnosis of melanoma or BCC using HFUS that will require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard healthcare setting, with a clearly defined and representative population of participants, would be required for a full and proper evaluation of accuracy. PMID- 30521684 TI - Visual inspection for diagnosing cutaneous melanoma in adults. AB - BACKGROUND: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. History-taking and visual inspection of a suspicious lesion by a clinician is usually the first in a series of 'tests' to diagnose skin cancer. Establishing the accuracy of visual inspection alone is critical to understating the potential contribution of additional tests to assist in the diagnosis of melanoma. OBJECTIVES: To determine the diagnostic accuracy of visual inspection for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with limited prior testing and in those referred for further evaluation of a suspicious lesion. Studies were separated according to whether the diagnosis was recorded face-to-face (in person) or based on remote (image-based) assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: CENTRAL; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Test accuracy studies of any design that evaluated visual inspection in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. We excluded studies reporting data for 'clinical diagnosis' where dermoscopy may or may not have been used. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. We investigated the impact of: in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise. MAIN RESULTS: We included 49 publications reporting on a total of 51 study cohorts with 34,351 lesions (including 2499 cases), providing 134 datasets for visual inspection. Across almost all study quality domains, the majority of study reports provided insufficient information to allow us to judge the risk of bias, while in three of four domains that we assessed we scored concerns regarding applicability of study findings as 'high'. Selective participant recruitment, lack of detail regarding the threshold for deciding on a positive test result, and lack of detail on observer expertise were particularly problematic.Attempts to analyse studies by degree of prior testing were hampered by a lack of relevant information and by the restricted inclusion of lesions selected for biopsy or excision. Accuracy was generally much higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio of 8.54, 95% CI 2.89 to 25.3, P < 0.001). Meta analysis of in-person evaluations that could be clearly placed on the clinical pathway showed a general trade-off between sensitivity and specificity, with the highest sensitivity (92.4%, 95% CI 26.2% to 99.8%) and lowest specificity (79.7%, 95% CI 73.7% to 84.7%) observed in participants with limited prior testing (n = 3 datasets). Summary sensitivities were lower for those referred for specialist assessment but with much higher specificities (e.g. sensitivity 76.7%, 95% CI 61.7% to 87.1%) and specificity 95.7%, 95% CI 89.7% to 98.3%) for lesions selected for excision, n = 8 datasets). These differences may be related to differences in the spectrum of included lesions, differences in the definition of a positive test result, or to variations in observer expertise. We did not find clear evidence that accuracy is improved by the use of any algorithm to assist diagnosis in all settings. Attempts to examine the effect of observer expertise in melanoma diagnosis were hindered due to poor reporting. AUTHORS' CONCLUSIONS: Visual inspection is a fundamental component of the assessment of a suspicious skin lesion; however, the evidence suggests that melanomas will be missed if visual inspection is used on its own. The evidence to support its accuracy in the range of settings in which it is used is flawed and very poorly reported. Although published algorithms do not appear to improve accuracy, there is insufficient evidence to suggest that the 'no algorithm' approach should be preferred in all settings. Despite the volume of research evaluating visual inspection, further prospective evaluation of the potential added value of using established algorithms according to the prior testing or diagnostic difficulty of lesions may be warranted. PMID- 30521685 TI - Smartphone applications for triaging adults with skin lesions that are suspicious for melanoma. AB - BACKGROUND: Melanoma accounts for a small proportion of all skin cancer cases but is responsible for most skin cancer-related deaths. Early detection and treatment can improve survival. Smartphone applications are readily accessible and potentially offer an instant risk assessment of the likelihood of malignancy so that the right people seek further medical attention from a clinician for more detailed assessment of the lesion. There is, however, a risk that melanomas will be missed and treatment delayed if the application reassures the user that their lesion is low risk. OBJECTIVES: To assess the diagnostic accuracy of smartphone applications to rule out cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with concerns about suspicious skin lesions. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design evaluating smartphone applications intended for use by individuals in a community setting who have lesions that might be suspicious for melanoma or atypical intraepidermal melanocytic variants versus a reference standard of histological confirmation or clinical follow-up and expert opinion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, we did not perform a meta-analysis for this review. For illustrative purposes, we plotted estimates of sensitivity and specificity on coupled forest plots for each application under consideration. MAIN RESULTS: This review reports on two cohorts of lesions published in two studies. Both studies were at high risk of bias from selective participant recruitment and high rates of non-evaluable images. Concerns about applicability of findings were high due to inclusion only of lesions already selected for excision in a dermatology clinic setting, and image acquisition by clinicians rather than by smartphone app users.We report data for five mobile phone applications and 332 suspicious skin lesions with 86 melanomas across the two studies. Across the four artificial intelligence-based applications that classified lesion images (photographs) as melanomas (one application) or as high risk or 'problematic' lesions (three applications) using a pre-programmed algorithm, sensitivities ranged from 7% (95% CI 2% to 16%) to 73% (95% CI 52% to 88%) and specificities from 37% (95% CI 29% to 46%) to 94% (95% CI 87% to 97%). The single application using store-and forward review of lesion images by a dermatologist had a sensitivity of 98% (95% CI 90% to 100%) and specificity of 30% (95% CI 22% to 40%).The number of test failures (lesion images analysed by the applications but classed as 'unevaluable' and excluded by the study authors) ranged from 3 to 31 (or 2% to 18% of lesions analysed). The store-and-forward application had one of the highest rates of test failure (15%). At least one melanoma was classed as unevaluable in three of the four application evaluations. AUTHORS' CONCLUSIONS: Smartphone applications using artificial intelligence-based analysis have not yet demonstrated sufficient promise in terms of accuracy, and they are associated with a high likelihood of missing melanomas. Applications based on store-and-forward images could have a potential role in the timely presentation of people with potentially malignant lesions by facilitating active self-management health practices and early engagement of those with suspicious skin lesions; however, they may incur a significant increase in resource and workload. Given the paucity of evidence and low methodological quality of existing studies, it is not possible to draw any implications for practice. Nevertheless, this is a rapidly advancing field, and new and better applications with robust reporting of studies could change these conclusions substantially. PMID- 30521686 TI - Teledermatology for diagnosing skin cancer in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Teledermatology provides a way for generalist clinicians to access the opinion of a specialist dermatologist for skin lesions that they consider to be suspicious without referring the patients through the normal referral pathway. Teledermatology consultations can be 'store-and-forward' with electronic digital images of a lesion sent to a dermatologist for review at a later time, or can be live and interactive consultations using videoconferencing to connect the patient, referrer and dermatologist in real time. OBJECTIVES: To determine the diagnostic accuracy of teledermatology for the detection of any skin cancer (melanoma, BCC or cutaneous squamous cell carcinoma (cSCC)) in adults, and to compare its accuracy with that of in-person diagnosis. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, CPCI, Zetoc, Science Citation Index, US National Institutes of Health Ongoing Trials Register, NIHR Clinical Research Network Portfolio Database and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies evaluating skin cancer diagnosis for teledermatology alone, or in comparison with face-to-face diagnosis by a specialist clinician, compared with a reference standard of histological confirmation or clinical follow-up and expert opinion. We also included studies evaluating the referral accuracy of teledermatology compared with a reference standard of face-to-face diagnosis by a specialist clinician. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where there were information related to the target condition of any skin cancer missing. Data permitting, we estimated summary sensitivities and specificities using the bivariate hierarchical model. Due to the scarcity of data, we undertook no covariate investigations for this review. For illustrative purposes, we plotted estimates of sensitivity and specificity on coupled forest plots for diagnostic threshold and target condition under consideration. MAIN RESULTS: The review included 22 studies reporting diagnostic accuracy data for 4057 lesions and 879 malignant cases (16 studies) and referral accuracy data for reported data for 1449 lesions and 270 'positive' cases as determined by the reference standard face-to-face decision (six studies). Methodological quality was variable with poor reporting hindering assessment. The overall risk of bias was high or unclear for participant selection, reference standard, and participant flow and timing in at least half of all studies; the majority were at low risk of bias for the index test. The applicability of study findings were of high or unclear concern for most studies in all domains assessed due to the recruitment of participants from secondary care settings or specialist clinics rather than from primary or community-based settings in which teledermatology is more likely to be used and due to the acquisition of lesion images by dermatologists or in specialist imaging units rather than by primary care clinicians.Seven studies provided data for the primary target condition of any skin cancer (1588 lesions and 638 malignancies). For the correct diagnosis of lesions as malignant using photographic images, summary sensitivity was 94.9% (95% confidence interval (CI) 90.1% to 97.4%) and summary specificity was 84.3% (95% CI 48.5% to 96.8%) (from four studies). Individual study estimates using dermoscopic images or a combination of photographic and dermoscopic images generally suggested similarly high sensitivities with highly variable specificities. Limited comparative data suggested similar diagnostic accuracy between teledermatology assessment and in person diagnosis by a dermatologist; however, data were too scarce to draw firm conclusions. For the detection of invasive melanoma or atypical intraepidermal melanocytic variants both sensitivities and specificities were more variable. Sensitivities ranged from 59% (95% CI 42% to 74%) to 100% (95% CI 48% to 100%) and specificities from 30% (95% CI 22% to 40%) to 100% (95% CI 93% to 100%), with reported diagnostic thresholds including the correct diagnosis of melanoma, classification of lesions as 'atypical' or 'typical, and the decision to refer or to excise a lesion.Referral accuracy data comparing teledermatology against a face-to-face reference standard suggested good agreement for lesions considered to require some positive action by face-to-face assessment (sensitivities of over 90%). For lesions considered of less concern when assessed face-to-face (e.g. for lesions not recommended for excision or referral), agreement was more variable with teledermatology specificities ranging from 57% (95% CI 39% to 73%) to 100% (95% CI 86% to 100%), suggesting that remote assessment is more likely recommend excision, referral or follow-up compared to in-person decisions. AUTHORS' CONCLUSIONS: Studies were generally small and heterogeneous and methodological quality was difficult to judge due to poor reporting. Bearing in mind concerns regarding the applicability of study participants and of lesion image acquisition in specialist settings, our results suggest that teledermatology can correctly identify the majority of malignant lesions. Using a more widely defined threshold to identify 'possibly' malignant cases or lesions that should be considered for excision is likely to appropriately triage those lesions requiring face-to-face assessment by a specialist. Despite the increasing use of teledermatology on an international level, the evidence base to support its ability to accurately diagnose lesions and to triage lesions from primary to secondary care is lacking and further prospective and pragmatic evaluation is needed. PMID- 30521687 TI - Reflectance confocal microscopy for diagnosing keratinocyte skin cancers in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is important to guide appropriate management and improve morbidity and survival. Basal cell carcinoma (BCC) is usually a localised skin cancer but with potential to infiltrate and damage surrounding tissue, whereas cutaneous squamous cell carcinoma (cSCC) and melanoma are higher risk skin cancers with the potential to metastasise and ultimately lead to death. When used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may help to identify cancers eligible for non-surgical treatment without the need for a diagnostic biopsy, particularly in people with suspected BCC. Any potential benefit must be balanced against the risk of any misdiagnoses. OBJECTIVES: To determine the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with any suspicious lesion and lesions that are difficult to diagnose (equivocal); and to compare its accuracy with that of usual practice (visual inspection or dermoscopy, or both). SEARCH METHODS: We undertook a comprehensive search of the following databases from inception to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated the accuracy of RCM alone, or RCM in comparison to visual inspection or dermoscopy, or both, in adults with lesions suspicious for skin cancer compared with a reference standard of either histological confirmation or clinical follow-up, or both. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities using the bivariate hierarchical model. For computation of likely numbers of true-positive, false-positive, false-negative, and true-negative findings in the 'Summary of findings' tables, we applied summary sensitivity and specificity estimates to lower quartile, median and upper quartiles of the prevalence observed in the study groups. We also investigated the impact of observer experience. MAIN RESULTS: The review included 10 studies reporting on 11 study cohorts. All 11 cohorts reported data for the detection of BCC, including 2037 lesions (464 with BCC); and four cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only one study also reported data for the detection of BCC or cSCC using dermoscopy, limiting comparisons between RCM and dermoscopy. Studies were at high or unclear risk of bias across almost all methodological quality domains, and were of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, unclear blinding of the reference test, and exclusions due to image quality or technical difficulties were observed. It was unclear whether studies were representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the participant and the interpreter blinded to clinical information that would normally be available in practice.Meta analysis found RCM to be more sensitive but less specific for the detection of BCC in studies of participants with equivocal lesions (sensitivity 94%, 95% confidence interval (CI) 79% to 98%; specificity 85%, 95% CI 72% to 92%; 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI 45% to 92%; specificity 95%, 95% CI 66% to 99%; 4 studies), although CIs were wide. At the median prevalence of disease of 12.5% observed in studies including any suspicious lesion, applying these results to a hypothetical population of 1000 lesions results in 30 BCCs missed with 44 false-positive results (lesions misdiagnosed as BCCs). At the median prevalence of disease of 15% observed in studies of equivocal lesions, nine BCCs would be missed with 128 false-positive results in a population of 1000 lesions. Across both sets of studies, up to 15% of these false-positive lesions were observed to be melanomas mistaken for BCCs. There was some suggestion of higher sensitivities in studies with more experienced observers. Summary sensitivity and specificity could not be estimated for the detection of cSCC due to paucity of data. AUTHORS' CONCLUSIONS: There is insufficient evidence for the use of RCM for the diagnosis of BCC or cSCC in either population group. A possible role for RCM in clinical practice is as a tool to avoid diagnostic biopsies in lesions with a relatively high clinical suspicion of BCC. The potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research. Importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy). PMID- 30521688 TI - Visual inspection and dermoscopy, alone or in combination, for diagnosing keratinocyte skin cancers in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is important to guide appropriate management, to reduce morbidity and to improve survival. Basal cell carcinoma (BCC) is almost always a localised skin cancer with potential to infiltrate and damage surrounding tissue, whereas a minority of cutaneous squamous cell carcinomas (cSCCs) and invasive melanomas are higher-risk skin cancers with the potential to metastasise and cause death. Dermoscopy has become an important tool to assist specialist clinicians in the diagnosis of melanoma, and is increasingly used in primary-care settings. Dermoscopy is a precision built handheld illuminated magnifier that allows more detailed examination of the skin down to the level of the superficial dermis. Establishing the value of dermoscopy over and above visual inspection for the diagnosis of BCC or cSCC in primary- and secondary-care settings is critical to understanding its potential contribution to appropriate skin cancer triage, including referral of higher-risk cancers to secondary care, the identification of low-risk skin cancers that might be treated in primary care and to provide reassurance to those with benign skin lesions who can be safely discharged. OBJECTIVES: To determine the diagnostic accuracy of visual inspection and dermoscopy, alone or in combination, for the detection of (a) BCC and (b) cSCC, in adults. We separated studies according to whether the diagnosis was recorded face-to-face (in person) or based on remote (image-based) assessment. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated visual inspection or dermoscopy or both in adults with lesions suspicious for skin cancer, compared with a reference standard of either histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic thresholds were missing. We estimated accuracy using hierarchical summary ROC methods. We undertook analysis of studies allowing direct comparison between tests. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in person test interpretation; use of a purposely-developed algorithm to assist diagnosis; and observer expertise. MAIN RESULTS: We included 24 publications reporting on 24 study cohorts, providing 27 visual inspection datasets (8805 lesions; 2579 malignancies) and 33 dermoscopy datasets (6855 lesions; 1444 malignancies). The risk of bias was mainly low for the index test (for dermoscopy evaluations) and reference standard domains, particularly for in-person evaluations, and high or unclear for participant selection, application of the index test for visual inspection and for participant flow and timing. We scored concerns about the applicability of study findings as of 'high' or 'unclear' concern for almost all studies across all domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic.The detection of BCC was reported in 28 datasets; 15 on an in-person basis and 13 image-based. Analysis of studies by prior testing of participants and according to observer expertise was not possible due to lack of data. Studies were primarily conducted in participants referred for specialist assessment of lesions with available histological classification. We found no clear differences in accuracy between dermoscopy studies undertaken in person and those which evaluated images. The lack of effect observed may be due to other sources of heterogeneity, including variations in the types of skin lesion studied, in dermatoscopes used, or in the use of algorithms and varying thresholds for deciding on a positive test result.Meta-analysis found in-person evaluations of dermoscopy (7 evaluations; 4683 lesions and 363 BCCs) to be more accurate than visual inspection alone for the detection of BCC (8 evaluations; 7017 lesions and 1586 BCCs), with a relative diagnostic odds ratio (RDOR) of 8.2 (95% confidence interval (CI) 3.5 to 19.3; P < 0.001). This corresponds to predicted differences in sensitivity of 14% (93% versus 79%) at a fixed specificity of 80% and predicted differences in specificity of 22% (99% versus 77%) at a fixed sensitivity of 80%. We observed very similar results for the image-based evaluations.When applied to a hypothetical population of 1000 lesions, of which 170 are BCC (based on median BCC prevalence across studies), an increased sensitivity of 14% from dermoscopy would lead to 24 fewer BCCs missed, assuming 166 false positive results from both tests. A 22% increase in specificity from dermoscopy with sensitivity fixed at 80% would result in 183 fewer unnecessary excisions, assuming 34 BCCs missed for both tests. There was not enough evidence to assess the use of algorithms or structured checklists for either visual inspection or dermoscopy.Insufficient data were available to draw conclusions on the accuracy of either test for the detection of cSCCs. AUTHORS' CONCLUSIONS: Dermoscopy may be a valuable tool for the diagnosis of BCC as an adjunct to visual inspection of a suspicious skin lesion following a thorough history-taking including assessment of risk factors for keratinocyte cancer. The evidence primarily comes from secondary-care (referred) populations and populations with pigmented lesions or mixed lesion types. There is no clear evidence supporting the use of currently-available formal algorithms to assist dermoscopy diagnosis. PMID- 30521689 TI - Exfoliative cytology for diagnosing basal cell carcinoma and other skin cancers in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management, reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin but has potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non-invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC it has the potential to provide an immediate diagnosis that avoids an additional clinic visit to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non-surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to better understand in which skin cancer situations it may be helpful. OBJECTIVES: To determine the diagnostic accuracy of exfoliative cytology for detecting basal cell carcinoma (BCC) in adults, and to compare its accuracy with that of standard diagnostic practice (visual inspection with or without dermoscopy). Secondary objectives were: to determine the diagnostic accuracy of exfoliative cytology for detecting cSCC, invasive melanoma and atypical intraepidermal melanocytic variants, and any other skin cancer; and for each of these secondary conditions to compare the accuracy of exfoliative cytology with visual inspection with or without dermoscopy in direct test comparisons; and to determine the effect of observer experience. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles. SELECTION CRITERIA: Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model. MAIN RESULTS: We synthesised the results of nine studies contributing a total of 1655 lesions to our analysis, including 1120 BCCs (14 datasets), 41 cSCCs (amongst 401 lesions in 2 datasets), and 10 melanomas (amongst 200 lesions in 1 dataset). Three of these datasets (one each for BCC, melanoma and any malignant condition) were derived from one study that also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality, providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of participants' prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in participants with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI 94.5% to 98.9%) and 90.1% (95% CI 81.1% to 95.1%). respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy. AUTHORS' CONCLUSIONS: The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity. Since decisions to treat low-risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality prevent us from drawing strong conclusions to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis. PMID- 30521690 TI - Optical coherence tomography for diagnosing skin cancer in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high-risk skin cancers, which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised, with potential to infiltrate and damage surrounding tissue. Anxiety around missing early cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Optical coherence tomography (OCT) is a microscopic imaging technique, which magnifies the surface of a skin lesion using near-infrared light. Used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, OCT may offer additional diagnostic information compared to other technologies. OBJECTIVES: To determine the diagnostic accuracy of OCT for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, basal cell carcinoma (BCC), or cutaneous squamous cell carcinoma (cSCC) in adults. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: We included studies of any design evaluating OCT in adults with lesions suspicious for invasive melanoma and atypical intraepidermal melanocytic variants, BCC or cSCC, compared with a reference standard of histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardised data extraction and quality assessment form (based on QUADAS-2). Our unit of analysis was lesions. Where possible, we estimated summary sensitivities and specificities using the bivariate hierarchical model. MAIN RESULTS: We included five studies with 529 cutaneous lesions (282 malignant lesions) providing nine datasets for OCT, two for visual inspection alone, and two for visual inspection plus dermoscopy. Studies were of moderate to unclear quality, using data-driven thresholds for test positivity and giving poor accounts of reference standard interpretation and blinding. Studies may not have been representative of populations eligible for OCT in practice, for example due to high disease prevalence in study populations, and may not have reflected how OCT is used in practice, for example by using previously acquired OCT images.It was not possible to make summary statements regarding accuracy of detection of melanoma or of cSCC because of the paucity of studies, small sample sizes, and for melanoma differences in the OCT technologies used (high-definition versus conventional resolution OCT), and differences in the degree of testing performed prior to OCT (i.e. visual inspection alone or visual inspection plus dermoscopy).Pooled data from two studies using conventional swept-source OCT alongside visual inspection and dermoscopy for the detection of BCC estimated the sensitivity of OCT as 95% (95% confidence interval (CI) 91% to 97%) and specificity of 77% (95% CI 69% to 83%).When applied to a hypothetical population of 1000 lesions at the mean observed BCC prevalence of 60%, OCT would miss 31 BCCs (91 fewer than would be missed by visual inspection alone and 53 fewer than would be missed by visual inspection plus dermoscopy), and OCT would lead to 93 false-positive results for BCC (a reduction in unnecessary excisions of 159 compared to using visual inspection alone and of 87 compared to visual inspection plus dermoscopy). AUTHORS' CONCLUSIONS: Insufficient data are available on the use of OCT for the detection of melanoma or cSCC. Initial data suggest conventional OCT may have a role for the diagnosis of BCC in clinically challenging lesions, with our meta-analysis showing a higher sensitivity and higher specificity when compared to visual inspection plus dermoscopy. However, the small number of studies and varying methodological quality means implications to guide practice cannot currently be drawn.Appropriately designed prospective comparative studies are required, given the paucity of data comparing OCT with dermoscopy and other similar diagnostic aids such as reflectance confocal microscopy. PMID- 30521692 TI - Pre-emptive and preventive opioids for postoperative pain in adults undergoing all types of surgery. AB - BACKGROUND: Postoperative pain is a common consequence of surgery and can have deleterious effects. It has been suggested that the administration of opioid analgesia before a painful stimulus may improve pain control. This can be done in two ways. We defined 'preventive opioids' as opioids administered before incision and continued postoperatively, and 'pre-emptive opioids' as opioids given before incision but not continued postoperatively. Both pre-emptive and preventive analgesia involve the initiation of an analgesic agent prior to surgical incision with the aim of reducing intraoperative nociception and therefore postoperative pain. OBJECTIVES: To assess the efficacy of preventive and pre-emptive opioids for reducing postoperative pain in adults undergoing all types of surgery. SEARCH METHODS: We searched the following electronic databases: CENTRAL, MEDLINE, Embase, AMED, and CINAHL (up to 18 March 2018). In addition, we searched for unpublished studies in three clinical trial databases, conference proceedings, grey literature databases, and reference lists of retrieved articles. We did not apply any restrictions on language or date of publication. SELECTION CRITERIA: We included parallel-group randomized controlled trials (RCTs) only. We included participants aged over 15 years old undergoing any type of surgery. We defined postincision opioids as the same intervention administered after incision whether single dose (as comparator with pre-emptive analgesia) or continued postoperatively (as comparator with preventive analgesia) (control group). We considered studies that did and did not use a double-dummy placebo (e.g. intervention group received active drug before incision and placebo after incision; control group received placebo before incision and active drug after incision). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were: early acute postoperative pain (measured within six hours and reported on a 0-to-10 scale) and respiratory depression. Our secondary outcomes included: late acute postoperative pain (24 to 48 hours and reported on a 0-to-10 scale), 24-hour morphine consumption, and adverse events (intraoperative bradycardia and hypotension). We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: We included 20 RCTs, including one unpublished study with 1343 participants. Two studies were awaiting classification as the full text for these studies was not available. One study evaluated pre-emptive opioids, and 19 studies evaluated preventive opioids. We considered only one study to be at low risk of bias for most domains. The surgeries and opioids used varied, although roughly half of the included studies were conducted in abdominal hysterectomy, and around a quarter used morphine as the intervention. All studies were conducted in secondary care.Pre-emptive opioids compared to postincision opioidsFor pre-emptive opioids in dental surgery, there may be a reduction in early acute postoperative pain (mean difference (MD) -1.20, 95% confidence interval (CI) -1.75 to -0.65; 40 participants; 1 study; low-quality evidence). This study did not report on adverse events (respiratory depression, bradycardia, or hypotension). There may be a reduction in late acute postoperative pain (MD 2.10, 95% CI -2.57 to -1.63; 40 participants; 1 study; low-quality evidence). This study did not report 24-hour morphine consumption.Preventive opioids compared to postincision opioidsFor preventive opioids, there was probably no reduction in early acute postoperative pain (MD 0.11, 95% CI -0.32 to 0.53; 706 participants; 10 studies; I2 = 61%; moderate-quality evidence). There were no events of respiratory depression in four studies (433 participants). There was no important reduction in late acute postoperative pain (MD -0.06, 95% CI -0.13 to 0.01; 668 participants; 9 studies; I2 = 0%; moderate-quality evidence). There may be a small reduction in 24-hour morphine consumption (MD -4.91 mg, 95% CI -9.39 mg to -0.44 mg; 526 participants; 11 studies; I2 = 82%; very low-quality evidence). There may be similar rates of bradycardia (risk ratio (RR) 0.33, 95% CI 0.01 to 7.88; 112 participants; 2 studies; I2 = 0%; low-quality evidence) and hypotension (RR 1.08, 95% CI 0.25 to 4.73; 88 participants; 2 studies; I2 = 0%; low-quality evidence). AUTHORS' CONCLUSIONS: Due to the low quality of the evidence, we are uncertain whether pre-emptive opioids reduce postoperative pain. Based on the trials conducted thus far, there was no clear evidence that preventive opioids result in reductions in pain scores. It was unclear if there was a reduction in morphine consumption due to very low-quality of evidence. Too few studies reported adverse events to be able to draw any definitive conclusions. Once assessed, the two studies awaiting classification may alter the conclusions of the review. PMID- 30521691 TI - Computer-assisted diagnosis techniques (dermoscopy and spectroscopy-based) for diagnosing skin cancer in adults. AB - BACKGROUND: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and cutaneous squamous cell carcinoma (cSCC) are high-risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Computer-assisted diagnosis (CAD) systems use artificial intelligence to analyse lesion data and arrive at a diagnosis of skin cancer. When used in unreferred settings ('primary care'), CAD may assist general practitioners (GPs) or other clinicians to more appropriately triage high-risk lesions to secondary care. Used alongside clinical and dermoscopic suspicion of malignancy, CAD may reduce unnecessary excisions without missing melanoma cases. OBJECTIVES: To determine the accuracy of CAD systems for diagnosing cutaneous invasive melanoma and atypical intraepidermal melanocytic variants, BCC or cSCC in adults, and to compare its accuracy with that of dermoscopy. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. SELECTION CRITERIA: Studies of any design that evaluated CAD alone, or in comparison with dermoscopy, in adults with lesions suspicious for melanoma or BCC or cSCC, and compared with a reference standard of either histological confirmation or clinical follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities separately by type of CAD system, using the bivariate hierarchical model. We compared CAD with dermoscopy using (a) all available CAD data (indirect comparisons), and (b) studies providing paired data for both tests (direct comparisons). We tested the contribution of human decision-making to the accuracy of CAD diagnoses in a sensitivity analysis by removing studies that gave CAD results to clinicians to guide diagnostic decision-making. MAIN RESULTS: We included 42 studies, 24 evaluating digital dermoscopy-based CAD systems (Derm-CAD) in 23 study cohorts with 9602 lesions (1220 melanomas, at least 83 BCCs, 9 cSCCs), providing 32 datasets for Derm-CAD and seven for dermoscopy. Eighteen studies evaluated spectroscopy-based CAD (Spectro-CAD) in 16 study cohorts with 6336 lesions (934 melanomas, 163 BCC, 49 cSCCs), providing 32 datasets for Spectro-CAD and six for dermoscopy. These consisted of 15 studies using multispectral imaging (MSI), two studies using electrical impedance spectroscopy (EIS) and one study using diffuse reflectance spectroscopy. Studies were incompletely reported and at unclear to high risk of bias across all domains. Included studies inadequately address the review question, due to an abundance of low-quality studies, poor reporting, and recruitment of highly selected groups of participants.Across all CAD systems, we found considerable variation in the hardware and software technologies used, the types of classification algorithm employed, methods used to train the algorithms, and which lesion morphological features were extracted and analysed across all CAD systems, and even between studies evaluating CAD systems. Meta-analysis found CAD systems had high sensitivity for correct identification of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in highly selected populations, but with low and very variable specificity, particularly for Spectro CAD systems. Pooled data from 22 studies estimated the sensitivity of Derm-CAD for the detection of melanoma as 90.1% (95% confidence interval (CI) 84.0% to 94.0%) and specificity as 74.3% (95% CI 63.6% to 82.7%). Pooled data from eight studies estimated the sensitivity of multispectral imaging CAD (MSI-CAD) as 92.9% (95% CI 83.7% to 97.1%) and specificity as 43.6% (95% CI 24.8% to 64.5%). When applied to a hypothetical population of 1000 lesions at the mean observed melanoma prevalence of 20%, Derm-CAD would miss 20 melanomas and would lead to 206 false-positive results for melanoma. MSI-CAD would miss 14 melanomas and would lead to 451 false diagnoses for melanoma. Preliminary findings suggest CAD systems are at least as sensitive as assessment of dermoscopic images for the diagnosis of invasive melanoma and atypical intraepidermal melanocytic variants. We are unable to make summary statements about the use of CAD in unreferred populations, or its accuracy in detecting keratinocyte cancers, or its use in any setting as a diagnostic aid, because of the paucity of studies. AUTHORS' CONCLUSIONS: In highly selected patient populations all CAD types demonstrate high sensitivity, and could prove useful as a back-up for specialist diagnosis to assist in minimising the risk of missing melanomas. However, the evidence base is currently too poor to understand whether CAD system outputs translate to different clinical decision-making in practice. Insufficient data are available on the use of CAD in community settings, or for the detection of keratinocyte cancers. The evidence base for individual systems is too limited to draw conclusions on which might be preferred for practice. Prospective comparative studies are required that evaluate the use of already evaluated CAD systems as diagnostic aids, by comparison to face-to-face dermoscopy, and in participant populations that are representative of those in which the test would be used in practice. PMID- 30521693 TI - Pharmacological interventions for acute hepatitis C infection. AB - BACKGROUND: Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required. PMID- 30521694 TI - Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pulmonary disease (COPD): a systematic review and network meta analysis. AB - BACKGROUND: Long-acting bronchodilators such as long-acting beta-agonist (LABA), long-acting muscarinic antagonist (LAMA), and LABA/inhaled corticosteroid (ICS) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease (COPD) to control symptoms such as dyspnoea and cough, and prevent exacerbations. A number of LABA/LAMA combinations are now available for clinical use in COPD. However, it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class. OBJECTIVES: To compare the efficacy and safety of available formulations from four different groups of inhalers (i.e. LABA/LAMA combination, LABA/ICS combination, LAMA and LABA) in people with moderate to severe COPD. The review will update previous systematic reviews on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta-analysis (NMA). SEARCH METHODS: We identified studies from the Cochrane Airways Specialised Register, which contains several databases. We also conducted a search of ClinicalTrials.gov and manufacturers' websites. The most recent searches were conducted on 6 April 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that recruited people aged 35 years or older with a diagnosis of COPD and a baseline forced expiratory volume in one second (FEV1) of less than 80% of predicted. We included studies of at least 12 weeks' duration including at least two active comparators from one of the four inhaler groups. DATA COLLECTION AND ANALYSIS: We conducted NMAs using a Bayesian Markov chain Monte Carlo method. We considered a study as high risk if recruited participants had at least one COPD exacerbation within the 12 months before study entry and as low risk otherwise. Primary outcomes were COPD exacerbations (moderate to severe and severe), and secondary outcomes included symptom and quality-of-life scores, safety outcomes, and lung function. We collected data only for active comparators and did not consider placebo was not considered. We assumed a class/group effect when a fixed-class model fitted well. Otherwise we used a random-class model to assess intraclass/group differences. We supplemented the NMAs with pairwise meta analyses. MAIN RESULTS: We included a total of 101,311 participants from 99 studies (26 studies with 32,265 participants in the high-risk population and 73 studies with 69,046 participants in the low-risk population) in our systematic review. The median duration of studies was 52 weeks in the high-risk population and 26 weeks in the low-risk population (range 12 to 156 for both populations). We considered the quality of included studies generally to be good.The NMAs suggested that the LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations followed by LAMA in the both populations.There is evidence that the LABA/LAMA combination decreases moderate to severe exacerbations compared to LABA/ICS combination, LAMA, and LABA in the high-risk population (network hazard ratios (HRs) 0.86 (95% credible interval (CrI) 0.76 to 0.99), 0.87 (95% CrI 0.78 to 0.99), and 0.70 (95% CrI 0.61 to 0.8) respectively), and that LAMA decreases moderate to severe exacerbations compared to LABA in the high- and low-risk populations (network HR 0.80 (95% CrI 0.71 to 0.88) and 0.87 (95% CrI 0.78 to 0.97), respectively). There is evidence that the LABA/LAMA combination reduces severe exacerbations compared to LABA/ICS combination and LABA in the high-risk population (network HR 0.78 (95% CrI 0.64 to 0.93) and 0.64 (95% CrI 0.51 to 0.81), respectively).There was a general trend towards a greater improvement in symptom and quality-of-life scores with the combination therapies compared to monotherapies, and the combination therapies were generally ranked higher than monotherapies.The LABA/ICS combination was the lowest ranked in pneumonia serious adverse events (SAEs) in both populations. There is evidence that the LABA/ICS combination increases the odds of pneumonia compared to LAMA/LABA combination, LAMA and LABA (network ORs: 1.69 (95% CrI 1.20 to 2.44), 1.78 (95% CrI 1.33 to 2.39), and 1.50 (95% CrI 1.17 to 1.92) in the high-risk population and network or pairwise OR: 2.33 (95% CI 1.03 to 5.26), 2.02 (95% CrI 1.16 to 3.72), and 1.93 (95% CrI 1.29 to 3.22) in the low-risk population respectively). There were significant overlaps in the rank statistics in the other safety outcomes including mortality, total, COPD, and cardiac SAEs, and dropouts due to adverse events.None of the differences in lung function met a minimal clinically important difference criterion except for LABA/LAMA combination versus LABA in the high-risk population (network mean difference 0.13 L (95% CrI 0.10 to 0.15). The results of pairwise meta-analyses generally agreed with those of the NMAs. There is no evidence to suggest intraclass/group differences except for lung function at 12 months in the high-risk population. AUTHORS' CONCLUSIONS: The LABA/LAMA combination was the highest ranked treatment group to reduce COPD exacerbations although there was some uncertainty in the results. LAMA containing inhalers may have an advantage over those without a LAMA for preventing COPD exacerbations based on the rank statistics. Combination therapies appear more effective than monotherapies for improving symptom and quality-of-life scores. ICS-containing inhalers are associated with an increased risk of pneumonia.Our most comprehensive review including intraclass/group comparisons, free combination therapies, 99 studies, and 20 outcomes for each high- and low-risk population summarises the current literature and could help with updating existing COPD guidelines. PMID- 30521695 TI - Vaccines for preventing invasive salmonella infections in people with sickle cell disease. AB - BACKGROUND: Salmonella infections are a common bacterial cause of invasive disease in people with sickle cell disease especially children, and are associated with high morbidity and mortality rates. Although available in some centres, people with sickle cell anaemia are not routinely immunized with salmonella vaccines. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether routine administration of salmonella vaccines to people with sickle cell disease reduces the morbidity and mortality associated with infection. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.We also conducted a search of the LILACS database and the World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) and ClinicalTrials.gov (www.clinicaltrials.gov).Date of most recent searches: 17 October 2018. SELECTION CRITERIA: We planned to select all randomized controlled trials that compared the use of either the inactivated vaccine or an oral attenuated vaccine with a placebo among people with sickle cell disease. Equally, studies that compared the efficacy of one vaccine type over another were to be selected for the review. DATA COLLECTION AND ANALYSIS: No trials of salmonella vaccines in people with sickle cell disease were found. MAIN RESULTS: There is an absence of randomized controlled trial evidence relating to the scope of this review. AUTHORS' CONCLUSIONS: It is expected that salmonella vaccines may be useful in people with sickle cell disease, especially in resource-poor settings where the majority of those who suffer from the condition are found. Unfortunately, there are no randomized controlled trials on the efficacy and safety of the different types of salmonella vaccines in people with sickle cell disease. We conclude that there is a need for a well-designed, adequately-powered, randomized controlled trial to assess the benefits and risks of the different types of salmonella vaccines as a means of improving survival and decreasing mortality from salmonella infections in people with sickle cell disease. However, we believe that there are unlikely to be any trials published in this area, therefore, this review will no longer be regularly updated. PMID- 30521696 TI - Psychosocial interventions to reduce alcohol consumption in concurrent problem alcohol and illicit drug users. AB - BACKGROUND: Problem alcohol use is common among people who use illicit drugs (PWID) and is associated with adverse health outcomes. It is also an important factor contributing to a poor prognosis among drug users with hepatitis C virus (HCV) as it impacts on progression to hepatic cirrhosis or opioid overdose in PWID. OBJECTIVES: To assess the effectiveness of psychosocial interventions to reduce alcohol consumption in PWID (users of opioids and stimulants). SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, and PsycINFO, from inception up to August 2017, and the reference lists of eligible articles. We also searched: 1) conference proceedings (online archives only) of the Society for the Study of Addiction, International Harm Reduction Association, International Conference on Alcohol Harm Reduction and American Association for the Treatment of Opioid Dependence; and 2) online registers of clinical trials: Current Controlled Trials, ClinicalTrials.gov, Center Watch and the World Health Organization International Clinical Trials Registry Platform. SELECTION CRITERIA: We included randomised controlled trials comparing psychosocial interventions with other psychosocial treatment, or treatment as usual, in adult PWIDs (aged at least 18 years) with concurrent problem alcohol use. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included seven trials (825 participants). We judged the majority of the trials to have a high or unclear risk of bias.The psychosocial interventions considered in the studies were: cognitive-behavioural coping skills training (one study), twelve-step programme (one study), brief intervention (three studies), motivational interviewing (two studies), and brief motivational interviewing (one study). Two studies were considered in two comparisons. There were no data for the secondary outcome, alcohol-related harm. The results were as follows.Comparison 1: cognitive-behavioural coping skills training versus twelve-step programme (one study, 41 participants)There was no significant difference between groups for either of the primary outcomes (alcohol abstinence assessed with Substance Abuse Calendar and breathalyser at one year: risk ratio (RR) 2.38 (95% confidence interval [CI] 0.10 to 55.06); and retention in treatment, measured at end of treatment: RR 0.89 (95% CI 0.62 to 1.29), or for any of the secondary outcomes reported. The quality of evidence for the primary outcomes was very low.Comparison 2: brief intervention versus treatment as usual (three studies, 197 participants)There was no significant difference between groups for either of the primary outcomes (alcohol use, measured as scores on the Alcohol Use Disorders Identification Test (AUDIT) or Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) at three months: standardised mean difference (SMD) 0.07 (95% CI -0.24 to 0.37); and retention in treatment, measured at three months: RR 0.94 (95% CI 0.78 to 1.13), or for any of the secondary outcomes reported. The quality of evidence for the primary outcomes was low.Comparison 3: motivational interviewing versus treatment as usual or educational intervention only (three studies, 462 participants)There was no significant difference between groups for either of the primary outcomes (alcohol use, measured as scores on the AUDIT or ASSIST at three months: SMD 0.04 (95% CI -0.29 to 0.37); and retention in treatment, measured at three months: RR 0.93 (95% CI 0.60 to 1.43), or for any of the secondary outcomes reported. The quality of evidence for the primary outcomes was low.Comparison 4: brief motivational intervention (BMI) versus assessment only (one study, 187 participants)More people reduced alcohol use (by seven or more days in the past month, measured at six months) in the BMI group than in the control group (RR 1.67; 95% CI 1.08 to 2.60). There was no difference between groups for the other primary outcome, retention in treatment, measured at end of treatment: RR 0.98 (95% CI 0.94 to 1.02), or for any of the secondary outcomes reported. The quality of evidence for the primary outcomes was moderate.Comparison 5: motivational interviewing (intensive) versus motivational interviewing (one study, 163 participants)There was no significant difference between groups for either of the primary outcomes (alcohol use, measured using the Addiction Severity Index-alcohol score (ASI) at two months: MD 0.03 (95% CI 0.02 to 0.08); and retention in treatment, measured at end of treatment: RR 17.63 (95% CI 1.03 to 300.48), or for any of the secondary outcomes reported. The quality of evidence for the primary outcomes was low. AUTHORS' CONCLUSIONS: We found low to very low-quality evidence to suggest that there is no difference in effectiveness between different types of psychosocial interventions to reduce alcohol consumption among people who use illicit drugs, and that brief interventions are not superior to assessment-only or to treatment as usual. No firm conclusions can be made because of the paucity of the data and the low quality of the retrieved studies. PMID- 30521697 TI - Catalyst-Controlled 1,2- and 1,1-Arylboration of alpha-Alkyl Alkenylarenes. AB - Two methods are reported that achieve the 1,2- and 1,1-arylboration of alpha alkyl alkenylarenes. In the case of 1,2-arylboration, the formation of quaternary centers was achieved through a rare cross-coupling of a tertiary organometallic complex. 1,1-Arylboration was accomplished through catalyst optimization and occurs through a beta-hydride elimination/reinsertion cascade. In both cases, enantioselective variants are presented as well as mechanistic investigation. PMID- 30521698 TI - Discovery of affinity-based probes for Btk occupancy assay. AB - Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of the aforementioned diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the Btk protein by these Btk covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12. 12 has been used in Btk occupancy assay for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. PMID- 30521699 TI - Intensive versus standard multifactorial cardiovascular risk factor control in screen-detected type 2 diabetes: 5 year and longer-term modelled outcomes of the ADDITION-Leicester study. AB - AIMS: Diabetes treatment algorithms recommend intensive intervention in those with a shorter duration of disease. Screening provides opportunities for earlier multifactorial cardiovascular risk factor control. Using data from the ADDITION Leicester study (NCT00318032), we estimated the effects of this approach on modelled risk of diabetes related complications in screen-detected patients. METHODS: 345(41% South Asian) people with screen-detected type 2 diabetes were cluster randomised to receive 5-years of 1)intensive multifactorial risk factor intervention or 2)standard treatment according to national guidance. Estimated 10 20 year risk of ischaemic heart disease, stroke, congestive cardiac failure and death were calculated using UK-PDS risk equations. RESULTS: Compared to standard care, mean treatment differences for intensive management at 5 years were; 11.7(95%CI:-15.0,-8.4) and -6.6(-8.8,-4.4) mmHg for systolic and diastolic blood pressure, respectively; -0.27 (-0.66, -0.26) % for HbA1c; and -0.46(-0.66; 0.26), -0.34 (-0.51; -0.18), and -0.19 (-0.28; -0.10) mmol/l for total cholesterol, LDL-cholesterol, and triglycerides, respectively. There was no significant weight gain in the intensive group despite additional medication use. Modelled risks were consistently lower for intensively managed patients. Absolute risk reduction associated with intensive treatment at 10 and 20 years were 3.5% and 6.2% for ischaemic heart disease and 6.3% and 8.8% for stroke. Risk reduction for congestive heart failure plateaued after 15 years at 5.3%. No differences were observed for blindness and all-cause death. CONCLUSION: Intensive multifactorial intervention in a multi-ethnic population with screen-detected type 2 diabetes results in sustained improvements in modelled ischaemic heart disease, stroke and congestive cardiac failure. PMID- 30521700 TI - [Thanks to our reviewers 2017]. AB - No Abstract available. PMID- 30521701 TI - [Infrapectineal plate for repair with minimal invasion of quadrilateral blade acetabular fractures: description new implant and paramedial access]. AB - INTRODUCTION: Quadrilateral plate fractures are the most difficult to reduce and fix. Different techniques have been developed for quadrilateral plate osteosynthesis. The objective of this work was to create an implant and a novel approach to simplify and improve acetabular fracture osteosynthesis. MATERIAL AND METHODS: A total of 83 patients were studied. Pelvic CT scan images of both acetabula were measured at the proximal and distal posterior column. Implant length, diameters and morphological characteristics were determined. The anatomical features of a novel surgical approach are described. The paramedian approach was performed on a cadaveric specimen to determine its anatomical safety. RESULTS: The screws measured 20 * 6 * 8 mm (length * core diameter x head diameter), with internal threads of 4.5 mm. The Kolmogorov-Smirnov (Lilliefors) test was used, where p had to be 0.05. Plates were previously determined to be 10 mm wide and 3 mm thick, of variable length. Instruments were developed to surmount difficulties. DISCUSSION: This new procedure and implant could make the repair of acetabular fractures easier and offers several advantages. Clinical trials are needed to assess the benefits of this proposal. The newly described method can allow acetabular fracture osteosynthesis to be performed safely, avoid iatrogenic injury to anatomical structures and achieve better results. PMID- 30521702 TI - [Functional results and complications of the use of the proximal femoral nail in the treatment of intertrochanteric hip fractures]. AB - INTRODUCTION: Cephalomedullary nails are used for the treatment of hip fractures; however, there are few studies that allow identifying data on the complications of the use of these devices and the results in terms of restoration of the functionality of the patient. METHODS: A cross-sectional study of patients with femur fracture was conducted during the period from January 2008 to December 2012. Data on demographic and clinical variables were collected. Telephone follow up was performed up to six postoperative months. A descriptive analysis was done using absolute and relative frequency measurements. Quantitative variables are presented with averages and standard deviation or median and interquartile range, according to the normality of the data. RESULTS: 82.9% of the patients managed to walk with or without help within six months after surgery; anemia (16.2%), urinary tract infection (9.7%), pneumonia (9.5%) and myocardial infarction (0.7%) were the main complications. Of the patients included, 57.1% had an ASA level 3; a mortality rate of 16% was identified. DISCUSSION: Cephalomedullary nails show positive results regarding recovery of functional mobility and a low prevalence of complications, with similar mortality to that reported in the literature at 6 months of follow up. PMID- 30521703 TI - [Prevalence of osteoporosis and osteopenia in patients occupationally active]. AB - BACKGROUND: Osteoporosis is a public health problem worldwide, affecting more than 200 million people. It is estimated that 30 to 50% of postmenopausal women suffer from it. According to the International Osteoporosis Foundation (IOF), osteoporosis is a disease characterized by a decrease in the density and quality of bones. The objective of this work was to know the prevalence of osteoporosis and osteopenia in healthy active workers. METHODS: Retrospective, observational study with active male and female workers in whom bone mineral density was evaluated by dual X-ray absorptiometry (DXA) of the hip and spine. The evaluation time was from June 2009 to June 2010. RESULTS: A total of 1,431 patients were recruited: 258 (18%) men and 1,173 (82%) women. According to the international parameters, the diagnoses of the central densitometries were, overall: 572 normal subjects (40%), 601 (42%) with osteopenia and 258 (18%) with osteoporosis. DISCUSSION: The results show that degenerative alterations in patients with osteoporosis or osteopenia are frequent, even among young people. PMID- 30521704 TI - [Continuous vs. intermitent intravenous analgesia for primary total knee replacement: analysis of the quality of the pain control, hospital stay and costs]. AB - BACKGROUND: The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Total knee arthroplasty is one of the orthopedic surgeries that manifests more pain in the first 24-48 hours, needing a multimodal analgesic therapy. The objective of this work is to compare two different intravenous analgesic modes applied to patients undergoing a primary total knee arthroplasty, analyzing the quality of pain control, hospital stay and costs. MATERIAL AND METHODS: Simple blind, comparative and prospective study comprised of 42 patients operated of total knee arthroplasty secondary to degenerative arthritis in the period between May 2016 and May 2017. RESULTS: The distribution of pain showed significant differences (p 0.0401) between both groups, indicating that the application of continuous pump for analgesia controls this symptom early. The hospital stay, on average, was different in the groups (p = 0.001), estimating about 15 hours less following the use of continuous pump. This strategy is globally more economic. DISCUSSION: The continuous infusion pump of analgesia compared with intermittent formal intravenous regimen showed better control of pain, decreasing the perception of pain by the patient, bettering the tolerance to physical therapy and reducing, on average, 15 hours of hospital stay, and thus, the final costs of the surgery. PMID- 30521705 TI - [Complex fractures of the clavicles lateral third]. AB - BACKGROUND: Fractures of the lateral third of the clavicle represent 18% of all clavicle fractures. Even though non-displaced fractures can be managed conservatively, displaced fractures have a non-union percentage of 30%. Multiple approaches have been proposed to manage the displaced fractures. The objective of this study was to record the prevalence of fractures of the lateral third of the clavicle with involvement of the clavicular-acromial joint, as well as to briefly review the treatment performed in our center and compare it with the current literature. MATERIAL AND METHODS: Retrospective, cross-sectional, descriptive and observational study, which consisted in a review of the records of patients with a diagnosis of fracture of the lateral third of the clavicle with an injury to the clavicular-acromial joint. RESULTS: Lateral third fractures accounted for 24% of all clavicle fractures. Distribution by sex: 10: 2, men: women. Left shoulder predominance, 8:4. The predominant maneuvers were anatomical plate for the lateral third of the clavicle (50% of the cases), coracoclavicular cerclage technique plus resection of the lateral third of the clavicle (25%), plate hook (8.3%), Mumford combined with Waever/Dunn (8.3%), anchor plus Kirschner rods (8.3%). DISCUSSION: The choice of the appropriate treatment will depend on the type of fracture and specific characteristics of each patient. We suggest the use of the coracoclavicular cerclage technique in cases in which the lateral fragment is multifragmented, irreducible or smaller in size than its osteosynthesis would allow, performing plasty of clavicular and coracoclavicular ligaments. PMID- 30521706 TI - [Quantification of changes in the external morphology of the back by means of surface topography based on structured light in idiopathic scoliosis in adolescents after a year of treatment with orthopedic corse]. AB - BACKGROUND: To quantify the morphological changes in the surface of the back of adolescents with idiopathic scoliosis as a result of treatment with braces and to correlate them with radiographic changes. MATERIAL AND METHODS: An analytical, cohort, prospective study on a sample of 31 adolescents with idiopathic scoliosis. We divided them into two groups: eleven treated with braces and twenty without them. Quantification of the deformity was performed on two separate occasions with an interval of one year using three systems: 1) angle of trunk rotation (scoliometer); 2) surface topography; 3) full spine X-rays. RESULTS: No statistically significant differences were detected between the initial and final assessment of the topographic and radiographic variables in the group with braces. In the untreated group, only in measures with the scoliometer significant differences were registered. A positive correlation was found between the Cobb angle difference of the main curve with two topographic variables that quantify the asymmetry in the axial and coronal plane, respectively. DISCUSSION: In following patients with scoliosis treated with braces, we should consider and evaluate not only radiographic parameters such as the Cobb angle, but also clinical and topographic parameters that quantify the external deformity of the back, as there is a clinical-radiographic discrepancy amply demonstrated in the literature. The improvement of the external shape of the back is a very important factor for the patient, and can influence a better completion of the orthopedic treatment. In our study, the scoliotic curve and external deformity of the back remained stable during the follow-up period in both treated and untreated patients. PMID- 30521707 TI - [Postoperative functional angular anatomy in patients with anterior cruciate ligament with autologous graft]. AB - BACKGROUND: Reconstruction of the anterior cruciate ligament (ACL) aims to restore the original anatomy. The clinical outcome could be imperfect when graft placement is not in an anatomical position; moreover, the conventional transtibial reconstruction of the ACL often locates the graft away from the anatomical site, leading to abnormal biomechanical behavior and kinematics of the knee. The objective of this work was to assess the importance of the angular reconstruction of the anterior cruciate ligament during arthroscopic replacement and to compare the postoperative functional results. MATERIAL AND METHODS: We studied 21 patients to whom the IKDC 2000 form of objective and subjective evaluation was applied; radiographic evaluation in anteroposterior and lateral bending at 30o. We made an statistical analysis with Pearson P, correlating the anteroposterior and lateral angulation of the graft direction and the subjective projection of the operated knee function, as well as age and time of evolution with the operated knee. RESULTS: We included 21 patients of 18 to 56 years of age; follow-up: one to three years. Objective evaluation: 95.24% normal and 4.76% almost normal. Subjective assessment: average 84.31% (range 70.93 to 97.99%), CI 95%. AP angle: 68.8o, range: 62o to 77o. Average sagittal angle: 64.9o, range: 58o to 75o. Correlations: AP angle and subjective function -0.19, angle in sagittal and subjective function -0.54, age and subjective function -0.77, duration and subjective function -0.74. Function average: 84.31%. DISCUSSION: The anatomical angular reconstruction of the ACL graft is key to the stability of the knee; the evaluated patients got a more similar direction to that of the native ACL, better stability and knee function. PMID- 30521708 TI - [Interlocking femoral nail and total knee Arthroplasty in one stage for a patient with a femoral diaphyseal stress fracture]. AB - We present the case of an 81-year-old woman who was followed up by the Rheumatology Service for osteoporosis and treated with bisphosphonates for more than five years. She reported a fracture of the distal third of the contralateral femur by a low energy mechanism, treated with retrograde intramedullary nailing the previous year. She presented a clinic of cruralgia and left gonalgia, without previous trauma. A scintigraphy and radiographs were performed to support the diagnosis of stress fracture of the distal third of the left femur and osteonecrosis of the left internal femoral condyle. Thinking about the possible complications of performing two interventions in an elderly patient, we decided to complete the treatment in a single time and by the same surgical approach, trying to resolve the osteonecrosis and the fracture at the same time, with the objective of an early rehabilitation and lower morbidity. A femoral retrograde prophylactic nailing was performed to stabilize the stress fracture and a retentive primary knee prosthesis was implanted for the posterior cruciate ligament by the same surgical approach. There were no incidents in the immediate postoperative period, with ambulation beginning with help 48 hours after the intervention. The fracture consolidated and the patient presented a good functional result of the knee, both in the immediate postoperative period and at three years of follow-up. PMID- 30521709 TI - [Dedifferentiated diaphyseal juxtacortical osteosarcoma of ulna with metastasis to the lung]. AB - Dedifferentiated parosteal osteosarcoma is a variant in which a high grade osteosarcoma coexists with a parosteal osteosarcoma. We report the case of a 20 year-old female patient who presented with six months of evolution of pain and functional limitation of the right forearm, with no apparent cause; radiographs were performed, observing a tumoral lesion in the diaphysis of the right ulna. Physical examination showed pain upon palpation in the diaphysis of the ulna and limitation of prone-supination. Axial computed tomography of the thorax revealed metastatic disease in the upper lobe of the left lung. An incisional biopsy was performed on the right ulna, with a report of dedifferentiated parosteal osteosarcoma. Therefore, the patient was managed with neoadjuvant chemotherapy with cisplatin and doxorubicin until completing three cycles. Surgical treatment consisted of intercalary resection of the diaphysis of the right ulna, plus reconstruction of the microvascularized autologous graft of the right fibular diaphysis and graft stabilization with 3.5 mm dynamic compression plate (DCP) and one-third tubular plate. In the same procedure, pulmonary metastasectomy was performed by thoracoscopy. Post-surgical histopathological report with 100% necrosis. Currently, the patient is asymptomatic, with no evidence of tumor activity. Dedifferentiated parosteal osteosarcoma is a rare pathology, but should be suspected as a differential diagnosis in the presence of a parosteal osteosarcoma; it should be taken into account that this disease can metastasize due to its dedifferentiated pattern. It is important to plan a surgical treatment that allows an adequate functional reconstruction, always taking into account the oncological principle. PMID- 30521710 TI - [Calcaneal fractures: controversies and consensus]. AB - Calcaneal fractures are the most common tarsal fractures and their treatment is still debated today. We intend in this update to highlight the points of controversy and clarify the consensus, especially in the treatment of intra articular fractures, as well as to describe the management of major complications. PMID- 30521711 TI - [Syndrome of vertebral destruction: understanding to practice]. AB - The term "vertebral destruction syndrome" comprises pathologies causing structural changes in the spine, mainly in the vertebral body, producing mechanical deformity and neurological involvement. The pathologies found in this definition may be infectious, metabolic or tumoral. Vertebral osteomyelitis is a disease that occurs mainly in adults > 50 years; we speak of spondylodiscitis when the condition affects the disc and vertebral body. The most important organism in vertebral osteomyelitis is Staphylococcus aureus, seen in over 50% of cases. Tumors of the spine can start from local or adjacent spinal injuries or distant ones, and spread through the blood or lymphatic system. Metastases account for about 97% of all tumors of the spine. Primary tumors that most commonly spread to the spine are lung, prostate, breast and kidney. Metabolic bone diseases are a group of disorders that occur as a result of changes in the calcium metabolism. The spine contains large amounts of metabolically active cancellous bone, which must withstand axial loads during stance. Osteoporosis is a metabolic disease that most commonly affects the spine; it is characterized by low bone mass. The diagnosis of these entities is important for the treatment and prognosis of the patient. The term "vertebral destruction syndrome" proposes a notarized scheme aimed at improving the patients prognosis and his/her prompt treatment. PMID- 30521712 TI - New HHS Secretary Price faces a crushing inbox. AB - AS HHS secretary, Dr. Tom Price may be torn between orders to repeal the ACA and pressure from insurers to stabilize the marketplace in order to maintain coverage for 20 million people. PMID- 30521713 TI - This much is clear: No one knows what's happening on ACA repeal. PMID- 30521714 TI - HHS reaches into sparse toolbox for ACA exchange fixes. PMID- 30521716 TI - What comes next for Anthem and Cigna. PMID- 30521715 TI - Former FDA chief cites five things to watch for on drug approvals and keeping medications safe. PMID- 30521717 TI - No experience necessary. PMID- 30521719 TI - Recognizing accomplished leaders in healthcare. PMID- 30521718 TI - Paying for population health: Quality measures are growing as part of execs' pay incentives. AB - Health system and hospital executive pay is still primarily linked to hitting financial targets, but a growing minority of providers ties CEO paychecks to population health improvement. PMID- 30521720 TI - Wrong-to-try. AB - The Trump administration has thrown its weight behind giving patients the "right to-try" experimental drugs outside clinical trials. While such laws purport to offer hope for the dying, they will actually slow medical progress. PMID- 30521721 TI - Immigration ban violates our core values and will likely weaken American healthcare. AB - We as Americans pride ourselves on our core values of fairness and compassion and want our country to be a worldwide beacon for human rights, religious freedom, innovation and opportunity. PMID- 30521722 TI - Using EHRs to manage warfarin. PMID- 30521724 TI - Delirium: Suspect it, spot it and stop it. AB - Delirium is an acute confusional state common in older adults in hospital. Nurses must be alert to risk factors and act to prevent or manage this distressing but reversible condition. PMID- 30521723 TI - 'We don't need more patients in our hospitals. We need healthier people in our communities'. AB - Last July's merger of Providence Health & Services of Renton, Wash., and St. Joseph Health of Irvine, Calif., gave the combined 50-hospital chain a greater presence in the highly competitive Los Angeles market. Modern Healthcare Editor Merrill Goozner last week spoke with Dr. Richard Afable, CEO of St. Joseph Hoag Health, part of St. Joseph Health, about the merger's implication for competition in the L.A. basin. PMID- 30521725 TI - Nurses' role in Long-term conditions care. AB - Nurses have a key role to play in caring for those with long-term conditions. But a model of care used throughout the country and funded from the national health budget is needed. PMID- 30521727 TI - Integrating aged care in the nursinq curriculum. AB - First-year students from Whitireia New Zealand are gaining rich Learning opportunities during clinical placements at local aged- care facilities. PMID- 30521726 TI - Working holistically to provide safe care. AB - Supporting the elderly to live safely at home is the aim of one of the country's newest nurse practitioners, older adults, Sheryl Haywood. PMID- 30521728 TI - Revolutionising aged care. AB - A model of care developed in Amsterdam has been transplanted to the shores of Lake Rotorua. PMID- 30521729 TI - Rewards arise out of ARC's chaLLenges. AB - Due to the autonomous nature o the work, an RN in aged residential care can develop and use her skills to a high degree, a dedicated aged-care nurse believes. PMID- 30521730 TI - Coping with the outbreak of campylobacter. AB - Coping with the recent campylobacter outbreak which devastated Havelock North was a professional and personal challenge for a Hawke's Bay nurse practitioner. PMID- 30521732 TI - Introducing interRAI to aaed care. AB - New Zealand is the first country to have imple- mented interRAI nationally. Nurses describe some of the benefits and challenges involved. PMID- 30521731 TI - Maintaining quality care for older adults. AB - More than 100 nurses and caregivers attended NZNO's 10th national gerontology section conference, held in Christchurch for the first time earlier this month. The two-day programme explored the theme 'Back to our future' - getting back to aged care's roots of caring and person-centredness - during 11 plenary presentations and 15 abstracts. These pages Look at a few of the highlights. PMID- 30521733 TI - Building healthy bones. AB - With worLdwide figures of one in three women and one in five men aged 50 years and over LikeLy to suffer an osteoporotic fracture, action must be taken early to buiLd strong bones throughout Life. PMID- 30521734 TI - Postgraduate study - to do or not to do?. PMID- 30521735 TI - Continuing a tradition of caring. AB - A Dunedin caregiver continues a whanau tradition of caring and advocacy. PMID- 30521737 TI - Countries call for actior on safe staffing. AB - An international Torum on tne nursing worKTorce wans sitronger action to ensure safe staffing. PMID- 30521736 TI - Aged care needs more staff. AB - As residents in aged-care facilities become increasingly frail, the need for mandated staffing levels becomes even more urgent. PMID- 30521738 TI - ICU nurses key boosters for organ donations. PMID- 30521739 TI - Identification of risk factors and diagnostic methodology in serositis by M. tuberculosis AB - Background: Tuberculosis is a public health problem, extrapulmonary presentations have increased, it is difficult to diagnose because of the low bacillary load. Objective: To identify risk factors and to evaluate the efficiency of diagnostic methods in pleural, meningeal, peritoneal and pericardial tuberculosis. Methods: Prospective study of cases and controls. A multiple conditional logistic regression model was used to identify risk factors. Biopsy was performed and 7 mL of fluid was extracted from the affected site, Lowestein-Jensen and MGITI960 culture, Ziehl-Neelsen staining, adenosine deaminase and endpoint PCR directed to the insertion sequence 1S6110 for M. tuberculosis were performed. Results: 116 patients were included, in 58 M. tuberculosis was confirmed by positive culture (meningeal Tb 34 cases, pleural 14, peritoneal 8, pericardial 2 cases) and 58 serositis of non-tuberculous etiology. Being a carrier of HIV and living with people infected with tuberculosis were the main risk factors OR = 3.6 and OR = 6.8. The staining had sensitivity of 25.9%, PCR of 65.5% and adenosine deaminase with 82.8% Conclusions: Conventional diagnostic methods had low efficacy, adenosine deaminase and molecular biology techniques are the most useful, in our environment these tests should be performed immediately in patients with risk factors and suspected serositis of tuberculous origin. PMID- 30521740 TI - Cost of medical attention in patients with Chronic Obstructive Pulmonary Disease AB - Background: The chronic obstructive pulmonary disease is a preventable entity, when it develops the patient suffers severe complications, with a high economic impact for the patient and for health services. Objetive: To determine the cost of medical care in patients with chronic obstructive pulmonary disease (COPD). Methods: Using a cost design, the files of patients with COPD who attended the pulmonology clinic were analyzed. The size of the sample (n = 265) was calculated with the formula of averages of a finite population. The sample units were captured with the simple random technique. The study variables were: sociodemographic characteristics, characteristics of COPD, annual use profile, unit cost per service, total cost per service and total cost of medical care. The analysis plan included averages, percentages, confidence intervals and health expenditure projections. Results: The average annual cost of patient care with COPD was $ 89 479.08, of which $ 61 267.63 corresponded to medications. With a COPD prevalence of 25% in a population of 46 million, the calculated cost of care was $ 347 805 183 960. Conclusion: The cost of medical care in patients with COPD was high, at the expense of medications. PMID- 30521741 TI - Maternal and perinatal outcomes of expectant treatment of severe preeclampsia AB - Background: In severe preeclampsia (SP), pregnancy interruption is the first recommendation. However, some patients receive expectant treatment. Objetive: To determine maternal and perinatal results of expectant treatment of SP in the intensive care unit (ICU) of a high-specialty hospital. Methods: Observational, descriptive and retrospective study; the files of 40 pregnant patients with SP managed in the ICU with expectant treatment were reviewed. The prolongation of the pregnancy, the maternal and perinatal complications, the stay in ICU and in the hospital were recorded. Descriptive statistics were used for statistical analysis. Results: Mean maternal age was 30.2 +/- 5.04 years and gestational age 30.02 +/- 3.18 weeks. Gestation was prolonged 7.5 +/- 0.95 days. Maternal complications occurred in 60% (24 cases): thrombocytopenia 48.9%, HELLP syndrome 17.8%, pulmonary edema 4.45%, acute kidney injury 4.45%, deterioration of chronic kidney disease 4.45%, oligohydramnios 4.45%, uterine hemorrhage 4.45%, platelet transfusion 4.45%, eclampsia 2.2%, intravascular coagulation 2.2%, surgical reintervention 2.2%, without mortality. ICU stay was 3.42 +/- 1.85 days and hospital stay 8.8 +/- 4.82 days. 41 premature newborns were treated (100%) and complications were reported in 74.20% (23 cases): respiratory insufficiency 53.65%, neonatal intensive care 39.02%, growth restriction 21.95%, unreliable fetal status 9.75% and mortality 24.39%. Intensive care stay was 8.5 +/- 5.47 days and hospital stay 26.8 +/- 23.2 days. Conclusions: Prolongation of pregnancy was similar to what has been reported in previous studies. Due to the high percentage of maternal and perinatal complications, expectant treatment is not recommended. PMID- 30521742 TI - Amyloid-degrading enzymes in Alzheimer's disease: from molecules to genetic therapy AB - Alzheimer's disease (AD) is the main form of dementia in elderly population worldwide. By 2010 it was estimated that 35.6 million of people were living with this disease, and it was projected that this figure will triple by the year 2050. According to amyloid hypothesis, production and aggregation of amyloid beta (A beta) peptide is the initial step in AD development. A-beta peptide is generated through proteolytic processing of amyloid precursor protein (APP); whereas its degradation depends on the action of a group of proteins collectively known as amyloiddegrading enzymes (ADE), which are reduced during aging and particularly in AD. Genetic therapy consists in the restoration of the genetic expression of a deficient protein to treat a disease. Brain restoration or overexpression of ADE reduces the levels and aggregates of A-beta, and improves learning and memory in animal models of AD. In this review we will describe the role of ADE in the regulation of A-beta levels, as well as its potential use in genetic therapy against AD. PMID- 30521744 TI - Pharmacological treatment of obesity AB - More than 70% of the population in Mexico is overweight or obese, affecting mainly people in productive age. Obesity is associated with the development of diseases that increase cardiovascular risk (diabetes mellitus, hypertension or atherogenic dyslipidemia), diseases that limit the quality of life of the patient (osteoarthrosis or sleep apnea) and even with the increase in the incidence of certain types of cancer (breast or colon). It is evident that the decrease of at least 5% of body weight induces improvement in all these factors; however, in some patients it is difficult to achieve this goal only with lifestyle modifications. In this review we analyze some drugs approved for weight control by national and international agencies that can serve as an auxiliary in conjunction with diet and exercise. Treatment must be individualized according to each patient characteristics, with an adequate evaluation of their risks and benefits. PMID- 30521745 TI - Zika transmission ways, can it be transmitted from person to person? AB - In this article we describe the main transmission mechanisms of the Zika virus, from those already known, such as zoonotic and anthroponotic transmission of the virus, perinatal, occupational transmission, by blood products and by sexual contact. Given the possibility of person-to-person transmission, some measures of attention are proposed as the necessary studies are advanced to confirm or discard it. PMID- 30521746 TI - Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs). AB - Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate NF-kappaB signaling. Moreover, expression of PD-L1 and CD80 on PD-1+ MDSCs was higher than on PD-1- MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in PD-1+ MDSCs than in PD-1- MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that PD-1+ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules. PMID- 30521748 TI - Shedding Light on the Basis Set Dependence of the Minnesota Functionals: Differences Between Plane Waves, Slater Functions and Gaussians. AB - The Minnesota family of exchange-correlation (xc) functionals are among the most popular, accurate and abundantly used functionals available to date. However, their use in plane-wave based first principles MD has been limited by their sparse availability. Here, we present an implementation of the M05, M06 and M11 families of xc functionals within a plane wave/pseudopotential framework allowing for a comprehensive analysis of their basis set dependence. While it has been reported that in Gaussian bases, some members of the Minnesota family only converge slowly to the basis set limit, we show that converged energies can be conveniently obtained from plane waves if sufficiently dense integration meshes are used. Based on the HC7/11 database, we assess the influence of basis set type on the calculation of reaction enthalpies and show that complete basis set values obtained in plane waves may occasionally differ notably from their atom-centred counterparts. We provide an analysis of the origin of these differences and discuss implications on practical usage. PMID- 30521747 TI - The C2 Pedicle Width, Pars Length, and Laminar Thickness in Concurrent Ipsilateral Ponticulus Posticus and High-Riding Vertebral Artery: A Radiological Computed Tomography Scan-Based Study. AB - Study Design: Retrospective radiological study. Purpose: We aimed to determine the prevalence of ponticulus posticus (PP) and high-riding vertebral artery (HRVA) occurring simultaneously on the same side (PP+HRVA) and in cases of PP+HRVA, to assess C2 radio-anatomical measurements for C2 pars length, pedicle width, and laminar thickness. Overview of Literature: PP and HRVA predispose individuals to vertebral artery injuries during atlantoaxial fixation. In cases of PP+HRVA, the construct options thus become limited. Methods: Consecutive computed tomography scans (n=210) were reviewed for PP and HRVA (defined as an internal height of <2 mm and an isthmus height of <5 mm). In scans with PP+HRVA, we measured the ipsilateral pedicle width, pars length, and laminar thickness and compared them with controls (those without PP or HRVA). Results: PP was present in 14.76% and HRVA in 20% of scans. Of the 420 sides in 210 scans, PP+HRVA was present on 13 sides (seven right and six left). In scans with PP+HRVA, the C2 pars length was shorter compared with controls (13.69 mm in PP+HRVA vs. 20.65 mm in controls, p<0.001). The mean C2 pedicle width was 2.53 mm in scans with PP+HRVA vs. 5.83 mm in controls (p<0.001). The mean laminar thickness was 4.92 and 5.48 mm in scans with PP+HRVA and controls, respectively (p=0.209). Conclusions: The prevalence of PP+HRVA was approximately 3% in the present study. Our data suggest that, in such situations, C2 pedicle width and pars length create important safety limitations for a proposed screw, whereas the translaminar thickness appears safe for a proposed screw. PMID- 30521749 TI - Ligand density and linker length are critical factors for multivalent nanoparticle-receptor interactions. AB - Although there is a large number of studies available evaluating the therapeutic efficacy of targeted polymeric nanoparticles, little is known about the critical attributes that can further influence their uptake into target cells. In this study, varying cRGD ligand densities (0-100% surface functionalization) were combined with different PEG spacer lengths (2/3.5/5kDa) and the specific receptor binding of targeted core-shell structured PLGA/PLA-PEG nanoparticles was evaluated using alphavbeta3 integrin overexpressing U87MG glioblastoma cells. Nanoparticles with 100% surface functionalization and short PEG2k linkers displayed a high propensity to form colloidal clusters, allowing for the cooperative binding to integrin receptors on the cellular membrane. In contrast, the high flexibility of longer PEG chains enhanced the chance of ligand entanglement and shrouding, decreasing the number of ligand-receptor binding events. As a result, the combination of short PEG2k linkers and a high cRGD surface modification synergistically increased the uptake of nanoparticles into target cells. Even though to date, the nanoparticles size and its degree of functionalization are considered to be major determinants for controlling the uptake efficiency of targeted colloids, these results strongly suggest that the role of the linker length should be carefully taken into consideration for the design of targeted drug delivery formulations in order to maximize the therapeutic efficacy and minimize adverse side effects. PMID- 30521750 TI - Direct Observation of Ion Pairing in Aqueous Nitric Acid Using 2D Infrared Spectroscopy. AB - Ion-ion interactions and ion pairing play an important role in the properties of concentrated electrolyte solutions, yet remain difficult to study due to the heterogeneous and highly dynamic behavior of these systems. In concentrated acid solutions these questions take on a further level of complexity, because the structure of the aqueous proton itself is uncertain, and may be influenced by the counterion. Here, we address these questions by studying the IR spectra of nitric acid as a function of concentration in H2O, and comparing these to the spectra of several alkali nitrate salts. We show how the close proximity between cations and NO3- ions in solution at high concentration affect the IR spectra, and therefore the molecular structures. Using 2D IR spectroscopy, we demonstrate the formation of contracted ion pair configurations in nitric acid solutions between NO3- ions and H+(aq) via the observation of a distinct anisotropic intermolecular crosspeak between these species. By studying the concentration dependence of this spectral feature, we show that this ion-paired configuration exists in solution at concentrations as low as 2M, and suggests that the structure of H+(aq) solvation complex in these ion pairs differs from the structure in bulk solution. PMID- 30521751 TI - Controlling the Activity and Stability of Electrochemical Interfaces Using Atom by-Atom Metal Substitution of Redox Species. AB - Understanding the molecular-level properties of electrochemically-active ions at operating electrode-electrolyte interfaces (EEI) is key to the rational development of high-performance nanostructured surfaces for applications in energy technology. Herein, an electrochemical cell coupled with ion soft landing is employed to examine the effect of "atom-by-atom" metal substitution on the activity and stability of well-defined redox-active anions, PMoxW12-xO403- (x = 0,1,2,3,6,9,12), at nanostructured ionic liquid EEI. A striking observation made by in situ electrochemical measurements and further supported by theoretical calculations is that substitution of only (1-3) tungsten by molybdenum atoms in the PW12O403- anions results in a substantial spike in their first reduction potential. Specifically, PMo3W9O403- showed the highest redox activity in both in situ electrochemical measurements and as part of a functional redox supercapacitor device, making it a "super-active redox anion" compared to all other PMoxW12-xO403- species. Electronic structure calculations showed that metal substitution in PMoxW12-xO403- causes the lowest unoccupied molecular orbital (LUMO) to protrude out locally making it the "active site" for reduction of the anion. Several critical factors contribute to the observed trend in redox activity including: (i) multiple isomeric structures populated at room temperature, which affect the experimentally-determined reduction potential, (ii) substantial decrease of the LUMO energy upon replacement of W atoms with more electronegative Mo atoms, (iii) structural relaxation of the reduced species produced after the first reduction step. Our results illustrate a path to achieving superior performance of technologically-relevant EEIs in functional nanoscale devices through understand-ing of the molecular-level electronic properties of specific electroactive species with "atom-by-atom" precision. PMID- 30521752 TI - A Single-Step Gold Nanoparticle-Blood Serum Interaction Assay Reveals Humoral Immunity Development and Immune Status of Animals from Neonates to Adults. AB - A well-developed, functional immune system is paramount to combat harmful attack from pathogenic organisms and prevent infectious diseases. Newborn animals and humans have only limited immunity upon birth, but their immune functions are expected to develop within weeks to months and eventually to reach a maturity that will provide full protection. Despite the importance of immune activity in animal and human health management, there is no convenient test available that allows for rapid assessment of the state of immune function in non-laboratory settings. Here we report an extremely simple and rapid blood test that may be used in point-of-care clinics or field settings to evaluate the humoral immune status of animals. The test detects a cooperative interaction between a gold nanoparticle and arguably the three most important proteins involved in the immune system: immunoglobulin M (IgM), immunoglobulin G (IgG) and at least one complement protein, C3, in the blood serum. Such interactions cause the gold nanoparticles to form clusters and aggregates. The average particle size of the gold nanoparticle-serum mixture, measured by dynamic light scattering, corresponds positively to the immune status and activity of the subject. Our study demonstrates that the test may be used not only for monitoring the immune function development from neonates to adults, but also for detecting active immune responses during infection. Although data reported here are largely based on murine and bovine models, it is likely that this test will be applicable to humans as well. PMID- 30521754 TI - Oxidative Coupling of Carbazoles: A Substituent-Governed Regioselectivity Profile. AB - Oxidative C-C coupling of carbazoles possessing various substituents are demonstrated, in presence of organic (metal-free) recyclable oxidants, such as, DDQ or CA/H+ for accessing bicarbazole regioisomers. Differently substituted carbazoles are examined to showcase regioselectivity discrimination (3,3'- versus 1,3'-bicarbazoles), and preferences based on sterics and electronics in oxidative coupling. Finally, a mechanism that involves carbazole radical cation has been traced (evidenced) and proposed based on the UV-vis-NIR absorption and EPR spectroscopy results. This study underlines the strategic chemical preparation of a series of bicarbazoles in an efficient manner. PMID- 30521753 TI - Aneurysmal Subarachnoid Hemorrhage Onset Alters Pyruvate Metabolism in Poor-Grade Patients and Clinical Outcome Depends on More: A Cerebrospinal Fluid Metabolomic Study. AB - Cerebral metabolism alterations influence cerebrospinal fluid (CSF) composition, and is sensitive to brain injury. In subarachnoid hemorrhage (SAH) patients, Fisher scale, Hunt-Hess scale and World Federation of Neurological Societies (WFNS) grading scales evaluating SAH severity are inadequate to predict long-term outcome; therefore, in an effort to determine metabolite pattern disparity and discover corresponding biomarkers, we designed an untargeted CSF metabolomic research covering a board range of metabolites of SAH patients with different severity and outcome. The present study demonstrated SAH altered cerebrospinal fluid metabolome involving carbohydrate, lipid and amino acids metabolism. Pyruvate metabolism was enhanced in SAH patients with Hunt-Hess scale above III, and CSF pyruvate level was significantly associated with WFNS grading scale above III. There is no significant variation among CSF metabolome in SAH patients with merely different amount and distribution of bleeding. SAH patients with unfavorable outcome present upregulated CSF amino acids level and enhanced lipid biosynthesis. The present study provides novel possibility of early identification of patients who might possess unfavorable outcome and further clarification of the underlying pathophysiology. PMID- 30521755 TI - Quantitative Detection of Fipronil and Fipronil-Sulfone in Sera of Black-Tailed Prairie Dogs and Rats after Oral Exposure to Fipronil by Camel Single-Domain Antibody-Based Immunoassays. AB - The insecticide fipronil can be metabolized to its sulfone in mammalian species. Two camel single-domain antibodies (VHHs) F1 and F6, selective to fipronil and fipronil-sulfone, respectively, were generated and used to develop enzyme linked immunosorbent assays (ELISAs) for the detection of the two compounds in the sera of black-tailed prairie dogs and rats. The limits of detection of fipronil and fipronil-sulfone in the rodent sera by the corresponding ELISAs were 10 and 30 ng mL-1, and the linear ranges were 30-1000 and 75-2200 ng mL-1. ELISAs showed a good recovery for fipronil and fipronil-sulfone co-spiked in the control sera of the black-tailed prairie dogs (90-109%) and rats (93-106%). The VHH-based ELISAs detected fipronil and fipronil-sulfone in the sera of the rodents that received a repeated oral administration of fipronil. The average concentration of fipronil sulfone was approximately 3.2-fold higher than fipronil in the prairie dog sera (1.15 vs 0.36 MUg mL-1) and rat sera (1.77 vs 0.53 MUg mL-1). ELISAs agreed well with a liquid chromatography-mass spectrometry method for the quantification of both fipronil and fipronil-sulfone in real serum samples. Fipronil-sulfone was identified as the predominant metabolite of fipronil in the black-tailed prairie dog and rat sera. PMID- 30521756 TI - Light-Induced Activation of Forbidden Exciton Transition in Strongly Confined Perovskite Quantum Dots. AB - We report the strong light-induced activation of forbidden exciton transition in CsPbBr3 perovskite quantum dots mediated by the symmetry-breaking polaron that modifies the optical selection rule of the confined exciton transition. The activated forbidden transition results in an intense pump-induced absorption in the transient absorption spectra above the bandgap, where the original parity forbidden transition was located. In contrast to many other semiconductor quantum dots, photoexcitation of exciton in CsPbBr3 quantum dots creates a sufficiently large perturbation via lattice-distorting polaron, which turns on the formally forbidden transition. Compared to the bulk or weakly confined CsPbBr3, the activation of the forbidden transition in strongly confined quantum dots is much more prominent due to the stronger influence of the polaron on exciton transitions in the confined space. This nonlinear optical property highlights the intimate coupling of the photoexcited charge carriers with the lattice in the CsPbBr3 quantum dots, allowing access to the forbidden exciton transitions with light. PMID- 30521758 TI - World Alliance for Breastfeeding Action (WABA) News. PMID- 30521757 TI - Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3): A Randomized Controlled Trial. AB - RATIONALE: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. OBJECTIVES: To evaluate the efficacy and safety of solriamfetol (JZP 110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. METHODS: Double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol 37.5, 75, 150, and 300 mg with placebo. MEASUREMENTS AND MAIN RESULTS: Of 476 randomized participants, 459 were included in the pre specified efficacy analyses. Co-primary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P <0.05), with dose-dependent effects observed at week 1 maintained over the study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on Patient Global Impression of Change (key secondary endpoint; P <0.05). Adverse events were reported in 47.9% of placebo- and 67.9% of solriamfetol-treated participants; 5 participants experienced serious adverse events (2 [1.7%] placebo, 3 [0.8%] solriamfetol); none were deemed related to study drug. The most common adverse events with solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7.0%), and nasopharyngitis (5.1%). CONCLUSIONS: Solriamfetol significantly increased wakefulness and reduced sleepiness in participants with obstructive sleep apnea and excessive sleepiness; most adverse events were mild or moderate in severity. Clinical trial registration available at www.clinicaltrials.gov, ID NCT02348606. PMID- 30521759 TI - Myocardial Injury in Critically Ill Patients with Community-acquired Pneumonia: A Cohort Study. AB - RATIONALE: Myocardial injury, as reflected by elevated cardiac troponin levels in plasma, is common in patients with community-acquired pneumonia (CAP), but its temporal dynamics and etiology remain unknown. OBJECTIVES: Our aim was to determine the incidence of troponin release in patients with CAP and identify risk factors which may point to underlying etiologic mechanisms. METHODS: We included consecutive patients admitted with severe CAP to two intensive care units in the Netherlands between 2011 and 2015. High-sensitivity cardiac troponin I was measured daily during the first week. We used multivariable linear regression to identify variables associated with troponin release on admission, and mixed-effects regression to model the daily rise and fall of troponin levels over time. RESULTS: Among 200 eligible patients, 179 were included, yielding 792 observation days. A total of 152 (85%) patients developed raised troponin levels >26 ng/L. Baseline factors independently associated with troponin release included coronary artery disease (176% increase, 95% CI 11-589), smoking (248% increase, 95% CI 33-809), and higher APACHE IV score (2% increase, 95% CI 0.8 3.3), whereas Staphylococcus aureus as a causative pathogen was protective (70% reduction, 95% CI 18-89). Time-dependent risk factors independently associated with daily increase in troponin concentrations included reduced platelet count (2.3% increase, 95% CI 0.6-4), tachycardia (1.5% increase, 95% CI 0.1-2.9), hypotension (6.2% increase, 95% CI 2.1-10.6) dobutamine use (44% increase 95% CI 12-85), prothrombin time (8.2% increase, 95% CI 0.2-16.9), white-cell count (1.7% increase, 95% CI 0-3.5), and fever (22.7% increase, 95% CI 0.1-49.6). CONCLUSIONS: Cardiac injury develops in a majority of patients with severe CAP. Myocardial oxygen supply-demand mismatch and activated inflammation/coagulation are potential causes of this injury. Clinical trial registered with ClinicalTrials.gov (NCT01905033). PMID- 30521760 TI - Analysis of femurs from mice embarked on board BION-M1 biosatellite reveals a decrease in immune cell development, including B cells, after 1 wk of recovery on Earth. AB - Bone loss and immune dysregulation are among the main adverse outcomes of spaceflight challenging astronaut's health and safety. However, consequences on B cell development and responses are still under-investigated. To fill this gap, we used advanced proteomics analysis of femur bone and marrow to compare mice flown for 1 mo on board the BION-M1 biosatellite, followed or not by 1 wk of recovery on Earth, to control mice kept on Earth. Our data revealed an adverse effect on B lymphopoiesis 1 wk after landing. This phenomenon was associated with a 41% reduction of B cells in the spleen. These reductions may contribute to explain increased susceptibility to infection even if our data suggest that flown animals can mount a humoral immune response. Future studies should investigate the quality/efficiency of produced antibodies and whether longer missions worsen these immune alterations.-Tascher, G., Gerbaix, M., Maes, P., Chazarin, B., Ghislin, S., Antropova, E., Vassilieva, G., Ouzren-Zarhloul, N., Gauquelin-Koch, G., Vico, L., Frippiat, J.-P., Bertile, F. Analysis of femurs from mice embarked on board BION-M1 biosatellite reveals a decrease in immune cell development, including B cells, after 1 wk of recovery on Earth. PMID- 30521762 TI - Writing in Public Health: A New Program From the Association of Schools and Programs of Public Health. PMID- 30521761 TI - Pharmacotherapy of Obstructive Sleep Apnea: Is Salvation Just Around a Corner? PMID- 30521763 TI - Geospatial Analysis of Birth Records to Target Programming for Mothers With Gestational Diabetes Mellitus in Michigan, 2013. AB - OBJECTIVES:: The incidence of gestational diabetes mellitus (GDM) in the United States has increased during the past several decades. The objective of this study was to use birth records and a combination of statistical and geographic information system (GIS) analyses to evaluate GDM rates among subgroups of pregnant women in Michigan. MATERIALS AND METHODS:: We obtained data on maternal demographic and health-related characteristics and regions of residence from 2013 Michigan birth records. We geocoded (ie, matched to maternal residence) the birth data, calculated proportions of births to women with GDM, and used logistic regression models to determine predictors of GDM. We calculated odds ratios (ORs) from the exponentiated beta statistic of the logistic regression test. We also used kernel density estimations and local indicators of spatial association (LISA) analyses to determine GDM rates in regions in the state and identify GDM hot spots (ie, areas with a high GDM rate surrounded by areas with a high GDM rate). RESULTS:: We successfully geocoded 104 419 of 109 168 (95.6%) births in Michigan in 2013. Of the geocoded births, 5185 (5.0%) were to mothers diagnosed with GDM. LISA maps showed a hot spot of 8 adjacent counties with high GDM rates in southwest Michigan. Of 11 064 births in the Southwest region, 829 (7.5%) were to mothers diagnosed with GDM, the highest rate in the state and a result confirmed by geospatial analyses. PRACTICE APPLICATIONS:: Birth data and GIS analyses may be used to measure statewide pregnancy-associated disease risk and identify populations and geographic regions in need of targeted public health and maternal-child health interventions. PMID- 30521765 TI - Electronic "Sniffer" Systems to Identify the Acute Respiratory Distress Syndrome: A Systematic Review. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) results in substantial mortality but remains underdiagnosed in clinical practice. Automated ARDS "sniffer" systems, tools that can automatically analyze electronic medical record data, have been developed to improve recognition of ARDS in clinical practice. OBJECTIVE: To perform a systematic review examining the evidence underlying automated sniffer systems for ARDS detection. DATA SOURCES: MEDLINE and Scopus databases through October 2018 to identify studies of tools using routinely available clinical data to detect patients with ARDS. DATA EXTRACTION: Study design, tool description, and diagnostic performance were extracted by two reviewers. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was used to evaluate each study for risk of bias in 4 domains: patient selection, index test, reference standard, and study flow and timing. SYNTHESIS: Among 480 studies identified, nine met inclusion criteria, evaluating six unique ARDS sniffer tools. Eight studies were derivation and/or temporal validation designs, with one also evaluating the effect of implementing a tool in clinical practice. A single study performed an external validation of previously published ARDS sniffer tools. Studies reported a wide range of sensitivities (43% to 98%) and positive predictive values (26% to 90%) for detection of ARDS. Most studies had potential for high risks of bias identified in their study design, including patient selection (5 of 9), reference standard (4 of 9), and flow and timing (3 of 9). In the single external validation without any perceived risks of biases, performance of ARDS sniffer tools were worse. CONCLUSIONS: Sniffer systems developed to detect ARDS had moderate to high predictive value in their derivation cohorts, although most studies had potential for high risks of bias in study design. Methodological issues may explain some of the variability in tool performance. There remains an ongoing need for robust evaluations of ARDS sniffer systems and their impact on clinical practice. PROSPERO Registration: CRD42015026584. PMID- 30521764 TI - Identification and Modulation of Microenvironment is Crucial for Effective MSC Therapy in Acute Lung Injury. AB - RATIONALE: There are controversial reports on applications of mesenchymal stromal cells (MSCs) in patients with acute respiratory distress syndrome (ARDS). OBJECTIVE: We hypothesized that lung microenvironment was the main determinant of beneficial versus detrimental effects of MSCs during ARDS. METHODS: Lung proteome was profiled in three models of injury induced by acid instillation and/or mechanical ventilation in mice. Human gene of glutathione peroxidase-1 (GPx-1) was delivered prior to MSC administration; or MSCs carrying human gene of interleukin-10 (MSCIL-10) or hepatocyte growth factor (MSCHGF) were administered after lung injury. An inhibitory cocktail against IL-6, fibronectin and oxidative stress was used in in vitro studies utilizing human small airway epithelial cells (SAECs) and human MSCs after exposure to plasma of ARDS patients. MEASUREMENTS AND MAIN RESULTS: Distinct proteomic profiles were observed in three lung injury models. Administration of MSCs protected lung from ventilator-induced injury, while it worsened acid-primed lung injuries associated with fibrotic development in lung environment that had high levels of IL-6 and fibronectin along with low antioxidant capacity. Correction of microenvironment with GPx-1, or treatment with MSCIL-10 or MSCHGF after acid-primed injury, reversed the detrimental effects of native MSCs. Proteomic profiles obtained in the mouse models were also similarly observed in human ARDS. Treatment with the inhibitory cocktail in samples of ARDS patients retained protective effects of MSCs in SAECs. CONCLUSION: MSCs can be beneficial or detrimental depending on microenvironment at the time of administration. Identification of potential beneficiaries appears to be crucial to guide MSC therapy in ARDS. PMID- 30521766 TI - Shining Sunlight on Industry Payments in Oral and Maxillofacial Surgery: The Sunshine Act. AB - PURPOSE: To characterize industry payments to oral and maxillofacial surgeons (OMSs) and to determine the accuracy of the Centers for Medicare and Medicaid Services (CMS) Open Payments Databases. MATERIALS AND METHODS: This was a cross sectional study of the CMS General and Research Payments Databases in 2016 for clinicians categorized as OMSs. General payments include consulting fees, honoraria, gifts, entertainment, food and beverage, travel and education, and others. Research payments include payments associated with research. Variables collected included number of OMSs who received payments, type of and number of payments, total amount paid, geographic distribution, and proportion of funding allotted to research. The accuracy of payee categorization was determined by verifying a random selection of 5% of those categorized as "OMS" in the database with publicly available data. To assess impact on research productivity, the h index of research payment recipients was calculated. RESULTS: A total of 6,720 OMSs received industry compensation in 2016. Accuracy was 88% (297 of 336) in the General Payments Database and 50% (4 of 8) in the Research Payments Database. OMSs received 28,456 general payments totaling $5,971,800.79. The average number of payments and the average amount per payment were 4.27 and $1,597.60, respectively. The CMS reported total research payments of $23,592.17. The 4 verified OMSs received a total of $18,500 in research payments and had an average h-index of 3.25 (range, 0 to 8). The most common payments made were for food and beverage (80.2%), travel and lodging (5.83%), education (3.91%), compensation for services other than consulting (3.1%), and gifts (3.03%). Research accounted for 0.07% of all payments. CONCLUSION: Although industry payments to OMSs were common, research funding was negligible. Most industry value transfers were related to food and beverage or travel and lodging. Clinicians were accurately classified in the CMS General Payments Database but not in the Research Payments Database. PMID- 30521767 TI - Is physical activity associated with resting heart rate in boys and girls? A representative study controlled for confounders. AB - OBJECTIVE: Investigate the relationship between different domains of physical activity and resting heart rate (RHR) in boys and girls. METHOD: The sample included 1011 adolescents, aged between 10 and 17 years. RHR was measured by a heart rate monitor and physical activity was assessed in total and in three different domains (school, occupational, and sports practice) by a questionnaire. Anthropometry was directly obtained for body mass index and central fat. Ethnicity, sedentary behavior, and smoking habits were self-reported and used to adjust the analysis, through hierarchical linear regression. RESULTS: Total physical activity was associated with low RHR in boys (beta=-0.52; 95% CI: -0.92, -0.12) and girls (beta=-0.67; 95% CI: -1.07, -0.28). Although sporting physical activities were associated with low RHR in both boys (beta=-0.58; 95% CI: -1.05, 0.11) and girls (beta=-0.87; 95% CI: -1.34, -0.39), occupational physical activity was related to low RHR only in boys (beta=-1.56; 95% CI: -2.99, -0.14). CONCLUSION: The practice of physical activity in the sport practice domain and total physical activity were related to low RHR in both sexes, while occupational physical activities were associated with RHR only in boys. PMID- 30521768 TI - Preterm newborn's postnatal growth patterns: how to evaluate them. AB - OBJECTIVES: There are several factors that influence the postnatal growth of preterm infants. It is crucial to define how to evaluate the growth rate of each preterm child and its individual trajectory, the type of growth curve, either with parameters of prescriptive curves for healthy preterm infants with no morbidities or, in the case of preterm infants and their "bundle of vulnerabilities", growth curves that may represent how they are actually growing, with the aim of directing appropriate nutritional care to each gestational age range. DATA SOURCES: The main studies with growth curves for growth monitoring and the appropriate nutritional adjustments that prioritized the individual trajectory of postnatal growth rate were reviewed. PubMed and Google Scholar were searched. DATA SYNTHESIS: The use of longitudinal neonatal data with different gestational ages and considering high and medium-risk pregnancies will probably be essential to evaluate the optimal growth pattern. CONCLUSIONS: Prioritizing and knowing the individual growth trajectory of each preterm child is an alternative for preterm infants with less than 33 weeks of gestational age. For larger preterm infants born at gestational age >33 weeks, the Intergrowth 21st curves are adequate. PMID- 30521769 TI - Structure and biomechanics of the antennal grooming mechanism in the southern green stink bug Nezara viridula. AB - Insects devote a high amount of time to self-groom to remove foreign material, especially from their sensory appendages. Using various microscopy techniques and behavioural experiments on intact and ablated insects, the present study investigates the antennal grooming of the green stinkbug Nezara viridula, which represents a serious pest of different crops in most areas of the world. The antennal grooming behaviour encompass an action of scraping involving the tibial comb complex (tibial comb + fossula) of both forelegs, generally followed by the tibial comb complex grooming of one leg using the tarsal hairy pad of the opposite leg (rubbing). From our observations, we can exclude a role in the antennal grooming of other structures such as the foretibial apparatus, while we show an involvement of this last structure in repositioning the stylets inside the labium. The external and internal morphology (cryo-scanning and transmission electron microscopy) and the evidence for the presence of the elastic protein resilin (confocal laser scanning microscopy) in some parts of both the tibial comb complex and the foretibial apparatus are shown and their functional roles are discussed. For the first time we demonstrated here the multipurpose role of the basitarsal hairy pad that is involved in antennal grooming and adhesion to the substrate. PMID- 30521770 TI - Neuronal Polarization Packs a One-Two Punch. AB - In this issue of Neuron, Ambrozkiewicz et al. (2018) define a new molecular circuit controlling neuronal polarization and migration through the transcription factor SOX9 to coordinate the production of regulators of both protein synthesis and degradation. PMID- 30521772 TI - A Path(way) to Keeping Your Synapses on an Even Keel. AB - In this issue of Neuron, Harris et al. (2018) show that a signal transduction pathway normally exploited by the innate immune system in recognizing foreign agents plays a critical role in controlling a synapse's ability to maintain stability in the efficacy of synaptic transmission over both rapid and prolonged timescales. PMID- 30521771 TI - Astrocytes "Chordinate" Synapse Maturation and Plasticity. AB - A key step in excitatory synapse maturation is the switch in AMPA receptor subunit composition to GluA2-containing calcium-impermeable receptors. Now, Blanco-Suarez et al. (2018) demonstrate that astrocyte-secreted chordin-like 1 drives this process, enabling synapse maturation and limiting plasticity. PMID- 30521773 TI - CHD2: One Gene, Many Roles. AB - Mutations in the chromodomain helicase DNA-binding 2 (CHD2) gene have been found in patients with a range of neurodevelopmental disorders. In this issue of Neuron, Kim et al. (2018) showed that Chd2 haploinsufficiency compromises cortical development, synaptic function, and memory in mice. PMID- 30521774 TI - Conducting the Neural Symphony of Memory Replay. AB - Hippocampal sharp-wave ripple oscillations and sequence replay events are important for memory. Ramirez-Villegas et al. present a model that dissects cellular mechanisms of SWR generation in the CA3-CA1 circuit, and explains the network features of slow-gamma coordination and sequence replay. PMID- 30521776 TI - Hierarchical Predictive Information Is Channeled by Asymmetric Oscillatory Activity. AB - Predictive coding and neural oscillations are two descriptive levels of brain functioning whose overlap is not yet understood. Chao et al. (2018) now show that hierarchical predictive coding is instantiated by asymmetric information channeling in the gamma and alpha/beta oscillatory ranges. PMID- 30521775 TI - An Unbiased View of Neural Networks: More than Meets the Eye. AB - In this issue of Neuron, Mace et al. (2018) use whole-brain functional ultrasound imaging in mice to unveil the circuits involved reflexive eye movements. They separated the sensory and motor networks and discovered that certain eye movements robustly suppress the amygdala. PMID- 30521777 TI - Physiological Models of Human Neuronal Development and Disease. AB - Human neural network development occurs at stages inaccessible to longitudinal monitoring. By transplanting human neurons to the adult mouse brain, recent studies explore human neural circuit formation in realistic cellular and physiological environments, establishing new models for human neurodevelopmental disorders. PMID- 30521778 TI - Cracking the Function of Layers in the Sensory Cortex. AB - Understanding how cortical activity generates sensory perceptions requires a detailed dissection of the function of cortical layers. Despite our relatively extensive knowledge of their anatomy and wiring, we have a limited grasp of what each layer contributes to cortical computation. We need to develop a theory of cortical function that is rooted solidly in each layer's component cell types and fine circuit architecture and produces predictions that can be validated by specific perturbations. Here we briefly review the progress toward such a theory and suggest an experimental road map toward this goal. We discuss new methods for the all-optical interrogation of cortical layers, for correlating in vivo function with precise identification of transcriptional cell type, and for mapping local and long-range activity in vivo with synaptic resolution. The new technologies that can crack the function of cortical layers are finally on the immediate horizon. PMID- 30521779 TI - Whole-Brain Functional Ultrasound Imaging Reveals Brain Modules for Visuomotor Integration. AB - Large numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ~100 MUm. We detected 87 active brain regions during visual stimulation that evoked the optokinetic reflex, a visuomotor behavior that stabilizes the gaze both horizontally and vertically. Using a genetic mouse model of congenital nystagmus incapable of generating the horizontal reflex, we identified a subset of regions whose activity was reflex dependent. By blocking eye motion in control animals, we further separated regions whose activity depended on the reflex's motor output. Remarkably, all reflex-dependent but eye motion-independent regions were located in the thalamus. Our work identifies functional modules of brain regions involved in sensorimotor integration and provides an experimental approach to monitor whole-brain activity of mice in normal and disease states. PMID- 30521780 TI - The potential role of the sphaeractinomyxon collective group (Cnidaria, Myxozoa) in the life cycle of mugiliform-infecting myxobolids, with the morphological and molecular description of three new types from the oligochaete Tubificoides insularis. AB - Three new types of sphaeractinomyxon (Cnidaria, Myxozoa) are described from the coelomic cavity of the marine oligochaete Tubificoides insularis, collected from the Alvor estuary, Algarve, Portugal. Another known type is also registered from this location and host: Sphaeractinomyxon type 10 of Rangel et al., 2016, which was originally described from the marine oligochaete Tubificoides pseudogaster in the Aveiro estuary, Portugal. Phylogenetic analysis revealed the case isolates and all other available SSU rRNA sequences of sphaeractinomyxon clustering within a clade containing Myxobolus spp. that infect mullets, thus suggesting that this collective group plays a role in the life cycle of mugiliform-infecting myxobolids. Also clustering within this clade were all types of tetraspora and endocapsa, calling into question the distinctiveness of these collective groups. Acknowledging a previous work showing that the pansporocysts of sphaeractinomyxon produce a variable number of actinospores, we suggest that the tetraspora collective group be deemed invalid and its types transferred to sphaeractinomyxon. In turn, endocapsa requires validation through the description of new types truly differentiating them from sphaeractinomyxon. PMID- 30521781 TI - The effect of spinal mobilization with leg movement in patients with lumbar radiculopathy - A double blind randomized controlled trial. AB - OBJECTIVES: To evaluate the effect of spinal mobilization with leg movement (SMWLM) on low back and leg pain intensity, disability, pain centralization and patient satisfaction in subjects with lumbar radiculopathy. DESIGN: A double blind randomized controlled trial. SETTING: General Hospital PARTICIPANTS: Sixty adults (mean age 44 years) with sub-acute lumbar radiculopathy INTERVENTIONS: Subjects were randomly allocated to receive SMWLM, exercise and electrotherapy (n = 30) or exercise and electrotherapy alone (n = 30). All subjects received 6 sessions over 2 weeks. MAIN OUTCOME MEASURES: The primary outcomes were leg pain intensity and Oswestry disability index score. Secondary variables were low back pain intensity, global rating of change (GROC), straight leg raise (SLR) and lumbar range of motion (ROM). Variables were evaluated blind at base line, post intervention, and 3 and 6 months follow-up. RESULTS: Significant and clinically meaningful improvement occurred in all outcome variables. At 2 weeks the SMWLM group had significantly greater improvement than the control group in leg pain (MD 2.4, 95% CI 2.0 to 2.7) and disability (MD 3.9 (5.5 to 2.2). Similarly at 6 months the SMWLM group had significantly greater improvement than the control group in leg pain (MD 4.4, 95% CI 4.0 to 4.8) and disability (MD 4.7 (6.3to 3.1). The SMWLM group also reported greater improvement in the GROC and in SLR ROM. CONCLUSION: In patients with lumbar radiculopathy, the addition of SMWLM provided significantly improved benefits in terms of leg and back pain, disability, SLR ROM and patient satisfaction in the short-and long-term. PMID- 30521782 TI - Proton leak regulates mitochondrial reactive oxygen species generation in endothelial cell activation and inflammation - A novel concept. AB - Mitochondria are capable of detecting cellular insults and orchestrating inflammatory responses. Mitochondrial reactive oxygen species (mtROS) are intermediates that trigger inflammatory signaling cascade in response to our newly proposed conditional DAMP (damage associated molecular patterns). We recently reported that increased proton leak regulates mtROS generation and thereby exert physiological and pathological activation of endothelial cells. Herein, we report the recent progress in determining the roles of proton leak in regulating mtROS, and highlight several important findings: 1) The majority of mtROS are generated in the complexes I and III of electron transport chain (ETC); 2) Inducible proton leak and mtROS production are mutually regulated; 3) ATP synthase-uncoupled ETC activity and mtROS regulate both physiological and pathological endothelial cell activation and inflammation initiation; 4) Mitochondrial Ca2+ uniporter and exchanger proteins have an impact on proton leak and mtROS generation; 5) MtROS connect signaling pathways between conditional DAMP-regulated immunometabolism and histone post-translational modifications (PTM) and gene expression. Continuous improvement of our understanding in this aspect of mitochondrial function would provide novel insights and generate novel therapeutic targets for the treatment of sterile inflammatory disorders such as metabolic diseases, cardiovascular diseases and cancers. PMID- 30521783 TI - MicroRNA-19a regulates the proliferation, migration and invasion of human gastric cancer cells by targeting CUL5. AB - Gastric cancer is one of the prevalent types of cancers and despite improvements in its treatment, the overall survival is still far from descent. The dearth of efficient biomarkers, chemotherapeutic agents and therapeutic targets form a major hurdle in the treatment of the gastric cancer. Accumulating evidences suggest that MicroRNAs (miRs) may prove important therapeutic targets/agents for the management of cancers including gastric cancer. Herein, we examined the expression of miR-19a by qRT-PCR in gastric cancer and attempted to explore its potential role. It was found that the expression of miR-19a is significantly (p < 0.05) enhanced in the gastric cancer tissues as well as the gastric cancer cell lines. Inhibition of miR-19a in gastric cancer cells suppressed the proliferation migration and invasion of the gastric cancer cells. Bioinformatic analysis revealed CUL5 to be the potential target of miR-19a. Contrary, to the expression of miR-19a, the expression of CUL5 was significantly (p < 0.05) downregulated in all the gastric cancer tissues and cell lines. However, inhibition of miR-19a in SNU-16 gastric cancer cells could cause upsurge of CUL5 expression. Overexpression of CUL-5 was found to exhibit similar effects on the proliferation, migration and invasion of the SNU-16 gastric cancer cells as that of miR-19a suppression. Additionally, overexpression of CUL5 could at least partially abolish the effects of miR-19a suppression on the proliferation, migration and invasion of SNU-16 gastric cancer cells. Finally, overexpression of miR-19a caused inhibition of the xenografted tumors in vivo indicating the potential of miR-19a as therapeutic target for gastric cancer. PMID- 30521784 TI - Carbon disulfide induces embryo loss by perturbing the expression of the mTOR signalling pathway in uterine tissue in mice. AB - Understanding of the mechanism of embryo loss is critical for successful pregnancy considering an increase in the incidence of infertility. In this study, we focus on the effect of alterations in the expression of the AKT/AMPK/mTOR signalling pathway in mouse uterine tissue after embryo loss induced by harmful environmental exposure to carbon disulfide (CS2). CS2 is a material used in certain production processes, and women are sometimes exposed to it in occupational settings. We created an animal model of gestating mice exposed to CS2 on gestation days 3 (GD3), 4 (GD4), 5 (GD5) and 6 (GD6) with various corresponding endpoints after the exposure. The uterine tissue was collected according to the endpoint time series to detect the expression levels of mTOR, p mTOR, pAKT, and pAMPK using western blot, RT-PCR, immunohistochemistry staining, and ELISA. Dietary supplementation with N-carbamoyl glutamic acid (NCG) was used to verify the effect of the mTOR signalling pathway on embryo loss caused by CS2. We detected down-regulation of the levels of the mTOR and p-mTOR proteins; the levels of these two proteins were decreased by 49.35% and 51.44% at the GD5 endpoint after GD3 exposure and by 38.55% and 59.51% after GD4 exposure, respectively. The change in the expression level of mTOR mRNA was consistent with the protein expression, and the mRNA level at the GD5 endpoint was decreased by 55.0% after GD4 exposure (P < 0.05). Additionally, protein expression levels of pAKT were decreased by 49.05%, and the levels of pAMPK were increased by 25.51% at the GD5 endpoint after GD4 exposure (P < 0.05). A similar trend was observed for pAKT and pAMPK at the GD4 endpoint after GD3 exposure, at the GD6 endpoint after GD5 exposure, and at the GD7 endpoint after GD6 exposure (P < 0.05). Supplementation with NCG contributed to recovery from the effects of CS2 by increasing the protein expression levels of mTOR and pAKT by 47.54% and 63.79% (P < 0.05), respectively, while the pAMPK protein level was decreased by 37.15% (P < 0.05) at the GD5 endpoint after GD4 exposure. It should be noted that the number of implanted embryos was significantly increased after supplementation with NCG. Our results indicate that down-regulation of mTOR at the time of implantation is regulated by pAKT and pAMPK, that may be an important factor for embryo loss induced by CS2. PMID- 30521785 TI - Molecular optimization of autotransporter-based tyrosinase surface display. AB - Display of recombinant enzymes on the cell surface of Gram-negative bacteria is a desirable feature with applications in whole-cell biocatalysis, affinity screening and degradation of environmental pollutants. One common technique for recombinant protein display on the Escherichia coli surface is autotransport. Successful autotransport of an enzyme largely depends on the following: (1) the size, sequence and structure of the displayed protein, (2) the cultivation conditions, and (3) the choice of the autotransporter expression system. Common problems with autotransporter-mediated surface display include low expression levels and truncated fusion proteins, which both limit the cell-specific activity. The present study investigated an autotransporter expression system for improved display of tyrosinase on the surface of E. coli by evaluating different variants of the autotransporter vector including: promoter region, signal peptide, the recombinant passenger, linker regions, and the autotransporter translocation unit itself. The impact of these changes on translocation to the cell surface was monitored by the cell-specific activity as well as antibody based flow cytometric analysis of full-length and degraded passenger. Applying these strategies, the amount of displayed full-length tyrosinase on the cell surface was increased, resulting in an overall 5-fold increase of activity as compared to the initial autotransport expression system. Surprisingly, heterologous expression using 7 different translocation units all resulted in functional expression and only differed 1.6-fold in activity. This study provides a basis for broadening of the range of proteins that can be surface displayed and the development of new autotransporter-based processes in industrial-scale whole cell biocatalysis. PMID- 30521786 TI - Locomotor central pattern generator excitability states and serotonin sensitivity after spontaneous recovery from a neonatal lumbar spinal cord injury. AB - The spinal locomotor central pattern generator (CPG) in neonatal mice exhibits diverse output patterns, ranging from sub-rhythmic to multi-rhythmic to fictive locomotion, depending on its general level of excitation and neuromodulatory status (Sharples and Whelan, 2017). We have recently reported that the locomotor CPG in neonatal mice rapidly recovers the ability to produce neurochemically induced fictive locomotion following an upper lumbar spinal cord compression injury (Zuchner et al., 2018). Here we address the question of recovery of multi rhythmic activity and the serotonin-sensitivity of the CPG. In isolated spinal cords from control and 3 days post-injury mice, application of dopamine and NMDA elicited multi-rhythmic activity with slow and fast components. The slow component comprised 10-20 second episodes of activity that were synchronous in ipsilateral or all lumbar ventral roots, and the fast components involved bursts within these episodes that displayed coordinated patterns of alternation between ipsilateral roots. Rhythm strength was the same in control and injured spinal cords. However, power spectral analysis of signal within episodes showed a reduced peak frequency after recovery. In control spinal cords, serotonin triggered fictive locomotion only when applied at high concentration (30 uM, constant NMDA). By contrast, in about 50% of injured preparations fictive locomotion was evoked by 2-3 times lower serotonin concentrations (10-15 uM). This increased serotonin sensitivity was correlated with post-injury changes in the expression of specific serotonin receptor transcripts, but not of dopamine receptor transcripts. PMID- 30521787 TI - Cabazitaxel and Thymoquinone co-loaded Lipospheres as a Synergistic Combination for Breast Cancer. AB - Cabazitaxel as microtubule inhibitor and thymoquinone as HDAC inhibitor affects the important genes like p53, STAT3, Bax, BCL-2, p21 and down regulation of NF kappaB are reported for potential activity against breast tumors. However, poor aqueous solubility and permeability hinders the delivery of these drugs to target site. To address the delivery challenges cabazitaxel and thymoquinone co-loaded lipospheres were developed. Lipospheres are the lipid based self-assemblies of particle size below 150 nm were prepared with more than 90% entrapment efficiency for both the drugs. In vitro drug release studies revealed there was a sustained diffusion controlled drug release from liposphere matrix leading to decrease in particle size with increase in zeta potential. Cytotoxicity studies on MCF-7 and MDA-MB-231 cells demonstrated cabazitaxel and thymoquinone as synergistic combination for the treatment of breast cancer which was proved by CompuSyn software. Enhanced efficacy of developed lipospheres can be due to rapid cellular internalization which was observed in confocal laser scanning microscopy. Drastic changes in cancer cell morphology such as nuclear fragmentation were observed upon treatment with these lipospheres in comparison to combination solution as observed in fluorescent imaging which are the hall marks of apoptosis. Cell cycle analysis and apoptosis studies confirmed the increased Sub G1 phase arrest as well as cell death due to apoptosis. Thus, as per observed results, it can be concluded that cabazitaxel and thymoquinone co-loaded lipospheres are the efficient delivery vehicles in management of breast cancer. PMID- 30521788 TI - PEG-grafted phospholipids in vesicles: Effect of PEG chain length and concentration on mechanical properties. AB - Incorporation of low molecular weight poly-ethylene glycol (PEG) - grafted phospholipids in vesicle bilayers is known to increase the circulation time of liposomal drug delivery vehicles. Mechanical properties of giant unilamellar DPPC vesicles containing varying concentrations of DSPE-PEG (PEG MW: 550, 1000 and 2000) were measured by micropipette aspiration assay or osmotic swelling. While the area compressibility modulus did not change significantly, the bending modulus and water permeability of the bilayer was found to increase with increasing mole fraction of DSPE-PEG. This increase was more pronounced for higher molecular weight PEG. The measured bending modulus agreed with that predicted by scaling theory only at low mole fractions of DSPE-PEG. The water permeability was also measured as a function of the increase in area per lipid (due to steric repulsion between PEG chains), and for the same area per lipid, the PEG chain with MW 550 provided a greater resistance to water transport across the vesicle membrane compared to PEG 1000 and 2000. Lysis tension of the membrane, determined by osmotic lysis method at different loading rates showed a decrease in membrane strength on inclusion of the polymer lipid. These results suggest that liposome lifetime in the circulation and the rate of drug delivery are affected by the molecular weight and concentration of PEG in the bilayer. PMID- 30521789 TI - Comparison of electroencephalogram (EEG) response to MDPV versus the hallucinogenic drugs MK-801 and ketamine in rats. AB - Synthetic cathinones, often marketed as 'bath salts', have been reported to induce an excited delirium syndrome with characteristic symptoms such as paranoid, hallucination and even aggression. 3,4-Methylenedioxypyrovalerone (MDPV), a norepinephrine-dopamine reuptake inhibitor (NDRI), is one of the psychoactive ingredients in bath salts. The present study utilized cortical EEG and brain microdialysis in rats to compare the effects of MDPV (0.25, 1 and 2 mg/kg, i.p.) with the hallucinogenic drugs MK-801 (0.05, 0.1 and 0.5 mg/kg, i.p.) and ketamine (5, 15 and 25 mg/kg, i.p.). Results revealed that MDPV similar to MK 801 and ketamine caused a dose-dependent increase in the cortical EEG synchronization. In addition, all three drugs produced an increase in DA efflux in the prefrontal cortex (FCx). However, there existed difference between the three drugs. In contrast to MDPV, MK-801 and ketamine had only moderate or little effects on DA efflux in the nucleus accumbens (NAcc). Except for ketamine, the effects of MDPV and MK-801 on EEG synchronization were blocked by the D1 receptor antagonist SCH23990 (0.1 mg/kg, i.p.) and D2 receptor antagonist sulpiride (100 mg/kg, i.p.). SCH23990 or sulpiride had no effect on ketamine-induced increases in EEG synchronization. In summary, the present comparative studies suggest that DA in the FCx, but unlikely the NAcc, exerts a critical role in increasing EEG synchronization associated with the excited delirium syndrome. Neural circuits consisting of glutamatergic and GABAergic neurons responsible for the hallucinogenic effect are discussed in the context of hyperdopamine and dysconnection theories for hallucinatory behaviors. PMID- 30521790 TI - CNB-001, a pleiotropic drug is efficacious in embolized agyrencephalic New Zealand white rabbits and ischemic gyrencephalic cynomolgus monkeys. AB - Ischemic stroke is an acute neurodegenerative disease that is extremely devastating to patients, their families and society. Stroke is inadequately treated even with endovascular procedures and reperfusion therapy. Using an extensive translational screening process, we have developed a pleiotropic cytoprotective agent with the potential to positively impact a large population of brain ischemia patients and revolutionize the process used for the development of new drugs to treat complex brain disorders. In this unique translational study article, we document that the novel curcumin-based compound, CNB-001, when administered as a single intravenous dose, has significant efficacy to attenuate clinically relevant behavioral deficits following ischemic events in agyrencephalic rabbits when administered 1 h post-embolization and reduces infarct growth in gyrencephalic non-human primates, when administered 5 min after initiation of middle cerebral artery occlusion. CNB-001 is safe and does not increase morbidity or mortality in either research species. Mechanistically, CNB 001 inhibits human 5- and 15-lipoxygenase in vitro, and can attenuate ischemia induced inflammatory markers, and oxidative stress markers, while potentially promoting synaptic plasticity mediated by enhanced brain-derived neurotrophic factor (BDNF). PMID- 30521791 TI - Overexpression of heat shock protein HSP90AA1 and translocase of the outer mitochondrial membrane TOM34 in HCV-induced hepatocellular carcinoma: A pilot study. AB - OBJECTIVE: Identification of new molecular markers to enhance early diagnosis, prognosis and/or treatment of hepatocellular carcinoma (HCC) is a need. TOM34 (34 kDa-translocase of the outer mitochondrial membrane) protein expression deregulation has demonstrated to be involved in the growth of many cancers. Here, we aimed at evaluating serum TOM34 and some heat shock proteins (HSPA4, HSPA1B, and HSP90AA1) expressions in hepatitis C virus (HCV)-related cirrhosis and HCV induced HCC relative to controls and correlating these expressions to the clinicopathological data. METHODS: Serum specimens were collected from 90 patients with HCV associated complications (30 cirrhotic, 30 early HCC and 30 late HCC) and 60 controls. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed for relative quantification of the four target genes using the Livak method. In silico network analysis was also executed to explore the contribution of the genes in liver cancer. RESULTS: The serum TOM34 and HSP90AA1 transcripts were significantly upregulated in HCC patients compared to cirrhotic ones with more up-regulation in late HCC patients. Receiver operating characteristic analysis showed the optimum cutoff value of 0.625 corresponding to 71.7% sensitivity and 56.7% specificity, and an area under the curve (AUC) of 0.705 to discriminate HCC from cirrhotic groups (P = .002). In multivariate analysis, ordination plot showed obvious demarcation between the study groups caused by the higher levels of TOM34 among other variables. CONCLUSIONS: TOM34 and its partner HSP90AA1 might be used as a potential biomarker for monitoring HCV-induced HCC progression in the Egyptian population. Future large-scale validation studies are warranted. PMID- 30521792 TI - Anti-inflammatory and antioxidant effect of melatonin on recovery from muscular trauma induced in rats. AB - In recent decades, the number of people who practice sports has grown exponentially, increasing the number of muscular injuries. Trauma injury occurs when the muscle is exposed to a sudden compression force. Melatonin (MLT) has often been cited in the literature as a potent antioxidant and anti-inflammatory agent. This study was designed to evaluate MLT action on muscle tissue in Wistar rats in an experimental model of muscle trauma. Twenty-eight Wistar rats were used, divided into four groups: CO (Control), CO + MLT (Control + Melatonin), T (Trauma) and T + MLT (Trauma + Melatonin). MLT (20 mg/kg) was administered (ip) daily at dusk until day 7. The trauma occurred on day 1, 2 h before the first MLT application. On day 8, muscle tissue was collected for histological analysis (HE), immunohistochemistry (TNF-alpha and NFkappaB), evaluation of oxidative stress through analysis of lipoperoxidation by TBARS and activity of SOD and GPx enzymes, and analysis of nitrites and nitrates. In the evaluation of TBARS and SOD, we observed a significant increase in the T group and a significant decrease in the T + MLT group. In the evaluation of GPx, there was a significant increase in the T group and a significant decrease in the T + MLT group. The histological analysis of muscle tissue revealed structural changes of muscle fibers and inflammatory infiltrate in the T group but a decrease in this damage in the T + MLT group. In the immunohistochemical evaluation, increased expression of TNFalpha and NFkappaB proteins in the T group was observed and a significant decrease of this expression in the T + MLT group. MLT was shown to attenuate oxidative damage and to diminish the expression of inflammatory proteins and tissue damage in this experimental model. PMID- 30521793 TI - Past and future trends of Cryptosporidium in vitro research. AB - Cryptosporidium is a genus of single celled parasites capable of infecting a wide range of animals including humans. Cryptosporidium species are members of the phylum apicomplexa, which includes well-known genera such as Plasmodium and Toxoplasma. Cryptosporidium parasites cause a severe gastro-intestinal disease known as cryptosporidiosis. They are one of the most common causes of childhood diarrhoea worldwide, and infection can have prolonged detrimental effects on the development of children, but also can be life threatening to HIV/AIDS patients and transplant recipients. A variety of hosts can act as reservoirs, and Cryptosporidium can persist in the environment for prolonged times as oocysts. While there has been substantial interest in these parasites, there is very little progress in terms of treatment development and understanding the majority of the life cycle of this unusual organism. In this review, we will provide an overview on the existing knowledge of the biology of the parasite and the current progress in developing in vitro cultivation systems. We will then describe a synopsis of current and next generation approaches that could spearhead further research in combating the parasite. PMID- 30521794 TI - A risk-scoring model for the prediction of delayed bleeding after colorectal endoscopic submucosal dissection. AB - BACKGROUND AND AIMS: Delayed bleeding is an important adverse event after colorectal endoscopic submucosal dissection (ESD). We aimed to investigate the incidence and risk factors of delayed bleeding after colorectal ESD, and to develop a risk scoring model for predicting delayed bleeding. METHODS: This retrospective multicenter study was performed at 5 centers. The derivation and validation cohorts comprised 1189 patients from 1 center and 415 patients from the other 4 centers. We investigated the incidence and risk factors of delayed bleeding. Then, we developed a risk scoring model for predicting delayed bleeding using the data of the derivation cohort. We validated the scoring system in the validation cohort. RESULTS: Delayed bleeding occurred in 34 (2.9%) patients in the derivation cohort. In multivariate analysis, the risk factors of delayed bleeding were tumor location in the rectosigmoid colon (odds ratio [OR], 6.49; 95% confidence interval [CI], 1.96-21.42; P=0.002), large tumor (>=30 mm; OR, 2.10; 95% CI, 1.01-4.40; P=0.048), and use of antiplatelet agents except for aspirin alone (OR, 4.04; 95% CI, 1.44-11.30; P=0.008). These 3 factors were incorporated into a risk scoring model for prediction of delayed bleeding. As the score based on this system increased, the incidence of delayed bleeding increased in the validation cohort. CONCLUSIONS: The risk scoring model incorporating tumor location, tumor size, and use of antiplatelet agents can quantitatively predict the risk of delayed bleeding after colorectal ESD. PMID- 30521795 TI - Peri-Procedural Antithrombotic Management from a Patient Perspective: A Qualitative Analysis. AB - BACKGROUND: Peri-procedural antithrombotic medication management is a complex, often confusing process for patients and their providers. Communication difficulties often lead to suboptimal medication management resulting in delayed or cancelled procedures. METHODS: We conducted telephone surveys with patients taking chronic antithrombotic medications who had recently undergone an endoscopy procedure. In the survey, we sought to better understand the peri-procedural process for patients taking antithrombotic medications. We conducted a content analysis of patients' unstructured responses from the peri-procedural patient phone calls. We used a multi-step group coding process to analyze responses. Relationships between different themes and categories were analyzed using original quotes and retrieving thematic segments from the transcripts. RESULTS: The survey was administered to 81 patients. 74/81 (91%) of respondents said they understood the plan to manage their antithrombotic, but 21/81 (26%) of respondents were not completely satisfied with the coordination, communication, and management of their medications. Five primary themes emerged from the content analysis as patient-centered design features affecting peri-procedural care: (1) patients require accurate and timely information; (2) a patient's prior experience with antithrombotic therapy affects their understanding of the process; (3) patients prefer receiving their information from a single source, and also prefer (4) different methods of instruction; (5) finally, patients expect their clinician(s) to be available through the peri-procedural management process. CONCLUSION: To optimize the peri-procedural medication management communication process, patients desire timeliness, accuracy, and adaptiveness to prior patient experience while offering a single, consistently available point of contact. PMID- 30521796 TI - Healthcare Providers' Advice on Lifestyle Modification in the US Population: Results from the National Health and Nutrition Examination Survey 2011-2016. AB - OBJECTIVE: Healthcare providers are encouraged to prescribe lifestyle modifications for preventing and managing obesity and associated chronic conditions. However, the pattern of lifestyle advice provision is unknown. We investigate the prevalence of advised lifestyle modification according to weight status and chronic conditions in a US nationally representative sample. METHODS: Adults 20-64 years (n=11,467) from National Health and Nutrition Examination Study between 2011 and 2016 were analyzed, with weight status, and chronic conditions (high blood pressure, high blood cholesterol, osteoarthritis, coronary heart disease and type 2 diabetes mellitus). Lifestyle modification advice by healthcare providers included increase physical activity/exercise, reduce dietary fat/calories, control/lose weight, and all of above. RESULTS: High blood pressure (32.7%) and cholesterol (29.3%) were highly prevalent compared to osteoarthritis (7.4%), type 2 diabetes (5.7%) and coronary heart disease (3.7%). Those with type 2 diabetes received considerably frequent advice (56.5%; 95%CI: 52.4%-60.6%) than those with high blood pressure (31.4%; 95%CI:29.3%-33.6%) and cholesterol (27.0%; 95%CI:24.9%-29.3%). Prevalence of lifestyle advice exhibited substantial increases with graded BMI and comorbidity (all P<0.001). After adjusting for comorbid conditions, advice were more commonly reported among women, those overweight/obese, non-white, or insured. Remarkably low proportion of overweight (21.4: 95%CI: 18.7-24.3%) and obese (44.2%;95%CI:41.0%-47.4%) adults free of chronic conditions reported receiving any lifestyle advice. CONCLUSIONS: Prevalence of lifestyle modification advised by healthcare providers is generally low among US adults with chronic conditions, and worryingly low among those without chronic conditions however overweight or obese. Prescribed lifestyle modification is a missing opportunity in implementing sustainably strategies reducing chronic condition burden. PMID- 30521797 TI - Rare lesion in the uterine cervix with irregular vaginal bleeding. PMID- 30521798 TI - Extent of Lymphadenectomy and Postoperative Major Complications Among Women with Endometrial Cancer Treated with Minimally Invasive Surgery. AB - BACKGROUND: In patients with endometrial cancer sentinel lymphadenectomy is used to accurately prognosticate extent of disease and has been proposed as a method to decrease the incidence of medical and surgical complications associated with more extensive lymphadenectomy. It is unknown if patients who undergo traditional lymphadenectomy experience major postoperative complications at the same rates as those who undergo sentinel lymphadenectomy or those who do not undergo lymphadenectomy. OBJECTIVE: To compare the incidence of major postoperative complications among endometrial cancer patients undergoing total laparoscopic hysterectomy with traditional lymphadenectomy versus sentinel or no lymphadenectomy. STUDY DESIGN: Patients with endometrial cancer who underwent total laparoscopic hysterectomy recorded in the National Surgical Quality Improvement Program (NSQIP) database 2015-2016 were identified using current procedural terminology (CPT) and international classification of diseases (ICD) codes. Primary exposure was extent of lymphadenectomy. Primary outcome was major postoperative complications as defined by the Clavien-Dindo scale. Associations were examined with bivariable tests and multivariable logistic regression. RESULTS: 3,282 women with endometrial cancer who underwent total laparoscopic hysterectomy were identified; 2,049 (62.4%) did not undergo lymphadenectomy, 1,089 (33.2%) underwent traditional lymphadenectomy and 144 (4.4%) underwent sentinel lymphadenectomy. Traditional lymphadenectomy had the highest rate of major complications (3.6%) compared with sentinel (2.0%) and no lymphadenectomy (2.0%) (p=0.03). Patients who underwent traditional lymphadenectomy also had the longest operating room times and procedures that were most surgically complex (171 min, 30.6 RVU) compared with patients who underwent sentinel lymphadenectomy (166 min, 24.9 RVU) or no lymphadenectomy (141 min, 15.0 RVU) (all p<0.001). Patients who underwent traditional lymphadenectomy had nearly twice the odds of a major complication (aOR 1.8 95%CI 1.2-2.9) and need for readmission (aOR 2.2 95% CI 1.5 - 3.4) compared to those who underwent sentinel or no lymphadenectomy. The incidence of readmission after traditional lymphadenectomy was higher (4.6%) than after sentinel lymphadenectomy (1.4%) and no lymphadenectomy (2.2%, p<0.001). CONCLUSIONS: Sentinel lymphadenectomy among patients undergoing total laparoscopic hysterectomy for endometrial cancer was associated with a decreased incidence of major postoperative complication and need for readmission when compared with traditional lymphadenectomy. PMID- 30521799 TI - Vascular and metabolic profiles in offspring born to pregnant mice with metabolic syndrome treated with inositols. AB - BACKGROUND: Inositols (INOs) supplementation during pregnancy, specifically the combination of myo-inositol (MI) and D-chiro-inositol (DCI), has been reported to improve vascular parameters in women with gestational diabetes mellitus. We demonstrated previously that offspring born to pregnant mice lacking endothelial nitric oxide synthase (eNOS+/-) gene have hypertension (HTN) as adults and when fed high fat diet (HFD) develop a metabolic syndrome (MS) phenotype. OBJECTIVE: Our aim was to evaluate if INOs treatment in pregnancy complicated by MS improves the vascular and metabolic profile in mice offspring programmed in utero to develop HTN and MS. STUDY DESIGN: Heterozygous eNOS+/- mice fed a HFD manifest a MS phenotype. Female eNOS+/- mice with MS were bred with wild type (WT) male.On gestational day 1, pregnant females were randomly allocated to receive either a mixture of INOs (MI/DCI: 7.2/0.18 mg/mL) or water as placebo until delivery. The female offspring obtained were genotyped and categorized as: WT (genetically normal, with eNOS gene) and eNOS+/- offspring (genetically modified, heterozygous for eNOS gene). Both offspring developed in an abnormal uterine environment due to maternal MS. At 9-10 weeks of age, the offspring underwent a glucose tolerance test (GTT) and systolic blood pressure (SBP) measurement. Then, the mice were sacrificed and carotid arteries were isolated for evaluation of vascular responses. Responses to phenylephrine (PE), in the presence and absence of a non specific nitric oxide inhibitor (L-NAME), the vasodilator acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed. RESULTS: GTT showed lower glucose levels in both eNOS+/-INOs (P=0.03) and WT-INOs (P=0.05) offspring born to MS dams on INOs supplementation compared to offspring born to untreated dams. SBP was higher in eNOS+/- offspring compared to WT (169 +/- 7 vs. 142 +/- 9 mmHg, respectively, P=0.04) and INOs treatment decreased SBP in WT-INOs (110 +/- 10 mmHg, P=0.01) but not in eNOS+/-INOs offspring. Maximal (%Max) contractile response to PE was higher in eNOS+/- offspring born to MS dams and was decreased in those born to MS dams treated with INOs (%Max, eNOS+/-, 123 +/- 7 vs. eNOS+/ INOs, 82 +/- 11 mmHg, P=0.007). No differences were seen in PE contractile responses in WT offspring born to MS dams treated or not with INOs (WT, 92 +/- 4 vs WT-INOs, 75 +/- 7). L-NAME response was decreased in eNOS+/-INOs and WT-INOs offspring compared to untreated ones. ACh vasorelaxation was impaired in eNOS+/- and WT offspring born to MS dams, and maternal INOs treatment improved offspring vascular relaxation in both offspring (P=0.01 and P=0.03, respectively). No differences were seen in response to SNP. CONCLUSION: Inositols supplementation improved glucose tolerance, SBP and vascular responses in adult eNOS+/- and WT offspring born to dams with MS. Interestingly, WT born to MS dams show an altered vascular profile similar to eNOS+/- offspring and exhibit an improved response to INOs treatment. Our findings suggest that the benefits of INOs treatment are more pronounced in offspring exposed to environmental factors in utero, and less likely in those due to genetic factors. PMID- 30521800 TI - Does Maternal Age at Retrieval Influence the Implantation Potential of Euploid Blastocysts? AB - BACKGROUND: Age-related decline in reproductive potential is mainly due to the increased incidence of aneuploidy. Furthermore, two recent studies have shown that euploid embryos of older women may have a lower implantation potential compared to those of younger women, suggesting that aging might compromise embryos beyond their ploidy status. However, the inherent limitations of these studies preclude solid conclusions. OBJECTIVE: To determine whether maternal age at retrieval affects the implantation potential of euploid blastocysts. STUDY DESIGN: It is a retrospective cohort study that was conducted at an academic medical center. Patients who underwent frozen-thawed euploid embryo transfers (FET) between 2013 and 2016 were included. Cycles were divided into the following five age groups: <35, 35-37, 38-40, 41-42, and >42 years old. Blastocysts were assessed before biopsy and assigned the following morphological grades: excellent (3-6AA), good (3-6AB, 3-6BA), average (2-6BB), and poor (3-6BC, 3-6CB, 3-6CC). The main outcome measures were implantation (IR) and live birth (LBR) rates. Chi square (chi2) and Fisher's exact tests were used to compare categorical variables. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and controlled for confounders. RESULTS: A total of 785 FET cycles (870 blastocysts) were included. Excellent-quality blastocysts were associated with a significantly higher LBR compared with good- (78.8% vs. 63.8%), average- (78.8% vs. 54.2%) and poor-quality counterparts (78.8% vs. 28.3%). Poor-quality embryos yielded a higher spontaneous abortion (SAB) rate compared with average-, good-, and excellent-quality blastocysts (25.0%, 9.0%, 6.9%, and 2.4%, respectively). Embryos biopsied on day 5 had a significantly higher LBR compared with those biopsied on day 6 (60.0% vs. 46.6%). The five age groups (<35, 35-37, 38-40, 41 42, and >42 years) had comparable IRs (56.5%, 52.9%, 55.4%, 59.1%, and 71.4%, respectively), LBRs (55.1%, 51.3%, 53.5%, 52.4%, and 61.9%, respectively), and SAB rates (8.8%, 7.9%, 8.3%, 14.3, and 13.3%, respectively). Older women had fewer euploid embryos, but they were of comparable morphology and developed at a similar rate to the blastocyst stage as compared to those of younger women. CONCLUSIONS: Maternal age at retrieval influences the number of euploid embryos but, contrary to previously published studies, it does not affect their implantation potential. The morphodynamic characteristics of embryos, as reflected by blastocyst morphology and speed of development, are critical for selecting among euploid embryos. PMID- 30521801 TI - A value proposition for trough level-based anti-TNFalpha drug dosing. AB - Treatment of inflammatory bowel diseases and rheumatic disorders with anti-tumor necrosis factor alpha (TNFalpha) drugs is expensive, while a significant proportion of patients does not show adequate clinical response. Therapeutic drug monitoring (TDM) enables patient-specific anti-TNFalpha therapy. The role of laboratory tests in clinical care has recently been described in a value proposition framework. It describes care processes, stakeholders, costs, risks, benefits and patient outcomes based on the use of a laboratory test in a clinical care pathway. We have applied this concept to the use of TDM for anti-TNFalpha drugs, describing evidence that supports the intervention and its cost effectiveness, steps that need to be adjusted in the care pathway, possible treatment algorithms and measures to assess adoption of this framework into clinical practice. For effective TDM, an assay for measurement of drug levels together with appropriate target ranges and an anti-drug-antibody assay have to be implemented. Also, instead of only reporting the drug concentration, laboratorians, pharmacists and clinicians should deliver added value by introducing a TDM-based treatment algorithm into clinical practice. Thus, to maximize effectiveness of TDM of anti-TNFalpha therapy in routine care, adjustment of current care pathways and cooperation of many stakeholders are needed. PMID- 30521803 TI - Human-powered pop-up resting shelter for sampling cavity-resting mosquitoes. AB - Methods for collecting mosquitoes without the use of electricity are advantageous in remote field locations where electricity is not present or is unreliable. Here we report on the development and evaluation of a human-powered system for sampling cavity-resting mosquitoes. The system is composed of a spring-steel framed resting shelter and pneumatic lid that "pumps" mosquitoes resting within the shelter into a capture chamber when the resting shelter is manually compressed. Field evaluation of the system in the Everglades of Florida, USA indicates that the human-powered system is not statistically different than resting shelter vacuum aspiration with regard to the number or physiological status of the adults sampled. Culex (Melanoconion) females dominated collections, indicating that this system would have greatest utility in sampling vectors of zoonotic Alphaviruses in the American tropics. PMID- 30521802 TI - Single layer colloid centrifugation technique improves motility, viability and chromatin integrity of ram spermatozoa after thawing. AB - The cell membrane of ram spermatozoa is more sensitive to the freezing process than in other species due to its composition. As a result, the quality and viability of frozen thawed ram spermatozoa are often poor, which together with the specific structure of the ewe's cervix are the main reasons for lower fertility in ewes after intracervical insemination. In the present study we investigated the effects of semen centrifugation through a single layer of a species-specific colloid (Androcoll-O) on post-thaw quality of ram spermatozoa. Motility, viability and morphology were analysed 0, 6, 12 and 24 h after thawing. DNA fragmentation index (%DFI) of the samples was assessed 0 h after thawing, by SCSATM. Membrane and acrosome integrity of spermatozoa were analysed by Sybr 14/PI/PNA test 0 h after thawing. The proportion of motile spermatozoa was significantly higher in SLC - selected samples in comparison to control (not SLC selected) samples at 0, 6, 12 (P < 0.001) and 24 h (P < 0.05). The proportion of viable spermatozoa was also significantly higher in SLC - selected samples in comparison to control samples at all times (P < 0.001). The proportion of abnormal acrosomes and morphologically abnormal spermatozoa (MAS) were significantly lower in SLC - selected samples compared to control samples at all times (P < 0.001). Analysis of chromatin stability revealed significantly lower %DFI values in SLC - selected samples compared to control samples (P < 0.001). The SYBR-14/PI/PNA test also revealed significantly better values in SLC - selected compared to control samples (P < 0.05). In conclusion, single layer colloid centrifugation significantly improved post-thaw quality and longevity of ram spermatozoa, making it suitable for artificial insemination initiatives. PMID- 30521804 TI - Economic cost of malaria at household in high and low transmission areas of central India. AB - The cost burden of malaria at the household level, resulting from complex social, economic, and epidemiological factors, is enormous. This study was carried out to estimate the economic burden of malaria at the household level in low and high malaria transmission areas of central India. We conducted surveys with households in which at least one member had suffered from malaria in the three months preceding the survey. The human capital method was used to estimate the cost of malaria at the household level. We found that the total cost per episode of malaria was higher in high transmission areas than low transmission areas; direct costs were generally higher for adults than for children. Males spent more on diagnosis and treatment than females, and the mean work absenteeism due to malaria was higher among male adult patients than among females, though work time lost due to child illness was lower for male caregivers. Households belonging to high and middle socioeconomic status (SES) spent significantly more on malaria illness than those of low SES. However, the economic burden of malaria relative to annual incomes was highest among low SES households. Populations belonging to high transmission areas were more vulnerable to malarial infection due to geo climatic, demographic, socioeconomic, and cultural factors, as well as the relatively poor access to health facilities that characterize these regions. Additionally, poor health-seeking practices not only increase the cost burden but also adversely affect patients' health and productivity, which lead to opportunity losses while imposing a greater economic burden on households. PMID- 30521805 TI - A diagnostic study comparing conventional and real-time PCR for Strongyloides stercoralis on urine and on faecal samples. AB - Strongyloides stercoralis is a soil-transmitted helminth with a wide distribution in tropical and subtropical areas. The diagnosis of S. stercoralisinfection can be challenging, due to the low sensitivity of microscopic examination of stool samples and coproculture. In the last decade, different in-house molecular biology techniques for S. stercoralis have been implemented. They demonstrated good accuracy, although sensitivity does not seem sufficiently high yet. Recently, a novel PCR technique has been evaluated for the detection of S. stercoralis DNA in urine. Aim of this work was to compare the sensitivity of the real-time PCR (qPCR) on feces routinely used at the Centre for Tropical Disease (CTD) of Negrar, Verona, Italy, with that of the novel based PCR on urine. As secondary objective, we evaluated a Urine Conditioning Buffer (r) (Zymoresearch) with the aim of improving nucleic acid stability in urine during sample storage/transport at ambient temperatures. Patients attending the CTD and resulting positive at routine screening with serology for S. stercoralis were invited, previous written consent, to supply stool and urine samples for molecular biology. A convenience sample of 30 patients was included. The sensitivity of qPCR on feces resulted 63%, and that of based PCR on urine was 17%. In all the samples treated with the Urine Conditioning Buffer (r) there was no detectable DNA. In conclusion, the sensitivity of the novel technique resulted low, and needs further implementation before being considered as a valid alternative to the validated method. PMID- 30521806 TI - Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption. AB - BACKGROUND & AIMS: The nuclear receptor subfamily 0 group B member 2 (NR0B2, also called SHP) is expressed at high levels in liver and intestine. Postprandial fibroblast growth factor 19 (human FGF19, mouse FGF15) signaling increases the transcriptional activity of SHP. We studied the functions of SHP and FGF19 in intestines of mice, including their regulation of expression of the cholesterol transporter NPC1-like intracellular cholesterol transporter 1 (NPC1L1) and cholesterol absorption. METHODS: We performed histologic and biochemical analyses of intestinal tissues from C57BL/6 and SHP-knockout mice and performed RNA-seq analyses to identify genes regulated by SHP. The effects of fasting and refeeding on intestinal expression of NPC1L1 was examined in C57BL/6, SHP-knockout, and FGF15-knockout mice. Mice were given FGF19 daily for 1 week; fractional cholesterol absorption, cholesterol and bile acid (BA) levels, and composition of BAs were measured. Intestinal organoids were generated from C57BL/6 and SHP knockout mice and cholesterol uptake was measured. Luciferase reporter assays were performed with HT29 cells. RESULTS: We genes that regulate lipid and ion transport in intestine, including NPC1L1, to be upregulated and cholesterol absorption was increased in SHP-knockout mice compared with C57BL/6 mice. Expression of NPC1L1 was reduced in C57BL/6 mice following refeeding after fasting, but not in SHP-knockout or FGF15-knockout mice. SHP-knockout mice had altered BA composition compared with C57BL/6 mice. FGF19 injection reduced expression of NPC1L1, decreased cholesterol absorption, and increased levels of hydrophilic BAs, including tauro-alpha- and -beta-muricholic acids; these changes were not observed in SHP-knockout mice. Sterol regulatory element binding transcription factor 2 (SREBF2), which regulates cholesterol, activated transcription of NPC1L1. FGF19 signaling led to phosphorylation of SHP, which inhibited SREBF2 activity. CONCLUSIONS: Postprandial FGF19 and SHP inhibit SREBF2, which leads to repression of intestinal NPC1L1 expression and cholesterol absorption. Strategies to increase FGF19 signaling to activate SHP might be developed for treatment of hypercholesterolemia. PMID- 30521807 TI - Racial Disparities in Incidence of Young-onset Colorectal Cancer and Patient Survival. AB - BACKGROUND & AIMS: Increasing rates of young-onset colorectal cancer (CRC) have attracted substantial research and media attention, but we know little about racial disparities among younger adults with CRC. We examined racial disparities in young-onset CRC by comparing CRC incidence and relative survival among younger (age <50 years) adults, in 2 time periods. METHODS: Using data from the Surveillance, Epidemiology, and End Results program of cancer registries, we estimated CRC incidence rates (per 100,000 persons ages 20 - 54 years) from 1992 through 2014, for different time periods (1992-1996 vs 2010-2014) and races (white vs black). Relative survival was calculated as the ratio of observed survival to expected survival in a comparable, cancer-free population. RESULTS: From 1992-1996 to 2010-2014, CRC incidence increased from 7.5/100,000 to 11.0/100,000 in white individuals and from 11.7/100,000 to 12.7/100,000 in black individuals. The increase in rectal cancer was larger in whites (from 2.7/100,000 to 4.5/100,000) than in blacks (from 3.4/100,000 to 4.0/100,000); in the 2010 2014 time period, black and whites had similar rates of rectal cancer. Compared to whites, blacks had smaller increases in relative survival with proximal colon cancer but larger increases in survival with rectal cancer (from 55.3% to 70.8%). CONCLUSION: In an analysis of the Surveillance, Epidemiology, and End Results database, we found racial disparities in incidence of young-onset CRC and patient survival for cancer of the colon, but minimal difference for rectal cancer. Well documented and recent increases in young-onset CRC have been largely due to increases in rectal cancer, especially in whites. PMID- 30521808 TI - Cardiovascular development and survival require Mef2c function in the myocardial but not the endothelial lineage. AB - MEF2C is a member of the highly conserved MEF2 family of transcription factors and is a key regulator of cardiovascular development. In mice, Mef2c is expressed in the developing heart and vasculature, including the endothelium. Loss of Mef2c function in germline knockout mice leads to early embryonic demise and profound developmental abnormalities in the cardiovascular system. Previous attempts to uncover the cause of embryonic lethality by specifically disrupting Mef2c function in the heart or vasculature failed to recapitulate the global Mef2c knockout phenotype and instead resulted in relatively minor defects that did not compromise viability or result in significant cardiovascular defects. However, previous studies examined the requirement of Mef2c in the myocardial and endothelial lineages using Cre lines that begin to be expressed after the expression of Mef2c has already commenced. Here, we tested the requirement of Mef2c in the myocardial and endothelial lineages using conditional knockout approaches in mice with Cre lines that deleted Mef2c prior to onset of its expression in embryonic development. We found that deletion of Mef2c in the early myocardial lineage using Nkx2-5Cre resulted in cardiac and vascular abnormalities that were indistinguishable from the defects in the global Mef2c knockout. In contrast, early deletion of Mef2c in the vascular endothelium using an Etv2::Cre line active prior to the onset of Mef2c expression resulted in viable offspring that were indistinguishable from wild type controls with no overt defects in vascular development, despite nearly complete early deletion of Mef2c in the vascular endothelium. Thus, these studies support the idea that the requirement of MEF2C for vascular development is secondary to its requirement in the heart and suggest that the observed failure in vascular remodeling in Mef2c knockout mice results from defective heart function. PMID- 30521809 TI - Expression of the neuropeptides RFamide and LWamide during development of the coral Acropora millepora in relation to settlement and metamorphosis. AB - Neuropeptides play critical roles in cnidarian development. However, although they are known to play key roles in settlement and metamorphosis, their temporal and spatial developmental expression has not previously been characterized in any coral. We here describe Acropora millepora LWamide and RFamide and their developmental expression from the time of their first appearance, using in situ hybridization and FMRFamide immunohistochemistry. AmRFamide transcripts first appear in the ectoderm toward the oral end of the planula larva following blastopore closure. This oral bias becomes less apparent as the planula develops. The cell bodies of AmRFamide-expressing cells are centrally located in the ectoderm, with narrow projections to the mesoglea and to the cell surface. As the planula approaches settlement, AmRFamide expression disappears and is undetectable in the newly settled polyp. Expressing cells then gradually reappear as the polyp develops, becoming particularly abundant on the tentacles. AmLWamide transcripts first appear in ectodermal cells of the developing planula, with minimal expression at its two ends. The cell bodies of expressing cells lie just above the mesoglea, in a position distinct from those of AmRFamide-expressing cells, and have a narrow projection extending across the ectoderm to its surface. AmLWamide-expressing cells persist for most of the planula stage, disappearing shortly before settlement, but later than AmRFamide expressing cells. As is the case with AmRFamide, expressing cells are absent from the polyp immediately after settlement, reappearing later on its oral side. AmLWamide expression lags that of AmRFamide in both its disappearance and reappearance. Antibodies to FMRFamide stain cells in a pattern similar to that of the transcripts, but also cells in areas where there is no expression revealed by in situ hybridization, most notably at the aboral end of the planula and in the adult polyp. Adult polyps have numerous staining cells on the tentacles and oral discs, as well as an immunoreactive nerve ring around the mouth. There are scattered staining cells in the coenosarc between polyps and staining cells are abundant in the mesenterial filaments. The above results are discussed in the context of our knowledge of the behavior of coral planulae at the time of their settlement and metamorphosis. Corals are facing multiple environmental threats, and these results both highlight the need for, and bring us a step closer to, a mechanistic understanding of a process that is critical to their survival. PMID- 30521810 TI - Massive cytoplasmic transport and microtubule organization in fertilized chordate eggs. AB - Eggs have developed their own strategies for early development. Amphibian, teleost fish, and ascidian eggs show cortical rotation and an accompanying structure, a cortical parallel microtubule (MT) array, during the one-cell embryonic stage. Cortical rotation is thought to relocate maternal deposits to a certain compartment of the egg and to polarize the embryo. The common features and differences among chordate eggs as well as localized maternal proteins and mRNAs that are related to the organization of MT structures are described in this review. Furthermore, recent studies report progress in elucidating the molecular nature and functions of the noncentrosomal MT organizing center (ncMTOC). The parallel array of MT bundles is presumably organized by ncMTOCs; therefore, the mechanism of ncMTOC control is likely inevitable for these species. Thus, the molecules related to the ncMTOC provide clues for understanding the mechanisms of early developmental systems, which ultimately determine the embryonic axis. PMID- 30521811 TI - Cellular and Molecular Mechanisms of Regeneration in colonial and solitary Ascidians. AB - Regenerative ability is highly variable among the metazoans. While many invertebrate organisms are capable of complete regeneration of entire bodies and organs, whole-organ regeneration is limited to very few species in the vertebrate lineages. Tunicates, which are invertebrate chordates and the closest extant relatives of the vertebrates, show robust regenerative ability. Colonial ascidians of the family of the Styelidae, such as several species of Botrylloides, are able to regenerate entire new bodies from nothing but fragments of vasculature, and they are the only chordates that are capable of whole body regeneration. The cell types and signaling pathways involved in whole body regeneration are not well understood, but some evidence suggests that blood borne cells may play a role. Solitary ascidians such as Ciona can regenerate the oral siphon and their central nervous system, and stem cells located in the branchial sac are required for this regeneration. Here, we summarize the cellular and molecular mechanisms of tunicate regeneration that have been identified so far and discuss differences and similarities between these mechanisms in regenerating tunicate species. PMID- 30521812 TI - Structural Basis for the Function of the beta-Barrel Assembly-Enhancing Protease BepA. AB - The beta-barrel-assembly machinery (BAM) complex mediates the assembly of beta barrel membrane proteins in the outer membrane. BepA, formerly known as YfgC, interacts with the BAM complex and functions as a protease/chaperone for the enhancement of the assembly and/or degradation of beta-barrel membrane proteins. To elucidate the molecular mechanism underlying the dual functions of BepA, its full-length three-dimensional structure is needed. Here, we report the crystal structure of full-length BepA at 2.6-A resolution. BepA possesses an N-terminal protease domain and a C-terminal tetratricopeptide repeat (TPR) domain, which interact with each other. Domain cross-linking by structure-guided introduction of disulfide bonds did not affect the activities of BepA in vivo, suggesting that the function of this protein does not involve domain rearrangement. The full length BepA structure is compatible with the previously proposed docking model of BAM complex and TPR domain of BepA. PMID- 30521813 TI - Regulation of Human Hsc70 ATPase and Chaperone Activities by Apg2: Role of the Acidic Subdomain. AB - Protein aggregate reactivation in metazoans is accomplished by the combined activity of Hsp70, Hsp40 and Hsp110 chaperones. Hsp110s support the refolding of aggregated polypeptides acting as specialized nucleotide exchange factors of Hsp70. We have studied how Apg2, one of the three human Hsp110s, regulates the activity of Hsc70 (HspA8), the constitutive Hsp70 in our cells. Apg2 shows a biphasic behavior: at low concentration, it stimulates the ATPase cycle of Hsc70, binding of the chaperone to protein aggregates and the refolding activity of the system, while it inhibits these three processes at high concentration. When the acidic subdomain of Apg2, a characteristic sequence present in the substrate binding domain of all Hsp110s, is deleted, the detrimental effects occur at lower concentration and are more pronounced, which concurs with an increase in the affinity of the Apg2 mutant for Hsc70. Our data support a mechanism in which Apg2 arrests the chaperone cycle through an interaction with Hsc70(ATP) that might lead to premature ATP dissociation before hydrolysis. In this line, the acidic subdomain might serve as a conformational switch to support dissociation of the Hsc70:Apg2 complex. PMID- 30521814 TI - Winning smiles: Signalling reward by overlapping and non-overlapping emotional valence differentially affects performance and neural activity. AB - It is well-known that both emotional and motivational events greatly impact our behaviour. Based on previous work on the interplay between these two constructs, the present study aimed to test whether and how concurrent emotion and reward signals interact in terms of their basic valence, when both are equally relevant to the task. To this end, we employed a novel fMRI paradigm in which reward availability was explicitly signalled by positive, neutral, or negative facial expressions (using block-wise instructions). Hence, in contrast to previous studies combining reward cues with irrelevant emotional stimuli, the present paradigm required participants to process the emotional information in order to respond and receive the reward. Compared to no-reward trials, we found performance benefits in trials in which reward was signalled by positive emotion, and performance detriments in trials in which reward was signalled by negative emotion - even though the reward value of the positive and negative emotion trials was identical. Neurally, reward trials signalled by negative emotion were associated with increased activity in frontal cognitive control regions, indicative of an induced conflict arising from a mismatch in absolute valence between reward and emotion. In contrast, reward trials signalled by positive emotion did not differentially increase activity anywhere in the brain (despite being associated with behavioural facilitation), which seems to support the notion of an inherent, and hence effortless, mapping between positive/rewarding stimuli and approach behaviour. Together, we interpret these patterns in terms of overlapping and non-overlapping valence signals (and associated response tendencies), which can induce benefits and costs, respectively. PMID- 30521815 TI - Traces of Statistical Learning in the Brain's Functional Connectivity after Artificial Language Exposure. AB - Our environment is full of statistical regularities, and we are attuned to learn about these regularities by employing Statistical Learning (SL), a domain-general ability that enables the implicit detection of probabilistic regularities in our surrounding environment. The role of brain connectivity on SL has been previously explored, highlighting the relevance of structural and functional connections between frontal, parietal, and temporal cortices. However, whether SL can induce changes in the functional connections of the resting state brain has yet to be investigated. To address this question, we applied a pre-post design where participants (n=38) were submitted to resting-state fMRI acquisition before and after in-scanner exposure to either an artificial language stream (formed by 4 concatenated words) or a random audio stream. Our results showed that exposure to an artificial language stream significantly changed (corrected p < 0.05) the functional connectivity between Right Posterior Cingulum and Left Superior Parietal Lobule. This suggests that functional connectivity between brain networks supporting attentional and working memory processes may play an important role in statistical learning. PMID- 30521816 TI - Design, synthesis and anti-tumor evaluation of novel steroidal glycoconjugate with furoxan derivatives. AB - In this study, eighteen novel steroidal-furoxan derivatives with 3-glycosyl or 3 methoxy moiety (12a-c, 13a-c, 17a-c, 26a-c, 27a-c and 28a-c) were synthesized and their anti-proliferative activity was evaluated against eight drug-sensitive and three drug-resistant cancer cell lines HeLa, A2780, LNCaP, PC-3, MDA-MB-231, MCF 7, SW480, A549, MCF-7/ADR, A2780/CDDP and A2780/T. Most of them displayed significant anti-cancer potency in vitro with IC50 values at the nanomole level. Among them, 3-methoxy steroidal-furoxan hybrids expressed much better activity than that of 3-glycosyl substitute ones, while estrane and 5alpha-H-androstane scaffold were slightly more favorable to the improvement of anti-proliferative activity. Especially, compounds 27c and 28b showed the strongest cytotoxicity with IC50 values of 0.0007-0.034 and 0.0011-0.008 uM, respectively in five drug sensitive cancer cell lines. Furthermore, 3-glycoconjugates 13a, 13c, 17b and 3 methoxy compounds 27a, 27c, 28b displayed lower toxicity in nontumorigenesis cells HOSEC and expressed a good selectivity against malignant cells in vitro. Preliminary study of pharmacology showed that the introduction of glucose at 3 position in steroidal core seems unable to use glucose transporters to improve the selectivity against proliferation of malignant cells, while the NO-releasing capacity might explain the potent anti-neoplastic activity of these compounds. And compound 28b could induce the apoptosis and hardly affected the cell cycle of A2780. Then, the further study of these steroidal-furoxan hybrids merits to explore and develop a desirable anti-cancer candidate. PMID- 30521817 TI - The X Factor. AB - A 45-year-old Caucasian woman presented with chronic bilateral, painless, progressive, peripheral vision loss. She was found to have bilateral optic atrophy and non-enhancing multifocal white matter lesions on magnetic resonance imaging of the brain. Cerebrospinal fluid analysis showed elevated myelin basic protein. She was diagnosed as the carrier state of X-linked adrenoleukodystrophy (X-ALD). X-ALD can mimic the clinical and radiographic features of multiple sclerosis in a female carrier. To our knowledge, this is the first case report of bilateral optic atrophy in a female X-ALD carrier in the English ophthalmic literature. PMID- 30521818 TI - Hide and Seek. AB - A 51-year-old woman with a previous history of rheumatoid arthritis experienced painless and progressive visual loss in the left eye for three weeks. Fundus examination revealed optic disc pallor in her left eye. Magnetic resonance imaging of the brain and orbits showed enhancement of the pachymeninges and hypersignal at the left optic nerve. Meningeal biopsy was performed. Immunohistochemical staining for IgG4 revealed several IgG4-positive plasma cells, which in some areas reached the number of 50 cells/ high-power field. In this case, the clinical and histopatohological features of the patient met diagnostic criteria for rheumatoid arthritis and Ig G4-related disease, respectively. Rheumatoid arthritis sometimes occurs with abundant IgG4 plasma cells and fulfills the histological diagnostic criteria for IgG4 related disease. This case demonstrates that overlapping features of IgG4-RD and rheumatoid arthritis may present in a single patient. PMID- 30521819 TI - Metabolome-wide association study of anti-epileptic drug treatment during pregnancy. AB - Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one-carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED related metabolic changes during pregnancy. PMID- 30521820 TI - Activation of mitochondrial aldehyde dehydrogenase (ALDH2) by ALDA-1 reduces both the acquisition and maintenance of ethanol intake in rats: A dual mechanism? AB - A number of pre-clinical studies have shown that brain-generated acetaldehyde, the first metabolite of ethanol, exerts reinforcing effects that promote the acquisition of ethanol intake, while chronic intake maintenance appears to be mediated by alcohol-induced brain neuroinflammation/oxidative stress. Recently, it was described that N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (ALDA 1) activates aldehyde dehydrogenase-2 (ALDH2), enzyme that catalyzes the oxidation of ethanol-derived acetaldehyde to acetate. The aim of this study was to determine the effects of ALDA-1 on both the acquisition and the maintenance of alcohol intake in alcohol-preferring UChB rats. For ethanol acquisition studies, naive UChB rats were treated with five daily doses of ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) from one day before the start of ethanol exposure. For chronic intake studies, UChB rats exposed for 98 days to a free access to 10% ethanol and water were treated daily with ALDA-1 (12.5, 25 or 50 mg/kg, i.p.) for five days. The administration of ALDA-1 reduced by 72-90% (p < 0.001) the acquisition of ethanol consumption in naive rats. At chronic ethanol consumption, ALDA-1 reduced ethanol intake by 61-82% (p < 0.001). ALDA-1 administration increased by 3- and 2.3-fold the activity of ALDH2 in brain and liver, respectively. ALDA-1 did not affect saccharin consumption, nor it modified the rate of ethanol elimination. The study shows that the activation of ALDH2 by ALDA-1 is effective for inhibiting both the acquisition and the maintenance of chronic ethanol intake by alcohol-preferring rats. Thus, the activation of brain ALDH2 may constitute a novel approach in the treatment of alcohol use disorders. PMID- 30521821 TI - Bisphenol F causes disruption of gonadotropin-releasing hormone neural development in zebrafish via an estrogenic mechanism. AB - Gonadotropin releasing hormone (GnRH) neurons in the brain are the main controllers of reproduction and reproductive behavior in most vertebrates, and are susceptible to endocrine disruption by different bisphenols. While the endocrine disrupting properties of bisphenol A have been well documented, commonly used analogues such as bisphenol F (BPF) are not as well studied. In this study we examined the effects of early, low-dose, chronic BPF exposure on the development of the GnRH neural system in the zebrafish embryo. Using a transgenic zebrafish model system with GnRH3 neurons tagged with green fluorescent protein (GFP), developing GnRH neurons in both the terminal nerve (TN) and preoptic area (POA) were observed. These are neuronal populations with the former associated with allied reproductive behaviors and the latter associated with pituitary-gonadal axis control. Embryos were exposed in vitro to 0.25, 0.5 and 1 MUM BPF from fertilization to 3 days post fertilization (dpf). At 0.25 MUM BPF exposure, both POA- and TN- GnRH3 neurons showed significant reductions in neural area at 2 dpf that did not persist to 3 dpf. The higher BPF doses did not show neuron size differences at 2 dpf, but showed reduction in TN GnRH3 neuron area at 3 dpf. These effects of BPF were closely mimicked by different doses of estradiol. An estrogen antagonist, ICI, mitigated BPF effects on the embryo. This is the first study to show that BPF affects the developing GnRH neural system via an estrogen-mediated pathway. PMID- 30521823 TI - Pemphigus and hematologic malignancies: A population-based study of 11,859 patients. AB - *Hematologic malignancies have been reported sporadically in patients with pemphigus.*In the current study, significant associations were observed between pemphigus and chronic leukemia, multiple myeloma, and non-Hodgkin lymphoma.*Further research is needed to confirm these findings in other cohorts. PMID- 30521822 TI - Enzymes of glycerol-3-phosphate pathway in triacylglycerol synthesis in plants: Function, biotechnological application and evolution. AB - Triacylglycerols (TAG) are the major form of energy storage in plants. TAG are primarily stored in seeds and fruits, but vegetative tissues also possess a high capacity for their synthesis and storage. These storage lipids are essential to plant development, being used in seedling growth during germination, pollen development, and sexual reproduction, for example. TAG are also an important source of edible oils for animal and human consumption, and are used for fuel and industrial feedstocks. The canonical pathway leading to TAG synthesis is the glycerol-3-phosphate, or Kennedy, pathway, which is an evolutionarily conserved process in most living organisms. The enzymatic machinery for synthesizing TAG is well known in several plant species, and the genes encoding these enzymes have been the focus of many studies. Here, we review recent progress on the understanding of evolutionary, functional and biotechnological aspects of the glycerol-3-phosphate pathway enzymes that produce TAG. We discuss current knowledge about their functional aspects, and summarize valuable insights into genetically engineered plants for enhancing TAG accumulation. Also, we highlight the evolutionary history of these genes and present a meta-analysis linking positive selection to gene family and plant diversification, and also to the domestication processes in oilseed crops. PMID- 30521824 TI - Risk of venous thromboembolism in patients with mycosis fungoides and parapsoriasis: A Danish nationwide population-based cohort study. AB - *Active cancers and inflammation increase the risk for venous thromboembolism. It is unknown whether this applies to mycosis fungoides and parapsoriasis.*Patients with mycosis fungoides and parapsoriasis have increased risk for venous thromboembolism.*These findings should increase awareness of comorbidities as part of the disease spectrum in patients with mycosis fungoides and parapsoriasis. PMID- 30521825 TI - Trends of skin cancer mortality after transplantation in the United States: 1987 to 2013. AB - - -Organ transplant recipients are at high risk of skin cancer mortality.-This study defines population-based mortality from skin cancer posttransplantation and identifies recipients at increased risk of skin cancer mortality.-These findings can guide dermatologists in adopting skin cancerescreening protocols specific to the identified high- risk categories. PMID- 30521826 TI - Standardized laboratory monitoring with use of isotretinoin in acne. AB - -The optimal timing of laboratory tests for patients on isotretinoin treatment for acne is uncertain.-In this series, although abnormalities in serum lipids in patients receiving isotretinoin were not infrequent, they were mild to moderate, and were generally noted around the second month of treatment.-For healthy patients on isotretinoin, we recommend that a lipid panel and liver function test be performed at baseline and at month 2, when peak dosing is achieved. Further testing should be considered if a significant abnormal value is noted. PMID- 30521827 TI - The incidence of herpes zoster in cutaneous lupus erythematosus (CLE), dermatomyositis (DM), pemphigus vulgaris (PV), and bullous pemphigoid (BP). AB - The incidence of zoster is increased in many autoimmune diseases. This study found a significantly increased zoster incidence in dermatomyositis and cutaneous lupus erythematosus compared with a control group.Physicians should be aware of this risk and consider administering the vaccine against zoster to these patients if not contraindicated. PMID- 30521828 TI - A new automated device for quantifying mechanical nociceptive responses. AB - BACKGROUND: Traditional methods to assess pain in rodents depend on measures of nociceptive responses, most commonly from the hind paws. While these measures can quantify nociceptive responses to allow pharmacologic testing, they typically have high inter-experimenter variability and are not time-sensitive enough to correct with neural processes that occur on millisecond scales. NEW METHOD: We have invented a pain detection device that uses changes in skin conductance to measure nocifensive withdrawal responses. This device automatically records how long it takes for a rodent to withdraw its paw from the onset of peripheral noxious stimulation. RESULTS: with this pain device, we can record accurate timing (on the millisecond scale) for nociceptive responses, with high accuracy and consistency. Furthermore, we demonstrate that this device can allow us to distinguish the nociceptive response to mechanical noxious stimuli of different intensities. Finally, we demonstrate that this device can be digitally integrated to correlate behavior with neural activities in real-time. CONCLUSIONS: This study demonstrates a new automated, temporally specific method for quantifying nociceptive responses to facilitate rodent pain studies. PMID- 30521829 TI - Time-dependently slow-released multiple-drug eluting external sheath for efficient long-term inhibition of saphenous vein graft failure. AB - Coronary artery bypass graft surgery (CABG) is an effective therapeutic method for coronary artery disease. Great saphenous vein is the predominant graft due to the accessibility, sufficient length and suitable size matching with coronary artery. However, saphenous vein graft failure (SVGF) always restrict the long term success of CABG. In this study, a complex external sheath was prepared using multi-channel and coaxial electrospinning techniques. The sheath can slowly release fasudil dihydrochloride (100% at 63 days), everolimus (100% at 84 days) and simvastatin (31.87 +/- 1.55% at 20 weeks) to match the time-dependent pathological changes of SVGF through a cocktail pattern. In 16 weeks animal experiments, drug loaded sheath exhibited significantly greater efficacy in inhibiting neointima formation and ensuring graft patency than bare vein graft and empty sheath. Under the joint action of mechanical restriction of the sheath and the synergistic effect of loaded fasudil dihydrochloride and everolimus, the endothelium damage and the proliferation/migration of smooth muscle cells, which were thought to be the early cause of graft failure, could be efficiently alleviated. Moreover, the long-term patency could be expected due to the inhibition of atherosclerosis by the sustained released simvastatin. PMID- 30521830 TI - Hydrogels with prolonged release of therapeutic antibody: Block junction chemistry modification of 'ABA' copolymers provides superior anticancer efficacy. AB - In this study, we report a new series of vitamin E-functionalized 'ABA' triblock copolymers with carbamate block junction, which can form hydrogen-bonds. These polymers were synthesized via solvent- and catalyst-free nucleophilic addition between PEG-diamine and vitamin E-functionalized cyclic carbonate. The catalyst free synthesis enabled an easy purification step and recycling of excess monomers. The polymers formed hydrogels through self-assembly by simply dissolving in aqueous solution. The hydrogel stiffness was easily tuned by varying polymer concentration, PEG molecular weight and number of vitamin E molecules. The triblock copolymer with one vitamin E molecule on each end of PEG (20 kDa) formed hydrogel at a concentration of 4.0 wt% and above. The hydrogel showed pronounced shear-thinning behavior, and was injectable. Particularly, the hydrogel formed with carbamate block junction was stiffer than that with carbonate block junction, and provided more sustained antibody release. The hydrogel with carbamate block junction was loaded with the anticancer antibody Herceptin, which suppressed tumor growth over a significantly longer period of time as compared to the Herceptin-loaded hydrogel with carbonate block junction (90 days vs. 40 days). This hydrogel has potential for use as matrix for sustained delivery of antibodies. PMID- 30521831 TI - Macro-Nanomedicine: Targeting the big Picture. PMID- 30521832 TI - Race and income moderate the association between depressive symptoms and obesity. AB - Complex interrelationships between race, sex, obesity and depression have been well-documented. Because of differences in associations between socioeconomic status (SES) and health by race, determining the role of SES may help to further explicate these relationships. The aim of this study was to determine how race and income interact with obesity on depression. Combining data from the 2007-2014 National Health and Nutrition Examination Survey, depressive symptoms was measured with the Patient Health Questionnaire-9 and obesity was assessed as body mass index >=30 kg/m2. Three-way interactions between race, income and obesity on depressive symptoms were determined using ordered regression models. Significant interactions between race, middle income and obesity (OR = 0.66, 95% CI = 0.22 1.96) suggested that, among white women, obesity is positively associated with depressive symptoms across income levels, while obesity was not associated with depression for African American women at any income level. Obesity was only associated with depressive symptoms among middle-income white men (OR = 1.44, 95% CI = 1.02-2.03) and among high-income African American men (OR = 4.65, 95% CI = 1.48-14.59). The associations between obesity and depressive symptoms vary greatly by race and income. Findings from this study underscore the importance of addressing obesity and depression among higher income African American men. PMID- 30521833 TI - Sex differences in stress reactivity after intranasal oxytocin in recreational cannabis users. AB - Cannabis is the most widely used illicit drugs and the changing legal, political and cultural climate will likely increase cannabis use further. One factor that may underlie the transition from recreational use to problematic use is stress. The hormone oxytocin (OXT) modulates stress and may have therapeutic efficacy for substance use disorders, but few studies have examined OXT in cannabis users. Another factor is sex; although more men smoke cannabis, the transition from recreational to problematic use is faster in women. Using a within-subjects design, the effects of intranasal (i.n.) oxytocin (OXT; 40 IU) administration on stress reactivity (using the Trier Social Stress Test; TSST) and cannabis (5.6% THC) self-administration was assessed in recreational cannabis using men (n = 31) and women (n = 32) relative to i.n. placebo (PBO) and no-stress (NST) conditions. The TSST produced expected subjective and cardiovascular effects compared to the NST. However, in the i.n. OXT-TSST condition, positive subjective effects were lower and negative subjective effects were higher in women compared to PBO administration and compared to men. Further, latency to self-administer cannabis was longer in women than men and women self-administered less cannabis than men regardless of stress condition. There were no differences in cannabis craving as a function of sex, stress, or medication. These results suggest that OXT administration may lead to greater stress reactivity in recreational cannabis users, particularly women, and support growing evidence that sex differences should be carefully considered when examining the therapeutic potential of OXT. PMID- 30521834 TI - Development of a respiratory disease model for enterovirus D68 in 4-week-Old mice for evaluation of antiviral therapies. AB - Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics. This is the first report of a respiratory disease model for EV-D68 infection in mice. We adapted the virus by 30 serial passages in AG129 mice, which are deficient in IFN- alpha/beta and gamma receptors. Despite a lack of weight loss or mortality in mice, lung function measured by plethysmography, showed an increase in enhanced pause (Penh) on days 6 and 7 post-infection. In addition, as virus adapted to mice, virus titer in the lungs increased 320-fold, and the pro-inflammatory cytokines MCP-1 and RANTES increased 15-fold and 2-fold in the lung, respectively. In addition, a time course of mouse-adapted EV-D68 infection was determined in lung, blood, liver, kidney, spleen, leg muscle, spinal cord and brain. Virus in the lung replicated rapidly after intranasal inoculation of adapted virus, 106 CCID50/mL by 4 h and 108.3 CCID50/mL by 24 h. Virus then spread to the blood and other tissues, including spinal cord and brain. This mouse model for EV-D68 infection includes enhanced pause (Penh) as an indicator of morbidity, and viremia, virus titers and proinflammatory cytokines in the lung, and lung histopathology as indicators of disease. Our mouse-adapted virus has a similar antiviral profile to the original isolate as well as another respiratory picornavirus, rhinovirus-14. This model will be valuable in evaluating experimental therapies in the future. PMID- 30521835 TI - A potent prolyl tRNA synthetase inhibitor antagonizes Chikungunya and Dengue viruses. AB - Arboviruses represent a group of pathogens that can spread efficiently throughout human populations by hematophagous arthropod vectors. The mosquito-borne (re)emerging Chikungunya and Dengue viruses belong to the alphavirus and flavivirus genus, respectively, with no approved therapeutics or safe vaccines for humans. Transmitted by the same vector Aedes spp., these viruses cause significant morbidity and mortality in endemic areas. Due to the increasing likelihood of co-circulation and co-infection with viruses, we aimed to identify a pharmacologically targetable host factor that can inhibit multiple viruses and show that a potent antagonist of prolyl tRNA synthetase (halofuginone) suppresses both Chikungunya and Dengue viruses. Host tRNA synthetase inhibition may signify an additional approach to combat present and future epidemic pathogens. PMID- 30521837 TI - An examination of microcystin-LR accumulation and toxicity using tethered bilayer lipid membranes (tBLMs). AB - Microcystin-LR (MC-LR) is a potent cyanobacterial toxin responsible for animal and human poisonings worldwide. MC-LR is found in organisms throughout the foodweb, however there is conjecture regarding whether it biomagnifies. Few studies have investigated how MC-LR interacts with lipid membranes, a determinant of biomagnification potential. We tested whether 1 MUM MC-LR irreversibly associates with lipid bilayers or causes the creation of pore defects upon short and long-term exposure. Using tethered bilayer lipid membranes (tBLMs), we observed an increase in membrane conduction in tBLMs, representing an interaction of microcystin-LR with the lipid bilayer and a change in membrane packing properties. However, there were minimal changes in membrane capacitance upon short and long-term exposure, and MC-LR exhibited a rapid off-rate. Upon 24 h exposure to the toxin, no lipophilic multimeric complexes were detected capable of altering the toxin's off-rate. There was no evidence of the creation of new pores. This study demonstrates that MC-LR does not irreversibly imbed itself into lipids membranes after short or long-term exposure and suggests MC-LR does not biomagnify through the food web via lipid storage. PMID- 30521838 TI - A Xenopus tadpole alternative model to study innate-like T cell-mediated anti mycobacterial immunity. AB - Owing to the high incidence of multi-drug resistance and challenges posed by the complex and long duration of treatments, Mycobacterium tuberculosis (Mtb) infections remain a significant clinical burden, which would benefit from development of novel immuno-therapeutic-based treatment strategies. Among early immune effectors, invariant or innate-like (i)T cells are attracting attention because of their potential regulatory activity, which can shape anti mycobacterial immune responses. Unlike conventional T cells, iT cells express a semi-invariant T cell receptor, and respond rapidly and robustly to molecular patterns presented by MHC class I-like molecules. To date, functional studies of iT cells in vivo has been problematic and the role of iT cells in anti-Mtb responses remains unclear. Here, after reviewing the recent literature on anti mycobacterial iT cell immunity, we describe a novel alternative model system in the amphibian Xenopus laevis tadpoles during infection with Mycobacterium marinum (Mm). X. laevis tadpoles rely mostly on a few distinct prominent innate-like (i)T cell subsets, whose development and function are governed by distinct MHC class I like molecules. Thus, X. laevis tadpoles provide a convenient and cost-effective in vivo model uniquely suited to investigate the roles of iT cells during mycobacterial infections. We have developed reverse genetics and MHC tetramer technology to characterize this MHC-like/iT system in tadpoles. Our study in X. laevis provides evidence of a conserved convergent function of iT cells in host defenses against mycobacteria between mammals and amphibians. PMID- 30521836 TI - Are environmental factors for atopic eczema in ISAAC Phase Three due to reverse causation? AB - Some previously described environmental associations for atopic eczema (AE) may be due to reverse causation. We explored the role of reverse causation by comparing individual- and school-level results for multiple AE risk factors. ISAAC Phase Three surveyed children within schools (the sampling unit) on AE symptoms and potential risk factors. We assessed the effect of these risk factors on AE symptoms using mixed-effect logistic regression models, first with individual-level exposure data and second with school-level exposure prevalence. 546,348 children from 53 countries were included. At age 6-7 the strongest individual-level associations were with current paracetamol use (odds ratio=1.45, 95% confidence interval 1.37-1.54), which persisted at school-level (1.55, 1.10 2.21), antibiotics (1.41, 1.34-1.48) and early life paracetamol use (1.28, 1.21 1.36) with the former persisting at school-level while the latter was no longer observed (1.35, 1.00-1.82 and 0.94, 0.69-1.28 respectively). At age 13-14 the strongest associations at individual-level were with current paracetamol use (1.57, 1.51-1.63) and open-fire cooking (1.46, 1.33-1.62); both were stronger at school-level (2.57, 1.84-3.59 and 2.38, 1.52-3.73 respectively). Association with exposure to heavy traffic (1.31, 1.27-1.36) also persisted at school-level (1.40, 1.07-1.82). Most individual- and school level effects were consistent tending to exclude reverse causation. PMID- 30521839 TI - Soluble mannose receptor levels in blood correlate to disease severity in patients with community-acquired pneumonia. AB - PURPOSE: Community-acquired pneumonia (CAP) is the most common form of pneumonia and is a leading infectious cause worldwide. Identification of patients that are at risk to develop severe disease has proven to be a major challenge. Soluble mannose receptor (sMR; sCD206) is a new serum marker for macrophage activation. Recent studies showed that sMR levels are increased in patients suffering from severe infections making it a potential biomarker for improved discrimination of disease severity. For measuring sMR, no standardized assay is available. Aim of this study is to develop an assay for standardized measurement of sMR. Next, this assay was used to assess sMR plasma levels for its ability to predict severe disease development in a patient cohort for community-acquired pneumonia. METHODS: We developed a well-validated sandwich ELISA that enables standardized measurement of sMR in plasma and serum samples. Repeatability was tested by calculating the percentage coefficient of variation (%CV) within and between runs and within and between operators. sMR levels were assessed in a cohort of 100 patients with community-acquired pneumonia. RESULTS: All %CV values were <10%, indicating low variation. Higher sMR levels were observed in patients with severe disease when compared to patients without severe disease development (p = 0.004). Patients with sMR levels between 100-430 ng/ml had 22.7% chance to develop severe disease whereas patients with levels between 430-1000 ng/ml had 33.3% chance to develop severe disease. CONCLUSIONS: We suggest that sMR has potential as a new biomarker for the prediction of disease severity in patients with community acquired pneumonia. PMID- 30521840 TI - Mechanistic role of the CREB-regulated transcription coactivator 1 in cardiac hypertrophy. AB - The sympathetic nervous system is the main stimulator of cardiac function. While acute activation of the beta-adrenoceptors exerts positive inotropic and lusitropic effects by increasing cAMP and Ca2+, chronically enhanced sympathetic tone with changed beta-adrenergic signaling leads to alterations of gene expression and remodeling. The CREB-regulated transcription coactivator 1 (CRTC1) is activated by cAMP and Ca2+. In the present study, the regulation of CRTC1 in cardiomyocytes and its effect on cardiac function and growth was investigated. In cardiomyocytes, isoprenaline induced dephosphorylation, and thus activation of CRTC1, which was prevented by propranolol. Crtc1-deficient mice exhibited left ventricular dysfunction, hypertrophy and enlarged cardiomyocytes. However, isoprenaline-induced contractility of isolated trabeculae or phosphorylation of cardiac troponin I, cardiac myosin-binding protein C, phospholamban, and ryanodine receptor were not altered, suggesting that cardiac dysfunction was due to the global lack of Crtc1. The mRNA and protein levels of the Galphaq GTPase activating protein regulator of G-protein signaling 2 (RGS2) were lower in hearts of Crtc1-deficient mice. Chromatin immunoprecipitation and reporter gene assays showed stimulation of the Rgs2 promoter by CRTC1. In Crtc1-deficient cardiomyocytes, phosphorylation of the Galphaq-downstream kinase ERK was enhanced. CRTC1 content was higher in cardiac tissue from patients with aortic stenosis or hypertrophic cardiomyopathy and from two murine models mimicking these diseases. These data suggest that increased CRTC1 in maladaptive hypertrophy presents a compensatory mechanism to delay disease progression in part by enhancing Rgs2 gene transcription. Furthermore, the present study demonstrates an important role of CRTC1 in the regulation of cardiac function and growth. PMID- 30521842 TI - Development and biochemical characterization of a mouse model of Parkinson's disease bearing defective glucocerebrosidase activity. AB - GBA1 gene encode for the lysosomal membrane protein glucocerebrosidase (GCase). GBA1 heterozygous mutations profoundly impair GCase activity and are currently recognized as an important risk factor for the development of Parkinson's disease (PD). Deficits in lysosomal degradation pathways may contribute to pathological alpha-synuclein accumulation, thereby favoring dopaminergic neuron degeneration and associated microglial activation. However, the precise mechanisms by which GCase deficiency may influence PD onset and progression remain unclear. In this work we used conduritol-beta-epoxide (CBE), a potent inhibitor of GCase, to induce a partial, systemic defect of GCase activity comparable to that associated with heterozygous GBA1 mutations, in mice. Chronic (28 days) administration of CBE (50 mg/kg, i.p.) was combined with administration of a classic PD-like inducing neurotoxin, such as MPTP (30 mg/kg, i.p. for 5 days). The aim was to investigate whether a pre-existing GCase defect may influence the effects of MPTP in terms of nigrostriatal damage, microglia activation and alpha-synuclein accumulation. Pre-treatment with CBE had tendency to enhance MPTP-induced neurodegeneration in striatum and caused significant increase of total alpha synuclein expression in substantia nigra. Microglia was remarkably activated by CBE alone, without further increases when combined with MPTP. Overall, we propose this model as an additional tool to study pathophysiological processes of PD in the presence of GCase defects. PMID- 30521841 TI - Liver transplantation in patients with liver failure related to exertional heatstroke. AB - : Severe acute liver injury (sALI) is a grave complication of exertional heatstroke (EH). Liver transplantation (LT) may be a therapeutic option, but the criteria for, and timing of transplantation have not been clearly established. The aim of this study was to define the profile of patients who require transplantation in this context. PATIENTS AND METHODS: This was a multicentre, retrospective study of patients admitted with a diagnosis of EH-related sALI with a prothrombin time (PT) of less than 50%. RESULTS: Twenty-four male patients were studied. 15/24 patients (mean median nadir PT: 35% (29.5-40.5)) improved under medical therapy alone and survived. Nine of the 24 were listed for emergency LT. At the time of registration, the median PT was 10% (5 - 12) and all had numerous dysfunctional organs. Five patients (nadir PT: 12% (9-12)) were withdrawn from the list because of an elevation of PT values that mainly occurred between D2 and D3. Ultimately, four patients underwent transplantation as their PT persisted at < 10%, 3 days (2.75 - 3.25) after the onset of EH, and more than three organs dysfunctions. Three of these four patients were still alive one year later. Histological analysis of the four explanted livers demonstrated massive or sub massive necrosis, and little potential for effective mitoses, characterised by a "mitonecrotic" appearance. CONCLUSION: The first-line treatment for severe ALI related exertional heatstroke is medical therapy. LT is only a rare alternative and such a decision should not be taken too hastily. A persistence of PT <10%, without any signs of elevation after a median period of 3 days since the onset of heatstroke, was the trigger adopted in order to decide upon LT. LAY SUMMARY: Acute liver injury due to heatstroke can progress to acute liver failure (ALF) with organ dysfunction despite medical treatment; in such situations, liver transplantation (LT) may offer a therapeutic option. The classic criteria for LT appear to be poorly adapted to heatstroke-related ALF. Our study confirmed that the first-line therapy for heatstroke leading to ALI is medication, and that LT is only rarely necessary. A decision to perform transplantation should not made hastily, even in the event of severe liver failure Account must be taken of fluctuations in PT values and the patient's clinical status. Pathological investigations of explanted livers have showed little potential for effective mitosis, with diffuse "mitonecrotic" features. PMID- 30521843 TI - Optimal Risk Prediction in Upper Gastrointestinal Bleeding - A Quest for the Holy Grail. PMID- 30521844 TI - Recombinant Staphylococcal Antigen-F (r-ScaF), a novel vaccine candidate against methicillin resistant Staphylococcus aureus infection: Potency and efficacy studies. AB - Staphylococcus aureus is a human commensal and pathogen, its clinical importance is exacerbated by the spread of multi-drug resistant strains. The potential future failure of antibiotic therapy necessitates the development of novel control regimes, including new immunotherapeutic approaches. S. aureus has a large repertoire of surface components with potential for immunological targeting. The aim of this study was to evaluate the efficacy of a novel member of staphylococcal conserved antigen family (ScaF) as a factor to elicit cellular and humoral immunity. To determine the ScaF potential as a vaccine candidate, experimental groups of mice were immunized with recombinant Scaf (r-ScaF) formulated in Freund's and alum adjuvants or PBS and subsequently challenged in the sepsis model of S. aureus disease. The vaccine formulations induced robust cellular cytokines responses, including IFN-gamma and IL-17, as well as increased production of IgG2a rather than other subclass of IgGs. Active immunization with r-ScaF with adjuvants led to decreased mortality of infected mice and a lower associated bacterial burden in the internal organs in comparison to the control group. Taken together, our Results indicate to the possibility of the r-ScaF protein to be considered as an important component of a multivalent prophylactic vaccine candidate. PMID- 30521845 TI - Virulence properties of Vibrio vulnificus isolated from diseased zoea of freshness shrimp Macrobrachium rosenbergii. AB - Macrobrachium rosenbergii is one of the most economically important freshwater shimp, with fast growth and high nutrient content in the agricultural development of China. However, it had been suffering diseases infection, causing mass death and great economic losses. In the present study, a bacteria strain was isolated from the diseased zoea of M. rosenbergii and was identified as Vibrio vulnificus by biochemical characteristics and 16S rRNA homologous analysis. The infection test showed that the strain GXFL1-3 was pathogenic to zoea and postlarva of M. rosenbergii, and the half lethal dose (LD50) were 1.16 * 106 CFU/mL and 1.45 * 106 CFU/mL, respectively. Detection of virulence-associated genes by PCR indicated that GXFL1-3 was positive for fur, OmpU, acfA, flaA, vvhA, vvp and tcp, the detection of extracellular enzymes and hemolysin showed that GXFL1-3 was positive for protease, amylase, lecithin, urease and hemolysin activity, further supporting its pathogenicity. A duplex PCR for rapid detection of V. vulnificus was established. Only V. vulnificus could amplify two specific bands of flaA and fur, while the other six strains of Vibrio were negative. The minimum detectable amount of template was 2.4 * 103 CFU/mL through sensitivity test. PMID- 30521846 TI - Influence of various uropathogens on crystallization of urine mineral components caused by Proteus mirabilis. AB - Infectious urolithiasis is a consequence of long-standing urinary tract infections with urease-positive bacteria, especially Proteus spp. However, because of the often mixed nature of urinary tract infections, in the case of urinary stones formation, several species of bacteria may be involved in the process. The purpose of the study was to determine the impact of the bacterial species: Escherichia coli, Klebsiella pneumoniae, Providencia stuartii, Pseudomonas aeruginosa and Staphylococcus aureus on the crystallization caused by Proteus mirabilis. The studies were conducted in synthetic urine with the addition of P. mirabilis and a representative of another species. During the experiments the viability of bacteria, pH, presence and morphology of crystals, and the intensity of crystallization were assessed. Crystallization of calcium and magnesium phosphates occurred in all investigated configurations. However, there were differences observed in the course and intensity of crystallization between the mixed culture and the P. mirabilis culture. Although most intense crystallization took place in the pure culture of P. mirabilis it was also demonstrated that the presence of other uropathogens increased the survival of P. mirabilis. This synergistic effect could be responsible for the persistence and recurrence of urolithiasis in the urinary tract. PMID- 30521847 TI - Engineered Viral RNA Decay Intermediates to Assess XRN1-mediated decay. AB - Both RNA synthesis and decay must be balanced within a cell to achieve proper gene expression. Additionally, modulation of RNA decay specifically offers the cell an opportunity to rapidly reshape the transcriptome in response to specific stimuli or cues. Therefore, it is critical to understand the underlying mechanisms through which RNA decay contribute to gene expression homeostasis. Cell-free reconstitution approaches have been used successfully to reveal mechanisms associated with numerous post-transcriptional RNA processes. Historically, it has been difficult to examine all aspects of RNA decay in such an in vitro setting due, in part, to limitations on the ability to resolve larger RNAs through denaturing polyacrylamide gels. Thus, in vitro systems to study RNA decay rely on smaller, less biologically relevant RNA fragments. Herein, we present an approach to more confidently examine RNA decay parameters of large mRNA size transcripts through the inclusion of an engineered XRN1-resistant reporter RNA (xrRNA). By placing a 67 nucleotide xrRNA near the 3' end of any in vitro transcribed RNA with variable size or sequence context, investigators can observe the accumulation of the xrRNA as a readout of exoribonuclease-mediated 5' 3' decay. This approach may allow in vitro RNA decay assays to include full biologically relevant mRNA/mRNPs, extending their utility and allow improved experimental design considerations to promote biologically relevant outcomes. PMID- 30521848 TI - Novel metabolic disorders in skeletal muscle of Lipodystrophic Bscl2/Seipin deficient mice. AB - Bscl2-/- mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatosteatosis, muscular hypertrophy, and insulin resistance. Metabolic defects in Bscl2-/- mice with regard to glucose and lipid metabolism in skeletal muscle have never been investigated. Here, we identified Bscl2-/- mice displayed reduced intramyocellular triglyceride (IMTG) content but increased glycogen storage predominantly in oxidative type I soleus muscle (SM). These changes were associated with increased incomplete fatty acid oxidation and glycogen synthesis. Interestingly, SM in Bscl2-/- mice demonstrated a fasting duration induced insulin sensitivity which was further confirmed by hyperinsulinemic-euglycemic clamp in SM of overnight fasted Bscl2-/- mice but reversed by raising circulating NEFA levels through intralipid infusion. Furthermore, mice with skeletal muscle-specific inactivation of BSCL2 manifested no changes in muscle deposition of lipids and glycogen, suggesting BSCL2 does not play a cell-autonomous role in muscle lipid and glucose homeostasis. Our study uncovers a novel link between muscle metabolic defects and insulin resistance, and underscores an important role of circulating NEFA in regulating oxidative muscle insulin signaling in BSCL2 lipodystrophy. PMID- 30521849 TI - 5- lipoxygenase (ALOX5): genetic susceptibility to type 2 diabetes and vitamin D effects on monocytes. AB - The arachidonate 5-lipoxygenase (ALOX5) pathway has been implicated in chronic inflammatory disease which may be influenced by vitamin D due to vitamin D response elements (VDRE). We investigated an ALOX5 polymorphism (rs4987105) in patients with type 2 diabetes (T2D) and the in vitro effects of calcitriol (1,25(OH)2D3) on ALOX5 metabolism in monocytes of T2D patients and healthy controls (HC). 533 T2D and 473 HC were genotyped for the rs4987105 polymorphism. In addition, the 25(OH)D3 and 1,25(OH)2D3 plasma levels were measured in both cohorts. Further C-reactive protein (CRP) was determined in T2D patients. Our results demonstrate, that genotype CC and the allele C of ALOX5 rs4987105 polymorphism were more frequent in T2D compared to HC (OR = 1.44; 95% CI: 1.12 1.84; p < 0.05). Lower levels of both vitamin D metabolites (p < 0.0001 respectively) were found in the CC genotyped T2D patients compared to CC genotyped HC. In addition, CC genotyped T2D patients had higher levels of CRP compared to CT and TT genotyped T2D patients, (p < 0.01). In order to evaluate the impact of calcitriol in primary isolated monocytes, we isolated monocytes of 20 T2D patients and 20 HC. The cells were treated with 1,25(OH)2D3 and interleukin-1beta (IL-1beta) for 24 h. The following genes were analysed for expression changes: ALOX5, leukotriene A4 hydrolase (LTA4H), leukotriene B4 receptor type 1 (LTB4R1) and CD14. Treatment with IL-1beta+1,25(OH)2D3 increased ALOX5, LTA4H and LTB4R1 and CD14 mRNA in both T2D patients and HC (p < 0.0001, respectively). In addition, IL-1beta+1,25(OH)2D3 treatment led to higher ALOX5, LTA4H and CD14 mRNA levels in T2D patients compared to HC (p < 0.001, p < 0.05, p <= 0.05, respectively). In conclusion, ALOX5 rs4987105 allele C confers susceptibility to T2D, lower vitamin D metabolites and higher CRP levels complement this association. Additionally, IL-1beta+1,25(OH)2D3 treatment on, ALOX5, LTA4H and CD14 mRNA indicate a diabetes specific modulation. These findings identify a novel pathway in T2D potentially amenable for individualized therapeutic targeting. PMID- 30521850 TI - Enhancing effects of acute exposure to cannabis smoke on working memory performance. AB - Numerous preclinical studies show that acute cannabinoid administration impairs cognitive performance. Almost all of this research has employed cannabinoid injections, however, whereas smoking is the preferred route of cannabis administration in humans. The goal of these experiments was to systematically determine how acute exposure to cannabis smoke affects working memory performance in a rat model. Adult male (n = 15) and female (n = 16) Long-Evans rats were trained in a food-motivated delayed response working memory task. Prior to test sessions, rats were exposed to smoke generated by burning different numbers of cannabis or placebo cigarettes, using a within-subjects design. Exposure to cannabis smoke had no effect on male rats' performance, but surprisingly, enhanced working memory accuracy in females, which tended to perform less accurately than males under baseline conditions. In addition, cannabis smoke enhanced working memory accuracy in a subgroup of male rats that performed comparably to the worst-performing females. Exposure to placebo smoke had no effect on performance, suggesting that the cannabinoid content of cannabis smoke was critical for its effects on working memory. Follow-up experiments showed that acute administration of either Delta9-tetrahydrocannabinol (0.0, 0.3, 1.0, 3.0 mg/kg) or the cannabinoid receptor type 1 antagonist rimonabant (0.0, 0.2, 0.6, 2.0 mg/kg) impaired working memory performance. These results indicate that differences in the route, timing, or dose of cannabinoid administration can yield distinct cognitive outcomes, and highlight the need for further investigation of this topic. PMID- 30521851 TI - Genetic inactivation of hypoxia inducible factor 1-alpha (HIF-1alpha) in adult hippocampal progenitors impairs neurogenesis and pattern discrimination learning. AB - HIF-1alpha is a hypoxia-inducible protein that regulates many cellular processes, including neural stem cell maintenance. Previous work demonstrated constitutive stabilization of HIF-1alpha in neural stem cells (NSCs) of the adult mouse subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Genetic inactivation of NSC-encoded HIF-1alpha in the adult SVZ results in gradual loss of NSCs, but whether HIF-1alpha is required for the maintenance of SGZ hippocampal progenitors and adult hippocampal neurogenesis has not been determined. Here we tested the hypothesis that HIF-1alpha plays an essential role in the maintenance of adult hippocampal neurogenesis using Nestin-CreERT2/R26R YFP/Hif1afl/fl triple transgenic mice, in which HIF-1alpha was genetically inactivated in nestin+ hippocampal progenitors and their downstream progeny following tamoxifen exposure. We found that disruption of HIF-1alpha gene expression resulted in a marked 50% reduction of adult-generated dentate granule cells (DGCs) that was highly correlated with impaired hippocampal function, as assessed using two behavioral assays of pattern discrimination. These behavioral tests included the A-B contextual fear-conditioning task and the trial-unique, delayed nonmatching-to-location (TUNL) touch-screen operant chamber task. Our findings identify HIF-1alpha as a novel regulator of adult hippocampal neurogenesis under non-pathological conditions, and underscore the importance of neurogenesis for pattern discrimination learning. PMID- 30521852 TI - Bioactivity of soy-based fermented foods: A review. AB - For centuries, fermented soy foods have been dietary staples in Asia and, now, in response to consumer demand, they are available throughout the world. Fermentation bestows unique flavors, boosts nutritional values and increases or adds new functional properties. In this review, we describe the functional properties and underlying action mechanisms of soy-based fermented foods such as Natto, fermented soy milk, Tempeh and soy sauce. When possible, the contribution of specific bioactive components is highlighted. While numerous studies with in vitro and animal models have hinted at the functionality of fermented soy foods, ascribing health benefits requires well-designed, often complex human studies with analysis of diet, lifestyle, family and medical history combined with long term follow-ups for each subject. In addition, the contribution of the microbiome to the bioactivities of fermented soy foods, possibly mediated through direct action or bioactive metabolites, needs to be studied. Potential synergy or other interactions among the microorganisms carrying out the fermentation and the host's microbial community may also contribute to food functionality, but the details still require elucidation. Finally, safety evaluation of fermented soy foods has been limited, but is essential in order to provide guidelines for consumption and confirm lack of toxicity. PMID- 30521853 TI - Tools and strategies for constructing cell-free enzyme pathways. AB - Single enzyme systems or engineered microbial hosts have been used for decades but the notion of assembling multiple enzymes into cell-free synthetic pathways is a relatively new development. The extensive possibilities that stem from this synthetic concept makes it a fast growing and potentially high impact field for biomanufacturing fine and platform chemicals, pharmaceuticals and biofuels. However, the translation of individual single enzymatic reactions into cell-free multi-enzyme pathways is not trivial. In reality, the kinetics of an enzyme pathway can be very inadequate and the production of multiple enzymes can impose a great burden on the economics of the process. We examine here strategies for designing synthetic pathways and draw attention to the requirements of substrates, enzymes and cofactor regeneration systems for improving the effectiveness and sustainability of cell-free biocatalysis. In addition, we comment on methods for the immobilisation of members of a multi-enzyme pathway to enhance the viability of the system. Finally, we focus on the recent development of integrative tools such as in silico pathway modelling and high throughput flux analysis with the aim of reinforcing their indispensable role in the future of cell-free biocatalytic pathways for biomanufacturing. PMID- 30521854 TI - An Interactive and Low-Cost Full Body Rehabilitation Framework Based on 3D Immersive Serious Games. AB - Strokes, surgeries, or degenerative diseases can impair motor abilities and balance. Long-term rehabilitation is often the only way to recover, as completely as possible, these lost skills. To be effective, this type of rehabilitation should follow three main rules. First, rehabilitation exercises should be able to keep patient's motivation high. Second, each exercise should be customizable depending on patient's needs. Third, patient's performance should be evaluated objectively, i.e., by measuring patient's movements with respect to an optimal reference model. To meet the just reported requirements, in this paper, an interactive and low-cost full body rehabilitation framework for the generation of 3D immersive serious games is proposed. The framework combines two Natural User Interfaces (NUIs), for hand and body modeling, respectively, and a Head Mounted Display (HMD) to provide the patient with an interactive and highly defined Virtual Environment (VE) for playing with stimulating rehabilitation exercises. The paper presents the overall architecture of the framework, including the environment for the generation of the pilot serious games and the main features of the used hand and body models. The effectiveness of the proposed system is shown on a group of ninety-two patients. In a first stage, a pool of seven rehabilitation therapists has evaluated the results of the patients on the basis of three reference rehabilitation exercises, confirming a significant gradual recovery of the patients' skills. Moreover, the feedbacks received by the therapists and patients, who have used the system, have pointed out remarkable results in terms of motivation, usability, and customization. In a second stage, by comparing the current state-of-the-art in rehabilitation area with the proposed system, we have observed that the latter can be considered a concrete contribution in terms of versatility, immersivity, and novelty. In a final stage, by training a Gated Recurrent Unit Recurrent Neural Network (GRU-RNN) with healthy subjects (i.e., baseline), we have also provided a reference model to objectively evaluate the degree of the patients' performance. To estimate the effectiveness of this last aspect of the proposed approach, we have used the NTU RGB+D Action Recognition dataset obtaining comparable results with the current literature in action recognition. PMID- 30521855 TI - Neuroevolution as a Tool for Microarray Gene Expression Pattern Identification in Cancer Research. AB - Microarrays are still one of the major techniques employed to study cancer biology. However, the identification of expression patterns from microarray datasets is still a significant challenge to overcome. In this work, a new approach using Neuroevolution, a machine learning field that combines neural networks and evolutionary computation, provides aid in this challenge by simultaneously classifying microarray data and selecting the subset of more relevant genes. The main algorithm, FS-NEAT, was adapted by the addition of new structural operators designed for this high dimensional data. In addition, a rigorous filtering and preprocessing protocol was employed to select quality microarray datasets for the proposed method, selecting 13 datasets from three different cancer types. The results show that Neuroevolution was able to successfully classify microarray samples when compared with other methods in the literature, while also finding subsets of genes that can be generalized for other algorithms and carry relevant biological information. This approach detected 177 genes, and 82 were validated as already being associated to their respective cancer types and 44 were associated to other types of cancer, becoming potential targets to be explored as cancer biomarkers. Five long non-coding RNAs were also detected, from which four don't have described functions yet. The expression patterns found are intrinsically related to extracellular matrix, exosomes and cell proliferation. The results obtained in this work could aid in unraveling the molecular mechanisms underlying the tumoral process and describe new potential targets to be explored in future works. PMID- 30521856 TI - Bezlotoxumab Use as Adjunctive Therapy with the Third Fecal Microbiota Transplant in Refractory Recurrent Clostridium Difficile Colitis; A Case Report and Concise Literature Review. AB - Clostridium difficile is the most commonly reported pathogen to cause nosocomial infections in the United States with a high burden affecting morbidity, mortality and healthcare expenditure. The use of Fecal Microbiota Transplantation (FMT) is one of the current standard therapies for recurrent C. difficile infection (CDIr). One emerging promising approach is the use of monoclonal antibodies that bind to and neutralize C. difficile toxins such as Bezlotoxumab. We present the first case report on combining the third FMT with bezlotoxumab after the failure of standard-of-care antibiotics and two trials of FMT alone, with subsequent success in preventing the recurrence of refractory CDI for 12 weeks following treatment. This case highlight the need for further studies and guidelines to recommend the best combination among different treatment options and modalities. PMID- 30521857 TI - Nucleoside and N-acetyldopamine derivatives from the insect Aspongopus chinensis. AB - Two new nucleoside derivatives, named asponguanosines A and B (1 and 2), three new N-acetyldopamine analogues, aspongamides C-E (3-5), one new sesquiterpene, aspongnoid D (6), and three known compounds were isolated from the medicinal insect Aspongopus chinensis. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD and 13C NMR calculations. Biological activities of compounds 3-7 towards human cancer cells, COX-2, ROCK1, and JAK3 were evaluated. PMID- 30521858 TI - Renoprotective meroterpenoids from the fungus Ganoderma cochlear. AB - Nine multifarious new meroterpenoids, cochlearols E-M (1-9), along with seven known meroterpenoids 10-16, were isolated from the fruiting bodies of Ganoderma cochlear. Racemic 1, 6-8, 10 and 13 were separated by chiral HPLC. The structures were elucidated based on detailed spectroscopic analyses (HRESIMS, 1D/2D-NMR) and calculated electronic circular dichroism (ECD). Their biological activities against renal fibrosis were evaluated by using rat normal and diseased renal interstitial fibroblast cells (NRK49F). The results show that compounds 7a, 7b, and 10a exhibit potent proliferation inhibition in TGF-beta1-induced NRK-49F cells. PMID- 30521859 TI - Optimal control applied to a temperature dependent schistosomiasis model. AB - Schistosomiasis, the most common water-borne infection worldwide, continues to pose a serious public health challenge in developing nations and to travellers who visit these endemic regions. We apply optimal control on a temperature dependent schistosomiasis model. Our optimal control aims to minimize the pre patent and patent human population at minimal costs. Our analysis and results throughout the paper highlight the impact of optimal control shaping the future patterns of the disease. Our results show that optimal control can significantly reduce the schistosomiasis burden in the community and in some instance by more than three-folds. In addition, our results show that with low costs the optimal strategy will be carried out at or close to its maximum strength for a sufficiently long period of time, so as minimize the exposure and infection. With high costs, however, the control have to be implemented with reduce or even minimum, strength, to achieve an optimal balance between the costs and effects of control. Our findings suggests that optimal control theory can be useful on minimizing the infected host and vector. The study and its findings can provide a useful framework for designing cost-effective control for schistosomiasis. PMID- 30521860 TI - Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins. AB - Photodamage in chronically sun-exposed skin manifests clinically as deep wrinkles and histologically as extensive remodelling of the dermal extracellular matrix (ECM) and in particular, the elastic fibre system. We have shown previously that loss of fibrillin microfibrils, a key elastic fibre component, is a hallmark of early photodamage and that these ECM assemblies are susceptible in vitro to physiologically attainable doses of ultraviolet radiation (UVR). Here, we test the hypotheses that UVR-mediated photo-oxidation is the primary driver of fibrillin microfibril and fibronectin degradation and that prior UVR exposure will enhance the subsequent proteolytic activity of UVR-upregulated matrix metalloproteinases (MMPs). We confirmed that UVB (280-315 nm) irradiation in vitro induced structural changes to both fibrillin microfibrils and fibronectin and these changes were largely reactive oxygen species (ROS)-driven, with increased ROS lifetime (D2O) enhancing protein damage and depleted O2 conditions abrogating it. Furthermore, we show that although exposure to UVR alone increased microfibril structural heterogeneity, exposure to purified MMPs (1, -3, -7 and - 9) alone had minimal effect on periodicity. However, microfibril suspensions exposed to UVR and then MMPs were more structurally homogenous but the susceptibly of fibronectin to proteases was unaffected by prior UVR exposure. These observations suggest that both direct photon absorption and indirect production of ROS are important mediators of ECM remodelling in photodamage. We also show that fibrillin microfibrils are relatively resistant to proteolysis by MMPs -1, -3, -7 and - 9 but that these MMPs may selectively remove damaged microfibril assemblies. These latter observations have implications for predicting the mechanisms of tissue remodelling and targeted repair. PMID- 30521861 TI - MiR-15b is a key regulator of proliferation and apoptosis of chondrocytes from patients with condylar hyperplasia by targeting IGF1, IGF1R and BCL2. AB - OBJECTIVE: This study aimed to explore potential microRNAs (miRNAs), which participate in the pathological process of condylar hyperplasia (CH) through targeting specific proliferation- and apoptosis-related genes of chondrocytes. METHODS: Insulin-like growth factor 1 (IGF1), IGF1 receptor (IGF1R) and B-cell CLL/lymphoma 2 (BCL2) in CH cartilage were detected by real-time PCR, Western blot, immunohistochemistry and immunofluorescence. MiRanda and TargetScanS algorithms were used to predict certain miRNAs in CH chondrocytes concurrently modulating the above three genes. MiR-15b was screened and identified using real time PCR. After transfection of miR-15b mimics or inhibitor into CH chondrocytes, expression of the above three genes was detected by real-time PCR and western blot, meanwhile, cell proliferation and apoptosis was examined by CCK8, cell cycle assays, flow cytometry and Hoechst staining. Dual luciferase activity was performed to identify the direct regulation of miR-15b on IGF1, IGF1R and BCL2. RESULTS: Expression of IGF1, IGF1R and BCL2 increased in CH cartilage. Seven microRNAs concurrently correlated with IGF1, IGF1R and BCL2. Among them, only miR 15b significantly changed in CH chondrocytes. Overexpression of miR-15b in CH chondrocytes suppressed the expression of IGF1, IGF1R and BCL2, while it increased when miR-15b was knockdown. Furthermore, miR-15b suppressed their expression by directly binding to its 3'-UTR in these cells. Besides, miR-15b hampered chondrocytes proliferation through targeting IGF1 and IGF1R and accelerated chondrocytes apoptosis through targeting BCL2. CONCLUSION: Suppressed miR-15b contributed to enhanced proliferation capacity and weakened apoptosis of chondrocytes through augmentation of IGF1, IGF1R and BCL2, thereby resulting in development of CH. PMID- 30521862 TI - Antiasthmatic potential of Zizyphus jujuba Mill and Jujuboside B. - Possible role in the treatment of asthma. AB - Zizyphus jujuba Mill, a famous oriental traditional medicine, has been reported to exhibit diverse activities in biological systems including the respiratory system. However, a little information is available on its antiasthmatic activity. Jujuboside B (JB) is a natural saponin and one of the active constituent of fruits of Zizyphus jujuba. In the present investigation, JB was isolated from ethanolic extracts of fruits of Zizyphus jujuba (EZJF). EZJF and JB were then evaluated for anti-asthmatic activity using various screening methods. JB was additionally evaluated using ovalbumin (OVA) -induced allergic asthma in mice. Results obtained in the present study showed that EZJF and JB significantly inhibited clonidine-induced catalepsy, milk-induced leucocytosis and eosinophilia, clonidine-induced mast cell degranulation, and passive paw anaphylaxis. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid was considerably lowered and the severity of pulmonary inflammation was alleviated in the mice pretreated with JB. The high-level expression of T-helper type 2 (TH2) cytokines was markedly reduced in the serum, BAL fluid, and lung homogenates. Thus EZJF and JB showed potent anti-asthmatic activity. Hence EZJF and JB possess a potential role in the treatment of asthma. PMID- 30521863 TI - Animal Conflicts in Diploid Populations with Sexual Reproduction. AB - The classical, monomorphic, evolutionary games analyze competition among phenotypes while implicitly assuming monomorphic transmission of phenotypic attributes to successive generations. The recently formulated polymorphic evolutionary game theory (PEGT), which adds the underlying genetics and sexual reproduction to evolutionary games, has the potential to revolutionize game theoretical modeling of co-evolutionary processes. In this paper, I apply PEGT methods to the analysis of animal conflicts ? the oldest, and one of the best developed areas of evolutionary game modeling. Overall, the polymorphic results are consistent with the sequential assessment hypothesis. However, beyond the specific, the results indicate the need for a degree of caution applied to the existing evolutionary stability results ? as the polymorphic analysis shows that monomorphic ESS can be destabilized by sexual recombination. Finally, due to the novelty of the analytical approach, I make a particular emphasis on methodology: in particular, demonstrating how to combine generation of pertinent phenotypes with genetic plausibility considerations in the design of PEGT models. PMID- 30521864 TI - A network approach to quantifying radiotherapy effect on cancer: radiosensitive gene group centrality. AB - Radiotherapy plays a vital role in cancer treatment, for which accurate prognosis is important for guiding sequential treatment and improving the curative effect for patients. An issue of great significance in radiotherapy is to assess tumor radiosensitivity for devising the optimal treatment strategy. Previous studies focused on gene expression in cells closely associated with radiosensitivity, but factors such as the response of a cancer patient to irradiation and the patient survival time are largely ignored. For clinical cancer treatment, a specific pre treatment indicator taking into account cancer cell type and patient radiosensitivity is of great value but it has been missing. Here, we propose an effective indicator for radiosensitivity: radiosensitive gene group centrality (RSGGC), which characterizes the importance of the group of genes that are radiosensitive in the whole gene correlation network. We demonstrate, using both clinical patient data and experimental cancer cell lines, which RSGGC can provide a quantitative estimate of the effect of radiotherapy, with factors such as the patient survival time and the survived fraction of cancer cell lines under radiotherapy fully taken into account. Our main finding is that, for patients with a higher RSGGC score before radiotherapy, cancer treatment tends to be more effective. The RSGGC can have significant applications in clinical prognosis, serving as a key measure to classifying radiosensitive and radioresistant patients. PMID- 30521865 TI - Differentiation between persistent infection/colonization and re-infection/re colonization of Mycobacterium abscessus isolated from patients in Northeast Thailand. AB - Mycobacterium abscessus can cause true infection or be present in the host as a harmless colonist. The ability of M. abscessus to cause disease and develop drug resistance is known to have a genetic basis. We aimed to differentiate between persistent infection and reinfection using multilocus sequence typing (MLST) and to study the genetic diversity of M. abscessus relative to multi-organ infection and drug resistance in Northeast Thailand. DNA was extracted from 62 M. abscessus isolates (24 cases). The following genes were sequenced: argH, cya, glpK, gnd, murC, pta, purH and rpoB. Drug susceptibility tests were performed using broth microdilution. Subspecies classification and phylogeny were determined. Among the 24 cases (62 isolates), 19 cases (49 isolates) were of true NTM infection and 5 cases (13 isolates) examples of colonization. Two subspecies, M. abscessus subsp. massiliense (12 cases, 32 isolates) and M. abscessus subsp. abscessus (12 cases, 30 isolates) were identified. The major sequence type (ST) was ST227. Two clonal groups among patients were found; clonal cluster I (5 cases, 8 isolates) and clonal cluster II (2 cases, 4 isolates) but no epidemiological link was apparent. Reinfection (2 cases with different clones of M. abscessus strains; >9 SNPs different) and persistent infection (14 cases with the same clone; <6 SNPs) were distinguished based on a phylogeny. Based on these SNP cutoff values, 3 cases of persistent colonization (same strain through time) and 2 cases of re-colonization (different strains through time) were identified. M. abscessus subsp. abscessus was significantly associated with clarithromycin resistance (p < .001) and multi organ infection (p = .03). Molecular epidemiology based on MLST can be used to differentiate between reinfection vs persistent infection, persistent colonization vs re-colonization. ST227 was the main epidemic strain in Northeast Thailand. PMID- 30521866 TI - Fluorescence polarization assay: Diagnostic evaluation for porcine brucellosis. AB - Brucellosis in pigs, caused by the bacterium Brucella suis, is an important zoonotic infection. In the present study, fluorescence polarization assay (FPA) was standardized and compared with indirect enzyme linked immunosorbent assay (iELISA) and competitive ELISA (cELISA) for diagnosis of porcine brucellosis. Test performances were evaluated using representative panel (n = 100), samples from swine brucellosis outbreak (n = 300), samples from brucellosis suspected animals (n = 291) and sera samples from apparently healthy animals (n = 1121). With panel samples, the FPA cut-off >=11DeltamP was arrived with sensitivity (Se) and specificity (Sp) of 95.00 and 98.75%, respectively. Testing of samples from swine brucellosis outbreak, the diagnostic Se and Sp of 100 and 95.14% by iELISA, 73.91 and 100% by cELISA and 86.96 and 100% by FPA, respectively were recorded. Similarly, in case of swine brucellosis suspected samples, relative performance of FPA with cELISA had revealed higher kappa value of 0.864 with an accuracy of 93.47. Indirect ELISA was found to be highly sensitive but showed cross reactivity mainly for Yersinia enterocolitica O9 antibodies than cELISA and FPA. The high specificity of FPA test recorded in various types of samples in the study indicated that, FPA could serve as confirmatory test for individual animal diagnosis, outbreak confirmation, surveillance and quarantine of swine brucellosis cases. PMID- 30521867 TI - Evaluation of the automated BD Phoenix CPO Detect panel in combination with the beta-CARBA assay for detection and classification of carbapenemase-producing Enterobacterales. AB - Recently, the CPO Detect panel for the detection of carbapenemase-producing, Gram negative bacteria was introduced for the Phoenix semi-automated antimicrobial susceptibility testing system. The CPO Detect assay aims to detect carbapenemase activity (P/N test) and to type carbapenemase producers according to the Ambler classification (Ambler test). The P/N test-based detection of carbapenemase producers was 100% sensitive and 55.3% specific in the assessment of 57 carbapenemase-producing and 38 non-carbapenemase-producing Enterobacterales. False-positive test isolates in the P/N test arose from carbapenemase-non producing, but carbapenem-non-susceptible isolates. In contrast, using the Ambler test-based approach for carbapenemase detection resulted in a specificity of 100% and a sensitivity of 79%. In order to improve the overall performance, we established an algorithm that additionally included the colorimetric beta-CARBA assay as downstream test for P/N test-positive isolates, which remained un-typed in the Ambler test. This algorithm displayed an overall sensitivity and specificity of 98.3% and 100%, respectively. Our data demonstrate that the combination of the CPO Detect assay with the beta-CARBA test allows for rapid detection and classification of carbapenemase-producing Enterobacterales. PMID- 30521868 TI - Alpha-pinene attenuates UVA-induced photoaging through inhibition of matrix metalloproteinases expression in mouse skin. AB - AIM: The present study was designed to examine the role of alpha-pinene (AP) against skin photoaging in UVA-irradiated mice. MATERIALS AND METHODS: Swiss albino mice were subjected to UVA-irradiation at the rate of 10 J/cm2 per day for ten days, totally mouse received 100 J/cm2. One hour prior to each UVA-exposure, the mouse skin was topically treated with AP (100 mg kg/b.wt). Biochemical methods were employed to study the status of antioxidant enzymes and lipid peroxidation. Histopathological observations were performed using hematoxylin and eosin (H & E) and Verhoeff van Gieson (VVG) staining in the mouse skin. The inflammatory and apoptotic protein expression was studied by immunohistochemical and Western blot methods. The mRNA expression of matrix metalloproteinases was determined by qRT-PCR and Western blot analysis. KEY FINDINGS: We found that AP pretreatment substantially ameliorated UVA-induced depletion of antioxidant enzymes and prevented UVA-induced lipid peroxidation in the mouse skin. Further, AP effectively inhibited UVA-induced activation of pro-angiogenic (iNOS and VEGF), inflammatory proteins (TNF-alpha, IL-6, and COX-2) expression and prevented the activation of NF-kappaB p65 in the mouse skin. Additionally, AP inhibited UVA-mediated apoptotic mediators (Bax, Bcl-2, caspase-3 and caspase 9) expression in the mouse skin. Moreover, AP inhibited mRNA expression of matrix metalloproteinases (MMP-13 and MMP-9) and tissue type IV collagenase (MMP-2) expression in the mouse skin. Histological studies showed that AP remarkably prevented the dermal tissue damage in UVA-irradiated mice. CONCLUSION: Thus, AP treatment effectively prevented UVA-induced photoaging probably through its antioxidant property. PMID- 30521869 TI - Electro-acupuncture attenuates the mice premature ovarian failure via mediating PI3K/AKT/mTOR pathway. AB - AIMS: Electro-acupuncture (EA) is frequently recommended as a complementary therapy for premature ovarian failure (POF) in the clinical. However, little information exists about its potential treatment mechanisms. The study was designed to observe the effect of EA to ovarian function and fertility in POF mice model, and investigated its potential mechanisms on PI3K/AKT/mTOR signaling pathway. MATERIALS AND METHODS: Forty-five female C57/BL6 mice were divided into the Control, the Model and the EA group. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. The protein expression of PI3K, phospho-PI3K, AKT, phospho-AKT, mTOR, phospho-mTOR, S6, phospho-S6, 4E-BP1 and phospho-4E-BP1 were detected by western blotting. The data was presented as the ratio of phosphorylation protein to total protein. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-Mullerian hormone (AMH) levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. KEY FINDINGS: We found that primordial follicle counts were increased in EA group compared to Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in EA group significantly reduced compared to Model group. Serum FSH and LH levels in EA group were decreased compared to Model group, while, serum E2 and AMH levels in EA group were increased compared with Model group. The litter size in EA group was improved compared to Model group. SIGNIFICANCE: The effects of EA on the PI3K/AKT/mTOR signaling pathway may represent one of the mechanisms involved in attenuating the mice POF. PMID- 30521870 TI - Biased perspectives on formyl peptide receptors. AB - The innate immune system is the first line of defense against pathogenic threats. For the early pathogen recognition and activation of cell protective mechanisms, germline-encoded pattern recognition receptors (PRRs) detect characteristic and evolutionary conserved pathogen-associated molecular patterns (PAMPs). PRRs are therefore key elements in the innate immune response; in addition, they sense danger-associated molecular patterns (DAMPs) that are released by host cell molecules under pathophysiological conditions. Formyl peptide receptors (FPRs) are G-protein-coupled PRRs that respond to a surprisingly broad range of ligands, derived from both pathogens and host cells. Here, we exemplary discuss ligands in order to illustrate the wide pathophysiological relevance of the FPR signaling axis in case of e.g., chronic inflammations and to underscore its potential therapeutic value in the light of "biased agonism", a modern concept of GPCR (G protein coupled receptors) activation. These novel insights into the GPCR receptor biochemistry will hopefully (re)stimulate FPR-related research and lead to novel strategies for the urgently needed development of drugs with pharmacologically advantageous characteristics. PMID- 30521871 TI - 5-Azido-8-ethynyl-NAADP: A bifunctional, clickable photoaffinity probe for the identification of NAADP receptors. AB - Nicotinic acid adenine dinucleotide phosphate is an evolutionarily conserved second messenger, which mobilizes Ca2+ from acidic stores. The molecular identity of the NAADP receptor has yet to be defined. In pursuit of isolating and identifying NAADP-binding proteins, we synthesized and characterized a bifunctional probe that incorporates both a photoactivatable crosslinking azido moiety at the 5-position of the nicotinic ring and a 'clickable' ethynyl moiety to the 8-adenosyl position in NAADP. Microinjection of this 5N3-8-ethynyl-NAADP into cultured U2OS cells induced robust Ca2+ responses. Higher concentrations of 5N3-8-ethynyl were required to elicit Ca2+ release or displace 32P-NAADP in radioligand binding experiments in sea urchin egg homogenates. In human cell extracts, incubation of 32P-5N3-8-ethynyl-NAADP followed by UV irradiation resulted in selective labeling of 23 kDa and 35 kDa proteins and photolabeling of these proteins was prevented when incubated in the presence of unlabeled NAADP. Compared to the monofunctional 32P-5N3-NAADP, the clickable 32P-5N3-8-ethynyl NAADP demonstrated less labeling of the 23 kDa and 35 kDa proteins (~3-fold) but provided an opportunity for further enrichment through the 'clickable' ethynyl moiety. No proteins were specifically labeled by 32P-5N3-8-ethynyl-NAADP in sea urchin egg homogenate. These experiments demonstrate that 5N3-8-ethynyl-NAADP is biologically active and selectively labels putative NAADP-binding proteins in mammalian systems, evidencing a 'bifunctional' probe with utility for isolating NAADP-binding proteins. PMID- 30521872 TI - Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a long-term consequence of chronic inflammatory liver injury. Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products including lipopolysaccharide (LPS), which promotes hepatocarcinogenesis. Despite its clinical significance, the molecular mediator linking chronic inflammation with HCC development remains to be clarified. In this study, we explored the significant dual functions of active signal transducer and activator of transcription 3 (STAT3) in LPS-induced angiogenesis of HCC. The in vitro effects of active STAT3 in tumor cells and endothelial cells were assessed using angiogenesis assay, ELISA, confocal assay, flow cytometry and western blot. The in vivo role of active STAT3 was assessed in xenografts model in nude mice. Here we report a novel mechanism by which LPS/STAT3 signaling promotes the angiogenesis of HCC both in vitro and in vivo. STAT3 activated by LPS increases the production of vascular endothelial growth factor (VEGF) by tumor cells, which not only promotes the proliferation of HCC cells but also stimulates the migration and tubulogenesis of endothelial cells through STAT3 activation and hence promotes angiogenesis in HCC. Our findings not only provide a potential mechanism by which bacterial infection enhances HCC oncogenesis through promoting the angiogenesis in liver, but also suggest that targeting STAT3 might be an effective therapeutic strategy in HCC treatment considering the dual roles of STAT3 in angiogenesis. PMID- 30521873 TI - Tuning store-operated calcium entry to modulate Ca2+-dependent physiological processes. AB - The intracellular calcium signaling processes are tightly regulated to ensure the generation of calcium signals with the specific spatiotemporal characteristics that are required for regulating various cell functions. Compartmentalization of the molecular components involved in generating these signals at discrete intracellular sites ensures the signaling specificity and transduction fidelity of the signal for regulating downstream effector processes. Store-operated calcium entry (SOCE) is ubiquitously present in cells and is critical for essential cell functions in a variety of tissues. SOCE is mediated via plasma membrane Ca2+ channels that are activated when luminal [Ca2+] of the endoplasmic reticulum ([Ca2+]ER) is decreased. The ER-resident stromal interaction molecules, STIM1 and STIM2, respond to decreases in [Ca2+]ER by undergoing conformational changes that cause them to aggregate at the cell periphery in ER-plasma membrane (ER-PM) junctions. At these sites, STIM proteins recruit Orai1 channels and trigger their activation. Importantly, the two STIM proteins concertedly modulate Orai1 function as well as the sensitivity of SOCE to ER-Ca2+ store depletion. Another family of plasma membrane Ca2+ channels, known as the Transient Receptor Potential Canonical (TRPC) channels (TRPC1-7) also contribute to sustained [Ca2+]i elevation that is triggered following store depletion. Although the function of these channels overlaps with that of Orai1, they regulate distinct functions in the cells. Importantly, STIM1 is also required for plasma membrane localization and activation of TRPCs. In this review, we will discuss various molecular components and factors that govern the activation, regulation and modulation of the Ca2+ signal generated by Ca2+ entry pathways in response to depletion of ER-Ca2+ stores. PMID- 30521874 TI - Endonuclease G modulates the alternative splicing of deoxyribonuclease 1 mRNA in human CD4+ T lymphocytes and prevents the progression of apoptosis. AB - Apoptotic endonucleases act cooperatively to fragment DNA and ensure the irreversibility of apoptosis. However, very little is known regarding the potential regulatory links between endonucleases. Deoxyribonuclease 1 (DNase I) inactivation is caused by alternative splicing (AS) of DNase I pre-mRNA skipping exon 4, which occurs in response to EndoG overexpression in cells. The current study aimed to determine the role of EndoG in the regulation of DNase I mRNA AS and the modulation of its enzymatic activity. A strong correlation was identified between the EndoG expression levels and DNase I splice variants in human lymphocytes. EndoG overexpression in CD4+ T cells down-regulated the mRNA levels of the active full-length DNase I variant and up-regulated the levels of the non active spliced variant, which acts in a dominant-negative fashion. DNase I AS was induced by the translocation of EndoG from mitochondria into nuclei during the development of apoptosis. The DNase I spliced variant was induced by recombinant EndoG or by incubation with EndoG-digested cellular RNA in an in vitro system with isolated cell nuclei. Using antisense DNA oligonucleotides, we identified a 72-base segment that spans the adjacent segments of exon 4 and intron 4 and appears to be responsible for the AS. DNase I-positive CD4+ T cells overexpressing EndoG demonstrated decreased progression towards bleomycin-induced apoptosis. Therefore, EndoG is an endonuclease with the unique ability to inactivate another endonuclease, DNase I, and to modulate the development of apoptosis. PMID- 30521875 TI - Anticancer activity modulation of an innovative solid formulation of extra virgin olive oil by cultured zeolite scaffolds. AB - This paper deals with the design and manufacture of pure and hybrid synthetic (Mixed Matrix Membranes, MMMs) zeolite scaffolds (containing various amount of zeolite crystals dispersed in a polymeric matrix) to obtain new biomaterials. These scaffolds can potentially be used in the field of translational medicine to obtain innovative results to address tumorigenesis mechanisms with the promotion of an effort to deal with technical methods and information. Since olive oil has beneficial effects in healthy human cells and slows down and/or inhibits cell growth, the aim of this work was to monitor the protective and beneficial antitumor effects of olive oil in a new solid formulation (Spread Bio-Oil) on cancer cell cultured on zeolite scaffolds. In order to investigate the cytotoxicity of the new bio-oil spread and to test antiproliferative activity on the cancer cells we used two phenotypically different human breast cancer cell lines (MCF-7 and MDA-MB-231) seeded on various morphologies of zeolite membranes. We report the fabrication and characterization of pure and hybrid (MMMs) zeolite membranes and evaluated the intensively cell adhesion, spreading and cell growth by adhesion test, MTT, optical microscopy analyses and Scanning Electronic Microscopy (SEM) microphotography analyses. Our results demonstrate that both cell lines adhered and grow on all zeolite surfaces and that both show better viability after Spread Bio-Oil treatments. All cell adhesions are a specific membrane-type and, in particular, MCF-7 cells interact and adhere preferentially on pure zeolite membranes. Cancer cells seem to recognize and prefer the characteristics of the supports according to the following trend: Co-ZSM-5 > Co-S 1 > 13X. Moreover, Co-ZSM-5 zeolite membranes were the best scaffolds and MDA-MB 231 cells after administration of Spread Bio-Oil showed less viability with respect to MCF-7 responding better to all concentrations of the innovative food. Our data indicate that Spread Bio-Oil decreases at very low concentration values (5, 10, 25, 50, 100, 200 and 300 MUg/mL) cell proliferation in a dose- and time dependent manner. The work confirms both the superiority of pure zeolite scaffolds for cultures of human normal and cancer cells and Spread Bio-Oil as an innovative food preserving all the beneficial and healthy properties of the extra virgin olive oil from which it derives. PMID- 30521877 TI - Violence and aggression in young women: The importance of psychopathy and neurobiological function. AB - Psychopathy is one of the most researched risk factors for violence. Yet, research in women is sparse. The present study aimed to test if the link between the four-facet structure of psychopathy and interpersonal violence and aggression was moderated by neurobiological function (indexed by resting respiratory sinus arrhythmia; RSA). Results showed the lifestyle and affective facets were associated with reactive aggression and these associations were moderated by low resting RSA. The interpersonal, affective, and antisocial facets were associated with proactive aggression but no moderation effect was found. The affective and antisocial facets of psychopathy were associated with histories of interpersonal violence, however, only the affective facet was moderated by low RSA. This is the first study in young women to demonstrate the link between affective psychopathic traits and interpersonal violence and reactive aggression is via aberrant prefrontal cortex functioning. PMID- 30521876 TI - RIFM fragrance ingredient safety assessment, isopropyl butyrate CAS Registry Number 638-11-9. PMID- 30521878 TI - Daily energy expenditure of males following alternative reproductive tactics: Solitary roamers spend more energy than group-living males. AB - In many species, males follow alternative reproductive tactics (ARTs), where one tactic (called bourgeois) has much higher reproductive success than alternative tactics followed by males with lower competitive ability. The extent to which ARTs differ in energetic costs is unknown, but it is important to understand the fitness payoffs of ARTs. We studied male African striped mice (Rhabdomys pumilio) which follow one of three ARTs: heavy bourgeois males defend harems of females and have 10 times higher reproductive success than smaller roamers, which have ten times higher reproductive success than philopatric males, which remain in their natal group and are the smallest males. Bourgeois and philopatric males live in social groups that defend one territory, while roamers are solitary and roam over larger areas. We predicted that roamers will face higher energetic costs compared to group-living males because they do not gain thermoregulatory benefits of huddling in groups and might travel larger distances as they have larger home ranges. We measured daily energy expenditure (DEE) of 30 males, resting metabolic rate (RMR) of 79 males, travel distances and daily ranges of 31 males and changes in body mass of 51 males. Roamers had higher DEE and higher RMR than both types of group-living males. Philopatric males had shorter travel distances and smaller daily ranges than both roamers and bourgeois males, which did not differ from each other. This indicates that the higher DEE of roamers compared to bourgeois males cannot be explained by larger travel distances. Philopatrics gained body mass faster than bourgeois males and roamers, thereby increasing their competitive ability and thus the probability of later switching to a tactic of higher reproductive success. Our results suggest that roamers suffer energetic costs that might reduce their ability of gaining body mass and thus the likelihood of switching to the bourgeois tactic, indicating evolutionary trade-offs between investing energy into roaming versus gaining body mass. PMID- 30521879 TI - Alternate day fasting decreases preference for a calorically dense diet by increasing chow intake and altering meal pattern parameters. AB - Alternate day fasting (ADF) is an effective dietary strategy for weight loss in both humans and rats. However, fasting can elicit hyperphagia in rats, particularly upon access to a calorically dense, high-energy (HE) diet. To examine the effects of ADF on HE diet preference, male and female Sprague-Dawley rats were randomly assigned to receive either ad-libitum or alternate day access to both chow and HE food. Meal pattern analysis was conducted to provide a more detailed explanation of changes in HE preference. ADF rats had a decreased preference for the HE diet compared to controls. Both male and female ADF rats increased in overall intake of chow. However, for male ADF rats, the decrease in HE preference was driven by an increase in both size and number of chow meals; for females, it was driven only by an increase in number of chow meals. Meal size is controlled by both positive feedback (e.g. from the oral cavity) and negative feedback (e.g. from postoral inhibitory signals). Thus, for males, fasting appeared to increase orosensory stimulation and/or decrease sensitivity to inhibitory cues towards chow. For females, fasting appeared to decrease sensitivity to inhibitory cues towards chow. The decrease in HE preference observed in the current study may contribute to the effectiveness of ADF as a dietary strategy for weight loss. PMID- 30521880 TI - Classic Psychedelics: An integrative review of epidemiology, mystical experience, brain network function, and therapeutics. AB - The purpose of this paper is to provide an integrative review and offer novel insights regarding human research with classic psychedelics (classic hallucinogens), which are 5HT2AR agonists such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Classic psychedelics have been administered as sacraments since ancient times. They were of prominent interest within psychiatry and neuroscience in the 1950s to 1960s, and during this time contributed to the emergence of the field of molecular neuroscience. Promising results were reported for treatment of both end-of-life psychological distress and addiction, and classic psychedelics served as tools for studying the neurobiological bases of psychological disorders. Moreover, classic psychedelics were shown to occasion mystical experiences, which are subjective experiences reported throughout different cultures and religions involving a strong sense of unity, among other characteristics. However, the recreational use of classic psychedelics and their association with the counterculture prompted an end to human research with classic psychedelics in the early 1970s. We review recent therapeutic studies suggesting efficacy in treating psychological distress associated with life threatening diseases, treating depression, and treating nicotine and alcohol addictions. We also describe the construct of mystical experience, and provide a comprehensive review of modern studies investigating classic psychedelic occasioned mystical experiences and their consequences. These studies have shown classic psychedelics to fairly reliably occasion mystical experiences. Moreover, classic psychedelic-occasioned mystical experiences are associated with improved psychological outcomes in both healthy volunteer and patient populations. We also review neuroimaging studies that suggest neurobiological mechanisms of psychedelics. These studies have also broadened our understanding of the brain, the serotonin system, and the neurobiological basis of consciousness. Finally, we provide the most comprehensive review of epidemiological studies of classic psychedelics to date. Notable among these are a number of studies which have suggested the possibility that nonmedical naturalistic (non-laboratory) use of classic psychedelics is associated with positive mental health and prosocial outcomes, although it is clear that some individuals are harmed by classic psychedelics in non-supervised settings. Overall, these various lines of research suggest that classic psychedelics might hold strong potential as therapeutics, and as tools for experimentally investigating mystical experiences and behavioral brain function more generally. PMID- 30521881 TI - NEW INSIGHTS ON THE REGULATION OF CANCER CACHEXIA BY N-3 POLYUNSATURATED FATTY ACIDS. AB - Cancer cachexia is a multifactorial syndrome that develops during malignant tumor growth. Changes in plasma levels of several hormones and inflammatory factors result in an intense catabolic state, decreased activity of anabolic pathways, anorexia, and marked weight loss, leading to cachexia development and/or accentuation. Inflammatory mediators appear to be related to the control of a highly regulated process of muscle protein degradation that accelerates the process of cachexia. Several mediators have been postulated to participate in this process, including TNF-alpha, myostatin, and activated protein degradation pathways. Some interventional therapies have been proposed, including nutritional (dietary, omega-3 fatty acid supplementation), hormonal (insulin), pharmacological (clenbuterol), and nonpharmacological (physical exercise) therapies. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid, are recognized for their anti-inflammatory properties and have been used in therapeutic approaches to treat or attenuate cancer cachexia. In this review, we discuss recent findings on cellular and molecular mechanisms involved in inflammation in the cancer cachexia syndrome and the effectiveness of n-3 PUFAs to attenuate or prevent cancer cachexia. PMID- 30521882 TI - Body composition and sarcopenia: the next-generation of personalized oncology and pharmacology? AB - Body composition has gained increasing attention in oncology in recent years due to fact that sarcopenia has been revealed to be a strong prognostic indicator for survival across multiple stages and cancer types and a predictive factor for toxicity and surgery complications. Accumulating evidence over the last decade has unraveled the "pharmacology" of sarcopenia. Lean body mass may be more relevant to define drug dosing than the "classical" body surface area or flat fixed dosing in patients with cancer. Since sarcopenia has a major impact on patient survival and quality of life, therapeutic interventions aiming at reducing muscle loss have been developed and are being prospectively evaluated in randomized controlled trials. It is now acknowledged that this supportive care dimension of oncological management is essential to ensure the success of any anticancer treatment. The field of sarcopenia and body composition in cancer is developing quickly, with (i) the newly identified concept of sarcopenic obesity defined as a specific pathophysiological entity, (ii) unsolved issues regarding the best evaluation modalities and cut-off for definition of sarcopenia on imaging, (iii) first results from clinical trials evaluating physical activity, and (iv) emerging body-composition-tailored drug administration schemes. In this context, we propose a comprehensive review providing a panoramic approach of the clinical, pharmacological and therapeutic implications of sarcopenia and body composition in oncology. PMID- 30521883 TI - Cytochrome P450 epoxygenases and cancer: A genetic and a molecular perspective. AB - Cytochrome CYP450 epoxygenases catalyze the epoxidation of polyunsaturated fatty acids including arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. The arachidonic acid-derived products are potent pro-angiogenic lipids and promote tumor development and growth. On the other hand, eicosapentaenoic acid- and docosahexaenoic acid-derived products inhibit angiogenesis and play a protective role in certain pathological conditions including cancer. Increased expression of CYP2C epoxygenases, together with increased levels of their arachidonic acid-derived products, is often observed in tumors and tumor associated vasculature, making these enzymes an ideal target for anti-cancer therapies. Yet, given the pro- and anti-angiogenic action of these enzymes, a better understanding of the specific roles of their products in the regulation of endothelial cell function and cancer development is required. In this review, we provide an overview of the role of CYP450 epoxygenase-derived lipids, with emphasis on arachidonic acid-derived products, in the regulation of endothelial cell function both in physiological and pathological conditions. Moreover, we discuss the impact of genetic polymorphisms in CYP450 epoxygenases on cancer risk, and we discuss advantages and limitation of approaches to target these enzymes and their products in pathological angiogenesis and cancer. PMID- 30521884 TI - Targeting indoleamine-2,3-dioxygenase in cancer: Scientific rationale and clinical evidence. AB - Immunotherapy through immune checkpoint blockers (ICBs) is quickly transforming cancer treatment by improving patients' outcomes. However, innate and acquired resistance to ICBs remain a major challenge in clinical settings. Indoleamine 2,3 dioxygenases (IDOs) are enzymes involved in tryptophan catabolism with a central immunosuppressive function within the tumor microenvironment. IDOs are over expressed in cancer patients and have increasingly been associated with worse outcomes and a poor prognosis. Preclinical data have shown that combining IDO and checkpoint inhibition might be a valuable strategy to improve the efficacy of immunotherapy. Currently, several IDO inhibitors have been evaluated in clinical trials, showing favorable pharmacokinetic profiles and promising efficacy. This review describes the mechanisms involved in IDO-mediated immune suppression and its role in cancer immune escape, focusing on the potential clinical application of IDO inhibitors as an immunotherapy strategy for cancer treatment. PMID- 30521885 TI - RNA Therapy: Are we using the right Molecules? AB - Small-molecule and protein/antibody drugs mainly act on genome-derived proteins to exert pharmacological effects. RNA based therapies hold the promise to expand the range of druggable targets from proteins to RNAs and the genome, as evidenced by several RNA drugs approved for clinical practice and many others under active trials. While chemo-engineered RNA mimics have found their success in marketed drugs and continue dominating basic research and drug development, these molecules are usually conjugated with extensive and various modifications. This makes them completely different from cellular RNAs transcribed from the genome that usually consist of unmodified ribonucleotides or just contain a few posttranscriptional modifications. The use of synthetic RNA mimics for RNA research and drug development is also in contrast with the ultimate success of protein research and therapy utilizing biologic or recombinant proteins produced and folded in living cells instead of polypeptides or proteins synthesized in vitro. Indeed, efforts have been made recently to develop RNA bioengineering technologies for cost-effective and large-scale production of biologic RNA molecules that may better capture the structures, functions, and safety profiles of natural RNAs. In this article, we provide an overview on RNA therapeutics for the treatment of human diseases via RNA interference mechanisms. By illustrating the structural differences between natural RNAs and chemo-engineered RNA mimics, we focus on discussion of a novel class of bioengineered/biologic RNA agents produced through fermentation and their potential applications to RNA research and drug development. PMID- 30521886 TI - HOXA5 overexpression promotes osteosarcoma cell apoptosis through the p53 and p38alpha MAPK pathway. AB - Osteosarcoma is the most common malignant bone tumor in children and adolescents. Aberrant expression of HOXA5 results in various diseases, including cancers. However, the specific function and molecular mechanism of HOXA5 in osteosarcoma is not fully understood. In the present study, we focused on HOXA5 in U2OS and MG63 cells in vitro. We observed lower expression of HOXA5 in U2OS, MG63, and SaOS2 human osteosarcoma cells, compared with hFOB1.19 human osteoblastic cells. HOXA5 overexpression in U2OS and MG63 cells markedly reduced cell survival and proliferation and elevated cell apoptosis and caspase-3 activity. HOXA5 also activated the p38alpha MAPK pathway by increasing p53. Treating U2OS and MG63 cells with the p53 inhibitor alpha-pifithrin or the p38alpha MAPK inhibitor SB203580 led to higher cell survival and proliferation and lower cell apoptosis, compared with the pcDNA3.1-HOXA5 group. In conclusion, our study showed that the p53 and p38alpha MAPK signal axis facilitated HOXA5's role in inhibiting growth and stimulating apoptosis of osteosarcoma cells. PMID- 30521887 TI - Gene polymorphisms of angiotensin-converting enzyme and angiotensinogen and risk of idiopathic ischemic stroke. AB - OBJECTIVE: The renin-angiotensin system (RAS) is a hormonal signaling mechanism implicated in the atherosclerosis and regulation of blood pressure. Angiotensin converting enzyme (ACE) a key enzyme in the RAS, plays important roles in vascular remodeling atherosclerosis, and ischemic stroke. The aim of this study was to examine the possible contribution of the I/D in the ACE gene, M235T and T174M in the angiotensinogen (AGT) gene polymorphisms with ischemic stroke in young Mexican population. MATERIALS AND METHODS: A total of 224 patients with diagnosis of idiopathic ischemic stroke <=45 years of age, and 224 controls matched by age and gender, were recruited from 2006 and 2016. The I/D, M235T and T174M polymorphisms were determined in all participants by PCR-RFLP. RESULTS: There was a significant difference in the M235T genotype distribution (p = 0.01) and allele frequency between two groups (p = 0.01). Also, we found a significant difference in the T174M genotype distribution (p = 0.01) and the allele frequency between groups; (p = 0.02). In contrast, in I/D polymorphism, there was a similar genotype distribution; (p = 0.20) and allele distribution (p = 0.20). There were independent factors for ischemic stroke: M235T and T174M polymorphisms, smoking, hypertension, and familial history of atherothrombotic disease. The AGT levels were increased in the group of patients with stroke compared with the control group, but the AGT levels were not influenced by the allele or genotype in each polymorphism. CONCLUSIONS: The M235T and T174M polymorphisms represented an increased risk for stroke in young Mexican individuals. In contrast, the I/D was not associated with in the same group of patients. The AGT levels were higher in the acute phase of stroke, but it was not determined by the polymorphisms. PMID- 30521888 TI - Identification and molecular analysis of a lncRNA-HOTAIR transcript from secondary hair follicle of cashmere goat reveal integrated regulatory network with the expression regulated potentially by its promoter methylation. AB - The HOTAIR transcript is transcribed from the antisense strand within the HOXC gene cluster, and it is thought to play a role in regulating the inductive capacity of dermal papilla cells during the reconstruction of hair-follicle. In the current investigation, we firstly isolated and characterized a lncRNA-HOTAIR transcript from the secondary hair follicle of cashmere goat. Also, we analyzed its transcriptional pattern and methylation level of HOTAIR gene promoter in secondary hair follicle of cashmere goat during anagen and telogen stages. Nucleotide composition analysis indicated that the contents of Adenine (A) and Thymine (T) are higher than that of Guanine (G) and Cytosine (C) in lncRNA-HOTAIR transcript of cashmere goat with the highest frequency distribution of AG nucleotide pair (8.06%). The regulatory network analysis showed a directly or indirectly complex regulatory relationships between lncRNA-HOTAIR of cashmere goat and its potential target molecules: miRNAs, mRNAs and proteins. Also, we showed that lncRNA-HOTAIR was properly transcribed at both anagen and telogen stages of secondary hair follicle of cashmere goat with the anagen being significantly higher than telogen in its expression, which suggest that lncRNA HOTAIR transcript might be involved in the reconstruction of secondary hair follicle with the formation and growth of cashmere fiber. Taken together with methylation analysis of HOTAIR gene promoter, our data suggest that the promoter methylation of HOTAIR gene most likely is involved in its transcriptional suppression in secondary hair follicle of cashmere goat. PMID- 30521889 TI - Glucuronorhamnoxylan from Capsosiphon fulvescens inhibits the growth of HT-29 human colon cancer cells in vitro and in vivo via induction of apoptotic cell death. AB - Colorectal cancer is the third most diagnosed cancer and a leading cause of cancer death. Dissatisfaction with currently available anti-colorectal cancer drugs caused by unwanted side effects and low efficacy necessitates new therapeutic agents. In the present study, a sulfated glucuronorhamnoxylan polysaccharide (named SPS-CF) purified from a green alga Capsosiphon fulvescens was evaluated for its anti-cancer activity in vitro and in vivo against colorectal cancer. The SPS-CF treatment resulted in a dose-dependent inhibition of the HT-29 human colon cancer cell growth up to 40% at 500 MUg/mL. This inhibitory activity was shown to be mediated by upregulation of the cleavage of caspase-8, -9, -3 and poly (ADP-ribose) polymerase (PARP), induction of DNA fragmentation, and disruption of mitochondrial membrane potential (MMP), demonstrating that SPS-CF causes apoptotic death of HT-29 cancer cells though activation of caspase-dependant pathway. Administration of SPS-CF to BALB/c-nude mice bearing HT-29 cell-xenograft tumor also reduced the tumor growth. The results of this study demonstrated that the SPS-CF effectively inhibits the colorectal tumor growth both in vitro and in vivo by induction of apoptotic death of tumor cells, suggesting that it can be a potent ingredient for health beneficial foods or anti-cancer agents to prevent or ameliorate human colon cancer. PMID- 30521890 TI - Radiation-mediated molecular weight reduction and structural modification in carrageenan potentiates improved photosynthesis and secondary metabolism in peppermint (Mentha piperita L.). AB - In an attempt to gain insights into the possible relationship between the irradiation-mediated molecular weight reduction and structural modification and the growth-promotion activity, characterization of the polysaccharide before and after irradiation was carried out through Fourier Transform Infrared (FT-IR), Ultraviolet-visible (UV-vis) and Nuclear Magnetic Resonance (NMR) spectroscopic studies. Moreover, graded concentrations of irradiated carrageenan (IC) were applied through foliage to assess the performance of peppermint (Mentha piperita L.). Among the various concentrations of IC [0 (control), un-irradiated carrageenan (UC), 40, 80, 120, 160 and 200 mg L-1], the effect of 80 mg L-1 IC established to be most favorable for most of the parameters studied. Rubisco and phenylalanine ammonia lyase activities were maximally enhanced by 65.9% and 35.6% by the application of 80 mg L-1 IC, respectively; as compared to the control and UC. A maximum enrichment in the content (32.8%) and yield (88.3%) of essential oil was noted by the application of 80 mg L-1 IC, respectively. Results of the gas chromatography revealed that the contents of menthol and 1, 8-cineole were increased; however, menthone and menthyl-acetate contents were decreased by the application of IC over the control and UC. PMID- 30521891 TI - Physicochemical and functional properties of oleaster (Elaeagnus angustifolia L.) polysaccharides extracted under optimal conditions. AB - This research aimed to optimize the polysaccharides extraction of oleaster fruit and then to investigate the physicochemical and functional properties of extracted polysaccharides. Temperature, water to dry matter ratio, time, and alcohol ratio were considered as variables. Purity of extracted polysaccharides was considered as the response. Optimization of polysaccharides extraction from full grain oleaster showed that all variables had effects on the purity of extracted polysaccharides alone or by interacting with other variables. The results showed that the temperature, 60 degrees C; water to dry matter ratio, 53:1 (V/W); time, 5 h; and alcohol ratio of 2.9 (V/V) were the best conditions for achieving the highest purity in extracted polysaccharides. The extracted polysaccharides had the potential of emulsion formation with high stability; however, foamability was not observed in this polysaccharide. In addition, the solubility of polysaccharide powder was high, and it increased with an increase in temperature, which resulted in a decrease in water absorption indicating the effect of heat on the structure and the amount of water absorption of extracted polysaccharides. The results obtained from FTIR confirmed the polysaccharide nature of extracted powder, and the X-ray diffraction pattern of extracted polysaccharides showed its semi-crystalline structure. PMID- 30521892 TI - The novel cationic cell-penetrating peptide PEP-NJSM is highly active against Staphylococcus epidermidis biofilm. AB - A cationic cell-penetrating peptide PEP-NJSM was identified in human virus proteomes by a screening of charge clusters in protein sequences generating cell penetrating peptides (CPP). PEP-NJSM was selectively active against Gram positive Staphylococcus epidermidis as antibacterial agent with MIC value of 128 MUM compared to the Gram-negative Pseudomonas aeruginosa strain with MIC value exceeded 512 MUM. The selected peptide exhibited an important anti-biofilm activity even at sub-MIC levels. PEP-NJSM could prevent biofilm formation and increase the mortality of cells inside mature S. epidermidis biofilm. The results demonstrated that PEP-NJSM presented an important anti-adherent activity. It showed a S. epidermidis inhibition of biofilm formation >84% at a concentration of 256 MUM (2 X MIC) and remained active even at a concentration of 4 MUM with 32% of inhibition. The eradication of the established biofilm was observed at a concentration of 256 MUM with 55.7% of biofilm eradication. The peptide was active against mature biofilm even at low concentration of 0.5 MUM with approximately 22.9% of eradication. PEP-NJSM exhibited low hemolytic activity and cytotoxicity against mammalian cells. Our results demonstrate that PEP-NJSM could have a potential role in the treatment of diseases related to Staphylococcus epidermidis infection. PMID- 30521893 TI - Physicochemical responses and microbiological changes of bream (Megalobrama ambycephala) to pectin based coatings enriched with clove essential oil during refrigeration. AB - The effectiveness of pectin coatings enriched with clove essential oil (CEO), as new edible coatings were investigated to preserve bream (Megalobrama ambycephala) fillets during refrigeration over a period of 15 days. All samples were analyzed for physicochemical (pH, PV, TBA and TVB-N), microbiological (Total viable count, Psychrophilic bacteria, Lactic acid bacteria, Enterobacteriaceae, Pseudomonas spp., H2S producing bacteria) and organoleptic attributes. The results revealed that the CEO incorporation reduced the extent of lipid oxidation, as judged by PV, TBA and TVB-N, thus extending the shelf life of bream fillets by at least 15 days. Moreover, the application of pectin coatings with CEO improved the weight loss, water holding capacity, textural and color attributes of the bream samples significantly compared to untreated sample. Pectin coating along with CEO was effective in inhibiting bacterial growth especially in gram-negative bacteria, while the growth of lactic acid bacteria remained constant for most of the storage period. The effect on the microorganisms during storage was in accordance with biochemical indexes of the quality, representing the viability of these coatings for bream preservation. Thus, the coatings developed in present study could inhibit the development of lipid oxidation during cold storage, representing an option as a seafood preservative. PMID- 30521894 TI - Draft genome analysis of lignocellulolytic enzymes producing Aspergillus terreus with structural insight of beta-glucosidases through molecular docking approach. AB - Members of the genus Aspergillus are extensively studied ascomycetes because of their ability to synthesize high value-added compounds and enzymes of industrial interest. Precise whole genome assembly and gene annotation are significant for gene functional analyses. Here, we report the draft genome sequencing, assembly and whole genome analysis of Aspergillus terreus P14_T3, isolated from rumen sample of cattle fed with coconut-coir. A total of 13,340 protein-coding genes were predicted, among them 493 are involved in degradation of complex carbohydrate polysaccharides. Further, it was found that 29 genes, encoding beta glucosidase belong to Glycosyl hydrolase (GH) family 1 (3 gene), 3 (17 gene), 5 (4 gene), 17 (3 gene), 132 (2 gene). The tertiary structure of all the beta glucosidases was designed by homology modeling; modeled structure AtBgl1.3 (GH1), AtBgl3.1 (GH3), AtBgl5.4 (GH5), AtBgl17.1 (GH17) show classical (alpha/beta) TIM like barrel motif. Molecular docking of different beta-glucosidases with cellobiose revealed that conserved amino acids i.e. Glu, Trp, Arg, His, Tyr and Asp are taking part in substrate hydrolysis. Moreover, some other amino acids i.e. Ser, Phe, Gln and Asn are found to be involved in hydrogen bond formation and catalysis. These findings may provide valuable insights in designing beta glucosidases with higher cellulose-hydrolyzing efficiency. PMID- 30521895 TI - Development of methotrexate loaded fucoidan/chitosan nanoparticles with anti inflammatory potential and enhanced skin permeation. AB - In this study, fucoidan/chitosan nanoparticles were developed for the topical delivery of methotrexate towards the treatment of skin-related inflammatory diseases. Based on the fucoidan/chitosan (F/C) weight ratio, three different nanoparticles (1F/1C; 3F/1C; 5F/1C) were produced and characterized. Methotrexate was loaded in these polymeric nanoparticles achieving a drug loading of ca. 14% and an entrapment efficiency of 96, 87 and 80% for 1F/1C; 3F/1C and 5F/1C nanoparticles, respectively. Methotrexate-loaded fucoidan/chitosan nanoparticles exhibited size within the 300-500 nm range, positive zeta potential for 1F/1C nanoparticles (+60 mV) and negative surface charge for the 3F/1C and 5F/1C nanoparticles (-40 and -45 mV, respectively). Methotrexate loaded in 3F/1C and 5F/1C nanoparticles did not affect cells viability and presented lower cytotoxicity than free methotrexate, in fibroblasts and human keratinocytes. MTX loaded fucoidan/chitosan nanoparticles lead to a significant reduction of pro inflammatory cytokines produced by activated human monocytes. Skin permeation studies showed that methotrexate-loaded nanoparticles permeated the pig ear skin barrier reaching after 6 h, a 2.7- and 3.3-fold increase for 3F/1C and 5F/1C nanoparticles, relative to free methotrexate. In conclusion, fucoidan/chitosan nanoparticles, in particular the ratio 5F/1C, is safe, exerts an anti inflammatory effect and increase skin permeation thus can potentially be used for methotrexate topical delivery. PMID- 30521896 TI - Analysis of interaction between sulfated polysaccharides and HIV oligopeptides by surface plasmon resonance. AB - This study aims to quantitatively investigate the interaction between sulfated polysaccharides with potent anti-HIV activity, dextran and curdlan sulfates with negatively charged sulfate groups, and poly-l-lysine as a model protein and oligopeptides from a HIV surface glycoprotein gp120 with positively charged amino acids using surface plasmon resonance (SPR) and dynamic light scattering (DLS) to elucidate the anti-HIV mechanism of sulfated polysaccharides. The apparent association- (ka) and dissociation rate (kd) constants of dextran and curdlan sulfates against poly-l-lysine were ka = 6.92 * 104-2.17 * 106 1/Ms and kd = 4.29 * 10-5-2.22 * 10-4 1/s; these kinetic constants were dependent on the molecular weights and degree of sulfation of sulfated polysaccharides. For interaction, the three oligopeptides from the HIV gp120 were peptide A 297TRPNNNTRKRIRIQRGPGRA316 with several lysine (K) and arginine (R) in the V3 loop region, peptide B 493PLGVAPTKAKRRVVQREKR511 with several K and R in the C-terminus region, and oligopeptide C 362KQSSGGDPEIVTHSFNCGG380 with little basic amino acids in the CD4 binding domain. Sulfated polysaccharides exhibited strong interaction against oligopeptides A and B, (ka = 5.48 * 104-2.96 * 106 1/Ms. and kd = 1.74 * 10-4 6.24 * 10-3 1/s), no interaction was noted against oligopeptide C. Moreover, the particle size and zeta potential by DLS indicated the interaction between sulfated polysaccharides and oligopeptides A and B, suggesting the anti-HIV mechanism of sulfated polysaccharides to be the electrostatic interaction of negatively charged sulfated polysaccharides and HIV at the positively charged amino acid regions. PMID- 30521897 TI - Preparation of thin-film electrolyte from chitosan-containing ionic liquid for application to electric double-layer capacitors. AB - A novel thin-film electrolyte (TFE) based on chitosan (CS) with 1-ethyl-3 methylimidazolium tetrafluoroborate (EMImBF4) was prepared by a new procedure for use as a solid electrolyte in electric double-layer capacitors (EDLCs). In this system, EMImBF4 plays important roles as both a dissolving solution and a charge carrier for EDLC application. By analyzing and characterizing the obtained products, the CS-TFEs showed a surface without CS/EMImBF4 phase separation and with high thermal stability and good tensile properties. The electrochemical properties were measured as the charge-discharge performance, the discharge capacitance, and alternating-current impedance. A test cell with CS-TFE with a calculated dry thin-film content of 80 wt% EMImBF4 showed a comparable IR drop and higher discharge capacitance than a liquid-phase EMImBF4 system and also showed low electrode/electrolyte interfacial resistance. Consequently, this novel CS-TFE is suitable for high-performance EDLCs and improves the safety of such devices. PMID- 30521898 TI - Inhibitory effects of polysaccharide from Diaphragma juglandis fructus on alpha amylase and alpha-d-glucosidase activity, streptozotocin-induced hyperglycemia model, advanced glycation end-products formation, and H2O2-induced oxidative damage. AB - In present study, the in vitro and in vivo hemolysis inhibitory, protective effect against reactive oxygen species (ROS) induced oxidative damage in L02 cells, hypoglycemic, and antiglycation activities of DJP-2, a pure polysaccharide fraction from Diaphragma juglandis fructus, were investigated. Results demonstrated that DJP-2 showed remarkable hemolysis inhibitory activity. Pretreatment with DJP-2 markedly weakened the oxidative damage induced by H2O2 in hepatic L02 cells via strengthening the cell viability. DJP-2 also showed clear in vivo and in vitro hypoglycemic activities. Besides, DJP-2 with the concentration of 3 mg/mL exerted more significant antiglycation activities than aminoguanidine during 30 days of incubation. The results obtained in this study would be beneficial for the application of DJP-2 to treat various diseases related to oxidative stress and AGEs. The elucidation of the potential bioactivities of DJP-2 will facilitate its further study and application in the functional food industry and pharmaceuticals industry. PMID- 30521899 TI - Graft copolymeric flocculant using functionalized starch towards treatment of blast furnace effluent. AB - Herein, a novel binary graft copolymeric flocculant [St-g-(PAAm-co-PMETAC)] has been developed using starch, polyacrylamide (PAAm) and poly (2-methacryloyloxy ethyl trimethyl ammonium chloride) (PMETAC). The copolymer has been synthesised by grafting of PAAm and PMETAC chains on starch backbone using free radical polymerization. FTIR and 1H NMR spectral analyses have been used for structural confirmation of developed copolymer. Determination of molecular weight reveals that after grafting of (PAAm) and (PMETAC) on starch, the molecular weight as well as radius of gyration have been increased as compared to pristine starch. The surface morphology of starch and St-g-(PAAm-co-PMETAC) has been assessed by FESEM analysis. TGA/DTG along with MS analyser is able to track the pre-specified compounds over the entire period of degradation temperature. The synthesised graft copolymer i.e. St-g-(PAAm-co-PMETAC) demonstrates brilliant efficiency as flocculant towards the treatment of blast furnace effluent generated in integrated steel plant. PMID- 30521900 TI - Pilot-scale isolation and characterization of extracellular polymeric substances (EPS) from cell-free medium of Spirulina sp. LEB-18 cultures under outdoor conditions. AB - This objective of this work was to monitor the EPS production during the growth of Spirulina sp. LEB-18, evaluate the productivity and to characterize the exopolymers obtained on pilot-scale under outdoor conditions. The production of crude EPS occurred in all phases of biomass growth and was approximately ten folds higher than that biomass concentration of Spirulina sp. LEB-18 at the end cultivation, demonstrating the importance of the use of supernatant after harvesting of Spirulina to obtain high value bioproducts. The EPS extracted by Spirulina sp. LEB-18 are typically heteropolymers with one high molecular weight fraction (polysaccharides) with potential to be utilized as an alternative bioflocculant and another fraction of lower molecular mass (proteins). The presence of uronic acids, pyruvates and acyl groups of carbohydrates or carboxylic groups of amino acids in protein moiety is the main responsible for overall negative charge of EPS, which is also of biotechnological importance. Moreover, due to the pseudoplastic behavior of the solutions and high thermal stability, the obtained EPS can be widely applied in several industrial sectors, thus determining its technological and market potentiality. PMID- 30521901 TI - Structural characterization, teratogenicity and in vitro avian antimicrobial activity of posterior salivary gland (PSG) toxin from cuttlefish, Sepia prashadi. AB - A low molecular weight posterior salivary gland (PSG) toxin was isolated and purified from the cuttlefish Sepia prashadi by Reverse Phase High Performance Liquid Chromatography (RP-HPLC). The protein and neutral sugar content of the PSG toxin was determined to be 1.033 mg/g and 282 MUg/g. Fourier Transform Infrared (FT-IR) spectroscopy revealed the presence of upsilon-OH, upsilon-CO and delta-NH functional groups. Circular Dichroism (CD) spectroscopy and K2D2 analysis quantified the presence of 38.39% alpha-helix and 9.25% beta-sheet and 52.36% of beta-turn. Matrix Assisted Laser Desorption/Ionization-Time-of Flight/Mass Spectrometry (MALDI-TOF/MS) and MASCOT analysis revealed the amino acid sequence of MEMQSKQQNSKAPANRKIFPWMKTSAVATASKRVEMASLLNLQERQIKIWFQNRMKQKSQQPQTR (1.92 kDa) homologous to homeobox protein H4 of pufferfish, T. rubripes. The PSG toxin showed differential stability with pH and induced premature hatching in Zebrafish eggs and dose dependant developmental malformations in embryos with a Maximum tolerated dose of 1.85 MUM. The PSG toxin exhibited significant antibacterial activity with pronounced zone of inhibition against S. typhimurium (12.94 mm) and inhibited avian RBC binding of Newcastle Disease virus (NDV) at a titre value of 1/4. The present study strongly advocates the biomedical potential of the PSG toxin from S. prashadi and illustrates its promise as a potential avian antimicrobial agent of the future. PMID- 30521902 TI - Polysaccharide from a Tunisian red seaweed Chondrus canaliculatus: Structural characteristics, antioxidant activity and in vivo hemato-nephroprotective properties on maneb induced toxicity. AB - The present study aims to investigate the physicochemical and the structural features of polysaccharide isolated from the red marine macro alga Chondrus canaliculatus (C.C.P) using FT-IR, gel filtration high-pressure chromatograph, HPLC-FID and solid state 13C NMR analysis. C.C.P was even more tested in vitro for its potential antioxidant properties and in vivo for its hemato nephroprotective effects against fungicide - maneb (MB) - induced toxicity. Animals treated for 20 days were allocated into six groups per six rats each: group 1 served as vehicle control, group 2 received MB, group 3 received MB + C.C.P (100 mg/kg), group 4 MB + C.C.P (200 mg/kg), group 5 and 6 used as a positive control groups receiving only C.C.P; one 100 and the other 200 mg/kg, respectively. After MB injection, our data displayed a significant disruption in all hematological parameters associated with clear signs of nephrotoxicity. However, co-treatment with C.C.P at tow graded doses led to an effective healing process against MB's hematological, biochemical, and histological kidney's oxidative injuries. In summary, our data suggest that C.C.P could be a prospective potent antioxidant, nephro and hemato-protective agent. PMID- 30521903 TI - Influence of arabic gum on in vitro starch digestibility and noodle-making quality of Segoami. AB - The effects of arabic gum on the quality attributes of rice noodles were characterized in terms of physical properties as well as in vitro starch digestibility. Segoami (high amylose rice) was used to develop rice noodle with low predicted glycemic index (pGI). First, the processing condition for Segoami noodle was investigated at different levels of water content (100%-175%) and steaming time (1-5 min). The impact of various levels of arabic gum (0.5%-2%) of Segoami noodles was also evaluated. In the results, the optimal processing condition was determined at the condition of 150% water content and 1 min of steaming time, when the lowest cooking loss and highest cohesiveness were observed. The addition of arabic gum (0.5-1.5%) lifted down glucose release curve and significantly reduced pGI of Segoami noodles. The higher level of arabic gum showed the higher cooking loss, but lower hardness and cohesiveness. Consequently, the 1.5% level of arabic gum was most effective in reducing in vitro starch digestibility and improving cooking properties of Segoami noodles. PMID- 30521904 TI - Oxidation of cystatin imparted by riboflavin generated free radicals: Spectral analysis. AB - Thiol Protease inhibitors (cystatins) are endogenous natural inhibitors of cysteine proteases. They are present in all mammalians cells and body fluids. Cystatin are allocated into three major families. Family -I stefins, family -II cystatins and family -III kininogens, according to their amino acid sequence, molecular weight, carbohydrate content and disulphide bonds. It has been investigated that thiol proteases (cathepsin) and their endogenous inhibitor, cystatins have been closely associated with diseases like Alzheimer's, Prions, neurodegenerative diseases, cancer and diabetes. Photodynamic effect of various sensitizers' have long been applied to delineate structural and functional properties of biologically active proteins. Flavins are well known to photo oxidize amino acids which effects conformation of proteins. Riboflavin (Vit B2) with a recommended daily requirement of approximately 2-3 mg is a yellow pigment, It is widely distributed in human tissues and blood, in both free and conjugated forms. In the present Study it has been shown that cystatin purified from buffalo brain (BC) is susceptible to reactive oxygen species generated by photo activation of riboflavin. It was observed that Photo activated riboflavin leads to inactivation of BC. Major Loss of tryptophan intensity was observed in the presence of purified thiol protease inhibitor upon incubation with 50 MUM of riboflavin. In order to inspect the type of reactive oxygen species involved in inactivation of the inhibitor, different scavenger's were used namely glucose, potassium Iodide, sodium azide, manitol, thiourea, sodium benzoate, curcumin, quercetin, ascorbic acid and uric acid. It was found that Glucose, Potassium Iodide and sodium azide, have preventive effect on photo inactivation of the purified cystatin whilst other scavengers illustrated diminutive defensive effect. PMID- 30521905 TI - A paper sizing agent based on leather collagen hydrolysates modified by glycol diglycidyl ether and its compound performance. AB - In this research, collagen hydrolysates with different average molecular weights (Mn-) from leather collagen were chosen as raw materials. Five environmental friendly sizing agents (SA) were prepared by cross-linking collagen hydrolysates with glycol diglycidyl ether (GDE) and further grafting them with butyl acrylate (BA) and styrene (St). Then the compound sizing agents (SGDESA-x, x = 1, 2, 3 and 4) were obtained by simple physical mixing of GDESA and starch. The surface sizing performance of GDESA and compound sizing agents were studied. The research result shows that both physical, mechanical properties and water resistance of the corrugated paper coated by GDESA were significantly improved when Mn- of collagen hydrolysate was about 10,000, and its emulsion exhibited robust stability in long standing time. Furthermore, when the SGDESA-2 was used as a sizing agent, the coated corrugated paper exhibited strong water resistance, good physical and mechanical properties even after refolded for 20 times. PMID- 30521906 TI - Combined synergetic potential of metformin loaded pectin-chitosan biohybrids nanoparticle for NIDDM. AB - RATIONALE: Combined therapy is a promising approach over its preference to minimize the dose, adverse effects and enhanced therapeutic efficiency in a various diseases including diabetes. AIM: The present research work is to explore combined synergistic anti-diabetic potential of chitosan and pectin with Metformin (CPM) nano-formulation, with special emphasis on effect of Metformin when integrated with bio polymers. METHODS: The biohybrid nanoparticles (CPMNP) were formulated by ionic gelation process. The optimized formulation was examined various in vitro characterizations, in vivo anti-diabetic potential, biodistribution and targeting efficiency. RESULTS: The optimized biohybrid showed higher content of Metformin 92.1 +/- 3.3% and extended release. The pectin coated nanoparticles had smooth spherical morphology with 581.8 nm size and positive surface charge (+41.76 mV). The biohybrid regulated blood glucose, improved the glucose utilization in vital organs, control the dyslipdimea and renal impairment in diabetic rats. CPMNP-4 significantly enhanced the up regulation of IRA, GLUT-2 and GK receptor gene expression and down regulate the TNF-alpha and IL-6 in pancreas. Also, nanoparticles showed healthier biodistribution simultaneously capability to penetrate in vital organs. CONCLUSION: The combined synergistic effects of Metformin and biopolymers are due their corresponding mechanism to enhance glucose uptake, minimized the adverse effects during diabetic therapy. PMID- 30521907 TI - In vitro fermentation of O-acetyl-arabinoxylan from bamboo shavings by human colonic microbiota. AB - BSH-1 is an O-acetyl-arabinoxylan obtained from bamboo shavings. This study investigated its fermentation behavior by human colonic bacteria in vitro. Results showed that BSH-1 remarkably modulated the composition of colonic microbiota, mainly by increasing the growth of potential beneficial genera (i.e. Bifidobacterium, Lactobacillus, Bacteroides, Prevotella_7, Parabacteroides) and by decreasing the growth of potential harmful genera (i.e. Fusobacterium, Lachnospiraceae_UCG-008, Bilophila and Desulfovibrio). BSH-1 significantly promoted the production of short-chain fatty acids, especially acetic, propionic and n-butyric acids. After 48 h fermentation, the concentration of n-butyric acid in BSH-1 fermentation culture was increased by 2.41 times compared to the blank. During fermentation, the activity of acetyl xylan esterase, arabinofuranosidase, xylanase and xylosidase was enhanced. Moreover, free arabinose, xylose, xylobiose, xylotriose, xylotetraose, xylopentaose and xylohexaose were detected. These results suggest that BSH-1 could potentially be a functional ingredient to improve gut health. PMID- 30521908 TI - Chitosan-graft-poly(N-hydroxy ethyl acrylamide) copolymers: Synthesis, characterization and preliminary blood compatibility in vitro. AB - Poly(N-hydroxy ethyl acrylamide) was grafted onto chitosan in aqueous acidic medium using potassium per sulphate initiator to obtain polymer surfaces with blood compatibility for potential biomedical applications. Thermally cross-linked products were obtained upon drying at 60 degrees C overnight. Chemically cross linked films were prepared using methylene bis acrylamide (MBA) cross-linker. The products were characterized by FTIR, XRD and SEM analyses. Protein adsorption onto the film surfaces gave, on the average, 30% bovine serum albumin (BSA) and 10% human serum albumin (HSA) removal from aqueous solution, in vitro. Blood compatibility was evaluated with respect to activated prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet adhesion. PT and APTT values remained within normal ranges after blood-polymer contact, with chitosan graft-polyHEAA films, in vitro. Chitosan-graft-MBA or chitosan-graft (polyHEAA;MBA), and blank chitosan films produced higher PT and APTT values under similar experimental conditions with chitosan-graft-polyHEAA films, exhibiting blood anticoagulant activity. SEM pictures taken before and after contact with blood sample did not reveal any significant blood component adhesion on the chitosan-graft-(polyHEAA;MBA) film surface contrary to the observation made on the blank chitosan film. PMID- 30521909 TI - Enhancement of the carbohydrate content in Spirulina by applying CO2, thermoelectric fly ashes and reduced nitrogen supply. AB - This study focused on evaluating whether the injection of CO2, which is associated with the use of thermoelectric fly ashes and a reduced supply of nitrogen, affects the production of intracellular carbohydrates from Spirulina. For this purpose, the addition of 0.25 g L-1 of NaNO3, along with a 10% (v v-1) of CO2 injection, a flow rate of 0.3 vvm for 1 or 5 min, as well as 0, 120 and 160 ppm of fly ashes, was studied. The assays with 120 ppm of fly ashes presented the best kinetic parameters and CO2 biofixation rate, regardless of the CO2 injection time. Meanwhile, the experiments with 120 and 160 ppm of fly ash and CO2 injection for 1 min presented 63.3 and 61.0% (w w-1) of carbohydrates, respectively. Thus, this study represents an important strategy to increase the accumulation of carbohydrates in Spirulina, with potential application in the production of bioethanol. PMID- 30521910 TI - Study of the selenizing Codonopsis pilosula polysaccharides protects RAW264.7 cells from hydrogen peroxide-induced injury. AB - Codonopsis pilosula polysaccharides (CPPS) has been shown to possess a variety of biological activities. In previous study, CPPS was successfully modified to obtain its best selenizing Codonopsis pilosula polysaccharides (sCPPS5). The purpose of this study was to investigate the protective effect of the selenizing derivative of CPPS (sCPPS5) from H2O2-induced oxidative damage in RAW264.7 murine macrophages and the possible mechanism of this protection. Results showed that the sCPPS5 was significantly stronger than that of the corresponding unmodified polysaccharide, CPPS. Meanwhile, sCPPS5 treatment could improve the production of reactive oxygen species (ROS), antioxidant enzyme, MMP, caspases-3 and apoptosis capacity of H2O2-induced RAW264.7 cells. Moreover, the mechanism might be elucidated that sCPPS5 could increase expression level of Nrf2 and its downstream ARE gene battery, promote production of corresponding antioxidative enzymes and protein, and enhance Keap1-Nrf2/ARE signaling pathway to avoid male reproductive dysfunction. Overall, these results showed that sCPPS5 as a potent antioxidant could reduce reproductive oxidative stress damage related to Keap1-Nrf2/ARE pathway. PMID- 30521911 TI - Geodorum densiflorum rhizome lectin inhibits Ehrlich ascites carcinoma cell growth by inducing apoptosis through the regulation of BAX, p53 and NF-kappaB genes expression. AB - A lectin with a molecular mass of 12 +/- 1 kDa was isolated for the first time from Geodorum densiflorum (Lam.) rhizome (GDL). The lectin exhibited hemagglutination activity both in mice and human erythrocytes which was inhibited by 4-nitrophenyl-beta-D-glucopyranoside among the tested 26 sugars. The lectin was heat stable and showed its full activity in the pH range from 5.0 to 9.0. The lectin did not lose its activity in the presence of urea but the activity lost significantly when treated with EDTA. Divalent cation Ca2+ and Mg2+ also partially inhibited the activity of the lectin. The lectin strongly agglutinated Ehrlich ascites carcinoma (EAC) and inhibited the cells growth by 60% at 160 MUg/ml protein concentration but unable to inhibit the growth of HeLa cells in vitro. The growth inhibition was due to the induction of apoptosis in the EAC cells which was confirmed by annexin-V and caspase-3 substrate and finally by apoptosis-related genes expression. An intensive expression of anti-apoptotic Bcl X gene was observed only in untreated EAC cells while pro-apoptotic Bak and Bax genes expressed only in GDL treated EAC cells with the remarkable increase of the p53 gene expression. In the treated EAC cells NFkappaB expression was down regulated. PMID- 30521912 TI - Tuning the ring strain effect in acridine derivatives on binding affinity with G quadruplex-DNA: A computational and experimental study. AB - Search for inhibitors to stabilize the telomeric G-quadruplex in order to deter telomerase activity is an active area of research. Inhibitors play an important role to initiate the tumor cell mortalization process. This work reports for the first time of acridine derivative with four membered ammonium rings at the side chain to surpass the binding ability against BRACO-19 with G-quadruplex-DNA. It is known in the literature that acridine based molecule BRACO-19 can effectively bind with G-quadruplex-DNA. The computational study performed in this study revealed that the binding ability of acridine based molecule can be augmented with subtle variation in the molecular structure of the drug like candidates. Steered molecular dynamics (SMD) performed with the acridine derivatives and G quadruplex DNA showed the importance of ring strain to the side chain of those ligand molecules. The rupture force analysis, hydrogen bonding interactions and the calculated free energies in MM-PBSA method suggest that ligand 3 is superior than that of BRACO-19. The synthesized ligand 3 and BRACO-19 showed the binding constants obtained from ITC measurements are 4 * 106 mol-1 and 2.6 * 106, which corroborates the computational findings. PMID- 30521913 TI - Ammonium persulphate induced synthesis of polymethyl methacrylate grafted sodium alginate composite films with high strength for food packaging. AB - The graft copolymerization of methyl methacrylate (MMA) onto alginate was carried out in aqueous media by initiators of ammonium persulphate under a nitrogen gas atmosphere. Then, the grafting of PMMA chains onto the alginate backbone was confirmed through the study of Fourier transform infrared, X-ray diffraction, scanning electron microscopy and 1H nuclear magnetic resonance spectroscopy. At last, a thin and transparent polymethyl methacrylate grafted alginate film with high strength was obtained by the casting method. The effect of MMA/SA ratio or percentage of graft (G%) on mechanical properties, thermal stability (thermogravimetric analysis/differential thermogravimetry analyses), color, opacity and water resistance of composite films were characterized. Results showed the homogeneous transparent films could be obtained while G% was lower than 8.64%. After being grafted by PMMA, the tensile strength of the films was distinctly improved by 205.4%, as well the elongation at break (E%) by 41.7% while the MMA/SA (g/g) is 0.3. On the other hand, water resistance, thermal stability and crystallinity of the films were improved, however, the transparency was slightly decreased. PMID- 30521914 TI - Anticoagulant activity of two novel polysaccharides from flowers of Apocynum venetum L. AB - Two novel polysaccharides were obtained from flowers of Apocynum venetum L., and named as Vp2a-II and Vp3. Their average molecular weights were 7 kDa and 9 kDa, respectively. Methods of monosaccharide analysis, acid hydrolysis and methylation analysis, Fourier transform-infrared spectroscopy (FT-IR), gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to identify the structure of Vp2a-II and Vp3. Vp2a-II was composed of ->6) beta-d-Glcp-(1 -> 6)-alpha-d-Galp-(1-> residues. Vp3 was composed of alpha-d GlcpA-(3 -> alpha-d-GalpA residues. The anticoagulant activity was evaluated by activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), and fibrinogen (FIB) assays in vitro. Results indicated that Vp3 exhibited the anticoagulant activity. PMID- 30521915 TI - One-pot carbonization of chitosan/P123/PdCl2 blend hydrogel membranes to N-doped carbon supported Pd catalytic composites for Ullmann reactions. AB - Novel porous nitrogen-doped carbon supported Pd (Pd@N-C) catalytic composites were prepared by one-pot thermal carbonization of chitosan/poly(ethylene glycol) block-poly(propylene glycol)-block-poly(ethylene glycol)/PdCl2 (CS/P123/PdCl2) blend hydrogel membranes at different temperature in N2 atmosphere. The porous structure of the Pd@N-C catalytic composite was governed by both the addition of P123 and the carbonization temperature. At highest carbonization temperature of 900 degrees C, the prepared Pd@N-C catalytic composite from CS/P123/PdCl2 blend membrane showed the highest specific area (SBET) of 293.7 m2/g and total volume of pores (Vtot) of 0.79 cm3/g. The chemical state of the elements of C, N, O, Pd within the Pd@N-C catalytic composites were confirmed with X-ray photoelectron spectroscopy (XPS) measurements. Raman spectrum results showed that the prepared Pd@N-C catalytic composite contained mainly disordered carbon together with some graphite carbon. Pd nanoparticles sized in 5-20 nm dispersed well on the porous matrix of the carbon. The Pd@N-C catalytic composites showed excellent activities for the Ullmann homo-coupling reactions of aromatic halides, and can be recycled for 10 times. In such one-pot carbonization process, the polymer porogen is simultaneously decomposed without further etching and removal steps, which simplifies the preparation process and is beneficial to obtain Pd@N-C catalytic composites with desirable Pd loading. PMID- 30521916 TI - Mechanically magnified chitosan-based hydrogel as tissue adhesive and antimicrobial candidate. AB - The present article reports the development of chitosan (CS) based hydrogel series by varying the concentration of cross-linking agent i.e. N,N' methylenebisacrylamide (MBA) (0.8-1.4 wt%) via free-radical polymerization in aqueous medium. SEM image analysis confirmed the presence of porous 3D-network in the hydrogel. Prepared hydrogel series exhibited good tissue adhesive property along with antimicrobial activity against E. coli, K. pneumonia, S. aureus, C. albicans &M. gypseum bacteria with the good MIC (4-20 mm). The adhesive strength of hydrogel was found 14 kPa, which seems to be quite efficient in tissue adhesiveness applications, which was also validated and tested on Drosophila (Oregon-R) tissues, results were promising. Magnified mechanical strength i.e. storage modulus (G') and loss modulus (G") were found 106 Pa and 104 Pa, respectively, which makes the hydrogel a potential candidate in the biomedical field. Moreover, CS hydrogel showed good swelling ratio in aqueous medium up to 390% at room temperature. PMID- 30521917 TI - The polyphenolic-polysaccharide complex of Agrimonia eupatoria L. as an indirect thrombin inhibitor - isolation and chemical characterization. AB - The polyphenolic-polysaccharide complex was isolated from the dried aerial parts of the medicinal plant Agrimonia eupatoria L. using a multi-step process involving the degreasing of the plant material by extraction with organic solvents, followed by extraction with hot alkali, neutralization, further separation with organic solvents and dialysis. The complex was homogeneous with a molecular weight of about 55 * 103 g/mol and consisted mainly of carbohydrates and polyphenols matrix, composed of lignin-related units, with the dominance of dimethoxyphenyl structures. The carbohydrate moiety consists mostly of arabinogalactan associated with highly esterified rhamnogalacturonan. In vitro anticoagulant studies revealed the ability of the A. eupatoria complex to inhibit plasma clot formation, mainly in the intrinsic pathway of the blood coagulation cascade. Further studies on the mechanisms of this anticoagulant activity revealed that the isolate was primarily an indirect inhibitor of thrombin, mediated by antithrombin or by heparin cofactor II. Such mechanism of action is characteristic for highly sulfated glycosaminoglycans. PMID- 30521918 TI - Mulberry leaf polysaccharides suppress renal fibrosis. AB - A mulberry leaf polysaccharide (MLP-1) was prepared and partially characterised, and its anti-renal-fibrosis effects were investigated in streptozotocin (STZ) induced diabetic nephropathy (DN) rats. MLP-1, with a molecular weight of 2,792,624 Da, consisted of arabinose, glucose, xylose, rhamnose, and mannose in a molar ratio of 1:1.13:2.35:6.74:8.85. Intraperitoneal injection of MLP-1 (2 mL; 0.2-0.4 g/mL) daily for 8 weeks significantly decreased serum insulin, fasting blood glucose, and 24 h urinary albumin, as well as urine protein and connective tissue growth factors, of STZ-induced DN rats. All these results indicated that MLP-1 can effectively inhibit renal fibrosis and potentially treat DN. PMID- 30521919 TI - Polyethylene glycol-decorated doxorubicin/carboxymethyl chitosan/gold nanocomplex for reducing drug efflux in cancer cells and extending circulation in blood stream. AB - Polyethylene glycol (PEG)-decorated doxorubicin (Dox)/carboxymethyl chitosan (CMC)/gold nanoparticles (AuNPs) have been developed for cancer therapy. CMC was used as a reducing and stabilizing agent for the fabrication of AuNPs and Dox was loaded onto AuNPs as a chemotherapeutic agent. Dox-loaded CMC-stabilized AuNPs (Dox/CMC-AuNPs) with a mean diameter of 104.0 nm, zeta potential of -48.32 mV, and drug loading efficiency of 60.14% were prepared. PEG was attached to CMC AuNPs for enhancing systemic drug exposure and prolonging the circulation in blood stream. Compared with Dox/CMC-AuNPs, Dox-loaded PEGylated CMC-AuNPs (Dox/CMC-AuNPs-PEG) showed a reduced hydrodynamic size (71.2 nm), less negative zeta potential (-12.83 mV), and an enhanced Dox loading efficiency (73.14%). Dox/CMC-AuNPs and Dox/CMC-AuNPs-PEG exhibited sustained and pH-dependent drug release profiles and exhibited antiproliferation effects against the A549 cells. In a bi-directional transport study of Caco-2 cell monolayers, AuNPs reduced the efflux ratio, which indicated that the P-glycoprotein-mediated multidrug resistance (MDR) was overcome. Dox/CMC-AuNPs-PEG resulted in reduced drug clearance (CL) and improved half-life (t1/2), compared with Dox/CMC-AuNPs, in rats after intravenous administration. These results suggest that Dox/CMC-AuNPs PEG could be a promising nanotherapeutic approach to overcome MDR in cancer and prolong their circulation in the blood stream. PMID- 30521920 TI - Preparation and characterization of poly(epsilon-caprolactone) scaffolds modified with cell-loaded fibrin gel. AB - Poly(epsilon-caprolactone) (PCL) is one of the most commonly used polymers in the production of tissue engineered scaffolds for hard tissue treatments. Incorporation of cells into these scaffolds significantly enhances the healing rate of the tissue. In this study, PCL scaffolds were prepared by wet spinning technique and modified by addition of fibrinogen in order to form a fibrin network between the PCL fibers. By this way, scaffolds would have micro- and nanofibers in their structures. Drying of the wet spun constructs was achieved by application of ethanol dehydration or freeze drying techniques. Fibrinogen solutions (as low: 2 mg/mL; or high: 10 mg/mL concentrations) were added onto the scaffolds and fibrin formation was achieved via fibrinogen crosslinking. Results showed that ethanol dehydration led to film-like coating on the fibers while freeze-drying led to nanofiber bridges between PCL fibers establishing an interconnected web in the structure. Mechanical properties of the scaffolds were improved in the presence of the fibrin net. After the seeding of Saos-2 cells, higher attachment and homogeneous distribution of the cells was achieved on the samples modified with high concentration of fibrinogen. These scaffolds can be good candidates for the treatment of problematic bone defects. PMID- 30521921 TI - Influence of alkali treatment on physicochemical, pasting, morphological and structural properties of mango kernel starches derived from Indian cultivars. AB - Present investigation was aimed to characterize the influence of alkali treatment on physicochemical, pasting, morphological and structural properties of mango kernel starches from three cultivars viz. Safeda, Chausa, Dussheri when treated with 0.1, 0.25 and 0.5% NaOH for 0, 5 and 10 days at 25 degrees C. Alkali treated starches have shown significant reduction (p < 0.05) in water binding capacity and amylose content whereas significant increase was observed in solubility and swelling power when compared with their native counterparts. Pasting properties of modified starches have shown significant changes from their respective native ones with highest reduction observed in Dussheri. Morphology was slightly affected by alkali treatment reflected as dents and grooves on the surface of starch granules. X-ray diffraction patterns were typically A-type, similar to native starches with decrease in crystallinities. IR spectra remained unaffected even after prolonged treatment. Thus, the time duration and concentration of alkali had played critical role in changing the physicochemical, pasting and morphological properties of mango kernel starches that could be potentially utilized for application in innovative products to enhance their textural and sensory attributes. PMID- 30521922 TI - Characterization of polysaccharides isolated from Periploca angustifolia and its antioxidant activity and renoprotective potential against cadmium induced toxicity in HEK293 cells and rat kidney. AB - Periploca angustifolia has numerous biological properties and also used against various diseases. In our study, this plant has been used for biotechnological production of polysaccharides. The prevention action of polysaccharides isolated from P. angustifolia (PAPS) against Cd-caused oxidative stress in HEK293 cells and kidneys of rats was tested. PAPS were characterized by HPLC, FT-IT, DRX, 1D and 2D-MNR. PAPS present strong capacity to slow the rate of lipid peroxidation and protein glycation in vitro. In addition, the results indicated that the Cd treatment caused a significant decrease in HEK293 cells viability which wasattenuated by PAPS pre-treatment. Furthermore, our findings revealed that Cd injection increased the levels of urea and creatinine in the serum. The increased levels of protein oxidation and lipid peroxidation along with decreased activities of SOD, CAT and GPx were significantly (p < 0.01) ameliorated by PAPS pre-treatment. Finally, histopathological studies also supported the prevention action of PAPS. PMID- 30521923 TI - Medium composition optimization, structural characterization, and antioxidant activity of exopolysaccharides from the medicinal mushroom Ganoderma lingzhi. AB - To contribute towards effective exploitation and utilization of natural antioxidants, response surface methodology (RSM) was employed to optimize the medium composition for the production of exopolysaccharides from the medicinal mushroom Ganoderma lingzhi (GLEPS). An optimal medium for GLEPS production was gave through Plackett-Burman design, path of steepest ascent, and Box-Behnken design as follows: glucose (59.62 g/L), yeast extract (10.03 g/L), CaCO3 (0.2 g/L), thiamine (45.13 mg/L), KH2PO4 (1.0 g/L), peptone (1.5 g/L), Tween 80 (10.26 mL/L), ZnSO4 (0.3 g/L), mannitol (1.5 g/L), MgSO4 (0.5 g/L), and aspartate (8.86 g/L). The GLEPS yield obtained was 3.57 +/- 0.21 g/L-3.16-fold higher than that produced in basal medium alone. The resulting GLEPS rich in uronic acid, d mannose, l-rhamnose, and d-glucose, was a heteropolysaccharide with high molecular weights (475,000 kDa and 21.6 kDa, 87.97%). It was demonstrated that the GLEPS with higher carbohydrate and uronic acid contents exhibited strong in vitro antioxidant activities via radical scavenging, reductive capacity, and chelation of transition metal catalysis. These findings indicated that RSM is an efficient tool to predict the composition of culture medium required for maximizing GLEPS yield, and GLEPS had potent antioxidant activities and could be explored as a novel natural antioxidant in functional food or medicine. PMID- 30521924 TI - Exploring potential new galactomannan source of Retama reatam seeds for food, cosmetic and pharmaceuticals: Characterization and physical, emulsifying and antidiabetic properties. AB - In this study, physicochemical, interfacial and emulsifying properties of Retama reatam and guar galactomannans were comparatively investigated. The results showed that Retama reatam galactomannan is mainly composed of total carbohydrates (95.52%) and lower protein contents (0.87%). The sugars identified were mannose (Man) and galactose (Gal), with a Man:Gal ratio of 1.85 compared to guar gum (1.83). The results of thermal properties indicated were transition temperature (Tg) and melting temperature (Tm) very similar to those of the guar gum. Moreover, results also revealed that there is no significant difference in terms of equilibrium interfacial tension of Retama reatam gum at 10 and 20 degrees C. Moreover, preliminary tests show that stable oil-in-water nanoemulsions may be formulated using Retama reatam gum. Therefore, measurement of mean oil droplet diameter d (Wu et al., 2009; Huang et al., 2001) after heating at 80 degrees C, shows that stable nanoemulsions may be formulated using Retama reatam galactomannan. Further in vivo experiments confirmed that Retama reatam gum can reduce the glycemic index of starchy foods and inhibit the surge of postprandial blood glucose level. PMID- 30521925 TI - Loss of K607 and E877 interaction is a key reason for JAK2 K607N mutation caused acute myeloid leukemia. AB - Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. The acquired Janus kinase 2 (JAK2) K607N somatic mutation was detected in about 6.8% of acute myeloid leukemia (AML) patients. However, roles of JAK2 K607N mutation in the leukemogenesis of AML remain unclear. In this study, loss of interaction between K607 and E877 was identified as key reasons for JAK2 K607N mutation constitutive activation. JAK2 K607N and mutations (K607A, K607G and E877A) abolished the K607 and E877 interaction caused JAK2 constitutive activation. While, mutations (K607R, E877D) repairing this interaction reduced K607N mutation's activity. Furthermore, our studies showed that disruption of K607 and E877 interaction abolished JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, JAK2 K607N and mutations disrupted this interaction enhanced JAK2-STAT5 pathway activation and the proliferation of Ba/F3 cells. Thus our studies provide clues in understanding the leukemogenesis of JAK2 K607N mutation in AML. PMID- 30521926 TI - Nano-encapsulation using macrocyclic carbohydrate polymers (beta-cyclodextrins) of Periploca angustifolia extract: Physical stability and protective effect against cadmium-induced alterations in HepG2 cells. AB - The nano-encapsulation of Periploca angustifolia phenolic extract using the macrocyclic carbohydrate polymers (beta-cyclodextrins) is a most approach compared with other encapsulation methods. In this work, the beta-Cyclodextrins PAE complex stability has been evaluated by advanced analytical methods and techniques including HPLC, FTIR and XRD. The results showed that CdCl2 treatment caused a significant decrease in cell viability. The CdCl2-induced damage in the HepG2 cells were significantly ameliorated (p < 0.001) by treatment of the PAE and beta-Cyclodextrins-PAE complex. Thus, pretreatment with 100 MUg mL-1 of beta Cyclodextrins-PAE complex significantly protect HepG2 cells against cytotoxicity induced by cadmium exposure more effectively than PAE only. However, Cd intoxication significantly (p < 0.001) increased these enzymes activity. Additionally, reactive oxygen species generation was significantly decreased when cells were treated with nano-encapsulation PAE. The levels of supernatant antioxidant parameters including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and GSH were significantly (p < 0.001) decreased in Cd-treated cells with concomitant enhancement of lipid peroxidation. In addition, beta-Cyclodextrins-PAE pretreatment significantly (p < 0.01) inhibited Cd exposure activated the apoptotic pathway caspace-3 and caspace-9. This effect may be due to the ability of beta-Cyclodextrins molecules to enhance stability and permeability properties. PMID- 30521927 TI - Preparation and optimization of poly (lactic acid) nanoparticles loaded with fisetin to improve anti-cancer therapy. AB - Fisetin is a natural flavonoid with promising antitumor activity, whereas its clinical application is limited by its hydrophobic property. In this study, we aimed to load fisetin into poly(lactic acid) (PLA) nanoparticles to increase fisetin's solubility and therapeutic efficacy. Based on spontaneous emulsification solvent diffusion (SESD) method, the formulation of PLA nanoparticles was optimized by two successive experimental designs. One-factor-at a-time variation experiments were first applied to investigate the effects of four process variables on three responses, including drug encapsulation efficiency, average particles size and cumulative drug release ratio, followed by determining the possible ranges of these variables. Subsequently, the combinations of four variables at best levels were evaluated using a Taguchi orthogonal array design with regard to the same three responses. Eventually, the nanoparticle prepared by optimized procedure showed a narrow size distribution around 226.85 +/- 4.78 nm with a high encapsulation efficiency of 90.35%. The incorporation of fisetin in nanoparticles was subsequently confirmed by FT-IR and DSC spectroscopy. Furthermore, cytotoxicity assay against HCT116 colon cancer cells in vitro and antitumor test in a xenograft 4T1 breast cancer model in vivo demonstrated that the antitumor effect of drug-loaded nanoparticles was superior to that of free drug solution. PMID- 30521928 TI - Enhanced anxiety-like behavior emerges with weight gain in male and female obesity-susceptible rats. AB - Epidemiological data suggest that body mass index and obesity are strong risk factors for depression and anxiety. However, it is difficult to separate cause from effect, as predisposition to obesity may enhance susceptibility to anxiety, or vice versa. Here, we examined the effect of diet and obesity on anxiety-like behaviors in male and female selectively bred obesity-prone and obesity-resistant rats, and outbred Sprague-Dawley rats. We found that when obesity-prone and obesity-resistant rats do not differ in weight or fat mass, measures of anxiety like behavior in the elevated plus maze and open field are similar between the two groups. However, once weight and fat mass diverge, group differences emerge, with greater anxiety in obesity-prone relative to obesity-resistant rats. This same pattern was observed for males and females. Interestingly, even when obesity resistant rats were "forced" to gain fat mass comparable to obesity-prone rats (via prolonged access to 60% high-fat diet), anxiety-like behaviors did not differ from lean chow fed controls. In addition, a positive correlation between anxiety-like behaviors and adiposity were observed in male but not in female obesity-prone rats. Finally, diet-induced weight gain in and of itself was not sufficient to increase measures of anxiety in outbred male rats. Together, these data suggest that interactions between susceptibility to obesity and physiological alterations accompanying weight gain may contribute to the development of enhanced anxiety. PMID- 30521929 TI - Maternal and paternal origin differentially affect prosocial behavior and neural mechanisms in prairie voles. AB - This study tested the hypotheses that maternal and paternal effects differentially influence expression of their offspring's adult behavior and underlying neural mechanisms. We predicted that maternal influences would be greater than paternal influences on male offspring. We tested these hypotheses by cross-breeding two phenotypically-, behaviorally- and neuroanatomically-distinct populations of prairie voles (Microtus ochrogaster) from Illinois, which are highly prosocial, and Kansas, which are significantly less prosocial. Females from each population were crossed with males from the other population. F1 crosses were tested as adults to determine the effect of parentage on the expression of prosocial behavior and aggression, using a same-sex dyadic encounter and a heterosexual partner preference test, and for the expression of oxytocin (OT) and arginine vasopressin (AVP) in the paraventricular nucleus of the hypothalamus (PVN). As predicted, all significant differences in males, behavioral, OT and AVP immunoreactivity, were associated exclusively with maternal influences. There was a significant effect of treatment in the OT immunoreactivity of females. The effect of treatment in females' OT was associated with an interaction of population and sex, while same-sex social interactions differences were associated with population. Finally, in females, paternity influenced heterosexual bonds, with females with Illinois sires forming a partner preference. The results indicate that maternal influences dominate in male offspring, suggesting a parent-of-origin effect, while paternal effects are limited to selected prosocial behavioral expression in daughters. PMID- 30521930 TI - The allosteric dopamine D1 receptor potentiator, DETQ, ameliorates subchronic phencyclidine-induced object recognition memory deficits and enhances cortical acetylcholine efflux in male humanized D1 receptor knock-in mice. AB - Diminished dopamine D1 stimulation may contribute to cognitive impairment in Alzheimer's and Parkinson's diseases, schizophrenia, and other neuropsychiatric disorders. However, orthosteric D1 receptor (D1R) agonists produce receptor desensitization and an inverted U-shaped dose-response curve, but positive allosteric modulators (PAMs) do not. We examined the cognitive effects of DETQ, a D1R PAM, in mice genetically modified to express the human D1 receptor ("hD1 mice"). Phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate receptor antagonist, dosed seven days (subchronic), followed by withdrawal, produced a prolonged deficit in novel object recognition (NOR) memory, which was reversed by acute treatment with DETQ, with no evidence for an inverted U-shaped response. This was blocked by the D1R antagonist, SCH391660. Single doses of D1R agonists, SKF38393 and SKF82958, and the acetylcholinesterase inhibitor, rivastigmine, alone and the combination of subeffective doses of both, also restored NOR in both subchronic PCP-treated in hD1 mice. DETQ increased cortical and hippocampal acetylcholine efflux after both acute and subchronic dosing in hD1 mice. Subchronic but not acute DETQ, inhibited glutamate and GABA efflux. DETQ-induced acetylcholine efflux was absent in subchronic PCP-treated mice, indicating that restoration of NOR in subchronic PCP-treated mice does not require cortical acetylcholine efflux. This is additional evidence that DETQ stimulates D1R without producing an inverted-U-shaped response curve and increases neurotransmitter release in the mPFC and HIP without causing tolerance. The ability of D1 PAMs to improve cognition in humans with neuropsychiatric disorders without evidence of tolerance or an inverted-U-shaped response curve needs to be established clinically. PMID- 30521931 TI - 22kHz and 55kHz ultrasonic vocalizations differentially influence neural and behavioral outcomes: Implications for modeling anxiety via auditory stimuli in the rat. AB - The communicative role of ultrasonic vocalizations (USVs) in rats is well established, with distinct USVs indicative of different affective states. USVs in the 22 kHz range are typically emitted by adult rats when in anxiety- or fear provoking situations (e.g. predator odor, social defeat), while 55 kHz range USVs are typically emitted in appetitive situations (e.g., play, anticipation of reward). Previous work indicates that USVs (real-time and playback) can effectively communicate these affective states and influence changes in behavior and neural activity of the receiver. Changes in cFos activation following 22 kHz USVs have been seen in cortical and limbic regions involved in anxiety, including the basolateral amygdala (BLA). However, it is unclear how USV playback influences cFos activity within the bed nucleus of the stria terminalis (BNST), a region also thought to be critical in processing anxiety-related information, and the nucleus accumbens, a region associated with reward. The present work sought to characterize distinct behavioral, physiological, and neural responses in rats presented with aversive (22 kHz) compared to appetitive (55 kHz) USVs or silence. Our findings show that rats exposed to 22 kHz USVs: 1) engage in anxiety-like behaviors in the elevated zero maze, and 2) show distinct patterns of cFos activation within the BLA and BNST that contrast those seen in 55 kHz playback and silence. Specifically, 22 kHz USVs increased cFos density in the anterodorsal nuclei, while 55 kHz playback increased cFos in the oval nucleus of the BNST, without significant changes within the nucleus accumbens. These results provide important groundwork for leveraging ethologically-relevant stimuli in the rat to improve our understanding of anxiety-related responses in both typical and pathological populations. PMID- 30521932 TI - Lipopolysaccharide (LPS) induced sickness in early adolescence alters the behavioral effects of the short-chain fatty acid, propionic acid, in late adolescence and adulthood: Examining anxiety and startle reactivity. AB - Early life immune challenges are risk factors for neurodevelopmental disorders. In adolescence, they elicit behavioral symptoms that resemble clinical disorders. Stressors during this time may alter signaling from the gut microbiome, which increases the risk for psychiatric disorders. It was hypothesized that adolescent immune challenges may interact with a gut bacterial product, the short-chain fatty acid, propionic acid (PPA), to potentiate symptoms of anxiety and sensory abnormality. The present study investigated the effects of repeated lipopolysaccharide (LPS) exposure during early adolescence, on the behavioral effects of PPA in late adolescence and adulthood. Male adolescent rats were injected with LPS (0.2 mg/kg i.p.) or the vehicle on postnatal days (P) 28, P30, P32, and P34. They were later administered either PPA (500 mg/kg i.p.) or the vehicle during late adolescence on P40 and P43, and were subsequently tested on the light-dark anxiety test and acoustic startle response, respectively. In adulthood, the rats were again injected with PPA or the vehicle and tested on the light-dark and acoustic startle tasks on P74 and P77. The results of this study showed that LPS and PPA both decreased locomotor activity. PPA reduced vertical activity, percent prepulse inhibition, and acoustic startle response magnitude. LPS increased anxiogenic behaviors and induced a delayed increase in acoustic startle response magnitude in adulthood. Although no LPS and PPA interactions were found, the results of this study suggest that early adolescent immune activation can induce long-term behavioral changes that resemble the complex phenotypes of clinical disorders. PMID- 30521933 TI - Social context-dependent singing alters molecular markers of dopaminergic and glutamatergic signaling in finch basal ganglia Area X. AB - Dopamine (DA) is an important neuromodulator of motor control across species. In zebra finches, DA levels vary in song nucleus Area X depending upon social context. DA levels are high and song output is less variable when a male finch sings to a female (female directed, FD) compared to when he is singing by himself (undirected, UD). DA modulates glutamatergic input onto cortico-striatal synapses in Area X via N-methyl-D-aspartate (NMDA) and DA receptor mechanisms, but the relationship to UD vs. FD song output is unclear. Here, we investigate the expression of molecular markers of dopaminergic and glutamatergic synaptic transmission (tyrosine hydroxylase - TH, alpha-synuclein - alpha-syn) and plasticity (NMDA 2B receptor - GRIN2B) following singing (UD vs. FD) and non singing states to understand the molecular mechanisms driving differences in song output. We identified relationships between protein levels for these biomarkers in Area X based on singing state and the amount of song, measured as the number of motifs and time spent singing. UD song amount drove increases in TH, alpha syn, and NMDA 2B receptor protein levels. By contrast, the amount of FD song did not alter TH and NMDA 2B receptor expression. Levels of alpha-syn showed differential expression patterns based on UD vs. FD song, consistent with its role in modulating synaptic transmission. We propose a molecular pathway model to explain how social context and amount of song are important drivers of molecular changes required for synaptic transmission and plasticity. PMID- 30521934 TI - Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson's disease. AB - This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson's disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 post-lesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with L-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with L-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic L-dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesion-induced anxiety-like behaviour. We did not report any effect of chronic L-dopa exposure in the context of partial nigral cell loss. PMID- 30521935 TI - Pharmaceutical cocrystals: from serendipity to design to application. AB - The field of pharmaceutical cocrystals has reached a tipping point, particularly because cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit. Accounts of cocrystal investigations in the literature started in earnest in 2003 and patent applications soon followed. The frequency of both has steadily accelerated, demonstrating an enhanced understanding of the design, characterisation, and manufacture of cocrystals and heightened interest from industry. Indeed, there were four new product approvals from 2014 to 2017 and more are in the pipeline. Here, we review all marketed drug products that are based upon pharmaceutical cocrystal drug substances, starting with the first recorded example, Beta-Chlor(r) in 1963, with a particular emphasis on their discovery, rationale for use, and market impact. PMID- 30521936 TI - Behavior, experience, skill, and training: a four-pillar framework and tool for career development in science. AB - Technical expertise and a spirit of inquiry serve as cornerstones for a career in science. Within that career, there are multiple pathways across disciplines, therapeutic areas, and sectors. To optimize career planning, I showcase here a career development framework that integrates four pillars: behavior, experience, skill, and training (BEST). This framework encompasses interrelated elements that are crucial for career progression and reflects evolving priorities in today's network-oriented environment. Individuals can also leverage the framework as a tool to support short- and long-term career planning. PMID- 30521937 TI - Patatin-like lipolytic acyl hydrolases and galactolipid metabolism in marine diatoms of the genus Pseudo-nitzschia. AB - Diatoms are eukaryotic microalgae that play a pivotal role in biological and geochemical marine cycles. These microorganisms are at the basis of the trophic chain and their lipids are essential components (e.g. eicosapentaenoic acid, EPA) of aquatic food web. Galactolipids are the primary lipid components of plastid membranes and form the largest lipid family of diatoms. As source of polyunsaturated fatty acids (PUFAs), these compounds are also involved in the synthesis of lipoxygenase (LOX) products such as non-volatile oxylipins and polyunsaturated aldehydes. Here, we report the first identification of two genes, namely PmLAH1 and PaLAH1, coding for lipolytic enzymes in two diatoms of the genus Pseudo-nitzschia. Functional and modeling studies evidence a patatin-like domain endowed with galactolipase and phospholipase activity at the C-terminus of both proteins. Homologues of Pseudo-nitzschia LAH1 genes were retrieved in other diatom species so far sequenced in agreement with conservation of the functional role of these proteins within the lineage. PMID- 30521938 TI - Lipid-gene regulatory network reveals coregulations of triacylglycerol with phosphatidylinositol/lysophosphatidylinositol and with hexosyl-ceramide. AB - Lipid homeostasis is important for executing normal cellular functions and maintaining physiological conditions. The biophysical properties and intricate metabolic network of lipids underlie the coordinated regulation of different lipid species in lipid homeostasis. To reveal the homeostatic response among different lipids, we systematically knocked down 40 lipid metabolism genes in Drosophila S2 cells by RNAi and profiled the lipidomic changes. Clustering analyses of lipids reveal that many pairs of genes acting in a sequential fashion or sharing the same substrate are tightly clustered. Through a lipid-gene regulatory network analysis, we further found that a reduction of triacylglycerol (TAG) is associated with an increase of phosphatidylinositol (PI) and lysophosphatidylinositol (LPI) or a reduction of hexosyl-ceramide (HexCer) and hydroxylated hexosyl-ceramide (OH-HexCer). Importantly, negative coregulation between TAG and LPI/PI, and positive coregulation between TAG and HexCer, were also found in human Hela cells. Together, our results reveal coregulations of TAG with PI/LPI and with HexCer in lipid homeostasis. PMID- 30521939 TI - Extracellular FABP4 uptake by endothelial cells is dependent on cytokeratin 1 expression. AB - AIMS: The aim of this study is to determine the physical and functional interplay between fatty acid-binding protein 4 (FABP4) and its membrane receptor-like candidate protein, cytokeratin 1 (CK1), and to determine the effect of hindering CK1-mediated FABP4 cellular uptake on non-disturbed or metabolically stressed endothelial cells. METHODS: We monitored the direct interaction between FABP4 and CK1 using surface plasmon resonance, and the effects of blocking exogenous FABP4 (eFABP4) cellular uptake were determined by using specific siRNA to knock down the expression of CK1 in human umbilical vein endothelial cells (HUVECs). The expression and nuclear translocation of transcription factors involved in oxidative stress (NRF2) and inflammation (p65 subunit of NF-KB transcription factor) were determined by Western blotting analysis. RESULTS: Our data showed that FABP4 and CK1 bind to each other and that the putative FABP4 binding domain would be within the 151GIQEVTINQSLLQPLNVEID170 CK1 sequence. We determined that in non-disturbed or metabolically stressed endothelial cells, eFABP4 regulates the cellular response to oxidative stress. In addition, we also found that in the presence of palmitate, eFABP4 increases the pro-inflammatory effects induced by palmitate per se, probably due to an increase in the transport of palmitate inside cells, suggesting that these FABP4-mediated pro-oxidative and pro inflammatory effects are dependent on CK1 expression. CONCLUSIONS: We demonstrated that CK1 facilitates eFABP4 cellular uptake in endothelial cells. Therefore, the CK1-targeted inhibition of exogenous FABP4 cellular uptake might be a potential therapeutic strategy to protect endothelial cells against FABP4 induced activation of inflammation and oxidative stress. PMID- 30521940 TI - Downregulation of RTN1-C attenuates MPP+-induced neuronal injury through inhibition of mGluR5 pathway in SN4741 cells. AB - Reticulons (RTNs) are a group of membrane-bound proteins that are dominantly localized to the endoplasmic reticulum (ER). RTN1-C, one isoform of RTNs highly expressed in the brain, has been shown to mediate neuronal injury in cerebral ischemia models. The aim of this study was to investigate the role of RTN1-C in an in vitro model of Parkinson's disease (PD) mimicked by 1-Methyl-4 phenylpyridinium (MPP+) treatment in SN4741 cells. We found that MPP+ significantly increased the expression of RTN1-C, with no effect on RTN1-A and RTN1-B. Downregulation of RTN1-C using siRNA (Si-RTN1-C) markedly increased cell viability and inhibited apoptosis induced by MPP+ treatment. The results of western blot showed that downregulation of RTN1-C inhibited the surface expression of metabotropic glutamate receptor 5 (mGluR5) but had no effect on mGluR1. The protective effects of Si-RTN1-C were partially prevented by activating mGluR5, not mGluR1. In addition, the results of Ca2+ imaging showed that downregulation of RTN1-C attenuated intracellular Ca2+ release induced by MPP+, which could be nullified by activation of mGluR5 pathway. In conclusion, our data suggest that downregulation of RTN1-C protects SN4741 cells against MPP+ through mGluR5-mediated preservation of Ca2+ homeostasis. Therefore, RTN1-C might represent a therapeutic target for the treatment of neuronal injury in experimental PD models. PMID- 30521941 TI - Ecological niche modeling as a tool for prediction of the potential geographic distribution of Bacillus anthracis spores in Tanzania. AB - INTRODUCTION: Anthrax is caused by the spore-forming, Gram-positive bacterium Bacillus anthracis. The aim of the study was to predict the potential distribution of B. anthracis in Tanzania and produce epidemiological evidence for management of anthrax outbreaks in the country. MATERIALS AND METHODS: Maxent algorithm was used to predict risky areas for anthrax outbreaks based on the occurrence and environmental data in Arusha and Kilimanjaro regions and later transferring the model to predict the entire country. 70% of the specimens were used to train the model whereas 30% were used for model evaluation. RESULTS: Four regions of northern Tanzania are predicted to have a high risk for anthrax outbreaks while the southern and western regions had low-risk areas. Soil type (56.5%), soil pH (23.7%) and isothermally (10.4%) were the most important variables to the model prediction and the most significant soil types were solonetz, fluvisols, and lithosols. CONCLUSION: A strong risk level across districts of Tanzania Mainland was identified in this study. A total of 18 districts are predicted to have very high risks for an occurrence of anthrax outbreaks in Tanzania. These findings are important for policymakers to effectively mount targeted control measures of anthrax outbreaks in Tanzania. PMID- 30521942 TI - Left Atrial Appendage Closure Device Implantation in Patients with Prior Intracranial Hemorrhage. AB - BACKGROUND: The WatchmanTM device (Boston Scientific, MN), used for left atrial appendage closure (LAAC) was approved for stroke prevention in patients with atrial fibrillation (AF) and an appropriate rationale to avoid long-term oral anticoagulation. Patients with AF and prior intracranial hemorrhage (ICH) were excluded from clinical trials due to perceived risks of peri-operative anticoagulation. OBJECTIVE: We studied the efficacy and safety of LAAC using WatchmanTM in patients with AF and prior ICH. METHODS: In a multidisciplinary AF/stroke prevention clinic, 38 consecutive patients with AF and prior ICH underwent WatchmanTM implantation. Patients were enrolled in a prospectively maintained data registry. RESULTS: Patients' mean CHA2DS2-VASc was 5.0+/-1.3 and HASBLED 4.2+/-1.0. Prior ICH events were intraparenchymal (60%), subdural (24%) or subarachnoid bleeds (16%). The median event to implantation time was 637 days (minimum 60). WatchmanTM was implanted in all patients with no procedural complications. All patients completed 45 days of anticoagulation with: warfarin (55%), apixaban (37%) or dabigatran (8%). Transesophageal echocardiograms at 45 days showed no peridevice leak and one patient had a small filamentous echodensity on device which resolved with anticoagulation. While on anticoagulation, none of the patients developed recurrent ICH. Minor bleeding occurred in 1 patient (trauma related lower extremity hematoma, at 19 days). Upon 13.4 months (quartiles 8-19) of follow-up, there were no strokes, ICH or deaths. CONCLUSION: AF patients with prior ICH tolerated short-term anticoagulation for the purpose of WatchmanTM implantation. LAAC with attendant short-term anticoagulation appears to be both safe and effective in this patient population. PMID- 30521943 TI - Radiochemical synthesis and preclinical evaluation of 68Ga-labeled NODAGA hydroxypropyl-beta-cyclodextrin (68Ga-NODAGA-HPBCD). AB - A new renaissance started in the research and application of cyclodextrins a few years ago. 2-Hydroxypropyl-beta-cyclodextrin (HPBCD) is used in the formulation of drugs and recently orphan designation was granted for the treatment of Niemann Pick disease, type C. HPBCD is considered to be safe, but the exact mechanism of action and side effects are not completely explained. Labeled cyclodextrin derivatives are required to reveal the biological activity and in vivo distribution by imaging techniques. The aims of our study were to synthetize the 68Ga-labeled NODAGA-hydroxypropyl-beta-cyclodextrin (68Ga-NODAGA-HPBCD) and test the pharmacokinetic properties and in vivo distribution of this radiolabeled molecule. p-NCS-benzyl-NODA-GA (NODAGA) was conjugated to the 6-deoxy-6-monoamino (2-hydroxypropyl)-beta-cyclodextrin (NH2-HPBCD). The product (NODAGA-HPBCD) was analyzed by analytical RP-HPLC and verified with high resolution mass spectrometry. In the next step the NODAGA-HPBCD was labeled with Gallium-68 (68Ga). The 68Ga labeled NODAGA-HPBCD (68Ga-NODAGA-HPBCD) was characterized and the radiochemical purity (RCP%), partition coefficient (log P values), and in vitro stability was determined. Thereafter in vivo distribution and pharmacokinetic properties of 68Ga-NODAGA-HPBCD was monitored by positron emission tomography (PET). NODAGA-HPBCD was purified by preparative RP-HPLC and the purity was better than 98%. The radiochemical purity of the 68Ga-NODAGA-HPBCD was higher than 98%, the specific activity was 17.62 +/- 2.43 GBq/MUmol, and the decay corrected yield was 76.54 +/- 6.12% (n = 8). The octanol/water partition coefficient of 68Ga labeled NODAGA-HPBCD was found to be -3.07 +/- 0.11. In vivo dynamic and ex vivo biodistribution studies using control BALB/c mice revealed that 68Ga labeled NODAGA-HPBCD was mainly excreted by the kidney, due to its hydrophilic properties that has been proved by the partition coefficient. The accumulation of the radiotracer in abdominal organs was low, and no uptake was found in the brain. In conclusion 68Ga labeled NODAGA-HPBCD was successfully produced for the first time and tested in vitro and in vivo. The synthesized NODAGA-HPBCD was characterized and labeled with 68Ga successfully. Overall, the outcome of our study indicates that the in vivo behavior of radiolabeled cyclodextrins can be examined by PET techniques, thus these derivatives are suitable for further pharmacokinetic measurements. PMID- 30521944 TI - Identifying critical process steps to protein stability during spray drying using a vibrating mesh or a two-fluid nozzle. AB - The aim of this study was to identify critical steps to protein stability during spray drying using two different nozzle types: a vibrating mesh nozzle and a standard two-fluid nozzle in a Buchi B-90 spray dryer. l-Lactic dehydrogenase was used as a model protein as it is a heat and shear stress sensitive protein. Trehalose was used as excipient because of its excellent stabilizing capacities. The entire spray drying process was split up into smaller steps and after each step the enzymatic activity of the protein was measured. With the vibrating mesh nozzle in total 78% of activity was lost. About 68% was due to atomizing and heating and 10% was caused by dehydration and circulation of the liquid. With the two-fluid nozzle the total activity loss was only 23%, to which atomization, dehydration, and circulation contributed almost equally. Heating was not an issue, as the two-fluid nozzle could be cooled with water. In conclusion, the type and the configuration of the nozzle used for spray drying are important determinants for maintaining protein stability, as atomizing, heating, ultra sonication, and recirculation of the feed solution negatively influence it. The possibility to cool the two-fluid nozzle offers an important advantage to the vibrating mesh nozzle in the spray drying process of proteins. In this study, we show that, next to the optimization of the formulation, optimization of the spray drying process should be taken into account to maintain protein stability. PMID- 30521945 TI - Characterization of A dextran-budesonide prodrug for inhalation therapy. AB - Reducing the dosing frequency of corticosteroids may increase compliance and increase pulmonary targeting. The objective of this study was to evaluate whether a high molecular weight dextran-budesonide conjugate might be suitable for pulmonary slow release of the otherwise fast absorbed budesonide. An array of dextran-spacer-budesonide conjugates was prepared that differed in the molecular weight of dextran (20 kDa or 40 kDa) and the length of the dicarboxylic spacer (succinic, glutaric, and adipic anhydride). The conjugates were characterized for identity by proton nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectroscopy (FTIR), the degree of dextran-hydroxyl conjugation, purity, and physiological activation (release of budesonide). The 40 kDa dextran succinate-budesonide conjugate was formulated as a dry powder for pulmonary delivery and characterized for particle size distribution, particle morphology, and aerodynamic particle size. The degree of substitution (grams of budesonide in 100 g of conjugate) ranged from 4 to 10% for all six dextran-spacer-budesonide conjugates. Incubation at 37 degrees C and pH 7.4 in phosphate buffered saline resulted in release of 25-75% of the conjugated budesonide over an 8-hour period with the rate of release increasing with molecular weight of dextran and the length of the spacer. Modeling of the concentration time profiles of the released budesonide and budesonide-21-hemisucinate in phosphate buffered saline, suggested that budesonide is generated either directly or via the budesonide-21 hemisucinate pre-cursor. Data also suggested that the rate of budesonide generation likely depends on the position of budesonide on the dextran molecule. Spray-drying the 40 kDa dextran-succinate-budesonide produced respirable particles of the conjugate with a mass median aerodynamic particle size (MMAD) of 4 MUm. The slow generation of budesonide from the chemical delivery system might further improve the pharmacological profile of budesonide. PMID- 30521946 TI - Bipolar Disorder and 1513A>C P2RX7 polymorphism frequency. AB - Although the etiology of Bipolar Disorder (BD) remains unknown, a strong genetic component to the pathogenesis and risk for this disorder has been widely hypothesized. Several risk genes for BD have been identified; of these, the purinergic P2 * 7 receptor (P2 * 7R) constitutes a pro-inflammatory receptor and a potential risk gene candidate. The purpose of the present study was to assess the frequency of the 1513 A > C P2RX7 polymorphism (rs3751143; Glu496Ala), which leads to receptor loss-of-function, in 154 BD patients versus 184 control subjects. The existence of a differential modulation of P2 * 7R was also analyzed in 22 euthymic BD patients, in comparison to 18 healthy controls. Our data show a decrease in 1513C allele frequency (p = 0.045) and a potential increase in 1513 A A/AC (p = 0.055) genotype frequency in BD patients, compared to controls, indicating an enhanced function of the pro-inflammatory P2 * 7 receptor in BD subjects. Interestingly, no differences in P2RX7 gene and protein expression were found between euthymic BD patients and matched healthy controls. In conclusion, our results suggest that P2 * 7R might play a role in the pathophysiology of BD and add new information regarding this receptor as a potential biomarker for the prediction and diagnosis of the disorder. PMID- 30521947 TI - Prediction of neutrophil-to-lymphocyte ratio in the diagnosis and progression of autoimmune encephalitis. AB - OBJECTIVE: Autoimmune encephalitis (AIE) is a group of inflammatory disorders of the brain. The severity of AIE vary among individuals and it is always a challenge to predict. In this study, we measured the neutrophil-to-lymphocyte ratio (NLR), a novel potential biomarker of inflammatory status in other inflammatory diseases, in AIE patients and evaluated NLR as a biomarker for monitoring AIE progression. METHODS: The study participants consisted of 34 newly diagnosed AIE patients and 35 ages and sex-matched healthy controls. Demographic and clinical assessment data were reviewed and abstracted retrospectively. NLR levels were calculated from the peripheral blood tests. The relationship between mRS (the modified Ranking Scale) score and NLR levels, total white blood cells, absolute neutrophil counts and absolute lymphocyte counts were investigated. The performance of NLR in predicting severe AIE was also determined. RESULTS: Peripheral NLR level in AIE patients were significantly higher than in healthy controls (p < 0.001). Additionally, median NLR level in patients with severe impairments (using modified Ranking Scale, mRS>3) was significantly elevated (p < 0.001) compared to patients with mild to moderate impairments (mRS<=3). Spearman correlation analysis indicated that NLR and neutrophil counts were positively associated to mRS score (r = 0.595, p<0.001 for NLR, and r = 0.392, p = 0.022 for neutrophil counts). While lymphocyte counts were negatively correlated with mRS score (r=-0.522, p = 0.002). Multivariate logistic regression analysis revealed that increased NLR value was an independent risk factor for severe AIE (OR: 2.171, 95% CI: 1.218-3.868, p = 0.009). Furthermore, according to the ROC curve, the best NLR cut-off value to predict severe disease activity of AIE was 4.82, with a sensitivity of 78% and specificity of 88%. CONCLUSION: Our results suggest that NLR in peripheral blood may be a practical and reliable biomarker to monitor disease progression in patients with AIE. PMID- 30521948 TI - The involvement of iron responsive element (-) divalent metal transporter 1 mediated the spinal iron overload via CXCL10/CXCR3 pathway in neuropathic pain in rats. AB - BACKGROUND: Iron is pivotal for life, but it is toxic if in excess. Iron overload mediated by divalent metal transporter 1 (DMT1) in the central nervous system has participated in various neuroinflammatory diseases. Chemokine-induced neuroinflammation involves the development of pathological pain. Recently, chemokine CXCL10 is implicated in the pathogenesis of chronic pain, however, little is known about the potential link between iron accumulation and CXCL10 in pain condition. Here, we examined whether iron accumulation regulated neuropathic pain via CXCL10. METHODS: Pain behavior was assessed in a rat model of chronic constriction injury (CCI) of the sciatic nerve. Spinal expressions of CXCL10 and its receptor CXCR3 were measured using RT-qPCR. Western blot and atomic absorption spectrophotometer were employed to measure spinal DMT1 with/without iron responsive element [IRE (+) DMT1 and IRE (-) DMT1] and iron concentration. Iron chelator, recombinant CXCL10, and a selective CXCR3 antagonist NBI-74330 were injected to verify the mechanisms. RESULTS: We found that CCI induced long lasting increase of spinal iron concentration, IRE (-) DMT1 expression, CXCL10 and CXCR3 levels. Moreover, iron chelator attenuated neuropathic pain and inhibited the over-expression of CXCL10 and CXCR3 in a dose dependent manner. CCI induced mechanical allodynia and thermal hyperalgesia were also prevented by the delivery of NBI-74330. Exogenous CXCL10 elicited behavioral hypernociceptive state and CXCR3 over-expression in naive rats, which was reversed by the co administration of iron chelator. CONCLUSION: Our findings demonstrated the contribution of spinal abnormal iron accumulation in regulating CXCL10 pathway in the pathogenesis of neuropathic pain. PMID- 30521949 TI - Beneficial Effect of Curcumin Nanoparticles-Hydrogel on Excisional Skin Wound Healing in Type-I Diabetic Rat: Histological and Immunohistochemical Studies. AB - Management of diabetic wounds remains a major challenge in the medical field, mostly due to incompetent outcomes of treatments. Curcumin has been documented as anti-inflammatory, antioxidant, antimicrobial and antineoplastic agent in addition to wound healing activities. However, its poor aqueous solubility and impaired skin permeation handicap its topical pharmaceutical usage. Hydrogel loaded curcumin nanoparticle (Cur-NP/HG) could overcome this pitfall and enable extended topical delivery of curcumin. Rat model of diabetes mellitus (DM) type I was induced using single injection of 70mg/kg streptozotocin (STZ) followed by full thickness skin wound. Rats were divided into 4 groups. GpI: control non diabetic, GpII: diabetic non-treated, GpIII: diabetic treated with topical curcumin hydrogel (Cur/HG) and GpIV: diabetic treated with topical Cur-NP/HG. Histological assessment of epidermal regeneration, dermo-epidermal junction, leukocyte infiltration and collagen deposition, in addition to immunohistochemical staining for vascular endothelial growth factor (VEGF) and aquaporin-3 (AQP3) were performed. Diabetic rat possessed impaired wound closure, persistence of inflammation and decreased collagen deposition as compared to non diabetic control. Application of Cur/HG induced partial improvement of the healing process in diabetic rats. Cur-NP/HG treatment provoked obvious improvement of the healing process with complete re-epithelization, intact dermo epidermal junction, reorganization of the dermis with significantly increased collagen deposition and VEGF and AQP3 expression. These results illustrated that Cur-NP/HG have effectively improved the healing process in diabetic skin wound with substantial differences in the wound healing kinetics compared to wounds that received Cur/HG. PMID- 30521950 TI - Dynamic functional connectivity during task performance and rest predicts individual differences in attention across studies. AB - Dynamic functional connectivity (DFC) aims to maximize resolvable information from functional brain scans by considering temporal changes in network structure. Recent work has demonstrated that static, i.e. time-invariant resting-state and task-based FC predicts individual differences in behavior, including attention. Here, we show that DFC predicts attention performance across individuals. Sliding window FC matrices were generated from fMRI data collected during rest and attention task performance by calculating Pearson's r between every pair of nodes of a whole-brain atlas within overlapping 10-60s time segments. Next, variance in r values across windows was taken to quantify temporal variability in the strength of each connection, resulting in a DFC connectome for each individual. In a leave-one-subject-out-cross-validation approach, partial-least-square regression (PLSR) models were then trained to predict attention task performance from DFC matrices. Predicted and observed attention scores were significantly correlated, indicating successful out-of-sample predictions across rest and task conditions. Combining DFC and static FC features numerically improves predictions over either model alone, but the improvement was not statistically significant. Moreover, dynamic and combined models generalized to two independent data sets (participants performing the Attention Network Task and the stop-signal task). Edges with significant PLSR coefficients concentrated in visual, motor, and executive-control brain networks; moreover, most of these coefficients were negative. Thus, better attention may rely on more stable, i.e. less variable, information flow between brain regions. PMID- 30521951 TI - Adaptive task difficulty influences neural plasticity and transfer of training. AB - The efficacy of cognitive training is controversial, and research progress in the field requires an understanding of factors that promote transfer of training gains and their relationship to changes in brain activity. One such factor may be adaptive task difficulty, as adaptivity is predicted to facilitate more efficient processing by creating a prolonged mismatch between the supply of, and the demand upon, neural resources. To test this hypothesis, we measured behavioral and neural plasticity in fMRI sessions before and after 10 sessions of working memory updating (WMU) training, in which the difficulty of practiced tasks either adaptively increased in response to performance or was fixed. Adaptive training resulted in transfer to an untrained episodic memory task and activation decreases in striatum and hippocampus on a trained WMU task, and the amount of training task improvement was associated with near transfer to other WMU tasks and with hippocampal activation changes on both near and far transfer tasks. These findings suggest that cognitive training programs should incorporate adaptive task difficulty to broaden transfer of training gains and maximize efficiency of task-related brain activity. PMID- 30521952 TI - Visual stimulus-driven functional organization of macaque prefrontal cortex. AB - The extent to which the major subdivisions of prefrontal cortex (PFC) can be functionally partitioned is unclear. In approaching the question, it is often assumed that the organization is task dependent. Here we use fMRI to show that PFC can respond in a task-independent way, and we leverage these responses to uncover a stimulus-driven functional organization. The results were generated by mapping the relative location of responses to faces, bodies, scenes, disparity, color, and eccentricity in passively fixating macaques. The results control for individual differences in functional architecture and provide the first account of a systematic visual stimulus-driven functional organization across PFC. Responses were focused in dorsolateral PFC (DLPFC), in the ventral prearcuate region; and in ventrolateral PFC (VLPFC), extending into orbital PFC. Face patches were in the VLPFC focus and were characterized by a striking lack of response to non-face stimuli rather than an especially strong response to faces. Color-biased regions were near but distinct from face patches. One scene-biased region was consistently localized with different contrasts and overlapped the disparity-biased region to define the DLPFC focus. All visually responsive regions showed a peripheral visual-field bias. These results uncover an organizational scheme that presumably constrains the flow of information about different visual modalities into PFC. PMID- 30521953 TI - Freely chosen and instructed actions are terminated by different neural mechanisms revealed by kinematics-informed EEG. AB - Neurophysiological accounts of human volition are dominated by debates on the origin of voluntary choices but the neural consequences that follow such choices remain poorly understood. For instance, could one predict whether or not an action was chosen voluntarily based only on how that action is motorically executed? We investigated this possibility by integrating scalp electroencephalograms and index-finger accelerometer recordings acquired while people chose between pressing a left or right button either freely or as instructed by a visual cue. Even though freely selected and instructed actions were executed with equal vigor, the timing of the movement to release the button was comparatively delayed for freely selected actions. This chronometric difference was six-times larger for the beta-oscillations over the sensorimotor cortex that characteristically accompany an action's termination. This surprising modulation of an action's termination by volition was traceable to volition modulated differences in how the competing yet non-selected action was represented and regulated. PMID- 30521954 TI - Serum amyloid a as an indicator of impending xenograft failure: Experimental studies. AB - BACKGROUND: There is well-documented systemic inflammatory response in xenograft recipients to the presence of a pig graft. Serum amyloid A (SAA) is an inflammatory marker that is elevated in various pathological states. The assay used to measure it is (i) simple, (ii) relatively inexpensive, and (iii) provides an answer within minutes. METHOD: The levels of SAA (n=11) and C-reactive protein (C-RP) (n=8) were measured retrospectively in the serum of baboons with pig kidney transplants, who received therapy with an IL-6R inhibitor and a TNF-alpha antagonist. Immunohistochemistry (IHC) was used to identify amyloid A and C-RP expression in the native livers and deposition in the pig kidney grafts. RESULTS: One kidney graft underwent hyperacute rejection, 6 (55%) underwent acute antibody mediated rejection, 3 baboons (27%) were euthanized for serious systemic infections, and one was euthanized for acute gastric dilatation. The SAA increased temporarily after kidney transplantation, and increased again by the day of euthanasia, indicating moderate (n=3) or significant (severe) (n=8) inflammation. In contrast, as the baboons were receiving tocilizumab, C-RP did not increase. There was greater expression of amyloid A in baboon livers (by IHC) than of C-RP (mean OD 53 vs 1, p<0.01), and greater deposition of amyloid A than C-RP in the pig kidney grafts (mean OD 24 vs 2, p<0.001). Plasma fibrinogen negatively correlated with the expression of amyloid A in the liver (r=-0.72, p<0.05). The results of the SAA assay correlated with amyloid A expression in the liver and deposition in the kidney grafts. CONCLUSIONS: SAA is a sensitive, but non-specific, marker for inflammation in baboons with pig kidney grafts, and is not affected by therapy that suppresses the response of C-RP. The SAA assay is a rapid, reliable, and relatively inexpensive method of following the inflammatory state of baboons with pig xenografts. PMID- 30521955 TI - Spinal arachnoiditis ossificans: report of a quadruple triggered case. AB - BACKGROUND: Arachnoiditis ossificans (AO) is a rare condition often associated with previous spine surgery. Here we describe a unique case of a patient affected by ankylosing spondylitis (AS), presenting with progressive neurological deterioration due to AO. We also review the literature on evaluation and management of patients suffering from AO. CASE DESCRIPTION: The 65-year-old patient had a history of previous spinal trauma and related thoraco-lumbar surgery. Magnetic resonance imaging (MRI) revealed multiloculated intradural/extramedullary cysts on the posterior surface of the spinal cord at Th9-L1, with clustered nerve roots. Computed tomography (CT), with three dimensional (3D) reconstruction, demonstrated a likely ossification of both the dura and the arachnoid from Th9 to S1. Microsurgical debridement of scar tissue from previous surgery, drilling of posterior ossified plaques at Th11-Th12-L1, as well as marsupialization and drainage of arachnoid cysts at Th11-Th12, were performed. CONCLUSIONS: We submit that AS, spinal trauma, epidural hematoma and related surgery may be synergistic and independent factors in the etiopathogenesis of AO. This should be considered in patients with AS and/or a history of spinal surgery who present neurological worsening. PMID- 30521956 TI - Middle Meningeal Artery to Premeatal Anterior Inferior Cerebellar Artery Bypass Via Anterior Petrosectomy: An Anatomic Feasibility Study. AB - INTRODUCTION: Anterior-inferior cerebellar artery (AICA) aneurysms are rare with no optimal consensus on management strategies. When the treatment requires parent artery occlusion post-operative ischemic or neuropathic, complications can occur. OBJECTIVE: To evaluate the feasibility of direct revascularization of premeatal AICA using the middle meningeal artery (MMA) as the donor through an anterior petrosectomy (APA) window. METHODS: Ten specimens were used for the surgical simulation of the MMA-AICA bypass. The MMA was harvested from the dura down to the foramen spinosum (FS). An APA was performed on each specimen and the AICA was exposed up to its origin from the basilar artery. The lateral pontine (a2) segment was mobilized laterally and the end-to-end anastomosis was completed. Measurements of the required length of the AICA, MMA and their calibers at the anastomotic site were recorded. RESULTS: The MMA-AICA bypass was feasible in all the specimens. The mean length of AICA from the origin at the anastomotic site was 7.3+/-1.7 mm, with the mean length of MMA from FS being 34.6+/-5.1 mm. The mean calibers of the MMA were 2.1+/-0.2 mm at FS and 1.7+/-0.2 mm at the anastomosis. The a2 caliber was 1.6+/-0.3 mm with an average lateral mobilization of 7.6+/-2.7mm. CONCLUSION: Our study establishes the feasibility of an MMA-AICA bypass via a middle fossa approach. The matching caliber of the two arteries makes the end-to-end anastomosis easy to achieve. The MMA is a suitable donor artery that avoids the use of interposition graft and the complications of an extracranial-intracranial bypass. PMID- 30521957 TI - Posterior Extensive Circumferential Decompressive Reconstructive Technique in surgical treatment of Upper Thoracic Spine Compressive Lesions. AB - BACKGROUND DATA: Complexity in ventral surgical exposure, presence of scapula and large para-scapular musculature during posterior surgery are the main obstacles in operative treatment of Upper Thoracic Spine Compressive Lesions (UTSCL) like trauma, tuberculosis and neoplasm. Recently, the advantages of combined ventro dorsal surgery could be successfully gained using 1-stage posterior salvage technique with enough accessibility to all three spinal columns. PURPOSE: Retrospective evaluation of 35 patients with UTSCL treated by Posterior Extensive Circumferential Decompressive Reconstructive (PECDR) procedure. METHODS: Traumatic, tuberculosis and neoplastic lesions were involved between 2009 and 2012. All patients were examined pre, postoperatively and during follow up clinically (pain by Visual Analogue Scale VAS), neurologically {sensory and motor deficit (American Spine Injury Association (ASIA) grading}, functionally {Oswestry Disability Index (ODI)}, radiologically {kyphosis correction, loss of correction and fusion time} and laboratory in tuberculosis patients. Two authors plus an independent observer performed the final clinical, neurological and radiological examination. Operative time, hospital stay, blood loss and complications were documented. RESULTS: Mean follow up period was 36+/-5.5 months. Local symptoms, deformity correction and neurological recovery significantly improved postoperatively. Solid fusion was evident in 32 cases. No major complications were reported. Three patients developed wound infection and 3 had intercostal neuralgia both complications were resolved uneventfully and did not influence the outcomes. CONCLUSION: Due to difficult ventral exposure, PECDR technique is a feasible tool for maintained deformity correction, bony fusion, thecal decompression and functional improvement in surgical treatment of UTSCL. However, tuberculosis had better satisfactory results than traumatic and neoplastic lesions. PMID- 30521958 TI - Ultrasonic scalpel-assisted endoscopic endonasal surgery of infratemporal fossa: our first impressions. AB - BACKGROUND: Endoscopic endonasal transpterygoid approach is emerging as a valid option for treating selected tumors in the infratemporal fossa. Compared to traditional open approaches, the endoscopic endonasal approach (EEA) presents more difficulty in controlling bleeding and less choice in surgical instruments for endoscopic tumor dissection, which is often performed with bipolar forceps or steel dissectors. CASE DESCRIPTION: We describe the use of an ultrasonic scalpel device for performing endoscopic endonasal resection of two rare infratemporal fossa tumors (mature teratoma and hemangiopericytoma), which has not been reported in the literature so far. We also review the literature on endoscopic ultrasonic scalpel use. CONCLUSIONS: The ultrasonically activated scalpel is a safe, effective and simple to use device, which achieved excellent hemostasis and did not damage adjacent neuro-vascular structures. PMID- 30521959 TI - Epithelioid Osteoblastoma of the Temporal Bone: A Case Report. PMID- 30521960 TI - Carotid Endarterectomy for Medical Therapy-resistant Symptomatic Low-grade Stenosis. AB - BACKGROUND: Plaque characteristics play pivotal roles in ischemic events, but stenosis severity does not accurately reflect carotid plaque volume due to expansive remodeling in some patients with low-grade stenosis (LGS). OBJECTIVE: This study aimed to assess the safety, efficacy, and durability of carotid endarterectomy (CEA) for symptomatic LGS. METHODS: Study participants comprised 61 consecutive patients who underwent CEA for symptomatic carotid stenosis. Patients were divided into an LGS group (<50%, n=17) and a non-LGS group (>=50%, n=44). Patient characteristics and short- (within 30 days of CEA) and long-term outcomes were compared between groups for selective usage of internal shunt and the known complications of CEA. RESULTS: MRI-detected intraplaque hemorrhage was more significant in LGS than in non-LGS (P = .04). For short-term outcomes, no symptomatic infarcts, hyper-perfusion syndrome, or AMI was confirmed in either group. Internal shunts were used in 4 LGS (23.5%) and 6 non-LGS (13.6%). Asymptomatic diffusion-weighted imaging-positive lesions were confirmed in 2 LGS patients (11.8%) and 5 non-LGS patients (11.4%), neck hematoma in 1 LGS patient, and transient cranial nerve palsy in 1 LGS patient and 2 non-LGS patients, with no significant differences apparent between groups. For long-term outcomes, 5 non LGS patients showed restenosis (P = .17). Hemorrhagic stroke was not observed in either group. No significant differences were seen for infarct in the ipsilateral carotid territory, any ischemic stroke, AMI, or mortality. CONCLUSIONS: CEA represents a safe and feasible therapeutic option for a subset of patients with symptomatic LGS. PMID- 30521961 TI - Methadone therapy modulate the dendritic cells of heroin addicts. AB - Evidence from various studies suggests that narcotics abuse may exert adverse immunomodulatory effects on immune responses. The aim of this research was to understand the effects of detoxification with methadone on the percentage of dendritic cells (DCs) and expression of its markers in heroin addicts. In this study, myeloid DCs (CD11c+) and plasmacytoid DCs (CD123+) were examined in two groups. These groups comprised of 20 healthy volunteers and 20 chronic heroin addicts, before and after detoxification with methadone. The percentages of myeloid DCs and plasmacytoid DCs were lower in addict subjects than in the control. The HLA-DR expression on DCs was significantly lower in addict subjects than in the control, whereas CD11c and CD123 expression in DCs subsets were increased in them. Most of these changes were modified after the methadone therapy. Dendritic cells are essential to the initiation of primary immune responses, therefore the disruption of their function can be one of the reasons for the increased prevalence of infections in heroin addicts. The methadone therapy can improve the imposed changes by heroin. PMID- 30521962 TI - Protective effect of forsythoside B against lipopolysaccharide-induced acute lung injury by attenuating the TLR4/NF-kappaB pathway. AB - Acute lung injury (ALI), which is mainly triggered by infection, pneumonia, vasculitis, and sepsis, has no specific and effective therapy except for primary supportive treatment or bedside care. Excessive inflammation caused by innate immune cells is the major characteristic of ALI. Forsythoside B, a phenylethanoside compound, possesses good antioxidant and anti-bacterial properties in vivo and in vitro. In this study, the therapeutic potential of forsythoside B and its mechanism of action were investigated in a lipopolysaccharide (LPS)-induced ALI mouse model. The results showed that LPS induced edema exudation and lung pathological changes in mice were significantly suppressed by forsythoside B pre-treatment. Furthermore, it also attenuated lung inflammation caused by LPS stimulation, evidenced by decreased inflammatory cell infiltration and down-regulated expression of cytokines, chemokines, and inducible enzymes. The anti-inflammation property of forsythoside B was confirmed in vitro using LPS-stimulated RAW 264.7 macrophages. Moreover, it alleviated LPS induced inflammation by inhibiting the activation of TLR4/NF-kappaB signaling pathway in vivo and in vitro. In conclusion, the results demonstrated that forsythoside B protects against LPS-induced ALI by attenuating inflammatory cell infiltration and suppressing TLR4/NF-kappaB-mediated lung inflammation. Therefore, it might be a potential therapeutic agent for ALI caused by sepsis. PMID- 30521963 TI - Ivabradine abrogates TNF-alpha-induced degradation of articular cartilage matrix. AB - Ivabradine is most commonly used for the treatment of worsening cardiac failure in patients who cannot tolerate the maximum dose of beta-blockers or in whom treatment with beta-blockers is contraindicated. While ivabradine is regarded as a highly selective "funny current" (If) inhibitor, the molecular mechanism behind the effect of this drug remains poorly understood. In the present study, we applied ivabradine in the context of osteoarthritis by treating primary human chondrocytes with tumor necrosis factor-alpha (TNF-alpha) and measuring degradation of the articular cartilage matrix as well as the expression of various enzymes and pro-inflammatory cytokines. Our results indicate that ivabradine significantly abrogated TNF-alpha-induced up-regulation of matrix metalloproteinase-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 at both the gene and protein levels. Notably, ivabradine attenuated TNF-alpha-induced reduction of type II collagen and aggrecan at both the mRNA and protein levels. Also, we found that ivabradine inhibited the expression and secretion of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) as well as the production of reactive oxygen species (ROS). Mechanistically, our results indicate that ivabradine abolished the activation of nuclear factor (NF-kappaB) by inhibiting nuclear translocation of NF-kappaB p65. Knockdown of HCN2 enhanced the protective effects of ivabradine against TNF-alpha- induced degradation of both type II collagen and aggrecan, suggesting that the inhibitory effects of ivabradine in ECM degradation might be mediated by HCN2. Our findings demonstrate that ivabradine may indeed have a potential application in preventing excessive degradation of the articular cartilage matrix, thereby preventing the pathological development and progression of osteoarthritis. PMID- 30521964 TI - Long non-coding RNA THRIL promotes LPS-induced inflammatory injury by down regulating microRNA-125b in ATDC5 cells. AB - BACKGROUND: Osteoarthritis is an age-related disorder of bone-joint that causes pain and disability in middle and older people. This study aimed to investigate the potential effects of long non-coding RNA (lncRNA) THRIL on lipopolysaccharide (LPS)-induced osteoarthritis cell injury model (ATDC5 cell inflammatory injury), as well as the possible internal molecular mechanisms. METHODS: Cell viability and apoptosis were assessed using CCK-8 assay and Guava Nexin assay, respectively. Cell transfection was conducted to change the expression of THRIL and microRNA-125b (miR-125b) in ATDC5 cells. qRT-PCR was performed to detect the expression of THRIL, miR-125b and pro-inflammatory cytokines IL-6, TNF-alpha and monocyte chemotactic protein 1 (MCP-1) in ATDC5 cells. ELISA was used to measure the concentrations of IL-6, TNF-alpha and MCP-1 in culture supernatant of ATDC5 cells. Finally, the protein expression of key factors involved in cell apoptosis, inflammatory response, JAK1/STAT3 and NF-kappaB pathways were evaluated using western blotting. RESULTS: LPS significantly induced ATDC5 cell inflammatory injury and up-regulated the expression of THRIL. Overexpression of THRIL aggravated the LPS-induced ATDC5 cell inflammatory injury. Suppression of THRIL had opposite effects. Moreover, THRIL negatively regulated the expression of miR 125b in ATDC5 cells. miR-125b participated in the effects of THRIL overexpression on LPS-induced ATDC5 cell inflammatory injury. Furthermore, overexpression of THRIL enhanced the LPS-induced JAK1/STAT3 and NF-kappaB pathways activation by down-regulating miR-125b. CONCLUSION: THRIL exerted pro-inflammatory roles in LPS induced osteoarthritis cell injury model. Overexpression of THRIL promoted LPS induced ATDC5 cell inflammatory injury by down-regulating miR-125b and then activating JAK1/STAT3 and NF-kappaB pathways. PMID- 30521965 TI - Engineering of pectin-dopamine nano-conjugates for carrying ruthenium complex: A potential tool for biomedical applications. AB - In this work, we designed polysaccharide-metal complex of dopamine-modified pectin linking ruthenium compound, which exhibited a certain inhibition specificity to human renal cell adenocarcinoma cell line 786-O. The chemical structure and physical properties of the polysaccharide-metal complex were well characterized by multiple analysis methods. The multi-spectral results revealed that pectin-dopamine have been successfully coordinated by ruthenium complex to form nano-conjugates, which self-assembled into relatively regular nanospheres of approximately 200 nm. The polysaccharide-metal complex has more amorphous and less viscosity than pectin, and cannot withstand as much strain as the pectin and pectin-dopamine systems. Pectin-dopamine can decrease the toxicity effect of Ru complex in normal cell line such as human normal renal epithelial cell line 293A. PMID- 30521966 TI - An affinity peptide exerts antiviral activity by strongly binding nervous necrosis virus to block viral entry. AB - Nervous necrosis virus (NNV) causes viral nervous necrosis (VNN), a disease that leads to almost 100% mortality among larvae and juvenile fish, severely affecting the aquaculture industry. VNN vaccines based on inactivated viruses or virus-like particles (VLPs) are unsuitable for fish fry with immature adaptive immune systems. Here, we applied an anti-NNV strategy based on affinity peptides (AFPs). Three phage display peptide libraries were screened against RBS, the VLP of orange-spotted grouper nervous necrosis virus (OGNNV). From the positive clones, a dodecapeptide with the highest binding capacity (BC) to RBS was selected. This AFP agglutinated or disrupted virion particles, inhibiting RBS entry into sea bass (SB) cells. To enhance BC and solubility, we amended the AFP sequence as "LHWDFQSWVPLL" and named as 12C. One to three copies of 12C in tandem were prokaryotically expressed with a maltose binding protein (MBP) linked by a flexible peptide. Of the recombinant proteins expressed, MBP-triple-12C (MBP T12C) exhibited the highest BC, efficiently blocked RBS entry, and strongly inhibited OGNNV infection at viral entry. Moreover, MBP-T12C bound the VLPs of all NNV serotypes, displaying broad-spectrum anti-NNV ability, and recognized only OGNNV and mud crab virus, demonstrating binding specificity. Therefore, these anti-NNV AFPs specifically bound NNV, aggregating or disrupting the viral particles, to reduce the contact probability between the virus and cell surface, subsequently inhibiting viral infection. Our results not only provided a candidate of anti-NNV AFP, but a framework for the development of antiviral AFP. PMID- 30521967 TI - TroCCL4, a CC chemokine of Trachinotus ovatus, is involved in the antimicrobial immune response. AB - CC chemokines are a large subfamily of chemokines that play an important role in the innate immune system. To date, several CC chemokines have been identified in fish species; however, the activities and functions of these putative chemokines remain ambiguous in teleosts, especially in the golden pompano, Trachinotus ovatus. Here, we characterized CC chemokine ligand 4 from T. ovatus (TroCCL4) and studied its functions. TroCCL4 contains a 294 bp open reading frame that encodes a putative peptide comprising 97 amino acids. TroCCL4 shares a high amino acid sequence similarity of 31.11%-78.35% with other CC chemokines sequences in humans and teleosts and has four cysteine residues that are conserved among other CC chemokines. TroCCL4 is also related to the macrophage inflammatory protein (MIP) group of CC chemokines. TroCCL4 expression was most abundant in immune organs and significantly upregulated in a time-dependent manner following Edwardsiella tarda infection. Recombinant TroCCL4 (rTroCCL4) induced the migration of peripheral blood leukocytes and the cellular proliferation of head kidney lymphocytes. In addition, rTroCCL4 inhibited the growth of Escherichia coli and E. tarda, indicating an antimicrobial function. Furthermore, the results of in vivo analysis showed that TroCCL4 overexpression in T. ovatus significantly enhanced macrophage activation; upregulated the gene expression of interleukin 1-beta (IL 1beta), interleukin 15 (IL15), interferon-induced Mx protein (Mx), tumor necrosis factor alpha (TNFalpha), complement C3, and major histocompatibility complex (MHC) class Ialpha and class IIalpha; and protected against bacterial infection in fish tissues. In contrast, knockdown of TroCCL4 expression resulted in increased bacterial dissemination and colonization in fish tissues. Taken together, our results provide evidence indicating that TroCCL4 has the ability to stimulate leukocytes and macrophages and enhance host immunity to defend against bacterial infection. PMID- 30521968 TI - Enrichment of common carp (Cyprinus carpio) fingerlings diet with Psidium guajava: The effects on cutaneous mucosal and serum immune parameters and immune related genes expression. AB - The present study aimed at evaluation of possible effects of Psidium guajava as immunostimulant on mucosal and serum immunity, as well as related genes expression in common carp (Cyprinus carpio) fingerlings. In an eight weeks feeding trial, fish were fed with experimental diets containing guava leaf powder [GLP] (0, 0.25, 0.5 and 1%). Then, skin mucus and serum immune parameters (total Ig, alkaline phosphatase activity, lysozyme activity), as well as immune related genes expression (TNF-alpha, IL1b, IL8) were measured. All levels of GLP inclusion in the diet brought about the increase in total Ig in the serum, while in the mucus only the highest level of GLP was effective. No significant differences were observed in mucus alkanine phosphatase activity, while fish fed 0.25% of GLP had noticeably higher serum lysozyme activity. The mucus total protein electrophoretic pattern revealed some differences between the control and the treated fish. Two high MW bands were present in the control group but not in the treated groups. Three bands with a low MW comprised between 35 and 17 mw were noticed in GLP fed carps and not in the control. Gene expression studies revealed no noticeable alterations in TNF-alpha gene between treated fish and control. However, the level of expression of IL-8 was strongly upregulated in fish fed 0.5 and 1% of GLP. Also, feeding on 0.5% of GLP significantly upregulated IL1b gene expression. Evaluation of growth performance revealed improved performance parameters in GLP treated groups. These results confirmed possible immunomodulatory and beneficial effects of GLP on common carp fingerlings. PMID- 30521969 TI - Early impact of pulmonary stereotactic fractionated body radiotherapy (SBRT) on Quality of Life (QoL): Benefit for patients with low initial scores (STRIPE trial). AB - INTRODUCTION: Quality of life (QoL) of comorbid patients with pulmonary malignancies is a key issue in considering stereotactic fractionated body radiotherapy (SBRT) indication. This study investigates the early impact of SBRT on QoL. METHODS: 100 patients with pulmonary lesions were treated with SBRT from 02/2011 to 11/2014 within the prospective, monocenter, phase II STRIPE trial. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core module (EORTC QLQ-C30) and the QLQ-LC13 lung cancer-specific questionnaire were used to evaluate QoL before and 2, 7 weeks after SBRT, then 3 monthly for 2 years. We report on the analysis of early changes from baseline to 7 week-Follow up (FU). Impact of patient- and treatment-related factors on the change in QoL was analyzed. RESULTS: QoL was assessed in 97 patients; compliance was 92% and 85% at baseline and 7 weeks after SBRT. No clinically relevant changes >=10 in QoL/Global health status (GHS), function scores and inquired symptoms were observed. Patients with baseline QoL below the median showed clinically relevant improvement in QoL/GHS (Delta16.7 +/- 25.3, p=0.003), Emotional Function (Delta14.4 +/- 25.4, p=0.013), and fatigue (Delta -10.1 +/- 26.5, p=0.089), in contrast to patients with high initial scores. No changes were observed in the dichotomized subgroups of initial Karnofsky Index, Charlson Comorbidity Index, age, diagnosis and tumor localization. CONCLUSIONS: In short term FU QoL is well maintained after pulmonary SBRT. Especially patients with low initial QoL/GHS scores show benefit from SBRT with respect to QoL. PMID- 30521971 TI - EGFR-mutant SCLC exhibits heterogeneous phenotypes and resistance to common antineoplastic drugs. AB - INTRODUCTION: Approximately 5% of patients with EGFR-activating mutations acquire EGFR-TKIs resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR-mutant SCLC that has transformed from adenocarcinoma remain unclear. METHODS: In this study, we established 2 EGFR mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR-TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome. RESULTS: These 2 EGFR-mutant SCLC cell lines displayed 2 different phenotypes: suspensive and adherent. Both phenotypes shared the same genomic alterations analyzed by array-based comparative genomic hybridization (aCGH) assay. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in adherent cells. Principal component analysis (PCA) and hierarchical clustering analysis of RNA microarray revealed that these 2 cell lines displayed a unique gene expression pattern that was distinctly different from that in NSCLC and classical SCLC cells. Combined treatment using an EGFR-TKI and an AKT inhibitor attenuated cell viabilities in our 2 cell lines. Moreover, the use of a histone deacetylase (HDAC) inhibitor significantly inhibited the cell viabilities of both cell lines in vitro and in vivo. CONCLUSION: Our findings suggest that EGFR-mutant SCLC may be a distinct subclass of SCLC that exhibits epithelial mesenchymal transition (EMT) phenotypes, and adding an AKT or HDAC inhibitor to pre-existing therapies may be one of the therapeutic choices for transformed EGFR mutant SCLC. PMID- 30521970 TI - The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy: A post-hoc analysis of the ADJUVANT trial (CTONG 1104). AB - INTRODUCTION: Adjuvant gefitinib therapy prolonged disease-free survival (DFS) in patients with resected early-stage epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized. METHODS: Overall, 222 stage N1-N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure, sites and data of first treatment failure were recorded. A post-hoc analysis of treatment failure patterns, which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat (mITT) patients was conducted. RESULTS: There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the CNS in the gefitinib group (29/106 [27.4%]), extracranial metastases were most frequent in the VP group (32/87 [36.8%]). Temporal distribution analysis demonstrated lower tumor recurrence with gefitinib than with VP 0-21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9-15 months with VP and 24-30 months with gefitinib. The highest peak for CNS metastases post-surgery occurred after 12-18 months with VP and 24-36 months with gefitinib. CONCLUSIONS: Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant TKIs may be considered as a treatment option in resected stage N1-N2 EGFR-mutant NSCLC but longer duration should be explored. PMID- 30521972 TI - Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients with ALK-positive NSCLC Following Treatment with Crizotinib. AB - INTRODUCTION: The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib in the real-world clinical setting. METHODS: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) who received crizotinib, during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of 5 medical specialists. RESULTS: The safety analysis set included 2,028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade >=3. Pulmonary oedema-like shadows with or without diffuse alveolar damage pattern were observed in the crizotinib associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. The ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age >=55 years, ECOG PS 2-4, smoking history, previous or concomitant ILD and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. CONCLUSIONS: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD. PMID- 30521973 TI - Loss of enzyme activity in mutated B4GALNT1 gene products in patients with hereditary spastic paraplegia results in relatively mild neurological disorders: Similarity with phenotypes of B4galnt1 knockout mice. AB - B4GALNT1 is an enzyme essential for the synthesis of complex gangliosides, whose absence leads to progressive neurodegeneration with aging in mice. Recently, eleven cases of hereditary spastic paraplegia with mutation in the coding region of B4GALNT1 were reported. However, changes in the enzymatic activity of their products have never been studied. We have constructed expression vectors for individual mutant cDNAs, and examined their activities by cell-free in vitro enzyme assays, and flow cytometry of cells transfected with their expression vectors. Among them, almost all mutant genes showed the complete loss of B4GALNT1 activity in both the in vitro enzyme assays and flow cytometry. Two mutants exceptionally showed weak activity. One of them, M4, had a mutation at amino acid 228 with a premature termination codon. Interestingly, the intensity of fluorescence of GM2 measured by flow cytometry was equivalent between the WT and M4 mutant, although the positive cell population was relatively small in M4. Western immunoblotting of cell lysates from transfectants with cDNA plasmids revealed 67-kDa bands except those containing premature termination codons or frame-shift mutation. Taken together with the clinical findings of patients, loss of enzyme activity may be responsible for the clinical features of hereditary spastic paraplegia, whereas the intensity of neurological disorders was relatively milder than expected. These clinical features of patients including those with male hypogonadism are very similar to the abnormal phenotypes detected in B4GALNT1-deficient mice. PMID- 30521974 TI - Pulmonary impairment following respiratory viral infections is associated with high mortality in allogeneic hematopoietic cell transplant recipients. AB - INTRODUCTION: Pulmonary impairment predicts increased mortality in many settings, and respiratory viral infection (RVI) causes considerable morbidity and mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT). We hypothesized that pulmonary impairment following respiratory viral infection, defined as a decline of forced expiratory volume in 1 second values by >=10%, may identify allo-HCT recipients at high risk for mortality. METHODS: We studied all allo-HCT recipients at our institution who had RVI with respiratory syncytial virus, parainfluenza virus, or influenza from 2004-2013 and had pre-RVI and post RVI pulmonary function tests. We used competing risk regression models to identify risk factors for 2-year non-relapse mortality (NRM) as the primary outcome after RVI and relapse-related mortality as a competing risk. RESULTS: From 223 eligible patients, pulmonary impairment following RVI was associated with over a 3-fold increase in 2-year NRM (pulmonary impairment: 25.3%; no impairment: 7.4%, univariate sub-hazard ratio [SHR] 3.9, 95% confidence interval [CI] 1.9-8.1, p<0.001). After adjusting for age and systemic steroid use, pulmonary impairment following RVI was still associated with increased 2-year NRM (SHR, 3.3 [95% CI, 1.6-6.9]; p=0.002). After adjustment for race and GVHD prophylaxis, chronic GVHD at the time of RVI (OR, 2.8 [95% CI, 1.4-5.4]; p=0.003) and lymphopenia (OR, 2.2 [95% CI, 1.1-4.2]; p=0.02) were associated with increased odds of pulmonary impairment, whereas use of non-myeloablative conditioning was associated with reduced odds of pulmonary impairment (OR, 0.4 [95% CI, 0.2-0.8]; p=0.006). CONCLUSION: In allo-HCT recipients with RVIs, pulmonary impairment following RVI is associated with high NRM at 2 years. PMID- 30521976 TI - An integrated quantitative proteomic and metabolomics approach to reveal the negative regulation mechanism of LamB in antibiotics resistance. AB - Previously, a maltose-specific channel porin, LamB was found to be associate with multi-drug resistance in a lamB deleted strain, but the exact mechanisms require further elucidation. Herein, differential protein expression between the Escherichia coli mutant strain DeltalamB and the wild type strain BW25113, with and without ciprofloxacin (CFLX), was identified using iTRAQ based liquid chromatography-tandem mass spectrometry (LC-MS/MS); while differential metabolite expression was examined using gas chromatography-mass spectrometry (GC-MS). Further Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that lamB deletion leads to a decrease in several key metabolic pathways such as tricarboxylic acid (TCA) cycle, pentose phosphate pathway and glycolysis/gluconeogenesis. When examining the DeltalamB strain without CFLX, many aminoacyl-tRNA biosynthesis and pyrimidine metabolism-related proteins were unaltered, but the addition of CFLX resulted in reduced levels. These findings indicate that a lamB deletion may confer antibiotic resistance by relieving the pressure of protein translation and DNA replication. To further examine antibiotic resistance, exogenous metabolites, including maltose, and several amino acids metabolites were evaluated to determine whether the resistance level could be reduced in the presence of CFLX. The obtained results indicate that lamB knockout may increase bacterial antibiotics resistance by decreasing metabolic pathway activity levels. PMID- 30521977 TI - Dirhodium (II) complex interferes with iron-transport system to exert antibacterial action against Streptococcus pneumoniae. AB - Drug resistance in bacteria is becoming a significant threat to global public health, and the development of novel and efficient antibacterial compounds is urgently needed. Recently, rhodium complexes have attracted attention as antimicrobial agents, yet their antibacterial mechanism remains unknown. In this study, we observed that the dirhodium (II) complex Rh2Ac4 inhibited Streptococcus. pneumoniae growth without significant cytotoxic side-effects on host cells in vitro. We subsequently investigated the antibacterial mechanism of Rh2Ac4 using iTRAQ-based proteomics combined with cellular and biochemical assays. Bioinformatics analysis on the proteomic alterations demonstrated that six molecular functional groups, including metal ion binding and twelve metabolic pathways, were significantly affected after treatment with Rh2Ac4. The interaction network analysis of metal ion binding proteins suggested that Rh2Ac4 decreased the protein expression levels of SPD_1652, SPD_1590 and Gap, which are associated with haem uptake/metabolism. Cellular and biochemical assays further confirmed that Rh2Ac4 could be taken up by bacteria via the PiuABCD haem-uptake system. The structurally similar Rh complex may compete with Fe-haem to decrease Fe-uptake via the PiuABCD system, disrupting iron metabolism to exert its antibacterial activity against S. pneumoniae. These data indicate that Rh2Ac4 is a promising new drug for the treatment of S. pneumoniae infections. PMID- 30521975 TI - Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. AB - Non-graft-versus-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complications and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care. PMID- 30521978 TI - Proteomic analysis of olfactory bulb suggests CACNA1E as a promoter of CREB signaling in microbiota-induced depression. AB - Major depressive disorders impact approximately 17% of the population worldwide, whose high morbidity and considerable adversity have resulted in enormous social and economic burden. In addition, clinically depressed patients often show reduced volume of olfactory bulb (OB) and decreased olfactory sensitivity. Although mounting evidence conveyed that the gut microbiota may implicate the pathophysiology of major depressive disorder (MDD) via the microbe-gut-brain axis, knowledge about its distinctive molecular mechanism is rudimentary. Herein, iTRAQ coupled with LC-MS/MS was applied to compare the OB proteome between "pathological microbiota" and "healthy microbiota" germ-free mice. A set of 367 proteins were differentially identified in the OB, including 119 up-regulated and 248 down-regulated proteins compared with the levels in controls. A combined analysis with significantly changed OB proteins from CUMS depression model supported the role of CREB signaling, whose dysregulation is likely to disrupt the axonogenesis of OB under microbiota condition. With that, the down-regulated CACNA1E and its downstream proteins (CALM/ CaMKII/ CREB/ BDNF) in CREB pathway were validated by Western blot. Meanwhile, the canonical pathways involved Nuclear Receptor Signaling highlighted the fecal microbiota transplantation (FMT) model, which would be a new breakthrough for depressive research. These findings enrich the previous research achievements about the gut microbiota in psychiatric disorders, providing a creative insight into the intricate mechanisms of OB dysfunction in depression. SIGNIFICANCE: Emerging evidence has shown that gut microbiota can greatly influence brain functions and even behaviors. As one of the post-developmental neurogenesis areas for the adult brain, the OB is becoming increasingly important in the study of the pathogenesis of depression. Using an iTRAQ-based proteomics, we identified 367 altered proteins in the OB of fecal microbiota transplanted mouse, which provide a novel insight for further research of the "microbiota-gut-brain axis". In addition, combined analyses with the CUMS depression model and the validation of key proteins by Western blot may assist in the investigation of OB dysfunction in mental sickness. PMID- 30521979 TI - First ethnobotanical inventory and phytochemical analysis of plant species used by indigenous people living in the Maromizaha forest, Madagascar. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Characterized by one of the highest rates of endemism and biodiversity in the world, Madagascar provides a wide variety of medicinal plants, that could represent a potential source of new drugs. The main aim of this study was to investigate the potential medicinal properties of the plant species used by indigenous people in Maromizaha forest and to provide the first ethnobotanical inventory of the area. MATERIALS AND METHODS: Data were collected through open semi-structured interviews with local informants, the reported plants were collected and identified to create a specimen herbarium. Informant Consensus Factor (ICF) was calculated for each ailment category mentioned in the use-reports. A selection of seven medicinal plants was submitted to phytochemical and antimicrobial analysis. The results were discussed and compared with those described in ethnobotanical and pharmacological literature. RESULTS: One hundred and three villagers were interviewed and a total of 509 use reports were recorded. Information on 117 plant species belonging to 57 botanical families were provided. 12 categories of indigenous uses were recognized, among them the higher ICF values were recorded for cardiovascular complaints (0.75), general and unspecific diseases (0.74), digestive disorders (0.69), and diseases of the skin (0.55). The traditional medicinal uses of 18 species (15 endemic) were described for the first time. In total, 22 different bioactive compounds were identified; polyphenols, monoterpenes, organic acids, and vitamin C were observed in the chemical composition of all the analyzed samples. Macaranga perrieri showed the highest values of both total polyphenolic compounds and antioxidant activity. Antimicrobial activity was observed in leaf and bark extracts of Dilobeia thouarsii. CONCLUSION: These results confirmed the importance of investigating the traditional use of plant species, suggesting the crucial role of ethnobotanical studies for rural development, biodiversity conservation, and the sustainable use of plant resources in the studied area. PMID- 30521980 TI - Genus Psoralea A review of the traditional and modern uses, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Psoralea (Fabaceae) harbours 105 accepted species that are extensively used by local peoples and medicinal practitioners of China, India, and other countries for treatment of tooth decay, psoriasis, leucoderma, leprosy, kidney problems, tuberculosis, indigestion, constipation and impotence. Presently, pharmacological research reports are available on only few species namely Bituminaria bituminosa (Syn: P. bituminosa), P. canescens, P. corylifolia, P. esculenta, P. plicata and P. glandulosa which are valued for their chemical constituents and traditional uses. AIM OF THE REVIEW: This review article provides explicit information on traditional uses, phytochemistry, and pharmacological activities of selected Psoralea species. The possible trends and perspectives for future research on these plants are also discussed. MATERIALS AND METHODS: An extensive and systematic review of the extant literature was carried out, and the data under various sections were identified using a computerized bibliographic search via the PubMed, Web of Science and Google Scholar, CAB Abstracts, MEDLINE, EMBASE, INMEDPLAN, NATTS as well as several websites. KEY FINDINGS: A total of 291 bioactive compounds from 06 species of genus Psoralea have been isolated and characterized. However, P. bituminosa alone possess nearly 150 compounds. These bioactive compounds belong to different chemical classes, including flavonoids, coumarins, furanocoumarins, chalcones, quinines, terpenoids and some others due to which these species exhibit significant anti-oxidant, anti-bacterial, anti-fungal, anti-viral, anti helmintic, anti-diabetic, diuretic, hepatoprotective, anti-cancer and anti-tumour activities. P. corylifolia L. (Babchi), a Chinese traditional medicinal plant has been used in traditional medicine for many decades for its healing properties against numerous skin diseases such as leprosy, psoriasis and leucoderma. CONCLUSIONS: The in vitro studies and in vivo models have provided a simple bio scientific justification for various ethnopharmacological uses of Psoralea species. From the toxicological perspective, the root, leaf, and seed extracts and their preparations have been proven to be safe when consumed in the recommended doses. But, meticulous studies on the pharmaceutical standardization, mode of action of the active constituents, and sustainable conservation of Psoralea species are needed, to meet the growing demands of the pharmaceutical industries, and to fully exploit their preventive and therapeutic potentials. PMID- 30521981 TI - Interferons Transcriptionally Up-Regulate MLKL Expression in Cancer Cells. AB - Interferons (IFNs) are key players in the tumor immune response and act by inducing the expression of IFN-stimulated genes (ISGs). Here, we identify the mixed-lineage kinase domain-like pseudokinase (MLKL) as an ISG in various cancer cell lines. Both type I and type II IFNs increase the expression of MLKL indicating that MLKL up-regulation is a general feature of IFN signaling. IFNgamma up-regulates mRNA as well as protein levels of MLKL demonstrating that IFNgamma transcriptionally regulates MLKL. This notion is further supported by Actinomycin D chase experiments showing that IFNgamma-stimulated up-regulation of MLKL is prevented in the presence of the transcriptional inhibitor Actinomycin D. Also, knockdown of the transcription factor IFN-regulatory factor 1 (IRF1) and signal transducer and activator of transcription (STAT) 1 as well as knockout of IRF1 significantly attenuate IFNgamma-mediated induction of MLKL mRNA levels. Up regulation of MLKL by IFNgamma provides a valuable tool to sensitize cells towards necroptotic cell death and to overcome apoptosis resistance of cancer cells. PMID- 30521982 TI - Water drop-surface interactions as the basis for the design of anti-fogging surfaces: Theory, practice, and applications trends. AB - Glass- and polymer-based materials have become essential in the fabrication of a multitude of elements, including eyeglasses, automobile windshields, bathroom mirrors, greenhouses, and food packages, which unfortunately mist up under typical operating conditions. Far from being an innocuous phenomenon, the formation of minute water drops on the surface is detrimental to their optical properties (e.g., light-transmitting capability) and, in many cases, results in esthetical, hygienic, and safety concerns. In this context, it is therefore not surprising that research in the field of fog-resistant surfaces is gaining in popularity, particularly in recent years, in view of the growing number of studies focusing on this topic. This review addresses the most relevant advances released thus far on anti-fogging surfaces, with a particular focus on coating deposition, surface micro/nanostructuring, and surface functionalization. A brief explanation of how surfaces fog up and the main issues of interest linked to fogging phenomenon, including common problems, anti-fogging strategies, and wetting states are first presented. Anti-fogging mechanisms are then discussed in terms of the morphology of water drops, continuing with a description of the main fabrication techniques toward anti-fogging property. This review concludes with the current and the future perspectives on the utility of anti-fogging surfaces for several applications and some remaining challenges in this field. PMID- 30521983 TI - Reasonable expectations of privacy in non-disclosure of familial genetic risk: What is it reasonable to expect? AB - Where there is conflict between a patient's interests in non-disclosure of their genetic information to relatives and the relative's interest in knowing the information because it indicates their genetic risk, clinicians have customarily been able to protect themselves against legal action by maintaining confidence even if, professionally, they did not consider this to be the right thing to do. In ABC v St Georges Healthcare NHS Trust ([2017] EWCA Civ 336) the healthcare team recorded their concern about the wisdom of the patient's decision to withhold genetic risk information from his relative, but chose to respect what they considered to be an unwise choice. Even though professional guidance considers that clinicians have the discretion to breach confidence where they believe this to be justified, (Royal College of Physicians, Royal College of Pathologists and the British Society of Human Genetics, 2006; GMC, 2017) clinicians find it difficult to exercise this discretion in line with their convictions against the backdrop of the legal prioritisation of the duty to maintain confidence. Thus, the professional discretion is not being freely exercised because of doubts about the legal protection available in the event of disclosure. The reliance on consent as the legal basis for setting aside the duty of confidence often vetoes sharing information with relatives. This paper argues that an objective approach based on privacy, rather than a subjective consent based approach, would give greater freedom to clinicians to exercise the discretion which their professional guidance affords. PMID- 30521984 TI - The Bacterial Metabolite Indole Inhibits Regeneration of the Planarian Flatworm Dugesia japonica. AB - Planarian flatworms have been used for over a century as models for regeneration. Planarians live in aquatic environments with constant exposure to microbes, but the mechanisms by which bacteria may mediate planarian regeneration are largely unknown. We characterized the microbiome of laboratory populations of the planarian Dugesia japonica and determined how individual bacteria impact D. japonica regeneration. Eight to ten taxa in the phyla Bacteroidetes and Proteobacteria consistently occur across planarian colonies housed in different research laboratories. Individual members of the D. japonica microbiome can delay regeneration including the development of eye spots and blastema formation. The microbial metabolite indole is produced in significant quantities by two bacteria that are consistently found in the D. japonica microbiome and contributes to delays in regeneration. Collectively, these results provide a baseline understanding of the bacteria associated with the planarian D. japonica and demonstrate how metabolite production by host-associated microbes can affect regeneration. PMID- 30521985 TI - Physiological and biochemical effect of silver on the aquatic plant Lemna gibba L.: Evaluation of commercially available product containing colloidal silver. AB - This paper aims to evaluate the effects of a product containing colloidal silver in the aquatic environment, using duckweed Lemna gibba as a model plant. Therefore, growth parameters, photosynthetic pigments content and protein content as physiological indices were evaluated. Changes in the content of non-enzymatic antioxidants and activity of several antioxidant enzymes, alongside with the accumulation of hydrogen peroxide and lipid peroxidation end-products were assessed to explore the potential of colloidal silver to induce oxidative stress. The commercially available colloidal silver product contained a primary soluble form of silver. The treatment with colloidal silver resulted in significant physiological and biochemical changes in L. gibba plants and a consequent reduction of growth. Accumulation of silver caused altered nutrient balance in the plants as well as a significant decrease in photosynthetic pigments content and protein concentration. The antioxidative response of L. gibba plants to treatment with colloidal silver was inadequate to protect the plants from oxidative stress caused by metal accumulation. Silver caused concentration dependent and time-dependent hydrogen peroxide accumulation as well as the elevation of lipid peroxidation levels in L. gibba plants. The use of commercially available products containing colloidal silver, and consequent accumulation of silver, both ionic and nanoparticle form in the environment, represents a potential source of toxicity to primary producers in the aquatic ecosystem. PMID- 30521986 TI - Phyllodes tumors of the breast. The treatment results for 340 patients from a single cancer centre. AB - PURPOSE: The primary treatment of choice for patients with phyllodes tumor of the breast (PTB) is surgery. Two major problems regarding the treatment of such patients remain unclear: what is the appropriate surgical margin and what role is played by adjuvant radiotherapy (ART). METHODS: The study provides a retrospective review of all patients with PTB treated between 1952 and 2013 at a single institute. The histology slides were re-examined based on WHO criteria. The clinical characteristics and therapy outcomes were obtained. The five-year survival with no evidence of disease (NED) was used as the end point. RESULTS: The study population comprised 340 women with PTB. Fifty-five percent of the patients were diagnosed with the benign, 11.8% with borderline and 33.2% with malignant PTB. All the patients received primary treatment with surgery (mastectomy-27.1%, and BCS- 72.9%). Local recurrence (LR) was found in 28 (9.1%) of these patients. Four patients with borderline and 8 with malignant PTB who were treated with BCS and had tumor-free margins < cm received ART. None of these patients had LR and all survived 5 years NED. Of the 340 patients from our group, 294 (86.4%) survived five-years NED. CONCLUSION: The prognosis for benign PTB is excellent and can be cured with surgery alone. A sufficient margin would be 0.1 cm (data from the literature) or 0.2-0.4 cm (our study). We recommend application of ART for such patients but the role of ART in patients with borderline and malignant PTB treated with BCS and with surgical margin < cm remains uncertain. PMID- 30521987 TI - A PALB2 truncating mutation: Implication in cancer prevention and therapy of Hereditary Breast and Ovarian Cancer. AB - Explaining genetic predisposition in Hereditary Breast and Ovarian Cancer (HBOC) families without BRCA mutations is crucial. Germline PALB2 inactivating mutations were associated with an increased risk of HBOC due to its role in DNA repair through cooperation with BRCA proteins. The prevalence and penetrance of PALB2 mutations in Spanish HBOC patients remains unexplained. PALB2 mutation screening has been conducted in 160 high-risk BRCA-negative patients and 320 controls. We evaluated four predicted splicing disruption variants and large genomic rearrangements by multiplex ligation-dependent probe amplification. We have found a frameshift mutation which segregates in an early onset cancer family; and four rare missense variants. None of the variants tested for a predicted splicing disruption showed an aberrant transcript pattern. No large genomic rearrangements were detected. Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population. PALB2 screening may improve genetic counselling through prevention measures, pedigree management and PARP inhibitor therapy selection. PMID- 30521988 TI - Computational study of new 1,2,3-triazole derivative of lithocholic acid: Structural aspects, non-linear optical properties and molecular docking studies as potential PTP 1B enzyme inhibitor. AB - We have reported synthesis of a novel 1,2,3-triazole conjugate of lithocholic acid by 1,3-dipolar cycloaddition reaction. The molecular properties such as geometry, conformations, bond lengths and dihedral angles were investigated theoretically. The bond order analysis was performed using Wiberg bond order (WBO), Fuzzy bond order (FBO) and Laplacian bond order (MBO) method. Electronic properties of molecule such as electrostatic surface potential analysis, frontier molecular orbital analysis, reduced density gradient, total density of states, and global chemical reactivity indices have been investigated. The nonlinear optical properties were also investigated. Total dipole moment, mean polarizability and hyperpolarizability were found to be much higher than standard urea molecule which suggests that it could act as potential NLO material. The molecular docking calculations are also performed to investigate its potential as PTP 1B enzyme inhibitor. PMID- 30521989 TI - Effect of proteases secreted from a marine isolated bacterium Bacillus vietnamensis on the corrosion behaviour of different alloys. AB - The adverse corrosion and corrosion inhibitory effects of the marine isolated bacterium Bacillus vietnamensis were determined on different alloys. The corrosion rates of the steel alloys increased in the presence of Bacillu vietnamensis; although the alloys containing Cu were found to be protected from corrosion when exposed to this bacterium. The first assay bacterial mechanism confirmed the presence of protease enzyme, which was then identified by LC-MS/MS analysis. We proposed that Cu ions coordinated with proteases and bonded with water molecules. This coordination process decreased the oxygen availability in the environment, thereby inhibiting the corrosion of the copper alloys. PMID- 30521990 TI - Gastric wall fat halo sign in patients without intestinal disease. AB - PURPOSE: To investigate the relationship between gastric wall fat halo sign and visceral obesity with potentially associated diseases. MATERIALS AND METHODS: Between September 2015 and April 2017, 90 patients with gastric wall fat halo signs and 130 controls were prospectively evaluated. Patient height, weight, body mass index (BMI), sex, age, subcutaneous fat area (SFA), visceral fat area (VFA), total fat area (TFA), percentage of visceral fat (VF%) and the presence of colic or ileal fat halo signs, hepatic steatosis and aortic calcified plaques were recorded for the two groups. Cut-off values for the VFA, TFA, and VF% were determined and the diagnostic efficacy was calculated using receiver operating characteristic (ROC) curve analysis. RESULTS: No significant differences were found in age, BMI and SFA, but the VFA, VF%, TFA and frequencies of colic or ileal fat halo signs, hepatic steatosis and aortic calcified plaques were significantly higher in the patient group. The areas under the ROC curve (AUCs) were 0.803, 0.770 and 0.596 for VFA, VF% and TFA, respectively. The diagnostic efficacies of VFA and VF% were significantly higher than those of the TFA. CONCLUSION: Gastric wall fat halo signs may be observed in overweight people, especially those with increased VFA and VF%. Additionally, these signs are usually observed along with fat halo signs of the colon or terminal ileum. However, extensive studies are needed to clarify the relationship between gastric wall fat halo signs and type 2 diabetes, cardiovascular diseases and metabolic syndrome. PMID- 30521991 TI - Combined juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia (JPS/HHT) with MRI and endoscopic correlation. AB - Juvenile polyposis syndrome (JPS) may coexist with hereditary hemorrhagic telangiectasia (HHT) due to implication of the SMAD4 gene in a subset of both diseases. To the best of our knowledge, we present the first case in the radiologic literature on the MRI findings in a patient with this rare combined diagnosis undergoing workup for burden of disease. PMID- 30521992 TI - Prevalence and correlates of physical inactivity among older adults in Malaysia: Findings from the National Health and Morbidity Survey (NHMS) 2015. AB - Malaysia has an increasingly aging population. Despite the substantial benefits of physical activity for healthy aging, older adults are considered the most physically inactive segment of the Malaysian population. The purpose of this study was to determine the prevalence of physical inactivity among older adults in Malaysia and its correlates. We analysed data on adults aged >=60 years (n = 3790) from the National Health and Morbidity Survey (NHMS) 2015, a cross sectional, nationwide population-based survey covering information on socio demographic characteristics, physical activity and other lifestyle-related variables, health conditions, and functional limitations. Individuals included in this study were classified as physically active or physically inactive. Logistic regression was used to determine factors associated with physical inactivity. The overall prevalence of physical inactivity among older adults aged >=60 years old was 48.8%. Physical inactivity was significantly more prevalent among females, older age groups, Indians, those being single/widowed/divorced, those with no formal education, those who reported high sedentary time (>=7 h/day), those with diabetes, anaemia, and functional limitations (p < 0.001). In fully adjusted analyses, females, older age, high household income (>=MYR4000), inadequate fruits and vegetables consumption (<5 servings/day), high sedentary time, having diabetes, and having mobility impairment were all associated with physical inactivity. Approximately half of the Malaysian older population are physically inactive. Identifying the correlates of physical inactivity among Malaysian older adults will help to develop public health policies and interventions that encourage active living among older people and promote healthy aging in Malaysia. PMID- 30521993 TI - Ultrasonic torsion welding of ageing-resistant Al/CFRP joints: Properties, microstructure and joint formation. AB - Ultrasonic metal welding is a promising process for joining light metals with fiber-reinforced thermoplastics. The technique is characterized by high reproducibility, short process times, low energy input, no additional filler materials and finally the possibility of extensive process data logging. With this process, dissimilar aerospace materials are ultrasonically welded and the applied process parameters are optimized by statistical methods. A prediction of ageing resistance is possible by the evaluation of the electrical resistivity of the multi-material-joints. With the help of detailed process parameter recording and microscopic investigations, the bonding mechanism of hybrid AA5024/(GF-)CF PEEK joints is explained and the kinematics of bonding formation is presented in detail. PMID- 30521994 TI - A multifunctional compound ebselen reverses memory impairment, apoptosis and oxidative stress in a mouse model of sporadic Alzheimer's disease. AB - Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1-10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 MUl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl 2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ. PMID- 30521995 TI - Stroke risk and outcomes in epilepsy patients: Two retrospective cohort studies based on National Health Insurance in Taiwan. AB - BACKGROUND AND AIMS: The risk of stroke in epileptic patients and the impact of epilepsy history on stroke patients' outcome have not been studied completely. Our purpose is to evaluate whether patients with epilepsy have increased risk of stroke or post-stroke mortality. METHODS: In Study I, we conducted a retrospective cohort study of 6746 patients with newly diagnosed epilepsy and 26,984 persons without epilepsy between 2000 and 2008, in the database of National Health Insurance in Taiwan. The incidences and risks of stroke during the follow-up period were compared between cohorts until the end of 2013. In Study II, we conducted a nested cohort study of 484,990 hospitalized patients with newly diagnosed stroke between 2000 and 2009. We compared the short-term mortality and complications during stroke admission between stroke patients with previous epilepsy and those without epilepsy. RESULTS: The epileptic cohort had an increased stroke risk (hazard ratio [HR] 2.24, 95% CI 2.02 to 2.49). The relationship between epilepsy and stroke risk remains significant in every age group and both sexes. Among hospitalized stroke patients, history of epilepsy was associated with complications, including pneumonia (odds ratio [OR] 1.08, 95% CI 1.00 to 1.18), urinary tract infection (OR 1.16, 95% CI 1.08 to 1.26), and longer stay (p < 0.0001) during the index stroke admission. CONCLUSIONS: Epileptic patients face increased stroke risk and adverse outcomes of stroke admission. It is necessary to develop a prevention strategy for stroke in epileptic patients. PMID- 30521996 TI - Investigation on the binding of aloe-emodin with tyrosinase by spectral analysis and molecular docking. AB - In this paper, the inhibitory kinetics of aloe-emodin on the activity of tyrosinase and the inhibitory mechanism have been investigated by using spectroscopic and molecular docking techniques. The results showed that aloe emodin inhibited tyrosinase activity in a competitive manner. The binding constants, number of binding sites and thermodynamic parameters obtained at different temperature suggested that aloe-emodin spontaneously binds to tyrosinase at one binding site, mainly via electrostatic forces. Analysis by UV vis absorption (UV), circular dichroism (CD) and molecular docking indicated that aloe-emodin bound directly into the catalytic cavity and that binding of aloe emodin to tyrosinase induced conformational changes of the enzyme and blocked the catalytic center of the enzyme preventing binding of the substrate, which caused the inhibition of the tyrosinase activity. PMID- 30521997 TI - Fast sensing of imidacloprid residue in tea using surface-enhanced Raman scattering by comparative multivariate calibration. AB - This study focused on the fabrication of a rapid, highly sensitive and inexpensive technique for the quantification of imidacloprid residue in green tea, based on surface-enhanced Raman scattering (SERS) using highly roughned surface flower shaped silver nanostructure (as SERS substrate) coupled with the chemometrics algorithm. The basic principle of this method is imidacloprid yielded SERS signal after adsorption on Ag-NF under laser excitation by the electromagnetic enhancement and the intensity of the peak is proportional to the concentration ranging from 1.0 * 103 to 1.0 * 10-4 MUg/mL. Among the models used, the GA-PLS (Genetic algorithm-partial least square) exhibited superiority to quantify imidacloprid residue in green tea. The model achieved Rp (correlation coefficient) of 0.9702 with RPD of 4.95% in the test set and RSD for precision recorded up to 4.50%. Therefore, the proposed sensor could be employed to quantify imidacloprid residue in green tea for the safeguarding of quality and human health. PMID- 30521998 TI - A perspective on biogenic synthesis of platinum nanoparticles and their biomedical applications. AB - In recent era, the interest on inorganic nanoparticles is augmenting due to their engrossing and uncanny properties. Among them, platinum nanoparticles (PtNPs) are highly remarkable owing to their intrinsic physicochemical and biological properties making them an effective candidate towards catalytic and biomedical applications. Nevertheless, conventional physical and chemical methodologies of PtNPs synthesis are among the most prevalent protocols to synthesize PtNPs of desired shape and size. However, the above methods create notable concern to health and environment due to the use of harsh and toxic chemicals as well as violent reaction conditions. Hence, an economic, eco-friendly, non-toxic and sustainable route for the synthesis of PtNPs is the need of the hour to circumvent the shortcomings associated with conventional methodologies. In this aspect, the approach of green synthesis has lightened up the way for the environmentally benign synthesis of PtNPs. Interestingly, this review focuses chiefly on the green synthesis of PtNPs from various biological entities such as microorganisms, plants, seaweeds and other innovative miscellaneous protocols. Furthermore, it also summarizes the potential biomedical applications of PtNPs especially as an antibacterial agent and their role as nanomedicine. Overall, the emerging biogenic synthesis of PtNPs makes it feasible to foresee more promising biomedical outcomes in the upcoming future. PMID- 30521999 TI - Examining the factor structure of the self-report Yale-Brown Obsessive Compulsive Scale Symptom Checklist. AB - Obsessive-compulsive symptom dimensions are important in studies about the pathogenesis and treatment of obsessive-compulsive disorder. More than 30 factor analytic studies using the Yale-Brown Obsessive Compulsive Scale Symptom Checklist (Y-BOCS-SC) interview version have been published. However, a drawback of the Y-BOCS-SC interview is that it is time-consuming for the clinician. Baer's self-report version of the Y-BOCS-SC could be a less time-consuming alternative. The purpose of this study was to examine the factor structure of Baer's self report Y-BOCS-SC. In a sample of 286 patients, we performed two factor analyses, one using categories and one using items of the Y-BOCS-SC. Using category-level data, we identified four factors; when using items we identified six factors. Symptom dimensions for contamination/cleaning, symmetry/repeating/counting/ordering and hoarding were found in both analyses. The impulsive aggression, pathological doubt, sexual, religious somatic and checking categories formed one factor in the analysis using category-level data and divided into three factors using item-level data. These factors correspond with studies using the interview version and support our hypothesis that the self report version of the Y-BOCS-SC could be an alternative for the interview version. PMID- 30522000 TI - Metabolic syndrome, depression and anhedonia among young adults. AB - The aim of this study was to assess the association between anhedonia and metabolic syndrome (MetS) in a well-characterized community sample of individuals with a current depressive episode. This is a cross-sectional study with young adults aged 24-30 years old. Depressive episode and the presence of anhedonia was assessed using the Mini International Neuropsychiatric Interview - Plus version (MINI Plus). The MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III). The sample included 931 subjects, being 22 had depression without anhedonia, whereas 55 had depression with anhedonia. MetS was more prevalent among subjects with depression and anhedonia (43.6%) when compared to individuals without anhedonia and population control group. Moreover, subjects with depression and anhedonia have a significant increase of levels of glucose, triglycerides, total-cholesterol and LDL-cholesterol, as well as significant decreased in the HDL-cholesterol level. The present study showed that individuals with depression and anhedonia present higher prevalence of MetS. Our study suggests that the use of the concept of anhedonia may contribute to a better understanding of the complex relationship between depression and metabolic syndrome. PMID- 30522001 TI - Impact of short-term traffic-related air pollution on the metabolome - Results from two metabolome-wide experimental studies. AB - Exposure to traffic-related air pollution (TRAP) has been associated with adverse health outcomes but underlying biological mechanisms remain poorly understood. Two randomized crossover trials were used here, the Oxford Street II (London) and the TAPAS II (Barcelona) studies, where volunteers were allocated to high or low air pollution exposures. The two locations represent different exposure scenarios, with Oxford Street characterized by diesel vehicles and Barcelona by normal mixed urban traffic. Levels of five and four pollutants were measured, respectively, using personal exposure monitoring devices. Serum samples were used for metabolomic profiling. The association between TRAP and levels of each metabolic feature was assessed. All pollutant levels were significantly higher at the high pollution sites. 29 and 77 metabolic features were associated with at least one pollutant in the Oxford Street II and TAPAS II studies, respectively, which related to 17 and 30 metabolic compounds. Little overlap was observed across pollutants for metabolic features, suggesting that different pollutants may affect levels of different metabolic features. After observing the annotated compounds, the main pathway suggested in Oxford Street II in association with NO2 was the acyl-carnitine pathway, previously found to be associated with cardio respiratory disease. No overlap was found between the metabolic features identified in the two studies. PMID- 30522002 TI - Developing crash prediction models using parametric and nonparametric approaches for rural mountainous freeways: A case study on Wyoming Interstate 80. AB - Interstate 80 in Wyoming is one of the busiest freight corridors that is characterized with harsh winter conditions and challenging mountainous roadway sections. The fatality rates in Wyoming are always typically higher than the national level. The 402-mile I-80 corridor in Wyoming was selected by the USDOT FHWA for piloting connected vehicle technology to improve the safety and mobility of heavy trucks. To accurately quantify the effectiveness of the pilot, evaluation of the pre-deployment safety performance is essential. Unlike other studies, the full 402-mile of I-80 corridor passing through Wyoming was investigated as a requirement of the USDOT. Homogeneous segmentation was used to divide the corridor based on horizontal and vertical roadway characteristics. A transferability analysis was conducted to investigate whether a short portion of the corridor would be representative of the whole 402-miles of I-80. Results showed that the whole 402 miles should be considered in the analysis due to the radical changes throughout the corridor. Several SPFs were developed using three models; negative binomial (NB) model, spatial autoregressive (SAR) model, and non parametric multivariate adaptive regression splines (MARS). Comparisons were performed for the developed models. Crash prediction models for total crashes and Fatal and Injury (F + I) crashes in addition to truck crashes were calibrated utilizing five years of crash data from 2012 to 2016. The results obtained from the three statistical approaches showed that MARS model provided a better model fit compared to NB and SAR models, given the lower AIC values for the developed models. Yet, SAR models showed the significant spatial dependency between the neighbor roadway segments. Additionally, the NB model showed its superiority on SAR when the spatial correlation was not significant. Parametric and non parametric techniques should be interchangeably used in developing SPFs according to the modeling needs. PMID- 30522003 TI - Using horizontal curve speed reduction extracted from the naturalistic driving study to predict curve collision frequency. AB - Many models have been developed to predict collision frequency and evaluate safety performance on horizontal curves. The approach used in data collection or some assumptions made in the analysis methodology might lead to inaccurate results. For example, manual data collection, equipment limitations, and field experiments involving monitoring driving behavior for a specific region for a short-term are potential sources of errors in data collection. This paper aims at overcoming some of these issues in developing models to evaluate safety performance of horizontal curves and predict the curve collision frequency. The developed models relate expected collision frequency on horizontal curves to the speed reduction from the approach tangent to the curve, which is commonly used as a major geometric design consistency measure. The methodology to achieve this objective included three tasks; data collection, evaluating and modeling the viable speed reduction parameters, and developing safety performance models to estimate collision frequency on horizontal curves. Individual drivers' trips on 49 horizontal curves on rural two-lane highways in rolling and mountainous terrains in Washington State were extracted from the Naturalistic Driving Study (NDS) database. Models were developed to relate different speed reduction parameters to curve characteristics. These models were then applied to 1430 horizontal curves in Washington State to estimate the speed reduction parameters and relate them to collision frequency. Several safety performance models were developed which show that speed reduction, as a design consistency measure, is directly related to collision frequency on horizontal curves. Furthermore, the speed reduction parameters are more significant variables in predicting collision frequency than all curve geometric parameters. PMID- 30522004 TI - Disgust, impulsivity and depressive dimensions in subjects at risk for bulimia nervosa and/or binge eating disorder. AB - PURPOSE: the study aims to assess the depressive symptoms, the disgust feeling and the impulsivity index in subjects showing a high risk of binge eating disorder (BED) and/or bulimia nervosa (BN) through a cross-sectional study of 150 participants. RESULTS: There was no significant difference regarding age, sex, employment and marital status between subjects at high risk for BED/BN (Group A) and controls (Group B). However, participants in group A presented higher scores of depressions (p = 0.021), impulsivity (p = 0.027) and Disgust (p = 0.030) with significant associations. CONCLUSION: The neurobiological basis for these associations might be related to a dysfunction in the insular cortex. PMID- 30522005 TI - Epigenetics and meditation. AB - In the last decade, epigenetics has taken center stage to explain the relationships between stress exposure, health and behavior. Acquired or inherited epigenetic changes modulate gene expression states without modifying the DNA sequence itself, they can be long-lasting, yet, they are potentially reversible. Several studies have explored whether meditation-based interventions can influence gene expression profiles towards healthier directions, identifying candidate genes and biological pathways that seem to be sensitive to contemplative practices. However, to date, the clinical implications of these molecular outcomes and their potential long-lasting epigenetic bases remain mostly unknown. The present article addresses these topics from a broad perspective and analyzes future research questions and perspectives at the crossroads of contemplative sciences and epigenetics. PMID- 30522006 TI - Food up-take and reproduction performance of Daphnia magna under the exposure of Bisphenols. AB - Because the application of Bisphenol A (BPA) was restricted, many substitutes, such as Bisphenol F (BPF) and Bisphenol S (BPS), were developed as BPA substitutes. Therefore, environmental impacts of BPA and its substitutes on aquatic organisms should be concerned, especially their combined toxicity. In this study, the impacts of BPA, BPF, BPS and their mixture on the feeding behavior, reproduction and physiological function of daphnids were synthetically evaluated, involving the duration and mode of exposure. In short-term exposure tests, feeding rates of D. magna decreased after exposure to BPA, BPF, BPS and their mixture, while the inhibition reversed into stimulation in the recovery period. It may benefit from overcompensation of D. magna. In long-term exposure tests, the inhibition effect on the reproduction and growth of the exposed D. magna was difficult to recover, and only some experimental groups have a certain recovery. In conclusion, environmental risk of BPA, BPF, BPS and their mixture on the behavior of D. magna increased with prolonged exposure time. Moreover, relative activities of trypsin, amylase (AMS), acetylcholinesterase (AChE), carbonic anhydrase (CA), glutathione peroxidase (GPx) and super oxidase dimutase (SOD) of the exposed daphnids decreased in most treatment groups, indicating the disorder of digestive, nervous and antioxidative system of D. magna. Interestingly, inhibition of enzymes activities decreased with the increase of the exposure time, which implied the tolerance may be occurred. PMID- 30522007 TI - Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans. AB - Secretion of the stress hormone cortisol follows a circadian rhythm and is stimulated following stress exposure. Cortisol regulates the transcription of several genes, primarily through activation of the glucocorticoid receptor (GR). Previously, we showed an upregulation of PERIOD genes PER1 and PER3 after pharmacological/glucocorticoid challenge in vivo and in vitro. The current study aims to investigate the temporal association between unstimulated, diurnal cortisol secretion and the expression of selected GR-target genes (PER1, PER2, PER3, FKBP5, GILZ and SDPR) in vivo to determine the timing of the most pronounced coupling between cortisol and mRNA expression. Unstimulated plasma and saliva cortisol concentrations and gene expression levels in whole blood were measured every 15 min from early morning until 16:00 h in 18 healthy men. Time lagged correlations of cortisol concentrations with mRNA expression levels were assessed allowing lags between -240 and + 240 min. Strong positive correlations at non-zero lags between cortisol levels and the expression of FKBP5 (plasma: r = 0.74 (CI = 0.65-0.81), p < 0.001, lag + 90 min; saliva: r = 0.71 (CI = 0.61 0.78), p < 0.001, lag + 75 min), and GILZ (plasma: r = 0.59 (CI = 0.46-0.69), p < 0.001, lag + 30 min; saliva r = 0.53 (CI = 0.41-0.63), p < 0.001, lag +15 min) were observed. Expressions of PERIOD genes and SDPR correlated only weakly with cortisol (all |r| < 0.25). Our findings demonstrate strong correlations between cortisol secretion and gene expression in humans under unstimulated conditions. The observed time-lags can guide future research aiming to characterize glucocorticoid-dependent gene expression in clinical samples with stress-related disorders. PMID- 30522008 TI - Loricate choanoflagellates (Acanthoecidae) from warm water seas?A I. Conioeca gen. nov. and Nannoeca Thomsen. AB - The main outcome of this and subsequent papers is to provide a baseline survey of heterotrophic protist diversity from warm water marine ecosystems, exemplified by loricate choanoflagellates (Acanthoecida). Loricate choanoflagellates are heterotrophic, nano-sized protists that are ubiquitous in marine and brackish water habitats. They dwell in a lorica formed by silicified costal strips organized in species specific patterns. The single anteriorly directed flagellum is surrounded by a collar formed by microvilli which together constitute the feeding apparatus. Keystone benefits from this warm water survey, which covers all three major oceans, is an improved understanding of global biogeographical patterns, and a further consolidation of the morphospecies matrix, that constitutes a highly essential reference framework for the current efforts to provide barcodes for as many species of loricate choanoflagellates as possible, based on e.g. single cell pipetting techniques. We describe here Conioeca gen. et sp. nov., which is so far distributionally confined to warm water habitats, and elaborate on the morphological variability encountered within the N. minuta complex. This leads to both the circumscription of a new N. minuta form A as well as the description of N. mexicana sp. nov. PMID- 30522009 TI - A dual-sensitive mesoporous silica nanoparticle based drug carrier for cancer synergetic therapy. AB - A multifunctional envelope-type mesoporous silica nanoparticle (MSN) was delicately designed for subcellular co-delivery of drug and therapeutic peptide to tumor cells. Firstly, a kind of cell apoptosis peptide (KLAKLAK)2 (KLA) was anchored on surface of MSN via disulfide bond to obtain MSN-SS-KLA. Subsequently, anticancer drug doxorubicin hydrochloride (DOX) was loaded into the pores of MSN SS-KLA. Then, the drug loaded MSN-SS-KLA (DOX@MSN-SS-KLA) was further coated with bovine serum albumin (BSA) to obtain a biological media stable MSN based drug delivery system (DDS), DOX@MSN-SS-KLA/BSA, for cancer synergetic therapy. The results show that stability of the DOX@MSN-SS-KLA/BSA is much better than that of DOX@MSN-SS-KLA and it could keep well dispersed in serum for more than 24 h. After accumulating at tumor site by EPR effect, the DOX@MSN-SS-KLA/BSA could be effectively phagocytosed by HeLa cells and release apoptotic peptide KLA as well as DOX simultaneously responding to reductive stimulus inside the cells. In vitro cell experiment results show that the DOX@MSN-SS-KLA/BSA complex exhibits much better inhibition on HeLa cells compared with pure DOX, indicating that co delivery of KLA and DOX is expected to achieve synergetic therapy of cancer. PMID- 30522010 TI - Chitosan microparticles embedded with multi-responsive poly(N-vinylcaprolactam-co itaconic acid-co-ethylene-glycol dimethacrylate)-based hydrogel nanoparticles as a new carrier for delivery of hydrophobic drugs. AB - In this paper, chitosan was used as protective agent for dual temperature-/pH sensitive poly(N-vinylcaprolactam-co-itaconic acid-co-ethylene- glycol dimethacrylate)- based hydrogel nanoparticles (poly(NVCL-co-IA-co-EGDMA)) aiming avoid their undesirable colloidal destabilization at different conditions of body human tissues. Thus, poly(NVCL-co-IA-co-EGDMA) was embedded into chitosan and a new solid dispersion was prepared via spray-drying and ketoprofen was used as carrier. Two different sizes of hydrogel nanoparticles (120.6 nm and 185.9 nm) were evaluated and they exhibited a drug encapsulation efficiency of the 39.6% and 57.8%, respectively. The smaller nanoparticles showed to be faster for releasing of ketoprofen at pH 7.4 and 37 degrees C due to their larger surface area and higher swelling ability. Chitosan played a role of a secondary barrier for the ketoprofen diffusion, extending its release compared to hydrogel nanoparticles alone. Among two concentrations (40 wt% and 70 wt%) of hydrogel nanoparticles related to chitosan, the first one induced higher percentages of ketoprofen release: 74.2% against 64.6%. In addition, the interactions between chitosan matrix and poly(NVCL-co-IA-co-EGDMA) did not change the multi-responsive behavior of hydrogels, suggesting the chitosan was efficient for keeping integrity of nanoparticles hydrogels. Chitosan/poly(NVCL-co-IA-co-EGDMA) hybrid microparticles seems to be a promising new carrier for release of hydrophobic drugs, such as ketoprofen. PMID- 30522011 TI - Evaluation of hetero-multivalent lectin binding using a turbidity-based emulsion agglutination assay. AB - Lectin hetero-multivalency, binding to two or more different types of ligands, has been demonstrated to play a role in case of both LecA (a Pseudomonas aeruginosa adhesin) and Cholera Toxin subunit B (a Vibrio cholerae toxin). In order to screen the ligand candidates that involve in hetero-multivalent binding from large molecular libraries, we present a turbidity-based emulsion agglutination (TEA) assay that can be conducted in a high-throughput format using the standard laboratory instruments and reagents. The benefit of this assay is that it relies on the use of emulsions that can be formed using ultrasonication, minimizing the bottleneck of substrate surface functionalization. By measuring the change in turbidity, we could quantify the lectin-induced aggregation rate of oil droplets to determine the relative binding strength between different ligand combinations. The TEA results are consistent with our prior binding results using a nanocube sensor. The developed TEA assay can serve as a high-throughput and customizable tool to screen the potential ligands involved in hetero-multivalent binding. PMID- 30522012 TI - Elaboration of a thermosensitive smart biomaterial: From synthesis to the ex vivo bioadhesion evaluation. AB - Alginate and chitosan are polysaccharides that are widely used in the biomedical field, especially as wound dressings. Controlled bioadhesion is an advanced functionality that offers the potential to reduce injuries due to the stripping off of the biomaterial. Herein, we report the efficient grafting of poly N(isopropylacryamide) (PNIPAM), a thermosensitive polymer that exhibits a lower critical solution temperature (LCST) at 32 degrees C on the alginate/chitosan polyelectrolyte complex (PEC) surface. In vitro studies did not exhibit a cytotoxic effect, and cells adhered preferentially on the LCST on PNIPAM grafted surfaces, as reported in the literature. Ex vivo investigations revealed that the adhesive behavior of the biomaterials was not the same on the liver and pancreas. The effect of the temperature on the bioadhesion to organs was unexpected, as PNIPAM surfaces exhibited higher adhesion at low temperature. The PNIPAM was therefore able to confer PEC matrix thermosensitivity, but due to the application force, interactions between PNIPAM chains and their substrate could influence bioadhesion on tissues. PMID- 30522013 TI - A sensitive biosensing method for detecting of ultra-trace amounts of AFB1 based on "Aptamer/reduced graphene oxide" nano-bio interaction. AB - A simple, low-cost and sensitive label-free aptasensor assembled with assisting reduced graphene oxide nanosheets as the signal amplifier was fabricated and applied for detecting ultra-low levels of Aflatoxin B1(AFB1) through a nano-bio interaction system. The conditions of different modified glassy carbon electrodes as the base of aptasensor were investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The performance of the fabricated aptasensor was evaluated by FESEM, HRTEM and AFM images. The proposed biosensor detected AFB1sensitively in a wide linear range (0.5 nM-4MUM) by DPV with a considerable low limit of detection (LOD = 0.07 nM) and good repeatability (RSD = 2.9) and stability. Finally, the present aptasensor was applied successfully for monitoring AFB1 with appropriate recoveries in pasteurized cow milk and human blood plasma as real samples. PMID- 30522014 TI - Wuzhi capsule (Schisandra Sphenanthera extract) attenuates liver steatosis and inflammation during non-alcoholic fatty liver disease development. AB - OBJECTIVE: Wuzhi (WZ) capsule contains an ethanol extract of Schisandra sphenanthera. The efficacy of WZ in treating non-alcoholic fatty liver disease (NAFLD) has not yet been elucidated. The present study assessed the effects of WZ on NAFLD. MATERIAL AND METHODS: A C57BL/6 male mouse model of NAFLD was established by feeding the animals a methionine-choline-deficient (MCD) diet. Mice fed the basal diet were used as controls. Both groups were randomly administered WZ or vehicle by gavage for 5 weeks. Body weight change, liver/body weight ratio, metabolic parameters, and histological changes were assessed. Serum levels of IL-1beta, IL-6, IL-10, and TNF-alpha were analysed by ELISA; mRNA expression of these genes in the liver was studied by real-time PCR. Western blotting was used to analyse the protein levels of PPAR-alpha, PPAR-gamma, MCAD, LCAD, and p65 in the liver. RESULTS: After 5 weeks of the MCD diet, the liver/body weight ratio of WZ mice was higher than that of control mice. Liver histology revealed significantly less steatosis, inflammation, and necrosis, which was confirmed by decreased intrahepatic triglycerides and serum ALT in WZ treated mice. WZ also reduced the liver mRNA expression of IL-1beta, IL-6, and TNF-alpha and the serum levels of IL-1beta and IL-6. Sensitivity to steatohepatitis due to WZ administration correlated significantly with alterations in the expression of PPAR-alpha/gamma, as well as the NF-kappaB signalling pathway. CONCLUSIONS: WZ plays a protective role against MCD-induced steatohepatitis. The underlying mechanism likely involves the upregulation of PPAR-alpha/gamma and downregulation of the NF-kappaB signalling pathway. Based on its beneficial effects on the liver, WZ is a promising therapeutic for NAFLD patients. PMID- 30522015 TI - Long non-coding RNA SNHG6 enhances cell proliferation, migration and invasion by regulating miR-26a-5p/MAPK6 in breast cancer. AB - The long non-coding RNA (lncRNA) has recently been shown to be important regulators involved in the progression of various human cancers. Small nucleolar RNA host gene 6 (SNHG6) is a recently identified cancer-related lncRNA. However, the clinical significance and biological function of SNHG6 in breast cancer (BC) are still unclear. In the present study, we found that SNHG6 was highly expressed in BC tissues and cell lines, which was associated with poorer clinicopathologic features. Knockdown of SNHG6 inhibited BC cell proliferation, migration and invasion in vitro and in vivo using CCK-8, Edu staining, transwell assays and nude mice model. Moreover, bioinformatics analysis and luciferase reporter experiments indicated that SNHG6 serves as an endogenous sponge by directly binding to miR-26a-5p and down-regulating miR-26a-5p expression. MiR-26a-5p overexpression significantly enhanced the effect of SNHG6 knockdown on the cell behaviors in BC. Furthermore, bioinformatics analysis and luciferase reporter indicated that MAPK6 was validated as a target of miR-26a-5p. Therefore, our study may reveal a novel SNHG6/miR-26a-5p/MAPK6 pathway regulatory axis in BC pathogenesis. SNHG6 may serve as a potential prognostic and therapeutic target in the treatment of BC. PMID- 30522016 TI - Er Shen Wan extract alleviates polyuria and regulates AQP 2 and AVPR 2 in a rat model of spleen-kidney Yang deficiency-induced diarrhea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Er Shen Wan (ESW), has been empirically used for treating spleen-kidney Yang deficiency (SKYD) syndrome in Traditional Chinese medicine (TCM) for centuries and shows a variety of activities. The medicinal formula is a mixture of two component herbs, Psoraleae Fructus (PF, Bu-Gu-Zhi in Chinese) and Myristicae Semen (MS, Rou-Dou-Kou in Chinese). The current study was designed to evaluate ESWP antidiuretic treatment of polyuria and to explore potential mechanisms of renal water metabolism in the rat model of SKYD-induced diarrhea. MATERIALS AND METHODS: An animal model of 'SKYD-induced diarrhea syndrome' has been established to evaluate the therapeutic effect and action mechanism according to the clinical syndrome and symptoms. The optimal dose (3.5 g/kg) of ESWP was given to rats by gavage for two weeks. Urinary volumes after 24 h were recorded. After the end of the trial, macroscopic morphological and histological examination of the kidney were conducted. Serum levels of Arginine vasopressin (AVP) and aldosterone (ALD) were also measured. Additionally, quantitative real-time RT-PCR (RT-qPCR) and immunohistochemistry (IHC) analyses were performed to clarify the regulation of aquaporin 2 (AQP 2) and arginine vasopressin type 2 receptor (AVPR 2) in the kidney at the gene and tissue expression levels respectively. RESULTS: After the administration of ESWP, urinary output volume after 24 h was found to be significantly decreased in rats. Elevated plasma levels of AVP and ALD were detected. Histological kidney damage appeared to be impeded, and histological disease scores were reduced. In addition, the expression levels of AQP 2 and AVPR 2 were significantly increased. CONCLUSION: This study suggests that ESWP may elicit significant effects on the treatment of polyuria. Potential mechanisms at least partially involve hormone regulation, and alleviating renal pathological damage. Simultaneously, ESWP may alter renal water absorption by increasing AQP 2 and AVPR 2 expression levels. Thus, the in vivo experimental evidence indicates that ESWP has a therapeutic effect on the SKYD syndrome, which is consistent with its traditional usage. PMID- 30522017 TI - PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. AB - Colorectal cancer (CRC), as a prominent cause of cancer-related deaths, has historically been notable worldwide and many attempts have been made to raise the overall survival of CRC patients. Immune response has long been a question of great interest in a wide range of fields such as cancer therapies and anti-tumor immunity through checkpoint inhibitors, specifically anti PD-1/ PD-L1 interaction, is a new line of research for treatment of CRC patients. Following the successful development of anti-PD-1 for melanoma, renal cell carcinoma, and non-small cell lung cancer, several clinical trials have been conducted on monoclonal antibodies (MAbs) against PD-1 in CRC. There is a growing body of literature that recognizes the importance of anti-PD-1 therapy for MSI (Microsatellite instability) tumors among CRC subtypes. We present a comprehensive knowledge of immune therapy through PD-1/PD-L1 blockade that argues how efficient the process is, in colon cancer carcinoma. In this review, we discuss the responsiveness of immunotherapy on PD-1/PD-L1 blockade and various tactics for overcoming weak responses to these checkpoint inhibitors in CRC. More research using controlled trials is required to enable new discoveries to provide continued success with immune-based therapies and grounds for optimism about the future of CRC patients. PMID- 30522018 TI - Neuromuscular activation of the knee and hip extensor muscles during high intensity interval and moderate-intensity constant cycling. AB - We aimed to test the hypothesis that the magnitude of differences in muscle activation of the knee and hip extensor muscles between high-intensity interval exercise (HIE) and moderate-intensity constant exercise (CE) would be greater for the gluteus maximus than for the quadriceps femoris muscle. Participants were 11 male middle- or long-distance runners. The HIE (4 sets, 4-min induration, performed at 80-85%VO2peak and followed by a 3-min period of cycling at < 30%VO2peak) and CE (28-min, performed at or near 60%VO2peak) were completed on different days, with the total exercise duration and work being identical for both protocols. Surface electromyography (EMG) was recorded from the following muscles: vastus lateralis, vastus medialis, rectus femoris, gluteus maximus, and biceps femoris. The EMG amplitude, normalised over a period of 28 min for both protocols, was significantly greater during HIE than during CE for the gluteus maximus (HIE: 43 +/- 4% versus CE: 24 +/- 7%) and rectus femoris (HIE: 62 +/- 23% versus CE: 47 +/- 18%), but had no effect of the exercise protocol on the EMG amplitude of other muscles. These findings indicate that the relative contribution of the gluteus maximus and rectus femoris to the cycling movement can be enhanced using a HIE protocol, in middle- and long-distance runners. PMID- 30522019 TI - Nonlinear electrokinetic motion of electrically induced Janus droplets in microchannels. AB - The nonlinear electrokinetic motion of electrically induced Janus droplets (EIJDs) in a microchannel is studied in this paper. The EIJDs were fabricated by operating the positively charged aluminum oxide nanoparticles to partially cover the oil droplets with electric field. The nanoparticle coverage of the EIJDs changes with the electric field strength, which leads to the variation of the electrophoretic mobility of the EIJDs. Therefore, the electrokinetic velocity of the EIJDs in a microchannel changes nonlinearly with the electric field strength. In this research, the variations of the nanoparticle coverage under both constant and time-varying electric fields were studied first. The results indicate that the nanoparticle coverage of the EIJDs decreases with the increase of the electric field strength, and an empirical equation for calculating nanoparticle coverage as a function of the electric field was derived. Under time-varying electric field, the variation of nanoparticle coverage lags behind the change of electric field, and the nanoparticle coverage changes differently under different time-varying electric fields. The experimental results of the electrokinetic motion of the EIJDs in a microchannel confirm that the electrokinetic velocity increases nonlinearly with the electric field. Due to the lag of the nanoparticle coverage change, the variation of the electrokinetic velocity in a microchannel is different between the increasing and decreasing periods of the time-varying electric field. PMID- 30522020 TI - Full length foot orthoses have an immediate treatment effect and modify gait of children with idiopathic toe walking. AB - BACKGROUND: There remains a substantial lack of evidence to support the use of foot orthoses as a conservative treatment option for idiopathic toe walking (ITW). Encouraging heel contact during gait is one of the primary goals of most interventions in paediatric ITW. RESEARCH QUESTION: Does the combined treatment of high-top boots and orthoses increase the number of heel contacts during gait and change spatio-temporal gait parameters? METHODS: This within subject designed randomised controlled trial recruited fifteen children diagnosed with ITW (n = 10 males). They were fitted with bilateral custom made rigid contoured carbon fibre foot orthoses placed inside high-top boots. To analyze the effect of this treatment, heel contacts and spatio-temporal parameters measured by an 8.3 m Gaitrite(r) mat were compared to barefoot walking and shod walking. RESULTS: An immediate increase in heel contact (p = 0.021) was observed in the combined treatment only. Gait changes included a large increase in stride time in the combined treatment condition compared to barefoot walking (p = 0.006). This was associated with a decrease in the percentage of swing phase in the gait cycle (p < 0.010), an increase in stance phase (p < 0.010) and an increase in double support time (p < 0.001). SIGNIFICANCE: These results suggest the hardness and thickness of the shoe and stiffness of the orthosis midsole may lead to improved local dynamic stability and foot position awareness with increased sensory feedback provided through the entire length of the foot. Further research is indicated to validate this treatment option on long term outcomes in this population group. PMID- 30522021 TI - A 'Fingerprint' of locomotor maturation: Motor development descriptors, reference development bands and data-set. AB - BACKGROUND: When aiming at studying and monitoring locomotor development in childhood, innovative indexes for the characterization of motor control performance and wearable technologies have highlighted the potential of significant advances. In particular, quantitative assessment of motor performance during natural walking (NW) and tandem walking (TW) has been proposed to highlight manifestations of motor automaticity and complexity, respectively. RESEARCH QUESTION: This work aims at providing a quantitative overview of metrics characterizing locomotor maturation in a typically developing population, by analysing NW and TW. The final goal is to propose a novel graphical representation of motor development from childhood to adulthood, providing metrics for quantitative assessment with reference bands and data-set, supporting data interpretation and longitudinal assessment. METHODS: 112 typically developing participants (age groups: 6-, 7-, 8-, 9-, 10-, 15-, and 25 years) walked in NW and in TW at self-selected speed. 3D acceleration and angular velocity of lower trunk and shanks were collected. Temporal parameters, their variability, and nonlinear metrics characterizing human movement (harmonic ratio, short-term Lyapunov exponents, multiscale entropy, and recurrence quantification analysis) were calculated. Effect of age was analysed on the different parameters and a graphical polar plot was defined to represent parameters that showed age effect in at least one of the two tasks. RESULTS: Age effect was shown on temporal parameters, their variability, multiscale entropy and recurrence quantification analysis. These parameters were selected for monitoring locomotor development and presented on an ad-hoc designed polar plot showing age-group reference bands. SIGNIFICANCE: Graphic results outline locomotor differences with maturation at first glance. The patterns in NW and TW allow to characterize specific aspects of locomotor maturation, to evaluate in which area changes occur and towards which direction, depending on the task. The novel database containing participants' raw collected data is made available as additional result of the present study. PMID- 30522022 TI - Healed impact trauma to a Neolithic cattle frontal bone: A posthuman perspective. AB - Trauma associated with slaughter is identified occasionally archaeologically in the cranial remains of domesticated animals, with evidence for pole-axing occurring in Europe, especially from the Roman period onwards. The injury typically extends through the frontal bone and sinuses to penetrate the braincase, causing haemorrhage, loss of consciousness, brain damage, and death. Evidence for slaughter methods in the British Neolithic, however, is lacking. We report such evidence from a healed blunt-force impact trauma to the frontal bone of a domestic cattle skull from Beckhampton Road Neolithic long barrow, Wiltshire. The injury suggests a failed attempt at slaughter. To our knowledge, this is the first such report for domestic cattle from the British Neolithic. We contextualise this discovery, drawing on research into the role and meaning of faunal remains from Neolithic long barrows in Wiltshire. This work has been undertaken from a posthuman perspective. Thus, we demonstrate the opportunities for paleopathologists to inform and engage within posthumanist interpretative frameworks. PMID- 30522023 TI - Systemic thrombolysis in haemodynamically unstable pulmonary embolism: The earlier the better? AB - INTRODUCTION: The temporal window for the administration of systemic thrombolysis (ST) in acute pulmonary embolism (PE) has not yet been clarified. We assessed the relationship between short-term cardiovascular (CV) mortality and time of ST administration. MATERIAL AND METHODS: Among 394 consecutive patients admitted between January 2010 and June 2017 with a confirmed PE, we retrospectively review the clinical and instrumental data of those labelled as high-risk PE (n = 76, 41 males, mean aged 64.7 +/- 9.1 years old). RESULTS: A receiving operating curve (ROC) analysis established the optimal temporal threshold for the administration of the ST, in respect to the 30-day CV mortality at 8.5 h from the symptom onset (Area under Curve 0.79 +/- 0.6, 95% CI 0.73-0.86, p < 0.0001). Mantel-Cox analysis showed that there was a significant difference in the distribution of survival between patients treated within 8.5 h from the beginning of symptoms onset to those treated after 8.6 h [log rank (Mantel-Cox) chi-square 9.68 p = 0.002]. Cox-regression analysis demonstrated that the administration of ST after 8.6 h from the symptom's onset was an independent predictor of 30-day CV mortality in high-risk PE patients (HR 7.81, 95% CI 1.84-33.05, p = 0.005), independently from the occurrence of major bleeding events (HR 5.89, 95% CI 1.38 25.13, p = 0.01), previous CAD (HR 3.31, 95& CI 1.07-10.231. p = 0.03), RV/LV ratio after 2 h from the administration ST > 1 (HR (12.91, 95% CI 3.04-54.77, p = 0.001) and PAH at discharge (HR 3.86, 95% CI 2.22-4.68, p = 0.002). CONCLUSIONS: ST administered within 8.5 h from symptoms onset may be associated with a reduced 30-day CV mortality in high-risk PE patients. PMID- 30522024 TI - Disruption of function: Neurophysiological markers of cognitive deficits in retired football players. AB - OBJECTIVE: Recent studies demonstrate that sports-related concussions can have negative consequences on long-term brain health. The goal of the present study was to determine whether retired Canadian Football League (CFL) athletes with a history of concussions exhibit alterations in neurocognitive functioning, along with changes in physical, social, and psychological health. METHODS: Our study compared nineteen retired CFL athletes' concussion histories to eighteen healthy age-matched controls with no history of concussion. Self-report inventories were used to assess depression, memory, attention, and general health. Neurophysiological markers of cognitive function were evaluated with event related brain potentials (ERPs) as measured in two protocols: (1) A Mismatch Negativity (MMN) protocol for assessing the automatic early attentional brain mechanism; and, (2) a P300 auditory oddball task for assessing consciously controlled attention. RESULTS: Relative to controls, CFL players exhibited: response delays and reduced amplitudes in neurophysiological responses; overall decreases in cognitive function; and poorer scores on self-reports of physical, social, and psychological health; reflecting problems in all three categories. CONCLUSION: Our findings demonstrate that multiple concussions sustained over several years can lead to altered cognitive and psychosocial function. SIGNIFICANCE: Neurophysiological markers of conscious and pre-conscious attention provide an objective assessment for evaluating long-term cognitive consequences of concussion. PMID- 30522025 TI - A simple yet sensitive colorimetric nitrite ions assay based on diazotization with p-Aminobenzoic and coupling with phloroglucinol in acidic medium. AB - Immoderate intake of nitrite (NO2-) is deleterious human health and may result in causing dangerous diseases. In this study, nitrite detection system was successfully fabricated based on a unique diazo-coupling reaction of p Aminobenzoic acid (PABA) and phloroglucinol (1, 3, 5-trihydroxybenzene). Upon the presence of NO2- in an acid medium, p-Aminobenzoic acid could not only form diazonium ion easily but also couple with p-Aminobenzoic acid, and results forming yellow water-soluble azo dye that shows maximum absorption at 434 nm. Under the further accurate determination condition, such as acid concentration, amount of reagents and time required, the naked-eye detection of NO2- showed excellent selectivity in compared with some anions. Especially, diazotization and coupling reaction proposed here is very fast and control of pH and temperature are unnecessary. Moreover, the color is stable for several days and Beer's law is obeyed over a wide range. Reliable detection can be made in the range of 0.05 to 1 p.p.m. of nitrite ion. Detection limit was calculated to be 0.024 p.p.m. (0.52 MU M) by UV-visible spectroscopy and 0.05 p.p.m. (1.09 MU M) by naked-eye. By using an electrochemical method, IR, SEM, and 1HNMR, the sensing mechanism can be easily verified. More importantly the proposed method was successfully applied for the determination of nitrite in a real water sample. PMID- 30522026 TI - The impact of dam flushing event on dissolved trace elements concentrations: Coupling integrative passive sampling and discrete monitoring. AB - Sediments accumulation in reservoirs induces water storage capacities reduction and flood risks increases rendering dam flushing or dredging events compulsory for security reasons. Short transient events like dam flushing monitoring is still a great challenge because the suspended sediments and contaminants concentrations increases could occur over only few hours/days and cover tens of kilometres. Since 1942, 21 dam flushing events have been performed on the Upper Rhone River (from Lake Geneva in Switzerland to Lyon in France) in order to evacuate accumulated sediments behind the Verbois dam (Switzerland). We designed an original sampling strategy to assess the 2016 dam flushing event consequences on the spatio-temporal dynamics of dissolved trace elements concentration and to reveal how passive sampling monitoring (Diffusive Gradient in Thin films, DGT) could improve this evaluation. Cr, Mn, Fe, Co, Ni, Cu, Zn, Cd, Pb, As and Hg dissolved concentrations were monitored by discrete and passive sampling at 3 stations over 160 km downstream the Verbois dam. Since dissolved Fe, Cu, Cd, Cr, Pb, Zn and Hg concentrations did not show great variations during the flushing event, the DGT efficiency was not fully demonstrated for these elements. In contrast, a sharp increase of Mn, Ni, Co and As dissolved concentrations (up to 22 times) was recorded, resulting mainly from a release from resuspended sediment. The dissolved As increase was mainly caused by reduced arsenic (AsIII) increase, even monitored 160 km downstream the Verbois dam. The DGT measurements were highly representative of trace elements concentrations and As speciation dynamics in comparison with discrete sampling. Although relatively high dispersion was highlighted for some elements DGT measurements during the flushing event, we showed that DGTs are robust and powerful time-integrative tools to monitor many trace elements more efficiently than discrete sampling during a short transient event on a large spatial scale. PMID- 30522027 TI - On-line measurement of fluorescent aerosols near an industrial zone in the Yangtze River Delta region using a wideband integrated bioaerosol spectrometer. AB - In this work, we present on-line fluorescent aerosol measurements by the wideband integrated bioaerosol spectrometer (WIBS-4A) near an industrial zone in Nanjing, a megacity in the Yangtze-River-Delta (YRD) region. The fieldwork was conducted from April 1 to May 8, 2014. A TSI. 3321 aerosol-particle-sizer (APS) was simultaneously deployed to measure the total number size distribution of aerosol with diameter from 0.8-20 MUm. Both WIBS-4A and APS reported similar number concentration and temporal profiles (R2 = 0.72). However, the daily average number of potential bioaerosols was only 0.5 +/- 0.2% of the total particles detected by the WIBS-4A and displayed a completely different diurnal profile from that of APS. In addition, WIBS-4A can only provide integrated fluorescent signals, which strongly limited the potential to specifically identify the bioaerosols. Accordingly, hierarchical-agglomerative-cluster-analysis (HACA) was utilized to identify and speciate the potential bioaerosols from the WIBS-4A dataset. By maximizing the total distances among all potential cluster centers, a 12-cluster solution was accepted as the optimum result. These clusters were further identified according to their fluorescent signatures, size, and morphology, i.e., non-bioaerosols, bacteria, and fungal spores and/or pollen fragments. Bacteria were the dominant bioaerosol species detected in this work. The diurnal profiles of bioaerosols correlated very well with relatively humidity (RH), reaching daily maxima around 3 AM~6 AM, indicating the presence of humidity controlled bioaerosol emission mechanism, i.e., bacteria may flourish under moderate ambient temperature, RH, and the absence of UV radiation. The size- and AF-distributions of bioaerosols indicated that bioaerosols normally varied substantially in size and assumed a rather irregular shape. Although the number concentration of bioaerosols was relatively small, most bioaerosols can efficiently serve as ice nuclei by providing rough and irregular surfaces, verified by the observation results. Therefore, WIBS-4A measurements can still be informative for investigations of bioaerosols in the atmosphere, especially when HACA method was incorporated into the data processing. PMID- 30522028 TI - Quantifying streamflow response to climate variability, wastewater inflow, and sprawling urbanization in a heavily modified river basin. AB - Considering the growing recognition that human activity and climate variability are critical stressors influencing river regimes, there is an urgent need to identify the contribution of these fundamental factors. Here we examine the runoff changes of a wastewater-effluent dominated river flowing in a heavily modified urban environment. The study concerns the Utrata River basin (727 km2), central Poland, a challenging human-natural system for investigating changes in hydrological processes. The new insights into the present-day functioning of a system are provided through the quantification of runoff changes resulting from the following factors operating simultaneously: climate, wastewater, and urbanization. We adopted and applied the water balance and elasticity-based methods to assess the contribution of particular factors. Climatic data were provided by the gridded observational dataset, while runoff comes from observed daily streamflow values at the stream gauging station. Satellite-derived estimates of evapotranspiration acquired from Operational Simplified Surface Energy Balance (SSEBop) were assimilated into the conceptual framework to provide a robust representation of the system. To determine the changes in urban water budget components, two distinct periods were determined: the baseline period (1951-1960), with a relatively low level of urbanization (9.8%), and the change period (2007-2016), with controlled wastewater inflow and urbanization reaching almost 20%. The results show that in the change period, the mean annual runoff increment attributed to climate variability amounted to 68 mm; the contribution of wastewater inflow - 36 mm; and the contribution attributed to urban-induced changes - -43 mm. Thus, the relative contributions of human activity and climate were estimated as 54% and 46%, respectively. The results demonstrate that in a heavily modified environment, the hydrological effects of human activity can exceed those caused by climate variability. Moreover, wastewater inflow and climate impact can mask decreases in the streamflow induced by urban land fragmentation and land management practices. PMID- 30522029 TI - Methane emissions from anaerobic sludge digesters in Mexico: On-site determination vs. IPCC Tier 1 method. AB - Wastewater treatment is an important source of methane (CH4) emissions. In most large-size aerobic treatment plants, the excess sludge is digested in anaerobic reactors (AD), with the concomitant CH4 emissions. The guidelines of the Intergovernmental Panel on Climate Change (IPCC) have been adopted worldwide for quantifying the national emission inventories, which include wastewater treatment plants (WWTP) as a key category. The IPCC recommends using default emission factors (Tier 1) for countries with limited available data (such as Mexico and most developing countries). However, these estimates have a high degree of uncertainty, owing to the lack of reliable information about the operation process and local environmental conditions. In order to reduce uncertainty in the estimation of CH4 emission from WWTP in Mexico, a country-specific emission factor was determined for AD associated with activated sludge process. This was accomplished with on-site data obtained from the AD of six activated sludge WWTP. In addition, the measured CH4 emissions were compared to those resulting from the application of the IPCC Tier 1 method, using the recommended default methane correction factor (MCF: 0.8) as well as alternate values (0.32 and 0.26) recently proposed by the authors. Results show that the IPCC Tier 1 method, using the recommended MCF, highly overestimate CH4 emissions compared with the values obtained on-site. In contrast, the alternate MCF achieved better estimations than the IPCC-recommended MCF, much closer to the observed emission values. The CH4 emission factor proposed as country (Mexico) specific value is 0.49 kg CH4/kg BODrem, which would allow the application of IPCC Tier 2 method. By doing so, the uncertainty associated with CH4 emission from aerobic treatment plants with AD would be reduced. This, in turn, would provide important information for implementing appropriate CH4 mitigation strategies for the water sector. PMID- 30522030 TI - Temporal fluctuations in young-of-the-year yellow perch mercury bioaccumulation in lakes of northeastern Minnesota. AB - Identifying what determines fish mercury (Hg) bioaccumulation remains a key scientific challenge. While there has been substantial research on spatial variation in fish Hg bioaccumulation, the factors that influence temporal fluctuations in fish Hg have received less attention to date. In this study, we built upon a growing body of research investigating young-of-the-year (YOY) yellow perch Hg bioaccumulation and investigated annual fluctuations in YOY yellow perch Hg in six lakes in northeastern Minnesota over eight years. After accounting for spatial variation between the study lakes, we used model averaging to identify the lake physiochemical and climate factors that best explain temporal variation in fish biomass and fish Hg. Fish biomass of YOY yellow perch had a positive relationship with chlorophyll-alpha and total Kjeldahl nitrogen and a negative relationship with dissolved iron and dissolved oxygen. There was a positive relationship between annual variation in yellow perch Hg concentration and annual variation in lake total suspended solids, dissolved Fe and pH. Additionally, there was a negative relationship between fish Hg concentration and lake total Kjeldahl nitrogen and growing degree days. Together, our results suggest that annual variation in allochthonous inputs from the watershed, in-lake processes, and climate variables can explain temporal patterns in Hg bioaccumulation and growth biodilution is an important process controlling yellow perch Hg concentrations. PMID- 30522031 TI - An environmental flow determination method for integrating multiple-scale ecohydrological and complex ecosystem processes in estuaries. AB - This paper presents an environmental flow methodology that was developed to accommodate shallow, highly dynamic micro-tidal estuaries found along the wave dominated coast of South Arica. This method differs to most other approaches that primarily focus on larger permanently open systems having unrestricted inlets. Following an adaptive, design science research approach, the 7-step method adopted both ecohydrological and ecosystem-based concepts, encapsulating key hydrologicalhydrodynamic-biogeochemical processes, as well as biotic responses. The procedure also addresses a key challenge often encountered in applying these approaches to complex estuarine systems - the mismatch of temporal and spatial scales between abiotic processes and biotic responses. The method simplifies and aggregates abiotic processes to appropriate scales suitable for analysis of biotic responses, by introducing concepts such zoning and major physical states that characterize an estuary. The method's flexibility in data requirements lends itself to applications in countries where data is limited or where differences exist in data quality between systems. Essential in any environmental flow determination process, however, is long-term monitoring to incrementally improve confidence of the input data, but also to evaluate whether allocated flows achieve desired objectives set. Future challenges include refining the method to accommodate flow changes within much shorter timeframes and in conjunction with escalating global change pressures amongst other; pollution, living resource exploitation and physical destruction of habitat. PMID- 30522032 TI - Viability-based quantification of antibiotic resistance genes and human fecal markers in wastewater effluent and receiving waters. AB - Antibiotic resistance is a public health issue with links to environmental sources of antibiotic resistance genes (ARGs). ARGs from nonviable sources may pose a hazard given the potential for transformation whereas ARGs in viable sources may proliferate during host growth or conjugation. In this study, ARGs in the effluent from three municipal wastewater treatment plants (WWTPs) and the receiving surface waters were investigated using a viability-based qPCR technique (vPCR) with propidium monoazide (PMA). ARGs sul1, tet(G), and blaTEM, fecal indicator marker BacHum, and 16S rRNA gene copies/mL were found to be significantly lower in viable-cells than in total concentrations for WWTP effluent. Viable-cell and total gene copy concentrations were similar in downstream samples except for tet(G). Differences with respect to season in the prevalence of nonviable ARGs in surface water or WWTP effluent were not observed. The results of this study indicate that qPCR may overestimate viable-cell ARGs and fecal indicator genes in WWTP effluent but not necessarily in the surface water >1.8 km downstream. PMID- 30522033 TI - Effects of ofloxacin on nitrogen removal and microbial community structure in constructed wetland. AB - Constructed wetlands (CWs) have emerged as a promising technology for the purification of micro-polluted water. However, their nitrogen removal performance can be significantly degraded by design, operational, and environmental factors. The present study investigates the effects of ofloxacin (OFL: 0.1, 10, and 1000 MUg L-1) and plants (Cyperus alternifolius L. and Typha angustifolia L.) on nitrogen removal in a micro-polluted CW system over a duration of 12 weeks. The effects were evaluated by investigating NH4-N and NO3-N removal efficiency, nitrification genes (amoA-AOA and amoA-AOB), denitrification genes (nirK and nirS), fungal 18S rRNA gene and microorganism community structure. The results showed that in unplanted CWs, OFL increased the NH4-N removal efficiency (from 72.6% to 80.7-82.1%), the abundances of amoA-AOA, nirS, nirK and fungal 18S rRNA gene, and the bacterial diversity but decreased the abundance of both amoA-AOB and bacterial richness. In contrast, both the nitrogen removal efficiency (83.4 89.5% for NH4-N and 33.8-38.5% for NO3-N) and bacterial diversity/richness were not significantly affected by OFL in planted CWs. In planted systems, OFL increased the relative abundance of Arthrobacter, Pseudomonas, and Enterococcus, which are proven antibiotic-resistant bacteria. This study showed that CWs are able to remove nitrogen from antibiotic-contaminated micro-polluted water, which might primarily be attributed to the presence of plants that protect the microorganism community. PMID- 30522034 TI - Impact of eutrophication on arsenic cycling in freshwaters. AB - Many arsenic-bearing freshwaters are facing with eutrophication and consequent algae-induced anoxia/hypoxia events. However, arsenic cycling in eutrophic waters and its impact on public health are poorly understood. Laboratory simulation experiments are performed in this study to investigate the effect of algal blooms on the cycling of arsenic in a sediment-water-air system. We found that the anoxia induced by the degradation of algal biomass promoted an acute arsenic (mostly As(III)) release within two days from sediment to both the water and atmosphere, and the release effluxes were proportional to the algae dosage. The reduction and methylation of arsenic were enhanced at the sediment-water interface, owing to the significant increase in arsenate reductase genes (arrA and arsC), and arsenite methyltransferase genes (arsM) caused by increased anoxia. The analysis of synchrotron-based X-ray absorption spectroscopy indicated that the concomitantly released natural organic matter (NOM) and sulfur (S) at the sediment-water interface reduced the As(III) release to a certain extent in the later reducing period of incubation, by forming As2S3 (43-51%) and As(III)-Fe NOM (28-35%). Our results highlight the needs for the in-situ assessment of volatile arsenic in eutrophic freshwaters with its risk to human and animal health. PMID- 30522035 TI - Long-term functional outcome after decompressive suboccipital craniectomy for space-occupying cerebellar infarction. AB - OBJECTIVES: Suboccipital decompressive craniectomy (SDC) is considered the best treatment option in patients with space-occupying cerebellar infarction and clinical signs of deterioration. The primary purpose of this study was to evaluate long-term functional outcome in patients one year after SDC for space occupying cerebellar infarction, and secondly, to determine factors associated with outcome. PATIENTS AND METHODS: All patients treated with SDC due to space occupying cerebellar infarction between January 2009 and October 2015 were included in the study. Data was retrospectively collected from patient records, CT/MRI scans and surgical protocols. Long-term functional outcome was determined by the modified Rankin Scale (mRS) and mRS >= 4 was defined as unfavorable outcome. RESULTS: Twenty-two patients (16 male, 6 female) were included in the study. Median age was 53 years. Nine patients were treated with external ventricular drainage as an initial treatment attempt prior to SDC. Median time from symptom onset (stroke ictus) to initiation of the SDC surgery was 48 h (IQR 28-99 hours) and median GCS before SDC was 8 (IQR 5-10). At follow up, median mRS was 3 (IQR 2-6). Outcome was favorable (mRS 0-3) in 12 patients and unfavorable in 10 (3 with major disability, 7 dead). Brainstem infarction and bilateral cerebellar infarction were associated with unfavorable outcome. CONCLUSIONS: In this small study, functional long-term outcome in patients with space-occupying cerebellar infarction treated by SDC was acceptable and comparable to previously published results (favorable outcome in 54% of patients). Brainstem infarction and bilateral cerebellar infarction were associated with unfavorable outcome. PMID- 30522036 TI - Urgency to build a connection: Midwives' experiences of being 'with woman' in a model where midwives are unknown. AB - OBJECTIVE: The objective of this study was to explore midwives' experiences of being 'with woman' in the intrapartum period within the context of an unknown midwife model. DESIGN: A descriptive phenomenological design was used with individual in-depth interviews. Transcribed interviews were analysed using thematic analysis that incorporated the data analysis framework offered by Amadeus Giorgi. SETTING: Hospitals within Western Australia providing intrapartum care to women where the midwife is not usually known to them. PARTICIPANTS: Ten midwives were interviewed and recruitment ceased when data saturation was reached. FINDINGS: Findings confirm the importance of building a connection to enable partnership with the woman and provide woman-centred care that is inclusive of her partner. Factors influencing midwives' ability to be 'with woman' included the 'systems' approach to childbearing as well as common birth interventions prevalent within the public hospital system. Midwives experienced both rewards and challenges associated with being 'with woman' in the unknown midwife model, adaptability and self-awareness were features that enhanced the ability to be 'with woman' within this model. KEY CONCLUSIONS: Findings present new knowledge about being 'with woman', a phenomenon so central to the profession of midwifery, yet previously unexplored in the empirical domain. Insights gained reveal the intersection between the phenomenon and the unknown midwife model and highlight characteristics of the midwives that facilitate being 'with woman' such as adaptive expertise. IMPLICATIONS FOR PRACTICE: Understanding the concept of being 'with woman' through the lived experience of midwives provides unique insight into the applied practices of the phenomenon. Characteristics of being 'with woman' as well as attributes and strengths demonstrated by the midwives provides important data for education and development of the profession. Explicating the challenges faced by midwives seeking to be 'with woman' in the unknown midwife model is useful for health leaders of service delivery and policy development to consider innovative ways to enhance this important practice advised by professional philosophy. PMID- 30522037 TI - Social support and second trimester depression. AB - BACKGROUND: Depression is the most prevalent psychiatric disease during and after pregnancy (Aktas and Yesilcicek, 2015). Social supportive system (SSS) serves to protect against the development of depressive symptoms (Moshki and Cheravi, 2016). The mitigating effect of SSS on depression among expectant Chinese women is unclear. OBJECTIVES: To evaluate the SSS for pregnant women in Shanghai, China and identify any correlation between social support components and perinatal depression. METHODS: This is a quantitative study using a cross sectional self reporting survey. Two thousand pregnant women were recruited during their second trimester routine pregnancy check-up. Descriptive statistics were used to analyze the socio-demographic and perinatal characteristics, level of social support and depression among the study group. The correlation analysis was conducted between groups of different socio-economic and perinatal factors and SSS, as well as between different SSS components and perinatal depression. RESULTS: Components of social support most influencing perinatal depression were "Support from partner", "The number of close friends accessible of getting support" and "Support from colleagues" [r = -0.226, 0.206, -0.200, respectively]. Among the different components of the SSS, the items ranking high were: "Support from partner", "The living conditions in the last year" and "Support from parents". Meanwhile, "Support from neighborhood", "Participation in group activities" and "The number of close friends accessible of getting support" ranked low. CONCLUSION: Support from the family may be a protective factor against perinatal depression among Chinese pregnant women. The study of social support during pregnancy could help us preferably understand and effectively use social resources to guide and support women in pregnancy. Context-tailored support enhancement should be based on the availability of social networks. PMID- 30522038 TI - Does exclusive breastfeeding relate to the longer duration of breastfeeding? A prospective cohort study. AB - OBJECTIVES: Suboptimal breastfeeding contributes to morbidity and mortality in children. Studies in high-income countries (HICs) show that exclusive breastfeeding (EBF) is associated with longer breastfeeding duration. The aim of this study was to determine whether maternal reports of EBF at six months are associated with longer duration of breastfeeding during the first two years of life in a low and middle-income country (LMIC) setting, and to identify determinants of breastfeeding duration. METHODS: This prospective cohort includes data from an EBF promotion program in Demak District, Central Java Province, Indonesia, with a non-randomized pretest-posttest control group. Mothers and infants were followed through 26 months postnatal age. Data were analyzed using Cox proportional hazard regression with time to cessation of EBF as the outcome. RESULTS: A total of 147 families were included in the study. Longer EBF duration was not associated with prolonged duration of breastfeeding. Longer breastfeeding duration was associated with mothers who disagreed with a statement of being ashamed to breastfeed (HR 0.035, 95%CI 0.003,0.44). Risk factors for shorter breastfeeding duration included mothers' plan to breastfeed for less than 24 months (HR 4.28 95%CI 1.91,9.60), mothers' belief that breastfeeding less than 24 months was the norm (HR 2.98 95%CI 1.31,6.77) and exposure to EBF promotion (HR:4.09 95%CI 2.14,7.82). CONCLUSIONS: In a LMIC community where long breastfeeding duration is common, EBF is not associated with breastfeeding duration. However, modifiable behavioral factors were significant predictors of breastfeeding duration. We therefore recommend that prolonged breastfeeding duration can be achieved through programs that improve breastfeeding behavior. PMID- 30522039 TI - The prevalence and prognostic value of myelin oligodendrocyte glycoprotein antibody in adult optic neuritis. AB - BACKGROUND AND OBJECTIVE: Adult demyelinating optic neuritis (ON) with positive myelin-oligodendrocyte glycoprotein antibody (MOG-Ab) has distinct clinical features. This study aimed to investigate the point prevalence, relationship with steroid dependency and prognosis value of MOG-Ab in adult ON. METHODS: Clinical data analysis was undertaken in adults with ON admitted between December 2014 and January 2016. Patients were classified into three groups based on aquaporin-4 antibody (AQP4-Ab) and MOG-Ab status: AQP4-ON, MOG-ON and seronegative-ON. RESULTS: A total of 158 adults with ON (190 eyes) were assessed, including 31 MOG ON (19.6%), 67 AQP4-ON (42.4%) and 60 seronegative-ON (38.0%) cases. The female to-male ratio was significantly lower in MOG-ON (1.8:1) than that in AQP4-ON (8.6:1) groups (p = .005). The median age, percentage of bilateral ON and visual loss at the nadir at onset was similar among the three groups. Thirty-eight eyes (76%) in the MOG-ON group showed good visual recovery (>20/40) in the final visit, which is statistically better than that in the AQP4-ON and seronegative-ON groups (p < .001 and p = .006, resoectively). Fifteen adults with ON (9.5%) showed dependency on steroid, which was particularly prominent in the MOG-ON group (11/31, 35.5%) and rarely presented in the AQP4-ON (2, 3.0%) and seronegative-ON (2, 3.3%) groups. Results suggested less loss of pRNFL in MOG-ON than that in AQP4-ON group (p < .001), and a larger proportion of canalicular segment involved in MOG-ON adults (p = .007 and p < .001). CONCLUSION: MOG-ON had the smallest proportion of acute demyelinating ON in Chinese adults. One third of adults with MOG-ON predominantly showed a substantial dependency on steroids and relapse on steroid reduction or cessation, which rarely presented in AQP4-ON and seronegative-ON adults. PMID- 30522040 TI - Corticosteroid-dependent tuberculous meningitis: A case report. PMID- 30522041 TI - The reality of hierarchical morphological structure in multimorphemic words. AB - This cross-modal priming study is one of the first to empirically test the long held assumption that individual morphemes of multimorphemic words are represented according to a hierarchical structure. The results here support the psychological reality behind this assumption: Recognition of trimorphemic words (e.g., unkindness or [[un-[kind]]-ness]) was significantly facilitated by prior processing of their substrings when the substrings served as morphological constituents of the target words (e.g., unkind), but not when the substrings were not morphological constituents of the target words (e.g., kindness). This morphological structural priming occurred independently of the linear positions of morphological constituents. PMID- 30522042 TI - The effect of unilateral lingual nerve injury on the kinematics of mastication in pigs. AB - OBJECTIVE: This study evaluates the effect of unilateral lingual sensory loss on the spatial and temporal dynamics of jaw movements during pig chewing. DESIGN: X ray Reconstruction of Moving Morphology (XROMM) was used to reconstruct the 3 dimensional jaw movements of 6 pigs during chewing before and after complete unilateral lingual nerve transection. The effect of the transection were evaluated at the temporal and spatial level using Multiple Analysis of Variance. Temporal variables include gape cycle and phase durations, and the corresponding relative phase durations. Spatial variables include the amplitude of jaw opening, jaw yaw, and mandibular retraction-protraction. RESULTS: The temporal and spatial dynamics of jaw movements did not differ when chewing ipsilateral versus contralateral to the transection. When compared to pre-transection data, 4 of the 6 animals showed significant changes in temporal characteristics of the gape cycle following the transection, irrespective of chewing side, but the specific response to the lesion was highly dependent on the animal. On the other hand, in affected individuals the amplitude of jaw movements was altered similarly in all 3 dimensions: jaw opening and protraction-retraction increased whereas jaw yaw decreased. CONCLUSION: The variable impact of this injury in this animal model suggests that individuals use different compensatory strategies to adjust or maintain the temporal dynamics of the gape cycle. Because the amplitude of jaw movements are more adversely affected than their timing, results suggest that maintaining the tongue-jaw coordination is critical and this can come at the expense of bolus handling and masticatory performance. PMID- 30522043 TI - Effects of anterior tongue strengthening exercises on posterior tongue strength in healthy young adults. AB - OBJECTIVE: The aim of the present study was to investigate whether anterior tongue muscle strengthening exercises can affect the strength of posterior tongue muscles. DESIGN: Eleven healthy subjects (20.6 +/- 1.2 years) were included. The subjects exercised by pushing the anterior tongue to the palate 30 times, three times a day, 3 days a week for 8 weeks. The exercise intensity was set at 60% of maximum tongue pressure (MTP) in the first week and 80% of MTP for the remainder of training. After the completion of training, MTP measurements were continued every month for another 3 months to evaluate whether training effects were sustained. RESULTS: MTP was significantly increased after 8 weeks of training compared with before training. No significant differences were seen between MTP immediately after completion of training and MTP 1-3 months after completion of training. However, MTP was significantly higher 1-3 months after completion of training than before training. CONCLUSIONS: The present study showed significant increases in both anterior and posterior MTPs by anterior tongue muscle strengthening exercises. In the future, a database on tongue muscle strengthening exercises in elderly persons, patients with dysphagia, etc. will need to be generated, with the aim of preventing frailty. PMID- 30522044 TI - Associations Between PET Parameters and Expression of Ki-67 in Breast Cancer. AB - OBJECTIVES: Numerous studies investigated relationships between positron emission tomography and proliferation index Ki-67 in breast cancer (BC) with inconsistent results. The aim of the present analysis was to provide evident data about associations between standardized uptake value (SUV) and expression of Ki-67 in BC. METHODS: MEDLINE library, SCOPUS and EMBASE data bases were screened for relationships between SUV and Ki-67 in BC up to April 2018. Overall, 32 studies with 1802 patients were identified. The following data were extracted from the literature: authors, year of publication, number of patients, and correlation coefficients. Associations between SUV and Ki-67 were analyzed by Spearman's correlation coefficient. RESULTS: Associations between SUVmax derived from 18F FDG PET and Ki-67 were reported in 25 studies (1624 patients). The pooled correlation coefficient was 0.40, (95% CI = [0.34; 0.46]). Furthermore, 7 studies analyzed associations between SUVmax derived from 18F-fluorthymidin (FLT) PET and Ki-67 (178 patients). The pooled correlation coefficient was 0.54, (95% CI = [0.37; 0.70]). CONCLUSION: SUVmax correlated moderately with expression of Ki-67 and, therefore, cannot be used as a surrogate marker for tumor proliferation. Further studies are needed to evaluate associations between PET parameters and histopathological findings like hormone receptor status in breast cancer. PMID- 30522045 TI - Synergistic Activity of Paclitaxel, Sorafenib, and Radiation Therapy in advanced Renal Cell Carcinoma and Breast Cancer. AB - Advanced cancer has been shown to be associated with a higher percentage of epigenetic changes than with genetic mutations. Preclinical models have shown that the combination of paclitaxel, sorafenib, and radiation therapy (RT) plays a crucial role in renal cell carcinoma (RCC) and breast cancer. This study aimed to investigate the involvement of mitochondrial cytochrome c-dependent apoptosis in the mechanism of action of a combination of paclitaxel, sorafenib, and RT in RCC and breast cancer. RCC and breast cancer cell lines were exposed to paclitaxel and sorafenib alone or combined in the presence of radiation, and cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The synergistic anticancer effects of the combination therapy on cell cycle and intracellular signaling pathways were estimated using flow cytometry and immunoblot analysis. RCC and breast cancer cell line xenograft models were used to examine the antitumor activity in vivo. Our results suggest that paclitaxel, sorafenib, and RT synergistically decreased the viability of RCC and breast cancer cells and significantly induced their apoptosis, as shown by caspase-3 cleavage. Paclitaxel, sorafenib, and radiation cotreatment reduced antiapoptotic factor levels in these cells and, thereby, significantly reduced the tumor volume of RCC and breast cancer cell xenografts. The current study suggests that paclitaxel, sorafenib, and radiation cotreatment was more effective than cotreatment with paclitaxel or sorafenib and radiation. These findings may offer a new therapeutic approach to RCC and breast cancer. PMID- 30522046 TI - Effect of a cauliflower (Brassica oleraceae var. Botrytis) leaf powder-enriched diet on performance, carcass and meat characteristics of growing rabbit. AB - The aim of this study was to investigate the effect of a cauliflower leaf powder (CLP)-enriched diet on the performance, quality and antioxidative potential of rabbit meat. No significant differences were found for live performance parameters between rabbits fed with standard (SD) and CLP diet. Dietary supplementation influenced the meat traits of rabbits: CLP meat showed significantly lower drip loss after 48 h, cooking loss, and a significantly higher lightness (L*) and redness (a*) values, vitamin A and vitamin E content, and oxidative stability, compared to SD meat. Moreover, the CLP supplementation caused a significant decrease in SFA and increase in PUFA percentage of rabbit intramuscular fat. The statistical analysis also showed a significant effect of dietary fortification on phenolic content and antioxidant activity of rabbit meat which resulted higher in meat of CLP group. This study highlighted that dietary fortification with CLP is a valid strategy to produce rabbit meat with better technological and functional quality. PMID- 30522047 TI - Quality improvement: A practical nursing program's admission test. AB - INTRODUCTION: Academic institutions are under pressure to maintain a nearly flawless retention rate, while graduating successful students. The use of standardized admission tests to provide data driven decisions regarding applicant selection is common. The varying reliability and validity of current standardized tests inspired a large Canadian academic institution to use a faculty developed admission test for admission to its practical nursing (PN) program. METHODS: The target population for this project was a purposive, convenience sample of graduated PN students from a large publically funded polytechnic institution in southern Ontario, Canada, who had completed the Canadian Practical Nurse Registration Examination (CPNRE) within 2014-2016 (n = 293). Data was obtained retrospectively, and included program entry grade-point average (GPA) and CPNRE result, as well as chemistry, English, biology, and math admission test scores. RESULTS: The predictors of chemistry, English, math admission test scores, and program entry GPA did not have an effect beyond the effects of the model's predictors. In this model, the R2 suggests that 9% of the variance can be explained, and 91% not explained. In consideration of all independent variables, findings indicate that mean biology admission test scores (M =74.96) are a predictor of student CPNRE success. Additionally, students who pass the CPNRE have a higher program GPA. CONCLUSIONS: Academic factors including program entry GPA, English, math, biology and chemistry admission scores are a fragment of the characteristics to be considered when determining the predictability of success in PN students. Therefore, it is imperative that program admission processes identify and measure nonacademic program entry criteria, as academic criterion have limited predictability. Furthermore, in isolation, academic admission criteria could be used to identify at-risk-students for appropriate remediation/counselling or as a placement test. PMID- 30522048 TI - Incidence of future arrests in adults involved in the criminal justice system with opioid use disorder receiving extended release naltrexone compared to treatment as usual. AB - BACKGROUND: Criminal justice involved (CJS) populations with opioid use disorder (OUD) have high rates of relapse, future arrests, and death upon release. While medication for OUD (MOUD) reduces opioid relapse, concerns regarding diversion and stigma limit treatment in CJS populations. Extended release naltrexone (XR NTX), as an opioid antagonist, may be more acceptable to CJS administrators. However, the impact of XR-NTX on criminal recidivism remains unknown. METHODS: Arrest data from a published randomized trial comparing XR-NTX to treatment as usual (TAU) was captured by self-report and official state arrest records. Comparisons of future arrests, time to first arrest and total number of arrests were performed using chi square tests and multivariable generalized regression models. Secondary outcomes explored differences in arrests by type and severity of crime, use of opioid and other drugs, and study phase. RESULTS: Of 308 participants randomized, 300 had arrest data. The incidence of arrests did not differ between XR-NTX (47.6%) and TAU (42.5%) participants. (ChiSq p = 0.37). Additionally, there was no significant difference in time to first arrest (adjusted HR 1.35, CI 0.96-1.89) and number of arrests per participant (adjusted IR 1.33, CI 0.78-2.27). Controlling for gender, age, previous criminal activity, and use of non-opioid drugs, logistic regression demonstrated no significant difference in incidence of arrests between groups (adjusted OR 1.38, 95% CI 0.85 2.22). CONCLUSIONS: We detected no significant difference in arrests between CJS participants with OUD randomized to XR-NTX or TAU. Despite its efficacy in reducing opioid use, XR-NTX alone may be insufficient to reduce criminal recidivism. PMID- 30522049 TI - Highly effective and safe intermediate based on deep eutectic medium for carrier less-three phase hollow fiber microextraction of antiarrhythmic agents in complex matrices. AB - For the first time, three phase hollow fiber liquid phase microextraction using an influential, and green middle phase comprised a new relatively-hydrophobic deep eutectic solvent (three-phase HF-LPME-DES) was developed for trace analyses of antiarrhythmic drugs in biological and environmental samples. The extraction solvent was easily synthesized by mixing the green and cheap raw materials, namely choline chloride and 1-phenylethanol (ChCl: Ph-ETOH), in the ambient temperature. Good compatibility to pores of hollow-fiber, high ability for extraction of ionizable organic compounds with no need to any carrier agents, and easy availability in the laboratory environment turned this new proposed deep eutectic intermediate to a worthy generation of the supported liquid membrane (SLM). Final determination was accurately done by high performance liquid chromatography-ultraviolet detection (HPLC-UV). After effective statistical optimization of main parameters, the valid analytical features were found to be: wide linear dynamic ranges (LDRs) of 0.8 to 500 ng mL-1 with the determination coefficients (R2s) higher than 0.98, low detection limits (LODs) of 0.3-0.8 ng mL 1, and logical precision (relative standard deviations (%RSDs, n = 3) of 5.2 6.5%). Also, enrichment factors and extraction recoveries were 110-135 and 44 54%, respectively. These satisfactory results confirmed the potent effectiveness of the proposed microextraction procedure for achievement to clean and proper enrichment of the aforesaid compounds in highly complex real samples. PMID- 30522050 TI - Mothers' feelings about infants' negative emotions and mother-infant interactions among the Gamo of Southern Ethiopia. AB - Parents' exposure to stressful ecosocial situations, like inadequate resources, is linked to parents' perceptions of infants' fussing and crying and less sensitive caregiving. However, studies supporting these findings predominantly come from Western contexts of parenting and infant care. Ecosocial situations may have different effects on parenting and infants in distinct cultural contexts. In this study, the link between Gamo mothers' expressions of stress about their infants' negative emotional displays (N = 29 mothers and infants) and mother infant interactions was investigated. Mothers who expressed stress in response to their infants' negative emotions demonstrated fewer interactions overall with their infants compared to mothers who did not express stress. Regression analyses showed that mothers who did not express stress had infants that fussed and cried more in their presence than infants of mothers who did not express stress, albeit insignificant. These results are discussed in the context of Gamo infancy in Southern Ethiopia. PMID- 30522051 TI - Microbubble aeration enhances performance of vacuum membrane distillation desalination by alleviating membrane scaling. AB - Membrane fouling, especially inorganic fouling due to salt crystal formation and deposition on the membrane surface, is still a major technical issue in membrane distillation (MD) applications. In this study, microbubble aeration (MBA) was included in a laboratory-scale vacuum membrane distillation (VMD) rig and its effect on a desalination process was examined. Without MBA, serious membrane scaling occurred during desalination of simulated high-salinity sea water (100 g.L-1 salt concentration), which resulted in a dramatic reduction of permeate flux to essentially zero after 120 min. Scanning electron microscopy showed that a layer of large cuboid salt crystals uniformly covered the membrane surface. However, membrane scaling was mitigated with the introduction of MBA, resulting in the improved VMD desalination performance, which was positively correlated with pump pressure in the microbubble (MB) generator. Results showed that the effective processing time of the VMD desalination processing cycle was respectively prolonged to 150, 180, and more than 300 and 360 min (cf. 120 min without MBA) when the pump pressure was respectively at 0.1, 0.2, 0.3 and 0.4 MPa, leading to the increase of cumulative water production. Further studies found that larger numbers of MBs of smaller size were produced at higher pump pressure, which are more beneficial for increasing water vapor production and alleviating salt precipitation. The difference in zeta potential between the MBs in distilled water (about -30 mV) and that in SW100 solution (about -2 mV) demonstrated that MBA not only effectively mitigated the negative effect of concentration polarization by enhancing the surface shear rate at the membrane surface, but also reduced salt precipitation probably due to the MBs attracting counterions to the gas-water interface. Finally, energy consumption analysis of the modified VMD desalination process revealed that MBA, while itself only adding about 3% to the total energy consumption at varied pump pressures, was able to improve the specific energy consumption, especially at higher pump pressures. Together, these results demonstrate that MBA is an effective way of improving the performance of VMD desalination of water. PMID- 30522052 TI - Airborne bacteria in a wastewater treatment plant: Emission characterization, source analysis and health risk assessment. AB - Wastewater treatment plants (WWTPs) are major sources of airborne bacteria, which could pose health risks to WWTP workers and surrounding residents. In this study, air samples were collected from various treatment facilities of a typical WWTP. Community compositions of airborne bacteria were identified by high-throughput sequencing technique. SourceTracker was used to determine the percentages of airborne bacteria from wastewater, sludge, ambient air, and other environment. Health risks associated with airborne bacteria were estimated based on the average daily dose rates (ADD) of exposure by inhalation and skin contact. Concentrations of airborne bacteria varied in a wide range of 23-4878 CFU/m3. The main emission sources of airborne bacteria were treatment facilities with aeration, mechanical agitation, and located indoors. For treatment facilities located indoors, higher percentages of airborne bacteria were associated with wastewater and sludge, while more airborne bacteria were originated from the ambient air for outdoor installations. Opportunistic pathogens such as Micrococcus, Bacteroides, Chryseobacterium, Pseudomonas, and Acinetobacter, were detected in airborne bacteria. Inhalation was the main pathway for on-site workers exposure to airborne bacteria. Due to the presence of opportunistic pathogens, strict control measures should be employed in WWTPs to reduce the infection risks. PMID- 30522053 TI - Seasonal occurrence and fate of chiral pharmaceuticals in different sewage treatment systems in Hong Kong: Mass balance, enantiomeric profiling, and risk assessment. AB - Concern about the presence of chiral pharmaceuticals in the environment from wastewater discharge is mounting. In this work, the occurrence and fate of atenolol, metoprolol, venlafaxine, and chloramphenicol, including 10 different stereoisomers, were investigated in sewage and sludge from diverse treatment processes in 4 sewage treatment plants (STPs) in Hong Kong via 4 sampling campaigns over a period of 2 years. The average amounts of individual pharmaceuticals entering the STPs ranged from 4.91 g/d to 6290 g/d, with sludge carrying much lower amounts than the discharged effluent. Mass balance analysis revealed that: larger quantities of these pharmaceuticals were released during the dry seasons, biodegradation was the primary removal mechanism for atenolol and chloramphenicol, and the removal via primary sedimentation and disinfection processes was insignificant (<30%). Selectivity toward R-(+)-atenolol, S-(-) metoprolol, and R-(-)-venlafaxine was mostly found across secondary-treated effluent samples. Sold as an enantiopure pharmaceutical in R,R-para-form, chloramphenicol was preferentially eliminated after biological process. This is the first study on the occurrence of chloramphenicol enantiomers in the aquatic environment. Ecotoxicological assessment indicated that atenolol and metoprolol could pose risks to marine fish in effluent-receiving waters (i.e., the western waters and Victoria Harbor) of Hong Kong, while R-(+)-atenolol could pose a risk to protozoans five times higher than the S-(-)-enantiomer. PMID- 30522054 TI - Patient readiness for hospital discharge and its relationship to discharge preparation and structural factors: A cross-sectional study. AB - BACKGROUND: Nursing discharge preparation is vital to successful hospital-to-home transitions. However, despite a wealth of evidence on its effectiveness, little is known of the structure- and process-related factors that facilitate or impede its use in clinical practice. Specifically, the associations between unit size and type, leadership support, skill mix, staffing, nurse and patient characteristics, discharge teaching and patient readiness for discharge have rarely been studied. OBJECTIVES: This study aimed to explore the associations between structure-individual characteristics (i.e., unit, nurse and patient characteristics) and process-related (i.e., teaching of self-care and symptom management) factors and patient readiness for hospital discharge. DESIGN: A secondary data analysis of the multicentre observational "Matching Registered Nurse services with changing care demands (MatchRN)" study. SETTING AND PERIOD: Data were collected between September 2015 and January 2016 on 123 surgical, medical and mixed units in 23 Swiss acute care hospitals. PARTICIPANTS: A total of 1833 registered nurses and 1755 patients were included in the analyses. METHODS: Structure-, process- and patient readiness-related hospital discharge variables were assessed using validated items either from existing instruments or self-developed. Multilevel mixed-effects logistic regression was used to test associations. RESULTS: Fewer than half of the patients hospitalized (47.8%) reported readiness for hospital discharge. Fifty-eight percent reported receiving discharge preparation interventions for self-care and 30% for symptom management. Patients' readiness for hospital discharge was significantly lower in larger units (beta = -0.001; 95% confidence interval (CI) = -0.002 to -0.001) and on medical units (beta = -0.44; 95% CI = -0.70 to -0.19). Higher nurses' experience (beta = .004; 95% CI = 0.001 to 0.01), better patient self-reported health (beta = -0.11; 95% CI = -0.17 to -0.05), higher patient ratings of self-care teaching (beta = 1.33; 95% CI = 1.07-1.59) and symptom management teaching (beta = 0.79; 95% CI = 0.52-1.06) were significantly associated with greater patient readiness for hospital discharge. CONCLUSIONS: Patient readiness for hospital discharge is associated with process- and structure-related factors. Our findings suggest that, for successful uptake in clinical practice, the development and implementation of effective discharge preparation programs should consider the structural context, i.e., patient population, unit size, and experience of nurses within the team. Further research, using a more accurate measure of patient readiness for hospital discharge, is needed to test associations with the nurse work environment and staffing. PMID- 30522055 TI - Neuroprotective effects of a novel carnosine-hydrazide derivative on hippocampal CA1 damage after transient cerebral ischemia. AB - Ischemia-reperfusion injuries produce reactive oxygen species that promote the peroxide lipid oxidation process resulting in the production of an endogenic lipid peroxide, 4-hydroxy-trans-2-nonenal (4-HNE), a highly cytotoxic aldehyde that induces cell death. We synthesized a novel 4-HNE scavenger - a carnosine hydrazide derivative, l-carnosine hydrazide (CNN) - and examined its neuroprotective effect in a model of transient ischemia. PC-12 cells were pre incubated with various doses (0-50 mmol/L) of CNN for 30 min, followed by incubation with 4-HNE (250 MUM). An MTT assay was performed 24 h later to examine cell survival. Transient ischemia was induced by bilateral common carotid artery occlusion (BCCO) in the Mongolian gerbil. Animals were assigned to sham-operated (n = 6), placebo-treated (n = 12), CNN pre-treated (20 mg/kg; n = 12), CNN post treated (100 mg/kg; n = 11), and histidyl hydrazide (a previously known 4-HNE scavenger) post-treated (100 mg/kg; n = 7) groups. Heat shock protein 70 immunoreactivity in the hippocampal CA1 region was evaluated 24 h later, while delayed neuronal death using 4-HNE staining was evaluated 7 days later. Pre incubation with 30 mmol/L CNN completely inhibited 4-HNE-induced cell toxicity. CNN prevented delayed neuronal death by >60% in the pre-treated group (p < 0.001) and by >40% in the post-treated group (p < 0.01). Histidyl hydrazide post treatment elicited no protective effect. CNN pre-treatment resulted in high heat shock protein 70 and low 4-HNE immunoreactivity in CA1 pyramidal neurons. Higher 4-HNE immunoreactivity was also found in the placebo-treated animals than in the CNN pre-treated animals. Our novel compound, CNN, elicited highly effective 4-HNE scavenging activity in vitro. Furthermore, CNN administration both pre- and post BCCO remarkably reduced delayed neuronal death in the hippocampal CA1 region via its induction of heat shock protein 70 and scavenging of 4-HNE. PMID- 30522056 TI - Discovery and development of small molecule modulators targeting glutamine metabolism. AB - Cancer cells have been confirmed diverge significantly from normal cells on the metabolic properties. Energy production in cancer cells is abnormally dependent on the glycolysis pathway and other atypical metabolic characteristics such as increased fatty acid synthesis and increased rates of glutamine metabolism. Among these metabolic features of cancers, glutamine metabolism has been reported to be the main energy supply for the growth and viability of a potentially large subset of malignant tumors. In addition, the significance of glutamine metabolism in cancer cells derives from the ability of donate its nitrogen and carbon atoms for the synthesis of important biologically substances. During recent years, emerging evidences have proved the inhibitors targeting glutamine metabolism pathway could be efficient anticancer drugs. Therefore, in this review, we would briefly introduce the regulation of glutamine metabolism, and then summarize the recent advances of small molecule modulators targeting various nodes in glutamine signaling pathway. The current potential obstacles and future therapeutic perspectives in glutamine metabolism are also put forward in order to provide reference for the drug discovery of novel and potent glutamine metabolism modulators. PMID- 30522057 TI - Impairment of the antifibrotic prostaglandin E2 pathway may influence neutrophil extracellular traps-induced fibrosis in the mare endometrium. AB - Prostaglandin E2 (PGE2) has contradictory effects in many organs. It may have proinflammatory, anti-inflammatory, or anti-fibrotic roles, depending on the type of receptors to which it binds. By signaling through its receptors EP2 and EP4, PGE2 mediates anti-inflammatory and anti-fibrotic actions. In spite of chronic endometrial fibrosis (endometrosis) being a major cause of mare infertility, its pathogenesis is not fully understood. We have shown that contact of mare endometrium in vitro with neutrophil extracellular traps (NETs) proteases favors endometrial collagen type I production. Therefore, we investigated the involvement of the PGE2 pathway in collagen deposition in mare endometrium, challenged in vitro with proteases present in NETs. Mare endometria (Kenney and Doig categories I/IIA and IIB/III), obtained in the follicular phase (FLP) and mid-luteal phase (MLP), were incubated for 24 h with components found in NETs (elastase, cathepsin-G, and myeloperoxidase). Secretion of PGE2 and transcripts for specific PGE synthase (PGES) and PGE2 receptors (EP2 and EP4) were evaluated. Impaired PGE2 production and low EP2 transcript abundance depended on the endometrial category and estrous cycle phase. Impairment of PGE2 and/or EP2 might play a role in FLP (category IIB/III) and MLP (I/IIA) endometrial fibrogenesis because of the reduction in its antifibrotic capacity. In conclusion, priming of the endometrium with endogenous ovarian steroids might inhibit the antifibrotic PGE2 pathway either in healthy or pathologic tissues with collagen formation after NETs proteases action. PMID- 30522058 TI - Online behavior of people visiting a scientific website on epilepsy. AB - We investigated the online behavior of Internet users consulting the website of the Italian Chapter of the International League Against Epilepsy (Lega Italiana Contro l'Epilessia [LICE]). We obtained the visualization statistics of the LICE website using AWStats (https://awstats.sourceforge.io/) and Google Trends (https://trends.google.com/trends/), and compared the statistics of years 2010, 2014, and 2017. The following variables were analyzed: number of unique visitors and visits, visit duration, the day of week and rush hours, most downloaded documents, most viewed pages, keyphrases and keywords used for online searches, origins of searches, and geographic trends of Google searches related to the LICE. The total numbers of unique visitors, visits and page views remained quite stable over time. Most visits (70 to 76.7%) lasted less than 30 s. The most frequent keyphrases and keywords used for online searches were related to clinical guidelines and driving license. Among the most frequently downloaded documents were general guides on epilepsy. The pages with the list of epilepsy centers endorsed by the LICE and those with the list of LICE guidelines were among those most frequently viewed, together with educational videos. Most users directly accessed the website without being referred from external links. No information on geographic origin of Google searches was available. The visualization statistics suggested two distinct populations of visitors. The first one is likely represented by physicians who seek specialist information on diagnosis and management of epilepsy, including guidelines. The second population is represented by lay people who seek accessible and easily comprehensible information to better understand epilepsy and know which centers are best for its management. PMID- 30522059 TI - Long-term seizure outcome in frontal lobe epilepsy surgery. AB - PURPOSE: The purpose of this study was to report long-term seizure outcome in patients who underwent frontal lobe epilepsy (FLE) surgery. METHOD: This retrospective study included 44 consecutive subjects who underwent resective surgery for intractable FLE at IRCCS NEUROMED (period 2001-2014), followed up for at least 2 years (mean: 8.7 years). All patients underwent noninvasive presurgical evaluation and/or invasive electroencephalography (EEG) monitoring when nonconcordant data were obtained or epileptogenic zone was hypothesized to be close to the eloquent cortex. Electroclinical, neuroimaging, surgical data, and histology were compared to seizure outcome. RESULTS: Mean epilepsy duration was 19 years; mean age at surgery was 31.6 years. Preoperative magnetic resonance imaging (MRI) showed a frontal lesion in 86.4 % of cases. Scalp video electroencephalography (VEEG) monitoring detected a focal ictal onset in 90% of cases. Twenty-seven patients (61.4%) underwent invasive recordings. Resections involved dorsolateral (47.7%), medial (9%), orbital (13.6%), and rolandic (13.6%) region. Lobectomy within functional boundaries was performed in the remaining 7 cases (16%). Transient and permanent neurological deficits were observed in 2 and 3 cases, respectively. Histology revealed focal cortical dysplasia (45.5%), World Health Organization (WHO) I-II grade tumors (15.9%), gliosis (22.7%), vascular malformations (4.5%), Rasmussen encephalitis (6.8%), and normal tissue (4.5%). At last observation 68.1% of patients were in Engel's class I, 11.4% in class II, 9% in class III, and 11.4% in class IV. A favorable outcome was associated with focal ictal scalp EEG onset (p = 0.0357). CONCLUSION: Surgery is a safe treatment option in drug-resistant FLE with a satisfying long-term outcome. These data highlight the importance of an appropriate selection of potential surgical candidates. PMID- 30522060 TI - A systematic review of sudden unexpected death in epilepsy (SUDEP) in childhood. AB - BACKGROUND: Sudden Unexpected Death in Epilepsy (SUDEP) is a significant cause of death in childhood epilepsy, and causes considerable concern to patients and their families. Despite this, the condition remains poorly understood. This systematic review investigates the risk factors, pathophysiology, and circumstances associated with childhood SUDEP. It aimed to explore the etiology of SUDEP and inform clinicians approaching SUDEP risk disclosure. METHODS: A structured electronic database search of MEDLINE, CENTRAL, EMBASE, and ISI web of science was conducted. Studies were included if they described clinical details of one or more patients, aged 18 years of age and below, who had SUDEP. Two reviewers independently reviewed each article for data extraction and quality assessment. RESULTS: Information on 108 cases of pediatric SUDEP was extracted from 22 included studies. These comprised five cohort studies, four retrospective case control studies, seven case series, and five case reports. Factors that appeared to be linked to pediatric SUDEP included those associated with severe epilepsy (early age of onset, high seizure frequency, intellectual impairment and developmental delay, multiple antiepileptic drug therapy, and structural abnormalities). The majority of included studies was noncomparative and had significant risk of bias. CONCLUSIONS: There is currently insufficient evidence to determine the etiology of pediatric SUDEP. Current best practice to prevent pediatric SUDEP is to optimize the management of epilepsy. A national SUDEP registry would provide invaluable high-quality data and insights into modifiable risk factors, genetic predispositions, and novel prevention strategies. PMID- 30522061 TI - Intraventricular blood flow with a fully dynamic mitral valve model. AB - Mitral valve (MV) leaflets affect the formation, growth, and decay of vortices in the left ventricle (LV) during diastolic filling. The shape and motion of MV leaflets are simplified in most studies due to computational restrictions. In this study, we present a newly developed mathematical method to model the dynamic movement of valve leaflets and annulus, which is based on in vivo data obtained with magnetic resonance imaging (MRI). In the present method, we solve a boundary value problem where the MV surface is initially unknown. The resultant MV shapes are included in a dynamic motion model of the LV to assess the change of intraventricular flow patterns. To estimate the effects of the MV on left intraventricular flow, a LV model without MV leaflets was also simulated for comparison. Our study showed that the presence of the MV and the shape of its leaflets significantly altered the formation and evolution of vortex structures in the LV. The various MV leaflet shapes accelerate the transvalvular flow distinctly, leading to different formation and development of vortex structures. PMID- 30522062 TI - It can be beautiful or destructive: Street-involved youth's perceptions of their romantic relationships and resilience. AB - INTRODUCTION: This study examined romantic relationships among street-involved youth through the overlapping perspectives of resilience, attachment and social bonding. The main goal was to assess how youth understand their romantic attachment bonds as supporting or undermining resilience. While there are qualitative reports on how the social relationships of street-involved youth are linked to resilience, romantic relationships have yet to be differentiated with regard to resilience. This paper also builds on existing research by providing further information on the characteristics of their romantic relationships, and the impact of street life and risky behaviours within relationships. METHODS: Twenty-one youth (11 men and 10 women) in shelters, in a Canadian metropolitan city, aged 16-24 years, participated in semi-structured interviews. A thematic analysis of the data was conducted exploring how the youth understand their romantic attachments as well as their links in supporting or undermining resilience. RESULTS: Results indicated that connection, support, validation, and encouragement within a relationship were of value to the youth's resilience, in the form of addressing drug use, achieving goals, supporting self-worth, and promoting positive coping. The youth also reported many negative experiences within their romantic relationships, including dating violence and the stress of street-life, which they saw as undermining their resilience. A key finding was that the youth had considerable difficulty integrating the positive and negative aspects of their relationships. Overall the findings highlight the co-occurrence of positive and negative romantic experiences, and support the importance of developing healthy relationship programs for street-involved youth. Key words: street-involved; homeless; youth; romantic relationship; resilience; dating violence. PMID- 30522063 TI - Longer schooling but not better off? A quasi-experimental study of the effect of compulsory schooling on biomarkers in France. AB - Less schooling is associated with increased biological risks for chronic disease, but whether increasing years of schooling through policy interventions reduces these risks remains unclear. We examine the effect of a major education reform introduced in 1959 that raised the minimum school leaving age from 14 to 16 years in France, offering a unique natural experiment. We assess the causal impact of increased schooling duration on 16 biomarkers of cardiovascular, metabolic, organ and immune function in a large cohort of men and women born around 1953. Using a Regression Discontinuity Design, we find that the reform led to a significant increase in schooling duration among children from disadvantaged families; but longer schooling did not translate into better biomarker profiles in adulthood. Eligibility to the reform had no impact on the biomarker profile of respondents from intermediate or high social class families, while it led to increased blood pressure and white cells counts in adulthood among those from low parental social class. These findings were robust across several sensitivity analyses. They emphasize the importance of considering the institutional context and the respondents' social origins when evaluating the health effects of compulsory schooling reforms. Our results do not necessarily question the premise that education leads to better health, but they suggest that law-mandated increases in schooling alone may not improve the health of disadvantaged groups. PMID- 30522064 TI - Simultaneous analysis of acetylcarnitine, proline, hydroxyproline, citrulline, and arginine as potential plasma biomarkers to evaluate NSAIDs-induced gastric injury by liquid chromatography-tandem mass spectrometry. AB - Although major adverse effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are gastric injury, assessment of NSAIDs-induced gastrointestinal adverse effects is mostly dependent on endoscopy due to the lack of plasma biomarkers. Several amino acids associated with collagenase activity and gastric mucosal mass have been suggested as plasma biomarker candidates for gastric injury. Therefore, this study aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the plasma biomarker candidates, i.e., acetylcarnitine, proline, hydroxyproline, citrulline, and arginine and evaluate their potential as a biomarker for NSAIDs-induced gastric injury. The method utilized simple protein precipitation with methanol and D4-citrulline as an internal standard (IS). The assay resulted in the lower limit of quantification (LLOQ) of 0.1 MUg/mL for acetylcarnitine and 1 MUg/mL for proline, hydroxyproline, citrulline, and arginine in the surrogate blank plasma. The intra and inter-day accuracy ranged 82.5-111.2% for acetylcarnitine, 95.4-103.3% for proline, 98.9-106.4% for hydroxyproline, 99.5-103.5% for citrulline, and 87.4 105.3% for arginine. The precision was within 6.17%, 3.63%, 6.20%, 6.31%, and 6.17% for acetylcarnitine, proline, hydroxyproline, citrulline, and arginine, respectively. The developed assay was successfully applied to monitor the changes of the plasma levels of the five amino acids in rats and Beagle dogs following repeated oral administrations of aceclofenac. In rats, plasma concentrations of proline, hydroxyproline, and citrulline were significantly reduced after 4 days of aceclofenac administration compared to the control group. In dogs, plasma concentrations of proline and citrulline were significantly decreased after 7 days of aceclofenac administration compared to those obtained after the first aceclofenac administration. These data indicate that plasma levels of proline, hydroxyproline, and citrulline may be used as quantitative biomarkers of NSAIDs induced gastric damage. The present assay could also be utilized to monitor the changes of these amino acids as potential indicators for various physiological and pathophysiological conditions. PMID- 30522065 TI - A photoelectrochemical sensing strategy based on single-layer MoS2 modified electrode for methionine detection. AB - MoS2, a typical transition metal disulfide, is widely used in the photoelectrochemical (PEC) sensor construction. In general, MoS2 based PEC sensor are "signal-on" strategies. Surprisingly, we discovered that the PEC response of MoS2 was quenched by methionine greatly. Based on this discovery, a reduction PEC sensing strategy utilized MoS2 modified electrode for methionine detection was fabricated for the first time. Experimental factors, such as, bias potential, volume of MoS2 and pH were studied. Under optimized conditions, the decreased intensity of the photocurrent signal was proportional to the logarithmic value of methionine concentrations from 0.1 nM to 1 MUM with the detection limit of 0.03 nM. Moreover, this method exhibited good performance of excellent selectivity. And it showed potential applications in the practical determination of methionine in real-life sample. This strategy not only expands the PEC detection method but also provides a simple, rapid response, good selectivity and high sensitivity way to detect methionine. PMID- 30522066 TI - The legacy of colonial fire management policies on traditional livelihoods and ecological sustainability in savannas: Impacts, consequences, new directions. AB - Land occupation and management systems have defined fire regimes and landscapes for millennia. The savanna biome is responsible for 86% of all fire events, contributes to 10% of the total carbon emissions annually and is home to 10% of the human population. European colonization has been associated with the implementation of fire suppression policies in many tropical savanna regions, markedly disrupting traditional fire management practices and transforming ecosystems. In this paper we assess savanna burning approaches from pre-colonial to contemporary eras in three regions: northern Australia, southern Africa and Brazil. In these regions, fire suppression policies have led to (i) conflicts between government authorities and local communities; (ii) frequent late dry season wildfires and/or (iii) woody encroachment. Such consequences are facilitating changes to fire management policies, including recognition and incorporation of traditional ecological knowledge in contemporary community-based adaptive savanna fire management. Such programs include implementation of prescribed early dry season fires and, in some regions, generating income opportunities for rural and traditional communities through the reduction of late dry season wildfires and associated greenhouse gas emissions. We present a brief history of fire management policies in these three important savanna regions, and identify ongoing challenges for implementation of culturally and ecologically sustainable fire management policies. PMID- 30522067 TI - Socioeconomic differences among resident, users and neighbour populations of a protected area in the Brazilian dry forest. AB - Protected areas are an important strategy to safeguard biodiversity. However, if social development is not considered, biological conservation targets may not be achieved. In this empirical study, we assess the relationship between poverty and conservation goals in dry forests within a 62,000-ha Brazilian National Park (Caatinga biome). We conducted 81 structured household interviews between January and July of 2016 to assess socioeconomic, resource management and land-use variables. We used non-parametric analysis of variance to test for differences in socioecological variables among families living inside and outside the Park and both (double dwelling). The majority of families (76%) residing inside the Park were living below the poverty line while less than 14% in outside and double dwelling residences faced the same issue. Families living inside the park had lower socioeconomic conditions such as limited water availability, poor house infrastructure, low income, and high dependence on firewood than outside and double dwelling families. They were also more dependent on external financial support and natural resources. We found that failures in protected areas inception and implementation have driven people towards a mutually reinforcing and declining situation in which negative socioeconomic outcomes are associated with nature degradation. Therefore, our results suggest that the future of dry forests, characterized worldwide by the presence of low-income populations, will be largely dependent on conservation strategies that address poverty alleviation and human well-being. PMID- 30522068 TI - Two-stage microbial conversion of crude glycerol to 1,3-propanediol and polyhydroxyalkanoates after pretreatment. AB - With increasing demand for biodiesel, crude glycerol as a by-product in biodiesel production has been generated and oversupplied. This study, therefore, explored the pretreatment and a subsequent two-stage microbial system to convert crude glycerol into high value-added products: 1,3-propanediol (1,3-PDO) and polyhydroxyalkanoates (PHAs). After pretreatment, long chain fatty acids (LCFAs) could be effectively removed from crude glycerol to eliminate the inhibition effects on subsequent microbial process. In the anaerobic fermentation, when fed treated crude glycerol increased from 20 g/L to 100 g/L, 1,3-PDO yield decreased from 0.438 g/g to 0.345 g/g and accompanied carboxylic acids shifted from acetate and lactate dominant to lactate overwhelmingly dominant. Meanwhile, the relative abundance of Clostridiales sustained around 50% but Enterobacteriales increased from 19% to 53%. Further fed glycerol increase to 140 g/L resulted in severe substrate inhibition, which could be relieved by intermittent feeding. In aerobic process, glycerol anaerobic digestion effluent (ADE) was fed to the consortium of Bacillus megaterium and Corynebacterium hydrocarbooxydans for selectively consumption of carboxylic acids and residual glycerol from 1,3-PDO to produce PHAs as a secondary high value-added product. The consortium accumulated maximum 8.0 g/L poly (3-hydroxybutyrate) (PHB), and 1,3-PDO purity increased from initial 27.7% to almost 100% when fed with 100 g/L glycerol ADE. Overall, this study provided comprehensive and insightful information on microbial conversion of crude glycerol to high value-added products after pretreatment. PMID- 30522071 TI - Hybrid colloidal suspensions tailored as gels to remove radioactive bitumen stains. AB - Vacuumable gels have been developed in the nuclear industry to decontaminate solid surfaces with little or no mechanical operations and without producing any liquid effluents. These gels can be spread on the contaminated surface and rapidly trap the radio-contaminants by sorption after corroding the substrate down to several tens of microns if necessary. The gel then dries and eventually fractures into a non-powdery solid that is easily removable by brushing or vacuum cleaning. This process was initially developed for the nuclear decontamination of metallic surfaces but innovative formulations are being developed for wide range of applications. This paper introduces two such formulations designed to remove sticky organic layers, bitumen in this study. We show that adding an organic bio solvent, limonene, allows bitumen layers to be dissolved, absorbed in the liquid state into the gel matrix, and then removed from the substrate as solid waste after drying. Substituting an organic co-solvent (ethanol) for some of the limonene improves the overall efficiency of the process by decreasing the drying time of the gel and limiting the diffusion of the dissolved bitumen without affecting the dissolving power of the gel. Finally, the performance of these gels is demonstrated for the removal of nuclear contaminated (137Cs) bitumen stains. PMID- 30522069 TI - Occurrence and levels of micropollutants across environmental and engineered compartments in Austria. AB - Occurrence and concentration of a broad spectrum of micropollutants are investigated in Austrian river catchments, namely polycyclic aromatic hydrocarbons (PAHs), polybrominated diphenyl ethers (PBDEs), organotin compounds, perfluoroalkyl acids (PFAAs) and metals. The parallel analysis across multiple environmental and engineered compartments sheds light on the ratio of dissolved and particulate transport and on differences in concentration levels between point and diffuse emission pathways. It is found that some PAHs and organotins are present in rivers, groundwater and bulk deposition at higher concentrations than in municipal wastewater effluents. Among PFAAs and metals, highest concentrations were recorded either in atmospheric deposition or in discharges from wastewater treatment plants. The relevance of the analysis across compartments is best shown by the case of perfluorooctanesulfonic acid (PFOS). Despite municipal wastewater effluents being the emission pathway with highest concentrations, this study reveals that not only rivers, but also atmospheric deposition and groundwater sometimes exceed the environmental quality standard for surface waters. Moreover, this work reveals partially counterintuitive patterns. In rivers with treated wastewater discharges, increasing levels of dissolved compounds were measured at rising flow conditions, whereas the opposite would be expected owing to the dilution effect. This might derive from the mobilisation from soil or suspended particulate matter or rather find its explanation in high concentrations in atmospheric deposition. These hypotheses require however being tested through targeted studies. Additional future research includes the analysis of how regional or catchment specific characteristics might alter the relative importance of different emission pathways, and the modelling of emission and river loads to assess their relative contribution to river pollution. PMID- 30522070 TI - An approach to the implementation of Low Impact Development measures towards an EcoCampus classification. AB - Impervious cover has important hydrologic impacts, namely the increased runoff volume and peak discharges in the rainwater network, which can lead to significant consequences like rapid urban floods with social, environmental and economic implications. LID (Low Impact Development) consist of distributed runoff management measures, like green roofs, pervious pavements, waterways covered with vegetation and filter trails, among others, that seek to control stormwater in the origin, reducing imperviousness. These solutions avoid increased runoff rate and volume, increase infiltration and groundwater recharge. The main goal of the research work here presented is to study the hydrological impact of LID's in UTAD (University of Tras-os-Montes e Alto Douro) campus, which is an institution focused on sustainability, since it has defined in its Strategic Plan to achieve, in a near future, an EcoCampus classification. To achieve the proposed goal, the campus area was studied in detail in order to evaluate the technical possibility of LID's implementation. A peak discharge comparison was made between the current situation and the one with LID's implementation, using the rational method. The results showed that peak discharges reduction between 68 and 95% may be achieved with LID solutions in UTAD campus. PMID- 30522072 TI - Management of slurry in Gran Canaria Island with full-scale natural treatment systems for wastewater (NTSW). One year experience in livestock farms. AB - The aim of this work is to describe the performance of three full-scale natural treatment systems for wastewater, which operated in an integrated manner in livestock pig farms (1000-1500pigsintotal) over one year. Slurry management was performed with these natural treatment systems operating under the normal waste loading conditions of the livestock farms in which were integrated. The systems were comprised of elements such as first generation digesters, subsurface flow constructed wetlands and facultative ponds. The facilities, located on the island of Gran Canaria (Spain), enabled the study of viable alternatives for effluent management characterized by low-cost treatments. The systems were evaluated in terms of chemical oxygen demand removal efficiency, operating with variable organic loading. Values of between 80% and 90% were obtained. A comparison was also made of first-generation cascade flow digester operation (<70% removal efficiency), with complete-mix digesters (<20% removal efficiency), and finally with facultative ponds combined with subsurface flow constructed wetlands (<91% removal efficiency). It was also verified that when natural treatment systems for wastewater combine different elements they have better removal efficiency and better response to load and/or flow changes. PMID- 30522073 TI - How much of a market is involved in a biodiversity offset? A typology of biodiversity offset policies. AB - Biodiversity offsets (BO) are increasingly promoted and adopted by governments and companies worldwide as a policy instrument to compensate for biodiversity losses from infrastructure development projects. BO are often classified as 'market-based instruments' both by proponents and critics, but this representation fails to capture the varieties of how BO policies actually operate. To provide a framing for understanding the empirical diversity of BO policy designs, we present an ideal-typical typology based on the institutions from which BO is organised: Public Agency, Mandatory Market and Voluntary Offset. With cross-case comparison and stakeholder mapping, we identified the institutional arrangements of six BO policies to analyse how the biodiversity losses and gains are decided. Based on these results, we examined how these six policies relate to the BO ideal types. Our results suggested that the government, contrary to received wisdom, plays a key role not just in enforcing mandatory policies but also in determining the supply and demand of biodiversity units, supervising the transaction or granting legitimacy to the compensation site. Mandatory BO policies can be anything from pure government regulations defining industry liabilities to liability-driven markets where choice sets for trading credits are constrained and biodiversity credit prices are negotiated under state supervision. It is important to distinguish between two processes in BO: the matching of biodiversity losses and gains (commensurability) and the trading of biodiversity credits (commodification). We conclude that the commensurability of natural capital is restricted in BO policies; biodiversity is always exchanged with biodiversity. However, different degrees of commodification are possible, depending on the policy design and role of price signals in trading credits. Like payments for ecosystem services, the price of a biodiversity credit is most commonly based on the cost of management measures rather than the 'value' of biodiversity; which corresponds to a low degree of commodification. PMID- 30522074 TI - The adoption of sustainable practices: A supplier's perspective. AB - Suppliers' adoption of sustainable practices plays a critical role for global companies to improve environmental performance. Based on the absorptive capacity theory, this study empirically explores how suppliers' knowledge bases and power relationships influence their adoption of sustainability practices. A longitudinal case study with eight suppliers has been conducted. We find that the adoption of leading sustainable practices requires a supplier's good knowledge base whereas a supplier can adopt imitating and toddling sustainable practices even if it has a limited knowledge base. Both the power of internal sustainability teams and external buyers enhance the effects of suppliers' knowledge bases on the adoption of sustainable practices. Suppliers choose the strategy used in adopting sustainable practices according to the configuration of internal and external power. The results enhance the current understandings of the mechanisms through which knowledge bases and power relationships affect the adoption of sustainable practices. The findings can also help global companies improve the effectiveness of their supplier development efforts and enhance the environmental performance of supply chains. PMID- 30522075 TI - Tobacco and cannabis co-use and interrelatedness among adults. AB - Cannabis and tobacco co-use is prevalent, but consensus regarding the reasons for co-use among adults and the degree of interrelatedness between these substances is lacking. Reasons for co-use have been explored with younger users, but little data exists for more experienced users with entrenched patterns of co-use. The goal of this study was to examine characteristics and patterns of cannabis tobacco co-use among adults in the Southeastern United States (US), where there is a legal landscape of generally restrictive cannabis legislation coupled with more permissive tobacco control compared to other US regions. Participants (N = 432) were regular cannabis users recruited through Amazon Mechanical Turk. Measures included demographics, patterns of cannabis and tobacco use, and reasons for co-use. Within this sample, 42% were current users of tobacco (n = 182). Cannabis-tobacco co-users were older and had more years of cannabis use than cannabis-only users. Among the co-using sub-sample, there was little consistency in the reasons for co-use, suggesting individual differences in the use of both substances. High levels of cannabis-tobacco interrelatedness (i.e., temporally concurrent use) were associated with smoking more cigarettes (tobacco) per day and greater nicotine dependence scores when compared to users with low levels of interrelatedness. Though these results are limited by a small sample size and generalizability issues, there were individual differences in cannabis-tobacco relatedness, which may be of importance when considering treatment strategies for cannabis, tobacco, or both. With additional research, personalized strategies adapted to cannabis-tobacco relatedness profiles among co-users may be warranted as a treatment strategy. PMID- 30522076 TI - Investigating associations between caffeinated beverage consumption and later alcohol consumption among early adolescents. AB - Previous research has demonstrated that caffeinated beverage consumption predicts alcohol consumption among early adolescents. This study aimed to investigate this association in two ways: (1) by examining if this association remained significant once other established risk factors for alcohol were adjusted for statistically; and (2) by considering three possible moderators of this association: gender, sensation-seeking, and parental monitoring. Data from the Camden Youth Development Study, a longitudinal, community-based study of middle school students, were used. Youth were initially assessed in 6th and 7th grade and followed-up 16 months later. Self-reports of frequency of energy drink, coffee, and alcohol consumption, as well as sensation-seeking, perceived peer and best friend alcohol use, alcohol expectancies, and parental monitoring, were used. Results indicated that both energy drink and coffee consumption predicted later alcohol consumption, even after adjusting for other risk factors for alcohol consumption. Parental monitoring was a significant moderator of this link, such that youth who consumed energy drinks and reported low parental monitoring were particularly at risk for later alcohol consumption. These findings indicate that the link between earlier caffeine consumption and later alcohol consumption is not simply due to the co-occurrence of caffeine consumption with other risk factors for alcohol use. In addition, risk associated with early energy drink consumption appears to be particularly pronounced for youth in families characterized by low parental monitoring. PMID- 30522077 TI - Case report: Disseminated pulmonary mucormycosis involving spleen in diabetic patient with aggressive surgical approach. AB - INTRODUCTION: Mucormycosis is a life threatening fungal infection that occurs in immunocompromised patients. PRESENTATION OF CASE: A 36-year-old Saudi male with known case of Insulin-Dependent Diabetes Mellitus (IDDM), who was presented with productive cough and diarrhea. Computed tomography (CT) revealed a disseminated fungal invasion of the lungs and spleen with invading the fundus of the stomach. An aggressive surgical approach and amphotericin B treatment resolved his condition. DISCUSSION: Disseminated Mucormycosis in one organ can spread hematogenously to other organs and can cause severe morbidity and mortality in high risk individuals. The diagnosis of mucormycosis is usually delayed, Antifungal therapy alone is insufficient for mucormycosis, and surgical debridement for all infected tissue is often required. CONCLUSION: Mucormycosis is a life threating infection, and usually the diagnosis late because of non specific clinical, radiological feature and need biopsy for confirmation of the organism. The cornerstone for the management and increase the survival rate remain on rapid diagnosis, treatment of the underlying predisposing condition, and urgent surgical debridement. PMID- 30522078 TI - A giant sacrococcygeal teratoma in adult female: A case report. AB - INTRODUCTION: Sacrococcygealteratoma is very rare in adults with only few cases reported in literature. It is a slow growing benign cystic tumor with 1-2% chance for malignant transformation and may attain a huge size causing pressure effect on pelvic and intra-abdominal organs. When grows caudally, it causes discomfort, skin excoriation and cosmetic disfigurement. PRESENTATION OF CASE: We present a giant, long standing Sacrococcygeal teratoma in an adult female patient which caused her significant obstructing lower gastrointestinal and urinary symptoms besides the discomfort and disfigurement of the sacral region. DISCUSSION: Sacrococcygeal teratomas are commonly present early in life but are very rare to be seen in adults with such a huge size in such a place where it interfered with patient sitting and sleeping. Diagnosis of our case was suspected by clinical examination, ultrasound and MRI while histopathology confirmed the diagnosis. It was completely excised along with the coccyx with primary wound closure and had a good postoperative recovery. Up till now, 18 months follow-up using clinical, biochemical and radiological assessment revealed no evidence of recurrence. CONCLUSION: Sacococcygeal teratoma should be considered in the differential diagnosis of large pelvic masses in adults. In the presence of an extra-corporal and deep intra pelvic extension, we recommend the posterior perineal approach for excision as it has convenient control over the mass during surgery and good cosmetic results. PMID- 30522079 TI - Clostridium septicum: A usual suspect? Aortic rupture following right hemicolectomy: A case report. AB - INTRODUCTION: There is a known association between Clostridium Septicum, mycotic aneurysm and colon neoplasm. CASE PRESENTATION: We report the case of a 90 year old female admitted with abdominal pain to the general surgery unit. Admission CT scan demonstrated a thick walled caecum and pericaecal inflammation suspicious for a perforated carcinoma. This was subsequently confirmed at colonoscopy with biopsy demonstrating a poorly differentiated adenocarcinoma. A laparoscopic right hemicolectomy was completed the following week after perioperative workup and intravenous antibiotic therapy. On the 9th postoperative day, fever and rising inflammatory markers prompted repeat abdominal CT scan which demonstrated a mycotic aneurysm of the upper abdominal aorta. After discussion with the vascular surgery and infectious diseases team, along the patient and family, the decision was made to palliate. The patient died at home from presumed spontaneous rupture two weeks after discharge. DISCUSSION: Mycotic aneurysm in colonic malignancy is a rare and often lethal complication. C. Septicum is causative in over 70% of cases with concomitant colonic malignancy. CONCLUSION: Mycotic aneurysm should be considered in any deteriorating patient with concomitant colonic malignancy. PMID- 30522080 TI - Submuscular gluteal abcess: An unusual presentation of rare sacral tuberculosis. AB - INTRODUCTION: Both gluteal abscess and sacral tuberculosis are rare entities in spinal tuberculosis cases. Even in endemic country, this atypical presentation may be the cause of delayed diagnosis and treatment. PRESENTATION OF CASE: A 51 year-old woman was admitted with painless massive lump on both of her thighs that have been enlarging for the past 6 months. She had a history of previous tuberculosis treatment. From the MRI examination submuscular gluteal abscess, which was an extension of the sacral tuberculosis, were found. Open debridement and biopsy were performed, which confirmed the suspicion of tuberculosis. Oral anti tuberculosis drugs were administered after. There was no recurrence and complication at the final follow up. DISCUSSION: Cold abscess formation is common in spine tuberculosis however the formation of gluteal abscess as the extension of sacral tuberculosis is rare. Although MRI's specificity in determining the underlying cause is poor, it has a great role not only determining the location and size of the lesion, but also to describe anatomical pathophysiology of the abscess dissemination from sacral tuberculosis. CONCLUSION: Despite the limitation of the study and the rarity of this case, tuberculosis should be made as the main differential diagnosis for atypical sacral lesion that occurs with submuscular gluteal abscess. PMID- 30522081 TI - Action co-representation and the sense of agency during a joint Simon task: Comparing human and machine co-agents. AB - Recent studies have suggested that individuals are not able to develop a sense of joint agency during joint actions with artificial systems. We sought to examine whether this lack of joint agency is linked to individuals' inability to co represent the machine-generated actions. Fifteen participants observed or performed a Simon response time task either individually, or jointly with another human or a computer. Participants reported the time interval between their response (or the co-actor response) and a subsequent auditory stimulus, which served as an implicit measure of participants' sense of agency. Participants' reaction times showed a classical Simon effect when they were partnered with another human, but not when they collaborated with a computer. Furthermore, participants showed a vicarious sense of agency when co-acting with another human agent but not with a computer. This absence of vicarious sense of agency during human-computer interactions and the relation with action co-representation are discussed. PMID- 30522082 TI - Measurement of absolute gamma-ray emission probabilities in the decay of 227Ac in equilibrium with its progeny. AB - The emission probabilities of gamma rays produced in the 227Ac decay series were determined by high-resolution gamma-ray spectrometry of sources with standardised activity. The sources were prepared quantitatively on glass discs by drop deposition of a solution with 227Ac in radioactive equilibrium with its daughter nuclides. Their activity was measured by a primary standardisation technique based on alpha-particle counting at a defined low solid angle. Four laboratories performed gamma-ray spectrometry and derived absolute gamma-ray intensities. Mean values were calculated and compared with literature data and the currently recommended evaluated data. New values on certain gamma-ray emission probabilities are proposed. PMID- 30522083 TI - Removal of per- and polyfluoroalkyl substances using super-fine powder activated carbon and ceramic membrane filtration. AB - Contamination of drinking water sources with per- and polyfluoroalkyl substances (PFASs) is a major challenge for environmental engineers. While granular activated carbon (GAC) is an effective adsorbent-based treatment technology for long-chained PFASs, GAC is less effective for removal of short-chained compounds, necessitating a more complete treatment strategy. Super-fine powder activated carbon (SPAC; particle diameter <1 um) is potentially a superior adsorbent to GAC due to high specific surface area and faster adsorption kinetics. This study served to evaluate SPAC coupled with ceramic microfiltration (CMF) for PFAS removal in a continuous flow system. Comparison of PFAS mass loading rates onto SPAC and GAC to 10% breakthrough of PFASs using contaminated groundwater indicates that SPAC has nearly double the adsorption potential of GAC. Limitations reaching breakthrough for the SPAC system led to additional higher mass loading experiments where PFAS adsorption onto SPAC reached 2990 MUg/g (for quantifiable PFASs), 480x greater than GAC and is thought to be a function of adsorbent size, pore content and PFAS chain length. Additional analysis of system performance through the application of liquid chromatography quadrupole time-of flight mass spectrometry (LC-QToF-MS) revealed the presence of additional PFASs in influent samples that were removed by the SPAC/CMF system. PMID- 30522084 TI - Remediation of cadmium, lead and zinc in contaminated soil with CETSA and MA/AA. AB - Soil washing, which is used to remove heavy metals from soil, is dependent on suitable washing agents. However, there is still a lack of economical, environmentally friendly washing agents with high removal efficiency. In this study, three washing agents, carboxyalkylthiosuccinic acid (CETSA), copolymer of maleic and acrylic acid (MA/AA) and ethylenediamine tetra acetic acid (EDTA), were used to remove heavy metals from contaminated soil. The influence of washing solution concentration, pH and washing time on heavy metals removal was also investigated. The cadmium (Cd), lead (Pb), and zinc (Zn) removal efficiencies increased as washing solution concentrations increased from 0 to 60 g L-1, while they declined as pH increased from 3 to 8. Despite fluctuations between 90 and 120 min, heavy metal removal efficiencies increased continuously from 10 to 90 min. The three agents also effectively reduced the potential risks of Cd, Pb, and Zn in contaminated soil, but only CETSA and MA/AA produced no significant changes in chemical properties. Fourier transform infrared spectroscopy revealed that the hydroxyl, carboxyl, carbonyl, methoxyl, and sulfur groups were related to the heavy metal ions from the soil colloids. Thus, CETSA and MA/AA were suitable washing agents for remediation of heavy metals contaminated soil. PMID- 30522085 TI - A label-free impedimetric aptasensor for the detection of Bacillus anthracis spore simulant. AB - Herein, we report an impedimetric DNA-based aptamer sensor for a single-step detection of B. anthracis spore simulant (B. cereus spore). Specifically, we designed a miniaturized label-free aptasensor for B. cereus spores based on a gold screen-printed electrode functionalized with B. cereus spores-binding aptamer (BAS-6R). Several parameters were optimized to fabricate the aptasensor such as the concentration of DNA aptamer solution (0.5 uM), the time (48 h), the temperature (4 degrees C), and the pH (7.5) for aptamer immobilization on the working electrode surface. Once the aptasensor was developed, it was tested against B. cereus spores 14579 evaluating the effect of incubation time and MgCl2 concentration. Under the optimized conditions (incubation time equal to 3 h and absence of MgCl2), B. cereus spores 14579 were detected with a linear range between 104 CFU/ml and 5 * 106 CFU/ml and a detection limit of 3 * 103 CFU/ml. Furthermore, the study of selectivity toward B. cereus 11778, B. subtilis, Legionella pneumophila, and Salmonella Typhimurium has demonstrated the capability of this sensor to detect B. cereus spores, proving the suitability of the DNA-based sensing element combined with a portable instrument for a label free measurement on site of B. anthracis spore simulant. PMID- 30522086 TI - The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design. AB - BACKGROUND: Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines. OBJECTIVE: The objective is to evaluate the clinical and economic impact of early invasive management with coronary angiography in T2MI in terms of all-cause mortality and cost effectiveness. DESIGN: This prospective, pragmatic, multicenter, randomized trial among patients with suspected supply demand ischemia leading to troponin elevation (n=1,800; T2MI [1,500], chronic myocardial injury [300]) compares the impact of invasive angiography (or computed tomography angiography as per local preference) within 5 days of randomization versus conservative management (with or without functional testing at clinician discretion) on all-cause mortality by 2 years. Randomized treatment allocation will be stratified by baseline estimated risk of mortality using the Acute Physiology, Age, and Chronic Health Evaluation (APACHE) III risk score. Cost-effectiveness will be evaluated by follow-up on clinical events, quality of life, and resource utilization over 24 months. SUMMARY: Ascertaining the most appropriate first-line investigative strategy for these commonly encountered high-risk T2MI patients in a randomized comparative study will be pivotal in informing evidence-based guidelines that lead to better patient and health care outcomes. PMID- 30522087 TI - (Pyrrolo-pyridin-5-yl)benzamides: BBB permeable monoamine oxidase B inhibitors with neuroprotective effect on cortical neurons. AB - An extensive study was performed to develop a series of (pyrrolo-pyridin-5 yl)benzamides as reversible MAO-B inhibitors. Compounds 14 (NTZ-2020, hMAO-B IC50 = 1.11 nM, Ki = 0.56 nM, >9000-fold selective versus MAO-A) and 15 (NTZ-2027, hMAO-B IC50 = 3.27 nM, Ki = 1.45 nM, SI > 3058) are identified as the most promising BBB permeable derivatives within the series of (1H-pyrrolo[3,2 b]pyridine-5-yl)benzamides, combining both high potency and selectivity with optimal physicochemical and drug-like properties required for CNS active drugs. Extended photophysical analysis, including single X-ray analysis, quantum chemical calculations and spectroscopic experiments provided insights into their tautomerism and structural behavioral, which relates to their biologically active form. The reversible MAO-B inhibitor 14 (NTZ-2020) exhibits a neuroprotective effect on cortical neuron survival and induces neurite network outgrowth. These effects are associated with a good BBB penetration of 14 that was confirmed in a triple cell neurovascular unit (NVU) model. PMID- 30522088 TI - Hot spots for GPCR signaling: lessons from single-molecule microscopy. AB - G protein-coupled receptors (GPCRs) are among the best-studied membrane receptors, mainly due to their central role in human physiology, involvement in disease and relevance as drug targets. Although biochemical and pharmacological studies have characterized the main steps in GPCR signaling, how GPCRs produce highly specific responses in our cells remains insufficiently understood. New developments in single-molecule microscopy have made it possible to study the protein-protein interactions at the basis of GPCR signaling in previously inconceivable detail. Using this approach, it was recently possible to follow individual receptors and G proteins as they diffuse, interact and signal on the surface of living cells. This has revealed hot spots on the plasma membrane, where receptors and G proteins undergo transient interactions to produce rapid and local signals. Overall, these recent findings reveal a high degree of dynamicity and complexity in signaling by GPCRs, which provides a new basis to understand how these important receptors produce specific effects and might pave the way to innovative pharmacological approaches. PMID- 30522089 TI - Load-bearing capacity under fatigue and survival rates of adhesively cemented yttrium-stabilized zirconia polycrystal monolithic simplified restorations. AB - This study evaluated the fatigue failure load, number of cycles for failure and survival probability of 2nd and 3rd generation yttrium-stabilized zirconia (YSZ) adhesively cemented to a dentin analogue substrate. Disc-shaped specimens (n = 10; O = 10 mm; thickness = 1.0 mm) were produced from four 2nd generation YSZs (Lava Plus, 3M ESPE; Vita In-Ceram YZ-HT, VITA Zahnfabrik; Zirlux FC, Ivoclar Vivadent; Katana ML-HT, Kuraray) and two 3rd generation YSZs (Katana UTML and Katana STML, Kuraray). Each YSZ disc was adhesively cemented (Multilink Automix System) onto its dentin analogue pair (epoxy resin, O = 10 mm; thickness = 2.5 mm). Fatigue tests were conducted through step-stress approach (load ranging from 400 to 2600 N; step-size of 200 N; 20,000 cycles per step, 20 Hz) and the obtained data were analyzed using Kaplan Meier and Mantel-Cox tests. Surface topography and phase transformation (m-, t-, and c-phases) inspections after particle air-abrasion of the YSZs were performed, as well as fractographic analysis of the failed specimens. Second-generation zirconia materials presented higher fatigue failure load, number of cycles for failure, and survival probability than 3rd generation. Similar topographical characteristics of the YSZs could be noted. Phase transformation (t- to m-phase) after YSZ air-abrasion was only observed for 2nd generation materials. All failures started from the surface/sub-surface defects located at the cementation interface. 2nd generation zirconia presented higher load-bearing capacity under cyclic loading than 3rd generation materials. PMID- 30522090 TI - Agreement is very low between a clinical prediction rule and physiotherapist assessment for classifying the risk of poor recovery of individuals with acute whiplash injury. AB - BACKGROUND: A prognostic clinical prediction rule (whiplash CPR) has been validated for use in individuals with acute whiplash associated disorders (WAD). The clinical utility of this tool is unknown. OBJECTIVES: To investigate: 1) the level of agreement between physiotherapist- and whiplash CPR-determined prognostic risk classification of people with acute WAD; 2) which clinical findings are used by physiotherapists to classify prognostic risk; and 3) whether physiotherapists plan to differ the number of treatment sessions provided based on prognostic risk classification. DESIGN: Pragmatic, observational. METHOD: 38 adults with acute WAD were classified as low, medium, or high risk of poor recovery by their treating physiotherapist (n = 24) at the conclusion of the initial consultation. A weighted Cohen's kappa examined the agreement between physiotherapist estimated risk classification and the whiplash CPR. Physiotherapists' reasons for classification were provided and summarised descriptively. Kruskal-Wallis and post-hoc Dunn's tests compared projected number of treatment sessions between risk subgroups. RESULTS: Physiotherapist agreement with the whiplash CPR occurred in 29% of cases (n = 11/38), which was less than what is expected by chance (K = -0.03; 95%CI -0.17 to 0.12). Physiotherapists most frequently considered range of movement (n = 23/38, 61%), a premorbid pain condition (n = 14/38, 37%), response to initial physiotherapy treatment (n = 12/38, 32%), and pain intensity (n = 12/38, 32%) when classifying prognostic risk. The projected number of treatment sessions was not different between risk groups using classifications provided by the physiotherapists (chi2(2) = 2.69, p = 0.26). CONCLUSIONS: Physiotherapists should consider incorporating the whiplash CPR into current assessment processes to enhance accuracy in prognostic decision making. PMID- 30522091 TI - Behavioral problems are associated with cognitive and language scores in toddlers born extremely preterm. AB - OBJECTIVE: To evaluate the relationship of parent-reported child behaviors on the Child Behavior Checklist (CBCL) to cognition, language, and motor skills on the Bayley Scales of Infant and Toddler Development - III (Bayley-III) in toddlers born extremely preterm. STUDY DESIGN: Toddlers born extremely preterm (gestational ages 22 0/7 to 26 6/7 weeks) were tested at 22-26 months corrected age with Bayley-III while parents completed the CBCL. Socio-demographic variables and medical history were recorded. Linear regression models were used to assess the relationship of Bayley-III cognitive, motor, and language scores with CBCL scores, adjusting for medical and socio-demographic factors. RESULTS: Internalizing, affective, and pervasive development problem behavior scores on the CBCL correlated significantly with lower Bayley-III cognitive, language, and motor scores on unadjusted and adjusted analyses. Although externalizing and anxiety problems were significantly associated with cognitive and language scores on unadjusted analysis, the relationships were not significant after adjusting for socio-economic factors. CBCL scores were similar for boys and girls, with the exception of the pervasive developmental problem scale; boys had significantly more problems than girls (p = 0.02). CONCLUSIONS: This study showed that parent reported behavior problems were related to lower cognitive, language, and motor development in toddlers born extremely preterm. Early findings of behavioral problems in toddlers born extremely premature may help identify children at greater risk for later learning difficulties. Adding a measure of behavior to the evaluation of these children may help better understand factors that can contribute to delays, especially in cognition and language. PMID- 30522092 TI - In silico Leishmania proteome mining applied to identify drug target potential to be used to treat against visceral and tegumentary leishmaniasis. AB - New therapeutic strategies against leishmaniasis are desirable, since the treatment against disease presents problems, such as the toxicity, high cost and/or parasite resistance. As consequence, new antileishmanial compounds are necessary to be identified, as presenting high activity against Leishmania, but low toxicity in mammalian hosts. In the present study, a Leishmania proteome mining strategy was developed, in order to select new drug targets with low homology to human proteins, but that are considered relevant for the parasite' survival. Results showed a hypothetical protein, which was functionally annotated as a glucosidase-like protein, as presenting such characteristics. This protein was associated with the metabolic network of the N-Glycan biosynthesis pathway in Leishmania, and two specific inhibitors - acarbose and miglitol - were predicted to be potential targets against it. In this context, miglitol [1-(2-Hydroxyethyl) 2-(hydroxymethyl)piperidine-3,4,5-triol] was tested against stationary promastigotes and axenic amastigotes of the Leishmania amazonensis and L. infantum species, and results showed high values of antileishmanial inhibition against both parasite species. Miglitol showed also efficacy in the treatment of Leishmania-infected macrophages; thus denoting its potential use as an antileishmanial candidate. In conclusion, this work presents a new drug target identified by a proteome mining strategy associated with bioinformatics tools, and suggested its use as a possible candidate to be applied in the treatment against disease. PMID- 30522093 TI - High Circulating Alarin Levels Are Associated with Presence of Metabolic Syndrome. AB - BACKGROUND/AIMS: Alarin has been reported to be related with increased food intake and body weight. The relationship of circulating Alarin with insulin resistance or metabolic syndrome (MetS), however, is unknown. This study aimed to investigate the physiological role of Alarin and its association with MetS in humans. METHODS: Newly diagnosed MetS patients (n=237) and age-matched healthy subjects (n=192) were recruited for this study. Oral glucose tolerance test, treadmill exercise, lipid infusions and euglycemic-hyperinsulinemic clamp (EHCs) were performed. Circulating Alarin and TNFalpha levels were measured by ELISA. RESULTS: Circulating Alarin levels were significantly higher in MetS patients compared with healthy subjects (0.46 +/- 0.22 vs. 0.41 +/- 0.14 ug/L, P < 0.01). In all studied subjects, circulating Alarin levels were positively correlated with WC, blood pressure, FBG, triglyceride, HbA1c, HOMA-IR, AUCglucose, and TNFalpha (P < 0.05 or P < 0.01). Multivariate logistic regression analyses revealed that circulating Alarin levels were correlated with MetS and insulin resistance. There was no significant change of circulating Alarin levels in the subjects with treadmill exercise for 45 min. In healthy individuals, however, glucose challenge, acute hyperglycemia and lipid infusions resulted in increased circulating Alarin levels, while acute hyperinsulinaemia transiently decreased circulating Alarin levels. CONCLUSION: The present study provides the evidence that circulating Alarin levels are associated with MetS and insulin resistance. PMID- 30522094 TI - Direct Effect of Septic Plasma in Human Cell Lines Viability. AB - BACKGROUND: Sepsis is a life-threatening condition often associated with a high incidence of multiple organs injury. Several papers suggested the immune response by itself, with the production of humoral inflammatory mediators, is crucial in determining organ injury. However, little is known of how sepsis directly induces organ injury at the cellular levels. To assess this point, we set up an in vitro study to investigate the response of renal tubular cells (RTCs), monocytes (U937) and hepatocytes (HepG2) after 24 h-incubation with septic patients' plasma. METHODS: We enrolled 26 septic patients ("test" group). We evaluated cell viability, apoptosis and necrosis by flow cytometer. Caspase-3,-8,-9 and cytochrome-c concentrations have been analyzed using the Human enzyme-linked immunosorbent assay kit. RESULTS: We found that a decrease of cell viability in all cell lines tested was associated to the increase of apoptosis in RTCs and U937 (p < 0.0001) and increase of necrosis in HepG2 (p < 0.5). The increase of apoptosis in RTCs and U937 cells was confirmed by higher levels of caspase-3 (p < 0.0001). We showed that apoptosis in both RTCs and U937 was triggered by the activation of the intrinsic pathway, as caspase-9 and cytochrome-c levels significantly increased (p < 0.0001), while caspase-8 did not change. This assumption was strengthened by the significant correlation of caspase-9 with both cytochrome-c (r = 0.73 for RTCs and r = 0.69 for U937) and caspase-3 (r = 0.69 for RTCs and r = 0.63 for U937). CONCLUSION: Humoral mediators in septic patients' plasma induce apoptosis. This fact suggests that apoptosis inhibitors should be investigated as future strategy to reduce sepsis-induced organ damages. PMID- 30522095 TI - Clinical Drug Response Prediction by Using a Lq Penalized Network-Constrained Logistic Regression Method. AB - BACKGROUND/AIMS: One of the most important impacts of personalized medicine is the connection between patients' genotypes and their drug responses. Despite a series of studies exploring this relationship, the predictive ability of such analyses still needs to be strengthened. METHODS: Here we present the Lq penalized network-constrained logistic regression (Lq-NLR) method to meet this need, in which the predictors are integrated into the gene expression data and biological network knowledge and are combined with a more aggressive penalty function. Response prediction models for two cancer targeting drugs (erlotinib and sorafenib) were developed from gene expression data and IC50 values from a large panel of cancer cell lines by utilizing the proposed approach. Then the drug responders were tested with the baseline tumor gene expression data, yielding an in vivo drug sensitivity prediction. RESULTS: These results demonstrated the high effectiveness of this approach. One of the best results achieved by our method was a correlation of 0.841 between the cell line in vitro drug response and patient's in vivo drug response. We then applied these two drug prediction models to develop a personalized medicine approach in which the subsequent treatment depends on each patient's gene-expression profile. CONCLUSION: The proposed method is much better than the existing approach and can capture a more accurate reflection of the relationship between genotypes and phenotypes. PMID- 30522096 TI - Usual Interstitial Pneumonia Pattern in the Lower Lung Lobes as a Prognostic Factor in Idiopathic Pleuroparenchymal Fibroelastosis. AB - BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare interstitial pneumonia that is characterized by stiffness in both the upper lobes and pleura, which is evident on high resolution computed tomography (HRCT) of the chest. However, prognostic factors for IPPFE have not been identified yet. OBJECTIVE: We aimed to investigate the clinical prognostic factors affecting survival in patients with IPPFE. METHODS: Between April 2009 and September 2017, we enrolled 36 patients who were clinically diagnosed with IPPFE, using HRCT. These patients were classified as either short survival (dead within 12 months from the diagnosis of IPPFE) or long survival (survived for greater than 12 months) groups. We retrospectively analyzed the clinical characteristics, serum markers, pulmonary function test results, and HRCT findings. RESULTS: Twelve patients were classified into the short survival and 24 were categorized into long survival categories. At the time of diagnosis, the incidence of coexistence of a usual interstitial pneumonia (UIP) pattern in the lower lobes on HRCT in the short survival was significantly higher than that in the long survival. Multivariate analysis revealed that a UIP pattern in the lower lobes on HRCT was the only independent variable for poor prognosis. The median survival time from diagnosis in patients with IPPFE was 24 months. Of these patients with IPPFE, the survival time with a UIP pattern was significantly shorter than in those without a UIP pattern. CONCLUSION: Our findings suggest that a UIP pattern in the lower lobes at the time of diagnosis was an independent prognostic factor for IPPFE. PMID- 30522097 TI - Efficacy of Clutch Cutter for Standardizing Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score-Matched Analysis. AB - BACKGROUND/AIMS: The purpose of this study was to evaluate the safety and efficacy of gastric endoscopic submucosal dissection (ESD) using the Clutch Cutter (CC), a scissor-type knife, compared with those of procedures using conventional devices. METHODS: This single-center retrospective study evaluated 237 patients with early gastric cancer: 83 who underwent ESD using the CC group and 154 who underwent ESD using the insulated-tip knife 2 (IT2 group). Clinicopathological features and technical outcomes were compared between the 2 groups using a propensity score-matched analysis. RESULTS: In 61 pairs of matched patients, there was no significant difference in R0 resection, perforation, or postoperative bleeding between the CC and IT2 groups. Comparisons between the 2 groups showed similar treatment outcomes for an expert endoscopist. Nevertheless, there were significant differences between the 2 groups for nonexperts in terms of self-completion (61.7 and 24.5%, respectively, p < 0.001), mean procedure times (45 and 61 min, respectively, p = 0.002), and mean numbers of intraoperative bleeding points and bleeding points requiring hemostatic forceps (3 and 0 vs. 8 and 3, respectively, p < 0.001). CONCLUSION: Better self completion rates and shorter procedure times were noted for gastric ESD using the CC by nonexperts than for that using IT2, probably due to hemostatic efficacy. PMID- 30522098 TI - Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways. AB - Smoking is considered to be the main source of indoor pollution, and it has been identified as an important environmental factor contributing to asthma onset. We know that T helper 2 (Th2) response plays a crucial role in the process of asthma disease. We have investigated the reaction of cigarette smoke extract (CSE) on Th polarization which is controlled by dendritic cells (DCs). Stimulated by CSE, immature DCs from murine bone marrow showed upregulated levels of TIM4. Cocultured with CD4+ T cells, stimulated DCs increased the ratio of IL-4+ versus IFN-gamma+ of CD4+ T cells. This suggests a differentiation towards Th2 response. Moreover, antibodies against TIM4 reversed the upexpression of the IL-4+/IFN gamma+ ratio provoked by CSE, indicating that the Th2 polarization which was induced by CSE is via TIM4 mechanisms. CSE could activate mitogen-activated protein kinase pathways like ERK and p38. Upregulation of TIM4 expression by CSE stimulation was found to be inhibited by an ERK inhibitor but not p38 and JNK. In conclusion, DC-induced Th2 polarization is a hallmark of CSE allergy, and this aspect can be explained by CSE-induced TIM4 expression. PMID- 30522099 TI - miR-202 Enhances the Anti-Tumor Effect of Cisplatin on Non-Small Cell Lung Cancer by Targeting the Ras/MAPK Pathway. AB - BACKGROUND/AIMS: KRas is usually mutated in non-small cell lung cancer (NSCLC). The mutated KRas gene is a negative prognostic indicator that promotes tumor proliferation, metastasis, and drug resistance in NSCLC, and thus has become a target for cancer therapy. This study is focused on the effects of the microRNA (miR)-202/KRas axis in regulating chemosensitivity in NSCLC. METHODS: Quantitative reverse transcriptase real-time PCR analysis was performed to examine the expression of miR-202. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assays were performed to evaluate the sensitivity of cisplatin against NSCLC cells. The miR-202/KRas axis was confirmed by western blot and luciferase reporter assays. Cell apoptosis was measured by flow cytometry. KRas expression, MEK1/2 and ERK1/2 phosphorylation, and activation of caspase-9 and caspase-3 were detected by western blot. RESULTS: A significant decrease in miR-202 expression was observed in NSCLC cells both in vivo and in vitro. In addition, miR-202 expression was associated with drug resistance. Recovery of miR-202 expression levels was found to increase the sensitivity of both NCI-H441 and A549 NSCLC cells to cisplatin treatment. Mechanically, as the Ras/mitogen-activated protein kinase (MAPK) pathway was aberrantly activated in NCI-H441 and A549 NSCLC cells, the overexpression of miR-202 was found to inhibit the Ras/MAPK pathway by targeting the KRas gene. As a result, increased miR-202 expression expanded apoptosis signaling induced by cisplatin in NSCLC cells. CONCLUSION: The miR-202/KRas axis controlled the chemosensitivity of NSCLC by mediating the Ras/MAPK pathway. Thus, the combination of platinum-based drugs with miR-202 may represent a novel strategy to enhance the anti-tumor effect against NSCLC. PMID- 30522100 TI - Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism. AB - BACKGROUND/AIMS: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. METHODS: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-beta (TGF-beta) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (alpha-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. RESULTS: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of alpha-SMA and Col1A1, suppressed alpha-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the alpha-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. CONCLUSION: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway. PMID- 30522101 TI - Blocking TRPA1 and TNF-alpha Signal Improves Bortezomib-Induced Neuropathic Pain. AB - BACKGROUND/AIMS: Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of multiple myeloma. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. The purpose of this study was to examine the underlying mechanisms leading to neuropathic pain induced by BTZ. METHODS: ELISA and western blot analysis were used to examine the levels of tumor necrosis factor alpha (TNF-alpha) and its receptor, transient receptor potential ankyrin 1 (TRPA1) and intracellular p38 MAPK and JNK signal in the lumbar dorsal root ganglion. Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. RESULTS: Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). Our data also showed that protein expression of TRPA1 was upregulated in the dorsal root ganglion of BTZ rats and blocking TRPA1 attenuated mechanical pain and cold sensitivity in control rats and BTZ rats (P< 0.05 vs. vehicle control). Notably, the inhibitory effect of blocking TRPA1 on mechanical pain and cold sensitivity was smaller in BTZ rats than that in control rats. In addition, a blockade of TNF alpha attenuated intracellular p38-MAPK and JNK signal in the dorsal root ganglion. This also decreased TRPA1 expression and alleviated mechanical hyperalgesia and cold hypersensitivity in BTZ rats. CONCLUSION: We revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ. The data also suggest that blocking TRPA1 and tumor necrosis factor alpha is beneficial to alleviate neuropathic pain during BTZ intervention. PMID- 30522102 TI - Clinicopathologic Features and Prognostic Factors in Alpha-Fetoprotein-Producing Colorectal Cancer: Analysis of 78 Cases. AB - BACKGROUND/AIMS: Alpha-fetoprotein-producing colorectal cancer (AFPP-CRC) is quite rarely seen. This study aimed to elucidate the clinicopathologic characteristics and prognostic factors of AFPP-CRC. METHODS: Among 5,051 colorectal cancer patients receiving surgery in the Fudan University Shanghai Cancer Center from 2006 to 2016, we identified 78 patients with elevated serum level of AFP (> 10 ug/L) preoperatively. A propensity score matching (PSM) analysis was performed which matched 75 AFPP-CRC patients to the same number of AFP-negative colorectal cancer (AFPN-CRC) patients. Kaplan-Meier curves were compared using the log-rank test and multivariable analysis was performed to evaluate the effect of AFP-positivity while adjusting confounding factors. 27 patients were available for immunohistochemical analysis. We conducted functional experiments to characterize the tumorigenicity of AFP. RESULTS: Patients with AFPP-CRC had a significantly higher incidence of advanced TNM stage and liver metastasis. Overall survival was significantly different between two groups before and after PSM, and AFP-positivity was one of the strongest predictors of overall survival in the multivariable model (HR 4.11, CI 95%: 1.43-11.76, p = 0.009) after PSM. We further investigated prognostic factors affecting prognosis in AFPP-CRC and found that the presence of liver metastasis was the only independent prognostic factor (HR 4.95, CI 95%: 1.48-16.48, p = 0.009). AFP expression was significantly positively correlated with HGF and c-Met expression. Transwell invasion assay revealed significantly increased cell motility with AFP overexpression. CONCLUSION: AFP-positivity is a significant negative predictor of overall survival in patients with colorectal cancer, which may be mediated by HGF/c-Met signaling pathway. PMID- 30522104 TI - Association of Central Venous Oxygen Saturation Variability and Mortality in Hemodialysis Patients. AB - BACKGROUND: Central venous oxygen saturation (ScvO2) is correlated with cardiac output. In most patients, ScvO2 declines during hemodialysis (HD) due to factors such as reduced preload, myocardial stunning, and intermittent arrhythmias. Previous research has shown that low ScvO2 is associated with higher mortality in chronic HD patients. In this research, we tested the hypothesis that ScvO2 variability is associated with all-cause mortality. METHODS: We conducted a retrospective study in 232 chronic HD patients with central venous catheter as vascular access. ScvO2 was recorded 1* per minute during dialysis using the Crit Line monitor. A 6-month baseline comprising at least 10 dialysis treatments with ScvO2 recordings preceded a follow-up period of up to 3 years. The coefficient of variation (CV) of ScvO2 (100 times the ratio of the standard deviation and mean of ScvO2) served as a measure of ScvO2 stability during baseline. Patients were stratified by median population CV of ScvO2 during baseline, and survival during follow-up was compared between the 2 groups by Kaplan Meier and multivariate Cox analysis. The association between CV of ScvO2 and all-cause mortality during follow-up was further assessed by Cox analysis with a spline term for CV of ScvO2. RESULTS: The mean CV +/- standard deviation of ScvO2 in our population was 6.1 +/- 2.7% and the median was 5.3%. Univariate Kaplan-Meier analysis (p = 0.043) and multivariate Cox analysis (hazard ratio [HR] 1.16; p = 0.0005) indicated that a CV of ScvO2 > 5.3% was significantly associated with increased mortality. In Cox analysis with spline term, a CV of ScvO2 > 11% was associated with a significantly increased HR for all-cause mortality. CONCLUSION: High ScvO2 variability during dialysis is associated with increased all-cause mortality. PMID- 30522103 TI - Down-Regulation of Laminin (LN)- alpha5 is Associated with Preeclampsia and Impairs Trophoblast Cell Viability and Invasiveness Through PI3K Signaling Pathway. AB - BACKGROUND/AIMS: Preeclampsia (PE) is a gestational disorder defined as hypertension and proteinuria, which is deemed a major cause of maternal and neonatal mortality and morbidity worldwide. The aim of this study was to investigate the expression patterns of placental laminin (LN)-alpha5 expression in normal and PE pregnancies, as well as evaluating the effects of LN-alpha5 on trophoblast proliferation, apoptosis, and invasion. METHODS: LN-alpha5 expression levels were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), and further confirmed by western blotting and immunofluorescence staining. Cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry. Cell invasion was assessed by matrigel-based transwell assay. LN-alpha5 DNA methylation in placentas was determined by bisulfite sequencing PCR (BSP). RESULTS: LN-alpha5 expression levels in PE placentas were significantly lower than that of normal pregnancies. Deficiency in LN-alpha5 expression resulted in decreased trophoblast proliferation and invasion but increased cell apoptosis, meanwhile, PI3K/AKT/mTOR signaling pathway was impaired by LN-alpha5 silencing. LN-alpha5 promoter methylation didn't show significant difference between PE and normal placentas. CONCLUSION: LN-alpha5 downregulation is associated with PE placenta and impairs trophoblast viability and invasiveness, which could be a causative factor of PE pathogenesis. PMID- 30522105 TI - Taxifolin Inhibits Receptor Activator of NF-kappaB Ligand-Induced Osteoclastogenesis of Human Bone Marrow-Derived Macrophages in vitro and Prevents Lipopolysaccharide-Induced Bone Loss in vivo. AB - It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF kappaB ligand (RANKL) as well as the protection effects in lipopolysaccharide induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-kappaB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis. PMID- 30522106 TI - Difficult Patient Behavior in Dialysis Facilities. AB - Difficult behavior exhibited by dialysis patients is a spectrum that includes nonadherence, verbal or physical abuse, and threatening acts. Such behaviors may lead to harmful consequences to the patient, other patients, the facility, and staff and can culminate in involuntary discharge. It is important to recognize that these "difficult behaviors" may be due to underlying psychosocial or medical issues, which places an onus on care providers to explore further. According to the Conditions for Coverage (CfC) for dialysis facilities, it falls upon the medical director to coordinate and oversee policies for patient satisfaction, patient safety and rights, involuntary discharges, and adverse events and outcomes. Thus, medical directors are liable for their own actions, and their staff for which they have oversight, for harm or perceived harm to patients in response to difficult behaviors. Guidelines to deal with specific patient behavior scenarios have been published by the Decreasing Dialysis Patient Conflict National Task Force of the Forum of end-stage renal disease (ESRD) Networks. The common denominator for these difficult scenarios is impaired communication, and the majority of patient concerns involve issues with staff, policies, treatments, and diet. Involuntary discharge of a patient should always be viewed as a last resort, and there is a structured process described in the CfC that requires the involvement of the respective ESRD Network and the facility medical director. As physicians, we are bound by ethical and growing legal obligations to act in an appropriate, ethical, and fair manner to patients who are considered to be "difficult." PMID- 30522107 TI - beta-Elemene Inhibits Human Sperm Function by Affecting Sperm Vitality and Intracellular Calcium. AB - BACKGROUND/AIMS: beta-Elemene is a bioactive sesquiterpene compound that exhibits a potent anti-tumor effect and is used in various clinical applications. However, little is known about its effect on the male reproductive system. The objective of this study was to investigate the in vitro actions of beta-elemene on human sperm function and elucidate the underlying mechanism. METHODS: The cytotoxicity of beta-elemene toward MCF-10A, MDA-MD-231, and A549 cells was evaluated with cell proliferation and colony formation assays. Additionally, human sperm were treated with different concentrations (0, 10, 20, 40, 80, 160, and 320 uM) of beta-elemene in vitro. The characteristics in human sperm essential for fertilization, including vitality, motility, capacitation, acrosome reaction, responsiveness to progesterone, and intracellular calcium concentration ([Ca2+]i) were examined with a computer-assisted sperm analysis system, chlortetracycline staining, and a fluorescent Ca2+ indicator. RESULTS: A comprehensive evaluation of sperm motility, especially hyperactivated motility, revealed that treatments with 40-320 MUM beta-elemene decreased human sperm vitality, motility (total motility, progressive motility, and curvilinear velocity), and penetrating ability in a dose-dependent manner, but were non-toxic or minimally toxic toward MCF-10A, MDA-MD-231, and A549 cells. Although 10 and 20 MUM beta-elemene did not affect sperm vitality and motility, these concentrations increased the spontaneous acrosome reaction and inhibited progesterone-induced sperm functions by affecting sperm [Ca2+]i. CONCLUSION: These results suggest that beta-elemene inhibits human sperm function by affecting sperm vitality and [Ca2+]i. These observations must be considered when using beta-elemene to treat cancer patients who may wish to preserve their fertility. PMID- 30522108 TI - Early-Stage Translational Research in Perinatal Medicine. AB - BACKGROUND: Pre-clinical research, which encompasses studies in animals and in the laboratory, has made significant contributions to the improvement of neonatal outcomes. METHODS: Here, we describe examples of how pre-clinical research can be the starting point on the journey to the development of new interventions to improve neonatal care and outcomes and discuss recent progress in ensuring methodological and ethical rigour in pre-clinical research involving animal models. RESULTS: Studies in pregnant sheep led to the serendipitous discovery that preterm lambs born after exogenous corticosteroid exposure were able to aerate their lungs. Subsequent clinical trials confirmed that antenatal corticosteroids given to women at risk of preterm delivery substantially reduce mortality and morbidity in babies born preterm. Animal research also contributed to discoveries in the mechanism of brain injury after hypoxic ischaemic encephalopathy, leading to the use of therapeutic hypothermia as an effective treatment. However, animals are sentient creatures and there are significant ethical concerns with their use in studies to benefit human health. Mandated institutional animal research ethics committees ensure adherence to ethical requirements. To provide high-quality data which can be translated into clinical research, pre-clinical research needs to follow rigorous standards of study design and reporting. The ARRIVE guidelines provide guidance for pre-clinical research similar to that provided in the CONSORT guidelines for clinical trials and are gaining acceptance among researchers and journal editors. CONCLUSION: Improved scientific rigour in the use of animal research will increase the likelihood that pre-clinical research will continue to translate into improved neonatal outcomes. PMID- 30522109 TI - Developing a Process for Returning Medically Actionable Genomic Variants to Latino Patients in a Federally Qualified Health Center. AB - AIM: To develop a process for returning medically actionable genomic variants to Latino patients receiving care in a Federally Qualified Health Center. METHODS: Prior to recruitment, researchers met with primary care providers to (1) orient clinicians to the project, (2) establish a process for returning actionable and nonactionable results to participants and providers through the electronic health record, and (3) develop a process for offering clinical decision support for follow-up education and care. A Community Advisory Board was engaged to provide input on recruitment strategies and materials for conveying results to participants. Participants in the Sangre Por Salud (Blood for Health) Biobank with hyperlipidemia or colon polyps represented the pool of potentially eligible participants. RESULTS: A total of 1,621 individuals were invited to participate and 710 agreed to an in- person consenting visit (194 no-showed and 16 declined). Over 12-months, 500 participants were enrolled. Participants were primarily Spanish-speaking (81.6%), female (74.2%), and enrolled because of hyperlipidemia (95.4%). All but 2 participants opted to receive primary (i.e., related to enrollment phenotypes) as well as secondary actionable results. CONCLUSION: Efforts to bring precision medicine to community-based health centers serving minority patients may require multilevel engagement activities to include individuals, providers, health systems, and the community. PMID- 30522110 TI - Bilateral Lateral Rectus Recession for the Treatment of Recurrent Exotropia after Bilateral Medial Rectus Resection. AB - PURPOSE: To evaluate the efficacy of bilateral lateral rectus muscle recession (BLR) to treat recurrent exotropia after bilateral medial rectus muscle resection (BMR). METHODS: Twenty-four patients who underwent BLR for recurrent exotropia and were followed up for more than 6 months were included in this retrospective study. All of them had prior BMR. The angle of deviation, success rates, near stereopsis, and surgical effect of BLR were evaluated. Surgical success was defined as postoperative deviations <=10 prism diopters (PD). RESULTS: The overall mean follow-up time after reoperation for patients was 24.13 +/- 15.01 months (range 6-60 months). The mean angle of deviation at distance was significantly reduced from -37.75 +/- 14.93 PD to +1.50 +/- 6.43 PD (p < 0.001). Twenty-two (91.6%) of 24 patients had successful outcomes, 1 (4.2%) had overcorrection, and 1 (4.2%) had undercorrection at the last follow-up. Improved stereopsis after reoperation was observed in 78.3% (18/23) of the patients. The mean surgical effect was 2.78 +/- 0.71 PD/mm. CONCLUSION: Based on our results, BLR could be an effective and safe method for treating recurrent exotropia after a moderate to large amount of BMR. PMID- 30522111 TI - miR-122 Targets X-Linked Inhibitor of Apoptosis Protein to Sensitize Oxaliplatin Resistant Colorectal Cancer Cells to Oxaliplatin-Mediated Cytotoxicity. AB - BACKGROUND/AIMS: Although oxaliplatin is one of the most effective chemotherapeutic drugs used to treat colorectal cancer (CRC), long-term administration usually induces acquired drug resistance during the course of treatment. Thus, there is an urgent need to explore novel strategies to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of microRNA-122 (miR-122) on reversing oxaliplatin resistance in CRC. METHODS: The expression of miR-122 in CRC cells was examined by quantitative reverse transcriptase real-time PCR. The cytotoxicity of oxaliplatin against CRC cells was evaluated by Cell Counting Kit-8 assays. Mitochondrial membrane potentials and cell apoptotic rates were measured by flow cytometry. Cellular protein expression and interactions were detected by western blot and co immunoprecipitation. RESULTS: Established oxaliplatin-resistant SW480 and HT29 cells (SW480/OR and HT29/OR) expressed significantly higher levels of X-linked inhibitor of apoptosis protein (XIAP) and lower levels of miR-122 compared with normal SW480 and HT29 cells, respectively. Our results showed that the downregulation of miR-122 was responsible for the overexpression of XIAP in these oxaliplatin-resistant CRC cells. We then found that the recovery of miR-122 expression can sensitize SW480/OR and HT29/OR cells to oxaliplatin-mediated apoptosis through the inhibition of XIAP expression. CONCLUSION: Upregulation of XIAP in CRC cells is responsible for the acquired resistance to oxaliplatin. Furthermore, miR-122 reversed oxaliplatin resistance in CRC by targeting XIAP. PMID- 30522112 TI - Virtual Reality Simulation in Peritoneal Dialysis Training: The Beginning of a New Era. AB - BACKGROUND/AIM: Peritonitis rates in peritoneal dialysis (PD) vary considerably not only across countries but also between centers in the same country. Patient education has been shown to significantly reduce infection rates but up till now training lacks standardization with patients being trained using different methods and media (e.g., illustrations, videos). As a result, patients may be insufficiently experienced in performing PD, which might be one of the causes for high peritonitis rates. To address these issues, we developed a PD training program based on virtual reality (VR). METHODS: To become acquainted with the PD procedure, patients are equipped with a VR headset and controllers. They are presented with a virtual PD set, which simulates the feeling of sitting in front of a real PD set. The patient is enabled to run through the program as often as necessary to become familiarized with the whole PD procedure. The aim is to standardize, facilitate, and accelerate the individual learning process. To compare the effect of the applied training method to traditional training, a randomized controlled trial is underway. CONCLUSION: Previous studies on the effectiveness of learning showed that VR training applications are superior to traditional methods, such as text- or video-based training. However, no study has been undertaken in the context of dialysis. We believe that the implementation of VR training programs in clinical practice will be beneficial in improving the patient's proficiency, and thereby the quality and safety of PD. PMID- 30522113 TI - Getting "Stuck" in the Future or the Past: Relationships between Dimensions of Time Perspective, Executive Functions, and Repetitive Negative Thinking in Anxiety. AB - BACKGROUND/AIM: Anxiety disorders are associated with impairments in several aspects of cognitive processing. In this study we investigated three such aspects, i.e., time perspective, repetitive negative thinking (worry and rumination), and executive functioning, in persons with anxiety disorders compared to healthy controls and examined the influence of negative past and negative future time perspective and executive functioning on worry and rumination. METHOD: Thirty-six psychiatric outpatients with anxiety disorders (mean age = 30.83, SD = 11.74; 30 females and 6 males) and 44 healthy controls (mean age = 28.89, SD = 9.54; 24 females and 20 males) completed inventories of time perspective and repetitive negative thinking, and tasks measuring executive functioning (shifting and inhibition). RESULTS: The groups (patient vs. control) differed significantly on all time perspective dimensions (past, present, and future), with largest effect sizes observed for negative past and negative future. Regression analyses with executive functioning, negative past, and negative future time perspectives as predictors, and worry and rumination as outcomes, showed that negative past time perspective was the best predictor for rumination, whereas negative future time perspective more strongly predicted worry. Executive functioning was not a significant predictor of either worry or rumination. CONCLUSIONS: Individuals with anxiety disorders demonstrated systematic biases in all time perspective dimensions, particularly negative past and negative future time perspective, which was further related to worry and rumination. Thus, interventions targeting temporal focus may be one way of reducing repetitive negative thinking. A major limitation of this study was the use of a cross-section design. PMID- 30522114 TI - Gastric Adenocarcinoma Predictive Long Intergenic Non-Coding RNA Promotes Tumor Occurrence and Progression in Non-Small Cell Lung Cancer via Regulation of the miR-661/eEF2K Signaling Pathway. AB - BACKGROUND/AIMS: Long non-coding RNAs (lncRNAs) play vital roles in carcinogenesis as oncogenes or tumor suppressor genes. This study explored the biological function of lncRNA gastric adenocarcinoma predictive long intergenic non-coding RNA (GAPLINC) in human non-small cell lung cancer (NSCLC). METHODS: GAPLINC expression in NSCLC specimens and cell lines was detected by qRT-PCR and Western blot. The effect of GAPLINC on cell proliferation was investigated using CCK8-assay, colony formation assay, and xenograft model. The effects of GAPLINC on apoptosis and cell cycle were determined using flow cytometry. The mechanism of GAPLINC involved in NSCLC was explored using Western blot, luciferase reporter assay, and RNA fluorescence in situ hybridization. RESULTS: We found that GAPLINC expression was up-regulated in NSCLC tissues and cell lines. Overexpression of GAPLINC was associated with poor prognosis in patients with NSCLC. Silencing of GAPLINC significantly inhibited cell proliferation, promoted apoptosis, and induced cell cycle arrest in the G0/G1 phase. Results from xenograft transplantation showed that GAPLINC silencing inhibited the tumor growth in vivo. Interestingly, GAPLINC silencing decreased the expression of eukaryotic elongation factor-2 kinase (eEF2K) protein both in vivo and in vitro. Bioinformatic analysis and luciferase reporter confirmed that miR-661 targeted GAPLINC and eEF2K 3'-UTR and was negatively correlated with the expression of GAPLINC and eEF2K. CONCLUSION: Our findings indicate that GAPLINC promotes NSCLC tumorigenesis by regulating miR-661/eEF2K cascade and provide new insights for the pathogenesis underlying NSCLC and potential targets for therapeutic strategy. PMID- 30522115 TI - Gliquidone Alleviates Diabetic Nephropathy by Inhibiting Notch/Snail Signaling Pathway. AB - BACKGROUND/AIMS: Diabetic nephropathy is a common complication of diabetes. This study explored the renal protective effect and possible mechanism of gliquidone in mice with diabetic nephropathy. METHODS: Animal model of diabetic nephropathy was established in KKAy mice. The renal protective effect of gliquidone was studied by evaluating the kidney function through measures of urinary protein, blood urea nitrogen (BUN), serum creatinine (Scr) and serum triglyceride (TG) that were performed using an automatic biochemical analyzer. The levels of oxidative stress indicators, such as nitric oxide (NO), superoxide dismutase (SOD) and malondialdehyde (MDA), were evaluated in renal tissue homogenates using the automatic biochemical analyzer. The inhibitory effect of gliquidone on renal interstitial fibrosis and its association with Notch / Snail1 signaling pathway in diabetic nephropathy was investigated using molecular biological techniques. RESULTS: It was found that low-, medium- and high-dose gliquidone improved the mice's general health condition, such as mental status, fur condition, eating, and drinking. Gliquidone reduced the body weight and the kidney weight /body weight ratio of mice. Gliquidone improved the kidney function, indicated by reductions in urinary protein, blood urea nitrogen, and serum creatinine and triglyceride. Gliquidone treatment increased levels of nitric oxide and superoxide dismutase, but decreased level of malondialdehyde. The expression of Jagged1/Notch1/hes1/Snail1/alpha-SMA decreased, while the expression of E cadherin increased in gliquidone-treated kidneys. High dose gliquidone showed the best effect, one that was similar to that of the positive control drug irbesartan. CONCLUSION: Taken together, our results suggested that gliquidone can ameliorate the diabetic symptoms of diabetic nephropathy through inhibiting Notch / Snail1 signaling pathway, improving anti -oxidative response and delaying renal interstitial fibrosis. The efficacy of gliquidone is dose-dependent. PMID- 30522116 TI - Potential Role of microRNA-183 as a Tumor Suppressor in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Disseminated tumors, known as metastases, are responsible for ninety-percent of mortality due to cancer. Epithelial to mesenchymal transition, a phenomenon required for morphological conversion of non-motile discoid shaped epithelial cells to highly motile spindle-shaped mesenchymal cells, is thought to be a pre-requisite for metastatic progression. Metastasis-associated 1 (MTA1) protein is a prime inducer of EMT and metastatic progression in all solid tumors including hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate the expression and function of MTA1 in HCC have not been elucidated. METHODS: In silico prediction algorithms were used to find microRNAs (miRNAs) that may target MTA1. We examined the relationship between the expression of MTA1 and miR-183 using quantitative real time PCR. We also determined the levels of the MTA1 protein using immunohistochemistry. Reporter assays, in the presence and absence of the miR-183 mimic, were used to confirm MTA1 as a bona fide target of miR183. The effect of miR-183 on HCC pathogenesis was determined using a combination of in vitro migration and invasion assay, together with in vivo xenograft experiments. The correlation between miR-183 and MTA1 expression was also studied in samples from HCC patients, and in The Cancer Genome Atlas dataset. RESULTS: Analysis of the sequence database revealed that MTA1 is a putative target of miR-183. MTA1 protein and RNA expression showed opposite trends to miR-183 expression in breast, renal, prostate, and testicular tissue samples from cancer patients, and in the metastatic HCC cell line HepG2. An inverse correlation was also observed between MTA1 (high) and miR-183 (low) expression within samples from HHC patients and in the TCGA dataset. Reporter assays in HepG2 cells showed that miR-183 could inhibit translation of a reporter harboring the wild-type, but not the mutant miR-183 3'-untranslated region (UTR). In addition, miR-183 significantly inhibited in vitro migration and invasion in HepG2 cells, and in vivo hepatic metastasis. CONCLUSION: Our results reveal a novel post-transcriptional regulatory mechanism for MTA1 expression via miR-183, which is suppressed during HCC pathogenesis. PMID- 30522117 TI - Development and Application of a New PCR Method for Detection of Blumeria graminis f. sp. tritici. AB - We developed new PCR assays that target beta-tubulin (TUB2) and 14 alpha demethylase (CYP51) genes and used them for the species-specific detection of Blumeria graminis f. sp. tritici (Bgt). Based on fungi DNA sequences available in the NCBI (National Center for Biotechnology Information) GenBank database we developed simplex and duplex PCR assays. The specificities of the primer sets were evaluated using environmental samples of wheat leaves collected during the 2015/2016 growing season across Poland. Primer sets LidBg17/18 and LidBg21/22 strongly amplified fragments of the expected length for all 67 tested samples. Primer specificity was confirmed using field samples of Zymoseptoria tri-tici, Puccinia triticina (syn. P. recondita f. sp. tritici), P. striiformis f. sp. tritici, and Pyrenophora tritici-repentis. PMID- 30522118 TI - Downregulation of microRNA-376a in Gastric Cancer and Association with Poor Prognosis. AB - BACKGROUND/AIMS: MicroRNAs have a significant role in the tumorigenesis and progression of cancers, including gastric cancer (GC). Our study aimed to identify a novel biomarker to predict the prognosis of patients with GC. METHODS: The GC microarray dataset, GSE28700, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed miRNAs (DEMs). The downregulation of miR-376a expression was verified in GC cell lines and 82 paired GC tissues by performing RT-qPCR and the correlation between its expression and clinicopathological characteristics was also explored. The target genes of miR-376a were predicted using TargetScan7.1, miRDB, and DIANA website tools. A functional enrichment analysis was performed to explore the biological role of the common target genes. RESULTS: Bioinformatics analysis found that miR 376a was downregulated in GC tissues. Compared with the control group, RT-qPCR results showed that the expression of miR-376a in GC cell lines and tissues were also significantly decreased. The expression of miR-376a was statistically associated with T and N stage. Survival analysis with Kaplan-Meier showed that GC patients in the low expression group had a poorer prognosis than those in the high expression group (median survival of 26.4 and 46.9 months, respectively). Univariate and multivariate analysis demonstrated that low miR-376a expression was an independent prognostic marker for poor survival. Functional enrichment analysis indicated that the common targets genes were involved in cell-cell communication, VEGF and mTOR1-mediated signaling, and epithelial-to-mesenchymal transition (EMT). CONCLUSION: The results suggest that miR-376a could play an important role in the tumorigenesis and progression of GC and act as a novel therapeutic target and prognostic indicator in patients with GC. PMID- 30522120 TI - HBPD Table of Contents Vol. 17, Nr. 4, 2018. PMID- 30522119 TI - EDS Society News. PMID- 30522121 TI - HBPD Table of Contents Vol. 17, No. 5, 2018. PMID- 30522122 TI - Microbial Intervention as a Novel Target in Treatment of Non-Alcoholic Fatty Liver Disease Progression. AB - BACKGROUND/AIMS: Emerging evidence suggests a close link between gut microbiota and non-alcoholic fatty liver disease (NAFLD). In this study, we aimed to investigate the association between gut microbiota and the DNA methylation of adiponectin (an adipocyte-specific adipocytokine) in rats, following diet-induced NAFLD. METHODS: 50 male SD rats were randomly divided into five groups with or without a high fat diet (HFD), antibiotics, and probiotics, in order to establish an imbalanced gut microbiota and probiotic treatment model in NAFLD rats. After 13 weeks of treatment, blood, liver, and cecal tissue samples were collected. Serum lipids, liver function indexes by biochemical analyzers, and changes in liver pathology with hematoxylin-eosin (HE) and masson staining were detected. Furthermore, the serum adiponectin by enzyme-linked immunosorbent assay (ELISA) and liver adiponectin methylation levels in the promoter regions by pyrophosphate sequencing were determined. High throughput Illumina sequencing targeted microbial 16S genes, bioinformatics and statistical analysis identified cecal associated gut microbiota. RESULTS: HFD with antibiotic exposure showed the most severe steatohepatitis and a severe gut microbiota alteration. Reduced bacterial diversity was also seen and the abundances of Firmicutes, Lactobacillus, Cyanobacteria, Acidobacteria, Chlamydiae, Chlamydiales, Rubrobacteria, Verrucomicrobia, Blautia, Shewanella, Bacteroides, Bacteroides acidifaciens, and Bacteroides uniformis, were shown to be partly reversed by probiotic treatment. Decreased serum adiponectin levels and increased DNA methylation levels of adiponectin promoter regions were also markedly associated with the NAFLD progression during gut microbiota alteration. CONCLUSION: Our results suggested that both gut microbiota alteration and adiponectin variability may be drivers of NAFLD progression and that targeting the gut microbiota, such as via administration of a probiotic, may delay NAFLD progression via adiponectin. PMID- 30522123 TI - Inhibition of Erythrocyte Cell Membrane Scrambling Following Energy Depletion and Hyperosmotic Shock by Alectinib. AB - BACKGROUND/AIMS: The anaplastic lymphoma kinase (ALK) inhibitor alectinib is clinically used for the treatment of ALK positive non-small-cell lung cancer. At least in part the substance is effective by triggering suicidal death or apoptosis of tumor cells. Erythrocytes are lacking mitochondria and nuclei, key organelles of apoptosis but are, similar to apoptosis of nucleated cells, able to enter suicidal erythrocyte death or eryptosis. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress, and increase of cytosolic Ca2+ activity ([Ca2+]i). The present study explored, whether alectinib influences eryptosis. METHODS: Flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-V-binding and cell volume from forward scatter. Measurements were made without or with energy depletion (glucose deprivation for 48 hours), hyperosmotic shock (+550mM sucrose for 6 hours), oxidative stress (50 min exposure to 0.3 mM tert-butylhydroperoxide), and Ca2+ loading (60 minutes treatment with 1 uM Ca2+ ionophore ionomycin). RESULTS: A 48 hours exposure of human erythrocytes to alectinib (150-600 ng/ml) did not significantly modify the percentage of annexin-V-binding cells and forward scatter. Energy depletion, hyperosmotic shock, oxidative stress and Ca2+ loading were each followed by profound and significant increase of the percentage annexin V-binding erythrocytes and a significant decrease of forward scatter. The effects of energy depletion and hyperosmotic shock, but not of oxidative stress or Ca2+ loading on annexin-V-binding were significantly blunted in the presence of alectinib (150-600 ng/ml). In none of the conditions was forward scatter significantly modified by alectinib. CONCLUSION: Alectinib inhibits cell membrane scrambling following energy depletion and hyperosmotic shock. PMID- 30522124 TI - Impact of Hybrid Therapy Comprising Peritoneal Dialysis and Hemodialysis on Acute Cardiovascular Events. AB - BACKGROUND: The impact of hybrid therapy comprising peritoneal dialysis (PD) and hemodialysis on cardiovascular events in PD patients remains unclear. OBJECTIVE: We aimed to evaluate the effect of hybrid therapy on cardiovascular events. METHODS: A total of 93 PD patients undergoing hybrid therapy for >=3 years were divided into 2 groups according to left ventricular ejection fraction (LVEF): lower ejection fraction (LEF [n = 29], LVEF < 60%) and normal ejection fraction (NEF [n = 64], LVEF >=60%). Hospitalization rates and echocardiographic parameters were evaluated. RESULTS: The 1-year hospitalization rate for acute cardiovascular events decreased after the therapy initiation in both groups (LEF: 0.36-0.11, p = 0.02 and NEF: 0.43-0.06, p < 0.001). In generalized linear mixed models, LVEF (44 +/- 15%) improved at 1, 2, and 3 years after initiation (53 +/- 18, 55 +/- 17, and 58 +/- 7%; p < 0.05) in the LEF group, whereas, in the NEF group, LVEF (68 +/- 5%) was maintained at 1, 2, and 3 years after initiation (67 +/- 8, 67 +/- 9, and 68 +/- 9%; p > 0.05). Mitral inflow E velocity to tissue Doppler e' ratio was maintained at the same level at 1-3 years after initiation in both groups. Left ventricular mass index (LVMI; 189 +/- 41 g/m2) was decreased at 1 (178 +/- 35 g/m2; p = 0.8), 2 (160 +/- 45 g/m2; p = 0.008), and 3 (166 +/- 47 g/m2; p = 0.05) years after initiation in the LEF group, whereas in the NEF group, LVMI (157 +/- 45 g/m2) was maintained at 1, 2, and 3 years after initiation (153 +/- 40, 155 +/- 54, and 158 +/- 52 g/m2; p > 0.05). CONCLUSION: Hybrid therapy decreased acute cardiovascular events and improved systolic cardiac function in PD patients in the LEF group. PMID- 30522125 TI - Neurofilament Light in the Serum and Cerebrospinal Fluid of Hip Fracture Patients with Delirium. AB - BACKGROUND: Delirium is associated with new-onset dementia, suggesting that delirium pathophysiology involves neuronal injury. Neurofilament light (NFL) is a sensitive biomarker for neuroaxonal injury. METHODS: NFL was measured in cerebrospinal fluid (CSF) (n = 130), preoperative serum (n = 192), and postoperative serum (n = 280) in hip fracture patients, and in CSF (n = 123) and preoperative serum (n = 134) in cognitively normal older adults undergoing elective surgery. Delirium was diagnosed with the Confusion Assessment Method. RESULTS: Median serum NFL (pg/mL) was elevated in delirium in hip fracture patients (94 vs. 54 pre- and 135 vs. 92 postoperatively, both p < 0.001). Median CSF NFL tended to be higher in hip fracture patients with delirium (1,804 vs. 1,636, p = 0.074). Serum and CSF NFL were positively correlated (rho = 0.56, p < 0.001). CONCLUSION: Our findings support an association between neuroaxonal injury and delirium. The correlation between serum and CSF NFL supports the use of NFL as a blood biomarker in future delirium studies. PMID- 30522126 TI - Identifying Potentially Modifiable Factors Associated with Treatment Non Adherence in Paediatric Growth Hormone Deficiency: A Systematic Review. AB - BACKGROUND: Despite the developments of recombinant growth hormone (rhGH) treatment and the benefits in long-term clinical health outcomes, evidence has shown that many children with growth hormone deficiency (GHD) still fail to achieve their target adult height. Suboptimal outcomes have been largely attributed to treatment non-adherence. METHODS: A search of 11 electronic databases was undertaken to identify relevant articles, published in English, between 1985 and 2018. Additional search strategies included hand-searching topic review articles to identify eligible studies. Articles were screened against the inclusion eligibility criteria and data on sample characteristics, study design, outcomes, and key findings was extracted. The results were narratively synthesised and categorised using the COM-B theoretical framework. RESULTS: Twenty-one full-text articles were assessed for eligibility, of which 6 articles met the inclusion criteria. The prevalence of non-adherence in the included studies varied from 7 to 71%. Potentially modifiable factors associated with rhGH non-adherence were categorised within the COM-B framework; key factors included: a lack of knowledge and understanding of the condition and treatment, discomfort and pain associated with injections, and the quality of the healthcare professional-patient relationship. CONCLUSION: This review highlights the scope of the adherence problem evident amongst the paediatric GHD population and in addition presents the wide range of potentially modifiable factors that explain this health-related behaviour. PMID- 30522127 TI - Tracking Arteriovenous Fistula Maturation: A Novel Approach. AB - BACKGROUND: The time between the creation of an arteriovenous fistula (AVF) and its successful use is significantly longer in hemodialysis (HD) patients in the United States compared to those in other countries, and there is an urgent need to reduce the residence time of central-venous catheters (CVC). METHODS: Successful AVF creation and maturation results in typical hemodynamic changes, such as an increase in cardiac output and upper body blood flow (UBBF). In patients with CVC as vascular access, we measured once per minute intradialytic central-venous oxygen saturation (ScvO2) and hemoglobin levels simultaneously using the Crit-Line Monitor. Under conditions of stable upper body oxygen consumption and arterial oxygen saturation, ScvO2 and hemoglobin concentration allows the calculation of estimated UBBF (eUBBF). In a quality improvement project, we used ScvO2 and eUBBF to track the hemodynamic changes accompanying AVF maturation. RESULTS: Out of 11 patients (9 incident to HD, 1 female, age 61 +/- 13 years), AVF maturation was successful in 9. In 1 patient, the AVF did not mature. One patient died from sudden cardiac death with a maturing AVF. In the 9 patients with successful AVF maturation, ScvO2 increased from 60.9 +/- 2.7% prior to AVF creation to 73.4 +/- 3.6% a week after AVF creation (19.6 +/- 6.3% increase). eUBBF increased from 1.3 +/- 0.3 to 2.2 +/- 0.6 L/min (62.7 +/- 37.5% increase); no material ScvO2 or eUBBF changes occurred in the other 2 patients. CONCLUSION: Our results indicate the potential utility of ScvO2 and eUBBF to track the hemodynamic response to AVF maturation. To what extent these insights translate into shortening of the time between AVF creation and successful cannulation warrants further investigations. PMID- 30522128 TI - Photoinactivation of the Staphylococcus aureus Lactose-Specific EIICB Phosphotransferase Component with p-azidophenyl-beta-D-Galactoside and Phosphorylation of the Covalently Bound Substrate. AB - BACKGROUND: The phosphoenolpyruvate (PEP):lactose phosphotransferase system of Staphylococcus aureus transports and phosphorylates lactose and various phenylgalactosides. Their phosphorylation is catalyzed by the Cys476 phosphorylated EIIB domain of the lactose-specific permease enzyme IICB (EIICBLac). Phosphorylation causes the release of galactosides bound to the EIIC domain into the cytoplasm by a mechanism not yet understood. RESULTS: Irradiation of a reaction mixture containing the photoactivatable p-azidophenyl-beta-D galactopyranoside and EIICBLac with UV light caused a loss of EIICBLac activity. Nevertheless, photoinactivated EIICBLac could still be phosphorylated with [32P]PEP. Proteolysis of photoinactivated [32P]P-EIICBLac with subtilisin provided an 11-kDa radioactive peptide. Only the sequence of its first three amino acids (-H-G-P-, position 245-247) could be determined. They are part of the substrate binding pocket in EIICs of the lactose/cellobiose PTS family. Surprisingly, while acid treatment caused hydrolysis of the phosphoryl group in active [32P]P~EIICBLac, photoinactivated [32P]P-EIICBLac remained strongly phosphorylated. CONCLUSION: Phosphorylation of the -OH group at C6 of p nitrenephenyl-beta-D-galactopyranoside covalently bound to EIICLac by the histidyl-phosphorylated [32P]P~EIIBLac domain is a likely explanation for the observed acid resistance. Placing p-nitrenephenyl-beta-D-galactopyranoside into the active site of modelled EIICLac suggested that the nitrene binds to the -NH- group of Ser248, which would explain why no sequence data beyond Pro247could be obtained. PMID- 30522129 TI - Predicted short and long-term impact of deworming and water, hygiene, and sanitation on transmission of soil-transmitted helminths. AB - BACKGROUND: Regular preventive chemotherapy (PCT) targeting high-risk populations is an effective way to control STH in the short term, but sustainable long-term STH control is expected to require improved access to water, sanitation, and hygiene (WASH). However, experimental studies have not been able to conclusively demonstrate the benefit of WASH in preventing STH (re-)infections. We investigated the impact of WASH on STH infections during and after PCT using mathematical modelling. METHODS AND FINDINGS: We use the individual-based transmission model WORMSIM to predict the short and long-term impact of WASH on STH transmission in contexts with and without PCT. We distinguish two WASH modalities: sanitation, which reduces individuals' contributions to environmental contamination; and hygiene, which reduces individuals' exposure to infection. We simulate the impact of varying levels of uptake and effectiveness of each WASH modality, as well as their combined impact. Clearly, sanitation and hygiene interventions have little observable short-term impact on STH infections levels in the context of PCT. However, in the long term, both are pivotal to sustain control or eliminate infection levels after scaling down or stopping PCT. The impact of hygiene is determined more by the effectiveness of the intervention than its overall uptake, whereas the impact of sanitation depends more directly on the product of uptake and the effectiveness. INTERPRETATION: The impact of WASH interventions on STH transmission highly depends on the worm species, WASH modality, and uptake and effectiveness of the intervention. Also, the impact of WASH is difficult to measure in the context of ongoing PCT programmes. Still, we show a clear added benefit of WASH to sustain the gains made by PCT in the long term, such that PCT may be scaled down or even stopped altogether. To safely stop or scale down PCT, policy for WASH and PCT should be integrated. PMID- 30522131 TI - Masthead. PMID- 30522130 TI - Innate antimicrobial immunity in the skin: A protective barrier against bacteria, viruses, and fungi. PMID- 30522132 TI - Shuhan Zhu, MD and James Otis, MD, FAAN. PMID- 30522133 TI - Headache and Pain. PMID- 30522134 TI - Cluster Headache and Other Trigeminal Autonomic Cephalalgias. AB - The trigeminal autonomic cephalalgias are a group of distinct primary headache disorders that share common characteristics of strict unilateral headache often accompanied by unilateral cranial autonomic features. Cluster headache is the most well-known example, but other than neurologists, practitioners often have limited familiarity with these disorders and treatment options. Delays in diagnosis are typical and treatment options remain suboptimal, associated with limited scientific research into these brain disorders. Improved familiarity with core clinical features by health care providers should lead to earlier referral to specialists, and this education is the responsibility of headache medicine specialists. Optimistically, the last few years have seen lobbying for more federal research support in headache medicine and there has been renewed interest by private industry in potential new treatments for trigeminal autonomic cephalalgias. PMID- 30522135 TI - Migraine and Tension-Type Headache. AB - Migraine and tension-type headache (TTH) are common primary disorders that carry significant morbidity and socioeconomic effect. In this article, we will review the epidemiology, presentation, and diagnosis of these disorders. First-line acute treatment for migraine consists of analgesics, triptans, and antiemetics, while nonsteroidal anti-inflammatory drugs are the mainstay treatment for TTH. Patients with frequent or chronic headaches warrant prophylactic therapy. For migraine, various classes of preventives can be used (beta-blockers, tricyclics, antiepileptics, botulinum toxin), with the choice of therapy tailored to the patient's risk factors and symptoms. For TTH, tricyclics have the most evidence as prophylactic therapy. A new class of medication, monoclonal antibodies to calcitonin gene receptor peptide or its receptor, became available in 2018, and is the first class of medication specifically designed to treat migraine. In addition to pharmacotherapy, we will also review nonpharmacologic interventions as well as neuromodulation for migraine. PMID- 30522136 TI - Posttraumatic Headache. AB - Posttraumatic headaches are among the most challenging complaints after mild traumatic brain injury (mTBI). They are a debilitating problem experienced by patients after TBI of all severities. Up to 90% of mild TBI patients experience headache, particularly if female and with a premorbid history of primary headache. Tension headache has classically been the most common subtype, but in military populations migraine has dominated. Posttraumatic headache encompasses a spectrum of headache types that overlap heavily with common primary headache disorders, but also autonomic cephalgias as well as several secondary headache conditions. It is important to understand the evolution of postconcussion syndrome as a concept, and the challenges associated with diagnosing and treating multidomain drivers effectively. The first-line treatments for posttraumatic headache are typically the same as those used in nontraumatic headache, with additional considerations for cognitive side effects, posttraumatic epilepsy, and coexisting injuries resulting in neuropathic pain or medication overuse. PMID- 30522137 TI - Headache in Pregnancy, the Puerperium, and menopause. AB - Headache is a neurologic disorder that displays gender dichotomy. It is well established that there is a strong link between migraine headache and sex hormones, specifically estrogen, which influences the severity of migraines during the menstrual cycle, pregnancy, and menopause. Furthermore, the epidemiology of headaches during pregnancy and the postpartum period is very distinct from that in males or nonpregnant females, in part due to the hemodynamic and hematologic changes that occur during pregnancy. These changes put women at higher risk for cerebral venous thrombosis, hemorrhagic stroke, and hypertensive disorders of pregnancy like preeclampsia, eclampsia, posterior reversible encephalopathy syndrome, and reversible cerebral vasoconstriction syndrome. Headache in pregnancy and the puerperium can be a cause of heightened anxiety in most women, who are concerned not only about the effect of the headache itself on the pregnancy but also about the effect of the treatment options on the pregnancy and the fetus. In this review, we discuss the latest literature on type and distribution of headaches during pregnancy and the postpartum period, and provide a digestible overview of the safety profile of commonly used abortive and prophylactic medications. We also discuss important considerations when treating migraine during menopause. PMID- 30522138 TI - Radicular Pain Syndromes: Cervical, Lumbar, and Spinal Stenosis. AB - Back pain is a top primary and urgent care complaint; radicular pain can be caused by herniation of the nucleus pulposus (intervertebral disc), spinal stenosis, or degenerative changes to the vertebrae. The focus of this clinical review will be the clinical approach and treatment of lumbar radicular pain, cervical radicular pain, and spinal stenosis. Usually localized through neurological history, exam, and imaging, specific signs and symptoms for lumbar radicular, spinal stenosis, and cervical radicular pain can help determine etiology. Once radicular back pain has been diagnosed, a multitude of treatment options are available from rest and physical therapy to medications, epidurals, and surgery. The most common and accepted are reviewed. With accurate diagnosis, safe and effective pain management can be employed to shorten radicular episodes and manage recurrent or chronic radicular syndromes. Using a step-wise approach from diagnosis to conservative therapy to potential surgery, radicular pain syndromes can improve or resolve, and patients may achieve a better functional status and quality of life. PMID- 30522139 TI - Myofascial Pain. AB - Myofascial pain syndromes arise from acute and chronic musculoskeletal pain and often have a referred neuropathic component. It affects more than three quarters of the world's population and is one of the most important and overlooked causes of disability. The origins of pain are thought to reside anywhere between the motor end plate and the fibrous outer covering of the muscle, with involvement of microvasculature and neurotransmitters at the cellular level. Diagnosis is made by clinical examination for the presence of myofascial trigger points, though some ancillary tests may provide supportive evidence. The mainstay of treatment is regular physical therapy with the goal of restoration of normal muscle laxity and range of motion. Adjunct therapies including pharmacologic and nonpharmacologic interventions provide varying degrees of benefit in refractory cases, and onabotulinum toxin A injection has the most evidence of efficacy for these patients. Here, we discuss the epidemiology, pathophysiology, and diagnostic and therapeutic options for the evaluation and treatment of myofascial pain syndrome. PMID- 30522140 TI - Neuropathic Pain. AB - Neuropathic pain management is challenging, and typically requires a multifaceted approach. There are several treatment options, both pharmacologic and nonpharmacologic. Of the available pharmacologic agents, those with the strongest supporting evidence include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and certain antiseizure agents. There is emerging evidence for the use of cannabinoids, but conclusive studies are not available. Nonpharmacologic therapies that have been utilized in the management of neuropathic pain include acupuncture, massage therapy, and reflexology. Despite their use as adjunctive therapies in clinical practice, the current evidence supporting their use is not strong. For the management of neuropathic pain, combination therapies are generally employed. Additional studies for emerging therapies are still needed. PMID- 30522141 TI - Prescription Medication Misuse. AB - In the United States, there is a prescription medication misuse crisis including increases in unintentional drug overdose deaths, medications obtained on the illicit market (i.e., diversion), and in the number of individuals seeking treatment for addiction to prescription medications. Neurologists manage patients suffering from conditions (e.g., pain, seizures, spasticity) where the prescriptions of medications with misuse potential are indicated. It is therefore imperative that neurologists understand which medications are liable to misuse and institute strategies to minimize the harm associated with these medications. The authors review the most common medications prescribed by neurologist with misuse potential, and briefly discuss the behaviors that are suggestive of medication misuse and tools for monitoring patients to minimize medication related harm from misuse. PMID- 30522142 TI - [Results of Reinsertion of the Distal Achilles Tendon]. AB - BACKGROUND: Reattachment of the distal Achilles tendon to the posterior calcaneus following distal Achilles tendon tears/avulsions or after excision of large posterior heel spurs is a challenging task for the orthopaedic surgeon. PATIENTS/MATERIAL AND METHODS: Between 2005 and the end of 2015, 22 patients who underwent repair/reconstruction of a lesion of the distal Achilles tendon were identified from our electronic records. Calcaneal reinsertions were performed following distal Achilles tendon tears/avulsions (n = 15) or following excision of a large symptomatic posterior heel spur (n = 7). The respective outcome was evaluated comparatively using the VISA-A - G (Victorian Institute of Sports Assessment-Achilles tendon, German version) questionnaire (100 = maximum). Data were collected preoperatively (n = 11/22), and prospectively at three, six, and 12 months postoperatively (n = 5 - 11/22). Two further retrospective follow-ups were performed 12 - 114 and 21 - 149 months postoperatively (n = 17/22 and 22/22, respectively). All data were analysed retrospectively. Complications were searched from the electronic files. RESULTS: Transosseous sutures and different anchor techniques (Panalok(r), Corkscrew(r), SpeedBridge(r)) were generally performed. Preoperatively, the VISA-A - G score was 27.3 +/- 13.5 (6 - 45) following distal Achilles tendon reinsertions for avulsions and 45.3 +/- 49.0 (0 100) when reattachment was performed after resection of a large posterior heel spur (p = 0.831). At the final follow-up, VISA-A - G values were 89.4 +/- 13.9 (54 - 100) following distal Achilles tendon tear/avulsion and 82.5 +/- 24.5 (51 - 100), when Achilles tendons were reattached after posterior heel spur excisions (p = 0.969). There were no complications in the "heel spur group". In the Achilles tendon tear/avulsion group, four out of seven patients with Panalok(r) repairs developed a fistula. One patient suffered a thromboembolism. None of these complications affected the long-term outcome. CONCLUSIONS: This study demonstrates good long-term outcomes after distal Achilles tendon reinsertion. Knotless double row anchor repair provides a greater area of compression, simplifies and standardises the repair/reconstruction, and provides safety against fistula. These implants are therefore recommended for safe and effective reattachment of the distal Achilles tendon. PMID- 30522143 TI - Pharmacokinetics of Prenylflavonoids following Oral Ingestion of Standardized Epimedium Extract in Humans. AB - Leaves of the Epimedium plant are traditionally consumed for bone health and other indications. The aim of this study was to establish the safety and pharmacokinetics of the metabolites of prenylflavonoids (icariin, icariside I, icariside II, icaritin, and desmethylicaritin) following single doses of a defined Epimedium prenylflavonoid extract in humans. A single oral dose of 370, 740, or 1110 mg of a standardized Epimedium prenylflavonoid extract was administered to 30 healthy male subjects in a randomized, placebo-controlled trial. Serum samples were collected over a 48-h period and analyzed by liquid chromatography-tandem mass spectrometry and non-compartmental pharmacokinetic modelling. Epimedium prenylflavonoid extracts were well tolerated and no adverse effects were observed. The principle metabolites detected in the serum were icariside II and desmethylicaritin. Icariside II had a T max of between 4.1 - 4.3 h, reaching a maximum AUC0->infinity of 23.0 (17.5, 29.9) h*ng/mL (median [IQR: interquartile range]) with the highest dose of the Epimedium prenylflavonoid. On the other hand, desmethylicaritin had a delayed T max of 24.1 - 24.4 h and reached a maximum AUC0->infinity of 126.1 (62.4, 202.9) h*ng/mL. The median maximum plasma concentration and AUC0->infinity of desmethyliciaritin showed an increase with higher doses of the Epimedium prenylflavonoid (p < 0.05). Icariin, icariside I, and icaritin levels were below detection limits. Levels of Epimedium prenylflavonoid metabolites observed in this study were consistent with levels demonstrated to have anti-osteoporotic effects in cellular and animal studies. Coupled with the favorable safety profile of the extract observed, further studies are required to explore the utility of Epimedium prenylflavonoid extracts to prevent osteoporosis in postmenopausal women. PMID- 30522144 TI - The Efficacy of Tiapride and Carbamazepine Combination Therapy in Reducing Alcohol Withdrawal Symptoms: A Systematic Review and Meta-Analysis. AB - The combination of tiapride (TIA) and carbamazepine (CBZ) as an alternative treatment option to benzodiazepines and clomethiazole has been investigated by several investigations. We performed a systematic review and meta-analysis to further explore the efficacy of this combination in order to render more definite answers whether this combination can be recommendable in the clinical practice. We systematically searched electronic databases including PubMed (MEDLINE), EMBASE, OVID, Cochrane, Google Scholar, and Scopus for human studies. Statistical homogeneity was checked by chi2 test and I2 using Cochran heterogeneity statistic. Our analysis showed a significant efficacy of the combination of TIA and CBZ in reducing alcohol withdrawal syndrome (AWS) (p<0.0001, z-value: 4.07). The cumulative analysis illustrated that the favorable efficacy of this combination therapy has been consistent over time. Our study shows that the combination of TIA/CBZ is an effective treatment in management of AWS in patients with alcohol abstinence. However, the safety of this combination could not be proven, so we recommend its prescription after an informed consent. PMID- 30522145 TI - Effect of Sodium Glucose Co-Transporter-2 Inhibition on the Aldosterone/Renin Ratio in Type 2 Diabetes Mellitus. AB - The aldosterone to renin ratio (ARR) is recommended for case detection of primary aldosteronism (PA). Several factors including medications can undermine its diagnostic accuracy. The objective was to explore the effect of Sodium Glucose Co Transporter-2 Inhibition on the ARR in patients with type 2 diabetes mellitus (T2DM) who were prescribed a Sodium Glucose Co-Transporter-2 Inhibitor (SGLT-2i) as part of routine clinical care. The primary outcomes were intra-individual changes in aldosterone, renin and ARR. Participants were recruited at routine diabetes outpatient visits as part of a prospective longitudinal study. Eligible participants were prescribed standard doses of empagliflozin and sampled at baseline (pre-SGLT-2i) and at their next routine outpatient visit (post-SGLT-2i). After a mean of 198 (+/-87) days on SGLT-2i treatment (n=20), there was a significant reduction in HbA1c, BMI, eGFR and serum triglycerides and a significant increase in serum creatinine and sodium. Compared with baseline, there was a significant increase in median direct renin concentration (mIU/l) [40.3 (6.2-249.5) vs. 70.2 (7.0, 551.0) (p=0.005)] and no significant change in median plasma aldosterone concentration (pmol/l) [296 (101, 685) vs. 273 (101, 794) (p=0.541)] with a significant reduction in median ARR (pmol/mIU) [6.9 (0.6 70.7) vs. 5.3 (0.2-39.3) (p=0.007)]. The proportion of participants with a screen positive ARR decreased from 20% (pre-SGLT-2i) to 5% (post-SGLT-2i) (p=0.248). Although performed in a relatively small cohort of medically complex patients, the study indicates that SGLT-2i therapy has the potential to cause false negative screening for PA in the setting of T2DM. Future confirmatory studies should include patients with confirmed PA. PMID- 30522146 TI - Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients. AB - Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol <=50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60+/-10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain. PMID- 30522147 TI - The Effect of Vitamin D Supplementation on Prostate Cancer: A Systematic Review and Meta-Analysis of Clinical Trials. AB - Vitamin D has received attention for its potential to disrupt cancer processes. However, its effect in the treatment of prostate cancer is controversial. This study aimed to assess the effect of vitamin D supplementation on patients with prostate cancer. In the present study, PubMed, Scopus, ISI Web of Science, and Google Scholar were searched up to September 2017 for trials that evaluated the effect of vitamin D supplementation on prostate specific antigen (PSA) response, mortality, and its possible side effects in participants with prostate cancer. The DerSimonian and Laird inverse-weighted random-effects model was used to pool the effect estimates. Twenty-two studies (16 before-after and 6 randomized controlled trials) were found and included in the meta-analysis. The analysis of controlled clinical trials revealed that PSA change from baseline [weighted mean difference (WMD)=-1.66 ng/ml, 95% CI: -0.69, 0.36, p=0.543)], PSA response proportion (RP=1.18, 95% CI: 0.97, 1.45, p=0.104) and mortality rate (risk ratio (RR)=1.05, 95% CI: 0.81-1.36; p=0.713) were not significantly different between vitamin D supplementation and placebo groups. Single arm trials revealed that vitamin D supplementation had a modest effect on PSA response proportion: 19% of those enrolled had at least a 50% reduction in PSA by the end of treatment (95% CI: 7% to 31%; p=0.002). Although before-after studies showed that vitamin D increases the PSA response proportion, it does not seem that patients with prostate cancer benefit from high dose vitamin D supplementation and it should not be recommended for the treatment. PMID- 30522148 TI - ? PMID- 30522149 TI - ? PMID- 30522150 TI - ? PMID- 30522151 TI - ? PMID- 30522152 TI - ? PMID- 30522154 TI - ? PMID- 30522153 TI - ? PMID- 30522155 TI - ? PMID- 30522156 TI - ? PMID- 30522158 TI - ? PMID- 30522157 TI - ? PMID- 30522159 TI - [The future of laparoscopy and robotics in urology]. AB - The introduction of robotics led to a decrease in the importance of classical laparoscopy. Nevertheless laparoscopy and retroperitoneoscopy underwent significant technological improvements during the last decade, including introduction of 4k Ultra HD video technology, 3D-HD-videosystems, minaturised instruments, advanced sealing devices, instruments with 7 degrees of freedom, and ergonomic platforms Ethos Chair(r). The monopoly of robotic surgical devices will end in 2019, because key patents of Intuitive Surgical will expire. This will lead to an interesing competition among new manufacturers of robotic surgical devices, which however have to prove that they meet the high quality standard of the current da Vinci series, such as type of console, arrangement of robotic arms, technology of 3D-videosystem, and quality and degrees of freedom of end effectors. There are also robotic systems used in endourology: Avicenna Roboflex(r) and the AquaBeam(r)-System for robot-assisted aquablation therapy of the prostate. While Roboflex improves the ergonomics of flexbile ureteroscopy, AquaBeam may for the first time eliminate the surgeon. PMID- 30522160 TI - [Augmented reality and virtual reality in the operating theatre status quo und quo vadis]. AB - INTRODUCTION: Virtual reality (VR) is an artificially simulated environment permitting interaction. On the other hand, augmented reality (AR) is an enhanced version of reality created by the use of technology to overlay digital information on an image of something being viewed through a device. Both technologies have partially been implemented in clinical daily routine. Surgical applications of VR and AR are currently evaluated. Yet it is still unclear which possibilities these new and versatile applications offer for physicians. INTENTION: The goal of this article was to assess current and future use of AR und VR, with a special focus on surgery. We also summarised obstacles for AR and VR use as well as potential clinical improvements through these new technologies. METHODS: Systematic literature research in PubMed with inclusion of reviews referring to AR and VR, especially focused on articles on surgery. Keywords were Augmented Reality, Virtual Reality, Telementoring and Telesurgery. Furthermore we briefly analysed the investment volume and investment strategy in medicine from the ten largest private technology companies of the USA. RESULTS: The keyword "Augmented Reality" leads to 1222 articles and 119 reviews, while "Virtual Reality" offered 7766 articles and 878 reviews. In recent years, the amount of published articles has increased. 45 articles were included. Multiple AR- and VR applications are already integrated in surgical daily routine. The next promising applications will concern the possibility of intraoperative overlap with radiological imaging via AR-tools, as well as telementoring and the use of AR and VR in surgical and anatomical education. The expected - but unproven - advantages include cost savings, reduction in complications, comprehensive knowledge acquisition and improvement in surgical results. In addition, we notice enormous financial investment by technology companies in this sector. CONCLUSION: Due to their tremendous potential, AR and VR technologies will be increasingly integrated into surgery. However, the benefit of these new technologies for relevant endpoints are currently unclear. This should be examined in rigorous clinical trials. Physicians should play a key role in this technological revolution to exploit the potential of AR and VR for their patients. PMID- 30522161 TI - [Implementation of telemedicine in daily care of urological patients]. AB - Due to demographic changes and aging in the German population combined with the shortage of doctors, new techniques are needed to ensure urological patient care in the future. Telemedicine offers great potential to facilitate patient monitoring in their familiar surroundings and to ameliorate patient's compliance with the suggested therapy concept. Through optimal and reliable transfer of patient data, telemedicine helps to optimise patient satisfaction with urological therapies, binds them to their doctor and raises diagnostic safety. For a successful use of telemedicine, detailed education of participating patients and urologists as well as detailed fault monitoring are required. PMID- 30522162 TI - [The UroLift(r) system for treatment of the benign prostatic syndrome (BPS)]. AB - Minimally-invasive treatment options for patients with LUTS due to benign prostatic obstruction (BPO) become more and more important because they provide equal long-term efficacy compared with the reference method TURP, while having a more favourable safety profile. There are promising results for PUL (Prostatic Urethral Lift - UroLift) with low complication rates. UroLift is clearly superior regarding the preservation of sexual functions without impairment of ejaculatory function. PMID- 30522163 TI - [The Rezum system in the treatment of male lower urinary tract symptoms (LUTSs) due to benign prostatic obstruction (BPO)]. AB - The classical algorithm of the management of male lower urinary tract symptoms (LUTSs) due to benign prostatic hyperplasia (BPH) includes a surgical approach in case pharmacological therapy has failed. Emerging minimally-invasive treatments (MITs) offer potential for rapid symptomatic relief, reducing the morbidity of invasive BPH surgery. Convective interstitial radiofrequency water vapour thermal ablation of the prostate with the Rezum(r) system is a novel MIT for the treatment of bothersome moderate-to-severe lower urinary tract symptoms associated with BPH. It provides early effective and durable relief of storage and voiding LUTSs, preserving both erectile and ejaculatory function and improving quality of life. The procedure allows the treatment of a wide spectrum of prostate gland morphologies including intravesical prostatic protrusion, median lobe protrusion or elevated bladder neck. In selected patients, this procedure can also be offered for first-line treatment to prevent symptom progression and may thus be used as an alternative to long-term pharmaceutical treatment in order to avoid potential side-effects of drugs. This review describes this new technology and its clinical application and presents the current clinical evidence that supports the efficacy, safety and prospects of the Rezum procedure to date. PMID- 30522164 TI - [Genetic profiling in the diagnosis of hereditary prostate cancer: Where do we stand?] AB - Prostate cancer has a heterogeneous genetic profile compared with other tumour entities. Accordingly, there are also various mutations that increase the risk of prostate cancer. Some genetic variants only have a mild impact, whereas other gene mutations (BRCA1 /2; HOXB13) may increase the risk significantly. All in all, a man with a negative family history is unlikely to be a carrier of mutations that are associated with an increased risk of PCa. However, this likelihood increases if the family history is positive for a known mutation or if there are relatives who were affected at an early age. In such cases, genetic counselling and testing should be considered, with a particular focus on BRCA1/2 mutations and HOXB13 mutations. However, genetic profiling has not had the potential to replace PSA testing, mpMRI of the prostate gland and/or prostate biopsies as part of cancer screening or the diagnostic algorithm in the general population. The presence of mutations associated with PCa merely allows patients to undergo screening earlier and in tighter intervals and possibly receive earlier definitive treatment. PMID- 30522165 TI - ? PMID- 30522166 TI - Pitfall in genetic screening in a pregnancy involving an allogeneic hematopoietic stem cell transplantation recipient. PMID- 30522167 TI - T-cell immunology of the lung: maintaining the balance between host defence and immune pathology. AB - Respiratory immunology poses the dual questions of how to grapple with lung infection as one of the greatest unmet global health needs of our time, while also dealing with the growing challenge posed by chronic diseases of excessive or inappropriate lung inflammation and immunity, such as chronic obstructive lung disease and asthma. These separate branches of pulmonary research are linked by the clear observation that, in a tissue as fragile as the lung, protection from microbial attack may come at the cost of chronic inflammatory damage. A number of recent studies have considered specific aspects of this double-edged sword, including the diversity of responses to fungal exposure, sources and consequences of interleukin-17 immunity, and the role of tertiary lymphoid follicles in the lung. PMID- 30522168 TI - [Application and prospect of liquid biopsy in clinicopathologic diagnosis]. PMID- 30522169 TI - [Detection of circulating tumor DNA in epidermal growth factor receptor-TKI relapsed non-small cell lung cancer patients using next-generation sequencing and an analysis of the resistant mechanisms]. AB - Objective: Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) samples from tyrosine kinase inhibitor (TKI)-naive non-small cell lung cancers (NSCLC) and TKI-relapsed NSCLC to investigate the clinical value. Methods: A total of 381 plasma samples from patients who were diagnosed with lung cancer in Cancer Hospital Chinese Academy of Medical Sciences from March 2017 to May 2018 were enrolled in the study. NGS was performed using a custom-designed panel that covers 10 lung cancer-related driven genes. Paired plasma-tissue samples from 39 patients were collected to analyses the sensitivity and specificity of detecting driver gene mutations using ctDNA. NGS was also performed on plasma samples from TKI-relapsed patients to identify TKI resistance mechanisms. Results: Thirty-nine plasma samples collected from 39 NSCLC patients (including 21 female and 18 male) with corresponding tissue biopsies were analyzed for the sensitivity and specificity. The average age was 56 years (range 29 to 82 years). A high concordance of 84.62% (33/39) was observed between ctDNA and tissue biopsies. Compared with tissue biopsies, NGS sensitivity for ctDNA was 82.14% and specificity was 90.91%.Among these 39 patients, 34 were advanced stage patients (III-IV stage). The concordance, sensitivity, and specificity for ctDNA among the advanced stage patients were 88.24% (30/34), 86.36% (29/34) and 91.67% (31/34), respectively. Among the 381 plasma samples [including 231 TKI-naive patients and 150 epithelial growth factor receptor(EGFR)-TKI relapsed patients], EGFR mutation was the most common driver gene among the 221 TKI-naive lung adenocarcinoma patients (32.58%, 72/221). For 133 patients who progressed after first-generation EGFR-TKI, T790M was found to be the most frequent resistant mechanism (39.10%, 52/133), as well as bypass activation (3.01%, 4/133; such as MET amplification and ERBB2 amplification). Among those first-generation EGFR-TKI relapsed patients with EGFR sensitive mutations, T790M was detected in 53.06% (52/98). For the 17 patients who progressed after third-generation EGFR-TKI, C797S was found to be the most common resistant mechanism (4/17). Conclusions: The concordance, sensitivity and specificity between ctDNA and tissue biopsies are acceptable. ctDNA analysis provides valuable information for lung cancer patients' targeted treatment, especially for patients not fitted for biopsies. PMID- 30522170 TI - [Comparison of epidermal growth factor receptor (EGFR) gene T790M mutation by droplet digital PCR and Super-ARMS PCR in plasma ctDNA samples of non-small cell lung cancer patients with the resistance to EGFR-tyrosine kinase inhibitor]. AB - Objective: To compare droplet digital PCR (ddPCR) and Super-amplification refractory mutation system (ARMS) in the detection of T790M mutation of epidermal growth factor receptor (EGFR) in the plasma of non-small cell lung cancer patients who had developed resistance to EGFR tyrosine kinase inhibitor (TKI) , and to investigate the clinical application of ddPCR. Methods: Plasma samples were collected from non-small cell lung cancer patients who had acquired EGFR-TKI resistance at Shanghai Pulmonary Hospital, Tongji University, from May 2017 to November 2017. Extracted ctDNA was analyzed by ddPCR and Super-ARMS to evaluate the T790M mutation status of EGFR gene. Results: A total of 37 patients with activating EGFR mutation that acquired resistance to EGFR-TKI were selected in the study, including 17 male and 20 female with a median age of 64 years (range 40-83 years). Before TKI treatment, all the patients harbored EGFR inhibitor sensitive mutations but without T790M mutation. After acquiring resistance to EGFR-TKI treatment, the T790M mutation rate detectable by ddPCR was 45.9% (17/37). In contrast, the mutation rate of T790M detectable by Super-ARMS was 35.1% (13/37, P<0.05). For the 13 positive cases detected by Super-ARMS (DeltaCt<8), they were all positive by ddPCR assay; Among the 10 negative cases detected by Super-ARMS (DeltaCt>=8), there were 3 cases positive by ddPCR assay. For patients without DeltaCt by Super-ARMS assay, there was one weak positive case detectable by ddPCR assay. Among 17 EGFR T790M positive patients, 9 received EGFR inhibitor Osimertinib treatment, and 7 of them had good therapeutic response after the treatment. Conclusions: While a significant correlation between the two methods is shown. ddPCR is more sensitive than Super-ARMS in the detection of EGFR T790M mutation, indicating that it is a better method in guiding target drug therapy of non-small cell lung cancer patients after acquiring the resistance to EGFR-TKI. PMID- 30522171 TI - [Detection of epidermal growth factor receptor mutations using bronchial washing fluid in lung cancer patients with negative results by rapid on-site evaluation]. AB - Objective: To evaluate the clinical application of bronchial washing fluid (BWF) in the detection of epidermal growth factor receptor (EGFR) gene mutation in lung cancer patients during diagnostic bronchoscopic procedure. Methods: Patients with suspected lung cancer lesions but failed to be identified as malignancy by rapid on-site cytologic evaluation (ROSE) were enrolled. Performed blocker PCR for EGFR mutation detection using the supernatant and cell pellet of BWF samples and compared the detective results to the EGFR mutation status detected using histologic tumor samples. Results: A total of 85 BWF and paired histological samples were collected at Fudan University Affiliated Zhongshan Hospital from October 2016 to June 2017. There were 46 male and 39 female, with a mean age of 61 years (range 30-87 years). Thirty-one patients had benign diseases and 54 patients had primary lung cancer. Among these 54 lung cancer patients, the diagnoses were made basing on bronchoscopic biopsy samples in 31 patients. The detection rate of EGFR gene mutation in BWF samples was 100.0% concordant with that using histological samples.Another 23 cases whose bronchoscopic biopsy failed to establish malignant diagnoses were further identified by other sampling methods including surgical resection, lung biopsy, etc. A total of 15 patients were identified as EGFR mutated type by pathologic detection or clinically effect assessment, and BWF could detect 11 of them, accounting for 11/15 of all cases. Overall, BWF had achieved an overall accuracy of 95.3% (81/85) comparing to paired tumor histologic samples. Conclusions: BWF is an effective complementary specimen to bronchoscopic biopsy samples in EGFR gene mutation detection in patients with suspected lung cancer lesion and negative biopsy results evaluated by ROSE during bronchoscopy. PMID- 30522172 TI - [Diagnostic and therapeutic values of interphase fluorescence in situ hybridization in B-cell lymphomas: a clinicopathologic analysis of 604 cases]. AB - Objective: To investigate the feasibility and value of interphase fluorescence in situ hybridization (FISH) in the pathological diagnosis, differential diagnosis and therapeutic assessment of B-cell lymphomas. Methods: The cohort included 604 cases of B-cell lymphoma which were collected at West China Hospital from May 2010 to December 2016.And all were subjected to interphase FISH using 11 break apart or fusion probes (MYC, bcl-2, bcl-6, IRF4, MYC/IgH, bcl-2/IgH, CCND1/IgH, IgH, API2/MALT1, p53/ATM, and D13S319/CEP12). Results: The median age of the 604 B-cell lymphoma patients was 47.7 (aged 2-90) years including 372 men and 232 women. All the cases was divided into 463 large B cell lymphomas(LBL) and 141 small B cell lymphomas, and the total interphase FISH positive rate was 59.8% (361/604). Among the 463 LBL, 12.5% (58/463), 9.5% (44/463) and 2.2% (10/463) of cases showed MYC, bcl-6 and bcl-2 gene rearrangements respectively; and 363 diffuse large B cell lymphoma (DLBCLs) were reclassified as germinal center B cell (GCB) subtype (38.6%, 140/363) and non-GCB subtype (61.4%, 223/363) by Hans algorithm. The rearrangement rates in GCB and non-GCB DLBCL were 45.7%(64/140)and 21.5%(48/223; P=0.001), respectively. Compared to the non-GCB DLBCL, GCB DLBCL showed higher MYC and bcl-2 gene rearrangements (P=0.001). Eleven (2.4%, 11/463) cases had MYC and bcl-6 or bcl-2 gene rearrangement (double-hit lymphoma); one (0.2%, 1/463) case had MYC, bcl-6 and bcl-2 gene rearrangements (triple-hit lymphoma); two (0.4%, 2/463) cases had bcl-2 and bcl-6 gene rearrangements. MYC translocation and MYC/IgH fusion were detected in 94.2%(81/86) and 83.7%(72/86) cases of Burkitt lymphomas. IRF4 rearrangement was detected in two cases of IRF4+ LBCL. Genetic abnormalities were detected in 9/19, 100%(29/29), 30.8%(12/39) and 68.5%(37/54) cases of follicular lymphoma, mantle cell lymphoma, MALT lymphoma and chronic lymphocytic leukemia, respectively. Conclusions: Interphase FISH can rapidly and accurately detect the genetic changes in B-cell lymphomas. Different genetic changes are specifically valuable to the diagnosis, differential diagnosis, prognosis evaluation and treatment guidance of various B-cell lymphomas. PMID- 30522173 TI - [Pigmented microcystic chromophobe renal cell carcinoma: a clinicopathologic analysis of five cases]. AB - Objective: To investigate the clinicopathologic features, diagnostic and differential diagnostic aspects of pigmented microcystic chromophobe renal cell carcinoma (ChRCC). Methods: Five cases of pigmented microcystic ChRCC were collected at Zhejiang Provincial People's Hospital from January 2013 to January 2018. The clinical features, gross and histological appearances, immunohistochemistry and prognosis were analyzed and the relevant literature was reviewed. Results: There were 3 men and 2 women with age range of 45 years to 72 years (mean 57 years). All tumors were incidentally identified by imaging examinations. Grossly, the tumors were well-demarcated and showed diameters ranging from 1.8 cm to 4.0 cm(mean 2.9 cm). On cross section, the tumors were brown to gray tan with solid cut-surface mixed with multiple cysts of variable sizes. Hemorrhage was common, central scar was not seen. Microscopically, the tumors were composed predominantly of irregular and variable-sized microcystic or tubulocystic patterns, with extensive cribriform structures formation and focal adenomatous rearrangements seen in one case each, and focal pseudo-papillary structures (lacking true fibro-vascular cores) seen in two cases. Microscopic calcifications and psammoma bodies were present in all tumors. Four tumors composed mostly of eosinophilic cells whereas 1 predominated in plant-like cells. Brown pigmentations, either intracytoplasmic or extracytoplasmic, were noted in all five cases. The tumor cells had irregular, low-grade nuclei (Paner grade: 1) frequently with binucleation and perinuclar halos. Tumor necrosis or sarcomatous transformation was not seen. By immunohistochemistry, the tumor cells expressed CK, EMA, and E-cadherin diffusely and strongly in five cases; and CK7 and CD117 diffusely in four cases. They were negative for vimentin, CD10, CA9, AMACR/P504s, TFE3, HMB45, Melan A, S-100 protein, synaptophysin and chromogranin. Partial nephrectomies were performed for all five patients; there was no tumor recurrences or metastases at a follow-up of 2 to 55 months (mean, 17 months). Conclusions: Pigmented microcystic ChRCC is a rare histological variant of ChRCC with relatively indolent behavior, and shows morphologic heterogeneity which can elicit a wide range of differential diagnoses. Careful attentions to search for typical features of classic ChRCC with the use of immunohistochemistry can help to distinguish this tumor from its many mimickers. PMID- 30522174 TI - [Expression of CD117, MITF and NAT10 and their prognostic values in sinonasal mucosal melanoma]. AB - Objective: To investigate the correlation between the expression of CD117, MITF, NAT10 and clinical parameters in sinonasal mucosal melanoma (SNMM). Methods: Formalin-fixed paraffin-embedded tumor specimens of 80 cases of SNMM at the Eye, Ear, Nose and Throat Hospital, Fudan University, from December 1999 to November 2013 were analyzed for CD117, MITF and NAT10 expression by immunohistochemistry. Results: There were 40 men and 40 women. The median age was 61 years, age 26 to 85 years. There was no correlation of the expression of CD117, MITF and NAT10 with the patients' age, gender, tumor site, stage, therapy method and brain metastases (P>0.05). The expression of MITF and NAT10 was associated with lymph node metastasis and the tumors were more likely to metastasize when MITF and NAT10 were positive. However, expression of CD117 had no correlation with lymph node metastasis. Log-rank test revealed that the expression of CD117 was correlated with both three-year and five survival rate (P=0.012, P=0.023; respectively) and patients with tumor having low expression of CD117 had the worse outcome. COX test revealed that low CD117 expression, advanced age and lymph node metastasis were independent risk factors (P<0.05). No significant association was found between the expression of CD117, MITF and NAT10 with disease free survival (P>0.05). Conclusions: Patients with SNMM expressing low level of CD117 have decreased survival rate. Tumors with high level of MITF and NAT10 expression are more likely to metastasize. The expression level of CD117 can be used as an important indicator for the patient survival, and the expression of MITF and NAT10 can be used as a predictor of tumor metastasis. PMID- 30522175 TI - [Clinicopathologic and molecular features of myoepithelial tumors of salivary glands]. AB - Objective: To investigate the clinicopathological, and molecular characteristics of myoepithelial tumors (MTs) of salivary glands. Methods: A total of 37 MTs cases including 13 malignant epithelial tumors (MMTs) and 24 benign epithelial tumors (BMTs) of salivary glands were identified from the archives of the Department of Pathology, General Hospital of Eastern Theater Command, dating from 2006 to 2016. Clinical features, histological patterns, immunohistochemical characteristics and status of EWSR1 gene rearrangement by fluorescence in situ hybridization (FISH) analysis were reviewed in all cases. Results: Clinically, 37 MTs cases mainly occurred in the parotid glands, when most of the patients presented with painless masses. Of the 13 MMTs cases, male to female ratio was 7?6, and the median age was 62 years old. Of the 24 BMTs cases, male to female ratio was 5?7, and the median age was 54 years old. Immunohistochemically, 37 MTs cases were positive for CKpan, and at least one myoepithelial marker. Twenty six of 37 MTs cases were analyzable for the EWSR1 gene break by FISH. Based on the previous evaluation criterion, the EWSR1 translocation was detected in 4 cases of 11 MMTs, and 4 cases of 15 BMTs. According to the main histological composition of tumor cells, 4 EWSR1-positive MMTs covered 2 clear-cell cases and 2 epithelioid-cell cases, when 4 EWSR1-positive BMTs covered 2 clear-cell cases, 1 plasmacytoid-cell case, and 1 spindle-cell case. Conclusions: Males and females are affected equally. MTs express immunoreactivity for CKpan, and at least one myoepithelial marker. The EWSR1 rearrangement is present in a subset of MTs, with variable morphological characteristics, and has no statistical significance on clinical behavior. PMID- 30522176 TI - [Gangliocytic paragangliomas: a clinicopathologic study]. AB - Objective: To investigate the clinicopathological features of gangliocytic paraganglioma(GP). Methods: Clinical data and pathological diagnosis of the 4 cases of GP were obtained through the medical record inquiry from January 2011 to December 2017 at the First Affiliated Hospital of Zhengzhou University. Routine HE staining and immunohistochemistry of CKpan, Syn, CgA, CD56, NSE and NF were performed. Clinical follow-up of the patients was obtained through telephone communication. Results: All 4 patients, including 2 male and 2 female patients, presented with intermittent abdominal pain and distention. The median age was 56 years. Preoperative CT showed local thickening of the duodenum wall with slight enhancement in all four cases. Endoscopic ultrasonography showed low level echo in the mucous layer and submucosa involved by the tumor in 3 of 4 cases. The maximal diameter of the tumor ranged from 0.6 to 1.8 cm with an average of 1.2 cm. Microscopically, the tumors consisted of epithelioid, spindle and ganglion like cells, and the proportion of the three cell types was different among cases. Epithelioid cells expressed CKpan, Syn, CgA and CD56. Spindle cells expressed S 100 protein and SOX-10 and ganglion-like cells expressed NF, Syn, CgA and CD56.All tumour cells expressed NSE. All 4 patients had no recurrence a post surgery follow-up period of 3 to 30 months. Conclusions: GP of the duodenum is a benign tumor with excellent prognosis after endoscopic excision. Although its incidence is very low, its diagnosis should be considered for any mass lesion of the duodenum, especially involving mucosa and submucosa of the second dudenal segment. PMID- 30522177 TI - [Effect of GSK-3beta inhibitor on the expression of RANK-RANKL in rats kidney tissue with diabetic nephropathy]. AB - Objective: To investigate the effect and significance of GSK-3beta inhibitor(LiCl)and RANK-RANKL on the renal tissue of diabetic nephropathy(DN) rats. Methods: SD rats were divided into normal control group (NC), DN model group (DN) and GSK-3beta inhibitor intervention group (LiCl). Twenty-four hour urine protein of rats were determined by Coomassie brilliant blue. Kidney tissue sections were stained by HE. The expression of GSK-3beta, RANK and RANKL protein were determined by immunohistochemistry staining. The mRNA of GSK-3beta, RANK, RANKL was detected by RT-qPCR. Results: Compared with NC group[(14.72+/-3.37)g], the level of 24-hour urinary protein[(154.17+/-20.65)g] increased significantly in DN group; compared with DN Group, the level of 24-hour urinary protein [(107.22+/-31.15)g]decreased in LiCl group(P<0.05). Compared with NC group(2.10+/ 0.60, 1.10+/-0.20, 1.21+/-0.20; 19.52+/-3.20, 1.80+/-1.10, 1.81+/-0.50), the pathological changes of renal tissues of DN group aggravated, the mRNA and expression of protein of GSK-3beta, RANK and RANKL increased(9.10+/-2.15, 8.95+/ 2.40, 9.90+/-2.60; 32.70+/-7.20, 19.20+/-4.32, 20.92+/-5.90); compared with DN group, the pathological changes of renal tissues of LiCl group alleviated, mRNA and the expression of protein of factors above declined(2.70+/-0.80, 2.32+/-0.65, 3.58+/-1.10; 22.35+/-3.25, 4.20+/-2.42, 5.90+/-2.36; P<0.05). Conclusion: RANK and RANKL play an important role in the development of DN, LiCl influence Wnt and NF-kappaB signal pathway down-regulating RANK and RANKL to suspend development of diabetic nephropathy. PMID- 30522178 TI - [Lymphoepithelioma-like carcinoma: a clinicopathologic analysis of 6 cases]. PMID- 30522179 TI - [Histopathological observation of portal hypertensive enteropathy]. PMID- 30522180 TI - [Evaluation system before molecular detection of liquid-based cytology samples from non-small cell lung cancer and analysis of epidermal growth factor receptor gene mutation status]. PMID- 30522181 TI - [An improved method for paraffin embedding technique in prostate punctured tissue]. PMID- 30522182 TI - [Peritoneal multicystic mesothelioma: report of a case]. PMID- 30522183 TI - [Cranial fascitis: report of a case]. PMID- 30522184 TI - [Mixed reproductive cell tumor of the pancrea: report of a case]. PMID- 30522185 TI - [Mitotically active sclerosing stromal tumor of the ovary with Meigs' syndrome and elevated serum cancer antigen 125 levels: report of a case]. PMID- 30522186 TI - [WT1-positive congential mesoblastic nephroma: report of a case]. PMID- 30522188 TI - [Research progrss on resistance of PD1/PD-L1 signal pathway]. PMID- 30522187 TI - [Interpret on 2017 WHO classification of the parathyroid tumours]. PMID- 30522189 TI - [Landscape of POLE mutant-type endometrial carcinoma]. PMID- 30522190 TI - [Peripheral small airway dysfunction differences between idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension]. AB - Objective: To investigate the peripheral small airway dysfunction differences between idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Impulse oscillmetory system testing (IOS) and pulmonary function testing (PFT) were performed in IPAH and CTEPH patients and 30 healthy control group. We also carried out a subgroup analysis depending on their medical history of airway diseases. Results: We included 42 IPAH and 47 CTEPH patients (with or without airways disease: 8 vs. 34 and 17 vs. 34, respectively). Compared with CTEPH patients, IPAH patients were younger but had more serious pulmonary vessel resistance and mean pulmonary arterial resistance. Compared with IPAH patients, CTEPH patients had significant impaired peripheral small airway dysfunction with decreased of MEF(50) (% pred), MMEF(75/25) evaluated by PFT and R5-R20, Delta R5-R20 and AX measured by IOS [10.6(2.0, 33.0) vs. 2.5(-5.0, 16.5); 22.1(14.0, 32.6) vs. 15.5 (7.0, 23.2); 7.64(4, 18.6) vs. 6(3, 11) respectively, all P<0.05]. Subgroup analysis revealed there were no significant peripheral small dysfunction differences in IPAH patients with or without airway diseases. CTEPH patients had a higher proportion of airway diseases and more serious peripheral dysfunction than IPAH patients with airway diseases. Compared with control healthy group, peripheral airway dysfunction was more obvious even in IPAH and CTEPH patients without airway diseases. Conclusion: Compared with IPAH, CTEPH patients were older, but had better hemodynamics and a higher proportion of airway diseases. The peripheral airway dysfunction were more serious in CTEPH patients without airway diseases than IPAH patients without airway diseases and healthy controls group. PMID- 30522191 TI - [Respiratory virus infections and inflammatory cytokines in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease]. AB - Objective: To investigate the characteristics of respiratory viral infections, and correlation between inflammatory cytokines and respiratory virus infections in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD). Methods: A prospective cohort of patients with acute exacerbations of COPD was enrolled. The sputum of all patients were collected, and 15 respiratory viruses were detected using multi-channel real-time fluorescence quantitative PCR. The clinical characteristics associated with viral infections were analyzed. The peripheral blood of the patients was collected and cytokines including IL-6, IL-8, RANTES, IP-10, sIL-2R, IFN-gamma, TNF-alpha in the serum were detected by ELISA. Association of these cytokines with respiratory viral infections was evaluated and a discriminant model was established. Results: A total of 99 patients with acute exacerbations of COPD were enrolled in this study. Thirty four cases (34.3%, 34/99) were positive for viral detection. Among them, the positive rate of influenza A virus was the highest (38.2%, 13/34), followed by rhinovirus (35.3%, 12/34). Multifactor logistic regression analysis showed that, fever, COPD assessment test (CAT) score in stable stage, serum IP-10 and TNF alpha levels were correlated with respiratory viral infections in patients with acute exacerbations of COPD. The levels of serum IP-10 and sIL-2R increased significantly in patients with influenza A virus. Conclusions: Respiratory viral infections were common in acute exacerbations of COPD. Influenza A virus and rhinovirus were the two most common viruses. Fever was a common symptom. Patients with severe respiratory symptoms at stable stage were susceptible to viral infection. Viral infection was associated with an increase in systemic inflammatory levels, most significantly in influenza virus infection. A discriminant model composed of fever, CAT score in stable stage, serum IP-10 and TNF-alpha levels can be used to predict respiratory viral infections in acute exacerbations of COPD. PMID- 30522192 TI - [The computed tomography angiography features of Dieulafoy disease of the bronchus]. AB - Objectives: To summarize the computed tomography angiography(CTA) features of Dieulafoy disease of the bronchus. Methods: The clinical, imaging and pathological data of Dieulafoy disease of the bronchus diagnosed in our hospital from July 4, 2010 to June 20, 2016 were retrospectively analyzed, and the CTA imaging features of the abnormal bronchial arteries were summarized. Results: There were 6 cases of bronchial Dieulafoy disease, 5 males and 1 female, with an average age of (55+/-15) years. Three cases had smoking history, and 2 cases had underlying diseases such as tuberculosis and acute myeloid leukemia. The common manifestations were hemoptysis, fever and pneumonia. Three patients got CTA examination, and bronchial arteries of Dieulafoy disease of the bronchus were circuitous and dilated, with the vascular diameter lager than 2 mm, no gradual narrowing but sudden truncation. Some circuitous vessels went into bronchial lumen as nodules. The bronchoscopy biopsy of 2 cases of bronchial nodules led to severe hemorrhage, with one death and one survival by successful management. Conclusions: Bronchial arteries of Dieulafoy disease of the bronchus were circuitous and dilated, and some circuitous vessels went into bronchial lumen as nodules, this demonstration can be used to diagnose Dieulafoy disease of the bronchus. For patients with hemoptysis, bronchial biopsy should only be performed after CTA examination if this disease is suspected. PMID- 30522193 TI - [Signaling pathway of M2-type polarization induced by Mycobacterium tuberculosis specific peptide E7 in monocyte-macrophages]. AB - Objective: To explore the signal pathway of M2-type polarization induced by Mycobacterium tuberculosis (MTB)-specific peptide E7. Methods: Monocyte macrophages were divided into blank control group, M1 positive stimulus group [co stimulated with lipopolysaccharide and gamma interferon (IFN-gamma)], M2 positive group(co-stimulated with IL-4 and IL-13), and E7 experimental group (with MTB specificity polypeptide E7 stimulated). The expression of M1 type markers CD(16), IL-6, TNF-alpha and M2 type markers CD(163), CD(206), IL-10 were detected at 12, 18, 24 and 36 h. Furthermore, peroxisome proliferators-activated receptors-gamma (PPAR-gamma) blocker was used in the blank control group, M2-positive stimulus group and E7 experimental stimulus group. T test was used to compare the expression of PPAR-gamma and CD(163) before and after the addition of blockers. Results: Compared with the positive control group and the blank control group, the expression of TNF-alpha in the E7 experimental group gradually reached the peak when macrophages were stimulated for 18 h(the relative expression was 20.02), and then the expression of TNF-alpha gradually decreased and the expression of CD(163) increased. The expression of CD(163) peaked at 24 h (the relative expression was 2.44). After adding the inhibitor, the expression of PPAR gamma in E7 stimulation group was lower than before blocking (before blocking 0.94+/-0.06, after blocking 0.69+/-0.09, P=0.028). CD(163) expression level was significantly lower than that before blocking (before blocking 3.95+/-0.61, after blocking 2.87+/-0.20, P=0.047). Conclusion: The MTB-specific peptide E7 induced differentiation of macrophages into M2 type, a process that may be involving PPAR gamma in just another kinase-signal transducer and activator of transcription pathway. PMID- 30522195 TI - [Research progress of circulating tumor DNA methylation in non-small cell lung cancer]. PMID- 30522194 TI - [The role and mechanism of regulatory T cells in indirect acute lung injury]. AB - Objective: To study the role and mechanism of CD(4)(+) CD(25)(+) FoxP3(+) regulatory T cells (Tregs) in the pathophysiological process of indirect acute lung injury (iALI) in mice. Methods: The iALI model was successfully induced by shock/cecal ligation and puncture method. Sham (n=8), cecal ligation and puncture (CLP, n=10), and hemorrhage (Hem, n=12) groups were established as controls. Two experimental groups were established: CLP+Hem (n=15) without Tregs adoptive transfer (AT), and CLP+Hem with Tregs adoptive transfer (CLP+Hem+AT, n=14). The number of Tregs, subsets of lymphocytes, neutrophil activity, apoptosis, cytokine levels and histopathological changes were measured in the lung tissue of each group. The protein exudation and the expression of IL-10 in bronchoalveolar lavage fluid (BALF) were also detected. After in vitro cell co-culture, the proliferation of activated T cells and the expression of IL-10, INF-gamma and iNOS protein were detected. Results: The percentage and the absolute cell number of CD(4)(+) CD(25)(+) FoxP3(+) Tregs in lung tissue of iALI mice were (2.530+/ 0.086)%, and (1.441+/-0.090)*10(4)/ml, respectively, which were significantly higher than the control groups (P<0.05). Adoptive transfer of Tregs could significantly decrease CD3-positive T lymphocytes, myeloperoxidase (MPO) activity, caspase-3 activity in lung tissue as well as protein leakage in BALF (P<0.05). Meanwhile interleukin-10 (IL-10) levels in lung tissue and BALF were up regulated from (121.4+/-43.76) pg/ml to (201.0+/-61.96) pg/ml (t=2.776, P<0.05) and (206.2+/-90.88) pg/ml to (339.4+/-109.5) pg/ml (t=2.477, P<0.05), respectively. Histopathology was also significantly improved. The proliferation of activated T lymphocytes in the adoptive transfer Treg (AT-Treg) group (n=5) was significantly lower than that in the natural regulatory T cell (N-Treg) group (n=5, t=7.485, P<0.01) and the negative control group (n=5, t=16.66, P<0.01). However, iNOS enzyme inhibitor L-NMMA could significantly reduce the T cell proliferation (P<0.05). Conclusion: CD(4)(+)CD(25)(+)FoxP3(+) Tregs could reduce inflammatory reaction in mice with iALI, and the iNOS signaling pathway may be involved in this process. PMID- 30522196 TI - [Immune checkpoint inhibitors-associated interstitial lung disease]. PMID- 30522197 TI - [Research progress and perspective on the applications of whole exome sequencing in venous thromboembolism]. PMID- 30522198 TI - [Research progress of biomarkers in early stage lung cancer]. PMID- 30522199 TI - [The microbiome in chronic obstructive pulmonary disease]. PMID- 30522200 TI - [Risk factors, diagnosis and treatment of peri-implant diseases]. AB - With the wide spread of dental implantation, more and more soft and hard tissue illness related to dental implants occurred. According to a statistical analysis, about 1/4 to 1/2 patients are under the risk of suffering from peri-implant diseases. Peri-implant diseases include peri-implant mucotitis and peri implantitis. The former is connected with soft tissue while the latter is related to hard tissue around dental implant. This article reviews the diagnosis, classification and treatment of peri-implant diseases. PMID- 30522201 TI - [Role of occlusion in complications of implant rehabilitation]. AB - Peri-implantitis, restoration loosening and fracture, implant structural damage are common post-restorative complications in implant rehabilitation. With an increasing incidence, they may occur in implant-supported single or splinted crowns, bridges, overdenture or fixed denture. Possible causes involve not only the design of implant components structure and characteristics of restorative materials, but also the design of restoration and the occlusal function and structure of patients. Despite the hard texture of teeth, occlusal force may cause abrasion to occlusal and proximal aspects, as well as mesial migration of tooth, leading to continuous change of occlusal structure and function through the whole life. It should be considered in implant placement surgery, design and maintenance of restorations. From considerations of occlusal function and structure, the present article reviews and elaborates the effect, potential hazard, management and prophylaxis of post-implant-restorative complications. PMID- 30522202 TI - [Design of points, lines and planes in the reconstruction of occlusion and the risk control in implantation]. AB - Occlusion reconstruction involves various factors, such as joints, muscles, teeth and mental states. The relationship between implantation complications and occlusion, especially in the method of reducing the risk of implantation during occlusal reconstruction, is more and more emphasized by clinicians. This article mainly summarized the essentials of occlusal factors, such as mandibular position, cusp inclination and occlusal contacts, Spee's curve, Wilson curve and occlusal plane, in clinical treatment from the perspective of static geometry, dynamic functional movement in points, lines and planes, in order to accomplish precise occlusion reconstruction to achieve a stable and functional occlusion reconstruction, i.e. comfortable mandibular position, reasonable protrusive and lateral guidance, firm retrusive control and stable posterior supports, and to maintain the stability of implant. PMID- 30522203 TI - [Aesthetic complications of immediate implant placement of anterior teeth]. AB - In the anterior tooth zone, the criteria of successful implant restoration is not only to ensure a high survival rate of implant, but also to provide long-lasting and stable aesthetic outcomes. As for the rehabilitation of anterior teeth, immediate implant placement might achieve a survival rate similar to those of delayed implant placement and significantly reduce treatment time, whereas several aesthetic complications such as gingival recession, loss of interdental papilla, exposure of implant margin could also occur. Therefore, an important issue need to be solved is that how to avoid or handle the aesthetic complications of immediate implant placement of anterior teeth. This article mainly discusses the clinical features, possible etiologies and handling methods of aesthetics complications in rehabilitation of anterior teeth using immediate implant placement. PMID- 30522204 TI - [Analysis of risk factors of 19 fractured implants]. AB - Objective: To analyze the incidence and possible risk factors of 19 fractured implants out of 8 468 implants in 3 184 cases. Methods: During the 22-year clinical practice, clinical records of 18 patients with 19 fractured implants in 3 184 cases with 8 468 implants were analyzed to determine the following factors: location of the fractured implants, prosthodontics option, date of implant fracture, dimensions of fractured implants, complications prior to implant fracture and parafunctional habit. An evaluation of fractured implants was performed to identify possible factors that may predispose an implant to a higher risk of fracture. Results: Overall, the average duration of service of the implants was (7.0+/-4.5) years. Implant fracture occurred in 7 Camlog implants, 7 Nobel replace implants, 3 Ankylos implants and 2 Branemark implants. No Thommen implant fractures were recorded. Amongst the 19 fractured implants, 8 occurred at the thinnest wall portion of the implant neck, 8 at the end of screw and 3 at the self-tapping thread region. All fractures were observed after functional loading. Furthermore, 9/19 (47.4%) of fractures occurred in the maxilla, indicating similar incidence rates in both arches (P=0.065). Most of fractures (16/19) occurred in the molar region and 18/19 in single implant-supported restorations. Totally 17 cases had received metal occlusal restorations. In 6 cases (35.5%), previous bone destruction apically extending to the level of implant fracture was documented before any clinical signs of fracture. Three fractured implants were removed and simultaneously re-implanted with larger-diameter implants, while the rest of the cases were left to heal, followed by a second-stage surgery. Conclusions: Within the limitation of this analysis, the study demonstrated that appropriate implant-abutment connection design, implant diameter, prosthetic strategy and bone resorption are crucial to the long-term performance of implants. There is no significant difference of fractures rates in both archs. PMID- 30522205 TI - [Clinical evaluation of two transalveolar methods for sinus augmentation with placing 1 204 implants immediately]. AB - Objective: To compare the clinical outcomes of posterior maxillary implant surgery when using the regular transalveolar approach or with the crestal approach-sinus (CAS-KIT), a device for maxillary sinus membrane elevation by the crestal approach using a special drilling system and hydraulic pressure. Methods: In this retrospective study 887 patients during Jan 2012 to July 2015 in Hangzhou Dental Hospital with underwent either regular transalveolar approach or CAS-KIT approach for maxillary augmentation; whereas 11 patients dropped out for the reason of serious membrane perforations. Totally, 876 patients with 1 204 plants, placed immediately after transalveolar maxillary augmentation, were included in this study. The data analysis was performed by radiological measures to assess the changes in height of maxillary sinus floor after the transalveolar augmentation at different time points. In addition, the complications after surgery, failure rates, osseointegration condition and the performance of rehabilitation were evaluated as well. Results: Five hundred and three patients were experienced with regular transalveolar approach, and 7 patients were drop out for the serious membrane perforations. Thus, 496 patients received 653 implants in this group; the average lifted range in maxillary sinus floor height changes was (4.08+/-3.45) mm. The complications were minor membrane perforations during procedure in 64 patients, postoperative maxillary sinus infection happening in 2 patients and 13 patients experienced rehabilitation failure. Three hundred and eighty-four patients had CAS-KIT approach with 4 patients dropped out. Three hundred and eighty patients get 551 implants with the mean lifted range of (8.36+/-4.07) mm in maxillary sinus floor height changes. Minor membrane perforations during procedure occurred in 31 people and 2 got postoperative maxillary sinus infection. The 4 year overall survival rate of 1 204 implants was 97.26%, with four implants fell off after 3 months of rehabilitation and one implant occurred after one year of rehabilitation. Conclusions: The regular transalveolar sinus lift technique is easier and time saving, but the compromised lifting range in maxillary sinus floor height and the comparatively high occurrence of intraoperative membrane perforations should be concerned. Using CAS KIT could be an alternative method to perform maxillary sinus augmentation with a reduced incidence of complications. There was no statistically difference in implant failure rates and incidence of postoperative maxillary sinus infection between two groups. PMID- 30522206 TI - [Endoscopy-assisted transoral removal of deep hilar and intraparenchymal stones in the Wharton's duct]. AB - Objective: To investigate the different surgical approaches and long-term outcomes of endoscopy-assisted transoral removal of deep hilar and intraparenchymal stones in the Wharton's duct. Methods: From January 2008 to March 2018, 481 consecutive patients with deep hilar and intraparenchymal calculi in the Wharton's duct underwent endoscopy-assisted transoral removal at Deparment of Oral and Maxillofacial Radiology, Peking University School and Hospital of Stomatology. There were 250 males and 231 females. Their ages ranged from 9-86 years. We operated 476 patients under local anesthesia on an outpatient basis, and the remaining 5 were operated under general anesthesia. On the basis of ultrasonography, spiral CT, sialography and endoscopy, the calculi were classified into 4 types: hilum stones (located at the hilum or proximally with a distance <5 mm from the hilum), infra-hilum stones (intra-glandular stones with a distance of 5-10 mm from the hilum), intraparenchymal stones (with a distance >=10 mm from the hilum), and multiple stones (concomitant hilum and intra glandular stones). The treatment approaches included: hilum duct slitting, intraparenchymal duct slitting, submandibulotomy and intraductal retrieval. The success rate, immediate safety and effectiveness of different types of stones were evaluated. After surgery, the patients were followed up, and gland function was analyzed on the basis of clinical symptoms and signs. Results: The calculi sizes varied from 3 to 25 mm, with a mean of 7.8 mm. The calculi were located in the right submandibular gland in 259 patients, in the left submandibular gland in 219 patients and in bilateral glands in 3 patients. The calculi were successfully removed in 446 glands, with a success rate of 92.1% (446/484). The success rate varied according to the stone sites: 97.8% (363/371) for hilum stones, 64.4% (29/45) for infra-hilum stones, 4/16 for intraparenchymal stones and 96.2% (50/52) for multiple stones. The main treatment methods applied included hilum duct slitting in 347 glands, intraparenchymal duct slitting in 13, submandibulotomy in 4, intraductal retrieval in 73, and hilum duct slitting accompanied by intraductal retrieval in 9. Ductal breakage occurred in 2 glands. All patients complained of mild to moderate pain with a duration of 3-7 days. Nine had temporal lingual nerve injury. During 3-120 months' follow-up (mean 36 months) of the total 484 glands, 1.6% (7/446) developed ranula, 1.3% (6/446) experienced obturation of the main duct and 2.0% (9/446) had recurrent stones. The remaining 95.1% (424/446) glands were symptom-free with good function. Conclusions: Endoscopy-assisted transoral removal of deep hilar and intraparenchymal submandibular calculi is a safe and effective gland-preserving procedure. According to the depth, size and number of the calculi, variant surgical approaches should be attempted to maximize the success rate and to minimize the side effects. PMID- 30522207 TI - [Bone remodeling in patients with juvenile condylar resorption after stabilization splint treatment]. AB - Objective: To investigate bone remodeling in patients with different types of juvenile condylar resorption after stabilization splint treatment using cone-beam CT (CBCT). Methods: Fifty-nine juvenile condylar resorption patients (114 sides of condyle) treated with stabilization splint from January 2012 to May 2018 in Department of Temporomandibular Joint, Stomatological Hospital of Chongqing Medical University were selected as splint group, while twenty-four patients (48 sides of condyle) who underwent natural remodeling without stabilization splint treatment after 6-12 months were severed as control group. Pre-and post-treatment CBCT was taken for all patients. There were three types of condyles (including type I, type II and type III) before treatment and four types of condyles (including progression, no changes, stable without new bone and remodeled with new bone) after treatment. Progression and no change were considered as poor curative effect, and stable without new bone and remodeled with new bone were considered to be effective. The vertical distance of the condylar height was measured and compared before and after treatment in the two groups. Results: Significant difference in treatment outcome was found in types I and II between the splint group and the control group (Z=-2.874, P=0.004; Z=-3.874, P=0.000), and no significant difference was found in type III between the two groups (Z= 0.617, P=0.537). The difference of condylar progression percentage [splint group: 43% (15/35), control group: 80% (16/20)] was statistically significant between the two groups in type II (chi(2)=7.139, P=0.011), and no significant difference was found in types I and III between the two groups (chi(2)=0.103, P=0.748; chi(2)=1.249, P=0.540). In two groups, the condylar height difference before and after treatment in type II condylar resorption was statistically significant (P<0.05). Conclusions: Stabilization splint treatment was effective in patients with different types of juvenile condylar resorption, especially in type I. However, it was difficult to reverse the height reduction of the condylar bone regardless of treatment. PMID- 30522208 TI - [Lingual orthodontic treatment with mini-implant-aided distalization of maxillary and mandibular dentitions]. PMID- 30522209 TI - [Miniscrew-assisted total arch distalization]. PMID- 30522210 TI - [Functional reconstruction of serious anterior maxillary and mandibular defect]. PMID- 30522211 TI - [Research progress in maxillary sinus mucosal disease associated with maxillary sinus floor lifting]. AB - Maxillary sinus augmentation is an effective procedure to gain bone height for implant placement in an atrophic posterior maxilla. But maxillary sinus diseases are prevalent in patients scheduled for sinus lift procedures. The presence of these diseases may increase the difficulties in performing the surgery and the risk of developing postoperative complications. This paper summarizes and introduces the common maxillary sinus mucosa diseases related to maxillary sinus augmentation. PMID- 30522212 TI - [Research progress in the application of implantoplasty in the treatment of peri implantitis]. AB - Peri-implantitis is a kind of serious complication after tooth implantation. The absorption of alveolar bone lead to the exposure of rough implant surface, which would result in poor long-term therapeutic effect. Implantoplasty promises a better long-term therapeutic effect than bone augmentation technique. This article will introduce implantoplasty from two aspects: therapeutic effect and its influencing factor, safety and effectiveness. PMID- 30522213 TI - [New insight of craniofacial and oral findings of the RASopathies]. AB - The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), NS with multiple lentigines (NSML), neu-rofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1 like syndrome (NFLS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the crani-ofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. PMID- 30522214 TI - [Application of intraoperative CT in oral and maxillofacial surgery]. AB - With the introduction of the concept of precision surgery and the development of modern compound operating rooms, intraoperative computerized tomography (ICT) came into being. Due to the multidisciplinary nature of ICT, its use in oral and maxillofacial surgery has also been increasing in recent years. This article describes the application of ICT in oral and maxillofacial trauma, orthognathic surgery, and craniofacial tumor treatment, and analyzes its advantages and limitations. PMID- 30522215 TI - [Thought and perspectives of environment and human health]. PMID- 30522216 TI - [Progress and challenge of HIV prevention in China]. PMID- 30522217 TI - [Strategy of expanded HIV testing in the era of antiretroviral therapy]. PMID- 30522218 TI - [The association between the characteristics of egocentric network and HIV prevalence among men who have sex with men]. AB - Objective: This study aimed to analyze the association between the characteristics of egocentric network and HIV prevalence among men who have sex with men (MSM) through social network analysis. Methods: The study was conducted in Guangzhou city from November 2016 to June 2017 using convenient sampling method. Participants were recruited from 13 voluntary counseling and testing (VCT) locations. Data were collected by using nomination generation and nomination interpretation methods. Questionnaire includes two parts, the first part about the social tie, and the second one about social demography and behavioral characteristics of respondents and their nominees. The multivariate logistic regression was applied to quantify the association. Results: 8.67%(93/1 073) HIV antibody positive MSM had been detected in 1 073 respondents who nominated 4 301 partners in total. Compared to egocentric sexual network with a size of 1-2, the size of sexual network larger than 3 (OR=1.68, 95%CI: 1.07-2.65) were associated with HIV infection. Compared to egocentric risk sexual network with a size of 1-2, the size of risk sexual networks larger than 3 (OR=1.87, 95%CI: 1.06-3.31) were associated with HIV infection. There were no significant association between marital similarity of respondents and their nominees, the type of the relationship of sexual partners and HIV prevalence (P>0.05). Conclusion: The composition of social network in MSM is related to their susceptibility of HIV infection. MSM population with a large sexual network is more susceptible to HIV infection. PMID- 30522219 TI - [Risk of HIV infection and its factors among men who have sex with men: a geosocial networking application-based survey in Beijing of China, 2017]. AB - Objective: To assess risk of HIV infection and its risk factors among men who have sex with men (MSM) in Beijing, China. Methods: We conducted a cross sectional online survey in October, 2017. Inclusion criteria of participants were: aged 18 year or more; resided in Beijing; conducted homosexual activities in past six months; self-reported HIV status as negative or unclear. Demographic information, HIV test history, social media use, and high-risk sexual behaviors were collected by a self-reporting questionnaire, and a HIV risk assessment tool was used to assess HIV risk of MSM, 5 388 particpants were finally enrolled in the study. Logistic regression model was used to analyze factors associated with risk of HIV infection. Results: Of the total 5 388 participants, most were 18-29 years old (64.35%), and the proportion of medium and high HIV risk score was 40.36%. The odds of medium and high HIV risk score among MSM who logged onto the app 1-20 times per week and>20 times per week were higher comparing with those who logged onto the app<1 time per week (OR=1.22, 95%CI: 1.02-1.46; OR=1.69, 95%CI: 1.38-2.06, respectively); MSM who completed college or higher education had lower probability of medium and high HIV infection risk, comparing with those who only had high school education level (OR=1.25, 95%CI:1.09-1.43) or junior or below education level (OR: 1.27, 95%CI: 1.05-1.53); MSM who did not conduct HIV test in past year had lower risk of medium and high HIV infection risk comparing with MSM who conducted HIV test in past year (OR=0.87, 95%CI: 0.77-0.99), and those who reported their HIV infection status unclear had higher probability of medium and high HIV infection risk than MSM who reported their HIV infection status negative (OR: 1.63, 95%CI: 1.44-1.86). Conclusion: The proportion of MSM who were in medium and high HIV infection risk score was high in Beijing. Lower level of education, high frequency of social media use, conducted HIV test in past year, and unclear of their own HIV infection status were associated with medium and high level of HIV infection risk. PMID- 30522220 TI - [Analysis on influencing factors of unprotected sexual behavior among men who have sex with men based on structural equation model]. AB - Objective: To analyze the influencing factors and mechanism for unprotected sexual behavior of men who have sex with men (MSM) in China. Methods: MSM who are more than 16 years old and have had homosexual sexual behaviors in recent years were recruited from five cities (Tianjin, Harbin, Nanjing, Chongqing and Xi'an) with active MSM population during 2013-2014 through network, site recruitment and peer recommendation using convenient sampling method. 3 519 subjects were included in this study. The sexual behavior related information of MSM in five cities was investigated using questionnaires. The confirmatory factor analysis was used to construct the measurement model by using the robust estimation method based on the weighted least square method to estimate parameters, and the final model was determined through evaluation and modification. Results: A total of 3 519 subjects were (29.9+/-8.76) years old, with a clear sexual orientation of 3 223 (91.6%), and 2 287 (65.0%) were aware of free HIV/AIDS treatment policies. The proportion of using condom last time was 77.2% (n=2 718), and the proportion of using condom every time was 36.9% (n=1 299) and 43.2% (n=1 521) respectively for the past six months with fixed and temporary partners. Structural equation model provided a good fit, the root mean square error of approximation, comparative fit index and non-normed fit index was 0.07, 0.97, 0.95, respectively. Knowing AIDS knowledge, educational level and sexual orientation had direct effects on unprotected sexual behavior, and the path coefficients were 0.179,-0.049 and -0.159, respectively. While the role of interventions was indirect, the path coefficient was 0.147. Conclusion: Lower education and unclear sexual orientation are disadvantages for reducing unprotected sexual behavior. Interventions mainly affect the unprotected sexual behavior by improving the level of HIV/AIDS knowledge. Increasing the comprehensive knowledge of MSM through intervention should be highly valued. PMID- 30522221 TI - [Qualitative research on factors of HIV testing among men who have sex with men in China based on Blued]. AB - Objective: To understand the cognition and attitudes of men who have sex with men (MSM) towards HIV testing and explore in-depth reasons preventing them from testing. Methods: The function of "opinion" in Blued, a gay geo-social networking application (GSN), was adopted to collect qualitative data of ideas and attitudes towards HIV testing of the users between December 2017 and January 2018. The data was analyzed based on grounded theory approach. Results: 28 269 Blued users participated in the activity and 1 977 posted comments. Four key themes were identified, i.e. no/low risk of contracting HIV, stigmatization of HIV testing, long-term relationship and conventional impediments of HIV testing. Conclusion: The cognition and attitudes of the target population derived from the analysis of "opinion" function in Blued, such as the stigmatization of the behavior of HIV testing influencing the attitude of HIV testing, could help researchers build a more accurate detection and promotion strategy instead of a very general intervention on the public. PMID- 30522222 TI - [Qualitative study on unprotected sexual behaviors among male students who have sex with men in Beijing]. AB - Objective: To investigate the related factors of unprotected sexual behaviors among male students who have sex with men in Beijing. Methods: Male students who have sex with men were recruited from May 2018 to July 2018 at two voluntary counseling and testing (VCT) clinics in Beijing by convenient sampling method. Information being collected during in-depth personal interviews with a semi structured outline included ways to seek sexual partners, sexual partners characteristics, attitude of condom use, incidence and causes of unprotected sexual behaviors, rush poppers and alcohol use. The text information was summarized and analyzed by Nvivo 11.0 software. Results: A total of 35 male students who have sex with men were recruited and interviewed, the median of age was 22 years old (P(25)-P(75): 21-24 years old). We found that incomprehensive knowledge of condom use, low risk perception of non-anal sexual behaviors, rush poppers and alcohol use were risk factors of unprotected sexual behaviors on individual level. Besides, sex with regular sex partners, partners who were much older or not from campus, and insertive partners are more likely to be unprotected. Furthermore, refusal of condom use by sexual partners and low self efficacy of decision-making on condom use were the main reasons for unprotected sexual behaviors among male student who have sex with men. Conclusion: Lack of condom use knowledge, low risk perception of non-anal sexual behaviors and insufficient ability to refuse non-condom requirements for regular sex partners, partners who were much older or not from campus, and insertive partners are related factors of unprotected sexual behaviors among male students who have sex with men. PMID- 30522223 TI - [HIV and syphilis infection and related medical treatment status of low-fee female sex workers in three provinces of China, 2012-2015]. AB - Objective: To understand the HIV and syphilis infection and related treatment status of low-fee female sex workers (FSWs) in 3 provinces of China. Methods: Four cross-sectional survey data of low-fee FSWs from six cities (counties) in Guangxi, Yunnan and Hunan Province between October 2012 and July 2015 were obtained from the national science and technology major special project intervention study for reducing sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS) in low-fee FSWs' database, which included social demographic characteristics, sexual service characteristics and related medical care seeking behaviors, etc. A total of 2 050 subjects were included in the database. Results: The age of the subjects was (35.16+/-9.76) years old, with a minimum age of 15 and a maximum age of 67. Those who use condoms every time in commercial sex accounted for 58.9% (n=1 206). Among the reasons of not using condom, the proportion of client reluctant to use was the highest (81.0% (n=682)). Only 38.1% (n=782) was tested for HIV in the last six months. HIV confirmed positive rate was 6.8% (n=139), previous positive accounts for 76.3% (n=106). Rate of antiviral therapy was 55.4% (n=77). By the end of 2015, the loss rate of antivirus treatment was 18.2% (n=14). Those who self-reported symptoms of sexually transmitted diseases in the last 6 months accounted for 9.4% (n=191). 50.3% (n=96) of reporters chose to go to formal hospitals, 23.0% (n=44) chose to go to private clinics and 20.4% (n=39) chose their own medication. The syphilis infection rate was 13.5% (n=277), among them, 91.3% (n=253) were asymptomatic. Conclusion: Among low-fee FSWs, the rates of HIV and syphilis infection are higher, the condom consistent use rate, HIV antibodies and syphilis test rate are lower. In this group, active seeking medical idea is poor, the rate of anti-virus treatment and the rate of seeking medical treatment in formal medical institutions is low. PMID- 30522224 TI - [Estimating HIV incidence among female sex workers and injection drug users in Dehong Prefecture, 2009-2017]. AB - Objective: To obtain HIV incidence among injection drug users (IDU) and female sex workers (FSW) in Dehong Prefecture, Yunnan Province during 2009-2017. Methods: We recruited drug users and female sex workers from all sentinel surveillance sites across Dehong Prefecture during 2009-2017. A total of 10 480 IDU and 18 126 FSW in Dehong Prefecture were recruited by fingerprint technique. Data about drug uses, commercial sexual behavior, sociodemographic characteristics was collected by structured questionnaire. HIV-positive patients who were long-term infected or with CD4(+) T cell count was <=200 were not included for further HIV incidence testing. Also, those who self-identified as on antiretroviral treatment (ART) or AIDS cases were also excluded. A total of 841 and 157 plasma specimens from IDU and FSW that met the inclusion criterion were finally included, respectively. Limiting antigen avidity enzyme immunoassay(LAg Avidity EIA) were performed to calculate the HIV incidence among these two sub populations. Results: A total of 3 444 IDU were HIV-positive, among which 884 (25.7%) were Burmese with age of (30.4+/-7.7), and 2 560 were Chinese with age of (36.6+/-7.3). Among 228 HIV-positive FSW, 109 (47.8%) were Burmese with age of (27.1+/-6.3), 119 (52.5%) were Chinese with age of (29.9+/-11.1). For IDU, the estimated HIV incidence among Burmese in 2009-2010, 2011-2012, 2013-2014, 2015 2017 was 4.20% (95%CI: -0.55%-8.95%), 7.75% (95%CI: 2.95%-12.55%), 11.79% (95%CI: 5.38%-18.20%), 10.30% (95%CI: 5.67%-14.94%), respectively, while Chinese were 3.11% (95%CI: 1.59%-4.64%), 0.03% (95%CI: -0.03%-0.08%), 1.55% (95%CI: 0.54% 2.57%), 0.58% (95%CI: -0.06%-1.04%), respectively. In 2009-2011, 2012-2014, 2015 2017, estimated HIV incidence among Burmese FSW was 0.22% (95%CI: -0.21%-0.64%), 1.24%(95%CI: 0.15%-2.32%), 0.55%(95%CI: 0.01%-1.08%). Whereas, estimated HIV incidence among Chinese FSW was 0.62% (95%CI: 0.25%-0.98%), 0.11% (95%CI: -0.04% 0.26%), 0.22% (95%CI: 0-0.44%). Conclusion: HIV incidences among Chinese IDU and FSW are on the downward trend, while Burmese IDU and FSW seem to be gaining momentum. PMID- 30522225 TI - [Analysis on late HIV diagnosis among newly reported human immunodeficiency virus/acquired immunodeficiency syndrome cases between 2009 and 2017 in medical institutions]. AB - Objective: To analyze the proportion of late HIV diagnosis and the factors associated with late HIV diagnosis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) cases newly reported by medical institutions in China from 2009 to 2017. Methods: Data of adult HIV/AIDS cases newly reported by medical institutions in China from 2009 to 2017 were downloaded from the AIDS prevention and control information system of China's disease prevention and control information system. The basic information, sample source, transmission route, flow of HIV/AIDS patients and the first CD4(+) T lymphocyte count were analyzed in 293 187 cases who had been tested for CD4(+) T lymphocyte count within 91 days of diagnosis. The multivariate logistic regression was used to analyze the late HIV diagnosis relevant factors. Results: A total of 293 187 newly reported HIV/AIDS cases in medical institutions were analyzed, and the mean age was (44.7+/-15.6) years. The proportion of late diagnosis in all cases was 68.4% (200 503 cases). From 2009 to 2017, the proportions of late diagnosis were 71.7% (6 263/8 737), 69.5% (8 283/11 917), 69.2% (13 230/19 116), 67.0% (17 186/25 669), 66.5% (21 833/32 834), 66.4% (26 541/39 944), 67.2% (31 257/46 536), 69.6% (35 920/51 646) and 70.4% (39 990/56 789) respectively. Compare with female cases, the OR (95%CI) of male cases with late diagnosis was 1.18 (1.15-1.20). Compared with the 18 to 29 years old group, the 30 to 39 years, 40 to 49 years, 50 to 59 years and 60 years old and over groups have higher risk of late diagnosis with OR (95%CI) values about 1.65 (1.61-1.69), 2.13 (2.08-2.19), 2.25 (2.18-2.31) and 2.33 (2.26-2.39) respectively. Compared with the college education level and above group, OR (95% CI) values of junior middle school and below group was 1.11 (1.08-1.14); and OR (95%CI) values of senior high school and equal level education group was 1.08 (1.04-1.11). Compared with the migrant population, the resident population has higher risk of late diagnosis (OR=1.06, 95%CI: 1.04-1.08). Compared with other national minorities, Han nationality has higher risk of late diagnosis (OR=1.33, 95%CI: 1.30-1.36). Compared with divorce, widowed and other marital status, married spouse have higher risk of late diagnosis (OR=1.08, 95%CI: 1.06-1.10). Compared with patients receiving other testing services, the OR (95%CI) values of examination before blood transfusion or blood products, pregnancy and childbirth examination, STD clinic and preoperative examination were 1.16 (1.08-1.25), 0.52 (0.50-0.54), 0.63 (0.61 0.64), 0.66 (0.65-0.68) respectively. Conclusion: The proportion of late HIV diagnosis of newly reported HIV/AIDS cases in medical institutions in China was relatively high from 2009 to 2017 and the factors associated with late HIV diagnosis included male, Han nationality, old age group, low educational level, married spouse, other testing services and resident population. PMID- 30522226 TI - [Initial follow-up and CD(4)(+) T cell count test of newly reported students HIV cases in China, 2013-2017]. AB - Objective: To analyze first follow-up and CD(4)(+) T (CD(4)) cell count test of newly reported students HIV cases in China from 2013 to 2017. Methods: Data were collected from both Case Reporting Cards and Follow-up Cards from China Information System for HIV/AIDS Control and Prevention between 1(s)t January 2013 and 31(st) December 2017. The inclusion criteria are 15-24 years old students who were newly diagnosed with HIV infection. Logistic regression model was used to analyze relevant factors of the first CD(4) test results less than 200 CD(4) cells/MUl. Results: There were 12 037 newly diagnosed students HIV cases from 2013 to 2017. Most cases were male (97.7%), 19-22 years old (65.1%) and Han ethnicity (90.5%). At the time of diagnosis, the route of HIV infection was most frequently homosexual contact (82.2%). The majority of cases (46.9%) were diagnosed at HIV voluntary counseling and testing (VCT) location. About 2 465 (20.6%) students had unprotected intercourse in the past 3 months, of which 1 387 (56.8%) had 1 sexual partner, 610 (25.0%) with 2 sexual partners, 273 (11.2%) with 3 partners and 170 (7.0%) with more than 4 partners. 11.0% and 28.9% of cases had initial CD(4) counts less than 200 cells/MUl and 200-349 cells/MUl. Compared to the male, younger than 18 years old and diagnosed at VCT location, female (OR=2.09, 95%CI: 1.51-2.89), aged 21 to 22 years (OR=1.25, 95%CI: 1.06 1.47), diagnosed in hospital settings (OR=2.20, 95%CI: 1.89-2.57) and preoperative testing (OR=1.36, 95%CI: 1.07-1.73) had greater proportion of the first CD(4) test result less than 200 CD(4) cells/MUl. Conclusion: The number of newly diagnosed students HIV cases significantly increased in past 5 years, and the proportion of late diagnosis was high. Female, aged 21 to 22 years, diagnosed in hospital settings and preoperative testing were related to the first CD(4) test result less than 200 CD(4) cells/MUl. PMID- 30522227 TI - [Confirmatory process and follow-up of 1 case with long-term HIV infection in Shandong]. AB - Objective: To describe the confirmation process and long-term follow-up results of 1 case of HIV with long term progression. Methods: The subject was a HIV infected man aged 27 years old. The first HIV antibody positive was detected by ELISA in August 7(th), 2013. Close contacts were identified as 3 homosexual partners who had been contacted before infection and the first sexual partner had been unable to get in touch. Adopting the first epidemiological survey questionnaire of AIDS comprehensive prevention and control information system in China, the investigators conducted face-to-face surveys on the general demographic characteristics and behavioral characteristics of the subject. After the first ELISA test result was positive, 4 rapid detections of colloid selenium, ELISA, western-blot, CD4(+)T and viral load test were followed up (August 14(th), 21(st), 30(th) and September 16(th), 2013). Long term follow-up was performed to detect CD4(+)T and viral load to observe the progress of the case after the diagnosis of infection. Results: The duration of sexual behavior was from 2011 to 2012 between the subject and his 1(st) sexual partner. During the study, repeated HIV antibody ELISA test results were negative. Sexual behavior maintained from January to April 2013 between the subject and his 2(nd) partner and the last one unprotected homosexual acts took place in April 2013. After the traceability survey, the 2(nd) sexual partner was an AIDS patient who had antiretroviral therapy in the anti HIV treatment module of AIDS comprehensive prevention information system. The subject and his 3(rd) partner maintained their sexual behavior from May to October 2013. The two ELISA tests of the 3(rd) partner were negative. Because of the need for hospital operation in August 7, 2013, the subject was tested for HIV antibody by ELISA and the result was positive while western blot test showed that the HIV-1 antibody was not confirmed (band type was gp160/gp120/p24). In the subsequent follow-up, 4 rapid detections of colloid selenium, ELISA and western-blot were conducted and all the results were positive (western-blot band type was gp160/gp120/gp41/p24/p17). Results of continuous follow-up for 5 years showed that the first four CD4(+)T cell counts were as follows: 520, 616, 834, 879. The following 22 CD4(+)T counts sustained at a high level and the median was 895 cells/MUl. A total of 5 follow-up visits were conducted to detect viral load exceeding 1 000 copies/ml and the remaining 19 test results were lower than 1 000 copies/ml except that no viral load was detected in 2 follow-up visits. The result of homology analysis showed that the HIV types of the case and its 2(nd) sexual partner were all HIV-1 CRF_01AE. The similarity of gag region gene was 97.5%. So we inferred that the 2(nd) sexual partner was its source of infection, and the case was infected at the end of April 2013 with the last unprotected homosexual behavior. Conclusion: The infected person was found to be an early HIV infection. Continuous follow-up test results indicated that the case belonged to a HIV long-term nonprogressor. PMID- 30522228 TI - [Spatial-temporal analysis on the human immunodeficiency virus/acquired immunodeficiency syndrome among permanent residence and migrants in Shanghai, 2005-2015]. AB - Objective: To describe the spatial and temporal characteristics of human immunodeficiency virus/acquired immunodeficiency syndrome(HIV/AIDS) in permanent residents and migrants in Shanghai during 2005 to 2015 and provide suggestions for the HIV/AIDS prevention. Methods: The data of HIV/AIDS was collected from the National HIV/AIDS Comprehensive Information Management System based on report date. The population data was collected from the statistical yearbook of Shanghai. Spatial analysis was conducted using the hotspots model in ArcGIS. SaTScan software was employed to determine the distribution of HIV clusters in space, time or both. Results: During 2005 to 2015, a total of 13 498 cases of HIV/AIDS were reported in Shanghai. The prevalence of HIV increased from 0.025/10(5) (450 cases) to 0.093/10(5) (2 236 cases). The prevalence of AIDS increased from 0.002/10(5) (32 cases) to 0.028/10(5) (683 cases). Hotspot analysis showed that the hot spot of incidence of migrants had moved from Hongkou (2005) (Z=2.96, P=0.003) to Changning (2006-2015) (all Z>1.96, P<0.05); whereas the hot spot of incidence of permanent residents had moving from Jinshan (2005 2007) (all Z>2.58, P<0.01) to downtown area (2006-2015) (all Z>1.96, P<0.05). The spatial high clusters of HIV and AIDS were same, including Huangpu, Xuhui, Changning, Jingan, Putuo, Hongkou and Yangpu; The temporal high clusters of HIV cases among permanent residents were 2011 to 2015, and the spatial clusters were Huangpu, Xuhui, Changning, Jingan. The temporal high clusters of HIV cases among migrants were 2014 to 2015, and the spatial clusters was Xuhui, Changning, Jingan. Conclusion: The total HIV/AIDS incidence in Shanghai was clustered in downtown area. The cluster of the incidence of the permanent residents had moving towards that of migrants, indicating the cluster area deserves a close surveillance. PMID- 30522229 TI - [Epidemiological characteristics and latent class analysis of non-marital heterosexual behaviors among human immunodeficiency virus/acquired immunodeficiency syndrome individuals in Jiangmen, Guangdong province between 2015 and 2017]. AB - Objective: To study the epidemiological characteristics and latent classes of non marital heterosexual transmission among human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) individuals in Jiangmen, Guangdong province between 2015 and 2017. Methods: HIV/AIDS cases from Chinese HIV/AIDS Comprehensive Response Information Management System were collected from January 1, 2015 to December 31, 2017. Inclusion criteria of HIV/AIDS were heterosexual transmission, non-marital heterosexual contact and older than 15 years. Exclusion criteria were homosexual contact, repeated reports, injecting drugs, current address in the non-Jiangmen area and not classified non-marital heterosexual contact. A total of 665 HIV/AIDS cases were included in this study. The general demographic characteristics (gender, age, ethnicity, education, occupation, etc.), floating population characteristics, HIV high-risk behaviors, HIV testing and other information were collected from database. Chi square test was used to compare the infection status of HIV/AIDS with different characteristics through commercial channels, and the latent class model was used to analyze the latent classes of HIV/AIDS. Results: Among 665 cases, the age was (48.73+/-15.61) years old. And 46.5% (309/665) cases were married and 73.8% (491/665) were male. Four classes were identified as heterogeneous sub-population by the latent class analysis: the first class occupied 40.13% (267 cases) with feature of nearly equal proportion of males and females and higher proportion of non-service industry workers; the second class occupied 37.40% (248 cases) with features of more than 46 years old, nearly all males, high proportion of farmers, high proportion of marital status, low education and the low propensity of floating; the third class occupied 11.90% (79 cases) with feature of cases from voluntary HIV testing and counseling in center for disease control and prevention; the forth class occupied 10.57% (70 cases) with the feature of less 45 years old, high proportion of service industry workers, no marital history and higher education. Conclusions: HIV/AIDS transmitted by non-marital heterosexual sex in Jiangmen city during 2015-2017 could be divided into four latent classes according to epidemic characteristics, which could provide appropriate classified guidance for AIDS prevention and treatment. PMID- 30522230 TI - [The effect of nutrition intervention on the body composition and blood glucose in newly diagnosed patients with type 2 diabetes mellitus complicated with overweight and obesity]. AB - Objective: To study the effect of nutrition intervention on the body composition and blood glucose in newly diagnosed patients with type 2 diabetes mellitus complicated with overweight and obesity. Methods: A total of 84 newly diagnosed patients with type 2 diabetes mellitus complicated with overweight and obesity were selected from the department of endocrinology in China-Japan Friendship Hospital from April 2015 to December 2016. Basic information and body composition of these patients were collected and measured. Also the food frequency questionnaire (FFQ) was used to investigate the dietary status in the past month, and calculate the intake of energy, three major nutrients and dietary fiber. All patients received nutrition intervention by nutritionist for three months as requested by Diabetes guidelines. After 3-month intervention, blood glucose, body composition and dietary status were examined again. Relevant indicators of patients were compared before and after the intervention. All patients were divided into three groups according to the degree of body mass index (BMI)'s change: <5%, 5%-10% and >10%. The differences of body weight, muscle, body fat rate, visceral fat index and blood glucose level among three groups were quantified. Results: There were 53 male patients with age (41.5+/-8.9) years and HbA1c (7.5+/-0.4)%, and 31 female patients with age (40.1+/-8.5) years with HbA1c (7.6+/-0.5)%. The intake of energy, carbohydrate and fat of patients were significantly decreased (P<0.05) and dietary fiber was significantly increased (P<0.05) after nutrition intervention. The body weight, muscle mass, fat mass and visceral fat index were also significantly decreased (P<0.05). The average decrease of fat was about 2.8 kg accounting for 73.7% (2.8 kg/3.8 kg) of the total weight loss. The body fat rate decreased from (31.2+/-3.1)% to (28.8+/ 3.2)% (P<0.05). The fasting blood glucose and postprandial blood glucose were both decreased significantly after intervention (P<0.05). Among three BMI decreased groups, there was no significant difference in body weight and muscle mass (P>0.05), but a significant difference in body fat rate and visceral fat index (P<0.05). The body fat rate, visceral fat index, fasting blood glucose and postprandial blood glucose had more decreases with the greater amount of weight loss (P<0.05). Conclusion: The three-month nutrition intervention could change the dietary habit and components of patients with type 2 diabetes mellitus by reducing the blood glucose, body fat rate and visceral fat index significantly. The degree of reduced BMI is positively related to the decrease of fasting blood glucose and postprandial blood glucose. PMID- 30522231 TI - [Study on direct economic burden and influencing factors in patients with cervical cancer and precancerous lesions]. AB - Objective: To account the direct cost of uterine cervix carcinoma treatment in China and to explore the related factors which influence the direct financial burden of the disease. Methods: Data was collected through the medical record system and telephone interviews in 14 county-level hospitals and 9 provincial and municipal hospitals from 14 provinces/municipalities enrolled in the Chinese National Health Industry Research Project in 2015. The direct financial burden of uterine cervix carcinoma treatment consisted of the direct medical cost and the direct non-medical cost of treatment in different pathological cervical cancer stages and precancerous lesions. Multiple liner regression method was used to analyze the factors affecting the costs. Results: The age of the 3 246 patients was (46.40+/-10.43) years, including 2 423 patients from provincial and municipal hospitals and 823 patients from county-level hospitals. The direct financial burden for one patient of pathological uterine cervix carcinoma stage or precancerous lesion ranged from 10 156.3 yuan to 75 716.4 yuan in provincial and municipal hospitals, and for patients from county-level hospitals, the cost was between 4 927.9 yuan and 47 524.8 yuan per person. There was a wide gap between the direct financial burden of patients in different disease stages. The direct financial burden of patients with precancerous lesions ranged from 4 927.9 yuan per person to 11 243.0 yuan per person, as for patients of pathological uterine cervix carcinoma stages, the direct financial burden was between 29 274.6 yuan and 75 716.4 yuan per person. The factors which influence direct financial burden would include: the levels of the hospital, pathological period, medicare reimbursement, days of treatment, and the methods of treatment (P<0.001). Conclusion: The direct financial burden of diseases in patients with pathological uterine cervix carcinoma stage or precancerous lesion differed in different levels of hospital and pathological periods. In addition, medicare reimbursement, days of treatment, and the methods of treatment all had impact on it. PMID- 30522232 TI - [Status and associated factors of rush poppers use among newly-diagnosed HIV positive men who have sex with men in Wuhan, 2016]. PMID- 30522233 TI - [Analysis on use of rush poppers and its related factors among men who have sex with men in city and county level of Mianyang]. PMID- 30522234 TI - [Investigation of risk behaviors on AIDS between foreign female sex workers in Yunnan border, 2015]. PMID- 30522235 TI - [A prospective cohort study to explore retention rate and behavior change among medium-to-low-tier female sex workers in Yuanzhou district, Yichun city]. PMID- 30522236 TI - [Primary drug resistance among newly reported HIV infections in Dehong Prefecture of Yunnan province, 2016]. PMID- 30522237 TI - [Epidemic characteristics on incidence and mortality of stroke of Tianjin residents from 2007 to 2015]. PMID- 30522238 TI - [Empirical validity study of rating scale on job competency for preventive medicine undergraduate]. PMID- 30522239 TI - [Epidemiologic characteristics and strategies on prevention and control of sexually transmitted human immunodeficiency virus/acquired immunodeficiency syndrome in China]. AB - At present, sexual route is the main transmission route of AIDS in China, and its role in the process of AIDS epidemic has been evolving. Various modes of transmission in sexual transmission and the prevention and control strategies adopted by China have also been changing. This paper mainly summarizes the epidemic characteristics of different periods and different modes of transmission of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) in China in recent years. The strategies of prevention and control were described from seven aspects, including health education, promotion of condom use, expanded testing, HIV/AIDS antiviral treatment, pre-exposure prophylactic medication, post exposure prophylactic medication, social organization participation and sexually transmitted diseases prevention and control. Only when innovative and targeted measures according to the evolution of the HIV/AIDS epidemic and various specific methods are complemented by each other, can the transmission of HIV/AIDS through sexual route be effectively prevented and controlled. PMID- 30522240 TI - [Review on methods in the disease burden assessment attributable to household air pollution]. AB - In the past decades, people's work and life styles have dramatically changed during the rapid economic development and urbanization in China. A national survey reported that Chinese adults spend an average of 81% of daily time in indoor environment. Exposure to indoor air pollution plays key roles for human health but is likely to be neglected due on the relatively lower concentration levels and lower awareness among common people. Till now, published studies focus more on the pollution levels or the toxicological effects of indoor air pollutants but there is a lack of disease burden assessment attributable to indoor air pollution. In this review, several international studies were introduced on the disease burden estimation attributable to indoor air pollution, as well as the estimation methods. The current situation of national study was also reviewed. The strengths and limitations of the representative international studies were discussed. This review is helpful in providing data to guide the research on disease burden assessment attributable to indoor air pollution in China, and further helps to prioritize the indoor air pollution control based on disease burden ranking among pollutants and motivate public policies to protect the public health. PMID- 30522241 TI - Correction. PMID- 30522242 TI - Correction. PMID- 30522243 TI - Correction. PMID- 30522244 TI - Correction. PMID- 30522245 TI - Correction. PMID- 30522246 TI - Effect of a Simulation of 241Am Deposition Pattern in the Leg Bones on the Detection Efficiency of a High Purity Germanium Detector. AB - A computational model using an MCNPX version 2.6.0 code and a leg voxel phantom was previously constructed and validated against the in vivo measurements of the United States Transuranium and Uranium Registries (USTUR) case 0846 leg. Using the MCNPX model, different simulation scenarios of Am distribution in the bones and tissue material of a leg were performed, and their effects on the detection efficiency and activity calculation were examined. The purpose of this work is to ensure and increase the simulation sensitivity of real contaminated human bones and reduce the simulated efficiency error associated with the distribution of Am activity within the leg bones when using a high purity germanium [HP(Ge)] detector. The results showed that the simulated detection efficiency obtained from the uniform distribution of Am in the leg bones was underestimated by a factor of up to 0.3 compared with the measured and simulated detection efficiency obtained from the non-uniform distribution of Am in different sections of the leg bones. The p-value of a one-way analysis of variance (ANOVA) F-test among the mean values of the simulated detection efficiencies was calculated and provided evidence of a significant difference. The uncertainty in the bone activity estimate could be quite large (25% to 30%) if calibration of detection efficiency is based on assuming a uniform distribution of Am in the phantom to estimate the USTUR case 0846 leg activity. It is therefore recommended that during calibration of detectors, a non-uniform distribution of Am in different sections of the bones should be used rather than a uniform distribution. Additionally, an assumption of a uniform distribution of Am will simulate Am activity deposited in the leg bones of a real contamination case inadequately. PMID- 30522247 TI - Radiocarbon Concentrations in Environmental Samples Collected Near the Spent Nuclear Fuel Reprocessing Plant at Rokkasho, Aomori, Japan, During Test Operation Using Spent Nuclear Fuel. AB - The contribution of atmospheric discharged C to local C concentrations was investigated by analysis of C in environmental samples collected around the spent nuclear fuel reprocessing plant in Rokkasho, Aomori, Japan. From June 2006 to October 2011, the range of monthly averaged specific activities in atmospheric CO2 collected 2.6 km from the plant was 0.226-0.279 Bq g C; at several sampling times, the observed concentrations were higher than the background value. Specific activities of atmospheric C simulated with an atmospheric dispersion model coupled with a mesoscale weather model reproduced the measured values fairly well, supporting the idea that the higher measured specific activities were due to C discharged from the reprocessing plant. For investigation of the C distribution around the facility, samples of Cyperus microiria, wild annual sedge, were collected from nine locations. Plant samples collected east and west of the facility in 2008 showed slightly higher specific activities than samples collected at the other locations, reflecting the prevailing wind direction. The measured C specific activities in vegetable, polished rice, pasture, and milk samples collected around the facility did not differ significantly from the background value (except for one polished rice sample, which had a value slightly higher than background). The annual committed effective radiation dose to humans resulting from consumption of the polished rice was estimated as 3.6 * 10 mSv, which is negligibly small compared with 1 mSv, an index of the dose limit for the general public. PMID- 30522248 TI - A Dose-Dependent Hematological Evaluation of Whole-Body Gamma-Irradiation in the Gottingen Minipig. AB - There is a great deal of interest in the establishment of a standardized animal model for the acute radiation syndrome to allow development of diagnostic approaches and countermeasure treatments following radiological terrorist events. Due to physiological, anatomical, and biochemical similarities to humans, the minipig is an attractive large animal model for evaluating countermeasure efficacy. This study was conducted in order to aid in the establishment of the minipig, and the Gottingen minipig in particular, as an animal model for the hematopoietic acute radiation syndrome. Animals were exposed whole-body to Co at doses of 0 (sham control), 0.25, 0.5, 0.75, 1.0, and 2.0 Gy, and hematological parameters followed in time from pre-irradiation to post-irradiation Day 7. Following irradiation, a dose-dependent decrease in total white blood cells was observed, which was determined to be statistically different as compared to control animals at all dose levels above 0.25 Gy at 24 h post-irradiation. Similarly, a dose-dependent reduction in both absolute lymphocyte count and absolute neutrophil count occurred by the earliest time point measured for all exposed animals. A significant decrease in platelets was observed at post irradiation Day 7 in animals exposed only at the highest (2.0 Gy) level. The platelet-to-lymphocyte ratio generated for exposures ranging from 0.25-2.0 Gy was able to differentiate response between high and low exposure levels even at 7 d post exposure. In conclusion, the present study supports the development of the Gottingen minipig as a suitable large animal model to study radiation-induced hematopoietic syndrome. PMID- 30522249 TI - Radiation Dose Responses, Thresholds, and False Negative Rates in a Series of Cataract Surgery Prevalence Studies among Atomic Bomb Survivors. AB - In order to find imperfect sensitivity or the false-negative rate of cataract surgery due to latent clinically significant or severe cataract and a dose response threshold, cataract surgery prevalence data analysis was made for each of the two-year periods from 1986 through 2005 among atomic bomb survivors. Using the latent variable regression model published earlier, cataract prevalence studies allowing for false-negative and/or false-positive rates were conducted in each of the 10 two-year periods during 1986 to 2005. As the best statistical model for prevalence data, a logistic model with a non-negligible false negative rate was selected for analysis. The commonly used naive logistic analysis resulted in an average odds ratio (OR) at 1 Gy of 1.33 (95%CI: 1.28, 1.38) for cataract surgery with no linear time trend (p = 0.334), and the OR at 1 Gy with the model allowing for sensitivity was 1.48 (95%CI: 1.40, 1.56) for clinically significant or severe cataract with no linear time trend (p = 0.263). Cataract surgery is an imperfect surrogate for clinically significant cataract, and the sensitivity increased from 0.15 to 0.50 during the 20 y with increasing rate of sensitivity per 2-y period of approximately 22%. The dose-response threshold based on a naive logistic model for cataract surgery ranged from 0.04-1.03 Gy (simple average of 0.41 Gy) with no linear time trend (p = 0.620) in the 10 2-y periods compatible with the no dose response threshold model in all periods. PMID- 30522250 TI - A Comparison of Measurements and Calculations of the Effects of Scattered Radiation on Dosimeter Calibration in a Calibration Range. AB - The method presented provides an alternative to the shadow shield method for experimentally measuring the contribution due to scattering radiation in a calibration range. Scattering of 0.6616 MeV photons from a Cs irradiator in a calibration range does not only occur due to the walls and floor of the range. It also occurs due to the source material itself, its encapsulation, the brass cup that holds the source, the two stainless tubes that surround the source capsule and the brass cup, and the irradiator structure that surrounds the aforementioned objects. The shadow shield method underestimates this scattering radiation that originates in the irradiator. By measuring the uncollided effective activity using a CZT detector and a total effective activity using a survey meter, the contribution of scattered radiation (including all of the abovementioned sources of scatter) to the effective source activity is able to be measured. In this paper, the measured mean effective source activities for a Cs irradiator in a calibration range are reported for a CZT detector and a survey meter. The measured activities are compared among themselves and with the results of MCNP calculations. From these comparisons, the new alternative method for measuring the scatter contribution was validated by agreement in both the MCNP calculations and experimental measurements that scattering contributed about 28% to the overall effective activity of the range. PMID- 30522252 TI - Dosimetry of the Texas A&M University AGN-201M Research Reactor under Accident Conditions. AB - The AGN-201M at Texas A&M University is a small research reactor designed to be simple and easy to use for educational purposes. To ensure radiological safety in the reactor facility, dose equivalent rate measurements were taken near the reactor and at the operating console at various power levels. These measurements were then linearly extrapolated for two postulated reactivity accidents: a reactor pulse and a slow power transient. It was found that the highest integral dose equivalent near the reactor during the postulated accident involving a step increase of 2% Deltak k reactivity is 51 +/- 4 mSv. PMID- 30522251 TI - ICNIRP Guidelines on Limits of Exposure to Laser Radiation of Wavelengths between 180 nm and 1,000 MUm. AB - Since the publication of the ICNIRP Revision of the Guidelines on Limits of Exposure to Laser Radiation (), further research supports amending the retinal thermal exposure limits in terms of spot size dependence, pulse duration dependence for short pulses and wavelength dependence between 1,200 nm and 1,400 nm. A detailed discussion of the rational for the changes is presented in the Appendix of these Guidelines (Rationale for updating the Guidelines). PMID- 30522253 TI - News and Notices. PMID- 30522254 TI - Health Physics Society Prospectus: An Affiliate of the International Radiation Protection Association (IRPA). PMID- 30522255 TI - Health Physics Society Affiliate Members. PMID- 30522256 TI - It is time to reconsider the unnecessary division of premedical and medical studies. PMID- 30522257 TI - History of Japanese medical education. AB - Since medical education programs in Korea and Japan seem to mutually influence each other, this review article provides a history of Japanese medical education, focusing on the way in which it influenced and was influenced by Korean medical education. In the late 19th century, the University of Tokyo established the core medical school, disseminating its scholarship and system to other medical schools. In the early 20th century, the balance between the quality and quantity of medical education became a new issue; in response, Japan developed different levels of medical school, ranging from imperial universities to medical colleges and medical vocational schools. After World War II, all of Japan's medical schools became part of the university system, which was heavily regulated by the Ministry of Education (MOE) Standard for the Establishment of Universities. In 1991, MOE deregulated the Standard; since 2000, several new systems have been established to regulate medical schools. These new approaches have included the Model Core Curriculum, 2-year mandatory postgraduate training, and a medical education accreditation system. Currently, most medical schools are nervous, as a result of tighter regulatory systems that include an accreditation system for undergraduate education and a specialty training system for postgraduate education. PMID- 30522258 TI - Improving a newly adapted teaching and learning approach: Collaborative Learning Cases using an action research. AB - PURPOSE: Although medical curricula are now better structured for integration of biomedical sciences and clinical training, most teaching and learning activities still follow the older teacher-centric discipline-specific formats. A newer pedagogical approach, known as Collaborative Learning Cases (CLCs), was adopted in the medical school to facilitate integration and collaborative learning. Before incorporating CLCs into the curriculum of year 1 students, two pilot runs using the action research method was carried out to improve the design of CLCs. METHODS: We employed the four-phase Kemmis and McTaggart's action research spiral in two cycles to improve the design of CLCs. A class of 300 first-year medical students (for both cycles), 11 tutors (first cycle), and 16 tutors (second cycle) were involved in this research. Data was collected using the 5-points Likert scale survey, open-ended questionnaire, and observation. RESULTS: From the data collected, we learned that more effort was required to train the tutors to understand the principles of CLCs and their role in the CLCs sessions. Although action research enables the faculty to improve the design of CLCs, finding the right technology tools to support collaboration and enhance learning during the CLCs remains a challenge. CONCLUSION: The two cycles of action research was effective in helping us design a better learning environment during the CLCs by clarifying tutors' roles, improving group and time management, and meaningful use of technology. PMID- 30522259 TI - The development of a community-based medical education program in Korea. AB - PURPOSE: The introduction of community-based medical education would help improve the quality of primary care. This paper suggests learning objectives and an educational program for community-based medical education. METHODS: The educational program was developed in a 1-day consensus workshop. Twenty experts, including faculty members from family medicine department of a college of medicine in Seoul and community-based preceptors, participated in the program. A needs-assessment survey was conducted among community-based preceptors before the workshop. Through this workshop, we derived learning objectives and a standardized curriculum for community-based medical education. RESULTS: In the questionnaire before the workshop, community-based preceptors voiced concerns over the program's potential costs and the time required for teaching. The learning objectives and educational programs derived from the workshop's consensus were consistent with the characteristics of the primary care. Based on the results of this workshop, the joint expert team developed a standard educational program on two core topics: clinical teaching and mentoring. CONCLUSION: From this curriculum development process, participants could construct a more standardized curriculum for community-based medical education. Future studies are needed to evaluate the long-term outcomes of these educational programs, such as the learners' satisfaction and achievement. PMID- 30522260 TI - Effects of medical communication curriculum on perceptions of Korean medical school students. AB - PURPOSE: The study examines changes in students' self-assessment of their general communication (GC) and medical communication (MC) competencies, as well as perceptions of MC concepts. METHODS: Participants included 108 second year medical students enrolled at a Korean medical school studying an MC curriculum. It was divided into three sections, and participants responded to questionnaires before and after completing each section. To assess perceived GC and MC competency, items based on a 7-point Likert scale were employed; a single open ended item was used to examine students' perceptions of MC. Statistical analysis was conducted to gauge GC and MC competency, whereas semantic network analysis was used to investigate students' perceptions of MC. RESULTS: Students perceived their GC competency to be higher than MC. Perceived MC competency differed significantly across the three sections, whereas no differences were found for GC. There were no statistically significant differences after completing the curriculum's second and third sections; however, the vocabulary students used to describe MC concepts became more scholarly and professional. In the semantic networks, the link structure between MC-related words decreased in linearity and looseness, becoming more complex and clustered. The words 'information' and 'transfer' proved integral to students' perceptions; likewise, 'empathy' and 'communication' became closely connected in a single community from two independent communities. CONCLUSION: This study differed from prior research by conducting an in-depth analysis of changes in students' perceptions of MC, and its findings can be used to guide curriculum development. PMID- 30522261 TI - Experience of nursing students about the barriers to patient education: a qualitative study in Iran. AB - PURPOSE: Patient education is a dynamic and continuous process that should be implemented during the entire time of hospital stay and even afterward. Studies have shown the typically poor quality of patient education in Iran and its failure to convey the required knowledge and skills to patients. The purpose of this study was to survey the experience of nursing students in regard to the challenges of patient education in hospitals. METHODS: This qualitative study was conducted using the conventional qualitative content analysis approach on a sample of 21 undergraduate nursing students (4th semester and beyond), which was drawn from the Qom Nursing and Midwifery School through purposive sampling with maximum variation. Data were collected through semi-structured interviews conducted over a period of 45 to 75 minutes, and were analyzed using the conventional qualitative content analysis. RESULTS: Results were derived from the experiences of 21 nursing students (nine males, 12 females) about the research subject. The primary themes identified in the study were the student-related, patient-related, instructor-related, education environment-related, and curriculum-related barriers to patient educations. CONCLUSION: Participants believed that patient education in Iranian hospitals is faced with many challenges. Nursing instructors and curriculum planners should ensure more emphasis on patient education at the initial semesters of nursing education curriculum and make sure that it is included in the evaluation of students. Hospital officials should provide a dedicated education environment with suitable facilities, tools, and atmosphere for patient education. Also, special education programs need to be developed for less educated patients. PMID- 30522262 TI - The relationship between non-cognitive student attributes and academic achievements in a flipped learning classroom of a pre-dental science course. AB - PURPOSE: The purpose of this study was to examine whether non-cognitive student attributes such as learning style and personality type affected academic performance in a flipped learning classroom of a pre-dental undergraduate science course. METHODS: 'Biodiversity and Global Environment,' a 15-week, 3-credit course, was designed as a flipped class in Seoul National University School of Dentistry in 2017. Second-year pre-dental students were required to enroll in the course and to engage in online learning and in-class discussion. The Kolb's Learning Style Inventory and the Myers-Briggs Type Indicator were conducted to measure non-cognitive student factors. Independent samples t-test and multivariate regression analyses were used to examine the relationships between self-rated measurements and academic achievement. RESULTS: More than half of the students enrolled in the flipped science course had an assimilator learning style (50%), followed by convergers (24%), accommodators (16%), and divergers (10%), and their personality types were dominated by the introverted, sensing, thinking, and judging types, respectively. Examining group differences using the t-test demonstrated a significant relationship between the diverger group and higher academic success. In particular, the multivariate regression analysis indicated that both thinking types and female students performed better in discussion than feeling types and male students. CONCLUSION: To operate the flipped learning classroom more effectively in medical and dental education, the instructor should carefully develop and apply a more tailored facilitation and relevant assessment by considering student learning styles and personality types. PMID- 30522263 TI - Comparison of results between modified-Angoff and bookmark methods for estimating cut score of the Korean medical licensing examination. AB - PURPOSE: The purpose of this study was to apply alternative standard setting methods for the Korean Medical Licensing Examination (KMLE), a criterion referenced written examination, and to compare them to the conventional cut score used on the KMLE. METHODS: The process and results of criterion-referenced standard settings (i.e., the modified-Angoff and bookmark methods) were evaluated. The ratio of passing and failing examinees determined using these alternative standard setting methods was compared to the results of the conventional criteria. Additionally, the external, internal and procedural evaluation of these methods were reviewed. RESULTS: The modified-Angoff method yielded the highest cut score, followed sequentially by the conventional method and the bookmark method. The classification agreement between the modified-Angoff and bookmark methods was 0.720 measured by Cohen's kappa coefficient. The intra panelist classification consistency of modified-Angoff method was higher than bookmark method. However, the inter-panelist classification consistency was vice versa. The standard setting panelists' survey results showed that the procedures of both methods were satisfactory, but panelists had more confidence in the results of the modified-Angoff method. CONCLUSION: The modified-Angoff method showed results that were more similar to those of the conventional method. Both new methods showed very high concordance with the conventional method, as well as with each other. The modified-Angoff method was considered feasible for adoption on the KMLE. The standard setting panelists responded positively to the modified Angoff method in terms of its practical applicability, despite certain advantages of the bookmark method. PMID- 30522264 TI - Learning experience of undergraduate medical students during 'model preparation' of physiological concepts. AB - PURPOSE: Learning physiological concepts and their practical applications in the appropriate contexts remains a great challenge for undergraduate medical students. Hence the present study aimed to analyze the learning experience of undergraduate medical students during an active learning process of 'preparation of models' depicting physiological concepts. METHODS: A total of 13 groups, involving 55 undergraduate medical students with three to five individuals in each group, were involved in model preparation. A total of 13 models were exhibited by the students. The students shared their learning experiences as responses to an open-ended questionnaire. The students' responses were analyzed and generalized comments were generated. RESULTS: Analysis of the results showed that the act of 'model preparation' improved concept understanding, retention of knowledge, analytical skills, and referral habits. Further, the process of 'model preparation' could satisfy all types of sensory modality learners. CONCLUSION: This novel active method of learning could be highly significant in students' understanding and learning physiology concepts. This approach could be incorporated in the traditional instructor-centered undergraduate medical curriculum as a way to innovate it. PMID- 30522265 TI - Nurturing instead of depleting empathy during medical education: a medical student's perspective. PMID- 30522266 TI - Twin principles for need-based attendance policy in undergraduate medical education. PMID- 30522267 TI - Predominant N-haloacetamide and haloacetonitrile formation in drinking water via the aldehyde reaction pathway. AB - In drinking water disinfection, switching from free chlorine to alternative chemical disinfectants such as monochloramine may result in the formation of different classes of toxic disinfection byproducts (DBPs). Haloacetonitriles (HANs) and haloacetamides (HAMs) are two currently unregulated nitrogen containing DBP (N-DBP) groups commonly found in water disinfected with monochloramine that have been shown to be more cyto- and genotoxic than regulated DBPs. For the first time, this study confirms the formation of HAN and HAM dominant species found in disinfected water, dichloroacetonitrile and dichloroacetamide, from the reaction between monochloramine and dichloroacetaldehyde via the aldehyde reaction pathway. Results from experiments with natural water treated with labelled 15N-monochloramine confirmed the relevance of the aldehyde pathway. Monochloramine reacted quickly with dichloroacetaldehyde reaching equilibrium with the carbinolamine 2,2-dichloro-1 (chloroamino)ethanol (K1=1.87x104 M-1s-1). Then, 2,2-dichloro-1 (chloroamino)ethanol underwent two parallel reactions where, (1) it slowly dehydrated to 1,1-dichloro-2-(chloroimino)ethane (k2=1.09x10-5 s-1) and further decomposed to dichloroacetonitrile, and (2) it was oxidized by monochloramine (k3= 4.87x10-2 M-1s-1) to form a recently reported N-DBP, the N-haloacetamide N,2,2-trichloroacetamide. At high pH, dichloroacetonitrile hydrolyzed to dichloroacetamide (k_4^0=3.12x10-7 s-1, k_4^OH=3.54 M-1s-1). Additionally, trichloroacetaldehyde was also produced from the reaction of dichloracetaldehyde and monochloramine (k5=2.12x10-2 M-1s-1) under the presence of monochlorammonium ion, a product of monochloramine protonation. Within the N-haloacetamide family, N,2,2-trichloroacetamide (LC50=3.90x10-4 M) was found to be more cytotoxic than N chloroacetamide but slightly less potent than N,2-dichloroacetamide. PMID- 30522268 TI - Theoretical Evaluation of the Reaction Mechanism of Serine Hydroxymethyltransferase. AB - Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylene THF. SHMT is a folate pathway enzyme and is therefore of considerable medical interest since this is an important intervention point for anti-malarial, anti-cancer and anti-bacterial treatments. Despite considerable experimental effort the precise reaction mechanism of SHMT remains unclear. In this study we explore the reaction mechanism of SHMT with its natural substrates to determine the roles of each active site residue and the nature and the sequence of chemical steps. Molecular dynamics (MD) methods were employed to generate a starting structure which was then investigated using hybrid quantum mechanical/molecular mechanical (QM/MM) simulations using a QM region that encompasses 12 key residues and two substrates as well as explicit solvent. Our results show that the catalytic reaction proceeds according to retro aldol synthetic process with His129 acting as the general base in the reaction. This steps see the cleavage of the high energy C-C bond and formation of formaldehyde as an intermediate and is in line with experimental evidence. In contrast to previous suggestions, the pyridyl ring of the external PLP-serine aldimine substrate appears to exists in deprotonated form throughout the process, being stabilized by Asp208 via H-bonding alone and though electrostatic interactions with Arg371, Lys237 and His211 which were modelled explicitly. This knowledge has the potential to impact the design and development of new inhibitors. PMID- 30522269 TI - Correction to Top-Down Proteomics: Ready for Prime Time? PMID- 30522270 TI - Acoustic interactions for robot audition: A corpus of real auditory scenes. AB - The Acoustic Interactions for Robot Audition corpus is introduced for research on sound source localization and separation, and for multi-user speech recognition. Its aim is to evaluate and train Robot Audition techniques, as well as Auditory Scene Analysis in general. It was recorded in six real-life environments with different noise presence and reverberation time, using two array configurations: an equilateral triangle, and a three-dimensional 16-microphone array set over a hollow plastic body. It includes clean speech data for static sources and tracking information for mobile sources. It is freely available at https://aira.iimas.unam.mx/. PMID- 30522271 TI - Natural-frequency splitting of a guitar string caused by a non-uniform magnetic field. AB - A magnet can affect the vibration of the metal strings in a musical instrument. Here it is shown that a magnetic field can cause splitting of a metal guitar string's normally degenerate transverse vibration modes, leading to a beat note in the resulting sound. A distributed-spring model accurately predicts the natural frequencies of a vibrating guitar string in the non-uniform magnetic field. PMID- 30522272 TI - Velocity dispersion and backscatter in marrow-filled and water-filled trabecular bone samples in vitro. AB - The phase velocity and the backscatter coefficient were measured in 28 bovine femoral trabecular bone samples filled with marrow and water in vitro from 0.2 to 0.6 MHz. The phase velocities decreased approximately linearly with increasing frequency and the average dispersion rate of -34 ms-1 MHz-1 in the marrow-filled samples was higher than that of -42 ms-1 MHz-1 in the water-filled samples. The backscatter coefficients exhibited nonlinear, monotonically increasing dependences on the frequency and the average value of the exponent n = 2.92 (frequency dependence) in the marrow-filled samples was higher than the value of n = 2.79 in the water-filled samples. PMID- 30522273 TI - On heating of tissues by shear waves generated by ultrasound. AB - An additional heating caused by the shear wave generated by an ultrasonic wave incident on a soft tissue boundary is considered for different tissue parameters and wave frequencies in the MHz range. The shear wave structure and the space time dynamics of the temperature field are studied for three realistic examples of tissue parameters. It is shown that in viscous tissues the shear component can significantly contribute to the heating in a narrow layer near the boundary. PMID- 30522274 TI - Automatic detection of fish sounds based on multi-stage classification including logistic regression via adaptive feature weighting. AB - This paper presents a method for automatic detection of fish sounds in an underwater environment. There exist two difficulties: (i) features and classifiers that provide good detection results differ depending on the underwater environment and (ii) there are cases where a large amount of training data that is necessary for supervised machine learning cannot be prepared. A method presented in this paper (the proposed hybrid method) overcomes these difficulties as follows. First, novel logistic regression (NLR) is derived via adaptive feature weighting by focusing on the accuracy of classification results by multiple classifiers, support vector machine (SVM), and k-nearest neighbors (k NN). Although there are cases where SVM or k-NN cannot work well due to divergence of useful features, NLR can produce complementary results. Second, the proposed hybrid method performs multi-stage classification with consideration of the accuracy of SVM, k-NN, and NLR. The multi-stage acquisition of reliable results works adaptively according to the underwater environment to reduce performance degradation due to diversity of useful classifiers even if abundant training data cannot be prepared. Experiments on underwater recordings including sounds of Sciaenidae such as silver croakers (Pennahia argentata) and blue drums (Nibea mitsukurii) show the effectiveness of the proposed hybrid method. PMID- 30522275 TI - Importance of glottis landmarks for the assessment of cleft lip and palate speech intelligibility. AB - The present work explores the acoustic characteristics of articulatory deviations near g(lottis) landmarks to derive the correlates of cleft lip and palate speech intelligibility. The speech region around the g landmark is used to compute two different acoustic features, namely, two-dimensional discrete cosine transform based joint spectro-temporal features, and Mel-frequency cepstral coefficients. Sentence-specific acoustic models are built using these features extracted from the normal speakers' group. The mean log-likelihood score for each test utterance is computed and tested as the acoustic correlates of intelligibility. Derived intelligibility measure shows significant correlation (rho = 0.78, p < 0.001) with the perceptual ratings. PMID- 30522276 TI - Digital acoustic sensor performance across the infrasound range in non-isolated conditions. AB - The next generation of acoustic sensors is emerging to supplement legacy sensors traditionally used in regional and global networks. These devices operate under similar principles as traditional sensors, without the need of a separate external digitizer. The calibration of these sensors against their predecessors is crucial to the modernization of conventional technologies. This work describes the characterization of the next-generation MB3 digital microbarometer and the iPrecision smartphone microphone in a non-isolated calibration room across the infrasound (i.e., 0.01-20 Hz) range. The intent is to evaluate nominal instrument performance before deployment. A portable rotary subwoofer is used as a controllable infrasound source to generate single-tone sinusoidal and broadband noise pressure waves in a room configured for calibration purposes. For each device, comparison measurements are made, from which the digital sensitivity and the parametric response is developed. The results provide insight into the performance of the sensors in non-isolated environments. By overlapping the responses of the test sensors, digital sensor performance across the infrasound range can be benchmarked. These responses may serve as a double-reference scheme in future pressure measurements and digital calibrations of acoustic sensors. PMID- 30522277 TI - Automatic intonation classification using temporal patterns in utterance-level pitch contour and perceptually motivated pitch transformation. AB - Second language learners of British English (BE) are typically trained for four intonation classes: Glide-up, Glide-down, Dive, and Take-off. Automatic four-way intonation classification could be useful to evaluate a learner's pronunciation. However, such automatic classification is challenging without having manually annotated tones, typically considered in intonation analysis and classification tasks. In this, a three-dimensional feature sequence is proposed representing temporal patterns in the utterance-level f0 contour using a perceptually motivated pitch transformation. Hidden Markov model based classification experiments conducted using a training material for teaching BE intonation demonstrate the benefit of the proposed approach over the baseline scheme considered. PMID- 30522278 TI - Feasibility study of acoustic imaging for human thorax using an acoustic contrast source inversion algorithm. AB - In this work, an acoustic imaging method based on contrast source inversion and its feasibility in quantitatively reconstructing compressibility, attenuation, and density of human thorax is studied. In the acoustic wave equation, the inhomogeneity in density makes the relationship between the contrasts and the total pressure highly nonlinear. To reduce this nonlinearity, two contrast sources are introduced to ensure symmetry in the equation, such that the inverse problem can be solved efficiently by alternately updating two contrast sources and two contrasts. Moreover, to improve the stability of the algorithm, the multiplicative regularization scheme with two additive regularization factors is applied. Using this algorithm, acoustic parameters of human thorax from low frequency ultrasound measurement are reconstructed. Numerical results show that the acoustic parameters of human thorax can be properly reconstructed at frequency of tens of kHz using this algorithm. PMID- 30522279 TI - A description of echolocation clicks recorded in the presence of True's beaked whale (Mesoplodon mirus). AB - True's beaked whales (Mesoplodon mirus) were encountered on two separate shipboard surveys on 24 July 2016 and 16 September 2017 in the western North Atlantic Ocean. Recordings were made using a hydrophone array towed 300 m behind the ship. In 2016, three different groups were sighted within 1500 m of the ship; clicks were recorded for 26 min. In 2017, a single group of five whales was tracked over the course of five hours in which the ship maintained a distance <4000 m from the group. A total of 2938 frequency-modulated (FM) clicks and 7 buzzes were recorded from both encounters. Plausible inter-click-intervals (ICIs) were calculated from 2763 clicks, and frequency and duration measurements were calculated from 2150 good quality FM clicks. The median peak frequencies were 43.1 kHz (2016, n = 718) and 43.5 kHz (2017, n = 1432). Median ICIs were 0.17 s (2016) and 0.19 s (2017). The spectra and measurements of the recorded clicks closely resemble Gervais's beaked whale clicks (Mesoplodon europaeus) and distinguishing between the two species in acoustic data sets proves difficult. The acoustic behavior of True's beaked whales was previously unknown; this study provides a description of echolocation clicks produced by this species. PMID- 30522280 TI - Tonpilz-type vector sensor for the estimation of underwater sound wave direction. AB - Typical underwater Tonpilz transducers detect the magnitude of an acoustic pressure, a scalar quantity, by means of piezoceramic rings, and convert this pressure into a proportional electric voltage. The scalar sensor has no directional sensitivity. This paper proposes a new vector sensor based on the Tonpilz transducer that is sensitive to both the magnitude and direction of an incoming acoustic wave. The piezoceramic rings of the new Tonpilz-type vector sensor are divided into four quadrant segments. The direction of an incoming acoustic wave is identified by combining the output voltages of the four piezoceramic segments in a particular manner. The operation frequency range of the vector sensor follows that of conventional Tonpilz transducers. The feasibility of this new structural design has been confirmed through a three dimensional simulation of the operation of the vector sensor with the finite element method. The validity of the new design is verified by fabricating and characterizing an experimental prototype of the vector sensor. PMID- 30522281 TI - Age-related perceptual difference of Kyungsang Korean accent contrast: A diachronic observation. AB - This study investigated the perception of lexical pitch accent contrasts between innovative and conservative listeners under a sound change. Younger and older listeners speaking Kyungsang Korean participated in the 2AFC identification task. The participants responded to stimuli systematically varying spectral and temporal F0 properties (i.e., peak duration, onset/peak F0 values) and talker voices (i.e., older vs younger talker). Results showed that younger listeners utilized the temporal cue differently from older listeners, and listeners' perception also varied by talker age. Discussion was made in terms of consistency between the perception and production and the effect of social information in speech perception. PMID- 30522282 TI - Vocal emotion recognition performance predicts the quality of life in adult cochlear implant users. AB - Clinical tests of cochlear implant (CI) outcomes in sentence recognition cannot fully reflect CI users' self-reported quality of life (QoL). Here, vocal emotion recognition scores, speech reception thresholds (SRTs), and demographic factors were tested as predictors of QoL scores assessed with the Nijmegen Cochlear Implant Questionnaire in postlingually deafened adult CI users. After correction for multiple comparisons, vocal emotion recognition scores were significantly correlated with QoL scores in all subdomains (social interaction, self-esteem, etc.), while SRTs and duration of CI use were not. Vocal emotion recognition may thus be used in clinic to accurately and broadly predict QoL with CIs. PMID- 30522283 TI - Thermal boundary layer limitations on the performance of micromachined microphones. AB - This work examines the extent to which thermal boundary layer effects limit the performance of micromachined microphones. The acoustic impedance of the cavity formed by the microphone enclosure is calculated using both analytical and finite element methods. A thermal correction to the cavity impedance is included to account for the transition of compression and expansion within the enclosure from adiabatic to isothermal when the thermal boundary layer that forms at the walls of the enclosure becomes large compared to the enclosure dimensions. The thermal correction to the cavity impedance contains a resistive term that results from thermal relaxation losses and contributes thermal-acoustic noise to the system. A lumped-element network model for the microphone response which includes the thermally corrected enclosure impedance is presented and compared to measured results for a case study device. The relative noise power contribution of each noise source considered in the model is calculated. It is shown that the noise due to the resistive term of the enclosure cavity impedance becomes significant when the enclosure volume is small. This sets a theoretical limit on the noise floor that can be achieved by a micromachined microphone with given enclosure dimensions. PMID- 30522284 TI - Noise characterization of a subsea tidal kite. AB - This paper presents the first noise measurements of a quarter-scale subsea tidal kite (anchored to the sea floor by a tether and flying in a figure-eight configuration in the water column) operating in field conditions. Challenges in the measurement and post-processing of the data are detailed. Results are presented for three operating conditions of the kite: (1) varying turbine rotations per minute (RPM), (2) varying kite speed, and (3) a twisted tether. Turbine RPM was identified as the main parameter influencing noise emissions. PMID- 30522285 TI - Ultrasound tomography in bone mimicking phantoms: Simulations and experiments. AB - Bone quality assessment for osteoporosis diagnosis is usually performed using dual energy X-ray absorptiometry or X-ray quantitative computed tomography. Recent research demonstrated that both methods are inaccurate in diagnosing osteoporosis since they rely only on the bone mineral density. The literature on bone quantitative ultrasound suggests that ultrasonic waves are sensitive to multiple significant bone parameters such as mechanical properties, the bone volume fraction, and the micro-architecture. Typical ultrasound tomography techniques are limited to image objects with a low speed of sound contrast relative to a background medium. In this study, the possibility of adapting a more advanced ultrasound inversion technique referred to as the hybrid algorithm for robust breast ultrasound tomography for velocity mapping of bone mimicking phantoms was examined. The cortical bone thickness and the cortical bone speed of sound, which are directly related to the bone elastic properties, are parameters strongly correlated with the overall bone quality. A finite element model and an experimental test bench were developed to adapt the hybrid algorithm for robust breast ultrasound tomography to bone quality assessment. Although artefacts were present in the images generated, the results obtained enabled discrimination of a healthy bone phantom over an osteoporotic bone phantom based on the cortical bone thickness and the average cortical bone velocity. The speed of sound inside the cortical region of the bone phantoms was underestimated by 9.38% for the osteoporotic phantom, and by 10.68% for the healthy phantom relative to the values supplied by the bone phantom manufacturer, but there was a difference of 3.97% between the two samples. The difference between the measured cortical bone thickness of the reconstructed image and the X-ray computed tomography images was on average 0.4 mm. PMID- 30522286 TI - Translational dynamics of individual microbubbles with millisecond scale ultrasound pulses. AB - It is established that radiation forces can be used to transport ultrasound contrast agents, particularly for molecular imaging applications. However, the ability to model and control this process in the context of therapeutic ultrasound is limited by a paucity of data on the translational dynamics of encapsulated microbubbles under the influence of longer pulses. In this work, the translation of individual microbubbles, isolated with optical tweezers, was experimentally investigated over a range of diameters (1.8-8.8 MUm, n = 187) and pressures (25, 50, 100, 150, and 200 kPa) with millisecond pulses. Data were compared with theoretical predictions of the translational dynamics, assessing the role of shell and history force effects. A pronounced feature of the displacement curves was an effective threshold size, below which there was only minimal translation. At higher pressures (>=150 kPa) a noticeable structure emerged where multiple local maxima occurred as a function of bubble size. The ability to accurately capture these salient features depended on the encapsulation model employed. In low Reynolds number conditions (i.e., low pressures, or high pressures, off-resonance) the inclusion of history force more accurately fit the data. After pulse cessation, bubbles exhibited substantial displacements consistent with the influence of history effects. PMID- 30522287 TI - Analytical modeling of dissipative silencers. AB - This paper applies ideas originally developed in the field of acoustics of multiscale porous media to the analytical modeling of dissipative silencers. Analytical models for the long-wavelength acoustical properties of different types of dissipative silencers, such as pod silencers, lined ducts, splitters, and bar silencers, are introduced in this work. Some of these models account for the possibility of using different porous materials in a given silencer. For instance, a model for a splitter silencer comprising baffles made of different porous materials is derived. Examples of the sound transmission behavior of the said types of silencers are presented to evidence that the dissipation of sound energy is largely influenced by pressure diffusion occurring in the porous constituents. The predictions of the analytical models are in good agreement with finite element calculations. PMID- 30522288 TI - REVIEWS OF ACOUSTICAL PATENTS. AB - The purpose of these acoustical patent reviews is to provide enough information for a Journal reader to decide whether to seek more information from the patent itself. Any opinions expressed here are those of the reviewers as individuals and are not legal opinions. Printed copies of United States Patents may be ordered at $3.00 each from the Commissioner of Patents and Trademarks, Washington, DC 20231. Patents are available via the Internet at http://www.uspto.gov. PMID- 30522289 TI - Acoustically relevant properties of four crude oils at oceanographic temperatures and pressures. AB - Inversions of models of broadband acoustic scattering to detect and quantify weakly scattering targets, such as oil droplets in seawater, require precise knowledge of the physical properties that determine scattering. When the characteristic impedance contrast between a target and the surrounding medium is weak, small differences between the true and modeled impedance can cause significant errors in modeled scattering. For crude oil, currently available empirical models of density and sound speed are derived from measurements made at reservoir conditions (high temperature and pressure), which may not be relevant to oceanographic conditions due to phase changes in the oil. Measurements of the density and sound speed, as well as thermal characterization of phase changes via differential scanning calorimetry, of four crude oils at oceanographically relevant temperatures and pressures were made and compared to a commonly used empirical model for sound speed and density. Significant deviations between the measured and modeled values were found and different empirically fit models were developed. A literature review of sound speed data was also performed, and the innovative empirical model shows improvement over the commonly used empirical model for both the data measured here and the measurements in the literature. PMID- 30522290 TI - Frequency-dependent behavior of media containing pre-strained nonlinear inclusions: Application to nonlinear acoustic metamaterials. AB - One emerging research area within the fields of acoustic and elastic metamaterials involves designing subwavelength structures that display elastic instabilities in order to generate an effective medium response that is strongly nonlinear. To capture the overall frequency-dependent and dispersive macroscopic response of such heterogeneous media with subwavelength heterogeneities, a theoretical framework is developed that accounts for higher-order stiffnesses of a resonant, nonlinear inclusion that varies with a macroscopic pre-strain, and the inherent inertia associated with an inclusion embedded in a nearly incompressible elastic matrix material. Such a model can be used to study varying macroscopic material properties as a function of both frequency and pre-strain and the activation of such microscale instabilities due to an external, macroscopic loading, as demonstrated with a buckling metamaterial inclusion that is of interest due to its tunable and tailorable nature. The dynamic results obtained are consistent with similar static behavior reported in the literature for structures with elastic instabilities. PMID- 30522291 TI - Listening through hearing aids affects spatial perception and speech intelligibility in normal-hearing listeners. AB - Cubick and Dau [(2016). Acta Acust. Acust. 102, 547-557] showed that speech reception thresholds (SRTs) in noise, obtained with normal-hearing listeners, were significantly higher with hearing aids (HAs) than without. Some listeners reported a change in their spatial perception of the stimuli due to the HA processing, with auditory images often being broader and closer to the head or even internalized. The current study investigated whether worse speech intelligibility with HAs might be explained by distorted spatial perception and the resulting reduced ability to spatially segregate the target speech from the interferers. SRTs were measured in normal-hearing listeners with or without HAs in the presence of three interfering talkers or speech-shaped noises. Furthermore, listeners were asked to sketch their spatial perception of the acoustic scene. Consistent with the previous study, SRTs increased with HAs. Spatial release from masking was lower with HAs than without. The effects were similar for noise and speech maskers and appeared to be accounted for by changes to energetic masking. This interpretation was supported by results from a binaural speech intelligibility model. Even though the sketches indicated a change of spatial perception with HAs, no direct link between spatial perception and segregation of talkers could be shown. PMID- 30522292 TI - The size of the tongue movement area affects the temporal coordination of consonants and vowels-A proof of concept on investigating speech rhythm. AB - Recent research has revealed substantial between-speaker variation in speech rhythm, which in effect refers to the coordination of consonants and vowels over time. In the current proof-of-concept study, the hypothesis was investigated that these idiosyncrasies arise, in part, from differences in the tongue's movement amplitude. Speech rhythm was parameterized by means of the percentage over which speech is vocalic (%V) in the German pronoun "sie" [zi?]. The findings support the hypothesis: all else being equal, idiosyncratic %V values behaved proportionally to a speaker's tongue movement area. This research underlines the importance of studying language-external factors, such as a speaker's individual tongue movement behavior, to investigate variation in temporal coordination. PMID- 30522293 TI - Low background noise increases cognitive load in older adults listening to competing speech. AB - This letter describes a dual-task paradigm sensitive to noise masking at favorable signal-to-noise ratios (SNRs). Two competing sentences differing in voice and context cues were presented against noise at SNRs of +2 and +6 dB. Listeners were asked to repeat back words from both competing sentences while prioritizing one of them. Recognition of the high-priority sentences was high and did not depend on the SNR. In contrast, recognition of the low-priority sentences was low and showed a significant SNR effect that was related to the listener's working memory capacity. This suggests that even subtle noise masking causes cognitive load in competing-talker situations. PMID- 30522294 TI - Spatial filters suppress ripple artifacts in the computation of acoustic fields with the angular spectrum method. AB - The angular spectrum method (ASM) is an effective tool for propagating wave fields between parallel planes through decomposition of the field into a series of independent plane waves. One source of error is interference from mirror sources introduced through the inherent periodicity of the fast Fourier transform (FFT) used to implement this method numerically. Here, spatial filters attenuate waves propagating at large angles, which are sensitive to mirror sources. Simulations show that this suppresses the ripple artifact whilst preserving the accuracy of the ASM-computed fields. To achieve comparable performance without filtering requires up to a 13.5-fold increase in computation time. PMID- 30522295 TI - Auditory attention switching with listening difficulty: Behavioral and pupillometric measures. AB - Pupillometry has emerged as a useful tool for studying listening effort. Past work involving listeners with normal audiological thresholds has shown that switching attention between competing talker streams evokes pupil dilation indicative of listening effort [McCloy, Lau, Larson, Pratt, and Lee (2017). J. Acoust. Soc. Am. 141(4), 2440-2451]. The current experiment examines behavioral and pupillometric data from a two-stream target detection task requiring attention-switching between auditory streams, in two participant groups: audiometrically normal listeners who self-report difficulty localizing sound sources and/or understanding speech in reverberant or acoustically crowded environments, and their age-matched controls who do not report such problems. Three experimental conditions varied the number and type of stream segregation cues available. Participants who reported listening difficulty showed both behavioral and pupillometric signs of increased effort compared to controls, especially in trials where listeners had to switch attention between streams, or trials where only a single stream segregation cue was available. PMID- 30522296 TI - Dispersion of elastic waves in a layer interacting with a Winkler foundation. AB - Dispersion of plane harmonic waves in an elastic layer interacting with a one- or two-sided Winkler foundation is analyzed. The long-wave low-frequency polynomial approximations of the full transcendental dispersion relations are derived for a relatively soft foundation. The validity of the conventional engineering formulation of a Kirchhoff plate resting on an elastic foundation is investigated. It is shown that this formulation has to be refined near the cutoff frequency of bending waves. The associated near cutoff expansion is obtained for both cases. A simple explicit formula demonstrating veering of bending and extensional waves is presented for a one-sided foundation. PMID- 30522297 TI - Simultaneous electromagnetic articulography and electroglottography data acquisition of natural speech. AB - This paper reports on the concurrent use of electroglottography (EGG) and electromagnetic articulography (EMA) in the acquisition of EMA trajectory data for running speech. Static and dynamic intersensor distances, standard deviations, and coefficients of variation associated with inter-sample distances were compared in two conditions: with and without EGG present. Results indicate that measurement discrepancies between the two conditions are within the EMA system's measurement uncertainty. Therefore, potential electromagnetic interference from EGG does not seem to cause differences of practical importance on EMA trajectory behaviors, suggesting that simultaneous EMA and EGG data acquisition is a viable laboratory procedure for speech research. PMID- 30522298 TI - Frequency interferences of two-unit quartz resonator arrays excited by lateral electric fields. AB - The coupled thickness-twist and face-shear vibrations of the lateral-field excitation (LFE) two-unit resonator array are analyzed, and the frequency interference and shift of LFE resonator arrays are both studied. Different from most of the quartz resonator arrays based on thickness-field-excitation, the resonator array in this study operates with LFE generated by a pair of electrodes on the top surface of the resonator. By using Mindlin's first-order theory of piezoelectric plates, the electrically forced vibrations are analyzed. The effects of various structural parameters on the frequency interference and shift are examined; furthermore, the corresponding mechanisms are discussed. Varying trends of the frequency interference and shift with various structural parameters are verified by the finite element method. The results are crucial for avoiding frequency interferences between two adjacent units in parameter design of the resonator array operating on LFE. PMID- 30522299 TI - Effects of the relative timing of opposite-polarity pulses on loudness for cochlear implant listeners. AB - The symmetric biphasic pulses used in contemporary cochlear implants (CIs) consist of both cathodic and anodic currents, which may stimulate different sites on spiral ganglion neurons and, potentially, interact with each other. The effect on the order of anodic and cathodic stimulation on loudness at short inter-pulse intervals (IPIs; 0-800 MUs) is investigated. Pairs of opposite-polarity pseudomonophasic (PS) pulses were used and the amplitude of each pulse was manipulated independently. In experiment 1 the two PS pulses differed in their current level in order to elicit the same loudness when presented separately. Six users of the Advanced Bionics CI (Valencia, CA) loudness-ranked trains of the pulse pairs using a midpoint-comparison procedure. Stimuli with anodic-leading polarity were louder than those with cathodic-leading polarity for IPIs shorter than 400 MUs. This effect was small-about 0.3 dB-but consistent across listeners. When the same procedure was repeated with both PS pulses having the same current level (experiment 2), anodic-leading stimuli were still louder than cathodic leading stimuli at very short intervals. However, when using symmetric biphasic pulses (experiment 3) the effect disappeared at short intervals and reversed at long intervals. Possible peripheral sources of such polarity interactions are discussed. PMID- 30522300 TI - Efficient characterization of individual differences in compression ratio preference. AB - While wide dynamic range compression (WDRC) is a standard feature of modern hearing aids, it can be difficult to fit compression settings to individual hearing aid users. The goal of the current study was to develop a practical test to learn the preference of individual listeners for different compression ratio (CR) settings in different listening conditions (speech-in-quiet and speech-in noise). While it is possible to exhaustively test different CR settings, such methods can take many hours to complete, making them impractical. Bayesian optimization methods were used to find CR preferences in individual listeners in a relatively short amount of time. Using this practical preference learning test, individual differences in CR preference were examined across a relatively wide range of CR settings in different listening conditions. In experiment 1, the accuracy of the preference learning test in normal hearing listeners was verified. In experiment 2, it is shown that individual hearing impaired listeners differ in their CR preferences, and listeners tended to prefer the CR setting identified by the preference learning test over both linear gain or the National Acoustics Lab--Nonlinear 2 CR prescription based on their audiograms. PMID- 30522301 TI - Energy shielding by cavitation bubble clouds in burst wave lithotripsy. AB - Combined laboratory experiment and numerical simulation are conducted on bubble clouds nucleated on the surface of a model kidney stone to quantify the energy shielding of the stone caused by cavitation during burst wave lithotripsy (BWL). In the experiment, the bubble clouds are visualized and bubble-scattered acoustics are measured. In the simulation, a compressible, multi-component flow solver is used to capture complex interactions among cavitation bubbles, the stone, and the burst wave. Quantitative agreement is confirmed between results of the experiment and the simulation. In the simulation, a significant shielding of incident wave energy by the bubble clouds is quantified. The magnitude of shielding can reach up to 90% of the energy of the incoming burst wave that otherwise would be transmitted into the stone, suggesting a potential loss of efficacy of stone comminution. There is a strong correlation between the magnitude of the energy shielding and the amplitude of the bubble-scattered acoustics, independent of the initial size and the void fraction of the bubble cloud within a range addressed in the simulation. This correlation could provide for real-time monitoring of cavitation activity in BWL. PMID- 30522302 TI - Effects of signal bandwidth and noise on individual speaker identification. AB - Two experiments were conducted to evaluate the effects of increasing spectral bandwidth from 3 to 10 kHz on individual speaker recognition in noisy conditions (+5, 0, and -5 dB signal-to-noise ratio). Experiment 1 utilized h(Vowel)d (hVd) signals, while experiment 2 utilized sentences from the Rainbow Passage. Both experiments showed significant improvements in individual speaker identification in the 10 kHz bandwidth condition (6% for hVds; 10% for sentences). These results coincide with the extant machine recognition literature demonstrating significant amounts of individual speaker information present in the speech signal above approximately 3-4 kHz. Cues from the high-frequency region for speaker identity warrant further study. PMID- 30522303 TI - Acoustic radiation force exerted on a small spheroidal rigid particle by a beam of arbitrary wavefront: Examples of traveling and standing plane waves. AB - The analytical solution of the acoustic radiation force exerted by a beam of arbitrary shape on a small spheroidal rigid particle suspended in an ideal fluid is presented. The particle is assumed to be much smaller than the wavelength, i.e., the so-called long-wavelength approximation. Based on this theoretical development, closed-form expressions for the radiation force of a traveling and standing plane wave exerted on a prolate spheroidal particle are derived in the dipole approximation. As validation, the previous analytical result considering a standing wave interacting with a spheroid in axisymmetric configuration is recovered, as well as numerical results obtained with the boundary-element method. PMID- 30522304 TI - Alternating direction method of multipliers for weighted atomic norm minimization in two-dimensional grid-free compressive beamforming. AB - An algorithm is developed based on alternating direction method of multipliers to solve the weighted atomic norm minimization in two-dimensional grid-free compressive beamforming. Simulations and experiments are carried out to compare this algorithm with the off-the-shelf interior point method based sdpt3 solver in cvx toolbox. Whether a standard uniform rectangular array or a non-uniform array constructed by a small number of microphones is utilized, this algorithm is feasible and faster. PMID- 30522305 TI - Two-step hybrid calibration of remote microphones. AB - A two-step, hybrid procedure to calibrate the remote microphones is presented. The calibration obtained in this manner can be directly applied to the measured pressure spectrum without resorting to any modeling or assumptions about the shape of the calibration curve. To demonstrate an application of the methodology, measurements of wall pressure fluctuations underneath a zero pressure gradient turbulent boundary layer were made. The calibrated pressure spectrum is shown to be qualitatively and quantitatively consistent with previous experimental studies and an empirical model, indicating the accuracy of the hybrid calibration technique. PMID- 30522306 TI - Ultrasonic sector imaging using plane wave synthetic focusing with a convex array transducer. AB - Synthetic transmit focusing (STF) methods using unfocused waves or plane waves (PWs) have recently been investigated extensively. However, STF using PWs with a convex array (PWSTF-CA) has not been rigorously studied for high-resolution sector imaging. In this paper, the authors suggest an analytical model for accurate characterization of the spatial beam patterns of PWSTF-CA using a large range of either uniformly or non-uniformly distributed PW angles. On the basis of the model, a frame-based PWSTF-CA approach with non-uniform PW angles is suggested to achieve superior image quality at a higher frame rate than conventional transmit focusing (CTF). The analytical model can also be used for optimal selection of a set of PW angles to scan the entire sectorial field of view and its subsets employed for STF at each imaging point. The authors also investigate how to select transmit subarrays for each of the PWs to obtain the best spatial resolution. A theoretical analysis and simulations are conducted for the verification of the analytical model and the optimal utilization strategy of PWSTF-CA. The results indicate that the PWSTF-CA improves not only the frame rate but also the contrast, signal-to-noise ratio, and resolution compared with the CTF, as in the case of PWSTF with linear arrays. PMID- 30522307 TI - Guided acoustic wave interaction with flanged junctions in water-filled steel pipelines. AB - The interactions of guided acoustic waves with pipelines and associated components has become a topic of interest due to their application in water pipeline condition assessment. In this paper, guided acoustic wave interactions with flanged junctions in a water-filled pipeline are investigated by an analytical model and experimental measurements. In the model, axial wavenumbers, displacement, and stress profiles of the main pipeline and flange junction components are calculated by an existing cylindrical waveguide analytical model. These components are then concatenated together using mode matching to determine the overall theoretical characteristics. Experiments with a flanged water-filled steel pipeline are carried out to verify model predictions. Transmitted signals are acquired using acoustic transducers uniformly spaced along the pipeline axis to separate individual modes and extract mode amplitudes. Transmission losses are estimated by comparing the extracted amplitudes in a pipeline with and without the flanged junction. Both theoretical predictions and experimental results indicate that the flanged junction interacts with pipeline wall dominant modes by transforming them into waterborne modes and as a result guides acoustic power into the water medium. The flange is shown to cause a small transmission loss in waterborne modes as compared to the pipeline without flanges. PMID- 30522308 TI - Sparse Bayesian learning for beamforming using sparse linear arrays. AB - Sparse linear arrays such as co-prime and nested arrays can resolve more sources than the number of sensors. In contrast, uniform linear arrays (ULA) cannot resolve more sources than the number of sensors. This paper demonstrates this using Sparse Bayesian learning (SBL) and co-array MUSIC for single frequency beamforming. For approximately the same number of sensors, co-prime and nested arrays are shown to outperform ULA in root mean squared error. This paper shows that multi-frequency SBL can significantly reduce spatial aliasing. The effects of different sparse sub-arrays on SBL performance are compared qualitatively using the Noise Correlation 2009 experimental data set. PMID- 30522309 TI - Acoustic resonances in gas-filled spherical bulb with parabolic temperature profile. AB - Acoustics is used to probe the temperature profile within a sulfur plasma lamp. A spherically symmetric temperature profile is assumed that drops with the square of the radius, consistent with a constant volumetric heating model. Acoustic resonance frequencies are calculated exactly in the case of an ideal gas. Experimental measurement of a few resonant frequencies allows determination of the temperature profile curvature. This technique can be viewed as an extension of ultrasonic resonant spectroscopy to systems that are highly non-uniform due to off-equilibrium energy flow. PMID- 30522310 TI - Effects of intelligibility on within- and cross-modal sentence recognition memory for native and non-native listeners. AB - The goal of the study was to examine whether enhancing the clarity of the speech signal through conversational-to-clear speech modifications improves sentence recognition memory for native and non-native listeners, and if so, whether this effect would hold when the stimuli in the test phase are presented in orthographic instead of auditory form (cross-modal presentation). Sixty listeners (30 native and 30 non-native English) participated in a within-modal (i.e., audio audio) sentence recognition memory task (Experiment I). Sixty different individuals (30 native and 30 non-native English) participated in a cross-modal (i.e., audio-textual) sentence recognition memory task (Experiment II). The results showed that listener-oriented clear speech enhanced sentence recognition memory for both listener groups regardless of whether the acoustic signal was present during the test phase (Experiment I) or absent (Experiment II). Compared to native listeners, non-native listeners had longer reaction times in the within modal task and were overall less accurate in the cross-modal task. The results showed that more cognitive resources remained available for storing information in memory during processing of easier-to-understand clearly produced sentences. Furthermore, non-native listeners benefited from signal clarity in sentence recognition memory despite processing speech signals in a cognitively more demanding second language. PMID- 30522311 TI - Development and validation of a spectro-temporal processing test for cochlear implant listeners. AB - Psychophysical tests of spectro-temporal resolution may aid the evaluation of methods for improving hearing by cochlear implant (CI) listeners. Here the STRIPES (Spectro-Temporal Ripple for Investigating Processor EffectivenesS) test is described and validated. Like speech, the test requires both spectral and temporal processing to perform well. Listeners discriminate between complexes of sine sweeps which increase or decrease in frequency; difficulty is controlled by changing the stimulus spectro-temporal density. Care was taken to minimize extraneous cues, forcing listeners to perform the task only on the direction of the sweeps. Vocoder simulations with normal hearing listeners showed that the STRIPES test was sensitive to the number of channels and temporal information fidelity. An evaluation with CI listeners compared a standard processing strategy with one having very wide filters, thereby spectrally blurring the stimulus. Psychometric functions were monotonic for both strategies and five of six participants performed better with the standard strategy. An adaptive procedure revealed significant differences, all in favour of the standard strategy, at the individual listener level for six of eight CI listeners. Subsequent measures validated a faster version of the test, and showed that STRIPES could be performed by recently implanted listeners having no experience of psychophysical testing. PMID- 30522312 TI - Segmentation of binaural room impulse responses for speech intelligibility prediction. AB - The two most important aspects in binaural speech perception-better-ear-listening and spatial-release-from-masking-can be predicted well with current binaural modeling frameworks operating on head-related impulse responses, i.e., anechoic binaural signals. To incorporate effects of reverberation, a model extension was proposed, splitting binaural room impulse responses into an early, useful, and late, detrimental part, before being fed into the modeling framework. More recently, an interaction between the applied splitting time, room properties, and the resulting prediction accuracy was observed. This interaction was investigated here by measuring speech reception thresholds (SRTs) in quiet with 18 normal hearing subjects for four simulated rooms with different reverberation times and a constant room geometry. The mean error with one of the most promising binaural prediction models could be reduced by about 1 dB by adapting the applied splitting time to room acoustic parameters. This improvement in prediction accuracy can make up a difference of 17% in absolute intelligibility within the applied SRT measurement paradigm. PMID- 30522313 TI - Improving the soundscape quality of urban areas exposed to aircraft noise by adding moving water and vegetation. AB - Research shows that the sight of trees and the sound of moving water improve the soundscape quality of outdoor spaces exposed to road traffic noise. Effects are attributed to non-energetic masking, visual attentional distortion, and congruence between sight and hearing. However, there is no literature on such effects for aircraft noise. Aircraft noise varies from other traffic sources, i.e., in terms temporal variability, duration, and spectral composition, complicating the application of findings without further research. In a virtual reality experiment reported in this article, participants were asked to rate scenarios with different sound levels of flyovers, urban typologies, vegetation, and/ or water features. The results showed a significant improvement of the soundscape quality when (1) vegetation and (2) moving water were present, and especially when (3) vegetation and moving water were presented simultaneously, especially for residential areas in terms of the relative change. Moving water also reduced the saliency of aircraft flyovers significantly, changing the constellation of fore- and background sounds. Moving water raised the perceived audibility of the most dominant sound source too, which could be attributed to non-energetic masking effects. The findings of this study indicate that soundscape strategies can complement noise abatement in areas prone to aircraft noise. PMID- 30522314 TI - Sound field reconstruction using multipole equivalent source model with un-fixed source locations. AB - The equivalent source methods (ESM) that have been developed to this point can generally be classified into two categories: one in which a relatively large number of lower order sources are fixed at various locations, and one in which a series of higher order sources are fixed at one location. The present work started with a model in the latter category, but the individual sources were then allowed to move separately to locations which were determined by using a nonlinear optimization procedure based on the measured sound field data. To test this approach, experiments were conducted using a small loudspeaker cabinet; measurements were made using an array of microphones on all sides of the loudspeaker. It was found that by allowing the source components to move, the sound field representation in both the near and far fields was improved, particularly at high frequencies, compared to the model with fixed source locations. By comparison with results obtained from boundary element calculations based on laser vibrometer measurements of the loudspeaker's diaphragm and tweeter velocities, it was found that the proposed ESM can also be used to accurately predict the sound pressure distribution on the source surface. PMID- 30522315 TI - Examining replicability of an otoacoustic measure of cochlear function during selective attention. AB - Attention to a target stimulus within a complex scene often results in enhanced cortical representations of the target relative to the background. It remains unclear where along the auditory pathways attentional effects can first be measured. Anatomy suggests that attentional modulation could occur through corticofugal connections extending as far as the cochlea itself. Earlier attempts to investigate the effects of attention on human cochlear processing have revealed small and inconsistent effects. In this study, stimulus-frequency otoacoustic emissions were recorded from a total of 30 human participants as they performed tasks that required sustained selective attention to auditory or visual stimuli. In the first sample of 15 participants, emission magnitudes were significantly weaker when participants attended to the visual stimuli than when they attended to the auditory stimuli, by an average of 5.4 dB. However, no such effect was found in the second sample of 15 participants. When the data were pooled across samples, the average attentional effect was significant, but small (2.48 dB), with 12 of 30 listeners showing a significant effect, based on bootstrap analysis of the individual data. The results highlight the need for considering sources of individual differences and using large sample sizes in future investigations. PMID- 30522316 TI - Playability of the wolf note of bowed string instruments. AB - Playability is an important aspect of the evaluation of bowed string instruments. The well-known "wolf note" of a cello is a particularly obvious playability issue, and it has been suggested that susceptibility to wolfiness might be deduced directly from a measurement of the Schelleng minimum bow force for the playing of a steady note. This prediction is explored by comparing physical measurements with the experience of players after making controlled mechanical changes to a cello. Experienced luthiers and musicians made subjective judgements of changes in the severity of the wolf note, under blinded conditions. The results strongly suggest a direct and intimate link between the measurable acoustical parameter and perceptual discrimination. This simple acoustical measurement can help instrument makers to identify problem notes, and to assess the effectiveness of different possible interventions. PMID- 30522317 TI - Self-localization of a mobile swarm using noise correlations with local sources of opportunity. AB - Groups of coordinated underwater vehicles or sensors are powerful tools for monitoring the ocean. A requirement of many coordinated surveys is to determine a spatial reference between each node in a swarm. This work considers the self localization of a swarm of independently moving vehicles using acoustic noise from a dominating incoherent source recorded by a single hydrophone onboard each vehicle. This method provides an inexpensive and infrastructure-free spatial reference between vehicles. Movement between the vehicles changes the swarm geometry and a self-localization estimate must be generated from data collected on short time scales. This challenges past self-localization approaches for acoustic arrays. To overcome this challenge, the proposed self-localization algorithm jointly estimates the vehicle geometry and the directionality of the ambient noise field, without prior knowledge of either estimate. To demonstrate this method, experimental results are provided when a boat is the main dominating source. The results demonstrate the ability to both estimate the direction of arrival of the boat and the relative positions of the vehicles in the swarm. The approach in this paper is not limited to moving vessels. Simulations are provided to examine three different factors that affect the proposed solution: inter vehicle motion, vehicle geometry, and the azimuthal variance of the noise field. PMID- 30522318 TI - Fundamental-frequency discrimination based on temporal-envelope cues: Effects of bandwidth and interference. AB - Both music and speech perception rely on hearing out one pitch in the presence of others. Pitch discrimination of narrowband sounds based only on temporal-envelope cues is rendered nearly impossible by introducing interferers in both normal hearing listeners and cochlear-implant (CI) users. This study tested whether performance improves in normal-hearing listeners if the target is presented over a broad spectral region. The results indicate that performance is still strongly affected by spectrally remote interferers, despite increases in bandwidth, suggesting that envelope-based pitch is unlikely to allow CI users to perceive pitch when multiple harmonic sounds are presented at once. PMID- 30522319 TI - ACOUSTICAL STANDARDS NEWS. AB - American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, S3/SC 1, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, animal bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes a catalog of Acoustical American National Standards. To receive a copy of the latest Standards catalog, please contact asastds@acousticalsociety.org.Comments are welcomed on all material in Acoustical Standards News.This Acoustical Standards News section in JASA and other information on the Standards Program of the Acoustical Society of America are available via the ASA home page: http://acousticalsociety.org. PMID- 30522320 TI - Nonlinear ultrasound parameter to monitor cell death in cancer cell samples. AB - A scaling subtraction method was proposed to analyze the radio frequency data from cancer cell samples exposed to an anti-cancer drug and to estimate a nonlinear parameter. The nonlinear parameter was found to be well correlated (R2 = 0.62) to the percentage of dead cells in apoptosis and necrosis. The origin of the nonlinearity may be related to a change in contacts between cells, since the nonlinear parameter was well correlated to the average total coordination number of binary packings (R2 >= 0.77). These results suggest that the scaling subtraction method may be used to early quantify chemotherapeutic treatment efficiency. PMID- 30522321 TI - A straightforward method for estimating the size of leaks in water pipelines using acoustic transients. AB - A straightforward explicit expression is derived for estimating the size and position of leaks in a water pipeline using the acoustic transient response. Experimental results are provided for a water pipeline with multiple leaks to demonstrate the usefulness and performance of the proposed approach. The form of the leak estimation expression can be further combined with an existing explicit expression derived for blockage detection. Using this combined expression it is also demonstrated that the proposed approach can detect and estimate leaks and blockages when they are simultaneously present in pipelines. PMID- 30522322 TI - An analysis of beamforming algorithms for passive bottom reflection-loss estimation. AB - This study provides an argument cautioning against the use of adaptive beamforming (ABF) techniques in conjunction with a known method for estimating the bottom reflection loss from natural marine ambient noise. This application of ABF has been investigated in the past with rather inconsistent results. Furthermore, no formal proof that ABF algorithms do indeed provide an estimate of the bottom reflection loss is available. This study moves from a recent derivation of the relationship between the bottom reflection coefficient and the Fourier transform of the marine-noise spatial coherence function. The circumstances under which the beamforming operation approximates a discrete Fourier transform (DFT) of the spatial coherence function estimated from array data are analyzed. It is shown that, under certain conditions, conventional beamforming is equivalent to directly computing the DFT of the coherence function, as long as some subtle details are properly taken into account. Furthermore, it is shown that ABF cannot be guaranteed, in general, to perform this operation, and therefore provide an estimate of the bottom reflection coefficient. The conclusions are demonstrated on simulated and measured data. PMID- 30522323 TI - A synaptic theory of internal delays. AB - Neurons in the medial superior olive perform a coincidence analysis between inputs from the two ears, as predicted by Jeffress [J. Comp. Psychol. 41, 35-39 (1948)]. Jeffress also correctly predicted inputs to express a range of internal delays for which he invoked axonal delay lines. These, however, cannot explain that the inputs of many binaural neurons differ by a combination of a time delay and a phase shift. This study proposes an alternative source of internal delay. An interaural asymmetry in the activation threshold of the inner hair cell synapses is shown to reproduce the main features of internal delays of binaural neurons. PMID- 30522324 TI - Modeling underwater hearing and sound localization in the frog Xenopus laevis. AB - Animals that are small compared to sound wavelengths face the challenge of localizing a sound source since the main cues to sound direction-interaural time differences (ITD) and interaural level differences (ILD)-both depend on size. Remarkably, the majority of terrestrial vertebrates possess internally coupled ears (ICE) with an air-filled cavity connecting the two eardrums and producing an inherently directional middle-ear system. Underwater, longer wavelengths and faster sound-speed reduce both ITD and ILD cues. Nonetheless, many animals communicate through and localize underwater sound. Here, a typical representative equipped with ICE is studied: the fully aquatic clawed frog Xenopus laevis. It is shown that two factors improve underwater sound-localization quality. First, inflated lungs function as Helmholtz resonator and generate directional amplitude differences between eardrum vibrations in the high-frequency (1.7-2.2 kHz) and low-frequency (0.8-1.2 kHz) range of the male advertisement calls. Though the externally arriving ILDs practically vanish, the perceived internal level differences are appreciable, more than 10 dB. As opposed to, e.g., lizards with thin and flexible eardrums, plate-like eardrums are shown to be Xenopus' second key to successfully handling aquatic surroundings. Based on ICE, both plate-like eardrums and inflated lungs functioning as Helmholtz resonators explain the phonotaxis performance of Xenopus. PMID- 30522325 TI - Hearing sensitivity evaluated by the auditory brainstem response in Miniopterus fuliginosus. AB - This study evaluated the hearing sensitivity of Miniopterus fuliginosus, a frequency-modulating (FM) bat species, by measuring the auditory brainstem responses in the inferior colliculus. The average audiogram was U-shaped. The mean threshold decreased gradually as the frequency increased from 16 to 40 kHz and then decreased rapidly as the frequency reached 46 kHz, with the peak sensitivity occurring at the terminal portion of the echolocation pulse between frequencies of 44 and 56 kHz. The shape of audiogram of M. fuliginosus is consistent with other FM bats, and is compared with its vocalization behavior. PMID- 30522326 TI - Cross-language differences in how voice quality and f 0 contours map to affect. AB - The relationship between prosody and perceived affect involves multiple variables. This paper explores the interplay of three: voice quality, f 0 contour, and the hearer's language background. Perception tests were conducted with speakers of Irish English, Russian, Spanish, and Japanese using three types of synthetic stimuli: (1) stimuli varied in voice quality, (2) stimuli of uniform (modal) voice quality incorporating affect-related f 0 contours, and (3) stimuli combining specific non-modal voice qualities with the affect-related f 0 contours of (2). The participants rated the stimuli for the presence/strength of affective colouring on six bipolar scales, e.g., happy-sad. The results suggest that stimuli incorporating non-modal voice qualities, with or without f 0 variation, are generally more effective in affect cueing than stimuli varying only in f 0. Along with similarities in the affective responses across these languages, many points of divergence were found, both in terms of the range and strength of affective responses overall and in terms of specific stimulus-to-affect associations. The f 0 contour may play a more important role, and tense voice a lesser role in affect signalling in Japanese and Spanish than in Irish English and Russian. The greatest cross-language differences emerged for the affects intimate, formal, stressed, and relaxed. PMID- 30522327 TI - Acoustic remote sensing for source localization and atmospheric tomography: Applications of the cross-correlation Green's function retrieval method. AB - In this work, the application of the cross-correlation Green's function retrieval method for source localization and atmospheric acoustic tomography is presented. Open field experimental measurements of an acoustic source, with an impulsive waveform, are conducted for the evaluation of an array system. Of particular interest are the source localization and sound speed estimation capabilities of the array system. The cross-correlation delay-and-sum beamformer is used to estimate source directivity and sound speed. This beamformer inherently employs the cross-correlation Green's function retrieval method between a pair of receivers. The beamforming results adequately identify the various source directions as well as the scatterers along the propagation path. Reasonable sound speed estimates are obtained at the peak frequency of the retrieved Green's functions. In the case of atmospheric acoustic tomography, the estimated sound speed from the array system can serve as an average background sound speed in a tomographic inversion algorithm. Utilizing a tomographic inversion algorithm with radial basis functions and the estimated sound speed, the reconstruction of temperature and wind velocity profiles are demonstrated. PMID- 30522328 TI - Three-dimensional printable ultrasound transducer stabilization system. AB - When using ultrasound imaging of the tongue for speech recording/research, submental transducer stabilization is required to prevent the ultrasound transducer from translating or rotating in relation to the tongue. An iterative prototype of a lightweight three-dimensional-printable wearable ultrasound transducer stabilization system that allows flexible jaw motion and free head movement is presented. The system is completely non-metallic, eliminating interference with co-recorded signals, thus permitting co-collection and co registration with articulometry systems. A motion study of the final version demonstrates that transducer rotation is limited to 1.25 degrees and translation to 2.5 mm-well within accepted tolerances. PMID- 30522329 TI - Characteristics of vocalisations recorded from free-ranging Shepherd's beaked whales, Tasmacetus shepherdi. AB - Beaked whales (family Ziphiidae) are among the least studied of all the large mammals. This is especially true of Shepherd's beaked whale (Tasmacetus shepherdi), which until recently had been very rarely sighted alive, with nothing known about the species' acoustic behaviour. Vocalisations of Shepherd's beaked whales were recorded using a hydrophone array on two separate days during marine mammal surveys of the Otago submarine canyons in New Zealand. After carefully screening the recordings, two distinct call types were found; broadband echolocation clicks, and burst pulses. Broadband echolocation clicks (n = 476) had a median inter-click-interval (ICI) of 0.46 s and median peak frequency of 19.2 kHz. The burst pulses (n = 33) had a median peak frequency of constituent clicks (n = 1741) of 14.7 kHz, and median ICI of 11 ms. These results should be interpreted with caution due to the limited bandwidth used to record the signals. To the authors' knowledge, this study presents the first analysis of the characteristics of Shepherd's beaked whale sounds. It will help with identification of the species in passive acoustic monitoring records, and future efforts to further analyse this species' vocalisations. PMID- 30522330 TI - From fragments to identity: reminiscence, life review and well-being of holocaust survivors. An integrative review. AB - OBJECTIVES: Survivors of the Holocaust have reached an age during which it is common for them to look back on their lives. Previous research has shown that reminiscence can take on either adaptive ('self-positive') or detrimental ('self negative') forms, which in turn are differently linked to psychological well being. Thus, the question of "why" and "how" Holocaust survivors recall their autobiographical memories may hold important information about the underlying coping processes at play. This review aims to give insight into the current state of research on these questions. METHOD: A systematic literature search was conducted, looking for articles reporting quantitative and qualitative research on reminiscence and narrative styles, life review and well-being of Holocaust survivors. A methodological quality assessment was undertaken. RESULTS: 23 articles met the criteria for inclusion. These articles focused either on reminiscence functions or on content and structure of life narratives. Such autobiographical reports were shaped by the experience of Holocaust. However, actual well-being was particularly determined by positive life events. Studies found evidence for resilience and ongoing effort to integrate the past into a coherent review. The link between reminiscence and health remains stable even after massive trauma. Contextual influences (such as culture) and age are discussed as possible covariates. CONCLUSIONS: The results show that Holocaust survivors are able to use reminiscence in a functional way, though they are increasingly more vulnerable as they reach very old age. The link between past suffering and present well-being gets stronger with age. Other stressful life experiences after the Holocaust must be considered as exacerbating factors. This review also presents the implications for therapy and open research questions are discussed. PMID- 30522331 TI - Assessing hostility in patients with chronic obstructive pulmonary disease (COPD). AB - COPD is a disease that can adversely affect patients' psychology. The purpose of this study is to investigate whether COPD patients feel increased hostility, and if hostility is associated with socio-economic factors. A cross-sectional study was conducted in 203 COPD patients in primary health care services in Greece, using the hostility and direction of hostility questionnaire HDHQ. Patient demographics, smoking habits, body mass index (BMI) and disease grade were also recorded. The results showed significant differences between males and females, with women exhibiting higher hostility (p = 0.004). Age correlates negatively with hostility, with younger patients showing higher values. Patients who continue to smoke (p = 0.005), and those in a very poor financial situation, have a much higher level of hostility. Regarding family status, married patients show the least hostility. In patients with very severe COPD and those with low education (p = 0.035) there is a high level of self-criticism. In conclusion, patients with COPD, still smokers, single, low-income and low-educated, especially female patients, have a higher risk of developing hostility. These findings suggest a need for further research in order to clarify the complexity of the different risk factors. PMID- 30522332 TI - Management of Extremity Venous Thrombosis in Neonates and Infants: An Experience From a Resource Challenged Setting. AB - We aimed to evaluate the outcome of different treatment modalities for extremity venous thrombosis (VT) in neonates and infants, highlighting the current debate on their best tool of management. This retrospective study took place over a 9 year period from January 2009 to December 2017. All treated patients were referred to the vascular and pediatric surgery departments from the neonatal intensive care unit. All patients underwent a thorough history-taking as well as general clinical and local examination of the affected limb. Patients were divided into 2 groups: group I included those who underwent a conservative treated with the sole administration of unfractionated heparin (UFH), whereas group II included those who were treated with UFH plus warfarin. Sixty-three patients were included in this study. They were 36 males and 27 females. Their age ranged from 3 to 302 days. Forty-one (65%) patients had VT in the upper limb, whereas the remaining 22 (35%) had lower extremity VT. The success rate of the nonsurgical treatment was accomplished in 81% of patients. The remaining 19% underwent limb severing, due to established gangrene. The Kaplan-Meier survival method revealed a highly significant increase in both mean and median survival times in those groups treated with heparin and warfarin compared to heparin-only group ( P < .001). Nonoperative treatment with anticoagulation or observation (ie, wait-and-see policy) alone may be an easily applicable, effective, and a safe modality for management of VT in neonates and infants, especially in developing countries with poor or highly challenged resource settings. PMID- 30522333 TI - Associations Between Unhealthy Lifestyle Behaviors and Metabolic Syndrome by Gender in Young Adults. AB - OBJECTIVE:: Unhealthy lifestyle behaviors, such as smoking, drinking, betel-quid chewing, insufficient exercise, and inadequate sleep are significantly correlated with metabolic syndrome (MetS). To further understand this relationship, this study examined the main effect of unhealthy lifestyle behaviors and their interaction on MetS by gender in young adults. METHOD:: A cross-sectional study involving 694 young adults from a national survey was performed in which demographic characteristics, unhealthy lifestyle behaviors, anthropometric measurements, and blood chemistry panels were collected during face-to-face interviews. RESULTS:: The prevalence of MetS among young adults was 17.4% and was greater in males than females (19.0% vs. 7.8%). The unhealthy lifestyle-behavior risk factors associated with MetS included smoking (odds ratio [ OR] = 4.53) and physical activity ( OR = 0.51) among males and betel-quid chewing ( OR = 8.90) and less sleep ( OR = 0.08) among females. Significant interaction effects were observed between the abovementioned behaviors and gender for the risk of developing MetS. CONCLUSION:: These results can guide health-care providers in reducing MetS risk by encouraging young adult males to reduce or quit cigarette smoking and maintain optimum levels of physical activity and young adult females to quit chewing betel quid and obtain appropriate amounts of sleep. PMID- 30522334 TI - Subcutaneous Insulin Administration: Sufficient Progress or Ongoing Need? PMID- 30522335 TI - A longitudinal study of the relationship between intimate partner violence and postpartum unsafe sex among newly diagnosed HIV-infected South African women. AB - HIV-positive women who engage in postpartum unsafe sex are at risk for sexually transmitted infection (STI), unintended pregnancy, and secondary transmission of HIV to uninfected partners. One factor that may increase risk for postpartum unsafe sex among HIV-positive women is intimate partner violence (IPV) victimization; few studies, however, have examined this association. This longitudinal study examined whether patterns of psychological, physical, and sexual IPV, assessed during pregnancy, predicted unsafe sex at 14 weeks postpartum among South African women diagnosed as HIV-positive during pregnancy (n = 561). In a latent class analysis, we identified three distinct patterns of IPV victimization: non-victims (74%), moderate IPV (20%), and multiform severe controlling IPV (5%). Compared to non-victims, victims of multiform severe controlling IPV were significantly more likely to engage in postpartum unsafe sex (p = .01), even after adjusting for potential confounding factors. Moderate IPV was not associated with postpartum unsafe sex. Findings support the need for targeted sexual risk reduction interventions for HIV-positive pregnant women who have experienced severe patterns of IPV. PMID- 30522336 TI - A Proposed Framework for a Globally Applicable Pragmatic Approach to Using Facilitated Regulatory Pathways. AB - BACKGROUND:: As regulatory agencies come under increased pressure to review medicines of critical importance through efficient regulatory systems to provide equitable access, the benefits of using expedited review pathways are being explored. These facilitated regulatory pathways (FRPs) provide a variety of review strategies that can also expedite assessments. Stringent regulatory authorities (SRAs) use primary FRPs to accelerate development or to shorten review time. Some emerging national regulatory authorities can implement primary FRPs but are more likely to use secondary FRPs that rely on or recognize an SRA or reference agency decision, the World Health Organization Collaborative Prequalification of Medicines Programme, "altruistic" reviews, or collaborative work sharing. Despite their availability, there are no formal guidelines or consensus for the definition, basic elements, or best practices for FRPs. METHODS:: Herein, we present a 4-step pragmatic approach to a framework designed to help agencies determine how best to use FRPs. Each step is based on characteristics identified through research, surveys, literature assessments, regulatory capacity categorization analyses, and practical experience. RESULTS:: Step 1 assesses 4 domains of the environment preparedness, step 2 offers process criteria that should be in place to effectively use an FRP, step 3 tiers agencies through a self-assessment of readiness and capacity, and step 4 provides a pathway for agencies to determine the most relevant FRP for their use. Target timelines are proposed for FRPs. CONCLUSIONS:: This framework represents the first endeavor to holistically address the multifaceted aspects that should be considered for the effective use of an FRP. PMID- 30522337 TI - The Sniffin' Sticks Odor Discrimination Memory Test: A Rapid, Easy-to-Use, Reusable Procedure for Testing Olfactory Memory. AB - OBJECTIVES:: Neurodegenerative diseases can alter odor memory in addition to inducing quantitative impairment, and olfactory memory can be tested using the validated olfactory memory test with encapsulated odors (Odor Discrimination Memory Test [ODMT]). The aim of this study was to investigate the new Sniffin' Sticks ODMT (SSODMT), which is comparable with the ODMT. METHODS:: The SSODMT was administered to 48 subjects (30 women, 18 men; mean age, 34.6 +/- 16.3 years). Olfactory function was assessed using the 16-item Sniffin' Sticks Identification Test. The ODMT was administered to a subgroup of 10 subjects to assess the comparability of the SSODMT and the ODMT. Test-retest reliability was studied in another 20 subjects (10 women, 10 men; mean age, 32.9 +/- 16.4 years). RESULTS:: The mean SSODMT score was 10.7 +/- 1.8 (range, 5-12). SSODMT test scores were significantly correlated with Sniffin' Sticks Identification Test scores ( r67 = 0.66, P < .001) and were significantly negatively correlated with subject age ( r48 = -0.70, P < .001). SSODMT and ODMT scores were highly and significantly correlated, indicating that the test results were comparable ( r10 = 0.75, P < .05). Test-retest analysis revealed a significant correlation ( r20 = 0.68, P < .001). CONCLUSIONS:: These results demonstrate the usefulness of the new SSODMT and its comparability with the ODMT. The SSODMT is an easy, rapid, and low-cost tool that is suitable for routine use in evaluating odor memory. PMID- 30522338 TI - Pharmacists' Perspectives on Practice, Availability, and Barriers Related to Opioids in Georgia. AB - OBJECTIVES:: To explore pharmacists' perspectives on practice, availability, and barriers related to opioids. METHODS:: This cross-sectional study evaluated pharmacists' perspectives on practice, availability, and barriers related to opioids. Electronic surveys were distributed to pharmacists practicing in Georgia via Survey Monkey. The chi2 or Fisher Exact test was used to test differences in practice, availability, and barriers with respect to type of pharmacy and location of pharmacy. RESULTS:: Most participating pharmacists practiced in an independent (47%) or community chain pharmacies (37%). The majority checked the Prescription Drug-Monitoring Program (PDMP) on a regular basis (73%), and about a third reported contacting the prescriber prior to dispensing. The most common barrier included concerns about diversion (82%) and illicit use (90%). About two thirds reported experiencing a shortage of opioids. Significant differences ( P < .05) were found between types of pharmacy in dispensing practices, availability, and barriers. No significant differences were found with respect to pharmacy location. CONCLUSION:: Findings suggest that pharmacists are facing challenges in availability of opioids and are employing stewardship approaches to optimize dispensing practices. This research provides insight regarding broken links in the "pain relief chain" and identifies opportunities to improve the accessibility of opioids when medically indicated. Pharmacists can play an important role in addressing the opioid crisis as well as providing quality care to patients with cancer seeking pain relief. PMID- 30522339 TI - Obtaining quality data using behavioral measures of impulsivity in gambling research with Amazon's Mechanical Turk. AB - BACKGROUND AND AIMS: To date, no research has examined the viability of using behavioral tasks typical of cognitive and neuropsychology within addiction populations through online recruitment methods. Therefore, we examined the reliability and validity of three behavioral tasks of impulsivity common in addiction research in a sample of individuals with a current or past history of problem gambling recruited online. METHODS: Using a two-stage recruitment process, a final sample of 110 participants with a history of problem or disordered gambling were recruited through MTurk and completed self-report questionnaires of gambling involvement symptomology, a Delay Discounting Task (DDT), Balloon Analogue Risk Task (BART), Cued Go/No-Go Task, and the UPPS-P. RESULTS: Participants demonstrated logically consistent responding on the DDT. The area under the empirical discounting curve (AUC) ranged from 0.02 to 0.88 (M = 0.23). The BART demonstrated good split-third reliability (rhos = 0.67 to 0.78). The tasks generally showed small correlations with each other (rhos = +/ 0.06 to 0.19) and with UPPS-P subscales (rhos = +/-0.01 to 0.20). DISCUSSION AND CONCLUSIONS: The behavioral tasks demonstrated good divergent validity. Correlation magnitudes between behavioral tasks and UPPS-P scales and mean scores on these measures were generally consistent with the existing literature. Behavioral tasks of impulsivity appear to have utility for use with problem and disordered gambling samples collected online, allowing researchers a cost efficient and rapid avenue for conducting behavioral research with gamblers. We conclude with best-practice recommendations for using behavioral tasks using crowdsourcing samples. PMID- 30522341 TI - Vitamin C for Pregnant Smokers to Improve Infant Lung Function: An Orange a Day Keeps the Respirologist Away? PMID- 30522340 TI - Exploring dimensions of social support and resilience when providing care at the end of life: a qualitative study. AB - BACKGROUND: Research shows that formal and informal social support can facilitate resilience in carers. There is a paucity of research exploring social support and resilience amongst recently bereaved informal carers. AIM: To examine how the presence or absence of distinct dimensions of social support facilitate or hinder resilience in recently bereaved informal carers. PARTICIPANTS: 44 bereaved carers, who had been identified by GP as 'main carer' of someone recently deceased (3-12 months), aged between 38 and 87 years old (mean= 67). METHODS: Thematic analysis then the Ecological Framework of Resilience as an organisational tool to develop overarching themes in the data. We used the Sherbourne and Stewart model to identify social support that was lacking as well as social support that was present. RESULTS: A range of social support types were identified. There was an emphasis on the importance of relationships with both health professionals and family members, including the care recipient. However, social support was not necessary for resilience if the participant had other resources. CONCLUSIONS: Social support for carers providing end of life care is almost exclusively based around end of life care 'work'. In comparison to other research our study suggests that relationships with family and health professionals are paramount. Multidimensional support is needed for carers to enhance their resilience. PMID- 30522342 TI - What does the ecological and epidemiological evidence indicate about the potential for cannabinoids to reduce opioid use and harms? A comprehensive review. AB - Pre-clinical research supports that cannabinoids reduce opioid dose requirements, but few studies have tested this in humans. This review evaluates ecological and epidemiological studies that have been cited as evidence that medical cannabis use may reduce opioid use and opioid-related harms. Medline and Embase were searched for relevant articles. Data were extracted on study setting, analyses approach, covariates, and outcomes. Eleven ecological and 14 epidemiological studies were found. In ecological studies, states that allow medical cannabis laws have reported a slower rate of increase in opioid overdose deaths compared with states without such laws. These differences have increased over time and persisted after controlling for state sociodemographic characteristics and use of prescription monitoring programmes. Few studies have controlled for other potential confounders such as opioid dependence treatment and imprisonment rates. Some epidemiological studies provide evidence that cannabis availability may reduce opioid use, but are limited by selection bias, cross-sectional designs, and self-reported assessments of the opioid-sparing effects of cannabis. Some epidemiological and ecological studies suggest that cannabis may reduce opioid use and harms, although important methodological weaknesses were identified. Well designed clinical studies may provide more conclusive evidence on whether cannabinoids can reduce opioid use and related harm. PMID- 30522344 TI - Differential Response and Children Re-Reported to Child Protective Services: County Data From the National Child Abuse and Neglect Data System (NCANDS). AB - Child protection systems that implement differential response (DR) systems screen to route referrals to an investigation response (IR) or alternative response (AR). AR responses emphasize family engagement, assessment of family needs, and service linkage. Usually, AR state-level policy does not require child welfare staff to make a maltreatment determination. Jurisdictions implement DR systems differently, leading to variations in the proportion of AR cases, risk levels of cases served, and the ways families access and use services. County data from the National Child Abuse and Neglect Data System were analyzed for six states from 2004 to 2013 that implemented DR. Variation in county-level AR rates were associated with county-level re-report rates using regression models with risk adjustments for socioeconomic and other county characteristics. Counties had 3% fewer re-reports overall for each percentage increase in AR use; higher levels of AR use are related to lower levels of re-reporting. When county AR and IR cases were analyzed separately, increasing rates of AR were associated with lower re report rates for IR cases, but higher re-report rates for AR cases. Findings for the AR and IR subgroup must be interpreted with caution as a number of technical factors may be driving these results. PMID- 30522343 TI - Oral Vitamin C (500 mg/day) to Pregnant Smokers Improves Infant Airway Function at 3 Months (VCSIP): A Randomized Trial. AB - RATIONALE: We reported a randomized trial demonstrating daily supplemental vitamin C to pregnant smokers significantly improved newborn pulmonary function tests. The current study tests these results in a new cohort utilizing infant pulmonary function tests. OBJECTIVE: To determine if infants of pregnant smokers randomized to daily supplemental vitamin C would have improved forced expiratory flows (FEFs) at 3 months of age compared to those randomized to placebo, and to investigate the association of the alpha5 nicotinic acetylcholine receptor. METHODS: Randomized, double-blind, placebo-controlled trial conducted at three centers. Two hundred fifty-one pregnant smokers were randomized at 13 to 23 weeks of gestation: 125 randomized to vitamin C (500mg/day) and 126 to placebo. MEASUREMENTS: The primary outcome was FEFs at 3 months of age performed with the raised volume rapid thoracic compression technique (Jaeger/Viasys). MAIN RESULTS: The infants of pregnant smokers randomized to vitamin C (n=113) had the following FEFs at three months of age compared to those randomized to placebo (n=109) as measured by FEF75 (200.7 vs 188.7 mL/sec [adjusted 95% CI for difference, -3.33 to 35.64]; p=0.10), FEF50 (436.7 vs 408.5 mL/sec [adjusted 95% CI for difference, 6.10 to 61.30]; p=0.02), and FEF25-75 (387.4 vs 365.8 mL/sec [adjusted 95% CI for difference, 0.92 to 55.34]; p=0.04). Infant FEFs appeared to be negatively associated with the maternal risk alleles for the alpha5 nicotinic acetylcholine receptor (rs16969968). CONCLUSIONS: These results extend our previous findings and demonstrate improved FEF50 and FEF25-75, predetermined secondary outcomes, at 3 months of age in infants after vitamin C supplementation to pregnant smokers. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01723696. PMID- 30522345 TI - Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex. AB - BACKGROUND: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. OBJECTIVES: To examine the influence of obesity and sex on phenytoin LDs. METHODS: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. RESULTS: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 ug/mL [IQR = 1.4-2.0]; nonobese: 1.8 ug/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 ug/mL [IQR = 1.2-2.1]; female: 1.7 ug/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations. PMID- 30522346 TI - Steglatro (Ertugliflozin): A New Option in the SGLT-2 Inhibitor Market for the Treatment of Type 2 Diabetes Mellitus. AB - OBJECTIVE: The purpose of this article is to review the pharmacological aspects of ertugliflozin and its clinical trials, which led to Food and Drug Administration (FDA) approval for the treatment of type 2 diabetes mellitus (T2DM). DATA SOURCES: A MEDLINE/PubMed (May 2013 to October 2018) search was conducted using the following keywords: ertugliflozin, sodium glucose co transporter 2 inhibitor, SGLT2 inhibitor, type 2 diabetes mellitus, hyperglycemia. Study Selection and Data Extraction Quantify: We included English language articles evaluating ertugliflozin pharmacology, pharmacokinetics, efficacy, and safety in humans for blood glucose reduction in human subjects. DATA SYNTHESIS: Ertugliflozin has been FDA approved and considered both safe and efficacious for the treatment of T2DM with hemoglobin A1C reductions ranging from -0.6% to -1.16%. Safety outcomes appear to be similar to that of other SGLT2 inhibitors. Relevance to Patient Care and Clinical Practice: With this approval, patients and clinicians now have another oral option for treating this difficult disease while minimizing hypoglycemia and other unwanted adverse drug reactions. CONCLUSIONS: With the number of patients with diabetes growing, additional safe and effective treatment options available for clinicians and patients is important. Ertugliflozin appears to be an effective and safe therapy as both single and add-on therapy. PMID- 30522347 TI - Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. AB - OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer. DATA SOURCES: A PubMed search was performed using the terms 'Ribociclib', 'Kisqali', and 'LEE011' between May 2018 and November 2018. References of published articles and reviews were also assessed for additional information. STUDY SELECTION AND DATA EXTRACTION: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib were evaluated. DATA SYNTHESIS: Ribociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is Food and Drug Administration (FDA) approved in combination with endocrine therapy for treatment of HR+/HER2- advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women. Three phase III trials have evaluated ribociclib in combination with endocrine therapy, including letrozole, anastrozole, tamoxifen, and fulvestrant. These studies found that ribociclib 600 mg/d, 21 days on, 7 days off, leads to a significantly greater median progression-free survival (PFS), ranging from 8 to 13 months. Ribociclib is well tolerated in elderly patients, maintains health related quality of life, and significantly reduces pain scores. The dose-limiting toxicities found in phase I studies were neutropenia, thrombocytopenia, and QTc prolongation. Common adverse effects seen in phase III trials include neutropenia, leukopenia, nausea, diarrhea, vomiting, and fatigue. Relevance to Patient Care and Clinical Practice: Literature on the safety and efficacy of ribociclib as well as its place in therapy in comparison to other FDA-approved CDK4/6 inhibitors for breast cancer is discussed. CONCLUSIONS: Ribociclib, when added to endocrine therapy, significantly improves PFS and has manageable toxicity in premenopausal/perimenopausal and postmenopausal women with HR+/HER2- advanced breast cancer. PMID- 30522348 TI - Potential Use of Artificial Intelligence for Regulatory Intelligence: Biopharmaceutical Industry's Views. AB - BACKGROUND:: Pharmaceutical companies rely on regulatory intelligence (RI) to analyze information from internal and external sources. To facilitate RI activities, companies are seeking ways to harness technology to optimize their capabilities. Specifically, there is a growing interest for artificial intelligence (AI) to enhance RI activities. However, exploration of the potential utility of AI and related technologies will be key to begin unlocking these tools for the regulatory community. METHODS:: To identify potential development paths for these technologies, we interviewed over 30 global regulatory leaders at 22 pharmaceutical companies and 3 leading companies in RI and AI technologies. Thirteen of the 22 pharmaceutical companies also provided responses to a subsequent informational survey. RESULTS:: This study elucidated potential value proposition, barriers, and risks to integrating AI into the RI field. Twenty of the 22 participating companies consider that AI offers significant opportunity for RI activities of data processing (mining, searching, monitoring, alerting). Thirty-two percent of companies envisage use in data synthesis (combining different types of information across formats), 36% in data analysis (trends, patterns, predictive analytics), and 23% in decision making. Additionally, results of this research provided insights about the potential role of precompetitive consortia, which may enhance future actualization. CONCLUSIONS:: Opportunity presents for AI to enhance quality, speed, and efficiency of RI activities. This assessment of the current technology landscape revealed a lack of fully developed AI tools; however, the RI community demand is beginning to be recognized. Therefore, now more than ever, the timing to advance AI within the RI field is right. PMID- 30522349 TI - A bona fide need for a non-intravenous cyanide medical countermeasure. PMID- 30522350 TI - Insertable cardiac monitors: current indications and devices. AB - INTRODUCTION: Recurrent unexplained syncope is a well-established indication for an insertable cardiac monitor (ICM). Recently, the indications for an ICM has been expanded. Areas covered: This review article discusses the current indications for ICMs and gives an overview of the latest generation of commercially available ICMs. Expert commentary: The 2018 ESC Syncope guidelines have expanded the indications for an ICM to patients with inherited cardiomyopathy, inherited channelopathy, suspected unproven epilepsy, and unexplained falls. ICMs are also increasingly used for the detection of subclinical atrial fibrillation in patients with cryptogenic stroke. Whether treatment of subclinical atrial fibrillation with oral anticoagulation prevents recurrent stroke is yet unknown. The current generation of ICMs are smaller, easier to implant, have better diagnostics and are capable of remote monitoring. The Reveal LINQ (Medtronic) is the smallest ICM and has the most extensive performance and clinical data. The BioMonitor 2 (Biotronik) is the largest ICM but has excellent R-wave amplitudes, longest longevity and reliable remote monitoring. The Confirm Rx (Abbott) is capable to provide mobile data transmission enabled by a smartphone app. Future generation of ICMs will incorporate heart failures indices to facilitate remote monitoring of heart failure patients. PMID- 30522351 TI - Datura and Brugmansia plants related antimuscarinic toxicity: an analysis of poisoning cases reported to the Taiwan poison control center. AB - INTRODUCTION: Datura and Brugmansia plants, especially Datura species, have been used for their hallucinogenic effects in the United States and Europe; whereas Datura plants have been used as a traditional medicine in many Asian countries. This study was conducted to better understand the pattern and outcome of Datura/Brugmansia plant related poisoning in Taiwan. METHODS: This is a retrospective case series study of all cases with Datura/Brugmansia exposure reported to the Taiwan Poison Control Center between 1986 and 2015. Data for patients with relevant poisoning were reviewed and abstracted. Logistic regression analysis was used to identify potential predictors of the severity of poisoning; bivariate analysis was employed to assess the effectiveness of physostigmine in the treatment of Datura/Brugmansia poisoning. RESULTS: A total of 203 cases involving 114 Datura exposures and 89 Brugmansia suaveolens exposures were eligible for analysis. Using Datura/Brugmansia for a medicinal purpose by the patients without consulting Chinese medicine practitioners was the most common reason of poisoning (81.2%); whereas only 2% of the patients were poisoned after medicinal use associated with the prescription from Chinese medicine practitioners. None of the 203 patients had used Datura/Brugmansia plant for recreational purpose. Most frequently observed clinical effect was mydriasis (53.2%), followed by confusion (40%), tachycardia (35.5%), dry mouth (35.5%), dizziness (34%), dry skin (32.5%), and delirium (31%). Seventy-three cases (36%) had severe effects; none of them died. Misidentification of the plants and ingestion of plant parts other than flowers were positively associated with the severity of poisoning. Forty patients (19.7%) received physostigmine therapy and patients receiving physostigmine had an earlier resolution of central nervous system toxicity than those who did not. CONCLUSIONS: Medicinal use without consulting Chinese medicine practitioners is the main reason for Datura/Brugmansia poisoning in Taiwan. Consumption of parts other than flowers and misidentification of the plants predicted the severity of poisoning in this study. Patients who received physostigmine appear to have earlier improvement in the central nervous system effects. No adverse events were reported from physostigmine administration. PMID- 30522352 TI - An update: emerging drugs for tinnitus. AB - INTRODUCTION: During the last decade, a number of candidate drugs for the treatment of tinnitus have emerged with the hope of alleviating the burden of millions of sufferers with a persisting ringing in their ears. Knowledge of the pathophysiologic mechanisms has progressed remarkably in the recent years, which has led to the identification of potential new drug targets for the treatment of tinnitus. However, pharmacologic interventions are still limited. Areas covered: In this editorial results from recent Phase 3 and Phase 2a trials investigating the NMDA receptor antagonist AM-101 from Auris Medical, the AMPA receptor antagonist BGG492 from Novartis and the Kv3 modulator AUT00063 from Autifony Therapeutics will be discussed. In this context, we will reevaluate the translational development approach from animal models to clinical trials and seize this opportunity to debate and improve future R&D in tinnitus pipeline. Expert opinion: In spite of huge advances in pathophysiologic knowledge and research methodology in the last decades, pharmaceutical research in tinnitus still represents a high-risk field. Important research directions include the identification of potential therapeutic targets and the development of objective outcome measurements to facilitate translational research. PMID- 30522353 TI - The factors impeding health system reform in Iraqi Kurdistan region. AB - The relatively poor health outcomes in Iraq have been attributed to the inability to address the shortfalls in the public health model. Calls for health system reform in Iraqi Kurdistan Region started in 2004; however, few, if any, significant changes have been achieved since then. This research examines the factors impeding public health system reform in the Iraqi Kurdistan Region, as perceived by the health policy makers, through 11 in-depth, unstructured interviews. Participants attributed the delay in reform to 16 impeding factors that can be categorized into 5 major themes: historical, ethical, cultural, political and institutional. The intricate network of these inter-dependent factors provides a possible explanation for the failure or unsustainability of reform efforts. Reform initiatives might have a better chance of success if they take into consideration the well-established and unique background and social construct in Iraq, as well as the impact of decades of conflict and insecurity, both of which influence the individual and institutional reasoning and behaviour across the entire health system. PMID- 30522354 TI - Two-level reverse Bohlman transsoseous approach for treatment of symptomatic pseudarthrosis. AB - Surgical treatment for high-grade spondylolisthesis with high sacral slope remains controversial and no definitive gold standard procedure has been identified. The Bohlman technique, in which a fibular strut is reamed posteriorly across the L5-S1 disc space in an oblique, inferior to superior trajectory, has been increasingly utilized. Recently, a Reverse Bohlman technique has been described, in which a graft is reamed anteriorly across a single disc space in a superior to inferior trajectory. Case Report A 55 year-old male with complete lumbarization of S1 (referred to as L6) and previous L5-L6-S1 posterior instrumented fusion presented, with progressively worsening low back pain and lower extremity radicular pain. After failing conservative management, he underwent a 2-level Reverse Bohlman approach to place a titanium mesh interbody graft (cage) anteriorly from L5 to S1, crossing the L5-6 and L6-S1 disc spaces. Here we describe for the first time a Reverse Bohlman technique spanning two disc spaces in a patient with a transitional lumbosacral anomaly and high sacral slope. At 6 months post-operative follow up, the patient reported near complete resolution of symptoms. PMID- 30522355 TI - Antimicrobial properties of rosin acids-loaded nanoparticles against antibiotic sensitive and antibiotic-resistant foodborne pathogens. AB - Rosin acids (RA) from coniferous trees are used in folk medicine for healing various skin infections. Despite the antimicrobial potential of RA, their poor solubility in aqueous media may limit their use. In this work RA-loaded polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles (RA-NPs) with enhanced antimicrobial properties against foodborne bacterial pathogens were produced. RA-NPs were prepared by solvent displacement technique and characterized for relevant colloidal features by dynamic light scattering, laser Doppler anemometry and transmission electron microscopy. Association of RA to NPs occurred with high yields (86% w/w). RA and RA-NPs (~130 nm) were strongly active against antibiotic-sensitive Gram + pathogens, i.e. Clostridium perfringens, Listeria monocytogenes and antibiotic-resistant Staphylococcus aureus. However, both failed in inhibiting the growth of Gram - pathogens (Campylobacter jejuni, Campylobacter coli, Escherichia coli and Salmonella enterica). Association to NPs enhanced the antimicrobial activity of RA. MIC, IC50, IC90, and MBC values of RA NPs were ten-times lower than RA. RA-NPs did not change the intrinsic toxicity potential of RA. This is the first study on the enhancement of the antimicrobial activity of RA when associated to nanocarriers. This approach may be an effective strategy to produce aqueous-based RA solutions with enhanced antimicrobial activity against antibiotic-sensitive and antibiotic-resistant Gram + pathogens. PMID- 30522356 TI - Formative Research for an Innovative Smartphone Application to Improve Distribution of Healthy Foods to Corner Stores in Baltimore City. AB - We sought to collect information about the operations of wholesalers and store owner perceptions of smartphones to plan for and create a smartphone application that will facilitate the distribution of healthy foods to corner stores. In-depth interviews were conducted with wholesalers, corner store owners, distributors, and food environment experts in Baltimore City, Maryland, which included providing feedback for a mockup of the app. Store owners that were comfortable with smartphones liked the idea of the app because it was economically practical, culturally suitable, simple and easy to use, and provided a large variety of items at a fair or low price. We found that barriers to uptake among corner store owners would be high delivery costs, no foreign language capability, and a complicated user interface. This work will inform future projects that will utilize mHealth technology to improve distribution of healthier foods in food deserts. PMID- 30522357 TI - Berg adder (Bitis atropos) envenoming: an analysis of 14 cases. AB - INTRODUCTION: The berg adder (Bitis atropos) is a little-studied, lesser-known viperid snake found in southern Africa and there is limited information available regarding the manifestations of envenoming. MATERIALS AND METHODS: This observational series of 14 cases documents features of berg adder envenoming over a period of 16 years (1987-2003). Clinical features of envenomed patients: All 14 patients developed local cytotoxic effects. Thirteen patients developed systemic effects manifesting and documented in varying degrees. These include (1) prominent vomiting (2) disturbances in cranial nerve function (anosmia and altered taste, an ophthalmological triad of ptosis, mydriasis and visual disturbances including loss of accommodation, and dysphagia) (3) a global decrease in motor power where mechanical ventilation was often required for respiratory failure and (4) hyponatraemia (lowest value recorded 111 mmol/L), sometimes with associated convulsions. DISCUSSION: The full range of polypeptides present in berg adder venom is yet to be characterised. However, two closely related phospholipases A2 (PLA2; PLA2-1 and PLA2-2) have been purified from the venom of B. atropos and clinical evidence suggests that a natriuretic peptide is also possibly present. Envenoming results in distinctive, sometimes life threatening, manifestations. PMID- 30522358 TI - XPG polymorphisms and their association with lung cancer susceptibility, overall survival and response in North Indian patients treated with platinum-based doublet chemotherapy. AB - AIM: The study investigates association of XPG polymorphism with lung cancer susceptibility, overall survival and clinical outcomes in North Indian population. RESULTS: A significant protective effect was observed for 2228959 C/A polymorphism with lung cancer and its histological subtypes. An increased hazard ratio (HR) was observed in 17655 G/C variant among small-cell lung carcinoma patients with mutant genotype (HR: 2.55; p = 0.05). Individuals treated with irinotecan-cisplatin/carboplatin regimen showed a longer survival time (HR1: 0.04; median survival time [MST]: 32.5 months). Subjects treated with pemetrexed cisplatin/carboplain regimen were associated with higher mortality rate in lung cancer patients (HR1: 1.83; MST: 9.13 months). Conclusion: 2228959 C/A polymorphism contributes to protective effect in lung cancer patients. 2228959 C/A polymorphism might be associated with favorable prognosis in lung cancer risk. PMID- 30522359 TI - Response to "Letter Regarding: Increased Early Revision Rate With the INFINITY Total Ankle Prosthesis". PMID- 30522360 TI - Tonsillar herniation as a complication of lumboperitoneal shunt: case report and literature review. AB - Tonsillar herniation is a rare and seldom reported complication after lumboperitoneal (LP) shunting. There have been only few reports that have presented possible options for treatment with varying degrees of success. In this report, we describe a rare case of tonsillar herniation after LP shunting and review related literature. A 17-year-old girl with hydrocephalus related to a traumatic brain injury underwent implantation of an adjustable pressure shunt (valve setting2.5) and a small lumen peritoneal catheter via the L4-L5 interspinal space. One month later, she was admitted to the emergency room with a Glasgow Coma Scale score ofE1M1Vt and dilated pupil. Image studies demonstrated new-onset tonsillar herniation and a mild cervical syrinx. Emergent suboccipital decompressive craniectomy, C1 laminectomy, and duraplasty were performed. This was followed with ligation of the LP shunt and implantation of a ventriculoperitoneal (VP) shunt a few days later. The patient's Glasgow Coma Scale score gradually recovered to 6, which was her previous neurologic status. Tonsillar herniation as a complication after LP shunting is best treated with decompression, ligation or removal of the LP shunt, and a shift to a VP shunt. The tonsillar herniation should be rapidly addressed to avoid persistent symptoms or progression of the neurologic deficits. PMID- 30522361 TI - Higher offset cross-linked polyethylene acetabular liners: is wear a significant clinical concern? AB - INTRODUCTION:: Total hip arthroplasty (THA) is the 2nd most common total joint replacement surgery in the United States. However, not all THA devices perform well and need revised for several reasons including dislocation. Higher offset acetabular liners reduce this problem by creating a more anatomically/biomechanically natural hip joint, increasing soft-tissue tension, and accommodating larger femoral heads in smaller acetabular cups via increased polyethylene thickness. To our knowledge, however, in vivo wear (another failure mode) performance of offset acetabular liners remains unknown. METHODS:: 2 cohorts of 40 individuals (0-mm, 4-mm offset acetabular liners, respectively) from a single surgeon's consecutive caseload were assessed. 6-week/5-year post-op radiographs were compared using a validated method using SolidWorks software to assess in vivo linear and volumetric wear rates. Resultant surgical offset was also quantified using this method. RESULTS:: Linear wear rate for 0-mm and 4-mm offset cohorts were 0.01 +/- 0.09 mm/year and 0.08 +/- 0.12 mm/year, respectively. Volumetric wear rate for 0-mm and 4-mm offset cohorts were 30.4 +/- 20.4 mm3/year and 61.6 +/- 42.1 mm3/year, respectively. Both of these were statistically significant. Neither linear nor volumetric wear rate was correlated with resultant surgical offset. DISCUSSION:: To our knowledge, this is the 1st study to compare in vivo wear performance of 0-mm and 4-mm offset acetabular liners. Although linear and volumetric wear rates were different between cohorts, neither reached previously established osteolysis thresholds. Moreover, wear rates were not correlated with resultant surgical offset. Finally, no patients in either cohort showed signs of osteolysis nor needed revision. As such, the clinical relevance of the wear rate differences is potentially less significant. PMID- 30522362 TI - Collagenous Spherulosis in Well-Differentiated Papillary Mesothelioma in a Female With Multilocular Peritoneal Inclusion Cysts. AB - Multilocular peritoneal inclusion cysts are mesothelial tumor-like lesions with or without small foci of florid papillary mesothelial hyperplasia that might simulate serous epithelial papillary lesions or well-differentiated papillary mesothelioma (WDPM) of the peritoneum. The papillary cores in papillary mesothelial hyperplasia and in WDPM display a variety of different histomorphologic features. To our knowledge, collagenous spherulosis in WDPM was not previously described or illustrated in the literature. Collagen spherules have been described in several miscellaneous benign and malignant lesions of the breast, prostate, salivary gland, and cutaneous adnexal tumors. They sometimes impose a diagnostically challenging cribriform growth pattern. We report a case of a young adult woman who presented with a large painful palpable multicystic mass in the right iliac fossa and pelvis. Histologically, it showed features of multilocular peritoneal inclusion cysts with an incidental finding of a small nodule demonstrating morphologic and immunohistochemical features of WDPM. The papillary cores revealed uniform homogenous eosinophilic round collagenous spheres with a cribriform pattern. The unusual finding of collagen spherules may expand the morphologic spectrum of mesothelial papillary lesions, the differential diagnosis of female pelvic peritoneal and omental epithelial and nonepithelial lesions and might cause some diagnostic confusion on small specimens. It may also shed some light on the pathophysiology and role of mesothelial and submesothelial stromal cells in the variable morphologic patterns of the stroma of papillary cores in different mesothelial lesions. PMID- 30522363 TI - Periocular Sebaceous Carcinoma With Apocrine Differentiation: A Case Report and Review of the Literature. AB - A 61-year-old man presented with a dome-shaped tumor in the right eyelid. Histology revealed a cutaneous neoplasm with lobular growth pattern. It was composed of large basaloid cells, cells with sebaceous differentiation, and glandular structures with apocrine features. The immunohistochemical study revealed diffuse expression of CK7, EMA, and androgen receptors in the neoplastic cells. Gross cystic disease fluid protein-15 highlighted the luminal cells, consistent with apocrine differentiation. These findings fit with a sebaceous carcinoma with focal glandular apocrine differentiation ("sebo-apocrine" carcinoma). Metastasis to regional lymph nodes were diagnosed 12 months after the surgical procedure. After 3 years of follow-up, the patient is alive, with evidence of persistent locoregional metastasis, but no evidence of distant metastasis. Most cutaneous adnexal tumors present only one cell type of differentiation, but hybrid/combined tumors can occur. Despite "sebo-apocrine" tumors are not unexpected, due to their common origin in the follicular-sebaceous apocrine unit, they are very rarely reported. PMID- 30522364 TI - The effects of preconception examinations on birth defects: A population-based cohort Study in Dongguan City, China. AB - OBJECTIVE: To evaluate the effect of preconception examinations programs on the prevention of birth defects in Dongguan City during 2013-2017. METHODS: The data were from preconception examinations system and the birth defects surveillance system during 2013-2017. The study population included 63 175 infants born to mothers accepted preconception examinations during pregnancy (the screening group) and 649 862 infants whose mother did not check (the control group). The infants included for stillbirth, dead fetus, live birth between 28 weeks of gestation and 7 days after birth and legal pregnancy termination. The risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to examine for the association between birth defects and preconception examinations. We also conducted a stratified analysis based on infant gender and disease classification, and maternal age and region. RESULTS: The incidence of birth defects in the screening group was 134.55/10000, while that in the control group was 241.53/10000. Preconception examinations can effectively reduce the incidence of birth defects (BDs) (RR: 0.557, 95%CI: 0.520-0.597). Bifid spine (RR: 0.076, 95%CI: 0.011-0.545), anencephalia (RR: 0.134, 95%CI: 0.033-0.543) and anorectal atresia or stenosis (RR: 0.151, 95%CI: 0.048-0.471) were controlled best, and Down syndrome (RR: 0.684, 95%CI: 0.435-1.075) was no effect. Young maternal age (14-19 years) and eld maternal age will increase the risk of birth defects. Preconception examinations had the best effect for pregnant women under 25 years of age (RR: 0.465, 95%CI: 0.387-0.559), and were relatively poor for women aged 30~34 years (RR: 0.678, 95%CI: 0.593-0.776). The incidence of the urban was significantly higher than that of the rural. The effect of preconception examinations to prevent birth defects was more effective in urban areas (RR: 0.453, 95%CI: 0.391-0.525) than in rural areas (RR: 0.577, 95%CI: 0.533-0.625). The incidence of BDs in males was higher than that in females. CONCLUSIONS: By implementing preconception examinations project, birth defects in Dongguan have been well controlled. This can provide reference for other developing countries to prevent birth defects. PMID- 30522365 TI - Underscoring interstrain variability and the impact of growth conditions on associated antimicrobial susceptibilities in preclinical testing of novel antimicrobial drugs. AB - In the era of multidrug resistant (MDR) organisms, reliable efficacy testing of novel antimicrobials during developmental stages is of paramount concern prior to introduction in clinical trials. Unfortunately, interstrain variability is often underappreciated when appraising the efficacy of innovative antimicrobials as preclinical testing of a limited number of standardized strains in unvarying conditions does not account for the vastness and potential for hyperdiversity among and within microbial populations. In this review, the importance of accounting for interstrain variability's potential to impact breadth of novel drug efficacy evaluation in the early stages of drug development will be discussed. Additionally, testing under varying microenvironmental conditions that may influence drug efficacy will be discussed. Biofilm growth, the influence of polymicrobial growth, mechanisms of antimicrobial resistance, pH, anaerobic conditions, and other virulence factors are some of critical issues that require more attention and standardization during preclinical drug efficacy evaluation. Furthermore, potential solutions for addressing this issue in pre-clinical antimicrobial development are proposed via centralization of microbial characterization and drug target databases, testing of a large number of clinical strains, inclusion of mutator strains in testing and the use of growth parameter mathematical models for testing. PMID- 30522366 TI - Maternal serum TXNDC5 levels and thiol/disulphide homeostasis in preeclamptic pregnancies. AB - OBJECTIVE: To investigate thiol/disulphide homeostasis (TDH) and thioredoxin domain-containing 5 (TXNDC5) level in early and late-onset preeclampsia. MATERIALS AND METHODS: In this cross-sectional study, 24 pregnant women with early-onset preeclampsia and 26 pregnant women with late-onset preeclampsia were compared with 30 pregnant women with no obstetric complications. The serum TXNDC5 levels and thiol/disulphide homeostasis were measured. RESULTS: Serum TXNDC5 levels were significantly higher in the early-onset and late-onset preeclampsia groups compared with the control group (p < 0.05). Native thiol and total thiol levels were significantly lower in the early-onset and late-onset preeclampsia groups than control group. The disulphide levels were found as significantly high in early preeclamptic patients compared to control group (p < 0.05). The highest levels of TXNDC5 and the lowest levels of native thiol and total thiol were found in early-onset preeclampsia group. No significant difference was found between the patients with early onset and late onset preeclampsia regarding to TXNDC5 levels and thiol/disulphide homeostasis (p > 0.05). CONCLUSION: Serum TXNDC5 levels were significantly higher in patients with early-onset and late-onset preeclampsia. The dynamic thiol/disulphide homeostasis was impaired in favour of the oxidized state in patients with preeclampsia. PMID- 30522367 TI - Singing voice: acoustic parameters after vocal warm-up and cool-down. AB - PURPOSE: The aim of this study was to evaluate the effect of the vocal warm-up and cool-down on the singing voice through Fundamental Frequency (F0), Jitter, Shimmer and harmonics-to-noise ratio (HNR). METHODS: Thirty-two female singing students were recorded four times while uttering the vowel [a] for at least 5''. The first two recordings were collected before and after a vocal warm-up session and the last two before and after a vocal cool-down session. Between those sessions the participants underwent an intense vocal activity. RESULTS: Results showed significant variations in the average values of the parameters measured. The mean value of the F0 after intense vocal activity turned to be higher than the one measured before the warm-up session, as well as the mean F0 measured after singing compared to the one measured after the vocal warm-up. On the other end, the mean F0 after the vocal cool-down resulted to be lower than that measured before. After the vocal warm-up session Jitter and Shimmer decreased while HNR increased. In addition, a decrease was detected in comparison with the average value of Jitter and Shimmer before vocal warm-up and after vocal cool down, whereas HNR increased. There was also a decrease between the Shimmer before the vocal warm-up and after an intense phonatory activity while HNR increased. CONCLUSIONS: Our study highlights the effect of the vocal warm-up on acoustic parameters. The reduction in F0 observed after the cool-down session confirms its positive effect in helping professional vocal recovery and reducing vocal fold tension. PMID- 30522368 TI - The relationship between maternal anemia during pregnancy with preterm birth: a systematic review and meta-analysis. AB - OBJECTIVE: Iron deficiency anemia is the most common cause of anemia during pregnancy. Other causes of anemia include parasitic diseases, micronutrient deficiencies, and genetic hemoglobin apathies. Maternal anemia during pregnancy is the most important public health problem. Since, the relationship between maternal anemia by the months of pregnancy and premature birth has been reported differently in various studies; thus, this study aims to determine the relationship between maternal anemia during pregnancy and premature birth. METHODS: This systematic review and meta-analysis article was designed based on the recommendations of PRISMA. This study was performed from 1990 to 2018. Articles extracted using related keywords such as maternal, anemia, premature birth, and pregnancy in databases, including: Cochrane, Medline, Medlib, Web of Science, PubMed, Scopus, Springer, Science Direct, Embase, Google Scholar, Sid, Irandoc, Iranmedex and Magiran. Relative risk and its confidence interval were extracted from each of the studies. The random effects model was used to combine study results and heterogeneity among the studies measured using I2 index. RESULTS: Overall 18 studies with sample sizes of 932 090 were entered into the meta-analysis. The overall relationship between maternal anemia during pregnancy and premature birth was not significant (1.56 [95% CI: 1.25-1.95]). Maternal anemia in the first trimester increases the risk of premature birth (relative risk, 1.65 [95% CI: 1.31-2.08]). But, this relationship was not significant in the second (relative risk, 1.45 [95% CI: 0.79-2.65]) and third trimester (relative risk, 1.43 [95% CI: 0.82-2.51]). CONCLUSION: Maternal anemia during pregnancy can be considered as a risk factor for premature birth. PMID- 30522369 TI - Association of uterine rupture with pregestational diabetes in women undergoing trial of labor after cesarean delivery. AB - OBJECTIVE: To evaluate the association of pregestational diabetes with uterine rupture during a trial of labor with one prior cesarean delivery. STUDY DESIGN: A retrospective study of women undergoing trial of labor after cesarean. The study group consisted of women with pregestational diabetes, and control group was women without pregestational diabetes. Primary outcome was uterine rupture. Data was extracted from the USA. Natality Database from 2012 to 2016. Maternal and neonatal outcomes were analyzed. Multivariable logistic regression analysis was used to estimate risks of uterine rupture, and maternal and neonatal outcomes. RESULTS: There were 359 504 women undergoing labor after cesarean, with 3508 women with pregestational diabetes and 355 996 without. The prevalence of uterine rupture among women with pregestational diabetes undergoing labor after cesarean was 0.5%, while among women without pregestational diabetes it was 0.2% (adjusted odds ratio [OR] 2.03 [95% CI 1.18-3.51]; p = 0.01). There was an increased risk of unplanned hysterectomy among pregnancies complicated by pregestational diabetes (adjusted OR 3.06 [95% CI 1.41-6.66]). CONCLUSION: Women undergoing a trial of labor who have pregestational diabetes had a higher rate of uterine rupture than women without a history of pregestational diabetes. PMID- 30522370 TI - Pharmacotherapy for opioid addiction in community corrections. AB - Pharmacotherapy for opioid addiction with methadone, buprenorphine, and naltrexone has proven efficacy in reducing illicit opioid use. These treatments are under-utilized among opioid-addicted individuals on parole, probation, or in drug courts. This paper examines the peer-reviewed literature on the effectiveness of pharmacotherapy for opioid addiction of adults under community based criminal justice supervision in the US. Compared to general populations, there are relatively few papers addressing the separate impact of pharmacotherapy on individuals under community supervision. Tentative conclusions can be drawn from the extant literature. Reasonable evidence exists that illicit opioid use and self-reported criminal behaviour decline after treatment entry, and that these outcomes are as favourable among individuals under criminal justice supervision as the general treatment population. Surprisingly, there is no conclusive evidence regarding the extent to which pharmacotherapy impacts the likelihood of arrest and incarceration among individuals under supervision. However, given the proven efficacy of these three medications in reducing illicit opioid use and the evidence that, in the general population, methadone and buprenorphine treatment are associated with reduction in overdose mortality, the use of all three pharmacotherapies among patients under criminal justice supervision should be expanded while more data are collected on their impact on arrest and incarceration. PMID- 30522371 TI - Early versus delayed removal of indwelling urinary catheter after elective caesarean delivery: systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Timing of removal of the indwelling urinary catheter after elective caesarean delivery (CD) is controversial. Early removal could be associated with fewer urinary symptoms. OBJECTIVE: This review aims to evaluate the evidence from published randomized clinical trials (RCTs) about the outcomes of early versus delayed removal of indwelling urinary catheter after elective caesarean delivery (CD). DATA SOURCES: Electronic databases were searched using the following MeSH terms (early Or Late Or immediate OR delayed removal) AND (Urinary catheter) AND (caesarean section OR caesarean delivery OR CS) Methods of study selection. All RCTs assessing the timing of removal of urinary catheter were considered for this meta-analysis. One hundred seventy-two studies were identified of which three studies deemed eligible for this review. Quality and risk of bias assessment were performed for all studies. DATA EXTRACTION: Two researchers independently extracted the data from the individual articles and entered into RevMan software. The relative risk (RR), the weighted mean difference (WMD) and 95% confidence interval (CI) were calculated. The extracted outcomes were significant bacteriuria, urinary symptoms (urinary retention necessitating recatheterization, dysuria, urinary frequency, urgency) postoperative oral rehydration and length of hospital stay. RESULTS: Three RCTs (early removal: n = 298 and delayed removal: n = 311) were included. The pooled estimate showed that early removal significantly reduced dysuria (RR = 0.60, 95% CI [0.38, 0.95], p = 0.03), urinary frequency (RR = 0.32, 95% CI [0.16, 0.66], p = 0.002) and significant bacteriuria (RR = 0.49, 95% CI [0.30, 0.83], p = 0.007) than delayed removal. CONCLUSIONS: This meta analysis suggests that early removal of the indwelling urinary catheter in patients who underwent elective CD showed significant less dysuria, less urinary frequency and a decrease in the incidence of significant bacteriuria. PMID- 30522372 TI - Production of human tissue-type plasminogen activator (htPA) using in vitro cultured transgenic pig mammary gland cells. AB - Tissue plasminogen activator (tPA) is a protein involved in the breakdown of blood clots. We have previously produced a human tPA (htPA)-overexpressing transgenic pig using a mammary gland-specific promoter. In this study, we have established a transgenic pig mammary gland cell line that produces recombinant htPA. The mammary gland cells grew well and retained their character over long periods of culture. There was no difference in the extent of apoptosis in transgenic cells compared to wild-type mammary gland cells. In addition, the transgenic mammary gland cells expressed and secreted htPA into the conditioned media at a concentration similar to that in milk. This transgenic cell line represents a simple and ethical method for recombinant htPA production. PMID- 30522373 TI - Cost-utility analysis of alemtuzumab in comparison with interferon beta, fingolimod, and natalizumab treatment for relapsing-remitting multiple sclerosis in Austria. AB - BACKGROUND: Multiple sclerosis (MS), a chronic progressive, demyelinating, inflammatory disease, affects 2.5 million people worldwide. Approximately 63% of cases are classified as relapsing-remitting MS (RRMS) at the time of diagnosis. The aim of this cost-utility analysis is to evaluate alemtuzumab versus interferon beta (intramuscular [IM] interferon beta-1a, subcutaneous [SC] interferon beta-1a, SC interferon beta-1b, and SC pegylated interferon beta-1a) in previously treated and versus SC interferon beta-1a, fingolimod, and natalizumab in untreated RRMS patients to determine the incremental cost effectiveness ratio among the treatment alternatives as prices, the route, and the frequency of administration of considered products vary significantly. METHODS: The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; ?/quality-adjusted life-year [QALY] gained). Markov modeling with a 10 year time horizon was carried out. During each 3-month cycle, patients maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS), or showed EDSS progression in SPMS; experienced relapses; suffered from an adverse event (AE); changed treatment; or died. A published network meta-analysis (NMA) was used for indirect comparison. The possibility of a therapy switch was considered. Clinical input data and resource utilization data were derived from the literature. Costs were extracted from price lists published in Austria and were calculated from the payer's perspective. RESULTS: In treatment naive patients, alemtuzumab is associated with costs of ?132,663 and 5.25 QALYs in a 10-year time horizon. Costs for SC interferon beta amount to ?164,159 and generate 4.85 QALYs. Also, in the pre treated patients, alemtuzumab dominated comparators by accumulating higher total QALYs (4.88) and lower total costs (?137.409) compared to interferon beta-1a (?200.133), fingolimod (?240.903), and natalizumab (?247.758). CONCLUSION: The analysis shows that alemtuzumab is a cost-saving alternative to treat RRMS in pretreated and therapy naive patients. From the patient perspective alemtuzumab improves quality of life. PMID- 30522374 TI - Systematic review of sex-based differences in opioid-based effects. AB - There are several biological factors that might play a role in physiological response to opioids and/or the onset of problematic opioid use; however, sex based differences in non-analgesic opioid-based effects are poorly understood. The goal of this review is to provide a current analysis of the pre-clinical literature on sex-based differences in response to endogenous and exogenous opioids, including the interplay between sex hormones and opioid receptor mediated neuronal activity and associated behaviours. A systematic search was performed on the following terms within PubMed between March and April 2018: 'opioid oestrogen', 'opioid progesterone', 'opioid oestradiol', and 'opioid testosterone'. Pre-clinical research on the non-analgesic, sex-based effects of opioids is disparate, both in terms of methodology and outcomes, which prohibits a cohesive summary of the results. Themes from the pre-clinical literature suggest that opioid receptor binding, coupling, and density vary as a function of hormone exposure. Findings also suggest that interactions between endogenous opioid and stress systems may differ between males and females as a function of ovarian hormones. Given the current opioid-related public health crisis, there is a pressing need to increase systematic pre-clinical and clinical research on sex based differences in opioid-effects and opioid use disorder. PMID- 30522375 TI - Desmoplastic Small Round Cell Tumors With Atypical Presentations: A Report of 34 Cases. AB - OBJECTIVES: Desmoplastic small round cell tumor (DSRCT) is an aggressive round cell sarcoma that arises in the abdominal cavity/pelvis of young males. We sought to expand its clinicopathologic spectrum. METHODS: Cases of DSRCT presenting in patients >30 years of age or tumors arising outside of the abdominal cavity/pelvis were retrieved. RESULTS: Thirty-four cases were identified. Sixteen tumors arose at atypical sites (head/neck, intracranial, thigh, axilla/shoulder, inguinal/paratesticular, intraosseous, and uterine corpus). The remaining 18 patients were older than 30 years, and their tumors involved the abdomen or pelvis. The majority of cases showed areas with classic histology, while 6 cases exhibited solid growth and 5 showed macronodular architecture. Cytologic appearance included round cell, rhabdoid, epithelioid, and small cell. CONCLUSION: DSRCT may arise at nonabdominal locations in both pediatric and adult populations, as well as intra-abdominally in older adults, and these tumors exhibit high rates of metastasis and morbidity. PMID- 30522376 TI - Evaluation of Noxious Consequence of Bark Extract of Onosma echioides Linn Root: Hematology, Biochemistry, and Histopathological Findings. AB - Onosma echioides is a perennial herb widely used for the treatment of various ailments such as sciatica, gout, and rheumatism. This study focused on toxicological assessment of bark extract of O. echioides root. In subacute toxicity study, 20 Sprague Dawley rats (140 +/- 10 g body weight) were randomly grouped into two groups of 10 rats each (5 male and 5 female). Effect of the n hexane extract of O. echioides (100 mg/kg body weight/day) was studied for a period of 28 days using control and treated groups. Effects of the extract on body weight, food consumption, water intake, serum glucose, and hematology, biochemistry, and histopathology were evaluated. The histopathology was carried out to evaluate the degenerative changes in liver, heart, and kidney. Result of acute toxicity study showed dose-dependent increase in mortality. LD50 was found to be 1,000 mg/kg body weight. The subacute toxicity data showed that the treated group did not show any change in behavior and urinalysis whereas an increase in body weight was observed in the male treated group. A significant but nontoxic effect was observed on food and water consumption. Significant increases in RBC (female treated group; **p < .01), neutrophil (both male and female treated group; **p < .01), MCV (female treated group, **p < .01), MCH (both male and female treated groups; **p < .01), and MCHC (both male and female treated groups; *p < .05) levels were observed; a significant changes were observed in total bilirubin (*p < .05), BUN (**p < .01), potassium (*p < .05), and ALT (**p < .01) levels. The relative organ weights of vital organs at this dose did not show any significant change. In conclusion, the toxicity data showed that the bark extract of O. echioides root does not possess any adverse effect at a fixed dose, which provides a support for its further safety study and biocompatibility application. PMID- 30522377 TI - Acute Care Pharmacy Practice: A Perspective for Pharmacy Students, Residents, and Other Health-Care Providers. AB - PURPOSE:: To describe the acute care setting with a specific focus on acute care pharmacy practices. SUMMARY:: Acute care is the sector of health care where time sensitive episodes of illness are managed. Acute care pharmacy practice includes both hospital and clinical pharmacists serving, in a variety of domains, as medication experts and authority on patient-centered medication therapy. Pharmacists serving in this area can have a beneficial impact on patient care and the health-care system. CONCLUSION:: The demand for acute care services is likely to grow as the population continues to grow and age. Pharmacists are key members of interdisciplinary teams in the acute care setting. PMID- 30522378 TI - Budget impact analysis of niraparib and olaparib for maintenance treatment of platinum-sensitive, recurrent ovarian cancer in the US. AB - AIMS: This study aimed to evaluate the budget impact of niraparib and olaparib in patients with platinum-sensitive, recurrent ovarian cancer from a US third party payer perspective. MATERIALS AND METHODS: A budget impact model was constructed to assess the additional per member per month (PMPM) costs associated with the introduction of niraparib and olaparib, two poly ADP ribose polymerase (PARP) inhibitors recently approved to be used in platinum-sensitive, recurrent ovarian cancer patients with and without a BRCA mutation. The model assessed both pharmacy costs and medical costs. Pharmacy costs included adjusted drug costs, coinsurance, and dispensing fees. Medical costs included costs associated with disease monitoring and management of adverse events from the treatment. Epidemiological data from the literature were used to estimate the target population size. The analysis used one-year time frame and patients were assumed on treatment until disease progression or death. All costs were computed in 2017 USD. One-way sensitivity analyses were conducted to evaluate the model robustness. RESULTS: In a hypothetical plan of 1,000,000 members, 206 patients were estimated to be potential candidates for niraparib or olaparib maintenance treatment after applying all epidemiological parameters. At listed 30-day supply WAC prices of $14,750 for niraparib and $13,482 for olaparib, budget impacts of these two drugs were $0.169 PMPM and $0.156 PMPM, respectively, most of which were contributed by pharmacy costs. Sensitivity analyses suggested that assumptions around market share, platinum-sensitive rate after first treatment, and WAC prices affected results the most. LIMITATIONS: In this model, it was assumed that adopting niraparib and olaparib would not affect utilization of existing medications. Also, the estimated clinical parameters from clinical trials could differ from real-world data. PMID- 30522379 TI - Cystic Anastomosing Hemangioma of the Ovary: A Case Report With Immunohistochemical and Ultrastructural Analysis. AB - In this article, we present a case of anastomosing hemangioma that shows cystic change. The tumor was a unilocular cystic lesion consisting of 2 distinct layers. The inner layer was composed of a proliferation of capillary-sized blood vessels resembling red pulp of the spleen. The outer layer was composed of stromal cells that resembled Leydig or steroid cell tumor of the ovary. An immunohistochemical examination confirmed endothelial and stromal characteristics of the layers, respectively. An ultrastructural analysis revealed absence of Reinke crystalloids in the stromal cells. We conclude that anastomosing hemangioma may rarely arise from the ovary as a cystic tumor and may be accompanied with luteinization of stromal cells. PMID- 30522380 TI - [Possibilities for Suicide Prevention Through Architecture in Child and Adolescent Psychiatry]. AB - Possibilities for Suicide Prevention Through Architecture in Child and Adolescent Psychiatry Abstract. In Germany, departments of Child and Adolescent Psychiatry are responsible for the treatment of young people with acute suicidal tendencies. Therefore, it is important to consider means of preventing suicide already during the construction and business operations of these institutions. Approaches to structural suicide prevention can be divided into restrictive and atmospheric therapeutic measures. The latter includes ways to create an antisuicidal environment and to establish a setting amenable to close support and care by mental-health professionals. Restrictive measures comprise security measures and means of avoiding potential hazards, for example, through life-threatening jumps (e. g., staircases) or intentional strangulation (e. g., employing materials with predetermined breaking points). In addition to security issues, architectural and creative aspects must be incorporated to enable a suicide-preventive atmosphere, that is, satisfying protective needs, creating positive distractions (panoramic views, activities, occupational therapy opportunities), and using positive physiological and natural influences (such as colors and light). Secure access to a pleasant and protected external area as well as exercise spaces is also essential. Architects and construction managers should work closely with the institution's health personnel (e. g., doctors, therapists, and psychiatric nursing staff) during the planning stages for Departments of Child and Adolescent Psychiatry in order to come up with solutions that comprise appropriate, practical, and functional requirements and safety-restrictive measures. Thus, an inviting and atmospherically pleasant space can be created that simultaneously provides suicide prevention and protection, where adolescents with psychiatric disorders can be treated by mental-health professionals. PMID- 30522381 TI - Species dilemma of musk deer (Moschus spp) in India: molecular data on cytochrome c oxidase I suggests distinct genetic lineage in Uttarakhand compared to other Moschus species. AB - Musk deer are of high conservation priority owing to poaching pressure because of its musk pod. Representation of musk deer status using genetics is poorly documented in India, and it is not confirmed as to how many species of musk deer are present. We characterize for the first time, the genetic diversity of musk deer from Uttarakhand using Cytochrome Oxidase sub-unit (COI) gene (486 bp) and compared with the data available for other species. Results revealed the presence of six haplotypes in the Uttarakhand population amongst 17 sequences. Of these, 12 sequences shared the single haplotype. The intra-species sequences divergence was 0.003-0.017, whereas divergence with other species of musk deer was 0.071 0.081. Bayesian phylogenetic tree revealed that samples from Uttarakhand formed a separate clade with respect to other species of musk deer, whereas three species distributed in China clustered in the same clade and showed low sequences divergence, i.e., 0.002-0.061. Because of different ecomorph reported, we suggest using the barcoding based approach for inter and intra-species distinction and delineating species boundaries across the range for effective conservation. Besides, systematic classification, DNA barcoding would also help in dealing wildlife offence cases for disposal of the legal report in court. PMID- 30522382 TI - Reviewing Student Research: Can We Consider Bad Science to Be Ethical? PMID- 30522383 TI - Electrospun PCL, gold nanoparticles, and soy lecithin composite material for tissue engineering applications. AB - Soy lecithin has been shown to play a critical role in cell signaling and cellular membrane structure. In addition, it has been shown to increase biocompatibility, hydrophilicity, and decrease cytotoxicity. Gold nanoparticles have also shown to improve cellularity. Lecithin, gold nanoparticles, and polycaprolactone (PCL) solutions were electrospun in order to develop unique mesh materials for the treatment of osteoarthritis. The electrospinning parameters were optimized to achieve different solution ratios for fiber optimization. The amount of lecithin mixed with PCL varied from 30 wt.% to 50 wt.% . Gold nanoparticles (1% to 10% concentrations) were also added to lecithin-PCL mixture. The mechanical and chemical properties of the fiber mesh were analyzed via contact angle test, tensile mechanical tests, Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). Cell viability was measured using a WST-1 Assay. Scanning electron microscopy confirmed the successful formation of fiber mesh. The compositions of 40% soy lecithin with PCL in 40% solvent (40:40) resulted in the most well-formed fiber mesh. DSC melt temperatures were statically insignificant; uniaxial stresses and the moduli resulted in no significant difference between the test composition and pristine PCL compositions. WST-1 assay revealed all compositions were non-cytotoxic. Overall, the addition of lecithin increased hydrophilicity while maintaining cell viability and the mechanical and chemical properties of PCL. This study demonstrated that it is possible to successfully electrospin a lecithin, gold nanoparticle, and polycaprolactone scaffold for tissue engineering applications. PMID- 30522384 TI - Standardizing the Use of Albumin in Large Volume Paracentesis. AB - BACKGROUND:: Albumin after large volume paracentesis (LVP) reduces paracentesis induced circulatory dysfunction (PICD). The most efficacious dose of albumin for LVP is unclear. OBJECTIVE:: To evaluate the impact of implementing a standardized LVP order set on albumin utilization and patient outcomes. METHODS:: This is a retrospective review of patients with ascites due to cirrhosis who received a therapeutic paracentesis at a large, academic institution. Primary outcome was amount of albumin used prior to and after order set implementation. Albumin doses were standardized in the order set to 25 g (5-6 L removed), 50 g (7-10 L), and 75 g (>10 L). Patient outcomes were rates of hyponatremia, renal impairment, and hypotension. RESULTS:: There were 100 patients included in each arm of the final analysis. Patients prior to order set implementation received a higher amount of albumin per liter removed compared to those post-implementation (8.3 g/L vs 6.5 g/L, respectively; P < .01). There were no significant differences between groups in absolute changes in serum sodium (0 mEq/L vs -1 mEq/L, P = .64), serum creatinine (0.06 mg/dL vs 0.05 mg/dL, P = .94), or systolic blood pressure (-4 mm Hg vs -3 mm Hg, P = .96). There were no differences between groups in rates of hyponatremia (1.6% vs 6.6%, P = .21), renal impairment (11.3% vs 11.5%, P = .97), or hypotension (17.4% vs 17.6%, P = .97). CONCLUSIONS:: Use of an order set to guide albumin dosing based on amount of ascitic fluid removed during LVP resulted in a significant reduction in the amount of albumin given with no difference in adverse effects. PMID- 30522385 TI - Dry eye after Lester Jones tube insertion for epiphora. AB - PURPOSE: To report the occurrence of dry eye after Lester Jones tube (LJT) insertion. METHODS: Retrospective case series from a single unit. The dacrocystorhinostomy (DCR) was carried out using both endoscopic and external approachs; however, insertion of LJT used the same method as either a primary or secondary procedure. Dry eye as an outcome measure was only confirmed after three separate visits using the presence of both patient symptoms and dry eye signs with none preceding tube insertion. RESULTS: Fifty-four patients underwent consecutive LJT insertion over a 5-year period. Mean age was 52.6 (range 25-73 years). The majority were female 39 (72%). Revision surgery was required in 15 (27%) with 3 or more occurring in 6 (11%). In total, 9 patients developed dry eyes (17%). Mean age was 60 (range 47-73) years, 5 females and 4 males. Four of the dry eye individuals had undergone primary LJT insertion and the remaining five received their first LJT 6-24 (mean 15) months post-DCR. Two dry eye patients had previously undergone LASIK and radiotherapy. CONCLUSION: A risk of dry eye following LJT placement is higher than the literature suggests. This should be considered and counseled, especially in those who have underlying pre disposing factors. Ease of removal may be a desirable attribute in such cases. PMID- 30522386 TI - Innovative delivery of Cu(II) ions by a nano-structured hydroxyapatite: potential application in planta to enhance the sustainable control of Plasmopara viticola. AB - Battiston, E., Antonielli, L., Di Marco, S., Fontaine, F., and Mugnai, L. 2018. Innovative delivery of Cu(II) ions by a nano-structured hydroxyapatite: potential application in planta to enhance the sustainable control of Plasmopara viticola. Downy mildew caused by Plasmopara viticola is probably the most serious disease affecting grapevine (Vitis vinifera L.) and is capable of causing consistent yield losses. In organic viticulture, the only acceptable and effective means to control the disease is by applications of copper-based fungicides. However, the use of copper in agriculture is expected to be further restricted by European countries because of its critical ecotoxicological and phytotoxicological profile. Research on ways to reduce the effective amounts of copper by developing innovative formulations as well as optimization of the distribution and persistence of copper-based pesticides for downy mildew control appears to be a promising approach. The present research investigated the delivery properties of biomimetic synthetic hydroxyapatite (HA) to enhance the biological activity of Cu(II) ions. To this aim, four Cu(II) compounds were formulated with the innovative HA component and applied in an in vitro antifungal assay against Botrytis cinerea, a common grapevine pathogen suitable for in vitro activity tests, and finally in in-planta efficacy assays against P. viticola under greenhouse conditions. The in vitro results highlighted a different inhibition activity for each Cu(II) compound and indicated a different interaction between the cupric compounds and HA, potentially related to different delivery mechanisms of Cu(II) from HA. Under greenhouse conditions, further findings on the biological activity of the applied formulations were gained, especially on the efficacy of various concentrations of HA in the formulations, on the influence of dose variation of the formulation and the treatment efficiency, and persistence under rain-washing effect. The present study revealed promising findings on the formulation based on the HA particles and the soluble Cu(II) compound, which resulted in reduced disease severity and incidence in all the experimental conditions, including the lower Cu(II) dosage and the rain-washing effect. This suggests that co-formulation of the three insoluble Cu(II) compounds with HA might significantly enhance the adsorption and release of Cu(II) ions by HA particles. PMID- 30522387 TI - Cefuroxime-induced anaphylaxis with prominent central nervous system manifestations: A case report. AB - Cefuroxime is a second-generation cephalosporin antibiotic that causes immediate hypersensitivity reactions, ranging from mild urticaria to severe anaphylactic shock. Anaphylactic reactions typically involve multiple systems, most notably, the skin and the respiratory and cardiovascular systems. Here, we report the unusual case of a patient who presented with oral cefuroxime-induced anaphylaxis with prominent neurologic manifestations. To identify the drug responsible for the anaphylaxis, we performed skin tests. Based on positive skin-prick test results, the diagnosis of cefuroxime-induced anaphylaxis was confirmed. Therefore, we suggest that clinicians should consider the possibility of a drug induced anaphylactic reaction when neurologic but not cutaneous symptoms are present. The skin-prick test is a safe and useful diagnostic tool to confirm this kind of immediate drug hypersensitivity. PMID- 30522388 TI - Multimorbidity and Hospital Admissions in High-Need, High-Cost Elderly Patients. AB - OBJECTIVE: The aim was to clarify which pairs or clusters of diseases predict the hospital-related events and death in a population of patients with complex health care needs (PCHCN). METHOD: Subjects classified in 2012 as PCHCN in a local health unit by ACG(r) (Adjusted Clinical Groups) System were linked with hospital discharge records in 2013 to identify those who experienced any of a series of hospital admission events and death. Number of comorbidities, comorbidities dyads, and latent classes were used as exposure variable. Regression analyses were applied to examine the associations between dependent and exposure variables. RESULTS: Besides the fact that larger number of chronic conditions is associated with higher odds of hospital admission or death, we showed that certain dyads and classes of diseases have a particularly strong association with these outcomes. DISCUSSION: Unlike morbidity counts, analyzing morbidity clusters and dyads reveals which combinations of morbidities are associated with the highest hospitalization rates or death. PMID- 30522389 TI - Intraclass Correlation Coefficients for Planning Cluster Randomized Trials in Community-Dwelling Older Adults. AB - OBJECTIVES: With the emerging trends, more cluster randomized trials will be conducted in older adults, where facilities are randomized rather than individuals. Similarity of individuals from a facility (intraclass correlation coefficient/ICC) plays a critical role, but not readily available. We document ICCs for measures commonly used in community-dwelling older adults and discuss implications. METHOD: Secondary analysis of a range of baseline measures from the On the Move cluster randomized trial, whose ICCs were computed using a linear mixed model. RESULTS: Self-reported disability measures related to facility characteristics and sense of community had the greatest ICCs (>0.10), while mobility performance measures had 0.05 to 0.10, and cognitive measure 0.11. DISCUSSION: The ICCs for measures commonly used in older adults are of a sufficient magnitude to have a substantial impact on planned sample size of a study and credibility of results, and should be taken into consideration in study planning and data analysis. PMID- 30522390 TI - Self-Reported Sensory Impairments and Changes in Cognitive Performance: A Longitudinal 6-Year Follow-Up Study of English Community-Dwelling Adults Aged ?50 Years. AB - OBJECTIVE: To investigate the influence of single and dual sensory impairments prospectively on cognition in adults aged ?50 years. METHOD: Community-dwelling English adults ( n = 4,621) were followed up from 2008 to 2014. Self-reported hearing and vision were collected in 2008. Change in cognitive performance on working memory and executive function between 2008 and 2014 was evaluated. RESULTS: Compared with good hearing and good vision, respectively, poor hearing and poor vision were associated with worse cognitive function (hearing: unstandardized coefficient B = 0.83, 95% Confidence Interval [CI] = [0.29, 1.37]; vision: B = 1.61, 95% CI = [0.92, 2.29] adjusted for age, sex, baseline cognition). Compared with no sensory impairment, dual sensory impairment was associated with worse cognition ( B = 2.30, 95% CI = [1.21, 3.39] adjusted for age, sex, baseline cognition). All associations remained after further adjustment for sociodemographic characteristics, lifestyle factors, chronic conditions, falls, mobility, depression, and lack of companionship. DISCUSSION: The findings are important as age-related sensory impairments are often preventable or modifiable, which may prevent or delay cognitive impairment. PMID- 30522391 TI - The Association Between Intimate Partner Violence and 30-Year Cardiovascular Disease Risk Among Young Adult Women. AB - Intimate partner violence (IPV), the physical, sexual, psychological abuse or control by a former or current intimate partner, affects almost one third of women in the United States. IPV exposure can result in many negative outcomes including physical injury, increased stress, and depression. Currently, there is a growing body of literature examining the link between IPV victimization and poor heart health. However, there is little known on how IPV affects cardiovascular disease (CVD) risk among young adult women and what outcomes associated with IPV victimization may be increasing this risk. A secondary analysis of the National Longitudinal Study of Adolescent to Adult Health (Add Health) was conducted to examine the association between past-year IPV exposure and 30-year CVD risk score among a representative sample of young adult women in the United States. Regression analyses were run to examine the relationship between IPV and 30-year CVD risk score. The results of the bivariate analyses suggested that past-year IPV exposure may have a small but significant impact on 30-year CVD risk score; however, this finding becomes insignificant when important covariates are introduced into the model highlighting the complexity of IPV and its co-occurring phenomenon. The findings of this study reveal that 30 year CVD risk in the context of IPV victimization should continue to be examined in this population as CVD risk may continue to grow as one experiences IPV. Future research should examine possible mediating factors in this relationship as well as biological markers that may help better understand this relationship. PMID- 30522392 TI - Looking Through Dementia: What Do Commercial Stock Images Tell Us About Aging and Cognitive Decline? AB - Commercial stock images are existing, artificially constructed visuals used by businesses and media outlets to articulate certain values, assumptions and beliefs. Despite their pervasiveness and accessibility, little is known about the ways in which stock images communicate meanings relating to health and illness. This study examines a broad range of common stock images that depict dementia and aging, revealing the tendency for older people with dementia to be represented in objectifying and de-humanizing terms-emphasizing disease and deficit at the expense of the whole person, whereas precluding any possibility of enduring personhood. As well as introducing a multimodal critical discourse approach that can be adopted by other researchers examining the ideological underpinnings of health and illness imagery, this study underscores the importance of critically interrogating stock photography-a much neglected, yet profoundly influential, cultural resource that can shape the ways we think about and respond to illness and disease. PMID- 30522393 TI - Using a Flexible Diary Method Rigorously and Sensitively With Family Carers. AB - Health and social science researchers are increasingly interested in the range of new possibilities and benefits associated with diary methods, particularly using digital devices. In this article, we explore how a flexible diary method, which enables participants to choose the device (i.e., paper notebook, tablet, or computer) and medium (i.e., text, photographs, sketches) through which they narrate their experiences, can be used to promote sensitive and rigorous research engagement with family carers to people with dementia. We used a diary interview method with 10 carers over the course of 6 weeks to explore how they experience and interpret the changing behaviors of their cognitively impaired kin. We reflect on how the quality of diary data can be enhanced alongside the ethical dimensions of research with carer populations, through different forms of diary keeping, regular interaction with participants, reflexive practice, and follow-up interviews. PMID- 30522394 TI - The efficacy of superior rectus recession with simultaneous inferior oblique disinsertion on superior oblique palsy with superior rectus contracture. AB - PURPOSE: The information about superior rectus (SR) recession in cases with SR contracture coexisting with superior oblique palsy (SOP) is very limited in previous literature. The aim of this study is to evaluate the effect of SR recession, as a combined procedure with inferior oblique (IO) disinsertion, in long-standing SOP with secondary SR contracture. METHODS: The medical records of the 145 patients operated for SOP were retrospectively reviewed and 15 patients who underwent SR recession met the inclusion criteria. The mean follow-up was 50.4 months. RESULTS: The preoperative angle of deviation was within the range of 16-35 prism dioptres (PD) with a mean of 23.0 +/- 5.03 PD. In all of the cases, SR recession was performed in combination with IO disinsertion. Adult patients (12) underwent adjustable SR recession. Postoperative overcorrection developed in 3 cases (20%), and in 12 patients, the postoperative vertical deviation was within the range of 0-5 PD with a mean of 1.41 +/- 1.88 PD. The overcorrected three patients underwent botulinum toxin A (BTXA) injection into the ipsilateral inferior rectus muscle. The deviation is well controlled by BTXA injection in two patients, whereas the other one was considered as masked bilateral SOP and underwent IO disinsertion in the other eye. CONCLUSION: Our results suggested that SR recession in combination with IO disinsertion is an effective procedure to control large vertical deviations in SOP with SR contracture in the majority of cases. However, the risk of overcorrection should be considered despite adjustable SR weakening and BTXA injection seems efficient to rescue overcorrections in long term. PMID- 30522395 TI - Excellent Patient Care Must Be Our Priority Always, No Matter What Is Said in the Media. PMID- 30522396 TI - Investigations on the Timing of Fruit Infection by Fungal Pathogens Causing Fruit Rot of Deciduous Holly. AB - Fruit rot of deciduous holly is an emerging fungal disease that is affecting plant production across midwestern and eastern U.S. nurseries. To determine the growth stage(s) of host susceptibility to infection by the major pathogens associated with the disease, Alternaria alternata and Diaporthe ilicicola, and minor pathogens such as Colletotrichum fioriniae and Epicoccum nigrum, we conducted two sets of experiments over two consecutive seasons. In the first case we monitored the presence of the pathogens as well as disease progression in a commercial nursery under natural conditions by collecting plant tissues from the flower bud stage until fruit maturity. The target pathogens were consistently isolated from asymptomatic samples at all stages of fruit development and from symptomatic samples at fruit maturity across the 2 years of collection. A significant increase in fungal isolation frequency, primarily species of Alternaria and Colletotrichum, was observed right after flowering, but fruit rot symptoms only developed on mature fruit. In the second case we artificially inoculated containerized plants maintained outdoor at our research farm with individual or combined pathogens at different fruit developmental stages, and we assessed disease incidence on mature fruit to determine the time of host susceptibility to infection and, indirectly, whether pathogens in the fungal complex carry out latent infections. D. ilicicola could cause latent infection on deciduous holly fruit when inoculated at the full bloom and petal fall stages, and all inoculations made on wounded mature fruit resulted in fruit rot. These findings suggest that flowering represents a critical period to manage D. ilicicola infections and that mature fruit should be protected from any injury to avoid disease. In both experiments a negative correlation between disease incidence and temperature was found; however, the decrease in temperature also coincided with fruit ripening. The effects of temperature and changes in physiological properties of the fruit during maturation on disease development should be further investigated to fully interpret these findings. PMID- 30522397 TI - Street food in Maputo, Mozambique: Availability and nutritional value of homemade foods. AB - BACKGROUND:: A nutrition transition is occurring in the urban areas of developing countries, where street food makes an important contribution to daily food intake. AIM:: We aimed to characterise street food offer in Maputo, Mozambique, and to evaluate the nutritional composition of the most common homemade foods. METHODS:: A cross-sectional study was conducted in 2014. Streets in the surroundings (500 m buffer) of randomly selected public transport stops in KaMpfumu district, Maputo, were canvassed to identify all street food vending sites ( n = 968). Information regarding vending site characteristics and the food offered was gathered through interview and observation. Samples ( n = 80) of the most common homemade foods were collected for laboratorial analysis. RESULTS:: Most street food vending sites identified were stationary (77.4%) and sold exclusively industrial food (51.9%). Frequency of fruit, beverages and food other than fruit was 24.5%, 32.5% and 73.9%, respectively. Fried cakes were the most energy-dense (430 kcal/100 g), and richest in fats (21.0g/100 g) and carbohydrates (53.4 g/100 g). The richest sources of protein were the stewed meat/fish/liver dishes (10.7-11.6 g/100 g). Fried cakes showed the lowest sodium and potassium content (90 mg/100 g and 81 mg/100 g, respectively) whereas hamburgers exhibited the highest content of those micronutrients (455 mg/100 g and 183 mg/100 g, respectively). Stewed liver dishes presented the highest sodium/potassium ratio (11.95). Fried snacks presented the highest trans-fatty acid content (0.20 g/100 g). CONCLUSIONS:: Street food in Maputo is abundant and scattered throughout the urban district, exhibiting high variability in the nutritional composition of homemade foods. Public health policies should be targeted to improve the street food offer, promoting nutrient-dense foods and the reduction of added salt. PMID- 30522398 TI - Provider perceptions on the management of lupus during pregnancy: barriers to improved care. AB - BACKGROUND: More than half of pregnancies in women with systemic lupus erythematosus (lupus) result in adverse outcomes for the mother or the fetus. We sought to identify aspects of current rheumatologic care that could be improved to decrease the frequency of poor outcomes. METHODS: Focus groups with clinical rheumatologists, based on the PRECEDE/PROCEED framework, identified factors that influenced care. A group of women with lupus on their reproductive journey contributed to our understanding of the dilemmas and care provided. RESULTS: Medically ill-timed pregnancies and medication non-adherence during pregnancy were identified by rheumatologists as the two key dilemmas in care. We identified several communication gaps as key modifiable barriers to optimal management. The approach to physician-patient communication was often unsuitable to sensitive discussions about pregnancy planning. The communication of treatment plans was frequently hampered by gaps in knowledge and both physician and patient confidence in the data, encouraging non-adherence among nervous patients. Finally, local rheumatologists and obstetricians/gynecologists providers frequently did not communicate, leading to varying treatment plans and confusion for patients. CONCLUSIONS: To decrease the frequency of ill-timed pregnancy and medication non-adherence it will be essential to empower rheumatologists, and women with lupus to have open and accurate conversations about pregnancy planning and management. PMID- 30522399 TI - Is systemic lupus erythematosus different in urban versus rural living environment? Data from the Cretan Lupus Epidemiology and Surveillance Registry. AB - BACKGROUND: Examining urban-rural differences can provide insights into susceptibility or modifying factors of complex diseases, yet limited data exist on systemic lupus erythematosus (SLE). OBJECTIVE: To study SLE risk, manifestations and severity in relation to urban versus rural residence. METHODOLOGY: Cross-sectional analysis of the Crete Lupus Registry. Demographics, residency history and clinical data were obtained from interviews and medical records ( N=399 patients). Patients with exclusively urban, rural or mixed urban/rural residence up to enrolment were compared. RESULTS: The risk of SLE in urban versus rural areas was 2.08 (95% confidence interval: 1.66-2.61). Compared with rural, urban residence was associated with earlier (by almost seven years) disease diagnosis - despite comparable diagnostic delay - and lower female predominance (6.8:1 versus 15:1). Rural patients had fewer years of education and lower employment rates. Smoking was more frequent among urban, whereas pesticide use was increased among rural patients. A pattern of malar rash, photosensitivity, oral ulcers and arthritis was more prevalent in rural patients. Residence was not associated with organ damage although moderate/severe disease occurred more frequently among rural-living patients (multivariable adjusted odds ratio: 2.17, p=0.011). CONCLUSION: Our data suggest that the living environment may influence the risk, gender bias and phenotype of SLE, not fully accounted for by sociodemographic factors. PMID- 30522400 TI - DNA Methylation Inhibitor 5-Aza-2'-Deoxycytidine Modulates Endometrial Receptivity Through Upregulating HOXA10 Expression. AB - Endometrial receptivity is a critical factor for embryo implantation. A decrease in endometrial homeobox A10 (HOXA10) expression is associated with hypermethylation of its promoter and lower endometrial receptivity in animals and humans. 5-Aza-2'-deoxycytidine (AZA) is a DNA methyltransferase inhibitor. However, whether demethylation of the HOXA10 gene could increase the receptivity of the human endometrium remains unknown. Homeobox A10 promoter methylation was analyzed using bisulfite genomic sequencing polymerase chain reaction. Quantitative real time polymerase chain reaction and Western blotting were used to analyze the expression of HOXA10 and its downstream target genes (integrin subunit beta 3 [ITGB3] and insulin growth factor binding protein 1 [IGFBP1]) in Ishikawa cells treated with or without AZA for 24 hours. Their protein expression was analyzed with or without HOXA10 siRNA treatment. The effect of AZA on embryo implantation was examined using a Jeg-3 spheroid-endometrial cell attachment assay. The percentage of methylated CpG islands in the HOXA10 promoter was 72.0% without AZA treatment. However, it was 38% and 35% in the 1 and 10 MUM AZA treatment groups, respectively. 5-Aza-2'-deoxycytidine strongly induced the expression of HOXA10, ITGB3, and IGFBP1 messenger RNA and their protein expression. Homeobox A10 knockdown led to decreased expression of HOXA10, ITGB3, and IGFBP1, with or without AZA treatment. The attachment rate of Jeg-3 spheroids increased significantly from 82% (control) to 95% (AZA 1 MUM) and 96% (AZA 10 MUM) after AZA treatment. 5-Aza-2'-deoxycytidine could upregulate the expression of ITGB3 and IGFBP1 via HOXA10 upregulation, and upregulation of ITGB3 and IGFBP1 plays an important role in endometrial receptivity during implantation. 5-Aza-2' deoxycytidine may improve endometrial receptivity by upregulating the expression of HOXA10. PMID- 30522401 TI - Variation Among Orchardgrass (Dactylis glomerata) Germplasm for Choke Prevalence Caused by Epichloe typhina. AB - Orchardgrass, or cocksfoot (Dactylis glomerata L.), is a cool-season forage grass susceptible to the choke disease caused by Epichloe typhina. Choke has been reported in orchardgrass seed production fields across the temperate regions of the world, but fungicides have not been efficacious in reducing choke incidence or prevalence. To assess the potential for genetic resistance or tolerance of orchardgrass to choke, we evaluated the variation in orchardgrass cultivars and accessions for choke prevalence and characterized infected plants for endophyte secondary metabolite and mating type gene presence. Significant variation was detected across years and locations. Choke prevalence did not always increase with the age of the stand, nor did choke prevalence correlate with flowering time or swathing time of the entries. Both mating types of E. typhina were detected in approximately equal proportions, and no evidence for loline, ergot alkaloid, or indole-diterpene biosynthesis was found. Plants with multiple infected tillers often showed more than one mating type present in the plant, indicating multiple infection events rather than a single infection event that spread to multiple tillers. Both accessions and cultivars with significant choke, and no choke, were detected, which constitute sources of germplasm for further testing and breeding. PMID- 30522402 TI - Maternal Oxidative Stress, Placental Morphometry, and Fetal Growth in Diabetic Rats Exposed to Cigarette Smoke. AB - The diabetic syndrome affects pregnancy, contributing to placental functional and structural disruptions and impaired fetal development, with many reports indicating tobacco-associated morbidity and perinatal mortality. In our study, an experimental rat model of diabetes and cigarette smoke exposure in pregnant rats was used to determine the impact of the combination of diabetes and exposure to cigarette smoke during pregnancy on maternal oxidative stress biomarkers and placental and fetal development. Diabetes was induced by streptozotocin, and dams were exposed to cigarette smoke by mainstream smoke generated by a mechanical smoking device and delivered into a chamber. Four groups of dams were studied: nondiabetic (C, control) and diabetic (D) exposed to filtered air and nondiabetic (CS) and diabetic (DS) exposed to cigarette smoke prior to and during pregnancy. Maternal oxidative stress biomarkers, placental morphology, and fetal growth were determined close to term. The combination of diabetes and cigarette smoke resulted in elevated maternal blood glucose levels and increased number of small fetuses. Placentas from the DS group showed increased junctional zone and decreased labyrinthine area. The morphological alterations were characterized by extensive vascular congestion, thickness, and hyalinization of the vascular walls, numerous decidual cells with abundant glycogen, and macrophages with cytoplasmic inclusions of hemosiderin. Additionally, they showed increased glycogen accumulation and junctional zone structural derangement with ectopic giant cells. No alterations were observed in maternal oxidative stress status. Thus, our result suggests that diabetes makes pregnant rats more susceptible to the adverse effects of exposure to cigarette smoke on placental morphometry and fetal growth. PMID- 30522403 TI - The impact of retrieval suppression on conceptual implicit memory. AB - When people suppress retrieval of episodic memories, it can induce forgetting on later direct tests of memory for those events. Recent reports indicate that suppressing retrieval affects less conscious, unintentional retrieval of unwanted memories as well, at least on perceptually-oriented indirect tests. In the current study we examined how suppressing retrieval affects conceptual implicit memory for the suppressed content, using a category verification task. Participants studied cue-target words pairs in which the targets were exemplars of 22 semantic categories, such as vegetables or occupations. They then repeatedly retrieved or suppressed the targets in response to the cues for some of those pairs. Afterwards, they were exposed to the targets intermixed with novel items, one at a time, and asked to verify the membership of each of the words in a semantic category, as quickly as possible. Judgment response times to studied words were faster than to unstudied exemplars, reflecting repetition priming, as has been previously observed. Strikingly, the beneficial effects of prior exposure on response time were eliminated for targets that had been suppressed. Follow-up explicit memory tests also demonstrated that retrieval suppression continued to disrupt episodic recall for the items that had been just been re-exposed on the category verification test. These findings support the contention that the effects of retrieval suppression are not limited to episodic memory, but also affect indirect expressions of those memories on conceptually oriented tests, raising the possibility that underlying semantic representations of suppressed content are affected. PMID- 30522404 TI - Characterization of inflammatory infiltrate of ulcerative dermatitis in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice. AB - Ulcerative dermatitis (UD) is an idiopathic, spontaneous and progressive disease typically affecting C57BL/6 aged mice with an unknown aetiopathogenesis. For this study, we evaluated 25 cases of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice. Formalin fixed, paraffin-embedded skin samples were submitted to morphological investigations. Immunohistochemical analysis was performed to characterize and quantify inflammatory cells using CD3, CD45/B220, CD4, CD8 and IL-17 antibodies. Mast cell-bound IgE was investigated by immunofluorescence, whereas serum and cryopreserved skin samples were collected for molecular analysis. Student's t test (two-tailed) was performed to assess significant differences between the two groups. Affected skin showed extensive areas of ulceration and diffuse, severe and mixed inflammatory infiltrates. No relevant changes were observed in control mice. Immunohistochemical analysis showed a predominant CD3 + CD4 + leukocyte population with fewer CD45/B220 and IL-17 immunolabelled cells and mast cell bound IgE. Increases in TNFalpha, IL-1beta and Il-6 mRNA expression were observed in the skin of affected animals compared to controls. Serum TNFalpha and IL-6 did not vary between affected and control mice. Inflammatory infiltrates and cytokine expression were consistent with both Th2/IgE and Th17 differentiation, a typical pattern of a type I hypersensitivity reaction. Overall, our data suggest an allergic-based aetiopathogenesis of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice. PMID- 30522405 TI - Reducing ethnic inequalities in bowel screening participation in New Zealand: A randomised controlled trial of telephone follow-up for non-respondents. AB - OBJECTIVE: To test whether a telephone follow-up service for high-needs ethnic groups increases bowel screening participation in non-responders to postal invitations. METHODS: Maori, Pacific, and Asian ethnicity individuals who failed to return a bowel screening test kit within four weeks of it being posted were randomly allocated (1:1) to a telephone active follow-up service or a control group. The active follow-up service made multiple attempts to contact the invitee and provide support. Participation rates at eight weeks' post-randomisation were compared, and the effect of the intervention on overall participation rates was imputed. RESULTS: A total of 3828 eligible individuals were allocated to active follow-up and 3773 to the control group. The imputed potential overall increase in participation in the active follow-up group was 2.0% (95% CI = 0.6%-3.4%); however, the impact of follow-up varied significantly by ethnicity and deprivation. The imputed increase in participation was significant for Maori (5.2; CI = 1.8%-8.5%) and Pacific (3.6%; CI = 0.7%-6.4%), but not for Asian ethnicities (0.7%; CI=-1.1%-2.4%). In addition, the imputed increase was significant among high deprivation participants (3.9%; CI = 2.0%-5.9%), but not among low deprivation participants (0.3%; CI=-1.6%-2.2%). CONCLUSIONS: Active follow-up led to higher bowel screening participation in Maori and Pacific but not in Asian ethnicities and was more effective in high deprivation subjects. Active follow-up significantly reduced but did not eliminate ethnic inequalities in bowel screening participation. PMID- 30522406 TI - Predictors for Receiving Medication and/or Psychotherapy in Children Newly Diagnosed With ADHD: A Longitudinal Population-Based Cohort Study. AB - OBJECTIVE: The aim of this study is to identify characteristics predicting the use of medication and/or psychotherapy after a first ADHD diagnosis. METHOD: This cohort study was based on German claims data including 12,250 treatment-naive children aged 5 to 12 years with an incident ADHD diagnosis in 2010. Logistic regression models were used to estimate associations between children's characteristics at first diagnosis and the chosen treatment within the following 5 years. RESULTS: Medication use was associated with male sex, an ADHD diagnosis "with hyperactivity," comorbid depression, and comorbid developmental and conduct disorders. Male sex and comorbid neurotic and somatoform, conduct, and emotional disorders were associated with psychotherapy only. Receiving both treatments instead of medication only-was associated with comorbid depression, neurotic and somatoform, conduct, and emotional disorders. CONCLUSION: In case of equal access to both treatment options, patients, for example, with externalizing symptoms were more prone to receive medication and/or psychotherapy than the average child diagnosed with ADHD. PMID- 30522407 TI - Accelerated Aging: The Role of Socioeconomic, Social, Demographic, and Biological Factors on Bone Mineral Density. AB - We investigate socioeconomic, social, demographic, and biological variables that are associated with chronic stress in the body to assess whether they have an effect on bone mineral density (BMD) as an indicator of accelerated aging. Multiple regression models were derived from data in the Midlife in the United States: A National Longitudinal Study of Health and Well-Being, Waves 1 (1995 1996) and 2 (2004-2006). Three BMD variables were used as outcomes: femoral, femoral neck, and spine T scores. The sample included 333 men and women aged 34 80. Poverty and C-reactive protein were related to BMD for spine T scores, partially consistent with hypotheses. But, marital status, perceived support of a partner, and education were not associated. Friend strain was discovered to have a relationship with BMD. More variables, and from a broader context, need to be examined together to understand what affects reduced BMD, given the high costs of accelerated aging. PMID- 30522408 TI - Surgical nurses' knowledge and practices about informed consent. AB - BACKGROUND:: Informed consent involves patients being informed, in detail, of information relating to diagnosis, treatment, care and prognosis that relates to him or her. It also involves the patient explicitly demonstrating an understanding of the information and a decision to accept or decline the intervention. Nurses in particular experience problems regarding informed consent. RESEARCH QUESTION AND DESIGN:: This descriptive study was designed to determine nurse knowledge and practices regarding their roles and responsibilities for informed consent in Turkey. The research was performed using 92 nurses who work at the surgical clinics. Data collection form was prepared by the researchers with assistance from the literature, and the data were evaluated by the SPSS 12.0 data analysis program. ETHICAL CONSIDERATION:: This study was approved by the Medicine and Health Sciences Research and Ethics Committee of the university. Written consent was received from the nurses. FINDINGS:: Among the nurses who participated in this study, 39.1% indicated that they were responsible for obtaining informed consent. It was also found that 90.2% of the nurses informed patients before providing nursing interventions and 32.6% of the nurses obtained consent from patients, and 90.0% of the nurses who indicated that they obtain patient consent only obtain verbal consent. Among all of the nurses, 21.7% agreed that informed consent needs to be obtained in order to protect the medical staff legally. DISCUSSION:: It is argued that a lack of official procedures at hospitals regarding informed consent and insufficient information being provided to healthcare providers has caused problems regarding informed consent. CONCLUSION:: The nurses in this study lacked information regarding their role in obtaining informed consent from patients and they often performed incomplete and/or incorrect practices within the framework of their required role. It is believed that an increased level of education along with the creation of official policies and procedures would contribute towards solving these problems. PMID- 30522409 TI - Outcome of knee arthroplasty in patients aged 65 years or less: A prospective study of 232 patients with 2-year follow-up. AB - BACKGROUND AND AIMS:: Previous studies have reported lower implant survival rates, residual pain, and higher patient dissatisfaction rates following knee arthroplasty in younger knee arthroplasty patients. We aimed to assess the real world effectiveness of knee arthroplasty in a prospective non-selected cohort of patients aged 65 years or less with 2-year follow-up. MATERIAL AND METHODS:: In total, 250 patients (272 knees) aged 65 years or less were enrolled into this prospective cohort study. Patient-reported outcome measures were used to assess the outcome. RESULTS:: The mean Oxford Knee Score and all Knee Injury and Osteoarthritis Outcome Score subscales increased significantly (p < 0.001) from preoperative situation to the 2-year follow-up. Significant increase (p < 0.001) in physical activity was detected in High-Activity Arthroplasty Score and RAND-36 Physical Component Score (PCS). Pain was also significantly (p < 0.001) relieved during the follow-up. Total disappearance of pain was rare at 2 years. Patients with milder (Kellgren-Lawrence grade 2) osteoarthritis were less satisfied and reported poorer patient-reported outcome measure than those with advanced osteoarthritis (Kellgren-Lawrence grade 3-4). There was no difference in the outcome (any patient-reported outcome measure) between patients who underwent total knee arthroplasty and those who received unicondylar knee arthroplasty. CONCLUSION:: We found that measured with a wide set of patient-reported outcome measures, both total knee arthroplasty and unicondylar knee arthroplasty resulted in significant pain relief, as well as improvement in physical performance and quality of life in patients aged 65 years or less. Real-world effectiveness of these procedures seems to be excellent. 15% of patients still had residual symptoms and were dissatisfied with the outcome at 2 years after the operation. PMID- 30522410 TI - Natural control of HIV infection in young women in South Africa: HPTN 068. AB - BACKGROUND: Some individuals control HIV replication without antiretroviral (ARV) therapy. OBJECTIVE: To analyze viral suppression in young women in rural South Africa enrolled in a trial evaluating a behavioral intervention for HIV prevention. METHODS: Plasma samples were obtained from women ages 13-24 (81 infected at enrollment, 164 seroconverters). ARV testing was performed using an assay that detects 20 ARV drugs. Women were classified as viremic controllers if they were virally suppressed for >=12 months with no ARV drug use. RESULTS: Samples from 216/245 (88.2%) women had no ARV drugs detected at their first HIV positive visit. Thirty-four (15.7%) of the 216 women had a viral load <2,000 copies/mL. Fifteen of the 34 women were followed for >=12 months; 12 were virally suppressed with no ARV drugs detected during follow-up. These women were classified as viremic controllers (overall: 12/216 = 5.6%). The median CD4 cell count at the first HIV-positive visit was higher among the 12 controllers than among the 204 women who were not using ARV drugs (759 vs. 549 cells/mm3, p = 0.02). Some women had a viral load <40 copies/mL at a single study visit, but none were classified as elite controllers (viral load <40 copies/mL for >=12 months with no ARV drug use). CONCLUSIONS: In this cohort, 5.6% of women who were not using ARV drugs had sustained viral suppression. This represents a minimum estimate of the frequency of viremic controllers in this cohort, since some women were not followed long enough to meet the criteria for classification. PMID- 30522411 TI - Chimney parallel grafts and thoracic endovascular aortic repair for blunt traumatic thoracic aortic injuries: A systematic review. AB - BACKGROUND: Whilst the management of blunt traumatic thoracic aortic injury has seen a paradigm shift to an 'endovascular first' approach, the limitations of thoracic endovascular aortic repair remain. An inadequate proximal landing zone limits the use of thoracic aortic stent grafts and in an emergent polytrauma setting, aortic arch debranching via open surgery may not be practical or feasible. A wholly endovascular approach to debranching utilising 'off-the-shelf' stents and parallel graft techniques may represent a possible solution. Hence, we sought to perform a systematic review investigating the use of chimney graft techniques alongside thoracic aortic stenting in blunt traumatic thoracic aortic injury. METHODS: We performed the systematic review in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Searches were performed on Medline (PubMed), Web of Science and Scopus to identify articles describing the use of chimney grafts in traumatic aortic transection (PROSPERO: CRD42017082549). RESULTS: The systematic search revealed 172 papers, of which 88 duplicates were removed resulting in 84 papers to screen. Based on title, abstract and full text review, six articles were included for final analysis. There were nine patients in total with an average age of 41 (three females, five males, one unspecified), all with significant polytrauma, secondary to the mechanism of injury. A variety of stents were used between centres, with techniques showing a predominance to stenting of the left subclavian artery (77%, n = 7). The technical success rate was 82%, with two (18%) cases of type 1 endoleaks, of which one resolved spontaneously. CONCLUSIONS: Despite the encouraging results, this by no means provides for a firm conclusion given the small sample size. Patients should still be judiciously selected on a case-by-case basis when employing the chimney graft technique. Larger cohort studies are needed to establish these findings. PMID- 30522412 TI - Vocational Community College Students' Conversations about Binge Drinking. AB - The large amount of vocational community college students that continue showing binge-drinking behavior might be an indication that interventions targeting this behavior have not been hugely successful. It might be that these interventions targeted beliefs that are less or not related with vocational community college binge-drinking behavior. The aim of this study was to identify vocational community college students' salient beliefs about binge drinking. In the context of the integrative model of behavioral prediction, we applied deductive qualitative content analysis of conversations about binge drinking. The analysis of vocational community college students' conversations about binge drinking revealed a significant amount of salient beliefs, such as cognitive and affective outcome beliefs and efficacy beliefs. These beliefs may be important indicators of vocational community college students' binge drinking. Moreover, to our knowledge, this study was the first to reveal a new set of beliefs, namely social judgment beliefs (i.e., vocational community college students' judgments about their peers' binge-drinking behavior). We believe that our study yielded salient beliefs that may serve as input for future interventions targeting binge drinking among vocational community college students. PMID- 30522413 TI - Anaerobic biodegradation of pyrene by Klebsiella sp. LZ6 and its proposed metabolic pathway. AB - Pyrene is one of the polycyclic aromatic hydrocarbons, which are a potential threat to ecosystems due to their mutagenicity, carcinogenicity, and teratogenicity. In this study, several bacteria were isolated from oil contaminated sludge and their capacity to biodegrade pyrene was investigated. Of these bacteria, the monoculture strain LZ6 showed the highest pyrene anaerobic biodegradation rate of 33% after 30 days when the initial concentration was 50 mg/L, and was identified as Klebsiella sp. LZ6 by morphological observation, the GENIII technology of Biolog, and 16S rDNA gene sequence analysis. The influence of various culture parameters on the biodegradation of pyrene were evaluated, and Klebsiella sp. LZ6 all showed the high degradation rate at an inoculum of 10-20% (v/v), pH 6.0-8.4, temperature 30 degrees C-38 degrees C, and initial pyrene concentration of 50-150 mg/L. The intermediate metabolites of the anaerobic biodegradation were analyzed by GC-MS. Several metabolites were identified, such as pyrene, 4,5-dihydro-, phenanthrene, dibenzo-p-dioxin, and 4-hydroxycinnamate acid. The anaerobic metabolic pathway for the degradation of pyrene was inferred by the products. It seems that pyrene was first reduced to pyrene,4,5-dihydro- by the adding of two hydrogen atoms, and then the carbon-carbon bond cleavage at saturated carbon atoms generated phenanthrene. PMID- 30522414 TI - Hollow S-nitrosothiols nanoparticle with polymeric brushes for nitric oxide (NO) releasing as tumor targeted chemotherapy. AB - A kind of tumor targeting nitric oxide donor nanoparticle with brushes is described in this paper. The poly(4-vinylphenylboronic acid) polymeric brush, which shows glucose and pH dual responsiveness, endows the ability of hollow S nitrosothiols nanoparticle to accurate recognition and binding with the sialic acid over-expressed type tumor cells, such as HepG2 and MCF-7 cells. In vitro experiments, including cells capture and release experiments, confocal fluorescence microscope characterization, cytotoxicity assay with different cells, demonstrate the selective recognition and the controlled NO release to kill tumor cells for these S-nitrosothiols nanoparticles. Low concentration of the released NO from the S-nitrosothiols nanoparticles in the transmission would participate physiological activity and avoid serious side effects because the endogenous nature and the physiological necessity to regulate normal biological functions. To the best of our knowledge, this is the first report about polymer nanoparticles as NO donors with functional brushes to selectively identify tumor cells and release NO in a controlled manner. PMID- 30522415 TI - Role of coke-bounded environmentally persistent free radicals in phenanthrene degradation by hydrogen peroxide. AB - Emission of polycyclic aromatic hydrocarbons (PAHs) is accompanied with the discharge of carbonaceous particles during the coke production. To degrade the adsorbed PAHs, hydrogen peroxide (H2O2) was applied as an oxidizing agent, which might be activated by the inherent environmentally persistent free radicals (EPFRs) on coke particles. The transformation of phenanthrene (PHE), selected as model molecule, was achieved in H2O2/coke particle system without the addition of additional activating agent. This process consumed the particle-bounded EPFRs, inducing the decreasing of spin density from 1.92 * 1018 to 4.4 * 1017 spins g-1 in 30 min of reaction time. Electron paramagnetic resonance (EPR) technique coupled with spin trapping agent 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) was used to probe the potential formation of reactive oxygen species. A higher capture [*OH] concentration was observed with larger decreases in EPFRs concentration, indicating that EPFRs were the main contributor to the formation of *OH. The obtained results suggested that the activation of H2O2 by EPFRs on coke particles resulted in the generation of hydroxyl radical (*OH), which then back-reacted with adsorbed PHE. The finding of this study shed light on a new remediation technology for toxic carbonaceous byproducts discharged during the coke production. PMID- 30522416 TI - Laparoscopy for blunt abdominal trauma: A Challenging Endeavor. AB - BACKGROUND AND AIMS:: Laparoscopy in blunt abdominal trauma is challenging because of multiple associated injuries, higher trauma score values and higher morbidity and mortality, as compared with patients with penetrating abdominal trauma. The aim of this study was to investigate the role of laparoscopy in the management of blunt abdominal trauma patients and to highlight related challenges. MATERIAL AND METHODS:: Over a 4-year period, patients managed laparoscopically for blunt abdominal trauma were retrospectively analyzed. Perioperative details, indications for laparoscopy and conversion, complications, and length of hospital stay were discussed. RESULTS:: A total of 35 stable patients underwent laparoscopy. The mean Injury Severity Score was 12 (4-38). Therapeutic laparoscopy was performed in 15 (56%) and diagnostic in 12 (44%) patients. Eight (23%) patients were converted to therapeutic laparotomy. Intraoperative bleeding, complex injuries, visualization problem, and equipment failure necessitated conversion. Three (30%) patients with negative computed tomography scan had therapeutic laparoscopy for mesenteric injuries. There were no missed injuries. The mean length of hospital stay was 11 days in both groups. CONCLUSION:: Laparoscopy for stable patients is feasible and safe. Multiple injuries make laparoscopy more difficult, and advanced laparoscopic skills are required. The conversion rate is high; however, the non-therapeutic laparotomies were completely eliminated in this study. PMID- 30522417 TI - Molecular systematics of two sister clades, the Fusarium concolor and F. babinda species complexes, and the discovery of a novel microcycle macroconidium producing species from South Africa. AB - Multilocus DNA sequence data were used to investigate species identity and diversity in two sister clades, the Fusarium concolor (FCOSC) and F. babinda species complexes. Of the 109 isolates analyzed, only 4 were received correctly identified to species and these included 1/46 F. concolor, 1/31 F. babinda, and 2/3 F. anguioides. The majority of the F. concolor and F. babinda isolates were received as F. polyphialidicum, which is a heterotypic synonym of the former species. Previously documented from South America, Africa, Europe, and Australia, our data show that F. concolor is also present in North America. The present study expands the known distribution of F. babinda in Australia to Asia, Europe, and North America. The molecular phylogenetic results support the recognition of a novel Fusarium species within the FCOSC, which is described and illustrated here as F. austroafricanum, sp. nov. It was isolated as an endophyte of kikuyu grass associated with a putative mycotoxicosis of cattle and from plant debris in soil in South Africa. Fusarium austroafricanum is most similar morphologically to F. concolor and F. babinda but differs from the latter two species in producing (i) much longer macroconidia in which the apical cell is blunt to slightly papillate and the basal cell is only slightly notched and (ii) macroconidia via microcycle conidiation on water agar. BLASTn searches of the whole genome sequence of F. austroafricanum NRRL 53441 were conducted to predict mycotoxin potential, using genes known to be essential for the synthesis of several mycotoxins and biologically active metabolites. Based on the presence of intact gene clusters that confer the ability to synthesize mycotoxins and pigments, we analyzed cracked corn kernel cultures of F. austroafricanum via liquid chromatography-mass spectrometry (LC-MS) but failed to detect these metabolites in vitro. PMID- 30522418 TI - Effect of diets containing sulfate or chloride-based anionic salts, fed to grazing prepartum dairy cows, on concentrations of Ca in plasma, disease incidence and milk yield. AB - AIMS: To compare the effect of two partial mixed ration diets containing either sulfate or chloride-based anionic salts, fed to grazing prepartum dairy cows, on concentrations of Ca, Mg, P and beta-hydroxybutyrate (BHB) in plasma, disease incidence and milk yield during the early postpartum period. METHODS: The study was conducted on a seasonal-calving grazing dairy farm located in Benton (MO, USA). In August 2016, two groups of 200 cows were randomly assigned at 30 days before expected parturition to receive either a sulfate or chloride-based anionic diet, to achieve a dietary cation-anion difference (DCAD) of -25 mEq/kg DM. Cows were fed partial mixed rations to provide 50% of their DM intake, with 50% provided by grazing fescue pasture. Urine samples were collected from 20 cows from each group once a week for 5 weeks until calving for pH assessment. At parturition, 42 cows per group were selected at random and blood samples collected on Days 1, 2, 3 and 7 postpartum. The study continued until 100 cows per group calved. Health events and cumulative milk yield until 30 days postpartum were recorded. Concentrations of Ca, P, and Mg in plasma at Days 1, 2, 3, and 7, and BHB in plasma at Day 7 postpartum were assessed. RESULTS: Mean urine pH was lower in cows in the chloride than sulfate group (p <= 0.06) on four of five sampling occasions. Mean concentrations of Ca in plasma on Day 1 were 2.00 (95% CI = 1.94-2.05) and 1.91 (95% CI = 1.88-1.97) mmol/L for the chloride and sulfate groups, respectively (p = 0.15), and on Day 3 were 2.03 (95% CI = 1.97-2.08) and 1.90 (95% CI = 1.84-1.96) mmol/L, respectively (p = 0.038). Concentrations of Mg, P and BHB in plasma and incidence of diseases postpartum were similar in both groups (p > 0.05). There were no cases of clinical hypocalcaemia in either group. CONCLUSIONS AND CLINICAL RELEVANCE: Prepartum cows fed a partial mixed ration with a negative DCAD containing chloride-based anionic salts and free access to a fescue pasture had lower prepartum urine pH, and higher concentrations of total Ca in plasma during the first week postpartum, than cows receiving a partial mixed ration containing sulfate-based anionic salts. PMID- 30522419 TI - [Surveillance of resistance in the intensive care units using a cumulative antibiogram]. AB - Empiric treatment with broad-spectrum antibiotics exerts condensed pressure in intensive care units (ICUs) for the selection of multidrug-resistant bacteria. Multidrug-resistant gram-negative bacteria became the focus of interest owing to limited treatment options and negative effects on patient survival. Cumulative antibiograms can guide selection of correct empiric treatment, de-escalation treatment according to antibiogram results and development of policies in fight against antibiotic resistance. In this study, we aimed to determine the antibiotic resistance rates of gram-negative bacilli in the intensive care units of the public hospitals in the region where we are connected by using the cumulative antibiogram result and to show the change of resistance over the years and to determine whether there is any difference between the hospitals. Gram negative bacilli were isolated from ICUs of state hospitals in the second Istanbul State Hospitals Association area during 2014-2016. Isolates were identified using Vitek MS (bioMerieux, France) system and tested for antibiotic susceptibility with Vitek 2 (bioMerieux, France) system according to the Clinical and Laboratory Standards Institute (CLSI) criteria followed during those years. Cumulative antibiogram reports for these strains were prepared according to the CLSI M39-A4 guide. Gram-negative bacilli were divided into three groups: non fermentative, urinary enteric, and non-urinary enteric bacilli. Total number of strains isolated during three years from these groups were 2626, 1390 and 2011, respectively. Annual trends of susceptibility during the aforementioned years were evaluated. Hospitals were also classified into five groups and differences were evaluated in the susceptibility profiles of these hospitals. Among the non fermentative bacilli, Acinetobacter baumannii complex was the most commonly isolated species and the most resistant bacteria against antibiotics. The susceptibility rates of A.baumannii complex against the beta-lactam group of antibiotics were < 10%. Colistin susceptibility rates of A.baumannii complex and Pseudomonas aeruginosa isolates were over 98%. Among the non-urinary enteric bacilli, K.pneumoniae was the most commonly isolated species displaying maximum antibiotic resistance. Susceptibility rates for colistin, which is the last resort for treating resistant gram-negative bacteria, ranged between 73% and 80%. Escherichia coli, which was the second most common isolated species among non urinary bacilli, had susceptibility rates over 90% to carbapenems along with colistin and tigecycline. Although E.coli was the most commonly isolated species among urinary enteric bacilli, K.pneumoniae and Proteus mirabilis were the most resistant isolates. A statistically significant decrease in susceptibility rates against all antibiotics was observed in P.mirabilis isolates between the years 2015-2016. Carbapenem susceptibility rates decreased below 70%. E.coli, Serratia spp., and Stenotrophomonas maltophilia had similar susceptibility profiles among different hospitals, indicating homogenous distribution, whereas other species had different profiles, indicating a more heterogenic distribution, among hospitals. The reports of this study were generated according to a standard guide and they clearly revealed the seriousness of antibiotic resistance in our region which represents approximately one-fourth area of Istanbul. When all the results were considered, best empiric treatment option for enteric bacilli except K.pneumoniae was carbapenems. For K.pneumoniae infections there is no reliable choice other than colistin but a de-escalation treatment can be planned according to antibiogram results. Similarly colistin is the first choice in empiric treatment of infecitons due to non-enteric bacilli. However, the heterogeneity of the susceptibility profile observed in the hospitals, which are geographically close to each other, indicated the difference in the flora of the intensive care unit of hospitals. It would be appropriate to prepare cumulative antibiogram reports similar to those in the present study, to prevent complications, reduce costs and improve patient prognosis in the intensive care units of hospitals and these reports should become part of the infection control policies applied in hospitals. PMID- 30522420 TI - [Investigation of the presence of pantone-valentine leukocidin in Staphylococcus aureus strains isolated from orthopedic surgical site infections]. AB - Staphylococcus aureus is one of the most clinically important bacteria causing infection in humans. It is an important pathogen in surgical site infections (SSIs), especially after orthopedic surgery. Pantone-valentine leukocidin (PVL) has a great importance in the virulence of S.aureus because it can destroy polymorphonuclear cells by necrosis or apoptosis. The spread of PVL positive S.aureus is a great concern, since it may become an important factor for increased morbidity and mortality in SSIs, especially after surgery. In this study, we aimed to investigate the presence of PVL in S.aureus strains isolated from patients who had surgical site infections after orthopedic surgery, and also the clinical status of these patients. Between 2013 and 2017, 101 patients who had SSIs due to S.aureus after orthopedic surgery were included in the study. Identification of the strains was determined by conventional methods and "Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry" (MALDI-TOF MS). Methicillin resistance was determined by Kirby-Bauer disc diffusion method and automated system (Vitek 2, bioMerieux, France). The PVL gene region was investigated by polymerase chain reaction (PCR) method by using the primers Luk PV-1 and Luk-PV-2. The duration of the patients' hospitalization, C-reactive protein (CRP) and sedimentation levels and clinical status were obtained from the hospital information system, retrospectively. Fifteen (14.9%) of the isolates were methicillin resistance S.aureus (MRSA) and 86 (85.1%) were methicillin susceptibility S.aureus (MSSA). PVL positivity was detected in 14 (13.9%) isolates (3 MRSA, 11 MSSA). The mean hospital stays in PVL-negative patients were 17 (5-73) days and 46 (21-103) days in PVL-positive patients. It was observed that the serologic markers CRP and sedimentation were between 5-7 and 40-60 in PVL negative patients, and between 11-20 and 90-110 in PVL positive patients, respectively. In PVL-negative patients, serologic markers improved in 7-10 days, while in PVL-positive patients they were improved in 17-32 days. Osteomyelitis occurred in six patients (2 PVL positive MRSA, 1 PVL positive MSSA and 3 PVL negative MRSA). In two of the patients who have developed osteomyelitis with PVL positive MRSA, PVL gene positive S.aureus isolates were observed in their orthopedic SSIs. We also determined that these isolates increased the hospitalization days, improvement time of serological markers and mortality. It is worrisome to isolate PVL-positive S.aureus strains in SSIs. Therefore, we believe that it would be useful to take infection control measures to prevent the spread of these strains in the hospital setting. PMID- 30522422 TI - [Relation of cervical cancer with the results of human papillomavirus (HPV) screening carried out via hybrid capture 2 method on 52.000 women in Erzurum]. AB - Cervical cancer is a common female cancer that could be diagnosed early with screening methods. Almost all cases are caused by human papilloma virus (HPV) infection. Therefore, detecting the presence of HPV DNA is important for early diagnosis and treatment. Regular determination of screening tests enables early detection of patients with the risk of cervical cancer. For this purpose, since August 2014 a new screening program has been carried out by Early Diagnosis, Screening and Training of Cancer Centers (KETEM). The aims of our study were to detect the HPV prevalence in Erzurum and determine the major HPV types under the scope of population based cervical cancer screening program. Female patients between the ages of 30-65 were included in the study. Pap-smear and HPV DNA samples were taken simultaneously. The samples were examined in a national central laboratory. The study was performed using conventional methods in pap smear samples. Pap-smear samples from HPV (-) patients were not included in the pathological evaluation. Pathological results of the pap-smear samples, which were taken from the HPV (+) cases, were sent to KETEM by national central laboratory and then these results were used. Within the scope of this study, 52.000 women were screened. Among all these women 2.4% of the cases were HPV DNA positive. HPV DNA samples were screened by Hybrid capture 2 (Qiagen, Germany) method. The highest positivity was observed at age 40 with 65 cases (5.1%) and the lowest positivity was observed at age 65 with 2 cases (0.1%). 60.1% of the HPV positive cases were at 30-45 age group, 35.2% were at 45-60 age group and 4.6% were at 65 and above age group. The most common type was HPV 16 with the frequency of 12.2% and this was followed by HPV 31 with 7.4% and HPV 51 with 6.7%,HPV 52 with 4.4% and HPV 68 with 4.3% frequencies. The rate of the HPV 18, which is the type of HPV that carries high risk for causing cervical cancer, was 3.0%. 49.2% of the HPV positive cases had single and 50.8% of them contained more than one type of HPV. The most common pathological appearance was "low grade cervical intraepithelial lesion" (LGSIL) detected in 115 cases (9.2%) and "atypical squamous cells of unknown significance" (ASC-US) detected in 93 cases (7.4%). Cases that had abnormal cytology were referred to colposcopy. Consequently, it was concluded that regional screening is important in terms of the determination of the HPV type for the early diagnosis of cervical cancer and vaccination so prevalence studies should be increased and supported. PMID- 30522423 TI - [Investigation of antifungal activities of some disinfectants on Candida albicans]. AB - Disinfectants may have fungicidal or fungistatic effects against fungal cells. The mechanism of action of disinfectants on fungal cells believed to be similar to the antibacterial activity. The aim of this study was to demonstrate the efficacy of some disinfectants against Candida albicans and to investigate the relationship between virulence and disinfectant resistance. In this study, the susceptibility of 417 clinical C.albicans and reference isolates against disinfectants were determined. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of disinfectants were obtained by using broth microdilution (BMD) assay. Epidemiological cut-off values (ECVs) were determined by using the MIC and MFC values. Crystal violet assay was carried out to investigate membrane permeability in disinfectant resistant and susceptible isolates. Rhodamine 6G (R6G) flourescence stain was used to show the increase in the number of efflux pumps among selected isolates. The relationship between virulence and disinfectant resistance was determined by in vitro and in vivo investigations. Virulence factors secretory acid proteinase (SAP), phospholipase, esterase, hemolytic activity and slime factor production were examined in vitro. In vivo virulence assay was performed by infecting Galleria mellonella larvae. The relationship between virulence factors and disinfectant resistance was evaluated according to the mortality rates of G.mellonella larvae. The range of MIC values for benzalkonium chloride (BZC) and chlorhexidine digluconate (CHX), triclosan (TRC) and sodium hypochlorite (SHC) were 0.25-8 mg/L, 0.06-4 mg/L and 256-16.384 mg/L, respectively. ECV values for BZC, CHX, TRC and SHC were determined as 4, 2, 1 and 4096 mg/L, respectively. The rate of crystal violet uptake was found between 26.5-57.6% for disinfectant susceptible isolates, and between 33-79.2% for resistant isolates. It is concluded that the disinfectant resistance was related with efflux pumps. Due to the lack of number of isolates that were used in this assay, the relationship between disinfectant resistance and virulence factors could not be assessed. There was no difference in the mortality of larvae infections caused by disinfectant resistant and susceptible isolates. As a result, in this study, resistant isolates against BZC, CHX, SHC and TRC were found among 417 isolates. Input and output of disinfectants were found to be associated with the cell membrane efflux pumps of C.albicans. PMID- 30522424 TI - [Evaluation of the reproductive potential of Encephalitozoon intestinalis in four different cell line]. AB - Microsporidia are parasites that can cause infections in many vertebrate and invertebrate organisms and produce small spores resistant to environmental conditions. As they are obligate intracellular parasites, axenic cultures cannot be performed. The aim of this study was to investigate the reproductive potential of the parasite in human colon epidermal adenocarcinoma (Caco-2), human monocytic (U937), African green monkey renal epithelial (VERO) and human kidney epithelial (HEK-293) cell lines of tissue and organs where the parasite is located by following the culture of the parasites and the amount of spores for six weeks. RPMI-1640 medium was used for the cultivation of U937 cells, while DMEM was used for other cell lines and the immature U937 cells were stimulated with Phorbol-12 Myristate-13-Acetate before infection. All of the host cell groups were infected with freshly collected Encephalitozoon intestinalis spores in ratio 1:30 and free spores in the culture media were removed after overnight incubation at 37 degrees C under 5% CO2 condition for parasite invasion. The first release of the spores from the infected cells was observed and recorded by following for six weeks. Furthermore, the spore density released from each cell groups was evaluated by measuring the parasite load by Thoma cell counting chamber and quantified by real time PCR. As a result of the study, it was observed that four cell lines could be infected by E.intestinalis and the spore production can be maintained for six weeks. It was observed that the monolayer macrophages and CaCo-2 cells, started to be detached from the culture flasks in few days following the parasite invasion, thus decreasing the number of host cells. After 1-2 weeks, HEK-293 cells were also detached from the surface, thus negatively affected the pure spore production by contaminating the media with dead host cell suspension. Spores started to appear in VERO cell media at the end of the second week after initial infection, while it took longer time for other cells to start releasing spores. Over the course of six weeks, the VERO cell line had the highest spore producing potential among the other cell lines. In conclusion, this study compared the potential for reproduction of E.intestinalis in three human cell lines and monkey originated VERO cell line. This study demonstrated that cells derived from the tissues or organs where Microsporidia species causes disseminated infections could be infected by the parasitic spores in vitro. Additionally, the parasite can survive and propagate longer than six weeks. The authors believe that the results of this study will contribute to the further studies related to the parasite in the area of genetics, pharmacology, biochemistry, immunology and eradication studies. PMID- 30522421 TI - [Evaluation of 2015-2016 MOTAKK HBV DNA and HCV RNA external quality assessment national program results]. AB - MOTAKK, as a national external quality control program has been launched to evaluate the molecular detection of viral infections including HBV DNA and HCV RNA in molecular microbiology diagnostic laboratories in Turkey. This program is prepared in compliance with ISO 17043:2010 (Conformity assessment general requirements for proficiency testing) standards, and aims to take the place of external quality control programs from abroad, contributing to standardization and accuracy of molecular diagnostic tests in our country. The aim of this study was to evaluate 2015 and 2016 results of the MOTAKK External Quality Control Program for HBV DNA and HCV RNA viral load . The calls were announced on the web page of MOTAKK (www.motakk.org). The quality control samples were sent to participating laboratories in 2015 and 2016. Main stocks were prepared from patients with chronic hepatitis B and C who had viral load detection with reference methods according to WHO reference materials for viral load studies to improve quality control sera. From these main stocks, samples with different viral loads were prepared from dilutions of plasma with HBV, HCV, HAV, HIV, Parvovirus B19 and CMV negative serologic markers. Quality control samples were sent to the participating laboratories along with the negative samples in the cold chain. The laboratories accomplished the related tests within 2-3 weeks and entered their results on the MOTAKK web page. These results were analysed according to ISO 13528 (Statistical methods for use in proficiency testing by interlaboratory comparison) and scoring reports were created by a software developed by MOTAKK and sent to participating labs. Each laboratory evaluated their own results in comparison with the other laboratory results, reassessed the tests via observing the distance from the mean result and the reference values. The number of laboratories participating in the HBV DNA and HCV RNA external quality control program was 70-73 in 2015-2016. Participants were able to comply with the program tools, registering, entering results and receiving the results reports without problem. In HBV panel, 72.6-89.1% and 84.7-90.3% of the participant laboratories were in 1 standard deviation (SD) in 2015-2016, respectively. In HCV panel, 70.8-89.1% and 84.7-90.3% of the participant laboratories were in 1 SD in 2015-2016, respectively. A national external quality control program for HBV DNA and HCV RNA in Turkey has been prepared for the first time with this project and implemented successfully. All the data provided in the MOTAKK external quality control program final report, compensate all the data provided by the quality control program final reports from abroad; additionally, the report allows comparison of used technologies and commercial products. PMID- 30522425 TI - [Investigation of Microsporidia prevalence with calcofluor white and uvitex 2B chemiluminescence staining methods and molecular analysis of species in diarrheal patients]. AB - Microsporidia, obligate intracellular parasites, were first defined by Nageli in 1857. Microsporidia phylum consists of 200 genus and 1500 species. They have a wide host spectrum including insects, fish, and mammals. It has been shown that they may also infect humans and may be existed both in symptomatic and asymptomatic forms. There are eight species infecting humans, which include Anncaliia (Brachiola, Nosema), Encephalitozoon, Entrocytozoon, Microsporidium, Nosema, Pleistophora, Trachipleistophor, and Vittaforma. The species most commonly infect humans are Encephalitozoon intestinalis and Enterocytozoon bieneusi. The aim of this study was to determine the prevalence of Microsporidia by using two different chemiluminescence stains, namely uvitex 2B and calcoflour and detect species by molecular analysis in diarrheal patients. For this purpose, we studied stool samples of 200 patients with diarrhea sent to Gazi University Health Practice and Research Hospital, Microbiology Laboratory and Ankara Numune Training and Research Hospital Microbiology Laboratory between 2012-2013. The stool samples were stained with chemiluminescent stains uvitex 2B and calcoflour methods; the Microsporidia prevalence was found to be 38% (77/200) by fluorescent microscopic examination. Statistically an excellent consistency was found between the chemiluminescent stains uvitex 2B and calcoflour (Cohen's kappa= 0.881). A statistical analysis for the consistency of uvitex 2B and calcoflour in terms of numerical density (low, high) and luminescence of spores (dim, bright) showed a moderate consistency between the two stains with respect to determining numerical density of spores (Cohen's kappa= 0.354), while there was no consistency in terms of luminescence of spores (Cohen's Kappa= 0.001). No significant difference was found between the Microsporidia prevalence with respect to age group or clinics (p > 0.05). A sex-based analysis showed that Microsporidia prevalence was more common in women (50%) than men (30.8%) (p< 0.05). In 77 samples that were detected positive for Microsporidia with uvitex 2B and calcoflour stains determination of genus and species level were done by using multiplex nested polymerase chain reaction (PCR) method. With this technique, seven (9.1%) of 77 isolates were detected as E.bieneusi, and 70 (90.9%) as Encephalitozoon spp. When the Microsporidia genus was considered, the Microsporidia prevalence did not show differences with respect to age, sex, and referring clinics (p> 0.05). In our study 44 (62.9%) of 70 Encephalitozoon spp. were E.intestinalis, 22 (31.4%) were E.cuniculi, and 4 (5.7%) were E. hellem. No statistical difference was found in the distribution of Encephalitozoon spp. with age, sex, and referring clinic (p> 0.05). We concluded that examination of stool samples with the chemiluminescent stain uvitex 2B and/or calcoflour would be useful for the initial stage of Microsporidia diagnosis; furthermore, the multiplex nested PCR method was considered useful for determination of genus and species. In our country, there is a small number of molecular reports about Microsporidia prevalence in stool samples. Molecular methods should be used more commonly for the evaluation of treatment options in diarrheal patients and detection of Microsporidia epidemiology. PMID- 30522426 TI - [Investigation of the diagnostic value of anti-dense fine speckled 70/lens epithelium derived growth factor p75 autoantibody for autoimmune diseases]. AB - Antinuclear antibodies (ANA) are the autoantibodies that are produced against nuclear antigens in the cell nucleus and/or cytoplasm, and are one of the important diagnostic criteria in systemic autoimmune rheumatic diseases (SARD). Until today, several methods have been developed for detecting ANA's. However, indirect immunofluorescence (IIF) technique, that is also known as one of the oldest methods, is still the most commonly used one. Typically, anti-dense fine speckled 70/Lens epithelium derived growth factor p75 (anti-DFS70/LEDGF p75) autoantibody can be detected via IIF method where in HEp-2 (human larynx carcinoma) cells are used. The dense fine speckled (DFS) pattern method can be masked and remain unnoticed by the IIF method when it exists with the other ANA. Anti-DFS70 autoantibodies seldomly appear in SARD patients compared to healthy individuals. Moreover, these antibodies may appear in different chronic inflammatory conditions like interstitial cystitis, chronic fatigue syndrome, atopic dermatitis and Vogt-Koyanagi-Harada syndrome. The aim of this study was to determine the frequency of anti-DFS70 autoantibodies by immunblot (IB) method in patients sera with and without DFS70 staining pattern by IIF and to determine if the presence of anti-DFS70 has a clinical impact when included in ANA testing algorithm. In our study, a total of 60 patients' sera in which DFS pattern was defined by IIF method and 67 patients' sera in which other patterns observed were included in the study and anti-DFS70 autoantibody was investigated by IB method in these sera. In 67 patient samples which have shown the other patterns three (4.5%) samples were determined to be anti-DFS70 positive by IB. In 55 patients who were determined to have IIF-DFS pattern (+)/IB anti-DFS70 (+), 6 (11%) were diagnosed as SARD and the other antinuclear antibodies (ANA) were found as negative by IB. In the other group with the other ANA patterns detected, none of the SARD-diagnosed 22 patients had shown anti-DFS70 by IB method. Sixteen (26.6%) samples in the group that was positive for the IIF-DFS pattern were obtained from rheumatology and physical therapy and rehabilitation clinics, 32 (47.7%) samples were from the group in which other patterns observed and were also obtained from those clinics. DFS pattern was detected significantly more frequent in the samples from other clinics in comparison to the samples from rheumatology and physical therapy and rehabilitation clinics (p= 0.018). In our study, it was concluded that DFS pattern can be defined by IIF method by only specialists, however, since homogeneous-like and mixed patterns can be confused especially in low titers, there is a need for a second well-validated immunological test that could detect anti-DFS70 auto-antibody. PMID- 30522427 TI - [Investigation of antinuclear antibodies in chronic hepatitis B patients]. AB - Antinuclear antibodies (ANA) facilitate the diagnosis and evaluation of patients in many systemic autoimmune conditions. Besides, ANA may also be detected in chronic infectious diseases. Although a number of investigations associated with autoantibody positivity in patients with chronic hepatitis C were reported, autoantibody positivity in patients with chronic hepatitis B remain rarely addressed in the literature. The aim of this study was to evaluate the antinuclear antibody (ANA), antimitocondrial antibody (AMA), anti-smooth muscle antibodies (ASMA) and anti-liver-kidney microsomal antigen (LKM) antibodies in chronic hepatitis B patients. Serum samples were obtained from adult patients with chronic hepatitis B diagnosis according to "European Association for the Study of the Liver (EASL)" criteria. Samples were taken from 47 patients (22 female, 25 male) with treatment-naive, histologically-proven chronic hepatitis B. Cases co-infected with HCV and/or HIV or that also had systemic autoimmune diseases were excluded. As a control group, 30 healthy blood donors were included in the study. Autoantibodies, including ANA, AMA, ASMA and LKM were detected with indirect immunofluorescence (IIF) method (Euroimmune, Lubeck, Germany) and evaluated by fluorescence microscope (Eurostar III plus, Germany). Positive results were graded into 4 levels ( "+", "++","+++" and "++++") from weak to strong Positive samples were studied with a immunoblotting method (ANA Profile 3, Euroimmun, AG) for the detection of extractable nuclear antigen (ENA). The positive results were detected in 8 (17%) of the HBV patients while all the samples were negative in the control group. The difference between the groups was significant (p< 0.05). Among the 47 serum samples tested, none of the patients were positive for AMA, ASMA, LKM. ANA was present in eight of the serum samples in which six were female and two were male patients. Among the IIF patterns of ANA positivity, one mixed pattern (homogeneous and nucleolar) and one cytoplasmic anti-golgi antibody pattern were detected. Positivity grade was ''++''. Other positive patterns were nucleolar (two patients), granular (two patients), ribozomal (one patient) and homogeneous (one patient) and positivity grade was ''+''. ENA was detected in three samples. Two of them was granular pattern positive samples. SS-A was borderline (+/-) in one and SS-B was borderline (+/-) in one of the samples. In the mixed pattern positive sample, histon was detected as ''+''. Autoantibody positivity between the patient and control groups were statistically significant (p< 0.05). The difference between autoantibody positivity and gender/age was not statistically significant. In conclusion, autoimmune manifestations may be detected in patients with chronic hepatitis B. Low level titer of antibodies such as ANA, AMA, ASMA or LKM may be present in such patients. An increased frequency of these autoantibodies may be associated with non-autoimmune conditions such as chronic viral infection even in treatment naive patients. PMID- 30522428 TI - [A Rickettsia case caused by Rickettsia conorii]. AB - Rickettsia species are gram-negative intracellular, small pleomorphic coccobacilli in the Rickettsiaceae family. This genus is serologically and genotypically divided into four groups as spotted fever group, typhus group, Rickettsia belli and Rickettsia canadensis. Rickettsia conorii (R.conorii subsp. conorii) in the spotted fever group was reported to cause mediterranean spotted fever in Europe, especially in mediterranean countries including Turkey. The major vectors of Rickettsia species are ticks, and in some species fleas or mites. In this report a case with R.conorii infection was presented. A 46-year old female patient, who had anorexia, fatigue, muscle aches, chills and high fever was admitted to a health institution. The patient was diagnosed as influenza. There was no regression in the patient's complaints with the recommended treatment. The patient was examined in our infectious diseases clinic and had several symptoms like severe muscle and joint pain with significant headache, and rashes at her body including hands and feet. The patient had a single eschar in the upper midline of the belly that matched tick biting and pink small maculopapular scars on the trunk, arms, legs, feet, and hands. Considering a Rickettsia pre-diagnosis, liquid electrolyte and doxycycline 2 x 100 mg oral treatment was started. On the third day of treatment, high fever, muscle and joint pain were decreased. On the fifth day, active skin lesions were started to fade. R.conorii IgM and IgG were negative in the first serum sample of the patient. In the biopsy sample taken from eschar tissue, Rickettsia spp. was detected as positive with rt-PCR. PCR was used by using the specific regions of the genetically specific gltA and ompA genes in the biopsy specimens and then the PCR products were determined by DNA sequence analysis. The DNA sequence results were compA red with Genbank data and determined that the gltA sequence was 99%, similar to R.conorii with accession number JN182786 and the ompA sequence was 99%, similar to R.conorii with accession number KR401144. When the phylogenetic tree was created, it was observed that the etiological agent was R.conorii. A week after the treatment, in the second serum sample R.conorii IFA IgM 1/192 titer and IgG 1/320 titer were detected as positive. In this case report, we have presented a Rickettsia case, clinically diagnosed as Rickettsia, serologically negative in the acute phase, PCR positive, with post-treatment seroconversion and etiologic agent determined as R.conorii. PMID- 30522429 TI - [Case of pneumonia associated sepsis accompaning pulmonary myiasis]. AB - Myiasis; is defined as the infestation of dead or living tissues of humans and animals by the diptera larvae. It is prevalent all over the world, especially in tropical and subtropical countries with low socioeconomic status. Myiasis of humans has been associated with low socioeconomic status, alcoholism, mental or neurological diseases, poor personal hygiene, patients with varicose veins, diabetes, malnutrition, advanced stage cancer, pediculosis, immunosuppression, sexually transmitted disease, gingivitis and other oral cavity lesions. Myiasis is most commonly seen as skin invasion in the human body, but can be observed in many areas such as eye, ear, nose, throat, urogenital, intestinal, cerebral and tracheopulmonary. Tracheo pulmonary myiasis is a very rare condition. This report presents a case of pneumonia-associated sepsis in a patient with a tracheostomy accompanied by third-stage larval Sarcophagidae. A 51-year-old male patient developed hypoxic brain injury after myocardial infarction 10 months ago before his admission to the hospital. Tracheostomy and percutaneous endoscopic gastrostomy were performed. Shortness of breath and fever were present for five days. The patient has been admitted to the emergency service with the reason for the deterioration of the general situation. The patient was unconscious. Purulent secretion in the tracheostomy area and bilateral crepitation rales in the lung bases were detected. Leukocyte level was normal with C reactive protein (CRP) 14 mg/dl. Nodular infiltration was detected bilaterally in the middle and lower zones, more prominently in the right thoracic computerized tomography. Seftriaxon, moxifloxacin and fluid therapy were initiated in the patient who was admitted with pneumonia-related sepsis diagnosis. The tracheostomy cannula has changed. On the fourth day of admission, Sarcophagidae third stage larvae were detected in deep tracheal aspiration. Treatment of piperacillin/tazobactam and teicoplanin was started by discontinuing the current antibiotherapy of the patient who had no clinical response and elevated CRP level, 18 mg/dl. The patient was discharged on the 25th day of hospitalization with improved clinical and laboratory responses. Complete healing was observed in the control performed by the home care unit. Bed-dependent, lack of self-care, and poor tracheostomy hygiene were risk factors for this patient. In this case, fluid therapy and antibiotic treatment for sepsis was given but no treatment for myiasis. Larva has been considered to have prepared a base for pneumonia due to the foreign body effect and secretion accumulation. Untreated injuries, especially those with impaired oxygenation, leave the eggs of adult flies and provide a suitable environment for larval development. Therefore, should be given importance to combat with flies and regular tracheostomy care in bedside and tracheostomized patients. PMID- 30522431 TI - Correction to: 12th European Headache Federation Congress jointly with 32nd National Congress of the Italian Society for the Study of Headaches. AB - After publication of this supplement [1], it was brought to our attention that e mail errors were apparent in the following abstracts. This has now been included in this correction. PMID- 30522430 TI - Dynamic cerebral autoregulation after confinement in an isolated environment for 14 days. AB - BACKGROUND: To develop human space exploration, it is necessary to study the effects of an isolated and confined environment, as well as a microgravity environment, on cerebral circulation. However, no studies on cerebral circulation in an isolated and confined environment have been reported. Therefore, we investigated the effects of a 14-day period of confinement in an isolated environment on dynamic cerebral autoregulation. METHODS: We participated in an isolation and confinement experiment conducted by the Japan Aerospace Exploration Agency in 2016. Eight healthy males were isolated and confined in a facility for 14 days. Data were collected on the days immediately before and after confinement. Arterial blood pressure waveforms were obtained using a finger blood pressure monitor, and cerebral blood flow velocity waveforms in the middle cerebral artery were obtained using transcranial Doppler ultrasonography for 6 min during quiet rest in a supine position. Dynamic cerebral autoregulation was evaluated by transfer function analysis between spontaneous variability of beat to-beat mean arterial blood pressure and mean cerebral blood flow velocity. RESULTS: Transfer function gain in the low- and high-frequency ranges increased significantly (0.54 +/- 0.07 to 0.69 +/- 0.09 cm/s/mmHg and 0.80 +/- 0.05 to 0.92 +/- 0.09 cm/s/mmHg, respectively) after the confinement. CONCLUSION: The increases observed in transfer function gain may be interpreted as indicating less suppressive capability against transmission from arterial blood pressure oscillation to cerebral blood flow velocity fluctuation. These results suggest that confinement in an isolated environment for 14 days may impair dynamic cerebral autoregulation. TRIAL REGISTRATION: UMIN000020703 , Registered 2016/01/22. PMID- 30522432 TI - Genome-wide identification, molecular evolution, and expression analysis of auxin response factor (ARF) gene family in Brachypodium distachyon L. AB - BACKGROUND: The auxin response factor (ARF) gene family is involved in plant development and hormone regulation. Although the ARF gene family has been studied in some plant species, its structural features, molecular evolution, and expression profiling in Brachypodium distachyon L. are still not clear. RESULTS: Genome-wide analysis identified 19 ARF genes in B. distachyon. A phylogenetic tree constructed with 182 ARF genes from seven plant species revealed three different clades, and the ARF genes from within a clade exhibited structural conservation, although certain divergences occurred in different clades. The branch-site model identified some sites where positive selection may have occurred, and functional divergence analysis found more Type II divergence sites than Type I. In particular, both positive selection and functional divergence may have occurred in 241H, 243G, 244 L, 310 T, 340G and 355 T. Subcellular localization prediction and experimental verification indicated that BdARF proteins were present in the nucleus. Transcript expression analysis revealed that BdARFs were mainly expressed in the leaf and root tips, stems, and developing seeds. Some BdARF genes exhibited significantly upregulated expression under various abiotic stressors. Particularly, BdARF4 and BdARF8 were significantly upregulated in response to abiotic stress factors such as salicylic acid and heavy metals. CONCLUSION: The ARF gene family in B. distachyon was highly conserved. Several important amino acid sites were identified where positive selection and functional divergence occurred, and they may play important roles in functional differentiation. BdARF genes had clear tissue and organ expression preference and were involved in abiotic stress response, suggesting their roles in plant growth and stress resistance. PMID- 30522433 TI - Comparative genomic analysis of Parageobacillus thermoglucosidasius strains with distinct hydrogenogenic capacities. AB - BACKGROUND: The facultatively anaerobic thermophile Parageobacillus thermoglucosidasius produces hydrogen gas (H2) by coupling CO oxidation to proton reduction in the water-gas shift (WGS) reaction via a carbon monoxide dehydrogenase-hydrogenase enzyme complex. Although little is known about the hydrogenogenic capacities of different strains of this species, these organisms offer a potentially viable process for the synthesis of this alternative energy source. RESULTS: The WGS-catalyzed H2 production capacities of four distinct P. thermoglucosidasius strains were determined by cultivation and gas analysis. Three strains (DSM 2542T, DSM 2543 and DSM 6285) were hydrogenogenic, while the fourth strain (DSM 21625) was not. Furthermore, in one strain (DSM 6285) H2 production commenced earlier in the cultivation than the other hydrogenogenic strains. Comparative genomic analysis of the four strains identified extensive differences in the protein complement encoded on the genomes, some of which are postulated to contribute to the different hydrogenogenic capacities of the strains. Furthermore, polymorphisms and deletions in the CODH-NiFe hydrogenase loci may also contribute towards this variable phenotype. CONCLUSIONS: Disparities in the hydrogenogenic capacities of different P. thermoglucosidasius strains were identified, which may be correlated to variability in their global proteomes and genetic differences in their CODH-NiFe hydrogenase loci. The data from this study may contribute towards an improved understanding of WGS-catalysed hydrogenogenesis by P. thermoglucosidasius. PMID- 30522434 TI - Small-intestinal TG2-specific plasma cells at different stages of coeliac disease. AB - BACKGROUND: In coeliac disease, ingestion of gluten induces the production of transglutaminase 2 (TG2)-targeted autoantibodies by TG2-specific plasma cells present at high frequency in the small intestinal mucosa in untreated disease. During treatment with a gluten-free diet (GFD), the number of these cells decreases considerably. It has not been previously investigated whether the cells are also present prior to development of villous atrophy, or in non-responsive patients and those with dietary lapses. We aimed to define the frequency of small bowel mucosal TG2-specific plasma cells in coeliac disease patients with varying disease activity, and to investigate whether the frequency correlates with serum and small intestinal TG2-targeting antibodies as well as mucosal morphology and the number of intraepithelial lymphocytes. RESULTS: Mucosal TG2-specific plasma cells were found in 79% of patients prior to development of mucosal damage, in all patients with villous atrophy, and in 63% of the patients after 1 year on GFD. In these disease stages, TG2-specific plasma cells accounted for median of 2.3, 4.3, and 0.7% of all mucosal plasma cells, respectively. After long-term treatment, the cells were present in 20% of the patients in clinical remission (median 0%) and in 60% of the patients with poor dietary adherence (median 5.8%). In patients with non-responsive coeliac disease despite strict GFD, the cells were found in only one (9%) subject; the cells accounted for 2.4% of all plasma cells. A positive correlation between the percentage of TG2-specific plasma cells and serum TG2 antibody levels (rS = 0.69, P < 0.001) and the intensity of mucosal TG2-targeting IgA deposits (rS = 0.43, P < 0.001) was observed. CONCLUSIONS: Our results show that TG2-specific plasma cells are already detectable prior to villous atrophy, and that generally their frequency increases during overt disease. By contrast, on GFD, the percentage of these cells decreases. Overall, the presence of TG2-specific plasma cells in the small bowel mucosa mirrors the presence of gluten in the diet, but the frequency is not always parallel to the level of serum or intestinal TG2 antibodies. These findings increase the knowledge about the development of the TG2 plasma cell responses especially in the early phases of coeliac disease. PMID- 30522435 TI - Proto-oncogenes in a eukaryotic unicellular organism play essential roles in plasmodial growth in host cells. AB - BACKGROUND: The eukaryotic unicellular protist Plasmodiophora brassicae is an endocellular parasite of cruciferous plants. In host cortical cells, this protist develops a unicellular structure that is termed the plasmodium. The plasmodium is actually a multinucleated cell, which subsequently splits and forms resting spores. The mechanism for the growth of this endocellular parasite in host cell is unclear. RESULTS: Here, combining de novo genome sequence and transcriptome analysis of strain ZJ-1, we identified top five significant enriched KEGG pathways of differentially expressed genes (DEGs), namely translation, cell growth and death, cell communication, cell motility and cancers. We detected 171 proto-oncogenes from the genome of P. brassicae that were implicated in cancer related pathways, of which 46 were differential expression genes. Three predicted proto-oncogenes (Pb-Raf1, Pb-Raf2, and Pb-MYB), which showed homology to the human proto-oncogenes Raf and MYB, were specifically activated during the plasmodial growth in host cortical cells, demonstrating their involvement in the multinucleate development stage of the unicellular protist organism. Gene networks involved in the tumorigenic-related signaling transduction pathways and the activation of 12 core genes were identified. Inhibition of phosphoinositol-3 kinase relieved the clubroot symptom and significantly suppressed the development process of plasmodia. CONCLUSIONS: Proto-oncogene-related regulatory mechanisms play an important role in the plasmodial growth of P. brassicae. PMID- 30522436 TI - Chronic morbidity and reported disability among older persons from the India Human Development Survey. AB - BACKGROUND: The burden of disability and chronic morbidity among the elderly has been increasing substantially in India in recent years. Yet, the use of nationally representative data to investigate the relationship between chronic morbidity and reported disability in the country has been minimal. The objective of this study is twofold: i) to quantify the association between chronic morbidities and overall disabilities in the activities of daily living (ADLs) among elderly people in India, and ii) to understand how various chronic morbidities influence individual ADLs, specifically, walking, toileting and dressing. METHODS: We used data from the India Human Development Survey-II (IHDS II) as a basis for this study. We computed the Katz Index of independence in ADL to examine the burden of disability among the elderly. Ordered logistic regression was carried out to examine the effect of chronic morbidities on: i) the disability index (where 0 = no disability; 1 = disability in 1 or 2 ADLs; and 2 = disability in 3 ADLs), and ii) disabilities in three ADLs in the population over-60 years of age in India. RESULTS: The percentage of people scoring lower Katz index (indicating severe and mild disability) in at least one of the three ADLs is very high in India (17.91% for males and 26.21% for females). Irrespective of the type of ADL, the Katz score is lower in elderly females than in elderly males. Elderly people who are illiterate and belong to the poorest wealth quintile report lower Katz scores in ADL. Both bivariate and multivariate analyses confirm that all three types of chronic morbidities are positively and significantly associated with a disability condition in the ADLs. Yet, the effects of morbidities vary greatly according to the type of disability. For instance, while diabetes affect walking (OR: 2.56; 95% CI: 2.29-2.86), and toileting (OR: 2.63; 95% CI: 2.26-3.07), high blood pressure mainly affects walking (OR: 2.29, 95% CI: 2.09-2.5) and dressing disabilities (OR: 2.13, 95% CI: 1.84-2.46). CONCLUSIONS: Chronic morbidity is a decisive factor in old age disability. It is crucial to reduce chronic morbidity in a timely way to minimise the enormous associated burden of disability. PMID- 30522437 TI - A high density SLAF-SNP genetic map and QTL detection for fibre quality traits in Gossypium hirsutum. AB - BACKGROUND: Upland Cotton (Gossypium hirsutum) is a very important cash crop known for its high quality natural fiber. Recent advances in sequencing technologies provide powerful tools with which to explore the cotton genome for single nucleotide polymorphism marker identification and high density genetic map construction toward more reliable quantitative trait locus mapping. RESULTS: In the present study, a RIL population was developed by crossing a Chinese high fiber quality cultivar (Yumian 1) and an American high fiber quality line (CA3084), with distinct genetic backgrounds. Specific locus amplified fragment sequencing (SLAF-seq) technology was used to discover SNPs, and a genetic map containing 6254 SNPs was constructed, covering 3141.72 cM with an average distance of 0.5 cM between markers. A total of 95 QTL were detected for fiber quality traits in three environments, explaining 5.5-24.6% of the phenotypic variance. Fifty-five QTL found in multiple environments were considered stable QTL. Nine of the stable QTL were found in all three environments. We identified 14 QTL clusters on 13 chromosomes, each containing one or more stable QTL. CONCLUSION: A high-density genetic map of Gossypium hirsutum developed by using specific locus amplified fragment sequencing technology provides detailed mapping of fiber quality QTL, and identification of 'stable QTL' found in multiple environments. A marker-rich genetic map provides a foundation for fine mapping, candidate gene identification and marker-assisted selection of favorable alleles at stable QTL in breeding programs. PMID- 30522438 TI - "As du Coeur" study: a randomized controlled trial on quality of life impact and cost effectiveness of a physical activity program in patients with cardiovascular disease. AB - BACKGROUND: Physical activity programs (PAP) in patients with cardiovascular disease require evidence of cost-utility. To assess improvement in health-related quality of life (QoL) and reduction of health care consumption of patients following PAP, a randomized trial was used. METHODS: Patients from a health insurance company who had experienced coronary artery disease or moderate heart failure were invited to participate (N = 1891). Positive responders (N = 50) were randomly assigned to a progressively autonomous physical activity (PAPA) program or to a standard supervised physical activity (SPA) program. The SPA group had two supervised sessions per week over 5 months. PAPA group had one session per week and support to aid habit formation (written tips, exercise program, phone call). To measure health-related quality of life EQ-5D utility score were used, before intervention, 6 months (T6) and 1 year later. Health care costs were provided from reimbursement databases. RESULTS: Mobility, usual activities and discomfort improved significantly in both group (T6). One year later, EQ-5D utility score was improved in the PAPA group only. Total health care consumption in the intervention group decreased, from a mean of 4097 euros per year before intervention to 2877 euros per year after (p = 0.05), compared to a health care consumption of 4087 euros and 4180 euros per year, in the total population of patients (N = 1891) from the health insurance company. The incremental cost effectiveness ratio was 10,928 euros per QALYs. CONCLUSION: A physical activity program is cost-effective in providing a better quality of life and reducing health care consumption in cardiovascular patients. TRIAL REGISTRATION: ISRCTN77313697 , retrospectively registered on 20 November 2015. PMID- 30522439 TI - Cluster oligonucleotide signatures for rapid identification by sequencing. AB - BACKGROUND: Oligonucleotide signatures (signatures) have been widely used for studying microbial diversity and function in wet-lab settings, but using them for accurate in silico identification of organisms from high-throughput sequencing (HTS) data is only a proof of concept. Existing signature design programs for sequence signatures (signatures matching exactly one sequence) or clade signatures (signatures matching every sequence in a phylogenetic clade) are not able to identify all possible polymorphic sites for sequences with high similarity and perform poorly when handling large genome sequencing datasets. RESULTS: We introduce cluster signatures: subsequences that match perfectly and exclusively any group of sequences in a data set. Cluster signatures provide complete recall for primer/probe design and increased discrimination between sequences beyond that of clade signatures. Using cluster signatures for in silico identification of HTS targets achieves good precision/recall and running time performance. This method has been implemented into an open source tool, the Automated Oligonucleotide Design Pipeline (adop), included in supplementary material and available at: https://bitbucket.org/wenchen_aafc/aodp_v2.0_release . CONCLUSIONS: Cluster signatures provide a rapid and universal analysis tool to identify all possible short diagnostic DNA markers and variants from any DNA sequencing dataset. They are particularly useful in discriminating genetic material from closely related organisms and in detecting deleterious mutations in highly or perfectly conserved genomic sites. PMID- 30522440 TI - Molecular epidemiology and clinical features of hand, foot and mouth disease in northern Thailand in 2016: a prospective cohort study. AB - BACKGROUND: Hand, foot and mouth disease (HFMD) is a major communicable disease in children <=6 years old, particularly in several countries in the Asia-Pacific Region, including Thailand. HFMD impacts public health and the economy, especially in northern Thailand. METHODS: A prospective cohort study was conducted to estimate the incidence rate and to identify the serotype and clinical features of HFMD among children in northern Thailand. A validated questionnaire and throat swab were used for data collection. Polymerase chain reaction (PCR) was used to detect human enterovirus and identify its serotypes. Participants were recruited from 14 hospitals in two provinces in northern Thailand, specifically, Chiang Rai and Pha Yao Province, between January 1, 2016, and December 31, 2016. Chi-square or Fisher's exact test was used to detect the associations of signs and symptoms with HFMD serotype. Logistic regression was used to detect the associations of variables with a positive enterovirus at alpha = 0.05. RESULT: In total, 612 children aged <=6 years from Chiang Rai and Pha Yao Province who were diagnosed with HFMD by a throat swab were recruited for the analysis. Approximately half of the cohort was male (57.2%), 57.5% was aged < 2 years, and 57.5% lived in rural areas. The incidence rate was 279.72/100,000 person-years in Chiang Rai Province and 321.24 per 100,000 person-years in Pha Yao Province. Additionally, 42.5% of children were positive for human enterovirus; among these children, 56.1% were positive for enterovirus-A (EV-A), 17.7% were positive for coxsackievirus (CV), and 26.2% were positive for other human RNA enteroviruses. During the study period, 21 distinct outbreaks of HFMD were recognized. Four to five patients (total 92 patients) were selected from each outbreak for identifying its serotype; enterovirus-A71 (EV-A71) was detected in 34.8% of HFMD cases, coxsackievirus-A16 (CV-A16) in 26.1%, coxsackivirus-A6 (CV-A6) in 15.2%, coxsackievirus-A10 (CV-A10) in 10.9%, coxsackievirus-A4 (CV-A4) in 2.2%, coxsackievirus-B2 (CV-B2) in 2.2%, human rhinovirus in 2.2%, and unknown serotype in 6.4%. Multivariable analysis demonstrated that a history of breastfeeding for <=6 months was associated with a higher chance of enterovirus infection than a history of breastfeeding > 6 months, and children who had mother who worked as farmers, daily wage employees, and unprofessional skilled jobs had a greater chance of enterovirus infection than those who had unemployed mothers. Coxsackievirus-infected children had a higher rate of rashes on the buttocks, knee, and elbow and fever but a lower rate of lethargy and malaise than EV-A71 infected children. CONCLUSIONS: EV-A71 is a major cause of HFMD in children < 6 years old in northern Thailand, but rash, fever, and mouth ulcers are mostly found in participants with coxsackievirus infection. Breastfeeding should be promoted during early childhood for at least 6 months to prevent HFMD particularly those mother who are working in unprofessional skill jobs. PMID- 30522441 TI - How is the evolution of tumour resistance at organ-scale impacted by the importance of the organ for fitness? AB - BACKGROUND: A strong variability in cancer incidence is observed between human organs. Recently, it has been suggested that the relative contribution of organs to organism fitness (reproduction or survival) could explain at least a part of the observed variation. The objective of this study is to investigate theoretically the main factors driving the evolution of tumour resistance mechanisms of organs when their relative contribution to organism fitness is considered. We use a population-scale model where individuals can develop a tumour in a key organ (i.e. in which even a small tumour can negatively impact organism fitness), an auxiliary organ (i.e. in which only a large tumour has a relatively significant impact) or both organs because of metastasis. RESULTS: Our simulations show that natural selection acts in two different ways to prevent cancer in a key and an auxiliary organs. In the key organ, the strategy mostly selected is the highest resistance and only a high cost of resistance mitigates this behavior. Inversely, we observe that a low resistance strategy can be selected in the auxiliary organ when the development of the tumour is slow and the effect of a large tumour on the mortality of the organism is relatively weak. Nevertheless, if the tumour can spread to a key organ, higher resistance strategies are selected in the auxiliary organ. CONCLUSION: Finally, our study demonstrates that the relative contribution of organs to the organism fitness and the metastatic propensity of the tumour influence the evolution of tumour resistance at organ scale and should be considered by studies aiming to explain the variability in cancer incidence at organ-scale. PMID- 30522442 TI - Determinants of client satisfaction to skilled antenatal care services at Southwest of Ethiopia: a cross-sectional facility based survey. AB - BACKGROUND: Patient satisfaction to Antenatal care services has traditionally been linked to the quality of services given and the extent to which specific needs are met. Even though data in this area was limited in Ethiopia, improving quality of care was one of the strategies in health sector development program IV. This study, therefore, attempted to assess client satisfaction to skilled antenatal care services in the study area. METHODS AND MATERIALS: A cross sectional facility based survey was conducted among women who were attending antenatal care clinic, using quantitative method triangulated with qualitative data collection. Participants were selected using systematic sampling method according to the flow pregnant women to the antenatal care clinics. The study was carried out in all functional public health centers in the district. During the survey, 405 women were interviewed. A logistic regression model was applied to control for confounders. RESULTS: Out of the total respondents, overall satisfied to skilled antenatal care services were about 277(68%). The most common specific component of antenatal care that had good-satisfaction by the respondents was "Privacy" at examination (81.7%). Most satisfied health education session was "Diet and nutrition" session (82.2%). Absence of sonar test, no doctor and long waiting time were commonest causes of dissatisfaction. Respondents who have > 2 previous antenatal care visit were 3 times more likely (AOR = 2.93; 95% CI, 1.21, 7.12) to have satisfaction to antenatal care services as compared to those with < 1 visit. Women whose current visit fourth were 9 times more likely (AOR = 9.02, 95% CI; 1.76, 46.1) to be satisfied for antenatal services than those who were in the first visit. Women with family monthly income of $US 25-100 per month were 60% (AOR = 0.4, 95% CI; 0.2, 0.8) less likely to have satisfaction by skilled antenatal care services than those who had monthly household income below $US 25. CONCLUSION AND RECOMMENDATION: Women who reported good-satisfaction to overall skilled antenatal care services were highest as compared to previous Ethiopian study findings. Demographic, economic, obstetric and distance factors were independent predictors of satisfaction to skilled antenatal care services. Non natives must be encouraged to seek satisfying services. PMID- 30522443 TI - Antimicrobial peptide similarity and classification through rough set theory using physicochemical boundaries. AB - BACKGROUND: Antimicrobial peptides attract considerable interest as novel agents to combat infections. Their long-time potency across bacteria, viruses and fungi as part of diverse innate immune systems offers a solution to overcome the rising concerns from antibiotic resistance. With the rapid increase of antimicrobial peptides reported in the databases, peptide selection becomes a challenge. We propose similarity analyses to describe key properties that distinguish between active and non-active peptide sequences building upon the physicochemical properties of antimicrobial peptides. We used an iterative supervised machine learning approach to classify active peptides from inactive peptides with low false discovery rates in a relatively short computational search time. RESULTS: By generating explicit boundaries, our method defines new categories of active and inactive peptides based on their physicochemical properties. Consequently, it describes physicochemical characteristics of similarity among active peptides and the physicochemical boundaries between active and inactive peptides in a single process. To build the similarity boundaries, we used the rough set theory approach; to our knowledge, this is the first time that this approach has been used to classify peptides. The modified rough set theory method limits the number of values describing a boundary to a user-defined limit. Our method is optimized for specificity over selectivity. Noting that false positives increase activity assays while false negatives only increase computational search time, our method provided a low false discovery rate. Published datasets were used to compare our rough set theory method to other published classification methods and based on this comparison, we achieved high selectivity and comparable sensitivity to currently available methods. CONCLUSIONS: We developed rule sets that define physicochemical boundaries which allow us to directly classify the active sequences from inactive peptides. Existing classification methods are either sequence-order insensitive or length-dependent, whereas our method generates the rule sets that combine order-sensitive descriptors with length-independent descriptors. The method provides comparable or improved performance to currently available methods. Discovering the boundaries of physicochemical properties may lead to a new understanding of peptide similarity. PMID- 30522444 TI - Risk factors for hypertensive disorders of pregnancy among mothers in Tigray region, Ethiopia: matched case-control study. AB - BACKGROUND: Hypertensive disorders of pregnancy are a global public health concern both in developed and developing countries. However, evidences regarding the risk factors of hypertensive disorders of pregnancy are limited particularly in Ethiopia. The aim of the study was to assess risk factors associated with hypertensive disorders of pregnancy among mothers in public hospitals of Tigray. METHODS: The study was conducted in seven public hospitals of Tigray region, Ethiopia from June 2017 to November 2017. A facility based matched case-control study was employed to select 110 cases and 220 controls who were pregnant women. Cases and controls were matched by parity status. A case was a mother diagnosed to have hypertensive disorders of pregnancy by an obstetrician in the antenatal period while a control was a mother who did not have a diagnosis of hypertensive disorders of pregnancy. Data were collected by face to face interview technique using a pretested questionnaire and a checklist. Conditional logistic regression analysis was used to identify the independent predictor variables. Adjusted matched odds ratio with its corresponding 95% confidence interval was used and significance was claimed at P-value less than 0.05. Overall findings were presented in texts and tables. RESULTS: Rural residents were at greater odds of suffering from hypertensive disorders (OR = 3.7, 95% CI; 1.9, 7.1). Similarly, mothers who consume less amount of fruits in their diet had 5 times higher odds of developing hypertensive disorders than those who consume fruits regularly (OR = 5.1, 95% CI; 2.4, 11.15). Overweight (BMI > 25 Kg/m2) mothers were also at risk of developing hypertensive disorders of pregnancy as compared with the normal and underweight mothers (AOR = 5.5 95% CI; 1.12, 27.6). The risk of developing hypertensive disorders of pregnancy was 5.4 times higher among diabetic mothers. CONCLUSION: Rural residence, less fruit consumption, multiple pregnancy, presence of gestational diabetes mellitus and pre-pregnancy overweight were identified as independent risk factors in this study. It is recommended that health care givers may use these factors as a screening tool for the prediction, early diagnoses as well as timely interventions of hypertensive disorders of pregnancy. PMID- 30522445 TI - ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk "BCG failure" non muscle invasive bladder cancer: 3 years follow-up outcomes. AB - BACKGROUND: In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the "gold" standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA(r)-MMC in patients with HGNMIBC unresponsive to BCG. METHODS: We carried out a prospective, single center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA(r)-MMC treatment in 26 (21 male, 5 female) consecutive patients with "BCG refractory" HGNMIBC on a 3 years follow-up. EMDA(r)-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current. EMDA(r)-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations. Follow up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract. We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival. RESULTS: At the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle invasive disease. At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05). Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%). CONCLUSIONS: In the field of alternative strategies to radical cystectomy, the EMDA(r)-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a "bladder sparing" therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results. TRIAL REGISTRATION: EudraCT2017-002585-43. 17 June 2017 (retrospectively registered). PMID- 30522446 TI - Is Toxoplasma gondii infection correlated with nonalcoholic fatty liver disease?- a population-based study. AB - BACKGROUND: Previous studies have suggested that Toxoplasma gondii (T. gondii) infection might be associated with fatty liver disease. However, the relationship between non-alcoholic fatty liver disease (NAFLD) and T. gondii infection has not been investigated in a large population. We aimed to study the relationship between those two diseases using a population-based dataset from the United States. METHODS: The data were collected from the third National Health and Nutrition Examination Survey (NHANES III) between 1988 and 1994. Statistical analysis was applied to compare the prevalence of NAFLD in anti-T. gondii antibody-positive participants with antibody-negative ones. RESULTS: A total of 9465 persons with a mean age of 44.33 +/- 16.21 years, 46.9% of which were males, were included in the final analysis. Their mean BMI was 27.60 +/- 5.96 kg/m2. A total of 2520 participants (26.62%) were positive for the T. gondii antibody. There was an increasing trend of seroprevalence of T. gondii with age (P for trend < 0.001). The incidence of NAFLD in the seropositive group was higher than that in the seronegative group (27.10% vs 23.40%, p < 0.001). In addition to this, metabolic biomarkers, including serum lipid, fasting blood-glucose, and uric acid were also significantly higher in the seropositive group. However, multivariate analysis revealed that T. gondii infection was not an independent risk factor for NAFLD. Age was independently correlated with both the prevalence of T. gondii and NAFLD. CONCLUSIONS: Patients with T. gondii infection may have a higher prevalence of NAFLD. Age may have an effect on the increase of NAFLD in the T. gondii seropositive population. PMID- 30522447 TI - Left ventricular-arterial coupling is associated with prolonged mechanical ventilation in severe post-cardiac surgery patients: an observational study. AB - BACKGROUND: Weaning post-cardiac surgery patients from mechanical ventilation (MV) poses a big challenge to these patients. Optimized left ventricular-arterial coupling (VAC) may be crucial for reducing the MV duration of these patients. However, there is no research exploring the relationship between VAC and the duration of MV. We performed this study to investigate the relationship between left ventricular-arterial coupling (VAC) and prolonged mechanical ventilation (MV) in severe post-cardiac surgery patients. METHODS: This was a single-center retrospective study of 56 severe post-cardiac surgery patients from January 2015 to December 2017 at the Department of Critical Care Medicine of Peking Union Medical College Hospital. Patients were divided into two groups according to the duration of MV (PMV group: prolonged mechanical ventilation group, MV > 6 days; Non-PMV group: non-prolonged mechanical ventilation group, MV <= 6 days). Hemodynamics and tissue perfusion data were collected or calculated at admission (T0) and 48 h after admission (T1) to the ICU. RESULTS: In terms of hemodynamic and tissue perfusion data, there were no differences between the two groups at admission (T0). Compared with the non-prolonged MV group after 48 h in the ICU (T1), the prolonged MV group had significantly higher values for heart rate (108 +/- 13 vs 97 +/- 12, P = 0.018), lactate (2.42 +/- 1.24 vs.1.46 +/- 0.58, P < 0.001), and Ea/Ees (5.93 +/- 1.81 vs. 4.05 +/- 1.20, P < 0.001). Increased Ea/Ees (odds ratio, 7.305; 95% CI, 1.181-45.168; P = 0.032) and lactate at T1 (odds ratio, 17.796; 95% CI, 1.377-229.988; P = 0.027) were independently associated with prolonged MV. There was a significant relationship between Ea/EesT1 and the duration of MV (r = 0.512, P < 0.01). The area under the receiver operating characteristic (AUC) of the left VAC for predicting prolonged MV was 0.801, and the cutoff value for Ea/Ees was 5.12, with 65.0% sensitivity and 90.0% specificity. CONCLUSIONS: Left ventricular-arterial coupling was associated with prolonged mechanical ventilation in severe post-cardiac surgery patients. The assessment and optimization of left VAC might be helpful in reducing duration of MV in these patients. PMID- 30522448 TI - Genetic variation of dynamic fiber elongation and developmental quantitative trait locus mapping of fiber length in upland cotton (Gossypium hirsutum L.). AB - BACKGROUND: In upland cotton (Gossypium hirsutum L.), genotypes with the same mature fiber length (FL) might possess different genes and exhibit differential expression of genes related to fiber elongation at different fiber developmental stages. However, there is a lack of information on the genetic variation influencing fiber length and its quantitative trait loci (QTLs) during the fiber elongation stage. In this study, a subset of upland cotton accessions was selected based on a previous GWAS conducted in China and grown in multiple environments to determine the dynamic fiber length at 10, 15, 20, and 25 days post-anthesis (DPA) and maturity. The germplasm lines were genotyped with the Cotton 63 K Illumina single-nucleotide polymorphism (SNP) array for GWAS. RESULTS: A total of 25, 38, 57, 89 and 88 SNPs showed significant correlations with fiber length at 10, 15, 20 and 25 DPA and maturity, respectively. In addition, 60 more promising SNPs were detected in at least two tests and two FL developmental time points, and 20 SNPs were located within the confidence intervals of QTLs identified in previous studies. The fastest fiber-length growth rates were obtained at 10 to 15 DPA in 69 upland cotton lines and at 15 to 20 DPA in 14 upland cotton accessions, and 10 SNPs showed significant correlations with the fiber-length growth rate. A combined transcriptome and qRT-PCR analysis revealed that two genes (D10G1008 and D13G2037) showed differential expression between two long-fiber genotypes and two short-fiber genotypes. CONCLUSIONS: This study provides important new insights into the genetic basis of the time dependent fiber-length trait and reveals candidate SNPs and genes for improving fiber length in upland cotton. PMID- 30522449 TI - Different mutational characteristics of the subsets of EGFR-tyrosine kinase inhibitor sensitizing mutation-positive lung adenocarcinoma. AB - BACKGROUND: A subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved. METHODS: Targeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package. RESULTS: In the study cohort, the C > A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P = 0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C > A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P = 0.0497 and P = 0.0055, respectively, Mann Whitney U test). Smoking-related signature 4 was observed only in the L858R subgroup, while ignature 30 and 5 was observed in both groups. CONCLUSIONS: Lung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups. PMID- 30522450 TI - Improving living and dying for people with advanced dementia living in care homes: a realist review of Namaste Care and other multisensory interventions. AB - BACKGROUND: Seventy percent of people with advanced dementia live and die in care homes. Multisensory approaches, such as Namaste Care, have been developed to improve the quality of life and dying for people with advanced dementia but little is known about effectiveness or optimum delivery. The aim of this review was to develop an explanatory account of how the Namaste Care intervention might work, on what outcomes, and in what circumstances. METHODS: This is a realist review involving scoping of the literature and stakeholder interviews to develop theoretical explanations of how interventions might work, systematic searches of the evidence to test and develop the theories, and their validation with a purposive sample of stakeholders. Twenty stakeholders - user/patient representatives, dementia care providers, care home staff, researchers -took part in interviews and/or workshops. RESULTS: We included 85 papers. Eight focused on Namaste Care and the remainder on other types of sensory interventions such as music therapy or massage. We identified three context-mechanism-outcome configurations which together provide an explanatory account of what needs to be in place for Namaste Care to work for people living with advanced dementia. This includes: providing structured access to social and physical stimulation, equipping care home staff to cope effectively with complex behaviours and variable responses, and providing a framework for person-centred care. A key overarching theme concerned the importance of activities that enabled the development of moments of connection for people with advanced dementia. CONCLUSIONS: This realist review provides a coherent account of how Namaste Care, and other multisensory interventions might work. It provides practitioners and researchers with a framework to judge the feasibility and likely success of Namaste Care in long term settings. Key for staff and residents is that the intervention triggers feelings of familiarity, reassurance, engagement and connection. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016047512. PMID- 30522451 TI - Mortality & recurrent seizure risk after new-onset seizure in HIV-positive Zambian adults. AB - BACKGROUND: Recurrent seizure risks in HIV-positive people with new-onset seizure are largely unknown, making it challenging to offer optimal recommendations regarding antiepileptic drug (AED) initiation. Existing outcomes data is limited, and risk factor identification requires a diagnostic assessment, which is often unavailable in regions heavily effected by HIV, like sub-Saharan Africa. METHODS: HIV-positive Zambian adults with new-onset seizure were enrolled in a prospective cohort study to determine seizure recurrence and risk factors for recurrence. Seizure etiology was evaluated, and recurrent seizures and medication usage were assessed during clinic visits. Due to unexpectedly high mortality rates, predictors of death were evaluated using proportional hazards with Gray's test to compare cumulative incidence functions for recurrent seizure across groups adjusting for the competing outcome of death. RESULTS: 95 patients were enrolled (mean age 37 years, 43% female, 83% with Karnofsky > 50) and followed for a mean of 293 days (median 241 (IQR: 29-532)). At presentation, 50 (53%) were in status epilepticus. The majority (91, 85%) had advanced HIV disease and 65 (68%) were not on combined antiretroviral therapy (cART). After extensive workup, seizure etiology remained unknown in 16 (17%). Average time to cART initiation after enrollment was 61 days. During follow up, 37 (39%) died and 23 (24%) had recurrent seizure. Most deaths (25/37, 68%) occurred in the first 60 days post index seizure. Individuals with advanced HIV were more likely to die (HR: 19.1 [95% CI: 1.1-333.4]) as were those whose seizure etiology remained unknown (HR: 2.2 [95% CI: 1.1-4.4]). Among participants that survived from enrolment to the end of data collection on 10 May 2013 (n = 58), 20 (34%) experienced recurrent seizures. CONCLUSIONS: New-onset seizure among HIV-positive Zambian adults is associated with high mortality despite good functional status prior to presentation. Advanced HIV infection and failure to identify an underlying seizure etiology are associated with greater mortality. Recurrent seizures occur in over a third of survivors within only 2 years of follow-up. This provides evidence to support AED initiation after first seizure in HIV-positive individuals with advanced HIV disease at the time of presentation though the risks of AED-cART interactions remain a concern and warrant further study. PMID- 30522452 TI - Differential response of silencing HvIcy2 barley plants against Magnaporthe oryzae infection and light deprivation. AB - BACKGROUND: Phytocystatins (PhyCys) act as endogenous regulators of cysteine proteases (CysProt) involved in various physiological processes. Besides, PhyCys are involved in plant reactions to abiotic stresses like drought or darkness and have been used as effective molecules against different pests and pathogens. The barley PhyCys-CysProt system is considered a model of protease-inhibitor regulation of protein turnover. Thirteen barley cystatins (HvCPI-1 to HvCPI-13) have been previously identified and characterized. Among them HvCPI-2 has been shown to have a relevant role in plant responses to pathogens and pests, as well as in the plant response to drought. RESULTS: The present work explores the multiple role of this barley PhyCys in response to both, biotic and abiotic stresses, focusing on the impact of silencing this gene. HvIcy-2 silencing lines behave differentially against the phytopathogenic fungus Magnaporthe oryzae and a light deprivation treatment. The induced expression of HvIcy-2 by the fungal stress correlated to a higher susceptibility of silencing HvIcy-2 plants. In contrast, a reduction in the expression of HvIcy-2 and in the cathepsin-L and -B like activities in the silencing HvIcy-2 plants was not accompanied by apparent phenotypical differences with control plants in response to light deprivation. CONCLUSION: These results highlight the specificity of PhyCys in the responses to diverse external prompts as well as the complexity of the regulatory events leading to the response to a particular stress. The mechanism of regulation of these stress responses seems to be focused in maintaining the balance of CysProt and PhyCys levels, which is crucial for the modulation of physiological processes induced by biotic or abiotic stresses. PMID- 30522454 TI - A contribution to the validation of the Italian version of the Body Image Scale (BIS). AB - BACKGROUND: The Body Image Scale (BIS) is a 10-item mono-factorial scale, designed to capture distress and symptoms related to body image in cancer patients. This paper describes the conversion and psychometric evaluation of an Italian BIS version. METHODS: After the back-translation procedure, the Italian version of the BIS, together with the Hospital Anxiety and Depression Scale and the Short Form 36 Health Survey Questionnaire, have been administered to a sample of Italian adult females, surgically treated for a breast cancer at least one year before. RESULTS: Data on 109 participants were analyzed. The response rate was 92.5%. Response prevalence was adequate for 9 out of 10 items. Principal component analysis showed a one-factor structure. Internal consistency (Cronbach's alpha =0.924) was good. The BIS correlated with the theoretically pertinent subscales of the other administered tools and was able to discriminate participants (discriminant validity) according to the undertaken surgical treatment (p = 0.031). CONCLUSIONS: This study supports the valid and reliable use also of the Italian version of the BIS. PMID- 30522453 TI - Labour outcomes in caseload midwifery and standard care: a register-based cohort study. AB - BACKGROUND: Research on caseload midwifery in a Danish setting is missing. This cohort study aimed to compare labour outcomes in caseload midwifery and standard midwifery care. METHODS: A historical register-based cohort study was carried out using routinely collected data about all singleton births 2013-2016 in two maternity units in the North Denmark Region. In this region, women are geographically allocated to caseload midwifery or standard care, as caseload midwifery is only available in some towns in the peripheral part of the uptake areas of the maternity units, and it is the only model of care offered here. Labour outcomes of 2679 all-risk women in caseload midwifery were compared with those of 10,436 all-risk women in standard midwifery care using multivariate linear and logistic regression analyses. RESULTS: Compared to women in standard care, augmentation was more frequent in caseload women (adjusted odds ratio (aOR) 1.20; 95% CI 1.06-1.35) as was labour duration of less than 10 h (aOR 1.26; 95% CI 1.13-1.42). More emergency caesarean sections were observed in caseload women (aOR 1.17; 95% CI 1.03-1.34), but this might partly be explained by longer distance to the maternity unit in caseload women. When caseload women were compared to women in standard care with a similar long distance to the hospital, no difference in emergency caesarean sections was observed (aOR 1.04; 95% CI 0.84 1.28). Compared to standard care, infants of caseload women more often had Apgar <=7 after 5 min. (aOR 1.57; 95% CI 1.11-2.23) and this difference remained when caseload women were compared to women with similar distance to the hospital. For elective caesarean sections, preterm birth, induction of labour, dilatation of cervix on admission, amniotomy, epidural analgesia, and instrumental deliveries, we did not obseve any differences between the two groups. After birth, caseload women more often experienced no laceration (aOR 1.17; 95% CI 1.06-1.29). CONCLUSIONS: For most labour outcomes, there were no differences across the two models of midwifery-led care but unexpectedly, we observed slightly more augmentation and adverse neonatal outcomes in caseload midwifery. These findings should be interpreted in the context of the overall low intervention and complication rates in this Danish setting and in the context of research that supports the benefits of caseload midwifery. Although the observational design of the study allows only cautious conclusions, this study highlights the importance of monitoring and evaluating new practices contextually. PMID- 30522455 TI - Plasma homocysteine levels and intracranial plaque characteristics: association and clinical relevance in ischemic stroke. AB - BACKGROUND: Elevated plasma homocysteine (Hcy) is an independent risk factor for ischemic stroke. This study aimed to evaluate the association between Hcy levels and intracranial plaque characteristics and to investigate their clinical relevance in ischemic stroke. METHODS: Ninety-four patients with intracranial atherosclerosis (ICAS) were enrolled. Plasma Hcy levels were measured. Intracranial plaque characteristics including plaque enhancement, stenosis ratio, T2 and T1 hyperintense components were assessed on high-resolution magnetic resonance imaging. Logistic regression model was constructed to analyze the association between high Hcy levels and plaque characteristics, and their synergistic effects to predict the likelihood for ischemic stroke, while adjusting for demographics and traditional atherosclerotic risk factors. RESULTS: Elevated Hcy level was associated with strong plaque enhancement independently of age, sex, serum creatinine levels and other atherosclerotic risk factors ((P < 0.001, OR 6.00, 95% confidence interval [CI] 2.28-15.74). Both strong plaque enhancement (P = 0.026, OR 5.63, 95% CI 1.23-25.81) and high Hcy level (P = 0.018, OR 6.20, 95% CI 1.36-28.26) were correlated with acute ischemic stroke. The combination of them strengthened the ability to stratify the likelihood for ischemic stroke, with an improved area under the receiver operating characteristic curve (AUC) of 0.871, significantly higher than that of strong plaque enhancement (0.755) and high Hcy level (0.715) alone (P < 0.05 for both). CONCLUSIONS: High Hcy level appears to have association with intracranial strong plaque enhancement. The combined assessment of plasma Hcy levels and plaque enhancement may improve ischemic stroke risk stratification. PMID- 30522456 TI - OMCD: OncomiR Cancer Database. AB - BACKGROUND: microRNAs (miRNAs) are crucially important in the development of cancer. Their dysregulation, commonly observed in various types of cancer, is largely cancer-dependent. Thus, to understand the tumor biology and to develop accurate and sensitive biomarkers, we need to understand pan-cancer miRNA expression. CONSTRUCTIONS: At the University of Minnesota, we developed the OncomiR Cancer Database (OMCD), hosted on a web server, which allows easy and systematic comparative genomic analyses of miRNA sequencing data derived from more than 9500 cancer patients tissue samples available in the Cancer Genome Atlas (TCGA). OMCD includes associated clinical information and is searchable by organ-specific terms common to the TCGA. CONCLUSIONS: Freely available to all users ( www.oncomir.umn.edu/omcd/ ), OMCD enables (1) simple visualization of TCGA miRNA sequencing data, (2) statistical analysis of differentially expressed miRNAs for each cancer type, and (3) exploration of miRNA clusters across cancer types. DATABASE URL: www.oncomir.umn.edu/omcd. PMID- 30522457 TI - Intravitreal dexamethasone implant therapy for the treatment of cystoid macular Oedema due to hydroxychloroquine retinopathy: a case report and literature review. AB - BACKGROUND: Cystoid macular oedema (CMO) is an uncommon complication associated with hydroxychloroquine (HCQ) retinopathy threatening central vision. We report a patient with HCQ retinopathy and CMO, for which an intravitreal dexamethasone implant was used, which led to complete resolution of oedema. CASE PRESENTATION: A 57-year-old woman with systemic lupus erythematosus (SLE) complaining of blurred vision in both eyes was diagnosed with bilateral HCQ retinopathy and CMO based on characteristic photoreceptor defects and cystoid spaces on optical coherence tomography, hypo-autofluorescence on fundus autofluorescence, and corresponding visual field defects. After treatment with systemic acetazolamide and topical dorzolamide, CMO showed partial resolution in the right eye. Owing to worsening renal function, an intravitreal dexamethasone implant was placed in the right eye, which resulted in resolution of CMO and visual improvement from 20/50 to 20/30. CONCLUSION: Intravitreal dexamethasone implant may be effective for the treatment of CMO in HCQ retinopathy, particularly for the cases refractory to systemic or topical carbonic anhydrase inhibitors. PMID- 30522458 TI - Continuous support during labour in childbirth: a Cross-Sectional study in a university teaching hospital in Shanghai, China. AB - BACKGROUND: Fear or anxiety could result in adverse consequences on the course of labour. To date, family members are still not permitted in the delivery rooms in the majority of hospitals in China, and continuous support from hospital professional staff is also limited. This study aimed to evaluate the benefits of continuous support by family members and hospital professional staff during labour in China. METHODS: In this Cross-Sectional study, 362 primiparous pregnancies who self-requested to receive continuous or one to one support with vaginal delivery and 362 primiparous pregnant women with routine hospital maternal care were included from a university teaching hospital. Data on the length of labour, postpartum haemorrhage (PPH), use of pain relief, use of oxytocin, fetal distress, emergency caesarean section and apgar score at 1 and 5 min were retrospectively collected from hospital medical data-base and compared between the two groups. RESULTS: Multiple linear regressions adjusting for maternal age, BMI and birth weight, revealed the estimated length of labour for women with routine hospital maternal care was 2.03 times (95%CI 1.86 to 2.21) the duration of women with supportive care (median time, 3.05 h vs 1.5 h). In addition, Fisher's exact test showed the emergency caesarean section rate was significantly lower in women with supportive care compared to women with routine hospital maternal care (3.3% vs 24%). CONCLUSION: Our results suggest that continuous support from family members together with hospital professional staff should be considered as part of intrapartum care in hospitals in China. PMID- 30522459 TI - Vaccination in England: a review of why business as usual is not enough to maintain coverage. AB - BACKGROUND: The vaccine system in England underwent radical changes in 2013 following the implementation of the Health and Social Care Act. There have since been multi-year decreases in coverage of many vaccines. Healthcare professionals have reported finding the new system fragmented and challenging. This study aims to produce a logic model of the new system and evaluate the available evidence for interventions to improve coverage. METHODS: We undertook qualitative document analysis to develop the logic model using process evaluation methods. We performed a systematic review by searching 12 databases with a broad search strategy to identify interventions studied in England conducted between 2006 and 2016 and evaluated their effectiveness. We then compared the evidence base to the logic model. RESULTS: We analysed 83 documents and developed a logic model describing the core inputs, processes, activities, outputs, outcomes and impacts of the new vaccination system alongside the programmatic assumptions for each stage. Of 9,615 unique articles, we screened 624 abstracts, 45 full-text articles, and included 16 studies: 8 randomised controlled trials and 8 quasi experimental studies. Four studies suggest that modifications to the contracting and incentive systems can increase coverage, but changes to other programme inputs (e.g. human or capital resources) were not evaluated. Four multi-component intervention studies modified activities and outputs from within a GP practice to increase coverage, but were part of campaigns or projects. Thus, many potentially modifiable factors relating to routine programme implementation remain unexplored. Reminder/recall systems are under-studied in England; incentive payments to adolescents may be effective; and only two studies evaluated carer information. CONCLUSIONS: The evidence base for interventions to increase immunisation coverage in the new system in England are limited by a small number of studies and by significant risk of bias. Several areas important to primary care remain unexplored as targets for interventions, especially modification to organisational management. PMID- 30522460 TI - The impact of immigration detention on mental health: a systematic review. AB - BACKGROUND: The number of asylum seekers, refugees and internally displaced people worldwide has increased dramatically over the past 5 years. Many countries are continuing to resort to detaining asylum seekers and other migrants, despite concerns that this may be harmful. In light of the considerable body of recent research, this review aims to update and expand on a 2009 systematic review on the mental health consequences of detention on adult, adolescent and child immigration detainees, which found (on the basis on 9 studies) that there was consistent evidence that immigration detention had adverse effects on mental health. METHODS: Three databases were searched using key terms relating to immigration detention and mental health. Electronic searches were supplemented by reference screening. Studies were included if they were quantitative, included individuals detained for immigration purposes, reported on mental health problems and were published in peer-reviewed journals. Two reviewers independently screened papers for eligibility, and a further two reviewers completed quality appraisals for included studies. RESULTS: Twenty- six studies (21 of which were not included in the 2009 review) reporting on a total of 2099 participants were included in the review. Overall, these studies indicated that adults, adolescents and children experienced high levels of mental health problems. Anxiety, depression and post-traumatic stress disorder were most commonly reported both during and following detention. Higher symptom scores were found in detained compared to non-detained refugees. In addition (and more clearly than was evident in 2009), detention duration was positively associated with severity of mental symptoms. Greater trauma exposure prior to detention was also associated with symptom severity. CONCLUSIONS: The literature base reviewed in this paper consistently demonstrated severe mental health consequences amongst detainees across a wide range of settings and jurisdictions. There is a pressing need for the proper consideration of mental health and consequent risk of detention related harm in decisions surrounding detention as well as for improved care for individuals within detention facilities. Recommendations based on these findings are presented, including increased focus on the identification of vulnerability and on minimising the duration of detention. PMID- 30522461 TI - Early post-operative serum albumin level predicts survival after curative nephrectomy for kidney cancer: a retrospective study. AB - BACKGROUND: Previous studies have shown that albumin-related systemic inflammation is associated with the long-term prognosis of cancer, but the clinical significance of an early (<= 7 days) post-operative serum albumin level has not been well-documented as a prognostic factor in patients with renal cell cancer. METHODS: We retrospectively included patients hospitalized for kidney cancer from January 2009 to May 2014. First, the receiver operating characteristic analysis was used to define the best cut-off of an early post operative serum albumin level in determining the prognosis, from which survival analysis was performed. RESULTS: A total of 329 patients were included. The median duration of follow-up was 54.8 months. Patients with an early post operative serum albumin level < 32 g/L had a significantly shorter median recurrence-free survival (RFS; 49.1 versus 56.5 months, P = 0.001) and median overall survival (OS; 52.2 versus 57.0 months, P = 0.049) than patients with an early post-operative serum albumin level >= 32 g/L. After adjusting for age, BMI, tumor stage, post-operative hemoglobin concentration, and pre-operative albumin, globulin, and hemoglobin levels, multivariate Cox regression showed that an early post-operative serum albumin level < 32 g/L was an independent prognostic factor associated with a decreased RFS (HR = 3.60; 95% CI,1.05-12.42 [months], P = 0.042) and decreased OS (HR = 9.95; 95% CI, 1.81-54.80 [months], P = 0.008). CONCLUSION: An early post-operative serum albumin level < 32 g/L is an independent prognostic factor leading to an unfavorable RFS and OS. Prospective trials and further studies involving additional patients are warranted. PMID- 30522462 TI - Protocol for a single-centre, parallel-arm, double-blind randomised trial evaluating the effects of tourniquet use in total knee arthroplasty on intra operative and post-operative outcomes. AB - BACKGROUND: Tourniquet use during total knee replacement is common, yet uncertainty exists regarding its benefits and harms. The primary aim of the current study is to investigate whether tourniquet use during total knee replacement leads to greater reduction in quadriceps strength than non-tourniquet use at three months post-surgery. Secondary aims include investigating the effects of tourniquet use on: quadriceps strength at day 2 and 5, and 12 months post-surgery; pain and analgesia requirements; self-reported physical function and quality of life; blood loss and replacement; surgeon satisfaction with the intra-operative visual field; operation and anaesthetic time; complications; cement mantle quality; patient satisfaction; and hospital length of stay. METHODS: The study is a single centre, parallel-arm, double-blind (participant and assessor), randomised trial with 1:1 random allocation. Participants will be undergo total knee replacement with or without tourniquet. Linear mixed models will be used for group comparisons of continuous outcomes available at multiple timepoints. Other continuous outcomes that are assessed at baseline and once/twice at follow-up will be analysed using linear regression. Categorical outcomes will be analysed using logistic regression models. DISCUSSION: This study will provide high-quality evidence regarding the effects of tourniquet use during total knee replacement, which can be used to inform surgeon decision making. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000425291 . Retrospectively registered 23 March 2018. PMID- 30522463 TI - Elevated Hsp90-beta contributes to differential diagnosis of pleural effusion caused by lung cancer and correlates with malignant biological behavior of lung cancer. AB - BACKGROUND: Hsp90-beta has been investigated to be correlated with the occurrence and development of tumor. The intention of this research was to test the level of Hsp90-beta in malignant pleural effusion (MPE) of patients with lung cancer and disclose the clinical significance of Hsp90-beta as a potential tumor marker for differential diagnosis of pleural effusion caused by lung cancer. METHODS: The level of Hsp90-beta was determined using enzyme-linked immunosorbent assay. Calculations of the Hsp90-beta threshold, the sensitivity and specificity for distinguishing MPE from benign pleural effusion were performed using receiver operator characteristic curve. RESULTS: The level of Hsp90-beta in MPE of lung cancer patients was higher than that in control individuals (P < 0.05) and increased MPE Hsp90-beta was correlated with the pathological differentiation, tumor size and lymphatic metastasis (P < 0.05). The cutoff value of Hsp90-beta produced by receiver operator characteristic curve for distinguishing lung cancer from control individuals were 1.659 ng/mL and the sensitivity and specificity were 93.46 and 79%. CONCLUSIONS: Increased Hsp90-beta in MPE was correlated with malignant biological behavior of lung cancer patients, indicating that the level of Hsp90-beta could be a tool of referential value for differential diagnosis of pleural effusion caused by lung cancer. PMID- 30522464 TI - High-yield production of human Dicer by transfection of human HEK293-EBNA1 cells grown in suspension. AB - BACKGROUND: Dicer is a 219-kDa protein that plays key roles in gene regulation, particularly as the ribonuclease III enzyme responsible for cleaving precursor miRNA substrates. Its enzymatic activity is highly regulated by protein factors, and this regulation can impact on the levels of miRNAs and modulate the behavior of a cell. To better understand the underlying mechanisms of regulation, detailed enzymatic and structural characterization of Dicer are needed. However, these types of studies generally require several milligrams of recombinant protein, and efficient preparation of such quantities of pure human Dicer remains a challenge. To prepare large quantities of human Dicer, we have optimized transfection in HEK293-6E cells grown in suspension and streamlined a purification procedure. RESULTS: Transfection conditions were first optimized to achieve expression levels between 10 and 18 mg of recombinant Dicer per liter of culture. A three step purification protocol was then developed that yields 4-9 mg of purified Dicer per liter of culture in a single day. From SEC-MALS/RI analysis and negative stain TEM, we confirmed that the purified protein is monomerically pure ( >= 98%) and folds with the characteristic L-shape geometry. Using an electrophoretic mobility shift assay, a dissociation constant (Kd) of 5 nM was measured for Dicer binding to pre-let-7a-1, in agreement with previous reports. However, when probing the cleavage activity of Dicer for pre-let-7a-1, we measured kcat (7.2 +/- 0.5 min- 1) and KM (1.2 +/- 0.3 MUM) values that are much higher than previously reported due to experimental conditions that better respect the steady-state assumption. CONCLUSIONS: The expression and purification protocols described here provide high yields of monomerically pure and active human Dicer. Cleavage studies of a pre-let-7 substrate with this purified Dicer reveal higher kcat and KM values than previously reported and support the current view that conformational changes are associated with substrate binding. Large quantities of highly pure Dicer will be valuable for future biochemical, biophysical and structural investigations of this key protein of the miRNA pathway. PMID- 30522465 TI - Difference in whole spinal alignment between supine and standing positions in patients with adult spinal deformity using a new comparison method with slot scanning three-dimensional X-ray imager and computed tomography through digital reconstructed radiography. AB - BACKGROUND: A precise comparison of supine and standing whole spine alignment in both the coronal and sagittal planes, including the pelvic parameters, has not been reported. Furthermore, previous studies investigated positional differences in the Cobb angle only in young patients with idiopathic scoliosis. The difference in alignment has never been investigated in a population of patients with adult spinal deformity (ASD). In most cases, ASD patients are aware of the symptoms when standing and tend to stoop with back pain, whereas the symptoms disappear when lying on a bed. Therefore, it is important to elucidate the positional differences in the deformity in older adults. The purposes of this study are to establish a method for comparing whole spine alignment between supine and standing, and to clarify the positional difference of the alignment in the patients with ASD. METHODS: Twenty-four patients with ASD (mean age: 60.1 years, range 20-80 years; 24 women) were evaluated. A slot-scanning three dimensional X-ray imager (EOS) was used to assess the whole spine in the standing position. Computed tomography was used to assess the whole spine in the supine position. The computed tomography DICOM dataset of the whole spine in the supine position was transformed to two-dimensional (coronal and sagittal) digital reconstructed radiography images. The digital reconstructed radiography images were input for three-dimensional measurement by the EOS software and compared with the standing whole spine alignment measured by EOS. RESULTS: The mean intraclass correlation coefficients (supine, standing) of intra-rater / inter rater reliabilities for the measured parameters were 0.981, 0.984 / 0.970, 0.986, respectively. The Cobb and rotation angles of the major curve, mostly the thoracolumbar area, were significantly greater in the standing position than in the supine position. Lumbar lordosis during standing was significantly kyphotic. With respect to the pelvic parameters, the sacral slope was significantly smaller in the standing position than in the supine position. Pelvic tilt and pelvic incidence were significantly greater in the standing position than in the supine position. CONCLUSIONS: The lumbar to pelvic parameters and the major curve in standing position significantly deteriorate compared with the supine position in patients with ASD. PMID- 30522466 TI - Lung hyperinflation and functional exercise capacity in patients with COPD - a three-year longitudinal study. AB - BACKGROUND: Lung hyperinflation contributes to dyspnea, morbidity and mortality in chronic obstructive pulmonary disease (COPD). The inspiratory-to-total lung capacity (IC/TLC) ratio is a measure of lung hyperinflation and is associated with exercise intolerance. However, knowledge of its effect on longitudinal change in the 6-min walk distance (6MWD) in patients with COPD is scarce. We aimed to study whether the IC/TLC ratio predicts longitudinal change in 6MWD in patients with COPD. METHODS: This prospective cohort study included 389 patients aged 40-75 years with clinically stable COPD in Global Initiative for Chronic Obstructive Lung Disease stages II-IV. The 6MWD was measured at baseline, and after one and 3 years. We performed generalized estimating equation regression analyses to examine predictors for longitudinal change in 6MWD. Predictors at baseline were: IC/TLC ratio, age, gender, pack years, fat mass index (FMI), fat free mass index (FFMI), number of exacerbations within 12 months prior to inclusion, Charlson index for comorbidities, forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and light and hard self-reported physical activity. RESULTS: Reduced IC/TLC ratio (p < 0.001) was a statistically significant predictor for decline in 6MWD. With a 0.1-unit decrease in baseline IC/TLC ratio, the annual decline in 6MWD was 12.7 m (p < 0.001). Study participants with an IC/TLC ratio in the upper quartiles maintained their 6MWD from baseline to year 3, while it was significantly reduced for the patients with an IC/TLC ratio in the lower quartiles. Absence of light and hard physical activity, increased age and FMI, decreased FEV1 and FVC, more frequent exacerbations and higher Charlson comorbidity index were also predictors for lower 6MWD at any given time, but did not predict higher rate of decline over the timespan of the study. CONCLUSION: Our findings demonstrated that patients with less lung hyperinflation at baseline maintained their functional exercise capacity during the follow-up period, and that it was significantly reduced for patients with increased lung hyperinflation. PMID- 30522467 TI - Paediatric poisoning in rural Sri Lanka: an epidemiological study. AB - BACKGROUND: Acute paediatric poisoning is a common public health concern for both developed and developing countries. The type of agent and underlying cause differ depending on the social, cultural, economic and educational background. The objectives of this study were to identify the incidence and pattern of paediatric poisoning in a rural district in Sri Lanka and establish whether tertiary referral hospital data are a useful surrogate for estimating district level epidemiology of paediatric poisoning. METHODS: A subset of epidemiological data were obtained from March 2011 to February 2013 from a randomized controlled trial (SLCTR/2010/008) conducted in 45 hospitals in Kurunegala district. RESULTS: The age adjusted annual incidence of all cause of acute poisoning in children aged 1 to 12 years in the study area was 60.4 per 100,000. The incidence of poisoning of younger age group (1 to 6 years; 76 per 100,000) was significantly higher than older age group (7 to 12 years; 41 per 100,000) (p = 0.0001) in Kurunegala district. The annual incidence rate of paediatric admissions due to deliberate self-poisoning is 18 per 100,000 population. This study also established that admission data from primary hospitals provided the most accurate epidemiological information on paediatric poisoning. CONCLUSIONS: In rural districts of Sri Lanka, acute paediatric poisoning cases were less frequent and less severe compared to adult poisoning cases (426-446 per 100,000 population). The incidence of poisoning was significantly higher among young children with compared to old children. In this study, deliberate self-poisoning among older children was more frequently seen than in other comparable countries. Because most of the admissions are directed to and managed by primary hospitals, data from referral hospitals alone cannot be used to represent the true incidence of acute poisoning within a district. The data set from all the primary hospitals (n = 44) yielded more accurate poisoning incidence amongst a paediatric population. PMID- 30522468 TI - Clinical Management of Malignant Insulinoma: a single Institution's experience over three decades. AB - BACKGROUND: Malignant insulinoma is extremely rare and accounts for only 10% of total insulinoma cases. The goal of this study is to retrospectively analyze clinical data from 15 patients with malignant insulinoma treated at Peking Union Medical College Hospital (PUMCH) from 1984 to April 2017. METHODS: "Malignant insulinoma" was used as the keywords in the PUMCH medical record retrieval system to search and obtain patients' clinical information. We identified subjects diagnosed with malignant insulinoma based on clinical or surgical pathological signs and subsequently analyzed their clinical data. RESULTS: Eight males and seven females with a median age at diagnosis of 40 years (38-54 years) were included. Eight patients (53%) had developed metastases at diagnosis, while the others (46.67%) developed metastases during the follow-up visits. The major sites of metastasis were the liver (86.7%), local tissues and blood vessels (33%) and abdominal lymph nodes (13%). All patients displayed neuroglycopenic (100%) and/or autonomic (60%) symptoms, mostly during fasting periods (73.3%), with an average blood glucose level of 1.66 +/- 0.51 mmol/L. A total of 93% of the patients had one primary pancreatic lesion, 53% had a lesion in the head of the pancreas, and 47% had a lesion in the tail of the pancreas, with diameters ranging between 0.9 and 6.0 cm. Most liver metastases were multiple lesions. Selective celiac arteriography yielded 100% sensitivity for both primary pancreatic lesions and liver metastases. Most patients received synthetical treatments, including surgery, chemoembolization, and octreotide. CONCLUSIONS: Malignant insulinomas have a similar diagnostic process to that of benign insulinomas but require far more comprehensive therapies to alleviate hypoglycemic symptoms and extend patients' survival. PMID- 30522469 TI - What are the perceived added values and barriers of regulating long-term care in the home environment using a care network perspective: a qualitative study. AB - BACKGROUND: Changes in Dutch policy towards long-term care led to the Dutch Health and Youth Care Inspectorate testing a regulatory framework focusing on care networks around older adults living independently. This regulatory activity involved all care providers and the older adults themselves. METHODS: Semi structured interviews with the older adults, and focus groups with care providers and inspectors were used to assess the perceived added value of, and barriers to the framework. RESULTS: The positive elements of this framework were the involvement of the older adults in the regulatory activity, the focus of the framework on care networks and the open character of the conversations with the inspectors. However, applying the framework requires a substantial investment of time. Care providers often did not perceive themselves as being part of a care network around one person and they expressed concerns about financial and privacy issues when thinking in terms of care networks. CONCLUSIONS: The experiences of the client were seen as important in regulating long-term care. Regulating care networks as a whole puts cooperation between care providers involved around one person on the agenda. However, barriers for this form of regulation were also perceived and, therefore, careful consideration when and how to regulate care networks is recommended. PMID- 30522470 TI - Childhood road traffic injuries in Canada - a provincial comparison of transport injury rates over time. AB - BACKGROUND: In Canada, road traffic injuries are the leading cause of death among children and youth <=19. Across the country, there is variability in road traffic injury prevention policies and legislation. Our objective was to compare pediatric road traffic related injury hospitalization and death rates across Canadian provinces. METHODS: Population-based hospitalization and death rates per 100,000 were analyzed using data from the Discharge Abstract Database and provincial coroner's reports. Road traffic related injuries sustained by children and youth <=19 years were analyzed by province and cause between 2006 and 2012. RESULTS: The overall transport-related injury morbidity rate for children in Canada was 70.91 per 100,000 population between 2006 and 2012. The Canadian population-based injury hospitalization rates from all transport-related causes significantly decreased from 85.51 to 58.77 per 100,000 (- 4.42; p < 0.01; - 5.42; - 3.41) during the study period. Saskatchewan had the highest overall transport related morbidity rate (135.69 per 100,000), and Ontario had the lowest (47.12 per 100,000). Similar trends were observed for mortality rates in Canada. CONCLUSIONS: Transport-related injuries among children and youth have significantly decreased in Canada from 2006 to 2012; however the rates vary by province and cause. PMID- 30522471 TI - CCSchool: a multicentre, prospective study on improving continuum of care in children and adolescents with mental health problems associated with school problems in Germany. AB - BACKGROUND: Most psychiatric disorders in childhood and adolescence cause impairment in academic performance. Early interventions in school are thought to reduce the burden of disorder and prevent chronicity of disorder, while a delay in reachable help may result in more severe symptoms upon first time presentation, often then causing upon first-time presentation immediate need of inpatient care. METHODS: The study aims at reducing hospitalization rates and increasing social participation and quality of life among children and adolescents by establishing collaborations between schools, mental health care services and youth welfare services. CCSchool offers children and adolescents, aged six to 18 years, who present with psychiatric problems associated to school problems, a standardized screening and diagnostic procedure as well as treatment in school if necessary. Students can participate in CCSchool in three federal states of Germany if they a) show symptoms vindicating a mental health diagnosis, b) present with confirmed school problems and c) have a level of general functioning below 70 on the children global assessment of Functioning (C-GAF). Intervention takes place in three steps: module A (expected n = 901, according to power calculation) with standardized diagnostic procedures; module B (expected n = 428) implies a school-based assessment followed by a first intervention; module C (expected n = 103) offering school-based interventions with either four to six sessions (basic, 80% of patients) or eight to 12 sessions (intensive, 20% of patients). Primary aim is to evaluate the effectiveness of CCSchool, in reducing the need of hospitalization in children with mental health problems. The analyses will be conducted by an independent institute using mainly data collected from patients and their caregivers during study participation. Additionally, claims data from statutory health insurances will be analysed. Relevant confounders will be controlled in all analyses. DISCUSSION: Evaluation may show if CCSchool can prevent hospitalizations, enhance social participation and improve quality of life of children and adolescents with mental health problems by providing early accessible interventions in the school setting. TRIAL REGISTRATION: Deutsches Register Klinischer Studien, Trial registration number: DRKS00014838 , registered on 6th of June 2018. PMID- 30522472 TI - Evaluation of the theoretical optimal angle of the tibial tunnel in transtibial anatomic posterior cruciate ligament reconstruction by computed tomography. AB - BACKGROUND: "Killer turn" effect is a critical explanation for the recurrent posterior laxity following transtibial posterior cruciate ligament (PCL) reconstruction, which affected by the angle of the tibial tunnel. Meanwhile, excessive tunnel angle would have an adverse impact on the healing of tendon to bone. The purpose was to evaluate the theoretical optimal angle of the tibial tunnel in transtibial anatomic PCL reconstruction. METHODS: The measurements were performed on CT sagittal plane, including the thickness of cancellous bone (L1), the theoretical optimal angle of the tibial tunnel (TOA, which was measured between tibial plateau and the extension cord connecting the center of PCL insertion site with a point 5 mm superior from marrow cavity vertex), L2 - the distance from anterior tunnel aperture to anterior end of tibial plateau, L3 - the distance from anterior tunnel aperture to tibial tuberosity (lowest edge of patellar ligament attachment). RESULTS: The value of TOA and L3 were 35.4 +/- 7.9 degrees and 26.8 +/- 11.4 mm, respectively. L1 and L2 were higher in males than females (L1, P = 0.002; L2, P = 0.046). Regarding age, L1, TOA, L2 and L3 were higher in the 46-60 years group than 31-45 years group (P = 0.02, P = 0.001, P = 0.038, P = 0.032, respectively). With regard to height, L1 was lower in group I - < 1.66 m than group II - 1.66 to 1.75 m and group III - > 1.75 m (I v II, P = 0.015, I v III, P = 0.026). L2 was also lower in group I than group II and group III (I v II, P = 0.026, I v III, P = 0.006). TOA and L3 showed no significant differences among sex and height groups (P > 0.05). CONCLUSIONS: TOA (35.4 degrees +/- 7.9 degrees ) and L3 (26.8 +/- 11.4 mm) could be used as a reference for ideal tibial tunnel placement in transtibial anatomic PCL reconstruction, so as to prevent recurrent PCL laxity and ensure good graft healing. However, further clinical validation is needed. PMID- 30522473 TI - National survey: current prevalence and characteristics of home mechanical ventilation in Hungary. AB - BACKGROUND: Home mechanical ventilation is an established treatment for chronic respiratory failure resulting in improved survival and quality of life. Technological advancement, evolving health care reimbursement systems and newly implemented national guidelines result in increased utilization worldwide. Prevalence shows great geographical variations and data on East-Central European practice has been scarce to date. The aim of the current study was to evaluate prevalence and characteristics of home mechanical ventilation in Hungary. METHODS: We conducted a nationwide study using an online survey focusing on patients receiving ventilatory support at home. The survey focused on characterization of the site (affiliation, type), experience with home mechanical ventilation, number of patients treated, indication for home mechanical ventilation (disease type), description of home mechanical ventilation (invasive/noninvasive, ventilation hours, duration of ventilation) and description of the care provided (type of follow up visits, hospitalization need, reimbursement). RESULTS: Our survey uncovered a total of 384 patients amounting to a prevalence of 3.9/100,000 in Hungary. 10.4% of patients received invasive, while 89.6% received noninvasive ventilation. The most frequent diagnosis was central hypopnea syndromes (60%), while pulmonary (20%), neuromuscular (11%) and chest wall disorders (7%) were less frequent indications. Daily ventilation need was less than 8 h in 74.2%, between 8 and 16 h in 15.4% and more than 16 h in 10.4% of patients reported. When comparing sites with a limited (< 50 patients) versus substantial (> 50 patients) case number, we found the former had significantly higher ratio of neuromuscular conditions, were more likely to ventilate invasively, with more than 16 h/day ventilation need and were more likely to provide home visits and readmit patients (p < 0,001). CONCLUSIONS: Our results show a reasonable current estimate and characterization of home mechanical ventilation practice in Hungary. Although a growing practice can be assumed, current prevalence is still markedly reduced compared to international data reported, the duality of current data hinting to a possible gap in diagnosis and care for more dependent patients. This points to the importance of establishing home mechanical ventilation centers, where increased experience will enable state of the art care to more dependent patients as well, increasing overall prevalence. PMID- 30522474 TI - Investigation and management of moderate to severe inpatient hyponatraemia in an Australian tertiary hospital. AB - BACKGROUND: Hyponatraemia is the most common electrolyte disturbance amongst hospitalised patients. Both American and European guidelines recommend fluid restriction as first line treatment for SIADH, however differ on second line recommendations. The objective of this study was to examine investigation and management of hyponatraemia in hospitalised patients in an Australian tertiary hospital. METHODS: A retrospective audit was conducted of electronic medical records and laboratory data of inpatients with serum sodium (Na) <=125 mmol/L, admitted over a 3 month period to the Princess Alexandra Hospital, Brisbane, Australia. The main outcomes measured included: demographic characteristics, investigations, accuracy of diagnosis, management strategy, change in Na and patient outcomes. RESULTS: The working clinical diagnosis was considered accurate in only 37.5% of cases. Urine Na and osmolality were requested in 72 of 152 patients (47.4%) and in 43 of 70 euvolaemic patients (61.4%). Thyroid function tests (67.1%) and morning cortisol (45.7%) were underutilized in the euvolaemic group. In the SIADH cohort, fluid restriction resulted in a median (IQR) 7.5 mmol/L (4-10.5) increase in Na after 3 days; no treatment resulted in a median 0 mmol/L (- 0.5-1.5) change. Oral urea was utilized in 5 SIADH patients where Na failed to increase with fluid restriction alone. This resulted in a median 10.5 mmol/L (3.5-13) increase in Na from baseline to day 3. There were no cases of osmotic demyelination. The median length of stay was 8 days (4-18.5). Mortality was 11.2% (17 patients). There was a weak but significant correlation between nadir serum Na and mortality (R = 0.18, P = 0.031). CONCLUSION: Inpatient hyponatraemia is often inadequately investigated, causing errors in diagnosis. Treatment is heterogeneous and often incorrect. In cases with hyponatraemia refractory to fluid restriction, oral urea presents an effective alternative treatment. PMID- 30522475 TI - Correction to: "His mind will work better with both of us": a qualitative study on fathers' roles and coparenting of young children in rural Pakistan. AB - After publication of the original article [1], the authors wanted to make an amendment in the Acknowledgments section as Muneera Rasheed requested to be removed. This correction article shows the original and revised version of the "Acknowledgments". The original article was not updated. PMID- 30522476 TI - A ceramic bone substitute containing gentamicin gives good outcome in trochanteric hip fractures treated with dynamic hip screw and in revision of total hip arthroplasty: a case series. AB - BACKGROUND: The primary objective was to investigate the clinical and radiological outcome in patients undergoing major hip surgery using a novel antibiotic containing bone substitute for local augmentation in trochanteric fracture fixation or revision of total hip arthroplasty (THA). METHODS: We implanted a novel biphasic bone substitute CERAMENTTM|G consisting of hydroxyapatite, calcium sulphate and gentamicin for bone regeneration and local antibiotic delivery in 20 patients treated surgically for trochanteric femoral fracture or uncemented hip revision. Preoperative, postoperative, 3 months and 1 year clinical and radiological assessment were performed including registration of any complications. In one trochanteric fracture patient, histological analyses were performed of bone biopsies taken at removal of hardware. RESULTS: None of the trochanteric fractures or revision of THA showed any large migration. No local wound disturbances were seen and no infection was observed at one year follow-up. All trochanteric fractures healed at 3 months with a minimal sliding screw displacement on average 3 mm. Radiological analysis showed signs of bone remodeling and new bone formation in the substitute, illustrated also by histology in the biopsies taken from one trochanteric fracture at one year post op. CONCLUSIONS: Local CERAMENTTM|G was shown to be safe in a limited prospective major hip surgery study. Remodeling of the bone graft substitute was observed in all patients. TRIAL REGISTRATION: EU-CTR2018-004414-18 Retrospectively registered on November 20, 2018. PMID- 30522477 TI - Comparative analysis of interactions between aryl hydrocarbon receptor ligand binding domain with its ligands: a computational study. AB - BACKGROUND: Aryl hydrocarbon receptor (AhR) ligands may act as potential carcinogens or anti-tumor agents. Understanding how some of the residues in AhR ligand binding domain (AhRLBD) modulate their interactions with ligands would be useful in assessing their divergent roles including toxic and beneficial effects. To this end, we have analysed the nature of AhRLBD interactions with 2,3,7,8 tetrachlorodibenzo-rho-dioxin (TCDD), 6-formylindolo[3,2-b]carbazole (FICZ), indole-3-carbinol (I3C) and its degradation product, 3,3'-diindolylmethane (DIM), Resveratrol (RES) and its analogue, Piceatannol (PTL) using molecular modeling approach followed by molecular dynamic simulations. RESULTS: Results showed that each of the AhR ligands, TCDD, FICZ, I3C, DIM, RES and PTL affect the local and global conformations of AhRLBD. CONCLUSION: The data presented in this study provide a structural understanding of AhR with its ligands and set the basis for its functions in several pathways and their related diseases. PMID- 30522478 TI - The virtual patient as a learning tool: a mixed quantitative qualitative study. AB - BACKGROUND: The use of simulation in medical education has been widely accepted. There are different types of medical simulators that vary in both accuracy to emulate the real world (fidelity) and cost of development or acquisition. There is significant evidence that supports the use of high-fidelity simulators (i.e. mannequins or dummies) to prepare students for clinical environments, less attention has been given to low-fidelity simulators. This article aims to present evidence regarding the effectiveness of a low-fidelity simulator: Virtual Patient (VP), which develops several interactive computer-based clinical scenarios, seeking to promote an alternative learning environment and the development of necessary medical skills such as clinical reasoning in students of medicine. METHODS: A quasi-experimental study was designed to investigate the results on the development of history taking and clinical reasoning skills in a group of undergraduate medical students, in a course devised under the concepts of constructivism in education, which used the Virtual Patient as the fundamental teaching tool. Results were measured through a mixed, quantitative and qualitative study, triangulating the results of the students' skills evaluation when facing a clinical case represented by an actor patient before and after the course. Additionally, the description of the students' and tool's performance was measured by way of a qualitative study. RESULTS: The comparison of the students' skills on the evaluation matrix before-and-after the course evidenced a statistically significant advance (p < 0.01) in all aspects (interview, physical exam, clinical judgment, relevance of medical exams, and presentation of case). Students described the VP as an easy-to-use and motivating tool for learning without stress, especially at the beginning of their career. VP allowed them to create logical and structured processes, to be wrong without consequences, and to review and reassess information available. From the professor perspective, it allowed a better follow-up of the students' learning process and favored reflections on the teaching-learning process. CONCLUSIONS: VP proved to be a valuable and useful tool for the development of clinical reasoning and history taking skills in medical students, as part of a constructivist learning course. PMID- 30522479 TI - WISP1 mediates lung injury following hepatic ischemia reperfusion dependent on TLR4 in mice. AB - BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is a common pathological phenomenon, which causes hepatic injury as well as remote organ injuries such as the lung. Several mediators, such as oxidative stress, Ca2+ overload and neutrophil infiltration, have been implied in the pathogenesis of liver and remote organ injuries following reperfusion. WNT1 inducible signaling pathway protein 1 (WISP1) is an extracellular matrix protein that has been associated with the onset of several malignant diseases. Previous work in our group has demonstrated WISP1 is upregulated and contributes to proinflammatory cascades in hepatic IRI. However, the role of WISP1 in the pathogenesis of lung injury after hepatic IRI still remains unknown. METHODS: Male C57BL/6 mice were used to examine the expression and role of WISP1 in the pathogenesis of lung injuries after hepatic IRI and explore its potential mechanisms in mediating lung injuries. RESULTS: We found WISP1 was upregulated in lung tissues following hepatic IRI. Treatment with anti-WISP1 antibody ameliorated lung injuries with alteration of cytokine profiles. Administration with rWISP1 aggravated lung injuries following hepatic IRI through excessive production of proinflammatory cytokines and inhibition of anti-inflammatory cytokines. CONCLUSIONS: In this study, we concluded that WISP1 contributed to lung injuries following hepatic IRI through TLR4 pathway. PMID- 30522480 TI - Two-component cyclase opsins of green algae are ATP-dependent and light-inhibited guanylyl cyclases. AB - BACKGROUND: The green algae Chlamydomonas reinhardtii and Volvox carteri are important models for studying light perception and response, expressing many different photoreceptors. More than 10 opsins were reported in C. reinhardtii, yet only two-the channelrhodopsins-were functionally characterized. Characterization of new opsins would help to understand the green algae photobiology and to develop new tools for optogenetics. RESULTS: Here we report the characterization of a novel opsin family from these green algae: light inhibited guanylyl cyclases regulated through a two-component-like phosphoryl transfer, called "two-component cyclase opsins" (2c-Cyclops). We prove the existence of such opsins in C. reinhardtii and V. carteri and show that they have cytosolic N- and C-termini, implying an eight-transmembrane helix structure. We also demonstrate that cGMP production is both light-inhibited and ATP-dependent. The cyclase activity of Cr2c-Cyclop1 is kept functional by the ongoing phosphorylation and phosphoryl transfer from the histidine kinase to the response regulator in the dark, proven by mutagenesis. Absorption of a photon inhibits the cyclase activity, most likely by inhibiting the phosphoryl transfer. Overexpression of Vc2c-Cyclop1 protein in V. carteri leads to significantly increased cGMP levels, demonstrating guanylyl cyclase activity of Vc2c-Cyclop1 in vivo. Live cell imaging of YFP-tagged Vc2c-Cyclop1 in V. carteri revealed a development-dependent, layer-like structure at the immediate periphery of the nucleus and intense spots in the cell periphery. CONCLUSIONS: Cr2c-Cyclop1 and Vc2c-Cyclop1 are light-inhibited and ATP-dependent guanylyl cyclases with an unusual eight-transmembrane helix structure of the type I opsin domain which we propose to classify as type Ib, in contrast to the 7 TM type Ia opsins. Overexpression of Vc2c-Cyclop1 protein in V. carteri led to a significant increase of cGMP, demonstrating enzyme functionality in the organism of origin. Fluorescent live cell imaging revealed that Vc2c-Cyclop1 is located in the periphery of the nucleus and in confined areas at the cell periphery. PMID- 30522481 TI - Delivering postpartum family planning services in Nepal: are providers supportive? AB - BACKGROUND: Health service providers play a key role in addressing women's need for pregnancy prevention, especially during the postpartum period. Yet, in Nepal, little is known about their views on providing postpartum family planning (PPFP) services and postpartum contraceptive methods such as immediate postpartum intra uterine devices (PPIUD). This paper explores the perspectives of different types of providers on PPFP including PPIUD, their confidence in providing PPFP services, and their willingness to share their knowledge and skills with colleagues after receiving PPFP and PPIUD training. METHODS: In-depth interviews were conducted with 14 obstetricians/gynecologists and nurses from six tertiary level public hospitals in Nepal after they received PPFP and PPIUD training as part of an intervention aimed at integrating PPFP counseling and insertion into routine maternity care services. The interviews were audio recorded, transcribed, and analyzed using a thematic approach. RESULTS: Providers identified several advantages of PPFP, supported the provision of such services, and were willing to transfer their newly acquired skills to colleagues in other facilities who had not received PPFP and PPIUD training. However, many providers identified several supply-side and training-related barriers to providing high quality PPFP services, such as, (i) lack of adequate human resources, particularly a FP counselor; (ii) work overload; (iii) lack of private space for counseling; (iv) lack of IUDs and information, education and counseling materials; and (v) lack of support from hospital management. CONCLUSIONS: Providers appeared to be motivated to deliver quality PPFP services and transfer their knowledge to colleagues but identified several barriers which prevented them from doing so. Future efforts to improve provision of quality PPFP services should address the barriers identified by providers. PMID- 30522482 TI - Short- and long-term reproducibility of diffusion-weighted magnetic resonance imaging of lower extremity musculature in asymptomatic individuals and a comparison to individuals with spinal cord injury. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) of skeletal muscle has the potential to be a sensitive diagnostic and/or prognostic tool in complex, enigmatic neuromusculoskeletal conditions such as spinal cord injury and whiplash associated disorder. However, the reliability and reproducibility of clinically accessible DW-MRI parameters in skeletal muscle remains incompletely characterized - even in individuals without neuromusculoskeletal injury - and these parameters have yet to be characterized for many clinical populations. Here, we provide normative measures of the apparent diffusion coefficient (ADC) in healthy muscles of the lower limb; assess the rater-based reliability and short- and long-term reproducibility of the ADC in the same muscles; and quantify ADC of these muscles in individuals with motor incomplete spinal cord injury. METHODS: Twenty individuals without neuromusculoskeletal injury and 14 individuals with motor incomplete spinal cord injury (SCI) participated in this investigation. We acquired bilateral diffusion-weighted MRI of the lower limb musculature in all participants at 3 T using a multi-shot echo-planar imaging sequence with b-values of 0, 100, 300 and 500 s/mm2 and diffusion-probing gradients applied in 3 orthogonal directions. Outcome measures included: (1) average ADC in the lateral and medial gastrocnemius, tibialis anterior, and soleus of individuals without neurological or musculoskeletal injury; (2) intra- and inter-rater reliability, as well as short and long-term reproducibility of the ADC; and (3) estimation of average muscle ADC in individuals with SCI. RESULTS: Intra- and inter-rater reliability of the ADC averaged 0.89 and 0.79, respectively, across muscles. Least significant change, a measure of temporal reproducibility, was 4.50 and 11.98% for short (same day) and long (9-month) inter-scan intervals, respectively. Average ADC was significantly elevated across muscles in individuals with SCI compared to individuals without neurological or musculoskeletal injury (1.655 vs. 1.615 mm2/s, respectively). CONCLUSIONS: These findings provide a foundation for future studies that track longitudinal changes in skeletal muscle ADC of the lower extremity and/or investigate the mechanisms underlying ADC changes in cases of known or suspected pathology. PMID- 30522483 TI - Sera of patients with axial spondyloarthritis (axSpA) enhance osteoclastogenic potential of monocytes isolated from healthy individuals. AB - BACKGROUND: Axial spondyloarthritis (axSpA) is characterized by significant bone loss caused by dysregulation of physiological bone turnover, possibly resulting from intensified differentiation of osteoclasts. The aim of this study was to reevaluate the levels of osteoclastogenesis-mediating factors: soluble RANKL, M CSF, OPG and other cytokines in sera of untreated, with sDMARDs and/or bDMARDs, axSpA patients and to test whether these sera influence differentiation of healthy monocytes towards osteoclast lineage. METHODS: Bone remodeling molecules (RANKL, M-CSF, OPG, IL-6, OSM, IL-17A, TGFbeta, and TNFalpha) were evaluated in 27 patients with axSpA and 23 age and sex-matched controls. Disease activity (BASDAI, ASDAS) and inflammatory markers (ESR, CRP) were assessed. Monocytes obtained from healthy individuals were cultured in vitro in presence of sera from 11 randomly chosen axSpA patients and 10 controls, with addition of exogenous M CSF and/or RANKL or without. Osteoclastic differentiation was assessed analyzing osteoclast markers (cathepsin K and RANK at mRNA level) and with osteoclast specific staining. RESULTS: axSpA patients' sera levels of soluble RANKL were significantly lower and M-CSF, IL-6, OSM, IL-17A and TNFalpha significantly higher in comparison to controls, whereas of OPG and TGFbeta were comparable in both groups. Numbers of generated in vitro osteoclasts and cathepsin K mRNA levels did not differ between cultures supplemented with sera of healthy and axSpA patients, both in the absence and presence of M-CSF. Instead, addition of exogenous RANKL boosted osteoclastogenesis, which was significantly higher in cultures with axSpA sera. Furthermore, sera from axSpA patients induced substantially higher levels of RANK mRNA, independently of M-CSF and RANKL stimulation. CONCLUSION: We show that, paradoxically, serum levels of soluble RANKL observed in axSpA are in fact significantly lower in comparison to healthy blood donors. Our results indicate that sera of axSpA patients - in contrary to healthy subjects - contain circulating, soluble factors (presumably IL-6, OSM, IL 17A, TNFalpha and others) able to stimulate healthy monocytes responsiveness to even relative low RANKL serum levels, by inducing high RANK mRNA expression and - as a net effect - boosting their osteoclastogenic potential. We suggest also that locally produced RANKL in axSpA may induce overactive osteoclasts from their precursors. PMID- 30522484 TI - Results from a proactive follow-up intervention to improve linkage and retention among people living with HIV in Uganda: a pre-/post- study. AB - BACKGROUND: Despite gains in HIV testing and treatment access in sub-Saharan Africa, patient attrition from care remains a problem. Evidence is needed of real world implementation of low-cost, scalable, and sustainable solutions to reduce attrition. We hypothesized that more proactive patient follow-up and enhanced counseling by health facilities would improve patient linkage and retention. METHODS: At 20 health facilities in Central Uganda, we implemented a quality of care improvement intervention package that included training lay health workers in best practices for patient follow-up and counseling, including improved appointment recordkeeping, phone calls and home visits to lost patients, and enhanced adherence counseling strategies; and strengthening oversight of these processes. We compared patient linkage to and retention in HIV care in the 9 months before implementation of the intervention to the 9 months after implementation. Data were obtained from facility-based registers and files and analysed using multivariable logistic regression. RESULTS: Among 1900 patients testing HIV-positive during the study period, there was not a statistically significant increase in linkage to care after implementing the intervention (52.9% versus 54.9%, p = 0.63). However, among 1356 patients initiating antiretroviral therapy during the follow-up period, there were statistically significant increases in patient adherence to appointment schedules (44.5% versus 55.2%, p = 0.01) after the intervention. There was a small increase in Ministry of Health-defined retention in care (71.7% versus 75.7%, p = 0.12); when data from the period of intervention ramp-up was dropped, this increase became statistically significant (71.7% versus 77.6%, p = 0.01). The increase in retention was more dramatic for patients under age 19 years (N = 84; 64.0% versus 83.9%, p = 0.01). The cost per additional patient retained in care was $47. CONCLUSIONS: Improving patient tracking and counseling practices was relatively low cost and enhanced patient retention in care, particularly for pediatric and adolescent patients. This approach should be considered for scale-up in Uganda and elsewhere. However, no impact was seen in improved patient linkage to care with this proactive follow-up intervention. TRIAL REGISTRATION: Pan African Clinical Trial Registry #PACTR201611001756166 . Registered August 31, 2016. PMID- 30522485 TI - Exploring the ethics of global health research priority-setting. AB - BACKGROUND: Thus far, little work in bioethics has specifically focused on global health research priority-setting. Yet features of global health research priority setting raise ethical considerations and concerns related to health justice. For example, such processes are often exclusively disease-driven, meaning they rely heavily on burden of disease considerations. They, therefore, tend to undervalue non-biomedical research topics, which have been identified as essential to helping reduce health disparities. In recognition of these ethical concerns and the limited scholarship and dialogue addressing them, we convened an international workshop in September 2015. The workshop aimed to initiate discussion on the appropriate relationship between global and national levels of health research priority-setting and to begin exploring what might be ethically required for priority-setting at each of those levels. MAIN TEXT: This paper comprises our reflections following the workshop. Its main objective is to launch a research agenda for the ethics of global health research priority-setting. We identify three domains of global health research priority-setting-scope, underlying values and substantive requirements, and procedural considerations. For each domain, specific research questions are highlighted and why they need to be explored is explained. Some preliminary thoughts and normative arguments as to how the research questions might be answered are also offered. For example, we provide initial ideas about the appropriate relationship between different priority-setting levels and what values and substantive considerations should guide or underpin global health research priority-setting as a matter of justice. CONCLUSION: We anticipate that framing a new research agenda for the ethics of global health research priority-setting will spur ethicists, researchers, and policymakers to refocus their efforts on developing more rigorous and ethically sound approaches to priority-setting. PMID- 30522486 TI - Fitness to practise sanctions in UK doctors are predicted by poor performance at MRCGP and MRCP(UK) assessments: data linkage study. AB - BACKGROUND: The predictive validity of postgraduate examinations, such as MRCGP and MRCP(UK) in the UK, is hard to assess, particularly for clinically relevant outcomes. The sanctions imposed on doctors by the UK's General Medical Council (GMC), including erasure from the Medical Register, are indicators of serious problems with fitness to practise (FtP) that threaten patient safety or wellbeing. This data linkage study combined data on GMC sanctions with data on postgraduate examination performance. METHODS: Examination results were obtained for UK registered doctors taking the MRCGP Applied Knowledge Test (AKT; n = 27,561) or Clinical Skills Assessment (CSA; n = 17,365) at first attempt between 2010 and 2016 or taking MRCP(UK) Part 1 (MCQ; n = 37,358), Part 2 (MCQ; n = 28,285) or Practical Assessment of Clinical Examination Skills (PACES; n = 27,040) at first attempt between 2001 and 2016. Exam data were linked with GMC actions on a doctor's registration from September 2008 to January 2017, sanctions including Erasure, Suspension, Conditions on Practice, Undertakings or Warnings (ESCUW). Examination results were only considered at first attempts. Multiple logistic regression assessed the odds ratio for ESCUW in relation to examination results. Multiple imputation was used for structurally missing values. RESULTS: Doctors sanctioned by the GMC performed substantially less well on MRCGP and MRCP(UK), with a mean Cohen's d across the five exams of - 0.68. Doctors on the 2.5th percentile of exam performance were about 12 times more likely to have FtP problems than those on the 97.5th percentile. Knowledge assessments and clinical assessments were independent predictors of future sanctions, with clinical assessments predicting ESCUW significantly better. The log odds of an FtP sanction were linearly related to examination marks over the entire range of performance, additional performance increments lowering the risk of FtP sanctions at all performance levels. CONCLUSIONS: MRCGP and MRCP(UK) performance are valid predictors of professionally important outcomes that transcend simple knowledge or skills and the GMC puts under the headings of conduct and trust. Postgraduate examinations may predict FtP sanctions because the psychological processes involved in successfully studying, understanding and practising medicine at a high level share similar mechanisms to those underlying conduct and trust. PMID- 30522488 TI - Aldehyde dehydrogenase serves as a biomarker for worse survival profiles in ovarian cancer patients: an updated meta-analysis. AB - BACKGROUND: The purpose of this comprehensive meta-analysis was to assess the association of aldehyde dehydrogenase (ALDH) expression with overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) in ovarian cancer patients. METHODS: Systematic searches of Pubmed databases was performed to identify relevant literature published before February 28, 2018. A total of 14 studies (13 articles) with 2210 ovarian cancer patients were pooled. All included studies were performed by using Immunohistochemistry (IHC) for detection of ALDH expression. Hazard ratio (HR) and 95% confidence interval (CI) were extracted from included studies to evaluate the correlation of ALDH expression with OS and DFS/PFS. RESULTS: High expression of ALDH was associated with worse OS (HR: 1.43; 95% CI: 1.18-1.73) and poor DFS/PFS (HR: 1.55, 95% CI: 1.12-2.14). No evidence of publication bias was observed in OS (Begg's test, P = 0.113; Egger's test, P = 0.355) and DFS/PFS (Begg's test, P = 0.655; Egger's test, P = 0.189) in ovarian cancer patients. The subgroup of studies with cut-off value of low expression showed that high expression of ALDH was correlated with poor OS (HR: 1.36; 95% CI: 1.14-1.62) and DFS/PFS (HR: 1.79; 95% CI: 1.45-2.20) in ovarian cancer patients, with no observed heterogeneity (OS: I2 = 0%, P = 0.45; DFS/PFS: I2 = 0%, P = 0.55). CONCLUSION: In conclusion, high expression of ALDH is correlated with worse survival profiles in ovarian cancer patients, indicating that ALDH might act as a potential molecular biomarker for prognosis of ovarian cancer. PMID- 30522487 TI - Exploring the gap between coverage, access, and utilization of long-lasting insecticide-treated nets (LLINs) among the households of malaria endemic districts in Bangladesh. AB - BACKGROUND: Malaria is still a major public health concern in Bangladesh in spite of mass distribution of long-lasting insecticide-treated nets (LLINs) as a key preventive strategy. There might be a considerable gap between coverage and actual use of nets by the population in endemic areas. This study intended to assess the gap between coverage, access to and use of LLINs among the households in malaria-endemic settings in Bangladesh. METHODS: This cross-sectional study collected data from 2640 households of 13 endemic districts of Bangladesh through three-stage cluster random sampling. The gap between coverage, access and use of LLINs were calculated using the procedure established by the Roll Back Malaria Monitoring and Evaluation Reference Group. To support the quantitative findings, qualitative data were also collected through in-depth interview, focus group discussion and key informant interview and analysed accordingly. RESULTS: Of 2640 total households, 77.4% (n = 2044) possessed at least two LLINs, 56.8% (n = 1499) had insufficient access, and 18.8% (n = 495) had excess LLINs. Members of 77.9% (n = 2056) households had used LLINs the previous night and 6.0% (n = 68) did not use LLINs despite having sufficient access. LLIN use was lower in non-hill track areas, in Bengali community, in richer households and households with more than four members. Moreover, qualitative findings revealed that the major reasons behind not using LLINs were insufficient access, sleeping outside the home, migration, perceived low efficacy of LLINs, or fear of physical side effects. CONCLUSION: Closing the access gap by providing enough nets through solid investment and well-designed behavioural change interventions are crucial for achieving and sustaining universal coverage. PMID- 30522489 TI - Quantification of three-dimensional soft tissue artifacts in the canine hindlimb during passive stifle motion. AB - BACKGROUND: Three-dimensional joint kinematics during canine locomotion are commonly measured using skin marker-based stereophotogrammetry technologies. However, marker-related errors caused by the displacement of the skin surface relative to the underlying bones (i.e., soft tissue artifacts, STA) may affect the accuracy of the measurements and obscure clinically relevant information. Few studies have assessed STA in canine limbs during kinematic analysis. The magnitudes and patterns of the STA and their influence on kinematic analysis remain unclear. Therefore, the current study aims to quantify the in vivo STA of skin markers on the canine thigh and crus during passive joint motion. The stifle joints of ten dogs were passively extended while the skin markers were measured using a motion capture system, and skeletal kinematics were determined using a CT to-fluoroscopic image registration method. RESULTS: The skin markers exhibited considerable STA relative to the underlying bones, with a peak amplitude of 27.4 mm for thigh markers and 28.7 mm for crus markers; however, the amplitudes and displacement directions at different attachment sites were inconsistent. The markers on the cranial thigh and lateral crus closer to the stifle joint had greater STA amplitudes in comparison to those of other markers. Most markers had STA with linear and quadratic patterns against the stifle flexion angles. These STA resulted in underestimated flexion angles but overestimated adduction and internal rotation when the stifle was flexed to greater than 90 degrees . CONCLUSIONS: Marker displacements relative to the underlying bones were prominent in the cranial aspect of the thigh and the proximal-lateral aspect of the crus. The calculated stifle kinematic variables were also affected by the STA. These findings can provide a reference for marker selection in canine motion analysis for similar motion tasks and clarify the relationship between STA patterns and stifle kinematics; the results may therefore contribute to the development of STA models and compensation techniques for canine motion analysis. PMID- 30522490 TI - Pseudorabies detected in hunting dogs in Alabama and Arkansas after close contact with feral swine (Sus scrofa). AB - BACKGROUND: Pigs (Sus scrofa) are the natural hosts of pseudorabies virus (PRV), also known as Aujeszky's disease. Infection in mammals, with the exception of humans, typically causes extreme itching, facial swelling, and excessive salivation, followed by death in non-suid species. The risk to susceptible mammals was assumed to decrease when PRV was eliminated from U.S. commercial swine in 2004, though the virus remains endemic in feral swine. Infected feral swine pose a threat to the disease-free status of the commercial swine industry, and to other animals, including dogs, that come in direct or indirect contact with them. Since dogs are commonly used for hunting feral swine, they are at high risk of exposure. CASE PRESENTATION: The following report describes the progression of pseudorabies infection in dogs in two states after exposure to feral swine. The first case occurred in a dog in Alabama after participation in a competitive wild hog rodeo. The second case occurred in multiple dogs in Arkansas after hunting feral swine, and subsequent consumption of the offal. The antibody prevalence of feral swine in the two states where the dogs were exposed is also examined. CONCLUSIONS: Dogs that are used for hunting feral swine are at high risk of exposure to pseudorabies because the disease is considered endemic in feral swine in the U.S. PMID- 30522491 TI - Treatment persistence and adherence and their consequences on patient outcomes of generic versus brand-name statins routinely used to treat high cholesterol levels in Spain: a retrospective cost-consequences analysis. AB - BACKGROUND: High blood lipoprotein concentrations are one of the major risk factors for cardiovascular diseases. Drug therapy is the base of treatment; statins in particular. Both brand-name and generic presentations are available for statin therapy of high cholesterol levels. Factors that may influence their use in routine medical practice include, among others, patient persistence and adherence to treatment as prescribed by physicians. The aim of this retrospective analysis was to provide real-world evidence of treatment persistence and adherence and their consequences on economic and patient outcomes of generic versus brand-name statins routinely used to treat high cholesterol levels in Spain. METHODS: Existing real-world electronic medical records abstracted from a database of two regions in Spain were analyzed. The analysis compared generic versus brand-name statins data from subjects' who started treatment between July 1, 2010 and June 30, 2012. Treatment persistence, adherence expressed as medication possession ratio (MPR), healthcare resource utilization and their costs were analyzed together with patient's at-goal rates of low-density lipoprotein-cholesterol (LDL-c), incidence of any major cardiovascular event (CVE) and all-cause mortality during a 5-year follow-up period. Multivariate analyses were applied. RESULTS: A total of 13,244 records were included. Persistence was lower with generics; adjusted hazard ratio -HR- [95% confidence interval]: 0.86 [0.82-0.91], p < 0.001) and MPR was also lower: 61.5% vs. 65.1% (p < 0.001). Less patients with generics reached their LDL-c goal: 39.2% [38.3 40.2%] vs. 42.0% [40.2-43.7%]; adjusted odds ratio; 0.87 [0.80-0.95], p = 0.003. Compared to brand-name statins, the observed probability of occurrence of a CVE; HR: 1.31 [1.15-1.50], p < 0.001, and also all-cause deaths; HR: 1.36 [1.15-1.62], was significantly higher with generics; p < 0.001 in both cases. Adjusted mean total healthcare cost per patient was also higher with generic than with brand name statins: ?9118 (9059-9176) vs. ?7980 (7853-8808) [adjusted difference: ?1137 (997-1277), p < 0.001]. CONCLUSION: This retrospective cost-consequences analysis found poorer treatment persistence and adherence in patients who first started therapy with generic instead of brand-name statins in routine medical practice in Spain. Also, patients receiving generics were more unlikely to reach LDL-c goals, showed increased probability of having CVE and all-cause mortality at a higher cost to payers. PMID- 30522492 TI - Open versus closed vitrification system of human oocytes and embryos: a systematic review and meta-analysis of embryologic and clinical outcomes. AB - BACKGROUND: The objective of this study was to carry out a systematic review and meta-analysis of embryologic and clinical outcomes following open versus closed vitrification of human oocytes and embryos. METHODS: An electronic literature search was conducted in main electronic databases up to June 30, 2018 using the following key terms: 'oocyte', 'embryo', 'blastocyst', 'vitrification', 'cryopreservation', 'device', 'survival rate', 'pregnancy rate', etc. A meta analysis was performed using a random effect model to estimate the value of risk ratios (RRs) and 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were carried out to further confirm the results. RESULTS: Twelve (Eight prospective and four retrospective) studies comparing open versus closed vitrification of human oocytes or embryos were included. For prospective studies on oocytes, no evidence for a significant difference in cryosurvival rate (RR = 0.91, 95% CI: 0.80-1.03, P = 0.14; n = 2048) or clinical pregnancy rate (RR = 1.29, 95% CI: 0.80-2.06, P = 0.30; n = 150) was observed. Additionally, there were no significant differences between the two methods concerning secondary endpoints included positive betaHCG rate, implantation rate, miscarriage rate, ongoing pregnancy rate, live birth rate, cancellation rate, babies born per transferred blastocysts, or multiple birth rate (P > 0.05). The results of the retrospective studies were similar as the prospective studies. CONCLUSIONS: It is still impossible to conclude that closed vitrification system could be a substitution for open system in human oocyte and embryo cryopreservation based on current evidence. Therefore, more well-designed prospective studies addressing these issues are still warranted. PMID- 30522494 TI - T cell-lymphoma in the eyelid of a 9-year-old English Setter. AB - BACKGROUND: Eyelid tumours are frequently found in dogs, most of these being benign. In case of an ulcerating eyelid tumour, malignancy must be considered. We report a unique case of a low-grade peripheral T-cell lymphoma in the eyelid of a 9-year-old English Setter. CASE PRESENTATION: A 9-year-old Setter presented with a 6-month history of an eyelid ulcer. A malignant eyelid neoplasm was suspected, and the lesion was surgically excised. No other treatment was applied, and 19 months after excision the dog was still well. Histopathology revealed a diffuse lymphocytic infiltrate in the eyelid skin. Ulceration of the epithelium was seen, and the underlying tumour was composed of round and poorly demarcated pleomorphic tumour cells. The cytoplasm was pale and the nuclei heterogeneous. Numerous mitoses were present. The tumour cells stained strongly for CD3. The final diagnosis was a peripheral T-cell lymphoma not otherwise specified (NOS). CONCLUSIONS: This is the first described case of a solitary T-cell lymphoma NOS in the haired eyelid skin in a dog. Lymphoma should be considered in case of a persistent eyelid ulcer and a biopsy should be performed. T-cell lymphoma is generally an aggressive disease; however, indolent cases are well known, and as this case shows, complete excision of a solitary T-cell lymphoma can be curable. Canine cutaneous epitheliotropic T-cell lymphoma is an important differential diagnosis, which must be recognized as the prognosis is very poor and systemic treatment is mandatory. The sub-classification of canine lymphoma is not complete, and further studies are needed to identify lymphoma subgroups and provide treatment guidelines. PMID- 30522493 TI - Interplay between Plasmodium falciparum haemozoin and L-arginine: implication for nitric oxide production. AB - BACKGROUND: Plasmodium falciparum haemozoin, a detoxification product of digested haemoglobin from infected erythrocytes, is released into the bloodstream upon schizont rupture and accumulates in leukocytes. High levels of haemozoin correlate with disease severity. Some studies have shown that concentrations of the substrate of inducible nitric oxide synthase (iNOS), L-arginine, as well as nitric oxide are low in patients infected with P. falciparum malaria. The present study investigates, in vitro, the role of P. falciparum haemozoin on nitric oxide production, iNOS expression in macrophages, and the possible interaction between L-arginine and haemozoin. METHODS: Plasmodium falciparum haemozoin was obtained from in vitro cultures through magnetic isolation. Phagocytosis of haemozoin by immortalized bone marrow derived macrophages was detected by confocal reflection combined with fluorescence microscopy. Nitrite concentrations in the supernatants was evaluated by Griess assay as a standard indication of nitric oxide production, while iNOS expression was detected on cell extracts by western blotting. Detection of L-arginine in haemozoin-treated or untreated media was achieved by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Haemozoin synergizes in vitro with interferon-gamma to produce nitric oxide. However, when mouse macrophages were stimulated with haemozoin, a proportional increase of nitric oxide was observed up to 25 MUM of haemozoin, followed by a decrease with doses up to 100 MUM, when nitric oxide release was completely abrogated. This was not due to reactive oxygen species production, nor to an effect on iNOS activity. Interestingly, when at 24 h, haemozoin-treated macrophages were washed and incubated in fresh medium for further 24 h, the nitric oxide production was restored in a dose-response manner. Similar results were seen when L-arginine-enriched media was used in the stimulation. Moreover, muramyldipeptide, a strong nitric oxide inducer, was unable to activate macrophages to release nitric oxide in the presence of haemozoin-treated medium. By LC-MS/MS a complete depletion of L-arginine was observed in this haemozoin treated, conditioned medium. CONCLUSIONS: It is proposed that haemozoin interacts with L-arginine reducing its availability for iNOS, and thus decreasing nitric oxide production. The clinical (or pathological) implications of these results are discussed. PMID- 30522496 TI - Dyslipidemia and non-small cell lung cancer risk in Chinese population: a case control study. AB - BACKGROUND: Numerous studies reported that dyslipidemia was associated with cancer risk. However, few studies investigated the associations between dyslipidemia and non-small cell lung cancer (NSCLC). METHODS: Four hundred twenty four histologically confirmed NSCLC cases and 414 controls, matched for age and sex, were enrolled to examine the relationship between dyslipidemia and NSCLC. Demographic and clinical data were obtained from patients' medical records and telephone interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: Abnormal triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels showed statistically significant coexistence with NSCLC compared with controls. Higher levels of TG were associated with a higher risk of NSCLC (OR = 1.541, 95% CI, (1.072-2.215)). The odds ratios (ORs) for NSCLC for normal and high levels of HDL-C versus those with a low level of HDL-C were 0.337(95% CI, (0.242-0.468)) and 0.288(95% CI, (0.185-0.448)), respectively. After adjustment for age, sex, smoking status, hypertension, body mass index, diabetes and lipid profiles, the adjusted OR for normal and high levels of HDL-C were 0.320(95% CI, (0.218-0.470)) and 0.233(95% CI, (0.134-0.407)), respectively. However, after adjustment, high levels of TG increased the risk of NSCLC but not significantly (OR = 1.052, 95% CI (0.671 1.649)). CONCLUSIONS: This study provided evidence that dyslipidemia increased the risk of NSCLC in Chinese population. PMID- 30522495 TI - Risk and protective factors for substance use among Iranian university students: a national study. AB - BACKGROUND: Substance use is a major mental health concern among university students. It may result in behavioral and academic problems, psychiatric disorders, and infectious diseases. Thus, this study investigated the risk and protective factors of substance use among Iranian university students. METHODS: This was a cross-sectional study. A number of 7330 students were selected from 30 universities in Iran. The participants completed a researcher-designed questionnaire. It measured life time, previous year and previous month's substance use, demographic characteristics, and a body of risk and protective factors including, religious beliefs, self-esteem, stress and psychological pressure, sensation seeking, attention seeking, anger and aggression, depression and anxiety, parents' positive attitude towards substance use, lack of intimacy between family members, plus substance use, smoking cigarettes or hookah, alcohol consumption, and prescribed medications use by their family members, easy access to illegal drugs, peers' positive attitude towards substance use, peers' drug use, perceived prevalence of substance use among students, and negative attitude toward university. The data were analyzed using descriptive statistics and multivariate logistic regression analysis. RESULTS: Participants' anger and aggression, depression and anxiety, participants' positive attitude towards substances, low level of religious beliefs, peers and family member's substance use, and parent's positive attitude towards substance significantly and strongly predicted using cigarette/hookah, alcohol, hard drugs, and prescribed medications. Having a negative attitude toward university significantly predicted using all types of substance (except for prescribed medications). Low self-esteem predicted using cigarette/hookah, and alcohol use. Perceived availability of illegal drugs predicted hard drugs and prescribed medications' consumption. Finally, peers' positive attitude toward drugs anticipated cigarette/hookah use. CONCLUSION: Prevention programs are most needed among Iranian students. They should be comprehensive in nature and focus on students' psychoeducation about substances and their related negative consequences, plus promotion of students' life skills, and integrate family- and peer-based preventive interventions. PMID- 30522497 TI - Generalizing remotely supervised transcranial direct current stimulation (tDCS): feasibility and benefit in Parkinson's disease. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has been shown to improve common symptoms of neurological disorders like depressed mood, fatigue, motor deficits and cognitive dysfunction. tDCS requires daily treatment sessions in order to be effective. We developed a remotely supervised tDCS (RS-tDCS) protocol for participants with multiple sclerosis (MS) to increase accessibility of tDCS, reducing clinician, patient, and caregiver burden. The goal of this protocol is to facilitate home use for larger trials with extended treatment periods. In this study we determine the generalizability of RS-tDCS paired with cognitive training (CT) by testing its feasibility in participants with Parkinson's disease (PD). METHODS: Following the methods in our MS protocol development, we enrolled sixteen participants (n = 12 male, n = 4 female; mean age 66 years) with PD to complete ten open-label sessions of RS-tDCS paired with CT (2.0 mA * 20 min) at home under the remote supervision of a trained study technician. Tolerability data were collected before, during, and after each individual session. Baseline and follow-up measures included symptom inventories (fatigue and sleep) and cognitive assessments. RESULTS: RS-tDCS was feasible and tolerable for patients with PD, with at-home access leading to high protocol compliance. Side effects were mostly limited to mild sensations of transient itching and burning under the electrode sites. Similar to prior finding sin MS, we found preliminary efficacy for improvement of fatigue and cognitive processing speed in PD. CONCLUSIONS: RS-tDCS paired with CT is feasible for participants with PD to receive at home treatment. Signals of benefit for reduced fatigue and improved cognitive processing speed are consistent across the PD and MS samples. RS-tDCS can be generalized to provide tDCS to a range of patients with neurologic disorders for at-home rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02746705 . Registered April 21st 2016. PMID- 30522498 TI - Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. AB - BACKGROUND: The 'classic' organic acidaemias (OAs) (propionic, methylmalonic and isovaleric) typically present in neonates or infants as acute metabolic decompensation with encephalopathy. This is frequently accompanied by severe hyperammonaemia and constitutes a metabolic emergency, as increased ammonia levels and accumulating toxic metabolites are associated with life-threatening neurological complications. Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia. Due to the urgency required, diagnostic evaluation and initial management of patients with suspected OAs should proceed simultaneously. Paediatricians, who do not have specialist knowledge of metabolic disorders, have the challenging task of facilitating a timely diagnosis and treatment. This article outlines how the underlying pathophysiology and biochemistry of the organic acidaemias are closely linked to their clinical presentation and management, and provides practical advice for decision-making during early, acute hyperammonaemia and metabolic decompensation in neonates and infants with organic acidaemias. CLINICAL MANAGEMENT: The acute management of hyperammonaemia in organic acidaemias requires administration of intravenous calories as glucose and lipids to promote anabolism, carnitine to promote urinary excretion of urinary organic acid esters, and correction of metabolic acidosis with the substitution of bicarbonate for chloride in intravenous fluids. It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate. Treatment with N-carbamyl-L-glutamate can rapidly normalise ammonia levels by stimulating the first step of the urea cycle. CONCLUSIONS: Our understanding of optimal treatment strategies for organic acidaemias is still evolving. Timely diagnosis is essential and best achieved by the early identification of hyperammonaemia and metabolic acidosis. Correcting metabolic imbalance and hyperammonaemia are critical to prevent brain damage in affected patients. PMID- 30522499 TI - Intimate partner violence and depression among pregnant women in the North west region of Cameroon: a research proposal. AB - OBJECTIVES: Intimate partner violence (IPV) in pregnancy is a major public health concern due to its harmful effects on both the mother and the unborn foetus. In this study, we aim to assess the prevalence and correlates of both IPV and depression in pregnant women in the northwest region of Cameroon. Specifically: (1) To determine the prevalence of IPV in a group of pregnant women in the northwest region of Cameroon. (2) To determine the prevalence of depression amongst these women. (3) To assess the various sociodemographic determinants of IPV in these women. (4) To determine if IPV is associated with depression and to assess other sociodemographic and clinical correlates of depression. RESULTS: This cross-sectional study will include a minimum of 369 pregnant women recruited by convenience sampling from primary and secondary healthcare facilities in the northwest region of the country. Data be collected via a printed questionnaire administered by a trained healthcare professional. IPV will be assessed using the World Health Organisation Violence Against Women Instrument and depression will be assessed using the Patient Health Questionnaire-9. Multivariable logistic regression will be used to identify independent predictors of IPV and depression. PMID- 30522500 TI - Mitochondrial haplogroup H is related to CD4+ T cell recovery in HIV infected patients starting combination antiretroviral therapy. AB - BACKGROUND: The mitochondrial DNA (mtDNA) seems to influence in a large number of diseases, including HIV infection. Moreover, there is a substantial inter individual variability in the CD4+ recovery in HIV-infected patients on combination antiretroviral therapy (cART). Our study aimed to analyze the association between mtDNA haplogroups and CD4+ recovery in HIV-infected patients on cART. METHODS: This is a retrospective study of 324 naive cART patients with CD4+ < 200 cells/mm3, who were followed-up during 24 months after initiating cART. All patients had undetectable HIV viral load during the follow-up. Besides, we included 141 healthy controls. MtDNA genotyping was performed by using Sequenom's MassARRAY platform. The primary outcome variable was the slope of CD4+ recovery. Patients were stratified into two groups by the median slope value of CD4+ (9.65 CD4+ cells/mm3/month). Logistic regression analyses were performed to calculate the odds of CD4+ recovery according to mtDNA haplogroups. RESULTS: Our study included European HIV-infected patients within the N macro-cluster. The baseline values of CD4+ T-cells were similar between groups of patients stratified by the P50th of the slope of CD4+ T-cells recovery. Patients in the low CD4+ T-cells recovery group were older (p = 0.001), but this variable was included in the multivariate models. When we analyzed the frequencies of mtDNA haplogroups, no significant differences between HIV-infected individuals and healthy controls were found. We did not find any significant association between mtDNA haplogroups and the slope of CD4+ T-cells recovery by linear regression analysis. However, Patients carrying haplogroup H had a higher odds of having a better CD4+ recovery (> 9.65 CD4+ cells/mm3/month) than patients without haplogroup H (p = 0.032). The adjusted logistic regression showed that patients carrying haplogroup H had a higher likelihood of achieving a CD4+ recovery > 9.65 CD4+ cells/mm3/month [adjusted odds ratio (aOR) = 1.75 (95% CI = 1.04; 2.95); p = 0.035]. CONCLUSIONS: European mitochondrial haplogroup H was associated with the improved CD4+ recovery in HIV-infected patients starting cART with CD4+ < 200 cells/mm3. PMID- 30522501 TI - Improved patient-reported outcomes in patients with psoriatic arthritis treated with abatacept: results from a phase 3 trial. AB - BACKGROUND: To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA). METHODS: Patients with PsA were randomised (1:1) to subcutaneous abatacept 125 mg weekly/placebo for 24 weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs <= upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements >= minimal clinically important differences (MCIDs) and >= normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed. RESULTS: In total population, numerically higher improvements in most PROs were reported with abatacept (n = 213) versus placebo (n = 211) at both time points (P > 0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements >= MCID and >= NV at week 16. At week 16, all PRO improvements were numerically greater (P > 0.05) in patients with baseline CRP > ULN versus CRP <= ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naive versus TNFi exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers. CONCLUSIONS: Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naive subpopulations. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013. PMID- 30522502 TI - How do macro-level structural determinants affect inequalities in mental health? a systematic review of the literature. AB - BACKGROUND: In Europe and elsewhere there is rising concern about inequality in health and increased prevalence of mental ill-health. Structural determinants such as welfare state arrangements may impact on levels of mental health and social inequalities. This systematic review aims to assess the current evidence on whether structural determinants are associated with inequalities in mental health outcomes. METHODS: We conducted a systematic review of quantitative studies published between 1996 and 2017 based on search results from the following databases Medline, Embase, PsychInfo, Web of Science, Sociological Abstracts and Eric. Studies were included if they focused on inequalities (measured by socio-economic position and gender), structural determinants (i.e. public policies affecting the whole population) and showed a change or comparison in mental health status in one (or more) of the Organisation for Economic Cooperation and Development (OECD) countries. All studies were assessed for inclusion and study quality by two independent reviewers. Data were extracted and synthesised using narrative analysis. RESULTS: Twenty-one articles (17 studies) met the inclusion criteria. Studies were heterogeneous with regards to methodology, mental health outcomes and policy settings. More comprehensive and gender inclusive welfare states (e.g. Nordic welfare states) had better mental health outcomes, especially for women, and less gender-related inequality. Nordic welfare regimes may also decrease inequalities between lone and couple mothers. A strong welfare state does not buffer against socio-economic inequalities in mental health outcomes. Austerity measures tended to worsen mental health and increase inequalities. Area-based initiatives and educational policy are understudied. CONCLUSION: Although the literature on structural determinants and inequalities in mental health is limited, our review shows some evidence supporting the causal effects of structural determinants on mental health inequalities. The lack of evidence should not be interpreted as lack of effect. Future studies should apply innovative methods to overcome the inherent methodological challenges in this area, as structural determinants potentially affect both levels of mental health and social inequalities. PMID- 30522503 TI - Immune adaptor protein SKAP1 (SKAP-55) forms homodimers as mediated by the N terminal region. AB - OBJECTIVE: Immune cell adaptor protein SKAP1 couples the antigen-receptor (TCR/CD3) with the activation of LFA-1 adhesion in T-cells. Previous work by ourselves and others have shown that SKAP1 can directly bind to other adaptors such as ADAP and RapL. However, it has been unclear whether SKAP1 can form homodimers with itself and the regions within SKAP1 that mediated homodimer formation. RESULTS: Here, we show that SKAP1 and SKAP2 form homodimers in cells. Homodimer formation of immune adaptor protein SKAP1 (SKAP-55) are mediated by residues A17 to L21 in the SKAP1 N-terminal region. SKAP1 dimer formation was not needed for its binding to RapL. These data indicate that the pathway linking SKAP1 to RapL is not dependent on the homo-dimerization of SKAP1. PMID- 30522504 TI - Efficacy and safety of polydioxanone thread embedded at specific acupoints for non-specific chronic neck pain: a study protocol for a randomized, subject assessor-blinded, sham-controlled pilot trial. AB - BACKGROUND: This study aims to evaluate the efficacy and safety of thread embedding acupuncture (TEA) with polydioxanone thread embedded at various acupoints, compared with sham TEA, for the treatment of non-specific chronic neck pain. METHODS/DESIGN: This study will be an 8-week-long, two-armed, parallel, randomized, subject-assessor-blinded, sham-controlled pilot trial. Fifty eligible patients will be randomly allocated into the real TEA group or the sham TEA group. The real TEA group will receive TEA treatment at 14 fixed acupoints in the neck region. The sham TEA group will receive the same treatment as the real TEA group, but with a sham device with the thread removed. Both groups will receive treatment once a week for a total of four sessions. The primary outcome will be the mean change in the visual analog scale (VAS) from baseline to week 6 (2 weeks post intervention). Clinical relevance (ratio of the number of patients with decreases on the VAS of >=15 mm or with percentiles >= 30% and >= 50% relative to baseline to the total number of patients), Neck Disability Index, pressure pain threshold, the Hospital Anxiety and Depression Scale, EuroQol 5-Dimensions questionnaire, Patient Global Impression of Change, blinding test, and adverse events will be used to assess secondary outcomes. DISCUSSION: The results of this study will provide valuable data for a large-scale clinical trial to evaluate the clinical effects of polydioxanone TEA in the treatment of patients with non specific chronic neck pain. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, KCT0002452 . Registered on 6 September 2017. PMID- 30522505 TI - Suture wear particles cause a significant inflammatory response in a murine synovial airpouch model. AB - BACKGROUND: Commonly used contemporary orthopaedic sutures have been identified as a potential causative factor in the development of post-arthroscopic glenohumeral chondrolysis. Currently, little is known about the body's immune response to these materials. The aim of this study was to examine the biological response of synovial tissue to three commonly used orthopaedic sutures, using a murine airpouch model. METHODS: Fifty rats were used in this study (ten per group). An airpouch was created in each rat, and test materials were implanted. Test materials consisted of an intact polyethylene terephthalate suture with a polybutilate coating (suture A), an intact polyethylene suture braided around a central polydiaxannone core (suture B), an intact polyethylene/polyester cobraid suture with a silicone coating (suture C), and particles of suture C (particles C). Rats were sacrificed at 1 or 4 weeks following implantation. Histological (multinucleated giant cell count) and immunohistochemical (expression of matrix metalloproteinases MMP-1,-2,-3,-9,-13) markers of inflammation were examined. RESULTS: Multinucleated giant cells were present in all specimens containing suture material but not in the control specimens. No significant differences were found in the number of giant cells between the intact suture groups at either time point. Significantly higher numbers of giant cells were noted in the particles C group compared to the intact suture C group at both time points (p = 0.021 at 1 week, p = 0.003 at 4 weeks). Quantitative analysis of immunohistochemical staining expression at 4 weeks showed that significantly more MMP (-1,-2,-9,-13) was expressed in the particles C group than the intact suture C group (p = 0.024, p = 0.009, p = 0.002, and p = 0.007 for MMP-1, MMP-2, MMP-9, and MMP-13, respectively). No significant difference was seen in the expression of MMP-3 (p = 0.058). CONCLUSIONS: There were no differences observed between the biological reactivity of commonly used intact orthopaedic sutures A, B, and C. However, wear particles of suture C elicited a significantly greater inflammatory response than intact suture alone. This was confirmed by increased numbers of multinucleated giant cells as well as MMP ( -1,-2,-9,-13) expression. Further studies are needed to determine whether this inflammatory response may play a role in the development of post-arthroscopic glenohumeral chondrolysis or interfere with biological healing. These findings have important clinical implications relating to surgical technique and surgical implant design. PMID- 30522506 TI - EZH2 variants differentially regulate polycomb repressive complex 2 in histone methylation and cell differentiation. AB - BACKGROUND: Polycomb repressive complex 2 (PRC2) is responsible for establishing and maintaining histone H3K27 methylation during cell differentiation and proliferation. H3K27 can be mono-, di-, or trimethylated, resulting in differential gene regulation. However, it remains unknown how PRC2 specifies the degree and biological effects of H3K27 methylation within a given cellular context. One way to determine PRC2 specificity may be through alternative splicing of Ezh2, PRC2's catalytic subunit, during cell differentiation and tissue maturation. RESULTS: We fully characterized the alternative splicing of Ezh2 in somatic cells and male germ cells and found that Ezh's exon 14 was differentially regulated during mitosis and meiosis. The Ezh2 isoform containing exon 14 (ex14-Ezh2) is upregulated during cell cycle progression, consistent with a role in maintaining H3K27 methylation during chromatin replication. In contrast, the isoform lacking exon 14 (ex14D-Ezh2) was almost exclusively present in spermatocytes when new H3K27me2 is established during meiotic differentiation. Moreover, Ezh2's transcript is normally controlled by E2F transcription activators, but in spermatocytes, Ezh2's transcription is controlled by the meiotic regulator MYBL1. Compared to ex14-EZH2, ex14D-EZH2 has a diminished efficiency for catalyzing H3K27me3 and promotes embryonic stem cell differentiation. CONCLUSIONS: Ezh2's expression is regulated at transcriptional and post-transcriptional levels in a cellular context-dependent manner. EZH2 variants determine functional specificity of PRC2 in histone methylation during cell proliferation and differentiation. PMID- 30522507 TI - Cryogenically preserved RBCs support gametocytogenesis of Plasmodium falciparum in vitro and gametogenesis in mosquitoes. AB - BACKGROUND: The malaria Eradication Research Agenda (malERA) has identified human to-mosquito transmission of Plasmodium falciparum as a major target for eradication. The cornerstone for identifying and evaluating transmission in the laboratory is standard membrane feeding assays (SMFAs) where mature gametocytes of P. falciparum generated in vitro are offered to mosquitoes as part of a blood meal. However, propagation of "infectious" gametocytes requires 10-12 days with considerable physico-chemical demands imposed on host RBCs and thus, "fresh" RBCs that are <= 1-week old post-collection are generally recommended. However, in addition to the costs, physico-chemical characteristics unique to RBC donors may confound reproducibility and interpretation of SMFAs. Cryogenic storage of RBCs ("cryo-preserved RBCs") is accepted by European and US FDAs as an alternative to refrigeration (4 degrees C) for preserving RBC "quality" and while cryo preserved RBCs have been used for in vitro cultures of other Plasmodia and the asexual stages of P. falciparum, none of the studies required RBCs to support parasite development for > 4 days. RESULTS: Using the standard laboratory strain, P. falciparum NF54, 11 SMFAs were performed with RBCs from four separate donors to demonstrate that RBCs cryo-preserved in the gaseous phase of liquid nitrogen ( 196 degrees C) supported gametocytogenesis in vitro and subsequent gametogenesis in Anopheles stephensi mosquitoes. Overall levels of sporogony in the mosquito, as measured by oocyst and sporozoite prevalence, as well as oocyst burden, from each of the four donors thawed after varying intervals of cryopreservation (1, 4, 8, and 12 weeks) were comparable to using <= 1-week old refrigerated RBCs. Lastly, the potential for cryo-preserved RBCs to serve as a suitable alternative substrate is demonstrated for a Cambodian isolate of P. falciparum across two independent SMFAs. CONCLUSIONS: Basic guidelines are presented for integrating cryo-preserved RBCs into an existing laboratory/insectary framework for P. falciparum SMFAs with significant potential for reducing running costs while achieving greater reliability. Lastly, scenarios are discussed where cryo-preserved RBCs may be especially useful in enhancing the understanding and/or providing novel insights into the patterns and processes underlying human-to-mosquito transmission. PMID- 30522508 TI - Comparison of complaints to the intensive care units and those to the general wards: an analysis using the Healthcare Complaint Analysis Tool in an academic medical center in Taiwan. AB - BACKGROUND: The management of complaints in the setting of intensive care may provide opportunities to understand patient and family experiences and needs. However, there are limited reports on the structured application of complaint analysis tools and comparisons between healthcare complaints in the critical care setting and other settings. METHODS: From the complaint management database of a university-affiliated medical center in Taiwan, we retrospectively identified the records of healthcare complaints to the intensive care units (ICUs) from 2008 to 2016. Complaints to the general wards in the same period were randomly selected from the database with twice the number of that of the ICU complaints. We coded, typed, and compared the complaints from the two settings according to the Healthcare Complaint Analysis Tool. RESULTS: We identified 343 complaints to the ICUs and randomly selected 686 complaints to the general wards during the 9-year study period. Most (94.7%) of the complaints to the ICUs came from the family members, whereas more complaints to the general wards came from the patients (44.2%). A total of 1529 problems (441 from ICU and 818 from general wards) were identified. Compared with the general ward complaints, in the ICU there were more complaints with multiple problems (25.1% vs. 16.9%, p = 0.002), complaints were referred more frequently to the nurses (28.1% vs. 17.5%, p < 0.001), and they focused more commonly on the care on the ICU/ward (60.5% vs. 54.2%, p = 0.029). The proportions of the three domains (clinical, management, and relationship) of complaints were similar between the ICU and general ward complaints (p = 0.121). However, in the management domain, the problems from ICU complaints focused more on the environment than on the institutional processes (90.9% vs. 74.5%, p < 0.001), whereas in the relationship domain, the problems focused more on communication (17.9% vs. 8.0%) and less on listening (34.6% vs. 46.5%) (p = 0.002) than the general ward complaints. CONCLUSIONS: A structured typing and systematic analysis of the healthcare complaints to the ICUs may provide valuable insights into the improvement of care quality, especially to the perceptions of the ICU environment and communications of the patients and their families. PMID- 30522509 TI - Surgical approach and management outcomes for junction tuberculous spondylitis: a retrospective study of 77 patients. AB - BACKGROUND: Junction tuberculous spondylitis involves the stress transition zone of the spine and has a high risk of progression to kyphosis or paraplegia. Problems still exist with treatment for spinal junction tuberculosis. This study investigated the surgical approach and clinical outcomes of junction spinal tuberculosis. METHODS: From June 1998 to July 2014, 77 patients with tuberculous spondylitis were enrolled. All patients received 2-3 weeks of anti-tuberculous treatment preoperatively; treatment was prolonged for 2-3 months when active pulmonary tuberculosis was present. The patients underwent anterior debridement and were followed up for an average of 29.4 months clinically and radiologically. RESULTS: The cervicothoracic junction spine (C7-T3) was involved in 15 patients. The thoracolumbar junction spine (T11-L2) was involved in 39 patients. The lumbosacral junction spine (L4-S1) was involved in 23 patients. Two patients with recurrence underwent reoperation; the drugs were adjusted, and all patients achieved bone fusion. The preoperative cervicothoracic and thoracolumbar kyphosis angle and lumbosacral angle were 31.4 +/- 10.9 degrees , 32.9 +/- 9.2 degrees , and 19.3 +/- 3.7 degrees , respectively, and the corresponding postoperative angles were ameliorated significantly to 9.1 +/- 3.2 degrees , 8.5 +/- 2.9 degrees , and 30.3 +/- 2.8 degrees . The preoperative ESR and C-reactive protein level of all patients were 48.1 +/- 11.3 mm/h and 65.5 +/- 16.2 mg/L which decreased to 12.3 +/- 4.3 mm/h and 8.6 +/- 3.7 mg/L at the final follow-up, respectively. All patients that had neurological symptoms achieved function status improvement at different degrees. CONCLUSION: For spinal tuberculosis of spinal junctions, anterior debridement, internal fixation, and fusion can be preferred and achieved. If multiple segment lesions are too long or difficult for operation of anterior internal fixation, combining posterior pedicle screw fixation is appropriate. PMID- 30522510 TI - Socioeconomic and lifestyle factors associated with HPV infection in pregnant women: a matched case-control study in Beijing, China. AB - BACKGROUND: Human papillomavirus (HPV) infection plays key role in the development of cervical cancer. The purpose of this study was to investigate socioeconomic and lifestyle factors associated with HPV infection in pregnant women in Beijing, China. METHODS: An age matched case-control study designed with 66 women as the case group (HPV positive) and 132 women as the control group (HPV negative) was carried out in two hospitals in Beijing. Socioeconomic and lifestyle factors were obtained using a standard questionnaire. Cervical cells from study subjects were collected for HPV detection. An unconditional logistic regression model with backward stepwise selection was performed to predict the odds ratio (OR) and 95% confidence interval (CI) for the significant factors associated with HPV infection. RESULTS: The analyses of present data show that alcohol consumption during pregnancy was the strongest significant factor (OR = 3.35, 95% CI = 1.40-8.03, p = 0.007) when comparing the case (HPV positive) group with the control (HPV negative) group. There were no statistical differences observed in any of the socioeconomic factors when comparing the case and control groups. CONCLUSION: The results of this study may help to prevent HPV infection in China by providing evidence to support improving the national policy on alcohol restriction and introducing public health interventions, especially for pregnant women in Beijing. PMID- 30522511 TI - Cordycepin reduces weight through regulating gut microbiota in high-fat diet induced obese rats. AB - BACKGROUND: An increasing number of studies have shown that obesity is the key etiological agent of cardiovascular diseases, nonalcoholic fatty liver disease, type 2 diabetes and several kinds of cancer and that gut microbiota change was one of the reasons suffering from obesity. At present, the gut microbiota has gained increased attention as a potential energy metabolism organ. Our recent study reported that cordycepin, a major bioactive component separated from Cordyceps militaris, prevented body weight gain in mice fed a high-fat diet directly acting to adipocytes, however, the effect of cordycepin regulating gut microbiota keeps unknown. METHODS: In this research, we synthesized cordycepin (3 deoxyadenosine) by chemical methods and verified that cordycepin reduces body weight gain and fat accumulation around the epididymis and the kidneys of rats fed a high-fat diet. Furthermore, we used high-throughput sequencing on a MiSeq Illumina platform to test the species of intestinal bacteria in high-fat-diet induced obese rats. RESULTS: We found that cordycepin modifies the relative abundance of intestinal bacteria in high-fat-diet-induced obese rats. However, cordycepin did not alter the variety of bacteria in the intestine. Cordycepin treatment dramatically reversed the relative abundance of two dominant bacterial phyla (Bacteroidetes and Firmicutes) in the high-fat-diet-induced obese rats, resulting in abundance similar to that of the chow diet group. CONCLUSION: Our study suggests that cordycepin can reduce body weight and microbiome done by cordycepin seems be a result among its mechanisms of obesity reduction. PMID- 30522512 TI - Improving overall health of children living with HIV through an oral health intervention in Cambodia: study protocol for a randomized controlled trial. AB - BACKGROUND: Currently, the number of children living with HIV is the highest ever. This has led to an increased focus on a healthy life expectancy in this population. Improving oral health status may contribute to improved immunity, which could in turn lead to greater overall health in this population. This study aims to evaluate the effectiveness of an oral health intervention in improving oral health and immune status among children living with HIV in Cambodia. METHODS: A randomized controlled trial will be conducted in Phnom Penh from May 2018 to April 2020. Among 520 dyads of children living with their respective caregivers, half will be randomly allocated to the intervention group and the other half to the control group. Children aged 3-15 years who are currently receiving antiretroviral therapy at the National Pediatric Hospital will be recruited. In addition, 260 HIV-uninfected children (age-matched to the intervention group) will be recruited from the communities. They, together with their caregivers, will comprise the second control group. The main components of the intervention will include oral health education sessions for the children, as well as daily oral self-care under the supervision of their caregivers. The primary study outcome will be the change in oral health status including the number of decayed, missing, or filled permanent teeth, and the secondary outcome will be CD4 count. The effects of the intervention will be assessed by comparing outcome indicators between the children in the intervention and those in the control groups. DISCUSSION: This trial will investigate the effects of an oral health intervention on the improvement of oral health and immune status among children living with HIV and determine the differences compared with the control groups. This intervention would encourage the promotion of oral health interventions among children living with HIV and thus contribute to delaying the onset of AIDS. TRIAL REGISTRATION: Current Controlled Trials, International Standard Randomized Controlled Trial Number Register, ISRCTN15177479 . Registered on 17 January 2018. PMID- 30522513 TI - Correction to: Prediction of smoking by multiplex bisulfite PCR with long amplicons considering allele-specific effects on DNA methylation. AB - Upon publication of the original article [1], it was noticed that the Figure captions of Figs. 2 and 3 were incorrectly given. The correct Figure captions are given below. PMID- 30522515 TI - The risks of cancer development in systemic lupus erythematosus (SLE) patients: a systematic review and meta-analysis. AB - BACKGROUND: Although accumulating data have suggested the development of cancer in systemic lupus erythematosus (SLE) patients, these results remain inconsistent. To examine such a putative association, this analysis reports the association between SLE and the risks of 24 cancer types. METHODS: Online databases PubMed, EMBASE, and Web of Science were searched comprehensively for eligible studies, published up to 15 May 2018. Pooled standardized incidence rates (SIRs) with 95% confidence intervals (CIs) were utilized to reveal their associations. RESULTS: A total of 24 eligible studies were ultimately enrolled. Our results indicated that SLE was associated with increased risk of overall cancers, cancer risk in both genders, non-Hodgkin's lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, cervix, vagina/vulva, renal, bladder, esophagus, gastric, hepatobiliary, lung, oropharynx, larynx, non-melanoma skin, and thyroid cancers. Additionally, SLE could reduce the risk of prostate cancer and cutaneous melanoma; however, it was not significantly associated with breast, uterus, ovarian, pancreatic, colorectal, or brain cancers. CONCLUSIONS: Our results shed light SLE being correlated with increased risk for 16 involved cancers and decreased risk for prostate cancer and cutaneous melanoma. This comprehensive meta-analysis provides epidemiological evidence supporting the associations between SLE and cancer risk. This evidence could be utilized to drive public policies and to help guide personalized medicine to better manage SLE and reduce associated cancer morbidity and mortality. PMID- 30522516 TI - Withdrawing attempt and its related factors among Iranian substance users: a case control study. AB - BACKGROUND: Substance dependence is considered as an important health disorder with a wide and serious range of psychosocial effects. With regard to the large number of people with substance dependency in Iran and high failure rate of quitting attempts, the aim of this study was to identify contributing factors to quitting substance dependency among patients in Yasuj the capital of Kohgilooyeh and Boyerahmad province. METHODS: This case-control study was conducted on 150 current substance users (as control group) and 187 patients who voluntarily introduced themselves to governmental and private residential treatment camps (as case group). The participants in the case group were selected via two stage cluster sampling among those admitted to residential treatment camps. Those in the control group were selected via snowball sampling among current substance users. RESULTS: Based on the results from multiple logistic regression analysis, significant associations were observed between attempting to withdraw substance use and father's education (OR high school or university /illiterate = 0.36, 95%CI: 0.18 to 0.72, P = 0.004) and smoking (OR yes/no = 4.26, 95%CI = 1.90 to 9.57, P < 0.001) were identified. CONCLUSIONS: This study introduced father's education as an obstacle to attempting to quit substance dependency. This finding can be justified by easier access to money and therefore less financial pressure in providing drugs among those with wealthier families. Also, smoking was more common among those who registered with the camps. This is possibly due to the quitters attempt to replace the drugs with cigar smoking as an alternative. Training families in helping their members in preventing or quitting substance dependency is a potentially useful approach. Studies are needed to define whether the common belief that smoking helps in withdrawing substance use is helpful. PMID- 30522514 TI - Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development. AB - BACKGROUND: Lysine-specific histone demethylase 5C (KDM5C) belongs to the jumonji family of demethylases and is specific for the di- and tri-demethylation of lysine 4 residues on histone 3 (H3K4 me2/3). KDM5C is expressed in the brain and skeletal muscles of humans and is associated with various biologically significant processes. KDM5C is known to be associated with X-linked mental retardation and is also involved in the development of cancer. However, the developmental significance of KDM5C has not been explored yet. In the present study, we investigated the physiological roles of KDM5C during Xenopus laevis embryonic development. RESULTS: Loss-of-function analysis using kdm5c antisense morpholino oligonucleotides indicated that kdm5c knockdown led to small-sized heads, reduced cartilage size, and malformed eyes (i.e., small-sized and deformed eyes). Molecular analyses of KDM5C functional roles using whole-mount in situ hybridization, beta-galactosidase staining, and reverse transcription-polymerase chain reaction revealed that loss of kdm5c resulted in reduced expression levels of neural crest specifiers and genes involved in eye development. Furthermore, transcriptome analysis indicated the significance of KDM5C in morphogenesis and organogenesis. CONCLUSION: Our findings indicated that KDM5C is associated with embryonic development and provided additional information regarding the complex and dynamic gene network that regulates neural crest formation and eye development. This study emphasizes the functional significance of KDM5C in Xenopus embryogenesis; however, further analysis is needed to explore the interactions of KDM5C with specific developmental genes. PMID- 30522517 TI - Manifolds boosting severe acute malnutrition burden among children in and around Wolaita Zone, Southern Ethiopia: mini-review. AB - OBJECTIVES: Severe acute malnutrition (SAM) has been considered as the complex nutritional problem within developing countries. Alleviating its occurrence also exists in an anxiety. A series of studies were conducted to disclose evidences and documented by here author. Moreover key messages were abstracted with this review easing access of texts. RESULTS: Due to pitiable sanitary practices 30% of cow milk had massive bacterial isolates like Escherichia coli; while usage of raw milk has been common do. Besides the mean severe household food insecurity was 6.5% and practice of family planning was 30%; whilst family size subsists as predictor for household food insecurity. The habits of exclusive breastfeeding, timely initiation of complementary feeding and apt complementary feeding were 78%, 34% and 11%, respectively with awareness as predictor. On the other hand SAM has been recognized as problem in children and treated mainly in outpatient therapeutic program by curative foods. Yet the provided foods were shared due to severe household food insecurity causing SAM recovery rate intolerable. So children get severely underfed by multidimensional determinants and need multifaceted strategies starting from awareness creation and alleviating household food insecurity. PMID- 30522518 TI - Proportion and factors of death among preterm neonates admitted in University of Gondar comprehensive specialized hospital neonatal intensive care unit, Northwest Ethiopia. AB - OBJECTIVE: Neonatal mortality accounts for 43% of under-five child mortality in Ethiopia where preterm is the second leading cause of neonatal death and steadily increased in low-income countries. Therefore, assessing the proportion of death and associated factors among preterm neonates has a paramount importance in designing an effective strategy to intervene and achieve sustainable development goal. RESULTS: In this study proportion of preterm neonatal death in this study was 28.8% [95% CI (25.1, 32.9)]. Complications during index pregnancy [AOR = 1.92, 95% CI (1.09, 3.38)], gestational age [AOR = 0.78, 95% CI (0.69, 0.91)], small for gestational age [AOR = 2.42, 95% CI (1.33, 4.38)], APGAR score at birth < 7 [AOR = 2.39, 95% CI (1.34, 4.27)], hyaline membrane disease [AOR = 5.15, 95% CI (2.83, 9.36)], neonatal respiratory distress at admission [AOR = 1.93, 95% CI (1.13, 3.31)], presence of jaundice [AOR = (3.39, 95% CI (1.90, 6.05)], received kangaroo mother care [AOR = 0.13, 95% CI (0.05, 0.35)], and hypoglycemia at admission [AOR = 3.86, 95% CI (2.12, 7.06)] were statistically significant. The proportion of preterm neonatal death was high. Ministry of health and responsible organizations should give special attention for preterm neonates to prevent life threatening complications. PMID- 30522519 TI - Surgical outcome of jejunum-jejunum intussusception secondary to Rapunzel syndrome: a case report. AB - BACKGROUND: Adult intestinal intussusception is a rare condition caused by the mechanical disruption of bowel motility. A bezoar is defined as indigestible material inside the gastrointestinal tract that develops into a trapped mass; the most frequent bezoar is a trichobezoar. When a trichobezoar extends into the small intestine it is defined as Rapunzel's syndrome. Literature describing complications related to this pathology remains scarce. CASE PRESENTATION: A 16 year-old Mexican girl presented to our emergency room with acute abdomen and a presumptive diagnosis of intestinal obstruction. Computed tomography was suggestive of intussusception. Surgery confirmed a jejunal-jejunal intussusception with a mass within the gastric cavity extending into her small intestine, corresponding to a trichobezoar. A manual intussusception reduction and a gastrotomy with extraction of the trichobezoar were performed. CONCLUSIONS: We present a case of a jejunum intussusception as a complication of Rapunzel syndrome. Our patient had a favorable outcome after surgical intervention with a manual intussusception reduction, with retrograde displacement of the trichobezoar into the gastric lumen, and a complete extraction through a gastrostomy. Follow-up included psychiatric evaluation. PMID- 30522520 TI - Correction to: Giant nonfunctioning adrenal tumors: two case reports and review of the literature. AB - In the publication of this article [1], there is an error in the Family Name and Given Name of the authors since these were interchanged. PMID- 30522521 TI - Successful outcome of disseminated mucormycosis in a 3-year-old child suffering from acute leukaemia: the role of isavuconazole? A case report. AB - BACKGROUND: The use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful. CASE PRESENTATION: We describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring. CONCLUSIONS: This case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B. PMID- 30522522 TI - The eye of the beholder: orbital metastases from midgut neuroendocrine tumors, a two institution experience. AB - BACKGROUND: Metastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT. CASE PRESENTATIONS: Patient 1 is a 72 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy. Patient 2 is a 68 year old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control. Patient 3 is a 63 year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly. Patient 4 is a 72 year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since. Patient 5 is a 61 year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease. CONCLUSIONS: NETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients. PMID- 30522523 TI - Citizen science charts two major "stomatotypes" in the oral microbiome of adolescents and reveals links with habits and drinking water composition. AB - BACKGROUND: The oral cavity comprises a rich and diverse microbiome, which plays important roles in health and disease. Previous studies have mostly focused on adult populations or in very young children, whereas the adolescent oral microbiome remains poorly studied. Here, we used a citizen science approach and 16S profiling to assess the oral microbiome of 1500 adolescents around Spain and its relationships with lifestyle, diet, hygiene, and socioeconomic and environmental parameters. RESULTS: Our results provide a detailed snapshot of the adolescent oral microbiome and how it varies with lifestyle and other factors. In addition to hygiene and dietary habits, we found that the composition of tap water was related to important changes in the abundance of several bacterial genera. This points to an important role of drinking water in shaping the oral microbiota, which has been so far poorly explored. Overall, the microbiome samples of our study can be clustered into two broad compositional patterns (stomatotypes), driven mostly by Neisseria and Prevotella, respectively. These patterns show striking similarities with those found in unrelated populations. CONCLUSIONS: We hypothesize that these stomatotypes represent two possible global optimal equilibria in the oral microbiome that reflect underlying constraints of the human oral niche. As such, they should be found across a variety of geographical regions, lifestyles, and ages. PMID- 30522525 TI - Potential drug incompatibilities in the neonatal intensive care unit: a network analysis approach. AB - BACKGROUND: There is little information on the frequency of drug incompatibilities in neonatal intensive care units (NICU) and the agents most commonly involved in them. The objective of the study was to characterize potential Drug Incompatibilities (DI) in the NICU by frequency, type and combination of drugs. METHODS: Between August 2015 and December 2016, all neonates admitted for more than 24 h and who received any drug treatment were included in this cohort study conducted in the NICU of a teaching maternity hospital in Brazil. Patient data were collected from patient records and prescription orders, and the compatibilities of all drug pairs were classified using the Trissel'sTM 2 IV Compatibility tool. Network analysis was performed in order to visualize the drug pairs commonly involved in potential DI. RESULTS: The study population consisted of 281 neonates with a median NICU length of stay of 11 days (range 2-184) and received 1343 intravenous medications. A total of 1114 potential DI were identified, 469 (42.1%) were restricted compatibilities, 348 (31.2%) unknown compatibilities and 297 (26.7%) documented incompatibilities. The incidence of documented incompatibilities in the NICU was 25.0% patient-days (95% confidence interval (CI) 19.4-30.7% patient-days). Incompatible potential DI affected 46.3% (95%CI 40.3-52.3%) of the neonates. Ampicillin (408 of 1114 pairs), gentamicin (216 of 1114 pairs) and aminophylline (197 of 1114 pairs) were the main medicines involved in potential DI. CONCLUSION: Potential DI are extremely common in NICU, with half of the population susceptible to simultaneous administration of incompatible medications. More research is needed to understand the actual drug incompatibilities and their clinical outcomes. PMID- 30522524 TI - Parasite reduction ratio one day after initiation of artemisinin-based combination therapies and its relationship with parasite clearance time in acutely malarious children. AB - BACKGROUND: In acute falciparum malaria, asexual parasite reduction ratio two days post-treatment initiation (PRRD2) >= 10 000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives. However, there is little evaluation of alternative measures; for example, parasite reduction ratio one day after treatment initiation (PRRD1) and its relationship with parasite clearance time (PCT) or PRRD2. This study evaluated the use of PRRD1 as a measure of responsiveness to antimalarial drugs. METHODS: In acutely malarious children treated with artesunate-amodiaquine (AA), artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DHP), the relationships between PRRD1 or PRRD2 and PCT, and between PRRD1 and PRRD2 were evaluated using linear regression. Agreement between estimates of PCT using PRRD1 and PRRD2 linear regression equations was evaluated using the Bland-Altman analysis. Predictors of PRRD1 > 5000 per half cycle and PRRD2 >= 10 000 per cycle were evaluated using stepwise multiple logistic regression models. Using the linear regression equation of the relationship between PRRD1 and PCT previously generated in half of the DHP-treated children during the early study phase, PCT estimates were compared in a prospective blinded manner with PCTs determined by microscopy during the later study phase in the remaining half. RESULTS: In 919 malarious children, PRRD1 was significantly higher in DHP- and AA-treated compared with AL-treated children (P < 0.0001). PRRD1 or PRRD2 values correlated significantly negatively with PCT values (P < 0.0001 for each) and significantly positively with each other (P < 0.0001). PCT estimates from linear regression equations for PRRD1 and PRRD2 showed insignificant bias on the Bland-Altman plot (P = 0.7) indicating the estimates can be used interchangeably. At presentation, age > 15 months, parasitaemia > 10 000/MUl and DHP treatment independently predicted PRRD1 > 5000 per half cycle, while age > 30 months, haematocrit >=31%, body temperature > 37.4 degrees C, parasitaemia > 100 000/MUl, PRRD1 value > 1000 and no gametocytaemia independently predicted PRRD2 >= 10 000 per cycle. Using the linear regression equation generated during the early phase in 166 DHP treated children, PCT estimates and PCTs determined by microscopy in the 155 children in the later phase were similar in the same patients. CONCLUSIONS: PRRD1 and estimates of PCT using PRRD1 linear regression equation of PRRD1 and PCT can be used in therapeutic efficacy studies. TRIAL REGISTRATION: Pan African Clinical Trial Registration PACTR201709002064150, 1 March 2017, http://www.pactr.org. PMID- 30522526 TI - Evaluation of free radical scavenging capacity of methoxy containing-hybrids of thiosemicarbazone-triazole and their influence on glucose transport. AB - BACKGROUND: Diabetes mellitus is a metabolic disease in which the body is unable to produce insulin or respond to insulin production, consequently leading to abnormal metabolism of carbohydrates, lipids and proteins causing elevation of glucose in the blood. Oxidative stress, an imbalance between the production of free radicals and body antioxidant system has been implicated in the pathogenesis of diabetes. Free radicals attack important macromolecules leading to cell damage. Antioxidants are intimately involved in the prevention of damage caused by free radicals. METHODS: The anti-diabetic effects of hybrid compounds (2a-h) of thiosemicarbazone and triazole containing methoxy groups at C (4) positions were tested against genes involved in glucose metabolism (Glut-4, Mef2a and Nrf 1) using quantitative real time PCR (qPCR). Free radical scavenging capacity (FRAP, TEAC, DPPH and ORAC) of the hybrids was also carried out by using established antioxidant capacity assays. RESULTS: From the results, hybrid compounds 2b and 2h showed more pronounced effects in up-regulating diabetes associated genes which are important in the up-regulation of glucose uptake. All the hybrid compounds also showed free radical scavenging abilities. CONCLUSION: In conclusion, hybrid compounds (2b and 2h) can be useful as potential drugs for the management of diabetes mellitus. PMID- 30522527 TI - Defining and conceptualising data harmonisation: a scoping review protocol. AB - BACKGROUND: Data harmonisation is an important intervention to strengthen health systems functioning. It has the potential to enhance the production, accessibility and utilisation of routine health information for clinical and service management decision-making. It is important to understand the range of definitions and concepts of data harmonisation, as well as how its various social and technical components and processes are thought to lead to better health management decision-making. However, there is lack of agreement in the literature, and in practice, on definitions and conceptualisations of data harmonisation, making it difficult for health system decision-makers and researchers to design, implement, evaluate and compare data harmonisation interventions. This scoping review aims to synthesise (1) definitions and conceptualisations of data harmonisation as well as (2) explanations in the literature of the causal relationships between data harmonisation and health management decision-making. METHODS: This review follows recommended methodological stages for scoping studies. We will identify relevant studies (peer-reviewed and grey literature) from 2000 onwards, in English only, and with no methodological restriction, in various electronic databases, such as CINAHL, MEDLINE via PubMed and Global Health. Two reviewers will independently screen records for potential inclusion for the abstract and full-text screening stages. One reviewer will do the data extraction, analysis and synthesis, with built-in reliability checks from the rest of the team. We will use a combination of sampling techniques, including two types of 'purposeful sampling', a methodological approach that is particularly suitable for a scoping review with our objectives. We will provide (a) a numerical synthesis of characteristics of the included studies and (b) a narrative synthesis of definitions and explanations in the literature of the relationship between data harmonisation and health management decision-making. DISCUSSION: We list potential limitations of this scoping review. To our knowledge, this scoping review will be the first to synthesise definitions and conceptualisations of data harmonisation in the literature as well as the underlying explanations in the literature of the causal links between data harmonisation and health management decision-making. PMID- 30522528 TI - Pisa syndrome associated with mirtazapine: a case report. AB - BACKGROUND: Mirtazapine is a noradrenergic and specific serotonergic antidepressant; its pharmacological profile indicates a low risk for dopaminergic adverse effects. To date, there has been only a single case report of Pisa syndrome associated with mirtazapine. CASE PRESENTATION: The authors report a case involving a 79-year-old woman with bipolar disorder, in whom Pisa syndrome occurred after introduction of mirtazapine, and completely disappeared 3 days after suspension of the drug. CONCLUSIONS: Aspects of this particular case suggest that Pisa syndrome is a possible side effect of Mirtazapine. PMID- 30522529 TI - Interventions integrating health and academic interventions to prevent substance use and violence: a systematic review and synthesis of process evaluations. AB - BACKGROUND: Within increasingly constrained school timetables, interventions that integrate academic and health education to reduce substance use and violence may hold promise as a category of intervention that can positively affect both academic and health outcomes. There are no current systematic reviews exploring the effectiveness of such interventions or factors that affect their implementation. METHODS: A total of 19 bibliographic databases and 32 websites were searched. References were also extracted from the reference lists of included studies, and experts and authors were contacted to identify relevant studies. We included reports with no restrictions on language or date. References were screened on title/abstract and those not thus excluded were screened on full report. Data extraction and appraisal followed the Critical Appraisal Skills Programme, Evidence for Policy and Practice Information and Co-ordinating Centre and Cochrane tools. Extracted process data were qualitatively meta-synthesised for common themes. RESULTS: Seventy-eight thousand four hundred fifty-one unique references were identified, and 62 reports were included. A total of 16 reports (reporting on 15 studies of 12 interventions) evaluated process. Key facilitators of integrated academic and health curricula were supportive senior management and alignment of the intervention with school ethos; a positive teaching environment, including positive perceptions around the ability to be flexible in the adaptation and delivery of integrated academic and health curricula; positive pre existing student and teacher attitudes towards intervention content; and parental support of interventions, largely through reinforcement of messaging at home. Important barriers were over-burdened teachers, with little time to learn and implement integrated curricula. CONCLUSION: Several useful facilitating and inhibiting factors linked to the implementation of interventions that integrate academic and health education for reduced substance use and/or violence were identified, providing tentative but insightful evidence of context-specific issues that may impact intervention success. However, overall, there is still a considerable gap in our understanding of how to achieve the successful implementation of these interventions. PMID- 30522530 TI - Uncovering complex microbiome activities via metatranscriptomics during 24 hours of oral biofilm assembly and maturation. AB - BACKGROUND: Dental plaque is composed of hundreds of bacterial taxonomic units and represents one of the most diverse and stable microbial ecosystems associated with the human body. Taxonomic composition and functional capacity of mature plaque is gradually shaped during several stages of community assembly via processes such as co-aggregation, competition for space and resources, and by bacterially produced reactive agents. Knowledge on the dynamics of assembly within complex communities is very limited and derives mainly from studies composed of a limited number of bacterial species. To fill current knowledge gaps, we applied parallel metagenomic and metatranscriptomic analyses during assembly and maturation of an in vitro oral biofilm. This model system has previously demonstrated remarkable reproducibility in taxonomic composition across replicate samples during maturation. RESULTS: Time course analysis of the biofilm maturation was performed by parallel sampling every 2-3 h for 24 h for both DNA and RNA. Metagenomic analyses revealed that community taxonomy changed most dramatically between three and six hours of growth when pH dropped from 6.5 to 5.5. By applying comparative metatranscriptome analysis we could identify major shifts in overall community activities between six and nine hours of growth when pH dropped below 5.5, as 29,015 genes were significantly up- or down- expressed. Several of the differentially expressed genes showed unique activities for individual bacterial genomes and were associated with pyruvate and lactate metabolism, two-component signaling pathways, production of antibacterial molecules, iron sequestration, pH neutralization, protein hydrolysis, and surface attachment. Our analysis also revealed several mechanisms responsible for the niche expansion of the cariogenic pathogen Lactobacillus fermentum. CONCLUSION: It is highly regarded that acidic conditions in dental plaque cause a net loss of enamel from teeth. Here, as pH drops below 5.5 pH to 4.7, we observe blooms of cariogenic lactobacilli, and a transition point of many bacterial gene expression activities within the community. To our knowledge, this represents the first study of the assembly and maturation of a complex oral bacterial biofilm community that addresses gene level functional responses over time. PMID- 30522531 TI - Incidence and etiology of fever following seasonal influenza vaccination in hospitalized patients. AB - We conducted a retrospective cohort to examine the incidence and etiology of fever postinfluenza vaccination among hospitalized patients during the 2015-2016 influenza season. Fever occurred in 63 (1.5%) of 4,185 vaccinated patients. Medical patients had fever predominantly associated with concurrent infections; surgical patients had fever explained by noninfectious etiologies. PMID- 30522532 TI - Comparison between household food purchase and individual food consumption in Brazil. AB - OBJECTIVE: The present study aimed to compare Household Budget Survey (HBS) data on food purchasing and individual food consumption, collected in the same nationwide survey. DESIGN: Food purchase information for each household was collected by a seven-day collective acquisition diary, applied to 55 970 households. Food consumption information was obtained from household members over 10 years old by the application of two non-consecutive food records in a sub sample of the HBS. Cooking and correction factors were applied when necessary, and all food items reported were grouped into twelve main food groups. Food purchase and consumption data were presented as absolute weight (g/person per d) and as relative contribution to energy intake (%) for the overall study population, which was stratified according to household income. SETTING: Brazil.ParticipantsNational estimates of food consumption and purchase for Brazil. RESULTS: The greatest differences between purchase and consumption data (purchase minus consumption) were observed for meat (-168 g), beans/legumes (-48 g), roots/tubers (-36 g) and fruits (-31 g). When expressed in terms of energy contribution, the highest differences were found for cereals (13 %) and oils and fats (11 %). Differences between purchase and consumption data were generally lower in the highest compared with the lowest household income quintile; and were lower for most main food groups when considering only foods reported as being eaten at home. CONCLUSIONS: With few exceptions, food purchase expressed as relative energy contribution, as opposed to absolute weight, can provide a good picture of actual consumption in the Brazilian population. PMID- 30522533 TI - Disability discrimination and avoidance in later life: prevalence, disability differentials and association with mental health. AB - : ABSTRACTBackground:Later life is a period of increased risk of disability, but there is little quantitative evidence regarding the exclusion of older people (through discrimination and avoidance) due to their health conditions. This study aims to (1) measure the prevalence of disability exclusion in later life, (2) examine how experiences of exclusion differ by disability type, and (3) investigate the association of exposure to exclusion with psychological distress. METHODS: Using data from the 2015 ABS Survey of Disability, Ageing and Carers, we calculated the prevalence of people aged 55 years and over with a disability experiencing discrimination and engaging in avoidance behaviors, disaggregated by 18 detailed disability types. Modified Log-Poisson models were fitted to estimate Prevalence Ratios to measure the association between exclusion and psychological distress, stratified by disability type. RESULTS: In 2015, about 5% of Australians aged 55 years and over with a disability reported experiencing an instance of disability discrimination, and one in four reported avoiding a situation or context due to their disability. Accounting for psychosocial comorbidities and with extensive demographic controls, exposure to disability avoidance (PR = 1.9, 95% CI 1.7, 2.1) or discrimination (PR = 1.7, 95% CI 1.4, 2.1) almost doubled the probability of experiencing psychological distress. Effects were heightened for individuals reporting specific disabilities including sensory and speech and physical disabilities as well as those reporting a head injury, stroke, or acquired brain injury. CONCLUSIONS: Despite protections against disability discrimination in legislation, discrimination and avoidance due to disability is prevalent and is associated with poor mental health outcomes. PMID- 30522534 TI - Considering Age-Related Hearing Loss in Neuropsychological Practice: Findings from a Feasibility Study. AB - ABSTRACTHearing loss is highly prevalent in older adults and can pose challenges for neuropsychologists, as assessment and intervention procedures often involve orally presented information which must be accurately heard. This project examined the hearing status of 20 clients (mean age = 71 years) in a hospital based outpatient neuropsychology clinic, and explored whether information about hearing loss informed neuropsychologists' clinical practice. A research assistant administered a brief hearing screening test to each participant. Four treating neuropsychologists were asked to comment on their client's hearing status before and after being shown their client's hearing screen test results. Screening revealed that the majority of participants had at least mild hearing loss, and that the neuropsychologists were relatively accurate (60%) at estimating their clients' hearing status. Neuropsychologists used information about a client's hearing status to make recommendations that clients pursue audiologic services, and to educate clients and family members about hearing loss and communication. PMID- 30522535 TI - A regional collaboration between competing healthcare systems to establish influenza season parameters. PMID- 30522536 TI - Development and assessment of the content validity of the professional good practices scale in nursing homes. AB - ABSTRACTRecent approaches in the care of older people have led to a greater emphasis on good practices to prevent elder abuse. The instruments assessing good practices are very limited, and those focused on elder abuse have rarely considered subtle forms, especially in institutional settings. The aim of this study was to develop and assess the content validity of a good practices scale for professionals working in nursing homes. An extensive literature review of the tools assessing professionals' good-bad practices towards older people was conducted. A preliminary scale based on Kayser-Jones' (1990) [Old, Alone and Neglected: Care of the Aged in Scotland and the United States. Berkeley, CA: University of California Press] types of abuse was developed, including four subscales: Personalization, Humanization, Absence of Infantilization, and Absence of Victimization. Content validity was analyzed through a panel of eight experts. Rovinelli and Hambleton's index of item-objective congruence was used to analyze the items' inclusiveness in the assigned subscale to establish their representativeness. Items' relevance and clarity were analyzed using the paired comparison method. The final version of the scale included 56 items, with appropriate levels of item objective-congruence, relevance, and clarity. This instrument will allow professionals to detect and develop awareness and intervention programs that aim to promote good practices in nursing homes. PMID- 30522537 TI - Impact of expanded influenza post-exposure prophylaxis on healthcare worker absenteeism at a tertiary care center during the 2017-2018 season. PMID- 30522539 TI - A novel color additive for bleach wipes indicates surface coverage and contact time to improve thoroughness of cleaning. PMID- 30522538 TI - Point-prevalence study of antimicrobial use in public hospitals in southern Sri Lanka identifies opportunities for improving prescribing practices. AB - A point-prevalence study of antimicrobial use among inpatients at 5 public hospitals in Sri Lanka revealed that 54.6% were receiving antimicrobials: 43.1% in medical wards, 68.0% in surgical wards, and 97.6% in intensive care wards. Amoxicillin-clavulanate was most commonly used for major indications. Among patients receiving antimicrobials, 31.0% received potentially inappropriate therapy. PMID- 30522540 TI - Surgical site infections following hip and knee arthroplastic surgery: Trends and risk factors of Staphylococcus aureus infections. AB - We investigated surgical site infections (SSIs) following hip and knee arthroplasties to evaluate predictors of SSI. We found a significant increase in deep Staphylococcus aureus (SA) SSIs despite the decreasing overall SSI rate. The risk of deep SA-SSI differed between genders and among age groups and was affected by timing of surgery. PMID- 30522541 TI - Sharing is not always a good thing: Use of a DNA marker to investigate the potential for ward-to-ward dissemination of healthcare-associated pathogens. AB - A DNA marker inoculated onto portable equipment on a medical ward was disseminated to other wards when equipment was shared and to a physician work room and the hospital cafeteria by personnel. These results demonstrate the plausibility of pathogen transmission in healthcare facilities in the absence of shared ward exposure. PMID- 30522542 TI - Establishing a mass prophylaxis clinic during a hospital scabies outbreak. PMID- 30522543 TI - Twins Working Together: Collaboration or Contest/Twin Research: Molar Pregnancy; Social Support; Conjoined Twins; Immune Discordance/Headlines: Twin Politicians; Multiple Birth Marriages; Guinness World Record; Museum of Memory and Human Rights (Santiago, Chile). AB - Twin research has found genetic influence underlying vocational interests, work values, and job satisfaction. In addition, numerous studies have shown that monozygotic (MZ) twins generally display greater within-pair cooperation and social closeness than dizygotic (DZ) twins. These findings are illuminated by exploring the occupational histories of two female twin pairs, one set MZ and the other set DZ. This is followed by a review of timely twin-based research reports on molar pregnancy, social support, conjoined twinning, and immune discordance. Finally, news items regarding identical twin politicians, multiple birth marriages, a new Guinness World Record for twins, and a twin-family story from the Museum of Memory and Human Rights in Santiago, Chile are both interesting and informative. PMID- 30522544 TI - Use of diagnostic stewardship practices to improve urine culturing among SHEA Research Network hospitals. AB - This survey investigated interventions used by acute-care hospitals to reduce the detection of asymptomatic bacteriuria. Half of the respondents reported using reflex urine cultures but with varied urinalysis criteria and perceived outcomes. Other diagnostic stewardship interventions for urine culture ordering and specimen quality were less common. PMID- 30522545 TI - Characterizing the Effects of Sex, APOE E4, and Literacy on Mid-life Cognitive Trajectories: Application of Information-Theoretic Model Averaging and Multi model Inference Techniques to the Wisconsin Registry for Alzheimer's Prevention Study. AB - OBJECTIVES: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline. METHODS: Here, we used longitudinal cognitive data from 1256 late-middle aged adults from the Wisconsin Registry for Alzheimer's Prevention study to examine the effects of sex, apolipoprotein E (APOE) E4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age. RESULTS: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (~40-70 years). CONCLUSIONS: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS, 2018, 00, 01 15). PMID- 30522546 TI - Orientation and verbal fluency in the English Longitudinal Study of Ageing: modifiable risk factors for falls? AB - : ABSTRACTObjectives:To determine the relationship between falls and deficits in specific cognitive domains in older adults. DESIGN: An analysis of the English Longitudinal Study of Ageing (ELSA) cohort. SETTING: United Kingdom community based. PARTICIPANTS: 5197 community-dwelling older adults recruited to a prospective longitudinal cohort study. MEASUREMENTS: Data on the occurrence of falls and number of falls, which occurred during a 12-month follow-up period, were assessed against the specific cognitive domains of memory, numeracy skills, and executive function. Binomial logistic regression was performed to evaluate the association between each cognitive domain and the dichotomous outcome of falls in the preceding 12 months using unadjusted and adjusted models. RESULTS: Of the 5197 participants included in the analysis, 1308 (25%) reported a fall in the preceding 12 months. There was no significant association between the occurrence of a fall and specific forms of cognitive dysfunction after adjusting for self-reported hearing, self-reported eyesight, and functional performance. After adjustment, only orientation (odds ratio [OR]: 0.80; 95% confidence intervals [CI]: 0.65-0.98, p = 0.03) and verbal fluency (adjusted OR: 0.98; 95% CI: 0.96-1.00; p = 0.05) remained significant for predicting recurrent falls. CONCLUSIONS: The cognitive phenotype rather than cognitive impairment per se may predict future falls in those presenting with more than one fall. PMID- 30522547 TI - Older Men's Definitions of Frailty - The Manitoba Follow-up Study. AB - : ABSTRACTBackground: There is little empirical research into lay definitions of frailty. OBJECTIVES: (1) To explore the definitions of frailty among older men, and (2) to explore if these definitions match commonly used clinical definitions of frailty. METHODS: Analysis of open-ended questions to survey data from a prospective cohort study of older airmen. The definitions of frailty were elicited, and grouped according to themes. RESULTS: 147 men responded (mean age: 93). There was considerable heterogeneity in older men's' definitions of frailty, and no theme of frailty was predominant. The most common theme was impairment in activities of daily living. Older men's' definition of frailty was not consistent with any commonly used medical theory of frailty. CONCLUSIONS: Most older men think frailty is important, but their definitions are not consistent. Frailty may be a heterogeneous experience, which different people experience differently. PMID- 30522548 TI - Understanding the factors influencing low-income caregivers' perceived value of a federal nutrition programme, the Special Supplemental Nutrition Program for Women, Infants and Children (WIC). AB - OBJECTIVE: Retention of participants has been an issue in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). It has been suggested that the perceived value of WIC may affect whether participants remain in the programme. The present study aimed to explore this phenomenon. DESIGN: Using a constructivist approach, thirty-one individual in-depth interviews were conducted. Transcripts were analysed using constant comparative analysis. Social, cultural and environmental factors that contribute to the value of WIC were explored as the phenomenon of interest. SETTING: Eight WIC clinics across the State of Illinois, USA.ParticipantsThirty-one caregivers of children enrolled in WIC for at least 6 months. RESULTS: Several factors influenced perceived value of WIC at the interpersonal (level of social support), clinic (value of WIC services v. programme administration issues), vendor (shopping difficulties), community and systems levels (other programme use, stigma and restrictions on food choice). Other themes existed along continua, which overlapped several levels (continuum of perceived need and perceived value of infant formula). CONCLUSIONS: Many caregivers value WIC, especially before their child turns 1 year old. Improvements are needed at the clinic, during shopping and within the food packages themselves in order to increase perceived value of WIC. PMID- 30522549 TI - Quality control of hospital preparations: Establishment of a simple and rapid method for quantifying ulinastatin in vaginal suppositories. AB - Ulinastatin vaginal suppositories, used to prevent threatened premature delivery, are frequently used in hospitals. However, there is no established method for quantifying ulinastatin contained in suppositories. Therefore, we investigated a simple and efficient method for quantifying ulinastatin contained in suppositories. Our analytical method involved removal of the base; optimising the enzyme inhibition reaction time and enzyme reaction time; and measuring the absorbance. The modified method was reproducible, operation time was significantly shortened, and cost was reduced to approximately 1/17 of that of the previously reported method. This simple and rapid quantitative method could contribute to the improvement of quality control of ulinastatin vaginal suppositories as an extemporaneous hospital preparation. PMID- 30522550 TI - Bioavailability of propylthiouracil from two formulation tablets. AB - Bioavailability studies were performed for 50 mg propylthiouracil tablets (Jelfa, Poland) versus 50 mg propycil tablets (Solvay, Germany). An open-label, two phase, crossover study was conducted with 15 healthy subjects. All subjects were randomly assigned a drug assignment number from I to XV, which was used throughout the experimental period. Dosing periods for both formulation tablets: Propylthiouracil, Jelfa vs. Propycil, Solvay were separated by at least 7 days washout period. Following single dose drug administration, venous blood samples were obtained at the required times for 12 h and the drug serum levels were determined by HPLC and used for PK analysis. PK parameters were calculated by the computer program TopFit 2.0. HPLC chromatograms show retention times for propylthiouracil and methylthiouracil (internal standard) of 5.97 and 2.75 min, respectively at 20 degrees C, providing adequate separation from each other and from endogenous serum components. Pharmacokinetic parameters for both tablets were not significantly different. Serum concentration-time profiles are superimposed for the above tablets according to an open one-compartment body model. EBA for Propythiouracil Jelfa tablets vs. Propycil tablets was 96.8%, and not significantly different. Some authors applied a two-compartment body model for the calculation of propylthiouracil pharmacokinetic parameters, which approach is not rational according to our data. PMID- 30522551 TI - GLP-1 attenuates Ang II-induced proliferation and migration in rat aorta smooth muscle cells via inhibition of the RhoA/ROCK2 signaling pathway. AB - Glucagon-like peptide 1 (GLP-1), a neuroendocrine hormone produced by the gastrointestinal tract, plays a significant role in blood glucose regulation; drugs derived from GLP-1 are currently used for the treatment of type 2 diabetes. In addition to regulating glucose homeostasis, the protective effects of GLP-1 on the cardiovascular system are also of interest. However, the vascular protective mechanisms of GLP-1 remain unclear. The present study was designed to evaluate the role of GLP-1 in the proliferation and migration of vascular smooth muscle cells, and the underlying mechanisms. In this study, proliferation, migration, cyclin D1 expression, and phosphorylation of MLC, as well as RhoA and Rho associated coiled-coil forming protein kinase 2 (ROCK2) expression, were increased in rat aorta smooth muscle cells (RASMCs) following incubation with angiotensin II (Ang II). These effects were significantly attenuated by GLP-1, forskolin (a cAMP activator) and Y-27632 (a ROCK2 inhibitor). However, H89 (a PKA inhibitor) inhibited the action of GLP-1, both in terms of inhibition of RASMC proliferation and migration, and RHOA/ROCK2 expression. These results indicate that GLP-1 inhibits Ang II-induced RASMC proliferation and migration via the cAMP/PKA/RhoA/ROCK2 signaling pathway. Our data suggest that GLP-1 should be considered for use in the clinical treatment of cardiovascular diseases, in addition to its current use in the treatment of diabetes mellitus. PMID- 30522552 TI - Functional expression of breast cancer resistance protein and cholesterol effect in human erythrocyte membranes. AB - In human erythrocyte membranes, various influx and efflux transporters are functionally expressed. However, their transport characteristics and modulation under disease states are not fully understood. In this study, we first examined the expression and detailed transport characteristics of breast cancer resistance protein (BCRP), an efflux ABC transporter, using inside-out membrane vesicles (IOVs) prepared from human erythrocytes, and then studied the effect of membrane cholesterol on BCRP function. The expression of BCRP was confirmed by western blotting; most of them being homodimers. The uptake of lucifer yellow (LY), a fluorescent BCRP substrate, into IOVs was time-, temperature-, and ATP-dependent, and the concentration of ATP which induced half-maximal stimulation of LY uptake was calculated to be 0.39 mM. The uptake of LY by IOVs was saturable with a Km value of 166 MUM, and was inhibited by various BCRP inhibitors and substrates, such as fumitremorgin C and mitoxantrone. When membrane cholesterol content was increased by treating IOVs with cholesteryl hemisuccinate, LY uptake decreased with increasing cholesterol content. These results suggest that transport activity of BCRP in human erythrocyte membranes may be suppressed under disease states, such as hypercholesterolemia, that increase membrane cholesterol content. PMID- 30522553 TI - The anti-apoptotic effect of nerve growth factor on propofol-induced neurotoxicity in hippocampal neurons is Rac1 dependent. AB - Propofol has been considered as a near-ideal anesthetic agent since its introduction 40 years ago. However, the side effects of propofol including bacterial contamination, hyperlipidemia, and neurotoxicity also aroused attention. Nerve growth factor (NGF) plays a pivotal role in the development, differentiation, and survival of the neurons of the peripheral and central nervous system. In the present study, we found that NGF alleviated the apoptosis induced by propofol in hippocampal neurons. Furthermore, NGF treatment augmented the protein abundance and mRNA level of Rac1 while silencing Rac1 significantly blunted the effects of NGF upon propofol-induced apoptosis. In conclusion, NGF decreased propofol-induced apoptosis and this effect was Rac1 dependent. PMID- 30522554 TI - Loss of miR-217 promotes osteosarcoma cell proliferation through targeting SETD8. AB - Recently, many kinds of microRNAs (miRNAs) have been found to play a critical role in progression of osteosarcoma (OS). miR-217 was reported to function as a tumor suppressor in a number of human cancers but its precise mechanism to exert the suppressive role remains to be investigated. In this study, we found that miR 217 was downregulated in OS tissues and its downregulation predicts poor overall survival of OS patients. Importantly, we found that a lower expressed miR-217 in OS cell lines inhibited the cell proliferation and invasion in vitro. By bioinformatic analysis, we found that miR-217 targeted the SET Domain-Containing Protein 8 (SETD8), and there was a negative correlation between them in OS tissues. Furthermore, we found that miR-217 abolished the stimulation effect of SETD8 on cell proliferation and invasion. Taken together, our data provide solid evidence that miR-217 functions as tumor suppressor in OS, and its tumor suppressive effect is exerted through interaction with SETD8. PMID- 30522555 TI - A cell-internalizing peptide endows tumstatin7 with enhanced antitumor properties. AB - Tumstatin7 (CNYYSNS) is an antitumor peptide derived from the NC1 domain of Type IV collagen that has been associated with tumor angiogenesis. In this work, we generated a peptide composed of tumstatin7 fused to TAT, a cell-internalizing peptide consisting of 11 amino acids. Tumstatin7-TAT was internalized by cells and triggered cell death. The new peptide was more potent in inducing B16F10 melanoma cell apoptosis in vitro than the shorter tumstatin7. Whereas tumstatin7 TAT significantly reduced tumor cell viability, tumstatin7 showed only weak effects even at the highest treatment concentration applied. Both tumstatin7-TAT and tumstatin7 inhibited cell migration in an in vitro wound healing model, and the former was more effective than the latter in inhibiting tumor growth in vivo. Combining the cell-internalizing property of TAT with the tumor-specific property of tumstatin7 may provide a useful adjunct to tumor therapy. PMID- 30522556 TI - Walnut oil promotes healing of wounds and skin defects in rats via regulating the NF-kB pathway. AB - The effects of walnut oil on wound healing and skin injury repair was observed in Sprague-Dawley (SD) rats, and mechanism of action was investigated. Normal SD rats were divided into an experimental group and a control group. Each group was observed at4 time points (day [D]3, D7, D14, and D21). In both groups, a skin wound was created on the back of the rats, with the spine as the central axis. In the experimental group, the wound was covered with walnut oil, and then bandaged and fixed with sterile gauze. In the control group, the wound was bandaged with vaseline gauze. At each corresponding time point, the wound area and wound healing time of each rat were examined. Epithelial cells of the wound tissues were observed using haematoxylin and eosin staining and immunohistochemical analysis,and the numbers of inflammatory cells and capillaries were counted. A western blot method was used to detect the expression of nuclear factor (NF) kappaB and epidermal growth factor (EGF) in the wound tissues of both groups. Meanwhile, enzyme-linked immunosorbent analysis (ELISA) was used to detect the expression of transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-1 in rat sera. A total of 48 SD rats completed the experiment. Healing time of residual wounds in the experimental group was 10.0+/-3.5 days, which was significantly shorter than that in the control group (18.0+/-6.0 days) (p<0.05). The wound healing rates in the experimental group were 54.14 % (D3) and 91.2 3% (D7), whereas those in the control group were 22.12% (D3) and 54.84% (D7 (p<0.05).Histological examinations revealed no epithelial cells on D3, D7, D14, and D21 in both the experimental and control groups. However, the number of inflammatory cells decreased significantly and the number of capillaries increased significantly in the experimental group compared to control (p<0.05). NF-kappaB expression was significantly lower, EGF expression significantly higher in the in the experimental group. Conversely, ELISA showed a significant increase in the expression of TGF-beta1 and MMP-1 in rat sera in the experimental group. So we conclude that walnut oil has significant effects in promoting the healing of skin defect wounds in SD rats. PMID- 30522557 TI - High glucose induces the apoptosis of HUVECs in mitochondria dependent manner by enhancing VDAC1 expression. AB - Mellithemia are diabetic patients' emblematic syndrome, which would induce vasculopathy resulting from apoptosis of vascular endothelial cells. The pathological mechanism of high glucose-induced apoptosis of vascular endothelial cells is investigated in the present study utilizing HUVEC cells. As high glucose induced apoptosis is caused by elevated mitochondrial permeability-mediated release of mitochondrial cytochrome c, voltage-dependent anion channel (VDAC1), the controller of mitochondrial permeability, and its regulator Bax were investigated. Our results suggest that upregulation of VDAC1 is the central event in high glucose-induced cell apoptosis, since silencing VDAC1 reduced high glucose-induced upregulation of mitochondrial/cellular Bax; thus silencing VDAC1 recovered the high glucose-reduced binding of Bax to VDAC1, which finally reduced the high mitochondrial permeability. Besides, high glucose increased VDAC1 expression by elevating the expression of SREBP1 and SREBP2, the tanscriptional factor of VDAC1. Those findings indicate that SREBP1 or SREBP2/VDAC1 could be novel targets for the prevention of diabetic vasculopathy. PMID- 30522558 TI - Retinoic acid increases the anticancer effect of paclitaxel by inducing differentiation of cancer stem cells in melanoma. AB - Malignant melanoma is a highly lethal disease, and advanced stages of melanoma have proven to be resistant to many chemotherapeutic drugs including temozolomide and paclitaxel. Cancer stem cells (CSCs) have been identified and isolated in different cancers including melanoma, and have been proven playing important role in the drug resistance. Retinoic acid (RA) is a promising anticancer agent, which can induce differentiation of CSCs. The main purpose of the present study was to evaluate the possible RA-induced differentiation of melanoma CSCs and sensitization of melanoma CSCs to paclitaxel. Our results show that CSCs of human melanoma A375 cells was more tolerant to paclitaxel than other non-CSCs melanoma cells. On the contrary, RA had stronger inhibitory effect on melanoma CSCs than on non-CSCs. At the same time, RA could arrest the cell cycle of CSCs and reduce the expression of Sox-2, Oct-4 in CSCs of melanoma, thereby induced the differentiation of CSCs and increased its sensitivity to paclitaxel. With this study we concluded that RA increases the anticancer effect of paclitaxel by inducing differentiation of cancer stem cells in melanoma, and the combined application of RA and paclitaxel may be more effective in the treatment of melanoma. PMID- 30522559 TI - Antiviral activity of propolis special extract GH 2002 against Varicella zoster virus in vitro. AB - Propolis is a generic name for a biological substance produced by bees used for multiple purposes in folk medicine. Propolis special extract GH 2002 is crude propolis highly purified by a special procedure and freed from the accompanying substances like pollen, wax, resins. The cytotoxic and antiherpetic effect of propolis extracts against Varicella zoster virus (VZV) was analysed in cell culture, and revealed a moderate cytotoxicity on lung fibroblasts with a CC50 of 380 MUg/ml. The 50 % inhibitory concentration (IC50) of GH 2002 propolis extract for VZV plaque formation was determined at 64 MUg/ml. The propolis extract exhibited high levels of antiviral activity against VZV in viral suspension tests, infectivity was significantly reduced by 93.9 % and a direct concentration dependent antiviral activity could be demonstrated. In order to determine the mode of virus suppression by propolis, the extract was added at different times during the viral infection cycle. Addition of propolis to uninfected cells (pretreatment cells) prior to infection or to infected cells (replication) during intracellular replication had no or only minor effect on virus multiplication. However, propolis exhibited high anti-VZV activity when viruses were pretreated with propolis prior to infection thus indicating an unspecific interaction between the virus and propolis. The antiviral activity is comparable to acyclovir. PMID- 30522560 TI - Applicability of hemodialysis clearance parameter for vancomycin therapeutic drug monitoring during continuous hemodiafiltration in an infant. AB - Cases requiring vancomycin administration planning in infants undergoing continuous hemodiafiltration (CHDF) are extremely rare. Here, we report a single case in which vancomycin therapeutic drug monitoring and administration planning were implemented for an infant requiring CHDF. The patient was diagnosed with wound infection after gastrostomy and enterotomy surgery and received vancomycin treatment for infection with methicillin-resistant Staphylococcus epidermidis. The vancomycin trough serum concentration was successfully controlled within the acceptable range. Additionally, we discuss the potential usefulness of applying the CHDF clearance parameter for the fine management of vancomycin serum concentration in a pediatric patient undergoing CHDF. PMID- 30522561 TI - Relationship between the administration of nicardipine hydrochloride and the development of delirium in patients on mechanical ventilation. AB - A history of hypertension is a known risk factor for delirium in patients in intensive care units, but the effect of antihypertensive agents on delirium development is unclear. Nicardipine, a calcium channel blocker, is widely used in ICU as a treatment agent for hypertensive emergency. This study investigated the relationship between the administration of nicardipine hydrochloride and delirium development in patients under mechanical ventilation. We conducted a medical chart review of 103 patients, who were divided into two groups according to the use of nicardipine hydrochloride. The prevalence of delirium was compared with respect to factors such as age, sex, laboratory data, and medical history, by multivariate analysis. 21 patients (20.4 %) were treated with nicardipine hydrochloride in 103 patients. The treatment and non-treatment groups differed significantly in age (72 vs. 65 years) and history of high blood pressure (57% vs. 11%). Multivariate analysis revealed that patients in the treatment group developed delirium significantly less often than those in the non-treatment group (19% vs. 48%). These results suggested that treatment of high blood pressure with nicardipine hydrochloride is a possible method for preventing the development of delirium. PMID- 30522562 TI - Adolescent Tobacco Uptake and Other Substance Use: A Latent Class Analysis. AB - Objective: The purpose of this study was to identify patterns of tobacco uptake and other substance use, from early to late adolescence. Methods: We used weighted latent class analysis, conducted separately for 7th, 9th, and 11th graders, to assess patterns of susceptibility, ever and current use of combustible tobacco and e-cigarettes, and other substance use (ie, current alcohol, binge drinking, and marijuana). Data were from Wave 3 of the Texas Adolescent Tobacco and Marketing Surveillance System (n = 2733; N = 461,069), collected in fall 2015. Multinomial regression was used to examine differences in class membership by demographic factors. Results: Two latent classes were identified in 7th grade, 3 classes in 9th grade, and 4 classes in 11th grade models. In each grade, classes included both a "no risk" and a "tobacco susceptible" class. For 9th grade, there was an additional "tobacco ever use" class, and 11th grade had the same additional class as well as an "all products use" class. Conclusion: Distinct patterns of polysubstance use emerged as grade level increased, supporting a stage-sequential model of onset and progression across developmental age groups. Future research can examine other factors affecting transitions across these stages. PMID- 30522563 TI - Gun Retailers' Willingness to Provide Gun Storage for Suicide Prevention. AB - Objectives: We examined factors grounded in the theory of planned behavior that influence gun retailers' willingness to provide temporary, voluntary firearm storage for suicide prevention. Methods: We conducted a cross-sectional survey of gun retailers in the US mountain west. Analyses included descriptive statistics and ordered logistic regression. Results: Ninety-five gun retailers responded to the survey (25% response rate) and 67.6% (95% CI: 59.6, 75.6) stated that they would be very or somewhat likely to provide temporary gun storage. Firearm retailers who agreed with the statements: "Our store can be an important part of the effort to improve gun safety in my community" (OR: 1.86, 95% CI: 1.1, 3.14) and that offering storage provided "The chance to be seen as a positive member of the community" (OR: 1.49, 95% CI: 1.00, 2.22) were more likely to state that they would be willing to provide storage. Conclusions: Firearm retailers are potentially important storage partners for means safety and suicide prevention efforts. Additional research and practice innovations are needed to assess gun retailers' willingness to provide gun storage and partner on suicide prevention efforts in other geographic regions. PMID- 30522564 TI - The Interrelationship between Race, Social Norms, and Dietary Behaviors among College-attending Women. AB - Objective: The association between social norms and dietary behaviors is well documented, but few studies examine the role of race. The aim of this study was to determine the interrelationships among race, social norms, and dietary behaviors. Methods: We used data from the Healthy Friends Network Study (a pilot study of women attending a southern university). Dietary behaviors, social norms, and self-identified race were obtained. Results: African Americans had lower odds of daily vegetable (OR = 0.55, 95% CI = 0.38-0.79) and fruit consumption (OR = 0.45, 95% CI = 0.30-0.67), but no race difference in frequent consumption of fatty/fried/salty/sugary foods was observed in fully adjusted models. Proximal descriptive norms were associated with all dietary behaviors, but distal injunctive social norms were associated with lower odds of frequent unhealthy food consumption (OR = 0.10, 95% CI = 0.05-0.21). Race differences in family descriptive norms were found to mediate race differences in vegetable and fruit consumption by 7%-9%. However, race differences in friend and family injunctive norms mediated 20%-50% of the effects of race on frequent unhealthy food consumption. Conclusions: Proximal injunctive norms account for race differences in unhealthy food consumption. Future studies should further explicate the mechanisms and seek to utilize social norms in behavior change interventions. PMID- 30522565 TI - Characterizing Alcohol Use Behaviors among Homeless Men and Women. AB - Objectives: In this study, we characterized alcohol use behaviors by sex among sheltered homeless adults and explored associations with health and readiness to change drinking behaviors. Methods: Participants (N = 581; 63.7% men; Mage = 43.6, 29.4% white) self-reported alcohol use and readiness to change drinking behaviors. Sex differences were analyzed via Wilcoxon ranksum, chi-square tests, logistic regression, and ANCOVAs. Results: Overall, 38.5% of the sample met criteria for current at-risk drinking, 39.7% self-reported a history of alcohol problems, and 22.9% reported having a formal alcohol use disorder (AUD) diagnosis. Among current alcohol users, 83.8% reported at-risk drinking. Men had more drinks per drinking day, more drinks per week, and more drinking days per week when compared to women. No sex differences were found for at-risk drinking, self-reported alcohol problems, probable alcohol abuse/dependence, AUD diagnosis, readiness to change drinking, or recent alcohol/substance abuse counseling. Conclusions: High rates of at-risk drinking were found among alcohol users. Homeless men and women did not exhibit differences in several manifestations of problematic alcohol use. Alcohol use interventions might be equally appealing to both sexes given equivalent readiness to change drinking; however, rates of recent treatment receipt were low. PMID- 30522566 TI - Increasing Home Smoking Restrictions Boosts Underserved Moms' Bioverified Quit Success. AB - Objectives: Standard smoking cessation treatments remain relatively ineffective in vulnerable populations. This study tested whether efforts to restrict residential smoking mediated the counseling treatment - smoking cessation association in a child tobacco smoke exposure (TSE) reduction trial. Methods: Maternal smokers (N = 300) with young children from low-income minority communities were randomized to counseling or standard care control to promote child TSE reduction. Secondary mediation analyses controlled for factors associated with smoking cessation. Results: Counseling group mothers were more likely than controls to increase home smoking restrictions (OR = 1.9, 95% CI 1.1 3.4) and quit smoking (OR = 11.0, 95% CI 6.3-19.2). As hypothesized, increasing home smoking restrictions improved likelihood of bioverified quit status at end of treatment (OR = 2.5, 95% CI 1.1-5.9) and partially mediated the association between counseling intervention and quit status. Conclusions: Results suggest that among maternal smokers known to experience increased challenges to quitting smoking, encouraging efforts to protect children from TSE by increasing home smoking restrictions may be an important counseling intervention element that facilitates smoking cessation. PMID- 30522567 TI - Factor Analysis Test of an Ecological Model of Physical Activity Correlates. AB - Objectives: The fit of measured variables into a social-ecological model of correlates of physical activity is rarely tested. In this study, we examined the factor structure of correlates of moderate/vigorous physical activity (MVPA) within a hypothesized social-ecological model. Methods: We measured 46 possible personal, social and environmental correlates of MVPA in 2779 adolescents participating in the Project EAT-2010 study. Confirmatory (CFA) and exploratory factor analyses (EFA) were used to determine the factor structure. Associations of factor scores with self-reported MVPA were calculated with linear regression. Results: A 6-factor CFA model did not show adequate fit. Eight factors were identified using EFA (Root Mean Square Error [RMSEA] 90% CI: 0.053 to 0.055; CFI = 0.82). A factor representing the mix of personal and social correlates showed the strongest association with MVPA. Conclusions: The 8-factor model supports independent clustering of possible environmental correlates of MVPA, but indicates that social and personal correlates may not cluster independently. The factor most strongly correlated with MVPA represented a mix of personal and social correlates. Future work will be needed to better understand how mechanisms for developing physical activity work within and across levels of the social ecological framework. PMID- 30522568 TI - Beliefs about E-cigarettes: A Focus Group Study with College Students. AB - Objectives: In this study, we consider how best to prevent recreational uptake of e-cigarettes among tobacco nonusers; it is important to investigate the underlying beliefs that young adults have about e-cigarettes and package elements. Methods: Using the focus group method of belief elicitation, we explore underlying belief structures that undergraduate students at a large Midwestern public university have about e-cigarettes. Beliefs are analyzed using the constantcomparative approach and categorized using the theory of planned behavior. Results: Participants describe a dual view, wherein e-cigarettes are a cool and causal item to use at a party, while holding a negative stigma toward everyday use. They acknowledged confusion over nicotine and focused on the flavors and smoke tricks as attractions to the product. In response to package elements, participants describe the flavors and modified risk statement as undermining the health warning. Conclusions: Findings suggest it may be useful to supplement the required warning labels with a public education campaign that improves understanding of nicotine and to regulate the amount of nicotine permissible in e-cigarettes in order to prevent addiction in recreational users, while at the same time supporting use of the product for smoking cessation. PMID- 30522569 TI - Electronic Cigarette Policy Recommendations: A Scoping Review. AB - Objective: There is a lack of consensus on whether e-cigarettes facilitate or threaten existing tobacco prevention strategies. This uncertainty is reflected in organizations' conflicting e-cigarette position statements. We conducted a scoping review of position statements in published and gray literature to map the range and frequency of e-cigarette use recommendations. Methods: We collected 81 statements from international health organizations. Two coders independently performed qualitative content analysis to categorize e-cigarette recommendations. We explored differences based on organization type, geography, and the year recommendations were published. Results: We identified 5 recommendation types: encourage smokers to use ecigarettes as a cessation aid or as an alternative source of nicotine (N = 5); support individuals who use e-cigarettes to quit smoking (N = 20); avoid using until more research is available (N = 19); restrict access based on available evidence (N = 30); and prohibit e-cigarette marketing and sale (N = 7). Conclusion: Organizations presented diverse e-cigarette use recommendations. The variation related to organizations' differing tobacco prevention priorities and level of confidence in current e-cigarette research. These differences may create confusion. Additional research can examine whether this variability influences stakeholders' attitudes or behavior. PMID- 30522570 TI - Chronic Health Condition Influences on Client Perceptions of Limited or Non choice Food Pantries in Low-income, Rural Communities. AB - Objectives: Food insecurity and diet-related chronic health conditions are interrelated problems in rural communities. The population facing such outcomes may rely on food pantries as a way to gain access to food. Many food pantries use a traditional distribution model that restricts choice. Yet, dietary recommendations and the need to economize food resources place many challenges on households. In this research, we sought to determine whether clients self reporting chronic health conditions in their households have unique perceptions about food pantries and their ability to meet needs. Methods: We surveyed clients (N = 612) of limited or non-choice rural pantries, each representing a unique household. We classified clients into 3 groups: no chronic condition; one chronic condition or more, but no diabetes; one chronic condition or more including diabetes. We compared group perceptions of pantries. Results: All conditions desired more choice, and more preference for certain food groups such as produce and dairy. Clients with chronic conditions and diabetes in their household had a greater percentage of negative comments about the choices offered and were less comfortable talking to volunteers. Conclusions: Rural pantries may serve clients with chronic health conditions by offering client choice and by engaging with them regarding needs and preferences. PMID- 30522571 TI - Application of the Transtheoretical Model to Physical Activity and Exercise Behaviors in African-American Adolescents. AB - Objectives: In this study, we examined the inter-relationships between Transtheoretical Model (TTM) constructs (stages of change, self-efficacy, decisional balance, processes of change) and determined the utility of TTM to predict physical activity in African-American youth. Methods: A community-based sample of 109 African-American youth (62% girls, age: 14.8 +/- 0.2 years) were included in this analysis. TTM constructs were assessed using the Patient Centered Assessment and Counseling for Exercise questionnaire. Moderate-to vigorous physical activity (MVPA) and total physical activity (TPA) were measured objectively using accelerometry. Results: Higher self-efficacy was observed at higher stages of change in both boys and girls (p = .02). Despite higher MVPA (p < .001) and TPA (p < .001) in boys, there were no sex differences in TTM constructs (p > .05). Stages of change predicted MVPA in girls, with those in the maintenance stage reporting significantly more MVPA compared to those in precontemplation/contemplation (p = .03) and preparation stages (p = .04). Cons predicted higher TPA in boys only (p = .02). Conclusions: These findings suggest specific TTM constructs relate to physical activity in African-American youth and the importance of these constructs may differ by sex. PMID- 30522572 TI - College Student Beliefs and Behavior Regarding Sharing When Smoking Hookahs. AB - Objectives: We examined college students' beliefs and behavior regarding sharing when smoking a hookah, a practice that may involve substantial risk of disease transmission. Methods: We carried out a cross-sectional Web-based survey of undergraduate ever users of hookah (N = 970) at a US university in 2007. Results: Hookah sharing started at initiation of hookah use. The first-time participants smoked hookah, 96.9% shared it, and 97.5% were with friends either in a hookah lounge (59.5%) or at a friend's home (30%). Participants shared a hookah when they first smoked it because sharing was acceptable with friends, family, or trusted others, normative etiquette, not problematic/harmful, cheaper, or the only smoking option. Participants did not use a mouth tip when they first smoked a hookah because it is not necessary with friends/family, there was no tip available, they were unaware of tips, or did not want to use one. Conclusions: Overwhelmingly, hookah sharing started at smoking initiation. Efforts are needed to create an environment in which sharing hookah practices are less acceptable such as increasing awareness of potential health risks of sharing, particularly among youth, and providing disposable hoses, disposable mouth tips, and proper hookah device cleaning practices in private and public hookah venues settings. PMID- 30522573 TI - Changes in Leisure Time Physical Activity Preferences and Hypertension Risk. AB - Objectives: In this study, we examined the association between changes in leisure time physical activity (LTPA) preference (the extent to which participants liked or disliked certain types of physical activity) and the incidence of hypertension; we also assessed whether the association differed between urban and rural China. Methods: Based on longitudinal data from 2687 Chinese adults between 2004 and 2011, we performed multivariate logistic regressions were to assess the aforementioned association. We conducted stratified analyses to examine the urban rural differences in this association. Results: The mean age was 40.0 (Standard Deviation = 12.5), and the mean BMI was 23.7 (Standard Deviation = 3.3). Adjusted estimates show that relative to respondents with no changes in LTPA preference, respondents who reduced preference were more likely to develop hypertension (OR = 1.92, 95% CI = 1.13-3.28). This association, however, was statistically significant among urban residents (OR = 2.19, 95% CI = 1.04-4.60), but not rural participants. Conclusions: Changes in LTPA preference and development of hypertension were significantly correlated, especially among urban Chinese. Hypertension prevention programs may identify the groups at elevated risk by examining levels and changes of LTPA preferences. PMID- 30522575 TI - Modeling the Mixed Effects of Living Standard and Consumer-oriented Behavior on Obesity. AB - Objective: This study investigates how daily consumer-oriented behaviors affect the prevalence of obesity in the older population in China. The demographic characteristics and living standard indicators are considered to capture the effects of various factors on obesity. Methods: This study employs the discrete choice regressions to investigate the associations among 18 influential covariates and obesity for aging adults in China in 2013. The multi-level nature of collected data is also considered by utilizing mixed-effects models. The data set, including 18,617 randomly chosen observations from the China Health and Retirement Longitudinal Survey 2013 is used in the regressions. Results: This study concerns the diversity of covariates representing the various daily consuming behaviors relating to the evolving living standard. A statistically significant association was found between the sedentary behavior and obesity for the aged people in China. The result also shows that aging women in China may have an increased propensity toward obesity compared to men. Conclusion: Daily consumer-oriented behaviors, including their influence on physical activity, can significantly reduce the risk of obesity; moreover, some sedentary behaviors, such as prolonged Internet use, likely will increase it. Important behaviors contributing to obesity are identified. PMID- 30522574 TI - A Cafeteria Personnel Intervention to Improve the School Food Environment. AB - Objective: In this study, we examined the impact of an intervention targeting food service personnel on Smarter Lunchroom adherence in school cafeterias. Methods: This study used a quasi-experimental design, conducted in a Virginia school district serving predominantly African-American children, all eligible for free meals. In 2014-15, cafeteria managers (N = 38) from 43 schools were trained (and tasked with training their staff) on principles of behavioral economics and choice architecture designed to enhance students' food selections via modifications to the cafeteria environment. Booster trainings were conducted in 2015-16. Cafeteria personnel completed post-intervention surveys; trained raters conducted objective cafeteria environment ratings, assessing adherence with Smarter Lunchroom principles, at baseline, post-intervention, and one-year follow up. Sales data also were examined. Results: Cafeteria personnel were satisfied (3.91 [of 5]+/-0.70) with the training and confident (4.18+/-0.52) in their ability to make changes. Overall adherence to Smarter Lunchroom principles increased 6.47% at post-intervention and 6.93% at follow-up (p = .001; partial eta2 = .21-.24), with a corresponding decrease in sugared-beverage sales at post intervention (p = .001). Conclusions: This environmental-level intervention focused on training cafeteria personnel was associated with increased adherence to Smarter Lunchroom principles, sustained over 2 years. Future research should investigate the impact of this intervention on students' dietary behaviors in a rigorously designed trial. PMID- 30522576 TI - Adolescent Depression: National Trends, Risk Factors, and Healthcare Disparities. AB - Objectives: This study examines national trends in the prevalence, risk factors, and treatment of depression among adolescents and investigate disparities in their mental health service use in the US. Methods: Data for adolescents aged 12 to 17 years (N = 95,856) who participated in the annual, cross-sectional National Survey on Drug Use and Health (NSDUH) from 2011 to 2016 were pooled and analyzed. Time trends and predictors of adolescents' depression and treatment were examined using Pearson's chi2 test and multivariable logistic regression. Results: The prevalence of adolescents' 12-month depression increased steadily from 8.3% to 12.9% over the years, but their use of mental health services remained largely stable. Higher rates of depression were observed in females, older adolescents, and those from single-mother households. Having less authoritative parents and negative school experiences significantly predicted adolescent depression. Lower rates of treatment and medication use were found among racial/ethnic minorities and adolescents without any insurance. Whereas having less authoritative parents decreased adolescents' likelihood of using healthcare services, negative school experiences significantly increased their chances of using treatments and medication. Conclusions: A growing number of adolescents with untreated depression were noted over time. Enhanced psychoeducation, continued policy efforts, and expanded service capacity are warranted. PMID- 30522577 TI - Motivating Inactive Seniors to Participate in Physical Activity: A Pilot RCT. AB - Objectives: We investigated the potential of social support in an adherence intervention to foster physical activity (PA) among sedentary older adults. Methods: We compared 2, 9-week intervention programs aimed at increasing PA levels in older persons. One program offered PA alone, whereas the other combined a PA program with a social adherence intervention (PASAI). The interventions involved 39 sedentary older adults living in senior congregate housing in Israel, each randomly assigned to an intervention program. Information about PA levels, self-efficacy, and social support for exercise was collected through personal interviews before, after, and at a one-month follow-up. At follow-up, participants were asked to report whether they remained in contact with other group members. Results: PASAI program participants showed significantly higher levels of PA compared to PA program participants. Both self-efficacy and social support were associated with changes in PA. In the PASAI program, 67% of participants remained in contact with other group members; by contrast, PA participants did not maintain any contact. Conclusion: Self-efficacy perception and on-going social support encourage adherence to PA. PMID- 30522578 TI - Grit is Associated with Food Security among US Parents and Adolescents. AB - Objectives: We investigated whether the Short Grit Scale (Grit-S) predicted odds of food insecurity (FI) among adults and their children. Methods: A cross sectional panel of parent-child dyads completed an online questionnaire. Eligible dyads included parents with household income below the 2015 median ($52,250 USD/year) and their self-selected household child between the ages of 13 to 17 years. An online questionnaire assessed: (1) FI using the 18-item Household Food Security Survey Module and the Food Security Survey Module for Youth; (2) perseverance and determination using the validated 8-item Grit-S; and (3) sociodemographic FI predictors. Logit regression models estimated the relationship between odds of FI and predictors among parents and children, separately. Results: Among 252 parents, 61.1% reported household FI. Parents' Grit-S score (N = 179) was associated with a significantly lower odds of household FI (OR= 0.4; 95%CI= 0.2, 0.8; p < .01) while adjusting for established predictors. Mean (+/-SD) Grit-S was 3.1 (+/-0.7). Children's Grit-S score (N = 178) was associated with a significantly lower odds of child FI (OR= 0.6; 95%CI= 0.4, 0.9; p < .05) while adjusting for established predictors. Conclusions: Perseverance and determination, also known as "grit," may be one further explanation for why some poor households are food secure. PMID- 30522579 TI - Financial Distress and Smoking-induced Deprivation in Smokers with Depression. AB - Objectives: Tobacco use may be related to financial strain in people with depression. This study explored the relationship among tobacco expenditures, financial distress, and smoking-induced deprivation (SID) in smokers with and without depression. Methods: Adult tobacco users in the United States (N = 234) completed a survey assessing depression (PHQ-8>=10), sociodemographics, tobacco use and spending, financial satisfaction and distress, and SID. Regression models controlling for income compared outcomes between participants with (N = 96) and without (N = 138) depression. Results: Participants with depression were 4 times more likely to report SID (32% vs 8%, p = .00). Smokers with depression had lower financial satisfaction, greater worry about being able to meet monthly living expenses, higher frequency of being unable to afford a leisure activity, higher frequency living paycheck to paycheck, and lower confidence in finding money for an emergency (p < .01). In smokers with depression, higher tobacco expenditures were independently associated with greater odds of SID and higher levels of financial distress (p < .01). Conclusions: About one-third of smokers with depression forego essentials to pay for tobacco. Tobacco interventions may alleviate financial strain in people with depression. PMID- 30522580 TI - Needed Improvements in Diabetes Prevention and Management in Brazil. AB - INTRODUCTION: Diabetes mellitus is one of the most common chronic diseases worldwide and its prevalence continues to increase. Adherence to good health behaviors provides better control of the disease. This study analyzed trends in the prevalence of diabetes among Brazilian adults between 2006 and 2016 and compared the frequency of key health behaviors between people with and without diabetes. METHODS: We analyzed data from 572,437 Brazilian adults interviewed between 2006 and 2016 by using the Surveillance System of Risk and Protection Factors for Chronic Diseases by Telephone Survey (Vigitel). We used regression models to investigate significant trends in the prevalence of diabetes and differences in adherence to health behaviors between people with and without diabetes. RESULTS: The prevalence of diabetes increased significantly from 5.5% to 8.9% (P <.001), being higher among women, older adults, and those with less than a high school education. The greatest increase was observed among these groups with higher prevalence. People with diabetes had a lower frequency of risk behaviors and a higher frequency of protective behaviors when compared to people without diabetes. The greatest differences were observed in the consumption of soft drinks and sugar-sweetened beverages (9.5% vs 25.0%) and alcoholic beverages (9.0% vs 17.9%), and the smallest differences were related to regular consumption of fruits and vegetables (40.7% vs 34.0%) and meats with excess fat (24.3% vs 32.2%). People with diabetes reported less leisure-time physical activity (PRa, 0.92 [P < .001]) and less transport-related physical activity (PRa, 0.84 [P <.001]) than those without diabetes. CONCLUSION: Diabetes prevalence increased between 2006 and 2016. People with diabetes had better dietary habits than those without diabetes, but still had risk behaviors such as insufficient physical activity. PMID- 30522581 TI - Poverty and Cancer Disparities in Ohio. AB - INTRODUCTION: Poverty is associated with higher cancer rates, cancer risk factors such as tobacco use and obesity, and lack of access to cancer screening and treatment. This analysis examined differences in cancer outcomes and associated factors among the poorest counties and the most affluent counties in Ohio. METHODS: We compared cancer incidence and mortality rates and prevalence of selected cancer risk factors between the 12 poorest counties in Ohio and the 10 most affluent counties in Ohio from January 1, 2011, through December 31, 2015. We also compared stage at diagnosis of selected cancers and the health insurance and treatment status of people with cancer. RESULTS: The mortality rate for all cancers combined was 19% higher in the poorest counties (192.2 per 100,000) than in the most affluent counties (161.9 per 100,000). Cervical cancer and other smoking-related cancers had higher rates in the poorest counties, where they were more likely to be diagnosed at a late stage. The prevalence was significantly higher in Ohio's poorest counties for current tobacco smoking (25.6% vs 17.1%), obesity (32.7% vs 28.3%), and physical inactivity (29.7% vs 23.0%). Among people with cancer, a smaller percentage had private health insurance (42.9% vs 33.0%) and a greater percentage had no treatment (8.9% vs 10.4%) in the poorest counties. CONCLUSION: This study demonstrates disparities in cancer incidence, mortality, and stage, and differences in cancer risk factors, health insurance, and treatment status between Ohio's poorest and most affluent counties. This information may help to target public health interventions for the prevention, early detection, and control of cancer. PMID- 30522582 TI - Enhanced Enforcement of Laws to Reduce Alcohol Overservice Among Licensed Establishments in New Mexico, 2004-2008. AB - Limited information exists about the effectiveness of interventions to enforce laws prohibiting alcohol sales to intoxicated patrons in licensed establishments. New Mexico Behavioral Risk Factor Surveillance System data were used to evaluate an intervention on binge drinking intensity in licensed (eg, bars) versus unlicensed (eg, homes) locations. The proportion of binge drinkers in licensed locations who consumed 8 or more drinks on a binge drinking occasion decreased from 42.1% in 2004-2005 to 22.6% in 2007-2008 (adjusted odds ratio, 0.4; 95% confidence interval, 0.2-0.9), while the proportion in unlicensed locations was essentially unchanged. Enhanced enforcement of overservice laws may reduce excessive drinking in licensed establishments. PMID- 30522583 TI - Social Determinants of Health and What Mothers Say They Need and Want After Release From Jail. AB - Identifying the biopsychosocial needs of mothers who have been released from jail is critical to understanding the best ways to support their health and stability after release. In May through August 2014, we interviewed 15 mothers who had been released from an urban jail about their reentry experiences, and we analyzed transcripts for themes. Eight domains of community reentry emerged through analysis: behavioral health services, education, employment, housing, material resources, medical care, relationships with children, and social support. Participants defined barriers to successful reentry, which paralleled the social determinants of health, and shared suggestions that could be used to mitigate these barriers. PMID- 30522584 TI - Correlation Between Personal Health History and Depression Self-Care Practices and Depression Screening Among African Americans With Chronic Conditions. AB - Little is known about the influence of personal health history and depression self-care practices on screening for depression by health care providers among African Americans with chronic conditions. African Americans (N = 203) aged 18 years or older and living with at least one chronic health condition in a metropolitan city completed a 45-item community perceptions survey. The number of depression symptoms experienced per month was positively associated with screening for depression by a health care provider; perceived ability to identify depression symptoms was inversely associated with screening by a health care provider. Understanding patients' health history and self-care practices can initiate provision of information or support services to improve patient-provider communication about depression. PMID- 30522585 TI - Attitudes, Beliefs, and Cost-Related Medication Nonadherence Among Adults Aged 65 or Older With Chronic Diseases. AB - INTRODUCTION: Cost-related medication nonadherence (CRN) can negatively affect chronic disease prevention and management in an aging population. Limited data are available on the interacting influences among such factors as availability of financial resources, attitudes and beliefs of patients, and CRN. The objective of this study was to examine the causal paths among financial resource availability, patient attitudes and beliefs, and CRN. METHODS: We used a nationally representative sample (n = 4,818) from the 2015 National Health Interview Survey; selected respondents were aged 65 or older, had a diagnosis of hypertension or diabetes or both, and were prescribed medication for at least 1 of these conditions. We performed structural equation modeling to examine whether perceived medication affordability, access to health care, and patient satisfaction influenced the effects of financial resource availability on CRN (skipped doses, took less medicine, or delayed filling a prescription to save money). RESULTS: Six percent of respondents reported CRN in the previous 12 months. The model showed a good to fair fit, and all paths were significant (P < .05) except for age. The effects of financial resource availability on CRN was mediated through perceived medication affordability, access to health care, and patient satisfaction with health care services. CONCLUSION: This study suggests that patients' attitudes and beliefs can mediate the effects of financial resource availability on CRN. We call for senior-friendly public health interventions that can address these modifiable barriers to reduce CRN among older adults with chronic conditions. PMID- 30522586 TI - Resveratrol Limits Lipogenesis and Enhance Mitochondrial Activity in HepG2 Cells. AB - PURPOSE: The aim of this study was to evaluate the effect of resveratrol on de novo lipogenesis in HepG2 cells caused by high glucose concentrations. Increased lipogenesis in the liver is the main reason for the development of nonalcoholic fatty liver disease (NAFLD) - currently one of the most common chronic liver diseases. In developed countries, this disease is mostly associated with nutritional disorders, resulting from the increasing consumption of monosaccharides. Resveratrol is a natural polyphenol with a promising potential for NAFLD treatment. METHODS: The steatosis of HepG2 cells was visualized using the intracellular lipid staining by Nile Red dye with a fluorescence microscope. This study also evaluated the effect of resveratrol on the mitochondrial activity (MitoTracker Green staining), dsDNA (Hoechst 33342 staining) and the viability of HepG2 cells treated with high glucose concentrations (25 and 33 mM). RESULTS: Current study showed that high glucose concentrations induced fat-overloading in HepG2 cells (microvacuolar steatosis occurred in most of the cells). Resveratrol (20 MUM) limits the steatosis induction in HepG2 cells by glucose and increased the mitochondrial activity of cells. Resveratrol did not affect the viability of HepG2 cells. CONCLUSION: This beneficial effect could be helpful in the treatment of NAFLD. PMID- 30522587 TI - Identifying Women With a History of a Hypertensive Disorder of Pregnancy: Values, Challenges, and Opportunities. PMID- 30522588 TI - Addressing the Needs of International Patients at End of Life in a Tertiary Care Medical Center. PMID- 30522589 TI - The Impact of Mediators of Health Literacy on Clinical Outcomes in Cardiovascular Diseases. PMID- 30522590 TI - Current, Emerging, and Anticipated Therapies for Sickle Cell Disease. PMID- 30522591 TI - Electronic Algorithm Is Superior to Hospital Discharge Codes for Diagnoses of Hypertensive Disorders of Pregnancy in Historical Cohorts. AB - OBJECTIVES: To develop and validate criteria for the retrospective diagnoses of hypertensive disorders of pregnancy that would be amenable to the development of an electronic algorithm, and to compare the accuracy of diagnoses based on both the algorithm and diagnostic codes with the gold standard, of physician-made diagnoses based on a detailed review of medical records using accepted clinical criteria. PATIENTS AND METHODS: An algorithm for hypertensive disorders of pregnancy was developed by first defining a set of criteria for retrospective diagnoses, which included relevant clinical variables and diagnosis of hypertension that required blood pressure elevations in greater than 50% of readings ("the 50% rule"). The algorithm was validated using the Rochester Epidemiology Project (Rochester, Minnesota). A stratified random sample of pregnancies and deliveries between January 1, 1976, and December 31, 1982, with the algorithm-based diagnoses was generated for review and physician-made diagnoses (normotensive, gestational hypertension, and preeclampsia), which served as the gold standard; the targeted cohort size for analysis was 25 per diagnosis category according to the gold standard. Agreements between (1) algorithm-based diagnoses and (2) diagnostic codes and the gold standard were analyzed. RESULTS: Sensitivities of the algorithm for 25 normotensive pregnancies, 25 with gestational hypertension, and 25 with preeclampsia were 100%, 88%, and 100%, respectively, and specificities were 94%, 100%, and 100%, respectively. Diagnostic code sensitivities were 96% for normotensive pregnancies, 32% for gestational hypertension, and 96% for preeclampsia, and specificities were 78%, 96%, and 88%, respectively. CONCLUSION: The electronic diagnostic algorithm was highly sensitive and specific in identifying and classifying hypertensive disorders of pregnancy and was superior to diagnostic codes. PMID- 30522592 TI - End-of-Life Care for Seriously Ill International Patients at a Global Destination Medical Center. AB - OBJECTIVE: To characterize the end-of-life care of all international patients who died at a global destination medical center from January 1, 2005, through December 31, 2015. PATIENTS AND METHODS: We performed a retrospective review of all adult international patients who died at a global destination medical center from January 1, 2005, through December 31, 2015. RESULTS: Eighty-two international patients from 25 countries and 5 continents died during the study period (median age, 59.5 years; 59% male). Of the study cohort, 11% (n=9) completed an advance directive, 61% (n=50) died in the intensive care unit, 26% (n=21) had a full code order at the time of death, and 73% (n=19 of 26) receiving cardiopulmonary resuscitation did not survive the resuscitation process. CONCLUSION: Seriously ill international patients who travel to receive health care in the United States face many barriers to receiving high-quality end-of life care. Seriously ill international patients are coming to the United States in increasing numbers, and little is known about their end-of-life care. There are many unique needs in the care of this complex patient population, and further research is needed to understand how to provide high-quality end-of-life care to these patients. PMID- 30522593 TI - Time Trends in Outcomes After Aneurysmal Subarachnoid Hemorrhage Over the Past 30 Years. AB - OBJECTIVE: To analyze trends in mortality rates, functional outcomes, and treatment in patients with aneurysmal subarachnoid hemorrhage (aSAH) over the past 3 decades. PATIENTS AND METHODS: We conducted a retrospective review of consecutive patients with aSAH treated at Mayo Clinic in Rochester, Minnesota, between January 1, 1985, and December 31, 2014. RESULTS: A total of 1173 patients identified were grouped by decade of treatment: 1985 to 1994, n=274; 1995 to 2004, n=461; and 2005 to 2014, n=438. Overall, the use of endovascular techniques increased progressively from 5.1% (14) in 1985 to 1994 to 65.5% (287) in 2005 to 2014. This corresponded to a progressive decrease in the rate of clipping from 78.8% (216) in 1985 to 2004 to 21.5% (94) in 2005 to 2014 (P<.001). The percentage of patients admitted with poor clinical grade also increased from 22.3% (61) in 1985 to 1994 to 24.1% (111) in 1995 to 2004 and 29.5% (129) in 2005 to 2014 (P=.06). The in-hospital mortality rate decreased from 22.6% (62) in 1985 to 1994 to 16.3% (75) in 1995 to 2004 and remained relatively constant at 16.7% (73) in 2005 to 2014. Good functional outcome at 3- to 6-month follow-up improved significantly from 64.8% (173) in 1985 to 1994 to 72% (332) in 1995 to 2004 and 78.8% (345) in 2005 to 2014 (P<.001). CONCLUSION: Outcomes in patients with aSAH have markedly improved over the past 3 decades, in terms of both in-hospital survival and functional recovery of survivors. Higher rates of endovascular coiling over time paralleled these improvements in clinical outcomes. More detailed investigation is necessary to determine whether this or other factors may directly explain the favorable trends in survival and functional recovery over time. PMID- 30522594 TI - New-Onset Diabetes and Preexisting Diabetes Are Associated With Comparable Reduction in Long-Term Survival After Liver Transplant: A Machine Learning Approach. AB - OBJECTIVE: To identify key predictors and survival outcomes of new-onset diabetes after transplant (NODAT) in liver transplant (LT) recipients by using the Scientific Registry of Transplant Recipients. PATIENTS AND METHODS: Data of all adult LT recipients between October 1, 1987, and March 31, 2016, were analyzed using various machine learning methods. These data were divided into training (70%) and validation (30%) data sets to robustly determine predictors of NODAT. The long-term survival of patients with NODAT relative to transplant recipients with preexisting diabetes and those without diabetes was assessed. RESULTS: Increasing age (odds ratio [OR], 1.01; 95% CI, 1.00-1.02; P<=.001), male sex (OR, 1.09; 95% CI, 1.05-1.13; P=.03), and obesity (OR, 1.13; 95% CI, 1.08-1.18; P<.001) were significantly associated with NODAT. Sirolimus as a primary immunosuppressant carried a 33% higher risk of NODAT than did tacrolimus (OR, 1.33; 95% CI, 1.22-1.45; P<.001) at 1 year after LT. Patients with NODAT had significantly decreased 10-year survival than did those without diabetes (63.0% vs 74.9%; P<.001), similar to survival in patients with diabetes before LT (58.9%). CONCLUSION: Using a machine learning approach, we found that older, male, and obese recipients are at especially higher risk of NODAT. Donor features do not affect risk. In addition, sirolimus-based immunosuppression is associated with a significantly higher risk of NODAT than other immunosuppressants. Most importantly, NODAT adversely affects long-term survival after LT in a manner similar to preexisting diabetes, indicating the need for more aggressive care and closer follow-up. PMID- 30522595 TI - Medical Cannabis. AB - Medicolegal realities surrounding "medical marijuana" or "medical cannabis" are rapidly evolving in the United States. Clinicians are increasingly being asked by patients to share information about or certify them for medical cannabis. In order to engage in informed discussions with patients or be comfortable certifying them in states with medical cannabis laws, clinicians may benefit from an understanding of the current state of medical knowledge about medical cannabis. Intended for the generalist and subspecialist, this review provides an overview of the legal status, pharmacology, benefits, risks, and abuse liability of medical cannabis along with a general framework for counseling patients. PMID- 30522596 TI - Management Options for Irritable Bowel Syndrome. AB - Irritable bowel syndrome (IBS) is associated with diverse pathophysiologic mechanisms. These mechanisms include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, and superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal up-regulation, and activation of secretory processes in the epithelial layer. Novel approaches to treatment include lifestyle modification, changes in diet, probiotics, and pharmacotherapy directed to the motility, sensation, and intraluminal milieu of patients with IBS. Despite recent advances, there is a need for development of new treatments to relieve pain in IBS without deleterious central or other adverse effects. PMID- 30522597 TI - Validity of Mobile-Based Technology vs Direct Observation in Measuring Number of Steps and Distance Walked in 6 Minutes. PMID- 30522599 TI - Correction. PMID- 30522598 TI - Association Between Pancreatic Cancer and Dipeptidyl Peptidase-4 Inhibitors Use in a Case-Control Study. PMID- 30522600 TI - Solitary Fibrous Tumor: A Giant Pleural Mass. PMID- 30522601 TI - Intracholecystic Papillary-Tubular Neoplasm of the Gallbladder. PMID- 30522602 TI - Immaculate Conception of Los Venerables by Bartolome Estaban Murillo. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 30522603 TI - Understanding the Role of Obesity Trajectories in the Development of Left Ventricular Dysfunction: Another Step on the Path to Heart Failure Screening? PMID- 30522604 TI - The Mechanics of Machine Learning: From a Concept to Value. PMID- 30522605 TI - Directional Doppler in Cardiology: A 50-Year Journey. AB - In 1968, while cardiologists were focused on cardiac structures imaged by ultrasound, Daniel Kalmanson in Paris, France, devised a new ultrasonic modality, directional continuous-wave Doppler, enabling him to record instantaneous cardiovascular blood flow velocities with recognition of their direction (relative to the transducer) in vessels. An innovative presentation of Doppler data also made velocity traces physiologically understandable. Following the noninvasive study of the arterial and venous beds, flow velocity in the right (1969) and left (1970) cardiac chambers was studied by means of a directional Doppler catheter. The curtain was then raised for the renewal of our pathophysiologic understanding of cardiac dynamics and the adoption of a new methodology. Technological evolution paved the way for clever researchers to pioneer important advances, diversifying the technique. Guided by the early principles, which are still valid in 2018, directional Doppler finally gained acceptance from the entire scientific community. PMID- 30522606 TI - Pulsed Doppler Echocardiography: An Historical Perspective. AB - Over the past six decades, echocardiography has evolved into an important technique for not only imaging cardiac structures, but also, by employing the Doppler equation, for assessing cardiac blood flow and tissue velocities. This review focuses on pulsed Doppler echocardiography: its principles, early development, and clinical applications. Important clinical applications include: (1) measurement of flow velocities, stroke volumes, and regurgitant and shunt volumes; (2) assessment of time intervals, e.g., pulmonary artery acceleration time as a measure of pulmonary artery pressure and resistance or the timing of mitral regurgitation in hypertrophic cardiomyopathy; (3) detection of turbulent flow in regurgitation, stenoses, and shunts, enhanced by the implementation of color Doppler; and (4) evaluation of left ventricular diastolic function in conjunction with pulsed tissue Doppler and deformation (strain) measurements. PMID- 30522608 TI - Tales from the Swamp: Influencing Legislation That Influences Our Practice. PMID- 30522607 TI - Radiation Exposure of Cardiac Sonographers. PMID- 30522609 TI - Echocardiography's Role in Cardio-Oncology. PMID- 30522610 TI - Working to take the PCHD Community to New Heights. PMID- 30522611 TI - Can sputum microscopy be replaced? PMID- 30522612 TI - Tuberculosis and HIV co-infection; the deadly duos in vulva. AB - Human Immunodeficiency Virus induced immune suppression leads the way for various infections with tuberculosis being the most common. Tuberculosis of the vulva is an extremely rare entity and is seen in only 1-2% of genital TB with increased risk in HIV co-infection. The co-infection places an immense burden on health care systems and poses particular diagnostic & therapeutic challenges with high mortality and morbidity. We present, here, a rare case of a 47 years postmenopausal female, who presented with itchy ulcerating lesions in the vulva with diagnostic dilemma turned to be vulval tuberculosis and during investigations, was found to be co-infected with HIV. The early diagnosis of TB and HIV in atypical looking lesions of vulva with high index of suspicion could lead to improved outcome. PMID- 30522613 TI - Tuberculosis infection control measures at health care facilities offering HIV and tuberculosis services in India: A baseline assessment. AB - BACKGROUND: Tuberculosis (TB) is one of world's oldest infectious disease and ranks alongside HIV as leading infectious killer. Tuberculosis infection control especially in HIV and TB care facilities has warranted attention after the recent health care-associated outbreaks in South Africa. The aim of this study was to describe the tuberculosis infection control measures implemented by HIV and TB care facilities in five high HIV burden provinces in India. METHODS: Baseline assessment of 30 high burden Antiretroviral centers and TB facilities was conducted during Oct 2015-Dec 2015 by AIC trained staff using a structured format. RESULTS: Thirty HIV and TB care facilities in five high HIV burden provinces were enrolled. Facility infrastructure and airborne infection control practices were highly varied between facilities. TB screening and fast tracking at ART centers is happening at majority of centers however inadequate TB infection control training, poor compliance to administrative and personal protective measures and lack of mechanism for health care workers surveillance need attention. CONCLUSIONS: Local specific TB infection control interventions to be designed and implemented at HIV and TB care facilities including implementation of administrative, environmental and use of personal protective equipment's with the training of staff members. Health care workers surveillance needs to be prioritized considering the rising instances of tuberculosis among Health care workers. PMID- 30522615 TI - A cross sectional study to assess the Tuberculosis Treatment Providers in the mid hills of India. AB - BACKGROUND: A high level of knowledge about Tuberculosis amongst the Multi Purpose Workers (MPWs) is the cornerstone for the successful implementation of Directly Observed Treatment Short-course (DOTS) strategy under the Revised National Tuberculosis control Programme of India. In this regard, the evaluation of MPWs, the major workforce of the Health Department of Solan district, has never been done in the past. Hence the present study was undertaken. METHODS: Objective: To evaluate the knowledge about Tuberculosis among the MPW DOT and non DOT Providers. DESIGN: A cross sectional study amongst 174MPWs of the five Tubercular Units was conducted. Informed written consent was obtained. A pretested self-administered questionnaire was used. Data was analyzed in Microsoft Excel 2010 and IBM SPSS statistics version 21 software. RESULTS: 85.6 per cent of the study participants were or had been DOT Providers. Only 9.2 per cent of the workers had received RNTCP Modular training whereas, 87.4 per cent had received just the 'On the Spot training' about DOTS. The difference in knowledge by Gender distribution across the five TUs was found significant. CONCLUSION: There is inadequate knowledge of tuberculosis amongst the MPW DOT and Non DOT Providers. Hence regular Modular and refresher trainings are recommended. PMID- 30522614 TI - Prevalence of allergic bronchopulmonary aspergillosis in asthmatic patients: A prospective institutional study. AB - BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an allergic inflammatory response to colonization by Aspergillus species, most commonly Aspergillus fumigatus. AIM: To study the prevalence of ABPA in asthmatic patients presenting to our institute. MATERIALS AND METHODS: All consecutive asthma patients attending our allergy clinic Out Patient Department (OPD) over a period of 20 months were tested with skin prick test (SPT) for Aspergillus antigens and those who were found positive were further evaluated for ABPA using Greenberger's criteria. RESULTS: Seventy consecutive asthmatic patients were screened by SPT using Aspergillus antigens. Thirteen patients (18.57%) were found to be SPT positive, out of which nine patients (12.9%) were diagnosed as having ABPA using Greenberger's criteria. ABPA was common among 25-35 age group with no gender predilection. ABPA patients had longer duration of illness, predominantly mixed pattern in PFT, higher mean absolute eosinophil count (AEC) and serum total IgE compared to non-ABPA asthmatic patients. Specific IgE for A. fumigatus was positive in all ABPA patients and serum precipitins were positive in seven patients (77.58%). Chest X-ray abnormalities were seen in five patients (55.6%) and HRCT showed central bronchiectasis in eight patients (88.9%) with varying other radiological features. None were sputum fungal culture positive and five patients (55.6%) have been misdiagnosed as pulmonary tuberculosis in the past. CONCLUSION: The prevalence of ABPA is significantly higher in bronchial asthma patients presenting to tertiary care centers and hence awareness is required among physicians for early diagnosis and management of ABPA to achieve better asthma control and to avoid permanent lung damage. PMID- 30522616 TI - The clinical utility of cycle of threshold value of GeneXpert MTB/RIF (CBNAAT) and its diagnostic accuracy in pulmonary and extra-pulmonary samples at a tertiary care center in India. AB - BACKGROUND: There are knowledge gaps in the in-depth analysis of the most promising and robust diagnostic tool, GeneXpert MTB/RIF (CBNAAT). The cycle of threshold (CT) value of the CBNAAT test and its clinical implications has not been explored much. AIMS AND OBJECTIVES: The study aimed at (a) estimating the diagnostic accuracy and incremental yield of Xpert MTB/RIF in various specimens (b) establishing the association between CT value category (high, medium, low, very low) and culture time-to-positivity (TTP). METHODS: A total of 1000 samples, both pulmonary and extra-pulmonary were collected from presumptive TB cases in a large tertiary care hospital. Sensitivity and specificity of CBNAAT was calculated with culture as the gold standard. The association of CT value with culture TTP was also studied. RESULTS: The overall sensitivity of CBNAAT was 88.5%, with bronchial washing specimen being the most sensitive (92.3%) and pleural fluid being the least (66.7%). In smear negative individuals, the sensitivity of CBNAAT was 80.9%. The additional yield of CBNAAT over smear microscopy was 10.9%. It was observed that as we move from high to very low CT category, culture positivity decreases significantly (p<0.001), whereas time taken for culture growth increases (p<0.001). CONCLUSION: CBNAAT is a robust test for accurate diagnosis of tuberculosis both pulmonary and extra-pulmonary, smear negative as well, especially in resource-limited settings. The correlation between CT value and culture TTP has potential in predicting bacillary load, though further studies are required. PMID- 30522617 TI - Delineating the factors associated with recurrence of tuberculosis in programmatic settings of rural health block, Himachal Pradesh, India. AB - BACKGROUND: Tuberculosis (TB) recurrence observed to be an important event in its treatment and has future implications under national TB control efforts. The present study was carried out to assess the recurrence rate along with its risk factors among patients undergoing treatment for TB under Revised National TB Control Program (RNTCP). MATERIAL AND METHODS: Total 204 patients in health block of district Una, Himachal Pradesh were studied using pretested structured interviewer-administered questionnaire. Along with univariate a non-hierarchal multi-way frequency analysis (MFA) was done to study the one and multi-way effects between the discrete variables included in a hypothesized model. The variables were under-nutrition, pulmonary TB, injecting drug use (IDU), multi drug resistant (MDR) TB, and past TB (recurrent cases). RESULTS: Total 29 cases (14.2%) had recurrence (17.7/100,000 population) with significantly high fraction for alternate residence (Recurrent: 50.0%, Non-recurrent: 47.4%; p = 0.001), Multi-drug resistance (MDR) TB (Recurrent: 13.8%, Non-recurrent: 2.3%; p = 0.003), and sputum negative patients (Recurrent: 51.7%, Non-recurrent: 14.5%; p = 0.000). Non-recurrent cases had significantly high fraction for sputum positive cases (Recurrent: 48.3%, Non-recurrent: 72.1%; p = 0.011), and extra-pulmonary TB (Recurrent: 00.0%, Non-recurrent: 13.4%; p = 0.036). MFA observed all significant one-way effects. Significant two-way effects were IDU and pulmonary TB (p = 0.001), MDR and past TB (p = 0.004), IDU and past TB (p = 0.019), and IDU and MDR TB (p = 0.039). CONCLUSION: Proportion of TB recurrence was expected with a significant difference between the history of change of residence, MDR-TB, pulmonary and extra-pulmonary nature of the disease. Hypothesized model observed with a significant association of IDU, pulmonary TB, MDR-TB and past TB. PMID- 30522618 TI - Treatment seeking pathways in pediatric tuberculosis patients attending DOTS centers in urban areas of Delhi. AB - BACKGROUND: The treatment seeking pathways prior to initiation of Direct Observed Treatment Short-course Therapy (DOTS), provides the extent of patient and health system delays among pediatric tuberculosis (TB) patients. OBJECTIVES: The study attempted to understand the treatment seeking pathways of pediatric TB patients under revised national tuberculosis control program (RNTCP). STUDY DESIGN AND SETTING: It was a prospective observational study carried out from January 2015 to December 2015. A predesigned, pretested and semi-structured questionnaire was used to interview 141 caregivers of pediatric patients (0-14 years) at two chest clinics selected purposively. RESULTS: Thirteen different treatment seeking pathways were identified and fever was the commonest symptom (41.8%) for seeking care from 1st health facility. Median time taken from onset of symptoms to first consultation varied from 1 to 144 weeks. More than half of the study subjects were first taken to a private practitioner (64.5%) followed by a pharmacist (19.1%) and trust in provider was the commonest reason for choosing the first care-provider in 52 (41.1%), followed by easy access or convenience in 49 (34.8%). CONCLUSION: A significant delay was found in treatment initiation of patients with extra pulmonary tuberculosis (EPTB), those belonging to lower socio economic class families, low literacy level of parents, who went to private facility first and availed more than three health facilities before diagnosis. PMID- 30522619 TI - Tuberculosis diagnostic and treatment practices in private sector: Implementation study in an Indian city. AB - SETTING: Implementation study in private health facilities in an Indian metropolis. OBJECTIVES: Improve Tuberculosis (TB) care by private practitioners (PPs). METHODS: PPs from a defined city area were imparted short training in TB care and linkages made with public facilities; subsequent practices were recorded. RESULTS: Of 364 presumptive TB patient records, 70 (19.3%) did not conform to its definition. Of the conforming, 174 (59.2%) had presumptive pulmonary TB (PTB), 53 (18%) presumptive extra-pulmonary (EPTB) and 67 (24%) had both. Of conforming presumptive PTB, most underwent Chest X-ray and sputum examination in private laboratories. Tissue based diagnostics were not advised for most presumptive EPTB patients. Of 101 cases diagnosed with TB, 82% were new, 23% known diabetic and 4.7% human immune deficiency virus (HIV) reactive out of 64 tested. Most were notified and initiated treatment within 15 days of diagnosis. One-fourth was prescribed standard treatment regimen and treatment was not directly observed for most. One third was initial defaulters or lost during treatment; 62% of PTB and 46% EPTB cases initiated on treatment in private were successfully treated. Of successfully treated PTB cases, 61% had undergone follow up sputum examination. CONCLUSION: Much intensified support mechanisms are needed to improve TB care in private sector. PMID- 30522620 TI - Time to sputum culture conversion and treatment outcome among the first cohort of multidrug resistant tuberculosis patients in a high burden country. AB - BACKGROUND: Sputum conversion considered the most important interim indicator of the efficacy of anti-tuberculosis treatment was assessed at varying time points among the first cohort of multidrug resistant tuberculosis (MDR-TB) patients in a National TB Control Programme. METHODS: A retrospective study was conducted for the period between 2010 and 2013, at the premiere MDR-TB treatment center in Nigeria. Genexpert, culture and drug susceptibility tests were carried out. Total duration of treatment was 20 months. RESULTS: A total of 115 patients were studied consisting of 76 (66.1%) males and 39 (33.9%) females with ages ranging between 15 and 65 years. Median time to sputum conversion was 2.06 months (95% confident interval [CI] = 1.82, 2.30). At the end of the first month, 43 (37.4%) patients sputum converted, increasing to 104 (90.4%) at the end of three months. There was no significant interaction with Human Immunodeficiency Virus (HIV) status. Overall treatment success was 69.4%. The default rate was 8.7% (10/115) and 25 (21.7%) deaths were recorded. CONCLUSION: The treatment success rate in the study was high with most of cases with or without HIV infection, achieving sputum culture conversion within 2 months of commencing treatment. Expansion of MDR-TB treatment services is necessary to reduce the death rate. PMID- 30522621 TI - "Identification of Non-Tuberculous Mycobacterium by LPA (CM/AS) assay, HPLC and biochemical test: which is feasible for RNTCP?" AB - INTRODUCTION: Non-tuberculous mycobacteria (NTM) causing clinical disease have become increasingly common and more diverse. The development of fast, inexpensive, and reliable tests to identify nontuberculous mycobacteria is need of the hour especially under the Revised National TB Control Programme (RNTCP). The Aim of the study was to check the Diagnostic efficacy of the GenoType Mycobacterium CM/AS assay compared with HPLC and Biochemical Test for Identification of Non-Tuberculous Mycobacteria under the Revised Tuberculosis Control Programme. METHODS AND RESULT: It is a cross-sectional study, the suspected NTM culture isolates from the RNTCP accredited laboratories were sent to NRL for speciation and Identification. The culture positive isolates were subjected to Biochemical Identification Test, HPLC and LPA CM/AS. The LPA had 98.23% sensitivity, 50% specificity, 99.56% positive predictive value (PPV) and 20% Negative predictive value (NPV) when compared to HPLC considering Biochemical test as Gold reference standard. The comparison of HPLC and LPA for identification of each species using Mc Nemers Chi square test shown no significant difference between these tests. CONCLUSION: Considering Cost, Time and ease of performing the techniques, we recommend first do the basic biochemical test to rule out MTBC from NTM. Then do HPLC and further if results are unclear do LPA CM/AS kit for species confirmation. SIGNIFICANCE AND IMPACT OF STUDY: NTM are emerging as important causative agents of pulmonary and extra pulmonary disease, the ability to recognize disease caused by NTM and subsequently treat such disease has become increasingly important. The identification of NTM up to its species level using HPLC and LPA CM/AS should gain importance in all TB reference Laboratories. PMID- 30522622 TI - Potential of adjunctive Mycobacterium w (MIP) immunotherapy in reducing the duration of standard chemotherapy against tuberculosis. AB - INTRODUCTION: The need to shorten the treatment duration in tuberculosis has always been felt. Immunotherapy in combination with chemotherapy has been considered a promising approach for this purpose into tuberculosis. We studied the adjuvant immunotherapeutic activity of Mycobacterium indicus pranii (MIP or Mw) in combination with conventional chemotherapy using guinea pig of pulmonary tuberculosis infected with Mycobacterium tuberculosis H37Rv via aerosol. METHODS: Experimental animals treated with standard chemotherapy and immunotherapy (MIP) separately and in combination of both. Guinea pig lungs evaluated following infection and subsequent therapy at predefine time point. Various cytokine mRNA expressions levels were quantified by quantitative reverse transcriptase PCR at the 4th, 8th and 12th week post-infection of M. tuberculosis. RESULTS: We determined the time required for bacterial clearance from guinea pig lungs. Standard chemotherapy (RvCh) compared to the animals where chemotherapy plus Mw immunotherpay (RvChMwT) was given. It took 12 weeks to achieve bacterial clearance in the RvCh group while this was achieved in 8 weeks in RvChMwT group. Pro-inflammatory cytokines (IFN-gamma, IL-2, IL-12p35 and TNF-alpha) level were higher in RvCh, RvChMwT and RvMwT group, while the IL-10 and TGF-beta were suppressed. CONCLUSION: Cytokine expression level showed that Mw in conjunction with chemotherapy enhances the effect of pro-inflammatory cytokines (such as, IFN gamma, IL-2, IL-12 and TNF-alpha) and reduces the production and effect of anti inflammatory cytokines (like IL-10 and TGF-beta) thereby restoring the pro inflammatory / anti-inflammatory cytokines balance. Thus, the present study indicates that subject to rigorous testing by other parameters, Mw (MIP) as adjunct immunotherapy has potential for reducing treatment duration. PMID- 30522623 TI - Metformin associated inflammation levels regulation in type 2 diabetes mellitus tuberculosis coinfection patients - A case report. AB - IFN-gamma elevation is one of the indicators of successful treatment in active tuberculosis (TB) infection due to macrophage and Th-1 activation in inducing autophagy process. However, IL-10 also inhibits interferon-mediated mycobactericid activities by blocking IFN-gamma; signaling pathways in autophagy. Therefore, ratio IFN-gamma/IL-10 has to be greater than 1 (>1) then IFN-gamma remains has anti-mycobacterium. Metformin (MET) is a potent combination drug to elevate anti-TB efficacy and able to regulate inflammation. In this study, an observational clinical study was done in diabetes mellitus (DM)-TB co-infection outpatients at Surabaya Paru Hospital. This study evaluated how MET therapy; affected inflammation. MET was used at least 2 months, accompanying with insulin and; anti-TB and as comparison to non MET group. The result in this study MET increased both pro-inflammatory and anti-inflammatory cytokines, thus MET may consider as adjunct therapy in DM-TB coinfection patients due; to its ability in Th-1 and Th-2 immuno-regulating response, especially to enhance IFN-gamma; and to reduce insulin associated IL-10 upregulation. PMID- 30522624 TI - Concomitant methicillin-resistant Staphylococcus aureus infection in tubercular sacroiliitis masquerading as anti-tubercular drug resistance: Role for molecular diagnosis. AB - A 23-year-old female on anti-tubercular therapy for tuberculous sacroiliitis presented with right sided gluteal and thigh abscess. Suspecting treatment failure, surgical evacuation of purulent material was done. The bacteriological isolation showed positivity for methicillin-resistant Staphylococcus aureus. Although the microbiological and histopathology examination of the specimen were negative for tubercular isolates, the cartridge based -nucleic acid amplification tests revealed positive genes for Mycobacterium tuberculosis and additional primers showed sensitivity for rifampicin and isoniazid. She was adequately treated with vancomycin for six weeks and anti-tubercular drugs for eight months and followed till the bony ankyloses at 18 months. This is a rare case based scenario wherein concomitant staphylococcal infection in tubercular sacroiliitis masqueraded as anti-tubercular drug resistance. The cartridge-based nucleic acid amplification test for tuberculosis is a rapid and sensitive modality in identifying mycobacteria even mixed infections and also determine drug resistance. There are fewer consensuses in the literature regarding the drugs and duration of anti-tubercular regime for tuberculous sacroiliitis with most regimes using four drugs between six to eighteen months. PMID- 30522625 TI - Two unusual reports of urogenital tuberculosis: One 'putty' kidney and another in association with benign prostatic hyperplasia. AB - In India urogenital tuberculosis is the second commonest form of extra-pulmonary tuberculosis. Kidney is the highest and prostate is the least affected urogenital organ. But the extreme stage of renal tuberculosis named as 'putty' kidney is a rare manifestation. In general most cases of urogenital tuberculosis are quasi symptomatic, and therefore an uttermost apprehension is needed from physicians to intercept such cases at the earliest. In this presentation we describe a case of 'putty' kidney, and another incidental association of prostate tuberculosis with benign prostatic hyperplasia. PMID- 30522626 TI - What is the role of "T reg Cells" in tuberculosis pathogenesis? PMID- 30522628 TI - Editorial overview: Autoimmunity: A new frontier awaits. PMID- 30522627 TI - World AIDS Day 2018. PMID- 30522629 TI - Reprint of: Cardiovascular Health Promotion: An Issue That Can No Longer Wait. PMID- 30522630 TI - Reprint of: Cardiovascular Disease Prevention by Diet Modification: JACC Health Promotion Series. AB - Reduction in excess calories and improvement in dietary composition may prevent many primary and secondary cardiovascular events. Current guidelines recommend diets high in fruits, vegetables, whole grains, nuts, and legumes; moderate in low-fat dairy and seafood; and low in processed meats, sugar-sweetened beverages, refined grains, and sodium. Supplementation can be useful for some people but cannot replace a good diet. Factors that influence individuals to consume a low quality diet are myriad and include lack of knowledge, lack of availability, high cost, time scarcity, social and cultural norms, marketing of poor-quality foods, and palatability. Governments should focus on cardiovascular disease as a global threat and enact policies that will reach all levels of society and create a food environment wherein healthy foods are accessible, affordable, and desirable. Health professionals should be proficient in basic nutritional knowledge to promote a sustainable pattern of healthful eating for cardiovascular disease prevention for both healthy individuals and those at higher risk. PMID- 30522631 TI - Reprint of: Prevention and Treatment of Tobacco Use: JACC Health Promotion Series. AB - Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among youth and smoking cessation among established smokers are key for reducing smoking prevalence and the associated negative health consequences. Proven tobacco cessation treatment includes pharmacotherapy and behavioral support, which are most effective when provided together. First-line medications (varenicline, bupropion, and nicotine replacement) are effective and safe for patients with CVD. Clinicians who care for patients with CVD should give as high a priority to treating tobacco use as to managing other CVD risk factors. Broader tobacco control efforts to raise tobacco taxes, adopt smoke-free laws, conduct mass media campaigns, and restrict tobacco marketing enhance clinicians' actions working with individual smokers. PMID- 30522632 TI - Reprint of: Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. AB - People who maintain ideal cardiovascular heath have a low lifetime risk of cardiovascular disease. Therefore, encouraging people to achieve ideal cardiovascular health represents an important opportunity to improve the prevention of cardiovascular disease. However, preventing cardiovascular disease by promoting ideal cardiovascular health requires shifting the focus from treating disease after it develops to preventing cardiovascular events before they happen by slowing the progression of atherosclerosis. Because atherogenic lipoproteins play a central causal role in the initiation and progression of atherosclerosis, maintaining optimal lipid levels is necessary to achieve ideal cardiovascular health. This review describes the cumulative effect of lipid carrying lipoproteins on the risk of cardiovascular disease, estimates the magnitude of the clinical benefit that can be achieved by maintaining optimal lipid levels, identifies the most effective timing for implementing strategies designed to achieve optimal lipid levels, and provides a clinical pathway to help people achieve the lipid levels necessary for ideal cardiovascular health. PMID- 30522633 TI - Reprint of: Prevention and Control of Hypertension: JACC Health Promotion Series. AB - Hypertension, the leading risk factor for cardiovascular disease, originates from combined genetic, environmental, and social determinants. Environmental factors include overweight/obesity, unhealthy diet, excessive dietary sodium, inadequate dietary potassium, insufficient physical activity, and consumption of alcohol. Prevention and control of hypertension can be achieved through targeted and/or population-based strategies. For control of hypertension, the targeted strategy involves interventions to increase awareness, treatment, and control in individuals. Corresponding population-based strategies involve interventions designed to achieve a small reduction in blood pressure (BP) in the entire population. Having a usual source of care, optimizing adherence, and minimizing therapeutic inertia are associated with higher rates of BP control. The Chronic Care Model, a collaborative partnership among the patient, provider, and health system, incorporates a multilevel approach for control of hypertension. Optimizing the prevention, recognition, and care of hypertension requires a paradigm shift to team-based care and the use of strategies known to control BP. PMID- 30522634 TI - Reprint of: Positive Psychological Well-Being and Cardiovascular Disease: JACC Health Promotion Series. AB - Facets of positive psychological well-being, such as optimism, have been identified as positive health assets because they are prospectively associated with the 7 metrics of cardiovascular health (CVH) and improved outcomes related to cardiovascular disease. Connections between psychological well-being and cardiovascular conditions may be mediated through biological, behavioral, and psychosocial pathways. Individual-level interventions, such as mindfulness-based programs and positive psychological interventions, have shown promise for modifying psychological well-being. Further, workplaces are using well-being focused interventions to promote employee CVH, and these interventions represent a potential model for expanding psychological well-being programs to communities and societies. Given the relevance of psychological well-being to promoting CVH, this review outlines clinical recommendations to assess and promote well-being in encounters with patients. Finally, a research agenda is proposed. Additional prospective observational studies are needed to understand mechanisms underlying the connection between psychological well-being and cardiovascular outcomes. Moreover, rigorous intervention trials are needed to assess whether psychological well-being-promoting programs can improve cardiovascular outcomes. PMID- 30522635 TI - Reprint of: Healthy Weight and Obesity Prevention: JACC Health Promotion Series. AB - Overweight and obesity have reached epidemic levels in the United States and worldwide, and this has contributed to substantial cardiovascular and other health risks. However, controversy exists concerning the causes of obesity and effective modalities for its prevention and treatment. There is also controversy related to the concept of metabolically healthy obesity phenotype, the "obesity paradox," and on the importance of fitness to protect individuals who are overweight or obese from cardiovascular diseases. In this state-of-the-art review, the authors focus on "healthy weight" with the emphasis on the pathophysiologic effects of weight gain on the cardiovascular system; mechanistic/triggering factors; and the role of preventive actions through personal, education/environment, and societal/authoritative factors, as well as factors to provide guidance for caregivers of health promotion. Additionally, the authors briefly review metabolically healthy obesity, the obesity paradox, and issues beyond lifestyle consideration for weight loss with medications and bariatric surgery. PMID- 30522636 TI - Reprint of: Promoting Physical Activity and Exercise: JACC Health Promotion Series. AB - Physical inactivity is one of the leading modifiable risk factors for global mortality, with an estimated 20% to 30% increased risk of death compared with those who are physically active. The "behavior" of physical activity (PA) is multifactorial, including social, environmental, psychological, and genetic factors. Abundant scientific evidence has demonstrated that physically active people of all age groups and ethnicities have higher levels of cardiorespiratory fitness, health, and wellness, and a lower risk for developing several chronic medical illnesses, including cardiovascular disease, compared with those who are physically inactive. Although more intense and longer durations of PA correlate directly with improved outcomes, even small amounts of PA provide protective health benefits. In this state-of-the-art review, the authors focus on "healthy PA" with the emphasis on the pathophysiological effects of physical inactivity and PA on the cardiovascular system, mechanistic/triggering factors, the role of preventive actions through personal, education/environment, and societal/authoritative factors, as well as factors to provide guidance for caregivers of health promotion regarding PA. Sustainable and comprehensive programs to increase PA among all individuals need to be developed and implemented at local, regional, national, and international levels to effect positive changes and improve global health, especially the reduction of cardiovascular disease. PMID- 30522638 TI - Editorial. PMID- 30522637 TI - Reprint of: Blood Sugar Regulation for Cardiovascular Health Promotion and Disease Prevention: JACC Health Promotion Series. AB - The primary objective of this study was to analyze the most up-to-date evidence regarding whether and how blood sugar regulation influences cardiovascular health promotion and disease prevention by carrying out an umbrella review. Three separate, systematic literature searches identified 2,343 papers in total. Overall, 44 studies were included for data extraction and analysis. The included systematic reviews and meta-analyses published between January 1, 2016, and December 31, 2017, were of good to very good quality (median Overview Quality Assessment Questionnaire score = 17). Identified evidence suggests that cardiovascular disease (CVD) prevention services should consider regulation of blood glucose as a key target for intervention. Furthermore, the recommendations for effective intervention and service development/training described here for prevention of CVD should be adopted into evidence-based practice guidelines. Multidisciplinary teams should be formed to deliver multicomponent interventions in community-based settings. There may be substantial opportunities for integrating CVD and diabetes prevention services. PMID- 30522639 TI - 30 years of developmental haemostasis: what have we learnt and how are we applying this knowledge. PMID- 30522640 TI - The Last Hurrah. PMID- 30522641 TI - Bruce J. Hillman, MD, Founding Editor-in-Chief, Journal of the American College of Radiology 2004-2018. PMID- 30522642 TI - Re: "Reducing Variability of Radiation Dose in CT". PMID- 30522644 TI - Erratum. PMID- 30522643 TI - Author's Response. PMID- 30522645 TI - Left Main PCI With DES Versus CABG: Cautionary Note or Cause for Concern? PMID- 30522647 TI - Coronary Bypass Surgery for Diabetes and Multivessel Disease: Forget the SYNTAX. PMID- 30522646 TI - SYNTAX Score in Patients With Diabetes Undergoing Coronary Revascularization in the FREEDOM Trial. AB - BACKGROUND: Diabetes mellitus (DM) is associated with complex coronary artery disease (CAD), which in turn results in increased morbidity and mortality from cardiovascular disease. OBJECTIVES: This study sought to evaluate the utility of SYNTAX score (SS) for predicting future cardiovascular events in patients with DM and complex CAD undergoing either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). METHODS: The FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial randomized patients with DM and multivessel CAD to undergo either PCI with drug-eluting stents or CABG. The SS was calculated retrospectively by a core laboratory. The endpoint of hard cardiovascular events (HCE) was a composite of death from any cause, nonfatal myocardial infarction, and nonfatal stroke, while the endpoint of major adverse cardiac and cerebrovascular events (MACCE) was a composite of HCE and repeat revascularization. RESULTS: A total of 1,900 patients were randomized to PCI (n = 953) or CABG (n = 947). The SS was considered an independent predictor of 5-year MACCE (hazard ratio per unit of SS: 1.02; 95% confidence interval: 1.00 to 1.03; p = 0.014) and HCE (hazard ratio per unit of SS: 1.03; 95% confidence interval: 1.01 to 1.04; p = 0.002) in the PCI cohort, but not in the CABG group. There was a higher incidence of MACCE in PCI patients with low, intermediate, and high SS compared with those who underwent CABG (36.6% vs. 25.9%, p = 0.02; 43.9% vs. 26.8%, p < 0.001; 48.7% vs. 29.7%, p = 0.003, respectively). CONCLUSIONS: In DM patients with multivessel CAD, the complexity of CAD evaluated by the SS is an independent risk factor for MACCE and HCE only in patients undergoing PCI. The SS should not be utilized to guide the choice of coronary revascularization in patients with DM and multivessel CAD. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450). PMID- 30522648 TI - Invasive Functional Test in Patients With Angina and Suspected CAD: Search More to Learn More. PMID- 30522649 TI - Build the Wall of Evidence. PMID- 30522650 TI - Left Ventricular Dyssynchrony Predicts the Cardiomyopathy Associated With Premature Ventricular Contractions. AB - BACKGROUND: The pathophysiology of cardiomyopathy associated with premature ventricular contractions (PVCs) remains unclear. OBJECTIVES: This study prospectively explored cardiomyopathy development in a swine model of paced ectopic beats. METHODS: A total of 35 swine underwent pacemaker implantation. A group exposed to paced bigeminy from the right ventricular apex (RVA) for 14 weeks (RVA PVC) (n = 10) were compared with a group exposed to regular pacing from the RVA at 140 beats/min (RV-140) (n = 5) and a control group (n = 5). To test the role of ectopic beat dyssynchrony, further groups were exposed for 12 weeks to bigeminy from the right ventricular free wall (RVFW PVC) (n = 5), the left ventricular epicardium (LV Epi PVC) (n = 5) or the right atrium (premature atrial complex) (n = 5). RESULTS: After 14 weeks, the mean left ventricular ejection fraction (LVEF) was significantly lower in the RVA PVC group than in the RV-140 or control groups (p < 0.05). LVEF declined significantly in the LV Epi PVC (65.2 +/- 2.4% to 39.7 +/- 3.0%; p < 0.01) and RVFW PVC (66.1 +/- 2.6% to 48.6 +/- 2.7%; p < 0.01) groups, with final LVEF significantly lower and ventricular fibrosis significantly higher in the LV Epi PVC group compared with all others (p < 0.05). Protein levels of pRyR2, NCX-1, CaMKII-alpha, and PLN were up-regulated and levels of SERCA2a were down-regulated in the LV Epi PVC group compared with the control group (p < 0.05). Longer ectopic beat QRS duration and greater LV dyssynchrony were significantly associated with larger declines in LV systolic function. CONCLUSIONS: In a swine model of paced ectopic beats, PVC induced cardiomyopathy is phenotypically distinct from a tachycardia-induced cardiomyopathy. Cardiomyopathy severity is strongly associated with severity of the hemodynamic derangement associated with the paced ectopic beats, particularly the extent of LV dyssynchrony. PMID- 30522651 TI - Premature Ventricular Complex-Induced Cardiomyopathy: Providing Insights on the Pathogenesis. PMID- 30522652 TI - Medical Therapy for Long-Term Prevention of Atherothrombosis Following an Acute Coronary Syndrome: JACC State-of-the-Art Review. AB - Following an acute coronary syndrome (ACS), heightened predisposition to atherothrombotic events may persist for years. Advances in understanding the pathobiology that underlies this elevated risk furnish a mechanistic basis for devising long-term secondary prevention strategies. Recent progress in ACS pathophysiology has challenged the focus on single "vulnerable plaques" and shifted toward a more holistic consideration of the "vulnerable patient," thus highlighting the primacy of medical therapy in secondary prevention. Despite current guideline-directed medical therapy, a consistent proportion of post-ACS patients experience recurrent atherothrombosis due to unaddressed "residual risk": contemporary clinical trials underline the pivotal role of platelets, coagulation, cholesterol, and systemic inflammation and provide a perspective on a personalized, targeted approach. Emerging data sheds new light on heretofore unrecognized residual risk factors. This review aims to summarize evolving evidence relative to secondary prevention of atherothrombosis, with a focus on recent advances that promise to transform the management of the post-ACS patient. PMID- 30522653 TI - Arrhythmic Mitral Valve Prolapse: JACC Review Topic of the Week. AB - There is an increasing awareness of the association between mitral valve prolapse and sudden cardiac death. There are several clinical risk factors associated with an increased risk of mitral valve prolapse-related sudden cardiac death, most of which can be evaluated with noninvasive diagnostic modalities. For example, characteristic changes on the electrocardiogram (T-wave inversions in the inferior leads), complex ventricular ectopy, a spiked configuration of the lateral annular velocities by echocardiography, and evidence of myocardial fibrosis by cardiac magnetic resonance imaging have all been implicated as markers of risk. Herein, the authors review the reported incidence of sudden death to mitral valve prolapse, the clinical profile of at-risk patients, and the basic components necessary to initiate and perpetuate ventricular arrhythmias (substrate and trigger) as well as potential interventions to consider for those at highest risk. PMID- 30522654 TI - ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. AB - Dual antiplatelet therapy (DAPT) is the cornerstone of pharmacological treatment aimed at preventing the atherothrombotic complications in patients with a variety of coronary artery disease (CAD) manifestations. Prescribers of DAPT are confronted with a number of challenges that include selecting the appropriate P2Y12 inhibitor and determining the optimal duration of DAPT with the scope of minimizing the risk of ischemic and bleeding complications in light of each patient's clinical characteristic and circumstance. Recently, a guideline writing committee from the American College of Cardiology/American Heart Association (ACC/AHA) and a task force from the European Society of Cardiology (ESC) released their respective focused update recommendations on "Duration of DAPT in Patients with CAD" (ACC/AHA) and "DAPT in CAD" (ESC). This paper aims to review the ACC/AHA and ESC updates for DAPT to delineate common domains, consistent messages, and differences in recommended management strategies across the Atlantic. PMID- 30522655 TI - A Project to Improve Global Cardiovascular Care: JACC Spanish. PMID- 30522656 TI - Quantitative Definition of Severe Functional Mitral Regurgitation. PMID- 30522657 TI - Rhabdomyolysis: A Noncardiac Source of Increased Circulating Concentrations of Cardiac Troponin T? PMID- 30522658 TI - Asymptomatic Severe Aortic Stenosis With Preserved Ejection Fraction: Early Surgery Versus Conservative Management. PMID- 30522659 TI - Hospital Charges Associated With Inpatient Troponin Testing. PMID- 30522660 TI - Reply: Hospital Charges Associated With Inpatient Troponin Testing. PMID- 30522661 TI - Prevalence of Diabetes Mellitus in Patients With Takotsubo Syndrome, Precipitated by Nonphysical or No Triggers. PMID- 30522662 TI - Reply: Prevalence of Diabetes Mellitus in Patients With Takotsubo Syndrome, Precipitated by Nonphysical or No Triggers. PMID- 30522664 TI - The Era of Drug-Coated Balloons: Are All Created Equal? PMID- 30522663 TI - Sustainable Antirestenosis Effect With a Low-Dose Drug-Coated Balloon: The ILLUMENATE European Randomized Clinical Trial 2-Year Results. AB - OBJECTIVES: The aim of this study was to assess the safety and effectiveness of a next-generation low-dose drug-coated balloon (DCB) designed to optimize the amount of drug transferred into the vessel wall and to maximize the amount of time the drug resides in the vessel wall. BACKGROUND: Several randomized controlled studies evaluating various DCBs have demonstrated a significantly higher patency rate compared with noncoated percutaneous transluminal angioplasty balloons at 1 year. However, the data are limited and vary by DCB at longer follow-up time points. An earlier generation low-dose DCB failed to demonstrate significant treatment effect at 2 years, raising questions regarding the durability of low-dose DCBs. METHODS: In this prospective, multicenter trial, 294 patients were randomized (3:1) to treatment with a DCB or an uncoated percutaneous transluminal angioplasty balloon. Assessments at 2 years included primary patency with duplex ultrasonography, clinically driven target lesion revascularization, and functional outcomes. RESULTS: Primary patency at 2 years was significantly higher in the DCB cohort (75.9% vs. 61.0%; p = 0.025), and the rate of clinically driven target lesion revascularization was significantly lower (12.1% vs. 30.5%; p < 0.001). There were no major limb amputations in either group. The rates of all-cause (6.5% vs. 5.1%; p = 1.00) and cardiovascular related (1.6% vs. 1.7%; p = 1.00) mortality were similar between groups. Functional improvements over baseline were sustained in both groups, with 60% fewer reinterventions in the DCB group. CONCLUSIONS: A sustained treatment effect is achievable with a low-dose DCB with an optimized coating formulation. This trial demonstrated for the first time a statistically significantly higher primary patency rate for a low-dose DCB versus PTA at 2 years. (CVI Drug Coated Balloon European Randomized Clinical Trial; NCT01858363). PMID- 30522666 TI - Drug-Coated Balloons for In-Stent Restenosis: A Fierce Fight for a "Me-Too" Space. PMID- 30522668 TI - Value of Drug-Coated Balloons in Small-Vessel Disease: Have They Come of Age? PMID- 30522665 TI - Comparison of 2 Different Drug-Coated Balloons in In-Stent Restenosis: The RESTORE ISR China Randomized Trial. AB - OBJECTIVES: The aim of the present study was to evaluate the angiographic efficacy, clinical safety, and effectiveness of the Restore paclitaxel-coated balloon in a randomized trial designed to enable the approval of the new device in China. BACKGROUND: Drug-coated balloon (DCB) angioplasty offers an effective treatment for in-stent restenosis. Restore is a new DCB with a SAFEPAX shellac ammonium salt excipient that can avoid drug washing off during catheter delivery to the target lesion site. METHODS: In the noninferiority RESTORE ISR China (Compare the Efficacy and Safety of RESTORE DEB and SeQuent Please in Chinese Patient With Coronary In-stent Restenosis) trial, eligible patients with first occurrence of drug-eluting stent ISR were randomized to the Restore DCB or SeQuent Please DCB in a 1:1 ratio stratified by diabetes. Angiographic and clinical follow-up was planned at 9 months and 1 year, respectively, in all patients. The study was powered for the primary endpoint of 9-month in-segment late loss. RESULTS: Between May 2016 and July 2017, a total of 240 subjects at 12 sites were randomized to either the Restore group (n = 120) or the SeQuent Please group (n = 120). Nine-month in-segment late loss was 0.38 +/- 0.50 mm with Restore versus 0.35 +/- 0.47 mm with SeQuent Please; the 1-sided 97.5% upper confidence limit of the difference was 0.17 mm, achieving noninferiority of Restore compared with SeQuent Please (p for noninferiority = 0.02). Both DCBs had similar 1-year rates of target lesion failure (13.3% vs. 12.6%; p = 0.87). CONCLUSIONS: In this head-to-head randomized trial, the Restore DCB was noninferior to the SeQuent Please DCB for the primary endpoint of 9-month in segment late loss. (Compare the Efficacy and Safety of RESTORE DEB and SeQuent Please in Chinese Patient With Coronary In-stent Restenosis; NCT02944890). PMID- 30522669 TI - A First-in-Human Evaluation of a Novel Mesh-Covered Stent for Treatment of Carotid Stenosis in Patients at High Risk for Endarterectomy: 30-Day Results of the SCAFFOLD Trial. AB - OBJECTIVES: The primary purpose of this study was the composite of major adverse events through 30 days post-index procedure or ipsilateral stroke from 30 days to 1 year (365 days). Presented here is the composite of death, stroke, and myocardial infarction (MI) through 30 days. BACKGROUND: Rates of minor stroke have been higher with carotid artery stenting (CAS) compared with carotid endarterectomy (CEA). The study hypothesized that a stent with mesh covering may improve plaque stabilization during CAS, reduce plaque protrusion, and lead to reduced stroke rates. METHODS: The SCAFFOLD trial, a prospective, multicenter, single-arm clinical trial evaluating the GORE carotid stent (GCS), enrolled patients at increased risk for adverse events from CEA with severe carotid artery stenosis (defined as symptomatic >=50% or asymptomatic >=80%). The SCAFFOLD trial screening committee was implemented to determine adherence to the study protocol. Patients were evaluated for the primary endpoint, the composite of death, stroke, and MI through 30 days. RESULTS: A total of 312 patients were enrolled, treated, and reviewed by the SCAFFOLD trial screening committee, of which 265 were included in the primary analysis population. The 30-day rate of death, stroke, or MI was 3.0% (95% confidence interval: 1.3% to 5.9%) and the stroke or death rate was 1.5%. The 30-day stroke rate was 1.1%. The 2 deaths in the study were not stroke related. CONCLUSIONS: Low death, stroke, or MI rates were demonstrated with GCS in patients at high risk for CEA. The 30-day stroke rate of 1.1% suggests that the carotid stent mesh covering may reduce the neurologic events associated with CAS when used in appropriately selected patients. PMID- 30522670 TI - Use of Dual-Layered Stents in Endovascular Treatment of Extracranial Stenosis of the Internal Carotid Artery: Results of a Patient-Based Meta-Analysis of 4 Clinical Studies. AB - OBJECTIVES: The aim of this study was to evaluate the clinical efficacy of dual layered mesh-covered carotid stent systems (DLS) for carotid artery stenting (CAS). BACKGROUND: The need to minimize the risk for plaque debris prolapsing between stent struts following CAS has resulted in the development of DLS. Small clinical studies evaluating 2 available devices, Roadsaver and CGuard, have been recently published; none of these studies is sufficiently powered to test the role of common risk factors on the occurrence of stroke at 30 days post-CAS. METHODS: A search was performed of multiple electronic databases for studies larger than 100 cases of CAS with DLS. Four single-arm prospective studies were identified, and individual patient data were collected. The primary endpoint was the occurrence of stroke at 30 days; secondary endpoints were technical and procedural success, periprocedural stroke, and in-hospital and 30-day rates of death. RESULTS: The Roadsaver and CGuard stents were used in similar proportions, and technical success was achieved in all procedures (100% [n = 556]). There were 6 periprocedural strokes (1.08%; all minor). During 30-day follow-up, there was 1 death (0.17%) from myocardial infarction and 1 additional minor stroke (0.17%). The cumulative 30-day mortality rate was 0.17%, and the incidence of stroke at 30 days was 1.25%. No predictors of stroke at 30 days could be identified. CONCLUSIONS: This meta-analysis suggests that DLS can be safely used for CAS, and their use minimizes the incremental risk related to symptomatic status and other risk factors. PMID- 30522667 TI - Drug-Coated Balloon Versus Drug-Eluting Stent for Small-Vessel Disease: The RESTORE SVD China Randomized Trial. AB - OBJECTIVES: The aim of this study was to evaluate the angiographic efficacy and clinical outcomes of the Restore paclitaxel-coated balloon in a randomized trial designed to enable its approval with an indication for small-vessel disease (SVD). BACKGROUND: Higher rates of restenosis and stent thrombosis limit the effectiveness of drug-eluting stent (DES) treatment of SVD. Whether a drug-coated balloon (DCB)-only strategy is effective in de novo SVD is not yet established. METHODS: In the noninferiority RESTORE SVD China trial, eligible patients with reference vessel diameter >=2.25 and <=2.75 mm were randomized to the Restore DCB or the RESOLUTE Integrity DES in a 1:1 ratio stratified by diabetes and number of lesions treated. Patients with RVD >=2.00 and <2.25 mm were enrolled in a nested very small vessel registry. Angiographic and clinical follow-up were planned at 9 months and 1 year, respectively, in all patients. The study was powered for the primary endpoint of 9-month in-segment percentage diameter stenosis. RESULTS: Between August 2016 and June 2017, a total of 230 subjects at 12 sites were randomized to the DCB group (n = 116) or DES group (n = 114); 32 patients were treated with the DCB in the very small vessel cohort. Nine-month in-segment percentage diameter stenosis was 29.6 +/- 2.0% with the DCB versus 24.1 +/- 2.0% with the DES; the 1-sided 97.5% upper confidence limit of the difference was 10.9%, achieving noninferiority of the DCB compared with the DES (p for noninferiority < 0.001). The DCB and DES had comparable 1-year rates of target lesion failure (4.4% vs. 2.6%, p = 0.72). CONCLUSIONS: In this multicenter randomized trial, the Restore DCB was noninferior to the RESOLUTE DES for 9-month in-segment percentage diameter stenosis. (Assess the Efficacy and Safety of RESTORE Paclitaxel Eluting Balloon Versus RESOLUTE Zotarolimus Eluting Stent for the Treatment of Small Coronary Vessel Disease; NCT02946307). PMID- 30522671 TI - A New Milestone in Carotid Stenting? PMID- 30522672 TI - 30-Day Readmissions After Endovascular Thrombectomy for Acute Ischemic Stroke. AB - OBJECTIVES: The authors sought to investigate the incidence, predictors, and causes of 30-day nonelective readmissions after endovascular thrombectomy (EVT). BACKGROUND: Randomized trials have demonstrated that EVT improves outcomes in patients with acute ischemic stroke. METHODS: The Nationwide Readmissions Database, years 2013 and 2014, was used to identify hospitalizations for a primary diagnosis of acute ischemic stroke during which patients underwent EVT, with or without intravenous thrombolysis. The incidence and reasons of 30-day readmissions were investigated. A hierarchical Cox regression model was used to identify independent predictors of 30-day nonelective readmissions. A propensity score-matched analysis was performed to compare the risk of 30-day nonelective readmissions in those who underwent EVT versus thrombolysis alone. RESULTS: Among 2,055,365 weighted hospitalizations with acute ischemic stroke and survival to discharge, 10,795 (0.5%) underwent EVT. The 30-day readmission rate was 12.4% within a median of 9 days (interquartile range: 4 to 18 days). Diabetes mellitus, coagulopathy, Medicare or Medicaid insurance, and gastrostomy during the index hospitalization were independent predictors of 30-day readmission, but coadministration of thrombolytics with EVT was not an independent predictor. The most common reasons for readmission were infections (17.2%), cardiac causes (17.0%), and recurrent stroke or transient ischemic attack (14.8%). Compared with thrombolysis alone, the hazard of 30-day readmissions was similar (hazard ratio: 0.98; 95% confidence interval: 0.91 to 1.05; p = 0.55). CONCLUSIONS: In patients hospitalized with acute ischemic stroke who underwent EVT, 30-day nonelective readmissions were common, occurring in approximately 1 in 8 patients, but were similar to those of patients treated with thrombolysis alone. Risk of readmission was associated with certain patient demographics, comorbidities, and complications, but not thrombolysis coadministration. Infections, cardiac causes, and recurrent stroke or transient ischemic attack are the most common reasons for readmission after EVT, emphasizing the need for comprehensive multidisciplinary treatment in the transition to outpatient care. PMID- 30522673 TI - Does Endovascular Thrombectomy for Ischemic Stroke Impact 30-Day Readmissions? PMID- 30522674 TI - First-in-Human Images of Coronary Atherosclerosis and Coronary Stents Using a Novel Hybrid Intravascular Ultrasound and Optical Coherence Tomographic Catheter. PMID- 30522676 TI - Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes. PMID- 30522675 TI - Functional Assessment and Acute Coronary Syndrome. PMID- 30522677 TI - Go With the Flow When Instantaneous Wave-Free Ratio-Fractional Flow Reserve Discordance Occurs: Indeed, Beware When Relying on Fractional Flow Reserve Alone. PMID- 30522678 TI - Reply: Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements. PMID- 30522679 TI - Clinical Randomized Trial Evaluating Novel, Microcrystalline, and Biocompatible Polymer Paclitaxel-Coated Balloon for the Treatment of Femoropopliteal Occlusive Disease: The BIOPAC Trial. PMID- 30522680 TI - New-Generation Drug-Eluting Stents for Left Main In-Stent Restenosis: The DELTA-2 Registry. PMID- 30522681 TI - The future of the sweetened beverages tax in Portugal. PMID- 30522682 TI - Language disintegration: communication ability in elderly immigrants with dementia. PMID- 30522683 TI - Consideration of local geographical variations in PM2.5 concentrations in China. PMID- 30522684 TI - Consideration of local geographical variations in PM2.5 concentrations in China - Authors' reply. PMID- 30522685 TI - Short DAPT Duration for Well-Covered Stents? PMID- 30522686 TI - Cardiac Magnetic Resonance Fingerprinting: Technical Overview and Initial Results. AB - Cardiovascular magnetic resonance is a versatile tool that enables noninvasive characterization of cardiac tissue structure and function. Parametric mapping techniques have allowed unparalleled differentiation of pathophysiological differences in the myocardium such as the delineation of myocardial fibrosis, hemorrhage, and edema. These methods are increasingly used as part of a tool kit to characterize disease states such as cardiomyopathies and coronary artery disease more accurately. Currently conventional mapping techniques require separate acquisitions for T1 and T2 mapping, the values of which may depend on specifics of the magnetic resonance imaging system hardware, pulse sequence implementation, and physiological variables including blood pressure and heart rate. The cardiac magnetic resonance fingerprinting (cMRF) technique has recently been introduced for simultaneous and reproducible measurement of T1 and T2 maps in a single scan. The potential for this technique to provide consistent tissue property values independent of variables including scanner, pulse sequence, and physiology could allow an unbiased framework for the assessment of intrinsic properties of cardiac tissue including structure, perfusion, and parameters such as extracellular volume without the administration of exogenous contrast agents. This review seeks to introduce the basics of the cMRF technique, including pulse sequence design, dictionary generation, and pattern matching. The potential applications of cMRF in assessing diseases such as nonischemic cardiomyopathy are also briefly discussed, and ongoing areas of research are described. PMID- 30522687 TI - 3-Dimensional Echocardiography: Latest Developments and Future Directions. AB - The ongoing refinements in 3-dimensional (3D) echocardiography technology continue to expand the scope of this imaging modality in clinical cardiology by offering new features that stem from the ability to image the heart in its complete dimensionality. Over the years, countless publications have described these benefits and tested new frontiers where 3D echocardiographic imaging seemed to offer promising ways to improve patients' care. These include improved techniques for chamber quantification and novel ways to visualize cardiac valves, including 3D printing, virtual reality, and holography. The aims of this review article are to focus on the most important developments in the field in the recent years, discuss the current utility of 3D echocardiography, and highlight several interesting future directions. PMID- 30522688 TI - Progress in Cardiovascular Imaging. PMID- 30522689 TI - Double Face of Statins at the Crossroad of Coronary Atherosclerotic Plaque and Aortic Valve Calcification? PMID- 30522690 TI - The Authors' Reply. PMID- 30522691 TI - Could Breast Arterial Calcification Predict the Risk of Coronary Artery Disease? PMID- 30522692 TI - The Authors Reply. PMID- 30522693 TI - Physical Function and Well-Being in HFpEF: The Constrained Mechanics and Compensatory Strategies. PMID- 30522694 TI - CD84 cell surface signaling molecule: An emerging biomarker and target for cancer and autoimmune disorders. AB - CD84 (SLAMF5) is a member of the SLAM family of cell-surface immunoreceptors. Broadly expressed on most immune cell subsets, CD84 functions as a homophilic adhesion molecule, whose signaling can activate or inhibit leukocyte function depending on the cell type and its stage of activation or differentiation. CD84 mediated signaling regulates diverse immunological processes, including T cell cytokine secretion, natural killer cell cytotoxicity, monocyte activation, autophagy, cognate T:B interactions, and B cell tolerance at the germinal center checkpoint. Recently, alterations in CD84 have been related to autoimmune and lymphoproliferative disorders. Specific allelic variations in CD84 are associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. In chronic lymphocytic leukemia, CD84 mediates intrinsic and stroma induced survival of malignant cells. In this review, we describe our current understanding of the structure and function of CD84 and its potential role as a therapeutic target and biomarker in inflammatory autoimmune disorders and cancer. PMID- 30522695 TI - Maintaining operative efficiency while allowing sufficient time for residents to learn. AB - BACKGROUND: Surgical residents desire independent operating experience but recognize that attendings have a responsibility to keep cases as short as possible. METHODS: We analyzed video and interviews of attending surgeons related to more than 400 moments in which the resident was the primary operator. We examined these moments for themes related to timing and pace. RESULTS: Our surgeons encouraged the residents to speed up when patient safety could be jeopardized by the case moving too slowly. In contrast, they encouraged the residents to slow down when performing a crucial step or granting independence. Attending surgeons encouraged speed through economical language, by substituting physical actions for words, and through the use of Intelligent Cooperation. Conversely, they encouraged slowing down via just-in-time mini-lectures and by questioning the trainee. CONCLUSIONS: We present recommendations for safe teaching in the operating room while simultaneously maintaining overall surgical flow. Teaching residents to operate quickly can save time and is likely based on an automaticity in teaching. Slowing a resident down is vital for trainee skill development and patient safety. PMID- 30522696 TI - ACS-NSQIP risk calculator predicts cohort but not individual risk of complication following colorectal resection. AB - OBJECTIVE: Compare the ACS-NSQIP risk calculator with institutional risk for colorectal surgery. METHODS: Actual and predicted outcomes were compared for both cohort and individuals. RESULTS: For the cohort, the risk calculator was accurate for 7/8 outcomes; there were more serious complications than predicted (19.4 vs 14.7%, p < 0.05). Risk calculator Brier scores and null Brier scores were comparable. PATIENTS: with better outcomes than predicted were current smokers (OR 4.3 95% CI 1.2-15.4), ASA >= 3 (OR 10.4, 95% CI 2.8-39.2), underwent total/subtotal colectomy (OR 3.5, 95% CI 1.1-12.2) or operated by Surgeon 2 (OR 2.9, 95% CI 1.4-11.6). Patients with serious complications who had low predicted risk had low ASA (OR 10.5, 95% CI 1.3-82.6), and underwent operation by Surgeon 2 (OR 11.8, 95% CI 2.5, 55.2). LIMITATIONS: Single center study, sample size may bias subgroup analyses. CONCLUSIONS: The ACS NSQIP calculator did not predict outcome better than sample risk. PMID- 30522697 TI - Biomimetic transformation of polyphosphate microparticles during restoration of damaged teeth. AB - OBJECTIVE: In the present study, we investigated the fusion process between amorphous microparticles of the calcium salt of the physiological polymer comprising orthophosphate units, of inorganic polyphosphate (polyP), and enamel. METHODS: This polymer was incorporated as an ingredient into toothpaste and the fusion process was studied by electron microscopy and by synchrotron-based X-ray tomography microscopy (SRXTM) techniques. RESULTS: The data showed that toothpaste, supplemented with the amorphous Ca-polyP microparticles (aCa-polyP MP), not only reseals tooth defects on enamel, like carious lesions, and dentin, including exposed dentinal tubules, but also has the potential to induce re mineralization in the enamel and dentin regions. The formation of a regeneration mineralic zone on the tooth surface induced by aCa-polyP-MP was enhanced upon exposure to artificial saliva, as demonstrated by SRXTM. Energy dispersive X-ray analysis revealed an increase in the calcium/phosphorus atomic ratio of the enamel deposits to values characteristic for the particles during the treatment with polyP applied in the toothpaste, indicating a fusion of the particles with the tooth mineral. SIGNIFICANCE: Our results suggest that toothpaste enriched with aCa-polyP-MP is a promising biomimetic material for accelerating enamel and dentin restoration. PMID- 30522698 TI - Effect of slow-cooling protocol on biaxial flexural strengths of bilayered porcelain-ceria-stabilized zirconia/alumina nanocomposite (Ce-TZP/A) disks. AB - OBJECTIVE: The present study investigated the biaxial flexural strengths of bilayered ceria-stabilized zirconia/alumina nanocomposite (Ce-TZP/A) disks with various layering porcelains veneered using a slow-cooling protocol. METHODS: Five porcelain materials (VITA VM9, Cercon Ceram Kiss, and Vintage ZR with experimental coefficient of thermal expansions; CTEs of 8.45, 9.04, and 9.61ppm/ degrees C) were veneered on Ce-TZP/A disks and slow-cooled after firing to fabricate bilayered specimens (core-to-porcelain thickness: 0.8mm/1.5mm). Biaxial flexural strengths of the specimens with the porcelain layer in tension were tested based on the piston-on-three-ball method (ISO 6872:2008). The data were statistically analyzed using Weibull distribution and Fisher's exact test. RESULTS: Tensile stresses were observed in the entire porcelain layer while compressive stress at the surface of the Ce-TZP/A layer shifted to tensile stress at the interface between the materials. The cases of small CTE mismatches between the materials showed high Weibull characteristic strengths at the internal and external surfaces of the specimens, except the VM9 group (CTE: 9.0-9.2ppm/ degrees C). The maximum tensile stress was observed on the surface of the porcelain layer, where cracks originated and continuously propagated into the Ce TZP layer. The Ce-TZP/A fractured into two pieces for large CTE mismatches between the materials, resulting in significantly lower flexural strengths than those fracturing into three pieces for small CTE mismatches. SIGNIFICANCE: Flexural strengths and fracture behaviors of bilayered porcelain-Ce-TZP/A disks were influenced by the CTE mismatches, and a small CTE mismatch between the materials was preferred when using a slow-cooling protocol. PMID- 30522699 TI - A potential role for SMAD9 in goose follicular selection through regulation of mRNA levels of luteinizing hormone receptor. AB - The egg production of poultry depends on follicular development and selection. Nonetheless, the mechanism underlying the priority of selecting of hierarchical follicles is completely unknown. SMAD9 is one of the important transcription factors in the BMP/SMAD pathway and is involved in goose follicular initiation. To identify its potential role in determination of the goose follicle hierarchy, we used BMP type I receptor inhibitor LDN-193189 both in vivo and in vitro and found that SMAD9 mRNA expression decreased in the presence of LDN-193189. While the level of SMAD9 mRNA decreased after treatment with LDN-193189, we found that the egg production (7.08 eggs per bird per year) of the animals increased, estradiol (E2) levels significantly increased, but the levels of progesterone (P4) remained unchanged. We also detected a significant increase in luteinizing hormone receptor (LHR) mRNA expression, but no change in follicle-stimulating hormone receptor (FSHR) mRNA amounts. The in vitro experimental results indicated that SMAD9 knockdown by RNA interference noticeably reduced E2 and P4 biosynthesis and FSHR and LHR mRNA expression in goose granulosa cells. Chromatin immunoprecipitation assay of goose granulosa cells revealed that phospho-SMAD9 bound to the LHR promoter and possibly regulated its transcriptional activity. These findings revealed that SMAD9 is differentially expressed in goose follicles, and acts as a key player in the control over goose follicular selection. PMID- 30522700 TI - Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. AB - OBJECTIVE: To evaluate safety, tolerability, and antitumor activity of pembrolizumab monotherapy in patients with programmed death ligand 1 (PD-L1) expressing advanced ovarian cancer enrolled in the multicohort, phase Ib KEYNOTE 028 trial. METHODS: Key inclusion criteria were age >=18 years; advanced ovarian epithelial, fallopian tube, or primary peritoneal carcinoma; failure of previous therapy; and tumor PD-L1 positivity. Patients received pembrolizumab (10 mg/kg every 2 weeks) for <=24 months or until disease progression/intolerable toxicity. Tumor response was assessed per RECIST v1.1 (investigator review). Adverse events (AEs) were graded using CTCAE version 4.0. Primary end point was confirmed objective response rate (ORR) per RECIST v1.1 (investigator review); data cutoff date was February 20, 2017. RESULTS: Twenty-six patients (median age, 57.5 years) with PD-L1-positive advanced metastatic ovarian cancer received pembrolizumab; 38.5% had metastatic disease, and 73.1% previously received >=3 lines of therapy. Treatment-related AEs (TRAEs) occurred in 19 (73.1%) patients, most commonly arthralgia (19.2%), nausea (15.4%), and pruritus (15.4%). One grade 3 TRAE (increased plasma transaminase level) occurred. No deaths and no treatment discontinuations due to TRAEs occurred. After a median follow-up duration of 15.4 months, ORR was 11.5% (1 complete response, 2 partial responses); 7 patients (26.9%) achieved stable disease. Median progression-free and overall survival were 1.9 (95% CI, 1.8-3.5) and 13.8 (95% CI, 6.7-18.8) months, respectively. CONCLUSION: Pembrolizumab conferred durable antitumor activity with manageable safety and toxicity in patients with advanced PD-L1-positive ovarian cancer and is under further investigation in an ongoing phase II trial, KEYNOTE-100. PMID- 30522701 TI - CyPass stent withdrawal: The end of suprachoroidal MIGS? PMID- 30522702 TI - Bmp4 inhibits goose granulosa cell apoptosis via PI3K/AKT/Caspase-9 signaling pathway. AB - Bone morphogenetic protein 4 (BMP4) has an important role in regulating cellular proliferation, differentiation and apoptosis. It, however, is still unclear as to the mechanisms by which BMP4 regulates the apoptosis of granulosa cells (GCs) in geese. In the present study, there was cloning of the full-length coding sequence of goose BMP4 gene, which consisted of 1212 nucleotides encoding 403 amino acids. Its deduced amino acid sequence comprised one signal peptide, one TGFbeta pro peptide and one mature peptide domain. Results from conducting the quantitative real-time PCR (qPCR) indicated the relative abundances of BMP4 mRNA in geese GCs increased gradually from the relative abundances in pre-hierarchical follicles that were 4 to 6 mm in diameter to that in the fifth largest (F5) follicle and then relative abundances of BMP4 mRNA decreased with further development as the largest (F1) follicle. Results from use of the TUNEL assay indicated that overexpression of the goose BMP4 gene suppressed GC apoptosis and this was confirmed when relative abundances of the CAD, Caspase-9 and Caspase-3 proteins were determined using western blotting. In addition, overexpression of the BMP4 gene induced phosphorylation of AKT, which was inhibited with use of the PI3K inhibitor, LY294002. Co-transfection of BMP4 and LY294002 resulted in increased relative abundances of Caspase-9 and CAD proteins but had no effect on that of Caspase-3. Taken together, these results suggested that expression of the BMP4 gene resulted in a reduction in Caspase-9 protein leading to inhibition of GC apoptosis via the PI3K/AKT signaling pathway in geese. PMID- 30522703 TI - Sex-related gonadal gene expression differences in the Russian sturgeon (Acipenser gueldenstaedtii) grown in stable aquaculture conditions. AB - The Russian sturgeon (Acipenser gueldenstaedtii) is a primitive freshwater fish and a source of caviar. In the present study, the gonadal transcriptomes of male and female Russian sturgeons grown in stable aquaculture conditions were analyzed. RNA sequencing of whole-gonad transcriptomes from pools of 4-year old fish (five females, four males), resulted in the identification of 28,170 unique transcripts. Of these, 16,191 could be annotated by similarity to gene sequences from other species. There were 392 transcripts that showed differential abundance by a factor of 20-fold or more between the sexes; 272 of these were annotated; of these, 175 and 97 were in greater abundance in ovaries and testes, respectively. Functional annotation and clustering of the genes with differential abundances of mRNA allowed for identification of several clusters. Thus, a group of transcriptional regulators and factors involved in cell division, especially septins, were in greater abundance in the ovaries; while a different set of transcription factors (including sox6 and sox30) and a group of protein kinases were in greater abundance in the testes. The transcript abundances of nine highly abundant candidate transcripts, as well as of two additional genes previously known to be involved in reproduction, cyp19 (p450 aromatase) and foxl2, were assessed in the individual samples by qRT-PCR. Of these, five (including cyp19 and foxl2) were in greater abundance in ovaries, while the abundance of ighm1 mRNA was greater in testes. Phylogenetic analysis based on the k1c18 keratin gene placed the sturgeon sequence nearest those of other primitive fish species, supporting the ancient origin of the sturgeon. In conclusion, this study details transcriptome differences between male and female sturgeon and identifies key genes that may contribute to sexual determination and differentiation. PMID- 30522704 TI - Occult cancer screening and idiopathic venous thromboembolic disease: Where do we stand? PMID- 30522705 TI - [Thromboembolic risk in repatriated patients with traumatic lower-limb injuries]. AB - INTRODUCTION: Venous thromboembolism (VTE) is a public health problem. Medical repatriation of patients with traumatic lower-limb injuries is common. There are no specific recommendations for the prevention of deep vein thrombosis (DVT). The main objective was to determine the incidence of VTE in this high-risk population and to determine associated risk factors. MATERIALS AND METHODS: This was a prospective study including patients repatriated to France following lower-limb trauma and hospital discharge. A physical examination and a venous ultrasound were systematically performed on arrival. Reasons for repatriation, methods of VTE prevention and risk factors for VTE were studied. The positive diagnosis of deep venous thrombosis (DVT) was done by Doppler ultrasound. RESULTS: Fifty-two patients with lower-limb trauma were included. Six cases of DVT, four asymptomatic and two symptomatic with pulmonary embolisms were diagnosed. Two patients with asymptomatic DVT did not have preventive anticoagulation. No patient with preventive anticoagulation had symptomatic DVT. Smoking and the absence of preventive anticoagulation were significant risk factors for VTE. DISCUSSION: Repatriation of patients with lower-limb trauma in discharge is associated with an increased risk of VTE. Preventive anticoagulation appears to be effective in preventing DVT. Systematic Doppler imaging can reveal asymptomatic DVT. Our study did not evaluate specifically the interest of venous compression associated to preventive anticoagulation for VTE prevention. Specific recommendations on VTE prevention during repatriation of patients with lower-limb trauma are needed. CONCLUSION: Preventive anticoagulation should be systematically discussed during repatriation of patients with lower-limb trauma, in the absence of major bleeding risk. Due to the existence of asymptomatic DVT, venous Doppler ultrasound should also be systematically discussed despite the absence of official recommendations. PMID- 30522706 TI - [Thrombophilia in systemic lupus erythematosus: A case-control study]. AB - INTRODUCTION: To investigate the thrombotic tendency in patients with systemic lupus erythematosus (SLE) by evaluating congenital and acquired abnormalities with an increased risk of thrombosis. PATIENTS AND METHODS: A total of 53 patients with SLE were included in the study. Fifty-three healthy controls paired by age and sex were assessed. Anticardiolipin antibodies (aCL), anti beta2 glycoprotein (abeta2GP), lupus anticoagulant (LAC), protein C (PC), protein S (PS), antithrombin (AT), acquired activated protein C, and homocysteinemia were evaluated. Comparisons for categorical variables were analyzed by Chi2 and student tests. RESULTS: The patients were all female and had a mean age of 30.6 years (16/58). The healthy controls were all female and their mean age was 30.8 years (17/56). Five patients (9.4%) developed venous thrombosis during the 24 months of follow-up. The antiphospholipid antibodies were positive in 17 patients (32.1%) and negative in all healthy controls (P=0.01). PS deficiency was noted in 17 patients (32.1%) and in 5 controls (P=0.004). Hyperhomocysteinemia was noted in 16 patients (30.2%) versus 3 controls (5.6%) (P=0.002). Test for PC deficiency and acquired activated protein C showed no significant difference between the two groups. No AT deficiency was found in the patients. The study of clinical and biological correlations based on the presence and absence of thrombophilic parameters concluded to a significant association between Protein C deficit and thrombosis (P=0.02) and acquired activated protein C resistance and thrombosis (P=0.04). There was no significant association between the APL and thrombosis. CONCLUSION: Thrombophilic abnormalities were significantly more frequent in lupus patients than in healthy controls. Thrombotic events were significantly associated with PC deficit and acquired protein C resistance. There was no correlation between antiphospholipid antibodies and thrombosis. PMID- 30522707 TI - [Follow-up of patients with chronic obstructive arterial disease, some months after their rehabilitation: Assessment of a therapeutic education program]. AB - : Vascular rehabilitation (VR) is becoming increasingly important in the management of the arterial patient. Therapeutic Patient Education (TPE) is an integral part of rehabilitation programs and aims to transform patients' lifestyle habits. The effectiveness of patient management at short-term no longer needs to be demonstrated, but we can question the effectiveness of education over the long term, some months following a rehabilitation program. OBJECTIVE: This study aims to assess, in the long term, the effects of TPE in VR, and to observe the transformation of certain lifestyle habits of patients. METHOD: We convened 68 patients (51 men and 17 women) 6 months and 1 year after VR treatment during which these patients participated in an TPE program. We assessed: knowledge by questionnaire, walking range, weight and body composition by impedimetric techniques. RESULTS: We found that patients improved their knowledge at the end of rehabilitation 45.8 (+/-7.6) of good responses on average, compared to 36.2 (+/-8.6) at the beginning of rehabilitation and these results are consolidated 6 months after 43.4 (+/-7.5) and 1 year after 44.1 (+/-8.1). We also found that walking distances during treadmill testing and outdoor walking improved at the end of rehabilitation and were maintained at six months and one year. Finally, weight, fat mass and lean mass decreased slightly compared to the end of rehabilitation. Only 7 patients out of 22 gave up smoking. CONCLUSION: An education program concerning risk factor management during vascular rehabilitation enables patients to acquire knowledge that can be used to maintain new lifestyle habits and stabilize their health status. PMID- 30522708 TI - [Prevalence and risk factors of sub-renal abdominal aortic aneurysm in an Algerian population aged over 60]. AB - INTRODUCTION: The prevalence of abdominal aortic aneurysm (AAA) in the general population in our country is not known, our aim was to evaluate it in patients over 60 years of age, to specify the risk factors and to evaluate the extension of aneurysmal disease and multisite subclinical atherosclerosis. METHODS: Descriptive, transversal, study collecting the data of a systematic ultrasound screening of sub-renal AAA in subjects receiving care in two Algerian hospital structures. Epidemiological data, AAA risk factors, cardiovascular disease risk factors (CVD RF) and the personal history (cardiovascular diseases, chronic obstructive pulmonary disease) and family history of AAA were collected during the screening. An abdominal echography was performed in all patients. A biological and morphological assessment was carried out for AAA cases detected. Multivariate logistic regression analysis was used to study the factors associated with AAA. RESULTS: Systematic screening for 600 patients revealed an overall AAA prevalence of 2.2% (n=13). In multivariate analysis a positive association with AAA was observed with active smoking, its duration in years and its intensity in year-packages; with hypertension, dyslipidemia and a history of cardiovascular events. While a negative association was observed with a smoking cessation of more than 20 years, type 2 diabetes and android obesity. The study of detected AAA cases found five cases of aneurysm isolated from the primary iliac artery but no popliteal and/or femoral aneurysm. The carotids were atheromatous in more than 80% of cases and the arteries of the lower limbs in more than one-third of cases. CONCLUSION: The prevalence of AAA in our population (2.2%) corresponds to the prevalence reported recently in Europe, but it would have been higher if the screening had targeted males and smokers. The factors associated with AAA in our patients are similar to those described in the literature. PMID- 30522709 TI - Venous leiomyosarcoma arising from the radiocephalic vein. AB - Vascular leiomyosarcoma is a very rare soft tissue neoplasma. We are reporting a vascular leiomyosarcoma case arising from an unusual site: the radiocephalic vein. Despite a poor prognosis, after surgery and radiotherapy, the patient was alive without signs of recurrence two years later. PMID- 30522710 TI - [Catatonic melancoly and venous thromboembolism: A risky combination]. AB - Catatonia is defined as a psychiatric syndrome. This syndrome is strongly associated with venous thromboembolism. As a difficult diagnosis in these patients, psychiatrists and vascular physicians should be aware of this association. We report here a clinical case of this association and discuss the diagnosis difficulties and therapeutics options. PMID- 30522711 TI - [Pulmonary embolism and complete atrioventricular block]. AB - Complete atrioventricular block is a rare complication of pulmonary embolism. We describe the case of a black African patient, aged 42 years, who presented to the emergency department of Abidjan Heart Institute for sudden onset dyspnea and hemoptysis. ECG revealed a third degree atrioventricular block. Computed tomographic angiography showed proximal pulmonary embolism of the right main pulmonary artery. To our knowledge, this is the first case of complete atrioventricular block in pulmonary embolism in Sub-Saharan Africa. In case of pulmonary embolism, clinical and electrocardiographic monitoring is necessary in order to identify this uncommon and potentially serious outcome. PMID- 30522712 TI - [Contribution of the maximal exercise test to diagnosis the vascular origin of leg pain in athletes]. AB - Leg pain is a common debilitating symptom in athletes. Vascular disease is not often proposed as a possible cause. Maximal exercise with measure of the ankle brachial index after exercise can be an interesting diagnostic test. We report an illustrative case where an athlete presented leg pain revealing arterial disease disclosed by exercise. Interestingly, sub-maximal exercise did not cause pain, causing a delay in diagnosis. The vascular origin of leg pain can be detected with a maximal exercise test that induces the symptomatic pain or at least clinical discomfort. PMID- 30522713 TI - Context Matters: Adolescent Neighborhood and School Influences on Young Adult Body Mass Index. AB - PURPOSE: Both schools and neighborhoods play important roles in determining adolescent weight status, but little is known about their relative importance, particularly in predicting long-term weight outcomes. We assessed the impacts of both school and neighborhood socioeconomic composition, social connectedness, and built environment during adolescence on weight status in young adulthood. METHODS: The study sample consisted of 14,625 respondents from Waves I and IV of the National Longitudinal Study of Adolescent to Adult Health. Data were analyzed using cross-classified multilevel modeling to examine the joint effect of adolescents' school and neighborhood predictors on body mass index (BMI) 13 years later. RESULTS: Living in a neighborhood with lower average parent education during adolescence, and attending a school with lower average parent education, were each associated with higher BMI in young adulthood. Living in a neighborhood with more physical activity resources predicted lower young adult BMI, independent of adolescent weight, parent obesity status, and demographic characteristics. School physical activity resources and perceptions of social connectedness (in the school or neighborhood) were not significantly associated with young adult BMI. CONCLUSIONS: These findings highlight the importance of school and neighborhood socioeconomic composition during adolescence on young adult weight status. Results also suggest that improving neighborhood infrastructure may promote healthy weight. PMID- 30522714 TI - Preface to patient centered clinical anaesthesiology. PMID- 30522715 TI - The patient's surgical journey and consequences of poor recovery. AB - Quality of recovery is a multidimensional construct that affects individual patients in different ways and during different time periods. The evaluation of quality of recovery requires patient-reported outcome measurement tools that are sensitive in detecting change with time and are preferably objective rather than subjective by nature. Current surgical outcomes are still predominantly focused on the avoidance of complications and reduced cost. The new era of 'value-based care' implies that outcomes of importance to the patient should be a vital metric in determining quality of surgical care. However, it is critical to maintain the high standards of surgical safety and cost containment as we move forward to address value-based care. An apparently successful surgery can result in poor recovery outcomes such as cognitive decline, persistent pain, reduced functional ability, loss of independence or inability to return to work. The special edition of Best Practice will focus on the multidimensional construct of quality of recovery, how to measure it and how it may apply in different populations. PMID- 30522716 TI - Defining quality of recovery - What is important to patients? AB - Postoperative recovery is a complex process with several interrelated domains. Traditionally, the absence of negative physiological symptoms like nausea and pain, along with avoidance of major postoperative complications, has been the standard set by clinicians and hospitals for a satisfactory postoperative recovery. Nonetheless, evidence from recent studies reports these items to be the least important from the patient point of view. Effective communication, active involvement of the patient in their healthcare decisions, and empathy from healthcare providers are rated by patients as significant factors for their quality of recovery. Although challenging to study, the development of a multimodal, patient-centered approach to evaluate the postsurgical period is critical for a truly comprehensive assessment of recovery quality. This review provides an overview of our current understanding of how patient factors like satisfaction can be impacted by the Anesthesia Care Team and how overall quality of recovery is related to perioperative patient experiences. PMID- 30522717 TI - Approaches to the measurement of post-operative recovery. AB - Modern recovery assessment has progressed from that which addressed purely physiological restitution in the immediate post-operative period to that which is a multi-dimensional construct existing as a continuum and which follows a predictable trajectory. Recovery tools differ in their derivation, validation and scope of assessment. Importantly, few are validated for repeat measures, an aspect crucial when assessing the temporal nature of modern recovery. Recovery can be assessed as a continuous or dichotomous outcome and as occurring within an individual patient or within a group. Dichotomisation of recovery assessment mandates that a threshold be determined, above which recovery is deemed to have occurred. Ideally, recovery is assessed as a dichotomous outcome using the patient as their own pre-operative comparator, thus allowing recovery assessment at an individual patient, as well as group, level and overall as well as within each recovery domain. PMID- 30522718 TI - Integration of satisfaction and quality of recovery. AB - Among patient-reported outcomes, patient satisfaction and quality of recovery are key measures of patient-centred care. The measurement of patient satisfaction should use validated, multidimensional scales. There are general scales that aim to evaluate the entire perioperative period and scales focused on specific periods (post-operative) or techniques (loco-regional anaesthesia). Recovery assessment tools (such as the PostopQRS) share some domains with satisfaction scales and also have major differences by construction. As such, recovery and satisfaction scales are complementary. Because there is no reference value of patient satisfaction, the scales are used to compare two management strategies or to follow similar populations of patients with time. Improving patient satisfaction goes beyond quality improvement. In a large database, the highest satisfaction was associated with the lowest morbidity and mortality. Thus, it is likely that the process of improving quality changes multiple components of medical management, hence improving several patient outcomes. PMID- 30522719 TI - A matter of perspective - Objective versus subjective outcomes in the assessment of quality of recovery. AB - Current post-operative recovery assessment exists as a dichotomy, maintaining objectivity whilst providing relevance to patient-centred care. Both objective and subjective measures are utilised in modern recovery assessment and are best viewed as complimentary. At institutional and provider levels, performance indicators are utilised as surrogates for quality of recovery but only if these indicators are assessed in the clinical context from which they are derived. Patient-reported outcomes prioritise the patient's perspective of symptoms and care, which are the most important aspects at the time of assessment but are limited by their susceptibility to response shift and recall bias. Ideally, quality of recovery is assessed using objective measures in concert with measures of clinical complexity and in parallel with patient-reported outcomes. PMID- 30522720 TI - The future of recovery - Integrated, digitalised and in real time. AB - Traditional perioperative risk prediction recovery identifies patient populations at risk of suboptimal recovery but not individual patients in whom this actually occurs and in whom timely intervention is beneficial. Patient-focused recovery emphasises a return to a semblance of normality and an ability to perform activities previously undertaken. A patient's sense of self-efficacy and engagement in their own care positively influences functional improvement and emotive recovery. The future of recovery assessment is that which is individualised, digitalised, integrated and in real time. Real-time recovery (RTR) assessment is the contemporaneous collection, analysis and reporting of data that enable the identification of suboptimal recovery in individual patients in a timeframe that minimises the delay in the implementation of the targeted treatment. There is a need to validate the clinical utility of existing biometric technology, wireless hybrid devices and digitalised platforms in providing both clinician and patient with RTR data and to determine the effect, if any, that RTR has on patient engagement and outcome. PMID- 30522721 TI - Cognitive self-assessment scales in surgical settings: Acceptability and feasibility. AB - Pre-existing cognitive impairment is associated with poor surgical outcomes, long hospital stays, and increased morbidity and mortality. This necessitates the use of screening tools to evaluate preoperative cognitive status in elderly surgical patients. Given the growing population of older adults and increased prevalence of cognitive impairment, it is necessary to investigate whether staff administered or self-administered cognitive screening examinations provide more sensitive information about pre-existing (preoperative) cognitive status. Self administered Gerocognitive Screening Examination (SAGE) was developed out of the need for a cognitive self-assessment scale in the clinic. At our institution, SAGE was given to 189 elderly surgical patients to evaluate baseline cognitive status, and preliminary results are promising that self-assessment scales are both feasible and acceptable in the surgical setting. PMID- 30522723 TI - Introduction to Seminars in Neurology. PMID- 30522724 TI - Fetal Cerebrovascular Maturation: Effects of Hypoxia. AB - The human cerebral vasculature originates in the fourth week of gestation and continues to expand and diversify well into the first few years of postnatal life. A key feature of this growth is smooth muscle differentiation, whereby smooth muscle cells within cerebral arteries transform from migratory to proliferative to synthetic and finally to contractile phenotypes. These phenotypic transformations can be reversed by pathophysiological perturbations such as hypoxia, which causes loss of contractile capacity in immature cerebral arteries. In turn, loss of contractility affects all whole-brain cerebrovascular responses, including those involved in flow-metabolism coupling, vasodilatory responses to acute hypoxia and hypercapnia, cerebral autoregulation, and reactivity to activation of perivascular nerves. Future strategies to minimize cerebral injury following hypoxia-ischemic insults in the immature brain might benefit by targeting treatments to preserve and promote contractile differentiation in the fetal cerebrovasculature. This could potentially be achieved through inhibition of receptor tyrosine kinase-mediated growth factors, such as vascular endothelial growth factor and platelet-derived growth factor, which are mobilized by hypoxic and ischemic injury and which facilitate contractile dedifferentiation. Interruption of the effects of other vascular mitogens, such as endothelin and angiotensin-II, and even some miRNA species, also could be beneficial. Future experimental work that addresses these possibilities offers promise to improve current clinical management of neonates who have suffered and survived hypoxic, ischemic, asphyxic, or inflammatory cerebrovascular insults. PMID- 30522722 TI - Initial combination therapy with ambrisentan + tadalafil on pulmonary arterial hypertension-related hospitalization in the AMBITION trial. AB - BACKGROUND: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy. PMID- 30522725 TI - The Critical Role of the Central Autonomic Nervous System in Fetal-Neonatal Transition. AB - The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions. PMID- 30522726 TI - Understanding Fetal Heart Rate Patterns That May Predict Antenatal and Intrapartum Neural Injury. AB - Electronic fetal heart rate (FHR) monitoring is widely used to assess fetal well being throughout pregnancy and labor. Both antenatal and intrapartum FHR monitoring are associated with a high negative predictive value and a very poor positive predictive value. This in part reflects the physiological resilience of the healthy fetus and the remarkable effectiveness of fetal adaptations to even severe challenges. In this way, the majority of "abnormal" FHR patterns in fact reflect a fetus' appropriate adaptive responses to adverse in utero conditions. Understanding the physiology of these adaptations, how they are reflected in the FHR trace and in what conditions they can fail is therefore critical to appreciating both the potential uses and limitations of electronic FHR monitoring. PMID- 30522727 TI - Circulatory Changes and Cerebral Blood Flow and Oxygenation During Transition in Newborns With Congenital Heart Disease. AB - This review aims to describe how the complex events of cardiovascular transition may affect the brain of infants with congenital heart disease (CHD). In particular, we describe the vulnerabilities of the neonatal brain in the transitional period during and immediately after delivery and propose management strategies that can potentially influence neurodevelopmental outcomes in this patient population. Delayed brain development has been identified in the third trimester fetus with certain forms of CHD. Neonates with critical CHD are at risk for brain injury even before their neonatal operation. The transitional period from fetal to neonatal life is marked with hemodynamic changes that can affect cerebral blood flow and oxygenation and may exacerbate injury and influence outcome. We propose specific perinatal management strategies tailored to maternal fetal pairs aimed at optimizing hemodynamic stability, especially cerebral blood flow and oxygenation, to maximize the neurodevelopmental potential of infants with CHD. PMID- 30522728 TI - It's All About the Brain-Neuromonitoring During Newborn Transition. PMID- 30522729 TI - Brain Injury During Transition in the Newborn With Congenital Heart Disease: Hazards of the Preoperative Period. AB - Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population. PMID- 30522730 TI - Introduction to Special Issue on Perceptual Learning. PMID- 30522731 TI - Study Registration: Encouraging the Practice of Hypothetical-Deductive Research in the Journal. AB - Earlier this year, we shared with you our commitment to supporting the dissemination of research that is well designed, carefully conducted, and properly interpreted, and our belief that authors, reviewers, editors, publishers, and readers should jointly strive to ensure the integrity of the science that we publish.1 Toward this end, we are pleased to announce a new submission type beginning in 2019: Registered Reports. PMID- 30522732 TI - Mobile Health (mHealth): Building the Case for Adapting Emerging Technologies for Justice-Involved Youth. AB - The term justice-involved youth encompasses a broad range of youth. It can include youth who have not been detained and have been placed on probation or diversion programs, as well re-entry populations transitioning out of detention facilities or stated custody and placed on probation or parole. There are more than 1.3 million juvenile arrests per year, and on any given day there are 50,821 youth incarcerated in the United States. Of the 716,000 delinquency cases, probation is court-ordered for approximately half.1 Even among these youth who are supervised in the community, rates of mental health and substance use disorders are high, with more than two-thirds reporting substance use problems or other mental health disorders.2 However, these youth often have a hard time connecting to and staying in treatment,3 and recidivism is high-most commonly for failing to satisfy the myriad (and well intentioned) conditions of their probation.4 Dual diagnosis (ie, co-occurring psychiatric and substance use disorders) in justice-involved youth is one of the most significant predictors of recidivism,5 and, as such, closing the gap between need and receipt of substance use and mental health treatment for justice-involved youth could potentially offset rates of re-offending into adulthood.6 Despite high rates of mental health and substance use disorders among justice-involved adolescents, only 15% of detained youth receive mental health treatment for their condition(s); this number falls to 8% once these youth re-enter the community.7 These statistics regarding treatment receipt among justice-involved youth are important to consider not only from a health care perspective but also in terms of public health significance and policy. PMID- 30522733 TI - Clinical Affective Neuroscience. AB - Affective neuroscience is a promising young field in neuroscience for understanding the basis of many types of psychopathology. It describes the scientific investigation of the neural basis of affect, emotion, and feelings. These phenomena arise from mental processes that are not always directly observable, which complicates discovering their neural basis. Nevertheless, as it has done for other inferred processes, such as memory and language, neuroscience should transform our emotion-based patient formulations and lead to novel, targeted therapeutics for emotional issues. In this Translations article, we aim to provide a brief introduction to affective neuroscience for clinicians, beginning with defining key terms and then reviewing clinical applications. PMID- 30522734 TI - Intellectual Disabilities in Juvenile Justice: The Case for Screening. AB - Recent efforts to reform and improve the juvenile justice system have overlooked one critically important issue-the widespread failure to routinely screen for intellectual and developmental disabilities (I/DD) in young offenders. Pursuant to the Americans with Disabilities Act and Individuals with Disabilities Education Act, offenders with I/DD must receive appropriate accommodations. Yet across the country, adolescents and adults with I/DD must engage with the juvenile justice system without appropriate supports and often with their disabilities unknown to corrections staff, lawyers, judges, and other personnel. PMID- 30522735 TI - Does Methylphenidate Normalize Brain Dysfunction During Fear Learning in Adolescents With Disruptive Behavior Disorders? AB - Conduct disorder (CD) and oppositional defiant disorder (ODD), collectively termed disruptive behavior disorders (DBDs), are a major cause of impairment and suffering in those affected by these conditions and their families and communities. The prevalence of DBDs is estimated at 5-14% in school-aged children,1 and they are costly to society and linked with negative adult outcomes.2 Unfortunately, few effective psychological treatments are available, and there is a lack of evidence-based pharmacological treatments for DBDs.3 The present study by Van Lith et al.4 investigates whether acute methylphenidate administration normalizes low brain activity during fear conditioning in adolescents with DBDs within the context of a randomized controlled trial. While the group of DBD youth who were given placebo showed reduced amygdala activity during fear conditioning relative to healthy controls, those taking methylphenidate showed an apparent normalization of amygdala activity. PMID- 30522736 TI - Zooming In and Zooming Out: A Network Perspective on the Comorbidity of Depression and Anxiety. AB - Several statistical techniques are available to shed light on the structure of psychopathology, and each is valuable in its own way. It is, however, important to realize that the results of these techniques are substantially influenced by the structure of the studied instrument. Network analyses are no exception and do not perform miracles. However, they are unique in embracing the diversity of psychopathology, as the approach is both specific, by zooming in on individual symptoms, and transdiagnostic, by zooming out on the broad spectrum of psychopathology. Therefore, I genuinely believe that it will move our field forward. PMID- 30522737 TI - Why Is Maternal Depression Related to Adolescent Internalizing Problems? A 15 Year Population-Based Study. AB - OBJECTIVE: Exposure to maternal depression during early childhood is a well documented risk factor for offspring's internalizing problems, but the long-term risk and the psychosocial mechanisms underlying the association remain largely unknown. We examined whether maternal depression during early childhood was associated with offspring internalizing problems in adolescence, and the extent to which negative parenting, peer victimization, and poor friendship quality during middle childhood mediated this association. METHOD: We report on a population-based sample of children (n = 1,443) followed-up from 5 months to 15 years. We use yearly assessments of the exposure variable, that is, maternal depression (5 months to 5 years); the putative mediators, that is, peer victimization, friendship quality, and parenting practices (6-12 years); and assessment of the outcome variables at 15 years: self-reported major depressive (MD), generalized anxiety (GA), and social phobia (SP) symptoms. Structural equation modeling was used to test mediation by peer and family relationships. RESULTS: Exposure to maternal depression during early childhood was associated with higher levels of adolescent MD, GA, and SP. Peer victimization was the only significant mediator and explained 35.9% of the association with adolescent MD, 22.1% of that with GA, and 22.1% of that with SP. CONCLUSION: Exposure to maternal depression prior to age 5 years was associated with depression, anxiety, and social phobia extending to adolescence via its impact on peer victimization during middle childhood. Particular attention should be paid to victimization as one potential psychosocial factor via which maternal depression is associated with adolescent internalizing problems. PMID- 30522738 TI - A Developmental Twin Study of Emotion Recognition and Its Negative Affective Clinical Correlates. AB - OBJECTIVE: Youth with psychiatric disorders distinguished by irritability, including depression and associated trait neuroticism, show deficits in the ability to recognize facial expressions of emotion, particularly happiness. However, the contribution of genetic and environmental factors to this ability remains unknown. The present study examined this trait in twins to assess the genetic and environmental influences on face-emotion recognition abilities and their association with irritability, neuroticism, and depression. METHOD: Child and adolescent twins (N = 957 from 496 families) 9 to 17 years old rated their irritability (on the Affective Reactivity Index), neuroticism (on the Junior Eysenck Personality Questionnaire), and depression (on the Short Mood and Feelings Questionnaire) and completed a face-emotion labeling task. Faces depicting anger, disgust, fear, happiness, sadness, and surprise were morphed with a neutral face, yielding 10 levels of increasing emotional expressivity. Biometrical twin analyses evaluated contributions of genetic and environmental factors to the etiology of face-emotion recognition and its association with irritability, neuroticism, and depression. RESULTS: Recognition of each emotion was heritable; common and specific sets of genetic factors influenced all emotions and individual emotions, respectively. Irritability, neuroticism, and depression were modestly and negatively correlated with emotion recognition, particularly the recognition of happiness. For irritability and neuroticism, this correlation appeared largely due to genetic factors. CONCLUSION: This study maps genetic and environmental contributions to face-emotion recognition and its association with irritability, neuroticism, and depression. Findings implicate common genetic factors in deficits regarding the recognition of happiness associated with irritability and neuroticism in childhood and adolescence. PMID- 30522739 TI - Effects of Methylphenidate During Fear Learning in Antisocial Adolescents: A Randomized Controlled fMRI Trial. AB - OBJECTIVE: Although the neural underpinnings of antisocial behavior have been studied extensively, research on pharmacologic interventions targeting specific neural mechanisms remains sparse. Hypoactivity of the amygdala and ventromedial prefrontal cortex (vmPFC) has been reported in antisocial adolescents, which could account for deficits in fear learning (amygdala) and impairments in decision making (vmPFC), respectively. Limited clinical research suggests positive effects of methylphenidate, a dopamine agonist, on antisocial behavior in adolescents. Dopamine is a key neurotransmitter involved in amygdala and vmPFC functioning. The objective of this study was to investigate whether methylphenidate targets dysfunctions in these brain areas in adolescents with antisocial behavior. METHOD: A group of 42 clinical referred male adolescents (14 17 years old) with a disruptive behavior disorder performed a fear learning/reversal paradigm in a randomized double-blinded placebo-controlled pharmacologic functional magnetic resonance imaging study. Participants with disruptive behavior disorder were randomized to receive a single dose of methylphenidate 0.3 to 0.4 mg/kg (n = 22) or placebo (n = 20) and were compared with 21 matched healthy controls not receiving medication. RESULTS: In a region of-interest analysis of functional magnetic resonance imaging data during fear learning, the placebo group showed hyporeactivity of the amygdala compared with healthy controls, whereas amygdala reactivity was normalized in the methylphenidate group. There were no group differences in vmPFC reactivity during fear reversal learning. Whole-brain analyses showed no group differences. CONCLUSION: These findings suggest that methylphenidate is a promising pharmacologic intervention for youth antisocial behavior that could restore amygdala functioning. CLINICAL TRIAL REGISTRATION INFORMATION: Fear Conditioning During Specific Conditions in Antisocial Adolescents: A Neuroimaging Study. http://www.trialregister.nl/trialreg/index.asp; NTR4088. PMID- 30522740 TI - Mental Health Problems and Onset of Tobacco Use Among 12- to 24-Year-Olds in the PATH Study. AB - OBJECTIVE: To examine whether mental health problems predict incident use of 12 different tobacco products in a nationally representative sample of youth and young adults. METHOD: This study analyzed Wave (W) 1 and W2 data from 10,533 12- to 24-year-old W1 never tobacco users in the Population Assessment of Tobacco and Health (PATH) Study. Self-reported lifetime internalizing and externalizing symptoms were assessed at W1. Past 12-month use of cigarettes, electronic nicotine delivery systems (ENDS), traditional cigars, cigarillos, filtered cigars, pipe, hookah, snus pouches, other smokeless tobacco, bidis and kreteks (youth only), and dissolvable tobacco was assessed at W2. RESULTS: In multivariable regression analyses, high-severity W1 internalizing (adjusted odds ratio [AOR] = 1.5, 95% CI = 1.3-1.8) and externalizing (AOR = 1.3, 95% CI = 1.1 1.5) problems predicted W2 onset of any tobacco use compared to no/low/moderate severity. High-severity W1 internalizing problems predicted W2 use onset across most tobacco products. High-severity W1 externalizing problems predicted onset of any tobacco (AOR = 1.6, 95% CI = 1.3-1.8), cigarettes (AOR = 1.4, 95% CI = 1.0 2.0), ENDS (AOR = 1.8, 95% CI = 1.5-2.1), and cigarillos (AOR = 1.5, 95% CI = 1.0 2.1) among youth only. CONCLUSION: Internalizing and externalizing problems predicted onset of any tobacco use. However, findings differed for internalizing and externalizing problems across tobacco products, and by age, gender, and race/ethnicity. In addition to screening for tobacco product use, health care providers should screen for a range of mental health problems as a predictor of tobacco use. Interventions addressing mental health problems may prevent youth from initiating tobacco use. PMID- 30522741 TI - Parenting Is an Environmental Predictor of Callous-Unemotional Traits and Aggression: A Monozygotic Twin Differences Study. AB - OBJECTIVE: Callous-unemotional (CU) traits increase risk for children to develop severe childhood aggression and conduct disorder. CU traits are typically described as highly heritable, and debate continues about whether the parenting environment matters in their etiology. Strong genetically informed designs are needed to test for the presence of environmental links between parenting practices and CU traits. Our objective was to determine whether parental harshness and parental warmth were related to children's aggression or CU traits when accounting for genetically mediated effects. METHOD: We examined 227 monozygotic twin pairs (454 children) drawn from population-based and at-risk samples of twin families, leading to oversampling of twins living in poverty. We computed multi-informant difference scores combining mother and father reports of their harshness and warmth toward each twin, and differences in mother reports of each twin's aggression and CU traits. RESULTS: Twin differences in parental harshness were related to differences in both aggression and CU traits, such that the twin who received harsher parenting had higher aggression and more CU traits. Differences in parental warmth were uniquely related to differences in CU traits, such that the twin receiving warmer parenting evidenced lower CU traits. These effects were not moderated by child sex, age, or family income, with the exception that the relationship between differential parental harshness and differential child aggression was stronger among low-income families. CONCLUSION: Parenting is related to child CU traits and aggression, over and above genetically mediated effects, with low parental warmth being a unique environmental correlate of CU traits. PMID- 30522742 TI - Networks of Depression and Anxiety Symptoms Across Development. AB - OBJECTIVE: Frequent co-occurrence and bidirectional longitudinal associations have led some researchers to question the boundaries between depression and anxiety. A longitudinal investigation of the interconnected symptom structure of these constructs may help determine the extent to which they are distinct, and whether this changes over development. Therefore, the present study used network analysis to examine these symptom-symptom associations developmentally from early childhood to mid-adolescence. METHOD: We analyzed data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 1,147). Depression and anxiety symptoms were assessed on 7 occasions between ages 5 and 14 years using maternal reports. Regularized partial correlation networks were constructed at each time point, and diagnostic boundaries were explored using empirical tests of network modularity (ie, clustering of symptom nodes). Nonparametric permutation tests were used to determine whether symptoms became more associated over development, and network centrality was examined to identify developmental changes in the overall importance of specific symptoms. RESULTS: Symptoms formed highly interconnected networks, as evidenced by strong associations between depression and anxiety symptoms and a lack of distinct clustering. There was some evidence of an increase in overall connectivity as children aged. Feeling "anxious/fearful" and "unhappy/sad" were consistently the most central symptoms over development. CONCLUSION: Minimal clustering of nodes indicated no separation of depression and anxiety symptoms from early childhood through mid-adolescence. An increase in connectivity over development suggests that symptoms may reinforce each other, potentially contributing to the high levels of lifetime continuity of these disorders. PMID- 30522743 TI - Physical and Psychosocial Impact of a University-Based, Volunteer Student-Led Running Program for Children With Autism Spectrum Disorder. AB - Children with autism spectrum disorder (ASD) are frequently excluded from group sports.1 This accentuates the social isolation inherent in their condition, perpetuates cycles of perceived incompetence in physical activity, and increases susceptibility to weight gain influenced by psychotropic medications.2 In a 2015 study of 376 children with ASD, 18.1% of children were overweight and 17% were obese.3 Scarcity of opportunity to participate on athletic teams can contribute to this liability and compound the social isolation inherent in the condition.4-6 Thus, programs that combine relationship building with physical conditioning present a double opportunity to offset significant hurdles for children with ASD. To address these needs locally, a group of volunteer college student-athletes (led by co-author Annie Marggraff) established a weekly Sunday afternoon program for athletic opportunity for children with ASD in the community. The program, Bear Cubs Running Team, was piloted over 5 successive semesters at Washington University in St. Louis, Missouri to empower children with ASD to set achievable physical conditioning goals, provide a forum to support their families, and increase college students' awareness of barriers against and opportunities to meaningful improvements in health and quality of life. PMID- 30522744 TI - A Proposal to Address the Workforce Shortage in Child and Adolescent Psychiatry. AB - Drs. Findling and Stepanova1 end their Commentary on the workforce shortage in child and adolescent psychiatry with the following statement: "We should use our field's rich traditions and unique insights to establish new ways of doing more for the youths we are honored to serve" (p. 301). They rightly state that "we are proud of our field being able to provide a comprehensive family-centered approach to pediatric mental health care, which often requires substantial time and effort" (p. 301). Unfortunately, they do not specify what a child and adolescent psychiatrist can add to a "comprehensive family-centered approach," which, more often than not, should be provided by a well-educated family medicine practitioner or pediatrician. Another recent study addressed the recruitment problem in child and adolescent psychiatry2 and recognized the emotional stresses during child and adolescent psychiatry training. PMID- 30522745 TI - Drs. Stepanova and Findling Reply. AB - We read with interest the Letter to the Editor1 that was provided to us in response to our Commentary on the workforce shortage.2 We thank Dr. Hoffman, who suggested that we provide concrete steps toward decreasing the workforce shortage and emphasized the importance of child and adolescent psychiatrists (CAPs) providing psychotherapy. The Letter to the Editor prompted us to re-emphasize some key topics that we mentioned previously and to discuss several new points. PMID- 30522746 TI - Tread Softly. AB - Had I the heaven's embroidered cloths, Enwrought with golden and silver light, The blue and the dim and the dark cloths Of night and light and the half-light; I would spread the cloths under your feet: But I, being poor, have only my dreams; I have spread my dreams under your feet; Tread softly because you tread on my dreams. -W.B. Yeats In Caroline Elton's Also Human: The Inner Lives of Doctors, she references The Cloths of Heaven to evidence her awareness of the responsibility she carries when lecturing hopeful future doctors on the tougher side of medicine. As an occupational psychologist whose specialty is physicians and trainees with career difficulties, she knows the wisdom she shares can be deflating. Elton recounts trying to heed the last line of Yeats' poem- "Tread softly because you tread on my dreams"-before speaking to medical school applicants at a talk organized by the British Medical Journal. PMID- 30522747 TI - Invisible Allies: Thanking Our Reviewers. AB - Reviewing manuscripts is hard work. We wish to express our heartfelt appreciation to the 575 hard workers listed below, who so diligently served their Journal between July 1, 2017, and June 30, 2018. Our additional gratitude to our eight colleagues (Guido K.W. Frank, James F. Leckman, Christel Middeldorp, Lawrence Scahill, Joel Stoddard, Argyris Stringaris, Peter Szatmari, and Bonnie T. Zima) who served as ad hoc action editors and helped ensure that all manuscripts, our own included, were treated under the same editorial standards. We also would like to acknowledge the three colleagues who are completing their terms on our Editorial Board (Kelly N. Botteron, Melissa P. DelBello, and Mary Margaret Gleason) and the four colleagues who will be joining the Editorial Board in 2019 (Matthew G. Biel, Alice Charach, Laura M. Prager, and S. Evelyn Stewart). We are also appreciative that Michael H. Bloch will continue his service to the Journal as one of our Editors-At-Large for Methodology and Statistics. PMID- 30522748 TI - Transparency: Disclosure of Financial Interests. AB - In keeping with the Journal's policies,1 we provide a listing of disclosures for all members of the editorial masthead and the ad hoc editors (marked with an asterisk) as of October 19, 2018. This list, based on annually updated signed statements on file in the editorial office, includes all biomedical financial interests and potential conflicts of interest disclosed for the previous 24 months and the foreseeable future. PMID- 30522749 TI - Recovery of Kidney Dysfunction After Transcatheter Aortic Valve Implantation (from the Northern New England Cardiovascular Disease Study Group). AB - Acute Kidney Recovery (AKR) is a potential benefit of transcatheter aortic valve implantation (TAVI). We determined the incidence and predictors of AKR in a multicenter prospective registry of TAVI. After excluding patients on dialysis or who died within 48 hours postprocedure, we reviewed 1,502 consecutive patients underwent TAVI in Northern New England from 2012 to 2017. Patients were categorized into 3 groups based on the change in postprocedure estimated glomerular filtration rate (eGFR): Acute Kidney Injury (AKI, decrease in eGFR >25%), AKR (increase in eGFR >25%) or no change in kidney function on discharge creatinine following TAVI. We then focused in patients with baseline chronic kidney disease (CKD defined as eGFR <=60 ml/min; n = 755) and developed multivariate predictor models to determine the clinical and procedural variables associated with AKR. For the TAVI cohort (n = 1,502), the overall incidence of AKR was 17.8%. AKR was threefold higher in patients with eGFR <=60 ml/min as compared to those with eGFR >60 ml/min (26.6% vs 8.9%, p < 0.001). In the CKD population, hospital complications were similar among patients with no change in renal function and AKR; patients with AKI had a higher rate of hospital mortality, pacemaker implantation, length of hospitalization, and transfusions. Using multivariable logistic regression, moderate to severe lung disease, eGFR < 50 ml/min and previous aortic valve surgery were found to be independent predictors of AKR. Patients with diabetes mellitus, baseline anemia, and Society of thoracic surgeons score >6.1 were less likely to develop AKR. In conclusion, AKR occurred in 1 of 4 of all TAVI patients with baseline CKD and was a more frequent phenomena than AKI. Patients with decreased lung function, previous aortic valve surgery and worse baseline renal function were more likely to demonstrate AKR, whereas patients with diabetes mellitus, baseline anemia, and higher Society of thoracic risk scores were less likely to see improvements in renal function after TAVI. PMID- 30522750 TI - Key mechanisms of cognitive behavioural therapy in irritable bowel syndrome: The importance of gastrointestinal related cognitions, behaviours and general anxiety. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterised by abdominal pain and altered bowel movements. Cognitive behavioural therapy (CBT) has been shown to be effective in reducing symptom severity in IBS and enhancing quality of life/functioning. The present study sought to identify how CBT achieves change in these outcomes. METHOD: Secondary analysis was conducted on 149 patients with irritable bowel syndrome who had been randomised to cognitive behavioural therapy plus an antispasmodic medication or antispasmodic alone. Single and sequential mediation was modelled using structural equation modelling. Gastrointestinal (GI) related avoidance behaviour, safety behaviour, cognitions and general anxiety were included as mediators. RESULTS: GI safety behaviours, cognitions and general anxiety mediated treatment effect on the outcomes of symptom severity and work and social adjustment. Avoidance behaviour was not a significant mediator for either outcome. Sequential mediation models indicated that unhelpful GI related cognitions reduced before anxiety did, and this sequential path (R?GI related cognitions?anxiety?outcome) was significant for both symptom severity (b = -0.22, CI [-0.40 to -0.90], p = .005) and work and social adjustment (b = -0.26, CI [-0.44 to -0.11], p = .003) where 'R' is randomisation. Reduction in GI safety behaviours also preceded reduction in anxiety. This sequence (R ?GI safety behaviours?anxiety?outcome) was significant for both symptom severity (b = -0.11, CI [-0.24 to -0.01], p = .049) and work and social adjustment (b = -0.12, CI [-0.23 to -0.03], p = .03). CONCLUSION: Results suggest that it is important for psychological treatments to target IBS specific factors for change. PMID- 30522751 TI - Post-Trial Sustainability and Scalability of the Benefits of a Medical Home for High-Risk Children with Medical Complexity. AB - OBJECTIVE: To assess the sustainability of the benefits relative to usual care of a medical home providing comprehensive care for high-risk children with medical complexity (>=2 hospitalizations or >=1 pediatric intensive care unit [PICU] admission in the year before enrollment) after we made comprehensive care our standard practice and expanded the program. STUDY DESIGN: We conducted pre-post comparisons of the rate of children with serious illness (death, PICU admission, or >7-day hospitalization) and health-system costs observed after program expansion (March 2014-June 2015) to those during the clinical trial (March 2011 August 2013) for each of the trial's treatment groups (usual care, n = 96, and comprehensive care, n = 105; primary analyses), and among all children given comprehensive care (nPost-trial = 233, including trial usual care children who transitioned to comprehensive care post-trial and newly enrolled medically complex children, and nTrial = 105; secondary analyses). We also analyzed the findings for the trial patients as a 2-phase stepped-wedge study. RESULTS: In intent-to-treat analyses, rates of children with serious illness and costs were reduced or unchanged post-trial vs trial for the trial's usual care group (rate ratio [RR], 0.36; 95% CI, 0.20-0.64; cost ratio [CR], 0.68; 95% CI, 0.28-1.68), the trial's comprehensive care group (RR, 0.74; 95% CI, 0.39-1.41; CR, 0.67; 95% CI, 0.51-0.89), and among all children given comprehensive care (RR, 0.97; 95% CI, 0.61-1.52; CR, 0.75; 95% CI, 0.61-0.93). Conservative stepped-wedge analyses identified overall benefits with comprehensive care across both study periods (RR, 0.46; 95% CI, 0.30-0.72; CR, 0.64; 95% CI, 0.43-0.99). CONCLUSIONS: Major benefits of comprehensive care did not diminish with post-trial program expansion. PMID- 30522752 TI - Sedentary leisure-time in relation to mortality and survival time. AB - OBJECTIVE: To examine the association between sedentary leisure-time and all cause mortality and differences in survival time. DESIGN: Prospective cohort study. METHODS: Information on sedentary leisure-time, defined as TV viewing and/or sitting reading, was collected from 72003 Swedish adults who were 45-83 (median 60) years of age and completed a self-administered questionnaire at baseline and were followed up for 17years through linkage with the Swedish Death Register. RESULTS: The association between sedentary leisure-time and all-cause mortality was modified by age with a more pronounced association in middle-aged (<60years of age) than in older adults (>=60years of age) (p-interaction<0.001). During follow-up, 3358 and 15217 deaths occurred in the middle-aged and older age group, respectively. The multivariable-adjusted hazard ratios for the highest (>6h/day) versus lowest category (<1h/day) of sedentary leisure-time were 1.72 (95% confidence interval [CI] 1.29-2.30) in middle-aged adults and 1.19 (95% CI 1.05-1.36) in older adults. This corresponded to a difference in survival time of respectively 2.4 (95% CI -4.1 to -0.8) years and 1.5 (95% CI -2.2 to -0.7) years. CONCLUSIONS: Prolonged sedentary leisure-time was associated with a significantly decreased survival time up to 2.4 years in middle-aged adults. PMID- 30522753 TI - Diagnostic orientation of abdominal aortic graft infection using 18F-FDG PET/CT. PMID- 30522754 TI - ? PMID- 30522755 TI - ? PMID- 30522756 TI - [Motility disorders in the elderly]. AB - Motility disorders are frequent, especially in the elderly. They must not be ignored and require a systematic evaluation. Constipation, which many elderly people suffer from, must not be trivialised as it can impact on quality of life. Diarrhoea, the manifestation of which is more acute, requires fast and adapted treatment. PMID- 30522757 TI - [Gastro-intestinal infections with Clostridium difficile in the elderly]. AB - In view of its high frequency and its consequences which can be dramatic for patients, it is necessary to know how to identify Clostridium difficile infection. The high risk of an epidemic means it is especially important to know how to treat it, in terms of the hygiene and isolation rules, as well as which medication to use. PMID- 30522758 TI - [Gastrointestinal endoscopies in the elderly]. AB - There are numerous indications for gastrointestinal endoscopies in elderly people. These include notably bleeding of the digestive tract, unexplained anorexia, abdominal pain, a pathology of the colon or screening for cancerous lesions. These examinations are carried out by a multidisciplinary team. It is essential that the patient is informed as a certain amount of prior preparation is required to ensure the good quality of the examinations. PMID- 30522759 TI - [Colorectal cancer in geriatrics, an overview of current knowledge]. AB - Given its high frequency in elderly people and the lack of organised national screening after the age of 74, it is essential for caregivers to be aware of the symptoms and the tests which can lead to a diagnosis of cancer of the colon or rectum. It is also necessary to know which asssessment to carry out in order to gather all the elements concerning the cancer and to carry out a global evaluation of the patient before discussing treatment options through cross disciplinary consultation. PMID- 30522760 TI - [Colorectal cancer surgery in the elderly]. AB - Colorectal cancer risk factors increase with age, comorbidities, delayed diagnosis, obstruction, emergency and frailty. Surgery is the standard treatment as the survival rate for this pathology is the same as in young patients. It would appear that there is an excess morbidity and mortality of colorectal cancer surgery in the elderly. Early rehabilitation is to be favoured during the postoperative period. PMID- 30522761 TI - [Elderly people and new technologies: friends or enemies?] AB - Faced with the ageing of the French population, it is essential to envisage new technologies to improve the living conditions of elderly people and enable them to communicate more effectively. A study sought to understand the views of senior citizens and the caregivers who look after them regarding these new tools, their appropriation, the support required and their uses. This analysis highlights areas to reflect upon and improve in terms of the services which need to be provided to overcome the reticence of certain users. PMID- 30522762 TI - [Physicians and advance directives in geriatric setting]. AB - Advance directives (AD) are not sufficiently applied in geriatric setting despite their widespread dissemination since the publication of Claeys-Leonetti law. The aim of this study was to analyze geriatricians' knowledge of the concept of AD and to evaluate their practices in the process of patient information and AD collection. PMID- 30522763 TI - [May 68 as seen by the elderly]. AB - May 68 remains etched in everybody's mind. Fifty years on, many memories remain vivid and those who lived through this turbulent period. Yesterday's adults, today's senior citizens, share their testimonies. PMID- 30522764 TI - ? PMID- 30522765 TI - ? PMID- 30522766 TI - Activation of fibroblastic reticular cells in kidney lymph node during crescentic glomerulonephritis. AB - Crescentic glomerulonephritis is an inflammatory condition characterized by rapid deterioration of kidney function. Previous studies of crescentic glomerulonephritis have focused on immune activation in the kidney. However, the role of fibroblastic reticular cells, which reside in the stromal compartment of the kidney lymph node, has not been studied in this condition. We investigated the activation of kidney lymph node-resident fibroblastic reticular cells in nephrotoxic serum nephritis, a classic murine model of crescentic glomerulonephritis. We found that increased deposition of extracellular matrix fibers by fibroblastic reticular cells in the kidney lymph node was associated with the propagation of high endothelial venules, specialized blood vessels through which lymphocytes enter the lymph node, as well as with expansion of the lymphatic vasculature. The kidney lymph node also contained an expanding population of pro-inflammatory T cells. Removal of the kidney lymph node, depletion of fibroblastic reticular cells, and treatment with anti-podoplanin antibody each resulted in reduction of kidney injury. Our findings suggest that modulating the activity of fibroblastic reticular cells may be a novel therapeutic approach in crescentic glomerulonephritis. PMID- 30522768 TI - Arterial oxygen content regulates plasma erythropoietin independent of arterial oxygen tension: a blinded crossover study. AB - The production of erythropoietin (Epo) is modulated by renal tissue oxygen tension, which in principle depends on both arterial oxygen content (CaO2) and arterial oxygen tension (PaO2). Uncontrolled observational studies suggest that alterations in CaO2 fundamentally regulate Epo synthesis. We sought to establish whether reduced CaO2 enhances plasma Epo concentration independently of PaO2. In a blinded crossover study, 8 healthy young subjects were exposed to three conditions: room air (normoxia); 11% oxygen balanced in nitrogen, which lowers both CaO2 and PaO2 (hypoxia); and carbon monoxide plus normoxia, which decreases CaO2 to the same degree as hypoxia while preserving PaO2 (hypoxemia). Arterial blood samples were obtained prior to and throughout the 5 hours of exposure to each condition. In the hypoxic conditions, average CaO2 was reduced to similar levels, whereas PaO2 was only decreased with exposure to hypoxia. Plasma Epo concentration was increased in both hypoxic conditions relative to normoxia after 150 min of exposure and was augmented more than two-fold after 300 min, with no difference between hypoxic conditions. Reduced CaO2 induces similar increases in circulating Epo concentration irrespective of PaO2 manipulation, demonstrating that CaO2 is the critical variable regulating Epo production. PMID- 30522770 TI - Multimorbidity and Comorbidity are now separate MESH headings. PMID- 30522767 TI - The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury. AB - Acute kidney injury (AKI) leads to significant morbidity and mortality; unfortunately, strategies to prevent or treat AKI are lacking. In recent years, several preconditioning protocols have been shown to be effective in inducing organ protection in rodent models. Here, we characterized two of these interventions-caloric restriction and hypoxic preconditioning-in a mouse model of cisplatin-induced AKI and investigated the underlying mechanisms by acquisition of multi-layered omic data (transcriptome, proteome, N-degradome) and functional parameters in the same animals. Both preconditioning protocols markedly ameliorated cisplatin-induced loss of kidney function, and caloric restriction also induced lipid synthesis. Bioinformatic analysis revealed mRNA-independent proteome alterations affecting the extracellular space, mitochondria, and transporters. Interestingly, our analyses revealed a strong dissociation of protein and RNA expression after cisplatin treatment that showed a strong correlation with the degree of damage. N-degradomic analysis revealed that most posttranscriptional changes were determined by arginine-specific proteolytic processing. This included a characteristic cisplatin-activated complement signature that was prevented by preconditioning. Amyloid and acute-phase proteins within the cortical parenchyma showed a similar response. Extensive analysis of disease-associated molecular patterns suggested that transcription-independent deposition of amyloid P-component serum protein may be a key component in the microenvironmental contribution to kidney damage. This proof-of-principle study provides new insights into the pathogenesis of cisplatin-induced AKI and the molecular mechanisms underlying organ protection by correlating phenotypic and multi-layered omics data. PMID- 30522769 TI - Platelet retention in inflamed glomeruli occurs via selective prolongation of interactions with immune cells. AB - Platelet-leukocyte interactions promote acute glomerulonephritis. However, neither the nature of the interactions between platelets and immune cells nor the capacity of platelets to promote leukocyte activation has been characterized in this condition. We used confocal intravital microscopy to define the interactions of platelets with neutrophils, monocytes, and endothelial cells in glomerular capillaries in mice. In the absence of inflammation, platelets underwent rapid on/off interactions with immune cells. During glomerulonephritis induced by in situ immune complex formation, platelets that interacted with neutrophils or monocytes, but not with other intraglomerular cells, were retained in the glomerulus for prolonged durations. Depletion of platelets inhibited both neutrophil recruitment and activation. Inhibition of platelet activating factor reduced neutrophil recruitment without impacting reactive oxygen species generation, while blocking CXC chemokine ligand 7 (CXCL7) reduced both responses. In contrast, inhibition of the adenosine diphosphate and thromboxane A2 pathways inhibited neutrophil reactive oxygen species generation without affecting neutrophil adhesion. Thus, platelet retention in glomerular capillaries following immune complex deposition stems from prolongation of platelet interactions with immune cells but not other substrates. Pro-inflammatory mediators play divergent roles in promoting neutrophil retention and activation in glomerular capillaries. PMID- 30522771 TI - Preparation and evaluation of dummy-template molecularly imprinted polymer as a potential sorbent for solid phase extraction of imidazole fungicides from river water. AB - Dummy molecularly imprinted polymer (DMIP) for imidazole fungicides was prepared for the first time using alpha-(2,4-Dichlorophenyl)-1H-imidazole-1-ethanol (DCE) as the fragment template. The imprinting selectivity of DCE-DMIP was evaluated for climbazole (CBZ), clotrimazole (CMZ) and miconazole (MNZ) by liquid chromatography, imprinting factors of 10.9, 10.8 and >10.7 were achieved, respectively. Heterogeneous binding sites were found in the DCE-DMIP, the corresponding saturation capacity and dissociation constant for the high affinity binding sites were 13.05 MUmol g-1 and 0.4701 mmol L-1. High efficient method based on dummy molecularly imprinted solid phase extraction (DMISPE) coupled with HPLC was established for the selective enrichment of CBZ, CMZ and MNZ in river water using DCE-DMIP as sorbent. DMISPE conditions including sample loading pH/volume, selective washing and elution solvents were carefully optimized. The developed method showed good recoveries (84.2-95.0%) and precision (RSDs 1.7 5.0%, n = 5) for samples spiked at two different concentration levels (0.5 and 2.5 MUg L-1). The detection limits were ranged from 0.023 to 0.031 MUg L-1. The results demonstrated good potential of this method for sample pretreatment of azole fungicides in environmental water samples. PMID- 30522772 TI - Simplex-centroid design and Derringer's desirability function approach for simultaneous separation of phenolic compounds from Mimosa scabrella Bentham honeydew honeys by HPLC/DAD. AB - Honeydew honeys have been under-evaluated about their major phenolic compounds, especially Mimosa scabrella Bentham (bracatinga) honeydew honey. In this work, a fast and robust chromatographic method was optimized for simultaneous separation and quantification by HPLC/DAD of 18 phenolic compounds detected in bracatinga honeydew honey. A simplex-centroid design, central composite rotatable design and response surface-desirability function simultaneous optimization of Derringer and Suich were used, evaluating the mobile phase composition, flow rate and oven temperature to separate all the peaks. These multivariate procedures were efficient in determining the optimal separation conditions, using peak pair resolutions and run time as responses. The 18 peaks were separated in 25 min and the mobile phase gradient started with 1.6% MeOH, 3.3% ACN, 1.0% THF and 94.1% formic acid 0.1% changing to 10.0% MeOH, 33.3% ACN, 6.0% THF and 50.7% formic acid 0.1%, oven temperature of 33 degrees C and flow rate of 0.73 mL min-1. The method was validated according to Eurachem guidelines and considered accurate and robust. It was applied to 18 bracatinga honeydew honey samples in which 9 phenolic compounds were identified and quantified. PMID- 30522773 TI - Corrigendum to "Ohioensin F suppresses TNF-alpha-induced adhesion molecule expression by inactivation of the MAPK, Akt and NF-kappaB pathways in vascular smooth muscle cells" [Life Sci. 90 (2012) 396-406]. PMID- 30522774 TI - [Under-diagnosis of neuromuscular diseases in patients of 80 years and older]. AB - Myasthenia gravis (MG), amyotrophic lateral sclerosis and Guillain-Barre syndrome (GBS) have been classically considered as exceptional or unusual diseases in people with a geriatric profile. Over the past 25 years, several population-based studies have been conducted in the Osona area (Barcelona), which, for the first time, has led to describing the high global incidences in the elderly, especially those over 80 years-old. The results suggest the possibility of underdiagnosis of these neuromuscular diseases in the elderly, a fact that could be especially relevant in the case of MG and GBS, since they are 2potentially reversible entities with high mortality in the event of underdiagnosis and absence of treatment. PMID- 30522775 TI - Clinicopathologic characteristics and EGFR mutations in lung cancer patients aged below 45 years. AB - Patients aged <=45 years are rarely diagnosed as lung cancer. Therefore, this paper describes a retrospective study which was conducted to understand the clinicopathologic characteristics and epidermal growth factor receptor (EGFR) mutations in these young lung cancer patients. All patients diagnosed as lung cancer from January 2014 to December 2016 at Huai'an First People's Hospital were enrolled in this study. Their clinicopathologic manifestations and EGFR mutations were recorded, and the difference between those aged less than 45 years and those aged above 45 years was compared. A total of 1472 patients were enrolled in this study, including 73 (4.95%) younger patients (<=45 years old) and 1399 older patients (>45 years old). The proportions of female patients (57.5% vs 32.2%, P = 0.000), nonsmokers (79.5% vs 54.2%, P = 0.000), and adenocarcinoma (72.6% vs 54.8%, P = 0.000) were higher in the younger group, while the primary location of lung cancer and the selection of surgical treatment showed no significant difference between the 2 groups. Among all 1472 patients, there were 1410 cases of nonsmall cell lung carcinoma (NSCLC), whose stage distribution was significantly different between the 2 groups (stage I/II and carcinoma in situ: 38.0% vs 40.1%; stage III/IV: 62.0% vs 52.4%, P = 0.047). There was no significant difference in the number of T stage and N stage cases between the 2 groups. The EGFR mutation rate and overall survival were not significantly different between the 2 groups. In conclusion, lung cancer in young patients (<=45 years old) was associated with unique characteristics, with greater percentages of female patients, adenocarcinoma, nonsmokers, and advanced tumor stage. PMID- 30522776 TI - Mullerian adenosarcomas of the uterine cervix with sarcomatous overgrowth. AB - Mullerian adenosarcoma with sarcomatous overgrowth (MASO) of the uterine cervix is an extremely rare variant of adenosarcoma of the genital tract associated with aggressive clinical course. We searched the PubMed and Medline databases for MASO of the cervix and we identified and reviewed eleven cases published between years 2004 and 2017. The most common clinical picture includes abnormal vaginal bleeding, postcoital bleeding, pelvic pain and foul-smelling vaginal discharge. Therapeutic options for MASO are still undefined. Radical hysterectomy with sufficient tumour-free margins combined with adjuvant chemotherapy and radiotherapy should serve as an effective treatment tool with favourable outcome. PMID- 30522777 TI - Ventral attention and motor network connectivity is relevant to functional impairment in spatial neglect after right brain stroke. AB - Emerging research suggests spatial neglect after right stroke is linked to dysfunctional attention and motor networks. Advanced functional connectivity analysis clarified brain network recovery, however we need to know how networks participate in adaptive motor performance. We need to verify network changes associated with validated functional measures and spatial-motor performance in spatial neglect, especially in patients with large brain lesions and significant disability. This study tested whether disability-relevant spatial neglect associates with different patterns of resting state functional connectivity between motor, dorsal and ventral attention networks (MN, DAN and VAN). Right stroke patients had spatial neglect (n = 8) or not (n = 10) on the Behavioural Inattention Test-conventional. Spatial neglect patients had weaker intranetwork VAN connectivity, and reduced internetwork connectivity between VAN and left frontal eye field (DAN), and between VAN and the left primary motor area (MN). These network impairments might explain the co-occurrence of attention and motor deficits in spatial neglect, and open a path to assessing functional connectivity in clinical trials of combined spatial retraining and motor rehabilitation after stroke. PMID- 30522778 TI - Ability to process musical pitch is unrelated to the memory advantage for vocal music. AB - Listeners remember vocal melodies better than instrumental melodies, but the origins of the effect are unclear. One explanation for the 'voice advantage' is that general perceptual mechanisms enhance processing of conspecific signals. An alternative possibility is that the voice, by virtue of its expressiveness in pitch, simply provides more musical information to the listener. Individuals with congenital amusia provide a unique opportunity to disentangle the effects of conspecific status and vocal expressiveness because they cannot readily process subtleties in musical pitch. Forty-one participants whose musical pitch discrimination ability ranged from congenitally amusic to typical were tested. Participants heard vocal and instrumental melodies during an exposure phase, and heard the same melodies intermixed with timbre-matched foils in a recognition phase. Memory was better for vocal than instrumental melodies, but the magnitude of the advantage was unrelated to musical pitch discrimination or memory overall. The voice enhances melodic memory regardless of music perception ability, ruling out the role of pitch expressiveness in the voice advantage. More importantly, listeners across a wide range of musical ability can benefit from the privileged status of the voice. PMID- 30522779 TI - Trends and geographic pattern of stomach cancer mortality in Peru. AB - BACKGROUND: Stomach cancer mortality rates in South America are among the highest in the world. In Peru, stomach cancer has the highest absolute number of cancer deaths in both sexes combined. We estimated mortality rates for stomach cancer in Peru by sex and geographical region between 2008 and 2015. METHODS: We obtained death data for stomach cancer from the Peruvian Ministry of Health database. We estimated the age-standardized mortality rate (ASMR) per 100,000 persons using the direct method and the world standard population. RESULTS: A total of 25,020 deaths from stomach cancer were identified in the study period. At national level, stomach cancer mortality rates (per 100,000 population) for men ranged from 9.8 in 2008 to 8.8 in 2015 with a percent change of -16%, and for women from 8.8 in 2008 to 7.7 in 2015 with a percent change of -16.8%. The highlands had the highest mortality rates overall, mainly in Huancavelica and Huanuco. The rainforest had the lowest rates and the highest decline in stomach cancer ASMRs. The coast displayed intermediate rates overall. CONCLUSIONS: Within the study period, mortality rates from stomach cancer in Peru declined by 16%. The highlands had the highest mortality rates as compared to those from the coast or rainforest region. These geographical differences in mortality could reflect a different distribution in stomach cancer risk factors as the prevalence of H. pylori, poor dietary habits, low socioeconomic background of the Andean population and the lack of a decentralized health system. PMID- 30522780 TI - Skeletal phenotype of the neuropeptide Y knockout mouse. AB - Neuropeptide Y (NPY) is involved in multiple processes such as behavior, energy and bone metabolism. Previous studies have relied on global NPY depletion to examine its effects on bone. However, this approach is unable to distinguish the central or local source of NPY influencing bone. Our aim was to identify which cells within the skeleton express Npy and establish a model that will enable us to differentiate effects of NPY derived from different cell types. We have generated the NPY floxed (NPYflox) mice using CRISPR technology. By crossing the NPYflox mice with Hypoxanthine Phosphoribosyltransferase 1 (Hprt)-cre to generate a global knockout, we were able to validate and confirm loss of Npy transcript and protein in our global NPYKO. Global deletion of NPY results in a smaller femoral cortical cross-sectional area (-12%) and reduced bone strength (-18%) in male mice. In vitro, NPY-deficient bone marrow stromal cells (BMSCs) showed increase in osteogenic differentiation detected by increases in alkaline phosphatase staining and bone sialoprotein and osteocalcin expression. Despite both sexes presenting with increased adiposity, female mice had no alterations in bone mass, suggesting that NPY may have sex-specific effects on bone. In this study we identified Npy expression in the skeleton and examined the effect of global NPY depletion to bone mass. The differential impact of NPY deletion in cortical and cancellous compartments along with differences in phenotypes between in vitro and in vivo, highlights the complex nature of NPY signaling, indicative of distinct sources that can be dissected in the future using this NPYflox model. PMID- 30522781 TI - Overexpression of Toll-like receptor 4 enhances LPS-induced inflammatory response and inhibits Salmonella Typhimurium growth in ovine macrophages. AB - The Toll-like receptor 4 (TLR4) plays a crucial role in innate inflammatory responses, as it recognizes gram-negative bacteria (or their products) and contributes greatly to host defense against invading pathogens. Though TLR4 overexpressing transgenic sheep, resistant to certain diseases related with gram negative bacteria, had been bred in our previous research, the effects of overexpression of TLR4 on innate immune response remained unclear. In this study, TLR4 overexpressing ovine macrophages were obtained from peripheral blood, and it was found that the overexpression of TLR4 initially promoted the production of proinflammatory cytokines TNFalpha and IL-6 by activating TLR4-mediated IRAK4 dependent NF-kappaB and MAPK (JNK and ERK1/2) signaling following LPS stimulation. However, this effect was later impaired due to increased internalization of TLR4 into endosomal compartment of the macrophages. Then the overexpression of TLR4 triggered TBK1-dependent interferon-regulatory factor-3 (IRF-3) expression, which in turn led to the induction of IFN-beta and IFN inducible genes (i.e.IP10, IRG1 and GARG16). Understandably, an increased IFN beta level facilitated phosphorylation of STAT1 to induce expression of innate antiviral genes Mx1 and ISG15, suggesting that TLR4 overexpressing macrophages were equipped better against viral infection. Correspondingly, the bacterial burden in these macrophages, after infection with live S. Typhimurium, was decreased significantly. In summary, the results indicated that overexpression of TLR4 could enhance innate inflammatory responses, initiate the innate antiviral immunity, and control effectively S. Typhimurium growth in ovine macrophages. PMID- 30522782 TI - Strategies for Balloon-Uncrossable Chronic Total Occlusion Lesions. PMID- 30522784 TI - An aortic calcification in a seventeenth-century autopsy report: The case of Cardinal Camillo Melzi. PMID- 30522783 TI - [Clinical empathy among family and community medicine residents and tutors. The view of physicians and patients]. AB - AIM: To determine the degree of clinical empathy among family medicine residents and tutors. To gauge whether there is a relationship between physicians' self perceived empathy levels and their patients' assessments. STUDY DESIGN: Observational, cross-sectional survey. LOCATION: Primary Care Teaching Unit. Madrid. PARTICIPANTS: A survey was sent by email to all the Teaching Unit's family medicine tutors and residents. Responses were received from 50 residents (39.4%) and 41 tutors (45%). In addition, 428 patients were opportunistically recruited at a healthcare centre and their doctors were also interviewed. PRIMARY MEASUREMENT INSTRUMENTS: Empathy was measured using the Jefferson Scale of Empathy and the Jefferson Scale of Patient Perceptions of Physician Empathy. RESULTS: The tutors scored 2.53 points higher for cognitive empathy than the residents (P=.04). Emotional empathy scores declined among older tutors (r= 0.32; P=.05). The Spanish students (82% of the total) without previous work experience scored higher for overall empathy (P=.02). Final-year residents recorded significantly worse empathy assessments than the other residents. A positive correlation (r=0.72; P=.01) was observed between physicians' self perceived empathy and their patients' perceptions. CONCLUSIONS: Residents with previous work experience, final-year residents and those of Latin American origin score lower for empathy. There is a strong relationship between physicians' self perceived empathy and their patients' views of their empathy levels. PMID- 30522785 TI - Digital pathology: semper ad meliora. AB - This review is an evidence-based summary of digital pathology: past, present and future. It discusses digital surgical pathology and the cytopathology digitisation challenge as well as the performance of digital histopathology and cytopathology as a diagnostic tool, particularly in contrast to user perceptions. Time and cost efficiency of digital pathology, learning curves, education and quality assurance, with the importance of validation of systems, is emphasised. The review concludes with a discussion of digital pathology as a source of 'big data' and where this might lead pathologists in the digital pathology future. PMID- 30522786 TI - PCSK9: from biology to clinical applications. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial protein governing the circulating levels of low density lipoprotein-cholesterol (LDL-C), by virtue of its pivotal role in the degradation of the LDL receptor (LDLR). In the last 15 years, in vitro and in vivo studies have allowed our understanding of the physiological role of PCSK9. In the current report, we review the key studies that have established the mode of action of PCSK9, leading to the development of PCSK9 inhibitors for clinical use. Data from clinical trials investigating these therapies clearly and unambiguously demonstrate the safety and efficacy of these new drugs that have the power to dramatically reduce LDL-C and associated cardiovascular diseases. PMID- 30522787 TI - Nonfasting versus fasting lipid profile for cardiovascular risk prediction. AB - Before 2009 essentially all societies, guidelines, and statements required fasting before measuring a lipid profile for cardiovascular risk prediction. This was mainly due to the increase seen in triglycerides during a fat tolerance test. However, individuals eat much less fat during a normal day and nonfasting triglycerides have been shown to be superior to fasting in predicting cardiovascular risk. Lipids and lipoproteins only change minimally in response to normal food intake: in four large prospective studies, maximal mean changes were +0.3 mmol/L (26 mg/dL) for triglycerides, -0.2 mmol/L (8 mg/dL) for total cholesterol, -0.2 mmol/L (8 mg/dL) for LDL cholesterol, and -0.1 mmol/L (4 mg/dL) for HDL cholesterol. Further, in 108,602 individuals from the Copenhagen General Population Study in random nonfasting samples, the highest versus the lowest quartile of triglycerides, total cholesterol, LDL cholesterol, remnant cholesterol, non-HDL cholesterol, lipoprotein(a), and apolipoprotein B were all associated with higher risk of both ischaemic heart disease and myocardial infarction. Finally, lipid-lowering trials using nonfasting blood samples for assessment of lipid levels found that reducing levels of nonfasting lipids reduced the risk of cardiovascular disease. To date there is no sound scientific evidence as to why fasting should be superior to nonfasting when evaluating a lipid profile for cardiovascular risk prediction. Indeed, nonfasting samples rather than fasting samples have many obvious advantages. First, it would simplify blood sampling in the laboratory. Second, it would benefit the patient, avoiding the inconvenience of fasting and therefore needing to have blood drawn early in the day. Third, for individuals with diabetes, the risk of hypoglycaemia due to fasting would be minimised. Many countries are currently changing their guidelines towards a consensus on measuring a lipid profile for cardiovascular risk prediction in the nonfasting state, simplifying blood sampling for patients, laboratories, and clinicians worldwide. PMID- 30522788 TI - Improving the sensitivity of X-ray microanalysis in the analytical electron microscope. AB - A study of the influence of experimental parameters on the sensitivity of x-ray energy dispersive spectroscopy in the analytical electron microscope from 20-200 kV is conducted. Optimization of conditions in the next generation of aberration corrected AEM instrument coupled with an array configuration of SDD detectors can potentially yield a 10-20 fold improvement over older Si(Li) systems still in use today. PMID- 30522789 TI - Mortality rate and risk factors for gastrointestinal bleeding in elderly patients. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is burdened by high mortality rate that increases with aging. Elderly patients may be exposed to multiple risk factors for GIB. We aimed at defining the impact of GIB in elderly patients. METHODS: Since 2008, samples of elderly patients (age >= 65 years) with multimorbidity admitted to 101 internal medicine wards across Italy have been prospectively enrolled and followed-up (REPOSI registry). Diagnoses of GIB, length of stay (LOS), mortality rate, and possible risk factors, including drugs, index of comorbidity (Cumulative Illness Rating Scale [CIRS]), polypharmacy, and chronic diseases were assessed. Adjusted multivariate logistic regression models were computed. RESULTS: 3872 patients were included (mean age 79 +/- 7.5 years, F:M ratio 1.1:1). GIB was reported in 120 patients (mean age 79.6 +/- 7.3 years, F:M 0.9:1), with a crude prevalence of 3.1%. Upper GIB occurred in 72 patients (mean age 79.3 +/- 7.6 years, F:M 0.8:1), lower GIB in 51 patients (mean age 79.4 +/- 7.1 years, F:M 0.9:1), and both upper/lower GIB in 3 patients. Hemorrhagic gastritis/duodenitis and colonic diverticular disease were the most common causes. The LOS of patients with GIB was 11.7 +/- 8.1 days, with a 3.3% in hospital and a 9.4% 3-month mortality rates. Liver cirrhosis (OR 5.64; CI 2.51 12.65), non-ASA antiplatelet agents (OR 2.70; CI 1.23-5.90), and CIRS index of comorbidity >3 (OR 2.41; CI 1.16-4.98) were associated with GIB (p < 0.05). CONCLUSIONS: A high index of comorbidity is associated with high odds of GIB in elderly patients. The use of non-ASA antiplatelet agents should be discussed in patients with multimorbidity. PMID- 30522791 TI - Long-term effects of insulin resistance on appendicular lean muscle. PMID- 30522790 TI - The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance, beta-cell function, and diabetes in Hispanics and African Americans. AB - OBJECTIVE: The TG/HDL-C ratio is used as a marker of insulin resistance (IR) in Caucasians; however, there is limited data in other ethnic groups. We hypothesized that the TG/HDL-C ratio is associated with IR in Hispanics and African Americans (AA). RESEARCH DESIGN AND METHODS: Data from the Insulin Resistance Atherosclerosis Family Study was examined for associations between TG/HDL-C ratio and IR, beta-cell function and incident diabetes in non-diabetic Hispanics (n = 872, 63% female) and AA (n = 371, 61% female). Insulin sensitivity index (SI) and disposition index (DI) from frequently-sampled intravenous glucose tolerance tests were used as markers of IR and beta-cell function respectively. Incident type 2 diabetes was determined by fasting glucose >= 126 mg/dl or initiation of anti-hyperglycemia agents over 5 year follow-up. RESULTS: Higher TG/HDL-C ratio was associated with IR in Hispanic and AA men and women (P < 0.0002), as well as beta-cell function in Hispanic women and AA men and women (P < 0.02). TG/HDL-C predicted incident type 2 diabetes in women (area under the curves 0.703 and 0.795 for Hispanics and AA respectively). CONCLUSIONS: Similar to Caucasians, the TG/HDL-C ratio can be used to identify IR in Hispanics and AA, and may predict type 2 diabetes in women. PMID- 30522792 TI - Dendritic cell activation is blunted in patients with coronary artery disease and diabetes mellitus. AB - BACKGROUND: It has been shown that functional status of dendritic cells (DCs) in diabetic patients with unstable angina pectoris (UAP) are more mature and activated than diabetic patients without coronary artery disease (CAD) and none diabetic patients with UAP. Accordingly we aimed to assess the activation of DCs in patients with CAD with/and without Diabetes Mellitus (DM) and compare to those in subjects with normal coronary arteries (NCA). MATERIALS AND METHODS: Twenty three patients with severe CAD who were scheduled to coronary artery by-pass grafting surgery and 6 patients with angiographycally NCAs were included in the study. Activation of peripheral blood DCs have been analyzed by flow cytometric measures of CD86 activation. RESULTS: In patients with CAD and without DM, DC activation significantly increased after stimulation of oxidesized LDL (135 +/- 121 vs 248 +/- 197 p = 0.024). However this activation didn't significantly increased in patients with CAD and DM (100 +/- 20 vs 120 +/- 97, p = 0,54). Patients with NCAs and without DM showed marked activation of CD86 after stimulation with ox-LDL. CONCLUSION: We have documented that DC activation, upon stimulation of ox-LDL has blunted in patients with CAD compared to patients with NCAs. Moreover this defective activation is more pronounced in those with diabetic patients with CAD. PMID- 30522793 TI - Gestational diabetes mellitus alters DNA methylation profiles in pancreas of the offspring mice. AB - Gestational diabetes mellitus (GDM), which has an increasing global prevalence, contributes to the susceptibility to metabolic dysregulation and obesity in the offspring via epigenetic modifications. However, the underlying mechanism remains largely obscure. The current study established a GDM mice model to investigate the alternations in the metabolic phenotypes and genomic DNA methylation in the pancreas of the offspring. We found that in the GDM offspring, intrauterine hyperglycemia induced dyslipidemia, insulin resistance, and glucose intolerance. Meanwhile, altered DNA methylation patterns were exhibited in the pancreas and many differentially methylated regions (DMRs)-related genes were involved in glycolipids metabolism and related signaling pathways, including Agap2, Plcbr, Hnf1b, Gnas, Fbp2, Cdh13, Wnt2, Kcnq1, Lhcgr, Irx3, etc. Additionally, the overall hypermethylation of Agap2, verified by bisulfite sequencing PCR (BSP), was negatively correlated with its mRNA expression level. In conclusion, these findings suggest that the DNA methylation changes in the pancreatic genome of the GDM offspring may be associated with the glycolipid metabolism abnormalities, T2DM susceptibility, and obesity in the adult GDM offspring. PMID- 30522794 TI - Outcomes of empiric aminoglycoside monotherapy for Pseudomonas aeruginosa bacteremia. AB - We evaluated 30-day mortality in patients with Pseudomonas aeruginosa bacteremia. There was no significant difference in mortality among patients who received functional aminoglycoside monotherapy versus inappropriate empiric therapy. Among patients given appropriate empiric therapy, functional aminoglycoside monotherapy was associated with less favorable outcomes compared to beta-lactam monotherapy. PMID- 30522795 TI - Modified maxillary vestibular approach with subperiostal intranasal dissection for surgical extractions of mesiodentes impacted in the floor of the nasal cavity. AB - INTRODUCTION: Impacted mesiodentes in the inverted position may interfere with the base of the nasal cavity or the nasal septum. They can rarely erupt into the nose as well. Traditionally they are extracted via intraoral approaches (transpalatal or vestibular). Also, an endoscopically assisted transnasal approach can be used. In this paper, the authors are the first to present a group of patients suffering from impacted mesiodentes who have been surgically treated using a modified maxillary vestibular approach with subperiostal intranasal dissection. MATERIAL AND METHOD: The prospective study was completed in the time period 12/2013-6/2017. The inclusion criteria were: 1. Mesiodens impacted in the inverted position extending to the base of the nasal cavity or into the nasal septum without concomitant pathological lesion and without eruption into the nasal cavity. 2. Localization of the mesiodens at the level of or dorsally to the roots of the upper middle incisors in the sagittal plane or ventrally to the roots of these teeth, but with the crown extending significantly posteriorly to the base of the nasal cavity.3. Indication for extraction because of clinical or orthodontic reasons. RESULTS: In total, 9 patients were enrolled into the group. In these patients, surgical extractions of 9 mesiodentes were performed using the alternative approach described above. All extractions were done according to a uniform surgical protocol. The mean age of the patients was 11.7 +/- 3.1 years (age range 7-17 years). The crown's most cranial point exceeded the bone of the nasal cavity on average by2.0 +/- 1.4 mm (in the range 0-5 mm). 8 mesiodentes were conical, 1 was tuberculate. Surgical procedure and postoperative healing were always without any complications. CONCLUSION: For the removal of midline supernumerary teeth, the modified maxillary vestibular approach with subperiostal intranasal dissection in comparison to the intraoral palatal approach provides less postoperative morbidity and a lower risk of complications (smaller surgical wound, minimal exposure of maxilla, minimal bone loss, reduced risk of damage to the roots of the upper incisors, lower risk of damage to the nasopalatine neurovascular bundle, good visibility in the surgical field, easier surgery, and finally no need of postoperative palatal splint). For oral and maxillofacial surgeons the presented technique represents a more traditional way of surgical tooth extraction than the endoscopically assisted transnasal approach. PMID- 30522796 TI - The feasibility of rib grafts in long span mandibular defects reconstruction: A long term follow up. AB - AIMS: To evaluate the efficiency of reconstruction of long span mandibular defects using split rib bundle bone graft. MATERIALS AND METHODS: Six hundred patients with long span mandibular defects (more than 6 cm long), following resection of aggressive mandibular tumours, were reconstructed with split rib bundle bone graft technique. Immediate reconstruction was performed in all patients. A reconstruction plate was used to support the graft. Two ribs were harvested from the right side of the chest, split into four halves and used to restore the continuity of the mandible. The inclusion criterion was post-surgical mandibular bony defects without soft tissue deficiency. Defects with a history of previous or need of future irradiation were excluded. RESULTS: The appearance of the patients was accepted in 550 patients. Functional reconstruction was done in 320 patients by osseointegrated dental implants (after 15 months), and removable prosthesis in 150 patients. Infection was minor in 31 patients, moderate in 47 patients and severe in 42 patients. Partial loss of graft, up to 25%, due to moderate infection was reported. Total or near total loss of graft due to severe infection was corrected by reoperation six months later. CONCLUSIONS: This technique is simple, safe, and can be effectively used to reconstruct long-span mandibular defects with minimal complications in selected patients. PMID- 30522797 TI - Fulminant acute disseminated encephalomyelitis in children. AB - Acute disseminated encephalomyelitis (ADEM) is a typically monophasic inflammatory demyelinating disease of the central nervous system with a favorable outcome. However, 2% of ADEM involves acute hemorrhagic leukoencephalitis (AHLE), which is a fulminant and hyperacute variant of ADEM with a poor outcome and high mortality. There are limited case reports of fulminant ADEM including AHLE in children. Herein, we report two pediatric cases of fulminant ADEM. Both cases had a rapid deterioration of consciousness, repetitive seizures, and brain edema on neuroimaging, in addition to atypical neuroradiological findings on magnetic resonance imaging (MRI), a reversible splenial lesion in case 1, and bilateral frontal and occipital cortical lesions in case 2. Both cases were treated with early high-dose methyl-prednisolone and immunoglobulin, while therapeutic hypothermia was also initiated in case 2 after the patient exhibited a decerebrate posture and irregular breathing pattern. Both cases had a favorable outcome. Further case reports on pediatric fulminant ADEM are required to clarify the various clinical types, and to examine the efficacy of various treatment modalities for fulminant ADEM and AHLE in children. PMID- 30522798 TI - Ventral hippocampal overexpression of Cannabinoid Receptor Interacting Protein 1 (CNRIP1) produces a schizophrenia-like phenotype in the rat. AB - Adolescent cannabis use has been implicated as a risk factor for schizophrenia; however, it is neither necessary nor sufficient. Previous studies examining this association have focused primarily on the role of the cannabinoid receptor 1 (CB1R) with relatively little known about a key regulatory protein, the cannabinoid receptor interacting protein 1 (CNRIP1). CNRIP1 is an intracellular protein that interacts with the C-terminal tail of CB1R and regulates its intrinsic activity. Previous studies have demonstrated aberrant CNRIP1 DNA promoter methylation in post-mortem in human patients with schizophrenia, and we have recently reported decreased methylation of the CNRIP1 DNA promoter in the ventral hippocampus (vHipp) of a rodent model of schizophrenia susceptibility. To examine whether augmented CNRIP1 expression could contribute to the pathology of schizophrenia, we performed viral-mediated overexpression of CNRIP1 in the vHipp of Sprague Dawley rats. We then tested these rats for behavioral correlates of schizophrenia symptoms, followed by electrophysiology to determine the effects on the dopamine system, known to underlie psychosis. Here, we report that overexpression of vHipp CNRIP1 induces impairments in latent inhibition and social interaction, similar to those observed in individuals with schizophrenia and in rodent models of the disease. Furthermore, rats overexpressing vHipp CNRIP1 displayed a significant increase in ventral tegmental area (VTA) dopamine neuron population activity, a putative correlate of psychosis. These data provide evidence that alterations in CNRIP1 may contribute to the pathophysiology of schizophrenia, as overexpression is sufficient to produce neurophysiological and behavioral correlates consistently observed in rodent models of the disease. PMID- 30522799 TI - Characterizing Bariatric Surgery Utilization and Complication Rates in the Adolescent Population. AB - INTRODUCTION: Bariatric surgery is an increasingly common treatment of morbid obesity in the United States and has demonstrated effective weight loss and improvement of comorbidities. We used the National Surgical Quality Improvement Program (NSQIP) data to characterize bariatric surgery utilization and complication rates in the adolescent population. METHODS: Demographics, surgical procedures, comorbidities, and 30-day outcomes of 2625 adolescents ages 18-21 who underwent bariatric surgery were analyzed from NSQIP data-bank from 2005 to 2015. RESULTS: 79.5% of patients were females. Majority of patients identified as Caucasian or Black/African American (BAA) at 66.7% (73% of US population) and 15.5% (12.6% of US population), respectively. 15.9% identified as Hispanic. Comorbidities included diabetes in 9.3% (7.8% NIDDM), hypertension (9.5%), and dyspnea on moderate exertion (13.2%). Sleeve Gastrectomy, Laparoscopic Roux-En-Y (RY) and Adjustable Gastric Banding (AGB) were the three most common procedures performed during the study period. There has been a sharp trend towards SG in recent years (11.4% in 2010, to 66.6% in 2015), while RY utilization declined (47.4% in 2010 to 28.6% in 2015). Surgical complications were 2.4%, with the most common being superficial surgical site infection (0.7%), UTI (0.7%), and organ space infection (0.4%). Reoperation and readmission rates within 30-days post operation were 1.5% and 4.1%, respectively. Those with complications had longer length-of-stays (2.7 vs. 1.8 days, P < 0.001), greater reoperation rates (OR = 9.6, P < 0.001) and readmission rates (OR = 11.8, P < 0.001). CONCLUSION: Morbid obesity is associated with significant comorbidity. SG is increasingly the most utilized form of bariatric surgery. While complications are low, they are associated with greater hospital length-of-stay, readmission, and reoperation rates. LEVEL OF EVIDENCE: Treatment Study, Level III. PMID- 30522800 TI - Predictive performance of an OVH-based treatment planning quality assurance model for prostate VMAT: Assessing dependence on training cohort size and composition. AB - Radiotherapy treatment planning quality assurance models are used to assess overall plan quality in terms of dose-volume characteristics, by predicting an optimal dosimetry based on a dataset of prior cases (the training cohort). In this study, a treatment planning quality assurance model for prostate cancer patients treated with volumetric modulated arc therapy was developed using the concept of the overlap volume histogram for geometric comparison to the training cohort. The model was developed on the publically available Erasmus iCycle dataset in order to remove the effect of plan quality/inter-planner variability on the model's predictive capabilities. The model was used to predict anus, rectum, and bladder dose volume histograms. Two versions were developed: the n = 114 case (leave-one-out method) which made predictions using the complete Erasmus dataset, and the similarity index (SI)-based model which used a smaller training cohort allocated in order of geometric similarity determined using an overlap volume histogram-derived SI. The difference in mean dose (predicted-achieved) of the SI model at cohort sizes of 10, 20, 30, 40, 50, 75, and 100 was compared to the leave-one-out method for 5 patients, in an attempt to determine the "optimum" cohort size for the SI-based model in this dataset. Performance of the optimized SI model was compared to the leave-one-out method for all patients using the following metrics: difference in mean and median dose, difference in V65Gy and V75Gy (rectum only), similarity of predicted and achieved mean dose, and mean dose volume histograms residual. The "optimum" cohort size for the SI-based model was determined to be 45. The SI-based model implementing this cohort size yielded slightly better outcomes in all performance metrics for the rectum and anus, but worse for the bladder. SI-based training cohort allocation can lead to better predictive efficacy, but the cohort size should be optimized for each individual organ. PMID- 30522801 TI - The Subacromial Balloon Spacer Versus Superior Capsular Reconstruction in the Treatment of Irreparable Rotator Cuff Tears: A Biomechanical Assessment. AB - PURPOSE: To compare the subacromial balloon spacer with superior capsular reconstruction (SCR) for the treatment of massive irreparable rotator cuff tears. METHODS: Eight male cadaveric shoulders were mounted on a custom shoulder simulator that permitted quasistatic deltoid and rotator cuff muscle loading. Four shoulder conditions were tested: intact, irreparable rotator cuff tear (torn), subacromial balloon spacer, and SCR. The primary outcomes were superior humeral head migration and functional shoulder abduction force, which were measured at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of shoulder abduction. RESULTS: In comparison to the intact condition, the torn condition resulted in a significant increase in superior humeral head migration at 0 degrees (P = .03) and 30 degrees (P = .02) of abduction. Insertion of the subacromial balloon spacer restored the humeral head position such that it was not significantly different from the intact condition (P = .18). Similarly, SCR restored the humeral head position such that it was not significantly different from the intact condition (P = .99). No significant differences were found between the balloon and SCR (P = .99). The functional abduction force was significantly decreased after tear creation (P = .01); however, the subacromial balloon (P = .40) and SCR (P = .99) restored functional abduction force comparable to the intact shoulder state. CONCLUSIONS: On the basis of the results, both techniques function to decrease superior humeral head migration and to restore more normal glenohumeral joint position and forces during various abduction positions. No substantial differences were identified between techniques at time zero. CLINICAL RELEVANCE: The results of this laboratory study indicate that the balloon and SCR both provided mechanical effects that restored the humeral head position from the superiorly migrated location. As such, similar clinical effects can be expected at time zero in patients with massive rotator cuff tears. PMID- 30522802 TI - Morphologic Factors Related to Repair Outcomes for Delaminated Rotator Cuff Tears: A Minimum 2-Year Retrospective Comparison Study. AB - PURPOSE: To evaluate clinical outcomes and repair integrity after en masse transosseous-equivalent suture bridge repair for delaminated rotator cuff tears and to analyze the morphologic factors related to clinical outcomes and repair integrity. METHODS: This study included 99 patients who underwent the technique of en masse transosseous-equivalent suture bridge repair for delaminated rotator cuff tears. Morphologic factors were estimated using magnetic resonance imaging, and clinical outcomes were evaluated using the University of California, Los Angeles score; American Shoulder and Elbow Surgeons score; and Constant shoulder score. The morphologic factors included the shape of delamination, retraction length of the bursal and articular layers, gap distance between the layers, and length of the intrasubstance cleavage. According to follow-up magnetic resonance imaging, cases were categorized into the intact or retear group. The morphologic factors were compared between the 2 groups, including the correlation between the morphologic factors and postoperative outcomes. RESULTS: Retears occurred in 26 of 99 cases (26%). In both the intact and retear groups, the University of California, Los Angeles, American Shoulder and Elbow Surgeons, and Constant scores improved postoperatively (P < .0001). The most common delamination shape was that of a more retracted articular layer in retears. We found no differences in retears in terms of the retraction length of the bursal layer, gap distance, and length of the intrasubstance cleavage. However, the retraction length of the articular layer differed significantly between the groups (P < .0001). No correlation between the morphologic factors and clinical outcomes was found. CONCLUSIONS: Arthroscopic en masse transosseous-equivalent suture bridge repair is a useful technique in delaminated tears to achieve optimal repair outcomes. In addition, although there was no correlation between the morphologic factors and postoperative clinical outcomes, the retraction length of the articular layer was identified as a significant factor influencing repair integrity. We recommend emphasizing the reduction of tension within the articular layer during the repair procedure. LEVEL OF EVIDENCE: Level III, retrospective comparison study. PMID- 30522803 TI - Angiographic Features of Intracranial Aneurysms in Ecuador. AB - BACKGROUND: Most of the literature describing morphological features of intracranial aneurysms (IAs) is from North-America, East-Asia, and Europe. There is limited data from South-America. We describe the epidemiologic and angiographic features of ruptured and unruptured IAs in a cohort of patients from Ecuador. METHODS: We conducted a retrospective analysis of prospectively acquired databases from 3 different tertiary hospitals over a 3-year period (2014-2017). In a per-patient basis, odd ratios (ORs) of ruptured presentation for each variable using a univariate logistic regression model were calculated. An aneurysm-based multivariate analysis was performed to calculate rupture ORs for each variable. RESULTS: Our sample included 557 patients with 761 IAs. Mean patient age was 52.2 years (range 18-82). Sixty-eight percent were women, and almost 90% presented with ruptured aneurysms and concomitant subarachnoid hemorrhage (SAH). Mean size of all the IAs was 6.4 mm +/- 3.98 mm. Most IAs were located in anterior circulation (96.6%): 28.4% medial cerebral artery, 24.4% anterior cerebral artery or anterior communicating artery (ACOM), and 23.5% posterior communicating artery (PCOM). Only 6 basilar tip aneurysms (0.8%) were reported. In the adjusted analysis, aneurysms located in the ACOM (OR 1.89, 95% CI 1.29-2.78) and PCOM (OR 1.84, 95% CI 1.25-2.71), size larger than 5 mm (OR 2.84, 95% CI 2.04-3.93) and 7 mm (OR 2.28, 95% CI 1.64-3.19), and those with non saccular morphology (OR 9.87, 95% CI 2.21-44.14) were significantly associated with ruptured presentation. CONCLUSIONS: The prevalence of posterior circulation IAs in Ecuador, particularly basilar tip aneurysms, is low when compared to previous reports from developed countries. In our sample, IAs greater than 5 mm (and >=7 mm) in size, ACOM and PCOM locations, and IAs with nonsaccular morphologies (blister and fusiform) were significantly associated with SAH presentation. PMID- 30522804 TI - Plasma Levels of Brain-Derived Neurotrophic Factor are Associated with Prognosis in the Acute Phase of Ischemic Stroke. AB - CONTEXT: Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neuronal survival, differentiation, and maturation. PURPOSE: To evaluate the levels of BDNF in the acute phase of stroke and their potential association with neurological impairment. METHODS: Patients in the acute phase of ischemic stroke were evaluated with the following clinical tools: National Institutes of Health Stroke Scale, modified Rankin scale, Gugging Swallowing Screen and Alberta Stroke Program Early CT Score. Blood samples were collected at 3 different moments of hospital stay. BDNF was measured through enzyme-linked immunosorbent assay. RESULTS: Patients who were discharged after 10 days had worse clinical outcomes and higher levels of BDNF since admission. There was correlation between BDNF levels and clinical parameters. CONCLUSION: BDNF levels were associated with clinical prognosis in the acute phase of ischemic stroke. PMID- 30522805 TI - Isolation of a novel embryonic stem cell cord blood-derived population with in vitro hematopoietic capacity in the presence of Wharton's jelly-derived mesenchymal stromal cells. AB - BACKGROUND: Recent studies highlight the existence of a population of cord blood (CB)-derived stem cells that bare embryonic features (very small embryonic-like stem cells [VSELs]) as the most primitive CB-stem cell population. In the present study, we present for the first time a novel and high purity isolation method of VSELs with in vitro hematopoietic capacity in the presence of Wharton's jelly derived mesenchymal stromal cells (WJ-MSCs). METHODS: The experimental procedure includes isolation upon gradually increased centrifugation spins and chemotaxis to Stromal cell-derived factor 1a (SDF-1a). Tauhis cell population is characterized with flow cytometry, alkaline phosphatase (ALP) staining and qRT PCR. The functional role of the isolated VSELs is assayed following co-culture with WJ-MSCs or bone marrow-derived mesenchymal stromal cells (BM-MSCs), whereas the stimulation of the quiescent VSEL population is verified via cell cycle analysis. The in vitro hematopoietic capacity is evaluated in methylcellulose cultures and also through induction of erythroid differentiation. RESULTS: The final isolated subpopulation is characterized as a small-sized CD45/Lineage /CXCR4+/CD133+/SSEA-4+cell population, positive in ALP staining and overexpressing the Oct3/4, Nanog and Sox-2 transcription factors. Upon the co culture with MSCs, a stimulation of the quiescent VSEL population is observed. An impressive increase in the co-expression of the CD34+/CD45+ markers is observed following the co-culture with the WJ-MSCs, which is confirmed by the intense clonogenic ability suggesting in vitro differentiation toward all of the hematopoietic cell lineages and successful differentiation toward erythrocytes. DISCUSSION: Conclusively, we propose a novel, rapid and rather simplified isolation method of CB-VSELs, capable of in vitro hematopoiesis. PMID- 30522806 TI - Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study. AB - OBJECTIVE: Knee osteoarthritis (OA) is a common skeletal impairment that can cause many limitations in normal life activities. Stem cell therapy has been studied for decades for its regenerative potency in various diseases. We investigated the safety and efficacy of intra-articular injection of placental mesenchymal stem cells (MSCs) in knee OA healing. METHODS: In this double-blind, placebo-controlled clinical trial, 20 patients with symptomatic knee OA were randomly divided into two groups to receive intra-articular injection of either 0.5-0.6 * 108 allogenic placenta-derived MSCs or normal saline. The visual analogue scale, Knee OA Outcome Score (KOOS) questionnaire, knee flexion range of motion (ROM) and magnetic resonance arthrography were evaluated for 24 weeks post treatment. Blood laboratory tests were performed before and 2 weeks after treatment. RESULTS: Four patients in the MSC group showed mild effusion and increased local pain, which resolved safely within 48-72 h. In 2 weeks post injection there was no serious adverse effect and all of the laboratory test results were unchanged. Early after treatment, there was a significant knee ROM improvement and pain reduction (effect size, 1.4). Significant improvements were seen in quality of life, activity of daily living, sport/recreational activity and decreased OA symptoms in the MSC-injected group until 8 weeks (P < 0.05). These clinical improvements were also noted in 24 weeks post-treatment but were not statistically significant. Chondral thickness was improved in about 10% of the total knee joint area in the intervention group in 24 weeks (effect size, 0.3). There was no significant healing in the medial/lateral meniscus or anterior cruciate ligament. There was no internal organ impairment at 24 weeks follow-up. CONCLUSION: Single intra-articular allogenic placental MSC injection in knee OA is safe and can result in clinical improvements in 24 weeks follow-up. TRIAL REGISTRATION NUMBER: IRCT2015101823298N. PMID- 30522807 TI - Constricting the Radiologic Lexicon: An Orwellian Errand? PMID- 30522808 TI - Using Hyperpolarized Xenon-129 MRI to Quantify Early-Stage Lung Disease in Smokers. AB - RATIONALE AND OBJECTIVES: Hyperpolarized xenon-129 magnetic resonance (MR) provides sensitive tools that may detect early stages of lung disease in smokers before it has progressed to chronic obstructive pulmonary disease (COPD) apparent to conventional spirometric measures. We hypothesized that the functional alveolar wall thickness as assessed by hyperpolarized xenon-129 MR spectroscopy would be elevated in clinically healthy smokers before xenon MR diffusion measurements would indicate emphysematous tissue destruction. MATERIALS AND METHODS: Using hyperpolarized xenon-129 MR we measured the functional septal wall thickness and apparent diffusion coefficient of the gas phase in 16 subjects with smoking-related COPD, 9 clinically healthy current or former smokers, and 10 healthy never smokers. All subjects were age-matched and characterized by conventional pulmonary function tests. A total of 11 data sets from younger healthy never smokers were added to determine the age dependence of the septal wall thickness measurements. RESULTS: In healthy never smokers the septal wall thickness increased by 0.04 MUm per year of age. The healthy smoker cohort exhibited normal pulmonary function test measures that did not significantly differ from the never-smoker cohort. The age-corrected septal wall thickness correlated well with diffusion capacity for carbon monoxide (R2 = 0.56) and showed a highly significant difference between healthy subjects and COPD patients (8.8 MUm vs 12.3 MUm; p < 0.001), but was the only measure that actually discriminated healthy subjects from healthy smokers (8.8 MUm vs 10.6 MUm; p < 0.006). CONCLUSION: Functional alveolar wall thickness assessed by hyperpolarized xenon-129 MR allows discrimination between healthy subjects and healthy smokers and could become a powerful new measure of early-stage lung disease. PMID- 30522809 TI - How Does Evolution in Phosphorus-Impoverished Landscapes Impact Plant Nitrogen and Sulfur Assimilation? AB - Phosphorus (P) fertilisers, made from rock phosphate, are used to attain high crop yields. However, rock phosphate is a finite resource and excessive P fertilisers pollute our environment, stressing the need for more P-efficient crops. Some Proteaceae have evolved in extremely P-impoverished environments. One of their adaptations is to curtail the abundance of ribosomal RNA, and thus protein, and tightly control the acquisition and assimilation of nitrogen (N) and sulfur. This differs fundamentally from plants that evolved in environments where N limits plant productivity, but is likely common in many species that evolved in P-impoverished landscapes. Here, we scrutinise the relevance of these responses towards developing P-efficient crops, focusing on plant species where 'P is in the driver's seat'. PMID- 30522810 TI - A Comparative Perspective on Extra-retinal Photoreception. AB - Ubiquitous in non-mammalian vertebrates, extra-retinal photoreceptors (ERPs) have been linked to an array of physiological, metabolic, behavioral, and morphological changes. However, the mechanisms and functional roles of ERPs remain one of the enduring questions of modern biology. In this review article, we use a comparative framework to identify conserved roles and distributions of ERPs, highlighting knowledge gaps. We conclude that ERP research can be divided into two largely unconnected categories: (i) identification and localization of photoreceptors and (ii) linkage of non-retinal light reception to behavioral and physiological processes, particularly endocrine systems. However, the emergence of novel gene editing and silencing techniques is enabling the unification of ERP research by allowing the bridging of this divide. PMID- 30522811 TI - A Preliminary Study of Clinical Trial Enrollment Decisions Among People With Mild Cognitive Impairment and Their Study Partners. AB - OBJECTIVE: All Alzheimer disease (AD) clinical trials, including those enrolling patients with mild cognitive impairment (MCI), require dyadic participation. The purpose of this study was to elucidate how people with MCI and their study partners decide whether to enroll in clinical trials. METHODS: This was a mixed methods interview study. We interviewed patient participants with a consensus research diagnosis of MCI and their study partners. Interviews examined how dyads decide whether to enroll in a clinical trial and whether AD biomarker testing affects willingness to enroll. RESULTS: Though most MCI patients and study partners would decide in partnership whether to enroll in a clinical trial, agreement was lower among nonspousal, compared with spousal, dyads. Deterrents to enrollment included concerns about patient safety and inconvenience, especially for study partners. Motivators to enrollment included altruism, the desire to contribute to research, hope for patient benefit, and the desire to learn more about the patient's condition. When asked open-ended questions about motivators to enroll in trials, few patients cited access to biomarker testing specifically, though most expressed a desire to undergo biomarker testing when asked directly. CONCLUSION: Spousal and nonspousal MCI dyads may approach clinical trial decisions differently. Future research should investigate how AD biomarker testing affects participants' willingness to enroll in trials. PMID- 30522812 TI - [Consensus document of the Spanish Society of Primary Care Physicians and the Spanish Chapter of Phlebology and Lymphology of the Spanish Society of Angiology and Vascular Surgery: Superficial vein thrombosis of the lower limbs in Primary Care]. AB - Superficial vein thrombosis of the lower limbs used to be considered a benign condition with a self-limiting clinical course. It is now known that its potential complications can be serious or even fatal, such as deep vein thrombosis or pulmonary thromboembolism. There are different forms of clinical presentation, risk factors and different treatments for its approach, mainly in Primary Care. The Vascular Diseases Working Group of the Spanish Society of Primary Care Physicians (SEMERGEN) has developed this update using current scientific evidence and jointly with the Spanish Chapter of Phlebology and Lymphology of the Spanish Society of Angiology and Vascular Surgery. PMID- 30522813 TI - Eosinophilic esophagitis: An evidenced-based approach to diagnosis and treatment. AB - Eosinophilic oesophagitis is a unique form of non-IgE-mediated food allergy characterised by oesophageal eosinophilic infiltration. The prevalence of EoE has grown to currently represent the first cause of dysphagia and food impaction in children and young adults. Avoiding food triggers is the only therapy targeting the cause of the disease, but none of the currently available food allergy tests adequately predicts food triggers for EoE. Strategies based on the empirical elimination of food are the most effective and convenient in clinical practice. Proton pump inhibitors constitute an effective first-line therapy in half of patients, through a direct anti-inflammatory effect independent of its action on gastric acid secretion. Topical glucocorticosteroids budesonide and fluticasone reduce eosinophilic inflammation and reverse symptoms. This review includes the most relevant aspects of the epidemiology, diagnosis, treatment and monitoring of eosinophilic oesophagitis. PMID- 30522814 TI - Robust control of uncertain feedback linearizable systems based on adaptive disturbance estimation. AB - In this paper, an adaptive disturbance estimation-based control of a class of uncertain feedback linearizable systems with the presence of, both, external perturbations as well as non-modeled dynamics is considered. The aim of the control design was to solve the tracking trajectory problem for a class of output based linearizable uncertain systems. An adaptive scheme is proposed for developing a state estimator of the uncertain dynamics. The estimation of both, the states and the uncertain dynamics is attained despite the limited knowledge of the plant and the information contained in the output signal. The uncertain section in the linearized system was approximated by a class of time-dependent combination of the system states. The observer implemented a parametric identifier to obtain the time varying parameters associated to the estimation of the uncertain section. This method ensured the adequate estimation process of the uncertainties/perturbations, measured in terms of the mean square error. Simultaneously, an adaptive gain associated to the observer adjusts its trajectories to provide the ultimate boundedness of the estimation error. Once the states of the uncertain system are obtained, a feedback controller rejects actively the perturbations that affect the system by a compensation scheme. Two numerical examples were developed to show the observer-based control performance. PMID- 30522815 TI - Position control for planar four-link underactuated manipulator with a passive third joint. AB - This paper presents a position control strategy based on the differential evolution (DE) algorithm for a planar four-link underactuated manipulator (PFUM) with a passive third joint, which is to move its end-point from any initial position to any target position. Based on the structural characteristic of the PFUM, a model reduction method is conceived to reduce the PFUM to a planar virtual three-link manipulator and a planar Acrobot in turn. Considering the existence of the angle constraint in the planar Acrobot, the DE algorithm is used to optimize and coordinate the control objective of each reduced system, and also to ensure the target angles of the planar Acrobot corresponding to the target position of the PFUM can be found. Simulations demonstrate the validity of the proposed control strategy. PMID- 30522816 TI - LED chip accurate positioning control based on visual servo using dual rate adaptive fading Kalman filter. AB - In this paper, to improve the positioning accuracy of LED chip, a dual rate adaptive fading Kalman filter algorithm with delay compensation is proposed and applied to the LED chip visual servo positioning system. Firstly, a structure of dual rate Kalman filter is introduced to the visual servo control system, which compensate the visual information delay and realize the accurate time sequential coordination of encoder and visual feedback. Then, considering the inaccuracy of system mathematical model, the adaptive forgetting factor is added to the iterative process of above algorithm, and the impact of accumulated model error on system stability is consequently mitigated. Finally, the experimental results show that the proposed method obviously decreases the positioning errors of LED chip and is robust to inaccuracy and uncertainty of system model parameters. PMID- 30522817 TI - Sonodynamic Therapy for Malignant Glioma Using 220-kHz Transcranial Magnetic Resonance Imaging-Guided Focused Ultrasound and 5-Aminolevulinic acid. AB - Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220 kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40 degrees C) after treatment with 200 ug/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature <=42 degrees C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma. PMID- 30522818 TI - Lumbar erector spinae plane block: Successful control of acute pain after lumbar spine surgery - A clinical report. AB - We report the successful clinical case of a patient scheduled for lumbar spine surgery in which we performed a bilateral single-shot erector spinae plane block as part of a multimodal analgesic strategy for pain control. Performing the block preoperatively dismissed the need for extra intraoperative opioids other than those for intubation, and enabled the use of paracetamol for analgesia only. Further, there was no need for hypotensive techniques, as the block provided satisfactory sympathetic blockade and regional vasodilation with a clear surgical field. Postoperatively, the patient had minor opioid consumption and was able to freely move without any motor impairment or pain from early on in the Post Anaesthesia Care Unit. The use of single-shot erector spinae plane block at the lumbar level for lumbar spine surgery analgesia emphasises its wide application and analgesic efficacy. PMID- 30522819 TI - Corrigendum to "Retrospective survey of severe fever with thrombocytopenia syndrome in patients with suspected rickettsiosis in Japan" [J Infect Chemother 23 (1) (2018) 45-50]. PMID- 30522820 TI - Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder. AB - Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction. PMID- 30522821 TI - How the Internally Organized Direction Sense Is Used to Navigate. AB - Head-direction cells preferentially discharge when the head points in a particular azimuthal direction, are hypothesized to collectively function as a single neural system for a unitary direction sense, and are believed to be essential for navigating extra-personal space by functioning like a compass. We tested these ideas by recording medial entorhinal cortex (MEC) head-direction cells while rats navigated on a familiar, continuously rotating disk that dissociates the environment into two spatial frames: one stationary and one rotating. Head-direction cells degraded directional tuning referenced to either of the externally referenced spatial frames, but firing rates, sub-second cell pair action potential discharge relationships, and internally referenced directional tuning were preserved. MEC head-direction cell ensemble discharge collectively generates a subjective, internally referenced unitary representation of direction that, unlike a compass, is inconsistently registered to external landmarks during navigation. These findings indicate that MEC-based directional information is subjectively anchored, potentially providing for navigation without a stable externally anchored direction sense. PMID- 30522822 TI - Reprint of Recovery programme for ICU survivors has no effect on relatives' quality of life: Secondary analysis of the RAPIT-study. AB - BACKGROUND: Relatives of intensive care patients are at risk of developing symptoms of anxiety, depression and posttraumatic stress resulting in reduced health-related quality of life. Recovery programmes for patients have been implemented, but their effect on relatives is uncertain. AIM: To determine whether relatives benefit from a recovery programme intended for intensive care survivors. RESEARCH DESIGN: A randomised controlled trial of 181 adult relatives: intervention group (n = 87), control group (n = 94). SETTING: Ten intensive care units in Denmark. MAIN OUTCOME MEASURES: Primary outcome: health-related quality of life (HRQOL). SECONDARY OUTCOMES: Sense of coherence (SOC), and symptoms of anxiety, depression and posttraumatic stress, compared to standard care at 12 months after intensive care discharge. RESULTS: No difference in HRQOL between groups was observed at 12 months (mean difference in mental component summary score, 1.35 [CI 95%: -3.13; 5.82], p = 0.55; and physical component summery score, 1.86 [CI 95%: -1.88; 5.59], p = 0.33). No differences were found in secondary outcomes. CONCLUSION: The recovery programme intended for intensive care survivors did not have an effect on the relatives. Future recovery programmes should be targeted to help both patient and family, and future research should be conducted on a larger scale to make conclusions with higher probability. PMID- 30522823 TI - Are cell phones an indicator of personal exposure to organophosphate flame retardants and plasticizers? AB - BACKGROUND: Exposure to organophosphate ester (OPE) flame retardants and plasticizers is widespread and is of concern due to their toxicity. OBJECTIVES: To investigate relationships between and within OPE concentrations in air, dust, hands, electronic product wipes and urinary metabolites with the goal of identifying product sources and exposure pathways. METHODS: Women in Toronto and Ottawa, Canada, provided a urine sample, two sets of hand wipes, access to their homes for air and dust sampling, and completed a questionnaire. OPE concentrations were obtained for air and floor dust in the bedroom (n = 51) and most used room (n = 26), hand wipes (n = 204), and surface wipes of handheld (n = 74) and non-handheld electronic devices (n = 125). All air, dust and wipe samples were analyzed for 23 OPE compounds; urine samples (n = 44) were analyzed for 8 OPE metabolites. RESULTS: Five-8 OPEs were detected in >80% of samples depending on the sample type. OPE median concentrations in hand wipes taken 3 weeks apart were not significantly different. Palms had higher concentrations than the back of hands; both were significantly correlated. Concentrations of 9 OPEs were significantly higher in surface wipes of handheld than non-handheld electronic devices. Six OPEs in hand wipes were significantly correlated with cell phone wipes, with two to four OPEs significantly correlated with tablet, laptop and television wipes. Multiple regression models using hand wipes, cell phone wipes and dust explained 8-33% of the variation in creatinine-adjusted urinary metabolites; air concentrations did not have explanatory power. OPEs in cell phone wipes explained the greatest variation in urinary metabolites. CONCLUSIONS: Handheld electronic devices, notably cell phones, may either be sources or indicators of OPE exposure through hand-to-mouth and/or dermal uptake. PMID- 30522824 TI - Emission of black carbon from rural households kitchens and assessment of lifetime excess cancer risk in villages of North India. AB - The use of biomass solid fuels (BSFs) for cooking, contribute significantly to the household air pollution (HAP) in developing countries. Emissions resulting from a variety of BSFs (cow dung cakes, wood, and agriculture residues) contain a significant amount of air pollutants, which are now recognized for their role in climatic change and adverse human health impacts. In the current study, daily variations in black carbon (BC) or Short-Lived Climate Forcer concentrations were studied from rural household kitchens using portable aethalometer. The hourly average concentration of BC ranges from 5.4 MUg.m-3 to 34.9 MUg.m-3 for various types of household kitchens. The peak levels of BC were found to be significantly higher, when compared to World Health Organization PM2.5 limits for ambient air and hence pose a threat to the health of the vulnerable population, i.e., women, children, older adults and those who have health problems. The study also highlights the variation of BC concentration in different kitchen type. The average BC concentration in indoor, outdoor and semi-open kitchen was observed to be 14.54, 14.28 and 24.69 MUg.m-3, respectively. The excess lifetime carcinogenic risk for cooking 4 h/day in these kitchens in the North Indian villages was estimated to be 1.25 * 10-7, 1.22 * 10-7, and 2.12 * 10-7 respectively. Age specific excess cancer deaths due to BC exposure were measured highest in children below four years of age in Chandigarh, India. Hence, there is a need to shift the BSF users to clean fuel alternatives to reduce the exposure to HAP. This can be achieved by generating local/regional evidences of BSFs associated health risks to support policy interventions. Further, more research is required to improve the air quality in indoor micro-environments and specifically in kitchens. NOVELTY: The first study reporting the near real-time measurements of BC from different types of rural households kitchens of north India. Diurnal pattern of BC concentration was also studied including the effect of chimney, ventilation and kitchen size on observed BC concentration. This study also estimates lifetime excess cancer risk due to BC exposure in rural households in India. The recent 'Global Burden of Disease' report identifies household air pollutants as a major cause of disease and disability in Asia. The study will help to plan suitable policies and intervention to reduce household air pollution in the region. PMID- 30522825 TI - Liver scalloping: Pseudomyxoma peritonei liver compression. AB - Pseudomyxoma peritonei is a rare tumor characterized by the presence of mucous disseminated throughout the peritoneal cavity generally arising from the rupture of an appendicular mucocele. Liver scalloping is a highly suggestive image of pseudomyxoma and corresponds to the indentation of the liver compressed by the gelatinous mucin. PMID- 30522826 TI - Management of postoperative complications may favour the centralization of distal pancreatectomies. Nationwide data on pancreatic distal resections in Finland 2012 2014. AB - BACKGROUND: Centralization of pancreatic surgery has proceeded in the last few years in many countries. However, information on the effect of hospital volume specifically on distal pancreatic resections (DP) is lacking. AIM: To investigate the effect of hospital volume on postoperative complications in DP patients in Finland. METHODS: All DP performed in Finland during the period 2012-2014 were analyzed, information having been retrieved from the appropriate national registers. Hospital volumes, postoperative pancreatic fistulae (POPF) and overall complications were graded. High volume centre (HVC) was defined as performing > 10 DPs, median volume centre (MVC) 4-9 DPs and low volume centre (LVC) fewer than 4 DP annually. RESULTS: A total of 194 DPs were performed at 18 different hospitals. Of these 42% (81) were performed in HVCs (2 hospitals), 43% (84) in MVCs (6 hospitals) and the remaining 15% (29) in LVCs (10 hospitals). Patient demographics did not differ between the hospital volume groups. The overall rate of clinically relevant POPF, Clavien-Dindo grade 3-5 complications, and 90-day mortality showed no significant differences between the different hospital volumes. Grade C POPF was found more often in LVCs, being 1.2% in HVCs, 0% in MCVs and 6.9% in LVCs, p = 0.030. More reoperations were performed in LVCs (10.3%) than in HVCs (1.2%) or MVCs (1.2%); p = 0.025. CONCLUSIONS: Even though the rate of postoperative complications after DP is not affected by hospital volume, reoperations were performed ten times more often in the low-volume centres. Optimal management of postoperative complications may favour centralization not only of PD, but also of DP. PMID- 30522827 TI - Validation of the Omni: A Novel, Multimodality, and Longitudinal Surgical Skills Assessment. AB - OBJECTIVE: The breadth of technical skills included in general surgery training continues to expand. The current competency-based training model requires assessment tools to measure acquisition, learning, and mastery of technical skill longitudinally in a reliable and valid manner. This study describes a novel skills assessment tool, the Omni, which evaluates performance in a broad range of skills over time. DESIGN: The 5 Omni tasks, consisting of open bowel anastomosis, knot tying, laparoscopic clover pattern cut, robotic needle drive, and endoscopic bubble pop, were developed by general surgery faculty. Component performance metrics assessed speed, accuracy, and quality, which were scaled into an overall score ranging from 0 to 10 for each task. For each task, ANOVAs with Scheffe's post hoc comparisons and Pearson's chi-squared tests compared performance between 6 resident cohorts (clinical years (CY1-5) and research fellows (RF)). Paired samples t-tests evaluated changes in performance across academic years. Cronbach's alpha coefficient determined the internal consistency of the Omni as an overall assessment. SETTING: The Omni was developed by the Department of Surgery at Duke University. Annual assessment and this research study took place in the Surgical Education and Activities Lab. PARTICIPANTS: All active general surgery residents in 2 consecutive academic years spanning 2015 to 2017. RESULTS: A total of 62 general surgery residents completed the Omni and 39 (67.2%) of those residents completed the assessment in 2 consecutive years. Based on data from all residents' first assessment, statistically significant differences (p < 0.05) were observed among CY cohorts for bowel anastomosis, robotic, and laparoscopic task metrics. By pair-wise comparisons, mean bowel anastomosis scores distinguished CY1 from CY3-5 and CY2 from CY5. Mean robotic scores distinguished CY1 from RF, and mean laparoscopic scores distinguished CY1 from RF, CY3, and CY5 in addition to CY2 from CY3. Mean scores in performance on the knot tying and endoscopic tasks were not significantly different. Statistically significant improvement in mean scores was observed for all tasks from year 1 to year 2 (all p < 0.02). The internal consistency analysis revealed an alpha coefficient of 0.656. CONCLUSIONS: The Omni is a novel composite assessment tool for surgical technical skill that utilizes objective measures and scoring algorithms to evaluate performance. In this pilot study, 3 tasks demonstrated discriminative ability of performance by CY, and all 5 tasks demonstrated construct validity by showing longitudinal improvement in performance. Additionally, the Omni has adequate internal consistency for a formative assessment. These results suggest the Omni holds promise for the evaluation of resident technical skill and early identification of outliers requiring intervention. PMID- 30522828 TI - Documenting or Operating: Where Is Time Spent in General Surgery Residency? AB - OBJECTIVE: The utilization of electronic health records (EHR) has become essential in the daily activities of physicians for documentation and as an information source. However, the amount of time spent by residents utilizing the EHR has not been thoroughly evaluated, particularly within surgical specialties. This study aims to analyze EHR usage by general surgery residents and to assess the association between this use and case volume at a single academic institution. DESIGN: For general surgery residents in clinical years (CY) 1-5, de identified login and logout time data between September 2016 and June 2017 were retrospectively extracted from the Epic EHR (Verona, WI). A binary time series was created for each resident to indicate and track over time whether he or she was utilizing the EHR system. Comparisons between categorical variables were performed with Fisher's exact test. Continuous variables were compared using Wilcoxon rank sum test. Longitudinal linear mixed-effects models were used to assess the EHR usage among the surgery residents. The association between EHR time and the number of operative cases logged was evaluated with Pearson's correlation coefficient. SETTING: This study was performed by the Department of Surgery in conjunction with the Office of Graduate Medical Education at Duke University Health System. PARTICIPANTS: All active general surgery residents during the 2016-2017 academic year. RESULTS: Thirty-six general surgery residents (28 males, 8 females) spent a median of 2.4 hours per day and 23.7 hours per week using the EHR. CY2 had the highest median usage per week (28.9 hours), while CY3 had the lowest (16.7 hours) but no significant difference based on EHR usage was found among the analyzed CYs (p = 0.164). Residents spent significantly more time logged into the EHR during the week compared to weekends and during the day compared to nights (all p < 0.001). For the residency program as a whole, a median of 151.5 total work hours per day was dedicated to documentation. On average, interns on dedicated night rotations spent 7% of their login time outside regularly scheduled duty hours while interns on dedicated day rotations spent 27%. There was no overall correlation between monthly case logs and EHR usage (r = 0.06, p = 0.30); however, CY2 had a significant negative correlation (r = -0.2, p = 0.038). CONCLUSIONS: In the era of a maximum 80-hour work week, general surgery residents spend a substantial portion, at least 30%, of their time utilizing the EHR. One third of EHR usage by interns occurred outside the scheduled 12-hour shift, demonstrating the difficulties of completing paperwork as part of the scheduled work day. Additionally, the lack of correlation to case logs is likely due to an underestimation of the documentation burden associated with operating, which includes preparatory effort and operative notes. Ultimately, these quantitative EHR usage results will be correlated to burnout prior to implementing programs to improve efficiency and decrease the burden of charting. PMID- 30522829 TI - Exonuclease I and III improve the detection efficacy of hepatitis B virus covalently closed circular DNA. AB - BACKGROUND: Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is an important biomarker of hepatitis B virus infection. However, the current methods are not specific and sensitive. The present study aimed to develop a specific and sensitive assay method for the quantification of HBV cccDNA. METHODS: Exonuclease I (Exo I) & Exonuclease III (Exo III) and specific primer probes are used in real time PCR. The virus particles isolated from peripheral blood mononuclear cells were used as negative control and HBV1.3 recombinant plasmid 3.2 kb circular DNA fragment was used as positive control. The methods of cccDNA detection were evaluated in cell lines, plasmid, animal model, patient serum and liver biopsies. RESULTS: A linear range of 101-107 copies/assay using specific primers for HBV cccDNA was established. HBV cccDNA were only detected in cell lines, animal model and liver tissue. It cannot be detected in serum samples. Intrahepatic HBV cccDNA level had good correlation with intrahepatic total HBV DNA level (r = 0.765, P < 0.001). CONCLUSIONS: The real-time quantitative PCR is an effective and feasible method for sensitive and specific detection of low copy number of cccDNA. The novel detection method is fast, provides high sensitivity and specificity and can be used in clinical practice. PMID- 30522830 TI - The efficacy and safety of ciclesonide for the treatment of perennial allergic rhinitis: a systematic review and meta-analysis. AB - INTRODUCTION: Allergic rhinitis is a chronic inflammatory disease which affects 1 out of 6 individuals. Perennial allergic rhinitis accounts for 40% of AR cases. Ciclesonide is one of the relatively new intranasal steroid for allergic rhinitis. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of ciclesonide in the treatment of perennial allergic rhinitis. METHODS: We searched Pubmed, Scientific Citation Index, Embase, Clinical Trial Registries for randomized controlled trials and Cochrane Central Register of Controlled Trials to find out the randomized controlled Trial comparing ciclesonide with placebo for PAR. RESULTS: Eight studies were included. In comparison with placebo groups, ciclesonide groups significantly decreased Reflective Total Nasal Symptom Score (MD=-0.56; 95% CI -0.72 to 0.39, p<0.00001) with heterogeneity (p=0.19, I2=24%), Instantaneous Total Nasal Symptom Score (MD=-0.57; 95% CI -0.75 to 0.39, p<0.00001) with heterogeneity (p=0.34, I2=11%). A significant effect for Reflective Nasal Symptom Score Subtotal (MD=-0.15; 95% CI -0.18 to -0.13, p<0.00001) with heterogeneity (p=0.12, I2=24%) was also demonstrated. Rhinoconjunctivitis quality of life questionnaire score (RQLQs) (MD=-0.27; 95% CI -0.39 to -0.15, p<0.00001) with heterogeneity (p=0.58, I2=0%) in the treatment of ciclesonide was also significantly reduced. In addition, the difference in Treatment-Emergent Adverse Events between the two groups was not significant. CONCLUSION: Ciclesonide can improve perennial allergic rhinitis without increasing adverse events. Ciclesonide may be another valuable choice for perennial allergic rhinitis in the future. PMID- 30522831 TI - Is the C-reactive protein/albumin ratio a prognostic and predictive factor in sudden hearing loss? AB - INTRODUCTION: Sudden hearing loss is a significant otologic emergency. Previous studies have revealed a coexistence of sudden hearing loss with chronic inflammation. The predictive importance of C-reactive protein/albumin values as a prognostic factor has been shown in various inflammatory and tumoral conditions. OBJECTIVES: The aim of this study was to determine whether the C-reactive protein/albumin ratio in sudden hearing loss can be used for prognostic purposes and whether there is a relationship between the neutrophil/lymphocyte ratio and the C-reactive protein/albumin ratio. METHODS: A retrospective examination was made of 40 patients diagnosed with idiopathic sudden hearing loss and a control group of 45 healthy subjects. The pure tone averages of all the patients were determined on first presentation and repeated at 3 months after the treatment. The patients were separated into 2 groups according to the response to treatment. The neutrophil/lynphocyte ratio and the C-reactive protein/albumin ratios were calculated from the laboratory tests. RESULTS: The patients included 16 females and 24 males with a mean age of 44.1+/-14.2 years and the control group was composed of 23 females and 22 males with a mean age of 42.2+/-13.8 years. The mean C-reactive protein/albumin ratio was 0.95+/-0.47 in the patient group and 0.74+/-0.13 in the control group. The difference was statistically significant (p=0.009). The mean C-reactive protein/albumin ratio was 0.79+/-0.12 in the response to treatment group and 1.27+/-0.72 in the non-response group, with no significant difference determined between the groups (p=0.418). The mean neutrophil/lymphocyte ratio was 3.52+/-3.00 in the response to treatment group and 4.90+/-4.60 in the non-response group, with no statistically significant difference determined between the groups (p=0.261). CONCLUSION: C reactive/albumin ratio was significantly higher in patients with sudden hearing loss than in the control group. Although C-reactive protein/albumin ratio was found to be lower in sudden hearing loss patients who responded to treatment compared to those who did not, the difference between two groups was not statistically significant. PMID- 30522832 TI - The Time for Opioid Stewardship Is Now. PMID- 30522833 TI - Reasons for Repeat Rapid Response Team Calls, and Associations with In-Hospital Mortality. AB - BACKGROUND: Previous publications noted increased mortality risk in patients subject to repeat rapid response team (RRT) calls. These patients were examined as a homogenous group, but there may be many reasons for repeat calls. Those potentially preventable by the rapid response system have not been investigated. METHODS: In a retrospective cohort study, patients with potentially preventable repeat calls were classified into two categories: type 1 (patients who had a repeat call following an initial call that ended despite the patient still triggering RRT calling criteria [T1-PRC]) and type 2 (patients with a repeat call within 24 hours of an initial call and for the same reason [T2-PRC]). In-hospital mortality for these patients and for those with repeat calls for all other reasons (ORC), were compared to patients with only a single call during their admission (SC). RESULTS: Mortality occurred in 31 (43.7%) T1-PRC, 13 (15.1%) T2 PRC, 56 (28.9%) ORC, and 289 (13.9%) SC patients. Univariate odds ratios (ORs), in comparison to SC patients, were 4.81 (95% confidence interval [CI]: 2.96-7.81; p < 0.001), 1.10 (95% CI: 0.60-2.02; p = 0.75), and 2.52 (95% CI: 1.80-3.52; p < 0.001), respectively. Mortality effects persisted for the T1-PRC and ORC groups after adjustment for patient, admission, and initial call characteristics with ORs of 4.07 (95% CI: 2.36-7.01; p < 0.001) and 2.29 (95% CI: 1.57-3.34; p < 0.001), respectively. CONCLUSION: This study found that repeat calls following an initial call that ended with ongoing breach of predefined calling criteria were strongly associated with increased mortality. This highlights the risk to patients when the RRT leaves reversible clinical deterioration unresolved at the end of a call. PMID- 30522834 TI - Consumption of oral antibiotic formulations for young children according to the WHO Access, Watch, Reserve (AWaRe) antibiotic groups: an analysis of sales data from 70 middle-income and high-income countries. AB - BACKGROUND: The 2017 WHO Model List of Essential Medicines for Children (EMLc) groups antibiotics as Access, Watch, or Reserve, based on recommendations of their use as first-choice and second-choice empirical treatment for the most common infections. This grouping provides an opportunity to review country-level antibiotic consumption and a potential for stewardship. Therefore, we aimed to review 2015 levels of oral antibiotic consumption by young children globally. METHODS: We analysed wholesale antibiotic sales in 70 middle-income and high income countries in 2015. We identified oral antibiotic formulations appropriate for use in young children (defined as child-appropriate formulations [CAFs]) using wholesale data from the IQVIA-Multinational Integrated Data Analysis System database, and we estimated 2015 antibiotic consumption in reference to the 2017 WHO EMLc Access, Watch, Reserve (AWaRe) antibiotic groups. We used three metrics for assessment of intra-country patterns: access percentage, defined as the number of CAF standard units of Access antibiotics divided by the total number of CAF standard units; amoxicillin index, defined as the number of amoxicillin CAF standard units divided by the total number of CAF standard units; and access-to watch index, defined as the ratio of Access-to-Watch CAF standard units. FINDINGS: The overall median volume of CAF antibiotic standard units sold in 2015 per country was 74.5 million (IQR 12.4-210.7 million). The median access percentage among the 70 countries was 76.3% (IQR 62.6-84.2). The amoxicillin index was low (median 30.7%, IQR 14.3-47.3). The median access-to-watch index was 6.0 (IQR 3.1-9.8). CAF antibiotic consumption patterns were highly variable between the 70 countries, without a clear difference between high-income and middle-income countries. INTERPRETATION: Antibiotics in the Access group have a key role in treating young children globally. A simple combination of metrics based on the AWaRe groups can be informative on individual countries' patterns of antibiotic consumption and stewardship opportunities. These metrics could support countries in the development of programmes to improve access to core Access antibiotics, particularly amoxicillin. FUNDING: Global Antibiotic R&D Partnership (German Federal Ministry of Health, Medecins Sans Frontieres, Netherlands Ministry of Health, Welfare and Sport, and UK Department for International Development). PMID- 30522835 TI - Be AWaRe: new metrics for paediatric antibiotic stewardship. PMID- 30522836 TI - Understanding influenza vaccination rates and reasons for refusal in caregivers and household contacts of cancer patients. AB - Cancer patients are at increased risk for morbidity and mortality from seasonal influenza but are known to respond poorly to influenza vaccination. This single center survey suggests that approximately one-third of cancer patients and their caregivers and family did not receive the vaccine in the prior season. Patients felt strongly that caregiver vaccination was important, whereas caregivers' decisions did not appear to be affected by the patients' disease. PMID- 30522837 TI - Identification of urinary tract infections using electronic health record data. AB - BACKGROUND: Population ascertainment of postoperative urinary tract infections (UTIs) is time-consuming and expensive, as it often requires manual chart review. Using the American College of Surgeons National Surgical Quality Improvement Program UTI status of patients who underwent an operation at the University of Colorado Hospital, we sought to develop an algorithm for identifying UTIs using data from the electronic health record. METHODS: Data were split into training (operations occurring between 2013-2015) and test (operations in 2016) sets. A binomial generalized linear model with an elastic-net penalty was used to fit the model and carry out variables selection. International classification of disease codes, common procedural terminology codes, antibiotics, catheterization, and common procedural terminology-specific UTI event rates were included as predictors. The Youden's J statistic was used to determine the optimal classification threshold. RESULTS: Of 6,840 patients, 134 (2.0%) had a UTI. The model achieved 92% specificity, 80% sensitivity, 100% negative predictive value, 16% positive predictive value, and an area under the curve of 0.94 using a decision threshold of 0.03. CONCLUSIONS: A model with 14 predictors from the electronic health record identifies UTIs well, and it could be used to scale up UTI surveillance or to estimate the impact of large-scale interventions on UTI rates. PMID- 30522838 TI - Kamishibai cards to sustain evidence-based practices to reduce health care associated infections. AB - BACKGROUND: Sustaining healthcare-associated infection (HAI) prevention practices is complex. We examined the use of Kamishibai Cards (K Cards) as a tool to encourage compliance interactions between leaders and staff. METHODS: We explored one unit of a children's hospital to assess acceptability of K Cards. Interactions were recorded (n = 14), and interviews were conducted (n = 22). We used the Health Belief Model (HBM) for analyses. Central line utilization, bundle compliance and rates of HAIs were also examined. RESULTS: Staff members consider K Card interactions reminders of bundle elements and acceptable for creating positive interactions. Although no causal inference can be made, during K Card implementation, CLABSI rates dropped from 1.83 in 2015 to 0.0 through June 2018. Central line utilization decreased by 3%. DISCUSSION: Moving beyond theory to providing practical sustainability tools is an important implementation step. Although our findings are not generalizable, capturing what occurred on one unit provides opportunity to discover how key leadership factors (communication and leadership style) influence the uptake, acceptability and sustained adoption of evidence-based practices. CONCLUSIONS: K Cards are a practical tool to sustain evidence-based practices and promote communication between leadership and staff - keeping compliance on the minds of frontline workers. PMID- 30522839 TI - Examining health care personal protective equipment use through a human factors engineering and product design lens. PMID- 30522840 TI - Case-control study investigating parameters affecting ventilator-associated events in mechanically ventilated patients. AB - We analyzed a set of clinical parameters using Cox proportional hazard regressions to yield significant factors associated with the development of ventilator-associated events. In our study, intubation site, certain comorbidities, morphine, prednisone, and nutrition emerged as factors. Additionally, we presented potential mechanisms the require further research to validate. PMID- 30522841 TI - Oncocytic cystadenoma and oncocytic cysts of the parotid gland occurring synchronously with a pleomorphic adenoma. PMID- 30522842 TI - Treatment of a calcifying epithelial odontogenic tumour with tube decompression: a case report. AB - Conservative treatment of odontogenic tumours with decompression or marsupialisation is not common, but can be done successfully in those with a cystic pattern. We present a calcifying epithelial odontogenic tumour that was treated by tube decompression and subsequent enucleation. PMID- 30522843 TI - No change in the teaching of oral and maxillofacial surgery to medical students. PMID- 30522844 TI - Scanning the Future of Medical Imaging. AB - The medical device industry is undergoing rapid change as innovation accelerates, new business models emerge, and artificial intelligence and the Internet of Things create disruptive possibilities in health care. On the innovation front, global annual patent applications related to medical devices have tripled in 10 years, and technology cycle times have halved in just 5 years. Connectivity has exploded-by 2021, the world will have more than three times as many smart connected devices as people-and more and more medical devices and processes contain integrated sensors. In this article, we report on recent McKinsey (McKinsey & Company, New York, New York) work to map start-ups and trends shaping the future of medical imaging. We identify technology clusters with prospects of future growth, look at some of their cutting-edge practices, and consider what the implications may be for our specialty. PMID- 30522845 TI - 13C-lutein is differentially distributed in tissues of an adult female rhesus macaque following a single oral administration: a pilot study. AB - Despite the growing awareness regarding lutein's putative roles in eyes and brain, its pharmacokinetics and tissue distribution in primates have been poorly understood. We hypothesized that 13C-lutein will be differentially distributed into tissues of an adult rhesus macaque (Macaca mulatta) 3 days following a single oral dose. After a year of prefeeding a diet supplemented with unlabeled lutein (1 MUmol/kg/d), a 19-year-old female was dosed with 1.92 mg of highly enriched 13C-lutein. Tissues of a nondosed, lutein-fed monkey were used as a reference for natural abundance of 13C-lutein. On the third day postdose, plasma and multiple tissues were collected. Lutein was quantified by high-performance liquid chromatography-photodiode array detector, and 13C-lutein tissue enrichment was determined by liquid chromatography quadrupole time-of-flight mass spectrometry. In the tissues of a reference monkey, 12C-lutein with natural abundance of 13C-lutein was detectable. In the dosed monkey, highly enriched 13C lutein was observed in all analyzed tissues except for the macular and peripheral retina, with the highest concentrations in the liver followed by the adrenal gland and plasma. 13C-lutein accumulated differentially across 6 brain regions. In adipose depots, 13C-lutein was observed, with the highest concentrations in the axillary brown adipose tissues. In summary, we evaluated 13C-lutein tissue distribution in a nonhuman primate following a single dose of isotopically labeled lutein. These results show that tissue distribution 3 days following a dose of lutein varied substantially dependent on tissue type. PMID- 30522846 TI - [Neuroimaging of Epstein-Barr virus-associated encephalitis]. PMID- 30522847 TI - The Toldt fascia: A historic review and surgical implications in complete mesocolic excision for colon cancer. AB - To clarify the anatomic concept of Toldt fascia, based on the literature review and the surgical anatomic dissection using laparoscopic or robotic approach. We undertook review of the historic literature and surgical videos from 250 patients with colorectal cancer operated on laparoscopically or robotically to discuss the surgical implications of Toldt fascia in complete mesocolic excision for colon cancer. Toldt fascia, sandwiched by the overlying mesothelial layer of the mesocolon and underlying mesothelial layer of the retroperitoneum, comprised loose fibrous tissues with minute vessels inside, and was contiguous from the ileocecal mesentery radix to the upper rectum. Surgical dissection plane is readily developed within the Toldt fascia; however, any attempt to dissect along the interface between Toldt fascia and the overlying mesocolon or underlying retroperitoneum failed. Within the anatomic territory of kidney, Toldt fascia fused with Gerota fascia, and then extended in all directions: upward to the dosal surface of the duodenum, liver and pancreas; medially to fuse with the adventitia layer of the abdominal aorta; laterally, it tapered at the area below the reflection of visceral and parietal peritoneum; and downward, it became a thin membranous structure covering the gonadal vessels, ureters and retroperitoneal structures and ended at the upper rectum, where it met the junction of endopelvic fascia and proper fascia of the rectum. The present study demonstrated that Toldt fascia is a natural embryonic dissection plane for the precise conduction of complete mesocolic excision for colon cancer. PMID- 30522848 TI - A food-based score and incidence of overweight/obesity: The Dietary Obesity Prevention Score (DOS). AB - BACKGROUND & AIMS: Given the enormous health, economic and societal consequences of the obesity pandemic, identifying effective primary prevention strategies represents a global priority. The aim of this study was to provide evidence on the association between adherence to a food-based score reflecting a set of targeted, well-informed, simple dietary recommendations and the incidence of overweight/obesity. METHODS: A total of 11,349 initially free of overweight/obesity young adults (mean [SD] age: 34.7 y [10.7]), were followed up biennially during a median of 9.3 years. The Dietary Obesity-Prevention Score (DOS) was created based on a priori evidence of foods associated with weight changes. The DOS positively weighted the consumption of vegetables, fruits, legumes, yogurt, nuts, fish, and a ratio of vegetable to animal protein; whereas the consumption of red meat, processed meat, saturated animal fat, refined grains, ultra-processed food, sugary beverages, beer and spirits were inversely weighted. Energy-adjusted tertiles of each item were used to build the DOS, ranging from 14 (lowest adherence) to 42 points (highest adherence). Adherence to the DOS was calculated at baseline and after 10 years of follow-up. We assessed both incident overweight/obesity (BMI >=25 kg/m2) and average yearly weight changes in grams per year (g/y). RESULTS: During 104,887 person-years, 2153 incident cases of overweight/obesity were identified. A higher adherence to the DOS at baseline was significantly associated with lower risk of future development of overweight/obesity [multivariable-adjusted HR (95% CI) for the highest vs. lowest quintile = 0.63 (0.54-0.74)], with a significant linear dose response relationship (p for trend < 0.001). When the analyses were updated with repeated measures, the results were similar and remained statistically significant. Consistently, increases in average yearly weight gain were significantly lower with better adherence to the DOS. CONCLUSIONS: In this Mediterranean cohort of university graduates, a higher adherence to a food-based score was significantly associated with lower risk of overweight/obesity and lower average annual weight gain. These findings may help counsel patients regarding dietary risks and raise awareness of weight gain before the onset of overweight/obesity. PMID- 30522849 TI - Fluorescent metal-doped carbon dots for neuronal manipulations. AB - There is a growing need for biocompatible nanocomposites that may efficiently interact with biological tissues through multiple modalities. Carbon dots (CDs) could serve as biocompatible fluorescence nanomaterials for targeted tissue/cell imaging. Important goals toward this end are to enhance the fluorescence quantum yields of the CDs and to increase their targetability to cells. Here, sonochemistry was used to develop a one-pot synthesis of CDs, including metal doped CDs (M@CDs), demonstrating how various experimental parameters, such as sonication time, temperature, and power of sonication affect the size of the CDs (2-10 nm) and their fluorescence properties. The highest measured quantum yield of emission was ~16%. Similarly, we synthesized CDs doped with different metals (M@CDs) including Ga, Sn, Zn, Ag, and Au. The interaction of M@CDs with neuron like cells was examined and showed efficient uptake and low cytotoxicity. Moreover, the influence of the M@CDs on the improvement of neurites during initiation and elongation growth phases were compared with pristine CDs. Our research demonstrates the use of M@CDs for imaging and for neuronal interactions. The M@CD nanocomposites are promising due to their biocompatibility, photo stability and potential selective affinity, paving the way for multifunctional biomedical applications. PMID- 30522850 TI - Adequate evidence to support improved outcomes in depression by primary care physicians compared to psychiatrists when using combinatorial pharmacogenomics. PMID- 30522852 TI - Global geriatric oncology: One size does not fit all. PMID- 30522851 TI - Views on a new surgical assistance method for implanting the glenoid component during total shoulder arthroplasty. Part 2: From three-dimensional reconstruction to augmented reality: Feasibility study. AB - INTRODUCTION: The main goal of this study was to propose a new method of surgical assistance for the implantation of a total shoulder prosthesis, with the use of augmented reality (AR). The advantage of this approach is that it supplements information, on the one hand pre-existing or disappeared due to a pathological process, such as the premorbid glenoid, and on the other hand already existing but not accessible to the surgeon during the procedure, such as the so-called "hidden" face of the scapula. MATERIAL AND METHODS: Several information preparation steps were needed. The first consisted in the three-dimensional (3D) rendering of the pathological glenoid, from a point cloud corresponding to the premorbid glenoid based on previously developed regression equations. A library of "healthy" generic glenoids was then created by hierarchical bottom-up analysis. From this database, a so-called adequate normal generic glenoid was fused and matched to the pathological glenoid reconstructed using a morphing technique. An experimental AR application was constructed. Smart glasses were used to display the prepared 3D information. RESULTS: A pathological 3D glenoid was reconstructed and used for the AR application. A complete display of the scene, reconstructed glenoid and full scapula was obtained. However, an offset from reality was observed. The main limitations were technical, related to the connected tool itself and the operating software. DISCUSSION/CONCLUSION: This was a feasibility study of the different steps required to apply AR, from information preparation to its visualization. A new parameter crossing experiment is needed to optimize each step of this process. LEVEL OF EVIDENCE: IV, Basic science study. PMID- 30522853 TI - Long non-coding RNA LINC00472 suppresses hepatocellular carcinoma cell proliferation, migration and invasion through miR-93-5p/PDCD4 pathway. AB - Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second leading cause of cancer-related deaths. In the present study, we have demonstrated that long non-coding RNA (lncRNA) LINC00472 was low expressed in human HCC tissues and cell lines compared with adjacent non-tumor liver tissues and normal liver cell lines respectively. LINC00472 was also low expressed in HCC tissues from patients with metastasis compared with tissues from patients without metastasis. Expression level of LINC00472 was positively correlated with patient overall survival (OS) rate. Forced expression of LINC00472 suppressed cell proliferation, migration, invasion and promoted cell apoptosis in HCC cells Huh-7 and SMMC-7721. MiR-93-5p was a direct target of LINC00472, and miR-93-5p directly targeted PDCD4. The miR-93-5p/PDCD4 pathway mediated the suppressing role of LINC00472 in HCC cells. Therefore, LINC00472 was an important tumor suppressor in human HCC, which could be used as a bio-marker for HCC therapy. PMID- 30522854 TI - Development of brain networks for social functions: Confirmatory analyses in a large open source dataset. AB - Human observers show robust activity in distinct brain networks during movie viewing. For example, scenes that emphasize characters' thoughts evoke activity in the "Theory of Mind" (ToM) network, whereas scenes that emphasize characters' bodily sensations evoke activity in the "Pain Matrix." A prior exploratory fMRI study used a naturalistic movie-viewing stimulus to study the developmental origins of this functional dissociation, and the links between cortical and cognitive changes in children's social development (Richardson et al., 2018). To replicate and extend this work, the current study utilized a large publicly available dataset (n = 241, ages 5-20 years) (Alexander et al., 2017) who viewed "The Present" (Frey, 2014) and completed a resting state scan (n = 200) while undergoing fMRI. This study provides confirmatory evidence that 1) ToM and pain networks are functionally dissociated early in development, 2) selectivity increases with age, and in ToM regions, with a behavioral index of social reasoning. Additionally, while inter-region correlations are similar when measured during the movie and at rest, only inter-region correlations measured during movie-viewing correlated with functional maturity. This study demonstrates the scientific benefits of open source data in developmental cognitive neuroscience, and provides insight into the relationship between functional and intrinsic properties of the developing brain. PMID- 30522855 TI - Clinical relevance of different handgrip strength indexes and cardiovascular disease risk factors: A cross-sectional study in suburb-dwelling elderly Chinese. AB - BACKGROUND: Reduced muscle strength, as measured by handgrip strength (HS), has been associated with an increased risk of cardiovascular disease (CVD). The aim of this study was to examine the association between different HS indexes and CVD risk factors in elderly Chinese individuals. We also determine optimal cutoffs of HS indexes for predicting CVD risk factors. METHODS: Data were obtained from 603 men and 789 women aged >=60 years (average age 66.8 +/- 6.4 y). These study participants were recruited in the suburb area of Tianjin, China. An individual was considered a patient when they exhibited any one of three CVD risk factors: diabetes mellitus, hypertension and dyslipidemia. All participants were interviewed face-to-face. In addition, serum samples were collected from all participants, and all participants underwent measures of anthropometry and HS. RESULTS: The optimal cutoffs were 0.376 of HS/weight in men and 0.726 of HS/body fat mass in women for predicting diabetes mellitus. The adjusted odds ratios (ORs) of at least one CVD risk factor for those with low muscle strength identified by HS/body fat mass were 2.14 (95% confidence interval [CI]: 1.53, 3.44; p < 0.001) in men and 2.32 (95% CI: 1.60, 3.29; p < 0.001) in women. CONCLUSIONS: HS/body fat mass appear to be the index best associated with CVD risk factors except diabetes mellitus in men. The optimal cutoffs of HS indexes have the potential to identify elderly adults at risk of CVD. PMID- 30522856 TI - Nonintubated laryngomicrosurgery with Transnasal Humidified Rapid-Insufflation Ventilatory Exchange: A case series. AB - BACKGROUND: Nonintubation anaesthesia for laryngomicrosurgery (LMS) provides both excellent visualization of the surgical field and complete examination on vocal cord. However, adequate oxygenation remains challenging during nonintubated LMS. Recently, transnasal humidified rapid-insufflation ventilator exchange (THRIVE) has been reported effectively maintaining apneic oxygenation in patient with difficult airways. The feasibility and safety of nonintubated LMS with THRIVE was evaluated in this case series. METHODS: From September 2016 to February 2017, a total of 23 patients receiving nonintubated LMS were included. Anaesthesia was induced and maintained through target-controlled propofol infusion and muscle relaxation with THRIVE oxygen support. Perioperative data were collected from medical records and analysed. RESULTS: The mean (+/-SD) duration of the operation was 12.4 (+/-4.4) min. The mean (+/-SD) total anaesthesia time (from induction to emergence) was 24.1 (+/-6.4) min. 22 patients received nonintubated LMS with surgical satisfaction without intraoperative desaturation. One patient who underwent laryngeal tumour biopsy experienced a single episode of desaturation. A 5.5-mm tracheal tube was needed for short-term mechanical ventilation to regain SpO2 to 100%. No significant complication was noted in all patients. All patients discharged as per schedule on the next day after surgery as intubated LMS patients in our hospital. CONCLUSIONS: Nonintubated LMS with THRIVE is a feasible and safe alternative to intubated LMS with a small size tracheal tube to provide a better surgical field. However, for patients with easy-bleeding tumor, intubated LMS remains suggestive for better airway protection. PMID- 30522857 TI - Henoch-Schonlein Purpura After Living Donor Liver Transplantation: Report of the First Case. AB - Henoch-Schonlein purpura (HSP) is a systemic vasculitis affecting the small vessels that mainly presents in children and young adults. It is characterized by tissue deposition of immunoglobulin A (IgA) immune complexes with the classic manifestations of purpura, arthritis, arthralgia, and gastrointestinal and renal involvements. We report a case of HSP nephritis that occurred 2 years after living-donor liver transplantation (LDLT). After pulse steroid administration, the patient's symptoms disappeared and blood markers normalized. To the best of our knowledge, this is the first HSP case to be reported in a liver transplant recipient. PMID- 30522858 TI - An Intraoperative Portal Vein Flow > 123 mL/min Per 100 g Predicts a Better Survival of Patients After Liver Transplantation. AB - OBJECTIVE: To assess the importance of intraoperative portal vein flow measurement during liver transplantation in relation to postoperative complications and graft and patient survival. MATERIALS AND METHODS: Retrospective review including 291 patients who had all the information and covering a period of 10 years (2007-2017). Using a receiver operating characteristic curve, a cut-off point that would have the greatest impact on the probability of being alive at 5 years was established. In relation to this value, 2 groups were formed (low and high flow) and demographic variables, intraoperative variables, postoperative complications, and graft and patient survival were compared. RESULTS: A portal flow of 123 mL/min per100 g of liver tissue was established (area under the curve = 0.58), obtaining a low-flow (n = 129) and a high-flow group (n = 162). The 2 groups were similar in their preoperative characteristics, except for a higher proportion of preoperative ascites, a higher Model for End-Stage Liver Disease score and a lower weight of donors in the high-flow group. The arterial and portal flows were significantly higher in the high-flow group. In the postoperative period, the high-flow group presented a higher rate of ascites. The 5-year survival rate of patients was significantly higher in the high-flow group (76% vs 84%, P = .03). CONCLUSIONS: Patients undergoing liver transplantation with an intraoperative portal vein flow measurement >123 mL/min per 100 g present a greater 5-year survival rate. PMID- 30522859 TI - Impact of Positive Donor-Specific HLA Antibodies Crossmatch on Graft Survival in ABO-Incompatible Liver-Kidney Transplantation: A Case Report. AB - We present a patient with positive donor-specific antibodies (DSA) and crossmatch of ABO-incompatible (ABOi) combined liver and kidney transplantation (CLKT). Antibody-mediated rejection did not occur and the graft had survived for over one year at the time of writing without infectious complications. A 56-year-old man with positive DSA and positive crossmatch underwent living donor CLKT. The preoperative protocol for ABOi consisted of a single dose of rituximab and total plasma exchange (TPE). The result of anti-B antibody titer for IgG was 1:32. The evaluations of complement-dependent cytotoxicity and flow cytometry cross-match revealed a change from T+/B+ to T-/B+. The patient required adult living donor CLKT. Acute rejection episodes were treated using antithymocyte globulin, and the kidney required 7 days' treatment to recover. No further rejection and infectious episodes have been observed in past 13 months since the transplant. DSA and crossmatches are important for antibody detection and analysis. In the rituximab era, TPE can be used to achieve a successful decrease in antibody titer. In countries with a severe shortage of cadaveric organ donors, it may be possible to select ABOi candidate donors with positive DSA and crossmatch. PMID- 30522861 TI - Yimon Aye: Crossing Borders with Chemical Biology. PMID- 30522862 TI - A Primer on Data Analytics in Functional Genomics: How to Move from Data to Insight? AB - High-throughput methodologies and machine learning have been central in developing systems-level perspectives in molecular biology. Unfortunately, performing such integrative analyses has traditionally been reserved for bioinformaticians. This is now changing with the appearance of resources to help bench-side biologists become skilled at computational data analysis and handling large omics data sets. Here, we show an entry route into the field of omics data analytics. We provide information about easily accessible data sources and suggest some first steps for aspiring computational data analysts. Moreover, we highlight how machine learning is transforming the field and how it can help make sense of biological data. Finally, we suggest good starting points for self learning and hope to convince readers that computational data analysis and programming are not intimidating. PMID- 30522860 TI - Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families. AB - BACKGROUND: Abetalipoproteinemia, a recessive disease resulting from deleterious variants in MTTP (microsomal triglyceride transfer protein), is characterized by undetectable concentrations of apolipoprotein B, extremely low levels of low density lipoprotein cholesterol in the plasma, and a total inability to export apolipoprotein B-containing lipoproteins from both the intestine and the liver. OBJECTIVE: To study lipid absorption after a fat load and liver function in 7 heterozygous relatives from 2 abetalipoproteinemic families, 1 previously unreported. RESULTS: Both patients are compound heterozygotes for p.(Arg540His) and either c.708_709del p.(His236Glnfs*11) or c.1344+3_1344+6del on the MTTP gene. The previously undescribed patient has been followed for 22 years with ultrastructure analyses of both the intestine and the liver. In these 2 families, 5 relatives were heterozygous for p.(Arg540His), 1 for p.(His236Glnfs*11) and 1 for c.1344+3_1344+6del. In 4 heterozygous relatives, the lipid absorption was normal independent of the MTTP variant. In contrast, in 3 of them, the increase in triglyceride levels after fat load was abnormal. These subjects were additionally heterozygous carriers of Asp2213 APOB in-frame deletion, near the cytidine mRNA editing site, which is essential for intestinal apoB48 production. Liver function appeared to be normal in all the heterozygotes except for one who exhibited liver steatosis for unexplained reasons. CONCLUSION: Our study suggests that a single copy of the MTTP gene may be sufficient for human normal lipid absorption, except when associated with an additional APOB gene alteration. The hepatic steatosis reported in 1 patient emphasizes the need for liver function tests in all heterozygotes until the level of risk is established. PMID- 30522863 TI - Targeting NPRL2 to enhance the efficacy of Olaparib in castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) lacks effective treatment, and studies have shown that PARPi inhibitors, such as Olaparib, are somewhat effective; however, the efficacy of Olaparib in CRPC still needs to be further improved. Nitrogen permease regulator-like 2 (NPRL2) is reported to be a tumor suppressor candidate gene and is closely related to the DNA repair pathway, which can affect the sensitivity of many chemotherapeutic drugs. However, there is no research on whether NPRL2 is associated with sensitivity to Olaparib. Hence, in the present study, we examined the NPRL2 expression levels in several PCa cell lines (LNCaP, PC3, and enzalutamide-resistant LNCaP, named LNPER) by Western blot. In addition, we investigated the role of NPRL2 expression and silencing in cell proliferation and in the regulation of ataxia telangiectasia mutated (ATM), which can mediate DNA repair and sensitivity to Olaparib. Furthermore, we performed in vitro and in vivo experiments to determine the mechanism of action of NPRL2 in adjusting Olaparib sensitivity. Our findings demonstrated that the NPRL2 expression level was upregulated in PCa cells, especially CRPC cells. NPRL2 overexpression promoted growth and resistance to Olaparib, and NPRL2 silencing inhibited proliferation, enhanced sensitivity to Olaparib, and increased CRRL2 expression in PCa cells. In addition, the Olaparib-induced growth delay in NPRL2 silenced PC3 tumors in mice correlated with ATM signaling downregulation, an apoptosis increase and migration/invasion suppression. Our results indicate that NPRL2 silencing enhances sensitivity to Olaparib treatment in CRPC and that NPRL2 may serve as a potential therapeutic target and predict resistance to Olaparib in CRPC. PMID- 30522864 TI - Induction of steady-state glomeruloid sphere by self-assembly from human embryonic kidney cells. AB - The glomerulus is a network of capillaries known as a tuft, located at the beginning of a nephron in the kidney. Here we describe a novel method for the induction of a macroscopically visible three-dimensional glomerulus-like sphere (GLS). This procedure did not require any additional cytokines and completed the formation of spheres within 24 h. After the formation was complete, GLS maintained a steady state for at least five days without proliferation and without a decrease in viability. Therefore, this procedure assists various assays for a prolong period of time. Overall, our protocol allows for a very simple mixing of cells from different sources to obtain fine-grained and highly dispersed GLSs. The kidney filtration barrier is a unique structure characterized by a complex three-dimensional framework of podocytes and endothelial cells. GLS exhibited the induction of many podocyte-specific gene profiles similar to those in adult human kidneys, suggesting that the sphere formation process is important for the maturation of podocytes. Focal segmental glomerulosclerosis (FSGS) is one of the major causes of steroid-resistant nephrotic syndrome, and some circulating permeability factors in the patient's serum FSGS have been implicated in the pathogenesis of the disease. Serum from patients with FSGS induced the collapse of GLS, which imitates the appearance of glomerulosclerosis in patients. In conclusion, the investigation and use of GLS may provide a novel method to elucidate the molecular mechanisms underlying complicated and unexplained events in glomeruli in a similar condition in adult kidneys. PMID- 30522865 TI - Inhibition of mitochondrial respiration overcomes hepatocellular carcinoma chemoresistance. AB - The clinical management of advanced hepatocellular carcinoma (HCC) is challenging due to its resistance to chemotherapy. In our work, we demonstrate that an antiparasitic drug atovaquone at clinically relevant concentrations is active against chemoresistant HCC. We show that atovaquone inhibits proliferation and induces apoptosis in not only HCC parental cells but also cells exposed to long time culture of chemotherapeutic agents. Consistently, the combination of atovaquone with cisplatin or doxorubicin achieved remarkably greater efficacy than single drug alone. Mechanistically, atovaquone overcomes HCC chemoresistance via supressing mitochondrial respiration and inducing oxidative stress. Atovaquone but not cisplatin or doxorubicin is ineffective in mitochondrial respiration-deficient rho0, confirming mitochondria as a specific upstream target of atovaquone. Interestingly, we show that prolonged exposure of HCC cells to chemotherapeutic agents induces higher level of mitochondrial respiration, suggesting that tumors which develop chemoresistance after chemotherapy might be more dependent on mitochondrial respiration than primary tumors and explaining the sensitivity of chemoresistant HCC cells to atovaquone. We further show that atovaquone at tolerable does significantly inhibits chemoresistant HCC growth in mice throughout the duration of treatment. In line with in vitro data, we observe the increased oxidative stress in atovaquone-treated tumors. Our findings highlight the dependency of chemoresistant HCC on mitochondrial respiration and demonstrate that atovaquone is a potential drug to overcome HCC chemoresistance. PMID- 30522866 TI - TLR4-dependent upregulation of the platelet NLRP3 inflammasome promotes platelet aggregation in a murine model of hindlimb ischemia. AB - Platelets play a critical role in the pathophysiology of peripheral arterial disease (PAD). The mechanisms by which muscle ischemia regulates aggregation of platelets are poorly understood. We have recently identified the Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) expressed by platelets as a critical regulator of platelet activation and aggregation, which may be triggered by activation of toll-like receptor 4 (TLR4). In this study, we performed femoral artery ligation (FAL) in transgenic mice with platelet-specific ablation of TLR4 (TLR4 PF4) and in NLRP3 knockout (NLRP3-/-) mice. NLRP3 inflammasome activity of circulating platelets, as monitored by activation of caspase-1 and cleavage of interleukin-1beta (IL-1beta), was upregulated in mice subjected to FAL. Genetic ablation of TLR4 in platelets led to decreased platelet caspase 1 activation and platelet aggregation, which was reversed by the NLRP3 activator Nigericin. Two weeks after the induction of FAL, ischemic limb perfusion was increased in TLR4 PF4 and NLRP3-/- mice as compared to control mice. Hence, activation of platelet TLR4/NLRP3 signaling plays a critical role in upregulating platelet aggregation and interfering with perfusion recovery in muscle ischemia and may represent a therapeutic target to improve limb salvage. PMID- 30522867 TI - The Emergence of Social Norms and Conventions. AB - The utility of our actions frequently depends upon the beliefs and behavior of other agents. Thankfully, through experience, we learn norms and conventions that provide stable expectations for navigating our social world. Here, we review several distinct influences on their content and distribution. At the level of individuals locally interacting in dyads, success depends on rapidly adapting pre existing norms to the local context. Hence, norms are shaped by complex cognitive processes involved in learning and social reasoning. At the population level, norms are influenced by intergenerational transmission and the structure of the social network. As human social connectivity continues to increase, understanding and predicting how these levels and time scales interact to produce new norms will be crucial for improving communities. PMID- 30522868 TI - What is the optimal time-to-conception after bariatric surgery? PMID- 30522869 TI - Strategies for diagnosing and managing gastric diverticulum in sleeve gastrectomy. PMID- 30522870 TI - The evolutionary history of Southern Africa. AB - The genomic variability of Southern African groups is characterized by an exceptional degree of diversity, which is the result of long-term local evolutionary history, migrations and gene-flow. Over the last few years several investigations have identified and described signatures related to these processes, revealing how ancient and more recent events have shaped the structure and ancestry composition of local populations. Here we discuss recent insights into the genetic history of the Southernmost part of the African continent provided by the analysis of modern and ancient genomes. Future work is expected to clarify the population dynamics associated with the emergence of Homo sapiens across Africa and the details of the process of dispersion and admixture associated with the arrival of Bantu-speaking groups in the region. PMID- 30522871 TI - In reply to "Animal models for neurotoxicity assessment in cardiac arrest". PMID- 30522872 TI - Influenza vaccination and critical patient protection: responsibility of healthcare workers. PMID- 30522873 TI - Predictors of CPAP adherence following stroke and transient ischemic attack. AB - OBJECTIVE: Continuous positive airway pressure (CPAP) has been shown to improve functional, motor and cognitive outcomes in post-stroke obstructive sleep apnea (OSA). However, rates of CPAP adherence are often low and factors impacting CPAP adherence remain under-explored. Our objective was to determine predictors of CPAP adherence in patients who had a stroke or transient ischemic attack (TIA). METHODS: We screened 313 stroke/TIA patients for OSA using in-hospital polysomnography or the ApneaLink home sleep apnea test. Potential predictors were recorded at baseline and adherence to CPAP was recorded during a six-month follow up visit. Selected variables from our univariate analyses were included in multivariate regression models to determine predictors of CPAP adherence. For our logistic regression analyses, CPAP adherence (CPAP use of >=4 h per night) was the dependent outcome variable. In our linear regression analyses, total CPAP use per week (recorded in hours) was the dependent outcome variable. RESULTS: Eighty eight patients (mean age 67.81 +/- 13.09 years, 69.32% male, mean body mass index 27.93 +/- 5.23 kg/m2) were diagnosed with OSA, prescribed CPAP, and assessed for adherence at a six-month follow-up visit. In these 88 patients, 46 (52.27%) were adherent with CPAP therapy. From our regression models, two significant predictors of CPAP adherence were identified: greater functional status (p = 0.04) and not endorsing daytime tiredness (p = 0.047) post-stroke/TIA. CONCLUSION: Patients with greater functional capacity and those with less daytime fatigue demonstrated stronger adherence to CPAP therapy. Our findings may facilitate future treatment strategies for enhancing CPAP adherence in the vulnerable stroke/TIA population. PMID- 30522874 TI - Response to "prospective memory impairment in idiopathic REM sleep behavior disorder". PMID- 30522875 TI - Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data. AB - OBJECTIVE: Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored suvorexant effects on sleep problems and their impact on daytime function. METHODS: Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (>=65 years) and non-elderly (18-64 years old) insomnia patients. Age-adjusted (non elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. RESULTS: The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo <0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, >=6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo <0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of life, was improved to a greater extent by suvorexant than placebo. CONCLUSIONS: Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS. GOV IDENTIFIER: NCT01097616, NCT01097629. PMID- 30522876 TI - Experimental evaluation of pressure drop for flows of air and heliox through upper and central conducting airway replicas of 4- to 8-year-old children. AB - Airway resistance describes the ratio between pressure drop and flow rate through the conducting respiratory airways. Analytical models of airway resistance for tracheobronchial airways have previously been developed and assessed without upper airways positioned upstream of the trachea. This work investigated pressure drop as a function of flow rate and gas properties for upper and central airway replicas of 10 child subjects, ages 4-8. Replica geometries were built based on computed tomography scan data and included airways from the nose through 3-5 distal branching airway generations. Pressure drop through the replicas was measured for constant inspiratory flows of air and heliox. For both the nose throat and branching airways, the relationship between non-dimensional coefficient of friction, CF, with Reynolds number, Re, was found to resemble the turbulent Blasius equation for pipe flow, where CF?Re-0.25. Additionally, pressure drop ratios between heliox and air were consistent with analytical predictions for turbulent flow. The presence of turbulence in the branching airways likely resulted from convection of turbulence produced upstream in the nose and throat. An airway resistance model based on the Blasius pipe friction correlation for turbulent flow was proposed for prediction of pressure drop through the branching bronchial airways downstream from the upper airway. PMID- 30522877 TI - Does force myography recorded at the wrist correlate to resistance load levels during bicep curls? AB - Resistance strength training is a proven method to improve bone density and muscle strength. A solution capable of automatically detecting the resistance force level exerted by a user from a wrist-based device can offer great convenience to the trainee and hence facilitate a better training outcome. In this short communication, we present our investigation aimed at exploring if force myographic (FMG) signals recorded at the wrist can predict the relative resistance levels that are associated with different weights. Specifically, we investigated the Spearman's correlations between the wrist FMG signal features and the dumbbell weights during a bicep curl exercise. 10 volunteers were recruited to perform a total of 100 curl actions, which included both the hammer and regular curls while the wrist FMG signals were being recorded. Three sets of weights ranging from 0.2 lb to 8 lb were used. For the hammer curls, a median correlation coefficient of 0.92 with an interquartile range (IQR) of 0.03 was obtained. For the regular curls, a 0.94 median correlation with a 0.02 IQR was obtained. We also used the data from the first 36 curls to generate a classifier model and applied it onto the rest of the data. An averaged validation accuracy of 88% was obtained. The results of this study showed the potential use of wrist FMG signal to detect different levels of the load during exercises; such information could potentially be used as feedback in fitness, sports, and rehabilitation activities. PMID- 30522878 TI - Frequency-dependent contributions of sagittal-plane foot force to upright human standing. AB - Quiet standing is a mechanically unstable postural objective that humans typically perform with ease. Control of upright posture requires stabilization of both translational and rotational degrees-of-freedom that is accomplished by neuro-muscular coordination. This coordination produces a force at the ground foot interface (F) that is quantified by magnitude, direction (thetaF), and point of application (center-of-pressure, CP). Previous research has shown that the nervous system controls muscle activation such that CP motion occurs at both slow and fast time scales. However, it is unknown how thetaF varies with respect to CP and how that relationship varies across time scales. We present a novel method for assessing the frequency-dependent relative variation in thetaF and CP. The center-of-pressure (CP) and direction of the ground-on-foot force (F) in the sagittal-plane during quiet standing were decomposed into 0.2 Hz-width frequency bands within 0.4-8.0 Hz. The relation between the direction and CP was approximately linear with a slope positively related to frequency. These frequency-dependent features of F have critical implications for understanding balance strategy because the translational and rotational acceleration effects of F were coupled, but with opposite phasing at high versus low frequencies. Such results suggest a system tuned for one stability mode at low frequencies and another mode at higher frequencies. This frequency-wise approach to examining the translational and rotational effects of humans' preferred F may be useful for establishing balance rehabilitation metrics, directing study of the underlying neural mechanisms responsible for the observed coordination, and for setting a biometric standard to inform biomimetic prosthetics and robotics. PMID- 30522879 TI - Is Pelvic Floor sEMG a Measure of Women's Sexual Response? AB - INTRODUCTION: Pelvic floor surface electromyography (sEMG) is often used in the assessment and treatment of individuals with pelvic floor abnormalities to measure muscle tone and neural control of the pelvic floor muscles (PFM); however, little is known about the role of the PFM in sexual arousal. AIM: The aim of this pilot study was to examine whether changes in deep and superficial PFM activity-assessed with sEMG-can be observed during the presentation of sexual stimuli. METHODS: Deep PFM sEMG activity was assessed with a vaginal probe. Superficial PFM activity was assessed with sEMG electrodes placed over the bulbocavernosus and perianal muscles. 15 sexually healthy women (mean age 27 years) watched a series of neutral, anxiety-evoking, and sexually explicit films. Continuous subjective sexual arousal was measured using a handheld arousometer. MAIN OUTCOME MEASURE: Changes in microvolts were measured by sEMG sensors, from neutral to anxiety-evoking and neutral to sexually explicit films. RESULTS: There was an increase in intravaginal and perianal sEMG for both the erotic and anxiety films. Bulbocavernosus sEMG responses did not differ among the 3 films. Concordance between self-reported continuous sexual arousal for the erotic film and bulbocavernosus sEMG (r = 0.349) was not significantly different than concordance using intravaginal sEMG (r = 0.293) or perianal sEMG (r = 0.236). CLINICAL IMPLICATIONS: Understanding more about which parts of the PFM respond specifically to sexual stimuli may have implications for measuring the effects of treatments aimed at improving sexual response in women. STRENGTH & LIMITATIONS: The results of this pilot study provide a preliminary understanding of which pelvic floor muscles respond to sexual stimuli. A limitation of this study was the small sample size. CONCLUSION: Taken together, these findings suggest that intravaginal and perianal sEMG respond to erotic stimuli, whereas bulbocavernosal sEMG responses do not. Hannan-Leith MN, Dayan M, Hatfield G, et al. Is Pelvic Floor Surface Electromyography a Measure of Women's Sexual Response? A Pilot Study. J Sex Med 2019;XX:XXX-XXX. PMID- 30522880 TI - The first Japanese case of familial porphyria cutanea tarda diagnosed by a UROD mutation. PMID- 30522881 TI - Glucocorticoid insensitivity by staphylococcal enterotoxin B in keratinocytes of allergic dermatitis is associated with impaired nuclear translocation of the Glucocorticoid Receptor alpha. AB - BACKGROUND: staphylococcal enterotoxin plays an important role in patients with glucocorticoid (GC)-resistant atopic dermatitis (AD), but the exact mechanism is not fully understood. OBJECTIVE: The aim of this study was to investigate the mechanisms underlying the ability of staphylococcal enterotoxin B (SEB) to induce steroid insensitivity through impaired nuclear translocation of GRalpha in keratinocytes. METHODS: The steroid-resistant AD induced by SEB was assessed by analyzing dermatitis score, dermal thickness, scratching behavior, infiltrating cells/HPF, levels of SEB-specific IgE and IgG2a antibody. In addition, dexamethasone (DEX)-induced GRalpha nuclear translocation and keratinocyte derived cytokines and chemokines were analyzed in the lesional keratinocytes of AD and in HaCaT cells. Furthermore, the expressions of immunophilins FKBP51, FKBP52 and HSP90 responsive to GC in HaCaT cells were determined in the presence of SEB. RESULTS: SEB dose-dependently diminished the inhibitory effect of DEX on dermatitis score, dermal thickness, scratching behavior, infiltrating cells/HPF, keratinocyte-derived cytokines and chemokines such as RANTES, MCP-1, TSLP and GM CSF. In vivo and in vitro data showed that in the presence of DEX, SEB dose dependently caused a marked decrease of GRalpha nuclear translocation in lesional keratinocytes of AD and in HaCaT cells. Importantly, in the presence of DEX, SEB increased the expression of FKBP51 and the product of keratinocyte-derived cytokines and chemokines in HaCaT cells. CONCLUSION: These results demonstrate that GC insensitivity by SEB in keratinocytes of AD is associated with impaired nuclear translocation of the GRalpha. Increased DEX-induced FKBP51 by SEB may contribute to accumulation of the GRalpha in cytoplasm of keratinocytes. PMID- 30522882 TI - Brahma deficiency in keratinocytes promotes UV carcinogenesis by accelerating the escape from cell cycle arrest and the formation of DNA photolesions. AB - BACKGROUND: Ultraviolet radiation (UVR) is the principal cause of keratinocyte skin cancers. Previous work found that levels of the chromatin remodelling protein, Brahma (Brm), are diminished during the progression from actinic keratoses to cutaneous squamous cell carcinomas in humans, and its loss in UV irradiated mouse skin causes epidermal hyperplasia and increased tumour incidence. METHODS: The skins of mice and mouse and human keratinocytes deficient in Brm were exposed to UVR and evaluated for cell cycle progression and DNA damage response. OBJECTIVE: To identify the mechanisms by which loss of Brm contributes to UVR-induced skin carcinogenesis. RESULTS: In both mouse keratinocytes and HaCaT cells, Brm deficiency led to an increased cell population growth following UVR exposure compared to cells with normal levels of Brm. Cell cycle analysis using a novel assay showed that Brm-deficient keratinocytes entered cell cycle arrest normally, but escaped from cell cycle arrest faster, enabling them to begin proliferating earlier. In mouse keratinocytes, Brm primarily affected accumulation in G0/G1-phase, whereas in HaCaT cells, which lack normal p53, accumulation in G2/M-phase was affected. Brm-deficient keratinocytes in mouse skin and human cell cultures also had higher levels of UVR induced cyclobutane pyrimidine dimer photolesions. These effects occurred without any compensatory increase in DNA repair or cell death to remove photolesions or the cells that harbor them from the keratinocyte population. CONCLUSION: The loss of Brm in keratinocytes exposed to UVR enables them to resume proliferation while harboring DNA photolesions, leading to an increased fixation of mutations and, consequently, increased carcinogenesis. PMID- 30522883 TI - The association between blood urea nitrogen to creatinine ratio and mortality in patients with upper gastrointestinal bleeding. AB - BACKGROUND AND STUDY AIMS: Azotaemia is commonly identified among patients with upper gastrointestinal bleeding (UGIB) due to absorption of blood products in the small bowel. Previous studies have found blood urea nitrogen-to-creatinine (BUN/Cr) ratio to be significantly elevated among patients UGIB bleeding compared to patients with lower GI bleeding. However, no studies have explored the relationship between BUN/Cr ratio and mortality. This study is aimed at investigating how BUN/Cr ratio relates to outcomes for UGIB patients. PATIENTS AND METHODS: This study was conducted prospectively at a university-affiliated teaching hospital with approximate 70,000 annual emergency department (ED) visits. Data from a total of 258 adult UGIB patients were collected between March 1, 2011 and March 1, 2012. Cox regression analysis was used to identify risk factors for 30-day mortality. RESULTS: Malignancy and Rockall score were associated with increased risk of 30-day mortality (Unadjusted hazard ratio (HR): 3.87, 95% CI: 1.59-9.41, p = 0.0029; HR: 1.31, 95% CI: 1.02-1.71, p = 0.0476, respectively). However, BUN/Cr > 30 was associated with lower risk of 30-day mortality (HR: 0.32, 95% CI: 0.11-0.97, p = 0.0441). CONCLUSIONS: A BUN/Cr ratio of >30 was found to be an independent risk factor for mortality and may be useful for pre-endoscopic assessment. Development of future risk scoring systems might warrant consideration of including BUN/Cr ratio as a parameter for estimating risk. PMID- 30522884 TI - Rare diseases hiding in the cardiomyopathy clinic - The importance of seeing and observing. PMID- 30522885 TI - Impact of systemic immune-mediated diseases on clinical features and prognosis of patients with biopsy-proved myocarditis. AB - INTRODUCTION: Myocarditis has been described in association with many systemic immune-mediated diseases (SIDs). However, the role of SIDs in influencing clinical presentation and outcome of patients with a new diagnosis of biopsy proved myocarditis, has never been investigated so far. METHODS: We enrolled 25 consecutive cases with biopsy-proved myocarditis in the context of SIDs, and controls with isolated myocarditis, matched 1:1 by age, gender, ethnicity and clinical presentation. All of the patients presented with acute symptoms, normal coronary arteries, and no previous history of myocarditis. Detailed diagnostic workup, including blood exams, echocardiogram, arrhythmia monitoring and cardiac magnetic resonance (CMR) were obtained at baseline and at defined time points, up to 12-month follow-up (FU). RESULTS: At presentation, patients with SIDs had more commonly inflammatory biomarkers elevation, signs of associated pericarditis, and replacement fibrosis at histology, as compared to controls (18 vs. 6, 20 vs. 12, and 21 vs. 11, respectively; all p < 0.05). The Lake Louise criteria at CMR were negative in 19 vs. 10 patients with and without underlying SIDs, respectively (p = 0.021). Baseline ECG, in-hospital arrhythmia telemonitoring and echocardiographic findings were not significantly different between groups (all p = n.s.). At 12-month FU, the composite major endpoint of cardiac death, end-stage heart failure or malignant ventricular arrhythmias was significantly more common in cases than in controls (7 vs. 1, respectively, p = 0.049). CONCLUSION: In patients with a new diagnosis of myocarditis, the presence of underlying SIDs is associated with distinct baseline clinical features and a significantly worse 1 year outcome. PMID- 30522886 TI - The impact of continuous positive airway pressure treatment on the recurrence of atrial fibrillation post cardioversion: A randomized controlled trial. AB - BACKGROUND: Observational data suggest that positive airway pressure (PAP) treatment of obstructive sleep apnea (OSA) can reduce the risk of recurrent atrial fibrillation (AF) post-direct current cardioversion (DCCV) or catheter ablation. METHODS: We conducted a study of adult patients with AF and sleep apnea, stratified by age and gender, who underwent successful DCCV to sinus rhythm, and who were randomized to receive PAP or usual care. Those with sleepiness, significant cardiac or respiratory disease were excluded. Patients were followed for <=1 year. Primary outcome assessed was time to AF recurrence. Secondary outcomes included sleepiness and quality of life measured using the Epworth Sleepiness Scale (ESS) and Functional Outcome of Sleep Questionnaire (FOSQ) respectively. RESULTS: Of 1757 patients that were screened, 34 underwent polysomnography for this study, 25 of whom had an apnea-hypopnea index (AHI) >5/h. Twelve were randomized to PAP therapy and 13 to usual care. All eligible patients were found to have OSA. There were no differences in body mass index, blood pressure, ejection fraction, AHI, or nocturnal oxygen parameters between intervention and control groups (all p > 0.05). AF recurred in 25% of patients in the PAP and control groups, at 129.0 +/- 166.5 versus 109.3 +/- 73.2 days respectively, p = 0.98; there were no differences in ESS (5.8 +/- 2.6 versus 5.7 +/- 2.3; p = 0.17) or FOSQ (18.3 +/- 1.5 versus 17.5 +/- 1.9; p = 0.26) at follow up. CONCLUSIONS: This is the first randomized controlled trial assessing the impact of treatment of OSA on recurrence of AF post-DCCV, and did not detect a difference between those treated with PAP versus usual care. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, identifier number: NCT00263757. PMID- 30522887 TI - Rotational and translational positions determine the structural and dynamic impact of a single ribonucleotide incorporated in the nucleosome. AB - Ribonucleotides misincorporated by replicative DNA polymerases are by far the most common DNA lesion. The presence of ribonucleotides in DNA is associated with genome instability, causing replication stress, chromosome fragility, gross chromosomal rearrangements, and other mutagenic events. Furthermore, nucleosome and chromatin assembly as well as nucleosome positioning are affected by the presence of ribonucleotides. Notably, nucleosome formation is significantly reduced by a single ribonucleotide. Single ribonucleotides are primarily removed from DNA by the ribonucleotide excision repair (RER) pathway via the RNase H2 enzyme, which incises the DNA backbone on the 5'-side of the ribonucleotide. While the structural implications of a single ribonucleotide in free duplex DNA have been well studied, how a single ribonucleotide embedded in nucleosomal DNA impacts nucleosome structure and dynamics, and the possible consequent impact on RER, have not been explored. We have carried out 3.5 MUs molecular dynamics simulations of a single ribonucleotide incorporated at various translational and rotational positions in a nucleosome core particle. We find that the presence of the 2'-OH group on the ribose impacts the local conformation and dynamics of both the ribonucleotide and nearby DNA nucleotides as well as their interactions with histones; the nature of these disturbances depends on the rotational and translational setting, including whether the ribose faces toward or away from the histones. The ribonucleotide's preferred C3'-endo pucker is stabilized by interactions with the histones, and furthermore the ribonucleotide can cause dynamic local duplex disturbance involving an abnormal C3'-endo population of the adjacent deoxyribose pucker, minor groove opening, ruptured Watson-Crick pairing, and duplex unwinding that are governed by translation-dependent histone nucleotide interactions. Possible effects of these disturbances on RER are considered. PMID- 30522888 TI - Clomiphene Citrate for the Treatment of Hypogonadism. AB - INTRODUCTION: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamic pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility. AIM: To review the literature regarding the use of CC in the setting of hypogonadism. METHODS: A review of the relevant literature through September 2018 was performed via PubMed. MAIN OUTCOME MEASURE: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized. RESULTS: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated. CONCLUSION: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2018;XX:XXX-XXX. PMID- 30522889 TI - Fear of birth: Prevalence, counselling and method of birth at five obstetrical units in Norway. AB - BACKGROUND: There is increasing evidence that fear of birth can have long-term effects on the childbearing woman and the method of birth. AIM: To examine differences between five hospitals in Norway in the occurrence of fear of birth, counselling received and method of birth. METHOD: Source data was from the Norwegian cohort of the Bidens study and retrieved through a questionnaire and electronic patient records from five different hospitals in Oslo, Drammen, Tromso, Alesund and Trondheim, which included 2145 women. The Wijma Delivery Expectancy Questionnaire measured fear of birth, and a cut-off of >=85 was used to define fear of birth. RESULTS: In total, 12% of the women reported fear of birth, with no significant differences between the different units. A total of 8.7% received counselling according to hospital obstetrical records, varying significantly from 5.7% in Drammen to 12.7% in Oslo. Only 24.9% of the women with fear of birth had counselling at their hospital. All the units provided counselling for women with fear, but the content varied. Overarching aims included helping women develop coping strategies like writing a birth plan and clearing up issues regarding prior births. A secondary objective was to prevent unnecessary caesarean section. Both primi- and multiparous women who reported fear of birth had a twofold increased risk of a planned caesarean section. CONCLUSION: There were no differences between five Norwegian hospitals regarding the occurrence of fear of birth. Counselling methods, resources, level of commitment and the number of women who received counselling varied; thus, hospital practices differed. PMID- 30522890 TI - Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development. AB - Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models. Additionally, we discuss current and potential future applications of PBPK in the drug discovery and development timeline for mAbs, spanning from identification of potential target molecules to prediction of potential drug-drug interactions. Finally, we conclude with a discussion of currently available PBPK models for mAbs that could be implemented in the drug development process. PMID- 30522891 TI - Myeloid and lymphoid activation markers in AIDS and non-AIDS presenters. AB - HIV infection is characterized by a state of chronic activation of the immune system, which is not completely reversed by antiretroviral treatment (ART). The aim of this study was to assess myeloid and lymphoid activation markers during HIV infection, before and one year after ART initiation, in AIDS and non-AIDS presenters. Treatment naive HIV positive patients were enrolled in this study. Myeloid dendritic cell (mDC), plasmacytoid dendritic cell (pDC), slanDC, monocyte and T-lymphocyte cell counts and activation status, were assessed by flow cytometry in peripheral blood samples. Soluble (s)CD14 and sCD163 were assessed in plasma samples using ELISA assays. Statistical analyses were performed using GraphPad Prism and Minitab Express. Thirty-four ART naive HIV-1 infected subjects were enrolled in this study (22 non-AIDS and 12 AIDS presenters). Seventeen healthy donors (HD) were included as control group. Although circulating mDC levels resulted unchanged, HLA-DR expression was decreased on mDCs of HIV positive subjects compared to HD (p < 0,0001). AIDS presenters showed the lowest level of expression of HLA-DR on mDCs. Circulating levels of pDCs were decreased in HIV patients compared to HD (p < 0,001), without any changes in HLA-DR expression. SlanDC cell counts were extremely reduced in AIDS presenters, compared to non-AIDS presenters and HD (p < 0,01 and p < 0,0001, respectively) and showed higher HLA-DR expression in HIV patients compared to HD (p < 0,01). Intermediate monocyte (IM) cell counts were increased in AIDS and non-AIDS presenters compared to HD (p < 0,001 and p < 0,001 respectively). Furthermore, IM expansion was directly correlated to HIV viral load (p = 0,036) and independent from CD4 cell counts and activation levels. Plasma concentrations of sCD14 and sCD163 resulted increased in HIV infected subjects compared to HD (p < 0,0001 and p < 0,001), with the highest levels observed in AIDS presenters. After 1 year, ART was able to increase pDC and decrease IM absolute cell counts and modify HLA DR expression on mDCs and slanDCs, approaching the levels observed in HD. ART reduced also CD4 and CD8 activation levels. In conclusion, in untreated HIV infected subjects circulating dendritic cells resulted altered either in numbers or in HLA-DR expression, especially in AIDS presenters. IM absolute counts were equally increased in AIDS and non-AIDS presenters. ART was able to reduce myeloid and lymphoid inflammation in both advanced and non-advanced HIV patients, confirming the role of ART in hampering disease progression and immune activation associated non-AIDS events. PMID- 30522892 TI - Prevalence and antimicrobial susceptibility of bacterial pathogens isolated from urine specimens received in rizgary hospital - Erbil. AB - BACKGROUND: Urinary tract infection (UTI) is a common health-associated problem worldwide. Like other medical conditions, UTI patients may suffer from poor treatment outcomes due to the emergence of antimicrobial resistance. Determining patterns of antimicrobial susceptibility in uropathogens will guide physicians to choose the best antibiotics for treating affected patients. In this project we aimed to evaluate the frequencies of pathogens associated with UTI and their antimicrobial susceptibility patterns. METHODS: This study was conducted on 2692 urine samples of patients visited Rizgary Teaching Hospital in Erbil city. Aerobic bacterial growth identification and antimicrobial susceptibility tests were performed using VITEK(r)2 compact system. RESULTS: Our data show that more than 20% of all studied samples were negative for bacterial growth; only 16.72% of them were pathogenic bacteria in which 82.44% of them were Gram negative bacteria (GNB) and the rest were Gram positive bacteria (GPB). Escherichia coli was the most frequent, and Acinetobacter baumannii was the most resistant GNB. Staphylococcus haemolyticus was the most frequent, and Enterococcus faecalis was the most resistant GPB. In general GNB were highly resistant to Ticarcillin and Cefepime, and GPB were also resistant to Ticarcillin, and Tigecycline antibiotics. CONCLUSIONS: The amount of negative culture growth indicates that symptoms only based diagnosis for UTI detection is unreliable. E. coli is the most UTI related pathogen, E. faecalis and A. baumannii were among highly antibiotic resistant bacteria. Finally, since many of GNG and GPB isolates were resistant to several antibiotics, there might be a high possibility for multi drug resistant among local population in Erbil. PMID- 30522893 TI - Is Aspergillus lateral device ready to implement to the daily practice? The question rising from the new European Invasive Aspergillosis management guideline. PMID- 30522894 TI - Frequency and risk factors for liver disease following pancreatitis: A population based cohort study. AB - BACKGROUND & AIMS: Both liver disease (LD) and pancreatitis pose substantial burdens. There have been no general population-based studies on frequency of LD after an episode of pancreatitis. The aim of this study was to investigate the occurrence of LD in a population-based cohort of patients following pancreatitis. METHODS: Nationwide data on the general population of nearly 3 million people were used to identify retrospectively diagnoses of acute pancreatitis, chronic pancreatitis (CP), LD and cirrhosis from 1998 to 2016. Acute pancreatitis was categorised as first (FAP) or recurrent (RAP) episode. Number of pancreatitis recurrences prior to LD diagnosis was determined. RESULTS: A total of 20,931 pancreatitis patients were included, of which 874 developed LD following pancreatitis. The incidence of LD in FAP was 115.59 (95% confidence interval 102.19-128.98), in RAP - 217.63 (95% confidence interval 173.31-261.94), and in CP - 539.43 (95% confidence interval 494.72-584.13) patients per 100,000 pancreatitis patients per year. There was a significant increase in the probability of LD with increasing number of pancreatitis recurrences and, for the same number of pancreatitis recurrences, LD was significantly more frequent after CP than RAP (hazard ratio 1.666 (95% confidence interval 1.322-2.098; p = <0.001)). CONCLUSIONS: The frequency of LD increases from FAP to RAP to CP. While number of pancreatitis recurrences is a significant risk factor for development of LD, there is a higher probability of LD following CP than RAP even for the same number of recurrences. Interventions preventing pancreatitis and its progression may lower the burden of LD. PMID- 30522895 TI - Immunization Coverage of Children in Care of the Child Welfare System in High Income Countries: A Systematic Review. AB - CONTEXT: Children in care of the child welfare system tend to underutilize preventive health services compared with other children. The purpose of this systematic review was to assess current knowledge regarding immunization coverage levels for children in the child welfare system and to determine barriers and supports to them utilizing immunization services. EVIDENCE ACQUISITION: Articles published in Medline, Embase, Cochrane Library, CINAHL, SocINDEX, and ERIC from January 1, 2000 to October 13, 2017 were searched. Thesis and conference databases and relevant websites were also examined. Studies were included if written in English, from high-income countries, and addressed immunizations for children in the child welfare system. Independent dual screening, extraction, and quality appraisal were conducted between October 2016 and December 2017, followed by narrative synthesis. EVIDENCE SYNTHESIS: Of 2,906 records identified, 33 met inclusion criteria: 21 studied coverage, two studied barriers/supports, and ten studied both. Nineteen studies were moderate or high quality and thus included in the narrative synthesis; 15 studied coverage, one studied barriers/supports, and three studied both. Most studies found lower coverage among children in child welfare. The few studies that explicitly studied barriers/supports to immunization identified that a collaborative and coordinated approach between health and social services was key to service delivery to this population. CONCLUSIONS: This review highlights that children in care of the child welfare system are at risk of poor immunization coverage. There is a need for high quality studies on this issue, with a focus on assessing supports/barriers to immunization in this population. PMID- 30522896 TI - The effect of facial expression on facial symmetry in surgically managed unilateral cleft lip and palate patients (UCLP). AB - AIM: To evaluate the symmetry of facial expression in surgically managed UCLP patients. MATERIALS AND METHODS: The study was conducted on 13 four-year-old children. Facial images were captured at rest and at maximum smile using stereophotogrammetry. A generic mesh, which is a mathematical facial mask consisting of a fixed number of indexed vertices, was utilised for the assessment of facial asymmetry. This was quantified by measuring the disparity between the left- and right-hand sides of the face after superimposing the original 3D images on their mirror copies. RESULTS: Residual asymmetries at rest were identified at the vermillion of the upper lip and at the nares with a deviation of the philtrum towards the scar tissue. Vertical and anteroposterior asymmetries were identified on the cleft side. At maximum smile, the asymmetry increased noticeably at the vermillion of the upper lip and at the alar base. In the mediolateral direction, the philtrum deviated towards the cleft side with a significant increase of the asymmetry scores. DISCUSSION: Asymmetry of the upper lip has significantly increased at maximum smile as a result of the upward forces of all perioral lifting muscles, which affected the lip directly. CONCLUSIONS: The innovation of this study is the measurement of facial asymmetry for the objective outcome measure of the surgical repair of UCLP. The philtrum was the main site of residual asymmetry, which indicates the need for refining the primary repair of the cleft lip. Further corrective surgery may be required. PMID- 30522897 TI - Prevalence and predictors of high-on treatment platelet reactivity during prasugrel treatment in patients with acute coronary syndrome undergoing stent implantation. AB - BACKGROUND: ADP-antagonists such as prasugrel have reduced but yet not overcome the phenomenon of high-on treatment platelet reactivity (HRPR), that has been shown to increase the rate of major cardiovascular events after an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI). However, the exact prevalence and the principal determinants of suboptimal platelet inhibition in patients treated with dual antiplatelet therapy (DAPT) with prasugrel have not been completely clarified and were therefore the aim of the present study. METHODS: We included patients (<75 years and >60kg) treated with DAPT (aspirin+prasugrel) after PCI, mainly for an ACS. Platelet function test evaluation was performed at 1-3 months from discharge. HRPR was assessed by multiplate impedance aggregometry and defined for results above upper limit of normal after ADP stimulation. RESULTS: We included 190 post-ACS patients. HRPR with prasugrel was observed in 19 patients (10%). The prevalence of HRPR was stable in different high-risk subgroups of patients (female gender, hypercholesterolemic, and chronic kidney disease) whereas it was increased in diabetic patients (p=0.045), with a significant interaction between diabetic status and HRPR (p=0.04). However, at multivariate analysis, an impaired metabolic status, with higher levels of glycosylated hemoglobin and low-density lipoprotein (LDL) cholesterol, but not diabetic status, emerged as independent predictors of HRPR with prasugrel [OR (95% CI)=2.1 (1.32-3.33), p=0.002 and OR (95% CI)=1.03 (1.01-1.05), p=0.003, respectively], with a stronger linear relationship between ADP-mediated platelet aggregation and glycosylated hemoglobin levels (r=0.24, p=0.002), than for LDL-cholesterol (r=0.13, p=0.09). CONCLUSIONS: In post-ACS patients treated with PCI and receiving DAPT with prasugrel, HRPR is observed in about 10% of patients. Impaired metabolic status, and especially elevated glycosylated hemoglobin, emerged as independent predictors of the suboptimal effectiveness of prasugrel. PMID- 30522898 TI - Design, synthesis, biological evaluation, structure-activity relationship, and toxicity of clinafloxacin-azole conjugates as novel antitubercular agents. AB - Based on the advantages of azole molecules and fluoroquinolone drugs, we designed and synthesized 34 clinafloxacin-azole conjugates using fragment-based drug design and drug combination principles. The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis (H37Rv), Hela cell as well as Gram-positive and Gram-negative bacteria were assayed. The bioassay results revealed that most of the target molecules had anti-tuberculosis (anti TB) activity, of which 14 compounds had very strong anti-TB activity [minimum inhibitory concentration (MIC) < 2 MUM]. In addition, the compounds with strong activity towards H37Rv had weak activity towards Gram-negative and Gram-positive bacteria, showing obvious selectivity towards H37Rv. Predicted toxicity data indicated that 27 molecules were less toxic or equivalent to that of the original drug (clinafloxacin). Especially, it is demonstrated that compound TM2l exhibited the strongest anti-TB activity (MIC = 0.29 MUM), low antibacterial activity, negligible toxicity, and good drug-likeness values, which can be considered as an ideal lead molecule for future optimization. PMID- 30522899 TI - Design, synthesis and biological evaluation of bifunctional inhibitors of membrane type 1 matrix metalloproteinase (MT1-MMP). AB - Collagen degradation and proMMP-2 activation are major functions of MT1-MMP to promote cancer cell invasion. Since both processes require MT1-MMP homodimerization on the cell surface, herein we propose that the use of bifunctional inhibitors of this enzyme could represent an innovative approach to efficiently reduce tumor growth. A small series of symmetrical dimers derived from previously described monomeric arylsulfonamide hydroxamates was synthesized and tested in vitro on isolated MMPs. A nanomolar MT1-MMP inhibitor, compound 6, was identified and then submitted to cell-based assays on HT1080 fibrosarcoma cells. Dimer 6 reduced MT1-MMP-dependent proMMP-2 activation, collagen degradation and collagen invasion in a dose-dependent manner with better results even compared to its monomeric analogue 4. This preliminary study suggests that dimeric MT1-MMP inhibitors might be further developed and exploited as an alternative tool to reduce cancer cell invasion. PMID- 30522900 TI - A strategic approach to the synthesis of ferrocene appended chalcone linked triazole allied organosilatranes: Antibacterial, antifungal, antiparasitic and antioxidant studies. AB - A series of ferrocene appended chalcone allied triazole coupled organosilatranes (FCTSa 7-FCTSa 12) were synthesised with the aim of amalgamating the pharmacological action of the constituting moieties into a single molecular scaffold. All the synthesised silatranes were well characterized by various spectroscopic techniques like IR, 1H NMR, 13C NMR and elemental analysis. Organosilatranes were then evaluated for their biological alacrity against bacterial and fungal strains compared with the standard drugs Rifampicin and Amphotericin B respectively. The ferrocene conjugates were found to be only moderately effective against the tested microbes. However, the organosilatranes conceded excellent efficacy against parasite G. lamblia with FCTSa 11 arraying the leading results. On the other hand against another parasite T. vaginalis, FCTSa 8 has emerged as an outstanding composite. Further, Total Antioxidant Assay (TAA) with 2,2'-azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid) revealed FCTSa 10 to be the best claimant for radical scavenging activity. Along these lines, introducing some different substituents in the synthesised hybrids may act as a useful strategy for increasing the biological profile of the drugs. PMID- 30522901 TI - Differential Expression of PD-L1 Between Sporadic and VHL-Associated Hereditary Clear-Cell Renal Cell Carcinoma and Its Correlation With Clinicopathological Features. AB - BACKGROUND: Programmed death ligand-1 (PD-L1) is a potential predictive biomarker for immunotherapy in several malignancies. However, the expression level and clinical significance of PD-L1 in von Hippel-Lindau (VHL)-associated hereditary clear-cell renal cell carcinoma (ccRCC) remain unclear. PATIENTS AND METHODS: Surgical specimens were recruited from 129 patients with sporadic ccRCC and 26 patients with VHL-associated hereditary ccRCC. The PD-L1 expression level was assessed using immunohistochemistry. Correlations between PD-L1 expression and clinicopathological features were analyzed. RESULTS: In sporadic ccRCC, the positive expression rate of PD-L1 was 47.3% (61/129). Positive PD-L1 expression was correlated with advanced tumor T stage (P = .011), higher Fuhrman nuclear grade (P = .022), poor disease-free survival (P = .037), and sex (P = .025). In the VHL-associated hereditary ccRCC, positive PD-L1 expression rate was 34.6% (9/26), lower than that in sporadic ccRCC. Positive PD-L1 was correlated with higher Fuhrman nuclear grade (P = .008), but not with sex, age, tumor stage, or the onset age of VHL-associated tumors. CONCLUSION: Positive PD-L1 expression was correlated with the aggressive clinicopathological features in sporadic and VHL associated hereditary ccRCC. Whether PD-L1 expression level in ccRCC is related to the effectiveness of programmed death-1/PD-L1 checkpoint inhibitor immunotherapy needs to be further investigated. PMID- 30522902 TI - Role of serum cholinesterase in patients treated with salvage radical prostatectomy. AB - BACKGROUND: Serum cholinesterase (ChE) a serine hydrolase that catalyses the hydrolysis of esters of choline, is involved in cellular proliferation and differentiation, therefore affecting carcinogenesis. The aim of this study was to understand the prognostic role of preoperative serum ChE in patients with radiation-recurrent prostate cancer (CaP) treated with salvage radical prostatectomy (SRP). MATERIAL AND METHODS: This retrospective study included 214 patients with radiation-recurrent CaP treated with SRP from January 2007 to December 2015 at 5 academic centers. Patients were considered with abnormal/decreased ChE levels if <5 kU/l. Biochemical recurrence-free and metastases-free (MFS) survival analyses were performed. RESULTS: Median serum ChE level was 6.9 (interquartile range) 6-7.7) kU/l. Serum ChE level (<5 kU/l) was decreased in 25 (11.7%) patients. Decreased serum ChE level was associated with lower body mass index (P = 0.006) and metastasis to lymph nodes (P = 0.004). In multivariable analysis, continuous ChE was an independent predictor of MFS (hazard ratio [HR] 0.48, confidence interval [CI] 0.33-0.71, P < 0.001), overall survival (HR 0.68, CI 0.48-0.96, P = 0.03) and cancer-specific survival (HR 0.41, CI 0.2-0.84, P = 0.01). Serum ChE improved the C-index (by 2.54%) to 87.8% for prediction of overall survival and (by 3%) to 92% for prediction of MFS. CONCLUSION: Preoperative serum ChE is associated with the development of metastasis in patients with radiation-recurrent CaP who underwent SRP. The biological underpinning of this association with the biological and clinical aggressiveness of CaP needs to be further elucidated. PMID- 30522903 TI - Analyzing the current practice patterns and views among urologists regarding focal therapy for prostate cancer. AB - INTRODUCTION AND OBJECTIVE: Focal therapy (FT) for localized prostate cancer (CaP) has been shown to have encouraging short-term oncological outcomes, excellent preservation of functional outcomes and is increasing in popularity in urologic community. We aim to evaluate the preferences and practice trends among urologists regarding this treatment strategy. METHODS: A 20 item online questionnaire was designed to collect information on urologists' views and use of FT. The survey was sent to the members of the Endourological Society and the American Urological Association. Multivariate logistic regression analysis was done to determine predictors for utilization of FT. RESULTS: A total of 425 responses were received [American Urological Association: 319, Endourological Society: 106]. Mean age of respondents was 53(SD: 11.3) years. Although half of the respondents (50.8%) believed FT to be moderate to extremely beneficial in the treatment of CaP, only 24.2% (103) of the respondents currently utilize FT in their practice. Respondents who were fellowship trained in urologic oncology were more likely to consider FT to be at least moderately beneficial (P < 0.001). Surgeon's experience (greater than 15 years in urology practice) (P = 0.025) and seeing more than 10 patients with new CaP diagnosis per month (P = 0.002) were independent predictors of FT utilization for localized CaP. While the most common setting for utilization of FT was in patients with unilateral intermediate-risk (72.8%) CaP, a small percentage of respondents also used FT for patients with unilateral high-risk CaP and bilateral intermediate risk (21.4% and 10.7%, respectively). Most common reasons for not using FT were the lack of belief in 'index lesion theory' (63.2%), lack of experience (41.3%), lack of belief in FT's efficacy (41.1%), lack of infrastructure (35.8%), difficult salvage treatment in cases of recurrence (22.7%) and high cost (21.8%). About 57.6% would use FT more often in an office or outpatient setting if they had access to reliable and cost effective options. CONCLUSIONS: Only a quarter of our respondents utilize FT in their practice with surgeon's experience being the important independent predictor for using FT. Majority of respondents though consider FT to be beneficial in CaP management, would use it more often if provided more reliable and cost-effective options. Over time, experience and accessibility to reliable methods to perform FT may lead to further utilization of this novel treatment strategy. PMID- 30522904 TI - Physical activity after mild traumatic brain injury: What are the relationships with fatigue and sleep quality? AB - OBJECTIVES: To determine self-reported physical activity (PA) levels and relationships with fatigue and sleep quality in adolescents and young adults after mild traumatic brain injury (mTBI). SETTING: Follow-up 6-18 months after visiting the emergency department of one of 2 general hospitals. PARTICIPANTS: Forty-nine adolescents and young adults aged 12-25 years (mean 18.4 years), 22 (45%) male with mTBI. DESIGN: Cross-sectional survey study. MAIN OUTCOME MEASURES: The Activity Questionnaire for Adults and Adolescents (AQuAA), with results dichotomized into meeting or not meeting Dutch Health Enhancing PA recommendations (D-HEPA), the Checklist Individual Strength (CIS, 4 subscores) and the Pittsburgh Sleep Quality Index (PSQI, total score) were administered. RESULTS: Twenty-five participants (51%) did not meet the D-HEPA recommendations. After adjusting for sex, BMI and age, not meeting the recommendations was associated with a higher CIS Total Score (OR 1.04 95%CI 1.01, 1.07) but not with PSQI Total Score (OR 0.99, 95%CI 0.80, 1.21). CONCLUSIONS: In adolescents and young adults with mTBI the level of reported PA is associated with fatigue but not with sleep quality. It remains to be established whether interventions aiming to promote PA should primarily be focused on PA or fatigue or both. PMID- 30522905 TI - Implementation of The Lancet Commission on Global Surgery in India. PMID- 30522906 TI - Comparison of vaccination with rhesus CMV (RhCMV) soluble gB with a RhCMV replication-defective virus deleted for MHC class I immune evasion genes in a RhCMV challenge model. AB - A human cytomegalovirus (HCMV) vaccine to prevent infection and/or reduce disease associated with congenital infection or visceral disease in transplant recipients is a high priority, but has remained elusive. We created a disabled infectious single cycle rhesus CMV (RhCMV) deleted for glycoprotein L (gL) and the MHC class I immune evasion genes Rh178 and Rh182-189, and restored its epithelial cell tropism by inserting the Rh128-131A genes. The resulting virus, RhCMVRDeltagL/178/182-189, was used to vaccinate rhesus monkeys intramuscularly and was compared with vaccination of animals with soluble RhCMV glycoprotein B (gB) in alum/monophosphoryl lipid A or with PBS as a control. At 4 weeks after the second vaccination, an increased frequency of RhCMV-specific CD8 T cells was detected in animals vaccinated with the RhCMVRDeltagL/178/182-189 vaccine compared to animals vaccinated with soluble gB. In contrast, monkeys vaccinated with soluble gB had 20-fold higher gB antibody titers than animals vaccinated with RhCMVRDeltagL/178/182-189. Titers of neutralizing antibody to RhCMV infection of fibroblasts were higher in animals vaccinated with gB compared with RhCMVRDeltagL/178/182-189. Following vaccination, monkeys were challenged subcutaneously with RhCMV UCD59, a low passage virus propagated in monkey kidney epithelial cells. All animals became infected after challenge; however, the frequency of RhCMV detection in the blood was reduced in monkeys vaccinated with soluble gB compared with those vaccinated with RhCMVRDeltagL/178/182-189. The frequency of challenge virus shedding in the urine and saliva and the RhCMV copy number shed at these sites was not different in animals vaccinated with RhCMVRDeltagL/178/182-189 or soluble gB compared with those that received PBS before challenge. Although the RhCMVRDeltagL/178/182-189 vaccine was superior in inducing cellular immunity to RhCMV, it induced lower titers of neutralizing antibody and antibody to gB than the soluble gB vaccine; after challenge, animals vaccinated with soluble gB had a lower frequency of virus detection in the blood than those vaccinated with RhCMVRDeltagL/178/182-189. PMID- 30522907 TI - The uptake of adolescent vaccinations through the School Immunisation Program in specialist schools in Victoria, Australia. AB - BACKGROUND: As part of the National Immunisation Program (NIP) students in Australia receive adolescent immunisations through the School Immunisation Program at 12 to 13 years. For children with disabilities attending specialist schools, no vaccine uptake data is collected at this time point. We aimed to determine uptake of diphtheria-tetanus-pertussis (dTpa) and Human Papillomavirus (HPV) immunisations amongst young people with disabilities in specialist schools in Victoria. METHODS: A prospective cohort study was conducted in Victoria, Australia. Data was collected on immunisation days in the 2017 school year from specialist schools in Victoria. The school immunisation coordinator entered data online for eligible students for receipt of dTpa and HPV on each school immunisation day. Demographic data, motor and intellectual function of students and reasons for non-receipt of dTpa and HPV vaccine were recorded. Data were analysed using descriptive statistics. RESULTS: Of 73 eligible specialist schools in Victoria, 28 (38%) participated. dTpa was received by 63% (237/374) of participating students and HPV dose 1 (HPV1) was received by 66% (76/114) females and 67% (174/260) male students respectively. Three doses of HPV were received by only 41% (100/241) of students. The main reasons for missed immunisation were absence from school, lack of consent and inability to immunise due to the student's behaviour and/or anxiety. CONCLUSION: This is the first study in Australia to report that uptake of adolescent immunisations in specialist schools for young people with a disability is significantly lower than in mainstream settings. Comparative data during the same time period for students in mainstream schools demonstrated higher uptake, at 89% for dTpa and 75% for three doses of HPV. These data highlight the inequity of receipt of school-based immunisations for this group of adolescents, the barriers to which could be more thoroughly explored through qualitative inquiry from a socio-ecological perspective. PMID- 30522908 TI - Care received at the end of life in emergency services from the perspective of caregivers: A qualitative study. AB - OBJECTIVE: To discover the experiences of end-of-life patients attended by the emergency services, through the discourse of the family caregivers who accompanied the family member in this care transit. METHOD: A qualitative approach study, based on the paradigm of hermeneutical phenomenology. In total, 81 family caregivers participated. The techniques used were the in-depth interview and the discussion group, with a total of 5 discussion groups and 41 interviews. The period of data collection was carried out between January 2013 and June 2014. RESULTS: In the network of discourses obtained with respect to "Urgent Care", all the codes were grouped in relation to a single argumentative line: deficiencies in urgent care. Among them, we found different dimensions that are established depending on the different times of care, or the different determinant aspects of these deficiencies: disorganization of the care received, lack of experience of the professionals in emergencies, application of general protocols in the emergency services, inadequate care in the treatment received, delays in emergency care. CONCLUSIONS: In general, we highlight the dissatisfaction of the family members with respect to the care received from the emergency services. The needs of these types of situation are not covered from these services and are of low quality. Therefore, it is necessary to reorient the care protocols for these patients. PMID- 30522909 TI - Working together to learn new oral hygiene techniques: Pilot of a carepartner assisted intervention for persons with cognitive impairment. AB - We pilot tested a carepartner-assisted intervention to improve oral hygiene in persons with cognitive impairment (participants) and help carepartners become leaders who can adapt approaches that foster participants' ability to develop new skills for oral hygiene care. Following the intervention, we conducted interviews with participants and carepartners to understand their challenges in working together to learn new oral hygiene skills. Participants reported challenges such as frustration using the electric toothbrush correctly, lack of desire to change, uncertainty about correctness of technique, and difficulty sustaining two minutes of toothbrushing. Carepartners reported challenges such as learning a new way of toothbrushing, learning new communication techniques, switching from instructing to working together, learning to balance leading with being too bossy, and being mindful of word choices. Findings suggested that despite challenges, participants were able to learn adaptive strategies to support new oral hygiene behaviors with support of the carepartner as the adaptive leader. PMID- 30522910 TI - Reversible cerebellar herniation after epidural blood patch in a patient with spontaneous intracranial hypotension. PMID- 30522911 TI - Transjugular intrahepatic portosystemic shunt (TIPS) placement: A comparison of outcomes between patients with hepatic hydrothorax and patients with refractory ascites. AB - PURPOSE: To compare the outcomes in patients who had transjugular intrahepatic portosystemic shunts (TIPS) placed for hepatic hydrothorax with those who had it placed for refractory ascites. MATERIALS AND METHODS: One hundred and forty-seven patients who underwent TIPS placement for refractory fluid accumulation were included. There were 97 men and 50 women with a mean age of 56.1+/-9.7 (SD) years (range: 25-81 years). Of those, 32 patients (32/147; 21.8%) had refractory hepatic hydrothorax and 115 (115/147; 78.2%) had refractory ascites. Electronic medical records were reviewed for all patients to determine demographic, procedural related, and outcomes data. Both traditional analysis and a propensity score matching analysis were performed, to account for differences in baseline laboratory values, etiology of cirrhosis, age, and average number of paracenteses/thoracenteses per week. Survival analysis was also performed to compare post-TIPS survival by indication. RESULTS: Differences in response rates, in terms of fluid accumulation reductions, at 1, 3, and 6 months were not significant (P=0.19, P=0.33, and P=0.28, respectively). A successful propensity score matching was made between 24 hepatic hydrothorax and 46 ascites patients. After propensity score matching the response rates at 1, 3, and 6 months remained non-significant (P=0.3, P=0.71, and P=0.78 respectively). No differences in mean overall survival were found between hepatic hydrothorax patients (672 days) and ascites patients (1224 days) (P=0.15). CONCLUSION: The clinically relevant outcomes of improvement in fluid accumulation and overall survival do not appear to be significantly different in patients who have TIPS placed for refractory hepatic hydrothorax or and those who have TIPS placed for ascites. PMID- 30522912 TI - The FUTURE Trial: A Multicenter Randomised Controlled Trial on Target Biopsy Techniques Based on Magnetic Resonance Imaging in the Diagnosis of Prostate Cancer in Patients with Prior Negative Biopsies. AB - BACKGROUND: Guidelines advise multiparametric magnetic resonance imaging (mpMRI) before repeat biopsy in patients with negative systematic biopsy (SB) and a suspicion of prostate cancer (PCa), enabling MRI targeted biopsy (TB). No consensus exists regarding which of the three available techniques of TB should be preferred. OBJECTIVE: To compare detection rates of overall PCa and clinically significant PCa (csPCa) for the three MRI-based TB techniques. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomised controlled trial, including 665 men with prior negative SB and a persistent suspicion of PCa, conducted between 2014 and 2017 in two nonacademic teaching hospitals and an academic hospital. INTERVENTION: All patients underwent 3-T mpMRI evaluated with Prostate Imaging Reporting and Data System (PIRADS) version 2. If imaging demonstrated PIRADS >=3 lesions, patients were randomised 1:1:1 for one TB technique: MRI-transrectal ultrasound (TRUS) fusion TB (FUS-TB), cognitive registration TRUS TB (COG-TB), or in-bore MRI TB (MRI-TB). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary (overall PCa detection) and secondary (csPCa detection [Gleason score >=3+4]) outcomes were compared using Pearson chi-square test. RESULTS AND LIMITATIONS: On mpMRI, 234/665 (35%) patients had PIRADS >=3 lesions and underwent TB. There were no significant differences in the detection rates of overall PCa (FUS-TB 49%, COG TB 44%, MRI-TB 55%, p=0.4). PCa detection rate differences were -5% between FUS TB and MRI-TB (p=0.5, 95% confidence interval [CI] -21% to 11%), 6% between FUS TB and COG-TB (p=0.5, 95% CI -10% to 21%), and -11% between COG-TB and MRI-TB (p=0.17, 95% CI -26% to 5%). There were no significant differences in the detection rates of csPCa (FUS-TB 34%, COG-TB 33%, MRI-TB 33%, p>0.9). Differences in csPCa detection rates were 2% between FUS-TB and MRI-TB (p=0.8, 95% CI -13% to 16%), 1% between FUS-TB and COG-TB (p>0.9, 95% CI -14% to 16%), and 1% between COG-TB and MRI-TB (p>0.9, 95% CI -14% to 16%). The main study limitation was a low rate of PIRADS >=3 lesions on mpMRI, causing underpowering for primary outcome. CONCLUSIONS: We found no significant differences in the detection rates of (cs)PCa among the three MRI-based TB techniques. PATIENT SUMMARY: In this study, we compared the detection rates of (aggressive) prostate cancer among men with prior negative biopsies and a persistent suspicion of cancer using three different techniques of targeted biopsy based on magnetic resonance imaging. We found no significant differences in the detection rates of (aggressive) prostate cancer among the three techniques. PMID- 30522913 TI - Reply from Authors re: Jens. J. Rassweiler, Marcel Fiedler-Hruza. The Learning Curve for Robot-assisted Partial Nephrectomy: There is Much Beyond a Trifecta. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.10.022: The Clinical Implications of Surgical Learning Curve Analysis: Can We Optimize Patient Outcomes Using Structured Training Programs? PMID- 30522914 TI - Robotic Urologic Surgical Interventions Performed with the Single Port Dedicated Platform: First Clinical Investigation. AB - We report the first clinical investigation for surgical procedures performed using the da Vinci SP robotic surgical platform (Intuitive Surgical, Sunnyvale, CA, USA) during the first 10 days (September 28-October 12, 2018) after the system was installed at our institution. The aim of the study was to determine the feasibility and safety of major urologic procedures, measured as the rate of conversions and the incidence of perioperative complications. Secondary aims of the study consisted of key perioperative surgical outcomes, including operative time, blood loss, and length of stay. Pathology data were reported. Data collection was performed under institutional review board approval (IRB 13-780). A total of nine patients were treated (3 robot-assisted radical prostatectomies, 3 transperitoneal robot-assisted partial nephrectomies, 1 simple cystectomy with intracorporeal ileal conduit urinary diversion, 2 ureteral reimplantations). No intraoperative complications occurred. In six cases the surgeries were performed according to a pure single-site approach. The mean operative time was slightly longer than that reported for the corresponding multiarm robotic procedures in the literature, which can easily be explained by the expected learning curve. One minor and one major complication occurred. A learning curve exists when embarking with this surgery. Further investigations are awaited. PMID- 30522915 TI - Re: Tuan Zea Tan, Mathieu Rouanne, Kien Thiam Tan, Ruby Yun-Ju Huang, Jean-Paul Thiery. Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta cohort Analysis of 2411 Tumors. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2018.08.027. PMID- 30522916 TI - Individual white matter bundle trajectories are associated with deep brain stimulation response in obsessive-compulsive disorder. AB - BACKGROUND: The ventral anterior limb of the internal capsule (vALIC) is a target for deep brain stimulation (DBS) in obsessive-compulsive disorder (OCD). Conventional surgical planning is based on anatomical landmarks. OBJECTIVE/HYPOTHESIS: We hypothesized that treatment response depends on the location of the active DBS contacts with respect to individual white matter bundle trajectories. This study thus aimed to elucidate whether vALIC DBS can benefit from bundle-specific targeting. METHODS: We performed tractography analysis of two fiber bundles, the anterior thalamic radiation (ATR) and the supero-lateral branch of the medial forebrain bundle (MFB), using diffusion weighted magnetic resonance imaging (DWI) data. Twelve patients (10 females) who had received bilateral vALIC DBS for at least 12 months were included. We related the change in OCD symptom severity on the Yale-Brown obsessive-compulsive scale (Y-BOCS) between baseline and one-year follow-up with the distances from the active contacts to the ATR and MFB. We further analyzed the relation between treatment response and stimulation sites in standard anatomical space. RESULTS: We found that active stimulation of the vALIC closer to the MFB than the ATR was associated with better treatment outcome (p = 0.04; r2 = 0.34). In standard space, stimulation sites were largely overlapping between treatment (non)responders, suggesting response is independent of the anatomically defined electrode position. CONCLUSION: These findings suggest that vALIC DBS for OCD may benefit from MFB-specific implantation and highlight the importance of corticolimbic connections in OCD response to DBS. Prospective investigation is necessary to validate the clinical use of MFB targeting. PMID- 30522917 TI - Open letter from Chinese HIV professionals on human genome editing. PMID- 30522918 TI - Gene-edited babies: Chinese Academy of Medical Sciences' response and action. PMID- 30522920 TI - Confronting the most challenging risk factor: non-adherence. PMID- 30522919 TI - Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA): a pragmatic, open-label, randomised controlled trial. AB - BACKGROUND: Primary prevention of cardiovascular disease often fails because of poor adherence among practitioners and individuals to prevention guidelines. We aimed to investigate whether ultrasound-based pictorial information about subclinical carotid atherosclerosis, targeting both primary care physicians and individuals, improves prevention. METHODS: Visualization of asymptomatic atherosclerotic disease for optimum cardiovascular prevention (VIPVIZA) is a pragmatic, open-label, randomised controlled trial that was integrated within the Vasterbotten Intervention Programme, an ongoing population-based cardiovascular disease prevention programme in northern Sweden. Individuals aged 40, 50, or 60 years with one or more conventional risk factors were eligible to participate. Participants underwent clinical examination, blood sampling, and ultrasound assessment of carotid intima media wall thickness and plaque formation. Participants were randomly assigned 1:1 with a computer-generated randomisation list to an intervention group (pictorial representation of carotid ultrasound plus a nurse phone call to confirm understanding) or a control group (not informed). The primary outcomes, Framingham risk score (FRS) and European systematic coronary risk evaluation (SCORE), were assessed after 1 year among participants who were followed up. This study is registered with ClinicalTrials.gov, number NCT01849575. FINDINGS: 3532 individuals were enrolled between April 29, 2013, and June 7, 2016, of which 1783 were randomly assigned to the control group and 1749 were assigned to the intervention group. 3175 participants completed the 1-year follow-up. At the 1-year follow-up, FRS and SCORE differed significantly between groups (FRS 1.07 [95% CI 0.11 to 2.03, p=0.0017] and SCORE 0.16 [0.02 to 0.30, p=0.0010]). FRS decreased from baseline to the 1-year follow-up in the intervention group and increased in the control group (-0.58 [95% CI -0.86 to -0.30] vs 0.35 [0.08 to 0.63]). SCORE increased in both groups (0.13 [95% CI 0.09 to 0.18] vs 0.27 [0.23 to 0.30]). INTERPRETATION: This study provides evidence of the contributory role of pictorial presentation of silent atherosclerosis for prevention of cardiovascular disease. It supports further development of methods to reduce the major problem of low adherence to medication and lifestyle modification. FUNDING: Vasterbotten County Council, the Swedish Research Council, the Heart and Lung Foundation, the Swedish Society of Medicine, and Carl Bennet Ltd, Sweden. PMID- 30522921 TI - Chinese Academy of Engineering calls for actions on the birth of gene-edited infants. PMID- 30522923 TI - Secondary malignant giant cell tumor of bone with histone H3.3 mutation: A case series. PMID- 30522924 TI - Effect of intraoperative soft tissue balance on postoperative recovery of ambulatory and balancing function in posterior-stabilized total knee arthroplasty. AB - BACKGROUND: The effectiveness of total knee arthroplasty (TKA) on ambulatory and balancing function recovery should be quantitatively investigated. The present study aimed to evaluate ambulatory function using 3m-timed up and go (TUG) test and balancing function using one-leg standing time (ST) from before and after TKA, and to analyze the effects of intraoperative soft tissue balance on the postoperative improvement of their functions after TKA. METHODS: The study included 65 patients with varus-type knee osteoarthritis who underwent primary posterior-stabilized (PS) TKA. The TUG test and ST were performed preoperatively, 1 month and 12 months after TKA. The intraoperative soft tissue balance, medial and lateral joint looseness (MJL, LJL) were evaluated with both femoral trial in place and patellofemoral joint reduced using the OFR tensor(r) with the knee at 0, 10, 30, 45, 60, 90, 120, and 135 degrees . The influences of MJL and LJL on the improvement in TUG test time and ST and the 2011 Knee Society Knee Scoring System (2011 KSS) 12 months after TKA were investigated. RESULTS: The mean TUG test times and ST were 12.7 and 13.1, 13.5 and 15.4, and 10.9 and 19.2 s preoperatively, 1 month and 12 months after TKA, respectively. The MJL at 10, 30 and 90 degrees flexion was significantly negatively correlated with improvement in the TUG test time and the MJL at 0 degrees flexion was significantly negatively correlated with improvement in the ST. However, the LJL was not significantly correlated with improvement in the TUG test time and the ST. The MJL at 45, 60, and 90 degrees flexion was significantly negatively correlated with the 12-month postoperative score on the activities subscale of the 2011 KSS. CONCLUSIONS: The higher intraoperative medial knee stability may be associated with the better postoperative improvement in ambulatory function and activities subscale of the 2011 KSS after PS-TKA. PMID- 30522925 TI - Venous perfusion assist system has no additional effect compared to simple elevation on post-operative edema in patients with distal radial fracture treated with volar locking plate fixation: A randomized controlled trial. AB - BACKGROUND: While limb elevation and other methods for reducing hand edema are commonly used in clinical practice, alternative methods, such as compression and venous perfusion assist system (VPAS), have emerged. This study compared the efficacy of VPAS to limb elevation in decreasing hand edema after surgery for distal radial fracture (DRF) treated by a volar locking plate (VLP). METHODS: A randomized controlled trial was conducted in 102 patients to compare VPAS and elevation methods for edema reduction following VLP fixation for DRF. Changes in edema were measured using the tape measure method along with other parameters on the next day and at one, three, six, and 12 weeks postoperatively. RESULTS: There were no significant differences in edema reduction or other factors between the VPAS and elevation groups at any measurement point. CONCLUSIONS: VPAS appears to confer no measurable advantage over management with elevation for edema reduction after VLP fixation of DRF. TRIALS REGISTRY: This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN000015640). PMID- 30522926 TI - Translation, cross-cultural adaptation, reliability and validity of the Persian version of the ACL-QOL questionnaire in patients with anterior cruciate ligament reconstruction. AB - BACKGROUND: Quality of life (QOL) measures can be used to make sound clinical decisions after reconstruction of the anterior cruciate ligament (ACL). The purpose of the present study was to translate and cross-culturally adapt the Anterior Cruciate Ligament Quality of Life (ACL-QOL) questionnaire into the Persian language and to evaluate its psychometric properties. METHODS: The process of translation and cross-cultural adaptation followed the World Health Organization method. One hundred and forty-five patients with ACL reconstruction (ACL-R) filled out the Persian versions of ACL-QOL and the SF-36 Questionnaire. The measurement properties of internal consistency, agreement, criterion validity, floor and ceiling effects were measured. 40 out of 145 patients with ACL-R completed the Persian version of the ACL-QOL questionnaire twice for the test-retest reliability. RESULTS: The questionnaire had high internal consistency (Cronbach's alpha = 0.96). The intraclass correlation was excellent for reliability and agreement in five domains and overall score (ICC 0.87, 0.74, 0.90, 0.85, 0.81 and 0.89; p < 0.001). The standard error of measurement and the minimum detectable change were found to be 3.28 points and 9.9 points, respectively. There was a strong correlation between each item and the total score of the Persian version of ACL-QOL questionnaire. The questionnaire showed strong and moderate criterion validity (r = 0.61, r = 0.37) with SF-36 physical component score and mental component score, respectively. No ceiling and floor effects were observed. CONCLUSIONS: Persian version of the ACL-QOL questionnaire has acceptable reliability and validity and can be used in assessing Iranians quality of life after ACL reconstruction. PMID- 30522927 TI - Accuracy of acetabular cup placement using CT-based navigation in total hip arthroplasty: Comparison between obese and non-obese patients. AB - BACKGROUND: In obese patients, malpositioning of the acetabular cup increases the risk of dislocation in total hip arthroplasty (THA). The aim of this study was to determine whether obesity affects the accuracy of acetabular cup positioning using a computed tomography (CT)-based navigation system. METHODS: We retrospectively evaluated 226 consecutive patients who underwent cementless primary THAs assisted by the CT-based hip navigation system. We divided the patients into three groups according to body mass index (BMI) and examined the difference between preoperative planning and postoperative implantation angles from CT data. RESULTS: There was no significant correlation between BMI and both inclination and anteversion differences (R = 0.028 and R = 0.045, respectively). There were no significant differences among the BMI < 25, 25 ? BMI < 30, and BMI ? 30 groups (p value: 0.725, 0.934, respectively); between the BMI < 25 and BMI ? 25 groups (p value: 0.542, 0.697, respectively); and between the BMI < 30 and BMI ? 30 groups with regard to inclination and anteversion (p value: 0.859, 0.456, respectively). Moreover, similar findings were observed with regard to the distance between the preoperative planning and postoperative cup positioning for the transverse, anteroposterior, and craniocaudal axes of the pelvis. CONCLUSION: We found that the accuracy of acetabular cup placement using CT based-navigation in THA was not affected in obese patients. Therefore, THAs with a CT-based navigation system are considered useful in obese patients. PMID- 30522928 TI - Effects of postoperative dietary intake on functional recovery of patients undergoing cardiac surgery. AB - BACKGROUND AND AIM: Among elderly patients undergoing cardiac surgery, malnutrition is very common and related to muscle wasting known as sarcopenia. Cardiac surgery causes a further decline of nutritional status due to reduced dietary intake (DI); however, the impact of postoperative DI on functional recovery is unclear. METHODS AND RESULTS: We enrolled 250 consecutive patients undergoing cardiac surgery. Daily DI was measured between postoperative days 3 and 7. Patients were categorized as having sufficient or insufficient DI based on whether their DI met or was less than estimated total energy requirements. Functional capacity was measured using the 6-minute walking distance (6MWD) preoperatively and at discharge. Mean postoperative DI was 22.4 +/- 3.0 kcal/kg/day, and postoperative DI was insufficient in 92 patients (36.8%). The prevalence of sarcopenia was not different by postoperative DI. Although there was no significant difference in preoperative 6MWD results (P = 0.65), the sufficient DI group had longer 6MWD at discharge than the insufficient DI group (P = 0.04). In multivariate regression analysis, preoperative poor nutritional status (beta = -0.29), duration of surgery (beta = -0.18), and postoperative DI (beta = 0.40) remained statistically significant predictors for improvement of 6MWD (P < 0.0001, adjusted R2 = 0.41). CONCLUSIONS: Postoperative DI was independently associated with functional recovery, but preoperative sarcopenia was not. Regardless of preoperative nutritional status or the presence of sarcopenia, aggressive nutritional intervention in the early stage after surgery helps support functional recovery. PMID- 30522929 TI - Coexistence of secondary chondrosarcoma and lung carcinoma metastasis in the humerus of a patient with Ollier's disease: A case report. AB - Tumor-to-tumor metastasis in the same bone is an extremely rare condition. Limited number of case reports exists for coincidence of benign and malign neoplasms but none for malignant to malignant metastasis. Occurrence of several individual malignancies in the same patient may eventually cause such coexistences. We report an Ollier's disease patient with malignant transformation to chondrosarcoma complicated by a pathologic fracture and eventually whose pathological examination revealed that the lesion was not only the chondrosarcoma but an accompanying metastasis from existing lung adenocarcinoma. This report includes clinical, radiological, histological diagnostic challenges in an unexpected lesion and a review of literature. PMID- 30522930 TI - Brain-penetrant heat shock protein amplifier arimoclomol enhances GCase activity in in vitro Gaucher disease models. PMID- 30522922 TI - Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. AB - BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas. METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1.8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1.4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152. FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48.2 months (95% CI 35.2-not evaluable) in the A+CHP group and 20.8 months (12.7-47.6) in the CHOP group (hazard ratio 0.71 [95% CI 0.54-0.93], p=0.0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group. INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile. FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center. PMID- 30522931 TI - The partial inhibition of hypothalamic IRX3 exacerbates obesity. AB - BACKGROUND: The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. METHODS: Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. FINDINGS: IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. INTERPRETATION: Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation. FUND: Sao Paulo Research Foundation grants 2013/07607-8 (LAV) and 2017/02983-2 (JDJ); NIH grants R01DK083567 (YBK). PMID- 30522932 TI - A novel mechanism of synaptic and cognitive impairments mediated via microRNA-30b in Alzheimer's disease. AB - BACKGROUND: It is widely accepted that cognitive and memory deficits in Alzheimer's disease (AD) primarily result from synaptic failure. However, the mechanisms that underlie synaptic and cognitive dysfunction remain unclear. METHODS: We utilized molecular biology techniques, electrophysiological recordings, fluorescence in situ hybridization (FISH), immuno- and Golgi staining, chromatin immunoprecipitation (CHIP); lentivirus (LV)-based microRNA overexpression and 'sponging', and behavioral tests to assess upregulated miR-30b causing synaptic and cognitive declines in APP transgenic (TG) mice. FINDINGS: We provide evidence that expression of miR-30b, which targets molecules important for maintaining synaptic integrity, including ephrin type-B receptor 2 (ephB2), sirtuin1 (sirt1), and glutamate ionotropic receptor AMPA type subunit 2 (GluA2), is robustly upregulated in the brains of both AD patients and APP transgenic (TG) mice, an animal model of AD, while expression of its targets is significantly downregulated. Overexpression of miR-30b in the hippocampus of normal wild-type (WT) mice impairs synaptic and cognitive functions, mimicking those seen in TG mice. Conversely, knockdown of endogenous miR-30b in TG mice prevents synaptic and cognitive decline. We further observed that expression of miR-30b is upregulated by proinflammatory cytokines and Abeta42 through NF-kappaB signaling. INTERPRETATION: Our results provide a previously undefined mechanism by which unregulated miR-30b causes synaptic and cognitive dysfunction in AD, suggesting that reversal of dysregulated miR-30b in the brain may prevent or slow cognitive declines in AD. FUND: This work was supported by National Institutes of Health grants R01NS076815, R01MH113535, R01AG058621, P30GM103340 Pilot Project, and by the LSUHSC School of Medicine Research Enhancement Program grant (to C.C.). PMID- 30522933 TI - Circulating osteogenic precursor cells: Building bone from blood. AB - Circulating osteogenic precursor (COP) cells constitute a recently discovered population of circulating progenitor cells with the capacity to form not only bone but other mesenchymal tissues. There is a small, but growing body of literature exploring these cells, but with a great deal of disagreement and contradiction within it. This review explores the origins and biological characterization of these cells, including the identification strategies used to isolate these cells from the peripheral blood. It also examines the available knowledge on the in vitro and in vivo behaviour of these cells, in the areas of plastic adherence, differentiation capacity, proliferation, and cellular homing. We also review the implications for future use of COP cells in clinical practice, particularly in the area of regenerative medicine and the treatment and assessment of musculoskeletal disease. PMID- 30522934 TI - Association between ambient PM2.5 and emergency department visits for psychiatric emergency diseases. AB - BACKGROUND: Whether or not short-term exposure to particulate matter <2.5 MUm in diameter (PM2.5) increases the risk of psychiatric emergency diseases is unclear. METHODS: The study was performed in a metropolis from January 2015 to December 2016. The exposure was PM2.5, and the confounders were weather (temperature and humidity) and other pollutants (PM10, SO2, CO, O3, and NO2). The outcomes were emergency department (ED) visits with psychiatric disease codes (F00-F99 in ICD10 codes). General additive models were used for the statistical analysis to calculate the adjusted relative risks (ARRs) and 95% confidence intervals (95% CIs) for the daily number of ED visits with a lag of 1 to 3 days following a 10 MUg/m3 increase in PM2.5. RESULTS: During the study period, a total of 67,561 ED visits for psychiatric diseases were identified and tested for association with PM2.5. Daily ED visits for all psychiatric diseases were not associated with PM2.5 in the model that was not adjusted for other pollutants. The ARR (95% CI) in the model adjusted for SO2 was 1.011 (1.002-1.021) by 10 MUg/m3 of PM2.5 on Lag 1 for all psychiatric diseases (F00-F99). The ARR (95% CI) in the model adjusted for O3 was 1.015 (1.003-1.029) by 10 MUg/m3 of PM2.5 on Lag 1 for F40 F49 (Neurotic, stress-related and somatoform disorders). CONCLUSION: An increase in PM2.5 showed a significant association with an increase in ED visits for all psychiatric diseases (F00-F99) and for neurotic, stress-related and somatoform disorders (F40-F49) on lag day 1. PMID- 30522935 TI - Can corticosteroids reduce the mortality of patients with severe sepsis? A systematic review and meta-analysis. AB - BACKGROUND: The effects of corticosteroids on clinical outcomes of patients with sepsis remains controversial. We aimed to further determine the effectiveness of corticosteroids in reducing mortality in adult patients with severe sepsis by comparison with placebo. METHODS: Pubmed, Embase, Medline, Cochrane Central Register of Controlled Trials (CENTRAL) as well as the Information Sciences Institute (ISI) Web of Science were searched for all controlled studies that compared corticosteroids and placebo in adult patients with severe sepsis. The primary outcome was the mortality 28-day mortality and the secondary outcomes were mortality at longest follow up, occurrence, and reoccurrence of septic shock. RESULTS: A total of 19 trials involving 7035 patients were pooled in our final analyses. No significant heterogeneity was found in any of the outcome measures. Compared with placebo, corticosteroids were associated with a lower 28 day mortality (RR 0.91, 95% CI 0.85-0.98, Z = 2.57, P = 0.01) both in patients having sepsis and in those who developed septic shock (RR 0.92, 95% CI 0.85-0.99, Z = 2.19, P = 0.03), while no significant difference was found in mortality with the longest follow up in patients either having sepsis (RR 0.94, 95% CI 0.89 1.00, Z = 1.93, P = 0.05), or occurrence (RR 0.83, 95% CI 0.56-1.24, Z = 0.90, P = 0.37) or reoccurrence of septic shock (RR 1.08, 95% CI 1.00-1.16, Z = 1.89, P = 0.06). CONCLUSIONS: Corticosteroids were effective in reducing the 28-day mortality in patients with severe sepsis and in those with septic shock. PMID- 30522936 TI - Does hospital mode of arrival influence women's decisions to participate in research? PMID- 30522937 TI - Using spatial regression methods to evaluate rural emergency medical services (EMS). AB - Emergency Medical Services (EMS) are acute services provided outside of the hospital. EMS are crucial in rural environments where hospitals are often far away and difficult to access. Establishing EMS performance measures is critical in improving a rural community's access to these services and eliminating systemic inequalities. However, an absence of data leads to challenges in developing objective and quantifiable service metrics. EMS data are regularly collected through the National EMS Information System (NEMSIS), yet the manner of data collection and quality of data vary across agencies. Moreover, the amount and complexity of information makes data analyses difficult, subsequently effecting EMS leaderships' ability to identify improvement needs. This study used NEMSIS data to exemplify approaches for establishing two data-driven performance measures. The measures used in this study - timely service and service coverage - are both dependent on the mobility and accessibility of the EMS transportation network. Two types of spatial models: the spatial econometric model and geographically weighted regression (GWR) model, were developed and then compared to the linear regression model to help identify response time factors. GWR performed best in terms of goodness-of-fit statistics and was chosen to help understand how factors (e.g., weather, transportation) impact the timely provision of EMS in rural areas. The GWR results provided additional insights through the particular spatial patterns of the coefficient estimates and their statistical significance to EMS practitioner for their references to reduce local response times. PMID- 30522938 TI - Comments on Shenfu injection for improving cellular immunity and clinical outcome in patients with sepsis or septic shock. PMID- 30522939 TI - Ethnopharmacology of Cuscuta epithymum: A comprehensive review on ethnobotany, phytochemistry, pharmacology and toxicity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cuscuta epithymum (L.) L. (C. epithymum; Convolvulaceae) is a parasitic plant that has long been used locally and traditionally in Asia, Europe and other regions. AIM OF THE REVIEW: The study intends to reflect the significance of the C. epithymum in traditional medicine. This review aims to grant insight into the species' botany, pharmacological activities and phytochemistry with distinctive emphasis on its ethnomedicinal and traditional applications in all over the world. The review endeavors to rule out any inconsistency between the species' traditional application and its pharmacological activity, and presenting any coherence existing. MATERIALS AND METHODS: The books on ethnomedicine and the main medieval Persian medicine textbooks including Makhzan Al- Advieh, The canon of medicine, Zakhireh kharazmshahi and etc were explored for C. epithymum. Additionally, information on the ethnobotany, phytochemistry, morphology, taxonomy, modern medicinal uses, and pharmacological activities were collected in electronic databases including Google Scholar, Science Direct, Scopus, and PubMed using the keywords "Cuscuta epithymum," "traditional medicine," "ethnomedicine," "phytochemistry," "pharmacology" and "activity." Then, the available articles from 1975 to 2017 were employed for this study. RESULTS: C. epithymum is a rootless plant, widely distributed and available in every continent except Antarctica. It was used traditionally in formularies or by rural people and as geriatric drug, detergent, purgative, disorders in the melancholic humor, joint, kidney, urinary tract, gastrointestinal system, nervous system, etc. In modern medicine, the extract of C. epithymum showed anti-microbial, cytotoxic, anticonvulsant, anti-urease, immune stimulatory, hepatoprotective effect, and antioxidant activity. The main phytochemical constituents are alkaloids; saponins; tannins; triterpenoids; steroids; carbohydrates; aromatic compounds; flavonoids and the hydroxycinnamic acid derivatives. CONCLUSION: The modern pharmacological studies have validated the traditional and ethnobotanical uses of C. epithymum. However, many aspects of this herb have not been studied yet. In addition, information about the phytochemistry and toxicological profile is insufficient. Owing to the extensive traditional uses of C. epithymum. Hence further studies on pharmacological activities, phytochemistry, and toxicity and adverse effects seem to be necessary to appraise the medicinal values of C. epithymum. PMID- 30522940 TI - Trichorhinophalangeal syndrome. AB - Trichorhinophalangeal syndrome I (TPRSI) has an autosomal dominant inheritance; the proportion of "de novo" cases is unknown1. It is characterized by unique facial features, bulbous nose, flat and elongated nasolabial furrow, thin hair and slow growth. Skeletal abnormalities that include short phalanges and metacarpals -brachydactyly-, cone-shaped epiphyses, hip dysplasia and short stature1-3. PMID- 30522941 TI - Effectiveness and Safety of Rituximab in Systemic Lupus Erythematosus: A Case Series Describing the Experience of 2 Centers. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs and systems. B cells have a critical role in the pathogenesis of SLE. Rituximab (RTX) is a drug composed of chimeric monoclonal antibodies against the CD20 protein, producing a depletion of B lymphocytes. OBJECTIVE: To analyze the effectiveness and safety of RTX in patients with SLE in clinical practice. METHODS: Collection of retrospective variables of the medical records of 20 patients with SLE treated with RTX in 2hospitals (Hospital de la Santa Creu i Sant Pau, and Hospital del Mar, in Barcelona, Spain). We evaluated demographic, clinical, serological and treatment variables. RESULTS: There was a statistically significant association in the following variables collected in the study before and after treatment: there was a decrease in the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) (P<.001), erythrocyte sedimentation rate (P=.017), use of glucocorticoids (P=.025) and IgM values (P=.031), as well as an increase in the C4 values (P=.014) after treatment with RTX. A patient with SLE, antiphospholipid syndrome, complex comorbidity and multiorgan lupus involvement died after developing a septic process, months after receiving a single treatment cycle with RTX. CONCLUSIONS: Although RTX currently has no official indication approved for SLE, our data suggest that it may be effective in reducing the activity of the disease and as a steroid-sparing agent, with an acceptable safety profile. However, larger follow-up periods with a greater number of patients are needed to solve the remaining doubts about the use of RTX in SLE. PMID- 30522942 TI - Tophaceous Gout in a Woman. PMID- 30522943 TI - Prevalence and Demographic Characteristics of Sjogren's Syndrome in Colombia, Based on Information from the Official Ministry of Health Registry. AB - OBJECTIVE: To calculate the prevalence and describe the main demographic characteristics of Sjogren's syndrome in adults in Colombia. MATERIAL AND METHODS: Descriptive cross-sectional study which utilized data from the Integral Information System of Social Protection of the Ministry of Health of the Republic of Colombia during the years 2012 to 2016. RESULTS: 58,680 cases of Sjogren's syndrome were identified, with a prevalence in those over 18 years of age of 0.12%; 82% were women, with a female:male ratio of 4.6:1, with a higher prevalence in the age group of 65 to 69 years. The departments with the highest numbers of cases were Bogota DC (24,885), Antioquia (9,040) and Valle del Cauca (5,277); however, the departments with the highest prevalences were Caldas (0.42%), Bogota DC (0.32%) and Antioquia (0.14%). CONCLUSIONS: We present demographic and epidemiological information on Sjogren's syndrome in Colombia. There are very few epidemiological studies of this disorder. However, a prevalence similar to that reported in countries of the region such as Brazil (0.17%) and Argentina (0.17%) was documented. PMID- 30522945 TI - Coexistence of Systemic Lupus Erythematosus and Myasthenia Gravis: An Unusual Case of Polyautoimmunity. AB - The relevance of polyautoimmunity, defined as the presence of 2or more autoimmune diseases in the same individual, is one of the issues not yet elucidated in medical practice. The coexistence of myasthenia gravis (MG) and systemic lupus erythematosus (SLE) is a clinical challenge due to the possible differential diagnoses of muscle involvement in patients with SLE. We present the case of a patient who came to the emergency room of Hospital Universitario San Ignacio in Bogota, Colombia, with a previous diagnosis of SLE, who developed acute weakness in the context of a systemic infection, with a clinical and electrophysiological diagnosis of MG. PMID- 30522946 TI - Macrovascular venous invasion of pancreatic neuroendocrine tumours: impact on surgical outcomes and survival. AB - BACKGROUND: This study evaluates the impact of macrovascular venous invasion (MVI) on surgical and survival outcomes of pancreatic neuroendocrine tumours (PNETs). METHODS: We retrospectively reviewed data of 125 patients operated for PNETs. Operative, pathological,and survival outcomes were compared between PNETs with and without MVI. RESULTS: Macrovascular venous invasion was detected in 25 of 125 PNETs (20%) presenting as tumour thrombi (n = 12) or venous wall invasion (n = 13). MVI was associated with larger tumours, a higher rate of lymph node involvement, less differentiated tumours, and a higher rate of perineural invasion. Resection of PNETS with MVI more often necessitated combined hepatic, venous and multivisceral resections, had a higher rate of intraoperative blood transfusion (p = 0.04) but similar morbidity (44% vs. 42%) and mortality (0 vs. 1%) as PNETs without MVI. PNETs with MVI had a lower median overall survival rate (60 vs. 149 months; p = 0.03). Multivariate analysis revealed that PNETs of the pancreatic head, synchronous liver metastases and higher tumour grade were prognostic factors for overall survival. CONCLUSIONS: MVI is found in more advanced PNETs. Resection of PNETs with MVI is characterized by increased transfusion rate and reduced overall survival. PMID- 30522948 TI - Use of Drug Coated Balloons in Femoropopliteal Atherosclerotic Disease: It's a Kind of Magic. PMID- 30522947 TI - Contemporary analysis of complications associated with biliary stents during neoadjuvant therapy for pancreatic adenocarcinoma. AB - BACKGROUND: With the increasing use of biliary stents for neoadjuvant therapy (NT) for pancreatic adenocarcinoma (PDAC), the risk of post pancreaticoduodenectomy (PD) infection remains relevant. This study documents the contemporary incidence of stent-related complications (SRC) during NT and to analyze their impact on surgical infections. METHODS: Consecutive patients from a single institution (2011-15) with resected PDAC treated with biliary decompression, NT, and PD were analyzed. Stent-related complications (SRC) were compared among patients with/without prospectively documented composite pre- and post-operative infections (surgical site infection [SSI], organ space infection [OSI], and cholangitis). RESULTS: Of 114 total patients, (median 164 days, initial stent to surgery), 95% had initial endoscopic (vs. percutaneous) stenting. Initial stents were often plastic (80/114, 70%), with 43/114 (38%) undergoing routine exchange to metal stent before NT. Fifteen (13%) patients had stent cholangitis during NT requiring antibiotics and/or stent exchange. There were 33/114 (29%) patients with SRC, requiring 66 exchanges. Post-PD rates of SSI, OSI, and cholangitis were 23%, 5%, and 4%, respectively [composite rate 30%]. On multivariate analysis, SRC were not associated with composite surgical infections (p > 0.05). CONCLUSIONS: Although SRC occurred in almost one-third of PDAC patients during NT, with appropriate intervention, there was no association with increased surgical infections. PMID- 30522944 TI - Spanish Registry of Recent-onset Psoriatic Arthritis (REAPSER study): Aims and methodology. AB - AIMS: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2years of symptom evolution. METHODS: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. CONCLUSIONS: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis. PMID- 30522949 TI - An Organoid-Based Preclinical Model of Human Gastric Cancer. AB - BACKGROUND & AIMS: Our goal was to develop an initial study for the proof of concept whereby gastric cancer organoids are used as an approach to predict the tumor response in individual patients. METHODS: Organoids were derived from resected gastric cancer tumors (huTGOs) or normal stomach tissue collected from sleeve gastrectomies (huFGOs). Organoid cultures were treated with standard-of care chemotherapeutic drugs corresponding to patient treatment: epirubicin, oxaliplatin, and 5-fluorouracil. Organoid response to chemotherapeutic treatment was correlated with the tumor response in each patient from whom the huTGOs were derived. HuTGOs were orthotopically transplanted into the gastric mucosa of NOD scid gamma mice. RESULTS: Whereas huFGOs exhibited a half maximal inhibitory concentration that was similar among organoid lines, divergent responses and varying half maximal inhibitory concentration values among the huTGO lines were observed in response to chemotherapeutic drugs. HuTGOs that were sensitive to treatment were derived from a patient with a near complete tumor response to chemotherapy. However, organoids resistant to treatment were derived from patients who exhibited no response to chemotherapy. Orthotropic transplantation of organoids resulted in the engraftment and development of human adenocarcinoma. RNA sequencing revealed that huTGOs closely resembled the patient's native tumor tissue and not commonly used gastric cancer cell lines and cell lines derived from the organoid cultures. CONCLUSIONS: The treatment of patient-derived organoids alongside patients from whom cultures were derived will ultimately test their usefulness to predict individual therapy response and patient outcome. PMID- 30522950 TI - Forensic characteristics and phylogenetic analysis of both Y-STR and Y-SNP in the Li and Han ethnic groups from Hainan Island of China. AB - Hainan Island is the southernmost and smallest Chinese province, isolated from the mainland. The Li and Han ethnic groups account for over 98% of the population on the island. However, the Li ethnic group is an indigenous community of Hainan Island, with great differences in culture, language and origin with respect to the Han, the largest ethnic group. Here, we studied these two ethnic groups from the perspective of the Y-chromosome single nucleotide polymorphisms (Y-SNPs) and short tandem repeats (Y-STRs) to unravel their forensic and phylogenetic characteristics. A total of 302 unrelated male samples from the Li and Han ethnic groups in Hainan Island were genotyped by a combination of three separate typing systems (next-generation sequencing and pyrosequencing for the Y-SNPs and capillary electrophoresis for the Y-STRs), a previously developed high-resolution panel containing 141 Y-SNPs and 27 Y-STRs. The haplotype diversity of the Li ethnic group reached 0.9997, and 49 terminal haplogroups were observed in the Li and Han ethnic groups. Haplogroup O1b1a1a1a1a1b-CTS5854 was the most predominant haplogroup, including 44.12% of Li individuals. Median-joining trees showed little gene flow between the Li and Han individuals, as well as between the Li and other ethnic groups in Hainan Island. Our results indicated that 1) in contrast with the Han ethnic group, a low degree of genetic diversity was observed in the Li ethnic group; 2) there was limited gene flow between the Li and Han ethnic groups; and 3) founder effect was identified in the Li ethnic group in Hainan Island. PMID- 30522951 TI - Discovery and structure-activity relationship of imidazolinylindole derivatives as kallikrein 7 inhibitors. AB - A series of imidazolinylindole derivatives were discovered as novel kallikrein 7 (KLK7, stratum corneum chymotryptic enzyme) inhibitors. Structure-activity relationship (SAR) studies led to the identification of potent human KLK7 inhibitors. By further modification of the benzenesulfonyl moiety to overcome species differences in inhibitory activity, potent inhibitors against both human and mouse KLK7 were identified. Furthermore, the complex structure of 25 with mouse KLK7 could explain the SAR and the cause of the species differences in inhibitory activity. PMID- 30522952 TI - 5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy. AB - We describe the discovery and optimization of 5-substituted-N pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5 mg/kg/h. PMID- 30522953 TI - Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2) inhibitors possessing a key intramolecular hydrogen bond - Part 2. AB - The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5 azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration. PMID- 30522954 TI - Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn 1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors. AB - A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti proliferation against multiple B-cell lymphoma cell lines in vitro. Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC50 value of 4.2 nM. In particular, 8 and 9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment. PMID- 30522955 TI - Synthesis and biological evaluation of novel analogues of Gly-l-Pro-l-Glu (GPE) as neuroprotective agents. AB - This study investigated the anti-inflammatory effects of novel pseudotripeptides (GPE 1-3) as potential candidates to counteract neuroinflammation processes in Alzheimer's disease. GPE 1-3 pseudotripeptides are synthetic derivatives of Gly-l Pro-l-Glu (GPE), the N-terminal tripeptide of IGF-1, obtained through the introduction of isosteres of the amidic bond (aminomethylene unit) to increase the metabolic stability of the native tripeptide. The results showed that all synthetic derivatives possessed higher half-lives (t1/2 > 4 h) than GPE (t1/2 = 30 min) in human plasma and had good water solubility. The biological results demonstrated that GPE 1-3 had protective properties in several experimental models of treated THP-1 cells. Notably, the novel pseudotripeptides influenced inflammatory cytokine expression (IL-1beta, IL-18, and TNF-alpha) in Abeta25-35-, PMA-, and LPS-treated THP-1 cells. In PMA-differentiated THP-1 macrophages, both GPE 1 and GPE 3 reduced the expression levels of all selected cyto-chemokines, even though GPE 3 showed the best neuroprotective properties. PMID- 30522956 TI - Triazolopyrimidine and triazolopyridine scaffolds as TDP2 inhibitors. AB - Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (TOP2) mediated DNA damages and causes cellular resistance to clinically used TOP2 poisons. Inhibiting TDP2 can potentially sensitize cancer cells toward TOP2 poisons. Commercial compound P10A10, to which the structure was assigned as 7-phenyl triazolopyrimidine analogue 6a, was previously identified as a TDP2 inhibitor hit in our virtual and fluorescence-based biochemical screening campaign. We report herein that the hit validation through resynthesis and structure elucidation revealed the correct structure of P10A10 (Chembridge ID 7236827) to be the 5 phenyl triazolopyrimidine regioisomer 7a. Subsequent structure-activity relationship (SAR) via the synthesis of a total of 47 analogues of both the 5 phenyl triazolopyrimidine scaffold (7) and its bioisosteric triazolopyridine scaffold (17) identified four derivatives (7a, 17a, 17e, and 17z) with significant TDP2 inhibition (IC50 < 50 uM), with 17z showing excellent cell permeability and no cytotoxicity. PMID- 30522957 TI - Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors. AB - Colony stimulating factor-1 receptor (CSF-1R or FMS) and it ligand, CSF-1, signaling regulates the differentiation and function of tumor-associated macrophages (TAMs) that play an important role in tumor progression. Derivatives of thieno[3,2-d]pyrimidine were synthesized and evaluated as kinase inhibitors of FMS. The most representative compound 21 showed strong activity (IC50 = 2 nM) against FMS kinase and served as candidate for proof of concept. Anti-tumor activity alone and/or in combination with paclitaxel was examined via a tumor cell growth inhibition assay and via an in vitro tumor invasion assay using human breast adenocarcinoma cells. PMID- 30522959 TI - Tardive dyskinesia: Who gets it and why. AB - Tardive dyskinesia (TD) is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA). Identified risk factors include the type of antipsychotic agent, being greater for those of first generation antipsychotics (FGA), the duration of illness and cumulative dose of DRBA and advanced age. Female sex and African and Caucasian ethnicity are additional potential risk factors. Because only a subset of people taking DRBA's develops TD, genetics may play a role. Susceptibility gene candidates include those involved in DRBA metabolism and the targets or receptors of DRBA's. Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme. Heparan sulfate proteoglycan 2 (HSPG 2) gene is another potential gene involved with development of TD. The pathogenesis of TD is unknown, however there are three main theories proposed: dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade, oxidative stress and maladaptive synaptic plasticity each of which is discussed further in this article. Tardive dyskinesia (TD) is a potentially permanent and disabling adverse effect from certain medications. By definition TD is the insidious onset of rhythmic, repetitive, stereotypic movements of the face, mouth and tongue, often with involvement of the trunk and extremities that occur as a result of dopamine receptor blocking agents (DRBA) [1]. The term tardive refers to the delayed onset of the disorder. The mean prevalence of TD is estimated to be 25.3% in psychiatric patients taking antipsychotics [2]. Compared to the number of people taking these drugs, TD represents a minority. TD is a potentially permanent condition; stopping the offending agent does not always alleviate the condition. Therefore, prevention of TD by avoiding DRBA's if at all possible is ideal. However, there is no apparent way to predict who will develop TD and there are some cases in which DRBA's are necessary for treatment of chronic conditions. As TD has been present since the development of DRBA's, possible risk factors for its development have been studied. Solmi et al. (2018) [3] have written a comprehensive review on this subject. PMID- 30522958 TI - The movement disorder spectrum of SCA21 (ATX-TMEM240): 3 novel families and systematic review of the literature. AB - Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) was recently found to be caused by mutations in TMEM240, with still limited knowledge on the phenotypic spectrum and disease course. Here we present five subjects from three novel SCA21 families from different parts of the world (including a novel c.196G > A, p.G66R TMEM240 variant from Colombia), demonstrating that, in addition to cerebellar ataxia, not only hypokinetic features (hypomimia, bradykinesia), but also hyperkinetic movement disorders (poly-mini-myoclonus, proximal myoclonus) are a recurrent part of the phenotypic spectrum of SCA21. Presenting first prospective longitudinal data, our results provide examples of two different disease trajectories: while it was inherently progressive in adult-onset cases, a dramatically improving trajectory was observed in an infantile-onset case. A systematic review of all previously reported SCA21 patients (n = 42) demonstrates that SCA21 is a relatively early-onset SCA (median onset age 18 years; range 1-61 years) with frequent non-cerebellar involvement, including hyporeflexia (69%), bradykinesia (65%), slow saccades (38%) and pyramidal signs (17%). Our results characterize SCA21 as a multisystem disorder with substantial extra-cerebellar involvement, including a wide spectrum of hypo- as well as hyperkinetic movement disorders as well as damage to the midbrain, corticospinal tract and peripheral nerves. However, in contrast to the current perspective on SCA21 disease, cognitive impairment is not an obligatory feature of the disease. The disease course is inherently progressive in adult-onset subjects, but might also be characterized by improvement in infantile-onset cases. These findings have important consequences of the work-up and counseling of SCA21/ATX-TMEM240 patients. PMID- 30522960 TI - Reliability of the talocalcaneal angle for the evaluation of hindfoot alignment. AB - INTRODUCTION: Recent studies suggest that hindfoot deformity should be considered in the surgical treatment of tarsal coalitions. Many authors have used the angle between the talus and the calcaneus (TCA) for decision-making. However, its reliability has not been demonstrated and the measurement technique has not been standardized. The objective of this study was to standardize the TCA measurement technique, and to evaluate the inter and intra-observer reproducibility of the proposed technique. METHODS: The foot CT scans of a group of 30 patients between 10 and 17 years of age were analysed. Ten patients had talocalcaneal coalitions, ten calcaneonavicular coalitions and ten had no coalitions. The inter and intra observer reproducibility of the TCA was evaluated by the intraclass correlation coefficient (ICCs). A mixed-effects ANOVA model was used to calculate the ICCs for ICC2 agreement (A, 1). This procedure was applied to the three observers (inter-observer variability), and to the test-retest of observer 1 (intra observer variability). A two-tailed p value of <=.05 was considered significant. RESULTS: The inter-observer and intra-observer agreements were excellent for the TCA. Inter-observer agreement: ICC2 (A, 1)=.95 (p<.001, CI 95%: .77-.93). Intra observer agreement: ICC2 (A, 1)=.99 (p<.001, CI 95%: .97-.99). CONCLUSION: The TCA is a reliable way to evaluate hindfoot alignment. This method of measurement, as described in this study, can be safely used for surgical planning in patients with tarsal coalitions. PMID- 30522961 TI - Superior capsular reconstruction of irreparable rotator cuff tear using autologous hamstring graft. AB - OBJECTIVE: The aim of this study was to investigate the clinical results and radiographic findings after superior capsular reconstruction (SCR) of postero superior symptomatic irreparable rotator cuff tears (PSIRCT) using a new SCR technique using autologous hamstring graft MATERIAL AND METHODS: From 2014 to 2016, 8 shoulders of 8 patients (mean age 59.6 years) with PSIRCT underwent SCR using autologous hamstring graft. Physical examination, X-ray and MRI were performed before the surgery and 12 months after it. A descriptive analysis was performed of the variables, and the non-parametric test of signs comparing the measurements taken before the operation and 12 months after it. RESULTS: We found an improvement in the Constant test from 49 before the SCR to 77.25 one year after the operation. The mean active flexion significantly increased from 99.3 degrees to 142.5 degrees . The mean preoperative AH distance increased from 5.25 (range from 3 to 7) before surgery to 8.18 (range from 6 to 10.5) after the SCR. There were no tears of the graft during follow-up. CONCLUSION: SCR with a hamstring graft improves the function of the shoulder in PSIRCT, and is an alternative technique for treating these injuries without closing the door to other types of surgery. PMID- 30522962 TI - Classification of the transverse pattern of Mason II radial head fractures and its usefulness in arthroscopic osteosynthesis. Anatomo-surgical study. AB - OBJECTIVE: The management of MasonII fracture pattern assisted by arthroscopy is a valid technique that provides good results. The objective of this study was to draw attention to the usefulness of the location of the fracture in the head of the radius in defined quadrants with respect to the bicipital tuberosity through CT. This would help to plan the optimal forearm position to access each quadrant and foresee the specific difficulties of each one. MATERIAL AND METHOD: We dissected 4 specimens of cryopreserved cadaver. We divided the radial head into 4 quadrants with regard to the bicipital tuberosity, objectifying the change of position in pronation and maximum supination with respect to the sigmoid cavity and neurovascular structures. RESULTS: The head of the radio moves with pronosupination, so there are areas of convergence between the different quadrants. Quadrant1 is approached in supination via an anteromedial portal. Quadrant2 is approached in maximum pronation through a lateral portal. Quadrant3 can be approached through lateral portals, with the forearm in neutral position and in pronation. Quadrant4 is accessible with the forearm in a neutral position and in supination through a lateral portal. CONCLUSIONS: Depending on the location of the fracture in the head of the radius with respect to the bicipital tuberosity, we will need access through a specific arthroscopic portal, with the medial quadrants (anteromedial and posteromedial) being the most technically demanding. PMID- 30522963 TI - SKF-10047, a prototype Sigma-1 receptor agonist, augmented the membrane trafficking and uptake activity of the serotonin transporter and its C-terminus deleted mutant via a Sigma-1 receptor-independent mechanism. AB - The serotonin transporter (SERT) is functionally regulated via membrane trafficking. Our previous studies have demonstrated that the SERT C-terminal deletion mutant (SERTDeltaCT) showed a robust decrease in its membrane trafficking and was retained in the endoplasmic reticulum (ER), suggesting that SERTDeltaCT is an unfolded protein that may cause ER stress. The Sigma-1 receptor (SigR1) has been reported to attenuate ER stress via its chaperone activity. In this study, we investigated the effects of SKF-10047, a prototype SigR1 agonist, on the membrane trafficking and uptake activity of SERT and SERTDeltaCT expressed in COS-7 cells. Twenty-four hours of SKF-10047 treatment (>200 MUM) accelerated SERT membrane trafficking and robustly upregulated SERTDeltaCT activity. Interestingly, these effects of SKF-10047 on SERT functions were also found in cells in which SigR1 expression was knocked down by shRNA, suggesting that SKF 10047 exerted these effects on SERT via a mechanism independent of SigR1. A cDNA array study identified several candidate genes involved in the mechanism of action of SKF-10047. Among them, Syntaxin3, a member of the SNARE complex, was significantly upregulated by 48 h of SKF-10047 treatment. These results suggest that SKF-10047 is a candidate for ER stress relief. PMID- 30522965 TI - Atypical nasal mass. PMID- 30522964 TI - Pioglitazone improves visceral sensation and colonic permeability in a rat model of irritable bowel syndrome. AB - Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-gamma activation by pioglitazone may be useful for IBS treatment. PMID- 30522966 TI - Ibrutinib: searching for a partner drug. PMID- 30522968 TI - Drug development for glioma: are we repeating the same mistakes? PMID- 30522967 TI - Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial. AB - BACKGROUND: Glioblastoma is a highly vascularised tumour and there are few treatment options after disease recurrence. Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases. We aimed to assess the efficacy and safety of regorafenib in the treatment of recurrent glioblastoma. METHODS: REGOMA is a randomised, multicentre, open-label phase 2 trial done in ten centres in Italy. Eligible patients (aged >=18 years) with histologically confirmed glioblastoma, Eastern Cooperative Oncology Group performance status 0 or 1, and documented disease progression after surgery followed by radiotherapy and temozolomide chemoradiotherapy were randomly assigned (1:1) by a web-based system, stratified by centre and surgery at recurrence (yes vs no), to receive regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle or lomustine 110 mg/m2 once every 6 weeks until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02926222, and is currently in follow-up. FINDINGS: Between Nov 27, 2015, and Feb 23, 2017, 124 patients were screened and 119 eligible patients were randomly assigned to receive regorafenib (n=59) or lomustine (n=60). Median follow-up was 15.4 months (IQR 13.8-18.1). At the analysis cutoff date, 99 (83%) of 119 patients had died: 42 (71%) of 59 in the regorafenib group and 57 (95%) of 60 in the lomustine group. Overall survival was significantly improved in the regorafenib group compared with the lomustine group, with a median overall survival of 7.4 months (95% CI 5.8-12.0) in the regorafenib group and 5.6 months (4.7-7.3) in the lomustine group (hazard ratio 0.50, 95% CI 0.33-0.75; log-rank p=0.0009). Grade 3-4 treatment-related adverse events occurred in 33 (56%) of 59 patients treated with regorafenib and 24 (40%) of 60 with lomustine. The most frequent grade 3 or 4 adverse events related to regorafenib were hand-foot skin reaction, increased lipase, and blood bilirubin increased (in six [10%] of 59 patients each). In the lomustine group, the most common grade 3 or 4 adverse events were decreased platelet count (eight [13%] of 60 patients), decreased lymphocyte count (eight [13%]), and neutropenia (seven [12%]). No death was considered by the investigators to be drug related. INTERPRETATION: REGOMA showed an encouraging overall survival benefit of regorafenib in recurrent glioblastoma. This drug might be a new potential treatment for these patients and should be investigated in an adequately powered phase 3 study. FUNDING: Veneto Institute of Oncology and Bayer Italy. PMID- 30522969 TI - Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. AB - BACKGROUND: Both single-agent ibrutinib and chlorambucil plus obinutuzumab have shown superior efficacy to chlorambucil monotherapy and are standard first-line treatments in chronic lymphocytic leukaemia. We compared the efficacy of the combination of ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in first-line chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: iLLUMINATE is a multicentre, randomised, open-label, phase 3 trial done at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the EU, and the USA in patients with previously untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma, either aged 65 years or older or younger than 65 years with coexisting conditions. Patients were randomly assigned (1:1) using a blocked randomisation schedule, stratified by Eastern Cooperative Oncology Group performance status and cytogenetics, to receive ibrutinib plus obinutuzumab (oral ibrutinib [420 mg once daily continuously] combined with intravenous obinutuzumab [100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1 and on day 1 of subsequent 28-day cycles, for a total of six cycles]) or chlorambucil plus obinutuzumab (oral chlorambucil [0.5 mg/kg bodyweight on days 1 and 15 of each 28-day cycle for six cycles] combined with the same obinutuzumab regimen). Allocation concealment was achieved using an interactive web response system. Patients and investigators were not masked to treatment assignment. The primary endpoint was progression free survival assessed by a masked independent review committee in the intention to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT02264574), and patient enrolment is complete. FINDINGS: Between Oct 6, 2014, and Oct 12, 2015, 229 patients were enrolled and randomly assigned to receive ibrutinib plus obinutuzumab (n=113) or chlorambucil plus obinutuzumab (n=116). After a median follow-up of 31.3 months (IQR 29.4-33.2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33.6-non-estimable]) than in the chlorambucil plus obinutuzumab group (19.0 months [15.1-22.1]; hazard ratio 0.23; 95% CI 0.15-0.37; p<0.0001). Estimated 30-month progression-free survival was 79% (95% CI 70-85) in the ibrutinib plus obinutuzumab group and 31% (23-40) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse events in both groups were neutropenia and thrombocytopenia. Serious adverse events occurred in 65 (58%) of 113 patients treated with ibrutinib plus obinutuzumab and 40 (35%) of 115 patients treated with chlorambucil plus obinutuzumab. Ibrutinib or chlorambucil treatment-related deaths were reported in one (1%) of 113 patients in the ibrutinib plus obinutuzumab group (sudden death) and one (1%) of 115 patients in the chlorambucil plus obinutuzumab group (neuroendocrine carcinoma of the skin). INTERPRETATION: Ibrutinib plus obinutuzumab is an efficacious and safe chemotherapy-free combination treatment in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma independent of high risk features and provides an alternative first-line treatment option for these patients. FUNDING: Pharmacyclics LLC, an AbbVie Company, and Janssen Research and Development. PMID- 30522970 TI - Immune response to purified protein derivative in infants from helminth sensitized mothers - A cases series. AB - BACKGROUND: Maternal exposure to antibodies, cytokines or parasitic antigens during gestation may alter the degree of immune competence of offspring. Here we describe the production of cytokines and chemokines, and the ability to activation of the immune response in infants from mothers sensitized to helminths. METHODS: It were selected five infants born to helminth-seropositive mothers but who were negative for current helminth infection. Whole blood was cultured without stimulus, with phytohemagglutinin mitogen (5 MUg/ml, 24 h) or with purified protein derivative (PPD) (1 MUg/ml, 24 h), and the supernatant was assessed for presence of Th1/Th2 cytokines (IFN-gamma, TNF-alpha, IL-10, IL-5, IL 4 and IL-2) and chemokines (CXCL10, CCL2, CXCL9, CCL5 and CXCL8) by cytometric bead array. RESULTS: All infants produced CCL5. Two infants demonstrated a mixed profile of Th1 (CXCL9) and Th2 (CCL2) chemokines in the presence of CXCL10, while one infant showed skewing towards Th2 without CXCL10 and two of them had been impaired immune response (children from sensitized to Schistosoma mansoni mothers). CONCLUSION: Infants with Th1 and Th2 profile chemokines demonstrated a good response to vaccination, indicated by CXCL10 levels, but not infants predominantly Th2-skewed profile. These results highlight that children from mothers sensitized to S. mansoni may lead to ineffective immune response to PPD, while mothers sensitized to Ascaris lumbricoides showed no such impairment. PMID- 30522971 TI - Abnormalities in gray matter microstructure in young adults with 22q11.2 deletion syndrome. AB - BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) is a genetic, neurodevelopmental disorder characterized by a chromosomal deletion and a distinct cognitive profile. Although abnormalities in the macrostructure of the cortex have been identified in individuals with 22q11DS, it is not known if there are additional microstructural changes in gray matter regions in this syndrome, and/or if such microstructural changes are associated with cognitive functioning. METHODS: This study employed a novel diffusion MRI measure, the Heterogeneity of Fractional Anisotropy (HFA), to examine variability in the microstructural organization of the cortex in healthy young adults (N = 30) and those with 22q11DS (N = 56). Diffusion MRI, structural MRI, clinical and cognitive data were acquired. RESULTS: Compared to controls, individuals with 22q11DS evinced increased HFA in cortical association (p = .003, d = 0.86) and paralimbic (p < .0001, d = 1.2) brain areas, whereas no significant differences were found between the two groups in primary cortical brain areas. Additionally, increased HFA of the right paralimbic area was associated with poorer performance on tests of response inhibition, i.e., the Stroop Test (rho = -0.37 p = .005) and the Gordon Diagnostic System Vigilance Commission (rho = -0.41 p = .002) in the 22q11DS group. No significant correlations were found between HFA and cognitive abilities in the healthy control group. CONCLUSIONS: These findings suggest that cortical microstructural disorganization may be a neural correlate of response inhibition in individuals with 22q11DS. Given that the migration pattern of neural crest cells is disrupted at the time of early brain development in 22q11DS, we hypothesize that these neural alterations may be neurodevelopmental in origin, and reflect cortical dysfunction associated with cognitive deficits. PMID- 30522972 TI - Reduced neural sensitivity to rapid individual face discrimination in autism spectrum disorder. AB - BACKGROUND: Individuals with autism spectrum disorder (ASD) are characterized by impairments in social communication and interaction. Although difficulties at processing social signals from the face in ASD have been observed and emphasized for many years, there is a lot of inconsistency across both behavioral and neural studies. METHODS: We recorded scalp electroencephalography (EEG) in 23 8-to-12 year old boys with ASD and 23 matched typically developing boys using a fast periodic visual stimulation (FPVS) paradigm, providing objective (i.e., frequency tagged), fast (i.e., few minutes) and highly sensitive measures of rapid face categorization, without requiring any explicit face processing task. We tested both the sensitivity to rapidly (i.e., at a glance) categorize faces among other objects and to individuate unfamiliar faces. OUTCOMES: While general neural synchronization to the visual stimulation and neural responses indexing generic face categorization were undistinguishable between children with ASD and typically developing controls, neural responses indexing individual face discrimination over the occipito-temporal cortex were substantially reduced in the individuals with ASD. This difference vanished when faces were presented upside-down, due to the lack of significant face inversion effect in ASD. INTERPRETATION: These data provide original evidence for a selective high-level impairment in individual face discrimination in ASD in an implicit task. The objective and rapid assessment of this function opens new perspectives for ASD diagnosis in clinical settings. PMID- 30522973 TI - Structural white matter networks in myotonic dystrophy type 1. AB - The myriad of neuropsychiatric manifestations reported in myotonic dystrophy type 1 may have its origin in alterations of complex brain network interactions at the structural level. In this study, we tested the hypothesis that altered white matter microstructural integrity and network organisation were present in a cohort of individuals with DM1 compared to unaffected controls, which was expected to be associated with CNS related disease manifestations of DM1. We performed a cross-sectional neuropsychological assessment and brain MRI in 25 myotonic dystrophy type 1 (DM1) patients and 26 age, sex and educational level matched unaffected controls. Patients were recruited from the Dutch cohort of the OPTIMISTIC study, a concluded trial which had included ambulant, genetically confirmed DM1 patients who were severely fatigued. We applied graph theoretical analysis on structural networks derived from diffusion tensor imaging (DTI) data and deterministic tractography to determine global and local network properties and performed group-wise comparisons. Furthermore, we analysed the following variables from structural MRI imaging: semi-quantitative white matter hyperintensity load andwhite matter tract integrity using tract-based spatial statistics (TBSS). Structural white matter networks in DM1 were characterised by reduced global efficiency, local efficiency and strength, while the network density was compatible to controls. Other findings included increased white matter hyperintensity load, and diffuse alterations of white matter microstructure in projection, association and commissural fibres. DTI and network measures were associated (partial correlations coefficients ranging from 0.46 to 0.55) with attention (d2 Test), motor skill (Purdue Pegboard test) and visual constructional ability and memory (copy subtest of the Rey-Osterrieth Complex Figure Test). DTI and network measures were not associated with clinical measures of fatigue (checklist individual strength, fatigue subscale) or apathy (apathy evaluation scale - clinician version). In conclusion, our study supports the view of brain involvement in DM1 as a complex network disorder, characterised by white matter network alterations that may have relevant neuropsychological correlations. This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013; grant agreement n degrees 305,697) and the Marigold Foundation. PMID- 30522975 TI - Degree of Planning of Sexual Intercourse Among Men From China, Japan, and Taiwan Taking Medication for Erectile Dysfunction: Findings of an Observational, Cross Sectional Survey. AB - INTRODUCTION: Management of erectile dysfunction (ED) is beset with assumptions around spontaneity of sexual intercourse, requiring candor between the physician and patient if appropriate treatment is to be implemented. AIM: To evaluate the degree to which men who take ED medications plan for and have sex. METHODS: Men from China, Japan, and Taiwan aged 40-70 years who had taken ED medications within the past 3 months were invited to participate anonymously in an online, self-administered survey that enquired about frequency and advance planning of sex, time between taking ED medication and intercourse, and treatment satisfaction. Data were analyzed using descriptive statistics. MAIN OUTCOME MEASURE: Frequency of planning of sexual intercourse, planning and ED medication dosing interval, and frequency of ED medication use. RESULTS: Data from 604 respondents (mean age 50.8 years) from China (n = 254), Japan (n = 250), and Taiwan (n = 100) were collected. Men used ED medications a median of <=4 times per month in all 3 territories. 76% who used ED medication during the past 3 months planned for sex on specific occasions, with 59% and 52% agreeing that they plan for sex on specific days of the week and times of the day, respectively. Most commonly, men planned for sex up to several hours to a day beforehand, with 94% taking ED medication within 4 hours of sex. Satisfaction with ED medication was generally high and related to erection rigidity, speed of onset, and safety. CONCLUSION: Knowledge of the degree to which individuals with ED plan for sex may have important implications for the appropriate prescription of ED medication. The high degree of planning around sexual activities exhibited by men taking ED medication suggests there is a need for appropriate counseling to ensure that treatment is aligned with patient behavior. Jiann BP, Nakajima K, Dighe S, et al. Degree of planning of sexual intercourse among men from China, Japan, and Taiwan taking medication for erectile dysfunction: Findings of an observational, cross sectional survey. Sex Med 2018;XX:XXX-XXX. PMID- 30522974 TI - The spinal and cerebral profile of adult spinal-muscular atrophy: A multimodal imaging study. AB - : Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. METHODS: Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. RESULTS: In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. CONCLUSIONS: Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation. PMID- 30522976 TI - Testosterone Insufficiency in Human Immunodeficiency Virus-Infected Women: A Cross-Sectional Study. AB - INTRODUCTION: Now that HIV infection has become a chronic disease, optimizing health status is an important goal of care for HIV-infected patients. Testosterone insufficiency (TI) can compromise health status, but little is known about the prevalence of TI and possible related factors in HIV-infected women. AIM: To investigate the prevalence of TI among HIV-infected women attending our HIV outpatient clinic, and to study the relationship between TI and sexual function, fatigue, health status, and depression. METHODS: 56 HIV-infected women aged >=18 years who attended the HIV outpatient clinic of the Amsterdam University Medical Center, The Netherlands, were included. Blood samples were taken for endocrinologic testing and patients filled out 6 validated questionnaires measuring sexual function, fatigue, health, and depression. MAIN OUTCOME MEASURE: TI, the Female Sexual Function Index, the Female Sexual Distress Scale-Revised, the Multidimensional Fatigue Inventory, the Medical Outcomes Studies Short Form 36-item health survey, and the Beck Depression Inventory were assessed. RESULTS: A relatively high prevalence of TI, 37%, was found. Plasma viral load and CD4 cell count did not differ between women with or without TI. Clinical fatigue, physical fatigue, and impaired cognitive function were significantly more prevalent in women with TI. Women with TI also tended to report decreased sexual desire, reduced physical activity, increased mental fatigue, reduced physical function, increased health distress, and clinical depression. CONCLUSION: We recommend that in all HIV-positive women with complaints typical for TI, testosterone is measured, and that in women with TI, testosterone replacement be considered as a treatment option. However, given that complaints are also prevalent in HIV-positive women without TI, the approach to women with these complaints should include sexual and psychological evaluation. Laan ETM, Prins JM, van Lunsen RHW, et al. Testosterone Insufficiency in Human Immunodeficiency Virus-Infected Women: A Cross-Sectional Study. Sex Med 2018;XX:XXX-XXX. PMID- 30522977 TI - Combination High Flow Priapism With Low Flow Priapism: Case Report. AB - INTRODUCTION: Priapism is defined as a persistent penile erection lasting longer than 4 hours and unrelated to sexual activity. It is one of the most common emergencies treated by urologists. Advances in understanding the pathophysiology of various types of priapism have led to targeted management strategies according to type of priapism. AIM: The aims of this article is report the case of a 24 year-old man who was presented in the emergency department with a combination of high flow priapism with low flow priapism. METHODS: This case report documents the case of a patient who presented in the emergency department with a high flow priapism that then became to a ischemic priapism. CONCLUSION: Priapism is one of the most common emergencies treated by urologists. Advances in understanding the pathophysiology of various types of priapism have led to targeted management strategies as was shown in our case. Carvajal A, Benavides JA. Combination High Flow Priapism With Low Flow Priapism: Case Report. Sex Med 2018;XX:XX-XX. PMID- 30522978 TI - Needs and Expectations of Patients with Erectile Dysfunction: An Update on Pharmacological Innovations in Phosphodiesterase Type 5 Inhibition with Focus on Sildenafil. AB - INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5-Is) have an excellent efficacy and tolerability profile and remain the first-line choice for the treatment of erectile dysfunction (ED). However, ED is still an underdiagnosed and undertreated condition, and many men prematurely discontinue therapy with conventional dosage formulations despite successful intercourse. AIM: To review the unmet needs and expectations of patients with ED and describe the latest pharmaceutical innovations in the field of PDE5-I formulations designed to address these needs, with particular reference to a new orodispersible film (ODF) formulation of the PDE5-I, sildenafil. METHODS: Online literature search in PubMed and the Cochrane Library. MAIN OUTCOME MEASURE: To identify English language publications relevant to the aims of the present review. RESULTS: Improved recognition and management of ED would enable the early diagnosis of underlying and comorbid conditions that contribute to ED, leading to improved patient health and health-related quality of life. To ensure successful outcomes and patient and partner satisfaction, the complex and personal issues that influence the patient's needs and expectations regarding treatment for ED must be considered along with their personal experiences and preferences. Innovative drug delivery systems, including orally disintegrating formulations, have been developed as alternatives to conventional dosage forms with the aim of improving patient convenience and acceptability and enhancing compliance. These alternative formulations include the sildenafil ODF, which is designed to improve acceptance and compliance over conventional solid dosage forms and extend the treatment options for men with ED by offering a convenient and discrete dosage form of a drug with proven efficacy. CONCLUSION: The sildenafil ODF is an example of an innovative dosage formulation for ED that can be used interchangeably with the conventional film-coated formulation to better address the needs and expectations of men with ED. Jannini EA, Droupy S. Needs and Expectations of Patients with Erectile Dysfunction: An Update on Pharmacological Innovations in Phosphodiesterase Type 5 Inhibition with Focus on Sildenafil. Sex Med 2018;XX:XX XX. PMID- 30522979 TI - Factors affecting implementation of digital health interventions for people with psychosis or bipolar disorder, and their family and friends: a systematic review. AB - Digital health interventions present an important opportunity to improve health care for people with psychosis or bipolar disorder, but despite their potential, integrating and implementing them into clinical settings has been difficult worldwide. This Review aims to identify factors affecting implementation of digital health interventions for people affected by psychosis or bipolar disorder. We searched seven databases and synthesised data from 26 studies using the Consolidated Framework for Implementation Research. Attitudes and beliefs about interventions were crucial factors for both staff and service users, with negative attitudes and scepticism resulting in a lack of motivation to engage with interventions or complete them. The complexity of the interventions was a barrier for people with psychiatric symptoms, low premorbid intelligence quotient, or minimal information technology skills. The accessibility and adaptability of interventions were key facilitators, but insufficient resources, finances, and staff time were barriers to implementation. Interventions need to be user friendly and adaptable to the needs and capabilities of people with psychosis or bipolar disorder, and the staff who support their implementation. Service users and staff should cofacilitate the process of developing and implementing the interventions. PMID- 30522980 TI - Strategies not accompanied by a mental health professional to address anxiety and depression in children and young people: a scoping review of range and a systematic review of effectiveness. AB - This Review reports on a scoping review followed by a systematic review to consider interventions designed to address or manage depression or anxiety in children and young people up to the age of 25 years without the need to involve mental health professionals. The scoping review identified 132 approaches, 103 of which referred to children or young people (younger than 25 years). These approaches included social interaction, engagement with nature, relaxation, distraction, sensory stimulation, physical activity, altering perceptions, engaging in hobbies, self-expression, and exploration. A systematic review of effectiveness studies from the literature identified in the scoping review found only 38 studies on seven types of intervention that met the inclusion criteria. 16 studies were based on cognitive or behavioural principles (15 on digital interventions and one on bibliotherapy), ten focused on physical exercise, five on light therapy, three on dietary supplements, two on massage therapy, one on online peer support, and one on contact with a dog. Most studies focused on adolescents or young adults. Evidence suggested that light therapy could be effective for season depression and that digital interventions based on attention bias modification are ineffective for anxiety. Mixed evidence was available on the effectiveness of computerised cognitive behavioural therapy for depression and anxiety, and of physical exercise for depression. All other studies had insufficient certainty to obtain even tentative conclusions about effectiveness. These results highlight the disparity between the extensive range of approaches identified in the scoping review and the restricted number and focus found in the systematic review of effectiveness of these approaches. We call for an expanded research agenda that brings evaluation rigour to a wide range of self or community approaches. PMID- 30522981 TI - Tuberculosis in medieval and early modern Denmark: A paleoepidemiological perspective. AB - Millions of people worldwide have sickened and died from tuberculosis in recent centuries. Yet for most of human existence, the impact of tuberculosis on society is largely unknown. It is, indeed, unknowable without methods suitable for estimating disease prevalence in skeletal samples. Here such a procedure is applied to medieval and early modern Danish skeletons, and it shows how disease prevalence varied with differences in socioeconomic conditions. The approach is based on sensitivity and specificity estimates from modern skeletons. To augment our understanding of tuberculosis in Danish history, 713 adult skeletons were examined, all from Ribe. Tuberculosis increased from 17% to 40% in the medieval to early modern periods in Ribe. Low status (29%) people were more likely to contract the disease than those of high status (10%). The general model, derived from the modern expression of tuberculosis, fits the early modern sample better than it does the medieval skeletons. Differences in the model's fit indicate the skeletal expression changed over time. Notably, rib lesions increased in frequency from the medieval to early modern periods. The approach developed here can provide insights into host-pathogen relationships and disease expression in future work with tuberculosis and other diseases that affect the skeleton. PMID- 30522983 TI - Quo vadis, aspirin? PMID- 30522984 TI - The invisible army of women in interventional cardiology: EAPCI Women mission to make them visible. PMID- 30522982 TI - Seroepidemiological and molecular investigations of infections with Crimean-Congo haemorrhagic fever virus in Kazakhstan. AB - OBJECTIVES: The aim of this study was to detect the seroprevalence of Crimean Congo haemorrhagic fever virus (CCHFV) in patients with fever of unknown origin (FUO) in endemic (Kyzylorda) and non-endemic (Almaty) oblasts of Kazakhstan. METHODS: Paired serum samples from 802 patients with FUO were collected. Serum samples were investigated by ELISA to detect IgG and IgM antibodies against CCHFV. Sera with suspected acute infection were further investigated by RT-PCR to detect the viral RNA. RESULTS: IgG antibodies were detected in 12.7% of the sera from both oblasts. Acute infection was shown by IgM ELISA in four patients from Kyzylorda, with only one developing severe CCHF. Viral RNA was found by RT-PCR in the other three patients' sera. Phylogenetic analysis of partial L and S segments revealed CCHFV genotype Asia 2 and a possible reassortment between the genotypes Asia 1/Asia 2. Animal husbandry, such as working with cattle and horses, was significantly associated with CCHFV seropositivity. CONCLUSIONS: The antibodies and viral RNA detected in sera indicate that mild or even asymptomatic CCHFV infections are presented in Kazakhstan. This study describes the circulation of CCHFV in the so far non-endemic Almaty oblast for the first time. In conclusion, physicians treating patients with FUO in Kazakhstan should be aware of mild CCHF. PMID- 30522985 TI - PCI in TAVI patients: who, why and when? PMID- 30522986 TI - Percutaneous revascularisation of chronic occluded coronaries - availability of the retrograde approach increases technical success and the quality of life despite more frequent complications. PMID- 30522987 TI - A golden age for interventional cardiology as patient-centred care emerges from our technical preoccupations. PMID- 30522988 TI - Crossing the Digital Divide in Online Self-Management Support: Analysis of Usage Data From HeLP-Diabetes. AB - BACKGROUND: Digital health is increasingly recognized as a cost-effective means to support patient self-care. However, there are concerns about whether the "digital divide," defined as the gap between those who do and do not make regular use of digital technologies, will lead to increased health inequalities. Access to the internet, computer literacy, motivation to use digital health interventions, and fears about internet security are barriers to use of digital health interventions. Some of these barriers disproportionately affect people of older age, black or minority ethnic background, and low socioeconomic status. HeLP-Diabetes (Healthy Living for People with type 2 Diabetes), a theoretically informed online self-management program for adults with type 2 diabetes, was developed to meet the needs of people from a broad demographic background. OBJECTIVE: This study aimed to determine whether there was evidence of a digital divide when HeLP-Diabetes was integrated into routine care. This was achieved by (1) comparing the characteristics of people who registered for the program against the target population (people with type 2 diabetes in inner London), (2) comparing the characteristics of people who registered for the program and used it with those who did not use it, and (3) comparing sections of the website visited by different demographic groups. METHODS: A retrospective analysis of data on the use of HeLP-Diabetes in routine clinical practice in 4 inner London clinical commissioning groups was undertaken. Data were collected from patients who registered for the program as part of routine health services.. Data on gender, age, ethnicity, and educational attainment were collected at registration, and data on webpage visits (user identification number, date, time, and page visited) were collected automatically by software on the server side of the website. RESULTS: The characteristics of people who registered for the program were found to reflect those of the target population. The mean age was 58.4 years (SD=28.0), over 50.0% were from black and minority ethnic backgrounds, and nearly a third (29.8%) had no qualifications beyond school leaving age. There was no association between demographic characteristics and use of the program, apart from weak evidence of less use by the mixed ethnicity group. There was no evidence of the differential use of the program by any demographic group, apart from weak evidence for people with degrees and school leavers being more likely to use the "Living and working with diabetes" (P=.03) and "Treating diabetes" (P=.04) sections of the website. CONCLUSIONS: This study is one of the first to provide evidence that a digital health intervention can be integrated into routine health services without widening health inequalities. The relative success of the intervention may be attributed to integration into routine health care, and careful design with extensive user input and consideration of literacy levels. Developers of digital health interventions need to acknowledge barriers to access and use, and collect data on the demographic profile of users, to address inequalities. PMID- 30522989 TI - Characterizing Tweet Volume and Content About Common Health Conditions Across Pennsylvania: Retrospective Analysis. AB - BACKGROUND: Tweets can provide broad, real-time perspectives about health and medical diagnoses that can inform disease surveillance in geographic regions. Less is known, however, about how much individuals post about common health conditions or what they post about. OBJECTIVE: We sought to collect and analyze tweets from 1 state about high prevalence health conditions and characterize the tweet volume and content. METHODS: We collected 408,296,620 tweets originating in Pennsylvania from 2012-2015 and compared the prevalence of 14 common diseases to the frequency of disease mentions on Twitter. We identified and corrected bias induced due to variance in disease term specificity and used the machine learning approach of differential language analysis to determine the content (words and themes) most highly correlated with each disease. RESULTS: Common disease terms were included in 226,802 tweets (174,381 tweets after disease term correction). Posts about breast cancer (39,156/174,381 messages, 22.45%; 306,127/12,702,379 prevalence, 2.41%) and diabetes (40,217/174,381 messages, 23.06%; 2,189,890/12,702,379 prevalence, 17.24%) were overrepresented on Twitter relative to disease prevalence, whereas hypertension (17,245/174,381 messages, 9.89%; 4,614,776/12,702,379 prevalence, 36.33%), chronic obstructive pulmonary disease (1648/174,381 messages, 0.95%; 1,083,627/12,702,379 prevalence, 8.53%), and heart disease (13,669/174,381 messages, 7.84%; 2,461,721/12,702,379 prevalence, 19.38%) were underrepresented. The content of messages also varied by disease. Personal experience messages accounted for 12.88% (578/4487) of prostate cancer tweets and 24.17% (4046/16,742) of asthma tweets. Awareness-themed tweets were more often about breast cancer (9139/39,156 messages, 23.34%) than asthma (1040/16,742 messages, 6.21%). Tweets about risk factors were more often about heart disease (1375/13,669 messages, 10.06%) than lymphoma (105/4927 messages, 2.13%). CONCLUSIONS: Twitter provides a window into the Web-based visibility of diseases and how the volume of Web-based content about diseases varies by condition. Further, the potential value in tweets is in the rich content they provide about individuals' perspectives about diseases (eg, personal experiences, awareness, and risk factors) that are not otherwise easily captured through traditional surveys or administrative data. PMID- 30522990 TI - Adherence to a Mindfulness and Relaxation Self-Care App for Cancer Patients: Mixed-Methods Feasibility Study. AB - BACKGROUND: Cancer is highly prevalent worldwide and can cause high levels of distress in patients, which is often neglected in medical care. Smartphone apps are readily available and therefore seem promising to deliver distress-reducing interventions such as mindfulness and relaxation programs. OBJECTIVE: This study aimed to evaluate the feasibility of a mindfulness and relaxation app for cancer patients. We looked at characteristics of participating patients in a mobile health (mHealth) study, including adherence to the app intervention, predictors for adherence, and patients' feedback regarding the app. METHODS: In this prospective observational study with a mixed-methods approach, cancer patients received a mindfulness and relaxation self-care app. Cancer patients were recruited online and through hospitals in Switzerland. We assessed self-reported measures (eg, quality of life, anxiety, depressive symptoms, openness to experience, resistance to change) at baseline, and the app gathered data on patients' practicing time. With 8 semistructured interviews, we obtained patients' feedback about the app and recommendations for improvements. We looked at 3 dimensions of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework (reach, adoption, and maintenance) and analyzed data for adherence for the first 10 weeks of the app intervention. We report descriptive statistics for patient characteristics and app use. For the prediction of adherence, we used Kaplan-Meier analyses with log-rank tests and a Cox proportional hazards regression. RESULTS: Data from 100 cancer patients (74 female) showed that 54 patients were using the app exercises continuously until week 10. In continuous app users, the median number of exercises per week dropped from 4 (interquartile range, IQR 1-7) at week 1 to a median of 2 (IQR 1-4) at week 10. Our analyses revealed 4 significant predictors for better adherence: female gender, higher openness to experience, higher resistance to change, and more depressive symptoms. Interviews revealed that the patients generally were satisfied with the app but also made suggestions on how to improve it. CONCLUSIONS: Our study indicates that a mindfulness and relaxation mHealth intervention for cancer patients is feasible with acceptable adherence and largely positive feedback from patients. TRIAL REGISTRATION: German Clinical Trials Register DRKS00010481; https://www.drks.de/drks_web/navigate.do?navigation Id=trial.HTML&TRIAL_ID=DRKS00010481 (Archived by WebCite at http://www.webcitation.org/73xGE1B0P). PMID- 30522991 TI - Exploring the Utility of Community-Generated Social Media Content for Detecting Depression: An Analytical Study on Instagram. AB - BACKGROUND: The content produced by individuals on various social media platforms has been successfully used to identify mental illness, including depression. However, most of the previous work in this area has focused on user-generated content, that is, content created by the individual, such as an individual's posts and pictures. In this study, we explored the predictive capability of community-generated content, that is, the data generated by a community of friends or followers, rather than by a sole individual, to identify depression among social media users. OBJECTIVE: The objective of this research was to evaluate the utility of community-generated content on social media, such as comments on an individual's posts, to predict depression as defined by the clinically validated Patient Health Questionnaire-8 (PHQ-8) assessment questionnaire. We hypothesized that the results of this research may provide new insights into next generation of population-level mental illness risk assessment and intervention delivery. METHODS: We created a Web-based survey on a crowdsourcing platform through which participants granted access to their Instagram profiles as well as provided their responses to PHQ-8 as a reference standard for depression status. After data quality assurance and postprocessing, the study analyzed the data of 749 participants. To build our predictive model, linguistic features were extracted from Instagram post captions and comments, including multiple sentiment scores, emoji sentiment analysis results, and meta variables such as the number of likes and average comment length. In this study, 10.4% (78/749) of the data were held out as a test set. The remaining 89.6% (671/749) of the data were used to train an elastic-net regularized linear regression model to predict PHQ-8 scores. We compared different versions of this model (ie, a model trained on only user-generated data, a model trained on only community-generated data, and a model trained on the combination of both types of data) on a test set to explore the utility of community-generated data in our predictive analysis. RESULTS: The 2 models, the first trained on only community generated data (area under curve [AUC]=0.71) and the second trained on a combination of user-generated and community-generated data (AUC=0.72), had statistically significant performances for predicting depression based on the Mann-Whitney U test (P=.03 and P=.02, respectively). The model trained on only user-generated data (AUC=0.63; P=.11) did not achieve statistically significant results. The coefficients of the models revealed that our combined data classifier effectively amalgamated both user-generated and community-generated data and that the 2 feature sets were complementary and contained nonoverlapping information in our predictive analysis. CONCLUSIONS: The results presented in this study indicate that leveraging community-generated data from social media, in addition to user-generated data, can be informative for predicting depression among social media users. PMID- 30522992 TI - Using the Social-Local-Mobile App for Smoking Cessation in the SmokeFreeBrain Project: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Smoking is considered the main cause of preventable illness and early deaths worldwide. The treatment usually prescribed to people who wish to quit smoking is a multidisciplinary intervention, combining both psychological advice and pharmacological therapy, since the application of both strategies significantly increases the chance of success in a quit attempt. OBJECTIVE: We present a study protocol of a 12-month randomized open-label parallel-group trial whose primary objective is to analyze the efficacy and efficiency of usual psychopharmacological therapy plus the Social-Local-Mobile app (intervention group) applied to the smoking cessation process compared with usual psychopharmacological therapy alone (control group). METHODS: The target population consists of adult smokers (both male and female) attending the Smoking Cessation Unit at Virgen del Rocio University Hospital, Seville, Spain. Social Local-Mobile is an innovative intervention based on mobile technologies and their capacity to trigger behavioral changes. The app is a complement to pharmacological therapies to quit smoking by providing personalized motivational messages, physical activity monitoring, lifestyle advice, and distractions (minigames) to help overcome cravings. Usual pharmacological therapy consists of bupropion (Zyntabac 150 mg) or varenicline (Champix 0.5 mg or 1 mg). The main outcomes will be (1) the smoking abstinence rate at 1 year measured by means of exhaled carbon monoxide and urinary cotinine tests, and (2) the result of the cost-effectiveness analysis, which will be expressed in terms of an incremental cost-effectiveness ratio. Secondary outcome measures will be (1) analysis of the safety of pharmacological therapy, (2) analysis of the health-related quality of life of patients, and (3) monitoring of healthy lifestyle and physical exercise habits. RESULTS: Of 548 patients identified using the hospital's electronic records system, we excluded 308 patients: 188 declined to participate and 120 did not meet the inclusion criteria. A total of 240 patients were enrolled: the control group (n=120) will receive usual psychopharmacological therapy, while the intervention group (n=120) will receive usual psychopharmacological therapy plus the So-Lo-Mo app. The project was approved for funding in June 2015. Enrollment started in October 2016 and was completed in October 2017. Data gathering was completed in November 2018, and data analysis is under way. The first results are expected to be submitted for publication in early 2019. CONCLUSIONS: Social networks and mobile technologies influence our daily lives and, therefore, may influence our smoking habits as well. As part of the SmokeFreeBrain H2020 European Commission project, this study aims at elucidating the potential role of these technologies when used as an extra aid to quit smoking. TRIAL REGISTRATION: ClinicalTrials.gov NCT03553173; https://clinicaltrials.gov/ct2/show/record/NCT03553173 (Archived by WebCite at http://www.webcitation.org/74DuHypOW). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/12464. PMID- 30522993 TI - Evaluating the Effectiveness and Safety of the Electroencephalogram-Based Brain Machine Interface Rehabilitation System for Patients With Severe Hemiparetic Stroke: Protocol for a Randomized Controlled Trial (BEST-BRAIN Trial). AB - BACKGROUND: We developed a brain-machine interface (BMI) system for poststroke patients with severe hemiplegia to detect event-related desynchronization (ERD) on scalp electroencephalogram (EEG) and to operate a motor-driven hand orthosis combined with neuromuscular electrical stimulation. ERD arises when the excitability of the ipsi-lesional sensorimotor cortex increases. OBJECTIVE: The aim of this study was to evaluate our hypothesis that motor training using this BMI system could improve severe hemiparesis that is resistant to improvement by conventional rehabilitation. We, therefore, planned and implemented a randomized controlled clinical trial (RCT) to evaluate the effectiveness and safety of intensive rehabilitation using the BMI system. METHODS: We conducted a single blind, multicenter RCT and recruited chronic poststroke patients with severe hemiparesis more than 90 days after onset (N=40). Participants were randomly allocated to the BMI group (n=20) or the control group (n=20). Patients in the BMI group repeated 10-second motor attempts to operate EEG-BMI 40 min every day followed by 40 min of conventional occupational therapy. The interventions were repeated 10 times in 2 weeks. Control participants performed a simple motor imagery without servo-action of the orthosis, and electrostimulation was given for 10 seconds for 40 min, similar to the BMI intervention. Overall, 40 min of conventional occupational therapy was also given every day after the control intervention, which was also repeated 10 times in 2 weeks. Motor functions and electrophysiological phenotypes of the paretic hands were characterized before (baseline), immediately after (post), and 4 weeks after (follow-up) the intervention. Improvement in the upper extremity score of the Fugl-Meyer assessment between baseline and follow-up was the main outcome of this study. RESULTS: Recruitment started in March 2017 and ended in July 2018. This trial is currently in the data correcting phase. This RCT is expected to be completed by October 31, 2018. CONCLUSIONS: No widely accepted intervention has been established to improve finger function of chronic poststroke patients with severe hemiparesis. The results of this study will provide clinical data for regulatory approval and novel, important understanding of the role of sensory-motor feedback based on BMI to induce neural plasticity and motor recovery. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000026372; https://upload.umin.ac.jp/cgi-open bin/ctr_e/ctr_view.cgi? recptno=R000030299 (Archived by WebCite at http://www.webcitation.org/743zBJj3D). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/12339. PMID- 30522994 TI - Capturing Expert Knowledge for the Personalization of Cognitive Rehabilitation: Study Combining Computational Modeling and a Participatory Design Strategy. AB - BACKGROUND: Cognitive impairments after stroke are not always given sufficient attention despite the critical limitations they impose on activities of daily living (ADLs). Although there is substantial evidence on cognitive rehabilitation benefits, its implementation is limited because of time and human resource's demands. Moreover, many cognitive rehabilitation interventions lack a robust theoretical framework in the selection of paper-and-pencil tasks by the clinicians. In this endeavor, it would be useful to have a tool that could generate standardized paper-and-pencil tasks, parameterized according to patients' needs. OBJECTIVE: In this study, we aimed to present a framework for the creation of personalized cognitive rehabilitation tasks based on a participatory design strategy. METHODS: We selected 11 paper-and-pencil tasks from standard clinical practice and parameterized them with multiple configurations. A total of 67 tasks were assessed according to their cognitive demands (attention, memory, language, and executive functions) and overall difficulty by 20 rehabilitation professionals. RESULTS: After assessing the internal consistency of the data-that is, alpha values from .918 to .997-we identified the parameters that significantly affected cognitive functions and proposed specific models for each task. Through computational modeling, we operationalized the tasks into their intrinsic parameters and developed a Web tool that generates personalized paper-and-pencil tasks-the Task Generator (TG). CONCLUSIONS: Our framework proposes an objective and quantitative personalization strategy tailored to each patient in multiple cognitive domains (attention, memory, language, and executive functions) derived from expert knowledge and materialized in the TG app, a cognitive rehabilitation Web tool. PMID- 30522995 TI - Bleeding Complications after Pediatric Kidney Biopsy: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND OBJECTIVES: Kidney biopsy is an essential tool for the diagnosis and treatment of patients with kidney disease; however, because of its invasive nature, bleeding complications may arise. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a meta-analysis of prospective or retrospective observational studies and randomized, controlled trials in pediatric patients undergoing native or transplant kidney biopsy in an inpatient or outpatient setting in MEDLINE-indexed studies from January 1998 to November 1, 2017 to determine the proportion of patients who develop hematoma, need blood transfusion, or need an additional intervention due to a complication after kidney biopsy. RESULTS: Twenty-three studies of 5504 biopsies met inclusion criteria. The proportion of patients developing hematoma after biopsy was between 11% (95% confidence interval, 7% to 17%) and 18% (95% confidence interval, 9% to 35%) using two analyses that included different time periods. The proportion needing blood transfusion was 0.9% (95% confidence interval, 0.5% to 1.4%). The proportion needing an additional intervention due to postbiopsy complication was 0.7% (95% confidence interval, 0.4% to 1.1%). Secondary analysis was not possible due to lack of data in the original manuscripts on laboratory values, needle gauges, number of needle passes, age of patient, or performer (attending versus trainee). Analysis with metaregression found that use of real-time ultrasound during biopsy did not modify the risk for hematoma, requirement of a blood products transfusion, or requirement of an additional procedure after biopsy. Analysis with metaregression comparing native biopsies with transplant biopsies did not reveal that biopsy type (native kidney biopsy versus transplant kidney biopsy) was associated with the need for a blood transfusion or requirement of an additional intervention after biopsy. CONCLUSIONS: The development of perinephric hematoma after kidney biopsy is not an infrequent finding. The proportion of patients requiring blood transfusion or needing an additional intervention as a result of kidney biopsy in pediatric patients is significantly smaller. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2018_12_06_CJASNPodcast_19_01_.mp3. PMID- 30522996 TI - Incretins and cancer of the bile duct in type 2 diabetes. PMID- 30522998 TI - Seven days in medicine: 28 November to 4 December 2018. PMID- 30522997 TI - A young woman with fever and loss of consciousness. PMID- 30522999 TI - Evaluating patient and public involvement in research. PMID- 30523001 TI - Augmenting CAR T Cells with PD-1 Blockade. AB - For patients with B-cell malignancies who experience poor initial responses to chimeric antigen receptor T-cell therapy, the addition of immune checkpoint blockade may prove beneficial, according to clinical reports presented at the 2018 American Society of Hematology Annual Meeting. PMID- 30523000 TI - Doctors from ethnic minority backgrounds earn less than white colleagues. PMID- 30523002 TI - Personalized Medicine Applied to AML. AB - In the Beat AML Master Trial, researchers are genomically sequencing patients newly diagnosed with acute myeloid leukemia, and using the results to assign therapies. The approach, which has identified several promising treatments, demonstrates how personalized medicine can be applied in a clinical setting. PMID- 30523003 TI - Age-Dependency of Blood-Brain Barrier Penetration by cis- and trans-Permethrin in the Rat. AB - Permethrin (PER), a Type I pyrethroid, is the most widely used insecticide in domestic settings in the U.S. The overall objective of this study was to assess the efficiency of the blood-brain barrier (BBB) as an obstacle to the cis (CIS) and trans (TRANS) isomers of PER, and to determine whether its barrier function changes during maturation of the rat. Experiments were conducted to quantify brain uptake of CIS and TRANS in postnatal day (PND) 14, 21 and 90 Sprague-Dawley rats. The common carotid artery of anesthetized rats was perfused for 2 or 4 min with 1, 10 or 50 MUM 14C-CIS or 14C-TRANS in 4% albumin. Brain deposition of each isomer was inversely related to age, with levels in the youngest animals >5 times those in adults. Brain uptake was linear over the 50-fold range of pyrethroid concentrations, indicative of passive, non-saturable BBB permeation. The extent of uptake of toxicologically-relevant concentrations of CIS and TRANS was quite similar. Thus, dissimilar BBB permeation does not contribute to the greater acute neurotoxic potency of CIS, but greater permeability of the immature BBB to CIS and TRANS may contribute to the increased susceptibility of pre-weanling rodents to the insecticides. PMID- 30523004 TI - Mental Health Act must be updated to give patients power over care, says review. PMID- 30523005 TI - Helen Salisbury: The third presence. PMID- 30523006 TI - Acute Management of Upper Gastrointestinal Bleeding. PMID- 30523007 TI - Interoperability of Infusion Pumps With Electronic Health Records. PMID- 30523008 TI - Boot Camp for Caregivers of Children With Medically Complex Conditions. AB - BACKGROUND: The safe transition of children with complex medical conditions who are dependent on technology from hospital to home requires that caregivers receive specialized training from qualified health care professionals. Inadequate caregiver training can lead to discharge delays and hospital readmissions, often resulting in caregiver distress. OBJECTIVE: To determine the effectiveness of a structured boot camp-style predischarge training program for caregivers of pediatric patients with complex medical conditions. METHODS: We conducted a quasi experimental interventional study to compare outcomes before and after implementation of the training program, which involved 34 caregivers. Pre-boot camp data were collected retrospectively from the medical records of 34 control patients. RESULTS: After program implementation, statistically significant decreases were found in mean unit length of stay (92 vs 60 days; P = .02), mean discharge training days (60 vs 16 days; P < .001), and median total parental stress score, expressed as a percentile (49 vs 45; P < .001). More than 90% of caregiver participants were very satisfied with the program. On the basis of minimal length of stay limits, cost savings were estimated at between $53 300 and $69 900 per patient. CONCLUSION: The results of this study indicate that the training program is a valuable tool to track and verify caregiver education, reduce hospital length of stay, increase caregiver satisfaction, decrease caregiver stress, and reduce medical costs. PMID- 30523009 TI - Advances in Evidence-Based Pulmonary Care. PMID- 30523011 TI - Capnography Monitoring During Procedural Sedation and Analgesia. AB - Procedural sedation is used to alleviate pain and anxiety associated with diagnostic procedures in the acute care setting. Although commonly used, procedural sedation is not without risk. Key to reducing this risk is early identification of risk factors through presedation screening and monitoring during the procedure. Electrocardiogram, respiratory rate, blood pressure, and pulse oximetry commonly are monitored. These parameters do not reliably identify airway and ventilation compromise. Capnography measures exhaled carbon dioxide and provides early identification of airway obstruction and hypoventilation. Capnography is useful in patients receiving supplemental oxygen. In these patients, oxygen desaturation reported by pulse oximetry may lag during episodes of respiratory depression and apnea. Capnography indicates partial pressure of end-tidal carbon dioxide and provides information regarding airway integrity and patterns of ventilation compromise. Implementation of this technology may provide an additional layer of safety, reducing risk of respiratory compromise in patients receiving procedural sedation. PMID- 30523010 TI - Alternative Modes of Mechanical Ventilation. AB - Modern mechanical ventilators are more complex than those first developed in the 1950s. Newer ventilation modes can be difficult to understand and implement clinically, although they provide more treatment options than traditional modes. These newer modes, which can be considered alternative or nontraditional, generally are classified as either volume controlled or pressure controlled. Dual control modes incorporate qualities of pressure-controlled and volume-controlled modes. Some ventilation modes provide variable ventilatory support depending on patient effort and may be classified as closed-loop ventilation modes. Alternative modes of ventilation are tools for lung protection, alveolar recruitment, and ventilator liberation. Understanding the function and application of these alternative modes prior to implementation is essential and is most beneficial for the patient. PMID- 30523012 TI - Acute Respiratory Distress Syndrome and Prone Positioning. AB - Acute respiratory distress syndrome continues to have high morbidity and mortality despite more than 50 years of research. The Berlin definition in 2012 established risk stratification based on degree of hypoxemia and the use of positive end-expiratory pressure. The use of prone positioning as a treatment modality has been studied for more than 40 years, with recent studies showing an improvement in oxygenation and decreased mortality. The studies also provide evidence to support the methodology and length of treatment time. Recent guidelines include several ventilator strategies for acute respiratory distress syndrome, including prone positioning. Protocols and procedures discussed in this article ensure successful prone repositioning and prevention of complications related to the procedure itself. PMID- 30523013 TI - Reducing Tracheostomy-Related Pressure Injuries. AB - An interprofessional team was established to prevent tracheostomy-related acquired pressure injuries. The team performed an in-depth analysis of practice from tracheostomy insertion through postinsertion care. A literature evaluation identified best practices, and a root cause analysis for all tracheostomy-related pressure injury cases identified common causes. Lessons learned from the practice and literature reviews drove care standardization and reduced variation. Preimplementation and postimplementation data were analyzed to determine the effectiveness of improvement interventions. Improvement strategies included use of a more flexible tracheostomy tube, standardization of suturing, timing of suture removal, application of a hydrocolloid dressing at time of insertion and a foam dressing after suture removal, and caregiver education regarding early identification of and interventions for complications related to sutures and swelling. The result has been an 80% reduction of tracheostomy-related acquired pressure injuries systemwide. PMID- 30523014 TI - Tunneled Pleural Catheter: Treatment for Recurrent Pleural Effusion. AB - Recurrent pleural effusion is a symptom of several end-stage diseases and is associated with limited life expectancy. Patients with this condition have disabling symptoms resulting in reduced quality of life and often receive inconsistent treatment due to delayed recognition of pleural effusion, repeat procedures, and lengthy hospitalizations. Placement of a tunneled pleural catheter allows the patient to manage his or her symptoms at home, yet this treatment remains underused because of provider misconceptions and unfamiliarity with the intervention. This article provides an overview of the indications for placement of a tunneled pleural catheter, possible complications, and management strategies, and introduces evidence-based clinical decision support tools to enhance provider knowledge. In addition, the article describes the implementation and evaluation of a performance improvement initiative on the use of tunneled pleural catheters in a multifaceted health care system. PMID- 30523015 TI - Peer Reviewers for 2018. PMID- 30523016 TI - Call For Papers. PMID- 30523017 TI - Application of Hotspotting in Acute Care Settings. PMID- 30523018 TI - Silence: A Never Event. PMID- 30523019 TI - Partha Kar: Stan Lee's lessons for the NHS. PMID- 30523020 TI - New health standards aim to improve care of homeless people. PMID- 30523021 TI - NK cell infiltrates and HLA class I expression in primary HER2+ breast cancer predict and uncouple pathological response and disease-free survival. AB - PURPOSE: We investigated the value of tumor-infiltrating NK cells (TI-NK) and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer. EXPERIMENTAL DESIGN: TI-NK cells and HLA-I were determined by immunohistochemistry in pre-treatment tumor biopsies from two cohorts of HER2-positive breast cancer patients [discovery cohort (n=42) and validation cohort (n=71)]. TIL were scored according to international guidelines. Biomarker association with pathological complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune-cell populations concomitant to NK cell enrichment in HER2-positive tumors from the TCGA (n=190). RESULTS: TI NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (p<0.0001), independently of clinicopathological factors. A >=3 TI-NK cells/50xHPF cut off predicted pCR in the discovery and validation cohort [OR 188 (11-3154); OR 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR 0.07 (0.01-0.6), p=0.01; HR 0.3 (0.08-1.3), p=0.1]. NK-, activated dendritic- and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective anti-tumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR. CONCLUSIONS: This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR. PMID- 30523022 TI - Molecular subtype not immune response drives outcomes in endometrial carcinoma. AB - PURPOSE: Tumors with high mutation load are thought to engender stronger immune responses which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TIL) and immunosuppressive factors across the four molecular subtypes of endometrial cancer (EC), which have characteristic mutation rates ranging from low to ultra-high. EXPERIMENTAL DESIGN: 460 ECs were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into four molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wildtype (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex immunohistochemistry and tested for associations with ProMisE subtype, survival, and other clinicopathological parameters. RESULTS: Two major TIL patterns were observed. TIL high tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE); however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TIL low tumors were generally devoid of immunological features and more prevalent in p53abn and p53wt ECs, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, TIL clusters, only ProMisE showed independent prognostic significance. CONCLUSIONS: Immune response correlates with EC molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within EC molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy. PMID- 30523023 TI - Keratinocyte Carcinomas: Current concepts and future research priorities. AB - Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are keratinocyte carcinomas (KC), the most frequently diagnosed cancers in fair skinned populations. Ultraviolet radiation (UVR) is the main driving carcinogen for these tumors but immunosuppression, pigmentary factors, and aging are also risk factors. Scientific discoveries have improved the understanding of the role of human papillomaviruses (HPV) in cSCC as well as the skin microbiome and a compromised immune system in the development of both cSCC and BCC. Genomic analyses have uncovered genetic risk variants, high-risk susceptibility genes, and somatic events that underlie common pathways important in KC tumorigenesis and tumor characteristics which have enabled development of prediction models for early identification of high-risk individuals. Advances in chemoprevention in high-risk individuals and progress in targeted and immune-based treatment approaches have the potential to decrease the morbidity and mortality associated with these tumors. As the incidence and prevalence of KC continue to increase, strategies for prevention, including effective sun protective behavior, educational interventions and reduction of tanning bed access and usage are essential. Gaps in our knowledge requiring additional research in order to reduce the high morbidity and costs associated with KC include better understanding of factors leading to more aggressive tumors, the roles of microbiome and HPV infection, prediction of response to therapies including immune checkpoint blockade, and how to tailor both prevention and treatment to individual risk factors and needs. PMID- 30523024 TI - Peripheral Mechanisms Mediating the Sustained Anti-Diabetic Action of FGF1 in the Brain. AB - We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we employed the Zucker diabetic fatty fa/fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic beta-cell function after hyperglycemia onset. We report that while icv injection of FGF1 delays the onset of beta-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. Based on our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by a ~2-fold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of beta-cell function and stimulation of HGU via increased hepatic glucokinase activity. PMID- 30523025 TI - PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity. AB - Mitochondria-associated ER membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that pyruvate dehydrogenase kinase 4 (PDK4) interacts with and stabilizes IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction and ER stress. Furthermore, Pdk4-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation. PMID- 30523026 TI - FoxO Transcription Factors are Critical Regulators of Diabetes-Related Muscle Atrophy. AB - Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are suppressed by insulin and thus are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with muscle-specific triple knockout of FoxO1/3/4 and induced diabetes in these M FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitin-proteasome degradation and autophagy alterations, characterized by increased LC3 containing vesicles, and elevated levels of p-ULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ-FoxO TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from type 1 diabetics after short-term insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes. PMID- 30523027 TI - Multimodal Imaging of the Initial Stages of Diabetic Retinopathy. Different Disease Pathways in Different Patients. AB - To evaluate the prevalence of different disease pathways (ischemia, neurodegeneration and edema) in the initial stages of diabetic retinopathy (DR).In this retrospective cross-sectional study, eyes were grouped by DR severity using the 7-field ETDRS protocol (levels 10-20, 35 and 43-47). Neurodegeneration was identified by thinning of the retinal nerve fiber layer (RNFL) and/or ganglion cell layer (GCL). Edema was identified by thickening of the inner nuclear layer (INL), outer plexiform layer (OPL), or full retina. Ischemia was identified by metrics of retinal vessel density.142 eyes from 142 patients (28% women) aged 52-88 years were imaged. Vessel density (ischemia) was significantly different between ETDRS groups (p<0.020). On multivariate regression analysis, it remained significantly different between stages of the disease and showed associations with age (p<0.001), gender (p=0.028) and metabolic control (p=0.034). No significant differences between ETDRS groups were found in retinal thinning (neurodegeneration) or retinal thickness (edema). Eyes with the same ETDRS retinopathy grading from different diabetic patients show that the prevalence of different disease pathways, varies between patients even within the same severity group.Ischemia (capillary dropout) is the only disease pathway that shows correlation with retinopathy severity and metabolic control. PMID- 30523028 TI - Identification of Specific MicroRNAs in Neutrophils of type 2 Diabetic Mice: Overexpression of microRNA-129-2-3p Accelerates Diabetic Wound Healing. AB - Neutrophils are involved in the first stage of acute inflammation. Following injury, they are mobilized and recruited to the injured tissue. In diabetes, wound healing is delayed and aberrant, leading to excessive recruitment and retention of neutrophils that fail to promote angiogenesis and prolong inflammation. However, the exact pathological mechanisms of diabetic-derived neutrophils in chronic inflammation remain unclear. Here, microRNA (miRNA) profiling of neutrophils from bone marrow in type 2 diabetic mice was performed using a microarray. miRNAs regulate the post-transcriptional expression of target mRNAs and are important in countering inflammation-related diseases. Our study revealed that miRNAs exhibited differential expression in diabetic-derived neutrophils compared with non-diabetic-derived neutrophils, especially miR-129 family members. miR-129-2-3p directly regulated the translation of Casp6 and Ccr2, which are involved in inflammatory responses and apoptosis. Furthermore, miR-129-2-3p overexpression at the wound site of type 2 diabetic mice accelerated wound healing. These results suggest possible involvement of miR-129-2-3p in diabetic-derived neutrophil dysfunction and that retention kinetics of neutrophils and chronic inflammation may be initiated via miR-129-2-3p-regulated genes. This study characterized changes in global miRNA expression in diabetic derived neutrophils and systematically identified critical target genes involved in certain biological processes related to the pathology of diabetic wound healing. PMID- 30523029 TI - Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL. AB - OBJECTIVE: The sodium-glucose cotransporter 2 inhibitors (SGLT2is) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of EXSCEL to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole. RESEARCH DESIGN AND METHODS: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2is at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. RESULTS: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25 1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 m2 per year). CONCLUSIONS: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline. PMID- 30523030 TI - Participating in Mental, Social, and Physical Leisure Activities and Having a Rich Social Network Reduce the Incidence of Diabetes-Related Dementia in a Cohort of Swedish Older Adults. AB - OBJECTIVE: The effect of a healthy lifestyle on diabetes-related dementia remains unknown. We examined whether an active lifestyle and rich social network may counteract the increased risk of dementia in people with diabetes. RESEARCH DESIGN AND METHODS: Dementia-free older adults from the Swedish National Study on Aging and Care in Kungsholmen (n = 2,650) were followed up for 10 years. Diabetes was ascertained on the basis of medical history, medication use, medical records, or glycated hemoglobin (HbA1c) >=6.5% and prediabetes as HbA1c between 5.7 and 6.5%. Dementia was diagnosed by specialists following standard criteria. An active lifestyle was defined as a moderate to high (vs. low) level of engagement in leisure activities or a rich social network (having moderate to rich [vs. poor] social connections and support). Hazard ratios (HRs) of dementia risk were derived from Cox regression models. RESULTS: There were 246 incident dementia cases during follow-up. Those with diabetes (n = 243), but not those with prediabetes (n = 921), had greater risk of dementia (adjusted HR 2.0 [95% CI 1.4 2.9]) than diabetes-free participants. Participants with diabetes but low level of engagement in leisure activities (HR 4.2 [95% CI 2.2-8.2]) or a poor social network (HR 3.4 [95% CI 1.9-6.1]) had greater dementia risk than diabetes-free participants with moderate to high levels of leisure activity engagement or a moderate to rich social network. In participants with diabetes, an active lifestyle (high level of engagement in leisure activities or a rich social network) was associated with less of a raised risk (HR 1.9 [95% CI 1.1-3.4]). CONCLUSIONS: An active and socially integrated lifestyle may significantly counteract the detrimental effect of diabetes on dementia risk. PMID- 30523031 TI - General and Abdominal Obesity and Incident Distal Sensorimotor Polyneuropathy: Insights Into Inflammatory Biomarkers as Potential Mediators in the KORA F4/FF4 Cohort. AB - OBJECTIVE: To investigate the associations between different anthropometric measurements and development of distal sensorimotor polyneuropathy (DSPN) considering interaction effects with prediabetes/diabetes and to evaluate subclinical inflammation as a potential mediator. RESEARCH DESIGN AND METHODS: This study was conducted among 513 participants from the Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort (aged 62-81 years). Anthropometry was measured at baseline. Incident DSPN was defined by neuropathic impairments using the Michigan Neuropathy Screening Instrument at baseline and follow-up. Associations between anthropometric measurements and DSPN were estimated by multivariable logistic regression. Potential differences by diabetes status were assessed using interaction terms. Mediation analysis was conducted to determine the mediation effect of subclinical inflammation in these associations. RESULTS: After a mean follow-up of 6.5 years, 127 cases with incident DSPN were detected. Both general and abdominal obesity were associated with development of DSPN. The odds ratios (95% CI) of DSPN were 3.06 (1.57; 5.97) for overweight, 3.47 (1.72; 7.00) for obesity (reference: normal BMI), and 1.22 (1.07; 1.38) for 5-cm differences in waist circumference, respectively. Interaction analyses did not indicate any differences by diabetes status. Two chemokines (C-C motif chemokine ligand 7 [CCL7] and C-X-C motif chemokine ligand 10 [CXCL10]) and one neuron-specific marker (Delta/Notch-like epidermal growth factor related receptor [DNER]) were identified as potential mediators, which explained a proportion of the total effect up to 11% per biomarker. CONCLUSIONS: General and abdominal obesity were associated with incident DSPN among individuals with and without diabetes, and this association was partly mediated by inflammatory markers. However, further mechanisms and biomarkers should be investigated as additional mediators to explain the remainder of this association. PMID- 30523032 TI - Insulin Clearance After Oral and Intravenous Glucose Post-Gastric Bypass and Gastric Banding Weight Loss. AB - OBJECTIVE: Hepatic insulin clearance is a significant regulator of glucose homestasis. We hypothesized that the improvement in insulin clearance rates (ICRs) under fasting conditions and in response to oral and intravenous (IV) glucose would improve similarly after Roux-en-Y gastric bypass (RYGB) and adjustable gastric banding (AGB) as a function of weight loss; the difference in ICR after oral and IV glucose stimulation will be enhanced after RYGB compared with AGB, an effect mediated by glucagon-like peptide 1 (GLP-1). RESEARCH DESIGN AND METHODS: In study 1, the ICR was calculated under fasting condition (F-ICR), after oral glucose (O-ICR), and after an isoglycemic IV glucose clamp (IV-ICR) in individuals from an established cohort with type 2 diabetes mellitus (T2DM) before, after 10% matched weight loss, and 1 year after either RYGB (n = 22) or AGB (n = 12). In study 2, O-ICR was studied in a separate cohort of individuals with T2DM (n = 22), before and 3 months after RYGB, with and without exendin9-39 infusion. RESULTS: In study 1, age, BMI, T2DM duration and control, and ICR did not differ between RYGB and AGB preintervention. Weight loss at 1 year was two times greater after RYGB than after AGB (31.6 +/- 5.9% vs. 16.6 +/- 9.8%; P < 0.05). RYGB and AGB both significantly increased F-ICR, O-ICR, and IV-ICR at 1 year. ICR was inversely associated with insulinemia. The difference between IV ICR and O-ICR was significantly greater after RYGB versus AGB. GLP-1 antagonism with exendin9-39 led to an increase in O-ICR in subjects post-RYGB. CONCLUSIONS: Weight loss increased ICR, an effect more pronounced after RYGB compared with AGB. Our data support a potential role for endogenous GLP-1 in the control of postprandial ICR after RYGB. PMID- 30523033 TI - Retinopathy and RAAS Activation: Results From the Canadian Study of Longevity in Type 1 Diabetes. AB - OBJECTIVE: The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long standing (>=50 years duration) type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. RESULTS: Twelve (16%) of the 75 participants had NDR, 39 (52%) had NPDR, and 24 (32%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. CONCLUSIONS: PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes. PMID- 30523034 TI - Incidence and Determinants of Intraocular Lens Implantation in Type 2 Diabetes: The Fremantle Diabetes Study Phase II. AB - OBJECTIVE: To compare the incidence of intraocular lens (IOL) implantation for cataracts between people with and without type 2 diabetes and to determine associated risk factors in those with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants with type 2 diabetes (n = 1,499) from the community-based observational Fremantle Diabetes Study Phase II (FDS2) were age, sex, and zip code matched 1:4 with residents without diabetes. IOL implantation status was ascertained between entry (2008-2011) and the end of 2016 using validated data linkage. Age-specific incidence rates and incidence rate ratios (IRRs) for cataract surgery were calculated. Predictors of IOL implantation in FDS2 participants were assessed using proportional hazards and competing risk regression modeling. RESULTS: The crude IRR (95% CI) for cataract surgery in FDS2 participants (mean +/- SD age 62.8 +/- 10.8 years at entry) versus the matched group without diabetes was 1.50 (1.32-1.71), with the highest relative risk in those aged 45-54 years at the time of surgery (7.12 [2.05-27.66]). Competing risk analysis showed that age at entry, diabetes duration, serum HDL cholesterol, serum triglycerides, a severe hypoglycemic episode in the past year, and Asian and southern European ethnicity increased the risk of cataract surgery in participants with type 2 diabetes (P <= 0.025). CONCLUSIONS: People with type 2 diabetes, especially those in younger age-groups, are at a significantly increased risk of cataract surgery than matched people without diabetes. Multifaceted prevention strategies should be incorporated as part of routine care. As well as limiting ultraviolet light exposure, these might include lipid modifying treatment and strategies to avoid severe hypoglycemia. PMID- 30523036 TI - Minerva: an alignment and reference free approach to deconvolve linked-reads for metagenomics. AB - Emerging Linked-Read technologies (aka Read-Cloud or barcoded short-reads) have revived interest in short-read technology as a viable way to understand large scale structure in genomes and metagenomes. Linked-Read technologies, such as the 10x Chromium system, use a microfluidic system and a specialized set of 3' barcodes (aka UIDs) to tag short DNA reads sourced from the same long fragment of DNA; subsequently, the tagged reads are sequenced on standard short read platforms. This approach results in interesting compromises. Each long fragment of DNA is only sparsely covered by reads, no information about the ordering of reads from the same fragment is preserved, and 3' barcodes match reads from roughly 2-20 long fragments of DNA. However, compared to long read technologies the cost per base to sequence is far lower, far less input DNA is required, and their base error rate is that of Illumina short-reads.In this paper, we formally describe a particular algorithmic issue common to across Linked-Read technology: the deconvolution of reads with a single 3' barcode into clusters that represent single long fragments of DNA. We introduce Minerva, A graph-based algorithm that approximately solves the barcode deconvolution problem for metagenomic data (where reference genomes may be incomplete or unavailable). Additionally, we develop two demonstrations where the deconvolution of barcoded reads improves downstream results: improving the specificity of taxonomic assignments and improving the specificity of k-mer based clustering. To the best of our knowledge, we are the first to address the problem of barcode deconvolution in metagenomics. PMID- 30523035 TI - Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life. AB - OBJECTIVE: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features). RESEARCH DESIGN AND METHODS: A Markov decision model was developed to estimate incremental costs and quality adjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework. RESULTS: Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%. CONCLUSIONS: Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus. PMID- 30523037 TI - Rapid reversible changes in compartments and local chromatin organization revealed by hyper-osmotic shock. AB - Nuclear architecture is decisive for the assembly of transcriptional responses. However, how chromosome organization is dynamically modulated to permit rapid and transient changes of transcription in response to environmental challenges remains unclear. Here we show that hyper-osmotic stress disrupts different levels of chromosome organization, ranging from A/B compartment changes to reduction in the number and insulation of topologically associating domains (TADs). Concomitantly, transcription is greatly affected, TAD borders weaken, and RNA Polymerase II runs off from hundreds of transcription end sites. Stress alters the binding profiles of architectural proteins, which explains the disappearance of local chromatin organization. These processes are dynamic, and cells rapidly reconstitute their default chromatin conformation after stress removal, uncovering an intrinsic organization. Transcription is not required for local chromatin re-organization while compartment recovery is partially dependent. Thus, nuclear organization in mammalian cells can be rapidly modulated by environmental changes in a reversible manner. PMID- 30523038 TI - Increased IP-10 production by blood-nerve barrier in multifocal acquired demyelinating sensory and motor neuropathy and multifocal motor neuropathy. AB - OBJECTIVE: Dysfunction of the blood-nerve barrier (BNB) plays important roles in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). The aim of the present study was to identify the candidate cytokines/chemokines that cause the breakdown of the BNB using sera from patients with CIDP and MMN. METHODS: We determined the levels of 27 cytokines and chemokines in human peripheral nerve microvascular endothelial cells (PnMECs) after exposure to sera obtained from patients with CIDP variants (typical CIDP and multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]), MMN and amyotrophic lateral sclerosis (ALS), and healthy controls (HC), using a multiplexed fluorescent bead-based immunoassay system. RESULTS: The induced protein (IP)10 level in the cells in both the MADSAM and MMN groups was markedly increased in comparison with the typical CIDP, ALS and HC groups. The other cytokines, including granulocyte colony-stimulating factor,vascular endothelial growth factor (VEGF) and interleukin-7, were also significantly upregulated in the MADSAM group. The increase of IP-10 produced by PnMECs was correlated with the presence of conduction block in both the MADSAM and MMN groups. CONCLUSION: The autocrine secretion of IP-10 induced by patient sera in PnMECs was markedly upregulated in both the MADSAM and MMN groups. The overproduction of IP-10 by PnMECs leads to the focal breakdown of the BNB and may help to mediate the transfer of pathogenic T cells across the BNB, thereby resulting in the appearance of conduction block in electrophysiological studies of patients with MADSAM and MMN. PMID- 30523040 TI - Health gains make actions to curb climate change cost neutral, says WHO. PMID- 30523039 TI - The ColoCare Study - A paradigm of transdisciplinary science in colorectal cancer outcomes. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death. Biomarkers to predict treatment outcomes are needed, as is evidence whether post diagnosis diet and lifestyle can affect well-being and clinical outcomes. The international ColoCare Consortium aims to identify new biologic markers (e.g., metabolomic, transcriptomic, metagenomic, genetic, epigenetic, proteomic) that predict clinical outcomes, and to characterize associations between modifiable risk factors (e.g., diet, supplement use, physical activity) with short-term and long-term patient-reported and clinical outcomes among CRC patients. METHODS/RESULTS: ColoCare is recruiting newly diagnosed CRC patients across six sites in the U.S. and one in Germany. As of April 2018 we have recruited >2,000 patients across all sites. Our projected enrollment is >4,000 multiethnic CRC patients. The study includes uniformly collected, comprehensive sets of data and biospecimens at multiple time points up to 5 years after diagnosis. Treatment and clinical data are abstracted from medical records and centrally harmonized. Biospecimens are archived according to standardized procedures. Our initial studies demonstrated metabolic differences in adipose tissue types. We further reported on associations of biological factors (e.g., inflammation, DNA methylation, metabolomics) with lifestyle factors (e.g., adiposity, smoking, physical activity, dietary supplement use) or joint associations with clinical outcomes. CONCLUSION: ColoCare is a consortium for the investigation of multi level factors relevant to CRC survivorship. IMPACT: The combination of a comprehensive set of biospecimens collected at multiple time points, jointly with detailed assessments of health behaviors and other prognostic factors, results in a unique resource that facilitates wide-ranging, innovative, and impactful research on CRC. PMID- 30523041 TI - Automated profiling of growth cone heterogeneity defines relations between morphology and motility. AB - Growth cones are complex, motile structures at the tip of an outgrowing neurite. They often exhibit a high density of filopodia (thin actin bundles), which complicates the unbiased quantification of their morphologies by software. Contemporary image processing methods require extensive tuning of segmentation parameters, require significant manual curation, and are often not sufficiently adaptable to capture morphology changes associated with switches in regulatory signals. To overcome these limitations, we developed Growth Cone Analyzer (GCA). GCA is designed to quantify growth cone morphodynamics from time-lapse sequences imaged both in vitro and in vivo, but is sufficiently generic that it may be applied to nonneuronal cellular structures. We demonstrate the adaptability of GCA through the analysis of growth cone morphological variation and its relation to motility in both an unperturbed system and in the context of modified Rho GTPase signaling. We find that perturbations inducing similar changes in neurite length exhibit underappreciated phenotypic nuance at the scale of the growth cone. PMID- 30523042 TI - From ED overcrowding to jail overcrowding: a cautionary tale of a Serial Inebriate Programme (SIP). AB - INTRODUCTION: Community-based programmes have been implemented to curtail ED use by individuals with chronic public intoxication. Among these programmes is the Serial Inebriate Programme (SIP), which aims to reduce use of ED and emergency medical services. We present the results of an evaluation of the SIP in Santa Cruz, California, including data on the participants' police and jail history, information not considered in prior analyses of SIPs. METHODS: In the present study, we used a retrospective cohort to evaluate the effectiveness of the SIP in Santa Cruz, California from 2013 to 2015. Specifically, we looked at the programme effects on participants' arrests, nights in jail, use of the local ED and ambulance services after programme adjudication. RESULTS: The median number of visits to the ED for participants before and after adjudication was reduced from 4 to 1, and participants showed a significant decrease in their number of jail bookings following adjudication (-4.5 bookings; p=0.004). However, the average number of nights in jail served by participants after adjudication was 2.1 times the average number of nights spent in jail spent before programme adjudication (58.5 vs 27.6 nights in jail for postadjudication and preadjudication groups, respectively; p=0.009). CONCLUSIONS: Our findings suggest that the Santa Cruz SIP had some impact in reducing participants' use of emergency services, but at the cost of increased jail time. The burdens of placing chronically intoxicated individuals in jail for extended periods of time are not trivial and should not be overlooked when designing and implementing a SIP. PMID- 30523043 TI - High field metabolic rates of wild harbour porpoises. AB - Reliable estimates of field metabolic rates (FMRs) in wild animals are essential for quantifying their ecological roles, as well as for evaluating fitness consequences of anthropogenic disturbances. Yet, standard methods for measuring FMR are difficult to use on free-ranging cetaceans whose FMR may deviate substantially from scaling predictions using terrestrial mammals. Harbour porpoises (Phocoena phocoena) are among the smallest marine mammals, and yet they live in cold, high-latitude waters where their high surface-to-volume ratio suggests high FMRs to stay warm. However, published FMR estimates of harbour porpoises are contradictory, with some studies claiming high FMRs and others concluding that the energetic requirements of porpoises resemble those of similar sized terrestrial mammals. Here, we address this controversy using data from a combination of captive and wild porpoises to estimate the FMR of wild porpoises. We show that FMRs of harbour porpoises are up to two times greater than for similar-sized terrestrial mammals, supporting the hypothesis that small, carnivorous marine mammals in cold water have elevated FMRs. Despite the potential cost of thermoregulation in colder water, harbour porpoise FMRs are stable over seasonally changing water temperatures. Varying heat loss seems to be managed via cyclical fluctuations in energy intake, which serve to build up a blubber layer that largely offsets the extra costs of thermoregulation during winter. Such high FMRs are consistent with the recently reported high feeding rates of wild porpoises and highlight concerns about the potential impact of human activities on individual fitness and population dynamics. PMID- 30523044 TI - Intraocular pressure change after injection of intravitreal dexamethasone (Ozurdex) implant in Korean patients. AB - BACKGROUND/AIMS: To analyse intraocular pressure (IOP) changes over a period of 1 year after intravitreal dexamethasone (DEX, Ozurdex) implant injection and to compare the results with those of previously published studies that involved non Asian populations. METHODS: A retrospective observational study was conducted. A total of 540 eyes of 503 patients who received DEX implant injection and were diagnosed with macular oedema (ME) due to various retinal diseases were examined. IOP was measured prior to injection and at 1 week, 1 month, 2 months, 3 months, 6 months and 12 months after DEX implant injection. IOP elevation was divided into four categories: postinjection IOP of >35 mm Hg, >30 mm Hg and >25 mm Hg, and an IOP elevation of >10 mm Hg, relative to the baseline measurement. RESULTS: The mean baseline IOP was 13.45+/-2.95. The mean IOP gradually increased until 2 months postinjection (IOP=16.85+/-5.96 mm Hg, p<0.001) and then gradually decreased until 12 months postinjection (IOP=13.80+/-4.04mm Hg, p=0.16). IOP was >25 mm Hg in 57 eyes (10.6%), >30mm Hg in 29 eyes (5.4%) and >35mm Hg in 9 eyes (1.7%); IOP exhibited >10 mm Hg elevation from the baseline IOP in 61 eyes (11.3%). Overall, the incidence rate of IOP elevation after DEX treatment was 12.6% (68 eyes). Among the 68 eyes (12.6%) with elevated IOP, 60 (11.1%) required treatment: 59 (10.9%) required IOP-lowering medication and 1 (0.2%) ultimately required surgical interventions. CONCLUSIONS: The incidence of adverse IOP elevation requiring the prolonged use of IOP-lowering medication and surgical intervention after DEX implantation was significantly lower than the incidence reported in previous Western population-based studies. Intravitreal DEX injection may therefore be an effective and relatively safe treatment modality for ME in Asian patients. PMID- 30523045 TI - Combination of multimodal imaging features predictive of choroidal nevus transformation into melanoma. AB - AIM: To characterise combinations of multimodal imaging risk factors and predictive value for choroidal nevus transformation into melanoma. METHODS: This is a retrospective review of multimodal imaging features for 3806 choroidal nevi from 1 January 2007 through 1 January 2017. Kaplan-Meier estimates and Cox regression analyses were used to calculate 5-year percentages of growth to melanoma and HR. RESULTS: Using multimodal imaging, six risk factors predictive of choroidal nevus transformation into melanoma were identified, namely tumour thickness >2 mm, subretinal fluid, symptoms of visual acuity loss to 20/50 or worse, orange pigment, hollow acoustic density and tumour largest basal diameter >5 mm. Kaplan-Meier 5-year estimated tumour growth was found in 1% of nevi with no risk factors, 11% (range 9%-37%) with one factor, 22% (12%-68%) with two factors, 34% (21%-100%) with three factors, 51% (0%-100%) with four factors and 55% (0%-100%) with five factors. HR for growth was 0.1 with no factor, 2.1-7.8 with one factor, 1.8-12.1 with two factors, 4.0-24.4 with three factors, 4.6 170.0 with four factors and 12.0-595.0 with five factors. The highest HR with each combination of two, three, four or five risk factors always included symptoms of visual acuity loss and orange pigment. CONCLUSION: Six risk factors for choroidal nevus transformation into melanoma by multimodal imaging have been identified. Risk for transformation into melanoma is 1% when no factors are present, and approaches 100% with specific combinations of three or more risk factors. Understanding how combinations of factors influence risk of transformation into melanoma can guide counselling and treatment decisions. PMID- 30523046 TI - GPR120 protects lipotoxicity-induced pancreatic beta-cell dysfunction through regulation of PDX1 expression and inhibition of islet inflammation. AB - G-protein coupled receptor 120 (GPR120) has been shown to act as an omega-3 unsaturated fatty acid sensor and is involved in insulin secretion. However, the underlying mechanism in pancreatic beta cells remains unclear. To explore the potential link between GPR120 and beta-cell function, its agonist DHA and GSK137647AS were used in palmitic acid (PA)-induced pancreatic beats-cell dysfunction, coupled with GPR120 KD in MIN6 cells and GPR120 KO mice to identify the underlying signalling pathways. In vitro and ex vivo treatments of MIN6 cells and islets isolated from WT mice with DH and GSK restored pancreatic PDX1 expression levels and beta-cell function via PA-induced elevation of proinflammatory chemokine and activation of NF-kB, JNK and p38MAPK signalling pathways. On the contrary, these GPR120 agonism-mediated protective effects were abolished in GPR120 KD cells and islets from GPR120 KO mice. Furthermore, GPR120 KO mice displayed glucose intolerance and insulin resistance relative to WT littermate, and beta-cell functional related genes were decreased while inflammation was exacerbated in islets with increased macrophages in pancreas from GPR120 KO mice. DHA and GSK supplementation ameliorated glucose tolerance and insulin sensitivity, as well as improved pdx1 expression and islet inflammation in diet-induced obese WT mice, but not in GPR120 KO mice. These findings indicate that GPR120 activation is protective and against lipotoxicity indcued pancreatic beta-cell dysfunction, via the mediation of PDX1 expression and inhibition of islet inflammation, and that GPR120 activation may serve as a preventative and therapeutic target for obesity and diabetes. PMID- 30523047 TI - First identification of PODXL nonsense mutations in autosomal dominant focal segmental glomerulosclerosis. AB - Recently, a novel heterozygous missense mutation c.T1421G (p. L474R) in the PODXL gene encoding podocalyxin, was identified in an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. However, this PODXL mutation appeared not to impair podocalyxin function and it is necessary to identify new PODXL mutations and determine their causative role for FSGS. In this study, we report the identification of a heterozygous nonsense PODXL mutations (Arg326X) in a Chinese pedigree featured by proteinuria and renal insufficiency with AD inheritance by whole exome sequencing (WES). Total mRNA and PODXL protein abundance were decreased in available peripheral blood cell samples of two affected patients undergoing hemodialysis, compared to those in healthy controls and hemodialysis controls without PODXL mutation. We identified another novel PODXL heterozygous nonsense mutation (c.C1133G; p.Ser378X) in a British-Indian pedigree of AD-FSGS by WES. In vitro study showed that, human embryonic kidney (HEK) 293T cells transfected with the pEGFP-PODXL-Arg326X or pEGFP-PODXL-Ser378X plasmid expressed significantly lower mRNA and PODXL protein compared to cells transfected with the wild-type plasmid. Blocking nonsense-mediated mRNA decay (NMD) significantly restored the amount of mutant mRNA and PODXL proteins, which indicated that the pathogenic effect of PODXL nonsense mutations is likely due to NMD, resulting in podocalyxin deficiency. Functional consequences caused by the PODXL nonsense mutations were inferred by siRNA knockdown in cultured podocytes and podocalyxin downregulation by siRNA resulted in decreased RhoA and ezrin activities, cell migration and stress fiber formation. Our results provided new data implicating heterozygous PODXL nonsense mutations in the development of FSGS. PMID- 30523048 TI - KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations. AB - Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75- (CD34+) and CD34-p75- (CD34-) tumor subpopulations were characterized as melanoma-propagating cells (MPCs) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemo-resistance. In this study, we demonstrate that CD34+ and CD34- subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift towards a more drug-tolerant, CD34- state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor-sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key melanoma-propagating cell subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma. PMID- 30523049 TI - Genome-wide sequencing of cell-free DNA identifies copy number alterations that can be used for monitoring response to immunotherapy in cancer patients. AB - Inhibitors of the PD-1/PD-L1/CTLA4 immune checkpoint pathway have revolutionized cancer treatment. Indeed, some patients with advanced, refractory malignancies achieve durable responses; however, only a subset of patients benefit, necessitating new biomarkers to predict outcome. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising method for monitoring response. We describe the use of low-coverage, genome-wide sequencing of cfDNA, validated extensively for non-invasive prenatal testing (NIPT), to detect tumor-specific copy number alterations, and the development of a new metric--the genome instability number (GIN)--to monitor response to these drugs. We demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease. Finally, we provide evidence for delayed kinetics in responses to checkpoint inhibitors relative to molecularly targeted therapies. Overall, these data demonstrate a proof of concept for using this method for monitoring treatment outcome in patients with cancer receiving immunotherapy. PMID- 30523050 TI - The secretome engages STAT3 to favor a cytokine-rich microenvironment in mediating acquired resistance to FGFR inhibitors. AB - Acquired resistance severely hinders the application of small molecule inhibitors. Our understanding of acquired resistance related to fibroblast growth factor receptors (FGFRs) is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFR inhibitors. The secretome drives acquired resistance by activating the transcription factor STAT3 via its cognate receptors. Moreover, macrophages and fibroblasts could interact with cancer cells to enhance acquired resistance by promoting exaggerated and dynamic cytokine secretion, as well as STAT3 activation. We also found that Hsp90 and HDAC inhibitors could substantially and simultaneously suppress the proliferation of resistant cells, the secretion of multiple cytokines and the activation of STAT3. Our study offers translational insights concerning the poor efficacy observed in patients with macrophage- and fibroblast-rich lung cancers and breast tumors after treatment with FGFR inhibitors in clinical trials. PMID- 30523051 TI - Hemodynamic provocation with acetazolamide shows impaired cerebrovascular reserve in adults with sickle cell disease. AB - Sickle cell disease is characterized by chronic hemolytic anemia and vascular inflammation, which can diminish the vasodilatory capacity of the small resistance arteries, making them less adept at regulating cerebral blood flow. Autoregulation maintains adequate oxygen delivery, but when vasodilation is maximized, the low arterial oxygen content can lead to ischemia and silent cerebral infarcts. We used magnetic resonance imaging of cerebral blood flow to quantify whole-brain cerebrovascular reserve in 36 adult patients with sickle cell disease (mean age, 31.9 +/- 11.3 years) and 11 healthy controls (mean age, 37.4 +/- 15.4 years), and we used high-resolution 3D FLAIR magnetic resonance imaging to determine the prevalence of silent cerebral infarcts. Cerebrovascular reserve was calculated as the percentage change in cerebral blood flow after a hemodynamic challenge with acetazolamide. Co-registered lesion maps were used to demonstrate prevalent locations for silent cerebral infarcts. Cerebral blood flow was elevated in patients with sickle cell disease compared to controls (median [interquartile range]: 82.8 [20.1] vs 51.3 [4.8] mL/100g/min, P <0.001). Cerebral blood flow was inversely associated with age, hemoglobin, and fetal hemoglobin, and correlated positively with bilirubin, and LDH, indicating that cerebral blood flow may reflect surrogates of hemolytic rate. Cerebrovascular reserve in sickle cell disease was decreased by half compared to controls (34.1 [33.4] vs 69.5 [32.4] %, P <0.001) and was associated with hemoglobin and erythrocyte count indicating anemia-induced hemodynamic adaptations. 29/36 patients (81%) and 5/11 controls (45%) had silent cerebral infarcts (median volume of 0.34 vs 0.02 mL, P=0.03). Lesions were preferentially located in the borderzone. In conclusion, patients with sickle cell disease have a globally reduced cerebrovascular reserve as determined by arterial spin labeling with acetazolamide and reflects anemia induced impaired vascular function in sickle cell disease. This study was registered at clinicaltrials.gov: NCT02824406. PMID- 30523052 TI - Generation of anti-idiotypic antibodies to detect anti-spacer antibody idiotopes in acute thrombotic thrombocytopenic purpura patients. AB - In autoantibody-mediated autoimmune diseases, autoantibody profiling allows to stratify patients and link autoantibodies with disease severity and outcome. However, in immune-mediated thrombotic thrombocytopenic purpura patients, stratification according to antibody profiles and their clinical relevance has not been fully explored. We aimed at developing a new type of autoantibody profiling assay for immune-mediated thrombotic thrombocytopenic purpura based on the use of anti-idiotypic antibodies. Anti-idiotypic antibodies against 3 anti spacer autoantibodies were generated in mice and were used to capture the respective anti-spacer idiotopes from 151 acute immune-mediated thrombotic thrombocytopenic purpura plasma samples. We next deciphered these anti-spacer idiotope profiles in immune-mediated thrombotic thrombocytopenic purpura patients and investigated if these limited idiotope profiles could be linked with disease severity. We developed 3 anti-idiotypic antibodies that recognized particular idiotopes in the anti-spacer autoantibodies II-1, TTP73 or I-9, that are involved in ADAMTS13 binding. Thirty-five, 24 and 42% of patients were positive for antibodies with the II-1, TTP73 and I-9 idiotopes, respectively. Stratifying patients according to the corresponding 8 anti-spacer idiotope profiles revealed an until now unknown insight into the anti-spacer II-1, TTP73 and I-9 idiotope profiles in these patients. Finally, these limited idiotope profiles showed no association with disease severity. We successfully developed 3 anti-idiotypic antibodies that allowed us to determine the profiles of the anti-spacer II-1, TTP73 and I-9 idiotopes in immune-mediated thrombotic thrombocytopenic purpura patients. Increasing the number of patients and/or future development of additional anti-idiotypic antibodies against other anti-ADAMTS13 autoantibodies might allow to identify idiotope profiles of clinical, prognostic value. PMID- 30523053 TI - Targeting BCL2 with venetoclax is a promising therapeutic strategy for "double protein-expression" lymphoma with MYC and BCL2 rearrangements. AB - Double-hit and double-protein-expression lymphoma with MYC and BCL2 rearrangements is a rare mature B-cell neoplasm characterized by germinal center B-cell phenotype, abundant protein expression of MYC and BCL2, rapid disease progression, and a poor prognosis. In this study, we showed the potential benefit of BCL2 inhibitor venetoclax against this disease. Immunohistochemistry on the lymphoma tissues confirmed that overexpression of MYC and BCL2 was observed more frequently in this subtype than in other germinal center B-cell-like diffuse large B-cell lymphomas. In contrast, another prosurvival protein MCL1 was less expressed in this subtype, even when compared with in non-double-hit and double protein-expression type. Furthermore, in vitro studies using two "double-hit" and double-protein-expression lymphoma-derived cell lines Karpas231 and OCI-Ly8 clearly showed that low concentration of venetoclax but not MCL1 inhibitor S63845 was sufficient to induced apoptosis in the two lines, compared with in other germinal center B-cell-derived cell lines BJAB and SU-DHL10. These results indicate that the survival of this type of lymphoma depends predominantly on BCL2 rather than MCL1. Unexpectedly, we found that venetoclax not only disrupts the interaction between BCL2 and proapoptotic protein BIM, but also leads to dephosphorylation of BCL2 and further downregulated MCL1 protein expression probably through modulation of the protein phosphatase 2A B56alpha activity in Karpas231 and OCI-Ly8. Indeed, low concentration of venetoclax induced substantial apoptosis in the primary lymphoma cells, regardless of high protein expression of MCL1 associated with venetoclax resistance. Venetoclax clearly triggers the signal transduction related to BCL2 and MCL1 in double-hit and double-protein-expression lymphoma cells. PMID- 30523054 TI - Loss of plasmacytoid dendritic cell differentiation is highly predictive for post induction measurable residual disease and inferior outcomes in acute myeloid leukemia. AB - Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia. Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in acute myeloid leukemia is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast to plasmacytoid dendritic cell ratio greater than 10 was strongly associated with inferior overall and relapse-free survival (Hazard ratio 2.79 (95% confidence interval: 0.98-7.97, p=0.077) and 3.83 (95% confidence interval: 1.51-9.74, p=0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio<10) showed a higher rate of measurable residual disease clearance at later pre-transplant time-points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio>=10) (6/12, 50% vs 2/18, 11%, p=0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in acute myeloid leukemia. PMID- 30523055 TI - Impact of Induction Regimen and of Allogeneic Hematopoietic Cell Transplantation on Outcome in Younger Adults Patients with Acute Myeloid Leukemia with a Monosomal Karyotype. AB - Monosomal karyotype (MK) confers a poor prognosis in patients with acute myeloid leukemia (AML). Here, we determined the impact of the type of remission-induction chemotherapy and the impact of having a donor in younger AML patients with a MK included in two phase III trials. In the first trial, patients were randomized to receive either daunorubicin (DNR), mitoxantrone (MTX), or idarubicin (IDA) in addition to standard-dose cytarabine (SDAC) and etoposide for induction chemotherapy. In the second trial, patients were randomized between either SDAC or high dose cytarabine (HiDAC) induction, both with DNR and etoposide. In both trials, patients who achieved a complete remission with (CR) or without (CRi) complete hematological recovery received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a donor or an autologous HSCT (auto-HSCT) otherwise. In comparison to patients with intermediate risk cytogenetics without MK (n=1584) and with adverse cytogenetics without MK (n=218), MK+ patients (n=188) were more likely not to achieve a CR/CRi (odds ratio=2.85, 95% confidence interval, CI: 2.10-3.88) and had shorter overall survival (OS) (hazard ratio, HR=2.44, 95% CI: 2.08-2.88) and OS from CR/CRi (HR=2.73, 95% CI: 2.17-3.45). There was no impact of the type of anthracycline or of SDAC vs HiDAC on outcomes in MK+ patients. Among MK+ patients who achieved a CR/CRi, HLA-identical related donor availability was associated with longer survival from CR/CRi (HR=0.59, 95% CI: 0.37-0.95). In summary, these data suggest no benefit of HiDAC in MK+ patients but better OS associated with allo-HSCT. PMID- 30523056 TI - HLA discrepancy between graft and host rather than that graft and first donor impact the second transplant outcome. AB - Second allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for patients with hematologic malignancies. However, it is unclear whether HLA discrepancy between graft and first donor has an impact on the outcome of second HSCT. We retrospectively analyzed 646 patients receiving second HSCT after an initial HLA mismatched (MM) transplantation. With regard to graft versus host, the one-allele mismatch (1 MM) group (subhazard ratio [SHR], 1.88; 95% CI, 0.79-4.45; p=0.163) and more than one-allele mismatch group (>= 2 MM) (SHR, 1.84; 95% CI, 0.75-4.51; p=0.182) had higher risks of grade III-IV acute GVHD compared to the HLA-matched (0 MM) group. In contrast, no difference in risk of acute GVHD was found among the 0, 1, and >= 2 MM group with respect to graft vs. first donor. With regard to graft vs. host, the >= 2 MM group showed a significantly higher risk of treatment-related mortality (TRM) (SHR, 1.90; 95% CI, 1.04-3.50; p=0.038) compared to the 0 MM group, while the risk of relapse was slightly lower in the >= 2 MM group (SHR, 068; 95% CI, 0.44-1.06; p=0.086). In contrast, with regard to graft vs. first donor, there were no significant differences in TRM or relapse among the three groups. These findings suggested that HLA discrepancy between graft and host induces transplant-related immunological responses in second HSCT leading to an increase in TRM, in contrast, the biological effects of HLA discrepancy between graft and first donor on outcome may be negligible. PMID- 30523057 TI - False-negative Rates for MYC FISH Probes in B-cell Neoplasms. PMID- 30523058 TI - Structural insights into the molecular mechanism underlying Sirt5-catalyzed desuccinylation of histone peptides. AB - Histone modification is a ubiquitous regulatory mechanism involved in a variety of biological processes, including gene expression, DNA damage repair, cell differentiation, and ontogenesis. Succinylation sites on histones have been identified and may have functional consequences. Here, we demonstrate that human sirtuin 5 (Sirt5) catalyzes the sequence-selective desuccinylation of numerous histone succinyl sites. Structural studies of Sirt5 in complex with four succinyl peptides indicate an essential role for the conserved main chain hydrogen bonds formed by the succinyl lysine (0), +1, and +3 sites for substrate-enzyme recognition. Furthermore, biochemical assays reveal that the proline residue at the +1 site of the histone succinylation substrate is unfavorable for Sirt5 interaction. Our findings illustrate the molecular mechanism underlying the sequence-selective desuccinylase activity of Sirt5 and provide insights for further studies of the biological functions associated with histone succinylation and Sirt5. PMID- 30523059 TI - Glycerol-3-phosphate acyltransferases 3 and 4 direct glycerolipid synthesis and affect functionality in activated macrophages. AB - Macrophage classical M1 activation via TLR4 triggers a variety of responses to achieve the elimination of foreign pathogens. During this process, there is also an increase in lipid droplets which contain large quantities of triacylglycerol (TAG) and phospholipid (PL). The functional consequences of this increment in lipid mass are poorly understood. Here we studied the contribution of glycerolipid synthesis to lipid accumulation, focusing specifically on the first and rate-limiting enzyme of the pathway: glycerol-3-phosphate acyltransferase (GPAT). Using bone marrow derived macrophages (BMDM) treated with Kdo2-lipid A (KLA), we showed that glycerolipid synthesis is induced during macrophage activation. GPAT4 protein level and GPAT3/GPAT4 enzymatic activity increase during this process, and these two isoforms were required for the accumulation of cell TAG and PL. The phagocytic capacity of Gpat3-/- and Gpat4-/- BMDM was impaired. Additionally, inhibiting fatty acid beta-oxidation reduced phagocytosis only partially, suggesting that lipid accumulation is not necessary for the energy requirements for phagocytosis. Finally, Gpat4-/- BMDM expressed and released more pro-inflammatory cytokines and chemokines after macrophage activation, suggesting a role for GPAT4 in suppressing inflammatory responses. Together these results provide evidence that glycerolipid synthesis directed by GPAT4 is important for the attenuation of the inflammatory response in activated macrophages. PMID- 30523060 TI - The split protein phosphatase system. AB - Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and phosphatases. Protein kinases are well characterized, but protein phosphatases have been relatively neglected. Protein phosphatase 1 (PP1) catalyzes the dephosphorylation of a major fraction of phospho-serines and phospho-threonines in cells and thereby controls a broad range of cellular processes. In this review, I will discuss how phosphatases were discovered, how the view that they were unselective emerged and how recent findings have revealed their exquisite selectivity. Unlike kinases, PP1 phosphatases are obligatory heteromers composed of a catalytic subunit bound to one (or two) non-catalytic subunit(s). Based on an in-depth study of two holophosphatases, I propose the following: selective dephosphorylation depends on the assembly of two components, the catalytic subunit and the non-catalytic subunit, which serves as a high-affinity substrate receptor. Because functional complementation of the two modules is required to produce a selective holophosphatase, one can consider that they are split enzymes. The non-catalytic subunit was often referred to as a regulatory subunit, but it is, in fact, an essential component of the holoenzyme. In this model, a phosphatase and its array of mostly orphan substrate receptors constitute the split protein phosphatase system. The set of potentially generalizable principles outlined in this review may facilitate the study of these poorly understood enzymes and the identification of their physiological substrates. PMID- 30523061 TI - Protective effects of duloxetine against cerebral ischemia-reperfusion injury via TRPM2 inhibition. AB - The activation of transient receptor potential melastatin 2 (TRPM2), an oxidative stress-sensitive Ca2+-permeable channel, contributes to the aggravation of cerebral ischemia-reperfusion (CIR) injury. Recent studies indicated that a treatment with the antidepressant duloxetine for 24 h (long-term) attenuated TRPM2 activation in response to oxidative stress in neuronal cells. To examine the direct effects of antidepressants on TRPM2 activation, we examined their short-term (0-30 min) treatment effects on H2O2-induced TRPM2 activation in TRPM2 expressing human embryonic kidney 293 cells using the Ca2+ indicator fura-2. Duloxetine exerted the strongest inhibitory effects on TRPM2 activation among the seven antidepressants tested. These inhibitory effects appeared to be due to the inhibition of H2O2-induced TRPM2 activation via an open-channel blocking-like mechanism because duloxetine reduced the sustained phase, but not the initial phase of increases in intracellular Ca2+ concentrations ([Ca2+]i). In a whole cell patch-clamp study, duloxetine reduced the TRPM2-mediated inward current during the opening state of channels. We also examined the effects of duloxetine in a mouse model of CIR injury. The administration of duloxetine to wild-type mice attenuated CIR injury, similar to that in Trpm2 knockout (KO) mice. The administration of duloxetine did not reduce CIR injury further in Trpm2 KO mice, suggesting that it exerts neuroprotective effects against CIR injury by inhibiting TRPM2 activation. Regarding drug repositioning, duloxetine may be a useful drug in reperfusion therapy for ischemic stroke because it has already been clinically used in therapeutics for several disorders, including depression. PMID- 30523062 TI - A comparative study of the pharmacokinetics of clozapine N-oxide and clozapine N oxide hydrochloride salt in rhesus macaques. AB - Translating chemogenetic techniques from non-human primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side-effects, including five FDA boxed warnings. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethyl sulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30-240 min post-administration) following a range of doses (3-10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6-7 fold higher plasma concentrations of CNO as that of CNO-DMSO, and relatively less clozapine (3-5% clozapine/CNO in CNO-DMSO group and 0.5-1.5% clozapine/CNO in CNO HCl group). Both groups had large between subjects variability, pointing to the necessity to perform individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2-6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared to CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain. PMID- 30523063 TI - Estrogen Dependent Disruption of Adiponectin-Connexin43 Signaling Underlies Exacerbated Myocardial Dysfunction in Diabetic Female Rats. AB - The reasons for the higher severity of type 2 diabetes (T2DM)-associated cardiomyopathy in women, despite their inherent estrogen (E2)-dependent cardioprotection, remain unknown. We hypothesized that the reliance of the healthy females' hearts on augmented adiponectin (APN)-connexin43 (Cx43) signaling becomes paradoxically detrimental when disrupted by T2DM in an E2 dependent manner. We tested this hypothesis in high fat-low dose streptozotocin diabetic rats and their controls with the following designations: (a) sham operated (SO); (b) ovariectomized (OVX); (c) ovariectomized with E2 supplementation (OVX+E2); and (d) male. E2-replete (SO or OVX+E2) diabetic rats exhibited higher mortality and greater increases in left ventricular (LV) mass, and reduced LV developed pressure, LV contractility and fractional shortening, but preserved ejection fraction. Further, compared to respective nondiabetic counterparts, the hearts of these E2-replete diabetic rats exhibited greater upregulation of cardiac estrogen receptor alpha (ERalpha) and reductions in Cx43 expression and in the phosphorylation levels of the survival molecules pERK1/2 and pAKT. While serum APN was reduced independent of sex and ovarian hormone status in all DM, cardiac APN was most drastically reduced in DM SO rats. The present translational findings are the first to implicate ovarian hormones/E2 in the exacerbated myocardial dysfunction in diabetic females, and to suggest a pivotal role for malfunctioning cardiac APN-Cx43 signaling in this sex/E2 specific clinical problem. PMID- 30523064 TI - Dendritic spines in early postnatal Fragile X mice are insensitive to novel sensory experience. AB - Autism spectrum disorders (ASD) are often associated with atypical sensory processing and sensory hypersensitivity, which can lead to maladaptive behaviors, such as tactile defensiveness. Such altered sensory perception in ASD could arise from disruptions in experience-dependent maturation of circuits during early brain development. Here, we tested the hypothesis that synaptic structures of primary somatosensory cortex (S1) neurons in Fragile X syndrome (FXS), which is a common inherited cause of autism, are not modulated by novel sensory information during development. We used chronic in vivo two-photon microscopy to image dendritic spines and axon 'en passant' boutons (EPB) of layer 2/3 pyramidal neurons in S1 of male and female wild type (WT) and Fmr1 knockout (KO) mice, a model of FXS. We found that a brief (overnight) exposure to dramatically enhanced sensory inputs in the second postnatal week led to a significant increase in spine density in WT mice, but not in Fmr1 KO mice. In contrast, axon EPB dynamics were impervious to this novel sensory experience in mice of both genotypes. We surmise that the inability of Fmr1 KO mice to modulate post-synaptic dynamics in response to increased sensory input, at a time when sensory information processing first comes online in S1 cortex, could play a role in altered sensory processing in FXS.SIGNIFICANCE STATEMENTVery few longitudinal in vivo imaging studies have investigated synaptic structure and dynamics in early postnatal mice. Moreover, those studies tend to focus on the effects of sensory input deprivation, a process that rarely occurs during normal brain development. Early postnatal imaging experiments are critical because a variety of neurodevelopmental disorders, including those characterized by autism, could result from alterations in how circuits are shaped by incoming sensory inputs during critical periods of development. In this study, we focused on a mouse model of Fragile X syndrome and demonstrate how dendritic spines are insensitive to a brief period of novel sensory experience. PMID- 30523065 TI - Input-specific synaptic location and function of the alpha5 GABAA receptor subunit in the mouse CA1 hippocampal neurons. AB - Hippocampus-dependent learning processes are coordinated via a large diversity of GABAergic inhibitory mechanisms. The alpha5 subunit-containing GABAA receptor (alpha5-GABAAR) is abundantly expressed in the hippocampus populating primarily the extrasynaptic domain of CA1 pyramidal cells, where it mediates tonic inhibitory conductance and may cause functional deficits in synaptic plasticity and hippocampus-dependent memory. However, little is known about synaptic expression of the alpha5-GABAAR and, accordingly, its location site-specific function. We examined the cell- and synapse-specific distribution of the alpha5 GABAAR in the CA1 stratum oriens/alveus (O/A) using a combination of immunohistochemistry, whole-cell patch-clamp recordings and optogenetic stimulation in hippocampal slices obtained from mice of either sex. In addition, the input-specific role of the alpha5-GABAAR in spatial learning and anxiety related behavior was studied using behavioral testing and chemogenetic manipulations. We demonstrate that alpha5-GABAAR is preferentially targeted to the inhibitory synapses made by the vasoactive intestinal peptide (VIP)- and calretinin (CR)-positive terminals onto dendrites of somatostatin-expressing interneurons. In contrast, synapses made by the parvalbumin-positive inhibitory inputs to O/A interneurons showed no or little alpha5-GABAAR. Inhibiting the alpha5-GABAAR in control mice in vivo improved spatial learning but also induced anxiety-like behavior. Inhibiting the alpha5-GABAAR in mice with inactivated CA1 VIP input could still improve spatial learning and was not associated with anxiety. Together, these data indicate that the alpha5-GABAAR-mediated phasic inhibition via VIP input to interneurons plays a predominant role in the regulation of anxiety while the alpha5-GABAAR tonic inhibition via this subunit may control spatial learning.SIGNIFICANCE STATEMENTThe alpha5-GABAAR subunit exhibits high expression in the hippocampus, and regulates the induction of synaptic plasticity and the hippocampus-dependent mnemonic processes. In CA1 principal cells, this subunit occupies mostly extrasynaptic sites and mediates tonic inhibition. Here, we provide evidence that, in CA1 somatostatin-expressing interneurons, the alpha5-GABAAR subunit is targeted to synapses formed by the VIP and calretinin-expressing inputs, and plays a specific role in the regulation of anxiety-like behavior. PMID- 30523066 TI - Dissociable forms of uncertainty-driven representational change across the human brain. AB - Environmental change can lead decision makers to shift rapidly among different behavioral regimes. These behavioral shifts can be accompanied by rapid changes in the firing pattern of neural networks. However, it is unknown what the populations of neurons that participate in such "network reset" phenomena are representing. Here we examined 1) whether and where rapid changes in multivariate activity patterns are observable with fMRI during periods of rapid behavioral change, and 2) what types of representations give rise to these phenomena. We did so by examining fluctuations in multi-voxel patterns of BOLD activity from male and female human subjects making sequential inferences about the state of a partially observable and discontinuously changing variable. We found that, within the context of this sequential inference task, the multivariate patterns of activity in a number of cortical regions contain representations that change more rapidly during periods of uncertainty following a change in behavioral context. In motor cortex, this phenomenon was indicative of discontinuous change in behavioral outputs, whereas in visual regions the same basic phenomenon was evoked by tracking of salient environmental changes. In most other cortical regions, including dorsolateral prefrontal and anterior cingulate cortex, the phenomenon was most consistent with directly encoding the degree of uncertainty. However, in a few other regions, including orbitofrontal cortex, the phenomenon was best explained by representations of a shifting context that evolve more rapidly during periods of rapid learning. These representations may provide a dynamic substrate for learning that facilitates rapid disengagement from learned responses during periods of change.SIGNIFICANCE STATEMENTBrain activity patterns tend to change more rapidly during periods of uncertainty and behavioral adjustment, yet the computational role of such rapid transitions is poorly understood. Here we identify brain regions with fMRI BOLD activity patterns that change more rapidly during periods of behavioral adjustment and use computational modeling to attribute the phenomenon to specific causes. We demonstrate that the phenomenon emerges in different brain regions for different computational reasons, the most common being the representation of uncertainty itself, but that in a selective subset of regions including orbitofrontal cortex the phenomenon was best explained as a shifting latent state signal that may serve to control the degree to which recent temporal context affects ongoing expectations. PMID- 30523067 TI - Lateralized suppression of alpha-band EEG activity as a mechanism of target processing. AB - Alpha-band (8-12 Hz) electroencephalogram (EEG) activity has been linked to visual attention since the earliest EEG studies. More recent studies using spatial cuing paradigms have shown that alpha is suppressed over the hemisphere contralateral to a to-be-attended location, suggesting that alpha serves as a mechanism of preparatory attention. Here, we demonstrate that alpha also plays a role in active target processing. EEG activity was recorded from a group of healthy male and female human subjects in two visual search experiments. In addition to alpha activity, we also assessed the N2pc event-related potential component, a lateralized transient EEG response that has been tightly linked with the focusing of attention on visual targets. We found that the visual search targets triggered both an N2pc component and a suppression of alpha-band activity that was greatest over the hemisphere contralateral to the target (which we call target-elicited lateralized alpha suppression or TELAS). In Experiment 1, both N2pc and TELAS were observed for targets presented in the lower visual field but were absent for upper-field targets. However, these two lateralized effects had different time courses, and they responded differently to manipulations of crowding in Experiment 2. These results indicate that lateralized alpha-band activity is involved in active target processing and is not solely a preparatory mechanism, and they further indicate that TELAS and N2pc reflect related but separable neural mechanism of visuospatial attention.SIGNIFICANCE STATEMENTThe very first EEG studies demonstrated that alpha-band (8-12 Hz) EEG oscillations are suppressed when people attend to visual information, and more recent research has shown that cuing an individual to expect a target at a specific location produces lateralized suppression in the contralateral hemisphere. Thus, lateralized alpha may serve as a preparatory mechanism. In the present study, we found that a similar lateralized alpha effect is triggered by the appearance of a visual target even though the location could not be anticipated, demonstrating that alpha also serves as an active mechanism of target processing. Moreover, we found that alpha lateralization can be dissociated from other lateralized measures of target selection, indicating that it reflects a distinct mechanism of attention. PMID- 30523068 TI - Chronic energy depletion due to iron deficiency impairs dendritic mitochondrial motility during hippocampal neuron development. AB - During development, neurons require highly integrated metabolic machinery to meet the large energy demands of growth, differentiation, and synaptic activity within their complex cellular architecture. Dendrites/axons require anterograde trafficking of mitochondria for local ATP synthesis to support these processes. Acute energy depletion impairs mitochondrial dynamics, but how chronic energy insufficiency affects mitochondrial trafficking and quality control during neuronal development is unknown. Since iron deficiency (ID) impairs mitochondrial respiration/ATP production, we treated mixed-sex embryonic mouse hippocampal neuron cultures with the iron chelator deferoxamine (DFO) to model chronic energetic insufficiency and its effects on mitochondrial dynamics during neuronal development. At 11 days in vitro (DIV), DFO reduced average mitochondrial speed by increasing the pause frequency of individual dendritic mitochondria. Time spent in anterograde motion was reduced; retrograde motion was spared. The average size of moving mitochondria was reduced and the expression of fusion and fission genes was altered, indicating impaired mitochondrial quality control. Mitochondrial density was not altered suggesting that respiratory capacity and not location is the key factor for mitochondrial regulation of early dendritic growth/branching. At 18DIV, the overall density of mitochondria within terminal dendritic branches was reduced in DFO-treated neurons, which may contribute to the long-term deficits in connectivity and synaptic function following early-life ID. The study provides new insights into the cross-regulation between energy production and dendritic mitochondrial dynamics during neuronal development and may be particularly relevant to neuropsychiatric and neurodegenerative diseases, many of which are characterized by impaired brain iron homeostasis, energy metabolism and mitochondrial trafficking.SIGNIFICANCE STATEMENTThis study uses a primary neuronal culture model of iron deficiency to address a gap in understanding of how dendritic mitochondrial dynamics are regulated when energy depletion occurs during a critical period of neuronal maturation. At the beginning of peak dendritic growth/branching, iron deficiency reduces mitochondrial speed through increased pause frequency, decreases mitochondrial size, and alters fusion/fission gene expression. At this stage, mitochondrial density in terminal dendrites is not altered, suggesting that total mitochondrial oxidative capacity and not trafficking is the main mechanism underlying dendritic complexity deficits in iron-deficient neurons. Our findings provide foundational support for future studies exploring the mechanistic role of developmental mitochondrial dysfunction in neurodevelopmental, psychiatric, and neurodegenerative disorders characterized by mitochondrial energy production and trafficking deficits. PMID- 30523069 TI - Visceral fat is associated with elevation of serum alanine aminotransferase and gamma glutamyltransferase in middle-aged Chinese adults. AB - BACKGROUND: Elevation of hepatic enzymes is associated with insulin resistance, dyslipidaemia and obesity. However, the factors behind elevation of liver enzymes remain unclear. The aim of this study was to compare the role of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in relation with serum alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) in middle-aged Chinese adults. METHODS: We performed a cross-sectional study on 959 adults aged 40-65 without hepatitis. VAT and SAT were measured at the level of L4 L5 by MRI. Pearson correlation and linear regression were performed to assess the association of VAT/SAT with serum ALT and GGT. Logistic regression was used to evaluate the association of VAT and SAT with high ALT (>=40 U/L) and high GGT (>=35 U/L). RESULTS: VAT had higher correlation coefficient r with ALT and GGT than SAT. VAT, but not SAT, was associated with ALT (males: beta=0.15, p=0.01; females: beta=0.17, p=0.02) and GGT (males: beta=0.39, p<0.0001) in linear regression. VAT remained to be associated with GGT in males (beta=0.33, p=0.0001) when was further adjusted. Logistic regression showed that VAT was associated with elevated GGT (OR=2.218, p=0.043) in males but not in females and no such association was observed for SAT. CONCLUSIONS: Increased VAT, but not SAT, was associated with elevation of hepatic enzymes including ALT and GGT. Moreover, VAT was associated with elevated GGT independent of insulin resistance and subcutaneous fat in males. PMID- 30523070 TI - Views of UK doctors in training on the timing of choosing a clinical specialty: quantitative and qualitative analysis of surveys 3 years after graduation. AB - BACKGROUND: Workforce studies show a declining proportion of UK junior doctors proceeding directly to specialist training, with many taking career breaks. Doctors may be choosing to delay this important career decision. AIM: To assess doctors' views on the timing of choosing a clinical specialty. METHODS: Surveys of two cohorts of UK-trained doctors 3 years after qualification, in 2011 and 2015. RESULTS: Presented with the statement 'I had to choose my career specialty too soon after qualification', 61% agreed (27% strongly) and 22% disagreed (3% strongly disagreed). Doctors least certain about their choice of specialty were most likely to agree (81%), compared with those who were more confident (72%) or were definite regarding their choice of long-term specialty (54%). Doctors not in higher specialist training were more likely to agree with this statement than those who were (72% vs 59%). Graduate medical school entrants (ie, those who had completed prior degrees) were less likely to agree than non-graduates (56% vs 62%). Qualitative analysis of free text comments identified three themes as reasons why doctors felt rushed into choosing their future career: insufficient exposure to a wide range of specialties; a desire for a greater breadth of experience of medicine in general; and inadequate career advice. CONCLUSIONS: Most UK-trained doctors feel rushed into choosing their long-term career specialty. Doctors find this difficult because they lack sufficient medical experience and adequate career advice to make sound choices. Workforce trainers and planners should enable greater flexibility in training pathways and should further improve existing career guidance. PMID- 30523071 TI - Clocks in the clinic: circadian rhythms in health and disease. AB - Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a '24/7' lifestyle where activity often occurs during the body's 'biological night', resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility. PMID- 30523072 TI - Milk feed osmolality and adverse events in newborn infants and animals: a systematic review. AB - BACKGROUND: High feed osmolality (or osmolarity) is often suggested to be linked with adverse gastrointestinal events in preterm infants. AIM: To systematically review the literature on milk feed osmolality and adverse gastrointestinal events in newborn and low birthweight infants and animals. METHODS: MEDLINE, Embase, CAB Abstracts, Current Contents, BIOSIS Previews and SciSearch were searched from inception to May 2018 to identify potentially relevant studies. INCLUSION CRITERIA: randomised controlled or observational studies of newborn and low birthweight infants or animals investigating the effects of milk-based feeds with different osmolalities. Only full-text, English-language papers were included. RESULTS: Ten human and six animal studies met the inclusion criteria. Of human studies, seven reported no differences in adverse events with varying feed osmolalities; one reported delayed gastric emptying with feed osmolarity of 539 mOsm/L compared with lower levels; one reported higher necrotising enterocolitis (NEC) incidence with feed osmolarity of 650 mOsm/L compared with 359 mOsm/L; one found higher NEC incidence with the lowest feed osmolality (326 mOsm/kg compared with 385 mOsm/kg). Of animal studies, two reported delayed gastric emptying with feed osmolarity >624 mOsm/L, one reported decreased survival due to dehydration with dietary osmolarities >=765 mOsmol/L and none reported increased NEC incidence with differing feed osmolalities. No clear mechanisms were found, and diet composition differences limited the interpretations regarding the independent impact of osmolality. CONCLUSIONS: There is no consistent evidence that differences in feed osmolality in the range 300-500 mOsm/kg are associated with adverse gastrointestinal symptoms in neonates. PMID- 30523073 TI - Utility of the Seattle Heart Failure Model for palliative care referral in advanced ambulatory heart failure. AB - BACKGROUND: Physicians face uncertainty when predicting death in heart failure (HF) leading to underutilisation of palliative care. To facilitate decision making, we assessed the Seattle Heart Failure Model (SHFM) as a referral tool by evaluating its performance in predicting 1-year event-free survival from death, heart transplant (HTx), and ventricular assist device (VAD) implantation. METHODS: We retrospectively reviewed the charts of consecutive patients with advanced ambulatory HF with New York Heart Association Class III/IV HF and a left ventricular ejection fraction of <=40% from 2000 to 2016. We evaluated SHFM's performance by using the Cox proportional hazards model, its discrimination using the c-statistic, its calibration by comparing the observed and predicted survival and its clinical utility by hypothetically assessing the proportion of patients adequately or inadequately referred to palliative care. RESULTS: We included 612 patients in our study. During the 1-year follow-up, there were 83 deaths, 4 HTx and 1 VAD. Although SHFM showed very good discrimination (c-statistic=0.71) and adequate calibration in medium to low-risk patients, it underestimated event-free survival by 12% in high-risk patients. SHFM's clinical utility was limited: 33% of eligible patients would have missed the opportunity for referral and only 27% of referred patients would have benefited. CONCLUSION: Use of SHFM could result in a high proportion of referrals while capturing the majority of patients who may benefit from palliative care. Though this may be a more encompassing and safer alternative than current referral practices, it could lead to many early referrals. PMID- 30523074 TI - Behind the wheel safety in palliative care: a literature review. AB - BACKGROUND: Driving is a complex activity that requires physical abilities and adequate executive and cognitive functioning. There is concern among specialist palliative care services about patients continuing to drive despite having progressive incurable illnesses, comorbidities and medications to manage their symptoms. OBJECTIVES: To determine the quality of literature available about driving that would apply to palliative care patients, specifically in relation to road test or simulated driving scores and neurocognitive testing. METHOD: A literature search based on systematic principles was conducted on the Ovid Medline, PsycINFO, Embase and CINAHL database up to 14 October 2018. Patient populations with life-limiting illness such as cancer, cardiorespiratory and neurological diagnoses were included. RESULTS: 37,546 articles were screened. 14 articles satisfied the search criteria. Six studies focused on patients with multiple sclerosis (MS). Four studies investigated driving ability in patients with Huntington's disease. The remaining four articles studied heart failure, chronic obstructive pulmonary disease (COPD), interstitial lung disease and patients with cancer. In the road test studies, 19%-47% of patients with MS and Huntington's failed the behind-the-wheel assessment. The simulated driving scores in seven studies demonstrated statistically significant differences in errors made between study participants and controls. Divided attention was found in seven studies to be associated with poorer road-test or simulated driving ability. CONCLUSIONS: This review highlights the scarcity of studies available for patients who would be known to palliative care services. For most patient groups, a battery of neurocognitive tests combined with a road-test or simulated driving assessment is still considered the best practice in determining driving safety. PMID- 30523075 TI - Bacterial FtsZ protein forms phase-separated condensates with its nucleoid associated inhibitor SlmA. AB - Macromolecular condensation resulting from biologically regulated liquid-liquid phase separation is emerging as a mechanism to organize intracellular space in eukaryotes, with broad implications for cell physiology and pathology. Despite their small size, bacterial cells are also organized by proteins such as FtsZ, a tubulin homolog that assembles into a ring structure precisely at the cell midpoint and is required for cytokinesis. Here, we demonstrate that FtsZ can form crowding-induced condensates, reminiscent of those observed for eukaryotic proteins. Formation of these FtsZ-rich droplets occurs when FtsZ is bound to SlmA, a spatial regulator of FtsZ that antagonizes polymerization, while also binding to specific sites on chromosomal DNA. The resulting condensates are dynamic, allowing FtsZ to undergo GTP-driven assembly to form protein fibers. They are sensitive to compartmentalization and to the presence of a membrane boundary in cell mimetic systems. This is a novel example of a bacterial nucleoprotein complex exhibiting condensation into liquid droplets, suggesting that phase separation may also play a functional role in the spatiotemporal organization of essential bacterial processes. PMID- 30523076 TI - Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. AB - Barrier tissues are primary targets of environmental stressors and home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. Here, we show that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type-17 program associated with a poised type-2 state. Thus, in the context of injury and exposure to inflammatory mediators such as IL-18, these cells rapidly release type-2 cytokines, thereby acquiring contextual functions. Notably, such acquisition of a type-2 effector program promotes tissue repair. Aberrant type-2 responses can also be unleashed in the context of local defects in immunoregulation. Thus, commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local immunity and tissue adaptation to injury. PMID- 30523077 TI - Functionally diverse type V CRISPR-Cas systems. AB - Type V CRISPR-Cas systems are distinguished by a single RNA-guided RuvC domain containing effector, Cas12. Although effectors of subtypes V-A (Cas12a) and V-B (Cas12b) have been studied in detail, the distinct domain architectures and diverged RuvC sequences of uncharacterized Cas12 proteins suggest unexplored functional diversity. Here, we identify and characterize Cas12c, g, h, and i. Cas12c, h, and i demonstrate RNA-guided double-stranded (ds) DNA interference activity. Cas12i exhibits markedly different efficiencies of crRNA spacer complementary and non-complementary strand cleavage resulting in predominant dsDNA nicking. Cas12g is an RNA-guided RNase with collateral RNase and single stranded DNase activities. Our study reveals the functional diversity emerging along different routes of type V CRISPR-Cas evolution and expands the CRISPR toolbox. PMID- 30523078 TI - Bad metallic transport in a cold atom Fermi-Hubbard system. AB - Strong interactions in many-body quantum systems complicate the interpretation of charge transport in such materials. To shed light on this problem, we study transport in a clean quantum system: ultracold 6Li in a two-dimensional (2D) optical lattice, a testing ground for strong interaction physics in the Fermi Hubbard model. We determine the diffusion constant by measuring the relaxation of an imposed density modulation and modeling its decay hydrodynamically. The diffusion constant is converted to a resistivity using the Nernst-Einstein relation. That resistivity exhibits a linear temperature dependence and shows no evidence of saturation, two characteristic signatures of a bad metal. The techniques we develop here may be applied to measurements of other transport quantities, including the optical conductivity and thermopower. PMID- 30523079 TI - Spin transport in a Mott insulator of ultracold fermions. AB - Strongly correlated materials are expected to feature unconventional transport properties, where charge, spin, and heat conduction are potentially independent probes of the dynamics. In contrast to charge transport, the measurement of spin transport in such materials is highly challenging. Here we observe spin conduction and diffusion in a system of ultracold fermionic atoms that realizes the half-filled Fermi-Hubbard model. For strong interactions, spin diffusion is driven by super-exchange and doublon-hole-assisted tunneling, and strongly violates the quantum limit of charge diffusion. The technique developed in this work can be extended to finite doping, which can shed light on the complex interplay between spin and charge in the Hubbard model. PMID- 30523080 TI - Spectrally resolved helium absorption from the extended atmosphere of a warm Neptune-mass exoplanet. AB - Stellar heating causes atmospheres of close-in exoplanets to expand and escape. These extended atmospheres are difficult to observe because their main spectral signature-neutral hydrogen at ultraviolet wavelengths-is strongly absorbed by interstellar medium. We report the detection of the near-infrared triplet of neutral helium in the transiting warm Neptune-mass exoplanet HAT-P-11b using ground-based, high-resolution observations. The helium feature is repeatable over two independent transits, with an average absorption depth of 1.08 +/- 0.05%. Interpreting absorption spectra with 3D simulations of the planet's upper atmosphere suggests it extends beyond 5 planetary radii, with a large scale height and a helium mass loss rate ? 3*105 g?s-1 A net blue-shift of the absorption might be explained by high-altitude winds flowing at 3 km?s-1 from day to night-side. PMID- 30523082 TI - Temperature-dependent hypoxia explains biogeography and severity of end-Permian marine mass extinction. AB - Rapid climate change at the end of the Permian Period (~252 million years ago) is the hypothesized trigger for the largest mass extinction in Earth's history. We present model simulations of the Permian/Triassic climate transition that reproduce the ocean warming and oxygen (O2) loss indicated by the geologic record. The effect of these changes on animal survival is evaluated using the Metabolic Index (Phi), a measure of scope for aerobic activity governed by organismal traits sampled in diverse modern species. Modeled loss of aerobic habitat predicts lower extinction intensity in the tropics, a pattern confirmed with a spatially explicit analysis of the marine fossil record. The combined physiological stresses of ocean warming and O2 loss can account for more than half the magnitude of the "Great Dying." PMID- 30523081 TI - Ground-based detection of an extended helium atmosphere in the Saturn-mass exoplanet WASP-69b. AB - Hot gas giant exoplanets can lose part of their atmosphere due to strong stellar irradiation, affecting their physical and chemical evolution. Studies of atmospheric escape from exoplanets have mostly relied on space-based observations of the hydrogen Lyman-alpha line in the far ultraviolet which is strongly affected by interstellar absorption. Using ground-based high-resolution spectroscopy we detect excess absorption in the helium triplet at 1083 nm during the transit of the Saturn-mass exoplanet WASP-69b, at a signal-to-noise ratio of 18. We measure line blue shifts of several km s-1 and post transit absorption, which we interpret as the escape of part of the atmosphere trailing behind the planet in comet-like form. PMID- 30523083 TI - Animals and the zoogeochemistry of the carbon cycle. AB - Predicting and managing the global carbon cycle requires scientific understanding of ecosystem processes that control carbon uptake and storage. It is generally assumed that carbon cycling is sufficiently characterized in terms of uptake and exchange between ecosystem plant and soil pools and the atmosphere. We show that animals also play an important role by mediating carbon exchange between ecosystems and the atmosphere, at times turning ecosystem carbon sources into sinks, or vice versa. Animals also move across landscapes, creating a dynamism that shapes landscape-scale variation in carbon exchange and storage. Predicting and measuring carbon cycling under such dynamism is an important scientific challenge. We explain how to link analyses of spatial ecosystem functioning, animal movement, and remote sensing of animal habitats with carbon dynamics across landscapes. PMID- 30523086 TI - News at a glance. PMID- 30523087 TI - What now for human genome editing? PMID- 30523085 TI - Chess, a Drosophila of reasoning. PMID- 30523084 TI - Open-source discovery of chemical leads for next-generation chemoprotective antimalarials. AB - To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action. PMID- 30523089 TI - Uncertainty boosts Brexit jitters for U.K. scientists. PMID- 30523088 TI - For China, a CRISPR first goes too far. PMID- 30523090 TI - Universal flu vaccine is 'an alchemist's dream'. PMID- 30523091 TI - Demotion dismays researchers at storied Danish museum. PMID- 30523092 TI - Taking aim. PMID- 30523093 TI - At arm's length. PMID- 30523094 TI - Barrier(less) islands. PMID- 30523095 TI - Toward a chemical vaccine for malaria. PMID- 30523096 TI - Climate change and marine mass extinction. PMID- 30523097 TI - Bioenergetics through thick and thin. PMID- 30523099 TI - Mastering board games. PMID- 30523098 TI - Endothelial cell adaptation in regeneration. PMID- 30523100 TI - Flawed analyses of U.S. auto fuel economy standards. PMID- 30523101 TI - Model vs. experiment to predict crop losses. PMID- 30523102 TI - Model vs. experiment to predict crop losses-Response. PMID- 30523103 TI - No conflict of interest in data monitoring. PMID- 30523104 TI - Semiconducting polymer blends that exhibit stable charge transport at high temperatures. AB - Although high-temperature operation (i.e., beyond 150 degrees C) is of great interest for many electronics applications, achieving stable carrier mobilities for organic semiconductors at elevated temperatures is fundamentally challenging. We report a general strategy to make thermally stable high-temperature semiconducting polymer blends, composed of interpenetrating semicrystalline conjugated polymers and high glass-transition temperature insulating matrices. When properly engineered, such polymer blends display a temperature-insensitive charge transport behavior with hole mobility exceeding 2.0 cm2/V.s across a wide temperature range from room temperature up to 220 degrees C in thin-film transistors. PMID- 30523105 TI - Building two-dimensional materials one row at a time: Avoiding the nucleation barrier. AB - Assembly of two-dimensional (2D) molecular arrays on surfaces produces a wide range of architectural motifs exhibiting unique properties, but little attention has been given to the mechanism by which they nucleate. Using peptides selected for their binding affinity to molybdenum disulfide, we investigated nucleation of 2D arrays by molecularly resolved in situ atomic force microscopy and compared our results to molecular dynamics simulations. The arrays assembled one row at a time, and the nuclei were ordered from the earliest stages and formed without a free energy barrier or a critical size. The results verify long-standing but unproven predictions of classical nucleation theory in one dimension while revealing key interactions underlying 2D assembly. PMID- 30523106 TI - A general reinforcement learning algorithm that masters chess, shogi, and Go through self-play. AB - The game of chess is the longest-studied domain in the history of artificial intelligence. The strongest programs are based on a combination of sophisticated search techniques, domain-specific adaptations, and handcrafted evaluation functions that have been refined by human experts over several decades. By contrast, the AlphaGo Zero program recently achieved superhuman performance in the game of Go by reinforcement learning from self-play. In this paper, we generalize this approach into a single AlphaZero algorithm that can achieve superhuman performance in many challenging games. Starting from random play and given no domain knowledge except the game rules, AlphaZero convincingly defeated a world champion program in the games of chess and shogi (Japanese chess), as well as Go. PMID- 30523108 TI - A valley valve and electron beam splitter. AB - Developing alternative paradigms of electronics beyond silicon technology requires the exploration of fundamentally new physical mechanisms, such as the valley-specific phenomena in hexagonal two-dimensional materials. We realize ballistic valley Hall kink states in bilayer graphene and demonstrate gate controlled current transmission in a four-kink router device. The operations of a waveguide, a valve, and a tunable electron beam splitter are demonstrated. The valley valve exploits the valley-momentum locking of the kink states and reaches an on/off ratio of 8 at zero magnetic field. A magnetic field enables a full range tunable coherent beam splitter. These results pave a path to building a scalable, coherent quantum transportation network based on the kink states. PMID- 30523107 TI - Room-temperature cycling of metal fluoride electrodes: Liquid electrolytes for high-energy fluoride ion cells. AB - Fluoride ion batteries are potential "next-generation" electrochemical storage devices that offer high energy density. At present, such batteries are limited to operation at high temperatures because suitable fluoride ion-conducting electrolytes are known only in the solid state. We report a liquid fluoride ion conducting electrolyte with high ionic conductivity, wide operating voltage, and robust chemical stability based on dry tetraalkylammonium fluoride salts in ether solvents. Pairing this liquid electrolyte with a copper-lanthanum trifluoride (Cu@LaF3) core-shell cathode, we demonstrate reversible fluorination and defluorination reactions in a fluoride ion electrochemical cell cycled at room temperature. Fluoride ion-mediated electrochemistry offers a pathway toward developing capacities beyond that of lithium ion technology. PMID- 30523109 TI - Photonic crystals for nano-light in moire graphene superlattices. AB - Graphene is an atomically thin plasmonic medium that supports highly confined plasmon polaritons, or nano-light, with very low loss. Electronic properties of graphene can be drastically altered when it is laid upon another graphene layer, resulting in a moire superlattice. The relative twist angle between the two layers is a key tuning parameter of the interlayer coupling in thus-obtained twisted bilayer graphene (TBG). We studied the propagation of plasmon polaritons in TBG by infrared nano-imaging. We discovered that the atomic reconstruction occurring at small twist angles transforms the TBG into a natural plasmon photonic crystal for propagating nano-light. This discovery points to a pathway for controlling nano-light by exploiting quantum properties of graphene and other atomically layered van der Waals materials, eliminating the need for arduous top down nanofabrication. PMID- 30523110 TI - Salmonella persisters undermine host immune defenses during antibiotic treatment. AB - Many bacterial infections are hard to treat and tend to relapse, possibly due to the presence of antibiotic-tolerant persisters. In vitro, persister cells appear to be dormant. After uptake of Salmonella species by macrophages, nongrowing persisters also occur, but their physiological state is poorly understood. In this work, we show that Salmonella persisters arising during macrophage infection maintain a metabolically active state. Persisters reprogram macrophages by means of effectors secreted by the Salmonella pathogenicity island 2 type 3 secretion system. These effectors dampened proinflammatory innate immune responses and induced anti-inflammatory macrophage polarization. Such reprogramming allowed nongrowing Salmonella cells to survive for extended periods in their host. Persisters undermining host immune defenses might confer an advantage to the pathogen during relapse once antibiotic pressure is relieved. PMID- 30523114 TI - New tick seen in nine US states is an emerging disease threat, warns CDC. PMID- 30523113 TI - A short guide to working remotely. PMID- 30523112 TI - A DNA methylation reader complex that enhances gene transcription. AB - DNA methylation generally functions as a repressive transcriptional signal, but it is also known to activate gene expression. In either case, the downstream factors remain largely unknown. By using comparative interactomics, we isolated proteins in Arabidopsis thaliana that associate with methylated DNA. Two SU(VAR)3 9 homologs, the transcriptional antisilencing factor SUVH1, and SUVH3, were among the methyl reader candidates. SUVH1 and SUVH3 bound methylated DNA in vitro, were associated with euchromatic methylation in vivo, and formed a complex with two DNAJ domain-containing homologs, DNAJ1 and DNAJ2. Ectopic recruitment of DNAJ1 enhanced gene transcription in plants, yeast, and mammals. Thus, the SUVH proteins bind to methylated DNA and recruit the DNAJ proteins to enhance proximal gene expression, thereby counteracting the repressive effects of transposon insertion near genes. PMID- 30523115 TI - Regulatory light chain phosphorylation augments length-dependent contraction in PTU-treated rats. AB - Force production by actin-myosin cross-bridges in cardiac muscle is regulated by thin-filament proteins and sarcomere length (SL) throughout the heartbeat. Prior work has shown that myosin regulatory light chain (RLC), which binds to the neck of myosin heavy chain, increases cardiac contractility when phosphorylated. We recently showed that cross-bridge kinetics slow with increasing SLs, and that RLC phosphorylation amplifies this effect, using skinned rat myocardial strips predominantly composed of the faster alpha-cardiac myosin heavy chain isoform. In the present study, to assess how RLC phosphorylation influences length-dependent myosin function as myosin motor speed varies, we used a propylthiouracil (PTU) diet to induce >95% expression of the slower beta-myosin heavy chain isoform in rat cardiac ventricles. We measured the effect of RLC phosphorylation on Ca2+ activated isometric contraction and myosin cross-bridge kinetics (via stochastic length perturbation analysis) in skinned rat papillary muscle strips at 1.9- and 2.2-um SL. Maximum tension and Ca2+ sensitivity increased with SL, and RLC phosphorylation augmented this response at 2.2-um SL. Subtle increases in viscoelastic myocardial stiffness occurred with RLC phosphorylation at 2.2-um SL, but not at 1.9-um SL, thereby suggesting that RLC phosphorylation increases beta myosin heavy chain binding or stiffness at longer SLs. The cross-bridge detachment rate slowed as SL increased, providing a potential mechanism for prolonged cross-bridge attachment to augment length-dependent activation of contraction at longer SLs. Length-dependent slowing of beta-myosin heavy chain detachment rate was not affected by RLC phosphorylation. Together with our previous studies, these data suggest that both alpha- and beta-myosin heavy chain isoforms show a length-dependent activation response and prolonged myosin attachment as SL increases in rat myocardial strips, and that RLC phosphorylation augments length-dependent activation at longer SLs. In comparing cardiac isoforms, however, we found that beta-myosin heavy chain consistently showed greater length-dependent sensitivity than alpha-myosin heavy chain. Our work suggests that RLC phosphorylation is a vital contributor to the regulation of myocardial contractility in both cardiac myosin heavy chain isoforms. PMID- 30523111 TI - A mechanistic classification of clinical phenotypes in neuroblastoma. AB - Neuroblastoma is a pediatric tumor of the sympathetic nervous system. Its clinical course ranges from spontaneous tumor regression to fatal progression. To investigate the molecular features of the divergent tumor subtypes, we performed genome sequencing on 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208 of these tumors. We found that patients whose tumors lacked telomere maintenance mechanisms had an excellent prognosis, whereas the prognosis of patients whose tumors harbored telomere maintenance mechanisms was substantially worse. Survival rates were lowest for neuroblastoma patients whose tumors harbored telomere maintenance mechanisms in combination with RAS and/or p53 pathway mutations. Spontaneous tumor regression occurred both in the presence and absence of these mutations in patients with telomere maintenance negative tumors. On the basis of these data, we propose a mechanistic classification of neuroblastoma that may benefit the clinical management of patients. PMID- 30523116 TI - Sarcomere length-dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin. AB - Cardiac performance is tightly regulated at the cardiomyocyte level by sarcomere length, such that increases in sarcomere length lead to sharply enhanced force generation at the same Ca2+ concentration. Length-dependent activation of myofilaments involves dynamic and complex interactions between a multitude of thick- and thin-filament components. Among these components, troponin, myosin, and the giant protein titin are likely to be key players, but the mechanism by which these proteins are functionally linked has been elusive. Here, we investigate this link in the mouse myocardium using in situ FRET techniques. Our objective was to monitor how length-dependent Ca2+-induced conformational changes in the N domain of cardiac troponin C (cTnC) are modulated by myosin-actin cross bridge (XB) interactions and increased titin compliance. We reconstitute FRET donor- and acceptor-modified cTnC(13C/51C)AEDANS-DDPM into chemically skinned myocardial fibers from wild-type and RBM20-deletion mice. The Ca2+-induced conformational changes in cTnC are quantified and characterized using time resolved FRET measurements as XB state and sarcomere length are varied. The RBM20 deficient mouse expresses a more compliant N2BA titin isoform, leading to reduced passive tension in the myocardium. This provides a molecular tool to investigate how altered titin-based passive tension affects Ca2+-troponin regulation in response to mechanical stretch. In wild-type myocardium, we observe a direct association of sarcomere length-dependent enhancement of troponin regulation with both Ca2+ activation and strongly bound XB states. In comparison, measurements from titin RBM20-deficient animals show blunted sarcomere length-dependent effects. These results suggest that titin-based passive tension contributes to sarcomere length-dependent Ca2+-troponin regulation. We also conclude that strong XB binding plays an important role in linking the modulatory effect of titin compliance to Ca2+-troponin regulation of the myocardium. PMID- 30523117 TI - Persistence of false paradigms in low-power sciences. AB - We develop a model describing how false paradigms may persist, hindering scientific progress. The model features two paradigms, one describing reality better than the other. Tenured scientists display homophily: They favor tenure candidates who adhere to their paradigm. As in statistics, power is the probability (absent any bias) of denying tenure to scientists adhering to the false paradigm. The model shows that because of homophily, when power is low, the false paradigm may prevail. Then, only an increase in power can ignite convergence to the true paradigm. Historical case studies suggest that low power comes either from lack of empirical evidence or from reluctance to base tenure decisions on available evidence. PMID- 30523118 TI - Modulation of HIF-2alpha PAS-B domain contributes to physiological responses. AB - Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix loop-helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF 2alpha PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2alpha target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2alpha PAS-B domain suppressed HIF-2alpha activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF 2alpha hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2alpha on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2alpha in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders. PMID- 30523120 TI - The multifaceted role of fibrinogen in tissue injury and inflammation. AB - The canonical role of the hemostatic and fibrinolytic systems is to maintain vascular integrity. Perturbations in either system can prompt primary pathological endpoints of hemorrhage or thrombosis with vessel occlusion. However, fibrin(ogen) and proteases controlling its deposition and clearance, including (pro)thrombin, and plasmin(ogen), have powerful roles in driving acute and reparative inflammatory pathways that impact the spectrum of tissue injury, remodeling and repair. Indeed, fibrin(ogen) deposits are a near universal feature of tissue injury, regardless of the nature of the inciting event, including injuries driven by mechanical insult, infection, or immunological derangements. Fibrin can modify multiple aspects of inflammatory cell function by engaging leukocytes through a variety of cellular receptors and mechanisms. Studies on the role of coagulation system activation and fibrin(ogen) deposition in models of inflammatory disease and tissue injury have revealed points of commonality, as well as context-dependent contributions of coagulation and fibrinolytic factors. However, there remains a critical need to define the precise temporal and spatial mechanisms by which fibrinogen-directed inflammatory events may dictate the severity of tissue injury and coordinate the remodeling and repair events essential to restore normal organ function. Current research trends suggest that future studies will give way to the identification of novel hemostatic factor targeted therapies for a range of tissue injuries and disease. PMID- 30523119 TI - Ibrutinib for the treatment of Bing-Neel syndrome: A multicenter study. AB - The treatment of patients with Bing-Neel syndrome (BNS) is not standardized. We included patients with Waldenstrom macroglobulinemia (WM) and a radiological and/or cytological diagnosis of BNS treated with ibrutinib monotherapy. Response assessment was based on criteria for BNS from the 8th International Workshop for WM. Survival from from BNS diagnosis (BNS survival), survival from ibrutinib initiation to last follow-up or death (ibrutinib survival) and time from ibrutinib initiation to ibrutinib discontinuation for toxicity, progression or death (event-free survival, EFS) were estimated. Twenty-eight patients were included in our study. The median age at BNS diagnosis was 65 years. Ibrutinib was the first line of treatment for BNS in 39% of patients. Ibrutinib was administered orally at a dose of 560 mg and 420 mg once daily in 46% and 54% of patients, respectively. Symptomatic and radiologic improvements were seen in 85% and 60% of patients within 3 months of therapy. At best response, 85% of patients had improvement or resolution of BNS symptoms, 83% had improvement or resolution of radiological abnormalities, and 47% had cleared the disease in the cerebrospinal fluid. The 2-year EFS rate on ibrutinib was 80% (95% CI 58-91%), the 2-year ibrutinib survival rate was 81% (95% CI 49-94%) and the 5-year BNS survival rate was 86% (95% CI 63-95%). Ibrutinib therapy is effective in patients with BNS and should be considered as a treatment option in these patients. PMID- 30523122 TI - DUO delivers for duvelisib. PMID- 30523121 TI - Natural, not immune; classical, not alternative. PMID- 30523123 TI - How deep is the myeloma iceberg? PMID- 30523124 TI - CiTE antibody for AML. PMID- 30523125 TI - TLT-1: please release me, let me go. PMID- 30523126 TI - Stool can soften GVHD. PMID- 30523127 TI - Extensive Kaposi sarcoma infiltration in bone marrow in a patient with HIV. PMID- 30523128 TI - Young K, Conley B, Romero D, et al. BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood. 2012;120(20):4263-4273. PMID- 30523129 TI - Schuetz C, Neven B, Dvorak CC, et al. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014;123(2):281-289. PMID- 30523130 TI - Scarfo I, Ormhoj M, Frigault MJ, et al. Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Blood. 2018;132(14):1495-1506. PMID- 30523131 TI - Does adult alcohol consumption combine with adverse childhood experiences to increase involvement in violence in men and women? A cross-sectional study in England and Wales. AB - OBJECTIVES: To examine if, and to what extent, a history of adverse childhood experiences (ACEs) combines with adult alcohol consumption to predict recent violence perpetration and victimisation. DESIGN: Representative face-to-face survey (n=12 669) delivered using computer-assisted personal interviewing and self-interviewing. SETTING: Domiciles of individuals living in England and Wales. PARTICIPANTS: Individuals aged 18-69 years resident within randomly selected locations. 12 669 surveys were completed with participants within our defined age range. MAIN OUTCOME MEASURES: Alcohol consumption was measured using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and childhood adversity using the short ACEs tool. Violence was measured using questions on perpetration and victimisation in the last 12 months. RESULTS: Compliance was 55.7%. There were strong positive relationships between numbers of ACEs and recent violence perpetration and victimisation in both sexes. Recent violence was also strongly related to positive AUDIT-C (>=5) scores. In males, heavier drinking and >=4ACEs had a strong multiplicative relationship with adjusted prevalence of recent violent perpetration rising from 1.3% (95% CIs 0.9% to 1.9%; 0 ACEs, negative AUDIT-C) to 3.6% (95% CIs 2.7% to 4.9%; 0 ACEs, positive AUDIT-C) and 8.5% (95% CI 5.6% to 12.7%; >=4ACEs, negative AUDIT-C) to 28.3% (95% CI 22.5% to 34.8%; >=4ACEs, positive AUDIT-C). In both sexes, violence perpetration and victimisation reduced with age independently of ACE count and AUDIT-C status. The combination of young age (18-29 years), >=4ACEs and positive AUDIT-C resulted in the highest adjusted prevalence for both perpetration and victimisation in males (61.9%, 64.9%) and females (24.1%, 27.2%). CONCLUSIONS: Those suffering multiple adverse experiences in childhood are also more likely to be heavier alcohol users. Especially for males, this combination results in substantially increased risks of violence. Addressing ACEs and heavy drinking together is rarely a feature of public health policy, but a combined approach may help reduce the vast costs associated with both. PMID- 30523132 TI - Cross-sectional and prospective follow-up study to detect early signs of cardiac dysfunction in obesity: protocol of the CARDIOBESE study. AB - INTRODUCTION: In view of the increasing occurrence of both obesity and heart failure, a growing overlap of these two clinical entities in the near future is expected. Significant advances in our understanding of the pathophysiological consequences of obesity for the cardiovascular system have been made over the past two decades. However, to optimise management and treatment of obesity patients, further research is required to improve early identification of cardiac dysfunction in obesity and to gain insight in the underlying pathophysiology. The CARdiac Dysfunction In OBesity - Early Signs Evaluation (CARDIOBESE) study has been designed to address these issues. METHODS AND ANALYSIS: CARDIOBESE is a cross-sectional multicentre study of 100 obesity patients scheduled for bariatric surgery (body mass index (BMI) >=35 kg/m2) without known cardiovascular disease, and 50 age-matched and gender-matched non-obese controls (BMI <30 kg/m2). Echocardiography, blood and urine biomarkers and Holter monitoring will be used to identify parameters that are able to show cardiac dysfunction at a very early stage in obesity patients (primary objective). Furthermore, a prospective follow up study of obesity patients before and 1 year after bariatric surgery will be done to gain insight in the pathophysiology of obesity causing cardiac dysfunction (secondary objective). ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee Toetsingscommissie Wetenschappelijk Onderzoek Rotterdam e.o. (TWOR). Inclusion of patients and controls is almost complete. Analyses of the investigations are currently being performed, and dissemination through peer-reviewed publications and conference presentations is expected from the first quarter of 2019. By identifying early markers of cardiac dysfunction in obesity, and by understanding the underlying pathophysiology of the abnormalities of these markers, the CARDIOBESE study may provide guidance for risk stratification, monitoring and treatment strategies for obesity patients. PMID- 30523134 TI - Lessons learnt on transparency, scientific process and publication ethics. The short story of a long journey to get into the public domain unpublished data, methodological flaws and bias of the Cochrane HPV vaccines review. PMID- 30523133 TI - PRedicting Outcomes For Crohn's dIsease using a moLecular biomarkEr (PROFILE): protocol for a multicentre, randomised, biomarker-stratified trial. AB - BACKGROUND: The course of Crohn's disease (CD) varies substantially between individuals, but reliable prognostic markers do not exist. This hinders disease management because patients with aggressive disease are undertreated by conventional 'step-up' therapy (in which treatment is gradually escalated in response to refractory or relapsing disease) while those with more indolent disease would be exposed to unnecessary treatment-related toxicity if a more aggressive 'top-down' approach was indiscriminately used. The Predicting outcomes for Crohn's disease using a molecular biomarker trial will assess whether a prognostic transcriptional biomarker, that we have developed and validated, can improve clinical outcomes by facilitating personalised therapy in CD. This represents the first the biomarker-stratified trial in inflammatory bowel disease. METHODS AND ANALYSIS: This biomarker-stratified trial will compare the relative efficacy of 'top-down' and 'accelerated step-up' therapy between biomarker-defined subgroups of patients with newly diagnosed CD. 400 participants from ~50 UK centres will be recruited. Subjects within each biomarker subgroup (IBDhi or IBDlo) will be randomised (1:1) to receive one of the treatment strategies until trial completion (48 weeks). The primary outcome is the incidence of sustained surgery and steroid-free remission from the completion of induction treatment through to week 48. Secondary outcomes include mucosal healing, quality-of-life assessments and surrogate measures of disease burden including number of flares, cumulative steroid exposure, number of hospital admissions and number of Crohn's-related surgeries (assessed hierarchically). Analyses will compare the relative benefit of the treatment strategies in each biomarker-defined subgroup, powered as an interaction analysis, to determine whether the biomarker can accurately match patients to the most appropriate therapy. ETHICS AND DISSEMINATION: Ethical approval has been obtained and recruitment is under way at sites around the UK. Following trial completion and data analysis, the results of the trial will be submitted for publication in peer reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN11808228; Pre-results. PMID- 30523135 TI - Catalogue of bias: publication bias. PMID- 30523136 TI - Drug discovery today: no molecules required. PMID- 30523137 TI - Bias in Neuroradiology Peer Review: Impact of a "Ding" on "Dinging" Others. AB - BACKGROUND AND PURPOSE: The validity of radiology peer review requires an unbiased assessment of studies in an environment that values the process. We assessed radiologists' behavior reviewing colleagues' reports. We hypothesized that when a radiologist receives a discrepant peer review, he is more likely to submit a discrepant review about another radiologist. MATERIALS AND METHODS: We analyzed the anonymous peer review submissions of 13 neuroradiologists in semimonthly blocks of time from 2016 to 2018. We defined a discrepant review as any one of the following: 1) detection miss, clinically significant; 2) detection miss, clinically not significant; 3) interpretation miss, clinically significant; or 4) interpretation miss, clinically not significant. We used random-effects Poisson regression analysis to determine whether a neuroradiologist was more likely to submit a discrepant report during the semimonthly block in which he or she received one versus the semimonthly block thereafter. RESULTS: Four hundred sixty-eight discrepant peer review reports were submitted; 161 were submitted in the same semimonthly block of receipt of a discrepant report and 325 were not. Receiving a discrepant report had a positive effect on submitting discrepant reports: an expected relative increase of 14% (95% CI, 8%-21%). Notably, receiving a clinically not significant discrepant report (coefficient = 0.13; 95% CI, 0.05-0.22) significantly and positively correlated with submitting a discrepant report within the same time block, but this was not true of clinically significant reports. CONCLUSIONS: The receipt of a clinically not significant discrepant report leads to a greater likelihood of submitting a discrepant report. The motivation for such an increase should be explored for potential bias. PMID- 30523138 TI - Disproportionate International Contributions to Subspecialties of Neuroradiology in the American Journal of Neuroradiology. PMID- 30523139 TI - Absence of Disproportionately Enlarged Subarachnoid Space Hydrocephalus, a Sharp Callosal Angle, or Other Morphologic MRI Markers Should Not Be Used to Exclude Patients with Idiopathic Normal Pressure Hydrocephalus from Shunt Surgery. AB - BACKGROUND AND PURPOSE: Several studies have evaluated the use of MR imaging markers for the prediction of outcome after shunt surgery in idiopathic normal pressure hydrocephalus with conflicting results. Our aim was to investigate the predictive value of a number of earlier proposed morphologic MR imaging markers in a large group of patients with idiopathic normal pressure hydrocephalus. MATERIALS AND METHODS: One hundred sixty-eight patients (mean age, 70 +/- 9.3 years) with idiopathic normal pressure hydrocephalus, subjected to standardized quantification of clinical symptoms before and after shunt surgery, were included in the study. Outcome was calculated using a composite score. Preoperative T1, FLAIR, and flow-sensitive images were analyzed regarding the presence of 13 different morphologic MR imaging markers. RESULTS: The median Evans index was 0.41 (interquartile range, 0.37-0.44). All patients had an aqueductal flow void sign present and white matter hyperintensities. The median callosal angle was 68.8 degrees (interquartile range, 57.7 degrees -80.8 degrees ). Dilated Sylvian fissures were found in 69%; focally dilated sulci, in 25%; and widening of the interhemispheric fissure, in 55%. Obliteration of the sulci at the convexity was found in 36%, and 36% of patients were characterized as having disproportionately enlarged subarachnoid space hydrocephalus. Sixty-eight percent of patients improved after surgery. None of the investigated MR imaging markers were significant predictors of improvement after shunt surgery. CONCLUSIONS: Disproportionately enlarged subarachnoid space hydrocephalus, a small callosal angle, and the other MR imaging markers evaluated in this study should not be used to exclude patients from shunt surgery. These markers, though they may be indicative of idiopathic normal pressure hydrocephalus, do not seem to be a part of the mechanisms connected to the reversibility of the syndrome. PMID- 30523140 TI - Bone Subtraction Iodine Imaging Using Area Detector CT for Evaluation of Skull Base Invasion by Nasopharyngeal Carcinoma. AB - BACKGROUND AND PURPOSE: Conventional CT has generally lower detectability of bone marrow invasion than MR imaging due to lower tissue contrast. The purpose of this study was to compare the diagnostic performance of conventional CT alone or in combination with bone subtraction iodine imaging using area detector CT for the evaluation of skull base invasion in patients with nasopharyngeal carcinoma. MATERIALS AND METHODS: Forty-four consecutive patients who underwent contrast enhanced CT using 320-row area detector CT and contrast-enhanced MR imaging for nasopharyngeal carcinoma staging between April 2012 and November 2017 were enrolled in this retrospective study. Bone subtraction iodine images were generated by subtracting pre- and postcontrast volume scans using a high resolution deformable registration algorithm. Two blinded observers evaluated skull base invasion at multiple sites (sphenoid body, clivus, bilateral base of the pterygoid process, and petrous bone) using conventional CT images alone or in combination with bone subtraction iodine images. Examination of MR and CT images by an experienced neuroradiologist was the reference standard for evaluating sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: Twenty-six patients (59%) showed skull base invasion at 84 sites on the reference standard. Conventional CT plus bone subtraction iodine images showed higher sensitivity (92.9% versus 78.6%, P = .02) and specificity (95.6% versus 86.1%, P = .01) than conventional CT images alone for evaluating skull base invasion. The area under the receiver operating characteristic curve for conventional CT plus bone subtraction iodine (0.98) was significantly larger (P < .001) than the area under the receiver operating characteristic curve for conventional CT alone (0.90). CONCLUSIONS: Conventional CT plus bone subtraction iodine performs more closely to the accuracy of combining CT and MR imaging compared with conventional CT alone. PMID- 30523141 TI - MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma. AB - BACKGROUND AND PURPOSE: Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma. MATERIALS AND METHODS: In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance. RESULTS: Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma. CONCLUSIONS: This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups. PMID- 30523142 TI - Compressed Sensing-Sensitivity Encoding (CS-SENSE) Accelerated Brain Imaging: Reduced Scan Time without Reduced Image Quality. AB - BACKGROUND AND PURPOSE: Compressed sensing-sensitivity encoding is a promising MR imaging acceleration technique. This study compares the image quality of compressed sensing-sensitivity encoding accelerated imaging with conventional MR imaging sequences. MATERIALS AND METHODS: Patients with known, treated, or suspected brain tumors underwent compressed sensing-sensitivity encoding accelerated 3D T1-echo-spoiled gradient echo or 3D T2-FLAIR sequences in addition to the corresponding conventional acquisition as part of their clinical brain MR imaging. Two neuroradiologists blinded to sequence and patient information independently evaluated both the accelerated and corresponding conventional acquisitions. The sequences were evaluated on 4- or 5-point Likert scales for overall image quality, SNR, extent/severity of artifacts, and gray-white junction and lesion boundary sharpness. SNR and contrast-to-noise ratio values were compared. RESULTS: Sixty-six patients were included in the study. For T1-echo spoiled gradient echo, image quality in all 5 metrics was slightly better for compressed sensing-sensitivity encoding than conventional images on average, though it was not statistically significant, and the lower bounds of the 95% confidence intervals indicated that compressed sensing-sensitivity encoding image quality was within 10% of conventional imaging. For T2-FLAIR, image quality of the compressed sensing-sensitivity encoding images was within 10% of the conventional images on average for 3 of 5 metrics. The compressed sensing sensitivity encoding images had somewhat more artifacts (P = .068) and less gray white matter sharpness (P = .36) than the conventional images, though neither difference was significant. There was no significant difference in the SNR and contrast-to-noise ratio. There was 25% and 35% scan-time reduction with compressed sensing-sensitivity encoding for FLAIR and echo-spoiled gradient echo sequences, respectively. CONCLUSIONS: Compressed sensing-sensitivity encoding accelerated 3D T1-echo-spoiled gradient echo and T2-FLAIR sequences of the brain show image quality similar to that of standard acquisitions with reduced scan time. Compressed sensing-sensitivity encoding may reduce scan time without sacrificing image quality. PMID- 30523143 TI - Osseous versus Nonosseous Spinal Epidural Arteriovenous Fistulas: Experiences of 13 Patients. AB - BACKGROUND AND PURPOSE: Spinal epidural arteriovenous fistulas are rare vascular malformations. We present 13 patients with spinal epidural arteriovenous fistulas, noting the various presenting symptom patterns, imaging findings related to bone involvement, and outcomes. MATERIALS AND METHODS: Among 111 patients with spinal vascular malformations in the institutional data base from 1993 to 2017, thirteen patients (11.7%) had spinal epidural arteriovenous fistulas. We evaluated presenting symptoms and imaging findings, including bone involvement and mode of treatment. To assess the treatment outcome, we compared initial and follow-up clinical status using the modified Aminoff and Logue Scale of Disability and the modified Rankin Scale. RESULTS: The presenting symptoms were lower back pain (n = 2), radiculopathy (n = 5), and myelopathy (n = 7). There is overlap of symptoms in 1 patient (No. 11). Distribution of spinal epidural arteriovenous fistulas was cervical (n = 3), thoracic (n = 2), lumbar (n = 6), and sacral (n = 2). Intradural venous reflux was identified in 7 patients with congestive venous myelopathy. The fistulas were successfully treated in all patients who underwent treatment (endovascular embolization, n = 10; operation, n = 1) except 2 patients who refused treatment due to tolerable symptoms. Transarterial glue (n = 7) was used in nonosseous types; and transvenous coils (n = 3), in osseous type. After 19 months of median follow-up, the patients showed symptom improvement after treatment. CONCLUSIONS: Although presenting symptoms were diverse, myelopathy caused by intradural venous reflux was the main target of treatment. Endovascular treatment was considered via an arterial approach in nonosseous types and via a venous approach in osseous types. PMID- 30523144 TI - Understanding Subdural Collections in Pediatric Abusive Head Trauma. AB - Life-threatening physical abuse of infants and toddlers is frequently correlated with head injuries. A common variant of the abusive head trauma is the shaken baby syndrome. The present review article sheds light on subdural collections in children with abusive head trauma and aims at providing a recent knowledge base for various medical disciplines involved in diagnostic procedures and legal proceedings. To this end, the different subdural collection entities are presented and illustrated. The pathophysiologic background is explained. Differential and age-diagnostic aspects are discussed and summarized by tabular and graphic overviews. Two problematic constellations frequently occurring during initial CT investigations are evaluated: A mixed-density subdural collection does not prove repeated trauma, and hypodense subdural collections are not synonymous with chronicity. The neuroradiologic analysis and assessment of subdural collections may decisively contribute to answering differential diagnostic and forensic questions. In addition to more reference data, a harmonization of terminology and methodology is urgently needed, especially with respect to age diagnostic aspects. PMID- 30523145 TI - Solitary Parathyroid Adenoma Localization in Technetium Tc99m Sestamibi SPECT CT and Multiphase Multidetector 4D CT. AB - BACKGROUND AND PURPOSE: Minimally invasive parathyroid surgery relies critically on image guidance, but data comparing the efficacy of various imaging modalities are scarce. Our aim was to perform a blinded comparison of the localizing capability of technetium Tc99m sestamibi SPECT, multiphase multidetector 4D CT, and the combination of these 2 modalities (technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT). MATERIALS AND METHODS: We reviewed the records of 31 (6 men, 25 women; median age, 56 years) consecutive patients diagnosed with biochemically confirmed primary hyperparathyroidism between November 2009 and March 2010 who underwent preoperative technetium Tc99m sestamibi SPECT and multiphase multidetector 4D CT performed on the same scanner with pathologic confirmation by resection of a single parathyroid adenoma. Accuracy was determined separately for localization to the correct side and quadrant using surgical localization as the standard of reference. RESULTS: Surgical resection identified 14 left and 17 right parathyroid adenomas and 2 left inferior, 12 left superior, 11 right inferior, and 6 right superior parathyroid adenomas. For left/right localization, technetium Tc99m sestamibi SPECT achieved an accuracy of 93.5% (29 of 31), multiphase multidetector 4D CT achieved 96.8% accuracy (30 of 31), and technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT achieved 96.8% accuracy (30 of 31). For quadrant localization, technetium Tc99m sestamibi SPECT accuracy was 67.7% (21 of 31), multiphase multidetector 4D CT accuracy was 87.1% (27 of 31), and technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT accuracy was 93.5% (29 of 31). Reader diagnostic confidence was consistently ranked lowest for technetium Tc99m sestamibi SPECT and highest for technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT. CONCLUSIONS: For left/right localization of parathyroid adenomas, all modalities performed equivalently. For quadrant localization, technetium Tc99m sestamibi SPECT + multiphase multidetector 4D CT is superior to technetium Tc99m sestamibi SPECT. PMID- 30523146 TI - Y-Stent-Assisted Coiling of Wide-Neck Bifurcation Intracranial Aneurysms: A Meta Analysis. AB - BACKGROUND: Y-stent-assisted coiling for wide-neck intracranial aneurysms required further investigation. PURPOSE: Our aim was to analyze outcomes after Y stent placement in wide-neck aneurysms. DATA SOURCES: We performed a systematic search of 3 data bases for studies published from 2000 to 2018. STUDY SELECTION: According to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines, we included studies reporting Y-stent-assisted coiling of wide-neck aneurysms. DATA ANALYSIS: Random-effects meta-analysis was used to pool the following: aneurysm occlusion rate, complications, and factors influencing the studied outcomes. DATA SYNTHESIS: We included 27 studies and 750 aneurysms treated with Y-stent placement. The immediate complete/near-complete occlusion rate was 82.2% (352/468; 95% CI, 71.4%-93%; I2 = 92%), whereas the long-term complete/near-complete occlusion rate was 95.4% (564/598; 95% CI, 93.7%-97%; I2 = 0%) (mean radiologic follow-up of 14 months). The aneurysm recanalization rate was 3% (20/496; 95% CI, 1.5%-4.5%; I2 = 0%), and half of the recanalized aneurysms required retreatment. The treatment-related complication rate was 8.9% (63/614; 95% CI, 5.8%-12.1%; I2 = 44%). Morbidity and mortality after treatment were 2.4% (18/540; 95% CI, 1.2%-3.7%; I2 = 0%) and 1.1% (5/668; 95% CI, 0.3% 1.9%; I2 = 0%), respectively. Crossing Y-stent placement was associated with a slightly lower complication rate compared with the kissing configuration (56/572 = 8.4%; 95% CI, 5%-11%; I2 = 46% versus 4/30 = 12.7%; 95% CI, 3%-24%; I2 = 0%). Occlusion rates were quite comparable among Enterprise, Neuroform, and LVIS stents, whereas the Enterprise stent was associated with lower rates of complications (8/89 = 6.5%; 95% CI, 1.6%-11%; I2 = 0%) compared with the others (20/131 = 14%; 95% CI, 5%-26%; I2 = 69% and 9/64 = 11%; 95% CI, 3%-20%; I2 = 18%). LIMITATIONS: This was a small, retrospective series. CONCLUSIONS: Y-stent assisted coiling yields high rates of long-term angiographic occlusion, with a relatively low rate of treatment-related complications. Y-stent placement with a crossing configuration appears to be associated with better outcomes. Although Y configuration can be obtained using many types of stents with comparable occlusion rates, the Enterprise stent is associated with lower complication rates. PMID- 30523148 TI - SUMOylation coordinates BERosome assembly in active DNA demethylation during cell differentiation. AB - During active DNA demethylation, 5-methylcytosine (5mC) is oxidized by TET proteins to 5-formyl-/5-carboxylcytosine (5fC/5caC) for replacement by unmethylated C by TDG-initiated DNA base excision repair (BER). Base excision generates fragile abasic sites (AP-sites) in DNA and has to be coordinated with subsequent repair steps to limit accumulation of genome destabilizing secondary DNA lesions. Here, we show that 5fC/5caC is generated at a high rate in genomes of differentiating mouse embryonic stem cells and that SUMOylation and the BER protein XRCC1 play critical roles in orchestrating TDG-initiated BER of these lesions. SUMOylation of XRCC1 facilitates physical interaction with TDG and promotes the assembly of a TDG-BER core complex. Within this TDG-BERosome, SUMO is transferred from XRCC1 and coupled to the SUMO acceptor lysine in TDG, promoting its dissociation while assuring the engagement of the BER machinery to complete demethylation. Although well-studied, the biological importance of TDG SUMOylation has remained obscure. Here, we demonstrate that SUMOylation of TDG suppresses DNA strand-break accumulation and toxicity to PARP inhibition in differentiating mESCs and is essential for neural lineage commitment. PMID- 30523147 TI - Prominin-1 controls stem cell activation by orchestrating ciliary dynamics. AB - Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases. PMID- 30523149 TI - Patient-Centered Oncology or Population-Centered Oncology-Which Do We Want, and Which Tradeoffs Are We Willing To Accept? PMID- 30523150 TI - O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis. AB - The addition of a single beta-D-N-acetylglucosamine sugar (O-GlcNAc) by O-GlcNAc transferase (OGT) and O-GlcNAc removal by O-GlcNAcase (OGA) maintain homeostatic O-GlcNAc levels on cellular proteins. Changes in protein O-GlcNAcylation regulate cellular differentiation and cell fate decisions, but how these changes affect erythropoiesis, an essential process in blood cell formation remains unclear. Here, we investigated the role of O-GlcNAcylation in erythropoiesis by using G1E ER4 cells, which carry the erythroid-specific transcription factor GATA-binding protein 1 (GATA-1) fused to the estrogen receptor (GATA-1ER), and therefore undergo erythropoiesis after beta-estradiol (E2) addition. We observed that during G1E-ER4 differentiation, overall O-GlcNAc levels decrease and physical interactions of GATA-1 with both OGT and OGA increase. RNA-Seq-based transcriptome analysis of G1E-ER4 cells differentiated in the presence of the OGA inhibitor Thiamet-G (TMG) revealed changes in expression of 433 GATA-1 target genes. ChIP results indicated that the TMG treatment decreases the occupancy of GATA-1, OGT, and OGA at the GATA-binding site of the lysosomal protein transmembrane 5 (LAPTM5) gene promoter. TMG also reduced the expression of genes involved in differentiation of NB4 and HL60 human myeloid leukemia cells, suggesting that O-GlcNAcylation is involved in the regulation of hematopoietic differentiation. Sustained treatment of G1E-ER4 cells with TMG before differentiation reduced hemoglobin-positive cells and increased stem/progenitor cell surface markers. Our results show that alterations in O-GlcNAcylation disrupt transcriptional programs controlling erythropoietic lineage commitment, suggesting a role for O-GlcNAcylation in regulating hematopoietic cell fate. PMID- 30523151 TI - Aurora B kinase activity-dependent and -independent functions of the chromosomal passenger complex in regulating sister chromatid cohesion. AB - The chromosomal passenger complex (CPC) is a master regulator of mitosis. CPC consists of inner centromere protein (INCENP), Survivin, Borealin, and the kinase Aurora B, plays key roles in regulating kinetochore-microtubule attachments and spindle assembly checkpoint signaling. However, the role of CPC in sister chromatid cohesion, mediated by the cohesin complex, remains incompletely understood. Here we show that Aurora B kinase activity contributes to centromeric cohesion protection partly through promoting kinetochore localization of the kinase Bub1. Interestingly, disrupting the interaction of INCENP with heterochromatin protein 1 (HP1) in HeLa cells selectively weakens cohesion at mitotic centromeres without detectably reducing the kinase activity of Aurora B. Thus, through this INCENP-HP1 interaction, the CPC also protects centromeric cohesion independently of Aurora B kinase activity. Moreover, the requirement for the INCENP-HP1 interaction in centromeric cohesion protection can be bypassed by tethering HP1 to centromeres or by depleting the cohesin release factor Wapl. We provide further evidence suggesting that the INCENP-HP1 interaction protects centromeric cohesion by promoting the centromere localization of Haspin, a protein kinase that antagonizes Wapl activity at centromeres. Taken together, this study identifies Aurora B kinase activity-dependent and -independent roles for the CPC in regulating centromeric cohesion during mitosis in human cells. PMID- 30523152 TI - Metabolic fingerprinting for diagnosis of fibromyalgia and other rheumatologic disorders. AB - Diagnosis and treatment of Fibromyalgia (FM) remains a challenge owing to the lack of reliable biomarkers. Our objective was to develop a rapid biomarker-based method for diagnosing FM by using vibrational spectroscopy to differentiate patients with FM from those with Rheumatoid Arthritis (RA), Osteoarthritis (OA) or Systemic Lupus Erythematosus (SLE), and to identify metabolites associated with these differences. Blood samples were collected from patients with a diagnosis of FM (n=50), RA (n=29), OA (n=19), or SLE (n=23). Bloodspot samples were prepared, and spectra collected with portable FT-IR and FT-Raman microspectroscopy and subjected to metabolomics analysis by ultra-HPLC (uHPLC), coupled to a photodiode array (PDA) and tandem MS/MS. Unique IR and Raman spectral signatures were identified by pattern recognition analysis and clustered all study participants into classes (FM, RA and SLE) with no misclassifications (p < 0.05, and interclass distances > 2.5). Furthermore, the spectra correlated (R= 0.95 and 0.83 for IR and Raman, respectively) with FM pain severity measured with fibromyalgia impact questionnaire revised version (FIQR) assessments. Protein backbones and pyridine-carboxylic acids dominated this discrimination and might serve as biomarkers for syndromes such as FM. uHPLC-PDA-MS/MS provided insights into metabolites significantly differing among the disease groups, not only in molecular m/z+ and m/z- values but also in UV-vis chromatograms. We conclude that vibrational spectroscopy may provide a reliable diagnostic test for differentiating FM from other disorders and for establishing serologic biomarkers of FM-associated pain. PMID- 30523153 TI - Structural insights into non-covalent ubiquitin activation of the cIAP1 UbcH5B~ubiquitin complex. AB - Ubiquitin (Ub)-conjugating enzymes and Ub ligases control protein degradation and regulate many cellular processes in eukaryotes. Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a central role in apoptosis and tumor necrosis factor signaling. It harbors a C-terminal RING domain that homodimerizes to recruit E2~Ub (~ denotes a thioester bond) complex to catalyze Ub transfer. Non-covalent Ub binding to the backside of the E2 Ub-conjugating enzyme UbcH5 has previously been shown to enhance RING domain activity, but the molecular basis for this enhancement is unclear. To investigate how dimeric cIAP1 RING activates E2~Ub for Ub transfer and what role non-covalently bound Ub has in Ub transfer, here we determined the crystal structure of the cIAP1 RING dimer bound to both UbcH5B covalently-linked to Ub (UbcH5B-Ub) and a non-covalent Ub to 1.7 A resolution. The structure along with biochemical analyses revealed that the cIAP1 RING domain interacts with UbcH5B-Ub and thereby promotes the formation of a closed UbcH5B-Ub conformation that primes the thioester bond for Ub transfer. We observed that the non-covalent Ub binds to the backside of UbcH5B and abuts UbcH5B's alpha1beta1 loop, which, in turn, stabilizes the closed UbcH5B-Ub conformation. Our results disclose the mechanism by which cIAP1 RING dimer activates UbcH5B~Ub and indicate that non-covalent Ub binding further stabilizes the cIAP1-UbcH5B~Ub complex in the active conformation to stimulate Ub transfer. PMID- 30523154 TI - The mitochondrial chaperone Prohibitin 1 negatively regulates interleukin-8 in human liver cancers. AB - Prohibitin 1 (PHB1) is a mitochondrial chaperone whose expression is dysregulated in cancers. In liver cancer, PHB1 acts as a tumor suppressor but the mechanisms of tumor suppression are incompletely understood. Here we aimed to determine PHB1 target genes to better understand how PHB1 influences liver tumorigenesis. Using RNA-seq analysis, we found interleukin-8 (IL-8) to be one of the most highly upregulated genes following PHB1 silencing in HepG2 cells. Induction of IL-8 expression also occurred in multiple liver and non-liver cancer cell lines. We examined samples from 178 patients with hepatocellular carcinoma (HCC) and found that IL-8 mRNA levels were increased, while PHB1 mRNA levels were decreased, in the tumors compared to adjacent non-tumorous tissues. Notably, HCC patients with high IL-8 expression have significantly reduced survival. An inverse correlation between PHB1 and IL-8 mRNA levels is found in HCCs with reduced PHB1 expression. To understand the molecular basis for these observations, we altered PHB1 levels in liver cancer cells. Overexpression of PHB1 resulted in lowered IL-8 expression and secretion. Silencing PHB1 increased JNK and NF-kappaB activity, induced nuclear accumulation of c-JUN and p65 and enhanced their binding to the IL-8 promoter containing AP-1 and NF-kappaB elements. Conditioned medium from PHB1 silenced HepG2 cells increased migration and invasion of parental HepG2 and SK hep-1 cells, and this was blocked by co-treatment with neutralizing IL-8 antibody. In summary, our findings show that reduced PHB1 expression induces IL-8 transcription by activating NF-kappaB and AP-1, resulting in enhanced IL-8 expression and release to promote tumorigenesis. PMID- 30523155 TI - Adaptor protein complex-1 (AP-1) is recruited by the HEATR5 protein Laa1 and its cofactor Laa2 in yeast. AB - Cellular membrane trafficking mediated by the clathrin adaptor protein complex-1 (AP-1) is important for the proper composition and function of organelles of the endo-lysosomal system. Normal AP-1 function requires proteins of the HEAT repeat containing 5 (HEATR5) family. Although HEATR5 proteins were first identified based on their ability to interact with AP-1, the functional significance of this interaction was unknown. We used bioinformatics-based phenotypic profiling and information from genome-wide fluorescence microscopy studies in the budding yeast Saccharomyces cerevisiae to identify a protein, Laa2, that mediates the interaction between AP-1 and the yeast HEATR5 protein Laa1. Further characterization of Laa2 revealed that it binds to both Laa1 and AP-1. Laa2 contains a motif similar to the characterized gamma-ear-binding sites found in other AP-1-binding proteins. This motif in Laa2 is essential for the Laa1-AP-1 interaction. Moreover, mutation of this motif disrupted AP-1 localization and function, and causes effects similar to mutations that remove the gamma-ear of AP 1. These results indicate that Laa2 mediates the interaction between Laa1 and AP 1 and reveal that this interaction promotes the stable association of AP-1 with membranes in yeast. PMID- 30523156 TI - Thioesterase superfamily member 2 promotes hepatic insulin resistance in the setting of Glycerol-3-phosphate acyltransferase 1-induced steatosis. AB - Hepatic insulin resistance in the setting of steatosis is attributable at least in part to the accumulation of bioactive lipids that suppress insulin signaling. The mitochondria-associated glycerol-3-phosphate acyltransferase 1 (GPAT1) catalyzes the first committed step in glycerolipid synthesis, and its activity diverts fatty acids from mitochondrial beta-oxidation. GPAT1 overexpression in mouse liver leads to hepatic steatosis even in the absence of overnutrition. The mice develop insulin resistance owing to the generation of saturated diacylglycerol and phosphatidic acid molecular species that reduce insulin signaling by activating PKCε and by suppressing mTORC2, respectively. Them2, a mitochondria-associated acyl-CoA thioesterase, also participates in the trafficking of fatty acids into oxidative versus glycerolipid biosynthetic pathways. Them2 -/- mice are protected against diet-induced hepatic steatosis and insulin resistance. To determine whether Them2 contributes to hepatic insulin resistance due to hepatic overexpression of GPAT1, recombinant adenovirus was used to overexpress GPAT1 in livers of chow fed Them2 +/+ and Them2 -/- mice. Hepatic GPAT1 overexpression led to steatosis in both genotypes. In the setting of GPAT1 overexpression, glucose tolerance was reduced in Them2 +/+ but not Them2 -/- mice, without influencing whole body insulin sensitivity or basal hepatic glucose production. Improved glucose tolerance in Them2 -/- mice was associated with reduced PKCε translocation. Preserved insulin receptor activity was supported by T308 phosphorylation of Akt following GPAT1 overexpression in Them2 /- hepatocytes. These findings suggest a pathogenic role of Them2 in the biosynthesis of glycerolipid metabolites that promote hepatic insulin resistance. PMID- 30523157 TI - Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response. AB - Dysregulation of the ErbB family of receptor tyrosine kinases is involved in the progression of many cancers. Antibodies targeting the dimerization domains of family members EGFR and HER2 are approve cancer therapeutics, but efficacy is restricted to a subset of tumors and resistance often develops in response to treatment. A third family member, HER3, heterodimerizes with both EGFR and HER2 and has also been implicated in cancer. Consequently, there is strong interest in developing antibodies that target HER3, but to date, no therapeutics have been approved. To aid the development of anti-HER3 antibodies as cancer therapeutics, we combined antibody engineering and functional genomics screens to identify putative mechanisms of resistance or synthetic lethality with antibody-mediated anti-proliferative effects. We developed a synthetic antibody called IgG 95, which binds to HER3 and promotes ubiquitination, internalization and receptor down-regulation. Using an shRNA library targeting enzymes in the ubiquitin proteasome system, we screened for genes that effect response to IgG 95 and uncovered the E3 ubiquitin ligase RNF41 as a driver of IgG 95 anti-proliferative activity. RNF41 has been shown previously to regulate HER3 levels under normal conditions and we now show that it is also responsible for down-regulation of HER3 upon treatment with IgG 95. Moreover, our findings suggest that down regulation of RNF41 itself may be a mechanism for acquired resistance to treatment with IgG 95 and perhaps other anti-HER3 antibodies. Our work deepens our understanding of HER3 signaling by uncovering the mechanistic basis for the anti-proliferative effects of potential anti-HER3 antibody therapeutics. PMID- 30523158 TI - Leucine-Rich Repeats and Calponin Homology containing 4 regulates the innate immune response. AB - Toll-like Receptors (TLRs) are pathogen-recognition receptors that trigger the innate immune response. Recent reports have identified accessory proteins that provide essential support to TLR function through ligand delivery and receptor trafficking. Herein, we introduce leucine-rich repeats (LRR) and calponin homology containing 4 (Lrch4) as a novel TLR accessory protein. Lrch4 is a membrane protein with 9 LRRs in its predicted ectodomain. It is widely expressed across murine tissues, and has two expression variants that are both regulated by lipopolysaccharide (LPS). Predictive modeling indicates that Lrch4 LRRs conform to the horseshoe-shaped structure typical of LRRs in pathogen-recognition receptors, and that the best structural match in the protein database is to the variable lymphocyte receptor of the jawless vertebrate, hagfish. Silencing Lrch4 attenuates cytokine induction by LPS and multiple other TLR ligands and dampens the in vivo innate immune response. Lrch4 promotes proper docking of LPS in lipid raft membrane microdomains. We provide evidence that this is through regulation of lipid rafts as Lrch4 silencing reduces cell surface gangliosides, a metric of raft abundance, as well as expression and surface display of CD14, a raft resident LPS co-receptor. Taken together, we identify Lrch4 as a broad-spanning regulator of the innate immune response and a potential molecular target in inflammatory disease. PMID- 30523159 TI - Muscle A-kinase-anchoring protein-beta-bound calcineurin toggles active and repressive transcriptional complexes of myocyte enhancer factor 2D. AB - Myocyte enhancer factor 2 (MEF2) transcription factors are key regulators of the development and adult phenotype of diverse tissues including skeletal and cardiac muscles. Controlled by multiple post-translational modifications, MEF2D is an effector for the Ca2+/calmodulin-dependent protein phosphatase calcineurin (CaN, PP2B, and PPP3). CaN-catalyzed dephosphorylation promotes the desumoylation and acetylation of MEF2D increasing its transcriptional activity. Both MEF2D and CaN bind the scaffold protein muscle A-kinase anchoring protein beta (mAKAPbeta), which is localized to the nuclear envelope, such that C2C12 skeletal myoblast differentiation and neonatal rat ventricular myocyte hypertrophy are inhibited by mAKAPbeta signalosome targeting. Using immunoprecipitation and DNA-binding assays, we now show that the formation of mAKAPbeta signalosomes is required for MEF2D dephosphorylation, desumoylation, and acetylation in C2C12 cells. Reduced MEF2D phosphorylation was coupled to a switch from type IIa histone deacetylase to p300 histone acetylase binding that correlated with increased MEF2D-dependent gene expression and ventricular myocyte hypertrophy. Together these results highlight the importance of mAKAPbeta signalosomes for regulating MEF2D activity in striated muscle, affirming mAKAPbeta as a nodal regulator in the myocyte intracellular signaling network. PMID- 30523160 TI - Regulator of telomere length 1 (RTEL1) mutations are associated with heterogeneous pulmonary and extra-pulmonary phenotypes. AB - RTEL1 mutations have been evidenced in 5-9% of familial pulmonary fibrosis, but the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly known.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lung of controls, RTEL1 and TERT mutation carriers.We identified 35 subjects, from 17 families. Median age at diagnosis of ILD was 55.2 years [28.0-80.6]. The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%) secondary ILD (n=7, 20%) and unclassifiable fibrosis or IPAF (n=7, 20%). The median transplant-free- and overall-survival were 39.2 and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations, including this series and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non idiopathic diseases, and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, alveolar macrophages and lymphocytes but not by fibroblast. PMID- 30523161 TI - Human diaphragm atrophy in ALS is not predicted by routine respiratory measures. AB - Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (NCT01583088). Myofibre type, size, and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength, and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed in multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity, maximal inspiratory pressure, sniff nasal inspiratory pressure, and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity correlated modestly with slow-twitch myofibre atrophy. Supine fall in vital capacity correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that inspiratory capacity, sniff nasal inspiratory pressure, and functional residual capacity were independent predictors of diaphragm slow-twitch - but not fast-twitch - atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function. PMID- 30523162 TI - Economic burden of bronchiectasis in Germany. AB - Estimates of healthcare costs for incident bronchiectasis patients are currently not available for any European country. Out of a sample of 4 859 013 persons covered by German statutory health insurance companies, 231 new bronchiectasis patients were identified in 2012. They were matched with 685 control patients by age, gender and Charlson Comorbidity Index and followed for 3 years.The total direct expenditure during that period per insured bronchiectasis patient was ?18,634.57 [95%CI: ?15,891.02-?23,871.12], nearly one third higher (ratio of mean 1.31 [95%CI: 1.02-1.68]) than for a matched control (p<0.001).Hospitalisation costs contributed to 35% of the total and were more than 50% higher in the bronchiectasis group (1.56 [95%CI: 1.20-3.01]; p<0.001); on average, bronchiectasis patients spent 4.9 more days [95%CI: 2.27-7.43] in hospital (p<0.001). Antibiotics expenditures per bronchiectasis outpatient (?413.81) were nearly five times higher than those for a matched control (4.85 [95%CI 2.72 8.64]).Each bronchiectasis patient had on average 40.5 [95%CI: 17.1-43.5] sick leave days and induced work-loss costs of ?4,230.49 [95%CI: ?2,849.58 ?5,611.20].The mortality rate for bronchiectasis and matched non-bronchiectasis patients after 3 years of follow up was 26.4% and 10.5%, respectively (p<0.001). Mortality in the bronchiectasis group was higher among those who also had COPD than in patients with bronchiectasis alone (35.9% and 14.6%, respectively; p<0.001).Although bronchiectasis is considered underdiagnosed, the mortality and associated financial burden in Germany are substantial. PMID- 30523163 TI - Reduced prevalence of latent TB infection in diabetes patients using metformin and statins. PMID- 30523164 TI - Mariana Wolfner: 2018 Genetics Society of America Medal. AB - The Genetics Society of America (GSA) Medal recognizes researchers who have made outstanding contributions to the field of genetics in the past 15 years. The 2018 GSA Medal has been awarded to Mariana Wolfner of Cornell University for her work on reproductive processes that occur around the time of fertilization. This includes characterization of seminal proteins in Drosophila melanogaster, which has uncovered a wealth of information about sexual conflict in evolution. PMID- 30523165 TI - Mogens Westergaard's Contributions to Understanding Sex Chromosomes. AB - A long-standing question in biology concerns the genetic mechanisms by which two sexes can evolve (botanists call this the dioecious condition and zoologists call it gonochory) from a functionally ancestral hermaphroditic state (without separate sexes). In 1932, H. J. Muller, one of the great 20th century geneticists but also a fine evolutionary biologist, pointed out that two mutations were necessary. It was therefore puzzling that sex determination often involves a single genetic locus. Muller believed that the evolution of a single-gene system was possible, because maize geneticists had synthesized a single-gene system with separate sexes. However, this system is highly artificial, requiring geneticists to actively eliminate the wild-type allele at one of the two genes involved. This genetic system cannot therefore explain the natural evolution of dioecy. In 1958, Westergaard reviewed studies from a diversity of flowering plants, and showed that the genetics of natural sex determination in plants does not support the maize system. Instead, the genetic results pointed to a model involving two separate factors, with close linkage creating a single genetic locus. Moreover, Westergaard also pointed out that a two-gene model offers a natural explanation for the evolution of suppressed recombination between sex chromosome pairs. Studying plants allowed genetic analyses of the early steps in the evolution of dioecy, using dioecious species that evolved recently from species without separate sexes, whereas Muller failed to fully understand such evolutionary changes because he focused on animals, where later changes have often happened and obscured the early stages. PMID- 30523166 TI - Evolutionary Virology at 40. AB - RNA viruses are diverse, abundant, and rapidly evolving. Genetic data have been generated from virus populations since the late 1970s and used to understand their evolution, emergence, and spread, culminating in the generation and analysis of many thousands of viral genome sequences. Despite this wealth of data, evolutionary genetics has played a surprisingly small role in our understanding of virus evolution. Instead, studies of RNA virus evolution have been dominated by two very different perspectives, the experimental and the comparative, that have largely been conducted independently and sometimes antagonistically. Here, we review the insights that these two approaches have provided over the last 40 years. We show that experimental approaches using in vitro and in vivo laboratory models are largely focused on short-term intrahost evolutionary mechanisms, and may not always be relevant to natural systems. In contrast, the comparative approach relies on the phylogenetic analysis of natural virus populations, usually considering data collected over multiple cycles of virus-host transmission, but is divorced from the causative evolutionary processes. To truly understand RNA virus evolution it is necessary to meld experimental and comparative approaches within a single evolutionary genetic framework, and to link viral evolution at the intrahost scale with that which occurs over both epidemiological and geological timescales. We suggest that the impetus for this new synthesis may come from methodological advances in next generation sequencing and metagenomics. PMID- 30523168 TI - Introgression of a Block of Genome Under Infinitesimal Selection. PMID- 30523167 TI - Triacylglycerol Metabolism in Drosophila melanogaster. AB - Triacylglycerol (TAG) is the most important caloric source with respect to energy homeostasis in animals. In addition to its evolutionarily conserved importance as an energy source, TAG turnover is crucial to the metabolism of structural and signaling lipids. These neutral lipids are also key players in development and disease. Here, we review the metabolism of TAG in the Drosophila model system. Recently, the fruit fly has attracted renewed attention in research due to the unique experimental approaches it affords in studying the tissue-autonomous and interorgan regulation of lipid metabolism in vivo Following an overview of the systemic control of fly body fat stores, we will cover lipid anabolic, enzymatic, and regulatory processes, which begin with the dietary lipid breakdown and de novo lipogenesis that results in lipid droplet storage. Next, we focus on lipolytic processes, which mobilize storage TAG to make it metabolically accessible as either an energy source or as a building block for biosynthesis of other lipid classes. Since the buildup and breakdown of fat involves various organs, we highlight avenues of lipid transport, which are at the heart of functional integration of organismic lipid metabolism. Finally, we draw attention to some "missing links" in basic neutral lipid metabolism and conclude with a perspective on how fly research can be exploited to study functional metabolic roles of diverse lipids. PMID- 30523170 TI - GENETICS Reviewer Index 2018. PMID- 30523169 TI - Identifying Signatures of Selection in Genetic Time Series. PMID- 30523171 TI - ISSUE HIGHLIGHTS. PMID- 30523173 TI - How do you assess quality of life? PMID- 30523172 TI - High prevalence of infection and low incidence of disease in child contacts of patients with drug-resistant tuberculosis: a prospective cohort study. AB - OBJECTIVE: We aimed to measure the prevalence and incidence of latent tuberculosis infection (LTBI) and tuberculosis (TB) disease in children in close contact with patients with drug-resistant TB (DR-TB) in a country with high DR-TB prevalence. DESIGN AND SETTING: This is a prospective cohort study of paediatric contacts of adult patients with pulmonary DR-TB in Armenia. Children were screened using tuberculin skin test, interferon-gamma release assay and chest X ray at the initial consultation, and were reassessed every 3-6 months for a period of 24 months. Children did not receive preventive treatment. MAIN OUTCOME MEASURES: Prevalence and incidence of LTBI and TB disease; factors associated with prevalent LTBI. RESULTS: At initial evaluation, 3 of the 150 children included were diagnosed with TB disease (2.0%). The prevalence of LTBI was 58.7%. The incidence of LTBI was 19.9 per 100 children per year, and was especially high during the first 6 months of follow-up (33.3 per 100 children per year). No additional cases with incident disease were diagnosed during follow-up. After adjustment, prevalent LTBI was significantly associated with the child's age, sleeping in the same house, higher household density, the index case's age, positive smear result and presence of lung cavities. CONCLUSIONS: Children in close contact with patients with DR-TB or in contact with very contagious patients had an increased risk of prevalent LTBI. Although none of the children developed TB disease during a 2-year follow-up period, screening for symptoms of TB disease, based on the prevalence of disease at recruitment, together with follow-up and repeated testing of non-infected contacts, is highly recommended in paediatric contacts of patients with DR-TB. PMID- 30523175 TI - News section PDF. PMID- 30523174 TI - Where do vet bodies stand on Brexit? PMID- 30523176 TI - 'Agriculture Bill needs more work and detail'. PMID- 30523177 TI - Vets speak up on Brexit. PMID- 30523178 TI - A ban on live exports after Brexit is possible, says RSPCA. PMID- 30523179 TI - Has the mystery of brown trout deaths been solved? AB - Every year, brown trout die in rivers in central Europe. But now, researchers think they have found the causative agent. Georgina Mills reports. PMID- 30523180 TI - In brief. PMID- 30523181 TI - The best ways to market your practice. PMID- 30523183 TI - Disease surveillance in England and Wales, November 2018. PMID- 30523182 TI - Hypoallergy diet for cats and dogs. PMID- 30523184 TI - Schmallenberg virus: a cyclical problem. PMID- 30523186 TI - Selected highlights from other journals. PMID- 30523185 TI - Is treatment with pimobendan associated with an increased risk of arrhythmias in dogs with heart disease? PMID- 30523187 TI - Environmental risk assessment of veterinary medicines. PMID- 30523188 TI - Tackling bovine TB. PMID- 30523189 TI - Tackling bovine TB. PMID- 30523190 TI - Tackling bovine TB. PMID- 30523191 TI - How do we make breeding dogs better? PMID- 30523192 TI - How do we make breeding dogs better? PMID- 30523193 TI - Work-life balance versus responsibility to patients. PMID- 30523194 TI - Work-life balance versus responsibility to patients. PMID- 30523195 TI - William Derek Tavernor. AB - A man of action who gave the impression that he always knew where he was going. PMID- 30523197 TI - Practice Marketing Award. PMID- 30523196 TI - From teacher to trailblazer. AB - Nalinika Obeyesekere was recently awarded the World Small Animal Veterinary Association's inaugural award for companion animal welfare in recognition of her contribution to raising standards of veterinary care in Sri Lanka. PMID- 30523198 TI - Veterinary nurse CPD. AB - A love of the outdoors is helping equine vet John Pate fight depression. As part of his recovery, he has applied to join the Fjallraven Polar 2019 expedition, which he hopes will inspire others to start a conversation about their mental health. PMID- 30523200 TI - Proteins and Clinical Mass Spectrometry: A Fairy Tale? PMID- 30523199 TI - Concurrent Single-Cell RNA and Targeted DNA Sequencing on an Automated Platform for Comeasurement of Genomic and Transcriptomic Signatures. AB - BACKGROUND: The comeasurement of both genomic and transcriptomic signatures in single cells is of fundamental importance to accurately assess how the genetic information correlates with the transcriptomic phenotype. However, existing technologies have low throughput and laborious work flows. METHODS: We developed a new method for concurrent sequencing of the transcriptome and targeted genomic regions (CORTAD-seq) within the same single cell on an automated microfluidic platform. The method was compatible with the downstream library preparation, allowing easy integration into existing next-generation sequencing work flows. We incorporated a single-cell bioinformatics pipeline for transcriptome and mutation analysis. RESULTS: As proof of principle, we applied CORTAD-seq to lung cancer cell lines to dissect the cellular consequences of mutations that result in resistance to targeted therapy. We obtained a mean detection of 6000 expressed genes and an exonic rate of 50%. The targeted DNA-sequencing data achieved a 97.8% detection rate for mutations and allowed for the identification of copy number variations and haplotype construction. We detected expression signatures of tyrosine kinase inhibitor (TKI) resistance, epidermal growth factor receptor (EGFR) amplification, and expansion of the T790M mutation among resistant cells. We also identified characteristics for TKI resistance that were independent of EGFR T790M, indicating that other alterations are required for resistance in this context. CONCLUSIONS: CORTAD-seq allows assessment of the interconnection between genetic and transcriptomic changes in single cells. It is operated on an automated, commercially available single-cell isolation platform, making its implementation straightforward. PMID- 30523202 TI - Half As Sad: A Plea for Narrative Medicine in Pediatric Residency Training. PMID- 30523201 TI - Species Typing of Nontuberculous Mycobacteria by Use of Deoxyribozyme Sensors. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) species are a rising threat, especially to patients living with pulmonary comorbidities. Current point-of-care diagnostics fail to adequately identify and differentiate NTM species from Mycobacterium tuberculosis (Mtb). Definitive culture- and molecular-based testing can take weeks to months and requires sending samples out to specialized diagnostic laboratories. METHODS: In this proof-of-concept study, we developed an assay based on PCR amplification of 16S ribosomal RNA (rRNA) rrs genes by using universal mycobacterial primers and interrogation of the amplified fragments with a panel of binary deoxyribozyme (BiDz) sensors to enable species-level identification of NTM (BiDz-NTMST). Each BiDz sensor consists of 2 subunits of an RNA-cleaving deoxyribozyme, which form an active deoxyribozyme catalytic core only in the presence of the complimentary target sequence. The target-activated BiDz catalyzes cleavage of a reporter substrate, thus triggering either fluorescent or colorimetric (visually observed) signal depending on the substrate used. The panel included BiDz sensors for differentiation of 6 clinically relevant NTM species (Mycobacterium abscessus, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium gordonae) and Mtb. RESULTS: Using the fluorescent BiDz-NTMST assay, we successfully identified the species of 38 clinical isolates. In addition, a subset of strains was tested with visual BiDz sensors, providing proof-of-concept for species typing of NTM by the naked eye. CONCLUSIONS: The BiDz-NTMST assay is a novel platform for rapid identification of NTM species. This method is highly specific and significantly faster than current tools and is easily adaptable for onsite diagnostic laboratories in hospitals or clinical laboratories. PMID- 30523203 TI - Celebrating the best in South Asian healthcare: who won a BMJ award? PMID- 30523204 TI - Hemin induces autophagy in a leukemic erythroblast cell line through the LRP1 receptor. AB - Hemin is an erythropoietic inductor capable of inducing autophagy in erythroid like cell lines. Low densitylipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor involved in a wide range of cellular processes, such as proliferation, differentiation and metabolism. Our aim was to evaluate whether LRP1 is responsible for hemin activity in K562 cells, with the results demonstrating a 3-fold increase in LRP1 gene expression levels ( p values < 0.001) when assessed by qRT-PCR. Moreover, a 70% higher protein amount was observed compared to control condition ( p values < 0.01) by Western blot. Time kinetic assays demonstrated a peak in LC3II levels after 8 h of hemin stimulation and the localization of LRP1 in the autophagosome structures. Silencing LRP1 by siRNA decreased drastically the hemin-induced autophagy activity byalmost 80% compared with control cells ( p values < 0.01). Confocal localization and biochemical analysis indicated a significant redistribution of LRP1 from early endosomes and recycling compartments to late endosomes and autophagolysosomes, where the receptor is degraded. We conclude that LRP1 is responsible forhemin induced autophagy activity in the erythroblastic cell line and that hemin-LRP1 complex activation promotes a self-regulation of the receptor. Our results suggest that hemin, via the LRP1 receptor, favors erythroid maturation by inducing an autophagic response, making it a possible therapeutic candidate to helps in the treatment of hematological disorders. PMID- 30523205 TI - The European research collaboration for Children's Interstitial Lung Disease (ChILDEU) ERS Clinical Research Collaboration. PMID- 30523206 TI - Improving the management of spontaneous pneumothorax. PMID- 30523207 TI - Improving the management of spontaneous pneumothorax. PMID- 30523208 TI - Dropping acid: why is cystic fibrosis mucus abnormal? PMID- 30523209 TI - Palliative care for patients with pulmonary fibrosis: symptom relief is essential. PMID- 30523210 TI - Current clinical management of smoke inhalation injuries: a reality check. PMID- 30523212 TI - [Think! According to the Chief Complaint, and with The Neuroradiologists' Bird's Eye]. AB - The remarkable progress of imaging diagnostic technology has nearly reached the point of determining the causative agent of neurodegenerative diseases, and it is becoming possible to capture detailed images that can reflect macro pathology. However, images are just images. In order to accomplish accurate image diagnosis in accordance with the chief complaint encountered in clinical practice, we must leave the chief complaint as the chief complaint, reevaluate the image on its own merits, and approach the disease condition from this new perspective. In this special feature, I would like to select the appropriate image examination based on the chief complaint of each patient, and furthermore to make use the imaging diagnostic technology to approach the disease condition, from the perspective of the experts of the neuroradiology whom I admire from the bottom of my heart. PMID- 30523211 TI - Proteome-wide tyrosine phosphorylation analysis reveals dysregulated signaling pathways in ovarian tumors. AB - The recent accomplishment of comprehensive proteogenomic analysis of high-grade serous ovarian carcinoma (HGSOC) tissues reveals cancer associated molecular alterations were not limited to variations among DNA, and mRNA/protein expression, but are a result of complex reprogramming of signaling pathways/networks mediated by the protein and post-translational modification (PTM) interactomes. A systematic, multiplexed approach interrogating enzyme substrate relationships in the context of PTMs is fundamental in understanding the dynamics of these pathways, regulation of cellular processes, and their roles in disease processes. Here, as part of Clinical Proteomic Tumor Analysis Consortium (CPTAC) project, we established a multiplexed PTM assay (tyrosine phosphorylation, and lysine acetylation, ubiquitylation and SUMOylation) method to identify protein probes' PTMs on the human proteome array. Furthermore, we focused on the tyrosine phosphorylation and identified 19 kinases are potentially responsible for the dysregulated signaling pathways observed in HGSOC. Additionally, elevated kinase activity was observed when 14 ovarian cancer cell lines or tumor tissues were subjected to test the autophosphorylation status of PTK2 (pY397) and PTK2B (pY402) as a proxy for kinase activity. Taken together, this report demonstrates that PTM signatures based on lysate reactions on human proteome array is a powerful, unbiased approach to identify dysregulated PTM pathways in tumors. PMID- 30523213 TI - [A Diagnostic Imaging Approach for Tremor]. AB - Tremor is one of the common movement disorders encountered in a clinical practice. Tremor is often difficult to diagnose and can be easily mistaken for another disorder, hence diagnostic imaging is employed to provide objective information. The morphometry, signal changes, neuromelanin, and iron deposition can be evaluated by MRI, whereas cardiac sympathetic nerve and dopamine transporter degeneration are detected by means of nuclear medicine. The purpose of this article is to provide an overview of the role and indications of imaging test, as well as a review of the methods in which the findings of images are interpreted. PMID- 30523214 TI - [Imaging-Based Diagnosis of Craniocervical Artery Dissections: A Strategy Focusing on the Pathological Condition and MRI Technique]. AB - Magnetic resonance imaging (MRI) is a non-invasive and useful imaging modality with a high contrast resolution to diagnose craniocervical artery dissections. However, to avoid misinterpretations and misdiagnosis, it is mandatory to understand not only the pathological condition of craniocervical artery dissection, but also the principles of MRI techniques. In this manuscript, the details of MRI findings, especially when using high-resolution vessel wall imaging, are discussed. PMID- 30523215 TI - [Diplopia/Double Vision]. AB - Here, I review the efficacy of radiological methods in the diagnosis of diplopia/double vision. The simplest technique for achieving a successful diagnosis is to capture a wide field-of-view image. In order to start the process of diagnosis, it is fundamental to first study the image findings. Analysis based on the principle of MECE or mutually exclusive collectively exhaustive is performed using four methods: deductive reasoning, fractionation, longitudinal study, and priority setting. The conventional practical procedure to attain a diagnosis is as follows. First, identify the location of the lesion by imaging, which will shorten the list of differential diagnosis. Second, obtain as much information as possible on the characteristics of the lesion in order to determine the pathology. Third, look for any associated findings, such as tortuous vasculature around the brain. Fourth, refer to all the available information; for example, the main complaint, clinical history, previous history, family history, physical findings, physiological findings, laboratory data, previous images, and other modalities. Finally, if still in doubt, one should consult with colleagues and the attending physician. However, because rationality (statistical analyses, such as posterior probability or positive predictive value with positive findings), predicted utility, and emotions play a factor in a person's decision making, it seems impossible to completely avoid oversights and misdiagnosis. PMID- 30523216 TI - [I Am Seeing a Human!: The Perception of an External Visual Stimulus Where None Exists]. AB - A visual hallucination (VH) is "the perception of an external visual stimulus where none exists". It frequently occurs in Lewy body disease (LBD): Parkinson's disease and dementia with Lewy bodies. Although the exact pathogenesis of VH in patients with LBD is not clearly understood, many neuroimaging studies (structure MRI: brain volume, functional MRI, positron emission tomography, and single photon emission computerized tomography) have reported reduced gray matter volume, altered activation, and reduced metabolism in the dorsal and ventral visual pathways. The results obtained from the neuroimaging studies suggest the presence of aberrant visual information processing. PMID- 30523217 TI - [Imaging-Based Diagnostic Approach to Abdominal Pain in Patients with Neurological and Neuropsychiatric Disorders]. AB - We focused on diseases causing both neurological and intestinal disorders and introduce representative cases with a case based review. We frequently encountered chronic constipation in patients with schizophrenia, dementia, and Parkinson's disease, and treated them with commonly used conservative management approaches. However, some serious diseases that require early diagnosis and treatment may also be present and should be identified. We discuss the pathophysiology and image features of these serious diseases. PMID- 30523218 TI - [The Basic Modules of the Neocortex]. AB - The mammalian neocortex contains diverse cell types but whether they organize into repeated modular circuits remains unknown. We discovered that major cell types in neocortical layer 5 form a lattice structure in many areas of the brain. Large-scale three-dimensional imaging revealed that distinct types of excitatory and inhibitory neurons form cell type-specific radial clusters termed microcolumns. Microcolumns form a hexagonal lattice tessellating a wide region of the neocortex. Neurons within individual microcolumns exhibit synchronized in vivo activity and visual responses with similar orientation preference and ocular dominance. During early postnatal development, microcolumns are coupled by cell type-specific gap junctions and later received convergent synaptic inputs. Thus, layer 5 neurons organize into a brain-wide modular system providing a template for cortical processing. PMID- 30523219 TI - [A Case of Sjogren's Syndrome with Multiple Stenoses of the Cerebral Arteries and Transient Neurological Symptoms and Signs]. AB - A 31-year-old woman was admitted to the hospital after several episodes of transient numbness in her fingers and dysarthria. No neurological symptoms and signs were observed in this patient on admission; however, blood tests revealed elevated amylase and immunoglobulin G levels, an increased erythrocyte sedimentation rate, and positive anti-Sjogren's-syndrome (SjS)-related antigen A antibodies. The cerebrospinal fluid examination revealed a slight increase in the cell count and protein content. Diffusion-weighted and fluid-attenuated inversion recovery images on magnetic resonance imaging showed high-signal-intensity lesions in the cerebral white matter and basal ganglia supplied by the left middle cerebral artery. A part of the lesions was enhanced by the administration of gadolinium contrast medium. Magnetic resonance angiography suggested stenosis in the left anterior, middle, and posterior cerebral arteries. The patient was thus diagnosed with acute cerebral infarction and was then treated with argatroban, edaravone, and clopidogrel. Furthermore, Schirmer's test, sialography, and salivary gland biopsy results led to the diagnosis of SjS. A nerve conduction study suggested concomitant mild polyneuritis or mononeuritis multiplex. Collectively, we speculate that cerebral arterial stenosis associated with SjS leads to transient ischemic attack-like episodes, transient neurological symptoms and signs, and cerebral infarction. (Received June 13, 2018; Accepted September 11, 2018; Published December 1, 2018). PMID- 30523220 TI - A CREB1/miR-433 reciprocal feedback loop modulates proliferation and metastasis in colorectal cancer. AB - Increasing evidence has indicated the prognostic value of miR-433 across a series of malignancy types. However, the underlying mechanisms involved in cancer progression haven't been sufficiently elucidated. In the present work, we found that miR-433 was downregulated in CRC tissues and cell lines. Ectopic expression of miR-433 obviously suppressed the proliferation, invasion and metastasis activity of CRC cells in vitro and in vivo. CREB1, CCAR1 and JNK1 were highly expressed and negatively correlated with miR-433 expression in CRC. CRC patients with higher expression of CREB1, CCAR1 or JNK1 presented a worse outcome relative to those with lower expression. CREB1 transactivated the expression of miR-433, and CREB1, CCAR1 and JNK1 simultaneously served as its targets, which in turn composed a feedback loop between CREB1 and miR-433. miR-433 blocked cell cycle progression and abolished EMT. Collectively, our study demonstrated the CREB1/miR 433 reciprocal feedback loop restrained the propagation, invasion and metastasis activities of CRC cells through abrogation of cell cycle progression and constraint of EMT. PMID- 30523221 TI - Abdominal aortic aneurysm in aged population. PMID- 30523222 TI - [Effect of EGCG on oxidative stress and Nrf2/HO-1 pathway in neurons exposed to oxygen-glucose deprivation/reperfusion]. AB - OBJECTIVE: To explore the effect of epigallocatechin gallate (EGCG) on oxidative stress and Nrf2/HO-1 pathway in neurons subjected to oxygen-glucose deprivation/reperfusion (OGD/R).? Methods: Primary cultured cerebral cortical neurons were prepared from Sprague-Dawley rats, and the OGD/R cell model was established. After pretreatment with EGCG at different concentrations (12.5, 25.0, 50.0 or 100.0 MUmol/L), the neurons were subjected to OGD/R. The cell viability, reactive oxygen species (ROS) level and malondialdehyde (MDA) content were assessed after reperfusion. The superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were measured. The expression of Nrf2 protein in nucleus, HO-1 mRNA and protein were detected.? Results: OGD/R treatment reduced the cell viability, elevated ROS level and MDA content, decreased SOD and GSH-Px activities. The expression of Nrf2 protein in nucleus, HO-1 mRNA and protein were increased (P<0.01). Pretreatment with EGCG promoted the survival of neurons exposed to OGD/R, decreased ROS level and MDA content while increased SOD and GSH Px activities. The levels of Nrf2 protein in nucleus, HO-1 mRNA and protein were upregulated (P<0.01).? Conclusion: EGCG can reduce the oxidative stress of neurons subjected to OGD/R, which may be related to activation of Nrf2/HO-1 signal pathway and enhancement of the antioxidant ability of neurons. PMID- 30523223 TI - [Serum levels of miRNA-183 in patients with esophageal squamous cell carcinoma and its diagnostic value]. AB - OBJECTIVE: To explore the changes of serum microRNA-183 levels in patients with esophageal squamous cell carcinoma (ESCC) and its clinical significance.? Methods: Fifty-one patients with ESCC and 55 healthy subjects from Department of Cardiothoracic Surgery, Second Xiangya Hospital, Central South Unicersity were selected for this study. Real-time quantitative polymerase chain reaction (RT qPCR) was used to determine the level of miRNA-183 in serum samples. Chi-square test and correlation analysis were used to investigate the relationship between serum miRNA-183 level and clinical and pathological parameters of ESCC. Diagnostic efficiency of miRNA-183 and combined carcinoembryonic antigen (CEA) examination for ESCC was analyzed by receiver operating characteristic (ROC) curve.? Results: 1) The levels of miR-183 in the patients with ESCC (4.47+/-1.54) were elevated compared with that in the healthy subjects (2.03+/-0.96), with significant difference (t=9.700, P<0.01). 2) The levels of serum miR-183 in ESCC patients were significantly different among patients with different TNM stages (chi2=4.049, P<0.01), which was not affected by gender, age, smoking, drinking, tumor location, tumor diameter, lymph node metastasis, depth of invasion and differentiation (all P>0.05). The levels of miR-183 were not associated with the serum CEA levels (P>0.05). 3) When the ROC curve analysis was used to diagnose ESCC with the optimal cutoff value of 4.502 for miR-183, the sensitivity, the specificity, the area under the curve (AUC) and 95% confidence interval was 78.9%, 76.2%, 0.762 and 0.830-0.922, respectively. When combined detection of serum miR-183 and CEA was used to diagnose ESCC, the sensitivity, specificity, AUC and 95% confidence interval was 82.3%, 92.6%, 0.877 and 0.814-0.935, respectively.? Conclusion: Serum miRNA-183 levels in ESCC patients may be increased, which can improve the diagnostic efficiency of ESCC when combined with CEA. Serum miRNA-183 levels is related with tumor TNM stage, which contributes to the judgment of tumor progression and efficacy prediction. PMID- 30523224 TI - [Effect of Parkinson's disease-relevant protein DJ-1 on cell proliferation, apoptosis, invasion and migration in human osteosarcoma cells]. AB - OBJECTIVE: To investigate the effect of Parkinson's disease related protein DJ-1 on the cell proliferation, apoptosis, invasion and migration in human osteosarcoma cells and the underlying molecular mechanisms. ? Methods: The protein expression levels of DJ-1 were detected in human osteosarcoma cell lines (MG-63, Saos-2, and U2OS) and human osteoblast cell line hFOB1.19 with or without deficiency in phosphatase and tensin homolog deleted from chromosome 10 (PTEN) were detected by Western blot. Osteosarcoma cells were treated with DJ-1 siRNA, and then the protein expression levels of DJ-1 were detected by Western blot. Cell survival rate of osteosarcoma cells was detected by cell counting kit-8 (CCK 8) assay. Cell apoptosis of osteosarcoma cells was measured by annexin V fluorescein isothiocyanate (FITC)/propidium iodide (PI) double staining method. Cell invasive and migration ability of osteosarcoma cells were examined by transwell invasion and migration assay. ? Results: Compared with that of human osteoblast cell line (hFOB1.19), the protein expression level of DJ-1 was significantly upregulated in human osteosarcoma cell lines (MG-63, Saos-2, and U2OS) (all P<0.05), and U2OS had the highest level of DJ-1 when compared with the other three cell lines (P<0.01). DJ-1 siRNA could significantly down-regulate the DJ-1 protein expression in U2OS cells, and also diminish the cell survival rate. Moreover, DJ-1 down-regulation of DJ-1 could promote cell apoptosis, suppress the ability of cell invasion and migration, and increase the PTEN protein expression level (all P<0.05). In addition, the protein expression level of PTEN was markedly up-regulated in human osteosarcoma cell lines when compared with that in the hFOB1.19 cells (P<0.05). ? Conclusion: DJ-1 can promote the cell proliferation, inhibit cell apoptosis, and decrease the ability of cell invasion and migration, and the potential underlying mechanisms may be associated with the up-regulation of PTEN protein expression. PMID- 30523225 TI - [Effect of AG490 on JAK2/STAT3 signaling pathway in human retinoblastoma HXO-RB44 cell lines]. AB - OBJECTIVE: To investigate the role of Janus kinase (JAK) inhibitor AG490 in the anti-proliferation and cell cycle in human retinoblastoma HXO-RB44 cell lines in vitro, and to explore its effect on the expression of JAK2/signal transducer and activator of transcription 3 (STAT3).? Methods: Cells were divided into an experiment group and a control group, and the experiment group was further divided into 6 sub-groups according to different AG490 concentrations (6.25, 12.50, 25.00, 50.00 or 100.00 MUmol/L). Cell proliferation in the different groups was analyzed by cell vitality determination. Cell cycle distribution and apoptosis rate were examined by flow cytometry. The protein levels of STAT3, p STAT3 and vascular endothelial growth factor (VEGF) were detected by Western blot.? Results: After 48 h treatment with AG490, the viability of HXO-RB44 cells was reduced in a concentration-dependent manner. Compared with the control group, there was no significant difference in the experiment groups except the 6.25 MUmol/L group (all P>0.05). The apoptosis rates in the experiment groups were significantly increased with increase in concentration of AG490 compared with that in the control group (all P<0.05). The cell ratio in the G1 phase in 50 or 100 MUmol/L group was increased, whereas the cell ratio in the S phase was decreased. Western blot results showed that the expressions of STAT3 and p-STAT3 in the experiment groups were dramatically reduced with the increase in concentration of AG490 compared with that in the control group (all P<0.05). VEGF expression didn't obviously change in the experiment groups with AG490 concentration less than 12.5 MUmol/L compared with that in the control group (both P>0.05), but there were significant differences in the other experiment groups (all P<0.05). ? Conclusion: JAK inhibitor AG490 can inhibit proliferation and promote apoptosis of the retinoblastoma HXO-RB44 cells through down regulation of JAK2/STAT3 signaling pathway. PMID- 30523226 TI - [Influence of nourishing yin and tonifying yang sequential therapy combined with Western medicine on TGF-beta1/Smads signaling pathway in anovulatory infertility rats with diminished ovarian reserve]. AB - OBJECTIVE: To explore the influence for combination of nourishing yin and tonifying yang sequential therapy (NYTYST) with Western medicine in treating anovulatory infertility rats with diminished ovarian reserve (DOR) based on TGF beta1/Smads signaling pathway. ? Methods: A total of 40 female rats were randomly divided into 5 groups, a normal control group, a model group, a Western medicine group, a NYTYST group and a combination group (n=8 in each group). The DOR model was established through orally taking tripterygium pill for continuous 2 weeks. The normal control group and the model group were treated with saline for 10 days. The Western medicine group was treated with hormone replacement therapy (HRT) and ovarian stimulation. The NYTYST group was treated with nourishing yin herbs in proestrus and tonifying yang herbs in late estrus and the combination group was treated with Chinese herb and Western drugs for 10 days. HE staining was used to observe histopathologic changes in ovary. Expression levels of transforming growth factor beta1 receptor (TGF-beta1R) in rats ovarian were detected by immunohistochemistry. Expression levels of Smad2, Smad3 and Smad7 protein in rat ovarian were detected by Western blot.? Results: Compared with the control group, the numbers of developing follicles, mature follicles and corpus luteum were decreased , while atrefic follicles were increased significantly in the model group (P<0.01); the levels of TGF-beta1R, Smad2 and Smad3 were decreased significantly, while Smad7 was increased significantly (P<0.01). Compared with the model group, the numbers of developing follicles, mature follicles and corpus luteum, Smad2 and Smad3 expression were increased, while atrefic follicles and Smad7 were decreased significantly in the treatment group (P<0.05 or P<0.01). The numbers of developing follicles and corpus luteum in the combination group was superior to the Western medicine group (P<0.05). Compared with the Western medicine group, the levels of TGF-beta1R, Smad2 and Smad3 were increased significantly, while Smad7 was decreased significantly in the combination group (P<0.05 or P<0.01). ? Conclusion: NYTYST combined with Western medicine can improve the function of ovaries reserve by up-regulation of TGF beta1R, Smad2 and Smad3 while down-regulation of Smad7 in DOR rats. PMID- 30523227 TI - [Honokiol attenuates lipopolysaccharide-induced acute respiratory distress syndrome via activation of mitochondrion-dependent Sirt3/AMPK pathway]. AB - OBJECTIVE: To explore the effects of honokiol (HKL) on pulmonary microvascular endothelial cells in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) and the underlying mechanisms.? Methods: In animal experiment, a total of 40 C57BL/6J mice were randomly divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+honokiol (HKL) intervention group (HKL group) and a LPS+HKL+nicotinamide (NAM) intervention group (NAM group) (n=10 in each group). In the cell experiment, the experiment cells were divided into a control group (Con group), a LPS intervention group (LPS group), a LPS+HKL intervention group (HKL group), a LPS+HKL+NAM intervention group (NAM group), and a LPS+HKL+compound C (CMC) intervention group (CMC group). The pathological changes of the lung tissues were evaluated by hematoxylin and eosin (HE) staining; the protein concentration, total cells and neutrophils in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the lung tissues were detected; the changes of pulmonary microvascular permeability were determined by Evans blue assay; the effect of HKL on the vitality of human pulmonary microvascular endothelial cells were examined by cell counting kit-8 (CCK-8); the inhibitors including NAM and CMC were applied to explore the molecular mechanism of the protective effects of HKL. The expression levels of Sirt3, caspase-3, cleaved caspase-3, Bcl-2, Bax, p-adenosine monophosphate activated protein kinase (p-AMPK) and AMPK in lung tissues or cells were detected by Western blot.? Results: In animal models, compared with the Con group, the mice in the LPS group displayed typical ARDS pathological changes, and the ratio of lung wet/dry weight (W/D) and MPO activity in the lung tissues, protein concentration, total cells and neutrophils in BALF, Evans blue leaking index (ELI), expression levels of cleaved caspase-3 were significantly increased (all P<0.05), while the expression levels of Sirt3 was obviously decreased (P<0.05). Compared with the LPS group, the above changes in the LPS group were significantly improved in the HKL group (all P<0.05); Compared with the HKL group, the curative effect of HKL intervention could be partly inhibited in the NAM group (P<0.05). In cell experiments, compared with the LPS group, the HPMECs viability in the HKL group was markedly improved (P<0.05), while the expression levels of Bcl-2 and Sirt3 were significantly upregulated (P<0.05), and the expression levels of Bax and cleaved caspase-3 were significantly downregulated (P<0.05), accompanied by the activation of AMPK pathway (P<0.05) in the HKL group. Compared with the HKL group, the curative effect of HKL intervention was partly inhibited in the CMC group (P<0.05).? Conclusion: HKL can significantly attenuate LPS-induced lung injury and inhibit the apoptosis of pulmonary microvascular endothelial cells through regulation of Sirt3/AMPK pathway. PMID- 30523228 TI - [Expression of interleukin-11 and its receptor in lung of mice with idiopathic pulmonary fibrosis]. AB - OBJECTIVE: To observe the expression changes of interleukin-11 (IL-11) and its receptor in mice with pulmonary fibrosis. ? Methods: C57BL/6 mice were randomly divided into a control group and a bleomycin (BLM) group (6 mice per group). BLM was injected into mice to induce idiopathic pulmonary fibrosis, while 50 MUL PBS was injected into the control rats. The lung tissue was collected 21 d later. HE staining was used to observe morphological changes in lung tissue. Real-time PCR was used to detect IL-11 and its receptor gene expression. Western blot and immunohistochemical staining were used to detect IL-11 receptor expression. ELISA was used to detect the content of serum IL-11 in mice. In addition, the gene and protein expression of IL-11 receptor in mouse fibroblasts were detected by real time PCR and Western blot, respectively. ? Results: HE staining showed a significant change in pulmonary fibrosis in mice 21 d after BLM injection. The IL 11 mRNA expression in lung and IL-11 level in serum were up-regulated. The gene and protein expression of IL-11 receptor in mice with pulmonary fibrosis were significantly increased. The results from the cell experiments showed that the gene and protein expression of IL-11 receptor in mouse fibroblasts were significantly increased by TGF-beta1.? Conclusion: The expression of IL-11 and its receptor are up-regulated in mice with pulmonary fibrosis induced by BLM, which might be an important mechanism for the development of pulmonary fibrosis. PMID- 30523229 TI - [Alpha-mangostin attenuates focal segmental glomerulosclerosis of mice induced by adriamycin]. AB - OBJECTIVE: To observe the protective effect of alpha-mangostin (alpha-MG) on focal segmental glomurular sclerosis (FSGS) induced by adriamycin.? Methods: Adriamycin nephropathy (AN) model was induced by adriamycin (10 mg/kg) via a tail vein. Then the mice were treated with alpha-MG (12.5 mg/kg) or normal salin once daily for 6 weeks. At the end of 6 weeks, the mice were sacrificed, and the kidneys and blood samples were collected. Histopathology of the kidneys were analyzed under the optical microscope. The serum levels of biochemical indicators, such as serum creatinine (SCr), blood urea nitrogen (BUN) and cholesterol were determined. The levels of superoxide anion, malondialdehyde (MDA), and glutathione (GSH), the activity of superoxide dismutase (SOD) and catalase (CAT) in kidney tissues were determined. Serum levels of IL-1beta, IL 18, IL-10 and adiponectin were determined. The levels of TGF-beta1, collagen I (Col I), alpha-SMA, silent information regulator 1 (Sirt1) and the nucleotide binding domain (NOD)-like receptor protein 3 (NLRP3) in kidney tissues were determined using immunohistochemical staining, Western blot, and RT-PCR.? Results: The levels of SCr, proteinuria, urine protein to creatinine ratio and serum cholesterol were attenuated in AN mice after alpha-MG treatment, while creatinine clearance rate and serum albumin were upregulated (P<0.05). alpha-MG treatment alleviated the glomerular and interstitial fibrosis, downregulated the expression of fibrosis markers, such as Col I and alpha-SMA (P<0.05). alpha-MG treatment reduced the production of superoxide anion, the levels of MDA and GSH, and increased the activity of CAT and SOD (P<0.05). alpha-MG treatment inhibitd the generation of pro-inflammatory cytokines, such as IL-1beta and IL-18 and promoted the production of anti-inflammatory cytokines, such as the IL-10 and adiponectin (P<0.05); alpha-MG treatment promoted the expression of Sirt1, inhibitd the expression of NLRP3 in kidney tissues (P<0.05).? Conclusion: alpha MG could attenuates FSGS of mice induced by adriamycin ameliorate and improve renal function. alpha-MG exerts its anti-inflammatory and anti-oxidative effects by up-regulation the expression of Sirt1 and suppression of NLRP3. PMID- 30523230 TI - [Vascular endothelial growth factor antibody attenuates diabetic peripheral neuropathic pain in rats]. AB - OBJECTIVE: To explore the role of vascular endothelial growth factor (VEGF) in diabetic peripheral neuropathic pain in rats.? Methods: Twenty-four adult male Sprague-Dawley rats aged 8 weeks were randomly divided into 3 groups (n=8 per group). The control group (C group): rats were intraperitoneally injected with sodium citrate solution at 10 mL/kg; the model group (M group): rats were intraperitoneally injected with streptozotocin at 65 mg/kg; the treatment group (T group): rats received intraperitoneal injection of anti-VEGF antibody (10 mg/kg) at the 1st, 3rd, 7th, 10th day after STZ treatment. Meanwhile, rats of C and M group were received with the same volume of sodium citrate solution. Blood glucose was measured before 1 day or at the 1st, 3rd, 7th or 14th day after receiving STZ. Body weight, paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were measured before 1 day or at the 1st, 3rd, 5th, 7th, 10th or 14th day after receiving STZ. All lumbar spinal cords were dissected to examine the p-protein kinase B (p-Akt) and transient receptor potential vanilloid 1 (TRPV1) expression by Western blot.? Results: After injection with STZ, the body weight showed significant differences at some time point between the M, T or C group (P<0.01); body weight of rat in the C group were increased gradually. Compared with the C group, the fast blood glucose in the M or the T Group at the same time points were increased significantly (P<0.01). The PWMT and PWTL of the M, T or C group were significant difference among various time points (P<0.01). The PWMT and PWTL in the M or T group were obviously reduced compared with those in the C group (P<0.01). Compared with the M group, the PWMT and PWTL in the T group were increased at the 10th or 14th day (P<0.01 or P<0.05). Compared with the C group, the p-Akt and TRPV1 levels in the M and T group were increased (P<0.01). Compared with the M group, p-Akt and TRPV1 levels in T group were decreased (P<0.01).? Conclusion: VEGF is able to regulate the expression of TRPV1 through PI3K/Akt pathway, which contributes to diabetic peripheral neuropathic pain in rats. Anti-VEGF treatment may be useful for alleviation of diabetic peripheral neuropathic pain. PMID- 30523231 TI - [Law of dominant eye's transformation after cataract phacoemulsification and intraocular lens implantation surgery]. AB - OBJECTIVE: To study the change of the dominant eye in the age-related cataract patients before and after surgery, to analyze the correlation between the orientation of the dominant eye and the visual quality, and to observe whether the patients with the change in dominant eye were converted to dizziness.? Methods: A total of 44 patients, with age-related cataract between 60 and 80 years old were enrolled. Group A: the non-dominant (secondary) eye served as the surgical eye (n=35); Group B: the dominant eye served as the surgical eye (n=9); Group C: the operation was performed on the contralateral eye after a month (n=28). Measurement of the dominant eye was performed before operation, 1 week after operation and 1 month after the operation. The changes in the uncorrected distance visual acuity (UCDVA), contrast sensitivity (CS), best corrected visual acuity (BCVA) and spherical equivalent (SE) between the dominant and non-dominant eye were compared.? Results: The UCDVA, CS, BCVA and SE were significantly improved at 1 day after the operation. There was significant difference between the 2 groups (P<0.05). Preoperative: in group A, the UCDVA, CS, BCVA of ocular dominance were better than the non-dominant eye with significant difference (P<0.05), while there was no significant difference between the SE (P>0.05); in group B, the UCDVA, CS, BCVA in the dominant eye were better than the non dominant eye's, but the difference was not statistically significant (P>0.05). After operation: the UCDVA, CS and BCVA in the dominant eye in group A and group B were higher than those of the non-dominant eye with statistical difference (P<0.05), but there was no statistical difference between SE (P>0.05). The dominant eye's transformation occurred in group A when the non-dominant eye's postoperative visual quality improved over the leading eye. The transformation rate was 60% in 1 week, and the conversion rate was 80% in 1 month. In group C, the dominant eye reduction rate was 100%, and the visual quality was not significant difference between the two eyes (P>0.05). After the operation, the patients with the dominant eye's transformation felt discomfort, which could be relieved within 1 week.? Conclusion: The location of the dominant eye was correlated with uncorrected visual acuity, contrast sensitivity, and the best corrected visual acuity. The dominant eye's transformation occurred when the non dominant eye's postoperative visual quality improved over the leading eye after the surgery. If the contralateral eye's surgery was performed in a short term, the dominant eye can be returned to the initial state. PMID- 30523232 TI - [Application of positron emission tomography in detection of myocardial glucose metabolism in rabbit cardiac arrest models]. AB - OBJECTIVE: To investigate the changes of myocardial glucose metabolism in rabbit cardiac arrest models and the effect of hydrogen intervention by 18F-fluroro-2 deoxyglucose (18F-FDG) positron emission tomography (PET) imaging.? Methods: Fifteen male New Zealand white rabbits were randomly divided into a hydrogen group (n=6), a control group (n=6) and a sham group (n=3). Cardiac arrest (CA) was induced by intravenous injection of potassium chloride. Conventional cardiopulmonary resuscitation (CPR) was initiated after five-minutes CA. The hydrogen group and the control group were mechanically ventilated into mixed gas with 4% hydrogen+96% oxygen and pure oxygen, respectively, for 30 minutes after CPR. Rats in the sham group was performed the same surgical procedure and was injected adrenaline and potassium chloride but did not induce CA. The vital signs at basic state and 30 min after return of spontaneous circulation (ROSC) were recorded in each group. The parameters of CPR were recorded in two CA groups. Myocardial glucose metabolism was assessed by positron emission tomography (PET) at basic state, 2 h and 24 h after ROSC. The maximum standardized uptake value (SUVmax) of 18F-FDG was measured.? Results: There were no significant differences in the basal body weight and vital signs among the three groups. There was no significant difference in the blood glucose level before PET examination. The 18F FDG SUVmax in the sham group at three time points was not significantly changed. In the hydrogen group and the control group, the 18F-FDG SUVmax at 2 h after ROSC were significantly higher than the basic level (1.89+/-0.47 vs 3.47+/-1.24 and 1.90+/-0.36 vs 4.26+/-0.80, respectively). Compared with the control group, the 18F-FDG SUVmax in the hydrogen group was lower at the point at 2 h after ROSC. The 18F-FDG SUVmax in the 2 CA group were down to the basic level at 24 h after ROSC (hydrogen group 2.02+/-0.64, control group 2.07+/-0.61).? Conclusion: Myocardial glucose metabolism in CA rabbits was increased significantly after ROSC, and hydrogen intervention can reduce the degree of glucose metabolism. PMID- 30523233 TI - [Magnetic resonance imaging features for primary brain lymphoma]. AB - OBJECTIVE: To investigate the magnetic resonance imaging (MRI) features for primary brain lymphoma and improve its diagnosis and differential diagnosis.? Methods: The clinical and MRI data from 14 patients with primary brain lymphoma were retrospectively reviewed.? Results: Fourteen patients, including 5 males and 9 females, were (55+/-8) years old. There were 9 patients with single lesion and 5 patients with multiple lesions (2-6 lesions). A total of 26 lesions were identified. All lesions located in supratentorium, such as the cerebral hemisphere, the basal ganglia, and the corpus callosum. Most of them deeply located in the brain. The lesions presented slightly low or equal signal on T1 weighted image (T1WI), slightly high or equal signal on T2-weighted image (T2WI), and slightly high or equal signal on disffusion-weighted imaging (DWI), in which 2 lesions showed central necrosis and 2 lesions included hemorrhage. All of them showed significant enhancement, 3 of them showed annular enhancement, and the rest showed nodular and mass enhancement. The degree of para-tumorous edema for different lesions was different, including 20 lesions with marked edema, 4 with moderate edema, and 2 with slight edema.? Conclusion: MRI features for primary brain lymphoma are specific. The tumors mostly locate in supratentorium and deep brain, showing multifocal growth, isointense to grey matter at T1WI and T2WI, marked enhancement, restricted diffusionon DWI, rare necrosis, and obvious space occupying effect. PMID- 30523234 TI - [Differential diagnosis for breast ductal carcinoma in situ and plasma cell mastitis by magnetic resonance imaging]. AB - OBJECTIVE: To investigate the magnetic resonance imaging (MRI) features for ductal carcinoma in situ (DCIS) and plasma cell mastitis (PCM) , and to improve diagnostic accuracy for DCIS and PCM. ? Methods: The MRI morphology confirmed by surgical pathology and dynamic enhancement for 35 patients with DCIS and 45 patients with PCM were retrospectively analyzed, which included T1 pre-scan high signal, enhanced distribution characteristics, internal strengthening mode, whether centrifugation or centripetal diffusion, dynamic enhancement curve morphology, diffusion-weighted imaging (DWI) signal characteristics, and apparent diffusion coefficient (ADC) values. ? Results: The segmental distribution, clustered ring, T1 pre-catheters diffusion and the dynamic delayed concentric diffusion were more common in DCIS than those in PCM (P<0.05). Regional distribution, internal heterogeneity enhancement, and enhanced delay period eccentric diffusion were more common in PCM than those in DCIS (P<0.05). In the PCM group, nipple repertoire, DWI center high signal, adjacent skin thickening, and sinus formation were significantly higher than those in the DCIS group (P<0.05).? Conclusion: Both DCIS and PCM show a non-mass like enhancement on MRI. Images in DCIS mostly show duct-like, branch-like and segment-like distribution. The internal enhancement mode is centripetal diffusion. Images in PCM mostly show regional distribution, and the inside displays heterogeneity enhancement with the adjacent skin thickening and nipple subsided. PMID- 30523235 TI - [Application of automated breast volume scanner and mammography in differentiation of small breast lesions with BI-RADS-US 4]. AB - OBJECTIVE: To evaluate the value of automatic breast volume scanner (ABVS) and mammography (MG) in differential diagnosis for small breast lesions with breast imaging reporting and data system ultrasound (BI-RADS-US) 4.? Methods: ABVS and MG were performed for 103 patients with 109 breast lesions, which were classified as BI-RADS-US 4 by conventional ultrasound (US). Postoperative pathological diagnosis served as gold standard. The diagnostic efficacy for US, US combined with MG, US combined with ABVS and the combination of three methods were compared.? Results: The sensitivity of US, US combined with MG, US combined with ABVS and the combination of three methods were 85.5%, 86.8%, 94.7% and 96.0%, respectively. The specificity for them were 66.7%, 69.7%, 81.8% and 84.9%, respectively. The accuracy for them were 79.8%, 81.6%, 90.8% and 92.7%, respectively. The area under the receiver operating characteristic (ROC) curve (AUC) for them were 0.76, 0.78, 0.88 and 0.90, respectively. The accuracy and AUC for US combined with ABVS in differential diagnosis of BI-RADS-US 4 small breast lesions were significantly higher than those of US and US combined with MG (P<0.05). There was no significant difference in sensitivity and specificity among these 3 groups (P>0.05). No significant difference was found in sensitivity, specificity, accuracy, and AUC between US combined with ABVS and the combination of three methods (P>0.05).? Conclusion: Combination of US with ABVS can improve the diagnostic efficacy of conventional US in differential diagnosis for BI-RADS-US 4 small breast lesions, and it is superior to US combined with MG. PMID- 30523236 TI - [Impact of the neglected Cysticercus cellulose infection on mental health among school-aged children in Tibetan agricultural areas]. AB - OBJECTIVE: To determine the impact of Cysticercus cellulose (C. cellulose) infection on mental health among school-aged children in Tibetan agricultural areas of Sichuan Province.? Methods: In October 2015, all primary schools located in Tibetan agricultural areas in Yajiang, Ruoergai, and Muli county of Sichuan Province were selected as the research sites. All school-aged children at five- and six-grade were enrolled for the study by a multistage stratified cluster sampling method. Antibodies against C. cellulose were detected. Mental Health Test and questionnaire survey were conducted for school-aged children to collect data. The impact of C. cellulose infection on mental health among school-aged children was analyzed with the multilevel linear regression.? Results: A total of 2 453 school-aged children were investigated. The C. cellulose seropositive rate was 6.03% (148/2 453). There were 0.16% (4/2 453) patients with seropositive accompanied by seizure, 2.28% (56/2 453) with seropositive accompanied by headache, 2.08% (51/2 453) with seropositive accompanied by frequent weak, and 0.41% (10/2 453) were seropositive accompanied by frequent nausea. The rate of C. cellulose infection was 4.53% (111/2 453). The mean score of the mental health test was 6.59+/-2.61. There were significant difference in score of mental health test in children whose demographic characteristics were different. The mental health scores of school-aged children were clustered at the school level. After controlling the factors of demographic characteristics, the result of multilevel model demonstrated that the factor of school-aged children with C. cellulose seropositive accompanied by headache was statistically significant (beta=1.14, P=0.017).? Conclusion: The status of C. cellulose infection among school-aged children in Tibetan agricultural areas is not optimistic. C. cellulose infection has impacted on mental health of local school-aged children. It is necessary to strengthen the prevention and control of C. cellulose infection in epidemic area. PMID- 30523237 TI - [Significance of the items for Dizziness Handicap Inventory in differential diagnosis of benign paroxysmal positional vertigo]. AB - OBJECTIVE: To explore the value of items for the Chinese version of Dizziness Handicap Inventory (DHI) in differential diagnosis of benign paroxysmal positional vertigo (BPPV) in patients with vertigo or dizziness first coming to the outpatient clinic.? Methods: A total of 322 patients with vertigo or dizziness, who came from Nanfang Hospital, Southern Medical University, were enrolled from April 2016 to February 2017. The Chinese version of DHI and Visual Analogue Scale (VAS) were completed by themselves. After detailed vestibular function examination, the patients were divided into a BPPV group, a normal vestibular group, and a abnormal vestibular group.? Results: The score of DHI-2 in the BPPV group was 5.52+/-2.10, which was higher than that in the normal vestibular group (3.94+/-2.91)(t=3.847, P<0.01) and the abnormal vestibular group (4.17+/-2.74)(t=4.149, P<0.01). There were significant differences in the DHI-2 among the 3 groups (F=9.870, t=4.515, P<0.01). The score of DHI-item 13 in the BPPV group was 3.09+/-1.39, which was higher than that in the normal vestibular group (1.97+/-1.63)(t=4.515, P<0.01) and the abnormal vestibular group (1.95+/ 1.70)(t=5.305, P<0.01). There were significant differences in the DHI-item 13 among the 3 groups (F=16.402, P<0.01). There was significant difference in VAS scores among the 3 groups (P<0.05). However, the t-test analysis showed that there was significant difference between the BPPV group and the vestibular abnormal group (P<0.05), while there was no significant difference between the BPPV group and the vestibular normal group (P>0.05).? Conclusion: DHI-2 and DHI item 13 should be included in the inquiry of disease history at the time of first diagnosis, which can be used to identify patients with BPPV quickly and effectively. PMID- 30523238 TI - [Research progress of long chain non-coding RNA H19 in anoxic environment mechanism]. AB - LncRNA H19 encoded by the H19 imprinting gene plays an important regulatory role in the cell. Recently study has found that in hypoxic cells, the expression of H19 gene changes, and the transcription factors and protein involved in the expression change accordingly. Through the involvement of specific protein 1 (SP1), hypoxia-inducible factor-1alpha (HIF-1alpha) binds directly to the H19 promoter and induces the up-regulation of H19 expression under hypoxic conditions. The tumor suppressor protein p53 may also mediate the expression of the H19 gene, in part by interfering with HIF-la activity under hypoxia stress. The miR675-5p encoded by exon 1 of H19 promotes hypoxia response by driving the nuclear accumulation of HIF-1alpha and reducing the expression of VHL gene, which is a physiological HIF-1alpha inhibitor. In addition, under the condition of hypoxia, the expression of transporter on cell membrane changes, and the transition of the intracellular glucose metabolism pathway from aerobic oxidation to anaerobic glycolysis is also involved in the involvement of H19. Therefore, H19 may be a key gene that maintains intracellular balance under hypoxic conditions and drives adaptive cell survival under conditions of hypoxia stress. PMID- 30523239 TI - [Role of cofilin in kidney disease]. AB - Cofilin is a actin-binding protein in eukaryotic cells. It plays a role in maintaining the steady state of the internal environment through regulating actin dynamics, which contributes to the development of various kinds of diseases. In recent 20 years, cofilin has been widely attracted due to its regulatory effect on cell phenotype, gene transcription, apoptosis and inflammation in renal tissue. Cofilin plays a regulatory role in pathological changes in proteinuria diseases such as minimal change nephropathy, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy. It could be one of the diagnosis index for glomerular podocyte injury. At the same time, cofilin plays a key role in maintaining the polarity and function of proximal tubular epithelial cells and it is involved in the regulation of kidney inflammation in a variety of kidney diseases, such as renal ischemia/reperfusion injury, diabetic nephropathy, and hypertensive nephropathy reaction. In addition, cofilin plays an important role in epithelial-to-mesenchymal transition (EMT) of tumor cells and epithelial cells in various tissues, suggesting that cofilin may be involved in the regulation of peritoneal dialysis-related EMT and fibrosis. Cofilin might turn into the new diagnosis and treatment target of kidney diseases. PMID- 30523240 TI - [18F-FDG PET/CT features on paraganglioma of testis with multiple lymph node and lung metastasis: A case report and literature review]. AB - OBJECTIVE: To determine the clinicopathological and imaging features in 18F fluoro-2-deoxyglucose (18F-FDG) positron emission tomography and computed tomography (PET/CT) for paraganglioma of testis, and to increase the diagnostic accuracy.? Methods: A case of paraganglioma of testis with multiple lymph node and lung metastasis were reported. PET/CT and pathological findings in the case were retrospectively analyzed.? Results: The patient presented with high blood pressure, high level of catecholamine, and urinary vanillylmandelic acid. The patient underwent 18F-FDG PET/CT, which showed the features including the right testis nodule with a star lesion nearby, the right spermatic cord, the lymphadenopathy of bilateral inguinal and retroperitoneum, the posterior basal segment of right lung nodule, and a lot of brown adipose tissues (BAT) in the whole body with intense FDG uptake. 18F-FDG PET/CT showed that the intense FDG uptake of the BAT disappeared after the excision of the right testis and metastasis of paraganglioma.? Conclusion: PET/CT shows great value in localization diagnose, clinical staging and curative evaluation. PET/CT plays a helpful role in revealing the BAT with 18F-DG avidity in the patients with paraganglioma with elevated blood pressure, high level catecholamine, and urinary vanillylmandelic acid. PMID- 30523241 TI - Combined Use of Circulating miR-133a and NT-proBNP Improves Heart Failure Diagnostic Accuracy in Elderly Patients. AB - BACKGROUND Circulating microRNAs (miRNAs) are emerging as novel biomarkers for detecting cardiovascular diseases. Here, circulating miR-133a and miR-221 were investigated as potential diagnostic biomarkers for heart failure (HF) patients, particularly in elderly patients. MATERIAL AND METHODS A total of 94 elderly HF patients (mean age=77.4 years old) and 31 healthy controls (age- and sex-matched) participated in this study. Plasma NT-proBNP levels were measured using an electrochemiluminescence immunoassay, and circulating miR-133a and miR-221 levels were examined using real-time quantitative PCR, with diagnostic efficacies determined for each independently and in combination. RESULTS MiR-133a expression increased by 4.6-fold (P<0.001) and miR-221 expression increased by 2.0-fold (P<0.001) in the elderly HF patients relative to the healthy controls. ROC curves were generated and AUC values of 0.863 for miR-133a (CI95%: 0.800-0.927), 0.718 for miR-221 (CI95%: 0.622-0.813), and 0.895 for NT-proBNP (CI95%: 0.841-0.948) were obtained. Unlike NT-proBNP, miR-133a and miR-221 were found to be unaffected by age, BMI, renal function, albumin, or Hb levels. More importantly, the diagnostic value of NT-proBNP was found to be improved when combined with any of the examined miRNA biomarkers alone or in a panel. When combining miR-133a with NT-proBNP, an AUC value of 0.975 (CI95%: 0.950-0.999) was obtained, which was significantly higher than for NT-proBNP alone (z=2.395, P=0.016). CONCLUSIONS miR 133a and miR-221 can serve as potential HF diagnostic biomarkers in elderly patients. Moreover, the diagnostic accuracy of NT-proBNP can be improved by the addition of miR-133a. PMID- 30523242 TI - Gelatinous Transformation of Bone Marrow in a Patient with Anorexia Nervosa: An Uncommon but Reversible Etiology. AB - BACKGROUND Anorexia nervosa is a relatively frequently encountered eating disorder. Beyond its psychiatric significance, it is associated with multiple hematological features such as cytopenia. It can be related to gelatinous transformation of the bone marrow. CASE REPORT We describe the case of a 20-year old male admitted for rapid involuntarily weight loss. He presented with extreme bradycardia with a heart rate of 30 beats per minute with recent psychomotor impairment. Routine laboratory tests showed pancytopenia, and cytolysis on liver function tests. Cardiac investigations did not reveal abnormalities except for sinus bradycardia. Bone marrow aspirate revealed hypo-cellular marrow with infiltration by gelatinous substance. In addition, bone marrow biopsy showed fat cell atrophy along with loss of hematopoietic elements in areas of gelatinous transformation. During the patient's hospital stay, he had a restrictive oral diet. Thus, after consulting with a psychiatric specialist, a diagnosis of anorexia nervosa complicated with gelatinous transformation of bone marrow, bradycardia, and acute hepatitis was made. After psychiatric treatment and nutritional care, the patient regained weight, had a normal heart rate and normal liver function tests, and his full blood count and bone marrow examination were within normal range. CONCLUSIONS Gelatinous transformation of bone marrow can be the revealing feature of anorexia nervosa and some potentially reversible associations might prove life threatening if misdiagnosed. Furthermore, lack of suspicion can lead to unwarranted investigations increasing the cost incurred in healthcare delivery. Our patient had 3 systems involved: cardiac, hepatic, and hematological systems. Gelatinous transformation of bone marrow, although a rare condition, must be considered in such patients. PMID- 30523243 TI - Success of kidney transplantations from deceased donors with acute kidney injury. AB - BACKGROUND The acceptance of organs from deceased donors with acute kidney injury (AKI) varies considerably, with uncertain outcomes. The current organ shortage has led to increased use of marginal donor organs. MATERIAL AND METHODS This retrospective, single-center study included 642 patients who underwent kidney allograft transplantation between 2005 and 2016. The recipients were categorized into 3 groups: AKI-1 (n=214), comprising donors with a peak serum creatinine (SCr) level of 1.1-2.0 mg/dl; AKI-2 (n=89), comprising donors with a peak SCr level >2 mg/dl; and non-AKI (n=339), comprising donors with normal kidney function (SCr <1.1 mg/dl). RESULTS The cumulative survival rates for patients and grafts did not significantly differ among the AKI-1, AKI-2, and non-AKI groups at the 1-year (91.6%/79.4%, 92.1%/83.1%, 95.3%/88.5%, respectively) and 5-year assessments (79.4%/67.8%, 86.8%/71.7%, 80.5%/71.1%, respectively). These findings were corroborated by mean SCr values and estimated glomerular filtration rates at the 1-year (2.08+/-1.7/51.16+/-23.45, 2.01+/-1.52/56.46+/-23.63, 1.81+/ 1.13/55.44+/-23.26 mg/dl, respectively) and 5-year assessments (1.91+/ 1.28/51.06+/-24.65, 1.74+/-0.66/57.44+/-31.21, 1.7+/-0.88/58.56+/-26.04 mg/dl, respectively). The incidence of delayed graft function in each group was 29.9%, 44.9%, and 28.6%, respectively. CONCLUSIONS Kidney transplantation from donors with AKI, although associated with a higher rate of delayed graft function, results in good long-term transplant survival and reliable kidney functionality after 5 years. The inclusion of donors with AKI may widely extend the pool of available organs; however, careful donor selection is necessary. PMID- 30523244 TI - The emerging role of lncRNAs in inflammatory bowel disease. AB - Dysregulation of long noncoding RNA (lncRNA) expression is linked to the development of various diseases. Recently, an emerging body of evidence has indicated that lncRNAs play important roles in the pathogenesis of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative Colitis (UC). In IBD, lncRNAs have been shown to be involved in diverse processes, including the regulation of intestinal epithelial cell apoptosis, association with lipid metabolism, and cell-cell interactions, thereby enhancing inflammation and the functional regulation of regulatory T cells. In this review, we aim to summarize the current knowledge regarding the role of lncRNAs in IBD and highlight potential avenues for future investigation. We also collate potentially immune-relevant, IBD-associated lncRNAs identified through a built-by association analysis with respect to their neighboring protein-coding genes within IBD susceptible loci. We further underscore their importance by highlighting their enrichment for various aspects of immune system regulation, including antigen processing/presentation, immune cell proliferation and differentiation, and chronic inflammatory responses. Finally, we summarize the potential of lncRNAs as diagnostic biomarkers in IBD. PMID- 30523245 TI - TGF-beta downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade. AB - Transforming growth factor (TGF)-beta signaling is increasingly recognized as a key driver in cancer. In progressive cancer tissues, TGF-beta promotes tumor formation, and its increased expression often correlates with cancer malignancy. In this study, we utilized adenoviruses expressing short hairpin RNAs against TGF beta1 and TGF-beta2 to investigate the role of TGF-beta downregulation in cancer cell death. We found that the downregulation of TGF-beta increased the phosphorylation of several SAPKs, such as p38 and JNK. Moreover, reactive oxygen species (ROS) production was also increased by TGF-beta downregulation, which triggered Akt inactivation and NOX4 increase-derived ROS in a cancer cell-type specific manner. We also revealed the possibility of substantial gene fluctuation in response to TGF-beta downregulation related to SAPKs. The expression levels of Trx and GSTM1, which encode inhibitory proteins that bind to ASK1, were reduced, likely a result of the altered translocation of Smad complex proteins rather than from ROS production. Instead, both ROS and ROS-mediated ER stress were responsible for the decrease in interactions between ASK1 and Trx or GSTM1. Through these pathways, ASK1 was activated and induced cytotoxic tumor cell death via p38/JNK activation and (or) induction of ER stress. PMID- 30523247 TI - Splanchnic Vein Thrombosis in Cirrhosis - Areas Still in the Shadow. PMID- 30523246 TI - A novel and safe small molecule enhances hair follicle regeneration by facilitating metabolic reprogramming. AB - Targeting hair follicle regeneration has been investigated for the treatment of hair loss, and fundamental studies investigating stem cells and their niche have been described. However, knowledge of stem cell metabolism and the specific regulation of bioenergetics during the hair regeneration process is currently insufficient. Here, we report the hair regrowth-promoting effect of a newly synthesized novel small molecule, IM176OUT05 (IM), which activates stem cell metabolism. IM facilitated stemness induction and maintenance during an induced pluripotent stem cell generation process. IM treatment mildly inhibited mitochondrial oxidative phosphorylation and concurrently increased glycolysis, which accelerated stemness induction during the early phase of reprogramming. More importantly, the topical application of IM accelerated hair follicle regeneration by stimulating the progression of the hair follicle cycle to the anagen phase and increased the hair follicle number in mice. Furthermore, the stem cell population with a glycolytic metabotype appeared slightly earlier in the IM-treated mice. Stem cell and niche signaling involved in the hair regeneration process was also activated by the IM treatment during the early phase of hair follicle regeneration. Overall, these results show that the novel small molecule IM promotes tissue regeneration, specifically in hair regrowth, by restructuring the metabolic configuration of stem cells. PMID- 30523248 TI - Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. AB - Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies. PMID- 30523249 TI - Quantum advantage for probabilistic one-time programs. AB - One-time programs, computer programs which self-destruct after being run only once, are a powerful building block in cryptography and would allow for new forms of secure software distribution. However, ideal one-time programs have been proved to be unachievable using either classical or quantum resources. Here we relax the definition of one-time programs to allow some probability of error in the output and show that quantum mechanics offers security advantages over purely classical resources. We introduce a scheme for encoding probabilistic one-time programs as quantum states with prescribed measurement settings, explore their security, and experimentally demonstrate various one-time programs using measurements on single-photon states. These include classical logic gates, a program to solve Yao's millionaires problem, and a one-time delegation of a digital signature. By combining quantum and classical technology, we demonstrate that quantum techniques can enhance computing capabilities even before full-scale quantum computers are available. PMID- 30523251 TI - Three-dimensional atomic scale electron density reconstruction of octahedral tilt epitaxy in functional perovskites. AB - Octahedral tilts are the most ubiquitous distortions in perovskite-related structures that can dramatically influence ferroelectric, magnetic, and electronic properties; yet the paradigm of tilt epitaxy in thin films is barely explored. Non-destructively characterizing such epitaxy in three-dimensions for low symmetry complex tilt systems composed of light anions is a formidable challenge. Here we demonstrate that the interfacial tilt epitaxy can transform ultrathin calcium titanate, a non-polar earth-abundant mineral, into high temperature polar oxides that last above 900 K. The comprehensive picture of octahedral tilts and polar distortions is revealed by reconstructing the three dimensional electron density maps across film-substrate interfaces with atomic resolution using coherent Bragg rod analysis. The results are complemented with aberration-corrected transmission electron microscopy, film superstructure reflections, and are in excellent agreement with density functional theory. The study could serve as a broader template for non-destructive, three-dimensional atomic resolution probing of complex low symmetry functional interfaces. PMID- 30523252 TI - Polycystic kidney disease. PMID- 30523250 TI - GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. AB - Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system. PMID- 30523253 TI - Irradiation-induced palladium-catalyzed decarboxylative desaturation enabled by a dual ligand system. AB - Generation of alkenes through decarboxyolefination of alkane carboxylates has significant synthetic value in view of the easy availability of a variety of carboxylic acids and the synthetic versatility of alkenes. Herein we report that palladium catalysts under irradiation with blue LEDs (440 nm) catalyze decarboxylative desaturation of a variety of aliphatic carboxylates to generate aliphatic alkenes, styrenes, enol ethers, enamides, and peptide enamides under mild conditions. The selection of a dual phosphine ligand system is the key enabler for the successful development of this reaction. The Pd-catalyzed decarboxylative desaturation is utilized to achieve a three-step divergent synthesis of Chondriamide A and Chondriamide C in overall 68% yield from simple starting materials. Mechanistic studies suggest that, distinct from palladium catalysis under thermal condition, irradiation-induced palladium catalysis involves irradiation-induced single-electron transfer and dynamic ligand dissociation/association process to allow two phosphine ligand to work synergistically. PMID- 30523254 TI - In vivo cell type-specific CRISPR knockdown of dopamine beta hydroxylase reduces locus coeruleus evoked wakefulness. AB - Locus coeruleus (LC) neurons in the brainstem have long been associated with attention and arousal. Optogenetic stimulation of LC-NE neurons induces immediate sleep-to-wake transitions. However, LC neurons also secrete other neurotransmitters in addition to NE. To interrogate the role of NE derived from the LC in regulating wakefulness, we applied in vivo cell type-specific CRISPR/Cas9 technology to disrupt the dopamine beta hydroxylase (dbh) gene selectively in adult LC-NE neurons. Unilateral dbh gene disruption abolished immediate arousal following optogenetic stimulation of LC. Bilateral LC-specific dbh disruption significantly reduced NE concentration in LC projection areas and reduced wake length even in the presence of salient stimuli. These results suggest that NE may be crucial for the awakening effect of LC stimulation and serve as proof-of-principle that CRISPR gene editing in adult neurons can be used to interrogate gene function within genetically-defined neuronal circuitry associated with complex behaviors. PMID- 30523255 TI - Hierarchical and programmable one-pot synthesis of oligosaccharides. AB - The programmable one-pot oligosaccharide synthesis method was designed to enable the rapid synthesis of a large number of oligosaccharides, using the software Optimer to search Building BLocks (BBLs) with defined relative reactivity values (RRVs) to be used sequentially in the one-pot reaction. However, there were only about 50 BBLs with measured RRVs in the original library and the method could only synthesize small oligosaccharides due to the RRV ordering requirement. Here, we increase the library to include 154 validated BBLs and more than 50,000 virtual BBLs with predicted RRVs by machine learning. We also develop the software Auto-CHO to accommodate more data handling and support hierarchical one pot synthesis using fragments as BBLs generated by the one-pot synthesis. This advanced programmable one-pot method provides potential synthetic solutions for complex glycans with four successful examples demonstrated in this work. PMID- 30523256 TI - Single-molecule imaging correlates decreasing nuclear volume with increasing TF chromatin associations during zebrafish development. AB - Zygotic genome activation (ZGA), the onset of transcription after initial quiescence, is a major developmental step in many species, which occurs after ten cell divisions in zebrafish embryos. How transcription factor (TF)-chromatin interactions evolve during early development to support ZGA is largely unknown. We establish single molecule tracking in live developing zebrafish embryos using reflected light-sheet microscopy to visualize two fluorescently labeled TF species, mEos2-TBP and mEos2-Sox19b. We further develop a data acquisition and analysis scheme to extract quantitative information on binding kinetics and bound fractions during fast cell cycles. The chromatin-bound fraction of both TFs increases during early development, as expected from a physical model of TF chromatin interactions including a decreasing nuclear volume and increasing DNA accessibility. For Sox19b, data suggests the increase is mainly due to the shrinking nucleus. Our single molecule approach provides quantitative insight into changes of TF-chromatin associations during the developmental period embracing ZGA. PMID- 30523257 TI - Thermal assisted self-organization of calcium carbonate. AB - Fabrication of mineral multi-textured architectures by self-organization is a formidable challenge for engineering. Current approaches follow a biomimetic route for hybrid materials based on the coupling of carbonate and organic compounds. We explore here the chemical coupling of silica and carbonate, leading to fabrication of inorganic-inorganic biomimetic structures known as silica carbonate biomorphs. So far, biomorphic structures were restricted to orthorhombic barium, strontium, and calcium carbonate. We demonstrate that, monohydrocalcite a hydrous form of calcium carbonate with trigonal structure can also form biomorphic structures, thus showing biomorphic growth is not dictated by the carbonate crystal structure. We show that it is possible to control the growth regime, and therefore the texture and overall shape, by tuning the growth temperature, thereby shifting the textural pattern within the production of a given architecture. This finding opens a promising route to the fabrication of complex multi-textured self-organized material made of silica and chalk. PMID- 30523258 TI - Physical and environmental drivers of Paleozoic tetrapod dispersal across Pangaea. AB - The Carboniferous and Permian were crucial intervals in the establishment of terrestrial ecosystems, which occurred alongside substantial environmental and climate changes throughout the globe, as well as the final assembly of the supercontinent of Pangaea. The influence of these changes on tetrapod biogeography is highly contentious, with some authors suggesting a cosmopolitan fauna resulting from a lack of barriers, and some identifying provincialism. Here we carry out a detailed historical biogeographic analysis of late Paleozoic tetrapods to study the patterns of dispersal and vicariance. A likelihood-based approach to infer ancestral areas is combined with stochastic mapping to assess rates of vicariance and dispersal. Both the late Carboniferous and the end Guadalupian are characterised by a decrease in dispersal and a vicariance peak in amniotes and amphibians. The first of these shifts is attributed to orogenic activity, the second to increasing climate heterogeneity. PMID- 30523259 TI - Real-time determination of enantiomeric and isomeric content using photoelectron elliptical dichroism. AB - The fast and accurate analysis of chiral chemical mixtures is crucial for many applications but remains challenging. Here we use elliptically-polarized femtosecond laser pulses at high repetition rates to photoionize chiral molecules. The 3D photoelectron angular distribution produced provides molecular fingerprints, showing a strong forward-backward asymmetry which depends sensitively on the molecular structure and degree of ellipticity. Continuously scanning the laser ellipticity and analyzing the evolution of the rich, multi dimensional molecular signatures allows us to observe real-time changes in the chemical and chiral content present with unprecedented speed and accuracy. We measure the enantiomeric excess of a compound with an accuracy of 0.4% in 10 min acquisition time, and follow the evolution of a mixture with an accuracy of 5% with a temporal resolution of 3 s. This method is even able to distinguish isomers, which cannot be easily distinguished by mass-spectrometry. PMID- 30523260 TI - Prediction of the strength and timing of sunspot cycle 25 reveal decadal-scale space environmental conditions. AB - The Sun's activity cycle governs the radiation, particle and magnetic flux in the heliosphere creating hazardous space weather. Decadal-scale variations define space climate and force the Earth's atmosphere. However, predicting the solar cycle is challenging. Current understanding indicates a short window for prediction best achieved at previous cycle minima. Utilizing magnetic field evolution models for the Sun's surface and interior we perform the first century scale, data-driven simulations of solar activity and present a scheme for extending the prediction window to a decade. Our ensemble forecast indicates cycle 25 would be similar or slightly stronger than the current cycle and peak around 2024. Sunspot cycle 25 may thus reverse the substantial weakening trend in solar activity which has led to speculation of an imminent Maunder-like grand minimum and cooling global climate. Our simulations demonstrate fluctuation in the tilt angle distribution of sunspots is the dominant mechanism responsible for solar cycle variability. PMID- 30523261 TI - An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma. AB - Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3beta phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G-csf expression to enhance polymorphonuclear myeloid derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development. PMID- 30523262 TI - A splice variant of human Bmal1 acts as a negative regulator of the molecular circadian clock. AB - Bmal1 is one of the key molecules that controls the mammalian molecular clock. In humans, two isoforms of Bmal1 are generated by alternative RNA splicing. Unlike the extensively studied hBmal1b, the canonical form of Bmal1 in most species, the expression and/or function of another human-specific isoform, hBmal1a, are poorly understood. Due to the lack of the N-terminal nuclear localization signal (NLS), hBMAL1a does not enter the nucleus as hBMAL1b does. However, despite the lack of the NLS, hBMAL1a still dimerizes with either hCLOCK or hBMAL1b and thereby promotes cytoplasmic retention or protein degradation, respectively. Consequently, hBMAL1a interferes with hCLOCK:hBMAL1b-induced transcriptional activation and the circadian oscillation of Period2. Moreover, when the expression of endogenous hBmal1a is aborted by CRISPR/Cas9-mediated knockout, the rhythmic expression of hPer2 and hBmal1b is restored in cultured HeLa cells. Together, these results suggest a role for hBMAL1a as a negative regulator of the mammalian molecular clock. PMID- 30523264 TI - Manipulating and monitoring nanoparticles in micellar thin film superstructures. AB - Understanding the dynamics of discrete self-assembled structures under influence of external triggers is of interest to harvest the potential of nano- and mesoscale materials. In particular, controlling the hierarchical organization of (macro)molecular and nanoparticle building blocks in monolayer superstructures is of paramount importance for tuning properties and characteristics. Here we show how the electron beam in cryo-transmission electron microscopy can be exploited to induce and follow local migration of building blocks and global migration of micellar aggregates inside micrometer-sized superstructures. We employ stroboscopic exposure to heat up and convert the vitrified superstructure into a liquid-like thin film under cryogenic conditions, resulting in controlled evaporation of water that finally leads to rupture of the micelle-containing superstructure. Micelle-embedded nanoparticles prove a powerful tool to study the complex hierarchically built-up superstructures, and to visualize both global movement of individual dendrimicelles and local migration of nanoparticles inside the micellar core during the exposure series. PMID- 30523265 TI - Phase diagram of Bi2Sr2CaCu2O8+delta revisited. AB - In cuprate superconductors, the doping of carriers into the parent Mott insulator induces superconductivity and various other phases whose characteristic temperatures are typically plotted versus the doping level p. In most materials, p cannot be determined from the chemical composition, but it is derived from the superconducting transition temperature, Tc, using the assumption that the Tc dependence on doping is universal. Here, we present angle-resolved photoemission studies of Bi2Sr2CaCu2O8+delta, cleaved and annealed in vacuum or in ozone to reduce or increase the doping from the initial value corresponding to Tc = 91 K. We show that p can be determined from the underlying Fermi surfaces and that in situ annealing allows mapping of a wide doping regime, covering the superconducting dome and the non-superconducting phase on the overdoped side. Our results show a surprisingly smooth dependence of the inferred Fermi surface with doping. In the highly overdoped regime, the superconducting gap approaches the value of 2Delta0 = (4 +/- 1)kBTc. PMID- 30523263 TI - Why rankings of biomedical image analysis competitions should be interpreted with care. AB - International challenges have become the standard for validation of biomedical image analysis methods. Given their scientific impact, it is surprising that a critical analysis of common practices related to the organization of challenges has not yet been performed. In this paper, we present a comprehensive analysis of biomedical image analysis challenges conducted up to now. We demonstrate the importance of challenges and show that the lack of quality control has critical consequences. First, reproducibility and interpretation of the results is often hampered as only a fraction of relevant information is typically provided. Second, the rank of an algorithm is generally not robust to a number of variables such as the test data used for validation, the ranking scheme applied and the observers that make the reference annotations. To overcome these problems, we recommend best practice guidelines and define open research questions to be addressed in the future. PMID- 30523266 TI - Impact of a Narrow Coastal Bay of Bengal Sea Surface Temperature Front on an Indian Summer Monsoon Simulation. AB - A dry bias in climatological Central Indian rainfall plagues Indian summer monsoon (ISM) simulations in multiple generations of climate models. Here, using observations and regional climate modeling, we focus on a warm coastal Bay of Bengal sea surface temperature (SST) front and its impact on Central Indian rainfall. The SST front, featuring sharp gradients as large as 0.5 degrees C/100 km, is colocated with a mixed layer depth (MLD) front, in a region where salinity variations are known to control MLD. Regional climate simulations coupling a regional atmospheric model with an ocean mixed layer model are performed. A simulation with observed MLD climatology reproduces SST, rainfall, and atmospheric circulation associated with ISM reasonably well; it also eliminates the dry bias over Central India significantly. Perturbing MLD structure in the simulations, we isolate the SST front's impact on the simulated ISM climate state. This experiment offers insights into ISM climatological biases in the coupled NCEP Climate Forecast System version-2. We suggest that the warm SST front is essential to Central Indian rainfall as it helps to sustain deep and intense convection in its vicinity, which may be a source for the vortex cores seeding the monsoon low-pressure systems. PMID- 30523267 TI - Mycoplasma hyopneumoniae resides intracellularly within porcine epithelial cells. AB - Enzootic pneumonia incurs major economic losses to pork production globally. The primary pathogen and causative agent, Mycoplasma hyopneumoniae, colonises ciliated epithelium and disrupts mucociliary function predisposing the upper respiratory tract to secondary pathogens. Alleviation of disease is reliant on antibiotics, vaccination, and sound animal husbandry, but none are effective at eliminating M. hyopneumoniae from large production systems. Sustainable pork production systems strive to lower reliance on antibiotics but lack of a detailed understanding of the pathobiology of M. hyopneumoniae has curtailed efforts to develop effective mitigation strategies. M. hyopneumoniae is considered an extracellular pathogen. Here we show that M. hyopneumoniae associates with integrin beta1 on the surface of epithelial cells via interactions with surface bound fibronectin and initiates signalling events that stimulate pathogen uptake into clathrin-coated vesicles (CCVs) and caveosomes. These early events allow M. hyopneumoniae to exploit an intracellular lifestyle by commandeering the endosomal pathway. Specifically, we show: (i) using a modified gentamicin protection assay that approximately 8% of M. hyopneumoniae cells reside intracellularly; (ii) integrin beta1 expression specifically co-localises with the deposition of fibronectin precisely where M. hyopneumoniae cells assemble extracellularly; (iii) anti-integrin beta1 antibodies block entry of M. hyopneumoniae into porcine cells; and (iv) M. hyopneumoniae survives phagolysosomal fusion, and resides within recycling endosomes that are trafficked to the cell membrane. Our data creates a paradigm shift by challenging the long held view that M. hyopneumoniae is a strict extracellular pathogen and calls for in vivo studies to determine if M. hyopneumoniae can traffic to extrapulmonary sites in commercially-reared pigs. PMID- 30523268 TI - A Perlin Noise-Based Augmentation Strategy for Deep Learning with Small Data Samples of HRCT Images. AB - Deep learning is now widely used as an efficient tool for medical image classification and segmentation. However, conventional machine learning techniques are still more accurate than deep learning when only a small dataset is available. In this study, we present a general data augmentation strategy using Perlin noise, applying it to pixel-by-pixel image classification and quantification of various kinds of image patterns of diffuse interstitial lung disease (DILD). Using retrospectively obtained high-resolution computed tomography (HRCT) images from 106 patients, 100 regions-of-interest (ROIs) for each of six classes of image patterns (normal, ground-glass opacity, reticular opacity, honeycombing, emphysema, and consolidation) were selected for deep learning classification by experienced thoracic radiologists. For extra validation, the deep learning quantification of the six classification patterns was evaluated for 92 HRCT whole lung images for which hand-labeled segmentation masks created by two experienced radiologists were available. FusionNet, a convolutional neural network (CNN), was used for training, test, and extra validation on classifications of DILD image patterns. The accuracy of FusionNet with data augmentation using Perlin noise (89.5%, 49.8%, and 55.0% for ROI-based classification and whole lung quantifications by two radiologists, respectively) was significantly higher than that with conventional data augmentation (82.1%, 45.7%, and 49.9%, respectively). This data augmentation strategy using Perlin noise could be widely applied to deep learning studies for image classification and segmentation, especially in cases with relatively small datasets. PMID- 30523269 TI - Band Gap Control in Bilayer Graphene by Co-Doping with B-N Pairs. AB - The electronic band structure of bilayer graphene is studied systematically in the presence of substitutional B and/or N doping, using density functional theory with van der Waals correction. We show that introduction of B-N pairs into bilayer graphene can be used to create a substantial band gap, stable against thermal fluctuations at room temperature, but otherwise leaves the electronic band structure in the vicinity of the Fermi energy largely unaffected. Introduction of B-N pairs into B and/or N doped bilayer graphene likewise hardly modifies the band dispersions. In semiconducting systems (same amount of B and N dopants), however, the size of the band gap is effectively tuned in the presence of B-N pairs. PMID- 30523270 TI - Piwi-like 1 and -2 protein expression levels are prognostic factors for muscle invasive urothelial bladder cancer patients. AB - Piwi-like proteins are essential for stem-cell maintenance and self-renewal in multicellular organisms. We analyzed the expression of Piwi-like 1 and Piwi-like 2 by immunohistochemistry (IHC) in 95 muscle invasive bladder cancer (MIBC) samples using tissue microarray. Application of an immunoreactive score (IRS) revealed 37 and 45 patients who were Piwi-like 1 and -2 positive (IRS > 2). IHC results were correlated with clinico-pathological and survival data. The expression of both proteins was positively correlated with each other, lymph node metastasis and expression of CK20 and GATA 3. A negative correlation for both proteins was detected for disease-specific survival (DSS), recurrence, Ki67/MIB1 proliferation index, and CK5 expression. Detection of Piwi-like 1 protein positivity was associated with poor DSS (P = 0.019; log rank test, Kaplan-Meier analysis), and in multivariate Cox's analysis (adjusted to tumor stage and tumor grade), it was an independent prognostic factor for DSS (RR = 2.16; P = 0.011). Piwi-like 2 positivity was associated with DSS (P = 0.008) and recurrence-free survival (RFS; P = 0.040), and in multivariate Cox's analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 2.46; P = 0.004) and RFS (RR = 3.0; P = 0.003). Most interestingly, in the basal type patient subgroup (CK5+/GATA3-), Piwi-like 2 positivity was associated with poorer DSS, OS and RFS (P < 0.001, P = 0.004 and P = 0.05; log rank test). In multivariate analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR = 12.70; P = 0.001), OS (RR = 6.62; = 0.008) and RFS (RR=13.0; P = 0.040). In summary, Piwi-like 1 and -2 positivity are associated with clinico-pathological factors and survival. Both Piwi-like proteins are suggested as biomarkers for MIBC patients. PMID- 30523271 TI - Novel Liposome Eencapsulated Guanosine Di Phosphate based Therapeutic Target against Anemia of Inflammation. AB - Hepcidin, master regulator of iron homeostasis, causes anemia under infectious and inflammatory conditions by reducing intestinal absorption of iron with decreased release of iron from macrophages and liver despite adequate iron stores leading to Anemia of Inflammation (AI). Many therapeutic trials have been carried out but none have been effective due to its adverse effects. In present study, we discover that Guanosine 5'-diphosphate (GDP) encapsulated in lipid vesicle (NH+) was found to inhibit NF-?B activation by limiting phosphorylation and degradation of I?Balpha, thus, attenuating IL-6 secretion from macrophage cells. Moreover, the suppressed IL-6 levels down regulated JAK2/STAT3 pathway with decrease inflammation-mediated Hamp mRNA transcription (HepG2) and increase iron absorption (Caco2) in HepG2/Caco2 co-culture model. Analogous results were obtained in acute and chronic AI mice model thus, correcting haemoglobin level. These results proved NH + GDP as novel therapeutic agent to overcome limitations and suggests it as potential drug to ameliorate AI. PMID- 30523272 TI - The complete mitochondrial genome of the Caribbean spiny lobster Panulirus argus. AB - Panulirus argus is a keystone species and target of the most lucrative fishery in the Caribbean region. This study reports, for the first time, the complete mitochondrial genome of Panulirus argus (average coverage depth nucleotide-1 = 70*) assembled from short Illumina 150 bp PE reads. The AT-rich mitochondrial genome of Panulirus argus was 15 739 bp in length and comprised 13 protein-coding genes (PCGs), 2 ribosomal RNA genes, and 22 transfer RNA genes. A single 801 bp long intergenic space was assumed to be the D-loop. Most of the PCGs were encoded on the H-strand. The gene order observed in the mitochondrial genome of Panulirus argus corresponds to the presumed Pancrustacean ground pattern. KA/KS ratios calculated for all mitochondrial PCGs showed values < 1, indicating that all these PCGs are evolving under purifying selection. A maximum likelihood phylogenetic analysis (concatenated PCGs [n = 13], 154 arthropods) supported the monophyly of the Achelata and other infraorders within the Decapoda. Mitochondrial PCGs have enough phylogenetic informativeness to explore high-level genealogical relationships in the Pancrustacea. The complete mitochondrial genome of the Caribbean spiny lobster Panulirus argus will contribute to the better understanding of meta-population connectivity in this keystone overexploited species. PMID- 30523273 TI - Loss of interneurons and disruption of perineuronal nets in the cerebral cortex following hypoxia-ischaemia in near-term fetal sheep. AB - Hypoxia-ischaemia (HI) in term infants is a common cause of brain injury and neurodevelopmental impairment. Development of gamma-aminobutyric acid (GABA)ergic circuitry in the cerebral cortex is a critical event in perinatal brain development. Perineuronal nets (PNNs) are specialised extracellular matrix structures that surround GABAergic interneurons, and are important for their function. Herein, we hypothesised that HI would reduce survival of cortical interneurons and disrupt PNNs in a near-term fetal sheep model of global cerebral ischaemia. Fetal sheep (0.85 gestation) received sham occlusion (n = 5) or 30 min of reversible cerebral ischaemia (HI group; n = 5), and were recovered for 7 days. Expression of interneurons (glutamate decarboxylase [GAD]+; parvalbumin [PV]+) and PNNs (Wisteria floribunda agglutinin, WFA) was assessed in the parasagittal cortex by immunohistochemistry. HI was associated with marked loss of both GAD+ and PV+ cortical interneurons (all layers of the parasagittal cortex and layer 6) and PNNs (layer 6). The expression and integrity of PNNs was also reduced on surviving GAD+ interneurons. There was a trend towards a linear correlation of the proportion of GAD+ neurons that were WFA+ with seizure burden (r2 = 0.76, p = 0.0534). Overall, these data indicate that HI may cause deficits in the cortical GABAergic system involving loss of interneurons and disruption of PNNs, which may contribute to the range of adverse neurological outcomes following perinatal brain injury. PMID- 30523274 TI - Integrating behavioural health tracking in human genetics research. PMID- 30523275 TI - First report of vampyrellid predator-prey dynamics in a marine system. AB - We report for the first time the in situ dynamics of a vampyrellid in a marine system. A high sampling frequency (twice-weekly) was applied in a tropical eutrophic lagoon (Rio de Janeiro, Brazil) for 5 years (2012-2016). The vampyrellid Hyalodiscus sp. specifically fed on the diatom Chaetoceros minimus during a short time window (~3 months), although the prey was intermittently detected as the dominant phytoplanktonic species over a longer period (~1 year). A classic Lotka-Volterra predator-prey dynamic was observed between the two partners, with a significant modification of the short-term oscillations of the prey. Specific abiotic preferences (i.e., relatively low temperature, intermediate salinity, and stratified conditions) associated with prey availability seemed to define this narrow temporal window of occurrence. Our results suggest that vampyrellids can be ecologically relevant in marine pelagic systems, with their impact on planktonic dynamics strongly depending on complex interactions between both biotic and abiotic factors. PMID- 30523276 TI - The selective pressures on the microbial community in a metal-contaminated aquifer. AB - In many environments, toxic compounds restrict which microorganisms persist. However, in complex mixtures of inhibitory compounds, it is challenging to determine which specific compounds cause changes in abundance and prevent some microorganisms from growing. We focused on a contaminated aquifer in Oak Ridge, Tennessee, USA that has large gradients of pH and widely varying concentrations of uranium, nitrate, and many other inorganic ions. In the most contaminated wells, the microbial community is enriched in the Rhodanobacter genus. Rhodanobacter abundance is positively correlated with low pH and high concentrations of uranium and 13 other ions and we sought to determine which of these ions are selective pressures that favor the growth of Rhodanobacter over other taxa. Of these ions, low pH and high UO22+, Mn2+, Al3+, Cd2+, Zn2+, Co2+, and Ni2+ are both (a) selectively inhibitory of a Pseudomonas isolate from an uncontaminated well vs. a Rhodanobacter isolate from a contaminated well, and (b) reach toxic concentrations (for the Pseudomonas isolate) in the Rhodanobacter dominated wells. We used mixtures of ions to simulate the groundwater conditions in the most contaminated wells and verified that few isolates aside from Rhodanobacter can tolerate these eight ions. These results clarify which ions are likely causal factors that impact the microbial community at this field site and are not merely correlated with taxonomic shifts. Furthermore, our general high throughput approach can be applied to other environments, isolates, and conditions to systematically help identify selective pressures on microbial communities. PMID- 30523278 TI - Structural assembly of the megadalton-sized receptor for intestinal vitamin B12 uptake and kidney protein reabsorption. AB - The endocytic receptor cubam formed by the 460-kDa protein cubilin and the 45-kDa transmembrane protein amnionless (AMN), is essential for intestinal vitamin B12 (B12) uptake and for protein (e.g. albumin) reabsorption from the kidney filtrate. Loss of function of any of the two components ultimately leads to serious B12 deficiency and urinary protein loss in humans (Imerslund-Grasbeck's syndrome, IGS). Here, we present the crystal structure of AMN in complex with the amino-terminal region of cubilin, revealing a sophisticated assembly of three cubilin subunits combining into a single intertwined beta-helix domain that docks to a corresponding three-faced beta-helix domain in AMN. This beta-helix-beta helix association thereby anchors three ligand-binding cubilin subunits to the transmembrane AMN. Electron microscopy of full-length cubam reveals a 700-800 A long tree-like structure with the potential of dimerization into an even larger complex. Furthermore, effects of known human mutations causing IGS are explained by the structural information. PMID- 30523277 TI - STING-dependent sensing of self-DNA drives silica-induced lung inflammation. AB - Silica particles induce lung inflammation and fibrosis. Here we show that stimulator of interferon genes (STING) is essential for silica-induced lung inflammation. In mice, silica induces lung cell death and self-dsDNA release in the bronchoalveolar space that activates STING pathway. Degradation of extracellular self-dsDNA by DNase I inhibits silica-induced STING activation and the downstream type I IFN response. Patients with silicosis have increased circulating dsDNA and CXCL10 in sputum, and patients with fibrotic interstitial lung disease display STING activation and CXCL10 in the lung. In vitro, while mitochondrial dsDNA is sensed by cGAS-STING in dendritic cells, in macrophages extracellular dsDNA activates STING independent of cGAS after silica exposure. These results reveal an essential function of STING-mediated self-dsDNA sensing after silica exposure, and identify DNase I as a potential therapy for silica induced lung inflammation. PMID- 30523279 TI - Publisher Correction: Paving possibilities. AB - In the version of this Research Highlight originally published, credit for the image was given to Siobhan Braybrook only. The correct credit should be to Rosa V. Vofeley and Siobhan Braybrook. This has now been amended. PMID- 30523280 TI - TH cells tune intestinal stem cell fate. PMID- 30523282 TI - Cancer immunoediting and resistance to T cell-based immunotherapy. AB - Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance. PMID- 30523281 TI - The genomic landscape of molecular responses to natural drought stress in Panicum hallii. AB - Environmental stress is a major driver of ecological community dynamics and agricultural productivity. This is especially true for soil water availability, because drought is the greatest abiotic inhibitor of worldwide crop yields. Here, we test the genetic basis of drought responses in the genetic model for C4 perennial grasses, Panicum hallii, through population genomics, field-scale gene expression (eQTL) analysis, and comparison of two complete genomes. While gene expression networks are dominated by local cis-regulatory elements, we observe three genomic hotspots of unlinked trans-regulatory loci. These regulatory hubs are four times more drought responsive than the genome-wide average. Additionally, cis- and trans-regulatory networks are more likely to have opposing effects than expected under neutral evolution, supporting a strong influence of compensatory evolution and stabilizing selection. These results implicate trans regulatory evolution as a driver of drought responses and demonstrate the potential for crop improvement in drought-prone regions through modification of gene regulatory networks. PMID- 30523283 TI - Human Herpesvirus 6A and 6B inhibit in vitro angiogenesis by induction of Human Leukocyte Antigen G. AB - We have previously reported that human herpesvirus 6 (HHV-6) infection of endothelial cells (ECs) induces the loss of angiogenic properties, through the expression of HHV-6 U94, possibly associated to the release of a soluble mediator. It is also known that the soluble isoform of HLA-G exhibits an anti angiogenic function, important in implantation, transplantation and neoplastic development. In this study, we analyzed the expression of HLA-G in HHV-6 infected ECs, showing that both HHV-6A and HHV-6B infection induce a potent up-modulation of HLA-G, including both membrane and soluble isoforms. Interestingly, HHV-6A and HHV-6B induced different isoforms of HLA-G. The virus-induced increase of HLA-G was likely due to the expression of the U94 viral gene, that by itself was able to reproduce the effect of whole virus. The effect of U94 was mediated by human transcription factor ATF3, that induced HLA-G activation by recognizing a consensus sequence on its promoter. Virus-induced inhibition of ECs angiogenic ability directly correlated to HLA-G expression and release, and the addition of anti-HLA-G antibody restored the angiogenic properties of HHV6-infected ECs. The induction of HLA-G expression in ECs might represent an important mediator of HHV 6 induced effects. PMID- 30523284 TI - Extra-Visual Systems in the Spatial Reorientation of Cavefish. AB - Disoriented humans and animals are able to reorient themselves using environmental geometry ("metric properties" and "sense") and local features, also relating geometric to non-geometric information. Here we investigated the presence of these reorientation spatial skills in two species of blind cavefish (Astyanax mexicanus and Phreatichthys andruzzii), in order to understand the possible role of extra-visual senses in similar spatial tasks. In a rectangular apparatus, with all homogeneous walls (geometric condition) or in presence of a tactilely different wall (feature condition), cavefish were required to reorient themselves after passive disorientation. We provided the first evidence that blind cavefish, using extra-visual systems, were able i) to use geometric cues, provided by the shape of the tank, in order to recognize two geometric equivalent corners on the diagonal, and ii) to integrate the geometric information with the salient cue (wall with a different surface structure), in order to recover a specific corner. These findings suggest the ecological salience of the environmental geometry for spatial orientation in animals and, despite the different niches of adaptation, a potential shared background for spatial navigation. The geometric spatial encoding seems to constitute a common cognitive tool needed when the environment poses similar requirements to living organisms. PMID- 30523286 TI - Transporters help clear cell corpses. PMID- 30523287 TI - Fixing a hole. PMID- 30523285 TI - The association between neonatal vitamin D status and risk of schizophrenia. AB - Clues from the epidemiology of schizophrenia, such as the increased risk in those born in winter/spring, have led to the hypothesis that prenatal vitamin D deficiency may increase the risk of later schizophrenia. We wish to explore this hypothesis in a large Danish case-control study (n = 2602). The concentration of 25 hydroxyvitamin D (25OHD) was assessed from neonatal dried blood samples. Incidence rate ratios (IRR) were calculated when examined for quintiles of 25OHD concentration. In addition, we examined statistical models that combined 25OHD concentration and the schizophrenia polygenic risk score (PRS) in a sample that combined the new sample with a previous study (total n = 3464; samples assayed and genotyped between 2008-2013). Compared to the reference (fourth) quintile, those in the lowest quintile (<20.4 nmol/L) had a significantly increased risk of schizophrenia (IRR = 1.44, 95%CI: 1.12-1.85). None of the other quintile comparisons were significantly different. There was no significant interaction between 25OHD and the PRS. Neonatal vitamin D deficiency was associated with an increased risk for schizophrenia in later life. These findings could have important public health implications related to the primary prevention of schizophrenia. PMID- 30523288 TI - The prevalence of mitochondrial mutations associated with aminoglycoside-induced deafness in ethnic Latvian population: the appraisal of the evidence. AB - Aminoglycosides are potent antibiotics which are used to treat severe gram negative infections, neonatal sepsis, and multidrug-resistant tuberculosis. Ototoxicity is a well-known side effect of aminoglycosides, and a rapid, profound, and irreversible hearing loss can occur in predisposed individuals. MT RNR1 gene encoding the mitochondrial ribosomal 12S subunit is a hot spot for aminoglycoside-induced hearing loss mutations, however, a variability in the nature and frequency of genetic changes in different populations exists. The objective of this study was to analyze MT-RNR1 gene mutations in a Baltic speaking Latvian population, and to estimate the prevalence of such genetic changes in the population-specific mitochondrial haplogroups. In the cohort of 191 ethnic non-related Latvians, the presence of two deafness-associated mutations, m.1555A>G and m.827A>G, three potentially pathogenic variations, m.961insC(n), m.961T>G and m.951G>A, and one unknown substitution, m961T>A was detected, and the aggregate frequency of all variants was 7.3%. All genetic changes were detected in samples belonged to the haplogroups H, U, T, and J. The presence of several aminoglycoside ototoxicity-related MT-RNR1 gene mutations in Baltic-speaking Latvian population indicates the necessity to include ototoxicity related mutation analysis in the future studies in order to determine the feasibility of DNA screening for patients before administration of aminoglycoside therapy. PMID- 30523289 TI - Electrostatic Origins of CO2-Increased Hydrophilicity in Carbonate Reservoirs. AB - Injecting CO2 into oil reservoirs appears to be cost-effective and environmentally friendly due to decreasing the use of chemicals and cutting back on the greenhouse gas emission released. However, there is a pressing need for new algorithms to characterize oil/brine/rock system wettability, thus better predict and manage CO2 geological storage and enhanced oil recovery in oil reservoirs. We coupled surface complexation/CO2 and calcite dissolution model, and accurately predicted measured oil-on-calcite contact angles in NaCl and CaCl2 solutions with and without CO2. Contact angles decreased in carbonated water indicating increased hydrophilicity under carbonation. Lowered salinity increased hydrophilicity as did Ca2+. Hydrophilicity correlates with independently calculated oil-calcite electrostatic bridging. The link between the two may be used to better implement CO2 EOR in fields. PMID- 30523290 TI - The two-fluid dynamics and energetics of the asymmetric magnetic reconnection in laboratory and space plasmas. AB - Magnetic reconnection is a fundamental process in magnetized plasma where magnetic energy is converted to plasma energy. Despite huge differences in the physical size of the reconnection layer, remarkably similar characteristics are observed in both laboratory and magnetosphere plasmas. Here we present the comparative study of the dynamics and physical mechanisms governing the energy conversion in the laboratory and space plasma in the context of two-fluid physics, aided by numerical simulations. In strongly asymmetric reconnection layers with negligible guide field, the energy deposition to electrons is found to primarily occur in the electron diffusion region where electrons are demagnetized and diffuse. A large potential well is observed within the reconnection plane and ions are accelerated by the electric field toward the exhaust region. The present comparative study identifies the robust two-fluid mechanism operating in systems over six orders of magnitude in spatial scales and over a wide range of collisionality. PMID- 30523291 TI - Microvascular and macrovascular endothelial function in two different types of primary aldosteronism. PMID- 30523292 TI - Association of blood pressure with estimates of 24-h urinary sodium and potassium excretion from repeated single-spot urine samples. AB - While the association between 24-h urinary sodium and potassium excretion with blood pressure is well established, the relationships of these ions to spot urine measurements are unclear. Our purpose is to assess the association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. Spot urine and blood pressure were collected annually during a 5-year period from 4360 Japanese workers with ages ranging from 19 to 55 years. Estimates of 24-h sodium and potassium excretion were based on Tanaka's formula. Overall, a single standard deviation increase in the estimated sodium excretion (36.5 mmol/day) was associated with a 1.3 mmHg higher systolic blood pressure and a 0.8 mmHg higher diastolic blood pressure (P < 0.001). A single standard deviation increase in estimated potassium excretion (8.9 mmol/day) was associated with a 1.1 mmHg lower systolic blood pressure and a 0.7 mmHg lower diastolic blood pressure (P < 0.001). As a combined measure of the excretion of both electrolytes, the estimated 24-h sodium-to-potassium ratio was positively associated with both blood pressures (P < 0.001). Associations of blood pressure with sodium and the sodium-to-potassium ratio increased with age and were stronger in men compared to women. Associations with potassium and the sodium-to potassium ratio were stronger in individuals who were overweight. The findings provide evidence for an association between blood pressure and the estimated 24-h sodium and potassium excretion from repeated single-spot urine samples. As convenient measures of dietary intake for each electrolyte, repeated spot urine samples may be useful for assessing hypertension risk, especially in men, older individuals, and overweight individuals. PMID- 30523294 TI - When remembering is rewarding. PMID- 30523293 TI - Pathophysiological mechanisms of mineralocorticoid receptor-dependent cardiovascular and chronic kidney disease. AB - Accumulating evidence has indicated the potential contributions of aldosterone and mineralocorticoid receptor (MR) to the pathophysiology of cardiovascular disease (CVD) and chronic kidney disease (CKD). Patients with primary aldosteronism have a higher risk of CVD and CKD than those with essential hypertension. MR is strongly expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, macrophages, glomerular mesangial cells, podocytes, and proximal tubular cells. In these cardiovascular and renal cells, aldosterone-induced cell injury is prevented by MR blockade. Interestingly, MR antagonists elicit beneficial effects on CVD and CKD in subjects with low or normal plasma aldosterone levels. Recent studies have shown that during development of CVD and CKD, cardiovascular and renal MR is activated by glucocorticoid and ligand-independent mechanisms, such as Rac1 signaling pathways. These data indicate that inappropriate activation of local MR contributes to cardiovascular and renal tissue injury through aldosterone dependent and -independent mechanisms. In this review, recent findings on the specific role of cardiovascular and renal MR in the pathogenesis of CVD and CKD are summarized. PMID- 30523295 TI - Interatomic force laws that evade dynamic measurement. AB - Measurement of the force between two atoms is performed routinely with the atomic force microscope. The shape of this interatomic force law is now found to directly regulate this capability: rapidly varying interatomic force laws, which are common in nature, can corrupt their own measurement. PMID- 30523296 TI - Emerging hydrovoltaic technology. AB - Water contains tremendous energy in a variety of forms, but very little of this energy has yet been harnessed. Nanostructured materials can generate electricity on interaction with water, a phenomenon that we term the hydrovoltaic effect, which potentially extends the technical capability of water energy harvesting and enables the creation of self-powered devices. In this Review, starting by describing fundamental properties of water and of water-solid interfaces, we discuss key aspects pertaining to water-carbon interactions and basic mechanisms of harvesting water energy with nanostructured materials. Experimental advances in generating electricity from water flows, waves, natural evaporation and moisture are then reviewed to show the correlations in their basic mechanisms and the potential for their integration towards harvesting energy from the water cycle. We further discuss potential device applications of hydrovoltaic technologies, analyse main challenges in improving the energy conversion efficiency and scaling up the output power, and suggest prospects for developments of the emerging technology. PMID- 30523297 TI - A carbon dioxide screw. PMID- 30523298 TI - Artificial neurons a la carte. PMID- 30523299 TI - Piercing the biofilm. PMID- 30523301 TI - A note on the Lena image. PMID- 30523300 TI - Photons gauge angstroms. PMID- 30523302 TI - More power from water. PMID- 30523303 TI - Polycystic kidney disease. AB - Cystic kidneys are common causes of end-stage renal disease, both in children and in adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are cilia-related disorders and the two main forms of monogenic cystic kidney diseases. ADPKD is a common disease that mostly presents in adults, whereas ARPKD is a rarer and often more severe form of polycystic kidney disease (PKD) that usually presents perinatally or in early childhood. Cell biological and clinical research approaches have expanded our knowledge of the pathogenesis of ADPKD and ARPKD and revealed some mechanistic overlap between them. A reduced 'dosage' of PKD proteins is thought to disturb cell homeostasis and converging signalling pathways, such as Ca2+, cAMP, mechanistic target of rapamycin, WNT, vascular endothelial growth factor and Hippo signalling, and could explain the more severe clinical course in some patients with PKD. Genetic diagnosis might benefit families and improve the clinical management of patients, which might be enhanced even further with emerging therapeutic options. However, many important questions about the pathogenesis of PKD remain. In this Primer, we provide an overview of the current knowledge of PKD and its treatment. PMID- 30523304 TI - Total, insoluble, and soluble dietary fiber intake and insulin resistance and blood pressure in adolescents. AB - BACKGROUND/OBJECTIVES: To evaluate sex and race differences in fiber intakes, which are understudied in adolescents, and to investigate whether low insoluble and soluble fiber intakes would be associated with higher risk for insulin resistance and blood pressure (BP). SUBJECTS/METHODS: A total of 754 black and white adolescents, 14 to 18 years old (49.2% blacks; 50.3% female), were previously recruited in Augusta, Georgia, USA, between 2001 and 2005. Diet was assessed with four to seven independent 24 h dietary recalls. RESULTS: The average daily consumption of total, insoluble, and soluble fiber were 10.9, 6.7, and 4.0 g, respectively. Only two adolescents met their daily fiber intake recommendation. Adjusted multiple linear regressions revealed that increasing dietary fiber intake from current averages to recommendation levels (12 g to 38 g in the male and 9.9 g to 25 g in the female) were associated with predicted decreases of 5.4 and 3.0 mg/dL fasting glucose, 7.0 and 5.0 mg/dL fasting insulin, 1.6 and 1.1 HOMA-IR, 6.3 and 3.7 mm Hg SBP, and 5.2 and 3.0 mm Hg DBP in the males and females, respectively (all p < 0.05). Furthermore, both insoluble and soluble fiber intakes were inversely associated with fasting insulin and HOMA IR (p < 0.05), whereas only soluble fiber intake was found to be associated with BP (p < 0.05). CONCLUSIONS: Fiber consumption in adolescents is far below daily recommended levels across all sex and race groups. Lower fiber intake of all types is associated with higher insulin level. Fiber Intake at recommendation levels may be associated with significant cardiometabolic benefits. PMID- 30523306 TI - Physical activity and energy balance. PMID- 30523305 TI - Four years after implementation of a national micronutrient powder program in Kyrgyzstan, prevalence of iron deficiency and iron deficiency anemia is lower, but prevalence of vitamin A deficiency is higher. AB - BACKGROUND/OBJECTIVES: In 2009, the Ministry of Health of Kyrgyzstan launched a national Infant and Young Child Nutrition (IYCN) program which included point-of use fortification of foods with micronutrient powders (MNP) containing iron, vitamin A, and other micronutrients. Caretakers of children aged 6-23 months were given 30 sachets of MNP every 2 months. Micronutrient surveys were conducted in 2009 and 2013. The objective of the study was to compare the prevalence of anemia and deficiencies of iron and vitamin A among children aged 6-29 months prior to the MNP program (2009) with those after full implementation (2013). SUBJECTS/METHODS: Cross-sectional national surveys were conducted in 2009 (n = 666) and 2013 (n = 2150). Capillary blood samples were collected to measure hemoglobin, iron (ferritin and soluble transferrin receptor [sTfR]) and vitamin A (retinol binding protein [RBP]) status, and inflammation status (C-reactive protein [CRP] and alpha-1-acid glycoprotein [AGP]). Ferritin, sTfR, and RBP were adjusted for inflammation; hemoglobin was adjusted for altitude. RESULTS: The prevalence of anemia was non-significantly lower in 2013 compared to 2009 (32.7% vs. 39.0%, p = 0.076). Prevalence of inflammation-adjusted iron deficiency (54.8% vs. 74.2%, p<0.001) and iron deficiency anemia (IDA, 25.5% vs. 35.1%, p = 0.003) were lower and the prevalence of inflammation-adjusted vitamin A deficiency was higher (4.3% vs. 2.0%, p = 0.013) in 2013 compared to 2009. CONCLUSIONS: Four years after the initiation of a national Infant and Young Child Nutrition program including the introduction of point-of-use fortification with MNP, the prevalence of iron deficiency and IDA is lower, but the prevalence of vitamin A deficiency is higher. PMID- 30523307 TI - Antimicrobial potential of endocannabinoid and endocannabinoid-like compounds against methicillin-resistant Staphylococcus aureus. AB - Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Staphylococcal biofilms are associated with increased antimicrobial resistance and are generally less affected by host immune factors. Therefore, there is an urgent need for novel agents that not only aim at multidrug-resistant pathogens, but also ones that will act as anti biofilms. In the present study, we investigated the antimicrobial activity of the endocannabinoid (EC) anandamide (AEA) and the endocannabinoid-like (EC-like), arachidonoyl serine (AraS) against methicillin resistant S. aureus strains (MRSA). We observed a strong inhibition of biofilm formation of all tested MRSA strains as well as a notable reduction of metabolic activity of pre-formed MRSA biofilms by both agents. Moreover, staphylococcal biofilm-associated virulence determinants such as hydrophobicity, cell aggregation and spreading ability were altered by AEA and AraS. In addition, the agents were able to modify bacterial membrane potential. Importantly, both compounds prevent biofilm formation by altering the surface of the cell without killing the bacteria. Therefore, we propose that EC and EC-like compounds may act as a natural line of defence against MRSA or other antibiotic resistant bacteria. Due to their anti biofilm action these agents could also be a promising alternative to antibiotic therapeutics against biofilm-associated MRSA infections. PMID- 30523308 TI - Image-based promoter prediction: a promoter prediction method based on evolutionarily generated patterns. AB - Prediction of promoter regions is crucial for studying gene function and regulation. The well-accepted position weight matrix method for this purpose relies on predefined motifs, which would hinder application across different species. Here, we introduce image-based promoter prediction (IBPP) as a method that creates an "image" from training promoter sequences using an evolutionary approach and predicts promoters by matching with the "image". We used Escherichia coli sigma70 promoter sequences to test the performance of IBPP and the combination of IBPP and a support vector machine algorithm (IBPP-SVM). The "images" generated with IBPP could effectively distinguish promoter from non promoter sequences. Compared with IBPP, IBPP-SVM showed a substantial improvement in sensitivity. Furthermore, both methods showed good performance for sequences of up to 2,000 nt in length. The performances of IBPP and IBPP-SVM were largely affected by the threshold and dimension of vectors, respectively. The source code and documentation are freely available at https://github.com/hahatcdg/IBPP . PMID- 30523309 TI - CaMKIIbeta regulates nucleus-centrosome coupling in locomoting neurons of the developing cerebral cortex. PMID- 30523310 TI - Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection. AB - The gamma-amino butyric acid (GABA)ergic system shapes the activation and function of immune cells. The present study was conducted to explore the regulation of GABA transporter (GAT)-2 on the differentiation of Th17 cells. Here we found that Th17 cells show higher abundance of GAT-2, and have distinct cellular metabolic signatures, such as the GABA shunt pathway, as compared to naive T cells. GAT-2 deficiency had little effect on the metabolic signature in naive T cells, but impaired the GABA uptake and GABA shunt pathway in Th17 cells. GAT-2 deficiency had little effect on T cell development and peripheral T cell homeostasis; however, its deficiency promoted Th17 cell differentiation in vitro. Mechanistically, GAT-2 deficiency promoted differentiation of Th17 cells through activation of GABA-mTOR signaling. In a mouse model of intestinal infection and inflammation, GAT-2 deficiency promoted Th17 responses. Collectively, GAT-2 deficiency promotes Th17 cell responses through activation of GABA-mTOR signaling. PMID- 30523312 TI - Timeline of events. PMID- 30523311 TI - Microanatomical dissection of human intestinal T-cell immunity reveals site specific changes in gut-associated lymphoid tissues over life. AB - Defining adaptive immunity with the complex structures of the human gastrointestinal (GI) tract over life is essential for understanding immune responses to ingested antigens, commensal and pathogenic microorganisms, and dysfunctions in disease. We present here an analysis of lymphocyte localization and T cell subset composition across the human GI tract including mucosal sites (jejunum, ileum, colon), gut-associated lymphoid tissues (isolated lymphoid follicles (ILFs), Peyer's patches (PPs), appendix), and mesenteric lymph nodes (MLNs) from a total of 68 donors spanning eight decades of life. In pediatric donors, ILFs and PP containing naive T cells and regulatory T cells (Tregs) are prevalent in the jejunum and ileum, respectively; these decline in frequency with age, contrasting stable frequencies of ILFs and T cell subsets in the colon. In the mucosa, tissue resident memory T cells develop during childhood, and persist in high frequencies into advanced ages, while T cell composition changes with age in GALT and MLN. These spatial and temporal features of human intestinal T cell immunity define signatures that can be used to train predictive machine learning algorithms. Our findings demonstrate an anatomic basis for age-associated alterations in immune responses, and establish a quantitative baseline for intestinal immunity to define disease pathologies. PMID- 30523313 TI - The Yearbook. PMID- 30523314 TI - Meningeal lymphatics in aging and Alzheimer's disease. PMID- 30523315 TI - Monitoring yellow fever. PMID- 30523316 TI - Understanding genetic disease with electronic records. PMID- 30523317 TI - The microbiome influence. PMID- 30523318 TI - A blood-based biomarker for checkpoint inhibition. PMID- 30523319 TI - Identifying atrial fibrillation. PMID- 30523320 TI - Environmental shaping of the microbiome. PMID- 30523321 TI - In utero correction of a genetic disorder. PMID- 30523322 TI - Gene therapy for beta thalassemia. PMID- 30523323 TI - In vivo detection of gut bleeding. PMID- 30523324 TI - Diversifying clinical trials. AB - Scientific common sense and social justice dictate that the safety and efficacy of new therapies must be tested in the patient populations in need of treatment. Yet a recent study found that African Americans have been dramatically underrepresented in US clinical trials for cancer drugs. Efforts to increase the participation of minorities in clinical trials must become a priority for all drug developers. PMID- 30523325 TI - Metformin action through the microbiome and bile acids. PMID- 30523326 TI - Treatments that made headlines in 2018. PMID- 30523327 TI - The emerging link between cancer, metabolism, and circadian rhythms. AB - The circadian clock is a complex cellular mechanism that, through the control of diverse metabolic and gene expression pathways, governs a large array of cyclic physiological processes. Epidemiological and clinical data reveal a connection between the disruption of circadian rhythms and cancer that is supported by recent preclinical data. In addition, results from animal models and molecular studies underscore emerging links between cancer metabolism and the circadian clock. This has implications for therapeutic approaches, and we discuss the possible design of chronopharmacological strategies. PMID- 30523328 TI - Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. AB - Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients. PMID- 30523331 TI - 6mA in stress tolerance across generations. PMID- 30523330 TI - Author Correction: Autophagy maintains tumour growth through circulating arginine. AB - In this Letter, 'released' should have been 'regulated' in the sentence starting: 'Deletion of Atg5 in the host similarly regulated circulating arginine and suppressed tumorigenesis...' This has been corrected online. PMID- 30523329 TI - Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy. AB - Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies. PMID- 30523332 TI - Dynamics and functions of lipid droplets. AB - Lipid droplets are storage organelles at the centre of lipid and energy homeostasis. They have a unique architecture consisting of a hydrophobic core of neutral lipids, which is enclosed by a phospholipid monolayer that is decorated by a specific set of proteins. Originating from the endoplasmic reticulum, lipid droplets can associate with most other cellular organelles through membrane contact sites. It is becoming apparent that these contacts between lipid droplets and other organelles are highly dynamic and coupled to the cycles of lipid droplet expansion and shrinkage. Importantly, lipid droplet biogenesis and degradation, as well as their interactions with other organelles, are tightly coupled to cellular metabolism and are critical to buffer the levels of toxic lipid species. Thus, lipid droplets facilitate the coordination and communication between different organelles and act as vital hubs of cellular metabolism. PMID- 30523333 TI - Chronic opioid usage on the rise in RA. PMID- 30523334 TI - Machine-learning-based patient-specific prediction models for knee osteoarthritis. AB - Osteoarthritis (OA) is an extremely common musculoskeletal disease. However, current guidelines are not well suited for diagnosing patients in the early stages of disease and do not discriminate patients for whom the disease might progress rapidly. The most important hurdle in OA management is identifying and classifying patients who will benefit most from treatment. Further efforts are needed in patient subgrouping and developing prediction models. Conventional statistical modelling approaches exist; however, these models are limited in the amount of information they can adequately process. Comprehensive patient-specific prediction models need to be developed. Approaches such as data mining and machine learning should aid in the development of such models. Although a challenging task, technology is now available that should enable subgrouping of patients with OA and lead to improved clinical decision-making and precision medicine. PMID- 30523335 TI - Crosstalking with Hippo. PMID- 30523336 TI - Theta-gamma coupling binds visual perceptual features in an associative memory task. AB - It is an integral function of the human brain to sample novel information from the environment and to integrate them into existing representations. Recent evidence suggests a specific role for the theta rhythm (4-8 Hz) in mnemonic processes and the coupling between the theta and the gamma rhythm (40-120 Hz) in ordering and binding perceptual features during encoding. Furthermore, decreases in the alpha rhythm (8-12 Hz) are assumed to gate perceptual information processes in semantic networks. In the present study, we used an associative memory task (object-color combinations) with pictures versus words as stimuli (high versus low visual information) to separate associative memory from visual perceptual processes during memory formation. We found increased theta power for later remembered versus later forgotten items (independent of the color judgement) and an increase in phase-amplitude coupling between frontal theta and fronto-temporal gamma oscillations, specific for the formation of picture-color associations. Furthermore, parietal alpha suppression and gamma power were higher for pictures compared to words. These findings support the idea of a theta-gamma code in binding visual perceptual features during encoding. Furthermore, alpha suppression likely reflects perceptual gating processes in semantic networks and is insensitive to mnemonic and associative binding processes. Gamma oscillations may promote visual perceptual information in visual cortical networks, which is integrated into existing representations by prefrontal control processes, working at a theta pace. PMID- 30523337 TI - The spatial epidemiology of sickle-cell anaemia in India. AB - Sickle-cell anaemia (SCA) is a neglected chronic disorder of increasing global health importance, with India estimated to have the second highest burden of the disease. In the country, SCA is particularly prevalent in scheduled populations, which comprise the most socioeconomically disadvantaged communities. We compiled a geodatabase of a substantial number of SCA surveys carried out in India over the last decade. Using generalised additive models and bootstrapping methods, we generated the first India-specific model-based map of sickle-cell allele frequency which accounts for the district-level distribution of scheduled and non scheduled populations. Where possible, we derived state- and district-level estimates of the number of SCA newborns in 2020 in the two groups. Through the inclusion of an additional 158 data points and 1.3 million individuals, we considerably increased the amount of data in our mapping evidence-base compared to previous studies. Highest predicted frequencies of up to 10% spanned central India, whilst a hotspot of ~12% was observed in Jammu and Kashmir. Evidence was heavily biased towards scheduled populations and remained limited for non scheduled populations, which can lead to considerable uncertainties in newborn estimates at national and state level. This has important implications for health policy and planning. By taking population composition into account, we have generated maps and estimates that better reflect the complex epidemiology of SCA in India and in turn provide more reliable estimates of its burden in the vast country. This work was supported by European Union's Seventh Framework Programme (FP7//2007-2013)/European Research Council [268904 - DIVERSITY]; and the Newton Bhabha Fund [227756052 to CH]. PMID- 30523339 TI - Cytokinesis defects and cancer. AB - Whole-genome and centrosome duplication as a consequence of cytokinesis failure can drive tumorigenesis in experimental model systems. However, whether cytokinesis failure is in fact an important cause of human cancers has remained unclear. In this Review, we summarize evidence that whole-genome-doubling events are frequently observed in human cancers and discuss the contribution that cytokinesis defects can make to tumorigenesis. We provide an overview of the potential causes of cytokinesis failure and discuss how tetraploid cells that are generated through cytokinesis defects are used in cancer as a transitory state on the route to aneuploidy. Finally, we discuss how cytokinesis defects can facilitate genetic diversification within the tumour to promote cancer development and could constitute the path of least resistance in tumour evolution. PMID- 30523340 TI - Immunosuppressive lymphatics. PMID- 30523341 TI - Regulatory networks in AML. PMID- 30523342 TI - Pathogenic TERT promoter variants in telomere diseases. AB - PURPOSE: The acquisition of pathogenic variants in the TERT promoter (TERTp) region is a mechanism of tumorigenesis. In nonmalignant diseases, TERTp variants have been reported only in patients with idiopathic pulmonary fibrosis (IPF) due to germline variants in telomere biology genes. METHODS: We screened patients with a broad spectrum of telomeropathies (n = 136), their relatives (n = 52), and controls (n = 195) for TERTp variants using a customized massively parallel amplicon-based sequencing assay. RESULTS: Pathogenic -124 and -146 TERTp variants were identified in nine (7%) unrelated patients diagnosed with IPF (28%) or moderate aplastic anemia (4.6%); five of them also presented cirrhosis. Five (10%) relatives were also found with these variants, all harboring a pathogenic germline variant in telomere biology genes. TERTp clone selection did not associate with peripheral blood counts, telomere length, and response to danazol treatment. However, it was specific for patients with telomeropathies, more frequently co-occurring with TERT germline variants and associated with aging. CONCLUSION: We extend the spectrum of nonmalignant diseases associated with pathogenic TERTp variants to marrow failure and liver disease due to inherited telomerase deficiency. Specificity of pathogenic TERTp variants for telomerase dysfunction may help to assess the pathogenicity of unclear constitutional variants in the telomere diseases. PMID- 30523338 TI - Metabolite changes in blood predict the onset of tuberculosis. AB - New biomarkers of tuberculosis (TB) risk and disease are critical for the urgently needed control of the ongoing TB pandemic. In a prospective multisite study across Subsaharan Africa, we analyzed metabolic profiles in serum and plasma from HIV-negative, TB-exposed individuals who either progressed to TB 3-24 months post-exposure (progressors) or remained healthy (controls). We generated a trans-African metabolic biosignature for TB, which identifies future progressors both on blinded test samples and in external data sets and shows a performance of 69% sensitivity at 75% specificity in samples within 5 months of diagnosis. These prognostic metabolic signatures are consistent with development of subclinical disease prior to manifestation of active TB. Metabolic changes associated with pre-symptomatic disease are observed as early as 12 months prior to TB diagnosis, thus enabling timely interventions to prevent disease progression and transmission. PMID- 30523343 TI - Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. AB - PURPOSE: Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework. METHODS: Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification. RESULTS: Of all gene-disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the National Institutes of Health Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence. CONCLUSION: Clinicians and laboratory diagnosticians should note that <60% of the genes on clinically available panels have Strong or Definitive evidence of association with hereditary colon cancer or polyposis, and >40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes. PMID- 30523344 TI - Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing. AB - PURPOSE: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). METHODS: Two large databases of individuals fulfilling NF2 criteria (n = 1361) and those tested for NF2 variants with criteria short of diagnosis (n = 1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the positive predictive value (PPV) with regard to definite diagnosis. RESULTS: There was no evidence for usefulness of old criteria "glioma" or "neurofibroma." "Ependymoma" had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged >=60 years had the lowest confirmation rate (6.6%) and reduced PPV (80%). Siblings as a first-degree relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus >=2 nondermal schwannomas reduced PPV to 67%. CONCLUSIONS: The present study confirms important deficiencies in NF2 diagnostic criteria. The term "glioma" should be dropped and replaced by "ependymoma." Similarly "neurofibroma" should be removed. Dropping "sibling" from first-degree relatives should be considered and testing of LZTR1 should be recommended for unilateral VS. PMID- 30523345 TI - A study of tuberculosis in road traffic-killed badgers on the edge of the British bovine TB epidemic area. AB - The role of badgers in the geographic expansion of the bovine tuberculosis (bTB) epidemic in England is unknown: indeed there have been few published studies of bTB in badgers outside of the Southwest of England where the infection is now endemic in cattle. Cheshire is now on the edge of the expanding area of England in which bTB is considered endemic in cattle. Previous studies, over a decade ago when bovine infection was rare in Cheshire, found no or only few infected badgers in the south eastern area of the county. In this study, carried out in 2014, road killed badgers were collected through a network of local stakeholders (farmers, veterinarians, wildlife groups, government agencies), and Mycobacterium bovis was isolated from 21% (20/94) badger carcasses. Furthermore, there was strong evidence for co-localisation of M. bovis SB0129 (genotype 25) infection in both badgers and cattle herds at a county scale. While these findings suggest that both badgers and cattle are part of the same geographically expanding epidemic, the direction of any cross-species transmission and the drivers of this expansion cannot be determined. The study also demonstrated the utility of using road killed badgers collected by stakeholders as a means of wildlife TB surveillance. PMID- 30523346 TI - Trans-silencing effect of the 3'RR immunoglobulin heavy chain enhancer on Igkappa transcription at the pro-B cell stage. PMID- 30523348 TI - Heterometallic grids: synthetic strategies and recent advances. AB - Supramolecular metallogrid complexes are metalloclusters involving metal ions in planar array arrangements and organic ligands in perpendicular arrangements at each corner of the metal sites. Such essentially metal ion arrays have attracted great attention in the last three decades owing to their variety of interesting optical, electronic and magnetic properties. Among them, metallogrids containing more than one type of metal, that is heterometallic grids, are rare but have more potential to engineer a higher level functionality into one molecule. However, until now, only dozens of heterometallic grids have been reported without any specific review. Herein, we aim to give an overview of the assembly strategies, the physicochemical properties, and finally some perspectives on the future development of heterometallic grids. PMID- 30523347 TI - Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling. AB - The B7-family inducible costimulator (ICOS) activates phosphoinositide-3 kinase (PI3K) and augments calcium mobilization triggered by the T-cell receptor (TCR). We surprisingly found that the entire cytoplasmic domain of ICOS is dispensable for its costimulation of calcium mobilization. This costimulatory function relies on the unique transmembrane domain (TMD) of ICOS, which promotes association with the tyrosine kinase Lck. TMD-enabled Lck association is also required for p85 recruitment to ICOS and subsequent PI3K activation, and Lck underlies both the bystander and costimulatory signaling activity of ICOS. TMD-replaced ICOS, even with an intact cytoplasmic domain, fails to support TFH development or GC formation in vivo. When transplanted onto a chimeric antigen receptor (CAR), the ICOS TMD enhances interactions between T cells and antigen-presenting target cells. Therefore, by revealing an unexpected function of the ICOS TMD, our study offers a new perspective for the understanding and potential application of costimulation biology. PMID- 30523349 TI - Hydrogen-bonding interactions and magnetic relaxation dynamics in tetracoordinated cobalt(ii) single-ion magnets. AB - Three tetracoordinated cobalt(ii) complexes with a series of unsymmetrical bidentate ligands were synthesized and crystallographically characterized. Although their static magnetic properties are similar, their dynamic magnetic properties differ drastically depending indirectly on intermolecular hydrogen bonding interactions. PMID- 30523350 TI - Representation of coupled adiabatic potential energy surfaces using neural network based quasi-diabatic Hamiltonians: 1,2 2A' states of LiFH. AB - An analytic quasi-diabatic representation of ab initio electronic structure data is key to the accurate quantum mechanical description of non-adiabatic chemical processes. In this work, a general neural network (NN) fitting procedure is proposed to generate coupled quasi-diabatic Hamiltonians (Hd) that are capable of representing adiabatic energies, energy gradients, and derivative couplings over a wide range of geometries. The quasi-diabatic representation for LiFH is used as a testing example. The fitting data including adiabatic energies, energy gradients and interstate couplings are obtained from a previously fitted analytical quasi-diabatic potential energy matrix, and are well reproduced by the NN fitting. Most importantly, the NN fitting also yields quantum dynamic results that reproduce those on the original LiFH diabatic Hamiltonian, demonstrating the ability of NN to generate highly accurate quasi-diabatic Hamiltonians. PMID- 30523351 TI - Two novel organic phosphorous-based MOFs: synthesis, characterization and photocatalytic properties. AB - Two novel metal-organic framework (MOF) photocatalysts with different structures [(Cu(H2L)(4,4'-bipy)0.5(H2O)] (1) and [Co(C14H14O6.5P2)(4,4'-bipy)0.5(H2O)2].H2O (2) were synthesized using a hydrothermal method using a phosphonate ligand [H4L = 1,1'-biphenylene-4,4'-bis(methylene)-bis(phosphonic acid)] and 4,4'-bipyridine ligand. All the samples were characterized by elemental analysis, thermal analysis, and single crystal X-ray diffraction. As novel porous materials, the two complexes showed active performance for the reduction of Cr(vi) to Cr(iii) and the photodegradation of methylene blue (MB) dye in aqueous solution under UV light. Control experiments showed that the pH value was vital for Cr(vi) reduction, meanwhile, the use of a hole scavenger of methanol promoted the photocatalytic reduction significantly. It was also demonstrated that complexes 1 and 2 were efficient for the degradation of MB. Moreover, the possible reaction mechanism of the reaction was also investigated in detail. Finally, the cyclic experiments indicated the two photocatalysts were stable and reusable, enabling them to be potential candidates for use in environment governance. PMID- 30523352 TI - Measurement of Nocturnal Scratching in Patients with Pruritus Using a Smartwatch: Initial Clinical Studies with the Itch Tracker App. AB - Three clinical studies were conducted to test a newly-developed app for smartwatches, which included an algorithm to measure nocturnal scratching using acceleration data. The first study in 5 patients with atopic dermatitis demonstrated high reliability of the app for measurement of scratching compared with video monitoring (positive predictive value 90.2 +/- 6.6%, sensitivity 84.6 +/- 10.2%, correlation of scratching duration per h r = 0.851-0.901, p < 0.001). The second study in 20 patients with atopic dermatitis and 10 healthy volunteers showed that total scratching duration in patients was significantly longer than in healthy volunteers and correlated positively with Eczema Area and Severity Index (EASI) scores. In the third study, conducted in an open-entry manner in which 201 evaluable participants measured nocturnal scratching, those who self reported itch or pruritic diseases had a significantly longer duration of scratching than those who did not. In conclusion, this app has a high reliability and potential clinical usefulness for measurement of nocturnal scratching. PMID- 30523353 TI - Anterior versus posterior instrumentation for treatment of thoracolumbar tuberculosis : A meta-analysis. AB - BACKGROUND: To compare clinical and functional outcomes of anterior versus posterior debridement and spinal fixation for surgical treatment of thoracolumbar tuberculosis. METHODS: A computer-based online search of the Cochrane Library, PubMed, EMBase, Wanfang, VIP, and the CNKI database was performed. The methodological quality of included studies was evaluated, and data analyses were performed using RevMan 5.0 software (The Nordic Cochrane Centre, The Cochrane Collaboration Copenhagen, Denmark). RESULTS: Eleven trials were studied, with eight performed in China, two in Egypt, and one in India. The results showed significant differences between the two operative approaches in terms of correction of kyphotic angle and intraoperative blood loss, but not in terms of operation time, hospital stay, fusion time, and loss of correction at the final follow-up. CONCLUSION: The anterior and posterior approaches are equally good methods for treatment of thoracolumbar tuberculosis. The anterior approach results in less blood loss, whereas posterior instrumentation is better suited for correction of kyphotic angle. PMID- 30523354 TI - ZmAPRG, an uncharacterized gene, enhances acid phosphatase activity and Pi concentration in maize leaf during phosphate starvation. AB - KEY MESSAGE: An uncharacterized gene, ZmAPRG, isolated by map-based cloning, enhances acid phosphatase activity and phosphate concentration in maize leaf during phosphate starvation. Acid phosphatase (APase) plays important roles in the absorption and utilization of phosphate (Pi) during maize growth. The information on genes regulating the acid phosphatase activity (APA) in maize leaves remains obscured. In a previous study, we delimited the quantitative trait locus, QTL-AP9 for APA to a region of about 546 kb. Here, we demonstrate that the GRMZM2G041022 located in the 546 kb region is a novel acid phosphatase-regulating gene (ZmAPRG). Its overexpression significantly increased the APA and Pi concentration in maize and rice leaves. Subcellular localization of ZmAPRG showed that it was anchored on the plasma and nuclear membrane. The transcriptome analysis of maize ZmAPRG overexpressing lines (ZmAPRG OE) revealed 1287 up regulated and 392 down-regulated genes. Among these, we found APase, protein phosphatase, and phosphate transporter genes, which are known to be implicated in the metabolism and utilization of Pi. We inferred the ZmAPRG functions as an upstream regulation node, directly or indirectly regulating APases, protein phosphatases, and phosphate transporter genes involved in Pi metabolism and utilization in maize. These findings will pave the way for elucidating the mechanism of APase regulation, absorption and utilization of Pi, and would facilitate maize breeding for efficient use of fertilizers. PMID- 30523355 TI - [Incidental findings in recurrent patella dislocation]. PMID- 30523356 TI - Blindness as an uncommon complication of Streptococcus pneumoniae systemic infection. PMID- 30523357 TI - Complete assessment of respiratory mechanics during pressure support ventilation. PMID- 30523358 TI - Unusual presentation of emphysematous pyelonephritis. PMID- 30523359 TI - Demographic characteristics and visual outcomes of open globe injuries in a tertiary hospital in Istanbul, Turkey. AB - PURPOSE: To evaluate the demographic characteristics and visual outcomes of patients with open globe injury (OGI) in a tertiary hospital in Istanbul, Turkey. METHODS: The data of patients admitted with OGI to Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey from January 2012 to December 2017 were reviewed retrospectively, and 100 of the 154 patients were included in the study. RESULTS: There were 79 (79%) male and 21 (21%) female patients with the average age of 33.7 +/- 20.7 (1-83). Presentation of the patients was more frequent in the first 3 days of the week (Monday 20%; Tuesday 17%; and Wednesday 20%) and within working hours (8 a.m.-5 p.m., 71%). The most common injury type was penetrating injury (75%), which was mostly caused by sharp objects (metal objects 32% and broken glass 22.7%). The ocular trauma score (OTS) was significantly higher in patients with penetrating injury and intraocular foreign body injury (p < 0.001), and those results were correlated with better visual prognosis. The patients with penetrating injury among the injury types and zone I injury among the injury zones had the highest final visual acuity. Patients in the age group of 0-14 years had statistically better visual outcome when compared to those in the other age groups (p = 0.003). CONCLUSIONS: The higher initial visual acuity and OTS, penetrating injury, zone I injury and pediatric age are good prognostic factors for OGI. Additionally, scheduling a prepared surgical team and tools in working hours will be beneficial according to the frequency of admissions. PMID- 30523360 TI - High prevalence of deep vein thrombosis in elderly hip fracture patients with delayed hospital admission. AB - PURPOSE: Deep vein thrombosis (DVT) is a common complication in hip fracture patients, associated with significant morbidity and mortality. Research has focused on postoperative DVT, with scant reports on preoperative prevalence. The aim of this study was to describe the prevalence of preoperative DVT in patients accessing medical care >= 48 h after a hip fracture. METHODS: We included elderly patients admitted >= 48 h after sustaining a hip fracture, between September 2015 and October 2017. Patients with a previous episode of DVT, undergoing anticoagulation therapy, with pathologic fractures or undergoing cancer treatment were excluded. Of 273 patients, 59 were admitted at least 48 h after the fracture. DVT screening by Doppler ultrasound of both lower extremities was carried upon hospital admission. We recorded age, sex, Charlson comorbidity index and ASA score, fracture type, time since injury, time from admission to surgery and total length of hospital stay. RESULTS: We studied 41 patients, 79 (+/- 10.34) years old. The delay from injury to admission was 120 h (48-696 h). Seven patients (17.1%) had a DVT upon admission. There were no significant differences between patients with and without DVT, regarding time from admission to surgery or the total length of the hospital stay. CONCLUSIONS: The prevalence of DVT in patients admitted >= 48 h after a hip fracture was 17.1%. The diagnosis and management of DVT did not increase time to surgery or hospital stay. Our results suggest routine screening for DVT in patients consulting emergency services >= 48 h after injury. PMID- 30523361 TI - Engineering oncolytic vaccinia virus with functional peptides through mild and universal strategy. AB - Oncolytic virotherapy is one of promising tumor therapy modalities. However, its therapeutic efficacy is still limited due to the immunogenicity and poor tumor targeting capability. In this report, an engineered oncolytic vaccinia virus (OVV) was constructed by site-specifically introducing azide groups to the envelope of OVV during the in situ assembling process of virions. Subsequently, dibenzocyclooctynes (DBCO) derivate T7 peptide and DBCO derivate self-peptide were simultaneously conjugated to the azide-modified OVV (azide-OVV) via copper free click chemistry. The infectivity of peptide-conjugated virus was well kept. Meanwhile, both of the targeting capacity to transferrin receptor (TfR) overexpressed tumor cells and the in vivo blood circulation time increased. Therefore, the growth of TfR-positive tumor could be significantly inhibited after intravenously injecting the engineered OVV, while no noticeable side effects. This construction strategy can be popularized to other enveloped oncolytic virus (OV), thus a universal engineering platform can be provided for OV cancer therapy. Graphical Abstract An engineered oncolytic vaccinia virus (OVV) was constructed by bioconjugating DBCO derivate T7 peptide and DBCO derivate self-peptide with azide-modified OVV via copper-free click chemistry. As a result, the tumor inhibit effect was significantly enhanced attributed to the prolonged in vivo circulation time and improved targeting recognition capability. PMID- 30523362 TI - Intracellular transport and regulation of transcytosis across the blood-brain barrier. AB - The blood-brain barrier is a dynamic multicellular interface that regulates the transport of molecules between the blood circulation and the brain parenchyma. Proteins and peptides required for brain homeostasis cross the blood-brain barrier via transcellular transport, but the mechanisms that control this pathway are not well characterized. Here, we highlight recent studies on intracellular transport and transcytosis across the blood-brain barrier. Endothelial cells at the blood-brain barrier possess an intricate endosomal network that allows sorting to diverse cellular destinations. Internalization from the plasma membrane, endosomal sorting, and exocytosis all contribute to the regulation of transcytosis. Transmembrane receptors and blood-borne proteins utilize different pathways and mechanisms for transport across brain endothelial cells. Alterations to intracellular transport in brain endothelial cells during diseases of the central nervous system contribute to blood-brain barrier disruption and disease progression. Harnessing the intracellular sorting mechanisms at the blood-brain barrier can help improve delivery of biotherapeutics to the brain. PMID- 30523363 TI - Stem cells within the shoot apical meristem: identity, arrangement and communication. AB - Stem cells are specific cells that renew themselves and also provide daughter cells for organ formation. In plants, primary stem cell populations are nurtured within shoot and root apical meristems (SAM and RAM) for the production of aerial and underground parts, respectively. This review article summarizes recent progress on control of stem cells in the SAM from studies of the model plant Arabidopsis thaliana. To that end, a brief overview of the RAM is provided first to emphasize similarities and differences between the two apical meristems, which would help in better understanding of stem cells in the SAM. Subsequently, we will discuss in depth how stem cells are arranged in an organized manner in the SAM, how dynamically the stem cell identity is regulated, what factors participate in stem cell control, and how intercellular communication by mobile signals modulates stem cell behaviors within the SAM. Remaining questions and perspectives are also presented for future studies. PMID- 30523364 TI - The role of dihydrosphingolipids in disease. AB - Dihydrosphingolipids refer to sphingolipids early in the biosynthetic pathway that do not contain a C4-trans-double bond in the sphingoid backbone: 3 ketosphinganine (3-ketoSph), dihydrosphingosine (dhSph), dihydrosphingosine-1 phosphate (dhS1P) and dihydroceramide (dhCer). Recent advances in research related to sphingolipid biochemistry have shed light on the importance of sphingolipids in terms of cellular signalling in health and disease. However, dihydrosphingolipids have received less attention and research is lacking especially in terms of their molecular mechanisms of action. This is despite studies implicating them in the pathophysiology of disease, for example dhCer in predicting type 2 diabetes in obese individuals, dhS1P in cardiovascular diseases and dhSph in hepato-renal toxicity. This review gives a comprehensive summary of research in the last 10-15 years on the dihydrosphingolipids, 3-ketoSph, dhSph, dhS1P and dhCer, and their relevant roles in different diseases. It also highlights gaps in research that could be of future interest. PMID- 30523365 TI - [Comparison of sublingual and intravenous administration of lorazepam in psychiatric emergencies in emergency medical services]. AB - BACKGROUND: Agitation is a frequent reason for emergency physician calls in psychiatric emergencies in the German preclinical emergency medical system. Benzodiazepines have proven to be effective in treating acute agitation. Although lorazepam has beneficial clinical and pharmacological properties it is hardly used by emergency physicians. The sublingual administration of lorazepam has many advantages compared to intravenous administration. MATERIAL AND METHODS: In an interventional trial lasting 18 months the efficacy, tolerance and onset of effects of sublingual and intravenous lorazepam in patients with agitation states in emergency duties were compared. The randomization to the intervention groups was subject to a time criterion. The sublingual administration of lorazepam over a period of 9 months was followed by an intravenous administration over the same period of time. The psychometric scales used were: PANSS-EC, CGI, CGI-Change, agitation-calmness evaluation scale, visual analog scale and sedation scale. Response to the intervention was defined by a 40% reduction on the PANSS-EC scale. RESULTS: A total of 37 individuals participated in the study (sublingual: n = 22, intravenous: n = 15). Lorazepam was effective in treating acute agitation. The effectiveness and tolerance of sublingual and intravenous lorazepam administration seems to be comparable. CONCLUSION: Sublingual administration of lorazepam is effective for treating acute agitation in emergency medical services. PMID- 30523366 TI - Correction to: Building the Prestige of Archivum Immunologiae et Therapiae Experimentalis: From a Little Known to an Internationally Recognized Journal. AB - According to JCR data, updated in October 2018 by Clarivate Analytics. PMID- 30523367 TI - Treatment of unstable knee osteochondritis dissecans in the young adult: results and limitations of surgical strategies-The advantages of allografts to address an osteochondral challenge. AB - Joint surface incongruence resulting from osteochondritis dissecans (OCD) alters the articular physiologic congruence, increasing the contact stress on adjacent joint surfaces and accelerating wear and the cascade of joint degeneration. Accordingly, the restoration of articular surface integrity is of major importance, especially in young adults where, in lesions left untreated or following simple fragment excision, early osteoarthritis can be anticipated. Therefore, the treatment algorithm in unstable knee OCD of the young adult foresees surgical options to restore the articular surface. Several procedures have been proposed, including refixation of the detached fragment bone marrow stimulation, osteochondral autograft implantation, fresh osteochondral allograft transplantation, and cell-based or cell-free regenerative techniques. The aim of this review was to summarize the evidence for these surgical strategies, reporting their results and limitations. The overall evidence documents positive results for each of the assorted surgical procedures applied to treat unstable OCD, thus indicating support for their selected use to treat osteochondral defects paying particular attention to their specific indications for the lesion characteristics. The fixation of a good quality fragment should be pursued as a first option, while unfixable small lesions may benefit from autografts. For large lesions, available cell-based or cell-free osteochondral scaffold are a feasible solution but with limitation in terms of regenerated tissue quality. In this light, fresh allografts may offer articular surface restoration with viable physiologic osteochondral tissue providing a predictably successful outcome, and therefore they may currently represent the most suitable option to treat unstable irreparable OCD lesion in young adults. LEVEL OF EVIDENCE: V. PMID- 30523368 TI - Primary repair of the anterior cruciate ligament: real innovation or reinvention of the wheel? PMID- 30523369 TI - Preoperative range of motion and applications of continuous passive motion predict outcomes after knee arthroplasty in patients with arthritis. AB - PURPOSE: This study evaluated the clinical efficacy of continuous passive motion (CPM) following knee arthroplasty and determined the predictors of effect sizes of range of motion (ROM) and functional outcomes in patients with knee arthritis. METHODS: A comprehensive electronic database search was performed for randomized controlled trials (RCTs), without publication year or language restrictions. The included RCTs were analyzed through meta-analysis and risk of bias assessment. Study methodological quality (MQ) was assessed using the Physiotherapy Evidence Database (PEDro) scale. Inverse-variance weighted univariate and multivariate metaregression analyses were performed to determine the predictors of treatment outcomes. RESULTS: A total of 77 RCTs with PEDro scores ranging from 6/10 to 8/10 were included. Meta-analyses revealed an overall significant favorable effect of CPM on treatment success rates [odds ratio: 3.64, 95% confidence interval (CI) 2.21-6.00]. Significant immediate [postoperative day 14; standard mean difference (SMD): 1.06; 95% CI 0.61-1.51] and short-term (3-month follow-up; SMD: 0.80; 95% CI 0.45-1.15) effects on knee ROM and a long-term effect on function (12-month follow-up; SMD: 1.08; 95% CI 0.28-1.89) were observed. The preoperative ROM, postoperative day of CPM initiation, daily ROM increment, and total application days were significant independent predictors of CPM efficacy. CONCLUSION: Early CPM initiation with rapid progress over a long duration of CPM application predicts higher treatment effect on knee ROM and function. The results were based on a moderate level of evidence, with good MQ and potential blinding biases in the included RCTs. An aggressive protocol of CPM has clinically relevant beneficial short-term and long-term effects on postoperative outcomes. LEVEL OF EVIDENCE: II. PMID- 30523370 TI - CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. AB - The interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a significantly reduced PD-1hi population. This reduction had little effect on CAR T cell proliferation but strongly augmented CAR T cell cytokine production and cytotoxicity towards PD-L1-expressing cancer cells in vitro. CAR T cells with PD 1 disruption show enhanced tumour control and relapse prevention in vivo when compared with CAR T cells with or without alphaPD-1 antibody blockade. Our study demonstrates a potential advantage of integrated immune checkpoint blockade with CAR T cells in controlling solid tumours and provides an alternative CAR T cell strategy for adoptive transfer therapy. PMID- 30523371 TI - Structure-based design of agarase AgWH50C from Agarivorans gilvus WH0801 to enhance thermostability. AB - AgWH50C, an exo-beta-agarase of GH50 isolated from Agarivorans gilvus WH0801, plays a key role in the enzymatic production of neoagarobiose, which has great application prospect in the cosmetics and pharmaceutical industry. In contrast, the poor thermostability becomes the main obstructive factor of glycoside hydrolase (GH) family 50 agarases, including AgWH50C. Herein, based on the AgWH50C crystal structure, we designed several mutants by a multiple cross-linked rational design protocol used thermostability predicting softwares ETSS, PoPMuSiC, and HotMuSiC. To our surprise, the mutant K621F increased its relative activity by as much as 45% and the optimal temperature increased to 38 degrees C compared to that of wild-type, AgWH50C (30 degrees C). The thermostability of K621F also exhibited a substantial improvement. Considering that the gelling temperature of the agarose is higher than 35 degrees C, K621F can be used to hydrolyze agarose for neoagarobiose production. PMID- 30523372 TI - Biological synthesis of high-conductive pili in aerobic bacterium Pseudomonas aeruginosa. AB - Bioelectrical nanowires as ecomaterials have great potential on environmental applications. A wide range of bacteria can express type IV pili (T4P), which are long protein fibers assembled from PilA. The T4P of Geobacter sulfurreducens are well known as "microbial nanowires," yet T4P of Pseudomonas aeruginosa (PaT4P) was believed to be poorly conductive. P. aeruginosa is an aerobic and electrochemically active bacterium. Its T4P have been known to be responsible for surface attachment, twitching motility and biofilm formation. Here, we show that PaT4P can be highly conductive while assembled by a truncated P. aeruginosa PilA (PaPilA) containing only N-terminus 61 amino acids. Furthermore, increasing the number of aromatic amino acids in the PaPilA1-61 significantly enhances the conductivity of pili and the bioelectricity output of P. aeruginosa in microbial fuel cell system, suggesting a potential application of PaT4P as a conductive nanomaterial. The N-terminal region of PilA from diverse eubacteria is highly conserved, implying a general way to synthesize highly conductive microbial nanowires and to increase the bioelectricity output of microbial fuel cell. PMID- 30523373 TI - Caveat regarding CMS Merit-based Incentive Payment Systems incidental adrenal nodule measure. AB - Current Medicare MIP measures encourage radiologists not to recommend follow-up for <= 1 cm adrenal nodules. However, a radiologist may be the first to discover a small, subclinical pheochromocytoma. As such, recognition of the enhancement pattern of pheochromocytoma is important to ensure detection and properly guide management, which begins with clinical and laboratory assessment for elevated catecholamines. PMID- 30523374 TI - IUGA committee opinion: laser-based vaginal devices for treatment of stress urinary incontinence, genitourinary syndrome of menopause, and vaginal laxity. AB - This committee opinion reviews the laser-based vaginal devices for treatment of genitourinary syndrome of menopause, vaginal laxity, and stress urinary incontinence. The United States Food and Drug Administration has issued a warning for unsubstantiated advertising and use of energy-based devices. Well-designed case-control studies are required to further investigate the potential benefits, harm, and efficacy of laser therapy in the treatment of genitourinary syndrome of menopause, vaginal laxity, and stress urinary incontinence. The therapeutic advantages of nonsurgical laser-based devices in urogynecology can only be recommended after robust clinical trials have demonstrated their long-term complication profile, safety, and efficacy. PMID- 30523375 TI - Changing surgical trends for female stress urinary incontinence in England. AB - INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) surgery has significantly evolved with the introduction of synthetic midurethral slings (MUS). However, following reports from the US Food and Drug Administration and European Commission, the use of vaginal meshes in urogynaecology has been largely scrutinised. We analysed trends in female SUI surgery in England from 2000 to 2017. METHODS: The Hospital Episode Statistics database was retrieved from the Health and Social Care Information Centre website. Specific four-character codes of the evolving OPCS-4 coding system were used to quantify SUI operations. RESULTS: We analysed 180,773 admissions from 2000 to 2017. A steep rise in MUS use was noted until 2008-2009, followed by a consistent drop, with a nadir of 6383 procedures in 2016-2017. Removal of MUS has become increasingly popular, with a peak of 591 in 2012-2013. Numbers for traditional continence operations remained low. Colposuspensions markedly decreased to 189 in 2012-2013, with a slight positive trend only in the last few years, while autologous sling use costantly dropped from 262 to 124 throughout the study period. Admissions for urethral bulking agents increased from 650 to 1324 in the last 2 years. CONCLUSIONS: MUS represents the most commonly performed procedure for SUI, despite an obvious reduction in the last 8 years. Urethral bulking agents are becoming more popular, while the numbers of colposuspensions and autologous slings are still low. Training programmes should take into account current shifts in surgical practice. PMID- 30523376 TI - Blastococcus deserti sp. nov., isolated from a desert sample. AB - A Gram-positive and aerobic actinobacterium, strain SYSU D8006T, was isolated from a desert sand sample collected from Gurbantunggut desert, China. Phenotypically, the strain was found to grow at 14-50 degrees C, pH 6.0-9.0 and in the presence of up to 4% (w/v) NaCl. The chemotaxonomic features of strain SYSU D8006T included menaquinone MK-9(H4) as the respiratory quinone, diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside as known polar lipids, iso-C15:0, iso-C16:0, C17:1 omega8c and C18:1 omega9c as the predominant fatty acids, and arabinose, galactose and glucose as the whole cell sugars. Strain SYSU D8006T shared the highest 16S rRNA gene sequence identity with Blastococcus jejuensis DSM 19597T (98.2%). Based on the analyses of the phenotypic, genotypic and phylogenetic characteristics, strain SYSU D8006T is characterized to represent a novel species of the genus Blastococcus, for which the name Blastococcus deserti sp. nov. is proposed. The type strain is SYSU D8006T (= CGMCC 1.15935T = KCTC 49026T = CPCC 204618T). PMID- 30523377 TI - Do individual differences in the distribution of activation between synergist muscles reflect individual strategies? AB - Individual differences in the distribution of activation between synergist muscles have been reported during a wide variety of tasks. Whether these differences represent actual individual strategies is unknown. The aims of this study were to: (i) test the between-day reliability of the distribution of activation between synergist muscles, (ii) to determine the robustness of these strategies between tasks, and to (iii) describe the inter-individual variability of activation strategies in a large sample size. Eighty-five volunteers performed a series of single-joint isometric tasks with their dominant leg [knee extension and plantarflexion at 25% of maximal voluntary contraction (MVC)] and locomotor tasks (pedalling and walking). Of these participants, 62 performed a second experimental session that included the isometric tasks. Myoelectrical activity of six lower limb muscles (the three superficial heads of the quadriceps and the three heads of the triceps surae) was measured using surface electromyography (EMG) and normalized to that measured during MVC. When considering isometric contractions, distribution of normalized EMG amplitude among synergist muscles, considered here as activation strategies, was highly variable between individuals (15.8% < CV < 42.7%) and robust across days (0.57 < ICC < 0.82). In addition, individual strategies observed during simple single-joint tasks were correlated with those observed during locomotor tasks [0.37 < r < 0.76 for quadriceps (n = 83); 0.30 < r < 0.66 for triceps surae (n = 82); all P < 0.001]. Our results provide evidence that people who bias their activation to a particular muscle do so during multiple tasks. Even though inter-individual variability of EMG signals has been well described, it is often considered noise which complicates the interpretation of data. This study provides evidence that variability results from actual differences in activation strategies. PMID- 30523378 TI - [Guideline: Auditive Processing and Perception Disorders: Definition : Guideline of the German Society of Phoniatrics and Pediatric Audiology]. AB - In accordance with international consensus papers, Auditory Processing Disorders are defined here as disorders of central processes of hearing, which enable, among other things, the pre-conscious and conscious analysis, differentiation, and identification of changes in time, frequency, and intensity of acoustic or auditory speech signals as well as processes of binaural interaction (e. g., for localization, lateralization, noise clearance, and summation) and dichotic processing. Following the establishment of a commission of experts from the German Society for Phoniatrics and Pediatric Audiology, the existing S1 guideline was revised and updated. In this chapter, a position is taken on the definition of this clinical disorder as well as on the delimitation of similar disorders. PMID- 30523379 TI - Adjuvant MRI-guided percutaneous cryoablation treatment for aneurysmal bone cyst. AB - Aneurysmal bone cysts are benign, expansile, lytic bone lesions that behave in a locally aggressive manner. Although radiography and computed tomography (CT) can detect the lesion, magnetic resonance imaging (MRI) is ideal for the demonstration of characteristic fluid-fluid levels, extent, and margins. Treatment typically consists of open surgical curettage with the addition of local adjuvants and bone grafting. Residual or recurring lesions may be treated using percutaneous cryoablation. Although CT guidance is often employed for image guidance, visualization and targeting of smaller clusters can be challenging in young children, secondary to the partially mineralized bone matrix in the immature skeleton. In such cases, the higher contrast resolution of interventional MRI affords direct visualization and targeting of small aneurysmal bone cysts, accurate monitoring of the extent of the growing ice ball beyond the lesion's margin, and avoidance of exposure to ionizing radiation. We report a case of a 5-year-old boy with recurrent or remaining aneurysmal bone cysts of the scapula after surgical excision and embolization, which were successfully treated using MRI-guided cryoablation. PMID- 30523380 TI - ? PMID- 30523381 TI - Randomized phase II trial of the prophylactic use of celecoxib for the prevention of oxaliplatin-related peripheral vascular pain in Capeox (YCOG1205). AB - PURPOSE: Capeox is widely used as an adjuvant chemotherapy regimen of colorectal cancer that does not require central vein catheter insertion. However, oxaliplatin-related vascular pain with peripheral administration is a major adverse event. We assessed the preventive effect of Celecoxib on oxaliplatin related vascular pain. METHODS: A multicenter study of the Yokohama Clinical Oncology Group (YCOG) in Japan. This study was an open label, randomized non comparative phase II study between Capeox without Celecoxib (C+ Group) and with it (C- group). The primary endpoint was the appearance frequency of grade >= 2 vascular pain according to the Verbal Rating Scale (VRS). RESULTS: Between October 2012 and February 2014, 81 patients were recruited to this study and randomly divided into 2 groups: 38 patients in the C- group and 39 patients in the C+ group. Four cases were excluded at the analysis stage because they had not received the allocated intervention. The rate of grade >= 2 vascular pain was 55.3% in the C- group and 53.8% in the C+ group (p = 1.000). CONCLUSIONS: Celecoxib was unable to prevent oxaliplatin-related vascular pain in this study. However, it may be able to decrease the vascular pain that patients already have. PMID- 30523382 TI - Instability of the steady state solution in cell cycle population structure models with feedback. AB - We show that when cell-cell feedback is added to a model of the cell cycle for a large population of cells, then instability of the steady state solution occurs in many cases. We show this in the context of a generic agent-based ODE model. If the feedback is positive, then instability of the steady state solution is proved for all parameter values except for a small set on the boundary of parameter space. For negative feedback we prove instability for half the parameter space. We also show by example that instability in the other half may be proved on a case by case basis. PMID- 30523383 TI - Calibration of parameters in Dynamic Energy Budget models using Direct-Search methods. AB - Dynamic Energy Budget (DEB) theory aims to capture the quantitative aspects of metabolism at the individual level, for all species. The parametrization of a DEB model is based on information obtained through the observation of natural populations and experimental research. Currently the DEB toolbox estimates these parameters using the Nelder-Mead Simplex method, a derivative-free direct-search method. However, this procedure presents some limitations regarding convergence and how to address constraints. Framed in the calibration of parameters in DEB theory, this work presents a numerical comparison between the Nelder-Mead Simplex method and the SID-PSM algorithm, a Directional Direct-Search method for which convergence can be established both for unconstrained and constrained problems. A hybrid version of the two methods, named as Simplex Directional Direct-Search, provides a robust and efficient algorithm, able to solve the constrained optimization problems resulting from the parametrization of the biological models. PMID- 30523384 TI - Analysis of the development of human foetal nasal turbinates using CBCT imaging. AB - PURPOSE: The morphological structure of the nasal cavity (NC) is important for endoscopic surgical treatment. The location of nasal turbinates, including the superior turbinate (ST), middle turbinate (MT) and inferior turbinate (IT), are well presented during the formation of the human NC in cone beam CT (CBCT) images. There is a complex relationship between the nasal sinuses, the maxillary sinus (MS), ethmoidal sinus and sphenoid sinus, during formation of the NC structure at the morphological level. There is a need to clearly define the relationships of these nasal elements at the ossification level, during development. METHODS: We investigated the three-dimensional construction of human foetal NC elements, including ST, MT, IT and vomer, using CBCT images from 16 weeks gestation (E16) to E31 (25 foetuses) and compared it to histochemical observations (E25). RESULTS: At the stage of ossification, the studied elements are elongated in the posterior region near the sphenoidal bone, showing that the locations of the ST, MT, and IT are important during formation of the NC. CBCT analysis revealed that the horizontal and vertical directions of nasal turbinates affect the formation of the human NC. CONCLUSION: The location and elongated development of the MT is one of the most important elements for NC formation. The relationship between the nasal sinus and nasal turbine at the level of ossification may provide useful information in clinical treatment of children. PMID- 30523385 TI - Pseudo-tear appearance of the posterior tibiotalar ligament on fluid-sensitive sequences. AB - PURPOSE: This study aimed at studying the MR imaging appearance of the tibiotalar ligament in asymptomatic volunteers. MATERIALS AND METHODS: Fourty-two ankles were imaged on a 3T MR system using proton density weighted images with fat saturation (TR, 2969 ms; TE 30 ms; NA, 2; slice thickness, 2.5 mm). Subjects with acute ankle conditions or history of previous trauma were not included in the study group. Images were obtained in the three orthogonal planes. The posterior tibiotalar ligament was assessed on coronal imaging, by consensus of two radiologists. The signal intensity was recorded as isointense, hypointense, or hyperintense relative to muscle. The morphology of the ligament was classified as homogenous or striated. Descriptive statistics were obtained. RESULTS: There were 8 men and 14 women with a mean age of 24.7 years (range 19-43 years). The ligaments were classified as hyperintense in 30/42 (70%) of ankles and isointense in 9/42 (21%) of ankles. A striated appearance was seen in 34/42 (80%) of ankles. CONCLUSION: The posterior deep deltoid ligament is commonly hyperintense. It is usually striated although it can be homogeneously hyperintense. This appearance simulates a tear. PMID- 30523386 TI - Phase II Trial of Transarterial Embolization Using an n-Butyl-2 Cyanoacrylate/Lipiodol Mixture (JIVROSG-0802). AB - PURPOSE: To evaluate the embolic effect and the safety of transarterial embolization (TAE) using n-butyl-2-cyanoacrylate (NBCA) in a prospective multicenter trial. MATERIALS AND METHODS: This study was an open-label, multicenter, phase II trial. The inclusion criteria were (1) active bleeding or pseudoaneurysm, (2) true aneurysm, (3) arteriovenous malformation (except cerebral lesion), (4) arteriovenous fistula, or (5) need for arterial distribution before transarterial treatment. Selective TAE with NBCA diluted 2-10 times was performed. The primary endpoint was the success rate of embolization with a per-patient analysis based on the angiographic findings. Secondary endpoints were safety, evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) version 4, and the success rate of embolization with a per-vessel calculation. RESULTS: Sixty-five patients were initially enrolled, but due to protocol violation in two patients, efficacy was ultimately analyzed in 63 patients (103 vessels) and safety was analyzed in 64 patients. The success rate per patient was 98.4% (62/63; 95% confidence interval (CI), 91.5-100.00), and the success rate per vessel was 99.0% (102/103; 95% CI, 94.7-100.0). Adverse events of grade 3 or above based on CTCAE version 4 occurred in 22/64 patients (34.4%). Twelve intraoperative or postoperative adverse events grade 3 or above, which may have been related to embolization using NBCA, occurred in 11/64 patients (17.2%). Three patients died after embolization using NBCA, but their deaths were unrelated to TAE. CONCLUSION: In this prospective multicenter clinical trial, the efficacy of TAE using NBCA was 98.4% and adverse events were clinically acceptable. LEVEL OF EVIDENCE: Level 3b. PMID- 30523387 TI - Double-Barreled and Branched Endografting for Thoracoabdominal Aortic Aneurysm: The Hexapus Technique. AB - OBJECTIVE: To treat thoracoabdominal aortic aneurysm (TAAA), we introduced an alternative "Hexapus" technique by double-barreled and branched endografting. TECHNIQUE AND RESULT: We established 2 transfemoral and 2 transaxillary access routes first and then deployed two abdominal bifurcated stentgrafts landing at the descending thoracic aorta through transfemoral routes, respectively. Two pairs of parallel stentgrafts were deployed via bilateral transaxillary route from each of contralateral limbs of main body stentgrafts to visceral arteries. Finally, we extended the ipsilateral limbs of main body stentgrafts to bilateral common iliac arteries as distal landings. The creation of six branches (four viscerals and two iliacs) resembles a hexapus. We have executed this Hexapus technique in three patients, and the final angiography during operation and postoperative 12-month image follow-up showed patent visceral branches and no any endoleaks. CONCLUSION: Our Hexapus technique is feasible in treating TAAA if patient is inoperable or no commercial fenestrated or branched stentgraft is available. PMID- 30523388 TI - SET domains and stress: uncovering new functions for yeast Set4. AB - Chromatin dynamics are central to the regulation of gene expression and genome stability, particularly in the presence of environmental signals or stresses that prompt rapid reprogramming of the genome to promote survival or differentiation. While numerous chromatin regulators have been implicated in modulating cellular responses to stress, gaps in our mechanistic understanding of chromatin-based changes during stress suggest that additional proteins are likely critical to these responses and the molecular details underlying their activities are unclear in many cases. We recently identified a role for the relatively uncharacterized SET domain protein Set4 in promoting cell survival during oxidative stress in Saccharomyces cerevisiae. Set4 is a member of the Set3 subfamily of SET domain proteins which are defined by the presence of a PHD finger and divergent SET domain sequences. Here, we integrate our new observations on the function of Set4 with known roles for other related family members, including yeast Set3, fly UpSET and mammalian proteins MLL5 and SETD5. We discuss outstanding questions regarding the molecular mechanisms by which these proteins control gene expression and their potential contributions to cellular responses to environmental stress. PMID- 30523389 TI - Fragmentation of brittle material by shock wave lithotripsy. Momentum transfer and inertia: a novel view on fragmentation mechanisms. AB - Shock wave lithotripsy is the only non-invasive stone therapy and in clinical use since 1980. In spite of decades with millions of patients treated, the mechanism of fragmentation is still under debate. Detailed knowledge of the fragmentation process is required for improvements regarding safety and efficiency. The purpose of this paper is to gain a deeper insight into the mechanism of fragmentation by drawing attention to basic physical laws of inertia and momentum transfer. Many fragmentation experiments are based on the overall efficiency of multiple shock waves in crushing kidney stones or artificial model stones utilizing small baskets or latex pouches. Due to the high dynamic nature of the fragmentation process, in vitro and in vivo, a detailed action of a single shock wave on a particular stone target is difficult to investigate. We utilized a bifilar stone suspension, which allowed us to observe horizontal movements of model stones, their return to the initial position and orientation for repeated exposure of separate identical shocks. The method does not describe the entire fragmentation process in detail but elucidates a mechanism, which may be effective throughout shock wave lithotripsy in general. Measurements on model stones in water revealed forces in the range of 370 N, acceleration values of 100,000-200,000 m/s2 (~ 10,000 g) and gained momentum of 3.7 * 10- 4 kg m/s we consider sufficient to break most human urinary stones. Fracture patterns of repeated identical shock waves show typical features supporting spallation (Hopkinson effect) and the mechanism of momentum transfer. Schlieren and photo-elastic images provide a visual impression of spatial stress in a transparent acrylic glass cylinder, cavitation fields outside and at the surface of the cylinder, which are compatible with the inertia model. The proposed mechanism covers coarse as well as fine fragmentation. Collapsing cavitation bubbles may have an impact on the fragmentation process but although expected, a direct action of micro-jets on sample surfaces could not be detected. PMID- 30523390 TI - Genetics of common complex kidney stone disease: insights from genome-wide association studies. AB - Kidney stone disease is a common disorder in Western countries that is associated with significant suffering, morbidity, and cost for the healthcare system. Numerous studies have demonstrated familial aggregation of nephrolithiasis and a twin study estimated the heritability to be 56%. Over the past decade, genome wide association studies have uncovered several sequence variants that confer increased risk of common complex kidney stone disease. The first reported variants were observed at the CLDN14 locus in the Icelandic population. This finding has since been replicated in other populations. The CLDN14 gene is expressed in tight junctions of the thick ascending limb of the loop of Henle, where the protein is believed to play a role in regulation of calcium transport. More recent studies have uncovered variants at the ALPL, SLC34A1, CASR, and TRPV5 loci, the first two genes playing a role in renal handling of phosphate, while the latter two are involved in calcium homeostasis. Although genetic data have provided insights into the molecular basis of kidney stone disease, much remains to be learned about the contribution of genetic factors to stone formation. Nevertheless, the progress made in recent years indicates that exciting times lie ahead in genetic research on kidney stone disease. PMID- 30523391 TI - The diagnostic accuracy of 18F-FDG PET/CT in diagnosing fracture-related infections. AB - PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) is frequently used to diagnose fracture-related infections (FRIs), but its diagnostic performance in this field is still unknown. The aims of this study were: (1) to assess the diagnostic performance of qualitative assessment of 18F FDG PET/CT scans in diagnosing FRI, (2) to establish the diagnostic performance of standardized uptake values (SUVs) extracted from 18F-FDG PET/CT scans and to determine their associated optimal cut-off values, and (3) to identify variables that predict a false-positive (FP) or false-negative (FN) 18F-FDG PET/CT result. METHODS: This retrospective cohort study included all patients with suspected FRI undergoing 18F-FDG PET/CT between 2011 and 2017 in two level-1 trauma centres. Two nuclear medicine physicians independently reassessed all 18F-FDG PET/CT scans. The reference standard consisted of the result of at least two deep, representative microbiological cultures or the presence/absence of clinical confirmatory signs of FRI (AO/EBJIS consensus definition) during a follow-up of at least 6 months. Diagnostic performance in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) was calculated. Additionally, SUVs were measured on 18F-FDG PET/CT scans. Volumes of interest were drawn around the suspected and corresponding contralateral areas to obtain absolute values and ratios between suspected and contralateral areas. A multivariable logistic regression analysis was also performed to identify the most important predictor(s) of FP or FN 18F-FDG PET/CT results. RESULTS: The study included 156 18F-FDG PET/CT scans in 135 patients. Qualitative assessment of 18F-FDG PET/CT scans showed a sensitivity of 0.89, specificity of 0.80, PPV of 0.74, NPV of 0.91 and diagnostic accuracy of 0.83. SUVs on their own resulted in lower diagnostic performance, but combining them with qualitative assessments yielded an AUC of 0.89 compared to an AUC of 0.84 when considering only the qualitative assessment results (p = 0.007). 18F-FDG PET/CT performed <1 month after surgery was found to be the independent variable with the highest predictive value for a false test result, with an absolute risk of 46% (95% CI 27 66%), compared with 7% (95% CI 4-12%) in patients with 18F-FDG PET/CT performed 1 6 months after surgery. CONCLUSION: Qualitative assessment of 18F-FDG PET/CT scans had a diagnostic accuracy of 0.83 and an excellent NPV of 0.91 in diagnosing FRI. Adding SUV measurements to qualitative assessment provided additional accuracy in comparison to qualitative assessment alone. An interval between surgery and 18F-FDG PET/CT of <1 month was associated with a sharp increase in false test results. PMID- 30523392 TI - Surgical Resection for Recurrent Intrahepatic Cholangiocarcinoma. AB - BACKGROUND: Although after R0 resection of intrahepatic cholangiocarcinoma (ICC) recurrence is frequent, most guidelines do not address strategies for this. The aim of this study was to analyze the outcome of repeated resection and to determine criteria when repeated resection is reasonable. METHODS: Between 2008 and 2016, we consecutively collected all cases of ICC (n = 176) in a prospective database and further analyzed them with a focus on tumor recurrence, its surgical treatment, overall survival and recurrence-free survival. RESULTS: Overall, a total of 22 explorations were performed for recurrent ICC in 17 patients. Resection rate was 18 repeated resections in 13 patients. Three patients underwent repeated resection twice and one patient three times. Recurrence was solitary in 7 patients and multifocal in 11 re-resected cases. Median overall survival (OS) of patients who underwent repeated resection was 65.2 months (interquartile range 37-126.5) with a 5-year OS rate of 62%, calculated from primary resection. Patients who underwent repeated resections had a significant better OS compared to those receiving chemotherapy, transarterial chemoembolization, selective internal radiotherapy, radiofrequency ablation or best supportive care (p < 0.001). CONCLUSION: Repeated resection of recurrent ICC is reasonable and associated with an improved survival. Re-exploration should be considered as long as resection is technically possible. PMID- 30523393 TI - Preoperative High-Resolution Manometry Criteria are Associated with Dysphagia After Nissen Fundoplication. AB - BACKGROUND: Dysphagia after Nissen fundoplication is challenging for patients. High-resolution manometry (HRM) has rarely been studied preoperatively to determine whether manometry values correlated with postoperative dysphagia after fundoplication. We aim to determine whether HRM criteria could predict dysphagia after Nissen fundoplication. METHODS: A retrospective review of single institution laparoscopic Nissen fundoplications (LNF) from 2013 to 2015 was completed. Dysphagia was graded using a standard scale. Four groups were: those with new postoperative dysphagia (ND), never had dysphagia (NV), continued dysphagia (CD), and resolved dysphagia (RD). Manometry criteria included distal contractile integral (DCI), contraction front velocity (CFV), distal latency (DL), integrated relaxation pressure (IRP), percent peristalsis (PP), and distal esophageal contraction amplitude (DECA). Statistical bootstrapping was used to power sample sizes for ANOVA analysis. RESULTS: Ninety-four patients were included in the original cohort. Statistical bootstrapping sample size was 2992 patients. Among patients who did not have dysphagia prior to LNF, no HRM metric was associated with developing new dysphagia. Among those with dysphagia prior to LNF, a higher DCI, CFV, DL, PP, and DECA were associated with resolution of dysphagia. The RD group was 2.77 times more likely to have a DCI >= 1000 mmHg-s cm compared with the CD group. CONCLUSIONS: HRM criteria could not predict the development of postoperative dysphagia. However, in those with preoperative dysphagia and strong manometry criteria, dysphagia is more likely to resolve after Nissen fundoplication. Meanwhile, in those with preoperative dysphagia and weak manometry, dysphagia may persist and these patients may be better served with a partial fundoplication. PMID- 30523394 TI - South African General Surgeon Preparedness for Humanitarian Disasters. AB - BACKGROUND: Humanitarian medical organizations provide surgical care for a broad range of conditions including general surgical (GS), obstetric and gynecologic (OBGYN), orthopedic (ORTHO), and urologic (URO) conditions in unstable contexts. The most common humanitarian operation is cesarean section. The objective of this study was to identify the proportion of South African general surgeons who had operative experience and current competency in GS, OBGYN, ORTHO, and URO humanitarian operations in order to evaluate their potential for working in humanitarian disasters. METHODS: This was a cross-sectional online survey of South African general surgeons administered from November 2017-July 2018. Rotations in OBGYN, ORTHO, and URO were quantified. Experience and competency in eighteen humanitarian operations were queried. RESULTS: There were 154 SA general surgeon participants. Prior to starting general surgery (GS) residency, 129 (83%) had OBGYN, 125 (81%) ORTHO, and 84 (54%) URO experience. Experience and competency in humanitarian procedures by specialty included: 96% experience and 95% competency for GS, 71% experience and 51% competency for OBGYN, 77% experience and 66% competency for ORTHO, and 86% experience and 81% competency for URO. 82% reported training, and 51% competency in cesarean section. CONCLUSIONS: SA general surgeons are potentially well suited for humanitarian surgery. This study has shown that most SA general surgeons received training in OBGYN, ORTHO, and URO prior to residency and many maintain competence in the corresponding humanitarian operations. Other low- to middle-income countries may also have broad-based surgery training, and the potential for their surgeons to offer humanitarian assistance should be further investigated. PMID- 30523395 TI - The Heterogeneity of Global Pediatric Surgery: Defining Needs and Opportunities Around the World. AB - BACKGROUND: The global burden of pediatric surgical conditions continues to remain inadequately addressed, particularly in low- and middle-income countries. Among the many factors contributing to this gap are a lack of access to care secondary to resource shortages and inequitable distribution, underfinancing of healthcare systems, poor quality of care, and contextual challenges such as natural disasters and conflict. The relative contribution of these and other factors varies widely by region and even with countries of a region. METHODS: This review seeks to discuss the heterogeneity of global pediatric surgery and offer recommendations for addressing the barriers to high-quality pediatric surgical care throughout the world. RESULTS: There is significant heterogeneity in pediatric surgical challenges, both between regions and among countries in the same region, although data are limited. This heterogeneity can reflect differences in demographics, epidemiology, geography, income level, health spending, historical health policies, and cultural practices, among others. CONCLUSION: Country-level research and stakeholder engagement are needed to better understand the heterogeneity of local needs and drive policy changes that contribute to sustainable reforms. Key to these efforts will be improved financing, access to and quality of pediatric surgical care. PMID- 30523396 TI - Occupational stress is associated with major long-term weight gain in a Swedish population-based cohort. AB - PURPOSE: Occupational stress and obesity are both increasing in prevalence, but prospective findings relating these conditions are inconsistent. We investigated if baseline as well as prolonged exposure to high job demands and low decision latitude were associated with major weight gain (>= 10% of baseline weight) in 3872 Swedish women and men examined three times over 20 years in the population based Vasterbotten Intervention Program. METHODS: Anthropometry was measured and participants completed questionnaires on job strain, diet, and other lifestyle factors. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for confounders. RESULTS: Adjusting for age, baseline low decision latitude was associated with major weight gain over 10- and 20-year OR (95% CI) 1.16 (1.00-1.33) and 1.29 (1.13-1.47), respectively (both sexes combined). After adjustment for diet quality and other confounders, the effect over 20 years remained 1.30 (1.13-1.50). Sex modified the effect of prolonged exposure to high job demands over at least 10 years (interaction p = 0.02), showing that high job demands was a risk factor of major weight gain over 20 years in women [1.54 (1.14-2.07)], but not in men [0.87 (0.63-1.19)]. Neither diet nor other lifestyle factors explained these associations. CONCLUSIONS: In conclusion, low decision latitude predicted major weight gain in women and men. In women, the results suggest an additional contribution to major weight gain from high job demands. PMID- 30523397 TI - The growing discrepancy between resident training in colonic surgery and the rising number of general surgery graduates. AB - PURPOSE: The decrease in resident operative experience due to working-hour directives and sub-specialization within general surgery is the subject of growing debate. This study aims to examine how the numbers of colectomies used for resident training have evolved since the introduction of working-hour directives and to place these results within the context of the number of new general surgeons. METHODS: Based on the nationwide database of the Swiss association for quality management in surgery, all segmental colectomies performed at 86 centers were analyzed according to the presence or absence of residents and compared to national numbers of surgical graduates. RESULTS: Of 19,485 segmental colectomies between 2006 and 2015, 36% were used for training purposes. Residents performed 4%, junior staff surgeons 31%, senior staff surgeons 55%, and private surgeons 10%. The percentage performed by residents decreased significantly, while the annual number of graduates increased from 36 to 79. Multivariate analysis identified statutory (non-private) health insurance (OR 7.6, CI 4.6-12.5), right colon resection (OR 3.5, CI 2.5-4.7), tertiary referral center (OR 1.9, CI 1.5-2.6), emergency surgery (OR 1.7, CI 1.3-2.3), and earlier date of surgery (OR 1.1, CI 1.0-1.1) as predictors for resident involvement. CONCLUSIONS: Only a low and declining percentage of colectomies is used for resident training, despite growing numbers of trainees. These data imply that opportunities to obtain technical proficiency have diminished since the implementation of working-hour directives, indicating the need to better utilize suitable teaching opportunities, to ensure that technical proficiency remains high. PMID- 30523398 TI - Guideline recommendations for treatment of patients with inflammatory bowel diseases are not implemented in clinical practice-results of a non-representative survey. AB - PURPOSE: There is a growing evidence for over-, under-, or misuse of health care in patients with inflammatory bowel disease. Most studies looked at treatment variability or used quality measures, which mostly capture supportive interventions rather than treatment of IBD in itself. We aimed to evaluate if current recommendations in clinical practice guidelines regarding the medical treatment of patients with inflammatory bowel diseases are being followed in Germany. METHODS: A questionnaire was sent to 1901 patients insured with two large German statutory sickness funds and an ICD 10 diagnosis of Crohn's disease (CD) or ulcerative colitis (UC). The questionnaire asked about drug treatment, indications for drug treatment, provision of surveillance endoscopies in ulcerative colitis patients, and smoking status in Crohn's disease patients. RESULTS: Out of 460 evaluable patients, 62.4% of UC patients and 53.9% of CD patients were treated with mesalamine according to guidelines, 91.3% of all patients were treated with glucocorticoids according to guideline recommendations, while only 75.6% received recommended immunosuppressive treatment. Of UC patients, 94.5% had surveillance colonoscopies at the recommended interval and 58.8% of CD patients were non-smokers. No predictor for overall treatment according to guidelines could be found while being of age older than 60 or being treated outside of a dedicated IBD clinic was associated with less immunosuppressive treatment. CONCLUSIONS: A large proportion of patients with IBD do not receive drug treatment in accordance with clinical practice guidelines. Quality improvement measures are much needed. PMID- 30523399 TI - Comparative efficacy and safety of phosphodiesterase type 5 inhibitors for erectile dysfunction in diabetic men: a Bayesian network meta-analysis of randomized controlled trials. AB - PURPOSE: To compare the efficacy and safety profiles of different phosphodiesterase-5 inhibitors (PDE5Is) administrations for erectile dysfunction (ED) in diabetic men, including on-demand (PRN) and regular regimens (OAD). MATERIALS AND METHODS: Searches were carried out in four electronic databases: PubMed (until April 17th, 2017); Scopus (until April 17th, 2017); Embase (until April 17th, 2017); and Cochrane (until April 18th, 2017). The outcomes for this study are as follows: (1) Global Assessment Question (GAQ) positive response rate; (2) changes from baseline to the end of the study in Erectile Function Domain of International Index of Erectile Function (IIEF-EF); and (3) treatment related adverse events (TRAEs). The comparative effects of PDE5I regimens were analyzed with random-effect models in a Bayesian Framework using the GeMTC R package. RESULTS: We identified 1056 records, of which 15 randomized trials with 5274 patients were included. The included studies covered eight kinds of PDE5I administration: avanafil PRN; mirodenafil PRN; sildenafil PRN; tadalafil PRN; tadalafil OAD; udenafil PRN; udenafil OAD; vardenafil PRN; and placebo. In surface under the cumulative ranking curve analysis, vardenafil PRN ranked first, third and first, and mirodenafil PRN ranked second, first and second in GAQ, IIEF EF, and TRAEs, respectively. CONCLUSIONS: PDE5I administrations were generally efficient and well-tolerated in diabetic men. Among these administrations, vardenafil PRN and mirodenafil PRN seem to have a possible advantage of efficacy and avoiding adverse effects compared to others. There is no significant difference between regular and on-demand regimens of PDE5Is. PMID- 30523400 TI - Donor kidney volume measured by computed tomography is a strong predictor of recipient eGFR in living donor kidney transplantation. AB - PURPOSE: The effect of living donor kidney allograft size on recipient outcomes is not well understood. In this study, we sought to investigate the relationship between preoperatively measured donor kidney volume and recipient estimated glomerular filtration rate (eGFR) in living donor kidney transplantation (LDKT). METHODS: We studied computed tomography (CT) donor kidney volumes and recipient outcomes for 438 LDKTs at the Toronto General Hospital between 2007 and 2016. Estimated glomerular filtration rate (eGFR) was calculated at 1, 3, and 6 months and a multivariable linear regression model was fitted to study the effect of donor kidney volume on recipient eGFR. RESULTS: The mean volume and weight of the donated kidneys were 157.3 (+/- 32.3) cc and 186.7 (+/- 48.7) g, respectively. Kidney volume was significantly associated with eGFR on multivariable analysis (P < 0.001). Specifically, for every 10 cc increase in kidney volume, there was a 1.68 mL/min, 1.25 mL/min and 0.97 mL/min rise in recipient eGFR at 1, 3, and 6 months, respectively. CONCLUSIONS: Donor kidney volume is a strong independent predictor of recipient eGFR in LDKT, and therefore, may be a valuable addition to predictive models of eGFR after transplant. Further research may determine if the inclusion of donor kidney volume in matching algorithms can improve recipient outcomes. PMID- 30523401 TI - Cytotoxic Natural Killer Subpopulations as a Prognostic Factor of Malignant Pleural Effusion. AB - BACKGROUND: Malignant pleural effusion (MPE) is a sign of advanced disease of poor prognosis. As natural killer (NK) cells are involved in the first line of tumour defence, we aimed to validate a new diagnostic and prognostic indicator for MPE based on NK subpopulations of pleural fluid (PF) and peripheral blood (PB). METHODS: NK subpopulations were determined in PF and PB in 71 patients with malignant, paramalignant or benign pleural effusion. The receiver operating characteristic (ROC) curves, Kaplan-Meier, multivariable Cox model and decision trees created with the CHAID (Chi-square automatic interaction detector) methodology were employed. RESULTS: We demonstrated that the PF/PB ratios of the CD56 bright CD16- and CD56 dim CD16- NK subpopulations were higher (p = 0.013 and p = 0.003, respectively) in MPEs and paramalignant pleural effusions (PPEs) than in benign ones, with an AUC of 0.757 and 0.741, respectively. The PF/PB ratio of CD16+ NK and CD57+ NK obtained a higher hazard ratio (HR) in the crude Cox's regression analysis. In the adjusted Cox's regression analysis, the PF/PB ratio of CD16+ NK gave the highest HR (HR 6.1 [1.76-21.1]) (p = 0.004). In the decision tree created for the MPE prognosis, we observed that the main predictor variable among the studied clinical, radiological, and analytical variables was lung mass, and that 92.9% of the patients who survived had a PF/PB ratio of the CD56 dim CD16+ NK subpopulation <= 0.43. CONCLUSIONS: Our data suggest that both the PF/PB ratios of cytotoxic subpopulations CD57+ NK and CD16+ NK are useful as a prognostic factor of MPE. Other subpopulations (CD56 bright CD16- and CD56 dim CD16- NK) could help to diagnose MPE. PMID- 30523402 TI - Simulating eutrophication in a metacommunity landscape: an aquatic model ecosystem. AB - Aquatic habitats are often characterized by both high diversity and the threat of multiple anthropogenic stressors. Our research deals with temporal and spatial aspects of two of the main threats for biodiversity, namely eutrophication and fragmentation. It is known that pulsed nutrient addition creates temporal differences in environmental conditions, promoting higher diversity by preventing the best competitor from dominating. Furthermore, a metacommunity landscape with intermediate connectivity increases autotrophs' diversity and stability. However, it is yet unclear if these two factors are additive in increasing diversity and if the effects extend to the consumer level. With the goal of understanding how eutrophication impacts biodiversity in a metacommunity landscape, we hypothesized that pulsed nutrient addition will increase diversity among both autotrophs and heterotrophs, and this effect will be even greater in a metacommunity landscape. We simulated eutrophication and fragmentation in a microcosm experiment using phytoplankton as primary producers and microzooplankton as grazers. Four treatment combinations were tested including two different landscapes (metacommunity and isolated community) and two forms of nutrient supply (pulsed and continuous): metacommunity/continuous nutrient addition (MC); metacommunity/pulsed nutrient addition (MP); isolated community/continuous nutrient addition (IC); isolated community/pulsed nutrient addition (IP). As expected, pulsed nutrient addition had a persistent positive effect on phytoplankton diversity, with a weaker influence of landscape type. In contrast, the grazer community strongly benefited from a metacommunity landscape, with less significance of pulsed or continuous nutrient addition. Overall, the metacommunity landscape with pulsed nutrient supply supported higher diversity of primary producers and grazers. PMID- 30523403 TI - Exercise intensity effects on total sweat electrolyte losses and regional vs. whole-body sweat [Na+], [Cl-], and [K+]. AB - PURPOSE: To quantify total sweat electrolyte losses at two relative exercise intensities and determine the effect of workload on the relation between regional (REG) and whole body (WB) sweat electrolyte concentrations. METHODS: Eleven recreational athletes (7 men, 4 women; 71.5 +/- 8.4 kg) completed two randomized trials cycling (30 degrees C, 44% rh) for 90 min at 45% (LOW) and 65% (MOD) of VO2max in a plastic isolation chamber to determine WB sweat [Na+] and [Cl-] using the washdown technique. REG sweat [Na+] and [Cl-] were measured at 11 REG sites using absorbent patches. Total sweat electrolyte losses were the product of WB sweat loss (WBSL) and WB sweat electrolyte concentrations. RESULTS: WBSL (0.86 +/ 0.15 vs. 1.27 +/- 0.24 L), WB sweat [Na+] (32.6 +/- 14.3 vs. 52.7 +/- 14.6 mmol/L), WB sweat [Cl-] (29.8 +/- 13.6 vs. 52.5 +/- 15.6 mmol/L), total sweat Na+ loss (659 +/- 340 vs. 1565 +/- 590 mg), and total sweat Cl- loss (931 +/- 494 vs. 2378 +/- 853 mg) increased significantly (p < 0.05) from LOW to MOD. REG sweat [Na+] and [Cl-] increased from LOW to MOD at all sites except thigh and calf. Intensity had a significant effect on the regression model predicting WB from REG at the ventral wrist, lower back, thigh, and calf for sweat [Na+] and [Cl-]. CONCLUSION: Total sweat Na+ and Cl- losses increased by ~ 150% with increased exercise intensity. Regression equations can be used to predict WB sweat [Na+] and [Cl-] from some REG sites (e.g., dorsal forearm) irrespective of intensity (between 45 and 65% VO2max), but other sites (especially ventral wrist, lower back, thigh, and calf) require separate prediction equations accounting for workload. PMID- 30523404 TI - Polygenic analysis suggests the involvement of calcium signaling in executive function in schizophrenia patients. AB - Cognitive deficits are increasingly recognized as a core dimension rather than a consequence of schizophrenia (SCZ). The previous evidence supports the hypothesis of shared genetic factors between SCZ and cognitive ability. The objective of this study was to test whether and to what extent the variation of disease relevant neurocognitive function in a sample of SCZ patients from the previous clinical interventional studies can be explained by SCZ polygenic risk scores (PRSs) or by hypothesis-driven and biomedical PRSs. The previous studies have described associations of the SNAP25 gene with cognition in SCZ. Likewise, the enrichment of several calcium signaling-related gene sets has been reported by genome-wide association studies (GWAS) in SCZ. Hypothesis-driven PRSs were calculated on the basis of the SNAP-25 interactome and also for genes regulated by phorbol myristate acetate (PMA), an activator of the signal transduction of protein kinase C (PKC) enzymes. In a cohort of 127 SCZ patients who had completed a comprehensive neurocognitive test battery as part of the previous antipsychotic intervention studies, we investigated the association between neurocognitive dimensions and PRSs. The PRS for SCZ and SNAP-25-associated genes could not explain the variance of neurocognition in this cohort. At a p value threshold of 0.05, the PRS for PMA was able to explain 2% of the variance in executive function (p = 0.05, uncorrected). The correlation between the PRS for PMA regulated genes and cognition can give hints for further patient-derived cellular assays. In conclusion, incorporating biological information into PRSs and other en masse genetic analyses may help to close the gap between genetic vulnerability and the biological processes underlying neuropsychiatric diseases such as SCZ. PMID- 30523405 TI - Systemic network for dietary inorganic phosphate adaptation among three organs. AB - Inorganic phosphate (Pi) secretion from the salivary glands and dietary Pi are key Pi sources. The regulatory mechanisms of Pi homeostasis in the salivary glands are unknown. We investigated how salivary Pi concentrations are regulated by dietary Pi in mouse models. Dietary manipulation significantly changed the levels of Npt2b protein in the salivary gland ductal cells. In addition, rapid feeding on a high-Pi diet increased the saliva Pi concentrations and led to rapid endocytosis of Npt2b in the apical membranes of the duct cells. Global Npt2b+/- mice exhibited increased salivary Pi concentrations and intestine-specific deletion of Npt2b after high Pi loading increased the salivary Pi concentrations. These findings indicate that Npt2b levels in the salivary glands affect the salivary Pi concentration and are regulated by dietary Pi. Intestinal Npt2b levels might also affect salivary Pi concentrations as well as renal Pi excretion. These findings suggest Pi is endogenously recycled by salivary Pi secretion, intestinal Pi absorption, and renal Pi excretion. PMID- 30523406 TI - Afferent nerve fibres in the wall of the rat urinary bladder. AB - Structure and distribution of afferent nerve fibres in the rat bladder were studied by fluorescence microscopy after selective staining with antibodies against neuropeptide CGRP. Afferent fibres are very abundant (by comparison with other viscera) and interconnected in all bladder parts: muscle, urothelium, connective tissue, blood vessels, serosa. Their highest concentration is beneath the urothelium in equatorial and caudal regions, where they form a plexus, while individually maintaining a tree-like structure with innumerable branches running without preferential orientation. In cranial regions, mucosal afferent fibres become rare or absent. Abundant fibres are found in the detrusor, within each muscle bundle, with long strings of varicosities parallel to muscle cells. Afferent fibres, invariably varicose over hundreds of micrometres of their terminal parts and while still branching, comprise chains of hundreds of varicosities. Varicosities are irregular in size, frequency and separation, without specialised terminal structures around them, or within or around the fibre's ending. The possibility that varicosities are transduction points for sensory inputs is discussed, with the implication of a process taking place over considerable length in each branch of each fibre. Interconnectedness of afferent nerves of various bladder tissues, distribution of varicosities over hundreds of micrometres along axonal branches, absence of clear target structures for the fibres, apparent irregularity in the size and sequence of varicosities suggest an innervation that is not rigidly wired with distinct sensory pathways. In fact, the structural evidence suggests extensive afferent integration at the periphery, with wide distribution of source points and broad range of physical detectors. PMID- 30523407 TI - Efficacy of abdominal peripheral nerve block and caudal block during robot assisted laparoscopic surgery: a retrospective clinical study. AB - PURPOSE: We retrospectively analyzed the efficacy of abdominal peripheral nerve block (PNB) and caudal block (CB) in patients undergoing robot-assisted laparoscopic radical prostatectomy (RARP). METHODS: Patients who underwent elective RARP at our hospital (Jan. 2015-Sept. 2016) were enrolled. We reviewed the 188 patients' anesthesia charts and medical records and divided the patients into three groups based on the anesthesia used in their cases: 76 patients in the total intravenous anesthesia (TIVA) group, 51 patients in the TIVA + abdominal PNB group (TI-PB group), and 61 patients in the TIVA + abdominal PNB + CB (TI-PB CB group). We compared the groups' amounts of anesthetic drug usage, anesthesia times, and the presence/absence of additional opioid administration in the recovery room. RESULTS: The perioperative opioid use during anesthesia was significantly greater in the TIVA group than in the TI-PB-CB group. The total amount of muscle relaxant was significantly higher (p < 0.001) in the TIVA group than the TI-PB-CB group: 60.0 (50.0-70.0) mg vs. 50.0 (40.0-60.0) mg. Although there were no significant differences in the operation time, the frequency of the use of additional opioid administration was significantly higher (p < 0.01) in the TIVA group than the TI-PB group: 23.7% vs. 2.0%, respectively. CONCLUSIONS: Although there was no influence on the anesthesia time, the muscle relaxant dose and the perioperative amount of opioid use were significantly less in the combined PNB + CB group. Our analyses suggest that not only PNB but also CB was useful for perioperative management in RARP. CLINICAL TRIAL REGISTRATION: 2016 1059. PMID- 30523408 TI - Crystalloid coloading vs. colloid coloading in elective Caesarean section: postspinal hypotension and vasopressor consumption, a prospective, observational clinical trial. AB - BACKGROUND: Maternal hypotension is a common side effect of spinal anaesthesia for Caesarean section. The combination of colloid coloading and vasopressors was considered our standard for its prevention and treatment. As the safety of hydroxyethyl starch is under debate, we replaced colloid with crystalloid coloading. OBJECTIVE: We hypothesize that the mean blood pressure drop is greater when coloading with crystalloids. DESIGN: Prospective, observational clinical trial. SETTING: Two-centre study conducted in Berlin, Germany. PATIENTS: Parturients scheduled for a Caesarean section were screened for eligibility. INTERVENTION: The study protocol and patient monitoring were based on the standard operating procedure for Caesarean section in both centres. The data from the crystalloid group were prospectively collected between November 2014 and July 2015. MAIN OUTCOME MEASURES: The primary endpoint was the median drop in mean blood pressure after induction of spinal anaesthesia. Secondary endpoints were incidence of hypotension (drop > 20% of baseline systolic pressure /drop < 100 mmHg), vasopressor and additional fluid requirements (mL), incidence of bradycardia (heart rate < 60 beats per minute), blood loss, Apgar score, and umbilical artery pH. In case of hypotension, patients received phenylephrine or cafedrine/theodrenaline according to their heart rate. A p < 0.05 was considered significant. RESULTS: 345 prospectively enrolled patients (n = 193 crystalloid group vs. n = 152 colloid group) were analysed. The median drop in mean blood pressure was greater in the crystalloid group [34 mmHg (25; 42 mmHg) vs. 21 mmHg (13; 29 mmHg), p < 0.001]. Incidences of hypotension [93.3% vs. 83.6%, p: 0.004] and bradycardia [19.7% vs. 9.9%, p: 0.012] were also significantly greater in the crystalloid group. Vasopressor requirements, blood loss and neonatal outcome were not different between the groups. CONCLUSIONS: Crystalloid coloading was associated with a greater drop in mean blood pressure and a higher incidence of hypotension when compared with colloid coloading. Neonatal outcome was, however, unaffected by the type of fluid. TRIAL REGISTRATION: DRKS00006783 ( http://www.drks.de ). PMID- 30523409 TI - Effect of the botanical formula LCS101 on the anti-cancer effects of radiation therapy. AB - BACKGROUND AND PURPOSE: The botanical formula LCS101 has been shown in clinical research to reduce chemotherapy-induced toxicities. In pre-clinical research, the formula demonstrated selective anti-cancer effects, in part as a result of radical oxygen species (ROS) activity of the botanical components. The present study examined the interaction between LCS101 and radiation therapy on cancer cell lines. METHODS: Incremental doses of LCS101 were added to breast adenocarcinoma (MCF7), prostate (DU145), transitional cell bladder carcinoma (T24), pancreatic epithelioid carcinoma (PANC-1), and osteosarcoma (U20S) cell lines 4 h after single-dose irradiation (range 0.5-4 Gy). Cell viability was tested using sulforhodamine B (SRB) assay after 1 week, with ROS activity examined using 1 mM of the ROS scavenger sodium pyruvate (ROS scavenger), testing cell viability with an SRB assay. RESULTS: The addition of LCS101 to MCF7 (breast) and DU-145 (prostate) cancer cell lines resulted in a dose-dependent increase in the antiproliferative effects of radiation treatment. The addition of pyruvate inhibited radiation-induced cell death in all of the cell lines treated with LCS101. CONCLUSIONS: The addition of the botanical formula LCS101 to irradiated cancer cells results in an apparent additive effect, most likely through a ROS-mediated mechanism. These findings support the use of LCS101 by patients undergoing radiation therapy, for both its clinical as well as anti cancer effects. PMID- 30523410 TI - Intermediate-term outcomes of our original multiple-knot technique using ePTFE sutures for anterior mitral leaflet prolapse. AB - PURPOSE: To define the outcomes of our original simple chordal replacement technique using ePTFE sutures for mitral regurgitation. METHODS: Between January, 2004 and March, 2014, 38 patients underwent mitral valve repair using our chordal replacement technique for anterior leaflet prolapse. The mitral regurgitation was caused by degenerative disease in 34 patients and infective endocarditis in 4 patients. RESULTS: The follow-up period was 66 +/- 37 months and the 5-year survival rate was 95 +/- 4%. Two patients had recurrent mitral regurgitation, caused by degenerative change not associated with the procedure. The 5-year rate of freedom from recurrent mitral regurgitation was 94 +/- 4%. In the late postoperative period, 15 (42%) patients had a mean pressure gradient > 5 mmHg. Stepwise logistic regression analysis showed that the use of a full ring (odds ratio 8.9; 95% confidence interval 1.2-64; p = 0.031) and a 26 mm annuloplasty (odds ratio 7.5; 95% confidence interval 1.1-50; p = 0.037) were significant independent risk factors for a mean pressure gradient > 5 mmHg. CONCLUSION: The intermediate-term outcomes of our original chordal replacement technique were not inferior to those in previous reports, although a 26 mm annuloplasty was found to be associated with a higher mitral valve gradient at rest. PMID- 30523411 TI - Benefit of cetuximab addition to a platinum-fluorouracil-based chemotherapy according to KRAS-LCS6 variant in an unselected population of recurrent and/or metastatic head and neck cancers. AB - OBJECTIVES: To evaluate the benefit of cetuximab (Cx) addition to platinum-based and 5-fluorouracil chemotherapy (PFU) in unselected recurrent and/or metastatic head and neck cancer patients (R/MHNC) according to KRAS-LCS6 variant status. METHODS: All patients who received at least two PFU +/- Cx cycles from 2004 to 2014 were retrospectively included into to two distinct study periods according to Cx implementation: patients treated by PFU alone before 2009 and those treated by PFU + Cx from 2009. Primary objective was to evaluate the progression-free survival (PFS) between the two groups. Secondary objectives were to analyze the overall survival (OS) between the two groups and the prognostic impact of KRAS LCS6 variant. Factors associated with survival were determined by a Cox multivariate analysis including age, WHO performance status (PS), type of treatment, KRAS-LCS6 variant, Charlson's score and p16 status. RESULTS: Overall, 134 patients were included: 59 (44%) in PFU group and 75 (56%) in PFU + Cx group. Baseline characteristics were well balanced including 30% of patients with 2-3 PS. Median PFS was significantly improved in PFU + Cx group compared to PFU group (6.1 vs 4.4 months, respectively, HR 0.68, p = 0.02) and with a trend for better OS. A KRAS-LCS6 variant was found in 27 (25%) of samples without prognostic impact neither in whole population nor according to treatment. In multivariate analysis, addition of Cx to PFU was the only factor significantly associated with a better PFS (p = 0.01, HR 0.6). CONCLUSION: Our results suggest that PFU + Cx combination may be effective in unselected population of R/MHNC regardless the KRAS-LCS6 variant status. PMID- 30523412 TI - DEPC modification of the CuA protein from Thermus thermophilus. AB - The CuA center is the initial electron acceptor in cytochrome c oxidase, and it consists of two copper ions bridged by two cysteines and ligated by two histidines, a methionine, and a carbonyl in the peptide backbone of a nearby glutamine. The two ligating histidines are of particular interest as they may influence the electronic and redox properties of the metal center. To test for the presence of reactive ligating histidines, a portion of cytochrome c oxidase from the bacteria Thermus thermophilus that contains the CuA site (the TtCuA protein) was treated with the chemical modifier diethyl pyrocarbonate (DEPC) and the reaction followed through UV-visible, circular dichroism, and electron paramagnetic resonance spectroscopies at pH 5.0-9.0. A mutant protein (H40A/H117A) with the non-ligating histidines removed was similarly tested. Introduction of an electron-withdrawing DEPC-modification onto the ligating histidine 157 of TtCuA increased the reduction potential by over 70 mV, as assessed by cyclic voltammetry. Results from both proteins indicate that DEPC reacts with one of the two ligating histidines, modification of a ligating histidine raises the reduction potential of the CuA site, and formation of the DEPC adduct is reversible at room temperature. The existence of the reactive ligating histidine suggests that this residue may play a role in modulating the electronic and redox properties of TtCuA through kinetically-controlled proton exchange with the solvent. Lack of reactivity by the metalloproteins Sco and azurin, both of which contain a mononuclear copper center, indicate that reactivity toward DEPC is not a characteristic of all ligating histidines. PMID- 30523413 TI - Cancer patients' needs for virtues and physicians' characteristics in physician patient communication: a survey among patient representatives. AB - BACKGROUND: Data on patients' needs with respect to physicians' ethical behavior and virtues are important but not available in most cases. PATIENTS AND METHODS: In an iterative process together with patients' representatives, we developed a standardized questionnaire which was distributed to the representatives of the Women's Self-Help after Cancer in Germany. We started with the classical ethical virtues and clustered them to characteristics. The patients' representatives were asked to rate in different communications settings. RESULTS: One hundred eighty six patients' representatives took part in the survey. For four communication situations (first communication on symptoms, diagnosis of cancer, choice of therapy, doubts on therapy), competence was rated as very important by 80-89% and as important by 6-7%; honesty as very important by 78-89% and as important by 5 12%; respect as very important by 66-71% and as important by 19-21%; and patience as very important by 55-68% and as important by 6-24%. Compassion was rated as less important, with only 24-31% rating it as very important and another 26-32% as important. Additional desires expressed by the participants were physicians having more time (9.1%) and a better relationship between physician and patient (7.0%). CONCLUSION: Competence, honesty, respect, and patience are important characteristics which should be focused on in communication training of medical students and physicians. In spite of compassion being rated as less important, training on compassion/empathy might help doctors to improve coping with the continuous confrontation with complications, progress, suffering, and death of their patients. PMID- 30523415 TI - Gender studies-a cell biological viewpoint. PMID- 30523414 TI - Efficacy and safety of once-monthly risedronate in osteoporosis subjects with mild-to-moderate chronic kidney disease: a post hoc subgroup analysis of a phase III trial in Japan. AB - Limited data are available on the safety and efficacy of anti-resorptive agents, particularly once-monthly bisphosphonates, for use in osteoporotic patients with chronic kidney disease (CKD). We conducted a post hoc analysis of data from a 12 month, randomized, double-blind, phase III study to evaluate the safety and efficacy of once-monthly risedronate (RIS-OM) 75 mg tablets in Japanese osteoporosis patients with mild-to-moderate CKD. Patients who received RIS-OM 75 mg were stratified by baseline estimated glomerular filtration rate (eGFR; >= 90, >= 60 to < 90, or >= 30 to < 60 mL/min/1.73 m2). Safety endpoints were incidence of adverse events (AEs) and percent change from baseline in eGFR, serum creatinine, calcium, and phosphorus. Efficacy endpoints were percent change from baseline in lumbar spine bone mineral density (BMD) and bone turnover markers (BTMs). In 420 patients included (age 67.7 +/- 6.7 years, women 98.8%), the incidence of all AEs, gastrointestinal disorders, acute phase reaction, non vertebral fractures, and renal and urinary disorders was not significantly different among subgroups. Interaction between subgroups and time was significant for eGFR (p = 0.010) and serum creatinine (p = 0.001) but considered to be regression to the mean and clinically insignificant. BMD significantly increased while BTMs significantly decreased from baseline with a similar degree of change among the subgroups. In conclusion, RIS-OM 75 mg showed consistent safety and efficacy in suppressing bone turnover and increasing BMD in Japanese primary osteoporosis patients with mild-to-moderate CKD. These results should, however, be interpreted with caution because the number of patients with moderate CKD was limited. PMID- 30523416 TI - A systematic review and meta-analysis of the effects of antenatal anxiety on postpartum outcomes. AB - To systematically review and meta-analyze research investigating the association between maternal anxiety during pregnancy and outcomes for mother and baby following the immediate delivery period. MEDLINE, Medline In-Process & Other Non Indexed Citations, PsycINFO, Embase, CINAHL, and the Cochrane library were searched. English-language, prospective studies providing data on outcomes following delivery in women with and without antenatal anxiety (defined by clinical diagnosis or score on validated scale) were included. Three-hundred fifty-eight articles were retrieved and 13 were included. Titles and abstracts were screened; two reviewers independently reviewed full text articles, conducted quality assessments, extracted, and checked the data. Where available for > 2 studies, random effect meta-analysis was conducted and heterogeneity was quantified. Subanalyses explored moderators, regardless of heterogeneity, including type of anxiety assessment and timing, among others. There were two outcomes that were amenable to meta-analysis. Antenatal anxiety was significantly associated with postpartum depression (PPD) measured within 6 months postpartum (pooled odds ratio [OR] = 2.64, 95% CI 2.02-3.46; 8 studies), regardless of restricting analyses to those studies controlling for prenatal depression (2.45, 1.77-3.39; 6 studies). Associations were also significant when PPD was measured at 1-3 months (2.57, 1.94-3.40; 7 studies) and 6-10 months (4.42, 1.45-13.49; 3 studies). Maternal anxiety was also associated with reduced odds of breastfeeding (0.63, 0.53-0.74; 5 studies). Antenatal anxiety is associated with PPD up to the first 10 months, independent of prenatal depression, and with lower odds of breastfeeding. PMID- 30523417 TI - CT-based dose recalculations in head and neck cancer radiotherapy: comparison of daily dose recalculations to less time-consuming approaches. AB - BACKGROUND: The goal of this study was to investigate if daily dose recalculations are necessary or if less time-consuming approaches can be used to identify dose differences to the planned dose in patients with head and neck cancers (H&N). METHODS: For 12 H&N patients treated with helical tomotherapy, daily dose calculations were performed retrospectively. Four different summation doses (SuDo) were calculated: DayDo (daily dose calculation), MVCTx2, MVCTx5, and MVCTx10 (dose calculations every second, fifth, and tenth fraction). Dose recalculations were depicted on the last contoured mega voltage CT (MVCT). The DayDo was compared to the planned dose and to the less time-consuming SuDo scenarios. The doses were assessed for the planning target volume (PTV) and the organs at risk (OARs): mandible (mand), spinal cord (SC), spinal cord +5 mm (SC+5 mm), parotid glands (PG). RESULTS: The ipsilateral PG, contralateral PG, and PTV volume decreased by -22.5% (range: -34.8 to 5.2%), -19.5% (-31.5 to 15.8%), and 2.6% (-16.7 to 0.2%), respectively. There was a significant median mean dose (Dmean) dose difference for DayDo compared to the planned dose for PG total of 1.9 Gy (-3.3 to 7.3 Gy). But less time-consuming SuDo compared to DayDo showed statistically significant but not clinically relevant (<2%) dose differences for several organs. Hence the small dose difference to the gold standard (DayDo), we recommend dose recalculations every fifth MVCT in order to identify the occurrence of dose differences compared to the planned dose. CONCLUSION: Daily dose calculations are the most precise to assess dose differences between actual and planned dose. Dose recalculations on every fifth MVCT (i. e., weekly control CTs) are an applicable and time-saving way of identifying patients with significant dose differences compared to the planned dose. PMID- 30523418 TI - Evaluating the management effectiveness of protected areas in Mongolia using the management effectiveness tracking tool. AB - The importance of management increases in the context of numerous and intensive inner and outer pressures on Protected Areas (PAs). The need to assess the management effectiveness (ME) in protected areas is increasing around the world. The ME assessment helps to improve the management of PAs and to develop a rational, long-term action plan. This study was conducted using the World Wildlife Fund for nature (WWF) Management Effectiveness Tracking Tools methodology (METT) to evaluate the ME of six PAs in central and eastern regions of Mongolia. The main purpose of this study was to assess ME and identify common threats of PAs across different natural zones and administrative areas in Mongolia. The results of this evaluation indicate that, the main threats faced by PAs in Mongolia are: (i) degradation of ecosystems, (ii) environmental pollution, and (iii) habitat fragmentation, resulting from over-exploitation and inappropriate use of natural resources. All six PAs examined have clear management goals and management decision-making systems however, their ME scores differ significantly. This research suggests that the administrative features of the individual PA influence management effectiveness and problems in the efficient implementation of management still need to be resolved. PMID- 30523419 TI - beta-Cyclodextrin-based inclusion complexes and nanocomposites of rivaroxaban for solubility enhancement. AB - Rivaroxaban (RIV) is an oral anticoagulant used in the prevention of venous thromboembolism in adult patients after total hip replacement or total knee replacement surgery. It is practically insoluble in water and buffer systems (pH 3-9). The present study was aimed to investigate the beta-CD-based inclusion complexes and nanocomposites of rivaroxaban (RIV) for solubility and dissolution enhancement. A novel solubility enhancement approach of inclusion complexation of RIV with beta-CD using spray drying method combined with high pressure homogenization as a particle engineering method was used. Change in crystallinity of RIV nanocomposites was assessed by DSC and PXRD. The interaction of drug with beta-CD was projected through 1H-NMR and FT-IR studies. Saturation solubility and in vitro dissolution study revealed a dramatic increase in solubility and dissolution of RIV, respectively. Thus, spray-dried beta-CD-based nanocomposites could be an innovative approach for solubility and dissolution enhancement of RIV. PMID- 30523420 TI - Aluminum cluster for CO and O2 adsorption. AB - Low temperature oxidation of CO to CO2 is an important process for the environment. Similarly adsorption of CO from the releasing sources is also of major concern today. Whereas the potential of gold and silver clusters is well proven for the catalysis of the above mentioned reaction, the potential of aluminum (Al) clusters remains unexplored. The present study proves that, similar to the transition metals, Al clusters can also be used for adsorption of gases. We first tested the potential of Al cluster as adsorbents for CO. The high binding energy (BE) values prove that Al clusters can be used for adsorbing both CO and O2. Since oxygen binding is more facile, we adsorbed oxygen on Al and then checked the effect of this O2 on the BE of CO. The results were obtained by DFT calculations at M062X/TZVP level of theory. Graphical abstract Activation of carbon monoxide (CO) on oxygen-adsorbed aluminum (Al) cluster. PMID- 30523421 TI - Real-time intradermal continuous glucose monitoring using a minimally invasive microneedle-based system. AB - Continuous glucose monitoring (CGM) has the potential to greatly improve diabetes management. The aim of this work is to show a proof-of-concept CGM device which performs minimally invasive and minimally delayed in-situ glucose sensing in the dermal interstitial fluid, combining the advantages of microneedle-based and commercially available CGM systems. The device is based on the integration of an ultra-miniaturized electrochemical sensing probe in the lumen of a single hollow microneedle, separately realized using standard silicon microfabrication methods. By placing the sensing electrodes inside the lumen facing an opening towards the dermal space, real-time measurement purely can be performed relying on molecular diffusion over a short distance. Furthermore, the device relies only on passive capillary lumen filling without the need for complex fluid extraction mechanisms. Importantly, the transdermal portion of the device is 50 times smaller than that of commercial products. This allows access to the dermis and simultaneously reduces tissue trauma, along with being virtually painless during insertion. The three-electrode enzymatic sensor alone was previously proven to have satisfactory sensitivity (1.5 nA/mM), linearity (up to 14 mM), selectivity, and long-term stability (up to 4 days) in-vitro. In this work we combine this sensor technology with microneedles for reliable insertion in forearm skin. In-vivo human tests showed the possibility to correctly and dynamically track glycaemia over time, with approximately 10 min delay with respect to capillary blood control values, in line with the expected physiological lag time. The proposed device can thus reduce discomfort and potentially enable less invasive real-time CGM in diabetic patients. PMID- 30523422 TI - Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction. AB - Myocardial infarction triggers infiltration of several types of immune cells that coordinate both innate and adaptive immune responses. These play a dual role in post-infarction cardiac remodeling by initiating and resolving inflammatory processes, which needs to occur in a timely and well-orchestrated way to ensure a reestablishment of normalized cardiac functions. Thus, therapeutic modulation of immune responses might have benefits for infarct patients. While such strategies have shown great potential in treating cancer, applications in the post infarction context have been disappointing. One challenge has been the complexity and plasticity of immune cells and their functions in cardiac regulation and healing. The types appear in patterns that are temporally and spatially distinct, while influencing each other and the surrounding tissue. A comprehensive understanding of the immune cell repertoire and their regulatory functions following infarction is sorely needed. Processes of cardiac remodeling trigger additional genetic changes that may also play critical roles in the aftermath of cardiovascular disease. Some of these changes involve non-coding RNAs that play crucial roles in the regulation of immune cells and may, therefore, be of therapeutic interest. This review summarizes what is currently known about the functions of immune cells and non-coding RNAs during post-infarction wound healing. We address some of the challenges that remain and describe novel therapeutic approaches under development that are based on regulating immune responses through non-coding RNAs in the aftermath of the disease. PMID- 30523423 TI - Effect of dosing regimen and microneedle pretreatment on in vitro skin retention of topically applied beta-blockers. AB - Topical beta-blocker formulations are commonly used to treat infantile hemangiomas (IHs); however, the skin concentrations and drug permeation through the skin have not been quantified. Microneedles (MNs) may increase local skin concentrations, which could further enhance lesion clearance and improve dosing regimens. The objective of this study was to quantify skin concentrations and drug permeation of two beta-blockers, propranolol and timolol, in vitro after application to intact skin and skin pretreated with solid MNs of two lengths. Propranolol skin concentrations and drug permeation were significantly higher than timolol skin concentrations for all study conditions, which is likely due to the lipophilic nature of propranolol compared to the hydrophilicity of timolol. Propranolol skin concentrations were significantly influenced by dosing regimen, as skin concentrations increased with increasing drug application. Pretreatment of the skin with solid 250 MUm and 500 MUm length MNs increased local skin concentrations of timolol; propranolol skin concentrations did not significantly increase after MN pretreatment. Propranolol and timolol permeation through the skin increased after MN pretreatment with both MN lengths for both compounds. Taken together, solid MN pretreatment prior to application of topical timolol may be beneficial for deep or mixed IHs upon further optimization of the MN treatment paradigm. PMID- 30523424 TI - At the intersection of medical geography and disease ecology: Mirko Grmek, Jacques May and the concept of pathocenosis. AB - Environmental historians are not sufficiently aware of the extent to which mid twentieth-century thinkers turned to medical geography-originally a nineteenth century area of study-in order to think through ideas of ecology, environment, and historical reasoning. This article outlines how the French-Croatian Mirko D. Grmek (Krapina, 1924-Paris, 2000), a major thinker of his generation in the history of medicine, used those ideas in his studies of historical epidemiology. During the 1960s, Grmek attempted to provide, in the context of the Annales School's research program under the leadership of Fernand Braudel, a new theoretical framework for a world history of disease. Its development was inspired by several sources, most notably the French-American Jacques M. May (Paris 1896-Tunisia, 1975), who was then pioneering an opening up of medical geography and movement towards the concept of disease ecology. The cornerstone of Grmek's "synthetic approach" to the field was the notion of "pathocenosis". The diverse uses of this notion in the course of time-from his early agenda focused on a longue duree history of diseases in Western Antiquity to his last, relating to the new epidemiological threat of (re)emerging infectious diseases, specifically HIV/aids-enables us firstly, to note how concepts of ecology sat uneasily alongside those of medical geography; secondly, to assess the reach and limits of his theoretical contribution to historical epidemiology; and thirdly, to understand better the uneven fortunes of his concept of pathocenosis at the end of the twentieth and beginning of the twenty-first centuries. PMID- 30523425 TI - Solution Processed Trilayer Structure for High-Performance Perovskite Photodetector. AB - Due to their outstanding performance, low cost, ease of fabrication, diverse photonic, and optoelectronic applications, metal halides perovskite have attracted extensive interest in photodetector applications. Currently, devices made by metal oxides, metal sulfides, and 2D materials had achieved good responsivity, but suffered from high dark current, slow response speed, small on off ratio, and poor stability. Whole performances of these photodetectors are not satisfactory. Here, a lateral perovskite (CH3NH3PbBr3)/Ethanolamine/TiO2 (in ethanol) trilayer photodetector is designed for achieving high performance. EA treatment enhances electron extraction and reduces undesired recombination. This trilayer device shows good performances with low dark current of 1.5 * 10-11 A, high on-off ratio of 2700, high photodetectivity of 1.51 * 1012 Jones, high responsivity of 0.13 A W-1, and high stability, comparative to conventional single layer devices. This work provides the way to improve the performance of metal halide perovskite photodetectors. PMID- 30523426 TI - Seagrass litter decomposition: an additional nutrient source to shallow coastal waters. AB - Seagrass ecosystems are vital for its regulatory services yet, highly threatened by degradation due to human pressures. Decomposition of two tropical seagrass species (Cymodocea serrulata and Cymodocea rotundata) was studied and compared, to understand their potential in generating additional nutrients to coastal waters. Release of carbon, nitrogen and phosphorus during the decomposition process of seagrass wracks was estimated in bacteria-active (non-poisoned) and bacteria-inhibited (poisoned) conditions from shore-washed fresh seagrass, sampled from Palk Bay, India. Incubation experiments for 25 days indicated a near three times higher concentration of dissolved organic carbon (DOC) in bacteria inhibited flasks compared to bacteria-active conditions for both species. The maximum leaching rates of DOC, TDN and TDP were found to be 294, 65.1 and 11.2 MUM/g dry wt/day, respectively. Further, higher release of dissolved inorganic nitrogen (DIN) (> 1.3 times) was documented from the bacteria-active flask, highlighting the significance of microbial process in generating bio-available nutrients from decaying seagrass. Faster decomposition (0.014 +/- 0.004 day-1) in the initial stages (up to 8 days) compared to the later stages (0.005 +/- 0.001 day-1) indicated a rapid loss of biomass carbon during the initial leaching process and its relative importance in the decomposition pathway. The decomposition rate is best described by a single-stage exponential decay model with a half-life of 41 days. It is estimated that the total seagrass litter available along the Palk Bay coast is about ~ 0.3 Gg with high potential of additional nitrogen (0.9 +/- 0.5 Mg) and phosphorus (0.3 +/- 0.1 Mg) supply to the adjacent coastal waters. PMID- 30523427 TI - A study on the aflatoxin M1 rate and seasonal variation in pasteurized cow milk from northwestern Iran. AB - Present study aims to assess aflatoxin M1 (AFM1) contamination in 100 samples of pasteurized milk which were conventionally gathered during spring, summer, autumn, and winter from supermarkets located in Maragheh city of northwestern Iran. Samples were evaluated for AFM1 with a high-performance liquid chromatography (HPLC) method and with fluorimetric detection. The results showed that approximately 44% (11.25) of samples in winter, 32% (8.25) of samples in spring, 24% (6.25) of samples in summer, and 20% (5.25) of samples in autumn had AFM1 concentrations that exceeded the limit (0.05 MUg/l) set by the European, Codex Alimentarius Commission and Iran standards. According to the statistical analysis of the data, there was no significant variation between the mean content of AFM1 during different seasons (P = 0.076). The results of our study suggest a high level of contamination of AFM1 in pasteurized milk in all seasons which may be due to the fact that milk supply for dairy factories is provided from dairy farms that are low in livestock feed quality. In Iran, pasteurized milk is consumed more than other milk products by all age groups. The total daily aflatoxin intake from contaminated milk and possibly other food products will be a significant risk to public health. PMID- 30523428 TI - Various Rejuvenation Behaviors of Zr-Based Metallic Glass by Cryogenic Cycling Treatment with Different Casting Temperatures. AB - The rejuvenation behavior of an Zr50Cu40Al10 (at.%) metallic glass upon cryogenic cycling treatment has been investigated. At a high casting temperature, the microstructure of the glass is quite homogenous and thus, internal stress cannot be generated during cycling. Therefore, the glass cannot be rejuvenated by cryogenic cycling treatment. In the contrary, by lowering the casting temperature, nano-sized heterogeneity can be induced and subsequently generates the internal stress and rejuvenates the glass. Once the glass is rejuvenated, the more induced free volume can plasticize the glass with a higher plastic strain. These findings point out that the synthesis conditions can tailor the heterogeneity of the glass and subsequently affect the following rejuvenation behavior upon thermal treatment. It can also help understand the mechanisms of rejuvenation of metallic glass upon cryogenic cycling treatment. PMID- 30523429 TI - Impact of PET reconstruction protocols on quantification of lesions that fulfil the PERCIST lesion inclusion criteria. AB - BACKGROUND: The aim of this study was to compare liver and oncologic lesion standardized uptake values (SUV) obtained through two different reconstruction protocols, GE's newest clinical lesion detection protocol (Q.Clear) and the EANM Research Ltd (EARL) harmonization protocol, and to assess the clinical relevance of potential differences and possible implications for daily clinical practice using the PERCIST lesional inclusion criteria. NEMA phantom recovery coefficients (RC) and SUV normalized for lean body mass (LBM), referred to as SUV normalized for LBM (SUL), of liver and lesion volumes of interest were compared between the two reconstruction protocols. Head-to-toe PET/CT examinations and raw data from 64 patients were retrospectively retrieved. PET image reconstruction was carried out twice: once optimized for quantification, complying with EARL accreditation requirements, and once optimized for lesion detection, according to GE's Q.Clear reconstruction settings. RESULTS: The two reconstruction protocols showed different NEMA phantom RC values for different sphere sizes. Q.Clear values were always highest and exceeded the EARL accreditation maximum for smaller spheres. Comparison of liver SULmean showed a statistically significant but clinically irrelevant difference between both protocols. Comparison of lesion SULpeak and SULmax showed a statistically significant, and clinically relevant, difference of 1.64 and 4.57, respectively. CONCLUSIONS: For treatment response assessment using PERCIST criteria, the harmonization reconstruction protocol should be used as the lesion detection reconstruction protocol using resolution recovery systematically overestimates true SUL values. PMID- 30523430 TI - Characterization of the lytic archaeal virus Drs3 infecting Methanobacterium formicicum. AB - Viruses are ubiquitous in the biosphere and greatly affect the hosts they infect. It is generally accepted that members of every microbial taxon are susceptible to at least one virus, and a plethora of bacterial viruses are known. In contrast, knowledge of the archaeal virosphere is still limited. Here, a novel lytic archaeal virus is described, designated "Drs3", as well as its host, Methanobacterium formicicum strain Khl10. This hydrogenotrophic methanogenic archaeon and its virus were isolated from the anaerobic digester of an experimental biogas plant in Germany. The tailed virus has an icosahedral head with a diameter of approximately 60 nm and a long non-contractile tail of approximately 230 nm. These structural observations suggest that the new isolate belongs to the family Siphoviridae, but it could not be assigned to an existing genus. Lysis of the host Khl10 was observed 40-44 h after infection. Lysis of the type strain Methanobacterium formicicum DSMZ 1535 was not observed in the presence of Drs3, pointing towards resistance in the type strain or a rather narrow host range of this newly isolated archaeal virus. The complete 37-kb linear dsDNA genome of Drs3 contains 39 open reading frames, only 12 of which show similarity to genes with predicted functions. PMID- 30523431 TI - Determinants of vitamin D status in physically active elderly in the Netherlands. AB - PURPOSE: Vitamin D deficiencies are common in elderly, which increases the risk for, e.g., bone fractures. Identification of determinants of vitamin D status may provide leads for specific deficiency prevention strategies. Although determinants of vitamin D status have been studied in various populations, this has not been examined in elderly that have a physically active lifestyle. METHODS: Vitamin D status of 450 physically active elderly who do not use vitamin D supplements was determined and information on possible determinants (demographic, dietary intake and physical activity) was collected around a prolonged four day walking event in July and analyzed in linear regression models. RESULTS: The average summertime serum 25(OH)D concentration was 88.8 +/- 22.4 nmol/L. Only 2% of the participants had a 25(OH)D concentration below 50 nmol/L. Dietary intake of vitamin D was 4.0 +/- 1.9 ug/day, and the participants spent 12.4 +/- 8.6 h/week on outdoor activities. In the multivariate model, lower age (= - 0.48, 95% CI - 0.80 to - 0.16), lower BMI (= - 0.86, 95% CI - 1.62 to - 0.10), being a moderate to high drinker versus a non-drinker (= 7.97, 95% CI 0.43 15.51) and more outdoor physical activity (= 0.25, 95% CI 0.01-0.50) were significantly associated with higher 25(OH)D concentrations. CONCLUSIONS: In physically active elderly, vitamin D status was very high in summertime, with few deficiencies, suggesting that elderly with a physical active lifestyle might not necessarily need supplements during the summer period. Lower age, lower BMI, higher alcohol intake and more outdoor physical activity had a significant association with vitamin D status. PMID- 30523432 TI - Obesity and mental health improvement following nutritional education focusing on gut microbiota composition in Japanese women: a randomised controlled trial. AB - PURPOSE: Gut microbiota composition was supposedly related to obesity and psychological factors. We examined the effects of a nutritional education intervention focusing on gut microbiota composition on obesity and psychological factors among obese women. METHODS: Forty-four obese Japanese women aged 40 or older were randomly assigned to either an intervention group (n = 22) or control group (n = 22). The intervention consisted of a 20-min dietary lecture and a 10 min counselling session by registered dieticians, every 2 weeks for eight consecutive weeks. Body weight, height, waist circumference, food frequency, and gut microbiota composition were measured, and self-rated health and psychological factors were scored before and after the intervention. RESULTS: All participants completed the 8 week program. After the intervention, dietary fibre intake (p < 0.01), frequency of vegetable consumption (p = 0.020), and frequency of milk and milk product consumption (p < 0.01) increased significantly in the intervention group compared with the control group. Body weight and body mass index (BMI; p < 0.001), waist circumference (p < 0.01), and the depression scale score (p < 0.01) decreased significantly, while significant improvements were found in self-rated health (p = 0.045) and microbiome diversity (p < 0.01). CONCLUSION: Nutritional education focusing on gut microbiota composition may improve obesity and psychological factors in obese women. PMID- 30523433 TI - Selenium and large artery structure and function: a 10-year prospective study. AB - PURPOSE: Despite selenium's beneficial effects in counteracting oxidative stress, inflammation, and vascular endothelial dysfunction, controversial results exist regarding the long-term associations between selenium and atherosclerosis, arterial stiffness, and hypertension. We investigated in normal and selenium deficient groups (and the total group), whether serum selenium relates to measures of large artery structure and function over 10 years. METHODS: This longitudinal study included black adults from rural and urban areas in South Africa. Serum selenium and blood pressure were measured at baseline (N = 987). At follow-up, carotid intima media thickness (IMT), cross-sectional wall area (CSWA), carotid-femoral pulse wave velocity (c-fPWV), and blood pressure were measured (N = 718). Selenium deficiency was classified as serum levels < 8 ug/100 ml. RESULTS: In multivariable-adjusted regression analyses performed in the normal selenium group, c-fPWV after 10 years was negatively associated with baseline selenium (beta = - 0.09; p = 0.016). In the normal selenium group, baseline (but not 10 years) blood pressure also associated negatively with baseline selenium (beta = - 0.09; p = 0.007). Both IMT (beta = 0.12; p = 0.001) and CSWA (beta = 0.10; p = 0.003) after 10 years associated positively with baseline selenium in the total, normal, and selenium-deficient groups. CONCLUSION: We found a long-term vascular protective association of selenium on arterial stiffness and blood pressure in Africans with normal selenium levels, supporting the notion that selenium fulfills a vascular protective role. In contrast, we found a potential detrimental association between selenium and carotid wall thickness, particularly evident in individuals within the highest quartile of serum selenium. PMID- 30523434 TI - Is There Value in Molecular Profiling of Soft-Tissue Sarcoma? AB - OPINION STATEMENT: Soft-tissue sarcomas represent a heterogeneous group of diseases accounting for up to 1% of cancer in adults and 15% of cancer in children. Introduction of next-generation sequencing (NGS) technologies has allowed to gain additional insight into the genetic diversity and complexity of sarcomas, including the potential therapeutic implications of some genetic alterations.Two large studies have investigated the role of targeted NGS to identify actionable mutations in patients with soft-tissue sarcomas. In these two studies, actionable alterations were identified in up to 50% of patients. Retrospective data suggest that genomically guided treatments may be associated with substantial clinical benefit in sarcoma patients with advanced disease. However, prospective data are lacking. The MULTISARC is a randomized phase 3 investigating the potential of NGS implementation to improve outcome of metastatic sarcoma patients.Overall, a significant proportion of soft-tissue sarcoma bears potential targetable genomic alteration that can be identified through NGS. There is still a lack of evidence to support routine implementation of NGS for the management of sarcoma patient. The MULTISARC randomized trial which randomized patients to tumor genetic profiling or not might confirm the role of NGS to improve outcome of metastatic sarcoma patients through the identification of additional genomically guided lines of treatment. PMID- 30523435 TI - Biodistribution, pharmacokinetics, and organ-level dosimetry for 188Re-AHDD Lipiodol radioembolization based on quantitative post-treatment SPECT/CT scans. AB - BACKGROUND: Rhenium-188-labelled-Lipiodol radioembolization is a safe and cost effective treatment for primary liver cancer. In order to determine correlations between treatment doses and patient response to therapy, accurate patient specific dosimetry is required. Up to date, the reported dosimetry of 188Re Lipiodol has been based on whole-body (WB) planar imaging only, which has limited quantitative accuracy. The aim of the present study is to determine the in vivo pharmacokinetics, bio-distribution, and organ-level dosimetry of 188Re-AHDD Lipiodol radioembolization using a combination of post-treatment planar and quantitative SPECT/CT images. Furthermore, based on the analysis of the pharmacokinetic data, a practical and relatively simple imaging and dosimetry method that could be implemented in clinics for 188Re-AHDD-Lipiodol radioembolization is proposed. Thirteen patients with histologically proven hepatocellular carcinoma underwent 188Re-AHDD-Lipiodol radioembolization. A series of 2-3 WB planar images and one SPECT/CT scan were acquired over 48 h after the treatment. The time-integrated activity coefficients (TIACs, also known as residence-times) and absorbed doses of tumors and organs at risk (OARs) were determined using a hybrid WB/SPECT imaging method. RESULTS: Whole-body imaging showed that 188Re-AHDD-Lipiodol accumulated mostly in the tumor and liver tissue but a non-negligible amount of the pharmaceutical was also observed in the stomach, lungs, salivary glands, spleen, kidneys, and urinary bladder. On average, the measured effective half-life of 188Re-AHDD-Lipiodol was 12.5 +/- 1.9 h in tumor. The effective half-life in the liver and lungs (the two organs at risk) was 12.6 +/- 1.7 h and 12.0 +/- 1.9 h, respectively. The presence of 188Re in other organs was probably due to the chemical separation and subsequent release of the free radionuclide from Lipiodol. The average doses per injected activity in the tumor, liver, and lungs were 23.5 +/- 40.8 mGy/MBq, 2.12 +/- 1.78 mGy/MBq, and 0.11 +/- 0.05 mGy/MBq, respectively. The proposed imaging and dosimetry method, consisting of a single SPECT/CT for activity determination followed by 188Re-AHDD-Lipiodol clearance with the liver effective half-life of 12.6 h, resulted in TIACs estimates (and hence, doses) mostly within +/- 20% from the reference TIACs (estimated using three WB images and one SPECT/CT). CONCLUSIONS: The large inter-patient variability of the absorbed doses in tumors and normal tissue in 188Re-HDD-Lipiodol radioembolization patients emphasizes the importance of patient-specific dosimetry calculations based on quantitative post treatment SPECT/CT imaging. PMID- 30523436 TI - Synthesis, characterization, molecular docking, analgesic, antiplatelet and anticoagulant effects of dibenzylidene ketone derivatives. AB - In this study dibenzylidene ketone derivatives (2E,5E)-2-(4-methoxybenzylidene)-5 (4-nitrobenzylidene) cyclopentanone (AK-1a) and (1E,4E)-4-(4-nitrobenzylidene)-1 (4-nitrophenyl) oct-1-en-3-one (AK-2a) were newly synthesized, inspired from curcuminoids natural origin. Novel scheme was used for synthesis of AK-1a and AK 2a. The synthesized compounds were characterized by spectroscopic techniques. AK 1a and AK-2a showed high computational affinities (E-value > - 9.0 kcal/mol) against cyclooxygenase-1, cyclooxygenase-2, proteinase-activated receptor 1 and vitamin K epoxide reductase. AK-1a and AK-2a showed moderate docking affinities (E-value > - 8.0 kcal/mol) against mu receptor, kappa receptor, delta receptor, human capsaicin receptor, glycoprotein IIb/IIIa, prostacyclin receptor I2, antithrombin-III, factor-II and factor-X. AK-1a and AK-2a showed lower affinities (E-value > - 7.0 kcal/mol) against purinoceptor-3, glycoprotein-VI and purinergic receptor P2Y12. In analgesic activity, AK-1a and AK-2a decreased numbers of acetic acid-induced writhes (P < 0.001 vs. saline group) in mice. AK-1a and AK-2a significantly prolonged the latency time of mice (P < 0.05, P < 0.01 and P < 0.001 vs. saline group) in hotplate assay. AK-1a and AK-2a inhibited arachidonic acid and adenosine diphosphate induced platelet aggregation with IC50 values of 65.2, 37.7, 750.4 and 422 uM respectively. At 30, 100, 300 and 1000 uM concentrations, AK-1a and AK-2a increased plasma recalcification time (P < 0.001 and P < 0.001 vs. saline group) respectively. At 100, 300 and 1000 ug/kg doses, AK-1a and AK-2a effectively prolonged bleeding time (P < 0.001 and P < 0.01 vs. saline group) respectively. Thus in-silico, in-vitro and in-vivo investigation of AK-1a and AK-2a reports their analgesic, antiplatelet and anticoagulant actions. PMID- 30523437 TI - Chemlistem: chemical named entity recognition using recurrent neural networks. AB - Chemical named entity recognition (NER) has traditionally been dominated by conditional random fields (CRF)-based approaches but given the success of the artificial neural network techniques known as "deep learning" we decided to examine them as an alternative to CRFs. We present here several chemical named entity recognition systems. The first system translates the traditional CRF-based idioms into a deep learning framework, using rich per-token features and neural word embeddings, and producing a sequence of tags using bidirectional long short term memory (LSTM) networks-a type of recurrent neural net. The second system eschews the rich feature set-and even tokenisation-in favour of character labelling using neural character embeddings and multiple LSTM layers. The third system is an ensemble that combines the results of the first two systems. Our original BioCreative V.5 competition entry was placed in the top group with the highest F scores, and subsequent using transfer learning have achieved a final F score of 90.33% on the test data (precision 91.47%, recall 89.21%). PMID- 30523438 TI - Quality of life and physician-reported developmental, cognitive, and social problems in children with benign external hydrocephalus-long-term follow-up. AB - INTRODUCTION: Benign external hydrocephalus (BEH) is characterized by too rapidly increasing head circumference in infants, combined with typical neuroimaging findings. Psychomotor developmental delay is typically seen during the first few years of life; after that, the children's development assumedly normalizes. However, little is known about the long-term effects of BEH. METHODS: In this retrospective population-based study, children diagnosed with BEH during the years 1994-2003 in Southern Norway were asked to participate. Included patients (age 8-18 years old) and their parents answered the PedsQL questionnaire. The patient's family physicians contributed by giving information from medical records, with special emphasis on developmental, cognitive, and social function. RESULTS: One hundred seventy-six children were identified with BEH. One hundred three patients and 86 parents completed the PedsQL questionnaire. Supplemental medical information for 142 of the patients was received, mainly from their family physicians. Children and adolescents with BEH score themselves better than the normative mean on health-related quality of life, while the parents score their BEH children within the normative mean, except for the school functioning subgroup, where they score significantly lower. Various developmental, physical, and social problems are reported, like mental retardation, speech problems, epilepsy, motor impairment, psychiatric disorders, and cognitive difficulties. Among these patients, there is a discrepancy in some areas between the child reported and parent-reported quality of life. CONCLUSIONS: Children and adolescents who were diagnosed with BEH during infancy generally do well. However, for some patients, there appear to be various developmental, social, and cognitive problems, and they seem to struggle more in school than their healthy peers. PMID- 30523439 TI - Effect of maternal and embryonic factors on frozen-thawed IVF-ET outcome after pre-equilibration with hyaluronan. AB - PURPOSE: To systematically evaluate the effect of maternal and embryonic factors on in vitro fertilization and embryo transfer (IVF-ET) outcomes among Chinese patients after using hyaluronan-enriched transfer medium (HETM). METHODS: This retrospective study included 637 frozen-thawed ET cycles. Patients were divided into subgroups based on their maternal or embryonic status or treatment procedures. The implantation, clinical pregnancy, delivery, and abortion rates were compared between the HETM and control groups. In addition, the implantation and clinical pregnancy rates were used to analyze the reciprocal effect of HETM and Preimplantation genetic screening (PGS) assessment. RESULTS: Maternal risk factors, especially maternal aging and a low number of retrieved oocytes, have a significant adverse impact on the efficacy of HETM usage. Endometrial preparation with artificial and natural cycles but not stimulated cycles showed a satisfying outcome after IVF-ET treatment. Compared with cleavage embryos, blastocyst stage embryo transfer showed more prominent improvement when using HETM. Prolonged pre equilibration treatment with HETM notably compromised the IVF-ET outcome. PGS based preselection could further facilitate the HETM-induced beneficial effect on IVF-ET outcomes. The body weight, length, and sex ratio of the neonate did not significantly differ between the HETM and control groups. CONCLUSION: Both the maternal and embryonic status or treatment procedures affected the IVF-ET outcomes after using HETM. HETM had a beneficial effect on advantaged IVF cycles but did not improve the outcomes of disadvantaged IVF cycles. Endometrial preparation with stimulated cycles is not recommended when using HETM. Prolonged pre-equilibration treatment must be avoided. PMID- 30523441 TI - Letter to the editor. PMID- 30523440 TI - Arrangement of myofibroblastic and smooth muscle-like cells in superficial peritoneal endometriosis and a possible role of transforming growth factor beta 1 (TGFbeta1) in myofibroblastic metaplasia. AB - PURPOSE: Superficial peritoneal endometriotic (pEM) lesions are composed of endometrial glands and stroma, in addition to a third component-myofibroblasts and smooth muscles (SM)-like cells. The latter develops secondary to a metaplasia. In this study, we characterised the third component cells in pEM according to differentiation markers in different micro-compartments. Furthermore, a possible effect of TGFbeta1 on myofibroblastic metaplasia in endometriotic epithelial cells was studied. METHODS: Seventy-six premenopausal patients were included. Peritoneal biopsies were excised from EM patients (n = 23), unaffected peritoneum (peritoneum from EM patients but without EM components, n = 5/23) and non-EM patients (n = 10). All peritoneal biopsies were immunolabeled for ASMA, calponin, collagen I, desmin, TGFbeta receptor 1 (R1), R2 and R3 in addition to ultrastructure examination by transmission electron microscopy (TEM) (n = 1). TGFbeta1 level was measured in peritoneal fluid (PF) (EM, n = 19 and non-EM, n = 13) collected during laparoscopy. Furthermore, TGFbeta1 effect on myofibroblastic metaplasia was studied in vitro. RESULTS: At the centre of pEM lesions, calponin immunolabeling outweighs the collagen I while in the periphery the reverse occurs. SM-like cells expressing desmin predominate at the periphery, while ASMA immunolabeling was detectable in all micro compartments. Both indicate an abundance of myofibroblasts at the centre of pEM lesions and SM-like cells in the periphery. Although activated TGFbeta1 in PF did not differ between EM and non-EM, it inhibited the cell proliferation of the endometriotic epithelial cells and induced an upregulation in ASMA and collagen IA2 expression as well. CONCLUSION: The abundance of the myofibroblasts and SM like cells points to a myofibroblastic metaplasia in pEM. Both cells are differentially arranged in the different micro-compartments of pEM lesions, with increasing cell maturity towards the periphery of the lesion. Furthermore, TGFbeta1 may play a role in the myofibroblastic metaplasia of the endometriotic epithelial cells. These findings provide a better insight in the micro-milieu in EM lesions, where most of the disease dynamics occur. PMID- 30523442 TI - A single center's experience with total arterial revascularization and spiral aneurysmorrhaphy for ischemic cardiac disease. AB - The restoration of left ventricular (LV) geometry in combination with coronary artery bypass grafting for the treatment of ischemic cardiac disease remains controversial. We hereby present the experience of our center with total arterial myocardial revascularization (TAMR) and spiral aneurysmorrhaphy for ischemic heart disease. A retrospective analysis of 101 patients with advanced cardiovascular disease who underwent TAMR and spiral aneurysmorrhaphy was performed. Spiral aneurysmorrhaphy is a modification of the linear aneurysmorrhaphy and was applied to patients who had a LV aneurysm with a diameter of less than 5 cm. Peri-operative and in-hospital data were retrieved. The majority of the patients were male (87.13%) with a mean age of 63.1 years. Mean pre-operative ejection fraction (EF) was 35.7% ranging between 20 and 65%. An average of 3.23 grafts was required per patient. Early mortality was 6.93% (one intra-operative and six in-hospital deaths). Addition of concomitant valve surgery was associated with prolonged total operative, cardiopulmonary bypass and cross-clamp time (p < 0.001), increased need for blood (p = 0.012) and plasma (p = 0.038), longer intensive care unit (ICU) stay (p = 0.045) and higher rate of post-operative cerebrovascular accident (p = 0.011). Furthermore, patients with a pre-operative EF between 30 and 50% had a shorter ICU stay (p = 0.045) and LoS (p = 0.029) compared with patients with EF <30%. Early mortality and post-operative complication rates following this combined procedure are in consistency with the relevant available data suggesting its feasibility regardless of the EF or addition of concomitant surgeries. Data from the follow-up of these patients are required to examine the long-term efficacy of this surgical modality. PMID- 30523443 TI - Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure. AB - Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (>= 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF. PMID- 30523444 TI - The accuracy of digital templating in uncemented total hip arthroplasty. AB - INTRODUCTION: Preoperative planning is an essential part of total hip arthroplasty (THA). It facilitates the surgical procedure, helps to provide the correct implant size and aims at restoring biomechanical conditions. In recent times, surgeons rely more and more on digital templating techniques. Although the conversion to picture archiving and communication system had many positive effects, there are still problems that have to be taken into consideration. OBJECTIVES: The core objective was to evaluate the impact of the planners' experience on the accuracy of predicting component size in digital preoperative templating of THA. In addition, the influence of overweight and obesity (according to WHO-criteria), patient's sex and component design on the accuracy of preoperative planning have been analysed. MATERIALS AND METHODS: The retrospective study included 632 consecutive patients who had primary uncemented THA. Digital templating was done using "syngo-EndoMap" software by Siemens Medical Solutions AG. Mann-Whitney U test and Kruskal-Wallis test have been used for statistical analysis. The accuracy of predicting component size has been evaluated by comparing preoperative planned sizes with implanted sizes as documented by the surgeons. The planner's experience was tested by comparing the reliability of preoperative planning done by senior surgeons or residents. The influence of BMI on predicting component size has been tested by comparing the accuracy of digital templating between different groups of BMI according to WHO criteria. The same procedure has been done for evaluating the impact of patient's sex and component design. RESULTS: The implant size was predicted exactly in 42% for the femoral and in 37% for the acetabular component. 87% of the femoral components and 78% of the acetabular cups were accurate within one size. Digital templating of femoral implant size was significantly more reliable when done by a senior surgeon. No difference was found for the acetabular component sizes. The BMI also had an impact on estimating the correct femoral implant size. In overweight patients, planning was significantly more inaccurate than normal weight people. Differences were seen in obese patients. However, these were not significant. Accuracy of acetabular components was not affected. The design of the prostheses and the patient's sex had no influence on predicting component size. CONCLUSIONS: Inexperience and overweight are factors that correlate with inaccuracy of preoperative digital templating in femoral components, whereas acetabular components seem to be independent of these factors. PMID- 30523445 TI - Treatment of scaphoid waist nonunion by one, two headless compression screws or plate with or without additional extracorporeal shockwave therapy. AB - INTRODUCTION: Scaphoid nonunion remains challenging for hand surgeons. Several treatment options are available such as: non-vascularized or vascularized bone grafting, with or without additional stabilization. In the last few decades, extracorporeal shockwave therapy (ESWT) has become an established procedure for treating delayed and nonunions. Purpose of this retrospective follow-up study was (a) to investigate union rate and clinical outcome of the different implants [either one/two headless compression screws (HCS) or a plate] and (b) union rate and clinical outcome using only surgery, or a combination of surgery and ESWT. MATERIALS AND METHODS: The study included 42 patients with scaphoid nonunions of the waist with a mean follow-up of 52 months. All patients received a non vascularized bone graft from the iliac crest and stabilization was achieved by using one, two HCS or a plate. ESWT was performed with 3000 impulses, energy flux density per pulse 0.41 mJ/mm2 within 2 weeks after surgery. Clinical assessment included range of motion (ROM), pain according to the Visual Analog Scale (VAS), grip strength, Disability of the Arm Shoulder and Hand Score, Patient-Rated Wrist Evaluation Score, Michigan Hand Outcomes Questionnaire and modified Green O'Brien (Mayo) Wrist Score. In addition, each patient had a CT scan of the wrist. RESULTS: A total of 33/42 (79%) patients showed union at the follow-up investigation. Patients treated with additional ESWT showed bony healing in 21/26 (81%) and without ESWT in 12/16 (75%). Patients that were stabilized using one HCS showed bony healing in 6/10 (60%), with two HCS 10/12 (83%) and by plate 17/20 (85%). The ESWT group had a significantly lower pain score according to the VAS and better modified Green O'Brien (Mayo) Score. No differences could be found in respect of ROM, grip strength, functional outcome score depending of which stabilization method was used. CONCLUSIONS: Stabilization of scaphoid waist nonunions with two HCS or plate showed higher union rates than a stabilization using only one HCS. In addition, ESWT combined with a nonvascularized bone graft from the iliac crest seems a suitable option for treating scaphoid nonunions. PMID- 30523446 TI - Patient-reported quality of life and pain after permissive weight bearing in surgically treated trauma patients with tibial plateau fractures: a retrospective cohort study. AB - INTRODUCTION: A Dutch survey among orthopedic surgeons and trauma surgeons showed that almost 90% of the surgeons do not follow protocols regarding the weight bearing aftercare for tibial plateau fractures. Clinical studies comparing permissive weight bearing (PWB) versus restricted weight bearing (RWB) after surgically treated tibial plateau fractures are not available. The aim of this study was to inventory potential differences in quality of life and pain, and number of complications in patients with surgically treated tibial plateau fractures who followed a PWB regime, relative to those that followed a RWB regime. MATERIALS AND METHODS: This retrospective cohort study included surgically treated trauma patients with tibial plateau fractures, who underwent rehabilitation according to PWB or RWB between 2005 and 2015. Data such as demographics, patient-reported quality of life and pain, and patient outcome were collected. RESULTS: This cohort study included 91 patients with a tibial plateau fracture (31 and 60 patients in the PWB and RWB groups respectively). No significant between-group differences in either age or gender were found. However, a significant difference in fracture type was found between groups, (p = 0.04). No significant differences were found in either patient-reported SF-12 or VAS scores between the PWB group and RWB group. Time to full weight bearing was significantly shorter in the PWB than in the RWB group, i.e., 14.7 versus 20.7 weeks, (p = 0.02). No significant differences were found regarding postoperative complications between the PWB and the RWB groups, i.e., 6.5% versus 10.0%, respectively. CONCLUSION: PWB after surgically treated tibial plateau fractures is safe and is related to a significantly reduced time to full weight bearing with no significant differences in patient-reported quality of life and pain or complication rates. PMID- 30523447 TI - High production of optically pure (3R)-acetoin by a newly isolated marine strain of Bacillus subtilis CGMCC 13141. AB - Acetoin is one of the bio-based platform chemicals and its optically pure isomers are important potential intermediates and precursors in the synthesis of novel optically active materials. (3R)-acetoin could be synthesized via enzymatic catalysis, whole-cell catalysis and fermentation. In this study a marine strain of Bacillus subtilis was isolated to produce optically pure (3R)-acetoin with glucose as carbon source. The effects of nutrients on the formation of (3R) acetoin and conversion of glucose to (3R)-acetoin were evaluated by Plackett Burman design, and the fermentation medium was optimized by central composite design. The impact of oxygen supply on the production of (3R)-acetoin was studied at different aeration rates. Under the optimal conditions, 83.7 g/L (3R)-acetoin with an optical purity of 99.4% was achieved by fed-batch fermentation, and the conversion of glucose to (3R)-acetoin was 91.5% of the theoretical value. The results indicate the industrial potential of this strain for (3R)-acetoin production via fermentation. PMID- 30523448 TI - Enhanced CO2 biofixation and protein production by microalgae biofilm attached on modified surface of nickel foam. AB - In this work, a photobioreactor with microalgae biofilm was proposed to enhance CO2 biofixation and protein production using nickel foam with the modified surface as the carrier for immobilizing microalgae cells. The results demonstrated that, compared with microalgae suspension, microalgae biofilm lowered mass transfer resistance and promoted mass transfer efficiency of CO2 from the bubbles into the immobilized microalgae cells, enhancing CO2 biofixation and protein production. Moreover, parametric studies on the performance of the photobioreactor with microalgae biofilm were also conducted. The results showed that the photobioreactor with microalgae biofilm yielded a good performance with the CO2 biofixation rate of 4465.6 umol m-3 s-1, the protein concentration of effluent liquid of 0.892 g L-1, and the protein synthesis rate of 43.11 g m-3 h 1. This work will be conducive to the optimization design of microalgae culture system for improving the performance of the photobioreactor. PMID- 30523449 TI - High-efficiency expression of Sulfolobus acidocaldarius maltooligosyl trehalose trehalohydrolase in Escherichia coli through host strain and induction strategy optimization. AB - Maltooligosyl trehalose trehalohydrolase (MTHase, EC 3.2.1.141) catalyzes the release of trehalose, a novel food ingredient, by splitting the alpha-1,4 glucosidic linkage adjacent to the alpha-1,1-glucosidic linkage of maltooligosyl trehalose. However, the high-yield preparation of recombinant MTHase has not yet been reported. In this study, a codon-optimized synthetic gene encoding Sulfolobus acidocaldarius MTHase was expressed in Escherichia coli. In initial expression experiments conducted using pET-24a (+) and E. coli BL21 (DE3), the MTHase activity was 10.4 U/mL and a large amount of the expression product formed inclusion bodies. The familiar strategies, including addition of additives, co expression with molecular chaperones, and expression with a fusion partner, failed to enhance soluble MTHase expression. Considering the intermolecular disulfide bond of MTHase, expression was investigated using a system comprising plasmid pET-32a (+) and host E. coli Origami (DE3), which is conducive to cytoplasmic disulfide bond formation. The MTHase activity increased to 55.0 U/mL, a 5.3-fold increase. Optimization of the induction conditions in a 3-L fermentor showed that when the lactose was fed at 0.2 g/L/h beginning at an OD600 of 40 and the induction temperature was maintained at 30 degrees C, the MTHase activity reached a maximum of 204.6 U/mL. This is the first report describing a systematic effort to obtain high-efficiency MTHase production. The high yield obtained using this process provides the basis for the industrial-scale production of trehalose. This report is also expected to be valuable in the production of other enzymes containing disulfide bonds. PMID- 30523450 TI - Accuracy of iodine density thresholds for the separation of vertebral bone metastases from healthy-appearing trabecular bone in spectral detector computed tomography. AB - PURPOSE: To evaluate quantitative iodine density mapping (IDM) with spectral detector computed tomography (SDCT) as a quantitative biomarker for separation of vertebral trabecular bone metastases (BM) from healthy-appearing trabecular bone (HTB). MATERIALS AND METHODS: IRB-approved retrospective single-center-study of portal venous SDCT datasets acquired between June 2016 and March 2017. Inclusion of 43 consecutive cancer patients with BM and 40 without. Target lesions and non affected control vertebrae were defined using follow-up imaging, MRI, and/or bone scintigraphy. ID and standard deviation were determined with ROI measures by two readers in (a) bone metastases, (b) HTB of BM patients and controls, and (c) ID of various vessels. Volumetric bone mineral density (vBMD) of the lumbar spine and age were recorded. Multivariate ROC analyses und Wilcoxon test were used to determine thresholds for separation of BM and HTB. p < 0.05 was considered significant. RESULTS: ID measurements of 40 target lesions and 83 reference measurements of HTB were acquired. Age (p < 0.0001) and vBMD (p < 0.05) affected ID measurements independently in multivariate models. There were significant differences of ID between metastases (n = 43) and HTB ID (n = 124; mean 5.5 +/- 0.9 vs. 3.5 +/- 0.9; p < 0.0001), however, with considerable overlap. In univariate analysis, increased ID discriminated bone lesions (AUC 0.90) with a maximum combined specificity/sensitivity of 77.5%/90.7% when applying a threshold of 4.5 mg/ml. Multivariate regression models improved significantly when considering vBMD, the noise of ID, and vertebral venous ID (AUC 0.98). CONCLUSION: IDM of SDCT yielded a statistical separation of vertebral bone lesions and HTB. Adjustment for confounders such as age and lumbar vBMD as well as for vertebral venous ID and lesion heterogeneity improved discrimination of trabecular lesions. KEY POINTS: * SDCT iodine density mapping provides the possibility for quantitative analysis of iodine uptake in tissue, which allows to differentiate bone lesions from healthy bone marrow. * Age and vBMD have a significant impact on iodine density measurements. * Iodine density measured in SDCT yielded highest sensitivity and specificity for the statistical differentiation of vertebral trabecular metastases and healthy trabecular bone using an iodine density threshold of 4.5 mg/ml (most performant)-5.0 mg/ml (optimized for specificity). PMID- 30523451 TI - Development of a radiomics nomogram based on the 2D and 3D CT features to predict the survival of non-small cell lung cancer patients. AB - OBJECTIVES: The aim of this study was to develop a radiomics nomogram by combining the optimized radiomics signatures extracted from 2D and/or 3D CT images and clinical predictors to assess the overall survival of patients with non-small cell lung cancer (NSCLC). METHODS: One training cohort of 239 and two validation datasets of 80 and 52 NSCLC patients were enrolled in this study. Nine hundred seventy-five radiomics features were extracted from each patient's 2D and 3D CT images. Least absolute shrinkage and selection operator (LASSO) regression was used to select features and generate a radiomics signature. Cox hazard survival analysis and Kaplan-Meier were performed in both cohorts. The radiomics nomogram was developed by integrating the optimized radiomics signature and clinical predictors, its calibration and discrimination were evaluated. RESULTS: The radiomics signatures were significantly associated with NSCLC patients' survival time. The signature derived from the combined 2D and 3D features showed a better prognostic performance than those from 2D or 3D alone. Our radiomics nomogram integrated the optimal radiomics signature with clinical predictors showed a significant improvement in the prediction of patients' survival compared with clinical predictors alone in the validation cohort. The calibration curve showed predicted survival time was very close to the actual one. CONCLUSIONS: The radiomics signature from the combined 2D and 3D features further improved the predicted accuracy of survival prognosis for the patients with NSCLC. Combination of the optimal radiomics signature and clinical predictors performed better for individualied survival prognosis estimation in patients with NSCLC. These findings might affect trearment strategies and enable a step forward for precise medicine. KEY POINTS: * We found both 2D and 3D radiomics signature have favorable prognosis, but 3D signature had a better performance. * The radiomics signature generated from the combined 2D and 3D features had a better predictive performance than those from 2D or 3D features. * Integrating the optimal radiomics signature with clinical predictors significantly improved the predictive power in patients' survival compared with clinical TNM staging alone. PMID- 30523452 TI - Reduced lateral occipital gray matter volume is associated with physical frailty and cognitive impairment in Parkinson's disease. AB - INTRODUCTION: To investigate the structural changes of the brain that correlate with physical frailty and cognitive impairments in Parkinson's disease (PD) patients. METHODS: Sixty-one PD patients and 59 age- and sex-matched healthy controls were enrolled. For each participant, a frailty assessment using Fried's criteria and comprehensive neuropsychological testing using the Wechsler Adult Intelligence Scale-III and Cognitive Ability Screening Instrument were conducted, and structural brain MR images were acquired for voxel-based morphometric analysis. The neuropsychological testing includes various tests in these five domains: attention, executive, memory, speech and language, and visuospatial functions. Exploratory group-wise comparisons of gray matter volume (GMV) in the PD patients and controls were conducted. Voxel-wise multiple linear regression analyses were conducted for physical frailty-related and cognitive impairment related GMV changes in the PD patients. Voxel-wise multiple linear regressions were also performed with the five cognitive domains separated using the same model. RESULTS: The PD patients exhibited diffuse GMV reductions in comparison to the controls. In the PD patients, physical frailty-related decreases in GMV were observed in the bilateral frontal and occipital cortices, while cognitive impairment-related decreases in GMV were observed in the bilateral frontal, occipital, and temporal cortices. These regions overlap in the lateral occipital cortex. After the five domains of cognitive functions were analyzed separately, physical frailty-related decreases in GMV still overlap in lateral occipital cortices with every domain of cognitive impairment-related decreases in GMV. CONCLUSION: Reduced GMV in the lateral occipital cortex is associated with cognitive impairment and physical frailty in PD patients. KEY POINTS: * Physical frailty in PD was associated with decreased GMV in the frontal and occipital cortices, while cognitive impairment was associated with decreased GMV in the frontal, temporal, and occipital cortices. * Physical frailty and cognitive impairment were both associated with decreased GMV in the lateral occipital cortex, which is part of the ventral object-based visual pathway. * Decreased GMV in the lateral occipital cortex may serve as a potential imaging biomarker for physical frailty and cognitive impairment in PD. PMID- 30523453 TI - Diabetes risk assessment with imaging: a radiomics study of abdominal CT. AB - OBJECTIVES: To identify CT markers for screening of early type 2 diabetes and assessment of the risk of incident diabetes using a radiomics method. METHODS: The medical records of 26,947 inpatients were reviewed. A total of 690 patients were selected and allocated to a primary cohort, a validation cohort, and a prediction cohort and used to build prediction models for diabetes. Three radiomics signatures were constructed using CT image features extracted from three regions of interest, i.e., in the pancreas, liver, and psoas major muscle. By incorporating radiomics signatures and other markers, we built a radiomics nomogram that could be used to screen for early diabetes and predict future diabetes. RESULTS: Of the three abdominal organs for which radiomics signature were constructed, that of the pancreas showed the best discriminatory power for early diabetes screening and prediction (C-statistics of 0.833, 0.846, and 0.899 for the primary cohort, validation cohort, and prediction cohort, respectively). The sensitivity and specificity of the nomogram for prediction of 3-year incident diabetes were 0.827 and 0.807, respectively. CONCLUSIONS: This study presents alternative radiomics markers that have potential for use in screening for undiagnosed type 2 diabetes and prediction of 3-year incident diabetes. KEY POINTS: * CT images may provide useful information to evaluate the risk of developing diabetes. * Radiomics score for diabetes prediction is based on subtle changes of abdominal organs detected by CT. * The radiomics signature of pancreas, a combination of five features of CT images, is efficient for early diabetes screening and prediction of future diabetes (AUC > 0.8). PMID- 30523454 TI - Differentiation of clear cell and non-clear cell renal cell carcinomas by all relevant radiomics features from multiphase CT: a VHL mutation perspective. AB - OBJECTIVES: To develop a radiomics model with all-relevant imaging features from multiphasic computed tomography (CT) for differentiating clear cell renal cell carcinoma (ccRCC) from non-ccRCC and to investigate the possible radiogenomics link between the imaging features and a key ccRCC driver gene-the von Hippel Lindau (VHL) gene mutation. METHODS: In this retrospective two-center study, two radiomics models were built using random forest from a training cohort (170 patients), where one model was built with all-relevant features and the other with minimum redundancy maximum relevance (mRMR) features. A model combining all relevant features and clinical factors (sex, age) was also built. The radiogenomics association between selected features and VHL mutation was investigated by Wilcoxon rank-sum test. All models were tested on an independent validation cohort (85 patients) with ROC curves analysis. RESULTS: The model with eight all-relevant features from corticomedullary phase CT achieved an AUC of 0.949 and an accuracy of 92.9% in the validation cohort, which significantly outperformed the model with eight mRMR features (seven from nephrographic phase and one from corticomedullary phase) with an AUC of 0.851 and an accuracy of 81.2%. Combining age and sex did not benefit the performance. Five out of eight all-relevant features were significantly associated with VHL mutation, while all eight mRMR features were significantly associated with VHL mutation (false discovery rate-adjusted p < 0.05). CONCLUSIONS: All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC. Most subtype-discriminative imaging features were found to be significantly associated with VHL mutation, which may underlie the molecular basis of the radiomics features. KEY POINTS: * All-relevant features in corticomedullary phase CT can be used to differentiate ccRCC from non-ccRCC with high accuracy. * Most RCC-subtype discriminative CT features were associated with the key RCC-driven gene-the VHL gene mutation. * Radiomics model can be more accurate and interpretable when the imaging features could reflect underlying molecular basis of RCC. PMID- 30523455 TI - Visualization of carotid vessel wall and atherosclerotic plaque: T1-SPACE vs. compressed sensing T1-SPACE. AB - OBJECTIVES: To compare visualization of carotid plaques and vessel walls between 3D T1-fast spin echo imaging with conventional SPACE (T1-SPACE) and with a prototype compressed sensing T1-SPACE (CS-T1-SPACE) METHODS: This retrospective study was approved by the institutional review board. Participants comprised 43 patients (36 males, 7 females; mean age, 71 years) who underwent carotid MRI including T1-SPACE and CS-T1-SPACE. The quality of visualization for carotid plaques and vessel walls was evaluated using a 5-point scale, and signal intensity ratios (SRs) of the carotid plaques were measured and normalized to the adjacent sternomastoid muscle. Scores for the quality of visualization were compared between T1-SPACE and CS-T1-SPACE using the Wilcoxon signed-rank test. Statistical differences between SRs of plaques with T1-SPACE and CS-T1-SPACE were also evaluated using the Wilcoxon signed-rank test, and Spearman's correlation coefficient was calculated to investigate correlations. RESULTS: Visualization scores were significantly higher for CS-T1-SPACE than for T1-SPACE when evaluating carotid plaques (p = 0.0212) and vessel walls (p < 0.001). The SR of plaques did not differ significantly between T1-SPACE and CS-T1-SPACE (p = 0.5971). Spearman's correlation coefficient was significant (0.884; p < 0.0001). CONCLUSIONS: CS-T1-SPACE allowed better visualization scores and sharpness compared with T1-SPACE in evaluating carotid plaques and vessel walls, with a 2.5 fold accelerated scan time with comparable image quality. CS-T1-SPACE appears promising as a method for investigating carotid vessel walls, offering better image quality with a shorter acquisition time. KEY POINTS: * CS-T1-SPACE allowed better visualization compared with T1-SPACE in evaluating carotid plaques and vessel walls, with a 2.5-fold accelerated scan time with comparable image quality. * CS-T1-SPACE offers a promising method for investigating carotid vessel walls due to the better image quality with shorter acquisition time. * Physiological movements such as swallowing, arterial pulsations, and breathing induce motion artifacts in vessel wall imaging, and a shorter acquisition time can reduce artifacts from physiological movements. PMID- 30523456 TI - Coronary CT angiography-derived plaque quantification with artificial intelligence CT fractional flow reserve for the identification of lesion-specific ischemia. AB - OBJECTIVES: We sought to investigate the diagnostic performance of coronary CT angiography (cCTA)-derived plaque markers combined with deep machine learning based fractional flow reserve (CT-FFR) to identify lesion-specific ischemia using invasive FFR as the reference standard. METHODS: Eighty-four patients (61 +/- 10 years, 65% male) who had undergone cCTA followed by invasive FFR were included in this single-center retrospective, IRB-approved, HIPAA-compliant study. Various plaque markers were derived from cCTA using a semi-automatic software prototype and deep machine learning-based CT-FFR. The discriminatory value of plaque markers and CT-FFR to identify lesion-specific ischemia on a per-vessel basis was evaluated using invasive FFR as the reference standard. RESULTS: One hundred three lesion-containing vessels were investigated. 32/103 lesions were hemodynamically significant by invasive FFR. In a multivariate analysis (adjusted for Framingham risk score), the following markers showed predictive value for lesion-specific ischemia (odds ratio [OR]): lesion length (OR 1.15, p = 0.037), non-calcified plaque volume (OR 1.02, p = 0.007), napkin-ring sign (OR 5.97, p = 0.014), and CT-FFR (OR 0.81, p < 0.0001). A receiver operating characteristics analysis showed the benefit of identifying plaque markers over cCTA stenosis grading alone, with AUCs increasing from 0.61 with >= 50% stenosis to 0.83 with addition of plaque markers to detect lesion-specific ischemia. Further incremental benefit was realized with the addition of CT-FFR (AUC 0.93). CONCLUSION: Coronary CTA-derived plaque markers portend predictive value to identify lesion-specific ischemia when compared to cCTA stenosis grading alone. The addition of CT-FFR to plaque markers shows incremental discriminatory power. KEY POINTS: * Coronary CT angiography (cCTA)-derived quantitative plaque markers of atherosclerosis portend high discriminatory power to identify lesion-specific ischemia. * Coronary CT angiography-derived fractional flow reserve (CT-FFR) shows superior diagnostic performance over cCTA alone in detecting lesion specific ischemia. * A combination of plaque markers with CT-FFR provides incremental discriminatory value for detecting flow-limiting stenosis. PMID- 30523457 TI - New MRI features improve subtype classification of hepatocellular adenoma. AB - OBJECTIVE: MRI is crucial for the classification of hepatocellular adenomas (HCA) into subtypes. Our objective was to review and increase MRI criteria for subtype classification and define the limits. METHODS: Pathological and radiological data of 116 HCAs were retrospectively analyzed to investigate MRI features of HCA pathological subtypes. Risk for complication was also evaluated with regard to subtype and tumor size. RESULTS: 38/43 (88%) HNF1alpha-mutated HCAs (H-HCAs) were discriminated by (i) fatty component (homogeneous or heterogeneous) and (ii) hypovascular pattern, with a sensitivity of 88% and a specificity of 97%. 51/58 (88%) inflammatory HCAs (IHCAs) displayed features of sinusoidal dilatation (SD) including three different patterns (global SD, atoll sign, and a new "crescent sign" corresponding to a partial peripheral rim, hyperintense on T2W and/or arterial phase with persistent delayed enhancement). Sensitivity was 88% and specificity 100%. However, some HCA remained unclassifiable by MRI: HCA remodeled by necrotic/hemorrhagic changes covering > 50% of the lesion, H-HCAs without steatosis, IHCAs without SD, beta-catenin-mutated and unclassified HCAs. Regarding malignant transformation (5/116) and bleeding (24/116), none was observed when the HCA diameter was smaller than 5.2 cm and 4.2 cm, respectively. CONCLUSION: Based on the largest series evaluated until now, we identified several non-described MRI features and propose new highly sensitive and specific MRI criteria. With the addition of these new features, 88% of the two main HCA subtypes could be identified. KEY POINTS: * HNF1alpha-mutated hepatocellular adenomas (H-HCA) are characterized by the presence of fat and hypovascular pattern in MRI. * Inflammatory hepatocellular adenomas (I-HCA) are characterized by different patterns translating sinusoidal dilatation including the newly described crescent sign. * No MRI specific pattern was identified for beta catenin-mutated HCA (b-HCA). PMID- 30523458 TI - Mathematical skills in children with pilocytic astrocytoma. AB - BACKGROUND: Pediatric patients with circumscribed cerebellar pilocytic astrocytoma (PA) tumors generally perform within the normal range on neuropsychological tests after a complete tumor resection. The outcome in academically relevant abilities such as mathematics, which in adults involve some cerebellar functions, is however much less understood. The aim of this study is to retrospectively investigate the neuroplasticity of mathematical skills and associated cognitive functions following cerebellar resection of PA in pediatric patients. METHODS: Twenty-two children (mean age = 11.2 + 1.8), including 11 PA patients (females = 6) and 11 healthy controls (females = 6), were administered a battery of mathematical (MaT) and neuropsychological tests. Single-case statistical analyses were carried out (Crawford's t) as well as between-group comparisons (Wilcoxon test). Spearman correlations between MaT and neuropsychological tests were calculated. RESULTS: Thirty-six percent of the patients showed difficulties in some mathematical tasks, 50% of them within a broader cognitive deficit. Verbal working memory was associated with MaT performance both in patients and controls while, crucially, visuospatial memory, and visual-motor integration were associated with MaT in patients only. Among patients, MaT correlated negatively with tumor size and positively with the interval surgery test. CONCLUSIONS: The results evince an overall recovery of mathematical abilities despite PA in the majority of patients. This functional reestablishment is supported by visuospatial and visuomotor integration functions that contribute to set up emerging mathematical skills in these patients. Higher levels of compensation are found in more developed tumors as compared to smaller ones. PMID- 30523459 TI - Identifying adherence barriers to oral endocrine therapy among breast cancer survivors. AB - PURPOSE: Approximately 70-80% of breast cancers are hormone receptor-positive (HR+). OET, including tamoxifen and aromatase inhibitors, is considered standard adjuvant therapy for HR+ breast cancer. Despite demonstrated benefits, nearly half of patients are non-adherent and over two-thirds discontinue therapy before the recommended 5 years. Our objective was to identify and summarize literature reported barriers associated with non-adherence/non-persistence to OET among breast cancer survivors. METHODS: A PUBMED literature search was conducted using the following terms: 'breast cancer,' 'oral endocrine therapy' or 'Tamoxifen' or 'Aromatase Inhibitors,' 'adherence,' or 'barriers.' The search was restricted to past six years. The abstracts of each result were reviewed and categorized as either patient-reported or physician-reported. All patient- and physician reported factors that affected adherence and persistence were listed and grouped together into the three main categories: Socio-demographic and medical parameters, general psychosocial parameters, and psychosocial parameters related to OET. RESULTS: A total of 320 articles were identified, of which 19 met inclusion criteria. Adverse drug reactions were the most commonly reported barrier but were generally underreported among physicians. Among patient-reported barriers, common social-demographic and medical parameters were age, comorbidity, and financial status. General psychosocial variables were lack of patient provider communication, depressive symptoms, and lack of perceived self-efficacy. Treatment toxicity was the most commonly reported psychosocial parameter related to OET. CONCLUSION: The determinants of non-adherence and non-persistence are multi-dimensional and influenced by several factors. The three categories of adherence barriers should be evaluated and considered when designing future interventions to enhance OET adherence for a tailored approach. PMID- 30523460 TI - 'After-hours' non-elective spine surgery is associated with increased perioperative adverse events in a quaternary center. AB - PURPOSE: 'After-hours' non-elective spinal surgeries are frequently necessary, and often performed under sub-optimal conditions. This study aimed (1) to compare the characteristics of patients undergoing non-elective spine surgery 'After hours' as compared to 'In-hours'; and (2) to compare the perioperative adverse events (AEs) between those undergoing non-elective spine surgery 'after-hours' as compared to 'in-hours'. METHODS: In this retrospective study of a prospective non elective spine surgery cohort performed in a quaternary spine center, surgery was defined as 'in-hours' if performed between 0700 and 1600 h from Monday to Friday or 'after-hours' if more than 50% of the operative time occurred between 1601 and 0659 h, or if performed over the weekend. The association of 'after-hours' surgery with AEs, surgical duration, intraoperative estimated blood loss (IOBL), length of stay and in-hospital mortality was analyzed using stepwise multivariate logistic regression. RESULTS: A total of 1440 patients who underwent non-elective spinal surgery between 2009 and 2013 were included in this study. A total of 664 (46%) procedures were performed 'after-hours'. Surgical duration and IOBL were similar. About 70% of the patients operated 'after-hours' experienced at least one AE compared to 64% for the 'in-hours' group (p = 0.016). 'After-hours' surgery remained an independent predictor of AEs on multivariate analysis [adjusted OR 1.30, 95% confidence interval (CI) 1.02-1.66, p = 0.034]. In hospital mortality increased twofold in patients operated 'after-hours' (4.4% vs. 2.1%, p = 0.013). This association lost significance on multivariate analysis (adjusted OR 1.99, 95% CI 0.98-4.06, p = 0.056). CONCLUSION: Non-elective spine surgery performed 'after-hours' is independently associated with increased risk of perioperative adverse events, length of stay and possibly, mortality. Research is needed to determine the specific factors contributing to poorer outcomes with 'after-hours' surgery and strategies to minimize this risk. These slides can be retrieved under Electronic Supplementary Material. PMID- 30523461 TI - Contributions of birthweight, annualised weight gain and BMI to back pain in adults: a population-based co-twin control study of 2754 Australian twins. AB - PURPOSE: To investigate associations between anthropometric measures (birthweight, weight gain and current BMI) and back pain; and to determine whether these associations differ between those born with low or full birthweight. METHODS: The cross-sectional associations between the lifetime prevalence of back pain and anthropometric measures (birthweight, weight gain and current BMI) among 2754 adult twins were investigated in three stages: total sample; within-pair case-control for monozygotic and dizygotic twins together; and within-pair case-control analysis separated by dizygotic and monozygotic. Results were expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Birthweight was not associated with back pain (OR 0.99; 95% CI 0.99 1.00), but a weak association was found between weight gain (OR 1.01; CI 1.00 1.01) or current BMI (OR 1.02; 95% CI 1.00-1.05) and back pain in the total sample analysis. These associations did not remain significant after adjusting for genetics. The associations did not differ between those whose were born with low or full birthweight. CONCLUSION: Birthweight was not associated with prevalence of back pain in adulthood. Weight gain and current BMI were weakly associated with back pain prevalence in the total sample analysis but did not differ between those born with low or full birthweight. However, the small magnitude association only just achieved significance and appeared to be confounded by genetics and the early shared environment. Our results suggest that a direct link between these predictors and back pain in adults is unlikely. These slides can be retrieved under Electronic Supplementary Material. PMID- 30523462 TI - Clinical outcomes after lumbar spine microdiscectomy: a 5-year follow-up prospective study in 100 patients. AB - BACKGROUND: To evaluate the effect of lumbar microdiscectomy (LM) in pain, disability and quality of life in a 5-year period and to identify potential demographic and clinical risk factors. METHODS: One hundred patients who underwent LM by the same surgeon participated in this prospective study. Clinical assessment was made with validated questionnaires preoperatively and up to 5 years postoperatively. Subsequently, associations between clinical outcomes and demographic data were recorded. RESULTS: In every assessment questionnaire, there was a significant improvement in the first postoperative month, which lasted up to 1 year post-discectomy. After that, improvement was statistically significant (p < 0.05) but without clinical importance. Women reported more pain preoperatively and 1 month after surgery. Urban residents also presented more pain preoperatively. Older patients had more pain, disability and worse quality of life 1-5 years postoperatively. Similarly, patients with lower education presented the worst scores in every questionnaire at the same time. Smokers reported less pain 1.5-4 postoperative years. Higher alcohol consumption and obesity were associated with lower levels of preoperative pain. However, obese patients had worse SF-36 and ODI scores after the 6th postoperative month. Patients with heavy jobs presented the worst preoperative ODI scores. CONCLUSION: Significant clinical improvement was recorded from the first postoperative month to the first postoperative year; stabilization was noticed later on. Feminine gender, urban residency, older age, low level of education, obesity and heavy physical occupation were negative prognostic factors. Oddly smoking and alcohol were correlated with less pain. PMID- 30523463 TI - The effect on outcomes of the application of circumferential cerclage cable following intramedullary nailing in reverse intertrochanteric femoral fractures. AB - INTRODUCTION: The aim of this study was to evaluate the effect on union results of the application of cerclage cable around the lateral femoral wall (LFW) in postoperative fracture displacement. PATIENTS AND METHODS: A retrospective evaluation was made of all the cases of reverse intertrochanteric fractures over a 7-year period in a trauma center. The study included 69 fractures treated with intramedullary nailing. The age of the patients, postoperative reduction quality and complications such as mechanical failure and non-union (1.4%) were obtained from the medical records. Changes in the neck-shaft angle, the amount of LFW displacement and telescoping of proximal femoral nail antirotation blades and lag screws were measured on anteroposterior and lateral radiographs. The functional evaluation of the Harris Hip Score was recorded at the final follow-up examination. RESULTS: The mean age of the patients was 56.31 years (range 18-93 years). Closed reduction was applied in 37 (53.7%) cases, open reduction in 10 (14.5%) and with cerclage cable in 22 (31.8%). Mechanical failure developed in 8 (11.5%) cases where cerclage cable was not used. In 2 of these 8 cases, open reduction was successful. In the patients where cerclage cable was applied, no mechanical failure developed and no case underwent revision surgery. In the cases where cerclage cable was not used, a significantly higher rate of telescoping was found. (p = 0.001). The application of cerclage cable was seen to significantly reduce the amount of LFW displacement (2.23 mm vs 8.86 mm) and shorten the time to partial weight bearing (p = 0.000). CONCLUSION: In reverse intertrochanteric fractures, the application of circumferential cerclage cable with cephalomedullary nailing contributes to primary stability and accelerates mobilization. Therefore, it can be considered a good option. It reduces the risk of failure internal fixation for intertrochanteric fracture. PMID- 30523464 TI - Accelerated Ponseti technique: efficacy in the management of CTEV. AB - The current standard practice of treatment for congenital talipes equinus varus (CTEV) is the Ponseti method of manipulation and casting which requires great compliance by caregivers for casting as well as bracing. There is inconclusive evidence regarding optimal cast change interval. This was a prospective non randomized study conducted at a tertiary care hospital in South India over a 2 year period with a minimum follow-up of 5 years. The patients were divided into 2 groups, one with cast change interval of 7 days and the other group at 3 days. Children with CTEV with age less than 1 year with no previous intervention were included in the study. Functional score devised by Ponseti was determined at final follow-up. The average number of casts in standard and accelerated group was 5.23 +/- 0.59 and 4.72 +/- 0.61 (p < 0.01). The average number of days required for correction of feet was 54.38 +/- 8.01 and 33.88 +/- 9.03 (p < 0.01) respectively, for standard and accelerated groups. The Pirani score showed a faster reduction in the accelerated group. This study is the longest prospective study published yet in literature, comparing standard and accelerated Ponseti protocols. Complication rate noted in our study was comparable to study by Morcuende but higher than other studies comparing the techniques. It increases compliance as well as reducing treatment and travel costs for parents, more so in developing countries. At 5-year follow-up, there is no significant difference in the functional outcome. PMID- 30523465 TI - The learning curve following adoption of a novel short-stem prosthesis in total hip arthroplasty: implications on short-term patient outcomes. AB - BACKGROUND: Short-stem (SS) hip prostheses for total hip arthroplasty (THA) have gained popularity as surgeons strive to reproduce physiological stress distributions at the proximal femur. Additionally, as THA indications continue to target younger populations, preservation of femoral bone stock for potential revision surgeries is particularly appealing. However, little is known regarding the short-term complications of each variety of short stem during the learning curve period. The purpose of this study is to evaluate the short-term complications among the THA recipients with the use of a novel SS hip prosthesis. METHODS: A retrospective chart review was performed of all patients undergoing primary THA utilizing an Echo Bi-Metric Microplasty hip stem. Patient demographics, surgical factors, complications and quality outcomes were collected utilizing our institution's data warehouse and verified by chart review. RESULTS: In total, 182 SSs were implanted in 168 patients undergoing primary THA. Of these, 5 (2.9%) patients sustained a periprosthetic fracture. Two fractures occurred during the index hospital admission, and 3 occurred in the post discharge period. Subset analysis demonstrated that 4 (80%) fractures had occurred during the initial learning curve period, within the first 30 surgical cases with a SS. CONCLUSION: Short-stem hip prostheses are a safe alternative for THA. The results of the present study demonstrate a fracture incidence of 2.9% among patients. However, surgeons should remain cautious when utilizing new implant system and expect a learning curve. In this study, 80% of periprosthetic fractures following SS THA occurred within the first 30 cases for experienced arthroplasty-trained surgeons. PMID- 30523466 TI - Effect of Tissue Material Properties in Blast Loading: Coupled Experimentation and Finite Element Simulation. AB - Computational models of blast-induced traumatic brain injury (bTBI) require a robust definition of the material models of the brain. The mechanical constitutive models of these tissues are difficult to characterize, leading to a wide range of values reported in literature. Therefore, the sensitivity of the intracranial pressure (ICP) and maximum principal strain to variations in the material model of the brain was investigated through a combined computational and experimental approach. A finite element model of a rat was created to simulate a shock wave exposure, guided by the experimental measurements of rats subjected to shock loading conditions corresponding to that of mild traumatic brain injury in a field-validated shock tube. In the numerical model, the properties of the brain were parametrically varied. A comparison of the ICP measured at two locations revealed that experimental and simulated ICP were higher in the cerebellum (p < 0.0001), highlighting the significance of pressure sensor locations within the cranium. The ICP and strain were correlated with the long-term bulk (p < 0.0001) and shear moduli (p < 0.0001), with an 80 MPa effective bulk modulus value matching best with experimental measurements. In bTBI, the solution is sensitive to the brain material model, necessitating robust validation methods. PMID- 30523467 TI - Objective Evaluation of Whole Body Kinematics in a Simulated, Restrained Frontal Impact. AB - The use of human body models as an additional data point in the evaluation of human-machine interaction requires quantitative validation. In this study a validation of the Global Human Body Models Consortium (GHBMC) average male occupant model (M50-O v. 4.5) in a restrained frontal sled test environment is presented. For vehicle passengers, frontal crash remains the most common mode, and the most common source of fatalities. A total of 55-time history traces of reaction loads and kinematics from the model were evaluated against corresponding PMHS data (n = 5). Further, the model's sensitivity to the belt path was studied by replicating two documented PMHS cases with prominent lateral and medial belt paths respectively. Results were quantitatively evaluated using open source CORA software. A tradeoff was observed; better correlation scores were achieved on gross measures (e.g. reaction loads), whereas better corridor scores were achieved on localized measures (rib deflections), indicating that subject specificity may dominate the comparison at localized anatomical regions. On an overall basis, the CORA scores were 0.68, 0.66 and 0.60 for force, body kinematics and chest wall kinematics. Belt force responses received the highest grouped CORA score of 0.85. Head and sternum kinematics earning a 0.8 and 0.7 score respectively. The model demonstrated high sensitivity to belt path, resulting in a 20-point increase in CORA score when the belt was routed closer to analogous location of data collection. The human model demonstrated overall reasonable biofidelity and sensitivity to countermeasures in frontal crash kinematics. PMID- 30523468 TI - Significance of 18F-Fluorodeoxyglucose (FDG) Uptake in Response to Chemoradiotherapy for Pancreatic Cancer. AB - BACKGROUND: A metabolic shift to glycolysis is reportedly involved in radioresistance. We examined whether pretreatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), which can detect enhanced glucose uptake, was able to predict the therapeutic response to chemoradiotherapy (CRT) in patients with pancreatic cancer (PC). METHODS: Of 125 PC patients (75 unresectable and 50 borderline resectable), 37 and 26 underwent induction chemotherapy before CRT and surgical resection after CRT, respectively. FDG-PET was performed at three different institutions. RESULTS: Of the 88 patients who underwent upfront CRT, 31 (35%), 34 (39%), and 23 (26%) showed a partial response (PR), stable disease, and progressive disease, respectively. The tumor PR rate was an independent factor associated with longer overall survival (OS) on multivariate analysis. We evaluated the optimal cut-off of maximum standardized uptake values (SUVmax) at initial diagnosis to detect the tumor PR rate at the three institutions separately. The SUVmax was independently associated with tumor response rate on multivariate analysis. In the low SUVmax group, induction chemotherapy had no significant impact on OS. In contrast, induction chemotherapy was significantly associated with longer OS in the high SUVmax group. CONCLUSIONS: FDG-PET SUVmax was significantly associated with the therapeutic response to CRT in PC patients. Moreover, induction chemotherapy may improve the prognosis of patients with a high SUVmax tumor. PMID- 30523469 TI - ASO Author Reflections: Can the Association Between Obesity and Colorectal Cancer Be Explained by an Unfavorable Tumor Immune Microenvironment? PMID- 30523470 TI - Outcomes in Peritoneal Dissemination from Signet Ring Cell Carcinoma of the Appendix Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is standard treatment for peritoneal dissemination from appendiceal cancer (AC); however, its role in high-grade histopathologic subtypes (high-grade mucinous carcinoma peritonei [HGMCP] and HGMCP with signet ring cells [HGMCP-S]) is controversial due to their aggressive behavior. This study analyzed clinical outcomes of high-grade AC after CRS/HIPEC. METHODS: A prospective database of CRS/HIPEC procedures for HGMCP performed from 1998-2017 was reviewed. Perioperative variables and survival were analyzed. RESULTS: Eighty-six HGMCP and 65 HGMCP-S were identified. HGMCP had more positive tumor markers (TM) (CEA/CA 125/CA-19-9) than HGMCP-S (63% vs 40%, p = 0.005). HGMCP had higher Peritoneal Cancer Index (32 vs 26, p = 0.097) and was less likely to have positive lymph nodes (LN) than HGMCP-S (28% vs 69%, p = < 0.001). Complete cytoreduction was achieved in 84% and 83%, respectively. PFS at 3- and 5-years was 59% and 48% for HGMCP vs 31% and 14% for HGMCP-S. Median PFS was 4.3 and 1.6 years, respectively (p < 0.001). OS at 3- and 5-years was 84% and 64% in HGMCP vs 38% and 25% in HGMCP-S. Median OS was 7.5 and 2.2 years, respectively (p < 0.001). LN negative HGMCP-S had longer median PFS and OS than LN positive HGMCP-S (PFS: 3.4 vs 1.5 years, p = 0.03; OS: 5.6 vs 2.1 months, p = 0.021). CONCLUSIONS: The aggressive histology of HGMCP-S is associated with poor OS, has fewer abnormal TM, and is more likely to have positive LN. However, CRS/HIPEC can achieve a 5-year survival of 25%, which may improve to 51% with negative LN. PMID- 30523471 TI - Response to Commentaries. PMID- 30523472 TI - Relationships Among Sexual Identity, Sexual Attraction, and Sexual Behavior: Results from a Nationally Representative Probability Sample of Adults in the United States. AB - Sexual orientation is a multi-dimensional concept, at a minimum comprised of sexual identity, sexual attraction, and sexual behavior. Our study aimed to assess relationships among self-identified sexual identity, sexual attraction, and sexual behaviors in a probability sample of adults in the U.S. and to identify associated factors with diverse patterns. We collected data from adults in the 2015 National Survey of Sexual Health and Behavior, an Internet-based nationally representative probability survey of the general U.S. population. Concordance between sexual identity versus sexual attraction and sexual behaviors was assessed using percent agreement. We identified correlates of discordance using logistic regression. Concordance between sexual identity versus sexual attraction and past-year sexual behaviors was 94% and 96%, respectively, though our sample was predominately composed of heterosexual individuals. Women and sexual minority individuals reported greater discordance across sexuality-related measures than men and heterosexual individuals. Younger adults (aged 18-24 years) were more likely to report sexual behaviors discordant with sexual identity compared with older adults (including those ages 25-34 years). Higher levels of educational attainment were significantly associated with less discordance of reported recent sexual activity and sexual identity. Measures of sexual identity, attraction, and behaviors are not interchangeable. Future research should consider multiple sexuality-related measures in order to capture the complexity and variability of sexualities. PMID- 30523473 TI - Toward Women Wanting. PMID- 30523474 TI - Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma. AB - Background The pivotal RESORCE trial showed that regorafenib was effective as second-line therapy for patients with advanced HCC who progressed on first-line sorafenib. Real-world data are needed to assess clinical outcomes and adverse events in the setting of daily practice. Methods Between April 2017 and August 2017, the Named Patient Program (NPP) was activated to provide controlled, pre approval access of regorafenib in Korea. This analysis is a multicenter retrospective study of patients who received regorafenib under the NPP. Results A total of 49 patients entered into this NPP, and 40 patients received regorafenib in five Korean institutions. All but one patient received regorafenib as second line therapy after progression on sorafenib, and 36 (90%) and 34 (85%) patients were classified as Child-Pugh A and BCLC stage C, respectively. The response rate was 10% (n = 4). The median progression-free survival (PFS) was 3.7 months (95% CI, 2.5-4.9 months), and the median overall survival (OS) was not reached. The 1 year OS rate was 54.6%. The time-to-progression (TTP) on prior sorafenib was significantly associated with PFS and OS. The most common grade 3-4 toxicities were hand-foot skin reaction (n = 3, 8%), hypertension (n = 2, 5%), and increased aspartate aminotransferase (n = 2, 5%). Conclusion Regorafenib was well-tolerated and effective in patients with advanced HCC who progressed on first-line sorafenib, with efficacy and safety outcomes consistent with those of the previous RESORCE trial. TTP on first-line sorafenib may predict the efficacy of subsequent regorafenib. PMID- 30523475 TI - Cognitive and Emotional Profiles of CU Traits and Disruptive Behavior in Adolescence: a Prospective Study. AB - In this study we followed 82-90 adolescents, 50% boys, from 15 to 16 years, investigating CU traits and disruptive behaviors as predictors of cognitive skills and arousal to emotional pictures. At age 15, CU traits were rated by adolescents and disruptive (aggregated ADHD-ODD-delinquent) behaviors were rated by parents and adolescents. At age 16, executive function, reaction time variability (RTV), IQ and arousal to negative pictures were assessed. The results showed that, with control for disruptive behaviors, CU traits predicted lower RTV, higher IQ and lower arousal to negative pictures. With control for CU traits, disruptive behaviors predicted lower spatial working memory, lower interference control and higher RTV. Our findings are of theoretical and clinical relevance as they point to highly diverging cognitive and emotional profiles of CU traits and disruptive behaviors. PMID- 30523476 TI - Validity and reliability of the ten-item Connor-Davidson Resilience Scale (CD RISC10) instrument in patients with axial spondyloarthritis (axSpA) in Singapore. AB - We aimed to assess the validity and reliability of the ten-item Connor-Davidson Resilience Scale (CD-RISC10) in patients with axial spondyloarthritis (axSpA) in Singapore. We used cross-sectional data from 108 patients with axSpA recruited from a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2017 to 2018. Analyses were guided by the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework. Face validity was assessed through cognitive debriefing interviews (CDIs). Internal consistency was assessed through Cronbach's alpha. Test-retest reliability was assessed through intraclass correlation (ICC). Measurement error was assessed through smallest detectable change (SDC). Construct validity was assessed through six a priori hypotheses through correlation of the CD-RISC10 score with other patient-reported outcome measures. Structural validity was assessed using confirmatory factor analysis (CFA). Fit indices evaluated were root-mean-square error of approximation (RMSEA), comparative fit index (CFI), Tucker-Lewis index (TFI), and standardized root-mean-squared residual (SRMR). Ten patients completed the CDIs and face validity was supported. Among 108 patients (median age: 37(21-77), 81.5% males, 93.5% Chinese), the CD-RISC10 demonstrated good internal consistency (Cronbach's alpha = 0.94), and excellent test-retest reliability [ICC = 0.964 (95% CI 0.937 0.980)]. SDC was calculated as 1.88. Construct validity was established by meeting five out of the six a priori hypotheses. Structural validity was supported as CFA confirmed a one-factor model, with adequate fit statistics after adding three covariances (RMSEA = 0.077; CFI = 0.975; TLI = 0.964; SRMR = 0.036). This study supports the CD-RISC10 as a valid and reliable measure of resilience for use in patients with axSpA. PMID- 30523477 TI - Granuloma annulare development in a patient with rheumatoid arthritis treated with tocilizumab: case-based review. AB - Granuloma annulare (GA) is the most common non-infectious disease. Despite the fact that it is a benign disease, it can be associated with a variety of disorders and certain drugs including biological disease-modifying anti-rheumatic drugs (bDMARDs). A 50-year-old man with a history of rheumatoid arthritis refractory to methotrexate, hydroxychloroquine and infliximab was treated with tocilizumab (TCZ), an interleukin-6 receptor antagonist, 162 mg subcutaneously every week. The patient responded very well to TCZ treatment with a decrease of acute phase reactants and reduction of disease activity score for 28-joints count. However, 3 months later he developed erythematous polycyclic eruptions affecting the lower extremities consistent with a diagnosis of GA which was confirmed by a skin biopsy. TCZ has been discontinued and the patient was treated with prednisone presenting complete resolution of skin manifestations after 4 weeks. This is the first case of GA development during TCZ treatment. Thus, we review the literature and discuss the relevant cases of GA development in patients treated with bDMARDs. When dealing with patients treated with these agents, all physicians should be aware of possible adverse events and the potential development of such complications. PMID- 30523478 TI - Economic production and biocontrol efficiency of lipopeptide biosurfactants from Bacillus mojavenis A21. AB - In the wake of an increased attention on the eco-friendly biopesticidal products and the rising market requirements for organic agents, lipopeptides compounds have been described as biological control agents which improve the overall health growth and development of plants. Nevertheless, their high production cost constitue the major flaw in their wide use to control plant diseases. The present article aims to formulate an economic media for lipopeptides production by Bacillus mojavensis A21 for application as natural fungicides for plant disease treatment. We herein demonstrated the suitability of the potato waste, as low cost substrate, for lipopeptides production. Moreover, sea water was found to be a good mineral salts sources. In the second part of this study, we investigate the inhibitory activity of A21 lipopeptides against the phtopathogenic Fusarium sp. The in vitro test showed a minimal inhibitory concentration of about 0.3 mg/ml. The microscopic examination, of the treated Fusarium revealed an excessive lysis of the mycelia ultrastructure with destructed spores. The in vivo antagonist activity was confirmed towards the infected potato tubers. A21 lipopeptides are effective in decreasing by about 78.26% and 60.68% when applied as preventive and curative treatments, respectively, as compared to the untreated tubers. PMID- 30523479 TI - Atypicalities of Gesture Form and Function in Autistic Adults. AB - While well-represented on clinical measures, co-speech gesture production has never been formally studied in autistic adults. Twenty-one verbally fluent autistic adults and 21 typically developing controls engaged in a controlled conversational task. Group differences were observed in both semantic/pragmatic and motoric features of spontaneously produced co-speech gestures. Autistic adults prioritized different functions of co-speech gesture. Specifically, they used gesture more than controls to facilitate conversational turn-taking, demonstrating a novel nonverbal strategy for regulating conversational dynamics. Autistic adults were more likely to gesture unilaterally than bilaterally, a motoric feature of gesture that was individually associated with autism symptoms. Co-speech gestures may provide a link between nonverbal communication symptoms and known differences in motor performance in autism. PMID- 30523480 TI - A Comparison of Evoked and Non-evoked Functional Networks. AB - The growing interest in brain networks to study the brain's function in cognition and diseases has produced an increase in methods to extract these networks. Typically, each method yields a different network. Therefore, one may ask what the resulting networks represent. To address this issue we consider electrocorticography (ECoG) data where we compare three methods. We derive networks from on-going ECoG data using two traditional methods: cross-correlation (CC) and Granger causality (GC). Next, connectivity is probed actively using single pulse electrical stimulation (SPES). We compare the overlap in connectivity between these three methods as well as their ability to reveal well known anatomical connections in the language circuit. We find that strong connections in the CC network form more or less a subset of the SPES network. GC and SPES are related more weakly, although GC connections coincide more frequently with SPES connections compared to non-existing SPES connections. Connectivity between the two major hubs in the language circuit, Broca's and Wernicke's area, is only found in SPES networks. Our results are of interest for the use of patient-specific networks obtained from ECoG. In epilepsy research, such networks form the basis for methods that predict the effect of epilepsy surgery. For this application SPES networks are interesting as they disclose more physiological connections compared to CC and GC networks. PMID- 30523481 TI - Preparation, optimization and swelling study of carboxymethyl sago starch (CMSS) acid hydrogel. AB - In this study, sago starch was modified in order to enhance its physicochemical properties. Carboxymethylation was used to introduce a carboxymethyl group into a starch compound. The carboxymethyl sago starch (CMSS) was used to prepare smart hydrogel by adding acetic acid into the CMSS powder as the crosslinking agent. The degree of substitution of the CMSS obtained was 0.6410. The optimization was based on the gel content and degree of swelling of the hydrogel. In this research, four parameters were studied in order to optimize the formation of CMSS acid hydrogel. The parameters were; CMSS concentration, acetic acid concentration, reaction time and reaction temperature. From the data analyzed, 76.69% of optimum gel content was obtained with 33.77 g/g of degree of swelling. Other than that, the swelling properties of CMSS-acid hydrogel in different media such as salt solution, different pH of phosphate buffer saline solution as well as acidic and alkaline solution were also investigated. The results showed that the CMSS-acid hydrogel swelled in both alkaline and salt solution, while in acidic or low pH solution, it tended to shrink and deswell. The production of the hydrogel as a smart material offers a lot of auspicious benefits in the future especially related to swelling behaviour and properties of the hydrogel in different types of media. PMID- 30523482 TI - Microbiome: An Emerging New Frontier in Graft-Versus-Host Disease. AB - Hematopoietic cell transplantation is an intensive therapy used to treat high risk hematological malignant disorders and other life-threatening hematological and genetic diseases. Graft-versus-host disease (GVHD) presents a barrier to its wider application. A conditioning regimen and medications given to patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) are capable of disturbing the homeostatic crosstalk between the microbiome and the host immune system and of leading to dysbiosis. Intestinal inflammation in the context of GVHD is associated with loss in microbial diversity that could serve as an independent predictor of mortality. Successful gastrointestinal decontamination using high doses of non-absorbable antibiotics likely affect allo HCT outcomes leading to significantly less acute GVHD (aGVHD). Butyrate-producing Clostridia directly result in the increased presence of regulatory T cells in the gut, which are protective in GVHD development. Beyond the microbiome, Candida, a member of the mycobiome, colonization in the gut has been considered as a risk factor in pathophysiology of aGVHD and reduction in GVHD is observed with antifungal prophylaxis with fluconazole. Reduced number of goblet cells and Paneth cells have been shown to associate with GVHD and has a significant impact on the micro- and mycobiome density and their composition. Lower levels of 3 indoxyl sulfate at initial stages after allo-HCT are related with worse GVHD outcomes and increased mortality. Increased understanding of the vital role of the gut microbiome in GVHD can give directions to move the field towards the development of improved innovative approaches for preventing or treating GVHD following allo-HCT. PMID- 30523483 TI - How Dye May Prevent Dying from Cancer: Perceiving Imperceptible Dysplasia in Inflammatory Bowel Disease. PMID- 30523484 TI - Prenatal Substance Use and Perceptions of Parent and Partner Use Using the 4P's Plus Screener. AB - Background Prenatal substance use screening is recommended. The 4 P's Plus screener includes questions on perceived problematic substance use in parents and partner that are not considered in risk stratification. Objectives This research examined the: (1) prevalence of self-reported problematic parental and partner substance use and associations with biochemically-verified prenatal substance use; (2) utility of self-reported perceptions of parent/partner substance use as proxies for prenatal substance use; and (3) degree to which the sensitivity of the 4P's Plus can be augmented with consideration of parent/partner questions in risk stratification. Methods A convenience sample of 500 pregnant women was recruited between January 2017 and January 2018. Participants completed the 4P's Plus and provided urine for drug testing. Diagnostic utility of problematic parent/partner substance use questions was assessed, then compared to the 4P's Plus used as designed, and to the 4P's Plus used with these 2 questions included in risk stratification. Results Half (51%) of respondents reported either partner or parental problematic substance use. When partner or parent problematic substance use were considered as proxies for prenatal substance use, sensitivity was 65% and specificity was 55%. When used as intended, sensitivity was 94% and specificity was 29%. Including partner/parent questions increased sensitivity to 96% but lowered specificity (19%). Partner substance use and combined partner/parent use were associated with prenatal substance use [adjusted odds ratio (aOR): 2.0 (1.2, 2.4; p = 0.006); aOR = 1.6 (1.1, 2.5, p = 0.04)]. Conclusions for Practice Sensitivity of the 4P's Plus may improve with inclusion of self-reported problematic partner/parent substance use items in risk stratification. PMID- 30523485 TI - The Impact of Fasting on the Psychological Well-Being of Muslim Graduate Students. AB - The main objective of this research was to evaluate the impact of fasting on the psychological well-being of Muslim graduate students. In a single-group pretest posttest research design, students who intended to fast in the month of Ramadan were asked to respond to a psychological well-being scale and its subscales before and after the end of fasting month of Ramadan. Findings show that fasting led to the promotion of overall psychological well-being, self-acceptance, autonomy, positive relations, environmental mastery, and personal growth among students who fasted in this month. PMID- 30523486 TI - The Evolution of Spirituality, Religion and Health Publications: Yesterday, Today and Tomorrow. AB - This research aims to present a bibliometric analysis of the published documents on spirituality, religion and health. Despite the increasing number of publications spirituality, religion and health research in recent years, there is still little information about the effects of these publications in the literature. "Religion," "spirituality," "spiritual," "health" and "medicine" keywords were used to search the Web of Science (WoS) database. Bibliometric analysis was conducted on the articles published between 1975 and 2017. The analysis was presented with network and density maps. The analysis also included the regression analysis to predict a number of publications in 2018. A total number of 1674 publications were found: 818 of these publications were articles. Of the 818 articles, 210 were religion, 198 were Public Environmental Occupational Health, 139 were Psychology, and 77 were performed in the field of Psychiatry. The most productive journal with 107 articles and 1129 citations was the Journal of Religion and Health. The USA (495; 60.5%) was the most productive country on spirituality, religion and health publications. The author who had the highest number of publications and citations was Koenig HG (33 publications; 4.03% and 1617 citations), the document who had the highest number of citations was Ellison CG and Levin JS (633 citations), and the author who had the highest number of citations in the references was Koenig HG, 2001, (126 citations). Duke Univ was the top institution in the number of publication (50 Article). This study will lead the researchers especially in terms of the important journals, active countries, authors, top-cited articles and current topics in spirituality, religion and health research. PMID- 30523487 TI - Creation of Straight-Chain Cationic Polysaccharide-Based Bile Salt Sequestrants Made from Euglenoid beta-1,3-Glucan as Potential Antidiabetic Agents. AB - PURPOSE: Straight-chain polysaccharides have a greater potential of selectively adsorbing hydrophobic bile salts than resin-based bile salt sequesters because of ionic and hydrophobic interactions; hence, they may possess antidiabetic activity. The feasibility of using cationic polysaccharides made from euglenoid beta-1,3-glucan (referred to as paramylon) as potential antidiabetic agents was examined by using in vitro and animal experiments. METHODS: Cationic straight chain polysaccharides were synthesized from euglenoid polysaccharide and glycidyltrimethylammonium chloride. The effects of administration of the synthetic polysaccharide on metabolic syndrome-related indicators were examined in high-fat diet-induced obesity mice. The degree of adsorption of bile salts by the polysaccharides was evaluated using spectroscopic analysis. RESULTS: Administration of the cationic paramylon derivatives significantly reduced body and mesenteric fat weight in high-fat diet-induced obesity mice. A noteworthy effect was that glucagon-like peptide-1 (GLP-1) secretion was approximately three times higher in diet-induced obesity mice receiving cationic paramylon derivatives than in those receiving cellulose as a control. CONCLUSIONS: Our results indicate that these cationic paramylon derivatives are potential GLP-1 secretagogues suitable for further study. PMID- 30523488 TI - Dopamine receptor density and white mater integrity: 18F-fallypride positron emission tomography and diffusion tensor imaging study in healthy and schizophrenia subjects. AB - Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and 18F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D2/D3 receptor density and white matter fractional anisotropy in each diagnostic group. AFNI regions of interest were acquired for 42 cortical Brodmann areas and subcortical gray matter structures as well as stereotaxically placed in representative white matter areas implicated in schizophrenia neuroimaging literature. Welch's t-test with permutation-based p value adjustment was used to compare means of z-transformed correlations between fractional anisotropy and 18F fallypride binding potentials in hypothesis-driven regions of interest in the diagnostic groups. Healthy subjects displayed an extensive pattern of predominantly negative correlations between 18F-fallypride binding across a range of cortical and subcortical gray matter regions and fractional anisotropy in rostral white matter regions (internal capsule, frontal lobe, anterior corpus callosum). These patterns were disrupted in subjects with schizophrenia, who displayed significantly weaker overall correlations as well as comparatively scant numbers of significant correlations with the internal capsule and frontal (but not temporal) white matter, especially for dopamine receptor density in thalamic nuclei. Dopamine D2/D3 receptor density and white matter integrity appear to be interrelated, and their decreases in schizophrenia may stem from hyperdopaminergia with dysregulation of dopaminergic impact on axonal myelination. PMID- 30523490 TI - ART Denial: Results of a Home-Based Study to Validate Self-reported Antiretroviral Use in Rural South Africa. AB - There is increasing interest in home based testing and treatment of HIV to expand access to treatment in sub-Saharan Africa. Such programs rely on self-reported HIV history and use of antiretroviral therapy (ART). However, the accuracy of self-reported ART use in community settings is not well described. In this study, we compared self-reported ART (SR-ART) use in a home based survey against biological exposure to ART (BE-ART), in a population study of older adults in South Africa. Health and Aging in Africa: a Longitudinal Study of an INDEPTH community in South Africa (HAALSI) is a cohort of adults aged 40 +. The baseline home-based interview included self-reported HIV status and ART use. All participants also underwent biological testing for HIV antibodies, viral load and exposure to emtricitabine (FTC) or lamivudine (3TC), which are included in all first-line and second-line ART regimens in the public-sector South African HIV program. We calculated the performance characteristics for SR-ART compared to BE ART and fit multivariable logistic regression models to identify correlates of invalid SR-ART responses. Of 4560 HAALSI participants with a valid HIV test result available, 1048 (23%) were HIV-positive and 734 [70% of people living with HIV (PLWH)] were biologically validated ART users (BE-ART). The sensitivity of SR ART use was 64% (95% CI 61-68%) and the specificity was 94% (95% CI 91-96%); the positive predictive value (PPV) was 96% (95% CI 94-98%) and negative predictive value (NPV) was 52% (95% CI 48-56%). We found no sociodemographic predictors of accurate SR-ART use. Over one in three individuals with detectable ART in their blood denied current ART use during a home-based interview. These results demonstrate ongoing stigma related to HIV and its treatment, and have important implications for community health worker programs, clinical programs, and research studies planning community-based ART initiation in the region. PMID- 30523491 TI - Onboard experiment investigating metal leaching of fresh hydrothermal sulfide cores into seawater. AB - We observed the initial release rate of metals from four fresh (i.e., without long time exposure to the atmosphere) hydrothermal sulfide cores into artificial seawater. The sulfide samples were collected by seafloor drilling from the Okinawa Trough by D/V Chikyu, powdered under inert gas, and immediately subjected to onboard metal-leaching experiments at different temperatures (5 degrees C and 20 degrees C), and under different redox conditions (oxic and anoxic), for 1-30 h. Zinc and Pb were preferentially released from sulfide samples containing various metals (i.e., Mn, Fe, Cu, Zn, Cd, and Pb) into seawater. Under oxic experimental conditions, Zn and Pb dissolution rates from two sulfide samples composed mainly of iron disulfide minerals (pyrite and marcasite) were higher than those from two other sulfide samples with abundant sphalerite, galena, and/or silicate minerals. Scanning electron microscopy confirmed that the high metal-releasing sample contained several galvanic couples of iron disulfide with other sulfide minerals, whereas the low metal-releasing sample contained fewer galvanic couples or were coated by a silicate mineral. The experiments overall confirmed that the galvanic effects with iron disulfide minerals greatly induce the initial release of Zn and Pb from hydrothermal sulfides into seawater, especially under warm oxic conditions. PMID- 30523489 TI - Predictors of Daily Adherence to HIV Pre-exposure Prophylaxis in Gay/Bisexual Men in the PRELUDE Demonstration Project. AB - Adequate adherence to pre-exposure prophylaxis (PrEP) is critical to prevent HIV infection, but accurately measuring adherence remains challenging. We compared two biological [blood drug concentrations in plasma and peripheral blood mononuclear cells (PBMC)] and two self-reported measures (facilitated recall to clinicians and self-report in online surveys) and identified predictors of daily PrEP adherence among gay and bisexual men (GBM) in their first 12 months on PRELUDE, an open-label, single-arm PrEP demonstration project in New South Wales, Australia. 327 participants were enrolled; 263 GBM attended their 12-month follow up visit (81% retention). Overall, 91% of blood samples had plasma drug concentrations indicative of taking 7 pills/week, and 99% had protective drug concentrations (>= 4 pills/week). Facilitated recall to clinicians identified 99% of participants with protective adherence as measured by PBMC drug concentrations. Daily adherence measured by facilitated recall was associated with behavioural practices including group sex (aOR 1.33, 95% CI 1.15-1.53, p < 0.001). Retained participants maintained high adherence to daily PrEP over 12 months, confirmed by four different measures. Facilitated recall to clinicians is a suitable measure for assessing PrEP adherence in populations engaged in care where there is established trust and rapport with patients. Trial registration: ClinicalTrials.gov NCT02206555. PMID- 30523492 TI - Cardiac tamponade caused by acute coxsackievirus infection related pericarditis complicated by aortic stenosis in a hemodialysis patient: a case report. AB - BACKGROUND: Pericardial effusion is observed in the majority of viral pericarditis cases; however, viral pericarditis accompanied by a large effusion resulting in cardiac tamponade is rare. CASE PRESENTATION: Here, we report the case of a 75-year-old hemodialysis patient with acute viral pericarditis complicated by aortic stenosis. The patient was referred with a diagnosis of aortic stenosis and pericardial effusion. The pericardial effusion had increased during the preoperative examinations, and the inflammatory reaction had progressed. We decided to abort the surgical intervention and start oral administration of anti-inflammatory agents. We subsequently performed a pericardiocentesis. High antibody titers to coxsackievirus were noted in the pericardial effusion. Since no recurrence of the pericardial effusion was observed, the patient underwent an aortic valve replacement 2 months later. The pericardium completely adhered to the heart. Pathological examination of the pericardium showed fibrous pericarditis without active inflammation. CONCLUSIONS: Here, we successfully treated a hemodialysis case with severe aortic stenosis complicated by cardiac tamponade and worsened by acute viral pericarditis. We waited for the pericarditis to resolve after administering anti-inflammatory agents and performed pericardial drainage before carrying out aortic valve replacement. The perioperative course of our case was unique and suggestive. PMID- 30523493 TI - Immunohistochemical detection of ALK protein identifies APC mutated medulloblastoma and differentiates the WNT-activated medulloblastoma from other types of posterior fossa childhood tumors. AB - Expression of the ALK gene strongly correlates with the WNT-activated medulloblastomas, which are routinely identified by detection of CTNNB1 mutation. However, some tumors have mutations in other than CTNNB1 genes. Therefore, we investigated if ALK expression may identify WNT-activated tumors without CTNNB1 mutation. In addition, we examined if ALK expression may differentiate WNT activated medulloblastoma from other malignant posterior fossa tumors. ALK expression was analyzed using immunohistochemistry (clone D5F3) in 70 patients with posterior fossa tumours. Among 55 medulloblastomas, 6 tumors showed ALK expression in > 50% of tumor cells. In one tumor, with ALK positive reaction, negative nuclear reaction against beta-catenin and the lack of CTNNB1 mutation, next generation sequencing revealed a presence of pathogenic variant c.3366_3369del in the APC gene, with homozygous deletion leading to inactivation of both copies in tumor cells. MLPA analysis displayed the presence of chromosome 6 monosomy, therefore, confirming the WNT type of this tumor. All analyzed 19 anaplastic ependymomas, 4 choroid plexus carcinomas and 2 atypical teratoid rhabdoid tumors were immunonegative for ALK expression. Therefore, we propose, that immunohistochemical detection of ALK protein should be highly recommended in routine investigation, in parallel to already established methods for identification and differentiation of WNT-activated medulloblastoma. PMID- 30523494 TI - Chronic kidney disease in low-middle income populations: a call to action for screening and prevention. PMID- 30523495 TI - Triggering agents and microbiome as environmental factors on Behcet's syndrome. AB - Environmental and other triggering factors are suggested to cause the onset and the clinical relapses of Behcet's syndrome (BS), a multi-systemic inflammatory disorder. In this review, environmental factors are discussed according to their interactions with etiopathogenesis, immune response and disease activity. Stress is a common self-triggering factor for most BS patients. Stimuli such as some foods can activate oral ulcers, and may be linked to the histamine content of the food. Oral/skin trauma and menstruation associated with hormonal factors aggravate, whereas allergy/atopy seem to alleviate the symptoms of BS. Infections are associated with BS, and microbial stimuli can activate inflammation in mucosal surfaces with increased Th1/Th17 responses. Fecal and oral microbiome patterns change in diversity and composition in BS. Better oral hygiene applications and anti-microbial interventions might be helpful to suppress oral ulcers in BS. PMID- 30523496 TI - An uncommon cause of acute flank pain: renal infarction. PMID- 30523497 TI - A young male with progressive dyspnea: Ebstein's anomaly. PMID- 30523498 TI - Cobalt Administration Causes Reduced Contractility with Parallel Increases in TRPC6 and TRPM7 Transporter Protein Expression in Adult Rat Hearts. AB - Exposure to circulating cobalt (Co2+) in patients with metal-on-metal orthopaedic hip implants has been linked to cardiotoxicity but the underlying mechanism(s) remain undefined. The aim of the current study was to examine the effects of Co2+ on the heart in vivo and specifically on cardiac fibroblasts in vitro. Adult male rats were treated with CoCl2 (1 mg/kg) for either 7 days or 28 days. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure Co2+ uptake into various organs of the body. Co2+ accumulated in the heart over time with significant levels evident after only 7 days of treatment. There was no evidence of cardiac remodelling following Co2+ treatment as assessed by heart weight:body weight and left ventricular weight:body weight. However, a decrease in fractional shortening, as measured using echocardiography, was observed after 28 days of Co2+ treatment. This was accompanied by increased protein expression of the ion transient receptor potential (TRP) channels TRPC6 and TRPM7 as assessed by quantitative immunoblotting of whole cardiac homogenates. Uptake of Co2+ specifically into rat cardiac fibroblasts was measured over 72 h and was shown to dramatically increase with increasing concentrations of applied CoCl2. Expression levels of TRPC6 and TRPM7 proteins were both significantly elevated in these cells following Co2+ treatment. In conclusion, Co2+ rapidly accumulates to significant levels in the heart causing compromised contractility in the absence of any overt cardiac remodelling. TRPC6 and TRPM7 expression levels are significantly altered in the heart following Co2+ treatment and this may contribute to the Co2+-induced cardiotoxicity observed over time. PMID- 30523499 TI - Potential value of the PixelShine deep learning algorithm for increasing quality of 70 kVp+ASiR-V reconstruction pelvic arterial phase CT images. AB - OBJECTIVE: To investigate the effect of a deep learning-based denoising algorithm, PixelShine (PS), on the quality of 70 kVp pelvic arterial phase CT images. MATERIALS AND METHODS: A retrospective analysis was performed on arterial phase pelvic CT images from 33 patients (body-mass index <= 20 kg/m2) obtained with a GE Revolution CT (70 kVp tube voltage; adaptive statistical iterative reconstruction-Veo-filtered back projection, 50% blending) and designated group A. Group B images were then obtained by applying PS to group A image datasets. Subjective image quality was evaluated by two radiologists with a 5-point scoring system; the scores of the groups were compared. Image signal was assessed using CT values of the urinary bladder. CT and standard deviation (SD) values of the gluteus maximus were measured, and SD values of the gluteus maximus were used to represent image noise. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the bladder were calculated. Image noise, SNR, and CNR of two groups were compared using paired t-tests. RESULTS: The subjective visual image quality scores of groups A and B, respectively, were 3.11 +/- 0.30 vs. 3.82 +/- 0.57; image noise was 15.79 +/- 2.05 Hounsfield units (HU) vs. 11.06 +/- 2.22 HU; SNRs of bladder were 0.50 +/- 0.23 vs. 0.79 +/- 0.39; and CNRs of bladder were 3.72 +/- 0.85 vs. 5.14 +/- 1.27. Group B showed better subjective image quality, lower image noise, and improved SNR and CNR, compared to group A; these differences were statistically significant (P < 0.05). The noise of group B was approximately 30% lower than that of group A; the SNR and CNR values of group B were improved by approximately 58% and 38%, respectively. CONCLUSION: Using 70 kVp +ASiR-V, PS can improve the image quality of pelvic arterial phase CT images, significantly reduce the image noise, and improve the SNR and CNR. PMID- 30523500 TI - Expression of Insulinoma-Associated Protein 1 (INSM1) and Orthopedia Homeobox (OTP) in Tumors with Neuroendocrine Differentiation at Rare Sites. AB - Insulinoma-associated protein 1 (INSM1) and orthopedia homeobox (OTP) are transcription factors that play a critical role in neuroendocrine (NE) and neuroepithelial cell development. INSM1 has been identified in multiple tumors of NE or neuroepithelial origin, whereas OTP expression has been mainly studied in NE tumors of pulmonary origin. Expression of OTP appears to correlate with poorer prognosis in pulmonary carcinoids; however, its expression patterns in other NE/neuroepithelial tumors need further investigation. Here, we assessed the diagnostic utility of INSM1 and OTP in tumors with NE differentiation at relatively uncommon sites including prostate, breast, and tumors of gynecologic origin. Thirty-two formalin-fixed, paraffin-embedded cases were used to construct a tissue microarray. Immunohistochemistry for INSM1 and OTP was performed and scored semi-quantitatively. INSM1 was diffusely expressed in 60% of gynecologic tumors, 71.4% of mammary carcinoma, and 25% of prostate adenocarcinoma with NE differentiation. Diffuse expression of OTP was detected in 50% of prostate adenocarcinoma with NE differentiation and 100% neuroendocrine carcinoma of the ovary. Immunostain for achaete-scute homolog 1, chromogranin, synaptophysin, and CD56 supported the NE and/or neuroepithelial differentiation of the tumors. In summary, INSM1 is expressed in most of the tumors with NE and neuroepithelial differentiation in this study, confirming the diagnostic utility of INSM1 as a novel and sensitive marker of NE/neuroepithelial differentiation. The expression of OTP in some NE tumors outside of lung expands the spectrum of tumors that may express this biomarker and should be considered when working up a NE tumor of unknown primary site. PMID- 30523501 TI - Lead poisoning as final diagnosis in a study of normocytic anemia. PMID- 30523502 TI - Robot-assisted stereotactic brainstem biopsy in children: prospective cohort study. AB - Tumours located within the brainstem comprise approximately a tenth of all paediatric brain tumours. Surgical biopsy of these tumours is technically challenging and has historically been associated with considerable risk. To this end, robot-assisted surgery theoretically allows for increased accuracy and precision. In this study we report our experience using the Neuromate robot (Renishaw, Gloucestershire, UK) to perform robot-assisted stereotactic biopsy in children with tumours located within the brainstem. An uncontrolled prospective cohort study was performed (phase II) according to the IDEAL model for safe surgical innovation. All cases were recorded on a prospectively maintained database. The database was searched over a 2-year period between the 1st December 2015 and the 31st November 2017 to identify all children with brainstem tumours that underwent robot-assisted stereotactic brain biopsy. When accessible, the post-operative MRI scans and pre-operative plans were compared to assess the target point localisation error (TPLE). Adverse events were recorded prospectively according to whether they resulted in increased hospital stay, caused neurological injury, or lead to death. In all, 11 consecutive children were identified with brain tumours located within the brainstem. In 10/11 cases specimens were diagnostic; in the remaining case a further biopsy was successful. The most frequent pathology was DIPG (7/15). Seven patients underwent an early post-operative volumetric MRI; the calculated median TPLE was 2.7 mm (range 0.5 4.2 mm). There were no surgical complications noted. Robot-assisted stereotactic biopsy in children appears to be feasible and safe. Research databases and comparative studies are warranted to further assess the technique. PMID- 30523503 TI - Social support buffers the negative effects of stress in cardiac patients: a cross-sectional study with acute coronary syndrome patients. AB - Cardiac patients who have social support generally have better prognosis than patients who lack social support. Several theoretical mechanisms have been proposed to explain this protective effect, including the capacity of social support to buffer the negative effects of stress. We tested this buffering effect in a study of patients hospitalized for acute coronary syndrome (ACS) in Spain. Several days after the cardiac event patients answered a questionnaire measuring stressful events during their lifetime, perceived social support around the time of the cardiac event, and depression symptoms in the past week. Results showed that stressful life events were related to depressive symptoms and worse renal function post-ACS only among patients with low perceived social support. Among patients who reported enough social support, lifetime stress was not related to depressive symptoms. No similar effects were observed on other prognostic indicators such as troponin levels or the number of obstructed arteries. These results suggest that social support can buffer the negative effects of stress on the mental and physical well-being of cardiac patients. PMID- 30523504 TI - Do ultraviolet photos increase sun safe behavior expectations via fear? A randomized controlled trial in a sample of U.S. adults. AB - Ultraviolet (UV) photos reveal the world in a different light spectrum, including damage that is caused by UV light. In the context of skin cancer control, UV photos have the potential to communicate fear because they reveal underlying skin damage. U.S. adults (N = 2219) were assigned to a 5 (visual: UV skin damage, sun exposure, sunburn, photoaging, and mole removal) * 3 (replication: three examples of each visual condition) * 4 (efficacy: no efficacy, text only, visual, visual + text) randomized controlled trial. Compared to all other visual conditions combined, UV skin damage visuals generated greater fear which triggered increased sun safe behavior expectations. Compared with other visual conditions separately, only mole removal visuals produced equivalent fear as UV skin damage visuals. Visual efficacy conditions appeared to nullify rather than magnify the indirect path through fear. The results suggest one way UV images impact sun safe behavioral expectations is via fear and that researchers should continue to examine the position of fear in fear appeal theories. PMID- 30523505 TI - Propagation of Extrinsic Fluctuations in Biochemical Birth-Death Processes. AB - Biochemical reactions are often subject to a complex fluctuating environment, which means that the corresponding reaction rates may themselves be time-varying and stochastic. If the environmental noise is common to a population of downstream processes, then the resulting rate fluctuations will induce statistical correlations between them. In this paper we investigate how such correlations depend on the form of environmental noise by considering a simple birth-death process with dynamical disorder in the birth rate. In particular, we derive expressions for the second-order statistics of two birth-death processes evolving in the same noisy environment. We find that these statistics not only depend on the second-order statistics of the environment, but the full generator of the process describing it, thus providing useful information about the environment. We illustrate our theory by considering applications to stochastic gene transcription and cell sensing. PMID- 30523506 TI - Lost in Datafication? - A Typology of (Emotion) Data Contextualization. AB - This article elaborates on the meaning of "context" for data created in interdisciplinary research on emotions. Particularly with regard to the potential reuse of scientific data, the elicitation of contexts can contribute to a better assessment of emotion data. Beyond a discussion of social scientific conceptualizations of "context" focusing on the situational and cultural contexts and their respective interrelations, this article presents the findings of an empirical study on datafication processes in interdisciplinary emotion research. Based on 123 survey responses and 15 in-depth interviews, a multitude of contextual dimensions will be reviewed. The typology of contexts, ranging from method-specific aspects and researchers' subjectivities to the contextual embeddedness of the research objects, provides a schema suitable for various epistemological approaches. The proposed typology can serve as a framework for emotion researchers to reflect on their research practice and interactions with research participants. The empirical findings also show the limitations of contextualization pertaining to tacit knowledge, implicit knowledge, embodied emotions and ethical considerations. The article concludes with suggestions for further research, pointing to intercultural settings, the integration of contexts and particular scenarios for data reuse. PMID- 30523507 TI - PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor resistant KIT-mutant xenograft models of gastrointestinal stromal tumors. AB - The purpose of the present study was to investigate the in vitro and in vivo activity of PLX9486, a tyrosine kinase inhibitor (TKI) targeting both primary KIT exon 9 and 11 and secondary exon 17 and 18 mutations in gastrointestinal stromal tumors (GISTs). Imatinib, a potent inhibitor of mutated KIT, has revolutionized the clinical management of advanced, metastatic GIST. However, secondary resistance develops mainly through acquired mutations in KIT exons 13/14 or exons 17/18. Second-line sunitinib potently inhibits KIT exon 13/14 mutants but is ineffective against exon 17 mutations. In our study, PLX9486 demonstrated in vitro nanomolar potency in inhibiting the growth and KIT phosphorylation of engineered BaF3 cells transformed with KIT exon 17 mutations (p.D816V) and with the double KIT exon 11/17 mutations (p.V560G/D816V). The in vivo efficacy of PLX9486 was evaluated using two imatinib-resistant GIST patient-derived xenograft (PDX) models. In UZLX-GIST9 (KIT: p.P577del;W557LfsX5;D820G), PLX9486 100 mg/kg/day resulted in significant inhibition of proliferation. Pharmacodynamic analysis showed a pronounced reduction in mitogen-activated protein kinase (MAPK) activation and other downstream effects of the KIT signaling pathway but no significant effect on KIT Y703 and Y719 phosphorylation. Similarly, in MRL-GIST1 (KIT: p.W557_K558del;Y823D) PLX9486 treatment led to significant tumor regression and strong inhibition of MAPK activation. Interestingly, the inhibitory effect on MAPK activation was evident even after a single dose of PLX9486. In conclusion, PLX9486 showed anti-tumor efficacy in patient-derived imatinib-resistant GIST xenograft models, mainly through inhibition of KIT signaling. These preclinical efficacy data encourage further testing of PLX9486 in the clinical setting. PMID- 30523508 TI - How the Comprehensive Cancer Control National Partnership shapes the public health workforce. AB - This paper explores how, through its extensive network of partners, the Comprehensive Cancer Control National Partnership (National Partnership) has provided a robust array of trainings, learning institutes, webinars, workshops, mentorship programs, and direct technical assistance to comprehensive cancer control programs and coalitions over the past 20 years. Mapping these activities to specific cancer control competencies revealed that the efforts of the National Partnership adequately address the core competencies necessary for an effective workforce and have the potential to increase practitioner capacity to adopt and implement evidence-based cancer control programs. Ensuring the continued availability and uptake of these tools, trainings and partnerships could potentially address gaps and barriers in the public health workforce related to evidence-based practice. PMID- 30523509 TI - Interplay between exercise and BMI; results from an equal access, racially diverse biopsy study. AB - PURPOSE: It is unclear if exercise and BMI interact to influence prostate cancer (PC) risk. We hypothesized BMI is linked with increased aggressive PC risk but this link will be attenuated with increased exercise. METHODS: Men undergoing prostate biopsy completed a questionnaire and metabolic equivalent (MET) hours of exercise was calculated. Of 695 men, 349 had PC; 161 low-grade, and 188 high grade. We assessed the link between exercise and PC risk, high-grade PC (Gleason 7-10), and low-grade PC (Gleason 2-6) using logistic and multinomial logistic regression. Analysis was stratified by BMI. Link between BMI and PC risk and aggressive PC was similarly tested. RESULTS: On multivariable analysis, there was no link between exercise and PC diagnosis in the entire cohort (p trend = 0.18 0.71) or across BMI groups (p trend = 0.15-0.97). For the entire cohort, higher BMI was linked with increased risk of high-grade PC (OR 1.06, p = 0.008). When stratified by exercise groups, the trend for higher BMI and increased risk of high-grade PC remained (OR 1.03-1.15, p = 0.02-0.66). There were no interactions between exercise and BMI in predicting PC risk (all p >= 0.31). CONCLUSIONS: Regardless of exercise, higher BMI was linked with higher risk of aggressive PC, while exercise was unrelated to PC risk. Confirmatory studies are needed. PMID- 30523510 TI - Non-Keratinizing Nasopharyngeal Carcinoma with Adenomatous Differentiation. AB - A case of non-keratinizing, EBV-positive (EBER-in situ hybridization), carcinoma with adenomatous differentiation is presented. The patient is a 40 year old male with T2N2M0 disease who received standard combined chemo- and radiotherapy with complete resolution of all tumor. The tumor cells were strongly positive for low molecular weight cytokeratins (AE1-3) and scattered cells expressed cytokeratin 20. No expression of cytokeratin 5/6, 7, p63, TTF-1, CDX2 or androgen receptor was detected. There was no evidence of recurrence or disease progression on follow-up after 19 months, which included post treatment MRI and PET-CT scans. PMID- 30523511 TI - Single-brand dual-chamber discriminators to prevent inappropriate shocks in patients implanted with prophylactic implantable cardioverter defibrillators: a propensity-weighted comparison of single- and dual-chamber devices. AB - PURPOSE: Comparisons of the efficacy of dual- vs. single-chamber implantable cardioverter defibrillators (ICDs) in preventing inappropriate shocks have had contradictory results. We investigated whether dual-chamber devices have a lower risk of inappropriate shocks and the specific role of supraventricular tachycardia (SVT) discriminators. METHODS: All heart failure (HF) patients without an indication for pacing and implanted with a prophylactic ICD were recruited from the nationwide multicenter UMBRELLA registry. Arrhythmic events were collected by remote monitoring and reviewed by a committee of experts. RESULTS: Among 782 patients, single-chamber ICDs were implanted in 537 (68.7%) and dual-chamber devices in 245 (31.3%). During a mean follow-up of 52.2 +/- 24.5 months, 109 inappropriate shocks were delivered in 49 patients (6.2%). In the propensity-score-matched analysis, dual-chamber ICDs were related to lower rates of inappropriate shocks as compared to single-chamber devices (0.9% vs. 11.8%, p = < 0.001, log-rank test). In multivariable Cox proportional analysis, independent predictors of inappropriate shock were history of atrial fibrillation (hazard ratio (HR) = 2.78, CI 1.37-5.64, p = 0.004), chronic kidney disease (HR = 6.15, CI 2.82-13.53, p < 0.001), and non-ischemic cardiomyopathy (HR = 2.84, CI 1.54-5.23, p = 0.001). Among ICD settings, PR logic was the only discriminator independently related to a reduced risk of inappropriate shocks (HR = 0.18, CI 0.06-0.48, p = 0.001), along with an SVT limit enabled over 200 bpm (HR = 0.24, CI 0.11-0.51, p < 0.001). CONCLUSIONS: In this nationwide cohort of primary prevention ICD-only patients, dual-chamber devices were related to lower risk of inappropriate shocks compared to single-chamber ICDs. Besides, PR logic and SVT limit > 200 bpm emerged as protective factors. PMID- 30523512 TI - Ethanol acutely antagonizes the refeeding-induced increase in mTOR-dependent protein synthesis and decrease in autophagy in skeletal muscle. AB - The purpose of this study was to determine the impact of acute ethanol administration on the major signal transduction pathways in skeletal muscle responsible for regulating the protein synthetic and degradative response to refeeding. Adult male C57Bl/6 mice were fasted overnight; mice were then either refed normal rodent chow for 30 min or a separate group of mice remained food deprived (i.e., fasted). Thereafter, mice were administered either 3 g/kg ethanol or saline. Gastrocnemius/plantaris was collected 1 h later and analyzed. Acute ethanol decreased basal and prevented the refeeding-induced increase in muscle protein synthesis. While ethanol prevented a nutrient-stimulated increase in S6K1 phosphorylation, it did not alter the increase in 4E-BP1 phosphorylation. Downstream of S6K1, ethanol also attenuated the refeeding-induced increase in S6 and eIF4B phosphorylation, as well as the decrease in eEF2 phosphorylation. Although ethanol decreased ERK and p90 RSK phosphorylation, activation of this signaling pathway was not altered by refeeding in either control or ethanol treated mice. Related to protein degradation, in vitro-determined proteasome activity and the content of total ubiquitinated proteins were not altered by ethanol and/or refeeding. Control mice appeared to exhibit a refeeding-induced decrease in autophagy as suggested by the increased FoxO3 and ULK1 phosphorylation and total p62 protein as well as decreased LC3B-II; however, ethanol blunted these refeeding-induced changes. These data suggest that ethanol can acutely prevent the normally observed mTOR-dependent increase in protein synthesis and reduction in autophagy in response to nutrient stimulation, but does not appear to acutely alter proteasome activity. PMID- 30523514 TI - Management of some extra-peritoneal rectal injuries without fecal diversion may be feasible, but high-quality evidence is still needed. PMID- 30523513 TI - Protective role of beta-blockers in chemotherapy-induced cardiotoxicity-a systematic review and meta-analysis of carvedilol. AB - Some randomized controlled trials (RCTs) have tested the efficacy of beta blockers as prophylactic agents on cancer therapy-induced cardiotoxicity; however, the quality of this evidence remains undetermined. This systematic review and meta-analysis study aims to evaluate the prophylactic effects of beta blockers, especially carvedilol, on chemotherapy-induced cardiotoxicity. RCTs were identified by searching the MEDLINE (PubMed), Embase (OvidSP), Cochrane CENTRAL (OvidSP), etc., until December 2017. Inclusion criteria were randomized clinical trial and adult cancer patients started beta-blockers before chemotherapy. We evaluated the mean differences (MD) by fixed- or random-effects model and the odds ratio by Peto's method. Primary outcome was the left ventricular ejection fraction (LVEF) of patients after chemotherapy, and secondary outcomes were all-cause mortality, clinically overt cardiotoxicity, and other echocardiographic measurements. In total, we included six RCTs that used carvedilol as a prophylactic agent in patients receiving chemotherapy. The LVEF was not significantly distinct between those using carvedilol and placebo after chemotherapy (MD, 1.74; 95% confidence interval (CI), - 0.18 to 3.66; P = 0.08). The incidence of clinically overt cardiotoxicity was lower in the carvedilol group compared with the control group (Peto OR, 0.42; 95% CI, 0.20-0.89; P = 0.02). Furthermore, after chemotherapy, the LV end-diastolic diameter did not increase in the carvedilol group compared with the placebo group (MD, - 1.41; 95% CI, - 2.32 to - 0.50; P = 0.002). The prophylactic use of carvedilol exerted no impact on the early asymptomatic LVEF decrease but seemed to attenuate the frequency of clinically overt cardiotoxicity and prevent ventricular remodeling. PMID- 30523515 TI - Management of retrorectal hematoma after stapled transanal rectal resection for prolapsed hemorrhoids associated with occult rectal prolapse and obstructed defecation syndrome. PMID- 30523516 TI - CO2 embolism can complicate transanal total mesorectal excision. AB - BACKGROUND: Carbon dioxide (CO2) embolism is a rare but potentially devastating complication of minimally invasive abdominal and retroperitoneal surgery. Characterized by a decrease in end-tidal CO2 (ETCO2) and oxygen saturation (SpO2), CO2 emboli can cause rapid intraoperative hypotension and cardiovascular collapse. Transanal total mesorectal excision (taTME) is a novel surgical approach for rectal resection, which requires high flow CO2 insufflation in a low volume operative field. In this setting, the incidence of CO2 embolism is unknown; we evaluate three cases of intraoperative CO2 embolism that occurred during the transanal portion of the TME dissection. METHODS: All taTME cases from December 2014 to March 2018 at a single institution were reviewed. Cases of CO2 embolism were identified intraoperatively and characterized using the operative reports and anesthesia records. The transanal/pelvic insufflation included a targeted pressure of 15 mm Hg, high flow and high smoke evacuation. Physiologic derangements and management of these instances were analyzed. The postoperative course was evaluated and any complications were noted. RESULTS: A total of 80 taTME were performed for benign and malignant disease. Three patients (4%) developed intraoperative evidence of CO2 embolism. Each instance occurred during the transanal portion of the dissection. Physiologic changes were marked by abrupt decrease in end-tidal ETCO2, SpO2, and blood pressure (BP). Management included immediate release of pneumopelvis, hemodynamic support with crystalloid or vasopressors, and placement of the patient in the Trendelenburg position with left side down. Within 10 min of the acute event, all patients had return of ETCO2, SpO2, and BP to pre-event levels. There were no intraoperative or postoperative sequelae including arrhythmia, myocardial infarction, stroke or death. No cases required conversion to open. CONCLUSIONS: During taTME, rare CO2 emboli may occur in the setting of venous bleeding during pneumopelvis, causing sudden, transient cardiovascular instability. Immediate recognition of rapid decrease in ETCO2, SpO2, and BP should be followed by desufflation of pneumopelvis, patient positioning in Trendelenburg and left lateral decubitus, and hemodynamic support. Increased awareness of this potential complication and maintaining a high index of suspicion will lead to preparedness of the anesthesia and surgery teams. PMID- 30523517 TI - Bioaccumulation, oxidative stress, immune responses and immune-related genes expression in northern snakehead fish, Channa argus, exposure to waterborne selenium. AB - The objective of this study was to evaluate the toxic effects on bioaccumulation, oxidative stress, immune responses and immune-related genes expression of Channa argus exposed for 28 days with waterborne selenium (0, 50, 100, 200, and 400 ug/L). After 28 days, the order of Se accumulation in tissues was kidney > liver > spleen > intestine > gill > muscle. Antioxidant parameters in liver and spleen of C. argus evidenced an oxidative stress condition in waterborne selenium. In addition, immunological parameters and immune-related gene expression were all enhanced with an increase in Se expose levels. Our results suggest that waterborne Se exposure can induce considerable Se accumulation, oxidative stress and immunotoxic effects on C. argus. PMID- 30523518 TI - Effects of minocycline and rapamycin in gamma-irradiated human embryonic stem cells-derived cerebral organoids. AB - Radiation induces DNA and protein damage and free radical formation, effectively establishing cellular senescence in a variety of models. We demonstrate the effects of two known pleiotropic drugs following gamma radiation damage in neurosphere/cerebral organoid system based on human embryonic stem cells. mTORC1 repression by rapamycin prior to irradiation, or metabolic activation by minocycline after irradiation, partially rescues neuroepithelium integrity, neurite-growing capacity, ventricle formation and extracellular acidification rate as an integral measure of metabolic output. Cerebral organoid model thus provides valid and robust readouts for radiation studies in a complex 3D setting. PMID- 30523519 TI - Mistletoe Versus Host Pine: Does Increased Parasite Load Alter the Host Chemical Profile? AB - Stress caused by parasitic plants, e.g. mistletoes, alters certain host-plant traits as a response. While several physical implications of the parasite-host relation have been well studied, shifts in the host chemical profile remain poorly understood. Here we compare the chemical profiles of mistletoe (Viscum album subsp. austriacum) leaves and host pine (Pinus nigra subsp. salzmannii) needles and we investigate chemical changes in host needles of trees with different parasite loads (control, low, medium, and high). Our results reveal that despite the intimate contact between mistletoe and host pine, their chemical profiles differed significantly, revealing extremely low concentrations of defense compounds (including a complete lack of terpenes) and high levels of N concentrations in mistletoe leaves. On the other hand, parasitized pines showed unique chemical responses depending on parasite loads. Overall, the content in monoterpenes increased with parasitism. Higher parasitized pines produced higher amounts of defense compounds (phenols and condensed tannins) than less parasitized trees, but amounts in samples of the same year did not significantly differ between parasitized and unparasitized pines. Highly parasitized pines accumulated less N than pines with other parasite loads. The strongest response was found in sesqui- and diterpenes, which were at lower levels in pines under medium and high parasitism. Chemical responses of pines to mistletoe parasitism resembled reactions to other kinds of stress. Low levels induced reactions resembling those against drought stress, while medium and high parasitism elicited responses comparable to those against burning and defoliation. PMID- 30523520 TI - Toxicity of Milkweed Leaves and Latex: Chromatographic Quantification Versus Biological Activity of Cardenolides in 16 Asclepias Species. AB - Cardenolides are classically studied steroidal defenses in chemical ecology and plant-herbivore coevolution. Although milkweed plants (Asclepias spp.) produce up to 200 structurally different cardenolides, all compounds seemingly share the same well-characterized mode of action, inhibition of the ubiquitous Na+/K+ ATPase in animal cells. Over their evolutionary radiation, milkweeds show a quantitative decline of cardenolide production and diversity. This reduction is contrary to coevolutionary predictions and could represent a cost-saving strategy, i.e. production of fewer but more toxic cardenolides. Here we test this hypothesis by tandem cardenolide quantification using HPLC (UV absorption of the unsaturated lactone) and a pharmacological assay (in vitro inhibition of a sensitive Na+/K+ ATPase) in a comparative study of 16 species of Asclepias. We contrast cardenolide concentrations in leaf tissue to the subset of cardenolides present in exuding latex. Results from the two quantification methods were strongly correlated, but the enzymatic assay revealed that milkweed cardenolide mixtures often cause stronger inhibition than equal amounts of a non-milkweed reference cardenolide, ouabain. Cardenolide concentrations in latex and leaves were positively correlated across species, yet latex caused 27% stronger enzyme inhibition than equimolar amounts of leaf cardenolides. Using a novel multiple regression approach, we found three highly potent cardenolides (identified as calactin, calotropin, and voruscharin) to be primarily responsible for the increased pharmacological activity of milkweed cardenolide mixtures. However, contrary to an expected trade-off between concentration and toxicity, later diverging milkweeds had the lowest amounts of these potent cardenolides, perhaps indicating an evolutionary response to milkweed's diverse community of specialist cardenolide-sequestering insect herbivores. PMID- 30523521 TI - Sudden blindness and deafness disclosing meningeal carcinomatosis in non-small cell lung cancer. PMID- 30523522 TI - Effects on Satisfaction and Service Engagement of Paliperidone Palmitate Compared with Oral Paliperidone in Patients with Schizophrenia: An Open Label Randomized Controlled Trial. AB - : BACKGROUND AND OBJECTIVE: Clinical practice guidelines recommend antipsychotic monotherapy, including oral and long-acting formulations, in the treatment of schizophrenia. This open-label, randomized, controlled trial aimed to evaluate the efficacy and tolerability in patients with schizophrenia of once-monthly long acting paliperidone palmitate (PP1M) compared with oral paliperidone extended release (ER), with a particular focus on satisfaction, subjective well-being, and service engagement. METHODS: Seventy-two consecutive outpatients with schizophrenia (DSM-5) were randomly assigned for 6 months to: (1) PP1M (50-150 mg equivalent) or (2) paliperidone ER (6-12 mg/day). Participants were assessed at baseline and after 6 months with the Treatment Satisfaction Questionnaire for Medication (TSQM); the Subjective Well-being under Neuroleptics Scale (SWN-K); the Service Engagement Scale (SES); the Clinical Global Impression-Schizophrenia (CGI-SCH); and the Personal and Social Performance (PSP) score. ANOVA repeated measures was performed. Intention-to-treat analysis with last observation carried forward was conducted. RESULTS: We found a significant within-subjects effect (trial duration) for all rating scale except for cognitive symptoms and the TSQM domain "side effects". A significant effect between subjects (treatment modality) was found for the CGI negative symptoms, the TSQM domains "overall satisfaction" and "convenience," and the SES. There were seven drop-outs (9.7%): twi due to hyperprolactinemia and five for lack of compliance. CONCLUSIONS: Significant differences between the two formulations were found. PP1M was superior to paliperidone ER on global treatment satisfaction and convenience, on service engagement, and in reducing negative symptoms. The trial was registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) with the code: ACTRN12618001113246. PMID- 30523523 TI - Progress in Developing Pharmacologic Agents to Treat Bulimia Nervosa. AB - This paper reviews past and current progress in developing pharmacologic agents for the treatment of individuals with bulimia nervosa (BN). We searched the literature and clinical trial registries for compounds studied in BN, the related condition, binge eating disorder (BED), and preclinical models of binge-eating behavior. Drug classes evaluated included antidepressants, antiepileptic drugs, stimulants and other medications for attention-deficit/hyperactivity disorder, opioid antagonists, and weight loss agents, among others. The only available drugs with established efficacy in BN at this time include antidepressants (especially selective serotonin reuptake inhibitors [SSRIs]) and the antiepileptic topiramate, though the efficacy of these compounds is modest at best. The only medications we found currently receiving empirical study in people with BN were fluoxetine, other serotonergic antidepressants, intranasal naloxone, lisdexamfetamine dimesylate, phentermine-topiramate combination, the antiandrogenic oral contraceptive ethinyl estradiol plus drospirenone, and prazosin. Preclinical models suggest that nociceptin receptor antagonists, the selective serotonin 5-HT2C receptor agonist lorcaserin, monoamine stabilizers, and selective orexin-1 receptor antagonists might be helpful. We found no evidence of a drug developed specifically for the treatment of individuals with BN. Future areas for research in the pharmacotherapy of BN are suggested. Importantly, until drugs are developed specifically for eating disorders, drugs developed for other conditions that are centrally acting and associated with beneficial psychotropic effects and/or reduced appetite or weight loss might be considered for repurposing in BN. PMID- 30523524 TI - Comparative toxicity of a food additive TiO2, a bulk TiO2, and a nano-sized P25 to a model organism the nematode C. elegans. AB - To help fill the knowledge gap regarding the potential human health impacts of food pigment TiO2, a comparative toxicity study was performed on a food-grade TiO2 (f-TiO2), a bulk TiO2 (b-TiO2), and a nano-sized TiO2 (Degussa P25), and in the nematode Caenorhabditis elegans. Acute phototoxicity and chronic toxicity effects including reproduction, lifespan, and vulval integrity were evaluated. The f-TiO2, b-TiO2, and P25 had a primary particle size (size range) of 149 (53 308) nm, 129 (64-259) nm, and 26 (11-52) nm, respectively. P25 showed the greatest phototoxicity with a 24-h LC50 of 6.0 mg/L (95% CI 5.95, 6.3), followed by the f-TiO2 (LC50 = 6.55 mg/L (95% CI 6.35, 6.75)), and b-TiO2 was the least toxic. All three TiO2 (1-10 mg/L) induced concentration-dependent effects on the worm's reproduction, with a reduction in brood size by 8.5 to 34%. They all caused a reduction of worm lifespan, accompanied by an increased frequency of age associated vulval integrity defects (Avid). The impact on lifespan and Avid phenotype was more notable for P25 than the f-TiO2 or b-TiO2. Ingestion and accumulation of TiO2 particles in the worm intestine was observed for all three materials by light microscopy. These findings demonstrate that the food pigment TiO2 induces toxicity effects in the worm and further studies are needed to elucidate the human health implication of such toxicities. PMID- 30523525 TI - Pesticides in three rural rivers in Guangzhou, China: spatiotemporal distribution and ecological risk. AB - Frequent and widespread pesticide use is a major concern for both human and environmental health. The aim of this study was to screen for 19 pesticides in rural rivers in Guangzhou, China, evaluating the potential impact of detected pesticides on the local ecosystem. Sampling was performed in rural rivers in three environment types: agricultural, industrial, and unpolluted, with sampling of water and sediments in both wet and dry seasons. A total of 11 pesticides were detected overall and their spatiotemporal distribution in water and ecological risk were assessed. Five pesticides were detected at concentrations above 100 ng L-1, with the highest concentration pesticides being dimethoate (1318 ng L-1) in surface water and quinalphos (328 ng g-1 dry weight (dw)) in sediments. The most commonly detected pesticides were chlorpyrifos, acetochlor, and butachlor with detection frequencies of 50-57% and 29-43%, in water and sediments, respectively. Samples from the agricultural rural river contained the most pesticides and at higher concentrations, as compared to industrial and unpolluted areas, especially during the wet season. Ecotoxicological risk assessment through Risk Quotients (RQs) showed that chlorpyrifos and fenvalerate pose high ecological risks in water and therefore, reduction of the source input of these pesticides is essential. PMID- 30523526 TI - Synthesis and applications of nano-TiO2: a review. AB - TiO2-based nanomaterials have attracted prodigious attention as a photocatalysts in numerous fields of applications. In this thematic issue, the mechanism behind the photocatalytic activity of nano-TiO2 as well as the critical properties have been reviewed in details. The synthesis routes and the variables that affect the size and crystallinity of nano-TiO2 have also been discussed in detail. Moreover, a newly emerged class of color TiO2, TiO2 in aerogel form, nanotubes form, doped and undoped form, and other forms of TiO2 have been discussed in details. Photocatalytic and photovoltaic applications and the type of nano-TiO2 that is more suitable for these applications have been discussed in this review. PMID- 30523527 TI - The protective effects of Nile tilapia (Oreochromis niloticus) scale collagen hydrolysate against oxidative stress induced by tributyltin in HepG2 cells. AB - Oxidative stress is regarded as one of the most important factors associated with many diseases, such as atherosclerosis, cancer, and diabetes. Various chemicals are released into the environment, causing environmental pollution. Importantly, many of them may cause damage to organisms through oxidative stress. In this work, we investigated the possible protective effects of Nile tilapia (Oreochromis niloticus) scale collagen hydrolysate (TSCH) (molecular weight approximately 4 kDa) against tributyltin (TBT)-induced oxidative stress in vitro. The results showed that pretreatment with TSCH protected against decreases in cell viability and changes in cell morphology in HepG2 cells exposed to TBT. Treatment with TSCH reduced the TBT-induced elevation in malondialdehyde (MDA) levels in HepG2 cells in a dose-dependent manner. Pretreatment with TSCH increased glutathione reductase (GR) and superoxide dismutase (SOD) activity. Moreover, TSCH decreased the expression of the proapoptotic protein Bax, reducing apoptosis. These results suggest that the protective mechanism of TSCH may be associated with its ability to scavenge MDA, increase antioxidant enzyme activity and downregulate the expression of Bax. PMID- 30523528 TI - Urbanization impact on residential energy consumption in China: the roles of income, urbanization level, and urban density. AB - This paper investigated the impact of urbanization on residential energy consumption (REC) in China by taking cognizance of the levels of income, urbanization and urban density. Threshold analyses were employed to investigate the nonlinear relationships based on the STIRPAT (Stochastic Impacts by Regression on Population, Affluence, and Technology) framework using a balanced panel dataset of 29 provinces of China over the period of 1998-2014. The common correlated effects mean group estimator (CCEMG) was used to address time-series cross-section (TSCS) issues. The results confirmed the existence of the nonlinear relationship between urbanization and REC in China. The impact of urbanization on REC varied at different economic development levels and urbanization levels. Specifically, urbanization decreased REC at the stage that per capita disposable income of urban residents (PDI) less than 2615 USD, while it increased REC at the stage that PDI higher than 2615 USD. Similarly, urbanization decreased REC at the stage that urbanization rate lower than 55.31% and increased REC after urbanization rate exceeded 55.31%. This study did not find evidence to support the urban environmental transition theory, indicating there was still no region in China had stepped into the win-win stage of urbanization and energy consumption. Furthermore, the nonlinear impact of urban density on REC was estimated and the results indicated that urban density exerted a positive effect on REC when urban density was lower than 808 inhabitants per square kilometer, while it was no longer relevant to REC after that threshold point. Based on these results, the corresponding countermeasures and suggestions to achieve low-carbon urbanization were put forward. PMID- 30523529 TI - Application of carotenoid to alleviate the oxidative stress caused by phenanthrene in wheat. AB - It is reported that the accumulated polycyclic aromatic hydrocarbons (PAHs) can cause wheat leaf chlorosis, and we identified that carotenoid (Car) and superoxide dismutase (SOD) are the two most active factors in antioxidant system in the previous study. Herein, we applied Car as an exogenous chemical added to alleviate the toxicity triggered by phenanthrene (a model PAH) in wheat seedlings. In the exogenous Car addition groups, we found that the leaf number would grow three, and the relative biomass and the relative root length of 20 mg L-1 Car added would take positive changes that increased by 171.35% and 108.08% of the phenanthrene-treated group at day 9, respectively. Under the subcellular structure, vacuole would be clear and clean, chloroplast and mitochondria shapes turned normal in the exogenous Car addition groups, and their osmophilic particle densities were much lower than the phenanthrene-treated group. Chlorophyll a, chlorophyll b, and total chlorophyll concentrations also recovered after Car was added in the phenanthrene treatments for 9 days. The activity of SOD, another active factor, also decreased when Car was added, and the values dropped to 16.54 and 24.61 U g-1 for the 10 and 20 mg L-1 Car addition groups, respectively. Like the SOD activity, malondialdehyde (MDA) concentrations of the two Car addition groups decreased to 26.50% and 26.87% of the phenanthrene treatment. The relative concentrations of 5 kinds of amino acids (valine, alanine, proline, aspartic acid, and lysine) recovered significantly, and the principal component analysis suggested that amino acid concentrations were in recovery progress when Car was added in phenanthrene treatments. Therefore, it is concluded that Car is an effective PAH toxicity relief. Our result offers a new way to improve the plant resistance to PAH pollution in the environment. Graphical abstract. PMID- 30523530 TI - Concentrations and chemical fractions of Cu, Zn, Cd, and Pb at ten metallurgical sites in China. AB - Metal pollution in urban soils due to smelting and electroplating has become a severe problem in China. In this study, the concentration, chemical fraction, and leaching behavior of typical metals (Cu, Zn, Cd, and Pb) in soil samples from ten metallurgical sites were studied. The results show that some of the soils were polluted with Cu and most were heavily polluted with multiple metals, especially Zn, Cd, and Pb. The average concentration of Cu, Zn, Cd, and Pb was 498, 4145, 89, and 5091 mg/kg, respectively. Chemical fractionation revealed that Cu, Zn, Cd, and Pb were mainly present in the acid-soluble fraction in polluted soils, but predominated in the residual fraction in unpolluted soils, demonstrating that allogenic metals in the soils were mostly present in the more labile fractions. Toxicity characteristic leaching procedure results were in agreement with the chemical fractionation study, indicating that the higher the total metal content, the higher the leachability, mobility, bioavailability, and potential toxicity to the environment, especially groundwater. Use of chemical fractionation results instead of total metal concentrations would provide better insight into the distribution and binding forms of metals for better assessment of their mobility and bioavailability. The study would provide much more important information for developing better remediation strategies for contaminated sites. PMID- 30523531 TI - Bisphenol S exposure affects gene expression related to intestinal glucose absorption and glucose metabolism in mice. AB - Bisphenol S, an industrial chemical, has raised concerns for both human and ecosystem health. Yet, health hazards posed by bisphenol S (BPS) exposure remain poorly studied. Compared to all tissues, the intestine and the liver are among the most affected by environmental endocrine disruptors. The aim of this study was to investigate the molecular effect of BPS on gene expression implicated in the control of glucose metabolism in the intestine (apelin and its receptor APJ, SGLT1, GLUT2) and in the liver (glycogenolysis and/or gluconeogenesis key enzymes (glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK)) and pro-inflammatory cytokine expression (TNF-alpha and IL-1beta)). BPS at 25, 50, and 100 MUg/kg was administered to mice in water drink for 10 weeks. In the duodenum, BPS exposure reduces significantly mRNA expression of sodium glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), apelin, and APJ mRNA. In the liver, BPS exposure increases the expression of G6Pase and PEPCK, but does not affect pro-inflammatory markers. These data suggest that alteration of apelinergic system and glucose transporters expression could contribute to a disruption of intestinal glucose absorption, and that BPS stimulates glycogenolysis and/or gluconeogenesis in the liver. Collectively, we reveal that BPS heightens the risk of metabolic syndrome. PMID- 30523532 TI - Recycled gypsum board acted as a mineral swelling agent for improving thermal conductivity characteristics in manufacturing of green lightweight building brick. AB - Lightweight building bricks manufactured from non-hazardous residues incorporating mineral foaming agents have been successfully developed over past two decades. Very little information is available on recycling and reutilization of construction and demolition waste used as the pore foaming agent in manufacturing lightweight brick. In this research, the mineral swelling agent was gypsum board recycled from construction and demolition waste. The mineral swelling agent effect on the characteristics of green lightweight building materials sintered from drinking water purification (DWP) sludge was investigated. Green lightweight building materials were contained up to 50% (wt%) mineral swelling agent and fired at a temperature ranged between 950 degrees C and 1050 degrees C. The experimental results indicated that lightweight building materials have successfully sintered between 1000 degrees C and 1020 degrees C and added up to 40% (wt%) recycled gypsum board. The sintered building materials have the characteristics of relatively high compressive strength, low bulk density, and thermal conductivity that were in compliance with relevant Taiwan criteria for application in lightweight building materials. To further consider the eco-friendly and environmental safety of lightweight building materials, the recycled gypsum board can act as a good mineral swelling agent, but can also enhance the chemical stabilization and reduce the metals leachability of lightweight materials based on acidic neutralization capacity (ANC) analysis results. To estimate the carbon dioxide emission in manufacturing and transportation of lightweight materials that sintered this experimental conditions, the estimated carbon dioxide reduction rates were approximately 28.6% and 16.7%, respectively, as a result of the energy saving. Experimental results have confirmed that the feasibility of recycled gypsum board used as a swelling agent and good potential for construction works in green lightweight building materials. PMID- 30523533 TI - Evidence for non-Newtonian behavior of intracranial blood flow from Doppler ultrasonography measurements. AB - Computational fluid dynamics (CFD) studies of intracranial hemodynamics often use Newtonian viscosity model to close the shear rate term in the Navier-Stokes equation. This is based on a commonly accepted hypothesis which state that non Newtonian effects can be neglected in intracranial blood flow. This study aims to examine the validity of such hypothesis to guide future CFD studies of intracranial hemodynamics. Doppler ultrasonography (DUS) measurements of systolic and diastolic vessel diameter and blood velocity were conducted on 16 subjects (mean age 50.6). The measurements were conducted on the internal carotid (ICA), middle cerebral (MCA), and anterior communicating (AComA) arteries. Systolic and diastolic wall shear stress (WSS) values were calculated via the Hagen-Poiseuille exact solution using Newtonian and three different non-Newtonian models: namely Carreau, power-law and Herschel-Bulkley models. The Weissenberg-Rabinowitsch correction for blood shear-thinning viscosity was applied to the non-Newtonian models. The error percentage between the two sets of models was calculated and discussed. The Newtonian hypothesis was tested statistically and discussed using paired t tests. Significant differences (P < 0.0001) were found between the Newtonian and non-Newtonian WSS in ICA. In MCA and AComA, similar differences were found except in the systole and diastole for the Herschel-Bulkley and power law models (P = 0.0669, P = 0.7298), respectively. The error between the Newtonian and non-Newtonian models ranged from - 27 to 30% (0.2 to 2.2 Pa). These values could affect the physical interpretation of IA CFD studies. Evidence suggests that the Newtonian assumption may be inappropriate to investigate intracranial hemodynamics. Graphical abstract The WSS estimation error resulting from using the Newtonian assumption compared to three non-Newtonian models for ICA, MCA, and AComA in systole and diastole conditions, based on TCCD measurements of 16 subjects. The error due to the Newtonian assumption ranged from 0.2 to 2.2 Pa (- 27 to 30%). These values could affect the physical interpretation of IA CFD studies. PMID- 30523534 TI - Image synthesis-based multi-modal image registration framework by using deep fully convolutional networks. AB - Multi-modal image registration has significant meanings in clinical diagnosis, treatment planning, and image-guided surgery. Since different modalities exhibit different characteristics, finding a fast and accurate correspondence between images of different modalities is still a challenge. In this paper, we propose an image synthesis-based multi-modal registration framework. Image synthesis is performed by a ten-layer fully convolutional network (FCN). The network is composed of 10 convolutional layers combined with batch normalization (BN) and rectified linear unit (ReLU), which can be trained to learn an end-to-end mapping from one modality to the other. After the cross-modality image synthesis, multi modal registration can be transformed into mono-modal registration. The mono modal registration can be solved by methods with lower computational complexity, such as sum of squared differences (SSD). We tested our method in T1-weighted vs T2-weighted, T1-weighted vs PD, and T2-weighted vs PD image registrations with BrainWeb phantom data and IXI real patients' data. The result shows that our framework can achieve higher registration accuracy than the state-of-the-art multi-modal image registration methods, such as local mutual information (LMI) and alpha-mutual information (alpha-MI). The average registration errors of our method in experiment with IXI real patients' data were 1.19, 2.23, and 1.57 compared to 1.53, 2.60, and 2.36 of LMI and 1.34, 2.39, and 1.76 of alpha-MI in T2-weighted vs PD, T1-weighted vs PD, and T1-weighted vs T2-weighted image registration, respectively. In this paper, we propose an image synthesis-based multi-modal image registration framework. A deep FCN model is developed to perform image synthesis for this framework, which can capture the complex nonlinear relationship between different modalities and discover complex structural representations automatically by a large number of trainable mapping and parameters and perform accurate image synthesis. The framework combined with the deep FCN model and mono-modal registration methods (SSD) can achieve fast and robust results in multi-modal medical image registration. Graphical abstract The workflow of proposed multi-modal image registration framework. PMID- 30523535 TI - Availability of legalized cannabis reduces demand for illegal cannabis among Canadian cannabis users: evidence from a behavioural economic substitution paradigm. AB - In the context of cannabis legalization, an important question among clinicians, policymakers, and the public is whether availability of legal cannabis will significantly reduce consumption (demand) of illegal cannabis. Using paradigms from behavioural economics, we tested the prediction that legal cannabis would be an asymmetrical substitute for illegal cannabis, with legal cannabis operating as a superior commodity based on its regulated status. In a sample of 289 adult cannabis users in Ontario, we found evidence of substitutability for both legal and illegal cannabis, but significantly lower substitutability of illegal for legal cannabis, a pattern that was also present for price elasticity (alpha) and Pmax. Thus, the data indicated asymmetric substitution such that the availability of legal cannabis substantially decreased demand for illegal cannabis, but a significantly smaller effect in reverse. These results suggest that the introduction of legal cannabis into the market may disrupt and reduce illegal purchases, contributing to the reduction of the potential harms associated with the illegal market. However, in revealing price windows in which legal cannabis is preferred over the contraband alternative, these data also have significant implications for pricing policies. PMID- 30523536 TI - Correction to: A Markov Model to Estimate Mortality Due to HIV/AIDS Using Viral Load Levels-Based States and CD4 Cell Counts: A Principal Component Analysis Approach. AB - In the original publication, the following text was missing from the beginning of the Methods section in the main text "This study uses similar methods to those previously published. PMID- 30523537 TI - Three-dimensional bone formation including vascular networks derived from dental pulp stem cells in vitro. AB - The regeneration of bone tissue is an active area of research, and future clinical applications are expected. Here, to establish new bone graft materials and an experimental bone tissue model, we generated united compact and spongy bone tissues containing vascular networks from human dental pulp stem cells in vitro. We applied the cell bead and cell sheet methods to construct three dimensional bone tissue, which was cultured using a circumfusion apparatus for 30 days. Using micro-computed tomography, we assessed structural differences between compact and spongy bone. Histological examinations revealed the presence of bone lacunae containing osteocytes, Haversian canal-like structures, and extensive vascularization. Furthermore, tartrate-resistant acid phosphatase (TRAP) staining positive osteoclast-like cells were also observed. Thus, the bone tissue generated using this method closely resembles native bone tissue and may possess bone remodeling ability. We successfully generated bone tissue containing blood vessel networks in vitro using this method. The generated bone tissue will likely be highly applicable to medical care, the study of osteogenesis, drug-screening assays, and drug development for bone tissue. PMID- 30523538 TI - Secondary Hyperparathyroidism in Patients with Biliopancreatic Diversion After 10 Years of Follow-up, and Relationship with Vitamin D and Serum Calcium. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) is a matter of concern after biliopancreatic diversion (BPD). The aim of this study was to investigate the relationship between SHPT, 25(OH)D, and calcium after BPD. DESIGN: A retrospective analysis in obese patients after BPD performed between 1998 and 2016. METHODS: Patients with at least 1 year of follow-up were included. SHPT was considered when PTH > 65 pg/mL in the absence of an elevated corrected calcium. 25(OH)D (ng/mL) status was defined as: deficiency < 20, insufficiency 20-29.9, and sufficiency >= 30. RESULTS: In total, 321 patients were included (76.6% women), with mean age 43.0 (10.5) years. Median follow-up was 6.0 (IQR 3.0-9.0) years. Mean body mass index was 49.8 (7.0) kg/m2. SHPT increased to a maximum of 81.9% in the ninth year of follow-up (95% CI: 1.5-9.1). Two years after surgery, 33.9% of patients with 25(OH)D sufficiency had SHPT (p = 0.001). Corrected calcium levels were lower in patients with PTH > 65 pg/mL when compared with PTH < 65 pg/mL; 1 year: 8.96 vs 9.1 mg/dL and 5 years: 8.75 vs 9.12 mg/dL (p < 0.01). After surgery, patients with PTH > 65 pg/mL and 25(OH)D sufficiency had lower corrected calcium levels when compared with subjects with PTH and 25(OH)D in normal range. Two years: 9.0 vs 9.2 mg/dL (p < 0.05) and 4 years: 8.9 vs 9.2 mg/dL (p < 0.01). CONCLUSIONS: Once 25(OH)D is sufficient, the increase in PTH persists associated with a decrease in serum corrected calcium. It is important to ensure a sufficient calcium intake in these patients in order to avoid SHPT and osteomalacia in the future. PMID- 30523539 TI - ERASE: a New Framework for Faculty to Manage Patient Mistreatment of Trainees. PMID- 30523540 TI - The Incidence of Meningitis in Patients with Traumatic Brain Injury Undergoing External Ventricular Drain Placement: A Nationwide Inpatient Sample Analysis. AB - BACKGROUND/OBJECTIVE: Infection is the most common complication of external ventricular drain (EVD) placement. National trends in the annual incidence of meningitis among patients with traumatic brain injury (TBI) who have undergone EVD placement have not been reported. METHODS: The Nationwide Inpatient Sample was used to select adults with a primary diagnosis of TBI who underwent EVD placement between 2002 and 2011. Annual rates of meningitis among patients who underwent EVD placement were determined. We also calculated mortality rates and length of stay (LOS). Potential factors associated with meningitis were evaluated in a binary logistic regression analysis. RESULTS: Out of 1,571,927 adult discharges with a primary diagnosis of TBI between 2002 and 2011, 39,029 (2.5%) underwent EVD placement. Of these, 1544 (4.3%) patients developed meningitis. There was no significant trend in the annual incidence of meningitis (p = 0.88), mortality (p = 0.55), or mean LOS (p = 0.13) during the study period. Meningitis and mortality rates remained stable when stratifying patients by hospital volume. In the binary logistic regression, acquired immunodeficiency syndrome, sepsis, and cerebrospinal fluid leak were associated with meningitis. CONCLUSIONS: The incidence of meningitis in patients who underwent EVD placement remained stable between 2002 and 2011. Further prospective studies are needed to identify approaches for preventing these infections. PMID- 30523541 TI - Cerebral Vascular Changes During Acute Intracranial Pressure Drop. AB - OBJECTIVE: This study applied a new external ventricular catheter, which allows intracranial pressure (ICP) monitoring and cerebral spinal fluid (CSF) drainage simultaneously, to study cerebral vascular responses during acute CSF drainage. METHODS: Six patients with 34 external ventricular drain (EVD) opening sessions were retrospectively analyzed. A published algorithm was used to extract morphological features of ICP recordings, and a template-matching algorithm was applied to calculate the likelihood of cerebral vasodilation index (VDI) and cerebral vasoconstriction index (VCI) based on the changes of ICP waveforms during CSF drainage. Power change (?P) of ICP B-waves after EVD opening was also calculated. Cerebral autoregulation (CA) was assessed through phase difference between arterial blood pressure (ABP) and ICP using a previously published wavelet-based algorithm. RESULTS: The result showed that acute CSF drainage reduced mean ICP (P = 0.016) increased VCI (P = 0.02) and reduced ICP B-wave power (P = 0.016) significantly. VCI reacted to ICP changes negatively when ICP was between 10 and 25 mmHg, and VCI remained unchanged when ICP was outside the 10-25 mmHg range. VCI negatively (r = - 0.44) and VDI positively (r = 0.82) correlated with ?P of ICP B-waves, indicating that stronger vasoconstriction resulted in bigger power drop in ICP B-waves. Better CA prior to EVD opening triggered bigger drop in the power of ICP B-waves (r = - 0.612). CONCLUSIONS: This study demonstrates that acute CSF drainage reduces mean ICP, and results in vasoconstriction which can be detected through an index, VCI. Cerebral vessels actively respond to ICP changes or cerebral perfusion pressure (CPP) changes in a certain range; beyond which, the vessels are insensitive to the changes in ICP and CPP. PMID- 30523542 TI - Antagonistic activity of Diplodia pinea against phytopathogenic fungi. AB - The ability of Diplodia pinea to inhibit Armillaria sp., Bjerkandera adusta, Botrytis cinerea, and Rhizoctonia sp. mycelium growth was analyzed using the double-culture method. Wild-type fungal strains were incubated in a biochemical oxygen demand incubator using potato agar dextrose medium at 24 +/- 2 degrees C for 35 days in darkness. D. pinea significantly inhibited the growth of all fungi species tested (30.75 to 98.37% inhibition) and showed moderate antagonistic activity (antagonistic index, 14.5). Chemical analysis of D. pinea culture broth extracts revealed steroids, triterpenes, and phenolic compounds. Alkaloids were qualitatively detected in the mycelium crude extract. The presence of these compounds may be related to the antagonistic activity observed. The inhibition ability of D. pinea is due to competition with the tested fungi for substrate and space. PMID- 30523543 TI - Natural history of bulla neogenesis for primary spontaneous pneumothorax: a propensity score analysis. AB - OBJECTIVE: For patients with recurrent primary spontaneous pneumothorax, surgery has been thought to be an acceptable treatment. However, even if bulla is completely resected, postoperative recurrence is relatively common due to bulla neogenesis. Bulla neogenesis seems to develop naturally in younger patients compared with the elderly, as theorized till date. If the complete development of bulla neogenesis is confirmed, surgical resection can be performed as the radical treatment. Then, we evaluated the relationship between bulla neogenesis and age. METHODS: Between February 2009 and July 2018, we consecutively enrolled 276 patients who underwent primary bullectomy for primary spontaneous pneumothorax in our hospital. Finally, high-resolution computed tomography findings/observations of 155 eligible patients were evaluated retrospectively. The relationship between bulla neogenesis and age was evaluated using univariate and multivariate analyses and an inverse probability of treatment-weighted method using the propensity score. RESULTS: The study included 58 patients aged < 20 years and 97 aged >= 20 years. Bulla neogenesis was present in 34 patients (21.9%). Bulla neogenesis developed significantly at age < 20 compared with age >= 20 (44.8 vs. 8.2%). Univariate and multivariate analyses showed that age < 20 years was a significant factor associated with bulla neogenesis (P < 0.001 and P = 0.018, respectively). The inverse probability of treatment-weighted method showed that age < 20 years was a significant factor associated with bulla neogenesis (P = 0.0057, hazard ratio 4.79). CONCLUSIONS: Surgical treatment may be delayed in young patients (age < 20 years), because bulla neogenesis is not completely developed by this time for primary spontaneous pneumothorax. PMID- 30523544 TI - De-airing an open stent graft to potentially reduce spinal cord injury. AB - We have occasionally observed a bubble leaving the suture line of an open stent graft; hence, we hypothesized that de-airing an open stent graft could potentially reduce spinal cord injury. Postoperative computed tomography often showed residual air in thoracic aortic aneurysms, confirmed by the presence of a certain amount of air in an open stent graft in a dry lab. We filled CO2 in the sterilized package of an open stent graft and subsequently filled it with saline, which absorbed the CO2 and entered into the gap of the graft. The clinical benefit of de-airing an open stent graft to reduce the incidence of spinal cord injury needs to be evaluated. PMID- 30523545 TI - Environmental temperature and air humidity and prevalence of maxillary sinus retention cysts: possible relationships (preliminary study). AB - OBJECTIVES: The aims of this study were to determine the prevalence of maxillary sinus retention cysts (MSRCs) and to evaluate the effects of mean temperature and mean air humidity on the prevalence of MSRCs in two cities in Turkey. METHODS: This retrospective study was conducted in Antalya and Erzurum, two cities with different air humidities and temperatures in Turkey. Panoramic images of patients who visited the Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Akdeniz University and Department of Oral and Maxillofacial Radiology, Faculty of Dentistry, Ataturk University for diagnostic purposes were evaluated. A total of 4800 panoramic images were included in the study. The mean age of the patients was 27.03 +/- 6.48 years. The prevalence of MSRCs was analyzed according to sex, mean temperature, and mean air humidity. Values of p < 0.05 were considered statistically significant. RESULTS: Among the 4800 panoramic images evaluated, 228 indicated the presence of MSRCs. MSRCs were found significantly more frequently in males than in females. The prevalence was 3% in Antalya and 6.5% in Erzurum, with a total prevalence of 4.8%. While there was a significant correlation between the total amount of cysts and monthly mean air humidity in Erzurum, the correlation effect size was very low. CONCLUSIONS: The total prevalence of MSRCs was 4.8%. There were no correlations between the frequency of MSRCs and the mean air humidity or mean temperature. PMID- 30523546 TI - Correction to: Efficacy of safinamide on non-motor symptoms in a cohort of patients affected by idiopathic Parkinson's disease. AB - The original version of this article contains an error in Table 2. The Authors realized that they submitted the previous version of Table 2. The correct version of Table 2 is shown here. PMID- 30523547 TI - The pathological spectrum behind migraine aura status: a case series. AB - BACKGROUND: The recently released International Classification of Headache Disorders-3rd edition (1) includes migraine aura status (MAS) among the complications of migraine (A1.4.5). It is defined as the recurrence of at least three auras over a period of 3 days, in a patient suffering from migraine fulfilling criteria for 1.2 Migraine with aura (MA) or one of its subtypes. CASE SERIES: We describe three cases of MAS secondary to an organic brain lesion: a migrainous infarction, an acute ischemic stroke secondary to a vertebral artery dissection, and an inflammatory demyelinating disease of the central nervous system. CONCLUSIONS: In front of a patient with a MAS, an organic lesion of the brain must be suspected, until a complete negative vascular and neuroradiological diagnostic workup has been performed. A spectrum of underlying pathologies (vascular or demyelinating diseases, epileptic or degenerative conditions) may cause a MAS-like clinical onset. The variability of aura symptoms may result in a real diagnostic challenge. PMID- 30523548 TI - Vis-a-vis: a focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis. AB - Cerebrovascular malformations include a wide range of blood vessel disorders affecting brain vasculature. Neuroimaging differential diagnosis can result unspecific due to similar phenotypes of lesions and their deep localization. Next generation sequencing (NGS) platforms simultaneously analyze several hundreds of genes and can be applied for molecular distinction of different phenotypes within the same disorder's macro-area. We discuss about the main criticisms regarding molecular bases of cerebral cavernous malformations (CCM) and brain arteriovenous malformations (AVM), highlighting both common pathogenic aspects and genetic differences leading to lesion development. Many recent studies performed on human CCM and AVM tissues aim to detect genetic markers to better understand molecular bases and pathogenic mechanism, particularly for sporadic cases. Several genes involved in angiogenesis show different expression patterns between CCM and AVM, and these could represent a valid starting point to project a NGS panel to apply for differential cerebrovascular malformation diagnosis. PMID- 30523549 TI - Early- and late-phase 18F-FP-CIT PET images in vascular parkinsonism due to midbrain infarct. PMID- 30523550 TI - Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia. AB - Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology. PMID- 30523551 TI - Gastroprotective effect of araloside A on ethanol- and aspirin-induced gastric ulcer in mice: involvement of H+/K+-ATPase and mitochondrial-mediated signaling pathway. AB - The aim of this study was to elucidate the gastroprotective activity and possible mechanism of involvement of araloside A (ARA) against ethanol- and aspirin induced gastric ulcer in mice. The experimental mice were randomly divided into control, model, omeprazole (20 mg/kg, orally) and ARA (10, 20 and 40 mg/kg, orally). Gastric ulcer in mice was induced by intragastric administration of 80% ethanol (10 mL/kg) containing 15 mg/mL aspirin 4 h after drug administration on day 7. The results indicated that ARA could significantly raise gastric juice volume and acidity; ameliorate gastric mucosal blood flow, gastric binding mucus volume, ulcer index and ulcer inhibition rate; suppress H+/K+-ATPase activity, which was confirmed by computer-aided docking simulations; inhibit the release of mitochondrial cytochrome c into the cytoplasm; inhibit caspase-9 and caspase-3 activities and down-regulate mRNA expression levels; down-regulate the mRNA and protein expressions of apoptosis protease-activating factor-1 and protein expression of cleaved poly(ADP ribose) polymerase-1; and up-regulate Bcl-2 mRNA and protein expressions and down-regulate Bax mRNA and protein expressions, thus elevating the Bcl-2/Bax ratio in a dose-dependent manner. Histopathological observations further provided supportive evidence for the aforementioned results. The results demonstrated that ARA exerted beneficial gastroprotective effects on alcohol- and aspirin-induced gastric ulcer in mice, which was related to suppressing H+/K+-ATPase activity as well as pro-apoptotic protein expression, and promoting anti-apoptotic protein expression, thus alleviating gastric mucosal injury and cell death. PMID- 30523552 TI - Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort). AB - BACKGROUND: Direct-acting antivirals (DAAs) are safe and effective for the treatment of HCV infection. However, data regarding their efficacy in patients with Child-Pugh B cirrhosis are scarce and their capability in improving liver function is debated. The aim of our study was to assess the clinical benefits of treatment with DAA in subjects with Child-Pugh B cirrhosis. METHODS: We conducted a prospective multicentre study among patients with Child-Pugh B cirrhosis of an Italian real-life HCV cohort (LINA cohort) who received treatment with DAAs. RESULTS: Among 89 patients enrolled, the rate of sustained virologic response 12 was 95.5%. No discontinuation occurred, no patient died during treatment. Most patients had Genotype 1 (1b 61.8%, 1a 11.2%). Conversely, 22.5%, 1.1% and 3.4% of patients had Genotype 2, 3 and 4, respectively. At last observation, 61.8% of patients switched to a Class A cirrhosis, 33.7% remained in Class B and 4.5 worsened to Child C (p < 0.001). Liver parameters significantly improved from baseline to 12 weeks after the end of treatment. Previous anti-HCV treatments and the presence of decompensated cirrhosis at 1 month of treatment were significantly associated with a decompensated cirrhosis at the last observation. CONCLUSIONS: Treatment with DAA in patients with Child-Pugh B cirrhosis is safe and leads to a very high rate of viral clearance, a significant rate of re compensation and an improvement in liver function. Further studies are needed to assess the impact of treatment on survival and quality of life in long-term follow-up. PMID- 30523553 TI - A new scoring system to predict Kawasaki disease with coronary artery lesions. AB - OBJECTIVES: To clarify the independent risk factors and construct a scoring system for Kawasaki disease (KD) with coronary artery lesions (CAL) at acute and subacute stages. METHOD: Data of KD inpatients at acute and subacute stages were reviewed in a tertiary care center from January 2009 to December 2014. RESULTS: A total of 2305 acute and subacute KD cases were enrolled in this study with a CAL rate of 24.1%. The OR (95%CI) values of male, total fever duration >= 8 days, IVIG resistance (IVIGR), albumin (ALB) <= 35.9 g/L, eosionphils (EO) >= 2.2%, and monocytes (MO) >= 5.9% were 1.45 (1.15-1.82), 1.78 (1.43-2.22), 1.42 (1.09-1.85), 1.53 (1.23-1.91), 1.17 (0.94-1.45), and 1.37 (1.09-1.69), respectively. In patients <= 6 months old, the OR (95%CI) values for total fever duration >=8 days, delayed diagnosis, and ALB <= 35.9 g/L were 3.61 (2.02-6.45), 3.49 (1.49 8.16), and 2.07 (1.14-3.74), respectively. ROC curve showed that the AUC value and sensitivity and specificity of predicting KD with CAL in patients <= 6 months old were 0.731, 64.7%, and 80.9%, respectively. CONCLUSIONS: The independent risk factors for acute and subacute KD combined with CAL, including being a boy, long fever duration, IVIGR, low ALB, elevated EO, and MO. Joint of parameters (total fever duration >= 8 days, delayed diagnosis, and ALB <= 35.9 g/L) can be used to predict the occurrence of CAL in KD patients <= 6 months old. PMID- 30523554 TI - Steroid-free remission in lupus: myth or reality; an observational study from a tertiary referral centre. AB - OBJECTIVE: Whether maintaining steroid-free remission is feasible in Indian patients with systemic lupus erythematosus (SLE). METHODS: In 148 patients with SLE including 78 lupus nephritis (LN) previously put into remission, steroid therapy was gradually tapered off. RESULTS: Patients received glucocorticoids for median 1855 days (interquartile range (IQR) 901-2834) before discontinuing. Median duration of follow-up was 539 days (IQR 266.25-840.75). Flare occurred in 31 patients (20.9%; 95% confidence interval (CI) 15.17-28.19, renal flare in 12.16% (18/148, 95% CI 7.83-18.41)). Most of the flares occurred in the first year of follow-up (41.9%, 13/31). Overall 93.5% (29/31) of flares occurred in those who received <= 8 years of glucocorticoids, compared to 6.5% (2/31) of flares in others (p = 0.009). Median flare-free survival was 611 days (95% CI 518 704). Multivariate Cox regression identified the following predictors of flare free survival: duration of disease (hazard ratio (HR) 0.89, 95% CI 0.84-0.94, p < 0.001), duration of glucocorticoid before discontinuing (HR 1.000086, 95% CI 1.000047-1.00012, p < 0.001) and second immunosuppressive (HR 1.89, 95% CI 1.251 2.87, p = 0.003). Additional risk factors of a renal flare-free survival among patients with LN were initial dose of glucocorticoids (HR 0.97, 95% CI 0.94-0.99, p = 0.005) and presence of haemolytic anaemia (HR 2.43, 95% CI 1.067-5.54, p = 0.035). CONCLUSIONS: About 20% patients undergo exacerbation of disease activity after glucocorticoid withdrawal. Treatment for >= 8 years before discontinuing and an additional immunosuppressive agent improve the chance of flare-free survival. PMID- 30523555 TI - Effect of double-layer structure in intramucosal gastric signet-ring cell carcinoma on lymph node metastasis: a retrospective, single-center study. AB - BACKGROUND: Among all types of gastric cancer (GC), signet-ring cell carcinoma (sig-GC) accounts for 4-17% of cases. The prognosis of early sig-GC is relatively good, with the 5-year survival rate at 99.7%. However, the correlation between histological features and lymph node metastasis (LNM) among pT1a (M) sig-GC remains unclear. Sig-GC often exhibits a double-layer structure (DLS) in the intramucosal layer, demonstrating functional differentiation into the normal gastric gland. Assumedly, the loss of the differentiation makes the DLS deranged, accounting for the occurrence of submucosal invasion and LNM. This study aimed to assess the proportion of DLS, to elucidate the correlation between histological features (including DLS) and LNM status, and to determine the LNM-negative condition in pT1a (M) sig-GC. METHODS: We reviewed the pathological data of 310 patients with 310 intramucosal sig-GCs who received gastrectomy with lymph node dissection. Immunohistochemistry was performed on all specimens to evaluate the presence of DLS. Furthermore, we review the clinicopathological features, including tumor size, lymphovascular invasion (LVI), ulceration (UL), and DLS results, and then statistically analyze the correlation between these features and LNM status. RESULTS: Overall, 129 pT1a (M) sig-GCs (42%) were DLS present. The univariate analysis revealed that "Tumor size > 20 mm", "UL present", and "DLS absent" were significant risk factors of LNM. The multivariate logistic regression analysis revealed only "DLS absent" as statistically significant. CONCLUSIONS: "DLS absent" is a risk factor of LNM detected by the multivariate analysis. In pT1a (M), LVI absent, UL absent, tumor size > 20 mm, sig-GC, no LNM occurred in "DLS present" cases. PMID- 30523556 TI - A false alarm of narcolepsy: obstructive sleep apnea masquerading as narcolepsy and depression. AB - PURPOSE: We report a case with symptoms and signs of obstructive sleep apnea (OSA), depression, and narcolepsy. Polysomnographic (PSG) and multiple sleep latency test (MSLT) findings, clinical characteristics, and diagnostic challenges in this case are discussed. METHODS: A 23-year-old single male presented with excessive daytime sleepiness, low mood, lack of energy, and snoring for 3 years. In addition, he reported excessive weight gain, lack of interest in work, partial loss of muscle tone during excitations, and sleep attacks during work and driving. He had experienced three episodes of sleep paralysis. The patient underwent a sleep study including PSG and MSLT. RESULTS: On baseline PSG, he had an apnea/hypopnea index (AHI) of 72.8/h. The MSLT showed a mean sleep latency of 3.8 min and two sleep-onset rapid eye movement periods (SOREMPs). On admission, he had an Epworth Sleepiness Scale (ESS) score of 21, and positive findings for depression in the clinical interview and psychometric scales. He was treated with continuous positive airway pressure without any medication. Follow-up PSG and MSLT were performed after 1 week, which showed an AHI of 0/h without SOREMPs. After 1 month, there was no sign of depression. CONCLUSIONS: This study reflects that OSA can present with cataplexy-like features and false positive MSLT results for narcolepsy, as well as depressive symptoms. The case highlights the complexity in which OSA can present to physicians, and emphasizes that clinicians should be aware that OSA can mimic narcolepsy and present with depressive symptoms. PMID- 30523557 TI - Reduction of sleep-disordered breathing following effective percutaneous mitral valve repair with the MitraClip system. AB - PURPOSE: This study tested the hypothesis that a reduction of pulmonary congestion achieved by a reduction of mitral regurgitation (MR) severity in heart failure (HF) patients is associated with reduced event lengths of sleep disordered breathing (SDB). METHODS: We prospectively enrolled 20 consecutive HF patients who underwent MitraClip implantation. Patients underwent cardiorespiratory polygraphic recording prior to and after percutaneous mitral valve repair (PMVR). Beyond routinely established indicators of apneas and hypopneas per hour (respiratory event index), we manually analyzed apnea event lengths. RESULTS: MitraClip implantation led to marked reduction of MR severity and a reduction in left atrial pressure. These hemodynamic changes were accompanied by changes in SDB: the subtype of SDB switched from CSA to OSA in 4 patients. Likewise, quantitative indicators of SDB were altered in both forms of SDB with a reduction in circulatory delay (CSA 38 +/- 14 vs. 33 +/- 15 s.; p = 0.002 and OSA 34 +/- 9 vs. 28 +/- 6 s.; p = 0.02) and a corresponding reduction in ventilation lengths in CSA patients (42 +/- 15 vs. 37 +/- 13 s.; p = 0.05). CONCLUSION: A reduction of pulmonary congestion as achieved by a decrease of left atrial pressure through successful MitraClip implantation is associated with a reduction in respiratory event lengths, further pointing towards a relation between SDB and HF. PMID- 30523558 TI - Psychometric properties of the Ethos Brief Index (EBI) using factorial structure and Rasch Analysis among patients with obstructive sleep apnea before and after CPAP treatment is initiated. AB - BACKGROUND: Continuous positive airway treatment (CPAP) is the recommended treatment for patients with obstructive sleep apnea (OSA). Outcome measures often focus on clinical and/or self-rated variables related to the medical condition. However, a brief validated instrument focusing on the whole life situation (i.e., ethos) suitable for clinical practice is missing. The aim of this study was to investigate factorial structure, categorical functioning of the response scale, and differential item functioning across sub-populations of the Ethos Brief Index (EBI) among patients with obstructive sleep apnea (OSA) before and after initiation of continuous positive airway pressure (CPAP). METHODS: A prospective design, including 193 patients with OSA (68% men, 59.66 years, SD 11.51) from two CPAP clinics, was used. Clinical assessment and overnight respiratory polygraphy were used to diagnose patients. Questionnaires administered before and after 6 months of CPAP treatment included EBI, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale, and global perceived health (initial item in SF 36). The validity and reliability of the EBI were investigated using Rasch and confirmatory factor analysis models. Measurement invariance, unidimensionality, and differential item functioning across gender groups, Apnea-Hypopnea Index, and ESS groups were assessed. RESULTS: The reliability of the EBI was confirmed using composite reliability and Cronbach's alpha. The results supported unidimensionality of the EBI in confirmatory factor analysis and the Rasch model. No differential item functioning was found. A latent profile analysis yielded two profiles of patients with low (n = 42) and high (n = 151) ethos. Patients in the low ethos group were younger and had higher depression scores, lower perceived health, and higher body mass index. CONCLUSIONS: The EBI is a valid tool with robust psychometric properties suitable for use among patients with OSA before and after treatment with CPAP is initiated. Future studies should focus on its predictive validity. PMID- 30523559 TI - Dimensions of Reproductive Attitudes and Knowledge Related to Unintended Childbearing Among U.S. Adolescents and Young Adults. AB - Measures of attitudes and knowledge predict reproductive behavior, such as unintended fertility among adolescents and young adults. However, there is little consensus as to the underlying dimensions these measures represent, how to compare findings across surveys using different measures, or how to interpret the concepts captured by existing measures. To guide future research on reproductive behavior, we propose an organizing framework for existing measures. We suggest that two overarching multidimensional concepts-reproductive attitudes and reproductive knowledge-can be applied to understand existing research using various measures. We adapt psychometric analytic techniques to analyze two data sets: the National Longitudinal Survey of Adolescent to Adult Health (Add Health) and the Relationship Dynamics and Social Life study (RDSL). Although the specific survey measures and sample composition of the two data sets are different, the dimensionality of the concepts and the content of the items used to measure their latent factors are remarkably consistent across the two data sets, and the factors are predictive of subsequent contraceptive behavior. However, some survey items do not seem strongly related to any dimension of either construct, and some dimensions of the two concepts appear to be poorly measured with existing survey questions. Nonetheless, we argue that the concepts of reproductive attitudes and reproductive knowledge are useful for categorizing and analyzing social psychological measures related to unintended fertility. The results can be used to guide secondary data analyses to predict reproductive behavior, compare results across data sets, and structure future data collection efforts. PMID- 30523560 TI - Correction to: The Use of Sideline Video Review to Facilitate Management Decisions Following Head Trauma in Super Rugby. AB - In the original article [1] reference was made to the Hawk-Eye system having been used as the sideline operating system during the 2015 season. PMID- 30523561 TI - Sustained low-efficiency dialysis for metformin-associated lactic acidosis in patients with acute kidney injury. AB - BACKGROUND: The choice of the specific modality and treatment duration of renal replacement therapy (RRT) to adopt in metformin-associated lactic acidosis (MALA) is still debated. We aimed to verify if sustained low-efficiency dialysis (SLED) is a rational choice in patients with MALA and acute kidney injury (AKI). METHODS: We collected serial serum metformin measurements, clinical parameters, and outcome data in ten consecutive patients (mean age 77 years [range 58-88], 5 males) admitted to our renal intensive care unit for suspected MALA associated with AKI and hemodynamic instability. Patients underwent a 16-h SLED session performed with either conventional dialysis machines or machines for continuous RRT (CRRT). A 2-compartment open-infusion pharmacokinetic model with first-order elimination was fitted to each subject's serum concentration-time data to model post-SLED rebound and predict the need for further treatments. RESULTS: Two patients died within 24 h after SLED start. Three patients needed one further dialysis session. Surviving patients (n = 8) were dialysis-free at discharge. Metformin levels were in the toxic range at baseline (median [range] 32.5 mg/l [13.6-75.6]) and decreased rapidly by the end of SLED (8.1 mg/l [4.5-15.8], p < 0.001 vs. baseline), without differences according to the dialysis machine used (p = 0.84). We observed a slight 4-h post-SLED rebound (9.7 mg/l [3.5-22.0]), which could be predicted by our pharmacokinetic model. Accordingly, we predicted that the majority of patients would need one additional dialysis session performed the following day to restore safe metformin levels. CONCLUSIONS: A 16-h SLED session, performed with either conventional dialysis machines or CRRT machines, allows effective metformin removal in patients with MALA and AKI. However, due to possible post-SLED rebound in serum metformin levels, one additional dialysis treatment is required the following day in the majority of patients. PMID- 30523562 TI - Subclinical AKI: ready for primetime in clinical practice? AB - There has been considerable progress over the last decade in the standardization of the acute kidney injury (AKI) definition with the publication of the RIFLE, AKIN, KDIGO and ERBP classification criteria. However, these classification criteria still rely on imperfect parameters such as serum creatinine and urinary output. The use of timed urine collections, kinetic eGFR (estimated glomerular filtration rate), real time measurement of GFR and direct measures of tubular damage can theoretically aid in a more timely diagnosis of AKI and improve patients' outcome. There has been an extensive search for new biomarkers indicative of structural tubular damage but it remains controversial whether these new markers should be included in the current classification criteria. The use of these markers has also led to the creation of a new concept called subclinical AKI, a condition where there is an increase in biomarkers but without clinical AKI, defined as an increase in serum creatinine and/or a decrease in urinary output. In this review we provide a framework on how to critical appraise biomarker research and on how to position the concept of subclinical AKI. The evaluation of biomarker performance and the usefulness of the concept 'subclinical AKI' requires careful consideration of the context these biomarkers are used in (clinical versus research setting) and the goal we want to achieve (risk assessment versus prediction versus early diagnosis versus prognostication). It remains currently unknown whether an increase in biomarkers levels without functional repercussion is clinically relevant and whether including biomarkers in classification criteria will improve patients' outcome. PMID- 30523563 TI - When kidneys and lungs suffer together. AB - A significant interaction between kidneys and lungs has been shown in physiological and pathological conditions. The two organs can both be targets of the same systemic disease (eg., some vasculitides). Moreover, loss of normal function of either of them can induce direct and indirect dysregulation of the other one. Subjects suffering from COPD may have systemic inflammation, hypoxemia, endothelial dysfunction, increased sympathetic activation and increased aortic stiffness. As well as the exposure to nicotine, all the foresaid factors can induce a microvascular damage, albuminuria, and a worsening of renal function. Renal failure in COPD can be unrecognized since elderly and frail patients may have normal serum creatinine concentration. Lungs and kidneys participate in maintaining the acid-base balance. Compensatory role of the lungs rapidly expresses through an increase or reduction of ventilation. Renal compensation usually requires a few days as it is achieved through changes in bicarbonate reabsorption. Chronic kidney disease and end-stage renal diseases increase the risk of pneumonia. Vaccination against Streptococcus pneumonia and seasonal influenza is recommended for these patients. Vaccines against the last very virulent H1N1 influenza A strain are also available and effective. Acute lung injury and acute kidney injury are frequent complications in critical illnesses, associated with high morbidity and mortality. The concomitant failure of kidneys and lungs implies a multidisciplinary approach, both in terms of diagnostic processes and therapeutic management. PMID- 30523564 TI - Efficacy of laser surgery versus radiotherapy for treatment of glottic carcinoma: a systematic review and meta-analysis. AB - Laser surgery and radiotherapy are the two most common ways to treat glottic carcinomas, which is more efficacious and remains controversial. PubMed, Embase, and Cochrane Library were searched to identify relevant studies of laser surgery versus radiotherapy in patients with glottic carcinomas through April 2017. Sensitivity analysis and subgroup analysis were performed to evaluate heterogeneity. Eighteen studies were selected, which included 2480 patients. Patients who had laser surgery had higher rates of laryngeal preservation (OR 3.852; 95% CI 1.922-7.721) and overall survival (OR 1.388; 95% CI 1.063-1.811) versus who had radiotherapy. No significant differences were observed between laser surgery and radiotherapy on local control (OR 1.186; 95% CI 0.759-1.854), recurrence (OR 0.758; 95% CI 0.445-1.289), or disease-specific survival (OR 1.597; 95% CI 0.887-2.876). There were clinical benefits for patients with glottic carcinoma after laser surgery compared with radiotherapy with respect to survival and laryngeal preservation. PMID- 30523565 TI - Prognostic and Predictive Epigenetic Biomarkers in Oncology. AB - Epigenetic patterns, such as DNA methylation, histone modifications, and non coding RNAs, can be both driver factors and characteristic features of certain malignancies. Aberrant DNA methylation can lead to silencing of crucial tumor suppressor genes or upregulation of oncogene expression. Histone modifications and chromatin spatial organization, which affect transcription, regulation of gene expression, DNA repair, and replication, have been associated with multiple tumors. Certain microRNAs (miRNAs), mainly those that silence tumor suppressor genes and occur in a greater number of copies, have also been shown to promote oncogenesis. Multiple patterns of these epigenetic factors occur specifically in certain malignancies, which allows their potential use as biomarkers. This review presents examples of tests for each group of epigenetic factors that are currently available or in development for use in early cancer detection, prediction, prognosis, and response to treatment. The availability of blood-based biomarkers is noted, as they allow sampling invasiveness to be reduced and the sampling procedure to be simplified. The article stresses the role of epigenetics as a crucial element of future cancer diagnostics and therapy. PMID- 30523566 TI - Robot-assisted abdominal wall surgery: a systematic review of the literature and meta-analysis. AB - PURPOSE: The number of robot-assisted hernia repairs is increasing, but the potential benefits have not been well described. The aim of this study was to evaluate the available literature reporting on outcomes after robot-assisted hernia repairs. METHODS: This is a qualitative review and meta-analysis of papers evaluating short-term outcomes after inguinal or ventral robot-assisted hernia repair compared with either open or laparoscopic approach. The primary outcome was postoperative complications and secondary outcomes were duration of surgery, postoperative length of stay and financial costs. RESULTS: Fifteen studies were included. Postoperative complications were significantly decreased after robot assisted inguinal hernia repair compared with open repair. There were no differences in complications between robot-assisted and laparoscopic inguinal hernia repair. For ventral hernia repair, sutured closure of the defect, retromuscular mesh placement and transversus abdominis release is feasible when using the robot. Length of stay was decreased by a mean of 3 days for robot assisted repairs compared with open approach. There were no differences in postoperative complications and the operative time was significantly longer for robot-assisted ventral hernia repair compared with laparoscopic or open approach. CONCLUSIONS: For ventral hernias that would normally require an open procedure, a robot-assisted repair may be a good option, as the use of a minimally invasive approach for these procedures decreases length of stay significantly. For inguinal hernias, the benefit of the robot is questionable. Randomized controlled trials and prospective studies are needed. PMID- 30523567 TI - A note on the relationship between age and health-related quality of life assessment. AB - PURPOSE: To extend existing analyses of whether and how the age of respondents is related to their time trade-off (TTO) valuations of hypothetical EQ-5D-3L health states, and to contribute to the existing debate about the rationale and implications for using age-specific utilities in health technology assessment (HTA). METHODS: We use data from the MVH UK valuation study. For each profile, the mean TTO value-adjusted by sex, education, self-reported health and personal experience of serious illness-is pairwise compared across the different age groups. A Bonferroni correction is applied to the multiple testing of significant differences between means. Smile plots illustrate the results. A debate regarding whether there is a case for using age-specific utilities in HTAs complements the analysis. RESULTS: Results show that the oldest respondents value health profiles lower than younger age groups, particularly for profiles describing problems in the mobility dimension. CONCLUSION: The findings raise the possibility of using age-specific value sets in HTAs, since a technology may not be cost-effective on average but cost-effective for a sub-group whose preferences are more closely aligned to the benefits offered by the technology. PMID- 30523568 TI - Relative impacts of fishing and eutrophication on coastal fish assessed by comparing a no-take area with an environmental gradient. AB - Understanding the relative impacts of pressures on coastal ecosystems is central for implementing relevant measures to reach environmental management objectives. Here, survey data on the species and size composition of coastal fish are evaluated in relation to fishing and eutrophication, by comparing a long-standing no-take area to an environmental gradient in the Baltic Sea. The no-take area represents an intermediate eutrophication level, but the species composition resembles that seen at low eutrophication in areas with fishing. The catch biomass of piscivores is 2-3 times higher in the no-take area than in the other areas, while the biomass of Cyprinids, generally benefitted by eutrophication, corresponds to that of areas with low eutrophication. The results support that fishing may generate eutrophication-like effects, and, conversely, that no-take areas may contribute to improving environmental status in impacted areas by enhancing piscivores, which in turn may contribute to further improvement in the food web. PMID- 30523569 TI - Capturing Biology in Flight. PMID- 30523570 TI - Gas-Phase Dynamics of Collision Induced Unfolding, Collision Induced Dissociation, and Electron Transfer Dissociation-Activated Polymer Ions. AB - Polymer characterizations are often performed using mass spectrometry (MS). Aside from MS and different tandem MS (MS/MS) techniques, ion mobility-mass spectrometry (IM-MS) has been recently added to the inventory of characterization technique. However, only few studies have focused on the reproducibility and robustness of polymer IM-MS analyses. Here, we perform collisional and electron mediated activation of polymer ions before measuring IM drift times, collision cross-sections (CCS), or reduced ion mobilities (K0). The resulting IM behavior of different activated product ions is then compared to non-activated native intact polymer ions. First, we analyzed collision induced unfolding (CIU) of precursor ions to test the robustness of polymer ion shapes. Then, we focused on fragmentation product ions to test for shape retentions from the precursor ions: cation ejection species (CES) and product ions with m/z and charge state values identical to native intact polymer ions. The CES species are formed using both collision induced dissociation (CID) and electron transfer dissociation (ETD, formally ETnoD) experiments. Only small drift time, CCS, or K0 deviations between the activated/formed ions are observed compared to the native intact polymer ions. The polymer ion shapes seem to depend solely on their mass and charge state. The experiments were performed on three synthetic homopolymers: poly(ethoxy phosphate) (PEtP), poly(2-n-propyl-2-oxazoline) (Pn-PrOx), and poly(ethylene oxide) (PEO). These results confirm the robustness of polymer ion CCSs for IM calibration, especially singly charged polymer ions. The results are also discussed in the context of polymer analyses, CCS predictions, and probing ion-drift gas interaction potentials. Graphical Abstract ?. PMID- 30523571 TI - An Antagonism Joint Action of Lead and Di-2-Ethylhexyl Phthalate Explains an Improved Ability of Learning and Memory after Combined Exposure in Weaning Rats. AB - Lead and di-2-ethylhexyl phthalate (DEHP) are widely distributed in the environment, and their neurotoxicity has caused a widespread concern. The complexity of environmental exposure provides the possibility of their combined exposure. The present study aims to describe a joint neurotoxicity and clarify the potential mechanism after combined exposure to lead and DEHP. A 2 * 3 factorial design was used to analyze either single effects or their interaction by a subchronic lead and DEHP exposure model of the male weaning rats. Similar to the previous study, lead or DEHP single exposure showed an increased neurotoxicity. Interestingly, our neurobehavioral test showed the rats in the combined exposure groups had a better ability of learning and memory compared with the single-exposure ones. It seemed to reflect an antagonism joint action in neurotoxicity after combined exposure. The content of dehydroepiandrosterone (DHEA) in serum and the mRNA level of brain-derived neurotrophic factor (Bdnf) in the hippocampus showed a similar trend to the ability of learning and memory. However, there was insufficient evidence to support the joint action on some indexes of oxidative stress such as malondialdehyde (MDA), the ratio of reduced glutathione(GSH) to oxidized glutathione(GSSG), gammaglutamylcysteine synthetase (gamma-GCS), glutathione-s transferase (GST), and nuclear factor E2-related factor 2 (Nrf2) mRNA expression in the hippocampus. In a word, our current study reminded a unique antagonism joint action of neurotoxicity after combined exposure to lead and DEHP, which may contribute to understanding some shallow mechanism of the joint toxicity due to the complexity of environmental pollutant exposure. PMID- 30523572 TI - Selenium Attenuates Staphylococcus aureus Mastitis in Mice by Inhibiting the Activation of the NALP3 Inflammasome and NF-kappaB/MAPK Pathway. AB - Mastitis is one of the most important diseases affecting the dairy industry in the world, and it also poses a great threat to human food safety. In this study, we explored whether selenium can inhibit the activation of the NALP3 inflammasome and NF-kappaB/MAPK pathway to achieve anti-inflammatory effects. Sixty BALB/c female mice were randomly divided into three groups according to diets of different selenium concentrations (high, normal, and low). After 90 days, mice fed the same selenium concentration were randomly divided into two smaller groups, one of which was inoculated with Staphylococcus aureus and the other injected with saline as a control. Through histopathologic examination staining, western blot, qPCR, and ELISA, the results showed that with increasing selenium concentrations, the expression levels of IL-1beta, TNF-alpha, NALP3, caspase-1, and ASC were decreased in mouse mammary tissue. Therefore, this study revealed that selenium can attenuate S. aureus mastitis by inhibiting the activation of the NALP3 inflammasome and NF-kappaB/MAPK pathway. PMID- 30523573 TI - The Effect of Mercury Chloride and Boric Acid on Rat Erythrocyte Enzymes. AB - The aim of this study was to investigate the effects of mercury chloride and boric acid on rat (Wistar albino) erythrocyte: glucose 6-phosphate dehydrogenase (G6PD), 6-phosphoglucona-te dehydrogenase (6PGD), thioredoxin reductase (TrxR), glutathione reductase (GR) and glutathione S-transferase (GST) enzymes in vivo, and the rat erythrocyte G6PD enzyme in vitro. In the in vivo study, 24 male rats were divated into three different groups: control (C), mercury chloride (M), and mercury chloride + boric acid (M + BA). At the completion of this study, a significant degree of inhibition for both G6PD and GST enzyme activity was observed in the M groups when compared to the C group (p < 0.05), and no significant effect was observed in the 6PGD enzyme. However, there was significantly increased TrxR and GR enzyme activity of both the M and M + BA groups (p < 0.05). In the in vitro study, the G6PD enzyme from rat erythrocytes was purified with 2',5'-ADP Sepharose-4B affinity chromatography, and the effect of both mercury chloride and boric acid on the enzyme activity was investigated. The results showed that boric acid increased the G6PD enzyme activity while the mercury ions that inhibited the enzyme activity (IC50 values of 346 MUM and Ki values of 387 MUM) were noncompetitive. PMID- 30523574 TI - Contingency awareness as a prerequisite for differential contextual fear conditioning. AB - Contingency awareness during conditioning describes the phenomenon of becoming consciously aware of the association between a conditioned stimulus (CS) and an unconditioned stimulus (US). Despite the fact that contingency awareness is necessary for associative learning in some conditioning paradigms, its role in contextual fear conditioning, a variant that uses a context-CS (CTX) instead of a cue, has not been characterized thus far. We investigated if contingency awareness is a prerequisite for contextual fear conditioning and if subjects classified as aware differ from unaware subjects on a hemodynamic, autonomic, and behavioral level. We used a computer-generated picture context as CTX and slightly painful electric stimulation as US while we recorded brain responses by functional magnetic resonance imaging (fMRI), and obtained skin conductance responses (SCR) and verbal ratings of emotional valence and arousal. SCR analyses revealed that only aware subjects became conditioned to the US-associated CTX (CTX+). Brain activity related to the CTX+ was more strongly pronounced in fear associated areas like the insula in the aware relative to the unaware group. Finally, the hippocampus was functionally connected to the cingulate cortex and posterior medial frontal gyrus in aware subjects relative to unaware subjects. These task-related differential connectivity patterns suggest that information exchange between the hippocampus and regions involved in the expression of conditioned fear and decision uncertainty is crucial for the acquisition of contingency knowledge. This study demonstrates the importance of contingency awareness for contextual fear conditioning and points to the hippocampus as a potential mediator for contingency learning in contextual learning. PMID- 30523575 TI - Effect of age, sex, and season on the prevalence of Linguatula serrata infestation in mesenteric lymph nodes of goats slaughtered in Tabriz, Iran. AB - This research was conducted to determine the prevalence and intensity of infection with nymphs of Linguatula serrata in mesenteric lymph nodes of the goats from northwest of Iran. Moreover, the intensity of infection of mesenteric lymph nodes was compared based on gross appearance and the morphological changes in these nodes. In addition, the effects of age, sex, and season on the prevalence of Linguatula serrata were assessed. In this study, mesenteric lymph nodes (n = 16,284) were randomly collected from 2132 goats slaughtered in the abattoir of Tabriz, Iran, from September 2013 to September 2017. The samples were categorized based on their gross appearance (color and consistency) and then were cut into small pieces and immersed in normal saline (0.9% NaCl) solution and left for 5 to 6 h to allow nymphs to come out from the tissue. The results showed that 1241 out of total 2132 (58. 2%) goats and 9282 out of total 16,284 mesenteric lymph nodes (57%) were infested with the nymphal stage of Linguatula serrata. It was also revealed that the infestation rate was age-dependent: as the goats grow older, the infestation increases. Further, the prevalence of Linguatula serrata nymphs in the mesenteric lymph nodes in various seasons was not significant (P > 0.05). The prevalence of infestation rate in female goats was significantly higher than of male goats (P < 0.05). Besides, the infestation rate in the black colored lymph nodes (75.88%) was significantly (P < 0.05) higher than those of hemorrhagic nodes (54.94%) and normal-colored nodes (22.65%). Moreover, the infestation rate of nymphs in the soft lymph nodes (83.91%) was significantly (P < 0.05) higher than those in normal (21.85%) and hard (32.43%) lymph nodes. Given the fact that the Linguatula serrata is a zoonotic parasite; thus, the inspection process should be meticulously done in an abattoir, especially in areas where residents consume raw or under-cooked liver and/or visceral organs of herbivores. PMID- 30523576 TI - Diabetes and Alzheimer's Disease: A Link not as Simple as it Seems. AB - Type 2 diabetes mellitus is associated with an increased risk to develop Alzheimer disease, however, the underlying mechanisms for this association are still unclear. In this review we will provide a critical overview of the major findings coming from clinical studies and animal models. PMID- 30523577 TI - Striatal Protection in nNOS Knock-Out Mice After Quinolinic Acid-Induced Oxidative Damage. AB - Under pathological conditions, nitric oxide can become a mediator of oxidative cellular damage, generating an unbalance between oxidant and antioxidant systems. The participation of neuronal nitric oxide synthase (nNOS) in the neurodegeneration mechanism has been reported; the activation of N-methyl-D aspartate (NMDA) receptors by agonist quinolinic acid (QUIN) triggers an increase in nNOS function and promotes oxidative stress. The aim of the present work was to elucidate the participation of nNOS in QUIN-induced oxidative stress in knock out mice (nNOS-/-). To do so, we microinjected saline solution or QUIN in the striatum of wild-type (nNOS +/+), heterozygote (nNOS+/-), and knock-out (nNOS-/-) mice, and measured circling behavior, GABA content levels, oxidative stress, and NOS expression and activity. We found that the absence of nNOS provides a protection against striatal oxidative damage induced by QUIN, resulting in decreased circling behavior, oxidative stress, and a partial protection reflected in GABA depletion. We have shown that nNOS-derived NO is involved in neurological damage induced by oxidative stress in a QUIN-excitotoxic model. PMID- 30523578 TI - Molecular Mechanisms of Early and Late LTP. AB - LTP is the most intensively studied cellular model of the memory and generally divided at least two distinct phases as early and late. E-LTP requires activation of CaMKII that initiates biochemical events and trafficking of proteins, which eventually potentiate synaptic transmission, and is independent of de novo protein synthesis. In contrast, L-LTP requires gene expression and local protein synthesis regulated via TrkB receptor- and functional prions CPEB2-3-mediated translation. Maintenance of LTP for longer periods depends on constitutively active PKMzeta. Throughout this review, current knowledge about early and late phases of LTP will be reviewed. PMID- 30523579 TI - Second generation of primaquine ureas and bis-ureas as potential antimycobacterial agents. AB - Here, we describe design and synthesis of twelve novel compounds bearing primaquine motif and hydroxy- or halogenamine linked by an urea or bis-urea spacer. Preparation of ureas 3a-f started with the conversion of primaquine to benzotriazolide 2 and aminolysis of the later compound by 4-(2-aminoethyl)phenol or amino alcohols bearing fluorine atom, cycloalkyl or trifluoromethyl group under microwave irradiation. The four-step sequence leading to bis-ureas 6a-f included preparation of benzotriazolide 2 and two intermediates, semicarbazide 4 and benzotriazole bis-urea 5, which upon aminolysis with the same aminophenol or amino alcohols gave the title compounds. Antimycobacterial screening detected three active compounds against Mycobacterium marinum and M. tuberculosis, namely 3b, 3f and 6f, derived from cyclobutyl amino alcohol or amino phenol. PMID- 30523580 TI - Silencing of FOXRED1 in C57b1/6 mice does not generate an appropriate animal model of Leigh syndrome. PMID- 30523581 TI - Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. AB - Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer's disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Abeta and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Abeta and the migration of astrocyte to Abeta. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia. PMID- 30523582 TI - Correction to: Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol. AB - In the original publication, the text in Table 2 stated 'Hypersensitivity to the active substance, to Ferinject, or to any of its excipients'. PMID- 30523583 TI - Perceived barriers to the preservation and improvement of children's oral health among Iranian women: a qualitative study. AB - AIM: To explore perceptions of Iranian mothers regarding barriers to preserving and improving oral health among their children. METHODS: The present qualitative study was part of a larger sequential exploratory mixed-method study conducted in Tehran, Iran, from April to May 2015. Data were collected via 10 focus group discussions and semi-structured interviews to gain an understanding of the perception held by the mothers of school-aged children about barriers to oral health improvement. Sampling was purposive and was continued until data saturation was reached. The study population consisted of 58 Iranian women who had at least one child in school. Data were analysed using conventional content analysis. RESULTS: Three key themes of oral health barriers were identified as follows: (1) barriers in the system or at the organisational level, (2) barriers at the provider level, and (3) barriers at the family level. Informants reported cost, lack of full-coverage insurance, low access to dental services, and fear and anxiety as the main barriers. CONCLUSIONS: The major barriers to oral health care were fear and the cost of dental treatments. These predictors need to be addressed when designing programs to increase access of children to dental services. PMID- 30523584 TI - Resource utilization and hospital readmission associated with gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices. AB - Gastrointestinal bleeding (GIB) occurs in up to 40% of patients with continuous flow (CF) left ventricular assist devices (LVADs). We sought to identify targets to improve hospital resource utilization and decrease readmissions after GIB. We performed a single-center, retrospective analysis of LVAD-associated GIB resulting in hospital admission between July 2011 and April 2014. Follow-up data were collected through March 2015. We analyzed 57 admissions for GIB in 23 patients. One or more diagnostic imaging study was performed in 47% of admissions, with a definite or probable source of GIB identified in 23%. A total of 76 endoscopies were performed (>= 1 endoscopy in 79% of admissions, >= 2 in 42%). Definite or probable bleeding sources were identified in 25% and 12% of endoscopies, respectively. Patients who underwent multiple endoscopies were no more likely to have a bleeding source identified (OR 1.48; 95% CI 0.50-4.32; p = 0.59) and had longer hospital stays (11.1 vs. 7.8 days, p < 0.02). Readmission rates for GIB at 30 and 90 days were 33% and 53%, respectively. A decrease in antiplatelet regimen at discharge was associated with lower rate of readmission for GIB (OR 0.16; 95% CI 0.03-0.82; p = 0.03) or any cause (OR 0.21; 95% CI 0.05 0.85; p = 0.04) at 30 and 90 days. GIB in patients with CF-LVADs is associated with significant in-hospital resource utilization and high rates of readmission. Imaging and endoscopy are common, but have low diagnostic yield and infrequently result in successful intervention. Strategies to reduce resource utilization and prevent readmission are warranted. PMID- 30523585 TI - Pericyte Biology: Development, Homeostasis, and Disease. AB - In the nineteenth century, a French researcher, Charles-Marie Benjamin Rouget, revealed a population of contractile cells associated with small blood vessels, which were initially named after him as the Rouget cells. In the twentieth century, a German scientist, Karl Wilhelm Zimmermann, called these cells "pericytes" due to their anatomical position located in a perivascular position. The word pericyte was derived from "peri" meaning "around" and "cyte" from the word "kytos" (cell), illustrating a cell encircling a blood vessel. Until now, pericytes are still identified partially based on their specific anatomical location and morphology. Pericytes are present in all vascularized tissues, surrounding blood vessel walls. They encircle endothelial cells and communicate with them along the length of the blood vessels by paracrine signaling and physical contacts. Previously, the accurate distinction of pericytes from other perivascular cells was difficult, as electron and light microscopy were the sole available techniques capable to image these cells, limiting the information acquired from those works. This resulted in the misleading assumption that pericytes are merely inert supporting cells, limited exclusively to the physiological function of vascular stability. In the last 10 years, the combination of fluorescent and confocal microscopy with genetic state-of-art techniques, such as fate lineage tracing, enabled remarkable progress in the discovery of multiple novel essential functions for pericytes in health and disease, before unexpected. Recently, the rapidly expanding understanding of the pathophysiological roles of pericytes drew the attention of several research groups. Now, we know, for instance, that pericytes may play immune functions: attract innate leukocytes to exit via sprouting blood vessels, regulate lymphocyte activation, and contribute to the clearance of toxic by-products, having direct phagocytic activity. Pericytes also may behave as stem cells, forming other cell populations, as well as regulate the behavior of other stem cells in their niches. Very little is known about the exact identity of pericyte ancestors within developing tissues, and there is evidence for multiple distinct developmental sources. Pericytes differ in their embryonic origins between tissues and also within the same organ. Importantly, pericytes from distinct tissues may differ in their distribution, morphology, expression of molecular markers, plasticity, and functions; and, even within the same organ, there are various pericyte subpopulations. This book describes the major contributions of pericytes to different organ biology in physiological and pathological conditions. Further insights into the biology of pericytes will have important implications for our understanding of organ development, homeostasis, and disease. This book's initial title was "Pericyte Biology: Development, Homeostasis, and Disease." However, due to the current great interest in this topic, we were able to assemble more chapters than would fit in one book, covering pericyte biology under distinct circumstances. Therefore, the book was subdivided into three volumes entitled: "Pericyte Biology: Novel Concepts," "Pericyte Biology in Different Organs," and "Pericyte Biology in Disease." Here, we present a selected collection of detailed chapters on what we know so far about pericytes. More than 30 chapters written by experts in the field summarize our present knowledge on pericyte biology. Here, we present a selected collection of detailed chapters on what we know so far about pericytes. More than 30 chapters written by experts in the field summarize our present knowledge on pericyte biology. PMID- 30523586 TI - The NG2 Proteoglycan in Pericyte Biology. AB - Studies of pericytes have been retarded by the lack of appropriate markers for identification of these perivascular mural cells. Use of antibodies against the NG2 proteoglycan as a pericyte marker has greatly facilitated recent studies of pericytes, emphasizing the intimate spatial relationship between pericytes and endothelial cells, allowing more accurate quantification of pericyte/endothelial cell ratios in different vascular beds, and revealing the participation of pericytes throughout all stages of blood vessel formation. The functional importance of NG2 in pericyte biology has been established via NG2 knockdown (in vitro) and knockout (in vivo) strategies that reveal significant deficits in blood vessel formation when NG2 is absent from pericytes. NG2 influences pericyte proliferation and motility by acting as an auxiliary receptor that enhances signaling through integrins and receptor tyrosine kinase growth factor receptors. By acting in a trans orientation, NG2 also activates integrin signaling in closely apposed endothelial cells, leading to enhanced maturation and formation of endothelial cell junctions. NG2 null mice exhibit reduced growth of both mammary and brain tumors that can be traced to deficits in tumor vascularization. Use of Cre-Lox technology to produce pericyte-specific NG2 null mice has revealed specific deficits in tumor vessels that include decreased pericyte ensheathment of endothelial cells, diminished assembly of the vascular basement membrane, reduced vessel patency, and increased vessel leakiness. Interestingly, myeloid specific NG2 null mice exhibit even larger deficits in tumor vascularization, leading to correspondingly slower tumor growth. Myeloid-specific NG2 null mice are deficient in their ability to recruit macrophages to tumors and other sites of inflammation. This absence of macrophages deprives pericytes of a signal that is crucial for their ability to interact with endothelial cells. The interplay between pericytes, endothelial cells, and macrophages promises to be an extremely fertile area of future study. PMID- 30523587 TI - Pericytes for Therapeutic Bone Repair. AB - Besides seminal functions in angiogenesis and blood pressure regulation, microvascular pericytes possess a latent tissue regenerative potential that can be revealed in culture following transition into mesenchymal stem cells. Endowed with robust osteogenic potential, pericytes and other related perivascular cells extracted from adipose tissue represent a potent and abundant cell source for refined bone tissue engineering and improved cell therapies of fractures and other bone defects. The use of diverse bone formation assays in vivo, which include mouse muscle pocket osteogenesis and calvaria replenishment, rat and dog spine fusion, and rat non-union fracture healing, has confirmed the superiority of purified perivascular cells for skeletal (re)generation. As a surprising observation though, despite strong endogenous bone-forming potential, perivascular cells drive bone regeneration essentially indirectly, via recruitment by secreted factors of local osteo-progenitors. PMID- 30523589 TI - The Microvascular Pericyte: Approaches to Isolation, Characterization, and Cultivation. AB - The microvascular pericyte was identified in 1873 by the French scientist Charles Benjamin Rouget and originally called the Rouget cell (Rouget.Sciences 88:916-8, 1879). However, it was not until the early 1900s that Rouget's work was confirmed, and the Rouget cell renamed the pericyte by virtue of its peri endothelial location (Dore. Brit J Dermatol 35:398-404, 1923; Zimmermann. Z Anat Entwicklungsgesch 68:3-109, 1923). Over the years a large number of publications have emerged, but the pericyte has remained a truly enigmatic cell. This is due, in part, by the paucity of easy and reliable methods to isolate and characterize the cell as well as its heterogeneity and pluripotent characteristics. However, more recent advances in molecular genetics and development of novel cell isolation and imaging techniques have enable scientists to more readily define pericyte function. This chapter will discuss general approaches to the isolation, characterization, and propagation of primary pericytes in the establishment of cell lines. We will attempt to dispel misinterpretations about the pericyte that cloud the literature. PMID- 30523588 TI - Pericyte Biology in Zebrafish. AB - The zebrafish is an outstanding model for studying vascular biology in vivo. Pericytes and vascular smooth muscle cells can be imaged as they associate with vessels and provide stability and integrity to the vasculature. In zebrafish, pericytes associate with the cerebral and trunk vasculature on the second day of development, as assayed by pdgfrbeta and notch3 markers. In the head, cerebral pericytes are neural crest derived, except for the pericytes of the hindbrain vasculature, which are mesoderm derived. Similar to the hindbrain, pericytes on the trunk vasculature are also mesoderm derived. Regardless of their location, pericyte development depends on a complex interaction between blood flow and signalling pathways, such as Notch, SONIC HEDGEHOG and BMP signalling, all of which positively regulate pericyte numbers.Pericyte numbers rapidly increase as development proceeds in order to stabilize both the blood-brain barrier and the vasculature and hence, prevent haemorrhage. Consequently, compromised pericyte development results in compromised vascular integrity, which then evolves into detrimental pathologies. Some of these pathologies have been modelled in zebrafish by inducing mutations in the notch3, foxc1 and foxf2 genes. These zebrafish models provide insights into the mechanisms of disease as associated with pericyte biology. Going forward, these models may be key contributors in elucidating the role of vascular mural cells in regulating vessel diameter and hence, blood flow. PMID- 30523590 TI - Pericytes in Veterinary Species: Prospective Isolation, Characterization and Tissue Regeneration Potential. AB - Although pericytes have long been known for their roles in blood vessel regulation, it was not until a decade ago that their tissue regeneration potential began to be considered, after studies showed that pericytes were the in vivo counterparts of mesenchymal stem/stromal cells (MSCs). The prospective isolation and culture expansion of pericytes brought great excitement as it opened the way to the therapeutic use of well-defined cell populations with known regenerative potential to overcome concerns associated with the use of traditional MSC preparations. Studies first in humans and later in the horse and other domestic species showed that indeed cultured pericytes had key characteristics of MSCs, namely, their immunophenotype and the abilities to grow clonally and to differentiate into mature mesenchymal cells both in vitro and vivo. Several studies with human pericytes, and to a much lesser extent with animal pericytes, have also shown significant promise in tissue repair in different disease models. This review summarizes current knowledge on the tissue regeneration properties of pericytes from domestic animals and outlines future steps necessary for realizing their full potential both in clinical veterinary medicine and in preclinical testing of human therapies using large animal models, including the need for robust approaches for isolation, culture and appropriate in vivo testing of the tissue regenerative properties of pericytes in these species. PMID- 30523591 TI - Pericytes in the Human Vocal Fold Mucosa. AB - 1. The human vocal fold is a vibrating tissue and vascular structures in organs which have the capacity to vibrate require a specific structure suitable for vibration. 2. The structure of the blood vessels is unique at the vocal fold edge as a vibrating tissue, where only small vessels, including arterioles, venules, and capillaries, are present. The capillaries are distributed in the superficial layer of the lamina propria (Reinke's space). 3. The blood vessels enter the vocal fold edge from the anterior or posterior end of the membranous vocal fold and run essentially parallel to the vocal fold edge. 4. Many pericytes can be seen around the capillaries in the human vocal fold mucosa. The cell bodies of the pericytes attach to capillary endothelial cells, and the branching processes encircle the capillaries and attach to the capillary endothelial cells at the tips. The processes of pericytes are in close contact with endothelial cells, sharing a common basement membrane with them. The tips of the processes form intercellular tight junctions with endothelial cells. 5. The pericytes in the vocal fold mucosa appear to provide mechanical support and protection to the capillary walls, particularly during phonation. The pericytes also appear to regulate the diameter of the capillary during and after phonation. Pericytes are also thought to be critical cells in vascular biology and angiogenesis, especially in revascularization following vocal fold tissue injury. 6. At birth, pericytes have already encircled the capillaries in the newborn vocal fold mucosa. The pericytes appear ready to provide support and protection of the blood vessels just after birth. 7. Vascular structures and their permeability are related to the specific structures and specific diseases of the human vocal fold mucosa as a vibrating tissue. PMID- 30523592 TI - Ca2+ Signalling in Pericytes. AB - Microcirculation is the generic name for the finest level of the circulatory system and consists of arteriolar and venular networks located upstream and downstream of capillaries, respectively. Anatomically arterioles are surrounded by a monolayer of spindle-shaped smooth muscle cells (myocytes), while terminal branches of precapillary arterioles, capillaries and all sections of postcapillary venules are surrounded by a monolayer of morphologically different perivascular cells (pericytes). Pericytes are essential components of the microvascular vessel wall. Wrapped around endothelial cells, they occupy a strategic position at the interface between the circulating blood and the interstitial space. There are physiological differences in the responses of pericytes and myocytes to vasoactive molecules, which suggest that these two types of vascular cells could have different functional roles in the regulation of local blood flow within the same microvascular bed. Also, pericytes may play different roles in different microcirculatory beds to meet the characteristics of individual organs. Contractile activity of pericytes and myocytes is controlled by changes of cytosolic free Ca2+concentration. In this chapter, we attempt to summarize the results in the field of Ca2+ signalling in pericytes especially in light of their contractile roles in different tissues and organs. We investigate the literature and describe our results regarding sources of Ca2+, relative importance and mechanisms of Ca2+ release and Ca2+ entry in control of the spatio temporal characteristics of the Ca2+ signals in pericytes, where possible Ca2+ signalling and contractile responses in pericytes are compared to those of myocytes. PMID- 30523593 TI - Pericytes Derived from Human Pluripotent Stem Cells. AB - Pericytes wrap blood microvessels and are believed to play important roles in vascular morphogenesis, maturation, and stability. In addition, pericytes have emerged as candidates for targeting cancer growth and for wound healing. In order to model these processes and test new therapies, it is desirable to have a reliable, scalable source of pericytes. Human pluripotent stem cells (hPSCs), which possess the ability to differentiate into any cell type in the body, have been used to generate pericytes in vitro quickly, consistently, and with high yields. In this chapter, we consider the differentiation of pericytes from hPSCs. We compare the approaches taken by multiple groups and discuss characterization of hPSC-pericytes. Studying pericyte differentiation in vitro provides the opportunity to identify factors influencing pericyte development and to establish the ontogenic relationships between pericytes and similar cells. The development of highly specific, defined pericyte populations from hPSCs will enable downstream applications requiring large quantities of cells, including tissue engineered models and cell therapies. PMID- 30523594 TI - Pericytes in Tissue Engineering. AB - Pericytes have crucial roles in blood-brain barrier function, blood vessel function/stability, angiogenesis, endothelial cell proliferation/differentiation, wound healing, and hematopoietic stem cells maintenance. They can be isolated from fetal and adult tissues and have multipotential differentiation capacity as mesenchymal stem cells (MSCs). All of these properties make pericytes as preferred cells in the field of tissue engineering. Current developments have shown that tissue-engineered three-dimensional (3D) systems including multiple cell layers (or types) and a supporting biological matrix represent the in vivo environment better than those monolayers on plastic dishes. Tissue-engineered models are also more ethical and cheaper systems than animal models. This chapter describes the role of pericytes in tissue engineering for regenerative medicine. PMID- 30523595 TI - Pericyte Secretome. AB - The role of pericytes seems to extend beyond their known function in angiogenesis, fibrosis and wound healing, blood-brain barrier maintenance, and blood flow regulation. More and more data are currently accumulating indicating that pericytes, uniquely positioned at the interface between blood and parenchyma, secrete a large plethora of different molecules in response to microenvironmental changes. Their secretome is tissue-specific and stimulus specific and includes pro- and anti-inflammatory factors, growth factors, and extracellular matrix as well as microvesicles suggesting the important role of pericytes in the regulation of immune response and immune evasion of tumors. However, the angiogenic and trophic secretome of pericytes indicates that their secretome plays a role in physiological homeostasis but possibly also in disease progression or could be exploited for regenerative processes in the future. This book chapter summarizes the current data on the secretory properties of pericytes from different tissues in response to certain pathological stimuli such as inflammatory stimuli, hypoxia, high glucose, and others and thereby aims to provide insights into the possible role of pericytes in these conditions. PMID- 30523596 TI - ? PMID- 30523597 TI - ? PMID- 30523598 TI - ? PMID- 30523599 TI - Prognostic Value of Knowledge of Cancer and Used Unconventional Therapy Methods on Quality of Life in Advanced, Metastatic Colorectal Cancer in Clinical Practice. AB - Colorectal cancer (CRC) is the third most common malignancy in the world and the second cause of cancer-related deaths. Despite the search for new therapeutic agents, there are still many doubts concerning the quality of life (QOL) improvement in palliative patients. In this study, we assessed the impact of oncology knowledge on QOL and the relationship between QOL and various environmental factors and unconventional treatment methods in patients with CRC treated with chemotherapy and targeted therapy. The results of first-line palliative chemotherapy in 330 patients with colorectal cancer treated between January 2010 and December 2016 in two centers were analyzed. The average age of patients was 66 +/- 11.7 years. Median survival time was 25 months. In multivariate analysis, the performance status and response to treatment had a significant effect on survival time. A trend towards shorter survival was also observed in patients receiving 5-FU monotherapy, in elderly patients and in patients with less oncology knowledge. A relationship between general quality of life and performance status (PS 0 vs. PS > 0), response to treatment and oncology knowledge was found. Patients with limited oncology knowledge more often used unconventional therapy methods in parallel with the treatment. In patients over 70 years of age and in patients with worse overall condition, 5-FU monotherapy was more commonly used (p < 0.01). The level of oncology knowledge of the treated patients observed in everyday clinical practice may be related to some parameters of treatment effectiveness assessment, such as QOL and may be related to the use of unconventional treatment methods. Those, in turn may have an impact on the QOL of the treated patients. PMID- 30523600 TI - Correction to: Morphogen Gradients. AB - The book was published with the following errors: In Chapter 1, figure 1 was stretched. This misconfiguration has now been modified. PMID- 30523601 TI - Long-term deterioration after one-stage unicompartmental knee arthroplasty and anterior cruciate ligament reconstruction. AB - PURPOSE: Treatment for unicompartmental knee osteoarthritis (OA) is controversial in young patients with concomitant anterior cruciate ligament (ACL) deficiency. The aim of the current study is to report long-term results after the combination of unicompartmental knee arthroplasty (UKA) and ACL reconstruction. METHODS: Retrospective study of one-stage medial UKA and ACL reconstruction was performed on eight patients at a mean age of 52 years (42-60). Clinical and radiological results were assessed and analyzed after a mean follow-up of 14.6 years. RESULTS: Patients were satisfied and mean personal satisfaction rate was 8.8 (4-10). At the last follow-up, mean WOMAC score was 26 (1-52) and mean global KSS was 154 (102-200). One revision surgery to total knee arthroplasty was performed 9 years after the combined procedure due to aseptic loosening. One more case of clinical deterioration was observed 13 years after index surgery. CONCLUSIONS: Combined UKA and ACL reconstruction can be a therapeutic option for young and active patients with concomitant knee instability and unicompartmental OA. The procedure is highly demanding and reliable only in hands of experienced surgeons. Overall, satisfactory outcome can be achieved at a minimum follow-up of 10 years. However, clinical deterioration can be observed in the long term. PMID- 30523602 TI - MiR-374a Activates Wnt/beta-Catenin Signaling to Promote Osteosarcoma Cell Migration by Targeting WIF-1. AB - MiR-374a was proved to take part in the initiation and development of several cancers. However, the molecular mechanism of miR-374a in osteosarcoma (OS) cells remains unclear. The aim of our research was to investigate the role of miR-374a in OS cells migration and clarify the potential mechanisms. Quantitative real time PCR (qRT-PCR) and western blot analysis were applied to evaluate the expression of miR-374a and Wnt inhibitory factor-1 (WIF-1). Bioinformatical methods and luciferase reporter assay were carried out to predict and confirm the combination of miR-374a and WIF-1. Transwell and wound healing assays were performed to detect the migration capacity of OS cells. Lithium chloride (LiCl) was used to investigate the role of LiCl-activated Wnt/beta-catenin signaling pathway in regulating cell migration. Our studies revealed that miR-374a was up regulated whereas WIF-1 was down-regulated in OS cells. Besides, WIF-1 was the target of miR-374a by performing luciferase reporter assay. By transfection of miR-374a inhibitor and/or WIF-1 siRNA to OS cells, we found that miR-374a promoted the migration of OS cells. In addition, the inhibition of WIF-1 abolished the miR-374a inhibitor-induced migration suppression of OS cells. LiCl experiment revealed that miR-374a promoted OS cells migration by regulating Wnt/beta-catenin signaling. In conclusion, miR-374a promotes OS cells migration by activating Wnt/beta-catenin signaling pathway via targeting WIF-1. PMID- 30523603 TI - Potential Properties of Lactobacillus plantarum F-10 as a Bio-control Strategy for Wound Infections. AB - In this study, Lactobacillus plantarum F-10, a promising probiotic strain isolated from fecal microbiota of healthy breastfed infant, was assessed as a bio control strategy for wound infections. Pseudomonas aeruginosa PAO1/ATCC 27853, methicillin-resistant Staphylococcus aureus ATCC 43300, and their hospital derived strains isolated from skin chronic wound samples were used as important skin pathogens. The cell-free extract (CFE) of the strain F-10 was shown to inhibit the growth of all pathogens tested, while no inhibition was observed when CFE was neutralized. The strain displayed no hemolysis and exhibited a strong auto-aggregating phenotype (51.48 +/- 1.45%, 5 h) as well as co-aggregation. Antibiotic resistance profile was found to be safe according to the European Food Safety Authority. Biofilm formation was measured by crystal violet assay and visualized with scanning electron microscopy and confocal laser scanning microscopy. One hundred percent reduction in biofilm formation of all pathogens tested was obtained by sub-MIC value (12.5 mg/ml) of CFE following 24-h co incubation. Inhibition of quorum sensing-controlled virulence factors (motility, protease and elastase activity, production of pyocyanin and rhamnolipid) of P. aeruginosa strains was also observed. DPPH radical scavenging activity of the CFE was determined as 88.57 +/- 0.49%. In conclusion, our results suggest that L. plantarum F-10 may represent an alternative bio-control strategy against skin infections with its antimicrobial, anti-biofilm, anti-quorum sensing, and antioxidant activity. PMID- 30523604 TI - ? PMID- 30523605 TI - Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta analysis. AB - PURPOSE: To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM. MATERIALS AND METHODS: We searched various biomedical databases from 1998 to 2018, for eligible studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system. RESULTS: We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69 77%), OS-12 rate 36% (95% CI 32-40%), PFS-6 rate 43% (95% CI 35-50%), PFS-12 rate 17% (95% CI 13-20%), and Grade 3 + AE rate 7% (95% CI 4-10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose-response [above or below 36 Gy in 2 Gy equivalent doses (EQD2)]. However, a short fractionation regimen (<= 5 fractions) seemed to provide superior PFS-6. CONCLUSION: The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM. PMID- 30523607 TI - Use of optical fluorescence agents during surgery for pituitary adenomas: current state of the field. AB - INTRODUCTION: Differentiation of normal pituitary from abnormal tumor tissue remains a surgical challenge despite improvements in optical visualization technology for pituitary adenoma (PA) surgery. During neurosurgical procedures for other tumor types, 5-aminolevulinic acid (5-ALA) has become a focus of investigation based on its high specificity in differentiating tumor tissue. However, the role of 5-ALA and other optical fluorescent agents in PA surgery remains less clear. OBJECTIVE: To perform a systematic review on the use of various optical fluorescent agents in PA surgery. METHOD: Using PRISMA guidelines, a systematic literature review to identify reports describing 5-ALA and other optical agents for fluorescence-guided surgery for PA was performed. Eleven research studies met inclusion criteria and were reviewed. RESULTS: In two studies, 5-ALA was not shown to be effective in aiding PA resection using standard neurosurgical endoscopic/microscopic approaches. 5-ALA photodynamic therapy was evaluated in two in-vitro models with inconsistent results. Intraoperative use of indocyanine green (ICG) concluded with varying results, but showed a tendency towards improved differentiation of functional PA. OTL38 showed potential for intraoperative identification of nonfunctioning PA, particularly in tumors with high folate receptor expression. One study reported clinically useful fluorescence following sodium fluorescein administration. CONCLUSION: We conclude that selected optical fluorescent agents, including ICG and folate receptors, are most likely to hold promise for clinical use in differentiating PA from normal tissue. PMID- 30523606 TI - Association of patterns of care, prognostic factors, and use of radiotherapy temozolomide therapy with survival in patients with newly diagnosed glioblastoma: a French national population-based study. AB - BACKGROUND: Glioblastoma is the most frequent primary malignant brain tumor. In daily practice and at whole country level, oncological care management for glioblastoma patients is not completely known. OBJECTIVES: To describe oncological patterns of care, prognostic factors, and survival for all patients in France with newly-diagnosed and histologically confirmed glioblastoma, and evaluate the impact of extended temozolomide use at the population level. METHODS: Nationwide population-based cohort study including all patients with newly-diagnosed and histologically confirmed glioblastoma in France in 2008 and followed until 2015. RESULTS: Data from 2053 glioblastoma patients were analyzed (male/female ratio 1.5, median age 64 years). Median overall survival (OS) was 11.2 [95% confidence interval (CI) 10.7-11.9] months. The first-line therapy and corresponding median survival (MS, in months) were: 13% did not receive any oncological treatment (biopsy only) (MS = 1.8, 95% CI 1.6-2.1), 27% received treatment without the combination of radiotherapy (RT)-temozolomide (MS = 5.9, 95% CI 5.5-6.6), 60% received treatment including the initiation of the concomitant phase of RT-temozolomide (MS = 16.4, 95% CI 15.2-17.4) whom 44% of patients initiated the temozolomide adjuvant phase (MS = 18.9, 95% CI 18.0-19.8). Only 22% patients received 6 cycles or more of adjuvant temozolomide (MS = 25.5, 95% CI 24.0-28.3). The multivariate analysis showed that the risk of mortality was significantly higher for the non-progressive patients who stopped at 6 cycles (standard protocol) than those who continued the treatment, hazard ratio = 1.5 (95% CI 1.2-1.9). CONCLUSION: In non-progressive patients, prolonging the adjuvant temozolomide beyond 6 cycles may improve OS. PMID- 30523608 TI - Silodosin: An Update on Efficacy, Safety and Clinical Indications in Urology. AB - INTRODUCTION: Silodosin determines smooth muscle relaxation in bladder and prostate tissues, increases bladder blood flow in conditions of chronic bladder ischemia and regulates the activity of transcriptional factors responsible for stromal growth and prostate hyperplasia. Phase III trials have already demonstrated the efficacy and safety of silodosin in the treatment of patients bothered by lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). OBJECTIVE: We aimed to describe the rationality for the use of silodosin and to summarize the current literature on the use of Silodosin for the treatment of LUTS. METHODS: PubMed and Web of Science were queried with the terms: 'silodosin' in combination (AND) with the terms 'lower urinary tract symptoms', 'LUTS', 'pathophysiology', 'symptoms' OR 'therapy'. Studies published in the last 10 years (2007-2017) in adults and core clinical journals in English were included. RESULTS: Silodosin 8 mg once-daily was superior to placebo in improving IPSS total score, voiding subscore, storage subscore and QoL score, and at least as effective as tamsulosin 0.4 mg once-daily in all the efficacy analyses. In addition, studies assessing the effect on urodynamic parameters showed that silodosin determined a higher improvement in the bladder outlet obstruction index compared to other alpha1 adrenergic receptor antagonists. Concerning the safety profile, long-term data (after 9 months of treatment) confirmed the limited effect of silodosin on the cardiovascular and gastrointestinal systems. Although ejaculatory disorders represented the main complaint of patients taking silodosin, the discontinuation rate due to this condition remained low even in a long-term follow-up study (7.5%). Encouraging findings showed that silodosin may be administered as a medical expulsive therapy for promoting spontaneous stone passage of distal ureteral stones < 10 mm, to relieve LUTS in patients who underwent prostate cancer brachytherapy and to increase the likelihood of successful trials without a catheter in patients experiencing acute urinary retention. CONCLUSION: Silodosin is one of the drugs approved for the treatment of BPH, being highly effective in improving not only LUTS but also urodynamic parameter impairments secondary to BPH. Moreover, it has shown efficacy as medical expulsive therapy for distal ureteral stones in previous prospective randomized trials. FUNDING: Sponsorship for this study and article processing charges were funded by Recordati. PMID- 30523609 TI - A new species of Eimeria Schneider, 1885 (Apicomplexa: Eimeriidae) from Harris's antelope squirrel Ammospermophilus harrisii Audubon & Bachman (Rodentia: Sciuridae). AB - Eimeria ammospermophili n. sp. (Apicomplexa: Eimeriidae) is described from 2 of 29 (7%) Harris's antelope squirrels Ammospermophilus harrisii Audubon & Bachman in Arizona, USA. Sporulated oocysts of this new species are ovoidal to ellipsoidal, 24-32 * 20-25 (29.0 * 22.7) um, with a pitted, bi-layered wall, an oocyst residuum and, occasionally, a polar granule. Sporocysts are ellipsoidal, 10-12 * 7-9 (11.0 * 7.9) um, with a Stieda body and sporocyst residuum; sporozoites are elongate with a spheroidal anterior refractile body and an ellipsoidal posterior refractile body. In addition, sporulated oocysts of Eimeria vilasi Dorney, 1962 are described from A. harrisii. This is the first report on the coccidia of this host species. PMID- 30523610 TI - Spirorchis spp. (Digenea: Schistosomatoidea) infecting map turtles (Cryptodira: Emydidae: Graptemys spp.) in southeastern North America: A new species, molecular phylogenies, and key to species. AB - Black-knobbed map turtles (Graptemys nigrinoda Cagle) and Alabama map turtles (Graptemys pulchra Baur) were infected with several blood flukes in Alabama (southeastern North America). Spirorchis paraminutus Roberts & Bullard n. sp. differs from its congeners by having a body that is 12-24* longer than wide, a testicular column of 10 testes that is 1/5-1/4 of the body length and located far posterior to the caecal bifurcation (the anterior-most testis is located in the posterior body half), and a common genital pore that is ventral to the ovary and 1/4-1/3 of the body length from the posterior extremity. These turtles and an Escambia map turtle (Graptemys ernsti Lovich & McCoy) were infected with Spirorchis elegans Stunkard, 1923, Spirorchis scripta Stunkard, 1923 and two innominate species of Spirorchis MacCallum, 1918. Phylogenetic analyses of the internal transcribed spacer region (ITS2) and large subunit rDNA (28S) recovered a monophyletic Spirorchis and the new species sister to Spirorchis collinsi Roberts & Bullard, 2016. PMID- 30523611 TI - New species of Rhinebothrium Linton, 1890 (Cestoda: Rhinebothriidea) parasitic in Australian stingrays (Elasmobranchii: Batoidea). AB - Seven new species of the cestode genus Rhinebothrium Linton, 1890 are reported from the spiral intestines of batoid elasmobranchs from the coasts of Australia. The new species are: Rhinebothrium dasyatidis n. sp. from the smooth stingray Bathytoshia brevicaudata (Hutton) from Spencer Gulf, South Australia; Rhinebothrium bunburyense n. sp. from the southern eagle ray, Myliobatis tenuicaudatus Hector from off Bunbury, Western Australia; Rhinebothrium vandiemeni n. sp. from the reticulate whipray, Himantura australis Last, Naylor & Manjaji-Matsumoto from off Cape van Diemen, Northern Territory; Rhinebothrium fluviorum n. sp. from the estuary stingray, Hemitrygon fluviorum (Ogilby) from Moreton Bay, Queensland; Rhinebothrium urolophi n. sp. from the wide stingaree Urolophus expansus McCulloch from off Beachport, South Australia; Rhinebothrium nickoli n. sp. from the brown whipray Maculabatis toshi (Whitley) and the reticulate whipray, Himantura australis Last, Naylor & Manjaji-Matsumoto, from Nickol Bay, Western Australia and from the white-spotted guitarfish Rhynchobatus australiae (Whitley) from off Broome, Western Australia and Rhinebothrium fungiforme n. sp. from the estuary stingray, Hemitrygon fluviorum (Ogilby) from Fog Bay in the Northern Territory. PMID- 30523612 TI - Descriptions of two new acanthocephalans (Rhadinorhynchidae) from marine fish off the Pacific coast of Vietnam. AB - Two rhadinorhynchid acanthocephalans are described from marine fishes off the Pacific coast of Vietnam. Sclerocollum neorubrimaris n. sp. (Gorgorhynchinae Van Cleave & Lincicome, 1940) is described from the spine-foot rabbitfish Siganus guttatus (Bloch) (Siganidae) off Nha Trang. The new species is similar to the type-species, Sclerocollum rubrimaris Schmidt & Paperna, 1978 in most measurements and counts but has a posterior cephalic ganglion, a sub-ventral female gonopore, and one dorsal paravaginal filament bundle. In S. rubrimaris, the cephalic ganglion is near the middle of the receptacle, the female gonopore is terminal with two paravaginal filament bundles. The new species is distinguished from three other species of Sclerocollum Schmidt & Paperna, 1978 in proboscis hook formulas and the position of the female gonopore and cephalic ganglion. The issue of the importance of the position of the cephalic ganglion at the generic and sub-generic levels in the Acanthocephala is discussed. Females of Australorhynchus multispinosus n. sp. (Gorgorhynchinae) are described from the red cornetfish Fistularia petimba Lacepede off Nha Trang in the Pacific south. It is distinguished from the only other species of the genus, Australorhynchus tetramorphacanthus Lebedev, 1967, by having more trunk spines extending beyond the level of the proboscis receptacle and a smaller proboscis with considerably fewer hooks. PMID- 30523613 TI - Nephrocystidium pickii Weissenberg, 1921 belongs to Myxozoa (Cnidaria) but is not conspecific with Myxidium lieberkuehni Butschli, 1882 (Myxozoa: Bivalvulida: Variisporina: Myxidiidae): molecular-genetic evidence. AB - We isolated and re-investigated Nephrocystidium pickii Weibetaenberg, 1921 (Myxozoa: Bivalvulida: Variisporina) using light microscopy and phylogenetic analysis of the small-subunit (SSU) ribosomal RNA gene. This species is a parasite of the northern pike Esox lucius L. (Actinopterygii: Esocidae) which localizes in the endothelial cells of the glomerular capillary. The results of the phylogenetic analysis including this species clarify its taxonomic status and show that although it is the closest relative to Myxidium lieberkuehni Butschli, 1882, the two organisms are not conspecific, contrary to the earlier hypotheses. The data obtained highlight the necessity of a profound taxonomic revision of the Myxozoa and the need to clarify species affiliation of extrasporogonic developmental stages of these organisms that occur in different organs of fish. PMID- 30523614 TI - Morphological and molecular evidence for synonymy of Corynosoma obtuscens Lincicome, 1943 with Corynosoma australe Johnston, 1937 (Acanthocephala: Polymorphidae). AB - Corynosoma obtuscens Lincicome, 1943 (Acanthocephala: Polymorphidae) is synonymised with Corynosoma australe Johnston, 1937 based on combined morphological and molecular evidence. Morphological comparison of C. obtuscens (24 males and 27 females) collected from a California sea lion Zalophus californianus (Lesson) in California, USA, with the type-specimens of C. obtuscens and C. australe, and with published data on C. australe collected from different hosts and regions showed no significant differences. The levels of genetic divergence in the cox1 sequences obtained from C. obtuscens from a California sea lion in the present study and C. australe from otariid seals from Argentina and penguins from Brazil ranged between 1.4-1.6% and was considered to represent intraspecific variability. Additionally, cox1 sequences were generated for Andracantha phalacrocoracis (Yamaguti, 1939), Corynosoma semerme (Forssell, 1904), C. strumosum (Rudolphi, 1802), C. validum Van Cleave, 1953 and C. villosum Van Cleave, 1953. Our results revealed inconsistency in the identification of material used as a source of the previously published sequence data for C. obtuscens and C. magdaleni Montreuil, 1958. PMID- 30523615 TI - Neurocognitive Impairment and Associated Genetic Aspects in HIV Infection. AB - HIV enters the central nervous system (CNS) early after infection. HIV-associated neurocognitive disorders (HAND) remain a serious complication of HIV infection despite available antiretroviral therapy (ART). Neurocognitive deficits observed in HAND are heterogeneous, suggesting a variability in individuals' susceptibility or resiliency to the detrimental CNS effects of HIV infection. This chapter reviews primary host genomic changes (immune-related genes, genes implicated in cognitive changes in primary neurodegenerative diseases), epigenetic mechanisms, and genetic interactions with ART implicated in HIV progression or HAND/neurocognitive complications of HIV. Limitations of the current findings include diversity of the HAND phenotype and limited replication of findings across cohorts. Strategies to improve the precision of future (epi)genetic studies of neurocognitive consequences of HIV infection are offered. PMID- 30523616 TI - Functions of Memory Across Saccadic Eye Movements. AB - Several times per second, humans make rapid eye movements called saccades which redirect their gaze to sample new regions of external space. Saccades present unique challenges to both perceptual and motor systems. During the movement, the visual input is smeared across the retina and severely degraded. Once completed, the projection of the world onto the retina has undergone a large-scale spatial transformation. The vector of this transformation, and the new orientation of the eye in the external world, is uncertain. Memory for the pre-saccadic visual input is thought to play a central role in compensating for the disruption caused by saccades. Here, we review evidence that memory contributes to (1) detecting and identifying changes in the world that occur during a saccade, (2) bridging the gap in input so that visual processing does not have to start anew, and (3) correcting saccade errors and recalibrating the oculomotor system to ensure accuracy of future saccades. We argue that visual working memory (VWM) is the most likely candidate system to underlie these behaviours and assess the consequences of VWM's strict resource limitations for transsaccadic processing. We conclude that a full understanding of these processes will require progress on broader unsolved problems in psychology and neuroscience, in particular how the brain solves the object correspondence problem, to what extent prior beliefs influence visual perception, and how disparate signals arriving with different delays are integrated. PMID- 30523617 TI - A mobile one-lead ECG device incorporated in a symptom-driven remote arrhythmia monitoring program. The first 5,982 Hartwacht ECGs. AB - BACKGROUND: In recent years many mobile devices able to record health-related data in ambulatory patients have emerged. However, well-organised programs to incorporate these devices are sparse. Hartwacht Arrhythmia (HA) is such a program, focusing on remote arrhythmia detection using the AliveCor Kardia Mobile (KM) and its algorithm. OBJECTIVES: The aim of this study was to assess the benefit of the KM device and its algorithm in detecting cardiac arrhythmias in a real-world cohort of ambulatory patients. METHODS: All KM ECGs recorded in the HA program between January 2017 and March 2018 were included. Classification by the KM algorithm was compared with that of the Hartwacht team led by a cardiologist. Statistical analyses were performed with respect to detection of sinus rhythm (SR), atrial fibrillation (AF) and other arrhythmias. RESULTS: 5,982 KM ECGs were received from 233 patients (mean age 58 years, 52% male). The KM algorithm categorised 59% as SR, 22% as possible AF, 17% as unclassified and 2% as unreadable. According to the Hartwacht team, 498 (8%) ECGs were uninterpretable. Negative predictive value for detection of AF was 98%. However, positive predictive value as well as detection of other arrhythmias was poor. In 81% of the unclassified ECGs, the Hartwacht team was able to provide a diagnosis. CONCLUSIONS: This study reports on the first symptom-driven remote arrhythmia monitoring program in the Netherlands. Less than 10% of the ECGs were uninterpretable. However, the current performance of the KM algorithm makes the device inadequate as a stand-alone application, supporting the need for manual ECG analysis in HA and similar programs. PMID- 30523618 TI - Correction to: Thiol-Redox Proteomics to Study Reversible Protein Thiol Oxidations in Bacteria. AB - This protocol was originally published (c) Springer Science+Business Media, LLC, part of Springer Nature 2018, but has now been made available (c) The Author(s) under a CC BY 4.0 license. PMID- 30523619 TI - AIDS-Associated Malignancies. AB - Malignancies were one of the earliest recognized manifestations that led to the description of the acquired immune deficiency syndrome (AIDS). The majority of cancers in AIDS patients are associated with coinfection with oncogenic viruses, such as Epstein-Barr virus, human herpesvirus 8, and human papillomavirus, with resulting malignancies occurring secondary to diminished immune surveillance against viruses and virus-infected tumor cells. Over 50% of AIDS lymphomas are associated with Epstein-Barr virus (EBV) and/or HHV8 infection. HHV8-associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). EBV is associated with several malignancies, including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Coinfection with HIV and HPV is associated with an increased risk of various squamous cell carcinomas of epithelial tissues. HAART has significantly impacted the incidence, management, and prognosis of AIDS-related malignancies. In addition to changing the natural history of HIV infection in regard to incidence and survival, HAART has dramatically decreased the incidence of certain virally mediated HIV-associated malignancies such as KS and primary CNS lymphoma. The beneficial effects of HAART on these tumors are attributed to drug-mediated HIV suppression and immune reconstitution. However, HAART has had a less favorable impact on EBV- and HPV-related malignancies. This chapter presents an overview of HIV-associated malignancies mediated by HHV-8, EBV, and HPV, and reviews the effect of HAART on the epidemiology, presentation, treatment, and outcomes of these cancers. PMID- 30523620 TI - Molecular Biology of KSHV in Relation to HIV/AIDS-Associated Oncogenesis. AB - Discovered in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with four human malignancies including Kaposi's sarcoma, primary effusion lymphoma, a subset of multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. These malignancies mostly occur in immunocompromised patients including patients with acquired immunodeficiency syndrome and often cause significant mortality because of the lack of effective therapies. Significant progresses have been made to understand the molecular basis of KSHV infection and KSHV-induced oncogenesis in the last two decades. This chapter provides an update on the recent advancements focusing on the molecular events of KSHV primary infection, the mechanisms regulating KSHV life cycle, innate and adaptive immunity, mechanism of KSHV-induced tumorigenesis and inflammation, and metabolic reprogramming in KSHV infection and KSHV-transformed cells. PMID- 30523621 TI - Kaposi's Sarcoma-Associated Herpesvirus (KSHV)-Associated Disease in the AIDS Patient: An Update. AB - In this book chapter, we review the current knowledge of the biology and pathogenesis of Kaposi's sarcomaassociated herpesvirus (KSHV). We describe the lifecycle of KSHV, the cancers associated with this virus, as well as current treatment modalities. PMID- 30523623 TI - Human Papillomavirus Infection and Cervical Cancer in HIV+ Women. AB - Human papillomavirus (HPV) is the first identified necessary cause of human cancers and is associated with nearly 100% of all cervical cancers. Compared to the general female populations, HIV+ women have higher prevalence and incidence of cervical HPV infections, higher risks of persistent HPV infections and subsequent cervical intraepithelial lesions, and a higher incidence of cervical cancer. Although the wide use of combined antiretroviral therapy (cART) has improved the immune function and the longevity of HIV+ women, the incidence of cervical cancer in HIV+ women has not declined. For HIV+ women who follow routine cervical cancer screenings, their incidence of cervical cancer is comparable to that in HIV-negative women. Thus, adherence to the recommended cervical cancer screening is still critical for HIV+ women to prevent cervical cancer. Prophylactic HPV vaccines may also benefit HIV+ women, but prospective studies are needed to determine the effectiveness of HPV vaccination on reducing cervical cancer incidence in HIV+ women. PMID- 30523622 TI - Molecular Biology of EBV in Relationship to HIV/AIDS-Associated Oncogenesis. AB - Herpesvirus-induced disease is one of the most lethal factors which leads to high mortality in HIV/AIDS patients. EBV, also known as human herpesvirus 4, can transform naive B cells into immortalized cells in vitro through the regulation of cell cycle, cell proliferation, and apoptosis. EBV infection is associated with several lymphoma and epithelial cancers in humans, which occurs at a much higher rate in immune deficient individuals than in healthy people, demonstrating that the immune system plays a vital role in inhibiting EBV activities. EBV latency infection proteins can mimic suppression cytokines or upregulate PD-1 on B cells to repress the cytotoxic T cells response. Many malignancies, including Hodgkin Lymphoma and non-Hodgkin's lymphomas occur at a much higher frequency in EBV positive individuals than in EBV negative people during the development of HIV infection. Importantly, understanding EBV pathogenesis at the molecular level will aid the development of novel therapies for EBV-induced diseases in HIV/AIDS patients. PMID- 30523624 TI - HPV-Associated Oropharyngeal Cancer in the HIV/AIDS Patient. AB - Since their discovery as the etiologic agents of cervical cancer in the mid 1970s, human papillomaviruses (HPVs) have been linked with a growing number of epithelial-derived tumors, including head and neck squamous cell carcinomas. HPV demonstrates a particular predilection for causing tumors of the oropharynx, with the majority of cases involving infection with high-oncogenic risk HPV-16. People living with HIV are at increased risk of infection with HPV- and HPV-related oral complications even with adequate control of their HIV infection with antiretroviral therapy. In this chapter, we discuss the molecular mechanisms that underlie HPV-mediated oncogenesis in the oropharynx. We also describe the progress that has been made in understanding the epidemiology of oral HPV infection and the determinants of oral HPV-related pathology. Finally, we examine what can be done to treat and prevent oral HPV infection, benign lesions, and cancer, particularly in the context of the HIV-positive patient. PMID- 30523625 TI - HPV-Associated Anal Cancer in the HIV/AIDS Patient. AB - The prevalence of anal human papillomavirus (HPV) infection and anal high-grade squamous intraepithelial lesion (HSIL) remain high among HIV-infected individuals on effective antiretroviral therapy (ART). The incidence of HPV-related anal cancers has continued to increase since the introduction of ART. Therefore, ART may confer only limited benefit with respect to reducing the risk of anal HSIL and cancer. Efforts are in progress to define the efficacy of secondary prevention programs for prevention of anal cancer. In the modern ART era, anal cancer recurrence and survival outcomes are similar in HIV-infected and HIV uninfected patients, but HIV-infected patients may experience more toxicities. This article reviews the current literature on HPV-associated anal cancer in the HIV-infected population, including epidemiology, screening, clinical characteristics, and treatment outcomes. PMID- 30523626 TI - Merkel Cell Carcinoma in the HIV-1/AIDS Patient. AB - Merkel cell carcinoma (MCC) is a highly aggressive, primary neuroendocrine cancer of the skin. The majority of MCC cases are associated with the recently discovered Merkel cell polyomavirus (MCPyV), while the remaining are caused by ultraviolet (UV) light-induced mutations from excessive sunlight exposure. The risk of developing MCC is much higher in the white population relative to all other races. Approximately 10% of all patients with MCC have some form of immunosuppression including HIV-1/AIDS, chronic inflammatory conditions, solid organ transplantation, or hematological malignancies. The age of onset of MCC is lower and the mortality is higher in immunosuppressed individuals than in immune competent patients. It is plausible that HIV-1/AIDS predisposes to virus-positive MCC, but it should be noted that HIV-1/AIDS increases the risk for developing of UV-induced skin cancers such as cutaneous squamous cell carcinoma and basal cell carcinoma and therefore may also increase the risk for virus-negative MCC. Surgical management is considered standard of care for localized Merkel cell carcinoma with current recommendations advising a wide local excision of the lesion. Most international guidelines support the use of local adjuvant radiotherapy coupled with tumor staging to improve the frequency of cure. For advanced, metastatic, and recurrent MCC, checkpoint blockade inhibitors targeting PD-1 and PD-L1 have shown remarkable activity including durable long-term. MCC in patients living with HIV-1/AIDS are treated with similar modalities as HIV-1 uninfected individuals with MCC. PMID- 30523627 TI - HIV-HBV and HIV-HCV Coinfection and Liver Cancer Development. AB - Liver diseases that are caused by the hepatitis B virus (HBV) and hepatitis C virus (HCV), including cirrhosis and hepatocellular carcinoma (HCC), have become increasingly important in patients infected with the human immunodeficiency virus (HIV) as their life expectancy is getting longer with successful anti-HIV therapy. Due to their shared transmission routes, dual infection by HIV and HBV or HIV and HCV, and triple infection by all three viruses are fairly common and affect millions of people worldwide. Whereas the immunodeficiency caused by HIV enhances the likelihood of HBV and HCV persistence, hepatotoxicity associated with anti-HIV therapy can worsen the liver diseases associated with HBV or HCV persistence. Evidence suggests HIV infection increases the risk of HBV- or HCV associated HCC risk although the precise mechanisms of enhanced hepatocarcinogenesis remain to be fully elucidated. Recent success in curing HCV infection, and the availability of therapeutic options effective in long-term suppression of both HIV and HBV replication, bring hope, fortunately, to those who are coinfected but also highlight the need for judicious selection of antiviral therapies. PMID- 30523628 TI - Contact urticaria with anaphylaxis to chlorocresol, chloroxylenol and thiourea. AB - Contact urticaria (CU) is defined as an immediate wheal-and-flare skin reaction following direct contact with a protein or chemical agent1,2 . CU has been described in association with numerous chemicals, including preservatives, antiseptics, fragrances and medicaments3-6 . CU syndrome ranges from localised urticaria (stage 1) to anaphylactoid reactions with shock (stage 4)7 . PMID- 30523629 TI - Bundle sheath extensions affect leaf structural and physiological plasticity in response to irradiance. AB - Coordination between structural and physiological traits is key to plants' responses to environmental fluctuations. In heterobaric leaves, bundle sheath extensions (BSEs) increase photosynthetic performance (light-saturated rates of photosynthesis, Amax ) and water transport capacity (leaf hydraulic conductance, Kleaf ). However, it is not clear how BSEs affect these and other leaf developmental and physiological parameters in response to environmental conditions. The obscuravenosa (obv) mutation, found in many commercial tomato varieties, leads to absence of BSEs. We examined structural and physiological traits of tomato heterobaric and homobaric (obv) near-isogenic lines (NILs) grown at two different irradiance levels. Kleaf , minor vein density and stomatal pore area index decreased with shading in heterobaric but not in homobaric leaves, which show similarly lower values in both conditions. Homobaric plants, on the other hand, showed increased Amax , leaf intercellular air spaces and mesophyll surface area exposed to intercellular airspace (Smes ) in comparison with heterobaric plants when both were grown in the shade. BSEs further affected carbon isotope discrimination, a proxy for long-term water-use efficiency. BSEs confer plasticity in traits related to leaf structure and function in response to irradiance levels and might act as a hub integrating leaf structure, photosynthetic function and water supply and demand. PMID- 30523630 TI - Biofilm-associated accumulation-associated protein (Aap): A contributing factor to the predominant growth of Staphylococcus epidermidis in platelet concentrates. AB - BACKGROUND AND OBJECTIVES: Staphylococcus epidermidis is a predominant contaminant of platelet concentrates (PCs), outcompeting other skin flora bacteria such as Staphylococcus capitis. The accumulation-associated protein (Aap), encoded by the aap gene, is involved in formation of bacterial aggregates (biofilms) in S. epidermidis and is absent in S. capitis. In this study, the role of S. epidermidis aap in enhancing biofilm formation and conferring an advantageous growth in PCs was investigated. MATERIALS AND METHODS: Biofilm formation assays of S. epidermidis 1457, S. epidermidis 1457?aap, S. capitis 517 and S. capitis 517 carrying S. epidermidis aap (S. capitis 517/pRBaap) were performed in glucose-supplemented trypticase soy broth (TSBg) and PCs. Additionally, competition assays with paired cultures (1:1 ratio) of S. epidermidis and S. capitis strains were seeded in PCs, followed by determination of viable counts of each organism at the end of PC storage. RESULTS: Staphylococcus epidermidis aap had no effect on biofilm formation in TSBg. By contrast in PCs, S. epidermidis 1457 showed higher biofilm formation than S. epidermidis 1457?aap (P < 0.05). Biofilm formation was also enhanced in S. capitis 517/pRBaap compared to S. capitis 517 (P = 0.054). Competition assays showed that S. epidermidis 1457 outcompeted S. capitis 517, and importantly, S. capitis 517/pRBaap outcompeted S. capitis 517 and S. epidermidis 1457?aap. CONCLUSION: This study demonstrated that S. epidermidis aap plays a role in biofilm formation in PCs conferring an advantageous proliferation to skin flora bacteria in this milieu. The molecular mechanisms of action of Aap merit further investigation. PMID- 30523631 TI - Fertility testing for men before marriage: Is it acceptable? AB - Addressing male infertility issue before marriage, at least to the mate and her family, seems reasonable to avoid several psychosocial, economic and biological consequences. Here, we intended to comprehend whether fertility testing (i.e. semen analysis) for men before marriage is acceptable and can be applied in Jordanian society. To achieve this contribution, we designed a questionnaire that shows the opinion of a sample of the Jordanian population in applying fertility testing for men before marriage. A total of 740 adult individuals (>18 years old, 364 males, 382 females) were selected randomly from different martial, economic, social, ethnic, religious and education statuses to fill the questionnaire. A total of 523 (70.11%) participants had a positive attitude towards applying fertility testing for men before marriage. This opinion was found not to be affected by gender (p = 0.305), age (p = 0.329), body mass index (p = 0.061), smoking (p = 0.059), monthly income (p = 0.094), education level (p = 0.131) and family members with infertility (p = 0.074); while, it is found to be affected by the social status of the participant (p = 0.004). In conclusion, applying fertility testing for men before marriage appears to be acceptable in Jordanian society. PMID- 30523632 TI - The dual role of KCNQ/M channels upon OGD or OGD/R insults in cultured cortical neurons of mice: Timing is crucial in targeting M-channels against ischemic injur ies. AB - KCNQ/M potassium channels play a vital role in neuronal excitability; however, it is required to explore their pharmacological modulation on N-Methyl- d-aspartic acid receptors (NMDARs)-mediated glutamatergic transmission of neurons upon ischemic insults. In the current study, both presynaptic glutamatergic release and activities of NMDARs were measured by NMDAR-induced miniature excitatory postsynaptic currents (mEPSCs) in cultured cortical neurons of C57 mice undergoing oxygen and glucose deprivation (OGD) or OGD/reperfusion (OGD/R). The KCNQ/M-channel opener, retigabine (RTG), suppressed the overactivation of postsynaptic NMDARs induced by OGD and then NO transient; RTG also decreased OGD induced neuronal death measured with MTT assay, suggesting the beneficial role of KCNQ/M-channels for the neurons exposed to ischemic insults. However, when the neurons exposed to the subsequent reperfusion, KCNQ/M-channels played a differential role from its protective effect. OGD/R increased presynaptic glutamatergic release, which was further augmented by RTG or decreased by KCNQ/M channel blocker, XE991. Reactive oxygen species (ROS) were produced partly in a NO-dependent manner. In addition, XE991 decreased neuronal injuries upon reperfusion measured with DCF and PI staining. Meanwhile, the addition of RTG upon OGD or XE991 upon reperfusion can reverse OGD or OGD/R-reduced mitochondrial membrane potential. Our present study indicates the dual role of KCNQ/M-channels in OGD and OGD/R, which will decide the fate of neurons. Provided that activation of KCNQ/M-channels has differential effects on neuronal injuries during OGD or OGD/R, we propose that therapy targeting KCNQ/M-channels may be effective for ischemic injuries but the proper timing is so crucial for the corresponding treatment. PMID- 30523633 TI - Persistent self-reported ear and hearing problems among World Trade Center exposed firefighters and emergency medical service workers, 2001-2017-A longitudinal cohort analysis. AB - BACKGROUND: The goal of this study was to estimate the impact of exposure to the World Trade Center (WTC) site on annual and persistent rates of otalgia and hearing impairment among Fire Department of the City of New York (FDNY) Firefighters and Emergency Medical Service Workers (EMS). METHODS: Responders completed routine physical health questionnaires at monitoring visits. We used logistic and marginal logistic regression models to explore the association between otalgia and hearing impairment and WTC arrival time. RESULTS: The highest exposed group had greater odds of persistent ear symptoms (OR 1.33, 95%CI 1.11 1.59) compared with the least-exposed; the odds of persistent hearing problems between the groups were not significantly different. We found consistent WTC exposure gradients when the average population odds of these outcomes were assessed each year. CONCLUSIONS: Our findings demonstrate that the odds of long term ear symptoms were significantly associated with the intensity of WTC exposure. PMID- 30523634 TI - Orthodontic compressive force modulates Ets-1/Tks5 pathway to promote the formation of circumferential invadopodia and the fusion of osteoclast precursors. AB - During orthodontic treatment a mechanical force is applied to the teeth. However, it remains unclear how mechanical force promotes the maturation and fusion of osteoclast precursors into osteoclasts. In this study, we aimed to explore the mechanism by which orthodontic compressive force promotes osteoclast maturation. We used a RAW264.7 macrophage-like cell line derived from Balb/c mice as the experimental model. We found that compressive force promoted the maturation of osteoclasts based on tartrate-resistant acid phosphatase staining and the formation of invadopodia based on immunstaining of Tks5 and F-actin. Moreover, we found that compressive force upregulated the expression of Ets-1 and Tks5 and promoted the activation of Ets-1 in RAW264.7 cells. Furthermore, we identified Tks5 as a transcription target of Ets-1 in RAW264.7 cells and demonstrated that Ets-1 mediates the effects of compressive force on Tks5 upregulation, invadopodia formation and cell fusion in osteoclasts. In conclusion, Ets-1 is upregulated by compressive force and it is essential to transducing the mechanical signal to promote invadopodia formation and osteoclast fusion. Our findings provide novel insight into the mechanism underlying osteoclast maturation and fusion during orthodontic treatment. PMID- 30523635 TI - Microchimerism in Ghanaian children recipients of whole blood transfusion for severe anaemia. AB - BACKGROUND AND OBJECTIVES: Transfusion-acquired microchimerism (TA-Mc) has been reported in major trauma but not in young children despite relative immunodeficiency who, in sub-Saharan Africa, often suffer severe anaemia related to haemoglobinopathies or primary malaria infections. We examined the hypothesis that such massive red cell destructions might provide conditions favourable to TA Mc, particularly when exposed to massive amounts of parasite antigens. MATERIALS AND METHODS: Twenty-seven female children <5 years transfused with male whole blood for severe anaemia (13 with acute malaria and 14 with other causes) were retrospectively identified, and a blood sample was collected >6 months post transfusion. Four whole blood samples from paediatric females transfused with blood from female donors and five secondary school female students never pregnant, never transfused were used as negative controls. RESULTS: Nineteen patients (70%) carried male Mc with four (15%) having high levels of Mc (>100 genome equivalent of male cells/million of host cells) compared to three controls (37.5%). There was no difference in frequency or quantity of male Mc between paediatric patients with severe malaria and paediatric patients with other causes of severe anaemia. TA-Mc was not correlated with patient age, duration of whole blood storage or lymphocyte load transfused. After a median of 7 months post transfusion, acute malaria did not increase the frequency of TA-Mc. One negative control appeared to carry low-level male cells. CONCLUSION: Transfusion-acquired microchimerism appears frequent in young children transfused with whole blood for severe anaemia. PMID- 30523636 TI - Serum vitamin D levels and erectile dysfunction: A systematic review and meta analysis. AB - Suboptimal levels of serum vitamin D levels have been implied to be associated with cardiovascular diseases and endothelial dysfunction, conditions closely associated with erectile dysfunction (ED). The present systematic review and meta analysis was performed to evaluate the vitamin D levels in subjects with ED compared to controls and the 5-item version of the international index of erectile function (IIEF-5) score in subjects with vitamin D deficiency compared to those without vitamin D deficiency in order to elucidate the role of vitamin D in the pathogenesis of ED. Studies evaluating the possible association between vitamin D levels and ED were initially screened and thus included following electronic literature search of database Cochrane Library, PUBMED, EMBASE and MEDLINE. Essential article information including outcome measures was extracted from the qualified studies by two independent authors, and STATA 12.0 software was used conducted the meta-analysis. Subgroup analyses were conducted by vitamin D detection methods and sample size. The standard mean difference (SMD) as well as the 95% confidence intervals (95% CIs) was applied to estimate the outcome measures. A total of seven articles were included in our meta-analysis with a total of 4,132 subjects. Pooled estimate was in favour of increased vitamin D levels in subjects without ED with a SMD of 3.027 ng/ml, 95%CI 2.290-3.314, p = 0.000. However, subgroup analysis showed an opposite trend, after one study with a sample size over 1,000 that could possibly influence the weight balance was excluded, with a SMD of 0.267, 95%CI -0.052 to 0.585, p = 0.101. We also identified about 0.320 higher in IIEF-5 score (95%CI = 0.146-0.494, p = 0.000) in subjects without vitamin D deficiency versus with vitamin D deficiency. Nevertheless, subgroup analysis based on vitamin D detection methods obtained differential results (radioimmunoassay subgroup, SMD(95%CI) = 0.573 (0.275 0.870), p = 0.000; immunoassay subgroup, SMD(95%CI) = 0.189 (-0.025 to 0.404), p = 0.084). In conclusion, results from the present meta-analysis did not provide a strong relationship between vitamin D and the risk of ED. However, the results should be interpreted with caution and more high quality studies are warranted. PMID- 30523637 TI - OVO homologue-like 1 promotes osteoblast differentiation through BMP2 expression. AB - OVO homologue-like 1 (OVOL1) encodes a C2H2 zinc finger protein and is an evolutionarily conserved gene in mammals. The OVOL1 expression is required for development. However, the function of OVOL1 in bone metabolism remains unreported. Here, we show for the first time the role of OVOL1 in osteoblast differentiation. To determine the role of OVOL1 in osteogenic differentiation, we analyzed OVOL1 expression in the preosteoblastic cell line. OVOL1 messenger RNA expression was induced during osteoblast differentiation. In addition, OVOL1 overexpression enhanced the expression of osteogenic genes including bone morphogenetic protein 2 (BMP2), the inhibitor of DNA binding 1 (Id1), distal-less homeobox 5 (Dlx5), runt-related transcription factor 2 (Runx2), osteocalcin (OC), and alkaline phosphatase (ALP). Moreover, mineralization of the extracellular matrix was increased by OVOL1 overexpression in MC3T3-E1 cells. Furthermore, knockdown of the OVOL1 experiment demonstrated that OVOL1 is required for osteoblast differentiation. Collectively, these results suggest that OVOL1 function as an important regulator of osteoblast differentiation by inducing BMP2 expression in MC3T3-E1 cells. PMID- 30523638 TI - The role of sphingosine-1-phosphate in skeletal muscle: Physiology, mechanisms, and clinical perspectives. AB - Sphingolipids were discovered more than a century ago and were simply considered as a class of cell membrane lipids for a long time. However, after the discovery of several intracellular functions and their role in the control of many physiological and pathophysiological conditions, these molecules have gained much attention. For instance, the sphingosine-1-phosphate (S1P) is a circulating bioactive sphingolipid capable of triggering strong intracellular reactions through the family of S1P receptors (S1PRs) spread in several cell types and tissues. Recently, the role of S1P in the control of skeletal muscle metabolism, atrophy, regeneration, and metabolic disorders has been widely investigated. In this review, we summarized the knowledge of S1P and its effects in skeletal muscle metabolism, highlighting the role of S1P/S1PRs axis in skeletal muscle regeneration, fatigue, ceramide accumulation, and insulin resistance. Finally, we discussed the physical exercise role in S1P/S1PRs signaling in skeletal muscle cells, and how this nonpharmacological strategy may be prospective for future investigations due to its ability to increase S1P levels. PMID- 30523639 TI - Dose- and time-dependent alterations in lipid metabolism after pharmacological PGC-1alpha activation in L6 myotubes. AB - Pyrroloquinoline quinone (PQQ) acts as a powerful modulator of PGC-1alpha activation and therefore regulates multiple pathways involved in cellular energy homeostasis. In the present study, we assessed the effects of L6 myotubes incubation with 0.5, 1, and 3 MUM PQQ solution for 2 and 24 hr with respect to the cells' lipid metabolism. We demonstrated that PQQ significantly elevates PGC 1alpha content in a dose- and time-dependent manner with the highest efficiency for 0.5 and 1 uM. The level of free fatty acids was diminished (24 hr: -66%), while an increase in triacylglycerol (TAG) amount was most pronounced after 0.5 MUM (2 hr: +93%, 24 hr: +139%) treatment. Ceramide (CER) content was elevated after 2 hr incubation with 0.5 uM and after prolonged exposure to all PQQ concentrations. The cells treated with PQQ for 2 hr exhibited decreased sphinganine (SFA) and sphinganine-1-phosphate (SFA1P) level, while 24 hr incubation resulted in an elevated sphingosine (SFO) amount. In summary, PGC 1alpha activation promotes TAG and CER synthesis. PMID- 30523640 TI - Prognostic relevance of miR-137 and its liver microenvironment regulatory target gene AFM in hepatocellular carcinoma. AB - MiR-137 has been identified as potential hepatocellular carcinoma (HCC) prognostic biomarkers. Highly relevant HCC prognostic biomarkers may be derived from combinations of miR-137 with its target genes involved in the regulation of liver microenvironment. This study aimed at the discovery of such a combination with improved HCC prognosis performance than miR-137 or its target gene alone in a significantly higher number of HCC patients than previous studies. Analysis of the differentially expressed micro RNAs (miRNAs) between cancer and noncancer tissues reconfirmed miR-137 to be among the most relevant prognostic miRNAs and the data of 375 HCC patients and 50 normal cases were from the Cancer Genome Atlas (TCGA) data sets. Target genes were identified by the established search methods and Kaplan-Meier survival analysis of HCC patients was used to evaluate the overall survival (OS) and recurrence-free survival (RFS). Cox proportional hazards regression indicated that the miR-137 and its target gene AFM combination is an independent prognostic factor for the OS and RFS in HCC. In vitro experiments validated that miR-137 could bind to 3'-untranslated region of the AFM and promote the invasion and metastasis of HCC cell lines. The expressions of miR-137 and its liver microenvironment regulatory target gene AFM in combination significantly correlated with HCC progression in a higher number of patients than in previous studies, which suggested their potential as prognostic biomarkers for HCC. PMID- 30523641 TI - A real-life evaluation of two platelet cross-matching programmes for the treatment of patients refractory to platelet transfusions. AB - BACKGROUND AND OBJECTIVES: Strategies for overcoming alloimmune refractoriness to random donor platelets are based on the use of compatible platelets selected from large panels of HLA-typed donors or cross-matching (XM). The aim of this study was to review the effectiveness of a platelet XM programme for treating refractory haematological patients at Milan's Policlinico Hospital (PHM) 2002 2014 and Spedali Civili in Brescia (SCB) 2013-2016. MATERIALS AND METHODS: A commercially available solid-phase antibody detection system was used for platelet antibody detection and XM. Forty-nine alloimmune refractory patients at PHM and 13 at SCB, respectively, received a median [IQR] of 12 [6-13] and 18 [13 15] XM compatible platelet transfusions after the detection of refractoriness. The absolute increases in post-transfusion platelet counts obtained using random, and XM platelets were retrieved from the patients' hospital records. RESULTS: The critical review at SCB showed that the median [IQR] 1 h post-transfusion increase in platelet counts was 3 * 109 /L [1-5] after 47/47 random platelet transfusions, and 10 * 109 /L [2-25] after 325/326 XM compatible platelet transfusions. The documentation concerning the outcomes of XM platelet transfusions at PHM was incomplete, and so the findings of the review were inconclusive. CONCLUSION: This retrospective analysis confirmed the effectiveness of the XM programme at SCB, but revealed defective data collection and retrieval methods at PHM, thus underlining the importance of such methods. The literature review accompanying this retrospective analysis identified a recently described algorithm for ensuring platelet support in refractory patients that optimally integrates the combined use of XM and HLA typing. PMID- 30523642 TI - International survey on the impact of parasitic infections: frequency of transmission and current mitigation strategies. AB - BACKGROUND AND OBJECTIVES: Globally, blood safety interventions have been successful in mitigating risk of the major transfusion-transmitted (TT) viruses. However, strategies that address risk from parasites are comparatively limited. TT parasites are often regional in nature, posing unique challenges; we sought to understand their impact on blood safety. MATERIALS AND METHODS: An electronic questionnaire was distributed to transfusion medicine leaders in 100 countries. The survey focused on specific questions pertaining to four parasitic diseases: babesiosis, Chagas, leishmaniasis and malaria. Respondents provided data on historical TT cases, local epidemiology, policies to mitigate risk and an assessment of public health perceptions for each aetiologic agent. RESULTS: Twenty-eight (28%) surveys were returned from countries in Europe (n = 13), the Americas (n = 6), Africa (n = 4), Asia (n = 3) and Oceana (n = 2). Historically, no cases of TT leishmaniasis were reported, TT babesiosis was exclusive to Canada and the USA, TT Chagas was limited to the Americas and Spain, while TT malaria was cosmopolitan. Mitigation efforts varied widely; malaria was the most frequently tested parasitic disease. The public's perception of risk for parasitic agents was low, while that of health authorities in endemic countries was higher. CONCLUSION: The global impact of parasitic infections on blood safety and related mitigation efforts varied widely by parasite epidemiology, test availability, public health priorities and socioeconomic constraints. While parasites continue to pose a risk to blood safety, the successful mitigation of viral risk has elevated the prominence of TT parasites in many locations, thereby requiring consideration of mitigation efforts. PMID- 30523643 TI - Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors worldwide. The Mucin 1 (MUC1) heterodimeric protein has been confirmed that is overexpressed in ESCC and induced adverse outcomes. However, the detailed mechanism(s) remained challenging. So, we investigated the relationship between MUC1-C and metabolism in ESCC cells. In the results, TP53-induced glycolysis and apoptosis regulator (TIGAR) was overexpressed and correlative with MUC1-C positively in ESCC tissue. Targeting MUC1-C inhibits AKT-mTORC-S6K1 signaling and blocks TIGAR translation. We found that the inhibitory effect of GO-203 on TIGAR was mediated by inhibition of AKT-mTOR-S6K1 pathway. The findings also demonstrated that the suppressive effect of GO-203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential. In xenograft tissues, GO 203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C-terminal subunit (MUC1-C) and TIGAR. This evidence supports the contention that MUC1-C is significant for metabolism in ESCC and indicated that MUC1-C is a potential target for the treatment of ESCC. PMID- 30523644 TI - A novel c.166A>T (p.Thr56Ser) mutation in GYPB*S accounting for unusual S antigen expression. AB - We found an individual with weakened S antigen expression on red blood cells (RBCs) during routine blood grouping. The proband was typed S+s+ by polyclonal antibodies, but the RBCs demonstrated different reactivity with three monoclonal anti-S. The proband did not have alloanti-S. Cloning and Sanger sequencing revealed that the proband had a c.166A>T (p.Thr56Ser) mutation in exon 4 of GYPB*S. When antibody screening of 60 455 blood donors was performed using the proband RBCs, no antibodies were detected. GYPB*S with c.166T should encode an unusual S antigen but the creation of a novel antigen remains to be investigated. PMID- 30523645 TI - D-lactate-selective amperometric biosensor based on the mitochondrial fraction of Ogataea polymorpha recombinant cells. AB - During the recent decades, a lot of data about the significance of D-lactate determination in food technology and quality control has been accumulated. Nowadays, the development of new methods for the determination of D-lactate is very relevant, especially with regards to biosensors. To construct a D-lactate selective biosensor, we suggest using the mitochondria of recombinant yeast cells of Ogataea (Hansenula) polymorpha "tr6" (gcr1 catX/Deltacyb2, prAOX_DLDH) overproducing D-lactate: cytochrome c-oxidoreductase (DLDH, EC 1.1.2.4) and lacking an L-lactate-specific enzyme (flavocytochrome b2 , E.C. 1.1.2.3). The usage of the pure enzyme is problematic due to the complexity of its isolation and stabilization because of the intramembranous localization of DLDH. The enzyme catalyzes D-lactate oxidation to pyruvate coupled with ferricytochrome c reduction to ferrocytochrome c. The constructed biosensor is characterized by high sensitivity (18.5 A.M-1 .m-2 ), a low detection limit (3 MUM of D-lactate), wide linear ranges, good selectivity and sufficient stability. The real samples analysis of D-lactate in dairy products was performed, and high correlation of the obtained results with the reference approach (0.7 < r < 1) and literature data was demonstrated. PMID- 30523646 TI - A systematic review of gut-immune-brain mechanisms in Autism Spectrum Disorder. AB - Despite decades of research, the etiological origins of Autism Spectrum Disorder (ASD) remain elusive. Recently, the mechanisms of ASD have encompassed emerging theories involving the gastrointestinal, immune, and nervous systems. While each of these perspectives presents its own set of supporting evidence, the field requires an integration of these modular concepts and an overarching view of how these subsystems intersect. In this systematic review, we have synthesized relevant evidences from the existing literature, evaluating them in an interdependent manner and in doing so, outlining their possible connections. Specifically, we first discussed gastrointestinal and immuno-inflammation pathways in-depth, exploring the relationships between microbial composition, bacterial metabolites, gut mucosa, and immune system constituents. Accounting for temporal differences in the mechanisms involved in neurodevelopment, prenatal and postnatal phases were further elucidated, where the former focused on maternal immune activation (MIA) and fetal development, while the latter addressed the role of immune dysregulation in contributing to atypical neurodevelopment. As autism remains, foremost, a neurodevelopmental disorder, this review presents an integration of disparate modules into a "Gut-Immune-Brain" paradigm. Existing gaps in the literature have been highlighted, and possible avenues for future research with an integrated physiological perspective underlying ASD have also been suggested. PMID- 30523647 TI - Acknowledgment: Guest Reviewers. PMID- 30523648 TI - Methylene Group Transfer in Carbonyl Compounds Discovered in Silico and Detected Experimentally. AB - Previously unknown transformation of aldehydes, ketones and carboxylic acid derivatives leads to the formation of substituted oxiranes, aziridines and azirines as shown by DFT and MP2 computations. Formations of 2,2-dimethyloxirane d8 from acetone-d6, phenylazirine-d2 from benzonitrile and 2-methyl-2-(4 hydroxyphenyl)-oxirane from 4-hydroxyacetophenone were detected experimentally by electrospray ionization mass-spectrometry with heated desolvating capillary. This reaction is a truly concerted process characterized by high activation barriers (activation enthalpies 320-480 kJ/mol). PMID- 30523649 TI - Embryo production by intracytoplasmic injection of sperm retrieved from Meishan neonatal testicular tissue cryopreserved and grafted into nude mice. AB - Testicular xenografting, combined with cryopreservation can assist conservation of the genetic diversity of indigenous pigs by salvaging germ cells from their neonatal testes. Using Meishan male piglets as an example, we examined whether testicular tissue would acquire the ability to produce sperm after cryopreservation and grafting into nude mice (MS group). For comparison, testicular tissue from neonatal Western crossbreed male piglets was used (WC group). Sixty days after xenografting (day 0 = grafting), MS grafts had already developed seminiferous tubules containing sperm, whereas in the WC grafts, sperm first appeared on day 120. The proportion of tubules containing spermatids and sperm was higher in the MS group than in the WC group between days 90 and 120. Moreover, in vitro-matured porcine oocytes injected with a single sperm obtained from the MS group on day 180 developed to the blastocyst stage. The blastocyst formation rate after injection of the xenogeneic sperm was 14.6%, whereas the ratio in the absence of such injection (attributable to parthenogenesis) was 6.7%. Thus, cryopreserved Meishan testicular tissue acquired spermatogenic activity in host mice 60 days earlier than Western crossbreed tissue. Such xenogeneic sperm are likely capable of generating blastocysts in vitro. PMID- 30523650 TI - High Thermal Conductivity in Boron Arsenide: from Prediction to Reality. AB - Modern first-principles calculations predict that the thermal conductivity of boron arsenide is second only to that of diamond, the best thermal conductor, which may be of benefit for waste heat management in electronic devices. With the optimization of single-crystal growth methods, large-size and high-quality boron arsenide single crystals have been grown and thermal conductivity measurements have verified the related predictions. Benefiting from the increased size and improved qualities, additional properties have been characterized. Important factors related to boron arsenide, remaining challenges, and the future outlook are addressed in this minireview. PMID- 30523651 TI - Systematic Review of Fertility Preservation Patient Decision Aids for Cancer Patients. AB - OBJECTIVE: Despite recommendations internationally for the timely provision of fertility information, cancer patients report unmet information needs, with poor provision and inadequate written information to assist in fertility preservation decision-making. Patient decision aids may be a useful resource in this setting to inform patients and guide decision-making. A systematic review of the literature on decision aids for fertility preservation in cancer patients would determine the effectiveness of these tools in supporting decision-making about fertility preservation and indicate their current use in clinical care. METHODS: A systematic review was conducted in March 2018, within electronic search databases Medline, EMBASE, PSYCH Info, PubMed, and Web of Science. An initial search identified 718 potentially relevant articles from databases and screening of relevant reference lists. RESULTS: A total of 12 papers, detailing 11 studies with a total of 772 participants, evaluating 9 decision aids, were included within the review. PtDAs were shown to significantly increase fertility preservation knowledge and decrease decisional conflict. Overall satisfaction with decision aids was high. Currently only two reviewed decision aids are available for cancer patients. Another tool has been integrated into a web page and one implementation study has been completed. CONCLUSIONS: Patient decision aids can serve as effective complements to current fertility counselling practices by increasing information satisfaction and decision-making outcomes. More research is needed into the appropriateness of these resources for patients across the reproductive-age range. Future implementation studies may assist in aiding dissemination of these tools into clinical practice. PMID- 30523652 TI - Anaphylaxis management in Australian schools: Review of guidelines and adrenaline autoinjector use. AB - Food allergy and anaphylaxis is increasing in Australian children, and anaphylaxis is relatively common in Australian schools. This review aims to provide an overview of current policies and practices for anaphylaxis management in Australian schools, including approaches to risk mitigation and anaphylaxis training. We reviewed literature related to anaphylaxis training in the school setting published between 2010 and 2018. Current anaphylaxis policies/guidelines were obtained from Australian education and health departments, and reports of suspected anaphylaxis and adrenaline autoinjector (AAI) use for 2016-2017 were obtained from education departments where available. Our review of policies/guidelines across Australian jurisdictions indicates inconsistent approaches to anaphylaxis management training. Almost half of Australian school anaphylaxis events required a general-use AAI, administered to students not identified as at risk of anaphylaxis. Development of clear, evidence-based, consistent guidelines related to anaphylaxis management and training in the school setting is imperative to minimise risk. PMID- 30523653 TI - Sexually dimorphic gene expression and transcriptome evolution provides mixed evidence for a fast-Z effect in Heliconius. AB - Sex chromosomes have different evolutionary properties compared to autosomes due to their hemizygous nature. In particular, recessive mutations are more readily exposed to selection, which can lead to faster rates of molecular evolution. Here, we report patterns of gene expression and molecular evolution for a group of butterflies. First, we improve the completeness of the Heliconius melpomene reference annotation, a neotropical butterfly with a ZW sex determination system. Then, we analyse RNA from male and female whole abdomens and sequence female ovary and gut tissue to identify sex and tissue specific gene expression profiles in H. melpomene. Using these expression profiles we compare: 1) sequence divergence and polymorphism; 2) the strength of positive and negative selection; and 3) rates of adaptive evolution, for Z and autosomal genes between two species of Heliconius butterflies, H. melpomene and H. erato. We show that the rate of adaptive substitutions is higher for Z than autosomal genes, but contrary to expectation, it is also higher for male biased than female biased genes. Additionally, we find no significant increase in the rate of adaptive evolution or purifying selection on genes expressed in ovary tissue, a heterogametic specific tissue. Our results contribute to a growing body of literature from other ZW systems that also provide mixed evidence for a fast-Z effect where hemizygosity influences the rate of adaptive substitutions. This article is protected by copyright. All rights reserved. PMID- 30523654 TI - Effects of a high energy and low protein diet on hepatic and plasma characteristics and Cidea and Cidec mRNA expression in liver and adipose tissue of laying hens with fatty liver hemorrhagic syndrome. AB - Cidea and Cidec are two members of Cell death-inducing DNA fragmentation factor alpha-like effector family proteins, which could be involved in lipid or fat metabolism. To better understand the roles of Cidea and Cidec in fatty liver hemorrhagic syndrome (FLHS), 150 healthy 155-day-old Hyline Brown laying hens were randomly divided into control group (fed with basic diet) and experimental group (fed with high-energy low-protein [HELP] diet). Analysis of the liver by tissue sectioning and hematoxylin and eosin staining showed that the HELP diet induced micro-vesicular steatosis in laying hens. Subsequently, based on the liver color scores and the range of lipid accumulation observed in histological examination, we classified livers with <50% vacuolization as mild FLHS and >50% as severe FLHS. The results showed that the levels of Cidea and Cidec mRNA expression were markedly elevated in the liver and adipose tissues with FLHS and the levels of Cidea and Cidec mRNA expression in the liver with severe FLHS were significantly higher than that in the liver with mild FLHS. Thus, the present study revealed that the Cidea and Cidec genes may be involved in pathways of FLHS formation. PMID- 30523655 TI - Rapid Construction of Structurally Diverse Quinolizidines, Indolizidines and Their Analogues via Ruthenium-Catalyzed Asymmetric Cascade Hydrogenation/Reductive Amination. AB - A rapid construction of enantioenriched benzo-fused quinolizidines, indolizidines and their analogues by ruthenium-catalyzed asymmetric cascade hydrogenation/reductive amination of quinolinyl- and quinoxalinyl-containing ketones has been developed. This reaction proceeds under mild reaction conditions, affording chiral benzo-fused aliphatic N-heterocyclic compounds with structural diversity in good yields (up to 95%) with excellent diastereoselectivity (up to > 20:1 dr) and enantioselectivity (up to > 99% ee). In addition, this catalytic protocol is applicable to the scale-up synthesis of quinolizidines and indolizidines analogues, and a highly efficient formal synthesis of (+)-gephyrotoxin was accomplished with this method. PMID- 30523656 TI - A biomass-derived carbon-based electrocatalyst for efficient N2 fixation to NH3 at ambient conditions. AB - Currently, the synthesis of NH3 mainly relies on the Haber-Bosch process which operates at high temperatures and pressures and releases large amount of CO2. Electrocatalytic N2 reduction offers an environmentally friendly alternative for sustainable NH3 production at ambient conditions. In this communication, we report the development of biomass-derived amorphous oxygen-doped carbon nanosheet (O-CN) with an oxygen doping concentration of 5.2 at% using tannin as the precursor. As a metal-free electrocatalyst for N2 reduction reaction, such O-CN shows high catalytic performances, capable of achieving a large NH3 yield of 20.15 MUg h-1 mg-1cat. and a high Faradic efficiency of 4.97% at -0.6 V vs. reversible hydrogen electrode (RHE) in 0.1 M HCl. Notably, it also shows strong electrochemical durability and selectivity. PMID- 30523657 TI - Re-programming of gene expression in the CS8 rice line over-expressing ADPglucose pyrophosphorylase induces a suppressor of starch biosynthesis. AB - The CS8 transgenic rice (Oryza sativa L.) lines, expressing an up-regulated glgC gene, produced higher levels of ADPglucose (ADPglc), the substrate for starch synthases. However, the increase in grain weight was much less than the increase in ADPglc levels suggesting one or more downstream rate-limiting steps. Endosperm starch levels were not further enhanced in double transgenic plants expressing both glgC and the maize brittle-1 gene, the latter responsible for transport of ADPglc into amyloplast. These studies demonstrate that critical processes within the amyloplast stroma restrict maximum carbon flow into starch. RNAseq analysis showed extensive re-programming of gene expression in the CS8 with 2073 genes up regulated and 140 down-regulated. One conspicuous gene, up-regulated ~15-fold, coded for a biochemically uncharacterized starch binding domain containing protein (SBDCP1) possessing a plastid transit peptide. Confocal microscopy and transmission electron microscopy analysis confirmed that SDDCP1 was located in the amyloplasts. Reciprocal immunoprecipitation and pull-down assays indicated an interaction between SBDCP1 and starch synthase IIIIa (SSIIIa), which was down regulated at the protein level in the CS8 line. Furthermore, binding by SBDCP1 inhibited SSIIIa starch polymerization activity in a non-competitive manner. Surprisingly, artificial microRNA gene suppression of SBDCP1 restored protein expression levels of SSIIIa in the CS8 line resulting in starch with lower amylose content and increased amylopectin chains with a higher degree of polymerization. Collectively, our results support the involvement of additional non-enzymatic factors such as SBDCP in starch biosynthesis. This article is protected by copyright. All rights reserved. PMID- 30523659 TI - Effects of a hybrid intervention combining exergaming and physical therapy among older adults in a long-term care facility. AB - AIM: Physical inactivity can cause physical frailty and sarcopenia. We investigated the effects of a hybrid intervention combining commercial exergaming with physical therapy, and clarified the reasons for physical inactivity among older adults. METHODS: This was a pilot study of older participants recruited from a long-term care facility assigned to either an experimental or a control group. The experimental group received a 90-min hybrid intervention twice a week for 12 weeks, whereas the control group received only assessment. The outcomes included muscle strength, walking speed, endurance, the Timed Up and Go test, the Berg Balance Scale, flow state, and safety. RESULTS: We enrolled 17 residents (42.5% of those eligible), with eight in the experimental group. After 12 weeks, the handgrip strength and Timed Up and Go test scores significantly improved in the experimental group. The number of participants with handgrip strength exceeding the cut-off for sarcopenia, Timed Up and Go test scores exceeding the minimal detectable change, and walking speed exceeding the minimum clinically significant difference were greater in the experimental group than in the control group. Furthermore, no significant adverse events were reported; all participants in the experimental group entered the flow state. Overall, 32.5% of participants reported physical inactivity with common reasons, including laziness (77%), a lack of interest (69%) and the hassle of engagement (46%). CONCLUSIONS: The hybrid intervention is safe and feasible, and could delay disability in older adults. Approximately one-third of the participants were physically inactive. Further study is required to reduce physical inactivity. Geriatr Gerontol Int 2018; **: **-**. PMID- 30523658 TI - Variation in outcome reporting in randomised controlled trials of interventions for the prevention and treatment of fetal growth restriction. AB - BACKGROUND: Fetal growth restriction (FGR) contributes to stillbirth, prematurity, neonatal and infant mortality and morbidity. Although FGR is well known to be associated with adverse outcomes for the mother and offspring, effective interventions for the prevention of FGR are yet to be established. The majority of pregnancies complicated by FGR are not detected antenatally and there are limited effective interventions for established FGR. Trials reporting interventions for the prevention and treatment of FGR may be limited by heterogeneity in the underlying pathophysiology. Systematic evaluation of available trials is hampered by the variation in the outcomes measured and reported. METHODS: We conducted a systematic review of randomised controlled trials investigating therapies for the prevention and treatment of FGR up to August 2018. We searched Medline, EMBASE and the Cochrane Central Register of Controlled Trials and systematically assessed studies, extracted and categorised data on which outcomes were reported in the included studies. RESULTS: The search identified 2609 citations of which 153 were selected for full text review and 72 were included in the final analysis. There were 44 trials relating to the prevention of FGR and 24 trials of interventions for the treatment of FGR. We identified 238 outcomes across the included studies. The most commonly reported were birthweight (88.2%), gestational age at birth (72.1%) and small for gestational age babies (67.6%). Few studies reported on any measure of neonatal morbidity (27.9%) and adverse effects of the interventions were reported in only 17.6% of trials. CONCLUSION: Significant variation in outcome reporting exists across trials of therapies for both prevention and treatment of FGR. The clinical applicability of future research would be enhanced by the development of a core outcome set for use in future trials. This article is protected by copyright. All rights reserved. PMID- 30523660 TI - Leucine regulates slow-twitch muscle fibers expression and mitochondrial function by Sirt1/AMPK signaling in porcine skeletal muscle satellite cells. AB - A previous study demonstrated that leucine upregulates the slow myosin heavy chain mRNA expression in C2C12 cells. However, the role of leucine in slow-twitch muscle fibers expression and mitochondrial function of porcine skeletal muscle satellite cells as well as its mechanism remain unclear. In this study, porcine skeletal muscle satellite cells cultured in differentiation medium were treated with 2 mM leucine for 3 days. Sirt1 inhibitor EX527, AMPK inhibitor compound C, and AMPKalpha1 siRNA were used to examine its underlying mechanism. Here we showed that leucine increased slow-twitch muscle fibers and mitochondrial function-related gene expression, as well as increased succinic dehydrogenase (SDH) and malate dehydrogenase (MDH) activities. Moreover, leucine increased the protein levels of Sirt1 and phospho-AMPK. We also found that AMPKalpha1 siRNA, AMPK inhibitor compound C, or Sirt1 inhibitor EX527 attenuated the positive effect of leucine on slow-twitch muscle fibers and mitochondrial function-related gene expression. Finally, we showed that Sirt1 was required for leucine-induced AMPK activation. Our results provide, for the first time, evidence that leucine induces slow-twitch muscle fibers expression and improves mitochondrial function through Sirt1/AMPK signaling pathway in porcine skeletal muscle satellite cells. PMID- 30523661 TI - Standardization of nitric oxide inhalation in extremely preterm infants in Japan. AB - BACKGROUND: In perinatal medicine, inhaled nitric oxide (iNO) has been an important tool for the treatment of full-term and late-preterm infants with persistent pulmonary hypertension of the newborn (PPHN) and hypoxemic respiratory failure (HRF). However, its use in more premature infants is controversial. To evaluate the current clinical practices regarding use of acute inhaled nitric oxide (iNO) therapy in extremely preterm infants, a nationwide survey was conducted in Japan. METHODS: A questionnaire survey was conducted from May to September, 2015. Questionnaires about PPHN and iNO treatment were sent to the doctor in charge of the neonatal care unit in 213 perinatal medical centers (PMCs) that possessed iNO equipment in Japan. RESULTS: A total of 143 of the 213 PMCs provided responses (67.1%). A diagnosis of PPHN was made exclusively by echocardiography in all PMCs. On determination of definitive PPHN diagnosis, iNO was selected in the majority of the PMCs (72%) and started from <= 10 ppm in the most of PMCs (49.7%) for extremely preterm infants. During iNO therapy, cardiac function was checked with echocardiography by a neonatologist every ~8 hours. Weaning of iNO treatment was started when differential SpO2 disappeared, SPO2 reached 100%, etc. After iNO concentration reached 5 ppm, it was decreased gradually and carefully in five steps, taking 12 - 24 hours to go from 5 to 0 ppm. CONCLUSIONS: This survey indicated that iNO was predominantly used in extremely preterm infants as early rescue therapy for PPHN based on echocardiography findings performed by a neonatologist. This article is protected by copyright. All rights reserved. PMID- 30523662 TI - Recent advances in New Caledonian biogeography. AB - The biota of New Caledonia is one of the most unusual in the world. It displays high diversity and endemism, many peculiar absences, and far-flung biogeographic affinities. For example, New Caledonia is the only place on Earth with both main clades of flowering plants - the endemic Amborella and 'all the rest', and it also has the highest concentration of diversity in conifers. The discovery of Amborella's phylogenetic position led to a surge of interest in New Caledonian biogeography, and new studies are appearing at a rapid rate. This paper reviews work on the topic (mainly molecular studies) published since 2013. One current debate is focused on whether any biota survived the marine transgressions of the Paleocene and Eocene. Total submersion would imply that the entire fauna was derived by long-distance dispersal from continental areas since the Eocene, but only if no other islands (now submerged) were emergent. A review of the literature suggests there is little actual evidence in geology for complete submersion. An alternative explanation for New Caledonia's diversity is that the archipelago acted as a refugium, and that the biota avoided the extinctions that occurred in Australia. However, this is contradicted by the many groups that are anomalously absent or depauperate in New Caledonia, although represented there by a sister group. The anomalous absences, together with the unusual levels of endemism, can both be explained by vicariance at breaks in and around New Caledonia. New Caledonia has always been situated at or near a plate boundary, and its complex geological history includes the addition of new terranes (by accretion), orogeny, and rifting. New Caledonia comprises 'basement' terranes that were part of Gondwana, as well as island arc and forearc terranes that accreted to the basement after it separated from Gondwana. The regional tectonic history helps explain the regional biogeography, as well as distribution patterns within New Caledonia. These include endemics on the basement terranes (for example, the basal angiosperm, Amborella), disjunctions at the West Caledonian fault zone, and great biotic differences between Grande Terre and the Loyalty Islands. PMID- 30523663 TI - Red blood cell transfusion in southern Finland from 2011 to 2016: a quality audit. AB - OBJECTIVES: The current trends in RBC use and pre- and post-transfusion Hb levels were analysed to improve practice and to provide international comparison. BACKGROUND: Indications for RBC transfusion have changed with growing scientific evidence. The lowest acceptable haemoglobin (Hb) level has decreased, and transfusing single units instead of pairs has become the new standard. Evidence based guidelines and patient blood management (PBM) programmes increase clinician awareness of rational RBC use. In Finland, however, no formal PBM programme has been established to date. METHODS: The study was registry-based, retrospective and observational. All RBC transfusions for adult patients from 2011 to 2016 in the southern region of Finland were analysed. RESULTS: RBC usage decreased from 34.9 to 27.5 units per 1000 population (P < 0.001). The percentage of single-unit transfusions increased from 57.9 to 66.7%, and the median pre- and post transfusion Hb levels decreased from 8.4 to 8.2 g dL-1 (P < 0.001) and 9.9 to 9.6 g dL-1 (P < 0.001), respectively. The proportion of transfusions with pre transfusion Hb >= 9.0 g dL-1 decreased during the study period but remained high, being 29.5% in 2011 and still 25.2% in 2016. CONCLUSIONS: Consumption of RBCs has decreased despite aging population and increasing healthcare performance demands. The results indicate more rational and evidence-based RBC use. Nevertheless, the transfusion rate and pre- and post-transfusion Hb are still sufficiently high to enable more restrictive transfusion practice. PMID- 30523664 TI - Treatment of actinic keratosis through inhibition of cyclooxygenase-2: Potential mechanism of action of diclofenac sodium 3% in hyaluronic acid 2.5. AB - Cyclooxygenase-2 (COX-2) and its metabolic product prostaglandin E2 (PGE2 ) are induced in response to growth factors, inflammatory cytokines, tumour promoters, activated oncogenes and, in the skin, ultraviolet (UV) radiation. Accumulating evidence suggests a role for the COX-2/PGE2 pathway in tumourigenesis in various tissue types including cutaneous squamous cell carcinoma. There is also strong evidence for a role in the development of actinic keratoses (AKs) - common dysplastic lesions of the skin associated with UV radiation overexposure - considered as part of a continuum with skin cancer. Non-steroidal anti inflammatory drugs (NSAIDs) exert their anti-inflammatory, analgesic and antipyretic effects by reversibly or irreversibly acetylating COX isoforms, inhibiting downstream prostaglandins, and may have a chemo-preventive role in malignancies, including skin cancer. Topical treatment of AK lesions with the NSAID diclofenac sodium 3% in combination with hyaluronic acid 2.5% has been shown to be effective and well tolerated, although the mechanism of action remains to be elucidated. This article is protected by copyright. All rights reserved. PMID- 30523665 TI - Comparisons of pedometer-determined weekday physical activity among Swedish school children and adolescents in 2000 and 2017 showed the highest reductions in adolescents. AB - AIM: This study compared differences in weekday physical activity among school children and adolescents in middle-class communities in south eastern Sweden in 2000 and 2017. METHODS: Data were drawn from two independent cross-sectional cohorts of children and adolescents aged eight, 11 and 14. The same six schools, protocols, procedures and instruments were used in both years, with 332 subjects in 2000 and 562 in 2017. Mean steps per day (SPD) were measured with a Yamax SW 200 pedometer. RESULTS: The mean weekday SPD was similar among eight-year-old girls in both years, but 8% (p=0.040) higher among eight-year-old boys in 2017. However, among 11-year-old children, the mean SPDs were 12% lower among both girls (p=0.033) and boys (p=0.001). The SPDs among 14-year-old adolescents were 24% (p=0.012) and 30% (p<0.001) lower among girls and boys, respectively. CONCLUSION: This school-based study from south eastern Sweden showed that weekday physical activity differed between age groups in 2000 and 2017. The highest reductions were seen among older children and adolescents, particularly 14-year old girls and boys. The only group that increased was eight-year-old boys, with no significant change in eight-year-old girls. A possible explanation might be the dramatically increased use of the Internet on phones and tablets. This article is protected by copyright. All rights reserved. PMID- 30523666 TI - Narrative review of therapies for chronic enteropathies in dogs and cats. AB - BACKGROUND: The optimal medical treatment for chronic enteropathy (CE) in dogs and cats is controversial. Sequential treatment using diet, antimicrobials, and immunosuppressive drugs is the most common strategy used by clinicians. OBJECTIVES: To review the evidence for the effectiveness of dietary, drug, and alternative health interventions for inducing clinical remission in dogs and cats with CE. ANIMALS: Retrospective study of dogs and cats with a diagnosis of chronic enteropathy. METHODS: MEDLINE and Centre for Agriculture and Bioscience International (CABI) databases (1950 to March 2017) were searched for randomized controlled trials (RCTs), observational studies, and case series. The primary outcome was induction of clinical remission. All studies were evaluated using the quality of evidence grading guidelines (I-IV), which assign a score defining the strength and quality of the evidence. RESULTS: Twenty-two studies (11 RCTs in dogs and 2 in cats and 9 cohort studies or case series) met the inclusion criteria for inducing remission of gastrointestinal (GI) signs. Of the 13 RCTs achieving grade I scores, 10 studies (totaling 218 dogs and 65 cats) compared single treatment: diet (n = 3), immunosuppressives (n = 3), antimicrobials (n = 2), anti-inflammatory drugs (n = 1), and probiotics (n = 1). Three case series (grade III) reported clinical remission using an elimination diet fed to 55 cats and use of enrofloxacin to induce remission in dogs with granulomatous colitis (2 studies totaling 16 dogs). CONCLUSIONS AND CLINICAL IMPORTANCE: The current evidence for treatment of CE is much greater in dogs than in cats. There is sufficient strong evidence to recommend the use of therapeutic GI diets, glucocorticoids, enrofloxacin, or some combination of these in dogs with CE. Therapeutic GI diets and glucocorticoids are most useful in cats with CE. PMID- 30523667 TI - Initiation of advance care planning in newly admitted nursing home residents in Flanders, Belgium: A prospective cohort study. AB - AIM: To describe (i) the timing of initiation of advance care planning (ACP) after nursing home admission; (ii) the association of dementia and physical health with ACP initiation; and (iii) if and how analgesic use and use of lipid modifying agents is related to ACP, in a cohort of newly admitted residents. METHODS: A prospective, observational cohort study of nursing home residents was carried out. Data were collected 3 months, 15 months (year 1) and 27 months (year 2) after admission, using a structured questionnaire and validated measuring tools. RESULTS: ACP was never initiated during the 2-year stay for 38% of the residents, for 22% ACP was initiated at admission, for 21% during year 1 and for 19% during year 2 (n = 323). ACP initiation was strongly associated with dementia, but not with physical health. Residents without dementia were more likely to have ACP initiation at admission or not at all, whereas ACP initiation was postponed for residents with dementia. Between admission and year 2, analgesic use increased (from 34% to 42%), and the use of lipid-modifying agents decreased (from 28% to 21%). Analgesic use increased more in residents with ACP initiation during year 1 and year 2. The use of lipid-modifying agents was not associated with ACP. CONCLUSIONS: The timing of ACP initiation differed significantly for residents with and without dementia, which highlights the importance of an early onset of ACP before residents lose their decision-making capacity. ACP conversations might create opportunities to discuss adequate pain and other symptom treatment, and deprescribing at the end of life. Geriatr Gerontol Int 2018; **: **-**. PMID- 30523668 TI - Optical study of stress hormone-induced nanoscale structural alteration in brain using partial wave spectroscopic (PWS) microscopy. AB - Chronic stress affects nano to microscale structures of the brain cells/tissues due to suppression of neural growths and reconnections, hence the neuronal activities. This results in depression, memory loss and even death of the brain cells. Our recently developed novel optical technique, partial wave spectroscopic (PWS) microscopy has nanoscale sensitivity, and hence, can detect nanoscale changes in brain tissues due to stress. In this study, we applied this technique to quantify the stress related structural changes in the corticosterone-treated mouse model of stress. Our results show that brains from corticosterone-treated mice showed higher nanoscale structural disorder in the hippocampal region as compared to the brain from normal (vehicle) mice. The increase in structural alteration correlates with the duration of the stress. We further quantified the relative changes and the spatial localization of these changes in this mouse model and found out that the maximum changes occurred nearly symmetrically in both regions of the hippocampus. The mRNA for stress-related genes, BDNF and TrkB were also significantly reduced in the hippocampus of corticosterone-treated mice compared to that in control mice. These results indicate that chronic corticosterone treatment induces nanoscale structural alterations in mouse brain that corresponds to changes in stress-related gene expression. This article is protected by copyright. All rights reserved. PMID- 30523669 TI - Equilibrium and Dynamic Absorption of Electrolyte Species in Cation/Anion Exchange Membranes of Vanadium Redox Flow Battery. AB - Vanadium redox flow batteries (VRFBs) rely on ion exchange membranes (IEMs) to separate the positive and negative compartments, while maintaining electrical neutrality of the cell, by allowing the transport of ionic charge carriers. Cation exchange membranes (CEMs) and anion exchange membranes (AEMs), the two principal types of IEM, have both been employed in VRFBs. The performance of these IEMs can be influenced by the absorption of species from the electrolyte. In this study, a typical commercial CEM (Nafion 117) and AEM (FAP 450), were examined with respect to vanadium uptake, after exposure to electrolyte at different states of charge (SOC). The two types of membrane were found to behave very differently, with the AEM showing very high selectivity for V(V), which resulted in a significant increase in area specific resistivity (ASR). In contrast, the CEM absorbed V(II) more strongly than vanadium in other oxidation states. These findings are essential for the development of an effective membrane for the VRFB application. PMID- 30523670 TI - Targeted next-generation sequencing approach for molecular genetic diagnosis of hereditary colorectal cancer: Identification of a novel single nucleotide germline insertion in adenomatous polyposis coli gene causes familial adenomatous polyposis. AB - BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease which primarily manifested with developing adenomas or polyps in colon or rectum. It is caused by the germline mutations in adenomatous polyposis coli (APC) gene. Patients with FAP are usually manifested with "hundreds or even thousands" adenomas or polyps in colon or rectum. However, without proper clinical diagnosis and timely surgical interventions, colorectal adenomas, or polyps gradually increase in size and in numbers which finally leads to colorectal cancer (CRC) at the mean age of 36 years of the patient. METHODS: In this study, we identified a family with FAP. In this family, FAP has been diagnosed clinically based on symptoms, medical test reports, and positive family history for three generations. In order to unveil the molecular genetic consequences underlying the disease phenotype, we performed next-generation sequencing with a customized and designed panel of genes reported to be associated with hereditary CRC. The variant identified by next-generation sequencing has been validated by Sanger sequencing. RESULTS: A heterozygous novel insertion [c.3992_3993insA; p.Thr1332Asnfs*10] in exon 16 of APC gene has been identified. This novel insertion is cosegregated well with the FAP phenotype among all the affected members of this family. This mutation causes a frameshift by the formation of a premature stop codon which finally results in the formation of a truncated APC protein of 1,342 amino acids instead of the wild type APC protein of 2,843 amino acids. Hence, this is a loss-of-function mutation. This mutation was not found in unaffected family members or in normal control individuals. CONCLUSION: Our present study emphasizes the importance of a novel approach of the gene panel-based high-throughput sequencing technology for easy and rapid screening for patients with FAP or CRC which will help the clinician for follow-up and management. PMID- 30523671 TI - Best Practices for Preparing a Single Cell Suspension from Solid Tissues for Flow Cytometry. AB - Preparing a single cell suspension is a critical step in any solid tissue flow cytometry experiment. Tissue dissection, enzymatic digestion, and mechanical dissociation are three significant steps leading to the degradation of the extracellular matrix and the isolation of single cells, allowing the generation of high-quality flow cytometry data. Cells and the extracellular matrix contain various proteins and other structures which must be considered when designing a tissue digestion protocol to preserve the viability of cells and the presence of relevant antigens while digesting matrix components and cleaving cell-cell junctions. Evaluation of the single cell suspension is essential before proceeding with the labeling of the cells as high viability and absence of cell debris and aggregates are critical for flow cytometry. The information presented should be used as a general guide of steps to consider when preparing a single cell suspension from solid tissues for flow cytometry experiments. (c) 2018 International Society for Advancement of Cytometry. PMID- 30523672 TI - Designing Multivalent Ligands to Control Biological Interactions: From Vaccines and Cellular Effectors to Targeted Drug Delivery. AB - Multivalent interactions in which multiple ligands on one object bind to multiple receptors on another are commonly found in natural biological systems. In addition, these interactions can lead to increased strength and selectivity when compared to the corresponding monovalent interaction. These attributes have also guided the design of synthetic multivalent ligands to control biological interactions. This review will highlight the recent literature describing the use of multivalent ligand display in the design of vaccines, immunomodulators, cell signaling effectors, and vehicles for targeted drug delivery. PMID- 30523673 TI - Lack of association of the IL-1RN and IL-10 polymorphisms with risk of psoriasis: A meta-analysis. AB - BACKGROUND: The present study carried out a meta-analysis to investigate whether the interleukin-1 receptor antagonist (IL-1RN) VNTR polymorphism and three IL-10 single-nucleotide polymorphisms (SNPs) rs1800896, rs3021097, and rs1800872 are associated with psoriasis risk. METHODS: Wanfang, China National Knowledge Infrastructure, Medline, and PubMed databases were searched for potential studies published until 2 November 2017. Forest plots were generated. RESULTS: Thirteen case-control studies were included in the review. The results of meta-analyses revealed no association of the IL-1RN*2 allele with psoriasis in the overall populations (odds ratio [OR] = 1.16, 95% confidence intervals [CI]: 0.89-1.50, p = 0.279), Asians (OR = 1.27, 95% CI: 0.73-2.23, p = 0.403), and Caucasians (OR = 1.04, 95% CI: 0.88-1.23, p = 0.669). Under the allelic model, there was no statistically significant association of psoriasis with the IL-10 SNPs rs1800896 (G allele vs. A allele: OR = 1.03, 95% CI: 0.90-1.18, p = 0.639), rs3021097 (C allele vs. T allele: OR = 1.17, 95% CI: 0.88-1.56, p = 0.288), and rs1800872 (C allele vs. A allele: OR = 1.01, 95% CI: 0.81-1.25, p = 0.951). No publication bias was found by Egger's test and Begg's funnel plots. CONCLUSION: Current published studies fail to support an association of the IL-1RN VNTR polymorphism and IL-10 SNPs rs1800896, rs3021097, and rs1800872 with psoriasis risk. PMID- 30523674 TI - The ethics of global psychiatric genomics: Multilayered challenges to integrating genomics in global mental health and disability-A position paper of the Oxford Global Initiative in Neuropsychiatric GenEthics (NeuroGenE). AB - Psychiatric genomics has the potential to radically improve the prevention and early intervention of serious mental and neurodevelopmental disorders worldwide. However, little work has been done on the ethics of psychiatric genomics-an oversight that could result in poor local uptake, reduced practical/clinical application, and ethical violations in this rapidly developing area of scientific research. As part of the Global Project of the Stanley Center for Psychiatric Research, the Global Initiative in Neuropsychiatric GenEthics (NeuroGenE) based at the University of Oxford aims to embed ethical inquiry within scientific investigation and engage with fundamental ethical questions around a psychiatric genomics approach to mental and neurodevelopmental disorder. This position paper sets out the core aims of the NeuroGenE research programme and explores the importance of a crosscutting research orientation in this field based on multidisciplinary methodologies which can ensure that efforts to translate and apply global psychiatric genomics in public policy and clinical practice are ethically grounded strategies, respectful of different cultures and contexts. PMID- 30523675 TI - Improving Quality, Reproducibility, and Usability of FRET-Based Tension Sensors. AB - Mechanobiology, the study of how mechanical forces affect cellular behavior, is an emerging field of study that has garnered broad and significant interest. Researchers are currently seeking to better understand how mechanical signals are transmitted, detected, and integrated at a subcellular level. One tool for addressing these questions is a Forster resonance energy transfer (FRET)-based tension sensor, which enables the measurement of molecular-scale forces across proteins based on changes in emitted light. However, the reliability and reproducibility of measurements made with these sensors has not been thoroughly examined. To address these concerns, we developed numerical methods that improve the accuracy of measurements made using sensitized emission-based imaging. To establish that FRET-based tension sensors are versatile tools that provide consistent measurements, we used these methods, and demonstrated that a vinculin tension sensor is unperturbed by cell fixation, permeabilization, and immunolabeling. This suggests FRET-based tension sensors could be coupled with a variety of immuno-fluorescent labeling techniques. Additionally, as tension sensors are frequently employed in complex biological samples where large experimental repeats may be challenging, we examined how sample size affects the uncertainty of FRET measurements. In total, this work establishes guidelines to improve FRET-based tension sensor measurements, validate novel implementations of these sensors, and ensure that results are precise and reproducible. (c) 2018 International Society for Advancement of Cytometry. PMID- 30523676 TI - One-stage random effects meta-analysis using linear mixed models for aggregate continuous outcome data. AB - The vast majority of meta-analyses uses summary/aggregate data retrieved from published studies in contrast to meta-analysis of individual participant data (IPD). When the outcome is continuous and IPD are available, linear mixed modelling methods canbe employed in a one-stage approach. This allows for flexible modelling of within-study variability and between-study effects and accounts for the uncertainty in the estimates of between-study and within-study residual variances. However, IPD are seldom available. For the normal outcome case we present a method to generate pseudo IPD from aggregate data using group mean, standard deviation and sample sizes within each study, i.e., the sufficient statistics. Analyzing the pseudo IPD with likelihood-based methods yields identical results as the analysis of the unknown true IPD. The advantage of this method is that we can employ the mixed modelling framework, implemented in many statistical software packages, and explore modelling options suitable for IPD, such as fixed study specific intercepts and fixed treatment effect model, fixed study specific intercepts and random treatment effects and both random study and treatment effects and different options to model the within-study residual variance. This allows choosing the most realistic (or potentially complex) residual variance structures across studies, instead of using an overly simple structure. We demonstrate these methods in two empirical datasets in Alzheimer's disease, where an extensive model, assuming all within-study variances to be free, fitted considerably better. In simulations the pseudo IPD approach showed adequate coverage probability, because it accounted for small sample effects. PMID- 30523677 TI - Impact of Presbyopia and Its Correction in Low- and Middle-Income Countries. AB - Presbyopia affects more than 1 billion people worldwide, and the number is growing rapidly due to the aging global population. Uncorrected presbyopia is the world's leading cause of vision impairment, and as with other causes, the burden falls unfairly on low- and middle-income countries (LMICs), where rates of presbyopic correction are as low as 10%. The importance of presbyopia as a cause of vision impairment is further underscored by the fact that it strikes at the heart of the productive working years, although it can be safely and effectively treated with a pair of inexpensive glasses. To galvanize action for programs to address uncorrected presbyopia in the workplace and beyond in LMICs, it is crucial to build a solid evidence base detailing the impact of presbyopia and its correction in important areas such as work productivity, activities of daily living, visual function, and quality of life. The aim of this review was to provide an up-to-date reference for program planners and policymakers seeking to build support for programs of presbyopia correction, particularly in low-resource settings. PMID- 30523678 TI - Reducing Holomycin Thiosulfonate to its Disulfide with Thiols. AB - The dithiolopyrrolone (DTP) natural products contain a unique ene-disulfide that is essential for their antimicrobial and anticancer activities. The ene-disulfide in some DTPs is oxidized to a cyclic thiosulfonate, but it is unknown how the DTP thiosulfonates react with biomolecules. We studied the reactivity of the thiosulfonate derivative of the DTP holomycin, oxo-holomycin, and discovered a unique redox reaction: oxo-holomycin is reduced to its parent disulfide, while oxidizing small molecule and protein thiols to disulfides. Our work reveals that the DTP core is a privileged scaffold that undergoes unusual redox chemistry. The redox chemistry of the DTP natural products may contribute to their mechanism of action. PMID- 30523679 TI - Highly Conductive Hydrogel Polymer Fibers toward Promising Wearable Thermoelectric Energy Harvesting. AB - The requirement of a portable electron is functioning as a driving force for a wearable energy instrument. Poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS), as one of the most promising organic electron materials, has been widely studied in energy conversion devices. However, the efforts for PEDOT:PSS fibers are insufficient to boost the development of wearable thermoelectric energy harvesting. Here, a highly conductive p-type PEDOT:PSS fiber was produced by gelation process, which was 3 orders of magnitude higher than that of previous hydrogel fibers. Surprisingly, a post-treatment with organic solvents such as ethylene glycol and dimethyl sulfoxide tripled their electrical conductivity with an only 5% decreased Seebeck coefficient, consequently leading to an optimized thermoelectric power factor. Furthermore, we assembled a p-n-type thermoelectric device connecting five pairs of p-type PEDOT:PSS fibers and n-type carbon nanotube fibers. This fiber-based device displayed an acceptable output voltage of 20.7 mV and a power density of 481.2 MUW.cm-2 with a temperature difference of ~60 K, which might pave the way for the development of organic thermoelectric fibers for wearable energy harvesting. PMID- 30523680 TI - Copper-Catalyzed Perfluoroalkylation of Allyl Phosphates with Stable Perfluoroalkylzinc Reagents. AB - A general and practical method for copper-catalyzed cross-coupling of allyl phosphates with stable perfluoroalkylzinc reagents has been developed. The reaction proceeds under mild reaction conditions with high efficiency, good functional group tolerance, high regio- and stereoselectivities, and provides a general, straightforward and useful access to allyl-perfluoroalkyl compounds. Preliminary mechanistic studies reveal that the allyl copper intermediate may be involved in the catalytic cycle. PMID- 30523681 TI - 3D Printed Graphene/PDMS Composites for Stretchable and Strain-Insensitive Temperature Sensors. AB - Materials possessing exceptional temperature sensitivity and high stretchability are of importance for real time temperature monitoring on three-dimensional components with complex geometries, when operating under various external deformation modes. Herein, we develop a stretchable temperature sensor consisting of cellular graphene/polydimethylsiloxane (PDMS) composite. The first of its kind, graphene based polymer composites with desired micro-structures are produced through a direct 3D ink writing technique. The resultant composites possess long-range ordered and precisely controlled cellular structure. Temperature sensing properties of three cellular structures, including grid, triangular, and hexagonal porous structures are studied. It is found that all three cellular composites present more stable sensitivities than solid composites under external strains, due to the fine porous structure can effectively share the external strain, and the composites with grid structure delivered particularly stable sensing performance, showing only ~15% sensitivity decrease at a large tensile strain of 20%. Taking full advantage of the composites with grid structure in terms of sensitivity, durability, and stability, practical applications of the composite are demonstrated to monitor the cooling process of a heated tube and measure skin temperature accompanying with arbitrary wristwork. PMID- 30523682 TI - One-pot Reaction between N-tosylhydrazones and 2-Nitrobenzyl Bromide: Route to NH free C2-Arylindoles. AB - A one-pot Barluenga coupling between N-tosylhydrazones and nitro-benzylbromide, followed by deoxygenation of ortho-nitrostyrenes, and subsequent cyclization has been developed providing a new way to synthesize various C2-arylindoles. This method exhibits a good substrate scope and functional group tolerance, and it allows an access to NH-free indoles, which can present a potential utility in medicinal chemistry applications. PMID- 30523683 TI - Enhanced-Fluidity Liquid Chromatography-Mass Spectrometry for Intact Protein Separation and Characterization. AB - Recent advances in analysis of proteins have increased the demand for more efficient techniques to separate intact proteins. Enhanced-fluidity liquid chromatography (EFLC) involves the addition of liquefied CO2 to conventional liquid mobile phases. The addition of liquefied CO2 increases diffusivity and decreases viscosity, which inherently leads to a more efficient separation. Herein, EFLC is applied to hydrophobic interaction chromatography (HIC) stationary phases for the first time to study the impact of liquefied CO2 to the chromatographic behavior of proteins. The effects of liquefied CO2 on chromatographic properties, charge state distributions (CSD) and ionization efficiencies were evaluated EFLC offered improved chromatographic performance compared to conventional liquid chromatography (LC) methods including a shorter analysis time, better peak shapes, and higher plate numbers. The addition of liquefied CO2 to the mobile phase provided an ESI-friendly and "supercharging" reagent without sacrificing chromatographic performance, which can be used to improve peptide and protein identification in large-scale application. PMID- 30523684 TI - Defective MnxZr1-xO2 solid solution for the catalytic oxidation of toluene: Insights into the oxygen vacancy contribution. AB - Oxygen vacancy is conducive to molecular oxygen adsorption and activation, and it is necessary to estimate its contribution on catalysts especially doped system for VOCs oxidation. Herein, a series of doped MnxZr1-xO2 catalysts with oxygen vacancy were prepared by substituting Zr4+ in zirconia with low-valent manganese (Mn2+) partially. Comparing with the corresponding mechanically mixed samples (MB x) without oxygen vacancy, MnxZr1-xO2 catalysts exhibited better toluene conversion and specific reaction rate, where the difference values were calculated to estimate the contribution of oxygen vacancy on catalytic performance. The increase of oxygen vacancy concentrations in MnxZr1-xO2 catalysts can boost the difference values, implying the enhancement of oxygen vacancy contribution. Density functional theory (DFT) calculations further confirmed the contribution of oxygen vacancy, and molecular oxygen is strongly absorbed and activated on defective Mn doped c-ZrO2 (111) surface with oxygen vacancy rather than perfect m-ZrO2 (-111) surface or prefect Mn doped c-ZrO2 (111) surface, thus resulting in the significant improvement of catalytic activity for toluene oxidation. In situ DRIFTS spectra revealed that the oxygen vacancy can alter the toluene degradation pathway and accelerate the intermediates to convert into CO2 and H2O, thus leading to a low activation energy and high specific reaction rate. PMID- 30523685 TI - Palladium-Catalyzed Tandem Carbocyclization and Hetroarylation for the synthesis of 2-(trifluoromethyl)indenylmethyleneindoles. AB - A palladium-catalyzed tandem cyclization and cross-coupling reaction of the ortho (2-chlorovinyl)-alkynylbenzenes with indoles/pyrroles is developed. The process proceeds via intramolecular carbocyclization and subsequent hetroarylation to afford previously unknown trifluoromethyl-containing indenylmethyleneindoles, which are potentially useful in drug design. PMID- 30523686 TI - DeltaMass: Automated detection and visualization of mass shifts in proteomic open search results. AB - Routine identification of thousands of proteins in a single LC/MS experiment has long become the norm. With these vast amounts of data more rigorous treatment of modified forms of peptides becomes possible. "open search" - a protein database search with a large precursor ion mass tolerance window, is becoming a popular method to evaluate possible sets of post-translational and chemical modifications in samples. Extraction of statistical information about modification from peptide search results requires additional effort and data processing, such as recalibration of masses and accurate detection of precursors in MS1 signals. Here we present a software tool DeltaMass which performs kernel density based estimation of observed mass shifts and allows for detection of very poorly resolved mass deltas and mapping them to known modifications from public databases augmented with some additionally generated possible chemical changes to the molecule. PMID- 30523687 TI - Block junction-functionalized all-conjugated donor-acceptor block copolymers. AB - Junction-functionalized donor-acceptor (D-A) block copolymers (BCPs) enable spatial and electronic control over interfacial charge dynamics in excitonic devices such as solar cells. Here we present the design, synthesis, morphology and electronic characterization of block junction-functionalized, all-conjugated, all-crystalline D-A BCPs. Poly(3-hexylthiophene) (P3HT), a single thienylated diketopyrrolopyrrole (ThxDPPThx, x=1 or 2) unit and poly{[N,N'-bis(2 octyldodecyl)-naphthalene-1,4,5,8-bis(dicarboximide)-2,6-diyl]-alt-5,5'-(2,2' bithiophene)} (PNDIT2) is used as donor, interfacial unit and acceptor, respectively. Almost all C-C coupling steps are accomplished by virtue of C-H activation. Synthesis of the macroreagent H-P3HT-ThxDPPThx, with x determining its C-H reactivity, is key to the synthesis of various BCPs of type H-P3HT ThxDPPThx-block-PNDIT2. Morphology is determined from a combination of calorimetry, transmission electron microscopy (TEM) and thin film scattering. Block copolymer crystallinity of P3HT and PNDIT2 is reduced indicating frustrated crystallization. A long period lp, is invisible from TEM, but shows up in resonant soft X-ray scattering experiments at a length scale of lp~ 60 nm. Photoluminescence of H-P3HT-ThxDPPThx indicates efficient transfer of the excitation energy to the DPP chain end, but is quenched in BCP films. Transient absorption and pump-push-photocurrent spectroscopies reveal geminate recombination (GR) as the main loss channel in as-prepared BCP films independent of junction functionalization. Melt-annealing increases GR as a result of the low degree of crystallinity and poorly defined interfaces, and additionally changes backbone orientation of PNDIT2 from face-on to edge-on. These morphological effects dominate solar cell performance and cause an insensitivity to the presence of the block junction. PMID- 30523688 TI - Surface-Adaptive and Initiator-Loaded Graphene as a Light-Induced Generator with Free Radicals for Drug-Resistant Bacteria Eradication. AB - Since generating toxic reactive oxygen (ROS) is largely dependent on oxygen, bacteria infected wounds hypoxia significantly inhibits photodynamic therapy's (PDT) antibacterial efficiency. Therefore, a novel therapeutic method for eradicating multidrug-resistant bacteria is developed based on the light activated alkyl free radical generation (that is oxygen-independent). According to the polydopamine coated carboxyl graphene (PDA@CG), an initiator-loaded and pH sensitive heat-producible hybrid of bactericides was synthesized. According to fluorescence/thermal imaging, under the low pH of the bacterial infection sites, this platform turned positively charged, which allows their accumulation in local infection site. The plasmonic heating effects of PDA@CG can make the initiator decomposed to generate alkyl radical (R*) under the followed near-infrared light (NIR) irradiation. As a result, oxidative-stress (OS) can be elevated, DNA damages in bacteria can be caused, and finally the bacteria even the multidrug resistance death can be caused under different oxygen tensions. Moreover, our bactericidal could promote wound healing in vivo and negligible toxicity in vivo and in vitro and eliminate abscess. Accordingly, the researcher proves that combination oxygen-independent free radical based therapy along with a stimulus responsiveness moiety not only can be used as an effective treatment of the multidrug-resistant bacteria infection, but also creates a use of a variety of free radicals for multidrug-resistant bacteria infection wounds treatment. PMID- 30523689 TI - Geometry Distortion and Small Polaron Binding Energy Changes with Ionic Substitution in Halide Perovskites. AB - Halide perovskites have demonstrated remarkable performance in optoelectronic applications. Despite extraordinary progress, questions remain about device stability. We report an in-depth computational study of small polaron formation, electronic structure, charge density, and reorganization energies of several experimentally relevant halide perovskites using isolated clusters. Local lattice symmetry, electronic structure, and electron-phonon coupling are interrelated in polaron formation in these materials. To illustrate this, first principles calculations are performed on (MA/Cs/FA)Pb(I/Br)3 and MASnI3. Across the materials studied, electron small polaron formation is manifested by Jahn-Teller like distortions in the central octahedron, with apical PbI bonds expanding significantly more than the equatorial bonds. In contrast, hole polarons cause the central octahedron to uniformly contract. This difference in manifestation of electron and hole polaron formation can be a tool to determine what is taking place in individual systems to systematically control performance. Other trends as the anion and cations are changed, are established for optimization in specific optoelectronic applications. PMID- 30523690 TI - Identification of hydroxypyrazine O-methyltransferase genes in Coffea arabica: a potential source of methoxypyrazines that cause potato taste defect. AB - The goal of this study is to identify Coffea arabica O-methyltransferase (OMT) genes involved in the biosynthesis of methoxypyrazines. High levels of 2 isopropyl-3-methoxypyrazine (IPMP) and 2-isobutyl-3-methoxypyrazine (IBMP) in coffee beans are associated with the potato taste defect (PTD). Among the 34 putative O-methyltransferase genes identified in the published genome of C. canephora, three genes are highly homologous to known hydroxypyrazine OMT genes. Genes of interest were amplified and sequenced from genomic DNA of single C. arabica beans grown in eight different locations, including regions with endemic PTD. Although C. arabica OMT target sequences were almost identical regardless of source location, individual beans shared numerous polymorphisms in each of the target genes. Two of the predicted C. arabica OMT enzymes were successfully expressed in Escherichia coli and purified, and one enzyme shows slow yet measurable turnover of both IBHP and IPHP, supporting a possible role of the coffee plant in PTD. PMID- 30523691 TI - A tandem mass spectrometry sequence database search method for identification of O-fucosylated proteins by mass spectrometry. AB - Thrombospondin type 1 repeats (TSRs), small adhesive protein domains with a wide range of functions, are usually modified with O-linked fucose, which may be extended to O-fucose-beta1,3-glucose. Collision-induced dissociation (CID) spectra of O-fucosylated peptides cannot be sequenced by standard tandem mass spectrometry (MS/MS) sequence database search engines because O-linked glycans are highly labile in the gas phase and are effectively absent from the CID peptide fragment spectra, resulting in a large mass error. Electron transfer dissociation (ETD) preserves O-linked glycans on peptide fragments, but only a subset of tryptic peptides with low m/z can be reliably sequenced from ETD spectra compared to CID. Accordingly, studies to date that have used MS to identify O-fucosylated TSRs have required manual interpretation of CID mass spectra even when ETD was also employed. In order to facilitate high-throughput, automatic identification of O-fucosylated peptides from CID spectra, we re engineered the MS/MS sequence database search engine Comet and the MS data analysis suite Trans-Proteomic Pipeline to enable automated sequencing of peptides exhibiting the neutral losses characteristic of labile O-linked glycans. We used our approach to re-analyze published proteomics data from Plasmodium parasites and identified multiple glycoforms of TSR-containing proteins. PMID- 30523692 TI - Correction to "Conjugated Energetic Salts Based on Fused Rings: Insensitive and Highly Dense Materials". PMID- 30523693 TI - Si-bridged Ladder Type Small Molecules Acceptors for High-Performance Organic Photovoltaics. AB - In this study, we synthesized 5,11-dihexyl-4,4,10,10-tetraoctylbenzo[1,2-b:4,5 b']bisthieno[4'',5''-b'':4''',5'''-b''']silolo[2'',3''-d:2''',3'''-d']thiophene (ArSi) as a ladder-type electron-rich core for the preparation of three A-D-A type nonfullerene acceptors (NFAs)-ArSiID, ArSiID-F, and ArSiID-Cl-featuring (3 oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (ID), 2-(5,6-difluoro-3-oxo-2,3 dihydro-1H-inden-1-ylidene)malononitrile (ID-F), and 2-(5,6-dichloro-3-oxo-2,3 dihydro-1H-inden-1-ylidene)malononitrile (ID-Cl) as peripheral electron-poor units, respectively. These molecules exhibit strong absorption covering the region of 600-850 nm. The incorporation of the halogen atoms onto the terminal units adjusted the energy levels and light harvesting ability of these materials. We employed the conjugated polymers J51 and PBDB-T, having middle optical energy gaps as donor together with these ArSiID and derivatives ArSiID-F and ArSiID-Cl as acceptor to study the blend film morphology and the corresponding OPV performances. After optimization with device engineering works, a PBDB-T:ArSiID-F based device with a PCE up to 9.4% was achieved. This study is the first case to examine the effects of various halogen modifications on the performance of ArSi derivatives that serve as NFAs for OPVs. Our findings should encourage further investigations on this rarely studied core structure for optoelectronic applications. PMID- 30523694 TI - EXPRESS: An On-Off-On Fluorescence Probe Based on Coumarin for Cu2+, Cysteine and Histidine Detections. PMID- 30523695 TI - Parents training parents: Lessons learned from a study of reciprocal imitation training in young children with autism spectrum disorder. AB - Parent-mediated interventions are cost-effective ways to increase access to appropriate treatment services to children with autism spectrum disorder. We aimed to engage parents working as partners within rural autism identification teams to facilitate prompt initiation of autism-specific treatment services and expand the amount of treatment available to young children with autism spectrum disorder. To do this, we sought to employ a two-phase training approach: (Phase 1) train parents to fidelity in an evidence-based parent-mediated intervention (reciprocal imitation training), and (Phase 2) evaluate the extent to which parents could effectively coach other parents of newly diagnosed children to implement reciprocal imitation training with their child. We experienced several unexpected barriers to completing all aspects of the Phase 1 training workflow. This led us to pivot toward a process evaluation. We used qualitative interviewing with our partner parents to systematically identify barriers and enhance the likelihood for successful future efforts at such an approach. The lessons we learned and recommendations for others attempting this type of research are presented. PMID- 30523696 TI - Skin adverse events in recently approved targeted therapies in solid malignancies. AB - Targeted anticancer therapies are an important weapon in the fight against cancer. Targeted therapies interfere with specific molecules necessary for tumor growth and cancer progression. They are divided mainly to either monoclonal antibodies or small molecules inhibitors. Their primary objective is to target directly and precisely the cancer cells leading to a minimal side-effects profile. The dermatologic adverse reactions of these targeted therapies is different from those seen with classical cytotoxic chemotherapy. Rashes, xerosis, hand-foot-skin reaction and mucositis are the most frequent side effects. In this paper, we aim to present a comprehensive review of the dermatologic side effects of targeted therapies including, specific side effects related to recently, approved targeted therapies. PMID- 30523697 TI - Molecular characterization of testicular germ cell tumors: chasing the underlying pathways. PMID- 30523698 TI - Effects of familiarization on odor hedonic responses and food choices in children with autism spectrum disorders. AB - This study assessed whether olfactory familiarization can render food odors more pleasant, and consequently food more attractive, to children with autism spectrum disorder. Participants were first presented with a series of food odors (session 1). Then, they were familiarized on four occasions (time window: 5 weeks) with one of the two most neutral odors (the other neutral odor was used as control) (session 2). In session 3, participants smelled the entire series of odors again. Both verbal and facial responses were compared from session 1 to session 3. After session 3, the children were presented with two identical foods (one containing the familiarized odor and one the control odor) and were asked to choose between these foods. Results revealed (1) a specific increase in positive emotions for the familiarized odor and (2) that 68% of the children chose the food associated with the "familiarized odor" (children who chose the "familiarized odor" food exhibited significantly more sensory particularities). These findings suggest that it is possible to modulate olfactory emotions and expand the dietary repertoire of children with autism spectrum disorder. Application of this paradigm may enable innovative prospects for food education in autism. PMID- 30523699 TI - A population-based examination of maltreatment referrals and substantiation for children with autism spectrum disorder. AB - Children with disabilities experience elevated rates of maltreatment, but little is known about the interaction of children with autism spectrum disorder with child protection systems. A population-based dataset of 24,306 children born in 2008 in Tennessee, which included 387 children with autism spectrum disorder identified through the Autism and Developmental Disabilities Monitoring network, was linked with state child protection records. Rates of maltreatment referrals, screening for further action, and substantiated maltreatment were examined for children with versus without autism spectrum disorder. Significantly more children with autism spectrum disorder (17.3%) than without (7.4%) were referred to the Child Abuse Hotline. Children with autism spectrum disorder were less likely than children without autism spectrum disorder to have referrals screened in for further action (62% vs 91.6%, respectively), but substantiated maltreatment rates were similar across groups (3.9% vs 3.4%, respectively). Girls versus boys with autism spectrum disorder were more likely to have substantiated maltreatment (13.6% vs 1.9%, respectively). The high percentage of children with autism spectrum disorder referred for allegations of maltreatment, the differential pattern of screening referrals in for further action, and the high levels of substantiated maltreatment of girls with autism spectrum disorder highlights the need for enhanced training and knowledge of the complex issues faced by children with autism spectrum disorder, their families, and state welfare agencies. PMID- 30523700 TI - Vitamin E Reduces Hypobaric Hypoxia-Induced Immune Responses in Male Rats. AB - Goswami, Ananda Raj, and Tusharkanti Ghosh. Vitamin E reduces hypobaric hypoxia induced immune responses in male rats. High Alt Med Biol 00:000-000, 2018.-In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects. PMID- 30523701 TI - Where We Walk Is What We See: Foundational Concepts and Analytical Techniques of Space Syntax. AB - The most difficult issue in writing a methods paper on Space Syntax is that it is not simply a method. It is a theory on which a methodology has been built. In the 40 years since introduction, both its theory and its methods have advanced, including the creation and development of computerized software. Essentially Space Syntax investigates layouts, seen in plan drawings; but this is done from mature theoretical arguments about function in those spaces. While theories of society were at the genesis of Space Syntax, it has branched into cognition, transportation, economics, and so on, and has been used to investigate buildings, cities, and regions. In the last decade or so, Space Syntax has been used in different ways to investigate healthcare facilities. This article concentrates on explaining the analytical techniques of Space Syntax. The theoretical underpinnings are minimally described-just enough for the reader to understand the basis of the methods. All examples provided are based on the same hypothetical hospital floor layout for ease of comprehension and comparison. Also, all Space Syntax concepts are italicized for identification. Since the theoretical aspects are not treated in detail, the reader is advised to pay particular attention to the citations for advanced comprehension. This cannot be overemphasized. PMID- 30523702 TI - The Effect of PTCH1 on Ovarian Cancer Cell Proliferation and Apoptosis. AB - OBJECTIVE: Patched (PTCH1) is an important receptor protein in the Hedgehog pathway and plays a tumor suppressor role in a variety of tumors. This study was to detect the expression of PTCH1 in ovarian cancer (OC) tissues to analyze the relationship between expression of PTCH1 and prognosis, and to explore its role in regulating OC cell proliferation and apoptosis. MATERIALS AND METHODS: OC tissues and normal ovarian tissues were collected to detect PTCH1 expression. SKOV3, A2780, Caov3, and IOSE80 cells were cultured in vitro to test PTCH1 expression. pIRES2-Scramble and pIRES2-PTCH1 were transfected into SKOV3 and A2780 cells, respectively. PTCH1 and Gli1 expressions were detected by western blot. Cell apoptosis was determined by flow cytometry. Cell proliferation was assessed by EdU staining. RESULTS: PTCH1 expression was significantly decreased in OC tissue compared with normal ovarian tissue and was associated with tumor size, TNM stage, and pathological grade (p < 0.05). The prognosis of patients with low PTCH1 expression was obviously worse than that of patients with high PTCH1 expression. The expression of PTCH1 in OC SKOV3, A2780, and Caov3 cells was markedly lower than that in normal ovarian epithelial IOSE80 cells. Transfection of pIRES2-PTCH1 apparently upregulated PTCH1 level, inhibited GLI1 expression and cell proliferation, and promoted apoptosis of SKOV3 and A2780 cells. CONCLUSION: PTCH1 level in OC was abnormally decreased and related to prognosis. Overexpression of PTCH1 inhibited GLI1 expression, attenuated OC cell proliferation, and induced apoptosis, suggesting that manipulation of PTCH1 expression might be a novel approach for the treatment of OC. PMID- 30523703 TI - Effectiveness and Safety of Polydioxanone Thread-Embedding Acupuncture as an Adjunctive Therapy for Patients with Chronic Nonspecific Neck Pain: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effectiveness and safety of treatment with thread embedding acupuncture (TEA) using polydioxanone in addition to usual care for patients with chronic nonspecific neck pain (CNP) compared with treatment with usual care alone. METHODS: A single-center, assessor-blinded, two-armed randomized controlled trial was performed. One hundred and six outpatients with CNP were randomly allocated into the TEA plus usual care (TU) group or the usual care (UC) group in a 1:1 ratio. TEA treatments in the neck region were provided once a week for 4 weeks, and usual care, as needed, was allowed. The primary outcome was the mean Neck Pain and Disability Scale (NPDS) score. Secondary outcomes included clinical relevance measured by using the clinically important difference (CID), pressure pain threshold (PPT), Hospital Anxiety and Depression Scale (HADS), EuroQol-5 Dimension (EQ-5D), and patient global impression of change (PGIC). Participants were assessed at baseline and at weeks 3, 5, and 9. Statistical analyses included analysis of covariance with baseline score as a covariate. RESULTS: The TU group showed significant improvement in NPDS scores compared with the UC group (adjusted group difference, week 5: 13.74 [95% confidence interval: 7.57-19.90]; p < 0.0001 and week 9: 17.46 [11.15-23.76]; p < 0.0001). The proportion of patients with a decrease on the NPDS score of >=11.5 points (minimal CID) was significantly higher in the TU group at weeks 5 and 9 than in the UC group. At weeks 5 and 9, significant differences were observed on the anxiety/depression subscale of HADS, EQ-5D, and PGIC between the two groups, but not the PPTs at three sites. Temporary stiffness was observed after TEA treatment, but no serious adverse events occurred. CONCLUSIONS: The results suggest that polydioxanone TEA is a safe and clinically beneficial adjunctive treatment for patients with CNP. PMID- 30523704 TI - Interdisciplinary Relationship Models for Complementary and Integrative Health: Perspectives of Chinese Medicine Practitioners in the United States. AB - OBJECTIVES: The combination of biomedicine and traditional and complementary medicine (T&CM) is often referred to as integrative medicine. However, the degree to which the medical disciplines are integrated varies between medical settings, and it is believed by some to be impossible due to epistemological and paradigmatic differences. Clinicians' perspectives are important determinants of how different medical disciplines are used together. This study explores the perspectives of experienced Chinese medicine practitioners when asked about the most ethical model (opposition, integration, or pluralism) for the relationship between biomedicine and T&CM. DESIGN: Thirty-one Chinese medicine practitioners, undertaking a doctoral upgrade program at the Pacific College of Oriental Medicine, participated in this study. Participants were asked to read a publication discussing three models (opposition, integration, and pluralism) for the relationship between biomedicine and T&CM and then discuss, via an online forum within Moodle learning management system, the most ethical model. An inductive content analysis of the forum posts was undertaken to identify common themes, followed by member checking. RESULTS: The data were found to contain six major and six minor themes. There was a clear preference for pluralism. The Chinese medicine practitioners expressed reservations about the integrative model, and, above all, cared about the quality of patient care. Much dialogue occurred around issues related to a power imbalance within health care, and possible cooptation issues. Paradigmatic differences and a lack of compatibility between biomedical research models and the practice of Chinese medicine were seen as problematic to the validity of research findings. Interprofessional education was viewed as critical for the development of respect, shared patient care, and referrals between clinicians from different disciplines. CONCLUSIONS: This study provides insight into the issues associated with combining biomedicine and T&CM that are perceived by Chinese medicine practitioners. Such insights are important for the development and management of clinical settings that provide complementary and integrative health care, especially as the provision of insurance coverage for T&CM increases. PMID- 30523705 TI - Brief Mindfulness-Based Interventions for Acute and Chronic Pain: A Systematic Review. AB - OBJECTIVES: Nonpharmacologic approaches have been characterized as the preferred means to treat chronic noncancer pain by the Centers for Disease Control and Prevention. There is evidence that mindfulness-based interventions (MBIs) are effective for pain management, yet the typical MBI may not be feasible across many clinical settings due to resource and time constraints. Brief MBIs (BMBIs) could prove to be more feasible and pragmatic for safe treatment of pain. The aim of the present article is to systematically review evidence of BMBI's effects on acute and chronic pain outcomes in humans. METHODS: A literature search was conducted using PubMed, PsycINFO, and Google Scholar and by examining the references of retrieved articles. Articles written in English, published up to August 16, 2017, and reporting on the effects of a BMBI (i.e., total contact time <1.5 h, with mindfulness as the primary therapeutic technique) on a pain-related outcome (i.e., pain outcome, pain affect, pain-related function/quality of life, or medication-related outcome) were eligible for inclusion. Two authors independently extracted the data and assessed risk of bias. RESULTS: Twenty studies meeting eligibility criteria were identified. Studies used qualitative (n = 1), within-group (n = 3), or randomized controlled trial (n = 16) designs and were conducted with clinical (n = 6) or nonclinical (i.e., experimentally-induced pain; n = 14) samples. Of the 25 BMBIs tested across the 20 studies, 13 were delivered with audio/video recording only, and 12 were delivered by a provider (participant-provider contact ranged from 3 to 80 min). Existing evidence was limited and inconclusive overall. Nevertheless, BMBIs delivered in a particular format-by a provider and lasting more than 5 min-showed some promise in the management of acute pain. CONCLUSIONS: More rigorous large scale studies conducted with pain populations are needed before unequivocally recommending BMBI as a first-line treatment for acute or chronic pain. PMID- 30523706 TI - Current profiles and early predictors of reading skills in school-age children with autism spectrum disorders: A longitudinal, retrospective population study. AB - This study explores current reading profiles and concurrent and early predictors of reading in children with autism spectrum disorder. Before the age of 3 years, the study cohort underwent a neurodevelopmental assessment following identification in a population-based autism screening. At age 8 years, reading, language and cognition were assessed. Approximately half of the sample ( n = 25) were 'poor readers' at age 8 years, meaning that they scored below the normal range on tests of single word reading and reading comprehension. And 18 were 'skilled readers' performing above cut-offs. The final subgroup ( n = 10) presented with a 'hyperlexic/poor comprehenders' profile of normal word reading, but poor reading comprehension. The 'poor readers' scored low on all assessments, as well as showing more severe autistic behaviours than 'skilled readers'. Group differences between 'skilled readers' and 'hyperlexics/poor comprehenders' were more subtle: these subgroups did not differ on autistic severity, phonological processing or non-verbal intelligence quotient, but the 'hyperlexics/poor comprehenders' scored significantly lower on tests of oral language. When data from age 3 were considered, no differences were seen between the subgroups in social skills, autistic severity or intelligence quotient. Importantly, however, it was possible to identify oral language weaknesses in those that 5 years later presented as 'poor readers' or 'hyperlexics'. PMID- 30523707 TI - Integrated comparison of the miRNAome and mRNAome in muscles of dermatomyositis and polymyositis reveals common and specific miRNA-mRNAs. AB - AIM: Dermatomyositis (DM) and polymyositis (PM) are refractory systemic autoimmune diseases with unknown pathogenesis. miRNAs is an important epigenetic mechanism to regulate gene expression. METHODS: We performed whole miRNAs analysis, transcription analysis and the association between miRNAome and mRNAome. RESULTS: For transcription and miRNAs analysis, there were common and specific mRNAs and miRNAs in the muscles of DM and PM. Among them, the expression levels of miR-196a-5p and CPM were negatively correlated in PM, miR-193b-3p and NECAP2 were negatively correlated in DM and PM. Protein carboxypeptidase M (CPM) plays roles in the degradation of extracellular proteins and in the migration and invasion of cancer cells, and protein NECAP2 plays roles in adaptor protein AP-1 mediated fast recycling from early endosomes. The functions of them in the pathogenesis of DM/PM need further studies. CONCLUSION: Our study identified and confirmed differentially miRNAs and mRNAs in DM and PM. Our observations have laid the groundwork for further diagnostic and mechanistic studies of DM and PM. PMID- 30523708 TI - Bart's Syndrome with Novel Frameshift Mutations in the COL7A1 Gene. AB - INTRODUCTION: Bart's syndrome, a hereditary mechanobullous disorder characterized by aplasia cutis congenita (ACC) with epidermolysis bullosa (EB), has not been genotyped frequently. CASE REPORT: A full-term female neonate had well-demarcated absence of skin on both legs at birth, with blisters and erosive patches developing immediately after birth. Electron microscopy showed blister formation under the lamina densa layer. Genetic studies revealed two heterogenous frameshift mutations in exons 31 and 109 of COL7A1. A diagnosis of Bart's syndrome, recessive dystrophic EB with ACC, was made. There was no pyloric atresia or ureteral stenosis, but congenital hypothyroidism was diagnosed 42 days after birth. CONCLUSION: The novel frameshift mutations in COL7A1 may result in Bart's syndrome and suggest the importance of genetic testing in diagnosis of this disease. PMID- 30523709 TI - Initial Diagnostic Work-Up of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists and American Society of Hematology Guideline. AB - PURPOSE: The College of American Pathologists (CAP) and the American Society of Hematology (ASH) developed an evidence-based guideline on the initial diagnostic work-up of acute leukemia (AL). Because of the relevance of this topic to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS: The CAP-ASH guideline on initial diagnostic work-up of AL was reviewed for developmental rigor by methodologists. Then, an ASCO Endorsement Expert Panel updated the literature search and reviewed the content and recommendations. RESULTS: The ASCO Expert Panel determined that the recommendations from the guideline, published in 2016, are clear, thorough, and based on the most relevant scientific evidence. ASCO fully endorsed the CAP ASH guideline on initial diagnostic work-up of AL and included some discussion points according to clinical practice and updated literature. CONCLUSION: Twenty seven guideline statements were reviewed. Some discussion points were included to better assess CNS involvement in leukemia and to provide novel insights into molecular diagnosis and potential markers for risk stratification and target therapy. These discussions are categorized into four sections: (1) initial diagnosis focusing on basic diagnostics and determination of risk parameters, (2) molecular markers and minimal residual disease detection, (3) context of referral to another institution with expertise in the management of AL, and (4) reporting and record keeping for better outlining and follow-up discussion. Additional information is available at: www.asco.org/hematologic-malignancies-guidelines . PMID- 30523710 TI - OCTN: A Small Transporter Subfamily with Great Relevance to Human Pathophysiology, Drug Discovery, and Diagnostics. AB - OCTN is a small subfamily of membrane transport proteins that belongs to the larger SLC22 family. Two of the three members of the subfamily, namely, OCTN2 and OCTN1, are present in humans. OCTN2 plays a crucial role in the absorption of carnitine from diet and in its distribution to tissues, as demonstrated by the occurrence of severe pathologies caused by malfunctioning or altered expression of this transporter. These findings suggest avoiding a strict vegetarian diet during pregnancy and in childhood. Other roles of OCTN2 are related to the traffic of carnitine derivatives in many tissues. The role of OCTN1 is still unclear, despite the identification of some substrates such as ergothioneine, acetylcholine, and choline. Plausibly, the transporter acts on the control of inflammation and oxidative stress, even though knockout mice do not display phenotypes. A clear role of both transporters has been revealed in drug interaction and delivery. The polyspecificity of the OCTNs is at the base of the interactions with drugs. Interestingly, OCTN2 has been recently exploited in the prodrug approach and in diagnostics. A promising application derives from the localization of OCTN2 in exosomes that represent a noninvasive diagnostic tool. PMID- 30523711 TI - Identification of an Arginase II Inhibitor via RapidFire Mass Spectrometry Combined with Hydrophilic Interaction Chromatography. AB - Peripheral arterial disease (PAD) is an occlusive disease that can lead to atherosclerosis. The involvement of arginase II (Arg II) in PAD progression has been proposed. However, no promising drugs targeting Arg II have been developed to date for the treatment of PAD. In this study, we established a method for detecting the activity of Arg II via high-throughput label-free RapidFire mass spectrometry using hydrophilic interaction chromatography, which enables the direct measurement of l-ornithine produced by Arg II. This approach facilitated a robust high-concentration screening of fragment compounds and the identification of a fragment that inhibits the activity of Arg II. We further confirmed binding of the fragment to the potential allosteric site of Arg II using a surface plasmon resonance assay. We concluded that the identified fragment is a promising compound that may lead to novel drugs to treat PAD, and our method for detecting the activity of Arg II can be applied to large-scale high-throughput screening to identify other structural types of Arg II inhibitors. PMID- 30523713 TI - Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies. AB - Over the past century, a multitude of derivatives of structural scaffolds with established antimicrobial potential have been prepared and tested, and a variety of new scaffolds have emerged. The effectiveness of antibiotics, however, is in sharp decline because of the emergence of drug-resistant microorganisms. The prevalence of drug resistance, both in clinical and community settings, is a consequence of bacterial ingenuity in altering pathways and/or cell morphology, making it a persistent threat to human health. The fundamental ability of pathogens to survive in a multitude of habitats can be triggered by recognition of chemical signals that warn organisms of exposure to a potentially harmful environment. Host immune defenses, including reactive oxygen intermediates and antibacterial substances, are among the multitude of chemical signals that can subsequently trigger expression of phenotypes better adapted for survival in that hostile environment. Thus, resistance development appears to be unavoidable, which leads to the conclusion that developing an alternative perspective for treatment options is vital. This review will discuss emerging medicinal chemistry approaches for addressing the global multidrug resistance in the 21st century. PMID- 30523712 TI - Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post Treatment Follow-Up of the MURANO Phase III Study. AB - PURPOSE: The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS: Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points. RESULTS: Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10-4) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (10-4 to less than 10-2) predicted improved PFS compared with high-level MRD (10-2 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration venetoclax rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION: With all patients having finished treatment, continued benefit was observed for venetoclax-rituximab compared with bendamustine rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen. PMID- 30523714 TI - Trainee editorial: psychiatry should be taught from day one in medical school?. PMID- 30523715 TI - Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke. AB - Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases. PMID- 30523717 TI - Effect of Unintentional Storage and Handling Errors of Inhaled Medications: What Does This Mean for Therapeutic Equivalence Considerations? AB - BACKGROUND: Currently, the equivalence and the substitutability of two inhaled medications are mainly driven by comparability of doses, in vitro performance, therapeutic equivalence and sameness, and handling of the inhalers. The packaging configuration is usually not considered as a factor. METHODS: Two capsule-based inhaled tiotropium-containing products that differ by their primary packaging configurations (blister versus bottle) were compared in terms of potential handling and resulting storage errors due to unintentional misuse. Use error scenarios were identified and investigated for both the blister-packaged tiotropium and the bottled tiotropium capsules. The impact of the air exposure resulting from the packaging interaction errors was evaluated in vitro using fine particle dose (FPD) and delivered dose. RESULTS: Numbers of potential errors and criticality in terms of the potential effect impact on the FPD were larger for the bottled product (between 40% and 90% loss on FPD related to initial dose). The loss of FPD could significantly impact the amount of medication that can actually reach the patient's lungs. CONCLUSION: When considering prescribing an inhaled medication, the specifics of the packaging and the patient's abilities and situation shall be taken into account to minimize possible handling and subsequent dosing errors. PMID- 30523718 TI - Using Gene Expression Profiling to Move Beyond MYC/BCL2 Rearrangements in High Grade Lymphoma. PMID- 30523716 TI - Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma. AB - PURPOSE: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. PATIENTS AND METHODS: We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. RESULTS: We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested. CONCLUSION: We have defined a clinically and biologically distinct subgroup of tumors within GCB DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management. PMID- 30523720 TI - Understanding Computer-Mediated Support Groups: A Revisit Using a Meta-Analytic Approach. AB - The increasing popularity of computer-mediated support groups (CMSGs) has drawn scholarly attention in recent decades. Fifteen empirical controlled studies have been published since Rains and Young's meta-analysis, showing mixed results, with a large variation of effect sizes ranging from -.77 to 1.33 in Cohen's d. To provide a better understanding of CMSGs, the current study meta-analyzed these 15 newly published studies along with the studies included in Rains and Young's meta analysis, and tested study design and demographic moderators that have not been examined before. In addition, the study also revisited group size as a moderator and provided updated results with a larger sample size. Theoretical and practical implications of findings are discussed. PMID- 30523719 TI - Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy. AB - PURPOSE: Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. PATIENTS AND METHODS: We defined a molecular high-grade (MHG) group by applying a gene expression-based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. RESULTS: The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell like cases. CONCLUSION: MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies. PMID- 30523721 TI - Quantum dot induced acute changes in lung mechanics are mouse strain dependent. AB - INTRODUCTION: Concerns have been raised regarding occupational exposure to engineered nanomaterials (ENMs). Potential impacts on lung function from inhalation exposures are of concern as the lung is a sensitive ENM target in animals. Epidemiological data suggest that occupational exposure to ENMs may impact respiratory and cardiovascular health. Quantum dots (QDs) are ENMs with outstanding semiconductor and fluorescent properties with uses in biomedicine and electronics. QDs are known to induce inflammation and cytotoxicity in rodents and high dose exposures impact lung function 2 weeks after exposure. However, effects of mouse strain and the temporality of QD effects on lung function at more occupationally relevant doses have not been well-established. OBJECTIVE: We evaluated the impact of QD exposure on respiratory mechanics in C57BL/6J and A/J mice. Previous work found a greater initial inflammatory response to QD exposure in A/J mice compared to C57BL/6J mice. Thus, we hypothesized that A/J mice would be more sensitive to QD-induced effects on lung mechanics. METHODS: C57BL/6J and A/J mice were exposed to 6 MUg/kg Cd equivalents of amphiphilic polymer-coated Cd/Se core, ZnS shell QDs via oropharyngeal aspiration. Lung mechanics were measured using forced oscillation, and inflammation was characterized by neutrophils and cytokines in bronchoalveolar lavage fluid. RESULTS: Both strains showed signs of QD-induced acute lung inflammation. However, lung mechanics were impacted by QD exposure in A/J mice only. CONCLUSIONS: Our findings suggest that susceptibility to QDs and similar ENM-induced changes in lung function may depend at least in part on genetic background. PMID- 30523722 TI - New drugs in preclinical and early stage clinical development in the treatment of heart failure. AB - INTRODUCTION: Heart failure (HF) represents a major health problem because of its high prevalence, high rates of hospitalizations, and mortality and significant healthcare costs. HF comprises a heterogeneous group of syndromes with different pathophysiology, clinical presentations, and response to therapy. Basic research has identified multiple putative therapeutic targets involved in the pathogenesis of HF and many promising drugs are under development. Areas covered: This review summarizes the main drugs currently in preclinical and clinical development for HF treatment. Drugs were identified by search of MEDLINE and PubMed and trials from registries (clinicaltrials.gov, clinicaltrialsregister.eu, pubmed.gov) from 2010. Expert opinion: Despite significant advances in the pharmacological treatment of HF with reduced ejection fraction, no treatment has yet convincingly shown to improve outcomes in patients with HF with preserved ejection fraction and acute HF. Many promising drugs emerged in preclinical models and small phase 2 trials, but with a few exceptions, they fail to meet the primary endpoints in larger adequately powered phase 3 trials. Which new drugs will prove valuable remains uncertain. Improving clinical outcomes, delaying or preventing HF worsening and reducing hospital admissions should be prioritized in future drug development programs. PMID- 30523723 TI - Valuation of EQ-5D-5L health states: a comparison of seven Asian populations. AB - OBJECTIVES: To compare the time trade-off (TTO) utility values of EQ-5D-5L health states elicited from different general populations in Asia. METHODS: We analyzed the TTO data from seven Asian EQ-5D-5L valuation studies in which utility values of 86 EQ-5D-5L health states were elicited from general population samples. An eight-parameter multiplicative regression model including five dimension parameters (mobility [MO], self-care, usual activities [UA], pain/discomfort, anxiety/depression) and three level parameters (level 2 [L2], level 3 [L3], and level 4 [L4]) was used to model the data from each of the populations. The model coefficients were compared to understand how the valuations of EQ-5D-5L health states differ. RESULTS: For dimension parameters, Korea and Indonesia generally had the highest and lowest values among the populations, respectively; UA and MO commonly had the highest and lowest values among the parameters, respectively. For level parameters, Singapore and Korea generally had the highest and lowest values, respectively; L2 showed less variance compared to L3 and L4. Koreans, Indonesians, and Singaporeans appeared to have different health preferences compared with other populations. CONCLUSION: Utility values of EQ-5D-5L health states differ among Asian populations, suggesting that each health system should establish and use its own value set. PMID- 30523725 TI - Lamotrigine as a mood stabilizer: insights from the pre-clinical evidence. AB - INTRODUCTION: Lamotrigine (LTG) is a well-established anticonvulsant that is also approved for the prevention of mood relapses in bipolar disorder. However, the mechanisms underlying LTG mood stabilizing effects remain unclear. Areas covered: Herein, the pre-clinical evidence concerning LTG's' mode of action in depression and mania is reviewed. Bottlenecks and future perspectives for this expanding and promising field are also discussed. Pre-clinical studies have indicated that neurotransmitter systems, especially serotoninergic, noradrenergic and glutamatergic, as well as non-neurotransmitter pathways such as inflammation and oxidative processes might play a role in LTG's antidepressant effects. The mechanisms underlying LTG's anti-manic properties remain to be fully explored, but the available pre-clinical evidence points out to the role of glutamatergic neurotransmission, possibly through AMPA-receptors. Expert opinion: A major limitation of current pre-clinical investigations is that there are no experimental models that recapitulate the complexity of bipolar disorder. Significant methodological differences concerning time and dose of LTG treatment, administration route, animal strains, and behavioral paradigms also hamper the reproducibility of the findings, leading to contradictory conclusions. Moreover, the role of other mechanisms (e.g. inositol phosphate and GSK3beta pathways) implicated in the mode of action of different mood-stabilizers must also be consolidated with LTG. PMID- 30523726 TI - Paraneoplastic syndrome - a rare but treatable cause of non-thyroid-related extraocular muscle enlargement. AB - Paraneoplastic syndrome is a rare but reversible cause of non-thyroid-related extraocular muscle enlargement. We present a 71-year-old lady with diplopia, restricted eye movements, suppressed thyroid-stimulating hormone and enlargement of all extraocular muscles while on thyroxine replacement for hypothyroidism. She had distant history of metastatic breast cancer treated with chemotherapy, surgical resection and tamoxifen. She had negative anti-thyroid autoantibodies and thyroid ultrasound was not consistent with autoimmune thyroid disease. Carcinoembryonic antigen and cancer antigens 15-3, 125 and 72-4 were elevated, and whole-body positron emission tomography-computed tomography showed avid liver, left adrenal and skeletal lesions, with liver biopsy confirming breast cancer recurrence. She received prednisone and chemotherapy (letrozole, palbociclib) and achieved normalisation of eye movements and reduction in her EOME at 9-month follow-up. Our case highlights the importance of exploring paraneoplastic syndrome as a treatable cause of EOME in a patient lacking features of thyroid orbitopathy and autoimmune thyroid disease. PMID- 30523724 TI - An economic evaluation of perioperative enteral nutrition in patients undergoing colorectal surgery (SANICS II study). AB - AIMS: The objective of this (trial based) economic evaluation was to assess, from a societal perspective, the cost-effectiveness of perioperative enteral nutrition compared with standard care in patients undergoing colorectal surgery. MATERIALS AND METHODS: Alongside the SANICS II randomized controlled trial, global quality of life, utilities (measured by EQ-5D-5L), healthcare costs, production losses, and patient and family costs were assessed at baseline, 3 months, and 6 months. Incremental cost effectiveness ratios (ICERs) (i.e. cost per increased global quality of life score or quality-adjusted life year [QALY] gained) and cost effectiveness acceptability curves were visualized. RESULTS: In total, 265 patients were included in the original trial (n = 132 in the perioperative enteral nutrition group and n = 133 in the standard care group). At 6 months, global quality of life (83 versus 83, p = 0.357) did not differ significantly between the groups. The mean total societal costs for the intervention and standard care groups were ?14,673 and ?11,974 respectively but did not reach the statistical significance (p = 0.109). The intervention resulted in an ICER of ?6276 per point increase in the global quality of life score. The gain in QALY was marginal (0.003) with an additional cost of ?2,941 and the ICUR (Incremental cost utility ratio) was estimated at ?980,333. LIMITATIONS: The cost elements for all the participating centers reflect the reference prices from the Netherlands. Patient-reported questionnaires may have resulted in recall bias. Sample size was limited by exclusion of patients who did not complete questionnaires at least at two time points. A power analysis based on costs and health related quality of life (HRQoL) was not performed. The economic impact could not be analyzed at 1 month postoperatively where the effects could potentially be higher. CONCLUSIONS: This study suggests that perioperative nutrition is not beneficial for the patients in terms of quality of life and is not cost effective. PMID- 30523727 TI - Letter to the editor: Efficacy and safety of a combination of HER2-targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis. PMID- 30523728 TI - From the laboratory concept to clinical trials: the journey of Otoimplant so far. AB - INTRODUCTION: Nowadays, the role of alloplastic prostheses has become more important in ossicular chain reconstruction. Especially, bioactive medical devices may be an alternative for those currently used on the market. Areas covered: Medical devices which are implanted for over 30 days in the body are required to fulfil strict requirements. It is crucial to ensure the proper level of biocompatibility, biological stability and lack of cytotoxicity of the implanted material. If a medical device is expected to play an additional role, e.g. act as a bioactive or bactericidal agent, supplementary tests should be conducted to assess the relevant qualities. The aim of this article is to present the sequence of procedures leading to the success of a middle ear prosthesis called Otoimplant - from a theoretical concept to the clinical trial. Expert commentary: However, to introduce a new prosthesis into the market, research such as, in vitro, in vivo and clinical trials are required to keep medical devices approved. This article describes a research path that medical device ought to negotiate before the clinical trials may start. PMID- 30523729 TI - Potential benefit of MRI-guided IMRT for flank irradiation in pediatric patients with Wilms' tumor. AB - PURPOSE/OBJECTIVE: Flank irradiation for Wilms' tumor (WT) is currently performed at our institute using a cone-beam computed tomography-guided volumetric modulated arc (VMATCBCT) workflow. By adding real-time magnetic resonance imaging (MRI) guidance to the treatment, safety margins could be reduced. The study purpose was to quantify the potential reduction of the planning target volume (PTV) margin and its dosimetric impact when using an MRI-guided intensity modulated radiation therapy (IMRTMRI) workflow compared to the VMATCBCT workflow. MATERIAL/METHODS: 4D-CT, MRI and CBCT scans acquired during preparation and treatment of 15 patients, were used to estimate both geometric, motion and patient set-up systematic (?) and random (sigma) errors for VMATCBCT and IMRTMRI workflows. The mean PTV (PTVmean) expansion was calculated using the van Herk formula. Treatment plans were generated using five margin scenarios (PTVmean +/- 0, 1 and 2 mm). Furthermore, the IMRTMRI plans were optimized with a 1.5T transverse magnetic field turned-on to realistically model an MRI-guided treatment. Plans were evaluated using dose-volume statistics (p<.01, Wilcoxon). RESULTS: Analysis of ? and sigma errors resulted in a PTVmean of 5 mm for the VMATCBCT and 3 mm for the IMRTMRI workflows in each orthogonal direction. Target coverage was unaffected by the margin decrease with a mean V95%=100% for all margin scenarios. For the PTVmean, an average reduction of the mean dose to the organs at risk (OARs) was achieved with IMRTMRI compared to VMATCBCT: 3.4 +/- 2.4% (p<.01) for the kidney, 3.4 +/- 2.1% (p<.01) for the liver, 2.8 +/- 3.0% (p<.01) for the spleen and 4.9 +/- 3.8% (p<.01) for the pancreas, respectively. CONCLUSIONS: Imaging data in children with WT demonstrated that the PTV margin could be reduced isotropically down to 2 mm when using the IMRTMRI compared to the VMATCBCT workflow. The former results in a dose reduction to the OARs while maintaining target coverage. PMID- 30523730 TI - Patient-reported complications related to colonoscopy: a prospective feasibility study of an email-based survey. AB - OBJECTIVE: This prospective pilot study assessed the feasibility of electronic email-based questionnaires about patient-reported complications after colonoscopy. MATERIAL AND METHODS: A newly internally validated questionnaire on patient-reported complications related to colonoscopy was conducted as an online survey. RESULTS: Out of 200 patients (mean age 65 years), 83% completed the first questionnaire immediately after the procedure, 77% completed the second follow-up questionnaire after 24 h at home, and 70% the third one after 30 d. Forty-four percent of the patients reported minor adverse events after 24 h, and 23% at the follow-up after 30 d. The rate of sick leave in the 30-d period after the colonoscopy was 6%. CONCLUSIONS: This study shows that email-based questionnaires give a high response rate independent of age or gender, but that the response rate declines with time after colonoscopy. Minor adverse events are underestimated, and colonoscopy could lead to sick leave in a minor subgroup of patients. PMID- 30523731 TI - Managing pulmonary complications in allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: Progress in allogeneic hematopoietic stem cell transplantation (HSCT) procedures have been associated with improved survival in HSCT recipients. However, they have also brought to light organ-specific complications, especially pulmonary complications. In this setting, pulmonary complications are consistently associated with poor outcomes, and improved management of these complications is required. Areas covered: We review the multiple infectious and noninfectious lung complications that occur both early and late after allogeneic HSCT. This includes the description of these complications, risk factors, diagnostic approach and outcome. A literature search was performed using PubMed indexed journals. Expert commentary: Multiple lung complications after allogeneic HSCT can be diagnosed concomitantly and require a multidisciplinary approach. A specific clinical evaluation including a precise analysis of a lung CT scan is necessary. Management of these lung complications, especially the noninfectious ones, is impaired by the lack of prospective, randomized control trials, suggesting preventive strategies should be developed. PMID- 30523732 TI - Bleeding Complications After Cardiac Arrest and Targeted Temperature Management, a Post Hoc Study of the Targeted Temperature Management Trial. AB - Target Temperature Management (TTM) is standard care following out of hospital cardiac arrest (OHCA). The aim of the study was to evaluate if treatment temperature (33 degrees C or 36 degrees C) or other predefined variables were associated with the occurrence of bleeding in the TTM study. This study is a predefined, post hoc analysis of the TTM trial, a multinational randomized controlled trial comparing treatment at 33 degrees C and 36 degrees C for 24 hours after OHCA with return of spontaneous circulation. Bleeding events from several locations were registered daily. The main outcome measure was occurrence of any bleeding during the first 3 days of intensive care. Risk factors for bleeding, including temperature allocation, were evaluated. Complete data were available for 722/939 patients. Temperature allocation was not associated with bleeding either in the univariable (p = 0.95) or in the primary multivariable analysis (odds ratio [OR] 0.95; 95% confidence interval [CI] 0.64-1.41, p = 0.80). A multiple imputation model, including all patients, was used as a sensitivity analysis, rendering similar results (OR 0.98; 95% CI 0.69-1.38, p = 0.92). Factors associated with bleeding were increasing age, female sex, and angiography with percutaneous coronary intervention (PCI) within 36 hours of cardiac arrest (CA) in both the primary and the sensitivity analysis. TTM at 33 degrees C, when compared to TTM at 36 degrees C, was not associated with an increased incidence of bleeding during the first 3 days of intensive care after CA. Increasing age, female gender, and PCI were independently associated with any bleeding the first 3 days after CA. PMID- 30523733 TI - The Effect of Serotonin on Penicillin-induced Epileptiform Activity. AB - This study was aimed at examining the epileptiform activity of the 5-HT2 serotonin receptor agonist and antagonist, and 5-hydroxytryptophan (5-HTP) in penicillin-induced epilepsy in albino Wistar rats. For this purpose, 90 albino male Wistar rats were used in this study. Epileptiform activity was induced by an injection of penicillin, an agonist of GABAA receptor, (500 IU, ic) into the somatomotor cortex. Thirty minutes after the injection of penicillin, 2,5 dimethoxy-4-iodoamphetamine (DOI, an agonist of 5-HT2 receptor) (0.5, 1, 2 and 4 mg/kg, ip), methysergide, an antagonist of 5-HT2 receptor, (1, 10, 20, 50 and 100 uM, icv) and 5-HTP, precursor of 5-HT, (25, 50, 75 and 100 mg/kg, ip) were administered, respectively. DOI, at the doses of 1 and 2 mg/kg, significantly decreased penicillin-induced epileptiform activity (p < 0.05). Methysergide, at the doses of 20, 50 and 100 uM, significantly increased the mean spike frequency of penicillin-induced epileptiform activity (p < 0.05). The doses of 50, 75 and 100 mg/kg of 5-HTP decreased the mean spike frequency of penicillin-induced epileptiform activity (p < 0.05). The mean of amplitude of penicillin-induced epileptiform activity did not significantly change in any of the groups (p > 0.05). The electrophysiological data from the present study suggest that serotonin 5-HT2 receptors have an important role in controlling penicillin induced epileptiform activity in the rat. PMID- 30523734 TI - Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy? AB - BACKGROUND: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated. RESULTS: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: >=2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009). CONCLUSION: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy. PMID- 30523736 TI - Proteomic insights into lysine acetylation and the implications for medical research. PMID- 30523735 TI - Statistical Analysis Plan for EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial. AB - BACKGROUND: EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) is a randomized, multicenter, double-blinded, placebo controlled phase 3 trial to test the hypothesis of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke (WUS) patients. OBJECTIVE: To formulate the detailed statistical analysis plan for the EXTEND trial prior to database lock. This statistical analysis plan is based on the published and registered EXTEND trial protocol and is developed by the blinded steering committee and management team. RESULTS: The developed EXTEND statistical analysis plan is transparent, verifiable, and predetermined before the database lock. It is consistent with reporting standards for clinical trials and provides for clear and open reporting. CONCLUSIONS: Publication of a statistical analysis plan serves to reduce potential trial analysis and reporting bias and outlines pre-specified analyses to quantify the benefits and harms of extending the thrombolysis time window to 9 h from stroke onset and in wake-up stroke patients. Trial registration: ClinicalTrials.gov number NCT00887328 registered 23/Apr/2009 and NCT01580839 (EXTEND International) registered 19/Apr/2012. PMID- 30523737 TI - Screening and Identification of Linear B Cell Epitopes Within the Nonstructural Proteins of Enterovirus 71. AB - Enterovirus 71 (EV-A71) has attracted widespread attention in the past decade because of its higher neurotropicity in addition to causing hand-foot-and-mouth disease (HFMD). Mapping epitopes of viral proteins may promote our understanding of antiviral humoral immunity, and is useful for clinical application. In this study, the linear B cell epitopes within nonstructural proteins of EV-A71 were identified using bioinformatics methods combined with peptide enzyme-linked immunosorbent assay (ELISA). Twenty epitopes were predicted and located at 2ABC (7), 3ABC (5), and 3D (8) protein, respectively. Of 20 epitope-containing peptides, 14 were verified by ELISA (S/CO >2.1), 9 of which had higher reactivity (S/CO >5.0). Furthermore, synthetic peptide SP09 (EV-A71-3ABC26-41) can react with healthy children sera, and its immunoreactivity was closest to that of EV A71-VP1 protein. The protein BLAST analysis revealed that SP09 may contain a common epitope due to the high homology of amino acid sequences with other members of human Enterovirus species A. These findings may be useful in the development serological tests for the diagnosis of HFMD caused by a broad range of human Enterovirus species A. PMID- 30523738 TI - The economic burden of psoriasis with high comorbidity among privately insured patients in the United States. AB - OBJECTIVE: To evaluate the impact of comorbidities on healthcare resource use (HRU), and direct and indirect work-loss-related costs in psoriasis patients. METHODS: Adults with psoriasis (>=2 diagnoses, the first designated as the index date) and non-psoriasis controls (no psoriasis diagnoses, randomly generated index date) were identified in a US healthcare claims database of privately insured patients (data between 01/2010 and 03/2017 were used). Psoriasis patients were stratified based on the number of psoriasis-related comorbidities (0, 1-2, or >=3) developed during the 12 months post-index. All outcomes were evaluated during the follow-up period spanning the index date until the end of continuous health plan eligibility or data cutoff. HRU and costs per-patient-per-year (PPPY) were compared in psoriasis and non-psoriasis patients with >=12 months of follow up. RESULTS: A total of 9,078 psoriasis (mean age 44 years, 51% female) and 48,704 non-psoriasis (mean age 41 years, 50% female) patients were selected. During the 12 months post-index, among psoriasis versus non-psoriasis patients, 71.0% versus 83.0% developed no psoriasis-related comorbidities, 26.3% versus 16.0% developed 1-2, and 2.6% versus 1.0% developed 3 or more psoriasis-related comorbidities. Compared to non-psoriasis patients, psoriasis patients had more HRU including outpatient visits (incidence rate ratios [IRRs]: 1.52, 2.03, and 2.66 for 0, 1-2, and >=3 comorbidities, respectively [all P < 0.01]) and emergency room visits (IRRs: 1.12, 1.59, and 2.45 for 0, 1-2, and >=3 comorbidities, respectively [all P < 0.01]) during the follow-up period. Psoriasis patients incurred greater total healthcare costs (mean cost differences [MCDs]: $1,590, $5,870, and $18,427, in patients with 0, 1-2, and >=3 comorbidities, respectively [all P < 0.01]), and work-loss-related costs (MCDs: $335, $655, and $1,695, in patients with 0, 1-2, and >=3 comorbidities, respectively [all P < 0.01]). CONCLUSIONS: HRU and cost burden of psoriasis are substantial, and increase with development of psoriasis-related comorbidities. PMID- 30523739 TI - The impact of external facial features on the construction of facial composites. AB - Witnesses may construct a composite face of a perpetrator using a computerised interface. Police practitioners guide witnesses through this unusual process, the goal being to produce an identifiable image. However, any changes a perpetrator makes to their external facial-features may interfere with this process. In Experiment 1, participants constructed a composite using a holistic interface one day after target encoding. Target faces were unaltered, or had altered external features: (i) changed hair, (ii) external-features removed or (iii) naturally concealed external-features (hair, ears, face-shape occluded by a hooded top). These manipulations produced composites with more error-prone internal-features: participants' familiar with a target's unaltered appearance less often provided a correct name. Experiment 2 applied external-feature alterations to composites of unaltered targets; although whole-face composites contained less error-prone internal-features, identification was impaired. Experiment 3 replicated negative effects of changing target hair on construction and tested a practical solution: selectively concealing hair and eyes improved identification. PMID- 30523740 TI - Comparison of Four Commercial IgG-Enzyme-Linked Immunosorbent Assays for the Detection of Tick-Borne Encephalitis Virus Antibodies. AB - Tick-borne encephalitis (TBE) is the most important arboviral disease in many parts of Europe and Asia. Both the diagnosis of TBE as well as the conduction of surveillance studies are based on the demonstration of specific antibodies. For reasons of simplicity, automatization, and quick availability of test results, enzyme-linked immunosorbent assays (ELISAs) are the method of choice for anti-TBE virus antibody detection. In this study, we evaluated four commercial IgG-ELISAs using 876 epidemiological plasma samples: the Enzygnost Anti-TBE/FSME Virus IgG assay (Siemens; assay 1), the Anti-FSME/TBE Virus ELISA (IgG) assay (Euroimmun; assay 2), the Anti-FSME/TBE Virus ELISA "Vienna" (IgG) assay (Euroimmun; assay 3), and the RIDASCREEN(r) FSME/TBE IgG EIA assay (R-Biopharm; assay 4). In total, discrepant results were observed for 37.2% of all samples. The evaluated assays significantly differed in qualitative data (p < 0.0001, Cochran-Mantel-Haenszel test) and showed Spearman's rank correlation coefficients ranging between 0.88 and 0.97 for quantitative data. The degree of disagreement between the different assays was exceptionally high for samples originating from blood donors with vaccination against TBE virus. For this sample group, the proportion of positive results was considerably higher for assay 3 (52.7%) and assay 4 (57%) than for assay 1 (7.5%) and assay 2 (6.4%), respectively, indicating that assays 1 and 2 are less suitable for the detection of vaccination antibodies than assays 3 and 4. Indirect immunofluorescence testing data available for a subset of samples (n = 238) mostly originating from nonflavivirus-vaccinated blood donors (n = 234) revealed problems in both sensitivity and specificity of the evaluated assays; whereas sensitivity issues were most prominent for the Euroimmun assay, specificity concerns were most pronounced for the Euroimmun Vienna and the RIDASCREEN assays. PMID- 30523741 TI - An expressive-arts-based life-death education program for the elderly: A qualitative study. AB - This study endeavors to investigate how healthcare workers, equipped with expressive arts methods, could foster life-death education for the elderly. Forty nine older adults aged 60 or above joined a 10-session expressive arts-based life death education program that was led by social workers equipped with expressive arts methods. An ethnographic research approach, with a post-treatment focus group (n = 17), was conducted with the participants. The results showed that expressive arts methods could enhance reorganization of life experiences, promote dealing with ambivalent emotion regarding life-death issues, improve communicating life-death issues with family members, and induce ideas to prepare for death. PMID- 30523742 TI - Effect of Lifestyle Coaching Including Telemonitoring and Telecoaching on Gestational Weight Gain and Postnatal Weight Loss: A Systematic Review. AB - BACKGROUND: Obesity during pregnancy, excessive gestational weight gain (GWG), and postpartum weight retention (PPWR) are associated with health risks for mothers and their offspring. Face-to-face lifestyle interventions can reduce GWG and PPWR, but they are resource-demanding and effects on long-term maternal and fetal outcomes are scarce. OBJECTIVES: To explore the existing literature about the effect of technology-supported lifestyle interventions including telemonitoring and-coaching on GWG and PPWR. METHODS: PudMed, MEDLINE, CINAHL, EMBASE (incl. The Cochrane databases), and Web of Science databases were searched for relevant studies published since 2000. Inclusion criteria were: lifestyle interventions to optimize GWG or PPWR with at least mobile applications or websites, focusing on physical activity (PA), healthy eating (HE), and/or psychological well-being, including self-monitoring with telemonitoring and telecoaching. RESULTS: The technology-supported interventions in seven study protocols and four pilot studies differed in terms of the used behavior change models, their focus on different lifestyle issues, and their intervention components for telemonitoring and telecoaching. Technology-supported interventions including telemonitoring and coaching can optimize GWG and PPWR, although not all results are significant. Effects on PA and HE are inconsistent. CONCLUSIONS: Technology-supported lifestyle interventions might affect GWG and PPWR, but more research is needed to examine the effectiveness, the usability, and the critical features of these interventions. PMID- 30523743 TI - Reaction Time of Healthy Older Adults Is Reduced While Walking Fast. AB - Attentional requirements of walking at various speeds in older adults were examined. Twenty healthy older adults (69.9 +/- 2.77 years; 8 males) were asked to walk a distance of 10 m at a self-selected speed as well as 30% quicker and 30% slower. Concurrently, reaction time (RT) was evaluated by having participants respond as fast as possible to randomly presented auditory stimuli. Results reveal that an accelerated walking speed generated faster RT than slow and self selected speeds, while no difference was found between the latter. Faster RTs during an accelerated walking speed may have been precipitated by the reduced equilibrium demands of the task. PMID- 30523744 TI - Effect of Fadrozole Exposure on Socioreproductive Behaviors and Neurochemical Parameters in Betta splendens. AB - Induction of all-male population in Siamese fighting fish, Betta splendens, has potential application in ornamental fish trade. In addition, the sexually dimorphic nature of aggressive behavior exhibited by this species has made it into an emerging model for behavioral studies. Fadrozole, an aromatase inhibitor, which has been used widely in masculinization, has captivated us to use it in this study. Twenty one days postfertilization (dpf), B. splendens fry were subjected to discrete immersion treatment with various concentrations of fadrozole, and eventually, analyses of various socioreproductive behaviors and analyses of stress markers such as dopamine in brain samples, sex hormones, cortisol, and glucose in plasma samples were performed. We observed that 91% of 50 MUg/L fadrozole treated fish developed as males. Interestingly, reproductive analyses of these males gave rise to two subgroups (A and B). Subsequent sociobehavioral analyses demonstrated a timid and subdued behavior in subgroup B males. Furthermore, estimation of stress markers such as dopamine levels in the brain tissue, cortisol, and glucose levels in blood plasma and sex hormone levels in blood plasma exhibited an endocrine disruption-mediated stress leading to altered behavior in these males. These findings will help in understanding the fadrozole-mediated masculinization and behavioral alterations following endocrine disruption. PMID- 30523745 TI - Selection Criteria of Zebrafish Male Donors for Sperm Cryopreservation. AB - Selection criteria for sperm cryopreservation are highly relevant in zebrafish since sperm quality is particularly variable in this species. Successful cryopreservation depends on high-quality sperm, which can only be ensured by the selection of breeders. Consequently, male selection and management are a priority to improve cryopreservation, and therefore, this study aimed to characterize optimal age and sperm collection frequency in zebrafish. For this purpose, males from wild type (AB) and from a transgenic line [Tg(runx2:eGFP)] were sampled at 6, 8, 12, and 14 months. For each age, sperm were collected at time 0 followed by samplings at 2, 7, and 14 days of rest. Sperm quality was assessed according to motility and membrane viability parameters. Quality assessment showed that Tg(runx2:eGFP) displayed significantly higher motility than AB and younger males showed higher motility in both lines. Sperm collection frequency affected membrane viability. While AB fish recovered sperm viability after 14 days of rest, Tg(runx2:eGFP) could not recover. Consequently, it may be important to study the sperm quality of each zebrafish line before sperm cryopreservation. Taking into consideration the results achieved in both lines, sperm collection should be performed between 6 and 8 months of age with a minimum collection interval of 14 days. PMID- 30523746 TI - Zebrafish Got Spicy: V Course and Symposium of the Latin American Zebrafish Network. AB - The V Latin American Zebrafish Network Course and Symposium was held from May 4 to 12, 2018 at the Institute of Biotechnology of the National Autonomous University of Mexico. A group of 19 students from eight different countries were selected and trained during a week in a variety of topics and techniques using zebrafish as a model, followed by a 2-day symposium. In this article, we want to point out not only the outstanding activities carried out during the course but also highlight the great experience, the knowledge, and the fantastic relationships we gained from those days. PMID- 30523747 TI - Local Dynamic Stability of the Locomotion of Lower Extremity Joints and Trunk During Backward Upslope Walking. AB - Backward slope walking was considered as a practical rehabilitation and training skill. However, its gait stability has been hardly studied, resulting in its limited application as a rehabilitation tool. In this study, the effect of walking direction and slope grade were investigated on the local dynamic stability of the motion of lower extremity joints and trunk segment during backward and forward upslope walking (BUW/FUW). The local divergence exponents (lambdaS) of 16 adults were calculated during their BUW and FUW at grades of 0%, 5%, 10%, and 15%. Mean standard deviation over strides (MeanSD) was analyzed as their gait variability. Backward walking showed larger lambdaS for the abduction adduction and rotational angles of knee and ankle on inclined surface than forward walking, while lambdaS for hip flexion-extension angle at steeper grades was opposite. No grade effect for any joint existed during BUW, while lambdaS increased with the increasing grade during FUW. As to the trunk, walking direction did little impact on lambdaS. Still, significant larger lambdaS for its medial-lateral and vertical motion were found at the steeper grades during both FUW and BUW. Results indicate that during BUW, the backward direction may influence the stability of joint motions, while the trunk stability was challenged by the increasing grades. Therefore, BUW may be a training tool for the stability of both upper and lower body motion during gait. PMID- 30523748 TI - Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide. AB - PURPOSE: Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem cell graft. METHODS: Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites. RESULTS: The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively. CONCLUSION: UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft. PMID- 30523749 TI - Unplanned Hospitalization Among Individuals With Cancer in the Year After Diagnosis. AB - PURPOSE:: Reducing acute care use is an important strategy for improving value in cancer care. However, little information is available to describe and compare population-level hospital use across cancer types. Our aim was to estimate unplanned hospitalization rates and to describe the reasons for hospitalization in a population-based cohort recently diagnosed with cancer. MATERIALS AND METHODS:: California Cancer Registry data linked with administrative inpatient data were used to examine unplanned hospitalization among individuals diagnosed with cancer between 2009 and 2012 (n = 412,850). Hospitalizations for maintenance chemotherapy, radiotherapy, or planned surgery were excluded. Multistate models were used to estimate age-adjusted unplanned hospitalization rates, accounting for survival. RESULTS:: Approximately 67% of hospitalizations in the year after diagnosis were unplanned, 35% of newly diagnosed individuals experienced an unplanned hospitalization, and 67% of unplanned hospitalizations originated in the emergency department (ED). Nonmalignancy principal diagnoses most frequently associated with unplanned hospitalization included infection (15.8%) and complications of a medical device or care (6.5%). Unplanned hospitalization rates were highest for individuals with hepatobiliary or pancreatic cancer (2.08 unplanned hospitalizations per person-year at risk), lung cancer (1.58 unplanned hospitalizations), and brain or CNS cancer (1.47 unplanned hospitalizations), and were lowest among individuals with prostate cancer (0.18 unplanned hospitalizations) and melanoma (0.25 unplanned hospitalizations). CONCLUSION:: The population burden of unplanned hospitalization among individuals newly diagnosed with cancer is substantial. Many unplanned hospitalizations originate in the ED and are associated with potentially preventable admission diagnoses. Efforts to reduce unplanned hospitalization might target subgroups at higher risk and focus on the ED as a source of admission. PMID- 30523751 TI - Modulation of Macrophage Polarization by Human Glomerular Mesangial Cells in Response to the Stimuli in Renal Microenvironment. AB - Mesangial cell (MC) activation and macrophage infiltration are 2 major events closely related with each other in mesangial proliferative glomerulonephritis. In the anti-Thy 1 nephritis model, macrophages mediate the damage and also the expansion of mesangium through secreting various inflammatory factors; however, in glomerular microenvironment how MCs affect macrophage activity in the presence of various stimuli have not yet been understood. In the present study, we found that resting human MCs (HMCs) constitutively expressed chemokine [C-C motif] ligand 2 (CCL-2) and interleukin (IL)-6 and induced M2 polarization of macrophages in the coculture system. HMC proliferation and migration and expression of IL-6, CCL-2, and macrophage colony-stimulating factor in HMCs were enhanced after platelet-derived growth factor (PDGF)-BB stimulation, among which CCL-2 was responsible for inducing the M2 polarization of macrophages. Furthermore, PDGF-BB-stimulated HMCs alleviated the classical activation of macrophages and drove more intensified M2 polarization of macrophages than resting HMCs did. However, lipopolysaccharide and interferon-gamma (IFN-gamma) stimulated HMCs maintained the M1 phenotype of cocultured macrophages. In conclusion, MCs actively participated in glomerular inflammation through influencing macrophage polarization. The interplay between MCs and infiltrated macrophages is finely modulated by secretory factors such as PDGF-BB and IFN gamma in response to the renal inflammatory microenvironment. PMID- 30523752 TI - Automating Treatment Summary Development Using Electronic Billing Information: A Pilot Study of Survivors of Head and Neck Cancer. AB - PURPOSE:: Although the provision of a treatment summary (TS) is a quality indicator in oncology, routine delivery of TSs remains challenging. Automatic TS generation could facilitate use, but data on accuracy are lacking in complex cancers such as head and neck cancer (HNC). We developed and evaluated an electronic platform to automate TS generation for HNC. METHODS:: The algorithms autopopulated TSs using data from billing records and an institutional cancer registry. A nurse practitioner used the medical record to verify the accuracy of the information and made corrections electronically. Inaccurate and missing data were considered errors. We described and investigated reasons for errors in the automatically generated TSs. RESULTS:: We enrolled a heterogeneous population of 43 survivors of HNC. Using billing data, the information on primary site, lymph node status, radiation, and chemotherapy use was accurate in 93%, 95%, 93%, and 95% of patients, respectively. Billing data captured surgery accurately in 77% of patients; once an omitted billing code was identified, accuracy increased to 98%. Chemotherapies were captured in 90% of patients. Using the cancer registry, month and year of diagnosis were accurate in 91% of cases; stage was accurate in 28% of cases. Reprogramming the algorithm to ascertain clinical stage when pathologic stage was unavailable resulted in 100% accuracy. The algorithms inconsistently identified radiation receipt and treating physicians from billing data. CONCLUSION:: It is feasible to automatically and accurately generate most components of TSs for HNC using billing and cancer registry data, although clinical review is necessary in some cases. PMID- 30523750 TI - Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. AB - PURPOSE: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase. RESULTS: Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v 0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia. CONCLUSION: Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis. PMID- 30523753 TI - GDNF enhances human blood-nerve barrier function in vitro via MAPK signaling pathways. AB - The human blood-nerve barrier (BNB) formed by endoneurial microvascular endothelial cells, serves to maintain the internal microenvironment in peripheral nerves required for normal axonal signal transduction to and from the central nervous system. The mechanisms of human BNB formation in health and disease are not fully elucidated. Prior work established a sufficient role for glial-derived neurotrophic factor (GDNF) in enhancing human BNB biophysical properties following serum withdrawal in vitro via RET-tyrosine kinase-dependent cytoskeletal remodeling. The objective of the study was to ascertain the downstream signaling pathway involved in this process and more comprehensively determine the molecular changes that may occur at human BNB intercellular junctions under the influence of GDNF. Proteomic studies suggested expression of several mitogen-activated protein kinases (MAPKs) in confluent GDNF-treated endoneurial endothelial cells following serum withdrawal. Using electric cell substrate impedance sensing to continuously measure transendothelial electrical resistance and static transwell solute permeability assays with fluoresceinated small and large molecules to evaluate BNB biophysical function, we determined MAPK signaling was essential for GDNF-mediated BNB TEER increase following serum withdrawal downstream of RET-tyrosine kinase signaling that persisted for up to 48 hours in vitro. This increase was associated with reduced solute permeability to fluoresceinated sodium and high molecular weight dextran. Specific GDNF mediated alterations were detected in cytoskeletal and intercellular junctional complex molecular transcripts and proteins relative to basal conditions without exogenous GDNF. This work provides novel insights into the molecular determinants and mechanisms responsible for specialized restrictive human BNB formation in health and disease. PMID- 30523754 TI - Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. PMID- 30523755 TI - TGF-beta secreted by tumor-associated macrophages promotes proliferation and invasion of colorectal cancer via miR-34a-VEGF axis. AB - Tumor-associated macrophages (TAMs) were reported to be involved in colorectal cancer (CRC) progression. However, its biological role and underlying mechanism in CRC remained to be elucidated. In this study, the expressions of the macrophage marker CD68 and transforming growth factor beta1 (TGF-beta1) in CRC tumor tissues and adjacent tissues were detected by immunohistochemistry. The expression levels of miR-34a, TGF-beta1 and vascular endothelial growth factor (VEGF) in CRC tumor tissues and peripheral blood macrophages were measured by quantitative real-time PCR (qRT-PCR) and western blot. TGF-beta1 levels in culture supernatant were detected by ELISA. The cell proliferation and invasion of human CRC cell lines CL187 and HCT116 were determined by MTT assay and Transwell assay, respectively. The results showed that the expression of miR-34a was downregulated whereas TGF-beta1 and VEGF were upregulated in CRC tumor tissues and peripheral blood macrophages. TGF-beta1 secreted by TAMs promoted the proliferation and invasion of CRC cells. TGF-beta1-mediated miR-34a downregulation contributed to the proliferation and invasion of CRC cells via upregulating VEGF. MiR-34a in vivo exerted anti-tumor effect in CRC via inhibiting VEGF expression. In conclusion, TGF-beta1 secreted by TAMs promoted CRC proliferation and invasion through regulating miR-34a/VEGF axis. Keywords: colorectal cancer; tumor-associated macrophages; TGF-beta1; proliferation; invasion. PMID- 30523756 TI - Randomized Phase II Trial of Cisplatin and Etoposide in Combination With Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511 Study. AB - PURPOSE: Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC). MATERIALS AND METHODS: Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10 level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate. RESULTS: A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade >= 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable. CONCLUSION: The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point. PMID- 30523757 TI - [E-Learning in bachelor-level nursing education in Germany and the role of the nurse educator - a Delphi survey]. AB - : E-Learning in bachelor-level nursing education in Germany and the role of the nurse educator - a Delphi survey Abstract. BACKGROUND: In addition to conventional face-to-face classes, e-learning is becoming more prevalent in tertiary-level nurse education. Its asynchronous, decentralized nature influences teaching and learning. AIM: This study examines current expert opinion on how e learning is affecting tertiary-level nurse education and the role of the nurse educator. METHODS: In a 3-wave Delphi survey, nurse educators, nursing students / alumni, information and communications technology (ICT-) specialists and members of the scientific community were recruited as experts and asked to give their opinions regarding e-Learning and its effects on nurse education and the nurse educator's role. The null-round (R0) instrument comprised open questions. The R0 data were analyzed utilizing qualitative content analysis and then used in conjunction with the results of an earlier literature review to generate items for standardized follow up rounds (R1&2). The R1&2-instrument consists of 14 statements pertaining to e-learning and 13 statements pertaining to the nurse educator's role. Participants were asked to indicate the degree to which they agree with each statement. R1&2-data were analyzed using statistical methods. The means and medians for R1&2 were compared with each other. In addition, the response behavior of each individual participant was analyzed and assessed as assimilating, divergent, stable or inexplicable. RESULTS: The size of the expert panel was: R0 = 8, R1&2 = 15; total panel mortality was n = 2. The analysis of standardized data provides the following representation of expert opinion: Participants viewed the effectiveness of e-learning as being not only dependent upon the domain of the learning objective (i. e. cognitive, affective), but also upon the complexity of the subject matter. According to the experts, face-to-face interaction is paramount to successful learning. The experts also recognized e learning's potential for facilitating cooperation between clinical and classroom settings, the continuity of teaching and learning, a better work-study-life balance, as well as knowledge transfer. Furthermore, the participants took the view that e-learning changes the nurse educator's role, requiring new / expanded didactical, pedagogical, administrative and technical competencies compared to traditional face-to-face teaching and learning. CONCLUSIONS: Nurse educators will need specific training to prepare them for their altered role. Blended learning offers more added value than pure online learning. PMID- 30523759 TI - Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline Summary. PMID- 30523758 TI - Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. AB - PURPOSE: Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. PATIENTS AND METHODS: In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. RESULTS: Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). CONCLUSION: NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS. PMID- 30523760 TI - Breastfeeding Duration and the Risk of Coronary Artery Disease. AB - BACKGROUND: Previous studies have suggested that prolonged breastfeeding has beneficial effects on the health of the mother including the reduction of long term risk of coronary artery disease (CAD). The mechanism of this association remains unclear. METHODS: We surveyed 643 women aged 40-65 years receiving outpatient care at Stanford University Hospital on their reproductive/lactation history, including 137 women (cases) with clinically confirmed CAD. Survey data were supplemented with traditional risk factor data for CAD obtained from the participant's medical record. We then conducted logistic regression analyses to assess the relationship between breastfeeding duration and case-control status for each of the two separate definitions of duration. The first was based on the participant's single longest duration of breastfeeding considering all live births reported and the second was based on a participant's total duration of breastfeeding summed over all live births. For each of these two definitions, we ran three sequential models each with a different reference group-(1) nulliparous women, (2) parous women that never breastfed, and (3) parous women with a short duration of breastfeeding-successively excluding women in the reference group of the previous model(s). RESULTS: Just over one-half (51.6%) of the women surveyed reported a history of breastfeeding. We found nominally significant associations (p = 0.04-0.12) for our multivariate analyses that modeled maximum duration of breastfeeding. When compared with nulliparous women, parous women who either never breastfed or always breastfed for <5 months had approximately double the risk of CAD. Among parous women, women who breastfeed for >=5 months at least once in their lifetime had a ~30% decrease risk of CAD compared with those who did not initiate breastfeeding. Among parous women who breastfed >=1 month, women who breastfed >=5 months had ~50% decreased risk of CAD. We found similar point estimates of effect for analogous analyses modeling maximum breastfeeding duration but p-values for these analyses were not significant. Unadjusted analyses demonstrated higher valued odds ratios and lower p-values suggesting the presence of some confounding by traditional risk factors. CONCLUSIONS: Parous women who breastfeed >=5 months in at least one pregnancy seem to be at decreased risk of CAD later in their life, whereas parous women who either never breastfed or discontinued breastfeeding early seem to be at increased risk. More research is needed to more reliably quantify and determine the nature of the relationship between parity, breastfeeding duration, and risk of CAD. PMID- 30523761 TI - TLR4 (toll-like receptor 4) activation suppresses autophagy through inhibition of FOXO3 and impairs phagocytic capacity of microglia. AB - Macroautophagy/autophagy is a lysosome-dependent catabolic process for the turnover of proteins and organelles in eukaryotes. Autophagy plays an important role in immunity and inflammation as well as metabolism and cell survival. Diverse immune and inflammatory signals induce autophagy in macrophages through pattern recognition receptors, such as toll-like receptors (TLRs). However, the physiological role of autophagy and its signaling mechanisms in microglia remain poorly understood. Microglia are phagocytic immune cells that are resident in the central nervous system and share many characteristics with macrophages. Here, we show that autophagy flux and expression of autophagy-related (Atg) genes in microglia are significantly suppressed upon TLR4 activation by lipopolysaccharide (LPS), in contrast to their stimulation by LPS in macrophages. Metabolomics analysis of the levels of phosphatidylinositol (PtdIns) and its 3-phosphorylated form, PtdIns3P, in combination with bioinformatics prediction, revealed an LPS induced reduction in the synthesis of PtdIns and PtdIns3P in microglia but not macrophages. Interestingly, inhibition of PI3K, but not MTOR or MAPK1/3, restored autophagy flux with concomitant dephosphorylation and nuclear translocation of FOXO3. A constitutively active form of FOXO3 also induced autophagy, suggesting FOXO3 as a downstream target of the PI3K pathway for autophagy inhibition. LPS treatment impaired phagocytic capacity of microglia, including MAP1LC3B/LC3 associated phagocytosis (LAP) and amyloid beta (Abeta) clearance. PI3K inhibition restored LAP and degradation capacity of microglia against Abeta. These findings suggest a unique mechanism for the regulation of microglial autophagy and point to the PI3K-FOXO3 pathway as a potential therapeutic target to regulate microglial function in brain disorders. PMID- 30523763 TI - Early Clinical and Economic Outcomes of Prophylactic and Acute Pathologic Fracture Treatment. AB - INTRODUCTION:: Pathologic fractures often contribute to adverse events in metastatic bone disease, and prophylactic fixation offers to mitigate their effects. This study aims to analyze patient selection, complications, and in hospital costs that are associated with prophylactic fixation compared with traditional acute fixation after completed fracture. MATERIALS AND METHODS:: The Nationwide Inpatient Sample database was queried from 2002 to 2014 for patients with major extremity pathologic fractures. Patients were divided by fixation technique (prophylactic or acute) and fracture location (upper or lower extremity). Patient demographics, comorbidities, complications, hospitalization length, and hospital charges were compared between cohorts. Preoperative variables were analyzed for potential confounding, and chi2 tests and Student's t tests were used to compare fixation techniques. RESULTS:: Cumulatively, 43,920 patients were identified, with 14,318 and 28,602 undergoing prophylactic and acute fixation, respectively. Lower extremity fractures occurred in 33,582 patients, and 10,333 patients had upper extremity fractures. A higher proportion of prophylactic fixation patients were white ( P = .043), male ( P = .046), age 74 years or younger ( P < .001), and privately insured ( P < .001), with decreased prevalence of obesity ( P = .003) and/or preoperative renal disease ( P = .008). Prophylactic fixation was also associated with decreased peri- and postoperative blood transfusions ( P < .001), anemia ( P < .001), acute renal failure ( P = .010), and in-hospital mortality ( P = .031). Finally, prophylactic fixation had decreased total charges (-$3,405; P = .001), hospitalization length ( P = .004), and extended length of stay (greater than 75th percentile; P = .012). CONCLUSION:: Prophylactic fixation of impending pathologic fractures is associated with decreased complications, hospitalization length, and total charges, and should be considered in appropriate patients. PMID- 30523762 TI - In vitro and in silico assessment of the developability of a designed monoclonal antibody library. AB - Despite major advances in antibody discovery technologies, the successful development of monoclonal antibodies (mAbs) into effective therapeutic and diagnostic agents can often be impeded by developability liabilities, such as poor expression, low solubility, high viscosity and aggregation. Therefore, strategies to predict at the early phases of antibody development the risk of late-stage failure of antibody candidates are highly valuable. In this work, we employ the in silico solubility predictor CamSol to design a library of 17 variants of a humanized mAb predicted to span a broad range of solubility values, and we examine their developability potential with a battery of commonly used in vitro and in silico assays. Our results demonstrate the ability of CamSol to rationally enhance mAb developability, and provide a quantitative comparison of in vitro developability measurements with each other and with more resource intensive solubility measurements, as well as with in silico predictors that offer a potentially faster and cheaper alternative. We observed a strong correlation between predicted and experimentally determined solubility values, as well as with measurements obtained using a panel of in vitro developability assays that probe non-specific interactions. These results indicate that computational methods have the potential to reduce or eliminate the need of carrying out laborious in vitro quality controls for large numbers of lead candidates. Overall, our study provides support to the emerging view that the implementation of in silico tools in antibody discovery campaigns can ensure rapid and early selection of antibodies with optimal developability potential. PMID- 30523764 TI - Patient-Centered Medical Homes in Community Oncology Practices: Changes in Spending and Care Quality Associated With the COME HOME Experience. AB - PURPOSE:: We examined whether the Community Oncology Medical Home (COME HOME) program, a medical home program implemented in seven community oncology practices, was associated with changes in spending and care quality. PATIENTS AND METHODS:: We compared outcomes from elderly fee-for-service Medicare beneficiaries diagnosed between 2011 and 2015 with breast, lung, colorectal, thyroid, or pancreatic cancer, lymphoma, or melanoma and served by COME HOME practices before and after program implementation versus similar beneficiaries served by other geographically proximate oncologists. Difference-in-differences analysis compared changes in outcomes for COME HOME patients versus concurrent controls. Propensity score matching and regression methods were adjusted for clinical and sociodemographic differences. Our primary outcome was 6-month medical spending per beneficiary. Secondary outcomes included 6-month out-of pocket spending, inpatient and ambulatory care-sensitive hospitalizations, readmissions, length of stay, and emergency department and evaluation and management visits. RESULTS:: Before COME HOME, 6-month medical spending was $2,975 higher for the study group compared with controls (95% CI, $1,635 to $4,315; P < .001) and increasing at a similar rate. After intervention, this difference was reduced to $318 (95% CI, -$1,105 to $1,741; P = .661), a significant change of -$2,657 (95% CI, -$4,631 to -$683; P = .008) or 8.1% savings relative to 6-month average spending ($32,866). COME HOME was also associated with significantly reduced (10.2 %) emergency department visits per 1,000 patients per 6-month period ( P = .024). There were no statistically significant differences in other outcomes. CONCLUSION:: COME HOME was associated with reduced Medicare spending and improved emergency department use. The patient centered medical home model holds promise for oncology practices, but improvements were not uniform. PMID- 30523765 TI - Erratum. PMID- 30523766 TI - Preface. PMID- 30523767 TI - De-Novo Ligand Design against Mutated Huntington Gene by Ligand-Based Pharmacophore Modeling Approach. AB - BACKGROUND: Huntington's disease is characterized by three side effects, including motor disturbances, psychiatric elements, and intellectual weakness. The onset for HD has nonlinear converse associations with the number of repeat sequences of the polyglutamine mutations, so that younger patients have a tendency for longer repeats length. This HD variation is because of a development of a polyglutamine (CAG) repeats in the exon 1 of the Huntingtin protein. METHODS: In the present study, a few derivatives utilized as a part of the treatment of HD, are used to create the pharmacophore model and based on the features of the pharmacophore model; an attempt is made to design the de-novo drug for the HD protein. HD protein structure was built and docked with the novel ligand, based on shared feature pharmacophore model, through a ligand-based pharmacophore modeling approach. RESULTS: The novel ligand contains 1 HBAs, 2 HBDs, and 2 aromatic rings. It fulfills all the properties of certain drug likeness rules, non-toxic in nature. In the docked complex the common interactive amino acids identified are SER 1035, ALA 1062, MET 1068, LEU 1031, and THR 1036, which confirmed the validity and stability of a ligand molecule to be used as a drug in the treatment of Huntington's disease. CONCLUSION: novel ligand can be used in clinical trials as a drug molecule against the mutations of HD gene and in laboratory procedures for efficacy analysis. PMID- 30523768 TI - Evaluation of Hospital Discharge Prescriptions in the Elderly and Younger Adults Using the Medication Regimen Complexity Index. AB - BACKGROUND: Advances in the clinical management of diseases have been accompanied by increasing complexity of treatment regimens. The complexity of medication regimen is of concern for patients as well as doctors as it may adversely affect patient compliance and treatment outcomes. It may result in medication errors, increased utilization of health resources owing to a reduction in treatment effectiveness, and increased risk of therapeutic failure. OBJECTIVE: To assess the complexity of medication regimen prescribed to patients on hospital discharge using the medication regimen complexity index (MRCI). METHOD: A cross-sectional, descriptive study was conducted. Hospital discharge prescriptions written for patients discharged from the General Medicine wards of a tertiary care teaching hospital in South India were scored for their complexity using MRCI. The correlation of age and gender with the MRCI scores was also assessed. Patients >=60 years of age were considered elderly. RESULTS: The median MRCI score for the 563 prescriptions studied was 14 (Interquartile range, 9-21). Elderly patients received a significantly more complex medication regimen compared with younger patients (p < 0.001) at the time of hospital discharge. Gender variation was seen with higher MRCI scores in females, but this was not statistically significant in the elderly group. CONCLUSION: MRCI scores are significantly high in elderly patients at the time of hospital discharge. Although a strong correlation is seen between the number of medications and the MRCI score, the latter helps to distinguish regimen complexity between prescriptions with the same number of medications. PMID- 30523769 TI - A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage. AB - OBJECTIVE: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on non-small cell lung cancer (NSCLCs) cells and the potential anti-tumor mechanisms. BACKGROUND: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. METHODS: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. RESULTS: Our results demonstrated that camptothecin derivative 3j showed greater antitumor effect in eleven 20(S)-O substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. And IC50 of 3j was 1.54+/- 0.41 MUM lower than irinotecan with an IC50 of 13.86+/-0.80 MUM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87+/-0.23 MUM lower than irinotecan (IC50+/-SD, 5.35+/-0.38 MUM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24 h of 3j (10 MUM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 +/- 4.4 %) compared with control cells (31.67 +/- 3.4 %). Similarly, the percentage of NCI-H1975 cell in S-phase significantly increased (to 83.99 +/- 2.4 %) compared with control cells (34.45 +/- 3.9 %) after treatment with 10MUM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA relaxation assay simultaneously confirmed that 3j supressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. CONCLUSION: Novel camptothecin derivative 3j has been demonstated as a promising antitumor agent and remain to be assessed in further studies. PMID- 30523770 TI - Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments. AB - BACKGROUND AND OBJECTIVE: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors. METHOD: A new esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling. RESULTS: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21-94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86-4.08 MUM. Molecular modelling against the TDP1 crystal structure showed good fit of the active esters in the catalytic pocket, explaining their potency. A non toxic dose of ester, containing a 3,7-dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549. CONCLUSION: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect. PMID- 30523771 TI - Germ plasm provides clues on meiosis: the concerted action of germ plasm granules and mitochondria in gametogenesis of the clam Ruditapes philippinarum. AB - SummaryGerm plasm-related structures (GPRS) are known to accompany meiotic cell differentiation but their dynamics are still poorly understood. In this study, we analyzed the ultrastructural mechanisms of GPRS transformation during oogenesis and spermatogenesis of the bivalve mollusc Ruditapes philippinarum (Manila clam), exploring patterns of GPRS activity occurring at meiosis onset, sex-specific difference/similarity of such patterns, and the involvement of mitochondria during GPRS-assigned events. In the two sexes, the zygotene-pachytene stage of meiosis is anticipated by three shared steps. First, the dispersion of germ plasm granules containing the germ line determinant VASA occurs. Second, the VASA protein deriving from germ plasm granules enters neighbouring mitochondria and appears to induce mitochondrial matter release, as supported by cytochrome B localization outside the mitochondria. Third, intranuclear VASA entrance occurs and the protein appears involved in chromatin reorganization, as supported by VASA localization in synaptonemal complexes. In spermatogenesis, these three steps are sufficient for the normal course of meiosis. In oogenesis, these are followed by the action of 'germ plasm granule formation complex', a novel type of structure that appears alternative to the Balbiani body. The possibility of germ plasm involvement in reproductive technologies is also suggested. PMID- 30523772 TI - Aiding the diagnosis of dissociative identity disorder: pattern recognition study of brain biomarkers. AB - BACKGROUND: A diagnosis of dissociative identity disorder (DID) is controversial and prone to under- and misdiagnosis. From the moment of seeking treatment for symptoms to the time of an accurate diagnosis of DID individuals received an average of four prior other diagnoses and spent 7 years, with reports of up to 12 years, in mental health services.AimTo investigate whether data-driven pattern recognition methodologies applied to structural brain images can provide biomarkers to aid DID diagnosis. METHOD: Structural brain images of 75 participants were included: 32 female individuals with DID and 43 matched healthy controls. Individuals with DID were recruited from psychiatry and psychotherapy out-patient clinics. Probabilistic pattern classifiers were trained to discriminate cohorts based on measures of brain morphology. RESULTS: The pattern classifiers were able to accurately discriminate between individuals with DID and healthy controls with high sensitivity (72%) and specificity (74%) on the basis of brain structure. These findings provide evidence for a biological basis for distinguishing between DID-affected and healthy individuals. CONCLUSIONS: We propose a pattern of neuroimaging biomarkers that could be used to inform the identification of individuals with DID from healthy controls at the individual level. This is important and clinically relevant because the DID diagnosis is controversial and individuals with DID are often misdiagnosed. Ultimately, the application of pattern recognition methodologies could prevent unnecessary suffering of individuals with DID because of an earlier accurate diagnosis, which will facilitate faster and targeted interventions.Declaration of interestThe authors declare no competing financial interests. PMID- 30523773 TI - Multi-Angle Plasma Focused Ion Beam (FIB) Curtaining Artifact Correction Using a Fourier-Based Linear Optimization Model. AB - We present a flexible linear optimization model for correcting multi-angle curtaining effects in plasma focused ion beam scanning electron microscopy (PFIB SEM) images produced by rocking-polishing schemes. When PFIB-SEM is employed in a serial sectioning tomography workow, it is capable of imaging large three dimensional volumes quickly, providing rich information in the critical 10-100 nm feature length scale. During tomogram acquisition, a "rocking polish" is often used to reduce straight-line "curtaining" gradations in the milled sample surface. While this mitigation scheme is effective for deep curtains, it leaves shallower line artifacts at two discretized angles. Segmentation and other automated processing of the image set requires that these artifacts be corrected for accurate microstructural quantification. Our work details a new Fourier-based linear optimization model for correcting curtaining artifacts by targeting curtains at two discrete angles. We demonstrate its capabilities by processing images from a tomogram from a multiphase, heterogeneous concrete sample. We present methods for selecting the parameters which meet the user's goals most appropriately. Compared to previous works, we show that our model provides effective multi-angle curtain correction without introducing artifacts into the image, modifying non-curtain structures or causing changes to the contrast of voids. Our algorithm can be easily parallelized to take advantage of multi-core hardware. PMID- 30523774 TI - Exploring absolute and relative measures of exposure to food environments in relation to dietary patterns among European adults. AB - OBJECTIVE: To explore the associations of absolute and relative measures of exposure to food retailers with dietary patterns, using simpler and more complex measures. DESIGN: Cross-sectional survey. SETTING: Urban regions in Belgium, France, Hungary, the Netherlands and the UK.ParticipantsEuropean adults (n 4942). Supermarkets and local food shops were classified as 'food retailers providing healthier options'; fast-food/takeaway restaurants, cafes/bars and convenience/liquor stores as 'food retailers providing less healthy options'. Simpler exposure measures used were density of healthy and density of less healthy food retailers. More complex exposure measures used were: spatial access (combination of density and proximity) to healthy and less healthy food retailers; density of healthier food retailers relative to all food retailers; and a ratio of spatial access scores to healthier and less healthy food retailers. Outcome measures were a healthy or less healthy dietary pattern derived from a principal component analysis (based on consumption of fruits, vegetables, fish, fast foods, sweets and sweetened beverages). RESULTS: Only the highest density of less healthy food retailers was significantly associated with the less healthy dietary pattern (beta = -129.6; 95 % CI -224.3, -34.8). None of the other absolute density measures nor any of the relative measures of exposures were associated with dietary patterns. CONCLUSIONS: More complex measures of exposure to food retailers did not produce stronger associations with dietary patterns. We had some indication that absolute and relative measures of exposure assess different aspects of the food environment. However, given the lack of significant findings, this needs to be further explored. PMID- 30523775 TI - Associations of plasma very-long-chain SFA and the metabolic syndrome in adults - ERRATUM. PMID- 30523776 TI - Invited review: Phenotyping strategies and quantitative-genetic background of resistance, tolerance and resilience associated traits in dairy cattle. AB - In dairy cattle, resistance, tolerance and resilience refer to the adaptation ability to a broad range of environmental conditions, implying stable performances (e.g. production level, fertility status) independent from disease or infection pressure. All three mechanisms resistance, tolerance and resilience contribute to overall robustness, implying the evaluation of phenotyping and breeding strategies for improved robustness in dairy cattle populations. Classically, breeding approaches on improved robustness rely on simple production traits, in combination with detailed environmental descriptors and enhanced statistical modelling to infer possible genotype by environment interactions. In this regard, innovative environmental descriptors were heat stress indicators, and statistical modelling focussed on random regression or reaction norm methodology. A robust animal has high breeding values over a broad spectra of environmental levels. During the last years, direct health traits were included into selection indices, implying advances in genetic evaluations for traits being linked to resistance or tolerance against infectious and non-infectious diseases. Up to now, genetic evaluation for health traits is primarily based on subjectively measured producer-recorded data, with disease trait heritabilities in a low-to-moderate range. Thus, it is imperative to identify objectively measurable phenotypes as suitable biomarkers. New technologies (e.g. mid-infrared spectrometry) offer possibilities to determine potential biomarkers via laboratory analyses. Novel biomarkers include measurable physiological traits (e.g. serum metabolites, hormone levels) as indicators for a current infection, or the host's reaction to environmental stressors. The rumen microbiome composition is proposed as a biomarker to detect interactions between host genotype and environmental effects. The understanding of host genetic variation in disease resistance and individual expression of robustness encourages analyses on the underlying immune response (IR) system. Recent advances have been made in order to infer the genetic background of IR traits and cows immunological competence in relation to functional and production traits. Thus, a last aspect of this review addresses the genetic background and current state of genetic control for resistance to economically relevant infectious and non-infectious dairy cattle diseases by considering immune-related factors. PMID- 30523777 TI - Tolerance of lamb and mouse oocytes to cryoprotectants during vitrification. AB - SummaryMouse and lamb oocytes were vitrified with, or exposed to, different cryoprotectants and evaluated for their effects on their survival and developmental competence after in vitro fertilization (IVF) and activation treatments. Control oocytes remained untreated, whilst the remainder were exposed to three different combinations of vitrification solutions [dimethyl sulfoxide (DMSO) + ethylene glycol (EG), EG only, or propanediol (PROH) + EG] and either vitrified or left unfrozen (exposed groups). Oocytes in the control and vitrified groups underwent IVF and developmental competence was assessed to the blastocyst stage. In lambs, survival rate in vitrified oocytes was significantly lower than for oocytes in the exposed groups (P <0.05). Blastocyst development was low in vitrified oocytes compared with controls (<6% vs 38.9%, P <0.01). Parthenogenetic activation was more prevalent in vitrified lamb oocytes compared with controls (P <0.05). No evidence of zona pellucida hardening or cortical granule exocytosis could account for reduced fertilization rates in vitrified lamb oocytes. Mouse oocytes demonstrated a completely different response to lamb oocytes, with survival and parthenogenetic activation rates unaffected by the vitrification process. Treatment of mouse oocytes with DMSO + EG yielded significantly higher survival and cleavage rates than treatment with PROH + EG (87.8% and 51.7% vs 32.7% and 16.7% respectively, P <0.01), however cleavage rate for vitrified oocytes remained lower than for the controls (51.7% vs 91.7%, P <0.01) as did mean blastocyst cell number (33 +/- 3.1 vs 42 +/- 1.5, P <0.05). From this study, it is clear that lamb and mouse show different tolerances to cryoprotectants commonly used in vitrification procedures, and careful selection and testing of species-compatible cryoprotectants is required when vitrifying oocytes to optimize survival and embryo development. PMID- 30523778 TI - Listeria monocytogenes: cell biology of invasion and intracellular growth. AB - The Gram-positive pathogen Listeria monocytogenes is able to promote its entry into a diverse range of mammalian host cells by triggering plasma membrane remodeling, leading to bacterial engulfment. Upon cell invasion, L. monocytogenes disrupts its internalization vacuole and translocates to the cytoplasm, where bacterial replication takes place. Subsequently, L. monocytogenes uses an actin based motility system that allows bacterial cytoplasmic movement and cell-to-cell spread. L. monocytogenes therefore subverts host cell receptors, organelles and the cytoskeleton at different infection steps, manipulating diverse cellular functions that include ion transport, membrane trafficking, post-translational modifications, phosphoinositide production, innate immune responses as well as gene expression and DNA stability. PMID- 30523779 TI - DNA sequence encodes the position of DNA supercoils. AB - The three-dimensional organization of DNA is increasingly understood to play a decisive role in vital cellular processes. Many studies focus on the role of DNA packaging proteins, crowding, and confinement in arranging chromatin, but structural information might also be directly encoded in bare DNA itself. Here we visualize plectonemes (extended intertwined DNA structures formed upon supercoiling) on individual DNA molecules. Remarkably, our experiments show that the DNA sequence directly encodes the structure of supercoiled DNA by pinning plectonemes at specific sequences. We develop a physical model that predicts that sequence-dependent intrinsic curvature is the key determinant of pinning strength and demonstrate this simple model provides very good agreement with the data. Analysis of several prokaryotic genomes indicates that plectonemes localize directly upstream of promoters, which we experimentaly confirm for selected promotor sequences. Our findings reveal a hidden code in the genome that helps to spatially organize the chromosomal DNA. PMID- 30523780 TI - Sae2/CtIP prevents R-loop accumulation in eukaryotic cells. AB - The Sae2/CtIP protein is required for efficient processing of DNA double-strand breaks that initiate homologous recombination in eukaryotic cells. Sae2/CtIP is also important for survival of single-stranded Top1-induced lesions and CtIP is known to associate directly with transcription-associated complexes in mammalian cells. Here we investigate the role of Sae2/CtIP at single-strand lesions in budding yeast and in human cells and find that depletion of Sae2/CtIP promotes the accumulation of stalled RNA polymerase and RNA-DNA hybrids at sites of highly expressed genes. Overexpression of the RNA-DNA helicase Senataxin suppresses DNA damage sensitivity and R-loop accumulation in Sae2/CtIP-deficient cells, and a catalytic mutant of CtIP fails to complement this sensitivity, indicating a role for CtIP nuclease activity in the repair process. Based on this evidence, we propose that R-loop processing by 5' flap endonucleases is a necessary step in the stabilization and removal of nascent R-loop initiating structures in eukaryotic cells. PMID- 30523781 TI - Images in neuroscience: Cervical bony lesion. PMID- 30523782 TI - Nucleocytoplasmic Shuttling of Geminivirus C4 Protein Mediated by Phosphorylation and Myristoylation Is Critical for Viral Pathogenicity. AB - Many geminivirus C4 proteins induce severe developmental abnormalities in plants. We previously demonstrated that Tomato leaf curl Yunnan virus (TLCYnV) C4 induces plant developmental abnormalities at least partically by decreasing the accumulation of NbSKeta, an ortholog of Arabidopsis BIN2 kinase involved in the brassinosteroid signaling pathway, in the nucleus through directing it to the plasma membrane. However, the molecular mechanism by which the membrane associated C4 modifies the localization of NbSKeta in the host cell remains unclear. Here, we show that TLCYnV C4 is a nucleocytoplasmic shuttle protein, and that C4 shuttling is accompanied by nuclear export of NbSKeta. TLCYnV C4 is phosphorylated by NbSKeta in the nucleus, which promotes myristoylation of the viral protein. Myristoylation of phosphorylated C4 favors its interaction with exportin-alpha (XPO I), which in turn facilitates nuclear export of the C4/NbSKeta complex. Supporting this model, chemical inhibition of N myristoyltransferases or exportin-alpha enhanced nuclear retention of C4, and mutations of the putative phosphorylation or myristoylation sites in C4 resulted in increased nuclear retention of C4 and thus decreased severity of C4-induced developmental abnormalities. The impact of C4 on development is also lessened when a nuclear localization signal or a nuclear export signal is added to its C terminus, restricting it to a specific cellular niche and therefore impairing nucleocytoplasmic shuttling. Taken together, our results suggest that nucleocytoplasmic shuttling of TLCYnV C4, enabled by phosphorylation by NbSKeta, myristoylation, and interaction with exportin-alpha, is critical for its function as a pathogenicity factor. PMID- 30523783 TI - The role of the otolaryngologist in the evaluation and management of headaches. AB - BACKGROUND: Headaches are commonly evaluated in otolaryngology and often represent a diagnostic dilemma. This review addresses rhinogenic headache as well as trigeminal neuralgia and migraine, both of which can masquerade as sinus headache and whose management increasingly involves otolaryngology intervention. Discussion considers diagnostic criteria and novel therapies and derives an algorithm for clinical decision-making. DATA SOURCES: OVID MEDLINE, Cochrane Library, and Google Scholar databases. METHODS: A literature search was performed to identify relevant articles published in the past 10 years addressing the diagnosis and management of rhinogenic headache, trigeminal neuralgia and/or migraine. FINDINGS: Rhinogenic headache: Identification of the specific cause must be achieved before treatment. No studies have mentioned the effect of certain therapies on the amelioration of headache. New techniques of balloon dilation for sinusitis are controversial, and their use remains contingent on surgeon preference. Removal of mucosal contact points has been shown to benefit quality of life in patients with contact point headache. Trigeminal neuralgia: Microvascular decompression is considered the gold standard for treatment, but percutaneous therapies can be effective for achieving pain control. Migraine: Patients who report amelioration of symptoms after targeted botulinum toxin injection may benefit from definitive decompression or nerve avulsion. Patients with mucosal contact points may have less favorable outcomes with migraine surgery if they are not simultaneously addressed. CONCLUSIONS: A comprehensive understanding of the diagnostic workup and therapeutic options available for common headache etiologies is key to the management of a patient presenting with headache attributed to a rhinogenic cause. PMID- 30523784 TI - Evolution of symptoms and quality of life during Zika virus infection: A 1-year prospective cohort study. AB - BACKGROUND: Although the complications of Zika virus infection have been well described, the clinical pattern has not been reported in enough detail to differentiate this infection from those with other arboviroses, and no longitudinal study has yet been published on the persistence of symptoms and quality of life. OBJECTIVES: were to describe bio-clinical pattern and quality of life during ZIKV infection, and their evolution. STUDY DESIGN: We present a 1 year clinical follow-up of 49 people infected with Zika virus in French Guiana, for whom the diagnosis was confirmed by RT-PCR in serum or urine. RESULTS: Fever was inconsistent (95% confidence interval (CI), 39-67). Exanthema (CI, 84-100) was maculopapular, with pruritus and conjunctivitis, variable over time and disappeared 12 days after the onset of symptoms (CI, 10-14). Joint pain (CI, 39 67) occurred mainly in the hands, wrists, knees and ankles and lasted for 10 days (CI, 7-13). Asthenia (CI, 61-85) scored low (3/10) but lasted for 19 days (CI, 16 22). The last two symptoms strongly limited patients' activities in the acute stage of the disease (RAPID-3 score, CI, 5-8). None of the patients had neurological complications, but 41% (CI, 27-55) had areflexia during the first month. CONCLUSIONS: We found no real chronic evolution or decreased quality of life, function or ability to work from the first month after symptom onset. PMID- 30523785 TI - The Hippo Pathway Prevents YAP/TAZ-Driven Hypertranscription and Controls Neural Progenitor Number. AB - The Hippo pathway controls the activity of YAP/TAZ transcriptional coactivators through a kinase cascade. Despite the critical role of this pathway in tissue growth and tumorigenesis, it remains unclear how YAP/TAZ-mediated transcription drives proliferation. By analyzing the effects of inactivating LATS1/2 kinases, the direct upstream inhibitors of YAP/TAZ, on mouse brain development and applying cell-number-normalized transcriptome analyses, we discovered that YAP/TAZ activation causes a global increase in transcription activity, known as hypertranscription, and upregulates many genes associated with cell growth and proliferation. In contrast, conventional read-depth-normalized RNA-sequencing analysis failed to detect the scope of the transcriptome shift and missed most relevant gene ontologies. Following a transient increase in proliferation, however, hypertranscription in neural progenitors triggers replication stress, DNA damage, and p53 activation, resulting in massive apoptosis. Our findings reveal a significant impact of YAP/TAZ activation on global transcription activity and have important implications for understanding YAP/TAZ function. PMID- 30523786 TI - Foxp1 Is Indispensable for Ductal Morphogenesis and Controls the Exit of Mammary Stem Cells from Quiescence. AB - Long-lived quiescent mammary stem cells (MaSCs) are presumed to coordinate the dramatic expansion of ductal epithelium that occurs through the different phases of postnatal development, but little is known about the molecular regulators that underpin their activation. We show that ablation of the transcription factor Foxp1 in the mammary gland profoundly impairs ductal morphogenesis, resulting in a rudimentary tree throughout life. Foxp1-deficient glands were highly enriched for quiescent Tspan8hi MaSCs, which failed to become activated even in competitive transplantation assays, thus highlighting a cell-intrinsic defect. Foxp1 deletion also resulted in aberrant expression of basal genes in luminal cells, inferring a role in cell-fate decisions. Notably, Foxp1 was uncovered as a direct repressor of Tspan8 in basal cells, and deletion of Tspan8 rescued the defects in ductal morphogenesis elicited by Foxp1 loss. Thus, a single transcriptional regulator Foxp1 can control the exit of MaSCs from dormancy to orchestrate differentiation and development. PMID- 30523787 TI - Improvement of the folliculogenesis by transplantation of bone marrow mesenchymal stromal cells in mice with induced polycystic ovary syndrome. AB - BACKGROUND: Many studies have reported that inflammation and oxidative stress are involved in the pathogenesis of polycystic ovary syndrome (PCOS). Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-oxidant and anti-inflammation properties. In this study, we investigate the beneficial effect of stem cell therapy on folliculogenesis in mice with induced PCOS METHODS: Mouse model of PCOS was performed through daily injection of testosterone enanthate (1 mg/100 g/body weight subcutaneous (s.c).) for a period of 5 weeks. Naval Medical Research Institute (NMRI) mice (21 days old) were divided into three groups: control, PCOS and PCOS + BM-MSCs. BM-MSCs were labeled with Hoechst 33342 (0.5 ug/mL) and then injected into the mice (106/animal, via the tail vein) at 1 and 14 days after PCOS confirmation. Mice were humanely killed at 2 weeks after last transplantation. Ovarian stereological studies were done. Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), testosterone, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha serum levels were measured. The levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) in serum were analyzed. Apoptotic index for ovarian follicles was assessed using Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). CD31 expression in ovarian vessels was assessed with the immunohistochemistry. RESULTS: There was a significant increase in the total volume of ovary, cortex, number of antral follicles, volume of oocyte and zona pellucida thickness, and there was a significant decrease in the primary and preantral follicles number in the PCOS + BM-MSCs group compared with the PCOS group. There was a significant increase in the serum level of FSH and TAC and a significant decrease in the serum level of testosterone, LH, MDA and percentage of TUNEL-positive apoptotic cells in the PCOS + BM-MSCs group in comparison with the PCOS group. DISCUSSION: BM-MSC transplantation improves folliculogenesis in mice with induced PCOS. BM MSC therapy can be an operative treatment for PCOS via anti-inflammatory, anti oxidant and anti-apoptotic properties. PMID- 30523788 TI - Bioactive factors secreted from mesenchymal stromal cells protect the intestines from experimental colitis in a three-dimensional culture. AB - BACKGROUND AIMS: Although mesenchymal stromal cells (MSCs) have shown therapeutic potential in intestinal tissue repair, controversy concerning their short survival and poor biodistribution in recipient tissues still remains. Therefore, we investigated the paracrine role of MSC in three-dimensional culture of colon with experimental colitis. METHODS: Colitis was induced in mice by oral administration of dextran sulfate sodium (DSS) for 7 days. Inflammatory responses were assessed on the basis of clinical signs, morphological, and histopathological parameters. On days 2 and 5, colonic explants were removed, and a three-dimensional culture was performed. The structural integrity of the intestinal mucosa was tested by treating the cultures with MSC or conditioned medium (CM) for 24 h, and then the colons were analyzed for histology/immunohistochemistry and interleukin (IL)-6 production. RESULTS: Histological analysis demonstrated that both MSC and CM treatment reduced colon damage in organ culture. An increase in cell proliferation (Ki-67 staining) was observed after CM treatment. Additionally, MSC treatment was able to reduce CD3+ cells. The therapeutic effect of MSC and CM was mediated by the downregulation of IL-6. DISCUSSION: The intestinal in vitro model has shown to be potentially useful for studying cellular interactions in a three-dimensional cell arrangement. Moreover, our results provide strong evidence that both MSC and CM treatments can alleviate colonic damage in organ culture. Importantly, these results suggest that MSC-secreted factors are able to protect the colon from inflammation caused by DSS-induced colitis independent of cell transplantation. PMID- 30523789 TI - Evaluation of the differentiation status of neural stem cells based on cell morphology and the expression of Notch and Sox2. AB - Neural stem cells (NSCs) isolated from a variety of sources are being developed as cellular therapies aimed at treating neurodegenerative diseases. During NSC culture and expansion it is important the cells do not differentiate prematurely because this may have an unfavorable effect on product quality and yield. In our study, we evaluated the use of Notch and Sox2 as markers for undifferentiated human and mouse NSCs. The expression of Notch2 and Sox2 during extensive-passage, low-oxygen culture and differentiation conditions were analyzed to confirm that the presence of these signature proteins directly correlates with the ability of NSCs to form new neurospheres and differentiate into multiple cell types. Using expression of Notch1, Notch2 and Sox2 as a reference, we then used flow cytometry to identify a specific morphological profile for undifferentiated murine and human NSCs. Our studies show that Notch and Sox2 expression, along with flow cytometry analysis, can be used to monitor the differentiation status of NSCs grown in culture for use in cellular therapies. PMID- 30523790 TI - How Structured Use Cases Can Drive the Adoption of Artificial Intelligence Tools in Clinical Practice. PMID- 30523793 TI - ASFA qualifications in apheresis. PMID- 30523796 TI - 57-Year-Old Man With Atypical Chest Pain. PMID- 30523794 TI - Different radiation techniques to deliver therapeutic dose to the axilla in patients with sentinel lymph node-positive breast cancer: Doses, techniques challenges and clinical considerations. AB - PURPOSE: To evaluate the coverage of different levels of axillary lymph nodes and organs at risk according to the field design of AMAROS study (levels I-II-III IV), breast tangents with supraclavicular and infraclavicular fields (levels II III-IV) and high tangent fields to the breast after breast-conserving surgery. MATERIALS AND METHODS: We delineated the axillary lymph nodes levels I-IV in 34 patients treated with breast-conserving surgery and sentinel lymph nodes biopsy. Field design according to AMAROS study - levels I-IV in patients without axillary dissection - as well as irradiation of levels II-IV used in N+ patients after axillary dissection, and also high tangent fields was simulated. Mean dose levels and volumes covered by 95% or 80% isodoses were evaluated. Doses to ipsilateral lung, heart and brachial plexus were compared. Paired t test was used. RESULTS: AMAROS study and levels II-IV plans delivered therapeutic dose to high axilla (levels II-IV), but the high tangent fields showed inefficacy to cover these volumes, P<0.001). In terms of organs at risk, especially, ipsilateral lung, AMAROS study plan was found to significantly increase the volume receiving at least 10Gy (I-IV:46.8%, II-IV: 39%), but also the volume receiving at least 20Gy (I-IV: 39.3%, II-IV: 31.3%), and V30Gy (I-IV: 34.2% vs II-IV: 26.1%), as well as the mean dose (I-IV: 18.6Gy, II-IV: 15.2Gy, P<0.001). CONCLUSIONS: The omission of axillary dissection and the axilla irradiation need is associated with high dose irradiation of the lungs, and with higher toxicity. The indication of axillary dissection or irradiation of low axilla could be individualized in relation with individual comorbidities and factors of risk. PMID- 30523795 TI - [Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: Case report of a complete pathological response and review of the literature]. AB - Patients with hepatocellular carcinoma who are on liver transplant waiting list usually require local treatment to limit any risk of tumour growth. Historically percutaneous radiofrequency ablation or transarterial chemoembolization represented the major therapeutic alternatives. Depending on the size, or the topography of the lesion these two techniques may not be feasible. Radiation therapy under stereotactic conditions has recently emerged in the management of localized hepatocellular carcinoma as an alternative to the focused therapies performed to date. We herein report the case of a 43-year-old patient harbouring a complete histological response on explant after liver stereotactic irradiation and discuss its role in the management of hepatocellular carcinoma before liver transplantation. PMID- 30523797 TI - Mid-term outcomes of mobile-bearing lateral unicompartmental knee arthroplasty. AB - BACKGROUND: This research was undertaken to evaluate Oxford Domed Lateral unicompartmental knee replacement (UKR) survival and clinical and radiological outcomes. The study also considered the influence of body mass index (BMI) on results and proposed contralateral healthy knee anatomic femorotibial angle (AFTA) as a predictor of postoperative knee alignment. METHODS: A retrospective evaluation of 41 primary Oxford Domed Lateral UKR performed in 41 patients in the same institution was undertaken on a patient group comprising of 10 men and 31 women with a mean age of 63 years (range: 38-81 years). A minimum follow-up of two years was required. RESULTS: The total revision rate was one out of 41 patients (2.4%), with a mean follow-up of 49 months (range: 25-84 months). One patient presented with a traumatic medial dislocation of the bearing after 15 months (resulting in an overall dislocation rate of 2.4%). The visual analogue scale (VAS) and the Oxford knee score (OKS) demonstrated significant postoperative improvement (P < 0.001). Survival at five years, with revision for any reason as the endpoint, was 97.5%. No significant correlation was observed between BMI and postoperative flexion angle, radiologically measured parameters, or pre- and postoperative VAS and OKS. Significant correlation was found (r = 0.77, P < 0.001) between postoperative and contralateral healthy knee anatomic femorotibial angles. CONCLUSIONS: The Oxford Domed Lateral UKR presents a low dislocation rate and excellent mid-term clinical and functional results. Contralateral healthy knee AFTA appears to be a predictor of postoperative knee alignment. PMID- 30523798 TI - Length of ICU Stay After Cardiac Surgery: Too Long or Too Short? PMID- 30523799 TI - Using Audience Response Systems for Real-Time Learning Assessments During Surgical Morbidity and Mortality Conference. AB - OBJECTIVE: Morbidity and mortality (M&M) conference is a mainstay of surgical education. However, its effectiveness is poorly described. The purpose of this study was to demonstrate the feasibility of a real-time audience response system for learner assessment during M&M. DESIGN: We integrated a web-based audience response system into weekly M&M conference. First, this platform collected qualitative responses about the role of M&M. Then, we used the platform to direct questions to attendees in real time. Questions focused on surgical risk estimation and classifying root causes. Responses were grouped by training and compared to a validated risk tool's prediction. Root cause assignment concordance was statistically compared using Cohen's kappa between the pluralities of faculty responses to that of trainees. SETTING: General surgical residency program based at a tertiary academic medical center. PARTICIPANTS: Affiliated categorical residents, preliminary residents, and clinical fellows. RESULTS: We enrolled 110 participants (38 faculty, 31 senior trainees, and 41 trainees). The majority of respondents (75.9%) cited education as the purpose of M&M, and all of respondents stated education as their personal motivation. Audience response questions were integrated into 34 unique case presentations. Mean absolute differences between predicted complication rates and attendees' predictions were highest for faculty (-9.4%, p = 0.009) and lowest for junior residents (-1.8%, p = 0.385). When assigning root cause of each morbidity, concordance between faculty and trainees was low to moderate (K = 0.41). CONCLUSIONS: Assessment of learning during M&M can be performed in real time with discrimination observed by learner experience level. These data support development of this response platform to trend learner performance over time and to monitor targeted educational interventions at future M&Ms. PMID- 30523800 TI - Distortions in the cubic primitive high-pressure phases of calcium. AB - The superconductivity in highly compressed calcium involves the occurrence of closely related low-symmetry structural patterns with exceptionally low coordination number. Earlier theoretical and experimental results are controversial and some findings are inconsistent with our later observations in the pressure range up to 60 GPa. This situation motivated the present concerted computational and experimental re-investigation of the structural arrangement of calcium slightly above the high-pressure limit of the bcc arrangement at low temperatures. We report here reproducible experimental evidence for a monoclinic distortion (mC4, space group (C2/c) of the calcium polymorph previously assigned to the tetragonal beta-Sn structure type. In accordance, the enthalpies calculated by electronic band structure calculations show the mC4 phase to be more stable than the undistorted beta-Sn type by about 100 meV in the entire phase space. The other low-temperature phase of calcium adopts space group Cmcm (oC4) rather than the earlier assigned Cmmm symmetry. These structural alterations substantially effect the density of states at the Fermi level and, thus, the electronic properties. PMID- 30523801 TI - Electronic structure of an Iron-Porphyrin derivative on Au(111). AB - Surface-bound porphyrins are promising candidates for molecular switches, electronics and spintronics. Here, we studied the structural and the electronic properties of Fe-tetra-pyridil-porphyrin adsorbed on Au(111) in the monolayer regime. We combined scanning tunneling microscopy/spectroscopy, ultraviolet photoemission, and two-photon photoemission to determine the energy levels of the frontier molecular orbitals. We also resolved an excitonic state with a binding energy of 420 meV, which allowed us to compare the electronic transport gap with the optical gap. PMID- 30523802 TI - A multichannel Au nanosensor for visual and pattern inspection of fatty acids. AB - Fatty acids (FAs) are important dietary sources of fuel for animals and structural components for cells. The number, position and configuration of olefins in the alkyl chains play important roles in the impacts of FAs on human health. Currently, structural profiling of FAs in edible oils and fats is an important issue in nutrition industries and food safety. Due to the lack of distinct functional groups, it is extremely difficult to discriminate FAs with structural difference by facile and in situ sensing methods. A few chemosensors have been developed for shape selective sensing of FAs, but their capability and performance were still limited. Herein, for the first time, we proposed a multichannel Au nanosensor for visual and pattern-generating inspection of FAs based on the highly selective binding ability of Ag+ to olefinic bonds and Ag+ regulable color variation of Au nanoparticles. As a result, the nanosensor showed good selectivity for five FAs with subtle structural difference as low as 5 nM. By further deriving three channel signals in respect of color and color depth, a signature-like signal pattern could be generated by principal component analysis for each FAs and even different FAs mixtures such as edible oils. Hence, structural variation of FAs in edible hot pot oils with heat treatment was successfully monitored by this Au nanosensor in time course. This sensor holds great promise in point-of-care inspection of edible oils and fats. PMID- 30523803 TI - First-principles investigation of the interface magnetic anisotropy of Fe/SrTiO3. AB - Interface effects in the magnetic nanostructures play a critical role in the magnetic properties. By using the first-principles density functional theory calculations, we investigate the electronic and magnetic properties of Fe/SrTiO3 interfaces, in which both the nonpolar surface SrTiO3(001) and the polar surface SrTiO3(110) are considered. A particular emphasis is placed on the magnetic anisotropy energy (MAE). Compare MAE of the Fe/SrTiO3 interfaces and the corresponding Fe monolayers, we find the Fe/SrTiO3(001) interface decreases MAE, while the Fe/SrTiO3(110) interface increases MAE. The interface orbital hybridization and orbital magnetic moments are detailly analyzed to understand the different interface magnetic anisotropy. Our investigation indicates that interface engineering can be an effective way to modulate the magnetic properties. PMID- 30523804 TI - One-step hydrothermal synthesis of fluorescence carbon quantum dots with high product yield and quantum yield. AB - A one-step hydrothermal synthesis of nitrogen and silicon co-doped fluorescence carbon quantum dots (N,Si-CQDs) from citric acid monohydrate and silane coupling agent KH-792 with high product yield (PY) of 52.56% and high quantum yield (QY) of 97.32% was developed. This greatly improves both PY and QY of CQDs and provides a new approach for a large-scale production of high-quality CQDs. Furthermore, N,Si-CQDs were employed as phosphors without dispersants to fabricate white light-emitting diodes (WLEDs) with the color coordinates at (0.29, 0.32). It is suggested that N,Si-CQDs have great potential as promising fluorescent materials to be applied in WLEDs. PMID- 30523805 TI - A mechanistic relative biological effectiveness model-based biological dose optimization for charged particle radiobiology studies. AB - In charged particle therapy, the objective is to exploit both the physical and radiobiological advantages of charged particles to improve the therapeutic index. Use of the beam scanning technique provides the flexibility to implement biological dose optimized intensity-modulated ion therapy (IMIT). An easy-to implement algorithm was developed in the current study to rapidly generate a uniform biological dose distribution, namely the product of physical dose and the relative biological effectiveness (RBE), within the target volume using scanned ion beams for charged particle radiobiological studies. Protons, helium ions and carbon ions were selected to demonstrate the feasibility and flexibility of our method. The general-purpose Monte Carlo simulation toolkit Geant4 was used for particle tracking and generation of physical and radiobiological data needed for later dose optimizations. The dose optimization algorithm was developed using the Python (version 3) programming language. A constant RBE-weighted dose (RWD) spread-out Bragg peak (SOBP) in a water phantom was selected as the desired target dose distribution to demonstrate the applicability of the optimization algorithm. The mechanistic repair-misrepair-fixation (RMF) model was incorporated into the Monte Carlo particle tracking to generate radiobiological parameters and was used to predict the RBE of cell survival in the iterative process of the biological dose optimization for the three selected ions. The post-optimization generated beam delivery strategy can be used in radiation biology experiments to obtain radiobiological data to further validate and improve the accuracy of the RBE model. This biological dose optimization algorithm developed for radiobiology studies could potentially be extended to implement biologically optimized IMIT plans for patients. PMID- 30523806 TI - Size and Shape Dependent Melting Temperature of Metallic Nanomaterials. AB - This study aims to characterize the size and shape dependent melting temperature of nanomaterials. Considering that surface atoms and interior atoms affect the melting of materials in different manners, thus we define an equivalent relationship between the contribution of surface atoms and interior atoms. Based on this definition, a criterion of melting is proposed through introducing a critical energy storage density of melting, the sum of the contribution of surface atoms and the interior atoms. According to the proposed criterion, a new theoretical model without any adjustable parameters is developed to characterize the size effect of melting temperatures of nanomaterials. The model predictions are in good agreement with the available experimental data or molecular dynamics simulations. This model uncovers the quantitative relationship between the melting temperature, size, atomic diameter and shape of nanomaterials. In addition, this model is extended to predict the size dependent glass transition temperatures of polymers. This study can help to better understand and characterize the size dependent melting temperatures of nanomaterials, as well as the size dependent glass transition temperatures of polymers. PMID- 30523807 TI - Neuromodulation by Combined Sensory and Motor Stimulation in the Peripheral Nerve: Tendon Organ Afferent Activity. AB - OBJECTIVE: Neuromuscular stimulation is a therapeutic approach to treat impairments such as stroke or pain, although the resulting inputs to the nervous system due to the stimulation are not well quantified. Stimulation activates both afferents and efferents, and the resulting neural activity is a mix of the effects of both: the changes in afferent activity due to efferent physiological actions plus the alterations due to afferent stimulation. This study quantitatively describes the resulting Golgi tendon organ Ib afferent activity in response to mixed afferent and efferent stimulation. APPROACH: Neural and stimulated action potentials interact by means of collision, neural resetting, and refractory block. We simulated the action potential patterns of Ib afferents in the human first dorsal interosseous during constant voluntary, stimulated, and combined contractions, varying both stimulation rate and location, and both with and without simultaneous Ib stimulation. MAIN RESULTS: Efferent stimulation affects the firing rate vs. force relationships of individual tendon organs, but the effects on the population mean are very small. In contrast, afferent stimulation changes the firing rate vs. force relationship of individual afferents by increasing the firing rate, decreasing the force resolution, broadening the distribution of action potential rates, and temporally phase locking a portion of the action potentials. Force resolution is retained in the population mean. The effects of afferent stimulation change with the stimulation rate and location, and with receptor firing rates. SIGNIFICANCE: This is the first quantitative description of the changes in afferent feedback during combined efferent and afferent nerve stimulation. The small effects of efferent stimulation on the population response implies that tendon organs could provide accurate force feedback during stimulated contractions. The effects of afferent stimulation can be altered by choice of stimulus rate and site and are generalizable to other afferents. . PMID- 30523808 TI - Kerma conversion factors for modern glass buildings in radioactively contaminated areas. AB - To improve the estimation of external gamma irradiation from deposited radioactivity in urban environments a model of a modern office or residential building with glass facades was set up with eleven different building heights. Kerma conversion factors for the floors inside the building from contamination on different types of surfaces were determined by using the Monte Carlo code MCNP6 for the primary gamma energies 0.3 MeV, 0.662 MeV and 3.0 MeV and for three different environmental scenarios. The kerma conversion factors were expressed as formulas for each possible deposition area for contaminants. The importance of the determined factors was shown by comparing them to previously generally used factors for multistorey house blocks. PMID- 30523809 TI - Artifacts in EEG of simultaneous EEG-fMRI: Pulse artifact remainders in the gradient artifact template are a source of artifact residuals after average artifact subtraction. AB - OBJECTIVE: The simultaneous application of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) opens up new ways to investigate the human brain. The EEG recordings of simultaneous EEG-fMRI, however, are overlaid to a great degree by fMRI related artifacts and an artifact reduction is mandatory before any EEG analysis. The most severe artifacts - the gradient artifact and the pulse artifact - are repetitive. Average artifact subtraction (AAS) technique exploits the repetitiveness and is presumably the most often used artifact reduction technique. In this method artifact templates are calculated by averaging over adjacent artifact epochs and subsequently the templates are subtracted to reduce the artifacts. Although the AAS technique is one of the best performing methods, artifact residuals are usually present in the resulting EEG after applying the AAS technique. This work aims at identifying sources of the artifact residuals. Approach: Application of the AAS technique to artificial EEG that is contaminated with artificial fMRI related artifacts. Main results: A new source of artifact residuals was identified. It was found that the AAS technique itself adds artifacts to the EEG during gradient artifact reduction, because the gradient artifact template is corrupted by pulse artifact remainders. Significance: This work shows that using a standard number of 25 epochs to calculate the gradient artifact template - as suggested by the inventors of AAS - results in substantial artifact residuals and consequently to a low EEG quality. Furthermore, the work discusses how potential solutions to this problem have serious side effects such as loss of adaptivity of the AAS technique. Hence, this problem must be considered carefully already in the design of simultaneous EEG-fMRI experiments. PMID- 30523810 TI - Inter-node superconductivity in strained Weyl semimetals. AB - The effects of a strain-induced pseudomagnetic field on inter-node spin-triplet superconducting states in Weyl semimetals are studied by using the quasiclassical Eilenberger formalism. It is found that the Cooper pairing with spins parallel to the pseudomagnetic field has the lowest energy among the spin-triplet states and its gap does not depend on the strength of the field. In such a state, both electric and chiral superconducting currents are absent. This is in contrast to the superconducting states with the spins of Cooper pairs normal to the field, which have a nonzero chiral current and are inhibited by the strain-induced pseudomagnetic field. The corresponding critical value of the field, which separates the normal and superconducting phases, is estimated. PMID- 30523811 TI - First-principles study of thermal expansion and thermomechanics of group-V monolayers: blue phosphorene, arsenene, and antimonene. AB - Using first-principles calculations based on quasiharmonic approximation, we systematically investigated the vibrational properties, thermal expansion and thermomechanics properties of three monoatomic group-V monolayers with honeycomb structure: blue phosphorene, arsenene and antimonene. It is found antimonene shows negative thermal expansion in the temperature range studied, while blue phosphorene and arsenene display small positive thermal expansion at high temperature. The physical mechanisms of their different thermal properties are explored. The results of Gruneisen theory are also exhibited for comparison, and the similarities and differences are studied. It is concluded the discrepancies arise from the high order anharmonicity of phonons. PMID- 30523812 TI - Anisotropic conductivity tensor by analyzing diffusion tensor for electrical brain stimulation (EBS). AB - Electrical brain stimulation (EBS) is a promising medical treatment method for brain neurological disorders through the direct or indirect excitation by injecting an electric current. At present, it is difficult to directly measure the distribution of the electric current delivered by electrodes inside tissues. By applying low-frequency ( < 1 kHz) external electrical brain stimulation (EBS), the low-frequency conductivity around the cells is uneven due to asymmetric cellular structures. We propose a method of electrical property imaging using the measured one component magnetic flux density by EBS and diffusion tensor imaging (DTI). The low-frequency electrical anisotropic conductivity tensor can be decomposed into the ion concentration and the mobility tensor of charge carriers. By analyzing the role of the diffusion tensor, we reconstruct the apparent anisotropic tensor by EBS using the $z$-component of measured magnetic flux density data and the estimated diffusion tensor. Using only the measured z component of magnetic flux density, the orthotropic conductivity tensor can be approximately recovered. The orthotropic conductvity tensor is not exact, but only reflects the extracellular space (ECS) effects. By comparing the components of orthotropic tensor and diffusion tensor, we stably determine a scale factor which primarily reflects the concentration of total ions in the extracellular space (ECS). Animal experiments verify that the proposed method recovers the anisotropic conductivity tensor which can visualize electrical properties during EBS of the brain. A direct reconstruction method for the apparent anisotropic conductivity tensor imaging during EBS was proposed to analyze unknown effects to brain tissue. PMID- 30523813 TI - Inter-subject analysis of transfer function coherence in studies of dynamic cerebral autoregulation. AB - OBJECTIVE: The gain and phase of the arterial blood pressure (BP)-cerebral blood flow velocity (CBFV) relationship, assessed by transfer function analysis (TFA), are widely used dynamic cerebral autoregulation (CA) metrics, but their reliability depend on the statistical significance of the magnitude squared coherence (MSC) function. We tested a new approach, based on inter-subject data, to estimate the confidence limits of MSC. Approach: Five minute beat-to-beat time series of mean arterial BP (MAP, Finometer) and CBFV (transcranial Doppler) were used for intra-subject (MAP and CBFV from same subject) and inter-subject (BP and CBFV swapped between subjects) estimates of MSC. The 95% confidence limit of MSC was obtained by non-parametric methods for the cases of single frequency harmonics in the range [0.02-0.50 Hz], and also from the mean value of all possible frequency intervals in this range. Main results: Intra-subject estimates of MSC were obtained from 100 healthy subjects (48 female, age range: 21-82 years old) allowing calculation of 9,900 inter-subject estimates, with 95% confidence limits in excellent agreement with classical values derived from surrogate random data. Confidence limits of MSC, derived from mean values, decreased asymptotically to around 0.16 with the increasing number of harmonics averaged. Significance: Replacing estimates of MSC at a single frequency harmonic by the mean calculated over the range [0.02-0.30 Hz] could lead to more robust studies of dynamic CA with greater acceptance of recordings, an important consideration in clinical studies where measurements tend to be more susceptible to noise and artefacts. . PMID- 30523814 TI - Engulfment control of platinum nanoparticles into oxidized silicon substrates for fabrication of dense solid-state nanopore arrays. AB - We found that platinum (Pt) nanoparticles, upon annealing at high temperature of 1000C, are engulfed into amorphous fused-silica or thermal oxide silicon substrates. The same phenomenon was previously published for gold (Au) nanoparticles. Similar to the Au nanoparticles, the engulfed Pt nanoparticles connect to the surface of the substrates through conical nanopores, and the size of the Pt nanoparticles decreases with increasing depth of the nanopores. We explain the phenomena as driven by the formation of platinum oxide by reaction of the platinum with atmospheric oxygen, with platinum oxide evaporating to the environment. We found that the use of Pt provides much better controllability than the use of Au. Due to the high vapor pressure of platinum oxide, the engulfment of the Pt nanoparticles into oxidized silicon (SiO2) substrates is faster than of Au nanoparticles. At high temperature annealing we also find that the aggregation of Pt nanoparticles on the substrate surface is insignificant. As a result, the Pt nanoparticles are uniformly engulfed into the substrates, leading to an opportunity for patterning dense nanopore arrays. Moreover, the use of oxidized Si substrates enables us to precisely control the depth of the nanopores since the engulfment of Pt nanoparticles stops at a short distance above the SiOx/Si interface. After subsequent etching steps, a membrane with dense nanopore through-holes with diameters down to sub-30 nm is obtained. With its simple operation and high controllability, this fabrication method provides an alternative for rapid patterning of dense arrays of solid-state nanopores at low-cost. PMID- 30523815 TI - Prediction of finger kinematics from discharge timings of motor units: implications for intuitive control of myoelectric prostheses. AB - Objective. The aim of the study was to characterize the accuracy in the identification of motor unit discharges during natural movements using high density electromyography (EMG) signals and to investigate their correlation with finger kinematics. Approach. High-density EMG signals of forearm muscles and finger joint angles were recorded concurrently during hand movements of 10 able-bodied subjects. EMG signals were decomposed into motor unit spike trains (MUSTs) with a blind-source separation method. The first principle component (FPC) of the low-pass filtered MUST was correlated with finger joint angles. Main results. On average, 25+/-5 motor units were identified during each individual finger task with an estimated decomposition accuracy > 85%. The FPC extracted from discharge rates was strongly associated to the joint angles (R = 0.79+/-0.11), and preceded the joint angles on average by 291+/-92 ms. Moreover, the FPC outperformed two time-domain features (the EMG envelop and the root mean square of EMG) in estimating joint angles. Significance. These results indicated the possibility of identifying individual motor unit behavior in dynamic natural contractions. Moreover, the strong association between motor unit discharge behaviors and kinematics proves the potential of the approach for the simultaneous and proportional control of prostheses. PMID- 30523816 TI - A feasibility study of spatiotemporally integrated radiotherapy using the LQ model. AB - Purpose: This paper investigates the feasibility of spatiotemporally modulated radiotherapy (STMRT) - integrated model with explicit constraints on the tumor dose heterogeneity. In particular, we demonstrate the effect of the tumor dose heterogeneity on the tumor biologically effective dose (BED) achievable and optimal fractionation. Methods: We propose an STMRT model that simultaneously optimizes the dose distributions and fractionation schedule for each individual case with the maximum and minimum constraints on the tumor BED to explicitly control the level of tumor dose heterogeneity. Sixteen thoracic phantom cases were planned using (1) STMRT and (2) standard fractionation (60 Gy in 30 fractions fixed) IMRT. Constraints on the organs-at-risk (OAR) BED were identical for both plans. BEDs were calculated using the alpha/beta ratio of 10 Gy for the tumor and 3 Gy for all OARs. The maximum tumor BED for STMRT plans was constrained to be less than 100-150% of the maximum tumor BED resulted from the standard fractionation plans. Results: The mean tumor BED from STMRT plans was up to 110.7, 128.3, 135.0, and148.0% of that from the standard fractionation plans when the maximum tumor BED was constrained to be less than 100, 120, 130, and 150% of the maximum BED achieved using the standard plans. The optimal number of fractions varied widely for different phantom geometries for the same radiobiological parameter values. The increase in the tumor BED and the range of optimal fractionation was larger with a larger tumor dose heterogeneity allowed. Conclusions: The results have shown the feasibility of personalizing fractionation schedule using an STMRT integrated model to deliver a maximum feasible BED to the tumor for a fixed OAR BED. The potential increase in the tumor BED was positively correlated to the tumor dose heterogeneity allowed. PMID- 30523817 TI - Electromagnetic tracking-based freehand 3D quasi-static elastography with 1D linear array: a phantom study. AB - Recent developments in hardware and scanning protocol have advanced conventional 2D quasi-static elastography to 3D level, which provides an intuitive visualization of lesions. A 2D linear array or scanning mechanism is typically required for 3D quasi-static elastography, requiring expensive and specifically designed hardware. In this study, we propose a novel method based on a commercial electromagnetic tracking system for freehand 3D quasi-static elastography with 1D linear array. Phantom experiments are preformed to validate the feasibility of the proposed method. During data acquisition, the probe contacts the surface of an elasticity phantom and moves in the elevational direction, while applying sinusoidal-like axial compression to the phantom. For each frame of ultrasound data, the 3D coordinates and orientations of the probe are obtained from an electromagnetic tracking system. A correlation-based algorithm is adopted to obtain a series of axial strain images. Volumetric strain data are reconstructed by using the recorded 3D coordinates and orientations of the probe corresponding to each strain image. The diameters of inclusions are then obtained from the slice plots of the volumetric strain data. The volumes of inclusions are estimated from the isosurface plots. The experimental result shows that the volume estimation of the inclusions has good accuracy with errors within 2%, while the diameters of the inclusions estimated from three orthogonal planes have larger errors up to 18%. In conclusion, the present framework would promise a reliable and effective solution for freehand 3D quasi-static elastography with 1D linear array. PMID- 30523818 TI - Suppression of wrinkle formation in graphene on Ir(111) by high-temperature, low energy ion irradiation. AB - Graphene on Ir(111) is irradiated with small fluences of 500?,eV He ions at temperatures close to its chemical vapor deposition growth temperature. The ion irradiation experiments explore whether it is possible to suppress the formation of wrinkles in Gr during growth. It is found that the release of thermal mismatch strain by wrinkle formation can be entirely suppressed for an irradiation temperature of $880^?circ$?,C. A model for the ion beam induced suppression of wrinkle formation in supported Gr is presented, and underpinned by experiments varying the irradiation temperature or involving intercalation subsequent to irradiation. PMID- 30523819 TI - Bag of deep features for preoperative prediction of sentinel lymph node metastasis in breast cancer. AB - Breast cancer is the most common female malignancy among women. Identifying sentinel lymph node (SLN) status is a crucial procedure for patients. However, the automated prediction of SLN status remains a challenging clinical task. In this paper, a novel structure is proposed, where an aggregation scheme of deep learning and bag-of-features (BOF) model is used for preoperative SLN metastasis prediction. A convolution neural network (CNN) is used for the extraction of deep features from the three 2D representative orthogonal views of a segmented 3D volume of interest, namely, axial, coronal, and sagittal image planes. Then, on the basis of the concatenation of three deep descriptors, a BOF model is conducted for encoding the three images to make features more compact and producing high-dimension sparse representation. In particular, a kernel fusion method that assembles all features is proposed for the construction of a discriminative support vector machine (SVM) classifier. The bag of deep feature model was experimented in the diffusion-weighted magnetic resonance imaging (DWI) database of 172 patients, including 74 SLN and 98 non-SLN. Result shows that the proposed method achieves significant outcome by testing AUC as high as 0.852 (95% confidence interval (CI): 0.716-0.988). The experimental results demonstrate that the proposed framework can potentially provide a noninvasive approach for automatically predicting SLN metastasis in patients with breast cancer. PMID- 30523820 TI - Improving gas sensing by CdTe decoration of individual aerographite microtubes. AB - Novel gas sensors have been realized by decorating clusters of tubular Aerographite with CdTe using magnetron sputtering techniques. Subsequently, individual microtubes were separated and electrically contacted on a SiO2/Si substrate with pre-patterned electrodes. Cathodoluminescence, electron microscopy and electrical characterization prove the successful formation of a polycrystalline CdTe thin film on Aerographite enabling an excellent gas response to ammonia. Furthermore, the dynamical response to ammonia exposure has been investigated, highlighting the quick response and recovery times of the sensor, which is highly beneficial for extremely short on/off cycles. Therefore, this gas sensor reveals a large potential for cheap, highly selective, reliable and low power gas sensors, which are especially important for hazardous gases such as ammonia. PMID- 30523821 TI - Laser-activated microparticles for multimodal imaging: ultrasound and photoacoustics. AB - The increasing personalization of medical treatment demands rened imaging and increased monitoring capabilities, as well as an improved efficacy through targeted drug delivery. Such a transition in health care can be facilitated by the use of multimodal contrast agents. In this paper, we present a novel type of multimodal contrast agents, that enhances contrast both in ultrasound and in photoacoustic imaging, while at the same time being capable of triggered drug delivery. Upon pulsed laser irradiation, polymeric microparticles - containing a dye and an oil core - can create a cavitation bubble that subsequently emits a strong acoustic wave. We investigated different formulations of these particles, by changing the oil content, dye concentration and probing conditions using a combination of pulsed laser excitation and an ultrasound chirp. We demonstrated that capsules with a core containing a low boiling point oil give the highest photoacoustic and acoustic response. The laser activation threshold for this system is high in the visible range, but within the near infrared medical limits. The same system also produces a stable bubble. US scattering by these stable bubbles results in medically relevant frequencies, making the particles of interest for biomedical and pre-clinical imaging. Finally, the system has potential to carry a functional drug-load, and a route to these applications is discussed. PMID- 30523822 TI - Pmma-XO (X=C, Si, Ge) monolayer as promising anchoring materials for lithium sulfur battery: a first-principles study. AB - Lithium-sulfur (Li-S) batteries hold a great promise for the next-generation Lithium-ion energy storage devices. A key issue in the Li-S batteries is, however, the dissolving and migrating of the soluble polysulfides during the charge and discharge processes and introducing anchoring materials in the batteries effectively prevent the problem and improve the cycling stability of the Li-S batteries. Herein, Pmma-XO (X=C, Si, Ge, Sn) monolayers are introduced as anchoring materials to confine the lithium polysulfides and their anchoring properties are studied with the density functional theory methods. Particularly, Pmma- SiO and GeO monolayers are studied for the first time, and our calculations show that these two materials are stable semiconductive monolayers with direct band-gaps and moderate binding with lithium polysulfides Li2Sn (n=8, 6, 4, 2 and 1). The Pmma- SiO and GeO trap Li2Sn species on their surfaces and keep them intact during the charge and discharge, and the adsorption of Li2Sn species leads to the enhanced conductivity of Pmma- SiO and GeO monolayers. Our study suggests that the Pmma- SiO and GeO monolayers are the promising anchoring materials for highly efficient Li-S batteries. PMID- 30523823 TI - Spike detection and spike sorting with a hidden Markov model improves offline decoding of motor cortical recordings. AB - Objective Detection and sorting (classification) of action potentials from extracellular recordings are two important pre-processing steps for brain computer interfaces (BCIs) and some neuroscientific studies. Traditional approaches perform these two steps serially, but using shapes of action potential waveforms during detection, i.e. combining the two steps, may lead to better performance, especially during high noise. We propose a hidden Markov model (HMM) based method for combined detecting and sorting of spikes, with the aim of improving the final decoding accuracy of BCIs. Approach The states of the HMM indicate whether there is a spike, what unit a spike belongs to, and the time course within a waveform. The HMM outputs probabilities of spike detection, and from this we can calculate expectations of spike counts in time bins, which can replace integer spike counts as input to BCI decoders. We evaluate the HMM method on simulated spiking data. We then examine the impact of using this method on decoding real neural data recorded from primary motor cortex of two Rhesus monkeys. Main results Our comparisons on simulated data to detection then-sorting approaches and combined detection-and-sorting algorithms indicate that the HMM method performs more accurately at detection and sorting (0.93 vs. 0.73 spike count correlation, 0.73 vs. 0.49 adjusted mutual information). On real neural data, the HMM method led to higher adjusted mutual information between spike counts and kinematics (monkey K: 0.034 vs. 0.027; monkey M: 0.033 vs. 0.022) and better neuron encoding model predictions (K: 0.016 dB improvement; M: 0.056 dB improvement). Lastly, the HMM method facilitated higher offline decoding accuracy (Kalman filter, K: 8.5% mean squared error reduction, M: 18.6% reduction). Significance The HMM spike detection and sorting method offers a new approach to spike pre-processing for BCIs and neuroscientific studies. . PMID- 30523824 TI - Filtration performance of novel microfibrous media embedded with nanofiber flocs for aerosol particle removal. AB - Ingestion and accumulation of sea salt and other impurities is a major challenge for high speed vessels, turbine engines, and other air breathing systems. The performance and reliability of filters are anticipated to be improved significantly after the rate of performance degradation is reduced via enhanced filtration media and well-designed filtration approaches. This study proposes to apply anionic surfactant to disperse the nanofibers thoroughly and employ cationic surfactant to flocculate the dispersed nanofibers into numerous small groups of nanofiber flocs. Using the wet-lay procedure in the lab, the novel porous microfiber media was then fabricated with small groups of nanofiber flocs together with activated carbon and polyester fibers. The unique nanofiber filter media was then evaluated for filtration performance using face velocity, pressure drop, and filtration efficiency parameters. Due to nanoflocced fiber inclusion, an anomalous region in the filtration efficiency versus pressure drop regime was observed where wall slip occurring at the nanostructured surface provided an unusually high level of filtration efficiency near the most penetrating particle size region of 0.1 to 0.4 um with a concomitant reduction in the normally encountered levels of pressure drop. This anomalous increase in the filtration efficiency versus pressure drop is a novel phenomenon and it is highly beneficial to aerosol filtration. The enhanced filtration reveals that the quality factor near the most penetrating particle size region increases significantly due to the inclusion of nanofiber flocs. The unique porous filtration media is expected to increase the dirt holding capacity and prolong the lifecycle of the turbine air filter systems. PMID- 30523825 TI - Hemocompatibility improvement of decellularized spleen matrix for constructing transplantable bioartificial liver. AB - Thrombogenicity is the predominant obstacle to successful implantation of decellularized spleen matrix (DSM). The aim of this study was to construct a transplantable functional bioartificial liver (BAL) with the use of DSM. This was achieved by layer-by-layer (LbL) electrostatic immobilization technique by using poly dimethyl diallyl ammonium chloride (PDADMAC) and heparin. After heparin immobilization, DSM gradually turned from translucent into completely opaque milky white. Toluidine blue staining showed strong positive staining of the entire coated DSM. In vitro diluted blood perfusion test showed that the splenic arterial pressure of the heparin-coated DSM was much lower than that of the non coated DSM. Then, we heterotopically transplanted the modified DSM into rat hepatic injury model for 6 h to evaluate the hemocompatibility in vivo. Overall, HE staining and vWF immunohistochemistry all confirmed that heparin-coated DSM has a satisfactory anticoagulant effect. Based on the heparin-coated DSM, BALs were built with the use of rat primary hepatocytes. Our results demonstrate that these heparin-coated BALs satisfied anticoagulant effects even after 6 hours. Immunofluorescence of ALB and G6PC also showed that hepatocytes in heparin-coated BAL have better cell viability and function than the non-coated group. However, serum analysis did not indicate a significant difference between the two groups but a slight trend of improvement with respect to serum albumin (ALB) and aspartate transaminase (ALT). In conclusion, we demonstrated that the BAL constructed by heparin-coated DSM can exert satisfactory short-term anticoagulant effects and can compensate for a certain degree of liver function. PMID- 30523826 TI - Zero energy states oriented tunability of spin polarization in zigzag-edged bowtie-shaped graphene nanoflake by electric field. AB - A comprehensive first-principles study of the correlation between the zero energy states and the tunability of the spin-selective semiconducting properties of zigzag-edged bowtie-shaped graphene nanoflakes (ZBGNFs) under electric field is presented for the first time. We demonstrate that the spin degenerate semiconducting ground state can be lifted by electric field. In particular, we find that the nullity defined by structural configuration determines the complexity and efficiency of the tunability of spin polarization. In origin, fine tuning spin dependent properties by electric field is the manipulation on spin polarized molecular orbitals energies. We expect this study to help design low dimensional molecular spintronics more effectively and controllably. PMID- 30523827 TI - Real-time gait event detection in a real-world environment using a laser-ranging sensor and gyroscope fusion method. AB - OBJECTIVE: Wearable gait event detection (GED) techniques have great potential for clinical applications by aiding the rehabilitation of individuals in their daily living environment. Unlike previous wearable GED techniques, which have been proposed for offline detection or laboratory settings, we aimed to develop a real-time GED system adapted for utilization in the daily living environment. Approach: This study presents a novel GED system in which foot clearance and sagittal angular velocity were incorporated to realize real-time GED in a real-world environment. The accuracy and robustness of the proposed system were validated in a real-world scenario that consisted of complex ground surfaces, i.e., varying inclinations. Forty-three subjects (23 to 83 years) were included in this study, and a total of 8866 gait cycles were recorded for analysis. Main results: The proposed system demonstrated consistently high performance in detecting toe off (TO) and heel strike (HS) events in indoor and outdoor walking data which was supported by high performance scores. The detection accuracy of the walking data reached 2.59+/-13.26 ms (indoor) and 3.31+/-14.78 ms (outdoor) for TO events, 3.36+/-15.92 ms (indoor) and 3.77+/ 16.99 ms (outdoor) for HS events. The proposed system showed better performance in detection precision than state-of-the-art real-time GED methods. Significance: The proposed system will benefit the development of long-term analysis and intervention techniques for use in clinics and daily living environments. PMID- 30523828 TI - Chronic intracochlear electrical stimulation at high charge densities results in platinum dissolution but not neural loss or functional changes in vivo. AB - OBJECTIVE: Although there are useful guidelines defining the boundary between damaging and non-damaging electrical stimulation they were derived from acute studies using large surface area electrodes in direct contact with cortical neurons. These parameters are a small subset of the parameters used by neural stimulators. More recently, histological examination of cochleae from patients that were long-term cochlear implant users have shown evidence of particulate platinum (Pt). The pathophysiological effect of Pt within the cochlea is unknown. We examined the response of the cochlea to stimulus levels beyond those regarded as safe, and to evaluate the pathophysiological response of the cochlea following chronic stimulation at charge densities designed to induce Pt corrosion. APPROACH: 19 guinea pigs were systemically deafened and implanted with a cochlear electrode array containing eight Pt electrodes of 0.05 0.075 or 0.2 mm2 area. Animals were electrically stimulated continuously for 28 days using charge balanced current pulses at charge densities of 400, 267 or 100 MUC/cm2/phase. Electrically-evoked auditory brainstem responses (EABRs) were recorded to monitor neural function. On completion of stimulation electrodes were examined using scanning electron microscopy (SEM) and cochleae examined histology. Finally, analysis of Pt was measured using Energy Dispersive X-ray Spectroscopy (EDS) and inductively coupled plasma mass spectrometry (ICP-MS). MAIN RESULTS: Compared with unstimulated control electrodes and electrodes stimulated at 100 MUC/cm2/phase, stimulation at 267 or 400 MUC/cm2/phase resulted in significant Pt corrosion. Cochleae stimulated at these high charge densities contained particulate Pt. The extent of the foreign body response depended on the level of stimulation; cochleae stimulated at 267 or 400 MUC/cm2/phase exhibited an extensive tissue response that included a focal region of necrosis close to the electrode. Despite chronic stimulation at high charge densities there was no loss of auditory neurons (ANs) in stimulated cochleae compared with their contralateral controls. Indeed, we report a statistically significant increase in AN density proximal to electrodes stimulated at 267 or 400 MUC/cm2/phase. Finally, there was no evidence of a reduction in AN function associated with chronic stimulation at 100, 267 or 400 MUC/cm2/phase as evidenced by stable EABR thresholds over the stimulation program. SIGNIFICANCE: Chronic electrical stimulation of Pt electrodes at 267 or 400 MUC/cm2/phase evoked a vigorous tissue response and produced Pt corrosion products that were located close to the electrode. Despite these changes at the electrode/tissue interface there was no evidence of neural loss or a reduction in neural function. PMID- 30523829 TI - Flexibility defines structure in crystals of amphiphilic DNA nanostars. AB - DNA nanostructures with programmable shape and interactions can be used as building blocks for the self-assembly of crystalline materials with prescribed nanoscale features, holding a vast technological potential. Structural rigidity and bond directionality have been recognised as key design features for DNA motifs to sustain long-range order in 3D, but the practical challenges associated with prescribing building-block geometry with sufficient accuracy have limited the variety of available designs. We have recently introduced a novel platform for the one-pot preparation of crystalline DNA frameworks supported by a combination of Watson-Crick base pairing and hydrophobic forces [Nano Lett., 17(5):3276-3281, 2017]. Here we use small angle X-ray scattering and coarse grained molecular simulations to demonstrate that, as opposed to available all DNA approaches, amphiphilic motifs do not rely on structural rigidity to support long-range order. Instead, the flexibility of amphiphilic DNA building-blocks is a crucial feature for successful crystallisation. PMID- 30523830 TI - PDE-constrained LDDMM via geodesic shooting and inexact Gauss-Newton-Krylov optimization using the incremental adjoint Jacobi equations. AB - The class of non-rigid registration methods proposed in the framework of PDE constrained Large Deformation Diffeomorphic Metric Mapping is a particularly interesting family of physically meaningful diffeomorphic registration methods. Inexact Gauss-Newton-Krylov optimization has shown an excellent numerical accuracy and an extraordinarily fast convergence rate in this framework. However, the Galerkin representation of the non stationary velocity fields does not provide proper geodesic paths. In this work, we propose a method for PDE-constrained LDDMM parameterized in the space of initial velocity fields under the EPDiff equation. The derivation of the gradient and the Hessian-vector products are performed on the final velocity field and transported backward using the adjoint and the incremental adjoint Jacobi equations. This way, we avoid the complex dependence on the initial velocity field in the computations. We also avoid the computation of the adjoint equation and its incremental counterpart that has been recently identified as a subtle problem in PDE-constrained LDDMM. The proposed method provides geodesics in the framework of PDE-constrained LDDMM, and it shows performance competing with benchmark PDE-constrained LDDMM and EPDiff-LDDMM methods. PMID- 30523831 TI - Single-channel UV/Vis dual-band detection with ZnCdS:Mn/ZnS core/shell quantum dots. AB - In an ultraviolet detection system, the Si-based photodetector could be sensitized with some kinds of fluorescent materials to enhance its response in the short-wavelength range. Thick-shell ZnCdS:Mn/ZnS core/shell quantum dots (QDs) exhibit unique advantage in UV signal sensitization due to their long PL lifetime, as well as stable emission matched with CCD's response. Herein, a single-channel UV panoramic detection system based on these Mn-doped QDs has been proposed. The QDs film was attached onto a Si-based CCD versus a tapered fiber, and an optical chopper was mounted before the QDs film. The long-lifetime fluorescence originating from UV signal could be still collected by the CCD when the chopper is in the "off" state, so the UV/Vis signal ratio is significantly enhanced. PMID- 30523832 TI - Magnetic impurity resonance states for different pairing symmetries in twisted bilayer graphene. AB - In this work, we study the magnetic impurity resonance states in the superconducting phase of 'magic' angle twisted bilayer graphene for different pairing symmetries. Using a two-orbital model on the emergent honeycomb lattice, we find that the resonance states are dramatically different for s-wave pairing and topological nontrivial pairings. When the magnetic impurity is located at one site of the emergent honeycomb lattice, i.e., the center of the AB spot of the moire pattern, the spacial distributions of the resonance states will break both the threefold and twofold rotation symmetries of D3 point group for pairing symmetries which belong to the irreducible representations of this point group. When the magnetic impurity is located at the center of the emergent honeycomb lattice i.e., the center of the AA spot of the moire pattern, the appearance of resonance peak at the position close to the impurity can be considered as a strong evidence of non-s-wave pairing. PMID- 30523833 TI - Multiscale Modeling and Decoding Algorithms for Spike-Field Activity. AB - OBJECTIVE: Behavior is encoded across multiple spatiotemporal scales of brain activity. Modern technology can simultaneously record various scales, from spiking of individual neurons to large neural populations measured with field activity. This capability necessitates developing multiscale modeling and decoding algorithms for spike-field activity, which is challenging because of the fundamental differences in statistical characteristics and time-scales of these signals. Spikes are binary-valued with a millisecond time-scale while fields are continuous-valued with slower time-scales. APPROACH: We develop a multiscale encoding model, adaptive learning algorithm, and decoder that explicitly incorporate the different statistical profiles and time-scales of spikes and fields. The multiscale model consists of combined point process and Gaussian process likelihood functions. The multiscale filter (MSF) for decoding runs at the millisecond time-scale of spikes while adding information from fields at their slower time-scales. The adaptive algorithm learns all spike-field multiscale model parameters simultaneously, in real time, and at their different time-scales. MAIN RESULTS: We validated the multiscale framework within motor tasks using both closed-loop brain-machine interface (BMI) simulations and non human primate (NHP) spike and local field potential (LFP) motor cortical activity during a naturalistic 3D reach task. Our closed-loop simulations show that MSF can add information across scales and that adaptive MSF can accurately learn all parameters in real time. We also decoded the 7 joint angular trajectories of the NHP arm using spike-LFP activity. These data showed that MSF outperformed single scale decoding, this improvement was due to addition of information across scales rather than dominance of one scale and was largest in the low-information regime, and the improvement was similar regardless of the degree of overlap between spike and LFP channels. SIGNIFICANCE: This multiscale framework provides a tool to study encoding across scales and may help enhance future neurotechnologies such as motor BMIs. PMID- 30523834 TI - Achieving short high-quality gate-all-around structures for horizontal nanowire field-effect transistors. AB - We introduce a fabrication method for gate-all-around nanowire field-effect transistors. Single nanowires were aligned perpendicular to underlying bottom gates using a resist-trench alignment technique. Top gates were then defined aligned to the bottom gates to form gate-all-around structures. This approach overcomes significant limitations in minimal obtainable gate length and gate length control in previous horizontal wrap-gated nanowire transistors that arise because the gate is defined by wet etching. In the method presented here gate length control is limited by the resolution of the electron-beam-lithography process. We demonstrate the versatility of our approach by fabricating a device with an independent bottom gate, top gate, and gate-all-around structure as well as a device with three independent gate-all-around structures with 300 nm, 200 nm, and 150 nm gate length. Our method enables us to achieve subthreshold swings as low as 38 mV/dec at 77 K for a 150 nm gate length. PMID- 30523835 TI - Hybridization of unoccupied molecular orbital with image potential state at Lead Phthalocyanine/Graphite interface. AB - The interaction of a molecular orbital with a surface state is important to understand the spatial distribution of the wave function at the molecule/substrate interface. In this study, we focus on hybridization of an unoccupied state of lead phthalocyanine (PbPc) with the image potential state (IPS) on a graphite surface. The hybridization modifies the energy-momentum dispersions of the IPS on PbPc films as observed by angle-resolved two-photon photoemission (AR2PPE). On the PbPc 1 monolayer (ML) film, the IPS band forms a band gap and back-folding appears at the first Brillouin zone boundary due to the periodic potential by the adsorbate lattice. The modification of the dispersion is accompanied by the intensity enhancement of the IPS. We attributed the origin of the modified dispersion and intensity enhancement to a hybridization of the IPS with a molecule-derived unoccupied level. From the photon energy-dependent measurement on multilayer films, we have found the diffuse unoccupied molecular level in the vicinity of the IPS. The tail part of the IPS wave function in the substrate is enhanced by the hybridization with the unoccupied state, and thus strengthens the transition from the occupied substrate band to the hybridized IPS. PMID- 30523836 TI - Fetal ECG extraction from time-varying and low-rank noninvasive maternal abdominal recordings. AB - OBJECTIVE: Noninvasive fetal electrocardiography is emerging as a low-cost and high-accuracy technology for fetal cardiac monitoring. Signal processing techniques have been used over the past fifty years in this domain. The current major challenges of this domain, addressed in this study are: 1) fetal electrocardiogram (fECG) extraction from few numbers of maternal abdominal channels in low signal-to-noise ratios; 2) online fECG extraction; 3) automatic and online signal quality assessment and channel selection; 4) accurate and robust fetal R-peak detection and ECG parameter extraction. Approach: Based on the theory of cyclostationarity, auxiliary maternal ECG channel(s) are synthetically constructed and augmented with the input channels. The augmented data are used to develop a robust multichannel source separation algorithm for online/offline fECG extraction, from as few as a single channel, and an accurate fetal R-peak detector using a two-pass matched filter. Several robust signal quality indexes (SQI) and a voting strategy are also proposed for automatic fetal signal quality assessment. Main results: It is shown that the fECG and the fetal R-peaks can be accurately extracted from standard online available datasets, for which classical source separation methods (requiring many channels) had previously failed. The signal quality indexes fully automate the extraction and channel selection procedure. Finally, the proposed R-peak detector is highly robust to background noise and residual maternal R-peak components. Significance: The proposed methods for fECG extraction, R-peak detection and automatic channel selection are evaluated (visually and numerically), on two online available datasets and compared with recently developed algorithms. The proposed algorithm is statistically shown to outperform the benchmarks in terms of average and standard deviation. . PMID- 30523837 TI - A novel route to the formation of 3D nanoflowers like hierarchical iron-oxide nanostructure. AB - The present work reports the formation of three-dimensional (3D) nanoflowers like morphology of iron-alkoxide via anodization of Fe-sheet in ethylene glycol (EG) electrolyte. XRD, FESEM, EDX, XPS, Raman and FTIR are applied to characterize the samples. SEM results show that the as-anodized sample is composed of 3D nanoflowers with hierarchical nanosheets beneath it. Average width of the nanoflower petal is ~ 25 nm and length is about 1 um. The 3D nanoflowers is transformed into spherical nanoparticles (NPs) with uniform size when calcined at elevated temperature. XRD and Raman results indicate that the 3D nanoflowers consist of akaganeite which transforms into magnetite and hematite by annealing. XPS and FTIR results confirm that the nanoflowers contain significant amount of F, C and OH, which are drastically decreased after annealing. The formation of 3D nanoflowers like morphology can be attributed to EG. A possible formation mechanism of 3D nanoflowers and their transformation into NPs is proposed. We show that morphology of the as-anodized iron-oxide can be tailored simply by changing the electrolyte. Anodization of Fe-sheet in glycerol based electrolyte under identical conditions produced nanotubes. PMID- 30523838 TI - Mechanisms of Friction Reduction of Nanoscale Sliding Contacts Achieved Through Ultrasonic Excitation. AB - Friction reduction is an important issue for proper functioning of nano-/micro electromechanical systems (N-/MEMS) due to their large surface to volume ratios and the inability of traditional liquid lubricants to effectively lubricate sliding contacts. One efficient technique to achieve substantially lowered friction at nanoscale, as well as superlubricity in some instances, was investigated with the coupling of ultrasonic actuation of the sliding contact in an atomic force microscope (AFM). Despite the successful application of ultrasonic AFM methods in achieving mechanical property measurements and nanoscale subsurface imaging of soft and hard materials, the mechanism of friction reduction in the microscopic contact and the influence of the ultrasonic parameters on friction reduction are still elusive. In this study, the effects of excitation amplitude, applied normal force, tip radius, and humidity on friction have been investigated in detail. Ultrasonic force microscopy (UFM) results are compared against those collected with conventional contact-AFM (C-AFM) and indicate that a reduction in the adhesive interaction between the tip and sample, as well as a reduction in the shear strength can explain the mechanisms of the friction reduction in UFM method. This study opens up a new door for the control of friction and wear, which is critical for the increased lifetime of AFM probes, N-/MEMS devices and would potentially bridge the gap between nanotribology and other fields, such as nanomachining, nanolithography and biomaterials imaging. PMID- 30523839 TI - Closed-loop cortical control of virtual reach and posture using cartesian and joint velocity commands. AB - OBJECTIVE: Brain-computer interfaces (BCIs) are a promising technology for the restoration of function to people with paralysis, especially for controlling coordinated reaching. Typical BCI studies decode Cartesian endpoint velocities as commands, but human arm movements might be better controlled in a joint-based coordinate frame, which may match underlying movement encoding in the motor cortex. A better understanding of BCI controlled reaching by people with paralysis may lead to performance improvements in brain-controlled assistive devices. Approach. Two intracortical BCI participants in the BrainGate2 pilot clinical trial performed a 3D endpoint virtual reaching task using two decoders: Cartesian and joint velocity. Task performance metrics (i.e. success rate and path efficiency) and single feature and population tuning were compared across the two decoder conditions. The participants also demonstrated the first BCI control of a fourth dimension of reaching, the arm's swivel angle, in a 4D posture matching task. Main Results. Both users achieved significantly higher success rates using Cartesian control, and joint controlled trajectories were more variable and significantly more curved. Neural tuning analyses showed that most single feature activity was best described by a Cartesian kinematic encoding model, and population analyses revealed only slight differences in aggregate activity between the decoder conditions. Simulations of a BCI user reproduced trajectory features seen during closed-loop joint control when assuming only Cartesian-tuned features passed through a joint decoder. With minimal training, both participants controlled the virtual arm's swivel angle to complete a 4D posture matching task, and achieved significantly higher success using a Cartesian+swivel decoder compared to a joint velocity decoder. Significance. These results suggest that Cartesian command interfaces may provide better BCI control of arm movements than other kinematic variables, even in 4D posture tasks with swivel angle targets. PMID- 30523840 TI - Transport characteristics and dwell time in bilayer Phosphorene barrier. AB - In this paper, transport properties, dwell time and electron conductance were theoretically investigated through a rectangular electrostatic potential barrier in bilayer phosphorene and compared the results with monolayer phosphorene and graphene. It has been shown that in bilayer phosphorene, in the presence of an interlayer induced bias, a four-band approximation describes transport process in the system. The results show that interlayer bias parameter drastically affect transport properties. These effects are including: (1) appearance of eight transmission and reflection coefficients from a band within the same band and between the two bands (2) appearing the anti-Klein tunnelling phenomenon and tuning the bias of system in such a way which is observed in specified biases and removed in other biases (3) tuning conductance of the system. Results of dwell time in bilayer phosphorene show that, this parameter in terms of barrier thickness has not a strictly ascending behaviour and in limited range of incident energies (incident angles), the dwell time in barrier reduces significantly which can be exploit in designing switching devices in nano-electronic. We found that increasing the interlayer bias decreases the intrinsic gap of the bilayer phosphorene where enable us to control the electron transmission rate in the system. In addition, our findings also demonstrate that by tuning the interlayer bias, a large electrical conductance can be achieved which can be used in semiconductor technology. Our study could serve as a basis for investigations of the basic physics of tunnelling mechanisms and using bilayer phosphorene as a proper candidate in low dimensional semiconductor industry. PMID- 30523841 TI - An Improved Strategy for Transferring and Adhering Thin Nanoporous Alumina Membrane onto Conducting Transparent Electrodes for Template Assisted Electrodeposition of High Aspect-Ratio Semiconductor Nanowires with Increased Optical Absorption. AB - This article presents a new method for transferring and enhancing the adhesion of thin nanoporous alumina (NPA) membranes onto non-atomically flat substrates like Fluorine doped Tin Oxide (FTO) coated glass. The study reports use of Glycerol as an additive to reduce the brittleness of the Polystyrene filler that was used to fill the pores of the NPA membrane. Besides, a new refluxing based method is reported here for complete removal of the Polystryrene filler from the porous channels of Alumina. The adhesion between NPA membrane and an underlying electrode was enhanced by electrodepositing a thin (~ 40 nm) intermediate layer of conducting polymer Polyaniline (PANI). The PANI layer acts as an efficient electrostatic adhesive between the NPA and the conducting glass electrode and ensured ultra-strong adhesion of NPA membrane that survived the harsh conditions of CdTe nanowire electrodeposition (60 degrees C temperature and acidic electrolyte) without delamination for 30 min. The resulting nanowires clearly templated the structure of NPA and displayed free-standing nanowires over a large area with diameter of around 60 nm and length approximately 2.8 um (aspect ratio ~ 47) and an areal density of 5.9 * 1012 nanowires/cm2. Total optical absorption measurement on the free-standing CdTe nanowires exhibited an enhancement by 45% over a wavelength range of 350 nm to 1400 nm as compared to CdTe planar thin film of same thickness. PMID- 30523842 TI - Emergence of topological phases by stacking of two-dimensional lattices with nonsymmorphic symmetry. AB - Topological semimetals have a variety of phases, whose Fermi surfaces can be nodal points, nodal lines and nodal loops. Here we construct four classes of 3D minimal models via vertically stacking a 2D nonsymmorphic lattice with and without breaking crystalline symmetries. As a result, four distinct topological phases can be generated in our minimal model, such as Dirac nodal line semimetals, Weyl nodal line semimetals, unconventional Weyl semimetals with topological charge C = 2, and weak topological insulators. Unexpectedly, Weyl nodal loops are generated without mirror symmetry protection, where nontrivial "drumhead" surface states emerge within the loops. PMID- 30523843 TI - Network physiology of "fight or flight" response in facial superficial blood vessels. AB - We introduced a novel framework to identify the dynamic pattern of blood flow changes in the cutaneous superficial blood vessels of the face for "fight or flight" responses through facial thermal imaging. For this purpose, a thermal data set was collected from 32 subjects in a mock crime scenario. Five facial areas including periorbital, forehead, perinasal, cheek and chin were selected on the face. Due to the cause and effect movement of blood in the facial cutaneous vasculature, the effective connectivity approach and graph analysis were used to extract causality features. The effective connectivity was quantified using a modified version of the multivariate Granger causality method among each pair of facial Region of Interests (ROIs). Validation was performed using statistical analysis, and the results demonstrated that the proposed method was statistically significant in detecting the physiological pattern of deceptive anxiety on the face. Moreover, the obtained graph is visualized by different schemes to show these interactions more effectively. We used machine learning techniques to classify our data based on the Granger causality values that result in more than 87% accuracy rate in discriminating between deceptive and truthful subjects. PMID- 30523844 TI - Structural, elastic and vibrational properties of celestite, SrSO4, from synchrotron X-ray diffraction, thermal diffuse scattering and Raman scattering. AB - In order to resolve inconsistencies encountered in published data for SrSO4 , the elasticity and the phase stability of celestite has been studied using thermal diffuse scattering, high pressure powder synchrotron X-ray diffraction, Raman scattering and DFT calculations. The structure of SrSO4 is found to be stable up to 62 GPa at ambient temperature. The preferred values for the components of the elastic stiffness tensor have been determined using X-ray thermal diffuse scattering and are (in GPa): c11 = 105, c22 = 92, c33 = 114, c44 = 16, c55 = 31, c66 = 26, c12 = 40, c13 = 52, c23 = 37. The preferred value for the bulk modulus is K=62(2) GPa. This work shows that thermal diffuse scattering collected at two temperatures allows for determination of the full elastic tensor of crystals with low space group symmetry. PMID- 30523845 TI - Tuning the size, composition and structure of Au and Co50Au50 nanoparticles by high-power impulse magnetron sputtering in gas-phase synthesis. AB - Gas phase synthesis of nanoparticles with different structural and chemical distribution is reported using a circular magnetron sputtering in an Ion Cluster Source by applying High-Power impulses (HIPIMS). The influence of the pulse characteristics on the final deposit was evaluated on Au nanoparticles. The results have been compared with the more common direct current (DC) approach. In addition, it is shown for the first time that High-Power impulses in magnetron based gas aggregation sources allows the growth of binary nanoparticles, CoAu in this case, with a variety of crystalline and chemical arrangements which are analyzed at the atomic level. PMID- 30523846 TI - New strategy to obtain high surface area anatase nanotube/AuNP photocatalyst. AB - Anatase nanotubes with high surface area (ca. 350 m2*g-1), containing gold nanoparticles, were successfully obtained from trititanate nanotubes, prepared by a template-free hydrothermal method, and calcined at 450 degrees C. The high surface area and tubular morphology were attained due to the presence of ionic silsesquioxane, which acts as anti-sintering agent for titania during calcination process, by forming a thin silica coating between anatase nanotubes. Additionally, the ionic silsesquioxane also acts as stabilizing and adhesion agent for gold nanoparticles on the surface of anatase nanotubes. The influence of the ionic silsesquioxane on the morphological and textural properties of anatase nanotubes was studied in three different moments during the synthesis: before, after and before/after nanotubes were rolled up. The photocatalytic activity of the nanotube samples was evaluated by hydrogen generation showing remarkable enhancement in hydrogen production and stability of catalyst when compare with the bare anatase sample and commercial P-25. PMID- 30523847 TI - Fabrication of perfusable 3D hepatic lobule-like constructs through assembly of multiple cell type laden hydrogel microstructures. AB - The in vitro reproduction of three-dimensional (3D) cellular construct to physiologically mimic human liver is highly desired for drug screening and clinical research. However, the fabrication of liver-mimetic 3D model using traditional bottom-up technologies is challenging owing to the complex architecture and specific functions of real liver tissue. This work proposes a versatile strategy for spatially assembling gear-like microstructures encapsulating multiple cell types, and reorganizing them into 3D lobule-like micro-architecture with physiological relevance to native liver tissue. Gear-like microstructures were fabricated by photo-crosslinking poly(ethylene glycol) diacrylate (PEGDA) hydrogel mixed with hepatocytes and fibroblasts, in a digital micromirror device (DMD)-based microfluidic channel. The microstructures were assembled through coordinated micromanipulation based on local fluid force, and spatially self-aligned through hydrophilic-hydrophobic interactions into a 3D integrated construct with lobule-like morphology and a perfusable central lumen. The resulting 3D lobule-like constructs allowed long-term co-culture of hepatocytes and fibroblasts with high cell viability. The co-cultured constructs enhanced hepatocyte proliferation and spreading, as well as liver functions including a 50% increase in albumin secretion and urea synthesis. For hepatotoxicity assessment, the 3D lobule-like construct enabled drug perfusion through its built-in lumen for simulation of drug diffusion in the liver, which could improve the response sensitivity and efficiency to hepatotoxic drug. These results demonstrated that this method provides a valuable 3D co-culture model with perfusable lobule-like architecture and physiological functions, which has potential applications in drug discovery and tissue engineering applications. PMID- 30523848 TI - Effect of pressure on the physical properties of the superconductor NiBi3. AB - We present an experimental study of the superconducting properties of NiBi3 as a function of pressure by means of resistivity and magnetization measurements and combine our results with DFT calculations of the band structure under pressure. We find a moderate suppression of the critical temperature Tc from ~ 4.1 K to ~ 3 K by pressures up to 2 GPa. By taking into account the change of the band structure as a function of pressure, we argue that the decrease in Tc is consistent with conventional, electron-phonon-mediated BCS-type superconductivity. PMID- 30523849 TI - Orbiton-Phonon coupling in Ir5+(5d4) double perovskite Ba2YIrO6. AB - Ba2YIrO6, a Mott insulator, with four valence electrons in Ir5+ d-shell (5d4) is supposed to be non-magnetic, with Jeff = 0, within the atomic physics picture. However, recent suggestions of non-zero magnetism have raised some fundamental questions about its origin. We focus on the phonon dynamics, probed via Raman scattering, as a function of temperature and different incident photon energies, as an external perturbation. Our studies reveal strong renormalization of the phonon self-energy parameters and integrated intensity for first-order modes, especially redshift of the few first-order modes with decreasing temperature and anomalous softening of modes associated with IrO6 octahedra, as well as high energy Raman bands attributed to the strong anharmonic phonons and coupling with orbital excitations. The distinct renormalization of second-order Raman bands with respect to their first-order counterpart suggest that higher energy Raman bands have significant contribution from orbital excitations. Our observation indicates that strong anharmonic phonons coupled with electronic/orbital degrees of freedom provides a knob for tuning the conventional electronic levels for 5d orbitals, and this may give rise to non-zero magnetism as postulated in recent theoretical calculations with rich magnetic phases. PMID- 30523850 TI - Plasmon-enhanced upconversion luminescence in pyrochlore phase YbxEr2-xTi2O7 thin film. AB - Pyrochlore phase YbxEr2-xTi2O7 (YETO) thin films have been prepared by employing a facile sol-gel method combining with spin-coating technique and post-annealing treatment at 700 C. High concentration of Yb3+ ions can promote the transformation from Yb3+/Er3+ co-doped anatase phase TiO2 to pyrochlore phase YETO at 700 C temperature. We find that the YETO thin film with 30 mol% Yb3+ ions exhibits the brightest upconversion (UC) emission. Moreover, introduction of Au nanorods (Au NRs) in the YETO thin film can further enhance the UC fluorescence. By adjusting the density of Au NRs, the UC emission intensity is increased by about 2.8-fold due to the excitation field enhancement caused by the localized surface plasmon resonance effect. PMID- 30523851 TI - Unraveling the physical properties and superparamagnetism in anti-site disorder controlled Fe2TiSn. AB - With an aim to control the anti-site disorder between Fe and Ti atoms in the full Heusler alloy, Fe2TiSn, we substitute small percentage of Ti at Fe site to form the Fe2-xTi1+xSn (0 <= x <= 0.1) series. Using the incident X-rays tuned to the Fe K-edge absorption energy, we record the high resolution synchrotron X-ray diffraction profiles and unambiguously show the reduction in anti-site disorder. In particular, the Fe - Ti anti-site disorder decreases up to an excess Ti - content of 0.07; further increase of Ti - content leads to disorder between Ti{Sn sites. Detailed characterization vis-a-vis the excess Ti content has been carried out in terms of its thermal and electrical transport, and magnetic properties. Signatures of strong spin fluctuation are seen in all the physical properties reported here. The much disputed high value of Sommerfeld constant has been shown to be a resultant of such strong spin fluctuations, thus ruling out the long standing controversy of heavy fermionic nature of Fe2TiSn. Magnetization and Seebeck coefficient show clear dependence on the disorder. Both, dc and ac magnetic measurements reveal the low temperature superparamagnetic nature of this system, comprising of large magnetic clusters ~ 3 nm in size. PMID- 30523852 TI - Suppression of axial growth by boron incorporation in GaAs nanowires grown by self-catalyzed molecular beam epitaxy. AB - The addition of boron to GaAs nanowires grown by self-catalyzed molecular beam epitaxy was found to have a strong effect on the nanowire morphology, with axial growth greatly reduced as the nominal boron concentration was increased. Transmission electron microscopy measurements show that the Ga catalyst droplet was unintentionally consumed during growth. Concurrent radial growth, a rough surface morphology and tapering of nanowires grown under boron flux suggest that this droplet consumption is due to reduced Ga adatom diffusion on the nanowire sidewalls in the presence of boron. Modelling of the nanowire growth puts the diffusion length of Ga adatoms under boron flux at around 700-1000nm. Analyses of the nanowire surfaces show regions of high boron concentration, indicating the surfactant nature of boron in GaAs. PMID- 30523853 TI - Local insight into the La-induced structural phase transition in multiferroic BiFeO3 ceramics by X-ray absorption fine structure spectroscopy. AB - Substitution of bismuth by rare-earth (RE) ions is of great technological importance to develop room-temperature BiFeO3-based multiferroic materials. Despite this interest, many fundamental properties and the structure-property correlations of RE-doped BiFeO3 remain poorly understood. Here we report a systematical experimental and theoretical exploration on the structural phase transition in Bi1-xLaxFeO3 (0 <= x <= 0.2) ceramics. By using x-ray absorption fine structure spectroscopy, we for the first time show that the La3+ dopants in fact substitute the Bi site of a secondary nanosized particles with orthorhombic Pbam symmetry instead of the long-believed parental rhombohedral R3c phase at all La3+ doping concentrations (0.001 <= x <= 0.2). This homogeneously mixed two phase compound cannot be detected by the x-ray diffraction until La content approaching x = 0.2. The finding is further supported by complementary studies of transmission electron microscopy and thermodynamic preference, and it casts serious challenges on the prevailing assumption of La3+ substitution on the Bi3+ site in R3c structure when x <= 0.1 as well as the previously proposed origin of enhanced functional properties based on morphotropic phase boundary. This new insight may ignite a revival on exploring the underlying multiferroic mechanisms in BiFeO3-based materials and facilitate the bottom-up design of novel multifunctional devices. PMID- 30523854 TI - Tailoring the capability of carbon nitride (C3N) nanosheets towards hydrogen storage upon light transition metal decoration. AB - To nurture full potential of hydrogen (H2) as a clean energy carrier, its efficient storage under ambient conditions is of great importance. Owing to the potential of material-based H2 storage as a promising option, we have employed here first principles density functional theory (DFT) calculations to study the H2 storage properties of recently synthesized C3N monolayers. Despite possessing fascinating structural and mechanical properties C3N monolayer weakly bind H2 molecules. However our van der Waals corrected simulations revealed that the binding properties of H2 on C3N could be enhanced considerably by suitable Sc and Ti doping. The stabilities of Sc and Ti dopants on C3N surface has been verified by means of reaction barrier calculations and ab initio molecular dynamics simulations. Upon doping with C3N, the existence of partial positive charges on both Sc and Ti causes multiple H2 molecules bind to the dopants through electrostatic interactions with adsorption energies that are within ideal range. A drastically high H2 storage capacity of 9.0 wt% could be achieved with two sided Sc/Ti doping that ensures the promise of C3N as high capacity H2 storage material. PMID- 30523855 TI - Photocatalytic and Antibacterial Activities of Silver and Iron Doped Titania Nanoparticles in Solution and Polyaspartic Coatings. AB - Visible region active photocatalytic coatings are of interest for antimicrobial activity in low light applications or those employing LED lights with limited UV content. This work examined Ag and Fe doped titania nanoparticles (nTiO2) with varying dopant ranges in polyaspartic polymer coatings for potential light and dark activity. First, the Ag and Fe doped nTiO2 were synthesized by sol-gel chemistry with varying dopant concentrations, then characterized with respect to their size and aggregate size distribution, crystallinity, and surface and band gap features. The photocatalytic activity was then tested with methylene blue (MB) under both AM1.5G and visible light. From both sample sets (Ag and Fe doped nTiO2), the best photo catalytically active sample materials were chosen for antibacterial tests with gram negative Escherichia coli (E. coli) and gram positive Bacillus subtilis (B. subtilis) in (a) solution and (b) polyaspartic nanocomposites under UV and visible irradiation. The results showed that Ag doped nTiO2 samples delivered the best and excellent antibacterial action, even in the dark, attributed to both an enhanced band gap and surface area, as well as a combination of photocatalytic activity and Ag being present at the nanoparticle's (NP) surface. No leaching of Ag at room temperature was observed from the nTiO2 structure, giving potential for next generation coatings that are both light and dark active. PMID- 30523856 TI - Continuous non-invasive determination of the nocturnal blood pressure variation using photoplethysmographic pulse wave signals - comparison of pulse propagation time, pulse transit time and RR-interval. AB - Cardiovascular diseases are the leading cause of death whereas nocturnal ambulatory blood pressure (BP) is the most potent predictor for cardiovascular risk. Volume clamp and Pulse Transit Time (PTT) are common methods for continuous non-invasive BP measurement, but have drawbacks during unsupervised ambulatory use and undisturbed sleep. The Pulse Propagation Time (PPT), defined as time between Pulse Wave Systolic Peak and Diastolic Peak, provides valid information about the pressure pulse waveform. However, the literature has not investigated the use of PPT for nocturnal BP variation determination and if such variation is affected by BP or heart rate (i.e., RRI). To assess whether the PPT method is suitable for ubiquitous nocturnal BP monitoring, we compared systolic blood pressure (SBP) estimates derived from PPT, PTT, and RRI signals with parallel recorded BP measurements. The RRI derived SBP signals were used as baseline for testing a potential heart rate dependency. This work provides an overview of blood pressure measurements, presents the developed real-time signal analysis, and describes the performance assessment. The signal analysis was validated with data records from 42 subjects acquired in an ergometry and sleep laboratory in equal parts. The algorithm achieved in the ergometry laboratory database a correlation coefficient between reference SBP and estimated SBPPPT of 0.89 (p < 0.001) with bias 0.1 mmHg and limits of agreement (LoA) -29.8 to 30.0 mmHg, SBPPTT of 0.97 (p < 0.001) with bias 0.0 mmHg and LoA -15.2 to 15.3 mmHg, and SBPRRI of 0.96 (p < 0.001) with bias 0.0 mmHg and LoA -19.5 to 19.5 mmHg. For the sleep laboratory database the correlation coefficient was for SBPPPT of 0.95 (p < 0.001) with bias 0.2 mmHg and LoA -18.3 to 18.8 mmHg, SBPPTT of 0.88 (p < 0.001) with bias 0.0 mmHg and LoA -25.0 to 24.9 mmHg, and SBPRRI of 0.88 (p < 0.001) with bias of 0.1 mmHg and LoA -23.6 to 23.7 mmHg. A heart rate dependency of PPT or PTT could be not found. The analysis of variance shows neither for the ergometry [F(3, 627) = 2.27, p = 0.08] nor the sleep laboratory [F(3, 327) = 2.28, p = 0.08] significant differences between the reference SBP values and the estimated. In conclusion, the PPT method seems to be an interesting alternative for continuous determination of SBP during simplified cardiovascular monitoring and sleep screening compared to more expensive devices based on volume clamp or PTT methods. PMID- 30523857 TI - Tiny nano-scale junction built on B/N doped single carbon nanotube. AB - The characteristic sizes of carbon nanotube (CNT) based devices are constantly reduced. However, the continuous miniaturization is still facing many problems and requires innovative ideas and structures. By regular doping Boron and Nitrogen atoms in a semiconducting single-wall carbon nanotube (SWCNT), we have constructed an nano-scale junction with rectifying characteristics. The I-V curve of our junction resembles the I-V curve of an ideal diode with a p-n junction. This junction channel is about 0.6nm wide and 3.4nm long, and the footprint is 5.1nm long. Under 0.5V bias, the junction has a leakage current of -8.81*10^-3 MUA, a rectifying ratio Ion/Ioff of 0.716*10^3, and a current density of 10.52 mA/MUm. Also, our study shows that how different dopant distribution influence I V curve. Such a nano-scale regular doping method is effective and important, compared with the traditional random doping method. PMID- 30523858 TI - One-step method to synthesize CH3NH3PbI3:MoS2 nanohybrids for high performance solution-processed photodetectors in visible region. AB - A facile method to synthesize CH3NH3PbI3:MoS2 nanohybrid for high-performance solution-processed photodetectors is presented. The interfacial charge carriers transfer due to the existence of heterojunction between the 2D MoS2 nanosheet and perovskite cuboids are utilized to enhance the device performance. The dark current of the photodiode Au/CH3NH3PbI3:MoS2/Au was suppressed and its photocurrent was enhanced as compared to pristine perovskite nanocrystal device Au/CH3NH3PbI3/Au. The lowest dark current of 0.34?10-9A was observed from photodiode Au/CH3NH3PbI3:MoS2/Au and the photoresponsivity and photosensitivity increase from 312 mA/W to 696 mA/W and from 9.02 to 87.47, respectively, showing an enhancement of 123.1% and 869.7%, also the rising-time and falling-time was reduced from 73ms to 50ms, and 60ms to 16ms, respectively, as compared to those for the pristine perovskite nanocrystal-based photodiode Au/CH3NH3PbI3/Au. Therefore, it provides the simple and effective approach to synthesize 2D nanosheet blended organic-inorganic nanohybrids for application in optoelectronic devices. PMID- 30523859 TI - Flexible intramedullary nails for limb lengthening: a comprehensive comparative study of three nails types. AB - This study aims to investigate the comparative study of calcium phosphate coatings for flexible intramedullary nails (FINs) used to lengthen long tubular bones. The presence of a calcium phosphate coating deposited by micro-arc oxidation or a composite coating based on a copolymer of vinylidene fluoride with tetrafluoroethylene (VDF-TeFE) and hydroxyapatite (HA) on the surface of the FIN significantly enhanced the regeneration of bone in the area of osteotomy during limb lengthening by combined osteosynthesis. The investigation of the physicochemical properties of the FIN coated with calcium phosphate via micro-arc oxidation demonstrated that the improved bone tissue formation resulted from favorable conditions for adhesion, proliferation, and differentiation of multipotent stem cells into osteoblasts on the coating surface. The composite coatings only stimulated the formation of bone tissue in vivo, primarily because of the piezoelectric properties of the VDF-TeFE copolymer. PMID- 30523861 TI - Shape deformation of a vesicle under axisymmetric non-uniform alternating electric field. AB - We suggest that non-uniform electric fields that are commonly used to study vesicle dielectrophoresis can be employed in hitherto relatively unexplored areas of vesicle deformation (for electromechanical characterisation) and electroporation. Conventionally, the tension generated in vesicles is commonly modeled to be entropic or enthalpic in origin. A comparison of the configuration of a vesicle in the enthalpic and entropic regimes as well as the cross over between the two regimes during vesicle deformation has eluded understanding. A lucid demonstration of this concept is provided by the study of vesicle deformation under axisymmetric quadrupole electric field and the shapes of the vesicles obtained using the entropic and the enthalpic approaches, show significant differences. A strong dependence of the final vesicle shapes on the ratio of electrical conductivities of the fluids inside and outside the vesicle as well as on the frequency of the applied quadrupole electric field is observed. A comparison with experimental data from the literature is also made. Moreover, an excess area dependent transition between the entropic and enthalpic regimes is observed. The method could be used to estimate electromechanical properties of the vesicle. PMID- 30523860 TI - Coarse Behavioral Context Decoding. AB - OBJECTIVE: Current brain-computer interface (BCI) studies demonstrate the potential to decode neural signals obtained from structured and trial-based tasks to drive actuators with high performance within the context of these tasks. Ideally, to maximize utility, such systems will be applied to a wide range of behavioral settings or contexts. Thus, we explore the potential to augment such systems with the ability to decode abstract behavioral contextual states from neural activity. APPROACH: To demonstrate the feasibility of such context decoding, we used electrocorticography (ECoG) and stereo-electroencephalography (sEEG) data recorded from the cortical surface and deeper brain structures, respectively, continuously across multiple days from three subjects. During this time, the subjects were engaged in a range of naturalistic behaviors in a hospital environment. Behavioral contexts were labeled manually from video and audio recordings; four states were considered: 'engaging in dialogue', 'rest', 'using electronics', and 'watching television'. We decode these behaviors using a factor analysis and support vector machine (SVM) approach. MAIN RESULTS: We demonstrate that these general behaviors can be decoded with high accuracies of 73% for a 4-class classifier for one subject and 71% and 62% for a 3-class classifier for two subjects. SIGNIFICANCE: To our knowledge, this is the first demonstration of the potential to disambiguate abstract naturalistic behavioral contexts from neural activity recorded throughout the day from implanted electrodes. This work motivates further study of context decoding for BCI applications using continuously recorded naturalistic activity in the clinical setting. PMID- 30523862 TI - Photocurrent spectra from PbS photovoltaic infrared detectors using silver nanowires as plasmonic nano antenna electrodes. AB - We discussed structural and electrical properties of PbS films by chemical bath deposition. The crystallite size of our films measured by transmission electron microscope was as large as 0.2 um in a lateral direction and 1 um in a vertical direction, and we obtained a high mobility value of 60 cm2V 1sec-1 at room temperature. We demonstrated PbS photovoitaic infrared detectors using silver nanowires as transparent electrodes, whose spectral response was measured by Fourier transform infrared spectrometer. The cut-off wavelength was ? 3 um at room temperature and ? 4 um at 10 K. At 100 K, a pronounced photocurrent peak was observed at lambda=3.7 MUm. Using FDTD (Finite difference time domain) simulations, we demonstrated that silver nanowires worked as nano antennas for generating surface plasmons, resulting in the enhancement of photocurrent. The pronounced photocurrent peak wavelength corresponds to the wavelength where the silver nanowires were located near the constructive interference. PMID- 30523863 TI - Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device. AB - Liver cell culture models are attractive in both tissue engineering and for development of assays for drug toxicology research. To retain liver specific cell functions, the use of adequate cell types and culture conditions, such as a 3D orientation of the cells and a proper supply of nutrients and oxygen, are critical. In this article, we show how extracellular matrix mimetic hydrogels can support hepatocyte viability and functionality in a perfused liver-on-a-chip device. A modular hydrogel system based on hyaluronan and poly(ethylene glycol) (HA-PEG), modified with cyclooctyne moieties for bioorthogonal strain-promoted alkyne-azide 1,3-dipolar cycloaddition (SPAAC), was developed, characterized, and compared for cell compatibility to hydrogels based on agarose and alginate. Hepatoma cells (HepG2) formed spheroids with viable cells in all hydrogels with the highest expression of albumin and urea in alginate hydrogels. By including an excess of cyclooctyne in the HA backbone, azide-modified cell adhesion motifs (linear and cyclic RGD peptides) could be introduced in order to enhance viability and functionality of human induced pluripotent stem cell derived hepatocytes (hiPS-HEPs). In the HA-PEG hydrogels modified with cyclic RGD peptides hiPS-HEPs migrated and grew in 3D and showed an increased viability and higher albumin production compared to when cultured in the other hydrogels. This flexible SPAAC crosslinked hydrogel system enabled fabrication of perfused 3D cell culture of hiPS-HEPs and is a promising material for further development and optimization of liver-on-a-chip devices. PMID- 30523864 TI - Combined head phantom and neural mass model validation of effective connectivity measures. AB - Objective Due to its high temporal resolution, electroencephalography (EEG) has become a promising tool for quantifying cortical dynamics and effective connectivity in a mobile setting. While many connectivity estimators are available, the efficacy of these measures has not been rigorously validated in real-world scenarios. The goal of this study was to quantify the accuracy of independent component analysis and multiple connectivity measures on ground-truth connections while exposed real-world volume conduction and head motion. Approach We collected high-density EEG from a phantom head with embedded antennae, using neural mass models to generate transiently interconnected signals. The head was mounted upon a motion platform that mimicked recorded human head motion at various walking speeds. We used cross-correlation and signal to noise ratio to determine how well independent component analysis recovered the original antenna signals. For connectivity measures, we computed the average and standard deviation across frequency of each estimated connectivity peak. Main results Independent component analysis recovered most antenna signals, as evidenced by cross-correlations primarily above 0.8, and maintained consistent signal to noise ratio values near 10 dB across walking speeds compared to scalp channel data, which had decreased signal to noise ratios of ~2 dB at fast walking speeds. The connectivity measures used were generally able to identify the true interconnections, but some measures were susceptible to spurious high-frequency connections inducing large standard deviations of ~10 Hz. Significance Our results indicate that independent component analysis and some connectivity measures can be effective at recovering underlying connections among brain areas. These results highlight the utility of validating EEG processing techniques with a combination of complex signals, phantom head use, and realistic head motion. PMID- 30523865 TI - Co-delivery Nanoparticles of Doxorubicin and Chloroquine for Improving the Anti cancer Effect in vitro. AB - To increase the efficacy of small molecule chemotherapeutic drug (SMCD) and reduce its toxic and side effects, we selected two model drugs DOX and CQ. DOX was a SMCD and CQ was a chemosensitizer with autophagy inhibition. Poly(lactic-co glycolic acid) (PLGA) and alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) were chosen as delivery carriers to design and prepare a novel type of drug co-delivery single-nanoparticles (DCDS-NPs) by emulsification solvent volatilisation, named NPDOX+CQ. The physicochemical properties of NPDOX+CQ were characterized. Then A549 cells and A549/Taxol cells were used for the in vitro anticancer effect. At the same time, cellular uptake, intracellular migration and anti-cancer mechanism of nanoparticles were studied. The NPs showed a uniform spherical shape with good dispersibility, and both drugs had good encapsulation efficiency loading capacity. In all formulations, NPDOX+CQ showed the highest in vitro cytotoxicity. The results showed that NPs could protect drugs from being recognised and excluded by P-glycoprotein (P-gp). Moreover, the results of the mechanistic study demonstrated that NPs were transported by autophagy process after being taken up by the cells. Therefore, during the migration of NPDOX+CQ, CQ could exert its efficacy and block autophagy so that DOX would not be hit by autophagy. Western Blot results showed that NPDOX+CQ has the best inhibition effect of autophagy. It can be concluded that the system can prevent the drug from being recognised and excluded by P-gp, and CQ blocks the process of autophagy so that the DOX is protected and more distributed to the nucleus of multidrug resistance (MDR) cell. The NPDOX+CQ constructed in this study provides a feasible strategy for reversing MDR in tumour cells. PMID- 30523866 TI - PVP intercalated metallic WSe2 as NIR photothermal agents for efficient tumor ablation. AB - Transition metal dichalogenides (TMDCs) with unique layered structures hold promising potential as transducers for photothermal therapy. However, the low photothermal conversion efficiency and poor stability in some cases limit their practical applications. Herein, we demonstrate the fabrication of an ultrathin homogeneous hybridized TMDC nanosheets and their use for highly efficient photothermal tumor ablation. In particular, the nanosheets were composed of metallic WSe2 intercalated with polyvinylpyrrolidone (PVP), which was facilely prepared through a solvothermal process from the mixture of selenourea crystals, WCl6 powder along with PVP polymeric nanogel. Our characterizations revealed that the obtained nanosheets exhibited excellent photothermal conversion efficiency, therapeutic demonstration with improved biocompatibility and physiological stability attributing to the combined merits of metallic phase of WSe2 and hydrophilic PVP insertion. Both the histological analysis of vital organs and in vitro/in-vivo tests confirmed the nanosheets as actively effective and biologically safe in this phototherapeutic technique. Findings from this non invasive experiment clearly emphasize the explorable therapeutic efficacy of the layered-based hybrid agents in future cancer treatment planning procedures. PMID- 30523867 TI - Resolution improvement of dipole source localization for artificial lateral lines based on multiple signal classification. AB - The lateral line is a critical mechanosensory organ that enables fish to perceive the surroundings accurately and rapidly. Massive efforts have been made to build an artificial lateral line system rivaling that of fish for underwater vehicles. Dipole source localization has become a standard problem for evaluating the sensing capabilities of the developed systems. In this paper we propose, for the first time, the MUSIC (multiple signal classification) method in order to achieve high-resolution dipole source localization based on spatial spectrum estimation. We also present the MVDR (minimum variance distortionless response) method by making an improvement to the previous Capon's method. Experiments are conducted on a linear prototype of lateral line canal and the localization performance of these two methods are compared. The results show that the MUSIC method provides an overall localization resolution improvement of 10.4% and maintains similar levels of localization accuracy compared with the MVDR method. Further studies show that the MUSIC method has the potential of localizing two closer incoherent dipole sources with a minimum lateral separation of 20 mm, versus 70 mm for the MVDR method, at a dipole-array distance of half the array length. Both localization methods have strong robustness to the vibrational state of the dipole source. Our work provides a promising and robust way to meet the high resolution and multi-source sensing requirements of underwater vehicles. PMID- 30523868 TI - Validation of new 2D ripple filters in proton treatments of spherical geometries and non-small cell lung carcinoma cases. AB - A ripple filter (RiFi) is a passive energy modulator used in scanned particle therapy to broaden the Bragg peak, thus lowering the number of accelerator energies required for homogeneous target coverage, which significantly reduces the irradiation time. As we have previously shown, a new 6 mm thick RiFi with 2D groove shapes produced with 3D printing can be used in carbon ion treatments with a similar target coverage and only a marginally worse planning conformity compared to treatments with in-use 3 mm thick RiFis of an older 1D design. Where RiFis are normally not used with protons due to larger scattering and straggling effects, this new design would be beneficial in proton therapy too. Measurements of proton Bragg curves and lateral beam profiles were carried out for different RiFi designs and thicknesses as well as for no RiFi at the Heidelberg Ionenstrahl-Therapiezentrum. Base data for proton treatment planning were generated with the Monte Carlo code SHIELD-HIT12A with and without the 2D 6 mm RiFi. Plans on spherical targets in water were calculated in TRiP98 for a systematic RiFi performance analysis and for comparisons with carbon ion plans for the same respective energy step sizes. Plans for 9 stage I static non small cell lung cancer patients were calculated in Eclipse 13.7.15. Dose-volume histograms, spatial dose distributions and dosimetric indexes were used for plan evaluation. Measurements confirm the functionality of the new 2D RiFi design, which reduces the beam spot size compared to 1D RiFis of the same thickness. Planning studies show that a 6 mm thick 2D RiFi could be used in proton therapy to lower the irradiation time. Although slightly worse planning conformity and dose homogeneity were found for plans with the RiFi compared to plans without, satisfactory results within the planning objective were obtained for all cases. PMID- 30523869 TI - The potential of constrained SAR focusing for hyperthermia treatment planning: analysis for the head & neck region. AB - Clinical trials have shown that hyperthermia is a potent adjuvant to conventional cancer treatments, but the temperatures currently achieved in the clinic are still suboptimal. Hyperthermia treatment planning simulations have potential to improve the heating prole of phased-array applicators. An important open challenge is the development of an eective optimization procedure that enables uniform heating of the target region while keeping temperature below a threshold in healthy tissues. In this work, we analyzed the eectiveness and eciency of a recently proposed optimization approach, i.e., focusing via constrained power optimization (FOCO), using 3D simulations of twelve clinical patient specic models. FOCO performance was compared against a clinically used particle swarm based optimization approach. Evaluation metrics were target coverage at the 25% iso-SAR level, target hotspot quotient, median target temperature (T50) and computational requirements. Our results show that, on average, constrained power focusing performs slightly better than the clinical benchmark (?T50 = +0.05C), but outperforms this clinical benchmark for large target volumes (>40 cm3, ?T50 = +0.39C). In addition, the results are achieved faster (-44%) and are repeatable because the approach is formulated as a convex optimization problem. PMID- 30523870 TI - 'Corrigendum: Role of Ni2+(d8) ions in electrical, optical and magnetic properties of CdS nanowires for optoelectronic and spintronic applications (2018 Nanotechnology 29 265602)'. AB - For the first time, 1D Ni ions doped CdS nanowires (NWs) were synthesized via chemical vapour deposition (CVD). The synthesized Cd0.886Ni0.114S NWs were single crystalline. We have reported here, investigation of optical, electrical and magnetic properties of prepared NWs for optoelectronic and spintronic applications. Successful incorporation of Ni ions in an individual CdS NW has been confirmed through several characterization tools: significant higher angle and phonon modes shift were observed in the XRD and Raman spectra. SEM-EDX and XPS analysis also confirmed the presence of Ni2+ ions. Room-temperature photoluminescence (RT-PL) showed multi-peaks: two emission peaks in the visible region centered at 517.1 nm (green), 579.2 nm (orange), and a broad-band near infrared (NIR) emission centered at 759.9 nm. Herein, the first peak showed 5 nm red-shift upon Ni2+ doping hinting the formation of exciton magnetic polarons (EMPs), and broad-NIR emission was observed in both chlorides and bromides which was assigned to d-d transition of Ni ions whose energy levels lie at 749.51 nm (13342 cm-1) and 750.98 nm (13316 cm-1) are very close to NIR emission. Orange emission was not only remained at same peak position but also its PL intensity significantly enhanced at 78 K and is assigned to d-d transition (3A2g -> 1Eg) of Ni2+ ions. It was observed that 11.4% Ni2+ ions doping enhance the conductivity of our sample around 20 times and saturation magnetization (Ms) increases from 7.2 * 10-5 Am2/Kg to 1.17 * 10-4 Am2/Kg which shows promise for optoelectronic and spintronic applications. PMID- 30523871 TI - Thermal echo in a finite one-dimensional harmonic crystal. AB - An instant homogeneous thermal perturbation in the finite harmonic one dimensional crystal is studied. Previously it was shown that for the same problem in the infinite crystal the kinetic temperature oscillates with decreasing amplitude described by the Bessel function of the first kind. In the present paper it is shown that in the finite crystal this behavior is observed only until a certain period of time when a sharp increase of the oscillations amplitude is realized. This phenomenon, further refereed to as the thermal echo, is realized periodically, with the period proportional to the crystal size. The amplitude for each subsequent echo is lower than for the previous one. It is obtained analytically that the time-dependance of the kinetic temperature can be described by an infinite sum of the Bessel functions with multiple indices. It is also shown that the thermal echo in the thermodynamic limit is described by the Airy function. PMID- 30523872 TI - Temperature dependent Young's modulus of ZnO nanowires. AB - A thermal resonant method was developed to accurately determine the temperature dependent Young's moduli of nanowires. In this method, the frequency spectra of a [0001]-oriented ZnO nanowire cantilever at elevated temperatures were measured using scanning laser Doppler vibrometry. The temperature-dependent Young's moduli were derived from the resonant frequencies using Euler-Bernoulli beam theory. It was found that the modulus of ZnO nanowires decreased linearly with the increase of temperature from 300 to 650 K, independent of the nanowire diameter ranged from 101 to 350 nm. The temperature coefficient that defines the linear relationship between the dimensionless modulus and temperature is -(1.087+/ 0.018)*10-4 K-1, which agrees with that of -(1.266+/ 0.549)*10-4 K-1, being calculated using molecular dynamics with a partially charged rigid ion model. PMID- 30523873 TI - Modeling slow-processing of toxin messenger RNAs in type-I Toxin-Antitoxin systems: post-segregational killing and noise filtering. AB - In type-I toxin-antitoxin (TA) systems, the action of growth-inhibiting toxin proteins is counteracted by the antitoxin small RNAs (sRNAs) that prevent the translation of toxin messenger RNAs (mRNAs). When a TA module is encoded on a plasmid, the short lifetime of antitoxin sRNA compared to toxin mRNAs mediates post-segregational killing (PSK) that contribute the plasmid maintenance, while some of the chromosomal encoded TA loci have been reported to contribute to persister formation in response to a specific upstream signal. Some of the well studied type-I TA systems such as hok/sok are known to have a rather complex regulatory mechanism. Transcribed full-length toxin mRNAs fold such that the ribosome binding site is not accessible and hence cannot be translated. The mRNAs are slowly processed by RNases, and the truncated mRNAs can be either translated or bound by antitoxin sRNA to be quickly degraded. We analyze the role of this extra processing by a mathematical model. We first consider the PSK scenario, and demonstrate that the extra processing compatibly ensures the high toxin expression upon complete plasmid loss, without inducing toxin expression upon acquisition of a plasmid or decrease of plasmid number to a non-zero number. We further show that the extra processing help filtering the transcription noise, avoiding random activation of toxins in transcriptionally regulated TA systems as seen in chromosomal ones. The present model highlights impacts of the slow processing reaction, offering insights on why the slow processing reactions are commonly identified in multiple type-I TA systems. PMID- 30523874 TI - Component manipulated magnetic anisotropy and damping in Heusler-like compound Co2+xFe1-xAl. AB - The component dependence of the magnetocrystalline anisotropy and the damping has been investigated in epitaxial Heusler-like compound Co2+xFe1-xAl films grown by molecular beam epitaxy with x=-0.4, -0.2, 0, 0.2, and 0.4. All the films show a component tunable four-fold magnetocrystalline anisotropy with the easy axis along [110] orientation. The time resolved magneto-optic Kerr effect measurements reveal that the damping constant can be tuned in a range of 0.0065 to 0.0156 with a minimum value of 0.0065 at x=-0.2. This work provides a new approach to manipulate the magnetic dynamic properties of Heusler alloy Co2FeAl by adjusting the proportion of Co and Fe. PMID- 30523875 TI - Compressed sensing reconstruction of synthetic transmit aperture dataset for volumetric diverging wave imaging. AB - A high volume rate and high performance ultrasound imaging method based on a matrix array is proposed by using compressed sensing (CS) to reconstruct the complete dataset of synthetic transmit aperture (STA) from three-dimensional (3D) diverging wave transmissions (i.e., 3D CS-STA). Hereto, a series of apodized 3D diverging waves are transmitted from a fixed virtual source, with the ith row of a Hadamard matrix taken as the apodization coefficients in the ith transmit event. Then CS is used to reconstruct the complete dataset, based on the linear relationship between the backscattered echoes and the complete dataset of 3D STA. Finally, standard STA beamforming is applied on the reconstructed complete dataset to obtain the volumetric image. Four layouts of element numbering for apodizations and transmit numbers of 16, 32, and 64 are investigated through computer simulations and phantom experiments. Furthermore, the proposed 3D CS-STA setups are compared with 3D single-line-transmit (SLT) and 3D diverging wave compounding (DWC). The results show that, i) 3D CS-STA has competitive lateral resolutions to 3D STA, and their contrast ratios (CRs) and contrast-to-noise ratios (CNRs) approach to those of 3D STA as the number of transmit events increases in noise-free condition. ii) the tested 3D CS-STA setups show good robustness in complete dataset reconstruction in the presence of different levels of noise. iii) 3D CS-STA outperforms 3D SLT and 3D DWC. More specifically, the 3D CS-STA setup with 64 transmit events and the Random layout achieves ~31% improvement in lateral resolution, ~14% improvement in ratio of the estimated-to-true cystic areas, a higher volume rate, and competitive CR/CNR when compared with 3D DWC. The results demonstrate that 3D CS-STA has great potential of providing high quality volumetric image with a higher volume rate. PMID- 30523876 TI - Magnetic properties of oxygen doped samarium clusters. AB - Here we present the results of experimental study of magnetic properties of samarium clusters doped with a single oxygen atom. In a recent theoretical study it was observed that for pure Sm clusters a transition from fully non-magnetic to weakly magnetic occurs due to a valence change occurring at a size of 8 atoms. Here we found, first, that pure Sm clusters could not be synthesized due to the strong oxidation tendency of Sm and the inability to sufficiently remove oxygen from the setup. Therefore, we studied Sm$_n$O clusters. Since the oxygen contributes to the binding, the valence transition for Sm$_{n}$O clusters should occur for a smaller cluster size than for pure Sm clusters. Indeed from our experiments the valence transition is predicted to occur for $n=4$ Sm atoms instead of 8. Furthermore, the observed magnetic moment as function of cluster size for Sm$_n$O clusters is also interesting. For $n>4$ there is a strong dependency of the magnetic moment on the cluster size. A large total magnetic moment is observed for Sm$_{6}$O, Sm$_{7}$O, Sm$_{13}$O and Sm$_{14}$O compared to the smaller moment for Sm$_{8}$O to Sm$_{12}$O and Sm$_{15}$O to Sm$_{18}$O. PMID- 30523877 TI - Thermodynamic limits to energy conversion in solar thermal fuels. AB - Solar thermal fuels (STFs) are an unconventional paradigm for solar energy conversion and storage which is attracting renewed attention. In this concept, a material absorbs sunlight and stores the energy chemically via an induced structural change, which can later be reversed to release the energy as heat. An example is the azobenzene molecule which has a cis-trans photoisomerization with these properties, and can be tuned by chemical substitution and attachment to templates such as carbon nanotubes, small molecules, or polymers. By analogy to the Shockley-Queisser limit for photovoltaics, we analyze the maximum attainable efficiency for STFs from fundamental thermodynamic considerations. Microscopic reversibility provides a bound on the quantum yield of photoisomerization due to fluorescence, regardless of details of photochemistry. We emphasize the importance of analyzing the free energy, not just enthalpy, of the metastable molecules, and find an efficiency limit for conversion to stored chemical energy equal to the Shockley-Queisser limit. STF candidates from a recent high throughput search are analyzed in light of the efficiency limit. PMID- 30523878 TI - Physics and design for 20 % and 25 % efficiency nanowire array solar cells. AB - Bottom-up fabricated single-junction III-V nanowire array solar cells have shown efficiency up to 15.3 %, which is approximately half of the conventional Shockley Queisser detailed balance efficiency limit of 33.6 %. Here, based on numerical and analytical opto-electronics modeling and analysis, we give guidelines for (i) geometry that gives strong absorption as well as (ii) the design of efficient p-n junction and electrical contacts in the nanowires to reach 20 % and 25 % efficiency. We exemplify the impact of 8 different optical and electrical loss mechanisms in a 15 % and a 25 % design. We also provide an analytical equation for estimating the efficiency drop due to resistive losses in the top contact layer for varying cell size. PMID- 30523879 TI - Development and flight performance of a biologically-inspired tailless flapping wing micro air vehicle with wing stroke plane modulation. AB - The tailless flapping-wing micro air vehicle (FW-MAV) is one of the most challenging problems in flapping-wing design due to its lack of tail for inherent flight stability. It must be designed in such a way that it can produce proper augmented control moments modulated by a closed-loop attitude controller for active stabilization. We propose a tailless FW-MAV with a wing stroke plane modulation mechanism, namely NUS-Roboticbird, which maneuvers by only using its flapping wings for both propulsion and attitude control. The flying vehicle has four wings comprised by two pairs, and each pair of wings and its stroke plane are driven by a motor and a servo, respectively. Attitude control moments of roll, pitch and yaw are generated by vectoring a pair of thrusts, which result from changing the flapping frequency (or motor speed) and wing stroke plane of the two pairs of wings. Free-flight tests show that the vehicle can climb and descend vertically (throttle control), fly sideways left and right (roll control), fly forwards and backwards (pitch control), rotate clockwise and counter-clockwise (yaw control), hover in mid-air (active self-stabilization), and maneuver in the figure-of-8 and fast forward/backward flight. These abilities are especially important for surveillance and autonomous flight in terms of obstacle avoidance in an indoor environment. Flight test data show that an effective mechanical control mechanism and control gains for attitude-controlled flights for roll, pitch and yaw are achieved, in particular, yaw control. Currently, the vehicle weighing 31 g and having a wingspan of 22 cm can perform fast forward flight at a speed of about 5 m s-1 (18 km h-1) and endure 3.5 min in flight with a useful payload of a 4.5 g onboard camera for surveillance. PMID- 30523880 TI - Nonlinear plasmonic response of doped nanowires observed by infrared nanospectroscopy. AB - We report a strong shift of the plasma resonance in highly doped GaAs/InGaAs core/shell nanowires for intense infrared excitation observed by scattering-type scanning near-field infrared microscopy. The studied nanowires show a sharp plasma resonance at a photon energy of about 125 meV in the case of continuous wave excitation by a CO2 laser. Probing the same nanowires with the pulsed free-electron laser with peak electric field strengths up to several 10 kV/cm reveals a power-dependent redshift to about 95 meV and broadening of the plasmonic resonance. We assign this effect to a substantial heating of the electrons in the conduction band and subsequent increase of the effective mass in the nonparabolic Gamma-valley. PMID- 30523881 TI - Raman spectroscopy of osteosarcoma cells. AB - Osteosarcoma is the most common primary malignant bone tumor. In the last years, several studies have demonstrated that the increase of Hydroxyapatite (HA) and Interleukin-6 (IL-6) syntheses compared to those expressed by normal osteoblasts could be used to detect the degree of malignancy of osteosarcoma cells. Conventional biochemical methods widely employed to evaluate bone cell differentiation, including normal and cancerous phenotypes, are time consuming and may require a large amount of cells. HA is a mineral form of calcium phosphate whose presence increases with maturation of osteosarcoma cells. Analogously, IL-6 is a fundamental cytokine whose production is highly increased in osteosarcoma cells. In this study, we employ Raman spectroscopy to the identification and discrimination of osteosarcoma cells from osteo-differentiated mesenchymal stromal cells (MSCs) by detecting the presence of HA and IL-6. However, while the identification of HA is facilitated by the characteristic peak at 960cm-1, corresponding to symmetric stretching (P-O) mode, the quantification of IL-6 it is much more elusive, being its Raman signal characterized by cysteine, but also by phenylalanine, amide I II and III whose signals are common to other proteins. Supported by an accurate multivariate analysis, the results show that Raman spectroscopy is a high sensitivity technique dealing out a direct and quantitative measurement of specific mineralization levels of osteosarcoma cells. In turn, by exploiting the Surface-Enhanced Raman Scattering stimulated by internalized Gold Nanoshells (AuNSs) and combined with scanning probe microscopies, we were able to employ Raman spectroscopy to study subcellular components locally. PMID- 30523882 TI - Formation of Si/organic interfaces using alkyne-functionalized cyclooctynes precursor-mediated adsorption of linear alkynes versus direct adsorption of cyclooctyne on Si(0 0 1). AB - Adsorption of ethynyl-cyclopropyl-cyclooctyne (ECCO), an alkyne-functionalized cyclooctyne, on Si(0 0 1) was studied by means of x-ray photoelectron spectroscopy (XPS) and scanning tunneling microscopy (STM). Together, XPS and STM results clearly indicate chemoselective adsorption of ECCO on Si(0 0 1) via a [2+2] cycloaddition of the strained triple bond of cyclooctyne without reaction of the ethynyl group. The results are compared to the adsorption of acetylene on Si(0 0 1): C2H2 adsorbs on Si(0 0 1) via a precursor-mediated reaction channel as it was shown by means of temperature dependent measurements of the sticking probability as well as by means of STM experiments at variable temperature. On the other hand, cyclooctyne adsorbs on Si(0 0 1) via a direct reaction channel. This qualitative difference in the reaction pathways of the two functionalities leads to the observed chemoselective adsorption of ECCO via the strained triple bond of cyclooctyne. As the ethynyl group stays intact, monolayers of ECCO on Si(0 0 1) form a well defined interface between the silicon substrate and further organic molecular layers which can be attached to the ethynyl functionality. PMID- 30523883 TI - Effect of pressure on the self-hole-doped superconductor RbGd2Fe4As4O2. AB - RbGd2Fe4As4O2 is a newly discovered self-hole-doped stoichiometric superconductor, which has a hybrid structure with separated double FeAs layers and exhibits a high superconducting transition temperature Tc = 35 K. Here, we report the effect of pressure (P) on its Tc and normal-state transport properties by measuring the temperature dependence of resistivity Res(T) under various quasi hydrostatic pressures up to 14 GPa with a cubic anvil cell apparatus. We found that the Tc is suppressed monotonically to ca. 12.5 K upon increasing pressure to 14 GPa with a slope change of Tc(P) at around 4 GPa. In addition, the low temperature normal-state Res(T), which is proportional to Tn, also evolves gradually from a non-Fermi-liquid with n = 1 at ambient pressure to a Fermi liquid with n = 2 at P ~ 4 GPa. Accompanying with the non-Fermi-liquid to Fermi liquid crossover, the quadratic temperature coefficient of resistivity, which reflects the effective mass of charge carriers, also experiences a significant reduction as commonly observed in the vicinity of a magnetic quantum critical point (QCP). Our results indicate that the stoichiometric RbGd2Fe4As4O2 at ambient pressure might be located near a QCP such that the enhanced critical spin fluctuations lead to the high-Tc superconductivity. The application of pressure should broaden the electronic bandwidth and weaken the spin fluctuations, and then restore a Fermi-liquid ground state with lower Tc. PMID- 30523884 TI - Sensitivity analysis of neurodynamic and electromagnetic simulation parameters for robust prediction of peripheral nerve stimulation. AB - Purpose: Peripheral Nerve Stimulation (PNS) has become an important limitation for fast MR imaging using the latest gradient hardware. We have recently developed a simulation framework to predict PNS thresholds and stimulation locations in the body for arbitrary coil geometries to inform the gradient coil optimization process. Our approach couples electromagnetic field simulations in realistic body models to a neurodynamic model of peripheral nerve fibers. In this work, we systematically analyze the impact of key parameters on the predicted PNS thresholds to assess the robustness of the simulation results. Methods: We analyze the sensitivity of the simulated thresholds to variations of the most important simulation parameters, including parameters of the electromagnetic field simulations (dielectric tissue properties, body model size, position, spatial resolution, and coil model discretization) and parameters of the neurodynamic simulation (length of the simulated nerves, position of the nerve model relative to the extracellular potential, temporal resolution of the nerve membrane dynamics). Results: We found that for the investigated setup, the subject-dependent parameters (e.g., tissue properties or body size) can affect PNS prediction by up to ~26% when varied in a natural range. This is in accordance with the standard deviation of ~30% reported in human subject studies. Parameters related to numerical aspects can cause significant simulation errors (>30%), if not chosen cautiously. However, these perturbations can be controlled to yield errors below 5% for all investigated parameters without an excessive increase in computation time. Conclusion: Our sensitivity analysis shows that patient specific parameter fluctuations yield PNS threshold variations similar to the variations observed in experimental PNS studies. This may become useful to estimate population-average PNS thresholds and understand their standard deviation. Our analysis indicates that the simulated PNS thresholds are numerically robust, which is important for ranking different MRI gradient coil designs or assessing different PNS mitigation strategies. PMID- 30523885 TI - Nanoshaping of glass forming metallic liquids by stretching: evading lithography. AB - Lithography-free nanomanufacturing by elongation and fracture of glass forming metallic liquid is presented. The viscous metallic liquid confined in a cavity is laterally downsized to nanoscale by stretching. The extent of size-reduction can be controlled by tuning the active volume of liquid and the viscous and capillary stresses. Very high aspect-ratio metal nanostructures can be fabricated without using lithography or expensive molds. A systematic study is performed using glass forming Pt-Cu-Ni-P alloy to understand the effects of viscosity, surface tension, pulling velocity, and cavity size on the evolution of cylindrical liquid column under tension. The results are quantitatively described using a phenomenological model based on lubrication theory and surface tension induced breakup of liquid filaments. A new manufacturing approach based on variable pulling velocity and/or spinning of metallic liquid is proposed for fabrication of complex geometries. PMID- 30523886 TI - Highly tunable multiple narrow emissions of dyed dielectric-metal core-shell resonators: towards efficient fluorescent labels. AB - We report a potential efficient fluorescent label based on the dyed dielectric metal core-shell resonators. By utilizing the near-field coupling between the dyes and the multipolar sharp cavity plasmon resonances, the dyed dielectric metal core-shell resonators with diameter of 1.02 MUm are demonstrated to be capable of supporting multiple spontaneous emission peaks with the linewidths as narrow as ~ 10 nm in visible range, and these reshaped fluorescent emissions are insensitive to the surrounding dielectric environment. Furthermore, these multiple narrow emission peaks show a precise tunability on the spectrum by simply separating a nanometric dielectric layer between the dielectric core and the metallic shell, which may provide an attractive spectral multiplexing strategy in the fields of cell biology and medical sciences. PMID- 30523887 TI - Subatomic-scale resolution with SPM: Co adatom on p(2 x 1)Cu(110):O. AB - We study limits of SPM subatomic resolution in imaging orbital magnetic features on a model system of a Co atom on a p(2 x 1)Cu(110):O surface. We show that scanning tunneling spectroscopies allow to determine the occupation of the Co d shells and the value of the Hubbard U in the DFT+U modeling and that standard near-contact AFM can in principle image the asymmetry due to partial lling of the d shells at close distances in the small-amplitude regime. Due to the partially ionic character of Co, a faint asymmetry is predicted to arise also in the electrostatic force. We anticipate these features to be even stronger for a transition metal adsorbate featuring larger departures from sphericality in charge/spin densities. PMID- 30523888 TI - Uniform tube models with single reflection site do not explain aortic wave travel and pressure wave shape. AB - OBJECTIVE: In hypertension research aortic pressure wave travel and wave shape play a central role. Presently the explanation of aortic pressure is mainly based on wave travel and reflection in tube models with a single distal reflection. Increased pulse pressure with age is assumed to result from increased magnitude of distal reflection (higher SVR), and earlier return of the reflected wave (higher PWV). However, recent in vivo data show that the reflected wave runs towards the periphery rather than towards the heart as tube models predict. Approach: We analyzed wave travel and reflections in tube models in comparison with in-vivo data. Main Results: In the arterial system many reflection sites exist while tube models only have a single site. At all arterial locations, reflection is determined by the global reflection coefficient, given by local characteristic impedance and loading input impedance. The input impedance phase at low frequencies is negative causing delay between reflected and forward waves. Normalized impedances in the aorta depend much less on location than found in tube models. Therefore, the reflected pressure wave is delayed with respect to the forward wave and does not run towards the heart as predicted by tube models. Reflection mainly results from arterial stiffness and geometry, and arrival time of the reflected wave at the heart depends little on PWV. Increased SVR plays an indirect role: higher (transmural) pressure means stiffer vessels thereby affecting reflection. Significance: Tube models should not be used for interpretation of wave-phenomena and explanation of pressure wave shape. PMID- 30523889 TI - Constrained temporal parallel decomposition for EEG-fMRI fusion. AB - Multimodal neuroimaging has become a common practice in neuroscience research. Simultaneous EEG-fMRI is a popular multimodal recording approach due to the complementary spatiotemporal relationship between the two modalities. Several data fusion techniques have been proposed in the literature for EEG-fMRI fusion, including joint-ICA and parallel-ICA frameworks. Previous EEG-fMRI fusion approaches have used sensor-level EEG features. Recently, we introduced source space ICA for EEG-MEG source reconstruction and component identification, which was shown to be a superior alternative to sensor-space ICA. Here, we extend source-space ICA to the fusion of EEG-fMRI data. Additionally, we incorporate the use of a paradigm signal and a lag-based signal decomposition approach to accommodate recent findings demonstrating the potentially variable lag structure between electrophysiological and BOLD signals. We evaluated this method on simulated concurrent EEG-fMRI during a boxcar task design, as well as real concurrent EEG-fMRI data from three participants performing an N-Back working memory task. The block diagram of the algorithm and corresponding source codes are provided. Based on the results of the real working memory task, for all three subjects, one frontal theta component, and one right posterior alpha component had the highest contribution coefficients (~0.5) to the paradigm-related fused component. There were also two more alpha band components with contribution coefficients of 0.3. The highest contributing fMRI component (~0.8) was one known in the literature to be related to the attention network. The second fMRI component was related to the well-known default mode network, with a contribution coefficient of 0.3. PMID- 30523890 TI - Simultaneous optimization of RBE-weighted dose and nanometric ionization distributions in treatment planning with carbon ions. AB - Inverse treatment planning in intensity modulated particle therapy (IMPT) with scanned carbon-ion beams is currently based on the optimization of RBE-weighted dose to satisfy requirements of target coverage and limited toxicity to organs-at risk and healthy tissues. There are many feasible IMPT plans that meet these requirements, which allows the introduction of further criteria to narrow the selection of a biologically optimal treatment plan. We propose a novel treatment planning strategy based on the simultaneous optimization of RBE-weighted dose and nanometric ionization details (ID) as a new physical characteristic of the delivered plan beyond LET. In particular, we focus on the distribution of large ionization clusters (more than 3 ionizations) to enhance the biological effect across the target volume while minimizing biological effect in normal tissues. Carbon-ion treatment plans for different patient geometries and beam configurations generated with the simultaneous optimization strategy were compared against reference plans obtained with RBE-weighted dose optimization alone. Quality indicators, inhomogeneity index and planning volume histograms of RBE-weighted dose and large ionization clusters were used to evaluate the treatment plans. We show that with simultaneous optimization, ID distributions can be optimized in carbon-ion radiotherapy without compromising the RBE-weighted dose distributions. This strategy can potentially be used to account for optimization of endpoints closely related to radiation quality to achieve better tumor control and reduce risks of complications. PMID- 30523891 TI - Approximate and explicit expression of optical forces and pull-in instability of a silicon nano-optomechanical device. AB - Nano-optomechanical systems actuated by optical forces enable many interesting scientific and technological applications. They are vulnerable to the effects of surface stress and Casimir forces. Therefore, calculation of optical forces is essential for the reliability applications of these advanced devices. In this paper, an approximate and explicit expression is developed for the evaluation of the optical force existing between a waveguide and a substrate through the effective refractive index. The influences of surface stress and Casimir forces on the pull-in instability of a silicon nano-optomechanical device actuated by optical forces are investigated. It is found that if neglecting the effect of surface stress, the maximum size, which indicates the device can be safely fabricated, will be over-predicted. The surface stress reduces the critical optical power and its effect is more significant for a slender waveguide. PMID- 30523892 TI - Critical Diffusivity in the Reversibility-Irreversibility Transition of Amorphous Solids Under Oscillatory Shear. AB - Recently it was shown that under oscillatory shear at zero temperature an amorphous solid transitions from asymptotically periodic to asymptotically diffusive steady-state at a critical maximal strain amplitude. Current understanding of the physics behind this transition is lacking. Here we show, using computer simulations, evidence that the diffusivity of the vector of coordinates of the particles comprising an amorphous solid, when subject to oscillatory shear, undergoes a second order phase transition at the reversibility irreversibility transition point. We explain how such a transition is consistent with dissipative forced dynamics on a complex energy landscape, such as is known to exist in amorphous solids. We demonstrate that as the forcing increases, more and more state-space volume becomes accessible to the system, making it less probable for the state-space trajectory of the system to self-intersect and form a limit-cycle, which explains the slowing-down observed at the transition. PMID- 30523893 TI - Electronic properties of hybrid organic/inorganic semiconductor pn-junctions. AB - Hybrid inorganic/organic semiconductor heterojunctions are candidates to expand the scope of purely organic or inorganic junctions in electronic and optoelectronic devices. Comprehensive understanding of bulk and interface doping on the junction's electronic properties is therefore desirable. In this work, we elucidate the energy level alignment and its mechanisms at a prototypical hybrid pn-junction comprising ZnO (n-type) and p-doped N,N'-di(1-naphthyl)-N,N'-diphenyl (1,1'-biphenyl)-4,4'-diamine (alpha-NPD) as semiconductors, using photoelectron spectroscopy. The level alignment can be quantitatively described by the interplay of contact-induced band and energy level bending in the inorganic and organic component away from the interface, and an interface dipole due to the push-back effect. By adjusting the dopant concentration in alpha-NPD, the position of the frontier energy levels of ZnO can be varied by over 0.5 eV and that of alpha-NPD by over 1 eV. The tunability of this pn-junction's energy levels evidences the substantial potential of the hybrid approach for enhancing device functionality. PMID- 30523894 TI - Synthesis of naked plasmonic/magnetic Au/Fe3O4 nanostructures by plasmon-driven anti-replacement reaction. AB - In this study, naked Au(core)/Fe3O4(shell) hybrid nanostructures are rapidly synthesized by plasmon-driven anti-replacement reaction. The Au nanoparticles are prepared by pulsed laser ablation in water. The mixture of Au nanoparticles and FeCl3 solution is irradiated under laser with specific wavelength. The Fe3+ ions are reduced to low valence species by the "hot electrons" in Au, and form the Fe3O4 spindles on the surface of Au nanoparticles. The Au nanoparticles are synchronously oxidized to Au+ and Au3+ ions by the "hot holes". The saturation magnetization and coercivity of Fe3O4 spindles are 48.7 emu/g and 218.9 Oe, respectively. Our work provides a facile route to obtain the naked Au/Fe3O4 plasmonic/magnetic nanostructures. PMID- 30523895 TI - Recent progress in synthesis, properties and applications of hexagonal boron nitride based heterostructures. AB - Featuring an absence of dangling bonds, large band gap, low dielectric constant, excellent chemical inertness, atomically thin hexagonal boron nitride (h-BN) is considered as an ideal candidate for the integration with graphene and other 2D materials. During the past years, great efforts have been devoted to the research area of h-BN based heterostructures from fundamental study to practical applications. In this review, we summarize the recent progress in the synthesis, novel properties and potential applications of h-BN based heterostructures, especially the synthesis technique. Firstly, various approaches for the preparation of both in-plane and vertical stacked h-BN based heterostructures are introduced in detail, including top-down strategies associated with exfoliation transfer processes and bottom-up strategies such as chemical vapor deposition (CVD)-based growth. Secondly, we discuss some novel properties arise in these heterostructures. Then, several promising applications in electronic and optoelectronic devices based on these heterostructures are also reviewed. Finally, we discuss the main challenges and possible research directions in this field. PMID- 30523896 TI - Effect of the radiation protective apron on the response of active and passive personal dosemeters used in interventional radiology and cardiology. AB - In fluoroscopy guided interventional procedures, workers use protection garments and often two personal dosemeters, the readings of which are used for the estimation of the effective dose; whereas the dosemeter above the protection can be used for the estimation of the equivalent dose of the lens of the eye. When a protective apron is worn the scattered field that reaches the dosemeter is different from the case where no protection is used; this study analyses the changes in the response of 7 passive and 8 active personal dosemeters (APDs) when they are placed above a lead or lead equivalent garment for S-Cs and X-ray diagnostics qualities. Monte Carlo simulations are used to support the experimental results. It is found that for passive dosemeters, the influence on the dosemeter's response of the lead or lead equivalent was within the range 15-38% for the X-rays qualities. This effect is smaller, of the order of 10%, when lead-free garments are used, and much smaller, within 1%-10%, for most of the APDs used in the study. From these results it is concluded that when comparing passive and active dosemeters' measurements worn above the protection, a difference of 20%-40% is expected. The effect is small when deriving the effective dose from double dosimetry algorithms, but it can be of major importance when eye lens monitoring is based on the use of the dosemeter worn above the protection. . PMID- 30523897 TI - Vibrational properties of germanane and fluorinated germanene in the chair, boat, and zigzag-line configurations. AB - The electronic and vibrational properties of germanane and fluorinated germanene are studied within Density Functional Theory (DFT) and Density Functional Perturbation Theory (DFPT) frameworks. Different structural configurations of germanane and fluorinated germanene are investigated. The energy difference between the different configurations are consistently smaller than the energy of thermal fluctuations for all the analyzed DFT functionals LDA, GGA, and hybrid functionals, which implies that, in principle, it is possible to find these different configurations in different regions of the sample as minority phases or local defects. We calculate the Raman and infrared spectra for these configurations by using ab initio calculations and compare it with available experimental spectra for germanane. Our results show the presence of minority phases compatible with the configurations analyzed in this work. As these low energy configurations are metaestable, the present work shows that the synthesis of these energy competing phases is feasible by selectively changing the synthesis conditions, which is an opportunity to expand in this way the availability of new two-dimensional compounds. PMID- 30523898 TI - Impedance measures for a better understanding of the electrical stimulation of the inner ear. AB - The performance of cochlear implant (CI) listeners is limited by several factors among which the lack of spatial selectivity of the electrical stimulation. Recently, many studies have explored the use of multipolar strategies where several electrodes are stimulated simultaneously to focus the electrical field in a restricted region of the cochlea. These strategies are based on several assumptions concerning the electrical properties of the inner ear that need validation. The first, often implicit, assumption is that the medium is purely resistive and that the current waveforms produced by several electrodes sum linearly. In Experiment 1, several impedance measurements were carried out in vitro and in eight CI users using sinusoidal and pulsatile waveforms to test this hypothesis. High-resolution voltage recordings (1.1-MHz sampling) were obtained and showed the resistivity assumption to be valid at 46.4 kHz, the highest frequency tested. However, these measures also revealed the presence of parasitic capacitive effects arising from the device at high frequency that could be deleterious to these strategies. Multipolar strategies also require an estimation of the contribution of each electrode to the overall electrical field. This can be partly obtained by measuring the impedance matrix. However, measuring the voltage on active electrodes (ie. the diagonal of the matrix) is not straightforward because of the polarization of the electrode-fluid interface. Existing multipolar strategies use linear extrapolation from measurements made at neighboring electrodes to infer this value. In Experiment 2, we use a simple model including a constant phase element in order to isolate the polarization component of the contact impedance. We show that this model can fit the high-resolution impedance measurements better than previous approaches in the CI field that used resistor-capacitance circuit models despite using the same number of variables. Implications for the design of multipolar strategies are discussed. PMID- 30523899 TI - Diffusion geometry approach to efficiently remove electrical stimulation artifacts in intracranial electroencephalography. AB - OBJECTIVE: Cortical oscillations, electrophysiological activity patterns, associated with cognitive functions and impaired in many psychiatric disorders can be observed in intracranial electroencephalography (iEEG). Direct cortical stimulation (DCS) may directly target these oscillations and may serve as therapeutic approaches to restore functional impairments. However, the presence of electrical stimulation artifacts in neurophysiological data limits the analysis of the effects of stimulation. Currently available methods suffer in performance in the presence of nonstationarity inherent in biological data. Approach: Our algorithm, Shape Adaptive Nonlocal Artifact Removal (SANAR) is based on unsupervised manifold learning. By estimating the Euclidean median of k-nearest neighbors of each artifact in a nonlocal fashion, we obtain a faithful representation of the artifact which is then subtracted. This approach overcomes the challenges presented by nonstationarity. Main results: SANAR is effective in removing stimulation artifacts in the time domain while preserving the spectral content of the endogenous neurophysiological signal. We demonstrate the performance in a simulated dataset as well as in human iEEG data. Using two quantitative measures, that capture how much of information from endogenous activity is retained, we demonstrate that SANAR's performance exceeds the state of-the-art algorithm, independent component analysis, in the time domain as well as the frequency domain. Significance: This approach allows for the analysis of iEEG data, single channel or multiple channels, during DCS, a crucial step in advancing our understanding of the effects of periodic stimulation and developing new therapies. . PMID- 30523900 TI - Resistive Switching in Sub-micrometric ZnO polycristalline Films. AB - Resistive switching devices are considered as the most promising alternative to conventional random access memories. They interestingly offer effective properties in terms of device scalability, low power-consumption, high read/write operation time, endurance and state retention. Moreover, neuromorphic circuits and synapse-like devices are envisaged with resistive switching modeled as memristors, opening the route toward beyond-Von Neumann computing architectures and intelligent systems. This work investigates how the resistive switching properties of zinc oxide thin films are related to both sputtering deposition process and device configuration, i.e. valence change memory (VCM) and electrochemical metallization memory (ECM). Different devices, with an oxide thickness ranging from 50 to 250 nm, are fabricated and deeply characterized. The electrical characterization evidences that, differently from typical nanoscale amorphous oxides employed for resistive RAMs (HfOx, WOx, etc..), sub-micrometric thicknesses of polycristalline ZnO layers with ECM configuration are needed to achieve the most reliable devices. The obtained results are deeply discussed, correlating the resistive switching mechanism to material nanostructure. PMID- 30523901 TI - High fidelity moving Z-Score based controlled breakdown fabrication of solid state nanopore. AB - We investigate the current transport characteristics in the electrolyte dielectric-electrolyte structure commonly used in the in-situ controlled breakdown (CBD) fabrication of solid-state nanopores. It is found that the stochastic breakdown process could lead to fidelity issues of false positives (an incorrect indication of a true nanopore formation) and false negatives (inability to detect initial nanopore formation). Robust and deterministic detection of initial physical breakdown to alleviate false positives and false negatives is critical for precise nanopore size control. To this end, we report a high fidelity moving Z-Score method based CBD fabrication of solid-state nanopore. We demonstrate 100% success rate of realizing the initial nanopore conductance of 3+/-1 nS (corresponds to size of 1.7+/-0.6 nm) regardless of the dielectric membrane characteristics. Our study also elucidates the Joule heating is the dominant mechanism for electric field-based nanopore enlargement. Single DNA molecule sensing using nanopores fabricated by this method was successfully demonstrated. We anticipate the moving Z-Score based CBD method could enable broader access to the solid state nanopore-based single molecule analysis. PMID- 30523902 TI - A stretchable and bendable all-solid-state pseudocapacitor with dodecylbenzenesulfonate-doped polypyrrole-coated vertically aligned carbon nanotubes partially embedded in PDMS. AB - We present an all-solid-state flexible and stretchable pseudocapacitor composed of dodecylbenzenesulfonate-doped polypyrrole (PPy(DBS))-coated vertically aligned carbon nanotubes (VACNTs) partially embedded in a polydimethylsiloxane (PDMS) substrate. VACNTs are grown via atmospheric-pressure chemical vapor deposition (APCVD) on a Si/SiO2 substrate and transferred onto PDMS. Then the PPy(DBS) film is coated with a surface charge of 300 mC/cm2 on individual carbon nanotubes (CNTs) via electropolymerization. The partial embedding of VACNTs in PDMS permits a rapid and facile integration of the PPy(DBS)/CNTs/PDMS structure to construct a flexible and stretchable supercapacitor electrode. The measured capacitance is 3.6 mF/cm2 with a PVA-KOH gel electrolyte at a scan rate of 100 mV/s, which is maintained under stretching from 0% to 150% and bending/twisting angles from 0 to 180. This all-solid-state stretchable supercapacitor shows a stable galvanostatic performance during 10000 charge/discharge cycles with its capacitance retained at 109%. PMID- 30523903 TI - The linear quadratic model: usage, interpretation and challenges. AB - The linear-quadratic model is one of the key tools in radiation biology and physics. It provides a simple relationship between cell survival and delivered dose: S=e^(-alphaD-betaD^2 ), and has been used extensively to analyse and predict responses to ionising radiation both in vitro and in vivo. Despite its ubiquity, there remains questions about its interpretation and wider applicability - Is it a convenient empirical fit or representative of some deeper mechanistic behaviour? Does a model of single-cell survival in vitro really correspond to clinical tissue responses? Is it applicable at very high and very low doses? Here, we review these issues, discussing current usage of the LQ model, its historical context, what we now know about its mechanistic underpinnings, and the potential challenges and confounding factors which arise when trying to apply it across a range of systems. PMID- 30523904 TI - Nanoscale charge transport and local surface potential distribution to probe defect passivation in Ag doped Cu2ZnSnS4 absorbing layer. AB - The performance of earth abundant Cu2ZnSnS4 (CZTS) material is limited by high deficit of open circuit voltage (VOC) which is mainly due to the easy formation of CuZn antisite defects. Suppression of CuZn defects is thus inevitably required for further developments in CZTS based solar cells. We studied systematic increase of Ag doping in CZTS thin film and investigated the nanoscale electrical properties using kelvin probe force microscopy (KPFM) and current sensing atomic force microscopy (CAFM) to probe CuZn defects. Crystallographic analysis indicated the successful partial substitution of Cu+ ions by large size Ag+ ions. The considerable decrease in grain boundary potential from 66.50 +/- 5.44 mV to 13.50 +/- 2.61 mV with Ag doping, suggesting the substantial decrease in CuZn defects. Consequently, CAFM measurement confirms the remarkable increment in minority carrier current with Ag doping and their local mobility in CZTS layer. Finally, the lower persistent photoconductivity (PPC) and fast decay response of photogenerated carriers for Ag doped CZTS photodetector further validate our results. This study provides a fresh approach of controlling deleterious CuZn defects in CZTS by tuning Ag content that may guide researchers to develop next generation high performance CZTS based solar cells. PMID- 30523905 TI - Density functional theory study of structural and thermodynamical stabilities of ferromagnetic MnX (X=P,As,Sb,Bi) compounds. AB - Density functional theory (DFT) calculations for deriving enthalpies of formation DeltaH for ferromagnetic MnX (X=P,As,Sb,Bi) compounds were made for the two competing structures, hexagonal B81 and orthorhombic B31. Standard calculations were performed by using pseudopotentials with the generalized-gradient-approximation (PBE) as exchange-correlation functional. Enhanced exchange-correlation interactions were included by making use of a so called DFT+U approach which requires Ueff=U-J as a parameter. Application of PBE potentials for all compounds and elementary phases (all-PBE) resulted in negative values of DeltaH for MnP and MnAs in both structures whereby the result for MnP B31 agrees very well with experiment. For MnSb and MnBi the all-PBE calculation gives a positive nonbonding DeltaH disagreeing with experiment. To overcome this discrepancy for MnSb and MnBi a DFT+U ansatz was employed for all compounds and elemental Mn. The values for Ueff ranging between 0.7 for MnBi and 1.4 eV for MnAs were determined by fitting the DFT results to measured data of .DeltaH. As a reference for pure Mn the gamma-Mn phase was taken with Ueff=1.3 eV by which choice the experimental volume is fitted. Atomic volumes and ionicities were derived applying Bader's concept resulting in ionicities of Mn less than +0.7. PMID- 30523906 TI - Progress in Cr- and Mn-based superconductors: a key issues review. AB - The presence of magnetic ions was believed to be detrimental to superconductivity in early stage. However, unconventional superconductivity was widely induced by doping or applying external pressure in magnetic systems such as heavy fermion, cuprate and iron-based superconductors, in which magnetic fluctuations are suggested to serve as the pairing glue for Cooper pairs. The discoveries of superconductivity in the magnetic compounds CrAs and MnP under high pressures have further enriched this family and provided new platforms to investigate the interplay between magnetism and superconductivity. They represent respectively the first superconductor among the transition metal Cr- and Mn-based compounds in which the electronic states near the Fermi level are dominated by Cr/Mn-3d electrons. Shortly after this discovery, new types of Cr-based quasi one dimensional superconductors $A$$_2$Cr$_3$As$_3$ (A=K, Rb, Cs, and Na) and $A$Cr$_3$As$_3$ were discovered at ambient pressure. The close proximity of superconductivity to magnetic instabilities in those systems suggests that the spin fluctuations may play crucial roles in mediating the Cooper pairing. In this article, we review the basic physical properties of those novel superconductors and the new progress achieved in recent studies. PMID- 30523907 TI - Analog control with two Artificial Axons. AB - The Artificial Axon is a recently introduced synthetic assembly of supported lipid bilayers and voltage gated ion channels, displaying the basic electrophysiology of nerve cells. Here we demonstrate the use of two artificial axons as control elements to achieve a simple task. Namely, we steer a remote control car towards a light source, using the sensory input dependent firing rate of the axons as the control signal for turning left or right. We present the result in the form of the analysis of a movie of the car approaching the light source. In general terms, with this work we pursue a constructivist approach to exploring the nexus between machine language at the nerve cell level and behavior. PMID- 30523908 TI - A randomized cross-over short-term study on the short-term effects of a zinc lactate containing mouthwash against oral malodour. AB - AIM: This randomized controlled cross-over-design-study investigated short-term effects on oral malodour of a zinc-lactate-containing mouthwash. Materials and Methods: Sixteen subjects (18-65 years) with an organoleptic score (OLS) >= 2 were included. Following rinses were used: A: a zinc-lactate-containing mouthwash (10ml/30s); B: a zinc-lactate-containing mouthwash (15ml/60s); C: a rinse without zinc-lactate (3 droplets/10ml tap water/30s) and D: tap water (10ml/30s). Each formulation was evaluated by two blinded examiners comparing OLS and three volatile-sulphur-compounds (VSC; H2S (hydrogen sulphide), CH3SH (methyl mercaptan) and (CH3)2S (dimethyl sulphide)) before, one and three hours after rinsing. Subject's perception was investigated with a visual-analogue-scale. Linear mixed models were used to compare all parameters simultaneously with respect to the four treatment groups with a significance level alpha<0.05. Results: OLS was significantly reduced by A and B compared to C and D after three hours (p<0.006). The sum of the 3 VSCs as well as H2S alone were significantly reduced by rinses A and B after one and three hours compared to rinses C and D (p<0.05). Significant differences were found between the four rinses for "Taste" (p=0.003), for "Change of mouth feeling" (p=0.001), for "Feeling of freshness" (p=0.002) and for "Effectiveness" (p=0.002) in favour of A & B. Conclusion: A zinc-lactate-containing mouthwash reduced OLS and VSC over a period of three hours with favourable patient reported outcomes. (ID: 144/09; University of Bonn, Germany). PMID- 30523909 TI - Generalized breast density metrics. AB - Mammograms represent data that can inform future risk of breast cancer. Data from two case-control study populations were analyzed. Population 1 included women (N = 180 age matched case-control pairs) with mammograms acquired with one indirect x-ray conversion mammography unit. Population 2 included women (N = 319 age matched case-control pairs) with mammograms acquired from 6 direct x-ray conversion units. The Fourier domain was decomposed into n concentric rings (radial spatial frequency bands). The power in each ring was summarized giving a set of measures. We investigated images in raw, processed and calibrated representations and made comparison with the percentage of breast density (BD) determined with the operator assisted Cumulus method. Breast cancer associations were evaluated with conditional logistic regression, adjusted for body mass index and ethnicity. Odds ratios (ORs), per standard deviation increase derived from the respective breast density distributions and 95% confidence intervals (CIs) were estimated. A measure from a lower radial frequency ring, corresponding 0.083-0.166 cycles/mm and BD had significant associations with risk in both populations. In Population 1, the Fourier measure produced significant associations in each representation: OR = 1.76 (1.33, 2.32) for raw; OR = 1.43 (1.09, 1.87) for processed; and OR = 1.68 (1.26, 2.25) for calibrated. BD also provided significant associations in Population 1: OR = 1.72 (1.27, 2.33). In Population 2, the Fourier measure produced significant associations for each representation as well: OR = 1.47 (1.19, 1.80) for raw; OR = 1.38 (1.15, 1.67) for processed; and OR = 1.42 (1.15, 1.75) for calibrated. BD provided significant associations in Population 2: OR = 1.43 (1.17, 1.76). Other coincident spectral regions were also predictive of case-control status. In sum, generalized breast density measures were significantly associated with breast cancer in both FFDM technologies. . PMID- 30523910 TI - Triaxially uniform high-quality AlxGa(1-x)N (x?50%) nanowires on template free sapphire substrate. AB - We have demonstrated the growth of high-quality AlxGa(1-x)N (x~50%) nanowires for the first time on the sapphire substrate without using GaN nanowires as the template by Plasma-Assisted Molecular Beam Epitaxy. Our newly developed process elucidates that depending on the substrate temperature and V/III ratio an AlGaN network is formed on sapphire substrate prior to the NWs growth. We find that the ledges of this kinked shaped network act as nucleation sites for the NW growth. The present observations suggest that availability of nucleation sites and higher substrate temperature during growth are the key parameters for the growth of homogeneous AlGaN NWs on the sapphire substrates. Energy Dispersive X-ray Spectroscopy, High-Resolution Transmission Electron Microscopy, Raman Spectroscopy, X-ray diffraction and Scanning Electron Microscopy analysis show that AlGaN NWs exhibit near-atomic scale compositional uniformity along the length as well as across the diameter. PMID- 30523911 TI - Synthesis of gadolinium-based Bi2S3 nanoparticles as cancer theranostics for dual-modality computed tomography /magnetic resonance imaging guided photothermal therapy. AB - Development of a safe, efficient and inexpensive multifunctional nanoplatform using a facile approach for multimodal imaging and therapeutic functions becomes more and more practically relevant but challenging. In this work, we demonstrated a novel nanocomposites (Bi2S3-Gd) for computed tomography (CT)/magnetic resonance (MR) imaging-guided photothermal therapy for cancer in vitro. It was achieved by modification of hydrophobic Bi2S3 with a smart amphiphilic gadolinium-chelated ligand. The as-prepared nanocomposites composed of low cost Bi2S3 and gadolinium complexes, showed high stability, excellent biocompatibility and good photostability. It was observed that Bi2S3-Gd nanocomposites could efficiently convert the NIR light into heat, and then suppressed the growth of tumor cells under NIR laser irradiation. Apart from serving as an effective photothermal agent, the as-prepared nanomaterials could induce an efficient contrast enhancement for both CT and MRI imaging at low concentrations of Bi and Gd, rendering more accurate diagnosis. This work suggests the potential of Bi2S3-Gd nanomaterials as a novel multifunctional nanoplatform for CT/MRI imaging-guided photothermal therapy for cancer. PMID- 30523912 TI - Dosimetry of indigenously developed 177Lu patch source for surface brachytherapy Experimental and Monte Carlo methods. AB - This paper describes the evaluation of dosimetry characteristics of an in-house developed 177Lu skin patch source for treatment of non-melanoma skin cancer. A 177Lu skin patch source based on Nafion-115 membrane backbone containing 3.46 +/- 0.01 mCi of activity was used. Activity measurement of the patch source was based on gamma ray spectrometry using a HPGe detector. The efficiencies of the HPGe detector were fitted using an orthogonal polynomial function. The absorbed dose rate to water at 5 um depth in water was determined using an extrapolation chamber, EBT3 Gafchromic film and compared with Monte Carlo methods. The correction factors such as Bragg-Gray stopping power ratio of water-to-air and chamber wall material being different from water, needed to be applied on measurements for establishing the dose rate at 5 um depth, were calculated using the Monte Carlo methods. Absorbed dose rate at 5 um depth in water (surface dose rate) measured using an extrapolation chamber and EBT3 Gafchromic film were 9.9 +/- 0.7 and 8.2 +/- 0.1 Gy h-1 mCi-1 respectively for the source activity of 3.46 +/- 0.01 mCi. The surface dose rate calculated using the Monte Carlo methods was 8.7 +/- 0.2 Gy h-1 mCi-1, which agrees reasonably well with measurement. The measured dose rate per mCi offers scope for ascertaining treatment time required to deliver the dose for propitious therapeutic outcome. Additionally, on-axis depth dose and lateral dose profiles at 5 um and 1 mm depth in water phantom were also calculated using Monte Carlo method. PMID- 30523913 TI - In-situ durability of various carbon supports against carbon corrosion during fuel starvation in PEM fuel cell cathode. AB - In this study, the degradation of different cathode carbon supports is investigated in PEMFCs. A platinum catalyst is synthesized using various carbon supports, such as Vulcan XC-72, graphite nano powder, and carbon nanotube, which are evaluated based on the fabrication of membrane-electrode-assemblies (MEAs). During the start-up and shutdown of PEMFCs, the individual electrode potential can be measured in-situ using a dynamic hydrogen electrode (DHE). The cathode potential increases instantaneously to 1.4 V in one attempt, when H2/air boundaries are developed on the anode side during the fuel starvation, leading to significant carbon corrosion. The corrosion rates of various carbon supports are calculated from the concentration of gases, such as CO2, CO, and SO2, emitted in the cathode outlet, measured directly in-situ by FT-IR gas analysis. The CNT supported Pt catalyst shows the best performance against carbon corrosion during fuel starvation, compared to commercial Pt/C catalyst and other types of carbon supports. PMID- 30523914 TI - Numerical investigation of low-noise airfoils inspired by the down coat of owls. AB - Numerical analysis of airfoil geometries inspired by the down coat of the night owl is presented. The bioinspired geometry consists of an array of 'finlet fences', which is placed near the trailing edge of the baseline (NACA 0012) airfoil. Two fences with maximum nondimensional heights, [Formula: see text] and [Formula: see text] are investigated, where [Formula: see text] is the displacement thickness at 2.9% chord upstream of the airfoil trailing edge. Wall resolved large eddy simulations are performed at chord-based Reynolds number, [Formula: see text], flow Mach number, [Formula: see text], and angle of attack, [Formula: see text]. The simulation results show significant reductions in unsteady surface pressure and farfield radiated noise with the fences, in agreement with the measurements available in the literature. Analysis of the results reveals that the fences increase the distance between the boundary layer turbulence (source) and the airfoil trailing (scattering) edge, which is identified to be the mechanism behind high-frequency noise reduction. These reductions are larger for the taller fence as the source-scattering edge separation is greater. Two-point correlations show that the fences reduce the spanwise coherence at low frequencies for separation distances greater than a fence pitch (distance between two adjacent fences) and increase the coherence for smaller distances, the increase being higher for the taller fence. This increase in coherence and the reduced obliqueness of the leading edge of the fence are hypothesized to be responsible for the small increase in farfield noise at low frequencies observed in the simulations with the taller fence. PMID- 30523915 TI - Energy-modulated X-ray fluorescence and luminescence emissions from therapeutic nanoparticles. AB - In this study, we have investigated the possibility of modulating X-ray fluorescence (XF) and X-ray luminescence (XL) emissions from therapeutic nanoparticles (NPs) by fine-tuning the energy of incident X-rays from benchtop X ray sources. We have carried out detailed experimental studies to determine the strength of XF and XL emissions from Y2O3:Eu3+ and LaF3:Tb3+ NPs being irradiated with X-rays from benchtop X-ray sources operated with different tube-voltages and coupled to various filter configurations. These studies demonstrated that low energy X-rays with average energy at around 10-15 keV are the most efficient to stimulate XL emission from the Y2O3:Eu3+ and LaF3:Tb3+ NPs. The efficiency falls quickly when X-ray energies go above or below the optimum energy range. As one would expect, X-rays with average energy just above the corresponding absorption edge of the target metal would be the most efficient in inducing XF emission. In this study, we have also demonstrated that one could fine-tune the incident X-ray energy to modulate the XL and XF emissions, such as (a) selectively inducing either XL or XF emission from the same type of NPs, (b) inducing preferential XL activation of Y2O3:Eu3+ over LaF3:Eu3+ or controlling the ratio of XL activation of these two types of NPs, and (c) introducing preferential XF emission from one type of NPs over the other. As a potential application, one could optimize the energy-characteristics of the incident X-rays to facilitate multiplexed combinatorial delivery of photodynamic therapy (X-PDT), where different agents could be administrated and then selectively activated in user-defined spatial and temporal patterns to fulfill combinatorial therapeutic effects. The understanding gained through this study could prove critical for enhancing the therapeutic delivery in X-PDT, and for attaining high-quality X-ray fluorescence computed tomography (XFCT) and X-ray luminescence computed tomography (XLCT) images while minimizing the X-ray dose to the sample. PMID- 30523916 TI - Cascaded systems analysis of a-Se/a-Si and a-InGaZnO TFT passive and active pixel sensors for tomosynthesis. AB - Medical imaging systems like full field digital mammography (FFDM) and digital breast tomosynthesis (DBT) commonly use amorphous selenium (a-Se) based passive pixel sensor (PPS) direct conversion x-ray detectors. On one hand, direct conversion detectors inherently offer better resolution characteristics in terms of a higher modulation transfer function (MTF), in comparison to the indirect CsI:Tl PPS x-ray imager. On the other hand, especially at lower doses, this superior performance of the direct imager is seldom retained in its detective quantum efficiency (DQE) curves. It is well known that a-Se PPS x-ray imagers suffer from high additive electronic noise originating from the from the amorphous silicon (a-Si) thin film transistor (TFT) array that is being used in the current back-plane technology. This degrades the noise power spectrum (NPS) and subsequently the overall DQE. To address this deficiency, we propose to replace the PPS back-plane by active pixel sensor (APS) back-plane technology, which has the potential to reduce the back-plane electronic noise by amplifying the input signal, especially at low doses. The proposed APS is based on amorphous In-Ga-Zn-O (a-IGZO) TFT technology, which can offer high mobility (5-20 cm2/V-s), low leakage current (< 10-13 A) and low flicker noise (Hooge's parameter alphaH ~ 1.5 * 10-3), leading to better imager noise performance. To test our hypothesis, we used linear cascaded systems analysis to model the imaging performance (MTF, NPS and DQE) of the PPS and APS a-Se direct imagers. This model was first validated using experimentally measured data obtained for a 85 um pixel pitch a-Se/a-Si TFT PPS imager. Using this model, we analyzed the noise performance of the direct a-Se and indirect CsI:Tl x-ray a-IGZO APS imagers at different dose and electronic noise levels. Obtained results clearly showed that lowering back-plane electronic noise can significantly improve the performance of the a-Se/a-IGZO TFT APS imager. Our simulated results showed that a higher DQE at lower radiation doses (maximum DQE of 0.6 can be achieved at an exposure level of 1 uGy) can be achieved with the a-Se detector, thereby making this combination a promising candidate for low dose applications like DBT. . PMID- 30523917 TI - Toward facile broadband photodetectors based on self-assembled ZnO nanobridge/rubrene heterointerface. AB - ZnO nanowire photodetectors have attracted much attention due to their excellent optoelectronic performances. However, the operating speed remains a challenge, and the scalability is also impeded by the uncontrolled transfer methods and sophisticated fabrication process. In this paper, we have fabricated an excellent ZnO nanobridge ultraviolet photodetector array by using a simple one-step method. The faster photoresponse speed and a broader response wavelength (from UV to visible range) have been achieved by constructing a type-II ZnO/rubrene heterointerface. Performance enhancement is believed to arise from the well matching band alignment and highly efficient separation of photogenerated electron-hole pairs at the heterointerface. Our strategy provides a simple and promising route to develop cost-effective and highly sensitive UV-Vis photodetectors. PMID- 30523918 TI - Highly efficient InGaN green mini-size flip-chip light-emitting diodes with AlGaN insertion layer. AB - We demonstrate highly efficient InGaN-based mini-size green light-emitting diodes (mLEDs) with AlGaN insertion layer in InGaN/GaN multiple quantum wells (MQWs) using metal organic chemical vapor deposition (MOCVD). High resolution transmission electron microscopy (HRTEM) results reveal that "V" defects within active region can be effectively reduced by the AlGaN insertion layer. Three dimension finite difference time domain (3D-FDTD) simulation shows a significant enhancement of light extraction efficiency (LEE) for the flip-chip mLEDs with distributed Bragg reflector (DBR). Very high performance 523 nm InGaN green mLEDs (0.025 mm2) with a high external quantum efficiency (EQE) of 38.0%, a high wall plug efficiency (WPE) of 32% and a low forward voltage of 2.8 V have been achieved at a working current density of 20 A/cm2, which are promising for display application. PMID- 30523919 TI - A comprehensive review of EEG-based brain-computer interface paradigms. AB - Advances in brain science and computer technology in the past decade have led to exciting developments in Brain-Computer Interface (BCI), thereby making BCI a top research area in applied science. The renaissance of BCI opens new methods of neurorehabilitation for physically disabled people (e.g., paralyzed patients and amputees) and patients with brain injuries (e.g., stroke patients). Recent technological advances such as wireless recording, machine learning analysis, and real-time temporal resolution have increased interest in electroencephalographic (EEG) based BCI approaches. Many BCI studies have focused on decoding EEG signals associated with whole-body kinematics/kinetics, motor imagery, and various senses. Thus, there is a need to understand the various experimental paradigms used in EEG-based BCI systems. Moreover, given that there are many available options, it is essential to choose the most appropriate BCI application to properly manipulate a neuroprosthetic or neurorehabilitation device. The current review evaluates EEG-based BCI paradigms regarding their advantages and disadvantages from a variety of perspectives. For each paradigm, various EEG decoding algorithms and classification methods are evaluated. The applications of these paradigms with targeted patients are summarized. Finally, potential problems with EEG-based BCI systems are discussed, and possible solutions are proposed. PMID- 30523920 TI - Flexible all-solid-state supercapacitors of polyaniline nanowire arrays deposited on MOFs decorated electrospun carbon nanofibers. AB - Porous carbons derived from metal-organic framework are promising materials for a number of energy and environmental related applications. To integrate the powder metal-organic framework derived carbon into feasible engineered materials, a facile strategy to fabricate integrated flexible film is developed by growth of metal organic framework nanoparticles on polyimide electrospun nanofibers following with calcination to fabricate freestanding porous carbon decorated carbon nanofiber membranes. Then vertically polyaniline nanowire arrays were uniformly deposited on the hierarchical porous carbon substrates by in situ polymerization. Thanks to the good distribution of MOFs derived porous carbon on carbon nanofibers and the compact configuration interwoven by conducting polymers, the designed hybrid electrode could directly used as freestanding electrode for supercapacitors, which displayed a high specific capacitance of 1268 F g-1. The assembled flexible solid-state supercapacitor based on the integrated electrodes demonstrated a high volumetric capacitance of 1973 mF cm-3 and a good capacitance retention of 84.9% after 10000 cycles, which could power a commercial light-emitting-diode (LED). This strategy may shed light on designing MOFs-based flexible materials for practical applications of supercapacitors and other electrochemical devices. PMID- 30523922 TI - Physics with reactor neutrinos. AB - N/A at Outline stage. PMID- 30523921 TI - A digital acoustofluidic device for on-demand and oil-free droplet generation. AB - We report a digital acoustofluidic device for on-demand and oil-free droplet generation. By applying a programmed radio frequency signal to a circular interdigital transducer, dynamically focused acoustic pressure profiles generated could raise up and dispense sample liquids from a reservoir to fast eject the droplets into the air. With optimization, our device allows on-demand droplet dispensing with precisely controlled generation time, sequence and accurate droplet volume. Moreover, we also demonstrate the generation of the droplet with a volume of 24 pL within 10 ms as well as the encapsulation of single cell into droplets. This acoustofluidic droplet generation technique is simple, biocompatible, and enables the on-demand droplet generation and encapsulation of many different biological materials with precise control, which is promising for single cell sampling and analysis applications. PMID- 30523923 TI - Validation of non-invasive brain temperature estimation models during swine therapeutic hypothermia. AB - OBJECTIVES: This paper introduces a mathematical model that can estimate deep brain temperature during therapeutic hypothermia based on a double sensor method. Although the cerebral temperature is more important than the non-cerebral core temperature during therapeutic hypothermia, pulmonary artery, rectal, and esophageal measurements (i.e., the typical core temperature measurement locations) have all been used for target temperature management. This is because there is no safe means of measuring the exact brain temperature. Approach. We applied a double sensor thermometer to the subject's forehead to measure the cerebral temperature non-invasively. Invasive and non-invasive brain temperature readings were acquired for 11 pigs, seven of which were used to develop an optimal model using jackknife resampling and four of which were used to test the model. Main Results. The logit model exhibited the best performance of 0.134 degrees C root-mean-square error and a 0.993 Lin's concordance correlation coefficient (CCC). Each test dataset had acceptable results in that each 95% limit of agreement was within the range of clinical acceptance of [-0.5 degrees C, 0.5 degrees C]. Three of the four datasets yielded an "almost perfect" score for Lin's CCC. Significance. Only a small number of studies have compared invasively and non-invasively measured brain temperatures, while most previous studies have concentrated on comparison with the core temperature. The possibility of measuring the exact brain temperature safely during therapeutic hypothermia using a double sensor method is demonstrated in this work. PMID- 30523924 TI - Design and fabrication of bi-functional TiO2/Al2O3 nanolaminates with selected light extraction and reliable moisture vapor barrier performance. AB - Bi-functional thin film with both selected light extraction and reliable moisture vapor barrier was proposed for simultaneous light management and encapsulation in the fields of lighting and display. Atomic layer deposition (ALD) was employed to obtain TiO2 and Al2O3 films with high uniformity, forming distributed Bragg reflector (DBR) structure. The DBRs exhibited excellent and tunable optical properties, as well as reliable moisture barrier performance. With increasing the DBR layers, the transmittances decreased obviously. The transmittance in the blue light region was as low as 0.66% for DBR with 6.5 pairs and the water vapor transmission rates (WVTR) value was 3.06*10-5 g/m2/day for DBR with 4.5 pairs. These DBRs were integrated in the red quantum dot (QD) based color converters excited by blue LED, enabling an obvious increase in red emission and a strong decrease in blue light transmittance. Furthermore, these DBRs can prolong the lifetime of QDs evidently by isolating the QDs from the moisture (oxygen) vapor. These results highlight the potentials for the exploitation of DBRs fabricated using ALD in the application of lighting and display devices based on QD photo luminescence and electro- luminescence. PMID- 30523925 TI - A depth-of-interaction encoding PET detector module with dual-ended readout using large-area silicon photomultiplier arrays. AB - The performance of a depth-of-interaction (DOI) encoding PET detector module with dual-ended readout of LYSO scintillator arrays using large-area SiPM arrays was evaluated. Each SiPM array, with a surface area 50.2 mm x 50.2 mm, consists of 12 x 12 C-series SiPMs from SensL (SensL, Inc). The LYSO array, with a total size of 46 mm x 46 mm and a pitch size of 1.0 mm, consists of a 46 x 46 array of 0.945 mm x 0.945 mm x 20 mm polished LYSO crystals, separated by Toray reflector. Custom front-end electronics were designed to reduce the 288 SiPM signals of one detector module to 9 signals, 8 for position information and 1 for timing information. Schottky diodes were used to block noise from SiPMs that did not detect a significant number of scintillation photons following a gamma interaction. Measurements of noise, signal, signal-to-noise ratio, energy resolution and flood histogram quality were obtained at different bias voltages (26.0 to 31.0 V in 0.5 V intervals) and at two temperatures (5 degrees C and 20 degrees C). Clear acrylic plates, 2.0 mm thick, were used as light guides to spread the scintillation photons. Timing resolution, depth of interaction resolution, and the effect of event rate on detector performance were measured at the bias voltage determined to be optimal for the flood histograms. Performance obtained with and without the noise-blocking Shottky diodes was also compared. The results showed that all crystals in the LYSO array can be clearly resolved, and performance improved when using diodes to block noise, and at the lower temperature. The average energy resolution, flood histogram quality, timing resolution and DOI resolution were 23.8 +/- 2.0 %, 1.54 +/- 0.17, 1.78 +/- 0.09 ns and 2.81 +/- 0.13 mm respectively, obtained at a bias voltage of 30.0 V and a temperature of 5 degrees C using the diode readout method. The event rate experiments showed that the flood histogram and energy resolution of the detector were not significantly degraded for an event rate of up to 150 000 counts/s. PMID- 30523926 TI - Experimental and analytical studies on the flexible, low-voltage electrothermal film based on the multi-walled carbon nanotube/polymer nanocomposite. AB - This paper presents multi-walled carbon nanotube (MWCNT)/poly(m-phenylene isophthalamide) (PMIA) nanocomposite films as electrothermal elements, which offer advantages in flexibility, low energy consumption and rapid temperature growth. The electrical properties, electrothermal behavior and thermal stability of the films were investigated as a function of MWCNT content. The percolation behavior analysis revealed MWCNTs built a continuously conductive network in PMIA matrix at the corresponding percolation threshold of ~0.06 wt%. The electrothermal behavior of the MWCNT/PMIA film was investigated by considering temperature response rapidity and electrothermal efficiency under different ambient conditions. For the film with 7.0 wt% MWCNTs under different ambient conditions, the film worked at a high heating rate of 1.0-8.2 degrees C/s and cooling rate of 0.75-7.0 degrees C/s under a low voltage of 3-12 V, due to the low electrical resistivity (4.5 Omega?cm) of the film. The prepared MWCNT/PMIA films supported more outstanding heating performance than conventional PI-Kanthal film, including good heating uniformity, higher electrothermal efficiency and heating/cooling rate. Moreover, the improved thermomechanical properties of the nanocomposite were observed by dynamic thermomechanical analysis (DMA). PMID- 30523927 TI - One-step synthesis of nail-like Mn-doped CdS/CdBr2 hetero nanostructures for potential lasing application. AB - Nanoscale heterostructures, which incorporate two or more materials such as core shell nanocrystals, core-crown nanoplates, or seeded nanorods, allow better control of the optical, electrical and magnetic properties that are inaccessible in single component nanostructure, yet their variety and controlled growth are still challenging. Here, a nail-like Mn-doped CdS/CdBr2 hetero-nanostructure, which has a hexagonal plate on top of a nanowire, is firstly fabricated by a simple one-step thermal evaporation process. According to the characterization results, its growth mechanism could be obtained, in which the manganese bromide precursor plays a critical role in the formation of such nail morphology. The amplified spontaneous emission of the "nanonail" is achieved at a low threshold at room-temperature, which come from the local and dense exciton scattering due to their interactions excited by fs pulse. These interesting nail-like heterostructures may provide promising templates for constructing high performance optoelectronic devices. PMID- 30523928 TI - Contour scanning, multi-leaf collimation and the combination thereof for proton pencil beam scanning. AB - In proton therapy, the lateral fall-off is often used to spare critical organs. It is therefore crucial to improve the penumbra for proton pencil beam scanning. However, previous work has shown that collimation may not be necessary for depths of >15cm in water. As such, in this work we investigate the effectiveness of a thin multi leaf collimator (just thick enough to completely stop protons with ranges of <15cm in water) for energy layer specific collimation in patient geometries, when applied in combination with both grid and contour scanned PBS proton therapy. For this, an analytical model of collimated beam shapes, based solely on data available in the treatment planning system, has been included in the optimization, with the resulting optimised plans then being recalculated using Monte Carlo in order to most accurately simulate the full physics effects of the collimator. For grid based scanning, energy specific collimation has been found to reduce the V30 outside the PTV by 19.8% for an example patient when compared to the same pencil beam placement without collimation. V30 could be even reduced by a further 5.6% when combining collimation and contour scanning. In addition, mixed plans, consisting of contour scanning for deep fields (max range >15cm WER) and collimated contour scanning for superficial fields (<15cm), have been created for four patients, by which V30 could be reduced by 0.8% to 8.0% and the mean dose to the brain stem by 1.5% to 3.3%. Target dose homogeneity however is not substantially different when compared to the best un-collimated scenario. In conclusion, we demonstrate the potential advantages of a thin, multi leaf collimator in combination with contour scanning for energy layer specific collimation in PBS proton therapy. PMID- 30523929 TI - A European survey on the regulatory status for the estimation of the effective dose and the equivalent dose to the lens of the eye when radiation garments are used. AB - Following the proposal of the ICRP for the reduction of dose limit for the lens of the eye which has been adopted by the International Atomic Energy Agency and the European Council a lot of concern has been raised about the implementation of proper dose monitoring methods defined in the national regulations and the harmonisation within European countries. EURADOS organised a survey at the end of 2017, through a web questionnaire, regarding the national dose monitoring regulations. The questions were related to: double dosimetry, algorithm for the estimation of the effective dose, methodology for the determination of the equivalent dose to the lens of the eye and structure of the national dose registry. The results showed that more than 50% of the countries that responded to the survey have legal requirements about the number and the position of dosemeters used for estimation of the effective dose when radiation protective garments are used. However, only in 5 out of 26 countries there are nationally approved algorithms for the estimation of the effective dose. Moreover, in 14 out of 26 countries there is a legal requirement to estimate the dose to the lens of the eye. All of the responding countries use a kind of national database for keeping the individual monitoring data but in only 12 out of 26 countries the estimated effective dose values are stored. The personal dose equivalent at depth 3 mm is stored in the registry of only 7 out of 26 countries. From the survey performed just before the implementation of the European Basic Safety Standards Directive it is concluded that the national occupational exposure framework require intensive and immediate work under the coordination of the competent authorities to be in line with the latest basic safety standards and achieve harmonisation within the European countries. PMID- 30523930 TI - Neural correlates of speech quality dimensions analyzed using electroencephalography (EEG). AB - OBJECTIVE: By means of subjective psychophysical methods, quality of transmitted speech has been decomposed into three perceptual dimensions named "discontinuity" (F), "noisiness" (N) and "coloration" (C). Previous studies using electroencephalography (EEG) already reported effects of perceived intensity of single quality dimensions on electrical brain activity. However, it has not been investigated so far, whether the dimensions themselves are dissociable on a electrophysiological level of analysis. APPROACH: Pursuing this goal in the present study, a high-quality (HQ) recording of a spoken word was degraded on each dimension at a time, resulting in three quality-impaired stimuli (F, N, C), which were on average described as being equal in perceived degradation intensity. Participants performed a three-stimulus oddball task, involving the serial presentation of different stimulus types: 1) HQ or degraded "standard" stimuli to establish sensory/perceptual quality references. 2) Degraded "oddball" stimuli to cause random, infrequent deviations from those references. EEG was employed to examine the neuro-electrical correlates of speech quality perception. MAIN RESULTS: Focus was put on modulations in the temporal and morphological characteristics of the P300 component of the event-related brain potential (ERP), whose subcomponents P3a and P3b are commonly linked to attentional orienting and task relevance categorization, respectively. Electrophysiological data analysis (N = 28) revealed significant modulations of P300 amplitude and latency by the perceptual dimensions underlying both quality references and oddball stimuli. SIGNIFICANCE: The present study exemplifies the utility of physiological methods like EEG for dissociating speech degradations not only based on perceived intensity level, but also their distinctive quality dimension. PMID- 30523931 TI - Li 1s core exciton in LiH studied by X-ray Raman scattering spectroscopy. AB - The Li 1s core excitation spectra in LiH was studied by means of X-ray Raman scattering (XRS) spectroscopy in a wide range of momentum transfers q. The analysis of the near-edge region of the measured spectra in combination with q-dependent ab initio calculations of XRS spectra based on the Bethe-Salpeter equation (BSE) reveals that the prominent peak at the excitation onset arises from two main contributions, a pre-edge peak associated to a p-type core exciton and strong transitions to empty states near the bottom of the conduction band, which is in contrast to previous experimental studies that attributed that feature to a single excitonic peak. The p like angular symmetry of the core exciton is supported by BSE calculations of the relative contributions to the XRS spectra from monopole and dipole transitions and by the observed decrease of its normalised intensity for increasing momentum transfers. Higher energy spectral features in the measured XRS spectra are well reproduced by BSE as well as by real-space multiple-scattering calculations. PMID- 30523932 TI - Robust optimization to reduce the impact of biological effect variation from physical uncertainties in intensity-modulated proton therapy. AB - PURPOSE: Robust optimization (RO) methods are applied to intensity-modulated proton therapy (IMPT) treatment plans to ensure their robustness in the face of treatment delivery uncertainties, such as proton range and patient setup errors. However, the impact of those uncertainties on the biological effect of protons has not been specifically considered. In this study, we added biological effect based objectives into a conventional RO cost function for IMPT optimization to minimize the variation in biological effect. Methods: One brain tumor case, one prostate tumor case and one head & neck tumor case were selected for this study. Three plans were generated for each case using three different optimization approaches: planning target volume (PTV)-based optimization, conventional RO, and RO incorporating biological effect (BioRO). In BioRO, the variation in biological effect caused by IMPT delivery uncertainties was minimized for voxels in both target volumes and critical structures, in addition to a conventional voxel-based worst-case RO objective function. The biological effect was approximated by the product of dose-averaged linear energy transfer (LET) and physical dose. All plans were normalized to give the same target dose coverage, assuming a constant relative biological effectiveness (RBE) of 1.1. Dose, biological effect, and their uncertainties were evaluated and compared among the three optimization approaches for each patient case. Results: Compared with PTV-based plans, RO plans achieved more robust target dose coverage and reduced biological effect hot spots in critical structures near the target. Moreover, with their sustained robust dose distributions, BioRO plans not only reduced variations in biological effect in target and normal tissues but also further reduced biological effect hot spots in critical structures compared with RO plans. Conclusion: Our findings indicate that IMPT could benefit from the use of conventional RO, which would reduce the biological effect in normal tissues and produce more robust dose distributions than those of PTV based optimization. More importantly, this study provides a proof of concept that incorporating biological effect uncertainty gap into conventional RO would not only control the IMPT plan robustness in terms of physical dose and biological effect but also achieve further reduction of biological effect in normal tissues. . PMID- 30523933 TI - A naphthalene-based fluorescent probe for ratiometric imaging of lysosomal hydrogen sulfide in living cells. AB - Hydrogen sulfide is an important gasotransmitter that exhibits various functions in physiological processes. We present a ratiometric fluorescence probe (SN-N3) for H2S by functionalizing naphthalene imide with 4-(azidomethyl)benzene as a H2S recognition moiety and a morpholine moiety as a lysosomal targeting unit. After reaction with H2S, the azido moiety is reduced to amine group, and the probe releases the self-immolative linker and regenerates the fluorophore with internal charge transfer effect. SN-N3 is responsive to H2S in a ratiometric mode, exhibiting excellent sensitivity and high selectivity. The probe is demonstrated to be localized in lysosomes with high specificity. More importantly, SN-N3 is successfully demonstrated to image lysosomal H2S in a ratiometric manner. Our design provides a novel tool to image H2S in living cells that would hold great potential in exploring various H2S-related physiological and pathological cellular processes. PMID- 30523934 TI - Computational design of metal-supported molecular switches: Transient ion formation during light- and electron-induced isomerisation of azobenzene. AB - In molecular nanotechnology, a single molecule is envisioned to act as the basic building block of electronic devices. Such devices may be of special interest for organic photovoltaics, data storage, and smart materials. However, more often than not the molecular function is quenched upon contact with a conducting support. Trial-and-error-based decoupling strategies via molecular functionalisation and change of substrate have in many instances proven to yield unpredictable results. The adsorbate-substrate interactions that govern the function can be understood with the help of first-principles simulation. Employing dispersion-corrected Density-Functional Theory (DFT) and linear expansion Delta-Self-Consistent-Field DFT, the electronic structure of a prototypical surface-adsorbed functional molecule, namely azobenzene adsorbed to (111) single crystal facets of copper, silver and gold, is investigated and the main reasons for the loss or survival of the switching function upon adsorption are identified. The light-induced switching ability of a functionalised derivative of azobenzene on Au(111) and azobenzene on Ag(111) and Au(111) is assessed based on the excited-state potential energy landscapes of their transient molecular ions, which are believed to be the main intermediates of the experimentally observed isomerisation reaction. We provide a rationalisation of the experimentally observed function or lack thereof that connects to the underlying chemistry of the metal-surface interaction and provides insights into general design strategies for complex light-driven reactions at metal surfaces. PMID- 30523936 TI - Probing the magnetoelectric effect in noncentrosymmetric superconductors by equal spin Andreev tunneling. AB - In noncentrosymmetric superconductors (NCSs), the conversion of a charge current into spin magnetization - the so called magnetoelectric effect - is the direct indicator of the unconventional, mixed-parity order parameter. This paper proposes a scheme to detect the magnetoelectric effect by anomalous, equal spin Andreev tunneling in NCS/ferromagnet contacts. The proposal relies on the ability to generate spin-polarized triplet pairing by passing an electric current through an NCS. Such an induced triplet pairing bears a similarity to the paradigmatic nonunitary pairing in triplet superfluids with a complex vector order parameter ${?bm d}$. The qualitative difference is that the induced nonunitary state can be realized in NCSs with a purely real ${?bm d}$ by breaking the time-reversal symmetry in current-biased setups. This offers a possibility to access the unconventional superconductivity in NCSs through electrical transport measurements. PMID- 30523935 TI - Associations of diet and lifestyle factors with common volatile organic compounds in exhaled breath of average-risk individuals. AB - BACKGROUND: Detection of diseases via exhaled breath remains an attractive idea despite persisting gaps in understanding the origin of volatile organic compounds (VOCs) and their relationship with the disease of interest. Data on factors potentially influencing the results of breath analysis remain rather sparse and often controversial. In this study, we aimed to investigate the associations of common VOCs in exhaled breath of average-risk individuals with socio-demographic and lifestyle factors, medical conditions as well as diet. Methods: Alveolar breath samples of 1,447 men and women were collected in the morning after fasting and were analyzed using gas-chromatography linked with mass spectrometry. Study participants were 40-64 years old, cancer-free, with overall good health status. The associations between selected VOCs and various factors determined from the questionnaire data were assessed using two-part-Wilcoxon test and Jonckheere-Terpstra trend test. Results: Fifteen VOCs where each of them was detected in at least 80% of the study population were included in this analysis. Statistically significant associations with various VOCs were demonstrated for gender and consumption of certain foods, such as coffee, leeks and garlic, while smoking was not associated with any of the analyzed compounds. Conclusion: Factors potentially modifying the composition of exhaled breath, such as dietary factors, deserve careful attention in the design and analysis of studies accessing the use of VOCs as diagnostic markers. ClinicalTrials.gov Identifier: NCT02047994. PMID- 30523937 TI - Mode confinement, interface mass-smudging, and sample length effects on phonon transport in thin nanocomposite superlattices. AB - We employ a semi-ab initio theoretical method to investigate mode confinement, interface mass-smudging, and sample length effects on phonon transport in thin nanocomposite superlattices. We present a detailed comparative study of numerical results showing the reduction in thermal conductivity due to each of these three effects for Si/Ge nanocomposite structures with planar superlattice (SL), embedded nanowire superlattice (NWSL), and embedded nandodot superlattice (NDSL) geometries. Importantly, it is found that any of these three types of thin period systems, with small amounts of interface mass smudging, can exhibit a room temperature conductivity significantly lower than the SiGe alloy conductivity, providing strong evidence that they could be used as efficient thermoelectric materials. It is also found that the room-temperature conductivity of each of the nanocomposite superlattices shows a weaker sample size dependence than do the component bulk conductivities. . PMID- 30523938 TI - Osteogenic potential of Rosuvastatin immobilized on silk fibroin nanofibers using argon plasma treatment. AB - To begin developing a silk fibroin (SF) nanofibrous scaffolds that could promote osteogenesis, whilst enabling to deliver an active amount of Rosuvastatin (RSV) to the cells in long-time period, the present study aims to immobilize RSV onto the SF nanofibers through the argon radio frequency. Thus, the effect of plasma exposure times (0, 1, 3, and 5 min) was investigated on the morphology, loading efficiency, release profile, and osteogenesis activity. The successful loading of RSV on the SF nanofibers was proved by Fourier transformed infrared spectroscopy, Differential scanning calorimetry, and energy dispersive spectroscopy. In vitro drug release studies demonstrated that the RSV release was prolonged over a period of 21 d for plasma treated mats, while the non-plasma treated samples released the whole drug after 72 h. Moreover, the dose of RSV was controlled by the plasma exposure times, in which the highest amount of the released RSV was achieved after 3 min exposing to plasma. As suggested by MTT assay, the released amounts of RSV had no toxicity on the seeded human adipose tissue-derived stem cells and enhanced their proliferation. Moreover, using real-time reverse transcriptase-polymerase chain reaction and alizarin red staining proved that RSV immobilized SF mats stimulate both early and late osteogenic gene differentiation in comparison with pure SF nanofibers. However, the highest differentiation was observed on the SF nanofibers treated with argon plasma for 3 min. The results support the potential of plasma treatment on sustained release of the RSV from SF nanofibers for osteogenesis enhancement. PMID- 30523939 TI - Chemistry in Confined Space through the eyes of surface science - Two-dimensional porous materials. AB - There are a rapidly growing number of studies showing exciting new opportunities in the way confinement effects on surfaces affect the properties of materials and their chemistry. These effects have been observed recently under two-dimensional (2D) van der Waals materials such as a graphene and boron nitride and for the case of supported 2D-porous oxides, including silicates, aluminosilicates and zeolite nanosheets. This review summarizes the current state of the art in this area of research and how confinement effects in two dimensional systems relate to those found in three-dimensional porous and layered materials. The focus of this review is put in 2D-materials with inherent porosity, such as 2D-porous oxides. An outlook is also given for the future of this exciting emerging area. PMID- 30523940 TI - A new method for modelling the tongue-and-groove in treatment planning systems. AB - Commercial TPSs typically model the tongue-and-groove (TG) by extending the projections of the leaf sides by a certain constant width. However, this model may produce discrepancies of as much as 7-10% in the calculated average doses, especially for the High Denition multi-leaf collimator (MLC) (Hernandez et al 2017). The purpose of the present study is to introduce and validate a new method for modelling the TG that uses a non constant TG width. We provide the theoretical background and a detailed methodology to determine the optimal shape of this TG width from measurements and we fit an empirical function to the TG width that depended on two parameters a1 and a2. Parameter a1 represents the TG width and a2 introduces a curvature correction in the width near the leaf tip end. The new TG model was implemented in MATLAB and when the curvature correction was zero (a2=0) it caused the same discrepancies as the constant width model used by the Eclipse TPS. On the other hand, when the experimentally determined a2 was used the new model's calculations were in close agreement with measurements, with all differences in average doses <1%. Additionally, film dosimetry was used to successfully validate the potential of the new TG model to recreate the fine spatial details associated to TG effects. We also showed that the parameters a1, a2 depend solely on the MLC design by evaluating three different linear accelerators for each MLC model considered, namely Varian's High Denition and Millennium120 MLCs. In conclusion, a new method was presented that greatly improves the TG modelling. The present method can be easily implemented in commercial TPSs and has the potential to further increase their accuracy, especially for MLCs with rounded leaf ends. PMID- 30523941 TI - Thermal conductivity of TiO2 nanotube: A molecular dynamics study. AB - The thermal conductivity of anatase TiO2 nanotubes was investigated using equilibrium molecular dynamics simulations based on Green-Kubo formalism. The calculated thermal conductivity of ~8.16 W/K?m for anatase crystal at room temperature agrees well with experimental value of ~8.5 W/K?m, demonstrating that the method used in our calculation can provide a good description for the thermal transport of TiO2. The dependence of the thermal conductivity of TiO2 nanotubes with temperature, tube size and chirality were studied in detail. The relationship between the thermal conductivity and the vibrational density-of states of the nanotubes was also investigated. PMID- 30523942 TI - Effects of Au nanoparticles and ZnO morphology on the photocatalytic performance of Au doped ZnO/TiO2 films. AB - Au doped ZnO nanocomposites on TiO2 seeding layer (AuZ/T) were fabricated by hydrothermal processing and their photocatalytic performance was investigated. It could be found that the AuZ/T with m-sized, lying ZnO bulks revealed optimal photocatalytic performance toward methyl orange (MO) under simulated sunlight, whose apparent degradation rate constant Kapp of 1.31 was about 20% higher compared to that of ZnO/TiO2 and 3 times higher compared to that of ZnO. The Au nanoparticles, TiO2 seeding layer and hydrothermal processing time imposed vital influence on the morphology of ZnO nanostructures, which played key roles in the formation of ZnO/TiO2 pn heterojunction and charge transfer (CT) inside it, as demonstrated by kinetics of transient photoluminescence (PL) decaying. The incorporation of Au nanoparticles not only induced the variations of ZnO crystallinity and reduction of ZnO band gap (Eg), but also generated the Schottky heterojunction of Au/ZnO and Au/TiO2, which would be beneficial to CT inside nanocomposites and separation of photo-generated electron-hole pairs, as verified by the remarkable PL suppression. The mechanism responsible for photocatalysis enhancement, which was resulted from the hybrid effects of Au nanoparticles and the ZnO morphology was discussed in details. PMID- 30523943 TI - Body motion during dynamic couch tracking with healthy volunteers. AB - INTRODUCTION: In precision radiotherapy, the intrafractional motion can cause a considerable uncertainty of the location of the tumor to be treated. An established approach is the expansion of the target volume to account for the motion. An alternative approach is couch tracking, in which the patient is continually moved to compensate the intrafractional motion. However, couch tracking itself might induce uncertainty of the patient's body position, because it is not perfectly fixed to the couch. METHODS AND MATERIALS: One hundred volunteers were positioned supine on a robotic couch. Optical markers were placed on the torso of the volunteers as well as on the couch, and their positions were tracked with an optical surface measurement system. Using these markers, the uncertainty of the body position relative to the couch position was estimated while the couch was static or moving. RESULTS: Over the included 85 volunteers, the median of the uncertainty increased by 0.8 mm (SI), 0.4 mm (LR), and 0.4 mm (AP) when the couch moved. CONCLUSION: Couch motion was found to increase the uncertainty of the body position relative to the couch. However, this uncertainty is one order of magnitude smaller than the intrafractional tumor motion amplitudes to be compensated. Therefore, even with body motion present, the couch tracking approach is a viable option. The study was registered at ClinicalTrials.gov (NCT02820532) and the Swiss national clinical trials portal (SNCTP000001878). PMID- 30523944 TI - Atomic layer etching of chrome using ion beams. AB - In this study, two Cr atomic layer etching (ALE) methods have been applied for the precise control of Cr etching. The first one involves O radical adsorption followed by Cl+ ion desorption (ALE with chemical ion desorption; chemical anisotropic ALE), and the second one involves Cl/O radical adsorption followed by Ar+ ion desorption (ALE with physical ion desorption; physical anisotropic ALE). Their effects on Cr etch characteristics were also investigated. For both the ALE methods, saturated Cr etch depth/cycle of 1.1 and 1.5 A/cycle were obtained for the chemical and physical anisotropic ALE, respectively, while maintaining near infinite etch selectivities with various Si-based materials like silicon, silicon dioxide, and silicon nitride. The Cr etch depth could be controlled precisely with atomic precision by controlling the etch cycles for both Cr ALE methods in addition to the infinite etch selectivities over Si-based materials. Further, the original surface roughness and chemical composition of Cr surface were maintained after Cr ALE. The ALE technique can be used to precisely control the thickness of materials, including metals such as Cr, without any surface damage. PMID- 30523945 TI - Noninvasive vascular occlusion with HIFU for venous insufficiency treatment: preclinical feasibility experience in rabbits. AB - Venous insufficiency is a common disease arising when veins of the lower limb become incompetent. A conventional surgical strategy consists in stripping the incompetent veins. However, this treatment option is invasive and carries complication risks. In the present study, we propose noninvasive high-intensity focused ultrasound (HIFU) to treat lower limbs venous insufficiency, in particular incompetent perforating veins (mean diameter between 2-6 mm). Sonication parameters were designed by numerical simulations using the k-Wave toolbox to ensure continuous coagulation of a vein with a diameter superior or equal to 2 mm. The selected ultrasound exposures were 4 seconds pulses in continuous wave mode. Two types of sonication were studied: (1) fixed pulses and (2) moving pulses at constant speed (0.75 mm.s-1) across the vein. The potential of these exposures to thermally occlude veins were investigated in vivo on rabbit saphenous veins. The impact of vein compression during ultrasonic exposure was also investigated. Fifteen rabbits were used in these trials. A total of 27 saphenous veins (mean diameter 2.0 +/- 0.6 mm) were sonicated with a transducer operated at 3 MHz. After a mean 15 days follow-up, rabbits were euthanized and venous samples were extracted and sent for histologic assessment. Only samples with the vein within the HIFU lesion were considered for analysis. Simulated thermal damage distribution demonstrated that fixed pulses and moving pulses respectively placed every 1.5 and 0.5 mm along the vein and delivered at an acoustic power of 85 W and for 4 seconds were able to induce continuous thermal damages along the vein segments. Experimentally, both treatment parameters (1) and (2) have proven effective to occlude veins with a success rate of 82%. Occlusion was always observed when compression was applied. Our results demonstrate that HIFU can durably and non-invasively occlude veins of diameters comparable to human veins. . PMID- 30523946 TI - Monte Carlo-based SPECT reconstruction within the SIMIND framework. AB - This paper presents the development and validation of a Monte Carlo-based singe photon emission computed tomography reconstruction program for parallel-hole collimation contained within the SIMIND Monte Carlo framework. The Monte Carlo code is used as an accurate forward-projector and is combined with a simplified back-projector to perform iterative tomographic reconstruction using the Maximum Likelihood Expectation Maximization and Ordered Subsets Expectation Maximization algorithms, together forming a program called SIMREC. The Monte Carlo simulation transforms the estimated source distribution directly from activity to counts in its projections. Hence, the reconstructed image is expressed in activity without reference to an external calibration. The program is tested using phantom measurements of spheres filled with 99mTc, 177Lu and 131I placed in air and centrally and peripherally in a water-filled elliptical phantom. The feasibility of applying the reconstruction to patients is also demonstrated for a range of radiopharmaceuticals. The deviation in total activity in the spheres ranged between -4.1 % and 6.2 % compared with the activity determined when preparing the phantom. The SIMREC program was found to be accurate with respect to activity estimation and to reconstruct visually acceptable images within a few hours when applied to patient examples. PMID- 30523947 TI - Near-infrared photodetection with plasmon-induced hot electrons using silicon nanopillar array structure. AB - A plasmon-induced hot-electron photodetector based on silicon nanopillar array is developed. The nanostructure is fabricated by reactive ion etching with a monolayer of self-assembled polystyrene nanosphere in hexagonal close-packed lattice as the mask. Light absorption and hot-electron generation are mainly enhanced by the surface plasmon polaritons formed at the surface of the gold film on the nanopillar sidewalls. The photoresponse spans two telecom wavebands, viz. the range of 1250-1600 nm, and has a value of 1.8 mA/W at 1310 nm. The proposed silicon nanopillar-based hot-electron infrared detector has great potentials for device integration in silicon photonics relying on the economic large-area fabrication process. PMID- 30523948 TI - Evaluating calf bioimpedance measurements for fluid overload management in a controlled environment. AB - OBJECTIVE: To evaluate the relationship between calf bioimpedance measurements and fluid removal in a controlled environment (hemodialysis) as a first step toward using these measurements for remote Congestive Heart Failure (CHF) monitoring. APPROACH: Calf bioimpedance measurements were recorded in 17 patients undergoing hemodialysis (9/17 (53%) CHF, 5/17 (30%) female). Measurements were performed before and after hemodialysis. Additional parameters related to hemodialysis and patient fluid status such as Estimated Dry Weight were also recorded. MAIN RESULTS: Calf bioimpedance changes depended on calf fluid status as assessed by calf normalized resistivity (CNR). Patients with lower calf fluid overload (as assessed by CNR greater than 0.1017 Omega m3/kg) had larger decreases in calf fluid than patients with higher calf fluid overload. High CNR patients had fluid changes within the calf that depended on the ultrafiltration rate, with patients with lower ultrafiltration rates experiencing fluid shifts from extracellular to intracellular fluid. Additionally, there were correlations between changes in calf extra-,intra- and total- water and the ultra- filtration volume removed for high CNR patients (R2 = 0.44, 0.42, 0.56, respectively, all p values < 0.05). SIGNIFICANCE: These results suggest that while the relationship between calf fluid status and total fluid status is complex, changes in calf volumes comparable to those expected in an ambulatory setting are measurable and relate to changes in total volume. This suggests that calf bioimpedance measurements for CHF remote monitoring warrant future investigation, as remote fluid status management could reduce fluid overload related hospitalizations in CHF patients. PMID- 30523949 TI - Monoclinic SrIrO3 - A Dirac semimetal produced by non-symmorphic symmetry and spin-orbit coupling. AB - SrIrO3 crystallizes in a monoclinic structure of distorted hexagonal perovskite at ambient pressure. The transport measurements show that the monoclinic SrIrO3 is a low-carrier density semimetal, as in the orthorhombic perovskite polymorph. The electronic structure calculation indicates a semimetallic band structure with Dirac bands at two high-symmetry points of Brillouin zone only when spin-orbit coupling is incorporated, suggesting that the semimetallic state is produced by the strong spin-orbit coupling. We argue that the Dirac bands are protected by the non-symmorphic symmetry of lattice. PMID- 30523950 TI - Cobalt sulfide/N,S-codoped defect-rich carbon nanotubes hybrid as an excellent bi functional oxygen electrocatalyst. AB - The design of high-efficient and durable bi-functional oxygen electrocatalysts is still a great challenge. In this work, a novel Co9S8 nanoparticles/N,S-codoped defect-rich carbon nanotubes (Co9S8/N,S-CNTs) was fabricated by an ingenious template method. CdS nanowires, as a sacrificial template, can be removed simultaneously during the carbonization process without additional post treatments. The large BET surface area (661.2 m2 g-1) and pore volume (1.49 cm3 g 1) of Co9S8/N,S-CNTs could largely enhance the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) activities by facilitating the mass transportation and exposing more active sites. The abundant defects produced by the evaporation of Cd and S doping could provide more active sites for ORR and OER. Coupling with Co9S8, Co9S8/N,S-CNTs possesses more defects in the carbon skeleton, better electron conductivity, and larger effective electrochemical area. Co9S8/N,S-CNTs not only performed excellent ORR activity with a half-wave potential of 0.823 V but also owned RuO2-like OER activity in alkaline solution. The potential difference (?E) between ORR and OER is as low as 0.78 V in 0.10 M KOH. The excellent bi-functional performance enables the potential to be utilized in fuel cells and metal-air batteries. PMID- 30523951 TI - MOVPE growth of GaP/GaPN core-shell nanowires: N incorporation, morphology and crystal structure. AB - Dilute nitride III-V nanowires (NWs) possess great potential as building blocks in future optoelectronical and electrochemical devices. Here, we provide evidence for the growth of GaP/GaPN core-shell NWs via metalorganic vapor phase epitaxy (MOVPE), both on GaP(111)B and on GaP/Si(111) hetero-substrates. The NW morphology meets the common needs for use in applications, i. e. they are straight and vertically oriented to the substrate as well as homogeneous in length. Moreover, no parasitical island growth is observed. Nitrogen was found to be incorporated on group V sites as determined from transmission electron microscopy (TEM) and Raman spectroscopy. Together with the incorporation of N, the NWs exhibit strong photoluminescence in the visible range, which we attribute to radiative recombination at N-related deep states. Independently of the N incorporation, a peculiar facet formation was found, with {110} facets at the top and {112} at the bottom of the NWs. TEM reveals that this phenomenon is related to different stacking fault densities within the zinc blende structure, which lead to different effective surface energies for the bottom and the top of the NWs. PMID- 30523952 TI - Hybrid graphene heterojunction photodetector with high infrared responsivity through barrier tailoring. AB - The graphene/Si heterojunction is attractive for high gain and broadband photodetection through photogating effect. However, the photoresponsivity in these devices are still limited to under 1 A/W if no narrowband absorption enhanced nanostructures were used. In this paper, the effects of barriers on photoresponse are systematically studied at 1550 nm wavelength. Different barrier heights are obtained through selection of substrates, graphene doping and electrical tuning. Lower barrier height for graphene side and higher barrier height for silicon side are found to be beneficial for better infrared photoresponse. Through Polyetherimide doping of graphene and back-gated electrical modulation, the responsivity finally reached 5.71A/W, which to our knowledge is among the best results for graphene-based infrared photodetectors with graphene adopted as light-absorption material It is found that the thermionic emission efficiency of indirect transition in graphene is related to the difference in emissioin barrier height, and the lifetime of photo-induced carriers in the channel can be enhanced by built-in potential. These results lay the foundation for the photodetection applicatioins of graphene/Si heterojunction in the longer-wavelength infrared region. PMID- 30523953 TI - Flexible and stretchable metallic glass micro-/nano-structures of tunable properties. AB - Flexible and stretchable nanostructures have broad technological applications. Although nanostructures synthesized with metallic glasses, the alloys of amorphous atomic structure, exhibit superior properties, they are typically too rigid to be used as flexible material with existing synthesis techniques. In this study, we report periodic and crumpled metallic glass nanostructures that can accommodate a large amount of stretching. We demonstrate that their morphologies and characteristic length scale can be well controlled and feature sizes as small as ~200 nm can be readily achieved. With their integrity maintained, the nanostructures can be stretched to the strain of ~100%, leading to broadly tunable properties. The approach is not limited to specific metallic glasses, but applicable to a wide range of glass forming alloys. This not only enables metallic glasses to be used under extreme stretching conditions, but also helps exploration of new functionalities of glassy materials. PMID- 30523954 TI - Spontaneous assembly of colloidal vesicles driven by active swimmers. AB - We explore the self-assembly process of colloidal structures immersed in active baths. By considering low-valence particles we numerically investigate the irreversible aggregation dynamics originated by the presence of run-and tumble swimmers. We observe the formation of long closed chains -- vesicles - densely filled by active swimmers. On the one hand the active bath drives the self-assembly of closed colloidal structures, and on the other hand the vesicles formation fosters the self-trapping of swimmers, suggesting new ways both to build structured nanomaterials and to trap microorganisms. PMID- 30523955 TI - Silicon nanosheets as co-initiators for diaryliodonium induced radical and cationic polymerization. AB - A system of silicon nanosheets and a diaryliodonium salt was found to initiate cationic and radical polymerizations. The polymerization relies on a syngergistic interaction between the silicon nanomaterial and the diaryliodonium salt, whereby the silicon nanomaterial acts as a co-initiator, inducing the decomposition of the diaryliodonium salt. The decomposition products, in turn, are able to initiate both cationic and radical polymerizations thereby enabling a mild and straightforward reaction procedure to obtain a variety of polymer/nanomaterial composites with cationically and radically polymerizable monomers. Most importantly, this work highlights the potential of using silicon nanomaterials' unique properties not just for physical applications, but also in chemical applications. PMID- 30523956 TI - Structural transformations and physical properties of (1-x) Na0.5Bi0.5TiO3-x BaTiO3 solid solutions near morphotropic phase boundary. AB - Piezoelectric and other physical properties are significantly enhanced at (or near) a morphotropic phase boundary (MPB) in ferroelectrics. MPB materials have attracted significant attention owing to both fundamental physics as well as the possibility of well-regulated energy and information storage devices which are dominated by lead (Pb)-based materials. Here, we report the crystal structure, Raman spectra, dielectric constant and polarization near the MPB of lead free (1 x) Na0.5Bi0.5TiO3 - x BaTiO3 (NBT - BT) (0.00 <= x <= 0.10) solid-solution, prepared by sol-gel auto combustion technique and sintered by microwave sintering technique. With the addition of BaTiO3 into Na0.5Bi0.5TiO3, it induces a structural phase transition from R3c (a single phase) to R3c+P4mm (a dual phase) close to x = 0.06 and 0.07 and transform to a high symmetry tetragonal phase P4mm at higher compositions (x = 0.08 to 0.10) as evident from our X-ray Rietveld refinement and Raman spectroscopic results. We perform first-principles calculations based on density functional theory that confirm a structural transition from a rhombohedral to a tetragonal phase under increasing x. In the prepared solid solution, an anomalous enhancement of remnant polarization (2Pr0) was observed for x = 0.06 and 0.07, which has been explained based on the existence of the MPB. On the other hand, the value of coercive field EC0 was found to be decreased linearly from x = 0.00 to 0.06; it is constant for higher compositions. Further details of the ferroelectric properties on the electric field poled samples have been studied and compared with the as-grown (unpoled) samples. PMID- 30523957 TI - An earthworm-inspired friction-controlled soft robot capable of bidirectional locomotion. AB - We present the design, fabrication, modeling and feedback control of an earthworm inspired soft robot capable of bidirectional locomotion on flat and angled platforms, by actively controlling the robot's coefficient of friction between the contacting surfaces. Earthworms are characterized by their segmented body structures, known as metameres. To locomote, their longitudinal and circular muscles contract and relax accord- ingly, generating a peristaltic wave that propagates backwards with respect to the worms' traveling direction. Simultaneously, setae from each metamere will protrude or retract to provide varying traction with the ground, enabling the worm to burrow or crawl. Here, we propose a soft robot that replicates an earth- worm's muscle and setae mechanisms, employing pneumatically- driven actuators and 3D-printed casings. Using the notion of controllable subspaces, we prove that friction is indispensable for robots of this type to generate any locomotion. Furthermore, we introduce a method to generate proper control inputs that lead to feedforward controlled locomotion in numerical simulation. In addition, a real-time friction variation-based feedback control algorithm is adopted to achieve crawling in experiments and the robot is shown to be capable of performing robust bidirectional crawling on various different surface textures as well as on inclines. PMID- 30523958 TI - Epiretinal stimulation with local returns enhances selectivity at cellular resolution. AB - OBJECTIVE: Epiretinal prostheses are designed to restore vision in people blinded by photoreceptor degenerative diseases, by directly activating retinal ganglion cells (RGCs) using an electrode array implanted on the retina. In present-day clinical devices, current spread from the stimulating electrode to a distant return electrode often results in the activation of many cells, potentially limiting the quality of artificial vision. In the laboratory, epiretinal activation of RGCs with cellular resolution has been demonstrated with small electrodes, but distant returns may still cause undesirable current spread. Here, the ability of local return stimulation to improve the selective activation of RGCs at cellular resolution was evaluated. Approach: A custom multi electrode array (512 electrodes, 10 MUm diameter, 60 MUm pitch) was used to simultaneously stimulate and record from RGCs in isolated primate retina. Stimulation near the RGC soma with a single electrode and a distant return was compared to stimulation in which the return was provided by six neighboring electrodes. Main Results: Local return stimulation enhanced the capability to activate cells near the central electrode (<30 um) while avoiding cells farther away (>30 um). This resulted in an improved ability to selectively activate ON and OFF cells, including cells encoding immediately adjacent regions in the visual field. Significance: These results suggest that a device that restricts the electric field through local returns could optimize activation of neurons at cellular resolution, improving the quality of artificial vision. PMID- 30523959 TI - Direct information transfer rate optimisation for SSVEP-based BCI. AB - In this work, a classification method for SSVEP-based BCI is proposed. The classification method uses features extracted by traditional SSVEP-based BCI methods and finds optimal discrimination thresholds for each feature to classify the targets. Optimising the thresholds is formalised as a maximisation task of a performance measure of BCIs called information transfer rate (ITR). However, instead of the standard method of calculating ITR, which makes certain assumptions about the data, a more general formula is derived to avoid incorrect ITR calculation when the standard assumptions are not met. This allows the optimal discrimination thresholds to be automatically calculated and thus eliminates the need for manual parameter selection or performing computationally expensive grid searches. The proposed method shows good performance in classifying targets of a BCI, outperforming previously reported results on the same dataset by a factor of 2 in terms of ITR. The highest achieved ITR on the used dataset was 62 bit/min. The proposed method also provides a way to reduce false classifications, which is important in real-world applications. PMID- 30523960 TI - Exciting vibrons in both frontier orbitals of a single hydrocarbon molecule on graphene. AB - Vibronic excitations in molecules are key to the fundamental understanding of the interaction between vibrational and electronic degrees of freedom. In order to probe the genuine vibronic properties of a molecule even after its adsorption on a surface appropriate buffer layers are of paramount importance. Here, vibrational progression in both molecular frontier orbitals is observed with submolecular resolution on a graphene-covered metal surface using scanning tunnelling spectroscopy. Accompanying calculations demonstrate that the vibrational modes that cause the orbital replica in the progression share the same symmetry as the electronic states they couple to. In addition, the vibrational progression is more pronounced for separated molecules than for molecules embedded in molecular assemblies. The entire vibronic spectra of these molecular species are moreover rigidly shifted with respect to each other. This work unravels intramolecular changes in the vibronic and electronic structure owing to the efficient reduction of the molecule-metal hybridization by graphene. PMID- 30523961 TI - Direct synthesis of ultralong platinum nanowires with prominent electrocatalytic performance using lanreotide biotemplate. AB - Due to the dependence of the morphology, size and composition of Pt-based nanomaterials on their catalytic properties, rational design can improve the utilization efficiency and catalytic performance of Pt. As inspired by this, the ultra-long Pt nanowires (ULPtNWs) with a diameter of 25 nm were prepared by a mild, green, direct peptide mediated biological template method. Impressively, the large electrochemically active surface area (57.2 m2 g-1) of ULPtNWs was obtained, and their peak current density towards the methanol oxidation was approximately three-fold better than commercial Pt/C catalyst owing to the high aspect ratio (1.6 * 103 or more). Additionally, the excellent poison resistance of product was demonstrated, which can attribute to the high (111) plane. These enhancements indicate that ULPtNWs as a promising catalyst have broad application prospects in direct methanol fuel cells (DMFCs) or other electrocatalytic fields. PMID- 30523962 TI - Combination of high-frequency SSVEP-based BCI and computer vision for controlling a robotic arm. AB - OBJECTIVE: Recent attempts in developing brain-computer interface (BCI) controlled robots have shown the potential of this area in the field of assistive robots. However, implementing the process of objects picking and placing using BCI-controlled robotic arm still remains challenging. BCI performance, system portability, and user comfortableness need to be further improved. APPROACH: In this study, a novel control approach, which combined high-frequency steady-state visual evoked potential (SSVEP)-based BCI and computer vision-based object recognition, was proposed to control a robotic arm for performing pick and place tasks that require control with multiple degrees of freedom. The computer vision could identify objects in the workspace and locate their positions, while the BCI allowed the user to select one of these objects to be acted upon by the robotic arm. The robotic arm was programmed to be able to autonomously pick up and place the selected target object without moment-by-moment supervision by the user. MAIN RESULTS: Online results obtained from 10 healthy subjects indicated that a BCI command for the proposed system could be selected from four possible choices in 6.5 s (i.e., 2.25 s for visual stimulation and 4.25 s for gaze shifting) with 97.75% accuracy. All subjects could successfully complete the pick and place tasks using the proposed system. SIGNIFICANCE: These results demonstrated the feasibility and efficiency of combining high-frequency SSVEP-based BCI and computer vision-based object recognition to control robotic arms. The control strategy presented here could be extended to control robotic arms to perform other complicated tasks. Keywords: Electroencephalography (EEG), steady-state visual evoked potential (SSVEP), brain-computer interface (BCI), robotic arm, computer vision . PMID- 30523963 TI - Portable multi-parameter electrical impedance tomography (EIT) for sleep apnea and hypoventilation monitoring: feasibility study. AB - Quantitative ventilation monitoring and respiratory event detection are needed for the diagnosis of sleep apnea and hypoventilation. We report the development of a portable device with a chest belt, nasal cannula and finger sensor to continuously acquire multi-channel signals including tidal volume, nasal pressure, respiratory effort, body position, snoring sound, ECG and SpO2. The unique feature of the device is the continuous tidal volume signal obtained from real-time lung ventilation images produced by the electrical impedance tomography (EIT) technique. The chest belt includes sixteen electrodes for real-time time difference EIT imaging and ECG data acquisitions. It also includes a microphone, accelerometer, gyroscope, magnetometer and pressure sensor to acquire, respectively, snoring sound, respiratory effort, body position and nasal pressure signals. A separate finger sensor is used to measure SpO2. The minute ventilation signal can be derived from the tidal volume signal and respiration rate. The experimental results from a conductivity phantom, four swine subjects and one human volunteer show that the developed multi-parameter EIT device could supplement existing polysomnography (PSG) and home sleep test (HST) devices to improve the accuracy of sleep apnea diagnosis. The portable device could be also used as a new tool for continuous hypoventilation monitoring of non-intubated patients with respiratory depression. Following the feasibility study in this paper, future validation studies in comparison with in-lab PSG, HST and end-tidal CO2 devices are suggested to find its clinical efficacy as a sleep apnea diagnosis and hypoventilation monitoring tool. PMID- 30523964 TI - Tumor co-segmentation in PET/CT using multi-modality fully convolutional neural network. AB - Automatic tumor segmentation from medical images is an important step for computer-aided cancer diagnosis and treatment. Recently, deep learning has been successfully applied to this task, leading to state-of-the-art performance. However, most of existing deep learning segmentation methods only work for a single imaging modality. PET/CT scanner is nowadays widely used in the clinic, and is able to provide both metabolic information and anatomical information through integrating PET and CT into the same utility. In this study, we proposed a novel multi-modality segmentation method based on a 3D fully convolutional neural network (FCN), which is capable of taking account of both PET and CT information simultaneously for tumor segmentation. The network started with a multi-task training module, in which two parallel sub-segmentation architectures constructed using deep convolutional neural networks (CNNs) were designed to automatically extract feature maps from PET and CT respectively. A feature fusion module was subsequently designed based on cascaded convolutional blocks, which re extracted features from PET/CT feature maps using a weighted cross entropy minimization strategy. The tumor mask was obtained as the output at the end of the network using a softmax function. The effectiveness of the proposed method was validated on a clinic PET/CT dataset of 84 patients with lung cancer. The results demonstrated that the proposed network was effective, fast and robust and achieved significantly performance gain over CNN-based methods and traditional methods using PET or CT only, two V-net based co-segmentation methods, two variational co-segmentation methods based on fuzzy set theory and a deep learning co-segmentation method using W-net. PMID- 30523965 TI - The huge effect of Mn substitution on the structural and magnetic properties of LaFeAsO: the La(Fe,Mn)AsO system. AB - The substitution of Mn for Fe on the sub-lattice in LaFeAsO has a remarkable impact on both structural and magnetic properties; for example, the structural and magnetic transition temperatures decrease of about 20 K in samples with a Mn content as low as x = 0.01. Such a dramatic effect results from the high stability of the substituting Mn2+ ion (3d5) in its high-spin state, which opposes any variation to its electronic state (configuration), perturbing thereby interactions within the Fe sub-lattice between the Fe ions surrounding the substituent. Several investigations ascertained that the structural transformation in LnFeAsO compounds (Ln: lanthanide) cannot be ascribed to lattice degrees of freedom, but rather to electronic or spin ones. In this context, even an extremely low concentration of Mn2+ ions diluted in the Fe sub lattice produces a reduction of the electronic degree of freedom of the system, thus hindering the structural transformation and the magnetic transition. PMID- 30523966 TI - Novel pressure-induced topological phase transitions of supercooled liquid and amorphous silicene. AB - This molecular dynamics (MD) simulation carries a detailed analysis of a pressure induced structural transition supercooled liquid and amorphous silicene (a silicene). Low-density models of supercooled liquid and a-silicene containing 10000 atoms are obtained by rapid cooling process from the melts. Then, a silicene model at T = 1000K, supercooled liquid model at T = 1500K and liquid silicon model at T = 2000K have been isothermal compressed step by step up to a high density in order to observe the pressure-induced structural changes. Specifically "Cairo tiling" pentagonal and square lattices of silicene are discovered in our calculations. Structural properties of those penta-silicene and tetra-silicene models have been carefully analyzed through the radial distribution functions, interatomic distances, bond-angle distributions under high pressure. The dependence of pressure on formation behaviors is calculated via pressure-volume and energy-density relationships. First order transition from low-density supercooled liquid/amorphous silicene to high-density penta-silicene and continuous transition from low-density liquid to high-density tetra-silicene are discussed. Atomic mechanism and sp3/sp2 hybridization evolution are inspected whereas the role of low-membered ring defects/boundary promises remarkable application and advanced research in future. PMID- 30523967 TI - Deep-learning based surface region selection for deep inspiration breath hold (DIBH) monitoring in left breast cancer radiotherapy. AB - Deep inspiration breath hold (DIBH) with surface supervising is a common technique for cardiac dose reduction in left breast cancer radiotherapy. Surface supervision accuracy relies on the characteristics of surface region. In this study, a convolutional neural network (CNN) based automatic region-of-interest (ROI) selection method was proposed to select an optimal surface ROI for DIBH surface monitoring. The curvature entropy and the normal of each vertex on the breast cancer patient surface were calculated and formed as representative maps for ROI selection learning. 900 ROIs were randomly extracted from each patient's surface representative map, and the corresponding rigid ROI registration errors (RE) were calculated. The VGG-16 (a 16-layer network structure developed by Visual Geometry Group(VGG) from University of Oxford) pre-trained on a large natural image database ImageNet were fine-tuned using 27 thousand extracted ROIs and the corresponding RE from thirty patients. The RE prediction accuracy of the trained model was validated on additional ten patients. Satisfactory RE predictive accuracies were achieved with the root mean square error (RMSE)/mean absolute error (MAE) smaller than 1mm/0.7mm in translations and 0.45 degrees /0.35 degrees in rotations, respectively. The REs of the model selected ROIs on ten testing cases is close to the minimal predicted RE with mean RE differences <1mm and <0.5 degrees for translation and rotation, respectively. The proposed RE predictive model can be utilized for selecting a quasi-optimal ROI in left breast cancer DIBH radiotherapy (DIBH-RT). PMID- 30523968 TI - Sulforaphane-conjugated selenium nanoparticles: Towards synergistic anticancer effect. AB - Sulforaphane-modified selenium nanoparticles can be prepared in a simple aqueous phase redox reaction through reduction of selenite with ascorbic acid. The sulforaphane molecules present in the reaction mixture adsorb on the nanoparticle surface, forming an adlayer. The resulting conjugate was examined with several physicochemical techniques, including microscopy, spectroscopy, X-ray diffraction, dynamic light scattering and zeta potential measurements. As shown in in vivo investigations on rats, the nanomaterial administered intraperitoneally is eliminated mainly in urine (and, to a lesser extent, in feces); however, it is also retained in the body. The modified nanoparticles mainly accumulate in the liver, but the basic parameters of blood and urine remain within normal limits. The sulforaphane-conjugated nanoparticles reveal considerable anticancer action, as demonstrated on several cancer cell cultures in vitro. This finding is due to the synergistic effect of elemental selenium and sulforaphane molecules assembled in one nanostructure (conjugate). On the other hand, the cytotoxic action on normal cells is relatively low. The high antitumor activity and selectivity of the conjugate with respect to diseased and healthy cells is extremely promising from the point of view of cancer treatment. . PMID- 30523969 TI - Strength, elasticity and the limits of energy dissipation in two related sea urchin spines with biomimetic potential. AB - The calcitic spines of the sea urchins Heterocentrotus mamillatus and H. trigonarius are promising role models for lightweight applications, bone tissue scaffolds and energy dissipating processes due to their highly porous and organized structure. Therefore, mechanical properties including Young's Modulus, strength, failure behaviour and energy dissipation efficiency have been investigated in depth with uniaxial compression experiments, 3-point bending tests and resonance frequency damping analysis. It was found that despite a very similar structure, H. trigonarius has a significantly lower porosity than H. mamillatus leading to a higher strength and Young's Moduli, but limited ability to dissipate energy. In order to show reliable energy dissipation during failure in uniaxial compression, a transition porosity of 0.55-0.6 needs to be exceeded. The most effective structure for this purpose is a homogeneous, foam-like structure confined by a thin and dense shell that increases initial strength and was found in numerous spines of H. mamillatus. Sharp porosity changes induced by dense growth layers or prominent wedges of the spines' radiating building principle act as structural weaknesses, along which large flakes can be spalled, reducing the energy dissipation efficiency considerably. The high strength and Young's Modulus at the biologically necessary high porosity levels of the spines is useful for Heterocentrotus and their construction therefore remains to be a good example of biomimetics. However, the energy dissipative failure behaviour may be regarded as a mere side effect of the structure. . PMID- 30523970 TI - Modulated electrochemical oxygen evolution catalyzed by MoS2 nanoflakes from atomic layer deposition (ALD). AB - Electrochemical water splitting into H2 and O2 has attracted wide attentions owing to the urgent need for clean and renewable energy sources. However, the scarcity and high-cost limit the large-scale application of noble metal catalysts such as IrO2 and RuO2. In this work, as a low-cost catalyst for the electrochemical O2 evolution reaction (OER), MoS2 nanoflakes were obtained by atomic layer deposition (ALD) using MoCl5 and H2S on carbon fiber paper (CFP) surface. According to the results of electrochemical measurements, the MoS2 nanoflakes exhibit an excellent catalytic activity, and the activity can be modulated by controlling the density and the internal resistance of MoS2 nanoflakes. Moreover, the plasma treatment can further improve the activity of MoS2 nanoflakes, and the reason was discussed through the measurements of contact angle, electrochemical impedance spectroscopy (EIS), and electrochemically active surface area (ECSA). The MoS2 nanoflakes obtained by ALD possess huge values for electrochemical OER as a catalyst. PMID- 30523971 TI - Eye tracking technology in sports-related concussion: a systematic review and meta-analysis. AB - OBJECTIVE: The development of objective quantitative tools for the assessment and monitoring of sports-related concussion is critical. Eye tracking is a novel tool that may provide suitable metrics. The aim of this review was to appraise current evidence for the use of eye tracking technology in sports-related concussion assessment and monitoring. Approach: A systematic literature review was conducted following the PRISMA guidelines. A search was run using Google Scholar, Microsoft Academic and PubMed for literature published between January 1980 and May 2018. Included were empirical research studies in English where at least 50% of the research participants were athletes, the participants were individuals with a diagnosis of concussion, and eye movements were measured using an eye tracking device. Main results: This systematic review integrates 21 publications on sports-related concussion and eye tracking technology, 9 of which also qualified for the meta-analysis. Overall, the literature reported significant findings for variables in each of the four classes of eye tracking measurements (movement, position, count, and latency). Meta-comparison was made for seven variables for the acute concussions (the difference between the concussed and the control groups was significant for all of them) and one variable for the latent concussions (the difference was not significant). Significance: Most saccadic and pursuit deficits may be missed during clinical examination, and therefore eye tracking technology may be a useful and sensitive screening and monitoring tool for sports-related concussions. The inconsistencies between the eye movement metrics and methodology still make inferences challenging, however, using tasks that are closely related to brain areas involved in executive functions (such as memory-based saccade or antisaccade tasks) in the acute injury phase holds promise in differentiating between athletes who have a concussion compared to those who do not. PMID- 30523972 TI - Oxide thin films as bioactive coatings. AB - Growth and survival of biological cells (eukaryotes and prokaryotes) on artificial environments often depend on their interactions with the specific surface. Various organic materials can be coated on substrates to assist cells adhesion and other subsequent cellular processes. However, these coatings are expensive, degrade over short time period, and may even interfere with the cells' signaling processes. Therefore, the use of inorganic surfaces in order to control cellular interactions is of scientific importance from fundamental and application perspectives. Among inorganic materials, oxide thin films have received considerable attention. Thin films of oxides have the advantage of tailoring the surfaces for cellular interactions while using negligible amount of the oxide material. Here, we review the lesser known application of inorganic oxide coatings as biocompatible and implantable platforms for different purposes, such as biofilm inhibition, cell culture and implant enhancements. PMID- 30523973 TI - Fully automated organ segmentation in male pelvic CT images. AB - Accurate segmentation of prostate and surrounding organs at risk is important for prostate cancer radiotherapy treatment planning. We present a fully automated workflow for male pelvic CT image segmentation using deep learning. The architecture consists of a 2D localization network followed by a 3D segmentation network for volumetric segmentation of prostate, bladder, rectum, and femoral heads. We used a multi-channel 2D U-Net followed by a 3D U-Net with encoding arm modified with aggregated residual networks, known as ResNeXt. The models were trained and tested on a pelvic CT image dataset comprising 136 patients. Test results show that 3D U-Net based segmentation achieves mean (+/-SD) Dice coefficient values of 90 (+/-2.0)% ,96 (+/-3.0)%, 95 (+/-1.3)%, 95 (+/-1.5)%, and 84 (+/-3.7)% for prostate, left femoral head, right femoral head, bladder, and rectum, respectively, using the proposed fully automated segmentation method. . PMID- 30523974 TI - A respiratory-guided 4D digital tomosynthesis. AB - The aim of this research was to introduce and evaluate a respiratory-guided slow gantry rotation 4D digital tomosynthesis (DTS). For each of 10 volunteers, 2 breathing patterns were obtained for 3 minutes, one under free breathing condition and the other with visual respiratory-guidance using an in-house developed respiratory monitoring system based on pressure sensing. Visual guidance was performed using a 4s cycle sine wave with an amplitude corresponding to the average of end-inhalation peaks and end-exhalation valleys from the free breathing pattern. The scan range was 40 degrees for each simulation, and the frame rate (FR) and gantry rotation speed (GRS) were determined so that one projection per phase should be included. Both acquisition time (AT) and the number of total projections to be acquired (NPA) were calculated. Applying the obtained respiration pattern and the corresponding sequence, virtual projections were acquired under a typical geometry of Varian on-board imager for two virtual phantoms, modified Shepp-Logan (mSL) and XCAT (extended Cardiac-Torso). For the XCAT, two different orientations were considered, anterior-posterior (i.e., coronal) and left-right (i.e., sagittal). Projections were sorted to 10 phases and image reconstruction was made using a modified filtered back-projection. Reconstructed images were compared with the planned breathing data (i.e., ideal situation) by SSIM (Structural Similarity) and NRMSE (Normalized Root-mean-square Error). For each case, simulation with guidance (SwG) showed motion-related artifact reduction compared to that under free-breathing (SuFB). SwG required less NPA but provided slightly higher SSIM and lower NRMSE values in all phantom images than SuFB did. In addition, the distribution of projections per phase was more regular in SwG. Through the proposed respiratory-guided 4D DTS, it is possible to reduce imaging dose while improving image quality. (Institutional Review Board approval: MC17DESI0086). PMID- 30523975 TI - Development and performance of a biomimetic artificial perilymph for in vitro testing of medical devices. AB - OBJECTIVE: Cochlear implants interface with the fluid in the cochlea called perilymph. The volume of this fluid present in human and animal model cochlea is prohibitively low for isolation for in vitro studies. Thus, there is a need for an artificial perilymph that reflects the complexity of this fluid in terms of competitive protein adsorption. Approach: This study established a biomimetic artificial perilymph (BAP) comprising serum albumin, immunoglobulin G, transferrin, inter-alpha-trypsin inhibitor, apolipoprotein A1 and complement C3 to represent the major components of human perilymph. Adsorption of the BAP components to platinum was analysed. Main results: It was established that this six component BAP provided competitive and complex adsorption behaviours consistent with biologically derived complex fluids. Additionally, adsorption of the BAP components to platinum cochlear electrodes resulted in a change in polarisation impedance consistent with that observed for the cochlear device in vivo. Significance: This study established a BAP fluid suitable for furthering the understanding of the implant environment for electroactive devices that interface with the biological environment. . PMID- 30523977 TI - Study on the Oxidation of Copper Nanowire Network Electrodes for Skin Mounttable Flexible, Stretchable and Wearable Electronics Applications. AB - Copper nanowires (Cu NWs) are suitable material as an electrode for flexible, stretchable and wearable devices due to their excellent mechanical properties, high transparency, good conductivity, and low cost, but oxidation problem limits their practical use and application. In order to use Cu NWs as an electrode for advanced flexible, stretchable and wearable devices attached directly to the skin, the influence of the body temperature on the oxidation of Cu NWs needs to be investigated. In this paper, the oxidation behavior of Cu NWs at high temperature (more than 80 degrees C) as well as body temperature is studied which has been remained largely questionable to date, and an effective encapsulation method is proposed to prevent the oxidation of Cu NWs electrode in the range of body temperatures. PMID- 30523976 TI - Reproducibility of dynamic cerebral autoregulation parameters: a multi-centre, multi-method study. AB - OBJECTIVE: Different methods to calculate dynamic cerebral autoregulation (dCA) parameters are available. However, most of these methods demonstrate poor reproducibility that limit their reliability for clinical use. Inter-centre differences in study protocols, modelling approaches and default parameter settings, have all led to a lack of standardisation and comparability between studies. We evaluated reproducibility of dCA parameters by assessing systematic errors in surrogate data resulting from different modelling techniques. APPROACH: Fourteen centres analysed 22 datasets consisting of two repeated physiological blood pressure measurements with surrogate cerebral blood flow velocity signals, generated using Tiecks curves (autoregulation index , ARI 0-9) and added noise. For reproducibility, dCA methods were grouped in three broad categories: 1. Transfer function analysis (TFA)-like output; 2. ARI-like output; 3. Correlation coefficient-like output. For all methods, reproducibility was determined by one way Intraclass Correlation Coefficient analysis (ICC). MAIN RESULTS: For TFA-like methods the mean (SD; [range]) ICC gain was 0.71 (0.10; [0.49-0.86]) and 0.80 (0.17; [0.36-0.94]) for VLF and LF (p=0.003) respectively. For phase, ICC values were 0.53 (0.21; [0.09-0.80]) for VLF, and 0.92 (0.13; [0.44-1.00]) for LF (p <0.001). Finally, ICC for ARI-like methods was equal to 0.84 (0.19; [0.41-0.94]), and for correlation-like methods , ICC was 0.21 (0.21; [0.056-0.35]). Significance: When applied to realistic surrogate data, free from the additional exogenous influences of physiological variability on cerebral blood flow, most methods of dCA modelling showed ICC values considerably higher than what has been reported for physiological data. This finding suggests that the poor reproducibility reported by previous studies may be mainly due to the inherent physiological variability of cerebral blood flow regulatory mechanisms rather than related to (stationary) random noise and the signal analysis methods. . PMID- 30523978 TI - A Review on Optical Imaging of DNA Nanostructures and Dynamic Processes. AB - DNA self-assembly offers a powerful means to construct complex nanostructures and program dynamic molecular processes such as strand displacement. DNA nanosystems pack high structural complexity in a small scale (typically, < 100 nm) and span dynamic features over long periods of time, which bring new challenges for characterizations. The spatial and temporal features of DNA nanosystems require novel experimental methods capable of high resolution imaging over long time periods. This article reviews recent advances in optical imaging methods for characterizing self-assembled DNA nanosystems, with particular emphasis on super resolved fluorescence microscopy. Several advanced strategies are developed to obtain accurate and detailed images of intricate DNA nanogeometries and to perform precise tracking of molecular motions in dynamic processes. We present state-of-the-art instruments and imaging strategies including localization microscopy and spectral imaging. We discuss how they are used in biological studies and biomedical applications, and also provide current challenges and future outlook. Overall, this review serves as a practical guide in optical microscopy for the field of DNA nanotechnology. PMID- 30523979 TI - Width-dependent phase crossover in transition metal dichalcogenide nanoribbons. AB - Two-dimensional (2D) transition metal dichalcogenides MX2 (M = Mo, W; X = S, Se) exhibit two phases: the ground state 2H and the metastable 1T. Here, WSe2 and MoS2 monolayers have been studied, and we show by comprehensive first-principles calculations that the stability of the two phases can be switched in MX2 nanoribbons. The 2H phase is found to have increasingly higher energy than the 1T phase at a smaller ribbon width, and the width for favoring the 1T phase reaches up to 2.50 nm for WSe2. The phase crossover is due to higher coordination of edge M atoms in 1T phase than in 2H phase and an interesting electronic reconstruction of 1T lattice in the ribbon interior. The edge configuration of 1T phase diminishes the edge dangling bonds and thereby enhances the stability of MX2 nanoribbons. Our findings underscore the importance of edges in determining the structures of 2D MX2 and are crucial for their future scientific studies and potential applications. PMID- 30523980 TI - Secondary electron emission and yield spectra of metals from Monte Carlo simulations and experiments. AB - In this work, we present a computational method, based on the Monte Carlo statistical approach, for calculating electron energy emission and yield spectra of metals, such as copper, silver and gold. The calculation of these observables proceeds via the Mott theory to deal with the elastic scattering processes, and by using the Ritchie dielectric approach to model the electron inelastic scattering events. In the latter case, the dielectric function, which represents the starting point for the evaluation of the energy loss, is obtained from experimental reflection electron energy loss spectra. The generation of secondary electrons upon ionization of the samples is also implemented in the calculation. A remarkable agreement is obtained between both theoretical and experimental electron emission spectra and yield curves. PMID- 30523982 TI - Detecting and interpreting myocardial infarction using fully convolutional neural networks. AB - OBJECTIVE: We aim to provide an algorithm for the detection of myocardial infarction that operates directly on ECG data without any preprocessing and to investigate its decision criteria. Approach: We train an ensemble of fully convolutional neural networks on the PTB ECG dataset and apply state-of-the art attribution methods. Main results: Our classifier reaches 93.3% sensitivity and 89.7% specificity evaluated using 10-fold cross-validation with sampling based on patients. The presented method outperforms state-of-the-art approaches and reaches the performance level of human cardiologists for detection of myocardial infarction. We are able to discriminate channel-specific regions that contribute most significantly to the neural network's decision. Interestingly, the network's decision is influenced by signs also recognized by human cardiologists as indicative of myocardial infarction. Significance: Our results demonstrate the high prospects of algorithmic ECG analysis for future clinical applications considering both its quantitative performance as well as the possibility of assessing decision criteria on a per example basis, which enhances the comprehensibility of the approach. PMID- 30523981 TI - Global Activity Shaping Strategies for a Retinal Implant. AB - OBJECTIVE: Retinal prostheses provide visual perception via electrical stimulation of the retina using an implanted array of electrodes. The retinal activation resulting from each electrode is not point-like; instead each electrode introduces a spread of retinal activation that may overlap with activations from other electrodes. With most conventional stimulation strategies this overlap leads to image blur. Here we propose a 'shaping' algorithm that uses multiple electrodes to manipulate the current between electrodes in a desired way. Approach: We assume a forward model for the conversion of electrode strengths to retinal activation. Three alternative global shaping algorithms are developed by calculating reverse models under different assumptions: linear inversion using singular value decomposition to produce the pseudoinverse, a linearly constrained quadratic program, and a binary quadratic program to partition the target pattern. The algorithms were assessed using both the mean squared error between the resulting images and desired images, as well as their adherence to the maximum allowed electrode currents. Main Results: Under wide activation spreads the linear inversion algorithm gave improved solutions but faced two limitations: under low-noise conditions the electrode amplitudes exceeded their set limit; the set of solutions did not include the possibility of using negative local currents to induce retinal activation. The linearly constrained quadratic program and binary quadratic program respectively addressed these problems, but required much greater computation time. Significance: This provides a framework for improving the resolution of future retinal implants, especially those with high density electrode arrays. . PMID- 30523983 TI - Use of an innovative and non-invasive device for virologic sampling of cough aerosols in patients with community and hospital acquired pneumonia: a pilot study. AB - BACKGROUND: The aetiology of lower respiratory tract infections is challenging to investigate. Despite the wide array of diagnostic tools, invasive techniques, such as bronchoalveolar lavage (BAL), are often required to obtain adequate specimens. PneumoniaCheckTM is a new device that collects aerosol particles from cough, allowing microbiological analyses. Up to now it has been tested only for bacteria detection, but no study has investigated its usefulness for virus identification. Methods: In this pilot study we included 12 consecutive patients with pneumonia. After testing cough adequacy via a Peak Flow Meter, a sampling with PneumoniaCheckTM was collected and a BAL was performed in each patient. Microbiological analyses for virus identification were performed on each sample and concordance between the two techniques was tested (sensitivity, specificity and positive/negative predictive values), taking BAL results as reference. Results: BAL was considered adequate in 10 patients. Among them, a viral pathogen was identified by PneumoniaCheckTM 6 times, each on different samples, whereas BAL allowed to detect the presence of a virus on 7 patients (14 positivities). Overall, the specificity for PneumoniaCheckTM to detect a virus was 100%, whereas the sensitivity was 66%. When considering only herpes viruses, PneumoniaCheckTM showed a lower sensitivity, detecting a virus in 1/4 of infected patients (25%). Conclusions: In this pilot study PneumoniaCheckTM showed a good correlation with BAL for non-herpes virologic identification in pneumonia patients, providing excellent specificity. Further studies on larger population are needed to confirm these results and define its place in the panorama of rapid diagnostic tests for lower respiratory tract infections. PMID- 30523984 TI - Biokinetics of 238Pu oxides: Inferences from bioassay data. AB - The bioassay data collected from several workers involved in 238Pu inhalation incidents have been analyzed using the most recent biokinetic models described in Occupational Intakes of Radionuclides (OIR) series of publications. Although all exposures were thought to be to 238Pu oxides, the observed urinary excretion patterns differed in different inhalation incidents. The urinary excretion from individuals involved in one of the incidents increased steadily with time peaking around 2-3 years before decreasing. This pattern is described in Part 4 of the OIR series using the '238PuO2, ceramic' model. This non-monotonic behavior, explained as being due to fragmentation and dissolution, was not specific to the incident, but was also observed in other incidents. The urinary excretion data collected from individuals involved in another incident showed dissolution behavior between Type M and Type S. Finally, the bioassay data from yet another incident showed a pattern that appears to represent behavior more insoluble than Type S, which is possibly a result of self-heating due to the decay heat from 238Pu. The urinary excretion patterns and the corresponding dose coefficients have been calculated and compared. PMID- 30523985 TI - Simulation of visual perception and learning with a retinal prosthesis. AB - The nature of artificial vision with a retinal prosthesis, and the degree to which the brain can adapt to the unnatural input from such a device, are poorly understood. Therefore, the development of current and future devices may be aided by theory and simulations that help to infer and understand what prosthesis patients see. A biologically-informed, extensible computational framework is presented here to predict visual perception and the potential effect of learning with a subretinal prosthesis. The framework relies on linear reconstruction of the stimulus from retinal responses to infer the visual information available to the patient. A simulation of the physiological optics of the eye and light responses of the major retinal neurons was used to calculate the optimal linear transformation for reconstructing natural images from retinal activity. The result was then used to reconstruct the visual stimulus during the artificial activation expected from a subretinal prosthesis in a degenerated retina, as a proxy for inferred visual perception. Several simple observations reveal the potential utility of such a simulation framework. The inferred perception obtained with prosthesis activation was substantially degraded compared to the inferred perception obtained with normal retinal responses, as expected given the limited resolution and lack of cell type specificity of the prosthesis. Consistent with clinical findings and the importance of cell type specificity, reconstruction using only ON cells, and not OFF cells, was substantially more accurate. Finally, when reconstruction was re-optimized for prosthesis stimulation, simulating idealized learning by the patient, the accuracy of inferred perception was much closer to that of healthy vision. The reconstruction approach thus provides a more complete method for exploring the potential for treating blindness with retinal prostheses than has been available previously. It may also be useful for interpreting patient data in clinical trials, and for improving prosthesis design. PMID- 30523986 TI - Role of tetrahedrally coordinated dopants in palladium hydrides on their superconductivity and inverse isotope effect. AB - Absorption of hydrogen by palladium causes PdH to become superconducting below Tc ~ 9 K. Due to the presence of one octapore and two tetrapores per each Pd atom, it is believed that Tc of PdHx>1 should increase further. Here, using ab initio calculation we show that (i) H placed in tetrapores of PdHx induces a wide optical gap in the phonon density of states, which significantly reduces the electron-phonon coupling, and that (ii) the energetically preferable octapores filled by H enable the 9-K superconductivity only. This scenario may close a long-standing problem of the high-Tc palladium hydrides. Moreover, simulating the pore population by H and D, within ab initio molecular dynamics, we are able to explain the inverse isotope effect in the framework of the Bardeen-Cooper-Schrieffer theory. PMID- 30523987 TI - A closer look at ultrasonic attenuation and heating in a tissue mimicking material. AB - A well-characterized ultrasound tissue-mimicking material (TMM) can be important in determining the acoustic output and temperature rise from high intensity therapeutic ultrasound (HITU) devices and also in validating computer simulation models. A HITU TMM previously developed and characterized in our laboratory has been used in our acoustic and temperature measurements as well as modeled in our HITU simulation program. A discrepancy between thermal measurement and simulation, though, led us to further investigate the TMM properties. We found that the 2-parameter analytic fit commonly used to represent the attenuation of the TMM in the computer modeling was not adequate over the entire frequency range of interest, 1 MHz to 8 MHz in this study, indicating that we and others may have not been characterizing TMMs, and possibly tissue, optimally. By comparing measurements and simulations, we found that a 3-parameter analytic fit for attenuation gave a more accurate value for attenuation at 1 MHz and 2 MHz, and using that fit the temperature rise measurements in the TMM that agreed more closely with the simulation results. PMID- 30523988 TI - Carbon-based polymer nanocomposites as dielectric energy storage materials. AB - Nanostructured polymeric materials based on conductive nanofillers have promising applications in the energy storage field owing to the extraordinary characteristics of the nanofillers. Conductive nanofillers, such as graphene nanoplatelets, are characterized by small size, extraordinary surface area to volume ratio, high aspect-ratio and extremely low electrical resistivity. In this work, the dielectric behaviors and the corresponding energy storage capabilities of high aspect-ratio carbon nanofiller/polymer composites were reviewed. At the electrical percolation point, a conductive composite exhibits a sudden and remarkable enhancement in dielectric constant and dielectric loss. The challenge is to maintain the increase in dielectric constant while preventing the increase in dielectric loss. Various physical and chemical methodologies have been followed to overcome this challenge including surface chemistry modifications, physical alignment of nanofillers and utilizing of hybrid mixtures. Promising results were reported to minimize the energy loss due to the conductive network formation. Nanocomposites with a dielectric constant of 103 and dielectric loss of only 0.08 were successfully fabricated. However, more work is still needed for a further enhancement in dielectric constant and reduction in the energy loss and to improve the storage capabilities of the nanocomposites. PMID- 30523989 TI - Fabry-Perot interferometry in Weyl semi-metals. AB - We show that the electrical transport across a minimal model for a time-reversal symmetry(TRS) breaking Weyl semi-metal (WSM) involving two Weyl nodes can be interpreted as an interferometer in momentum space. The interference phase depends on the distance between the Weyl nodes ($?vec{?delta k}$) and is {?it anisotropic}. It is further shown that a minimal inversion symmetry broken model for a WSM with four Weyl nodes effectively mimics a situation corresponding to having two copies of the interferometer due to the presence of an orbital pseudo-spin domain wall in momentum space. We point out that the value of the $?delta k$ and consequently the interference phase can be tuned by driving the WSMs resulting in oscillations in the two terminal conductance measured in the direction of splitting of the Weyl nodes. . PMID- 30523990 TI - Corrigendum: Numerical analysis of surface and edge states in slabs, stripes, rods and surface steps of topological insulators (N I Fedotov and S V Zaitsev Zotov 2018 J. Phys.: Condens. Matter 30 485301). AB - Corrigendum. PMID- 30523991 TI - Development of a novel drug targeting delivery system for cervical cancer therapy. AB - "Targeting peptides" have demonstrated their value in diagnostic imaging and therapy and novel peptide probes specific to cervical cancer were developed. In the M13KE phage dodecapeptide (12-mer) peptide library, the phage clone S7 showed the best binding to the cancer cells as confirmed by immunofluorescence and flow cytometry assays, was selected for continued studies. Its binding peptide, CSP3, was synthesized from the sequence of S7's 12-mer at the N-terminus of the minor coat protein pIII of this M13KE phage vector. The peptide's binding was analyzed by the same assays used for S7. It was also assessed using competitive inhibition and binding to a tissue chip. The results demonstrated that CSP3 peptide bound to cervical carcinoma cells with high sensitivity and specificity. The positive results indicated that the peptide CSP3, conjugated with nanomaterials and chemotherapeutics, may be developed as a targeting vehicle for therapeutic drug delivery against cervical cancer, especially cervical cancer with multiple drug resistance. For this aim, we prepared a CSP3 conjugated liposome drug delivery system containing doxorubicin (DOX) and microRNA101 (miR101) expression plasmids (CSP3-Lipo-DOX-miR101), and the primary result showed that the system demonstrated the significantly enhanced cytotoxicity to SiHa cells and DOX resistant SiHa cells, SiHa/ADR. Our results showed that CSP3 is a cervical cancer targeting 12aa peptide with high specificity and sensitivity, and the CSP3 conjugated drug delivery system, CSP3-Lipo-DOX-miR101 is of the promising potential to be developed as an efficient drug system for the therapy of cervical cancer. PMID- 30523992 TI - IPEM Topical Report: An evidence and risk assessment based analysis of the efficacy of tube and generator quality assurance tests on general x-ray units. AB - This work aims to assess the efficacy of current x-ray quality assurance (QA) testing regimes on tube and generator systems for general radiographic usage in the UK. 1393 sets of QA results data from 9 UK medical physics departments were collected and analysed. Test failure rates ranged from 0 % to 39% and were used to assess the likelihood of the test finding a fault. The magnitude of the recorded faults were used to assess the severity of the failure with due consideration to its impact on image quality and patient dose. The severity and likelihood of the faults were used along with a risk matrix to assess the efficacy of each test. 11 tests were graded 'orange' (indicating an effective test that should be continued), 4 tests were graded 'yellow' (indicating a less effective test that may be continued with a lower frequency considered), and 4 tests were graded green (indicating a low efficacy test that could be removed from test regimes). PMID- 30523993 TI - NO2 gas sensor based on graphene decorated with Ge quantum dots. AB - We report a highly sensitive and selective NO2 gas sensor based on germanium (Ge) quantum dots (GeQDs)/graphene hybrids. Graphene was directly grown on germanium through chemical vapor deposition (CVD) and the GeQDs were synthesized via molecular beam epitaxy (MBE). The samples were characterized by atomic force microscope (AFM), Raman spectra, scanning electron microscope (SEM), X-ray photoelectron spectroscope (XPS), and transmission electron microscope (TEM) with Energy Dispersive X-ray (EDX). By introducing GeQDs on graphene, the gas sensor sensitivity to NO2 was improved substantially. With the optimization of the growth time of GeQDs (600 s), the response sensitivity to 10 ppm NO2 can be as high as 3.88, which is 20 times higher than that of the graphene sensor without GeQDs decoration. In addition, the 600 s GeQDs/graphene hybrid sensors exhibit fast response and recovery rates, high selectivity and excellent stability. Our work may provide a new route to produce low-power consumption, portable, and room temperature gas sensor which is amenable to mass production. PMID- 30523994 TI - Modeling of high-fluence irradiation of amorphous Si and crystalline Al by linearly focused Ar ions. AB - Long time ion irradiation of surfaces under tilted incidence causes formation of regular nanostructures known as surface ripples. The nature of mechanisms leading to ripples is still not clear, this is why computational methods can shed the light on such a complex phenomenon and help to understand which surface processes are mainly responsible for it. In this work, we analyse the surface response of two materials, a semiconductor (silicon) and a metal (aluminium) under irradiation with the 250 eV and 1000 eV Ar ions focused at 70o from the normal to the surface. We simulate consecutive ion impacts by the means of molecular dynamics to investigate the effect on ripple formation. We find that the redistribution mechanism seems to be the main creator of ripples in amorphous materials, while the erosion mechanism is the leading origin for the pattern formation in crystalline metals. PMID- 30523995 TI - Asymmetrically optimized structure in a high-Tc single unit cell FeSe superconductor. AB - We report asymmetric Se heights in a single unit-cell FeSe on SrTiO3(001) substrate with the highest superconducting transition temperature (Tc) among the Fe-based superconductors revealed by total-reflection high-energy positron diffraction (TRHEPD) measurements. Among various iron-based superconductors, this single unit-cell FeSe on the SrTiO3(001) has been the best material to achieve the highest Tc above 50 K. We found the asymmetric Se heights of 1.44+/ 0.03 and 1.33+/-0.03 A from the single Fe layer by the intensity analysis based on dynamical diffraction theory. The average Se height results in 1.39+/-0.04 A, corresponding to the optimum value for Fe-based superconductors. In addition, the average of bond angles of Se-Fe-Se, 107.2+/-1.1 and 111.5+/-1.2 degrees becomes 109.3+/-1.6 degrees , which is close to the optimum value of 109.5 degrees for a regular tetrahedron. Thus, this single unit-cell FeSe is found to have asymmetrically optimized structure. Based on our first-principles calculations, the asymmetry does not change the bandwidth whereas it splits the electron bands at the M point only at the bottom. These calculations suggest that at low electron doping, the structural asymmetry is expected to lead to exotic properties of non-centrosymmetric superconductivity, whereas after a certain amount of electron doping, average anion height plays an important role for high Tc. PMID- 30523996 TI - Super Blinking and Biocompatible Nanoprobes Based on Dye Doped BSA Nanoparticles for Super Resolution Imaging. AB - As one of the super-resolved optical imaging technique, single molecule localization microscopy (SMLM) received considerable attention due to its impressive spatial resolution. Compared with other fluorescence imaging techniques, SMLM has one particular request for the fluorophores, that is, continuous "on" and "off" behaviors of their signals (referred to as "blinking"). Hence, we present here a kind of Super Blinking and biocompatible Nanoprobes (denoted as SBNs) for SMLM. The SBNs have two main advantages, first, they possess an outstanding fluorescence blinking. Second, they are biocompatible since they are based on bovine serum albumin (BSA). The SBNs are fabricated by doping organic dyes into BSA nanoparticles (NPs). We fabricated two kinds of SBNs, one was doped with Alexa Fluor 647 (A647) and the other was doped with Alexa Fluor 594 (A594). Especially for A594 doped SBNs, the improved blinking of A594 doped SBNs induced a better localization precision as compared with A594 alone. Moreover, SMLM imaging of breast cancer cells and exosomes using the SBNs was successfully realized with high spatial resolutions. The work demonstrated here provides a new strategy to prepare novel kinds of super blinking fluorescent agents for SMLM, which broadens the selection of suitable fluorophores for SMLM. PMID- 30523997 TI - Joint activity and attenuation estimation for PET with TOF data and single events. AB - Maximum likelihood reconstruction of activity and attenuation (MLAA) for PET data with time-of-flight (TOF) information can determine the activity distribution up to a scale, and the attenuation map Radon transform up to a related constant. Prior knowledge is widely used for the determination of the constant. However, prior knowledge could be inaccurate due to patient variation and may result in quantitation errors. Our goal is to develop a method that can determine the scale and the related constant in the TOF-MLAA algorithm to obtain quantitatively accurate activity and attenuation maps. Our idea is to utilize the single events which have depth dependent attenuation factors, contrary to coincidence events. We show that in a 2D case, with the combination of TOF information and single events, a unique solution of attenuation and activity can be achieved. A three-step iterative image reconstruction algorithm is developed. In each iteration, the activity distribution is first updated using the MLEM approach with TOF PET data; the attenuation map is then updated using MLTR with non-TOF data; finally, both activity distribution and attenuation map are updated using a scale estimated from single events. Noisy and noise-free projection data are generated for 2D XCAT phantoms through analytical simulation. Both scatter information and randoms information are assumed to be known. The proposed method and the conventional TOF-MLAA algorithm are used to reconstruct the simulated data. Conventional MLEM method with known attenuation map is implemented for comparison as well. Normalized root mean square error (NRMSE) and optimal constant are defined for the quantitative analysis of reconstructed images. Our proposed image reconstruction method achieves ~1% NRMSE for the activity map and ~5% NRMSE for the attenuation map with a correct scale after 150 iterations for noise-free data. Results of noisy simulations are consistent with noise-free data. In summary, we have proposed to use the single events for constant determination in TOF-MLAA algorithm to obtain a unique solution of attenuation map and activity distribution without prior information. Future work will be dedicated to the extension of our method to the 3D situation. PMID- 30523998 TI - Comparing Unet training with three different datasets to correct CBCT images for prostate radiotherapy dose calculations. AB - Image intensity correction is crucial to enable cone beam computed tomography (CBCT) based radiotherapy dose calculations. This study evaluated three different deep learning based correction methods using a U-shaped convolutional neural network architecture (Unet) in terms of their photon and proton dose calculation accuracy. CT and CBCT imaging data of 42 prostate cancer patients were included. For target ground truth data generation, a CBCT correction method based on CT to CBCT deformable image registration (DIR) was used. The method yields a deformed CT called (i) virtual CT (vCT) which is used to generate (ii) corrected CBCT projections allowing the reconstruction of (iii) a final corrected CBCT image. The single Unet architecture was trained using these three different datasets: (Unet1) raw and corrected CBCT projections, (Unet2) raw CBCT and vCT image slices and (Unet3) raw and reference corrected CBCT image slices. Volumetric arc therapy (VMAT) and proton pencil beam scanning (PBS) single field uniform dose (SFUD) plans were optimized on the reference corrected image and recalculated on the obtained Unet-corrected CBCT images. The mean error (ME) and mean absolute error (MAE) for Unet1/2/3 were -1/2/3 Hounsfield units (HU) and 48/88/56 HU. The 1% dose difference pass rates were better than 98.4% for VMAT for 8 test patients not seen during training, with little difference between Unets. Gamma evaluation results were even better. For protons a gamma evaluation was employed to account for small range shifts, and 2%/2mm pass rates for Unet1/2/3 were better than 85%/89% and 91%. A 3 mm range difference threshold was established. Only for Unet3 the 5th and 95th percentiles of the range difference distributions over all fields, test patients and dose profiles were within this threshold. A single Unet architecture was successfully trained using both CBCT projections and CBCT image slices. Since the results of the other Unets were poorer than Unet3, we conclude that training using corrected CBCT image slices as target data is optimal for PBS SFUD proton dose calculations, while for VMAT all Unets provided sufficient accuracy. . PMID- 30523999 TI - Realizing both giant magnetic anisotropy and quantum anomalous Hall effect in graphene with adsorbed Te-Co dimer. AB - To realize quantum anomalous Hall state at higher temperature, it needs to search for the magnetic topological insulators with giant magnetic anisotropy. We have studied the structural, magnetic and topological properties of graphene with adsorbed Te-A (A=Co, Rh, Ir) dimers by first-principles calculations and Wannier technique. Our results reveal that the system of Te-Co@G is an excellent magnetic topological insulator with both perpendicular magnetic anisotropy of 61.7 meV and large topological band-gap of 35.8 meV. Both the magnetic anisotropy and the band gap can be effectively tuned by the applied electric field. The dimers are stably adsorbed onto the graphene and the systems are robust against thermal fluctuation. Topological analysis reveals that the adsorption system is the Chern insulator with C=2. PMID- 30524000 TI - Achieving reliable coincidence resolving time measurement of PET detectors using multichannel waveform digitizer based on DRS4 chip. AB - Coincidence resolving time (CRT) is one of the most important physical performance measures for positron emission tomography (PET), as reconstruction with accurate time-of-flight information enhances the lesion detectability in patient studies. Accordingly, various PET detector designs and high-performance front-end readout circuits have been actively investigated to improve timing performance. The resulting PET detectors are often evaluated using multichannel waveform digitizers for versatile data analysis of the output signals. However, we have found that inappropriate data acquisition (DAQ) using a multichannel waveform digitizer based on the domino-ring-sampler 4 (DRS4) chip can lead to a considerable error when determining CRT. To address this issue, we performed CRT measurements using a pair of Hamamatsu R9800 photomultiplier tubes. Then, considering intra- and inter-chip sampling, we employed four different combinations of input channels into the CAEN DT5742B waveform digitizer and obtained 2D CRT maps according to the leading-edge discriminator threshold for assessing each DAQ scheme. The intra-chip CRT measurement exhibited unusual streak patterns in the 2D CRT map and yielded the artificially-low CRT information in PET detector pairs, whereas the inter-chip CRT measurement provided the reliable estimation of timing resolution. Further, we could prevent the high-frequency signal crosstalk among input channels within the DRS4 chip using the inter-chip CRT measurement. We expect that our findings will also be useful for achieving the reliable CRT measurements when using other single-chip based multichannel waveform digitizers. PMID- 30524001 TI - Effects of n-butyl amine incorporation on the performance of perovskite light emitting diodes. AB - The efficiency of perovskite light emitting diodes (PeLEDs) is crucially limited by leakage current and nonradiative recombination. Here we introduce n-butyl amine (BA) to modulate the growth of perovskite films as well as improve the performance of PeLEDs, and investigate in details the effects of BA incorporation on the structural, optical, and electrical characteristics of perovskite films. The results indicate that BA would terminate the grain surface and inhibit crystal growth, leading to increased radiative recombination. However, BA overload would make the films loose and recreate shunt paths. The electrical detriment of BA overload outweighs its optical benefit. As a result, optimal PeLEDs can be obtained only with moderate BA incorporation. PMID- 30524002 TI - A simple method to monitor the dose rate of secondary cosmic radiation at altitude. AB - Monitoring the ambient dose equivalent rate at aviation altitudes is an ambitious task which requires sophisticated dosemeter systems and the possibility to carry out such measurements on board aircraft. A rather simple approach has been investigated in this study: soundings with weather balloons up to an altitude of 30 km. This paper summarizes the measurements carried out between 2011 and 2016. The results indicate that annual measurements of the ambient dose equivalent rate at altitudes of around 20 km are a reliable tool to monitor the variation of the dose rate in the atmosphere owing to the solar activity. PMID- 30524003 TI - Quantized dislocations. AB - A dislocation, just like a phonon, is a type of atomic lattice displacement but subject to an extra topological constraint. However, unlike the phonon which has been quantized for decades, the dislocation has long remained classical. This article is a comprehensive review of the recent progress on quantized dislocations, aka the "dislon" theory. Since the dislon utilizes quantum field theory to solve materials defects problems, we adopt a pedagogical approach to facilitate understanding for both materials science and condensed matter communities. After introducing a few preliminary concepts of dislocations, we focus on the necessity and pathways of dislocation's quantization in great detail, followed by the interaction mechanism between the dislon and materials electronic and phononic degrees of freedom. We emphasize the formality, the new phenomena, and the predictive power. Imagine the leap from classical lattice wave to quantized phonon; the dislon theory may open up vast opportunities to compute dislocated materials at a full quantum many-body level. PMID- 30524004 TI - Preferentially Oriented TiO2 Nanotube Arrays on Non-Native Substrates and Their Improved Performance as Electron Transporting Layer in Halide Perovskite Solar Cells. AB - Anodically formed TiO2 nanotube arrays (TNTAs) constitute an optoelectronic platform that is being studied for use as a photoanode in photoelectrocatalytic cells, as an electron transport layer (ETL) in solar cells and photodetectors, and as an active layer for chemiresistive and microwave sensors. For optimal transport of charge carriers in these one-dimensional polycrystalline ordered structures, it is desirable to introduce a preferential texture with the grains constituting the nanotube walls aligned along the transport direction. Through X ray diffraction analysis, we demonstrate that choosing the right water content in the anodization electrolyte and the use of a post-anodization zinc ion treatment can introduce a preferential texture in sub-micron length transparent TNTAs formed on non-native substrates. The incorporation of 1.5 atom% of Zn in TiO2 nanotubes prior to annealing, was found to consistently result in the strongest preferential orientation along the [001] direction. [001] oriented, Zn-doped TNTAs exhibited a responsivity of 523 A/W at a bias of 2 V for 365 nm photons, which is among the highest reported performance values for ultraviolet photodetection using titania nanotubes. Furthermore, the textured nanotubes without a Zn2+ treatment showed a significantly enhanced performance in halide perovskite solar cells that used TNTAs as the ETL. PMID- 30524005 TI - Micro-channel sieve electrode for concurrent bidirectional peripheral nerve interface. Part A: Recording. AB - OBJECTIVE: Advancement in prosthetic limb technology requires corresponding improvements in the capability of the amputee to naturally control the device via original motor pathways while simultaneously receiving haptic feedback via sensory pathways. Recording efferent axonal activity using a peripheral neural interface (PNI) allows a good tradeoff between invasiveness and selectivity while possibly preserving the phenomenology of controlling the original limb. One such PNI, the thin-film transverse intrafascicular multichannel electrode (tfTIME), has been shown to be successful in controlling powered prosthetics. However, the tfTIME is highly susceptible to stimulation artifact; thus, using such a PNI to both record efferent motor signals while concurrently stimulating afferent sensory axons in the same nerve is problematic. The micro-channel sieve electrode could also provide a stable, selective, neural interface with larger signal-to noise levels that are less susceptible to concurrent stimulation artifact or other external noise effects. APPROACH: This study uses a computational model to compare recording levels of simulated ENGs across neural drive levels as well as basic control signals derived from the ENGs in both tfTIME and micro-channel sieve PNIs. A motor neuron pool model generated axon firing rates at a given neural drive. The time course of the corresponding extracellular currents of the myelinated motor axons were determined using core conductor axon models. Finite element models determined the contribution of the extracellular current from nodes of Ranvier on potentials recorded using each interface. Contributions from each node were combined to create the final ENG. MAIN RESULTS: ENGs recorded using the micro-channel sieves were shown to have much higher amplitudes compared to ENGs recorded using the tfTIMEs. Signal amplitudes also varied less as a function of axonal placement and spike timing, resulting in more consistent signals with amplitudes determined predominantly by neural drive. SIGNIFICANCE: Simulation results suggest that the micro-channel sieve provides higher quality control signals over tfTIME PNIs in decoding ENGs. Coupling these results with concurrent stimulation results of the companion paper (Part B: Stimulation) suggests that the micro-channel sieve is an optimal bidirectional PNI. PMID- 30524006 TI - Calculating Deep Brain Stimulation Amplitudes and Power Consumption by Constrained Optimization. AB - : Deep Brain Stimulation (DBS) consists of delivering electrical stimuli to a brain target via an implanted lead to treat neurological and psychiatric conditions. Individualized stimulation is vital to ensure therapeutic results, since DBS may otherwise become ineffective or cause undesirable side effects. Since the DBS pulse generator is battery-driven, power consumption incurred by the stimulation is important. In this study, target coverage and power consumption are compared over a patient population for clinical and model-based patient-specific settings calculated by constrained optimization. APPROACH: Brain models for five patients undergoing bilateral DBS were built. Mathematical optimization of activated tissue volume was utilized to calculate stimuli amplitudes, with and without specifying the volumes, where stimulation was not allowed to avoid side effects. Power consumption was estimated using measured impedance values and battery life under both clinical and optimized settings. RESULTS: It was observed that clinical settings were generally less aggressive than the ones suggested by unconstrained model-based optimization, especially under asymmetrical stimulation. The DBS settings satisfying the constraints were close to the clinical values. SIGNIFICANCE: The use of mathematical models to suggest optimal patient-specific DBS settings that observe technological and safety constraints can save time in clinical practice. It appears though that the considered safety constraints based on brain anatomy depend on the patient and further research into it is needed. This work highlights the need of specifying the brain volumes to be avoided by stimulation while optimizing the DBS amplitude, in contrast to minimizing general stimuli overspill, and applies the technique to a cohort of patients. It also stresses the importance of considering power consumption in DBS optimization, since it increases with the square of the stimuli amplitude and also critically affects battery life through pulse frequency and duty cycle. PMID- 30524007 TI - Pulsed laser assisted synthesis of gadolinium carbide/carbon shell dots with enhanced magnetic resonance properties. AB - For nanomaterials, it is a new stage to be utilized in bio-applications with low toxicity, good stability and fine dissolvability. Herein, we present a pulsed laser assisted carbon coating method for nanocrystals, and gadolinium carbide/carbon shell (GC/CS) dots with face-centered cubic structured gadolinium carbide core have been synthesized in toluene. Good stability of GC/CS dots was observed not only in ethanol but also in the immunoconjugates. The MTT assay had revealed the immunoconjugates with non-/low- cytotoxicities. As a kind of paramagnetic species, the GC/CS dots revealed an excellent enhancement in magnetic resonance imaging at high magnetic field 14.1T with ultralow concentrations. In terms of the relaxivity values of the 1-3 nm GC/CS sample, both "r" _"1" and "r" _"2" have been dramatically increased to 87.5 mM-1s-1 and 112.5 mM-1s-1 respectively, thereby bringing the great potential of the GC/CS dots to be utilized as advanced magnetic resonance agent for the diagnosis of cancers. PMID- 30524008 TI - Determination of kQ factors for cylindrical and plane-parallel ionization chambers in a scanned carbon ion beam by means of cross calibration. AB - The accuracy in the dosimetry of therapeutically used carbon beams is predominantly affected by the large uncertainty of the so-called kQ factor of the ionization chamber used for the measurements. Due to a lack of experimental data, the kQ factor of ionization chambers in carbon beams is still derived by calculation, and, for instance, a standard uncertainty of about 3% is given for kQ factors tabulated in the TRS-398 dosimetric protocol. Recently, kQ factors for two Farmer-type ionization chambers have been determined experimentally in the entrance channel of 429 MeV/u carbon ions, achieving about a threefold reduction of the uncertainty. To further improve the data basis on experimental kQ factors with low uncertainties, kQ factors for the same irradiation condition have now been determined for eight different cylindrical ionization chambers (NE2571, FC65 P, FC23-C, CC25, CC13, TM30010, TM30011, TM30012) and three different plane parallel ionization chambers (PPC-40, PPC-05, TM34001) by means of a cross calibration procedure. Generally, standard measurement uncertainties of 1.0% could be achieved. Deviations of less than 1.2% were found between the experimental and the tabulated kQ values. Moreover, the consideration of the experimental values with their smaller uncertainties in updated versions of the dosimetric protocols might enable a substantial reduction of the uncertainties in the dosimetry of carbon beams. PMID- 30524009 TI - A generalised shapelet-based method for analysis of nanostructured surface imaging. AB - The determination of quantitative structure-property relations is a vital but challenging task for nanostructured materials research due to the presence of large-scale spatially varying patterns resulting from nanoscale processes such as self-assembly and nano-lithography. Focusing on nanostructured surfaces, recent advances have been made in automated quantification methods for orientational and translational order using shapelet functions, originally developed for analysis of images of galaxies, as a reduced-basis for surface pattern structure. In this work, a method combining shapelet functions and machine learning is developed and applied representative set of experimental images of self-assembled surfaces from experimental characterization techniques including SEM, AFM, and TEM). The method is shown to be computational efficient and able to quantify salient pattern features including deformation, defects, and grain boundaries from a broad range of patterns typical of self-assembly processes. PMID- 30524010 TI - Topological boundaries and bulk wavefunctions in the SSH model. AB - Working in the context of the Su-Schreiffer-Heeger (SSH) model, the effect of topological boundaries on the structure and properties of bulk position space wavefunctions is studied for a particle undergoing a quantum walk in a one-dimensional lattice. In particular, we consider what happens when the wavefunction reaches a boundary at which the Hamiltonian changes suddenly from one topological phase to another and construct an exact solution for the wavefunction on both sides of the boundary. The reflection and transmission coefficients at the boundary are calculated as a function of the system's hopping parameters, and it is shown that for some parameter ranges the transmission coefficient can be made very small. Therefore, it is possible to arrange a high degree of bulk wavefunction localization within in each topological region, a fact that has information processing applications. This "topologically-assisted" suppression of transitions, although not of direct topological origin itself, exists because of the presence of an abrupt change in the properties of the Hamiltonian at the topological boundary. We give a quantitative examination of the reflection and transmission coefficients of incident waves at the boundary between regions of different winding number. PMID- 30524011 TI - The role of self-trapped excitons in polaronic recombination processes in lithium niobate. AB - Transient absorption and photoluminescence are experimentally investigated in the polaronic reference system lithium niobate, LiNbO3 (LN), with the aim to refine the microscopic model of small polaron dynamics in materials with strong electron-phonon coupling. As a unique feature, our study is performed by using two different spectroscopic methods, in crystals with dopants enhancing photorefraction or damage resistance, and over a broad temperature range from 15 400K. Although being self-consistent for particular experimental conditions, the hitherto used microscopic polaronic models reveal inconsistencies when applied to this larger data set. We show that comprehensive modeling is unlocked by the inclusion of an additional type of polaronic state with the following characteristics: (i) strongly temperature- and dopant-dependent relaxation times, (ii) an absorption feature in the blue-green spectral range, and (iii) a Kohlrausch-Williams-Watts decay shape with a temperature-dependent stretching factor beta(T) showing a behavior contrary to that of small, strong-coupling polarons. The hypothesis of self-trapped excitons (STEs, i.e., bound electron hole pairs strongly coupled to Nb5+ and O2- within a niobium-oxygen octahedron) and their pinning on defects as the microscopic origin of these characteristics is supported by a spectroscopic linkage of photoluminescence at low (15K) and elevated (300K) temperatures and explains the long-lifetime components in transient absorption as due to pinned STEs. PMID- 30524012 TI - Flexible devices fabricated by plate-to-roll nanoimprint lithography system. AB - Plate-to-roll nanoimprint lithography (P2RNIL) system has been developed to realize high speed, large scale and high resolution nanoimprint process. Imprinted patterns with line width less than 75nm at a speed of 22cm2/s on flexible substrate has been achieved. To improve the quality of the patterns imprinted on, we proposed a compliant mechanism which can realize passive alignment and minimize the lateral displacement between the template and substrate. Finite element analysis of this compliant mechanism was carried out. By using the P2RNIL system, wire-grid polarizers(up to 10030:1 extinction ratio and up to 88% transmittance) and transparent metal electrodes whose performance is in good accordance with simulated results were successfully fabricated. PMID- 30524013 TI - Topological 'Luttinger' invariants for filling-enforced non-symmorphic semimetals. AB - Luttinger's theorem is a fundamental result in the theory of interacting Fermi systems: it states that the volume inside the Fermi surface is left invariant by interactions, if the number of particles is held fixed. Although this is traditionally justified in terms of analytic properties of Green's functions, it can be viewed as arising from a momentum balance argument that examines the response of the ground state to the insertion of a single flux quantum [M. Oshikawa, Phys. Rev. Lett. 84, 3370 (2000)]. This reveals that the Fermi volume is a topologically protected quantity, whose change requires a phase transition. However, this sheds no light on the stability or lack thereof of interacting semimetals, that either lack a Fermi surface, or have perfectly compensated electron and hole pockets and hence vanishing net Fermi volume. Here, I show that semimetallic phases in non-symmorphic crystals possess additional topological 'Luttinger invariants' that can be nonzero even though the Fermi volume vanishes. The existence of these invariants is linked to the inability of non-symmorphic crystals to host band insulating ground states except at special fillings. I exemplify the use of these new invariants by showing that they distinguish various classes of two- and three-dimensional semimetals. . PMID- 30524014 TI - LET dependent response of GafChromic films investigated with MeV ion beams. AB - The change in optical properties of GafChromic films depends not only on the absorbed dose, but also on the linear energy transfer (LET) of the ionizing radiation. The influence of LET on the film dose-response relationship is especially important when films are applied for dosimetry of energetic charged particles. In the present study, we examined the response of the unlaminated EBT3 and MD-V3 films to proton, deuterium and helium beams with energies in the range of several megaelectronvolts (MeV). Films were exposed to doses up to 200 Gy and a model based on the bimolecular chemical reaction was chosen to fit the measured film signals. The LET in the active layers of the films and the dose correction factors were computed with Monte Carlo software TRIM. Signal quenching, observed for all ion beams in comparison to X-rays, was investigated as a function of the LET in the range of 10 - 100 keV/um. The response of the films got weaker with increasing the LET and showed no dependence on the ion species. The LET effect was quantified by introducing a modified expression for the relative effectiveness (RE) by which a unique RE value is assigned to a single LET. The RE defined in that way decreased from about 90% for LET of 10 keV/um to less than 50% for LET of 100 keV/um. Similar behavior was observed for EBT3 and MD-V3 film models. PMID- 30524015 TI - A Fluorescent Aptamer/Carbon Dots based Assay for Cytochrome c Protein Detection as a Biomarker of Cell Apoptosis. AB - Cytochrome c (Cyt c), a heme protein, can be a potential biomarker for cell apoptosis or even cancer diagnosis. In this work, a simple, rapid, sensitive and selective label-free assay for Cytochrome c (Cyt c) detection is introduced based on an interaction between nucleic acid aptamer biomolecules and surfaces of Carbon Dots (CDs). CDs are used as a fluorescent probes and Cyt c-aptamers as a sensing materials. Interactions of aptamers with CDs quench the fluorescent intensity of CDs. By addition of Cyt c biomolecule as an analyte to the solution and binding to the aptamers, CDs fluorescence turns on. Stronger binding affinity of the aptamers toward Cyt c than CDs, causes they leave the CDs surfaces and the fluorescence is recovered. The amount of recoveries corresponds linearly to the concentration of Cyt c and be used as the basis of detection. The method exhibited high sensitivity to Cyt c with a detection limit of 25.90 nM and a linear range from 40 nM to 240 nM. PMID- 30524016 TI - Calculation of absorbed dose in radiotherapy by solution of the linear Boltzmann transport equations. AB - Over the last decade, dose calculations which solve the linear Boltzmann transport equations have been introduced into clinical practice and are now in widespread use. However, knowledge in the radiotherapy community concerning the details of their function is limited. This review gives a general description of the linear Boltzmann transport equations as applied to calculation of absorbed dose in clinical radiotherapy. The aim is to elucidate the principles of the method, rather than to describe a particular implementation. The literature on the performance of typical algorithms is then reviewed, in many cases with reference to Monte Carlo simulations. The review is completed with an overview of the emerging applications in the important area of MR-guided radiotherapy. PMID- 30524017 TI - Extremely sensitive and wide-range silver ion detection via assessing the integrated surface potential of a DNA-capped gold nanoparticle. AB - With the rapid development of nanotechnology and its associated waste stream, public concern is growing over the potential toxicity exposure to heavy metal ions poses to the human body and the environment. Herein, we report an extremely sensitive Kelvin probe force microscopy (KPFM)-based platform for detecting nanotoxic materials (e.g., Ag+) accomplished by probing the integrated surface potential differences of a single gold nanoparticle on which an interaction between probe DNA and target DNA occurs. This interaction can amplify the surface potential of the nanoparticle owing to the coordination bond mediated by Ag+ (cytosine-Ag+-cytosine base pairs). Interestingly, compared with conventional methods, this platform is capable of extremely sensitive Ag+ detection (~1 fM) in a remarkably wide range (1 fM to 1 MUM). Furthermore, this platform enables Ag+ detection in a practical sample (general drinking water), and this KPFM-based technique may have the potential to detect other toxic heavy metal ions and single nucleotide polymorphisms by designing specific DNA sequences. PMID- 30524018 TI - Association of pre-treatment radiomic features with lung cancer recurrence following stereotactic body radiation therapy. AB - PURPOSE: To investigate the potential relationship between radiomic features extracted from pre-treatment CT images and clinical outcomes following stereotactic body radiation therapy (SBRT) for non- small-cell lung cancer (NSCLC). Methods: Seventy patients who received SBRT for stage-1 NSCLC were retrospectively identified. The tumor was contoured on pre-treatment free breathing CT images, from which 43 quantitative radiomic features were extracted to collectively capture tumor morphology, intensity, fine-texture, and coarse texture. Treatment failure was defined based on cancer recurrence, local cancer recurrence, and non-local cancer recurrence following SBRT. The univariate association between each radiomic feature and each clinical endpoint was analyzed using Welch's t-test, and p-values were corrected for multiple hypothesis testing. Multivariate associations were based on regularized logistic regression with a singular value decomposition to reduce the dimensionality of the radiomics data. Results: Two features demonstrated a statistically significant association with local failure: Homogeneity2 (p=0.022) and Long-Run-High-Gray Level-Emphasis (p=0.048). These results indicate that relatively dense tumors with a homogenous coarse texture might be linked to higher rates of local recurrence. Multivariable logistic regression models produced maximum values of , and , for the recurrence, local recurrence, and non-local recurrence endpoints, respectively. Conclusions: The CT-based radiomic features used in this study may be more associated with local failure than non-local failure following SBRT for stage I NSCLC. This finding is supported by both univariate and multivariate analyses. PMID- 30524019 TI - Time domain characterization for sleep apnea in oronasal airflow signal: a dynamic threshold classification approach. AB - OBJECTIVE: Apneas are the most common type of sleep-related breathing disorders; they cause patients to move from restorative sleep into inefficient sleep. The American Academy of Sleep Medicine (AASM) considers sleep apnea as a hidden health crisis that affects 29.4 million adults costing USA billions of Dollars. Traditional detection methods of sleep apnea are achieved by human observation of the respiration signals. This introduces limitations in terms of access and efficiency of diagnostic sleep studies. However, alternative device technologies have limited diagnostic accuracy for detecting apnea events although many of the previous investigational algorithms are based on multiple physiological channel inputs. Guided by the AASM recommendations for sleep apnea diagnostics, this paper investigates time domain metrics to characterize changes in oronasal airflow respiration signals during the occurrence of apneic events. Methods: A new algorithm is developed to derive a respiratory baseline from the oronasal airflow signal in order to detect sleep apnea events using a dynamically adjusted threshold classification approach. To demonstrate our results, we use polysomnography data of 30 patients with different apnea severity levels as reflected by their overnight Apnea Hypopnea Index (AHI), including patients with mild apnea (5<= AHI < 15), moderate apnea (15 <= AHI < 30), and severe apnea (AHI >= 30). Results: Our results indicate the ability to characterize sleep apnea events in oronasal airflow signals using the proposed dynamic threshold classification approach. Overall, the new algorithm achieved a sensitivity of 80.0%, specificity of 88.7%, and an area under receiver operating characteristics curve of 0.844. Significance: The present results contribute a new approach for progressive detection of sleep apnea using an adaptive threshold that is dynamically adjusted with respect to the patient's respiration baseline, making it potentially able to effectively generalize over patients with different apnea severity levels and longer monitoring periods. PMID- 30524020 TI - Hybrids made of defective nanodiamonds interacting with DNA nucleobases. AB - The characteristics of hybrids made of a defective nanodiamond and a biomolecule unit are investigated in this work. Focus is given on the interaction between the nanodiamond and a DNA nucleobase. The latter is placed close to the former in two different arrangements, realizing different bonding types. The nanodiamond includes a negatively charged nitrogen-vacancy center and is hydrogen terminated. Using quantum-mechanical calculations, we could elucidate the structural and electronic properties of such hybrids. Our study clearly identifies the importance of the relative orientation of the two components, the nanodiamond and the nucleobase, in the complex in controlling the electronic properties of the resulting hybrid. The position of the defect at the center or closer to its interface with the nucleobase further controls the electronic orbitals around the defect center, hence its optical activity. In the end, we discuss the relevance of our work in biosensing. PMID- 30524021 TI - Targeted polyethylenimine/(p53 plasmid) nano-complexes for potential antitumor applications. AB - Developments of the tumor targeted ability for carriers are paramountly important to promote the goal of gene delivery into the tumor lesions for safety and efficacy. Here we report on the synthesized PEI-FITC-FA polymer, which could condense the pp53 to form nano-complexes. These targeted nano-complexes have favorable physical properties and they were expected to improve antitumor gene efficiency by their particular dual tumor targeted capabilities. This work indicated that PEI-FITC-FA/pp53 nano-complexes were efficiently delivered into tumor cells, and subsequently induced the tumor cell apoptosis. Thus, the targeted cationic polymer PEI-FITC-FA could be used as an advanced nanocarrier for gene/drug delivery. PMID- 30524022 TI - High Temperature, Transparent, Superhydrophobic Teflon AF-2400/Indium Tin Oxide Nanocomposite Thin Films. AB - The outstanding properties of Teflon AF-2400-chemical, optical, etc.-inspired us to make modifications to enhance its hydrophobicity. The AF-2400/Indium Tin Oxide Nanoparticles Nanocomposite was prepared by a spin coating technique at room temperature, using the AF-2400 polymer as the matrix and indium tin oxide (ITO) nanoparticles as the filler. Different ITONs concentrations ranging from 3 mg/ml to 30 mg/ml were prepared to study the effect of nanoparticle loading on the films' properties and superhydrophobicity. The effect of spin speed and annealing temperature was also studied. Atomic force microscopy, x-ray photoelectron spectroscopy, and Uv-vis analysis were employed to characterize the prepared films. The results indicate that the film's low surface energy and Nano/micro features made it superhydrophobic. Increasing the ITON concentration to 15 mg/ml improved the superhydrophobicity of the composite film by increasing the surface roughness. The coating showed superhydrophobic behavior with a static contact angle around 152o and contact angle hysteresis less than 2o. The nanocomposite films also exhibited excellent thermal stability sustaining temperature as high as 240?C without losing its superhydrophobic behavior. Three models, Wenzel, Cassie-Baxter, and Shuttleworth-Bailey, were used to predict the static contact angle. The results confirmed that the latter model gave the best prediction. In addition to superhydrophobicity, the AF-2400/ITON films coated on a glass substrate showed very high transparency-around 95% in the visible and infrared range. An effective medium theory, the Bergman representation, was used to simulate the transmittance of the AF-2400/ITON Nanocomposites. The measured and simulated transmittance values were in good agreement in the visible range. Based on our results, this coating may be highly useful for many practical applications, including solar cell coatings, chemical resistance protective coatings and more. PMID- 30524023 TI - Efficient metallic nanowire welding using eddy current method. AB - In this study, M-NWs such as silver nanowires (AgNWs) and copper nanowires (CuNWs) were welded only at junction resistively by a novel method using indirect Eddy current through the inductive power transfer. By applying the inductive power of 45 kHz alternating current (AC) power indirectly for 6 s to the M-NW network deposited on polymer substrates, the decrease of sheet resistance up to ~67.9 % for AgNW and ~49.9 % for CuNWs could be obtained without changing the optical transmittance. For AgNWs, after the welding the decrease of surface roughness from 44.5 nm to 26.3 nm which is similar to a height of single layer AgNW (22.2 nm) for a bilayer junction could be also observed. For AgNWs coated on transparent flexible substrate, after the cyclic bending of 10,000 times, no change of resistance (DeltaR/R0) of the AgNWs after the welding was observed and the welded AgNWs were not easily peeled off from the substrate. It is believed that this novel welding method can be applied not only to all kinds of metal nanowires on various flexible low-temperature polymer substrates but also to large area at a short time and at low-cost. PMID- 30524024 TI - Nasopharyngeal carcinoma segmentation based on enhanced convolutional neural networks using multi-modal metric learning. AB - multi-modality examinations have been extensively applied in current clinical cancer management. Leveraging multi-modality medical images can be highly beneficial for automated tumor segmentation as they provide complementary information that could make the segmentation of tumors more accurate. This paper investigates CNN-based methods for automated nasopharyngeal carcinoma (NPC) segmentation using Computed Tomography (CT) and Magnetic Resonance (MR) images. Specially, a multi-modality convolutional neural network (M-CNN) is designed to jointly learn a multi-modal similarity metric and segmentation of paired CT-MR images. By jointly optimizing the similarity learning error and the segmentation error, the feature learning processes of both modalities are mutually guided. In doing so, the segmentation sub-networks are able to take advantage of the other modality's information. Considering that each modality possesses certain distinctive characteristics, we combine the higher-layer features extracted by a single-modality CNN (S-CNN) and M-CNN to form a combined CNN (C-CNN) for each modality, which is able to further utilize the complementary information of different modalities and improve the segmentation performance. The proposed M-CNN and C-CNN were evaluated on 90 CT-MR images of NPC patients. Experimental results demonstrate that our methods achieve improved segmentation performance compared to their counterparts without multi-modal information fusion and the existing CNN based multi-modality segmentation methods. PMID- 30524025 TI - Deep learning in the cross-time-frequency domain for sleep staging from a single lead electrocardiogram. AB - OBJECTIVE: This study classifies sleep stages from a single lead electrocardiogram (ECG) using beat detection, cardiorespiratory coupling in the time-frequency domain and a deep convolutional neural network (CNN). Approach: An ECG-derived respiration (EDR) signal and synchronous beat-to-beat heart rate variability (HRV) time series were derived from the ECG using previously described robust algorithms. A measure of cardiorespiratory coupling (CRC) was extracted by calculating the coherence and cross-spectrogram of the EDR and HRV signal in five-minute windows. A CNN was then trained to classify the sleep stages (wake, rapid-eye-movement (REM) sleep, non-REM (NREM) light sleep and NREM deep sleep) from the corresponding CRC spectrograms. A support vector machine was then used to combine the output of CNN with the other features derived from the ECG, including phase-rectified signal averaging (PRSA), sample entropy, as well as standard spectral and temporal HRV measures. The MIT-BIH Polysomnographic Database (SLPDB), the PhysioNet/Computing in Cardiology Challenge 2018 database (CinC2018) and the Sleep Heart Health Study (SHHS) database, all expert-annotated for sleep stages, were used to train and validate the algorithm. Main results: Ten-fold cross validation results showed that the proposed algorithm achieved an accuracy (Acc) of 75.4% and a Cohen's kappa coefficient of K = 0.54 on the out of sample validation data in the classification of Wake, REM, NREM light and deep sleep in SLPDB. This rose to Acc = 81.6% and K = 0.63 for the classification of Wake, REM sleep and NREM sleep and Acc = 85.1% and K = 0.68 for the classification of NREM sleep versus REM/wakefulness in SLPDB. Significance: The proposed ECG-based sleep stage classification approach that represents the highest reported results on non-electroencephalographic data and uses datasets over 10 times larger than those in previous studies. By using a state-of-the-art QRS detector and deep learning model, the system does not require human annotation and can therefore be scaled for mass analysis. . PMID- 30524026 TI - Dose reconstruction from PET images in carbon ion therapy: a deconvolution approach. AB - Dose and range verification have become important tools to bring carbon ion therapy to a higher level of confidence in clinical applications. Positron emission tomography is among the most commonly used approaches for this purpose and relies on the creation of positron emitting nuclei in nuclear interactions of the primary ions with tissue. Predictions of these positron emitter distributions are usually obtained from time-consuming Monte Carlo simulations or measurements from previous treatment fractions, and their comparison to the current, measured image allows for treatment verification. Still, a direct comparison of planned and delivered dose would be highly desirable, since the dose is the quantity of interest in radiation therapy and its confirmation improves quality assurance in carbon ion therapy. In this work, we present a deconvolution approach to predict dose distributions from PET images in carbon ion therapy. Under the assumption that the one-dimensional PET distribution is described by a convolution of the depth dose distribution and a filter kernel, an evolutionary algorithm is introduced to perform the reverse step and predict the depth dose distribution from a measured PET distribution. Filter kernels are obtained from either a library or are created for any given situation on-the-fly, using predictions of the beta+-decay and depth dose distributions, and the very same evolutionary algorithm. The applicability of this approach is demonstrated for monoenergetic and polyenergetic carbon ion irradiation of homogeneous and heterogeneous solid phantoms as well as a patient computed tomography image, using Monte Carlo simulated distributions and measured in-beam PET data. Carbon ion ranges are predicted within less than 0.5 mm and 1 mm deviation for simulated and measured distributions, respectively. PMID- 30524027 TI - MRI-based attenuation correction for brain PET/MRI based on anatomic signature and machine learning. AB - Deriving accurate attenuation maps for PET/MRI remains a challenging problem because MRI voxel intensities are not related to properties of photon attenuation and bone/air interfaces have similarly low signal. This work presents a learning based method to derive patient-specific computed tomography (CT) maps from routine T1-weighted MRI in their native space for attenuation correction of brain PET. We developed a machine-learning-based method using a sequence of alternating random forests under the framework of an iterative refinement model. Anatomical feature selection is included in both training and predication stages to achieve excellent performance. To evaluate its accuracy, we retrospectively investigated 17 patients, each of which has been scanned by PET/CT and MR for brain. The PET images were corrected for attenuation on CT images as ground truth, as well as on PCT images generated from MR images. The PCT images showed excellent accuracy with mean average error of 66.4+/-8.1 HU, average correlation coefficient of 0.974+/-0.018 and average Dice similarity coefficient larger than 0.85 for air, bone and soft tissue. The side-by-side image comparisons and joint histograms demonstrated very good agreement of PET images after correction by PCT and CT. The mean differences of voxel values in selected VOIs were less than 4%, the mean absolute difference of all active area is around 2.5%, and the mean linear correlation coefficient is 0.989+/-0.017 between PET images corrected by CT and PCT. This work demonstrates a novel learning-based approach to automatically generate CT images from routine T1-weighted MR images based on a random forest regression with patch-based anatomical signatures to effectively capture the relationship between the CT and MR images. Reconstructed PET images using the PCT exhibit errors well below accepted test/retest reliability of PET/CT indicating high quantitative equivalence. PMID- 30524028 TI - On the robustness of real-time myoelectric control investigations: A multiday Fitts' law approach. AB - BACKGROUND AND AIM: Real-time myoelectric experimental protocol is considered as means to quantify usability of myoelectric control schemes. While usability should be considered over time to assure clinical robustness, all real-time studies reported thus far are limited to a single session or day and thus the influence of time on real-time performance is still unexplored. In this study, the aim was to develop a novel experimental protocol in order to quantify the effect of time on real-time performance measures over multiple days using a Fitts' law approach. Methods: Four metrics: throughput, completion rate, path efficiency and overshoot, were assessed using three train-test strategies: (i) An artificial neural network (ANN) classifier was trained on data collected from the previous day and tested on present day (BDT) (ii) Trained and tested on the same day (WDT) and (iii) trained on all previous days including present day and tested on present day (CDT) in a week-long experimental protocol. RESULTS: It was found that on average, Completion rate (98.37 +/- 1.47 %) of CDT was significantly better (P<0.01) than BDT (86.25 +/- 3.46 %) and WDT (94.22 +/- 2.74 %). Throughput (0.40 +/- 0.03 bits/s) of CDT was significantly better (P=0.001) than BDT (0.38+/-0.03 bits/s). Offline analysis showed a different trend due to the difference in the training strategies. Conclusion: Results suggest that increasing the size of training set over time can be beneficial to assure robust performance of the system over time. . PMID- 30524029 TI - 90Y TOF-PET based EUD reunifies patient survival prediction in resin and glass microspheres radioembolization of HCC tumours. AB - Clinical studies reported a twofold ratio between the efficacies per Gy of resin versus glass spheres. Our aim is to investigate whether this difference could result from the different degrees of heterogeneity in sphere distribution between the two medical devices. The 90Y TOF-PET based equivalent uniform doses (EUD) was used for this purpose. Method: 58 consecutive HCC radioembolizations were retrospectively analyzed. Absorbed doses D and Jones-Hoban EUD in lesions were computed. Radioembolization efficacy was assessed using Kaplan-Meier survival curves. Results: In order to match together the glass and resin spheres survival curves using a 40Gy-threshold, an efficacy factor of 0.73 and 0.36 has to be applied on their absorbed dose, respectively. Using EUD, a nice matching between glass and resin survival curves was obtained with a better separation of the responding and not responding survival curves. Conclusion: The results clearly support the fact that the activity heterogeneity observed in 90Y TOF-PET post radioembolization does not only result from statistical noise, but also reflects the actual heterogeneity of the spheres distribution. Use of EUD reunifies the efficacy of the two medical devices. . PMID- 30524030 TI - Tuning the electronic structure of single-walled carbon nanotube by high-pressure H2 exposure. AB - We report on an electronic structure change of single-walled carbon nanotube (SWNT) on hexagonal boron nitride (h-BN) due to electron doping via high-pressure H2 exposure. The fractional coverage of hydrogenated carbon atom is estimated to be at least theta = 0.163 from the in situ Ids-Vg measurements of the release process. Raman spectroscopy and X-ray photoelectron spectroscopy (XPS) were carried out to support the in situ electrical measurements. In particular, we used the dissociative Langmuir-type model to yield the desorption coefficient kdes by fitting it to the in situ electrical data. Finally, we applied this hydrogenation method to the SWNT network on the commercial Si/SiO2 substrate to open the possibility of the scalable n-type semiconducting SWNT FETs. PMID- 30524031 TI - Maneuvering and stabilization control of a bipedal robot with a universal-spatial robotic tail. AB - This paper analyzes control methodologies to implement maneuvering and stabilization behaviors in a bipedal robot using a bioinspired robotic tail. Looking to nature, numerous animals augment their legs' functionality using a tail to assist with both maneuvering and stabilization; looking to the robotics literature, previous research primarily focuses on single-mass, pendulum-like tails designed to perform a specific task. The overarching goal of this research is to study how bioinspired tail designs may be used in conjunction with low complexity leg designs to achieve high-performance behaviors. In pursuit of this goal, this paper connects the serpentine Universal-Spatial Robotic Tail (USRT) with a biped consisting of a pair of Robotic Modular Legs to study the outer- and inner-loop control considerations necessary to achieve yaw-angle turning and stable leg lifting. The design and modeling of the tail and leg subsystems are presented, along with considerations for sensing the USRT's configuration in real time. In addition, two inner-loop controllers that map desired tail trajectories into actuation commands are presented: a prescribed velocity approach that only utilizes motor feedback, and a prescribed torque approach that incorporates both feedforward consideration of the tail dynamics and feedback consideration from the tail sensing. Two outer-loop controllers-one for yaw-angle steering (maneuvering), and one for roll-angle disturbance rejection when lifting a foot (stabilization)-are also defined. Case studies including simulation and experimental results are used to validate the outer-loop control approaches. PMID- 30524032 TI - Uncertainties associated with assessing Ontario uranium miners' exposure to radon daughters. AB - The Ontario uranium miners study is a large (n=28 546) cohort with low levels of radon exposure relative to other miner cohorts. Multiple methods were used over time to estimate annual occupational exposure to radon daughters including: mine specific extrapolations by mining engineers, area sampling in limited areas of the mines combined with approximate working time and lastly, consistent exposure sampling in different locations of the mine combined with workers' time cards. Nonetheless, estimating exposures involves assumptions that lead to some uncertainty in occupational exposure characterization arising from the assessment approach and variability within workplace, over time and by individual. An evaluation of the total uncertainty associated with radon daughter exposure estimation in Ontario miners over time has not been conducted. The objective of this study was to identify the contributing sources and assess the total uncertainty associated with estimating occupational radon daughter exposure among underground Ontario uranium miners over the course of uranium mining. The five sources of radon daughter exposure uncertainty evaluated were: natural variations in radon concentration, estimation of working time, precision of the radon measurement method, unintended errors during sampling, and record keeping and transcription of exposure data. These sources were examined separately for the period 1958 to 1967 and then 1968 onward due to changes in radon daughter concentration measurement practices between these periods. The magnitude of uncertainty associated with each of these sources over time were determined by reviewing historical literature on uranium mining in Ontario as well as through expert advice. Using the root sum square method, the total exposure radon daughter exposure uncertainty was found to be 53 to 67% in the earlier period of uranium mining from 1958 to 1967. This decreased to 31 to 39% for the period 1968 to 1996 with natural variations of radon daughter concentrations in mines accounting for the largest percentage of uncertainty. This assessment provides an initial step in understanding the effect of exposure uncertainty on risk estimates. The impact of this uncertainty on the dose-response relationship between radon and cancer risk will be assessed in future work. PMID- 30524033 TI - Collagen type-IV Langmuir and Langmuir-Schafer layers as model biointerfaces to direct stem cell adhesion. AB - In biomaterial development, the design of material surfaces that mimic the extra cellular matrix (ECM) in order to achieve favorable cellular instruction is rather challenging. Collagen-type IV (Col-IV), the major scaffolding component of Basement membranes, a specialized ECM with multiple biological functions, has the propensity to form networks by self-assembly and supports adhesion of cells such as endothelial cells or stem cells. The preparation of biomimetic Col-IV network like layers to direct cell responses is difficult. We hypothesize that the morphology of the layer, and especially the density of the available adhesion sites, regulates the cellular adhesion to the layer. The Langmuir monolayer technique allows for preparation of thin layers with precisely controlled packing density at the air-water (A-W) interface. Transferring these layers onto cell culture substrates using the Langmuir Schafer (LS) technique should therefore provide a pathway for preparation of BM mimicking layers with controlled cell adherence properties. In situ characterization using ellipsometry and polarization modulation-infrared reflection absorption spectroscopy of Col-IV layer during compression at the A-W interface reveal that there is linear increase of surface molecule concentration with negligible orientational changes up to a surface pressure of 25 mN.m-1. Smooth and homogeneous Col-IV network-like layers are successfully transferred by LS method at 15 mN.m 1 onto poly(ethyleneterepthalate) (PET), which is a common substrate for cell culture. In contrast, the organization of Col-IV on PET prepared by the traditionally employed solution deposition method results in rather inhomogeneous layers with the appearance of aggregates and multilayers. Progressive increase in the number of early adherent mesenchymal stem cells (MSCs) after 24 h by controlling the Col-IV density by LS transfer at 10, 15 and 20 mN.m-1 on PET is shown. LS method offers the possibility to control protein characteristics on biomaterial surfaces such as molecular density and thereby, modulate cell responses. PMID- 30524034 TI - Monte Carlo study on optimal breast voxel resolution for dosimetry estimates in digital breast tomosynthesis. AB - Digital Breast Tomosynthesis (DBT) is currently used as an adjunct technique to Digital Mammography (DM) for breast cancer imaging. Being a quasi-3D image, DBT is capable of providing depth information on the internal breast glandular tissue distribution, which may be enough to obtain an accurate patient-specific radiation dose estimate. However, for this, information regarding the location of the glandular tissue, especially in the vertical direction (i.e. x-ray source to detector), is needed. Therefore, a dedicated reconstruction algorithm designed to localize the amount of glandular tissue, rather than for optimal diagnostic value, could be desirable. Such a reconstruction algorithm, or, alternatively, a reconstructed DBT image classification algorithm, could benefit from the use of larger voxels, rather than the small sizes typically used for the diagnostic task. In addition, the Monte Carlo (MC) based dose estimates would be accelerated by the representation of the breast tissue with fewer and larger voxels. Therefore, in this study we investigate the optimal DBT reconstructed voxel size that allows accurate dose evaluations (i.e. within 5%) using a validated Geant4 based MC code. For this, sixty patient-based breast models, previously acquired using dedicated breast computed tomography (BCT) images, were deformed to reproduce the breast during compression under a given DBT scenario. Two re binning approaches were applied to the compressed phantoms, leading to isotropic and anisotropic voxels of different volumes. MC DBT simulations were performed reproducing the acquisition geometry of a SIEMENS Mammomat Inspiration system. Results show that isotropic cubic voxels of 2.73 mm size provide a dose estimate accurate to within 5% for 51/60 patients, while a comparable accuracy is obtained with anisotropic voxels of dimension 5.46 x 5.46 x 2.73 mm3. In addition, the MC simulation time is reduced by more than half in respect to the original voxel dimension of 0.273 x 0.273 x 0.273 mm3 when either of the proposed re-binning approaches is used. No significant differences in the effect of binning on the dose estimates are observed (Wilcoxon-Mann-Whitney test, p-value > 0.4) between the 0 degrees the 23 degrees (i.e. the widest angular range) exposure. PMID- 30524035 TI - Acute hemodynamic changes following high load and very low load lower body resistance exercise with and without the restriction of blood flow. AB - OBJECTIVE: To examine the acute changes in blood flow and blood pressure of very low load knee extensor exercise (15% one repetition maximum (1RM)) with and without different levels of applied pressure to determine how these effects might differ from high load exercise. We also sought to examine if this differed between men and women. APPROACH: A total of 90 participants (45 men, 45 women) were randomized into a very low load condition with no restriction 15/0, (n=21), a very low load condition with 40% arterial occlusion pressure (15/40, n=23), a very low load condition with 80% arterial occlusion pressure (15/80, n=22), and a traditional high load condition (70/0, n=24). Pre-post change in blood flow and blood pressure were compared across conditions. Evidence for or against the null hypothesis was quantified using Bayes Factors (BF10). MAIN RESULTS: For blood flow, there was no evidence that the changes were different across conditions (BF10: 0.902). However, only the very low load free flow condition (15/0) had evidence to suggest a change (mean, (standard deviation)) from baseline (5.3 (9.1) ml.min-1; BF10: 3.687). Systolic pressure increased ~17 mmHg for the 15/0, 15/40, and 70/0 conditions, with no change in the 15/80 condition. There was no effect of sex for any variable. SIGNIFICANCE: There was substantial variability in our blood flow measurements, making conclusions difficult for this variable. Of note, the blood pressure response was not augmented by blood flow restriction. The hemodynamic changes were also similar between sexes, indicating that men and women were not changing differently. PMID- 30524036 TI - Half-metallic surfaces in thin-film Ti2MnAl0.5Sn0.5. AB - Materials exhibiting a high degree of spin polarization in electron transport are in demand for applications in spintronics - an emerging technology utilizing a spin degree of freedom in electronic devices. Room-temperature half-metals are considered ideal candidates, as they behave as an insulator for one spin channel and as a conductor for the other spin channel. In addition, for nano-size devices, one has to take into account possible modification of electronic structure in thin-film geometry, due to the potential presence of surface/interface states. It has been shown that typically these states have a detrimental impact on half-metallicity, i.e. their presence results in reduced spin-polarization. Here, we employ density functional calculations to explore an inverse Heusler compound, Ti2MnAl0.5Sn0.5, which exhibits half-metallic electronic structure in bulk geometry. In particular, this material behaves as a regular metal for majority-spin, and as a semiconductor for minority-spin states. We show that in thin-film geometry, the type of termination surface has a decisive effect on half-metallicity of this material. In particular, we analyze six possible termination configurations, and show that for four of them, energy states emerge in the minority-spin band gap, significantly reducing the spin polarization of Ti2MnAl0.5Sn0.5. At the same time, our calculations indicate that two termination surfaces preserve half-metallic properties of this material. This result is somewhat unexpected, as most of the available literature reports reduction of the spin-polarization due to the presence of surface states. Thus, our results show that a judicious choice of the termination surface may be a crucial factor in nano-device applications, where highly spin-polarized current is needed. PMID- 30524037 TI - Design of a spherical applicator for intraoperative radiotherapy with a linear accelerator---a Monte Carlo simulation. AB - Currently only flat dose distributions can be generated by electron beams of a linear accelerator for intraoperative radiotherapy. However, spherical dose distributions are more desirable for certain types of cancers such as breast cancer and brain cancers. In this study, we propose the design of a spherical applicator for delivery of spherical dose distributions. The spherical applicator consists of an upper cylindrical collimator to collimate the electron beam, a middle scattering foil to scatter the beam and a lower hollow sphere with a modulator to shape the beam and a spherical shell used to contain the modulator. Monte Carlo codes EGSnrc/BEAMnrc and EGS4/DOSXYZ were employed to model the head of the Mobetron, the spherical applicator, and to calculate the dose distributions. Apart from the scattering foil made of tungsten, the region between the scattering foil and the inner surface of the modulator is empty whereas the remainder of the spherical applicator made of soft tissue-equivalent materials such as PMMA. As a measure of how close an object approaches a perfect circle, roundness was introduced to evaluate the dose distributions. In addition, the dose rate after modulation was investigated. A spherical applicator with a 20 mm-diametre cylindrical collimator and a 50-mm-diametre hollow sphere was designed. For electron beams of energies 4, 6, 9, and 12 MeV, the foil thickness was set to 0.3, 0.5, 0.7, and 1.2 mm, and the dose rate was about 30, 40, 50, and 60 cGy/min respectively. The roundness of the isodose curves in the coronal plane through the centre of the spherical applicator ranged from 0.01 to 0.12 cm whereas that in the axial plane ranged from 0.05 to 1.38 cm. Experiments are planned to further evaluate the feasibility of this spherical applicator design. PMID- 30524038 TI - Stability, spontaneous and induced polarization in monolayer MoC, WC, WS, and WSe. AB - Ferroelectricity in the ultra low thin films of the ferroelectric materials is a rare phenomenon due to the depolarization electric field established by the uncompensated surface charge. Using density functional theory based calculations, we design buckled honeycomb binary monolayer MoC, WC, WS, and WSe. The feasibility of their experimental synthesis is evident from their low formation energies, stable lattice vibrations, and high elastic stiffnesses. The difference in electronegativity of the building atoms and lack of inversion symmetry results in high spontaneous out-of-plane polarization whereas all the in-plane components cancel out. Existence of the mirror plane along the armchair direction vanishes the in-plane piezoelectric stress effects for a strain applied along the zigzag direction. However, a strain along the armchair direction on MoC and WC results in a high piezoelectric coefficient up to 10*10-10 C/m, about 3 times larger than that reported for monolayer MoS2. The polarization switching barriers for the out-of-plane components range from 0.55 to 2.70 eV per formula unit. PMID- 30524039 TI - Enhanced mechanical and cell adhesive properties of photo-crosslinked PEG hydrogels by incorporation of gelatin in the networks. AB - Although synthetic polymers may have suitable physicochemical properties for biomedical applications, biological properties are generally lacking. Poly(ethylene glycol) (PEG) is a frequently used polymer for the preparation of hydrogels. Due to its hydrophilic character, however, cellular interactions with PEG hydrogels are minimal or absent. To improve the cell adhesive properties of PEG hydrogels, we developed hybrid hydrogels based on PEG and the natural polymer gelatin. PEG dimethacrylate (PEG-dMA) and gelatin methacrylate (GelMA) macromers were prepared, which were photo-crosslinked in water in different ratios (75:25, 50:50 and 25:75 % (v/v)). The obtained hybrid networks showed macrophase separation, which could be prevented by photo-crosslinking in 0.5 % (v/v) acetic acid in water. The toughness of 50:50 % PEG-dMA:GelMA hydrogels prepared in 0.5 % acetic acid was 2.5 times higher than that of single polymer hydrogels made of PEG-dMA or GelMA. Hybrid hydrogels crosslinked in 0.5 % acetic acid supported the proliferation of human mesenchymal stem cells to the same extent as compared to 100 % gelatin hydrogel, whereas the cells did not proliferate on 100 % PEG hydrogel. In conclusion, our results show that both the cell adhesive and mechanical properties of a photo-crosslinked PEG network can be improved by incorporation of gelatin in the network. PMID- 30524040 TI - Reactive jet impingement bioprinting of high cell density gels for bone microtissue fabrication. AB - Advances in three-dimensional (3D) cell cultures offer new opportunities in biomedical research and drug development. However, there are still challenges to overcome, including the lack of reliability, repeatability and complexity of tissues obtained by these techniques. In this study, we describe a new bioprinting system called Reactive Jet Impingement (ReJI) for the bioprinting of cell-laden hydrogels. Droplets of gel precursor solutions are jetted at one another such that they meet and react in mid-air before the gel droplets fall to the substrate. This technique offers a combination of deposition rate, cell density and cell viability which is not currently matched by any other bioprinting technique. The importance of cell density is demonstrated in the development of bone microtissues derived from immortalized human bone marrow stem cells. The cells were printed with high viability within a collagen-alginate fibrin gel, and tissue specific gene expression shows significantly higher tissue maturation rates using the ability of the ReJI system to deposit gels with a high cell density. PMID- 30524041 TI - Statistical weights for model-based reconstruction in cone-beam CT with electronic noise and dual-gain detector readout. AB - Cone-beam CT (CBCT) systems commonly incorporate a flat-panel detector (FPD) with multiple-gain readout capability to reduce electronic noise and extend dynamic range. In this work, we report a penalized weighted least-squares (PWLS) method for CBCT image reconstruction with a system model that includes the electronic noise characteristics of FPDs, including systems with dynamic-gain or dual-gain (DG) readout in which the electronic noise is spatially varying. Statistical weights in PWLS were modified to account for the contribution of the electronic noise (algorithm denoted PWLS^DG), and the method was combined with a certainty based approach that improves the homogeneity of spatial resolution (algorithm denoted PWLS_Cert^DG). The methods were tested in phantom studies designed to stress DG readout characteristics and translated to a clinical study for CBCT of patients with head traumas. The PWLS^DG method demonstrated superior noise resolution tradeoffs compared to filtered back-projection (FBP) and conventional PWLS. For example, with spatial resolution (edge-spread function width) matched at 0.65 mm, PWLS^DG reduced variance by 28-39% and 15-25% compared to FBP and PWLS, respectively. The PWLS_Cert^DG method achieved more homogeneous spatial resolution than PWLS^DG while maintaining similar variance reduction. These findings were confirmed in clinical studies, which showed ~20% variance reduction in peripheral regions of the brain, potentially improving visual image quality in detection of epidural and/or subdural intracranial hemorrhage. The results are consistent with the general notion that incorporating a more accurate system model improves performance in optimization-based statistical CBCT reconstruction in this case, a more accurate model for (spatially varying) electronic noise to improve detectability of low-contrast lesions. PMID- 30524042 TI - Probing static discharge of polymer surfaces with nanoscale resolution. AB - Triboelectric charging strongly affects the operation cycle and handling of materials and can be used to harvest mechanical energy through triboelectric nanogenerator set-up. Despite ubiquity of triboelectric effects, a lot of mechanisms surrounding the relevant phenomena remain to be understood. Continued progress will rely on the development of rapid and reliable methods to probe accumulation and dynamics of static charges. Here, we demonstrate in-situ quantification of tribological charging with nanoscale resolution, that is applicable to a wide range of dielectric systems. We apply this method to differentiate between strongly and weakly charging compositions of industrial grade polymers. The method highlights the complex phenomena of electrostatic discharge upon contact formation to pre-charged surfaces, and directly reveals the mobility of surface charges. Systematic characterization of commercial polyethylene terephthalate samples revealed the compositions with the best antistatic properties and provided an estimate of characteristic charge density up to 5*10-5 C/m2. Large-scale molecular dynamics simulations were used to resolve atomistic level structural and dynamical details revealing enrichment of oxygen containing groups near the air-interface where electrostatic charges are likely to accumulate. PMID- 30524043 TI - Graphene and graphene nanomesh supported nickel clusters: Electronic, magnetic, and hydrogen storage properties. AB - Small-sized nanoparticles are widely used in applications, such as catalysis, nanoelectronics, and hydrogen storage. However, the small size causes a common problem: agglomeration on the support template. One solution is to use templates that limit the mobility of the nanoparticles. Graphene nanomeshes (GNMs) are two dimensional porous structures, with controllably passivated pores. In this work, we employ first principles calculations to investigate the potential for using GNMs as support templates for Ni clusters and, at the same time, study their magnetic and hydrogen storage properties. We consider two Ni clusters (Ni$_{6}$ and Ni$_{13}$) and two GNMs (O-terminated and N-terminated) comparing our results to those of isolated Ni clusters, and those of Ni clusters on graphene. High stability of the Ni clusters is found on the N-GNM in contrast to the O-GNM. We quantify the hydrogen storage capacity by calculating the adsorption energy for multiple H$_2$ molecules. The values on Ni$_{x}$/N-GNM are significantly reduced as compared to the corresponding isolated Ni$_{x}$ clusters, but a high hydrogen storage capacity is maintained. The fact that Ni$_{x}$/N-GNM hosts spin polarization is interesting for spintronic applications. PMID- 30524044 TI - Generalized stacking fault energy of carbon-alloyed paramagnetic gamma-Fe. AB - Generalized stacking fault energy (GSFE) is an important parameter for understanding the underlying physics governing the deformation mechanisms in face centred cubic (fcc) materials. In the present work, we study the long-standing question regarding the influence of C on the GSFE in austenitic steels at paramagnetic state. We calculate the GSFE in both gamma-Fe and Fe-C alloys using the Exact Muffin-Tin Orbitals (EMTO) method and the Vienna Ab initio Simulation Package (VASP). Our results show that the GSFE is increased by the presence of interstitial C, and the universal scaling law is used to verify the accuracy of the obtained stacking fault energies. The C-driven change of the GSFE is discussed considering the magnetic contributions. The effective energy barriers for stacking fault, twinning and slip formation are employed to disclose the C effect on the deformation modes, and we demonstrate that the magnetic structures as a function of volume explain the effect of paramagnetism on the C-driven changes of the stacking fault energies as compared to the hypothetical non magnetic case. PMID- 30524045 TI - Decoding motor neuron activity from epimysial thin-film electrode recordings following targeted muscle reinnervation. AB - OBJECTIVE: Surface electromyography (EMG) is currently used as a control signal for active prostheses in amputees who underwent targeted muscle reinnervation (TMR) surgery. Recent research has shown that it is possible to access the spiking activity of spinal motor neurons from multi-channel surface EMG. In this study, we propose the use of multi-channel epimysial EMG electrodes as an interface for decoding motor neurons activity following TMR. APPROACH: We tested multi-channel epimysial electrodes (48 detection sites) built with thin-film technology in an animal model of TMR. Eight animals were tested 12 weeks after reinnervation of the biceps brachii lateral head by the ulnar nerve. We identified the position of the innervation zone and the muscle fiber conduction velocity of motor units decoded from the multi-channel epimysial recordings. Moreover, we characterized the pick-up volume by the distribution of the motor unit action potential amplitude over the epimysium surface. MAIN RESULTS: The electrodes provided high quality signals with average signal-to-noise ratio >30 dB across 95 identified motor units. The motor unit action potential amplitude decreased with increasing distance of the electrode from the muscle fibers (P << 0.001). The decrease was more pronounced for bipolar compared to monopolar derivations. The average muscle fiber conduction velocity was 2.46 +/- 0.83 m/s. Most of the neuromuscular junctions were close to the region where the nerve was neurotized, as observed from the EMG recordings and imaging data. SIGNIFICANCE: These results show that epimysial electrodes can be used for selective recordings of motor unit activities with a pick-up volume that included the entire muscle in the rat hindlimb. Epimysial electrodes can thus be used for detecting motor unit activity in muscles with specific fascicular territories associated to different functions following TMR surgery. PMID- 30524046 TI - Temporal cooperativity of motor proteins under constant force: insights from Kramers' escape problem. AB - The microtubule-bound motors kinesin and dynein differ in many respects, a striking difference being that while kinesin is known to function mostly alone, dynein operates in large groups, much like myosinV in actin. Optical tweezer experiments in vitro have shown that the mean detachment time of a bead attached to [Formula: see text] kinesins under stall conditions is a slowly decreasing function of [Formula: see text], while for dyneins, the time increases almost linearly with [Formula: see text]. This makes dynein a team worker, capable of producing and sustaining a large collective force without detaching. We characterize this phenomenon as 'temporal cooperativity' under load. In general, it is unclear which biophysical properties of a single motor determine whether it behaves cooperatively or not in a group. Our theoretical analysis shows that this is determined by two dimensionless parameters: (i) the ratio of single molecule, load-independent detachment and attachment rates and (ii) the ratio of the applied force per motor to the detachment force of a single motor. We show that the attachment-detachment dynamics of a motor assembly may be mapped to the motion of a hypothetical, overdamped Brownian particle in an effective potential, the form of which depends on the load-dependence of binding and unbinding rate of the motor. In this picture, the total number [Formula: see text] of motors is proportional to the inverse temperature and cooperative behaviour arises from the trapping of the particle in the minima of the potential, when present. In the latter case, application of results from Kramers' theory predicts that the mean time of escape of the particle, equivalent to the mean detachment time of the bead under stall, increases exponentially with the number of motors, indicating cooperative behaviour. If the potential does not have minima, the detachment time depends only weakly on [Formula: see text], which suggests non-cooperative behaviour. In the large [Formula: see text] limit, the emergence of cooperative behaviour is shown to be similar to a continuous phase transition. PMID- 30524047 TI - Improved Hubbard-I approximation impurity solver for quantum impurity models. AB - We develop a fast impurity solver which is based on the combination of Hubbard-I approximation and hybridization expansion continuous-time quantum Monte Carlo algorithm. This solver inherits the advantages of both algorithms. In order to demonstrate the power and usefulness of this solver, we use it to study the magnetic phase transitions of single-band and two-band Hubbard models in the framework of single-site dynamical mean-field theory. The calculated results agree well with those obtained by hybridization expansion quantum impurity solver. It is suggested that this solver is very suitable to solve the multi orbital quantum impurity models efficiently and can be used to study more realistic systems with magnetic long-range order in the future. PMID- 30524048 TI - MEH-PPV photophysics: insights from the influence of a nearby 2D quencher. AB - The effect of 2D quenching on single chain photophysics was investigated by spin coating 13nm thick films of polystyrene lightly doped with MEH-PPV onto CVD grown graphene and observing the changes in several photoluminescent (PL) observables. With 99% of the PL quenched, we found a 60% drop in the PL lifetime, along with a significant blue-shift of the PL emission due to the preferential quenching of emission at longer wavelengths. During photobleaching, the blue spectral shift observed for isolated polymers was eliminated in the presence of the quencher up until 70% of the polymer was photobleached. Results were interpreted using a static disorder induced conjugation length distribution model. The quencher, by opening up a new non-radiative decay channel, ensures that excitons do not have sufficient time to migrate to nearby lower energy chromophores. The reduction of energy transfer into the lowest-energy chromophores thus reduces their rate of photobleaching. Finally, the difference between the quenched and non-quenched spectra allows the rate of energy transfer along the polymer backbone to be estimated at ~2ns-1. PMID- 30524049 TI - Diels-Alder adduct formation at solid interfaces between Fullerenes and Acenes. AB - Understanding organic-organic interfaces is rather challenging due to their large complexity regarding morphology, molecular orientation at the interface, interdiffusion, and energetics. One additional important but often neglected aspect are chemical reactions occuring at such interfaces. For solid interfaces between pentacene and Buckminster-Fullerene (C60) recently very efficient Diels-Alder adduct formation has been reported. Considering the importance of pentacene/C60 as prototypical donor-acceptor combination to study fundamental processes in organic photovoltaics, understanding this effect is essential. In this work, we provide detailed NEXAFS-based investigations with respect to the temperature-dependence and reaction zone depth of this effect. Moreover, we widely vary the interface morphology and observe that the Diels-Alder adduct formation is most efficient for bulk heterojunctions of pentacene and C60. By also investigating further material combinations such as PEN/C60-PCBM and interfaces between C60 and functionalized acenes, we observe trends for the occurrence of the Diels-Alder adduct formation correlated with the different chemical properties of the involved compounds. PMID- 30524050 TI - Network proteomics of human dermal wound healing. AB - Healing of wounds is critical to maintaining protection of human body against environmental factors. The mechanisms involving protein expression during this complex physiological process have not been fully elucidated. Here, we use the reverse-phase protein microarrays involving 94 phosphoproteins to study tissue samples from tubes implanted into healing dermal wounds in 7 human subjects tracked over 2 weeks. We compare the proteomic profiles to proteomes of controls obtained from skin biopsy from the same subjects. Compared to previous proteomic studies of wound healing, our approach is focused on wound tissue instead of wound fluid, and has the sensitivity to go beyond measuring only high-abundance proteins. To study the temporal dynamics of networks involved in wound healing, we applied two network analysis methods that integrate the experimental results with prior knowledge about protein-protein physical and regulatory interactions, as well as higher-level biological processes and associated pathways. We uncovered densely connected networks of proteins that are up- or down-regulated during human wound healing, as well as their relationships to microRNAs and to proteins outside of our set of targets we measured with proteomic microarrays. PMID- 30524051 TI - SnO2-rGO nanocomposite as an efficient electron transport layer for stable perovskite solar cells on AZO substrate. AB - Electron transport layer (ETL) plays an important role in realizing efficient and stable perovskite solar cells. There are continuous efforts in developing new types of low cost ETLs with improved conductivity and compatibility with perovskite and the conducting electrode. Here, in order to obtain high efficient and stable perovskite solar cells on ZnO: Al (AZO) substrate, reduced graphene oxide (rGO) is incorporated into SnO2 nanoparticles to form composite ETL. For planar perovskite solar cell on AZO substrates, SnO2-rGO with a low incorporation ratio of 3wt% rGO significantly enhances the device short circuit current density (Jsc) and the fill factor (FF) when compared to the device with pristine SnO2 ETL, leading to an overall power conversion efficiency (PCE) of 16.8% with negligible hysteresis. The effectiveness of the excited charge transfer process of SnO2-rGO ETL is revealed by time-resolved photoluminescence decay (TRPL), and by electrochemical impedance spectrum (EIS) measurements. Furthermore, the solar cell stability is also enhanced due to the incorporation of rGO in the ETL. This work provides a low cost and effective ETL modification strategy for achieving high performance planar PSCs. PMID- 30524052 TI - Effect of impurities on the long-distance & Zhang-Rice dimers in quantum magnet Sr14Cu24O41. AB - We study the effect of impurities on the two types of spin-dimers in the hybrid chain/ladder spin 1/2 quantum magnet Sr$_{14}$Cu$_{24}$O$_{41}$. Four different impurities were used, namely, the non-magnetic Zn (0.0025 and 0.01 per Cu) and Al (0.0025 and 0.01 per Cu), and magnetic Ni (0.0025 and 0.01 per Cu) and Co (0.01, 0.03, 0.05 and 0.1 per Cu). These impurities were doped in high-quality single crystals synthesized by the floating zone method. The magnetic susceptibility of pristine Sr$_{14}$Cu$_{24}$O$_{41}$ is analyzed rigorously to confirm that at low temperatures (T $<$ 5 K), the "free" spins in the chains undergo a long-distance dimerization as proposed in a recent study [Sahling et al. Nature Phys., ?textbf{11}, 255 (2015)]. The effect of impurity on these dimers is analyzed by measuring the specific heat down to T = 0.06 K. We found that even at the lower impurity concentration, the long-distance dimers are significantly severed, but the quantum entangled spin dimerized state of the chains persists. On the other hand, the other type of spin dimers that forms at relatively higher temperatures via an intervening Zhang-Rice singlet are found to be practically unaffected at the lower impurity concentration; but at 1?% doping, even these are found to be considerably severed. The effect of Co impurity turned out to be most unusual displaying a strongly anisotropic response, and with a dimerization gap that suppresses faster along the chain/ladder direction than perpendicular to it as a function of increasing Co concentration. PMID- 30524053 TI - Energy conversion from environmental fluctuations to coherent fields by Cooper pair box quantum meta-materials. AB - Electromagnetic waves propagating in open Cooper-Pair Boxes (CPBs) system is studied by using Maxwell-Bloch equations and Lindblad master equation. The results demonstrate an ensemble of CPBs as highly non-linear meta-material for electromagnetic waves. Incorporating the CPBs in a ring resonator or a Fabry Perot cavity, one finds that: (1) With weak environmental couplings and CPBs in superconducting phase dominant regime, the non-linearity is enhanced and the system exhibits regular optical hysteresis. (2) With finite environmental couplings and CPBs in charge dominant regime, the Josephson effect and environmental effect can constructively interplay to produce a gain. In the later case, the electromagnetic field would be amplified by the CPB medium, indicating energy conversion from the environment to coherent fields mediated by CPBs. PMID- 30524054 TI - Localized magnetic moments in metallic SrB6 single crystals. AB - The specific heat Cp of metallic SrB6 single crystals shows an anomalous behavior for T ? 5K which varies strongly with an applied magnetic field. This is consistent with a two--level Schottky system. We ascribe the excess of Cp in this temperature range to localized magnetic moments. In addition, features that are attributable to a partial ferromagnetic polarization of a conduction electron gas are observed. These results are supported by magnetization measurements and are compatible with the transport properties presented previously (DOI: 10.1103/PhysRevB.94.125141). . PMID- 30524055 TI - Measurement of entropic force from polymers attached to a pyramidal tip. AB - The measurement of the boundary shape dependence of the entropic force from long polymers was attempted. The pyramidal cone-plate geometry was chosen. The polymer molecules were covalently bound to a well-defined Au patch at the apex of a pyramidal cantilever tip of the atomic force microscope (AFM). A smooth hydrophobic plate was used as the second boundary to confine the polymer molecules. The use of the hydrophobic plate allows neglect of polymer adhesion forces. The measurements were made in salt water solution to decrease the effect of electrostatic forces from any uncompensated charges on the boundary. As the functionalized AFM tip approaches the flat hydrophobic surface, the induced entropic forces were measured as a function of the separation distance. The measured force-distance curves are compared with a model of polymer-mediated entropic force between scale-free objects and the Alexander-de Gennes theory for a polymer brush. PMID- 30524056 TI - Inter-subject transfer learning with end-to-end deep convolutional neural network for EEG-based BCI. AB - OBJECTIVE: Despite the effective application of deep learning in brain-computer interface (BCI) systems, the successful execution of this technique especially for inter-subject classification in cognitive BCI has not been accomplished yet. In this paper, we propose a framework based on deep convolutional neural network (CNN) to detect attentive mental state from single-channel raw electroencephalography (EEG) data. APPROACH: We develop an end-to-end deep CNN to decode the attentional information from EEG time-series. We also explore the consequence of input representations on the performance of deep CNN by feeding three different EEG representations into the network. To ensure the practical application of the proposed framework and avoid time-consuming re-trainings, we perform inter-subject transfer learning techniques as classification strategy. Eventually, to interpret the learned attentional patterns, we visualize and analyze the network perception of attention and non-attention classes. MAIN RESULTS: The average classification accuracy is 79.26% with only 15.83% of 120 subjects having the accuracy below 70% (a generally accepted threshold for BCI). This is while with inter-subject approach, it is literally hard to output high classification accuracy. This end-to-end classification framework surpasses the conventional classification methods for attention detection. The visualization results validate that the learned patterns from raw data are meaningful. SIGNIFICANCE: This framework significantly improves the attention detection accuracy with inter-subject classification. Moreover, this study sheds light into the research on end-to-end learning; the proposed network is capable to learn from raw data with the least amount of pre-processing which in turn eliminates the extensive computational load of time-consuming data preparation and feature extraction. PMID- 30524057 TI - An evaluation of computed tomography dose index measurements using a pencil ionization chamber and small detectors. AB - The aim of this study was to compare the values of the computed tomography dose index 100 (CTDI100) obtained using two small detectors (i.e. a small ionization chamber and a small solid state detector) with those obtained from a 100-mm pencil ionization chamber for various input CT parameters: beam width, kVp, mAs, pitch, and head-body phantom variation. The measurement of CTDI100 using the 100 mm pencil chamber was carried out in a single rotation of axial mode, while the measurement using small detectors was carried out in helical mode. The differences of CTDI100 values obtained with two small detectors were about 7% for all variations. The differences of CTDI100 values obtained with small detectors and a 100-mm pencil ionization chamber for beam widths of more than 4 mm were within 40%. However, for the narrowest beam widths (4 mm), the difference between them was very large (about 150%). PMID- 30524058 TI - Oxygen transporter for the hypoxic transplantation site. AB - Cell transplantation is a promising treatment for complementing lost function by replacing new cells with a desired function, e.g., pancreatic islet transplantation for diabetics. To prevent cell obliteration, oxygen supply is critical after transplantation, especially until the graft is sufficiently re vascularized. To supply oxygen during this period, we developed a chemical /electrical-free implantable oxygen transporter that delivers oxygen to the hypoxic graft site from ambient air by diffusion potential. This device is simply structured using a biocompatible silicone-based body that holds islets, connected to a tube that opens outside the body. In computational simulations, the oxygen transporter increased the oxygen level to >120 mmHg within grafts; in contrast, a control device that did not transport oxygen showed < 6.5 mmHg. In vitro experiments demonstrated similar results. To test the effectiveness of the oxygen transporter in vivo, we transplanted pancreatic islets, which are susceptible to hypoxia, subcutaneously into diabetic rats. Islets transplanted using the oxygen transporter showed improved graft viability and cellular function over the control device. These results indicate that our oxygen transporter, which is safe and easily fabricated, effectively supplies oxygen locally. Such a device would be suitable for multiple clinical applications, including cell transplantations that require changing a hypoxic microenvironment into an oxygen-rich site. PMID- 30524059 TI - Automatic sleep stages classification using respiratory, heart rate and movement signals. AB - OBJECTIVE: This paper presents an algorithm for non-invasive sleep stage identification using respiratory, heart rate and movement signals. The algorithm is part of a system suitable for long-term monitoring in a home environment, which should support experts analysing sleep. APPROACH: As there is a strong correlation between bio-vital signals and sleep stages, multinomial logistic regression was chosen for categorical distribution of sleep stages. Several derived parameters of three signals (respiratory, heart rate and movement) are input for the proposed method. Sleep recordings of 5 subjects were used for the training of a machine learning model and 30 overnight recordings collected from 30 individuals with about 27,000 epochs of 30-second intervals each were evaluated. MAIN RESULTS: The achieved rate of accuracy is 72% for Wake, NREM, REM (with Cohen's kappa value 0.67) and 58% for Wake, Light (N1 and N2), Deep (N3) and REM stages (Cohen's kappa is 0.50). Our approach has confirmed the potential of this method and disclosed several ways for its improvement. SIGNIFICANCE: The results indicate that respiratory, heart rate and movement signals can be used for sleep studies with a reasonable level of accuracy. These inputs can be obtained in a non-invasive way applying it in a home environment. The proposed system introduces a convenient approach for a long-term monitoring system which could support sleep laboratories. The algorithm which was developed allows for an easy adjustment of input parameters that depend on available signals and for this reason could also be used with various hardware systems. PMID- 30524060 TI - A high-density carbon fiber neural recording array technology. AB - OBJECTIVE: Microwire and Utah-style neural recording arrays are the predominant devices used for cortical neural recording, but the implanted electrodes cause a significant adverse biological response and suffer from well-studied performance degradation. Recent work has demonstrated that carbon fiber electrodes do not elicit this same adverse response, but these existing designs are not practically scalable to hundreds or thousands of recording sites. We present technology that overcomes these issues while additionally providing fine electrode pitch for spatial oversampling. Approach: We present a 32-channel carbon fiber monofilament-based intracortical neural recording array fabricated through a combination of bulk silicon microfabrication processing and microassembly. This device represents the first truly two-dimensional carbon fiber neural recording array. The density, channel count, and size scale of this array are enabled by an out-of-plane microassembly technique in which individual fibers are inserted through metallized and isotropically conductive adhesive-filled holes in an oxide passivated microfabricated silicon substrate. Main results: Five-micron diameter fibers are spaced at a pitch of 38 microns, four times denser than state of the art one-dimensional arrays. The fine diameter of the carbon fibers affords both minimal cross-section and three orders of magnitude greater lateral compliance than standard tungsten microwires. Typical 1 kHz impedances are on the order of hundreds of kiloohms, and successful in vivo recording is demonstrated in the motor cortex of a rat. 22 total units are recorded on 20 channels, with unit SNR ranging from 1.4 to 8.0. Significance: This is the highest density microwire-style electrode array to date, and this fabrication technique is scalable to a larger number of electrodes and allows for the potential future integration of microelectronics. Large-scale carbon fiber neural recording arrays are a promising technology for reducing the inflammatory response and increasing the information density, particularly in neural recording applications where microwire arrays are already used. PMID- 30524061 TI - Design and testing of a microcontroller that enables alpha particle irradiators to deliver complex dose rate patterns. AB - There is increasing interest in using alpha particle emitting radionuclides for cancer therapy because of their unique cytotoxic properties which are advantageous for eradicating tumor cells. The high linear energy transfer (LET) of alpha particles produces a correspondingly high density of ionizations along their track. Alpha particle emitting radiopharmaceuticals deposit this energy in tissues over prolonged periods with complex dose rate patterns that depend on the physical half-life of the radionuclide, and the biological uptake and clearance half-times in tumor and normal tissues. We have previously shown that the dose rate increase half-time that arises as a consequence of these biokinetics can have a profound effect on the radiotoxicity of low-LET radiation. The microcontroller hardware and software described here offer a unique way to deliver these complex dose rate patterns with a broad-beam alpha particle irradiator, thereby enabling experiments to study the radiobiology of complex dose rate patterns of alpha particles. Complex dose rate patterns were created by precise manipulation of the timing of opening and closing of the electromechanical shutters of an alpha-particle irradiator. An Arduino Uno and custom circuitry was implemented to control the shutters. The software that controls the circuits and shutters has a user-friendly Graphic User Interface (GUI). Alpha particle detectors were used to validate the programmed dose rate profiles. Circuit diagrams and downloadable software are provided to facilitate adoption of this technology by other radiobiology laboratories. PMID- 30524062 TI - Ga-SBA-3 A novel nanostructured material: synthesis, characterization and application. AB - This paper reports for the first time the incorporation of gallium into the structure of the mesoporous SBA-3 material in order to modify the intrinsic acidity of the material. The study indicates the effective incorporation of Ga into a network in tetrahedral form, with most in the interior of the lodging and a low proportion on the external surface. Gallium was introduced via post synthesis using Ga-Nitrate in appropriate conditions. The nanostructured material was characterized by ICP, XRD, NMR-MAS, XPS, FTIR, SEM, TEM and UV Vis., Pyridine was used as a probe molecule for the determination of its acidity following the amount and type of acidic sites by FTIR. In addition, aniline adsorption/desorption studies and subsequent in-situ polymerization, PANI/Ga-SBA 3, were carried out with the aim of producing a nanocomposite with conductive properties. The original material had good structural regularity and acidity of Bronsted and Lewis; the PANI/Ga-SBA-3 composite also showed a conductivity of 2.5x10-3 S/cm, higher than that of its homologs Al-SBA-3 and Al-MCM- 41. PMID- 30524063 TI - Marble-derived microcalcite improves bone healing in mice osteotomy. AB - Approximately 10% of all fractures result in delayed healing or non-unions. Bone healing can be improved by the application of osteoconductive and osteoinductive biomaterials. Microcalcite (MCA) as a naturally available calcium carbonate-based biomaterial derived from marble may have the potential to improve bone healing. Herein, we studied for the first time, if MCA in combination with platelet-rich plasma (PRP) can be used as a bone graft material for bone healing in vivo. For this purpose, osteotomies were induced in CD-1 mice (n = 60). Animals received into the osteotomy gap either MCA-loaded PRP (MCA + PRP; n = 20), PRP alone (PRP; n = 20) or no application (NONE; n = 20). Bone healing was evaluated at two and five weeks after osteotomy by micro-computed tomography (MUCT), histomorphometric, immunohistochemical and Western Blot analyses. MUCT of MCA + PRP femurs revealed more bone volume and an increased polar moment of inertia, indicating a higher biomechanical stability when compared to PRP and NONE femurs. Histomorphometry revealed an increased total callus area after two weeks and a reduced callus tissue area after five weeks in MCA + PRP and PRP animals compared to NONE animals, indicating an accelerated process of bone healing and remodeling over the study period. Moreover, histomorphometric analyses demonstrated an increased fraction of osseous tissue within the callus in MCA + PRP femurs when compared to PRP and NONE femurs. Immunohistochemical analyses showed increased numbers of Ki67+ cells in callus tissue of MCA + PRP femurs. Of interest, Western Blotting revealed a significantly reduced expression of BMP-4 in MCA + PRP animals, while the expression of BMP-2 did not reveal any significant differences between the groups. This indicates a modified balance between angiogenesis and osteogenesis due to MCA. In conclusion, the application of MCA with PRP improved bone healing in a murine osteotomy model and, thus, might be a promising novel bone graft material which may be of interest for clinical fracture treatment. PMID- 30524064 TI - Extraction of p-n junction properties and series resistance in GaAs nanowire based solar cells using light concentration. AB - Series resistance in solar cells limit their maximum conversion efficiency and thus should be minimized. Generally, such losses originate from deficiencies at the contact or absorber level. Quantifying them is the first step for tacking its reduction. In this work, we provide a new way to assess the series resistance in nanowire-based solar cells, which significantly underperforms predicted theoretical efficiency. We illuminate the devices at different levels of light intensity (from 1 to 1000 suns), which gives us insight in the carrier transport and series losses mechanism. We demonstrate the method on a device obtained by self-assembled GaAs nanowire p-n junction arrays on silicon. This analysis method provides a platform to distinguish the intrinsic response of the nanowire p-n junction from the series resistance effects. More generally, we provide a mean of optimizing the efficiency in next generation solar cells where contacts still have to be developed. PMID- 30524065 TI - Investigation of out-of-plane motion artifacts in two-dimensional noninvasive vascular ultrasound elastography. AB - Ultrasound noninvasive vascular elastography (NIVE) has shown its potential to measure strains of carotid arteries to predict plaque instability. When two dimensional (2-D) strain estimation is performed, either in longitudinal or cross sectional view, only in-plane motions are considered. The motions in elevation direction (i.e., perpendicular to the imaging plane), can induce estimation artifacts affecting the accuracy of 2-D NIVE. The influence of such out-of-plane motions on the performance of axial strain and axial shear strain estimations has been evaluated in this study. For this purpose, we designed a diseased carotid bifurcation phantom with a 70% stenosis and an in vitro experimental setup to simulate orthogonal out-of-plane motions of 1 mm, 2 mm and 3 mm. The Lagrangian speckle model estimator (LSME) was used to estimate axial strains and shears under pulsatile conditions. As anticipated, in vitro results showed more strain estimation artifacts with increasing magnitudes of motions in elevation. However, even with an out-of-plane motion of 2.0 mm, strain and shear estimations having inter-frame correlation coefficients higher than 0.85 were obtained. To verify findings of in vitro experiments, a clinical LSME dataset obtained from 18 participants with carotid artery stenosis was used. Deduced out-of-plane motions (ranging from 0.25 mm to 1.04 mm) of the clinical dataset were classified into three groups: small, moderate and large elevational motions. Clinical results showed that pulsatile time-varying strains and shears remained reproducible for all motion categories since inter-frame correlation coefficients were higher than 0.70, and normalized cross-correlations between radiofrequency images were above 0.93. In summary, the performance of LSME axial strain and shear estimations appeared robust in the presence of out-of-plane motions (< 2 mm) as encountered during clinical ultrasound imaging. PMID- 30524066 TI - Evaluation of the reconstructed dose from the three-dimensional dose module of a helical diode array: factors of influence and error detection. AB - The 3D-dose module (3DVH) of the ArcCHECK-phantom reconstructs the dose distribution in the phantom volume and transfers it to the patient geometry. Our aim was to evaluate the 3DVH-reconstructed dose systematically building up from simple to complex cases. Therefore, the influence of different field sizes without and with blocking the isocenter was tested. The dose distributions of different radiation techniques, error-free and error-induced VMAT-plans were verified by measuring with films and other detectors in the phantom. It was checked how the inclusion of the dose measured separately in the ArcCHECK isocenter affects the reconstruction. Thus it was also investigated which detector should be used for the dosimetry in the isocenter. Without including the isocentrically measured dose, the reconstruction for the smallest field (2x2 cm2) was 5% (6 MV) and 3.7% (10 MV) higher than measured with an ionization chamber. With increasing field size, the deviation decreased. For fields with blocked isocenters, the reconstructed dose was between -10.6% and 24% lower than determined with a microDiamond. Measurements with the Semiflex of the spinal plan resulted in higher doses than calculated by the treatment planning system (TPS) and measured with the film and the other detectors. Through the inclusion of the isocentric dose in the reconstruction its accordance with the film increased mostly. With exception of an error-induced head and neck plan, the induced errors in the reconstructed dose volume histogram became visible, but were underestimated. With the 3DVH-algorithm not every induced-error was detected. The 3DVH underestimated the dose in blocked areas. To protect organs at risk (OAR), these are often blocked. Consequently, there is a risk that a clinical decision is based on a 3DVH that underestimated the dose for the OAR. We recommend including the isocentric dose in the reconstruction. The detector used for the isocentric measurements should be carefully chosen. . PMID- 30524067 TI - The Electron-Ion Collider: Assessing the Energy Dependence of Key Measurements. AB - We provide an assessment of the energy dependence of key measurements within the scope of the machine parameters for a U.S. based Electron-Ion Collider (EIC) outlined in the EIC White Paper. We rst examine the importance of the physics underlying these measurements in the context of the outstanding questions in nuclear science. We then demonstrate, through detailed simulations of the measurements, that the likelihood of transformational scientic insights is greatly enhanced by making the energy range and reach of the EIC as large as practically feasible. PMID- 30524068 TI - Microbial synthesis of Pd-Pt alloy nanoparticles using Shewanella oneidensis MR-1 with enhanced catalytic activity for nitrophenol and azo dyes reduction. AB - Bimetallic nanoparticles (NPs) often exhibit improved catalytic performance due to the electronic and spatial structure changes. Herein, a novel green biosynthesis method for Pd-Pt alloy NPs using Shewanella oneidensis MR-1 was proposed. The morphology, size and crystal structure of Pd-Pt alloy NPs were studied by a suite of characterization techniques. Results showed Pd-Pt alloy NPs were successfully synthesized inside and outside the cell. The biosynthesized Pd Pt alloy NPs were polycrystalline and face-centered-cubic structure with the particle size ranged from 3 to 40 nm. Furthermore, the catalytic experiment demonstrated that the Pd-Pt alloy NPs exhibited the highest performance for the catalytic reduction of nitrophenol and azo dyes compared with the as-synthesized Pd and Pt monometallic NPs. This enlarged catalytic activity resulted from the synergistic effect of Pd and Pt element. Thereby, this paper provided a simple biosynthesis method for producing bimetallic alloy nanocatalyst with superior activity for contaminant degradation. PMID- 30524069 TI - Beyond Koopmans' theorem: Electron binding energies in disordered materials. AB - The topical review focuses on calculating ionization energies (IE), or electronic polarons in quasi-particle terminology, in large disordered systems, e.g. for a solute dissolved in a molecular solvent. The simplest estimate of the ionization energy is provided by one-electron energies in the Hartree-Fock theory, but the calculated quantities are not accurate. Density functional theory (DFT) as many body theory provides a principal opportunity for calculating one-electron energies including correlation and relaxation effects, i.e. the true energies of electronic polarons. We argue that such a principal possibility materializes within the concept of optimally tuned range-separated hybrid functionals (OT RSH). We describe various schemes for optimal tuning. Importantly, the OT-RSH scheme is investigated for systems capped with dielectric continuum, providing a consistent picture on the QM/dielectric boundary. Finally, some limitations and open issues of the OT-RSH approach are addressed. PMID- 30524070 TI - Autoencoders for learning template spectrograms in electrocorticographic signals. AB - OBJECTIVE: Electrocorticography (ECoG) based studies generally analyze features from specific frequency bands selected by manual evaluation of spectral power. However, the definition of these features can vary across subjects, cortical areas, tasks and across time for a given subject. We propose an autoencoder based approach for summarizing ECoG data with "template spectrograms", i.e. informative time-frequency (t-f) patterns, and demonstrate their efficacy in two contexts: brain-computer interfaces (BCIs) and functional brain mapping. APPROACH: We use a publicly available dataset wherein subjects perform a finger flexion task in response to a visual cue. We train autoencoders to learn t-f patterns and use them in a deep neural network to decode finger flexions. Additionally, we propose and evaluate an unsupervised method for clustering electrode channels based on their aggregated activity. MAIN RESULT: We show that the learnt t-f patterns can be used to classify individual finger movements with consisentently higher accuracy than with traditional spectral features. Furthermore, electrodes within automatically generated clusters tend to demonstrate functionally similar activity. SIGNIFICANCE: With increasing interest in and active development towards higher spatial resolution ECoG, along with the availability of large scale datasets from epilepsy monitoring units, there is an opportunity to develop automated and scalable unsupervised methods to learn effective summaries of spatial, temporal and frequency patterns in these data. The proposed methods reduce the effort required by neural engineers to develop effective features for BCI decoders. The clustering approach has applications in functional mapping studies for identifying brain regions associated with behavioral changes. PMID- 30524071 TI - Incorporating automatically learned pulmonary nodule attributes into a convolutional neural network to improve accuracy of benign-malignant nodule classification. AB - Existing deep-learning-based pulmonary nodule classification models usually use images and benign-malignant labels as inputs for training. Image attributes of the nodules, as human-nameable high-level semantic labels, are rarely used to build a convolutional neural network (CNN). In this paper, a new method is proposed to combine the advantages of two classifications, which are pulmonary nodule benign-malignant classification and pulmonary nodule image attributes classification, into a deep learning network to improve the accuracy of pulmonary nodule classification. For this purpose, a unique 3D CNN is built to learn image attribute and benign-malignant classification simultaneously. A novel loss function is designed to balance the influence of two different kinds of classifications. The CNN is trained by a publicly available lung image database consortium (LIDC) dataset and is tested by a nested cross-validation method to predict the risk of a pulmonary nodule being malignant. This proposed method generates the accuracy of 91.47%, which is better than many existing models. Experimental findings show that if the CNN is built properly, the nodule attributes classification and benign-malignant classification can benefit from each other. By using nodule attribute learning as a control factor in a deep learning scheme, the accuracy of pulmonary nodule classification can be significantly improved by using a deep learning scheme. PMID- 30524072 TI - Mixed type I and type II superconductivity due to intrinsic electronic inhomogeneities in the type II Dirac semimetal PdTe2. AB - The type II Dirac semimetal PdTe$_2$ is unique in the family of topological parent materials because it displays a superconducting ground state below 1.7 K. Despite wide speculations on the possibility of an unconventional topological superconducting phase, tunneling and heat capacity measurements revealed that the superconducting phase of PdTe$_2$ follows predictions of the microscopic theory of Bardeen, Cooper and Shrieffer (BCS) for conventional superconductors. The superconducting phase in PdTe$_2$ is further interesting because it also displays properties that are characteristics of type-I superconductors and are generally unexpected for binary compounds. Here, from scanning tunneling spectroscopic measurements we show that the surface of PdTe$_2$ displays intrinsic electronic inhomogeneities in the normal state which leads to a mixed type I and type II superconducting behaviour along with a spatial distribution of critical fields in the superconducting state. Understanding of the origin of such inhomogeneities may be important for understanding the topological properties of PdTe$_2$ in the normal state. PMID- 30524073 TI - Volume holographic recording in Al nanoparticles dispersed phenanthrenequinone doped poly(methyl methacrylate) photopolymer. AB - High-performance material plays a crucial role on holographic data storage which is a potential technology in area of high capacity data storage. We report a new kind of holographic storage material that is aluminum nanoparticles (Al NPs) dispersed phenanthrenequinone-doped poly(methyl methacrylate) (PQ/PMMA) material. Al NPs are synthesized in monomer solvent immediately and efficiently by method of laser ablation in liquids without chemical precursors. The synthetic Al NPs is a superb doping for holographic storage material, which can perfect the material to acquire higher diffraction efficiency in both traditional holography and polarization holography. With a 4h ablation period, our new material showed a diffraction efficiency improvement from 2.85% to 57.15% for traditional holography and 0.6% to 4.07% for polarization holography. It has splendid capacity of recording polarization hologram and traditional hologram, simultaneously. Additionally, our experiment indicated that our sample possess excellent ability for holographic position multiplexing recording in collinear holography system. It is anticipated that this universal laser ablation in liquid method will be a promising option for processing low-cost nano-doping holographic storage material. PMID- 30524074 TI - Growth optimization and characterization of regular arrays of GaAs/AlGaAs core/shell nanowires for tandem solar cells on silicon. AB - With a band gap value of 1.7 eV, Al0.2Ga0.8As is one of the ideal III-V alloys for the development of nanowire-based Tandem Solar Cells on silicon. Nevertheless, growing self-catalysed AlGaAs nanowires on silicon by solid-source molecular beam epitaxy is a very difficult task due to the oxidation of Al adatoms by the SiO2 layer present on the surface. Here we propose a nanowire structure including a p.i.n radial junction inside an Al0.2Ga0.8As shell grown on a p-GaAs core. The crystalline structure of such self-catalysed nanowires grown on an epi-ready Si(111) substrate (with a thin native SiO2 layer) was investigated by transmission electronic microscopy and photoluminescence. I(V) measurements performed on single nanowires have shown a diode-like behaviour corresponding to the radial p.i.n junction inside the Al0.2Ga0.8As shell. Moreover, a current generation under the electron beam was evidenced over the entire radial junction along the nanowires by means of electron beam induced current (EBIC) microscopy. The same structure was reproduced on patterned substrates with a SiO2 mask, producing an ordered hexagonal array. High and uniform yields from 83 to 87% of vertical nanowires were obtained on 0.9 x 0.9 cm2 patterned areas. EBIC mapping performed on these nanowires confirmed the good electrical properties of the radial junction within the nanowires. PMID- 30524075 TI - Enhanced interaction in TiO2/BiVO4 heterostructures via MXene Ti3C2 derived 2D-Carbon for highly efficient visible light photocatalysis. AB - Heterostructured photocatalysts play a significant role in contaminants removal by decreasing the recombination of the photo-induced charges. Herein, we presented novel TiO2/C/BiVO4 ternary hybrids employing a two-dimensional (2D) layered Ti3C2 MXene precursor, overcoming lattice mismatching of TiO2/BiVO4 binary heterostructures simultaneously. Raman and XPS analyses proved the strongly coupling effects of TiO2, carbon and BiVO4 components, and the heterostructures were identified by HRTEM results. Moreover, the ternary TiO2/C/BiVO4 composites exhibit excellent photocatalytic performance of Rhodamine B degradation, which is about 4 times higher than pure BiVO4 and twice than binary TiO2/BiVO4 heterostructures, reaching a reaction constant of 13.7*10-3 min 1 under visible-light irradiation (lambda>420 nm). In addition, the possible mechanism for dye elimination was proposed that RhB molecule was directly oxidized by photo-induced holes (h+) on the BiVO4 components and superoxide radical (O2.-) generated from conduction-band electrons of the heterostructures. This work will provide possibilities for developing visible-light responsive nanomaterials for efficient solar utilization. PMID- 30524076 TI - HIFU-induced changes in optical scattering and absorption of tissue over nine orders of thermal dose. AB - The optical properties of tissue change during thermal ablation. Multi-modal methods such as acousto-optic (AO) and photo-acoustic (PA) imaging may provide a real-time, direct measure of lesion formation. Baseline changes in optical properties have been previously measured over limited ranges of thermal dose for tissues exposed to a temperature-controlled water bath, however, there is scant data for optical properties of lesions created by HIFU. In this work, the optical scattering and absorption coefficients from 400-1300 nm of excised chicken breast exposed to HIFU were measured using an integrating sphere spectrophotometric technique. HIFU-induced spatiotemporal temperature elevations were measured using an infrared camera and used to calculate the thermal dose delivered to a localized region of tissue. Results obtained over a range of thermal dose spanning 9 orders of magnitude show that the reduced scattering coefficient increases for HIFU exposures exceeding a threshold thermal dose of CEM43 = 600 +/- 81 cumulative equivalent minutes. HIFU-induced thermal damage results in changes in scattering over all optical wavelengths, with a 2.5-fold increase for thermal lesions exceeding 70 degrees C. The tissue absorption coefficient was also found to increase for thermally lesioned tissue, however, the magnitude was strongly dependent on the optical wavelength and there was substantial sample-to sample variability, such that the existence of a threshold thermal dose could not be determined. Therapeutic windows, where the optical penetration depth is expected to be greatest, were identified in the near infrared regime centered near 900 nm and 1100 nm. These data motivate further research to improve the real time AO and PA sensing of lesion formation during HIFU therapy as an alternative to thermometry. PMID- 30524077 TI - Molecularly imprinted polymer based hybrid structure SiO2@MPS-CdTe/CdS: A novel fluorescence probe for Hepatitis A Virus. AB - A novel designed fluorescence molecularly imprinted polymer (MIP) probe made from CdTe/CdS quantum dot (QD)-based silica nanoparticles (SiO2@MPS-CdTe/CdS) was successfully created via a sol-gel process. The target virus - hepatitis A virus (HAV) was selectively captured by imprinted polymer layer, resulting in the fluorescence quenching of the QDs within 20 min, which could be explained by the energy transfer mechanism. Under optimized conditions, the limit of detection for the SiO2@MPS-CdTe/CdS MIP was as low as 88 pmol?L-1, and excellent linearity was obtained from 0.2 to 1.4 nM. Additionally, the nanosensor was successfully used to detect the HAV from a dilution of human serum, in which recoveries were in the range of 96.7%-103.8%. Overall, the current work proposes a novel and cost effective method to synthesize SiO2@MPS-CdTe/CdS MIPs for use as a tool to rapidly and efficiently detect HAV, and it also provides promising perspectives to further advance virus imprinting research. PMID- 30524078 TI - Micro-channel sieve electrode for concurrent bidirectional peripheral nerve interface. Part B: Stimulation. AB - OBJECTIVE: Successful use of a prosthetic limb by an amputee is facilitated by haptic feedback - both a sense of touch and proprioception. Stimulating afferent fibers within peripheral nerves has been shown to provide somatosensation enabling amputees to modulate the control of prosthetic limbs. Peripheral nerve interfaces (PNIs) have also been used to decode patients' motor intentions. It seems ideal to use PNIs to record efferent fibers for motor control while stimulating afferent fibers to create concurrent sensory feedback. However, while many PNIs claim to be bi-directional, few can both stimulate and record at the same time due to stimulation artifacts which are orders of magnitude larger than the recorded motor signals. This study uses computational modelling to compare the stimulation artifact at threshold levels of stimulation for thin-film transverse intrafascicular multichannel electrodes (tfTIMEs) with micro-channel sieve electrodes. APPROACH: Finite element models of micro-channel sieves and tfTIMESs were used to solve for electric fields generated during peripheral nerve stimulation. Electrophysiological responses were simulated using axon models. Stimulation artifacts were calculated for stimuli eliciting axonal action potentials. Simulations were carried out for multiple micro-channel geometries and electrode configurations. MAIN RESULTS: Stimulation artifacts generated for threshold stimulation currents are lower for micro-channel devices compared to tfTIMEs. Consequently, stimulus artifacts at threshold currents were substantially higher for the tfTIME. Micro-channel width has a moderate impact on recruitment thresholds and stimulus artifacts. Using the micro-channel sieve in bipolar and tripolar stimulation configurations greatly decreases stimulation artifacts particularly for optimized contact placements. Electroneurogram (ENG) signals from the companion paper were incorporated showing a great improvement in signal-to-artifact ratio for the micro-channel electrode compared to tfTIMEs. SIGNIFICANCE: Stimulating regenerated nerve tissue using micro-channel sieve electrodes can decrease stimulation artifacts and elicit neuronal responses at low stimulation amplitudes. Further analysis provides clues to optimal implementations of micro-channel devices. Finally, stimulation artifacts for simulated tfTIME devices were 2-3 orders of magnitude larger than ENG levels. In contrast, for some micro-channel configurations stimulation artifacts were 3-4 orders of magnitude smaller than ENG levels. PMID- 30524079 TI - Accurate tooth segmentation with improved hybrid active contour model. AB - In orthodontic diagnosis and oral treatment planning, 3D tooth model constructed by dental computed tomography (CT) images is an essential and useful assisted tool. In virtue of the higher spatial resolution and lower radiation of X-ray, cone beam computed tomography (CBCT) has been widely used in dental application. However, due to lower signal to noise ratio, vague and weak edge between tooth root and sockets as well as intensity inhomogeneity, the tooth root is easy to be under- segmented and appears false boundary. This paper presents a new hybrid active contour model in a variational level set formulation to segment the tooth root accurately. Initial shape and intensity information from the upper layer is used for next layer's enhancement and shape constraint. The hybrid level set model is constituted by multi-scale local likelihood image fitting (LLIF) energy term, prior shape constraint energy term with adaptive weight and reaction diffusion (RD) regularization energy term. For detailed interpretation of this hybrid energy model, the intensity information in a narrowband region outside the contour was used to enhance the contrast between tooth dentine and sockets. The LLIF energy term was incorporated into the level set function to overcome the edge fuzziness and intensity inhomogeneity. The shape prior energy term with adaptive weight was used to differentiate the constraint of the contour evolution inside and outside the level set function to improve the capability of curve topology changes. The RD energy term was introduced to effectively regularize the level set evolution. A new measurement for tooth segmentation evaluation was proposed for quantitative validation. The experimental result of the proposed method was compared with two other typical approaches, and was demonstrated to achieve a higher segmentation accuracy. PMID- 30524080 TI - Rhythmic Modulation of Thalamic Oscillations Depends on Intrinsic Cellular Dynamics. AB - Rhythmic brain stimulation has emerged as a powerful tool to modulate cognition and to target pathological oscillations related to neurological and psychiatric disorders. However, we lack a systematic understanding of how periodic stimulation interacts with endogenous neural activity as a function of the brain state and target. To address this critical issue, we applied periodic stimulation to a unified biophysical thalamic network model that generates multiple distinct oscillations, and examined thoroughly the impact of rhythmic stimulation on different oscillatory states. We found that rhythmic perturbation induces four basic response mechanisms: entrainment, acceleration, resonance and suppression. Importantly, the appearance and expression of these mechanisms depend highly on the intrinsic cellular dynamics in each state. Specifically, the low-threshold bursting of thalamocortical cells (TCs) in delta (delta) oscillation renders the network relatively insensitive to entrainment; the high-threshold bursting of TCs in alpha (alpha) oscillation leads to widespread oscillation suppression while the tonic spiking of TC cells in gamma (gamma) oscillation results in prominent entrainment and resonance. In addition, we observed entrainment discontinuity during alpha oscillation that is mediated by firing pattern switching of high threshold bursting TC cells. Furthermore, we demonstrate that direct excitatory stimulation of the lateral geniculate nucleus (LGN) entrains thalamic oscillations via an asymmetric Arnold tongue that favors higher frequency entrainment and resonance, while stimulation of the inhibitory circuit, the reticular nucleus, induces much weaker and more symmetric entrainment and resonance. These results support the notion that rhythmic stimulation engages brain oscillations in a state- and target-dependent manner. PMID- 30524081 TI - Growth of germanium nanowires with isobuthyl germane. AB - We demonstrate the feasibility of the use of isobutyl germane, a novel germanium source, for the vapor-liquid-solid growth of germanium nanowires on Si (111) substrates, using a thin gold layer as catalyst. The density and the diameter of the nanowires were controlled by varying the Au layer thickness and the isobutyl germane flow. The nanowires show perfect crystallinity and lengths from several hundreds of nm to 3-4 ?m. The use of isobutyl germane gives a considerable technological advantage in germanium nanowires research since it is a safer and more manageable germanium source and it allows to grow Ge nanowires in a standard vapor phase epitaxy system at 400 degrees C. . PMID- 30524082 TI - Measurement of UV radiation in commercial aircraft. AB - Ultraviolet Radiation (UVR) is significantly higher at aviation altitudes with respect to sea level. Cockpit windshields protect pilots from UV-B radiation but studies have shown that this is not necessarily the case for UV-A radiation. This work investigates the spectral properties of several windshields under flight conditions. Only one of the investigated windshields showed good UV-A attenuation. Furthermore, the altitude dependence of UV-A irradiance behind a windshield was measured with high spatial resolution. Measurements of the maximal UV irradiance behind the windshield surfaces and at the pilot's position are compared to the recommendations by the International Commission on Non-Ionizing Radiation Protection. Some recommended limits were exceeded at the surface of the windshields with direct sunlight and a large field of view. At the pilot's position, with a more realistic field of view, the unweighted recommended level could have been exceeded within tens of minutes by looking in the direction of the Sun without visor or other protective measures. The weighted recommended maximal UVR exposure was not exceeded, neither with the use of the visor at the pilot's position nor without it. The use of the visor for filtering direct sunlight was very effective in terms of UV-A reduction. PMID- 30524083 TI - Feature relevance in physiological networks for classification of obstructive sleep apnea. AB - OBJECTIVE: Physiological networks (PN) model couplings between organs in a high dimensional parameter space. Machine learning methods, in particular artifical neural networks (ANNs), are powerful on high-dimensional classification tasks. However, lack of interpretability of the resulting models has been a drawback in research. We assess relevant PN topology changes in obstructive sleep apnea (OSA) by novel ANN interpretation techniques. Approach: ANNs are trained to classify OSA based on the PNs of 48 patients and 48 age and gender matched healthy controls. The PNs consisting of 2812 links are derived from overnight biosignal recordings. The interpretation technique DeepLift is applied to the resulting ANN models, allowing for determination of the relevant features for classification decisions on individual subjects. The mean relevance scores of the features are compared to other machine learning methods (decision tree and random forests) and statistical tests on group differences. Main results: The ANN interpretation results show good agreement with the compared methods and 87% of the samples could be correctly classified. OSA patients show a significantly higher coupling (p < 0.001) in light sleep (N2) between breathing rate and EEG delta power in all electrode locations and to chin and leg muscular tone. In deep sleep (N3), OSA leads to significantly lower coupling (p < 0.01) in lateral connections of EEG theta and sigma power in central and frontal positions. Misclassified OSA patients had all mild/moderate AHIs and did not show PN topology changes. Both nights of these patients have been consistently misclassified as healthy. This may indicate, that the impact of respiratory events differs in subjects, thus forming different phenotypes. Significance: The proposed PN analysis provides a powerful and robust method to quantify a broad range of physiological interactions. Interpretability of the ANN make them a promising tool to identify new diagnostic markers in data-driven approaches. . PMID- 30524084 TI - Critical behavior of order parameter at the nonequilibrium phase transition of the Ising model. AB - After a quench of transverse field, the asymptotic long-time state of Ising model displays a transition from a ferromagnetic phase to a paramagnetic phase as the post-quench field strength increases, which is revealed by the vanishing of the order parameter defined as the averaged magnetization over time. We estimate the critical behavior of the magnetization at this nonequilibrium phase transition by using mean-field approximation. In the vicinity of the critical field, the magnetization vanishes as the inverse of a logarithmic function, which is significantly distinguished from the critical behavior of order parameter at the corresponding equilibrium phase transition, i.e. a power-law function. PMID- 30524085 TI - Enrichment of semiconducting single-walled carbon nanotubes by simple equipment and solar radiation. AB - High-purity semiconducting (s-) single-walled carbon nanotubes (SWCNTs) have great potential to replace silicon-based materials for microelectronic devices. However, the enrichment methods of s-SWCNTs usually required complex devices and non-renewable energy. In this study, instead of traditional heating method, renewable solar was employed to dramatically increase the heating rate and improve the reaction to be simple and more controllable, thereby highly selectively etch metallic (m-) SWCNTs by water. In this work, purified SWCNTs films were wetted by water and then exposed to focused solar radiation, causing the surface temperature of the SWCNT films reached to about 800 degrees C within 2 seconds. In this case, the m-SWCNTs could be selectively etched by water rapidly. Finally, s-SWCNTs with a purity of about 95wt% were obtained in several minutes without any complex devices or non-renewable energy. PMID- 30524086 TI - Coupling of local muscle deoxygenation and autonomic control depends on exercise intensity - insights from transfer entropy analysis. AB - OBJECTIVE: We analyzed the driving component between the periods of adjacent heartbeats (R-R intervals) and vastus lateralis-deoxygenation (%HHb) during incremental cycling. Considering a tight matching of local metabolism with systemic and local perfusion a coupling between indices of cardiovascular control (R-R variability) and %HHb is suggested. Further, an intensity-dependent coupling between R-R variability and %HHb was hypothesized, because a multitude of feedback- and feedforward-mechanisms to autonomic cardiovascular control as well as local vasodilating mechanisms are associated with muscle metabolism and thus exercise intensity. APPROACH: Ten male triathletes (age: 34+/-8 years) completed a test, including baseline (BAS, 50 W), a 25 W*min-1 ramp incremental phase until exhaustion and a recovery period (REC, 50 W). R-R intervals, %HHb and respiratory responses were simultaneously recorded. Five corresponding data segments were selected: BAS, before the first ventilatory threshold (preGET), between GET and the respiratory compensation point (preRCP), above RCP (postRCP), REC. Bivariate transfer entropy (BTE) was applied to determine the signal coupling between R-R and %HHb. MAIN RESULTS: During preGET and preRCP, the analysis yielded the dominating direction from %HHb to R-R intervals; while for postRCP the direction was reversed. No significant signal coupling was detectable for the BAS and REC segments. SIGNIFICANCE: Assuming that %HHb is related to the metabolic state of the working muscle, BTE results support the role of metaboreceptors in the systemic blood flow regulation at lower exercise intensities, while other mechanisms (e. g. baroreceptor and mechanoreceptor feedback, central command) modulating cardiovascular control may override this coupling at higher intensities. PMID- 30524087 TI - Photons in - numbers out: Perspectives in quantitative fluorescence microscopy for in situ protein counting. AB - The full understanding of cellular functions requires information about protein numbers for various biomolecular assemblies and their dynamics, which can be partly accessed by super-resolution fluorescence microscopy. Yet, many protein assemblies and cellular structures remain below the accessible resolution on the order of tens of nanometers thereby evading direct observation of processes, like self-association or oligomerization, that are crucial for many cellular functions. Over the recent years, several approaches have been developed addressing concentrations and copy numbers of biomolecules in cellular samples for specific applications. This has been achieved by new labeling strategies and improved sample preparation as well as advancements in super-resolution and single-molecule fluorescence microscopy. So far, none of the methods has reached a level of general and versatile usability due to individual advantages and limitations. In this article, important requirements of an ideal quantitative microscopy approach of general usability are outlined and discussed in the context of existing methods including sample preparation and labeling quality which are essential for the robustness and reliability of the methods and future applications in cell biology. PMID- 30524088 TI - CdSe tetrapod interfacial layer for improving electron extraction in planar hetero-junction perovskite solar cells. AB - We demonstrate the improvement in the efficiency of planar hetero-junction perovskite solar cells by employing cadmium selenide tetrapods (CdSe TPs) as an electron extraction layer. Insertion of the CdSe TP layer between the titanium oxide (TiO2) and perovskite film facilitates electron transfer at the TiO2/perovskite interface, as indicated by the significantly quenched steady state photoluminescence of the perovskite film. Furthermore, we observed a conductivity enhancement of the perovskite film by introducing CdSe TP layer. The combination of both effects induced by the TPs leads to enhancement in the carrier extraction as well as decreased recombination losses in perovskite solar cells. As a result, an efficiency of 13.5% is achieved in perovskite solar cells that incorporate the CdSe TP layer, which is 10% higher than that of the device without the CdSe TP layer. PMID- 30524089 TI - Experimental validation of estimated spatially variant radioisotope-specific point spread functions using published positron range simulations and fluorine-18 measurements. AB - In this work we compare spatially variant radioisotope-specific point spread functions (PSFs) derived from published positron range data with measured data using a high resolution research tomograph (HRRT). Spatially variant PSFs were measured on a HRRT for fluorine-18, carbon-11 and gallium-68 using an array of printed point sources. For gallium-68, this required modification of the original design to handle its longer positron range. Using the fluorine-18 measurements and previously published data from Monte-Carlo simulations of positron range, estimated PSFs for carbon-11 and gallium-68 were calculated and compared with experimental data. A double 3D Gaussian function was fitted to the estimated and measured data and used to model the spatially varying PSFs over the scanner field of view (FOV). Differences between the measured and estimated PSFs were quantified using the full-width-at-half-maximum (FWHM) and full-width-at-tenth maximum (FWTM) in the tangential, radial and axial directions. While estimated PSFs were generally in agreement with the measured PSFs over the entire FOV better agreement was observed (FWHM and FWTM differences of less than 10%) when using one of the two sets of positron range simulations, especially for gallium 68 and for the FWTM. Spatially variant radioisotope specific PSFs can be accurately estimated from fluorine-18 measurements and published positron range data. We have experimentally validated this approach for carbon-11 and gallium 68, and such an approach may be applicable to other radioisotopes such as oxygen 15 for which measurements are not practical. PMID- 30524090 TI - Radioluminescence in biomedicine: physics, applications, and models. AB - The electromagnetic spectrum contains different frequency bands useful for medical imaging and therapy. Short wavelengths (ionizing radiation) are commonly used for radiological and radionuclide imaging and for cancer radiation therapy. Intermediate wavelengths (optical radiation) are useful for more localized imaging and for photodynamic therapy. Finally, longer wavelengths are the basis for magnetic resonance imaging and for hyperthermia treatments. Recently, there has been a surge of interest for new biomedical methods that synergize optical and ionizing radiation by exploiting the ability of ionizing radiation to stimulate optical emissions. These physical phenomena, together known as radioluminescence, are being used for applications as diverse as radionuclide imaging, radiation therapy monitoring, phototherapy, and nanoparticle-based molecular imaging. This review provides a comprehensive treatment of the physics of radioluminescence and includes simple analytical models to estimate the luminescence yield of scintillators and nanoscintillators, Cherenkov radiation, air fluorescence, and biologically endogenous radioluminescence. Examples of methods that use radioluminescence for diagnostic or therapeutic applications are reviewed and analyzed in light of these quantitative physical models of radioluminescence. PMID- 30524091 TI - AF detection from ECG recordings using feature selection, sparse coding, and ensemble learning. AB - OBJECTIVE: The objective of this paper is to provide an algorithm for accurate, automated detection of atrial fibrillation from ECG signals. Four types of ECG signals are considered: normal signals, signals representing symptoms of atrial fibrillation (AF), other signals, and noisy signals. This paper represents follow up work to the authors' entry in the 2017 PhysioNET Challenge as reported in the 2017 Computing in Cardiology Conference. Approach: Our approach involves extracting features from the ECG waveform and training a machine learning classifier. In feature extraction, we calculate several statistical features related to the ECG signal and fiduciary points. We also used a disciplined method of feature selection to reduce the dimensionality of the feature space. We also employ sparse coding as an unsupervised feature extraction tool. The classifier we use is a decision tree-based ensemble learning classifier. Main results: When applied to the hidden test data reserved by the PhysioNet Challenge organizers, our classifier reports F1 scores of 0.91, 0.78, and 0.71 for the Normal, AF, and Other classes, respectively. The overall test score is 0.80, and is obtained by averaging the F1 scores for these three classes. Significance: This work demonstrates that feature selection and ensemble learning can be used to improve the performance of ECG based classification of atrial fibrillation. PMID- 30524092 TI - Photoplethysmography in dogs and cats: a selection of alternative measurement sites for pet monitor. AB - OBJECTIVE: Photoplethysmography (PPG) is an increasingly popular health and well being tool for monitoring heart rate and oxygen saturation. Due to pigmentation and hairiness of dogs and cats, a pulse oximeter is routinely placed solely on the tongue. As this approach is feasible only for the pet monitor use during surgical procedures, we investigate PPG signal quality on several other measurement sites that would be better tolerated by conscious animals. Approach: Acquired PPG signals are analyzed by four signal quality indices (SQI): mean baseline, signal power, kurtosis, and tolerance score. Main Results: In dogs, the metacarpus and tail can substitute for oral pulse oximeter placement since both measurement sites exhibited high PPG signal kurtosis and were considered well-tolerated. In cats, the digit could be used with some limitations. Significance: Pet monitors with pulse oximeter probes adjusted to promising measurement sites, could enable veterinarians and owners to monitor animals when fully awake. PMID- 30524093 TI - Raman scattering studies on very thin layers of gallium sulfide (GaS) as a function of sample thickness and temperature. AB - Gallium sulfide is a semiconducting material with a layered structure and a characteristic low interlayer interaction. Because of weak van der Waals forces, GaS crystals are relatively easy to exfoliate to very thin layers. In this work nanometric-GaS layers were obtained by a micro-mechanical exfoliation process and were transferred to Si/SiO2 substrate. The thickness of these layers was estimated from AFM measurements. Raman spectra were collected for different layer thicknesses ranging from one layer to bulk crystal. An analytical function fitted to experimental data is proposed to determine layer thickness from Raman measurements. For the first time, the Raman position and the FWHM of the main Raman peaks were measured on very thin GaS layers as a function of temperature in the range from 80 to 470 K. The first order temperature coefficients of the A1g Raman peaks were determined. Phonon decay due to anharmonic processes at temperatures above 300 K in layers of thickness below 4 nm was observed. Contribution of optical phonon scattering processes to thermal properties of very thin GaS layers is discussed. PMID- 30524094 TI - Enhanced light extraction from organic light-emitting diodes using a quasi periodic nano-structure. AB - Organic light-emitting diodes (OLEDs) with a quasi-periodic nano-structure (QPS) were fabricated via a combination of laser interference lithography (LIL) and reactive ion etching (RIE). The LIL process was used to generate a periodic pattern, whereas the RIE process was used as a supplement to add randomness to the periodic pattern. The period of the fabricated periodic pattern was determined by finite difference time domain (FDTD) solutions. The height and density of the QPS were controlled by the RIE etching time and were optimized. The resulting quasi-periodic nanostructure comprised silicon dioxide (SiO2) with a low refractive index (n = 1.4-1.5), and an external quantum efficiency (EQE) enhancement of 18% was achieved using the QPS device, without any viewing angle problems or spectral distortion, which are serious drawbacks of periodic patterns. PMID- 30524095 TI - Tunable dual emission in Mn2+-doped CsPbX3 (X=Cl, Br) quantum dots for high efficiency white light-emitting diodes. AB - Doping of Mn2+ into semiconductor nanocrystals has been demonstrated to endow them with novel electronic, optical and magnetic functionalities. In this paper, the Mn doped CsPbX3 (X=Br, Cl) quantum dots (QDs) were synthesized at room temperature via a facile strategy by introducing dimethyl sulfoxide (DMSO) MnBr2/PbX2 composite as precursor. The excitonic emission spectra of the as obtained Mn doped CsPbX3 QDs can be tuned from 517 nm to 418 nm by adjusting the ratio of PbBr2/PbCl2 precisely, and the luminescence mechanism of the doped QDs is discussed detailedly. Moreover, the highest quantum yield (PLQY) of of the Mn2+ emisison acheives 36.7%, which is comparable with the QDs prepared by the conventional hot-injection method. Denpending on the ratios of PbPb2/PbCl2, the energy tranfer rate from the band-edge to Mn2+ excited state is in the range of 0.006-20.42* 107 s-1. Furthermore, white light emitting diodes (LEDs) were sucessfully fabricated by combining the as-prepared Mn doped CsPbX3 QDs with commercial UV GaN chips, and the high luminous effeciency of the as-prepared white LEDs was developed to 55.9 lm/W-1. This work strongly support that the Mn doped CsPbX3 QDs are promising materials for the application in lighting and displaying fields. PMID- 30524096 TI - Imaging of soft materials using in-situ liquid-cell TEM. AB - The fast development of biological sciences has been significantly boosted by and rooted on the in-depth understanding of soft materials in terms of the dynamics and kinetics of their interactions with various environmental stimuli. Yet, the structural information of soft materials such as cells, bacteria, virus, and protein is difficult to be studied down to the nanoscale, especially when the materials are at their naturally hydrated environment. (Scanning) Transmission electron microscopy ((S)TEM) is one of few techniques capable of exploring material sciences at nanoscale resolution. The recent development of liquid cell (S)TEM technique provides unprecedented imaging and analysis capabilities in the real time study of soft material behaviors in the native liquid environment. By introducing liquid solutions into the (S)TEM chamber, such technique enables direct observation of in-solution samples at nanometer (or even higher) resolution against the high TEM vacuum and the liquid mass background. With the advent of liquid cell (S)TEM, fast-growing research is emerging recently and the bio-relevant fundamentals such as reaction dynamics and kinetics in liquid environment are being revealed for all kinds of soft materials. Therefore, it is an appropriate time to appropriately summarize the previous studies and reports on the study of soft material sciences using liquid cell (S)TEM. In this paper, a systematic review of recent work using liquid cell TEM in the study of soft materials is provided. The comparison between two dominant experimental approaches (i.e. the silicon nitride window-based cell and graphene layer-sealed cell) introducing liquid into (S)TEM specimen chamber is also discussed in terms of their pros and cons in the observation of specific soft materials. PMID- 30524097 TI - Online adaption approaches for intensity modulated proton therapy for head and neck patients based on cone beam CTs and Monte Carlo simulations. AB - PURPOSE: To develop an online plan adaptation algorithm for intensity modulated proton therapy (IMPT) based on fast Monte Carlo dose calculation and cone beam CT (CBCT) imaging. Methods: A cohort of 10 head and neck cancer patients with an average of 6 CBCT scans were studied. To adapt the treatment plan to the new patient geometry, contours were propagated to the CBCTs with a vector field (VF) calculated with deformable image registration between the CT and the CBCTs. Within the adaptive planning algorithm, beamlets were shifted following the VF at their distal falloff and raytraced in the CBCT to adjust their energies, creating a geometrically adapted plan. Four geometric adaptation modes were studied: unconstrained geometric shifts (Free), isocenter shift (Iso), a range shifter (RS), or isocenter shift and range shifter (Iso-RS). After evaluation of the geometrical adaptation, the weights of a selected subset of beamlets were automatically tuned using MC-generated influence matrices to fulfill the original plan requirements. All beamlet calculations were done with a fast Monte Carlo running on a GPU (Graphics Processing Unit). Results: Geometrical adaptation alone only worked with small anatomy changes. The weight-tuned adaptation worked for every fraction, with the Free and Iso modes performing similarly and being superior than the two range shifters modes. The mean V95 and V107 were 99.4 +/- 0.9 and 6.4 +/- 4.7 % in the Free mode with weight tuning. The calculation time per fraction was ~5 min, but further task parallelization could reduce it to ~1-2 min for delivery adaptation right after patient setup. Conclusions: An online adaptation algorithm was developed that significantly improved the treatment quality for inter-fractional geometry changes. Clinical implementation of the algorithm would allow delivery adaptation right before treatment and thus allow planning margin reductions for IMPT. PMID- 30524098 TI - Thermal creep and the skyrmion Hall angle in driven skyrmion crystals. AB - We numerically examine thermal effects on the skyrmion Hall angle for driven skyrmions interacting with quenched disorder. We identify a creep regime in which motion occurs via intermittent jumps between pinned and flowing states. Here the skyrmion Hall angle is zero since the skyrmions have time to relax into equilibrium positions in the pinning sites, eliminating the side-jump motion induced by the Magnus force. At higher drives we find a crossover to a viscous flow regime where the skyrmion Hall angle is finite and increases with increasing drive or temperature. Our results are in agreement with recent experiments which also show a regime of finite skyrmion velocity with zero skyrmion Hall angle crossing over to a viscous flow regime with a skyrmion Hall angle that increases with drive. PMID- 30524099 TI - Shear wave propagation in viscoelastic media: validation of an approximate forward model. AB - Many approaches to elastography incorporate shear waves; in some systems these are produced by acoustic radiation force push pulses. Understanding the shape and decay of propagating shear waves in lossy tissues is key to obtaining accurate estimates of tissue properties, and so analytical models have been proposed. In this paper, we reconsider a previous analytical model with the goal of obtaining a computationally straightforward and efficient equation for the propagation of shear waves from a focal push pulse. Next, this model is compared with an experimental optical coherence tomography system and with finite element models, in two viscoelastic materials that mimic tissue. We find that the three different cases - analytical model, finite element model, and experimental results - demonstrate reasonable agreement within the subtle differences present in their respective conditions. These results support the use of an efficient form of the Hankel transform for both lossless (elastic) and lossy (viscoelastic) media, and for both short (impulsive) and longer (extended) push pulses that can model a range of experimental conditions. PMID- 30524100 TI - Negative differential conductance effect and electrical anisotropy of 2D ZrB2 monolayers. AB - Two-dimensional (2D) metal-diboride ZrB2 monolayers was predicted theoretically as a stable new electronic material [A. Lopez-Bezanilla, Phys. Rev. Mater., 2018, 2, 011002 (R)]. Here, we investigate its electronic transport properties along the zigzag (z-ZrB2) and armchair (a-ZrB2) directions, using the density functional theory and non-equilibrium Green's function methods. Under low biases, the 2D ZrB2 shows a similar electrical transport along zigzag and armchair directions as electric current propagates mostly via the metallic Zr-Zr bonds. However, it shows an electrical anistropy under high biases, and its I-V curves along zigzag and armchair directions diverge as the bias voltage is higher than 1.4 V, as more directional B-B transmission channels are opened. Importantly, both z-ZrB2 and a-ZrB2 show a pronounced negative differential conductance (NDC) effect and hence they can be promising for the use in NDC-based nanodevices. PMID- 30524101 TI - Universal understanding of nematicity and magnetism in Fe-pnictides and FeSe. AB - By employing the mean field and variational Monte Carlo methods, we investigate the iron-based superconductors (FeSCs) based on a realistic five-orbital Hubbard model in which an off-site Coulomb interaction V is explicitly included. Our results demonstrate that V plays an important role in stabilizing the nematic state in both Fe-pnictides and FeSe. Below a critical Vc, the model is shown to lie in the striped antiferromagnetic ground state, and an increasing of V leads to an energy degeneracy between different magnetic configurations. This finding provides a natural explanation for the magnetism in Fe-pnictides with relatively small V , and more importantly, unveils the microscopic mechanism behind the absence of magnetic order in FeSe with larger V . Simultaneously, the common anisotropy of dxz and dyz orbital occupations in different magnetic configurations accounts for the similar orbital ordering observed in Fe-pnictides and FeSe. In addition, the unusual smallness of the Fermi surfaces in FeSe can be obtained when the renormalization effect of V on the band structure is taken into account. PMID- 30524102 TI - Measuring the nonlocality of different types of Majorana bound states in a topological superconducting wire. AB - According to the degree of topological protection, Majorana bound states (MBSs) can be divided into three types: ideal zero-energy MBSs (IMSs), finite-energy MBSs (FEMs) and zero-energy MBSs at parity crossing points (PMSs). Herein, we investigate the nonlocality of the three types of MBSs by comparing the conductance spectra between a normal lead (N)-topological superconducting wire (S)-normal lead (N) junction (NSN) and an NS junction. We find that for the FEM related tunnelling process, the decrease in the nonlocal processes is trivially accompanied by an increase in the local processes, whereas for the IMS-related tunnelling process, the left and right tunnelling processes are completely independent. Remarkably, the PMSs induce a nonlocal electron-blocking effect in which incoming electrons from the left lead cannot participle in the local Andreev reflection unless the right lead is present, even though no nonlocal tunnelling processes occur in the right lead of an NSN junction. We show that this PMS-mediated nonlocal electron-blocking effect is due to the nonlocal coupling from the left lead to the more distant PMS, and the phase difference between two end PMSs is $?pi/2$. Our findings provide an experimentally accessible method for characterizing MBSs by probing their different nonlocal signatures. PMID- 30524103 TI - Probing hole-doping of the weak antiferromagnet TiAu with first principles methods. AB - We investigate hole-doping by Sc substitution for Ti in the weak antiferromagnet (wAFM) system Ti(1-x)Sc(x)Au. Behavior reported so far fits a weak itinerant AFM picture, and experimentally leads to a quantum critical point (QCP) at x_c = 1/8. Here we study supercells with several rational fractions x of Ti replaced by Sc. We find, unexpectedly, definite local moment-like behavior, e.g. magnetic moments of the Ti atom comparable to or even larger than in the bulk persist even into the Ti-poor regime of this alloy system. Itinerant signatures persist, however, as the Ti 3d projected density of states displays van Hove singularity peaks near the Fermi level in most cases, revealing a striking similarity to nonmagnetic bulk TiAu. The current picture of this system, midway between itinerant and local moment, will be provided and discussed in light of experimental observations. PMID- 30524104 TI - Tuning the electronic structure of single-walled carbon nanotube by high-pressure H2 exposure. AB - We report on an electronic structure change of single-walled carbon nanotube (SWNT) on hexagonal boron nitride due to electron doping via high-pressure H2 exposure. The fractional coverage of hydrogenated carbon atom is estimated to be at least theta = 0.163 from the in situ I ds-V g measurements of the release process. Raman spectroscopy and x-ray photoelectron spectroscopy were carried out to support the in situ electrical measurements. In particular, we used the dissociative Langmuir-type model to yield the desorption coefficient k des by fitting it to the in situ electrical data. Finally, we applied this hydrogenation method to the SWNT network on the commercial Si/SiO2 substrate to open the possibility of the scalable n-type semiconducting SWNT FETs. PMID- 30524105 TI - Motor unit drive: A neural interface for real-time upper limb prosthetic control. AB - OBJECTIVE: Modern prosthetic limbs have made strident gains in recent years, incorporating terminal electromechanical devices that are capable of mimicking the human hand. However, access to these advanced control capabilities has been prevented by fundamental limitations of neural interfaces, which have remained virtually unchanged for nearly five decades. Consequently, nearly 23% of adults and 32% of children with major traumatic or congenital upper-limb loss abandon regular use of their myoelectric prostheses. To address this healthcare need, we have developed a noninvasive neural interface technology that maps natural neural increments of force and movement into biomechanically informed signals for improved prosthetic control. Approach: Our technology, referred to as motor unit drive (MU Drive), utilizes real-time machine learning algorithms for directly measuring motor unit firings from surface electromyographic signals recorded from residual muscles of amputated or congenitally missing limb. The extracted firings are transformed into biomechanically informed signals based on the force generating properties of individual motor units to provide a control signal that represents the intended movement. Main Results: We evaluated the characteristics of the MU Drive signals in comparison to conventional amplitude based myoelectric signals in healthy subjects as well as subjects with congenital or traumatic trans-radial limb-loss. Our analysis established a vital proof-of concept: MU Drive provided a responsive real-time signal with improved smoothness and more faithful replication of intended limb movement when compared to amplitude-based myoelectric methods. Significance: MU Drive provides the first noninvasive real-time access to robotic or prosthetic control signals based on the natural physiological mechanisms of the human nervous system. This new neural interface holds promise for improving prosthetic function by achieving advanced control that better reflects the user intent. Beyond immediate advantages in the field of prosthetics, MU Drive holds promise for advancing the control of exoskeletons, assistive devices, and other robotic rehabilitation applications. PMID- 30524106 TI - Optical properties of helical edge channels in zinc-blende-type topological insulators: Selection rules, circular and linear dichroism, circular and linear photocurrents. AB - We develop a theory of electron-photon interaction for helical edge channels in two-dimensional topological insulators based on zinc-blende-type quantum wells. It is shown that the lack of space inversion symmetry in such structures enables the electro-dipole optical transitions between the spin branches of the topological edge states. Further, we demonstrate the linear and circular dichroism associated with the edge states and the generation of edge photocurrents controlled by radiation polarization. PMID- 30524107 TI - Facet-selective group-III incorporation in InGaAs Template Assisted Selective Epitaxy. AB - InGaAs is a potential candidate for Si replacement in upcoming advanced technological nodes because of its excellent electron transport properties and relatively low interface defect density in dielectric gate stacks. Therefore, integrating InGaAs devices with the established Si platforms is highly important. Using template-assisted selective epitaxy (TASE), InGaAs nanowires can be monolithically integrated with high crystal quality, although the mechanisms of group III incorporation in this ternary material have not been thoroughly investigated. Here we present a detailed study of the compositional variations of InGaAs nanostructures epitaxially grown on Si(111) and Silicon-on-insulator substrates by TASE. We present a combination of XRD data and detailed EELS maps and find that the final Ga/In chemical composition depends strongly on both growth parameters and the growth facet type, leading to complex compositional sub structures throughout the crystals. We can further conclude that the composition is governed by the facet-dependent chemical reaction rates at low temperature and low V/III ratio, while at higher temperature and V/III ratio, the incorporation is transport limited. In this case we see indications that the transport is a competition between Knudsen flow and surface diffusion. PMID- 30524108 TI - Phonon thermal conduction in a graphene-C3N heterobilayer using molecular dynamics simulations. AB - Two-dimensional (2D) graphene (GRA) and polyaniline (C3N) monolayers are attracting the growing research interest due to its excellent electrical and thermal properties. In this work, in-plane and out-of-plane phonon thermal conduction of GRA-C3N heterobilayer are systematically investigated using classical molecular dynamics simulations. Effects of system size, temperature and interlayer coupling strength on the in-plane thermal conductivity (k) and out-of-plane interfacial thermal resistance (R) are evaluated. Firstly, a monotonic increasing trend of k with increasing system size is observed, while a negative correlation between thermal conductivity and temperature is revealed. Interlayer coupling strength is found to have a weak effect on the in-plane thermal conductivity of the heterobilayer. Secondly, at T = 300 K and chi = 1, the predicted R of GRA >C3N and C3N->GRA are 1.29*10-7 K m2 W 1 and 1.35*10-7 K m2 W-1, respectively, which indicates that there is no significant thermal rectification phenomenon. It can also be observed that R decreases monotonically with increasing temperature and coupling strength due to the enhanced Umklapp phonon scattering and the phonon transmission probability across the interface. Phonon density of states, phonon dispersions and participation ratios are evaluated to reveal the mechanism of heat conduction in the heterobilayer. This work contributes the valuable thermal information to modulate the phonon behaviors in 2D heterobilayer based nanoelectronics. PMID- 30524109 TI - Tracking Feature-Based Attention. AB - OBJECTIVE: Feature-based attention (FBA) helps one detect objects with a particular color, motion, or orientation. FBA works globally; the attended feature is enhanced at all positions in the visual field. This global property of FBA lets one use stimuli presented in the peripheral visual field to track attention in a task presented centrally. The present study explores the use of SSVEPs, generated by flicker presented peripherally, to track attention in a visual search task presented centrally. We evaluate whether this use of EEG to track FBA is robust enough to track attention when performing visual search within a dynamic 3D environment presented with a head-mounted display (HMD). Approach: Observers first performed a visual search task presented in the central visual field within a stationary virtual environment. The purpose of this first experiment was to establish whether flicker presented peripherally can produce SSVEPs during HMD use. The second experiment placed observers in a dynamic virtual environment in which observers moved around a racetrack. Peripheral flicker was again used to track attention to the color of the target in the visual search task. Results: SSVEPs produced by flicker in the peripheral visual field are influenced strongly by attention in observers with stationary or moving viewpoints. Offline classification results show that one can track an observer's attended color, which suggests that these methods may provide a viable means for tracking FBA in a real-time task. Significance: Current FBA and BCI studies primarily use foveal flicker to produce SSVEP responses. The present study's finding that one can use peripherally-presented flicker to track attention in dynamic virtual environments promises a more flexible and practical approach to BCIs based on FBA. . PMID- 30524110 TI - Homogeneous hydroxyapatite/alginate composite hydrogel promotes calcified cartilage matrix deposition with potential for three-dimensional bioprinting. AB - Calcified cartilage regeneration plays an important role in successful osteochondral repair, since it provides a biological and mechanical transition from the unmineralized cartilage at the articulating surface to the underlying mineralized bone. To biomimic native calcified cartilage in engineered constructs, here we test the hypothesis that hydroxyapatite (HAP) stimulates chondrocytes to secrete the characteristic matrix of calcified cartilage. Sodium citrate (SC) was added as a dispersant of HAP within alginate (ALG), and homogeneous dispersal of HAP within ALG hydrogel was confirmed using sedimentation tests, electron microscopy, and energy dispersive spectroscopy. To examine the biological performance of ALG/HAP composites, chondrocyte survival and proliferation, extracellular matrix (ECM) production, and mineralization potential were evaluated in the presence or absence of the HAP phase. Chondrocytes in ALG/HAP constructs survived well and proliferated, but also expressed higher levels of calcified cartilage markers compared to controls, including Collagen type X secretion, alkaline phosphatase (ALP) activity, and mineral deposition. Compared to controls, ALG/HAP constructs also showed an elevated level of mineralized matrix in vivo when implanted subcutaneously in mice. The printability of ALG/HAP composite hydrogel precursors was verified by 3D printing of ALG/HAP hydrogel scaffolds with a porous structure. In summary, these results revealed that HAP in ALG hydrogel does stimulate chondrocytes to secrete calcified matrix in vitro and in vivo and that ALG/HAP composites have the potential for 3D bioprinting and osteochondral regeneration. Key words: calcified cartilage; alginate; hydrogel; hydroxyapatite; minerals; bioprinting. PMID- 30524111 TI - Observation of dynamic charge stripes in Tm0.19Yb0.81B12 at the metal-insulator transition. AB - Accurate low temperature charge transport measurements in combination with high precision X-ray diffraction experiment have allowed detecting the symmetry lowering in the single domain Tm0.19Yb0.81B12 crystals that belong to the family of dodecaborides with metal-insulator transition. Basing on the fine structure analysis we discover the formation of dynamic charge stripes within the semiconducting matrix of Tm0.19Yb0.81B12. The charge dynamics in these conducting nano-size channels is characterized by broad-band optical spectroscopy that allowed estimating the frequency (~2.4?1011 Hz) of quantum motion of the charge carriers. It is suggested that cooperative Jahn-Teller effect in the boron sublattice is a cause of the large-amplitude rattling modes of the Tm and Yb ions responsible for the 'modulation' of the conduction band along one of the <110> directions through the variation of 5d-2p hybridization of electron states. PMID- 30524113 TI - GaP Nanowire Betavoltaic Device. AB - A betavoltaic device is reported that directly converts beta energy from a 63Ni radioisotope into electrical energy by impact ionization in a GaP nanowire array. The GaP nanowires are grown in a periodic array by molecular beam epitaxy on silicon using the self-assisted vapor-liquid-solid method. By growing GaP nanowires with large packing fraction and length on the order of the maximum beta range, the nanowires can efficiently capture the betas with high energy conversion efficiency while using inexpensive Si substrates. Monte Carlo simulations predict a betavoltaic efficiency in agreement with experimental results. The nanowire betavoltaic device can be used as a power source for nano /micro-systems such as mobile electronic devices, implantable medical devices, and wireless sensor networks. PMID- 30524112 TI - Phase-contrast breast CT: the effect of propagation distance. AB - X-ray phase imaging has the potential to dramatically improve soft tissue contrast sensitivity, which is a crucial requirement in many diagnostic applications such as breast imaging. In this context, a program devoted to perform in-vivo phase-contrast synchrotron radiation breast computed tomography is ongoing at the Elettra facility (Trieste, Italy). The used phase-contrast technique is the propagation-based configuration, which requires a spatially coherent source and a sufficient object-to-detector distance. In this work the effect of this distance on image quality is quantitatively investigated scanning a large breast surgical specimen at 3 object-to-detector distances (1.6, 3, 9 m) and comparing the images both before and after applying the phase retrieval procedure. The sample is imaged at 30 keV with a 60 um pixel pitch CdTe single-photon-counting detector, positioned at a fixed distance of 31.6~m from the source. The detector fluence is kept constant for all acquisitions. The study shows that, at the largest distance, a 20-fold SNR increase can be obtained by applying the phase-retrieval procedure. Moreover, it is shown that, for phase retrieved images, changing the object-to-detector distance does not affect spatial resolution while boosting SNR (4-fold increase going from the shortest to the largest distance). The experimental results are supported by a theoretical model proposed by other authors, whose salient results are presented in this paper. PMID- 30524114 TI - Accelerating quantitative susceptibility imaging acquisition using compressed sensing. AB - To evaluate the feasibility of compressed sensing (CS) for accelerating quantitative susceptibility mapping (QSM) acquisition in MR histology, control, demyelination, and remyelination mice were scanned using a modified 3D gradient echo pulse sequence (allowing undersampling the k-space in two phase dimensions) at 9.4 T. Fully sampled and compressed sensing data at various acceleration factors (4.0 ~ 16.0) were acquired with high spatial resolution of 22.5 MUm3 isotropic. For prospective scans, the local phase was reconstructed slice-by slice using a nonlinear reconstruction algorithm with phase cycling, and the QSM was calculated using the iLSQR method. Susceptibility values of major white matter tracts at various CS acceleration factors were compared with the fully sampled data as ground truth. The reconstructed QSM preserved major information with negligible artifacts, even at CS acceleration factors of 8.0 and 16.0. The maximum variation of susceptibility value of control mice was 5.8 % in the fimbria (FI) area with the acceleration factor of 16.0, compared to the ground truth. The maximum variation was 9.5 % in corpus callosum (CC) area of the demyelination mouse brain with the acceleration factor of 8.0. The maximum variation was 8.2 % in AC area of remyelination mouse brain with 16.0 acceleration factor. This preliminary study shows that CS can reduce the acquisition time of GRE MRI in MR histology without losing significant accuracy in quantitative susceptibility values. . PMID- 30524115 TI - Atomic ordering, magnetic properties, and electronic structure of Mn2CoGa Heusler alloy. AB - The magnetic properties and atomic arrangement of Mn2CoGa Heusler alloy were investigated experimentally and by theoretical calculations. The magnetic moment derived from spontaneous magnetization at 5 K was 2.06 MUB/f.u. and was close to the integer number of the expected value from theoretical calculation and the Slater-Pauling rule predicted by Galanakis et al. The Curie temperature and L21-B2 order disorder phase transition temperature were 741 and 1047 K, respectively. Powder neutron diffraction experiment results suggested that the atomic arrangement prefers an L21b-type structure rather than that of Hg2CuTi, being consistent with our previous results of high-angle annular dark-field-scanning transmission electron microscopic observations. The magnetic moments obtained were in good agreement with the theoretical values in the model of the L21b-type structure. The density of states obtained by the first-principles calculation combined with the coherent potential approximation in Mn2CoGa with the L21b-type crystal structure maintained the half-metallic character, even though disordering by Mn and Co atoms was introduced. PMID- 30524116 TI - Charge transport in GaAs nanowires: Interplay between conductivity through the interior and surface conductivity. AB - The charge transport through GaAs nanowires, partially p-doped and partially intrinsic, is analyzed by four-point resistance profiling along freestanding nanowires using a multip-STM. The charge transport channel in the undoped segment is assigned to the surface conductivity, while the interior of the nanowire is the conductance channel in the p-doped segment. The convoluted interplay between conduction through the interior of the nanowire and surface state conduction is studied in detail. Measurements of the I-V curves along the nanowires provide the experimental basis for the proposed charge transport model for the transition of the conduction from the interior to the surface of the nanowire. A voltage drop along the surface state conduction channel leads to an upward shift of the band edges at the surface. This results, for higher applied voltages, in the removal of the depletion layer and an opening of a conductance channel between the interior of the nanowire and the surface states. PMID- 30524117 TI - Theory of thermoelectricity in Mg3Sb2 with an energy- and temperature-dependent relaxation time. AB - We study the electronic transport coefficients and the thermoelectric figure of merit ZT in $n$-doped Mg$_3$Sb$_2$ based on density-functional electronic structure and Bloch-Boltzmann transport theory with an energy- and temperature dependent relaxation time. Both the lattice and electronic thermal conductivities affect the final ZT significantly, hence we include the lattice thermal conductivity calculated ab initio. Where applicable, our results are in good agreement with existing experiments, thanks to the treatment of lattice thermal conductivity and the improved description of electronic scattering. ZT increases monotonically in our T range (300 to 700 K), reaching a value of 1.6 at 700 K; it peaks as a function of doping at about 3$?times$10$^{19}$ cm$^{-3}$. At this doping, ZT$>$1 for T$>$500 K. PMID- 30524118 TI - From occult parodontopathy to splenic abscess leading to septic shock. AB - We present a case of a suspect splenic hematoma in an anticoagulated patient with an ignored diabetes mellitus, come to our emergency department. Lab tests showed increased CRP and INR, with an incoming hepatorenal syndrome. During the CT-scan the patient became unstable and the hemoglobin decreased. We decided for an emergency explorative laparotomy finding instead purulent collections with no evidence of bleeding, so we drained the pus and performed a splenectomy. After we excluded all the common primary sites of infection, we found out a severe chronic parodontopathy caused by multiple colonies of Candida albicans. KEY WORDS: Candida albicans, Parontopathy, Splenectomy, Splenic hematoma. PMID- 30524119 TI - High-Dose Static and Dynamic Intensity-Modulated Radiotherapy Combined with Chemotherapy for Patients with Locally Advanced Nasopharyngeal Carcinoma Improves Survival and Reduces Brainstem Toxicity. AB - BACKGROUND Intensity-modulated radiotherapy (IMRT) is the standard treatment for patients with nasopharyngeal cancer (NPC). However, the dose-volume criteria for adjacent anatomically normal organs at risk (OARs) remain controversial. The aim of this study was to evaluate the effects of higher than conventional doses of static and dynamic IMRT on the locoregional control of NPC, patient survival, and brainstem radiation toxicity. MATERIAL AND METHODS Patients (n=186) with stage III and stage IVa NPC underwent high-dose static and dynamic IMRT treatment (68 76.96 Gy) with or without chemotherapy for 34-57 days. Overall survival (OS), the presence of distant metastases, and brainstem toxicity were assessed. One-year, three-year, and five-year follow-up was performed. RESULTS High-dose IMRT alone or in combination with chemotherapy resulted in a 100% objective response rate and significantly improved OS rates, with one-year, three-year, and five-year OS rates of 94.1%, 89.8%, and 88.2%, respectively. The local recurrence rate (17.6%), and distant metastasis to the lung, liver, and bone (17.2%), and mortality (n=22) were reduced. Chemotherapy was the only factor that was significantly correlated with patient survival. Brainstem toxicity was reduced in patients treated with static IMRT (0.07%) and dynamic IMRT (0.08%). There were 26 additional factors that were not found to significantly affect brainstem toxicity. CONCLUSIONS High-dose static or dynamic IMRT combined with chemotherapy improved survival and reduces distal metastasis with a very low occurrence of brainstem toxicity in patients with locally advanced NPC. These findings might provide therapeutic guidance for clinicians when planning optimal dose-volume IMRT parameters. PMID- 30524120 TI - Mental health law in Cyprus. AB - The current Law for Psychiatric Care in the Republic of Cyprus was enacted in 1997 with amendments made in 2003 and 2007. The mental health law makes provision for the development and function of Psychiatric Centres for the care of the mentally ill. In contrast to the old Mental Health Law there is a major shift from a custodial approach to community care. Compulsory admissions under the Act, which require a Court Order, are made to a designated secure psychiatric in patient unit. The protection of patients' human rights is at the core of the Act. The Mental Health Commission, a Supervisory Committee and designated body for the Protection of the Rights of the Mentally Ill, assists in the correct implementation of the Mental Health Law. The Commission has a primarily advisory role but it is actively involved in monitoring the implementation of the Mental Health Law. PMID- 30524121 TI - Substance use problem in Sudan: elephant in the room. AB - Alcohol and cannabis were the two main substances of misuse among certain groups in Sudan, especially young adults. Over the past decade, there has been a surge in the use of other substances, including prescribed drugs, among young people and university students in particular. There are two major shortcomings: first, in the absence of reliable data, the extent of the problem is unknown; second, the preventive and treatment interventions so far being adopted are meagre. To describe the possible causes behind the escalation of this problem and to discuss applicable measures that need to be implemented to control this rapidly growing problem. The paper will highlight the current situation of substance use in Sudan, as well as suggesting preventive measures that need to be taken to curb this problem. Research and evidence-based preventive approaches are desperately needed to aid policy makers in controlling this problem. Culture-specific treatment interventions are also necessary. The implementation of a national substance misuse control strategy is of paramount importance. PMID- 30524122 TI - Mental health: taking its place as an essential element of sustainable global development. AB - As of 2015, with the adoption of the Sustainable Development Goals (SDGs), the United Nations has a new roadmap for development that will guide global and national agendas for the next 15 years. Mental health was explicitly included in the SDGs, for the first time being recognised as an essential component of development. This is a major achievement that has taken decades of unrelenting advocacy. Still, mental health lacks clear, measurable indicators within the SDGs, threatening its progress in the realm of global development. The task now is for the global mental health community to actively work within health systems, and with other sectors, to integrate mental health interventions and indicators into programmes aimed at other goals and targets. In this way, the direct impact of mental health on development and the impact of mental health on other development goals will be recognised and quantified. PMID- 30524123 TI - Restrictive environments: the challenge of implementing of Brunei's 2014 Mental Health Order. AB - In 2014, Brunei implemented the Mental Health Order, which replaced the 1929 Lunacy Act. This new legislation was designed to improve the treatment of mental disorders and to protect the rights and welfare of people with mental disorders. This short report describes the experience and challenge of implementing the new legislation, with a particular focus on the use of involuntary treatment and the restrictions imposed on people with mental disorders despite the new legislative framework. PMID- 30524124 TI - Deficiency of complement factor H-related proteins and autoantibody-positive hemolytic uremic syndrome in an infant with combined partial deficiencies and autoantibodies to complement factor H and ADAMTS13. AB - A 3-month-old male infant developed an extremely severe episode of atypical hemolytic uremic syndrome (aHUS) associated with partial deficiencies of full length complement factor H (FH; ~15% of infant normal) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (39% of normal) and autoantibodies reactive with both proteins. His FH and ADAMTS13 genes were normal, indicating that the partial deficiencies were acquired, probably as the result of autoantibodies against full-length FH and ADAMTS13. The child also had a homozygous deletion of the complement factor H-related (CFHR)3 CFHR1 portion in the complement factor H (CFH) gene cluster. He therefore had deficiency of CFHR proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) with an unusual early onset associated with a partial deficiency of ADAMTS13 and an anti-ADAMTS13 autoantibody. His clinical episode of aHUS responded to plasma infusion and subsequent treatment with mycophenolate and rituximab. We believe that this is the first report of DEAP-HUS in an infant with partial deficiencies in both ADAMTS13 and full-length FH acquired in association with autoantibodies to both proteins. PMID- 30524125 TI - Mental capacity in Colombia: a comparison with the UK. AB - Several international proclamations in the last decades have advocated for the dignity and autonomy of persons with mental disorders. Few discussions have been generated regarding the implication of this transition in low- and middle-income countries. The objective of this publication is to review how the concept of mental capacity has been defined in Colombian law. We then briefly compare the Colombian and UK situations and propose a few points of discussion, addressing some difficulties and challenges of both countries. Finally, we propose that the first steps in the Colombian context would be to strengthen understanding about mental capacity in medical schools, postgraduate and other health related programmes, the adoption of standardized tools to improve its assessment in everyday clinical settings and the establishment of community care services from collaborative efforts between governmental and civil organizations. PMID- 30524126 TI - Resilience in Haiti: is it culturally pathological? AB - Not for the first time in recent history, the people of Haiti have been obliged to fall back on their resilience strategies in the aftermath of Hurricane Matthew. Following the powerful earthquake that struck the country on 12 January 2010, the entire population had to find the resources to survive in the face of extensive material damage and loss of life: over 222 000 dead, more than 300 000 injured and between 4000 and 7000 amputees (UNDP, 2010). PMID- 30524127 TI - Mental health in the context of economic development. PMID- 30524128 TI - Residual renal function in incremental haemodialysis. AB - Background: Equivalent renal clearance (EKR) and standard clearance (stdK) are continuous-equivalent measures of urea clearance and include residual renal function (RRF), if calculated appropriately. RRF is qualitatively better than dialysis with equivalent urea clearance. Instructions for calculating stdKt/V (stdK scaled by urea distribution volume) and its target value (2.3) are presented in the Kidney Disease Outcomes Quality Initiative (KDOQI) 2015 guidelines. EKR targets have not been defined in the current guidelines. Methods: The stdKt/V in the presence of RRF was calculated with the classic double-pool urea kinetic model and with the Daugirdas modification, which accentuates the renal contribution. The EKR/V (EKR scaled by urea distribution volume) was calculated with nominal and adjusted renal clearance (renal urea clearance multiplied by a weighting factor). New prescriptions with different continuous clearance targets were generated by a computer program. Results: The contribution of RRF can be weighted flexibly in EKR/V by adjusting the renal clearance value. A new therapeutic index, EKR/V a (adjusted total EKR/V), was introduced. In 62 incremental dialysis sessions of 16 patients with a renal urea clearance (Kr) of over 1 mL/min, the Daugirdas stdKt/V was, on average, 7.5% higher than classic stdK/V and adjusted EKR/V was 14.4% higher than unadjusted EKR/V. Conclusions: The stdKt/V is not an optimal descriptor of haemodialysis urea clearance. With EKR/V, the role of RRF can be evaluated more sensibly. Using adjusted EKR/V as the target permits less frequent incremental dialysis. PMID- 30524129 TI - Mental health and integration in Asia Pacific. AB - This brief report examines the extent to which community-based treatment and integration support are provided for people living with mental illness across 15 selected Asia-Pacific economies. Some of the key findings are discussed in light of the diversity of economies and cultural contexts. PMID- 30524130 TI - Pandora's box. PMID- 30524131 TI - A fish out of water: experience of working with the Maori people in New Zealand. AB - Experiencing life and work in an alien culture initially just felt unsettling, but it also really challenged how I perceived myself and my abilities as a doctor. Being the outsider in a group has the ability to hold an uncomfortable and scrutinising mirror up to yourself. It also offers a unique opportunity to reconsider the skills, attributes and knowledge needed to be a psychiatrist. As psychiatrists, we intellectually know that culture is integral to a person's well being and the care we deliver will never be truly holistic until we encompass that. However, it was only when I was the fish out of water that I truly began to appreciate its significance. PMID- 30524132 TI - Inclusion of mental health in global economic development. AB - The APEC Mental Health Roadmap has a vision to strengthen mental health and reduce the economic impact of mental illness in the Asia Pacific. To facilitate its implementation, the APEC Digital Hub will heighten exchange and dissemination of best practices in Asia Pacific mental health partnerships, and increase multi sectoral recognition to invest in mental health to support economic growth. PMID- 30524133 TI - Collaboration Matters: Honey Bee Health as a Transdisciplinary Model for Understanding Real-World Complexity. AB - We develop a transdisciplinary deliberative model that moves beyond traditional scientific collaborations to include nonscientists in designing complexity oriented research. We use the case of declining honey bee health as an exemplar of complex real-world problems requiring cross-disciplinary intervention. Honey bees are important pollinators of the fruits and vegetables we eat. In recent years, these insects have been dying at alarming rates. To prompt the reorientation of research toward the complex reality in which bees face multiple challenges, we came together as a group, including beekeepers, farmers, and scientists. Over a 2-year period, we deliberated about how to study the problem of honey bee deaths and conducted field experiments with bee colonies. We show trust and authority to be crucial factors shaping such collaborative research, and we offer a model for structuring collaboration that brings scientists and nonscientists together with the key objects and places of their shared concerns across time. PMID- 30524134 TI - Association Between Ambient Air Pollution and Cardiac Morpho-Functional Phenotypes: Insights From the UK Biobank Population Imaging Study. AB - Background: Exposure to ambient air pollution is strongly associated with increased cardiovascular morbidity and mortality. Little is known about the influence of air pollutants on cardiac structure and function. We aim to investigate the relationship between chronic past exposure to traffic-related pollutants and the cardiac chamber volume, ejection fraction, and left ventricular remodeling patterns after accounting for potential confounders. Methods: Exposure to ambient air pollutants including particulate matter and nitrogen dioxide was estimated from the Land Use Regression models for the years between 2005 and 2010. Cardiac parameters were measured from cardiovascular magnetic resonance imaging studies of 3920 individuals free from pre-existing cardiovascular disease in the UK Biobank population study. The median (interquartile range) duration between the year of exposure estimate and the imaging visit was 5.2 (0.6) years. We fitted multivariable linear regression models to investigate the relationship between cardiac parameters and traffic related pollutants after adjusting for various confounders. Results: The studied cohort was 62+/-7 years old, and 46% were men. In fully adjusted models, particulate matter with an aerodynamic diameter <2.5 MUm concentration was significantly associated with larger left ventricular end-diastolic volume and end-systolic volume (effect size = 0.82%, 95% CI, 0.09-1.55%, P=0.027; and effect size = 1.28%, 95% CI, 0.15-2.43%, P=0.027, respectively, per interquartile range increment in particulate matter with an aerodynamic diameter <2.5 MUm) and right ventricular end-diastolic volume (effect size = 0.85%, 95% CI, 0.12-1.58%, P=0.023, per interquartile range increment in particulate matter with an aerodynamic diameter <2.5 MUm). Likewise, higher nitrogen dioxide concentration was associated with larger biventricular volume. Distance from the major roads was the only metric associated with lower left ventricular mass (effect size = 0.74%, 95% CI, -1.3% to -0.18%, P=0.01, per interquartile range increment). Neither left and right atrial phenotypes nor left ventricular geometric remodeling patterns were influenced by the ambient pollutants. Conclusions: In a large asymptomatic population with no prevalent cardiovascular disease, higher past exposure to particulate matter with an aerodynamic diameter <2.5 MUm and nitrogen dioxide was associated with cardiac ventricular dilatation, a marker of adverse remodeling that often precedes heart failure development. PMID- 30524135 TI - Assessing the causal role of body mass index on cardiovascular health in young adults: Mendelian randomization and recall-by-genotype analyses. AB - Background: Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference. Methods: In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418). Results: In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate. Conclusions: Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG. PMID- 30524136 TI - In Aptamers They Trust: The Caveats of the SOMAscan Biomarker Discovery Platform from SomaLogic. PMID- 30524138 TI - Time-averaged and transient pressure drop for flow boiling with saturated inlet conditions. AB - This study explores flow boiling pressure drop of FC-72 in a rectangular channel subjected to single-side and double-sided heating for vertical upflow, vertical downflow, and horizontal flow with positive inlet quality. Analysis of temporal records of pressure transducer signals is used to assess the influences of orientation, mass velocity, inlet quality, heat flux, and single-sided versus double-sided heating on magnitude of pressure drop oscillations, while fast Fourier transforms of the same records are used to capture dominant frequencies of oscillations. Time-averaged pressure drop results are also presented, with trends focusing on the competing influences of body force and flow inertia, and particular attention paid to the impact of vapor content at the test section inlet and the rate of vapor generation within the test section on pressure drop. Several popular pressure drop correlations are evaluated against the present pressure drop database. Predictions are presented for subsets of the database corresponding to low and high ranges of inlet quality and mass velocity. The correlations are ranked based on mean absolute error, overall data trends, and data spread. While most show general success in capturing the data trends, they do so with varying degrees of accuracy. PMID- 30524139 TI - Effects of two-phase inlet quality, mass velocity, flow orientation, and heating perimeter on flow boiling in a rectangular channel: Part 1 - Two-phase flow and heat transfer results. AB - Lack of understanding of flow boiling behavior in reduced gravity poses a major challenge to the development of future space vehicles utilizing two-phase thermal control systems (TCSs). A cost effective method to investigating the influence of reduced gravity on flow boiling is to perform ground experiments at different orientations relative to Earth gravity. This paper is the first part of a two part study aimed at exploring flow boiling mechanisms of FC-72 in a rectangular channel heated along one wall or two opposite walls. Experiments are performed in vertical upflow, vertical downflow and horizontal flow, subject to large variations in mass velocity, inlet quality and wall heat flux. Detailed measurements are used to investigate the influences of orientation, and therefore gravity, on boiling curve, local and average heat transfer coefficients, and pressure drop, and their relationship with interfacial behavior is captured with high-speed video. For horizontal flow, the effects of gravity are reflected in appreciable stratification across the channel at low mass velocities, with gravity aiding vapor removal from, and liquid return to the bottom heated wall, while accumulating vapor along the top heated wall. For vertical upflow and vertical downflow, with both single-sided and double-sided heating, there is far better symmetry in vapor formation along the channel. The heat transfer coefficient shows significant variations among the different orientations and heating configurations at low mass velocities, but becomes insensitive to orientation above 800 kg/m2 s, proving inertia around this mass velocity is effective at negating any gravity effects. For low mass velocities, pressure drops are fairly equal for vertical upflow and vertical downflow, but greater than for horizontal flows. However, fairly equal pressure drops are achieved at high mass velocities for all orientations. Overall, this study proves that gravity effects on two-phase pressure drop and two-phase heat transfer are dictated mostly by mass velocity and, to a lesser extent, by inlet quality. PMID- 30524140 TI - Effects of two-phase inlet quality, mass velocity, flow orientation, and heating perimeter on flow boiling in a rectangular channel: Part 2 - CHF experimental results and model. AB - This study is the second part of a two-part study exploring flow boiling of FC-72 along a rectangular channel with either one wall or two opposite walls heated for saturated inlet conditions. While the first part examined flow boiling interfacial behavior, boiling curves, local and average heat transfer coefficients, and pressure drops, this part is focused entirely on CHF measurement, flow visualization and modeling. Both single-sided and double-sided heating configurations are tested in horizontal flow, vertical upflow, and vertical downflow. For low mass velocities, high speed video analysis shows gravity has a dominant influence on interfacial behavior, with single-sided top wall heating yielding the lowest CHF values, and bottom-wall heating the highest. For both single-sided heating and double-sided heating, increasing mass velocity decreases the influence of orientation on CHF, with identical CHF values achieved at high mass velocities irrespective of orientation, and increasing inlet quality serves to decrease the mass velocity value required for inertia to completely overcome gravity effects. A separated flow model for two-phase inlet conditions is proposed to predict key flow variables necessary for CHF modeling. With a MAE <= 14%, this study proves that the combination of separated flow model and Interfacial Lift-off Model is highly effective at predicting CHF for saturated inlet conditions as it did in prior studies for sub-cooled inlet conditions. PMID- 30524137 TI - Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment. AB - Background: Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial. Methods: 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors. Results: Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R 2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; P=2x10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels. Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk. PMID- 30524141 TI - Assessment of body force effects in flow condensation, Part I: Experimental investigation of liquid film behavior for different orientations. AB - Body force effects in flow condensation vary depending on channel orientation and fluid mass velocity, making the design of systems intended to operate in multiple orientations more complicated than those at a fixed orientation. This study examines the effects of body force on liquid film development for flow condensation of FC-72 in horizontal, vertical upflow, and vertical downflow orientations. Two test sections are utilized, one capable of providing high-speed imaging of liquid film development, and the other designed to allow detailed measurements of flow condensation heat transfer coefficient. High speed imaging shows that for low FC-72 mass velocities, flow regimes differ significantly among the three orientations, with vertical upflow exhibiting falling film behavior, horizontal flow showing stratification, and vertical downflow displaying annular co-current flow. For the case of low mass velocity horizontal flow, interfacial disturbances in the form of a sinusoidal wave are clearly visible with wavelengths on the order of 1-10 mm. As mass velocity is increased, the liquid film is seen to exhibit similar behavior for all three orientations due to interfacial shear stress negating body force effects. Heat transfer measurements reinforce these trends, with circumferential variations in heat transfer coefficient present for horizontal flow at low mass velocities, and differences in the axial variations in heat transfer coefficient seen when comparing vertical upflow to vertical downflow. As mass velocity is increased, differences in heat transfer coefficient are reduced, with the highest mass velocities exhibiting almost no variation with orientation. This convergence of values indicates the ability of interfacial shear stress to mitigate body force effects at sufficiently high mass velocities. PMID- 30524142 TI - Assessment of body force effects in flow condensation, part II: Criteria for negating influence of gravity. AB - This study concerns the development of a set of mechanistic criteria capable of predicting the flow conditions for which gravity independent flow condensation heat transfer can be achieved. Using FC-72 as working fluid, a control-volume based annular flow model is solved numerically to provide information regarding the magnitude of different forces acting on the liquid film and identify which forces are dominant for different flow conditions. Separating the influence of body force into two components, one parallel to flow direction and one perpendicular, conclusions drawn from the force term comparison are used to model limiting cases, which are interpreted as transition points for gravity independence. Experimental results for vertical upflow, vertical downflow, and horizontal flow condensation heat transfer coefficients are presented, and show that, for the given test section, mass velocities above 425 kg/m2 s ensure gravity independent heat transfer. Parametric evaluation of the criteria using different assumed values of mass velocity, orientation, local acceleration, and exit quality show that the criteria obey physically verifiable trends in line with those exhibited by the experimental results. As an extension, the separated flow model is utilized to provide a more sophisticated approach to determining whether a given configuration will perform independent of gravity. Results from the model show good qualitative agreement with experimental results. Additionally, analysis of trends indicate use of the separated flow model captures physics missed by simpler approaches, demonstrating that use of the separated flow model with the gravity independence criteria constitute a powerful predictive tool for engineers concerned with ensuring gravity independent flow condensation heat transfer performance. PMID- 30524143 TI - Enceladus Plume Density from Cassini Spacecraft Attitude Control Data. AB - The plumes of Enceladus are of interest both as a geophysical phemonenon, and as an astrobiological opportunity for sampling internal material. Here we report measurements of the total mass density (gas plus dust, a combination not reported before except in the engineering literature) deduced from telemetry of Cassini's Attitude and Articulation Control System (AACS), as the spacecraft's thrusters or reaction wheels worked to maintain the desired attitude in the presence of gas drag torques during close flybys. The drag torque shows good agreement with the water vapor density measured by other instruments during the E5 encounter, but indicates a rather higher mass density on other passes (E3,E14), possibly indicating variations in gas composition and/or gas:dust ratio. The spacecraft appears to have intercepted about 0.2 grams of material, on flyby E21 in October 2015 indicating a peak mass density of ~5.5*10-11 kgm-3, the highest of all the flybys measured (E3,E5,E7,E9,E14,E21). PMID- 30524144 TI - Social Disadvantage and Instability in Older Adults' Ties to Their Adult Children. AB - Objective: We examine whether racial and socioeconomic factors influence older adults' likelihood of experiencing instability in their social network ties with their adult children. Background: Recent work shows that socially disadvantaged older adults' social networks are more unstable and exhibit higher rates of turnover, perhaps due to greater exposure to broader social-environmental instability. We consider whether this network instability applies to older adults' ties with their adult children, which are often the closest and most reliable social ties in later life. Methods: We use two waves of data from the National Social Life, Health, and Aging Project (N=1,456), a nationally representative, longitudinal study of older Americans. Through a series of multivariate regression models, we examine how race and education are associated with how frequently older adults reported being in contact with child network members, and how likely older adults were to stop naming their children as network members over time. Results: African American and less educated individuals reported significantly more frequent contact with their adult child network members than did whites and more educated individuals. Nevertheless, these populations were also more likely to stop naming their children as network confidants over time. Conclusion: African American and less educated older adults are at greater risk of losing access to the supports and other resources that are often provided by adult children, or of not being able to consistently draw on them as they age, despite the fact that these ties demonstrate greater potential for support exchange at baseline. PMID- 30524145 TI - Alternating Ring-Opening Metathesis Polymerization (AROMP) of Hydrophobic and Hydrophilic Monomers Provides Oligomers with Side-Chain Sequence Control. AB - We report the formation of oligomers with side-chain sequence control using ruthenium-catalyzed alternating ring-opening metathesis polymerization (AROMP). These oligomers are prepared through sequential, stoichiometric addition of bicyclo[4.2.0]oct-1(8)-ene-8-carboxamide (monomer A) at 85 degrees C and cyclohexene (monomer B) at 45 degrees C to generate sequences up to 24 monomeric units composed of (A-alt- B) n and (A'-alt-B) n microblocks, where n ranges from 1 to 6. Herein, monomer A has an alkyl side chain, and monomer A' has a glycine methyl ester side chain. Increasing microblock size from one to six results in an increasing water contact angle on spin-coated thin films, despite the constant ratio of hydrophilic and hydrophobic moieties. However, a disproportionately high contact angle was observed when n equals 2. Thus, the unique all-carbon backbone formed in the AROMP of bicyclo[4.2.0]oct-1(8)-ene-8-carboxamides and cyclohexene provides a platform for the nontemplated preparation of materials with specific sequences of side chains. PMID- 30524146 TI - Rationalizing Science: A Comparative Study of Public, Industry, and Nonprofit Research Funders. AB - In the context of more and more project-based research funding, commercialization and economic growth have increasingly become rationalized concepts that are used to demonstrate the centrality of science for societal development and prosperity. Following the world society tradition of organizational institutionalism, this paper probes the potential limits of the spread of such rationalized concepts among different types of research funders. Our comparative approach is particularly designed to study the role and position of nonprofit research funders (NPF), a comparison that is relevant as NPF could potentially be shielded from such rationalized pressures given their lack of profit gaining motives. By making a qualitative interview-based investigation we are able to describe how research funders rationalize their contributions to society at large, as well as their obligations to the researchers they fund. Four types of research funders are compared-independently wealthy philanthropists, fundraising dependent nonprofits, public agencies, and industry. We find that NPF, and especially philanthropists, are the least commercially geared type of funder, but that philanthropists also express least obligations to researchers funded. This is in sharp contrast to public research funders who, even more than industry, employ commercially geared rationalizations. We also find that both public and corporate funders express obligations to the researchers they fund. Our results indicate that there are limits to the spread of commercially tinted rationalizations among NPF, but that this does not necessarily mean an increased sense of obligations to the researchers funded, and by extension to the integrity of scientific pursuit. PMID- 30524147 TI - In adults with osteoarthritis of the knee, is conservative management more effective than intra-articular corticosteroid injections in relieving pain? AB - Clinical Question: In adults with osteoarthritis of the knee, do conservative management methods such as weight reduction, physical therapy, Tai Chi, non steroidal anti-inflammatory drugs (NSAIDs), and others provide more and longer pain relief and functionality of the knee, as well as overall well-being, when compared to corticosteroid knee injections? Answer: Yes. Although there are limited head-to-head trials directly comparing each alternative method to corticosteroid injections, overall evidence appears to indicate conservative methods as being more effective than injections, especially when considering long term pain relief and functionality. PMID- 30524148 TI - Experimental subaqueous burial of a bird carcass and compaction of plumage. AB - 'Exceptional fossils' of dinosaurs preserving feathers have radically changed the way we view their paleobiology and the evolution of birds. Understanding how such soft tissues preserve is imperative to accurately interpreting the morphology of fossil feathers. Experimental taphonomy has been integral to such investigations. One such experiment used a printing press to mimic compaction, done subaerially and without sediment burial, and concluded that the leaking of bodily fluid could lead to the clumping of feathers by causing barbs to stick together such that they superficially resemble simpler, less derived, filamentous structures. Here we use a novel, custom-built experimental setup to more accurately mimic subaqueous burial and compaction under low-energy, fine-grain depositional environments applicable to the taphonomic settings most plumage-preserving 'exceptional fossils' are found in. We find that when submerged and subsequently buried and compacted, feathers do not clump together and they maintain their original arrangement. Submersion in fluid in and of itself does not lead to clumping of barbs; this would only occur upon pulling feathers out from water into air. Furthermore, sediment encases the feathers, fixing them in place during compaction. Thus, feather clumping that leads to erroneously plesiomorphic morphological interpretations may not be a taphonomic factor of concern when examining fossil feathers. Our current methodology is amenable to further improvements that will continue to more accurately mimic subaqueous burial and compaction, allowing for various hypothesis testing. PMID- 30524149 TI - Select beta- and gamma-branched 1-alkylpyrazol-4-yl methylcarbamates exhibit high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase. AB - The widespread emergence of pyrethroid-resistant Anopheles gambiae has intensified the need to find new contact mosquitocides for indoor residual spraying and insecticide treated nets. With the goal of developing new species selective and resistance-breaking acetylcholinesterase (AChE)-inhibiting mosquitocides, in this report we revisit the effects of carbamate substitution on aryl carbamates, and variation of the 1-alkyl group on pyrazol-4-yl methylcarbamates. Compared to aryl methylcarbamates, aryl dimethylcarbamates were found to have lower selectivity for An. gambiae AChE (AgAChE) over human AChE (hAChE), but improved tarsal contact toxicity to G3 strain An. gambiae. Molecular modeling studies suggest the lower species-selectivity of the aryl dimethylcarbamates can be attributed to a less flexible acyl pocket in AgAChE relative to hAChE. The improved tarsal contact toxicity of the aryl dimethylcarbamates relative to the corresponding methylcarbamates is attributed to a range of complementary phenomena. With respect to the pyrazol-4-yl methylcarbamates, the previously observed low An. gambiae-selectivity of compounds bearing alpha-branched 1-alkyl groups was improved by employing beta- and gamma-branched 1-alkyl groups. Compounds 22a (cyclopentylmethyl), 21a (cyclobutylmethyl), and 26a (3-methylbutyl) offer 250-fold, 120-fold, and 96-fold selectivity, respectively, for inhibition of AgAChE vs. hAChE. Molecular modeling studies suggests the high species-selectivity of these compounds can be attributed to the greater mobility of the W84 side chain in the choline-binding site of AgAChE, compared to that of W86 in hAChE. Compound 26a has reasonable contact toxicity to G3 strain An. gambiae (LC50 = 269 MUg/mL) and low cross resistance to Akron strain (LC50 = 948 MUg/mL), which bears the G119S resistance mutation. PMID- 30524150 TI - Predicting Divine Action. AB - This article sets out a formal procedure for determining the probability that God would do a specified action, using our moral knowledge and understanding God as a perfect being. To motivate developing the procedure I show how natural theology - design arguments, the problems of evil and divine hiddenness, and the treatment of miracles and religious experiences as evidence for claims about God - routinely appeals to judgments involving these probabilities. To set out the procedure, I describe a decision-theoretic model for practical reasoning which is deontological so as to appeal to theists, but is designed not to presuppose any substantive moral commitments, and to accommodate normative and non-normative uncertainty. Then I explain how judgments about what we probably ought to do can be transformed into judgments about what God would probably do. Then I show the usefulness of the procedure by describing how it can help structure discussions in natural theology and a-theology, and how it offers an attractive alternative to 'skeptical theism'. PMID- 30524151 TI - Evaluating the Quality of Social Work Supervision in UK Children's Services: Comparing Self-Report and Independent Observations. AB - Understanding how different forms of supervision support good social work practice and improve outcomes for people who use services is nearly impossible without reliable and valid evaluative measures. Yet the question of how best to evaluate the quality of supervision in different contexts is a complicated and as yet-unsolved challenge. In this study, we observed 12 social work supervisors in a simulated supervision session offering support and guidance to an actor playing the part of an inexperienced social worker facing a casework-related crisis. A team of researchers analyzed these sessions using a customized skills-based coding framework. In addition, 19 social workers completed a questionnaire about their supervision experiences as provided by the same 12 supervisors. According to the coding framework, the supervisors demonstrated relatively modest skill levels, and we found low correlations among different skills. In contrast, according to the questionnaire data, supervisors had relatively high skill levels, and we found high correlations among different skills. The findings imply that although self-report remains the simplest way to evaluate supervision quality, other approaches are possible and may provide a different perspective. However, developing a reliable independent measure of supervision quality remains a noteworthy challenge. PMID- 30524152 TI - Effect of Amino Acids and Sodium Chloride on d-Sorbitol in Aqueous Solutions at Different Temperatures: Volumetric and Acoustic Approach. AB - Apparent molar volumes and apparent molar compressibilities for d-sorbitol in (0.05, 0.1, 0.2 and 0.3) mol.kg-1 aqueous solutions of l-alanine, l-cysteine and l-histidine and NaCl have been determined from measurements of solution density at T = (288.15, 298.15, 308.15 and 318.15) K and sound velocity at T = 298.15 K, as a function of the concentration of the sugar alcohol. The data were used to obtain the limiting apparent molar volumes, limiting apparent molar compressibilities and the corresponding transfer parameters. Limiting apparent molar expansibilities and their second order derivatives and volume interaction coefficients were also estimated. These parameters are discussed in terms of d sorbitol and co-solute (amino acid or sodium chloride) interactions in aqueous solutions. PMID- 30524153 TI - Adsorption and Aggregation Properties of Some Polysorbates at Different Temperatures. AB - Measurements of the surface tension of aqueous solutions of polysorbates (Tween 20, Tween 60 and Tween 80) at 293, 303 and 313 K were made. On the basis of the obtained results the Gibbs surface excess concentration of the Tweens at the water-air interface and critical micelle concentrations were determined. Knowing the Gibbs surface excess concentration and taking into account the difference between the limiting area occupied by water and Tween molecules at the water-air interface, the fraction occupied by Tween molecules was established. The limiting area occupied by the Tween molecule was calculated by applying the Joos equation. The area determined in such a way was confirmed by the calculations of cross section of Tween molecules based on the bond lengths and the angles between them as well as the average distance between the molecules, taking into account their different conformations. This area was used for calculation of the standard Gibbs energy of adsorption using the Langmuir equation. The standard Gibbs energy of Tweens adsorption at the water-air interface was also calculated from the hydrophobic part of Tween molecule-water interface tension and that of hydrophobic part. Using the determined values of standard Gibbs energy of adsorption at different temperatures, the standard enthalpy and entropy values were deduced. The standard thermodynamic functions of micellization were also determined and compared to the Gibbs energy of Tween molecules interactions through the water phase. PMID- 30524154 TI - Sexual Activities as Risk Factors of Rotator Cuff Lesions: A Prospective Cohort Study. AB - The aim of this study was to analyze the occurrence of rotator cuff impingement due to reduction of subacromial space height during complex shoulder motion to determine safety of sexual activities. The hypothesis was that such activities could be deleterious if not performed with precaution. To use a patient-specific 3D measurement technique coupling medical imaging and optical motion capture to evaluate the safety of various sexual positions according to subacromial compression. Descriptive laboratory study. A volunteer couple underwent Magnetic Resonance Imaging (MRI) and motion capture of their shoulders. Five common active and passive sexual positions were evaluated. Significant differences in subacromial space height were observed between the different performed actions. All active sexual positions requiring important pressure on the hands or elbows (e.g., scorpio) or weight lifting (e.g., superman) caused subacromial impingement. No subacromial impingement was however observed during passive sexual activities (e.g., basset hound). This study indicates that some sexual positions could potentially place the rotator cuff at risk. Such high-tech investigation shows promise in the areas of cause, intervention and education. The present findings may assist health professionals in providing them with preventive measures and is highly relevant for decision-making regarding health promoting initiatives. PMID- 30524155 TI - Sex and Relationships Education for Individuals with Cystic Fibrosis: A Service Based Approach. AB - Increasing life expectancy within cystic fibrosis (CF) raises challenges around previously neglected topics such as sexual and reproductive health (SRH). The study aimed to gather retrospective experiences of service provision around SRH to consider the role of the CF service, age of information provision and unmet needs highlighting possible improvements to provision. A mixed-methods retrospective survey-based design was employed. An Adult CF team participated in a consultation session generating survey questions around SRH. A 20-item online survey was constructed and disseminated to adult CF patients. Unmet needs were found in SRH provision in pediatric and adult CF services, with further information required by patients on topics including parenthood and fertility. Results support previous research findings highlighting the need for standardized provision around SRH. Age of SRH provision suggested individual differences in need within the pediatric service. Further research could explore format and specific age of SRH information provision. PMID- 30524156 TI - Does a 2-Week Sexual Health in Rehabilitation Course Lead to Sustained Change in Students' Attitudes?-A Pilot Study. AB - This pilot study aimed to explore if healthcare professional students participating in a 2-week elective course, Sexual Health in Rehabilitation (SHR), led to significant and sustained change in experienced competence and attitudes towards addressing sexual health in their future professions, when measured with the Students' Attitudes towards Sexual Health-Danish version (SA-SH-D). Comparison-group design, using the SA-SH-D at baseline, after the 2 weeks course and 3 months after completing the course. Participation in the SHR course significantly changed the students' attitudes; decreasing their fears of offending the patients and increasing their feelings of comfort in communicating about sexual health, and the results sustained during the follow-up period of 3 months. The results of the intervention suggest that a 2-week elective SHR course leads to sustained change healthcare students' attitudes towards addressing sexual health in their future profession. Sexual health education positively changed the students' attitudes, decreased their fears of offending the patients and increased their feelings of comfort in communicating about sexual health. The SA-SH-D is a useful tool to measure results of educational interventions aiming to change healthcare students' attitudes towards addressing sexual health in their future profession. Future research is recommended regarding students' attitudes towards addressing sexual health with persons living with disabilities. There is also a need to further research the effect of elective versus compulsory sexual health education in healthcare programs, to lessen the risk that healthcare students in their future profession will not be able to give equal care due to variation in competence and attitude. PMID- 30524157 TI - Learning Facial Action Units with Spatiotemporal Cues and Multi-label Sampling. AB - Facial action units (AUs) may be represented spatially, temporally, and in terms of their correlation. Previous research focuses on one or another of these aspects or addresses them disjointly. We propose a hybrid network architecture that jointly models spatial and temporal representations and their correlation. In particular, we use a Convolutional Neural Network (CNN) to learn spatial representations, and a Long Short-Term Memory (LSTM) to model temporal dependencies among them. The outputs of CNNs and LSTMs are aggregated into a fusion network to produce per-frame prediction of multiple AUs. The hybrid network was compared to previous state-of-the-art approaches in two large FACS coded video databases, GFT and BP4D, with over 400,000 AU-coded frames of spontaneous facial behavior in varied social contexts. Relative to standard multi label CNN and feature-based state-of-the-art approaches, the hybrid system reduced person-specific biases and obtained increased accuracy for AU detection. To address class imbalance within and between batches during training the network, we introduce multi-labeling sampling strategies that further increase accuracy when AUs are relatively sparse. Finally, we provide visualization of the learned AU models, which, to the best of our best knowledge, reveal for the first time how machines see AUs. PMID- 30524158 TI - Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling. AB - Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki-Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRD-obtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki-Miyaura cross-coupling products, from which 10 of the most lead like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns. PMID- 30524159 TI - Assessing the Effectiveness of Social Indices to Measure the Prevalence of Social Isolation in Neighbourhoods: A Qualitative Sense Check of an Index in a Northern English City. AB - Tackling the many negative health effects of social isolation has been identified as a policy priority in the UK and consequently many local authorities are developing strategies to ascertain its prevalence through the development of social indices. This paper provides a novel assessment of the emerging approach of developing indices to identify social isolation. It provides an overview of a selection of indices being developed by local authorities across England; considers the validity of such quantitative indices; and explores the extent to which more in-depth qualitative data collected at a neighbourhood level is additionally required. It draws on evidence of a social isolation index for older people created by a northern English local authority, assessing its validity through a qualitative sense check; an innovative approach which has not been attempted elsewhere. The paper contributes important knowledge to the growing literature in this field by further developing understanding around the most effective ways of identifying, measuring, and understanding social isolation at a local level. Our findings indicate that an index, alone, is insufficient to fully capture the multifaceted nature of social isolation as relevant indicators, unique to local spaces, which cannot easily be measured quantitatively, are often excluded. The paper offers a significant and original contribution to the debate for both academics who wish to gain a greater understanding of the role indices can play in identifying those most at risk of social isolation, as well as for policy makers and practitioners who are currently grappling with this challenging concept. PMID- 30524160 TI - Incidence of Cardiac Dysfunction After Brain Injury. AB - Introduction: Cardiovascular complications in patients with subarachnoid hemorrhage are considered to be a neurally mediated process rather than a manifestation of coronary artery disease. Aim: The aim of study is to show the incidence and type cardiac complications after traumatic and spontaneous SAH. Patients and methods: The study had prospective character in which included 104 patients, with diagnosed subarachnoid hemorrhage (SAH), in the period from 2014 to 2017. Two groups of patients were formed. Group I: patients with SAH caused by the rupture of a brain aneurysm. Group II: patients with SAH after traumatic brain injury. Results: Electrocardiogram (ECG) abnormalities was predominant after traumatic brain injury 74 %, with statistically significant difference atrial fibrillation 42.5 % (p = 0.043) and sinus bradycardia 31.4 % (p = 0.05). Hypertension are predominant in patients with spontaneous SAH with statistically significant difference (15 (27.7%) vs 36 (72%) p=0.034) and hypotension in group II (10 (18.5%) vs 2 (4%) p = 0.021 ) with traumatic SAH patients. The time in Intensive Care Unit (ICU) for traumatic SAH group was 6.1 +/- 5.2 days and 3.9 +/ 1.16 for spontaneous SAH group with statistical significance (p = 0.046). Respiratory support time was longer in traumatic SAH group (39.4 +/- 23.44 vs. 15.66 +/- 22.78) with p = 0.043. Conclusion: Cardiac dysfunction in patients with subarachnoid hemorrhage are considered to be a neurally mediated process rather than a manifestation of coronary artery disease. Early treatment of cerebral injury could be reduce incidence of cardiac complications after traumatic brain injury. Cardiac dysfunction in patients with SAH is still very high, despite substantial qualitative progress in their treatment. PMID- 30524161 TI - Impact of Clopidogrel Loading for Coronarography on Bleeding After Urgent First Time CABG. AB - Background: Excessive bleeding impairs outcome after coronary artery bypass grafting (CABG). Clopidogrel in combination with aspirin, given before percutaneous coronary intervention, have become the standard for stent thrombosis prevention. Some premedicated patients, however, are found to need surgical treatment, thus platelet inhibition caused by clopidogrel becomes a concern for post operation major bleeding. Aims: This study was designed to evaluate the impact of preoperative clopidogrel on bleeding and outcomes after coronary artery bypass graft surgery (CABG). Methods: The study represent a observational retrospective analysis of collected data. The follow up of 223 treated with clopidogrel and aspirin and 77 patients not receiving treatment with platelet antagonist 7 days before CABG are analyzed. Results: The groups were comparable in age, gender, body surface area, preoperative hematocrit, preoperative prothrombin time and prior myocardial infarction. The clopidogrel group had higher12h and 24h mean chest tube output (at 12h mean 519.7ml vs 353.1 ml, p < 0.05, at 24h mean 756.6 ml vs 563.5 ml, p<0.05). Moreover, reoperation for bleeding was 4.5-fold higher in the clopidogrel group (5.9% vs. 1.3%, p <0.01), and more transfusions of red blood cells (3.23U vs 2.6 U, p<0.05), platelets (1.53U vs 1.23U, p<0.01) and fresh frozen plasma (0.84U vs 0.36 U, p<0.01). The clopidogrel group also showed a longer mechanical ventilation time (16.9h vs 12.9 h p = 0.03) and trend towards more prolonged stay in ICU (2.08 days vs 1.7 days p= 0.048). Conclusions: Clopidogrel in combination with aspirin before CABG is associated with higher postoperative bleeding, exposure to blood products and morbidity. These findings raise concern regarding the routine administration of clopidogrel before anticipated but undecided coronary stent implantation. PMID- 30524162 TI - The Importance of Acinetobacter Species in the Hospital Environment. AB - Introduction: Acinetobacter species is associated with health care associated infections especially in patients on respiratory therapy equipment and indwelling catheters. They are becoming increasingly drug resistant. The knowledge of the prevalence and pattern of antimicrobial susceptibility pattern of Acinetobacter spp. is important. Aims: The study is undertaken to estimate the prevalence rate, risk factors and antimicrobial resistance pattern of isolates. in Acinetobacter spp. from various clinical samples. Material and Methods: The isolates of Acinetobacter species obtained from various clinical specimen. Specimens were processed by standard microbiological techniques. Antimicrobial sensitivity tests of the Acinetobacter isolates were done by modified Kirby-Bauer disc diffusion method. Results: Out of 622 isolates, 399 isolates were from inpatients (62,18%) and 223 were from outpatients (37,82%). More than 90% of isolates displayed resistance to ampicillin, amoxicillin-clavulanic acid, ceftazidime, caftriaxon and amikacin. Resistance to gentamicin, co-trimoxazole and ciprofloxacin were also common. Least resistance was seen to piperacillin-tazobactam and imipenem. A total of 125 Acinetobacter isolates were analyzed, out of which 78.4 % were multi drug resistant (MDR). Of these MDR isolates, 17.24% were pan-resistant. A. baumannii was the most common species responsible for wound infection (84,8%), pneumonia(96,15%), abscess (72.7%), urinary tract infection (85,7%) and septicemia(89,5%). Conclusion: Multi-drug resistant Acinetobacter has emerged as an important nosocomial pathogen. Antibiotic susceptibility testing is critical in the treatment of infections caused by Acinetobacter. Continued surveillance of prevalent organisms in ICUs, combined with preventive measures remains absolutely essential in efforts to prevent or limit the spread of Acinetobacter infection. PMID- 30524163 TI - Hepatitis C Treatment in Patients with Drug Addiction Is Effective or Not Effective? AB - Introduction: Patients with drug addiction have high risk for hepatitis C virus (HCV). Effective treatment response is essential to optimize treatment for drug abusers infected by hepatitis C virus. Aim: The aim of this present study was to show that hepatitis C treatment in patients with drug addiction is effective like patients without drug addiction. Material and Methods: Total amount of 57 patients with hepatitis C (25 drug abuser and 32 non-drug abuser) that referred to Shahid Motahari clinic of Shiraz were selected. All patients infected with HCV treated by combination regimens of ribavirin, sofosbuvir and interferon. Patients received sofosbuvir (400mg once a day) in combination with peg-IFN-alpha (92a180m/w>92b1/5m/kg/w) and RBV (under 75 kg 1000mg, over 75 kg 12000kg) for 12 weeks. The Kolmogorov-Smirnov test was used for testing normality. Associations between variables were analyzed using a Chi-square, Fisher exact, T student and Mann-Whitney U test. Results: Out of 25 HCV patients (43.9%) were drug addicts and 32 patients (56.1%) were non-drug addicts. Insomnia (61.4%), fatigue (63.1%) and debility (49.1%) were more common adverse effects of therapy in drug abusers and non-drug abusers. Alanine transaminase (ALT) and HCV RNA was normal in the end of therapy (EOT). White blood cell (WBC) count decreased in during two-week after starting of the treatment and then increased to normal levels at the end of treatment. Reduction of WBC count was considerable in during two-week. Hematologic result was not considerable. Reduction of hemoglobin was <10 g/dL in 9.37% of non-injecting drug addicts and <8.5 g/dL in 6.25% of injecting drug addicts. The results of this study did not demonstrated a significant relationship about sustained virologic response (SVR) between the drug abusers and non-drug abusers (P = 0.99). Conclusions: In conclusion, patients with drug addiction can receive hepatitis C treatment on the history of their past or current drug use status. Combination therapy with sofosbuvir plus peginterferon and ribavirin can lead to high treatment response in HCV patients were drug abuser. In addition, this treatment combination was with low discontinuation rates and low adverse effects. Effective intervention in HCV patients with drug addiction to reduce injection- related risk. PMID- 30524164 TI - Correlation of Serum Levels of Urokinase Activation Plasminogen (uPA) and Its Inhibitor (PAI-1) with Hormonal and HER-2 Status in the Early Invasive Breast Cancer. AB - Introduction: Breast cancer is the most common malignant tumor in women. On the list of causes of death immediately after lung cancer. It is a heterogeneous disease, considering the differences in morphological, cytogenetic, molecular, clinical and therapeutic aspects, so that the prognosis in a patient with the same histological grade and pathological status may vary. Aim: In this paper we wanted to identify the correlation between the assay of the serum values of uPA PAI-1 complexes and individual prognostic-predictive parameters, primarily with the status of estrogenic (Er), progesterogenic (PgR) and Her-2 receptors ("human epidermal growth factor). Material and methods: The study was conducted at the Clinic for General and Abdominal Surgery, University Clinical Center of Sarajevo (CCUS), from September 2016 to April 2017. The study included 66 patients, ages 18 to 75, in whom by the needle biopsy preoperatively was pathohistologically verified primary invasive breast cancer. Results: Two thirds of the sample were classified as invasive ductal carcinoma, similar to the percentage (68.2%) of pT2 size, and almost half in the grade G3. Lymph node status was negative in 54.5% of respondents, and positive in 31.8% of respondents. Most patients had positive estrogenic (83.3%) and progesterone receptors (62.1%). Almost 80% was Her-2 negative. The blood vessel invasion was present in 56.1%, while the neural invasion was present in less than a third of the sample (30.3%). Median values of uPA-PAI-1 complexes were 1.4 (interquartile range 0.9); almost 70% of the sample was negative for the status analysis of uPA-PAI-1 complex (<1). Discussion: A statistically significant difference was determined in the mean values of uPA-PAI 1 complexes in subgroups according to menopausal status, tumor size, histological grade, histological type (invasive ductal carcinoma vs. invasive lobular cancer versus invasive ductal carcinoma vs. invasive lobular cancer), status axillary lymph nodes, Ki67 status (as binary variables), invasion of the blood vessels and neural invasion, as well as subgroups according to the status of expression of hormonal (estrogen and progesterone) receptors. Conclusion: There is a statistically significant difference in the mean values of the uPA-PAI-1 complex and Her-2 receptor expression. Generally, in perspective, this would be the role played by the uPA/PAI-1 complex in breast cancer, which is that the elevated complex values have a negative prognosis and effect on survival, similar to the negative Her-2 receptor status. Complex uPA/PAI-1 is not a specific serum protein in breast cancer patients and cannot be taken as an individual prognostic predictive marker for mass pre- or post treatment screening and prediction. Unfortunately, none of the biomarkers are able to independently and fully identify patients of the unknown stage of the disease with better or worse prognosis or to identify cases of more aggressive tumor behavior of the same stage for timely inclusion of adjuvant therapy and reduction of the risk of metastatic disease. The decision on treatment and prognosis should be the result of a combination of all diagnostic, therapeutic, pathohistological and molecular genetic variables. PMID- 30524165 TI - Intraocular Pressure After Corneal Refractive Surgery. AB - Introduction: Laser in situ keratomileusis (LASIK), a refractive surgery procedure is being performed in a large number among people with refractive errors. In all the people undergoing the procedure, there is a potential risk to misdiagnose the glaucoma disease due to changes in central corneal thickness (CCT). In subjects who have undergone laser refractive interventions, intraocular tension may be lower and underestimated, and this can lead to later detection of glaucoma. Aim: The objective of this study was to analyze the intraocular pressure (IOP) after LASIK in patients with myopia. Methods: Thirty-seven patients underwent LASIK intervention to treat myopia. In total, 74 eyes were treated. Before the intervention, all patients underwent complete ophthalmologic examination, including the measurement of central corneal thickness (CCT) and measurement of IOP with non-contact tonometer. The IOP was also measured on days 1, 3 and 30 after the surgery. The mean IOP was taken for statistical analysis. Results: Seventy-four eyes of 37 patients (mean age 31.6) underwent LASIK intervention to treat myopia. Mean CCT before the intervention was 551.9 +/ 31.9um, while mean postoperative CCT was 469.8 +/-45.3um (p<0.0001). Mean preoperative IOP was 16.4mmHg while mean postoperative IOP was 11.0mmHg (p<0.0001). The average spherical equivalent was -5.9 diopters. Conclusions: The reduction of IOP after LASIK refractive surgery is significant. This reduction is about 1mmHg per 1 diopter. This should be taken into account in the future in these patients because, due to the underestimation of the IOP, the glaucoma disease may be overlooked. PMID- 30524166 TI - A Contribution into Developing a Model for Prostate Cancer Self-Care Mobile Application. AB - Introduction: New Healthcare models are developed with the focus on the community members and towards their self-accomplishment of the healthy activities. Mobile Health, as a newbie technology, seems to be appropriate to help prostate cancer self-care. Aim: this study aimed to provide a comparative model of mobile application for prostate cancer care self-care for Iranians. Material and Methods: This is an applied mixed method study, which was conducted in three phases from 2017 to 2018 as follows: 1) searching and thematic content analyzing of prostate cancer mobile applications and their related articles to extract technical features and clinical functions; 2) selecting the common extracted features and functions to design an initial model of the application; and 3) confirming validity of the features and functions through 2 rounds of Delphi technique. Results: This applied model was developed for the appropriate prostate cancer self-care, with such functionalities as user training, care, diagnosis, interaction, and alerting the user. Also, some technical features of the model include settings and data sharing. Conclusion: The applied model of mobile application for prostate cancer has been done in compliance with requirements of Iranian health information technologists, urologists and oncologists. It seems it would be of help in self-care of patients with needed to prostate cancer care. PMID- 30524167 TI - Chondrocyte Intracellular Matrix Strain Fields of Articular Cartilage Surface in Hyperglycemia Model of Rat: Cellular Morphological Study. AB - Introduction: Chondrocyte is one cell in articular cartilage was products many proteins, molecules, and other factors. The external influence of cartilage, such as: hyperglycemia was entering joint capsule and impact to the chondrocytes and the cartilage. Hyperglycemia caused modification of heparan sulfate proteoglycan 2 (perlecan) proteins through glycation process. Aim: The aim of this study was to analyze morphological changing of chondrocytes pericellular matrix by the influence of hyperglycemia. Material and Methods: Eighteen adult male rats were divided into six groups: control, rat treated with sugar intake was 0.5 mg/kg, 0.75 mg/ kg, 1mg/kg, 1.5 g/kg and 2 mg/kg of body weight. The animal model was dislocated and left knee was taken to observe changing of chondrocytes pericellular matrix strain fields by Scanning Electron Microscope (SEM) from perpendicular to femoral condylus cartilage. Results: Changing of chondrocytes intracellular matrix strain fields as changing of cell diameters and cell distances at group control and group I to group V, which cell diameters was lower level and cell distances was the highest level at over diet 2. This changing of intracellular matrix strain fields was corresponding to changing chondrocytes morphology in hyperglycemia condition, due to hypertrophic stage as adaptive responses. This research as based on next research for accomplish of hyperglycemia influence to morphology articular cartilage changing to prevent degeneration of cartilage towards osteoarthritis. Conclusions: Present study concludes that hyperglycemia influence to chondrocyte intracellular matrix strain fields changing. PMID- 30524168 TI - Neurocognitive Endophenotypes of Schizophrenia and Bipolar Disorder and Possible Associations with FKBP Variant rs3800373. AB - Introduction: Schizophrenia(SCZ) and Bipolar disorder (BD) are frequently occurring and impairing disorders that affect around 1% of the population. Important endophenotypes in the genetic research of SCZ and BD are cognitive functions. Core symptoms for SCZ and BD are impairments in working memory, declarative memory and attention, all of which fulfill the criteria for an endophenotype. The FK506 Binding Protein 5 (FKBP5) gene codes for a co-chaperone of the glucocorticoid receptor and has been reported to be associated with cognition. Aim: The aims of our research were to determine the degree of cognitive impairment in patients suffering from SCZ and BD and to explore the association of the FKBP5 variant rs3800373 genotype with the cognitive endophenotypes. Material and Methods: Patients and healthy controls were recruited over a period of two years from the Psychiatric Clinic, Clinical Center University of Sarajevo. Genotyping and neuropsychological assessments were performed for 263 subjects (129 SCZ, 53 BD, and 81 healthy controls [HC]). Neuropsychological assessments were performed for all patients with the Trail Making Test-A&B (TMT-A&B) and Digit-span forward&backwards tasks. The single nucleotide polymorphism (SNP) rs3800373 in the FKBP5 gene was genotyped using Infinium PsychArray Bead Chips. Results and Conclusion: SCZ and BD patients performed lower than HC in the TMT-A&B and in the Digit-span backwards task, while no differences were observed between SCZ and BD patients. While SCZ patients performed lower than HC in the Digit-span forwards task, there were no differences between BD and HC or between BD and SCZ. Rs 3800373 was not associated with performance in the TMT-A&B or Digit-span forwards&backwards tasks. SCZ and BD share largely overlapping neurocognitive characteristics. Rs3800373 was not associated with performance in the neuropsychological tests. However, given the limited sample size, the results do not exclude an association with the rs3800373 variant in a larger sample. Furthermore, as the analysis was limited to one SNP, the results cannot be generalized to other genetic variants in FKBP5. PMID- 30524169 TI - Predictive Analysis of Palmar Dermatoglyphics in Patients with Breast Cancer for Small Bosnian-Herzegovinian Population. AB - Introduction: Malignant breast cancer is the most common malignancy in women between 40 and 55 years of age. Dermatoglyphs are polygenetically determined properties, whose appearance and number are determined by a specific gene. They represent the skin reefs that are created by epidermis on the fingers or toes, palms and soles. Palmar dermatoglyphs have been used to estimate the hereditary basis of many diseases. Aim: The aim of the paper is to determine whether there is a statistically significant difference between the observed qualitative and quantitative parameters of both palms between the experimental and the control group. Material and Methods: A survey of the qualitative and quantitative properties of the palmar complex was carried out on a total of 100 female respondents. The first group included 50 women with breast cancer. Comparative data were used for the analysis of palmar dermatoglyphs in the second group of respondents, or 50 phenotypic healthy female subjects. The imprints of the palmar complex were taken using the printake ribbons, analyzed, and the data was then statistically processed and displayed in charts. An analysis of the number of reefs between two digital triradius was performed, followed by the determination of the axially triad position, as well as the ATD angle measurement. Results: Quantitative analysis of ATD-angle showed statistically significant difference between the left and right palms of the analyzed groups. However, the analysis of the number of reefs between triradius A-B, B-C, C-D did not show statistically significant results for both the left and right hand between the analyzed groups. Conclusion: These results indicate that the quantitative palmar parameter, ATD angle, can play a role in identifying women with increased risk of breast cancer. PMID- 30524170 TI - The Impact of Stress on Pressure Ulcer Wound Healing Process and on the Psychophysiological Environment of the Individual Suffering from them. AB - Introduction: The occurrence of a pressure ulcer constitutes a major psychological and physiological burden and it has been linked with a reduced quality of life and increased stress of the individual. Objective: The main objective was to investigate the impact that stress has on pressure ulcer healing process and on the psychophysiological environment of the individual suffering from them. Method: The scientific literature was reviewed through Cinahl, Pub med, EBSCO, Medline and Google scholar. The articles were chosen due to their direct correlation with the objective under study and their scientific relevance. Results: Increased stress has been demonstrated to increase the glucocorticoids levels affecting negatively the production of wound healing cytokines (IL1alpha, IL1beta and TNFalpha). Matrix metalloproteases has been identified to be unregulated in occasions of increased stress in acute wounds. Stress has also been correlated with poor health behaviors that may not have a direct link on the wound healing process, although they can in part explain or enhance some of the effects of stress on wound healing. Conclusion: The correlation between stress and wound healing in acute wounds has been thoroughly investigated and its negative effects have been established. The presence of a pressure ulcer can have a detrimental impact on the stress level of an individual although further investigation is needed to establish the role of stress in chronic wounds such as pressure ulcers. PMID- 30524171 TI - Rare Occurrence of Incidental Finding of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features in Hurthle Cell Adenoma. AB - Introduction: Hurthle cell adenoma is a rare benign lesion of the thyroid gland, however, controversies about its potential malignant behavior still remain. Among thyroid neoplasms, papillary carcinoma is the most common variant with great variety of histological subtypes demonstrating different biological behavior. Aim: To raise the awareness of possible coexistence of these two lesions and discussion about possible therapeutic approaches. Case report: A 42 year old female patient was examined because of the pain in the thyroid area. Cytological examination suggested Hurthle cell adenoma. Subsequently, right thyroid lobectomy was performed. Intraoperative frozen sections confirmed the diagnosis, yet final histological analysis revealed encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), now reclassified as noninvasive follicular thyroid neoplasm with papillary- like nuclear features (NIFTP) within the adenoma, which was not noticed through scintigraphy, ultrasound, cytological and frozen section analysis. Conclusions: Problems concerning both diagnostic and therapeutic approach to these lesions are being discussed, since opinions reported in the literature are divided, posing great challenge for the clinician in determining adequate therapeutic procedures. PMID- 30524172 TI - Giving Birth After Fertility Sparing Treatment of Embrional Carcinoma Figo III C: Case Report and Literature Review. AB - Introduction: Malignant ovarian germ cell tumors (MOGCTs) account for 2-5% of all ovarian cancers and among them pure embryonal cell cancer is rare condition (1, 2, 3, 4). Aim: To show successful pregnancy after unilateral salpingooopherectomy and chemotherapy in a girl with embryonal carcinoma of ovary (ECO). Case report: Patient had FIGO stage III c disease. After the surgical removal of the tumour, the patient underwent six cycles of adjuvant chemotherapy with bleomycin, etoposide and cisplatin (BEP). Eight years after chemotherapy she conceived spontaneously. The patient went through regular antenatal checkups in a consultation with a gynecological oncologist. In addition to all regular examinations and controls, monthly monitoring of carbohydrate antigen (CA) 125, human epididymis protein 4 (HE 4), Roma Index is also recommended. Congenital malformation excluded at 20 weeks of gestation by level III ultrasonography. At 39th gestational week, laparotomy as well as a C-section was done and the patient was managed successfully in giving birth to a healthy female baby. Three months after delivery, the woman was recurrence free and the infant did not show any problems. At the last follow-up visit (May 5, 2018), all the tumor markers were negative, and the control MRI and ultrasound examinations did not reveal tumor recurrence or pathological lymph nodes. Conclusion: Normal gonadal function and fertility are possible after fertility preservation surgery for ovarian germ cell malignancies, even with adjuvant chemotherapy. PMID- 30524173 TI - One Hundred Fifty Years of Organized Health Care Services in Bosnia and Herzegovina. AB - Introduction: Austro-Hungarian monarchy had great impact on healthcare system in Bosnia and Herzegovina (B&H), and consequences of that exist today. Aim: To launch of the section "The Most Influential Physicians in the Development of Health Care in Bosnia and Herzegovina", in which, within next issues of the Medical Archives will be presented the prominent physicians, dentists and pharmacists who gave contribution to development of healthcare system in B&H. Results: This paper provides a full overview from the literature about health care circumstances during 150 years in Bosnia and Herzegovina and important of the role health care institutions and of all the doctors working in B&H during the Austro-Hungarian administration. To some of them is devoted more attention in the texts about their life and work and their contribution to the development of the health service in B&H. Also, author gave description of the others, except for the medical activities who have contributed to our homeland, such as Dr. Jozef Kecet, Dr. Julije Makanec, Dr. Teodora Krajewska, Dr. Josef von Preindlsberger, Dr. Hamdija Karamehmedovic and others, but there are many more that we should know about and mention them. Conclusion: The fact is Austro Hungarian model of healthcare system in that time was functional for that period and great improvement in comparison to past and the fact is that that system represents a basis even for modern medicine in territory of B&H. PMID- 30524174 TI - The role of autophagy in the midgut epithelium of Parachela (Tardigrada). AB - The process of cell death has been detected in the midgut epithelium of four tardigrade species which belong to Parachela: Macrobiotus diversus, Macrobiotus polonicus, Hypsibius dujardini and Xerobiotus pseudohufelandi. They originated from different environments so they have been affected by different stressors: M. polonicus was extracted from a moss sample collected from a railway embankment; M. diversus was extracted from a moss sample collected from a petrol station; X. pseudohufelandi originated from sandy and dry soil samples collected from a pine forest; H. dujardini was obtained commercially but it lives in a freshwater or even in wet terrestrial environment. Autophagy is caused in the digestive cells of the midgut epithelium by different factors. However, a distinct crosstalk between autophagy and necrosis in tardigrades' digestive system has been described at the ultrastructural level. Apoptosis has not been detected in the midgut epithelium of analyzed species. We also determined that necrosis is the major process that is responsible for the degeneration of the midgut epithelium of tardigrades, and "apoptosis-necrosis continuum" which is the relationship between these two processes, is disrupted. PMID- 30524175 TI - Magnesium calcite in Muschelkalk limestones of the Polish part of the Germanic Basin. AB - Magnesium calcite, which is usually observed in many natural low-temperature environments, was identified in Triassic limestones of the Polish part of the Germanic Basin. The occurrence of unstable magnesium calcite in Triassic limestones is remarkable. High-Mg calcite was identified in all beds of the Muschelkalk Karchowice Formation: Lower Crinoidea Beds, Lower Biohermal Beds, Upper Crinoidea Beds and Upper Biohermal Beds. The general chemical formulas of magnesium calcite of mentioned unites are: (Ca0.87-0.80,Mg0.13-0.20)CO3, (Ca0.83 0.75,Mg0.17-0.25)CO3, (Ca0.81,Mg0.19)CO3, (Ca0.78-0.77,Mg0.22-0.23)CO3 respectively. This mineral originated probably during the early stage of diagenesis, during compaction of limestones deposited in a warm, shallow marine environment. Some amounts of magnesium come from high-Mg skeletons of marine organisms (such as echinoderms). Diagnenetic processes and the conditions in seawater, especially higher salinity, influence the preservation of high magnesium calcite in the Muschelkalk limestone of the Polish part of the Germanic Basin. PMID- 30524176 TI - New software and breast boundary landmarks to calculate breast volumes from 3D surface images. AB - Background: A method to accurately calculate breast volumes helps achieving a better breast surgery outcome. 3D surface imaging potentially allows these calculations in a harmless, quick, and practicable way. The calculated volume from a 3D surface image is dependent on the determined breast boundary and the method of chest wall simulation by software. Currently, there is no consensus on a robust set of breast boundary landmarks and validation studies on breast volume calculation software are scarce. The purposes of this study were to determine the robustness of newly introduced breast boundary landmarks and introduce and validate a new method to simulate a chest wall. Methods: Sixteen subjects who underwent a unilateral simple mastectomy were included. In addition to the natural skin fold of the breast, the sternomanubrial joint, the transition of the pectoral muscle curve into the breast curvature, and the midaxillary line were used as landmarks to indicate the breast boundary. The intra- and interrater variability of these landmarks was tested. Furthermore, new chest wall simulation software was validated on the breastless chest side of the subjects. Results: The intra- and interrater variability of the three breast boundary markers was small (mean 3.5-6.7 mm), and no significant difference was found between the intra- and interrater variability (p = 0.08, p = 0.06, and p = 0.10). The mean volume error of the most accurately simulated chest wall was 4.6 +/- 37 ml. Conclusion: The newly introduced landmarks showed to be robust and our new chest wall simulation algorithm showed accurate results.Level of Evidence: Level IV, diagnostic study. PMID- 30524177 TI - Discussing sexuality in the field of plastic and reconstructive surgery: a national survey of current practice in the Netherlands. AB - Background: Patient-reported outcomes have become increasingly important to assess the value of surgical procedures. Sexual function is a proven important constituent of quality of life, but is often overlooked by health care professionals. We aim to investigate to what extent plastic surgeons address or discuss issues concerning sexuality with their patients, and if there is a need for improvement. Methods: We developed a survey to assess whether topics pertaining to sexual function were discussed during plastic surgical consultations. In 2016, all 385 members of the Dutch Association for Plastic Surgery were invited via post mail to participate. Results: We received 106 completed surveys (27.5%). The median age of the respondents was 45 (29-66) years. Most participants (78.3%) indicated that they rarely to never discuss sexuality with their patients. Surgeons in the subspecialization gender and genital surgery discussed sexual function most frequently. Two thirds of all respondents indicated that their current knowledge on this topic was insufficient, yet there was generally no interest expressed in receiving additional training (78.6%). However, there was a need for proper patient brochures (43.4%) and an organized referral network (36.5%) regarding sexuality. Conclusions: In plastic surgery practice, sexuality appears to be a rarely discussed subject, with the gender and genital surgery subspecialties as the exception. Although professionals and patients emphasize the importance of sexuality, plastic surgeons express limited urge to be trained and prefer written patient information and referring patients to other healthcare professionals. The authors stimulate more education on sexuality during (continued) plastic surgery training.Level of Evidence: Not ratable. PMID- 30524178 TI - Homogenous-heterogeneous reactions in MHD flow of Powell-Eyring fluid over a stretching sheet with Newtonian heating. AB - This article addresses the effects of homogenous-heterogeneous reactions on electrically conducting boundary layer fluid flow and heat transfer characteristics over a stretching sheet with Newtonian heating are examined. Using similarity transformations, the governing equations are transformed into nonlinear ordinary differential equations. The constricted ordinary differential equations are solved computationally by shooting technique. The impact of pertinent physical parameters on the velocity, concentration and temperature profiles is discussed and explored via figures and tables. It is clear from figures that the velocity profile reduces for large values of fluid parameter B and Hartmann number H. Skin friction coefficient decreases for large values of Hartmann number H and fluid parameter B. Also, heat transfer rate monotonically enhances with conjugate parameter of Newtonian heating gamma and Prandtl number Pr. PMID- 30524179 TI - Working Memory Training for Adolescents With Cannabis Use Disorders: A Randomized Controlled Trial. AB - Adolescent cannabis use is associated with working memory impairment. The present randomized controlled trial assigned adolescents ages 14 to 21 enrolled in cannabis use treatment to receive either working memory training (experimental group) or a control training (control group) as an adjunctive treatment. Cognitive function, drug use, and other outcomes were assessed before and after training. We observed few differences in cognitive, functional, or self-reported drug use outcomes as a function of training group, although tetrahydrocannabinol (THC) urinalysis results favored the experimental group. These findings are similar to previous studies in substance users, which have shown limited transfer effects for working memory training. PMID- 30524180 TI - Examining the use of USEPA's Generic Attenuation Factor in determining groundwater screening levels for vapor intrusion. AB - A value of 0.001 is recommended by the United States Environmental Protection Agency (USEPA) for its groundwater-to-indoor air Generic Attenuation Factor (GAFG), used in assessing potential vapor intrusion (VI) impacts to indoor air, given measured groundwater concentrations of volatile chemicals of concern (e.g., chlorinated solvents). The GAFG can, in turn, be used for developing groundwater screening levels for VI given target indoor air quality screening levels. In this study, we examine the validity and applicability of the GAFG both for predicting indoor air impacts and for determining groundwater screening levels. This is done using both analysis of published data and screening model calculations. Among the 774 total paired groundwater-indoor air measurements in the USEPA's VI database (which were used by that agency to generate the GAFG) we found that there are 427 pairs for which a single groundwater measurement or interpolated value was applied to multiple buildings. In one case, up to 73 buildings were associated with a single interpolated groundwater value and in another case up to 15 buildings were associated with a single groundwater measurement (i.e, that the indoor air contaminant concentrations in all of the associated buildings were influenced by the concentration determined at a single point). In more than 70% of the cases (390 of 536 paired measurements in which horizontal building monitoring well distance was recorded) the monitoring wells were located more than 30 meters (and some up to over 200 meters) from the associated buildings. In a few cases, the measurements in the database even improbably implied that soil gas contaminant concentrations increased, rather than decreased, in an upward direction from a contaminant source to a foundation slab. Such observations indicate problematic source characterization within the dataset used to generate the GAFG, and some indicate the possibility of a significant influence of a preferential contaminant pathway. While the inherent value of the USEPA database itself is not being questioned here, the above facts raise the very real possibility that the recommended groundwater attenuation factors are being influenced by variables or conditions that have not thus far been fully accounted for. In addition, the predicted groundwater attenuation factors often fall far beyond the upper limits of predictions from mathematical models of VI, ranging from screening models to detailed computational fluid dynamic models. All these models are based on the same fundamental conceptual site model, involving a vadose zone vapor transport pathway starting at an underlying uniform groundwater source and leading to the foundation of a building of concern. According to the analysis presented here, we believe that for scenarios for which such a "traditional" VI pathway is appropriate, 10-4 is a more appropriately conservative generic groundwater to indoor air attenuation factor than is the EPA recommended 10-3. This is based both on the statistical analysis of USEPA's VI database, as well as the traditional mathematical models of VI. This result has been validated by comparison with results from some well documented field studies. PMID- 30524181 TI - Structural Models for Binary Repeated Measures: Linking Modern Longitudinal Structural Equation Models to Conventional Categorical Data Analysis for Matched Pairs. AB - The current widespread availability of software packages with estimation features for testing structural equation models with binary indicators makes it possible to investigate many hypotheses about differences in proportions over time that are typically only tested with conventional categorical data analyses for matched pairs or repeated measures, such as McNemar's chi-squared. The connection between these conventional tests and simple longitudinal structural equation models is described. The equivalence of several conventional analyses and structural equation models reveals some foundational concepts underlying common longitudinal modeling strategies and brings to light a number of possible modeling extensions that will allow investigators to pursue more complex research questions involving multiple repeated proportion contrasts, mixed between-subjects * within-subjects interactions, and comparisons of estimated membership proportions using latent class factors with multiple indicators. Several models are illustrated, and the implications for using structural equation models for comparing binary repeated measures or matched pairs are discussed. PMID- 30524182 TI - Predictive Factors for Success of Laparoscopic Splenectomy for ITP. AB - Background and Objectives: Therapy-resistant immune thrombocytopenia (ITP) is the most frequent indication of laparoscopic splenectomy (LS). It ensures the best results for this disease compared with possible second-line pharmacologic therapies. Therefore, learning about the safety of the surgical method and its long-term efficacy is important, as is selecting patients who respond to surgical treatment. Our purpose was to analyze the safety of LS and the short-and long term prognostic significance of known perioperative parameters. Methods: We performed 40 LSs for ITP from January 1, 2000, to January 1, 2015. We analyzed the roles of the perioperative parameters by using evidence-based guidelines. Results: Complete response (CR; platelet count over 100 * 109/L) occurred in 28 cases (70%) and partial response (PR; platelet count between 30 and 100 * 109/L) in 5 cases (12.5%). Below the age of 50, 9% (2/22) of the patients had no response (NR; platelet count not increasing over 30 * 109/L), 28% (5/18) over the age of 50 (P = .023) had no response. In the steroid-refractory group, 30% did not respond, whereas 100% of the steroid-dependent patients had a CR (NR: 7/23 steroid refractory vs 0/17 steroid dependent; P = .027). The patients were followed up for a mean of 10.9 +/- 6.9 years, and a long-term response (LTR) was detected in 21 of the responders (n = 33). Of the patients who originally had a CR, 71% also achieved LTR, whereas only 20% of the PR patients did. Conclusion: LS is safe and remains the most effective second-line treatment for ITP. In our study, younger age and response to preoperative steroids were predictive factors for the long-term success of splenectomy. PMID- 30524183 TI - Symptoms and Health Quality After Laparoscopic and Robotic Myomectomy. AB - Background and Objectives: To compare the symptom severity and health quality outcomes of women who underwent laparoscopic and robotic myomectomy. Methods: This was a prospective nonrandomized cohort study. The Uterine Fibroid Symptom and Health Related Quality of Life Questionnaire was administered to 33 laparoscopic myomectomy and 31 robotic myomectomy patients before and year after surgery. Symptom severity and health quality scores were compared between the preoperative and postoperative periods for laparoscopic and robotic myomectomy procedures. Results: The mean age, operation time, estimated blood loss, body mass index, largest fibroid diameter, length of hospital stay, and number of fibroids removed were comparable for both groups (P > .05). Symptom severity scores decreased significantly for both laparoscopic and robotic myomectomy patients at year after surgery (P < .05), and health-related quality of life scores increased significantly in both groups at 1 year after surgery (P < .05). Improvement in symptom severity and health quality was higher in the laparoscopy group; however, this was not statistically different from the robotic myomectomy group (P > .05). Conclusion: Laparoscopic and robotic myomectomy provide significant reductions in fibroid-associated symptom severity and significant improvement in quality of life at 1 year after surgery. The rate of improvement was comparable for both procedures. PMID- 30524184 TI - Origins of Robotic Surgery: From Skepticism to Standard of Care. AB - Background and Objectives: The uses of robotics in surgery were hypothesized as far back as 1967, but it took nearly 30 years and the nation's largest agency, the Department of Defense, in conjunction with innovative startups and established research agencies to complete the first fully functional multipurpose surgical robot. Currently, the most prominently available multipurpose robotic surgery system with US Food and Drug Administration approval is Intuitive Surgical Inc.'s da Vinci Surgical System, which is found in operating rooms across the globe. Although now ubiquitous for minimally invasive surgery, early surgical robot prototypes were specialty focused. Originally, multipurpose robotic systems were intended for long-distance trauma surgery in battlefield settings. While there were impressive feats of telesurgery, the marketable focus has veered from this goal. Initially developed through SRI International and Defense Advanced Research Projects Agency, surgical robotics reached private industry through two major competitors, who later merged. Methods: A thorough search of PubMed, Clinical Key, EBSCO, Ovid, ProQuest, and industry manufacturers' websites yielded 62 relevant articles, of which 51 were evaluated in this review. Conclusion: We analyzed the literature and referred to primary sources by conducting interviews with present and historical leaders in the field to yield a detailed chronology of surgical robotics development. As minimally invasive robotic procedures are becoming the standard of care, it is crucial to comprehensively document their historical context and importance as an emerging and evolving discipline. PMID- 30524185 TI - Efficacy of a New Crosslinked Hyaluronan Gel in the Prevention of Intrauterine Adhesions. AB - Background and Objectives: The authors sought to assess the effect of the use of a new crosslinked hyaluronan (NCH) gel on the prevention of intrauterine adhesions (IUAs) in women underwent curettage in the second trimester. Methods: Between June 2016 and September 2017, 60 patients who underwent curettage for retained placental tissue after medically induced or spontaneous pregnancy loss in the second trimester were enrolled in the study. The patients were randomly assigned to 1 of 2 groups: Group 1 patients received curettage plus NCH gel (intervention group), and group 2 patients received curettage alone (control group). The main outcomes were the rate and severity of IUA formation, which were assessed by follow-up hysteroscopy performed in the ensuing 2-6 months. Results: The hysteroscopic findings were available for 20 patients in group 1 and 28 patients in group 2. IUAs were observed in 6 patients in group 2, while no IUAs was observed in group 1 (P = .007). IUAs were staged as mild in 4 patients (14.28%) and moderate in 2 patients (7.14%) in group 2 according to the American Fertility Society classification of IUAs. Conclusions: Our study demonstrates that NCH gel appears to be able to reduce the formation of IUAs in women who undergo curettage in the second trimester, although larger controlled, randomized, multicenter studies are needed to confirm these results. PMID- 30524186 TI - A taxonomic revision of the Neotropical genus Cremastosperma (Annonaceae), including five new species. AB - We present a taxonomic revision of Cremastosperma, a genus of Neotropical Annonaceae occurring in lowland to premontane wet forest, mostly in areas surrounding the Andean mountain chain. We recognise 34 species, describing five as new here: from east of the Andes, C.brachypodum Pirie & Chatrou, sp. nov. and C.dolichopodum Pirie & Maas, sp. nov., endemic to Peru; C.confusum Pirie, sp. nov., from southern Peru and adjacent Bolivia and Brazil; and C.alticola Pirie & Chatrou, sp. nov., at higher elevations in northern Peru and Ecuador; and from west of the Andes, C.osicola Pirie & Chatrou, sp. nov. endemic to Costa Rica, the most northerly distributed species of the genus. We provide an identification key, document diagnostic characters and distributions and provide illustrations and extensive lists of specimens, also presenting the latter in the form of mapping data with embedded links to images available online. Of the 34 species, 22 are regional endemics. On the basis of the extent of occurrence and area of occupancy of species estimated from the distribution data, we designate IUCN threat categries for all species. Fourteen species proved to be endangered (EN) and a further one critically endangered (CR), reflecting their rarity and narrow known distributions. PMID- 30524187 TI - The Cuito catchment of the Okavango system: a vascular plant checklist for the Angolan headwaters. AB - This paper aims to provide a baseline for conservation planning by documenting patterns of plant diversity and vegetation in the upper catchment of the Cuito River. 417 species are recorded from this region. Nine of these are species potentially new to science. Ten species are newly recorded from Angola, with an additional species only recorded previously within Angola from the northern enclave of Cabinda. The 108 new provincial records for Moxico clearly indicate the lack of collections from Angola's largest province. We note the existence of extensive peat deposits in the Cuito river system for the first time and suggest that one of Barbosa's vegetation types in the area needs to be reassessed. PMID- 30524188 TI - Examining the utilisation and usefulness of social support for mothers with young children with autism spectrum disorder. AB - Background: Social support has been described as a vital resource for families with children with disability. Although the benefits of social support have been described, little is known about the utilisation patterns in families of young children with autism spectrum disorder (ASD). Method: In a community sample of 78 American families with children (2-6 years) with ASD, this study examined the utilisation and usefulness of social support. Child, family, and service variables related to social support were explored. Results: Mothers of children with ASD reported using a combination of formal and informal supports, and these were perceived to be helpful. Sociodemographic variables, child behaviour problems, satisfaction with the autism diagnostic process, and access to information about ASD predicted social support utilisation. Conclusion: Social support utilisation varies as a function of different child, family, and service variables. Understanding these variables may help professionals guide families in access to and use of social support. PMID- 30524189 TI - An anisotropic linear thermo-viscoelastic constitutive law: Elastic relaxation and thermal expansion creep in the time domain. AB - A constitutive material law for linear thermo-viscoelasticity in the time domain is presented. The time-dependent relaxation formulation is given for full anisotropy, i.e., both the elastic and the viscous properties are anisotropic. Thereby, each element of the relaxation tensor is described by its own and independent Prony series expansion. Exceeding common viscoelasticity, time dependent thermal expansion relaxation/creep is treated as inherent material behavior. The pertinent equations are derived and an incremental, implicit time integration scheme is presented. The developments are implemented into an implicit FEM software for orthotropic material symmetry under plane stress assumption. Even if this is a reduced problem, all essential features are present and allow for the entire verification and validation of the approach. Various simulations on isotropic and orthotropic problems are carried out to demonstrate the material behavior under investigation. PMID- 30524190 TI - Aptamer-conjugated multi-walled carbon nanotubes as a new targeted ultrasound contrast agent for the diagnosis of prostate cancer. AB - Early diagnosis is primarily important for the therapeutic and prognostic outcomes of malignancies including prostate cancer (PCa). However, the visuality and veracity of ultrasound imaging for the diagnosis and prognostic prediction of PCa remains poor at present. In this study, we developed a new nanoultrasound contrast agent by modifying multi-walled carbon nanotubes (MWCNTs) with polyethylene glycol (PEG) and anti-PSMA aptamer. The result showed that the modified MWCNTs offered better visuality and veracity and were able to target PCa cells more effectively as compared with the traditional contrast agent. The zeta potential was about - 38 mv. The length of this contrast agent was about 400 nm and the diameter of it was about 30 nm. The zeta potential, TEM, and FT-IR all proved the successful preparation of the agent. The vitro cytological study revealed good cell uptake and biocompatibility of the new contrast agent. The minimum detection concentration in vitro is 10 MUg/ml. The earliest stage of the detection was under the parameters of frequency = 6.0 MHz and medical index = 0.06. Both in vitro and in vivo ultrasound imaging demonstrated that the new nanoultrasound contrast agent had a good development effect, distribution, and metabolism, and may prove to be a good targeted ultrasound contrast agent, especially for PCa. PMID- 30524191 TI - Influence of size and surface capping on photoluminescence and cytotoxicity of gold nanoparticles. AB - Hydrophilic and homogeneous sub-10 nm blue light-emitting gold nanoparticles (NPs) functionalized with different capping agents have been prepared by simple chemical routes. Structure, average, size, and surface characteristics of these NPs have been widely studied, and the stability of colloidal NP solutions at different pH values has been evaluated. Au NPs show blue PL emission, particularly in the GSH capped NPs, in which the thiol-metal core transference transitions considerably enhance the fluorescent emission. The influence of capping agent and NP size on cytotoxicity and on the fluorescent emission are analyzed and discussed in order to obtain Au NPs with suitable features for biomedical applications. Cytotoxicity of different types of gold NPs has been determined using NPs at high concentrations in both tumor cell lines and primary cells. All NPs used show high biocompatibility with low cytotoxicity even at high concentration, while Au-GSH NPs decrease viability and proliferation of both a tumor cell line and primary lymphocytes. PMID- 30524192 TI - GQDs-MSNs nanocomposite nanoparticles for simultaneous intracellular drug delivery and fluorescent imaging. AB - Although number of stimuli-responsive drug delivery systems based on mesoporous silica nanoparticles (MSNs) have been developed, the simultaneous real-time monitoring of carrier in order to guarantee proper drug targeting still remains as a challenge. GQDs-MSNs nanocomposite nanoparticles composed of graphene quantum dots (GQDs) and MSNs are proposed as efficient doxorubicin delivery and fluorescent imaging agent, allowing to monitor intracellular localization of a carrier and drug diffusion route from the carrier. Graphene quantum dots (average diameter 3.65 +/- 0.81 nm) as a fluorescent agent were chemically immobilized onto mesoporous silica nanoparticles (average diameter 44.08 +/- 7.18 nm) and loaded with doxorubicin. The structure, morphology, chemical composition, and optical properties as well as drug release behavior of doxorubicin (DOX)-loaded GQDs-MSNs were investigated. Then, the in vitro cytotoxicity, cellular uptake, and intracellular localization studies were carried out. Prepared GQDs-MSNs form stable suspensions exhibiting excitation-dependent photoluminescence (PL) behavior. These nanocomposite nanoparticles can be easily DOX-loaded and show pH- and temperature-dependent release behavior. Cytotoxicity studies proved that GQDs MSNs nanocomposite nanoparticles are nontoxic; however, when loaded with drug, they enable the therapeutic activity of DOX via its active delivery and release. GQDs-MSNs owing to their fluorescent properties and efficient in vitro cellular internalization via caveolae/lipid raft-dependent endocytosis show a high potential for the optical imaging, including the simultaneous real-time optical tracking of the loaded drug during its delivery and release. Graphical abstract?. PMID- 30524193 TI - Tidal Love numbers of neutron stars in f(R) gravity. AB - The recent detection of gravitational waves from a neutron star merger was a significant step towards constraining the nuclear matter equation of state by using the tidal Love numbers (TLNs) of the merging neutron stars. Measuring or constraining the neutron star TLNs allows us in principle to exclude or constraint many equations of state. This approach, however, has the drawback that many modified theories of gravity could produce deviations from General Relativity similar to the deviations coming from the uncertainties in the equation of state. The first and the most natural step in resolving the mentioned problem is to quantify the effects on the TLNs from the modifications of General Relativity. With this motivation in mind, in the present paper we calculate the TLNs of (non-rotating) neutron stars in R2 -gravity. More precisely, by solving numerically the perturbation equations, we calculate explicitly the polar and the axial l=2 TLNs for three characteristic realistic equations of state and compare the results to General Relativity. Our results show that while the polar TLNs are slightly influenced by the R2 modification of General Relativity, the axial TLNs can be several times larger (in terms of the absolute value) compared to the general relativistic case. PMID- 30524194 TI - Mapping nonlinear gravity into General Relativity with nonlinear electrodynamics. AB - We show that families of nonlinear gravity theories formulated in a metric-affine approach and coupled to a nonlinear theory of electrodynamics can be mapped into general relativity (GR) coupled to another nonlinear theory of electrodynamics. This allows to generate solutions of the former from those of the latter using purely algebraic transformations. This correspondence is explicitly illustrated with the Eddington-inspired Born-Infeld theory of gravity, for which we consider a family of nonlinear electrodynamics and show that, under the map, preserve their algebraic structure. For the particular case of Maxwell electrodynamics coupled to Born-Infeld gravity we find, via this correspondence, a Born-Infeld type nonlinear electrodynamics on the GR side. Solving the spherically symmetric electrovacuum case for the latter, we show how the map provides directly the right solutions for the former. This procedure opens a new door to explore astrophysical and cosmological scenarios in nonlinear gravity theories by exploiting the full power of the analytical and numerical methods developed within the framework of GR. PMID- 30524195 TI - Oral health implications of increased cannabis use among older adults: Another public health concern? AB - Prevalence of cannabis use among older Americans (aged >= 65) appears to be rising, and emerging evidence associates cannabis use with several oral diseases. The burden of oral diseases among older Americans is great, but literature discussing potential implications of increasing rates of cannabis use and the oral health of older persons is lacking. This paper explores the latest trends in prevalence of cannabis use among older Americans and summarizes the literature on the oral health status of older adults and oral effects of cannabis use, and considers broad implications for oral health and public health policy and future research. Further studies on the effects cannabis use on the oral health of older adults are needed. Future research should investigate older subjects' susceptibility to cannabis-related oral diseases, as well as the proportions that develop disease. Policymakers may wish to tackle barriers to access of dental services for the older population, or target subsets of the population that suffer from comparably higher rates of oral diseases, while dental professionals may require training on managing underlying substance use behaviors in addition to clinical oral manifestations. PMID- 30524196 TI - Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and Matrix Metalloproteinases. AB - Neonates are highly susceptible to microbial infections which is partially attributable to fundamental phenotypic and functional differences between effector cells of the adult and neonatal immune system. The resolution of the inflammation is essential to return to tissue homeostasis, but given that various neonatal diseases, such as periventricular leukomalacia, necrotizing enterocolitis, or bronchopulmonary dysplasia, are characterized by sustained inflammation, newborns seem predisposed to a dysregulation of the inflammatory response. Targeted apoptosis of effector cells is generally known to control the length and extent of the inflammation, and previous studies have demonstrated that phagocytosis-induced cell death (PICD), a special type of apoptosis in phagocytic immune cells, is less frequently triggered in neonatal monocytes than in adult monocytes. We concluded that a rescue of monocyte PICD could be a potential therapeutic approach to target sustained inflammation in neonates. The EGFR ligand amphiregulin (AREG) is shed in response to bacterial infection and was shown to mediate cellular apoptosis resistance. We hypothesized that AREG might contribute to the reduced PICD of neonatal monocytes by affecting apoptosis signaling. In this study, we have examined a cascade of signaling events involved in extrinsic apoptosis by using a well-established in vitro E. coli infection model in monocytes from human peripheral blood (PBMO) and cord blood (CBMO). We found that CBMO shows remarkably higher pro-AREG surface expression as well as soluble AREG levels in response to infection as compared to PBMO. AREG increases intracellular MMP-2 and MMP-9 levels and induces cleavage of membrane-bound FasL through engagement with the EGF receptor. Our results demonstrate that loss of AREG rescues PICD in CBMO to the level comparable to adult monocytes. These findings identify AREG as a potential target for the prevention of prolonged inflammation in neonates. PMID- 30524197 TI - Plasma Asprosin Levels Are Associated with Glucose Metabolism, Lipid, and Sex Hormone Profiles in Females with Metabolic-Related Diseases. AB - Asprosin is a white adipose tissue-derived hormone that increases abnormally in mammals with insulin resistance. However, the role of asprosin in polycystic ovary syndrome (PCOS), a disease partly characterized by insulin resistance, and its potential connection with type 2 diabetes mellitus (T2DM) and PCOS has not been thoroughly elucidated to date. To investigate the association of asprosin with metabolic profiles, sex-related hormones, or inflammation in females with T2DM or PCOS, plasma asprosin and metabolic indicators were measured in 66 healthy females, 53 female patients with T2DM, and 41 patients with PCOS. Spearman's correlation analysis and binary logistic regression analysis models were used. Plasma asprosin was significantly higher in T2DM females than in healthy subjects (P < 0.001) and was positively correlated with fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and HOMA-IR (P < 0.05). Asprosin in PCOS subjects was also higher than in healthy subjects (P < 0.001) but lower than in T2DM subjects (P < 0.05), and it was positively correlated with FBG, HbA1c, HOMA IR, LDL-c, APOB, APOE, and testosterone (P < 0.05). The BMI-categorized subgroups of PCOS subjects also showed correlations of asprosin with metabolic profiles and sex-related hormones. Binary logistic regression analysis revealed that plasma asprosin level acted as an independent risk factor for T2DM or PCOS. These findings suggest the correlation of plasma asprosin level with glucose metabolism, lipid metabolism, sex-related hormones, and inflammation in females, supporting asprosin as a potential predictive factor for females with metabolic related diseases. This trial is registered with ChiCTR-ROC-17010719. PMID- 30524198 TI - Macrophage LRP1 Promotes Diet-Induced Hepatic Inflammation and Metabolic Dysfunction by Modulating Wnt Signaling. AB - Hepatic inflammation is associated with the development of insulin resistance, which can perpetuate the disease state and may increase the risk of metabolic syndrome and diabetes. Despite recent advances, mechanisms linking hepatic inflammation and insulin resistance are still unclear. The low-density lipoprotein receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is highly expressed in macrophages, adipocytes, hepatocytes, and vascular smooth muscle cells. To investigate the potential role of macrophage LRP1 in hepatic inflammation and insulin resistance, we conducted experiments using macrophage-specific LRP1-deficient mice (macLRP1-/- ) generated on a low density lipoprotein receptor knockout (LDLR-/- ) background and fed a Western diet. LDLR-/-; macLRP1-/- mice gained less body weight and had improved glucose tolerance compared to LDLR-/- mice. Livers from LDLR-/-; macLRP1-/- mice displayed lower levels of gene expression for several inflammatory cytokines, including Ccl3, Ccl4, Ccl8, Ccr1, Ccr2, Cxcl9, and Tnf, and reduced phosphorylation of GSK3alpha and p38 MAPK proteins. Furthermore, LRP1-deficient peritoneal macrophages displayed altered cholesterol metabolism. Finally, circulating levels of sFRP-5, a potent anti-inflammatory adipokine that functions as a decoy receptor for Wnt5a, were elevated in LDLR-/-; macLRP1-/- mice. Surface plasmon resonance experiments revealed that sFRP-5 is a novel high affinity ligand for LRP1, revealing that LRP1 regulates levels of this inhibitor of Wnt5a mediated signaling. Collectively, our results suggest that LRP1 expression in macrophages promotes hepatic inflammation and the development of glucose intolerance and insulin resistance by modulating Wnt signaling. PMID- 30524199 TI - Corrigendum to "Redox Signaling in Diabetic Nephropathy: Hypertrophy versus Death Choices in Mesangial Cells and Podocytes". AB - [This corrects the article DOI: 10.1155/2015/604208.]. PMID- 30524200 TI - Galectin-1 as an Emerging Mediator of Cardiovascular Inflammation: Mechanisms and Therapeutic Opportunities. AB - Galectin-1 (Gal-1), an evolutionarily conserved beta-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension. PMID- 30524201 TI - Antimicrobial susceptibility patterns of bacteria isolated from patients with ear discharge in Jimma Town, Southwest, Ethiopia. AB - Background: Otitis media is among the leading causes of childhood illnesses although it can also affect the adults resulting in frequent physician visits, drug prescription and a key contributor to antibiotic resistance. The aim of this study was to determine the risk factors, bacterial profile, and the antimicrobial susceptibility pattern of the isolates from patients with discharging ears which clinically equates to draining otitis media in developing countries with limited medical resources such as otoscope. Methods: A prospective cross-sectional study was conducted on 173 patients with draining otitis media. The ear discharge specimens were collected and analyzed by standard microbial techniques. The antibiotic susceptibility profiles were determined for 19 different antibiotics by the standard disk diffusion method. Data was analyzed by SPSS version 22 and the P value of less than 0.05 was considered as statistically significant. Results: Among 173 otitis media patients participated in the study; majority, 102(63%) were pediatrics, out of which 72 (41.61%) were in the age group of less than 4 years. Ear infection was bilateral in 39 (22.54%) and chronic in 100 (57.8%) of the patients. Pathogens were isolated from 160 (92.5%) of the patients with a total of 179 isolates. The predominant isolate was Staphylococcus aureus (30.72%) followed by Proteus spp. (17.89%). The result of this study showed that adult age (p = 0.031), rural residence (p = 0.005), previous history of health care visit and treatment (p = 0.000), upper respiratory tract infection (p = 0.018) and presence of cigarette smoker in the house (p = 0.022) had statistically significant association with chronic otitis media. Most of the isolated bacteria showed high level of resistance to ampicillin/amoxicillin (88.3%), penicillin G (79.5%) followed by trimethoprim /sulfamethoxazole (73.8%). Conversely, the majority of bacterial isolates showed moderate susceptibility to ciprofloxacin (72.9%), gentamicin (70.4%), and amikacin (69.3%). Bacterial isolates identified in this study showed trend of multiple drug resistance, majority (67%) being resistant to three or more antimicrobials. Conclusions: Majority of the bacterial isolates were multidrug resistant, hence, efforts to isolate microorganisms and determine the susceptibility pattern should be strengthened to improve the treatment outcome of otitis media instead of the usual trend of empirical treatment. PMID- 30524202 TI - Nurses' experiences of caring for patients with intellectual developmental disorders: a systematic review using a meta-ethnographic approach. AB - Background: Research suggests that registered nurses (RNs) do not feel adequately prepared to support patients with intellectual disability disorder (IDD). This is unsurprising, as few European health sciences curricula include undergraduate and graduate training courses in IDD. As RNs are often in the front line of care, eliciting in-depth knowledge about how they experience nursing this group of patients is vital. Our aim in this study was to develop a conceptual understanding about RNs' experiences of nursing patients with IDD. Method: We undertook a systematic review and meta-ethnography to synthesise qualitative research studies found in PubMed, CINAHL, PsycINFO, ERIC databases and by manual searching to identify additional studies. We condensed translatable second-order constructs, and developed an idiomatic translation. Finally, we formulated line of argument (LOA) syntheses to capture the core of the idiomatic translations. Results: We included eighteen published studies from eight countries involving 190 RNs. The RNs' experience of nursing patients with IDD were reflected in 14 LOAs. Six of these reflected a tentatively more distinctive and at times unique conceptualisation of RNs' experience of nursing this group of patients. The remaining eight LOAs represented a conceptualisation of nursing per se, a conceptualisation of nursing that was interpreted as a universal experience regardless of context and patient group. Conclusion: Lack of awareness and knowledge are likely breeding grounds for the 'otherness' that still surrounds this group of patients. In encounters between patients and RNs, focusing on the person behind the disability label could be one way to secure relevant nursing care for patients with IDD. Undertaking appropriate under- and postgraduate education alongside the implementation of nursing models focusing on patient centred care would help RNs in reducing the health and care inequalities this group of patients still face. Trial registration: PROSPERO 2017: CRD42017077703. PMID- 30524203 TI - MicroRNA-770 affects proliferation and cell cycle transition by directly targeting CDK8 in glioma. AB - Background: MicroRNAs play crucial roles in tumorigenesis and tumor progression. miR-770 has been reported to be downregulated in several cancers and affects cancer cell proliferation, apoptosis, metastasis and drug resistance. However, the role and underlying molecular mechanism of miR-770 in human glioma remain unknown and need to be further elucidated. Methods: The expression of miR-770 in glioma tissues and cell lines was measured by quantitative real-time PCR (qRT PCR) to explore the association of miR-770 expression with clinicopathological characteristics. The expression of CDK8 was detected by qRT-PCR and Western blotting in glioma tissues. A target prediction program and a dual-luciferase reporter assay were used to confirm that CDK8 is a target gene of miR-770. MTT and cell counting assays were used to assess the effect of miR-770 on glioma cell proliferation. The cell cycle distribution and apoptosis were examined by flow cytometry. CDK8 siRNA and overexpression were used to further confirm the function of the target gene. Results: We demonstrated that miR-770 expression was downregulated in human glioma tissues and cell lines. The overexpression of miR 770 inhibited glioma cell proliferation and cell cycle G1-S transition and induced apoptosis. The inhibition of miR-770 facilitated cell proliferation and G1-S transition and suppressed apoptosis. miR-770 expression was inversely correlated with CDK8 expression in glioma tissues. CDK8 was confirmed to be a direct target of miR-770 by using a luciferase reporter assay. The overexpression of miR-770 decreased CDK8 expression at both the mRNA and protein levels, and the suppression of miR-770 increased CDK8 expression. Importantly, CDK8 silencing recapitulated the cellular and molecular effects observed upon miR-770 overexpression, and CDK8 overexpression eliminated the effects of miR-770 overexpression on glioma cells. Moreover, both exogenous expression of miR-770 and silencing of CDK8 resulted in suppression of the Wnt/beta-catenin signaling pathway. Conclusions: Our study demonstrates that miR-770 inhibits glioma cell proliferation and G1-S transition and induces apoptosis through suppression of the Wnt/beta-catenin signaling pathway by targeting CDK8. These findings suggest that miR-770 plays a significant role in glioma progression and serves as a potential therapeutic target for glioma. PMID- 30524204 TI - ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2Q607R. AB - Background: RNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity. Dysregulation of A-to-I editing has been found associated with a number of nervous system diseases. However, the role of ADAR3, a brain specific high expression adenosine deaminase, in gliomas has rarely been investigated. In this study we illuminated the clinical significance and molecular features of ADAR3 in patients with glioma. Methods: 309 glioma samples from Chinese Glioma Genome Atlas were enrolled into this study. In validation sets, 601 glioma samples in TCGA, 410 glioma samples in REMBRANDT and 258 glioma samples in GSE16011 were obtained. Relationships between ADAR3 expression and prognosis related genomic alteration, outcome and gene ontology analysis were investigated. Moreover, the characteristic of GRIA2Q607R editing in gliomas has been investigated. Graphpad Prism 5.0, SPSS 16.0 and R language were used to perform statistical analysis and graphical work. Results: ADAR3 expression was down regulated along with glioma grade progression in CGGA dataset. ADAR3 was characteristically highly expressed in neural subtype and IDH1/2 mutant preference. Moreover, high expression of ADAR3 predicted a better prognosis in lower-grade glioma (LGG) patients and multivariate analysis suggested ADAR3 expression was an independent prognostic indicator. The results of the three other validation datasets showed similar findings. Bioinformatics analyses suggested that ADAR3 may play a role in the malignant transformation of glioma cells by affecting cell proliferation, angiogenesis or cell adhesion. Furthermore, the editing level of GRIA2Q607R was significantly correlated with ADAR3 expression. Conclusions: Our study demonstrated the clinical and molecular characterization of ADAR3 in glioma development and progression. ADAR3 expression was negatively associated with tumor malignant in the overall glioma patients. And it was a favorable independent prognostic indicator of LGG patients. ADAR3 appeared to act as a tumor suppressor in glioma cells. Therefore, ADAR3 represented a potential therapeutic target and useful prognostic factor for glioma patients. PMID- 30524205 TI - MicroRNA-218-5p inhibits cell growth and metastasis in cervical cancer via LYN/NF kappaB signaling pathway. AB - Background: We are committed to investigate miR-218-5 effects on the progression of cervical cancer (CC) cell and find out the molecular mechanism. Methods: GSE9750 was obtained from GEO database and R Limma package was applied to filter out dysregulated genes. The pathways were enriched by GSEA software, ClusterProfiler and enrichplot packages to predict the function of DEGs. The binding sites of LYN were detected by miRanda and TargetScan. The miR2Disease database was used to find miRNAs related with CC. The expression of miR-218-5p and LYN were quantified by qRT-PCR and that of LYN protein was measured by western blot. The targeted relationships between miR-218-5p and LYN were verified by dual-luciferase reporter assay. Colony formation assays, wound healing, transwell invasion assay and flow cytometer analysis were performed to investigate the roles that miR-218-5p and LYN played in migration, invasion and death of cervical carcinoma. Xenografts established in nude mice were used to assess tumor growth in vivo. Results: The highly expressed mRNA LYN was selected by microarray analysis in GSE9750. NF-kappaB signaling pathway was enriched base on GSEA results. The expression of miR-218-5p was lower but LYN was higher in CC primary tumors compared with normal control. In addition, miR-218-5p could regulate the expression of LYN in HeLa cells negatively. Overexpression of LYN could promote cell migration and invasion, but inhibit cell death in vitro, and also promote tumor formation in vivo via activating NF-kappaB signaling pathway which could be reversed by miR-218-5p. Conclusions: MiR-218-5p suppressed the progression of CC via LYN/NF-kappaB signaling pathway. PMID- 30524206 TI - Comorbidities are associated with different features of severe asthma. AB - Background: According to ATS/ERS document on severe asthma (SA), the management of these patients requires the identification and proper treatment of comorbidities, which can influence the control of asthma. Methods: The aim of this study was to assess the independent effect of different comorbidities on clinical, functional and biologic features of SA. Seventy-two patients with SA according to GINA guidelines were examined. We collected demographic data, smoking habit, asthma history, and assessment of comorbidities. Pulmonary function, inflammatory biomarkers, upper airway disease evaluation, asthma control and quality of life were carefully assessed. Results: The mean age of patients was 59.1 years (65.3% female, 5.6% current smokers). Comorbidities with higher prevalence were: chronic rhinosinusitis with or without nasal polyps (CRSwNP or CRSsNP), obesity and gastro-esophageal reflux (GERD), with some overlapping among them. In an univariate analysis comparing patients with single comorbidities with the other ones, asthmatics with CRSwNP had lower lung function and higher sputum eosinophilia; obese asthmatics had worse asthma control and quality of life, and tended to have lower sputum eosinophils; asthmatics with GERD showed worse quality of life. In multivariate analysis, obesity was the only independent factor associated with poor asthma control (OR 4.9), while CRSwNP was the only independent factor associated with airway eosinophilia (OR 16.2). Lower lung function was associated with the male gender and longer duration of asthma (OR 3.9 and 5.1, respectively) and showed a trend for the association with nasal polyps (OR 2.9, p = 0.06). Conclusion: Our study suggests that coexisting comorbidities are associated with different features of SA. PMID- 30524207 TI - Cost effectiveness of HIV and sexual reproductive health interventions targeting sex workers: a systematic review. AB - Background: Sex workers have high incidences of HIV and other sexually transmitted diseases. Although, interventions targeting sex workers have shown to be effective, evidence on which strategies are most cost-effective is limited. This study aims to systematically review evidence on the cost-effectiveness of sexual health interventions for sex workers on a global level. It also evaluates the quality of available evidence and summarizes the drivers of cost effectiveness. Methods: A search of published articles until May 2018 was conducted. A search strategy consisted of key words, MeSH terms and other free text terms related to economic evaluation, sex workers and sexual and reproductive health (SRH) was developed to conduct literature search on Medline, Web of Science, Econlit and the NHS Economic Evaluation Database. The quality of reporting the evidence was evaluated using the CHEERS checklist and drivers of cost-effectiveness were reported. Results: Overall, 19 studies met the inclusion criteria. The majority of the studies were based in middle-income countries and only three in low-income settings. Most of the studies were conducted in Asia and only a handful in Sub-Saharan Africa and Latin America. The reviewed studies mainly evaluated the integrated interventions, i.e. interventions consisted a combination of biomedical, structural or behavioural components. All interventions, except for one, were highly cost-effective. The reporting quality of the evidence was relatively good. The strongest drivers of cost-effectiveness, reported in the studies, were HIV prevalence, number of partners per sex worker and commodity costs. Furthermore, interventions integrated into existing health programs were shown to be most cost-effective. Conclusion: This review found that there is limited economic evidence on HIV and SRH interventions targeting sex workers. The available evidence indicates that the majority of the HIV and SRH interventions targeting sex workers are highly cost-effective, however, more effort should be devoted to improving the quality of conducting and reporting cost-effectiveness evidence for these interventions to make them usable in policy making. This review identified potential factors that affect the cost effectiveness and can provide useful information for policy makers when designing and implementing such interventions. PMID- 30524208 TI - The clinician-patient working alliance: Is it a significant predictor of psychiatric medication adherence in a sample of recently released parolees? AB - Persistent psychiatric symptoms can serve as a major barrier to the successful reintegration of parolees with mental illness. Thus, it is important to identify factors that might impact their mental health recovery, such as low adherence to their treatment regimen. Although many studies have examined the issue of psychiatric medication nonadherence, very few studies have focused specifically on justice-involved individuals. The strength of the clinician/patient working alliance has been found to be significantly associated with psychiatric medication adherence in prior research, but this relationship has not been assessed in a parolee population. Logistic regression analysis was used to determine if patient-rated working alliance was a significant predictor of low psychiatric medication adherence while taking into account alcohol/illegal drug use, age, and ethnicity in a sample of recently released parolees with mental illness (N=49). Patient-rated working alliance, age, and ethnicity were not significant predictors of low adherence. Alcohol/illegal drug use during the follow-up period was associated with a significantly increased likelihood of meeting the criteria for low medication adherence (OR=8.36; 95% CI=1.60, 43.66). The findings from this study highlight the importance of addressing alcohol and illegal drug use issues as part of the psychiatric treatment plan for returning prisoners with mental illness. PMID- 30524209 TI - Building a Hepatitis C Clinical Program: Strategies to Optimize Outcomes. AB - Purpose of review: An increasing number of specialists and non-specialists are developing clinical programs to treat and cure hepatitis C virus (HCV). The goal of this paper is to evaluate and describe optimal strategies to improve outcomes related to HCV care delivery. Recent findings: Screening and diagnosis of HCV should be guided by established recommendations. Given the recognized disparity in HCV diagnosis and linkage to care, a multi-modal approach involving care coordination and technology resources should be used to improve patient engagement. Access to HCV treatment may be optimized through systematic documentation, prior authorization, and appeal processes. Treatment monitoring should emphasize medication adherence, side effect and drug interaction management, as well as elimination of practical barriers. Finally, post-treatment engagement to promote liver health and reduce the risk of complications or reinfection maximizes the benefit of HCV treatment. Summary: The landscape of HCV treatment has evolved from a specialist-driven model with few patients qualifying for treatment to an opportunity for non-specialists and other providers to provide curative therapies in most patients. Innovative practice models that employ a multidisciplinary approach will likely improve screening, diagnosis, engagement, and treatment outcomes. PMID- 30524210 TI - Influence of Intimate Terrorism, Situational Couple Violence, and Mutual Violent Control on Male Victims. AB - The goal of the current study is to test - among samples of men - some previous findings relative to Johnson's (2008) typology of partner violence (PV). Among samples of exclusively women, Johnson has found that the frequency and severity of PV - and victims' mental health - are worse for female victims of intimate terrorism (IT) than of situational couple violence (SCV). However, such findings have rarely been tested in male victims of PV. Furthermore, although Johnson posits that mutual violent control (MVC) is relatively rare, other research suggests that it is about as common as IT and may be associated with worse PV and health. We examined the relative frequency and severity of various forms of PV, and the relative health and mental health between men who (a) experienced IT versus SCV, and (b) experienced IT versus MVC. Our two samples were 611 men who sought help for PV victimization and 1,601 men from a population-based sample. Our analyses showed that across samples, men who were victims of IT had significantly worse mental health than men who experienced SCV, and IT victims experienced more severe and frequent PV, including physical, sexual, and non physical forms of PV. Male victims of IT had worse mental and physical health than either men who perpetrated IT or experienced MVC, but men involved in MVC were involved in relationships with more types of PV than either male IT perpetrators or victims. Results are discussed in terms of their implications for Johnson's typology, future research, and service providers. PMID- 30524211 TI - Vacancy in shrinking downtowns: a comparative study of Quebec, Ontario, and New England. AB - In North America and around the globe, there has been emerging recognition of the size and scope of urban shrinkage, yet little is understood about how decline impacts commercial centers and downtowns. In order to facilitate geographically targeted policymaking, this paper examines the physical patterns of downtown decline in three distinct regions. We seek to test the hypothesis that differences in the process of urban decline in downtown districts vary due to national or historic context. Using statistical analysis and direct observations, we found that while the scale of population decline was greatest in New England, downtowns in both Ontario and Quebec have seen substantial decline and have appeared to have better weathered the change with respect to physical signs of decline. PMID- 30524212 TI - Environmental considerations in the Swedish building and construction industry: the role of costs, institutional setting, and information. AB - Despite increasing evidence that being an environment-friendly company not only benefits the environment but also makes long-term economic sense, the transition to a more sustainable society is extremely slow. This is true of the building and construction industry as well. At a strategic level, environmental issues have received more attention with the establishment of roles such as environmental managers and implementation of advanced environmental management systems. However, adoption has been slow in the absence of a holistic approach to environmental challenges, partly reinforced by a perception that giving more than the legally required level of environmental consideration will only add to costs without corresponding financial benefits. This raises the following question that the study aims to answer: What is the most important factor influencing decision makers' in adopting environmental considerations? To this end, it analysed questionnaire data collected from decision makers in the Swedish construction industry along with an in-depth case study of a specific building and construction company. The results show that decision makers perceive informational and institutional constraints on the adoption of environmental considerations. Lack of information is perceived as the biggest obstacle to environmental considerations. If information and knowledge about clients' and end users' financial benefits from adopting environmental considerations need to be exploited, they have to be supported by contractual forms that discard a short term focus on the investment costs of a building in favour of a focus on long term operational and maintenance costs and benefits. PMID- 30524213 TI - The unraveling of Amsterdam's unitary rental system. AB - The Netherlands has traditionally been considered an iconic 'unitary' rental housing market in which social and private sectors directly compete. More recently however, this unitary market has been undermined by changes in the status of housing associations, the privatization of social housing stock and the promotion of home ownership. It has subsequently been suggested that the Netherlands is drifting toward a 'dualist' system in which social and private sectors are critically unequal. This paper takes on this claim, providing, on the one hand, palpable evidence of the waning influence of the unitary housing system in the Netherlands and, on the other, a deeper examination of processes of dualisation as well as the outcomes. We focus on Amsterdam, where housing privatization has been most intense. We specifically draw on a geospatial analysis of changing tenure distributions at the neighbourhood level as well as a household analysis of the shifting profile of tenants and home owners to show how the unitary rental market, which helped establish Amsterdam as an iconic 'just city', has been unraveling. We demonstrate the relevance of the unitary/dualist model to understanding contemporary urban processes, especially those featuring social and economic polarization. PMID- 30524214 TI - Rent increase strategies and distributive justice: the socio-spatial effects of rent control policy in Amsterdam. AB - Rent controls and rent setting regulation in different contexts incorporate and balance different aims, in particular when securing affordability and the effective distribution of scarce housing by incorporating market mechanisms. As rent policy is frequently discussed in terms of affordability or market functioning in broad terms, small-scale distributive socio-spatial effects are often not regarded. In this paper, three strategies under the new rent sum policy are compared against the former policy and practice for Amsterdam, the Netherlands, to observe the effects of distributive justice. The new rent policy partly decentralizes rent increase decisions from the national level to local authorities and housing associations. Using microdata on all social housing units and their tenants' distributive justice, outcomes under the former policy and practice are observed for a 6-year period (2008-2014) and the effects of three different rent increase strategies under the new rent sum policy are forecasted for the same period, combining an ex ante and an ex post evaluation. The possibilities for housing associations to vary rent increases for different groups of tenants in order to improve distributive justice outcomes are explored. Results show that all three possible strategies decrease the observed affordability gap between new and long-term tenants. Valuing the distributions of these strategies by applying two different standards for distributive justice shows the rent sum policy may only result in modest improvements. PMID- 30524215 TI - Computing with biological switches and clocks. AB - The complex dynamics of biological systems is primarily driven by molecular interactions that underpin the regulatory networks of cells. These networks typically contain positive and negative feedback loops, which are responsible for switch-like and oscillatory dynamics, respectively. Many computing systems rely on switches and clocks as computational modules. While the combination of such modules in biological systems leads to a variety of dynamical behaviours, it is also driving development of new computing algorithms. Here we present a historical perspective on computation by biological systems, with a focus on switches and clocks, and discuss parallels between biology and computing. We also outline our vision for the future of biological computing. PMID- 30524216 TI - Scaling up genetic circuit design for cellular computing: advances and prospects. AB - Synthetic biology aims to engineer and redesign biological systems for useful real-world applications in biomanufacturing, biosensing and biotherapy following a typical design-build-test cycle. Inspired from computer science and electronics, synthetic gene circuits have been designed to exhibit control over the flow of information in biological systems. Two types are Boolean logic inspired TRUE or FALSE digital logic and graded analog computation. Key principles for gene circuit engineering include modularity, orthogonality, predictability and reliability. Initial circuits in the field were small and hampered by a lack of modular and orthogonal components, however in recent years the library of available parts has increased vastly. New tools for high throughput DNA assembly and characterization have been developed enabling rapid prototyping, systematic in situ characterization, as well as automated design and assembly of circuits. Recently implemented computing paradigms in circuit memory and distributed computing using cell consortia will also be discussed. Finally, we will examine existing challenges in building predictable large-scale circuits including modularity, context dependency and metabolic burden as well as tools and methods used to resolve them. These new trends and techniques have the potential to accelerate design of larger gene circuits and result in an increase in our basic understanding of circuit and host behaviour. PMID- 30524217 TI - Rough sets: past, present, and future. AB - Introduction of rough sets by Professor Zdzislaw Pawlak has completed 35 years. The theory has already attracted the attention of many researchers and practitioners, who have contributed essentially to its development, from all over the world. The methods, developed based on rough set theory alone or in combination with other approaches, found applications in many areas. In this article, we outline some selected past and present research directions of rough sets. In particular, we emphasize the importance of searching strategies for relevant approximation spaces as the basic tools in achieving computational building blocks (granules or patterns) required for approximation of complex vague concepts. We also discuss new challenges related to problem solving by intelligent systems (IS) or complex adaptive systems (CAS). The concern is to control problems using interactive granular computing, an extension of the rough set approach, for effective realization of computations realized in IS or CAS. These challenges are important for the development of natural computing too. PMID- 30524218 TI - Organizing Sequential Memory in a Neuromorphic Device Using Dynamic Neural Fields. AB - Neuromorphic Very Large Scale Integration (VLSI) devices emulate the activation dynamics of biological neuronal networks using either mixed-signal analog/digital or purely digital electronic circuits. Using analog circuits in silicon to physically emulate the functionality of biological neurons and synapses enables faithful modeling of neural and synaptic dynamics at ultra low power consumption in real-time, and thus may serve as computational substrate for a new generation of efficient neural controllers for artificial intelligent systems. Although one of the main advantages of neural networks is their ability to perform on-line learning, only a small number of neuromorphic hardware devices implement this feature on-chip. In this work, we use a reconfigurable on-line learning spiking (ROLLS) neuromorphic processor chip to build a neuronal architecture for sequence learning. The proposed neuronal architecture uses the attractor properties of winner-takes-all (WTA) dynamics to cope with mismatch and noise in the ROLLS analog computing elements, and it uses its on-chip plasticity features to store sequences of states. We demonstrate, with a proof-of-concept feasibility study how this architecture can store, replay, and update sequences of states, induced by external inputs. Controlled by the attractor dynamics and an explicit destabilizing signal, the items in a sequence can last for varying amounts of time and thus reliable sequence learning and replay can be robustly implemented in a real sensorimotor system. PMID- 30524219 TI - Melody Processing Characterizes Functional Neuroanatomy in the Aging Brain. AB - The functional neuroanatomical mechanisms underpinning cognition in the normal older brain remain poorly defined, but have important implications for understanding the neurobiology of aging and the impact of neurodegenerative diseases. Auditory processing is an attractive model system for addressing these issues. Here, we used fMRI of melody processing to investigate auditory pattern processing in normal older individuals. We manipulated the temporal (rhythmic) structure and familiarity of melodies in a passive listening, 'sparse' fMRI protocol. A distributed cortico-subcortical network was activated by auditory stimulation compared with silence; and within this network, we identified separable signatures of anisochrony processing in bilateral posterior superior temporal lobes; melodic familiarity in bilateral anterior temporal and inferior frontal cortices; and melodic novelty in bilateral temporal and left parietal cortices. Left planum temporale emerged as a 'hub' region functionally partitioned for processing different melody dimensions. Activation of Heschl's gyrus by auditory stimulation correlated with the integrity of underlying cortical tissue architecture, measured using multi-parameter mapping. Our findings delineate neural substrates for analyzing perceptual and semantic properties of melodies in normal aging. Melody (auditory pattern) processing may be a useful candidate paradigm for assessing cerebral networks in the older brain and potentially, in neurodegenerative diseases of later life. PMID- 30524220 TI - sPyNNaker: A Software Package for Running PyNN Simulations on SpiNNaker. AB - This work presents sPyNNaker 4.0.0, the latest version of the software package for simulating PyNN-defined spiking neural networks (SNNs) on the SpiNNaker neuromorphic platform. Operations underpinning realtime SNN execution are presented, including an event-based operating system facilitating efficient time driven neuron state updates and pipelined event-driven spike processing. Preprocessing, realtime execution, and neuron/synapse model implementations are discussed, all in the context of a simple example SNN. Simulation results are demonstrated, together with performance profiling providing insights into how software interacts with the underlying hardware to achieve realtime execution. System performance is shown to be within a factor of 2 of the original design target of 10,000 synaptic events per millisecond, however SNN topology is shown to influence performance considerably. A cost model is therefore developed characterizing the effect of network connectivity and SNN partitioning. This model enables users to estimate SNN simulation performance, allows the SpiNNaker team to make predictions on the impact of performance improvements, and helps demonstrate the continued potential of the SpiNNaker neuromorphic hardware. PMID- 30524221 TI - Interactions of BDNF Val66Met Polymorphism and Menstrual Pain on Brain Complexity. AB - The irregularity and uncertainty of neurophysiologic signals across different time scales can be regarded as neural complexity, which is related to the adaptability of the nervous system and the information processing between neurons. We recently reported general loss of brain complexity, as measured by multiscale sample entropy (MSE), at pain-related regions in females with primary dysmenorrhea (PDM). However, it is unclear whether this loss of brain complexity is associated with inter-subject genetic variations. Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin in the brain and is crucial to neural plasticity. The BDNF Val66Met single-nucleotide polymorphism (SNP) is associated with mood, stress, and pain conditions. Therefore, we aimed to examine the interactions of BDNF Val66Met polymorphism and long-term menstrual pain experience on brain complexity. We genotyped BDNF Val66Met SNP in 80 PDM females (20 Val/Val, 31 Val/Met, 29 Met/Met) and 76 healthy female controls (25 Val/Val, 36 Val/Met, 15 Met/Met). MSE analysis was applied to neural source activity estimated from resting-state magnetoencephalography (MEG) signals during pain free state. We found that brain complexity alterations were associated with the interactions of BDNF Val66Met polymorphism and menstrual pain experience. In healthy female controls, Met carriers (Val/Met and Met/Met) demonstrated lower brain complexity than Val/Val homozygotes in extensive brain regions, suggesting a possible protective role of Val/Val homozygosity in brain complexity. However, after experiencing long-term menstrual pain, the complexity differences between different genotypes in healthy controls were greatly diminished in PDM females, especially in the limbic system, including the hippocampus and amygdala. Our results suggest that pain experience preponderantly affects the effect of BDNF Val66Met polymorphism on brain complexity. The results of the present study also highlight the potential utilization of resting-state brain complexity for the development of new therapeutic strategies in patients with chronic pain. PMID- 30524222 TI - The Role of Endogenous Neuroprotective Mechanisms in the Prevention of Retinal Ganglion Cells Degeneration. AB - Retinal neurons are not able to undergo spontaneous regeneration in response to damage. A variety of stressors, i.e., UV radiation, high temperature, ischemia, allergens, and others, induce reactive oxygen species production, resulting in consecutive alteration of stress-response gene expression and finally can lead to cell apoptosis. Neurons have developed their own endogenous cellular protective systems. Some of them are preventing cell death and others are allowing functional recovery after injury. The high efficiency of these mechanisms is crucial for cell survival. In this review we focus on the contribution of the most recently studied endogenous neuroprotective factors involved in retinal ganglion cell (RGC) survival, among which, neurotrophic factors and their signaling pathways, processes regulating the redox status, and different pathways regulating cell death are the most important. Additionally, we summarize currently ongoing clinical trials for therapies for RGC degeneration and optic neuropathies, including glaucoma. Knowledge of the endogenous cellular protective mechanisms may help in the development of effective therapies and potential novel therapeutic targets in order to achieve progress in the treatment of retinal and optic nerve diseases. PMID- 30524223 TI - Orexin-A Exerts Neuroprotective Effects via OX1R in Parkinson's Disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by progressive and selective death of dopaminergic neurons. Orexin-A is involved in many biological effects of the body. It has been reported that orexin-A has protective effects in cellular models of PD. However, little is known about the protective effects of orexin-A in animal parkinsonian models and the cellular mechanism has not yet been fully clarified. The aim of this study was to evaluate the effects of orexin-A in MPTP mice model of PD as well as the possible neuroprotective mechanisms of orexin-A on dopaminergic neurons. The results from animal experiments demonstrated that orexin-A attenuated the loss of dopaminergic neurons and the decrease of tyrosine hydroxylase (TH) expression in the substantia nigra, normalized the striatal dopaminergic fibers, and prevented the depletion of dopamine and its metabolites in the striatum. MPTP-treated mice showed cognitive impairments accompanied with significant motor deficiency. Orexin-A improved MPTP-induced impairments in both motor activity and spatial memory. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor (BDNF) in dopaminergic neurons of the substantia nigra. Furthermore, the protective effects of orexin-A on MPTP parkinsonian mice could be blocked by orexinergic receptor 1 (OX1R) antagonist, SB334867. In another set of experiments with SH-SY5Y dopaminergic cells, orexin-A significantly induced the expression of BDNF in a dose and time-dependent manner. The upregulation of BDNF is mainly concerned with PI3K and PKC signaling pathways via OX1R. The present study demonstrated that orexin-A exerted neuroprotective effects on MPTP parkinsonian mice, which may imply orexin-A as a potential therapeutic target for PD. PMID- 30524224 TI - Thalamocortical Communication in the Awake Mouse Visual System Involves Phase Synchronization and Rhythmic Spike Synchrony at High Gamma Frequencies. AB - In the neocortex, communication between neurons is heavily influenced by the activity of the surrounding network, with communication efficacy increasing when population patterns are oscillatory and coherent. Less is known about whether coherent oscillations are essential for conveyance of thalamic input to the neocortex in awake animals. Here we investigated whether visual-evoked oscillations and spikes in the primary visual cortex (V1) were aligned with those in the visual thalamus (dLGN). Using simultaneous recordings of visual-evoked activity in V1 and dLGN we demonstrate that thalamocortical communication involves synchronized local field potential oscillations in the high gamma range (50-90 Hz) which correspond uniquely to precise dLGN-V1 spike synchrony. These results provide evidence of a role for high gamma oscillations in mediating thalamocortical communication in the visual pathway of mice, analogous to beta oscillations in primates. PMID- 30524225 TI - Phoenixin Expression Is Regulated by the Fatty Acids Palmitate, Docosahexaenoic Acid and Oleate, and the Endocrine Disrupting Chemical Bisphenol A in Immortalized Hypothalamic Neurons. AB - Phoenixin (PNX) is a newly identified reproductive peptide required for the estrous cycle. It is most highly expressed in the hypothalamus, where it is a positive regulator of gonadotropin-releasing hormone (GnRH) and kisspeptin. However, it is unknown what signals lie upstream of Pnx to coordinate its effects on GnRH and kisspeptin. We investigated the effects of the hormones, estrogen and leptin; the fatty acids, palmitate, docosahexaenoic acid (DHA), oleate and palmitoleate; and the endocrine disrupting chemical BPA on Pnx mRNA levels. We also examined whether the signaling pathways of nitric oxide, lipopolysaccharide, cAMP and protein kinase C could alter Pnx expression. Immortalized hypothalamic neurons were treated from 2 to 24 h with these compounds and Pnx mRNA levels were measured with RT-qPCR. Unexpectedly, only BPA as well as the fatty acids, palmitate, DHA and oleate, could alter Pnx expression; therefore suggesting that Pnx may fulfill a nutrient-sensing role in the hypothalamus. Our study is the first to delineate potential regulators of this novel neuropeptide, and our findings provide some insight into the functional role of PNX in the hypothalamus. PMID- 30524226 TI - The Temporal Dynamic Relationship Between Attention and Crowding: Electrophysiological Evidence From an Event-Related Potential Study. AB - Visual crowding is the difficulty experienced in identifying a target flanked by other objects within the peripheral visual field. Despite extensive research conducted on this topic, the precise relationship between attention and crowding is still debatable. One perspective suggests that crowding is a bottom-up and pre attentive process, while another suggests that crowding is top-down and attentional. A third perspective proposes that crowding is a combination of bottom-up and top-down processes. To address this debate, the current study manipulated the attention and distance between targets and flankers, while simultaneously measuring event-related potentials, in human participants. Results indicated that, compared to uncrowded targets, crowded targets elicited more negative frontal N1 and P2 activity and a less negative occipital N1 activity, regardless of whether targets were attended or unattended, and a more positive occipital P2 activity when they were attended. Furthermore, the crowded minus uncrowded difference amplitude was more negative over the frontal region and more positive over the occipital region when the targets were attended, compared to when they were unattended during the N1 and P2 stages. This suggests that crowding, a concept that originates from Gestalt grouping, occurs automatically and can be modulated by attention. PMID- 30524227 TI - Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury. AB - Dysregulation of microRNAs (miRNAs) has been found in injured spinal cords after spinal cord injury (SCI). Previous studies have shown that miR-133b plays an important role in the differentiation of neurons and the outgrowth of neurites. Recently, exosomes have been used as novel biological vehicles to transfer miRNAs locally or systemically, but little is known about the effect of the delivery of exosome-mediated miRNAs on the treatment of SCI. In the present study, we observed that mesenchymal stem cells, the most common cell types known to produce exosomes, could package miR-133b into secreted exosomes. After SCI, tail vein injection of miR-133b exosomes into rats significantly improved the recovery of hindlimb function when compared to control groups. Additionally, treatment with miR-133b exosomes reduced the volume of the lesion, preserved neuronal cells, and promoted the regeneration of axons after SCI. We next observed that the expression of RhoA, a direct target of miR-133b, was decreased in the miR-133b exosome group. Moreover, we showed that miR-133b exosomes activated ERK1/2, STAT3, and CREB, which are signaling pathway proteins involved in the survival of neurons and the regeneration of axons. In summary, these findings demonstrated that systemically injecting miR-133b exosomes preserved neurons, promoted the regeneration of axons, and improved the recovery of hindlimb locomotor function following SCI, suggesting that the transfer of exosome-mediated miRNAs represents a novel therapeutic approach for the treatment of SCI. PMID- 30524228 TI - Hypothalamic Microglial Activation in Obesity: A Mini-Review. AB - Emerging data demonstrate that microglia activation plays a pivotal role in the development of hypothalamic inflammation in obesity. Early after the introduction of a high-fat diet, hypothalamic microglia undergo morphological, and functional changes in response to excessive dietary saturated fats. Initially the resident microglia are affected; however, as diet-induced obesity persists, bone marrow derived myeloid cells gradually replace resident microglia. Genetic and pharmacological approaches aimed at dampening the inflammatory activity in the hypothalamus of experimental models of obesity have proven beneficial to correct the obese phenotype and improve metabolic abnormalities commonly associated with obesity. These approaches provide an experimental proof-of-concept that hypothalamic inflammation is central to the pathophysiology of obesity; understanding the details of the roles played by microglia in this process may help the development of preventive and therapeutic advances in the field. In this review, we discuss the potential mechanisms underlying hypothalamic microglial activation in high-fat induced obesity. PMID- 30524229 TI - Regulation of Adult Neurogenesis by Non-coding RNAs: Implications for Substance Use Disorders. AB - The discovery of non-coding RNAs (ncRNAs)has been one of the central findings from early genomic sequencing studies. Not only was the presence of these genes unknown previously, it was the staggering disproportionate share of the genome that was predicted to be encoded by ncRNAs that was truly significant in genomic research. Over the years the function of various classes of these ncRNAs has been revealed. One of the first and enduring regulatory programs associated with these factors was development. In the neurosciences, the discovery of adult derived populations of dividing cells within the brain was equally substantial. The brain was hypothesized to be plastic only in its neuronal connectivity, but the discovery of the generation of new neurons was a novel mechanism of neuronal and behavioral plasticity. The process of adult neurogenesis resembles early neuronal development and has been found to share many parallels in the proper stages of specified genetic programs. Adult neurogenesis has also been found to play a role in learning and memory involved in particular hippocampal-dependent behaviors. Substance use disorders (SUDs) are an example of a behavioral condition that is associated with and possibly driven by hippocampal alterations. Our laboratory has determined that hippocampal adult neurogenesis is necessary for a rodent model of methamphetamine relapse. Due to the previous research on ncRNAs in development and in other brain regions involved in SUDs, we posit that ncRNAs may play a role in adult neurogenesis associated with this disorder. This review will cover the regulatory mechanisms of various classes of ncRNAs on the coordinated genetic program associated with adult neurogenesis with a special focus on how these programs could be dysregulated in SUDs. PMID- 30524230 TI - Low Cost Interconnected Architecture for the Hardware Spiking Neural Networks. AB - A novel low cost interconnected architecture (LCIA) is proposed in this paper, which is an efficient solution for the neuron interconnections for the hardware spiking neural networks (SNNs). It is based on an all-to-all connection that takes each paired input and output nodes of multi-layer SNNs as the source and destination of connections. The aim is to maintain an efficient routing performance under low hardware overhead. A Networks-on-Chip (NoC) router is proposed as the fundamental component of the LCIA, where an effective scheduler is designed to address the traffic challenge due to irregular spikes. The router can find requests rapidly, make the arbitration decision promptly, and provide equal services to different network traffic requests. Experimental results show that the LCIA can manage the intercommunication of the multi-layer neural networks efficiently and have a low hardware overhead which can maintain the scalability of hardware SNNs. PMID- 30524231 TI - Simulation Study of Intermittent Axonal Block and Desynchronization Effect Induced by High-Frequency Stimulation of Electrical Pulses. AB - Deep brain stimulation (DBS) has been successfully used in treating neural disorders in brain, such as Parkinson's disease and epilepsy. However, the precise mechanisms of DBS remain unclear. Regular DBS therapy utilizes high frequency stimulation (HFS) of electrical pulses. Among all of neuronal elements, axons are mostly inclined to be activated by electrical pulses. Therefore, the response of axons may play an important role in DBS treatment. To study the axonal responses during HFS, we developed a computational model of myelinated axon to simulate sequences of action potentials generated in single and multiple axons (an axon bundle) by stimulations. The stimulations are applied extracellularly by a point source of current pulses with a frequency of 50-200 Hz. Additionally, our model takes into account the accumulation of potassium ions in the peri-axonal spaces. Results show that the increase of extracellular potassium generates intermittent depolarization block in the axons during HFS. Under the state of alternate block and recovery, axons fire action potentials at a rate far lower than the frequency of stimulation pulses. In addition, the degree of axonal block is highly related to the distance between the axons and the stimulation point. The differences in the degree of block for individual axons in a bundle result in desynchronized firing among the axons. Stimulations with higher frequency and/or greater intensity can induce axonal block faster and increase the desynchronization effect on axonal firing. Presumably, the desynchronized axonal activity induced by HFS could generate asynchronous activity in the population of target neurons downstream thereby suppressing over synchronized firing of neurons in pathological conditions. The desynchronization effect generated by intermittent activation of axons may be crucial for DBS therapy. The present study provides new insights into the mechanisms of DBS, which is significant for advancing the application of DBS. PMID- 30524232 TI - Shank and Zinc Mediate an AMPA Receptor Subunit Switch in Developing Neurons. AB - During development, pyramidal neurons undergo dynamic regulation of AMPA receptor (AMPAR) subunit composition and density to help drive synaptic plasticity and maturation. These normal developmental changes in AMPARs are particularly vulnerable to risk factors for Autism Spectrum Disorders (ASDs), which include loss or mutations of synaptic proteins and environmental insults, such as dietary zinc deficiency. Here, we show how Shank2 and Shank3 mediate a zinc-dependent regulation of AMPAR function and subunit switch from GluA2-lacking to GluA2 containing AMPARs. Over development, we found a concomitant increase in Shank2 and Shank3 with GluA2 at synapses, implicating these molecules as potential players in AMPAR maturation. Since Shank activation and function require zinc, we next studied whether neuronal activity regulated postsynaptic zinc at glutamatergic synapses. Zinc was found to increase transiently and reversibly with neuronal depolarization at synapses, which could affect Shank and AMPAR localization and activity. Elevated zinc induced multiple functional changes in AMPAR, indicative of a subunit switch. Specifically, zinc lengthened the decay time of AMPAR-mediated synaptic currents and reduced their inward rectification in young hippocampal neurons. Mechanistically, both Shank2 and Shank3 were necessary for the zinc-sensitive enhancement of AMPAR-mediated synaptic transmission and act in concert to promote removal of GluA1 while enhancing recruitment of GluA2 at pre-existing Shank puncta. These findings highlight a cooperative local dynamic regulation of AMPAR subunit switch controlled by zinc signaling through Shank2 and Shank3 to shape the biophysical properties of developing glutamatergic synapses. Given the zinc sensitivity of young neurons and its dependence on Shank2 and Shank3, genetic mutations and/or environmental insults during early development could impair synaptic maturation and circuit formation that underlie ASD etiology. PMID- 30524233 TI - Lithium Treatment Is Safe in Children With Intellectual Disability. AB - Lithium is a widely used and effective treatment for individuals with psycho neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo (n = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment (F = 11.03, p = 0.002 and F = 7.80, p = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group (F = 82.66, p < 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID. Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IPR 15007518. PMID- 30524234 TI - Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure. AB - Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL 0919 may be a powerful/effective antidepressant with fast-onset. PMID- 30524236 TI - Astrocyte Heterogeneity in the Adult Central Nervous System. AB - Astrocytes are the most abundant cell type in the central nervous system (CNS), providing critical roles in the overall maintenance and homeostasis. Over 100 years ago, Cajal first showed morphological depictions of different astrocyte populations. Surprisingly, to date astrocytes remain classified in two groups based on their morphological and neuroanatomical positioning. However, accumulating evidence over the past few years is showing that astrocytes are highly diverse throughout the CNS. Astrocyte heterogeneity is not surprisingly, as these cells interact with all other cells in the CNS. Like neurons, astrocytes may also have subpopulations that vary in their functionality. In this mini review, we will explore some of the recent evidence in the adult CNS of astrocyte diversity. First, we will review the very little literature on healthy adult astroglia heterogeneity, followed by the identification of different subpopulations in disease states and how this varies between human and mouse. Exploring this new area of neuroscience will hopefully provide researchers with a new perspective on astrocytes and their heterogeneity throughout the CNS. PMID- 30524235 TI - How Do Cells of the Oligodendrocyte Lineage Affect Neuronal Circuits to Influence Motor Function, Memory and Mood? AB - Oligodendrocyte progenitor cells (OPCs) are immature cells in the central nervous system (CNS) that can rapidly respond to changes within their environment by modulating their proliferation, motility and differentiation. OPCs differentiate into myelinating oligodendrocytes throughout life, and both cell types have been implicated in maintaining and modulating neuronal function to affect motor performance, cognition and emotional state. However, questions remain about the mechanisms employed by OPCs and oligodendrocytes to regulate circuit function, including whether OPCs can only influence circuits through their generation of new oligodendrocytes, or can play other regulatory roles within the CNS. In this review, we detail the molecular and cellular mechanisms that allow OPCs, newborn oligodendrocytes and pre-existing oligodendrocytes to regulate circuit function and ultimately influence behavioral outcomes. PMID- 30524237 TI - Soluble Fibrinogen Triggers Non-cell Autonomous ER Stress-Mediated Microglial Induced Neurotoxicity. AB - Aberrant or chronic microglial activation is strongly implicated in neurodegeneration, where prolonged induction of classical inflammatory pathways may lead to a compromised blood-brain barrier (BBB) or vasculature, features of many neurodegenerative disorders and implicated in the observed cognitive decline. BBB disruption or vascular disease may expose the brain parenchyma to "foreign" plasma proteins which subsequently impact on neuronal network integrity through neurotoxicity, synaptic loss and the potentiation of microglial inflammation. Here we show that the blood coagulation factor fibrinogen (FG), implicated in the pathogenesis of dementias such as Alzheimer's disease (AD), induces an inflammatory microglial phenotype as identified through genetic microarray analysis of a microglial cell line, and proteome cytokine profiling of primary microglia. We also identify a FG-mediated induction of non-cell autonomous ER stress-associated neurotoxicity via a signaling pathway that can be blocked by pharmacological inhibition of microglial TNFalpha transcription or neuronal caspase-12 activity, supporting a disease relevant role for plasma components in neuronal dysfunction. PMID- 30524238 TI - Spiking Pattern of the Mouse Developing Inner Hair Cells Is Mostly Invariant Along the Tonotopic Axis. AB - During development, the sensory cells of the cochlea, the inner hair cells (IHCs), fire spontaneous calcium action potentials. This activity at the pre hearing stage allows the IHCs to autonomously excite the auditory nerve fibers and hence, represents an efficient mechanism to shape the tonotopic organization along the ascending auditory pathway. Using calcium imaging, we show that the activity in the developing cochlea consists of calcium waves that propagate across the supporting and sensory cells. Both basal and apical IHCs were characterized by similar spontaneous calcium transients interspaced with silent periods, consistent with bursts of action potentials recorded in patch-clamp. In addition, adjacent auditory hair cells tend to have a synchronized [Ca2+]i activity, irrespective of their location along the base-to-apex gradient of the cochlea. Finally, we show that the mechanical ablation of the inner phalangeal cells (IPCs), a class of supporting cells, reduces the synchronized [Ca2+]i activity between neighboring sensory cells. These findings support the hypothesis that the tonotopic map refinement in higher auditory centers would depend on the synchronization of a discrete number of auditory sensory cells. PMID- 30524239 TI - Strategic Positioning of Connexin36 Gap Junctions Across Human Retinal Ganglion Cell Dendritic Arbors. AB - Connexin36 (Cx36) subunits form gap junctions (GJ) between neurons throughout the central nervous system. Such GJs of the mammalian retina serve the transmission, averaging and correlation of signals prior to conveying visual information to the brain. Retinal GJs have been exhaustively studied in various animal species, however, there is still a perplexing paucity of information regarding the presence and function of human retinal GJs. Particularly little is known about GJ formation of human retinal ganglion cells (hRGCs) due to the limited number of suitable experimental approaches. Compared to the neuronal coupling studies in animal models, where GJ permeable tracer injection is the gold standard method, the post-mortem nature of scarcely available human retinal samples leaves immunohistochemistry as a sole approach to obtain information on hRGC GJs. In this study Lucifer Yellow (LY) dye injections and Cx36 immunohistochemistry were performed in fixed short-post-mortem samples to stain hRGCs with complete dendritic arbors and locate dendritic Cx36 GJs. Subsequent neuronal reconstructions and morphometric analyses revealed that Cx36 plaques had a clear tendency to form clusters and particularly favored terminal dendritic segments. PMID- 30524240 TI - Molecular Pathology and Pharmacological Treatment of Autism Spectrum Disorder Like Phenotypes Using Rodent Models. AB - Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder with a high prevalence rate. The core symptoms of ASD patients are impaired social communication and repetitive behavior. Genetic and environmental factors contribute to pathophysiology of ASD. Regarding environmental risk factors, it is known that valproic acid (VPA) exposure during pregnancy increases the chance of ASD among offspring. Over a decade of animal model studies have shown that maternal treatment with VPA in rodents recapitulates ASD-like pathophysiology at a molecular, cellular and behavioral level. Here, we review the prevailing theories of ASD pathogenesis, including excitatory/inhibitory imbalance, neurotransmitter dysfunction, dysfunction of mTOR and endocannabinoid signaling pathways, neuroinflammation and epigenetic alterations that have been associated with ASD. We also describe the evidence linking neuropathological changes to ASD like behavioral abnormalities in maternal VPA-treated rodents. In addition to obtaining an understanding of the neuropathological mechanisms, the VPA-induced ASD-like animal models also serve as a good platform for testing pharmacological reagents that might be use treating ASD. We therefore have summarized the various pharmacological studies that have targeted the classical neurotransmitter systems, the endocannabinoids, the Wnt signal pathway and neuroinflammation. These approaches have been shown to often be able to ameliorate the ASD-like phenotypes induced by maternal VPA treatments. PMID- 30524241 TI - Inhibiting the NLRP3 Inflammasome With MCC950 Ameliorates Isoflurane-Induced Pyroptosis and Cognitive Impairment in Aged Mice. AB - Nod-like receptor protein 3 (NLRP3) inflammasome activation has been implicated in the pathogenesis of general anesthesia (GA)-induced neuroinflammation and cognitive impairment in aged rodents. However, the cellular basis for cognitive impairment is still not fully understood, and effective pharmacologic agents targeting the NLRP3 inflammasome during GA are lacking. This study explores the protective effects of the NLRP3 inflammasome inhibitor MCC950 on pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Seventy-two 15-month-old male C57BL/6 mice were randomized to receive 2 h of 1.5% isoflurane plus 30% oxygen (O2) or 30% O2 alone, respectively. MCC950 (10 mg/kg) or vehicle was intraperitoneally administered 30 min before gas inhalation. Brain tissues were harvested for histochemical analysis and biochemical assays. Learning and memory abilities were evaluated by behavioral tests. We found that isoflurane GA caused upregulations of hippocampal NLRP3, cleaved caspase-1, interleukin-1beta (IL 1beta), and IL-18 and the activation of pyroptosis, which is NLRP3 inflammasome dependent; this consequently gave rise to neuronal damage and cognitive impairment in aged mice. Interestingly, pretreatment with NLRP3 inflammasome inhibitor MCC950 not only provided a neuroprotective effect against the inflammasome activation but also ameliorated pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Our data demonstrate that pyroptosis is involved in NLRP3 inflammasome-mediated isoflurane-induced cognitive impairment in aged mice and suggest that inhibiting the NLRP3 inflammasome with MCC950 may have clinically therapeutic benefits for elderly patients undertaking GA. PMID- 30524242 TI - Sex- and Development-Dependent Responses of Rat Microglia to Pro- and Anti inflammatory Stimulation. AB - Addressing potential sex differences in pre-clinical studies is crucial for developing therapeutic interventions. Although sex differences have been reported in epidemiological studies and from clinical experience, most pre-clinical studies of neuroinflammation use male rodents; however, sexual dimorphisms in microglia might affect the CNS inflammatory response. Developmental changes are also important and, in rodents, there is a critical period of sexual brain differentiation in the first 3 weeks after birth. We compared rat microglia from sex-segregated neonates (P1) and at about the time of weaning (P21). To study transitions from a basal homeostatic state (untreated), microglia were subjected to a pro-inflammatory (IFNgamma + TNFalpha) or anti-inflammatory (IL-4) stimulus. Responses were compared by quantifying changes in nitric oxide production, migration, and expression of nearly 70 genes, including inflammatory mediators and receptors, inflammasome molecules, immune modulators, and genes that regulate microglial physiological functions. No sex differences were seen in transcriptional responses in either age group but the IL-4-evoked migration increase was larger in male cells at both ages. Protein changes for the hallmark molecules, NOS2, COX-2, PYK2 and CD206 correlated with mRNA changes. P1 and P21 microglia showed substantial differences, including expression of genes related to developmental roles. That is, P21 microglia had a more mature phenotype, with higher basal and stimulated levels of many inflammatory genes, while P1 cells had higher expression of phagocytosis-related molecules. Nevertheless, cells of both ages responded to IL-4 and IFNgamma + TNFalpha. We examined the Kv1.3 potassium channel (a potential target for modulating neuroinflammation) and the Kir2.1 channel, which regulate several microglia functions. Kv1.3 mRNA (Kcna3) was higher at P21 under all conditions and male P21 cells had higher mRNA and Kv currents in response to IFNgamma + TNFalpha. Overall, numerous transcriptional and functional responses of microglia changed during the first 3 weeks after birth but few sex-dependent changes were seen. PMID- 30524243 TI - Contribution of the Endosomal-Lysosomal and Proteasomal Systems in Amyloid-beta Precursor Protein Derived Fragments Processing. AB - Abeta peptides, the major components of Alzheimer's disease (AD) amyloid deposits, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have been reported to contribute to APP processing. However, the respective role of each of these pathways toward APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length wild type APP or the beta-secretase-derived C99 fragment (beta-CTF) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and Abeta peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by gamma-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 is mainly degraded by the proteasome and to a lesser extent by gamma-secretase. PMID- 30524244 TI - PDI Knockdown Inhibits Seizure Activity in Acute Seizure and Chronic Epilepsy Rat Models via S-Nitrosylation-Independent Thiolation on NMDA Receptor. AB - Redox modulation and S-nitrosylation of cysteine residues are the post translational modifications of N-methyl-D-aspartate receptor (NMDAR) to regulate its functionality. Recently, we have reported that protein disulfide isomerase (PDI) reduces disulfide bond (S-S) to free thiol (-SH) on NMDAR. Since PDI is a modulator of S-nitrosylation on various proteins, it is noteworthy whether PDI affects S-nitrosylation of NMDAR in acute seizure and chronic epilepsy models. In the present study, we found that acute seizures in response to pilocarpine and spontaneous seizures in chronic epilepsy rats led to the reduction in S nitrosylated thiol (SNO-thiol)-to-total thiol ratio on NMDAR, while they elevated nitric oxide (NO) level and S-nitrosylation on NMDAR. N-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor) did not affect seizure activities in both models, although it decreased SNO-thiol levels on NMDAR. However, PDI knockdown effectively inhibited pilocarpine-induced acute seizures and spontaneous seizures in chronic epilepsy rats, accompanied by increasing the SNO thiol-to-total thiol ratio on NMDAR due to diminishing the amounts of total thiols on GluN1 and GluN2A. Therefore, these findings indicate that PDI may not be a NO donor or a denitrosylase for NMDAR, and that PDI knockdown may inhibit seizure activity by the S-nitrosylation-independent thiolation on NMDAR. PMID- 30524245 TI - Mineralocorticoid Antagonist Improves Glucocorticoid Receptor Signaling and Dexamethasone Analgesia in an Animal Model of Low Back Pain. AB - Low back pain, a leading cause of disability, is commonly treated by epidural steroid injections that target the anti-inflammatory glucocorticoid receptor (GR). However, their efficacy has been controversial. All currently used epidural steroids also activate the pro-inflammatory mineralocorticoid receptor (MR) with significant potency. Local inflammation of the dorsal root ganglia (DRG), a rat model of low back pain, was used. This model causes static and dynamic mechanical allodynia, cold allodynia and guarding behavior (a measure of spontaneous pain), and activates the MR, with pro-nociceptive effects. In this study, effects of local Dexamethasone (DEX; a glucocorticoid used in epidural injections), and eplerenone (EPL; a second generation, more selective MR antagonist) applied to the DRG at the time of inflammation were examined. Mechanical and spontaneous pain behaviors were more effectively reduced by the combination of DEX and EPL than by either alone. The combination of steroids was particularly more effective than DEX alone or the model alone (3-fold improvement for mechanical allodynia) at later times (day 14). Immunohistochemical analysis of the GR in the DRG showed that the receptor was expressed in neurons of all size classes, and in non neuronal cells including satellite glia. The GR immunoreactivity was downregulated by DRG inflammation (48%) starting on day 1, consistent with the reduction of GR (57%) observed by Western blot, when compared to control animals. On day 14, the combination of DEX and EPL resulted in rescue of GR immunoreactivity that was not seen with DEX alone, and was more effective in reducing a marker for satellite glia activation/neuroinflammation. The results suggest that EPL may enhance the effectiveness of clinically used epidural steroid injections, in part by enhancing the availability of the GR. Thus, the glucocorticoid-mineralocorticoid interactions may limit the effectiveness of epidural steroids through the regulation of the GR in the DRG. PMID- 30524247 TI - Vestibular System and Self-Motion. AB - Detection of the state of self-motion, such as the instantaneous heading direction, the traveled trajectory and traveled distance or time, is critical for efficient spatial navigation. Numerous psychophysical studies have indicated that the vestibular system, originating from the otolith and semicircular canals in our inner ears, provides robust signals for different aspects of self-motion perception. In addition, vestibular signals interact with other sensory signals such as visual optic flow to facilitate natural navigation. These behavioral results are consistent with recent findings in neurophysiological studies. In particular, vestibular activity in response to the translation or rotation of the head/body in darkness is revealed in a growing number of cortical regions, many of which are also sensitive to visual motion stimuli. The temporal dynamics of the vestibular activity in the central nervous system can vary widely, ranging from acceleration-dominant to velocity-dominant. Different temporal dynamic signals may be decoded by higher level areas for different functions. For example, the acceleration signals during the translation of body in the horizontal plane may be used by the brain to estimate the heading directions. Although translation and rotation signals arise from independent peripheral organs, that is, otolith and canals, respectively, they frequently converge onto single neurons in the central nervous system including both the brainstem and the cerebral cortex. The convergent neurons typically exhibit stronger responses during a combined curved motion trajectory which may serve as the neural correlate for complex path perception. During spatial navigation, traveled distance or time may be encoded by different population of neurons in multiple regions including hippocampal-entorhinal system, posterior parietal cortex, or frontal cortex. PMID- 30524246 TI - Expression of DCX and Transcription Factor Profiling in Photothrombosis-Induced Focal Ischemia in Mice. AB - Adult neurogenesis is present in the dentate gyrus and the subventricular zone in mammalian brain under physiological conditions. Recently, adult neurogenesis has also been reported in other brain regions after brain injury. In this study, we established a focal striatal ischemic model in adult mice via photothrombosis (PT) and investigated how focal ischemia elicits neurogenesis in the striatum. We found that astrocytes and microglia increased in early post-ischemic stage, followed by a 1-week late-onset of doublecortin (DCX) expression in the striatum. The number of DCX-positive neurons reached the peak level at day 7, but they were still observed at day 28 post-ischemia. Moreover, Rbp-J (a key effector of Notch signaling) deletion in astrocytes has been reported to promote the neuron regeneration after brain ischemia, and we provided the change of gene expression profile in the striatum of astrocyte-specific Rbp-J knockout (KO) mice glial fibrillary acidic protein (GFAP-CreER:Rbp-Jfl/fl), which may help to clarify detailed potential mechanisms for the post-ischemic neurogenesis in the striatum. PMID- 30524248 TI - A Pipeline for Volume Electron Microscopy of the Caenorhabditis elegans Nervous System. AB - The "connectome," a comprehensive wiring diagram of synaptic connectivity, is achieved through volume electron microscopy (vEM) analysis of an entire nervous system and all associated non-neuronal tissues. White et al. (1986) pioneered the fully manual reconstruction of a connectome using Caenorhabditis elegans. Recent advances in vEM allow mapping new C. elegans connectomes with increased throughput, and reduced subjectivity. Current vEM studies aim to not only fill the remaining gaps in the original connectome, but also address fundamental questions including how the connectome changes during development, the nature of individuality, sexual dimorphism, and how genetic and environmental factors regulate connectivity. Here we describe our current vEM pipeline and projected improvements for the study of the C. elegans nervous system and beyond. PMID- 30524249 TI - A Descending Circuit Derived From the Superior Colliculus Modulates Vibrissal Movements. AB - The superior colliculus (SC) is an essential structure for the control of eye movements. In rodents, the SC is also considered to play an important role in whisking behavior, in which animals actively move their vibrissae (mechanosensors) to gather tactile information about the space around them during exploration. We investigated how the SC contributes to vibrissal movement control. We found that when the SC was unilaterally lesioned, the resting position of the vibrissae shifted backward on the side contralateral to the lesion. The unilateral SC lesion also induced an increase in the whisking amplitude on the contralateral side. To explore the anatomical basis for SC involvement in vibrissal movement control, we then quantitatively evaluated axonal projections from the SC to the brainstem using neuronal labeling with a virus vector. Neurons of the SC mainly sent axons to the contralateral side in the lower brainstem. We found that the facial nucleus received input directly from the SC, and that the descending projections from the SC also reached the intermediate reticular formation and pre-Botzinger complex, which are both considered to contain neural oscillators generating rhythmic movements of the vibrissae. Together, these results indicate the existence of a neural circuit in which the SC modulates vibrissal movements mainly on the contralateral side, via direct connections to motoneurons, and via indirect connections including the central pattern generators. PMID- 30524250 TI - Toward Identifying the Systems-Level Primitives of Cortex by In-Circuit Testing. PMID- 30524251 TI - Deficits in Behavioral Functions of Intact Barrel Cortex Following Lesions of Homotopic Contralateral Cortex. AB - Focal unilateral injuries to the somatosensory whisker barrel cortex have been shown cause long-lasting deficits in the activity and experience-dependent plasticity of neurons in the intact contralateral barrel cortex. However, the long-term effect of these deficits on behavioral functions of the intact contralesional cortex is not clear. In this study, we used the "Gap-crossing task" a barrel cortex-dependent, whisker-sensitive, tactile behavior to test the hypothesis that unilateral lesions of the somatosensory cortex would affect behavioral functions of the intact somatosensory cortex and degrade the execution of a bilaterally learnt behavior. Adult rats were trained to perform the Gap crossing task using whiskers on both sides of the face. The barrel cortex was then lesioned unilaterally by subpial aspiration. As observed in other studies, when rats used whiskers that directly projected to the lesioned hemisphere the performance of Gap-crossing was drastically compromised, perhaps due to direct effect of lesion. Significant and persistent deficits were present when the lesioned rats performed Gap-crossing task using whiskers that projected to the intact cortex. The deficits were specific to performance of the task at the highest levels of sensitivity. Comparable deficits were seen when normal, bilaterally trained, rats performed the Gap-crossing task with only the whiskers on one side of the face or when they used only two rows of whiskers (D row and E row) intact on both side of the face. These findings indicate that the prolonged impairment in execution of the learnt task by rats with unilateral lesions of somatosensory cortex could be because sensory inputs from one set of whiskers to the intact cortex is insufficient to provide adequate sensory information at higher thresholds of detection. Our data suggest that optimal performance of somatosensory behavior requires dynamic activity-driven interhemispheric interactions from the entire somatosensory inputs between homotopic areas of the cerebral cortex. These results imply that focal unilateral cortical injuries, including those in humans, are likely to have widespread bilateral effects on information processing including in intact areas of the cortex. PMID- 30524252 TI - Sexually-Relevant Visual and Chemosensory Signals Induce Distinct Behaviors and Neural Activation Patterns in the Social African Cichlid, Astatotilapia burtoni. AB - Across vertebrates, the use of multimodal (multiple sensory modalities) signals has evolved to convey important information to receivers. Information content of multimodal signals can be the same as or different from information in each unimodal signal, and are classified as redundant or non-redundant, respectively, based on receivers' behavioral responses. Despite the prevalence and importance of multimodal signaling across taxa, relatively little is known about how and where these signals are processed in the brains of receivers. We used the social African cichlid fish, Astatotilapia burtoni, to investigate how sexually-relevant visual and chemosensory uni- and multimodal signals from gravid (full of eggs) females influence behavior, brain activation patterns, and physiology in dominant males. We presented both visual and chemosensory signals either alone or together and found that males need sexually-relevant visual signals to engage in stereotypical courtship behaviors such as body quivers, waggles, and leads into spawning territories. However, the number of courtship behaviors was greater when males were exposed to multimodal visual-chemosensory signals, compared to either unimodal signal alone. When a female visual signal was absent, males increased swimming and overall activity in response to female-conditioned water compared to control water, suggesting that female-released chemosensory signals may stimulate male searching behavior and motivation. Importantly, we also tested anosmic (olfactory ablated) males to demonstrate that this behavior is primarily mediated by the olfactory system rather than gustation. Using the immediate early gene cfos as a proxy for neural activation, we also demonstrate differential activation in social and olfactory-relevant brain regions of dominant males exposed to unimodal and multimodal visual-chemosensory signals. We found at least one region that is preferentially activated by reception of signals from each sense, as well as regions that exhibit an additive effect on activation with multimodal visual-chemosensory stimulation. These data provide insight on how multimodal signals are processed in the brain and integrated with internal physiology of receivers to produce social behaviors, and lay the groundwork for future studies on the evolution of sensory perception. PMID- 30524253 TI - Neural Basis of Action Observation and Understanding From First- and Third-Person Perspectives: An fMRI Study. AB - Understanding the intentions of others while observing their actions is a fundamental aspect of social behavior. However, the differences in neural and functional mechanisms between observing actions from the first-person perspective (1PP) and third-person perspective (3PP) are poorly understood. The present study had two aims: (1) to delineate the neural basis of action observation and understanding from the 1PP and 3PP; and (2) to identify whether there are different activation patterns during action observation and understanding from 1PP and 3PP. We used a blocked functional magnetic resonance imaging (fMRI) experimental design. Twenty-six right-handed participants observed interactions between the right hand and a cup from 1PP and 3PP. The results indicated that both 1PP and 3PP were associated with similar patterns of activation in key areas of the mirror neuron system underlying action observation and understanding. Importantly, besides of the core network of mirror neuron system, we also found that parts of the basal ganglia and limbic system were involved in action observation in both the 1PP and 3PP tasks, including the putamen, insula and hippocampus, providing a more complete understanding of the neural basis for action observation and understanding. Moreover, compared with the 3PP, the 1PP task caused more extensive and stronger activation. In contrast, the opposite comparison revealed that no regions exhibited significantly more activation in the 3PP compared with the 1PP condition. The current results have important implications for understanding the role of the core network underlying the mirror neuron system, as well as parts of the basal ganglia and limbic system, during action observation and understanding. PMID- 30524254 TI - Modulation of Fear and Arousal Behavior by Serotonin Transporter (5-HTT) Genotypes in Newly Hatched Chickens. AB - The serotonin transporter (5-HTT) plays a key role in regulating serotonergic transmission via removal of serotonin (5-hydroxytryptamine, 5-HT) from synaptic clefts. Alterations in 5-HTT expression and 5-HT transmission have been shown to cause changes to adult behavior including fear. The objective of the present study was to investigate the 5-HTT role in fear in birds at the very early stages of post-hatching life. Using an avoidance test with an elevated balance beam, which was based on depth perception and the respective fear of heights, we assessed fear-related avoidance behaviors of newly hatched chicks of the three functional 5-HTT genotypes W/W, W/D and D/D. Newly hatched chicks of the genotype D/D, which was linked to high 5-HTT expression, showed less intensive avoidance responses as measured by decreased latency to jump than W/W and W/D chicks. Further, significantly fewer D/D hens than W/W hens showed fear-like behavior that resembled a freezing response. Furthermore, in an arousal test the arousal reaction of the chicks in response to an acute short-term visual social deprivation in the home compartment was assessed 5 weeks after hatching, which also revealed that D/D chicks exhibited decreased arousal reaction, compared to W/W chicks. Thus, the results indicate that fear responses differ in D/D chicks in the early post-hatching periods, possibly due to the different expression of 5 HTT respectively 5-HT levels in this strain. PMID- 30524255 TI - Synaptic Connectivity in Medium Spiny Neurons of the Nucleus Accumbens: A Sex Dependent Mechanism Underlying Apathy in the HIV-1 Transgenic Rat. AB - Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV 1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies. PMID- 30524256 TI - Effect of Neuromuscular Electrical Stimulation Training on the Finger Extensor Muscles for the Contralateral Corticospinal Tract in Normal Subjects: A Diffusion Tensor Tractography Study. AB - Objectives: Neuromuscular electrical stimulation (NMES) is a popular rehabilitative modality to improve motor function of the extremities and trunk. In this study, we investigated changes of hand function and the contralateral corticospinal tract (CST) with treatment by NMES on the finger extensor muscles for 2 weeks, using serial diffusion tensor tractography (DTT). Methods: Thirteen right handed normal subjects were recruited. Treatment was applied to the left hand (the NMES side), and the right hand was the control side. NMES was applied for 30 min/day, 7 days per week, for 2 weeks. Hand motor function was evaluated twice at pre-NMES and post-NMES training using grip strength (GS), Purdue pegboard test (PPT) and tip pinch. The fractional anisotropy (FA), mean diffusivity (MD) and tract volume (TV) of the CST in both hemispheres were measured using DTT. Results: On the control side, the clinical scores did not differ significantly between pre- and post-NMES training (p > 0.05). However, on the NMES side, PPT and tip pinch improved significantly (p < 0.05), although GS did not. TV of the right CST increased significantly at post-NMES training (p < 0.05) whereas FA and MD did not differ significantly (p > 0.05). By contrast, FA, MD and TV on the left CST did not change significantly (p > 0.05). Conclusion: We demonstrated facilitation of the contralateral CST with improvement of fine motor activity by 2 weeks of NMES training of peripheral muscles in normal subjects. We think our results can be applied to the normal subjects and patients with brain injury to improve the fine motor function of the hand and facilitate the normal CST or healing of the injured CST. PMID- 30524257 TI - Artificial Immune System-Negative Selection Classification Algorithm (NSCA) for Four Class Electroencephalogram (EEG) Signals. AB - Artificial immune systems (AIS) are intelligent algorithms derived from the principles inspired by the human immune system. In this study, electroencephalography (EEG) signals for four distinct motor movements of human limbs are detected and classified using a negative selection classification algorithm (NSCA). For this study, a widely studied open source EEG signal database (BCI IV-Graz dataset 2a, comprising nine subjects) has been used. Mel frequency cepstral coefficients (MFCCs) are extracted as selected features from recorded EEG signals. Dimensionality reduction of data is carried out by applying two hidden layered stacked auto-encoder. Genetic algorithm (GA) optimized detectors (artificial lymphocytes) are trained using negative selection algorithm (NSA) for detection and classification of four motor movements. The trained detectors consist of four sets of detectors, each set is trained for detection and classification of one of the four movements from the other three movements. The optimized radius of detector is small enough not to mis-detect the sample. Euclidean distance of each detector with every training dataset sample is taken and compared with the optimized radius of the detector as a nonself detector. Our proposed approach achieved a mean classification accuracy of 86.39% for limb movements over nine subjects with a maximum individual subject classification accuracy of 97.5% for subject number eight. PMID- 30524258 TI - Watch, Imagine, Attempt: Motor Cortex Single-Unit Activity Reveals Context Dependent Movement Encoding in Humans With Tetraplegia. AB - Planning and performing volitional movement engages widespread networks in the human brain, with motor cortex considered critical to the performance of skilled limb actions. Motor cortex is also engaged when actions are observed or imagined, but the manner in which ensembles of neurons represent these volitional states (VoSs) is unknown. Here we provide direct demonstration that observing, imagining or attempting action activates shared neural ensembles in human motor cortex. Two individuals with tetraplegia (due to brainstem stroke or amyotrophic lateral sclerosis, ALS) were verbally instructed to watch, imagine, or attempt reaching actions displayed on a computer screen. Neural activity in the precentral gyrus incorporated information about both cognitive state and movement kinematics; the three conditions presented overlapping but unique, statistically distinct activity patterns. These findings demonstrate that individual neurons in human motor cortex reflect information related to sensory inputs and VoS in addition to movement features, and are a key part of a broader network linking perception and cognition to action. PMID- 30524259 TI - Constraints of Metabolic Energy on the Number of Synaptic Connections of Neurons and the Density of Neuronal Networks. AB - Neuronal networks in the brain are the structural basis of human cognitive function, and the plasticity of neuronal networks is thought to be the principal neural mechanism underlying learning and memory. Dominated by the Hebbian theory, researchers have devoted extensive effort to studying the changes in synaptic connections between neurons. However, understanding the network topology of all synaptic connections has been neglected over the past decades. Furthermore, increasing studies indicate that synaptic activities are tightly coupled with metabolic energy, and metabolic energy is a unifying principle governing neuronal activities. Therefore, the network topology of all synaptic connections may also be governed by metabolic energy. Here, by implementing a computational model, we investigate the general synaptic organization rules for neurons and neuronal networks from the perspective of energy metabolism. We find that to maintain the energy balance of individual neurons in the proposed model, the number of synaptic connections is inversely proportional to the average of the synaptic weights. This strategy may be adopted by neurons to ensure that the ability of neurons to transmit signals matches their own energy metabolism. In addition, we find that the density of neuronal networks is also an important factor in the energy balance of neuronal networks. An abnormal increase or decrease in the network density could lead to failure of energy metabolism in the neuronal network. These rules may change our view of neuronal networks in the brain and have guiding significance for the design of neuronal network models. PMID- 30524260 TI - Analog Signaling With the "Digital" Molecular Switch CaMKII. AB - Molecular switches, such as the protein kinase CaMKII, play a fundamental role in cell signaling by decoding inputs into either high or low states of activity; because the high activation state can be turned on and persist after the input ceases, these switches have earned a reputation as "digital." Although this on/off, binary perspective has been valuable for understanding long timescale synaptic plasticity, accumulating experimental evidence suggests that the CaMKII switch can also control plasticity on short timescales. To investigate this idea further, a non-autonomous, nonlinear ordinary differential equation, representative of a general bistable molecular switch, is analyzed. The results suggest that switch activity in regions surrounding either the high- or low stable states of activation could act as a reliable analog signal, whose short timescale fluctuations relative to equilibrium track instantaneous input frequency. The model makes intriguing predictions and is validated against previous work demonstrating its suitability as a minimal representation of switch dynamics; in combination with existing experimental evidence, the theory suggests a multiplexed encoding of instantaneous frequency information over short timescales, with integration of total activity over longer timescales. PMID- 30524261 TI - Spiking Neurons Integrating Visual Stimuli Orientation and Direction Selectivity in a Robotic Context. AB - Visual motion detection is essential for the survival of many species. The phenomenon includes several spatial properties, not fully understood at the level of a neural circuit. This paper proposes a computational model of a visual motion detector that integrates direction and orientation selectivity features. A recent experiment in the Drosophila model highlights that stimulus orientation influences the neural response of direction cells. However, this interaction and the significance at the behavioral level are currently unknown. As such, another objective of this article is to study the effect of merging these two visual processes when contextualized in a neuro-robotic model and an operant conditioning procedure. In this work, the learning task was solved using an artificial spiking neural network, acting as the brain controller for virtual and physical robots, showing a behavior modulation from the integration of both visual processes. PMID- 30524262 TI - Heterogeneous Signaling at GABA and Glycine Co-releasing Terminals. AB - The corelease of several neurotransmitters from a single synaptic vesicle has been observed at many central synapses. Nevertheless, the signaling synergy offered by cotransmission and the mechanisms that maintain the optimal release and detection of neurotransmitters at mixed synapses remain poorly understood, thus limiting our ability to interpret changes in synaptic signaling and identify molecules important for plasticity. In the brainstem and spinal cord, GABA and glycine cotransmission is facilitated by a shared vesicular transporter VIAAT (also named VGAT), and occurs at many immature inhibitory synapses. As sensory and motor networks mature, GABA/glycine cotransmission is generally replaced by either pure glycinergic or GABAergic transmission, and the functional role for the continued corelease of GABA and glycine is unclear. Whether or not, and how, the GABA/glycine content is balanced in VIAAT-expressing vesicles from the same terminal, and how loading variability effects the strength of inhibitory transmission is not known. Here, we use a combination of loose-patch (LP) and whole-cell (WC) electrophysiology in cultured spinal neurons of GlyT2:eGFP mice to sample miniature inhibitory post synaptic currents (mIPSCs) that originate from individual GABA/glycine co-releasing synapses and develop a modeling approach to illustrate the gradual change in mIPSC phenotypes as glycine replaces GABA in vesicles. As a consistent GABA/glycine balance is predicted if VIAAT has access to both amino-acids, we test whether vesicle exocytosis from a single terminal evokes a homogeneous population of mixed mIPSCs. We recorded mIPSCs from 18 individual synapses and detected glycine-only mIPSCs in 4/18 synapses sampled. The rest (14/18) were co-releasing synapses that had a significant proportion of mixed GABA/glycine mIPSCs with a characteristic biphasic decay. The majority (9/14) of co-releasing synapses did not have a homogenous phenotype, but instead signaled with a combination of mixed and pure mIPSCs, suggesting that there is variability in the loading and/or storage of GABA and glycine at the level of individual vesicles. Our modeling predicts that when glycine replaces GABA in synaptic vesicles, the redistribution between the peak amplitude and charge transfer of mIPSCs acts to maintain the strength of inhibition while increasing the temporal precision of signaling. PMID- 30524264 TI - Enhancement of Visuospatial Working Memory by the Differential Outcomes Procedure in Mild Cognitive Impairment and Alzheimer's Disease. AB - In the present study we investigated the efficacy of the differential outcomes procedure (DOP) to improve visuospatial working memory in patients with Alzheimer's disease and mild cognitive impairment (MCI). The DOP associates correct responses to the to-be-remember stimulus with unique outcomes. Eleven patients diagnosed with Alzheimer's disease, 11 participants with MCI, and 17 healthy matched controls performed a spatial delayed memory task under the DOP and a control condition (non-differential outcomes -NOP-). We found that performance (terminal accuracy) was significantly better in the DOP condition relative to the NOP condition in all three groups of participants. AD patients performed worse, and took longer to benefit from the DOP. In line with previous animal and human research, we propose that the DOP activates brain structures and cognitive mechanisms that are less affected by healthy and pathological aging, optimizing in this way the function of the cognitive system. PMID- 30524263 TI - The Role of Calcium-Permeable AMPARs in Long-Term Potentiation at Principal Neurons in the Rodent Hippocampus. AB - Long-term potentiation (LTP) at hippocampal CA1 synapses is classically triggered by the synaptic activation of NMDA receptors (NMDARs). More recently, it has been shown that calcium-permeable (CP) AMPA receptors (AMPARs) can also trigger synaptic plasticity at these synapses. Here, we review this literature with a focus on recent evidence that CP-AMPARs are critical for the induction of the protein kinase A (PKA)- and protein synthesis-dependent component of LTP. PMID- 30524265 TI - New Perspectives on Roles of Alpha-Synuclein in Parkinson's Disease. AB - Parkinson's disease (PD) is one of the synucleinopathies spectrum of disorders typified by the presence of intraneuronal protein inclusions. It is primarily composed of misfolded and aggregated forms of alpha-synuclein (alpha-syn), the toxicity of which has been attributed to the transition from an alpha-helical conformation to a beta-sheetrich structure that polymerizes to form toxic oligomers. This could spread and initiate the formation of "LB-like aggregates," by transcellular mechanisms with seeding and subsequent permissive templating. This hypothesis postulates that alpha-syn is a prion-like pathological agent and responsible for the progression of Parkinson's pathology. Moreover, the involvement of the inflammatory response in PD pathogenesis has been reported on the excessive microglial activation and production of pro-inflammatory cytokines. At last, we describe several treatment approaches that target the pathogenic alpha-syn protein, especially the oligomers, which are currently being tested in advanced animal experiments or are already in clinical trials. However, there are current challenges with therapies that target alpha-syn, for example, difficulties in identifying varying alpha-syn conformations within different individuals as well as both the cost and need of long-duration large trials. PMID- 30524266 TI - Targeted Mutation (R100W) of the Gene Encoding NGF Leads to Deficits in the Peripheral Sensory Nervous System. AB - Nerve growth factor (NGF) exerts multifaceted functions through different stages of life. A missense mutation (R100W) in the beta-NGF gene was found in hereditary sensory autonomic neuropathy V (HSAN V) patients with severe loss of pain perception but without overt cognitive impairment. To better understand the pathogenesis of HSAN V, we generated the first NGFR100W knock in mouse model for HSAN V. We found that the homozygotes exhibited a postnatal lethal phenotype. A majority of homozygous pups died within the first week. Some homozygous pups could ingest more milk and survived up to 2 months by reducing litter size. Whole mount in situ hybridization using E10.5 embryos revealed that, compared to wild type, R100W mutation did not alter the gene expression patterns of TrkA and P75NTR in the homozygotes. We also found that the homozygotes displayed normal embryonic development of major organs (heart, lung, liver, kidney, and spleen). Furthermore, the homozygotes exhibited severe loss of PGP9.5-positive intra epidermal sensory fibers. Taken together, our results suggest that, as with HSAN V patients, the R100W mutation primarily affects the peripheral sensory nervous system in the mouse model. This novel mouse model makes it possible to further study in vivo how NGFR100W uncouple trophic function from nociception of NGF. PMID- 30524267 TI - Poor Sleep Quality Associates With Decreased Functional and Structural Brain Connectivity in Normative Aging: A MRI Multimodal Approach. AB - Sleep is a ubiquitous phenomenon, essential to the organism homeostasis. Notwithstanding, there has been an increasing concern with its disruption, not only within the context of pathological conditions, such as neurologic and psychiatric diseases, but also in health. In fact, sleep complaints are becoming particularly common, especially in middle-aged and older adults, which may suggest an underlying susceptibility to sleep quality loss and/or its consequences. Thus, a whole-brain modeling approach to study the shifts in the system can cast broader light on sleep quality mechanisms and its associated morbidities. Following this line, we sought to determine the association between the standard self-reported measure of sleep quality, the Pittsburgh Sleep Quality Index (PSQI) and brain correlates in a normative aging cohort. To this purpose, 86 participants (age range 52-87 years) provided information regarding sociodemographic parameters, subjective sleep quality and associated psychological variables. A multimodal magnetic resonance imaging (MRI) approach was used, with whole-brain functional and structural connectomes being derived from resting-state functional connectivity (FC) and probabilistic white matter tractography (structural connectivity, SC). Brain regional volumes and white matter properties associations were also explored. Results show that poor sleep quality was associated with a decrease in FC and SC of distinct networks, overlapping in right superior temporal pole, left middle temporal and left inferior occipital regions. Age displayed important associations with volumetric changes in the cerebellum cortex and white matter, thalamus, hippocampus, right putamen, left supramarginal and left lingual regions. Overall, results suggest that not only the PSQI global score may act as a proxy of changes in FC/SC in middle-aged and older individuals, but also that the age-related regional volumetric changes may be associated to an adjustment of brain connectivity. These findings may also represent a step further in the comprehension of the role of sleep disturbance in disease, since the networks found share regions that have been shown to be affected in pathologies, such as depression and Alzheimer's disease. PMID- 30524268 TI - A Novel hAPP/htau Mouse Model of Alzheimer's Disease: Inclusion of APP With Tau Exacerbates Behavioral Deficits and Zinc Administration Heightens Tangle Pathology. AB - The brains of those with Alzheimer's disease have amyloid and tau pathology; thus, mice modeling AD should have both markers. In this study, we characterize offspring from the cross of the J20 (hAPP) and rTg4510 (htau) strains (referred to as dual Tg). Behavior was assessed at both 3.5 and 7 months, and biochemical differences were assessed at 8 months. Additionally, mice were placed on zinc (Zn) water or standard lab water in order to determine the role of this essential biometal. Behavioral measures examined cognition, emotion, and aspects of daily living. Transgenic mice (dual Tg and htau) showed significant deficits in spatial memory in the Barnes Maze at both 3.5 and 7 months compared to controls. At 7 months, dual Tg mice performed significantly worse than htau mice (p < 0.01). Open field and elevated zero maze (EZM) data indicated that dual Tg and htau mice displayed behavioral disinhibition compared to control mice at both 3.5 and 7 months (p < 0.001). Transgenic mice showed significant deficits in activities of daily living, including burrowing and nesting, at both 3.5 and 7 months compared to control mice (p < 0.01). Dual Tg mice built very poor nests, indicating that non-cognitive tasks are also impacted by AD. Overall, dual Tg mice demonstrated behavioral deficits earlier than those shown by the htau mice. In the brain, dual Tg mice had significantly less free Zn compared to control mice in both the dentate gyrus and the CA3 of the hippocampus (p < 0.01). Dual Tg mice had increased tangles and plaques in the hippocampus compared to htau mice and the dual Tg mice given Zn water displayed increased tangle pathology in the hippocampus compared to htau mice on Zn water (p < 0.05). The dual Tg mouse described here displays pathology reminiscent of the human AD condition and is impaired early on in both cognitive and non-cognitive behaviors. This new mouse model allows researchers to assess how both amyloid and tau in combination impact behavior and brain pathology. PMID- 30524270 TI - Quantifying Dynamic Balance in Young, Elderly and Parkinson's Individuals: A Systematic Review. AB - Introduction: Falling is one of the primary concerns for people with Parkinson's Disease and occurs predominately during dynamic movements, such as walking. Several methods have been proposed to quantify dynamic balance and to assess fall risk. However, no consensus has been reached concerning which method is most appropriate for examining walking balance during unperturbed and perturbed conditions, particularly in Parkinson's Disease individuals. Therefore, this systematic review aimed to assess the current literature on quantifying dynamic balance in healthy young, elderly and Parkinson's individuals during unperturbed and perturbed walking. Methods: The PubMed database was searched by title and abstract for publications quantifying dynamic balance during unperturbed and mechanically perturbed walking conditions in elderly adults and PD. Inclusion criteria required publications to be published in English, be available in full text, and implement a dynamic balance quantification method. Exclusion criteria included clinical dynamic balance measures, non-mechanical perturbations, pathologies other than PD, and dual-tasking conditions. The initial database search yielded 280 articles, however, only 81 articles were included after title, abstract and full-text screening. Methodological quality and data were extracted from publications included in the final synthesis. Results: The dynamic balance articles included 26 Coefficient of Variation of Spatiotemporal Variability, 10 Detrended Fluctuation Analysis, 20 Lyapunov Exponent, 7 Maximum Floquet Multipliers, 17 Extrapolated Center of Mass, 11 Harmonic Ratios, 4 Center of Mass Center of Pressure Separation, 2 Gait Stability Ratio, 1 Entropy, 3 Spatiotemporal Variables, 2 Center of Gravity and Center of Pressure, and 2 Root Mean Square in the final synthesis. Assessment of methodological quality determined that 58 articles had a low methodological rating, a 22 moderate rating, and 1 having a high rating. Conclusion: Careful consideration must be given when selecting a method to quantify dynamic balance because each method defines balance differently, reflects a unique aspect of neuromuscular stability mechanisms, and is dependent on the walking condition (unperturbed vs. perturbed). Therefore, each method provides distinct information into stability impairment in elderly and PD individuals. PMID- 30524269 TI - Levels of Cortisol in CSF Are Associated With SNAP-25 and Tau Pathology but Not Amyloid-beta. AB - Objective: Preclinical studies have found both hyperactivity of hypothalamic- pituitary- adrenal (HPA) axis and synaptic degeneration are involved in the pathogenesis of Alzheimer's disease (AD). However, the data on the relationship of activity of HPA axis and synaptic degeneration in humans are limited. Methods: We compared CSF cortisol levels in 310 subjects, including 92 cognitively normal older people, 149 patients with mild cognitive impairment (MCI), and 69 patients with mild AD. Several linear and logistic regression models were conducted to investigate associations between CSF cortisol and synaptosomal-associated protein 25 (SNAP-25, reflecting synaptic degeneration) and other AD-related biomarkers. Results: We found that levels of cortisol in CSF were associated with SNAP-25 levels and tau pathologies but not amyloid-beta protein. However, there were no significant differences in CSF cortisol levels among the three diagnostic groups. Conclusion: The HPA axis may play a crucial role in synaptic degeneration in AD pathogenesis. PMID- 30524271 TI - Cannabinoid Receptor 2 Signalling Bias Elicited by 2,4,6-Trisubstituted 1,3,5 Triazines. AB - Cannabinoid receptor 2 (CB2) is predominantly distributed in immune tissues and cells and is a promising therapeutic target for modulating inflammation. In this study we designed and synthesised a series of 2,4,6-trisubstituted 1,3,5 triazines with piperazinylalkyl or 1,2-diethoxyethane (PEG2) chains as CB2 agonists, all of which were predicted to be considerably more polar than typical cannabinoid ligands. In this series, we found that triazines containing an adamantanyl group were conducive to CB2 binding whereas those with a cyclopentyl group were not. Although the covalent attachment of a PEG2 linker to the adamantyl triazines resulted in a decrease in binding affinity, some of the ligands produced very interesting hCB2 signalling profiles. Six compounds with notable hCB2 orthosteric binding were functionally characterised in three pathways; internalisation, cyclic adenosine monophosphate (cAMP) and ERK phosphorylation (pERK). These were predominantly confirmed to be hCB2 agonists, and upon comparison to a reference ligand (CP 55,940), four compounds exhibited signalling bias. Triazines 14 (UOSD017) and 15 were biased towards internalisation over cAMP and pERK, and 7 was biased away from pERK activation relative to cAMP and internalisation. Intriguingly, the triazine with an amino PEG2-piperazinyl linker (13 [UOSD008]) was identified to be a mixed agonist/inverse agonist, exhibiting apparent neutral antagonism in the internalisation pathway, transient inverse agonism in the cAMP pathway and weak partial agonism in the pERK pathway. Both the cAMP and pERK signalling were pertussis toxin (PTX) sensitive, implying that 13 is acting as both a weak agonist and inverse agonist at CB2 via Galphai/o. Compound 10 (UOSD015) acted as a balanced high intrinsic efficacy agonist with the potential to produce greater hCB2-mediated efficacy than reference ligand CP 55,940. As 10 includes a Boc protected PEG2 moiety it is also a promising candidate for further modification, for example with a secondary reporter or fluorophore. The highest affinity compound in this set of relatively polar hCB2 ligands was compound 16, which acted as a slightly partial balanced agonist in comparison with CP 55,940. The ligands characterised here may therefore exhibit unique functional properties in vivo and have the potential to be valuable in the future development of CB2 directed therapeutics. PMID- 30524272 TI - Recent Advances in Herbal Medicines for Digestive System Malignancies. AB - Herbal medicines, as an important part of traditional Chinese medicine (TCM), have been used to treat digestive system malignancies (DSM) for many years, and have gradually gained recognition worldwide. The role of herbal medicines in the comprehensive treatment of DSM is being improved from adjuvant treatment of the autologous immune function in cancer patients, to the treatment of both the symptoms and disease, direct inhibition of tumor cell growth and proliferation, and induction of tumor cell autophagy and apoptosis. Their specific mechanisms in these treatments are also being explored. The paper reviews the current anti tumor mechanisms of TCM, including single herbal medicines, Chinese herbal formulations, Chinese medicine preparations and TCM extract, and their application in the comprehensive treatment of digestive system tumors, providing a reference for clinical application of TCM. PMID- 30524273 TI - Resveratrol Brain Delivery for Neurological Disorders Prevention and Treatment. AB - Resveratrol (RES) is a natural polyphenolic non-flavonoid compound present in grapes, mulberries, peanuts, rhubarb and in several other plants. Numerous health effects have been related with its intake, such as anti-carcinogenic, anti inflammatory and brain protective effects. The neuroprotective effects of RES in neurological diseases, such as Alzheimer's (AD) and Parkinson's (PD) diseases, are related to the protection of neurons against oxidative damage and toxicity, and to the prevention of apoptotic neuronal death. In brain cancer, RES induces cell apoptotic death and inhibits angiogenesis and tumor invasion. Despite its great potential as therapeutic agent for the treatment of several diseases, RES exhibits some limitations. It has poor water solubility and it is chemically instable, being degraded by isomerization once exposed to high temperatures, pH changes, UV light, or certain types of enzymes. Thus, RES has low bioavailability, limiting its biological and pharmacological benefits. To overcome these limitations, RES can be delivered by nanocarriers. This field of nanomedicine studies how the drug administration, pharmacokinetics, and pharmacodynamics are affected by the use of nanosized materials. The role of nanotechnology, in the prevention and treatment of neurological diseases, arises from the necessity to mask the physicochemical properties of therapeutic drugs to prolong the half-life and to be able to cross the blood-brain barrier (BBB). This can be achieved by encapsulating the drug in a nanoparticle (NP), which can be made of different kinds of materials. An increasing trend to encapsulate and direct RES to the brain has been observed. RES has been encapsulated in many different types of nanosystems, as liposomes, lipid and polymeric NPs. Furthermore, some of these nanocarriers have been modified with targeting molecules able to recognize the brain areas. Then, this article aims to overview the RES benefits and limitations in the treatment of neurological diseases, as the different nanotechnology strategies to overcome these limitations. PMID- 30524274 TI - Nephroprotective Effects of Benzyl Isothiocyanate and Resveratrol Against Cisplatin-Induced Oxidative Stress and Inflammation. AB - This study was performed to compare the nephroprotective effects of benzyl isothiocyanate (BITC) and resveratrol (RES) and investigate the nephroprotective efficacy of their combination against cisplatin-induced acute renal injury. Five animal groups (each of eight) received either normal saline, a single intraperitoneal injection of cisplatin (20 mg/kg) at the sixth day, cisplatin plus oral RES (30 mg/kg) or BITC (100 mg/kg in diet), or a combination of both for 10 days. Compared to saline-treated mice, cisplatin-intoxicated mice had significantly higher (p < 0.05) serum levels of urea, creatinine, interleukin 1beta (IL-1beta), and tumor necrosis factor-alpha. Moreover, biochemical analysis of kidney tissue homogenates showed that cisplatin intoxication was associated with significantly higher (p < 0.05) tissue levels of malondialdehyde (MDA) and lower levels of reduced glutathione and activities of endogenous antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) in comparison to normal controls. Histopathological and immunohistochemical examinations of renal tissue slices from cisplatin-intoxicated mice showed interstitial leukocytic infiltration, tortuous tubules with vacuolated epithelium, luminal casts, and overexpression of cyclooxygenase-II enzyme. On the other hand, treatment with RES or BITC ameliorated all the previous parameters. The effects of both compounds were comparable in all assessed parameters, except IL-1beta serum concentration and renal tissue MDA concentration (which were significantly lower in the RES group). Interestingly, treatment with BITC and RES combination restored the normal concentrations of all the aforementioned biochemical parameters, as well as near normal histological and immunohistochemical pictures. In conclusion, BITC exerted nearly comparable nephroprotective, antioxidant, and anti-inflammatory effects to RES and the combination of both agents showed more potent nephroprotective effects against cisplatin than each one alone. PMID- 30524275 TI - QSAR-Based Virtual Screening: Advances and Applications in Drug Discovery. AB - Virtual screening (VS) has emerged in drug discovery as a powerful computational approach to screen large libraries of small molecules for new hits with desired properties that can then be tested experimentally. Similar to other computational approaches, VS intention is not to replace in vitro or in vivo assays, but to speed up the discovery process, to reduce the number of candidates to be tested experimentally, and to rationalize their choice. Moreover, VS has become very popular in pharmaceutical companies and academic organizations due to its time-, cost-, resources-, and labor-saving. Among the VS approaches, quantitative structure-activity relationship (QSAR) analysis is the most powerful method due to its high and fast throughput and good hit rate. As the first preliminary step of a QSAR model development, relevant chemogenomics data are collected from databases and the literature. Then, chemical descriptors are calculated on different levels of representation of molecular structure, ranging from 1D to nD, and then correlated with the biological property using machine learning techniques. Once developed and validated, QSAR models are applied to predict the biological property of novel compounds. Although the experimental testing of computational hits is not an inherent part of QSAR methodology, it is highly desired and should be performed as an ultimate validation of developed models. In this mini-review, we summarize and critically analyze the recent trends of QSAR based VS in drug discovery and demonstrate successful applications in identifying perspective compounds with desired properties. Moreover, we provide some recommendations about the best practices for QSAR-based VS along with the future perspectives of this approach. PMID- 30524276 TI - A Systematic Review of Medication Adherence Thresholds Dependent of Clinical Outcomes. AB - Background: In pharmacotherapy, the achievement of a target clinical outcome requires a certain level of medication intake or adherence. Based on Haynes's early empirical definition of sufficient adherence to antihypertensive medications as taking >=80% of medication, many researchers used this threshold to distinguish adherent from non-adherent patients. However, we propose that different diseases, medications and patient's characteristics influence the cut off point of the adherence rate above which the clinical outcome is satisfactory (thereafter medication adherence threshold). Moreover, the assessment of adherence and clinical outcomes may differ greatly and should be taken into consideration. To our knowledge, very few studies have defined adherence rates linked to clinical outcomes. We aimed at investigating medication adherence thresholds in relation to clinical outcomes. Method: We searched for studies that determined the relationship between adherence rates and clinical outcomes in the databases PubMed, EmbaseR and Web of ScienceTM until December 2017, limited to English-language. Our outcome measure was any threshold value of adherence. The inclusion criteria of the retrieved studies were (1) any measurement of medication adherence, (2) any assessment of clinical outcomes, and (3) any method to define medication adherence thresholds in relation to clinical outcomes. We excluded articles considered as a tutorial. Two authors (PB and IA) independently screened titles and abstracts for relevance, reviewed full-texts, and extracted items. The results of the included studies are presented qualitatively. Result: We analyzed 6 articles that assessed clinical outcomes linked to adherence rates in 7 chronic disease states. Medication adherence was measured with Medication Possession Ratio (MPR, n = 3), Proportion of Days Covered (PDC, n = 1), both (n = 1), or Medication Event Monitoring System (MEMS). Clinical outcomes were event free episodes, hospitalization, cortisone use, reported symptoms and reduction of lipid levels. To find the relationship between the targeted clinical outcome and adherence rates, three studies applied logistic regression and three used survival analysis. Five studies defined adherence thresholds between 46 and 92%. One study confirmed the 80% threshold as valid to distinguish adherent from non adherent patients. Conclusion: The analyzed studies were highly heterogeneous, predominantly concerning methods of calculating adherence. We could not compare studies quantitatively, mostly because adherence rates could not be standardized. Therefore, we cannot reject or confirm the validity of the historical 80% threshold. Nevertheless, the 80% threshold was clearly questioned as a general standard. PMID- 30524277 TI - Real World Experience of Disease Activity in Patients With Rheumatoid Arthritis and Response to Treatment With Varios Biologic DMARDs. AB - The current study investigate the disease activity and effectiveness of treatment in patients with RA on biological disease modifying antirheumatic drugs (bDMARDs) in combination with a conventional synthetic DMARD (csDMARD) and determine whether or not the benefits of different therapies were sustained over a follow up period of 1 year. 124 patients were selected with a mean age 55.26 +/- 13, 18SD years, meeting the 1987 ACR and /or ACR/ EULAR (2010) classification criteria for Rheumatoid arthritis (RA). Patients were arranged according to treatment regimens: Tocilizumab (TCL) - 30 patients, Certolizumab (CZP) - 16, Golimumab (GOL) - 22, Etanercept (ETN) 20, Adalimumab (ADA) 20, Rituximab (RTX) - 16. Disease activities was the primary concern. Independent joint assessor evaluated 28 joints on baseline, 6th and 12th month's thereafter. C-reactive protein (CRP) was used to measure the inflammatory process. DAS28-CRP, clinical disease activity index (CDAI) and simplified disease activity index (SDAI) were calculated. On baseline all of the patients' groups had severe disease activity (mean DAS28-CRP > 5.2, mean CDAI > 22, mean SDAI > 26. It was noted that, during the 6th month follow-up period all of the treatment groups significantly decreased DAS28-CRP, CDAI, SDAI and reach moderate disease activity. After 6th and 12th months of treatment all of the groups on bDMARDs had significantly lower disease activity. The GOL group reach remission only according to DAS28-CRP: 2.49 +/- 0.76, and low disease activity as measured by CDAI: 6.78 +/- 4.51 and SDAI 7.80 +/- 5.67. The other 5 groups after 12 months reach the level of low disease activity according to the three activity parameters: DAS28-CRP (TCL 3.07 +/- 0.73, CZP 3.06 +/- 0.65, ETN 2.85 +/- 0.55, ADA 3.15 +/- 0.82, RTX 2.90 +/- 0.70), CDAI (TCL 9.80 +/- 4.91, CZP - 9.33 +/- 4.22, ETN 7.97 +/- 3.80, ADA 10.00 +/- 5.25, RTX 7.48 +/- 2.99) and SDAI (TCL 10.45 +/- 5.14, CZP 9.94 +/- 4.43, ETN 9.03 +/- 4.25, ADA 10.50 +/- 5.61, RTX 8.08 +/- 3.24). The therapy with different bDMARDs added to a csDMARD led to very similar results - a minimal disease activity and a state of remission in the GOL treatment group only as per DAS28 CRP. PMID- 30524278 TI - High Doses of Bupleurum falcatum Partially Prevents Estrogen Deficiency-Induced Bone Loss With Anti-osteoclastogenic Activity Due to Enhanced iNOS/NO Signaling. AB - Background and Objective: Bupleurum falcatum (BF) extract, a natural product with anti-inflammatory properties, has been traditionally used to treat menopausal symptoms, but its role in osteoporosis, another serious health concern of menopausal women, remains unknown. Here we investigated whether and how BF prevents estrogen deficiency-induced bone loss using both in vitro and in vivo models. Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and subjected to oral BF treatment daily for 8 weeks. Additionally, pre-osteoclastic RAW 264.7 cells were employed to evaluate the effects of BF and its underlying mechanism on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in vitro. Results: A high dose of BF partially prevented ovariectomy (OVX)-induced bone loss and reduced the levels of tartrate-resistant acid phosphatase (TRAP) in serum and osteoclast numbers in femurs of OVX rats. Furthermore, BF clearly inhibited RANKL-induced osteoclast differentiation and bone resorption activity in RAW 264.7 cells. BF also inhibited the osteoclastogenic transcription factors c-Fos and nuclear factor of activated T cells c1 (NFATc1) and, consequently, downregulated the expression of osteoclast marker genes. Moreover, BF upregulated interferon-beta (IFN-beta)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) signaling, even though it had no impact on mitogen-activated protein kinases (MAPK) or NF-kappaB. The inhibition of osteoclast formation by BF was abrogated by iNOS-specific inhibitors. Consistent with cellular studies, BF upregulated iNOS protein expression in femurs from OVX rats. Conclusion: Taken together, our results indicate that BF partially prevented estrogen deficiency-induced bone loss with anti osteoclastogenic activity potentially due to enhanced iNOS/NO signaling. PMID- 30524279 TI - Involvement of CYP2E1 in the Course of Brain Edema Induced by Subacute Poisoning With 1,2-Dichloroethane in Mice. AB - This study was designed to explore the role of cytochrome P4502E1 (CYP2E1) expression in the course of brain edema induced by subacute poisoning with 1,2 dichloroethane (1,2-DCE). Mice were randomly divided into five groups: the control group, the 1,2-DCE poisoned group, and the low-, medium- and high-dose diallyl sulfide (DAS) intervention groups. The present study found that CYP2E1 expression levels in the brains of the 1,2-DCE-poisoned group were upregulated transcriptionally; in contrast, the levels were suppressed by DAS pretreatment in the intervention groups. In addition, the expression levels of both Nrf2 and HO-1 were also upregulated transcriptionally in the brains of the 1,2-DCE-poisoned group, while they were suppressed dose-dependently in the intervention groups. Moreover, compared with the control group, MDA levels and water contents in the brains of the 1,2-DCE-poisoned group increased, whereas NPSH levels and tight junction (TJ) protein levels decreased significantly. Conversely, compared with the 1,2-DCE- poisoned group, MDA levels and water contents in the brains of the intervention groups decreased, and NPSH levels and TJ protein levels increased significantly. Furthermore, pathological changes of brain edema observed in the 1,2-DCE-poisoned group were markedly improved in the intervention groups. Collectively, our results suggested that CYP2E1 expression could be transcriptionally upregulated in 1,2-DCE-poisoned mice, which might enhance 1,2 DCE metabolism in vivo, and induce oxidative damage and TJ disruption in the brain, ultimately leading to brain edema. PMID- 30524280 TI - Anti-Inflammatory Effect of a TCM Formula Li-Ru-Kang in Rats With Hyperplasia of Mammary Gland and the Underlying Biological Mechanisms. AB - Li-Ru-Kang (LRK), a formula of eight traditional Chinese medicines (TCM), has been used to treat hyperplasia of mammary gland (HMG) in TCM clinics. However, how LRK works in HMG patients is unclear. To explore the possible mechanisms of LRK against HMG, the network pharmacology was used to screen the potential targets and possible pathways that involved in LRK treated HMG. Rat HMG model induced by estrogen and progesterone was used to further verify the effects of the key molecules of LRK selected from the enriched pathways on HMG. Nipple heights and diameters were measured and uterus index was calculated. The histopathological changes of mammary gland tissue were detected by hematoxylin eosin (H&E) staining. Western blot was used to detect the phosphorylation of ERK, JNK, and P38. And immunohistochemistry staining was performed to evaluate the levels of estrogen receptor alpha (ERalpha), progesterone receptor (PR), nuclear factor-(NF-)kappaB (p65), interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), cyclooxygenases 2 (COX-2), inducible nitric oxide synthase (iNOS), 8-hydroxy-2'deoxyguanosine (8-OHdG), and nitrotyrosine (NT). Our results indicate that LRK treatment rescues significantly nipples height and diameter, decreases uterus index and ameliorates HMG. LRK treatment also markedly attenuates the over-expression of IL-1beta, TNF-alpha, COX-2, and iNOS, and suppressed the formation of 8-OHdG and NT. Furthermore, LRK treatment significantly inhibits the phosphorylation of JNK, ERK, and p38 and expression of NF-kappaB (p65), interestingly, LRK treatment has no effect on the expression of ERalpha and PR. Our data suggest that the LRK treatment protects the mammary glands from the damage of oxidative stress and inflammation induced by estrogen and progesterone, via suppresses of MAPK/NF-kappaB signaling pathways without affecting on the expression of ERalpha and PR. PMID- 30524281 TI - Anabolic Androgenic Steroids: Searching New Molecular Biomarkers. AB - Even if anabolic androgenic steroid (AAS) abuse is clearly associated with a wide spectrum of collateral effects, adolescents and athletes frequently use a large group of synthetic derivatives of testosterone, both for aesthetic uses and for improving performance. Over the last few years, the development of MicroRNA (miRNA) technologies has become an essential part of research projects and their role as potential molecular biomarkers is being investigated by the scientific community. The circulating miRNAs detection as a diagnostic or prognostic tool for the diagnosis and treatment of several diseases is very useful, because with a minimal quantity of sample (peripheral blood), miRNAs are very sensitive. Even more, miRNAs remain stable both at room temperature and during freeze-thaw cycles. These characteristics highlight the important role of miRNAs in the near future as new tools for anti-doping. The article provides a systematic review and meta-analysis on the role of miRNAs as new potential molecular biomarkers of AAS use/abuse. Particularly, this paper analyzed the "miRNA signature" use as biomarkers for health disorders, focusing on the organ damages which are related to ASS use/abuse. Moreover, this review aims to provide a future prospect for less invasive or non-invasive procedures for the detection of circulating miRNA biomarkers as doping assumption signaling. PMID- 30524282 TI - Therapeutic Effect of Ecklonia cava Extract in Letrozole-Induced Polycystic Ovary Syndrome Rats. AB - Polycystic ovary syndrome (PCOS) is an endocrinal disorder that afflicts mainly women of childbearing age. The symptoms of PCOS are irregular menstrual cycles, weight gain, subfertility and infertility. However, because the etiology is unclear, management and treatment methods for PCOS are not well established. Recently, natural substances have been used for PCOS therapy. Ecklonia cava (E. cava) is a well-known natural substance that attenuates the effects of inflammation, allergies, and cancer. In this study, we investigated the effects of E. cava extract in rats with PCOS. When rats with letrozole-induced PCOS were exposed to the E. cava extract, the regular estrus cycle was restored, similar to that in placebo rats. Hormone levels, including the levels of testosterone, estrogen, luteinizing hormone (LH), follicle stimulating hormone (FSH), and anti Mullerian hormone (AMH), were restored to their normal states. Histological analysis revealed that the polycystic ovary symptoms were significantly decreased in the E. cava-treated rats and were comparable to those of normal ovaries. At the transcriptional and translational levels, Ar, and Esr2 levels were markedly increased in the E. cava-treated rats with PCOS compared with the rats with letrozole-induced PCOS. These results suggest that the E. cava extract inhibits the symptoms of PCOS by restoring imbalanced hormonal levels and irregular ovarian cycles in letrozole-induced female rats. PMID- 30524283 TI - Secreted Cysteine-Rich Repeat Proteins "SCREPs": A Novel Multi-Domain Architecture. AB - Peptide toxins isolated from animal venom secretions have proven to be useful pharmacological tools for probing the structure and function of a number of molecular receptors. Their molecular structures are stabilized by posttranslational formation of multiple disulfide bonds formed between sidechain thiols of cysteine residues, resulting in high thermal and chemical stability. Many of these peptides have been found to be potent modulators of ion channels, making them particularly influential in this field. Recently, several peptide toxins have been described that have an unusual tandem repeat organization, while also eliciting a unique pharmacological response toward ion channels. Most of these are two-domain peptide toxins from spider venoms, such as the double-knot toxin (DkTx), isolated from the Earth Tiger tarantula (Haplopelma schmidti). The unusual pharmacology of DkTx is its high avidity for its receptor (TRPV1), a property that has been attributed to a bivalent mode-of-action. DkTx has subsequently proven a powerful tool for elucidating the structural basis for the function of the TRPV1 channel. Interestingly, all tandem repeat peptides functionally characterized to date share this high avidity to their respective binding targets, suggesting they comprise an unrecognized structural class of peptides with unique structural features that result in a characteristic set of pharmacological properties. In this article, we explore the prevalence of this emerging class of peptides, which we have named Secreted, Cysteine-rich REpeat Peptides, or "SCREPs." To achieve this, we have employed data mining techniques to extract SCREP-like sequences from the UniProtKB database, yielding approximately sixty thousand candidates. These results indicate that SCREPs exist within a diverse range of species with greatly varying sizes and predicted fold types, and likely include peptides with novel structures and unique modes of action. We present our approach to mining this database for discovery of novel ion-channel modulators and discuss a number of "hits" as promising leads for further investigation. Our database of SCREPs thus constitutes a novel resource for biodiscovery and highlights the value of a data-driven approach to the identification of new bioactive pharmacological tools and therapeutic lead molecules. PMID- 30524284 TI - Glutamyl-Prolyl-tRNA Synthetase Regulates Epithelial Expression of Mesenchymal Markers and Extracellular Matrix Proteins: Implications for Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF), a chronic disease of unknown cause, is characterized by abnormal accumulation of extracellular matrix (ECM) in fibrotic foci in the lung. Previous studies have shown that the transforming growth factor beta1 (TGFbeta1) and signal transducers and activators of transcription (STAT) pathways play roles in IPF pathogenesis. Glutamyl-prolyl-tRNA-synthetase (EPRS) has been identified as a target for anti-fibrosis therapy, but the link between EPRS and TGFbeta1-mediated IPF pathogenesis remains unknown. Here, we studied the role of EPRS in the development of fibrotic phenotypes in A549 alveolar epithelial cells and bleomycin-treated animal models. We found that EPRS knockdown inhibited the TGFbeta1-mediated upregulation of fibronectin and collagen I and the mesenchymal proteins alpha-smooth muscle actin (alpha-SMA) and snail 1. TGFbeta1-mediated transcription of collagen I-alpha1 and laminin gamma2 in A549 cells was also down-regulated by EPRS suppression, indicating that EPRS is required for ECM protein transcriptions. Activation of STAT signaling in TGFbeta1-induced ECM expression was dependent on EPRS. TGFbeta1 treatment resulted in EPRS-dependent in vitro formation of a multi-protein complex consisting of the TGFbeta1 receptor, EPRS, Janus tyrosine kinases (JAKs), and STATs. In vivo lung tissue from bleomycin-treated mice showed EPRS-dependent STAT6 phosphorylation and ECM production. Our results suggest that epithelial EPRS regulates the expression of mesenchymal markers and ECM proteins via the TGFbeta1/STAT signaling pathway. Therefore, epithelial EPRS can be used as a potential target to develop anti-IPF treatments. PMID- 30524285 TI - EGF Stimulates Rab35 Activation and Gastric Cancer Cell Migration by Regulating DENND1A-Grb2 Complex Formation. AB - Aims: The aim of this study was to reveal the specific molecular mechanisms by which DENND1A accepts EGF signaling and activates Rab35 in gastric cancer. Methods: The expression of proteins related to DENND1A was examined by western blot analysis. Activation of Rab35 was assessed by GST-pulldown. The interaction of DENND1A and Grb2 was assessed by GST-pulldown and co-immunoprecipitation assays. The relationship between DENND1A and cell migration and invasion was detected using wound healing and transwell by gene overexpression and RNA interference. Results: EGF stimulation significantly promoted cell migration, whereas transfection with siRab35 partially inhibited EGF-promoted cell migration. DENND1A is also involved in these processes and active Rab35. Moreover, DENND1A binds to the N-terminal and C-terminal SH3 domains of Grb2 through PRD. Of special interest is the observation that EGFR can recruit Grb2 DENND1A complex under EGF stimulation. Further results reveal that the higher the expression of DENND1A, the shorter progression-free survival of gastric cancer patients. Conclusion: In summary, we confirmed that EGF-Grb2-DENND1A-Rab35 signaling pathway with the interaction of DENND1A and Grb2 as a regulatory center could regulate gastric cancer cell migration and invasion. Ultimately, the expression level of DENND1A predicts the survival status of gastric cancer patients and may become one of the important targets for the treatment of gastric cancer. PMID- 30524286 TI - Gastrodin Ameliorates Cognitive Dysfunction in Diabetes Rat Model via the Suppression of Endoplasmic Reticulum Stress and NLRP3 Inflammasome Activation. AB - Patients with diabetes mellitus (DM) are at high risk for cognitive dysfunction. Endoplasmic reticulum stress (ERS) and inflammation play crucial roles in DM. Gastrodin (Gas), the main component of Gastrodia elata, possesses anti-oxidative stress, anti-inflammatory, and neuroprotective effects. This present study aims to investigate whether Gas could ameliorate cognitive dysfunction in DM and to explore its underlying mechanisms. Rats with streptozotocin-induced type 2 DM were used in this study. After administration of Gas for 5 weeks, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in serum, TNF-alpha, IL 1beta, MDA and SOD in the hippocampus were measured. Morris water maze, hematoxylin and eosin (HE) and Nissl staining were performed to assess the effects of Gas on cognitive function and hippocampal neuronal apoptosis. Protein levels of GLUT3, brain derived neurotrophic factor (BDNF), GRP78, PERK, P-PERK, TXNIP, ASC, NLRP3, CHOP, Bcl-2 and Bax were measured by using Western blot. The results showed that Gas could improve hyperglycemia and dyslipidemia in DM rats, as the levels of TC, TG LDL-C in serum were decreased. TNF-alpha, IL-1beta, MDA contents in the hippocampus were decreased, and SOD contents was increased in the hippocampus of DM rats. Inflammation, oxidative stress, ERS, and apoptosis were observed in the hippocampus of DM rats, accompanied with decreased expression of BDNF and GLUT3. Gas improved the cognitive deficits caused by diabetes and inhibited inflammation, oxidative stress, ERS, and apoptosis in the hippocampus. Furthermore, Gas substantially increased the expression of GLUT3, and inhibited hippocampal ERS and ERS-mediated apoptosis. Additionally, Gas increased the expression of BDNF and decreased the activation of NLRP3 inflammasome. These results suggested that by inhibiting ERS and NLRP3 inflammasome activation and increasing the expression of BDNF and GLUT3, Gas exhibits neuroprotective effects against cognitive dysfunction in DM. PMID- 30524287 TI - Unraveling the Novel Protective Effect of Patchouli Alcohol Against Helicobacter pylori-Induced Gastritis: Insights Into the Molecular Mechanism in vitro and in vivo. AB - Patchouli alcohol (PA), a natural tricyclic sesquiterpene extracted from Pogostemon cablin (Blanco) Benth. (Labiatae), has been found to exhibit anti Helicobacter pylori and anti-inflammatory properties. In this study, we investigated the protective effect of PA against H. pylori-induced gastritis in vitro and in vivo, and determined the underlying mechanism. In the in vivo experiment, a C57BL/6 mouse model of gastritis was established using H. pylori SS1, and treatments with standard triple therapy or 5, 10, and 20 mg/kg PA were performed for 2 weeks. Results indicated that PA effectively attenuated oxidative stress by decreasing contents of intracellular reactive oxygen species (ROS) and malonyldialdehyde (MDA), and increasing levels of non-protein sulfhydryl (NP-SH), catalase and glutathione (GSH)/glutathione disulphide (GSSG). Additionally, treatment with PA significantly attenuated the secretions of interleukin 1 beta (IL-1beta), keratinocyte chemoattractant and interleukin 6 (IL-6). PA (20 mg/kg) significantly protected the gastric mucosa from H. pylori-induced damage. In the in vitro experiment, GES-1 cells were cocultured with H. pylori NCTC11637 at MOI = 100:1 and treated with different doses of PA (5, 10, and 20 MUg/ml). Results indicated that PA not only significantly increased the cell viability and decreased cellular lactate dehydrogenase (LDH) leakage, but also markedly elevated the mitochondrial membrane potential and remarkably attenuated GES-1 cellular apoptosis, thereby protecting gastric epithelial cells against injuries caused by H. pylori. PA also inhibited the secretions of pro-inflammatory factors, such as monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor alpha (TNF-alpha) and IL-6. Furthermore, after PA treatment, the combination of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) and cysteine-aspartic proteases 1 (CASPASE-1), the expression levels of NLRP3 inflammasome-related proteins, such as thioredoxin-interacting protein (TXNIP), pro-CASPASE-1, cle CASPASE-1, and NLRP3 and genes (NLRP3 and CASPASE1) were significantly decreased as compared to the model group. In conclusion, treatment with PA for 2 weeks exhibited highly efficient protective effect against H. pylori-induced gastritis and related damages. The underlying mechanism might involve antioxidant activity, inhibition of pro-inflammatory factor and regulation of NLRP3 inflammasome function. PA exerted anti-H. pylori and anti-gastritis effects and thus had the potential to be a promising candidate for treatment of H. pylori-related diseases. PMID- 30524288 TI - Epigenetic Factors and Mitochondrial Biology in Yeast: A New Paradigm for the Study of Cancer Metabolism? AB - Bidirectional cross-talk between nuclear and mitochondrial DNA is fundamental for cell homeostasis. Epigenetic mechanisms regulate the inter-organelle communication between nucleus and mitochondria. Recent research highlights not only the retrograde activation of nuclear gene transcription in case of mitochondria dysfunction, but also the role of post-translational modifications of mitochondrial proteins in respiratory metabolism. Here we discuss some aspects and novel findings in Saccharomyces cerevisiae. In yeast, KAT-Gcn5 and DUB-Ubp8 have a role in respiration and are localized, as single proteins, into mitochondria. These findings, beside the canonical and widely known nuclear activity of SAGA complex in chromatin regulation, provide novel clues on promising aspects linking evolutionary conserved epigenetic factors to the re programmed metabolism of cancer cells. PMID- 30524289 TI - The Impact of Technology on Safe Medicines Use and Pharmacy Practice in the US. AB - For decades it has been suggested that pharmacists are under-utilized and could better use their knowledge and experience to improve the use of medicines. The traditional roles for pharmacists have been preparing and distributing medicines, but this has limited both the location where they work and the available time to work more closely with other healthcare professionals to improve both the effectiveness and safety of medicines. Newly emerging technologies have made this possible. Examples include robotics that automate preparation and distribution of medicines, electronic health information, clinical decision support systems, and machine readable coding on medicine packaged. As a result of the use of these technologies, pharmacists in hospitals are working outside the hospital pharmacy and spending more time in medication therapy management activities compared to traditional distribution roles. PMID- 30524290 TI - EGCG Reduces Obesity and White Adipose Tissue Gain Partly Through AMPK Activation in Mice. AB - (-)-Epigallocatechin-3-gallate (EGCG), which is the most abundant catechin in green tea, has many potential health benefits, including decreased weight gain and/or adipose tissue weight. Suggested mechanisms for body weight reduction by EGCG include: (1) a decrease in calorie intake and (2) activation of AMPK in liver, skeletal muscle, and white adipose tissue. However, only one study supports the AMPK hypothesis. To determine the role of AMPK in EGCG-induced reduction of body weight, we administrated 50 mg/kg and 100 mg/kg per day to mice, together with a high-fat diet (HFD), for 20 weeks. EGCG had a significant effect on obesity and decrease in epididymal adipose tissue weight, and also affected serum lipid characteristics, including triglyceride, cholesterol (CHOL), and high- and low-density lipoprotein CHOL (HDL-C, LDL-C) concentrations. In addition, EGCG increased the excretion of free fatty acids from feces. By measuring the mRNA expression levels of genes involved in lipid metabolism, we found that EGCG inhibited the expression of genes involved in the synthesis of de novo fatty acids (acc1, fas, scd1, c/ebpbeta, ppargamma, and srebp1) and increased the expression of genes associated with lipolysis (hsl) and lipid oxidization in white adipose tissue, in both the HFD and the EGCG groups. However, EGCG significantly increased the expression of genes involved in the synthesis of de novo fatty acids compared with the HFD group. Increased AMPK activity was found in both subcutaneous and epididymal adipose tissues. In conclusion, EGCG can decrease obesity and epididymal white adipose tissue weight in mice, only partially via activation of AMPK. PMID- 30524291 TI - RSL3 Drives Ferroptosis Through GPX4 Inactivation and ROS Production in Colorectal Cancer. AB - Ferroptosis is an iron-dependent, oxidative cell death, and is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. It has been implicated in various human diseases, including cancer. Recently, ferroptosis, as a non-apoptotic form of cell death, is emerging in specific cancer types; however, its relevance in colorectal cancer (CRC) is unexplored and remains unclear. Here, we showed that ferroptosis inducer RSL3 initiated cell death and ROS accumulation in HCT116, LoVo, and HT29 CRC cells over a 24 h time course. Furthermore, we found that ROS levels and transferrin expression were elevated in CRC cells treated with RSL3 accompanied by a decrease in the expression of glutathione peroxidase 4 (GPX4), indicating an iron-dependent cell death, ferroptosis. Overexpression GPX4 resulted in decreased cell death after RSL3 treatment. Therefore, RSL3 was able to induce ferroptosis on three different CRC cell lines in vitro in a dose- and time-dependent manner, which was due to increased ROS and an increase in the cellular labile iron pool. Moreover, this effect was able to be reversed by overexpression of GPX4. Taken together, our results suggest that the induction of ferroptosis contributed to RSL3-induced cell death in CRC cells and ferroptosis may be a pervasive and dynamic form of cell death for cancer treatment. PMID- 30524292 TI - Exosomes: Basic Biology and Technological Advancements Suggesting Their Potential as Ischemic Heart Disease Therapeutics. AB - Exosomes are small nano-sized vesicles that deliver biologically active RNA molecules and proteins to recipient cells through binding, fusion or endocytosis. There is emerging evidence that endogenous exosomes released by cardiovascular cells and progenitor cells impact cell survival and proliferation, thus regulating angiogenesis, cardiac protection and repair. These cardioprotective and regenerative traits have the potential to translate in to novel therapeutic options for post-ischaemic cardiac regeneration, thus potentially delaying the progression to ischaemic heart failure. Cellular stressors influence exosomes' secretion and the molecular composition of the exosome cargo, thus impacting on the above processes. Evidences are emerging that loading of proteins and RNAs in the exosomes cargos can be manipulated. Similarly, manipulation of exosomes surface proteins' expression to target exosomes to specific cells and tissues is doable. In addition, nature-inspired synthetic exosomes can be assembled to deliver specific clues to the recipient cells, including proliferative and differentiation stimuli, or shed paracrine signals enabling to reconstructing the heart homeostatic micro-environment. This review will describe exosome biogenesis and emerging evidence of exosome-mediated regenerative cell-to-cell communications and will conclude discussing possibilities of using exosomes to treat ischemic heart disease. PMID- 30524293 TI - Commentary: Voltage Gating of Mechanosensitive PIEZO Channels. PMID- 30524294 TI - Different Statistical Approaches to Characterization of Adipocyte Size in Offspring of Obese Rats: Effects of Maternal or Offspring Exercise Intervention. AB - Adipocyte size (AS) shows asymmetric distribution related to current metabolic state, e.g., adipogenesis or lipolysis. We profiled AS distribution using different statistical approaches in offspring (F1) of control (C) and obese (MO) mothers (F0) with and without F0 or F1 exercise. Offspring from F0 exercise were designated CF0ex and MOF0ex. Exercised F1 of sedentary mothers were designated CF1ex and MOF1ex. F1 retroperitoneal fat cross-sectional AS was measured by median, cumulative distributions, data dispersion and extreme values based on gamma distribution modeling. F1 metabolic parameters: body weight, retroperitoneal fat, adiposity index (AI), serum leptin, triglycerides (TG) and insulin resistance index (IRI) were measured. Male and female F1 AS showed different cumulative distribution between C and MO (p < 0.0001) therefore comparisons were performed among C, CF0ex and CF1ex groups and MO, MOF0ex and MOF1ex groups. MO AI was higher than C (p < 0.05) and male MOF1ex AI lower than MO (p < 0.05). Median AS was higher in male and female MO vs. C (p < 0.05). Male and female MOF0ex and MOF1ex reduced median AS (p < 0.05). Lower AS dispersion was observed in male CF1ex and MOF1ex vs. CF0ex and MOF0ex, respectively. MO reduced small and increased large adipocyte proportions vs. C (p < 0.05); MOF0ex increased small and MOF1ex the proportion of large adipocytes vs. MO (p < 0.05). MOF0ex reduced male IRI and female TG vs. MO (p < 0.05). MOF1ex reduced male and female leptin (p < 0.05); CF1ex reduced male leptin (p < 0.05). Conclusions: several factors, diet, physical activity and gender modify AS distribution. Conventional AS distribution methods normally do not include analyzes of extreme, large and small adipocytes, which characterize different phenotypes. Maternal high fat diet affects F1 AS distribution, which was programmed during development. F0ex and F1ex have gender specific F1 beneficial effects. AS distribution characterization helps explain adipose tissue metabolic changes in different physiological conditions and will aid design of efficacious interventions to prevent and/or recuperate adverse developmental programming outcomes. Finally, precise identification of effects of specific interventions as exercise of F0 and/or F1 are needed to improve outcomes in obese women and their obesity prone offspring. PMID- 30524295 TI - SGK1-FoxO1 Signaling Pathway Mediates Th17/Treg Imbalance and Target Organ Inflammation in Angiotensin II-Induced Hypertension. AB - It has been demonstrated that serum/glucocorticoid regulated kinase 1 (SGK1) and the downstream transcription factor forkhead box O1 (FoxO1) plays a critical role in the differentiation of T helper 17 cells/regulatory T cells (Th17/Treg). In the present study, we hypothesized that this SGK1-FoxO1 signaling pathway is involved in Th17/Treg imbalance and target organ damage in angiotensin II (AngII) induced hypertensive mice. Results show that SGK1 inhibitor EMD638683 significantly reversed renal dysfunction and cardiac dysfunction in echocardiography as indicated by decreased blood urine nitrogen and serum creatinine in AngII-infused mice. Flow cytometric assay shows that there was significant Th17/Treg imbalance in spleen and in renal/cardiac infiltrating lymphocytes as indicated by the increased Th17 cells (CD4+-IL17A+ cells) and decreased Treg cells (CD4+-Foxp3+). Consistently, real-time PCR shows that Th17 related cytokines including IL-17A, IL-23, and tumor necrosis factor alpha (TNF alpha) was increased and Treg-related cytokine IL-10 was decreased in renal and cardiac infiltrating lymphocytes in AngII-infused mice. Meanwhile, SGK1 protein level, as well as its phosphorylation and activity, was significantly increased in spleen in AngII-infused rats. Furthermore, it was found that splenic phosphorylated FoxO1 was significantly increased, whereas total FoxO1 in nuclear preparation was significantly decreased in AngII-infused mice, suggesting that increased FoxO1 phosphorylation initiate its translocation from cytoplasm to nucleus. Notably, all changes were significantly inhibited by the treatment of EMD638683. These results suggest that SGK1 was involved in Th17/Treg imbalance and target organ damage in AngII-induced hypertension. PMID- 30524296 TI - Glycolytic Response to Inflammation Over Time: Role of Myeloid HIF-1alpha. AB - The in vivo response to lipopolysaccharide (LPS) occurs rapidly and has profound physiological and metabolic effects. The hypoxia inducible (HIF) transcription factor is an intrinsic and essential part of inflammation, and is induced by LPS. To determine the importance of the HIF response in regulating metabolism following an LPS response, glucose uptake was quantified in a time dependent manner in mice lacking HIF-1alpha in myeloid cells. We found that deletion of HIF 1alpha has an acute protective effect on LPS-induced hypoglycemia. Furthermore, reduced glucose uptake was observed in the heart and brown fat, in a time dependent manner, following loss of HIF-1alpha. To determine the physiological significance of these findings, cardiovascular, body temperature, and blood pressure changes were subsequently quantified in real time using radiotelemetry measurements. These studies reveal the temporal aspects of HIF-1alpha as a regulator of the metabolic response to acute LPS-induced inflammation. PMID- 30524297 TI - Properties of the Permeability Transition of Pea Stem Mitochondria. AB - In striking analogy with Saccharomyces cerevisiae, etiolated pea stem mitochondria did not show appreciable Ca2+ uptake. Only treatment with the ionophore ETH129 (which allows electrophoretic Ca2+ equilibration) caused Ca2+ uptake followed by increased inner membrane permeability, membrane depolarization and Ca2+ release. Like the permeability transition (PT) of mammals, yeast and Drosophila, the PT of pea stem mitochondria was stimulated by diamide and phenylarsine oxide and inhibited by Mg-ADP and Mg-ATP, suggesting a common underlying mechanism; yet, the plant PT also displayed distinctive features: (i) as in mammals it was desensitized by cyclosporin A, which does not affect the PT of yeast and Drosophila; (ii) similarly to S. cerevisiae and Drosophila it was inhibited by Pi, which stimulates the PT of mammals; (iii) like in mammals and Drosophila it was sensitized by benzodiazepine 423, which is ineffective in S. cerevisiae; (iv) like what observed in Drosophila it did not mediate swelling and cytochrome c release, which is instead seen in mammals and S. cerevisiae. We find that cyclophilin D, the mitochondrial receptor for cyclosporin A, is present in pea stem mitochondria. These results indicate that the plant PT has unique features and suggest that, as in Drosophila, it may provide pea stem mitochondria with a Ca2+ release channel. PMID- 30524298 TI - Propulsive Power in Cross-Country Skiing: Application and Limitations of a Novel Wearable Sensor-Based Method During Roller Skiing. AB - Cross-country skiing is an endurance sport that requires extremely high maximal aerobic power. Due to downhill sections where the athletes can recover, skiers must also have the ability to perform repeated efforts where metabolic power substantially exceeds maximal aerobic power. Since the duration of these supra aerobic efforts is often in the order of seconds, heart rate, and pulmonary VO2 do not adequately reflect instantaneous metabolic power. Propulsive power (P prop) is an alternative parameter that can be used to estimate metabolic power, but the validity of such calculations during cross-country skiing has rarely been addressed. The aim of this study was therefore twofold: to develop a procedure using small non-intrusive sensors attached to the athlete for estimating P prop during roller-skiing and to evaluate its limits; and (2) to utilize this procedure to determine the P prop generated by high-level skiers during a simulated distance race. Eight elite male cross-country skiers simulated a 15 km individual distance race on roller skis using ski skating techniques on a course (13.5 km) similar to World Cup skiing courses. P prop was calculated using a combination of standalone and differential GNSS measurements and inertial measurement units. The method's measurement error was assessed using a Monte Carlo simulation, sampling from the most relevant sources of error. P prop decreased approximately linearly with skiing speed and acceleration, and was approximated by the equation Pprop(v,v ) = -0.54.v -0.71 .v + 7.26 W.kg-1. P prop was typically zero for skiing speeds >9 m.s-1, because the athletes transitioned to the tuck position. Peak P prop was 8.35 +/- 0.63 W.kg-1 and was typically attained during the final lap in the last major ascent, while average P prop throughout the race was 3.35 +/- 0.23 W.kg-1. The measurement error of P prop increased with skiing speed, from 0.09 W.kg-1 at 2.0 m.s-1 to 0.58 W.kg-1 at 9.0 m.s-1. In summary, this study is the first to provide continuous measurements of P prop for distance skiing, as well as the first to quantify the measurement error during roller skiing using the power balance principle. Therefore, these results provide novel insight into the pacing strategies employed by high-level skiers. PMID- 30524299 TI - Leucine Supplementation Improves Effort Tolerance of Rats With Hyperthyroidism. AB - Leucine is a regulator of protein metabolism in vivo and information on its action on effort tolerance of both animals and humans with hyperthyroidism is scarce. The objective of the present study was to verify the influence of leucine supplementation on the effort tolerance of Wistar rats with experimental hyperthyroidism. 40 animals were divided into four groups of ten: control (C), hormone (H), leucine (L), and hormone + leucine (HL). Hyperthyroidism was induced by daily administration of 20 MU?g100 g-1 of levothyroxine sodium in aqueous suspension by gavage. Leucine was supplemented by adding 5% of the amino acid to the conventional feed. The animals' blood was collected by cardiac puncture to analyze TSH, T4, and T3 levels. The effort tolerance was determined by the swimming test with a 7% load attached to animals' tails. Statistical analysis was performed using the Shapiro-Wilk normality test, followed by the analysis of variance (ANOVA) of repeated measures of two factors (treatment * time) and Tukey post hoc, with a significance level of p < 0.05. Administering thyroid hormone increased the swimming performance of rats after 14 and 21 days, but with a drop in performance at 28 days. The HL group, on the other hand, had a significantly higher swimming performance compared to the other groups after 28 days of treatment. Leucine supplementation associated with the experimental model of hyperthyroidism improved the performance of rats in a swimming test after 28 days of treatment. PMID- 30524300 TI - Marine Mammals' NMDA Receptor Structure: Possible Adaptation to High Pressure Environment. AB - Divers that are exposed to high pressure (HP) above 1.1 MPa suffer from High Pressure Neurological Syndrome (HPNS), which is implicated with central nervous system (CNS) malfunction. Marine mammals performing extended and deep breath-hold dives are exposed to almost 20 MPa without apparent HPNS symptoms. N-methyl-D aspartate receptor (NMDAR) has repeatedly been implicated as one of the major factors in CNS hyperexcitability as part of HPNS. Electrophysiological studies in rat brain slices at He HP showed a significant increase in the synaptic NMDAR response, followed by postsynaptic excitability changes. Molecular studies of Rattus norvegicus NMDARs have revealed that different subunit combinations of the NMDAR exhibit different, increased or decreased, current responses under He HP conditions. The purpose of the present research was to disclose if the breath hold deep diving mammals exhibit NMDAR structural modifications related to HP. We used sequence alignment and homology structure modeling in order to compare deep diving marine mammals' NMDARs to those of terrestrial mammals. We discovered that deep diving mammals have a special tertiary TMD structure of the GluN2A subunit that differs from that of the terrestrial mammals. In addition, the GluN2A subunit has a group of four conserved a.a. substitutions: V68L (N-terminal domain, NTD) and V440I (agonist-binding domain, ABD) are cetacean specific, E308D (N-terminal domain, NTD) and I816V (transmembrane domain, TMD) were also singularly found in some terrestrial mammals. Since I816V is localized in M4 alpha-helix region, which is critical for NMDAR activation and desensitization, we hypothesize that the presence of all 4 substitutions rather than a single one, is the combination that may enable HP tolerance. Furthermore, additional special substitutions that were found in the marine mammals' NTD may affect the Zn2+ binding site, suggesting less or no voltage-independent inhibition by this ion. Our molecular studies of NMDARs containing the GluN2A subunit showed that HP removal of the Zn2+ voltage-independent inhibition could be the mechanism explaining its current increase at HP. Thus, this mechanism could play a crucial role in the CNS hyperexcitability at HP. Less or no voltage-independent Zn2+ inhibition, different conformations of the TMD, and special mutation in the M4 alpha-helix region of cetaceans' NMDAR, may give them the advantage they need in order to perform such deep dives without CNS malfunction. PMID- 30524301 TI - Inflammation and Mechanical Stress Stimulate Osteogenic Differentiation of Human Aortic Valve Interstitial Cells. AB - Background: Aortic valve calcification is an active proliferative process, where interstitial cells of the valve transform into either myofibroblasts or osteoblast-like cells causing valve deformation, thickening of cusps and finally stenosis. This process may be triggered by several factors including inflammation, mechanical stress or interaction of cells with certain components of extracellular matrix. The matrix is different on the two sides of the valve leaflets. We hypothesize that inflammation and mechanical stress stimulate osteogenic differentiation of human aortic valve interstitial cells (VICs) and this may depend on the side of the leaflet. Methods: Interstitial cells isolated from healthy and calcified human aortic valves were cultured on collagen or elastin coated plates with flexible bottoms, simulating the matrix on the aortic and ventricular side of the valve leaflets, respectively. The cells were subjected to 10% stretch at 1 Hz (FlexCell bioreactor) or treated with 0.1 MUg/ml lipopolysaccharide, or both during 24 h. Gene expression of myofibroblast- and osteoblast-specific genes was analyzed by qPCR. VICs cultured in presence of osteogenic medium together with lipopolysaccharide, 10% stretch or both for 14 days were stained for calcification using Alizarin Red. Results: Treatment with lipopolysaccharide increased expression of osteogenic gene bone morphogenetic protein 2 (BMP2) (5-fold increase from control; p = 0.02) and decreased expression of mRNA of myofibroblastic markers: alpha-smooth muscle actin (ACTA2) (50% reduction from control; p = 0.0006) and calponin (CNN1) (80% reduction from control; p = 0.0001) when cells from calcified valves were cultured on collagen, but not on elastin. Mechanical stretch of VICs cultured on collagen augmented the effect of lipopolysaccharide. Expression of periostin (POSTN) was inhibited in cells from calcified donors after treatment with lipopolysaccharide on collagen (70% reduction from control, p = 0.001), but not on elastin. Lipopolysaccharide and stretch both enhanced the pro-calcific effect of osteogenic medium, further increasing the effect when combined for cells cultured on collagen, but not on elastin. Conclusion: Inflammation and mechanical stress trigger expression of osteogenic genes in VICs in a side-specific manner, while inhibiting the myofibroblastic pathway. Stretch and lipopolysaccharide synergistically increase calcification. PMID- 30524302 TI - Relationships Between Aerobic and Anaerobic Parameters With Game Technical Performance in Elite Goalball Athletes. AB - Our aims were to compare physiological parameters from the laboratory environment (LaB) and simulated goalball games (GaM), test relationships between physiological parameters in the laboratory and game technical performance (GTP), and examine the associations between physiological and technical responses during games. Seven elite athletes from the Brazilian National Team performed in LaB environment; (i) an incremental test to determine peak oxygen consumption (O2PEAK), its corresponding speed, and peak blood lactate concentration and (ii) submaximal and supramaximal efforts to estimate maximal anaerobic contribution (AnC). In GaM condition, simulated games were also performed to determine physiological responses throughout the game, and to analyze the GTP (number of throws, defenses, recovery, and density of actions). No correlations (unclear) were found between laboratory and games analyses for O2PEAK [47.3 (17.2) vs. 25.8 (18.2) mL?Kg-1?min-1], peak blood lactate concentrations [10.2 (5.4) vs. 2.0 (0.7) mM], and total AnC [21.0 (14.0) vs. 4.8 (6.1) mL Kg-1]. O2PEAK in the laboratory condition presented very likely correlations with throw and recovery frequency in games (r = -0.87 and confidence interval [CI] = 0.41; r = -0.90 and CI = 0.35; respectively). Oxygen consumption remained above baseline while blood lactate concentration remained unchanged during the games. The very likely correlation between anaerobic alactic contribution and action density (r = 0.95 and CI = 0.25) highlights the importance of the alactic metabolism. In general, our study demonstrates that goalball can be characterized as a high-intensity intermittent effort, where athlete performance is based on aerobic metabolism predominance while determinant actions are supplied by the anaerobic alactic metabolism. Specifically, higher values of LaB vs. GaM highlighted the need for standardization of specific protocols for goalball evaluation, mainly for the reproduction of ecologically valid values. In addition, O2PEAK correlated with recovery frequency in the LaB condition, demonstrating that passive or low intensity recovery between actions is fundamental to maintain performance. PMID- 30524303 TI - DLX3 Inhibits the Proliferation of Human Dental Pulp Cells Through Inactivation of Canonical Wnt/beta-Catenin Signaling Pathway. AB - Homeodomain gene Distal-less-3 (Dlx3) plays an important role during tooth development. Our previous studies indicate that DLX3 inhibits proliferation of human dental pulp cells (hDPCs). However, the mechanism of DLX3 regulating proliferation of hDPCs and maintaining the quiescence of the cells remain unknown. Given the importance of canonical Wnt signaling in the proliferation of dental pulp cell and tooth development, we hypothesized that DLX3 inhibited proliferation of hDPCs through inactivation of canonical Wnt signaling. With overexpression or knock-down of DLX3 in primary hDPCs, we found DLX3 down regulated canonical Wnt signaling and its downstream target genes. And when the DLX3 overexpressed-cells were treated with lithium chloride, the proliferation inhibition by DLX3 was reversed. We also found that DLX3 enhanced the expression of DKK1 and the reduced proliferation of hDPCs by DLX3 was reversed with knock down of DKK1. Furthermore, luciferase reporter assay and chromatin immunoprecipitation assay showed DLX3 was able to bind to Dkk1 promoter region from nucleotides (nt) -1656 to -1245, and stimulated Dkk1 promoter activity. Mutagenesis studies further revealed two DLX3 responsive elements in Dkk1 promoter. Taken together, our data indicate that DLX3 inhibits proliferation of hDPCs via inactivation of Wnt/beta-catenin signaling pathway by directly binding to Dkk1 promoter and increasing its expression. PMID- 30524304 TI - Targeted Ablation of Distal Cerebrospinal Fluid-Contacting Nucleus Alleviates Renal Fibrosis in Chronic Kidney Disease. AB - The potential function of distal cerebrospinal fluid-contacting nucleus (dCSF CNs) in chronic kidney disease (CKD) development is poorly understood. We hypothesized that dCSF-CNs might affect the renin-angiotensin system (RAS) in kidney injury progression, with dCSF-CNs ablation potentially alleviating local RAS and renal fibrosis in rats after five-sixths nephrectomy (5/6Nx). Part of rats were randomly administered artificial cerebrospinal fluid (aCSF) intracerebroventricularly (icv), followed by 5/6Nx or sham operation; and other part of rats were administered Cholera toxin B subunit conjugated with saporin (CB-SAP) for dCSF-CNs lesion before 5/6Nx. The effect of CB-SAP on dCSF-CNs ablation was confirmed by double immunofluorescence staining. RAS component, NOX2 and c-fos levels in the subfornical organ (SFO), hypothalamic paraventricular nucleus (PVN) and hippocampus, as well as tyrosine hydroxylase (TH) and c-fos positive cells in rostral ventrolateral medulla (RVLM) were assessed. Next, the levels of RAS components (angiotensinogen [AGT], angiotensin-converting enzyme [ACE], Ang II type 1 receptor [AT1R], angiotensin-converting enzyme 2 [ACE2], and Mas receptor), NADPH oxidases (NOX2 and catalase), inflammatory cytokines (monocyte chemotactic protein 1 [MCP-1] and IL-6), and fibrotic factors (fibronectin and collagen I) were assessed. Less CB-labeled neurons were found in dCSF-CNs of CB-SAP-treated rats compared with 5/6Nx animals. Meanwhile, CB-SAP downregulated AGT, Ang II, AT1R, NOX2, catalase, MCP-1, IL-6, fibronectin, and collagen I, and upregulated ACE2 and Mas receptor, compared with CKD rats. More TH and c-fos positive cells were found in RVLM of 5/6Nx rats but the number decreased after dCSF-CNs ablation. Targeted dCSF-CNs ablation could alleviate renal inflammation and fibrosis in chronic kidney injury by inhibiting cerebral and renal RAS/NADPH oxidase. PMID- 30524305 TI - Dynamic Cerebral Autoregulation Remains Stable During the Daytime (8 a.m. to 8 p.m.) in Healthy Adults. AB - Many functions of the human body possess a daily rhythm, disruptions of which often lead to disease. Dynamic cerebral autoregulation (dCA) stabilizes the cerebral blood flow to prompt normal neural function. However, whether dCA is stable across the day remains unknown. This study aimed to investigate the daily rhythm of dCA. Fifty-one healthy adults (38.294 +/- 13.279 years, 40 females) were recruited and received six dCA measurements per individual that were conducted at predefined time points: 8:00, 9:00, 11:00, 14:00, 17:00, and 20:00. Although the blood pressure fluctuated significantly, there was no statistical difference in phase difference and gain (autoregulatory parameters) across the six time points. This study demonstrates that dCA remains stable during the interval from 8 a.m. to 8 p.m. and underscores the importance of stable dCA in maintaining cerebral blood flow and neural function. PMID- 30524306 TI - Higher Proportion of Non-1-84 PTH Fragments in Peritoneal Dialysis Patients Compared to Hemodialysis Patients Using Solutions Containing 1.75 mmol/l Calcium. AB - Background: The prevalence of low- turnover bone disease (LTBD) in peritoneal dialysis (PD) patients is higher than in hemodialysis (HD) patients. LTBD patients may be at risk for vascular calcification, and cardiovascular disease. Current therapy for chronic kidney disease metabolic bone disorders (CKD-MBD) is guided by biochemical parameters, as bone biopsy is not used in routine clinical care. Methods: We assessed intact PTH (iPTH: 1-84PTH plus non-1-84PTH), 1-84PTH, and the 1-84PTH/non-1-84PTH ratio in 129 hemodialysis and 73 PD prevalent patients dialyzed with solutions containing 1.75 mmol/L calcium. Results: Hemodialysis and PD patients presented similar iPTH and tCa values and prevalence of putative LTBD as defined according to KDOQI iPTH cut-off levels or 1-84 PTH levels. However, iCa accounted for a higher percentage of tCa in PD (53%) than in hemodialysis (39%) p < 0.001, and the 1-84PTH/non-1-84PTH ratio was lower in PD than in hemodialysis patients (0.44 +/- 0.12) vs. (0.60 +/- 0.10), p < 0.001. The prevalence of putative LTBD when using the coexistence of 1-84PTH/non-1-84PTH ratio < 1.0 and iPTH < 420 pg/m, was higher in PD than in hemodialysis patients (73 vs. 16% respectively, p < 0.001). In a multivariate logistic regression analysis, dialysis modality was the main determinant of the 1-84PTH/non-1-84PTH ratio. Conclusion: Solutions containing 1.75 mmol/L calciums are associated to a higher proportion of non-1-84PTH fragments in PD than in HD patients. Different analytical criteria result in widely different estimates of LTBD prevalence, thus impairing the ability of clinicians to optimize therapy for CKD-MBD. PMID- 30524307 TI - A Renal Function Based Trade-Off Analysis of Non-vitamin K Antagonist Oral Anticoagulants in Nonvalvular Atrial Fibrillation. AB - Background: Non-vitamin K antagonist oral anticoagulants (NOACs) depend on some degree of renal excretion, and no head-to-head comparisons based on renal function is available. This study mainly investigated the trade-off property of NOACs in nonvalvular atrial fibrillation (NVAF) with varying degrees of renal function. Methods: A comprehensive search of Medline, Embase, Cochrane Library, and Clinical Trials.gov Website was performed for eligible randomized controlled trials (RCTs) that reported the efficacy and safety outcomes according to renal function of NOACs. Primary efficacy outcome was any Stroke or systemic embolism (S/SE). Major bleeding was considered as a primary safety outcome. Risk ratios (RRs) with their confidence intervals (CIs), the surface under the cumulative ranking curve (SUCRA), and trade-off analysis were conducted by renal function. Results: Finally, 5 phase III Clinical Trials (72961 NVAF patients) comparing NOACs with warfarin in NVAF patients were included. In terms of normal renal function, dabigatran-150 mg was ranked first for efficacy (SUCRA: 90.3), and edoxaban-30 mg was ranked first for safety (SUCRA: 93.3). Dabigatran-110 mg/150 mg, and apixaban-5 mg were regarded as the most effective and reasonably safe interventions in the trade-off analysis. Regarding mild renal impairment, edoxaban-60 mg was ranked first for efficacy (SUCRA: 97.8), and edoxaban-30 mg was ranked first for safety (SUCRA: 99.5). Edoxaban-60 mg and dabigatran-150 mg were accounted as the most effective and reasonably safe interventions. With regards to moderate renal impairment, dabigatran-150 mg was ranked first for efficacy (SUCRA: 95.1), and edoxaban-15 mg was ranked first for safety (SUCRA: 98.2). Apixaban-2.5 mg and Edoxaban-30 mg was considered as the reasonably effective and the safest interventions. Conclusions: Dabigatran-150 mg seems the most effective therapy in patients with normal renal function and moderate renal impairment, and edoxaban-60 mg in patients with mild renal impairment. Low dose edoxaban (15 and 30 mg) seems the safest intervention. Apixaban-2.5 mg and edoxaban-30 mg might be the best trade-off property in moderate renal insufficiency. HIGHLIGHTS Dabigatran-150 mg seems the most effective therapy for normal renal function and moderate renal impairment patients, edoxaban-60 mg for mild renal impairment patients.Low-dose edoxaban can be considered as a good choice in NVAF patients at high risk of bleeding.Apixaban-2.5 mg and edoxaban-30 mg might be the balanced option in NVAF patients with moderate renal insufficiency.STUDY REGISTRATION: PROSPERO Identifier, CRD42017054235. PMID- 30524308 TI - The Air-Breathing Paradise Fish (Macropodus opercularis) Differs From Aquatic Breathers in Strategies to Maintain Energy Homeostasis Under Hypoxic and Thermal Stresses. AB - Two major strategies are used by most fish to maintain energy homeostasis under hypoxia. One is to utilize alternative metabolic pathways to increase energy production, and the other is to limit energy expenditure by suppressing energy consuming processes, especially ionoregulation. Some anabantoid fishes live in tropical rivers, where hypoxic environments occur frequently. We previously found that under ambient hypoxia, anabantoid fishes do not downregulate Na+/K+-ATPase (NKA) activity to conserve energy in gills but instead increase the frequency of air-breathing respiration (ABR). In addition to the hypoxic condition, another factor that may cause cellular hypoxia in fish is abnormally high environmental temperatures. The frequency of such extreme thermal events has increased due to global climate change. In the present study, we examined whether the anabantoid fish, Macropodus opercularis employs the two strategies mentioned above to resist both ambient hypoxic and elevated thermal (cellular hypoxic) conditions. Results indicate that neither glucose metabolism nor gill NKA activity were altered by hypoxia (DO = 1.5 +/- 1 mg/L), but glucose metabolism was increased by thermal stress (34 +/- 1 degrees C). NH4 + excretion and ABR frequency were both increased under hypoxia, thermal or hypoxic-and-thermal treatments. In fish that were restricted from breathing air, increased mortality and glucose metabolism were observed under hypoxic or thermal treatments. These results suggest that for M. opercularis, increasing ABR is an important strategy for coping with unmet oxygen demand under hypoxic or thermal stress. This behavioral compensation allows anabantoid fish to physiologically withstand hypoxic and thermal stresses, and constitutes a mechanism of stress resistance that is unavailable to water breathing fishes. PMID- 30524309 TI - Analysis of Asperger Syndrome Using Genetic-Evolutionary Random Support Vector Machine Cluster. AB - Asperger syndrome (AS) is subtype of autism spectrum disorder (ASD). Diagnosis and pathological analysis of AS through resting-state fMRI data is one of the hot topics in brain science. We employed a new model called the genetic-evolutionary random Support Vector Machine cluster (GE-RSVMC) to classify AS and normal people, and search for lesions. The model innovatively integrates the methods of the cluster and genetic evolution to improve the performance of the model. We randomly selected samples and sample features to construct GE-RSVMC, and then used the cluster to classify and extract lesions according to classification results. The model was validated by data of 157 participants (86 AS and 71 health controls) in ABIDE database. The classification accuracy of the model reached to 97.5% and we discovered the brain regions with significant differences, such as the Angular gyrus (ANG.R), Precuneus (PCUN.R), Caudate nucleus (CAU.R), Cuneus (CUN.R) and so on. Our method provides a new perspective for the diagnosis and treatment of AS, and a universal framework for other brain science research as the model has excellent generalization performance. PMID- 30524310 TI - Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition. AB - Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-beta1 (TGFbeta1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of alpha-smooth muscle actin (alpha-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGFbeta1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF kappaB) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT. PMID- 30524311 TI - Transcriptomic Responses to Different Cry1Ac Selection Stresses in Helicoverpa armigera. AB - Helicoverpa armigera can develop resistance to Bacillus thuringiensis (Bt), which threaten the long-term success of Bt crops. In the present study, RNAseq was employed to investigate the midgut genes response to strains with different levels of resistance (LF5, LF10, LF20, LF30, LF60, and LF120) in H. armigera. Results revealed that a series of differentially expressed unigenes (DEGs) were expressed significantly in resistant strains compared with the LF-susceptible strain. Nine trypsin genes, ALP2, were downregulated significantly in all the six resistant strains and further verified by qRT-PCR, indicating that these genes may be used as markers to monitor and manage pest resistance in transgenic crops. Most importantly, the differences in DEG functions in the different resistant strains revealed that different resistance mechanisms may develop during the evolution of resistance. The immune and detoxification processes appear to be associated with the low-level resistance (LF5 strain). Metabolic process-related macromolecules possibly lead to resistance to Cry1Ac in the LF10 and LF20 strains. The DEGs involved in the "proton-transporting V-type ATPase complex" and the "proton-transporting two-sector ATPase complex" were significantly expressed in the LF30 strain, probably causing resistance to Cry1Ac in the LF30 strain. The DEGs involved in binding and iron ion homeostasis appear to lead to high-level resistance in the LF60 and LF120 strains, respectively. The multiple genes and different pathways seem to be involved in Cry1Ac resistance depending on the levels of resistance. Although the mechanisms of resistance are very complex in H. armigera, a main pathway seemingly exists, which contributes to resistance in each level of resistant strain. Altogether, the findings in the current study provide a transcriptome-based foundation for identifying the functional genes involved in Cry1Ac resistance in H. armigera. PMID- 30524312 TI - Targeting Non-coding RNA in Vascular Biology and Disease. AB - Only recently have we begun to appreciate the importance and complexity of the non-coding genome, owing in some part to truly significant advances in genomic technology such as RNA sequencing and genome-wide profiling studies. Previously thought to be non-functional transcriptional "noise," non-coding RNAs (ncRNAs) are now known to play important roles in many diverse biological pathways, not least in vascular disease. While microRNAs (miRNA) are known to regulate protein coding gene expression principally through mRNA degradation, long non-coding RNAs (lncRNAs) can activate and repress genes by a variety of mechanisms at both transcriptional and translational levels. These versatile molecules, with complex secondary structures, may interact with chromatin, proteins, and other RNA to form complexes with an array of functional consequences. A body of emerging evidence indicates that both classes of ncRNAs regulate multiple physiological and pathological processes in vascular physiology and disease. While dozens of miRNAs are now implicated and described in relative mechanistic depth, relatively fewer lncRNAs are well described. However, notable examples include ANRIL, SMILR, and SENCR in vascular smooth muscle cells; MALAT1 and GATA-6S in endothelial cells; and mitochondrial lncRNA LIPCAR as a powerful biomarker. Due to such ubiquitous involvement in pathology and well-known biogenesis and functional genetics, novel miRNA-based therapies and delivery methods are now in development, including some early stage clinical trials. Although lncRNAs may hold similar potential, much more needs to be understood about their relatively complex molecular behaviours before realistic translation into novel therapies. Here, we review the current understanding of the mechanism and function of ncRNA, focusing on miRNAs and lncRNAs in vascular disease and atherosclerosis. We discuss existing therapies and current delivery methods, emphasising the importance of miRNAs and lncRNAs as effectors and biomarkers in vascular pathology. PMID- 30524313 TI - New Approaches to Tay-Sachs Disease Therapy. AB - Tay-Sachs disease belongs to the group of autosomal-recessive lysosomal storage metabolic disorders. This disease is caused by beta-hexosaminidase A (HexA) enzyme deficiency due to various mutations in alpha-subunit gene of this enzyme, resulting in GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Tay-Sachs disease is characterized by acute neurodegeneration preceded by activated microglia expansion, macrophage and astrocyte activation along with inflammatory mediator production. In most cases, the disease manifests itself during infancy, the "infantile form," which characterizes the most severe disorders of the nervous system. The juvenile form, the symptoms of which appear in adolescence, and the most rare form with late onset of symptoms in adulthood are also described. The typical features of Tay-Sachs disease are muscle weakness, ataxia, speech, and mental disorders. Clinical symptom severity depends on residual HexA enzymatic activity associated with some mutations. Currently, Tay-Sachs disease treatment is based on symptom relief and, in case of the late onset form, on the delay of progression. There are also clinical reports of substrate reduction therapy using miglustat and bone marrow or hematopoietic stem cell transplantation. At the development stage there are methods of Tay-Sachs disease gene therapy using adeno- or adeno-associated viruses as vectors for the delivery of cDNA encoding alpha and beta HexA subunit genes. Effectiveness of this approach is evaluated in alpha or beta HexA subunit defective model mice or Jacob sheep, in which Tay-Sachs disease arises spontaneously and is characterized by the same pathological features as in humans. This review discusses the possibilities of new therapeutic strategies in Tay-Sachs disease therapy aimed at preventing neurodegeneration and neuroinflammation. PMID- 30524314 TI - Supine vs. Prone Position With Turn of the Head Does Not Affect Cerebral Perfusion and Oxygenation in Stable Preterm Infants <=32 Weeks Gestational Age. AB - Intraventricular hemorrhage (IVH) is a frequent major damage to the brain of premature babies <=32 weeks gestational age, and its incidence (20-25%) has not significantly changed lately. Because of the intrinsic fragility of germinal matrix blood vessels, IVH occurs following disruption of subependymal mono-layer arteries and is generally attributed to ischemia-reperfusion alterations or venous congestion, which may be caused by turn of the head. Therefore, supine position with the head in a midline position is considered a standard position for preterm infants during their first days of life. We asked whether a change in body position (supine vs. prone) linked with a turn of the head by 90 degrees in the prone position would change blood flow velocities and resistance indices in major cerebral arteries and veins of stable premature babies at two different time points (t0, day of life 2, vs. t1, day 9). Moreover, we assessed cerebral tissue oxygenation (cStO2) by near-infrared spectroscopy and determined correlations for changes in velocities and oxygenation. Twenty one premature infants [gestational age 30 (26-32) weeks] with sufficiently stable gas exchange and circulation were screened by ultrasonography and near-infrared spectroscopy. Peak systolic and end-diastolic blood flow velocities in the anterior cerebral arteries (29 +/- 6 m/s vs. 28 +/- 7 peak flow at t0, 36 +/- 8 vs. 35 +/- 7 at t1), the basilar artery, the right and the left internal carotid artery, and the great cerebral vein Galen (4.0 +/- 0.8 m/s vs. 4.1 +/- 1.0 maximum flow at t0, 4.4 +/- 0.8 vs. 4.4 +/- 1.0 at t1) did not show significant differences following change of body and head position. Also, there were no differences in cStO2 (83 +/ 7% vs. 84 +/- 7 at t0, 76 +/- 10 vs. 77 +/- 11 at t1) and in vital signs such as heart rate and blood pressure. We conclude that change in body position with turn of the head in the prone position does not elicit significant alterations in cerebral blood flow velocities or in oxygenation of cerebral tissues. Maturational changes in arterial flow velocities and cStO2 are not correlated. For this subgroup of premature infants at low risk of IVH our data do not support the concept of exclusive preterm infant care in supine position. PMID- 30524315 TI - The Roles of E93 and Kr-h1 in Metamorphosis of Nilaparvata lugens. AB - Metamorphosis is a crucial process in insect development. Ecdysone-induced protein 93 (E93) is a determinant that promotes adult metamorphosis in both hemimetabolous and holometabolous insects. Kruppel-homolog 1 (Kr-h1), an early juvenile hormone (JH)-inducible gene, participates in JH signaling pathway controlling insect metamorphosis. In the current study, an E93 cDNA (NlE93) and two Kr-h1 cDNA variants (NlKr-h1-a and NlKr-h1-b) were cloned from Nilaparvata lugens (Stal), one of the most destructive hemimetabolous insect pests on rice. Multiple sequence alignment showed that both NlE93 and NlKr-h1 share high identity with their orthologs from other insects. The expression patterns revealed that decreasing NlKr-h1 mRNA levels were correlated with increasing NlE93 mRNA levels and vice versa. Moreover, RNA interference (RNAi) assays showed that the knockdown of one of the two genes resulted in significantly upregulated expression of the other. Correspondingly, phenotypical observation of the RNAi insects revealed that depletion of NlE93 prevented nymph-adult transition (causing a supernumerary nymphal instar), while depletion of NlKr-h1 triggered precocious formation of incomplete adult features. The results suggest that Nlkr h1 and NlE93 are mutual repressors, fitting into the MEKRE93 pathway. The balance between these two genes plays a critical role in the metamorphosis of N. lugens determining the proper timing for activating metamorphosis during the nymphal stage. PMID- 30524316 TI - Differential T Cell Levels of Tumor Necrosis Factor Receptor-II in Children With Autism. AB - Autism spectrum disorders (ASD) are characterized by impairments in verbal and non-verbal communication, in social interactions, and often accompanied by stereotypical interests and behaviors. A role for immune dysfunction has long been implicated in ASD pathophysiology, behavioral severity, and co-morbidities. The pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) has been associated with ASD in some studies but little is known about its receptors. There are two receptors for TNFalpha, with TNFRI relaying many of the signals from TNFalpha, especially those that are rapid, whilst TNFRII relays later more long-term effects of TNFalpha. Proteolytic cleavage can lead to the soluble versions of these receptors which can neutralize the effects of TNFalpha. Here, we determined levels of TNFalpha and its receptors in 36 children with a confirmed diagnosis of ASD and 27 confirmed typically developing (TD) controls, 2 5 years-of-age. Children with ASD had higher levels of TNFRII on T cells compared to controls following cell stimulation. Levels of sTNFRII were decreased in cell supernatants following stimulation in ASD. Overall these data corroborate the role of inflammatory events in ASD and align with previous studies that have shown differential changes in cellular adaptive immunity in children with ASD. Future longitudinal analyzes of cellular immune function and downstream signaling from immune receptors will help further delineate the role of inflammation in ASD. PMID- 30524317 TI - Baclofen Response in Alcohol Dependent Patients Concurrently Receiving Antidepressants: Secondary Analysis From the BacALD Study. AB - Background and Aims: There is little information with regards to the efficacy of baclofen among alcohol patients concurrently receiving antidepressants (AD). The present study aimed to conduct a secondary analysis of the moderating role of antidepressants in the BacALD trial which evaluated the efficacy of baclofen to reduce alcohol consumption in alcohol dependent patients. Methods: Alcohol dependent patients (N = 104) were treated for 12 weeks with 30 mg/day of baclofen (21 = AD and 15 = no AD), 75 mg baclofen (19 = AD and 16 = no AD) or placebo (17 = AD and 16 = no AD). Patients were included in the trial if they were concurrently receiving anti-depressants upon enrolment but were excluded if they commenced antidepressants 2 months prior to enrolment. Patients were also excluded in the case of concurrent psychotropic medications, active major mental disorder such as bipolar disorder, psychosis, or history of suicide attempt. Predefined primary outcomes included time to lapse (any drinking), relapse (>5 drinks per day in men and >4 in women). Other outcomes included drinks per drinking day, number of heavy drinking days, and percentage days abstinent and frequency of adverse events. Results: For the number of days to first lapse, there was a trend of significance for the interaction baclofen * AD (Log Rank: chi2 = 2.98, P = 0.08, OR: 0.41, 95%CI: 0.15-1.12). For the number of days to relapse, there was a trend of significance for the interaction of baclofen * AD (Log Rank: chi2 = 3.72, P = 0.05, OR: 3.40, 95%CI: 1.01-11.46). Placing significant baseline variables into the models as covariates (tobacco, ALD) weakened these interactions (P's > 0.15). There were no significant effects of ADs on the frequency of adverse events reported (P's > 0.19). Conclusion: Concurrent receipt of ADs commenced more than 2 months prior to baclofen treatment did not negatively impact on drinking outcomes. Future research examining the interaction between commencing ADs during baclofen treatment on alcohol dependent patients is required. Trial Registration: ClinicalTrials.gov, NCT01711125, https://clinicaltrials.gov/ct2/show/NCT01711125. PMID- 30524318 TI - Latent Psychotic Symptom Profiles Amongst People Who Use Methamphetamine: What Do They Tell Us About Existing Diagnostic Categories? AB - The inability to distinguish clearly between methamphetamine-related psychosis and schizophrenia has led to the suggestion that "methamphetamine psychosis" does not represent a distinct diagnostic entity but rather that the drug has triggered a vulnerability to schizophrenia. We tested this possibility by exploring the latent class structure of psychotic symptoms amongst people who use the drug and examining how these latent symptom profiles correspond to a diagnosis of schizophrenia. Latent class analysis was carried out on the lifetime psychotic symptoms of 554 current methamphetamine users, of whom 40 met the DSM-IV criteria for schizophrenia. Lifetime diagnoses of schizophrenia and individual psychotic symptoms were assessed using the Composite International Diagnostic Interview. The chosen model found 22% of participants had a high propensity to experience a wide range of psychotic symptoms (schizophrenia-like), whereas the majority (56%) more specifically experienced persecutory delusions and hallucinations (paranoid psychosis) and had a lower probability of these symptoms than the schizophrenia like class. A third class (22%) had a low probability of all symptoms, with the exception of 34% reporting persecutory delusions. Participants in the schizophrenia-like class were more likely to meet diagnostic criteria for schizophrenia (26 vs. 3 and 1% for each of the other classes, p < 0.001) but the diagnosis failed to encompass 74% of this group. These results are consistent with there being a distinction between schizophrenia and methamphetamine-related psychotic symptoms, both in terms of the propensity to experience psychotic symptoms, as well as the symptom profile; however, this distinction may not be captured well by existing diagnostic classifications. PMID- 30524319 TI - Drug Addiction: From Neuroscience to Ethics. AB - In the present paper, we suggest a potential new ethical analysis of addiction focusing on the relationship between aware and unaware processing in the brain. We take the case of the opioids epidemics to argue that a consideration of both aware and unaware processing provides a more comprehensive ethical framework to discuss the ethical issues raised by addiction. Finally, our hypothesis is that in addition to identified Central Nervous System's neuronal/neurochemical factors contributing to addictive dynamics, the socio-economic status plays a causal role through epigenetic processes, originating the need for additional reward in the brain. This provides a strong base for a socio-political form of responsibility for preventing and managing addiction crisis. PMID- 30524320 TI - Serum Markers of Inflammation Mediate the Positive Association Between Neuroticism and Depression. AB - Background: The personality trait neuroticism has been implicated in a poor response to stress, may relate to increased concentrations of cytokines and the development of depression. Inflammatory mechanisms may also be associated with the onset, severity and symptoms of depression. Both are related to poor antidepressant treatment outcome. Therefore, mediators of inflammation may bridge the relationship between neuroticism and depression. Methods: To disentangle these interrelationships, the associations between neuroticism (according to NEO PIR-N), depressive symptoms (BDI-II scores) and serum levels of hsCRP, TNF-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, GM-CSF were investigated in a group of 212 participants, consisting of 37 depressed and 175 non-depressed subjects. A mediation model was used to investigate whether the impact of neuroticism on depressive symptoms may be mediated by cytokines. Results: Regression analyses revealed that IFN-gamma, IL-5, and IL-12-levels, but none of the anti-inflammatory cytokines, were associated with the overall neuroticism score and several of the cytokines were related to the different facets of neuroticism. TNF-alpha, IFN-gamma, IL-5, IL-12, and IL-13 were further related to the severity of depressive symptoms, as well as the somatic-affective and the cognitive dimensions of depression. Pro-inflammatory IFN-gamma, IL-5 and IL-12 were identified as mediators of the positive prediction of depression severity by the degree of neuroticism. Conclusions: The current findings demonstrate that conditions related to long-term stress, such as depression and high neuroticism, are related to an up-regulation of inflammatory agents. Neuroticism may increase stress perception and, thus, increase the production of pro-inflammatory messenger molecules which are involved in the development of depression. This evidence may contribute to future anti-inflammatory interventions, particularly in subjects with high neuroticism who are at risk for developing depression. Furthermore, depressed patients with high neuroticism and cytokine levels may require early escalations in the intensity of treatment, along with additional therapeutic elements to increase the rate of treatment success. PMID- 30524321 TI - Screening for ADHD-Related Symptoms in Preschoolers Should Be Considered-Results From a Representative Sample of 5-Year-Olds From a German Metropolitan Region. AB - Background: Early assessment and intervention are crucial to alleviate symptoms and prevent long-term negative outcomes in children suffering from Attention deficit/hyperactivity disorder (ADHD). In Germany, at present, no standardized screening for ADHD is routinely administered. This study aims to evaluate a potential screening measure in a study population that is representative for a primary school entrance exam population in a German metropolitan region. Methods: Based on various socio-demographic variables, a sample of n = 500 5-year-old children (58% boys, 42% girls), representative of a primary school entrance exam population from a German metropolitan region, was selected. Their parents completed a written survey consisting of the CBCL and a brief screening tool for ADHD symptomatology based on the DISYPS-II questionnaire. Demographic data were also collected. Results: The subscale "Attention problems" of the CBCL/4-18 showed results in the clinical range for n = 10 (2%) participants. The ADHD screening identified n = 23 (4.6%) participants as suspect of having ADHD with a statistically significant gender difference (n = 17 boys vs. n = 6 girls, p = 0.03). In n = 5 (1%) participants, all boys, both CBCL/4-18 and the ADHD screening were indicative of ADHD. Conclusions: Results indicate that screening for ADHD in this population may be both feasible and reasonable given the high prevalence and chronic nature of this disorder and the benefit of an early initiation of treatment. Results match previously reported figures for prevalence of ADHD-related symptoms and gender differences in preschool and older pediatric populations and thus do not support the hypothesis that the prevalence of ADHD in a metropolitan region is significantly higher than in other regions. PMID- 30524322 TI - Predictors of Persistent Medically Unexplained Physical Symptoms: Findings From a General Population Study. AB - Objective: To explore the persistency of Medically Unexplained Symptoms (MUS) and its prognostic factors in the general adult population. Knowledge of prognostic factors of MUS may indicate possible avenues for intervention development. Methods: Data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), a nationally representative face-to-face cohort study among the Dutch general population aged 18-64 years. We selected subjects with MUS at baseline and who participated at follow-up (N = 324) and reassessed those subjects for having MUS at 3 year follow-up. Logistic regression analyses were used to determine risk factors for persistency of MUS. Results: 36.4% of the subjects had persistent MUS at follow-up. In logistic regression analyses adjusted for sex and age, persistency of MUS was predicted by the number of comorbid chronic medical disorder(s), lower education, female sex, not having a paid job, parental psychopathology as well as lower functioning. In the logistic regression analysis in which all significant variables adjusted for sex and age were entered simultaneously, three variables predicted persistent MUS: parental psychopathology, the number of comorbid chronic medical disorder(s) and physical functioning, with odds ratios of 2.01 (1.20-3.38), 1.19 (1.01-1.40), and 0.99 (0.97-1.00), respectively. Conclusion: In the adult general population, MUS were persistent in over one third of the subjects with MUS at baseline. Persistency was significantly predicted by parental psychopathology, number of comorbid chronic medical disorders, and physical functioning. These findings warrant further research into early intervention and treatment options for persons with an increased risk of persistent MUS. PMID- 30524323 TI - Moral Emotions and Social Economic Games in Paranoia. AB - Impaired social cognitive processes are putative psychological mechanisms implicated in the formation and maintenance of paranoid beliefs. Paranoia denotes unfounded fears about the hostile intentions of others and is prevalent in a significant proportion of the general population. We investigated social cognition in healthy participants selectively recruited to have a broad occurrence of paranoid thinking (n = 89). Participants completed a novel computerized task of moral emotions and two social economic exchange games (Prisoner's Dilemma, Ultimatum Game) from the EMOTICOM neuropsychological test battery. Regression analyses revealed that delusional ideation predicted shameful feelings when the victim of deliberate harm by another person. Cooperative behavior on the Prisoner's Dilemma was greatest when the participant and opponent contributed equally to joint earnings. Participants demonstrated significantly more punishment behavior when contributions were unequal and stole more from the opponent using a suspicious strategy of gameplay. In addition, paranoid thinking was positively associated with more stealing from the cooperative opponent. On the Ultimatum Game, participants accepted significantly more unequal offers when the opponent contributed more and sensitivity to fairness was greatest when the participant contributed more. These data demonstrate that delusional ideation predicts a maladaptive emotional response to interpersonal harm and that paranoid thinking may lead to reduced cooperation toward mutual reward. The effects of paranoia on moral emotions and pro-social behavior at more severe levels of persecutory thinking warrant further investigation. PMID- 30524324 TI - Cognitive Profiles of Developmental Dysgraphia. AB - Developmental dysgraphia is a disorder of writing/spelling skills, closely related to developmental dyslexia. For developmental dyslexia, profiles with a focus on phonological, attentional, visual or auditory deficits have recently been established. Unlike for developmental dyslexia, however, there are only few studies about dysgraphia, in particular about the variability of its causes. Research has demonstrated high similarity between developmental dyslexia and dysgraphia. Thus, the aim of the study was to investigate cognitive deficits as potential predictors of dysgraphia, analogously to those for dyslexia, in order to identify dysgraphia profiles, depending on the particular underlying disorder. Different tests were carried out with 3rd and 4th grade school children to assess their spelling abilities, tapping into phonological processing, auditory sound discrimination, visual attention and visual magnocellular functions as well as reading. A group of 45 children with developmental dysgraphia was compared to a control group. The results showed that besides phonological processing abilities, auditory skills and visual magnocellular functions affected spelling ability, too. Consequently, by means of a two-step cluster analysis, the group of dysgraphic children could be split into two distinct clusters, one with auditory deficits and the other with deficits in visual magnocellular functions. Visual attention was also related to spelling disabilities, but had no characteristic distinguishing effect for the two clusters. Together, these findings demonstrate that a more fine-grained diagnostic view on developmental dysgraphia, which takes the underlying cognitive profiles into account, might be advantageous for optimizing the outcome of individuum-centered intervention programs. PMID- 30524325 TI - Psychosocial Hazards in the Workplace as an Aspect of Horizontal Segregation in the Nursing Profession. AB - The purpose of this article was to assess the influence of psychosocial hazards as a factor affecting the presence of men in the nursing profession. The article refers to the topic of particularly low representation of men among nursing staff in Poland, in comparison to what similar statistics show for other countries. The aim of the study was to assess whether the psychosocial hazards in the nursing profession constitute a significant factor in the small number of men present in this occupation. In this article psychosocial hazards are considered as all the aspects of management and work organization that may negatively affect the employee's mental and physical health. The research was conducted from September 2017 to April 2018 in the Podlaskie Voivodeship (Poland). A total of 640 respondents working as nurses in inpatient health care facilities, of which 87% were women and 13% were men, were included in the study. A standardized Work Design Questionnaire for an objective assessment of work stressfulness was used as a research tool. The research has been run by a group of experts, who explained the aim and the meaning of the particular questions to the surveyed group. Afterwards, based on the answers and observations of the responders, the experts filled in the questionnaire. The results of the study show that in almost all the evaluated aspects, the nursing profession was assessed more negatively by surveyed men than women. The most negative aspects reported by women included hazards (a score of 60), complexity (58.3), and haste (50.0), while those reported by men included haste (70.0), complexity (66.7), and hazards (65.0). As a conclusion it has been noticed, that results received from the research confirm that psychosocial hazards may have significant impact on the number of men present in the nursing profession in Poland. This study also suggests that the greater psychosocial hazards experienced by male nurses in the workplace may be an effect of the particularly low representation of men among practicing nursing staff. PMID- 30524326 TI - Ethical Leadership as Antecedent of Job Satisfaction, Affective Organizational Commitment and Intention to Stay Among Volunteers of Non-profit Organizations. AB - The aim of this paper is to investigate among a group of non-profit organizations: (a) the effect of ethical leadership (EL) on volunteers' satisfaction, affective organizational commitment and intention to stay in the same organization; (b) the role played by job satisfaction as a mediator in the relationship between EL and volunteers' intentions to stay in the same organization, as well as between EL and affective commitment. An anonymous questionnaire was individually administered to 198 Italian volunteers of different non-profit organizations. The questionnaire contained the Ethical Leadership Scale, the Volunteers Satisfaction Index, the Affective organization Scale, as well as questions regarding the participants' age, sex, type of work, level of education, length of their volunteer works, intention to volunteer in the following months in the same organization. The construct as well the effects of EL on volunteers is approached in light of the Social Exchange Theory and the Social Learning Theory. Structural equation models were used to test hypothesized relationships. The results confirm the role of mediation of volunteer satisfaction in the relationships between the variables studied. In particular, EL was found to be positively associated both with volunteers' intention of staying and with their affective commitment. In the first case this relationship is fully explained by the mediation of the volunteers' satisfaction, while the latter is explained by both direct and indirect factors. To the authors' knowledge, this the first attempt to understand the role played by EL on volunteers' behavior and, more in general, in the management of non-profit organizations. Findings are relevant both for practitioners and managers of non profit organization, since they suggest the relevance of the perception of EL by volunteers, as well as for scholars, since they further deepen the knowledge on EL and its effects on the followers. Limits of the study: the questionnaire was administered only among a group of non-statistical sample of volunteers. Furthermore, the study reached only volunteers from Italian non-profit organization. PMID- 30524327 TI - On Averting Negative Emotion: Remedying the Impact of Shifting Expectations. AB - This paper examines how people anticipate negative emotions when faced with an uncertain outcome and try to manage their expectations. While extant research streams remain equivocal on whether managing expectations always succeeds, this research examines situations in which setting a low expectation can have an adverse emotional impact and suggests ways to alleviate this negative consequence. Using goal setting and a false-feedback paradigm, we show that, although individuals who set low goals to manage expectations can end up feeling more disappointed than those who set high goals (study 1), this negative impact can be avoided when individuals are reminded of their initial goals at feedback, or made aware of inaccuracies in forecasting their future emotion (studies 1 and 2). PMID- 30524328 TI - Distributed Practice: Rarely Realized in Self-Regulated Mathematical Learning. AB - The purpose of the present study was to investigate the effect and use of distributed practice in the context of self-regulated mathematical learning in high school. With distributed practice, a fixed learning duration is spread over several sessions, whereas with massed practice, the same time is spent learning in one session. Distributed practice has been proven to be an effective tool for improving long-term retention of verbal material and simple procedural knowledge in mathematics, at least when the practice schedule is externally guided. In the present study, distributed practice was investigated in a context that required a higher degree of self-regulation. In total, 158 secondary school students were invited to participate. After motivational and cognitive characteristics of the students were assessed, the students were introduced to basic statistics, a topic of their regular curriculum. At the end of the introduction, the students could sign up for the study to further practice this content. Eighty-seven students did so and were randomly assigned either to the distributed or to the massed practice condition. In the distributed practice condition, they received three practice sets on three different days. In the massed practice condition, they received the same three sets, but all on one day. All exercises were worked in the context of self-regulated learning at home. Performance was tested 2 weeks after the last practice set. Only 44 students finished the study, which hampered the analysis of the effect of distributed practice. The characteristics of the students who completed the exercises were analyzed exploratory: The proportion of students who finished all exercises was significantly higher in the massed than in the distributed practice condition. Within the distributed practice condition, a significantly larger proportion of female students completed the exercises compared to male students. Additionally, among these female students, a larger proportion showed lower concentration difficulty. No such differential effects were revealed in the massed practice condition. Our results suggest that the use of distributed practice in the context of self-regulated learning might depend on learner characteristics. Accordingly, distributed practice might obtain more reliable effects in more externally guided learning contexts. PMID- 30524329 TI - Turning the Mirror on the Architects: A Study of the Open-Plan Office and Work Behaviors at an Architectural Company. AB - Following the rising cost of real estate and a desire to increase collaboration and communication among employees, the open-plan office has been trending over the past decades. Research about the impact of the open-plan office on humans is equivocal in endorsing this trend. The mixed results are further confounded following the specific job requirements, such as the need for privacy in jobs requiring a high level of concentration or, in contrast, the need for open workspace in jobs benefitting from team work and knowledge sharing. This study aims to understand the relationship between perceptions of three characteristics of the open-plan office (acoustical privacy, visual privacy, and office density), and the impact they yield on employees' judgment as well as affect-driven behaviors. The study benefits from the data from 456 employees located in 20 regional office locations within the same architectural firm. The restriction to employees of a design firm enables examinations of participants, who are already sensitive to the impacts of space by the nature of their work. The variables of interest included employee perception of the workspace (privacy, office density, and fit into workspace), employee rating of social relationships, self-reported mood (irritability) and optimal functioning (number of limited ability days), and work impacts (job satisfaction, work engagement, and job performance). The Model of behavior in an open-plan office setting based on affective events theory is adopted. Mediation roles of irritability and perception of fit into the workspace are examined. Structural equation modeling is applied to test the joint significance of the association between independent and dependent variables (direct effect) and the association between independent variables, mediator, and dependent variables (indirect effect). Nested structure of the data is accounted for by adjusting the standard errors for clustering. The significance of indirect and total effects is evaluated by the bootstrapping method. Our results show that working in the open-plan office limits the experience of privacy and intensifies the perception of intrusion among employees of an architectural company, mostly architects and designers. Additionally, employees' perception of lack of privacy and high office density negatively affect job satisfaction, work engagement, and internal work relation as well as increases the number of limited ability days. Interestingly, the lack of privacy and high office density seem to positively affect expressive personal relations among coworkers and job performance. We find supporting evidence for mediation roles of negative emotions, that is, irritability and perception of fit into the workspace. PMID- 30524330 TI - Visual Information Pianists Use for Efficient Score Reading. AB - When sight-reading music, pianists have to decode a large number of notes and immediately transform them into finger actions. How do they achieve such fast decoding? Pianists may use geometrical features contained in the musical score, such as the distance between notes, to improve their efficiency in reading them. The aim of this study is to investigate the visual information pianists rely on when reading music. We measured the accuracy of the musical score reading of 16 skilled pianists and investigated its relationship with the geometrical features. When a single note was presented, pianists easily read it when it was located within three ledger lines. When two notes with an octave interval were presented, interestingly, their readable range was extended compared to that of the single note. The pianists were also able to recognize the octave interval correctly even if they misread the height (or pitch) of the target notes. These results suggest that the pianists decoded two notes composing an octave interval as a single "two tone geometric pattern." Analyzing the characteristics of incorrect responses, we also found that pianists used the geometrical features of the spatial relationship between the note head and the ledger line, and that the cause of the misreading could be categorized into four types: [Type I] Confusion to a neighboring note having the same ledger line configuration; [Type II] Interference from a commonly used height note having the same note name; [Type III] Misunderstanding based on the appearance probability; [Type IV] Combination of the above three. These results all indicate that the pianists' abilities in score reading rely greatly on the correlation between the geometric features and playing action, which the pianists acquired through long-time training. PMID- 30524331 TI - Numerical Processing Impairment in 22q11.2 (LCR22-4 to LCR22-5) Microdeletion: A Cognitive-Neuropsychological Case Study. AB - Although progress has been made, the cognitive, biological and, particularly, the genetic underpinnings of math learning difficulties (MD) remain largely unknown. This difficulty stems from the heterogeneity of MD and from the large contribution of environmental factors to its etiology. Understanding endophenotypes, e.g., the role of the Approximate Number System (ANS), may help understanding the nature of MD. MD associated with ANS impairments has been described in some genetic conditions, e.g., 22q11.2 deletion syndrome (22q11.2DS or Velocardiofacial syndrome, VCFS). Recently, a girl with MD was identified in a school population screening. She has a new syndrome resulting from a microdeletion in 22q11.2 (LCR22-4 to LCR22-5), a region adjacent to but not overlapping with region 22q11.2 (LCR22-2 to LCR22-4), typically deleted in VCFS. Here, we describe her cognitive-neuropsychological and numerical-cognitive profiles. The girl was assessed twice, at 8 and 11 years. Her numerical-cognitive performance at both times was compared to demographically similar girls with normal intelligence in a single-case, quasi-experimental study. Neuropsychological assessment was normal, except for relatively minor impairments in executive functions. She presented severe and persistent difficulties in the simplest single-digit calculations. Difficulties in commutative operations improved from the first to the second assessment. Difficulties in subtraction persisted and were severe. No difficulties were observed in Arabic number writing. Difficulties in single-digit calculation co-occurred with basic numerical processing impairments in symbolic and non-symbolic (single-digit comparison, dot sets size comparison and estimation) tasks. Her difficulties suggest ANS impairment. No difficulties were detected in visuospatial/visuoconstructional and in phonological processing tasks. The main contributions of the present study are: (a) this is the first characterization of the neuropsychological phenotype in 22q11.2DS (LCR22-4 to LCR22.5) with normal intelligence; (b) mild forms of specific genetic conditions contribute to persistent MD in otherwise typical persons; (c) heterogeneity of neurogenetic underpinnings of MD is suggested by poor performance in non-symbolic numerical processing, dissociated from visuospatial/visuoconstructional and phonological impairments; (d) similar to what happens in 22q11.2DS (LCR22-2 to LCR22-4), ANS impairments may also characterize 22q11.2DS (LCR22-4 to LCR22-5). PMID- 30524332 TI - Emotional Roles of Mono-Aminergic Neurotransmitters in Major Depressive Disorder and Anxiety Disorders. AB - A growing body of researches support a role for dysfunction of serotoninergic, noradrenergic, and dopaminergic systems in the neurobiological processes involved in major depression disorder (MDD) and anxiety disorders (ADs). The physiological changes underlying abnormal signaling of 5-HT, NE, and DA may be due to either reduced presynaptic release of these neurotransmitters or aberrant signal transductions, and thus contributing to the alterations in regulation or function of receptors and/or impaired intracellular signal processing. Animal models demonstrate crucial responsiveness to disturbance of 5-HT, NE, and DA neurotransmissions. Postmortem and biochemical studies have shown altered concentrations of 5-HT, NE, and DA metabolites in brain regions that contribute importantly to regulation of mood and motivation in patients with MDD or ADs. Neuroimaging studies have found abnormal 5-HT, NE, and DA receptors binding and regulation in regard to receptor numbers. Medications that act on 5-HT, NE, and DA neurons or receptors, such as SSRIs and SNRIs, show efficacy in both MDD and ADs. The overlapping treatment response presumably suggests a common mechanism underlying the interaction of these disorders. In this paper, we reviewed studies from multiple disciplines to interpret the role of altered 5-HT, NE and DA mono amine neurotransmitter functions in both MDD and ADs. PMID- 30524333 TI - A Theory of Predictive Dissonance: Predictive Processing Presents a New Take on Cognitive Dissonance. AB - This article is a comparative study between predictive processing (PP, or predictive coding) and cognitive dissonance (CD) theory. The theory of CD, one of the most influential and extensively studied theories in social psychology, is shown to be highly compatible with recent developments in PP. This is particularly evident in the notion that both theories deal with strategies to reduce perceived error signals. However, reasons exist to update the theory of CD to one of "predictive dissonance." First, the hierarchical PP framework can be helpful in understanding varying nested levels of CD. If dissonance arises from a cascade of downstream and lateral predictions and consequent prediction errors, dissonance can exist at a multitude of scales, all the way up from sensory perception to higher order cognitions. This helps understand the previously problematic dichotomy between "dissonant cognitive relations" and "dissonant psychological states," which are part of the same perception-action process while still hierarchically distinct. Second, since PP is action-oriented, it can be read to support recent action-based models of CD. Third, PP can potentially help us understand the recently speculated evolutionary origins of CD. Here, the argument is that responses to CD can instill meta-learning which serves to prevent the overfitting of generative models to ephemeral local conditions. This can increase action-oriented ecological rationality and enhanced capabilities to interact with a rich landscape of affordances. The downside is that in today's world where social institutions such as science a priori separate noise from signal, some reactions to predictive dissonance might propagate ecologically unsound (underfitted, confirmation-biased) mental models such as climate denialism. PMID- 30524334 TI - Introducing and Testing the Creepiness of Situation Scale (CRoSS). AB - When people interact with novel technologies (e.g., robots, novel technological tools), the word "creepy" regularly pops up. We define creepy situations as eliciting uneasy feelings and involving ambiguity (e.g., on how the behave or how to judge the situation). A common metric for creepiness would help evaluating creepiness of situations and developing adequate interventions against creepiness. Following psychometrical guidelines, we developed the Creepiness of Situation Scale (CRoSS) across four studies with a total of N = 882 American and German participants. In Studies 1-3, participants watched a video of a creepy situation involving technology. Study 1 used exploratory factor analysis in an American sample and showed that creepiness consists of emotional creepiness and creepy ambiguity. In a German sample, Study 2 confirmed these subdimensions. Study 3 supported validity of the CRoSS as creepiness correlated positively with privacy concerns and computer anxiety, but negatively with controllability and transparency. Study 4 used the scale in a 2 (male vs. female experimenter) * 2 (male vs. female participant) * 2 (day vs. night) field study to demonstrate its usefulness for non-technological settings and its sensitivity to theory-based predictions. Results indicate that participants contacted by an experimenter at night-time reported higher feelings of creepiness. Overall, these studies suggest that the CRoSS is a psychometrically sound measure for research and practice. PMID- 30524335 TI - Employee Competitive Attitude and Competitive Behavior Promote Job-Crafting and Performance: A Two-Component Dynamic Model. AB - While competition has become increasingly fierce in organizations and in the broader market, the research on competition at an individual level is limited. Most existing research focuses on trait competitiveness. We argue that employee competitiveness can be state-like and can be demonstrated as an attitude toward and behavior representative of competition. We therefore propose a dynamic model with two separate components: competitive attitude and competitive behavior. Drawing upon self-determination theory and the person-environment interaction perspective, we examine how employee competitive attitude and competitive behavior can be influenced by both personal characteristics and team climate, which in turn leads to different work outcomes, as demonstrated in two studies. Study 1 developed measures for competitive attitude and competitive behavior. Study 2 collected data from salespeople in a large insurance company in three waves. The results showed that employee competitive attitude and behavior could be predicted by personality. Moreover, employee competitive attitude and behavior were related to sales performance in differential ways via job crafting, and these mediated relationships could be moderated by team climate. These findings support the two-component dynamic model combining competitive attitude and behavior, which helps promote understanding of the dynamics of competition and its consequences at the individual level. Theoretical and practical implications are also discussed. PMID- 30524336 TI - The Effect of Childhood Adversities and Protective Factors on the Development of Child-Psychiatric Disorders and Their Treatment. AB - Context: Families with high rates of childhood adversities (CAs) (multi problem families, MPF) have an increasing importance in public health-policy. Objective: The present study addresses the relationship between risk- and protective factors and the severity and treatment-outcome of mental disorders. Setting: Family therapeutic home-based treatment for MPF. We examined a clinical sample (N = 1031) of children between the age of 4 to 17, and a non-clinical sample of 148 children. We hypothesized that of all children of the clinical group have a predominance of risk factors and a higher number of psychopathological symptoms. Furthermore, we hypothesized that children with a predominance of protective factors benefit stronger from psychotherapy. Main Results: In the clinical sample, most children met the criteria of a psychopathological diagnosis (95.7%, as compared to 21.6% in the non-clinical sample) and showed significant higher rates of CAs and significant less protective factors as compared to the non clinical sample. The clinical group showed a significant reduction of psychopathological symptoms and benefited equally well from treatment. The number of risk factors was a significant predictor for a child from the non-clinical sample to meet the criteria of a psychopathological diagnosis, while the number of protective factors significantly predicted the absence thereof. Conclusion: Children and adolescents with high scores of CAs show significant associations with child psychiatric symptoms (d = 0.35; including all ICD-diagnosis such as, e.g., Asperger Syndrome, ADHD etc. with a higher rate of genetic etiology). Early life stressors, however, do not trigger an irreversible fate, as psychotherapy with young people with high numbers of risk factors does help to reduce psychopathological symptoms significantly (range of five outcome parameters: d = 0.31-0.72). PMID- 30524337 TI - Effect of Intranasal Oxytocin Administration on Human-Directed Social Behaviors in Shelter and Pet Dogs. AB - A wide variety of evidence has demonstrated that oxytocin is involved in socio cognitive skills in domestic dogs (Canis familiaris). The purpose was to evaluate the effect of oxytocin administration on socio-cognitive abilities in two populations of dogs with different levels of daily human contact: shelter and pet dogs. Additionally, the effect of different doses of oxytocin (i.e., 16 and 24 IU) was assessed. To this end, dogs were tested on two tasks: a sociability test to assess their social responses and a communicative task focused on the learning of gazing responses. Results showed that pet dogs performed better than shelter dogs on the sociability and the gazing tests showing the relevance of dogs' previous experience and learning when interacting with people. The administration of 16 IU as well as 24 IU of oxytocin improved the performance on the communicative learning task, producing an increment in gaze duration during extinction. This difference was observed in both pet and shelter dogs. Therefore, oxytocin seems to participate in the persistence of this communicative response. However, the treatment did not modify the behaviors during the sociability test. Furthermore, oxytocin appears to be beneficial to increase the communicative abilities of shelter dogs. PMID- 30524338 TI - Classification Videos Reveal the Visual Information Driving Complex Real-World Speeded Decisions. AB - Humans can rapidly discriminate complex scenarios as they unfold in real time, for example during law enforcement or, more prosaically, driving and sport. Such decision-making improves with experience, as new sources of information are exploited. For example, sports experts are able to predict the outcome of their opponent's next action (e.g., a tennis stroke) based on kinematic cues "read" from preparatory body movements. Here, we explore the use of psychophysical classification-image techniques to reveal how participants interpret complex scenarios. We used sport as a test case, filming tennis players serving and hitting ground strokes, each with two possible directions. These videos were presented to novices and club-level amateurs, running from 0.8 s before to 0.2 s after racquet-ball contact. During practice, participants anticipated shot direction under a time limit targeting 90% accuracy. Participants then viewed videos through Gaussian windows ("bubbles") placed at random in the temporal, spatial or spatiotemporal domains. Comparing bubbles from correct and incorrect trials revealed how information from different regions contributed toward a correct response. Temporally, only later frames of the videos supported accurate responding (from ~0.05 s before ball contact to 0.1 s afterwards). Spatially, information was accrued from the ball's trajectory and from the opponent's head. Spatiotemporal bubbles again highlighted ball trajectory information, but seemed susceptible to an attentional cuing artifact, which may caution against their wider use. Overall, bubbles proved effective in revealing regions of information accrual, and could thus be applied to help understand choice behavior in a range of ecologically valid situations. PMID- 30524339 TI - Comprehending Non-literal Language: Effects of Aging and Bilingualism. AB - A pressing issue that the twenty-first century is facing in many parts of the developed world is a rapidly aging population. Whilst several studies have looked at aging older adults and their language use in terms of vocabulary, syntax and sentence comprehension, few have focused on the comprehension of non-literal language (i.e., pragmatic inference-making) by aging older adults, and even fewer, if any, have explored the effects of bilingualism on pragmatic inferences of non-literal language by aging older bilinguals. Thus, the present study examined the effects of age(ing) and the effects of bilingualism on aging older adults' ability to infer non-literal meaning. Four groups of participants made up of monolingual English-speaking and bilingual English-Tamil speaking young (17-23 years) and older (60-83 years) adults were tested with pragmatic tasks that included non-conventional indirect requests, conversational implicatures, conventional metaphors and novel metaphors for both accuracy and efficiency in terms of response times. While the study did not find any significant difference between monolinguals and bilinguals on pragmatic inferences, there was a significant effect of age on one type of non-literal language tested: conventional metaphors. The effect of age was present only for the monolinguals with aging older monolinguals performing less well than the young monolinguals. Aging older bilingual adults were not affected by age whilst processing conventional metaphors. This suggests a bilingual advantage in pragmatic inferences of conventional metaphors. PMID- 30524340 TI - Psychological Hibernation in Antarctica. AB - Human activity in Antarctica has increased sharply in recent years. In particular during the winter months, people are exposed to long periods of isolation and confinement and an extreme physical environment that poses risks to health, well being and performance. The present study aimed to gain a better understanding of processes contributing to psychological resilience in this context. Specifically, the study examined how the use of coping strategies changed over time, and the extent to which changes coincided with alterations in mood and sleep. Two crews (N = 27) spending approximately 10 months at the Concordia station completed the Utrecht Coping List, the Positive and Negative Affect Schedule (PANAS), and a structured sleep diary at regular intervals (x 9). The results showed that several variables reached a minimum value during the midwinter period, which corresponded to the third quarter of the expedition. The effect was particularly noticeable for coping strategies (i.e., active problem solving, palliative reactions, avoidance, and comforting cognitions). The pattern of results could indicate that participants during Antarctic over-wintering enter a state of psychological hibernation as a stress coping mechanism. PMID- 30524341 TI - Assessment of Unilateral Spatial Neglect Using a Free Mobile Application for Italian Clinicians. AB - Background: Unilateral Spatial Neglect (USN) is traditionally assessed with paper and-pencil tests or computer-based tests. Thanks to the wide-spreading of mobile devices, and the extensive capabilities that they have in dealing complex elements, it is possible to provide clinicians with tools for cognitive assessment. Contemporary 3D engine is, in general generally, able to deploy complex 3D environments for iOS, Android and Windows mobile, i.e., most of the mobile phone and tablet operative systems. Results: This brand-new scenario and pressing requests from professionals, pushed us to build an application for the assessment of USN. Our first attempt was to replicate the classic cognitive tests, traditionally used at this purpose. Ecological assessment is difficult in real scenarios so we implemented virtual environments to assess patients' abilities in realistic situations. At the moment, the application is available only for iPad and iPhone for free, from the Apple Store, under the name of "Neglect App." The App contains traditional tests (e.g., barrage with and without distractors) and ecological tests (e.g., to distribute the tea in a table to close people). Scoring of each test is available to the clinicians through a database with the executed ecological tasks, that are stored locally. Conclusion: In conclusion, Neglect App is an advanced mobile platform for the assessment of Neglect. PMID- 30524342 TI - Orthographic Networks in the Developing Mental Lexicon. Insights From Graph Theory and Implications for the Study of Language Processing. AB - In this study, we examine the development of orthographic networks in the mental lexicon using graph theory. According to this view, words are represented by nodes in a network and connected as a function of their orthographic similarity. With a sampling approach based on a language corpus for German school children, we were able to simulate lexical development for children from Grade 1-8. By sampling different lexicon sizes from the corpus, we were able to analyze the content of the orthographic lexicon at different time points and examined network characteristics using graph theory. Results show that, similar to semantic and phonological networks, orthographic networks possess small-word characteristics defined by short average path lengths between nodes and strong local clustering. Moreover, the interconnectivity of the network decreases with growth. Implications for the study of the effect of network measures on language processing are discussed. PMID- 30524343 TI - Commentary : The Developmental Trajectory of the Operational Momentum Effect. PMID- 30524344 TI - Ich kann nicht anders: Social Heroism as Nonselfsacrificial Practical Necessity. AB - Most self-reports of heroic action in both reactive and social (proactive) cases describe the experience as involving a kind of necessity. This seems intuitively sound, but it makes it unclear why heroism is accorded strong approbation. To resolve this, I show that the necessity involved in heroism is a nonselfsacrificial practical necessity. (1) Approaching the intentional structure of human action from the perspective of embodiment, focusing especially on the predispositionality of pre-reflective skill, I develop a phenomenological interpretation of Bernard Williams' notion of "practical necessity" as an endogenous existential necessity. (2) I then offer a view of reactive heroism as instantiating this kind of necessity by literally embodying certain socially affirmed values in a way that is not self-sacrificial. This evinces a deep social bond, and it is this bond, rather than the action itself, that is the ground of approbation. (3) I then discuss how this construal of reactive heroism can be extended to cases of social heroism by way of a necessity that is internal to the agent's individual character. Similarly to reactive cases, a social hero literally embodies a certain ethical commitment such that her actions are likewise instances of nonselfsacrificial practical necessity. (4) I then discuss how the commitment perceived in cases of social heroism pertains to the actualization of "surplus validity," such that whereas the reactive hero is praised for embodying shared value, the social hero is praised for embodying a commitment to actualizing the concrete potential of such value more fully The approbation accorded to social heroism is therefore tied inextricably to a normative judgment concerning such immanent progressive transformation. PMID- 30524345 TI - Mechanisms of Epistemic Change-Under Which Circumstances Does Diverging Information Support Epistemic Development? AB - Background: The number of studies on how to foster change toward advanced epistemic beliefs (i.e., beliefs about the nature of knowledge and knowing) is continuously growing because these beliefs are an important predictor of learning outcomes. In past intervention studies, presenting diverging information (e.g., descriptions of studies yielding contradictory results) reliably led to epistemic change. However, prior research insufficiently examined which aspects of diverging information affect these changes. Aims: We investigated (1) if epistemic change differs depending on the (un)resolvability of contradictory information, (2) to what extent explicitly reflecting on diverging information supports epistemic change and (3) how topic-specific diverging information affects topic-and domain-specific epistemic beliefs. All confirmatory hypotheses were preregistered at OSF. Additionally, several exploratory analyses were conducted. Method: To examine the research questions, we employed a simple randomized pre-post design with four experimental groups. N = 185 psychology students participated in the study. Experimental groups differed in the kind of diverging information included: Students either read (1) information on students applying learning strategies (control), (2) unresolvable, or (3a) resolvable controversial information on gender stereotyping. In the latter condition (3b), an additional group of participants deliberately resolved apparent contradictions in a writing task. Results: Confirmatory latent change analyses revealed no significant group differences in epistemic change (i.e., beliefs in the control group also changed toward advanced epistemic beliefs). Using a different methodological approach, subsequent exploratory analyses nevertheless showed that presenting diverging information on gender stereotypes produced stronger topic specific epistemic change and change in justification beliefs in the treatment groups in contrast to the control group. However, effects in the treatment groups did not differ significantly depending on the resolvability of presented controversies or for the group which was instructed explicitly to integrate controversial findings. Conclusion: Contrary to our expectations, diverging information seems to foster epistemic change toward advanced beliefs regardless of the resolvability of presented information, while no final conclusion concerning effects of reflection could be drawn. Moreover, our findings indicate that effects of topic-specific interventions are more pronounced on topic specific measures. However, this relationship may vary depending on the epistemic belief dimension (e.g., justification beliefs) under investigation. PMID- 30524346 TI - Ten Years After Bariatric Surgery: Bad Quality of Life Promotes the Need of Psychological Interventions. AB - Background: This study aims to evaluate long-term quality of life (QoL) and primary clinical outcomes, 10 years after biliointestinal bypass (BIB) surgery. It was expected that, although BIB might show encouraging primary outcomes, long term QoL could be significantly impaired. Methods: Ninety patients were contacted for a phone interview [age 41.0 +/- 10.6 (mean +/- SD) years, age-range 31-65 years]. QoL (by SF-36) and the clinical situation (by ad hoc questionnaire) were collected. Data were analyzed with SPSS 22. SF-36 scores were compared with Italian normative data from general and healthy population. We also compared primary clinical outcomes and SF-36 scores between patients who reported high and low levels of satisfaction with BIB. Results: Considering SF-36 results, patients showed significant impairments in QoL compared to general and healthy populations. Sixty-five percent would repeat the BIB. All patients showed at least one chronic adverse event. It occurred a significant decrease in pre-post co-occurrence rates of diabetes (chi2 = 18.41; p < 0.001) and hypertension (chi2 = 50.27; p < 0.001). Large and significant weight loss indexes (i.e., percent excess weight loss (%EWL); body mass index) were observed between pre-post intervention. Conclusion: BIB showed promising primary clinical outcomes (i.e., hypertension, diabetes, and weight loss). However, subjects reported a significant impairment in all SF-36 domains. Ad hoc psychological interventions should be implemented to ameliorate the quality of life of these patients. PMID- 30524347 TI - Side Biases in Euro Banknotes Recognition: The Horizontal Mapping of Monetary Value. AB - Money is a special stimulus for humans, because of its relevance in everyday life. However, the basic mechanisms underlying money representation have not yet been fully investigated. Left-right asymmetries in the visual perception and evaluation of monetary value offer such a possibility. The pattern of these asymmetries can contribute to disentangle between numerical and emotional processes possibly involved in banknotes perception. In the present experiment, we tested the recognition of 5?and 100? banknotes presented in the left and right visual fields. Results show that the 100? banknote is recognized faster than the 5? banknote in the Right Visual Field (RVF), while there is no difference in the Left Visual Field (LVF). Our interpretation is that this effect is due to the matching between the positive valence conveyed by the 100? banknote and the side in which it is mapped (right-positive). We consider this result as evidence of a valence-based recognition of banknotes. PMID- 30524348 TI - An Empirical Analysis of Popular Press Claims Regarding Linguistic Change in President Donald J. Trump. AB - Linguistic features of a person's speech can change over time. It has been proposed that characteristics in the speech of President Donald J. Trump (DJT) have changed across time, though this claim has been based on subjective and anecdotal reports. A previous study of speech by Presidents of the United States identified an increase in the use of conversational fillers and non-specific nouns, and lower unique word counts, in the speech of President Ronald W. Reagan, but not in the speech of President George H.W. Bush. To empirically test claims of a systematic change in speech by DJT, we applied the same analysis by transcribing and analyzing publicly available Fox News interviews with DJT between 2011 and 2017. A regression analysis revealed a significant increase in the use of filler words by DJT over time. There was no significant change in numbers of unique words. The observed rise in filler words was significantly greater than filler-word change in President George H.W. Bush, and was not significantly different from the rise previously found in the speech of President Ronald W. Reagan. Identifying the reason for this linguistic change is not possible from speech samples alone, and the variables index linguistic change rather than being validated measures of change in cognitive ability. Nonetheless, features of the data such as the trajectory starting years before announcement of candidacy rule-out several potential explanations. To summarize, we find statistical evidence to support suggestions that speech by DJT has changed over time. PMID- 30524349 TI - Telerehabilitation Combined Speech-Language and Cognitive Training Effectively Promoted Recovery in Aphasia Patients. AB - The present study investigated the efficacy of a computerized intervention for aphasia that combined speech-language and cognitive training delivered on an inpatient unit or via telerehabilitation to discharged patients. Forty inpatient and discharged aphasia patients were recruited and randomly assigned to the training group or control group. Computerized speech-language and cognitive training was provided for 14 days to the inpatients and 30 days to the discharged patients. Compared with the control group, training group had significantly more improved language function as assessed by the Western Aphasia Battery (WAB) and practical communication skills as assessed by the Communicative Abilities in Daily Living Test (CADL). It was also found that the positive effects of the computerized training when delivered via telerehabilitation to the discharged group were smaller than the effects when delivered on the inpatient unit. The results suggest that combining speech-language and cognitive training program is efficacious in promoting the recovery of patients with aphasia, both inpatients and discharged patients, and that the program works even when administered from a remote location. PMID- 30524350 TI - Commentary: The Attraction Effect in Decision Making: Superior Performance by Older Adults. PMID- 30524351 TI - Pulvinar Lesions Disrupt Fear-Related Implicit Visual Processing in Hemianopic Patients. AB - The processing of emotional stimuli in the absence of awareness has been widely investigated in patients with lesions to the primary visual pathway since the classical studies on affective blindsight. In addition, recent evidence has shown that in hemianopic patients without blindsight only unseen fearful faces can be implicitly processed, inducing enhanced visual encoding (Cecere et al., 2014) and response facilitation (Bertini et al., 2013, 2017) to stimuli presented in their intact field. This fear-specific facilitation has been suggested to be mediated by activity in the spared visual subcortical pathway, comprising the superior colliculus (SC), the pulvinar and the amygdala. This suggests that the pulvinar might represent a critical relay structure, conveying threat-related visual information through the subcortical visual circuit. To test this hypothesis, hemianopic patients, with or without pulvinar lesions, performed a go/no-go task in which they had to discriminate simple visual stimuli, consisting in Gabor patches, displayed in their intact visual field, during the simultaneous presentation of faces with fearful, happy, and neutral expressions in their blind visual field. In line with previous evidence, hemianopic patients without pulvinar lesions showed response facilitation to stimuli displayed in the intact field, only while concurrent fearful faces were shown in their blind field. In contrast, no facilitatory effect was found in hemianopic patients with lesions of the pulvinar. These findings reveal that pulvinar lesions disrupt the implicit visual processing of fearful stimuli in hemianopic patients, therefore suggesting a pivotal role of this structure in relaying fear-related visual information from the SC to the amygdala. PMID- 30524352 TI - Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients. AB - In patients with temporal lobe epilepsy (TLE), presurgical magnetic resonance imaging (MRI) often reveals hippocampal atrophy, while neuropathological assessment indicates the different types of hippocampal sclerosis (HS). Different HS types are not discriminated in MRI so far. We aimed to define the volume of each hippocampal subfield on MRI manually and to compare automatic and manual segmentations for the discrimination of HS types. The T2-weighted images from 14 formalin-fixed age-matched control hippocampi were obtained with 4.7T MRI to evaluate the volume of each subfield at the anatomical level of the hippocampal head, body, and tail. Formalin-fixed coronal sections at the level of the body of 14 control cases, as well as tissue samples from 24 TLE patients, were imaged with a similar high-resolution sequence at 3T. Presurgical three-dimensional (3D) T1-weighted images from TLE went through a FreeSurfer 6.0 hippocampal subfield automatic assessment. The manual delineation with the 4.7T MRI was identified using Luxol Fast Blue stained 10-MUm-thin microscopy slides, collected at every millimeter. An additional section at the level of the body from controls and TLE cases was submitted to NeuN immunohistochemistry for neuronal density estimation. All TLE cases were classified according to the International League Against Epilepsy's (ILAE's) HS classification. Manual volumetry in controls revealed that the dentate gyrus (DG)+CA4 region, CA1, and subiculum accounted for almost 90% of the hippocampal volume. The manual 3T volumetry showed that all TLE patients with type 1 HS (TLE-HS1) had lower volumes for DG+CA4, CA2, and CA1, whereas those TLE patients with HS type 2 (TLE-HS2) had lower volumes only in CA1 (p <= 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 (p <= 0.003). In addition, TLE-HS2 had a higher volume (p = 0.016) and higher neuronal density (p < 0.001) than the TLE-HS1 in DG + CA4. Automatic segmentation failed to match the manual or histological findings and was unable to differentiate TLE-HS1 from TLE-HS2. Total hippocampal volume correlated with DG+CA4 and CA1 volumes and neuronal density. For the first time, we also identified subfield-specific pathology patterns in the manual evaluation of volumetric MRI scans, showing the importance of manual segmentation to assess subfield-specific pathology patterns. PMID- 30524353 TI - Functional Outcome and Safety of Intracranial Thrombectomy After Emergent Extracranial Stenting in Acute Ischemic Stroke Due to Tandem Occlusions. AB - Background and Purpose: Various endovascular approaches to treat acute ischemic stroke caused by extra- intracranial tandem occlusions (TO) exist: percutaneous transluminal angioplasty with or without emergent extracranial carotid stenting (ECS) due to high-grade stenosis preceded or followed by intracranial mechanical and/or aspiration thrombectomy (MT). Which treatment strategy to use is still a matter of debate. Methods: From our ongoing prospective stroke registry we retrospectively analyzed 1,071 patients with anterior circulation stroke getting endovascular treatment within 6 h of symptom onset. ECS prior to intracranial MT for TO (n = 222) was compared to MT as standard of care (control group; acute intracranial vessel occlusion without concomitant ipsilateral ICA-occlusion or high-grade stenosis [C; n = 849]). Good functional outcome (mRS <= 2 at 3 months), mortality rates, frequencies of symptomatic intracranial hemorrhage (sICH) and successful recanalization (Thrombolysis in Cerebral Infarction Score [TICI] 2b or 3) were assessed. In subgroup analyses we tried to detect possible influences of stroke etiology, dual inhibition of platelet aggregation (IPA; clopidogrel [CLO]: n = 83; ticagrelor [TIC]: n = 137; in combination with Aspirin) and intravenous thrombolysis (IVT). Results: Functional outcome was superior in TO (mRS 0-2: 44.6%) when compared with controls (36.0%; OR [95% CI]: 3.49 [1.59-7.67]; p = 0.002). There was no difference in all-cause mortality at 3 months (TO: 21.6%; C: 27.7%; 0.78 [0.47-1.29]; p = 0.324), in-hospital mortality (0.76 [0.45-1.30]; p = 0.324), sICH (TO: 3.2%; C: 5.0%; 0.70 [0.30-1.59]; p = 0.389), and TICI 2b/3 (TO: 89.1%; C: 88.3%; p = 0.813). In subgroup-analysis, TIC and CLO did not differ in functional outcome (TIC: 45.3%; CLO: 44.6%; 1.04 [0.51 2.09]; p = 0.920) and mortality rates (all-cause mortality: TIC: 23.4%; CLO: 16.9%; 0.75 [0.27-2.13]; p = 0.594). sICH was more frequent in TIC (n = 7 [5.1%]) vs. CLO (n = 0; p = 0.048). Conclusion: In our pre-selected cohort, ECS prior to intracranial MT in TO allowed for a good functional outcome that was superior compared to a control population. Mortality rates did not differ. Despite a dual IPA in TO, there was no increase in sICH. CLO and TIC for dual IPA did not differ in terms out outcome and mortality rates. A significant increase in sICH was observed after initial loading with TIC. PMID- 30524354 TI - The Peripheral Inflammatory Response to Alpha-Synuclein and Endotoxin in Parkinson's Disease. AB - The immune system is activated in Parkinson's Disease (PD), as evidenced by neuroinflammatory changes within the brain as well as elevated immune markers in peripheral blood. Furthermore, inflammatory cytokine levels in the blood are associated with disease severity and rate of progression. However, the factors driving this immune response in PD are not well established. We investigated cell extrinsic factors in systemic immune activation by using alpha-synuclein monomers and fibrils, as well as bacterial toxins, to stimulate peripheral blood mononuclear cells (PBMCs) derived from 31 patients and age/gender-matched controls. alpha-synuclein monomers or fibrils resulted in a robust cytokine response (as measured by supernatant cytokine concentrations and mRNA expression in cultured cells) in both PD and control PBMCs, similar to that induced by bacterial LPS. We found no PD vs. control differences in cytokine production, nor in mRNA expression. Levels of endotoxin within the recombinant alpha-synuclein used in these experiments were very low (0.2-1.3EU/mL), but nonetheless we found that comparable levels were sufficient to potentially confound our cytokine concentration measurements for a number of cytokines. However, alpha-synuclein monomers increased production of IL-1beta and IL-18 to levels significantly in excess of those induced by low-level endotoxin. In conclusion, this study: (i) highlights the importance of accounting for low-level endotoxin in antigen-PBMC stimulation experiments; (ii) indicates that cell-extrinsic factors may be a major contributor to immune activation in PD; and (iii) suggests that alpha synuclein may play a role in inflammasome-related cytokine production in the periphery. PMID- 30524355 TI - Regular Exercise Modifies Histopathological Outcomes of Pharmacological Treatment in Experimental Autoimmune Encephalomyelitis. AB - Background: Although it has been suggested that healthier lifestyle may optimize effects of the immunomodulation drugs for treating multiple sclerosis (MS), the knowledge regarding this kind of interactions is limited. Objective: The aim of the present study was to investigate the effects of treadmill exercise in combination with pharmacological treatment in an animal model for MS. Methods: C57BL/6J female mice were subjected to daily treadmill exercise for 4 weeks before immunization and 6 weeks before clinical presentation of disease. Dimethyl fumarate (DMF) or glatiramer acetate (GA) were administered after the first clinical relapse. Histopathological analyses were carried out in the lumbar spinal cord at peak disease and at 1 or 14 days post-treatment (dpt). Results: Exercised-GA treated animals demonstrated decreased astrocytic response in the spinal dorsal horn with an improvement in the paw print pressure. Exercised-DMF treated animals showed an increased microglial/macrophage response on both ventral and dorsal horn that were associated with clinical improvement and synaptic motoneuron inputs density. Conclusion: The present data suggest that prior regular exercise can modify the effects of pharmacological treatment administered after the first relapse in a murine model for MS. PMID- 30524356 TI - Gait Stability Training in a Virtual Environment Improves Gait and Dynamic Balance Capacity in Incomplete Spinal Cord Injury Patients. AB - Many patients with incomplete spinal cord injury (iSCI) have impaired gait and balance capacity, which may impact daily functioning. Reduced walking speed and impaired gait stability are considered important underlying factors for reduced daily functioning. With conventional therapy, patients are limited in training gait stability, but this can be trained on a treadmill in a virtual environment, such as with the Gait Real-time Analysis Interactive Lab (GRAIL). Our objective was to evaluate the effect of 6-weeks GRAIL-training on gait and dynamic balance in ambulatory iSCI patients. In addition, the long-term effect was assessed. Fifteen patients with chronic iSCI participated. The GRAIL training consisted of 12 one-hour training sessions during a 6-week period. Patients performed 2 minute walking tests on the GRAIL in a self-paced mode at the 2nd, and 3rd (baseline measurements) and at the 12th training session. Ten patients performed an additional measurement after 6 months. The primary outcome was walking speed. Secondary outcomes were stride length, stride frequency, step width, and balance confidence. In addition, biomechanical gait stability measures based on the position of the center of mass (CoM) or the extrapolated center of mass (XCoM) relative to the center of pressure (CoP) or the base of support (BoS) were derived: dynamic stability margin (DSM), XCoM-CoP distance in anterior-posterior (AP) and medial-lateral (ML) directions, and CoM-CoP inclination angles in AP and ML directions. The effect of GRAIL-training was tested with a one-way repeated measures ANOVA (alpha = 0.05) and post-hoc paired samples t-tests (alpha = 0.017). Walking speed was higher after GRAIL training (1.04 m/s) compared to both baseline measurements (0.85 and 0.93 m/s) (p < 0.001). Significant improvements were also found for stride length (p < 0.001) and stability measures in AP direction (XCoM-CoPAP (p < 0.001) and CoM-CoPAP-angle (p < 0.001)). Stride frequency (p = 0.27), step width (p = 0.19), and stability measures DSM (p = 0.06), XCoM-CoPML (p = 0.97), and CoM-CoPML-angle (p = 0.69) did not improve. Balance confidence was increased after GRAIL training (p = 0.001). The effects were remained at 6 months. Increased walking speed, stride length, AP gait stability, and balance confidence suggest that GRAIL-training improves gait and dynamic balance in patients with chronic iSCI. In contrast, stability measures in ML direction did not respond to GRAIL-training. PMID- 30524357 TI - Intracerebral Hemorrhage Induces Cardiac Dysfunction in Mice Without Primary Cardiac Disease. AB - Background: Intracerebral hemorrhage (ICH) is a life threatening stroke subtype and a worldwide health problem. In this study, we investigate brain-heart interaction after ICH in mice and test whether ICH induces cardiac dysfunction in the absence of primary cardiac disease. We also investigate underlying mechanisms such as oxidative stress and inflammatory responses in mediating cardiac dysfunction post-ICH in mice. Methods: Male, adult (3-4 m) C57BL/6J mice were subjected to sham surgery or ICH using an autologous blood injection model (n = 16/group). Cardiac function was evaluated at 7 and 28 days after ICH using echocardiography (n = 8/group per time point). Western blot and immunostaining analysis were employed to assess oxidative stress and inflammatory responses in the heart. Results: Mice subjected to ICH exhibited significantly decreased cardiac contractile function measured by left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) at 7 and 28 days after ICH compared to sham-control mice (p < 0.05). ICH induced cardiac dysfunction was significantly worse at 28 days than at 7 days after ICH (p < 0.05). ICH in mice significantly increased cardiomyocyte apoptosis, inflammatory factor expression and inflammatory cell infiltration in heart tissue, and induced cardiac oxidative stress at 7 days post-ICH compared to sham-control mice. Compared to sham-control mice, ICH-mice also exhibited significantly increased (p < 0.05) cardiomyocyte hypertrophy and cardiac fibrosis at 28 days after ICH. Conclusions: ICH induces significant and progressive cardiac dysfunction in mice. ICH increases cardiac oxidative stress and inflammatory factor expression in heart tissue which may play key roles in ICH-induced cardiac dysfunction. PMID- 30524358 TI - Serum Levels of Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor 1 Are Associated With Autonomic Dysfunction and Impaired Cerebral Autoregulation in Patients With Epilepsy. AB - Background: Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) may regulate the autonomic nervous system (ANS) in epilepsy. The present study investigated the role of IGF-1 and BDNF in the regulation of autonomic functions and cerebral autoregulation in patients with epilepsy. Methods: A total of 57 patients with focal epilepsy and 35 healthy controls were evaluated and their sudomotor, cardiovagal, and adrenergic functions were assessed using a battery of ANS function tests, including the deep breathing, Valsalva maneuver, head-up tilting, and Q-sweat tests. Cerebral autoregulation was measured by transcranial doppler during the breath-holding test and the Valsalva maneuver. Interictal serum levels of BDNF and IGF-1 were measured with enzyme-linked immunosorbent assay kits. Results: During interictal period, reduced serum levels of BDNF and IGF-1, impaired autonomic functions, and decreased cerebral autoregulation were noted in patients with epilepsy compared with healthy controls. Reduced serum levels of BDNF correlated with age, adrenergic and sudomotor function, overall autonomic dysfunction, and the autoregulation index calculated in Phase II of the Valsalva maneuver, and showed associations with focal to bilateral tonic-clonic seizures. Reduced serum levels of IGF-1 were found to correlate with age and cardiovagal function, a parameter of cerebral autoregulation (the breath-hold index). Patients with a longer history of epilepsy, higher seizure frequency, and temporal lobe epilepsy had lower serum levels of IGF-1. Conclusions: Long-term epilepsy and severe epilepsy, particularly temporal lobe epilepsy, may perturb BDNF and IGF-1 signaling in the central autonomic system, contributing to the autonomic dysfunction and impaired cerebral autoregulation observed in patients with focal epilepsy. PMID- 30524359 TI - Complications of Decompressive Craniectomy. AB - Decompressive craniectomy (DC) has become the definitive surgical procedure to manage medically intractable rise in intracranial pressure due to stroke and traumatic brain injury. With incoming evidence from recent multi-centric randomized controlled trials to support its use, we could expect a significant rise in the number of patients who undergo this procedure. Although one would argue that the procedure reduces mortality only at the expense of increasing the proportion of the severely disabled, what is not contested is that patients face the risk of a large number of complications after the operation and that can further compromise the quality of life. Decompressive craniectomy (DC), which is designed to overcome the space constraints of the Monro Kellie doctrine, perturbs the cerebral blood, and CSF flow dynamics. Resultant complications occur days to months after the surgical procedure in a time pattern that can be anticipated with advantage in managing them. New or expanding hematomas that occur within the first few days can be life-threatening and we recommend CT scans at 24 and 48 h postoperatively to detect them. Surgeons should also be mindful of the myriad manifestations of peculiar complications like the syndrome of the trephined and neurological deterioration due to paradoxical herniation which may occur many months after the decompression. A sufficiently large frontotemporoparietal craniectomy, 15 cm in diameter, increases the effectiveness of the procedure and reduces chances of external cerebral herniation. An early cranioplasty, as soon as the brain is lax, appears to be a reasonable choice to mitigate many of the late complications. Complications, their causes, consequences, and measures to manage them are described in this chapter. PMID- 30524360 TI - Perturbation-Based Balance Training to Improve Step Quality in the Chronic Phase After Stroke: A Proof-of-Concept Study. AB - Introduction: People with stroke often have impaired stepping responses following balance perturbations, which increases their risk of falling. Computer-controlled movable platforms are promising tools for delivering perturbation-based balance training under safe and standardized circumstances. Purpose: This proof-of concept study aimed to identify whether a 5-week perturbation-based balance training program on a movable platform improves reactive step quality in people with chronic stroke. Materials and Methods: Twenty people with chronic stroke received a 5-week perturbation-based balance training (10 sessions, 45 min) on a movable platform. As the primary outcome, backward, and forward reactive step quality (i.e., leg angle at stepping-foot contact) was assessed with a lean-and release (i.e., non-trained) task at pre-intervention, immediately post intervention, and 6 weeks after intervention (follow-up). Additionally, reactive step quality was assessed on the movable platform in multiple directions, as well as, the percentage side steps upon sideward perturbations. To ensure that changes in the primary outcome could not solely be attributed to learning effects on the task due to repeated testing, 10 randomly selected participants received an additional pre-intervention assessment, 6 weeks prior to training. Clinical assesments included the 6-item Activity-specific Balance Confidence (6-ABC) scale, Berg Balance Scale (BBS), Trunk Impairment Scale (TIS), 10-Meter Walking Test (10-MWT), and Timed Up and Go-test (TUG). Results: After lean-and-release, we observed 4.3 degrees and 2.8 degrees greater leg angles at post compared to pre-intervention in the backward and forward direction, respectively. Leg angles also significantly improved in all perturbation directions on the movable platform. In addition, participants took 39% more paretic and 46% more non paretic side steps. These effects were retained at follow-up. Post-intervention, BBS and TIS scores had improved. At follow-up, TIS and 6-ABC scores had significantly improved compared to pre-intervention. No significant changes were observed between the two pre-intervention assessments (n=10). Conclusion: A 5 week perturbation-based balance training on a movable platform appears to improve reactive step quality in people with chronic stroke. Importantly, improvements were retained after 6 weeks. Further controlled studies in larger patient samples are needed to verify these results and to establish whether this translates to fewer falls in daily life. Trial registration: The Netherlands National Trial Register (NTR3804). http://www.trialregister.nl/trialreg/admin/rctview.aspTC=3804. PMID- 30524361 TI - Neurofilament Light Chain: Blood Biomarker of Neonatal Neuronal Injury. AB - Background: Neurofilament light chain (NfL) is a highly promising biomarker of neuroaxonal injury that has mainly been studied in adult neurodegenerative disease. Its involvement in neonatal disease remains largely unknown. Our aim was to establish NfL plasma concentrations in preterm and term infants in the first week of life. Methods: Plasma NfL was measured by single molecule array immunoassay in two neonatal cohorts: cohort 1 contained 203 term and preterm infants, median gestational age (GA) 37.9 weeks (interquartile range [IQR] 31.9 39.4), in whom venous and arterial umbilical cord blood was sampled at birth and venous blood at day of life (DOL) 3; cohort 2 contained 98 preterm infants, median GA 29.3 weeks (IQR 26.9-30.6), in whom venous blood was sampled at DOL 7. Results: Median NfL concentrations in venous blood increased significantly from birth (18.2 pg/mL [IQR 12.8-30.8, cohort 1]) to DOL 3 (50.9 pg/mL [41.3-100, cohort 1]) and DOL 7 (126 pg/mL [78.8-225, cohort 2]) (p < 0.001). In both cohorts NfL correlated inversely with birth weight (BW, Spearman's rho -0.403, p < 0.001, cohort 1; R -0.525, p < 0.001, cohort 2) and GA (R -0.271, p < 0.001, cohort 1; R -0.487, p < 0.001, cohort 2). Additional significant correlations were found for maternal age at delivery, preeclampsia, delivery mode, 5-min Apgar, duration of oxygen supplementation, sepsis, and brain damage (intraventricular hemorrhage or periventricular leukomalacia). Multivariable logistic regression analysis identified the independent predictors of NfL in cohort 1 as BW (beta = -0.297, p = 0.003), delivery mode (beta = 0.237, p = 0.001) and preeclampsia (beta = 0.183, p = 0.022) and in cohort 2 as BW (beta = 0.385, p = 0.001) and brain damage (beta = 0.222, p = 0.015). Conclusion: Neonatal NfL levels correlate inversely with maturity and BW, increase during the first days of life, and relate to brain injury factors such as intraventricular hemorrhage and periventricular leukomalacia, and also to vaginal delivery. PMID- 30524362 TI - A Novel Non-invasive Approach for Measuring Upper Airway Collapsibility in Mice. AB - Introduction: Invasive procedures were previously developed for measuring pharyngeal collapsibility in rodents during expiration, when declining neuromuscular activity makes the airway unstable. We developed a non-invasive approach for streamlining collapsibility measurements by characterizing responses in physiologic markers of dynamic expiratory airflow obstruction to negative nasal pressure challenges. Methods: Anesthetized mice were instrumented to monitor upper airway pressure-flow relationships with head-out plethysmography while nasal pressure was ramped down from ~ +5 to -20 cm H2O over several breaths. Inspiratory and expiratory flow, volume, and timing characteristics were assessed breath-wise. Pcrit was estimated at transitions in expiratory amplitude and timing parameters, and compared to gold standard PCRIT measurements when nasal and tracheal pressures diverged during expiration. Predictions equations were constructed in a development data set (n = 8) and applied prospectively to a validation data set (n = 16) to estimate gold standard PCRIT. Results: The development data demonstrated that abrupt reversals in expiratory duration and tidal volume during nasal pressure ramps predicted gold standard PCRIT measurements. After applying regression equations from the development to a validation dataset, we found that a combination of expiratory amplitude and timing parameters proved to be robust predictors of gold standard PCRIT with minimal bias and narrow confidence intervals. Conclusions: Markers of expiratory airflow obstruction can be used to model upper airway collapsibility, and can provide sensitive measures of changes in airway collapsibility in rodents. This approach streamlines repeated non-invasive PCRIT measurements, and facilitates studies examining the impact of genetic, environmental, and pharmacologic factors on upper airway control. PMID- 30524363 TI - An Initial Passive Phase That Limits the Time to Recover and Emphasizes the Role of Proprioceptive Information. AB - In the present experiments, multiple balance perturbations were provided by unpredictable support-surface translations in various directions and velocities. The aim of this study was to distinguish the passive and the active phases during the pre-impact period of a fall. It was hypothesized that it should be feasible if one uses a specific quantitative kinematic analysis to evaluate the dispersion of the body segments trajectories across trials. Moreover, a multi-joint kinematical model was created for each subject, based on a new 3-D minimally invasive stereoradiographic X-ray images to assess subject-specific geometry and inertial parameters. The simulations allowed discriminating between the contributions of the passive (inertia-induced properties) and the active (neuromuscular response) components during falls. Our data show that there is limited time to adjust the way one fall from a standing position. We showed that the pre-impact period is truncated of 200 ms. During the initial part of a fall, the observed trajectory results from the interaction between the destabilizing external force and the body: inertial properties intrinsic to joints, ligaments and musculotendinous system have then a major contribution, as suggested for the regulation of static upright stance. This passive phase is later followed by an active phase, which consists of a corrective response to the postural perturbation. We believe that during a fall from standing height, it takes about 300 ms for postural responses to start correcting the body trajectory, while the impact is expected to occur around 700 ms. It has been argued that this time is sufficient to change the way one falls and that this makes it possible to apply safer ways of falling, for example by using martial arts fall techniques. Also, our results imply visual and vestibular information are not congruent with the beginning of the on-going fall. This consequence is to be noted as subjects prepare to the impact on the basis of sensory information, which would be uniquely mainly of proprioceptive origin at the fall onset. One limitation of the present analysis is that no EMG was included so far but these data are the subject of a future study. PMID- 30524364 TI - Early Recurrent Ischemic Lesions in Patients With Cryptogenic Stroke and Patent Foramen Ovale: An Observational Study. AB - Background: Randomized controlled trials indicate that patent foramen ovale (PFO) closure reduces risk of stroke recurrence in patients with cryptogenic stroke and PFO. However, the optimal time point for PFO closure is unknown and depends on the risk of stroke recurrence. Objective: We aimed to investigate risk of early new ischemic lesions on cerebral magnetic resonance imaging (MRI) in cryptogenic stroke patients with and without PFO. Methods: Cryptogenic stroke patients underwent serial MRI examinations within 1 week after symptom onset to detect early new ischemic lesions. Diffusion-weighted imaging (DWI) lesions were delineated, co-registered, and analyzed visually for new hyperintensities by raters blinded to clinical details. A PFO was classified as stroke-related in patients with PFO and a Risk of Paradoxical Embolism (RoPE) score >5 points. Results: Out of 80 cryptogenic stroke patients, risk of early recurrent DWI lesions was not significantly different in cryptogenic stroke patients with and without PFO. Similar results were observed in patients <=60 years of age. Patients with a stroke-related PFO even had a significantly lower risk of early recurrent ischemic lesions compared to all other patients with cryptogenic stroke (unadjusted odds ratio 0.23 [95% confidence interval 0.06-0.87], P = 0.030). Conclusion: Our data argue against a high risk of early stroke recurrence in patients with cryptogenic stroke and PFO. PMID- 30524365 TI - Can Daytime Napping Assist the Process of Skills Acquisition After Stroke? AB - Acquisition and reacquisition of skills is a main pillar of functional recovery after stroke. Nighttime sleep has a positive influence on motor learning in healthy individuals, whereas the effect of daytime sleep on neuro-rehabilitative training and relearning of the trained skills is often neglected. The aim of this study was to investigate the relationship between daytime sleep (napping) and the ability to learn a new visuomotor task in chronic stroke patients. The main hypothesis was that sleep enhances motor memory consolidation after training resulting in better motor performance after a period of daytime sleep. Thirty stroke survivors completed the study. They were randomized to one of three different conditions (i) wakeful resting, (ii) short nap (10-20 min), or (iii) long nap (50-80 min). All individuals trained the task with the contralesional, stroke-impaired hand, behavioral evaluation was performed after the break time (wake, nap), and 24 h later. Patients demonstrated a significant task-related behavioral improvement throughout the training. In contrast to the main hypothesis, there was no evidence for sleep-dependent motor consolidation early after the initial, diurnal break, or after an additional full night of sleep. In a secondary analysis, the performance changes of stroke survivors were compared with those of a group of healthy older adults who performed the identical task within the same experimental setup with their non-dominant hand. Performance levels were comparable between both cohorts at all time points. Stroke-related difficulties in motor control did not impact on the degree of performance improvement through training and daytime sleep did not impact on the behavioral gains in the two groups. In summary, the current study indicates that one-time daytime sleep after motor training does not influence behavioral gains. PMID- 30524366 TI - Clinical and Radiological Markers of Extra-Motor Deficits in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is now universally recognized as a complex multisystem disorder with considerable extra-motor involvement. The neuropsychological manifestations of frontotemporal, parietal, and basal ganglia involvement in ALS have important implications for compliance with assistive devices, survival, participation in clinical trials, caregiver burden, and the management of individual care needs. Recent advances in neuroimaging have been instrumental in characterizing the biological substrate of heterogeneous cognitive and behavioral deficits in ALS. In this review we discuss the clinical and radiological aspects of cognitive and behavioral impairment in ALS focusing on the recognition, assessment, and monitoring of these symptoms. PMID- 30524367 TI - Increased Level of Angiopoietin Like Proteins 4 and 8 in People With Sleep Apnea. AB - Objective: Obstructive sleep apnea (OSA) is a sleep disorder caused by the complete or partial obstruction of the upper airways. The worldwide prevalence of OSA is increasing due to its close association with obesity epidemic and multiple health complications, such as hypertension, cardiovascular disease, and Type 2 diabetes. Angiopoietin-like protein (ANGPTL)-4 and ANGPTL8 (betatrophin) have been suggested to play a role in the development of these diseases through their role in regulating the metabolism of plasma lipid molecules. This study was designed to evaluate ANGPTL4 and 8 levels in an OSA group and a control group to clarify the effect of OSA on ANGPTL4 and 8 levels. Methods: In total, 74 subjects were enrolled in this study, including 22 age- and body mass index (BMI)-matched controls with the Apnea Hypopnea Index (AHI) score of <5 events/h and 52 subjects with an AHI score of >5 events/h. Sleep apnea was assessed using a portable sleep test. ANGPTL4 and 8 levels were measured in plasma samples using enzyme-linked immunosorbent assay. Results: Mean AHI score (2.5 +/- 1.6) in the control group was significantly lower than that in the OSA group (22.9 +/- 17.9; p < 0.0001). Leptin, interleukin-(IL) 6, insulin, and HOMA-IR values were higher in the OSA group than in the control group. ANGPTL8 level was higher in the OSA group (1130.0 +/- 108.61 pg/mL) than in the control group (809.39 +/- 108.78 pg/mL; p = 0.041). Similarly, ANGPTL4 was higher in the OSA group (179.26 +/- 12.89 ng/mL) than in the control group (142.63 +/-7.99 ng/mL; p = 0.018). Conclusion: Our findings demonstrate that ANGPTL4 and 8 levels were increased in subjects with OSA, suggesting that the upregulation of these lipid metabolism regulators might play a role in lipid dysregulation observed in people with OSA. PMID- 30524368 TI - Metabolic and Cognitive Outcomes of Subchronic Once-Daily Intranasal Insulin Administration in Healthy Men. AB - Insulin acts in the brain to limit food intake and improve memory function. We have previously shown that 8 weeks of intranasal insulin delivered in four daily doses of 40 IU decrease body weight and enhance word list recall. In the present study, we investigated the effect on body composition, endocrine parameters, and memory performance of 8 weeks of once-daily administration of 160 IU in healthy men. We assumed that intranasal insulin administered before nocturnal sleep, a period of relative metabolic inactivity that moreover benefits memory formation, would be superior to insulin delivery in the morning and placebo administration. After a 2-week baseline period, healthy male normal-weight subjects (mean age, 27.1 +/- 0.9 years) received either placebo, 160 IU intranasal insulin in the morning, or 160 IU in the evening (n = 12 per group) for 8 consecutive weeks. Throughout the experiment, we measured body weight and body composition as well as circulating concentrations of glucose, insulin, adrenocorticotropin, cortisol, growth hormone, insulin-like growth-factor 1, adiponectin, and leptin. Declarative and procedural memory function was repeatedly assessed by means of, respectively, word list recall and word-stem priming. We found that neither morning nor evening insulin compared to placebo administration induced discernible changes in body weight and body composition. Delayed recall of words showed slight improvements by insulin administration in the evening, and serum cortisol concentrations were reduced after 2 weeks of insulin administration in the morning compared to the other groups. Results indicate that catabolic long term effects of central nervous insulin delivery necessitate repetitive, presumably pre-meal delivery schedules. The observed memory improvements, although generally weaker than previously found effects, suggest that sleep after intranasal insulin administration may support its beneficial cognitive impact. PMID- 30524369 TI - Vascular Endothelial Growth Factor (VEGF) Induced Downstream Responses to Transient Receptor Potential Vanilloid 1 (TRPV1) and 3-Iodothyronamine (3-T1AM) in Human Corneal Keratocytes. AB - This study was undertaken to determine if crosstalk among the transient receptor potential (TRP) melastatin 8 (TRPM8), TRP vanilloid 1 (TRPV1), and vascular endothelial growth factor (VEGF) receptor triad modulates VEGF-induced Ca2+ signaling in human corneal keratocytes. Using RT-PCR, qPCR and immunohistochemistry, we determined TRPV1 and TRPM8 gene and protein coexpression in a human corneal keratocyte cell line (HCK) and human corneal cross sections. Fluorescence Ca2+ imaging using both a photomultiplier and a single cell digital imaging system as well as planar patch-clamping measured relative intracellular Ca2+ levels and underlying whole-cell currents. The TRPV1 agonist capsaicin increased both intracellular Ca2+ levels and whole-cell currents, while the antagonist capsazepine (CPZ) inhibited them. VEGF-induced Ca2+ transients and rises in whole-cell currents were suppressed by CPZ, whereas a selective TRPM8 antagonist, AMTB, increased VEGF signaling. In contrast, an endogenous thyroid hormone-derived metabolite 3-Iodothyronamine (3-T1AM) suppressed increases in the VEGF-induced current. The TRPM8 agonist menthol increased the currents, while AMTB suppressed this response. The VEGF-induced increases in Ca2+ influx and their underlying ionic currents stem from crosstalk between VEGFR and TRPV1, which can be impeded by 3-T1AM-induced TRPM8 activation. Such suppression in turn blocks VEGF-induced TRPV1 activation. Therefore, crosstalk between TRPM8 and TRPV1 inhibits VEGFR-induced activation of TRPV1. PMID- 30524370 TI - Family History of Diabetes Is Associated With Delayed Fetal Postprandial Brain Activity. AB - Introduction: We have previously shown that fetuses of mothers with gestational diabetes mellitus (GDM) and insulin resistance exhibit a prolongation of fetal auditory event-related brain responses (fAER) compared to fetuses of normal glucose tolerant women during an oral glucose tolerance test (oGTT). This implies that maternal metabolism may program the developing fetal brain. We now asked whether a family history of type 2 diabetes without metabolic programing also impacts fetal brain activity. We therefore investigated brain activity in fetuses of normal glucose tolerant mothers with and without family history of type 2 diabetes (FHD+ and FHD-). Methods: A 75 g oGTT was performed in healthy pregnant women. Plasma glucose and insulin levels were measured after 0, 60, and 120 min. Each blood draw was preceded by fetal magnetoencephalographic (fMEG) recordings of fAER. From a group of 167 participants, a subsample of 52 metabolically healthy women, 37 with a negative, and 15 with a positive FHD (at least one first or second-degree relative) was carefully selected based on the following inclusion criteria: inconspicuous pregnancy, no GDM, BMI 18.5-30 kg/m2, no preterm birth and at least two fMEG with detectable fetal responses during oGTT. Results: An ANOVA showed a significant interaction between fMEG measurement time during the oGTT and FHD on fAER latency [F (2) = 4.163, p = 0.018]. Fetuses of mothers with FHD+ had a prolonged fAER (273 +/- 113 ms) compared to fetuses of mothers with FHD- (219 +/- 69 ms) at 60 min during the oGTT [F (1) = 4.902, p = 0.032]. There were no significant differences in age, BMI before pregnancy, weight gain during pregnancy and gestational age between the groups. Maternal glucose levels and insulin sensitivity were also not significantly different. Discussion: In addition to the previously shown influence of maternal metabolism on fetal brain activity, maternal family history of diabetes (FHD) is also linked to fetal postprandial brain activity. This indicates that genetic and/or epigenetic factors modulate the postprandial brain response of the developing fetus. PMID- 30524371 TI - Could Age, Sex and Physical Fitness Affect Blood Glucose Responses to Exercise in Type 1 Diabetes? AB - Closed-loop systems for patients with type 1 diabetes are progressing rapidly. Despite these advances, current systems may struggle in dealing with the acute stress of exercise. Algorithms to predict exercise-induced blood glucose changes in current systems are mostly derived from data involving relatively young, fit males. Little is known about the magnitude of confounding variables such as sex, age, and fitness level-underlying, uncontrollable factors that might influence blood glucose control during exercise. Sex-related differences in hormonal responses to physical exercise exist in studies involving individuals without diabetes, and result in altered fuel metabolism during exercise. Increasing age is associated with attenuated catecholamine responses and lower carbohydrate oxidation during activity. Furthermore, higher fitness levels can alter hormonal and fuel selection responses to exercise. Compounding the limited research on these factors in the metabolic response to exercise in type 1 diabetes is a limited understanding of how these variables affect blood glucose levels during different types, timing and intensities of activity in individuals with type 1 diabetes (T1D). Thus, there is currently insufficient information to model a closed-loop system that can predict them accurately and consistently prevent hypoglycemia. Further, studies involving both sexes, along with a range of ages and fitness levels, are needed to create a closed-loop system that will be more precise in regulating blood glucose during exercise in a wide variety of individuals with T1D. PMID- 30524372 TI - Metformin in Reproductive Biology. AB - Initially produced in Europe in 1958, metformin is still one of the most widely prescribed drugs to treat type II diabetes and other comorbidities associated with insulin resistance. Metformin has been shown to improve fertility outcomes in females with insulin resistance associated with polycystic ovary syndrome (PCOS) and in obese males with reduced fertility. Metformin treatment reinstates menstrual cyclicity, decreases the incidence of cesareans, and limits the number of premature births. Notably, metformin reduces steroid levels in conditions associated with hyperandrogenism (e.g., PCOS and precocious puberty) in females and improves fertility of adult men with metabolic syndrome through increased testosterone production. While the therapeutical use of metformin is considered to be safe, in the last 10 years some epidemiological studies have described phenotypic differences after prenatal exposure to metformin. The goals of this review are to briefly summarize the current knowledge on metformin focusing on its effects on the female and male reproductive organs, safety concerns, including the potential for modulating fetal imprinting via epigenetics. PMID- 30524373 TI - Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring. AB - Intrauterine growth restriction (IUGR) leads to the development of metabolic syndrome in adulthood. To explore the potential mechanisms of metabolic imprinting, we investigated the effect of malnutrition in utero on hepatic unfolded protein response (UPR)-related genes in IUGR offspring. An IUGR rat model was developed by feeding a low-protein diet to pregnant rats. The expression levels and activity of hepatic UPR genes were analysed by quantitative PCR (qPCR) arrays and western blotting. The hepatic UPR molecules heat-shock 70 kDa protein 4l (Hspa4l), mitogen-activated protein kinase 10 (Mapk10), and endoplasmic reticulum to nucleus signalling 2 (Ern2) were markedly downregulated in IUGR foetuses, but the expression of Mapk10 and Ern2 returned to normal levels at 3 weeks postnatal. In contrast, cAMP responsive element binding protein 3-like 3 (Creb3l3) was upregulated in hepatic tissues at embryo 20(E20), then restored to normal in adulthood (12 weeks). The protein levels of activating transcription factor 2 (Atf2) and Atf6, two key factors of the UPR pathway, were upregulated in the livers of IUGR foetuses, and the latter remained upregulated until 12 weeks. Combined with our previous findings showing an increase in hepatic gluconeogenesis enzymes in IUGR offspring, we speculated that aberrant intrauterine milieu impaired UPR signalling in hepatic tissues; these alterations early in life might contribute to the predisposition of IUGR foetuses to adult metabolic disorders. PMID- 30524374 TI - The Impact of Goiter and Thyroid Surgery on Goiter Related Esophageal Dysfunction. A Systematic Review. AB - Background: Patients with goiter referred for thyroidectomy report swallowing difficulties. This might be associated with esophageal compression and deviation as this is present in a significant number of patients. Studies on how goiter and subsequently its treatment affect the esophagus are sparse and point in various directions. Our aim was to investigate, through a systematic review, the impact of goiter and thyroidectomy on esophageal anatomy, esophageal physiology, and subjective swallowing dysfunction. Methods: The search period covered 1 January 1975 to 1 July 2018, using the scientific databases PubMed and EMBASE. Inclusion criteria were adult patients with goiter who were either observed or underwent thyroidectomy. Search terms were variations of the terms for goiter, esophagus, swallowing, and dysphagia. From an initial 3,040 titles, 55 full text evaluations led to the final inclusion of 27 papers. Seventeen papers investigated, prospectively, the impact of thyroidectomy on the esophagus, while five observational and five retrospective studies were also included. Results: Esophageal anatomy impairment: Esophageal deviation occurred in 14% and esophageal compression in 8-27% of goiter patients. The prevalence increased with goiter size and with the extent of substernal extension. The smallest cross sectional area of the esophagus increased by median 34% after thyroidectomy. Esophageal physiology changes: Goiter patients had increased esophageal transit time, positively correlated with goiter size, but unrelated to esophageal motility disturbances. Decrease in the upper esophageal sphincter pressure occurred early after surgery, and normalized within 6 months. Swallowing related patient-reported outcomes: Evaluated by validated questionnaires, swallowing symptoms worsened in the early period after thyroidectomy, but improved after 6 months, as compared to baseline. Conclusions: Thyroidectomy relieved patients with goiter from dysphagia, within 6 months of surgery probably via increase in the cross-sectional area of the esophagus. Attention to the impact by goiter on the esophagus is needed, and balanced and individualized information about the potential benefits and risks of thyroid surgery is crucial in the management of patients with goiter. PMID- 30524375 TI - Comparing Different Diagnostic Guidelines for Gestational Diabetes Mellitus in Relation to Birthweight in Sri Lankan Women. AB - Introduction: While the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria is widely adopted in many countries, clinicians have questioned the applicability of these diagnostic thresholds for different races/ethnicities. We first compared the prevalence of gestational diabetes mellitus (GDM) diagnosed with different criteria including IADPSG, World Health Organization (WHO) 1999 and Sri Lankan national guidelines, and subsequently related individual guidelines-specific GDM prevalence to offspring birthweight in Sri Lanka. Materials and Methods: We retrospectively collected data on singleton pregnancies (n = 795) from two tertiary hospitals in Sri Lanka. We applied three diagnostic guidelines to define GDM, namely IADPSG criteria, the Sri Lankan national and WHO 1999 guidelines. We calculated the age- and first booking BMI adjusted prevalence rates of GDM and assessed the association of GDM (using each guideline) with birthweight. Results: The age- and first booking BMI-adjusted GDM prevalence rates were 31.2, 28.0, and 13.1% for IADPSG criteria, Sri Lankan national and WHO 1999 guidelines, respectively. The IADPSG criteria identified 90 distinctive GDM cases at a lower cut-off of fasting glucose (from 5.1 to 5.5 mmol/L) while Sri Lankan national guideline identified 15 distinctive GDM cases at a lower cut-off for 2-h glucose (from 7.8 to 8.4 mmol/L). After adjusting for age, GDM diagnosed by IADPSG criteria was associated with higher birthweight [90.8 g, 95% CI: 10.8, 170.9], while the associations for GDM diagnosed either by Sri Lankan national or WHO 1999 guidelines were not significant. Conclusion: Adopting the IADPSG criteria for diagnosing GDM may be important in Sri Lankan pregnant population. PMID- 30524376 TI - GnRH Neurons Provide Direct Input to Hypothalamic Tyrosine Hydroxylase Immunoreactive Neurons Which Is Maintained During Lactation. AB - Gonadotropin releasing hormone (GnRH) neurons provide neuronal input to the preoptic area (POA) and the arcuate nucleus (Arc), two regions involved critically in the regulation of neuroendocrine functions and associated behaviors. These areas contain tyrosine hydroxylase immunoreactive (TH-IR) neurons, which play location-specific roles in the neuroendocrine control of both the luteinizing hormone and prolactin secretion, as well as, sexually motivated behaviors. Concerning changes in the activity of GnRH neurons and the secretion pattern of GnRH seen under the influence of rising serum estrogen levels and during lactation, we tested the hypothesis that the functional state of GnRH neurons is mediated via direct synaptic connections to TH-IR neurons in the POA and Arc. In addition, we examined putative changes of these inputs in lactating mice and in mothers separated from their pups. Confocal microscopic and pre embedding immunohistochemical studies on ovariectomized mice treated with 17beta estradiol (OVX+E2) provided evidence for direct appositions and asymmetric synapses between GnRH-IR fiber varicosities and TH-IR neurons in the POA and the Arc. As TH co-localizes with kisspeptin (KP) in the POA, confocal microscopic analysis was continued on sections additionally labeled for KP. The TH-IR neurons showed a lower level of co-labeling for KP in lactating mice compared to OVX+E2 mice (16.1 +/- 5% vs. 57.8 +/- 4.3%). Removing the pups for 24 h did not alter significantly the KP production in TH-IR neurons (17.3 +/- 4.6%). The mean number of GnRH-IR varicosities on preoptic and arcuate TH cells did not differ in the three animal models investigated. This study shows evidence that GnRH neurons provide direct synaptic inputs to POA and Arc dopaminergic neurons. The scale of anatomical connectivity with these target cells was unaltered during lactation indicating a maintained GnRH input, inspite of the altered hormonal condition. PMID- 30524377 TI - Shared Decision-Making in Growth Hormone Therapy-Implications for Patient Care. AB - Several studies have shown that adherence to growth hormone therapy (GHT) is not optimal. There are several reasons why patients may not fully adhere to their treatment regimen and this may have implications on treatment success, patient outcomes and healthcare spending and resourcing. A change in healthcare practices, from a physician paternalistic to a more patient autonomous approach to healthcare, has encouraged a greater onus on a shared decision-making (SDM) process whereby patients are actively encouraged to participate in their own healthcare decisions. There is growing evidence to suggest that SDM may facilitate patient adherence to GHT. Improved adherence to therapy in this way may consequently positively impact treatment outcomes for patients. Whilst SDM is widely regarded as a healthcare imperative, there is little guidance on how it should be best implemented. Despite this, there are many opportunities for the implementation of SDM during the treatment journey of a patient with a GH-related disorder. Barriers to the successful practice of SDM within the clinic may include poor patient education surrounding their condition and treatment options, limited healthcare professional time, lack of support from clinics to use SDM, and healthcare resourcing restrictions. Here we discuss the opportunities for the implementation of SDM and the barriers that challenge its effective use within the clinic. We also review some of the potential solutions to overcome these challenges that may prove key to effective patient participation in treatment decisions. Encouraging a sense of empowerment for patients will ultimately enhance treatment adherence and improve clinical outcomes in GHT. PMID- 30524378 TI - Adipocytes and Obesity-Related Conditions Jointly Promote Breast Cancer Cell Growth and Motility: Associations With CAP1 for Prognosis. AB - The global increase in overweight and obesity rates represent pressing public health concerns associated with severe comorbidities, amongst a rising incidence and impaired outcome of breast cancer. Yet, biological explanations for how obesity affects breast cancer are incompletely mapped. Herein, the joint impact by differentiated 3T3-L1 adipocytes and obesity-related metabolic conditions on breast cancer cells was evaluated in vitro and adipocyte-derived mediators assessed. Adipokine receptor expression was explored among breast cancer cell lines (n = 47) and primary breast tumors (n = 1,881), where associations with survival outcomes were investigated. Adipocytes and metabolic complications jointly stimulated breast cancer cell proliferation and motility, with phenotype specific differences. Resistin was among the top modulated adipokines secreted by 3T3-L1 adipocytes under obesity-associated metabolic conditions compared with normal physiology. The newly identified resistin receptor, CAP1, was expressed across a large panel of breast cancer cell lines and primary breast tumors. CAP1 was associated with poor tumor characteristics with higher CAP1 expression among estrogen receptor (ER)-negative tumors, relative to ER-positive tumors (P = 0.025), and higher histological grades (P = 0.016). High CAP1 tumor expression was associated with shorter overall survival (adjusted hazard ratio [HRadj] 1.54; 95% confidence interval [CI], 1.11-2.13) and relapse-free survival (HRadj 1.47; 95% CI, 1.10-1.96), compared with low or intermediate CAP1 expression, particularly among ER-positive tumors or lymph node positive tumors. Together, these translational data demonstrate that the adipocyte secretome promote breast cancer cell proliferation and motility and highlight a potential role of CAP1 regarding breast cancer outcome-results that warrant further investigation to elucidate the obesity-breast cancer link in human pathology. PMID- 30524379 TI - The Evolving Importance of Insulin Signaling in Podocyte Health and Disease. AB - Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide, occuring in approximately one-third of diabetic patients. One of the earliest hallmarks of DKD is albuminuria, often occurring following disruptions to the glomerular filtration barrier. Podocytes are highly specialized cells with a central role in filtration barrier maintenance; hence, podocyte dysfunction is a major cause of albuminuria in many settings, including DKD. Numerous studies over the last decade have highlighted the importance of intact podocyte insulin responses in the maintenance of podocyte function. This review summarizes our current perspectives on podocyte insulin signaling, highlighting evidence to support the notion that dysregulated podocyte insulin responses contribute toward podocyte damage, particularly during the pathogenesis of DKD. PMID- 30524380 TI - The Effect of High Dose Isoflavone Supplementation on Serum Reverse T3 in Euthyroid Men With Type 2 Diabetes and Post-menopausal Women. AB - Background: The health benefits of soy are widely reported but there are queries on the effect of soy isoflavones on thyroid function and the underlying mechanism of action. Materials and Methods: We examined the effect of soy isoflavones on reverse tri-iodothyronine (or 3,3',5'-tri-iodothyronine; rT3) in two studies comprising 400 patients: 200 men (study 1; 3 months) and 200 post-menopausal women (study 2; 6 months) who were randomized to consume 15 g soy protein with 66 mg of isoflavones (SPI) daily, or 15 g soy protein alone without isoflavones (SP) daily. Results: SPI supplementation increased rT3 serum concentration in both men 0.41 (0.12) vs. 0.45 (0.14) nmol/L and women 0.33 (0.12) vs. 0.37 (0.09) nmol/L at 3 months compared to SP that was not seen at 6 months. Thyroid stimulating hormone (TSH) serum concentrations increased while free thyroxine (fT4) concentrations decreased with 3 months of SPI compared to SP supplementation for both men and women. rT3 correlated with TSH in both studies (p = 0.03) but not with either fT3 or fT4. fT3 levels did not differ between the SPI and SP preparations. Conclusion: Soy isoflavones transiently increased rT3 levels within 3 months though reverted to baseline at 6 months. The mechanism for this would be either rT3 degrading deiodinase 1 and/or deiodinase 2 activities are transiently inhibited at 3 months, or inhibition of deiodinase 3, which generates rT3 from T4 is induced at 6 months. These changes were mirrored in the TSH concentrations, suggesting that short-term high dose isoflavone transiently impairs thyroid function in the first 3 months and may impact on general health during this period. ISRCTN Registry: ISRCTN 90604927; ISRCTN34051237. PMID- 30524381 TI - A New Role of OmpR in Acid and Osmotic Stress in Salmonella and E. coli. AB - Bacteria survive and respond to diverse environmental conditions and during infection inside the host by systematic regulation of stress response genes. E. coli and S. Typhimurium can undergo large changes in intracellular osmolality (up to 1.8 Osmol/kg) and can tolerate cytoplasmic acidification to at least pHi 5.6. Recent analyses of single cells challenged a long held view that bacteria respond to extracellular acid stress by rapid acidification followed by a rapid recovery. It is now appreciated that both S. Typhimurium and E. coli maintain an acidic cytoplasm through the actions of the outer membrane protein regulator OmpR via its regulation of distinct signaling pathways. However, a comprehensive comparison of OmpR regulons between S. Typhimurium and E. coli is lacking. In this study, we examined the expression profiles of wild-type and ompR null strains of the intracellular pathogen S. Typhimurium and a commensal E. coli in response to acid and osmotic stress. Herein, we classify distinct OmpR regulons and also identify shared OmpR regulatory pathways between S. Typhimurium and E. coli in response to acid and osmotic stress. Our study establishes OmpR as a key regulator of bacterial virulence, growth and metabolism, in addition to its role in regulating outer membrane proteins. PMID- 30524382 TI - A Population-Based Descriptive Atlas of Invasive Pneumococcal Strains Recovered Within the U.S. During 2015-2016. AB - Invasive pneumococcal disease (IPD) has greatly decreased since implementation in the U.S. of the 7 valent conjugate vaccine (PCV7) in 2000 and 13 valent conjugate vaccine (PCV13) in 2010. We used whole genome sequencing (WGS) to predict phenotypic traits (serotypes, antimicrobial phenotypes, and pilus determinants) and determine multilocus genotypes from 5334 isolates (~90% of cases) recovered during 2015-2016 through Active Bacterial Core surveillance. We identified 44 serotypes; 26 accounted for 98% of the isolates. PCV13 serotypes (inclusive of serotype 6C) accounted for 1503 (28.2%) isolates, with serotype 3 most common (657/5334, 12.3%), while serotypes 1 and 5 were undetected. Of 305 isolates from children <5 yrs, 60 (19.7%) were of PCV13 serotypes 19A, 19F, 3, 6B, and 23F (58/60 were 19A, 19F, or 3). We quantitated MLST-based lineages first detected during the post-PCV era (since 2002) that potentially arose through serotype switching. The 7 predominant emergent post-PCV strain complexes included 23B/CC338, 15BC/CC3280, 19A/CC244, 4/CC439, 15A/CC156, 35B/CC156, and 15BC/CC156. These strains accounted for 332 isolates (6.2% of total) and were more frequently observed in children <5 yrs (17.7%; 54/305). Fifty-seven categories of recently emerged (in the post PCV7 period) putative serotype-switch variants were identified, accounting for 402 isolates. Many of these putative switch variants represented newly emerged resistant strains. Penicillin-nonsusceptibility (MICs > 0.12 MUg/ml) was found among 22.4% (1193/5334) isolates, with higher penicillin MICs (2-8 MUg/ml) found in 8.0% (425/5334) of isolates that were primarily (372/425, 87.5%) serotypes 35B and 19A. Most (792/1193, 66.4%) penicillin nonsusceptible isolates were macrolide-resistant, 410 (34.4%) of which were erm gene positive and clindamycin-resistant. The proportion of macrolide-resistant isolates increased with increasing penicillin MICs; even isolates with reduced penicillin susceptibility (MIC = 0.06 MUg/ml) were much more likely to be macrolide-resistant than basally penicillin-susceptible isolates (MIC < 0.03 MUg/ml). The contribution of recombination to strain diversification was assessed through quantitating 35B/CC558-specific bioinformatic pipeline features among non CC558 CCs and determining the sizes of gene replacements. Although IPD has decreased greatly and stabilized in the post-PCV13 era, the species continually generates recombinants that adapt to selective pressures exerted by vaccines and antimicrobials. These data serve as a baseline for monitoring future changes within each invasive serotype. PMID- 30524383 TI - Germination and Growth Analysis of Streptomyces lividans at the Single-Cell Level Under Varying Medium Compositions. AB - Quantitative single-cell cultivation has provided fundamental contributions to our understanding of heterogeneity among industrially used microorganisms. Filamentous growing Streptomyces species are emerging platform organisms for industrial production processes, but their exploitation is still limited due to often reported high batch-to-batch variations and unexpected growth and production differences. Population heterogeneity is suspected to be one responsible factor, which is so far not systematically investigated at the single cell level. Novel microfluidic single-cell cultivation devices offer promising solutions to investigate these phenomena. In this study, we investigated the germination and growth behavior of Streptomyces lividans TK24 under varying medium compositions on different complexity levels (i.e., mycelial growth, hyphal growth and tip elongation) on single-cell level. Our analysis reveals a remarkable stability within growth and germination of spores and early mycelium development when exposed to constant and defined environments. We show that spores undergo long metabolic adaptation processes of up to > 30 h to adjust to new medium conditions, rather than using a "persister" strategy as a possibility to cope with rapidly changing environments. Due to this uniform behavior, we conclude that S. lividans can be cultivated quite robustly under constant environmental conditions as provided by microfluidic cultivation approaches. Failure and non-reproducible cultivations are thus most likely to be found in less controllable larger-scale cultivation workflows and as a result of environmental gradients within large-scale cultivations. PMID- 30524384 TI - A Metabolomics Approach Reveals Immunomodulatory Effects of Proteinaceous Molecules Derived From Gut Bacteria Over Human Peripheral Blood Mononuclear Cells. AB - There are strong evidences that probiotics influence the immune status of the host, in a strain-specific manner, acting in the gastrointestinal tract. On the hypothesis that certain extracellular proteins and peptides from gut bacteria may mediate part of this immunomodulation and assuming they are able to diffuse through the mucus layer and interact with immune cells we have developed this work. Our study attempts to understand the immunomodulatory mechanisms of (i) Pext, the extracellular protein fraction of Lactobacillus acidophilus DSM20079T, (ii) HM14, a peptide encrypted in an extracellular glycoside hydrolase from Bifidobacterium longum NCIMB 8809 and (iii) Escherichia coli O111:B4 lipopolysaccharide (LPS), a well-known pro-inflammatory molecule, over human peripheral blood mononuclear cells (PBMCs). An untargeted LC-ESI-QTOF-MS metabolomics approach was applied to reveal intracellular changes in treated PBMCs isolated from healthy donors. Differences in NADH arrest, NAD+ concentration reduction, as well as increases in palmitic acid and methanephrin were observed in HM14 and Pext treated-cells compared to those stimulated with LPS. This would support an anti-inflammatory molecular mechanism of action of such proteinaceous molecules. Moreover, this methodology has confirms the importance of metabolomics approaches to better understanding immune cell responses to gut bacterial-derived molecules. PMID- 30524385 TI - Putative Nitrogen-Fixing Bacteria Associated With the Rhizosphere and Root Endosphere of Wheat Plants Grown in an Andisol From Southern Chile. AB - Acidic ash derived volcanic soils (Andisols) support 50% of cereal production in Chile. Nitrogen (N) is essential for cereal crops and commonly added as urea with consequent environmental concerns due to leaching. Despite the relevance of N to plant growth, few studies have focused on understanding the application, management and ecological role of N2-fixing bacterial populations as tool for improve the N nutrition of cereal crops in Chile. It is known that N2-fixing bacteria commonly inhabits diverse plant compartments (e.g., rhizosphere and root endosphere) where they can supply N for plant growth. Here, we used culture independent and dependent approaches to characterize and compare the putative N2 fixing bacteria associated with the rhizosphere and root endosphere of wheat plants grown in an Andisol from southern Chile. Our results showed significantly greater bacterial loads in the rhizosphere than the root endosphere. Quantitative PCR results indicated that the copy number of the 16S rRNA gene ranged from 1012~1013 and 107~108 g-1 sample in rhizosphere and root endosphere, respectively. The nifH gene copy number ranged from 105~106 and 105 g-1 sample in rhizosphere and root endosphere, respectively. The total culturable bacteria number ranged from 109~1010 and 107~108 CFU g-1 sample in rhizosphere and 104~105 and 104 CFU g-1 sample in root endosphere using LB and NM-1 media, respectively. Indirect counts of putative N2-fixing bacteria were 103 and 102~103 CFU g-1 sample in rhizosphere and root endosphere using NFb medium, respectively. Sequencing of 16S rRNA genes from randomly selected putative N2-fixing bacteria revealed the presence of members of Proteobacteria (Bosea and Roseomonas), Actinobacteria (Georgenia, Mycobacterium, Microbacterium, Leifsonia, and Arthrobacter), Bacteroidetes (Chitinophaga) and Firmicutes (Bacillus and Psychrobacillus) taxa. Differences in 16S rRNA and putative nifH-containing bacterial communities between rhizosphere and root endosphere were shown by denaturing gradient gel electrophoresis (DGGE). This study shows a compartmentalization between rhizosphere and root endosphere for both the abundance and diversity of total (16S rRNA) and putative N2-fixing bacterial communities on wheat plants grown in Chilean Andisols. This information can be relevant for the design and application of agronomic strategies to enhance sustainable N-utilization in cereal crops in Chile. PMID- 30524386 TI - Genetic Differentiation, Diversity, and Drug Susceptibility of Candida krusei. AB - Candida krusei is a notable pathogenic fungus that causes invasive candidiasis, mainly due to its natural resistance to fluconazole. However, to date, there is limited research on the genetic population features of C. krusei. We developed a set of microsatellite markers for this organism, with a cumulative discriminatory power of 1,000. Using these microsatellite loci, 48 independent C. krusei strains of clearly known the sources, were analyzed. Furthermore, susceptibility to 9 antifungal agents was determined for each strain, by the Clinical and Laboratory Standards Institute broth microdilution method. Population structure analyses revealed that C. krusei could be separated into two clusters. The cluster with the higher genetic diversity had wider MIC ranges for six antifungal agents. Furthermore, the highest MIC values of the six antifungal agents belonged to the cluster with higher genetic diversity. The higher genetic diversity cluster might have a better adaptive capacity when C. krusei is under selection pressure from antifungal agents, and thus is more likely to develop drug resistance. PMID- 30524387 TI - Recovery of the Peptidoglycan Turnover Product Released by the Autolysin Atl in Staphylococcus aureus Involves the Phosphotransferase System Transporter MurP and the Novel 6-phospho-N-acetylmuramidase MupG. AB - The peptidoglycan of the bacterial cell wall undergoes a permanent turnover during cell growth and differentiation. In the Gram-positive pathogen Staphylococcus aureus, the major peptidoglycan hydrolase Atl is required for accurate cell division, daughter cell separation and autolysis. Atl is a bifunctional N-acetylmuramoyl-L-alanine amidase/endo-beta-N-acetylglucosaminidase that releases peptides and the disaccharide N-acetylmuramic acid-beta-1,4-N acetylglucosamine (MurNAc-GlcNAc) from the peptido-glycan. Here we revealed the recycling pathway of the cell wall turnover product MurNAc-GlcNAc in S. aureus. The latter disaccharide is internalized and concomitantly phosphorylated by the phosphotransferase system (PTS) transporter MurP, which had been implicated previously in the uptake and phosphorylation of MurNAc. Since MurP mutant cells accumulate MurNAc-GlcNAc and not MurNAc in the culture medium during growth, the disaccharide represents the physiological substrate of the PTS transporter. We further identified and characterized a novel 6-phospho-N-acetylmuramidase, named MupG, which intracellularly hydrolyses MurNAc 6-phosphate-GlcNAc, the product of MurP-uptake and phosphorylation, yielding MurNAc 6-phosphate and GlcNAc. MupG is the first characterized representative of a novel family of glycosidases containing domain of unknown function 871 (DUF871). The corresponding gene mupG (SAUSA300_0192) of S. aureus strain USA300 is the first gene within a putative operon that also includes genes encoding the MurNAc 6-phosphate etherase MurQ, MurP, and the putative transcriptional regulator MurR. Using mass spectrometry, we observed cytoplasmic accumulation of MurNAc 6-phosphate-GlcNAc in DeltamupG and DeltamupGmurQ markerless non-polar deletion mutants, but not in the wild type or in the complemented DeltamupG strain. MurNAc 6-phosphate-GlcNAc levels in the mutants increased during stationary phase, in accordance with previous observations regarding peptidoglycan recycling in S. aureus. PMID- 30524388 TI - Comparison of Serological and Molecular Methods With High-Throughput Sequencing for the Detection and Quantification of Grapevine Fanleaf Virus in Vineyard Samples. AB - Grapevine fanleaf virus (GFLV) is the main causal agent of fanleaf degeneration, the most damaging viral disease of grapevine. GFLV is included in most grapevine certification programs that rely on robust diagnostic tools such as biological indexing, serological methods, and molecular techniques, for the identification of clean stocks. The emergence of high throughput sequencing (HTS) offers new opportunities for detecting GFLV and other viruses in grapevine accessions of interest. Here, two HTS-based methods, i.e., RNAseq and smallRNAseq (focusing on the 21 to 27 nt) were explored for their potential to characterize the virome of grapevine samples from two 30-year-old GFLV-infected vineyards in the Champagne region of France. smallrnaseq was optimal for the detection of a wide range of viral species within a sample and RNAseq was the method of choice for full-length viral genome assembly. The implementation of a protocol to discriminate between low GFLV titer and in silico contamination (intra-lane contamination due to index misassignment) during data processing was critical for data analyses. Furthermore, we compared the performance of semi-quantitative DAS-ELISA (double antibody enzyme-linked immunosorbent assay), RT-qPCR (Reverse transcription quantitative polymerase chain reaction), Immuno capture (IC)-RT-PCR, northern blot for viral small interfering RNA (vsiRNA) detection and RNAseq for the detection and quantification of GFLV. While detection limits were variable among methods, as expected, GFLV diagnosis was consistently achieved with all of these diagnostic methods. Together, this work highlights the robustness of DAS-ELISA, the current method routinely used in the French grapevine certification program, for the detection of GFLV and offers perspectives on the potential of HTS as an approach of high interest for certification. PMID- 30524389 TI - Proteasomal Degradation Machinery: Favorite Target of HIV-1 Proteins. AB - Proteasomal degradation pathways play a central role in regulating a variety of protein functions by controlling not only their turnover but also the physiological behavior of the cell. This makes it an attractive target for the pathogens, especially viruses which rely on the host cellular machinery for their propagation and pathogenesis. Viruses have evolutionarily developed various strategies to manipulate the host proteasomal machinery thereby creating a cellular environment favorable for their own survival and replication. Human immunodeficiency virus-1 (HIV-1) is one of the most dreadful viruses which has rapidly spread throughout the world and caused high mortality due to its high evolution rate. Here, we review the various mechanisms adopted by HIV-1 to exploit the cellular proteasomal machinery in order to escape the host restriction factors and components of host immune system for supporting its own multiplication, and successfully created an infection. PMID- 30524390 TI - Evolutionary Evidence of Algal Polysaccharide Degradation Acquisition by Pseudoalteromonas carrageenovora 9T to Adapt to Macroalgal Niches. AB - About half of seaweed biomass is composed of polysaccharides. Most of these complex polymers have a marked polyanionic character. For instance, the red algal cell wall is mainly composed of sulfated galactans, agars and carrageenans, while brown algae contain alginate and fucose-containing sulfated polysaccharides (FCSP) as cell wall polysaccharides. Some marine heterotrophic bacteria have developed abilities to grow on such macroalgal polysaccharides. This is the case of Pseudoalteromonas carrageenovora 9T (ATCC 43555T), a marine gammaproteobacterium isolated in 1955 and which was an early model organism for studying carrageenan catabolism. We present here the genomic analysis of P. carrageenovora. Its genome is composed of two chromosomes and of a large plasmid encompassing 109 protein-coding genes. P. carrageenovora possesses a diverse repertoire of carbohydrate-active enzymes (CAZymes), notably specific for the degradation of macroalgal polysaccharides (laminarin, alginate, FCSP, carrageenans). We confirm these predicted capacities by screening the growth of P. carrageenovora with a large collection of carbohydrates. Most of these CAZyme genes constitute clusters located either in the large chromosome or in the small one. Unexpectedly, all the carrageenan catabolism-related genes are found in the plasmid, suggesting that P. carrageenovora acquired its hallmark capacity for carrageenan degradation by horizontal gene transfer (HGT). Whereas P. carrageenovora is able to use lambda-carrageenan as a sole carbon source, genomic and physiological analyses demonstrate that its catabolic pathway for kappa- and iota-carrageenan is incomplete. This is due to the absence of the recently discovered 3,6-anhydro-D-galactosidase genes (GH127 and GH129 families). A genomic comparison with 52 Pseudoalteromonas strains confirms that carrageenan catabolism has been recently acquired only in a few species. Even though the loci for cellulose biosynthesis and alginate utilization are located on the chromosomes, they were also horizontally acquired. However, these HGTs occurred earlier in the evolution of the Pseudoalteromonas genus, the cellulose- and alginate-related loci being essentially present in one large, late-diverging clade (LDC). Altogether, the capacities to degrade cell wall polysaccharides from macroalgae are not ancestral in the Pseudoalteromonas genus. Such catabolism in P. carrageenovora resulted from a succession of HGTs, likely allowing an adaptation to the life on the macroalgal surface. PMID- 30524391 TI - Biomolecular Interaction Studies Between Cytochrome PpcA From Geobacter sulfurreducens and the Electron Acceptor Ferric Nitrilotriacetate (Fe-NTA). AB - Geobacter sulfurreducens bacterium exhibits an enormous respiratory versatility, including the utilization of several toxic and radioactive metals as electron acceptors. This versatility is also replicated in the capability of the most abundant cytochrome in G. sulfurreducens, the periplasmic triheme cytochrome PpcA, to reduce uranium, chromium and other metal ions. From all possible electron transfer pathways in G. sulfurreducens, those involved in the iron reduction are the best characterized to date. Previously, we provided structural evidence for the complex interface established between PpcA and the electron acceptor Fe(III)-citrate. However, genetic studies suggested that this acceptor is mainly reduced by outer membrane cytochomes. In the present work, we used UV visible measurements to demonstrate that PpcA is able to directly reduce the electron acceptor ferric nitrilotriacetate (Fe-NTA), a more outer membrane permeable iron chelated form. In addition, the molecular interactions between PpcA and Fe-NTA were probed by Nuclear Magnetic Resonance (NMR) spectroscopy. The NMR spectra obtained for PpcA samples in the absence and presence of Fe-NTA showed that the interaction is reversible and encompasses a positively charged surface region located in the vicinity of the heme IV. Overall, the study elucidates the formation of an electron transfer complex between PpcA and a readily outer-membrane permeable iron chelated form. The structural and functional relationships obtained explain how a single cytochrome is designed to effectively interact with a wide range of G. sulfurreducens electron acceptors, a feature that can be explored for optimal bioelectrochemical applications. PMID- 30524392 TI - Water Filtered Infrared A and Visible Light (wIRA/VIS) Irradiation Reduces Chlamydia trachomatis Infectivity Independent of Targeted Cytokine Inhibition. AB - Chlamydia trachomatis is the major cause of infectious blindness and represents the most common bacterial sexually transmitted infection worldwide. Considering the potential side effects of antibiotic therapy and increasing threat of antibiotic resistance, alternative therapeutic strategies are needed. Previous studies showed that water filtered infrared A alone (wIRA) or in combination with visible light (wIRA/VIS) reduced C. trachomatis infectivity. Furthermore, wIRA/VIS irradiation led to secretion of pro-inflammatory cytokines similar to that observed upon C. trachomatis infection. We confirmed the results of previous studies, namely that cytokine secretion (IL-6, IL-8, and RANTES/CCL5) upon wIRA/VIS treatment, and the subsequent reduction of chlamydial infectivity, are independent of the addition of cycloheximide, a host protein synthesis inhibitor. Reproducible cytokine release upon irradiation indicated that cytokines might be involved in the anti-chlamydial mechanism of wIRA/VIS. This hypothesis was tested by inhibiting IL-6, IL-8, and RANTES secretion in C. trachomatis or mock-infected cells by gene silencing or pharmaceutical inhibition. Celastrol, a substance derived from Trypterygium wilfordii, used in traditional Chinese medicine and known for anti-cancer and anti-inflammatory effects, was used for IL-6 and IL-8 inhibition, while Maraviroc, a competitive CCR5 antagonist and anti-HIV drug, served as a RANTES/CCL5 inhibitor. HeLa cell cytotoxicity and impact on chlamydial morphology, size and inclusion number was evaluated upon increasing inhibitor concentration, and concentrations of 0.1 and 1 MUM Celastrol and 10 and 20 MUM Maraviroc were subsequently selected for irradiation experiments. Celastrol at any concentration reduced chlamydial infectivity, an effect only observed for 20 MUM Maraviroc. Triple dose irradiation (24, 36, 40 hpi) significantly reduced chlamydial infectivity regardless of IL-6, IL-8, or RANTES/CCL5 gene silencing, Celastrol or Maraviroc treatment. Neither gene silencing nor pharmaceutical cytokine inhibition provoked the chlamydial stress response. The anti-chlamydial effect of wIRA/VIS is independent of cytokine inhibition under all conditions evaluated. Thus, factors other than host cell cytokines must be involved in the working mechanism of wIRA/VIS. This study gives a first insight into the working mechanism of wIRA/VIS in relation to an integral component of the host immune system and supports the potential of wIRA/VIS as a promising new tool for treatment in trachoma. PMID- 30524393 TI - Evaluating the Value of Defensins for Diagnosing Secondary Bacterial Infections in Influenza-Infected Patients. AB - Acute respiratory infections by influenza viruses are commonly causes of severe pneumonia, which can further deteriorate if secondary bacterial infections occur. Although the viral and bacterial agents are quite diverse, defensins, a set of antimicrobial peptides expressed by the host, may provide promising biomarkers that would greatly improve the diagnosis and treatment. We examined the correlations between the gene expression levels of defensins and the viral and bacterial loads in the blood on a longitudinal, precision-medical study of a severe pneumonia patient infected by influenza A H7N9 virus. We found that DEFA5 is positively correlated to the blood load of influenza A H7N9 virus (r = 0.735, p < 0.05, Spearman correlation). DEFB116 and DEFB127 are positively and DEFB108B and DEFB114 are negatively correlated to the bacterial load. Then the diagnostic potential of defensins to discriminate bacterial and viral infections was evaluated on an independent dataset with 61 bacterial pneumonia patients and 39 viral pneumonia patients infected by influenza A viruses and reached 93% accuracy. Expression levels of defensins in the blood may be of important diagnostic values in clinic to indicate viral and bacterial infections. PMID- 30524394 TI - Shifts of Hydrogen Metabolism From Methanogenesis to Propionate Production in Response to Replacement of Forage Fiber With Non-forage Fiber Sources in Diets in vitro. AB - The rumen microbial complex adaptive mechanism invalidates various methane (CH4) mitigation strategies. Shifting the hydrogen flow toward alternative electron acceptors, such as propionate, was considered to be a meaningful mitigation strategy. A completely randomized design was applied in in vitro incubation to investigate the effects of replacing forage fiber with non-forage fiber sources (NFFS) in diets on methanogenesis, hydrogen metabolism, propionate production and the methanogenic and bacterial community. There are two treatments in the current study, CON (a basic total mixed ration) and TRT (a modified total mixed ration). The dietary treatments were achieved by partly replacing forage fiber with NFFS (wheat bran and soybean hull) to decrease forage neutral detergent fiber (fNDF) content from 24.0 to 15.8%, with the composition and inclusion rate of other dietary ingredients remaining the same in total mixed rations. The concentrations of CH4, hydrogen (H2) and volatile fatty acids were determined using a gas chromatograph. The archaeal and bacterial 16S rRNA genes were sequenced by Miseq high-throughput sequencing and used to reveal the relative abundance of methanogenic and bacterial communities. The results revealed that the concentration of propionate was significantly increased, while the concentration of acetate and the acetate to propionate ratio were not affected by treatments. Compared with CON, the production of H2 increased by 8.45% and the production of CH4 decreased by 14.06%. The relative abundance of Methanomassiliicoccus was significantly increased, but the relative abundance of Methanobrevibacter tended to decrease in TRT group. At the bacterial phylum level, the TRT group significantly decreased the relative abundance of Firmicutes and tended to increase the relative abundance of Bacteroidetes. The replacement of forage fiber with NFFS in diets can affect methanogenesis by shifting the hydrogen flow toward propionate, and part is directed to H2 in vitro. The shift was achieved by a substitution of Firmicutes by Bacteroidetes, another substitution of Methanobrevibacter by Methanomassiliicoccus. Theoretical predictions of displacements of H2 metabolism from methanogenesis to propionate production was supported by the dietary intervention in vitro. PMID- 30524395 TI - Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products. AB - Penicillium chrysogenum (renamed P. rubens) is the most studied member of a family of more than 350 Penicillium species that constitute the genus. Since the discovery of penicillin by Alexander Fleming, this filamentous fungus is used as a commercial beta-lactam antibiotic producer. For several decades, P. chrysogenum was subjected to a classical strain improvement (CSI) program to increase penicillin titers. This resulted in a massive increase in the penicillin production capacity, paralleled by the silencing of several other biosynthetic gene clusters (BGCs), causing a reduction in the production of a broad range of BGC encoded natural products (NPs). Several approaches have been used to restore the ability of the penicillin production strains to synthetize the NPs lost during the CSI. Here, we summarize various re-activation mechanisms of BGCs, and how interference with regulation can be used as a strategy to activate or silence BGCs in filamentous fungi. To further emphasize the versatility of P. chrysogenum as a fungal production platform for NPs with potential commercial value, protein engineering of biosynthetic enzymes is discussed as a tool to develop de novo BGC pathways for new NPs. PMID- 30524396 TI - Fructo-Oligosaccharide Alleviates Soybean-Induced Anaphylaxis in Piglets by Modulating Gut Microbes. AB - Soybean-induced anaphylaxis poses a severe threat to the health of humans and animals. Some commensal bacteria, such as Lactobacillus and Bifidobacteria, can prevent and treat allergic diseases. Prebiotic oligosaccharides, a food/diet additive, can enhance health and performance via modulating gut microbes and immune responses. The purpose of this study was to examine whether fructo oligosaccharides (FOS) could alleviate soybean-induced anaphylaxis by modulating gut microbes. Piglets (21 days of age) were sensitized with a diet containing 5% soybean and 30% peeled soybean meal. The treatment with 0.6% FOS started 1 day prior to sensitization and continued everyday thereafter. Blood was collected for measurements of immune indices. The DNA samples isolated from fresh intestinal contents of the middle jejunum (M-jejunum), posterior jejunum (P-jejunum), ileum, and cecum were used for gene sequencing based on 16S rRNA. Our results showed that there was an increase of glycinin-specific IgG, beta-conglycinin-specific IgG, total serum IgG and IgE, and occurrence of diarrhea in piglets sensitized with soybean antigen. There was a decrease in interleukin 4 (IL-4) and IL-10 and an increase of interferon-gamma (IFN-gamma) in piglets with FOS treatment, compared with the piglets without FOS treatment. Improvement of intestinal microbes was indicated mostly by the increase of Lactobacillus and Bifidobacteria in M-jejunum and the decrease of Proteobacteria in P-jejunum and ileum. The correlation analysis indicated that FOS treatment decreased those closely related to the key species of gut microbes. These results suggest that FOS can alleviate soybean antigen-induced anaphylaxis, which is associated with increased Lactobacillus and Bifidobacteria in M-jejunum and declined Proteobacteria in P jejunum and ileum of piglets. PMID- 30524397 TI - Genetic Diversity and the Spatio-Temporal Analyses of Hantaviruses in Shandong Province, China. AB - Hemorrhagic fever with renal syndrome (HFRS) is a serious public health problem in Shandong Province, China. We conducted an epizootiologic investigation and phylogeographic and phylodynamic analyses to infer the phylogenetic relationships of hantaviruses in space and time, and gain further insights into their evolutionary dynamics in Shandong Province. Our data indicated that the Seoul virus (SEOV) is distributed throughout Shandong, whereas Hantaan virus (HTNV) co circulates with SEOV in the eastern and southern areas of Shandong. Their distribution showed strong geographic clustering. In addition, our analyses indicated multiple evolutionary paths, long-distance transmission, and demographic expansion events for SEOV in some areas. Selection pressure analyses revealed that negative selection on hantaviruses acted as the principal evolutionary force, whereas a little evidence of positive selection exists. We found that several positively selected sites were located within major functional regions and indicated the importance of these residues for adaptive evolution of hantaviruses. PMID- 30524398 TI - Small RNA-Omics for Plant Virus Identification, Virome Reconstruction, and Antiviral Defense Characterization. AB - RNA interference (RNAi)-based antiviral defense generates small interfering RNAs that represent the entire genome sequences of both RNA and DNA viruses as well as viroids and viral satellites. Therefore, deep sequencing and bioinformatics analysis of small RNA population (small RNA-ome) allows not only for universal virus detection and genome reconstruction but also for complete virome reconstruction in mixed infections. Viral infections (like other stress factors) can also perturb the RNAi and gene silencing pathways regulating endogenous gene expression and repressing transposons and host genome-integrated endogenous viral elements which can potentially be released from the genome and contribute to disease. This review describes the application of small RNA-omics for virus detection, virome reconstruction and antiviral defense characterization in cultivated and non-cultivated plants. Reviewing available evidence from a large and ever growing number of studies of naturally or experimentally infected hosts revealed that all families of land plant viruses, their satellites and viroids spawn characteristic small RNAs which can be assembled into contigs of sufficient length for virus, satellite or viroid identification and for exhaustive reconstruction of complex viromes. Moreover, the small RNA size, polarity and hotspot profiles reflect virome interactions with the plant RNAi machinery and allow to distinguish between silent endogenous viral elements and their replicating episomal counterparts. Models for the biogenesis and functions of small interfering RNAs derived from all types of RNA and DNA viruses, satellites and viroids as well as endogenous viral elements are presented and discussed. PMID- 30524399 TI - Development of Freeze-Thaw Tolerant Lactobacillus rhamnosus GG by Adaptive Laboratory Evolution. AB - The industrial application of microorganisms as starters or probiotics requires their preservation to assure viability and metabolic activity. Freezing is routinely used for this purpose, but the cold damage caused by ice crystal formation may result in severe decrease in microbial activity. In this study, adaptive laboratory evolution (ALE) technique was applied to a lactic acid bacterium to select tolerant strains against freezing and thawing stresses. Lactobacillus rhamnosus GG was subjected to freeze-thaw-growth (FTG) for 150 cycles with four replicates. After 150 cycles, FTG-evolved mutants showed improved fitness (survival rates), faster growth rate, and shortened lag phase than those of the ancestor. Genome sequencing analysis of two evolved mutants showed genetic variants at distant loci in six genes and one intergenic space. Loss-of-function mutations were thought to alter the structure of the microbial cell membrane (one insertion in cls), peptidoglycan (two missense mutations in dacA and murQ), and capsular polysaccharides (one missense mutation in wze), resulting in an increase in cellular fluidity. Consequently, L. rhamnosus GG was successfully evolved into stress-tolerant mutants using FTG-ALE in a concerted mode at distal loci of DNA. This study reports for the first time the functioning of dacA and murQ in freeze-thaw sensitivity of cells and demonstrates that simple treatment of ALE designed appropriately can lead to an intelligent genetic changes at multiple target genes in the host microbial cell. PMID- 30524400 TI - The Influence of Viable Cells and Cell-Free Extracts of Lactobacillus casei on Volatile Compounds and Polyphenolic Profile of Elderberry Juice. AB - In this study, four strains of Lactobacillus casei, as viable cells or cell-free extracts (CFE), were added to elderberry juice in order to evaluate their effect on phenolic and aromatic profile. Two of them were able to grow in juice while the others showed zero-growth. The same strains were lysed and added as extracts in elderberry juice. Multivariate statistical analysis show a separation among samples containing growing cells, non-growing cells, CFE, highlighting the particularities of specific strains. Juices added with CFE presented the highest amount of esters. The strains showing growth phenotype cause an increase of phenyllactic acids. The highest concentration of volatile compounds, particularly of alcohols, terpenes and norisoprenoids (responsible for typical elderberry notes) was observed in samples with strains showing zero-growth. Moreover, a significant increase in anthocyanin content was observed in these samples, suggesting the possible use of Lactobacillus for increasing specific molecules, even for non-multiplying bacterial cell. Considering that this is the first study concerning the use of non-growing cells in fruit juice, the potential of strains is still to be explored and it may have a significant technological application in the development of a microbial collection useful for fruit juice industry. PMID- 30524401 TI - Influence of CO2 Degassing on the Microbial Community in a Dry Mofette Field in Hartousov, Czech Republic (Western Eger Rift). AB - The Cheb Basin (CZ) is a shallow Neogene intracontinental basin filled with fluvial and lacustrine sediments that is located in the western part of the Eger Rift. The basin is situated in a seismically active area and is characterized by diffuse degassing of mantle-derived CO2 in mofette fields. The Hartousov mofette field shows a daily CO2 flux of 23-97 tons of CO2 released over an area of 0.35 km2 and a soil gas concentration of up to 100% CO2. The present study aims to explore the geo-bio interactions provoked by the influence of elevated CO2 concentrations on the geochemistry and microbial community of soils and sediments. To sample the strata, two 3-m cores were recovered. One core stems from the center of the degassing structure, whereas the other core was taken 8 m from the ENE and served as an undisturbed reference site. The sites were compared regarding their geochemical features, microbial abundances, and microbial community structures. The mofette site is characterized by a low pH and high TOC/sulfate contents. Striking differences in the microbial community highlight the substantial impact of elevated CO2 concentrations and their associated side effects on microbial processes. The abundance of microbes did not show a typical decrease with depth, indicating that the uprising CO2-rich fluid provides sufficient substrate for chemolithoautotrophic anaerobic microorganisms. Illumina MiSeq sequencing of the 16S rRNA genes and multivariate statistics reveals that the pH strongly influences microbial composition and explains around 38.7% of the variance at the mofette site and 22.4% of the variance between the mofette site and the undisturbed reference site. Accordingly, acidophilic microorganisms (e.g., OTUs assigned to Acidobacteriaceae and Acidithiobacillus) displayed a much higher relative abundance at the mofette site than at the reference site. The microbial community at the mofette site is characterized by a high relative abundance of methanogens and taxa involved in sulfur cycling. The present study provides intriguing insights into microbial life and geo-bio interactions in an active seismic region dominated by emanating mantle-derived CO2-rich fluids, and thereby builds the basis for further studies, e.g., focusing on the functional repertoire of the communities. However, it remains open if the observed patterns can be generalized for different time-points or sites. PMID- 30524402 TI - Flux Connections Between Gluconate Pathway, Glycolysis, and Pentose-Phosphate Pathway During Carbohydrate Metabolism in Bacillus megaterium QM B1551. AB - Bacillus megaterium is a bacterium of great importance as a plant-beneficial bacterium in agricultural applications and in industrial bioproduction of proteins. Understanding intracellular processing of carbohydrates in this species is crucial to predicting natural carbon utilization as well as informing strategies in metabolic engineering. Here, we applied stable isotope-assisted metabolomics profiling and metabolic flux analysis to elucidate, at high resolution, the connections of the different catabolic routes for carbohydrate metabolism immediately following substrate uptake in B. megaterium QM B1551. We performed multiple 13C tracer experiments to obtain both kinetic and long-term 13C profiling of intracellular metabolites. In addition to the direct phosphorylation of glucose to glucose-6-phosphate (G6P) prior to oxidation to 6 phosphogluconate (6P-gluconate), the labeling data also captured glucose catabolism through the gluconate pathway involving glucose oxidation to gluconate followed by phosphorylation to 6P-gluconate. Our data further confirmed the absence of the Entner-Doudoroff pathway in B. megaterium and showed that subsequent catabolism of 6P-gluconate was instead through the oxidative pentose phosphate (PP) pathway. Quantitative flux analysis of glucose-grown cells showed equal partition of consumed glucose from G6P to the Embden-Meyerhof-Parnas (EMP) pathway and from G6P to the PP pathway through 6P-gluconate. Growth on fructose alone or xylose alone was consistent with the ability of B. megaterium to use each substrate as a sole source of carbon. However, a detailed 13C mapping during simultaneous feeding of B. megaterium on glucose, fructose, and xylose indicated non-uniform intracellular investment of the different carbohydrate substrates. Flux of glucose-derived carbons dominated the gluconate pathway and the PP pathway, whereas carbon flux from both glucose and fructose populated the EMP pathway; there was no assimilatory flux of xylose-derived carbons. Collectively, our findings provide new quantitative insights on the contribution of the different catabolic routes involved in initiating carbohydrate catabolism in B. megaterium and related Bacillus species. PMID- 30524403 TI - The XRE-DUF397 Protein Pair, Scr1 and Scr2, Acts as a Strong Positive Regulator of Antibiotic Production in Streptomyces. AB - The xenobiotic response element (XRE) transcription factors belong to a regulator family frequently found in Streptomyces that are often followed by small proteins with a DUF397 domain. In fact, the pair XRE-DUF397 has been proposed to comprise toxin-antitoxin (TA) type II systems. In this work, we demonstrate that one of these putative TA-systems, encoded by the genes SCO4441 and SCO4442 of Streptomyces coelicolor, and denominated Scr1/Scr2 (which stands for S. c oelicolor r egulator), does not behave as a toxin-antitoxin system under the conditions used as was originally expected. Instead the pair Scr1/Scr2 acts as a strong positive regulator of endogenous antibiotic production in S. coelicolor. The analysis of the 19 Streptomyces strains tested determined that overexpression of the pair Scr1/Scr2 drastically induces the production of antibiotics not only in S. coelicolor, but also in Streptomyces lividans, Streptomyces peucetius, Streptomyces steffisburgensis and Streptomyces sp. CA-240608. Our work also shows that Scr1 needs Scr2 to exert positive regulation on antibiotic production. PMID- 30524404 TI - A Rhodococcal Transcriptional Regulatory Mechanism Detects the Common Lactone Ring of AHL Quorum-Sensing Signals and Triggers the Quorum-Quenching Response. AB - The biocontrol agent Rhodococcus erythropolis disrupts virulence of plant and human Gram-negative pathogens by catabolizing their N-acyl-homoserine lactones. This quorum-quenching activity requires the expression of the qsd (quorum-sensing signal degradation) operon, which encodes the lactonase QsdA and the fatty acyl CoA ligase QsdC, involved in the catabolism of lactone ring and acyl chain moieties of signaling molecules, respectively. Here, we demonstrate the regulation of qsd operon expression by a TetR-like family repressor, QsdR. This repression was lifted by adding the pathogen quorum signal or by deleting the qsdR gene, resulting in enhanced lactone degrading activity. Using interactomic approaches and transcriptional fusion strategy, the qsd operon derepression was elucidated: it is operated by the binding of the common part of signaling molecules, the homoserine lactone ring, to the effector-receiving domain of QsdR, preventing a physical binding of QsdR to the qsd promoter region. To our knowledge, this is the first evidence revealing quorum signals as inducers of the suitable quorum-quenching pathway, confirming this TetR-like protein as a lactone sensor. This regulatory mechanism designates the qsd operon as encoding a global disrupting pathway for degrading a wide range of signal substrates, allowing a broad spectrum anti-virulence activity mediated by the rhodococcal biocontrol agent. Understanding the regulation mechanisms of qsd operon expression led also to the development of biosensors useful to monitor in situ the presence of exogenous signals and quorum-quenching activity. PMID- 30524406 TI - A Short-Term Response of Soil Microbial Communities to Cadmium and Organic Substrate Amendment in Long-Term Contaminated Soil by Toxic Elements. AB - Two long-term contaminated soils differing in contents of Pb, Zn, As, Cd were compared in a microcosm experiment for changes in microbial community structure and respiration after various treatments. We observed that the extent of long term contamination (over 200 years) by toxic elements did not change the total numbers and diversity of bacteria but influenced their community composition. Namely, numbers of Actinobacteria determined by phylum specific qPCR increased and also the proportion of Actinobacteria and Chloroflexi increased in Illumina sequence libraries in the more contaminated soil. In the experiment, secondary disturbance by supplemented cadmium (doses from double to 100-fold the concentration in the original soil) and organic substrates (cellobiose or straw) increased bacterial diversity in the less contaminated soil and decreased it in the more contaminated soil. Respiration in the experiment was higher in the more contaminated soil in all treatments and correlated with bacterial numbers. Considering the most significant changes in bacterial community, it seemed that particularly Actinobacteria withstand contamination by toxic elements. The results proved higher resistance to secondary disturbance in terms of both, respiration and bacterial community structure in the less contaminated soil. PMID- 30524405 TI - Improved Microbial Safety of Direct Ozone-Depurated Shellstock Eastern Oysters (Crassostrea virginica) by Superchilled Storage. AB - The effect of superchilled storage at -1 degrees C on the microbial safety of oyster depurated with 0.2, 0.4, and 0.6 mg/L ozone was studied for 14 days. Fecal coliforms (4,100-16,000 MPN/100 g), Escherichia coli (1,500-3,650 MPN/100 g), Vibrio cholerae non-O1/non-O139 (13.0-102.0 MPN/g), and Salmonella spp. (2.270 3.035 * 103 CFU/g) were initially present in raw oysters. After 6 h depuration, fecal coliform counts decreased (P < 0.05) to 300, 20 and 20 MPN/100 g for 0.2, 0.4, and 0.6 mg/L treatments, while a 0.3 log decrease in control oysters was observed. Initial E. coli counts decreased (P < 0.05) in oysters to 50, 20, and 20 MPN/100 g for 0.2, 0.4, and 0.6 mg/L treatments, respectively. A 1 log reduction in V. cholerae non-O1/non-139 levels were observed in 0.4 and 0.6 mg/L treatments after 2 and 4 h depuration. Salmonella spp. was not detected in oyster samples after 6 h depuration in 0.4 and 0.6 mg/L-ozone treatments. Considering the bacterial loads after depuration, at the end of superchilled storage the 0.4 mg/L-ozonated oysters attained lower (P < 0.05) fecal coliform levels (280 MPN/100 g) and E. coli counts in 0.4 and 0.6 mg/L-ozonated oysters (20 and 95 MPN/100 g, respectively). A 2-log decrease in V. cholerae non-O1/non-O139 levels on day 5 in 0.4 and 0.6 mg/L-ozonated oysters (< 0.3 MPN/g) was attained. V. cholerae non-O1/non-O139 counts in control oysters decreased 1 log on day 9 of superchilled storage. Salmonella spp. was not detected in ozonated and superchilled stored oysters. Levels of fecal coliforms, E. coli, Salmonella spp., and V. cholerae non-O1/non-O139 in non-ozone depurated oyster samples were higher than in control, 0.4 and 0.6 mg/L ozonated oyster samples during superchilled storage. The cumulative mortality rates after 14 days of storage for superchilled oysters (22.2%) was higher (P < 0.05) than 0.6 mg/L O3 (7.2%) and 0.4 mg/L O3 (5.8%) treatments, and control oysters (5.6%). pH values in control oysters decreased significantly (P < 0.05) throughout the storage period but not in oysters of both ozone treatments, indicating no detrimental effects on oyster survival. The results of this study suggest that superchilled storage enables ozonated shellstock oysters (0.4 mg/L-6 h) stored for 9 days to be safe human consumption. PMID- 30524407 TI - Assessing Response to Therapy for Nontuberculous Mycobacterial Lung Disease: Quo Vadis? AB - Assessing progression of disease or response to treatment remains a major challenge in the clinical management of nontuberculous mycobacterial (NTM) infections of the lungs. Serial assessments of validated measures of treatment response address whether the current therapeutic approach is on track toward clinical cure, which remains a fundamental question for clinicians and patients during the course of NTM disease treatment. The 2015 NTM Research Consortium Workshop, which included a patient advisory panel, identified treatment response biomarkers as a priority area for investigation. Limited progress in addressing this challenge also hampers drug development efforts. The Biomarker Qualification Program at the FDA supports the use of a validated treatment response biomarker across multiple drug development programs. Current approaches in clinical practice include microbiologic and radiographic monitoring, along with symptomatic and quality-of-life assessments. Blood-based monitoring, including assessments of humoral and cell-mediated NTM-driven immune responses, remain under investigation. Alignment of data collection schemes in prospective multicenter studies, including the support of biosample repositories, will support identification of treatment response biomarkers under standard-of-care and investigational therapeutic strategies. In this review, we outline the role of treatment monitoring biomarkers in both clinical practice and drug development frameworks. PMID- 30524408 TI - Biosynthesis of Nanomaterials by Shewanella Species for Application in Lithium Ion Batteries. AB - Nanomaterials exhibit extraordinary properties based on their size, shape, chemical composition, and crystal structure. Owing to their unique properties nanomaterials are preferred over their bulk counterparts for a number of applications. Although conventional physical and chemical routes were established for the massive production of nanomaterials, there are some drawbacks such as environmental burden and high cost that cannot be disregarded. Recently, there has been great interest toward the green synthesis of inorganic nanomaterials. It has been reported that dissimilatory metal reduction by microorganisms is a cost effective process to remediate toxic organic and inorganic compounds under anaerobic conditions. Particularly, members of the Shewanella genus have been utilized to produce various biogenic nanomaterials with unique micro/nanostructured morphologies through redox transformations as well as to remove harmful metals and metalloids in eco-efficient and environment-friendly methods under ambient conditions. In the present mini-review, we specifically address the active utilization of microbial respiration processes for the synthesis of novel functional biogenic nanomaterials by the members of the Shewanella genus. This biosynthetic method may provide alternative approaches to produce electrode materials for sustainable energy storage applications. PMID- 30524409 TI - Persistent Occurrence of Cryptosporidium hominis and Giardia duodenalis Subtypes in a Welfare Institute. AB - Few data are available on the transmission dynamics of intestinal protozoa in children in welfare institutes. In this study, fecal specimens were collected from 396 children in a welfare institute in Shanghai, China during December 2011 (207 specimens), June 2012 (78 specimens), and September 2013 (111 specimens), and examined for Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi by PCR analysis of the small subunit rRNA, triosephosphate isomerase, and internal transcribed spacer genes, respectively. The Cryptosporidium hominis and G. duodenalis assemblage A identified were further subtyped by multilocus sequence typing. Altogether, Cryptosporidium was detected in 39 (9.8%) children, with infection rates of 11.6% (24/207), 9.0% (7/78), and 7.2% (8/111) in December 2011, June 2012, and September 2013, respectively. Infection rates were higher in children of 0-12 months (20.4% compared to 0-7.3% in other age groups, P = 0.0001) and those with diarrhea (17.9% compared to 7.7% in those with no diarrhea, P = 0.006). In contrast, G. duodenalis was detected in 161/396 (40.7%), with infection rates of 48.3% (100/207), 35.9% (28/78), and 29.7% (33/111) in December 2011, June 2012, and September 2013, respectively. There were no significant gender- or diarrhea-associated differences, but the G. duodenalis infection rate in children of 13-24 months (50%) was significantly higher than in the age groups of 0-12 months and > 48 months (29.8-36.5%, P = 0.021). Co infection of Cryptosporidium and G. duodenalis was seen in 19 (4.8%) children, but no E. bieneusi infection was detected in this study. All Cryptosporidium positive specimens belonged to the subtype IaA14R4 of C. hominis, while all G. duodenalis-positive specimens belonged to sub-assemblage AII. Both were the same subtypes in a previous outbreak of cryptosporidiosis and giardiasis in a hospital ward hosting children from the welfare institute. Results of the study indicate that there was a persistent occurrence of limited C. hominis and G. duodenalis subtypes in the small enclosed community, with differences in age distribution and association with diarrhea occurrence between cryptosporidiosis and giardiasis. PMID- 30524410 TI - Clever Cooperation: Interactions Between EspF and Host Proteins. AB - EspF is a central effector protein of enterohemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium (CR) that is secreted through the type III secretion system to host cells. The interaction between EspF and host proteins plays an important role in bacterial pathogenesis. EspF protein binds to host SNX9 and N-WASP proteins to promote the colonization of pathogenic bacteria in intestinal epithelial cells; combines with cytokeratin 18, actin, 14 3-3zeta, Arp2/3, profilin, and ZO-1 proteins to intervene in the redistribution of intermediate filaments, the rearrangement of actin, and the disruption of tight junctions; acts together with Abcf2 to boost host cell intrinsic apoptosis; and collaborates with Anxa6 protein to inhibit phagocytosis. The interaction between EspF and host proteins is key to the pathogenic mechanism of EHEC and EPEC. Here, we review how EspF protein functions through interactions with these 10 host proteins and contributes to the pathogenicity of EHEC/EPEC. PMID- 30524411 TI - Out in the Cold: Identification of Genomic Regions Associated With Cold Tolerance in the Biocontrol Fungus Clonostachys rosea Through Genome-Wide Association Mapping. AB - There is an increasing importance for using biocontrol agents in combating plant diseases sustainably and in the long term. As large scale genomic sequencing becomes economically viable, the impact of single nucleotide polymorphisms (SNPs) on biocontrol-associated phenotypes can be easily studied across entire genomes of fungal populations. Here, we improved a previously reported genome assembly of the biocontrol fungus Clonostachys rosea strain IK726 using the PacBio sequencing platform, which resulted in a total genome size of 70.7 Mbp and 21,246 predicted genes. We further performed whole-genome re-sequencing of 52 additional C. rosea strains isolated globally using Illumina sequencing technology, in order to perform genome-wide association studies in conditions relevant for biocontrol activity. One such condition is the ability to grow at lower temperatures commonly encountered in cryic or frigid soils in temperate regions, as these will be prevalent for protecting growing crops in temperate climates. Growth rates at 10 degrees C on potato dextrose agar of the 53 sequenced strains of C. rosea were measured and ranged between 0.066 and 0.413 mm/day. Performing a genome wide association study, a total of 1,478 SNP markers were significantly associated with the trait and located in 227 scaffolds, within or close to (< 1000 bp distance) 265 different genes. The predicted gene products included several chaperone proteins, membrane transporters, lipases, and proteins involved in chitin metabolism with possible roles in cold tolerance. The data reported in this study provides a foundation for future investigations into the genetic basis for cold tolerance in fungi, with important implications for biocontrol. PMID- 30524412 TI - Effects of an Endophytic Fungus Umbelopsis dimorpha on the Secondary Metabolites of Host-Plant Kadsura angustifolia. AB - Fungal endophytes live widely inside plant tissues and some have been revealed to provide benefits to their host and ecological environment. Considering the fact that endophytes are engaged in remarkably stable long-term interactions with the host for their whole life cycle, it's conceivable that both partners have substantial influence on each other's metabolic processes. Here, we investigated the fermented products of an endophytic fungus Umbelopsis dimorpha SWUKD3.1410 grown on host-plant Kadsura angustifolia and wheat bran, respectively, to assess the impact of SWUKD3.1410 on the secondary metabolites of K. angustifolia. Twenty compounds (1-20) were isolated and identified as 11 schitriterpenoids (1-9, 17 18), two lignans (10, 20), two sesquiterpenoids (11-12), one trinorsesquiterpenoid (13), one monoterpene (14), one sterol (19), and two simple aromatic compounds (15-16) by the extensive 1D-, 2D-NMR and HR-ESI-MS data analysis. Except for nigranoic acid (1), compounds 2-19 have been firstly found from K. angustifolia. Of them, metabolites 2, 11, and 14 were identified to be new. Obtained results indicated that U. dimorpha SWUKD3.1410 could not only produce the same/similar components as its host does, and modify the host-plant components, but also enhance the production of these highly oxygenated schitriterpenoids/schinortriterpenoids in plants. This study suggested an interesting prospective for setting up alternative processing techniques to improve the quality of crude drugs derived from K. angustifolia and increase their values. PMID- 30524413 TI - Characterization of a New Cyclohexylamine Oxidase From Acinetobacter sp. YT-02. AB - Cyclohexylamine (CHAM) is widely used in various industries, but it is harmful to human beings and the environment. Acinetobacter sp. YT-02 can degrade CHAM via cyclohexanone as an intermediate. In this study, the cyclohexylamine oxidase (CHAO) gene from Acinetobacter sp. YT-02 was cloned. Amino acid sequence alignment indicated that the cyclohexylamine oxidase (CHAOYT-02) was 48% identical to its homolog from Brevibacterium oxydans IH-35A (CHAOIH-35). The enzyme was expressed in Escherichia coli BL21 (DE3), and purified to apparent homogeneity by Ni-affinity chromatography. The purified enzyme was proposed to be a dimer of molecular mass of approximately 91 kDa. The enzyme exhibited its maximum activity at 50 degrees C and at pH 7.0. The enzyme was thermolabile as demonstrated by loss of important percentage of its maximal activity after 30 min incubation at 50 degrees C. Metal ions Mg2+, Co2+, and K+ had certain inhibitory effect on the enzyme activity. The kinetic parameters K m and V max were 0.25 +/- 0.02 mM and 4.3 +/- 0.083 MUM min-1, respectively. The biochemical properties, substrate specificities, and three-dimensional structures of CHAOYT-02 and CHAOIH 35 were compared. Our results are helpful to elucidate the mechanism of microbial degradation of CHAM in the strain YT-02. In addition, CHAOYT-02, as a potential biocatalyst, is promising in controlling CHAM pollution and deracemization of chiral amines. PMID- 30524414 TI - Inhibitory Effect of Ursodeoxycholic Acid on Clostridium difficile Germination Is Insufficient to Prevent Colitis: A Study in Hamsters and Humans. AB - Introduction: Bile acids (BA) influence germination and growth of Clostridium difficile. Ursodeoxycholic acid (UDCA), a BA minor in human, used for cholestatic liver diseases, inhibits germination and growth of C. difficile in vitro, but was never tested in vivo with an infectious challenge versus control. We hypothesized that UDCA could prevent CDI. We evaluated the effects of UDCA on C. difficile in vitro and in hamsters, with pharmacokinetics study and with an infectious challenge. Then, we studied CDI incidence in UDCA-treated patients. Methods: We evaluated germination and growth of C. difficile, with 0.01, 0.05, and 0.1% UDCA. We analyzed fecal BA of hamsters receiving antibiotics and UDCA (50 mg/kg/day), antibiotics, or UDCA alone. Then, we challenged with spores of C. difficile at D6 hamsters treated with UDCA (50 mg/kg/day) from D1 to D13, versus control. In human, we analyzed the database of a cohort on CDI in acute flares of inflammatory bowel disease (IBD). As PSC-IBD patients were under UDCA treatment, we compared PSC-IBD patients to IBD patients without PSC. Results: In vitro, UDCA inhibited germination and growth of C. difficile at 0.05 and 0.1%, competing with 0.1% TCA (with 0.1%: 0.05% +/- 0.05% colony forming unit versus 100% +/- 0%, P < 0.0001). In hamsters, UDCA reached high levels only when administered with antibiotics (43.5% UDCA at D5). Without antibiotics, UDCA was in small amount in feces (max. 4.28%), probably because of UDCA transformation into LCA by gut microbiota. During infectious challenge, mortality was similar in animals treated or not with UDCA (62.5%, n = 5/8, P = 0.78). UDCA percentage was high, similar and with the same kinetics in dead and surviving hamsters. However, dead hamsters had a higher ratio of primary over secondary BA compared to surviving hamsters. 9% (n = 41/404) of IBD patients without PSC had a CDI, versus 25% (n = 4/12) of PSC-IBD patients treated with UDCA. Conclusion: We confirmed the inhibitory effect of UDCA on growth and germination of C. difficile in vitro, with 0.05 or 0.1% UDCA. However, in our hamster model, UDCA was inefficient to prevent CDI, despite high levels of UDCA in feces. Patients with PSC-IBD treated with UDCA did not have less CDI than IBD patients. PMID- 30524415 TI - Complete Genome Sequence of bla IMP-6-Positive Metakosakonia sp. MRY16-398 Isolate From the Ascites of a Diverticulitis Patient. AB - A novel species of carbapenemase-producing Enterobacteriaceae (CPE) was isolated from a patient diagnosed with sigmoid colon diverticulitis. At first, laboratory testing suggested it was Klebsiella oxytoca or Pantoea sp.; however, a complete genome sequence of the isolate, MRY16-398, revealed that it could be novel species, most similar to [Kluyvera] intestini, of which taxonomic nomenclature is still under discussion. Orthologous conserved gene analysis among 42 related bacterial strains indicated that MRY16-398 was classified as the newly proposed genus Metakosakonia. Further, MRY16-398 was found to harbor the bla IMP-6 gene positive class 1 integron (In722) in plasmid pMRY16-398_2 (IncN replicon, 47.4 kb in size). This finding implies that rare and opportunistic bacteria could be potential infectious agents. In conclusion, our results highlight the need for continuous monitoring for CPE even in nonpathogenic bacteria in the nosocomial environment. PMID- 30524416 TI - Taxonomic and Functional Metagenomic Profile of Sediment From a Commercial Catfish Pond in Mississippi. AB - Metagenomic analyses of microbial communities from aquatic sediments are relatively few, and there are no reported metagenomic studies on sediment from inland ponds used for aquaculture. Catfish ponds in the southeastern U.S. are eutrophic systems. They are fertilized to enhance algae growth and encourage natural food production, and catfish are fed with commercial feed from spring to fall. As result, catfish pond sediment (CPS) contains a very dense, diverse microbial community that has significant effects on the physiochemical parameters of pond dynamics. Here we conducted an in-depth metagenomic analysis of the taxonomic and metabolic capabilities of a catfish pond sediment microbiome from a southeastern U.S. aquaculture farm in Mississippi using Illumina next-generation sequencing. A total of 3.3 Gbp of sequence was obtained, 25,491,518 of which encoded predicted protein features. The pond sediment was dominated by Proteobacteria sequences, followed by Bacteroidetes, Firmicutes, Chloroflexi, and Actinobacteria. Enzyme pathways for methane metabolism/methanogenesis, denitrification, and sulfate reduction appeared nearly complete in the pond sediment metagenome profile. In particular, a large number of Deltaproteobacteria sequences and genes encoding anaerobic functional enzymes were found. This is the first study to characterize a catfish pond sediment microbiome, and it is expected to be useful for characterizing specific changes in microbial flora in response to production practices. It will also provide insight into the taxonomic diversity and metabolic capabilities of microbial communities in aquaculture. Furthermore, comparison with other environments (i.e., river and marine sediments) will reveal habitat-specific characteristics and adaptations caused by differences in nutrients, vegetation, and environmental stresses. PMID- 30524417 TI - A Surface Protein From Lactobacillus plantarum Increases the Adhesion of Lactobacillus Strains to Human Epithelial Cells. AB - Adhesion to epithelial cells is considered important for Lactobacillus to exert probiotic effects. In this study, we found that trypsin treatment decreased the adhesion ability of Lactobacillus plantarum AR326 and AR269, which exhibit good adhesion ability, and surface proteins extracts increased the adhesion of the strains with poor adhesion ability. By SDS-polyacrylamide gel electrophoresis and mass spectrometry analysis, the main component of the surface proteins was detected and identified as a protein of approximately 37 kDa. It was 100% homologous with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from L. plantarum WCFS1. The adhesion of AR326 and AR269 was decreased significantly by blocking with the anti-GAPDH antibody, and GAPDH restored the adhesion of AR326 and AR269 treated with trypsin. In addition, purified GAPDH significantly increased the adhesion of the strains with poor adhesion ability. These results indicated that GAPDH mediates the adhesion of these highly adhesive lactobacilli to epithelial cells and can be used to improve the adhesion ability of probiotics or other bacteria of interest. PMID- 30524419 TI - How the Fewest Become the Greatest. L. casei's Impact on Long Ripened Cheeses. AB - Members of the Lactobacillus casei group, including species classified currently as L. casei, L. paracasei, and L. rhamnosus, are among the most frequently found species in raw milk, hard cooked, long-ripened cheeses. Starting from very low numbers in raw milk, they become dominant in the cheese during ripening, selected by physical and chemical changes produced by cheese making and ripening. Their presence at different stages of cheese making and ripening is crucial in defining product features. For these reasons, the scientific community has been more and more interested in studying these "tiny but mighty microbes" and their implications during cheese making and ripening. The present paper reviews the current literature on the effect of L. casei in cheeses, with particular reference to the case of Parmigiano Reggiano and Grana Padano, two of the most famous PDO (Protected Designation of Origin) Italian cheeses. Recent advances regarding the selection of new wild strains able to persist until the end of ripening and carrying out slow but crucial activities resulting in specific aromatic features, are also presented. PMID- 30524418 TI - Commentary: Phyllostomid bat microbiome composition is associated to host phylogeny and feeding strategies. PMID- 30524420 TI - Heterogeneous Colistin-Resistance Phenotypes Coexisting in Stenotrophomonas maltophilia Isolates Influence Colistin Susceptibility Testing. AB - The polymyxin antibiotic colistin shows in vitro activity against Stenotrophomonas maltophilia. However, an increased incidence of colistin resistant isolates has been recently observed. In addition, in vitro evaluation of colistin susceptibility for this organism has been problematic. The aims of this study were to investigate the colistin-resistance phenotypes displayed by S. maltophilia and their potential association with the challenging determination of colistin susceptibilities for this organism by even the recommended method. Colistin-resistance phenotypes were inferred by use of the recommended broth microdilution method in different clinical isolates of S. maltophilia. Most of the strains showed non-interpretable minimum inhibitory concentrations (MICs) for colistin due to an incomplete growth inhibition in wells of the microdilution plate. In addition, the subpopulation of bacteria resistant to colistin showed an increased ability to form biofilms on the plastic surface of MIC plates. The observed incomplete growth inhibition in the microdilution plates is compatible with a progressive adaptation to colistin or a heterogeneous susceptibility to this antibiotic. Therefore, to determine the existence of heteroresistance or adaptive resistance, four colistin-resistant clinical isolates were subjected to serial Etest assays, growth rate analyses, and the population analysis profile test. The experiments indicated that these S. maltophilia isolates display a colistin-resistant sub-population that survives and multiplies in the presence of the antibiotic. Interestingly, this phenomenon might not be explainable by the natural background mutation rate alone since the development of a resistant sub population occurred upon the contact with the antibiotic and it was reversible. This complex colistin-resistance phenotype is exhibited differently by the different isolates and significantly affected colistin susceptibility testing. Furthermore, it can coexist with adaptive resistance to colistin as response to pre-incubation with sub-inhibitory concentrations of the antibiotic. Overall, the combined action of heterogeneous colistin-resistance mechanisms in S. maltophilia isolates, including colistin-induced biofilm formation, may hamper the correct interpretation of colistin susceptibility tests, thus having potentially serious implications on antimicrobial-therapy decision making. PMID- 30524421 TI - CD38-Specific Biparatopic Heavy Chain Antibodies Display Potent Complement Dependent Cytotoxicity Against Multiple Myeloma Cells. AB - CD38 is overexpressed by multiple myeloma cells and has emerged as a target for therapeutic antibodies. Nanobodies are soluble single domain antibody fragments derived from the VHH variable domain of heavy chain antibodies naturally occurring in camelids. We previously identified distinct llama nanobodies that recognize three non-overlapping epitopes of the extracellular domain of CD38. Here, we fused these VHH domains to the hinge, CH2, and CH3 domains of human IgG1, yielding highly soluble chimeric llama/human heavy chain antibodies (hcAbs). We analyzed the capacity of these hcAbs to mediate complement-dependent cytotoxicity (CDC) to CD38-expressing human multiple myeloma and Burkitt lymphoma cell lines. Combinations of two hcAbs that recognize distinct, non-overlapping epitopes of CD38 mediated potent CDC, in contrast to the hcAb monotherapy with only weak CDC capacity. Similarly, combining daratumumab with a hcAb that recognizes a non-overlapping epitope resulted in dramatically enhanced CDC. Further, introducing the E345R HexaBody mutation into the CH3 domain strongly enhanced the CDC potency of hcAbs to CD38-expressing cells. Exploiting their high solubility, we genetically fused two distinct nanobodies into heteromeric dimers via a flexible peptide linker and then fused these nanobody dimers to the hinge, CH2 and CH3 domains of human IgG1, yielding highly soluble, biparatopic hcAbs. These biparatopic hcAbs elicited CDC toward CD38-expressing myeloma cells more effectively than daratumumab. Our results underscore the advantage of nanobodies vs. pairs of VH and VL domains for constructing bispecific antibodies. Moreover, the CD38-specific biparatopic heavy chain antibodies described here represent potential new powerful therapeutics for treatment of multiple myeloma. PMID- 30524422 TI - The Tumor Necrosis Factor Superfamily Members TNFSF14 (LIGHT), Lymphotoxin beta and Lymphotoxin beta Receptor Interact to Regulate Intestinal Inflammation. AB - Over 1.5 million individuals in the United States are afflicted with inflammatory bowel disease (IBD). While the progression of IBD is multifactorial, chronic, unresolved inflammation certainly plays a key role. Additionally, while multiple immune mediators have been shown to affect pathogenesis, a comprehensive understanding of disease progression is lacking. Previous work has demonstrated that a member of the TNF superfamily, TNFSF14 (LIGHT), which is pro-inflammatory in several contexts, surprisingly plays an important role in protection from inflammation in mouse models of colitis, with LIGHT deficient mice having more severe disease pathogenesis. However, LIGHT is a single member of a complex signaling network. It signals through multiple receptors, including herpes virus entry mediator (HVEM) and lymphotoxin beta receptor (LTbetaR); these two receptors in turn can bind to other ligands. It remains unknown which receptors and competing ligands can mediate or counteract the outcome of LIGHT-signaling during colitis. Here we demonstrate that LIGHT signaling through LTbetaR, rather than HVEM, plays a critical role in the progression of DSS-induced colitis, as LTbetaR deficient mice exhibit a more severe disease phenotype. Further, mice deficient in LTalphabeta do not exhibit differential colitis progression compared to WT mice. However, deletion of both LIGHT and LTalphabeta, but not deletion of both LTalphabeta and LTbetaR, resulted in a reversal of the adverse effects associated with the loss of LIGHT. In sum, the LIGHT/LTalphabeta/LTbetaR signaling network contributes to DSS colitis, but there may be additional receptors or indirect effects, and therefore, the relationships between these receptors and ligands remains enigmatic. PMID- 30524423 TI - CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs. AB - CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137 signalosome formation, underscoring the key roles of TRAFs and of K63 and K48 ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer. PMID- 30524424 TI - Baseline Gastrointestinal Eosinophilia Is Common in Oral Immunotherapy Subjects With IgE-Mediated Peanut Allergy. AB - Rationale: Oral immunotherapy (OIT) is an emerging treatment for food allergy. While desensitization is achieved in most subjects, many experience gastrointestinal symptoms and few develop eosinophilic gastrointestinal disease. It is unclear whether these subjects have subclinical gastrointestinal eosinophilia (GE) at baseline. We aimed to evaluate the presence of GE in subjects with food allergy before peanut OIT. Methods: We performed baseline esophagogastroduodenoscopies on 21 adults before undergoing peanut OIT. Subjects completed a detailed gastrointestinal symptom questionnaire. Endoscopic findings were assessed using the Eosinophilic Esophagitis (EoE) Endoscopic Reference Score (EREFS) and biopsies were obtained from the esophagus, gastric antrum, and duodenum. Esophageal biopsies were evaluated using the EoE Histologic Scoring System. Immunohistochemical staining for eosinophil peroxidase (EPX) was also performed. Hematoxylin and eosin and EPX stains of each biopsy were assessed for eosinophil density and EPX/mm2 was quantified using automated image analysis. Results: All subjects were asymptomatic. Pre-existing esophageal eosinophilia (>5 eosinophils per high-power field [eos/hpf]) was present in five participants (24%), three (14%) of whom had >15 eos/hpf associated with mild endoscopic findings (edema, linear furrowing, or rings; median EREFS = 0, IQR 0-0.25). Some subjects also demonstrated basal cell hyperplasia, dilated intercellular spaces, and lamina propria fibrosis. Increased eosinophils were noted in the gastric antrum (>12 eos/hpf) or duodenum (>26 eos/hpf) in 9 subjects (43%). EPX/mm2 correlated strongly with eosinophil counts (r = 0.71, p < 0.0001). Conclusions: Pre-existing GE is common in adults with IgE-mediated peanut allergy. Eosinophilic inflammation (EI) in these subjects may be accompanied by mild endoscopic and histologic findings. Longitudinal data collection during OIT is ongoing. PMID- 30524425 TI - Dysregulated miRNAome and Proteome of PPRV Infected Goat PBMCs Reveal a Coordinated Immune Response. AB - In this study, the miRNAome and proteome of virulent Peste des petits ruminants virus (PPRV) infected goat peripheral blood mononuclear cells (PBMCs) were analyzed. The identified differentially expressed miRNAs (DEmiRNAs) were found to govern genes that modulate immune response based on the proteome data. The top 10 significantly enriched immune response processes were found to be governed by 98 genes. The top 10 DEmiRNAs governing these 98 genes were identified based on the number of genes governed by them. Out of these 10 DEmiRNAs, 7 were upregulated, and 3 were downregulated. These include miR-664, miR-2311, miR-2897, miR-484, miR 2440, miR-3533, miR-574, miR-210, miR-21-5p, and miR-30. miR-664 and miR-484 with proviral and antiviral activities, respectively, were upregulated in PPRV infected PBMCs. miR-210 that inhibits apoptosis was downregulated. miR-21-5p that decreases the sensitivity of cells to the antiviral activity of IFNs and miR-30b that inhibits antigen processing and presentation by primary macrophages were downregulated, indicative of a strong host response to PPRV infection. miR-21-5p was found to be inhibited on IPA upstream regulatory analysis of RNA-sequencing data. This miRNA that was also highly downregulated and was found to govern 16 immune response genes in the proteome data was selected for functional validation vis-a-vis TGFBR2 (TGF-beta receptor type-2). TGFBR2 that regulates cell differentiation and is involved in several immune response pathways was found to be governed by most of the identified immune modulating DEmiRNAs. The decreased luciferase activity in Dual Luciferase Reporter Assay indicated specific binding of miR-21-5p and miR-484 to their target thus establishing specific binding of the miRNAs to their targets.This is the first report on the miRNAome and proteome of virulent PPRV infected goat PBMCs. PMID- 30524426 TI - Microphysiologic Human Tissue Constructs Reproduce Autologous Age-Specific BCG and HBV Primary Immunization in vitro. AB - Current vaccine development disregards human immune ontogeny, relying on animal models to select vaccine candidates targeting human infants, who are at greatest risk of infection worldwide, and receive the largest number of vaccines. To help accelerate and de-risk development of early-life effective immunization, we engineered a human age-specific microphysiologic vascular-interstitial interphase, suitable for pre-clinical modeling of distinct age-targeted immunity in vitro. Our Tissue Constructs (TCs) enable autonomous extravasation of monocytes that undergo rapid self-directed differentiation into migratory Dendritic Cells (DCs) in response to adjuvants and licensed vaccines such as Bacille Calmette-Guerin (BCG) or Hepatitis B virus Vaccine (HBV). TCs contain a confluent human endothelium grown atop a tri-dimensional human extracellular matrix substrate, employ human age-specific monocytes and autologous non heat treated plasma, and avoid the use of xenogenic materials and exogenous cytokines. Vaccine-pulsed TCs autonomously generated DCs that induced single-antigen recall responses from autologous naive and memory CD4+ T lymphocytes, matching study participant immune-status, including BCG responses paralleling donor PPD status, BCG-induced adenosine deaminase (ADA) activity paralleling infant cohorts in vivo, and multi-dose HBV antigen-specific responses as demonstrated by lymphoproliferation and TCR sequencing. Overall, our microphysiologic culture method reproduced age- and antigen-specific recall responses to BCG and HBV immunization, closely resembling those observed after a birth immunization of human cohorts in vivo, offering for the first time a new approach to early pre clinical selection of effective age-targeted vaccine candidates. PMID- 30524427 TI - Suppression of Intestinal Epithelial Cell Chemokine Production by Lactobacillus rhamnosus R0011 and Lactobacillus helveticus R0389 Is Mediated by Secreted Bioactive Molecules. AB - Host intestinal epithelial cells (IEC) present at the gastrointestinal interface are exposed to pathogenic and non-pathogenic bacteria and their products. Certain probiotic lactic acid bacteria (LAB) have been associated with a range of host immune modulatory activities including down-regulation of pro-inflammatory gene expression and cytokine production by IEC, with growing evidence suggesting that these bacteria secrete bioactive molecules with immunomodulatory activity. The aim of this study was to determine whether two lactobacilli with immunomodulatory activity [Lactobacillus rhamnosus R0011 (Lr) and Lactobacillus helveticus R0389 (Lh)], produce soluble mediators able to influence IEC responses to Pattern Recognition Receptor (PRR) ligands and pro-inflammatory cytokines [Tumor Necrosis Factor alpha (TNFalpha), Interleukin-1beta (IL-1beta)], signals inducing IEC chemokine production during infection. To this end, the effects of cell-free supernatants (CFS) from Lr and Lh on IEC production of the pro-inflammatory chemokines interleukin (IL)-8 and cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by a range of host- or pathogen-derived pro-inflammatory stimuli were determined, and the impact on human HT-29 IEC and a primary IEC line (rat IEC-6) was compared. The Lr-CFS and Lh-CFS did not significantly modulate basal IL-8 production from HT-29 IECs or CINC-1 production from IEC-6 cells. However, both Lr-CFS and Lh-CFS significantly down-regulated IL-8 production from HT-29 IECs challenged with varied PRR ligands. Lr-CFS and Lh-CFS had differential effects on PRR-induced CINC-1 production by rat IEC-6 IECs, with no significant down-regulation of CINC-1 observed from IEC-6 IECs cultured with Lh-CFS. Further analysis of the Lr-CFS revealed down-regulation of IL-8 production induced by the pro-inflammatory cytokines IL-1beta and TNFalpha Preliminary characterization of the bioactive constituent(s) of the Lr-CFS indicates that it is resistant to treatment with DNase, RNase, and an acidic protease, but is sensitive to alterations in pH. Taken together, these results indicate that these lactobacilli secrete bioactive molecules of low molecular weight that may modulate host innate immune activity through interactions with IEC. PMID- 30524428 TI - Presence of Immune Complexes of IgG/IgM Bound to B2-glycoprotein I Is Associated With Non-criteria Clinical Manifestations in Patients With Antiphospholipid Syndrome. AB - Background: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder defined by the presence of both clinical (thromboembolic events or pregnancy morbidity) and laboratory (antiphospholipid antibodies, aPL) manifestations. Despite their importance, several clinical manifestations strongly associated with APS such as livedo reticularis (LR), thrombocytopenia, sicca ophthalmic(sicca), heart, or neurological manifestations are not included in the APS clinical classification criteria. Circulating immune complexes (CIC) formed by Beta-2-glycoprotein I (B2GPI) and aPL (B2-CIC) have been described and their presence has been related with thrombotic events. Methods: Cross-sectional and observational cohort study in APS patients with thrombotic symptomatology. Setting and Participants: Fifty-seven patients from the University Hospital Center Bezanijska Kosa (Belgrade, Serbia) who met the APS classification criteria (35 with primary APS and 22 with APS associated to systemic lupus erythematosus). This study aimed to determine the prevalence of B2-CIC in APS patients and to evaluate their association with clinical manifestations of APS not included in the classification criteria. Results: B2-CIC prevalence in APS patients was 19.3%. The presence of thrombocytopenia (OR:5.7), livedo reticularis (OR:5.6), sicca (OR:12.6), and leukopenia (OR:5.6) was significantly higher in patients with B2-CIC than in the rest of APS patients. C3 and C4 complement factor levels were significantly lower in B2-CIC positive patients, which suggests a greater consumption of complement. Patients with quadruple aPL positivity (triple aPL positivity plus the presence of B2-CIC) showed a higher prevalence of thrombocytopenia, leucopenia and LR than those with single/double aPL-positivity. No significant differences were found in the frequencies observed in patients with triple-only vs. single/double aPL-positivity. There were no significant differences between patients with primary APS and lupus-associated APS regarding the prevalence of B2-CIC and outcomes. Conclusions: Presence of B2-CIC is strongly associated with several non-criteria clinical manifestations related to APS and to higher complement consumption. More studies are required to better understand the clinical significance of B2-CIC. PMID- 30524429 TI - Distinct Migratory Properties of M1, M2, and Resident Macrophages Are Regulated by alphaDbeta2 and alphaMbeta2 Integrin-Mediated Adhesion. AB - Chronic inflammation is essential mechanism during the development of cardiovascular and metabolic diseases. The outcome of diseases depends on the balance between the migration/accumulation of pro-inflammatory (M1) and anti inflammatory (M2) macrophages in damaged tissue. The mechanism of macrophage migration and subsequent accumulation is still not fully understood. Currently, the amoeboid adhesion-independent motility is considered essential for leukocyte migration in the three-dimensional environment. We challenge this hypothesis by studying the contribution of leukocyte adhesive receptors, integrins alphaMbeta2, and alphaDbeta2, to three-dimensional migration of M1-polarized, M2-polarized, and resident macrophages. Both integrins have a moderate expression on M2 macrophages, while alphaDbeta2 is upregulated on M1 and alphaMbeta2 demonstrates high expression on resident macrophages. The level of integrin expression determines its contribution to macrophage migration. Namely, intermediate expression supports macrophage migration, while a high integrin density inhibits it. Using in vitro three-dimensional migration and in vivo tracking of adoptively transferred fluorescently-labeled macrophages during the resolution of inflammation, we found that strong adhesion of M1-activated macrophages translates to weak 3D migration, while moderate adhesion of M2-activated macrophages generates dynamic motility. Reduced migration of M1 macrophages depends on the high expression of alphaDbeta2, since alphaD-deficiency decreased M1 macrophage adhesion and improved migration in fibrin matrix and peritoneal tissue. Similarly, the high expression of alphaMbeta2 on resident macrophages prevents their amoeboid migration, which is markedly increased in alphaM deficient macrophages. In contrast, alphaD- and alphaM-knockouts decrease the migration of M2 macrophages, demonstrating that moderate integrin expression supports cell motility. The results were confirmed in a diet-induced diabetes model. alphaD deficiency prevents the retention of inflammatory macrophages in adipose tissue and improves metabolic parameters, while alphaM deficiency does not affect macrophage accumulation. Summarizing, beta2 integrin-mediated adhesion may inhibit amoeboid and mesenchymal macrophage migration or support mesenchymal migration in tissue, and, therefore, represents an important target to control inflammation. PMID- 30524430 TI - Novel Treatments in Lupus. AB - PURPOSE OF REVIEW: The standard treatment options for systemic lupus erythematosus (SLE) are focused on non-specific immunosuppression. Over the past few years, scientific studies and ongoing clinical trials have shifted the paradigm with rapid advances in developing biologics and small molecules. A number of monoclonal antibodies and small molecule inhibitors have been developed to target specific pathways involved in SLE. Many of these novel therapeutic agents are already being tested in clinical trials and they may 1 day reshape the landscape of SLE treatment. Herein we review potential future therapeutic options for SLE. PMID- 30524431 TI - Commensal Bacteria-Specific CD4+ T Cell Responses in Health and Disease. AB - Over the course of evolution, mammalian body surfaces have adapted their complex immune system to allow a harmless coexistence with the commensal microbiota. The adaptive immune response, in particular CD4+ T cell-mediated, is crucial to maintain intestinal immune homeostasis by discriminating between harmless (e.g., dietary compounds and intestinal microbes) and harmful stimuli (e.g., pathogens). To tolerate food molecules and microbial components, CD4+ T cells establish a finely tuned crosstalk with the environment whereas breakdown of these mechanisms might lead to chronic disease associated with mucosal barriers and beyond. How commensal-specific immune responses are regulated and how these molecular and cellular mechanisms can be manipulated to treat chronic disorders is yet poorly understood. In this review, we discuss current knowledge of the regulation of commensal bacteria-specific CD4+ T cells. We place particular focus on the key role of commensal-specific CD4+ T cells in maintaining tolerance while efficiently eradicating local and systemic infections, with a focus on factors that trigger their aberrant activation. PMID- 30524432 TI - Real World Lab Data: Patterns of Lymphocyte Counts in Fingolimod Treated Patients. AB - Objective: Fingolimod is approved for the treatment of highly active relapsing remitting multiple sclerosis (MS) patients and acts by its unique mechanism of action via sphingosine-1-phosphate receptor-modulation. Although fingolimod associated lymphopenia is a well-known phenomenon, the exact cause for the intra- and inter-individual differences of the fluctuation of lymphocyte count and its subtypes is still subject of debate. In this analysis, we aim to estimate the significance of the individual variation of distinct lymphocyte subsets for differences in absolute lymphocyte decrease in fingolimod treated patients and discuss how different lymphocyte subset patterns are related to clinical presentation in a long-term real life setting. Methods/Design: One hundred and thirteen patients with MS were characterized by complete blood cell count and immune cell phentopying of peripheral lymphocyte subsets before, at month 1 and every 3 months up to 36 months of fingolimod treatment. In addition, patients were monitored regarding clinical parameters (relapses, disability, MRI). Results: There was no significant association of baseline lymphocyte count and lymphocyte subtypes with lymphocyte decrease after fingolimod start. The initial drop of the absolute lymphocyte count could not predict the level of lymphocyte count during steady state on fingolimod. Variable CD8+ T cell and NK cell counts account for the remarkable intra- and inter-individual differences regarding initial drop and steady state level of lymphocyte count during fingolimod treatment, whereas CD4+ T cells and B cells mostly present a quite uniform decrease in all treated patients. Selected patients with lymphocyte count >1.0 GPT/l differed by higher CD8+ T cells and NK cell counts compared to lymphopenic patients but presented comparable clinical effectiveness during treatment. Conclusion: Monitoring of the absolute lymphocyte count at steady state seems to be a rough estimate of fingolimod induced lymphocyte redistribution. Our results suggest, that evaluation of distinct lymphocyte subsets as CD4+ T cells allow a more detailed evaluation to weigh and interpret degree of lymphopenia and treatment response in fingolimod treated patients. PMID- 30524433 TI - Dietary Methionine Improves the European Seabass (Dicentrarchus labrax) Immune Status, Inflammatory Response, and Disease Resistance. AB - Methionine presents a pivotal role in the regulation of many cellular events with crucial impact on the immune system, such as in processes involved in the control of inflammation and polyamines synthesis. Accordingly, the present study aimed to assess the modulatory effects of dietary methionine on the European seabass (Dicentrarchus labrax) immune status, inflammatory response and disease resistance to Photobacterium damselae subsp. piscicida (Phdp). For this purpose, fish were randomly distributed in three independent groups (three replicates per group) and each was fed the corresponding diet: a control diet (CTRL) formulated to meet the established amino acid requirements for the species; a diet supplemented with methionine at 0.5% of feed weight relative to the CTRL diet (8.2% of methionine concentration above CTRL); and one supplemented with methionine at 1% of feed weight to the CTRL diet (11.8% of methionine concentration above CTRL). To evaluate the immune status of fish fed with each of the diets before being submitted to bacterial infection fish were sampled from each group at 2 and 4 weeks after the beginning of feeding. Non-sampled fish were injected intraperitoneally with Phdp (5 * 103 cfu/fish) at 4 weeks after initiation of feeding and the inflammatory response (at 4, 24, and 48 h post infection) and survival (lasting 21 days post-infection) evaluated. Fish hematological profile, peripheral cell dynamics, plasma humoral immune parameters, leucocyte migration to the inflammatory focus and head-kidney gene expression were evaluated. Results show that methionine dietary supplementation improves seabass cellular immune status without evidence of activation of pro inflammatory mechanisms. Additionally, the observed enhanced immune status provided by methionine supplementation translated into an improved immune response to infection, as higher cellular differentiation/proliferation and recruitment to the inflammatory focus, improved plasma humoral immune parameters and modulation of key immune-related genes was observed. Lastly, after a bacterial challenge, higher survival was observed in fish fed supplemented diets, ultimately corroborating the positive effect of methionine administration for 4 weeks in the cellular immune status. PMID- 30524434 TI - A Novel Cellular Pathway of Antigen Presentation and CD4 T Cell Activation in vivo. AB - Dendritic cell activation of CD4 T cells in the lymph node draining a site of infection or vaccination is widely considered the central event in initiating adaptive immunity. The accepted dogma is that this occurs by stimulating local activation and antigen acquisition by dendritic cells, with subsequent lymph node migration, however the generalizability of this mechanism is unclear. Here we show that in some circumstances antigen can bypass the injection site inflammatory response, draining freely and rapidly to the lymph nodes where it interacts with subcapsular sinus (SCS) macrophages resulting in their death. Debris from these dying SCS macrophages is internalized by monocytes recruited from the circulation. This coordinated response leads to antigen presentation by monocytes and interactions with naive CD4 T cells that can drive the initiation of T cell and B cell responses. These studies demonstrate an entirely novel pathway leading to initiation of adaptive immune responses in vivo. PMID- 30524435 TI - Regulating Innate and Adaptive Immunity for Controlling SIV Infection by 25 Hydroxycholesterol. AB - Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-gamma-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-alpha cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection. PMID- 30524436 TI - Complement-Activating Capacity of Autoantibodies Correlates With Disease Activity in Bullous Pemphigoid Patients. AB - Background: Bullous pemphigoid is a subepidermal blistering skin disease, associated with autoantibodies to hemidesmosomal proteins, complement activation at the dermal-epidermal junction, and dermal granulocyte infiltration. Clinical and experimental laboratory findings support conflicting hypotheses regarding the role of complement activation for the skin blistering induced by pemphigoid autoantibodies. In-depth studies on the pathogenic relevance of autoimmune complement activation in patients are largely lacking. Therefore, the aim of this study was to investigate the pathogenic relevance of complement activation in patients with bullous pemphigoid. Complement activation by autoantibodies in vivo as measured by the intensity of complement C3 deposits in the patients' skin and ex vivo by the complement-fixation assay in serum was correlated with the clinical disease activity, evaluated by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Bullous Pemphigoid Disease Area Index (BPDAI), as well as, with further immunopathological findings in patients with bullous pemphigoid. Results: Complement-activation capacity of autoantibodies ex vivo, but not deposition of complement in the perilesional skin of patients, correlates with the extent of skin disease (measured by ABSIS and BPDAI) and with levels of autoantibodies. Conclusions: Our study provides for the first time evidence in patients for a pathogenic role of complement activation in bullous pemphigoid and should greatly facilitate the development of novel diagnostic tools and of more specific therapies for complement-dependent autoimmune injury. PMID- 30524437 TI - Social Networking of Group Two Innate Lymphoid Cells in Allergy and Asthma. AB - Allergic diseases including asthma, chronic rhinosinusitis, and atopic dermatitis are common conditions worldwide. While type 2 immune responses induced by T-cells significantly cause allergic inflammation, the recently identified group two innate lymphoid cells (ILC2s) are emerging as critical players in the development of allergy. Upon allergen exposure, ILC2s are rapidly activated by cytokines released by epithelial cells. Activated ILC2s release various effector cytokines altogether contributing to the pathogenesis of allergy and can even cause inflammation in the absence of T-cells, as observed in asthma. Although the factors inducing ILC2 activation have been identified, evidence suggests that multiple factors can enhance or repress ILC2 proliferation, trafficking, or secretion of effector cytokines upon allergic inflammation. In this review, we discuss the recent findings that influence ILC2 activation and the resulting effects on the pathogenesis of allergy. A better understanding of how ILC2s are modulated will open the door to the development of new therapeutic strategies against allergic diseases. PMID- 30524438 TI - Specific MHC-I Peptides Are Induced Using PROTACs. AB - Peptides presented by the class-I major histocompatibility complex (MHC-I) are important targets for immunotherapy. The identification of these peptide targets greatly facilitates the generation of T-cell-based therapeutics. Herein, we report the capability of proteolysis targeting chimera (PROTAC) compounds to induce the presentation of specific MHC class-I peptides derived from endogenous cellular proteins. Using LC-MS/MS, we identified several BET-derived MHC-I peptides induced by treatment with three BET-directed PROTAC compounds. To understand our ability to tune this process, we measured the relative rate of presentation of these peptides under varying treatment conditions using label free mass spectrometry quantification. We found that the rate of peptide presentation reflected the rate of protein degradation, indicating a direct relationship between PROTAC treatment and peptide presentation. We additionally analyzed the effect of PROTAC treatment on the entire immunopeptidome and found many new peptides that were displayed in a PROTAC-specific fashion: we determined that these identifications map to the BET pathway, as well as, potential off target or unique-to-PROTAC pathways. This work represents the first evidence of the use of PROTAC compounds to induce the presentation of MHC-I peptides from endogenous cellular proteins, highlighting the capability of PROTAC compounds for the discovery and generation of new targets for immunotherapy. PMID- 30524439 TI - Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab. AB - B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin. PMID- 30524440 TI - Control of the Germinal Center by Follicular Regulatory T Cells During Infection. AB - Follicular regulatory T cells (Tfr) are a unique subset of CD4 T cells that control and impact adaptive immune responses in the lymphoid follicles and germinal centers (GC). Since their relatively recent discovery, several studies have revealed that Tfr interact with other cells within this niche and shape ensuing responses. Recent advances defining the functional and developmental characteristics of Tfr have revealed key characteristics of Tfr differentiation, GC recruitment and retention, and regulatory properties. Further, Tfr shape the GC response and balance tolerance through interactions with Tfh, by modifying Tfh number, diversity and function, as well as with B cells. Mechanisms by which Tfr regulate the GC include cell-to-cell interactions with Tfh and B cells, as well as altering their environment through cytokine production and sequestration. Tfr have been shown to have a diverse T cell receptor (TCR) repertoire and can be specific for immunizing agents, demonstrating a potential role in vaccine development. Due to these important characteristics and functions, Tfr play a major role in immune tolerance, response to infection, and vaccine efficacy. PMID- 30524441 TI - Management of Autoimmune Encephalitis: An Observational Monocentric Study of 38 Patients. AB - Over the last years the clinical picture of autoimmune encephalitis has gained importance in neurology. The broad field of symptoms and syndromes poses a great challenge in diagnosis for clinicians. Early diagnosis and the initiation of the appropriate treatment is the most relevant step in the management of the patients. Over the last years advances in neuroimmunology have elucidated pathophysiological basis and improved treatment concepts. In this monocentric study we compare demographics, diagnostics, treatment options and outcomes with knowledge from literature. We present 38 patients suffering from autoimmune encephalitis. Antibodies were detected against NMDAR and LGI1 in seven patients, against GAD in 6 patients) one patient had coexisting antibodies against GABAA and GABAB), against CASPR2, IGLON5, YO, Glycine in 3 patients, against Ma-2 in 2 patients, against CV2 and AMPAR in 1 patient; two patients were diagnosed with hashimoto encephalitis with antibodies against TPO/TG. First, we compare baseline data of patients who were consecutively diagnosed with autoimmune encephalitis from a retrospective view. Further, we discuss when to stop immunosuppressive therapy since how long treatment should be performed after clinical stabilization or an acute relapse is still a matter of debate. Our experiences are comparable with data from literature. However, in contrary to other experts in the field we stop treatment and monitor patients very closely after tumor removal and after rehabilitation from first attack. PMID- 30524442 TI - Pathogenesis of Neisseria gonorrhoeae and the Host Defense in Ascending Infections of Human Fallopian Tube. AB - Neisseria gonorrhoeae is an obligate human pathogen that causes mucosal surface infections of male and female reproductive tracts, pharynx, rectum, and conjunctiva. Asymptomatic or unnoticed infections in the lower reproductive tract of women can lead to serious, long-term consequences if these infections ascend into the fallopian tube. The damage caused by gonococcal infection and the subsequent inflammatory response produce the condition known as pelvic inflammatory disease (PID). Infection can lead to tubal scarring, occlusion of the oviduct, and loss of critical ciliated cells. Consequences of the damage sustained on the fallopian tube epithelium include increased risk of ectopic pregnancy and tubal-factor infertility. Additionally, the resolution of infection can produce new adhesions between internal tissues, which can tear and reform, producing chronic pelvic pain. As a bacterium adapted to life in a human host, the gonococcus presents a challenge to the development of model systems for probing host-microbe interactions. Advances in small-animal models have yielded previously unattainable data on systemic immune responses, but the specificity of N. gonorrhoeae for many known (and unknown) host targets remains a constant hurdle. Infections of human volunteers are possible, though they present ethical and logistical challenges, and are necessarily limited to males due to the risk of severe complications in women. It is routine, however, that normal, healthy fallopian tubes are removed in the course of different gynecological surgeries (namely hysterectomy), making the very tissue most consequentially damaged during ascending gonococcal infection available for laboratory research. The study of fallopian tube organ cultures has allowed the opportunity to observe gonococcal biology and immune responses in a complex, multi-layered tissue from a natural host. Forty-five years since the first published example of human fallopian tube being infected ex vivo with N. gonorrhoeae, we review what modeling infections in human tissue explants has taught us about the gonococcus, what we have learned about the defenses mounted by the human host in the upper female reproductive tract, what other fields have taught us about ciliated and non-ciliated cell development, and ultimately offer suggestions regarding the next generation of model systems to help expand our ability to study gonococcal pathogenesis. PMID- 30524443 TI - Editorial: Non-coding RNAs and Graft versus Host Disease. PMID- 30524444 TI - Myocarditis Elicits Dendritic Cell and Monocyte Infiltration in the Heart and Self-Antigen Presentation by Conventional Type 2 Dendritic Cells. AB - Autoimmune myocarditis often leads to dilated cardiomyopathy (DCM). Although T cell reactivity to cardiac self-antigen is common in the disease, it is unknown which antigen presenting cell (APC) triggers autoimmunity. Experimental autoimmune myocarditis (EAM) was induced by immunizing mice with alpha-myosin loaded bone marrow APCs cultured in GM-CSF. APCs found in such cultures include conventional type 2 CD11b+ cDCs (GM-cDC2s) and monocyte-derived cells (GM-MCs). However, only alpha-myosin loaded GM-cDC2s could induce EAM. We also studied antigen presenting capacity of endogenous type 1 CD24+ cDCs (cDC1s), cDC2s, and MCs for alpha-myosin-specific TCR-transgenic TCR-M CD4+ T cells. After EAM induction, all cardiac APCs significantly increased and cDCs migrated to the heart-draining mediastinal lymph node (LN). Primarily cDC2s presented alpha myosin to TCR-M cells and induced Th1/Th17 differentiation. Loss of IRF4 in Irf4 fl/fl .Cd11cCre mice reduced MHCII expression on GM-cDC2s in vitro and cDC2 migration in vivo. However, partly defective cDC2 functions in Irf4 fl/fl .Cd11cCre mice did not suppress EAM. MCs were the largest APC subset in the inflamed heart and produced pro-inflammatory cytokines. Targeting APC populations could be exploited in the design of new therapies for cardiac autoimmunity. PMID- 30524445 TI - The c-Myc/miR17-92/PTEN Axis Tunes PI3K Activity to Control Expression of Recombination Activating Genes in Early B Cell Development. AB - Appropriate PI3K signals generated by the antigen receptor are essential to promote B cell development. Regulation of recombination activating gene (RAG)-1 and RAG-2 expression is one key process that is mediated by PI3K to ensure developmental progression and selection. When PI3K signals are too high or too low, expression of RAGs does not turn off and B cell development is impaired or blocked. Yet, the mechanism which tunes PI3K activity to control RAG expression during B cell development in the bone marrow is unknown. Recently we showed that a c-Myc/miR17-92/PTEN axis regulates PI3K activity for positive and negative selection of immature B cells. Here, we show that the c-Myc/miR17-92/PTEN axis tunes PI3K activity to control the expression of RAGs in proB cells. Using different genetically engineered mouse models we show that impaired function of the c-Myc/miR17-92/PTEN axis alters the PI3K/Akt/Foxo1 pathway to result in dis regulated expression of RAG and a block in B cell development. Studies using 38c 13 B lymphoma cells, where RAGs are constitutively expressed, suggest that this regulatory effect is mediated post-translationally through Foxo1. PMID- 30524446 TI - Death Associated to Methicillin Resistant Staphylococcus aureus ST8 Infection in Two Dolphins Maintained Under Human Care, Italy. AB - The present study describes the isolation of Methicillin-resistant Staphylococcus aureus (MRSA) from respiratory tract of 2 dolphins of different origin, a stranded juvenile Risso's dolphin (Grampus griseus) and a captive born common bottlenose dolphin (Tursiops truncatus) calf, which died in the same institution at 1-month distance from the other. A complete microbiological and genetic investigation confirmed the presence of MRSA clone-complex 8, sequence type (ST) 8, spa-type t008 in both individuals. This strain differs from the one previously reported in walruses and dolphins and has never been described in dolphins before, but it is randomly isolated from Italian human patients. Vertical transmission of the infection may also occurs in other species and considering the description and location of the pathological lesions, this seems to be the most likely route of transmission implied in the young bottlenose dolphin. Staphylococcus aureus is known as an opportunistic agent, usually secondary to other pathogens, but its multiple antibiotic resistance and its zoonotic implications suggest a thorough and strict application of animal management hygiene protocols. PMID- 30524447 TI - TCR Repertoire as a Novel Indicator for Immune Monitoring and Prognosis Assessment of Patients With Cervical Cancer. AB - There is increasing evidence that deep sequencing-based T cell repertoire can sever as a biomarker of immune response in cancer patients; however, the characteristics of T cell repertoire including diversity and similarity, as well as its prognostic significance in patients with cervical cancer (CC) remain unknown. In this study, we applied a high throughput T cell receptor (TCR) sequencing method to characterize the T cell repertoires of peripheral blood samples from 25 CC patients, 30 cervical intraepithelial neoplasia (CIN) patients and 20 healthy women for understanding the immune alterations during the cervix carcinogenesis. In addition, we also explored the signatures of TCR repertoires in the cervical tumor tissues and paired sentinel lymph nodes from 16 CC patients and their potential value in predicting the prognosis of patients. Our results revealed that the diversity of circulating TCR repertoire gradually decreased during the cervix carcinogenesis and progression, but the circulating TCR repertoires in CC patients were more similar to CIN patients than healthy women. Interestingly, several clonotypes uniquely detected in CC patients tended to share similar CDR3 motifs, which differed from those observed in CIN patients. In addition, the TCR repertoire diversity in sentinel lymphatic nodes from CC patients was higher than in tumor tissues. More importantly, less clonotypes in TCR repertoire of sentinel lymphatic node was associated with the poor prognosis of the patients. Overall, our findings suggested that TCR repertoire might be a potential indicator of immune monitoring and a biomarker for predicting the prognosis of CC patients. Although functional studies of T cell populations are clearly required, this study have expanded our understanding of T cell immunity during the development of CC and provided an experimental basis for further studies on its pathogenesis and immunotherapy. PMID- 30524449 TI - Chromatin Accessibility and Interactions in the Transcriptional Regulation of T Cells. AB - During T cell differentiation and activation, specific stimuli, and a network of transcription factors (TFs) are involved in orchestrating chromatin accessibility, establishing enhancer-promoter interactions, and regulating gene expression. Over the past few years, there have been new insights into how chromatin interactions coordinate differentiation during T cell development and how regulatory elements are programmed to allow T cells to differentially respond to distinct stimuli. In this review, we discuss recent advances related to the roles of TFs in establishing the regulatory chromatin landscapes that orchestrate T cell development and differentiation. In particular, we focus on the role of TFs (e.g., TCF-1, BCL11B, PU.1, STAT3, STAT5, AP-1, and IRF4) in mediating chromatin accessibility and interactions and in regulating gene expression in T cells, including gene expression that is dependent on IL-2 and IL-21. Furthermore, we discuss the state of knowledge on enhancer-promoter interactions and how autoimmune disease risk variants can be linked to molecular functions of putative target genes. PMID- 30524450 TI - Editorial: C-Reactive Protein in Age-Related Disorders. PMID- 30524448 TI - Signatures of T and B Cell Development, Functional Responses and PD-1 Upregulation After HCMV Latent Infections and Reactivations in Nod.Rag.Gamma Mice Humanized With Cord Blood CD34+ Cells. AB - Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation. PMID- 30524452 TI - Genetic Contribution of Emmer Wheat (Triticum dicoccon Schrank) to Heat Tolerance of Bread Wheat. AB - Rising global temperatures cause substantial yield losses in many wheat growing environments. Emmer wheat (Triticum dicoccon Schrank), one of the first wheat species domesticated, carries significant variation for tolerance to abiotic stresses. This study identified new genetic variability for high-temperature tolerance in hexaploid progeny derived from crosses with emmer wheat. Eight hexaploid and 11 tetraploid parents were recombined in 43 backcross combinations using the hexaploid as the recurrent parent. A total of 537 emmer-based hexaploid lines were developed by producing approximately 10 doubled haploids on hexaploid like BC1F1 progeny and subsequent selection for hexaploid morphology. These materials and 17 commercial cultivars and hexaploid recurrent parents were evaluated under two times of sowing in the field, in 2014-2016. The materials were genotyped using a 90K SNP platform and these data were used to estimate the contribution of emmer wheat to the progeny. Significant phenotypic and genetic variation for key agronomical traits including grain yield, TKW and screenings was observed. Many of the emmer derived lines showed improved performance under heat stress (delayed sowing) compared with parents and commercial cultivars. Emmer derived lines were the highest yielding material in both sowing dates. The emmer wheat parent contributed between 1 and 44% of the genome of the derived lines. Emmer derived lines with superior kernel weight and yield generally had a greater genetic contribution from the emmer parent compared to those with lower trait values. The study showed that new genetic variation for key traits such as yield, kernel weight and screenings can be introduced to hexaploid wheat from emmer wheat. These genetic resources should be explored more systematically to stabilize grain yield and quality in a changing climate. PMID- 30524451 TI - Soil-Plant Indices Help Explain Legume Response to Crop Rotation in a Semiarid Environment. AB - Crop productivity is typically affected by various soil-plant factors systematically as they influence plant photosynthesis, soil fertility, and root systems. However, little is known about how the productivity of legumes is related to crop rotation systems. The objectives of this study were to determine the effect of rotation systems on legume productivity and the relationships among legume productivity and soil-plant factors. Three annual legumes - chickpea (Cicer arietinum L.), pea (Pisum sativum L.), and lentil (Lens culinaris Medikus), were included in various diversified rotation systems and compared with legume monoculture in the 8-year rotation study. Soil N and water conditions, and canopy and root systems were evaluated at the end of 8-year rotation in the semiarid Canadian prairies. Results showed that diversified rotation systems improved leaf greenness by 4%, shoot biomass by 25%, nodule biomass by 44%, and seed yield by 95% for chickpea and pea, but such effects were not found for lentil. Pea monocultures increased root rot severity by threefold compared with diversified rotations, and chickpea monoculture increased shoot rot severity by 23%, root rot severity by 96% and nodule damage by 219%. However, all the legume monocultures improved soil N accumulation by an average 38% compared to diversified systems. Pea and chickpea displayed considerable sensitivity to plant biotic stresses, whereas lentil productivity had a larger dependence on initial soil N content. The 8-year study concludes that the rotational effect on legume productivity varies with legume species, the frequency of a legume appearing in the rotation, and the integration of relevant soil and plant indices. PMID- 30524453 TI - Mango Firmness Modeling as Affected by Transport and Ethylene Treatments. AB - More and more, tropical fruit are subjected to accelerated ripening at receiving markets until "ready to eat." We propose a kinetic model that incorporates the effects of temperature and ethylene on the firmness behavior of "Keitt" and "Kent" mangoes. Stiffness of individual mangoes, as measured by the acoustic firmness tester, was measured repeatedly over time. The firmness model assumes fixed levels of ethylene, established after the climacteric peak, that steadily induces production of softening enzymes that subsequently denaturalize. The initial level of these enzymes is assumed to be zero due to either the tree factor for freshly harvested mangoes, or due to chilling injury for reefer transported mangoes. The kinetic parameter set for "Keitt" mangoes was estimated based on a Spanish batch, freshly harvested and ripened under dynamic temperature scenarios, combined with a reefer transported Brazilian batch stored at four constant temperatures. Firmness data from reefer transported batches, from Brazil, Ivory Coast and Mali, stored at four constant temperatures were used to estimate a set of kinetic parameters for the "Kent" mangoes. Only a partial set of "Kent" kinetic parameters could be established due to the often already advanced stage of softening at the time of arrival. The effect of ethylene was investigated by applying external ethylene levels, varying from 0 to 100 MUL L-1. The effect of external application of ethylene was modeled by estimating EF, the ethylene factor, being a reflection of the internal ethylene level and ethylene sensitivity. The effect of ethylene application on softening was sometimes huge. For an Israeli "Keitt" batch a fifty times higher EF was found when the firmness behavior of low- (without ethylene application) and high temperature (with ethylene application) stored sub-batches were compared. However, this effect was sometimes also small, especially for reefer transported mangoes. For commercial application, a reliable prediction of the time until "ready to eat" is not possible because of the current inability to assess EF. Nevertheless, the proposed model described mango softening accurately, irrespective of the sourcing area and includes the effects of storage temperature and ethylene application. PMID- 30524454 TI - Advanced Proteomic Approaches to Elucidate Somatic Embryogenesis. AB - Somatic embryogenesis (SE) is a cell differentiation process by which a somatic cell changes its genetic program and develops into an embryonic cell. Investigating this process with various explant sources in vitro has allowed us to trace somatic embryo development from germination to plantlets and has led to the generation of new technologies, including genetic transformation, endangered species conservation, and synthetic seed production. A transcriptome data comparison from different stages of the developing somatic embryo has revealed a complex network controlling the somatic cell's fate, suggesting that an interconnected network acts at the protein level. Here, we discuss the current progress on SE using proteomic-based data, focusing on changing patterns of proteins during the establishment of the somatic embryo. Despite the advanced proteomic approaches available so far, deciphering how the somatic embryo is induced is still in its infancy. The new proteomics techniques that lead to the quantification of proteins with different abundances during the induction of SE are opening this area of study for the first time. These quantitative differences can elucidate the different pathways involved in SE induction. We envisage that the application of these proteomic technologies can be pivotal to identifying proteins critical to the process of SE, demonstrating the cellular localization, posttranslational modifications, and turnover protein events required to switch from a somatic cell to a somatic embryo cell and providing new insights into the molecular mechanisms underlying SE. This work will help to develop biotechnological strategies for mass production of quality crop material. PMID- 30524455 TI - Rice Calcineurin B-Like Protein-Interacting Protein Kinase 31 (OsCIPK31) Is Involved in the Development of Panicle Apical Spikelets. AB - Panicle apical abortion (PAA) causes severe yield losses in rice production, but details about its development and molecular basis remain elusive. Herein, a PAA mutant, paa1019, was identified among the progeny of an elite indica maintainer rice line Yixiang 1B (YXB) mutagenized population obtained using ethyl methyl sulfonate. The abortion rate of spikelets in paa1019 was observed up to 60%. Genetic mapping combined with Mutmap analysis revealed that LOC_Os03g20380 harbored a single-bp substitution (C to T) that altered its transcript length. This gene encodes calcineurin B-like protein-interacting protein kinase 31 (OsCIPK31) localized into the cytoplasm, and is preferentially expressed in transport tissues of rice. Complementation of paa1019 by transferring the open reading frame of LOC_Os03g20380 from YXB reversed the mutant phenotype, and conversely, gene editing by knocking out of OsCIPK31 in YXB results in PAA phenotype. Our results support that OsCIPK31 plays an important role in panicle development. We found that dysregulation is caused by the disruption of OsCIPK31 function due to excessive accumulation of ROS, which ultimately leads to cell death in rice panicle. OsCIPK31 and MAPK pathway might have a synergistic effect to lead ROS accumulation in response to stresses. Meanwhile the PAA distribution is related to IAA hormone accumulation in the panicle. Our study provides an understanding of the role of OsCIPK31 in panicle development by responding to various stresses and phytohormones. PMID- 30524456 TI - A Thermotolerant Variant of Rubisco Activase From a Wild Relative Improves Growth and Seed Yield in Rice Under Heat Stress. AB - Genes encoding thermostable variants of the photosynthesis heat-labile protein Rubisco activase (Rca) from a wild relative Oryza australiensis were overexpressed in domesticated rice (Oryza sativa). Proteomics was used to quantify the abundance of O. australiensis Rca (Rca-Oa) in the resulting plants. Plants were grown to maturity in growth rooms and from early tillering until immediately prior to anthesis, they were exposed to daytime maximum temperatures of 28, 40, and 45 degrees C and constant night temperatures of 22 degrees C. Non destructive measurements of leaf elongation and photosynthesis were used to compare the null segregant with a transfected line in which 19% of its total Rca content was the recombinant O. australiensis Rca (T-Oa-19). Height, fresh mass, panicle number, seed set, and seed number were measured at final harvest. Traits at maturity after heat stress at 45 degrees C correlated strongly with recombinant protein abundance. Seed number was far the most responsive trait to an increase in Rca-Oa abundance, improving by up to 150%. Leaf elongation rates (LER) and tiller number were significantly greater in the transformed plants in the first two weeks of exposure to 45 degrees C but tiller numbers later became equal in the two genotypes. Gas exchange measurements showed that T-Oa-19 had faster light induction of photosynthesis but not significantly higher CO2 assimilation rates, indicating that the carbon gain that resulted in large yield improvement after growth at 45 degrees C was not strongly correlated with an instantaneous measurement of steady-state photosynthesis. When plants were grown at 40 degrees C daytime maximum, there was no improvement in the final biomass, panicle or seed number when compared with 28 degrees C, indicating that the threshold for heat damage and beneficial effects of the thermostable Rca recombinant protein was between 40 and 45 degrees C, which corresponded to leaf temperatures in the range 38-42 degrees C. The results suggest that the thermotolerant form of Rca from O. australiensis was sufficient to enhance carbohydrate accumulation and storage by rice over the life of the plant, dramatically improving yields after exposure to heat throughout the vegetative phase. PMID- 30524457 TI - Role of Temperature and Coinfection in Mediating Pathogen Life-History Traits. AB - Understanding processes maintaining variation in pathogen life-history traits is a key challenge in disease biology, and of importance for predicting when and where risks of disease emergence are highest. Pathogens are expected to encounter tremendous levels of variation in their environment - both abiotic and biotic - and this variation may promote maintenance of variation in pathogen populations through space and time. Here, we measure life-history traits of an obligate fungal pathogen at both asexual and sexual stages under both single infection and coinfection along a temperature gradient. We find that temperature had a significant effect on all measured life-history traits while coinfection only had a significant effect on the number of sexual resting structures produced. The effect of temperature on life-history traits was both direct as well as mediated through a genotype-by-temperature interaction. We conclude that pathogen life history traits vary in their sensitivity to abiotic and biotic variation in the environment. PMID- 30524458 TI - Transgenerational Effects and Epigenetic Memory in the Clonal Plant Trifolium repens. AB - Transgenerational effects (TGE) can modify phenotypes of offspring generations playing thus a potentially important role in ecology and evolution of many plant species. These effects have been studied mostly across generations of sexually reproducing species. A substantial proportion of plant species are however reproducing asexually, for instance via clonal growth. TGE are thought to be enabled by heritable epigenetic modification of DNA, although unambiguous evidence is still scarce. On the clonal herb white clover (Trifolium repens), we tested the generality of clonal TGE across five genotypes and five parental environments including soil contamination and above-ground competition. Moreover, by genome wide-methylation variation analysis we explored the role of drought, one of the parental environments that triggered the strongest TGE. We tested the induction of epigenetic changes in offspring generations using several intensities and durations of drought stress. We found that TGE of different environments were highly genotype specific and all tested environments triggered TGE at least in some genotypes. In addition, parental drought stresses triggered epigenetic change in T. repens and most of the induced epigenetic change was maintained across several clonal offspring generations. We conclude that TGE are common and genotype specific in clonal plant T. repens and potentially under epigenetic control. PMID- 30524459 TI - Multi-Locus Genome-Wide Association Studies for 14 Main Agronomic Traits in Barley. AB - The agronomic traits, including morphological and yield component traits, are important in barley breeding programs. In order to reveal the genetic foundation of agronomic traits of interest, in this study 122 doubled haploid lines from a cross between cultivars "Huaai 11" (six-rowed and dwarf) and "Huadamai 6" (two rowed) were genotyped by 9680 SNPs and phenotyped 14 agronomic traits in 3 years, and the two datasets were used to conduct multi-locus genome-wide association studies. As a result, 913 quantitative trait nucleotides (QTNs) were identified by five multi-locus GWAS methods to be associated with the above 14 traits and their best linear unbiased predictions. Among these QTNs and their adjacent genes, 39 QTNs (or QTN clusters) were repeatedly detected in various environments and methods, and 10 candidate genes were identified from gene annotation. Nineteen QTNs and two genes (sdw1/denso and Vrs1) were previously reported, and eight candidate genes need to be further validated. The Vrs1 gene, controlling the number of rows in the spike, was found to be associated with spikelet number of main spike, spikelet number per plant, grain number per plant, grain number per spike, and 1,000 grain weight in multiple environments and by multi-locus GWAS methods. Therefore, the above results evidenced the feasibility and reliability of genome-wide association studies in doubled haploid population, and the QTNs and their candidate genes detected in this study are useful for marker assisted selection breeding, gene cloning, and functional identification in barley. PMID- 30524460 TI - Identification and Analysis of Rice Yield-Related Candidate Genes by Walking on the Functional Network. AB - Rice (Oryza sativa L.) is one of the most important staple foods in the world. It is possible to identify candidate genes associated with rice yield using the model of random walk with restart on a functional similarity network. We demonstrated the high performance of this approach by a five-fold cross validation experiment, as well as the robustness of the parameter r. We also assessed the strength of associations between known seeds and candidate genes in the light of the results scores. The candidates ranking at the top of the results list were considered to be the most relevant rice yield-related genes. This study provides a valuable alternative for rice breeding and biology research. The relevant dataset and script can be downloaded at the website: http://lab.malab.cn/jj/rice.htm. PMID- 30524461 TI - Modifications in Organic Acid Profiles During Fruit Development and Ripening: Correlation or Causation? AB - The pivotal role of phytohormones during fruit development and ripening is considered established knowledge in plant biology. Perhaps less well-known is the growing body of evidence suggesting that organic acids play a key function in plant development and, in particular, in fruit development, maturation and ripening. Here, we critically review the connection between organic acids and the development of both climacteric and non-climacteric fruits. By analyzing the metabolic content of different fruits during their ontogenetic trajectory, we noticed that the content of organic acids in the early stages of fruit development is directly related to the supply of substrates for respiratory processes. Although different organic acid species can be found during fruit development in general, it appears that citrate and malate play major roles in this process, as they accumulate on a broad range of climacteric and non climacteric fruits. We further highlight the functional significance of changes in organic acid profile in fruits due to either the manipulation of fruit specific genes or the use of fruit-specific promoters. Despite the complexity behind the fluctuation in organic acid content during fruit development and ripening, we extend our understanding on the importance of organic acids on fruit metabolism and the need to further boost future research. We suggest that engineering organic acid metabolism could improve both qualitative and quantitative traits of crop fruits. PMID- 30524462 TI - The Effects of Combined Abiotic and Pathogen Stress in Plants: Insights From Salinity and Pseudomonas syringae pv lachrymans Interaction in Cucumber. AB - Plants are often challenged by abiotic and biotic stresses acting in combination and the response to combinatorial stress differs from that triggered by each factor individually. Although salinity and pathogens are major stressors limiting plant growth and productivity worldwide, their interaction is poorly understood. The reactions to pathogens overlap with those to abiotic stresses, and reactive oxygen species (ROS) and stress hormones represent central nodes in the interacting signaling pathways. Usually, abiotic stress negatively affects plant susceptibility to disease. Specific focus of this review is on cucumber plants exposed to salt stress and thereafter infected with Pseudomonas syringae pv lachrymans (Psl). We addressed this problem by discussing the changes in photochemistry, the antioxidant system, primary carbon metabolism, salicylic acid (SA) and abscisic acid (ABA) contents. Salt-treated plants were more prone to infection and this effect was determined by changes in the hormonal and redox balance as well as the carboxylate metabolism and activities of some NADPH generating enzymes. Our detailed understanding of the interactive effects of biotic and abiotic stresses is fundamental to achieve enhanced tolerance to combination stress in agronomically important crops. PMID- 30524463 TI - Quantitative Genetics and Genomics Converge to Accelerate Forest Tree Breeding. AB - Forest tree breeding has been successful at delivering genetically improved material for multiple traits based on recurrent cycles of selection, mating, and testing. However, long breeding cycles, late flowering, variable juvenile-mature correlations, emerging pests and diseases, climate, and market changes, all pose formidable challenges. Genetic dissection approaches such as quantitative trait mapping and association genetics have been fruitless to effectively drive operational marker-assisted selection (MAS) in forest trees, largely because of the complex multifactorial inheritance of most, if not all traits of interest. The convergence of high-throughput genomics and quantitative genetics has established two new paradigms that are changing contemporary tree breeding dogmas. Genomic selection (GS) uses large number of genome-wide markers to predict complex phenotypes. It has the potential to accelerate breeding cycles, increase selection intensity and improve the accuracy of breeding values. Realized genomic relationships matrices, on the other hand, provide innovations in genetic parameters' estimation and breeding approaches by tracking the variation arising from random Mendelian segregation in pedigrees. In light of a recent flow of promising experimental results, here we briefly review the main concepts, analytical tools and remaining challenges that currently underlie the application of genomics data to tree breeding. With easy and cost-effective genotyping, we are now at the brink of extensive adoption of GS in tree breeding. Areas for future GS research include optimizing strategies for updating prediction models, adding validated functional genomics data to improve prediction accuracy, and integrating genomic and multi-environment data for forecasting the performance of genetic material in untested sites or under changing climate scenarios. The buildup of phenotypic and genome-wide data across large-scale breeding populations and advances in computational prediction of discrete genomic features should also provide opportunities to enhance the application of genomics to tree breeding. PMID- 30524464 TI - The Ecology of Plant Chemistry and Multi-Species Interactions in Diversified Agroecosystems. AB - Over the past few years, our knowledge of how ecological interactions shape the structure and dynamics of natural communities has rapidly advanced. Plant chemical traits play key roles in these processes because they mediate a diverse range of direct and indirect interactions in a community-wide context. Many chemically mediated interactions have been extensively studied in industrial cropping systems, and thus have focused on simplified, pairwise and linear interactions that rarely incorporate a community perspective. A contrasting approach considers the agroecosystem as a functioning whole, in which food production occurs. It offers an opportunity to better understand how plant chemical traits mediate complex interactions which can enhance or hinder ecosystem functions. In this paper, we argue that studying chemically mediated interactions in agroecosystems is essential to comprehend how agroecosystem services emerge and how they can be guaranteed through ecosystem management. First, we discuss how plant chemical traits affect and are affected by ecological interactions. We then explore research questions and future directions on how studying chemical mediation in complex agroecosystems can help us understand the emergence and management of ecosystem services, specifically biological control and pollination. PMID- 30524465 TI - Effects of Chilling on the Structure, Function and Development of Chloroplasts. AB - Chloroplasts are the organelles that perform energy transformation in plants. The normal physiological functions of chloroplasts are essential for plant growth and development. Chilling is a common environmental stress in nature that can directly affect the physiological functions of chloroplasts. First, chilling can change the lipid membrane state and enzyme activities in chloroplasts. Then, the efficiency of photosynthesis declines, and excess reactive oxygen species (ROS) are produced. On one hand, excess ROS can damage the chloroplast lipid membrane; on the other hand, ROS also represent a stress signal that can alter gene expression in both the chloroplast and nucleus to help regenerate damaged proteins, regulate lipid homeostasis, and promote plant adaptation to low temperatures. Furthermore, plants assume abnormal morphology, including chlorosis and growth retardation, with some even exhibiting severe necrosis under chilling stress. Here, we review the response of chloroplasts to low temperatures and focus on photosynthesis, redox regulation, lipid homeostasis, and chloroplast development to elucidate the processes involved in plant responses and adaptation to chilling stress. PMID- 30524466 TI - Identification of New Sources of Resistance to Wheat Stem Rust in Aegilops spp. in the Tertiary Genepool of Wheat. AB - Recent stem rust epidemics in eastern Africa and elsewhere demonstrated that wheat stem rust is a re-emerging disease posing a threat to wheat production worldwide. The cultivated wheat gene pool has a narrow genetic base for resistance to virulent races, such as races in the Ug99 race group. Wild relatives of wheat are a tractable source of stem rust resistance genes. Aegilops species in the tertiary genepool have not been exploited to any great extent as a source of stem rust resistance. We evaluated 1,422 accessions of Aegilops spp. for resistance to three highly virulent races (TTKSK, TRTTF, and TTTTF) of Puccinia graminis f. sp. tritici. Species studied include Ae. biuncialis, Ae. caudata, Ae. comosa, Ae. cylindrica, Ae. geniculata, Ae. neglecta, Ae. peregrina, Ae. triuncialis, and Ae. umbellulata that do not share common genomes with cultivated wheat. High frequencies of resistance were observed as 977 (68.8%), 927 (65.2%), and 850 (59.8%) accessions exhibited low infection types to races TTKSK, TTTTF, and TRTTF, respectively. Contingency table analyses showed strong association for resistance to different races in several Aegilops spp., indicating that for a given species, the resistance genes effective against multiple races. Inheritance studies in selected accessions showed that resistance to race TTKSK is simply inherited. PMID- 30524467 TI - SmbHLH37 Functions Antagonistically With SmMYC2 in Regulating Jasmonate-Mediated Biosynthesis of Phenolic Acids in Salvia miltiorrhiza. AB - Jasmonates (JAs) are integral to various defense responses and induce biosynthesis of many secondary metabolites. MYC2, a basic helix-loop-helix (bHLH) transcription factor (TF), acts as a transcriptional activator of JA signaling. MYC2 is repressed by the JASMONATE ZIM-domain (JAZ) proteins in the absence of JA, but de-repressed by the protein complex SCFCOI1 on perception of JA. We previously reported that overexpression of SmMYC2 promotes the production of salvianolic acid B (Sal B) in Salvia miltiorrhiza. However, the responsible molecular mechanism is unclear. Here, we showed that SmMYC2 binds to and activates the promoters of its target genes SmTAT1, SmPAL1, and SmCYP98A14 to activate Sal B accumulations. SmbHLH37, a novel bHLH gene significantly up regulated by constitutive expression of SmMYC2, was isolated from S. miltiorrhiza for detailed functional characterization. SmbHLH37 forms a homodimer and interacts with SmJAZ3/8. Overexpression of SmbHLH37 substantially decreased yields of Sal B. SmbHLH37 binds to the promoters of its target genes SmTAT1 and SmPAL1 and blocks their expression to suppress the pathway for Sal B biosynthesis. These results indicate that SmbHLH37 negatively regulates JA signaling and functions antagonistically with SmMYC2 in regulating Sal B biosynthesis in S. miltiorrhiza. PMID- 30524468 TI - Type 1 Diabetes Mellitus-Associated Genetic Variants Contribute to Overlapping Immune Regulatory Networks. AB - Type 1 diabetes (T1D) is a chronic metabolic disorder characterized by the autoimmune destruction of insulin-producing pancreatic islet beta cells in genetically predisposed individuals. Genome-wide association studies (GWAS) have identified over 60 risk regions across the human genome, marked by single nucleotide polymorphisms (SNPs), which confer genetic predisposition to T1D. There is increasing evidence that disease-associated SNPs can alter gene expression through spatial interactions that involve distal loci, in a tissue- and development-specific manner. Here, we used three-dimensional (3D) genome organization data to identify genes that physically co-localized with DNA regions that contained T1D-associated SNPs in the nucleus. Analysis of these SNP-gene pairs using the Genotype-Tissue Expression database identified a subset of SNPs that significantly affected gene expression. We identified 246 spatially regulated genes including HLA-DRB1, LAT, MICA, BTN3A2, CTLA4, CD226, NOTCH1, TRIM26, PTEN, TYK2, CTSH, and FLRT3, which exhibit tissue-specific effects in multiple tissues. We observed that the T1D-associated variants interconnect through networks that form part of the immune regulatory pathways, including immune-cell activation, cytokine signaling, and programmed cell death protein-1 (PD-1). Our results implicate T1D-associated variants in tissue and cell-type specific regulatory networks that contribute to pancreatic beta cell inflammation and destruction, adaptive immune signaling, and immune-cell proliferation and activation. A number of other regulatory changes we identified are not typically considered to be central to the pathology of T1D. Collectively, our data represent a novel resource for the hypothesis-driven development of diagnostic, prognostic, and therapeutic interventions in T1D. PMID- 30524469 TI - Dynamical Modeling of the Core Gene Network Controlling Flowering Suggests Cumulative Activation From the FLOWERING LOCUS T Gene Homologs in Chickpea. AB - Initiation of flowering moves plants from vegetative to reproductive development. The time when this transition happens (flowering time), an important indicator of productivity, depends on both endogenous and environmental factors. The core genetic regulatory network canalizing the flowering signals to the decision to flower has been studied extensively in the model plant Arabidopsis thaliana and has been shown to preserve its main regulatory blocks in other species. It integrates activation from the FLOWERING LOCUS T (FT) gene or its homologs to the flowering decision expressed as high expression of the meristem identity genes, including AP1. We elaborated a dynamical model of this flowering gene regulatory network and applied it to the previously published expression data from two cultivars of domesticated chickpea (Cicer arietinum), obtained for two photoperiod durations. Due to a large number of free parameters in the model, we used an ensemble approach analyzing the model solutions at many parameter sets that provide equally good fit to data. Testing several alternative hypotheses about regulatory roles of the five FT homologs present in chickpea revealed no preference in segregating individual FT copies as singled-out activators with their own regulatory parameters, thus favoring the hypothesis that the five genes possess similar regulatory properties and provide cumulative activation in the network. The analysis reveals that different levels of activation from AP1 can explain a small difference observed in the expression of the two homologs of the repressor gene TFL1. Finally, the model predicts highly reduced activation between LFY and AP1, thus suggesting that this regulatory block is not conserved in chickpea and needs other mechanisms. Overall, this study provides the first attempt to quantitatively test the flowering time gene network in chickpea based on data-driven modeling. PMID- 30524470 TI - A Novel 12q13.2-q13.3 Microdeletion Syndrome With Combined Features of Diamond Blackfan Anemia, Pierre Robin Sequence and Klippel Feil Deformity. AB - Diamond-Blackfan anemia (DBA) is a rare congenital erythroid aplasia with a highly heterogeneous genetic background; it usually occurs in infancy. Approximately 30-40% of patients have other associated congenital anomalies; in particular, facial anomalies, such as cleft palate, are part of about 10% of the DBA clinical presentations. Pierre Robin sequence (PRS) is a heterogeneous condition, defined by the presence of the triad of glossoptosis, micrognathia and cleft palate; it occurs in 1/8500 to 1/14,000 births. Klippel Feil (KF) syndrome is a complex of both osseous and visceral anomalies, characterized mainly by congenital development defects of the cervical spine. We describe the case of a 22-years-old woman affected by DBA, carrying a de novo deletion about 500 Kb-long at 12q13.2-q13.3 that included RPS26 and, at least, others 25 flanking genes. The patient showed craniofacial anomalies due to PRS and suffered for KF deformities (type II). Computed Tomography study of cranio-cervical junction (CCJ) drew out severe bone malformations and congenital anomalies as atlanto-occipital assimilation (AOA), arcuate foramen and occipito-condylar hyperplasia. Foramen magnum was severely reduced. Atlanto-axial instability (AAI) was linked to atlanto-occipital assimilation, congenital vertebral fusion and occipito-condyle bone hyperplasia. Basilar invagination and platybasia were ruled out on CT and Magnetic Resonance Imaging (MRI) studies. Furthermore, the temporal Bone CT study showed anomalies of external auditory canals, absent mastoid pneumatization, chronic middle ear otitis and abnormal course of the facial nerve bones canal. The described phenotype might be related to the peculiar deletion affecting the patient, highlighting that genes involved in the in the breakdown of extracellular matrix (MMP19), in cell cycle regulation (CDK2), vesicular trafficking (RAB5B), in ribonucleoprotein complexes formation (ZC3H10) and muscles function (MYL6 and MYL6B) could be potentially related to bone developmental disorders. Moreover, it points out that multiple associated ribosomal deficits might play a role in DBA-related phenotypes, considering the simultaneous deletion of three of them in the index case (RPS26, PA2G4 and RPL41), and it confirms the association among SLC39A5 functional disruption and severe myopia. This report highlights the need for a careful genetic evaluation and a detailed phenotype-genotype correlation in each complex malformative syndrome. PMID- 30524471 TI - Genetic and Epigenetic Alterations Underlie Oligodendroglia Susceptibility and White Matter Etiology in Psychiatric Disorders. AB - Numerous genetic risk loci are found to associate with major neuropsychiatric disorders represented by schizophrenia. The pathogenic roles of genetic risk loci in psychiatric diseases are further complicated by the association with cell lineage- and/or developmental stage-specific epigenetic alterations. Besides aberrant assembly and malfunction of neuronal circuitry, an increasing volume of discoveries clearly demonstrate impairment of oligodendroglia and disruption of white matter integrity in psychiatric diseases. Nonetheless, whether and how genetic risk factors and epigenetic dysregulations for neuronal susceptibility may affect oligodendroglia is largely unknown. In this mini-review, we will discuss emerging evidence regarding the functional interplay between genetic risk loci and epigenetic factors, which may underlie compromised oligodendroglia and myelin development in neuropsychiatric disorders. Transcriptional and epigenetic factors are the major aspects affected in oligodendroglia. Moreover, multiple disease susceptibility genes are connected by epigenetically modulated transcriptional and post-transcriptional mechanisms. Oligodendroglia specific complex molecular orchestra may explain how distinct risk factors lead to the common clinical expression of white matter pathology of neuropsychiatric disorders. PMID- 30524472 TI - Prognostic Analysis of Limited Resection Versus Lobectomy in Stage IA Small Cell Lung Cancer Patients Based on the Surveillance, Epidemiology, and End Results Registry Database. AB - Objective: The prognostic analysis of limited resection vs. lobectomy in stage IA small cell lung cancer (SCLC) remains scarce. Methods: Using the Surveillance, Epidemiology, and End Results registry (SEER) database, we identified patients who were diagnosed with pathological stage IA (T1a/bN0M0) SCLC from 2004 to 2013. The overall survival (OS) and lung cancer-specific survival (LCSS) rates of patients with different treatment schemes were compared in stratification analyses. Univariable and multivariable analyses were also performed to identify the significant predictors of OS and LCSS. Results: In total, we extracted 491 pathological stage IA SCLC patients, 106 (21.6%) of whom received lobectomy, 70 (14.3%) received sublobar resection and 315 (64.1%) received non-surgical treatment, respectively. There were significant differences among the groups based on different treatment schemes in OS (log-rank p < 0.0001) and LCSS (log rank p < 0.0001). Furthermore, in subgroup analyses, we did not identify any differences between sublober resection group and lobectomy group in OS (log-rank p = 0.14) or LCSS (log-rank p = 0.4565). Patients with four or more lymph node dissection had better prognosis. Multivariable analyses revealed age, laterality, tumor location, and N number were still significant predictors of OS, whereas age, tumor location, and N number were significant predictors of LCSS. Conclusion: Surgery is an important component of multidisciplinary treatment for stage IA SCLC patients and sublober resection is not inferior to lobectomy for the specific patients. PMID- 30524473 TI - Borders of Cis-Regulatory DNA Sequences Preferentially Harbor the Divergent Transcription Factor Binding Motifs in the Human Genome. AB - Changes in cis-regulatory DNA sequences and transcription factor (TF) repertoires provide major sources of phenotypic diversity that shape the evolution of gene regulation in eukaryotes. The DNA-binding specificities of TFs may be diversified or produce new variants in different eukaryotic species. However, it is currently unclear how various levels of divergence in TF DNA-binding specificities or motifs became introduced into the cis-regulatory DNA regions of the genome over evolutionary time. Here, we first estimated the evolutionary divergence levels of TF binding motifs and quantified their occurrence at DNase I-hypersensitive sites. Results from our in silico motif scan and experimentally derived chromatin immunoprecipitation (TF-ChIP) show that the divergent motifs tend to be introduced in the edges of cis-regulatory regions, which is probably accompanied by the expansion of the accessible core of promoter-associated regulatory elements during evolution. We also find that the genes neighboring the expanded cis-regulatory regions with the most divergent motifs are associated with functions like development and morphogenesis. Accordingly, we propose that the accumulation of divergent motifs in the edges of cis-regulatory regions provides a functional mechanism for the evolution of divergent regulatory circuits. PMID- 30524474 TI - Developmental Tuning of Epigenetic Clock. AB - Research in the field of gerontology has traditionally focused on later life stages. There is increasing evidence, however, that both the rate of age-related functional decline and the later-life health status can be programmed during early development. The central role of epigenetic mechanisms (methylation of DNA, histone modifications and regulation by non-coding RNAs) in mediating these long term effects has been elucidated. Both rate and direction of age-associated change of epigenetic patterns ("epigenetic drift") were shown to be largely dependent on early-life environmental conditions. Inter-individual divergences in epigenetic profiles may arise following the stochastic errors in maintaining epigenetic marks, but they may also be adaptively mediated by specific environmental cues. Recent cohort studies indicate that ticking rate of epigenetic clock, estimated by a DNA methylation-based methods, may be developmentally adjusted, and that individual's discrepancies among epigenetic and chronological age would be likely programmed early in development. In this Perspective article, recent findings suggesting the importance of early-life determinants for life-course dynamics of epigenetic drift are summarized and discussed. PMID- 30524475 TI - The Polymorphisms at PRSS1-PRSS2 and MORC4 Loci and the Risk of Post-ERCP Pancreatitis. AB - Background and Aim: The risks of post-ERCP pancreatitis (PEP) are identified as patient- and procedure-related factors. However, the genetic contribution for PEP is still unclear. Recent data show that the polymorphisms of PRSS1-PRSS2 (rs10273639) and MORC4 (rs12688220) are associated with recurrent acute pancreatitis and chronic pancreatitis. We aim to evaluate the association between these polymorphisms and post-ERCP pancreatitis in order to improve better prognosis and better care for these patients. Methods: This is a retrospective, case-control study which includes 49 cases and 97 controls that are age-, procedure-, and risk of PEP-matched with the cases in 1 : 2 fashion. The PEP was diagnosed and graded for severity according to the standard consensus, and the risk factors of PEP were identified according to the ESGE guideline. Polymorphisms at rs10273639 and rs12688220 were evaluated by TaqMan technique and were identified in 133 (40 cases and 93 controls) and 146 patients, respectively. Results: The demographic data between 2 groups are not significantly different. The genotype frequencies of PRSS1-PRSS2 (TT, TC, and CC) are 26, 13, and 1 vs. 67, 25, and 1 in cases and controls, respectively (p = 0.642). The genotype frequencies of MORC4 in female (TT, TC, and CC) are 8, 23, and 5 vs. 12, 26, and 21 in cases and controls, respectively (p = 0.071). The genotype frequencies of MORC4 in male (T and C) are 5 and 8 vs. 21 and 17 in cases and controls, respectively (p = 0.468). The allelic frequencies of MORC4 in combination of both genders (T, C) are 44 and 41 vs. 71 and 84 in cases and control, respectively (p = 0.431). In PEP cases, the allelic frequencies of PRSS1-PRSS2 (T and C) are 59 and 13 vs. 6 and 2 in mild and moderate/severe cases, respectively (p = 0.633). The allelic frequencies of MORC4 (T and C) are 38 and 39 vs. 4 and 4 in mild and moderate/severe cases, respectively (p = 0.972). Conclusion: Polymorphisms at PRSS1-PRSS2 and MORC4 are not associated with the risk or severity of post-ERCP pancreatitis. PMID- 30524476 TI - Effects of Appendectomy on the Onset and Course of Ulcerative Colitis in Chinese Patients. AB - Background: Previous epidemiological studies have suggested that appendectomy may be a protective factor against the development of ulcerative colitis (UC). However, the results of these studies were inconsistent, with rare studies in Chinese populations. Aim: This study examined the associations between appendectomy performed before UC diagnosis and the occurrence and clinical course of UC in Chinese patients. Methods: A case control study was conducted to compare the rate of appendectomy between UC patients and controls matched for age and sex at two Chinese hospitals. Clinical course of UC was compared between UC patients who underwent appendectomies before UC diagnosis and who did not. Results: 402 UC patients and 402 controls were included. The percentage of appendectomy performed before UC diagnosis in UC patients did not differ significantly from controls (2.74% vs 3.98%, P = 0.442). Subgroup analysis on the basis of localization of UC patients did not find significant difference from controls. The extent of disease involvement in UC patients who underwent appendectomy was smaller than patients who did not (P = 0.009). Appendectomy was found to be significantly related to the location of the disease independent of smoking status in multivariate analysis (P < 0.001). Appendectomy did not influence severity of disease and need for immunosuppressive treatment or colectomy. Conclusion: We did not find a significant negative association between appendectomy and the UC occurrence in Chinese patients. Appendectomy performed before UC diagnosis may reduce the extent of UC involvement. PMID- 30524477 TI - Factors Associated with Recurrent Ulcers in Patients with Gastric Surgery after More Than 15 Years: A Cross-Sectional Single-Center Study. AB - Aim: We aimed to establish the independent predictive factors (from Helicobacter pylori infection, biliary reflux, histologic features of the gastric mucosa, drugs, comorbidities, and social habits) for gastric stump ulcer occurrence more than 15 years after surgery. Methods: 76 patients with previous gastric surgery were included: 21 patients with gastric ulcer (marginal ulcer or ulcer of the rest of the gastric remnant-study group) and 55 controls (nonulcer group). Results: Helicobacter pylori infection tended to be higher in the control group than in the ulcer group (14.5% vs. 4.8%, p = 0.43), without statistical significance. Alcohol consumption had a significant positive association with ulcer (p = 0.008), while smoking (p = 0.064), low-dose aspirin (p = 0.063), and biliary reflux (p = 0.106) had a tendency toward statistical signification for positive association. On univariate analysis, smoking (p = 0.048, OR = 3.15, 95% CI: 1.01-9.93) and low-dose aspirin consumption (p = 0.067, OR = 2.63, 95% CI: 0.95-7.68) were significantly associated with ulcer. According to the multivariable regression model, alcohol consumption (OR = 6.68, 95% CI: 1.29 41.14) and biliary reflux (OR = 6.12, 95% CI: 1.36-38.26) remained significantly associated with increased odds of stump ulcer. Conclusion: Biliary reflux and alcohol consumption, but not Helicobacter pylori infection or gastrotoxic drug, seem to be the most important predictors for ulcer recurrence in patients with gastric surgery for peptic ulcer after more than 15 years. PMID- 30524478 TI - Corrigendum to "Computed Tomography Enterography: Quantitative Evaluation on Crohn's Disease Activity". AB - [This corrects the article DOI: 10.1155/2018/7351936.]. PMID- 30524479 TI - Lingual Abscess: Predisposing Factors, Pathophysiology, Clinical Manifestations, Diagnosis, and Management. AB - Lingual abscess is a rare disorder, and current knowledge regarding clinical manifestations and treatment modalities has not been well established. This study presented 6 cases of lingual abscess patients between January 2012 and December 2017. There were three men and three women. Median age was 54 years. Odynophagia and local pain were the common presenting symptoms. Local trauma was the main predisposing factor of anterior abscess, while lingual tonsillitis or infected thyroglossal cyst was the predisposing factor of posterior abscess. An impending airway obstruction was identified in two patients, requiring tracheostomy. All patients achieved an excellent outcome with a combination of surgical drainage and proper antibiotics as well as using proper investigation for detecting unusual areas of lingual abscess. According to the data from the study's results and review of the relevant literature, an abscess located at the anterior two thirds of the tongue is easy to diagnose while the posterior one-third of the tongue abscess is relative difficulty. Using contrast-enhanced computed tomography increases diagnostic accuracy, especially on the tongue base and deep space infection. The management strategies include (1) protecting the airway, (2) draining the abscess by needle aspiration or surgery, and (3) administering antibiotics early. Our series showed a superiority of surgical drainage when the patients present with marked tissue edema, deep loculated infection, and airway obstruction. PMID- 30524480 TI - Dandelion Chloroform Extract Promotes Glucose Uptake via the AMPK/GLUT4 Pathway in L6 Cells. AB - The number of patients with type 2 diabetes mellitus (T2DM) is increasing rapidly worldwide. Glucose transporter 4 (GLUT4) is one of the main proteins that transport blood glucose into the cells and is a target in the treatment of T2DM. In this study, we investigated the mechanism of action of dandelion chloroform extract (DCE) on glucose uptake in L6 cells. The glucose consumption of L6 cell culture supernatant was measured by a glucose uptake assay kit, and the dynamic changes of intracellular GLUT4 and calcium (Ca2+) levels were monitored by laser scanning confocal microscopy in L6 cell lines stably expressing IRAP-mOrange. The GLUT4 fusion with the plasma membrane (PM) was traced via myc-GLUT4-mOrange. GLUT4 expression and AMP-activated protein kinase (AMPK), protein kinase B (PKB/Akt), protein kinase C (PKC), and phosphorylation levels were determined by performing western blotting. GLUT4 mRNA expression was detected by real-time PCR. DCE up-regulated GLUT4 expression, promoted GLUT4 translocation and fusion to the membrane eventually leading to glucose uptake, and induced AMPK phosphorylation in L6 cells. The AMPK inhibitory compound C significantly inhibited DCE-induced GLUT4 expression and translocation while no inhibitory effect was observed by the phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin and PKC inhibitor Go6983. These data suggested that DCE promoted GLUT4 expression and transport to the membrane through the AMPK signaling pathway, thereby stimulating GLUT4 fusion with PM to enhance glucose uptake in L6 cells. DCE-induced GLUT4 translocation was also found to be Ca2+-independent. Together, these findings indicate that DCE could be a new hypoglycemic agent for the treatment of T2DM. PMID- 30524481 TI - Chemical Composition and Antifungal In Vitro and In Silico, Antioxidant, and Anticholinesterase Activities of Extracts and Constituents of Ouratea fieldingiana (DC.) Baill. AB - Ouratea fieldingiana (Gardner) Engl is popularly used for wound healing. This study describes the main chemical compounds present in extracts of O. fieldingiana and evaluates their biological potential by investigating antifungal, antioxidant, and anticholinesterase activities. The action mechanism of main antifungal compound was investigated by molecular docking using the enzyme sterol 14-alpha demethylase, CYP51, required for ergosterol biosynthesis. The seeds and leaves were extracted with ethanol in a Soxhlet apparatus and by maceration, respectively. Both extracts were subjected to silica gel column chromatography for isolation of main constituents, followed by purification in sephadex. The structures of compounds were established by 1H and 13C-NMR spectroscopy and identified by comparison with literature data as amentoflavone and kaempferol 3-O-rutinoside, respectively. The antioxidant activities of the extracts were determined by the DPPH and ABTS free radical inhibition methods. In general, the extracts with the highest antioxidant activity corresponded to those with higher content of phenolic compounds and flavonoids. The ethanol extracts and two isolated compounds presented relevant antifungal activity against several Candida strains. The in silico findings revealed that the compound amentoflavone coupled with the CYP450 protein due to the low energy stabilization (-9.39 kcal/mol), indicating a possible mechanism of action by inhibition of the ergosterol biosynthesis of Candida fungi. PMID- 30524482 TI - Electroacupuncture Mitigates Skeletal Muscular Lipid Metabolism Disorder Related to High-Fat-Diet Induced Insulin Resistance through the AMPK/ACC Signaling Pathway. AB - The aim of this work is to investigate the effect of electroacupuncture (EA) on insulin sensitivity in high-fat diet (HFD) induced insulin resistance (IR) rats and to evaluate expression of AMPK/ACC signaling components. Thirty-two male Sprague-Dawley rats were randomized into control group, HFD group, HFD+Pi (oral gavage of pioglitazone) group, and HFD+EA group. Acupuncture was subcutaneously applied to Zusanli (ST40) and Sanyinjiao (SP6). For Zusanli (ST40) and Sanyinjiao (SP6), needles were connected to an electroacupuncture (EA) apparatus. Fasting plasma glucose was measured by glucose oxidase method. Plasma fasting insulin (FINS) and adiponectin (ADP) were determined by ELISA. Triglyceride (TG) and cholesterol (TC) were determined by Gpo-pap. Proteins of adiponectin receptor 1 (adipoR1), AMP-activated Protein Kinase (AMPK), and acetyl-CoA carboxylase (ACC) were determined by Western blot, respectively. Compared with the control group, HFD group exhibits increased levels of FPG, FINS, and homeostatic model assessment of insulin resistance (HOMA-IR) and decreased level of ADP and insulin sensitivity index (ISI). These changes were reversed by both EA and pioglitazone. Proteins of adipoR1 and AMPK were decreased, while ACC were increased in HFD group compared to control group. Proteins of these molecules were restored back to normal levels upon EA and pioglitazone. EA can improve the insulin sensitivity of insulin resistance rats; the positive regulation of the AMPK/ACC pathway in the skeletal muscle may be a possible mechanism of EA in the treatment of IR. PMID- 30524483 TI - Sipjeondaebo-tang Alleviates Oxidative Stress-Mediated Liver Injury through Activation of the CaMKK2-AMPK Signaling Pathway. AB - Sipjeondaebo-tang (SDT) is used frequently as a herbal prescription to treat deficiency syndromes in traditional Korean medicine. We investigated the hepatoprotective effects of SDT against oxidative stress and attempted to clarify the underlying molecular mechanisms. SDT pretreatment reduced arachidonic acid (AA) plus iron-mediated cytotoxicity in a concentration-dependent manner and prevented changes in apoptosis-related protein expression. In addition, SDT pretreatment significantly reduced glutathione depletion, hydrogen peroxide production, and mitochondrial dysfunction via treatment with AA plus iron. SDT increased the phosphorylation of AMP-activated protein kinase (AMPK) in accordance with the phosphorylation of Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Experiments using an AMPK chemical inhibitor (Compound C) or CaMKK2 chemical inhibitor (STO-609) suggested that the CaMKK2-AMPK signaling pathway contributes to SDT-mediated protection of mitochondria and cells. Moreover, administration of SDT for 4 consecutive days to mice significantly reduced the alanine aminotransferase and aspartate aminotransferase activities induced by carbon tetrachloride, and the numbers of degenerated hepatocytes, infiltrated inflammatory cells, nitrotyrosine-positive cells, and 4 hydroxynonenal-positive cells in liver tissue. Therefore, SDT protects hepatocytes from oxidative stress via CaMKK2-dependent AMPK activation and has the therapeutic potential to prevent or treat oxidative stress-related liver injury. PMID- 30524485 TI - The nervous system in the cyclostome bryozoan Crisia eburnea as revealed by transmission electron and confocal laser scanning microscopy. AB - Introduction: Among bryozoans, cyclostome anatomy is the least studied by modern methods. New data on the nervous system fill the gap in our knowledge and make morphological analysis much more fruitful to resolve some questions of bryozoan evolution and phylogeny. Results: The nervous system of cyclostome Crisia eburnea was studied by transmission electron microscopy and confocal laser scanning microscopy. The cerebral ganglion has an upper concavity and a small inner cavity filled with cilia and microvilli, thus exhibiting features of neuroepithelium. The cerebral ganglion is associated with the circumoral nerve ring, the circumpharyngeal nerve ring, and the outer nerve ring. Each tentacle has six longitudinal neurite bundles. The body wall is innervated by thick paired longitudinal nerves. Circular nerves are associated with atrial sphincter. A membranous sac, cardia, and caecum all have nervous plexus. Conclusion: The nervous system of the cyclostome C. eburnea combines phylactolaemate and gymnolaemate features. Innervation of tentacles by six neurite bundles is similar of that in Phylactolaemata. The presence of circumpharyngeal nerve ring and outer nerve ring is characteristic of both, Cyclostomata and Gymnolaemata. The structure of the cerebral ganglion may be regarded as a result of transformation of hypothetical ancestral neuroepithelium. Primitive cerebral ganglion and combination of nerve plexus and cords in the nervous system of C. eburnea allows to suggest that the nerve system topography of C. eburnea may represent an ancestral state of nervous system organization in Bryozoa. Several scenarios describing evolution of the cerebral ganglion in different bryozoan groups are proposed. PMID- 30524484 TI - The Antineuroinflammatory Effect of Simvastatin on Lipopolysaccharide Activated Microglial Cells. AB - Microglial cells, upon hyperactivation, produce proinflammatory cytokines and other oxidative stress mediators causing neuroinflammation, which is associated with the progress of many neurodegenerative diseases. Suppressing the microglial activation has hence been used as an approach for treating such diseases. In this study, the antineuroinflammatory effect of simvastatin was examined in lipopolysaccharide (LPS)-activated rat C6 glioma cells. The cell proliferation and cytotoxic effect of LPS and simvastatin on C6 glioma cells was evaluated by (MTT) assay. Neuroinflammation was induced in differentiated cell lines by treatment with 3.125 MUg/mL of LPS for 12 h. Upon induction, the cell lines were treated with different concentrations (3.125, 6.25, 12.5, 25, 50, 100 MUM) of simvastatin and incubated in a humidified CO2 incubator for 24 to 48 h. The optimum concentrations of LPS and simvastatin were found to be 3.125 MUg/mL and 25 MUM, respectively, with a cell viability of more than 90% at 24 h postincubation. Furthermore, proinflammatory marker expression was analyzed by flow cytometry and showed a decrease in interferon-gamma, interleukin 6, nuclear factor-kappaB p65, and tumor necrosis factor-alpha in simvastatin-treated and LPS induced neuroinflammatory cells, and the mean fluorescent values were found to be 21.75 +/- 0.76, 20.9 +/- 1.90, 19.72 +/- 1.29, and 16.82 +/- 0.97, respectively, as compared to the untreated cells. Thus, we show that simvastatin has the potential to regulate the anti-inflammatory response in microglial cells upon LPS challenge. Hence, simvastatin can be employed as a potent anti-inflammatory drug against neuroinflammatory diseases and neurodegenerative disorders. PMID- 30524486 TI - A Stereotyped Syndrome with Retro-Ocular Pain, Photophobia, and Visual Disturbance Masquerading as Optic Neuritis: Case Series. AB - We describe here a case series of six patients referred to the Neuro ophthalmology service in Sheffield, UK with possible acute unilateral optic neuritis. Each patient had a triad of unilateral photophobia, ipsilateral retro ocular pain, and ipsilateral loss of vision. All patients had normal ocular examinations and investigation findings with no objective structural or functional abnormalities identified. Patients were treated by weaning-off regular analgesia and, where appropriate, commencing migraine prophylaxis. In the three patients with complete recovery of pain, there was also complete recovery of vision. We propose that this is a migraine syndrome and that the decreased visual acuity is a functional consequence of the pain and photophobia. PMID- 30524487 TI - Compressive Lesions of the Optic Chiasm: Subjective Symptoms and Visual Field Diagnostic Criteria. AB - We investigated the diagnostic ability of a new criterion (simple temporal depression) for compressive lesions of the optic chiasm. The subjects were 124 eyes with compressive lesions of the optic chiasm. The controls were 84 eyes. The Humphrey (Carl Zeiss) visual field test was used for visual field testing. The simple temporal depression index was calculated as the ratio of the sums of the thresholds for one line on the nasal side and temporal side of the vertical meridian. The result of new index was 87% sensitivity and 99% specificity. This result suggested that our new criterion will assist the diagnosis in the future. PMID- 30524488 TI - The Pulfrich Phenomenon: Practical Implications of the Assessment of Cases and Effectiveness of Treatment. AB - The Pulfrich phenomenon, originally described in normal observers, is a treatable disorder of the perception of movement in depth in cases of unilateral or asymmetric optic neuropathy. Treatment is highly bespoke and factors influencing treatment response and failure remain unclear. We assessed 25 adults with suspected Pulfrich phenomenon due to a range of conditions in two tertiary referral centres. Monocularly tinted spectacles were successful in reducing symptoms of the Pulfrich phenomenon under daylight conditions in nine subjects, eight of whom had optic neuritis. These spectacles were not effective at night and in patients with visual field defects due to ischaemic optic neuropathy, glaucoma, optic disc drusen or severe peripapillary retinal nerve fibre loss on optical coherence tomography. PMID- 30524489 TI - Macular and Retinal Nerve Fibre Layer Thinning in Xeroderma Pigmentosum: A Cross sectional Study. AB - The purpose of this study was to evaluate retinal thickness in different Xeroderma Pigmentosum (XP) complementation groups using spectral-domain optical coherence tomography (SD-OCT). This was a cross-sectional pilot study of 40 patients with XP. All patients had healthy-looking retinae and optic nerves on slit lamp biomicroscopy, and subtle or no neurological deficits. Patients were divided into two groups based on the known tendency for neurodegeneration associated with certain XP complementation groups. A third control group was obtained from a normative database. Using SD-OCT, we compared peripapillary retinal nerve fibre layer (pRNFL) and macular thickness between the groups. XP patients with a known tendency for neurodegeneration were found to have a statistically significant reduction in both pRNFL (p < 0.01) and macular thickness (p < 0.001) compared with healthy controls. In contrast, there was no statistically significant difference between pRNFL and macular thickness in XP patients not expected to develop neurodegeneration compared to the same control group. When both XP groups were compared, a statistically significant reduction in total pRNFL (p = 0.02) and macular thickness (p = 0.002) was found in XP patients predisposed to neurodegeneration. Our results suggest that pRNFL and macular thickness are reduced in XP patients with a known tendency for neurodegeneration, even before any marked neurological deficits become manifest. These findings demonstrate the potential role of retinal thickness as an anatomic biomarker and prognostic indicator for XP neurodegeneration. PMID- 30524490 TI - Optic Nerve Head Drusen: An Update. AB - Optic nerve head drusen are benign acellular calcium concretions that usually form early in life, just anterior to the lamina cribrosa. Improving imaging using optical coherence tomography suggests they are common and may be present in many clinically normal discs. These drusen may change in appearance in early life, but are generally stable in adulthood, and may be associated with visual field defects, anterior ischaemic optic neuropathy, or rarer complications. Based on long-term clinical data and optical coherence tomography, we propose a refined hypothesis as to the cause of optic disc drusen. Here we summarise recent findings and suggest future studies to better understand the forces involved. PMID- 30524491 TI - Case Report: Late Sequela of a Muslinoma Involving the Optic Chiasm. AB - An 84-year-old woman presented with 3 months of vertical binocular diplopia and difficulty reading at near. She had a history of bilateral ophthalmic artery aneurysm repair involving use of muslin in the 1990s. The patient then developed bitemporal hemianopsia secondary to muslin-induced inflammation ("muslinoma") extending to the optic chiasm, which required surgical decompression. She had a persistent bitemporal hemianopsia but was stable for two decades after surgery. In 2017, the patient re-presented with double vision. Exam showed a non-paretic diplopia due to a small angle comitant right hypertropia attributed to the retinal hemi-field slide. Repeat imaging showed no new aneurysm or recurrent muslinoma. This case had originally been reported two decades ago and represents the longest duration of recurrent symptoms from muslin-related optochiasmatic arachnoiditis in the English language ophthalmic literature. Clinicians should be aware of the potential of delayed and recurrent symptoms or signs years or even decades after muslin wrapping of aneurysms. PMID- 30524493 TI - Oculogyric Crisis with Downward Deviation - A Photo Essay. AB - Oculogyric crisis (OGC) describes the clinical phenomenon of sustained dystonic, conjugate and typically upward deviation of the eyes. A few cases with downward or lateral deviations have been described.1,2. PMID- 30524492 TI - Vision Loss from Choroidal and Pituitary Metastases Secondary to Renal Cell Carcinoma: A Case Report. AB - A 62-year-old male with a history of metastatic clear cell renal cell carcinoma (ccRCC) presented with decreased vision to 20/50 in the left eye. Fundus examination revealed an elevated, amelanotic mass lesion in the superotemporal macula, without involvement of the central macula by subretinal fluid or tumour. Given incongruity between the fundus findings and the degree of visual impairment, visual field testing was obtained, revealing a bitemporal hemianopia. Magnetic resonance imaging demonstrated optic chiasm compression by a pituitary mass, which had previously been overlooked on computed tomography imaging. Biopsy confirmed metastatic ccRCC to the pituitary, which presented simultaneously with the presumed choroidal metastasis. PMID- 30524494 TI - Photo Essay: Retinal Changes in Type 3 Gaucher Disease. AB - Ocular features of Gaucher disease include gaze abnormalities, corneal clouding, ocular deposits and pigmentary changes in the macula. We report the presence of bilateral fovea sparing macular deposits in a 21-year-old woman with type 3 Gaucher disease. Macular deposits occur due to glucocerebroside accumulation within histiocytes and retinal deposits might correlate with the degree of systemic infiltration. PMID- 30524495 TI - Computed Tomography Angiography of Bilateral Intracavernous Internal Carotid Artery Aneurysms. AB - Bilateral intracavernous internal carotid artery aneurysms are rare. They are more common in elderly females and are associated with hypertension. We present the computed tomography angiography findings of an 81-year-old female with history of hypertension who came complaining of diplopia and headache. Examination revealed bilateral sixth nerve palsy with left third nerve palsy. External ocular examination was normal. Computed tomography angiography was done and revealed bilateral intracavernous internal carotid artery aneurysms. She was referred to neurosurgery for further management. PMID- 30524496 TI - United Kingdom CSF Disorders Day 2017. AB - The management of patients with cerebrospinal fluid disorders requires a multi specialty approach involving specialists in neurosurgery, neurology, neuroradiology and neuro-ophthalmology. A symposium on CSF disorders was organised by the clinical and academic teams at University Hospitals Birmingham, United Kingdom. The meeting featured a synopsis of the latest scientific research on CSF disorders. Some of the more challenging and controversial issues facing the multi-speciality team were presented and discussed. A summary of the event is provided. PMID- 30524497 TI - List of Reviewers for Volume 42. PMID- 30524498 TI - Predictors of Change in Functional Outcome at six months and twelve months after Severe Injury: A Retrospective Cohort Study. AB - Background: There is increasing focus on long-term survival, function and quality of-life for trauma patients. There are few studies tracking longitudinal changes in functional outcome over time. The goal of our study was to compare the Glasgow Outcome Scale-Extended (GOSE) at 6 months and 12 months in blunt trauma survivors with an Injury Severity Score (ISS) of more than 15. Methods: Using the Singapore National Trauma Registry 2011-2013, patients with 6-month GOSE and 12-month GOSE scores were analysed. Patients were grouped into three categories-those with the same score at 6 months and 12 months, an improvement in score, and a worse score at 12 months. Ordinal regression was used to identify risk factors for improved score. Patients with missing scores at either 6 months or 12 months were excluded. Results: We identified 478 patients: 174 had an improvement in score, 233 stayed the same, and 71 had worse scores at 12 months compared to 6 months. On univariate ordinal regression, the following variables were associated with same or better function at 12-months compared to 6-months: male gender, being employed pre-injury, thoracic Abbreviated Injury Scale (AIS) of 3 or more, anatomical polytrauma (AIS of 3 or more in 2 or more body regions), and road traffic injury mechanism. Older age, low fall, increasing Charlson comorbidity scores, new injury severity score, and head and neck AIS of 3 or more were associated with worse function at 12 months compared to 6 months. ISS and revised trauma score were not significant predictors on univariate or multivariable analysis.On multivariable ordinal regression, motor vehicle mechanism (OR 2.78, 1.51-5.12, p = 0.001) was associated with improved function, while male gender (OR 1.36, 95% CI 1.02-1.82, p = 0.039) predicted improved function at 12 months. Conclusions: Females experience worse functional outcomes at 12 months, potentially due to majority of female injuries being low falls in the elderly. In contrast, motor vehicle injury patients had better functional outcomes at 12 months. Additional interventional strategies for high-risk groups should be explored. PMID- 30524499 TI - Application of metabolomics in toxicity evaluation of traditional Chinese medicines. AB - Traditional Chinese medicines (TCM) have a long history of use because of its potential complementary therapy and fewer adverse effects. However, the toxicity and safety issues of TCM have drawn considerable attention in the past two decades. Metabolomics is an "omics" approach that aims to comprehensively analyze all metabolites in biological samples. In agreement with the holistic concept of TCM, metabolomics has shown great potential in efficacy and toxicity evaluation of TCM. Recently, a large amount of metabolomic researches have been devoted to exploring the mechanism of toxicity induced by TCM, such as hepatotoxicity, nephrotoxicity, and cardiotoxicity. In this paper, the application of metabolomics in toxicity evaluation of bioactive compounds, TCM extracts and TCM prescriptions are reviewed, and the potential problems and further perspectives for application of metabolomics in toxicological studies are also discussed. PMID- 30524500 TI - Healthcare needs and health service utilization by Syrian refugee women in Toronto. AB - Objective: Access to healthcare is an important part of the (re)settlement process for Syrian refugees in Canada. There is growing concern about the healthcare needs of the 54,560 Syrian refugees who were admitted to Canada by May 2018, 80% of whom are women and children. We explored the healthcare needs of newcomer Syrian women, their experiences in accessing and using health services, and the factors and conditions that shape whether and how they access and utilize health services in the Greater Toronto Area (GTA). Method: This community-based qualitative descriptive interpretive study was informed by Yang & Hwang (2016) health service utilization framework. Focus group discussions were held with 58 Syrian newcomer women in the GTA. These discussions were conducted in Arabic, audio-recorded with participants' consent, translated into English and transcribed, and analyzed using thematic analysis. Results: Participants' health concerns included chronic, long-term conditions as well as new and emerging issues. Initial health insurance and coverage were enabling factors to access to services, while language and social disconnection were barriers. Other factors, such as beliefs about naturopathic medicine, settlement in suburban areas with limited public transportation, and lack of linguistically, culturally, and gender appropriate services negatively affected access to and use of healthcare services. Conclusion: Responding to the healthcare needs of Syrian newcomer women in a timely and comprehensive manner requires coordinated, multi-sector initiatives that can address the financial, social, and structural barriers to their access and use of services. PMID- 30524501 TI - Victimisation in a French population of children and youths with autism spectrum disorder: a case control study. AB - Background: Children and youths with autism spectrum disorder (ASD) have behavioural characteristics and severe social disabilities that make them vulnerable to victimisation. The current study explores the prevalence of peer victimisation in this population in France. Methods: We used the Juvenile Victimization Questionnaire-Screener Sum Version in a French sample of 39 children and youths with ASD and 53 typically developing (TD) children and youths and tested the association of the victimisation with socio-demographic factors and clinical factors of anxiety and post-traumatic stress. Results: The results indicate that 72% of the subjects with ASD had been victimised during the previous year and 94.9% during their entire lifetime. Of all students victimised at least once over the course of their lives, 75% had been victimised at school. Their peer victimisation score was significantly higher than in the TD group and was correlated to clinical factors such as a deficit in social skills and the severity of post-traumatic symptoms. Symptoms of anxiety were reported by parents of children and youths with ASD in 80% of cases. Conclusions: Children and youths with ASD are particularly vulnerable to victimisation at school. Discussion focuses on the importance of considering the impacts and needs of school integration of this population in France in order to prevent these phenomena and their consequences. PMID- 30524502 TI - Cell surface engineering and application in cell delivery to heart diseases. AB - Cell-based therapy has expanded its influence in cancer immunotherapy, regenerative medicine, and tissue engineering. Due to their secretory functions, differentiation capabilities, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, cells have become an attractive reagent for advanced therapeutic strategies. Therefore, the ability to modify cells and manipulate their functions according to intended therapeutic designs has been the central scientific interest in the field of biomedical research. Many innovative methods have been developed with genetic modification of cells being the most advanced cell surface engineering technique. Although genetic modification is a powerful tool, it has a limited applicability due to the permanent modifications made on cells. Alternatively, many endeavors have been made to develop surface engineering techniques that can circumvent the limitations of genetic modification. In this review, current methods of non genetic cell surface modification, including chemical conjugations, polymeric encapsulation, hydrophobic insertion, enzymatic and metabolic addition, will be introduced. Moreover, cell surface engineering plausible for cardiac remodeling and the future prospective will be discussed at the end. PMID- 30524503 TI - N2O and CH4 emission from Miscanthus energy crop fields in the infertile Loess Plateau of China. AB - Background: The greenhouse gas (GHG) mitigation is one of the most important environmental benefits of using bioenergy replacing fossil fuels. Nitrous oxide (N2O) and methane (CH4) are important GHGs and have drawn extra attention for their roles in global warming. Although there have been many works of soil emissions of N2O and CH4 from bioenergy crops in the field scale, GHG emissions in large area of marginal lands are rather sparse and how soil temperature and moisture affect the emission potential remains unknown. Therefore, we sought to estimate the regional GHG emission based on N2O and CH4 releases from the energy crop fields. Results: Here we sampled the top soils from two Miscanthus fields and incubated them using a short-term laboratory microcosm approach under different conditions of typical soil temperatures and moistures. Based on the emission measurements of N2O and CH4, we developed a model to estimate annual regional GHG emission of Miscanthus production in the infertile Loess Plateau of China. The results showed that the N2O emission potential was 0.27 kg N ha-1 year 1 and clearly lower than that of croplands and grasslands. The CH4 uptake potential was 1.06 kg C ha-1 year-1 and was slightly higher than that of croplands. Integrated with our previous study on the emission of CO2, the net greenhouse effect of three major GHGs (N2O, CH4 and CO2) from Miscanthus fields was 4.08 t CO2eq ha-1 year-1 in the Loess Plateau, which was lower than that of croplands, grasslands and shrub lands. Conclusions: Our study revealed that Miscanthus production may hold a great potential for GHG mitigation in the vast infertile land in the Loess Plateau of China and could contribute to the sustainable energy utilization and have positive environmental impact on the region. PMID- 30524504 TI - Expression of an endoglucanase-cellobiohydrolase fusion protein in Saccharomyces cerevisiae, Yarrowia lipolytica, and Lipomyces starkeyi. AB - The low secretion levels of cellobiohydrolase I (CBHI) in yeasts are one of the key barriers preventing yeast from directly degrading and utilizing lignocellulose. To overcome this obstacle, we have explored the approach of genetically linking an easily secreted protein to CBHI, with CBHI being the last to be folded. The Trichoderma reesei eg2 (TrEGII) gene was selected as the leading gene due to its previously demonstrated outstanding secretion in yeast. To comprehensively characterize the effects of this fusion protein, we tested this hypothesis in three industrially relevant yeasts: Saccharomyces cerevisiae, Yarrowia lipolytica, and Lipomyces starkeyi. Our initial assays with the L. starkeyi secretome expressing differing TrEGII domains fused to a chimeric Talaromyces emersonii-T. reesei CBHI (TeTrCBHI) showed that the complete TrEGII enzyme, including the glycoside hydrolase (GH) 5 domain is required for increased expression level of the fusion protein when linked to CBHI. We found that this new construct (TrEGII-TeTrCBHI, Fusion 3) had an increased secretion level of at least threefold in L. starkeyi compared to the expression level of the chimeric TeTrCBHI. However, the same improvements were not observed when Fusion 3 construct was expressed in S. cerevisiae and Y. lipolytica. Digestion of pretreated corn stover with the secretomes of Y. lipolytica and L. starkeyi showed that conversion was much better using Y. lipolytica secretomes (50% versus 29%, respectively). In Y. lipolytica, TeTrCBHI performed better than the fusion construct. Furthermore, S. cerevisiae expression of Fusion 3 construct was poor and only minimal activity was observed when acting on the substrate, pNP cellobiose. No activity was observed for the pNP-lactose substrate. Clearly, this approach is not universally applicable to all yeasts, but works in specific cases. With purified protein and soluble substrates, the exoglucanase activity of the GH7 domain embedded in the Fusion 3 construct in L. starkeyi was significantly higher than that of the GH7 domain in TeTrCBHI expressed alone. It is probable that a higher fraction of fusion construct CBHI is in an active form in Fusion 3 compared to just TeTrCBHI. We conclude that the strategy of leading TeTrCBHI expression with a linked TrEGII module significantly improved the expression of active CBHI in L. starkeyi. PMID- 30524505 TI - The application of NIPT using combinatorial probe-anchor synthesis to identify sex chromosomal aneuploidies (SCAs) in a cohort of 570 pregnancies. AB - Background: Non-invasive prenatal testing (NIPT) as alternative screening method had been proven to have very high sensitivity and specificity for detecting common aneuploidies such as T21, T18, and T13, with low false positive and false negative rates. Unfortunately, recent studies suggested that the NIPT achieved lower accuracy in sex chromosomal aneuploidies (SCAs) detection than autosomal aneuploidies detection. BGISEQ-500 powered by Combinatorial Probe-Anchor Synthesis (CPAS) and DNA Nanoballs (DNBs) technology that combined linear amplification and rolling circle replication to reduce the error rate while enhancing the signal. Therefore, NIPT based on CPAS might be a good method for SCAs screening in routine clinical practice. In the study, we intended to evaluate the clinical utility of NIPT based on CPAS on screening for fetal SCAs. Results: A total of 570 pregnant women were included in the retrospective study. Maternal blood samples were collected for NIPT; amniocentesis was performed on all pregnant women. NIPT was carried out by BGISEQ-500 sequencing platform based on CPAS. Karyotype analysis of amniotic cells was performed by standard G-banding techniques. 43 out of the total 570 pregnant women tested by NIPT showed fetal SCAs (19 of 45,X, 12 of 47,XXY, 10 of 47,XXX, and 2 of 47,XYY). The following amniocentesis confirmed that 26 cases were true positive (7 of true positive 45,X, 9 of true positive 47,XXY, 9 of true positive 47,XXX as well as 1 of 47,XYY) and the positive predictive value (PPV) for fetal SCAs was 60.47%. In addition, the PPV of advanced maternal age group (67.74%) was higher than the other indications group (45.45%) or serological screening high-risk /critical risk group (0%). Conclusions: NIPT based on CPAS could be a potential method for SCAs screening. However, it still had high false positive rates, especially for 45,X. The pregnant women with fetal SCAs detected by NIPT, especially those with non-age-related prenatal diagnostic indications, should be advised to accept invasive prenatal karyotype analysis. PMID- 30524506 TI - A decrease in anaerobic bacteria promotes Candida glabrata overgrowth while beta glucan treatment restores the gut microbiota and attenuates colitis. AB - Background: The intestinal microbiota plays a crucial role in the maintenance of gut homeostasis. Changes in crosstalk between the intestinal epithelial cells, immune cells and the microbiota are critically involved in the development of inflammatory bowel disease. In the experimental mouse model, the development of colitis induced by dextran sulfate sodium (DSS) promotes overgrowth of the opportunistic yeast pathogen Candida glabrata. Conversely, fungal colonization aggravates inflammatory parameters. In the present study, we explored the effect of C. glabrata colonization on the diversity of the gut microbiota in a DSS induced colitis model, and determined the impact of soluble beta-glucans on C. glabrata-host interactions. Results: Mice were administered a single inoculum of C. glabrata and were exposed to DSS treatment for 2 weeks in order to induce acute colitis. For beta-glucan treatment, mice were administered with soluble beta-glucans purified from C. glabrata (3 mg per mouse), orally and daily, for 5 days, starting on day 1. The number of C. glabrata colonies and changes in microbiota diversity were assessed in freshly collected stool samples from each tagged mouse, using traditional culture methods based on agar plates. An increase in Escherichia coli and Enterococcus faecalis populations and a reduction in Lactobacillus johnsonii and Bacteroides thetaiotaomicron were observed during colitis development. This decrease in L. johnsonii was significantly accentuated by C. glabrata overgrowth. Oral administration of beta-glucans to mice decreased the overgrowth of aerobic bacteria and IL-1beta expression while L. johnsonii and B. thetaiotaomicron populations increased significantly. beta-glucan treatment increased IL-10 production via PPARgamma sensing, promoting the attenuation of colitis and C. glabrata elimination. Conclusions: This study shows that the colonic inflammation alters the microbial balance, while beta-glucan treatment increases the anaerobic bacteria and promotes colitis attenuation and C. glabrata elimination. PMID- 30524507 TI - Exploring structural barriers to diabetes self-management in Alberta First Nations communities. AB - Background: Type 2 diabetes is highly prevalent in Canadian First Nations (FN) communities. FN individuals with diabetes are less likely to receive guideline recommended care and access specialist care. They are also less likely to be able to engage in optimal self-management behaviours. While the systemic and racial contributors to this problem have been well described, individuals' experiences with structural barriers to care and self-management remain under-characterized. Methods: We utilized qualitative methods to gain insight into the structural barriers to self-management experienced by FN individuals with diabetes. We conducted a qualitative descriptive analysis of a subcohort of patients with diabetes from FN communities (n = 5) from a larger qualitative study. Using detailed semi-structured telephone interviews, we inquired about participants' diabetes and barriers to diabetes self-management. Inductive thematic analysis was performed in duplicate using NVivo 10. Results: The structural barriers faced by this population were substantial yet distinct from those described by non-FN individuals with diabetes. For example, medication costs, which are usually cited as a barrier to care, are covered for FN persons with status. The barriers to diabetes self-management that were commonly experienced in this cohort included transportation-related difficulties, financial barriers to uninsured health services, and lack of accessible diabetes education and resultant knowledge gaps. Conclusions: FN Albertans with diabetes face a myriad of barriers to self management, which are distinct from the Non-FN population. In addition to the barriers introduced by colonialism and historical injustices, finances, geographic isolation, and lack of diabetes education each impede optimal management of diabetes. Programs targeted at addressing FN-specific barriers may improve aspects of diabetes self-management in this population. PMID- 30524508 TI - Pattern of physical activity can influence its efficacy on muscle and bone health in middle-aged men and women. AB - Purpose: This study aimed at investigating whether association between physical activity, and bone density and muscle strength depends on daily activity pattern. Methods: Loading dose of moderate-to-vigorous physical activity (MVPA) was measured using accelerometer on 54 men (M age = 54.1 years) and 59 women (M age = 52.1 years). Pattern of MVPA was quantified as number and length of MVPA bouts, and the length of break bouts between MVPA bouts. Knee extension torque (KET) and broadband ultrasound attenuation (BUA) of the calcaneus were also measured. Regression analysis was employed to examine the moderation effect of MVPA pattern. Results: Loading dose had a larger effect on BUA (b = .002, p = .035) and KET (b = .004, p = .01) with the increase of median length of MVPA bout, but had a smaller effect on KET with the increase of maximal length of break bout (b = - .015, p = .024). Conclusions: This study suggests that pattern of physical activity can influence its efficacy on muscle and bone health. PMID- 30524509 TI - Triple Smoking Cessation Therapy with Varenicline, Nicotine Patch and Nicotine Lozenge: A Pilot Study to Assess Tolerability, Satisfaction, and End-of-Treatment Quit Rates. AB - Introduction: The majority of attempts to stop smoking end in failure. One way to improve success may be to explore different combinations of existing cessation medications. Aims: This observational study examined "triple therapy" (varenicline + nicotine patch + nicotine lozenge) in 36 smokers trying to quit. Methods: A 12-week, observational study exploring tolerability, via adverse events (AEs) elicited at each of 9 phone assessments. Secondary outcomes included satisfaction rates, medication changes, and self-reported quit rates at week 12. Results: 35 of 36 participants reported at least one AE. Insomnia (75%), abnormal dreams (72%) and nausea (64%) were most common. Most were mild to moderate. No deaths, hospitalizations, cardiovascular events, or suicidality were reported. Six participants (17%) decreased the dose of at least one medication, 5 (14%) decreased the dose then discontinued at least one medication, and 13 (36%) discontinued at least one medication without trying a lesser dose. Participants were highly satisfied with their medications, and 58% reported quitting at 12 weeks, with 38% reporting prolonged abstinence. Conclusion: Despite high rates of AEs and medication changes, high rates of satisfaction and self-reported quitting, with no serious AEs, were observed with triple therapy. Additional data on tolerability and efficacy are needed. Trial Registration: clinicaltrials.gov number NCT02681510. PMID- 30524510 TI - Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition. AB - Introduction: Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods: To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results: We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions: Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. PMID- 30524511 TI - Towards photon radiotherapy treatment planning with high Z nanoparticle radiosensitisation agents: the Relative Biological Effective Dose (RBED) framework. AB - A novel treatment planning framework, the Relative Biological Effective Dose (RBED), for high Z nanoparticle (NP)-enhanced photon radiotherapy is developed and tested in silico for the medical exemplar of neoadjuvant (preoperative) breast cancer MV photon radiotherapy. Two different treatment scenarios, conventional and high Z NP enhanced, were explored with a custom Geant4 application that was developed to emulate the administration of a single 2 Gy fraction as part of a 50 Gy radiotherapy treatment plan. It was illustrated that there was less than a 1% difference in the dose deposition throughout the standard and high Z NP-doped adult female phantom. Application of the RBED framework found that the extent of possible biological response with high Z NP doping was great than expected via the dose deposition alone. It is anticipated that this framework will assist the scientific community in future high Z NP enhanced in-silico, pre-clinical and clinical trials. PMID- 30524512 TI - Meditation-Induced Near-Death Experiences: a 3-Year Longitudinal Study. AB - Near-death experiences (NDEs) are life transformational events that are increasingly being subjected to empirical research. However, to date, no study has investigated the phenomenon of a meditation-induced near-death experience (MI NDE) that is referred to in ancient Buddhist texts. Given that some advanced Buddhist meditators can induce NDEs at a pre-planned point in time, the MI-NDE may make NDEs more empirically accessible and thus advance understanding into the psychology of death-related processes. The present study recruited 12 advanced Buddhist meditators and compared the MI-NDE against two other meditation practices (i.e. that acted as control conditions) in the same participant group. Changes in the content and profundity of the MI-NDE were assessed longitudinally over a 3-year period. Findings demonstrated that compared to the control conditions, the MI-NDE prompted significantly greater pre-post increases in NDE profundity, mystical experiences and non-attachment. Furthermore, participants demonstrated significant increases in NDE profundity across the 3-year study period. Findings from an embedded qualitative analysis (using grounded theory) demonstrated that participants (i) were consciously aware of experiencing NDEs, (ii) retained volitional control over the content and duration of NDEs and (iii) elicited a rich array of non-worldly encounters and spiritual experiences. In addition to providing corroborating evidence in terms of the content of a "regular" (i.e. non-meditation-induced) NDE, novel NDE features identified in the present study indicate that there exist unexplored and/or poorly understood dimensions to NDEs. Furthermore, the study indicates that it would be feasible including ethically feasible-for future research to recruit advanced meditators in order to assess real-time changes in neurological activity during NDEs. PMID- 30524513 TI - Testing for an Effect of a Mindfulness Induction on Child Executive Functions. AB - Several sessions of mindfulness practice can exert positive gains for child executive functions (EF); however, the evidence for effects of a mindfulness induction, on EF for adults, is mixed and this effect has not been tested in children. The immediate effect of an age appropriate 3-min mindfulness induction on EF of children aged 4-7 years was tested. Participants (N = 156) were randomly assigned to a mindfulness induction or dot-to-dot activity comparison group before completing four measures of EF. A composite score for EF was calculated from summed z scores of the four EF measures. A difference at baseline in behavioural difficulties between the mindfulness induction and comparison group meant that data was analysed using a hierarchical regression. The mindfulness induction resulted in higher average performance for the composite EF score (M = 0.12) compared to the comparison group (M = - 0.05). Behavioural difficulties significantly predicted 5.3% of the variance in EF performance but participation in the mindfulness or comparison induction did not significantly affect EF. The non-significant effect of a mindfulness induction to exert immediate effects on EF fits within broader evidence reporting mixed effects when similar experimental designs have been used with adults. The findings are discussed with consideration of the extent to which methodological differences may account for these mixed effects and how mindfulness inductions fit within broader theoretical and empirical understanding of the effects of mindfulness on EF. PMID- 30524514 TI - The Effects of an Online Mindfulness Intervention on Perceived Stress, Depression and Anxiety in a Non-clinical Sample: A Randomised Waitlist Control Trial. AB - Mindfulness interventions have been shown to be effective for health and wellbeing, and delivering mindfulness programmes online may increase accessibility and reduce waiting times and associated costs; however, research assessing the effectiveness of online interventions is lacking. We sought to: (1) assess the effects of an online mindfulness intervention on perceived stress, depression and anxiety; (2) assess different facets of mindfulness (i.e. acting with awareness, describing, non-judging and non-reacting) as mechanisms of change and (3) assess whether the effect of the intervention was maintained over time. The sample was comprised of 118 adults (female, n = 95) drawn from the general population. Using a randomised waitlist control design, participants were randomised to either an intervention (INT) or waitlist control (WLC) group. Participants completed the online intervention, with the WLC group starting after a 6-week waitlist period. Participants completed measures of depression (PHQ-9), anxiety (GAD-7) and perceived stress (PSS-10) at baseline, post-treatment, 3- and 6-month follow-up. Participants who completed the mindfulness intervention (n = 60) reported significantly lower levels of perceived stress (d = - 1.25 [- 1.64, 0.85]), anxiety (d = - 1.09 [- 1.47, - 0.98]) and depression (d = - 1.06 [- 1.44, - 0.67]), when compared with waitlist control participants (n = 58), and these effects were maintained at follow-up. The effect of the intervention was primarily explained by increased levels of non-judging. This study provides support for online mindfulness interventions and furthers our understanding with regards to how mindfulness interventions exert their positive effects. PMID- 30524515 TI - Differences in Functional Connectivity of the Insula Between Brain Wave Vibration in Meditators and Non-meditators. AB - The majority of meditation involves focusing attention on internal events or sensations and becoming aware of emotions. The insula cortex, through a functional connection with the prefrontal cortex and other brain regions, plays a key role in integrating external sensory information with internal bodily state signals and emotional awareness. The purpose of this exploratory study was to examine the resting-state functional connectivity of the insula with other brain regions in meditation practitioners and control subjects. Thirty-five Brain Wave Vibration meditation practitioners and 33 controls without meditation experience were included in this study. All subjects underwent 4.68-min resting-state functional scanning runs using magnetic resonance imaging. The anterior and posterior insulae were chosen as seed regions for the functional connectivity map. Meditation practitioners showed significantly greater insula-related functional connectivity in the thalamus, caudate, middle frontal gyrus, and superior temporal gyrus than did controls. Control subjects demonstrated greater functional connectivity with the posterior insula in the parahippocampal gyrus. Our findings suggest that the practice of Brain Wave Vibration meditation may be associated with functional differences in regions related to focused attention, executive control, and emotional awareness and regulation. PMID- 30524516 TI - Explaining Variations in Mindfulness Levels in Daily Life. AB - Despite the apparent benefits of being mindful, people are often not very mindful. There seem to be forces that drive people toward as well as away from mindfulness. These forces are conceptualised in terms of competition for scarce attentional resources. To explore these forces and to test this framework, an experience sampling study was performed among people with an explicit intention to be mindful and an ongoing practice to examine concurrent associations between state mindfulness and daily life experiences that may affect it. Participants (N = 29, 1012 observations) filled out questions on momentary experiences at semi random intervals, five times a day, over a period of 7 to 10 days. Predictors of within-person variations in awareness of Present Moment Experience (PME) and non reactivity to PME were examined using multilevel analyses. Participants were more aware of PME when they had an activated intention to be mindful and when they felt good, and not very busy or hurried, and were not involved in social interaction. They were more reactive to PME when they experienced unpleasant affect, and when they were hurried or tired. An activated intention to be mindful was also associated with an increased tendency to analyse PME. Experiencing threat was associated with increased reactivity, but not with decreased awareness. Our study generally supports the idea that competition for attention can be a fruitful framework to describe mechanisms behind being or not being mindful. PMID- 30524517 TI - Health and Its Relationship with Residential Relocations of Older People to Institutions versus to Independent Dwellings. AB - Research into older people's relocations to independent dwellings has largely remained separate from research into moves to institutions. Yet, both types of moves could be a response to health problems and to a certain extent they could be substitutes for each other. Using Litwak and Longino's model of moves of older people, this study assesses the extent to which three commonly used health measures (limitations in activities of daily living [ADL], self-rated health, and the prevalence of [limiting] chronic conditions) predict older people's moves to subsidized care institutions and elsewhere, in one multinomial logistic regression model. The data were derived from the POLS survey for the Netherlands (N = 8306) enriched with administrative data on subsequent moves. In line with Litwak and Longino's model, the findings indicate that older people's moves to institutions were more likely among those with more severe health problems, whereas moves elsewhere were more likely among those with moderate health problems. Among the three investigated health measures, limitations in ADL had the strongest predictive value, and was the only one for which the difference in effect between relocations to care institutions and relocations elsewhere was statistically significant. PMID- 30524518 TI - A Child Health Index for Sweden's 290 Municipalities: A System of Indicators and Indices for Monitoring Children's Health on the Local Level. AB - This broad survey of children's health and wellbeing in Sweden's 290 municipalities converts freely available national data to a set of 13 high quality indicators, and makes local surveillance and comparisons possible. Combining the indicators, using equal weights, into relevant domains as 5 sub indices and then again into one summary index provides one index for the great picture, sub-indices for the various domains of child health and separate indicators for the detailed study of the basic components. This creates a simplified tool for decision makers and professionals in their task to monitor children's health on the local level. Children's health in the Swedish municipalities is generally good, with a mean Child Health Index of 88 out of 100, ranging from 81 to 93. Children in economically disadvantaged municipalities have, with few exceptions, more health problems and worse preconditions for health. The indicators Socio-economic standard, Tobacco in utero, Smoking households and Teenage abortions explain most of the municipality variations. But the broader range of indicators gives more information and is a better tool to consider strengths and weaknesses for each municipality, and is thus more useful for policy-oriented efforts. The real value of this kind of monitoring lies in a succession of comparable surveys. The generous, free and easily available data are not available in all other countries, but matters such as philosophy and design, indicator definitions and index constructions might be considered in other regions looking for ways to monitor children's health and wellbeing on local levels. PMID- 30524519 TI - School, Peer and Family Relationships and Adolescent Substance Use, Subjective Wellbeing and Mental Health Symptoms in Wales: a Cross Sectional Study. AB - Positive relationships with family, friends and school staff are consistently linked with health and wellbeing during adolescence, though fewer studies explore how these micro-systems interact to influence adolescent health. This study tests the independent and interacting roles of family, peer and school relationships in predicting substance use, subjective wellbeing and mental health symptoms among 11-16 year olds in Wales. It presents cross-sectional analyses of the 2013 Health Behaviour in School-aged Children survey, completed by 9055 young people aged 11 16 years. Multilevel logistic regression analyses are used to test associations of family communication, family support, relationships with school staff, school peer connectedness, and support from friends, with tobacco use, cannabis use, alcohol use, subjective wellbeing and mental health symptoms. Positive relationships with family and school staff were consistently associated with better outcomes. Support from friends was associated with higher use of all substances, while higher school peer connectedness was associated with better subjective wellbeing and mental health. Better relationships with school staff were most strongly associated with positive subjective wellbeing, and fewer mental health symptoms where pupils reported less family support. Support from friends was associated with higher cannabis use and worse mental health among pupils with lower family support. Relationships with family and school staff may be important in protecting young people against substance use, and improving wellbeing and mental health. Interventions focused on student-staff relationships may be important for young people with less family support. Interventions based on peer support should be mindful of potential harmful effects for pupils with less support from family. PMID- 30524520 TI - Application of Lactoferrin and alpha1-Antitrypsin in Gingival Retention Fluid to Diagnosis of Periodontal Disease. AB - Objectives: Periodontal disease is prevalent and has an inflammation associated with not only oral but also systemic pathologies. The diagnosis by biomarkers is required for clinical practice on periodontal disease. The lactoferrin and alpha1 antitrypsin were both inflammation-related molecules. The present study investigated the relationship between the periodontal status and the two biomarkers in gingival retention fluid (GRF). Patients and Methods: In 63 subjects with periodontitis, the GRF was sampled from maxillary anterior gingiva using a microbrush for 30 seconds. The lactoferrin and alpha1-antitrypsin levels in GRF were measured by an enzyme-link solvent immunoassay. Periodontal status was evaluated by probing pocket depth (PD) and bleeding on probing (BOP). Results: There was a higher level of these biomarkers in saliva (median (ng/mL), lactoferrin: 3611.9, alpha1-antitrypsin: 4573.3) than in GRF (lactoferrin: 61.0, alpha1-antitrypsin: 54.7). There was a mild-to-moderate but significantly positive correlation in lactoferrin or alpha1-antitrypsin between GRF and saliva. There was a positively mild-to-moderate accuracy (area under the curve: 0.60 0.81) of lactoferrin or alpha1-antitrypsin in GRF or in saliva to distinguish the severity of periodontal status. The cutoff level (ng/mL) of lactoferrin in GRF for detecting >=30% of PD >= 4 mm (moderate periodontitis) was 68.6 and for detecting >=20% of BOP (clinically active periodontitis) was 61.2. The cutoff level (ng/mL) of alpha1-antitrypsin in GRF for detecting >=30% of PD >= 4 mm was 54.5 and for detecting >=20% of BOP was 35.3. Conclusions: The data can promote an application of the measurements of lactoferrin and alpha1-antitrypsin in GRF to clinical practice on periodontal disease. PMID- 30524522 TI - Comment on "Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients". PMID- 30524521 TI - Protein-Based Salivary Profiles as Novel Biomarkers for Oral Diseases. AB - The Global Burden of Oral Diseases affects 3.5 billion people worldwide, representing the number of people affected by the burden of untreated dental caries, severe periodontal disease, and edentulism. Thus, much more efforts in terms of diagnostics and treatments must be provided in the fight of these outcomes. In this sense, recently, the study of saliva as biological matrix has been identified as a new landmark initiative in the search of novel and useful biomarkers to prevent and diagnose these conditions. Specifically, saliva is a rich reservoir of different proteins and peptides and accessible due to recent advances in molecular biology and specially in targeted and unbiased proteomics technologies. Nonetheless, emerging barriers are an obstacle to the study of the salivary proteome in an effective way. This review aims at giving an overall perspective of salivary biomarkers identified in several oral diseases by means of molecular biology approaches. PMID- 30524523 TI - Recurrent takotsubo cardiomyopathy can appear as transient midventricular ballooning syndrome. AB - We report a rare female case of typical takotsubo cardiomyopathy at the first admission and recurrent takotsubo cardiomyopathy with a unique pattern of contraction at the second admission. The condition manifested as akinesis in the middle portion of the left ventricle and hyperkinesis of the apex and base. Our case indicates that recurrent takotsubo cardiomyopathy can appear as transient midventricular ballooning syndrome, but it remains to be determined whether both diseases have a tendency to coexist. PMID- 30524524 TI - Dynamic left ventricular outflow tract obstruction due to anemia in a 71-year-old patient with sigmoid septum. AB - Sigmoid septum, although frequently observed in the elderly, has no pathophysiological significance in general. A 71-year-old woman with sigmoid septum developed acute heart failure because of a significant left ventricular outflow tract obstruction associated with the aggravation of anemia. This report provides the evidence that a hypercontractile cardiac state induced by anemia can be critical, especially in patients with sigmoid septum. Assessment of the left ventricular outflow tract pressure gradient is important in heart failure patients with sigmoid septum and dynamic obstruction. PMID- 30524526 TI - Characteristics of in vivo images from an in-stent restenosis lesion of a saphenous vein graft after bare-metal stent implantation: Assessment using optical coherence tomography. AB - Restenosis of saphenous vein grafts (SVG) after bare-metal stent (BMS) implantation remains a clinical problem. Recently, intravascular optical coherence tomography (OCT) has been proposed as a high resolution intravascular imaging modality, and is able to distinguish several components of intracoronary structures. In vivo images of in-stent restenosis (ISR) lesions in an SVG using OCT have not been reported. In this case report, we present the characteristics of in vivo OCT images from an ISR lesion of an SVG after BMS implantation. PMID- 30524525 TI - Therapeutic hypothermia with immunosuppressive drugs for a comatose renal transplant patient who survived out-of-hospital cardiac arrest. AB - A 31-year-old man suddenly collapsed at work. His colleagues witnessed the event, applied basic life support, and called for an ambulance. After the ambulance arrived, the initial rhythm was confirmed as ventricular fibrillation (VF) and he was defibrillated with an automated external defibrillator. Spontaneous circulation was regained at 8 min after collapse. He was thought to be a good candidate for therapeutic hypothermia because he was comatose and had survived outside hospital VF cardiac arrest due to cardiac etiology. However, he was taking immunosuppressive drugs after undergoing a kidney transplant. We obtained written, informed consent from the patient's family to start therapeutic hypothermia at 33.5-34.5 degrees C for 48 h, although he was at high risk for such induction. Serious complications and neurological deficits did not develop and the patient was referred to another hospital on day 42 for implantation with a cardioverter defibrillator. PMID- 30524527 TI - Catheter ablation of persistent atrial fibrillation solely guided by complex fractionated atrial electrograms in a patient with persistent left superior vena cava. AB - Catheter ablation in patients with persistent atrial fibrillation (AF) is challenging. There are few reports of catheter ablation for persistent AF with persistent left superior vena cava (PLSVC). We report an ablation case of persistent AF with PLSVC solely guided by complex fractionated atrial electrogram (CFAE). The subject was a 65-year-old man. Electroanatomic mapping system was used to integrate computed tomography data with 3D mapping data. We identified the CFAE sites on the electroanatomic mapping. Radiofrequency ablation was applied to the CFAE sites; the posterior aspect of left superior pulmonary vein (LSPV), the anterior ridge of left atrial appendage, and the roof at the anterior to the LSPV. After those ablations, AF was finally terminated by ablation in the middle of the PLSVC. Previous investigators have reported that pulmonary vein antrum isolation (PVAI) is effective for the management of patients with either paroxysmal or persistent AF. However, some patients experience episodes of AF despite successful PVAI, which implies that important triggers and perpetuators remain in the posterior left atrium, crista terminalis, superior vena cava, coronary sinus ostium, interatrial septum, and the ligament of Marshall/PLSVC. In conclusion, CFAE ablation was useful in a patient with persistent AF with PLSVC. PMID- 30524528 TI - A novel, accelerated method of desensitization in a patient with a documented hypersensitivity reaction to clopidogrel. AB - Current standard of care following a percutaneous coronary intervention with stent placement necessitates the use of dual anti-platelet therapy with aspirin and commonly clopidogrel. There is a subset of patients who have a significant clopidogrel allergy and life-threatening hypersensitivity reactions. Desensitization is the process of inducing tolerance to a sensitizing agent via repeated exposure to the agent. There have been previously reported protocols for clopidogrel desensitization. These protocols differ in length and dose escalation and a universally accepted clopidogrel desensitization protocol has yet to be established. We discuss here a novel accelerated approach to clopidogrel desensitization in a patient with a documented hypersensitivity reaction. PMID- 30524530 TI - Stenting of right coronary ostial occlusion due to thrombosed type A aortic dissection: One-year follow-up results. AB - A 52-year-old man experienced acute chest pain and was transferred to our hospital. An electrocardiogram showed ST-segment elevation in leads II, III, aVf, and V1 through V3. The diagnosis at the emergency room was inferior acute myocardial infarction (AMI), and emergent coronary angiography (CAG) was performed. While CAG showed subtotal occlusion of the right coronary artery (RCA) ostium, aortic dissection was suspected due to staining of the contrast agent distal to the occluded site of RCA. Intravascular ultrasound showed compression of the RCA ostium due to aortic dissection. We performed bare metal stent implantation, and contrast-enhanced computed tomography (CT) after stenting showed a thrombosed type A aortic dissection. The patient received medical treatment along with repeated CT and echocardiographic examinations, and was discharged without any events one month after admission. CAG six months after stenting and 64-multislice CT angiography one year later showed a patent RCA. Contrast-enhanced CT at six months showed complete resorption of the ascending aortic intramural hematoma, and 64-multislice CT at one year showed a descending aortic intramural hematoma. The patient is doing well one year after the onset. This is a rare case of successful medical treatment for acute type A aortic dissection complicated with AMI. PMID- 30524529 TI - A case of cardiac sarcoidosis masquerading as arrhythmogenic right ventricular cardiomyopathy awaiting heart transplant. AB - We report a case of 45-year-old man, who was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) and presented with right ventricular (RV) enlargement with a global decrease in RV contractility accompanied by impairment of left ventricular function. He was placed on the heart transplant waiting list. Endomyocardial biopsy from RV septal wall did not show any evidence of sarcoidosis or inflammatory change. Four years after he was put on the heart transplant waiting list, a computed tomography chest scan for the purpose of anatomical evaluation for coronary sinus prior to biventricular pacing lead implantation incidentally showed bilateral hilar lymphadenopathy, which suggested the possibility of sarcoidosis. Biopsy of the inguinal lymph node pathologically was consistent with sarcoidosis. The 2[18F]fluoro-2-deoxy-d-glucose positron emission tomography scanning (FDG-PET) demonstrated intense uptake in the myocardium, and the patient was finally diagnosed as having cardiac sarcoidosis. After steroid treatment, the abnormal FDG-PET uptake disappeared. The patient therefore represented a case of cardiac sarcoidosis masquerading as ARVC. It should be recognized that RV involvement is one of the manifestations in cardiac sarcoidosis. PMID- 30524531 TI - Myocardial infarction in a premenopausal woman with a decreased serum estrogen level due to leuprorelin acetate. AB - A 45-year-old premenopausal woman was admitted with acute myocardial infarction. Her serum estrogen level was decreased because of leuprorelin acetate administration, 3 months prior to admission for the treatment of uterine myoma. Emergency coronary angiography revealed diffuse narrowing of the distal half of the left anterior descending artery (LAD). The second coronary angiography after anti-anginal medication revealed significant improvement in LAD narrowing, which suggested prolonged coronary vasospasm. She had no coronary risk factors except for a positive family history. This case suggests that a decreased serum estrogen level could cause ischemic heart disease even in premenopausal women. PMID- 30524532 TI - Initial Japanese experience and long-term follow-up with a new active fixation coronary sinus lead, the StarFix 4195. AB - Technologies associated with cardiac resynchronization therapy (CRT) devices and lead systems have progressed. However, dislocation after coronary sinus (CS) lead placement continues to be a problem. Furthermore, CS lead positioning at the site of the ventricular latest activation (detected by echocardiography) is often problematic due to large vessel size leading to the lead placement (wedge site) near the apical site. The newly available active fixation CS lead (StarFix 4195) enabled us to anchor the CS lead at the target site regardless of vessel size and availability of a wedge site. We report on seven patients who had previously failed conventional CS lead positioning due to large vessel size and a low phrenic nerve stimulation threshold at the optimal site and lack of stabilization followed by dislocation at the target vein. We attempted to replace the original lead with the StarFix 4195. All patients successfully underwent StarFix 4195 lead replacement at the target site and responded to CRT in the long-term follow-up period. PMID- 30524535 TI - Editorial: Cardiac tumors: Histopathological aspects and assessments with cardiac noninvasive imaging. PMID- 30524533 TI - Stanford type B aortic dissection associated with pregnancy in patients with Marfan syndrome-A case report and review of the literature. AB - A 36-year-old female patient known to have Marfan syndrome (MFS) presented with Stanford type B aortic dissection (type B-AD) 3 days after delivery although she had taken oral beta-blocker and underwent prophylactic cesarean section at 34 weeks when she showed 42 mm of the ascending aorta. She was successfully treated medically without further progression of the dissection. A review of the literature revealed an additional 19 patients with MFS who suffered from type B AD associated with pregnancy. Of 20 patients, 1 (5%) died but the remaining 19 patients were successfully treated either medically (n = 9) or surgically (n = 10). Of 13 patients whose aortic diameter was known, 5 showed <40 mm of the ascending aorta. Pregnancy in MFS can be complicated by type B-AD with a peak around term delivery irrespective of the size of ascending aorta and even with beta-blocker. PMID- 30524534 TI - Cardiac metastatic melanoma: Imaging diagnostic clues. AB - A 47-year-old male was admitted to hospital for severe pericardial effusion; he had undergone surgical removal of cutaneous melanoma 10 years before. Echocardiography-guided pericardiocentesis revealed the presence of intramyocardial masses, which were better defined and characterized, together with pericardial involvement, by cardiac magnetic resonance. Pericardial fluid drained was negative for malignant cells, so video-assisted thoracoscopy was performed and pathologic tissue was biopsied, leading to the diagnosis of metastatic melanoma. Multidisciplinary approach and multimodality imaging played a key role in allowing the diagnostic workup in this complex case. . PMID- 30524536 TI - Intravascular findings of fibromuscular dysplasia on optical coherence tomography. AB - We present the case of a 29-year-old woman with right renal artery stenosis caused by fibromuscular dysplasia (FMD) who underwent optical coherence tomography (OCT)-guided percutaneous transluminal renal angioplasty. Using OCT, we could clearly observe intimal fibroplasia and medial hyperplasia that was indicative of FMD. Based on diagnosis of FMD by OCT, this patient was treated with plain old balloon angioplasty that resulted in adequate luminal opening without intimal dissection confirmed on final angiography and OCT. . PMID- 30524537 TI - Editorial: Optical coherence tomography in endovascular intervention for renal artery stenosis. PMID- 30524538 TI - Transcatheter closure of iatrogenic Gerbode defect with an Amplatzer duct occluder in a 23-year-old patient. AB - A 23-year-old man was referred to our center with hematuria and hemolysis. The patient had undergone mitral and tricuspid valve replacement 3 months previously. Echocardiography and catheterization revealed a Gerbode-type ventricular septal defect. A decision was made to occlude the defect interventionally. The patient's hematuria ceased immediately after the occlusion of the defect. . PMID- 30524539 TI - Concomitant takotsubo cardiomyopathy with PRES syndrome: A coincidence or a real heart-brain connection? AB - Takotsubo cardiomyopathy is a clinical entity characterized by reversible ventricular dysfunction in the absence of obstructive coronary artery disease. Posterior reversible encephalopathy syndrome is another rare clinical syndrome characterized by reversible neurological symptoms. Concomitant occurrence is increasingly reported leading to credence to hypothesis of "heart-brain connection". We present a case of a 60-year-old female admitted for neurological symptoms who developed takotsubo cardiomyopathy within 24 h of admission. . PMID- 30524540 TI - Rupture of pseudoaneurysm of the superficial femoral artery over four years after self-expandable nitinol stent implantation. AB - Postcatheterization pseudoaneurysm is one of the most common vascular complications of peripheral angiographic procedures. An 83-year-old male received endovascular treatment (EVT) for a total occlusion lesion of left superficial femoral artery (SFA) due to intermittent claudication. After the subintimal angioplasty procedure with implantation of three self-expandable nitinol stents, angiography revealed contrast staining outside the stent margins. Duplex ultrasonography immediately after the procedure confirmed a pseudoaneurysm of 12 mm in diameter. There was no change in the size of pseudoaneurysm during the follow-up period. Four years after the initial procedure, he was admitted to our hospital because of swelling and pain in his left thigh. The angiography showed stent fracture at the proximal shaft of the stent. Furthermore, a fractured fragment of the stent was lying within the ruptured pseudoaneurysm, and active extravasation of contrast medium was identified. Surgical repair of the pseudoaneurysm was performed. We report a case of spontaneous pseudoaneurysm rupture of the SFA that had developed because of subintimal stent placement 4 years previously. If pseudoaneurysm is confirmed after EVT with subintimal stent placement, it should be treated by surgical or percutaneous methods, regardless of its size. . PMID- 30524541 TI - A case of radiation-induced subclavian artery stenosis treated with percutaneous transluminal angioplasty. AB - We report on a female patient who underwent a standard radical mastectomy and radiation therapy for right breast cancer at the age of 50 years without recurrence. At the age of 76 years, she started to experience fatigue in the right upper limb. The symptom gradually worsened and she was admitted to our hospital for further investigation. With computed tomography scan and angiography, we observed a high degree of subclavian artery (SCA) stenosis and asymptomatic right common carotid artery (CCA) stenosis. After undergoing carotid artery stenting to the right CCA stenosis at another hospital, we performed percutaneous transluminal angioplasty to SCA. Although we chose to treat the highly calcified lesion only with a balloon and slightly decreased the degree of stenosis, her symptoms clearly improved. Since arterial severely stenotic lesions were limited in the area of radiation exposure while other part of the arteries looked smooth and relatively free of sclerosis, it was highly suspected that arterial injury was induced by radiation. There are few reports of radiation induced injury of upper limbs. However, this case suggests that we need to consider the possibility of radiation-induced arterial injury in patients with a history of radiation therapy. . PMID- 30524542 TI - Non-traumatic splenic rupture on dual antiplatelet therapy with aspirin and ticagrelor after stenting for acute coronary syndrome. AB - We report a case of non-traumatic splenic rupture in a 57-year-old man on dual antiplatelet therapy (DAPT) with aspirin and ticagrelor, seven months after percutaneous coronary intervention and drug-eluting stent implantation for non-ST elevation myocardial infarction. No splenic abnormalities were found at histopathological analysis after splenectomy, and no history of recent trauma was reported. Once restarted, DAPT after splenectomy, assessment of platelet function was performed by light transmittance aggregometry, showing a profound inhibition of platelet function by adenosine diphosphate, arachidonic acid, and collagen. Taking into account the bleeding risk associated with low on-treatment platelet reactivity, and to switch the patient from ticagrelor to a less potent P2Y12 inhibitor such as clopidogrel, cytochrome P450, genetic polymorphisms accounting for clopidogrel response variability were analyzed. The polymorphisms associated with lower response (CYP2C19*2, CYP2C19*3) were absent. Therefore, ticagrelor was withdrawn, and DAPT was continued with aspirin and clopidogrel. Rupture of the spleen may occur in the absence of major trauma or previous splenic diseases, and could be a complication of antithrombotic treatments. Moreover, low on-treatment platelet reactivity during DAPT is emerging as a possible risk factor for bleeding complications, so underlining the usefulness of assessing platelet function in special conditions to ensure that the patient receives the best tailored antiplatelet therapy. . PMID- 30524543 TI - Editorial: Diagnosis of cardiac sarcoidosis - What is the role of endomyocardial biopsy? PMID- 30524544 TI - Inadvertent consequences of percutaneous coronary intervention to treat unstable spontaneous coronary artery dissection. AB - We present two cases of spontaneous coronary artery dissection (SCAD), which were diagnosed and treated with emergent percutaneous coronary intervention (PCI). Patients with ongoing ischemia due to SCAD need emergent coronary revascularization with PCI or coronary artery bypass grafting. We discuss the difficulties of PCI to bail out unstable SCAD regardless of the modern techniques and modalities. Brief reviews of the literature with relevance are included. . PMID- 30524545 TI - Case of fibromuscular dysplasia with multiple aneurysms in a young woman. AB - We report a case of fibromuscular dysplasia (FMD). The patient was a 22-year-old female who had received treatment for hypertension for two years. She had also presented with hemorrhage caused by an annular ulcer in the small intestine. In March 2012, she had abdominal pain, was diagnosed with rupture of aneurysms of the gastroepiploic artery, and received embolization. In July 2012, she felt abdominal pain, presented with ruptured aneurysms of the left hepatic artery. She had abdominal pain again and suffered hemorrhagic shock. Contrast-enhanced computed tomography scanning of her abdomen revealed rupture of the left hepatic artery aneurysms and she received emergent coil embolization. Aneurysm expansion was noted, which suggested the necessity of early diagnosis and treatment, but the diagnosis was difficult because a few systemic findings were observed without any typical angiography findings. We decided to perform a small bowel resection for the complication of annular ulcers and reached a diagnosis of FMD according to pathological findings. Differential diagnosis between inflammatory and noninflammatory arteriopathy is difficult in many cases and often largely affects treatment policies. We experienced a rare case where we reached a definite diagnosis of FMD based on pathology of the small intestine ulcer. . PMID- 30524546 TI - Left ventricular outflow tract obstruction caused by massive mitral annular calcification in a patient with hypertensive heart disease. AB - Mitral annular calcification (MAC) is frequently observed, but it rarely causes left ventricular outflow tract (LVOT) obstruction (LVOTO). An 83-year-old woman with hypertension, diabetes, and dyslipidemia was admitted to our hospital because of exertional dyspnea. She was diagnosed with hypertensive heart disease. Her symptoms were exacerbated by exertion, and she had no symptoms at rest. Transthoracic echocardiography showed massive posterior MAC, a sigmoid septum, and LVOTO, with a peak gradient of 15.4 mmHg at rest. Systolic anterior motion of the anterior mitral leaflet was not found. Moreover, the LVOT gradient in the stress condition was evaluated, and an increased LVOT gradient (47.3 mmHg) and chest discomfort was noted after 20 MUg/kg/min of dobutamine was administered and the Valsalva maneuver was used. Hence, the patient was diagnosed with latent LVOTO. Interestingly, the distance between the septal wall, which was protruding into the left ventricular cavity, and the mitral valve coaptation, which was pushed up by the posterior MAC, had become closer, causing dynamic LVOTO. Since it is difficult to treat LVOTO with medication, ultimately, septal myectomy and mitral valve replacement were performed, which improved her symptoms. Evaluating the LVOT pressure gradient in stress condition is important in patients with MAC. . PMID- 30524547 TI - Epicardial implantation of a transvenous implantable cardioverter-defibrillator system in Ebstein's malformation with tricuspid valve repair. AB - In this case report, we describe the implant of a transvenous implantable cardioverter-defibrillator lead on the left ventricular epicardial surface of a young patient with Ebstein's anomaly, facilitating effective defibrillation and anti-tachycardia pacing. The difficulties of conventional placement in Ebstein's malformation as well as the technique and outcome of epicardial lead implantation of a transvenous defibrillator-pacer system are discussed. . PMID- 30524548 TI - Successful radiofrequency catheter ablation of sinoatrial nodal reentrant tachycardia after a total cavo-pulmonary connection procedure with an extra cardiac conduit. AB - We report a tachyarrhythmia case of a 32-year-old female with a single ventricle and heterotaxy syndrome. She had surgery involving a total cavo-pulmonary connection procedure using an extra-cardiac conduit (EC) at the age of 17 years. A tachycardia was repetitively induced with single atrial extrastimuli. An activation map was created revealing a centrifugal propagation pattern from the high atrial wall adjacent to the EC. At that site, a structure resembling the crista terminalis was recognized with intracardiac echocardiography. Therefore, high output energy was required to eliminate the tachycardia. It was thought to be a sinoatrial nodal reentrant tachycardia. . PMID- 30524549 TI - Editorial: Pericardial mass: Unusual interference with the right ventricular function. PMID- 30524550 TI - Trileaflet mitral valve associated with a bicuspid aortic valve. AB - The trileaflet mitral valve is a very rare congenital malformation with three equal size leaflets and three papillary muscles. In this article, we report the first case of trileaflet mitral valve associated with a bicuspid aortic valve in a patient referred for management of infective endocarditis. . PMID- 30524551 TI - Editorial: What is this cleavage of mitral valve - Commissure, indentation, cleft, or cleft-like indentation? PMID- 30524553 TI - Editorial: Left ventricular outflow tract obstruction is seen in various clinical settings of diverse patients. PMID- 30524552 TI - Reversible severe mitral regurgitation caused by systolic anterior motion of the mitral valve in the absence of left ventricular hypertrophy: A case report. AB - A 67-year-old woman with exertional dyspnea was referred to our hospital. Transthoracic echocardiography revealed severe mitral regurgitation and significant left ventricular (LV) outflow tract obstruction due to prominent systolic anterior motion (SAM) of the mitral valve without LV hypertrophy. Oral bisoprolol remarkably attenuated SAM. Two- or three-dimensional echocardiographic analysis demonstrated the elongation of anterior and posterior mitral leaflets and interventricular septum (IVS) bulging due to narrow aorto-mitral angle. In the present case, elongation of mitral leaflet and hyperkinetic motion of left ventricle, and IVS bulging due to narrow aorto-mitral angle possibly play important roles in the development of SAM. . PMID- 30524554 TI - Successful treatment of prolonged cardiopulmonary arrest of Kounis syndrome during coronary angioplasty. AB - We experienced a case of Kounis syndrome with cardiopulmonary arrest and severe coronary spasm. A 70-year-old man with cardiac pacemaker and chronic dialysis was treated for angina pectoris of the right coronary artery. After diagnostic coronary angiography of the right coronary artery, optical coherence tomography was performed with contrast medium and low-molecular-weight dextran. The patient's blood pressure unexpectedly dropped to 40 mmHg and erythema of the breast was noted. Electrocardiogram showed remarkable ST elevation in II, III, aVF leads. Coronary angiography showed total occlusion of the proximal right coronary artery. Although intracoronary infusion of sodium nitrate did not dilate the coronary artery promptly, coronary balloon angioplasty recovered the artery flow. Since severe anaphylaxis-related shock was contemplated, methyl prednisolone and epinephrine were administered intravenously. We could not introduce percutaneous cardiopulmonary support due to kinking of the vein. After 1 hour of cardiopulmonary resuscitation with frequent ventricular fibrillation and direct current shock, the sinus rhythm and blood pressure recovered. Following 2 months of intensive care treatment for other complications, including infection, the patient was discharged from hospital without any residual disability. . PMID- 30524556 TI - Complex single ostium coronary artery from the right coronary sinus with unique course of anomalous left circumflex coronary artery. AB - Single ostium coronary artery is a rare coronary artery anomaly. It is reported to occur in only 0.0448% of cases who underwent invasive coronary angiography. It can be associated with angina, arrhythmias, and possibly sudden death and is a clinically important entity to rule out in patients presenting with chest pain. We report the case of a 68-year old man who presented with worsening resting chest pain and underwent invasive coronary angiography and a single ostium coronary artery was identified. Subsequent coronary computed tomography (CT) angiography revealed it to be a unique variation of class R-III of Lipton classification of single ostium coronary artery. Lipton R-III single ostium coronary artery is rare and its incidence is reported to be 0.004% in patients who had invasive coronary angiography. In our case, anomalous left coronary circumflex artery was retroaortic course combined with intramyocardial course. It also divided into multiple obtuse marginal branches in the myocardium and never coursed along the anterior and lateral aspects of the arterioventricular groove. This variation has not been reported in the literature. Coronary CT angiography played an essential role to delineate this complex coronary anomaly. . PMID- 30524557 TI - Right ventricular undifferentiated pleomorphic sarcoma: A case report. AB - Undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma, is a neoplasm that occurs most often in the extremities, trunk, and retroperitoneum. Rarely, UPS can occur in the cardiac chambers and great vessels. The diagnosis of UPS is difficult to establish with noninvasive imaging techniques, and these tumors may be mistaken for benign neoplasms preoperatively. Surgical excision is the standard therapy, although the extent and location of the tumor may limit the ability to perform a complete resection. Adjuvant chemotherapy and/or radiation are often used for incomplete resections. We report the case of a 57-year-old woman with a large right ventricular UPS who presented with signs of right-sided heart failure. Preoperative imaging was suggestive of a myxoma; however, histopathologic evaluation of the specimen confirmed a diagnosis of UPS. Microscopic margins of the specimen were positive, and adjuvant chemotherapy was given. We discuss diagnostic and treatment considerations for this unusual cardiac tumor. . PMID- 30524558 TI - Rapid diagnosis of prosthetic valve endocarditis from Janeway lesions in a transcatheter aortic valve implantation patient. AB - Percutaneous transcatheter aortic valve implantation (TAVI), first introduced in 2002, is a viable solution for previously inoperable or high-risk patients with aortic stenosis, providing the benefit of valve replacement without the associated risks of surgery. When these patients develop prosthetic valve endocarditis (PVE), management is complicated, owing to their often, atypical presentations and baseline comorbidities. Moreover, it is often difficult to detect vegetations in such patients, even with transesophageal echocardiography. Here, we describe a case of post-TAVI PVE that was successfully treated medically after a rapid diagnosis was made based on physical examination. Our experience shows that physical examination continues to be important for rapid diagnosis of infective endocarditis, even in the era of structural heart disease intervention. . PMID- 30524559 TI - Lotus-in-Evolut R transcatheter aortic valve implantation for severe paravalvular leak. AB - Significant paravalvular leak (PVL) after transcatheter aortic valve implantation (TAVI) is associated with poor outcome. We present the case of an 83-year-old female with severe aortic stenosis who underwent TAVI with an Evolut-R valve (Medtronic, Minneapolis, MN, USA). An aortogram post-procedure showed aortic regurgitation thought to be moderately severe after post-dilatation. She deteriorated 24 h after her procedure and required a further intervention. She was salvaged with a Lotus (Boston Scientific, Marlborough, MA, USA) 'valve in valve' that completely eliminated PVL. . PMID- 30524560 TI - A runaway sternal wire: A rare case and outcome of sternal wire intravascular embolization. AB - We present a case of a 56-year-old man with history of coronary artery disease and prior two coronary bypass surgeries, who presented with chronic chest pain and was found to have a fractured sternal wire that migrated through the right ventricle and embolized to the right lower pulmonary artery without evident hemodynamic consequences. The sternal wire migration process, in part due to patient's poor medical compliance, was captured on serial computed tomography scans over a period of several years. . PMID- 30524561 TI - Successful emergent coil embolization of an inferior epigastric artery perforation in a neonate. AB - A 28-day-old neonate with a postoperative ventricular septal defect and coarctation of aorta suffered from a right inferior epigastric artery perforation at the time of a central venous catheter placement. It resulted in a rapid and extreme hemoglobin decrease and decrease in the systolic blood pressure. The contrast computed tomography scan revealed a large amount of retroperitoneal hemorrhaging and a hematoma. Pressure hemostasis was not effective in eliminating the extravasation and surgical hemostasis seemed uncertain to succeed, because the baby was too small and its condition was unstable. An emergent coil embolization using a Target(r) coil (Stryker Inc., Tokyo, Japan) was effective in completely eliminating the extravasation, resulting in saving its life. We speculated that a coil embolization was the only solution to rescue a neonate with a retroperitoneal hemorrhage due to an artery perforation. . PMID- 30524563 TI - Unroofed coronary sinus detected by 2D/3D echocardiography in a patient referred to catheter ablation for atrial fibrillation. AB - A 67-year-old female visited our echo lab for a preoperative screening exam before radiofrequency catheter ablation for atrial fibrillation. Transthoracic echocardiography revealed abnormal color flow signal in the right atrium, and following 2D/3D transesophageal echocardiography proved partial type of unroofed coronary sinus. Absence of associated congenital abnormalities was ruled out by Doppler and contrast echo examinations. Surgical findings confirmed exactly the same anatomical abnormalities as preoperative 2D/3D echocardiography. Echocardiography plays an important role in finding unexpected underlying cardiac diseases in patients who are referred to arrhythmia clinics. In the present case with atrial fibrillation, we could accurately diagnose an unroofed coronary sinus syndrome during preoperative transthoracic and transesophageal echocardiography prior to planned radiofrequency catheter ablation. . PMID- 30524562 TI - Isolated cardiac sarcoidosis diagnosed by electroanatomic voltage mapping-guided endomyocardial biopsy combined with magnetic resonance imaging and positron emission tomography. AB - Cardiac involvement in sarcoidosis is related to lethal arrhythmias and is considered a serious condition. Because steroid therapy is an effective treatment, early diagnosis of cardiac sarcoidosis (CS) is of paramount importance in respect to improving prognosis. However, the diagnostic yield of histologic examination by endomyocardial biopsy (EMB) in CS is usually low. We report the case of isolated CS histopathologically proven by electroanatomical voltage mapping (EVM)-guided EMB combined with cardiac magnetic resonance imaging (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). A 53-year-old man presented with general fatigue. Electrocardiography showed intermittent complete atrioventricular block and echocardiography showed reduced cardiac function. CMR showed late gadolinium enhancement (LGE) in the areas of myocardium with suspected sarcoidosis. Next, we performed an EVM-guided EMB and found a non caseating epithelioid granuloma in the right ventricular septum, which showed low voltage on EVM and LGE on CMR. FDG-PET showed accumulation in the same cardiac region. This case shows that EVM-guided EMB combined with diagnostic imaging can be a valuable approach in cases of suspected isolated CS. . PMID- 30524564 TI - Left atrial thrombus in a patient without mitral valve disease or atrial fibrillation. AB - A 54-year-old man presented with back pain. His medical history included hypertension and gout. There was no history of heart disease or arrhythmia. The electrocardiogram showed normal sinus rhythm. Chest computed tomography demonstrated a large calcified tumor (65 mm) in the left atrium (LA). The echocardiogram showed a round hyperechoic mass in the enlarged LA (56 mm) attached to the atrial septum without mitral valve disease. Urgent surgery for excision of the LA mass with the atrial septum and reconstruction by autologous pericardial patch was performed. There was no pathological change in the mitral valve. Due to surgical injury to the conduction system, implantation of a permanent pacemaker was required postoperatively. Histopathological examination revealed calcification, fibrosis, and thrombus formation. LA thrombus without any history of mitral valve disease or atrial fibrillation is rare. Although the mechanism of the present case was unclear, extensive calcified LA myxoma or undiagnosed patent foramen ovale might have been associated with the disease. . PMID- 30524565 TI - Impact of low-dose prednisolone on refractory pitting edema manifesting remitting seronegative symmetrical synovitis with pitting edema syndrome. AB - We encountered an elderly male patient who after cardiac surgery for mitral stenosis had refractory pitting edema in both legs involving painful leg joints after a 1-month history of waxing and waning arthralgia. His family doctor had prescribed a combination of diuretics, 40 mg furosemide and 25 mg spironolactone; however, pitting edema in his lower legs persisted. He was diagnosed with worsening of congestive heart failure because of a previous cardiac surgery and was transferred to our hospital. On admission, we closely observed the patient's condition and noticed that his body temperature increased to 38.0 degrees C every evening. Furthermore, his ankle joints felt feverish and were swollen. Therefore, we suspected polyarthritis as an etiology, although we initially suspected rheumatoid arthritis (RA). Antibody testing did not support RA diagnosis; therefore we concluded the association of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome with his condition. After daily treatment with 15 mg prednisolone, the refractory edema symptom dramatically improved. The concept of RS3PE syndrome could explain such as an impressive clinical course. . PMID- 30524566 TI - Acute myocarditis in bodybuilder from coxsackievirus and thyrotoxicosis. AB - A 25-year-old male with no past medical history presented with 1 day of chest pain. The patient had exercised with high intensity for a bodybuilding competition. He had fever, malaise, sore throat, and cough 1 week before presentation. He was tachycardic and tachypneic. Cardiac examination was unremarkable. Electrocardiogram showed diffuse ST segment elevation. Laboratory results showed leukocytosis, creatinine kinase 3078 unit/L, and troponin I 78.06 ng/mL. Coronary angiography revealed no occlusion. Echocardiogram showed ejection fraction of 45% with global hypokinesis. The next day, the patient became dyspneic, hypoxic, and hypotensive. Chest X-ray showed pulmonary edema requiring intubation for respiratory failure. Inotropic support and intra-aortic balloon pump were started. A viral panel was ordered and antibody titer of coxsackievirus B type 4 was >=1:640. On obtaining further history, it was found that he took liothyronine 75 mcg daily for 3 weeks. Thyroid-stimulating hormone was 0.015 U/mL and free T3 was 4.4 ng/mL. Burch-Wartofsky score was 75. Methimazole and hydrocortisone were started. Cardiac magnetic resonance imaging showed diffuse myocardial inflammation and edema. There was multifocal dense epicardial and midmyocardial necrosis in all segments. The patient was discharged on metoprolol and enalapril. The patient was instructed to refrain from supplements. . PMID- 30524567 TI - Giant congenital left ventricular diverticulum associated with infective endocarditis: A diagnosis made by tissue Doppler echocardiography. AB - Left ventricular (LV) diverticulum is a relatively rare condition, and it is important to differentiate it from pseudoaneurysm. The increasing use of noninvasive imaging modalities can help to demonstrate different types of ventricular outpouching structures. We report a case of congenital LV diverticulum that is much larger than the usual size and is diagnosed with tissue Doppler echocardiography and cardiac magnetic resonance imaging. Although a ventricular diverticulum is mostly asymptomatic, in the case of this particular patient, it has become complicated with infective endocarditis. . PMID- 30524568 TI - Spontaneous left atrial intramural hematoma associated with large hemorrhagic pericardial effusion. AB - Atrial intramural hematoma is a rare entity. It was reported to occur spontaneously especially in patients with recent history of cardiac surgery or cardiac trauma. In this report, a case of spontaneous intramural hematoma associated with large bloody stained pericardial effusion presented with progressive shortness of breath as the primary clinical manifestation is described. The diagnosis was tentatively achieved by transesophageal echocardiography and cardiac computed tomography scan and was later confirmed during surgery. The patient recovered uneventfully following surgery and follow up echocardiography demonstrated complete resolution of pre-existing hematoma. . PMID- 30524569 TI - Three years from 2014 to 2016 as Editor-in-Chief during the infancy of journal. PMID- 30524570 TI - Greeting from the new Editor-in-Chief. PMID- 30524571 TI - Cable externalization at the proximal portion of the superior vena cava coil in Riata implantable cardioverter defibrillator leads. AB - Many Riata (St. Jude Medical, St. Paul, MN, USA) implantable cardioverter defibrillator (ICD) leads have reportedly developed cable externalization. The most likely cause of cable externalization is insulation abrasion, which often occurs at the can or between the right ventricular coil and superior vena cava (SVC) coil. We report a rare case of an adult male whose ICD lead cable was externalized at the proximal portion of the SVC coil. This lead became fixed to the wall at the subclavian vein and SVC and became bent between these adhesions. Furthermore, the motion of this lead was affected by pulsation of the aortic arch. The ICD lead might develop inside-out abrasion due to mechanical stress evoked by pulsation of the aortic arch at this site. . PMID- 30524572 TI - Fatal cardiac anomaly of unguarded mitral orifice with asplenia syndrome. AB - We report the case of a newborn baby with an unguarded mitral orifice associated with asplenia syndrome, double-outlet right ventricle, dysplastic tricuspid valve, and pulmonary stenosis. This case was accompanied by severe tricuspid regurgitation and severe right ventricular hypertrophy. The patient had a fatal clinical course due to severe hypoxia and congestive heart failure. Unguarded mitral orifice is a rare disease in which there has been no previous report of lethal clinical course during the neonatal period. Prior reports stated that unguarded mitral orifice was a new constellation of defects and that its etiology and embryology could be classified in the same category because of similar associated malformations of double-outlet right ventricle and pulmonary stenosis or atresia. However, the present case was diagnosed on autopsy as also having asplenia syndrome. Therefore, it is possible that the genetic etiology of unguarded mitral orifice in this case was different from cases of non-heterotaxy. . PMID- 30524573 TI - Failure of steroid withdrawal guided by 18F-FDG PET in a patient with cardiac sarcoidosis. AB - A 71-year-old man diagnosed with cardiac sarcoidosis (CS) 11 years previously underwent implantation of an implantable cardioverter defibrillator due to sustained ventricular tachycardia. Over past decade, his condition of CS did not progress on the maintenance steroid dose of 7.5 mg per day. We attempted to taper and discontinue steroids according to the results of fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET). On the basis of the results, we reduced the oral steroid dose slowly. In spite of no abnormal 18F FDG uptake in the myocardium, advanced atrioventricular conduction block and deterioration of the ventricular pacing threshold occurred during the course of steroid withdrawal. Plasma brain natriuretic peptide (BNP) increased from 94 to 842 pg/ml. It was necessary to add new ventricular and atrial leads to synchronize atrial and ventricular contractions, and the pacing mode for bradycardia was changed to dual-chamber DDD-60 ppm. Fatigue disappeared, and BNP levels decreased to 147 pg/ml. 18F-FDG PET might have a limit to detect small scattered inflammatory foci. This case highlights the need for caution when reducing steroid doses in CS patients, guided by 18F-FDG PET only. . PMID- 30524574 TI - A case of transient apical hypertrophy associated with coronary vasospasm. AB - A 49-year-old woman was admitted to our hospital because of repeated loss of consciousness. On arrival, she was in cardiopulmonary arrest associated with arrhythmia of Torsades de pointes, and recovered from it after cardiopulmonary resuscitation and defibrillation. The administration of a beta-blocker and amiodarone was initiated to prevent ventricular tachycardia. On day 2, coronary angiography revealed non-obstructive coronary artery, and left ventriculography (LVG) exhibited hypokinesis in the anterior and apical wall. On day 20, an acetylcholine provocation test revealed a multivessel vasospasm, and LVG showed "spade-shaped left ventricle" in end-diastole because of apical hypertrophy. Transthoracic echocardiography (TTE) also showed apical wall thickness. Subsequent apical wall thickness gradually decreased and returned to normal on day 51 as observed on the TTE. Thus, we report a case of transient apical hypertrophy associated with coronary vasospasm, which was demonstrated by both the TTE and LVG. . PMID- 30524575 TI - Combination of drug-coated balloon angioplasty and excimer laser coronary angioplasty ablation for coronary restenosis of Kawasaki disease: A case report. AB - Coronary aneurysm is a well-known sequela of Kawasaki disease. Although ischemic heart disease often becomes problematic due to coronary aneurysm and severe calcification, there is no consensus on how to treat ischemic lesions in those with Kawasaki disease. We describe a case of successful percutaneous coronary intervention of the restenosis lesion within a coronary artery aneurysm accompanied by Kawasaki disease by using an excimer laser coronary angioplasty ablation technique followed by drug-coated balloon angioplasty. . PMID- 30524576 TI - Successful catheter intervention for deep vein thrombosis due to inferior vena cava stenosis after retrieval of a temporary inferior vena cava filter. AB - Inferior vena cava (IVC) stenosis is a well-known complication of the IVC filter. However, there are no previous reports of IVC stenosis caused by a temporary IVC filter. In this case report, we describe the case of a 35-year-old man who was referred to our center for the treatment of recurrent proximal deep vein thrombosis (DVT) and severe IVC stenosis that occurred after retrieval of a temporary IVC filter. We performed a catheter-directed thrombolysis and balloon angioplasty. DVT resolved effectively, and his leg symptoms resolved. . PMID- 30524577 TI - Lead displacement due to tension pneumothorax following permanent pacemaker implantation. AB - A 62-year-old female, who had undergone dual chamber pacemaker implantation through left subclavian approach, developed tension pneumothorax of left side. This resulted in shift of entire mediastinum and lead displacement with altered lead parameters. Pacemaker implantation can be complicated by tension pneumothorax in 0.6-5% of cases. Tension pneumothorax can cause mediastinal shift and rarely cause displacement of the leads. In our patient, shift of mediastinum with change of loops and position was associated with change of parameters requiring lead revision. . PMID- 30524578 TI - Acute myocarditis following high-dose interleukin-2 treatment. AB - We describe the case of a 49-year-old woman with metastatic renal carcinoma receiving treatment with high-dose interleukin-2 (IL-2) who developed acutely progressive dyspnea on exertion and an elevated troponin level. Cardiac magnetic resonance imaging (CMR) was used to establish the diagnosis of IL-2-associated cardiotoxicity, differentiating myocarditis from acute coronary syndrome (ACS) and preventing an unnecessary invasive coronary angiogram. . PMID- 30524579 TI - A case of Type-C Wolff-Parkinson-White syndrome with severe left ventricular dysfunction: Efficacy of catheter ablation. AB - The present case report describes a 59-year-old female with manifest Wolff Parkinson-White syndrome and severe left ventricular (LV) dysfunction, however, there was no indication of heart palpitations. The polarity of delta is consistent with the features of the right anteroseptal accessory pathways (APs). The echocardiography showed a remarkable dyssynchrony of the LV wall motion. To circumvent the cardiac dysfunctions, radiofrequency catheter ablation (RFCA) was successfully performed to disconnect the AP. Thereafter, the dyssynchrony disappeared, and the clinical reports observed 6 months following RFCA showed that the LV ejection fraction had been improved from 13% up to 48%, in addition to the improvement in other parameters. The RFCA prevented her from receiving a cardiac resynchronization therapy defibrillator as well as a heart transplantation. . PMID- 30524580 TI - A case of an explanted 26-year-old Carpentier-Edwards supra-annular valve in the tricuspid position. AB - Whether a mechanic or bioprosthetic valve is better for tricuspid valve replacement is still controversial. One problem of bioprostheses is structure valve deterioration. However, a bioprosthesis in the tricuspid position is more durable than that in the aortic and mitral positions. We report a case of an explanting Carpentier-Edwards supra-annular valve (CE-SAV) (Baxter Healthcare Corp., Irvine, CA, USA) in tricuspid position 26 years after tricuspid valve replacement. A 36-year-old female underwent total correction of tetralogy of Fallot at the age of five, and three years later she underwent tricuspid valve replacement for severe tricuspid regurgitation using a Bjork-Shiley valve. Two years later, the mechanical valve was explanted due to thrombus formation, and a 29-mm CE-SAV was implanted in tricuspid position. Twenty-six years after implantation, we explanted the valve due to structural valve deterioration. The leaflets of the valve were hard and stiff, and calcifications were present on all the leaflets. A small tear existed in the part of most calcified leaflet. To the best of our knowledge, this is the longest durability of CE-SAV in tricuspid position. . PMID- 30524581 TI - Successful management of huge floating thrombus within aortic arch in a patient with old myocardial infarction. AB - Few cases of a floating thrombus in an aorta have been reported without any systemic embolic complications. We report an unusual case of a huge floating thrombus (3 cm * 10 cm in size) in the aortic arch. The patient had a history of old myocardial infarction and had undergone successful percutaneous coronary intervention 16 years previously. The aortic thrombus was detected incidentally after echocardiography and computed tomography without any evidence of aortic dissection or distal embolization. The huge thrombus was removed successfully from the aortic arch by urgent surgery. PMID- 30524582 TI - Serial angiographic and endovascular documentation of peri-stent contrast stains after sirolimus-eluting stent implantation: Multiple cavity formations between entirely covered stent struts. AB - A 72-year-old woman with a history of treatment with a single sirolimus-eluting stent (SES) for right coronary artery stenosis 21 months previously, was hospitalized to undertake invasive coronary evaluation due to recurrence of symptoms of effort angina. At the time of 9 months of angiographic follow-up, no in-stent restenosis was detected, however, several contrast filled "dimples" were noticed outside the stent border. At this time, further increments in the numbers of dimple formation were documented, in addition to progression of stenosis at the distal non-stented portion. Intravascular ultrasound demonstrated multiple cavity formations between the stent struts, due to positive remodeling occurring at the previously relatively disease-free side of the vessel wall. Surprisingly, optical coherence tomography demonstrated all the stent struts, including those located adjacent to cavities, were exclusively covered with neointima or other tissue components, completely attaching to the vessel wall throughout the stented segment. No evident thrombus formation was detected in these cavities. Despite no exposed stent struts, a hypothetical concern remains because such cul-de-sac formations may produce local blood flow turbulence within stents, which may be potentially associated with activation of local platelet aggregation. Careful long-term follow-up may be necessary for these patients. PMID- 30524583 TI - Quadricuspid aortic valve illustrated by 64-slice multidetector computed tomography: Surgical treatment of a rare cause of severe aortic regurgitation. AB - The quadricuspid aortic valve (QAV) is a rare congenital malformation that usually presents with aortic regurgitation (AR). The first case was reported in 1862. Most cases were diagnosed at the time of surgery or postmortem examination. With advances in imaging techniques, more cases have been diagnosed before surgery. We describe a 59-year-old man whose QAV had not been noted until the current admission. Transthoracic echocardiography revealed dilation of the left ventricle, severe AR, and suspected QAV. The QAV was confirmed by transesophageal echocardiography and 64-slice multidetector computed tomography. This case was a QAV with three equal cusps and one smaller cusp (type B in Hurwitz and Roberts classification). Because the cardiac catheterization and aortography showed severe AR and a QAV, the patient underwent elective surgery. The surgery consisted of replacing the QAV by a mechanical prosthesis. There were no post operative complications. The patient revealed no symptoms in the post-operative 7 months. PMID- 30524584 TI - Acute embolic stroke in a patient with atrial fibrillation after electroconvulsive therapy. AB - Although patients with atrial fibrillation (AF) have an increased risk of embolic stroke, some clinicians hesitate to provide anticoagulation therapy for these patients during electroconvulsive therapy (ECT), which is widely applied for the treatment of intractable depression, bipolar disorder, and catatonic schizophrenia, because of potential intracerebral hemorrhage. We report on a 77 year-old female depressive patient with AF treated with aspirin but not on anticoagulation therapy because of poor compliance who developed embolic stroke 1 day after the last ECT. The CHADS2 score of this patient was 2 and included the age and hypertension. The present case suggests that anticoagulation therapy should be considered for patients with obvious risks of embolic stroke when they are subjected to ECT. PMID- 30524587 TI - A case of left ventricular diverticulum: Change of characteristics after myocardial infarction and usefulness of cardiac computed tomography. AB - A 72-year-old man with an old myocardial infarction was admitted to our hospital for cardiac reexamination. He had suffered from an inferior myocardial infarction when he was 60-year-old. The left ventriculogram had then shown a small contractile diverticulum at the apical portion of the left ventricle. Anterior myocardial infarction had recurred when he was 63-year-old. The left ventriculogram performed after the anterior myocardial infarction revealed that the diverticulum had become dilated and non-contractile. On admission, electrocardiography and chest X-ray showed no remarkable changes from the previous studies. Cardiac computed tomography (CT) demonstrated an apical left ventricular diverticulum with narrow communication to the main chamber and myocardial discontinuity of the wall at the site of the diverticulum. Tc-99m tetrofosmin myocardial images showed a perfusion defect in the apex. We presumed that a muscular left ventricular diverticulum had changed to the fibrous type after the anterior myocardial infarction. Cardiac CT imaging provides accurate evaluation of the left ventricular diverticulum and is useful for the differentiation between a left ventricular diverticulum and an aneurysm. PMID- 30524585 TI - A rare case of pericardial hemangioma with bloody pericardial effusion. AB - A 78-year-old woman presented with leg edema and exertional dyspnea. Echocardiography revealed a smooth-surfaced mass adjacent to the left atrium in the pericardial cavity with a massive pericardial effusion. Pericardiocentesis resulted in the drainage of a bloody effusion. Magnetic resonance imaging documented a mass having isointensity on T1- and hyperintensity on T2-weighted images. In addition, the mass was evenly enhanced with gadolinium 10 min after administration. By surgical resection, a 25 * 30 mm in diameter tumor was excised together with a left atrial wall portion. The pathological examination made a final diagnosis as hemangioma. Based on these findings, we report the rare case of pericardial hemangioma with a bloody pericardial effusion, which presented with heart failure symptoms. Although bloody pericardial effusion is considered a supportive characteristic for malignant tumors, we could preoperatively make a precise diagnosis of benign hemangioma by means of several imaging modalities. PMID- 30524586 TI - Infective endocarditis complicated with splenic abscess successfully treated with splenectomy followed by double valve replacement. AB - Splenic abscess (SA) is a rare complication of infective endocarditis (IE). A successful outcome lies with a choice between medical and surgical treatments. However, there is still insufficient evidence in the decision-making process. Our patient was a 73-year-old male who complained mainly of fever and general fatigue. An echocardiography showed vegetation of 10 mm in diameter and severe mitral and aortic regurgitation and a diagnosis was made of IE. Because of a recent brain embolism, we decided to treat him initially with medical therapy. Antibiotics were effective, but on the 28th day after starting treatment, he complained of left upper abdominal pain. An abdominal computed tomography scan showed SA. The administration of vancomycin did not improve the condition. We decided that he should undergo surgical treatment. A splenectomy was performed and 9 days after the splenectomy, the mitral and aortic valves were successfully replaced. There is still no clear-cut evidence to support the order of surgical interventions. Indeed, the current guidelines, which recommend that splenectomy is to be performed first, are not supported by strong evidence. The present case report showed that splenectomy before valve surgery successfully treated the patient. PMID- 30524588 TI - Recurrent takotsubo cardiomyopathy with variant forms of left ventricular dysfunction. AB - A 78-year-old man presented to our emergency department with dyspnea. The patient was diagnosed as having pneumonia from the chest X-ray which depicted mass-like opacity in the left lower lobe. On the 5th hospital day, electrocardiography showed giant negative T waves in pericardial leads and echocardiography demonstrated left ventricular apical akinesis and basal hyperkinesis. Accordingly, the patient was retrospectively diagnosed as having typical takotsubo cardiomyopathy. Two years later, the patient was admitted again to our hospital with pneumonia. On the 2nd hospital day, echocardiography showed left ventricular basal and mid-ventricular akinesis combined with normal apical wall motion. Ventricular wall motion was normalized within two months. The patient was finally diagnosed as having inverted takotsubo cardiomyopathy. Here, we report the patient who had recurrent takotsubo cardiomyopathy with variant forms of left ventricular dysfunction caused by repeated physical stress in two years. PMID- 30524589 TI - Post-transplant lymphoproliferative disorder as a cause of graft dysfunction after heart transplantation. AB - Post-transplantation lymphoproliferative disorders (PTLDs) are heterogeneous lymphoid proliferations representing a major complication of solid organ transplant. PTLDs are serious complications and may happen at different times after transplantation. Many risk factors are known, such as age, type of organ transplanted, Epstein-Barr virus (EBV) infection before transplant and immunosuppressive therapy. The PTLD incidence in solid organ transplant recipients is variable: from 1% in patients with renal allografts to 6-10% in patients with heart-lung transplantation, and up to 20% in lung transplant recipients. Many reports describe the evolution of PTLDs in heart transplant recipients, but PTLD as an unknown cause of graft dysfunction has never been reported. PMID- 30524590 TI - Transcatheter coil embolization of coronary artery fistulas. AB - Congenital coronary artery fistulas (CAFs), which have been known since 1865, are rare congenital cardiac abnormalities. Most of the CAFs are discovered incidentally during coronary angiography. We described our experience with successful transcatheter coil embolization of CAFs in an adult, leading to improvement of symptoms. The patient had chest pain or dyspnea on exertion. The CAFs originated from the left anterior descending coronary artery and the circumflex artery. They all drained into the pulmonary trunk. The coils were implanted through a microcatheter, which was passed through a 7F guiding catheter. The coils were used to occlude the CAFs completely. The procedures were uncomplicated. Patient's chest pain or dyspnea resolved after the procedures. Although the patient had small residual flow at the CAFs from the circumflex artery at follow-up coronary angiography, the patient was asymptomatic. Therefore, we considered the coil embolization to be successful. Transcatheter closure of CAFs with coil is a valid option, and can be regarded as an acceptable alternative to surgery nowadays. PMID- 30524591 TI - A case report: 201Tl/99mTc-Pyrophosphate dual-isotope myocardial SPECT for detecting annular subendocardial infarction induced by a transient shock. AB - The patient was a 74-year-old woman with angina pectoris, who had undergone percutaneous coronary intervention with stent placement in the right coronary artery on October 2, 2007. On November 12 of the same year, she suffered from paroxysmal atrial fibrillation. She was treated with pilsicainide hydrochloride administered by intravenous injection, which was followed by a sudden sinus standstill, with marked bradycardia and a shock state. The patient was then treated with a catecholamine, however, the shock state persisted for about an hour. An electrocardiogram revealed persistent ST depression in leads V4-6 along with elevation of the serum creatinine kinase. A coronary angiography performed on the admission day revealed no abnormality. On the third hospital day, a dual isotope myocardial SPECT using 201Tl and 99mTc-pyrophosphate demonstrated an annular accumulation of 99mTc-pyrophosphate concordant with the endocardium from apex to the mid-portion of the left ventricle, suggestive of subendocardial infarction. The case is reported here, as there are few reports of subendocardial infarction developing due to ischemia arising from a shock state. PMID- 30524592 TI - Late stent thrombosis after discontinuation of dual anti-platelet therapy in off label use of paclitaxel-eluting stent visualized by optical coherence tomography 3-vessel OCT study. AB - We observed late stent thrombosis image by optical coherence tomography (OCT) in vessels with off-label paclitaxel-eluting stents (PES) implantation. A 59-year old Japanese man was treated with a single on-label PES for chronic coronary artery disease in the left circumflex artery. After 9 months, he was implanted with two linked PESs in the left anterior descending artery (LAD) and a single PES in the right coronary artery (RCA). He was examined for suspicion of a colon tumor by fiberscope after discontinuation of dual anti-platelet therapy without consultation. He complained of chest pain and was transferred to our center. Emergency coronary angiography demonstrated thrombotic total occlusion of the proximal LAD in the two linked PESs. After thrombus aspiration therapy, OCT was performed to evaluate the stents in the 3 vessels. The off-label two linked PESs demonstrated the same average neo-intimal hyperplasia (NIH) thickness and percentage of uncovered stent struts compared with the on-label PES in the RCA by visualized OCT image. However, the heterogeneity of NIH in the LAD stent was significantly higher than the stents in the other two vessels. The implantation of the two linked off-label and the heterogeneity of NIH may increase hyperplatelet coagulability more than on-label single PES use. PMID- 30524593 TI - Dynamic narrowing of left ventricular outflow tract-Possible mechanism of latent left ventricular outflow tract obstruction. AB - It has been reported that left ventricular outflow tract (LVOT) obstruction can be provoked in patients even without significant left ventricular hypertrophy. We experienced a 74-year-old man with mild degree of left ventricular hypertrophy and latent LVOT obstruction which was successfully treated by alcohol septal ablation. LVOT was not narrow at end-diastole, but proximal septum was protruding further into LVOT during the ejection period, producing a dynamic narrowing of the LVOT. Alcohol septal ablation did not reduce the interventricular septal thickness nor enlarge LVOT. However, it limited the excursion of proximal septum. The effect of the treatment suggested the importance of the dynamic nature of LVOT in the mechanism of latent LVOT obstruction in this case. PMID- 30524594 TI - Coronary spasm as a cause of takotsubo cardiomyopathy and intraventricular obstruction. AB - A 79-year-old man presented to the emergency room because of chest pain on 3 successive mornings. An electrocardiogram (ECG) showed ST segment elevation in leads II, III, and aVF. Laboratory findings including cardiac enzymes, were within normal limits, except a positive result for the troponin T test. Two dimensional echocardiography revealed akinesis of the left ventricular apex and hyperkinesis of the basal wall. Doppler echocardiography revealed a significant subaortic pressure gradient. Emergent coronary angiography showed no significant coronary artery stenosis, but the ergonovine test induced a right coronary artery spasm with exaggeration of the ST segment elevation in II, III, and aVF leads. The computed tomography performed 2 weeks later showed normal left ventricular wall motion with sigmoid septum. The patient was diagnosed with takotsubo cardiomyopathy and intraventricular obstruction due to coronary spasm; he was treated with calcium channel blockers and nitrates. This case suggests the importance of differential diagnosis of the pathogenesis of takotsubo cardiomyopathy. PMID- 30524596 TI - Surgical experience of pericardial mesothelioma presenting as constrictive pericarditis. AB - We report two cases, which had been initially diagnosed with constrictive pericarditis but later were definitely diagnosed with mesothelioma after receiving pericardiectomy. The two patients complained of dyspnea. Chest computed tomography showed mild pericardial effusion and thickened pericardium, which was found enveloping the heart without any lumps. Pericardiectomy (phrenic nerve to phrenic nerve) was performed and post-operative histology confirmed malignant mesothelioma. One patient had recurrence near the pericardium at 7 months post operatively and died at 11 months post-operatively. Another patient, after receiving chemotherapy, is still alive at 16 months post-operatively. We consider that pericardial mesothelioma, an extremely rare disease exhibiting clinical signs similar to those of constrictive pericarditis, must be diagnosed at the early stage of its onset. PMID- 30524595 TI - An autopsy case of the rupture of a giant aneurysm in a saphenous vein graft: 18 years after CABG. AB - The saphenous vein is a widely used blood vessel for arterial bypass procedures. Failures of saphenous vein aortocoronary bypass grafts are predominantly the result of subsequent vein graft atherosclerotic disease. Rarely saphenous vein grafts undergo aneurysmal degeneration. This report describes a case of a ruptured aneurysm in a saphenous vein graft that occurred in an 82-year-old female who underwent a coronary artery bypass operation 18 years previously. We could not resuscitate her, but describe the autopsy findings in detail. PMID- 30524597 TI - Cardiac manifestations of Wegener's granulomatosis: Case report and review of the literature. AB - Wegener's granulomatosis, first characterized as a clinical syndrome in 1936, is a rare form of vasculitis of the small- and medium-sized blood vessels affecting mainly the upper and lower respiratory tracts as well as the kidneys. This review article describes the case of a 45-year-old man who developed aortic regurgitation and third degree heart block secondary to Wegener's granulomatosis. He subsequently presented to our institution 3 years later with pulmonary hemorrhage. The ensuing literature review reveals that historically clinical cardiac involvement in Wegener's has been rare, particularly with valvular lesions. However, recent literature has shown an increase in reported cases of cardiac valvular lesions in Wegener's. The presented case report along with recently reported case reports highlight the morbidity and mortality associated with such cardiac lesions. We believe routine cardiovascular supervision including echocardiography and electrocardiograms are important for the screening and monitoring of patients with Wegener's granulomatosis. PMID- 30524598 TI - A case of fulminant myocarditis associated with novel N1H1 influenza successfully treated by percutaneous cardiopulmonary support system. AB - We report a case of fulminant myocarditis associated with N1H1 influenza virus infection. N1H1 was confirmed by a polymerase chain reaction assay and she was treated with oseltamivir phosphate. She was admitted to the hospital because of respiratory distress, however, echocardiography revealed severely depressed wall motion followed by refractory ventricular fibrillation. Extracorporeal circulation by emergent percutaneous cardiopulmonary support system was required to maintain hemodynamic stability. Cardiac function was spontaneously and gradually restored within a week. Findings from biopsy samples taken on day 1 and day 23 were consistent with acute myocarditis. PMID- 30524600 TI - Spontaneous rupture of a giant coronary artery aneurysm causing cardiac tamponade: A case report. AB - A 62-year-old woman with a history of dyslipidemia and hypothyroidism was referred to our institution with syncope. Cardiac tamponade due to spontaneous rupture of a 50-mm aneurysm of the coronary artery was diagnosed by transthoracic echocardiography, enhanced computed tomography, and coronary angiography. Emergency surgery was performed, and despite developing postoperative complications such as acute renal insufficiency, the patient was discharged from hospital without sequelae 89 days later. Histological findings revealed cystic media degeneration, but neither significant atherosclerotic changes nor inflammatory cell infiltration. Although coronary artery aneurysms are comparatively rare and generally asymptomatic, those over 30 mm in diameter are considered to be at increased risk of rupture. A coronary artery aneurysm of about 50 mm ruptured in our patient, supporting this view. PMID- 30524599 TI - Multiple forms of atypical atrioventricular nodal reentrant tachycardia with different right- and left-sided retrograde slow pathways. AB - A 56-year-old man was admitted for the treatment of supraventricular tachycardia. After successful ablation of the left concealed accessory pathway, four fast-slow forms of atrioventricular nodal reentrant tachycardia associated with different right- and left-sided retrograde slow pathways were induced. The locations of retrograde slow pathway were observed at the left inferior paraseptum, left mid septum, right inferior paraseptum, and coronary sinus ostium, respectively. These retrograde slow pathways formed the integral limb of each tachycardia because conduction block of each slow pathway by catheter ablation was associated with the termination of tachycardia or abrupt change in the atrial activation sequence. PMID- 30524601 TI - Repeated intra-stent thrombus formation in a patient with acute coronary syndrome due to poor responsiveness to clopidogrel may be associated with cytochrome P-450 2C19*2 polymorphism. AB - A drug-eluting stent was implanted at the culprit lesion in a 65-year-old man with acute coronary syndrome. Nine days after the procedure, he suffered stent thrombosis, and a bare-metal stent was subsequently implanted. Twelve days after this second procedure, a follow-up angiogram showed a newly emerged thrombus at the site of stent implantation. Although the patient had continued dual anti platelet therapy with aspirin and clopidogrel since the first procedure, platelet optical aggregation test showed no inhibition of aggregation. Further, genetic analysis revealed him to be homozygous for the CYP2C19*2 polymorphism. This case suggests that the mechanism of stent thrombosis, while multi-factorial, is affected greatly by crossover of poor responsiveness to clopidogrel due to the CYP2C19*2 polymorphism. PMID- 30524602 TI - Recurrent intra-cardiac thrombosis-A unique presentation of prothrombin G20210 mutation. AB - We report a 49-year-old female patient with recurrent large left ventricular thrombus on echocardiogram in an apparently normal heart and insignificant cardiac past medical history. She underwent an excision of the left ventricular mass, final biopsy on which proved it to be a thrombus. Postoperative anti coagulation was initiated with enoxaparin and warfarin and the patient was followed up at a cardiology clinic 6 weeks later. A repeat trans-thoracic echocardiogram revealed a new mass arising from the left atrium. Considering the increased risk of repeat ventriculostomy, she was treated conservatively with her current management. During this time the patient's pro-thrombotic work-up revealed positive prothrombin G20210 mutation. A follow up trans-thoracic echocardiogram done 2 months later surprisingly revealed complete resolution of the intracardiac mass. Our patient had prothrombin G20210 mutation, an entity primarily known for deep venous thrombosis, which rarely causes intra-arterial thrombus, intra-cardiac being unreported. There are no established protocols for management of these cases. The rate of embolic episodes in mobile pedunculated thrombi is reported as high as 60%. Patients with prior embolism must be offered immediate surgery, especially if the thrombus is large with an irregular surface, pedunculated, and multiple in number. Aggressive anti-coagulation with close monitoring is essential. PMID- 30524603 TI - Endovascular management of subclavian artery stenosis using balloon expandable covered stents. AB - Covered stents have primarily been used in coronary arteries for exclusion of perforations, aneurysms, and fistulas. The use of covered stents to treat occlusive disease of first-order aortic branches has been proposed as a method to reduce intimal hyperplasia and improve patency rates, since they exclude plaque and prevent luminal encroachment through open struts, but their selective use in subclavian artery stenosis has not been previously reported. We present three cases of subclavian artery stenosis that were successfully treated via a percutaneous approach with covered stents. PMID- 30524604 TI - Suspicious seizures: Uncommon complication of PFO/ASA. AB - Brain abscesses have cardiac etiology in 5% of cases with valvular heart disease and endocarditis being the most common. Congenital heart disease with the risk of right to left shunt and paradoxical embolization is also a culprit. Our case describes a young patient with a prior undiagnosed patent foramen ovale (PFO), who presented with solitary brain abscess without any underlying primary source of infection. Since there was no evidence of contiguous spread of infection by computed tomography or magnetic resonance imaging scans, hematogenous spread of the streptococcal species was the most likely etiology. Transesophageal echocardiography (TEE) revealed no evidence of valvular endocarditis but did show intracardiac right-to-left shunting via a PFO. We suggest that all patients with a brain abscess of an unclear etiology caused be screened for a PFO with a TEE and bubble study. PMID- 30524605 TI - Renal thromboembolism in tako-tsubo cardiomyopathy in spite of anticoagulation. AB - An elderly lady was admitted with chest pain and an electrocardiogram depicting ST segment elevation, indicative of a myocardial infarction. She was treated with intra-venous tissue plasminogen activator. On coronary angiography there was a dilated and akinetic left ventricular apex but no significant coronary artery disease. She was diagnosed with tako-tsubo cardiomyopathy. An echocardiogram performed two days later demonstrated a thrombus in the left ventricular apex. Despite immediate anticoagulation with intravenous unfractionated heparin, she sustained a renal thromboembolic phenomenon. PMID- 30524606 TI - A case of acute heart failure due to abrupt rupture of aortic aneurysm into pulmonary artery. AB - Aorto-pulmonary fistula caused by ruptured aortic aneurysm is rare and sometimes difficult to diagnose, resulting in progression of heart failure. We report a case of acute heart failure due to abrupt rupture of aortic aneurysm into the pulmonary artery. Although it is difficult to make an early diagnosis of aorto pulmonary shunt, multi-detector computed tomography (MDCT) clearly detected this extracardiac shunt. Emergent surgical repair of aorto-pulmonary fistula was successfully achieved. MDCT is a useful modality to make an accurate diagnosis of extracardiac shunt and to decide the operative procedure non-invasively. PMID- 30524607 TI - Granulomatous endocarditis in a patient with Wegener's granulomatosis. AB - Echocardiographic examination of patients with granulomatous endocarditis in patients with Wegener's granulomatosis (WG) reveals vegetation-like lesions that may be misdiagnosed as infective endocarditis resulting in inappropriate therapy. Three-dimensional transesophageal echocardiography aids differential diagnosis. Here, we report the case of a WG patient with associated mitral and aortic granulomatous endocarditis. Although the patient was treated with prednisolone and cyclophosphamide, serial echocardiography did not reveal any significant changes in disease course. PMID- 30524608 TI - Bilateral spontaneous renal artery dissection. AB - Spontaneous renal artery dissection is a rare condition that precedes renal infarction. We describe a 48-year-old, normotensive healthy woman presenting with left flank pain of sudden onset. Enhanced abdominal computed tomography demonstrated a dissecting intimal flap of the left renal artery complicating renal infarction. Doppler ultrasonography, selective angiography, and intravascular ultrasound revealed a dissecting intimal flap, with a large false lumen and narrow true lumen, of the renal artery bilaterally. Conservative management was undertaken with anticoagulant and analgesic therapy, and the patient was discharged after an uneventful clinical course. PMID- 30524609 TI - A patient who developed toe necrosis due to poor blood circulation after an interdigital tick bite. AB - A 71-year-old female had worked on a farm in the mountains and noticed itching of the left 3rd toe. She visited a local hospital due to a color change to purple in this area. Attachment of a tick was observed between the left 2nd and 3rd toes, and it was extracted. However, due to persistent pain, she was referred to our department of cardiovascular medicine for close examination and treatment. Lower extremity angiography showed that vascular visualization was poor in the area supplied by the arteries distal to the tick bite site, but the other blood vessels of the toe were clearly visualized. Toe amputation was performed and pathological examination of a surgical specimen revealed that most blood vessels near the necrosis were occluded by thrombi. We speculated that tick bite reactions were associated with thrombogenic vasculopathy. This report shows a patient who developed toe necrosis due to poor blood circulation after an interdigital tick bite. PMID- 30524610 TI - Continuing versus New Antidepressant Use in Older Adults: US Prescribing Trends from 2006 to 2015. AB - Objectives: Antidepressant use has increased in older adults recently. This study examines the trends of antidepressant prescribing by prescription status (continuing vs. new prescriptions). Methods: Data were collected from 2006-2015 National Ambulatory Medical Care Survey (NAMCS), a nationally representative sample of office-based outpatient visits. I limited the sample to adults aged 65 or older (n=10,708 unweighted). Using a repeated cross-sectional design with survey sampling techniques, prevalence rates of antidepressant prescriptions were estimated by prescription status. Stratified analyses were also performed by key variables (e.g., age, gender, and race/ethnicity). Results: Continuing antidepressant prescriptions increased over time significantly (OR=1.07; 95% CI, 1.03-1.11), and no temporal trend was found in new antidepressant prescriptions. In stratified analyses, the increasing trends of continuing antidepressant prescriptions were pronounced in visits to primary care physicians (OR=1.06; 95% CI, 1.01-1.12). Conclusion: Increasing antidepressant prescribing trends were found in continuing prescriptions. Continued antidepressant prescribing among older adults should be monitored for appropriate use. PMID- 30524611 TI - Endoscopic lumbar discectomy and minimally invasive lumbar interbody fusion: a contrastive review. AB - Both percutaneous endoscopic lumbar discectomy (PELD) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) have been demonstrated as two common and effective choices for lumbar disc herniation (LDH) minimally invasive surgery. In order to get a better understanding of these two procedures, we made this contrastive review. By looking up recent literature and combining it with our clinical practice, the indications/contraindications, advantages/disadvantages as well as complications/recurrences of PELD and MIS TLIF were summarized in this review. It was concluded that PELD and MIS-TLIF are safe and effective minimally invasive operative techniques for symptomatic LDH treatment. A better understanding of these two procedures will help to improve clinical outcomes by selecting proper indications, and also benefit the further development of minimally invasive spine surgery. PMID- 30524612 TI - Early closure of the protective ileostomy after rectal resection should become part of the Enhanced Recovery After Surgery (ERAS) protocol: a randomized, prospective, two-center clinical trial. AB - Introduction: Protective loop ileostomy (PLI) is used to reduce the anastomotic leak rate after resection of the rectum. It is an effective, yet burdensome procedure contradicting the aims of enhanced recovery after surgery (ERAS) by slowing down recovery. Early closure (EC) of the PLI has the potential to change the situation, and it should become part of ERAS. Aim: To analyze the effectiveness of EC in ERAS patients. Material and methods: A randomized clinical trial was performed between October the 1st, 2016 and December the 31st, 2017. Fifty-eight adult patients (24 females, 34 males, mean age: 55.7 and 56.2) operated on for rectal carcinoma according to the ERAS protocol with PLI were randomly assigned to the late (L) or early (E) closure group (14 days after discharge). Time to start adjuvant chemotherapy, complication rate, and health care costs were analyzed. Results: There were no significant differences between groups regarding the length of surgery (83.2 +/-15.9 vs. 87.1 +/-21.7 min, in E and L, respectively), intraoperative blood loss (15.2 +/-7.5 vs. 17.3 +/-11.1 ml, respectively), median hospital stay, or the time to pass flatus and stool. The difference in the time needed to start the adjuvant treatment (38.7 +/-5.7 vs. 33.2 +/-5.8 days, p < 0.01), was compensated by the reduction of time living with a stoma (17.2 vs. 299.0 days) and health care costs: (43.68 vs. 698.42 USD). Conclusions: Early closure is a safe and effective therapeutic approach, improving the recovery. Therefore it should be implemented as part of the ERAS protocol for rectal cancer patients. PMID- 30524613 TI - Learning curve of totally laparoscopic distal gastrectomy for gastric cancer: a single teaching hospital study. AB - Introduction: Totally laparoscopic distal gastrectomy (TLDG) for gastric cancer has gradually gained popularity. However, the learning curve of TLDG is rarely reported. Aim: To determine the learning curve of TLDG for gastric cancer. Material and methods: We retrospectively reviewed and analyzed the medical records of 80 patients with gastric cancer who underwent TLDG with lymph node dissection from January 2016 to December 2017. We divided the patients into four groups based on when they underwent TLDG: group A (cases 1-20), group B (cases 21 40), group C (cases 41-60), and group D (cases 61-80). Comparative analyses of clinical data, including clinicopathologic characteristics, operative data, and postoperative course, were performed for these groups. Results: No significant difference was observed between the groups in various clinicopathologic characteristics. Total operative time for group A (168.3 +/-14.6 min) was significantly longer than for groups B (152.5 +/-10.5 min), C (154.2 +/-11.6 min), and D (155.3 +/-10.8 min), but there was no significant difference between groups B, C, and D. Anastomosis time for group A (27.5 +/-12.4 min) was significantly longer than for groups B (15.3 +/-4.6 min), C (16.6 +/-5.7 min), and D (15.4 +/-4.5 min), but there was no significant difference between groups B, C, and D. Non-anastomosis time, estimated blood loss, retrieved lymph nodes, time to first flatus, time to first oral intake, and postoperative hospital stay and complications showed no difference between the four groups. Conclusions: An experience of approximately 20 cases of TLDG was required to complete the learning curve. PMID- 30524614 TI - Evaluation of endoscopic mucosal resection and endoscopic submucosal dissection in submucosal lesions of the colon and rectum. AB - Introduction: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are commonly used for the minimally invasive treatment of submucosal lesions of the gastrointestinal tract. Aim: To evaluate the safety, efficacy, outcome and recurrence rate of EMR and ESD for mucosal and submucosal lesions in the colon and rectum. Material and methods: Records of 26 patients who underwent ESD and EMR for mucosal and submucosal lesions in the colon and rectum between January 2013 and March 2018 in our endoscopy unit were retrospectively reviewed. Results: A total of 26 patients (6 female and 20 male) were evaluated. The mean age of the patients was 58.03 +/-15.19 (21-80). Fifteen patients underwent ESD and EMR for rectal lesions. Tubular adenomas were found in 3 of these patients, tubulo-villous adenomas in 2, inflammatory polyps in 1, neuroendocrine tumors in 2 and carcinomas in 7 (intramucosal, in-situ and invasive). Eleven patients underwent ESD and EMR for colonic lesions. Villous adenomas were found in 2 of these patients, tubular adenoma showing dysplasia in 2, tubulo-villous adenomas showing dysplasia in 1 and carcinoma (in-situ, invasive and intramucosal) in 6. Two lesions were resected with secondary transanal local excision to obtain free margins. The follow-up period was 3 to 48 months and no recurrence was observed. Conclusions: The EMR and ESD are reliable minimally invasive techniques with a low rate of complications and short hospital stay in the treatment of colon and rectal lesions, including early stage carcinomas of different size and morphology. PMID- 30524615 TI - Laparoscopic splenectomy: posterolateral approach in patients with liver cirrhosis and portal hypertension with platelet count lower than 1 * 109/l. AB - Introduction: Laparoscopic splenectomy for massive splenomegaly secondary to liver cirrhosis and portal hypertension in patients with an extremely low platelet count (< 1 * 109/l) presents several challenges. The posterolateral laparoscopic splenectomy approach may be a feasible and safe technique for these patients. Aim: To evaluate the feasibility and safety of the posterolateral laparoscopic splenectomy approach in patients with platelet counts < 1 * 109/l secondary to liver cirrhosis and portal hypertension. Material and methods: In the period from January 2013 to December 2016, 11 patients with platelet counts < 1 * 109/l secondary to liver cirrhosis and portal hypertension underwent posterolateral laparoscopic splenectomy in our institution. Pre-, peri-, and postoperative medical managements were reviewed retrospectively. Results: Patients' median platelet count was 0.7 * 109/l at the time of inpatient admission. The median operating time was 75 min, and the median intraoperative blood loss was 30 ml. One patient underwent intraoperative transfusion. The median duration of postoperative hospital stay was 5 days. No intra- or postoperative complications ensued, all patients were followed for 12-32 months (median: 24 months), and none had postoperative complications. Conclusions: The posterolateral laparoscopic splenectomy approach is a feasible, safe technique in the treatment of patients with platelet counts < 1 * 109/l secondary to liver cirrhosis and portal hypertension. PMID- 30524616 TI - Quest for the optimal technique of laparoscopic splenectomy - vessels first or hilar transection? AB - Introduction: Throughout our 20 years of experience, we have used several different techniques for laparoscopic splenectomy (LS). However, two methods have been used most frequently: "vessels first" and "hilar transection". Aim: To evaluate the outcomes of LS performed with these two different approaches. Material and methods: It was an observational study based on retrospective analysis of consecutive patients undergoing LS in a tertiary referral surgical center in the period 1998-2017. We excluded patients with splenic trauma, initially submitted to open surgery, stapled transection of splenic hilum, partial resections of the spleen and other spleen-preserving procedures. Patients were divided into two groups: group 1 ("vessels first") with 188 patients, and group 2 ("hilar transection") with 287 patients. Results: Mean operative time was shorter (p < 0.001) and blood loss was lower (p < 0.001) in group 2. The need for blood transfusions and the conversion rate were higher in group 1 (p = 0.044 and p = 0.003 respectively). There was no difference in intraoperative adverse events (p = 0.179). Overall postoperative morbidity did not differ between groups (p = 0.081) and we noted mortality of 0.21% (1 patient of group 2). The morbidity rate associated with accidental injury of the pancreatic parenchyma was significantly higher in group 1 (p = 0.028). Median length of hospital stay was 4 days (range: 1-99) and did not differ between groups (p = 0.175). Conclusions: The "vessels first" technique is associated with longer operative time, higher blood loss and increased risk of conversion. "Hilar transection" is associated with lower incidence of local complications related most likely to accidental injury of the pancreatic tail. In the case of a large caliber of splenic vessels the "vessels first" approach remains the technique of choice. PMID- 30524617 TI - Comparison of slit mesh versus nonslit mesh in laparoscopic extraperitoneal hernia repair. AB - Introduction: Endoscopic hernia repair integrates the advantages of tension-free preperitoneal mesh support of the groin with the advantages of minimally invasive surgery procedures. Aim: To compare outcomes between slit mesh (SM) and nonslit mesh (NSM) placement in laparoscopic totally extraperitoneal (TEP) inguinal hernia repair. Material and methods: This is a retrospective study of 353 patients who underwent TEP inguinal hernia repair between January 2010 and December 2011. One hundred forty-nine and 154 hernias were operated on in the SM and NSM groups, respectively. Postoperative complications, recurrence, early postoperative pain, and chronic pain levels were evaluated. Results: In a total of 303 patients, hernia repair was performed as 395 direct and indirect hernias. Nonslit mesh was converted from TEP to transabdominal preperitoneal patch plasty (TAPP) in 4 patients in the group and 6 patients in the slit mesh group. The average operation time of the SM group was significantly higher than that of the NSM group (p < 0.001). In the evaluation of early postoperative pain, VAS levels of the NSM group were statistically significantly lower than those of the SR group in all evaluations (p = 0.001). The pain rate of the SM group after 3 months of chronic pain was significantly higher than that of the NSM group (p = 0.004). There was no difference in recurrence rate, 6th month chronic pain, wound infection or wound hematoma. Conclusions: The use of SM and NSM in TEP operations is not different in terms of recurrence and complications. However, the use of NSM gives better results in terms of early postoperative pain and chronic pain. PMID- 30524618 TI - Efficacy and reliability of the use of a needle grasper to prevent trocar site hernia. AB - Introduction: Port site herniation is one of the serious complications of laparoscopic surgery, which decreases its benefits. Closure of a fascia defect at the port site is an important problem of laparoscopic surgery, especially in obese patients. Aim: To evaluate needle grasper fascia closure. Material and methods: We closed the port site fascia using a percutaneous organ-holding device (needle grasper) in laparoscopic cholecystectomy patients. This study included 334 patients who underwent laparoscopic cholecystectomy between January 2015 and January 2017 in our hospital. Patients were divided into 2 fascia closure groups: group 1 with a standard simple suturing technique and group 2 with a needle grasper to close the port site. Patient demographics, operative details, and postoperative outcomes were collected and evaluated. Results: There were 243 female and 91 male (total 334) patients with the mean age of 49.18 +/-13.15 years. Only 1 patient in the BMI > 30 kg/m2 group of patients had port site hernia development with the needle grasper technique at the end of the 8-month follow-up period. The port site hernia incidence was higher in group 1 than group 2 (p < 0.001), but there was no significant difference in terms of operation duration between the two groups (p < 0.001, p = 0.709, respectively). In patients with a BMI > 30 kg/m2, both operation duration and port site hernia incidence were higher in simple suture closure than in the needle grasper technique (p < 0.001, p = 0.016, p = 0.005). Conclusions: The needle grasper technique is easy, simple, safe, fast, and effective for fascia closure of port sites. This method can also be applied in obese patients easily, safely and in a short time. PMID- 30524619 TI - Upper extremity surface electromyography signal changes after laparoscopic training. AB - Introduction: Objective measures of laparoscopic skill in training are lacking. Aim: To evaluate the changes in the surface electromyography (sEMG) signal during laparoscopic training, and to link them to intracorporeal knot tying. Material and methods: Ten right-handed medical students (6 female), aged 25 +/-0.98, without training in laparoscopy, were enrolled in the study. With no additional training, they tied intracorporeal single knots for 15 min. Then underwent laparoscopic training and redid the knot tying exercise. During both events, sEMG was recorded from 8 measurement points on the upper extremities and neck bilaterally. We analyzed changes in sEMG resulting from training and tried to find sEMG predictive parameters for higher technical competence defined by the number of knots tied after the training. Results: The average number of knots increased after the training. Significant decreases in activity after the training were visible for the non-dominant hand deltoid and trapezius muscles. Dominant and non-dominant hands had different activation patterns. Differences largely disappeared after the training. All muscles, except for the dominant forearm and non-dominant thenar, produced a negative correlation between their activities and the number of tied knots. The strongest anticorrelation occurred for the non-dominant deltoid (r = -0.863, p < 0.05). Relatively strong relationships were identified in the case of the non-dominant trapezius and forearm muscles (r = -0.587, r = -0.504). Conclusions: At least for some muscle groups there is a change in activation patterns after laparoscopic training. Proximal muscle groups tend to become more relaxed and the distal ones become more active. Changes in the non-dominant hand are more pronounced than in the dominant hand. PMID- 30524620 TI - Class I hysterectomy in stage Ia2-Ib1 cervical cancer. AB - Introduction: During the last 3 decades, the standard treatment for stage Ia2-Ib1 cervical cancer has been Piver-Rutledge class II or III radical hysterectomy. However, this surgery is associated with a high rate of urologic morbidity. Aim: To determine the efficacy of class I radical hysterectomy compared with class III radical hysterectomy in terms of morbidity, overall survival, and patterns of relapse in patients with Ia2-Ib1 cervical cancer undergoing primary surgery. Material and methods: A total of 101 patients with stage Ia2-Ib1 cervical cancer < 2 cm were randomized to class I and class III hysterectomy groups. Clinical, pathologic, and follow-up data were prospectively collected. Univariate analysis was carried out. Of the total patients, 45 were randomized to class I surgery and 56 to class III surgery. No significant differences were observed in terms of pathologic findings or adjuvant treatment (p > 0.05). The morbidity rates were higher after class III surgery. Results: The difference in recurrence rate between the class I and class III groups was not statistically significant (p > 0.05). The 5-year overall survival rate was 93% and 91%, respectively (p > 0.05). There were no significant differences in terms of recurrence rate or overall survival among patients with stage Ia2-Ib1 cervical cancer < 2 cm who underwent class I or radical (class III) hysterectomy. Morbidity was proportional to the extent of radicality. Conclusions: These data confirm the need for reducing surgical radicality in the treatment of patients with early cervical cancer, by tailoring the extent of resection according to the extent of disease. PMID- 30524621 TI - Complications and their treatment after midurethral tape implantation using retropubic and transobturator approaches for treatment of female stress urinary incontinence. AB - Introduction: Midurethral tape implantation procedures currently are the first line treatment for female stress urinary incontinence (SUI). Aim: To estimate the most common intraoperative and postoperative complications and their treatment methods after midurethral tape implantation using retropubic (tension-free vaginal tape - TVT) and transobturator (TOT) approaches for the treatment of female SUI. Material and methods: A retrospective descriptive study was performed on 367 women operated on due to SUI in the period from 2004 to 2015. The SUI diagnosis was confirmed by clinical history and physical examination. According to the surgical technique that was chosen for SUI treatment, all the patients were divided into two groups: the TVT group (n = 112) and the TOT group (n = 255). Results: In total, in 31 (8.45%) of 367 patients complications were observed after midurethral tape implantation. In the TVT group 18 (16.07%) of 112 patients experienced surgery-related complications compared to 13 (5.1%) of 255 patients in the TOT group (p = 0.0005). The most common intraoperative complication in the TVT group was bladder perforation. In the TOT group we had only occasional intraoperative complications. Acute urinary retention was the most common postoperative complication in both groups. It was observed in 13 (11.6%) patients in the TVT group and in 5 (1.96%) patients in the TOT group. Conclusions: The advantage of midurethral tape implantation using the TOT technique is that it is associated with lower incidence of intraoperative and postoperative complications compared to TVT. The most common complication in our series was acute postoperative urinary retention, which usually required an additional tape loosening procedure. PMID- 30524622 TI - Can intervals in extracorporeal shock wave lithotripsy sessions affect success in the treatment of upper ureteral stones? AB - Introduction: Managing upper ureteral stones with shock wave lithotripsy (SWL) has been done for many years. However, no conclusive data have been found on the intervals required between repeated SWL sessions. Aim: To identify the most optimal intervals between SWL sessions. Material and methods: Between September 2015 and December 2016, 80 patients undergoing elective outpatient lithotripsy who required repeated SWL sessions for ureteral stones were evaluated. These patients were categorised into two groups according to different SWL session intervals. The intervals between SWL sessions (n = 40) for the first group lasted one day, whereas those for the second group (n = 40) lasted 1 week. The data recorded during SWL included visual analogue scale (VAS) scores, total number of shocks, total energy used and number of sessions. The stone clearance rates, number of urinary tract infections, complication rates and VAS scores were compared between the two groups. Results: All patients' clinical outcomes after SWL therapy are shown in Table I. The stone clearance rate for group 1 was 70%, whereas that for group 2 was 72.5% (p = 0.805). Additionally, the number of urinary tract infections, complications and VAS scores were similar for both groups. In group 1, 3 patients had steinstrasse, two suffered from severe renal colic, and one had a urinary tract infection. In group 2, 3 patients endured steinstrasse, and 2 patients experienced severe renal colic during the study. Conclusions: Short-interval SWL sessions are safe and effective for treating upper ureteral stones, and such sessions do not increase complication rates. PMID- 30524623 TI - W-type suture in Anderson-Hynes laparoscopic pyeloplasty: a novel approach to an old technique. AB - Introduction: Anderson-Hynes (A-H) dismembered pyeloplasty has remained nearly unchanged since its introduction in 1949. The authors present a modification of the uretero-pelvic anastomosis as described by Anderson and Hynes. The new approach, called the W-type suture, is thought to be more watertight and associated with fewer complications than the original. Aim: To assess the effectiveness of the modification of Anderson-Hynes dismembered pyeloplasty named the W-type suture. Material and methods: The research is a retrospective study of 99 patients who underwent laparoscopic A-H pyeloplasty. In 49 patients unmodified laparoscopic A-H pyeloplasty was carried out. Fifty patients underwent laparoscopic A-H pyeloplasty with the anastomosis made using the aforementioned W type suture. To assess the effectiveness of the W-type suture, we compared urine leakage duration - a direct indicator of anastomosis tightness - and frequency of postoperative complications. Results: The mean duration of urinary leakage was 3 +/-1.16 days for the W-type suture anastomosis group and 3.57 +/-1.14 days for the unmodified A-H pyeloplasty group (p < 0.05). The frequency of post-operative complications did not statistically significantly differ between the groups except for fever (18.4% vs. 4%; p < 0.05). Conclusions: The analysis of the collected data showed that the W-type suture might be a promising alternative to a traditional approach of performing the ureteropelvic anastomosis. Further research should be done to minimize biases present in this study, which might have influenced our results. PMID- 30524624 TI - Three-dimensional digitizing and anatomic study of lumbar vertebral canal and pedicle in children. AB - Introduction: Spinal pedicle screw internal fixation has been widely used in adult spine injury fixation. Due to being in a period of continuous growth and development, the spine of children at different ages shows different characteristics from adults in terms of anatomy, physiological function, and biomechanics. Furthermore, because the pedicle of children is small, has large anatomic variation, and has complex adjacent relationships, the surgical risk is extremely high. How to improve the screwing accuracy is the key to the success of children's pedicle internal fixation. Therefore, applying the concept of digitized and individualized screwing will be of great significance to children's pedicle screwing. Aim: To investigate the morphologies, development patterns, and aging characteristics of the lumbar vertebral pedicle (LVP) in children aged 6-11 years, and to provide a theoretical basis for screw implantation and related biomechanical studies. Material and methods: A total of 60 children aged 6-11 years were selected for the intergroup measurement and statistical analysis of their lumbar diameter, pedicle diameter, screw canal length (SCL), etc. Results: Generally, the vertebral foramen diameter (ID), sagittal diameter (SD), pedicle width (PW), and SCL as well as the pedicle height (PH) exhibited an increasing trend with age and increasing vertebral sequence among children aged 6-11 years. Conclusions: By observing the LVP in children using 3D digital reconstruction technology, the morphology of the spinal canal and pedicles at different lumbar segments showed obvious development patterns, and the best treatment protocol should be selected according to the LVP characteristics in clinical applications. PMID- 30524625 TI - Minimally invasive transforaminal lumbar interbody fusion for dual-segment lower lumbar degenerative disease. AB - Introduction: Transforaminal lumbar interbody fusion (TLIF) has been widely used to treat degenerative lumbar diseases. The PIPELINE Access minimally invasive system allows reduction of the trauma to the patient during TLIF. Aim: To present our preliminary experience with the minimally invasive TLIF (mTLIF) technique performed on the first 7 patients with dual-segment lower lumbar degenerative disease (DS-LLDD). Material and methods: A retrospective analysis was performed on the first 7 patients with spondylolisthesis and foraminal stenosis operated upon between January 2011 and June 2013. All 7 patients underwent fusion at the L4-S1 level. Results: The pedicle screws entered the spinal canal in 2 patients. No other intraoperative or postoperative complications occurred with the mTLIF technique. Improvement of the leading symptom in the early postoperative period (sciatica: 7/7, low back pain: 7/7) was achieved in all patients. The mean improvements in the visual analog scale scores for low back and leg pain were 5.1 and 5.7 points, respectively. The mean Oswestry Disability Index scores were 52% (range: 20-74%) before surgery and 27% (range: 10-48%) at the 3-month follow-up (mean improvement: 25%). The average hospital stay was reduced to 6 days. Conclusions: Our initial experience suggests that the mTLIF technique is a viable method for treating DS-LLDD. Nevertheless, longer observations on larger groups of patients are needed to reliably evaluate the safety of the method and sustainability of the results. PMID- 30524626 TI - Modified endoscopic inferior meatal fenestration with mucosal flap for maxillary sinus diseases. AB - Introduction: This is a novel minimally invasive surgical method for maxillary sinus mucoceles and antrochoanal polyps. Aim: To describe a modified technique of inferior meatal fenestration with a mucosal flap for maxillary sinus diseases and to present a case series of subjects who underwent this procedure. The novel surgical technique and indications for this approach are also discussed. Material and methods: The authors analyzed data from 32 cases involving patients who underwent resection of maxillary sinus mucoceles and antrochoanal polyps via modified endoscopic inferior meatal fenestration with a mucosal flap in the period from January, 2011 to January, 2016. The group included 19 men and 13 women, and the patients' mean age was 36.2 years (range: 11-56 years). Preoperative and postoperative imaging studies were available in all cases and were reviewed. Results: Thirty-two cases are included in this study. The appearance of nasal and (or) maxillary sinus mucosa was observed in the follow-up at 1 month, 3 months and 6 months using endoscopes. Postoperative computed tomography was performed for only 9 patients in this study. The mean follow-up period was 56 (range: 10-82) months in these cases. All patients had an uneventful post-operative period. Postoperative symptoms were relieved gradually for 1 to 2 weeks after the operation. No patients experienced recurrent symptoms related to the mucocele. Mucocele and polyps recurrence was not observed. No patient showed re-stenosis and obstruction of the nasal cavity, facial pain or numbness during follow-up. Conclusions: Maxillary sinus mucoceles and antrochoanal polyps are completely excised via modified endoscopic inferior meatal fenestration with a mucosal flap. It could keep the nasal lateral wall intact. PMID- 30524627 TI - Safe laparoscopic surgery in median arcuate ligament syndrome. AB - The median arcuate ligament syndrome is a rare clinical condition with no standardized method of laparoscopic treatment. Exposure of the aorto-celiac axis might be considered as the most challenging part of the surgical procedure. It is important to secure total release while enabling adequate vision as the compressing musculofibrous ligament is located in the deepest part of the aorto celiac hiatus. A 29-year-old male patient presenting with recurrent abdominal pain and diagnosed with the median arcuate ligament syndrome underwent laparoscopic surgery. The patient was discharged without problems on the fourth day after the surgery. In this case report we present a maneuver that enables easy and safe exposure of the celiac trunk. PMID- 30524628 TI - Laparoscopic repair of a perforated duodenal ulcer: another use of a round ligament flap. AB - Management of a perforated duodenal ulcer is most commonly performed by laparoscopy and consists of suture of the perforation after performing lavage of the peritoneal cavity. In most cases, a flap is created, and an omental flap is usually the preferred choice because of its simplicity and its proximity to the site of duodenal perforation. However, in some cases, the greater omentum cannot be used due to the severity of peritonitis or due to previous surgical removal. We report a laparoscopic technique for surgical repair of a perforated duodenal ulcer using a round ligament flap. The present manuscript and the associated video highlight some important technical aspects to easily perform this procedure. PMID- 30524629 TI - Thoracoscopic removal of ectopic mediastinal parathyroid adenoma causing hyperparathyroidism: a rare entity. AB - Ectopic mediastinal parathyroid adenomas are uncommon. Here, we report the successful thoracoscopic removal of a mediastinal parathyroid adenoma from a patient with hypercalcemia. A 58-year-old female patient was referred to our department with persistent hypercalcemia. Serum calcium and phosphorus levels were 13.2 mg/dl and 2.5 mg/dl respectively, while the intact parathormone level was 798.9 pg/ml. Parathyroid computed tomography revealed a solid and well defined mass at the anterior mediastinum close to the distal aorta. Once the contrast was enhanced, our pre-diagnosis was ectopic parathyroid adenoma. The mass was detected at the anterior mediastinum, dissected free from the surrounding tissue and excised. The capsulated mass, which had a diameter of 3 * 1.5 * 0.7 cm, was confirmed as parathyroid adenoma histopathologically. Postoperative calcium and parathormone levels decreased dramatically to normal levels. Anterior mediastinal localization of an ectopic parathyroid adenoma is a rare entity. The transsternal approach is the most preferred method, but video thoracoscopy can be used safely and effectively. PMID- 30524630 TI - A case of nasopharyngeal angiofibroma removed using a minimally invasive endoscopic endonasal technique. AB - Nasopharyngeal angiofibroma is a rare head and neck tumor characterized by hypervascularity. With the development of various surgical devices and hemostatic agents, endoscopic endonasal surgery for nasopharyngeal angiofibroma, which is characterized by significant intraoperative bleeding, has become possible. We describe our experiences performing an effective endoscopic endonasal removal of a nasopharyngeal angiofibroma without embolization, using advanced devices and hemostatic agents. A 21-year-old male patient presented with massive epistaxis. The characteristic findings of angiofibroma were confirmed by computed tomography scan and nasal endoscopy. Navigation-guided endoscopic endonasal surgery was performed, and complementary devices and products were used to effectively remove the mass. Development of navigation, endoscopes, tissue handling devices, and hemostatic agents has enabled effective endoscopic endonasal removal of nasopharyngeal angiofibroma without embolization. PMID- 30524631 TI - Striving to Make Massage Therapy Accessible to Older Adults: an Interview with Niki Munk, PhD, LMT. AB - First she became a licensed massage therapist in Kentucky. Then, in a quest to improve the care she provided to her elderly clinical population, Niki Munk continued her journey by furthering her education and receiving her doctorate in gerontology. Dr. Munk, a massage therapy researcher at Indiana University's IUPUI campus, shares in this interview her optimism on the future of the massage therapy profession and massage therapy research. Dr. Munk also provides insight into the way she makes decisions, and from whom she would like to receive advice. PMID- 30524632 TI - A Survey of Licensed Massage Therapists' Perceptions of Skin Cancer Prevention and Detection Activities. AB - Background: Skin cancer is the most common cancer in the US. Training massage therapists (MTs) in skin cancer prevention and detection creates opportunity for reducing skin cancer burden. Little is known about MTs' perceptions of skin cancer prevention and detection, their discussions of these topics with clients, or their referral recommendations for suspicious skin lesions. Purpose: We surveyed MTs' perceptions of their role in engaging in conversations about skin cancer prevention, viewing the skin for suspicious lesions, and referring clients with such lesions to health care providers. Setting Participants Research Design: We administered an online survey from 2015-2017 of licensed MTs practicing in the US and at least age 21 years (n = 102); quantitative and qualitative data were analyzed in 2017. Main Outcome Measures: The main variables assessed were MTs perceptions of (a) appropriateness for asking clients about skin cancer history, skin cancer prevention, suspicious lesion referral and follow-up; and (b) comfort with recognizing and discussing suspicious lesions, recommending a client see a doctor for suspicious lesion, and discussing skin cancer prevention. Results: Quantitative data revealed that most MTs were amenable to discussing skin cancer prevention during appointments; few were engaging in these conversations. MTs were more comfortable discussing suspicious lesions and recommending that a client see a doctor than they were sharing knowledge about skin cancer and sun safety. Categories based on qualitative content analysis were: sharing information for the client's benefit, and concerns about remaining within scope of practice. Conclusions: MTs have boundaries for skin cancer risk-reduction content to include in a client discussion and remain in their scope of practice. These findings will help support a future educational intervention for MTs to learn about and incorporate skin cancer risk-reduction messages and activities into their practice. PMID- 30524633 TI - Effects of Massage as a Combination Therapy with Lumbopelvic Stability Exercises as Compared to Standard Massage Therapy in Low Back Pain: a Randomized Cross-Over Study. AB - Background: Little is known about the effects of providing massage as a combination therapy (CT) with lumbopelvic stability training (LPST) in management of chronic nonspecific low back pain (CLBP) among elite female weight lifters. It is unclear whether massage therapy (MT) together with LPST has any additional clinical benefits for individuals with CLBP. Purpose: The current study compares the therapeutic effects of CT against MT as a stand-alone intervention on pain intensity (PI), pain pressure threshold (PPT), tissue blood flow (TBF), and lumbopelvic stability (LPS) among elite weight lifters with CLBP. Setting: The study was conducted at the campus for National Olympic weight lifting training camp. Participants: A total of 16 professional female elite weight lifting athletes who were training for Olympic weight lifting competition participated in the study. Research Design: A within-subject, repeated measures, crossover, single-blinded, randomized allocation study. Intervention: The athletes were randomized into three sessions of CT and MT with a time interval of 24 hrs within sessions and a wash out period of four weeks between the sessions. Main Outcome Measures: The PI, PPT, TBF, and LPS were measured before and after each session repeatedly in both groups of intervention. The changes in the PI, PPT, TBF, and LPS were analyzed using repeated measures analysis of variance (ANOVA). Results: The results showed that the CT significantly demonstrated greater effects in reducing pain perception (45%-51%), improving pain pressure threshold (15% up to 25%), and increasing tissue blood flow (131%-152%) than MT (p < .001). Conclusion: The combination therapy of massage therapy and LPST is likely to provide more clinical benefits in terms of PI, PPT, and TBF when compared to massage as a stand-alone therapy among individuals with chronic nonspecific low back pain. PMID- 30524634 TI - Improving Body Mechanics Using Experiential Learning and Ergonomic Tools in Massage Therapy Education. AB - Introduction: Current industry data suggest that the rise in occupational injuries for massage therapists is contributing to a significant number leaving the profession after a few short years. While many massage therapists are taught methods for proper body mechanics and self-care within their career educational programs, there are few consistencies in the theoretical approaches to these concepts, even though it is a required component in massage therapy career training. Purpose: This study demonstrates a measurable and effective teaching method using a combination of experiential and transformative learning theory models and authentic ergonomics measurement tools to teach effective body mechanics in entry level career training that may be sustainable for new massage therapists entering the field. Methods: Four cohorts of students (N = 17) enrolled in a kinesiology course for massage therapists were studied using a mixed-methods time series experimental design. A pre- and post-test was conducted by utilizing two industry standard ergonomics risk factor assessment tools as measurable data for score comparison, to denote improvements in each student's risk factor tendencies and provide evidentiary support of learning transfer. Between the pre- and post-test, students participated in a series of experiential learning exercises within class sessions during the semester and completed two reflection journals discussing their experiences. Results: The results showed that there was a statistically significant reduction in ergonomics risk factor scores for all students studied. Conclusion: The success of this study demonstrates that the instructional design using experiential and transformative educational theory and general ergonomics concepts is an effective approach to teaching proper body mechanics to massage therapy students which can be adopted into universally accepted curriculum on many levels and could eventually contribute to reduction of occupational injury in the future. PMID- 30524635 TI - Commentary on Operationalizing Partnership Between a Traditional Research Institution and a Massage School. PMID- 30524636 TI - Inflammatory Breast Cancer: A Literature Review. AB - The multidisciplinary management of inflammatory breast cancer (IBC), which is the most aggressive form of breast cancer due to its rapid proliferation, has changed over the past three decades thanks to advances in medical treatments that represent the basis of treatment, without eliminating the use of locoregional treatments including surgery and radiotherapy in the localized stages. The molecular profile determination of IBC allows the orientation towards new targeted therapeutic strategies with an impact on survival. PMID- 30524637 TI - Serum Carcinoembryonic Antigen Level Predicts Cancer-Specific Outcomes of Resected Non-Small Cell Lung Cancer With Interstitial Pneumonia. AB - Background: It has been well accepted that the prognosis of non-small cell lung cancer (NSCLC) patients with interstitial pneumonia (IP) is significantly poor. However, there are only a few studies that indicated the prognostic factors, especially tumor markers, among NSCLC patients with IP. Methods: Forty-one NSCLC patients with IP who underwent surgery at our institution were included. Patients died of other diseases including postoperative acute exacerbation (AE) of IP were excluded. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. Results: The 5-year cancer-specific survival of overall and stage I patients were 37.4% and 39.2%, respectively. The 5-year cancer-specific survival of patients with high serum carcinoembryonic antigen (CEA) level was 9.4%, while that with normal serum CEA level was 55.6%. However, serum cytokeratin-19 fragment (CYFRA 21-1) and squamous cell carcinoma related antigen (SCC) levels were not associated with patients' survival. Furthermore, serum CEA level was significantly associated with poorer cancer specific survival in univariate and multivariate analyses. Conclusions: This study demonstrated that serum CEA level might serve as an efficient prognostic indicator after surgery in NSCLC with IP. PMID- 30524638 TI - Surgical Treatment of Trichilemmal Carcinoma. AB - Background: To investigate the clinicopathologic characteristics and prognostic factors of trichilemmal carcinoma (TC), and to determine an optimal treatment strategy for these patients. Methods: This retrospective study enrolled consecutive patients who were admitted to the Sun Yat-sen University Cancer Center between 1998 and 2012. Results: The key prognostic factors influencing the survival were lymph nodes metastasis and surgery margin. Multivariate analysis revealed that there was no risk factor for patient survival. Conclusions: Surgery margin and lymph nodes metastasis were prognostic factors that influenced the treatment outcome. Simple excision with 1 cm margins is safe, inexpensive and effective for the treatment of TC; and postoperative follow-up of the patient to facilitate early diagnosis of the recurrence and distant metastasis is necessary. Systemic chemotherapy should be considered for the distance metastases patients. PMID- 30524640 TI - EGFR Mutation Detection and Its Association With Clinicopathological Characters of Lung Cancer Patients. AB - Background: Lung cancer is the most common type of cancer worldwide with an estimation of 1.82 million new cancer cases diagnosed; and it is the leading cause of cancer-related deaths. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase identified as being highly expressed in cancer cells including lung cancers. The aim of the study is to determine the EGFR mutation status in non-small cell lung cancer (NSCLC) patients to investigate the association between the EGFR mutation status and clinicopathological characters of patients. Methods: The tissue samples of the lung cancer patients were collected bronchoscopically. The EGFR mutations of 70 NSCLC patients were determined by the immunohistochemistry (IHC). Results: EGFR mutations were present in 24 cases (34.29%), including 19 (79.13%) cases of exon 19 and five (20.83%) cases of exon 21 mutation. EGFR mutations were frequently associated with adenocarcinoma and non-smoker. Statistically significant association of EGFR mutations with adenocarcinoma subtypes and non-smokers was found (P < 0.05); and no significant association of EGFR mutation with the age of the patient (P = 0.4647) and the stage (P = 0.4578) of the tumor was found. When we compared between these two mutations, no significant association with age (P=0.614) and smoking status (P=0.127) was found in this study. Conclusions: EGFR mutations were significantly associated with female sex, non-smoker and adenocarcinoma subtypes. The analysis of EGFR mutation by the IHC method is a potentially useful tool to guide clinicians for personalized treatment of NSCLC patients of adenocarcinoma subtype. PMID- 30524639 TI - Role of Diffusion-Weighted Magnetic Resonance Imaging (DWMRI) in Assessment of Primary Penile Tumor Characteristics and Its Correlations With Inguinal Lymph Node Metastasis: A Prospective Study. AB - Background: Penile cancer is a rare malignancy. The extent of lymph node (LN) metastasis is the most important prognostic factor in penile cancer. However, preoperative prediction of LN involvement in clinically non-palpable LN is still a challenge. In absence of a reliable biomarker, attempts are being made to validate imaging characteristics as a predictive tool. The aim of the present study is to assess the primary penile tumor characteristics with diffusion weighted magnetic resonance imaging (DWMRI) and its correlations with inguinal LN status and tumor positivity in LN dissection specimen within normal sized LNs. Methods: Twenty-six patients with carcinoma penis underwent DWMRI of penis and pelvis. The apparent diffusion coefficient (ADC) values of primary tumor were compared with histological characteristics. Inclusion criteria encompassed all cases of clinically non-palpable inguinal LN and normal sized LN on imaging. All palpable inguinal nodes with pelvic lymphadenopathies were excluded from this study. Results: The primary tumor ADC ranged from 0.65 * 10-3 - 1.2 * 10-3 mm2/s (mean: 0.87 * 10-3 +/- 0.11 * 10-3 mm2/s). In pT1 and pT3 tumors, mean ADC values were 0.86 * 10-3 +/- 0.10 * 10-3 and 0.81 * 103 +/- 0.09 * 103 mm2/s, respectively. The mean ADC values for grade 1, grade 2 and grade 3 were 0.89 * 10 3, 0.82 * 10-3 and 0.80 * 10-3 mm2/s, respectively. The ADC value of < 0.95 * 10 3 mm2/s was positively correlated with pathological LN presence within normal sized LN. With mean ADC value of 0.87 * 10-3 +/- 0.11 * 10-3 mm2/s, sensitivity and positive predictive values for primary penile cancer were 100% and 84.61%, respectively. The mean ADC value for higher-grade and -stage tumor was low. The sensitivity and specificity of predicting LN metastasis by DWMRI were 87.22% and 80.90%, respectively. Conclusion: ADC value of primary tumor can help in prediction of LN metastasis in carcinoma penis with clinically and radiologically normal groin. PMID- 30524641 TI - Flexible Freestanding Carbon Nanofiber-Embedded TiO2 Nanoparticles as Anode Material for Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs), owning to the low cost, abundant resources, and similar physicochemical properties with lithium-ion batteries (LIBs), have earned much attention for large-scale energy storage systems. In this article, we successfully synthesize flexible freestanding carbon nanofiber-embedded TiO2 nanoparticles (CNF-TiO2) and then apply it directly as anode in SIBs without binder or current collector. Taking the advantage of flexible CNF and high structural stability, this anode exhibits high reversible capacity of 614 mAh.g-1 (0.27 mAh.cm-2) after almost 400 cycles and excellent capacity retention ability of ~100. PMID- 30524642 TI - AFM Characterization of the Internal Mammary Artery as a Novel Target for Arterial Stiffening. AB - Using the atomic force microscopy- (AFM-) PeakForce quantitative nanomechanical mapping (QNM) technique, we have previously shown that the adventitia of the human internal mammary artery (IMA), tested under dehydrated conditions, is altered in patients with a high degree of arterial stiffening. In this study, we explored the nanoscale elastic modulus of the tunica media of the IMA in hydrated and dehydrated conditions from the patients with low and high arterial stiffening, as assessed in vivo by carotid-femoral pulse wave velocity (PWV). In both hydrated and dehydrated conditions, the medial layer was significantly stiffer in the high PWV group. The elastic modulus of the hydrated and dehydrated tunica media was significantly correlated with PWV. In the hydrated condition, the expression activity of certain small leucine-rich repeat proteoglycans (SLRPs), which are associated with arterial stiffening, were found to be negatively correlated to the medial elastic modulus. We also compared the data with our previous work on the IMA adventitia. We found that the hydrated media and dehydrated adventitia are both suitable for reflecting the development of arterial stiffening and SLRP expression. This comprehensive study of the nanomechanical properties integrated with the proteomic analysis in the IMAs demonstrates the possibility of linking structural properties and function in small biological samples with novel AFM methods. The IMA is a suitable target for predicting arterial stiffening. PMID- 30524643 TI - Morphological Modification and Analysis of ZnO Nanorods and Their Optical Properties and Polarization. AB - We report on the effect of the morphological modification on optical properties and polarization of ZnO nanorods (NR). Here, the morphology and structure of the ZnO NR were modified by introducing different annealing temperatures. The increase of length and diameter and change in density of the ZnO NR were clearly observed by increasing the annealing temperature. We found that the samples show different oxygen vacancy (VO) and zinc interstitial (ZnI) concentrations. We suggest that the different concentrations of VO and ZnI are originated from morphological and structural modification. Our results reveal that optical absorption and polarization of ZnO NR could be enhanced by producing a high concentration of VO and ZnI. The modification of VO and ZnI promotes a decrease in the band gap and coexistence of high optical absorption and polarization in our ZnO NR. Our findings would give a broad insight into the morphological modification and characterization technique on ZnO NR. The high optical and polarization characteristics of ZnO NR are potential for developing the high performance nanogenerator device for multitype energy harvesting. PMID- 30524644 TI - Impact of a digital health intervention on asthma resource utilization. AB - Digital health interventions have been associated with reduced rescue inhaler use and improved controller medication adherence. This quality improvement project assessed the benefit of these interventions on asthma-related healthcare utilizations, including hospitalizations, emergency department (ED) utilization and outpatient visits. The intervention consisted of electronic medication monitors (EMMs) that tracked rescue and controller inhaler medication use, and a digital health platform that presented medication use information and asthma control status to patients and providers. In 224 study patients, the number of asthma-related ED visits and combined ED and hospitalization events 365 days pre- to 365 days post-enrollment to the intervention significantly decreased from 11.6 to 5.4 visits (p < 0.05) and 13.4 to 5.8 events (p < 0.05) per 100 patient-years, respectively. This digital health intervention was successfully incorporated into routine clinical practice and was associated with lower rates of asthma-related hospitalizations and ED visits. PMID- 30524645 TI - Intake of a fermented plant product attenuates allergic symptoms without changing systemic immune responses in a mouse model of Japanese cedar pollinosis. AB - Background: Japanese cedar pollinosis (JCP) is one of the most prevalent allergies in Japan. Within the past few decades, many food factors have been demonstrated to suppress symptoms of pollinosis and mast cell degranulation directly or indirectly. Herein, we conducted a study to clarify the anti-allergic potency of a fermented plant product (FPP) in JCP model mice. Methods: Mice were administered FPP, 10-fold-diluted FPP, or saline every day for 40 days by oral gavage and sensitized with major Japanese cedar pollen allergens (SBP). The numbers of sneezes were counted for 5 minutes after SBP nasal challenge. We analyzed the SBP-specific immunoglobulin titers, serum concentration of mast cell protease 1, and cytokine production from splenocytes stimulated with SBP. Results: The numbers of sneezes by the mice administered FPP were significantly suppressed compared to those administered saline. The 10-fold-diluted FPP also suppressed the number of sneezes compared to saline, although not significantly. Serum level of mast cell protease 1 tended to be suppressed in FPP-consumed mice compared to those in saline-treated mice. The SBP-specific immunoglobulin titers and cytokine production were comparable among the groups. Conclusions: Our results suggest that FPP intake could attenuate JCP symptoms without change of systemic immune responses. PMID- 30524646 TI - Allergen-specific IgE and IgG4 patterns among patients with different allergic diseases. AB - Background: In addition to allergen-specific IgE (sIgE), allergen-specific IgG4 (sIgG4) antibodies are also involved in the immune response resulting from an allergen exposure. The aim of our study was to analyze sIgE and sIgG4 patterns in the most common allergic disorders: bronchial asthma, upper airway disorders and atopic dermatitis. Methods: In this study a screening analysis of blood serum samples from 673 patients aged from 6 months to 17 years with different allergic entities was performed on microarrays. sIgE and sIgG4 levels to the most common allergens were estimated. Results: sIgE response to most pollen allergens is more strongly associated with respiratory diseases than with atopic dermatitis, while sIgE responses to cat and dog dander are more strongly associated with bronchial asthma than with atopic dermatitis and upper airway disorders such as rhinosinusitis and allergic rhinitis. A lower prevalence of sIgG4 to pollen allergens in cases of atopic dermatitis is observed compared with that in cases of asthma and upper airway disorders. Analyzing all the allergic disorders, one can see that sIgG4 response to inhalant allergens is strongly associated with sensitization to the corresponding allergen. Conclusion: Allergen-specific IgE and IgG4 patterns that are relevant to concrete allergic diseases differ by sIgE and sIgG4 prevalences to defined allergens. PMID- 30524647 TI - Omalizumab in the treatment of eosinophilic granulomatosis with polyangiitis (EGPA): single-center experience in 18 cases. AB - Background: Data are limited regarding the effectiveness of omalizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). Our aim was to evaluate the clinical and functional effectiveness of omalizumab in patients with EGPA in long-term follow-up. Methods: This study was a retrospective chart review of patients with EGPA who were treated with omalizumab injections between May 2012 and April 2018. Once treatment with omalizumab was started, data were collected at various time points: baseline, the 16th week, 1st year, and annually until the last evaluation. Results: Eighteen patients (16F/2M) with a mean age of 48.61 +/- 11.94 years were included. Data were available for all patients for the first year, 12 patients for the second year, 10 patients for the third year, 8 patients for the fourth year and 5 patients for the fifth year. All patients were on mean dosage of 15.77 +/- 7.6 mg/day oral corticosteroid (OCS) as daily bases for mean 8.61 +/- 4 years besides high-dose inhaler corticosteroid/long acting beta agonist. Antineutrophil cytoplasmic antibodies (ANCA) were positive in 2 patients, and 8 patients were diagnosed as having vasculitis by skin biopsy, one patient had polyneuropathy, and one patient had cardiac involvement.By considering the individual responses of patients and the level of improvement at the last evalulation, 10 (55.6%) patients responded completely, 1 responded partially, and 7 (38.9%) had no improvement. Omalizumab worked as a steroid-sparing agent in all patients and the daily OCS dose was reduced with a mean dosage of 6.28 mg/day at the end of the first year. The mean OCS reduction time for the whole group was 4 months. A reduction in asthma exacerbations/hospitalizations, improvement in forced expiratory volume in 1 second, and no decrease in the eosinophil count during treatment with omalizumab were also observed. Conclusions: Omalizumab improved asthma control in some patients with EGPA with uncontrolled asthma by reducing asthma exacerbations and oral steroid requirement. However, more data are needed before recommending widespread use of omalizumab in patients with EGPA. PMID- 30524649 TI - Beneficial Effects Exerted by Paeonol in the Management of Atherosclerosis. AB - Atherosclerosis, a chronic luminal stenosis disorder occurred in large and medium arteries, is the principle pathological basis of cardiovascular diseases with the highest morbidity and mortality worldwide. In oriental countries, traditional Chinese medicine Cortex Moutan has been widely used for the treatment of atherosclerosis-related illnesses for thousands of years. Paeonol, a bioactive monomer extracted from Cortex Moutan, is an important pharmacological component responsible for the antiatherosclerotic effects. Numerous lines of findings have established that paeonol offers beneficial roles against the initiation and progression of atherosclerotic lesions through inhibiting proatherogenic processes, such as endothelium damage, chronic inflammation, disturbance of lipid metabolism, uncontrolled oxidative stress, excessive growth, and mobilization of vascular smooth muscle cells as well as abnormality of platelet activation. Investigations identifying the atheroprotective effects of paeonol present substantial evidence for potential clinical application of paeonol as a therapeutic agent in atherosclerosis management. In this review, we summarize the antiatherosclerotic actions by which paeonol suppresses atherogenesis and provide newly insights into its atheroprotective mechanisms and the future clinical practice. PMID- 30524648 TI - Simultaneous Assessment of Cardiac Inflammation and Extracellular Matrix Remodeling after Myocardial Infarction. AB - Background: Optimal healing of the myocardium following myocardial infarction (MI) requires a suitable degree of inflammation and its timely resolution, together with a well-orchestrated deposition and degradation of extracellular matrix (ECM) proteins. Methods and Results: MI and SHAM-operated animals were imaged at 3,7,14 and 21 days with 3T magnetic resonance imaging (MRI) using a 19F/1H surface coil. Mice were injected with 19F-perfluorocarbon (PFC) nanoparticles to study inflammatory cell recruitment, and with a gadolinium-based elastin-binding contrast agent (Gd-ESMA) to evaluate elastin content. 19F MRI signal co-localized with infarction areas, as confirmed by late-gadolinium enhancement, and was highest 7days post-MI, correlating with macrophage content (MAC-3 immunohistochemistry) (rho=0.89,P<0.0001). 19F quantification with in vivo (MRI) and ex vivo nuclear magnetic resonance (NMR) spectroscopy correlated linearly (rho=0.58,P=0.020). T1 mapping after Gd-ESMA injection showed increased relaxation rate (R1) in the infarcted regions and was significantly higher at 21days compared with 7days post-MI (R1[s-1]:21days=2.8 [IQR,2.69-3.30] vs 7days=2.3 [IQR,2.12-2.5], P<0.05), which agreed with an increased tropoelastin content (rho=0.89, P<0.0001). The predictive value of each contrast agent for beneficial remodeling was evaluated in a longitudinal proof-of-principle study. Neither R1 nor 19F at day 7 were significant predictors for beneficial remodeling (P=0.68;P=0.062). However, the combination of both measurements (R1<2.34Hz and 0.55<=19F<=1.85) resulted in an odds ratio of 30.0 (CI95%:1.41-638.15;P=0.029) for favorable post-MI remodeling. Conclusions: Multinuclear 1H/19F MRI allows the simultaneous assessment of inflammation and elastin remodeling in a murine MI model. The interplay of these biological processes affects cardiac outcome and may have potential for improved diagnosis and personalized treatment. PMID- 30524650 TI - Distribution of Paraoxonase-1 (PON-1) and Lipoprotein Phospholipase A2 (Lp-PLA2) across Lipoprotein Subclasses in Subjects with Type 2 Diabetes. AB - Paraoxonase-1 (PON1) and lipoprotein phospholipase A2 (Lp-PLA2) may exert an important protective role by preventing the oxidative transformation of high- and low-density lipoproteins (HDL and LDL, respectively). The activity of both enzymes is influenced by lipidome and proteome of the lipoprotein carriers. T2DM typically presents significant changes in the molecular composition of the lipoprotein subclasses. Thus, it becomes relevant to understand the interaction of PON1 and Lp-PLA2 with the subspecies of HDL, LDL, and other lipoproteins in T2DM. Serum levels of PON1-arylesterase and PON1-lactonase and Lp-PLA2 activities and lipoprotein subclasses were measured in 202 nondiabetic subjects (controls) and 92 T2DM outpatients. Arylesterase, but not lactonase or Lp-PLA2 activities, was inversely associated with TD2M after adjusting for potential confounding factors such as age, sex, smoking, body mass index, hypertension, and lipoprotein subclasses (odds ratio = 3.389, 95% confidence interval 1.069-14.756). Marked difference between controls and T2DM subjects emerged from the analyses of the associations of the three enzyme activities and lipoprotein subclasses. Arylesterase was independently related with large HDL-C and small intermediate density lipoprotein cholesterol (IDL-C) in controls while, along with lactonase, it was related with small low-density lipoprotein cholesterol LDL-C, all IDL-C subspecies, and very low-density lipoprotein cholesterol (VLDL-C) in T2DM (p < 0.05 for all). Concerning Lp-PLA2, there were significant relationships with small LDL-C, large IDL-C, and VLDL-C only among T2DM subjects. Our study showed that T2DM subjects have lower levels of PON1-arylesterase compared to controls and that T2DM occurrence may coincide with a shift of PON1 and Lp-PLA2 towards the more proatherogenic lipoprotein subclasses. The possibility of a link between the two observed phenomena requires further investigations. PMID- 30524651 TI - Parenteral Succinate Reduces Systemic ROS Production in Septic Rats, but It Does Not Reduce Creatinine Levels. AB - In sepsis, reactive oxygen species (ROS) production is increased. This process takes place mainly within the electron transport chain. ROS production is part of the pathophysiology of multiple organ failure in sepsis. Succinate yields Dihydroflavine-Adenine Dinucleotide (FADH2), which enters the chain through complex II, avoiding complex I, through which electrons are lost. The aim of this work is to determine if parenteral succinate reduces systemic ROS production and improves kidney function. Rats with cecal ligation and puncture were used as model of sepsis, and 4 groups were made: Control group; Succinate group, which only received parenteral succinate; Sepsis group; and Sepsis which received parenteral succinate. Systemic ROS are measured 24 hours after the procedure. Rats subjected to cecal puncture treated with succinate had less systemic ROS than Septic untreated rats (p = 0.007), while there were no differences in creatinine levels (p = 0.07). There was no correlation between creatinine and systemic ROS levels (p = 0.3). We concluded that parenteral succinate reduces ROS levels, but it does not reduce creatinine levels. Since there is no correlation between both levels, the processes would not be related. PMID- 30524652 TI - Metallothionein-I + II Reduces Oxidative Damage and Apoptosis after Traumatic Spinal Cord Injury in Rats. AB - After spinal cord injury (SCI), some self-destructive mechanisms start leading to irreversible neurological deficits. It is known that oxidative stress and apoptosis play a major role in increasing damage after SCI. Metallothioneins I and II (MT) are endogenous peptides with known antioxidant, neuroprotective capacities. Taking advantage of those capacities, we administered exogenous MT to rats after SCI in order to evaluate the protective effects of MT on the production of reactive oxygen species (ROS) and lipid peroxidation (LP), as markers of oxidative stress. The activities of caspases-9 and -3 and the number of annexin V and TUNEL-positive cells in the spinal cord tissue were also measured as markers of apoptosis. Rats were subjected to either sham surgery or SCI and received vehicle or two doses of MT (10 MUg per rat) at 2 and 8 h after surgical procedure. The results showed a significant increase in levels of MT protein by effect of SCI and SCI plus treatment at 12 h, while at 24 h an increase of MT was observed only in the injury plus treatment group (p < 0.05). ROS production was decreased by effect of MT in lesioned tissue; likewise, we observed diminished LP levels by MT effect both in the sham group and in the group with SCI. Also, the results showed an increase in the activity of caspase-9 due to SCI, without changes by effect of MT, as compared to the sham group. Caspase-3 activity was increased by SCI, and again, MT treatment reduced this effect only at 24 h after injury. Finally, the results of the number of cells positive to annexin V and TUNEL showed a reduction due to MT treatment both at 24 and 72 h after the injury. With the findings of this work, we conclude that exogenously administered MT has antioxidant and antiapoptotic effects after SCI. PMID- 30524653 TI - Biological Effects of Tetrahydroxystilbene Glucoside: An Active Component of a Rhizome Extracted from Polygonum multiflorum. AB - Polygonum multiflorum Thunb. (PM), a traditional Chinese medicinal herb, has been widely used in the Orient as a tonic and antiaging agent. 2,3,5,4' Tetrahydroxystilbene-2-O-beta-D-glucoside (TSG, C20H22O9, FW = 406.38928) is one of the active components extracted from PM. TSG is an antioxidant agent, which exhibits remarkable antioxidative activities in vivo and in vitro. The antioxidant effect of TSG is achieved by its radical-scavenging effects. TSG can inhibit apoptosis and protect neuronal cells against injury through multifunctional cytoprotective pathways. TSG performs prophylactic and therapeutic activities against Alzheimer's disease, Parkinson's disease, and cerebral ischemia/reperfusion injury. It is also antiatherosclerotic and anti inflammatory. However, the mechanisms underlying these pharmacological activities are unclear. This study aimed at reviewing experimental studies and describing the effectiveness and possible mechanisms of TSG. PMID- 30524654 TI - Oxidative Stress, Maternal Diabetes, and Autism Spectrum Disorders. AB - Autism spectrum disorders (ASD) are a group of early-onset neurodevelopmental conditions characterized by alterations in brain connectivity with cascading effects on neuropsychological functions. To date, in the framework of an increasing interest about environmental conditions which could interact with genetic factors in ASD pathogenesis, many authors have stressed that changes in the intrauterine environment at different stages of pregnancy, such as those linked to maternal metabolic pathologies, may lead to long-term conditions in the newborn. In particular, a growing number of epidemiological studies have highlighted the role of obesity and maternal diabetes as a risk factor for developing both somatic and psychiatric disorders in humans, including ASD. While literature still fails in identifying specific etiopathological mechanisms, a growing body of evidence is available about the presence of a relationship between maternal immune dysregulation, inflammation, oxidative stress, and the development of ASD in the offspring. In this framework, results from high-fat diet animal models about the role played by oxidative stress in shaping offspring neurodevelopment may help in clarifying the pathways through which maternal metabolic conditions are linked with ASD. The aim of this review is to provide an overview of literature about the effects of early life insults linked to oxidative stress which may be involved in ASD etiopathogenesis and how this relationship can be explained in biological terms. PMID- 30524655 TI - The Potential Roles of Extracellular Vesicles in Cigarette Smoke-Associated Diseases. AB - Cigarette smoke contains more than 4,500 chemicals; most of which are highly reactive free radicals, which induce proinflammatory and carcinogenic reactions. Numerous efforts have focused extensively on the role of cigarette smoking as a cause of many diseases. Extracellular vesicles and exosomes have recently received increasing interest for their diagnostic and therapeutic roles in many diseases. However, research done on the role of extracellular vesicles and exosomes on cigarette smoke-induced chronic disease is still in its infancy. In this review, we summarize the recently addressed roles of extracellular vesicles and exosomes in the pathogenesis of cigarette smoke-related diseases, such as chronic obstructive pulmonary disease, cardiovascular disease, lung cancer, and oral cancer. Moreover, their potential utilization and future prospects as diagnostic biomarkers for cigarette smoke-related diseases are described. PMID- 30524656 TI - Protective Effects of Lycium barbarum Extracts on UVB-Induced Damage in Human Retinal Pigment Epithelial Cells Accompanied by Attenuating ROS and DNA Damage. AB - The medicinal herb Lycium barbarum fruit has been widely used for improving and maintaining the health of the eyes in the Far East for many centuries. This study is aimed at investigating whether protective effects generated from the aqueous (LBA) and ethanol (LBE) extracts of the L. barbarum fruit existed against oxidative stress-induced apoptosis in human retinal pigment epithelial cells. L. barbarum extracts LBA and LBE exerted the activity of ROS scavenging and rescued UVB irradiation-induced growth inhibition in retinal pigment epithelial ARPE-19 cells. Compared to LBA, the ethanol extract LBE exerted a superior protective activity on UVB-induced growth arrest in ARPE-19 cells. Both L. barbarum extracts significantly reduced cell cycle G2-arrest population in ARPE-19 cells. Furthermore, the cytometer-based Annexin V/propidium iodide staining assay further showed that both L. barbarum extracts protected ARPE-19 cells from UVB induced apoptosis. L. barbarum extracts also reduced the activation of gammaH2AX, a sensor of DNA damage in ARPE-19 cells in a dose-responsive manner. By using Ingenuity Pathway Analysis (IPA), the bioinformatics revealed that the protective effects of both LBA and LBE extracts might be involved in three signaling pathways, especially the Toll-like receptor (TLR) pathway associated with cellular proliferation. Our study suggests that both ethanol and aqueous extracts of L. barbarum exhibit antioxidant activity and rescue UVB-induced apoptosis of ARPE-19 cells. Collectively, the ethanol extract exerts a superior effect on rescuing UVB-induced growth arrest of ARPE-19 compared to the aqueous extract, which might be associated with the activation of TLR signaling. Our present work will benefit the preventive strategy of herbal medicine-based vision protection for treating eye diseases such as age-related macular degeneration in the future. PMID- 30524657 TI - Anti-Inflammatory and Antioxidant Properties of Black Mulberry (Morus nigra L.) in a Model of LPS-Induced Sepsis. AB - Sepsis is a complex disease and is the cause of many deaths worldwide. Sepsis pathogenesis involves a dysregulated inflammatory response with consequent production of inflammatory mediators and reactive species. The production and excessive release of these substances into the systemic circulation trigger various cellular and metabolic alterations that are observed during the disease evolution. Thus, more studies have been carried out to investigate the therapeutic potential of plants such as Morus nigra L., popularly known as black mulberry. Studies have shown that plants belonging to the Morus genus are rich in secondary metabolites such as flavonoids which are associated with important biological activities as antioxidant and anti-inflammatory actions. Based on this context, the objective of our study was to evaluate the anti-inflammatory and antioxidant properties of Morus nigra L. in a sepsis model induced by LPS. Male C57BL/6 mice were distributed in four groups: control, sepsis, sepsis treated with leaf extract of mulberry, and sepsis treated with mulberry pulp. The animals were treated with 100 MUL of their respective treatments for twenty-one days. Sepsis was induced at the 21st day with lipopolysaccharide (LPS) by intraperitoneal injection. The animals were euthanized 24 hours after receiving the LPS injection. The data obtained were analyzed in GraphPad Prism 6.0 software. Our results showed that treatment with either extract significantly decreased the number of leukocytes in the bronchoalveolar lavage fluid and serum levels of TNF in septic animals. Regarding the redox status, the treatments significantly decreased the antioxidant activity of the enzyme glutathione peroxidase. Regarding metalloproteinase type 2, it was observed that the treatment with black mulberry pulp was able to significantly reduce the activity of this enzyme concerning the sepsis group. Finally, these results together promoted an increase in the animal's survival that received the black mulberry leaf or pulp extract. PMID- 30524658 TI - Particulate Air Pollution, Blood Mitochondrial DNA Copy Number, and Telomere Length in Mothers in the First Trimester of Pregnancy: Effects on Fetal Growth. AB - Growing evidences have shown that particulate matter (PM) exposures during pregnancy are associated with impaired fetal development and adverse birth outcomes, possibly as a result of an exaggerated systemic oxidative stress and inflammation. Telomere length (TL) is strongly linked to biological age and is impacted by oxidative stress. We hypothesized that PM exposure during different time windows in the first trimester of pregnancy influences both mitochondrial DNA copy number (mtDNAcn), an established biomarker for oxidative stress, and TL. Maternal blood TL and mtDNAcn were analysed in 199 healthy pregnant women recruited at the 11th week of pregnancy by quantitative polymerase chain reaction. We also examined whether maternal mtDNAcn and TL were associated with fetal growth outcomes measured at the end of the first trimester of pregnancy (fetal heart rate, FHR; crown-rump length, CRL; and nuchal translucency, NT) and at delivery (birth weight, length, head circumference). The possible modifying effect of prepregnancy maternal body mass index was evaluated. PM10 exposure during the first pregnancy trimester was associated with an increased maternal mtDNAcn and a reduced TL. As regards ultrasound fetal outcomes, both FHR and CRL were positively associated with PM2.5, whereas the association with FHR was confirmed only when examining PM10 exposure. PM10 was also associated with a reduced birth weight. While no association was found between mtDNAcn and CRL, we found a negative relationship between mtDNAcn and fetal CRL only in overweight women, whereas normal-weight women exhibited a positive, albeit nonsignificant, association. As abnormalities of growth in utero have been associated with postnatal childhood and adulthood onset diseases and as PM is a widespread pollutant relevant to the large majority of the human population and obesity a rising risk factor, our results, if confirmed in a larger population, might represent an important contribution towards the development of more targeted public health strategies. PMID- 30524659 TI - A Novel Small Peptide Inhibitor of NFkappaB, RH10, Blocks Oxidative Stress Dependent Phenotypes in Cancer. AB - Background: The RH domain of GRK5 is an effective modulator of cancer growth through the inhibition of NFkappaB activity. The aim of this study was to identify the minimum effective sequence of RH that is still able to inhibit tumor growth and could be used as a peptide-based drug for therapy. Methods: Starting from the RH sequence, small peptides were cloned and tested in KAT-4 cells. The effects on NFkappaB signaling and its dependent phenotypes were evaluated by Western blot, TUNEL assay, proliferation assay, and angiogenesis in vitro. In vivo experiments were performed in KAT-4 xenografts in Balb/c nude mice. Results: A minimum RH ten amino acids long sequence (RH10) was able to interact with IkappaB, to increase IkappaB levels, to induce apoptosis, to inhibit KAT4-cell proliferation, NFkappaB activation, ROS production, and angiogenesis in vitro. In vivo, the peptide inhibited tumor growth in a dose-dependent manner. We also tested its effects in combination with chemotherapeutic drugs and radiotherapy. RH10 ameliorated the antitumor responses to cisplatin, doxorubicin, and ionizing radiation. Conclusion: Our data propose RH10 as a potential peptide-based drug to use for cancer treatment both alone or in combination with anticancer therapies. PMID- 30524660 TI - Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities. AB - Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches. PMID- 30524661 TI - The Possible Pathophysiological Outcomes and Mechanisms of Tourniquet-Induced Ischemia-Reperfusion Injury during Total Knee Arthroplasty. AB - Ischemia and reperfusion (I/R) injury induced by tourniquet (TQ) application leads to the release of both oxygen free radicals and inflammatory cytokines. The skeletal muscle I/R may contribute to local skeletal muscle and remote organ damage affecting outcomes after total knee arthroplasty (TKA). The aim of the study is to summarize the current findings associated with I/R injury following TKA using a thigh TQ, which include cellular alterations and protective therapeutic interventions. The PubMed database was searched using the keywords "ischemia reperfusion injury," "oxidative stress," "tourniquet," and "knee arthroplasty." The search was limited to research articles published in the English language. Twenty-eight clinical studies were included in this qualitative review. Skeletal muscle I/R reduces protein synthesis, increases protein degradation, and upregulates genes in cell stress pathways. The I/R of the lower extremity elevates local and systemic oxidative stress as well as inflammatory reactions and impairs renal function. Propofol reduces oxidative injury in this I/R model. Ischemic preconditioning (IPC) and vitamin C may prevent oxygen free radical production. However, a high dose of N-acetylcysteine possibly induces kidney injury. In summary, TQ-related I/R during TKA leads to muscle protein metabolism alteration, endothelial dysfunction, oxidative stress, inflammatory response, and renal function disturbance. Propofol, IPC, and vitamin C show protective effects on oxidative and inflammatory markers. However, a relationship between biochemical parameters and postoperative clinical outcomes has not been validated. PMID- 30524662 TI - Corrigendum to "Toxic Effects of Trazodone on Male Reproductive System via Disrupting Hypothalamic-Pituitary-Testicular Axis and Inducing Testicular Oxidative Stress". AB - [This corrects the article DOI: 10.1155/2018/7196142.]. PMID- 30524663 TI - Pharmaceutical Induction of PGC-1alpha Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage. AB - Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1alpha transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1alpha and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC 1alpha-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1alpha and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies. PMID- 30524665 TI - An adaptive dose-finding design based on both safety and immunologic responses in cancer clinical trials. AB - Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety and efficacy information. The 1st stage establishes the safety profile of each dose, with escalation decisions based on likelihood principles. Continuous immunologic outcomes are used to evaluate the relative efficacy of the doses. The 2nd stage employs an adaptive randomization to assign patients to doses showing higher efficacy. Safety is being continuously monitored throughout stage 2, where some doses may be 'closed' due to unacceptable toxicity. The proposed design is compared to the modified toxicity probability interval (mTPI) design using percent dose allocation and estimation of outcomes under different scenarios. We show that by using an efficacy-driven adaptive randomization with safety constraints, the allocation distribution is skewed towards more efficacious doses, and thus limit the number of patients exposed to toxic or non-therapeutic doses. PMID- 30524664 TI - 5-Aminolevulinic Acid-Based Photodynamic Therapy Pretreatment Mitigates Ultraviolet A-Induced Oxidative Photodamage. AB - Aim: To determine whether 5-aminolevulinic acid-based photodynamic therapy (ALA PDT) is effective in combating ultraviolet A- (UVA-) induced oxidative photodamage of hairless mice skin in vivo and human epidermal keratinocytes in vitro. Methods: In in vitro experiments, the human keratinocyte cell line (HaCaT cells) was divided into two groups: the experimental group was treated with ALA PDT and the control group was left untreated. Then, the experimental group and the control group of cells were exposed to 10 J/m2 of UVA radiation. ROS, O2 - species, and MMP were determined by fluorescence microscopy; p53, OGG1, and XPC were determined by Western blot analysis; apoptosis was determined by flow cytometry; and 8-oxo-dG was determined by immunofluorescence. Moreover, HaCaT cells were also treated with ALA-PDT. Then, SOD1 and SOD2 were examined by Western blot analysis. In in vivo experiments, the dorsal skin of hairless mice was treated with ALA-PDT or saline-PDT, and then, they were exposed to 20 J/m2 UVA light. The compound 8-oxo-dG was detected by immunofluorescence. Conclusion: In human epidermal keratinocytes and hairless mice skin, UVA-induced oxidative damage can be prevented effectively with ALA-PDT pretreatment. PMID- 30524666 TI - A New Application of Unsupervised Learning to Nighttime Sea Fog Detection. AB - This paper presents a nighttime sea fog detection algorithm incorporating unsupervised learning technique. The algorithm is based on data sets that combine brightness temperatures from the 3.7 MUm and 10.8 MUm channels of the meteorological imager (MI) onboard the Communication, Ocean and Meteorological Satellite (COMS), with sea surface temperature from the Operational Sea Surface Temperature and Sea Ice Analysis (OSTIA). Previous algorithms generally employed threshold values including the brightness temperature difference between the near infrared and infrared. The threshold values were previously determined from climatological analysis or model simulation. Although this method using predetermined thresholds is very simple and effective in detecting low cloud, it has difficulty in distinguishing fog from stratus because they share similar characteristics of particle size and altitude. In order to improve this, the unsupervised learning approach, which allows a more effective interpretation from the insufficient information, has been utilized. The unsupervised learning method employed in this paper is the expectation-maximization (EM) algorithm that is widely used in incomplete data problems. It identifies distinguishing features of the data by organizing and optimizing the data. This allows for the application of optimal threshold values for fog detection by considering the characteristics of a specific domain. The algorithm has been evaluated using the Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP) vertical profile products, which showed promising results within a local domain with probability of detection (POD) of 0.753 and critical success index (CSI) of 0.477, respectively. PMID- 30524667 TI - Identification of Differentially Expressed Profiles of Alzheimer's Disease Associated Circular RNAs in a Panax Notoginseng Saponins-Treated Alzheimer's Disease Mouse Model. AB - Circular RNAs (circRNAs) play vital roles in AD pathogenesis. Thus, developing therapeutic candidates targeting circRNA may provide a novel therapeutic strategy for AD treatment. Our previous studies showed that Panax notoginseng saponins (PNS) could significantly prohibit the pathological progress of AD. However, the mechanisms by which PNS attenuates AD progression is still unclear. The present study shows that PNS may exhibit an ability to modulate the expression of AD associated circRNAs. Specifically, PNS treatment leads to five circRNAs upregulation and two circRNAs downregulation, indicating that the therapeutic effect of PNS against AD may be associated with its role in the regulation of circRNA expression. Next, mmu_circRNA_013636 and mmu_circRNA_012180 were selected and GO and KEGG analyses were performed to further investigate the biological functions and potential mechanisms of these circRNAs. The results showed that the selected circRNAs were involved in AD-associated biological process and pathways, suggesting that these circRNAs may participate in AD pathogenesis. Collectively, our study indicates that the therapeutic effects of PNS on AD may be through modulating the expression of AD associated circRNAs and suggests that PNS is a potential circRNA-targeted agent against AD, which may provide useful resources for developing potential candidates targeting circRNAs against AD. PMID- 30524668 TI - Role of growth factors and oxygen to limit hypertrophy and impact of high magnetic nanoparticles dose during stem cell chondrogenesis. AB - Due to an unmet clinical need of curative treatments for osteoarthritic patients, tissue engineering strategies that propose the development of cartilage tissue replacements from stem cells have emerged. Some of these strategies are based on the internalization of magnetic nanoparticles into stem cells to then initiate the chondrogenesis via magnetic compaction. A major difficulty is to drive the chondrogenic differentiation of the cells such as they produce an extracellular matrix free of hypertrophic collagen. An additional difficulty has to be overcome when nanoparticles are used, knowing that a high dose of nanoparticles can limit the chondrogenesis. We here propose a gene-based analysis of the effects of chemical factors (growth factors, hypoxia) on the chondrogenic differentiation of human mesenchymal stem cells both with and without nanoparticles. We focus on the synthesis of two of the most important constituents present in the cartilaginous extracellular matrix (Collagen II and Aggrecan) and on the expression of collagen X, the signature of hypertrophic cartilage, in order to provide a quantitative index of the type of cartilage produced (i.e. hyaline, hypertrophic). We demonstrate that by applying specific environmental conditions, gene expression can be directed toward the production of hyaline cartilage, with limited hypertrophy. Besides, a combination of the growth factors IGF-1, TGF-beta3, with a hypoxic conditioning remarkably reduced the impact of high nanoparticles concentration. PMID- 30524669 TI - Poly-sarcosine and Poly(Ethylene-Glycol) Interactions with Proteins Investigated Using Molecular Dynamics Simulations. AB - Nanoparticles coated with hydrophilic polymers often show a reduction in unspecific interactions with the biological environment, which improves their biocompatibility. The molecular determinants of this reduction are not very well understood yet, and their knowledge may help improving nanoparticle design. Here we address, using molecular dynamics simulations, the interactions of human serum albumin, the most abundant serum protein, with two promising hydrophilic polymers used for the coating of therapeutic nanoparticles, poly(ethylene-glycol) and poly sarcosine. By simulating the protein immersed in a polymer-water mixture, we show that the two polymers have a very similar affinity for the protein surface, both in terms of the amount of polymer adsorbed and also in terms of the type of amino acids mainly involved in the interactions. We further analyze the kinetics of adsorption and how it affects the polymer conformations. Minor differences between the polymers are observed in the thickness of the adsorption layer, that are related to the different degree of flexibility of the two molecules. In comparison poly-alanine, an isomer of poly-sarcosine known to self-aggregate and induce protein aggregation, shows a significantly larger affinity for the protein surface than PEG and PSar, which we show to be related not to a different patterns of interactions with the protein surface, but to the different way the polymer interacts with water. PMID- 30524670 TI - Medicinal plants for gingivitis: a review of clinical trials. AB - Objectives: Periodontal diseases are among prevalent oral health problems which may ultimately lead to severe complications in oral cavity. Herbal products can be designed as single or multicomponent preparations for better oral health. This study aims to review current clinical trials on the effectiveness of herbal products in gingivitis. Materials and Methods: Electronic databases, including PubMed, Scopus, ScienceDirect and Cochrane library were searched with the keywords "gingivitis" in the title/abstract and "plant/ extract/ herb" in the whole text for clinical trials on herbal treatments for gingivitis. Data were collected from 2000 until January 2018. Only papers with English full-texts were included in our study. Results: Herbal medicines in the form of dentifrice, mouth rinse, gel, and gum were assessed in gingivitis via specific indices including plaque index, bleeding index, microbial count, and biomarkers of inflammation. Pomegranate, aloe, green tea, and miswak have a large body of evidence supporting their effectiveness in gingivitis. They could act via several mechanisms such as decrease in gingival inflammation and bleeding, inhibition of dental plaque formation, and improvement in different indices of oral hygiene. Some polyherbal formulations such as triphala were also significantly effective in managing gingivitis complications. Conclusion: Our study supports the efficacy and safety of several medicinal plants for gingivitis; however, some plants do not have enough evidence due to the few number of clinical trials. Thus, future studies are mandatory for further confirmation of the efficacy of these medicinal plants. PMID- 30524671 TI - Kalirin-7 plays a neuroprotective role in Neuro-2A cells injured by oxygen glucose deprivation and reperfusion through Rac1 activation. AB - Objectives: The study explored the neuroprotective role of Kalirin-7 (Kal-7) in Neuro-2A cells after oxygen-glucose deprivation and reperfusion (OGD/R) treatment. Materials and Methods: The study used an OGD/R model of mouse Neuro-2A neuroblastoma cells in vitro. Cells were transfected with pCAGGS-Kal-7 to up regulating kal-7. Then cell proliferation and apoptosis were respectively analyzed by Trypan blue exclusion method and flow cytometry. To examine the involvement of Rac1, cells were treated with Rac1-GTP inhibitor NSC23766 before treatment with OGD/R. Expressions of Bax, Bcl-2, Rac1, and down-stream targets of Rac1 were analyzed by Western blot. Results: Kal-7 significantly decreased OGD/R induced cell apoptosis (P<0.01), but no significant effects were observed on cell proliferation. Kal-7 increased the expressions of apoptosis-related protein of Bcl-2 and Rac1, but decreased the expression of Bax in Neuro-2A cells stimulated to OGD/R. Rac1 was activated by Kal-7 due to the increased levels of its down stream targets, p-p38 and p-PAK1. NSC23766 reduced the anti-apoptotic effect of Kal-7 as the enhanced apoptotic cell rate and increased Bax/Bcl-2 ratio. Conclusion: These findings suggest that the protective effects of Kal-7 against OGD/R injury in Neuro-2A cells were dependent in a Rac1 activation signaling. PMID- 30524672 TI - Sulfur dioxide reduces hippocampal cell death and improves learning and memory deficits in a rat model of transient global ischemia/reperfusion. AB - Objectives: According to recent the findings, sulfur dioxide (SO2) is produced by the cardiovascular system, influencing some major biological processes. Based on previous research, SO2 exhibits antioxidant effects and inhibits apoptosis following cardiac ischemia/reperfusion. Therefore, the objective of the current study was to examine the neuroprotective impact of SO2 following global cerebral ischemia/reperfusion (I/R). Materials and Methods: Forty-eight male Wistar rats that weighed 260-300 g, were randomly allocated into 4 groups: sham group (n=12), I/R group (n=12), and I/R+SO2 groups (NaHSO3 and Na2SO3; 1:3 ratio; 5 and 10 ug/kg, respectively; for 3 days, n=12). Cerebral ischemia model was prepared by occlusion of both common carotid arteries for 20 min. Saline as a vehicle and SO2 donor at doses 5 ug/kg (intraperitoneally) were injected for 3 days after reperfusion. Four days after ischemia, the passive avoidance memory test was carried out in four groups, and after behavioral assessment, necrosis, apoptosis, and antioxidant enzyme analysis were carried out. Results: O2 treatment could significantly improve memory impairments in rats with cerebral ischemia/reperfusion (I/R) (P<0.05). An increase in both superoxide dismutase and glutathione and a reduction in malondialdehyde were reported in the SO2 group versus the ischemic group (P<0.05). Moreover, SO2 could significantly decrease necrotic and apoptotic cells in the CA1 region (P<0.01). Conclusion: According to the findings, SO2 exerts significant neuroprotective effects on cerebral I/R due to its antioxidant activity. PMID- 30524673 TI - Bone marrow-derived mesenchymal stem cell and simvastatin treatment leads to improved functional recovery and modified c-Fos expression levels in the brain following ischemic stroke. AB - Objectives: The beneficial outcomes of bone marrow-derived mesenchymal stem cell (BMSC) treatment on functional recovery following stroke has been well established. Furthermore, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors have also been shown to increase neuronal survival and promote the movement of BMSCs towards the sites of inflammation. However, the precise mechanisms mediating the improved neurological functional recovery in stoke models following a combination treatment of Simvastatin and BMSCs still remained poorly understood. Materials and Methods: Here, an embolic stroke model was used to experimentally induce a focal ischemic brain injury by inserting a preformed clot into the middle cerebral artery (MCA). Following stroke, animals were treated either with an intraperitoneal injection of Simvastatin, an intravenous injection of 3 *106 BMSCs, or a combination of these two treatments. Results: Seven days after ischemia, the combination of Simvastatin and BMSCs led to a significant increase in BMSC relocation, endogenous neurogenesis, arteriogenesis and astrocyte activation while also reducing neuronal damage when compared to BMSC treatment alone (P<0.001 for all). In addition, based on western blot analysis, following stroke there was a significant decrease in c-Fos expression (P<0.001) in the combination treatment group. Conclusion: These results further demonstrate the synergistic benefits of a combination treatment and help to improve our understanding of the underlying mechanisms mediating this beneficial effect. PMID- 30524674 TI - Adiponectin alleviates blood hypercoagulability via inhibiting endothelial cell apoptosis induced by oxidative stress in septic rats. AB - Objectives: The purpose of this study was to detect the protective effects of adiponectin on coagulation dysfunction and its mechanism in sepsis of rats. Materials and Methods: The experimental samples were composed of sham group, model group that was underwent cecal ligation and puncture (CLP) and three adiponectin treatment groups that treated by adiponectin with different dose (72 MUg/kg, 96 MUg/kg and 120 MUg/kg) after CLP. The prothrombin time (PT), activated partial thromboplastin time (APTT) was measured, respectively, the level of malondialdehyde (MDA), tissue factor (TF), activated coagulation factor VIIa and Xa, p-selectin were detected, the histology structure of vascular was observed, the expressions of Caspase 9, Caspase 3, Bax, Bcl-2 and vWF in vascular were measured. Results: The results demonstrated that adiponectin treatment lengthened PT and APTT, reduced the expression of MDA, TF, activated coagulation factor VIIa, Xa and p-selectin in plasma of septic rats. Additionally, adiponectin treatment alleviated endothelial cell apoptosis and oxidative stress, down regulated the levels of Caspase 3, Caspase 9, Bax, Bcl-2 and vWF in vascular. Conclusion: These findings suggest that adiponectin treatment might be a promising therapeutic strategy for relieving septic endothelial cell injury and coagulation dysfunction via inhibiting endothelial cell apoptosis in septic rats. PMID- 30524675 TI - Effect of dehydroepiandrosterone on meiotic spindle structure and oocyte quality in mice. AB - Objectives: Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances in women with diminished ovarian reserve (DOR) and to reduce miscarriage rates by 50-80%. This study, therefore, assesses effects of DHEA on number of retrieved oocytes and meiotic spindles. Materials and Methods: A randomized, prospective, controlled study was conducted on eight groups, four groups of young mice and four elderly. All young and old groups received different oral doses (35, 50, 75 mg/kg) of DHEA for 3 months. Meiotic spindle assessment was done by immunocytochemical techniques using a confocal laser microscope (Leica TCS-4D). Results: Statistical surveys showed that in control young groups 80% (P=0.0845) and in the old control group 73.3% (P=0.000) of the meiotic spindles have a normal shape and structure; the difference was meaningful. The young with 50 mg/kg of DHEA in 85.4% and the young with 75 mg/kg of DHEA in 84.2% were normal in shape and structure. Statistical analysis showed that the difference was meaningless (P=0.845). The old group with 30 mg/kg of DHEA in 81.1%, the old with 50 mg/kg of DHEA in 83.9%, and the old with 75 mg/kg of DHEA in 79.0% showed normal shape and structure. The meiotic spindle disruption ratio in old mice showed a significant difference (P=0.000) in comparison with others in young groups. Statistical analysis showed that difference between DHEA and control groups is meaningful. But this difference was meaningless between DHEA groups. Conclusion: Results showed that DHEA has a positive and improvement effect on the meiotic spindle in old mice. PMID- 30524676 TI - Differential change in cortical and hippocampal monoamines, and behavioral patterns in streptozotocin-induced type 1 diabetic rats. AB - Objectives: Diabetes mellitus (DM) is a widespread metabolic disorder worldwide. Clinical physicians have found diabetic patients have mild to middle cognitive dysfunction and an alteration of brain monoaminergic function. This study explored the change in various patterns of behavioral models and brain monoamine function under streptozotocin (STZ)-induced type 1 diabetes. Materials and Methods: We established a type 1 DM model via intravenous injection with STZ (65 mg/kg) in rats. Three weeks after the STZ injection, various behavioral measurements including the inhibitory avoidance test, active avoidance test and Morris water maze were conducted. Finally, all rats were dissected and the concentrations of monoamines and their metabolites in cortex and hippocampus were measured by high performance liquid chromatography with electrochemical detection. Results: We found that STZ induced type 1 diabetes (hyperglycemia and lack of insulin) in rats. STZ-induced diabetic rats had cognitive impairment in acquisition sessions and long-term retention of the active avoidance test. STZ induced diabetic rats also had cognitive impairment in spatial learning, reference and working memory of the Morris water maze. STZ significantly reduced concentrations of norepinephrine (NE) in the cortex and dopamine (DA) in the hippocampus, but increased concentrations of DA and serotonin (5-HT) in the cortex 35 days after injection. The concentration of 5-HT in the hippocampus was also significantly increased. Conclusion: The data suggested that this cognitive impairment after a short-term period of STZ injection might be related to cortical NE dysfunction, differential alteration of cortical and hippocampal DA function, and brain 5-HT hyperfunction. PMID- 30524677 TI - Effects of insulin-loaded chitosan-alginate nanoparticles on RAGE expression and oxidative stress status in the kidney tissue of rats with type 1 diabetes. AB - Objectives: Chronic hyperglycemia leads to activation of the advanced glycation end products (AGE)-receptor (RAGE) for AGE axis and oxidative stress, which promote diabetic renal damage. This study examines the effect of insulin-loaded trimethyl chitosan nanoparticles on the kidney tissue of diabetic rats. Materials and Methods: Twenty-five male Wistar rats were randomly divided into 5 groups: normal control (C), diabetic group without treatment (DM), diabetic group treated with chitosan-based nanoparticle (DM+NP, 1 ml by gavage), diabetic group treated with 8 IU/kg insulin-loaded trimethyl chitosan nanoparticles (DM+N.in, 1 ml by gavage), and diabetic group treated with 8 IU/kg trade insulin (DM+SC.in, 0.2 ml by subcutaneous injection). The animals were treated from weeks 8 to 10. At the end of the study, serum urea, creatinine, and uric acid were measured. Also, the level of AGE and RAGE mRNA expression, and oxidative stress markers were studied in the kidney tissue. Results: Insulin-loaded nanoparticles similar to trade insulin could significantly reduce urea, creatinine, and uric acid parameters, while the elevated total antioxidant capacity (TAC), thiol groups, and catalase activity also reduced total oxidant status (TOS) and malondialdehyde (MDA) levels (P<0.05). However, the reduction in AGE and RAGE mRNA expression is not statistically significant in both treatments. Of course, the influence of insulin loaded trimethyl chitosan nanoparticles on the amelioration of all these parameters is higher compared to that of the injected form. No markedly significant differences were observed between these two kinds of treatments. Conclusion: This data reveals that insulin-loaded trimethyl chitosan nanoparticle is a better therapeutic approach than injected insulin. PMID- 30524678 TI - Evaluation of antibiotic activity of methicillin in healing of full-thickness infected wounds with sensitized methicillin resistant Staphylococcus aureus in the presence of HAMLET. AB - Objectives: The novel healing choices for handling of infections due to multidrug resistant Staphylococcus aureus are reguired. HAMLET has been reported to be able to sensitize bacterial pathogens to traditional antimicrobial agents. The aim was to assess wound healing activity of methicillin in presence of HAMLET in methicillin resistant S. aureus (MRSA) infected wounds. Materials and Methods: Fifty male rats were randomized into five groups of ten animals each. In CONTROL group, 0.1 ml sterile saline 0.9% solution was added to the wounds with no infection. In MRSA group, the wounds were infected with MRSA and only treated with 0.1 ml the sterile saline (0.9%) solution. In MRSA/HAMLET group, infected wounds were cured with HAMLET (100 ug). In group MRSA/ Met, animals with infected wounds were cured with 0.1 ml local use of 1 mg/ml methicillin. In MRSA/Met/HAMLET group, animals with infected wounds were cured with local use of 0.1 ml solution of methicillin (1 mg/ml) and HAMLET (100 ug). All test formulations were used for ten consecutive days, twice a day, beginning from first treatment. Results: Microbiological examination, planimetric, histological and quantitative morphometric studies, immunohistochemical staining for angiogenesis, determination of hydroxyproline levels and RT-PCR for Caspase 3, Bcl-2 and p53 showed that there was significant difference between animals in MRSA/Met/ HAMLET group compared to other groups (P<0.05). Conclusion: HAMLET could make methicillin beneficial for handling of MRSA infected wounds and had the prospective effect to consider this harmless agent for local application. PMID- 30524679 TI - Pioglitazone alleviates oxygen and glucose deprivation-induced injury by up regulation of miR-454 in H9c2 cells. AB - Objectives: Pioglitazone, an anti-diabetic agent, has been widely used to treat type II diabetes. However, the effect of pioglitazone on myocardial ischemia reperfusion injury (MIRI) is still unclear. Herein, the objective of this study is to learn about the regulation and mechanism of pioglitazone effects on oxygen glucose deprivation (OGD)-induced myocardial cell injury. Materials and Methods: A cellular injury model of OGD-treated H9c2 cells in vitro was constructed to simulate ischemic/reperfusion (I/R) injury. Then, various concentrations of pioglitazone (0, 2.5, 5, 7.5 and 10 MUM) were used for the treatment of H9c2 cells, and CCK-8, flow cytometry and western blot assays were performed to examine cell viability, apoptosis, and the protein levels of factors involved in cell cycle and apoptosis in OGD-treated cells. MiR-454 inhibitor was used to suppress miR-454 expression, and whether miR-454 was involved in regulating OGD induced cell injury was studied. Two key signal pathways were examined to uncover the underlying mechanism. Results: OGD reduced cell proliferation and induced apoptosis in H9c2 cells (P<0.05, P<0.01 or P< 0.001). OGD-induced injury was significantly attenuated by pioglitazone at the concentration of 5 MUM. Additionally, pioglitazone significantly up-regulated miR-454 expression in OGD injured cells (P< 0.05 or P< 0.01). MiR-454 suppression declined the protective effect of pioglitazone on OGD-injured H9c2 cells (P<0.05 or P< 0.01). Besides, pioglitazone activated PI3K/AKT and ERK/MAPK pathways via up-regulating miR-454. Conclusion: Pioglitazone protected H9c2 cells against OGD-induced injury through up-regulating miR-454, indicating a novel therapeutic strategy for treatment of MIRI. PMID- 30524680 TI - Neuroprotective effects of gallic acid in a rat model of traumatic brain injury: behavioral, electrophysiological, and molecular studies. AB - Objectives: Traumatic brain injury (TBI) is one of the main causes of intellectual and cognitive disabilities. Clinically, it is essential to limit the development of cognitive impairment after TBI. In the present study, the neuroprotective effects of gallic acid (GA) on neurological score, memory, long term potentiation (LTP) from hippocampal dentate gyrus (hDG), brain lipid peroxidation and cytokines after TBI were evaluated. Materials and Methods: Seventy-two adult male Wistar rats divided randomly into three groups with 24 in each: Veh + Sham, Veh + TBI and GA + TBI (GA; 100 mg/kg, PO for 7 days before TBI induction). Brain injury was made by Marmarou's method. Briefly, a 200 g weight was fallen down from a 2 m height through a free-falling tube onto the head of anesthetized animal. Results: Veterinary coma scores (VCS), memory and recorded hDG -LTP significantly reduced in Veh + TBI group at 1 and 24 hr after TBI when compared to Veh + Sham (P<0.001), respectively, while brain tissue content of interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha) and malondialdehyde (MDA) were increased significantly (P<0.001). Pretreatment of TBI rats with GA improved clinical signs, memory and hDG-LTP significantly (P<0.001) compared to Veh + TBI group, while brain tissue content of IL-1beta, IL-6, TNF alpha and MDA were decreased significantly (P<0.001). Conclusion: Our results propose that GA has neuroprotective effect on memory and LTP impairment due to TBI through decrement of brain lipid peroxidation and cerebral pro-inflammatory cytokines. PMID- 30524681 TI - Biological alterations in renal and hepatic tissues by a novel gold (III) anti cancerous compound. AB - Objectives: Newer organo-metallic, specifically gold (III) complexes with multiple ligands are currently being formulated with primary focus of having increased anti-cancerous properties and decreased cytotoxicity. In this study, histological toxicity profile of a newly formulated anti-cancerous gold (III) compound [trans-(+/-)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) was investigated by evaluation of kidney and liver tissues of rats treated by the compound. Materials and Methods: This is a quasi-experimental study. In acute toxicity component of the study, (n = 16) male rats weighing between 200-250 g were administered single, variable concentration of the gold (III) compound, [trans-(+/-)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) to determine LD50 (dose that is lethal to 50% of rats). An IP injection of 2.3 mg/kg (equivalent to 1/10 of LD50) was injected for 14 consecutive days to (n=10) male rats in the sub-acute component of the study. Autopsy preservation of liver and kidney tissue in buffered formalin, sample processing, histopathological evaluation, and comparison with unremarkable controls (n=5) was conducted sequentially. Results: A dose of 2.3 mg/kg did not produce any tubular necrosis in kidney specimens. Mild interstitial inflammation with prominence of plasma cells was the main histological alteration. Plasmacytic pyelitis was also seen. Varying extents of cytoplasmic vacuolization and mild focal lobular and portal inflammation were predominant hepatic microscopic findings. Conclusion: [trans (+/-)-1,2-(DACH)2Au]Cl3 Bis(trans-1,2-Diaminocyclohexane) produced no histological damage in renal and hepatic tissues of rats. This very limited sample animal-based study points to the relative safety of this new gold compound. However, there is a need to compare this compound with established drugs in a comparative non-animal based study. PMID- 30524682 TI - Effects of lipopolysaccharide-induced septic shock on rat isolated kidney, possible role of nitric oxide and protein kinase C pathways. AB - Objectives: Pathophysiology of sepsis-associated renal failure (one of the most common cause of death in intensive care units) had not been fully determined. The effect of nitric oxide and protein kinase C (PKC) pathways in isolated kidney of Lipopolysaccharide-treated (LPS) rats were investigated in this study. Materials and Methods: Vascular responsiveness to phenylephrine and acetylcholine in the presence and absence of a potent PKC inhibitor (chelerythrine) and nonspecific NO inhibitor (L-NAME) as well as responses to acetylcholine and sodium nitroprusside (SNP) were examined. Results: LPS (10 mg/kg, IP) treatment resulted in a lower systemic pressure and reduction of responses to vasoconstrictor and vasodilator agents (P<0.05 to P<0.01). The contractile response to phenylephrine and the relaxation response to acetylcholine were significantly blunted in isolated kidneys removed from LPS-treated rats. L-NAME (10 uM) preincubation modified the responses to acetylcholine in isolated kidneys of control animal (P<0.001) but not in LPS-treated rats. While, chelerythrine (10 uM) preincubation partially restored response to phenylephrine in LPS-treated tissues. Conclusion: Present study highlighted that five hours of intraperitoneal endotoxin injection is adequate to reduce renal basal perfusion pressure. These results also suggest that PKC inhibition may have a beneficial role in vascular hyporesponsiveness induced by LPS. Although our study partly elaborated on the effects of LPS on isolated renal vascular responses to vasoactive agents, further studies are required to explain how LPS exerts its renal vascular effects. PMID- 30524683 TI - Study of class 1 integrons in multidrug-resistant uropathogenic Escherichia coli isolated from different hospitals in Karachi. AB - Objectives: Escherichia coli is the key pathogen in the family producing ESBL (extended spectrum beta-lactamase) and associated with community-acquired infections. Therefore, this study was planned to determine the antibiotic susceptibility pattern of uropathogenic E. coli, prevalence of the ESBL gene group and class 1 integrons. Materials and Methods: Clinical isolates of uropathogenic E. coli were isolated from different hospitals of Karachi. Antibiotic susceptibility test was performed by Kirby-Bauer Methods. Presence of beta- lactamases genes (CTX, TEM, and SHV) and integron 1 were identified by polymerase chain reaction (PCR). Results: Out of 500, 105 isolates were identified as multi-drug resistant (MDR) uropathogenic E. coli. The subject MDR isolates showed the highest resistance to aztreonam, amoxil/ clavulanic acid, ampicillin, cotrimoxazole, ceftriaxone, cefipime, and cefuroxime. Genetic analysis showed that the majority of the MDR E. coli carry CTX M1 (57.1%) followed by TEM (33.3%) and SHV (9.5%). Moreover, 79% of MDR E. coli harbored class 1 integrons, whereas all three conserved genes for class 1 integrons were present in 58% of MDR E. coli. Conclusion: This study is helpful to provide information regarding the antibiotic susceptibility pattern, distribution ESBLs and class 1 integrons among uropathogenic E. coli. PMID- 30524684 TI - Momordica cymbalaria fruit extract attenuates high-fat diet-induced obesity and diabetes in C57BL/6 mice. AB - Objectives: The present study was aimed to evaluate the effect of methanolic fruit extract of Momordica cymbalaria (MeMC) against high-fat diet-induced obesity and diabetes in C57BL/6 mice. Materials and Methods: In the present study, six weeks old male C57BL/6 mice were divided into four groups. G-1 and G-2 served as lean control and HFD control, G-3 and G-4 received MeMC 25 and 50 mg/kg, BW doses; all the treatments were given for a period of 11 weeks. The parameters such as body weight, fasting blood glucose, insulin, cholesterol, free fatty acid, and oral glucose tolerance tests were performed, further, at the end of the study fasting body weight, and weights of organs such as the liver, heart, and adipose tissue were measured and the liver tissue was subjected to histopathology evaluation, and insulin resistance was expressed as HOMA-IR index. Results: The high-fat diet fed C57 mice showed significant elevation of body weight (P<0.01), blood glucose (P<0.01), insulin (P<0.01), cholesterol (P<0.01), free fatty acid (P<0.01), and HOMA-IR index (P<0.01) along with significant elevation of all organ weights and reduction in oral glucose tolerance (P<0.01) and brown adipose weight (P<0.01). The histopathology showed significant fatty infiltration and hypertrophy of hepatocytes. Interestingly, MeMC (50 mg/kg) alleviated all the HFD-induced perturbances significantly. Further, the HPLC analysis of MeMC revealed the presence of gallic acid and rutin as chief ingredients. Conclusion: MeMC possesses potent antidiabetic activity and ameliorates insulin resistance in HFD diet fed C57 mice. PMID- 30524685 TI - Cockroaches, locusts, and envenomating arthropods: a promising source of antimicrobials. AB - Objectives: To present a brief overview of various natural sources of antimicrobials with the aim of highlighting invertebrates living in polluted environments as additional sources of antimicrobials. Materials and Methods: A PubMed search using antibacterials, antimicrobials, invertebrates, and natural products as keywords was carried out. In addition, we consulted conference proceedings, original unpublished research undertaken in our laboratories, and discussions in specific forums. Results: Representative of a stupefying 95% of the fauna, invertebrates are fascinating organisms which have evolved strategies to survive germ-infested environments, yet they have largely been ignored. Since invertebrates such as cockroaches inhabit hazardous environments which are rampant with pathogens, they must have developed defense mechanisms to circumvent infections. This is corroborated by the presence of antimicrobial molecules in the nervous systems and hemolymph of cockroaches. Antimicrobial compounds have also been unraveled from the nervous, adipose, and salivary glandular tissues of locusts. Interestingly, the venoms of arthropods including ants, scorpions, and spiders harbor toxins, but also possess multiple antimicrobials. Conclusion: These findings have rekindled the hopes for newer and enhanced therapeutic agents derived from a plentiful and diverse resource to combat fatal infectious diseases. Such antimicrobials from unusual sources can potentially be translated into clinical practice, however intensive research is needed over the next several years to realize these expectations. PMID- 30524686 TI - Evaluating cytotoxic effects of recombinant fragaceatoxin C pore forming toxin against AML cell lines. AB - Objectives: Current therapeutic strategies for cancer are associated with side effects and lack of specificity in treatments. Biological therapies including monoclonal antibodies and immune effectors have been the subject of multiple research projects. Pore-forming proteins may become the other biological strategy to overcome the problems associated with current treatments. But detailed mechanisms of their action on target membranes remained to be elucidated. We aimed to study the cytotoxic effects of recombinant form of fragaceatoxin C on AML cell lines HL-60 and KG-1. Materials and Methods: We cloned the FraC gene in pET-28a (+) bacterial expression vector and the expressed recombinant FraC protein was purified by affinity chromatography. Then, cytotoxic effects of the recombinant protein were examined on two AML cell lines, HL-60 and KG-1. Effects of serum and calcium ion were explored by hemolysis assay in more details. Results: Our results showed that the recombinant C-terminal polyhistidine-tagged FraC protein has potent cytotoxic effects on both AML cell lines, with IC50=5.6, and 4.6 ug.ml-1 for HL-60 and KG-1 cells, respectively. Serum showed dose dependent and also time-dependent inhibitory effects on the hemolytic and cytotoxic activities of the FraC protein. Pre-incubation of the toxin with different concentrations of calcium ion also inhibited hemolytic activity of FraC toxin. Conclusion: Results of the present study showed that FraC has potential anti-tumor effects. By detailed investigation of the inhibition mechanism of serum and calcium effects in the future, it can be possible to design target sites for clinical applications of the toxin. PMID- 30524687 TI - Cell-specific targeting by engineered M13 bacteriophage expressing VEGFR2 nanobody. AB - Objectives: Filamentous bacteriophage M13 was genetically engineered to specifically target mammalian cells for gene delivery purpose. Materials and Methods: A vascular endothelial growth factor receptor 2 (VEGFR2)-specific nanobody was genetically fused to the capsid gene III of M13 bacteriophage (pHEN4/3VGR19). A mammalian expression construct containing Cop-green fluorescent protein (Cop-GFP), as a reporter gene, was amplified by PCR and then sub-cloned in the pHEN4/3VGR19 phagemid. The resulting construct was transfected into 293KDR cell. The recombinant phage was extracted and confirmed and then transduced into VEGFR2 expressing cell (293KDR). Results: Seventy-two hr after transfection, green fluorescence was detected in 30% of the cells. About 1% of the cells which transduced by recombinant phages were able to express GFP. Conclusion: It is hoped that the results from this study will help to find potential vectors to improve the efficiency of gene delivery. Taken together, we conclude that this newly-introduced vector can be used in cancer researches. PMID- 30524688 TI - Fetal microchimerism in mouse caerulein-induced pancreatitis model. AB - Objectives: Fetal microchimerism is the persistence of allogeneic cell population that transfer from the fetus to the mother. The aim of this study was to evaluate the presence of fetal microchimerism in the pancreas of the mouse with acute pancreatitis (AP). Materials and Methods: In this experimental study, female wild type mice were mated with male EGFP+. AP model was obtained by injection of caerulein two days after delivery. Sixty mice were divided into 3 groups: the virgin pancreatitis-induced animals, pregnant pancreatitis-induced animals mated with transgenic EGFP mice, and pregnant sham animals. To prove pancreatitis induction, the blood amylase and lipase were assessed; and pancreas was removed from a subpopulation of each group for histopathological examinations after 6 hr. The remaining mice were kept for 3 weeks and histopathological exanimation, immunohistochemistry, and PCR were performed. Results: EGFP+ cells were found in acini and around the blood vessels in the pancreas of pregnant pancreatitis induced animals. They differentiated to acinar, adipocyte-like, and mesenchymal like cells. PCR showed that 20% of the pregnant pancreatitis-induced animals were EGFP+. The histopathological study showed improvement in pancreatitis scores in the mice with history of pregnancy. Conclusion: It seems that pregnancy has a beneficial impact on caerulein-induced pancreatitis and improves the pancreatitis score in mouse. PMID- 30524689 TI - Camel whey protein enhances lymphocyte survival by modulating the expression of survivin, bim/bax, and cytochrome C and restores heat stress-mediated pathological alteration in lymphoid organs. AB - Objectives: Heat stress (HS) is a catastrophic stressor that dampens immunity. The current study investigates the effect of dietary administration with camel whey protein (CWP) on apoptotic pathway caused by HS. Materials and Methods: Forty-five male mice were divided into three groups: a control group; HS group; and HS mice that were orally supplemented with CWP (CWP-HS group). Results: We found that reactive oxygen species (ROS), pro-inflammatory cytokines (IL-6), and C reactive protein (CRP) were elevated in the HS group along with a significant increase of caspase-9 and -3 and decrease of total antioxidant capacity (TAC). HS mice revealed impaired phosphorylation of Bcl-2 and Survivin, as well as increased expression of Bax, Bim and cytochrome C. Additionally, we observed an aberrant distribution of HSP-70 expressing lymphocytes in the spleen and thymus of HS mice. Moreover, histopathological examination showed alterations on the architectures of immune organs. In comparison with CWP-HS group, we found that CWP restored the levels of ROS, IL-6, TAC and CRP induced by HS. Furthermore, CWP restored the expression of Bcl-2/Bax, improved the histopathological changes in immune organs and HSP-70 distribution in the spleen and thymus. Conclusion: Our findings revealed the possible ameliorative role of CWP supplementation against damages induced by exposure to HS. PMID- 30524690 TI - In vitro assessment of alendronate toxic and apoptotic effects on human dental pulp stem cells. AB - Objectives: Osteonecrosis of the jaw, as an exposed necrotic bone in the oral cavity, is one of the adverse effects of bisphosphonates, which have an affinity for bone minerals. This study investigates the cytotoxic effects of alendronate (ALN) as a nitrogen-containing bisphosphonate, on human dental pulp stem cells (hDPSCs). Materials and Methods: The mesenchymal stem cells (MSCs), obtained from third molar tooth pulps were characterized by immunophenotyping assay in order to identify surface markers to evaluate their expression. To detect multipotency hDPSCs, they were differentiate into osteocytes and adipocytes. Cell proliferation was measured by MTT assay. PI staining of DNA fragmentation by flowcytometry (sub-G1 peak) was performed for determination of apoptotic cells and Bax, Bcl-2, and cleaved caspase 3 expressions. Protein expression was detected by Western blotting. Results: As the results revealed, ALN decreased viable cells (in 0.8-100 uM) after 72 hr and 168 hr (P<0.001), significantly. ALN could lower cell proliferation in hDPSCs in a concentration and time-dependent manner. Sub-G1 peak as an indicator of flowcytometry histogram of treated cells by ALN, showed apoptosis was involved in ALN-induced cytotoxicity. Expressions of cleaved caspase 3 and Bax protein, as pro-apoptotic proteins, were increased and Bcl-2 protein as anti-apoptotic protein was decreased in response to increases in the concentration of ALN (0.8-25 uM). Conclusion: Long-term effects of ALN on cell proliferation and apoptosis in hDPSCs can result in either initiation or potentiation of ALN-induced osteonecrosis. PMID- 30524691 TI - Moderate aerobic exercise training decreases middle-aged induced pathologic cardiac hypertrophy by improving Klotho expression, MAPK signaling pathway, and oxidative stress status in Wistar rats. AB - Objectives: This study aimed to investigate the effect of aerobic training on serum levels of Klotho, cardiac tissue levels of H2O2 and phosphorylation of ERK1/2 and P38 as well as left ventricular internal diameter (LVID), the left ventricle wall thickness (LVWT) and fibrosis in middle-aged rats. Materials and Methods: Forty wistar rats, including young rats (n=10, 4 month-old) and middle aged rats (n=30, 13-15 months-old) were enrolled in this experimental study. The all young and 10 middle-aged rats were sacrificed (randomly) under deep anesthesia without any exercise training as normal young control and normal middle-aged control respectively. The remaining 20 middle-aged rats participated in 4 (n=10) or 8-week (n=10) aerobic exercise training. Results: There were significant differences in the plasmatic Klotho levels and the heart tissue levels of phosphorylated-ERK1/2 (p-ERK1/2), P-P38 and H2O2, LVWT, LVID and fibrosis between young and middle-aged rats (P=0.01). Plasmatic Klotho level was significantly increased after eight weeks training (P=0.011). Also, p-ERK1/2 was significantly decreased after eight weeks and p-P38 was significantly decreased in the fourth (P=0.01) and eight weeks of training (P=0.01). A similar decrease was reported for aging-induced H2O2 in the fourth (P=0.016) and eighth weeks (P=0.001). LVID was significantly increased in eight weeks, but LVWT and fibrosis was significantly reduced in the eighth week (P=0.011, P=0.028, P=0.001 respectively). Conclusion: Moderate aerobic training attenuates aging-induced pathological cardiac hypertrophy at least partially by restoring the Klotho levels, attenuating oxidative stress, and reduction in the phosphorylation of ERK1/2, P38 and fibrosis. PMID- 30524692 TI - Improvement of the functionality of pancreatic Langerhans islets via reduction of bacterial contamination and apoptosis using phenolic compounds. AB - Objectives: During type-1 diabetes treating by pancreatic islet transplantation, increasing oxidative stress and microbial contaminations are the main reasons of transplantation failure. In this study, we evaluated anti-apoptotic, antioxidant and antimicrobial potentials of phenolic compounds called ellagic acid (EA) and silybin on rat pancreatic islets. Materials and Methods: By doing MTT assay, effective concentrations of EA and silybin were determined as 1500 and 2100 MUM, respectively. Then, ELISA methods, flow cytometry and MIC were done to investigate antioxidant, anti-apoptotic and antibacterial effects of those compounds, respectively. Results: Results of FITC Annexin-V and PI staining via flow cytometry, and also caspase-3 and -9 activities performed that EA has anti apoptotic effects on pancreatic cells. Both compounds significantly diminished reactive oxygen species, and enhanced antioxidant power and insulin secretion. Furthermore, the minimum inhibitory concentration test indicated that these two have antibacterial effects on both Gram-positive and Gram-negative bacteria which usually contaminate the pancreatic islets. Conclusion: These findings support that use of EA and silybin can improve the function of islets which are used in transplantation, along with decreasing islets bacterial contamination. PMID- 30524693 TI - Ameliorating effect of encapsulated hepatocyte-like cells derived from umbilical cord in high mannuronic alginate scaffolds on acute liver failure in rats. AB - Objectives: In this study, effects of encapsulated umbilical cord stem cells (UCSCs)-derived hepatocyte-like cells (HLCs) in high mannuronic alginate scaffolds was investigated on CCl4-induced acute liver failure (ALF) in rats. Material and Methods: UCSCs were encapsulated in high mannuronic alginate scaffolds. Then the UCSCs differentiated into HLCs for treatment of CCl4-induced ALF in rats. Thirty rats randomly divided into 5 groups: Intoxicated group received only CCl4 to induce ALF. In other groups including cell-free, UCSCs and HLCs, alginate scaffolds were transplanted into the liver 4 days after CCl4 injection. Biochemical markers including albumin (ALB), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated. Histological changes and gene expression of ALB, alpha-fetoprotein (AFP), and cytokeratin 18 (CK-18) were also assessed. Results: Expression of CK-18 significantly increased in HLCs compared to the UCSCs in vitro. This indicates that UCSCs can effectively differentiate into the HLCs. In CCl4-intoxicated group, BUN, AST and ALT levels, and histological criteria, such as infiltration of inflammatory cells, accumulation of reticulocytes, nuclear pyknosis of hepatocyte and sinusoidal dilation, significantly increased. In this group, ALB secretion significantly decreased, while AFP expression significantly increased. Both UCSCs and HLCs encapsulated in alginate scaffolds effectively attenuated biochemical tests, improved liver cytoarchitecture, increased expression of ALB and reduced AFP expression. Conclusion: Finding of the present study indicated that encapsulation of UCSCs or HLCs in alginate mannuronic scaffolds effectively improve CCl4-induced ALF. PMID- 30524694 TI - Comparison of the effects of 17beta- estradiol treated and untreated mesenchymal stem cells on ameliorating animal model of multiple sclerosis. AB - Objectives: The current investigation was undertaken to evaluate the effects of 17beta- estradiol (17beta-ED) on the potential of the mesenchymal stem cells (MSCs) for modulation of immunity responses in an animal model of multiple sclerosis (MS). Materials and Methods: After isolation of MSCs, cells were cultured in presence of 100 nM 17beta-ED for 24 hr. Modeling of experimental autoimmune encephalomyelitis (EAE) was achieved by using guinea pig spinal cord homogenate, in addition to complete Freund's adjuvant in male Wistar rats. The processes of cell therapy were started following 12 days post-immunization. This duration allows all animals to develop a disability score. The achieved EAE clinical symptoms were regularly monitored every day until day 36, when all of examined rats were euthanized. Results: Cell therapy in the EAE rats with 17beta ED-primed MSCs exhibited more desirable consequences, which in turn lead to regression of the cumulative clinical score and neuropathological changes that are more than the therapy with untreated MSCs. The serum measures of myeloperoxidase (MPO), nitric oxide (NO) as well as splenocytes-originated pro inflammatory interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-alpha) were significantly decreased in EAE rats treated by 17beta-ED primed-MSCs compared to EAE rats that received untreated MScs. Conclusion: Combination of 17beta-ED and MSCs more effectively improved the signs and symptoms of EAE. PMID- 30524695 TI - The possibility of using shogaol for treatment of ulcerative colitis. AB - Objectives: This study aimed to investigate the effect of Shogaol on dextran sodium sulfate (DSS)- induced ulcerative colitis (UC) in mice compared to an immune-suppressant chemotherapeutic medicine, known as 6-thioguanine (6-TG). Materials and Methods: Thirty-six adult BALB/c mice were divided into six groups: group 1 (positive control): no DSS exposure and no treatment; group 2 (negative control): DSS exposure without treatment; group 3 (vehicle control): DSS exposure and olive oil treatment; group 4: DSS exposure and 0.3 mg/kg 6-TG treatment; group 5: DSS exposure and 20 mg/kg Shogaol treatment; and group 6: DSS exposure and 40 mg/kg Shogaol treatment. At day 16, the mice were euthanized and UC was evaluated according to colon length, histologically index score and expression scores of the epidermal growth factor receptor (EGFR). Results: The disease activity index (DAI) and histological index scores of mice treated with 40 mg/kg body weight (BW) Shogaol were approximately lower than the corresponding scores of mice treated with 6-TG. In addition, the rate of healing in the former mice was approximately 3 folds higher than that of the latter ones as indicated by the lack of EGFR expression in colonic glands and macrophages. Conclusion: These findings showed that the therapeutic effect of 40 mg/kg BW Shogaol could be better than 6-TG in the treatment of UC, and it may draw the attention regarding the priority of using this cheap plant-derived substance for treatment of the inflammatory bowel diseases because treatment with 6-TG is usually associated with adverse side effects. PMID- 30524696 TI - Mutational analysis of ARSB gene in mucopolysaccharidosis type VI: identification of three novel mutations in Iranian patients. AB - Objectives: Mucopolysaccharidosis VI (MPS VI) or Maroteaux-Lamy syndrome is a rare metabolic disorder, resulting from the deficient activity of the lysosomal enzyme arylsulfatase B (ARSB). The enzymatic defect of ARSB leads to progressive lysosomal storage disorder and accumulation of glycosaminoglycan (GAG) dermatan sulfate (DS), which causes harmful effects on various organs and tissues and short stature. To date, more than 160 different mutations have been reported in the ARSB gene. Materials and Methods: Here, we analyzed 4 Iranian and 2 Afghan patients, with dysmorphism indicating MPS VI from North-east Iran. To validate the patients' type of MPS VI, urine mucopolysaccharide and leukocyte ARSB activity were determined. Meanwhile, genomic DNA was amplified for all 8 exons and flanking intron sequences of the ARSB gene to analyze the spectrum of mutations responsible for the disorder in all patients. Results: Abnormal excretion of DS and low leukocyte ARSB activity were observed in the urine samples of all 6 studied patients. In direct DNA sequencing, we detected four different homozygous mutations in different exons, three of which seem not to have been reported previously: p.H178N, p.H242R, and p.*534W. All three novel substitutions were found in patients with Iranian breed. We further detected the IVS5+2T>C mutation in Afghan siblings and four different homozygous polymorphisms, which have all been observed in other populations. Conclusion: results indicated that missense mutations were the most common mutations in the ARSB gene, most of them being distributed throughout the ARSB gene and restricted to individual families, reflecting consanguineous marriages. PMID- 30524697 TI - Immunogenicity evaluation of plasmids encoding Brucella melitensis Omp25 and Omp31 antigens in BALB/c mice. AB - Objectives: Vaccination is one of the most effective means to protect humans and animals against brucellosis. Live attenuated Brucella vaccines are considered effective in animals but they may be potentially infectious to humans, so it is vital to improve the immunoprotective effects and safety of vaccines against Brucella. This study was designed to evaluate the immunogenicity of DNA vaccines encoding B. melitensis outer membrane proteins (Omp25 and Omp31) against B. melitensis Rev1 in a mouse model. Materials and Methods: For this propose, Omp25 and Omp31 genes were cloned (individually and together) into the eukaryotic expression vector pcDNA3.1/Hygro (+). Expressions of recombinant plasmids were confirmed by SDS-PAGE and Western blot analysis. Six groups of BALB/c mice (seven mice per group) were intramuscularly injected with three recombinant constructs, native pcDNA3.1/Hygro (+) and phosphate-buffered saline (PBS) as controls and subcutaneous injection of attenuated live vaccine Rev1. Results: Results indicated that DNA vaccine immunized BALB/c mice had a dominant immunoglobulin G response and elicited a T-cell-proliferative response and induced significant levels of interferon gamma (INF-gamma) compared to the control groups. Conclusion: Collectively, these finding suggested that the pcDNA3.1/Hygro DNA vaccines encoding Omp25 and Omp31 genes and divalent plasmid were able to induce both humoral and cellular immunity, and had the potential to be a vaccine candidate for prevention of B. melitensis infections. PMID- 30524698 TI - The osteogenesis of bacterial cellulose scaffold loaded with fisetin. AB - Objectives: Bacterial cellulose (BC) has applications in medical science, it is easily synthesized, economic and purer compared to plant cellulose. The present study aimed to evaluate BC, a biocompatible natural polymer, as a scaffold for the bone marrow mesenchymal stem cells (BMSCs) loaded with fisetin, a phytoestrogen. Materials and Methods: BC hydrogel scaffold was prepared from Gluconaceter xylinus and characterized through scanning electron microscopy (SEM). Biocompatibility of BC was measured by MTT assay, BMSCs were obtained from femur of rat and the osteogenic potential of the BC scaffold cultured with BMSCs and loaded with fisetin, was investigated by measuring the alkaline phosphatase (ALP) activity, alizarin red staining (ARS) and real-time PCR in terms of osteoblast-specific marker, osteocalcin (OCN) and osteopontin (OPN). Results: Biocompatibility results did not show any toxic effects of BC scaffold on BMSCs, while it increased cell viability. The data showed that BC loaded fisetin differentiated BMSCs into osteoblasts as demonstrated by ALP activity assays and ARS in vitro. Moreover, results from gene expression assay showed the expression of OCN and OPN genes was increased in cells that were seeded on the BC scaffold loaded with fisetin. Conclusion: According to the results of the present study, BC loaded with fisetin is an effective strategy to promote osteogenic differentiation and a proper localized delivery system, which could be a potential candidate in bone tissue engineering. PMID- 30524699 TI - Mangosteen peel extract (Garcinia mangostana L.) as protective agent in glucose induced mesangial cell as in vitro model of diabetic glomerulosclerosis. AB - Objectives: This study aims to evaluate the activity of mangosteen peels extract (MPE) as protection agent on induced-glucose mesangial cells (SV40 MES 13 cell line (Glomerular Mesangial Kidney, Mus Musculus)). Materials and Methods: MPE was performed based on maceration method. Cytotoxic assay was performed based on MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) method, while the level of TGF-beta1 (Transforming growth factor beta1) and fibronectin in glucose-induced mesangial cells were assayed and determined using ELISA KIT. Results: In viability assay, MPE 5 and 20 ug/ml has the highest activity to increase cells proliferation in glucose-induced mesangial cells at 5, 10, and 15 days of incubation in glucose concentration (5 and 25 mM) (P<0.05). In inhibitory activity of TGF-beta1 and fibronectin level, MPE 5 ug/ml (glucose-induced 5 mM) show the lowest level compared to positive control and other treatments (P<0.05). Conclusion: MPE can increase cell proliferation in glucose-induced mesangial cells and significantly reduce the level of TGF-beta1 and fibronectin. MPE activity has correlates to inhibit the diabetic glomerulosclerosis condition and may increase mesangial cell proliferation. PMID- 30524700 TI - Novel developments in Therapeutic Advances in Psychopharmacology. PMID- 30524701 TI - First-generation versus second-generation long-acting injectable antipsychotic drugs and time to relapse. AB - Background: The development of long-acting injectable formulations (LAIs) of second-generation antipsychotic drugs (SGAs) has been suggested as having advantage over first-generation antipsychotic (FGA) LAIs. In this study, we investigated the hypothesis that there was a longer time to relapse in patients with schizophrenia started on SGA LAI versus FGA LAI. Methods: Patients with a diagnosis of schizophrenia or schizoaffective disorder who were started on an SGA LAI while on an inpatient ward were identified through searching of the anonymised historical medical records at the South London and Maudsley NHS Foundation Trust. Patients starting FGA LAIs matched for diagnosis, age and date of hospital admission were identified. Time to readmission, discontinuation of LAI or death were identified. Kaplan-Meier plots were generated for each group, and the difference between groups analysed using log-rank methods. Results: There were 157 patients identified in each group. There was no difference in time to readmission, medication discontinuation or death in patients on SGA LAI versus FGA LAI. Conclusions: We found no evidence of advantage in terms of maintaining response in SGA LAI versus FGA LAI. Prescriber choice should be guided by other factors such as side-effect profile, patient acceptability and price. PMID- 30524702 TI - Anti-cytokine agents for anhedonia: targeting inflammation and the immune system to treat dimensional disturbances in depression. AB - The etiology of mood disorders is mechanistically heterogeneous, underscoring the need for a dimensional approach to identify and develop targeted treatments in psychiatry. Accumulating evidence implicates inflammation as an important contributor to the pathophysiology of depression and presents the immune system as a viable therapeutic target that may be more proximate to the pathogenic nexus of brain-based disorders in specific subpopulations. Anhedonia is a transdiagnostic (e.g. Parkinson's disease, diabetes mellitus, rheumatic diseases), yet specific, and clinically relevant symptom dimension subserved by well-characterized neurobiological and neurophysiological substrates of the positive valence systems (PVS). Brain circuits, nodes, and networks, as well as cellular and molecular pathways (e.g. dopaminergic transmission; excitotoxicity; synaptic plasticity), subserving anhedonia are preferentially affected by inflammatory processes. To our knowledge, no published randomized, controlled clinical trial in populations with mood disorders has, to date, primarily sought to determine the effects of an anti-inflammatory agent on PVS functions or pathophysiology. Three ongoing clinical trials aim to investigate the effects of anti-TNF-alpha biologic infliximab on measures of anhedonia [ClinicalTrials.gov identifier: NCT02363738], motivational behavior and circuitry [ClinicalTrials.gov identifier: NCT03006393], and glutamatergic changes in the basal ganglia [ClinicalTrials.gov identifier: NCT03004443] in clinical populations with unipolar or bipolar depression. Positive results would further instantiate the relevance of inflammatory processes and the immune system in the pathophysiology of mood disorders and provide the impetus to develop scalable treatments targeting inflammation and the immune system to mitigate transdiagnostic, dimensional disturbances in brain-based disorders. PMID- 30524703 TI - Medication nonadherence in bipolar disorder: a narrative review. AB - A number of effective maintenance medication options exist for bipolar disorder (BD) and these are regarded as the foundation of long-term treatment in BD. However, nonadherence to medication is common in BD. For example, a large data base study in the United States of America (USA) showed that approximately half of patients with BD were nonadherent with lithium and maintenance medications over a 12 month period. Such nonadherence carries a high risk of relapse due to the recurrent nature of the illness and the fact that abrupt cessation of treatment, particularly lithium, may cause rebound depression and mania. Indeed, medication nonadherence in BD is associated with significantly increased risks of relapse, recurrence, hospitalization and suicide attempts and a decreased likelihood of achieving remission and recovery, as well as with higher overall treatment costs. Factors associated with nonadherence include adverse effects of medication, complex medication regimens, negative patient attitudes to medication, poor insight, rapid-cycling BD, comorbid substance misuse and a poor therapeutic alliance. Clinicians should routinely enquire about nonadherence in a nonjudgmental fashion. Potential steps to improve adherence include simple pragmatic strategies related to prescribing including shared decision-making, psychoeducation with a clear focus on adherence, reminders (traditional and digital), potentially using a depot rather than an oral antipsychotic, managing comorbid substance misuse and improving therapeutic alliance. Financial incentives have been shown to improve adherence to depot antipsychotics, but this approach raises ethical issues and its long-term effectiveness is unknown. Often a combination of approaches will be required. The strategies that are adopted need to be patient specific, reflecting that nonadherence has no single cause, and chosen by the patient and clinician working together. PMID- 30524704 TI - Clozapine, HIV and neutropenia: a case report. AB - There is paucity of information on the use of clozapine in patients with HIV. Ethnicity, co-prescribed medications and possible drug-drug interactions are important considerations in evaluating risk of blood dyscrasias during clozapine treatment. Individuals with HIV should not be denied access to the most effective antipsychotic, but a multidisciplinary approach is essential for optimal outcome in such complex patients. PMID- 30524705 TI - The interrater reliability of static palpation of the thoracic spine for eliciting tenderness and stiffness to test for a manipulable lesion. AB - Background: Despite widespread use by manual therapists, there is little evidence regarding the reliability of thoracic spine static palpation to test for a manipulable lesion using stiffness or tenderness as diagnostic markers. We aimed to determine the interrater agreement of thoracic spine static palpation for segmental tenderness and stiffness and determine the effect of standardised training for examiners. The secondary aim was to explore expert consensus on the level of segmental tenderness required to locate a "manipulable lesion". Methods: Two experienced chiropractors used static palpation of thoracic vertebrae on two occasions (pragmatic and standardised approaches). Participants rated tenderness on an 11-point numerical pain rating scale (NPRS) and raters judged segmental stiffness based on their experience and perception of normal mobility with the requested outcomes of hypomobile or normal mobility. We calculated interrater agreement using percent agreement, Cohen's Kappa coefficients ( kappa ) and prevalence-adjusted bias-adjusted Kappa coefficients (PABAK). In a preliminary study, an expert panel of 10 chiropractors took part in a Delphi process to identify the level of meaningful segmental tenderness required to locate a "manipulable lesion". Results: Thirty-six participants (20 female) were enrolled for the reliability study on the 13th March 2017. Mean (SD) age was 22.4 (3.4) years with an equal distribution of asymptomatic (n = 17) and symptomatic (n = 17) participants. Overall, the interrater agreement for spinal segmental stiffness had Kappa values indicating less than chance agreement [ kappa range - 0.11, 0.53]. When adjusted for prevalence and bias, the PABAK ranged from slight to substantial agreement [0.12-0.76] with moderate or substantial agreement demonstrated at the majority of spinal levels (T1, T2 and T6 to T12). Generally, there was fair to substantial agreement for segmental tenderness [Kappa range 0.22-0.77]. Training did not significantly improve interrater agreement for stiffness or tenderness. The Delphi process indicated that an NPRS score of 2 out of 10 identified a potential "manipulable lesion". Conclusion: Static palpation was overall moderately reliable for the identification of segmental thoracic spine stiffness and tenderness, with tenderness demonstrating a higher reliability. Also, an increased agreement was found within the mid-thoracic spine. A brief training intervention failed to improve reliability. PMID- 30524706 TI - GM604 regulates developmental neurogenesis pathways and the expression of genes associated with amyotrophic lateral sclerosis. AB - Background: Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The peptide drug GM604 (GM6 or Alirinetide) was developed as a candidate ALS therapy, which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood. Methods: This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 h). Results: We identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors, whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors. Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes (STAT3, HOXD11, HES7, GLI1). We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR < 0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway. Conclusions: Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases. PMID- 30524707 TI - Effect of a cod protein hydrolysate on postprandial glucose metabolism in healthy subjects: a double-blind cross-over trial. AB - The increased prevalence of lifestyle diseases, such as the metabolic syndrome and type 2 diabetes mellitus (T2DM), calls for more knowledge on dietary treatments targeting the specific metabolic pathways involved in these conditions. Several studies have shown a protein preload before a meal to be effective in lowering the postprandial glycaemic response in healthy individuals and patients with T2DM. The aim of the present study was to assess the effect of a marine protein hydrolysate (MPH) from Atlantic cod (Gadus morhua) on postprandial glucose metabolism in healthy, middle-aged to elderly subjects. This double-blind cross-over trial (n 41) included two study days with 4-7 d wash-out in between. The intervention consisted of 20 mg of MPH (or casein as control) per kg body weight given before a breakfast meal. The primary outcome was postprandial response in glucose metabolism, measured by samples of serum glucose, insulin and plasma glucagon-like peptide 1 (GLP-1) in 20 min intervals for 180 min. In a mixed-model regression analysis, no differences were observed between MPH and control for postprandial glucose concentration (mean difference: 0.04 (95 % CI -0.17, 0.09) mmol/l; P = 0.573) or GLP-1 concentration (mean difference between geometric means: 1.02 (95 % CI 0.99, 1.06) pmol/l; P = 0.250). The postprandial insulin concentration was significantly lower after MPH compared with control (mean difference between geometric means: 1.067 (95 % CI 1.01, 1.13) mIU/l; P = 0.032). Our findings demonstrate that a single dose of MPH before a breakfast meal reduces postprandial insulin secretion, without affecting blood glucose response or GLP-1 levels, in healthy individuals. Further studies with repeated dosing and in target groups with abnormal glucose control are warranted. PMID- 30524708 TI - The potential for improving cardio-renal outcomes by sodium-glucose co transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. AB - Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes. PMID- 30524709 TI - Renal function at the time of nephrology referral but not dialysis initiation as a risk for death in patients with diabetes mellitus. AB - Background: Renal patients with diabetes mellitus are at very high risk of death before and after chronic dialysis initiation. Risk factors for death in this population are not clearly identified. Methods: We performed a retrospective survival analysis in 861 patients with diabetes mellitus consecutively followed up in the 2000-13 period in a nephrology setting. Results: The mean age was 70 +/- 10 years [men 65.2%; diabetes duration 13.7 +/- 10.3 years; mean estimated glomerular filtration rate (eGFR) 42.4 +/- 21.0 mL/min/1.73 m2). During follow up (median 60 months; up 15 years), 263 patients died (184 before and 79 after dialysis initiation) and 183 started chronic dialysis. In multivariate analyses, age, elevated systolic and low diastolic arterial pressures, peripheral artery disease, cancer, loop diuretic use and atrial fibrillation at baseline and acute kidney injury (AKI), heart failure (HF) and amputation during follow-up were identified as risk factors for death. After adjustments on these parameters, eGFRs at the time of the first outpatient visit-eGFR <45 mL/min/1.73 m2 {hazard ratio [HR] 1.58 [95% confidence interval (CI) 1.15-2.17]}, P = 0.005 and eGFR <30 [HR 1.53 (1.05-2.05)], P = 0.004, but not eGFR <60-were powerful risk factors for death. When initiation of dialysis was entered into the multivariate models, it was not associated with a risk of premature death [HR 1.19 (95% CI 0.91-1.55), P = 0.2069], even in patients >80 years of age [HR 1.08 (95% CI 0.64-1.81), P = 0.7793]. Conclusions: In patients with diabetes mellitus, high systolic and low diastolic arterial pressure, peripheral artery disease and development of AKI and HF are significant risk factors for death. In addition to these parameters, eGFR <45 mL/min/1.73 m2 at the time of referral is also a powerful risk factor for death. PMID- 30524710 TI - Isolated bilateral renal mucormycosis in apparently immunocompetent patients-a case series from India and review of the literature. AB - Background: Isolated renal mucormycosis (IRM) is a potentially fatal disease affecting immunocompromised hosts. IRM affecting apparently immunocompetent patients is rare, with few previous reports, mostly from India. We describe 10 cases of bilateral IRM with no underlying risk factors. Methods: We performed a retrospective analysis of cases of IRM from our hospital information system admitted between 2009 and 2016. We analyzed the data of this cohort of IRM, including epidemiological characteristics, clinical presentation, diagnostic procedures, treatment details and outcome. Results: In all, 10 cases of bilateral IRM were identified. All of them were males with a mean age of 24.7 years (range 10-42). Most patients were initially managed as acute bacterial pyelonephritis with acute kidney injury. A total of eight patients were diagnosed antemortem. Diagnostic clues include sepsis not controlled with broad-spectrum antibiotics and enlarged kidneys with or without hypodensities on ultrasound/computed tomography imaging. Three patients also gave a specific history of passing white flakes in their urine. Eight patients received specific antifungal therapy with amphotericin B with or without posaconazole. Three patients in whom the disease was apparently confined to the pelvicalyceal system underwent local irrigation with Amp-B. One patient underwent bilateral nephrectomy. Four patients succumbed to the disease while five patients were successfully treated. One patient was discharged against medical advice. Conclusions: IRM is a rare, life-threatening disease associated with high mortality even in immunocompetent individuals. Typical clinical and radiological findings and a high index of suspicion may help in early diagnosis, but definitive diagnosis requires histopathological and/or microbiological confirmation. Early and rapid diagnosis along with aggressive multidisciplinary management including initiation of specific antifungal therapy with or without surgical debridement is vital for a successful outcome. PMID- 30524711 TI - Treatment of multiple myeloma with renal involvement: the nephrologist's view. AB - Renal injury is a common complication in multiple myeloma (MM). In fact, as many as 10% of patients with MM develop dialysis-dependent acute kidney injury related to increased free light chain (FLC) production by a plasma cell clone. Myeloma cast nephropathy (MCN) is the most prevalent pathologic diagnosis associated with renal injury, followed by light chain deposition disease and light chain amyloidosis. Several FLC removal techniques have been explored to improve kidney disease in MM but their impact on renal clinical outcomes remains unclear. According to the evidence, high cut-off haemodialysis should be restricted to MM patients on chemotherapy with histological diagnosis of MCN and haemodialysis requirements. From our perspective, more efforts are needed to improve kidney outcomes in patients with MM and renal failure. PMID- 30524712 TI - Type B lactic acidosis from fluorouracil in fluorouracil, oxaliplatin and leucovorin treatment for carcinoma of the colon in a hemodialysis patient. AB - Type B lactic acidosis complicating malignancies is rare. Increased lactate production from abnormal metabolism of tumor tissue and extensive liver metastases impairing clearance are usual causes. Fluorouracil, commonly used as adjuvant cancer chemotherapy, is not well recognized among drugs that can lead to lactic acidosis. We report a hemodialysis patient, tumor free after surgery for colon carcinoma, developing acute severe lactic acidosis and encephalopathy. Pharmacogenetic studies failed to show common variants predisposing to the more typical patterns of fluorouracil toxicity. Routine monitoring of hemodialysis patients after fluorouracil is the only practical way to detect this potentially lethal complication. PMID- 30524713 TI - Treatment of fibrillary glomerulonephritis with use of repository corticotropin injections. AB - Fibrillary glomerulonephritis (FGN) is a rare idiopathic condition linked to malignancy, autoimmune disorders, monoclonal gammopathies and hepatitis C virus. It usually has a poor prognosis, resulting in progression to end-stage renal disease within a few years, given the lack of standardized treatment. Repository corticotrophin (RC) injections are approved for use in a variety of nephrotic syndromes, but are not routinely considered for treatment of FGN. We present a case in which a patient with FGN began treatment with RC 3 months after diagnosis. The patient has attained partial remission with complete resolution of nephrotic syndrome and stabilization of renal function. PMID- 30524714 TI - Using the newer Kidney Disease: Improving Global Outcomes criteria, beta-2 microglobulin levels associate with severity of acute kidney injury. AB - Beta-2-microglobulin (B2M) is a marker of proximal tubular injury and glomerular filtration. Analyses using older/non-standardized definitions have shown low efficacy of B2M to predict acute kidney injury (AKI). We assessed if elevated levels of B2M would associate with either the diagnosis of AKI [under current Kidney Disease: Improving Global Outcomes (KDIGO) criteria] or recovery from AKI. We performed a retrospective study, including children who had urine B2M (uB2M) and/or serum B2M (sB2M) measured by immunoturbidimetry in our clinical laboratory between January 2011 and December 2015. We defined AKI based on KDIGO criteria [increase of serum creatinine (sCr) 0.3 mg/dL over 48 h or >50% baseline over 7 days] or urine output <0.5 mL/kg/h for 24 h. Recovery from AKI was defined as a return to baseline sCr within 6 months. We calculated receiver operating characteristics (ROC) area under the curve (AUC). Of 529 patients, 245 developed AKI. Serum and uB2M associated with AKI development (AUCs 0.84 and 0.73, respectively). Patients had a graded higher median sB2M and uB2M with each higher AKI stage. sB2M differentiated Stage I from Stage III AKI (P < 0.001) and Stage II from Stage III AKI (P = 0.004). However, neither uB2M nor sB2M levels associated with recovery from AKI. Only older age {hazard ratio [HR] 0.97, [95% confidence interval (CI) 0.94-0.99]} and need for dialysis [HR 0.39 (95% CI 0.23 0.61)] predicted incomplete recovery after AKI. Using KDIGO criteria, sB2M and uB2M associate with the severity of AKI. Given its relative ease and lower cost, we suggest more widespread use of B2M for AKI detection. PMID- 30524715 TI - Nephrology in Bosnia and Herzegovina: impact of the 1992-95 war. AB - It has now been more than two decades since the end of the 1992-95 war in Bosnia and Herzegovina. This may well be the proper time to provide the nephrology community with an appraisal of the care of patients with chronic kidney disease in the pre-war, war and post-war periods in the European transitional country. This report on nephrology in Bosnia and Herzegovina draws attention to the hurdles faced for three turbulent years on that burdensome path of providing quality care, and the chance it offered in developing a successful transplant programme while facing the dreadful chaos of war and a migrant crisis. The perception of war and natural disasters is quite different, from the victim's point of view, from the standardized and well-arranged healthcare systems in the developed world. The guidelines, written in peace, are extremely useful, but are often hard to follow during natural disasters or barbarous wars. Each of the periods described had its specificities as well as its good and bad sides. Despite the unquestionable destructive nature of the war, it was a catalyst for nephrology in Bosnia and Herzegovina to move forward. PMID- 30524716 TI - Satellite cell function, intramuscular inflammation and exercise in chronic kidney disease. AB - Skeletal muscle wasting is a common feature of chronic kidney disease (CKD) and is clinically relevant due to associations with quality of life, physical functioning, mortality and a number of comorbidities. Satellite cells (SCs) are a population of skeletal muscle progenitor cells responsible for accrual and maintenance of muscle mass by providing new nuclei to myofibres. Recent evidence from animal models and human studies indicates CKD may negatively affect SC abundance and function in response to stimuli such as exercise and damage. The aim of this review is to collate recent literature on the effect of CKD on SCs, with a particular focus on the myogenic response to exercise in this population. Exercise is widely recognized as important for the maintenance of healthy skeletal muscle mass and is increasingly advocated in the care of a number of chronic conditions. Therefore a greater understanding of the impact of uraemia upon SCs and the possible altered myogenic response in CKD is required to inform strategies to prevent uraemic cachexia. PMID- 30524717 TI - Chronic kidney disease: considerations for monitoring skeletal muscle health and prescribing resistance exercise. AB - Skeletal muscle wasting has gained interest as a primary consequence of chronic kidney disease (CKD) due to the relationship between skeletal muscle mass, mortality and major adverse cardiovascular events in this population. The combination of reductions in physical function, skeletal muscle performance and skeletal muscle mass places individuals with CKD at greater risk of sarcopenia. Therefore the monitoring of skeletal muscle composition and function may provide clinical insight into disease progression. Dual-energy X-ray absorptiometry and bioelectrical impedance analysis are frequently used to estimate body composition in people with CKD within clinical research environments, however, their translation into clinical practice has been limited. Proxy measures of skeletal muscle quality can be obtained using diagnostic ultrasound, providing a cost effective and accessible imaging modality to aid further clinical research regarding changes in muscle composition. Clinicians and practitioners should evaluate the strengths and limitations of the available technology to determine which devices are most appropriate given their respective circumstances. Progressive resistance exercise has been shown to improve skeletal muscle hypertrophy of the lower extremities, muscular strength and health-related quality of life in end-stage renal disease, with limited evidence available in CKD predialysis. Fundamental principles (i.e. specificity, overload, variation, reversibility, individuality) can be used in the development of more advanced programs focused on improving specific neuromuscular and functional outcomes. Future research is needed to determine the applicability of skeletal muscle monitoring in clinical settings and the feasibility and efficacy of more advanced resistance exercise approaches in those with CKD predialysis. PMID- 30524718 TI - Implementing a theory-based intradialytic exercise programme in practice: a quality improvement project. AB - Background: Research evidence outlines the benefits of intradialytic exercise (IDE), yet implementation into practice has been slow, ostensibly due to a lack of patient and staff engagement. The aim of this quality improvement project was to improve patient outcomes via the introduction of an IDE programme, evaluate patient uptake and sustainability and enhance the engagement of routine haemodialysis (HD) staff with the delivery of the IDE programme. Methods: We developed and refined an IDE programme, including interventions designed to increase patient and staff engagement that were based on the Theoretical Domains Framework (TDF), using a series of 'Plan, Do, Study, Act' (PDSA) cycles. The programme was introduced at two UK National Health Service HD units. Process measures included patient uptake, withdrawals, adherence and HD staff involvement. Outcome measures were patient-reported functional capacity, anxiety, depression and symptomology. All measures were collected over 12 months. Results: A total of 95 patients were enrolled in the IDE programme; 64 (75%) were still participating at 3 months, decreasing to 41 (48%) at 12 months. Adherence was high (78%) at 3 months, decreasing to 63% by 12 months. The provision of IDE by HD staff accounted for a mean of 2 (5%) sessions per 3-month time point. Patients displayed significant improvements in functional ability (P = 0.01) and a reduction in depression (P = 0.02) over 12 months, but the effects seen were limited to those who completed the programme. Conclusions: A theory-based IDE programme is feasible and leads to improvement in functional capacity and depression. Sustaining IDE over time is complicated by high levels of patient withdrawal from the programme. Significant change at an organizational level is required to enhance sustainability by increasing HD staff engagement or access to professional exercise support. PMID- 30524719 TI - Rationale and design of the PHYSICALFAV trial: a randomized controlled trial to evaluate the effect of preoperative isometric exercise on vascular calibre and maturation of autologous arteriovenous fistulas. AB - Background: A good vascular access (VA) is vital for haemodialysis (HD) patients. HD with an autologous arteriovenous fistula (AVF) is associated with higher survival, lower health care costs and fewer complications. Although a distal forearm AVF is the best option, not all patients are good candidates for this approach and the primary failure rate ranges from 20% to 50%. The optimal AVF depends mainly on the anatomical and haemodynamic characteristics of the artery and the vein chosen for the anastomosis. These characteristics can be modified by performing physical exercise. VA guidelines suggest that isometric exercises should be performed both before and after the AVF is created. While the literature contains few data on the potential efficacy of preoperative exercise, small observational studies point to an improvement in venous and arterial calibre. Postoperative exercise also seems to improve maturation, although there is no consensus on the appropriate exercise protocol. Methods: The PHYSICALFAV trial (NCT03213756) is an open-label, multicentre, prospective, controlled, randomized trial designed to evaluate the usefulness of preoperative isometric exercise (PIE) in pre-dialysis patients or in prevalent HD patients who are candidates for a new AVF. Patients are randomized 1:1 to the PIE group (isometric exercises for 8 weeks) or the control group (no exercise). The main endpoint is whether the rate of primary failure is lower in the PIE group than in the control group. Results: The trial has already started, with 40 patients having been enrolled as of 21 March 2018; 26.5% of the estimated sample. PMID- 30524720 TI - Effect of sirolimus on carotid atherosclerosis in kidney transplant recipients: data derived from a prospective randomized controlled trial. AB - Background: In animal models, the mammalian target of rapamycin inhibitors (mTORIs) may prevent atherogenesis by the regulation of homeostasis of cholesterol and by a reduced inflammatory response. The aim of this study is to compare the carotid intima-media thickness (cIMT) between de novo tacrolimus/mycophenolate and tacrolimus/sirolimus at low doses. The cIMT is considered a surrogate marker of atherosclerosis. Methods: We evaluated cIMT at baseline and at 6 and 12 months after kidney transplantation in a database derived from a previously published trial. That trial had prospectively randomly assigned kidney transplant recipients older than 60 years of age to one of two groups: tacrolimus/sirolimus (n = 21) or tacrolimus/mycophenolate (n = 23). The cIMT was evaluated by using ultrasound in the common carotid artery wall on both sides. Results: The total and high-density lipoprotein cholesterol levels were higher in the sirolimus group at 6 and 12 months. The cIMT decreased over time at 6 and 12 months in the sirolimus group (P = 0.012); this decrease continued to be significant in a model adjusted for age, sex, presence of diabetes, statin use and smoking. Conclusions: The use of sirolimus plus tacrolimus de novo in kidney transplantation is associated with a reduction in cIMT after 12 months, a decrease more significant than seen with the combination of mycophenolate plus tacrolimus. This suggests a class effect of mTORI in the prevention of atherosclerosis. PMID- 30524721 TI - Residual renal function in incremental dialysis. AB - Incremental haemodialysis has the potential to allow better preservation of renal function, is less invasive to the patient and has lower cost. Despite these advantages, it is not commonly applied. This may be due to uncertainty about how to account for renal function in the prescription of dialysis and measurement of dose. In this issue, Vartia describes the practical basis for including the effect of renal function in the prescription and quantification of dialysis. He uses a well-known and validated urea kinetic model to calculate time average urea concentrations and the equivalent renal clearance (EKR) from dialysis. The effect of renal function is amplified by a weighting factor to account for the relatively greater effect of renal function compared with dialysis with the same urea clearance. In that way, patients on differing dialysis regimens can be dialysed with the same target dose. A further step would be to use a downward adjusting factor for dialysis to convert the urea clearance by dialysis (as EKR) to a glomerular filtration rate (GFR) equivalent. A factor of 0.75 is suggested. In that way, dialysis dose can be reported as GFR equivalent in mL/min/1.73 m2, comparable between different types of dialysis and also to renal function without dialysis. PMID- 30524722 TI - The reproducibility of cardiac magnetic resonance imaging measures of aortic stiffness and their relationship to cardiac structure in prevalent haemodialysis patients. AB - Background: Aortic stiffness is one of the earliest signs of cardiovascular disease (CVD) in patients with chronic kidney disease and an independent predictor of mortality. It is thought to drive left ventricular (LV) remodelling, an established biomarker for mortality. The relationship between direct and indirect measures of aortic stiffness and LV remodelling is not defined in dialysis patients, nor are the reproducibility of methods used to assess aortic stiffness using cardiac magnetic resonance (CMR) imaging. Methods: Using 3T CMR, we report the results of (i) the interstudy, interobserver and intra-observer reproducibility of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (aPWV) in 10 haemodialysis (HD) patients and (ii) the relationship between AAD, DAD and aPWV and LV mass index (LVMi) and LV remodelling in 70 HD patients. Results: Inter- and intra observer variability of AAD, DAD and aPWV were excellent [intraclass correlation (ICC) > 0.9 for all]. Interstudy reproducibility of AAD was excellent {ICC 0.94 [95% confidence interval (CI) 0.78-0.99]}, but poor for DAD and aPWV [ICC 0.51 ( 0.13-0.85) and 0.51 (-0.31-0.89)]. AAD, DAD and aPWV associated with LVMi on univariate analysis (beta = -0.244, P = 0.04; beta =-0.315, P < 0.001 and beta = 0.242, P = 0.04, respectively). Only systolic blood pressure, serum phosphate and a history of CVD remained independent determinants of LVMi on multivariable linear regression. Conclusions: AAD is the most reproducible CMR-derived measure of aortic stiffness in HD patients. CMR-derived measures of aortic stiffness were not independent determinants of LVMi in HD patients. Whether one should target blood pressure over aortic stiffness to mitigate cardiovascular risk still needs determination. PMID- 30524723 TI - Fungal peritonitis in peritoneal dialysis: a 34-year single centre evaluation. AB - Backgound: Fungal peritonitis (FP) is one of the most important causes of peritoneal dialysis (PD) failure, often burdened by increased morbility and mortality. This study evaluates the clinical course of FP cases that arose between 1983 and 2016 in a single PD unit. Methods: We conducted a retrospective observational analysis of FP episodes recorded in the Baxter POET (Peritonitis Organism Exit sites Tunnel infections) registry and clinical records. FP incidence rate, PD and patients' survival and clinical characteristics of the study population were analysed, taking into account the evolution of clinical practice during the study period as a result of technical innovation, scientific evidence and guideline history. Results: Fourteen FP cases (2.8%) were detected. The overall incidence of PD peritonitis was one episode/27 patient-months. Candida parapsilosis was the most frequently (50%) detected yeast. Seventy-five per cent of cases were considered secondary FP. This group experienced 2.6+/-1.7 bacterial peritonitis before FP, most frequently due to Staphylococcus and Enterococcus species. Most patients were treated with fluconazole for >=8 days. All subjects were hospitalized for a median time of 25 days. Tenckhoff catheter removal occurred in all cases of FP and all patients were transferred to haemodialysis. Two patients died. From December 2010 to December 2016, no FP episodes were recorded. Conclusions: FP is confirmed as a significant cause of PD drop out and increases patients' mortality risk. Prompt diagnosis of FP, targeted antifugal therapy and rapid PD catheter removal are essential strategies for improved patient and PD survival. PMID- 30524724 TI - Peritoneal dialysis fluid biocompatibility impact on human peritoneal membrane permeability. AB - Background: We have compared the effects of conventional lactate-based peritoneal dialysis fluid (CPDF) with respect to bicarbonate/lactate-based fluid on peritoneal ultrafiltration (UF) and peritoneal permeability, and on variations on gene expression in cells isolated from effluents of patients' peritoneal bags. Methods: This was a non-randomized sequential prospective study including all incident peritoneal dialysis (PD) patients (n = 40) recruited in our centre. Peritoneal equilibration tests (PETs) were performed using CPDF or BPDF both containing 2.27% glucose during a 48-h interval in four different sequences. Gene expression variation of selected genes was measured by reverse transcription polymerase chain reaction in mesothelial cells obtained from the total drained fluid during the PET. Results: In the overall study, the use of BPDF was associated with significantly lower mass transfer area coefficient for urea and creatinine, longer accelerated peritoneal examination test times for urea and creatinine, lower total pore area available for exchange over diffusion distance and lower UF. There were no differences in the gene expression of aquaporins 1-3, endothelial and inducible nitric oxide synthase (NOS3 and NOS2), or interleukin 6. The SNAIL and E-CADHERIN gene expression normalized ratio was evaluated in peritoneal effluents of cells obtained from CPDF and BPDF. We observed that the SNAIL/E-CADHERIN mRNA ratio decreased when the dialysis sequence started with BPDF and went on to CPDF, but not when the sequence was the opposite. Conclusion: This study shows that those patients who started PD treatment with BPDF were characterized by a better biocompatibility profile. BPDF associates with lower peritoneal permeability to small molecules and lower UF. PMID- 30524725 TI - Genome-wide differences in DNA methylation changes in caprine ovaries between oestrous and dioestrous phases. AB - Background: DNA methylation plays a vital role in reproduction. Entire genome DNA methylation changes during the oestrous phase (ES) and dioestrous phase (DS) in the ovaries of Guanzhong dairy goats were investigated using bisulphite sequencing to understand the molecular biological mechanisms of these goats' oestrous cycle. Results: We discovered distinct genome-wide DNA methylation patterns in ES and DS ovaries. A total of 26,910 differentially methylated regions were upregulated and 21,453 differentially methylated regions were downregulated in the ES samples compared with the DS samples (P-values <=0.05 and fold change of methylation ratios >=2). Differentially methylated region analysis showed hypomethylation in the gene body regions and hypermethylation in the joining region between upstream regions and gene bodies. The methylation ratios of the STAR, FGF2, FGF12, BMP5 and SMAD6 genes in the ES samples were lower than those of the DS samples (P-values <=0.05 and fold change of methylation ratios >=2). Conversely, the methylation ratios of the EGFR, TGFBR2, IGF2BP1 and MMD2 genes increased in the ES samples compared with the DS samples. In addition, 223 differentially methylated genes were found in the GnRH signalling pathway (KO04912), ovarian steroidogenesis pathway (KO04913), oestrogen signalling pathway (KO04915), oxytocin signalling pathway (KO04921), insulin secretion pathway (KO04911) and MAPK signalling pathway (KO04010). Conclusions: This study is the first large-scale comparison of the high-resolution DNA methylation landscapes of oestrous and dioestrous ovaries from dairy goats. Previous studies and our investigations have shown that the NR5A2, STAR, FGF2 and BMP5 genes might have potential application value in regulating caprine oestrus. PMID- 30524726 TI - p53-mediated adaptation to serine starvation is retained by a common tumour derived mutant. AB - Background: In response to oncogenic stress, the tumour suppressor protein p53 can induce the elimination of cells through induction of cell death or senescence, helping to restrain malignant progression. Conversely, under nutrient stress, p53 can protect cells by supporting metabolic adaptation. Many cancers express mutant p53 proteins that have lost the cell-elimination properties of wild-type p53. However, a previous report showed that a tumour-derived mutant can retain the ability to support cells under glutamine starvation. Results: We show that a commonly occurring p53 mutant, R248W, retains wild-type ability to support survival under serine starvation. R248W, but not R175H, can engage p21 and MDM2, which both function to limit oxidative stress and facilitate the switch to de novo serine synthesis. In vivo, the growth of R248W-expressing tumours is resistant to dietary depletion of serine and glycine, correlating with an increased capacity to limit ROS compared to tumours expressing R175H. Human cancers expressing this p53 mutant show a worse outcome. Conclusion: Our work shows that mutant p53s can selectively retain wild-type p53 functions that allow adaptation to serine starvation through the activation of antioxidant defence pathways. Tumours containing this p53 mutation are resistant to serine-limited conditions and less responsive to therapy. PMID- 30524728 TI - OSAS: its burden increases, not enough the awareness. PMID- 30524727 TI - Implementation of human biomonitoring in the Dehcho region of the Northwest Territories, Canada (2016-2017). AB - Background: Human biomonitoring represents an important tool for health risk assessment, supporting the characterization of contaminant exposure and nutrient status. In communities where country foods (locally harvested foods: land animals, fish, birds, plants) are integrated in the daily diet, as is the case in remote northern regions where food security is a challenge, such foods can potentially be a significant route of contaminant exposure. To assess this issue, a biomonitoring project was implemented among Dene/Metis communities of the Dehcho region of the Northwest Territories, Canada. Methods: Participants completed dietary surveys (i.e., a food frequency questionnaire and 24-h recall) to estimate food consumption patterns as well as a Health Messages Survey to evaluate the awareness and perception of contaminants and consumption notices. Biological sampling of hair, urine and blood was conducted. Toxic metals (e.g., mercury, lead, cadmium), essential metals (e.g., copper, nickel, zinc), fatty acids, and persistent organic pollutants (POPs) were measured in samples. Results: The levels of contaminants in blood, hair and urine for the majority of participants were below the available guidance values for mercury, cadmium, lead and uranium. However, from the 279 participants, approximately 2% were invited to provide follow up samples, mainly for elevated mercury level. Also, at the population level, blood lead (GM: 11 MUg/L) and blood cadmium (GM: 0.53 MUg/L) were slightly above the Canadian Health Measures Survey data. Therefore, although country foods occasionally contain elevated levels of particular contaminants, human exposures to these metals remained similar to those seen in the Canadian general population. In addition, dietary data showed the importance and diversity of country foods across participating communities, with the consumption of an average of 5.1% of total calories from wild-harvested country foods. Conclusion: This project completed in the Mackenzie Valley of the Northwest Territories fills a data gap across other biomonitoring studies in Canada as it integrates community results, will support stakeholders in the development of public health strategies, and will inform environmental health issue prioritization. PMID- 30524730 TI - Is antagonistic pleiotropy ubiquitous in aging biology? AB - Lay Summary: An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge. No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Here we briefly review the current state of knowledge on antagonistic pleiotropy both under wild and laboratory conditions. Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions. PMID- 30524731 TI - Sound the alarm: motorboat disturbance to fish embryos depends on engine type. PMID- 30524729 TI - From CPAP to tailored therapy for obstructive sleep Apnoea. AB - Obstructive Sleep Apnoea (OSA) is a common sleep disorder that is associated with daytime symptoms and a range of comorbidity and mortality. Continuous Positive Airway Pressure (CPAP) therapy is highly efficacious at preventing OSA when in use and has long been the standard treatment for newly diagnosed patients. However, CPAP therapy has well recognised limitations in real world effectiveness due to issues with patient acceptance and suboptimal usage. There is a clear need to enhance OSA treatment strategies and options. Although there are a range of alternative treatments (e.g. weight loss, oral appliances, positional devices, surgery, and emerging therapies such as sedatives and oxygen), generally there are individual differences in efficacy and often OSA will not be completely eliminated. There is increasing recognition that OSA is a heterogeneous disorder in terms of risk factors, clinical presentation, pathophysiology and comorbidity. Better characterisation of OSA heterogeneity will enable tailored approaches to therapy to ensure treatment effectiveness. Tools to elucidate individual anatomical and pathophysiological phenotypes in clinical practice are receiving attention. Additionally, recognising patient preferences, treatment enhancement strategies and broader assessment of treatment effectiveness are part of tailoring therapy at the individual level. This review provides a narrative of current treatment approaches and limitations and the future potential for individual tailoring to enhance treatment effectiveness. PMID- 30524732 TI - Patent challenges in the procurement and supply of generic new essential medicines and lessons from HIV in the southern African development community (SADC) region. AB - High medicines prices increasingly pose challenges for universal access to treatments of communicable and non-communicable diseases. New essential medicines are often patent-protected which sustains high prices in many countries, including in low- and middle-income countries. To respond to the HIV/AIDS crisis of the late nineties and to increase access to antiretroviral treatment, certain flexibilities contained in the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS flexibilities) have been clarified and in some respects strengthened at the global level. They have been applied by a number of countries to ensure access to lower-priced generic medicines to treat HIV/AIDS. Governments in the South African Development Community (SADC) have also used TRIPS flexibilities to gain access to lower-priced generic medicines. This paper documents 15 instances of the use of TRIPS flexibilities by eight SADC Member States during the period 2001-2016. Of those, six concerned least developed countries (LDCs) that declared non-enforcement of pharmaceutical patents pursuant to a new LDC transition provision. All instances occurred in the context of medicines procurement for HIV treatment. Such flexibilities can, however, also be used to overcome patent barriers to gain access to generic medicines for other diseases, including NCDs. The SADC, being a regional bloc with over 50% least developed country Members, can make use of the regional exception, a TRIPS flexibility that facilitates the production or procurement of generic medicines to the benefit of the entire region. SADC's Pharmaceutical Business Plan proposes strategies for increased collaboration and pooled procurement of medicines. PMID- 30524733 TI - The association between long working hours and work-related musculoskeletal symptoms of Korean wage workers: data from the fourth Korean working conditions survey (a cross-sectional study). AB - Background: It has been reported that long working hours are hazardous to the workers' health. Especially, work-related musculoskeletal disorders (WMSDs) have been considered as one of the significant health issues in workplace. The objective of this study was to identify the association between long working hours and work-related musculoskeletal symptoms. Methods: The analysis was conducted using data from the Fourth Korean Working Conditions Survey (KWCS). Subjects of this study were 24,783 wage workers and divided into three groups according to the weekly working hours, which were <= 40, 41-52 and > 52 h. The relationship between long working hours and work-related musculoskeletal symptoms was analyzed by multivariate logistic regression method after adjusting for general, occupational characteristics including specific working motions or postures and psychosocial factors. Results: Approximately 18.4% of subjects worked more than 52 h per week and 26.4 and 16.4% of male subjects and 33.0 and 23.4% of female subjects experienced work-related upper and lower limb pains, respectively, over the last 12 months. Moreover, the prevalence of upper and lower limb pain was increased in both genders as the weekly working hours increased. The odds ratios (ORs) of upper limb pain for those working 41-52 h and more than 52 h per week when adjusted for general, occupational characteristics including specific motions or postures and psychosocial factors were 1.36 and 1.40 for male workers and 1.26 and 1.66 for female workers compared to the reference group, respectively. Furthermore, ORs of lower limb pain for the same weekly working hour groups were 1.26 and 1.47 for male workers and 1.20 and 1.47 for female workers, respectively. Conclusions: Long working hours were significantly related to work-related musculoskeletal symptoms in Korean wage workers and appropriate interventions should be implemented to reduce long working hours that can negatively affect workers' health. PMID- 30524734 TI - Changes in gastrointestinal symptoms and food tolerance 6 months following weight loss surgery: associations with dietary changes, weight loss and the surgical procedure. AB - Background: Gastrointestinal (GI) co-morbidity is common in obese patients, but the effect of weight loss surgery on GI symptoms is incompletely elucidated. The aims of the present study were to explore changes in GI symptoms and food tolerance following weight loss surgery and to study whether such changes were associated with dietary modifications and/or the type of surgical procedure [Roux en-Y Gastric Bypass (RYGB) versus Vertical Sleeve Gastrectomy (VSG)]. Methods: Participants: Patients with morbid obesity scheduled for weight loss surgery.The patients filled in paper-based questionnaires addressing diet, GI symptoms (bloating, pain, satiety, constipation and diarrhea) and food tolerance/quality of alimentation (satisfaction about current food intake, tolerance to specific foods and frequency of vomiting/regurgitation/reflux) 6 months prior to and 6 months after the surgery. Patients with pre-existing major GI co-morbidity or previous major GI surgery were excluded. Results: Fifty-four patients (RYGB/VSG: 43/11) were included. Constipation and satiety increased and food tolerance decreased significantly after the surgery (all p-values < 0.05). The increase in satiety was significantly more notable after VSG than after RYGB (p < 0.05).The increase in satiety also correlated with an overall reduction in food tolerance (rho: -0.488, p < 0.01). Divergent changes were seen in the frequency of vomiting/regurgitation/reflux, with a decline after RYGB (p = 0.01) and an increase after VSG (p = 0.06). Intakes of energy, macronutrients, fiber and fluid decreased significantly after the surgery (all p-values < 0.05), but did not correlate with the changes in constipation, satiety or food tolerance (all p values > 0.05). Pre-operatively, total energy intake correlated with bloating and abdominal pain (rho = 0.343 and 0.310 respectively, p < 0.05 for both), but these correlations did not persist 6 months after the surgery (rho = 0.065 and 0.054 respectively, p > 0.05 for both). Conclusion: A high caloric intake may explain some of the GI symptoms experienced by non-operated obese patients. The worsening or new-onset of symptoms post-surgery is likely due to anatomical or physiological alterations following surgery. The increase in satiety and the decrease in food tolerance are likely explained by the restrictive nature of the surgeries, as satiety increased more after VSG than after RYGB and correlated with an overall reduction in food tolerance. PMID- 30524735 TI - Separating "good" from "bad" faecal dysbiosis - evidence from two cross-sectional studies. AB - Background: Faecal dysbiosis associated with the use of metformin has been conceived as a favourable ("good") dysbiosis and that with intake of non nutritive sweeteners (NNS) as unfavourable ("bad"). The study aimed to construct an alternative dysbiosis index (ADI) for the separation of the dysbioses into "good" and "bad", and to validate the ADI. Methods: Subjects with morbid obesity were included. Use of NNS and drugs were noted, IBS was classified according to the Rome III criteria and the severity measured with the Irritable bowel severity scoring system (IBSSS). Faecal dysbiosis was tested with GA-Map TM Dysbiosis test (Genetic Analysis AS, Oslo, Norway). The result was given as Dysbiosis Index (DI) scores 1-5, score > 2 indicates dysbiosis. An ADI was constructed and validated in subjects with IBS at another hospital. Results: Seventy-six women and 14 men aged 44.7 years (SD 8.6) with BMI 41.8 kg/m2 (SD 3.6) were included. Dysbiosis was associated with the use of NNS and metformin, but not with IBS or IBSSS. An ADI based on differences in 7 bacteria was positively and negatively associated with the "good" metformin dysbiosis and the "bad" NNS dysbiosis respectively. The ADI was also negatively associated with IBSSS (a "bad" dysbiosis). The negative associations between ADI and IBS and IBSS were confirmed in the validation group. Conclusions: The new ADI, but not the DI, allowed separation of the "good" and "bad" faecal dysbiosis. Rather than merely reporting dysbiosis and degrees of dysbiosis, future diagnostic tests should distinguish between types of dysbiosis. PMID- 30524736 TI - Brain activation to high-calorie food images in healthy normal weight and obese children: a fMRI study. AB - Background: Understanding how normal weight and obese young children process high calorie food stimuli may provide information relevant to the neurobiology of eating behavior contributing to childhood obesity. In this study, we used fMRI to evaluate whether brain activation to high-calorie food images differs between normal weight and obese young children. Methods: Brain activation maps in response to high-calorie food images and non-food images for 22 healthy, 8-10 years-old children (N = 11/11 for normal weight/obese respectively) were generated and compared between groups. Results: When comparing brain activation differences in response to viewing high-calorie food versus non-food images between normal weight and obese children, group differences were observed in areas related to memory and cognitive control. Specifically, normal weight children showed higher activation of posterior parahippocampal gyri (PPHG) and dorsomedial prefrontal cortex (DMPFC). Further ROI analyses indicated higher activation strength (Z scores) in the right PPHG (p = 0.01) and higher activation strength (p < 0.001) as well as a larger activation area (p = 0.02) in the DMPFC in normal weight than obese children. Conclusions: Normal weight and obese children process high-calorie food stimuli differently even from a young age. Normal weight children exhibit increased brain activation in regions associated with memory and cognitive control when viewing high-calorie food images. PMID- 30524737 TI - Obesity moderates the complex relationships between inflammation, oxidative stress, sleep quality and depressive symptoms. AB - Background: The relationship between obesity and depression is complex. This study assessed the impact of body mass index (BMI) on the link between BMI, inflammation, oxidative stress, sleep quality and self-reported depressive symptoms. Methods: We used data from the U.S. National Health and Nutritional Examination Survey 2005-2008 cycles (n = 9133; >=20y). Depressive symptoms and sleep quality were determined from questionnaires. C-reactive Protein (CRP) was used as a biomarker of inflammation and gamma-glutamyltransferase was used to assess oxidative stress. The relationship between depressive symptoms, sleep quality, and biomarkers were assessed with regression models. The moderating effects of BMI and sex were tested. Results: BMI was a significant moderator of the relationship between gamma-glutamyltransferase and depressive symptoms (p = 0.02), but not CRP or sleep quality. Higher BMI increased odds of depressive symptoms in women (OR (95% CI): 3.92 (1.85-8.30) for BMI >=25 to < 30 kg/m2; 3.17 (1.53-6.58) for BMI >=30 to < 35 kg/m2; and 7.38 (2.11-25.76) for BMI >=35 kg/m2). BMI was also a significant moderator of gamma-glutamyltransferase levels in those with vs without depressive symptoms. Those with depressive symptoms had 24% poorer sleep quality compared to those without depressive symptoms after adjusting for inflammation, oxidative stress and other confounders. Conclusions: The link between oxidative stress and depressive symptoms may be particularly relevant for females and people living with obesity. People with depressive symptoms also have a substantial reduction in sleep quality. Thus, research should examine these relationships prospectively to inform and improve the mental health of the adult population in developed countries. PMID- 30524738 TI - The complexity of reaching and maintaining a healthy body weight - the experience from adults with a mobility disability. AB - Background: People with a disability affecting their mobility are more likely to be overweight or obese than those without a mobility disability. The guidelines on how to prevent and treat overweight/obese adults in the general population have not been adapted to the needs of people with a mobility disability. A reasonable useful first step in the process of adapting such guidelines is to conduct a qualitative study of the perceived needs of these people. Aim: The aim was to explore the experienced importance of body weight among adults with a mobility disability and their perceived needs and actions to reach and maintain a healthy weight. Method: This was an explorative qualitative study based on individual interviews and qualitative content analysis. An inductive analysis of the interviews formed the basis for the establishment of sub-categories, main categories and, finally, a main theme. The twenty participants included in the study have had a mobility disability for more than two years before being recruited. Results: The overall theme, "The complex trajectory to a healthy weight", included four main categories. In the category (i) Vicious circle of problems, the participants perceived that everything was harder with the combination of a mobility disability and being overweight/obese with one factor making the other worse. In (ii) Strategies based on decisions and attempts, the participants talked about different ways of attempting to reach or maintain a healthy weight. In (iii) Internal resources, they spoke of awareness and motivation as contributory factors. In (iv) External resources - experienced and required, they spoke about feelings that their weight problems were not given high priority in primary health care. They found it difficult to get advice designed for persons with a mobility disability and felt that competence was lacking among health professionals. The participants asked for a team of professionals with adequate knowledge concerning mobility disabilities. Conclusions: People with a mobility disability combined with being overweight/obese have a complex living situation and health needs. The experiences communicated by participants may facilitate adaption of existing intervention programs or development of a new evidence-based obesity prevention program for primary health care settings. PMID- 30524739 TI - How does childhood socioeconomic position affect overweight and obesity in adolescence and early adulthood: a longitudinal study. AB - Background: Childhood socioeconomic position (SEP) has previously been associated with increased risk of overweight among children and adolescents. However, it remains uncertain whether the timing of exposure is important in relation to developing overweight in early adulthood. We aimed to examine how SEP during early (0-8 years) and late childhood (9-14 years) relates to overweight at age 15, 18 and 21. Methods: Longitudinal study in Western Denmark of 2879 young people (aged 15 in 2004). Exposure variables from registers were yearly household income, parental highest educational level and parental labour market participation (LMP), supplemented with questionnaire information about "family functioning" (age 15). Outcome variables were overweight and obesity, measured at three-time points.We analyzed the adjusted associations between childhood SEP and overweight and obesity using multinomial logistic regression, stratified on gender. Results: Early childhood: Parental lower educational level increased girls' risk of overweight and obesity at age 18 and 21 between RR = 1.8 (95% CI 1.0;3.4) and RR = 5.2 (95% CI 1.4;19.3). Girls reporting poor "family functioning" had up to twice the risk of overweight and obesity at age 21. Boys, whose fathers had a lower level of education had up to 2.4 times the risk of obesity at age 21. Parental low LMP increased boys' risk of obesity at age 18 and 21 between RR = 2.2 (95% CI 1.3;3.8) and RR = 2.8 (95% CI 1.3;6.1). Late childhood: Parental lower level of education tripled the risk of overweight and obesity among girls at age 18 and among both genders at age 21. Conclusion: This study confirmed to some extent that economic, social and psychological insecurity and inequality as measured by lower parental educational level, lower household income, low labour market participation and poor family function during childhood was associated with an increased risk of overweight and especially obesity in adolescence and early adulthood in both genders. Despite some imprecise measures, the direction of the associations pointed to several associations, which all were in the hypothesized direction. Timing of lower household income and parental low LMP in childhood seemed to be gender-specific in some way, but this warrants more studies. PMID- 30524740 TI - Discriminative ability of adiposity measures for elevated blood pressure among adolescents in a resource-constrained setting in northeast Nigeria: a cross sectional analysis. AB - Background: Several studies examining the association and discriminative ability of adiposity measures for prehypertension and hypertension among adolescents have reported varying outcomes. We aimed to determine the discriminative ability of the Body Mass index (BMI), Waist Circumference (WC), and Waist-to-Height Ratio (WHtR) adiposity measures for elevated blood pressure (prehypertension and hypertension combined) among adolescents in Gombe, northeast Nigeria. Methods: This cross-sectional study used a multi-stage sampling technique and involved 367 secondary school adolescent (10-18 years) boys and girls in Gombe Local Government Area, Gombe State, northeast Nigeria from January to September 2015. We examined and compared the associations and discriminative ability of the BMI, WC and the WHtR for elevated blood pressure using multiple logistic regression and receiver operating characteristics (ROC) curves. Area under the curves (AUC), odds ratio (OR) and 95% confidence intervals (CI) are reported. Results: All three measures of adiposity were strongly and positively associated with elevated blood pressure. The BMI obesity showed the strongest association with elevated blood pressure with odds that was double the odds of WC and triple that of WHtR [adjusted OR for BMI 15.3, 95% CI (4.8-27.9)]. The discriminative ability of adiposity measures for elevated blood pressure using AUC was comparable (0.786 for BMI, vs 0.780 for WC, vs 0.761 for WHtR). Conclusion: We provide evidence, here on the BMI, WC and WHtR to support the use of simple indirect measures of adiposity in evaluating adiposity-related risk including prehypertension and hypertension among Nigerian adolescents. PMID- 30524741 TI - Tranexamic acid therapy for postoperative bleeding after bariatric surgery. AB - Background: Tranexamic acid reduces blood loss associated with various surgical procedures. Postoperative bleeding caused by dissection or bleeding of the enteric staple lines is a well-known complication following bariatric surgery. Reoperation in order to restore hemostasis is frequently necessary (up to 2.5% in literature). The effect of conservative therapy using tranexamic acid for postoperative hemorrhage after bariatric surgery is still very much a novel technique. The aim is to present our results (reoperation rate and thrombo embolic complication rate) of tranexamic acid therapy for postoperative bleeding after bariatric surgery in comparison to those in existing literature. Methods: We retrospectively reviewed 1388 patients who underwent bariatric surgery (laparoscopic gastric bypass or laparoscopic gastric sleeve). Use of tranexamic acid, reoperation rate, transfusion rate and rate of thrombo-embolic complications were reviewed. Results: Forty-five of 1388 (3.2%) total patients experienced significant hemorrhage after bariatric surgery. Tranexamic acid was administered in 44 of these patients. A failure of the treatment with tranexamic acid was observed in four patients. The incidence of reoperation was 0.4% for the entire population. No thrombo-embolic complications were registered for patients receiving tranexamic acid. Conclusion: These findings suggest that the administration of tranexamic acid appears to be safe in reducing the reoperation rate for bleeding after bariatric surgery. PMID- 30524742 TI - Mothers' and fathers' media parenting practices associated with young children's screen-time: a cross-sectional study. AB - Background: A major contributor to the growing obesity crisis is screen based sedentary behaviour among young children. Media parenting practices may be an important determinant of children's screen time, however published research exploring the influence of parenting practices on children's screen time has mainly focused on children's television use and the parenting practices of the mother. This study examined children's use of mobile media devices (as well as television use) and included the role of fathers in media parenting, allowing a fuller understanding of the role mothers' and fathers' media parenting practices play on children's screen time in the current media environment. Methods: Secondary data analysis was conducted using data from 62 children between 1.5 and 5 years of age and their parents (39 mothers, 25 fathers), who were part of the Guelph Family Health Study - phase 2 pilot. Linear regression using generalized estimating equations was used to examine associations between media parenting practices and children's weekday and weekend screen-time. Results: Mothers' screen-time modeling, mealtime screen use, and use of screens to control behaviour were positively associated with children's weekday screen-time. Mothers' practices of monitoring screen-time and limiting screen-time were inversely associated with children's weekday screen-time. Fathers' mealtime screen use was positively associated with children's weekday screen-time; whereas fathers' monitoring screen-time and limiting setting were inversely associated with children's weekday screen-time. Fathers' modeling and use of screens to control behaviour was not significantly associated with children's weekday screen time. While most associations were similar for weekend day screen time there were a few differences: Fathers' use of screens to control behaviour was positively associated with children's weekend screen-time. Mothers' and fathers' modeling and mealtime screen use were not significantly associated with children's weekend screen time. Conclusion: Mothers' and fathers' media parenting practices were associated with children's screen-time. Interventions aimed at reducing children's screen-time should address both mothers' and fathers' media parenting practices. PMID- 30524743 TI - Understanding the psychosocial impact of weight loss following bariatric surgery: a qualitative study. AB - Background: Bariatric surgery leads to changes in mental health, quality of life and social functioning, yet these outcomes differ among individuals. In this study, we explore patients' psychosocial experiences following bariatric surgery and elucidate the individual-level factors that may drive variation in psychosocial outcomes. Methods: Eleven semi-structured focus groups with Michigan Bariatric Surgery Collaborative (MBSC) patients (n = 77). Interviews were audio recorded, transcribed verbatim, and analyzed using a grounded theory approach. Data on participant demographic characteristics were abstracted from the MBSC clinical registry. Results: Most focus group participants were female (89%), white (64%), and married (65%). We identified three major themes: (1) change in self-perception; (2) change in perception by others; and (3) change in relationships. Each theme includes 3 sub-themes, demonstrating a range of positive and negative psychosocial experiences. For example, weight loss led to increased self-confidence among many participants while others described a loss of self-identity. Some noted improved relationships with family or friends while others experienced worsening or even loss of relationships due to perceived jealousy. Conclusion: Weight loss following bariatric surgery leads to complex changes in self-perception and inter-personal relationships, which may be proximal mediators of commonly assessed mental health outcomes such as depression. Individuals considering bariatric surgery may benefit from anticipatory guidance about these diverse experiences, and post-surgical longitudinal monitoring should include evaluation for adverse psychosocial events. PMID- 30524744 TI - Developing a patient-centered outcome for targeting early childhood obesity across multiple stakeholders. AB - Background: Patient-centered outcome measures for childhood obesity are limited. Identifying outcomes that patients and families consider important could be a viable avenue for better engagement of patients and interventions that are efficacious and acceptable to patients. Latino children experience high rates of obesity, and under-recognition of obesity in preschool aged children is common. Methods: We used growth chart data to identify low-income, Latino children 2-5 years of age with obesity who decreased their adiposity (positive deviants) and a set of controls. We used qualitative interview data to identify themes around goals parents used in addressing weight. Then, we applied a modified Delphi approach across groups of caregivers and providers to identify common goals. We conducted focus groups to explore conflicts and congruency between caregivers and providers related to goals. Using the focus group data, we developed a decision tool for use between patients and providers relevant for early childhood obesity. Results: We identified 257 children who successfully reduced adiposity (positive deviants) from 1621 eligible growth charts. From interviews with 44 parents (21 positive deviants and 23 controls), we coded and categorized outcomes such as increased happiness, clothing size and improved activity. We recruited 81 parents, grandparents and health care providers to participate in the modified Delphi process of ranking outcomes by importance and feasibility. Focus groups (2, total n = 24) suggested potential methods for a common framework to discuss goals, including a modified growth chart. We created a decision-tool that incorporated a growth chart and a section for discussion of patient-centered goals. A final focus group (1, n = 10) provided feedback on the tool as acceptable and potentially useful. Conclusions: The development of a patient centered tool around achieving a healthy weight in early childhood identified common goals between providers and parents. While the tool has been developed, prospective testing of this patient-centered tool and its effects on engagement, parent motivation, and behavior change would be a useful next step. PMID- 30524745 TI - Prevalence and correlates of abdominal obesity among adults in Uganda: findings from a national cross-sectional, population based survey 2014. AB - Background: Overweight and obesity are associated with health complications the gravity of which, vary with the regional deposition of the excess fat. The Body Mass Index (BMI) is often used to measure obesity although is an inferior predictor of cardiovascular disease risk mortality and morbidity compared with measures of abdominal obesity. We analyzed data from Uganda's 2014 World Health Organization (WHO) STEPwise approach to surveillance of Non-communicable diseases (NCDs) survey to estimate the prevalence of abdominal obesity and associated factors to provide information on the prevention and control of overweight and obesity. Methods: Data were collected using the WHO STEPS protocol. Waist measurement was taken using a non-stretchable standard tape measure mid-way between the lowest rib and iliac crest with the subject standing at the end of gentle expiration. Participants with waist circumference > 102 cm for men and 88 cm for women were classified as abdominally obese. We used weighted modified Poisson regression with robust error variance to estimate the prevalence of abdominal obesity and associated factors. Results: Of the 3676 participants, 432 (11.8%) were abdominally obese; with the prevalence higher among females 412 (19.5%) compared with males 20 (1.3%). Compared with males, female participants were more likely to be abdominally obese Adjusted Prevalence Rate Ratio (APRR) 7.59 [5.58-10.33]. Participants who were married or cohabiting APRR 1.82 [1.29 2.57] and participants who were separated or divorced APRR 1.69 [1.17-2.46] were more likely to be abdominally obese compared with those who had never married before. Compared with rural dwellers, participants from urban areas were more likely to be abdominally obese APRR 1.29 [1.09-1.53]. Compared with participants with normal blood pressure, those with elevated blood pressure were more likely to be abdominally obese APRR 1.83 [1.57-2.14].Compared with participants without any education, those with secondary education were more likely to be abdominally obese APRR 1.42 [1.12-1.78]. Conclusions: There is a high prevalence of abdominal obesity among adults in Uganda which puts many at risk of developing associated metabolic complications. These data provide useful information for developing interventions and formulation of policies for the control and prevention of abdominal obesity in Uganda. PMID- 30524746 TI - Associations between gestational weight gain and rate of infancy weight gain in Hawai'i and Puerto Rico WIC participants. AB - Background: Excessive gestational weight gain and rapid infancy weight gain (RIWG) are associated with increased susceptibility to childhood obesity. Since low-income and minority children are particularly at risk, investigation of the associations between gestational weight gain and rate of infancy weight gain may inform childhood obesity prevention. This study investigated the associations between gestational weight gain and rate of infancy weight gain during the first four to six months postpartum in participants from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in Hawai'i and Puerto Rico. Methods: This was a cross-sectional secondary data analysis from a text message-based intervention in WIC participants in Hawai'i and Puerto Rico. The analysis included 80 mother/infant pairs from the control group who completed the follow-up visit when infants were four to six months old. Maternal weight, height, and gestational weight gain were self-reported. Infant weight was measured at baseline and follow-up. A proportional odds model was used to investigate the association between gestational weight gain and infancy weight gain rate (rapid or extremely rapid, on-track, or slow), adjusting for maternal age, pregravid body mass index (BMI) status, parity, and being up-to-date with infant vaccinations. Results: In comparison to recommended gestational weight gain, excessive and inadequate (under the recommended amount) gestational weight gain was associated with 77% decreased (adjusted odds ratio [AOR] = 0.23; 95% confidence interval [CI] = 0.08, 0.70; p = 0.01) and 71% decreased (AOR = 0.29; 95% CI = 0.09, 0.94; p = 0.04) odds of RIWG versus on-track or slow infant weight gain, respectively. In comparison to women with one child, women with two children (AOR = 0.31; 95% CI = 0.11, 0.87; p = 0.03) or three or four children (AOR = 0.24; 95% CI = 0.07, 0.88; p = 0.03) had significantly lower odds of RIWG versus on-track or slow infancy weight gain. Conclusions: Women with excessive or inadequate gestational weight gain had lower proportional odds of RIWG and were more likely to have slower infant weight gain than women who gained the recommended amount of weight. Trial registration: ClinicalTrials.gov Identifier; NCT02903186; September 16, 2016. PMID- 30524747 TI - Isolated end-stage renal disease in Sjogren's syndrome due to immune complex mediated glomerulonephritis. AB - Renal involvement is an uncommon extra-glandular manifestation in Sjogren's syndrome (SS). We present the case of a young male who presented with nephrotic range proteinuria and advanced irreversible renal disease, with positive anti-Ro antibody (Ab) and antineutrophil cytoplasmic antibody (ANCA) with myeloperoxidase (MPO) specificity. He was initially treated with steroids for suspected ANCA vasculitis but treatment was discontinued as there was no response and renal biopsy revealed interstitial lymphocytic infiltrates, advanced glomerular disease with immune complex mediated glomerulonephritis more suspicious for SS. SS usually affects exocrine glands and patients rarely have renal involvement in which cases it is commonly tubulo-interstitial nephritis. This report describes a rare case of anti-Ro Ab and MPO-ANCA positive patient with advanced irreversible renal disease due to immune-complex mediated glomerulonephritis felt to be due to SS and without any classic sicca symptoms. PMID- 30524748 TI - Conflict Detection and Logical Complexity. AB - Empirical evidence for the capacity to detect conflict between biased reasoning and normative principles has led to the proposal that reasoners have an intuitive grasp of some basic logical principles. In two studies, we investigate the boundary conditions of these logical intuitions by manipulating the logical complexity of problems where logical validity and conclusion believability conflict or not. Results pointed to evidence for successful conflict detection on the basic Modus Ponens (MP) inference, but also showed evidence for such a phenomenon on the more complex Modus Tollens (MT) inference. This suggests that both the MP and the MT inferences are simple enough for reasoners to have an intuitive grasp of their logical structure. The boundaries of logical intuition might thus reside in problems of greater complexity than these inferences. We also observed that on the invalid Affirmation of the Consequent (AC) and Denial of the Antecedent (DA) inferences, participants showed higher accuracy on the inference that was expected to be more complex (DA), and no evidence for successful conflict detection was found on these forms. Implications for the logical intuition framework are discussed. PMID- 30524749 TI - The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1): study protocol and review of literature. AB - Persistent pulmonary hypertension of the newborn (PPHN) is a relatively common condition which results in a mortality of up to 33%. Up to 40% of infants treated with nitric oxide (iNO) either have a transient response or fail to demonstrate an improvement in oxygenation. Milrinone, a selective phosphodiesterase 3 (PDE3) inhibitor with inotropic and lusitropic properties may have potential benefit in PPHN. This pilot study was developed to assess the impact of milrinone administration on time spent on iNO in infants with PPHN. This is a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation of 20 infants. In this pilot study, we hypothesise that infants >=34 weeks gestation and >= 2000 g with a clinical and echocardiography diagnosis of PPHN, intravenous milrinone used in conjunction with iNO will result in a reduction in the time spent on iNO. In addition, we hypothesise that milrinone treatment will lead to an improvement in myocardial performance and global hemodynamics when compared to iNO alone. We will also compare the rate of adverse events associated with the milrinone, and the pre-discharge outcomes of both groups. The purpose of this pilot study is to assess the feasibility of performing the trial and to obtain preliminary data to calculate a sample size for a definitive multi-centre trial of milrinone therapy in PPHN. Trial registration: www.isrctn.com; ISRCTN:12949496; EudraCT Number:2014-002988-16. PMID- 30524750 TI - Impact of relative dose intensity on bone marrow suppression induced by S-1: retrospective observational study. AB - Background: S-1 (a combination of tegafur, gimeracil, and oteracil) is used to treat various cancers. Bone marrow suppression is a dose-limiting toxicity of S 1. The relationship between relative dose intensity (RDI) and bone marrow suppression has not been investigated. Hence, we aimed to elucidate the threshold for RDI to identify bone marrow suppression induced by S-1. Methods: In this retrospective cohort study, patients who initiated S-1 treatment at Tokyo Women's Medical University, Medical Center East between June 2015 and June 2017 were included. Bone marrow suppression induced by S-1 was assessed using Common Terminology Criteria for Adverse Events version 4.0. The relationships between grade 3 or higher bone marrow suppression induced by S-1 and RDIs (i.e., 70, 75, and 80%) were investigated using the multivariate Cox proportional hazard model. Results: We identified 143 patients in this study. The median RDI was 78.8%. Bone marrow suppression induced by S-1 developed in 19 (13.3%) patients. The multivariate Cox proportional hazard model revealed that grade >= 2 lymphocytopenia was associated with bone marrow suppression induced by S-1 regardless of the threshold for RDI. In addition, RDI > 75% [hazard ratio (HR) = 1.71, p < 0.05] and RDI > 80% (HR = 1.65, p < 0.05) were associated with bone marrow suppression induced by S-1. Conclusions: Reduced dose of S-1 still has the risk of developing bone marrow suppression. Clinicians should assess RDI to identify high risk patients with bone marrow suppression induced by S-1. PMID- 30524751 TI - Comparative evaluation of ultrasonography with clinical respiratory score in diagnosis and prognosis of respiratory diseases in weaned dairy buffalo and cattle calves. AB - Background: Respiratory troubles have economic impacts in countries where livestock industry is an important segment of the agricultural sector, as well as these problems may cause significant economic losses for bovine producers. Various practical methods are used to assess diseases that affect the bovine respiratory system. Ultrasonography is a noninvasive tool that has been used frequently in diagnosis of various animal diseases. The present study was designed to establish whether thoracic ultrasonography is a diagnostic tool for detection of respiratory troubles in weaned buffalo and cattle calves, as well as to assess its prognostic value in comparison with clinical respiratory scores. Thirty five (15 buffalo and 20 cattle) calves were included. Twelve (6 buffalo and 6 cattle) clinically healthy calves were enrolled as controls. Results: Based on physical examinations, clinical respiratory scores (CRS), ultrasound lung scores (ULS) and postmortem findings, animals were classified into 4 groups as pulmonary emphysema (n = 8), interstitial pulmonary syndrome (n = 7), bronchopneumonia (n = 12), and pleurisy (n = 8). The mean values of CRS and ULS were significantly higher in diseased calves (P < 0.01). In calves with pulmonary emphysema and interstitial syndrome, thoracic ultrasonography revealed numerous comet-tail artifacts, which varied in numbers and imaging features. Furthermore, variable degrees of pulmonary consolidation with alveolograms and bronchograms were noticed in bronchopneumonic calves. In addition, thick irregular or fragmented pleura with pleural effusions and fibrin shreds were imaged in calves with pleurisy. A weak correlation was calculated between CRS and ULS (r = 0.55, P < 0.01). Hematologically, the counts of white blood cells, activities of aspartate aminotransferase and partial tensions of carbon dioxide were significantly increased in all diseased groups. Serum concentrations of total globulins were higher in claves with bronchopneumonia (P < 0.05). The partial tension of oxygen was decreased in all diseased calves (P < 0.05). Conclusions: Thoracic ultrasonography is a diagnostic tool for various lung troubles and assessment the grade and severity of pulmonary diseases, as well as it can be used as a follow-up tool for evaluating the prognosis of respiratory troubles and monitoring the efficacy of therapies. PMID- 30524752 TI - Women's informed choice and satisfaction with immediate postpartum long-acting reversible contraception in Georgia. AB - Background: Several state Medicaid agencies have recently started reimbursing for long-acting reversible contraception (LARC) placement immediately postpartum. Women's perspectives are critical for ensuring that this change increases access to LARC while empowering women to choose the method and timing of contraception that best meets their needs. We conducted a pilot study in Georgia, which recently changed its Medicaid reimbursement policy, to assess women's informed choice and satisfaction with immediate postpartum LARC. Methods: We sampled all women with a live birth paid for by Georgia Medicaid during November 2015 through February 2017 who received an immediate postpartum LARC. We then used a one-to one match to sample women who did not receive immediate postpartum LARC. Women were contacted via telephone for a 25-30 min interview regarding their knowledge, attitudes, and behaviors related to immediate postpartum LARC and their satisfaction with postpartum contraception. We calculated descriptive statistics and components of informed choice overall and by receipt of immediate postpartum LARC, using chi-square tests to calculate differences by group. Results: We approached 470 women and completed interviews with 51; 25 (49%) received immediate postpartum LARC (24 implants, 1 intrauterine device). Two-thirds reported their provider discussed the option of receiving immediate postpartum LARC during prenatal care, with over 90% reporting they received all the information they needed to make a decision. Most women believed the ideal time to begin using birth control postpartum is in the hospital immediately after delivery, although this differed significantly by women's receipt of immediate postpartum LARC. Most women who received immediate postpartum LARC reported they are very or extremely happy with their device, although 40% also reported wanting their device removed at some point. Conclusions: Women on Medicaid in Georgia report making informed choices regarding immediate postpartum LARC. Among those who received immediate postpartum LARC, women report high levels of satisfaction. PMID- 30524754 TI - Ebola virus, but not Marburg virus, replicates efficiently and without required adaptation in snake cells. AB - Ebola virus (EBOV) disease is a viral hemorrhagic fever with a high case-fatality rate in humans. This disease is caused by four members of the filoviral genus Ebolavirus, including EBOV. The natural hosts reservoirs of ebolaviruses remain to be identified. Glycoprotein 2 of reptarenaviruses, known to infect only boa constrictors and pythons, is similar in sequence and structure to ebolaviral glycoprotein 2, suggesting that EBOV may be able to infect reptilian cells. Therefore, we serially passaged EBOV and a distantly related filovirus, Marburg virus (MARV), in boa constrictor JK cells and characterized viral infection/replication and mutational frequency by confocal imaging and sequencing. We observed that EBOV efficiently infected and replicated in JK cells, but MARV did not. In contrast to most cell lines, EBOV-infected JK cells did not result in an obvious cytopathic effect. Surprisingly, genomic characterization of serial-passaged EBOV in JK cells revealed that genomic adaptation was not required for infection. Deep sequencing coverage (>10,000*) demonstrated the existence of only a single nonsynonymous variant (EBOV glycoprotein precursor pre-GP T544I) of unknown significance within the viral population that exhibited a shift in frequency of at least 10 per cent over six serial passages. In summary, we present the first reptilian cell line that replicates a filovirus at high titers, and for the first time demonstrate a filovirus genus-specific restriction to MARV in a cell line. Our data suggest the possibility that there may be differences between the natural host spectra of ebolaviruses and marburgviruses. PMID- 30524755 TI - Internal Limiting Membrane Flaps for Coexistent Macular Hole and Retinal Detachment in Eyes with Proliferative Diabetic Retinopathy. AB - Purpose: To evaluate logical surgical approaches to closing macular holes in eyes with proliferative diabetic retinopathy with retinal detachment. Methods: Retrospective, interventional case series. Results: 10 eyes in 10 patients were included in this study. The inverted internal limiting membrane (ILM) flap technique was used in 2 eyes, while inverted ILM insertion was used in 5 eyes, and free ILM flaps in 3 eyes. Closed macular holes and retinal reattachment were observed in all eyes. Best corrected visual acuity improved from 1.33 +/- 0.39 preoperatively to 1.02 +/- 0.36 postoperatively (p=0.03). Conclusion: Various surgical approaches utilized in managing macular holes may effectively close macular holes and reattach retinas. This trial is registered with NCT 03618498. PMID- 30524753 TI - "Still learning and evolving in our approaches": patient and stakeholder engagement among Canadian community-based primary health care researchers. AB - Plain English summary: Increasingly, health researchers are conducting their research in partnership with non-researchers such as patients and caregivers, advocacy groups, clinicians, and policymakers. The idea behind this partnership is to make research more relevant and appropriate. However, so far there is not much evidence about how this partnership or engagement actually affects research. We conducted an online survey of 12 teams in Canada that have engaged patients and other stakeholders in community based health research, partly as a requirement to obtain funding. We found that in many cases, the teams have engaged a wide variety and large number of stakeholders, and have involved them in many different stages of their research. Teams reported that their overall experience of this approach to research has been positive, but some challenges have been encountered along the way. Some teams found that it was difficult to communicate appropriately with all the stakeholders, and to keep them informed when research was going slowly. Other teams had trouble finding government representatives to work with. Several teams noted that engagement is time consuming, and requires a lot of effort. Nevertheless, all teams reported that they had learned from the experience, and found it valuable. As a result, Canadian health care researchers are better positioned to engage with patients and other stakeholders in the future. Abstract: Background Patient and other stakeholder engagement in research is increasingly important, but there is limited evidence of its impact. In 2013, the Canadian Institutes of Health Research launched a five-year Community Based Primary Health Care (CBPHC) initiative that funded 12 teams for innovative approaches to primary health care involving engagement with patients, communities, decision-makers, and clinicians across jurisdictions in Canada. The present study examines the extent of engagement by these teams, and the factors that affected it, either as challenges or opportunities. Methods We conducted a cross-sectional web-based survey across the 12 CBPHC Innovation Teams, in which we were also participants. We used a data collection tool developed by the Patient Centered Outcomes Research Institute that included both closed and open-ended questions. Results The quantitative data showed that the CBPHC Innovation teams have engaged with diverse stakeholders at different levels and in different stages of research. Almost all teams surveyed engaged with policymakers, most with clinicians and health system representatives, and more than half with patients, mostly at the level of consultation or collaboration. There were very few instances of stakeholder-led research reported. There was a near universal recognition of the importance of communications processes/tools in facilitating engagement, whereas time was the most commonly identified challenge. In almost all cases, challenges encountered were partially if not fully resolved.The qualitative findings showed that each team's engagement was contextualized by factors such as the jurisdictions and geographic scope of the project, the number and type of stakeholders engaged and their level of involvement. These intersected with the researchers' motivations for engagement, to give rise to diverse experiences, but ones that the CBPHC teams assessed positively as an approach to research. Conclusions Over the past five years, primary health care researchers in Canada have been actively engaging with patients and other stakeholders. The wide range, extent and nature of that engagement shows that these researchers have anticipated developments in this approach to research and are thus in a position to support and strengthen future efforts to understand the impact of this engagement on health care outcomes. PMID- 30524756 TI - Prevalence of Myopia among Children Attending Pediatrics Ophthalmology Clinic at Ohud Hospital, Medina, Saudi Arabia. AB - Introduction: Around half of the visually impaired population has uncorrected refractive errors (URE), and myopia constitutes a high proportion of them. URE should be screened and treated early to prevent long-term complications. The aim of this study was to determine the prevalence of myopia among all patients attending a pediatric outpatient clinic at Ohud Hospital in Medina, Saudi Arabia (KSA). Method: This study was conducted using a convenience sample of all patients attending the clinic (1500 patients) aged between 3 and 14 years, and they were enrolled in the study during the period from May 2017 until September 2017. Result: Of 1215 subjects, only 43 (3.54%) were diagnosed with myopia. Out of the study participants, 56.8% were female and the mean age was 9.7 +/- 3.6. Myopia was more prevalent in male participants than female participants (n = 525, 4%, n = 690, 3.1%, p=0.5). Low myopia was the most common form among the screened individuals. The level of myopia was associated with the degree of the strabismus angle. Approximately 22% of patients with myopia had >25 degrees strabismus angle. There was a statistically significant association with both near work indoor and outdoor activities on weekends and the level of myopia. Conclusion: The prevalence of myopia among pediatrics patients in Medina is 3.54%. We hope that the results of this study will contribute to a better understanding of this public health issue in Saudi Arabia in order to implant a strict screening program for early detection and interventions to reduce the risk of further progression of visual impairment. PMID- 30524757 TI - Comparative Analysis of the Safety and Functional Outcomes of Anterior versus Retropupillary Iris-Claw IOL Fixation. AB - Purpose: To compare the functional and clinical outcomes of the iris-claw intraocular lens (IOL) placed on the anterior versus posterior surface of the iris. Patients and Methods: A multicenter, retrospective study. Data on eyes that underwent anterior or retropupillary iris-claw IOL implantation because of inadequate capsular support secondary to complicated cataract surgery, trauma, and dislocated/opacified IOLs since January 2015 were analyzed. For study inclusion, evaluation results had to be available in the medical records both preoperatively and at 1 and 12 months after implantation. The following parameters were compared between the groups: best-corrected distance visual acuity (BCDVA), spherical and cylindrical refractive error, endothelial cell density (ECD), central macular thickness (CMT), and percentage and type of postoperative complications. Results: In total, 60 eyes of 60 patients aged 73 +/ 13 years were included: 28 eyes (47%) involved anterior, and 32 eyes (53%) retropupillary, iris-claw IOL fixations. Preoperatively, the groups were similar in all parameters except for a significantly higher proportion of retropupillary fixations in patients who had previously experienced a closed-globe trauma (p=0.03). The groups showed comparable improvements in BCDVA after surgery (final BCDVA: 0.34 +/- 0.45 vs. 0.37 +/- 0.50 logMAR in the anterior and retropupillary placement groups, respectively). During follow-up, no group difference was observed in refractive error or CMT. Both groups experienced similarly marked ECD loss and showed similar incidence of postoperative complications, with cystoid macular edema being the most common complication. Multivariable linear regression showed that BCDVA at 1 month was the best predictor of the final BCDVA. Conclusions: Anterior chamber and posterior chamber iris-claw IOL fixations proved equally effective and safe for aphakic correction in eyes with inadequate capsular support. PMID- 30524758 TI - CardioMEMS in a Busy Cardiology Practice: Less than Optimal Implementation of a Valuable Tool to Reduce Heart Failure Readmissions. AB - Introduction: Congestive heart failure is a leading cause of cardiovascular morbidity and mortality that results in a significant financial burden on healthcare expenditure. Though various strategies have been employed to reduce hospital readmissions, one valuable tool that remains greatly underutilized is the CardioMEMS (Abbott), a remote pulmonary artery pressure-monitoring system, which has been shown to help reduce heart failure rehospitalizations in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) trial. Methods: ICD-9/ICD-10 codes for chronic heart failure were used to identify patients who presented with congestive heart failure. Of this group, those eligible for CardioMEMS device placement, as based on the CHAMPION trial definition, were selected. Subsequently, a retrospective review of the electronic medical records was completed. All patients were on ACC/AHA guideline-directed medical therapy and had at least one hospital admission for NYHA class III symptoms. Results: 473 patients met the inclusion criteria, of which, 85 patients were found to be eligible for implantation of CardioMEMS device based on the CHAMPION trial definition. Only 18/85 patients received the device, roughly 21%, and the overall CardioMEMS implantation rate was only 4% (18/473) of the total cohort. Conclusion: Despite the benefits to patients and reducing healthcare expenditure, there has been a poor adaptation of this groundbreaking technology. Our study revealed that 79% of eligible heart failure patients did not receive the device. Therefore, efforts need to be undertaken to improve physician and patient education of the device to complement the current standard of care for congestive heart failure. PMID- 30524759 TI - Phenolic-Rich Baccaurea angulata Modulates Inflammatory Biomarkers of Atherosclerosis. AB - Purpose: Cardiovascular disease (CVD) is the leading and the most critical type of chronic disease. Atherosclerosis is the most common cause of CVD. Inflammation has been progressively acknowledged as a vital and central player in the pathophysiology of atherosclerosis. Baccaurea angulata is an underutilized fruit of the island of Borneo. It was obtained from Bau, Sarawak, Malaysia. In our previous studies, B. angulata did not only increase antioxidant enzyme activities, but also slowed the lipid peroxidation process in high-cholesterol fed rabbits. It was hypothesized that B. angulata fruit would exert an anti inflammatory effect. This study, therefore, aimed at evaluating and comparing the effects of three different B. angulata whole fruit (WF) juice doses on 11 serum inflammatory biomarkers of atherosclerosis. Methods: Thirty-five male New Zealand white rabbits were divided into seven groups (n=5). Group CH was fed 1% cholesterol diet only, group C1 was fed 1% cholesterol diet and 0.5 ml/kg/day B. angulata WF juice, group C2 was fed 1% cholesterol diet and 1.0 ml/kg/day B. angulata WF juice, group C3 was fed 1% cholesterol diet and 1.5 ml/kg/day B. angulata WF juice, group N was fed standard pellet only, group N1 was fed standard pellet and 0.5 ml/kg/day B. angulata WF juice, and group N2 was fed standard pellet and 1.0 ml/kg/day B. angulata WF juice for 12 weeks. Results: The administration of the various juices reduced the concentrations of induced serum inflammatory biomarkers. Conclusion: This protective effect of B. angulata fruit against cardiovascular risk might be due to its polyphenol content. PMID- 30524760 TI - Plasmablastic Lymphoma in an Immunocompetent Patient with MDS/MPN with Ring Sideroblasts and Thrombocytosis-A Case Report. AB - Plasmablastic lymphoma (PBL) is a rare, aggressive type of B-cell non-Hodgkin lymphoma with the vast majority of patients responding poorly to treatment or progressing shortly thereafter. Cyclophosphamide-doxorubicin-vincristine prednisolone (CHOP) or CHOP-like regimens have disappointing results in this setting. We report a case of PBL arising in a previously diagnosed myelodysplastic/myeloproliferative (MDS/MPN) with ring sideroblasts and thrombocytopenia (RS-T), HIV-negative patient treated with the combination of CHOP and bortezomib. The patient achieved complete metabolic response, which has lasted one year, longer by far than would have been expected with the sole use of CHOP. PMID- 30524761 TI - Is There a Role for Biweekly Romiplostim in the Management of Chronic Immune Thrombocytopenia (ITP)? A Report of Three Cases. AB - Romiplostim is a peptibody, which stimulates platelet production by a mechanism similar to that of endogenous thrombopoietin. It has an established indication as second-line therapy in patients with chronic immune thrombocytopenia (ITP). The agent is typically administered weekly; however, there are instances where a biweekly (i.e., alternate week) dosing may be feasible in a select group of patients. We conducted a retrospective case review to evaluate the efficacy and safety of biweekly administration of romiplostim in maintaining a platelet count of >30 * 109/L in three patients with chronic ITP. Treatment was started with a weekly injection (1 ug/kg) with a dose escalation to achieve a platelet count >30 * 109/L. Once stable on weekly romiplostim, these patients received biweekly administration. No bleeding complications were noted during biweekly dosing for these patients. The current findings suggest that lengthening the dose interval of romiplostim is feasible in select patients with chronic ITP to maintain stable platelet counts. Additional studies are therefore warranted to further evaluate biweekly dosing for romiplostim to increase convenience and decrease costs for patients with chronic ITP. PMID- 30524762 TI - Rare Coexistence of Acute Monoblastic Leukemia with Chronic Lymphocytic Leukemia. AB - Acute monoblastic leukemia (AMoL) is a rare hematopoietic neoplasm, and simultaneous occurrence of acute monoblastic leukemia with chronic lymphocytic leukemia is very rare and only a few cases have been reported in the literature. We here report a rare case of dual hematological malignancy in an 85-year-old male. The peripheral blood and bone marrow examination revealed dual population of atypical cells, comprising large cells with opened-up chromatin having monocytic appearance and small mature-appearing lymphocytes. Flowcytometric immunophenotyping confirmed the monocytic lineage of cells, whereas small lymphocytes showed the immunophenotype consistent with chronic lymphocytic leukemia (CLL). The final diagnosis was made as acute monoblastic leukemia with associated CLL. This is a rare case scenario, and this highlights the importance of careful morphological examination and flowcytometric immunophenotyping in the exact characterization of hematopoietic malignancies. PMID- 30524764 TI - Cardiovascular disease in racial/ethnic minority populations: illness burden and overview of community-based interventions. AB - Cardiovascular disease, the leading cause of death in the USA, poses a unique and multilateral burden to racial/ethnic minorities. The admixture of comorbid conditions, structural barriers, and psychosocial standing complicates the prevention, diagnosis, and management of cardiovascular disease in racial/ethnic minority populations and requires newer approaches to reduce existing disparities. A discussion of the cardiovascular disease risk burden is presented, along with an overview of multi-stratified considerations for improving racial/ethnic minority cardiovascular health via community engagement. PMID- 30524763 TI - Nonsurgical Intervention in a Preeclamptic Patient with Spontaneous Spinal Epidural Hematoma. AB - Background: Spontaneous epidural hematoma (SEH) is a rare finding in pregnancy, especially since most pregnant women do not have risk factors for developing SEH. The presence of epidural anesthesia can delay the diagnosis of SEH in pregnant patients. Immediate surgical decompression is the current standard of care for treating SEH. Case Presentation: We present the case of a 37-year-old pregnant woman with preeclampsia with severe features who developed neurological deficits that were initially attributed to her epidural anesthesia. She was eventually found to have SEH with spinal stenosis at T5-T6 on MRI. Oral antihypertensives were used to keep the patient's blood pressures within normal limits, and she subsequently had complete resolution of her neurological symptoms and her SEH on imaging. Conclusion: Preeclampsia may contribute to the development of SEH in pregnancy, and strict blood pressure control may potentially provide a safe and effective alternative to neurosurgery for these patients. PMID- 30524765 TI - Mancozeb Residue on Tomatoes in Central Uganda. AB - Background: Mancozeb belongs to a group of pesticides known as dithiocarbamates (DTC) that are a non-systemic group of pesticides extensively used in Uganda to protect crops from fungal diseases. Objectives: This study was done in 5 selected districts of Central Uganda with a focus on markets and farms to investigate the current mancozeb concentrations on tomatoes and identify key areas of improvement to minimize human exposure. Methods: Tomato samples were analyzed for mancozeb residue determined as carbon disulfide (CS2) by gas chromatography-mass spectrometer (GC-MS). Results: All the samples analyzed had detectable concentrations of mancozeb residue. It was observed that farm samples had mean concentrations of 1.03+/-0.28 mg/kg, while market samples had 0.77+/-0.49 mg/kg. The study also found that farmers applied 3-6 times the dosage of mancozeb recommended by manufacturers. Furthermore, the observed pre-harvest interval after application of mancozeb was 1-2 days as opposed to 3-7 days set by manufacturers. Conclusions: The observed practices at farms are likely to put farmers and final consumers at a risk of exposure to dithiocarbamates. PMID- 30524766 TI - Mercury and Lead Contamination in Three Fish Species and Sediments from Lake Rukwa and Catchment Areas in Tanzania. AB - Background: Mining activity in the catchment area of Tanzania's Lake Rukwa is suspected of adding to the lake and connected rivers' heavy metal load. There has been no study done, however, on the levels of mercury (Hg) and lead (Pb) in lake sediment and fish muscle, and what the results could mean for human health. Objectives: This study investigated the concentration of Hg and Pb in lake sediment and in the muscles of African sharptooth catfish (Clarias gariepinus), Lake Rukwa tilapia (Oreochromis rukwaensis) and Singida tilapia (Oreochromis esculentus) from Tanzania's Lake Rukwa and connected rivers. Methods: Concentrations of Hg and Pb in fish muscle and lake sediment were measured using inductively coupled plasma atomic emission spectroscopy (ICP-AES) and mercury analyzers, respectively. Results: Levels of Pb and Hg from C. gariepinus ranged between 0.01 to 1.9 MUg/g and 0.03 to 0.33 MUg/g, respectively. Pb and Hg in O. esculentus varied between 0.02 to 1.4 MUg/g and <0.01 to 0.29 MUg/g, respectively. Pb and Hg levels in O. rukwaensis ranged from 0.12 to 0.88 MUg/g and 0.12 to 0.88 MUg/g, respectively. On the other hand, concentrations of Pb and Hg in the sediment samples ranged between 0.02 to 16.23 MUg/g and from 0.01 to 1.43 MUg/g, respectively. Concentrations of Hg in the muscles of C. gariepinus and O. esculentus were above World Health Organization (WHO) permissible limits, indicating that they are not safe for human consumption. Concentrations of Pb in fish muscle samples were below WHO permissible limits and United States Environmental Protection Agency (USAEPA) provisional tolerable weekly intake (PTWI) standards. Furthermore, Hg and Pb in sediment were below the threshold value of Environment Canada and Florida's 'No effect level'. Conclusions: Although levels of Pb in fish samples and Hg and Pb levels in sediment were below international standards, it is important to consider that fish forms an important source of animal protein for local inhabitants, who are likely to consume more fish than considered by these standards. The study recommends further research on the levels of mercury and lead in humans, especially children and pregnant women. PMID- 30524767 TI - Heavy Metals Speciation and Human Health Risk Assessment at an Illegal Gold Mining Site in Igun, Osun State, Nigeria. AB - Background: There is increasing global concern over the health effects of heavy metals arising from various anthropogenic activities, especially mining. Mining activities in developing countries are often carried out at an artisanal level using a variety of extraction methods with human health and environmental consequences. Objectives: The broad objective of this study is to assess the chemical forms, distribution pattern, and health risks due to mining and processing techniques at a gold mining site in Igun, Osun State, Nigeria. Methods: Samples were collected from 28 active mine pits and sequentially extracted using standard methods. Extracts were analyzed for metals using inductively coupled plasma optical emission spectrometer (ICP/OES), while health risk was assessed using United States Environmental Protection Agency (USEPA) and Dutch methods. Chemical speciation of heavy metals and health risk assessment was calculated using mobile phase fraction summation. Results: Metals were exclusively present in the residual fractions, indicating that these metals are strongly bound to the resistant components of the soil matrix. The percentage in the residual fraction ranged from 9.41% (tin) to 99.42% (aluminium). The heavy metals geoaccumulation index for the site ranged from 0 (no contamination) to 6 (extremely contaminated). The cancer risk ranged from 6.17E-13 to 7.77E-05 and 2.73E-12 to 4.64E-04 for adults and children, respectively. Discussion: Cancer risk and non-cancer risk (hazard index) assessment showed that arsenic poses a higher risk in adults and children compared to other metals through the dermal exposure route. PMID- 30524768 TI - Sources of Mercury Exposure to Children in Low- and Middle-Income Countries. AB - Background: Many children in low- and middle-income countries face enhanced risks of exposure to contaminants via the environment, parental occupation, and other routes. While mercury (Hg) is a global pollutant whose transport properties allow it to have an impact even in pristine areas, the presence of significant Hg sources in the developing world can cause localized effects that are more severe than those observed in other areas. Objectives: This paper provides a narrative review of sources of Hg exposure to people in the developing world with a particular focus on children, and presents an overview of key aspects to this important issue. Methods: We searched Web of Knowledge and Google Scholar using keywords including combinations of "mercury" and one or more of the following: "children," "exposure," "breast milk," "artisanal mining," "prenatal," "religion," "medicine," "dental amalgam," "chlor-alkali," "VCM," "vaccine," "e waste," "industry," "beauty," "cosmetics," "strategies," "child labor," "costs," and "developing countries" to find peer-reviewed articles pertaining to Hg exposure in the developing world. Results: Sources of Hg exposure include mining, consumption, industrial operations, religious practices, traditional medicines, beauty products, vaccines, dental amalgams, and waste scavenging and recycling. Conclusion: Children in the developing world are often subject to higher levels of Hg exposure than those living in developed countries due to the higher prevalence of Hg-intensive industrial processes and consumer products, lack of environmental regulation, and limits in mobility and food choices, among other factors. This issue can be addressed through additional research to fill in data gaps on exposure sources, establish sound and enforceable policies, and increase education and participation in affected communities. Challenges to addressing this problem include limited resources for needed equipment, training, and manpower to implement solutions. PMID- 30524769 TI - Managing Used Lead Acid Batteries in India: Evaluation of EPR-DRS Approaches. AB - Background: India has a well-defined deposit refund system (DRS) based on the principles of extended producer responsibility (EPR) for recycling used lead acid batteries (ULABs). However, the presence of an informal sector and lack of monitoring have resulted in an ineffective system of recycling mainly driven by the interests of the informal sector. Objectives: The present study attempts to understand the existing recycling mechanism and comparatively analyses a base case and three alternative scenarios developed taking into consideration the existence of a very active informal recycling sector. Materials and Methods: A base case and three alternative scenarios which were developed for this study were evaluated. Scenario I is the base case scenario representing the existing system. Scenarios II and III integrate informal recycling with the mainstream recycling system through a separate collection agency. Scenario IV proposes a strong upstream-defined deposit refund where the manufacturer pays a 'green tax' and receives a refund on green recycling of ULABs. The major gains and losses both upstream and downstream in the recycling chain are analysed for all of the scenarios. Results: Scenario II was determined to be the most effective, as it takes care of the interests of both the formal and informal stakeholders. By using the services of the itinerant collectors and eliminating informal smelters, Scenario II strengthens formal recycling. The introduction of a separate collection agency in Scenarios II and III benefits almost all of the major stakeholders in the system. Scenario IV gives the manufacturer more responsibility for used batteries. In all four scenarios, the downstream stakeholders of the EPR-DRS were the major beneficiaries. Conclusions: A successful EPR-DRS for ULABs in India can be achieved by integrating informal recycling through the introduction of a separate collection agency, strengthening the upstream DRS, completely eliminating informal recycling, and effective compliance monitoring. PMID- 30524770 TI - Life Cycle Analysis and Global Environmental Health Issues. PMID- 30524771 TI - E-waste: A Challenge for Sustainable Development. AB - Background: E-waste has been identified as the fastest growing waste stream in the world at present. Rapid socio-economic development and technological advancement are the main drivers of this trend. The hazardous chemical components of e-waste have potential adverse impacts on ecosystems and human health if not managed properly. This represents an imminent challenge to achieving sustainable development goals. Although technologically developed countries are the main source of e-product production and e-waste generation, the generated volume has also been increasing in developing countries and those in transition due to transport and transfer from e-waste source countries. Consequently, developing countries are in a vulnerable situation due to their lack of inventory data, waste management policies and advanced technology for environmentally sound management. Objectives: This study aims to demonstrate that the present global e waste scenarios and health hazards could prolong the achievement of sustainable development targets. This study illustrates scenarios from different perspectives and raises concerns about e-waste, identifies information gaps, and provides a basis for knowledge and awareness building and technological improvement to facilitate global long-term sustainable development. Discussion: Total and per capita global e-waste generation has been increased along with socio-economic development. These products present a significant global challenge due to the hazardous chemicals they contain, their highly technical recycling requirements and the high overhead and costs of environmentally sound management, as well as their adverse impacts to human health. Although high-income countries are the main sources of this waste, low-income countries are experiencing an increase in e-waste due to the shifting process of both recently produced and used electric and electronic equipment (UEEE), as well as cheap management overhead costs. Consequently, they bear the greatest burden of adverse health hazards and ecosystem degradation, prolonging their achievement of sustainable development goals. Conclusions: Sustainability is being prioritized for all development activities by integrating societal, economic, environmental, technological, cultural, and gender perspectives. Considering the adverse potential eco toxicological impacts and diverse health effects of e-waste, an urgent global multilateral agreement is needed addressing its management (i.e., handling, storage, transportation, recycling, and final disposal), whether by land filling or incineration. Due to the global nature of the issue and the difficulty of establishing sustainable and environmentally sound processing of e-waste in low income countries, multinational negotiation and collaboration is the only realistic solution. Furthermore, comprehensive global e-waste management and policies could help to off-set the hazards of e-waste and are the best approach for achieving sustainable development. PMID- 30524772 TI - Introduction of Mercury-free Gold Extraction Methods to Medium-Scale Miners and Education of Health Care Providers to Reduce the use of Mercury in Sorata, Bolivia. AB - Background: Artisanal and small-scale miners in Bolivia release on the order of 120 tons of mercury annually. The mercury finds its way to the Amazon with catastrophic consequences for the biosphere. A project aimed at reducing the release of mercury was carried out in 2013 and 2014. Objectives: The project had two objectives: to test whether the mercury-free gold extraction method could be an alternative to whole ore amalgamation in medium-scale mining in Bolivia and to teach mercury toxicology to health care providers in the gold mining area. The mercury-free gold extraction method has been successfully introduced in other countries, but mainly in very small-scale mining communities. Materials and Methods: The targets in Bolivia were medium-scale miners processing over a hundred tons of ore per day. The chosen gold ores proved amenable to gold extraction using mercury-free extraction. Demonstrations of the mercury-free methods were carried out by processing similar quantities of gold ores using the amalgamation and the mercury-free method.Miners, mining communities and local health providers were informed on the toxicity of mercury. Health providers were shown how to conduct epidemiological surveillance. Posters explaining the path of mercury from the processing stations to local households were prepared. Conclusions: The gold ores tested during the project proved amenable to mercury free gold extraction using borax smelting. The miners also realized that gold recovery increased when performing mercury-free gold extraction. The miners decided to stop using mercury and a follow-up project cleaned their mining equipment for mercury and modified the processing lines. The health care providers were also successfully trained. PMID- 30524773 TI - Leaded Paint in Cambodia-Pilot-scale Assessment. AB - Background: Lead is a heavy metal that is well known to pose a threat to human health. Although the sale and use of lead paint has been banned in much of the developed world, lead is still commonly used in enamel paints in the developing world, including Cambodia. As Cambodia's economy grows, this may increase the purchase and use of lead-based paints, thus potentially exposing more of the population to the toxic effects of lead. Objective: This study was performed to evaluate the concentration of lead in enamel paints in Cambodia using a method that is quick, effective, and cost-efficient. Methods: A handheld X-ray fluorescence analyzer was used to evaluate 21 samples of enamel paint, including 8 replicates that were randomly purchased from three shops in Phnom Penh, Cambodia to evaluate the level of metals. All of the paint samples in the current study were manufactured in Thailand. Discussion: Ninety percent of the enamel paints sampled in Cambodia exceeded the voluntary standard of 100 MUg/g lead of the producing country, Thailand. The mean and median levels for lead were 11,833 MUg/g, and 4,961 MUg/g, respectively. Conclusion: Based on our pilot-scale assessment, high levels of lead appear to be common in enamel paints in Cambodia, and a fuller assessment of the situation is warranted. Import and production of such toxic products should be avoided and appropriate labeling and public warnings should be provided. PMID- 30524774 TI - Effect of Mercury Exposure on Renal Function and Hematological Parameters among Artisanal and Small-scale Gold Miners at Sekotong, West Lombok, Indonesia. AB - Background: Mercury is a toxic metal with effects on human health ranging from acute to chronic in a very short time of exposure. Artisanal and small-scale gold mining (ASGM) is the main source of direct human exposure to mercury. Human exposure to mercury (Hg) can occur through both direct inhalation of mercury vapor and consumption of material taken from contaminated areas. To protect the health of ASGM workers and surrounding communities, a health assessment of mercury exposure and its effects is urgently needed. However, analysis of hair and urine samples as a proof test for mercury toxicity is very expensive. Therefore other tests must be considered to identify the first symptoms of mercury toxicity in miners and the surrounding community. Objectives: The present study aimed to determine the effects of mercury exposure on renal function along with the hematological parameters of gold miners and the community as a first indication of mercury exposure symptoms. Methods: The study was designed as a purposive field sampling study and was conducted in 3 main villages in Sekotong District, West Lombok Regency, West Nusa Tenggara Province, Indonesia. The 100 subjects were miners that have been exposed to mercury for at least 5 years and their wives and children (non-miners) who lived around the gold processing area. Blood and urine samples were then obtained from the subjects. The miners and non miners were questioned about their mercury exposure over the previous 5 years, duration of exposure, and how mercury was handled in their daily life. Blood and urine samples were collected at the time of the study, around 10 ml of urine and 0.1 ml of blood (2 drops) were collected per subject. In order to determine the parallel results between the blood-urine and hair results, hair from the miners was collected at a different time for analysis. Results: The results showed that the subjects had low proteinuria, hemoglobin and hematocrit concentrations as a consequence of chronic mercury intoxication. This finding was parallel with results of high mercury concentrations in urine (>7 - 273.3 MUg/l) and miners' hair (>1 - 12.93 MUg/g). Miners and non-miners in the exposure area were found to have proteinuria levels of more than 0.3 g/L. Proteinuria (>=0.3 g/L) was observed in 92.6% of miners and 72.4% of non-miners. Conclusions: The results of the present study suggest that urinalysis of proteinuria and hemoglobin values can be used as a screening test to detect renal impairment due to mercury intoxication. PMID- 30524775 TI - Mercury Contamination of Skin-whitening Creams in Phnom Penh, Cambodia. AB - Background: In Cambodia, there is widespread use of skin-whitening creams containing levels of mercury that exceed Association of Southeast Asian Nations (ASEAN) guidelines by up to 35,000 times. Mercury in skin-whitening creams threatens to compromise the health of Cambodians. Objectives: It is important to provide essential information on sources of mercury so that Cambodians can avoid exposure to elevated levels of mercury and to support informed management of consumer goods. Methods: Students were directed to buy selected skin-whitening creams that were then sampled with replication in 2011 and 2015 and processed with X-ray fluorescence (XRF) at the University of Health Science (UHS), Phnom Penh, Cambodia. Discussion: The analysis of skin-whitening creams in Phnom Penh in 2015 was compared to analyses in 2008 and 2011 and showed that several creams produced in Asia no longer contain mercury. However, skin creams produced in Phnom Penh continue to use mercury and counterfeit products also are contaminated with mercury. Vendors occasionally identified Vietnam as a source of counterfeit products, but often the source was unknown. Mercury continues to be the metal of greatest concern in skin creams. Creams with more than 1,000 MUg/g of mercury are a common cause of dermatitis (27% of cases). A new XRF analyzer was also able to detect more lead and arsenic than that used in analyses performed in 2011, and these two metals also exceeded ASEAN guidelines. Arsenic contamination also reflected the presence of bismuth in creams. Conclusion: Some producers of skin whitening creams in Thailand, China and Taiwan appear to be aware of the risks of mercury contamination and have modified their products. However, other producers of skin-whitening creams continue to use mercury. XRF analysis allows for rapid screening of mercury in cosmetics and should be used to gather additional information on mercury content in cosmetics in support of public health efforts to stem the import, export and sales of skin creams containing mercury. PMID- 30524776 TI - Gender Disparity in Lung Function Abnormalities among a Population Exposed to Particulate Matter Concentration in Ambient Air in the National Capital Region, India. AB - Background: The World Health Organization (WHO) global air quality study shows that 27 Indian cities, including New Delhi, are among the one hundred cities with the worst air quality globally. The scope of airway obstruction cases among residents in locations with critical air pollution levels like particulate matter (PM) pollutants PM2.5 and PM1 has not been addressed in the National Capital region, India. Objectives: The present cross-sectional study was undertaken to assess the forced expiratory volume in one second (FEV1) % predicted abnormalities among residents living in the National Capital Region, India with respect to their exposure to particulate matter pollutants (PM1, PM2.5) in ambient air. Methods: Eight hundred and fifty-four residents, including 433 men and 421 women ranging in age from 18-70 years, living in the National Capital Region (NCR) of India participated in the study. Particulate matter concentrations in ambient air (PM2.5 and PM1) were monitored at 10 residential locations in the National Capital Region, India (New Okhla Industrial Development Authority (NOIDA) and Gurgaon). The lung function test (FEV1) was conducted using a spirometer. Results: The Indian Air Quality Index showed either very poor or severe levels for PM2.5 at all study locations. A significant negative linear relationship was found between higher concentrations of PM1 and reduced FEV1% predicted values (r = -0.8, p < 0.05). The prevalence of airway obstruction cases (79.6%, odds ratio 1.96, confidence interval 1.42-2.71) was higher (p<0.001) among female subjects compared to their male counterparts. Even though there was a significant decline in FEV1% predicted among 80% of cases in women, only 19.24% cases were in the moderate category and 6.18% cases in the severe category. The severe category of FEV1% predicted cases showed greater respiratory symptoms than the other two categories, which denotes higher risk among those in the severe category. The present study shows that obstruction cases increased from 1.97 to 7.40% and 2.73 to 14.93% in women, with a corresponding increase in PM1 and PM2.5 from the minimum to maximum concentration. Conclusions: Since the women in this study were non-smokers, the PM in ambient air can be considered to be the major reason for the decline in lung function. The sources of PM pollutants in the study locations are large scale infrastructural development activities such as building and road construction activities. Narrowed lung airways can alter the airway caliber or resistance and flow rates proportional to the airway radius, especially in smaller airways. The present study suggests the need for policy makers and stake holders to take the necessary steps to identify PM sources and reduce the emissions of PM concentrations in ambient air. PMID- 30524777 TI - Soil Contamination with Heavy Metals around Jinja Steel Rolling Mills in Jinja Municipality, Uganda. AB - Background: Soil contamination with heavy metals has severely increased over the last few decades, mainly from industrial wastes and human activities. Soil pollution is a source of danger to the health of people globally. Objectives: To assess the level of soil contamination with heavy metals around steel rolling mills in Jinja municipality, Uganda. Methods: Four composite soil samples were collected from each of the sides of the Jinja steel rolling mills, dried and digested. The digested solution samples were analyzed in triplicates for the levels of lead (Pb), zinc (Zn), cadmium (Cd), chromium (Cr), copper (Cu), and nickel (Ni), using a flame atomic absorption spectrometer (Savant AA model 2009); the analytical process was monitored using analytical standard solutions. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) software version 19 and Excel. Mean metal concentrations, standard deviations, medians, and skewness were obtained to describe heavy metal concentrations in the soil. Pollution load index and geo-accumulation indices were calculated to determine the level and extent of heavy metal contamination in the soil. Results: The mean concentration loads of the heavy metals in soils around the Jinja steel rolling mills were 43.15 mg/kg for Pb, 28.16 mg/kg for Zn, 0.93 mg/kg for Cd, 0.22 mg/kg for Cr, 80.96 mg/kg for Cu, and 9.40 mg/kg for Ni. The metal load distribution around the industry was in descending order: Left-hand side > Downwind side > Right-hand side > Upwind side. Results for the geo-accumulation index were 1.30 for Pb, -1.31 for Zn, 2.63 for Cd, -7.25 for Cr, 2.99 for Cu, and -1.19 for Ni. The overall pollution load index was 1.08. Conclusions: The concentration levels of heavy metals around the steel rolling mills did not appear to be of serious concern, except for copper and cadmium, which showed moderate pollution and moderate to strong pollution, respectively. All heavy metals were within the limits of the United States Environmental Protection Agency (USEPA) residential soil standards and the Dutch intervention soil standards. Overall, soils around the Jinja steel rolling mills were slightly polluted with heavy metals, and measures therefore need to be taken to prevent further soil contamination with heavy metals. PMID- 30524778 TI - Potential Human Health Risks of Tannery Waste-contaminated Poultry Feed. AB - Background: For over a decade, solid tannery waste has been converted into protein concentrate and used as a feed ingredient because of its cheap availability. However, as chromium sulfate is commonly used in the tanning process, the chromium (Cr) content of tanned skin-cut wastes (SCW) may enter the edible parts of poultry through feed. Therefore, there is a chance that Cr and other heavy metals may be present in the edible portion of poultry and consequently transfer to humans upon poultry consumption. Objectives: In this study, skin-cut wastes (SCW)-based poultry feed and the edible parts of chicken fed with this feed were analyzed to understand the potential health risks of their use as poultry feed. Methods: In the present study, the presence of heavy metal content in SCW, poultry feed, and edible portions of different kinds of chicken was determined using atomic absorption spectrophotometer methods and the associated health risk estimation was calculated by comparing the target hazard quotient (THQ) value and reference daily intake value. Results: The results revealed the presence of Cr content ranging from 0.12-3.11 mg/kg and lead (Pb) content ranging from 8.06-22.0 mg/kg in SCW. In addition, Cr and Pb were present in the range of 0.27-0.98 mg/kg and 10.27-10.36 mg/kg, respectively, in poultry feed. However, no cadmium (Cd) was found in SCW, but the presence of Cd ranged from 0.03-0.05 mg/kg in feed. When contaminated poultry feed was fed to live poultry, the presence of Cr, Pb and Cd was observed in the edible portions (i. e. skin, liver, gizzard, and meat). Irrespective of the edible parts and chicken type, Cr values ranged from 0.1-2.440 mg/kg; Pb values ranged from 0.257-1.750 mg/kg; and Cd values ranged from below detection limit (BDL) to 0.037 mg/kg. Conclusions: The estimated daily intake value, THQ, along with the aggregate hazard index value, indicated a potential risk to consumers through consumption of contaminated chicken. Therefore, the study results clearly demonstrate heavy metals accumulation in chicken due to feeding SCW-based feed. The contaminated chicken further transfers these heavy metals to humans through ingestion. Hence, there is a potential human health risk through consumption of contaminated chicken meat. PMID- 30524779 TI - Public Health Risk Assessment of Heavy Metal Uptake by Vegetables Grown at a Waste-water-Irrigated Site in Dhaka, Bangladesh. AB - Background: Wastewater is often used in developing countries for irrigation of crops. This wastewater often contains a number of heavy metals which are harmful to human health due to their non-biodegradable nature, long biological half-lives and their potential to accumulate in different body parts. There are many potential risks to human health from heavy metal contamination of vegetables grown at waste-water-irrigated sites. Objectives: This study was carried out to assess the concentration of heavy metals and the risk to human health by heavy metals (lead (Pb), nickel (Ni) and arsenic (As)) through the intake of locally grown vegetables collected from wastewater irrigated agricultural fields. The objectives of the present study were to determine concentrations of heavy metals in vegetables collected from the wastewater-irrigated fields, to calculate daily intake of heavy metals from the consumption of vegetables for both adults and children, and to evaluate their potential health risk. Methods: Twenty-seven samples of nine different types of vegetables were analyzed by an Atomic Absorption Spectrometer (AAS) (Varian AAS 240 F S). Results: The range of various metals in waste-water irrigated vegetables were not detected (ND)-0.188, 0.072 1.069 and ND-0.076 mg/kg for Pb, Ni and As, respectively. The highest mean concentration of all metals was detected in jute leaf, except for Pb which was found in the stem amaranth leaf. The mean concentration of all metals in all vegetables was within the safe limits of the World Health Organization/Food and Agricultural Organization (WHO/FAO) and China's national standards. The health risk index was more than 1 for As in jute leaf for both adults and children. The metal pollution index was highest (0.16 mg/kg) in jute leaf, whereas green papaya showed the lowest metal pollution index (MPI) value (0.005 mg/kg). Among all vegetables tested, the highest intake values of Ni and As were from consumption of jute leaf and the highest intake values of Pb from consumption of stem amaranth leaf for both adults and children. Conclusions: Higher values in the metal pollution index and health risk index indicate heavy metal contamination in wastewater-irrigated soils that present the potential for a significant negative impact on human health. PMID- 30524780 TI - Distribution and Risk Assessment of Heavy Metals in Surface Water from Pristine Environments and Major Mining Areas in Ghana. AB - Background: Ghana, like many countries in Africa, has a history of heavy metal pollution largely emanating from industrial effluent discharges and anthropogenic deposits on prevailing winds of pollutants from industrial activities. One of the biggest contributors to pollution in the Ghanaian environment is mineral mining. Objectives: The aim of this study was to determine the distribution and health risks of heavy metals in surface water from both pristine environments and major mining areas in Ghana. Methods: A total of 32 composite samples were collected between September and October, 2014 to assess concentrations of heavy metals and pollution levels, as well as cancer and non-cancer risks to human health from exposure to heavy metals from four major mining regions and four rain forest reserves in the Western, Ashanti, Brong Ahafo and Eastern regions of Ghana. Samples were analyzed using atomic absorption spectrometry. Results: The mean concentrations (mg/L) of heavy metals at the pristine sites ranged from 1.747 for iron (Fe) to 0.001 for mercury (Hg) and 0.453 for Fe to 0.002 for Hg at the mining sites. All the metals were found to be below World Health Organization (WHO) and United States Environmental Protection Agency (USEPA) recommended limits except for Hg, which was at the USEPA guideline limit. However, the concentrations of the metals from the mining sites were found to be slightly higher than those from the pristine sites. Conclusions: The concentrations of heavy metals in the Nyam, Subri, Bonsa and Birim Rivers from the mining sites and the Atiwa Range, Oda, Ankasa and Bosomkese Rivers from the pristine sites were found to be either below or within the USEPA and WHO's recommended limits for surface water. The health risk assessment values for the hazard quotient for ingestion of water (HQing), dermal contact (HQderm) and chronic daily intake (CDI) indicated no adverse effects as a result of ingestion or dermal contact from the rivers. However, arsenic (As) in both the pristine and mining sites and chromium (Cr) in the pristine sites pose a carcinogenic threat to the local residents. PMID- 30524781 TI - Review of Particulate Matter and Elemental Composition of Aerosols at Selected Locations in Nigeria from 1985-2015. AB - Background: Over the past 30 years, various studies in Nigeria have monitored atmospheric particulate matter loads and elemental composition of ambient air around diverse receptor sites. Objectives: A comparative discussion of the different sampling techniques, pre-treatment and analytical methods employed between 1985 and 2015. Methods: Air pollution indices from studies covered in this review were compared to relevant guideline standards such as the World Health Organization (WHO) 24-hr guideline and the United States Environmental Protection Agency (USEPA)'s National Ambient Air Quality Standard (NAAQS) daily permissible limits for fine particles of less than 2.5 micrometers in diameter (PM2.5) and coarse dust particles with a diameter of 10 micrometers (PM10) in ambient air. In addition, the sources of data for the average concentrations for PM2.5, PM10 and related metallic elements during 1985-2015 were assessed. Attempts were also made to compare varied particulate matter loads of atmospheric micro-environments in Nigeria with comparable micro-environments in selected cities around the world. Discussion: Results showed that PM2.5 concentration ranged from 5-248 MUg/m3, while PM10 concentration ranged from 18-926 MUg/m3, revealing that about 50% of the particulate matter loads in Nigeria exceeded both the WHO (25 MUg/m3, 50 MUg/m3) and NAAQS (35 MUg/m3, 150 MUg/m3) guideline limits for PM2.5 and PM10 respectively. PM2.5/PM10 ratios for the selected studies fall below the WHO guideline (0.5-0.8), suggesting that Nigerian aerosols are mainly made up of coarse, rather than fine particles. In addition, the order of the average highest concentrations of metallic elements for PM2.5 were magnesium (Mg) > strontium (Sr) > potassium (K) > zinc (Zn) > iron (Fe) > sodium (Na) > aluminium (Al) > chlorine (Cl) > lead (Pb) > silicon (Si), while those of PM10 were Sr > Zn > Fe > Mg > calcium (Ca) >Na > Pb > manganese (Mn) > K > Al. Conclusions: Seasonal variation of particulate matter loads revealed higher concentrations during the dry season than during the rainy season. In addition, particulate matter loads in rural areas were generally lower than in urban areas. Wind-blown dust from the Sahara Desert is the major contributor to particulate matter loads in northern zones of the country, while sea spray and crustal matter are the highest contributors to particulate matter loads in southern zones. PMID- 30524782 TI - Urinary Metal Levels in a Chilean Community 31 Years After the Dumping of Mine Tailings. AB - Background: Between 1938 and 1975, the city of Chanaral, located in the north of Chile, received 200 megatons of unregulated mining waste, which created an artificial beach 10 kilometers long and covering an area larger than 4 km2. In 1983, this deposit was classified as a serious case of marine pollution in the Pacific Ocean, according to the Organization for Economic Cooperation and Development. In 1989, dumping ceased due to a judicial order. Until now, the effects of this pollution on the population living around these mine tailings has been unknown. Objective: To determine the prevalence of exposure to metals by dust from mine tailings in Chanaral, a city located in the northern mining area of Chile. Methods: The level of urinary metals in a representative sample of adults from Chanaral was determined. Results: Urinary levels of total arsenic (44.6 MUg/L), inorganic arsenic (17.0 MUg/L) and nickel (2.8 MUg/L) were higher than in other areas of Chile. Levels of copper (17.9 MUg/L), mercury (1.6 MUg/L) and lead (0.9 MUg/L) exceeded international values. Of the total subjects, 67.5%, 30.4%, 29.4%, 16.9%, 13.2 and 9.3% presented with high levels of copper, nickel, total arsenic, inorganic arsenic, mercury and lead, respectively. Conclusion: Thirty-one years after suspension of the discharge of mining waste, the local population in this area remains exposed to metals from the mine tailings. Surveillance and remedial actions addressing the Chanaral mine tailings are needed. PMID- 30524783 TI - Incidence Rates of Tuberculosis among Children and Adolescents Living in Areas Most Affected by the Chernobyl Disaster. AB - Background: The Chernobyl accident has attracted the attention of healthcare experts all over the world due to the unprecedented scale of damage the disaster inflicted upon human health. Objectives: To examine incidence rates of tuberculosis and patterns among children and adolescents living in areas most affected by the Chernobyl disaster between 2004 and 2014. Methods: The tuberculosis incidence rate was calculated per 100,000 people. Incidence dynamics were traced for the period 2004 to 2014 and average rates were measured. Average incidence rates were calculated for different age groups, including 0-4 years, 5 9 years, 10-14 years, and 15-19 years, as well as the total value for all those between 0-19 years of age. Average incidence rates were estimated for tuberculosis, pulmonary tuberculosis and extrapulmonary tuberculosis. A comparative analysis of incidence rates of tuberculosis in areas more and less affected by the Chernobyl disaster was conducted. To avoid gender and age disparities among the population in the two different study areas, a method of direct standardization was applied. Results: Tuberculosis incidence rates showed identical patterns among the population across all areas in this region. At the same time, the incidence rates of tuberculosis, pulmonary tuberculosis, and extrapulmonary tuberculosis were higher among children and adolescents living in the most affected areas in comparison to those living in less affected areas. Conclusion: The results do not allow us to conclude whether radioactive pollution has a direct impact on incidence of tuberculosis among children and adolescents in the most radioactively contaminated areas. The author believes that the higher incidence rates of tuberculosis in the most affected areas are conditioned by a set of negative factors that have a pernicious influence on the general health of the population, and on the health of children and adolescents in the areas most affected by the Chernobyl disaster. PMID- 30524784 TI - Decolorization of Selected Synthetic Textile Dyes by Yeasts from Leaves and Fruit Peels. AB - Background: Discharge of textile dyes into the environment poses a significant threat. They are poorly biodegradable and toxic due to their complex composition and aromatic structures. In the search for alternatives to physical and chemical treatments, biodegradation of synthetic dyes by various microbes is emerging as an effective and promising approach. Objectives: The decolorization of synthetic dyes by yeast co-cultures and consortia from leaves and fruit peels was assessed at a 50 MUg/mL dye concentration. Methods: Yeasts isolates from leaves and fruit peels were screened for potential decolorization of synthetic dyes at 25-50 MUg/mL. Decolorization parameters were optimized for synergistic properties and development of yeast co-cultures and consortium. Possible decolorization reactions were initially assessed by cell immobilization, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and Fourier transform infrared spectroscopy (FTIR) analysis. Results: A total of 16 organisms were isolated from rose, mango, and pineapple leaves and pineapple fruit peels. Only 4 organisms showed high decolorization of four synthetic dyes: Direct Pink B, Disperse Yellow 5G, Direct Fast Orange S, and Reactive Turquoise Blue G. The optimum condition for best decolorizers of selected dyes at 50 MUg/mL were Candida guilliermondii (Y011) for Direct Pink B at pH 9, 37 degrees C; C. dubliniensis (Y014) for Disperse Yellow 5G at pH 4, 25 degrees C; C. guilliermondii (Y004) for Direct Fast Orange S at pH 7, 25 degrees C, and C. famata (Y003) for Reactive Turquoise Blue G at pH 4, 35 degrees C. None of the 4 yeast isolates showed any antagonistic activity when subjected to the lawn-spotting method for the formation of co-cultures and consortium. The best co-cultures obtained 61% decolorization of Direct Pink B, 65% decolorization of Disperse Yellow 5G, 41% decolorization of Direct Fast Orange S, and 50-51% decolorization of Reactive Turquoise Blue G. Immobilized yeast cells were active in decolorizing the dyes and SDS-PAGE analysis confirmed the presence of an extracellular protein. The results of FTIR also showed changes in the functional group of Direct Pink B, but minimal changes in the functional groups of Reactive Turquoise Blue G, indicating a different decolorization pathway. Conclusions: Yeasts in co-cultures and consortia can decolorize toxic synthetic dyes through different decolorization pathways such as enzyme degradation and bioaccumulation. This technique may have a use in the treatment of wastewater systems. PMID- 30524785 TI - Evaluation of Heavy Metal Pollution in the Suame Industrial Area, Kumasi, Ghana. AB - Background: Heavy metal pollution in industrial and residential areas in cities has become a public health issue in Ghana. Anecdotal evidence suggests that most industrial areas have elevated levels of heavy metals in soil. As a result of poor zoning and unregulated activities, large sections of seemingly industrial areas are also used as residential areas. There have been no studies on the levels of heavy metal contamination in such mixed activity locations. Objectives: The study was undertaken to identify possible heavy metals and their concentrations in soil samples collected from the Suame Industrial Area, Kumasi, Ghana. Methods: Soil samples were collected, processed and the concentration of copper (Cu), lead (Pb), zinc (Zn), cobalt (Co) and chromium (Cr) were analyzed using X-ray fluorescence (XRF). Results: The concentration of all metals exceeded the threshold limit values (TLV). They also exceeded the European Soil Bureau Network (ESBN) maximum allowable limits (MAL), and are therefore considered to be pollutants. The results, expressed as mean concentration+/-standard deviation mg/kg (percent above TLV) were Pb: 414.83+/-159.38 mg/kg (418.9%), Cr: 264.84+/ 189.15 mg/kg (353.1%), Co: 68.15+/-34.12 mg/kg (227.2%), Cu: 265.82+/-80.53 mg/kg (354.4%) and Zn: 3,215.84+/-4,074.54 mg/kg (1,607.9%). Furthermore, the concentrations of Pb and Co exceeded the United States Environmental Protection Agency (USEPA) residential soil regional screening levels (RSLs). Conclusions: The elevated metal concentrations found in the present study demonstrate that the site is heavily polluted with Pb, Co and Cr. This is attributed to unregulated activities at the site; therefore, measures should be put in place to ameliorate the effects of potential heavy metal toxicity to workers, local residents and the environment. Re-zoning of activities and clear demarcation of residential and industrial areas is advocated. PMID- 30524786 TI - Healthcare Waste Generation and Management in Public Healthcare Facilities in Adama, Ethiopia. AB - Background: Over the past few years there has been rising production of hazardous byproducts, including dioxins, furans, and mercury from indiscriminate handling and treatment of healthcare waste. This situation is worse in developing countries where there is a serious lack of reliable data on factors such as generation and characteristics of healthcare waste. Objectives: To investigate healthcare waste generation and current management practices of public healthcare facilities in Adama, Ethiopia. Methods: All departments and sections in studied healthcare facilities (one referral hospital and four health centers) were examined for the characterization and determination of healthcare waste generation based on World Health Organization (WHO) guidelines. Wastes were collected and measured daily for seven consecutive days. Plastic buckets and bags of different colors were used for different types of wastes. Plastic bags were removed every morning and their weights were measured every day at 8 am using a scale. Results: The average daily generation of healthcare waste from studied health centers ranged from 0.02 to 0.03 kg/patient/day, and the average daily waste generation of Adama referral hospital was 1.23 kg/bed/day. The healthcare waste generation rate was statistically different across the health service delivery sectors (p < 0.001). The proportion of hazardous healthcare waste generated in Adama referral hospital and health centers was 34.9% and 75%, respectively. There was no segregation of healthcare waste by type at the point of generation or pre-treatment of infectious waste in the studied healthcare facilities. Open pit burning and single chamber incinerators were the most utilized final treatment methods. Furthermore, there was a low level of awareness about safe healthcare waste management. Conclusions: The overall findings of this study indicate that the proportion of hazardous healthcare waste generated from the studied healthcare facilities was above the threshold set by the WHO. There is a lack of proper waste management systems in all public healthcare facilities in Adama, Ethiopia. Awareness raising activities on proper healthcare waste management should be undertaken targeting all healthcare workers. PMID- 30524787 TI - Use of the Physiologically Based Extraction Test for the Assessment of Bioaccessibility of Toxic Metals in Vegetables Grown on Contaminated Soils. AB - Background: An important concern for human health is the uptake of toxic metals by vegetables from soils and their consumption by humans. Objectives: To assess the oral bioaccessibility of metals in vegetables (spinach, pumpkin, celosia, okro leaves and waterleaf) grown on contaminated soils collected from five different sites in Lagos, Nigeria. Methods: The soil and vegetables were acid digested and the total metal concentrations (copper (Cu), cadmium (Cd), chromium (Cr), lead (Pb) and zinc (Zn)) were determined using a flame atomic absorption spectrophotometer. A bioaccessibility study of the edible parts of the vegetables was estimated using the modified in vitro physiologically based extraction test (PBET). Results: The results for total concentration showed that individual vegetable types differed in their levels of metal uptake. The values were in the range of 0.5-13.5 mg/kg for Cd, 2.0-221 mg/kg for Cu, 2.5-37.7 mg/kg for Cr, 10 250 mg/kg for Zn. Pb was below the detection limit. The transfer factor from soil to vegetable followed the order of Cd >Zn > Cu > Cr >Pb. Discussion: For the PBET study, metals were solubilized mostly in the gastric phase, and the results varied in the range of 0.4-114.4 mg/kg for Cu, 0.1-2.4 mg/kg for Cd, and 0.8-137 mg/kg for Zn, but there was little or no bioaccessibility in the intestinal phase. Cr and Pb were non-detectable in either the gastric or intestinal phase. Conclusions: Although the level of metals (Cd, Cu and Zn) available for absorption in the gastric phase were found to be low in most of the vegetables studied, the experiment revealed that metals are likely released in the human gut after intake of vegetables grown on contaminated soil. PMID- 30524788 TI - Distribution of Fluoride in the Phosphorite Mining Area of Hahotoe-Kpogame (Togo). AB - Background: Phosphorites in the mining area of Hahotoe-Kpogame contain high levels of fluoride that can cause illness among people living close to the mining and processing sites. Objectives: To assess the distribution of fluoride in the different areas around the phosphorite mining areas in Togo. Methods: Analyses were performed by molecular absorption spectrometer (HACH DR3800) according to the procedure manual at the geochemical laboratory of the University of Lome. The sodium 2 - (parasulfophenylazo) - 1,8 - dihydroxy - 3,6 - naphthalenedisulfonate (SPADNS) method was used to determine fluoride contents and the PhosVer(r) 3 with acid persulfate digestion method was used to measure phosphorus pentoxide (P2O5). GraphPad Prism version 3.0 software was used for the data processing. Results: The surface water of the mining sites had a fluoride content ranging from 0.38 to 3.52 mg/l (average = 1.33 mg/l; n = 10, n is the number of samples). Groundwater in this area had a fluoride content between 0.15 mg/l and 1.39 mg/l (average = 0.58 mg/l, n = 15). In the groundwater in the villages around the phosphorite processing plant, the fluoride content ranged between 0.15 and 0.63 mg/l (average = 0.41 mg/l; n = 22). The fluoride content in the water of the phosphorite mining area was higher than in Gbodjome (reference area). Meanwhile, assessment of the effluents discharged into the ocean had a fluoride content ranging from 12 to 20 mg/l. In dusts, the P2O5 and fluoride contents were 36.02% and 1.85%, respectively. Vegetables from the local market garden produce showed levels of fluoride up to 2.06%. The average contents of P2O5 and fluoride in one of the phosphorite profiles were 32.38% and 3.00%, respectively. A significant correlation was observed between P2O5 and fluoride. Conclusions: The correlation between P2O5 and fluoride in phosphorites shows that phosphorite mining is the main source of fluoride pollution in this area. PMID- 30524789 TI - Potentially Toxic Contamination of Cultivated Wetlands in Lagos, Nigeria. AB - Background: Active cultivation of wetlands without consideration of the quality of the sediment is a common practice in the city of Lagos. Wetlands in several parts of the city have been cleared for growing vegetables and other crops. As a buffer for all surface run-off from the surrounding areas, wetlands are a depository for whatever contaminants are sourced from the catchments; hence the need to ascertain the quality of sediment on which edible crops are grown to determine suitability for agriculture. Methods: Wetland water samples were tested for pH levels, electrical conductivity, and total dissolved solids. Randomly selected core samples from one of the cultivated wetland areas located in the city center were taken to up to 8 cm in depth, then dried, recovered from the barrel and divided into groups of the following depths: 0-2 cm, 2-4 cm, 4-6 cm, and 6-8 cm. The dried and divided samples were subsequently sieved and analyzed for metal content using inductively coupled plasma mass spectrometry. Results for copper (Cu), lead (Pb), zinc (Zn), nickel (Ni), chromium (Cr) and vanadium (V) were geochemically evaluated. Results: The wetland water samples were found to be acidic, ranging from 5.9-6.4. The electrical conductivity was 430-500 MUS/cm, and total dissolved solids, 280-320 mg/L. The metal content results (in mg/kg) for samples from 0-2, 2-4, 4-6 and 6-8 cm depths were: Cu (13-861, 12-752, 10-899 and 11-707); Pb (29-1646, 26-2660, 33-2400 and 25-1818); Zn (112-7237, 76-9908, 63 7517 and 47-6579); Ni (3-219, 3-178, 3-186 and 3-176); Cr (10-147, 9-157, 14-160 and 16-147); and V (14-72, 12-75, 17-77 and 19-77). The evaluated results showed that the selected metal concentrations exceeded various guideline values. Calculated geo-accumulation index, metal ratio, and enrichment factor showed marked enrichment of metals in the wetland sediment samples. Discussion: For the majority of the metals observed, the correlation matrix revealed strong positive relationships. For Cu, Pb, Zn, Ni, and Cr, there was a correlation matrix >0.8. This indicates similar origin and sourcing of the sediments. Vanadium, however, displayed a negative correlation with all the other elements. Conclusions: The study revealed that most of the cultivated sediment samples contained elevated levels of potentially toxic elements in the form of Pb, Cu, and Zn. The acidic nature of the wetlands water in the sediment samples also make them unsuitable for cultivation as the possibility of metal dissolution in transpirated water and bio-accumulation of potentially toxic elements in the cultivated vegetables is high. PMID- 30524790 TI - Comment on "Effect of Mercury Exposure on Renal Function and Hematological Parameters among Artisanal and Smallscale Gold Miners at Sekotong, West Lombok, Indonesia". PMID- 30524791 TI - Response to "Comment on 'Effect of Mercury Exposure on Renal Function and Hematological Parameters among Artisanal and Small-scale Gold Miners at Sekotong, West Lombok, Indonesia'". PMID- 30524792 TI - Publisher's Note. PMID- 30524793 TI - Levels of Polychlorinated Biphenyls in Plastic Resin Pellets from Six Beaches on the Accra-Tema Coastline, Ghana. AB - Background: Polychlorinated biphenyls (PCBs) are organic compounds, known to be carcinogenic and banned by the Stockholm Convention. PCBs are hydrophobic substances able to accumulate in organic materials, including plastic pellets. Plastic resin pellets are industrial raw materials that are remolded finished products for industrial and domestic use, commonly used for packaging. Plastic resin pellets were chosen as the medium for monitoring hydrophobic contaminants because they are able to adsorb PCB contaminants. Pellets can be unintentionally washed into the ocean where hydrophobic contaminants such as PCBs are also deposited. Objectives: We aimed to identify PCB congeners and quantify PCB pollution levels in the marine environment using resin plastic pellets collected from six beaches along the Accra-Tema coastline in Ghana. Methods: Plastic resin pellets (5 g) were extracted with 200 mL of n-hexane for 16 hours by Soxhlet extraction. Concentrations of PCBs from the extracts were determined using gas chromatography with an electron capture detector. Results: The individual PCB congeners detected were PCB 28, 52, 101, 105, 138, 153, 156 and 180. PCB 28 was detected at all six beaches, with a total concentration of 43.5 ng/g pellet (mean/beach 7.25 +/- 2.47 ng/g pellet; CV = 34%), while PCB 138 was only detected on one beach (Castle Beach) at a total concentration of 0.8 ng/g pellet. The concentration of PCBs ranged from 7.4 ng/g (Sunset Beach) to 47.5 ng/g (Castle Beach) (mean 16.4+/-15.4 ng/g per beach; CV=94%). Discussion: PCB concentrations at Castle Beach have been studied previously, showing an increase from 39 ng/g to 47.5 ng/g, whereas levels decreased significantly from 28 ng/g to 14.2 ng/g in Sakumono Beach over the span of three years. Conclusions: The concentrations of four detected PCB congeners (28, 52, 101 and 156) were significantly higher than the World Health Organization (WHO) allowable daily intake of 6 ng/g food per day for PCBs. A more efficient industrial and domestic waste disposal system is advocated for Ghana. PMID- 30524794 TI - Association of Low Birthweight and Indoor Air Pollution: Biomass Fuel Use in Bangladesh. AB - Background: More than 90% of all low birthweight (LBW) babies are born in developing countries, and half of the population in developing nations uses solid fuels as their primary source of energy for cooking. An association between household use of solid biomass fuels and reduced newborn weight has been found in a number of countries. Bangladesh has a high prevalence of LBW babies (22%), and 88% of the population use solid fuels for cooking. Objectives: This study aims to explore whether indoor air pollution is associated with LBW in Bangladesh, an important determinant of infant mortality and morbidity. Methods: The 2011 Bangladesh Demographic and Health Survey (BDHS) was used for the present analysis. The total number of births reported in the previous five years by respondents in the survey sample was 8,753. Mothers' recall of their baby's weight was the dependent dichotomous variable. A mixed effects logistic regression model was fitted using region as a random effect and several independent fixed effects. Results: High pollutant cooking fuels, such as coal and wood, resulted in higher odds of having a LBW child compared to use of electricity/gas (odds ratio (OR): 2.6, confidence interval (CI): 1.1-6.2 and OR: 1.1, CI: 1.0-1.2). Factors which lowered the odds include mothers with a bachelor's degree or higher education (OR: 0.6, CI: 0.4-0.9), third order children (OR: 0.8, CI: 0.6-0.9), fourth or higher order children (OR: 0.8, CI: 0.6-1.0), having a male child (OR: 0.7, CI: 0.7-0.8), and receiving sufficient antenatal care (OR: 0.8, CI: 0.6-0.9). Factors which increase the odds of having a LBW infant include mothers who are underweight compared to normal weight mothers (OR: 1.1, CI: 1.1-1.2), mistimed pregnancies (OR: 1.2, CI: 1.0-1.4), or unplanned pregnancies (OR: 1.3, CI: 1.0-1.7), compared to planned pregnancies. Conclusions: This is the first paper to show an association between use of highly pollutant biomass fuel and prevalence of LBW babies in Bangladesh, suggesting that besides polluting the air and causing respiratory illnesses, biomass fuel combustion may also affect the health of fetuses in utero. Further longitudinal studies are required to establish this finding among mothers in developing countries. PMID- 30524795 TI - Soil Pollution by Toxic Metals near E-waste Recycling Operations in Ibadan, Nigeria. AB - Background: Unsound recycling of e-waste releases toxic metals into environmental media and has deleterious health consequences to humans as the metals transfer to humans through the food chain, direct contact and inhalation. Objectives: This study assessed soil contamination with lead (Pb), copper (Cu), chromium (Cr), nickel (Ni) and cadmium (Cd) arising from crude e-waste recycling. Methods: Forty eight soil samples were collected from the vicinity of high-, medium- and low activity recycling operations in Ogunpa in Ibadan, Nigeria as well as from the botanical garden of the University of Ibadan for background samples. Total extractable metals were leached with aqua regia and the leachates were analyzed using flame atomic absorption spectrometry. Speciation analysis was also conducted on soil samples that showed high concentrations of metals to determine the distributions in various phases. Results: All soil samples were determined to be sandy loam in composition with pH and organic matter ranging from 7.1-7.9 and 1.56-1.81%, respectively. Metal concentrations (mg/kg) for soils from the study area ranged as follows: Pb, 269 - 5650; Cu, 203 - 3483; Cr, 3.30 - 42.4; Ni, 0.14 - 24.0; and Cd, below detection limit - 2.50. The results indicated enrichment in soil by all metals, especially Pb and Cu, which were many times higher compared with background concentrations. Additionally, average Pb and Cu concentrations were higher than regulatory limits for soil set by selected countries across the globe. Speciation studies indicated that about 65% and 88% of Pb and Cu, respectively, were liable to potential mobility with slight changes in natural conditions. Other metal concentrations, although with higher concentrations compared with background levels, were within the permissible limits in soils accepted by many countries across the globe. There were significant correlations between all metals, suggesting that they may have been released from a common source. Conclusions: Soils from the study area require urgent clean-up, especially for Pb and Cu, to safeguard human health and the environment. PMID- 30524796 TI - Distribution Of Heavy Metals in Surface Sediments from Streams and Their Associated Fishponds in Osun State, Nigeria. AB - Background: Heavy metals in water systems are a human health concern as they can enter the food chain. Objectives: Heavy metal and particle size determinations were used to determine the sediment quality of three fishponds in Osun State, Nigeria and their feeder streams. Methods: Sediment samples were collected in triplicates from the streams and their associated fishponds and the accumulations of nine heavy metals (lead (Pb), cobalt (Co), cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), iron (Fe), manganese (Mg), zinc (Zn)) in the sediment were investigated seasonally. Particle size distribution and textural class of the samples were also determined. Results: Metal concentrations recorded in bottom sediment varied widely and exhibited fluctuations among the different ponds and streams, especially in the values of Fe, Cu, Mn, Cr, Zn and Pb. There was a significant difference (p<0.05) in the concentrations of metals across the three investigated locations. The metals in the sediments occurred in the order of Fe>Cu>Ni>Zn>Pb>Cr>Mn>Co in Ilesha, Fe>Cu>Ni>Zn>Mn>Co>Pb>Cr in Osogbo and Zn>Fe>Ni>Mn>Cu>Co>Cr>Pb in Yakoyo. A closely related order of Fe>Mn>Ni>Zn>Cr>Cu>Se>Pb>Mo>Cd was observed in River Eku. The selected streams and their associated fishponds were fairly polluted, with the Yah fishpond (Ilesha) having the highest heavy metal pollution compared to Arula fishpond (Osogbo) and Ewuru/Rara fishpond (Yakoyo). The concentrations of accumulated heavy metals depended on the textural class of the sediment. Conclusion: Pollution has reached levels hazardous to human health compared to standard limits for aquaculture development. Stream and fishpond sediments should be analyzed at regular intervals as a quality assurance process to ensure that there are no toxic substances in the ponds, leading to possible bio-accumulation and magnification. This will help guarantee the health of the aquatic ecosystem, humans and the environment. PMID- 30524797 TI - Metal Contamination in Low-Cost Jewelry and Toys in Cambodia. AB - Background: The existence of lead-contaminated consumer products is a global issue. Toys and low-cost jewelry may contain toxic metals and Cambodia is known to have consumer products with toxic metals. Objectives: It is important to inform Cambodians about sources of toxic metals so that they can reduce their exposure risk, particularly for children. Methods: Student volunteers purchased, or brought from home, low-cost jewelry and toys to either the University of Health Science or a Don Bosco Institute in Phnom Penh, Cambodia, where they were analyzed using X-ray fluorescence (XRF). The initial analysis was performed in 2011. A subset of the 2011 samples was re-analyzed in 2015 using new preparation techniques and a new x-ray fluorescence (XRF) unit. Discussion: The analysis of low-cost jewelry in Phnom Penh in 2015 indicated that lead in jewelry clasps is a more serious health concern than was first perceived in 2011. Mercury, nickel, cadmium and copper were also found in toys, and occasionally these toys had been produced by well-known companies. Sources of jewelry production of samples in the present study are unknown. Lead in clasps in low-cost jewelry appeared to be the greatest risk to children in our sampling. Conclusion: One-third of toys and low cost jewelry exceeded the United States and European Union guidelines for heavy metals. XRF analysis allows for rapid screening of lead and other toxic metals and could be used to reduce the sales of low-cost jewelry and toys containing toxic metals. PMID- 30524798 TI - Environmental Performance of Xylene, Hydrochloric Acid and Ammonia Solution During Pap Stain for Diagnosing Cervical Cancer. AB - Background: Little importance has been placed on sustainability of the Papanicolaou (Pap) stain, the gold standard for the diagnosis of cervical cancer, for global environmental health. The standard Pap stain uses environmentally toxic and carcinogenic reactants such as xylene, hydrochloric acid and ammonia solution. Objectives: To eradicate the use of environmentally toxic and carcinogenic reactants through the validation of the Ecologic Papanicolaou (Eco Pap) test. Methods: Reagent handling strategies were divided in three phases: used Harris' progressive hematoxilin, polychromatic solution and direct mounting that were analyzed by PEED-Cytology, Staining Quality Index (ICT) and the Bethesda system 2014. Results: A total of 52,319 Pap smears stained with Eco-Pap were admitted (ICT=0.91). Validation of the Eco-Pap versus conventional staining was optimal (Kappa =0.89) and the sensitivity and specificity of the method were 57% and 98%, respectively. Eco-Pap reduced the environmental contamination produced by xylene (66 liters), hydrochloric acid and ammonia (5.5 liters each) over nine months, and all diagnoses coincided with the cytological details. Conclusions: The Eco-Pap is an innovative method that transforms Pap testing into a sustainable and supportable technology. PMID- 30524799 TI - Risk Factors and Rates of Hepatitis B Virus Infection among Municipal Waste Management Workers and Scavengers in Ilorin, Kwara State, Nigeria. AB - Background: Poor municipal waste management, including waste treatment and disposal methods, threatens the environment and public health in most developing countries. Lack of proper municipal waste segregation and transportation techniques has increased the potential for the transmission of pathogens such as hepatitis B virus (HBV). Objectives: This study addressed issues relating to the potential risk of infectious diseases and prevalence of HBV among municipal waste workers and scavengers in Ilorin metropolis, Nigeria. Methods: A cross-sectional study was conducted among municipal waste management workers and waste scavengers in Ilorin metropolis, Kwara State, Nigeria. A total of 120 respondents were administered questionnaires during the first stage of the study and participated in the second (testing) stage of the study. The prevalence of an HBV infection biological marker, the Australia antigen (HBsAg), and its association with exposure to waste, socio-demographic factors, and history of occupational injuries with sharp objects/needle sticks was examined. Results: The prevalence of HBV infection among municipal waste management workers and waste scavengers was 2.6% and 16.67% respectively, indicating that scavengers were at higher risk of HBV infection. Conclusions: Lack of proper occupational health safety management among municipal waste management workers was a possible risk factor for HBV infection through injury with sharp instruments. The possible pathway of virus transmission was waste segregation, which is usually carried out with bare hands, and lack of hygiene and occupational safety during waste management activities. Therefore, vaccination against HBV, personal hygiene practices and regular training on occupational safety will help to control risk of HBV infection among municipal waste workers and scavengers. PMID- 30524800 TI - Removal of Heavy Metal Ions from Household Drinking Water Using Acacia Galpinii Seeds and Seed Pods. AB - Background: Contamination of drinking water with heavy metals poses a human health threat, particularly in low-income countries where point-of-use water purification systems are beyond the reach of a majority of households. Objectives: The study was undertaken to evaluate the efficacy of Acacia galpinii (monkey thorn tree) biomass in removing lead (Pb (ll)), cadmium (Cd (ll)), calcium (Ca (ll)), and magnesium (Mg (ll)) ions from drinking water. Methods: A. Galpinii biomass from seed and seed pods was processed by pulverizing, Soxhlet oil extraction and particle size grading. The material was analyzed by X-ray fluorescence (XRF) and Fourier transform infrared (FTIR) spectrophotometry. Influence of the physiochemical parameters (contact time, initial concentration, adsorbent dosage, pH) on the effectiveness of the biomass in removing Pb (ll), Cd (ll), Ca (ll) and Mg (ll) ions was evaluated and the best fit adsorption isotherm model (Langmuir vs. Freundlich) was also determined. Results: Particle size, dose, contact time and pH all played significant roles in the effectiveness of metal removal for both seed and seed pod biomass. At biomass particle size <90 microns, 98% removal rates of Pb (II) ions were achieved for powdered seed pods compared with 65% for powdered seeds. The same trend was observed for Cd, Ca and Mg. Contact time for effective removal of metal ions by pod powder and seed powder was 90 minutes and 120 minutes, respectively. Maximum adsorption was achieved at solution pH 6-8 for all metals. Lead adsorption followed a Langmuir isotherm model with maximum adsorption capacities of 10.8932 for pod powder and 3.4412 for seed powder. Adsorption of Ca and Mg followed a Freundlich model, with adsorption capacity of 1.1789 for Ca and 1.4521 for Mg. Conclusions: Acacia galpinii seeds and seed pods are inexpensive, readily available and may serve as a cost effective means for treatment of drinking water for domestic users in low and middle income countries. PMID- 30524801 TI - Child Exposure to Lead in the Vicinities of Informal Used Lead-Acid Battery Recycling Operations in Nairobi Slums, Kenya. AB - Background: Child exposure to lead from informal used lead-acid battery (ULAB) recycling operations is a serious environmental health problem, particularly in developing countries. Objectives: We investigated child exposure to lead in the vicinities of ULAB recycling operations in the Dandora, Kariobangi and Mukuru slums in Nairobi between January and August 2015. Methods: Top soil (n = 232) and floor dust (n = 322) samples were collected from dwelling units (n = 120) and preparatory schools (n = 44) and analyzed using an inductively coupled plasma optical emission spectrometer at the Mines and Geological Department Laboratory in the Ministry of Mining, Nairobi. From the obtained lead levels in soil and house dust, child blood lead levels were subsequently predicted using the Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK), Windows version. Results: Lead loadings in all the floor dust samples from the Dandora, Kariobangi and Mukuru slums exceeded the United States Environmental Protection Agency (USEPA) guidance value for lead on floors with a range of 65.2 - 58,194 MUg/ft2. Control floor dust samples recorded lower lead loadings compared to the Dandora, Kariobangi and Mukuru slums. Lead concentration in 70.7% of the soil samples collected from waste dumps, industrial sites, residential areas, playgrounds and preparatory schools in Dandora, Kariobangi and Mukuru exceeded the respective USEPA guidance values for lead in soils. Lead concentration in 100% of control soil samples were below the respective USEPA limits. The IEUBK model predicted that nearly 99.9% of children <= 7 years old living near informal ULAB recycling operations in Dandora, Kariobangi and Mukuru were at risk of being lead poisoned, with predicted blood lead levels (BLL) above the Centers for Disease Control (CDC) reference value for blood lead. A total of 99.9% of exposed children living in the Mukuru slums are likely to have BLL above 34 MUg/dL. Conclusions: There is a need for coordinated efforts to decrease lead emissions from informal battery recycling in Nairobi slums and to remediate existing soils, particularly around battery workplaces and dumpsites. The BLL of local children should be clinically tested and appropriate intervention measures taken. PMID- 30524802 TI - Analysis of Artisanal Small-scale Gold Mining Sector in West Sumbawa Regency, Indonesia. AB - Background: The high value of gold reserves in West Sumbawa Regency (WSR) and West Nusa Tenggara Province, Indonesia has resulted in an increase in small-scale gold mining activity in this area. Artisanal and small-scale gold mining (ASGM) is an attractive alternative livelihood for rural workers because it has good potential to improve the wealth of a community. Miners need very little training to mine gold and the transition from traditional farming or fishing is easy to make. However, the key environmental consequence of ASGM in West Sumbawa is the extensive use of mercury and its impact on human health. Objectives: The ASGM activity in WSR is quite recent when compared to other ASGM activity in Indonesia. The current study was conducted to better understand the lifestyle, extent of mercury exposure, and the health of people living in WSR, West Nusa Tenggara Province, Indonesia. Methods: The present study was designed as a purposive field sampling study conducted in WSR, West Nusa Tenggara Province, Indonesia. The subjects were miners and families from three different sites within the WSR: individuals directly exposed to mercury, indirectly exposed individuals and non-exposed individuals. Hair mercury analysis was done with all subjects. Health questionnaires, physical examinations and socio-economic surveys were conducted with exposed subjects. Results: The ASGM sector in the WSR consists of a high number of migrant workers who have a great economic impact on the local area, high mercury use, a great deal of illegal mercury trading, and a high mercury concentration (>13 mg/kg) in their hair. The results suggest that ASGM activities affect the health of exposed and indirectly exposed individuals. Conclusions: The current scale of ASGM activity in the WSR is predicted to rise. ASGM activities in the WSR is an important challenge that needs to be addressed. PMID- 30524803 TI - Biodegradation of Pollutants in Waste Water from Pharmaceutical, Textile and Local Dye Effluent in Lagos, Nigeria. AB - Background: Discharged effluents from industry have been responsible for the deterioration of the aquatic environment in many parts of the world, especially in developing countries. Increasing industrialization and urbanization have resulted in the discharge of large amounts of waste into the environment, resulting in high pollution loads. Utilization of microbes such as fungi and bacteria have been used for pollution degradation. Objectives: The aim of this research was to utilize microbial agents such as fungi and bacteria to reduce pollutant loads such as heavy metals in effluent samples. Methods: Three types of effluent (pharmaceutical, textile effluent, and dye) were obtained from Surulere in Lagos Metropolitan Area, Nigeria. Heavy metals analysis was carried out using a flame atomic adsorption spectrophotometer according to standard methods. Samples were cultured for microbes and identified. Bacteria samples were inoculated on nutrient agar and incubated at 37 degrees C for 24 hours. Fungi counts were carried out using potato dextrose agar and incubated at 28 degrees C for 3-5 days. The isolated organisms were identified based on their morphological and biochemical characteristics. Then 100 mL of the effluents was dispensed into 250 mL flasks, and the pH of the medium was adjusted to 7.2 by the addition of either sodium hydroxide or hydrogen chloride and autoclaved at 121 degrees C for 15 minutes. The autoclaved flask was inoculated with 1 mL of bacteria and fungi for 21 days and pH was recorded properly every 48 hours. Results: The results of the physicochemical parameters indicated that conductivity, total suspended solids, total dissolved solids, turbidity, chemical oxygen demand and biochemical oxygen demand for all the three industrial effluents were higher than the World Health Organization (WHO) permissible limits. Heavy metal analysis results show that the effluents had high values for cadmium, above the WHO limit of 0.003 mg/L. Concentrations of zinc ranged from 0.136-1.690 mg/L, and nickel ranged between 0.004-0.037mg/L for the three effluents, within the WHO limit. The identified bacteria were Bacillus subtilis, Klebsiella pneumonia, Salmonella typhi and Bacillus cereus and isolated fungi were Aspergillus flavus and Penicillium chrysogenum. All the physicochemical parameters and heavy metal concentrations were reduced after the biodegradation study in the effluents. Conclusions: The responses observed in the various microbes indicated that the use of microbes for the reduction of environmental pollutants has an advantage over the use of other methods because it is environmentally friendly, low cost, and no new chemicals are introduced into the environment. This method should be encouraged for pollution reduction to bring about ecosystem sustainability advocated for Ghana. PMID- 30524804 TI - Examination of Lead and Cadmium in Water-based Paints Marketed in Nigeria. AB - Background: In spite of the availability of substitutes for lead and cadmium compounds in paints, manufacturers continue to produce paints with high levels of these metals. As the population continues to grow and there is a continued shift from oil-based to water-based paints, the sales and use of these paints will increase the exposure of humans and the environment to these metals. Objectives: We measured the levels of lead (Pb) and cadmium (Cd) in 174 paint samples marketed in Lagos and Ibadan, Nigeria. Paint samples from different manufacturers registered with and without Standards Organization of Nigeria (SON) were considered. Methods: Samples were acid digested using a microwave digester and the levels of the elements were determined using inductively coupled plasma optical emission spectroscopy (ICP-OES). Discussion: The levels of Cd and Pb (dry weight) in all samples ranged from 98-1999 MUg/g and 170-3231 MUg/g, respectively. All the samples were above the permissible limits of 90 ppm of the US Consumer Product Safety Commission and 100 ppm limit of the European Union (EU) for Pb and Cd in paint. Conclusions: We concluded that water-based paints marketed in Nigeria still contain substantial amounts of lead and cadmium which are detrimental to human health and the entire ecosystem. These metals are among the EU priority metals due to the increased risk of occupational exposure to humans and vulnerable groups such as children. PMID- 30524805 TI - Metallothionein and Glutathione Content as Biomarkers of Metal Pollution in Mussels and Local Fishermen in Abu Qir Bay, Egypt. AB - Background: When heavy metals accumulate in air, soil, and water, the risk of human exposure increases among industrial workers, as well as in people living near polluted areas. Heavy metals adversely affect a variety of bodily systems such as the cardiovascular, respiratory, endocrine, immune, and reproductive systems. In addition, long-term exposure and accumulation of heavy metals in the body may disturb oxidative stress genes and thus increase the susceptibility to various diseases. Objectives: The aim of this study is to estimate the metallothionein concentration in both mussel samples from Abu Qir Bay, Egypt and the blood of local fishermen as a biomarker of exposure to metal pollution. Methods: Levels of metallothionein and heavy metals were measured in mussels. Blood levels of metallothionein and heavy metals of local fishermen were measured and compared with a control group. The effect of heavy metal exposure on oxidative stress status was investigated through the determination of malondialdehyde (MDA), catalase and glutathione content. Results: The results of this study showed high concentrations of metallothionein in mussels and in fishermen's blood, accompanied by high concentrations of metals such as cadmium (Cd), copper (Cu), lead (Pb), chromium (Cr), and zinc (Zn). At the same time, a significant decrease in glutathione content and catalase enzyme activity was associated with a significant increase in the malondialdehyde concentrations in sera of fishermen. Conclusions: The present study found that the El Maadiya region is polluted with heavy metals, inducing oxidative stress in fishermen in the vicinity. These results reveal the necessity of further environmental monitoring in the study area in order to evaluate other types of pollutants and their effects on human health. PMID- 30524807 TI - Proceedings of the 8th International Conference on Children's Health and the Environment. PMID- 30524806 TI - Biodegradation of Methanol Using Thiosulphate as an Electron Acceptor Under Anaerobic Conditions. AB - Background: Methanol is a volatile organic compound commonly found in the effluent of the pulp and paper industries. Because of its toxicity, methanol can cause metabolic acidosis, neurologic sequelae, and even death when ingested. Information on biokinetic activity such as biodegradation rate of methanol and thiosulphate, biomass growth rate and biomass yield coefficient is limited in the literature. Objectives: To study the biomass growth rate and biomass yield coefficients of methanol and thiosulphate biodegradation. This research aims to increase knowledge of how to reduce the emission of toxic gas to the environment. Methods: The biodegradation trends of both methanol and thiosulphate were studied under anaerobic conditions using batch experiments at ambient temperature and alkaline conditions. Both supplement each other for their degradation. Methanol is an electron donor, whereas thiosulphate acts as an electron acceptor. A mixed culture from a previously used biomass in a biotrickling filter reactor from theUnited Nations Educational, Scientific and Cultural Organization (UNESCO), International Graduate Water Education Facility and fresh activated sludge from the Harnaschpolder wastewater treatment plant were used as a biomass source. Results: A specific biomass growth rate of biomass ranging from 0.04 to 1.7g per day was observed. The thiosulphate is biologically degraded by the biomass grown inside the reactor. The biodegradation rate of thiosulphate in the reactor varied from 0.02 to 0.80g per unit gram of biomass per day. A biodegradation rate of methanol in the reactor was observed in the range between 0.04 to 3.9g per unit gram of biomass per day. Bacterial biomass was grown as per the amount of methanol present inside the reactor. A maximum biomass yield coefficient of 0.7g biomass per gram of methanol was recorded. Thiosulphate was converted to sulphate that indirectly served as an electron acceptor for methanol degradation. Both degradation of methanol and thiosulphate in this experiment were in the range of the degradation rate shown for sulphate and organic compounds in other studies. Conclusion: Simultaneous removal of thiosulphate and methanol using an anaerobic bioreactor is promising and can be applied on an industrial scale. This finding is an important contribution to public health as it reduces the emission of toxic gas to the environment. PMID- 30524808 TI - Environmental Contamination in Nigeria. PMID- 30524809 TI - Environmental Working Conditions, Lung Function and Total Serum Bile Acids of Spray Painters Exposed to Organic Solvents in Ile-Ife, Nigeria. AB - Background: Nigeria has a growing spray painting industry, however, the burden of occupational health problems related to organic solvent exposure among spray painters in Nigeria is under-studied. Objectives: This study aimed to assess workshop characteristics and ambient concentration of total volatile organic compounds (VOCs) in spray painting workshops and to compare lung function status and total serum bile acid levels of spray painters and controls. Methods: A cross sectional study design was employed to survey 120 spray painters and 120 controls (electronic technicians). A semi-structured questionnaire was used to obtain data on socio-demographics characteristics of the respondents. Weight, height and lung function of respondents were measured. In addition, a checklist was used to survey the spray painting workshops. Total VOC levels were determined in 37 spray painting and 31 electronic workshops. Data were analyzed using Statistical Program for the Social Sciences (SPSS) version 20 and a p-value of <0.05 was considered to be statistically significant. Results: Windows were present in only 5 (13.5%) spray painting workshops and 23 (62%) workshops had a retractable tarpaulin at the entrance. Only 9 (24%) workshops had changing rooms, while fire extinguishers and first aid kits were not present in any of the surveyed workshops. A respirator with filter was sighted in only 1 (3%) workshop. The 8 hour time weighted average concentration of total VOCs in spray painting workshops was 13.4 ppm, which is above the national permissible exposure limits of 1.9 ppm. Forced vital capacity (FVC) percent predicted was significantly lower in spray painters (93.9 +/-10.8%) than controls (96.7+/- 8.2%) (t = -2.326, df=238 p< 0.001). In addition, forced expiratory volume in the first second (FEV1) percent predicted was lower in spray painters (94.6+/-12.2%) than controls (100.3+/-9.1%) (t=-4.058, df=238, p=0.002). FEV1/FVC% was significantly lower among spray painters (85.48+/-8.70%) compared with controls (87.88+/-6.22%) (t= 2.861 df=238, p= 0.005). Total serum bile acids was significantly elevated in painters (8.71+/-3.39 mmol/l) compared to controls (4.67 +/-2.15 mmol/l) (t=10.358, df=213, p<0.05). Conclusions: Spray painters in the present study conduct their activities in hazardous work settings. More needs to be done concerning workplace regulation and enforcements to ensure that spray painters comply with minimum standards of occupational safety, workplace hygiene and sanitation. Patient Consent: Obtained. Ethics Approval: Ethical approval was granted by the Health Research and Ethics Committee of the Institute of Public Health, Obafemi Awolowo University. PMID- 30524810 TI - Assessment of Air Pollutant Concentrations Near Major Roads in Residential, Commercial and Industrial Areas in Ibadan City, Nigeria. AB - Background: Urbanization, energy consumption, intensification of road traffic and rapid population growth pose significant challenges to ambient air quality. Therefore, regular monitoring of current air quality is essential. Objectives: The study investigated the concentration of sulfur dioxide (SO2), oxides of nitrogen (NOx), ozone (O3), ammonia (NH3) and carbon monoxide (CO) in ten different sites to investigate possible anthropogenic sources within Ibadan, Nigeria. Methods: Air samples were collected into specific absorbing solutions twice daily in the morning and afternoon for four weeks. The resulting solutions were analyzed following specific colorimetric techniques according to standard methods of analysis. Results: Average concentrations varied among the sampling areas. All were above background levels obtained at the control site. Overall concentrations were found to be 30+/-19 MUg/m3 (SO2), 63+/-16 MUg/m3 (NOx), 31+/ 18 MUg/m3 (O3), 463+/-180 MUg/m3 (NH3) and 0.59+/-0.21 ppm (CO). These concentrations were present at the study areas at 15, 31, 17, 5 and 3 times the background concentrations for SO2, NOx, O3, NH3 and CO, respectively. Conclusions: In spite of the short duration of sampling, the data can guide future long term monitoring of air quality in Nigeria. The level of SO2 exceeded World Health Organization limits within this short duration. This is an indication of the need for long term air quality monitoring with a sustainable plan for air pollution management. PMID- 30524811 TI - Lead Removal from Contaminated Shooting Range Soil using Acetic Acid Potassium Chloride Washing Solutions and Electrochemical Reduction. AB - Background: Cleanup of soils contaminated with toxic metals is a difficult task due to the method inefficiency and the destructive nature of clean-up techniques on soil ecosystems. Objectives: This study was performed to improve the removal efficiency of an acetic acid washing solution for the removal of lead (Pb) from soil. Acetic acid was used in combination with different concentrations of potassium chloride. In order to maximize the removal of Pb from the leachate, different electrode combinations were applied to the washing solutions. Methods: Acetic acid/potassium chloride washing solutions and electrochemical reduction were applied to lead-contaminated soil obtained from an impact berm of a major military shooting range in Ibadan, southwestern Nigeria. The soil was subjected to 5% acetic acid/5% potassium chloride (KCL) and 5% acetic acid/10% KCL solutions in an ex-situ batch experiment. The leachate was electrochemically reduced using 12 volt direct current with a current of 7 amps and 2.5 amps, with aluminum (Al)-Al, iron (Fe)-Fe, Al-Fe and Fe-Al electrodes. Results: The 5% acetic acid/5% KCL proved more efficient for Pb removal in soil with values ranging from 74.9% to 86.9% for 3% soil pulp densities with one washing time of 6 hours. Removal efficiency of Pb from the contaminated soil significantly decreased as the soil pulp density increased. The Al-Al and Al-Fe bipolar electrode combinations showed better removal efficiency of Pb from the leachates with values of 93.7% and 95.6% for 7 amps and 94.5% and 97.3% for 2.5 amps, respectively. Conclusions: The combined 5% acetic acid and 5% potassium chloride washing solution enhances the removal efficiency of Pb in soil and poses less risk to the soil ecosystem and the environment in general. PMID- 30524812 TI - Occurrence and Distribution of Arsenic, Antimony and Selenium in Shallow Groundwater Systems of Ibadan Metropolis, Southwestern Nigerian. AB - Background: Arsenic, antimony and selenium contamination of groundwater is of great concern due to the potential detrimental effects to human health. Objectives: This study investigates the occurrence and distribution of arsenic, antimony and selenium in the shallow groundwater system of Ibadan metropolis, southwestern Nigeria. Methods: A total of 210 groundwater samples were collected from 35 shallow wells (3.15-7.86 m) within the residential, commercial, industrial and agricultural areas of the metropolis during the dry and wet seasons. The average daily dose intake (ADD), hazard quotient (HQ) and hazard index (HI) of arsenic, antimony and selenium exposure in groundwater were calculated from these four studied areas for children and adults. Results: Average concentrations of arsenic, antimony and selenium in groundwater ranged between 2.17+/-3.49 to 33.8+/-37.2 MUg/L, 13.5+/-15.0 to 33.2+/-36.8 MUg/L and 7.33+/-6.22 to 46.3+/-22.4 MUg/L, respectively. A corresponding analysis relay plot showed the order of occurrence of these trace metals in groundwater to be antimony>selenium>arsenic. The principal component analysis biplot showed that arsenic, antimony and selenium were fairly distributed in all of the study areas, suggesting the influence of geogenic factors. A total of 74.3% of sampling locations had antimony levels slightly above the World Health Organization (WHO) safe limit of 20 MUg/L. Statistical t testing (0.05 confidence limit) showed a significant difference in seasonal levels of groundwater antimony concentration, with the dry season recording significantly higher levels with 100% of samples exceeding WHO safe limits. The chemical of highest potential human health concern is antimony, with a non-carcinogenic HQ risk factor >2 for both age groups. The overall non-carcinogenic HI was highest in the commercial area, 4.1989 for adults and 5.2487 for children. Conclusions: Antimony in groundwater within the Ibadan metropolis raises health concerns and a concerted effort is needed to identify its sources to avoid the risk of antimony toxicity. PMID- 30524813 TI - Lead and Cadmium Levels in Residential Soils of Lagos and Ibadan, Nigeria. AB - Background: Lead and cadmium are components of paints sold in Nigeria. These heavy metals are associated with adverse neurological, cardiovascular and other human health effects. Objectives: This study assesses the levels of lead and cadmium in topsoil of residential areas in Lagos and Ibadan potentially resulting from painting of buildings. Methods: Samples were pre-treated prior to metal determination using atomic absorption spectrophotometry. Metal speciation was determined using modified Tessier sequential extraction. Soil characteristics were determined by standard methods. Soil contamination was assessed using contamination factor, geo-accumulation and pollution load indices. The United States Environmental Protection Agency integrated exposure uptake biokinetic (IEUBK) model was used to estimate and predict children's blood lead levels (BLL). Results: Lead and cadmium concentrations in residential areas in Lagos and Ibadan ranged from 1.56-419 mg/kg and not detected-2.8 mg/kg, respectively. Metal contamination factor and pollution load index were highest at the Lagos low income settlement. Results of IEUBK modelling showed that the Lagos low income settlement had the highest probability density for children between 1-7 years of age with an estimated BLL of >10 MUg/dL. This population made up less than 0.01% of those within this age range. Conclusions: Lead and cadmium concentrations in soil around the residential buildings were higher than those in the control sample. Contamination factor and pollution load index showed significant contamination in average and low income settlements. These results suggested that there was accumulation of the metals in the soil, which can persist in the environment. This may pose serious health risks, especially to vulnerable groups such as children. PMID- 30524814 TI - Use of Agricultural Wastes for the Immobilization of Metals in Polluted Soils in Lagos State, Nigeria. AB - Background: An increase in human and industrial activities has led to an increase in the pollution of soils by metals. If these metals become bioavailable, there is potential for human exposure, leading to possible health effects. Remediation of soils is important to ensure that soil is suitable for agricultural purposes. Objectives: To explore the use of sawdust and cow dung to remediate contaminated soil by reducing the bioavailability of metals. Methods: Soil samples were collected from Oke Afa dumpsite and Owode Onirin metallic store and total metal concentrations were determined by digesting with aqua regia and analyzed using flame atomic absorption spectrophotometry. The effect of varied dosages (1-5 g) of cow dung and sawdust on the immobilization of the selected metals was investigated, and results were compared with disodium hydrogen phosphate (DSHP) amendments. A single reagent leaching test was carried out with 0.1 M calcium chloride to determine the bioavailability of metals before and after amendment. Results: Before amendment, the amount of bioavailable metal in the soil sample from Oke Afa dumpsite was 57.5 mg/kg, 194 mg/kg and 17.5 mg/kg for copper (Cu), lead (Pb) and zinc (Zn), respectively, while in the second soil sample, from Owode Onirin metallic store, the amount of bioavailable Cu, Pb and Zn was observed to be 19.9 mg/kg, 36.4 mg/kg and 11.1 mg/kg, respectively. Up to 73.4% of mobile Zn was immobilized using DSHP, while cow dung and saw dust were effective in the immobilization of Cu and Pb, but not Zn. Conclusions: Cow dung and sawdust reduced the bioavailability of copper and lead, while Zn can be effectively immobilized with the use of DSHP. It was generally observed that the bioavailability of heavy metals decreased with increasing dosage of the amendments. PMID- 30524815 TI - Concentration and Human Health Implications of Trace Metals in Fish of Economic Importance in Lagos Lagoon, Nigeria. AB - Background: The most significant sources of food-borne diseases are microbiological and chemical hazards. The health risk due to consumption of food from aquatic ecosystems contaminated with hazardous chemicals including metals has increased globally, especially in developing countries like Nigeria. Objectives: The concentration and human health implications of trace metals in fish of economic importance in Lagos lagoon were investigated by determining the degree of contamination with heavy metals of selected fish from Lagos lagoon and assessing the possible health risks associated with fish consumption. Methods: Fish of economic importance including Caranx hippos, Chrysichthys nigrodigitatus, Elops lacerta, Galeoides decadactylus, Ilisha africana, Liza falcipinnis, Lutjanus goreensis, Mugil cephalus, Pseudotolithus senegalensis, Sarotherodon spp, Sphyraena spp, and Tilapia spp were bought from fishermen fishing in Lagos lagoon. The fish tissue samples were digested and analyzed in five replicates for heavy metals (lead, cadmium, iron, manganese and zinc) using a Varian AA600 atomic absorption spectrometer. Results: There were considerable variations in the concentrations of heavy metals among different species. The twelve fish species collected from Lagos lagoon were found to contain various concentrations of heavy metals and the levels of accumulation of these heavy metals varied across different species. Lead, cadmium, and manganese were present in all the studied fish species at higher concentrations than the maximum allowable concentrations in fish recommended by the Food and Agricultural Organization (FAO) and World Health Organization (WHO). The target hazard quotient (THQ) estimated for individual heavy metals through consumption of different fish species was less than 1 for all individual heavy metal in all the fish species. Conclusions: Controls on the dumping of wastes in the lagoon are needed, along with regular monitoring. Currently, no potential non-carcinogenic health risks from ingestion of a single heavy metal through consumption of these fish species was found. PMID- 30524816 TI - A Call to Re-Evaluate the Role and Responsibility of the Physician in Environmental Health. PMID- 30524817 TI - Knowledge of and Adherence to the Cyanide Code Among Small-scale Gold Miners in Northern Tanzania. AB - Background: Tanzania has seen explosive development in small scale gold mining (SGM) operations. Recently, the use of cyanide has become more common in SGM, especially in the reprocessing of mercury-amalgamated tailings from artisanal mining sites. Objectives: The primary objective of this study was to examine the level of knowledge and adherence to the Cyanide Code among workers and managers at SGM operations in northwestern Tanzania that use cyanide for gold extraction, focusing on workers' safety. Methods: A cross-sectional study of workers and managers at 17 selected SGM sites was conducted. A random-cluster approach was used to recruit 215 mine workers and 23 mine managers who worked at the same sites for more than three months. Individuals participated in structured face-to face interviews. Site evaluation checklists were also administered to assess adherence. Results: The majority of the SGM workers (61.4%, n=132) were not aware of the Cyanide Code. Among the mine managers, 64.2% (n=15) were aware of the Cyanide Code. Fifty-four percent of workers and 39.1% of managers did not adhere to the Cyanide Code. Workers who reported being trained on the Cyanide Code were significantly more likely to have knowledge about the Cyanide Code guidelines compared to untrained workers (adjusted odds ratio =20.3, confidence interval: 7.5 - 54.8). Discussion: Wide variations in knowledge of and adherence to the Cyanide Code were found. A manager's knowledge of Cyanide Code was significantly associated with workers' knowledge. High worker and manager knowledge was associated with increased site safety performance. Even though all the SGM sites were physically visited, some potentially hazardous practices may not have been revealed by managers and workers because of fear of possible regulatory actions due to disclosure of concerns related to their operation's safety compliance. Conclusions: The limited knowledge of the Cyanide Code among workers and managers, combined with poor adherence to cyanide waste management practices, indicates that there is a need for education, health promotion and sensitization among workers and managers to improve worker safety and minimize environmental health impacts. Participant Consent: Obtained. Ethics Approval: Ethical approval was obtained from the Conjoint Catholic University of Health and Allied Sciences and Bugando Medical Centre Research Review and Ethics Committee (Ref. BREC/001/35/2014). Permission to conduct research in Geita District was obtained from the respective authorities at the regional and district levels and from owners of the SGM sites. PMID- 30524818 TI - Impact of Dumpsites on the Quality of Soil and Groundwater in Satellite Towns of the Federal Capital Territory, Abuja, Nigeria. AB - Background: Urbanization, industrialization and changes in consumption patterns have compounded the problem of solid waste management in Nigeria. Poor waste management threatens the well-being and health of the local population, particularly those living adjacent to dumpsites. Objectives: An assessment of the impact of dumpsites in a satellite town of the Federal Capital Territory, Abuja, Nigeria was carried out to determine the level of biophysical/chemical parameters (pH, temperature, conductivity, nutrients (calcium and magnesium), heavy metals (lead, chromium, zinc), and microbial burden) on the quality of soil and groundwater and their impact on health and the environment. Methods: Soil and ground water samples were collected in four different dumpsites (Bwari, Gwagwalada, Kuje and Azhatta) with reference samples taken from the Federal Capital Territory, Abuja, and taken to the laboratory for biophysical/chemical analysis using standard methods. Results: The results were compared with the national and World Health Organization (WHO) standard limits for soil and water respectively. Except for zinc, the average concentrations for heavy metals in the soil samples were higher in all four dumpsites than the permissible levels. Soil and water parameters that exceed the standard limits pose significant health and environment risks to nearby residents. Conclusions: There is a need for raising the awareness of residents living close to dumpsites and those who use the well or nearby streams for domestic activities on the need to carry out adequate water treatment prior to its use. PMID- 30524819 TI - Evaluation of Potentially Toxic Metal Contamination of Local Medicinal Plants and Extracts Sold in Ibadan, Nigeria. AB - Background: Extracts from medicinal plants have been widely used in the treatment of public health ailments, however, medicinal plants may be grown in polluted soil/water environments. Many of these plants are harvested and processed by local and illiterate natural healers and other vendors in an unhygienic manner. This results in the possibility of contamination with potentially toxic metals from the environment. Objectives: This study evaluated the concentrations of lead (Pb), cadmium (Cd), chromium (Cr), nickel (Ni), copper (Cu) and zinc (Zn) in 25 samples of different medicinal plants procured from stores in open markets in Ibadan, Nigeria. Methods: After procurement, the samples were air dried, pulverized and dry ashed. All ashes were dissolved with dilute acid solutions, filtered and the filtrates were stored for metal analysis. Samples with elevated metal concentrations were extracted with water and alcohol solutions to mimic the medicinal extracts obtained from these plants. Metal concentrations were analysed in all extracts and filtrates using atomic absorption spectrophotometry. Results: Metal concentrations (mg/kg dry weight) in all samples ranged as follows: Cu, 0.04 - 9.44; Zn, 0.36 - 35.4 and Pb, below detection limits (BDL) - 6.15. The concentrations of Cd, Cr and Ni in all samples were BDL. The concentrations of all metals in the samples were within accepted limits set for medicinal plants according to international regulatory bodies. All ethanol extracts and 1 out of 4 water extracts contained Pb. Conclusions: Medicinal plants could pose chronic metal toxicity effects from continual bioaccumulation along the food chain. Furthermore, extraction of active ingredients with water was deemed to be safer than the use of alcohol extracts. Continuous monitoring of these medicinal plant materials is needed. PMID- 30524820 TI - Retracted Human Health Risk of Chromium Intake From Consumption of Poultry Meat and Eggs in Dhaka, Bangladesh. AB - Background: Heavy metals contamination of food is a serious threat. Long term exposure may lead to human health risks. Poultry and eggs are a major source of protein, but if contaminated by heavy metals, have the potential to lead to detrimental effects on human health. Objectives: The objective of this study is to determine chromium concentrations in poultry meat (flesh and liver) and eggs collected from poultry farms in Dhaka, Bangladesh, to calculate the daily intake of chromium from the consumption of poultry meat and eggs for adults, and to evaluate their potential health risk by calculating the target hazard quotients (THQ). Methods: All samples of poultry feed, meat (flesh and liver) and eggs were analyzed by a graphite furnace atomic absorption spectrometer (AAS) (GFA- EX- 7i Shimadju, Japan). Results: Chromium concentrations were recorded in the range of not detected (ND) to 1.3926+/-0.0010 mg kg-1 and 0.0678+/-0.0001 mg kg-1 to 1.3764+/-0.0009 mg kg-1 in the liver of broiler and layer chickens, respectively. Chromium concentrations were determined in the range of 0.069+/-1.0004 mgkg-1 to 2.0746+/-0.0021 mg kg-1 and 0.0362+/-0.0002 mg kg-1 to 1.2752+/-0.0014 mg kg-1 in the flesh of broiler and layer chicken, respectively. The mean concentration of chromium in eggs was 0.2174-1.08 mg kg.-1 The highest concentration of chromium 2.4196+/-0.0019 mg kg-1 was found in egg yolk. Target hazard quotients values in all poultry flesh, liver and eggs samples were less than one, indicating no potential health risks to consumers. Conclusions: The estimated daily intake values of chromium were below the threshold limit. Thus, our results indicate that no adverse health effects are expected as a resultof ingestion of chicken fed with tannery waste. Ethics Approval: This study was approved by the Biosafety, Biosecurity & Ethical Committee of Jahangirnagar University. PMID- 30524821 TI - Resource Prospects of Municipal Solid Wastes Generatedin the Ga East Municipal Assembly of Ghana. AB - Background: Municipal solid wastes management has recently become an important public health concern. Municipal solid wastes are a major source of raw materials that could be used for resource recovery for diverse applications. Objectives: The present study aimed to determine the composition of municipal solid waste and recoverable resources from the waste of the Ga East Municipal Assembly (GEMA) in the Greater Accra region of Ghana. Methods: An exploratory approach was used to collect pertinent data from the Abloradgei dumpsite in GEMA using semi-structured interviews and focus group discussion. A field characterization study was undertaken to segregate and estimate the value of various components of collected waste. Dumpsite workers were asked about current general composition of MSW, mode of collection and disposal, record of sanitation-related diseases, use of modern treatment plant, waste management legislation and enforcement challenges, number of trucks received by the dumpsite per day, record on pretreatment of MSW before disposal, and use of personnel protective equipment. Results: The results showed that significant proportions (48.8%) of the municipal solid wastes were organic materials, while the remaining (51.2%) were inorganic materials. The results also showed that 63% of the municipal solid waste is collected with no sorting from the source and no modern treatment applied before dumping. It was estimated that the value of the recyclable materials in GEMA municipal solid waste amounts to Ghana Cedis (GHc) 9,381,960 (plastic); 985,111 (mixed glass); 5,160,078 (paper) and 11,586,770 (metal) with a total of GHc 27,113,919 ($10,845,568) equivalent to 2,106,339.2 m3 (74,384,667.5 ft3) per annum of biogas from these components with a market value of GHc 1,997,972.17 ($768, 393.62); 11,579 Mwh (1.32 Mw) of electricity and 9,535 Mwh (1.09 Mw) of heat. This is estimated to be lost with the current waste management practices. Conclusions: We recommend that GEMA institute sustainable recycling practices and utilization of biogas production technologies and prioritize sanitation and waste management education for the public, obligate home segregation of waste materials, involve workers by providing them with protective clothing, incorporate informal waste collectors and scavengers into the new system and collaborate with research institutions in waste-to-resource projects to ensure a more sustainable waste management system in the municipality. Participant Consent: Obtained. PMID- 30524822 TI - Assessment of Heavy Metal Concentrations in Pawpaw (Carica papaya Linn.) around Automobile Workshops in Port Harcourt Metropolis, Rivers State, Nigeria. AB - Background: Consumption of plants such as Carica papaya grown around automobile workshops is common in big cities in Nigeria. However, little is known about the heavy metals contamination of these consumables due to the influence of automobile emissions during maintenance activities. Objectives: This study aimed to assess heavy metal concentrations in C. papaya and supporting soils around automobile workshops in Port Harcourt Metropolis, Rivers State, Nigeria. Methods: Seven automobile workshops were used for the present study. First, 20 m * 20 m quadrats were laid out for soil and C. papaya tissue sampling. One composite soil sample was collected from the topsoil (0-15 cm depth) around each of the automobile workshops. Three C. papaya stands at least 30 cm apart around each workshop were used for the study and from these stands, tissues (root, stem, leaf, fruit) of C. papaya were collected. Standard laboratory techniques were used to determine the pH, electrical conductivity (EC) and heavy metals (lead (Pb), mercury (Hg), cadmium (Cd), copper (Cu), and zinc (Zn)) in the soil samples and C. papaya tissues. Pairwise t-test was used to determine significant differences (p<0.05) in the heavy metal concentrations in soil and C. papaya tissues between the sample and control sites, while correlation statistics were used to determine the relationship of heavy metal concentrations between soil and C. papaya tissues. Results: C. papaya tissues and supporting soil had significantly higher levels of pH, EC and heavy metals in the sampled plots than the control plot. The heavy metal concentrations in C. papaya and soil occurred in the decreasing order of Pb>Cu>Hg>Zn>Cd. The fruit of C. papaya had the highest mean concentrations of Pb (51.4+/-14.1 mg/kg) and Zn (26.4+/-1.9 mg/kg), while the leaf had the highest mean concentration of Hg (32.0+/-2.3 mg/kg). The pH, Cu and Zn in the supporting soil were significantly correlated with the levels in the C. papaya tissues. Conclusion: Bio-accumulation of heavy metals by C. papaya is evident around automobile workshops, and Pb, Hg, Cd concentrations were found to be above the permissible limits for human consumption according to World Health Organization (WHO) standards. Consumption of food materials grown around automobile workshops could pose health risks. PMID- 30524823 TI - Influence of a Dispersant on the Types and Growth of Microbial Hydrocarbon Degraders in a Crude Oil-contaminated Medium. AB - Background: Dispersants are first order response strategies for oil spill cleanup in an aquatic environment. However, their effects on the biodegradation capacity of indigenous hydrocarbon-degrading microorganisms are little known. Objectives: The influence of a dispersant (DS/TT/066) on the type(s) and growth of hydrocarbon-degrading bacteria (HDB) and hydrocarbon-degrading fungi (HDF) in a crude oil-contaminated medium (water) was investigated in the laboratory for 28 days. Methods: The experiment was set up in duplicates with the first set containing Forcados light crude oil (FLCO) alone in water while the other was a mixture of FLCO and DS/TT/066 (ratio 9:1 v/v). Identification and enumeration of HDB and HDF were conducted according to standard methods. Total petroleum hydrocarbons (TPH) in the test media was analyzed using a gas chromatography/flame ionization detector. Results: The results showed that HDB identified in the FLCO alone included Pseudomonas aeruginosa (day 0), Proteus vulgaris (day 14), P. aeruginosa and Kliebsiella pneumoniae (day 28). However, in the mixture, Escherichia coli was identified on day 14 in addition to the other species observed in FLCO alone. HDF identified in FLCO alone were Candida krusei and Candida albicans (days 0 and 14), Trichosporon cutaneum and C. albicans (day 28). In the mixture, HDF identified were C. albicans (day 0), C. albicans and Aspergillus spp. (days 14 and 28)" Furthermore, the mixture enhanced the growth of HDBF (average counts: 32.5 * 107 and 225 * 106 cfu/mL) compared to FLCO alone (17.5 * 107 and 17.5 * 106 cfu/mL) by day 14 respectively. Total petroleum hydrocarbon reduction was highest (85%) in the mixture compared to 5% in FLCO alone by day 14. Conclusions: The study demonstrated the biodegradation efficiency of E. coli, P. vulgaris (bacteria), C. albicans and Aspergillus spp. (fungi) in a crude oil-contaminated aquatic environment in conjunction with dispersant use. Further studies in the field are recommended in order to explore their potential for rapid and large scale crude oil clean-up operations. PMID- 30524824 TI - Enzymes as Biomarkers of Environmental Stress in African Catfish (Clarias gariepinus) in Osun State, Nigeria. AB - Background: Many natural aquatic bodies have been contaminated with heavy metals released from domestic, industrial and other anthropogenic activities. Fish are an important bioindicator species and play an important role in the monitoring of water pollution. Objectives: This study shows the effect of heavy metals on the distribution of glutathione S-transferases (GST), catalase, rhodanese and 3 mercaptopyruvate sulphur transferase (3-MST) isolated from the liver, gills, fins and muscle of Clarias gariepinus. Methods: Glutathione S-transferase, catalase, rhodanese and 3-mercaptopyruvate S-transferase enzymes were isolated from the liver and gills of fish by homogenization of each tissue (with specific buffers for each enzyme) and centrifugation. Serial dilutions of the crude enzymes were then assayed for residual enzymatic activities using standard enzyme assay protocol. Results: The results showed heavy metals in the liver and muscle of the investigated fish. This study indicated significant accumulation of heavy metals in the tissues/organ of the fish from Ilesha, Osogbo and Yakoyo fish ponds. These are three main towns in Osun State where the major occupation is fish farming. The relationship between enzymatic activities and heavy metal content in C gariepinus tissue showed positive and significant (p<0.05) correlations between lead (Pb) and GST as well as chromium (Cr) and GST. This implies that higher concentrations of Pb and Cr induced the expression of greater GST activity in the fish tissue. Conclusions: The study concluded that the pattern of response of GST, catalase, rhodanese and 3-MST activities in the various organs/tissues of C gariepinus to the heavy metals suggests that the excitation or inhibitions of their activities are organ specific. Further biochemical studies of fish tissues/organs are needed to characterize the enzymatic changes associated with heavy metal pollution. PMID- 30524825 TI - The Emerging Environmental and Public Health Problem of Electronic Waste in India. AB - Background: Monumental progress has been made in the area of information and communication technology, leading to a tremendous increase in use of electronic equipment, especially computers and mobile phones. The expansion of production and consumption of electronic equipment along with its shorter life span has led to the generation of tremendous amounts of electronic waste (e-waste). In addition, there is a high level of trans-boundary movement of these devices as second-hand electronic equipment from developed countries, in the name of bridging the digital gap. Objectives: This paper reviews e-waste produced in India, its sources, composition, current management practices and their environmental and health implications. Fixing responsibility for waste disposal on producers, establishment of formal recycling facilities, and strict enforcement of legislation on e-waste are some of the options to address this rapidly growing problem. Discussion: The exponential growth in production and consumption of electronic equipment has resulted in a surge of e-waste generation. Many electronic items contain hazardous substances including lead, mercury and cadmium. Informal recycling or disposing of such items pose serious threat to human health and the environment. Conclusions: Strict enforcement of waste disposal laws are needed along with the implementation of health assessment studies to mitigate inappropriate management of end-of-life electronic wastes in developing countries. PMID- 30524826 TI - Status of Air Pollution in Botswana and Significance to Air Quality and Human Health. AB - Background: Air pollution is an important issue in developed and industrialized countries. The most common sources of air pollution are anthropogenic activities such as construction dust, vehicular emissions and mining. For low- and middle income countries, biomass burning and indoor heating are the leading sources of air pollution. As more of the world undergoes development and human populations increase, industrialization is also increasing, along with the potential for air pollution. Objectives: This article reviews the status of air pollution to raise awareness of air quality and human health in Botswana. Discussion: Since independence, Botswana has experienced one of the highest economic development growth rates in the world. These changes have occurred as a result of economic growth and resource utilization associated with increased industrialization. However, there is growing worldwide concern about the effect and impact of pollution due to industrial growth. Botswana is ranked amongst the most polluted countries with serious air pollution, despite a population of just over 2 million. Conclusions: Rapid development and increased urbanization have had a major environmental impact around the world. This increased growth has the potential to lead to air quality degradation. Significant health threats are posed by industrial and vehicular emissions, especially in urban and peri-urban areas where the population is most concentrated. It is important that the linkage between air pollution and health effects is fully examined across all scales of life, especially in developing countries. In addition, programs should be devised to educate the public about the pollution impacts on health. PMID- 30524827 TI - Heavy Metal Contamination of Ground Water from an Unlined Landfill in Bulawayo, Zimbabwe. AB - Background: Developing countries such as Zimbabwe deal with challenges in solid waste management such as insufficient waste recycling, hazardous wastes that are not separated for safe disposal, and landfills that are not properly engineered to prevent groundwater pollution. For these reasons, landfills in developing countries pose serious environmental and public health hazards. Objectives: The objective of this study was to assess heavy metal release and groundwater pollution from an unlined landfill in Bulawayo, Zimbabwe. The purpose of the study was to explore environmental and public health risks posed by improperly managed landfills in developing countries. Methods: We assessed levels of metal release from Richmond landfill in the city of Bulawayo, Zimbabwe by measuring lead, cadmium, chromium and copper levels in landfill soil, leachate and plants. We also monitored metal levels in groundwater from boreholes located in a residential area in the vicinity and downgradient of the landfill within a range of 800-2135 m. Soil was characterized at the landfill to assess potential sources of heavy metals. Results: All metals that were assessed were present in landfill soil and in leachate. There was high metal accumulation in weeds that were growing at the landfill, indicating mobility and bioavailability of the metals. Groundwater from nearby boreholes had high levels of lead (Pb) and cadmium (Cd) which were negatively correlated to distance from the landfill (p<0.01), indicating contamination from the landfill. The Pb and Cd levels exceeded World Health Organization standards for drinking water quality, posing health hazards to the communities who rely on the water. Solid waste at the landfill consisted of soft plastics (33%), hard plastics (18.6%), metals (3%), paper (8%), electronic waste (0.8%), organics (15.3%) and various other types (21.3%). Discussion: A combination of factors may be attributed to groundwater contamination. These include the co-disposal of metallic and electronic wastes at the landfill, lack of membrane lining at the landfill, inadequate leachate management and the porous geo-physical characteristics of the sub-surface at the landfill site. Conclusions: Our study highlights adverse environmental and public health consequences of co-disposal of metals and electronic wastes at improperly engineered municipal landfills. This is a 'wake-up' call for policy makers in developing countries to improve solid waste management. PMID- 30524829 TI - A Market Basket Survey of Horticultural Fruits for Arsenic and Trace Metal Contamination in Southeast Nigeria and Potential Health Risk Implications. AB - Background: Elevated arsenic and trace metal contamination of the terrestrial food chain represents one of the most significant environmental risk exposures for human populations in developing countries. Metalloid and metal contamination in horticultural crop produce such as fruit is a public health concern in Nigeria. Local fruits are cheap sources of vitamins and minerals for the resident population and pose an important dietary threat of metal(loid) toxicity through consumption. Objectives: Market basket investigation of five locally grown (guava, pineapple, orange, and pawpaw) and imported (apple) fruits was conducted to measure the total concentrations of arsenic (As), mercury (Hg), copper (Cu), and lead (Pb) present in these fruits from southeastern Nigeria (Awka, Anambra). Methods: Fruits were analyzed for As and the three metals using atomic absorption spectrophotometry. Moisture content of fruits was determined and used to transform metal concentrations in dry weight to wet weight and compared to Codex food grade standards and assorted (sub)tropical fruits, edible and inedible peels. Results: The mean +/- standard deviation of elemental concentrations in dry weight ranged from 20.0+/-0.71-96.84+/-0.00 MUg g-1 for As, 0.02+/-0.02 - 0.89+/-0.33 MUg g-1 for Hg, 0.11+/-0.01 - 0.18+/-0.40 MUg g-1 for Cu, and <0.001 0.03+/-0.05 MUg g-1 for Pb. The As concentrations (wet weight) in fruits were ~32-166 orders of magnitude higher than Codex Alimentarius Commission (Codex) maximum As food grade levels. Guava and apple methyl Hg concentrations were ~6-~1 orders of magnitude higher than Codex maximum levels, while the content of Cu and Pb in fruits were within acceptable standard limits. Conclusions: The significant concentrations of As and Hg in the examined fruits indicate a potential public health threat. Efforts are needed to initiate and sustain continued monitoring of trace elements in fruits and food sold to consumers due to variation in contaminating sources to ensure food safety. Although a great deal of information exists on Hg toxicity, research on metalloids such as As remains limited in Nigeria and no reliable guidelines exist. Further research is recommended to determine the ecotoxicity of As in Nigeria. PMID- 30524828 TI - Contamination Levels and Sources of Heavy Metals and a Metalloid in Surface Soils in the Kumasi Metropolis, Ghana. AB - Background: Environmental contamination with heavy metals and metalloids due to industrial, smelting and mining activities have become common in large and growing cities. Kumasi is one of the most industrialized cities in Ghana and experiences metal pollution due to recent and past activities. Although metals are naturally abundant in the area, their accumulation in soils could potentially lead to adverse effects on local ecosystems. Objectives: The aims of this study were to determine the distribution, enrichment, geoaccumulation and sources of metals in Kumasi soils and to estimate the contamination factor (CF) and pollution load index (PLI) of these metals in soils. Methods: Concentrations of eight heavy metals and a metalloid were determined in 112 soil samples randomly collected from 31 sampling sites in the area. In addition, 5 soil samples were collected from a pristine site (Kwame Nkrumah University of Science and Technology Botanical Gardens) for data comparison, to determine the local background values for metal concentrations and to evaluate the extent of metal pollution in the study area. Results: Heavy metals such as zinc (Zn), lead (Pb), cadmium (Cd) and chromium (Cr) were enriched in 65, 32, 58 and 93% of the sampling sites, respectively, and geo-accumulation indexes for Cr, Zn, Cd, mercury (Hg) and Pb showed moderate to extreme contamination in 100, 97, 77, 65 and 45% of the sampling sites, respectively. Principal component and cluster analyses revealed that industrial activities including mining were the major sources of metals in Kumasi soils with high metal input in the community of Suame. Distribution maps revealed hotspots of Cd, nickel (Ni), arsenic (As), cobalt (Co), copper (Cu) and Pb in Suame. The highest CFs for Cu, Cd, Ni, As, Co and Pb highlighted anthropogenic inputs in Suame, while Hg was highest in Mbrom, Zn in Suntreso, and Cr in Aboabo. Conclusions: The PLI of metals revealed Suame as the most polluted study site, while Anomangye and Bomso were the least polluted. PMID- 30524830 TI - Assessment of the Pollution Status of Eleyele Lake, Ibadan, Oyo State, Nigeria. AB - Background: Lakes are a vital water resource, but are adversely affected by pollutants such as heavy metals and polychlorinated biphenyls (PCBs) from urban, agricultural and industrial activities. This can give rise to potential pollution related health problems such as cancer and infectious diseases. Risk assessments are necessary to determine the degree of pollution and its effects on human health and ecological systems. Objectives: This study assessed the pollution status and a risk assessment was calculated to determine the degree of the pollution and its effects on the human health and the ecological system of Eleyele Lake in Ibadan, Nigeria. Methods: Physical and chemical parameters, heavy metals and PCBs were determined in the lake water using standard methods from December 2013 to February 2014 at ten different sites of anthropogenic activity. Results: Water pH ranged from 6.00-7.50, while electrical conductivity ranged from 205.00-221.00 MUs/cm3. Dissolved oxygen ranged from 0.30-6.00 mg/L and total dissolved solids ranged from 105.00-113.00 mg/L. Phosphate levels ranged from 13 0.99 mg/L. Nitrate and sulphate in the dry season ranged from (3.10-3.80 and 35.81-40.97 mg/L) and (0.12-0.37 and 6.10-10.30 mg/L) in the wet season. Heavy metal concentrations were in the order cadmium (Cd) > zinc (Zn) > copper (Cu) > chromium (Cr) > lead (Pb) for the dry season and Cd > Zn > Cr > Pb > Cu for the wet season. Total PCBs ranged from 493.90-732.55 MUg/L and 52.00-390.03 MUg/L for the dry and wet seasons, respectively. All determined physical and chemical parameters were within permissible levels, while heavy metals and PCB concentrations were higher than permissible levels. Discussion: The hazard quotients and carcinogenic risk values were greater than acceptable limits, indicating that PCBs in Eleyele lake water pose adverse health effects to the local population. It was observed in this study that lower chlorinated PCBs were more prevalent than higher chlorinated PCBs. This may be attributed to the fact that the lower chlorinated PCBs are influenced by atmospheric deposition as a result of their volatility, and they are more susceptible to atmospheric transport than highly chlorinated PCBs. Conclusions: PCBs possess serious health risks to the population that depends on the lake as a source of domestic water and its aquatic organisms. Efforts are needed to reduce anthropogenic influence on the lake through strict environmental controls. PMID- 30524831 TI - Human Health Risk of Organochlorine Pesticides in Foods Grown in Nigeria. AB - Background: Production of foods safe for consumption is an important issue worldwide. Organochlorine pesticides (OCP) are often used to preserve crops. Their use can have serious impacts on human health. Objectives: This research aims at assessing OCP residues in food samples from markets in Lagos in southwestern Nigeria and their risk to human health. Methods: Sixteen food samples were collected from Lagos, Nigeria and analyzed for organochlorine pesticide residues. Extraction was performed using an ultrasonicator, and analysis was carried out using a gas chromatograph-electron capture detector. Risk assessment was carried out by determining the hazard quotient. Results: Results of the OCP residues found in the foods were generally low, with dichlorodiphenyldichloroethylene (p,p'-DDE) having the highest residue concentration. The concentration of p,p'-DDE was as high as 110 ng/g in pulses and 123 ng/g in Cameroon and chili peppers. The risk index was <1 in most cases, with the exception of dichlorodiphenyldichloroethane (p,p'-DDD) in fruits for children. Discussion: The results were generally lower than what has been documented in other parts of the world and suggest that consumption of the foods investigated in the present study in Nigeria may be considered safe for the 13 OCPs investigated. Conclusions: There is a need for continuous monitoring of these OCPs and investigation of carbamate and phosphate pesticide residues since they are more widely used in farming practices in Nigeria. PMID- 30524832 TI - Heavy Metals and Polycyclic Aromatic Hydrocarbons in Soil from E-waste Dumpsites in Lagos and Ibadan, Nigeria. AB - Background: Soil contamination from heavy metals and polycyclic aromatic hydrocarbons (PAHs) released during informal e-waste processing and disposal poses human and ecological health risks in Nigeria. Objectives: This study assesses the levels of heavy metals and PAHs in soils of e-waste dumpsites in Lagos and Ibadan, Nigeria. Methods: Composite soil samples were collected at depths of 0-15 cm, 15-30 cm and 30-45 cm from major e-waste dumpsites in Lagos and Ibadan and analyzed for lead (Pb), cadmium (Cd), copper (Cu), nickel (Ni), zinc (Zn), chromium (Cr) and PAHs to evaluate the potential contaminant contribution from e-waste activities. Control samples were collected at the Botanical Garden, University of Ibadan. Samples were analyzed for heavy metals after acid digestion using atomic absorption spectrophotometry, while PAHs were extracted using cold solvent extraction and quantified by gas chromatography-mass spectrometry. Blank determination and recovery studies were carried out for each metal. Contamination and ecological risks were assessed using soil contamination indices such as contamination factor, geo-accumulation and pollution load indices, and potential ecological risk index to categorize contaminant concentrations and associated impacts. Soil physico-chemical characteristics such as pH and total organic matter were also determined. Results: Metals concentrations in the dumpsite soils ranged from 114-2,840 mg/kg and not detectable - 6.50 mg/kg for Pb and Cd, and 42.8-5,390 mg/kg, 27.5-3,420 mg/kg, 11.0-128 mg/kg and 94.0-325 mg/kg for Cu, Zn, Ni and Cr, respectively. Serious metals accumulation was observed at every e-waste dumpsite, as shown by the pollution load index. The potential ecological risk values were between 584 and 10,402 at all of the dumpsites, signifying very high ecological risk. The total PAHs ranged from 1,756-2,224 MUg/kg at the 0-15 cm level, 1,664-2,152 MUg/kg at 15-30 cm and 278 MUg/kg in the top- and sub-soil of the control site. Discussion: The total PAHs in the soil of e-waste dumpsites was significantly higher than in the control soil. Conclusions: The results of this study indicate that indiscriminate dumping and open burning of e-waste are potential sources of PAH and toxic metal emissions, which can pose serious human health and ecological risks. PMID- 30524833 TI - Assessment of Dioxin and Furan Emission Levels and Management Practices in Addis Ababa, Ethiopia. AB - Introduction: An increase in population and related increased demand for health services, expansion of industries, and increasing transportation demands have increased the emission of dioxin and furan persistent organic pollutants (POPs) in Addis Ababa, Ethiopia. Objective: This study aimed to identify sources of dioxin and furan emissions, quantify their release into various environmental medias and assess related management practices. Methods: The standard United Nations Environmental Programme (UNEP) (2005) toolkit guide and default emission factor were used to identify the main anthropogenic sources and to quantify the amount of released dioxin and furan. Stratified random sampling techniques were applied to assess current management practices. Results: Nine main groups of dioxin and furan emission sources were identified. The emission of each source group was calculated by the activity rate data multiplied by an emission factor. The results found that about 138.85 g toxic equivalent(TEQ)/a(TEQ/year)of dioxin and furan were released to air, water, residue (materials remaining as sludge after sewage treatment or in the form of ash after incineration activity) and soil. Waste disposal activities recorded the largest release of dioxin and furan, accounting for 68.30 g TEQ/a of dioxin and furan to water and residue, 34.00 g TEQ/a to air and 0.64 g TEQ/a emitted into soil. Conclusions: Several sources of dioxin and furan emission were identified and the present study found that their management is inadequate. Waste disposal services are especially inadequate and generate higher amounts of dioxin and furan gasses. In addition, the organizations that are responsible for the release of dioxin and furan have no awareness of their release and inadequate management practices. The present study points to the need for reformulation of the national legal management framework, adoption of best available technology for disposal services such as incinerators with flue gas management, increasing public and stakeholders' awareness and participation and capacitating the responsible government organizations. PMID- 30524834 TI - Hossain MS, et al. Human Health Risk of Chromium Intake From Consumption of Poultry Meat and Eggs in Dhaka, Bangladesh. J Health Pollution. 2017;7(14):30-36. AB - [This retracts the article on p. 30 in vol. 7.]. PMID- 30524835 TI - Heavy Metal Pollution Near a Tannery in Ulaanbaatar, Mongolia. AB - Background: Due to an increase in population density and industrialization, the capital city of Mongolia, Ulaanbaatar, has been experiencing an increase in environmental pollution; especially soil contamination. Environmental pollutants include solid waste, silt and wastewater coming out of tanneries in three micro districts of the Khan-Uul district of Ulaanbaatar. Among the many types of chemicals these tanneries use, chromium (III) sulfate (Cr2(SO4)3) poses the most serious environmental health risk. In addition, the surrounding areas around the tanneries include schools, hospitals and residential buildings, presenting additional risks to the people living and working in this area. Objectives: The present study aims to identify heavy metal contamination in the tannery area using a portable x-ray fluorescence reader (XRF). Methods: The study area (112 ha) was divided into 6 zones depending on usage and XRF readings were taken in each zone. Results: Results showed a mean or median lead (Pb) concentration of 2 405 mg/kg (33+/-2), chromium (Cr) concentration of 18-10,752 mg/kg (685+/-80), zinc (Zn) concentration of 5-1,316 mg/kg (113+/-6.5), and arsenic (As) concentration of 0-84 mg/kg (10.2+/-0.46) Five soil samples were collected from sites where Cr concentrations were extremely elevated and analyzed in two different laboratories to confirm XRF readings. Using the results from XRF readings and two different lab results, heavy metal distribution mapping was produced using geographic information system (GIS) tools, statistical processing tools and pollution indices for each heavy metal were determined using base heavy metals content in the soil. The distribution percentage of each of the heavy metals in the topsoil was 37.7% for Pb, 78.5% for Cr, 43.8% for Zn, and 51.3% for As. Discussion: There are 140 tannery facilities in Mongolia of which 60 processing facilities reside in the Khan-Uul district of Ulaanbaatar. Tanneries use chromium (III) sulfate and other environmentally hazardous chemicals often in tandem with less costly technologies. This increases the amount of wastewater and contaminated silt going onto and into soil. The baseline level of heavy metals content was indicated by 7 XRF readings taken along the side of the Tuul river (relatively untouched soil). The present study shows that the Cr contamination in soil surrounding the tannery area was very high and the main source of the pollutants are wastewater and silt highly contaminated with chromium sulfate originating from the tanneries. Conclusions: The present study found that the tannery area is heavily contaminated and may pose serious threats to human health, the surrounding environment and underground water resources. In order to reduce the health risk of the people working and living in the study area and remove contamination and rehabilitate the area, further studies are needed to determine heavy metal leakage into soil and underground water and to determine the volume of work needed for neutralization and rehabilitation. PMID- 30524836 TI - Phytoremediation Using Bamboo to Reduce the Risk of Chromium Exposure from a Contaminated Tannery Site in Kenya. AB - Background: This study examines an intervention strategy to reduce the risk of chromium (Cr) exposure. It follows a previous Cr exposure investigation, which revealed that large volumes of Cr-contaminated waste were burnt on site. The study site had a long history of land-based waste disposal since 1994. Objective: The potential for phytoremediation using bamboo species to restore Cr contaminated soil was evaluated. Methods: Chromium levels and physico-chemical properties of the tannery and control soils were analyzed before transplanting six different bamboo species. Translocation, bio-concentration and bioaccumulation factors of the species were assessed for phytoremediation capabilities. Results: Chromium levels in the tannery soils ranged from 1337.0 to 3398.0 mg/kg dw. The chromium levels were significantly higher (P < 0.05) than those of the control soils (0.20 to 2.34 mg/kg dw) and markedly exceeded the recommended limit of 100 mg/kg dw. The physicochemical properties of the tannery soils were also significantly varied (P < 0.05) compared to the control soils. In all cases, the species grown in the tannery soils were tolerant to a wide range of prevailing conditions. All of the bamboo species in the present study had a 100% survival rate in the tannery soils, except for D. birmanicus, which had a survival rate of 83.3%. Moreover, growth performance of the species in the tannery and control soils as evaluated by height and clump diameters did not vary significantly (P > 0.05). However, Cr levels in the tannery differed significantly (P < 0.05) among the species and rhizosphere soils. D. asper, B. vulgaris, D. membranaceus and B. blumeana had a bio-concentration factor (BCF) > 1 and translocation factor (TF) < 1, indicating that they are suitable for phytostablization. On the contrary, B. bambos had a bioaccumulation factor (BAF) < 1 and TF > 1, indicating potential for phytoextraction, while D. birmanicus showed no potential for phytoextraction or phytostabilization. Conclusions: The present study identified D. asper, B. vulgaris, D. membranaceus and B. blumeana as suitable for restoration of Cr-contaminated tannery sites. Close monitoring of toxic metals is necessary during application of these species. Further studies are also recommended using a wide variety of bamboo species to optimize their application in phytoremediation. PMID- 30524837 TI - Accumulation of Heavy Metals by Wild Mushrooms in Ibadan, Nigeria. AB - Background: Many companies in Nigeria generate industrial effluents, including heavy metals. These metals can be accumulated by biota such as mushrooms, which are then eaten by the populace. Objectives: The present study investigates the metal content of wild mushrooms in order to educate the local population on the safety of their consumption. Methods: Seven different species of wild mushrooms (Cortinarius melliolens, Chlorophyllum brunneum, Pleurotus florida, Volvariella speciosa, Cantharellus cibarius, Entoloma spp and Coprinus africana) growing in Ibadan, southwest Nigeria were analyzed for their heavy metal (copper (Cu), cadmium (Cd) and lead (Pb)) contents using atomic absorption spectrophotometry. Results: The concentrations of the heavy metals in the mushrooms and substrate varied by site of collection. The highest concentrations of Cu (92.31+/-8.42 mg/kg), Pb (76.00+/-9.78 mg/kg) and Cd (92.45+/-12.34 mg/kg) were obtained in C. africana, P. florida and V. speciosa, respectively. The lowest contents of Cu (56.00+/-5.02 mg/kg), and Cd (67.92+/-5.89 mg/kg) were obtained from C. melliolens, while C. cibarius had the lowest concentration of Pb (40.00+/-3.56 mg/kg). The highest concentrations of Pb (20.40+/-3.43 mg/kg) and Cd (26.40+/ 4.34 mg/kg) were obtained in the substrate of C. molybdites, while the lowest Pb (12.40+/-2.12 mg/kg) and Cd (18.00+/-3.90 mg/kg) occurred in V. speciosa and C. cibarius, respectively. The bioaccumulation factors of the mushroom species studied ranged from 2.84 - 14.60. Conclusions: The present study found that heavy metal accumulation varied by species of mushroom, metal content of the substrate and the bioavailability of the metal in the mushroom. The level of metals in mushrooms in the present study was relatively high. Therefore, cultivation of mushrooms in heavy metal-free soil should be encouraged. PMID- 30524838 TI - Assessment of Radon Levels in Drinking Water Wells in St. Catherine, Jamaica. AB - Background: Radon is a known carcinogen and contaminant in drinking water wells, but is not monitored in drinking water quality programs in Jamaica. Objective: The present study was conducted to obtain radon data in local drinking water and evaluate potential health risks. The data will contribute to determining the level of compliance to public health criteria for radon and to develop a monitoring program based on the identified risks. Methods: This study assesses the concentration of radon in 22 drinking water wells in the parish of St. Catherine, Jamaica. Samples were collected for radon, with 12 other measurements gathered including pH, conductivity, TDS, alkalinity, hardness, phosphates, nitrates, chloride, sulfates, turbidity, well depth and geological features. The data were analyzed for compliance to international limits and association with geological and other parameters. Results: The average radon level was 18 Bq/L +/- 2 Bq/L and varied from a low of 11 Bq/L +/- 1 Bq/L to a high of 41 Bq/L +/- 1 Bq/L. There was a positive correlation between radon levels and both alkalinity and turbidity. No relationship of any significance, however, was identified with the other physicochemical parameters. All the study results fell within the European Union (EU) limit of 100 Bq/L, and well within the United States Environmental Protection Agency (USEPA) limit of 147 Bq/L. Most of the wells in this parish have radon levels exceeding the proposed USEPA limit of 11 Bq/L. The proposed limits are intended to support radon mitigation programs to manage radon in air. No limits are provided in the newest edition of the World Health Organization's (WHO) Guidelines for Safe Drinking Water Quality. Conclusions: Most wells in the study area met existing international limits. Almost all, however, did not meet the proposed USEPA limit for locations without radon mitigation programs. This indicates the need to establish national screening levels for radon, consistent with WHO and USEPA recommendations. PMID- 30524839 TI - Biochemical Effects of the Toxic Interaction of Copper, Lead and Cadmium on Clarias gariepinus. AB - Background: The presence of heavy metals in the aquatic environment is a concern because of potential toxicity and threats to plant and animal life. Objective: The present study evaluated the joint action toxicity and biochemical effects of sublethal concentrations of copper (Cu), lead (Pb) and cadmium (Cd) against Clarias gariepinus over a period of 28 days. Methods: We procured fingerlings (weight: 5-8 g; length: 4.5-6.0 cm) and juveniles (weight: 20-25 g; length: 14.5 17.5 cm) from a commercial fish farm in Bariga, Lagos state, Nigeria. Test toxicants were selected from the analyzed heavy metals in the field based on their deviation from World Health Organization, Federal Environmental Protection Agency and United States Environmental Protection Agency standards. Fish were randomly loaded into a 4-L glass aquaria for the bioassay per toxicant concentration of two replicates and untreated control (dechlorinated tap water). Results: The derived 96 hour lethal concentration 50 (LC50) value of Cu (2.11 mg/L) was the most toxic followed by Cd (24.18 mg/L) and Pb (34.48 mg/L), which was the least toxic of the singly tested pollutants. The analysis of dose response data of the joint action toxicity of Cu and Cd, and Cu and Pb determined 96 hour LC50 values of 1.804 mg/L and 2.15 mg/L, respectively. The interactions between the mixture of Cu:Cd conformed with the model of synergism (synergistic ratio (SR)>1 and relative toxic units (RTU)>1), while the interaction between Cu:Pb was found to be antagonistic (SR<1), with an SR value of 0.98. The biochemical effects study revealed that malondialdehyde (MDA) levels decreased significantly (P<0.05) in the exposed fish, reduced glutathione was not significant at (P<0.05), and levels of superoxide dismutase (SOD), catalase, glucose and cholesterol were significantly different (P<0.05). Discussion: The observed increased in the glutathione level in the Cu:Cd mixture and a corresponding decrease in MDA concentration in the liver of test animals revealed the ability of fish to overcome the effects of lipid peroxidation in this group because the Cu ion is displaced by Cd, and the fish were able to catalyze the breakdown of hydrogen peroxide via the Fenton reaction. Conclusions: Further studies on the joint action toxicity of heavy metals are needed in order to further determine their concentration in the local environment. Ethics Approval: Study protocols were approved by the Health Research Ethics Committee of the University of Lagos. PMID- 30524840 TI - Assessment of Pesticide-Related Pollution and Occupational Health of Vegetable Farmers in Benguet Province, Philippines. AB - Background: Agriculture accounts for 20% of the national income in the Philippines. In order to boost agricultural activity and prevent crop damage, farmers rely on pesticides for vector control and management. Objectives: The present study assessed the pesticide exposure and occupational health of agricultural farmers in the Philippines. The study site is one of the largest vegetable-producing provinces in the Philippines. Methods: This study employed both a survey questionnaire and physical health assessment, including a mental state examination. Pesticide exposure was estimated based on the duration of pesticide use, as well as the amount per spray application. The data results were segregated by gender, as women are also heavily engaged in agriculture in this part of the Philippines. Results: The results showed that pesticide exposure usually occurred during agricultural activities such as spray applications in the field (63.7%), mixing (38.4%), loading (34.1%) and field re-entry (9.7%). The most frequently used pesticides were Tamaron, Selecron, and Dithane. The mean duration of pesticide exposure was 14.23 years for males and 15.4 years for females. The longest used pesticide among males was Sumicidine (16.2 years), and Tamaron for females (18 years). In terms of amount used, the average was 147 ml per spray application for males and 65.5 ml for females. Exposure to pesticides was expressed in number of years and amount used per spray application, and the average exposure of males was 2,024.43 ml/years and 993.55 ml/years for females. Among farmers, 49% complained of being sick due to their work. Of those who became ill, a large percentage (69.8%) did not receive any medical attention. The most prevalent health symptoms were muscle pains (63.3%), muscle weakness (55%), and easy fatigability (52.4%). For the mini-mental state examination, abnormalities were found in 5.4% of males and 13.3% of females. The use of insecticides was associated with weakness, easy fatigability and weight loss. Discussion: The present study demonstrated frequent and significant duration of pesticide use among farmers in Benguet province, Philippines. Conclusions: Pesticide exposure was considerable among the farmers in the present study. The occupational health conditions reported by the study subjects can be linked to their pesticide use. Although this study assessed risk factors associated with general health symptoms, further investigation is needed to determine specific pesticide exposure-health correlations. Participant Consent: Obtained. Ethics Approval: The study was approved by the Research Ethics Board of the University of the Philippines, Manila, which is recognized and accredited by the Forum for Ethical Review Committees in Asia and the Western Pacific (FERCAP). PMID- 30524841 TI - Genetic, Reproductive and Hematological Toxicity Induced in Mice Exposed to Leachates from Petrol, Diesel and Kerosene Dispensing Sites. AB - Background: With a population of over 165,000,000, growing at an average rate of 2.7% per annum and an economic growth rate of about 5.7% in the past five years, the market for refined petroleum products in Nigeria is growing. As a result, the number of filling stations is increasing. Objectives: The present study evaluated the reproductive and genetic toxicity of simulated leachate of soil from petrol, diesel and kerosene dispensing sites in a filling station using the murine sperm abnormality test, sperm count and bone marrow micronucleus assay. Methods: Simulated leachate of soil collected from petrol, diesel and kerosene dispensing sites in a filling station was intraperitoneally administered to mice at different concentrations. Bone marrow micronucleus assay was carried out after 5 days exposure, while sperm morphology assay was carried out 35 days from the first day of exposure. Alterations to hematological parameters were evaluated and physico-chemical analysis of the leachate samples was also carried out. Results: The results showed a significant (p<0.05) concentration-dependent increase in abnormal sperm cells and decrease in mean sperm count in all the samples tested. Increased induction of micronucleated polychromatic erythrocytes was observed in the exposed mice. Hematological analysis showed a significant (p<0.05) increase in the values of white blood cell count (WBC), lymphocytes, neutrophils, monocytes, eosinophils and mean corpuscular volume (MCV), while a significant (p<0.05) reduction in basophils, hemoglobin, mean corpuscular hemoglobin (MCH), packed cell volume and mean corpuscular hemoglobin concentration (MCHC) values were observed. Discussion: In the present study, simulated leachates from soil obtained from petrol, diesel and kerosene dispensing sites were shown to cause genomic disruptions in germ and somatic cells, and hematotoxicity in an animal model. These observed reproductive, genetic and hemato-toxicities are believed to be caused by the presence of lead, copper, mercury, polycyclic aromatic hydrocarbons, and benzene in the samples. Conclusions: This study showed the negative impact of petroleum products in the contamination of soil, with a capability of inducing genetic damage in somatic and germ cells of exposed plants and animals. Ethics Approval: The study was approved by the ethical committee of the Federal University of Technology, Akure, Ondo State, Nigeria. PMID- 30524842 TI - Genotoxic, Histopathological and Oxidative Stress Responses in Catfish, Clarias gariepinus, Exposed to Two Antifouling Paints. AB - Background: Antifouling paints are enriched with biocides and employed in the maritime industry to protect moving and fixed surfaces from fouling activities of sea dwelling invertebrates. There is limited information on their effect on the non-target African catfish, Clarias gariepinus, a commonly consumed fish in Lagos. Objectives: This study investigated the effects of two commonly used antifouling paints (Berger TBT-free (A/F783 (H)), reddish brown color and Silka Marine lead based paint, pale orange color) on a non-target catfish species, Clarias gariepinus. Methods: The study involved an initial 96-hour acute toxicity assay followed by chronic toxicity evaluation (using 1/10th and 1/100th 96-hour median lethal concentration (LC50) values) for 28 days to determine the ability of the paints to induce micronucleus and red blood cell abnormalities, and histopathological as well as oxidative stress effects in the catfish.Examined anti-oxidative stress enzyme activities include superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione-s-transferase (GST). Results: Acute toxicity evaluation results indicated that the Berger paint was 16.1-times more toxic than Silka paint with 96-hour LC50 values of 0.71 mg/L and 11.49 mg/L, respectively. Results from the biochemical assay indicated significantly higher (P<0.05) levels of a lipid peroxidation product, malondialdehyde, in Silka-exposed catfish compared to the control. All enzymes showed significantly higher activities in Berger paint-exposed catfish compared to the control. There was evidence of micronucleated and binucleated cells in the red blood cells of fish exposed to both paints. Histopathological assessment indicated that the exposed fish gills showed evidence of abnormalities such as curved lamellae epithelial necrosis, epithelial lifting and hyperplasia. The liver samples of the catfish showed evidence of portal inflammation as well as mild to severe steatosis, while the gonads showed varying percentages of follicle degeneration. Conclusions: The present study combined an array of biomarkers to determine the negative health impacts of two commonly used antifouling paints on non-target catfish inhabiting Lagos Lagoon. Further in situ studies are recommended to determine the current status of the lagoon fish. Ethics Approval: Ethical approval was obtained from the Department of Zoology, University of Lagos, Post-Graduate Committee. Note that this work commenced before the establishment of the University of Lagos Ethical Committee for the use of animals and humans in scientific studies. The committee does not give retroactive approval but stands by existing approvals before its establishment. However, this study followed the World Medical Association principles on the treatment of animals used in research (https://www.wma.net/policies-post/wma-statement-on animal-use-in-biomedical-research/), and also American Fisheries Society Guidelines for the Use of Fishes in Research (https://fisheries.org/policy media/science-guidelines/guidelines-for-the-use-of-fishes-in-research/). PMID- 30524843 TI - Inventory of Obsolete Pesticide Warehouses in Tajikistan and Implications for Removal of Contaminated Soil. AB - Background: Tajikistan is an agrarian-industrial republic. A large portion of the Tajikistan economy relies on agriculture. With the rise of agriculture, especially cotton production, came the widespread use of pesticides. Abandoned and unsupervised pesticide storage warehouses have become a health and environmental problem. In many cases such sites, as well as significant areas of pesticide-contaminated land, remain accessible to the public. A survey and analysis of 26 former pesticide storage warehouse sites across Tajikistan revealed a country-wide pesticide exposure problem that threatens the health of vulnerable populations. Infrastructure and local governance issues are barriers to addressing this health crisis for rural residents. Objectives: The purpose of this article is to describe the issues surrounding former pesticide storage warehouses and their effect on the health of the population of Tajikistan. Materials and Methods: In 2012, the non-governmental organization (NGO), Pure Earth (formerly Blacksmith Institute), with the financial support of the Food and Agriculture Organization of the United Nations (FAO), Green Cross Switzerland and the European Union conducted surveys of 26 pesticide warehouses located throughout Tajikistan. The survey included detailed site assessments, including analysis of the maintenance of chemicals and soil testing. Results: Soil samples taken from the studied sites exceeded maximum permissible concentrations referenced by Pure Earth by several hundred times for dichlorodiphenyl trichloroethane (DDT) and hexachlorocyclohexane (HCH), as well as aldrin and dieldrin. Even the most polluted sites had families living on the premises. Conclusions: Pesticide contamination in Tajikistan is a serious and ongoing problem that requires the attention of local, state governments, and international non-governmental organizations. We recommend the development of a government-sponsored public education campaign to inform the population about the potential risks of exposure to obsolete pesticides. The dangers of agricultural use, former storage warehouses and disposal areas should be addressed. In addition, data from the 2012 surveys of 26 warehouses should be used to prioritize the four high-risk sites and develop preliminary clean-up plans for contaminated soil around warehouses to present to government ministries and NGOs. Competing Interests: The authors declare no competing financial interests. PMID- 30524844 TI - Assessment of Lead Exposure and Urinary-delta-aminolevulinic Acid Levels in Male Lead Acid Battery Workers in Tamil Nadu, India. AB - Background: Exposure to lead (Pb) affects multiple health outcomes and physiological systems. In adults, even small increases in blood Pb levels have been associated with decreased glomerular filtration rate, increased risk of hypertension and increased incidence of essential tremor. To date, there have been few Pb-exposure assessments using the United States Occupational Health and Safety Administration (OSHA) regulations. Objective: The aim of the present study was to assess Pb-exposure in terms of elevated blood lead levels (BLL) and urinary-delta-aminolevulinic acid (U-delta-ALA) levels of workers exposed to Pb in the lead acid battery industry in Tamil Nadu, India based on Pb exposure regulations set by the American Conference of Governmental Industrial Hygienists (ACGIH) and OSHA. Materials and Methods: BLLs and U-delta-ALA were estimated in 449 male workers exposed to Pb across ten different job categories in a lead acid battery factory. Worker BLLs were estimated using atomic absorption spectrophotometry and U-delta-ALA was estimated using spectrophotometry. Results: The Biological Exposure Index of the American Conference of Governmental Industrial Hygienists (BEI-ACGIH) were used to assess Pb exposure. BLLs <30 MUg/dL were found in 63.5% of workers, and 36.5% of workers had BLLs>30 MUg/dL. The present study also assessed Pb exposure using OSHA regulations and found that 83.3% of workers had BLLs <40 MUg/dL and 16.7% of workers had BLLs>40 MUg/dL. Among these workers, 0.7% of workers had BLLs >60 MUg/dL. An excessive excretion of U-delta-ALA (20-40 mg/L) was noted in pasting area workers (2.6%) followed by executives (2.2%) and assembly workers (0.9%). Conclusions: Workers in the job categories of pasting and assembly, as well as executives, are at high risk of Pb exposure compared to other job categories. We recommend placing humidifiers on the roof and keeping a water bath closer the to plate cutting area to reduce fugitive Pb dust emissions. We recommended workers with BLLs >60 MUg/dL be removed from jobs involving Pb exposure and return to work only when their BLLs are <40 MUg/dL. Participant consent: Obtained. Ethics Approval: The study was approved by the ethics committee of the Regional Occupational Health Centre (Southern) Bengaluru, part of the National Institute of Occupational Health of India. Competing Interests: The authors declare no competing financial interests. PMID- 30524845 TI - Floating Wetland Treatment of Acid Mine Drainage using Eichhornia crassipes (Water Hyacinth). AB - Background: Acid mine drainage (AMD) is a major environmental impact associated with the mining industry. Elevated acidic conditions resulting from the discharge of AMD into the surrounding environment can cause heavy metals to dissolve and transport through water streams and accumulate in the aquatic environment, posing a risk to the health of living organisms. There have been several novel approaches in the remediation of AMD involving passive treatment techniques. The constructed treatment wetland approach is a passive remediation option that has proven to be a cost effective and long-lasting solution in abating toxic pollutant concentrations. Objectives: The present study investigates the applicability of water hyacinth (Eichhornia crassipes), a tropical aquatic plant with reported heavy metal hyper-accumulation in microcosm floating wetland treatment systems designed to remediate AMD with copper (Cu) and cadmium (Cd) concentrations exceeding threshold limits. Methods: Twelve water hyacinth samples were prepared with varying concentrations of Cu (1 mg/L, 2 mg/L, 4 mg/L) and Cd (0.005 mg/L, 0.01 mg/L, 0.02 mg/L). Water samples of 5 ml each were collected from each sample at 24-hour intervals for analysis with an atomic absorption spectrometer. Results: Plant growth varied according to Cu and Cd concentrations and no plants survived for more than 14 days. There was a significant discrepancy in the rate at which the Cd concentrations abated. The rate of reduction was rapid for higher concentrations and after 24 hours a substantial reduction was achieved. There was a reduction in Cu concentration after the first 24-hour period, and after the next 24-hour period the concentrations were again elevated in the samples at initial concentrations of 2 mg/L and A4 mg/L. 4 mg/L Cu concentration was shown to be toxic to the plants, as they had low accumulations and rapid dying was evident. Conclusions: Water hyacinth has the capability to reduce both Cu and Cd concentrations, except at an initial concentration of 4 mg/L of Cu, which was toxic to the plants. Competing Interests: The authors declare no competing financial interests. PMID- 30524846 TI - Evaluation of Pollution of Soils and Particulate Matter Around Metal Recycling Factories in Southwestern Nigeria. AB - Background: Metal recycling factories (MRFs) have developed rapidly in Nigeria as recycling policies have been increasingly embraced. These MRFs are point sources for introducing potentially toxic elements (PTEs) into environmental media. Objectives: The aim of this study was to determine the constituents (elemental and mineralogy) of the wastes (slag and particulate matter, (PM)) and soils around the MRFs and to determine the level of pollution within the area. Methods: Sixty samples (30 slag samples, 15 soil samples and 15 PM samples) were collected for this study. The soils, slag and PM samples were analyzed for elemental constituents using inductively coupled plasma optical emission spectrometry. Mineralogy of the PM was determined using scanning electron microscope-energy dispersive spectroscopy (SEM-EDS), and soil mineralogy was determined by an X-ray diffractometer (XRD). Results: The results of the soil analyses revealed the following concentrations for the selected metals in mg/kg include lead (Pb) (21.0 2399.0), zinc (Zn) (56.0-4188.0), copper (Cu) (10.0-1470.0), nickel (Ni) (6.0 215.0), chromium (Cr) (921.0-1737.0) and cadmium (Cd) (below detectable limit (Bdl)-18.1). For the slags the results were Pb (68.0-.333.0), Zn (1364.0-3062), Cu (119.0-1470.0), Ni (12.0-675.0), Cr (297-1737) and Cd (Bdl-15.8). The results in MUg/g for the metal analysis in PM were Pb (4.6-160.0), Zn (18.0-471.0), Cu (2.5-11.0), Ni (0.8-4.2), and Cr (2.5-11.0), while Cd was undetected. The slags are currently utilized for filling the foundations of buildings and roads, providing additional pathways for the introduction of PTEs into the environment from the suspended materials generated from mechanical breakdown of the slags. Conclusions: The MRFs were found to have impacted the quality of environmental media through the introduction of PTEs, impairing soil quality, in addition to PM, which can have detrimental health consequences. Further studies on the health implications of these pollutants and their impacts on human health are needed. Competing Interests: The authors declare no competing financial interests. PMID- 30524847 TI - Polychlorinated Biphenyls in Brackish Water Fish in the River Niger, Nigeria. AB - Background: Anthropogenic polychlorinated biphenyls (PCBs) in aquatic environments poses human and ecological health risks in Nigeria. Objectives: This study determined the concentrations of PCBs in brackish water fish in the River Niger to assess the contamination status of fish consumed by the local population. Methods: The sampled fish species included Drepane africana, Mochokus niloticus, Chrysichthys nigrodigitatus, Pristipoma jubelini, Vomer septapinis, Pseudotolithus senegalensis, Mugil cephalus, Pseudotolithus elongatus, Sphyraena piscatorum and Lutjanus goreensis, purchased from landing sites. Six fish from each species were sampled, for a total of 60 samples. Twenty-seven (27) PCB congeners, #8, #18 #28, #44, #52, #60, #77, #81, #101, #105, #114, #118, #123, #126, #128, #138, #153, #156, #157, #167, #169, #170, #180, #185, #189, #195, and #206 were screened in the fish samples using standard methods. The PCBs were identified and quantified using gas chromatography (GC) (Hewlett Packard GC 5890 series 11 with electron capture detector). Confirmation was performed using Shimadzu GCMS QP2010. Results: The sum of the National Oceanic and Atmospheric Administration Agency (SigmaNOAA) PCBs occurred at the highest concentration of 1830.0+/-484.0 MUg/kg detected in Vomer septapinis, and the lowest in Pseudotolithus senegalensis, with a mean concentration of 795+/-169.3 MUg/kg. The concentration of dioxin-like (DL) PCBs was highest in Pristipoma jubelini (992.0+/-88.6 MUg/kg) and lowest (285.6+/-81.5 MUg/kg) in Drepane africana. The highest mean concentration (418.+/-177.6 MUg/kg) of International Council for the Exploration of the Seas-7 (ICES-7) PCBs was observed in Vomer septapinis. The heavier ICES-7 congeners PCB-138, PCB-153, and PCB-180 occurred at higher concentrations compared to the lighter molecular weight ICES-7: PCB-28, PCB-52, and PCB-101. The European Union (EU) marker PCB limit of 335 MUg/kg was exceeded in all the brackish water fishes with the exception of Mochokus niloticus, Pristipoma jubelini and Pseudotolithus senegalensis. Discussion: The total level of PCBs in the brackish fish samples was relatively high at >1000 MUg/kg (above the World Health Organization (WHO) and Food and Agriculture Organization of the United Nations (FAO) guideline of 1000 MUg/kg fresh weight). The EU guideline value for fish (220 MUg/kg fresh weight) was exceeded in about 80% of the brackish fish samples studied. Conclusions: Consumption of fish from the River Niger may expose humans to polychlorinated biphenyls. In addition, since contamination of the fish samples is an indication of river contamination, river water quality is of great concern and there is a need for additional PCB data on water quality to be distributed to the community, followed by mitigation measures. Competing interests: The authors declare no competing financial interests. PMID- 30524848 TI - Review of Environmental and Health Impacts of Mining in Ghana. AB - Mining has played an important role in the development of Ghana. Like all industries, mining has both benefits and risks for the people living in communities where minerals are found. How these environmental and health impacts are managed by the government, nearby communities and mining companies can either worsen or improve the lives of community inhabitants. The current analysis focuses on the environmental and health impacts of mining in Ghana and blends extant data from the literature as well as the co-authors' recent findings on the causes, status, trends, and consequences of mining in Ghana. The work reviews data on environmental and health impacts of mining such as pollution of water bodies, degradation of forest resources, depletion of soil nutrients, destruction of wildlife habitat, and reduction in quality and threats to human health. PMID- 30524849 TI - Review of the Spatial Distribution, Source and Extent of Heavy Metal Pollution of Soil in China: Impacts and Mitigation Approaches. AB - Background: China has undergone a rapid industrial revolution and urbanization during the past three decades. This expansion is largely responsible for the release of a large amount of heavy metals into soils and is increasingly raising concerns over the potential effects on human health and the environment. The problem is drawing increasing attention, especially after an extensive nationwide soil survey report in 2014. A number of studies have examined soil contamination by heavy metals in China. However, most of these studies have been small in scale and it is therefore challenging to get a general overview of the level of contamination across the entire country. Objectives: The present study is aimed at presenting a synthesized overview of the extent, pattern, and impact of heavy metal contamination of soils in China, including mitigation approaches. Methods: Eighty-six journal articles and other literature such as reports, internet sources, and statistical yearbooks were narratively and critically synthesized to compile a holistic summary of sources of heavy metals, the extent of pollution, spatial distribution and impact of heavy metal contamination in China. The major findings from these studies are presented, along with mitigation approaches applicable to China. Discussion: A synthesis of major findings from recent scientific journals shows that about 10.18% of farmland soils which supports 13.86% of grain production in China is affected by heavy metals. The main sources of pollution are anthropogenic activities. Even though the spatial distribution of pollution is highly variable owing to natural and human factors, provinces with intensive industrial activities such as Henan, Shandong, and Sichuan are more highly polluted than others. These regions are top grain producing areas and hence require close follow-up for development of feasible approaches to mitigating crop contamination and associated health risks emerging in parts of China. The government recently launched a program aimed at determining sound reclamation strategies. Conclusion: Mitigation of heavy metal contamination in China requires coordination of different actors and integration of all feasible reclamation approaches. Competing Interests: The authors declare no competing financial interests. PMID- 30524850 TI - Initial Inventory of Plastics Imports in Nigeria as a Basis for More Sustainable Management Policies. AB - Background: Plastic is a waste stream with recycling and recovery potential. However, the recycling rates for plastic in African countries are low. Furthermore, use and production of virgin plastics are increasing. Therefore, a high proportion of plastic waste is being disposed of in landfills and dumpsites. Plastic serves as fuel for open burning at landfills/dumpsites with associated releases and constitutes a large fraction of marine litter, making it a major and growing global pollution concern. Objectives: This study aims to develop an initial inventory of plastics in Nigeria towards the development of an effective plastics management frame. Methods: A search was conducted of the recent literature and the United Nations (UN) Comtrade database using harmonized system (HS) codes for import data of various polymer categories and major product categories containing plastic. Algebraic expressions were developed for calculation of the share of plastic in these products. Results: Approximately 14,200,000 tons of plastics in primary form were imported into Nigeria between 1996-2014. Approximately 3,420,000 tons total plastic were imported in the form of products and approximately 5,545,700 tons were imported as product components. Approximately 194,000 tons of plastic toys were imported over a six-year period. Discussion: The total amount of plastics imported in primary form and as products equals 17,620,000 tons. The total volume of imported plastic, newly produced plastic and plastic components going into the technosphere was 23,400,000 tons. The huge amount of plastic and other polymers entering the technosphere in Nigeria has important implications for marine litter, pollution, waste management and resource recovery. Conclusions: A huge volume of plastics has entered the Nigerian technosphere, with less than 12% of the resulting waste entering the recycling stream. There is a need for sustainable management of this crucial waste and resource category. Potential mitigating strategies include waste plastic reuse, recycling, waste conversion to energy, and appropriate plastic control policy frameworks. Competing Interests: The authors declare no competing financial interests. PMID- 30524851 TI - Adsorption of Potentially Toxic Metals from Mono and Multi-Metal Systems Using Groundnut and Shea Nut Shell Biochars. AB - Background: Adsorption is a unique and promising method for the removal of trace metals from an aqueous environment using cost-effective and readily available biochars. Objective: The present study examined mono and simultaneous adsorption of cadmium (Cd), mercury (Hg) and lead (Pb) onto biochars produced at pyrolysis temperatures of 350 +/- 5 degrees C and 700 +/- 5 degrees C. Methods: Fifty mg/l of trace metal ions with 2 g/50 ml of adsorbent dosage were leached at constant room temperature of 24 +/- 0.5 degrees C in the laboratory with a constant contact time of 72 minutes. A total of 126 elutes were obtained from the batch experiments and conveyed to the Ecological Laboratory at University of Ghana for the analysis. Results: In the mono-component system of Cd, Hg and Pb, removal efficiency was almost 100% using groundnut, shea nut shell, and a combination of groundnut and shea nut shell biochars. The experiment showed that shea nut shell biochars have the strongest affinity for trace metal ions in the mono aqueous phase. In the binary system, the removal efficiency was over 99.60% for cadmium and 100% for mercury. The ternary experiment showed an order of adsorption of Pb2+ > Hg2+ > Cd2+ for Cd, Hg and Pb ions onto groundnut and shea nut shells biochars. Fast pyrolysis temperatures and some types of biochar showed a slight increase in the adsorption efficiency of metal ions, but the increase was not statistically significant (p > 0.05). Conclusions: The study revealed that the Langmuir adsorption isotherm was the best fit model for trace metal ion adsorption onto biochars in the batch experiment. The interactive effects of binary and ternary metal systems onto biochars are antagonistic and synergistic in nature. Based on these results, it is recommended that further competitive adsorption studies of these biochars should be undertaken for accurate estimation of adsorption in natural environments. Competing Interests: The authors declare no competing financial interests. PMID- 30524852 TI - Phthalate and Metal Concentrations in Drinking Water in Lagos, Nigeria. AB - Introduction: There have been no studies, monitoring programs, or data about phthalate levels made available to the public on the safety of residential drinking water in Lagos, Nigeria. Objectives: The present study aimed to assess the concentrations of dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), and zinc (Zn), lead (Pb), chromium (Cr), and cadmium (Cd) in drinking water drawn from taps in three residential areas of the state. Methods: High performance liquid chromatography and atomic absorption spectroscopy were used to determine the concentrations of phthalates and metals, respectively. Results: All of the water samples collected throughout the sampling period contained DMP, while DEP and DBP were present in only some of the samples. The highest mean DMP, DEP, and DBP concentrations of 1.15+/-0.28 mg/l, 0.09+/-0.16 mg/l, and 0.28+/-0.33 mg/l, respectively, were found in water samples collected from Lagos Street (Ebute-metta East). In addition, the trace/toxic metal concentrations in the water samples were found to be low for Cr, but high for Cd, Pb, and Zn, especially when compared with World Health Organization (WHO) limit values for drinking water. Lead recorded the highest mean concentration of 0.087+/-0.021 mg/l in the water samples obtained from Apapa Road (Ebute-Metta West). In the same vein, the highest significant (P < 0.01) mean Cr concentration of 0.047+/-0.012 mg/l was found in the water samples obtained from Apapa Road (Ebute-Metta West). Conclusions: In view of the high concentrations of phthalates and metals in the water sampled in this study, and the potential adverse health effects of these contaminants, especially on children and women of child-bearing age, the Lagos State Government of Nigeria and the state water corporation are called upon to immediately institute a monitoring program to identify the sources of contaminants and take appropriate intervention measures. Competing Interests: The authors declare no competing financial interests. PMID- 30524853 TI - Integrated Geophysical and Hydro-chemical Investigations of Impact of the Ijemikin Waste Dump Site in Akure, Southwestern Nigeria, on Groundwater Quality. AB - Background: Improper waste disposal can negatively impact the ecosystem and constitutes a major human health risk. Objectives: The present study evaluated the environmental impact on groundwater quality of an open-air waste dump in Akure, southwestern Nigeria, using an integrated geophysical survey and hydro chemical analysis of water samples. Methods: The geophysical survey involved three dipole-dipole 2-D imaging profiles and seven vertical electrical soundings (VES) along three traverses. The dipole-dipole data were inverted using the Dipro for Windows software, while the VES data were quantitatively interpreted using partial curve matching and computer assisted 1-D forward modeling with the WINResist software. The VES interpretation results were used to generate geoelectric sections. For the hydro-chemical analysis, samples were taken from five hand-dug wells at various distances from the dumpsite. The samples were analyzed for temperature, pH, conductivity, total dissolved solids (TDS), and some major elements (calcium ion (Ca2+), magnesium ion (Mg2+), chloride ion (Cl ), nitrate (NO3 -), sulfate (SO4 2-)) whose concentration values were compared with World Health Organization (WHO) and Nigerian Industrial Standard (NIS) standards for assessment of groundwater quality. Results: The VES curves revealed three distinct geoelectric/geologic layers with thicknesses and resistivities in the range of 0.7 - 2.0 m and 31 - 55 Omegam for topsoil, 6.2 - 14.6 m and 13 - 114 Omegam for the weathered layer, and a fresh basement with resistivity values ranging from 344 - infinity Omegam.In the hydro-chemical analysis, pH values ranged between 7.57 - 7.8, electrical conductivity ranged from 884 - 1510 MUS/cm, and TDS ranged between 588 - 1008 mg/l. Concentration values of Ca2+ and Mg2+ ranged between 78 - 132 mg/l and 1.8 - 19 mg/l, respectively. Conclusions: The results from the combined electrical resistivity methods showed relatively low resistivity values at the topsoil and weathered layers and the hydro-chemical assessment of water samples indicated that the topsoil and groundwater within the dumpsite may have been polluted by leachate. Competing Interests: The authors declare no competing financial interests. PMID- 30524854 TI - Environmental Assessment and Blood Lead Levels of Children in Owino Uhuru and Bangladesh Settlements in Kenya. AB - Background: Lead exposure is linked to intellectual disability and anemia in children. The United States Centers for Disease Control and Prevention (CDC) recommends biomonitoring of blood lead levels (BLLs) in children with BLL >=5 MUg/dL and chelation therapy for those with BLL >=45 MUg/dL. Objectives: This study aimed to determine blood and environmental lead levels and risk factors associated with elevated BLL among children from Owino Uhuru and Bangladesh settlements in Mombasa County, Kenya. Methods: The present study is a population based, cross-sectional study of children aged 12-59 months randomly selected from households in two neighboring settlements, Owino Uhuru, which has a lead smelter, and Bangladesh settlement (no smelter). Structured questionnaires were administered to parents and 1-3 ml venous blood drawn from each child was tested for lead using a LeadCare (r) II portable analyzer. Environmental samples collected from half of the sampled households were tested for lead using graphite furnace atomic absorption spectroscopy. Results: We enrolled 130 children, 65 from each settlement. Fifty-nine (45%) were males and the median age was 39 months (interquartile range (IQR): 30-52 months). BLLs ranged from 1 MUg/dL to 31 MUg/dL, with 45 (69%) children from Owino Uhuru and 18 (28%) children from Bangladesh settlement with BLLs >5 MUg/dL. For Owino Uhuru, the geometric mean BLL in children was 7.4 MUg/dL (geometric standard deviation (GSD); 1.9) compared to 3.7 MUg/dL (GSD: 1.9) in Bangladesh settlement (p<0.05). The geometric mean lead concentration of soil samples from Owino Uhuru was 146.5 mg/Kg (GSD: 5.2) and 11.5 mg/Kg (GSD: 3.9) (p<0.001) in Bangladesh settlement. Children who resided <200 m from the lead smelter were more likely to have a BLL >=5 MUg/dL than children residing >=200 m from the lead smelter (adjusted odds ratio (aOR): 33.6 (95% confidence interval (CI): 7.4-153.3). Males were also more likely than females to have a BLL >=5 MUg/dL (39, 62%) compared to a BLL<5 MUg/dL [aOR: 2.4 (95% CI: 1.0-5.5)]. Conclusions: Children in Owino Uhuru had significantly higher BLLs compared with children in Bangladesh settlement. Interventions to diminish continued exposure to lead in the settlement should be undertaken. Continued monitoring of levels in children with detectable levels can evaluate whether interventions to reduce exposure are effective. Participant Consent: Obtained. Ethics Approval: Scientific approval for the study was obtained from the Ministry of Health, lead poisoning technical working group. Since this investigation was considered a public health response of immediate concern, expedited ethical approval was obtained from the Kenya Medical Research Institute and further approval from the Mombasa County Department of Health Services. The investigation was considered a non-research public health response activity by the CDC. Competing Interests: The authors declare no competing financial interests. PMID- 30524855 TI - Oxygenated Volatile Organic Compounds (Anti-freezing Agents) in Decorative Water based Paints Marketed in Nigeria. AB - Background: Consumer products such as paints are a potentially significant source of volatile organic compounds (VOCs) and oxygenated VOCs. Paints for construction and household use have been rapidly changing from oil-based to water-based paints and are one of the commonly identified sources of oxygenated VOCs in indoor environments. Objectives: Four different anti-freezing agents were identified and analyzed in 174 waterbased paint samples, purchased from popular paint markets in two metropolitan cities in Nigeria, Lagos and Ibadan. Methods: Paint samples were solvent extracted using acetonitrile and milli-Q water. Antifreezing agents in the extracts were identified and quantified using gas chromatography (GC)-mass spectrometry and a GC-flame ionization detector, respectively. Discussion: Four different anti-freezing agents were identified in the samples, ethylene glycol, diethylene glycol, triethylene glycol and propylene glycol. Their levels ranged from 1,000-1,980 ppm, diethylene glycol; 1,000-3,900 ppm, triethylene glycol; 1,090-2,510 ppm, propylene glycol and 1,350-2,710 ppm, ethylene glycol. Levels of anti-freezing agents in all of the paint samples were above the permissible limits of the European Union for VOCs in paints of 500 ppm. Results of multivariate statistical analyses clearly showed that triethylene glycol was the most commonly used anti-freezing agent in paints despite its numerous harmful health effects. Conclusions: We concluded that water-based paints marketed in Nigeria contain high concentrations of anti-freezing agents, which have harmful environmental and human health effects, especially to sensitive individuals such as children. Competing Interests: The authors declare no competing financial interests. PMID- 30524856 TI - Review of Heavy Metals Pollution in China in Agricultural and Urban Soils. AB - Background: The concentrations of heavy metals in soil and potential risks to the environment and public health are receiving increased attention in China. Objectives: The objective of this paper is to review and analyze heavy metals soil contamination in urban and agricultural areas and on a national scale in China. Methods: Initially, data on soil heavy metals concentration levels were gathered from previous studies and narratively analyzed. A further statistical analysis was performed using the geo-accumulation index (Igeo), Nemerow integrated pollution index (NIPI), mean, standard deviation (SD), skewness and kurtosis. Pollution levels were calculated and tabulated to illustrate overall spatial variations. In addition, pollution sources, remedial measures and impact of soil contamination as well as limitations are addressed. Results: The concentration level of heavy metals was above the natural background level in most areas of China. The problem was more prevalent in urban soils than agricultural soils. At the national level, the soil in most of the southern provinces and Beijing were heavily polluted. Even though the pollution condition based on Igeo was promising, the Nemerow integrated pollution level was the most worrisome. The soils in about 53% of the provinces were moderately to heavily polluted (NIPI>2). The effects were noticed in terms of both public and ecological health risks. The major sources were waste gas, wastewater, and hazardous residuals from factories and agricultural inputs such as pesticides. Efforts have been made to reduce the concentrations and health risks of heavy metals, including policy interventions, controlling contamination sources, reducing the phytoavailability of heavy metals, selecting and rearing of grain cultivars with low risk of contamination, paddy water and fertilizer management, land use changes, phytoremediation and engineering techniques. Conclusions: China is experiencing rapid economic and technological advancements. This increases the risk of heavy metals contamination of soil. If serious attention is not paid to this problem, soil toxicity and biological accumulation will continue to threaten the sustainability of China's development. Competing Interests: The authors declare no competing financial interests. PMID- 30524857 TI - Relationship between Metal Pollution and Gene Expression of Insulin-like Growth Factor II. AB - Background: Metals pollution plays an important role in the regulation of gene expression through interference with signal transduction pathways which are important for cell bioactivity. Objectives: The present study was conducted to estimate metallothionein levels in mussels as a biomarker of exposure to heavy metals in order to monitor the pollution of Abu Qir Bay, Egypt (El-Maadiya region) and to evaluate the impact of heavy metals on human health by examining insulin-like growth factor II (IGF-2) gene expression in peripheral blood mononuclear cells. Methods: One hundred and forty mussel samples (Andara dulofii) were collected from Abu-Qir Bay, stored in bags, preserved in an ice box, and then transported to the laboratory to acclimatize at 20 degrees C for three days in ethylene diamine tetra acetic acid (EDTA)-free synthetic sea water to determine the presence of metallothionein and five other metals (cadmium (Cd), lead (Pb), chromium (Cr), copper (Cu) and zinc (Zn)). Results: Results showed that mussels collected from the study area contained a measurable amount of metallothionein. In addition, results revealed an increased level of malondialdehyde coinciding with a decreased level of antioxidants, leading to oxidative stress in local fishermen. Conclusions: The present data demonstrated a significant increase in the gene expression of IGF-2 and a positive correlation between IGF-2 gene expression and the enzymatic activity of glutathione peroxidase in male subjects. Participant Consent: Obtained. Ethics Approval: Written consent was provided by the study participants and study approval was given by the ethics committee of Alexandria University (US Department of Health and Human Services, Registration of an Institutional Review Board, IORG0008812 Medical Research Institute, Expires 4/8/2019, OMB No:0990-0279). Competing Interests: The authors declare no competing financial interests. PMID- 30524858 TI - Insights and Tracking of Pollution Awareness Using Google Trends. AB - Background: Although pollution is the largest environmental cause of disease and premature death in the world today, it does not receive consistent and commensurate public attention. Objectives: This paper quantifies this phenomenon, tracks recent efforts, and offers strategies for improving pollution awareness. Methods: Google Trends allows a user to compare up to five terms or topics simultaneously. Results are displayed as a set of time series. The values displayed are not the actual search counts but percentages relative to the total searches across the specified geography (worldwide, country, state/province, and city) and time period. The resulting numbers are then scaled from 0 to 100 (to create an Interest Index) based on the proportion to all searches on all terms or topics. Discussion: Pollution interest can be quite different at a country level compared with the worldwide view. Predictably, pollution interest is highest in many of the countries most affected by pollution. However, many of the wealthiest countries show low interest in pollution. Conclusions: Solving any problem begins with awareness, which generates concern and understanding, followed by action. Determining what issues people are searching on provides a reliable barometer of the true interest in and awareness of an issue. Google Trends provides a mechanism to help track ongoing pollution problems and solutions. Disclaimer: The author serves as the Chief Technical Officer of Pure Earth. The author had no role in the review of or decision to accept this manuscript. Competing Interests: The author declares no competing financial interests. PMID- 30524859 TI - Continuous Publication and Other Editorial Changes. AB - Competing Interests. The author declares no competing financial interests. PMID- 30524860 TI - Farmers' Perception of the Health Effects of Agrochemicals in Southeast Nigeria. AB - Background: Agrochemicals are used by farmers in Southeast Nigeria to increase crop yields and food production. However, farmers are often illiterate and do not follow precautions for their usage and application, increasing the risk of exposures to humans and the environment. Objectives: The aim of the present study was to determine the extent of the use of agrochemicals by farmers, category or type used, ability to read instructions, exposure to agrochemicals during application and perception of the health effects of exposure to agrochemicals in Southeast Nigeria. Methods: From February-June 2017, a total of 200 farmers were surveyed using oral interviews and structured questionnaires. Data were analyzed using descriptive statistics. Respondents were asked about items such as socioeconomic characteristics, types and amounts of fertilizers and pesticides used, exposure during application and perceptions of the health effects of exposure to agrochemicals. Results: In the present study, the majority of farmers (74%) used inorganic fertilizers (nitrogen, phosphorus, and potassium (NPK)) and 26% used organic fertilizers (compost manure). Most of the farmers in the present study (65%) reported that they could not read agrochemical application instructions, 92% of farmers were exposed to agrochemicals during application, and most farmers (73%) reported falling sick after exposure to agrochemicals. Conclusions: We recommend that agricultural extension agents provide farmers with comprehensive training in agrochemical use to ensure their health and lower environmental risks. Participant Consent: Obtained. Ethics Approval: The study was approved by the Research Ethics Committee, Department of Agricultural Economics, Faculty of Agriculture, University of Nigeria, Nsukka. Competing Interests: The author declares no competing financial interests. PMID- 30524862 TI - Air Pollution Monitoring Around Residential and Transportation Sector Locations in Lagos Mainland. AB - Background: Industrialization and urbanization, while associated with increased productivity, are also potential causes of increased air pollution. Urban air quality has the potential to affect the health and wellbeing of residents of urban areas. Objectives: The present study investigated the levels of air pollutants around residential areas and transport sector locations (TSLs) in Lagos, Nigeria. Residential areas were defined as areas around inner streets and living quarters, while TSLs included busy roads, dual carriage roads, bus stops and major car parks in the Yaba Local Council Development Area of Lagos Mainland, Lagos, Nigeria. Methods: Air quality parameters were assessed in situ using calibrated hand-held devices at selected residential and TSLs. Each sampling location was geo-referenced and concentrations of the various parameters were used to plot distribution maps. Results: The findings from the monitoring exercise showed that levels of the measured air pollutants: carbon monoxide (CO), particulate matter (PM10 and PM2.5), sulphur dioxide (SO2), noise, temperature and humidity were within the ranges of 1.00 - 6.0 5.97 ppm, 43.345.2 - 127.2159.7 MUg/m3, 20.3 23.25 - 69.058.16 MUg/m3, 0.0 0 - 0.20.17 ppm, 47.7 50 - 65 70.1 dB, 26.2227.2 - 35.536.7 degrees C and 57.0157.6 - 91.8492.3%, respectively, around residential areas. Values of the measured air pollutants at the TSLs ranged as follows: 2.011.0 - 5.397.7 ppm, 103.3360.7 - 179.77404.0 MUg/m3, 50.2832.3 - 91.01184.0 MUg/m3, 0.00 - 0.40 ppm, 64.2153.1 - 71.1376.3 dB, 27.1826.2 27.9332.6 degrees C and 60.3660.0 - 75.0178.0%, respectively. Hydrogen sulphide (H2S), ammonia (NH3), nitrogen oxide (NO2) were below detection limits in both sampling locations while volatile organic carbons (VOCs) ranged from 0.00 - 0.10 ppm in the TSLs. Discussion: Most assessed air quality parameters were significantly higher around bus stops (P < 0.05), except for CO and humidity. In addition, PM10 and PM2.5 were much higher than the World Health Organization (WHO) guidelines. The results indicated that the quality of air (particulate matter) in the study area was poor, especially in the TSLs. Conclusions: The Federal Ministry of Environment, through its relevant agencies, must create policies to address urban air pollution, taking into consideration long term exposures and people that are most vulnerable within the population. Competing Interests: The authors declare no competing financial interests. PMID- 30524861 TI - Characterization, Spatial Variation and Risk Assessment of Heavy Metals and a Metalloid in Surface Soils in Obuasi, Ghana. AB - Background: Soil contamination with heavy metals and metalloids has become an increasingly important issue in recent years. Objectives: The present study examines possible contamination of the environment with metals from gold mining activities in Obuasi, Ghana. Methods: Soil samples were collected from commercial and residential areas and tailing dams in Obuasi in order to investigate the extent of lead (Pb), cadmium (Cd), mercury (Hg), copper (Cu), zinc (Zn), cobalt (Co), chromium (Cr), nickel (Ni) and arsenic (As) pollution, create thematic maps showing the extent of heavy metals pollution, identify the sources of pollution, and to assess risks to humans and the surrounding ecological system. Results: Mean concentrations of metals from the study were found in the order of As > Cu > Zn > Cr > Ni > Pb > Co > Hg > Cd. The results showed that all communities were severely polluted with As, and distribution maps highlighted two hot spots at the sulfite treatment plant and Pompura treatment plant tailings dams. Additionally, the levels of Pb, Cu and Zn were elevated around the city center where vehicular traffic is very dense. Principal component analysis indicated that mining activities may have significantly contributed to metal levels in Obuasi soils. The potential ecological risk (RI) indicated that soils in 41% of the communities pose very high risks to the surrounding ecological system, 50% pose considerable risk, and 9% pose a moderate risk. Arsenic and Hg contributed 73 and 15% of the RI, respectively. The average hazard quotient due to soil As exposure was 2.51 +/ 1.23 and ingestion of soils in 95% of the communities in the study area could pose non-carcinogenic health risks to children. Moreover, the average cancer risk for children from the communities was 1.13 * 10-3. Based on the United States Environmental Protection Agency (USEPA) recommendation for cancer risk of 10-6 to 10-4, the cancer risk for children (> 10-3) was higher in 45% of the studied communities. Conclusions: The central part of the study area is polluted with Pb, Zn and Cu, and As pollution is severe in all of the studied communities. The RI from all study sites revealed very high risk to the ecological system, including mammals. There could be non-cancer and cancer risks to Obuasi residents due to ingestion of As-contaminated soils, and children are particularly vulnerable. Competing Interests: The author declares no competing financial interests. PMID- 30524863 TI - Impact of Land Use on Concentrations of Potentially Toxic Elements in Urban Soils of Lagos, Nigeria. AB - Background: Among soil contaminants, potentially toxic elements (PTE) are of major significance because they are ubiquitous, toxic and persistent. Chronic exposure of humans to these elements has been linked with developmental delay, cancer, atherosclerosis and kidney damage, stomach ailments, respiratory problems, heart disease and cancer. Objectives: The present study aims to investigate current PTE concentrations in urban soils of Lagos, an example of a rapidly urbanizing megacity in a developing country. The variation in PTE (chromium (Cr), copper (Cu), iron (Fe), magnesium (Mn), nickel (Ni), lead (Pb) and zinc (Zn)) levels across different land use types was examined. Information from this study will be useful in the ranking of contaminated sites, environmental quality management, guidance for remediation, redevelopment of contaminated sites and will provide crucial information for general urban planning decisions. Methods: Five areas spread across four local government areas were selected, representing different socio-economic areas of Lagos (Victoria Island, Lagos mainland, Ikeja, Ifako-Ijaiye and Makoko). Sampling locations within the study areas were comprised of school playgrounds, roadsides, ornamental gardens, open spaces, train stations, industrial estates and dump sites. A total of 126 samples were collected. Results: The overall mean levels of PTE concentrations in this study were comparable to those found in large European cities where main pollution sources include traffic and current or former heavy manufacturing industries. Conclusions: Regulation and legislation on environmental issues, including effective solid waste management strategies and enforcement of emission standards should be emphasized in order to reduce the impact of PTE pollution on the inhabitants of urban areas in developing countries. Competing Interests: The authors declare no competing financial interests. PMID- 30524864 TI - Oil Spillage and Heavy Metals Toxicity Risk in the Niger Delta, Nigeria. AB - Background: Heavy metals are known to elicit toxic effects which negatively affect human health. Crude oil is known to contain heavy metals and oil spills contaminate the environment and can result in human exposures to heavy metals. As the seat of crude oil activities, the Niger Delta region experiences the highest rate of oil spills in Nigeria. Objective: The purpose of this study was to estimate the quantity of oil spilled into the Niger Delta region from 1976 through 2014 and to assess the resulting heavy metals exposures of the local population. Methods: Secondary data from governmental and non-governmental bodies were analyzed and the amount of oil spilled in the Niger Delta region from 1976 through 2014 was determined. The heavy metals present in crude oil from this region and the quantities released into the environment within the study period due to spillage were then extrapolated. Results: The Niger Delta region is continuously exposed to a higher rate of oil spills, and about 3.1 million barrels of crude oil enriched in manganese (Mn), iron (Fe), copper (Cu), zinc (Zn), lead (Pb), nickel (Ni), cobalt (Co), cadmium (Cd) and chromium (Cr) were spilled from 1976 to 2014 in this region. Therefore, the occupants of this region may be at risk of heavy metals toxicity. Conclusion: To minimize heavy metals exposure and toxicity in the Niger Delta region, effective strategies must be adopted to reduce oil spills. In addition, curtailment and remediation of oil spills should be more rapid. Competing Interests: The authors declare no competing financial interests. PMID- 30524866 TI - Concentrations and Human Health Risk of Heavy Metals in Rivers in Southwest Nigeria. AB - Background: Rivers are the most vital freshwater resources in the world. In Southwest Nigeria, anthropogenic activity stresses the quantity and quality of water resources. Methods: The present study examined the concentrations and human health risk of five heavy metals (manganese (Mn), arsenic (As), chromium (Cr), cadmium (Cd), and lead (Pb)) in selected rivers in Southwest Nigeria. The determination of heavy metals was carried out by atomic absorption spectrophotometry after digestion with a di-acid mixture 9:4 (v/v) (nitric acid: perchloric acid). Results: All rivers had higher concentrations of the five heavy metals in the dry season except for As in Dandaru (0.012 mg/L) and Asejire (0.016 mg/L). Manganese was observed to have the highest mean concentration among all the five metals in both the rainy and dry seasons across the sampled rivers. Generally, the annual mean concentration of metals followed the order: Mn>Cr>Cd>Pb>As in all the selected rivers. Discussion: The human health risk assessment showed that the hazard index and hazard quotient for ingestion of water for Cd and As in all the sampled rivers were higher than the acceptable limit of 1.0, indicating carcinogenic risk (CR) via direct ingestion of water. The CR via ingestion for As in all of the sampled rivers was above the remedial goal target of 1*10-6. The recorded values for chronic daily intake (CDI) were higher for Cr and Mn in all four sampled rivers. Conclusions: The results of the present study showed that As is a driver for carcinogenic risk through ingestion in all of the sampled rivers compared to other metals. Competing Interests: The authors declare no competing financial interests. PMID- 30524867 TI - Proceedings of the 9th International Conference on Children's Health and the Environment. PMID- 30524865 TI - Heavy Metal Contamination and Ecological Risk Assessment in Soils and Sediments of an Industrial Area in Southwestern Nigeria. AB - Background: Increased growth of industrial activities, especially in urban centers, is one of the main sources of toxic substances in Nigeria. The level of these impacts is not well known. Soil and sediment samples from one such industrial area were examined for their mineralogical composition and heavy metals contents in order to assess the level of contamination and potential ecological risk status. Methods: Mineralogical composition of the media and their heavy metals concentrations were determined using X-ray diffractometry and inductively coupled plasma-mass spectrometry methods, respectively. Ecological risk assessment was carried out using single (contamination factor, geo accumulation index, enrichment factor) and multi-elemental (contamination degree, pollution index and modified pollution index) standard indices. Results: The average heavy metal concentrations in soils and sediments followed the order magnesium (Mn) > chromium (Cr) > lead (Pb) > copper (Cu) > cadmium (Cd) > cobalt (Co) > nickel (Ni), with corresponding values for soils and sediments of 324.3, 79.9, 66.1, 40.7, 14.3, 9.1, 6.8 mg kg-1 and 266.8, 78.6, 40.6, 39.8, 12.9, 8.4, 4.6 mg kg-1, respectively. Principal component (PC) analysis of the results indicated three main sources of metals (industrial, vehicular activities and geogenic input). Evaluated contamination factor (Cf), enrichment factor (Ef) and geo-accumulation index (Igeo) revealed very high contamination for Pb, Cd and Cu in all of the samples, with calculated pollution index (PI) and modified pollution index (MPI) revealing that all the samples were severely polluted. Calculated potential ecological risk factor (ERi) within the industrial area demonstrated a strong potential ecological risk for Cd, Pb and Cu. Conclusions: Activities in the industrial area have affected the quality of the analyzed environmental media, with possible detrimental health consequences. Regular environmental monitoring of the industrial area and the formulation of appropriate policies that support reduction of contamination are strongly recommended. However, due to the limitations of comparing site samples with a single control sample in this work, further study is recommended to compliment this preliminary study. Competing Interests: The authors declare no competing financial interests. PMID- 30524868 TI - Introduction of Mercury-Free Gold Extraction to Small-Scale Miners in the Cabo Delgado Province in Mozambique. AB - Background: The majority of small-scale gold miners worldwide, including those in Mozambique, use mercury to extract gold. Over the last fifty years, gold production from small-scale mining has been accelerating and consequently the amount of mercury released to the environment has increased dramatically, causing major global health problems. In 2018, a team from the Danish non-governmental organization Dialogos introduced the mercury-free gold extraction method in the Cabo Delgado province in Mozambique in the villages of Waqueia and Nanlia. Objectives: The objective of this project was to teach local miners this method to reduce mercury pollution. An additional objective was to compare the local gold extraction method and the mercury-free gold extraction method in terms of gold recovery. The hypothesis was that the level of gold recovery would be higher with the mercury-free method compared to the locally used amalgamation method. Materials and Methods: An experimental study comparing the two gold extraction methods was carried out where local miners processed gold-bearing ore using their standard procedures with the amalgamation method and the Dialogos team processed an equivalent amount of gold-bearing ore with the mercury-free gold extraction method. The tests were carried out once at each mining site. Results: Under even circumstances in a controlled setting, the mercury-free method yielded up to 78% more gold than the amalgamation method normally used by the miners. Conclusions: The strengths of the mercury-free gold extraction method include low costs, higher gold yield, benign environmental impact, legality and needed chemicals are more readily available compared with the amalgamation method. However, the mercury-free method may be more time consuming than the amalgamation method, especially for beginners. Borax is typically available in developed urban areas, as it is commonly used in the welding industry and by jewelers, but can be hard to find in more remote villages. Competing Interests: The authors declare no competing financial interests. PMID- 30524869 TI - Effects of Arsenic, Iron and Fertilizers in Soil on Rice in Cambodia. AB - Background: In parts of Cambodia, irrigation with groundwater results in arsenic accumulation in soils and rice, leading to health concerns associated with rice consumption. A high concentration of iron in groundwater can precipitate arsenic and reduce its bioavailability, however high concentrations of arsenic and iron can also reduce rice production. Furthermore, concerns have been raised about chemical contamination from inorganic fertilizers used to grow rice. The relationship between soil geochemistry and arsenic concentrations in rice is not yet fully understood. Objectives: The primary objective of this project was to investigate the relationship between arsenic concentrations in irrigation water, soil and rice collected from different sites in Cambodia. A secondary objective was to explore arsenic and phosphorus levels in fertilizer samples obtained from the study area in Cambodia. Methods: The present study collected 61 well water samples, 105 rice samples, 70 soil samples, 11 inorganic fertilizer samples and conducted interviews with 44 families along the Mekong River in Cambodia. Analyses for metals, total arsenic, and arsenic species in the water and rice were conducted in Canada by inductively coupled plasma mass spectrometry. Analyses for metals, total arsenic and phosphorus in soils and inorganic fertilizers were conducted in Cambodia and Singapore by X-ray fluorescence. Results: The concentration of arsenic in rice paddy soils was highly variable and as much as 20 times higher near the irrigation wells than in more distal areas of the paddy. Two farmers in Preak Russey had integrated soil samples with arsenic levels above the concentration associated with toxicity to rice in Taiwan (40 mg/kg) and above the Dutch concentration requiring intervention or remediation (55 mg/kg). The highest total arsenic measured in soil was 95 mg/kg. In Preak Russey, the loading of arsenic from irrigation water was 3710 times greater than the loading of arsenic from inorganic fertilizers. Half of the commercial inorganic fertilizers had less than 50% of the labelled content of phosphorus. Conclusions: Emphasis should be placed on improving the management of irrigation water, not on inactivation of arsenic in soil. The high levels of iron in groundwater mitigate arsenic toxicity, but the accumulation of iron could later result in lower rice productivity. Irrigation of rice with groundwater is not likely sustainable. To improve rice productivity, the content of phosphorus in local inorganic fertilizers must be improved to world standards. X-ray fluorescence analysis can quickly identify poor quality fertilizers. Informed Consent: Obtained. Competing Interests: The authors declare no competing financial interests. PMID- 30524870 TI - Groundwater Irrigation and Arsenic Speciation in Rice in Cambodia. AB - Background: Arsenic bioaccumulation in rice is a global concern affecting food security and public health. Objective: The present study examined arsenic species in rice in Cambodia to characterize health risks with rice consumption and to clarify uncertainties with Codex guidelines. Methods: The present study collected 61 well water samples, 105 rice samples, 70 soil samples, and conducted interviews with 44 families in Preak Russey near the Bassac River and Kandal Province along the Mekong River in Cambodia. Analyses of metals, total arsenic and arsenic species were conducted in laboratories in Canada, Cambodia and Singapore. Results: Unlike in Bangladesh, rice with the highest total arsenic concentrations in Cambodia contains mostly organic arsenic, dimethylarsinic acid (DMA), which is unregulated and much less toxic than inorganic arsenic. The present study found that storing surface runoff in ditches prior to irrigation can significantly reduce the arsenic concentration in rice. It is possible to remove > 95% of arsenic from groundwater prior to irrigation with natural reactions. Conclusions: The provision of high quality drinking water in 2015 to Preak Russey removed about 95% of the dietary inorganic arsenic exposure. The extremes in arsenic toxicity that are still obvious in these farmers should become less common. Rice from the site with the highest documented levels of arsenic in soils and water in Cambodia passes current Codex guidelines for arsenic. Informed Consent: Obtained. Competing Interests: The authors declare no competing financial interests. PMID- 30524871 TI - Chemical Speciation and Characterization of Trace Metals in Dry Camellia sinensis and Herbal Tea Marketed in Nigeria. AB - Background: Trace metals from anthropogenic activities have been found to occur in tea brands and pose potential human health risks to consumers. Objectives: The present study assessed the concentrations of trace metals in green, black and herbal tea brands using a modified Community Bureau of Reference sequential extraction method. Methods: Fifteen (15) Camellia sinensis and eight (8) herbal tea samples commonly consumed in Nigeria were collected and analyzed for trace metals. The concentrations of cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), vanadium (V), and zinc (Zn) in extract fractions were analyzed using microwave plasma atomic emission spectroscopy (MP-AES). Results: Trace metals were detected in all of the samples investigated. The concentrations of trace metals in 4 stages (soluble/exchangeable/carbonates bound fraction, reducible fraction, oxidizable fraction, residual fraction) of sequential and pseudo-total metal extraction procedures are presented. The concentrations of Cd, Cr, Cu, Mn, Ni, Pb, V, and Zn in the exchangeable/carbonate bound fraction for green tea ranged between 0.27-1.47, ND-0.33, ND-0.44, 7.05 33.04, 0.23-0.69, ND-0.51, ND-0.16 and 0.18-1.99 mg/kg, ND-0.73, 0.15-0.36, 0.36 0.59, 1.38-30.07, 0.15-0.54, 0.05-0.76, 0.15-0.34 and 0.27-0.77 mg/kg and 0.54 0.64, 0.25-0.41, 0.35-0.47, 18.72-23.98, 0.30-0.55, 0.15-0.21, 0.15-0.23 and 0.30 0.48 mg/kg for hebal tea, respectively. Conclusion: The metal content in the investigated tea indicated low to enhanced concentrations. Locally produced black teas recorded relatively low trace metal contents compared to the green and herbal tea samples. The most bioavailable trace metal was Mn, while Zn was most preferably bound to the residual fraction. Cadmium, Cr, Cu, Ni, Pb, and V were distributed at varied concentrations among other extractable phases. Daily consumption of the investigated tea products may expose consumers to potentially toxic metals as well as essential elements. Competing Interests: The authors declare no competing financial interests. PMID- 30524872 TI - Role of National Policy in Improving Health Care Waste Management in Nigeria. AB - Background: As Nigeria strives to improve health services nationwide, there is a corresponding increase in laboratory testing, care and treatment activities, producing more healthcare waste that must be safely managed. In the past, Nigeria lacked an enabling environment for healthcare waste management, as it did not have a national health care waste management policy. However, in 2013 a policy and strategic plan for healthcare waste management was developed to address this problem. Objectives: The present study performed an environmental safeguard audit to determine the level of implementation of the 2013 national policy in the 36 states and Federal Capital Territory in Nigeria. We also sought to determine whether the 2013 national policy has had an impact on healthcare waste management. Methods: The present study was conducted in 1921 health facilities, selected using the probability proportional to size sampling method. Results: The present study found that 44.8% of health facilities surveyed had healthcare waste management work plans adapted from the 2013 national policy. In addition, 89.2% of health facilities segregated waste. This is an important improvement, as previous studies reported that there was little to no waste segregation at health facilities. Furthermore, 41.4% of health facilities had designated persons or units handling healthcare waste, in contrast to previous studies which found no designated person or unit responsible for healthcare waste. However, the quality of healthcare waste management varied across states and health facilities. Discussion: Following the introduction of healthcare waste management policy, health facilities in Nigeria have improved waste management practices. However, training, availability of required tools and functional governance structures are essential to the implementation of an effective healthcare waste management policy. Conclusions: The study findings show that safe healthcare waste management can be implemented if the government leads by providing policy and required resources, while health facilities put standard operating procedures in place to guide day to day healthcare waste management operations. Participant Consent: Obtained. Ethical Approval: The protocol was approved by the National Health Research Ethics Committee of Nigeria. Competing Interests: The authors declare no competing financial interests. PMID- 30524873 TI - Seroprevalence of Hepatitis B Virus and Compliance to Standard Safety Precautions among Scavengers in Ilorin Metropolis, Kwara State, Nigeria. AB - Background: Scavengers, due to the nature of their work, are at risk of various occupational hazards while sorting for materials for recycling and sale. They are exposed to blood borne infections such as hepatitis B virus (HBV) infection from injuries from sharps and contact with discarded materials due to non-compliance with standard precautions. Objective: The present study assessed the prevalence of HBV and compliance with safety precautions among scavengers in Ilorin Metropolis, Kwara State, Nigeria. Methods: A cross-sectional study was conducted among 236 scavengers (comprised of scavengers dealing with biomedical wastes and those that were not) using structured questionnaires during the first stage of the study and a second testing stage. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 20.0 for descriptive and inferential statistics at a 5% level of significance. Results: The prevalence of HBV infection among the scavengers was found to be 17.4%, indicating that scavengers are at high risk of HBV infection. There was a significant difference in the prevalence of HBV among scavengers that handled biomedical wastes and those that did not. The majority of the scavengers (74.2%) did not have knowledge of or use standard precautions such as personal protective equipment (PPE). The level of injuries was considerably high and the treatment of injuries among scavengers illustrated their lack of awareness of the hazards involved in their occupations, as the majority of respondents (51.3%) engaged in self-treatment of occupational injuries. Conclusions: The probable pathway for virus transmission was waste handling, especially biomedical waste, which is mostly handled with bare hands without standard safety precautions. Vaccination against HBV, proper personal hygiene practices, regular training in occupational safety, monitoring by regulatory agencies and inclusion of scavengers in a mandatory health insurance scheme are recommended to control the risk of HBV infection among scavengers. Informed Consent: Obtained. Ethical Approval: This study was approved by the Kwara State Ministry of Health Ethical Review Committee. Permission was also granted by the scrap dealers association through the Kwara State Environmental Protection Agency that oversees issues relating to the environment and public health in the state. Competing Interests: The authors declare no competing financial interests. PMID- 30524874 TI - Degradation of Polycyclic Aromatic Hydrocarbons by Moderately Halophilic Bacteria from Luzon Salt Beds. AB - Background: Polycyclic aromatic hydrocarbons (PAHs) are common environmental contaminants which are highly toxic due to their carcinogenic and mutagenic effects. They are released into the environment by incomplete combustion of solid and liquid fuels, accidental spillage of oils and seepage from industrial activities. One of the promising processes mitigating PAHs is through biodegradation. However, conventional microbiological treatment processes do not function well at high salt concentrations. Hence, utilization of halophilic bacteria should be considered. Objectives: This study aimed to assess the ability of halophilic bacteria isolated from local salt beds in Pangasinan and Cavite, the Philippines, to degrade PAHs pyrene, fluorene and fluoranthene. Methods: Polycyclic aromatic hydrocarbon-tolerant halophilic bacteria collected from two sampling sites were phenotypically characterized, molecularly identified and tested to determine their potential to degrade the PAHs pyrene, fluorene and fluoranthene at a hypersaline condition. Best PAH degraders were then assayed to identify the optimal degradation using such parameters as pH, temperature and PAH concentration. Testing for enzyme degradation was also done to determine their baseline information. Extraction and analysis of degraded PAHs were performed using centrifugation and UV-vis spectrophotometry. Results: Twelve isolates from both collection sites tolerated and grew in culture with selected PAHs. These were identified into four genera (Halobacillus, Halomonas, Chromohalobacter, and Pontibacillus). Selected best isolates in a series of biodegradation assays with the above-mentioned parameters were Halobacillus B (Collection of Microbial Strains (CMS) 1802) (=trueperi) (Gram-positive) for pyrene and fluoranthene, and Halomonas A (CMS 1901) (Gram-negative) for fluorene. Degrader biomass and PAH degradation were invariably negatively correlated. Qualitative tests with and without peptone as a nitrogen source implied enzymatic degradation. Discussion: Polycyclic aromatic hydrocarbons utilized by these halophilic bacteria served as a sole source of carbon and energy. Implications of biodegradation of the two best isolates show that high molecular weight (HMW) (4-ring) pyrene tends to be degraded better by Gram-positive bacteria and low molecular weight (3-ring) fluorene by Gram-negative degraders. Conclusions: Halophilic bacteria constitute an untapped natural resource for biotechnology in the Philippines. The present study demonstrated their potential use in bioremediation of recalcitrant hydrocarbons in the environment. Competing Interests: The authors declare no competing financial interests. PMID- 30524875 TI - Chemical Pollutants of Pharmaceutical Origin Present in the Environment. AB - Competing Interests. The author declares no competing financial interests. PMID- 30524876 TI - An intravascular magnetic wire for the high-throughput retrieval of circulating tumour cells in vivo. AB - The detection and analysis of rare blood biomarkers is necessary for early cancer diagnosis and to facilitate the development of tailored therapies. However, current methods for the isolation of circulating tumor cells (CTCs) or nucleic acids present in a standard clinical sample of only 5-10 mL of blood provide inadequate yields for early cancer detection and comprehensive molecular profiling. We have developed a flexible magnetic wire that can retrieve rare biomarkers from the subject's blood in vivo at a much higher yield. The wire is inserted and removed through a standard intravenous catheter and captures biomarkers that have been previously labeled with injected magnetic particles. In a proof-of-concept experiment in a live porcine model, we demonstrate the in vivo labeling and single-pass capture of viable model CTCs in less than 10 seconds. The wire achieves capture efficiencies that correspond to enrichments of 10-80 times the amount of CTCs in a 5-mL blood draw, and to 500-5,000 times the enrichments achieved by the commercially available Gilupi CellCollector. PMID- 30524878 TI - Impact of PD-L1 expression, driver mutations and clinical characteristics on survival after anti-PD-1/PD-L1 immunotherapy versus chemotherapy in non-small cell lung cancer: A meta-analysis of randomized trials. AB - Purpose: To investigate the impact of programmed death-ligand 1 (PD-L1) expression, oncogenic mutations, and clinical characteristics on survival after treatment with anti-PD-1/PD-L1 antibodies versus chemotherapy in non-small cell lung cancer (NSCLC). Patients and Methods: This meta-analysis included randomized trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy. Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) for the trial population and prespecified subgroups were extracted. We calculated pooled estimates of treatment efficacy using the fixed-effects or random-effects model when appropriate. All statistical tests were two sided. Results: Seven trials involving 3871 patients were included. The pooled results showed that anti-PD 1/PD-L1 immunotherapy significantly prolonged OS (HR: 0.73; 95% CI, 0.63 to 0.84) and PFS (HR: 0.84; 95% CI, 0.71 to 0.99) compared to chemotherapy. OS benefit from immunotherapy were observed in all PD-L1 expression subgroups (negative: HR, 0.79; 95% CI, 0.67 to 0.93; weak-positive: HR, 0.80; 95% CI, 0.67 to 0.95; strong positive: HR, 0.61; 95% CI, 0.47 to 0.78). Strong-positive PD-L1 expression showed a trend towards more benefit compared to weak-positive PD-L1 expression (interaction P = 0.08). KRAS mutant (HR: 0.60; 95% CI, 0.39 to 0.93), EGFR wild type (HR: 0.73; 95% CI, 0.61 to 0.87) and smoker (HR: 0.70; 95% CI, 0.60 to 0.83) subgroups achieved significant OS benefit from immunotherapy compared to corresponding subgroups. Survival benefit to immunotherapy was not significantly associated with histology, CNS metastases, age, gender and performance status. Conclusion: This study confirmed that treatment with anti-PD-1/PD-L1 improves overall survival compared with chemotherapy. Benefit was seen, regardless of PD L1 expression levels; however, PD-L1 strong-positive patients trended to have greatest benefit. Patients with a KRAS mutant or EGFR wild-type tumor have improved survival benefit from immunotherapy compared with KRAS wild-type or EGFR mutant NSCLC, respectively. PMID- 30524877 TI - TNFR2/BIRC3-TRAF1 signaling pathway as a novel NK cell immune checkpoint in cancer. AB - Natural Killer (NK) cells control metastatic dissemination of murine tumors and are an important prognostic factor in several human malignancies. However, tumor cells hijack many of the NK cell functional features compromising their tumoricidal activity. Here, we show a deleterious role of the TNFalpha/TNFR2/BIRC3/TRAF1 signaling cascade in NK cells from the tumor microenvironment (TME). TNFalpha induces BIRC3/cIAP2 transcripts and reduces NKp46/NCR1 transcription and surface expression on NK cells, promoting metastases dissemination in mice and poor prognosis in GIST patients. NKp30 engagement, by promoting the release of TNFalpha, also contributes to BIRC3 upregulation, and more so in patients expressing predominantly NKp30C isoforms. These findings reveal that in the absence of IL-12 or a Th1-geared TME, TNFalpha can be considered as a negative regulatory cytokine for innate effectors. PMID- 30524879 TI - PD-L1 expression with immune-infiltrate evaluation and outcome prediction in melanoma patients treated with ipilimumab. AB - Background: Tumor microenvironment may have a key role in providing immunological markers that can help predict clinical response to treatment with checkpoint inhibitors. We investigated whether the baseline expression of PD-L1 in advanced melanoma patients treated with ipilimumab may correlate with clinical outcome. Methods: PD-L1 expression was assessed in 114 patients with advanced melanoma treated with ipilimumab and, in a cohort of 77 patients, a comprehensive assessment using multispectral imaging to assess the presence and distribution of CD3+, CD8+, CD163+, FOXP3+ and PD-L1+ cells inside and at periphery of the tumor was performed. Results: PD-L1 status alone was not a predictive biomarker for response or survival. There was an association between clinical benefit from ipilimumab therapy with the coexistence of low densities of CD8+ and high densities of CD163+ PD-L1+ cells at the periphery of the tumor. Conclusions: To explain the association of this peculiar microenvironment with clinical benefit from ipilimumab, we proposed a model where baseline CD8 cells levels are low due to inhibitory effect of Tregs and to pro-tumor activity of TAM M2 (CD163+ PD-L1+ cells). Ipilimumab treatment causes a decrease of Treg cells, mediated by ADCC from macrophages, with a concomitant change in TAM polarization that switches from M2 to M1 with a subsequent attraction of CD8 cells and the increase of antitumor response. PMID- 30524880 TI - A single centre phase II trial to assess the immunological activity of TroVax(r) plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma - the SKOPOS trial. AB - Vaccines in combination with chemotherapy have been shown to be safe in different tumor types. We investigated the immunological activity of the TroVax(r) vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM). In this first line, open-label, single-arm, phase 2 study, patients with locally advanced or metastatic MPM were enrolled. Eligible patients received up to 9 intramuscular injections of TroVax(r), starting two weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks. The primary endpoint was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of six follow-up time points), with a target response rate of 64%. Of 27 patients, enrolled between Feb 2013-Dec 2014, 23 (85%) received at least three doses of TroVax(r) and one cycle of chemotherapy and were included in the per-protocol analysis (PPA). 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4. Thus, the study reached its primary endpoint. Disease control was observed in 87% of patients (partial response: 17.4%, stable disease: 69.6%). The median progression-free survival was 6.8 months and median overall survival 10.9 months. Treatment-related adverse events were comparable to those observed in patients with chemotherapy alone. Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (>20 months in n = 8/23, 34.8%) survival. In this phase 2 trial, TroVax(r) with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase 3 setting. PMID- 30524881 TI - PD-L2 amplification and durable disease stabilization in patient with urothelial carcinoma receiving pembrolizumab. AB - We report the immunological profile of a patient with upper-tract urothelial carcinoma experiencing stable disease on pembrolizumab for 20 months. The tumor exhibited extensive infiltration by CD8+ cytotoxic T lymphocytes, low-to-moderate mutational burden, no PD-L1 staining by commercially available immunohistochemical assays, but amplification of CD274 (coding for PD-L1) and/or PDCD1LG2 (encoding PD-L2) by fluorescence in situ hybridization. RNA-seq revealed multiple biomarkers of an ongoing immune response and compensatory immune evasion, including moderate PD-L1 levels coupled with robust PD-L2 expression. Pending validation in additional patients, these findings suggest that PD-L2 expression levels may constitute a biomarker of response to immune checkpoint blockade in urothelial carcinoma. PMID- 30524882 TI - Antigen-specificity and DTIC before peptide-vaccination differently shape immune checkpoint expression pattern, anti-tumor functionality and TCR repertoire in melanoma patients. AB - We have recently described that DNA-damage inducing drug DTIC, administered before peptide (Melan-A and gp100)-vaccination, improves anti-tumor CD8+ Melan-A specific T-cell functionality, enlarges the Melan-A+ TCR repertoire and impacts the overall survival of melanoma patients. To identify whether the two Ags employed in the vaccination differently shape the anti-tumor response, herein we have carried out a detailed analysis of phenotype, anti-tumor functionality and TCR repertoire in treatment-driven gp100-specific CD8+ T cells, in the same patients previously analyzed for Melan-A. We found that T-cell clones isolated from patients treated with vaccination alone possessed an Early/intermediate differentiated phenotype, whereas T cells isolated after DTIC plus vaccination were late-differentiated. Sequencing analysis of the TCRBV chains of 29 treatment driven gp100-specific CD8+ T-cell clones revealed an oligoclonal TCR repertoire irrespective of the treatment schedule. The high anti-tumor activity observed in T cells isolated after chemo-immunotherapy was associated with low PD-1 expression. Differently, T-cell clones isolated after peptide-vaccination alone expressed a high level of PD-1, along with LAG-3 and TIM-3, and were neither tumor-reactive nor polyfunctional. Blockade of PD-1 reversed gp100-specific CD8+ T-cell dysfunctionality, confirming the direct role of this co-inhibitory molecule in suppressing anti-tumor activity, differently from what we have previously observed for Melan-A+CD8+ T cells, expressing PD-1 but highly functional. These findings indicate that the functional advantage induced by combined chemo-immunotherapy is determined by the tumor antigen nature, T-cell immune-checkpoints phenotype, TCR repertoire diversity and anti-tumor T-cell quality and highlights the importance of integrating these parameters to develop effective immunotherapeutic strategies. PMID- 30524883 TI - Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer. AB - The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy. Here we tested whether a tumor-derived antigen source called DRibbles(r), which contain a pool of defective ribosomal products (DRiPs), long lived and short-lived proteins (SLiPs) and danger-associated molecular patterns (DAMPs), can be used to identify tumor-associated antigen (TAA)-specific responses in patients before or after immunotherapy treatment. Protein content, gene expression and non-synonymous - single nucleotide variants (ns-SNVs) present in UbiLT3 DRibbles were compared with prostate adenocarcinomas and the prostate GVAX vaccine cell lines (PC3/LNCaP). UbiLT3 DRibbles were found to share proteins, as well as match tumor sequences for ns-SNVs with prostate adenocarcinomas and with the cell lines PC3 and LNCaP. UbiLT3 DRibbles were used to monitor anti-tumor responses in patients vaccinated with allogeneic prostate GVAX. UbiLT3-DRibble-reactive CD8+ T-cell responses were detected in post-vaccine PBMC of 6/12 patients (range 0.85-22% of CD8+ cells) after 1 week in vitro stimulation (p = 0.007 vs. pre-vaccine). In conclusion, a cancer-derived autophagosome-enriched preparation, packaging over 100 proteins over-expressed in prostate cancer into microvesicles containing DAMPs, could be used to identify CD8+ T cells in peripheral blood from patients after prostate GVAX vaccination and may represent a general method to monitor anti-cancer T cell responses following immunotherapy. PMID- 30524884 TI - Low-dose cyclophosphamide depletes circulating naive and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy. AB - Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3hi and naive CD45RA+ Tregs were effectively decreased in all patients. In addition, a shift from naive and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment. PMID- 30524885 TI - Profiling targetable immune checkpoints in osteosarcoma. AB - Osteosarcomas are aggressive bone tumors for which therapeutic advances have not improved over several decades. Unlike most pediatric tumors, the osteosarcoma genome is remarkably unstable, characterized by numerous copy number alterations and chromosomal structural aberrations. In this study, we asked if the targetable immune checkpoints CD274 (PD-L1), PDCD1LG2 (PD-L2), CD276 (B7-H3) and IDO1 are impacted by copy number alterations in osteosarcoma. Of the 215 osteosarcoma samples investigated, PD-L1/PD-L2, B7-H3 and IDO1 were independently gained at frequencies of approximately 8-9%, with a cumulative frequency of approximately 24%. RNA sequencing data from two independent cohorts revealed that B7-H3 is the most highly expressed immune checkpoint gene among the four investigated. We also show that IDO1 is preferentially expressed in pediatric solid tumors and that increased protein expression of B7-H3 and IDO1 are significantly associated with inferior survival in patient samples. Using human osteosarcoma cell lines, we demonstrate that IDO1 is gained in MG63 and G292 cells and that the IDO1 inhibitor, epacadostat, inhibits the enzymatic activity of IDO1 in a dose dependent manner in these cells. Together, these data reveal the genomic and transcriptomic profiles of PD-L1, PD-L2, B7-H3 and IDO1 in osteosarcoma and identifies a potential context for targeted immunotherapeutic intervention in a subset of patients. PMID- 30524886 TI - An observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer. AB - After a case report of profound clinical response in a melanoma patient following treatment with an immune checkpoint inhibitor (ICI) and RANK-ligand inhibitor denosumab, we identified similar patients from electronic health records (EHR) and described patient characteristics and outcomes. This 2017 observational study used Flatiron Health's EHR database from ~255 US cancer clinics. Included were advanced melanoma or non-small-cell lung cancer (NSCLC) patients who received denosumab within 30 days of CTLA-4 (ipilimumab) or PD1 (pembrolizumab, nivolumab) inhibitors start with a minimum of 6 months of follow up. Real-world tumor response (rwTR) was analyzed for scans available up to 30 days after concomitant therapy. Preclinical experiments evaluated sequencing of ICI, denosumab vs monotherapy or control. Melanoma (n = 66) patients received concomitant denosumab/ICI for a mean 4.0 months, 3.1 months for NSCLC (n = 241). Two-thirds of patients had best rwTR evaluable (complete [CR], partial response [PR], stable disease [SD], or disease progression [PD]). Longer mean duration of concomitant exposure was associated with overall response rate (ORR; CR+PR) in melanoma (p = 0.0172), NSCLC (p < .0001), and combined cohorts (p < .0001). The disease control rate (ORR plus SD) was 56% amongst melanoma patients and 58% amongst NSCLC patients. Longer concomitant therapy was associated with increased overall survival, primarily in NSCLC (p < .0001). Preclinical data suggest that ICI initiated before or at same time as denosumab was optimal. Results provide proof of-concept that rwTR is associated with concomitant denosumab/ICI. Crude survival analyses supported the association of concomitant therapy and improved outcomes outside of clinical trials and warrant comparative study. PMID- 30524887 TI - Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation. AB - Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3 dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNgamma released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF2alpha) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNgamma and/or GCN2-peIF2alpha-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion. PMID- 30524888 TI - Bovine herpesvirus 4-based vector delivering the full length xCT DNA efficiently protects mice from mammary cancer metastases by targeting cancer stem cells. AB - Despite marked advancements in its treatment, breast cancer is still the second leading cause of cancer death in women, due to relapses and distal metastases. Breast cancer stem cells (CSCs), are a cellular reservoir for recurrence, metastatic evolution and disease progression, making the development of novel therapeutics that target CSCs, and thereby inhibit metastases, an urgent need. We have previously demonstrated that the cystine-glutamate antiporter xCT (SLC7A11), a protein that was shown to be overexpressed in mammary CSCs and that plays a key role in the maintenance of their redox balance, self-renewal and resistance to chemotherapy, is a potential target for mammary cancer immunotherapy. This paper reports on the development of an anti-xCT viral vaccine that is based on the bovine herpesvirus 4 (BoHV-4) vector, which we have previously showed to be a safe vaccine that can transduce cells in vivo and confer immunogenicity to tumor antigens. We show that the vaccination of BALB/c mice with BoHV-4 expressing xCT (BoHV-4-mxCT), impaired lung metastases induced by syngeneic mammary CSCs both in preventive and therapeutic settings. Vaccination induced T lymphocyte activation and the production of anti-xCT antibodies that can mediate antibody-dependent cell cytotoxicity (ADCC), and directly impair CSC phenotype, self-renewal and redox balance. Our findings pave the way for the potential future use of BoHV-4 based vector targeting xCT in metastatic breast cancer treatment. PMID- 30524889 TI - Immunological and classical subtypes of oral premalignant lesions. AB - Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality and may develop from oral premalignant lesions (OPL). An improved molecular classification of OPL may help refining prevention strategies. We identified two main OPL gene-expression subtypes, named immunological and classical, in 86 OPL (discovery dataset). A gene expression-based score was then developed to classify OPL samples from three independent datasets, including 17 (GSE30784),13 (GSE10174) and 15 (GSE85195) OPLs, into either one of the two gene expression subtypes. Using the single sample gene set enrichment analysis, enrichment scores for immune-related pathways were different between the two OPL subtypes. In OPL from the discovery set, loss of heterozygosities (LOH) at 3p14, 17p13, TP53, 9p21 and 8p22 and miRNA gene expression profiles were analyzed. Deconvolution of the immune infiltrate was performed using the Microenvironment Cell Populations-counter tool. A multivariate analysis revealed that decreased miRNA-142-5p expression (P = 0.0484) and lower T-cell, monocytic and myeloid dendritic cells (MDC) immune infiltration (T-cells, P = 0.0196; CD8 T cells, P = 0.0129; MDC, P = 0.0481; and monocytes, P = 0.0212) were associated with oral cancer development in the immunological subtype only. In contrast, LOH at 3p14 (P = 0.0241), 17p13 (P = 0.0348) and TP53 (P = 0.004) were associated with oral cancer development in the classical subtype only. In conclusion, we identified 2 subtypes of OPLs, namely immune and classical, which may benefit from different and specific personalized prevention interventions. PMID- 30524890 TI - MDR1 in immunity: friend or foe? AB - MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options. PMID- 30524891 TI - Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. AB - Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade. PMID- 30524892 TI - Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses. AB - Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28-35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs. PMID- 30524893 TI - Immune T cells can transfer and boost anti-breast cancer immunity. AB - This proof-of-concept study investigates the immune effects in metastatic breast cancer (MBC) patients after "vaccination" with activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2 BATs) followed by immune consolidation with immune ATC "boost" after high dose chemotherapy (HDC) and autologous stem cell transplant (SCT). Approximately 2 weeks after completion of vaccination portion of the study, immune T cells were obtained by leukopheresis, activated and expanded ex vivo and re-infused after HDC and SCT to test the hypothesis that transfer of immune unarmed ATC would accelerate reconstitution of anti-tumor activity after SCT. Eight metastatic breast cancer (MBC) patients received 8 infusions of HER2 BATs, low dose IL-2, and GM-CSF in the first part of the protocol to induce adaptive cellular and humoral responses. In the "boost" portion of the protocol, 6 of 8 patients received multiple infusions of unarmed ATC post SCT. There were no dose-limiting toxicities or delays in engraftment. Four of 6 patients tested for the immune correlative studies exhibited increases in anti-breast cancer (BrCa) cytotoxicity, antigen specific IFN-gamma Elispots, anti-BrCa antibodies and increased IL-12 and Th1 serum cytokine levels after HER2 BATs infusions. Anti-BrCa tumor responses were seen as early as 2 weeks after SCT and persisted up to 2 years post-SCT. One out of 6 patients' rapidly progressed and showed poor immune responses and high Th2 cytokine levels. There was a significant correlation (p < 0.002) between time to progression (TTP) and anti BrCa cytotoxicity by immune T cells. This is the first study to show that adoptive transfer of immune T cells after SCT accelerates reconstitution of anti BrCa specific immunity and correlates with delay TTP. PMID- 30524894 TI - IL-21 receptor signaling is essential for control of hepatocellular carcinoma growth and immunological memory for tumor challenge. AB - Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer. IL-21 regulates both innate and adaptive immune responses and has key roles in antitumor and antiviral responses. However, the role of IL-21 in HCC development is poorly defined. In the current study, we explored the role of IL-21R signaling in HCC growth by using IL-21R knockout mice and HCC mouse models. We discovered that IL-21R signaling deficiency promoted HCC growth in tumor-bearing mice. We showed that IL-21R deletion reduced T cells infiltration and activation as well as their function but increased the accumulation of myeloid-derived suppressor cells in tumor tissues to enhance HCC growth. Furthermore, loss of IL-21R signaling in tumor-bearing mice resulted in an imbalance of the systemic immune system characterized by decreased antitumor immune cells and increased immunosuppressive cells in the spleen and lymph nodes. In addition, we revealed that IL-21R signaling is critical for the expansion of antitumor immune cells in the memory immune response to tumor rechallenge. Finally, we showed that the transcriptional levels of IL-21 in the peritumoral region and IL-21R within the tumor are associated with survival and recurrence of HCC patients. In conclusion, our study demonstrates that IL-21R signaling is essential for controlling the development of HCC and immunological memory response to tumor challenge. PMID- 30524895 TI - Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1. AB - Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2-actin-LFA-1 axis is an effective strategy to potentiate the adoptive T cell immunotherapy. PMID- 30524896 TI - Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models. AB - Immune checkpoint blockade (ICB) is currently evaluated in patients with glioblastoma (GBM), based on encouraging clinical data in other cancers, and results from studies with the methylcholanthrene-induced GL261 mouse glioma. In this paper, we describe a novel model faithfully recapitulating some key human GBM characteristics, including low mutational load, a factor reported as a prognostic indicator of ICB response. Consistent with this observation, SB28 is completely resistant to ICB, contrasting with treatment sensitivity of the more highly mutated GL261. Moreover, SB28 shows features of a poorly immunogenic tumor, with low MHC-I expression and modest CD8+ T-cell infiltration, suggesting that it may present similar challenges for immunotherapy as human GBM. Based on these key features for immune reactivity, SB28 may represent a treatment resistant malignancy likely to mirror responses of many human tumors. We therefore propose that SB28 is a particularly suitable model for optimization of GBM immunotherapy. PMID- 30524897 TI - Induction of liver-specific intrahepatic myeloid cells aggregation expands CD8 T cell and inhibits growth of murine hepatoma. AB - Toll-Like Receptor 9 (TLR9) stimulation selectively triggers the formation of a cell cluster termed intrahepatic myeloid aggregation for T cell expansion" (iMATE) in a mouse chronic viral hepatitis model. iMATE expands cytotoxic T cells and controls viral hepatitis infection. The liver-specific immune response prompted this investigation of whether the effect could control tumor growth in the murine hepatic tumor model. Murine hepatic BNL cells were used to establish an orthotropic liver tumor model. We found that intravenous infusion of TLR 9 agonist, CpG oligodeoxynucleotide (ODN) induced iMATE formation in non-tumor parts of liver and suppressed the murine BNL tumor growth. The ratio of intra tumor CD8+ T cells have increased after CpG ODN. These cells expressed higher levels of effector and checkpoint molecules, and produce more Th1 cytokine upon ex vivo stimulation. The CD11b+Ly6ChiLy6G - subset of CD11b+ myeloid cells in the tumor microenvironment has increased. Both CD11b+Ly6ChiLy6G - and CD11b+Ly6CloLy6G+ subsets expressed higher level of interferon-gamma post CpG ODN treatment, although still presented a suppressive phenotype. Their suppressive ability was decreased, instead, the targeted CD8+ T cell proliferation was promoted at a higher dose of CD11b+Ly6ChiLy6G- cells. The phenomenon was further proven in DEN induced liver tumor model. In conclusion, systemic CpG ODN treatment induced iMATE formation that expanded effector CD8+ T cells to control tumor growth in the mouse hepatic tumor model. This novel strategy provides a new rationale for liver-specific tumor immunotherapy. PMID- 30524898 TI - Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma. AB - Sphingosine kinase 1 (SphK1) is the major source of the bioactive lipid and GPCR agonist sphingosine 1-phosphate (S1P). Although alterations in SphK1 expression and activity have been detected in various human malignancies, its potential molecular mechanisms in the development and sunitinib resistance of clear cell renal cell carcinoma (ccRCC) remain obscure. In this study, we aim to evaluate the clinical significance of SphK1 and to explore the therapeutic implications of combination approach for ccRCC patients. We identify upregulation of SphK1 significantly associated with poor prognosis of large cohort of ccRCC patients, which contributing to cell proliferation, colony formation, migration and survival. Suppression of SphK1 activity either by shRNA or pharmacologic inhibitior FTY720 suppresses cell growth in vitro and in vivo. A comprehensive phosphoprotein antibody array reveals that SphK1 overexpression promoted RCC progression by regulating the Akt/mTOR pathway. Moreover, FTY720 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that increased SphK1 kinase activation defines an important mechanism for sunitinib resistance, therefore contributes to tumour development and represents therapeutic targets for ccRCC. PMID- 30524900 TI - Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study. AB - Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods:Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results:Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1. PMID- 30524899 TI - CD27 stimulation unveils the efficacy of linked class I/II peptide vaccines in poorly immunogenic tumors by orchestrating a coordinated CD4/CD8 T cell response. AB - Despite their promise, tumor-specific peptide vaccines have limited efficacy. CD27 is a costimulatory molecule expressed on CD4+ and CD8+ T cells that is important in immune activation. Here we determine if a novel CD27 agonist antibody (alphahCD27) can enhance the antitumor T cell response and efficacy of peptide vaccines. We evaluated the effects of alphahCD27 on the immunogenicity and antitumor efficacy of whole protein, class I-restricted, and class II restricted peptide vaccines using a transgenic mouse expressing human CD27. We found that alphahCD27 preferentially enhances the CD8+ T cell response in the setting of vaccines comprised of linked class I and II ovalbumin epitopes (SIINFEKL and TEWTSSNVMEERKIKV, respectively) compared to a peptide vaccine comprised solely of SIINFEKL, resulting in the antitumor efficacy of adjuvant alphahCD27 against intracranial B16.OVA tumors when combined with vaccines containing linked class I/II ovalbumin epitopes. Indeed, we demonstrate that this efficacy is both CD8- and CD4-dependent and alphahCD27 activity on ovalbumin specific CD4+ T cells is necessary for its adjuvant effect. Importantly for clinical translation, a linked universal CD4+ helper epitope (tetanus P30) was sufficient to instill the efficacy of SIINFEKL peptide combined with alphahCD27, eliminating the need for a tumor-specific class II-restricted peptide. This approach unveiled the efficacy of a class I-restricted peptide vaccine derived from the tumor-associated Trp2 antigen in mice bearing intracranial B16 tumors. CD27 agonist antibodies combined with peptide vaccines containing linked tumor specific CD8+ epitopes and tumor-specific or universal CD4+ epitopes enhance the efficacy of active cancer immunotherapy. PMID- 30524901 TI - Trial Watch: Oncolytic viro-immunotherapy of hematologic and solid tumors. AB - Oncolytic viruses selectively target and kill cancer cells in an immunogenic fashion, thus supporting the establishment of therapeutically relevant tumor specific immune responses. In 2015, the US Food and Drug Administration (FDA) approved the oncolytic herpes simplex virus T-VEC for use in advanced melanoma patients. Since then, a plethora of trials has been initiated to assess the safety and efficacy of multiple oncolytic viruses in patients affected with various malignancies. Here, we summarize recent preclinical and clinical progress in the field of oncolytic virotherapy. PMID- 30524902 TI - Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma. AB - Pancreatic adenocarcinoma (PAC) has a poor prognosis. One treatment approach, investigated here, is to reinforce antitumor immunity. Dendritic cells (DCs) are essential for the development and regulation of adaptive host immune responses against tumors. A major role for DCs may be as innate tumoricidal effector cells. We explored the efficacy of vaccination with immature (i)DCs, after selecting optimal conditions for generating immunostimulatory iDCs. We used two models, C57BL/6Jrj mice with ectopic tumors induced by the PAC cell line, Panc02, and genetically engineered (KIC) mice developing PAC. Therapeutic iDC-vaccination resulted in a significant reduction in tumor growth in C57BL/6Jrj mice and prolonged survival in KIC mice. Prophylactic iDC-vaccination prevented subcutaneous tumor development. These protective effects were long-lasting in Panc02-induced tumor development, but not in melanoma. iDC-vaccination impacted the immune status of the hosts by greatly increasing the percentage of CD8+ T cells, and natural killer (NK)1.1+ cells, that express granzyme B associated with Lamp-1 and IFN-gamma. Efficacy of iDC-vaccination was CD8+ T-cell-dependent but NK1.1+ cell-independent. We demonstrated the ability of DCs to produce peroxynitrites and to kill tumor cells; this killing activity involved peroxynitrites. Altogether, these findings make killer DCs the pivotal actors in the beneficial clinical outcome that accompanies antitumor immune responses. We asked whether efficacy can be improved by combining DC-vaccination with the FOLFIRINOX regimen. Combined treatment significantly increased the lifespan of KIC mice with PAC. Prolonged treatment with FOLFIRINOX clearly augmented this beneficial effect. Combining iDC-vaccination with FOLFIRINOX may therefore represent a promising therapeutic option for patients with PAC. PMID- 30524903 TI - Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma. AB - T follicular helper cells (Tfh) play crucial roles in the development of humoral immunity. In the B cell-rich germinal center of lymphoid organs, they select for high-affinity B cells and aid in their maturation. While Tfh have known roles in B cell malignancies and have prognostic value in some epithelial cancers, their role in lung tumour initiation and development is unknown. Through immune cell deconvolution, we observed significantly increased Tfh in tumours from two independent cohorts of lung adenocarcinomas and found that this upregulation occurs early in tumour development. A subset of tumours were stained for T and B cells using multicolour immunohistochemistry, which revealed the presence of tumour-adjacent tertiary lymphoid organs in 17/20 cases each with an average of 16 Tfh observed in the germinal center. Importantly, Tfh levels were correlated with tumour mutational load and immunogenic cancer testis antigens, suggesting their involvement in mounting an active immune response against tumour neoantigens. PMID- 30524904 TI - PRAME and HLA Class I expression patterns make synovial sarcoma a suitable target for PRAME specific T-cell receptor gene therapy. AB - Synovial sarcoma expresses multiple cancer testis antigens that could potentially be targeted by T-cell receptor (TCR) gene therapy. In this study we investigated whether PRAME-TCR-gene therapy could be an effective treatment for synovial sarcoma by investigating the potential of PRAME-specific T-cells to recognize sarcoma cells and by evaluating the expression patterns of PRAME and HLA class I (HLA-I) in synovial sarcoma tumor samples. All PRAME expressing sarcoma cell lines, including 2 primary synovial sarcoma cell cultures (passage < 3), were efficiently recognized by PRAME-specific T-cells. mRNA FISH demonstrated that PRAME was expressed in all synovial sarcoma samples, mostly in an homogeneous pattern. Immunohistochemistry demonstrated low HLA-I baseline expression in synovial sarcoma, but its expression was elevated in specific areas of the tumors, especially in biphasic components of biphasic synovial sarcoma. In 5/11 biphasic synovial sarcoma patients and in 1/17 monophasic synovial sarcoma patients, elevated HLA-I on tumor cells was correlated with infiltration of T cells in these specific areas. In conclusion, low-baseline expression of HLA-I in synovial sarcoma is elevated in biphasic areas and in areas with densely infiltrating T-cells, which, in combination with homogeneous and high PRAME expression, makes synovial sarcoma potentially a suitable candidate for PRAME specific TCR-gene therapy. PMID- 30524906 TI - miR-17-5p-CXCL14 axis related transcriptome profile and clinical outcome in diffuse gliomas. AB - GBM tissues are comprised of not only tumor cells but also tumor-associated nontumor cells, such as stromal cells and immune cells, which dilute the purity of glioma cells and function in glioma biology. However, the roles of miRNAs in modulating glioma purity are not clarified. In total, 838 glioma samples with transcriptome data, including 537 RNAseq data from TCGA project and 301 microarray data from Chinese Glioma Genome Atlas (CGGA project), were recruited into our investigation. Tumor purity, molecular subtypes and IDH status were also available. R language was employed as the main tool for statistical analysis and graphical work. Screening miRNA profiling and paired TCGA samples' transcriptome data demonstrates that miR-17-5p expression harbors the most significant positive correlation with glioma purity among all miRNAs. CXCL14 shows robust negative correlation with miR-17-5p expression in TCGA and CGGA dataset. miR-17-5p directly targets CXCL14 and functions as a tumor-suppressor of GBM. CXCL14 showed lower expression in proneural subtype and may contribute as a potential marker for proneural subtype in glioma. Genes markedly correlated with CXCL14 are involved in essential functions associated with anti-tumor immune process. CXCL14 has a strong correlation with immune(T cells, Monocytic lineage and Neutrophils) and Fibroblasts within glioma environment. miR-17-5p and CXCL14 exhibited predictive values for high-grade glioma(HGG) patients: Higher miR-17-5p indicated significantly longer survival while lower CXCL14 indicated longer survival. Our results highlight the importance of the miR-17-5p-CXCL14 axis in regulating key steps of anti-tumor immune process and may serve as potential targets of immune treatments for gliomas. PMID- 30524905 TI - Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival. AB - To better understand the expression pattern of programmed death-ligand 1 (PD-L1) expression in different breast cancer types, we characterized PD-L1 expression in tumor and tumor-infiltrating immune cells, in relation to mutation rate, BRCA1 like status and survival. We analyzed 410 primary treatment-naive breast tumors comprising 162 estrogen receptor-positive (ER+) and HER2-, 101 HER2+ and 147 triple-negative (TN) cancers. Pathologists quantified tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor cells and TILs using whole slides and tissue microarray. Mutation rate was assessed by DNA sequencing, BRCA1 like status using multiplex ligation-dependent probe amplification, and immune landscape by multiplex image analyses of CD4, CD68, CD8, FOXP3, cytokeratin, and PD-L1. Half of PD-L1 scores evaluated by tissue microarray were false negatives compared to whole slide evaluations. We observed at least 1% of PD-L1-positive (PD-L1+) cells in 53.1% of ER+HER2-, 73.3% of HER2+, and 84.4% of TN tumors. PD L1 expression was higher in ductal compared to lobular carcinomas, also within ER+HER2- tumors (p = 0.04). High PD-L1+ TILs score (> 50%) was independently associated with better outcome in TN tumors (HR = 0.27; 95%CI = 0.10-0.69). Within TN tumors, PD-L1 and TIL scores showed a modest but significant positive association with the number of silent mutations, but no association with BRCA1 like status. Multiplex image analyses indicated that PD-L1 is expressed on multiple immune cells (CD68+ macrophages, CD4+, FOXP3+, and CD8+ T cells) in the breast tumor microenvironment, independent of the PD-L1 status of the tumor cells. We found no evidence that levels of PD-L1+ TILs in TN breast cancer are driven by high mutation rate or BRCA1-like status. PMID- 30524907 TI - Trial watch: Peptide-based vaccines in anticancer therapy. AB - Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor associated antigen; TNA: tumor neoantigen. PMID- 30524908 TI - Trial Watch: Toll-like receptor agonists in cancer immunotherapy. AB - Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy. PMID- 30524909 TI - Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden. AB - Harnessing the immune system by checkpoint blockade has greatly expanded the therapeutic options for advanced cancer. Since the efficacy of immunotherapies is influenced by the molecular make-up of the tumor and its crosstalk with the immune system, comprehensive analysis of genetic and immunologic tumor characteristics is essential to gain insight into mechanisms of therapy response and resistance. We investigated the association of immune cell contexture and tumor genetics including tumor mutational burden (TMB), copy number alteration (CNA) load, mutant allele heterogeneity (MATH) and specific mutational signatures (MutSigs) using TCGA data of 5722 tumor samples from 21 cancer types. Among all genetic variables, MutSigs associated with DNA repair deficiency and AID/APOBEC gene activity showed the strongest positive correlations with immune parameters. For smoking-related and UV-light-exposure associated MutSigs a few positive correlations were identified, while MutSig 1 (clock-like process) correlated non significantly or negatively with the major immune parameters in most cancer types. High TMB was associated with high immune cell infiltrates in some but not all cancer types, in contrast, high CNA load and high MATH were mostly associated with low immune cell infiltrates. While a bi- or multimodal distribution of TMB was observed in colorectal, stomach and endometrial cancer where its levels were associated with POLE/POLD1 mutations and MSI status, TMB was unimodal distributed in the most other cancer types including NSCLC and melanoma. In summary, this study uncovered specific genetic-immunology associations in major cancer types and suggests that mutational signatures should be further investigated as interesting candidates for response prediction beyond TMB. PMID- 30524910 TI - Potent immunosuppressive effects of the oncometabolite R-2-hydroxyglutarate. AB - Somatic gain-of-function mutations in isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) or isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) are bona fide oncogenic drivers of acute myeloid leukemia and glioma because the neomorphic enzymes catalyze the synthesis of R-2-hydroxylutarate (R-2-HG), an oncometabolite with robust epigenetic effects. Recent data indicate that R-2-HG released by malignant cells can accumulate in the extracellular space and be taken up by T lymphocytes, ultimately compromising their capacity to mediate anticancer immune responses. Thus, R-2-HG drives oncogenesis and tumor progression not only as a cancer cell-autonomous epigenetic modifier, but also as an immunosuppressive metabolite. Chemical inhibitors of mutant IDH1 and IDH2, which currently are under clinical evaluation, may therefore mediate dual anticancer effects by targeting cancer cells and, at the same time, relieving R-2 HG-mediated immunosuppression. PMID- 30524911 TI - Immunology of Wound Healing. AB - Purpose of Review: Chronic wounds are a tremendous burden on the healthcare system and lead to significant patient morbidity and mortality. Normal cutaneous wound healing occurs through an intricate and delicate interplay between the immune system, keratinocytes, and dermal cells. Each cell type contributes signals that drive the normal phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This paper reviews how various immunological cell types and signaling molecules influence the way wounds develop, persist, and heal. Recent Findings: Concurrent with the achievement of hemostasis, neutrophils are the first cells to migrate to the wound bed, brought in by pro-inflammatory signals including IL-8. Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state, where angiogenesis occurs and granulation tissue is laid down. Myofibroblasts, activated through contractile forces and signaling molecules, then drive remodeling, where granulation tissue becomes scar. Unchecked inflammation at this stage can result in abnormal scar formation. Summary: Although the derangement of immune signals at any stage can result in impaired wound healing, recent research has shown that the key transition point lies between the inflammatory and the proliferative phases. This review summarizes the events that facilitate this transition and discusses how this process can be disrupted, leading to chronic, non-healing wounds. PMID- 30524912 TI - Mechanisms of Action of Instillation and Dwell Negative Pressure Wound Therapy with Case Reports of Clinical Applications. AB - Negative pressure wound therapy (NPWT) has revolutionized the care of complex wounds since 1997. The addition of instillation (NPWTi-d) adds several potential benefits and challenges to clinicians dealing with complex wounds in a hospital setting. We surveyed the literature regarding the mechanism of action of these devices and reviewed our clinical experience to date. Potential mechanisms of action include the removal of microorganisms from the wound surface, dilution of cytotoxic molecules, upregulation of angiogenesis pathways, and maintenance of a moist wound environment. As we have extended our use of these devices to more complex wounds, we have taken advantage of and observed potential mechanisms of action, including facilitated removal of microorganisms, dilution of inflammatory and cytotoxic macromolecules, additional wound hydration, and enhanced angiogenesis through an intermittent application of NPWT. We have also observed complications, including bleeding, loss of a seal along the wound, and pain. NPWTi-d provides additional options for clinicians caring for complex wounds with favorable responses in wounds with significant contamination and those with poor inherent vascularity. Further studies to clarify the mechanisms of action, better define the wound types that would benefit, and techniques to manage complications using this device should further advance this field. PMID- 30524913 TI - Surgical Scar Recurrence of Bone Metastases to the Femur: A Case Report. AB - We report the case of a woman who presented with breast cancer metastases to the femur causing pathologic fracture of the femoral neck requiring surgery. She received adjuvant radiotherapy to the femur at that time that did not include the surgical scar tract. Almost four years after her surgery she presented with biopsy proven skin recurrence of breast cancer on the skin overlying her incision from her femoral surgery. Further imaging confirmed significant soft-tissue disease involving the underlying surgical scar tract. This case provides important information about the possibility of surgical scar recurrence after surgery for bone metastases which could indicate the need to include the area of the surgical scar tract and the entire prosthetic material in the post-operative radiotherapy volume. PMID- 30524914 TI - A Local Sensitivity Analysis of the Trial of Continuous or Interrupted Chest Compressions during Cardiopulmonary Resuscitation: Is a Local Protocol Change Required? AB - Objective The "Trial of Continuous (CCC) or Interrupted Chest Compressions (ICC) during Cardiopulmonary Resuscitation (CPR)" compared two CPR strategies for out of-hospital cardiac arrest (OHCA). Although results were neutral, there was suggestion of benefit for ICC. However, nearly 50% of study patients had a protocol violation; regional variations may have played a role in protocol adherence and outcomes. We analyzed our British Colombia (BC) cohort to decide whether a protocol change from CCC to ICC was justified. Methods This was a post hoc analysis of BC-enrolled study patients. The primary between-group comparison was favorable neurological outcome (modified Rankin scale <= 3) using intention to-treat. Secondary analyses compared those treated per-protocol (adjusted) and the top compliant clusters (unadjusted). We classified protocol violations using a structured algorithm. We used logistic regression and computed the difference in probabilities using the marginal standardization method with bootstrapping to calculate confidence intervals. Results There were 3769 patients included, with a median age of 69 years (IQR: 56-80). There were protocol violations in 3.2% of those in the CCC group and 27% of those in the ICC group. In patients randomized to CCC or ICC, 11.2% and 10.8% (risk difference 0.42%; 95% CI -1.58, 2.41) had favorable neurological outcomes, respectively. In the per-protocol and top compliant clusters comparisons, risk differences were 0.25% (95% CI -1.70, 2.25) and 2.95% (95% CI -0.68, 6.58). Conclusion Our comparisons suggest that CCC may be the preferred strategy in our region and is likely not resulting in worse outcomes. Based on the original study and our local analysis, we found no compelling reasons to change our local strategy from CCC to ICC. PMID- 30524916 TI - A Rare Desmoglein-2 Gene Mutation in Arrhythmogenic Right Ventricular Cardiomyopathy Inciting Incessant Ventricular Fibrillation. AB - A case of a 51-year-old female with history of hypertension and a significant family history of premature coronary artery disease presented to the hospital after cardiac arrest. She successfully completed a targeted temperature management therapy with full neurologic recovery. Her hospital course was complicated by several bouts of ventricular fibrillation (VF) arrest which was rescued by timely defibrillation, high quality cardiorespiratory resuscitation, and administration of antiarrhythmic medications and inotropic agents. An automatic implantable cardioverter defibrillator (AICD) was inserted for secondary prevention of sudden cardiac death (SCD). A targeted genetic testing for idiopathic ventricular fibrillation revealed a mutation in the desmoglein-2 (DSG2) gene involved in arrhythmogenic right ventricular cardiomyopathy (ARVC). Eventually, a ventricular fibrillation radiofrequency ablation prevented recurrence of fatal arrhythmia and its associated symptoms. PMID- 30524915 TI - Outcomes of Adjuvant Therapy for Stage IA Serous Endometrial Cancer. AB - PURPOSE: Serous adenocarcinoma is a rare, aggressive histologic subtype of endometrial cancer with a high rate of recurrence and a poor prognosis. The optimal adjuvant treatment for early-stage patients is unclear. Our objective was to evaluate the outcomes of stage IA serous endometrial cancers only treated at a single institution and determine whether our current approach of chemotherapy plus vaginal brachytherapy (VBT) is sufficient. METHODS: A retrospective chart review of our institution's pathology database, including all cases of stage IA serous endometrial carcinoma from 2000-2014 was completed. Kaplan-Meier estimates were calculated for Overall and Recurrence-Free Survival (OS and RFS); hazard ratios were calculated using Cox proportional hazards modeling for independent prognostic factors. RESULTS: There were 63 patients with stage IA serous endometrial cancer of whom 79.4% were surgically staged. Percent RFS was 76.5% at five years while OS was 84.7% for the whole cohort. One of the 23 patients receiving VBT and chemotherapy recurred at the vagina versus four of 32 patients who were observed. Two patients in the observation group recurred in the pelvis while there were no first pelvic recurrences in the VBT and chemotherapy group (non- significant). Overall survival was 95% in the brachytherapy and chemotherapy group versus 79.6% in the observation group (non-significant). Post operative management included observation (n=33), combination VBT and chemotherapy (n=21), or chemotherapy with or without external beam radiation therapy (EBRT) (n=9). DISCUSSION: We report one of the largest cohorts of serous endometrial cancer stage IA patients. Our results emphasize the inferior RFS and OS of stage IA serous versus endometrioid endometrial cancer patients. While some centers continue to use EBRT for these patients, our results demonstrate low pelvic recurrence rates with radiotherapy limited to VBT, as well as the high systemic risk regardless of treatment. We advocate for combination chemotherapy and brachytherapy given the poor outcomes in these patients. PMID- 30524917 TI - (Persistent) Organic pollutants in Germany: results from a pilot study within the 2015 moss survey. AB - Background: Since 1990, every 5 years, moss sampling is conducted within the European moss monitoring programme to assess the atmospheric deposition of airborne pollutants. Besides many other countries, Germany takes regularly part at these evaluations. Within the European moss monitoring 2015, more than 400 moss samples across Germany were taken according to a harmonized methodology for the assessment heavy metal and nitrogen input. In a pilot programme, eight of these sites were chosen for additional investigations on a broad range of organic contaminants to evaluate their accumulation in moss and thereby their presence in atmospheric deposition in Germany. Target compound classes comprised polycyclic aromatic hydrocarbons (PAH), polychlorinated dibenzodioxins and -furans (PCDD/F), dioxin-like and non-dioxin-like polychlorinated biphenyls (dl-PCB, ndl-PCB), polyfluorinated alkyl substances, classical flame retardants as well as emerging chlorinated and brominated flame retardants. In total, 120 target compounds were analysed. For some analytes, comparisons of accumulation in moss and tree leave samples were possible. Results: Except for certain flame retardants, PFAS, and ndl-PCB, substances of all other compound classes could be quantified in moss samples of all sites. Concentrations were highest for PAH (40-268 ng g-1) followed by emerging flame retardants (0.5-7.7 ng g-1), polybrominated diphenyl ethers (PBDE; 0.3-3.7 ng g-1), hexabromocyclododecane (HBCD; 0.3-1.2 ng g-1), dl PCB (0.04-0.4 ng g-1) and PCDD/F (0.008-0.06 ng g-1). Conclusions: Results show the widespread atmospheric distribution and deposition of organic contaminants across Germany as well as the suitability of moss as bioaccumulation monitor for most of these compound classes. Compared to nearby tree leaf samples, accumulation potential of moss appeared to be higher for pollutants of high octanol-air partition coefficient (KOA) and octanol-water partition coefficient (KOW). PMID- 30524918 TI - Simulation of herbicide impacts on a plant community: comparing model predictions of the plant community model IBC-grass to empirical data. AB - Background: Semi-natural plant communities such as field boundaries play an important ecological role in agricultural landscapes, e.g., provision of refuge for plant and other species, food web support or habitat connectivity. To prevent undesired effects of herbicide applications on these communities and their structure, the registration and application are regulated by risk assessment schemes in many industrialized countries. Standardized individual-level greenhouse experiments are conducted on a selection of crop and wild plant species to characterize the effects of herbicide loads potentially reaching off field areas on non-target plants. Uncertainties regarding the protectiveness of such approaches to risk assessment might be addressed by assessment factors that are often under discussion. As an alternative approach, plant community models can be used to predict potential effects on plant communities of interest based on extrapolation of the individual-level effects measured in the standardized greenhouse experiments. In this study, we analyzed the reliability and adequacy of the plant community model IBC-grass (individual-based plant community model for grasslands) by comparing model predictions with empirically measured effects at the plant community level. Results: We showed that the effects predicted by the model IBC-grass were in accordance with the empirical data. Based on the species-specific dose responses (calculated from empirical effects in monocultures measured 4 weeks after application), the model was able to realistically predict short-term herbicide impacts on communities when compared to empirical data. Conclusion: The results presented in this study demonstrate an approach how the current standard greenhouse experiments-measuring herbicide impacts on individual-level-can be coupled with the model IBC-grass to estimate effects on plant community level. In this way, it can be used as a tool in ecological risk assessment. PMID- 30524919 TI - Mix-&-Read Determination of Mercury(II) at Trace Levels with Hybrid Mesoporous Silica Materials Incorporating Fluorescent Probes by a Simple Mix-&-Load Technique. AB - Invited for this month's cover picture is the group of Dr. Knut Rurack at the Department of Analytical Chemistry; Reference Materials at the Bundesanstalt fur Materialforschung und -prufung (BAM) in Berlin (Germany). The cover picture shows how differences in color and fluorescence on a test strip can be easily read out with a mobile device. Two reference spots frame the sensitive spot that indicates the presence of trace amounts of HgII below the threshold in a natural water sample. This dipstick contains a hybrid material that combines boron dipyrromethene (BODIPY) probes sterically loaded into specifically tailored mesoporous silica particles, allowing for ultrasensitive HgII detection through enhanced fluorescence in a few seconds. The applicability in real water samples and fish extracts are also studied. Read the full text of their Full Paper at https://doi.org/10.1002/open.201800111. PMID- 30524920 TI - Functionalized Quinoxaline for Chromogenic and Fluorogenic Anion Sensing. AB - This Review article provides a comprehensive analysis of recent examples reported in the field of quinoxaline-based chromogenic and fluorogenic chemosensors for inorganic anions such as fluoride, cyanide, acetate, and phosphate, as well as their utility in biomolecular science. It commences with a discussion of the various structural motifs such as quinoxaline-based oligopyrroles, polymers, sulfonamides, cationic receptors, and miscellaneous receptors bearing mixed recognition sites in the same receptor. Advances are discussed in depth, where the focus of this review is to tackle mainly solution state anion sensing utilizing quinoxaline-based receptors using different spectroscopic techniques with reference to anion selectivity by colorimetric and fluorescence response. The various examples discussed in this Review illustrate how the integration of anion binding elements with the quinoxaline chromophore could result in anion responsive chemosensors. Over the years, it has been observed that structural modification of the quinoxaline moiety with different sets of signaling unit and recognition sites has resulted in a few anion specific chemosensors. PMID- 30524921 TI - Cyclopropylmethyl Protection of Phenols: Total Synthesis of the Resveratrol Dimers Anigopreissin A and Resveratrol-Piceatannol Hybrid. AB - We demonstrate the versatile use of the cyclopropylmethyl group to protect phenols through the total synthesis of two benzofuran-based natural products, that is, anigopreissin A and the resveratrol-piceatannol hybrid. This protecting group is a good alternative to the conventional methyl group, owing to the feasibility of introduction, stability under a variety of conditions, and its relative ease of removal under different acidic conditions. PMID- 30524922 TI - Importance of the Initial Oxidation State of Copper for the Catalytic Hydrogenation of Dimethyl Oxalate to Ethylene Glycol. AB - Exposing a Cu-based catalyst to a suitable temperature is of great importance to optimize its hydrogenation performance, as copper is sensitive to temperature. Herein, we investigated the effect of the initial oxidation state of copper, tuned by the reduction temperature, on its catalytic performance in the hydrogenation of dimethyl oxalate (DMO) to ethylene glycol (EG) through designing a series of catalysts with different reduction temperatures (200-350 degrees C). Among these catalysts, the Cu/SiO2 catalyst prepared by ammonia evaporation with a hydrogen reduction process at 250 degrees C showed the best performance in the hydrogenation of DMO with a conversion of 100 % and a selectivity to EG higher than 95 %. The relationship between the initial oxidation state of copper and catalytic performance was well established by characterizing the physicochemical properties of the Cu/SiO2 catalysts by XRD, TEM, H2 temperature-programmed reduction, N2O adsorption, and in situ reduction Auger electron spectroscopy. The initial oxidation state of copper determined the conversion of DMO and the distribution of the products, and it could be balanced by reducing the temperature to improve the activity of the catalyst. This work provides a reference for further exploration of the mechanism and guidance for the design of catalysts for the hydrogenation of esters. PMID- 30524923 TI - Rapid Synthesis of N-Tosylhydrazones under Solvent-Free Conditions and Their Potential Application Against Human Triple-Negative Breast Cancer. AB - Some N-tosylhydrazone derivatives were effectively synthesized under solvent-free conditions by using a grinding method at room temperature. The short reaction time, clean and mild process with simple workup and easy purification of the target compounds were salient features of the present protocol, which enables straightforward access to N-tosylhydrazones. Among the tosylhydrazone derivatives evaluated, compound 3 l exhibits excellent apoptosis-promoting and anticancer potential against triple-negative breast cancer (TNBC) cell lines. This research shows that our synthesized compound 3 l may be a desirable and effective therapeutic drug against TNBC. PMID- 30524924 TI - SBA15-Fluconazole as a Protective Approach Against Mild Steel Corrosion: Synthesis, Characterization, and Computational Studies. AB - A SBA15-Fluconazole composite (SBA15-Flu) was prepared to formulate a self healing coating for mild steel. The composite was obtained by dispersing SBA15 in a methanolic solution containing Fluconazole (Flu). The materials were characterized by using different techniques. Electrochemical impedance spectroscopy (EIS) was used for protective behavior evaluation of the coatings on mild steel substrates in an electrolytic solution prepared from sodium chloride and ammonium sulfate. The EIS results indicate that the inhibitor trapped in the SiO2 matrix is released when it comes into contact the aggressive solution, thus protecting the metal. To understand the inhibitor release mechanism, docking studies were used to model the SBA15-Flu complex, which allowed us to further determine polar and non-polar contributions to the binding free energy. An analysis of the electron density within the quantum theory of atoms in molecules and the non-covalent interaction index frameworks were also carried out for the most favorable models of SBA15-Flu. The results indicate that the liberation rate of the Flu molecules is mainly determined by the formation of strong O-H???O, O H???N, and O-H???F hydrogen bonds. PMID- 30524925 TI - Factors Controlling the Diels-Alder Reactivity of Hetero-1,3-Butadienes. AB - We have quantum chemically explored the Diels-Alder reactivities of a systematic series of hetero-1,3-butadienes with ethylene by using density functional theory at the BP86/TZ2P level. Activation strain analyses provided physical insight into the factors controlling the relative cycloaddition reactivity of aza- and oxa-1,3 butadienes. We find that dienes with a terminal heteroatom, such as 2-propen-1 imine (NCCC) or acrolein (OCCC), are less reactive than the archetypal 1,3 butadiene (CCCC), primarily owing to weaker orbital interactions between the more electronegative heteroatoms with ethylene. Thus, the addition of a second heteroatom at the other terminal position (NCCN and OCCO) further reduces the reactivity. However, the introduction of a nitrogen atom in the backbone (CNCC) leads to enhanced reactivity, owing to less Pauli repulsion resulting from polarization of the diene HOMO in CNCC towards the nitrogen atom and away from the terminal carbon atom. The Diels-Alder reactions of ethenyl-diazene (NNCC) and 1,3-diaza-butadiene (NCNC), which contain heteroatoms at both the terminal and backbone positions, are much more reactive due to less activation strain compared to CCCC. PMID- 30524926 TI - Structure Formation in Class I and Class II Hydrophobins at the Air-Water Interface under Multiple Compression/Expansion Cycles. AB - Hydrophobins are small amphiphilic fungal proteins empirically divided into two classes. We investigated the self-assembled structures of class I SC3 from S. commune and class II HFBII from T. reesei transferred to mica from the air-water interface by using the Langmuir-Schaefer (LS) technique and atomic force microscopy (AFM). The main focus is the influence of areal constraint and multiple compressions and expansions on the morphology of the protein films. SC3 shows a rather homogenous coverage of the mica surface, with fibrillary structures. Multiple compressions to a surface pressure of 13 mn m-1 led to a shortening of the fibrils. HFBII exhibits multilayered structures of varying thickness at higher surface pressures. Multiple compressions led to a variety of large, multilayer aggregates. Several compressions and expansions homogenized the films of both types. Both proteins showed similar dendritic structures with relevant length scales of at least several hundred nanometers at pressures of 13 mn m-1 and above, although the primary structures they assemble into are usually different in size and type, and range from fibrils to hexagonally ordered films. These dendritic structures may stem from a combination of mechanical influences, such as compressions, expansions, and the drying effect during LS transfer, which may simulate processes during physiological applications of hydrophobins, such as encapsulation or release of spores. PMID- 30524927 TI - Language and Reading: the Role of Morpheme and Phoneme Awareness. AB - Purpose of Review: Although spoken language in the form of meta-linguistic awareness is widely regarded as being involved in reading development, the extensive literature based on different experimental tasks, age groups, and languages makes it difficult to establish consensus about the type of awareness that is critical and the mechanisms underlying this relationship. The purpose of this review is to explore the links between reading and two specific aspects of meta-linguistic awareness, namely, phoneme awareness and morpheme awareness. Recent Findings: Research has uncovered distinct levels of meta-linguistic awareness that stand in different relationships to learning to read. Empirical findings support the reciprocal involvement of an awareness of phonemes and morphemes in reading development but the precise nature of the relationship between spoken and written language is subject to cross-language variation. Summary: A universal model of reading development is needed that is sufficiently flexible to allow interplay in the processing of phonology, orthography, and meaning in response to the linguistic characteristics of the spoken and written forms of the language being acquired. The linguistic characteristics that influence the development of phoneme and morpheme awareness are compared for alphabetic and morphographic orthographies and related to typical and atypical patterns of reading acquisition. PMID- 30524928 TI - Oral Polymorphonuclear Neutrophil Contributes to Oral Health. AB - Purpose of Review: Oral health is maintained in a dynamic equilibrium between the host immunity and the oral microbiome. Oral polymorphonuclear neutrophils (oPMNs) are important innate immune cells in the oral cavity. Recent Findings: The oPMNs play a co-controlling part in the maintenance of oral equilibrium. In human saliva, the oPMNs integrity is preserved, and their function remains unaffected. In general, oPMNs are in a higher state of baseline activation compared to peripheral PMNs. However, in periodontitis, the oPMNs' activation state can result in excessive release of damaging molecules in the extracellular environment. Summary: The presence of oPMNs may unwittingly negatively impact the integrity of the oral tissues. While most of the oPMN functions occur intracellularly, release of their potent active mediators into the extracellular environment may jeopardize oral homeostasis and its integrity. The dual nature of oPMNs, both beneficial and detrimental, remains a challenging and understudied topic. PMID- 30524929 TI - Cross-transmission in the Dental Office: Does This Make You Ill? AB - Purpose of Review: Recently, numerous scientific publications were published which shed new light on the possible risks of infection for dental healthcare workers and their patients. This review aimed to provide the latest insights in the relative risks of transmission of (pathogenic) micro-organisms in the dental office. Recent Findings: Of all different routes of micro-organism transmission during or immediately after dental treatment (via direct contact/via blood-blood contact/via dental unit water and aerosols), evidence of transmission is available. However, the recent results put the risks in perspective; infections related to the dental office are most likely when infection control measures are not followed meticulously. Summary: The risk for transmission of pathogens in a dental office resulting in an infectious disease is still unknown; it seems to be limited in developed countries but it cannot be considered negligible. Therefore, maintaining high standards of infection preventive measures is of high importance for dental healthcare workers to avoid infectious diseases due to cross contamination. PMID- 30524930 TI - Reparative Dentistry: Possibilities and Limitations. AB - Purpose of Review: Defective dental restorations are amongst the most common encounters in general dental practice. Replacement of defective restorations is often costly and commonly results in the sacrifice of sound tooth structure, thereby compromising the vitality of the dental pulp, potentially resulting in the acceleration of the restoration cycle and premature loss of the restored tooth. With advances in adhesive dentistry, 'reparative dentistry' is becoming an important area of minimally invasive dentistry. This article highlights the detrimental biological effects of restoration replacement and provides an overview of current knowledge and understanding of restoration repair as a safe and effective alternative approach to replacement. Recent Findings: The literature reviewed showed that a growing body of evidence from clinical studies indicates that repaired restorations have similar survival outcomes in patients with low and medium caries risk compared to replaced restorations and are clinically acceptable over a 12-year follow-up of clinical service. Teeth with repaired restorations are less likely to require aggressive interventions such as endodontic treatment or extraction compared to those with replaced restorations. Summary: Repair options should be carried out wherever possible as minimally interventional procedures in order to increase the longevity of the remaining part of the restoration and the restored tooth unit. Restoration replacement should be considered as the last resort when there are no other viable alternatives. PMID- 30524931 TI - Tooth Repair and Regeneration. AB - Purpose of Review: Current dental treatments are based on conservative approaches, using inorganic materials and appliances.This report explores and discusses the newest achievements in the field of "regenerative dentistry," based on the concept of biological repair as an alternative to the current conservative approach. Recent Findings: The review covers and critically analyzes three main approaches of tooth repair: the re-mineralization of the enamel, the biological repair of dentin, and whole tooth engineering. Summary: The development of a concept of biological repair based on the role of the Wnt signaling pathway in reparative dentin formation offers a new translational approach into development of future clinical dental treatments.In the field of bio-tooth engineering, the current focus of the researchers remains the establishment of odontogenic cell sources that would be viable and easily accessible for future bio-tooth engineering. PMID- 30524933 TI - Food Allergy and Asthma: Is There a Link? AB - Purpose of review: To describe and understand the links and interactions between food allergy and asthma. Recent findings: Food allergy and asthma are characterized by an increasing prevalence. Moreover, food allergy and asthma often coexist. Both conditions are associated with each other in different ways. It has been shown that food allergy is a risk factor of developing asthma. Atopic dermatitis appears to be the common denominator in this interaction. Loss-of function variants of the filaggrin mutation result in an impaired epidermal barrier function and have been shown to be a risk factor for the development of atopic dermatitis, allergies, and asthma. Early introduction of food allergens and optimal treatment of the skin barrier are preventive interventions for the development of food allergy and asthma. Asthma is also a risk factor for the development of severe or even fatal anaphylaxis in patients with food allergy. Isolated asthma is not a feature of a food allergic reaction; however, respiratory symptoms may be part of anaphylactic reactions. In addition, during an allergic reaction to food, non-specific bronchial hyperreactivity may increase. Cross-reactive allergens may be responsible for asthma-associated food allergy. This is particularly true for severe asthma upon ingestion of snail in patients allergic to house-dust mites. Finally, airborne allergens from occupational sources such as wheat, fish, and seafood may induce asthmatic reactions. This phenomenon is sometimes seen in non-occupational settings. Summary: Food allergy and asthma are interconnected with each other beyond the presence of simple comorbidity. Food allergy precedes and predisposes to asthma, and mutual interactions range from respiratory symptoms and bronchial hyperreactivity during food-induced anaphylaxis to severe asthma due to cross reactive food allergens and to occupational asthma upon exposure to airborne allergens. Moreover, coexisting asthma in food allergies may result in severe and sometimes fatal anaphylactic reactions. PMID- 30524932 TI - Primary Prevention of Airway Allergy. AB - Purpose of review: The aim of this paper is to review and summarize the current knowledge of prevention of airway allergy. Recent findings: Allergic rhinitis and asthma are allergic airway diseases. Due to their increasing incidence and socioeconomic burden, allergic airway diseases have recently gained attention worldwide. The primary prevention of allergic airway diseases focuses on offspring's gestational and childhood environment, such as maternal smoking and diet during pregnancy and breastfeeding as well as exposure to environmental microbes and irritants. Summary: Asthma and allergic rhinitis are a major public health problem worldwide. They have increasing prevalence and thus attempts to their prevention are mandatory. Rapid action needs to be taken to restrain smoking among children and adolescents in order to prevent burden of allergic airway diseases. Exposure to pollution and environmental issues concerning hygiene and lifestyle would also need to be actively addressed. More evidence is still needed in order to draw linings concerning maternal diet and other factors during the offspring's whole life span. PMID- 30524934 TI - Cognition-based variable admittance control for active compliance in flexible manipulation of heavy objects with a power-assist robotic system. AB - In the first step, a 1-DOF power-assist robotic system (PARS) is developed for lifting lightweight objects. Dynamics for human-robot co-manipulation of objects is derived that considers human cognition (weight perception). Then, admittance control with position feedback and velocity controller is derived using weight perception-based dynamics. Human subjects lift an object with the PARS, and HRI (human-robot interaction) and system characteristics are analyzed. A comprehensive scheme is developed to evaluate the HRI and performance. HRI is expressed in terms of physical HRI (maneuverability, motion, safety, stability, naturalness) and cognitive HRI (workload, trust), and performance is expressed in terms of manipulation efficiency and precision. To follow the guidance of ISO/TS 15066, hazard analysis and risk assessment are conducted. A constrained optimization algorithm is proposed to determine the values of the control parameters that produce optimum HRI and performance with lowest risk. Results show that consideration of weight perception in dynamics and control helps achieve optimum HRI and performance for a set of hard constraints. In the second step, a weight perception-based novel variable admittance control scheme is proposed as an active compliance to the system, which enhances the physical HRI, trust, precision and efficiency by 53.05%, 46.78%, 3.84% and 4.98%, respectively, and reduces workload by 35.38% and thus helps achieve optimum HRI and performance for a set of soft constraints. The risk reduces due to the active compliance. Then, effectiveness of the optimization and control algorithms is validated using a multi-DOF PARS for manipulating heavy objects, and intuitive and natural HRI and performance for power-assisted heavy object manipulation are achieved through calibrating HRI and performance with that for manipulation of lightweight object. PMID- 30524935 TI - Protein structural biology using cell-free platform from wheat germ. AB - One of the biggest bottlenecks for structural analysis of proteins remains the creation of high-yield and high-purity samples of the target protein. Cell-free protein synthesis technologies are powerful and customizable platforms for obtaining functional proteins of interest in short timeframes, while avoiding potential toxicity issues and permitting high-throughput screening. These methods have benefited many areas of genomic and proteomics research, therapeutics, vaccine development and protein chip constructions. In this work, we demonstrate a versatile and multiscale eukaryotic wheat germ cell-free protein expression pipeline to generate functional proteins of different sizes from multiple host organism and DNA source origins. We also report on a robust purification procedure, which can produce highly pure (> 98%) proteins with no specialized equipment required and minimal time invested. This pipeline successfully produced and analyzed proteins in all three major geometry formats used for structural biology including single particle analysis with electron microscopy, and both two dimensional and three-dimensional protein crystallography. The flexibility of the wheat germ system in combination with the multiscale pipeline described here provides a new workflow for rapid production and purification of samples that may not be amenable to other recombinant approaches for structural characterization. PMID- 30524936 TI - Vitamin D deficiency was common in all patients at a Swedish primary care centre, but more so in patients born outside of Europe. AB - Background: Vitamin D is associated with extra-skeletal processes, and vitamin D deficiency might contribute to the development of chronic diseases. Aim: To investigate vitamin D levels in an unselected patient population at a Swedish suburban primary care centre. Methods: Vitamin D levels were assessed in 102 patients aged 20 to 65 years visiting the primary care centre, independent of cause of visit, during 2 weeks in January 2014. The difference in vitamin D levels between patients born in Europe and patients born outside Europe was calculated using linear regression, adjusting for gender and age. The difference in prevalence of vitamin D deficiency (< 25 nmol/l) was calculated using logistic regression adjusting for gender, age, vitamin D supplement, and sun exposure. Results: Patients born outside Europe (n = 66) had 15 nmol/l [95% confidence interval (CI) 9.17-20.84] lower levels of vitamin D than patients born in Europe. Vitamin D deficiency was more common in patients born outside Europe (50%) than in patients born in Europe (11%, odds ratio 8.20 95% CI 2.49-26.98, p < 0.001). Conclusion: Lower levels of vitamin D and the prevalence of vitamin D deficiency were more common in patients born outside Europe compared to patients born in Europe. PMID- 30524937 TI - Are young adults appreciating the health promotion messages on diet and exercise? AB - Aim: This study aims to determine if current health promotion messages relating to diet and physical activity are sufficiently targeted towards young adults. In addition, we examine what elements of these messages might be improved to ensure they encourage improved diet and exercise behaviours within this underserved group. Subject and methods: Using qualitative methods, five focus group discussions (FGDs) and two semi-structured in-depth interviews were conducted among 19 young adults in Aberdeen City. An appropriate topic guide was developed for this purpose. After obtaining consent, all FGDs and interviews were audio recorded and transcribed verbatim. A thematic analysis was conducted that allowed for emerging themes to be identified from the data. Links between themes were established and key quotes identified. Results: Five major themes emerged: (1) exposure to health messages over time; (2) chains of healthy or unhealthy behaviours; (3) perceptions and attitudes towards health messages; (4) facilitators and barriers; (5) improving the usability of health messages. Conclusions: The results demonstrate that young adults did not find current health promotion messages engaging. These messages did not support them in overcoming their perceived barriers, nor were they suitably formatted or located for them. There were suggestions from young adults on how to improve these messages including using social media, presenting messages in more usable forms, and working with larger corporations to make these messages more effective. Tailoring these messages specifically for young adults could improve their diet and exercise behaviours, thereby helping to reduce future obesity levels and co morbidities within Scotland. PMID- 30524938 TI - The Instructive Role of the Bone Marrow Niche in Aging and Leukemia. AB - Purpose of review: In this review, we aim to discuss the role of the bone marrow microenvironment in supporting hematopoiesis, with particular focus on the contribution of the endothelial niche in dictating hematopoietic stem cell (HSC) fate. Recent findings: Evidence gathered in the past two decades revealed that specific cell types within the bone marrow niche influence the hematopoietic system. Endothelial cells have emerged as a key component of the HSC niche, directly affecting stem cell quiescence, self-renewal, and lineage differentiation. Physiological alterations of the bone marrow niche occurring in aging have been described to be sufficient to promote functional aging of young HSCs. Furthermore, a growing body of evidence suggests that aberrant activation of endothelial-derived signaling pathways can aid or trigger neoplastic transformation. Summary: Several groups have contributed to the characterization of the different cell types that comprise the complex bone marrow environment, whose function was long perceived as an undiscernible sum of many parts. Further studies will need to uncover niche cell-type-specific pathways, in order to provide new targets and therapeutic options that aim at withdrawing the microenvironmental support to malignant cells while sparing normal HSCs. PMID- 30524939 TI - Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies. AB - Purpose of Review: Muscular dystrophies (MDs) are a spectrum of muscle disorders, which are caused by a number of gene mutations. The studies of MDs are limited due to lack of appropriate models, except for Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), and certain type of limb-girdle muscular dystrophy (LGMD). Human induced pluripotent stem cell (iPSC) technologies are emerging to offer a useful model for mechanistic studies, drug discovery, and cell-based therapy to supplement in vivo animal models. This review will focus on current applications of iPSC as disease models of MDs for studies of pathogenic mechanisms and therapeutic development. Recent Findings: Many and more human disease-specific iPSCs have been or being established, which carry the natural mutation of MDs with human genomic background. These iPSCs can be differentiated into specific cell types affected in a particular MDs such as skeletal muscle progenitor cells, skeletal muscle fibers, and cardiomyocytes. Human iPSCs are particularly useful for studies of the pathogenicity at the early stage or developmental phase of MDs. High-throughput screening using disease-specific human iPSCs has become a powerful technology in drug discovery. While MD iPSCs have been generated for cell-based replacement therapy, recent advances in genome editing technologies enabled correction of genetic mutations in these cells in culture, raising hope for in vivo genome therapy, which offers a fundamental cure for these daunting inherited MDs. Summary: Human disease-specific iPSC models for MDs are emerging as an additional tool to current disease models for elucidating disease mechanisms and developing therapeutic intervention. PMID- 30524940 TI - Potential role of platelets for atherosclerotic events in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease with increased risk of cardiovascular events and mortality that can be attributed to accelerated atherosclerosis. This pilot study aimed to investigate if changes in blood parameters were compatible with atherosclerotic events in RA patients. To this aim, 45 RA women (aged more than 18 years), and 25 age and gender-matched healthy donors (HD) were included. Biomarkers of oxidative stress, platelet activation and platelet aggregation were analysed in RA patients at baseline and after six months of treatment with disease modifying anti-rheumatic drugs (DMARDs). Flow cytometry analysis revealed that ca. 4% of platelets was in activated state (evaluated in term of Annexin V and PAC-1 positivity) in RA patients at baseline, and that the 76% of platelets displayed mitochondrial hyperpolarization. Moreover, platelets from RA patients at baseline aggregated more than those from HD after whole blood treatment with adenosine diphosphate. Interestingly, platelet aggregation in patients at baseline positively correlated with disease activity measured by DAS28 score. After six months of treatment with DMARDs, platelet activation and platelet aggregation reached values comparable to those of HD. Our preliminary data suggest that platelets might play an active role in the atherosclerosis occurring in RA patients. PMID- 30524941 TI - The triheme cytochrome PpcF from Geobacter metallireducens exhibits distinct redox properties. AB - Electrogenic bacteria, such as Geobacter, can couple the oxidation of carbon sources to the reduction of extracellular electron acceptors; such acceptors include toxic and radioactive metals, as well as electrode surfaces, making Geobacter a suitable candidate for applied use in bioremediation and bioenergy generation. Geobacter metallireducens is more promising in this regard than the better studied Geobacter sulfurreducens, as it has more efficient Fe (III) reduction rates and can convert nitrate to ammonia. The operon responsible for nitrate reductase activity in G. metallireducens includes the gene encoding the cytochrome PpcF, which was proposed to exchange electrons with nitrate reductase. In the present work, we perform a biochemical and a biophysical characterization of PpcF. Spectroscopic techniques, including circular dichroism (CD), UV-visible, and nuclear magnetic resonance (NMR), revealed that the cytochrome is very stable (T m > 85 degrees C), contains three low-spin hemes, and is diamagnetic (S = 0) and paramagnetic (S = 1/2) in the reduced and oxidized states, respectively. The NMR chemical shifts of the heme substituents were assigned and used to determine the heme core architecture of PpcF. Compared to the PpcA-family from G. sulfurreducens, the spatial disposition of the hemes is conserved, but the functional properties are clearly distinct. In fact, potentiometric titrations monitored by UV-visible absorption reveal that the reduction potential values of PpcF are significantly less negative (-56 and -64 mV, versus the normal hydrogen electrode at pH 7.0 and 8.0, respectively). NMR redox titrations showed that the order of oxidation of the hemes is IV-I-III, a feature not observed for G. sulfurreducens. The different redox properties displayed by PpcF, including the small redox-Bohr effect and low reduction potential value of heme IV, were structurally rationalized and attributed to the lower number of positively charged residues located in the vicinity of heme IV. Overall, the redox features of PpcF suggest that biotechnological applications of G. metallireducens may require less negative working functional redox windows than those using by G. sulfurreducens. PMID- 30524942 TI - Trastuzumab induces PUMA-dependent apoptosis and inhibits tumor growth in gastric cancer. AB - Gastric cancer (GC) is one of the most prevalent cancers worldwide. Trastuzumab has been approved for the treatment of metastatic GC, gastroesophageal junction cancer, and breast cancer. However, the mechanisms involved in trastuzumab induced GC cell apoptosis remain largely unknown. In this study, we investigated the underlying mechanisms of trastuzumab-mediated suppression of GC cell growth both in vitro and in vivo. We found that trastuzumab treatment induces p53 upregulated modulator of apoptosis (PUMA) expression in GC cells, through the NF kappaB pathway following AKT inhibition and glycogen synthase kinase 3beta (GSK3beta) activation. We also observed that PUMA was necessary for trastuzumab induced apoptosis in GC cells. Moreover, PUMA deficiency suppressed apoptosis and the antitumor effect of trastuzumab in xenograft models. Finally, computerized tomography (CT) and immunohistochemistry results showed that patients with increased activation of PUMA were more sensitive to trastuzumab treatment than those with low PUMA expression. These results indicate that trastuzumab induces PUMA-dependent apoptosis and inhibits tumor growth in GC, suggesting that PUMA plays a critical role in mediating the antitumor effects of trastuzumab in GC. PUMA induction may be used as a marker of trastuzumab sensitivity. PMID- 30524943 TI - Quantitative analysis of sensitivity to a Wnt3a gradient in determination of the pole-to-pole axis of mitotic cells by using a microfluidic device. AB - Proper determination of the cell division axis is essential during development. Wnt3a is a known regulator of the cell division axis; however, the sensitivity of cells to Wnt3a signalling and its role in determining the cell division axis have not been measured to date. To address this gap, we took advantage of the asymmetric distribution of outer dense fibre 2 (ODF2/cenexin) proteins on centrosomes in dividing cells. To precisely quantify the sensitivity of cells to Wnt3a signalling, we developed a microfluidic cell culture device, which can produce a quantitative gradient of signalling molecules. We confirmed that mitotic SH-SY5Y neuroblastoma cells could detect a 2.5 ~ 5 * 10-3 nm.MUm-1 Wnt3a concentration gradient and demonstrated that this gradient is sufficient to affect the determination of the pole-to-pole axis of cell division during the later stages of mitosis. PMID- 30524944 TI - Transforming growth factor-beta blocks glucose-induced inflammation and apoptosis in corneal epithelial cells. AB - Diabetic retinopathy is the most important ocular complication associated with diabetes. Corneal defects due to diabetes mellitus (DM) may cause severe vision impairments. This study aimed to identify the effect of transforming growth factor-beta (TGF-beta) on biological events, such as apoptosis and inflammation, in the diabetic cornea. High-glucose treatment induced reactive oxygen species (ROS) production and several biological events, including apoptosis and inflammatory cytokine secretion, in human corneal epithelial cells. However, administration of TGF-beta significantly decreased ROS production, Annexin V positive cells, and levels of inflammatory cytokines. Sprague Dawley rats were injected with streptozotocin (STZ) as a model of DM. Inflammatory cytokine secretion, apoptosis, and inflammation were all increased by STZ treatment. However, apoptosis and inflammation were markedly reduced following TGF-beta treatment. In conclusion, TGF-beta can ameliorate the enhancement of apoptosis and inflammation in diabetic cornea in in vivo and in vitro. PMID- 30524945 TI - ZNF121 interacts with ZBRK1 and BRCA1 to regulate their target genes in mammary epithelial cells. AB - The novel zinc finger protein 121 (ZNF121) has been demonstrated to physically and functionally associate with the MYC oncoprotein to regulate cell proliferation and likely breast cancer development. To further understand how ZNF121 functions in cell proliferation and carcinogenesis, we identified and characterized the interaction of ZNF121 with zinc finger and BRCA1-interacting protein with a KRAB domain 1 (ZBRK1), a breast and ovarian cancer susceptibility protein 1 (BRCA1)-interacting protein, using the yeast two-hybrid assay and other approaches. We also found that ZNF121 bound to BRCA1. Functionally, ZFN121 suppressed the expression of ANG1 and HMGA2, two common downstream targets of ZBRK1 and BRCA1. Interestingly, ZNF121 also regulated the expression of BRCA1 and ZBRK1. These findings suggest that ZNF121 is likely a member of the BRCA1/CtIP/ZBRK1 repressor complex that plays a role in breast cancer. PMID- 30524946 TI - Interleukin-18 expression in oral squamous cell carcinoma: its role in tumor cell migration and invasion, and growth of tumor cell xenografts. AB - Oral squamous cell carcinoma (OSCC) is one of the most common head and neck malignancies. Advanced stages of the disease are associated with poor survival, highlighting a need for new treatment modalities. We previously showed that the proinflammatory cytokine interleukin-18 (IL-18) has a tumor suppressive role in OSCC. Here, we investigated the effects of IL-18 on proliferation, migration, and invasion of OSCC cells ex vivo and in vitro, and in nude mouse xenografts. We report that expression of tankyrase 2 (TNKS2), beta-catenin, and N-cadherin was higher in tumor cells than in normal mucosae, whereas the expression of IL-18 and E-cadherin was higher in normal than in tumor tissues. Elevated expression of IL 18 (P < 0.01) and E-cadherin (P = 0.034) was associated with tumor differentiation, whereas expression of TNKS2 (P < 0.01), beta-catenin (P = 0.012), and N-cadherin (P < 0.01) was associated with tumor de-differentiation. Furthermore, compared with the vector control, IL-18 overexpression promoted tumor cell migration and invasion (P < 0.01), but inhibited growth of tumor cell xenografts (P < 0.05). At the protein level, expression levels of IL-18 (P < 0.01), TNKS2 (P = 0.045), beta-catenin (P = 0.028), and N-cadherin (P = 0.068) were upregulated in tumor cells after IL-18 overexpression compared with those of the vector control mice, whereas expression levels of E-cadherin (P = 0.045) were decreased. In conclusion, our data suggest that IL-18 overexpression induces oral SCC cell invasion and metastasis by promoting the tumor cell epithelial mesenchymal transition via the Wnt/beta-catenin signaling pathway. PMID- 30524947 TI - Critical role of tristetraprolin and AU-rich element RNA-binding protein 1 in the suppression of cancer cell growth by globular adiponectin. AB - Adiponectin exhibits potent antitumor activities. Herein, we examined the molecular mechanisms underlying suppression of tumor growth by globular adiponectin (gAcrp). We demonstrated that gAcrp suppressed B-cell lymphoma 2 (Bcl 2) expression, an anti-apoptotic gene, by inducing its mRNA destabilization, which was accompanied with a decrease in cell viability and increased caspase-3 activity in hepatic cancer cells. In addition, gAcrp increased expression of tristetraprolin (TTP) and AU-rich element RNA-binding protein 1 (AUF1), which are mRNA stability regulatory proteins. Moreover, gAcrp-induced suppression of Bcl-2 expression was abrogated by knockdown of TTP or AUF1. These data indicate that gAcrp induces apoptosis of hepatic cancer cells by TTP- and AUF1-mediated Bcl-2 mRNA destabilization, and further suggest that TTP and AUF1 are novel targets mediating the antitumor activity of adiponectin. PMID- 30524948 TI - Establishment and characterization of a novel vincristine-resistant diffuse large B-cell lymphoma cell line containing the 8q24 homogeneously staining region. AB - Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT1, which lies adjacent to MYC, has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU-ML2, from a patient with diffuse large B-cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high-resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT1 regions. We also demonstrated a loss of heterozygosity for TP53 at 17p13 in conjunction with a TP53 frameshift mutation. Notably, AMU-ML2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC shRNA-mediated knockdown. Furthermore, genes involved in cyclin D, mTOR, and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU-ML2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities. PMID- 30524949 TI - Nephronectin mediates p38 MAPK-induced cell viability via its integrin-binding enhancer motif. AB - Nephronectin (NPNT) is an extracellular matrix (ECM) protein involved in kidney development. We recently reported intracellular NPNT as a potential prognostic marker in breast cancer and that NPNT promotes metastasis in an integrin dependent manner. Here, we used reverse-phase protein array (RPPA) to analyze NPNT-triggered intracellular signaling in the 66cl4 mouse breast cancer cell line. The results showed that the integrin-binding enhancer motif is important for the cellular effects upon NPNT interaction with its receptors, including phosphorylation of p38 mitogen-activated protein kinase (MAPK). Furthermore, analysis using prediction tools suggests involvement of NPNT in promoting cell viability. In conclusion, our results indicate that NPNT, via its integrin binding motifs, promotes cell viability through phosphorylation of p38 MAPK. PMID- 30524950 TI - Human nitrobindin: the first example of an all-beta-barrel ferric heme-protein that catalyzes peroxynitrite detoxification. AB - Nitrobindins (Nbs), constituting a heme-protein family spanning from bacteria to Homo sapiens, display an all-beta-barrel structural organization. Human Nb has been described as a domain of the nuclear protein named THAP4, whose physiological function is still unknown. We report the first evidence of the heme Fe(III)-based detoxification of peroxynitrite by the all-beta-barrel C-terminal Nb-like domain of THAP4. Ferric human Nb (Nb(III)) catalyzes the conversion of peroxynitrite to NO3- and impairs the nitration of free l-tyrosine. The rate of human Nb(III)-mediated scavenging of peroxynitrite is similar to those of all alpha-helical horse heart and sperm whale myoglobin and human hemoglobin, generally taken as the prototypes of all-alpha-helical heme-proteins. The heme Fe(III) reactivity of all-beta-barrel human Nb(III) and all-alpha-helical prototypical heme-proteins possibly reflects the out-to-in-plane transition of the heme-Fe(III)-atom preceding peroxynitrite binding. Human Nb(III) not only catalyzes the detoxification of peroxynitrite but also binds NO, possibly representing a target of reactive nitrogen species. PMID- 30524951 TI - Inhibitors of BMP-1/tolloid-like proteinases: efficacy, selectivity and cellular toxicity. AB - BMP-1/tolloid-like proteinases belong to the astacin family of human metalloproteinases, together with meprins and ovastacin. They represent promising targets to treat or prevent a wide range of diseases such as fibrotic disorders or cancer. However, the study of their pathophysiological roles is still impaired by the lack of well-characterized inhibitors and the questions that remain regarding their selectivity and in vivo efficiency. As a first step towards the identification of suitable tools to be used in functional studies, we have undertaken a systematic comparison of seven molecules known to affect the proteolytic activity of human astacins including three hydroxamates (FG-2575, UK383,367, S33A), the protein sizzled, a new phosphinic inhibitor (RXP-1001) and broad-spectrum protease inhibitors (GM6001, actinonin). Their efficacy in vitro, their cellular toxicity and efficacy in cell cultures were thoroughly characterized. We found that these molecules display very different potency and selectivity profiles, with hydroxamate FG-2575 and the protein sizzled being very powerful and selective inhibitors of BMP-1, whereas phosphinic peptide RXP-1001 behaves as a broad-spectrum inhibitor of astacins. Their use should therefore be carefully considered in agreement with the aim of the study to avoid result misinterpretation. PMID- 30524953 TI - Kingella kingae infective endocarditis in a healthy adult. PMID- 30524952 TI - Sulforaphane-induced metabolomic responses with epigenetic changes in estrogen receptor positive breast cancer cells. AB - Estrogen is a risk factor for breast cancer. The isothiocyanate sulforaphane (SFN), found in cruciferous vegetables, has been identified as an effective chemopreventive agent, and may prevent or treat breast cancer by reversing estrogen-induced metabolic changes. Here, we investigated metabolic changes in estrogen receptor-positive breast cancer (MCF-7) cells treated with estradiol (E2) and/or SFN to identify key metabolite panels that might provide new insights into the underlying mechanisms of the antitumor effects of SFN. Gas chromatography-mass spectrometry and ultra performance liquid chromatography-mass spectrometry (UPLC-Orbitrap- MS) were used to obtain the metabolic profiles of MCF-7 cells. The data were analyzed using Student's t-test and multivariate statistics, including principal component analysis and partial least squares discriminant analysis. Hydroxymethylation was detected by UPLC-Orbitrap- MS and verified by immunofluorescence assay. We report that significant changes in metabolites induced by E2 and SFN were associated with differences in glycolysis and energy metabolism, and also amino acid, purine, and folic acid metabolism. E2 may alter methylation and hydroxymethylation status via the folic acid pathway. We also identified biomarkers that may be of use in interpretation of the metabolic pathways evoked by the effects of E2 and SFN on breast cancer cells. The identified biomarkers associated with metabolic pathways provide new insight into the chemopreventive mechanisms of SFN. PMID- 30524954 TI - Anaplasmosis: An emerging tick-borne disease of importance in Canada. AB - Human Granulocytic Anaplasmosis (HGA) is an infection caused by the intracellular bacterium Anaplasma phagocytophilum. As a tick-borne disease, the public health impact of HGA continues to increase with range expansion of the disease vector. The clinical presentation of HGA is often a non-specific febrile illness. The presence of leukopenia, thrombocytopenia, and mild hepatic injury are frequently noted on laboratory investigations, which can be important diagnostic clues in attaining an appropriate diagnosis. Herein we present three cases of HGA, highlighting the spectrum of disease by which HGA can manifest. Although each case has their unique features, we outline important shared clinical elements to facilitate an empiric diagnosis while definitive laboratory investigations are pending. Our case series further serves to highlight the critical importance of prompt antimicrobial treatment to reduce morbidity and potential mortality. PMID- 30524955 TI - Pulmonary mucormycosis in an adolescent female with type 1 diabetes mellitus. AB - Mucormycosis is a relatively rare, life-threatening and opportunistic infection that affects immunocompromised patients. We present the unusual case of pulmonary mucormycosis in a 13-year-old Caucasian female that had recently been diagnosed with type 1 diabetes. Our case serves as an example to healthcare providers treating immunosuppressed patients with pneumonia to have a high clinical suspicion for fungal infections, as delay in diagnosis and treatment can result in disseminated disease and higher patient mortality risk. PMID- 30524956 TI - The Comparative Treatment of Intraventricular Chemotherapy by Ommaya Reservoir vs. Lumbar Puncture in Patients With Leptomeningeal Carcinomatosis. AB - Object: Leptomeningeal Carcinomatosis (LCM) represents a state of systemic malignant disease with poor prognosis. The purpose of this study is to compare overall survival (OS) between intraventricular chemotherapy through Ommaya reservoir (OR) and chemotherapy through lumbar puncture (LP) in LCM. Patients and Methods: Forty adult patients with LCM were included. All patients underwent lumbar puncture and Magnetic resonance imaging (MRI). Thirty patients received chemotherapy through LP and 10 undergone colocation of Ommaya reservoir for intraventricular chemotherapy. Results: The most common symptom was headache (Present in 50%). The cranial nerves most affected were VI and VII. Leptomeningeal enhancement was the most frequent finding in MRI. The OS in the LP group was 4 months and Ommaya group was 9.2 months (p = 0.0006; CI:1.8-3), with statistical differences in favor to Intraventricular treatment. Proportional hazard regression showed that receiving chemotherapy through Ommaya reservoir was a protective factor (Hazard ratio = 0.258, Standard Error = 0.112, p = 0.002 and 95% CI 0.110-0.606). Using KPS as a factor did not affect the hazard ratio of Ommaya reservoir itself. Conclusions: OS was significantly higher in patients with Ommaya reservoir in spite of Karnofsky Performance Status (KPS) previous to chemotherapy. Therefore, intraventricular chemotherapy should be preferred over lumbar puncture chemotherapy administration if there are resources available. PMID- 30524957 TI - Dysbiosis of the Salivary Microbiome Is Associated With Non-smoking Female Lung Cancer and Correlated With Immunocytochemistry Markers. AB - Background: Association between oral bacteria and increased risk of lung cancer have been reported in several previous studies, however, the potential association between salivary microbiome and lung cancer in non-smoking women have not been evaluated. There is also no report on the relationship between immunocytochemistry markers and salivary microbiota. Method: In this study, we assessed the salivary microbiome of 75 non-smoking female lung cancer patients and 172 matched healthy individuals using 16S rRNA gene amplicon sequencing. We also calculated the Spearman's rank correlation coefficient between salivary microbiota and three immunohistochemical markers (TTF-1, Napsin A and CK7). Result: We analyzed the salivary microbiota of 247 subjects and found that non smoking female lung cancer patients exhibited oral microbial dysbiosis. There was significantly lower microbial diversity and richness in lung cancer patients when compared to the control group (Shannon index, P < 0.01; Ace index, P < 0.0001). Based on the analysis of similarities, the composition of the microbiota in lung cancer patients also differed from that of the control group (r = 0.454, P < 0.001, unweighted UniFrac; r = 0.113, P < 0.01, weighted UniFrac). The bacterial genera Sphingomonas (P < 0.05) and Blastomonas (P < 0.0001) were relatively higher in non-smoking female lung cancer patients, whereas Acinetobacter (P < 0.001) and Streptococcus (P < 0.01) were higher in controls. Based on Spearman's correlation analysis, a significantly positive correlation can be observed between CK7 and Enterobacteriaceae (r = 0.223, P < 0.05). At the same time, Napsin A was positively associated with genera Blastomonas (r = 0.251, P < 0.05). TTF-1 exhibited a significantly positive correlation with Enterobacteriaceae (r = 0.262, P < 0.05). Functional analysis from inferred metagenomes indicated that oral microbiome in non-smoking female lung cancer patients were related to cancer pathways, p53 signaling pathway, apoptosis and tuberculosis. Conclusions: The study identified distinct salivary microbiome profiles in non-smoking female lung cancer patients, revealed potential correlations between salivary microbiome and immunocytochemistry markers used in clinical diagnostics, and provided proof that salivary microbiota can be an informative source for discovering non-invasive lung cancer biomarkers. PMID- 30524958 TI - Revitalizing the AZT Through of the Selenium: An Approach in Human Triple Negative Breast Cancer Cell Line. AB - Triple-negative breast cancer represents about 15% of all cases of breast cancer, and still represents a therapeutic challenge. 3'-Azido-3'-deoxythymidine (AZT) is a nucleoside reverse transcriptase inhibitor with antitumor activity. Chalcogenides compounds, such as selenium, are very important intermediates applied in organic synthesis. Our objective was to investigate the effect and the underlying cell death mechanisms of AZT and its derivatives, in human breast cancer cell lines. The inhibitory effect of AZT and derivatives (1072, 1073, and 1079) was determined by MTT assay (0.1, 1, 10, 50, and 100 MUM for concentrations and times 4, 24, 48, and 72 h) and Live/Dead in tumor cell lines MCF-7, MDA-MB 231 and also in non-tumor cell line CHO. Gene expression profiles related to apoptosis were investigated by qRT-PCR and induction of apoptosis was investigated by flow cytometry. MTT and Live/Dead assays showed that AZT derivatives decreased the rate of cell proliferation at concentrations of 50 and 100 MUM in tumor cell lines MCF-7 and MDA-MB 231 while the commercial AZT presented a low antitumoral potential in all strains tested. In flow cytometry analysis we demonstrated that derivatives of AZT induced apoptosis, with an increase in both initial and late stages in both tumor cell lines evaluated, especially in MDA-MB 231. Our data show that the AZT derivative 1072 increased the expression of transcripts of the genes caspase 3 and 8 in MDA-MB 231 cell line when compared to control, suggesting that the extrinsic pathway of apoptosis was activated. In conclusion, derivatives of AZT, especially 1072, induce cytotoxicity in vitro in the triple negative breast cancer cell line through activation of the extrinsic pathway of apoptosis. These compounds containing selenium in its formulation are potential therapeutic agents for breast cancer. PMID- 30524959 TI - Hyperoxygenation as a Therapeutic Supplement for Treatment of Triple Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) refers to a group of biologically aggressive breast cancers that do not express estrogen, progesterone or epidermal growth factor receptor 2 hormone receptors. Each subset of TNBC has a unique molecular profile and may require specific treatments. A combination of surgery and chemotherapy followed by radiation therapy is the standard treatment mode for TNBC patients. Tumor oxygen status (hypoxia) is a key factor that may compromise the effectiveness of radiation treatment, as it is known that hypoxia can confer radiation resistance. In this study, we characterized MDA-MB-231 orthotropic xenograft tumors with respect to tumor oxygen level and their response to supplemental oxygen therapy in combination with paclitaxel and radiation therapy. We observed that the TNBC tumors became severely hypoxic (pO2 < 4 mmHg) within 1 week of tumor growth and responded poorly to administration of respiratory hyperoxygenation (100% O2) to mitigate hypoxia. However, periodic administration of supplemental oxygen (100% O2; 60 min/day for 21 days) showed a significant inhibitory effect on tumor volume when compared to control (1,023 +/- 32 mm3 vs. 1,378 +/- 114 mm3; p < 0.05). Combination of supplemental oxygen with paclitaxel and radiation therapy led to a significant reduction in tumor growth when compared to radiation alone (239 +/- 40 mm3 vs. 390 +/- 32 mm3; p < 0.05). The therapeutic enhancement by supplemental oxygen is possibly attributed to increase in tumor oxygenation with paclitaxel at the time of radiation treatment. These findings may have important implications in the understanding of the role of oxygen and supplemental oxygen therapy for the treatment of TNBC patients. PMID- 30524960 TI - Defective Nuclear Lamina in Aneuploidy and Carcinogenesis. AB - Aneuploidy, loss or gain of whole chromosomes, is a prominent feature of carcinomas, and is generally considered to play an important role in the initiation and progression of cancer. In high-grade serous ovarian cancer, the only common gene aberration is the p53 point mutation, though extensive genomic perturbation is common due to severe aneuploidy, which presents as a deviant karyotype. Several mechanisms for the development of aneuploidy in cancer cells have been recognized, including chromosomal non-disjunction during mitosis, centrosome amplification, and more recently, nuclear envelope rupture at interphase. Many cancer types including ovarian cancer have lost or reduced expression of Lamin A/C, a structural component of the lamina matrix that underlies the nuclear envelope in differentiated cells. Several recent studies suggest that a nuclear lamina defect caused by the loss or reduction of Lamin A/C leads to failure in cytokinesis and formation of tetraploid cells, transient nuclear envelope rupture, and formation of nuclear protrusions and micronuclei during the cell cycle gap phase. Thus, loss and reduction of Lamin A/C underlies the two common features of cancer-aberrations in nuclear morphology and aneuploidy. We discuss here and emphasize the newly recognized mechanism of chromosomal instability due to the rupture of a defective nuclear lamina, which may account for the rapid genomic changes in carcinogenesis. PMID- 30524961 TI - Clinical and Genetic Factors to Inform Reducing Colorectal Cancer Disparitites in African Americans. AB - Colorectal cancer (CRC) is the third most prevalent and second deadliest cancer in the U.S. with 140,250 cases and 50,630 deaths for 2018. Prevention of CRC through screening is effective. Among categorized races in the U.S., African Americans (AAs) show the highest incidence and death rates per 100,000 when compared to Non-Hispanic Whites (NHWs), American Indian/Alaskan Natives, Hispanics, and Asian/Pacific Islanders, with an overall AA:NHW ratio of 1.13 for incidence and 1.32 for mortality (2010-2014, seer.cancer.gov). The disparity for CRC incidence and worsened mortality among AAs is likely multifactorial and includes environmental (e.g., diet and intestinal microbiome composition, prevalence of obesity, use of aspirin, alcohol, and tobacco use), societal (e.g., socioeconomic status, insurance and access to care, and screening uptake and behaviors), and genetic (e.g., somatic driver mutations, race-specific variants in genes, and inflammation and immunological factors). Some of these parameters have been investigated, and interventions that address specific parameters have proven to be effective in lowering the disparity. For instance, there is strong evidence raising screening utilization rates among AAs to that of NHWs reduces CRC incidence to that of NHWs. Reducing the age to commence CRC screening in AA patients may further address incidence disparity, due to the earlier age onset of CRC. Identified genetic and epigenetic changes such as reduced MLH1 hypermethylation frequency, presence of inflammation-associated microsatellite alterations, and unique driver gene mutations (FLCN and EPHA6) among AA CRCs will afford more precise approaches toward CRC care, including the use of 5 fluorouracil and anti-PD-1. PMID- 30524962 TI - Role and Regulation of Pro-survival BCL-2 Proteins in Multiple Myeloma. AB - Apoptosis plays a key role in protection against genomic instability and maintaining tissue homeostasis, and also shapes humoral immune responses. During generation of an antibody response, multiple rounds of B-cell expansion and selection take place in germinal centers (GC) before high antigen affinity memory B-cells and long-lived plasma cells (PC) are produced. These processes are tightly regulated by the intrinsic apoptosis pathway, and malignant transformation throughout and following the GC reaction is often characterized by apoptosis resistance. Expression of pro-survival BCL-2 family protein MCL-1 is essential for survival of malignant PC in multiple myeloma (MM). In addition, BCL 2 and BCL-XL contribute to apoptosis resistance. MCL-1, BCL-2, and BCL-XL expression is induced and maintained by signals from the bone marrow microenvironment, but overexpression can also result from genetic lesions. Since MM PC depend on these proteins for survival, inhibiting pro-survival BCL-2 proteins using novel and highly specific BH3-mimetic inhibitors is a promising strategy for treatment. This review addresses the role and regulation of pro survival BCL-2 family proteins during healthy PC differentiation and in MM, as well as their potential as therapeutic targets. PMID- 30524963 TI - Co-occurrence of Dermatomyositis and Polycythemia Unveiling Rare de Novo Neuroendocrine Prostate Tumor. AB - We present a case of dermatomyositis together with polycythemia as initial manifestations of a particularly rare type of prostate cancer. A 69-year-old man was hospitalized for facial erythema and symptoms of fatigue. Physical evaluation, serum creatinine phosphokinase and electromyography were consistent with dermatomyositis. In parallel, the hemoglobin level was 18.5 g/dL, serum erythropoietin levels were low normal and no JAK2 mutation was found. Given a strong suspicion of a paraneoplastic syndrome the patient underwent abdominal computed tomography revealing a prostate mass, enlarged iliac lymph nodes and a fracture of L1 due to metastasis. The unusual paraneoplastic manifestations prompted a more thorough immunohistologic examination of the needle biopsy specimen taken from the prostate, which led to the diagnosis of large cell neuroendocrine prostate carcinoma. It is a most rare type of prostate cancer, carrying a poor prognosis. To our knowledge, this is the first case in the literature associating a neuroendocrine cancer of the prostate with dermatomyositis. PMID- 30524964 TI - Genome-Wide Profiling of Prognostic Alternative Splicing Signature in Colorectal Cancer. AB - Background: This study was to explore differential RNA splicing patterns and elucidate the function of the splice variants served as prognostic biomarkers in colorectal cancer (CRC). Methods: Genome-wide profiling of prognostic alternative splicing (AS) events using RNA-seq data from The Cancer Genome Atlas (TCGA) program was conducted to evaluate the roles of seven AS patterns in 330 colorectal cancer cohort. The prognostic predictors models were assessed by integrated Cox proportional hazards regression. Based on the correlations between survival associated AS events and splicing factors, splicing networks were built. Results: A total of 2,158 survival associated AS events in CRC were identified. Interestingly, most of these top 20 survival associated AS events were adverse prognostic factors. The prognostic models were built by each type of splicing patterns, performing well for risk stratification in CRC patients. The area under curve (AUC) of receiver operating characteristic (ROC) for the combined prognostic predictors model could reach 0.963. Splicing network also suggested distinguished correlation between the expression of splicing factors and AS events in CRC patients. Conclusion: The ideal prognostic predictors model for risk stratification in CRC patients was constructed by differential splicing patterns of 13 genes. Our findings enriched knowledge about differential RNA splicing patterns and the regulation of splicing, providing generous biomarker candidates and potential targets for the treatment of CRC. PMID- 30524966 TI - A Unique Human Immunoglobulin Heavy Chain Variable Domain-Only CD33 CAR for the Treatment of Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) remains a challenging pediatric and adult disease. Given the elevated expression of the CD33 antigen on leukemic blasts, therapeutic approaches to AML now feature the approved antibody drug conjugate (Mylotarg, GO) and investigational CART cell approaches incorporating CD33-binding domains derived from humanized scFvs. We designed a functional chimeric antigen receptor utilizing a human targeting sequence, derived from a heavy chain variable domain, termed CAR33VH. Lentiviral-based expression vectors which encoded CAR constructs incorporating the novel binding domain (CAR33VH), or the My96 scFv control binder (My96CAR) in frame with a CD8 hinge and transmembrane domain, a 4-1BB costimulatory domain and a CD3 zeta activation domain, were transduced into primary human CD4+ and CD8+ T cells, and CAR expression was confirmed by flow cytometry. CAR33VH, similar to My96CAR, demonstrated robust and specific cytotoxicity in short-term and long-term co-incubation killing assays against CD33+ AML lines. In overnight cytokine release assays in which CAR T cells were challenged with the CD33+ tumor cells HL-60, MOLM-14 and KG-1a, CAR33VH elicited IFN-gamma, TNF-alpha and IL-2. This was seen with CD33+ cell lines, but not when CAR T were cultured alone. Studies with a CD33- cell line engineered to stably express the full length CD33 variant 1, or the naturally occurring CD33 splice variant 2, revealed that both CAR33VH and My96CAR, target the V domain of CD33, suggesting a similar therapeutic profile. Colony-formation assays utilizing peripheral blood CD34+ hematopoietic stem cells treated with CAR33VH, My96CAR, or with an untransduced T cell control, yielded similar numbers of BFU-E erythroid and CFU-GM myeloid colonies, suggesting a lack of CAR-related overt toxicity. In an in vivo AML model, NSG mice engrafted with MOLM-14 cells stably expressing firefly luciferase, both CAR33VH and CARMy96 efficiently eliminated tumors. In conclusion, we demonstrate for the first time the feasibility and efficacy of employing human variable domain-only binder derived from a phage display library in an anti-AML CAR design. CAR33VH, comprised of a human heavy-chain variable fragment-only antigen binding domain, was efficient in tumor killing in vitro and in vivo, and showed comparable functionality to the scFv-based My96CAR. PMID- 30524967 TI - Giant Intrapericardial Myxoma Adjacent to the Left Main Coronary Artery. AB - A 62-years-old woman was admitted to the hospital because of chronic cough, expectoration of thick mucus, hoarseness and tightness in the precordial area. Computed Tomography (CT) examination revealed the presence of a giant intrapericardial tumor with the dimensions of 80 * 38 * 32 mm. It was located anteriorly and laterally to the left atrium, posteriorly to the pulmonary trunk and the ascending aorta. This hypodense change modeled the left atrium without evidence of invasion. CT coronary angiography and 3-dimensional reconstruction were applied to enable precise planning of cardiac surgery. CT evaluation confirmed that it is possible to remove the tumor without damage to the adjacent left main coronary artery. The patient underwent cardiac surgery with sternotomy and cardiopulmonary bypass. A cohesive, smooth, vascularized tumor pedunculated to the left atrial epicardium was visualized. The location and dimensions corresponded to those determined by CT scan examination. The entire tumor was successfully dissected together with adjacent adipose and fibrous tissue. Histological evaluation revealed the presence of myxoid cells, blood vessels, degenerative changes, and microcalcifications embedded in profuse hyalinized stroma. Those histological features enabled identification of the intrapericardial tumor as a myxoma. Follow-up CT examination did not demonstrate any signs of recurrence of the myxoma. According to our knowledge, a myxoma located inside the pericardial sac has never been described before. PMID- 30524968 TI - Quantitative Proteomic Analysis Identifies MAPK15 as a Potential Regulator of Radioresistance in Nasopharyngeal Carcinoma Cells. AB - Since resistance to radiotherapy remains refractory for the clinical management of nasopharyngeal cancer (NPC), further understanding the mechanisms of radioresistance is necessary in order to develop more effective NPC treatment and improve prognosis. In this study, an integrated quantitative proteomic approach involving tandem mass tag labeling and liquid chromatograph-mass spectrometer was used to identify proteins potentially responsible for the radioresistance of NPC. The differential radiosensitivity in NPC model cells was examined through clonogenic survival assay, CCK-8 viability assay, and BrdU incorporation analysis. Apoptosis of NPC cells after exposure to irradiation was detected using caspase-3 colorimetric assay. Intracellular reactive oxygen species (ROS) was detected by a dichlorofluorescin diacetate fluorescent probe. In total, 5,946 protein groups were identified, among which 5,185 proteins were quantified. KEGG pathway analysis and protein-protein interaction enrichment analysis revealed robust activation of multiple biological processes/pathways in radioresistant CNE2-IR cells. Knockdown of MAPK15, one up-regulated protein kinase in CNE2-IR cells, significantly impaired clonogenic survival, decreased cell viability and increased cell apoptosis following exposure to irradiation, while over-expression of MAPK15 promoted cell survival, induced radioresistance and reduced apoptosis in NPC cell lines CNE1, CNE2, and HONE1. MAPK15 might regulate radioresistance through attenuating ROS accumulation and promoting DNA damage repair after exposure to irradiation in NPC cells. Quantitative proteomic analysis revealed enormous metabolic processes/signaling networks were potentially involved in the radioresistance of NPC cells. MAPK15 might be a novel potential regulator of radioresistance in NPC cells, and targeting MAPK15 might be useful in sensitizing NPC cells to radiotherapy. PMID- 30524965 TI - SIRT6 Is Involved in the Progression of Ovarian Carcinomas via beta-Catenin Mediated Epithelial to Mesenchymal Transition. AB - SIRT6 is involved in various cellular signaling pathways including those involved in tumorigenesis in association with beta-catenin. However, the role of SIRT6 in tumorigenesis has been controversially reported and the studies on the role of SIRT6 in ovarian cancers is limited. In this study, we evaluated the expression and roles of SIRT6 in conjunction with the expression of active beta-catenin in 104 human ovarian carcinomas and ovarian cancer cells. In human ovarian carcinomas, the expressions of SIRT6 and active beta-catenin were associated with higher tumor stage, higher histologic grade, and platinum-resistance. Moreover, nuclear expression of SIRT6 (104 ovarian carcinomas; P = 0.010, 63 high-grade serous carcinomas; P = 0.040), and activated beta-catenin (104 ovarian carcinomas; P = 0.013, 63 high-grade serous carcinomas; P = 0.005) were independent indicators of shorter overall survival of ovarian carcinoma patients in multivariate analysis. In OVCAR3 and OVCAR5 ovarian cancer cells, knock-down of SIRT6 significantly inhibited the migration and invasion of cells, but did not inhibit the proliferation of cells. SIRT6-mediated invasiveness of ovarian cancer cells was associated with the expression of epithelial-to-mesenchymal transition related signaling molecules such as snail, vimentin, N-cadherin, E-cadherin, and activated beta-catenin. Especially, SIRT6-mediated increase of invasiveness and activation of epithelial-to-mesenchymal transition signaling was attenuated by knock-down of beta-catenin. In conclusion, this study suggests that SIRT6-beta catenin signaling is involved in the epithelial-to-mesenchymal transition of ovarian cancer cells, and the expression of SIRT6 and active beta-catenin might be used as indicators of poor prognosis of ovarian carcinoma patients. In addition, our results suggest that SIRT6-beta-catenin signaling might be a new therapeutic target of ovarian carcinomas. PMID- 30524969 TI - Repeated Courses of Radiosurgery for New Brain Metastases to Defer Whole Brain Radiotherapy: Feasibility and Outcome With Validation of the New Prognostic Metric Brain Metastasis Velocity. AB - Purpose: Stereotactic radiosurgery (SRS) is the preferred primary treatment option for patients with a limited number of asymptomatic brain metastases. In case of relapse after initial SRS the optimal salvage treatment is not well defined. Within this retrospective analysis, we investigated the feasibility of repeated courses of SRS to defer Whole-Brain Radiation Therapy (WBRT) and aimed to derive prognostic factors for patient selection. Materials and Methods: From 2014 until 2017, 42 patients with 197 brain metastases have been treated with multiple courses of SRS at our institution. Treatment was delivered as single fraction (18 or 20 Gy) or hypo-fractionated (6 fractions with 5 Gy) radiosurgery. Regular follow-up included clinical examination and contrast-enhanced cMRI at 3-4 months' intervals. Besides clinical and treatment related factors, brain metastasis velocity (BMV) as a newly described clinical prognostic metric was included and calculated between first and second treatment. Results: A median number of 1 lesion (range: 1-13) per course and a median of 2 courses (range: 2 6) per patient were administered resulting in a median of 4 (range: 2-14) metastases treated over time per patient. The median interval between SRS courses was 5.8 months (range: 0.9-35 months). With a median follow-up of 17.4 months (range: 4.6-45.5 months) after the first course of treatment, a local control rate of 84% was observed after 1 year and 67% after 2 years. Median time to out of-field-brain-failure (OOFBF) was 7 months (95%CI 4-8 months). WBRT as a salvage treatment was eventually required in 7 patients (16.6%). Median overall survival (OS) has not been reached. Grouped by ds-GPA (<= 2 vs. >2) the survival curves showed a significant split (p = 0.039). OS differed also significantly between BMV-risk groups when grouped into low vs. intermediate/high risk groups (p = 0.025). No grade 4 or 5 acute or late toxicity was observed. Conclusion: In selected patients with relapse after SRS for brain metastases, repeat courses of SRS were safe and minimized the need for rescue WBRT. The innovative, yet easy to calculate metric BMV may facilitate treatment decisions as a prognostic factor for OS. PMID- 30524971 TI - Dual Transcriptomics of Host-Pathogen Interaction of Cystic Fibrosis Isolate Pseudomonas aeruginosa PASS1 With Zebrafish. AB - Pseudomonas aeruginosa is a significant cause of mortality in patients with cystic fibrosis (CF). To explore the interaction of the CF isolate P. aeruginosa PASS1 with the innate immune response, we have used Danio rerio (zebrafish) as an infection model. Confocal laser scanning microscopy (CLSM) enabled visualization of direct interactions between zebrafish macrophages and P. aeruginosa PASS1. Dual RNA-sequencing of host-pathogen was undertaken to profile RNA expression simultaneously in the pathogen and the host during P. aeruginosa infection. Following establishment of infection in zebrafish embryos with PASS1, 3 days post infection (dpi), there were 6739 genes found to be significantly differentially expressed in zebrafish and 176 genes in PASS1. A range of virulence genes were upregulated in PASS1, including genes encoding pyoverdine biosynthesis, flagellin, non-hemolytic phospholipase C, proteases, superoxide dismutase and fimbrial subunits. Additionally, iron and phosphate acquisition genes were upregulated in PASS1 cells in the zebrafish. Transcriptional changes in the host immune response genes highlighted phagocytosis as a key response mechanism to PASS1 infection. Transcriptional regulators of neutrophil and macrophage phagocytosis were upregulated alongside transcriptional regulators governing response to tissue injury, infection, and inflammation. The zebrafish host showed significant downregulation of the ribosomal RNAs and other genes involved in translation, suggesting that protein translation in the host is affected by PASS1 infection. PMID- 30524970 TI - An Experimental Pipeline for Initial Characterization of Bacterial Type III Secretion System Inhibitor Mode of Action Using Enteropathogenic Yersinia. AB - Dozens of Gram negative pathogens use one or more type III secretion systems (T3SS) to disarm host defenses or occupy a beneficial niche during infection of a host organism. While the T3SS represents an attractive drug target and dozens of compounds with T3SS inhibitory activity have been identified, few T3SS inhibitors have been validated and mode of action determined. One issue is the lack of standardized orthogonal assays following high throughput screening. Using a training set of commercially available compounds previously shown to possess T3SS inhibitory activity, we demonstrate the utility of an experiment pipeline comprised of six distinct assays to assess the stages of type III secretion impacted: T3SS gene copy number, T3SS gene expression, T3SS basal body and needle assembly, secretion of cargo through the T3SS, and translocation of T3SS effector proteins into host cells. We used enteropathogenic Yersinia as the workhorse T3SS expressing model organisms for this experimental pipeline, as Yersinia is sensitive to all T3SS inhibitors we tested, including those active against other T3SS-expressing pathogens. We find that this experimental pipeline is capable of rapidly distinguishing between T3SS inhibitors that interrupt the process of type III secretion at different points in T3SS assembly and function. For example, our data suggests that Compound 3, a malic diamide, blocks either activity of the assembled T3SS or alters the structure of the T3SS in a way that blocks T3SS cargo secretion but not antibody recognition of the T3SS needle. In contrast, our data predicts that Compound 4, a haloid-containing sulfonamidobenzamide, disrupts T3SS needle subunit secretion or assembly. Furthermore, we suggest that misregulation of copy number control of the pYV virulence plasmid, which encodes the Yersinia T3SS, should be considered as a possible mode of action for compounds with T3SS inhibitory activity against Yersinia. PMID- 30524972 TI - Disseminated Adenovirus Infection After Combined Liver-Kidney Transplantation. AB - Human adenovirus (HAdV) infections are well-described after hematopoietic stem cell transplantation but less well understood in solid organ transplantation (SOT). We describe a case of disseminated HAdV type 21 infection 5 months after combined liver-kidney transplantation, expanding the limited literature describing this infection in the SOT population. PMID- 30524973 TI - Effects of Rock Climbing Exercise on Physical Fitness among College Students: A Review Article and Meta-analysis. AB - Background: The aim of this study was to systematically determine the effects of rock climbing on College Students' physical fitness by means of Meta-analysis. Methods: Studies investigated the possible fitness benefits of rock climbing were identified through a computerized search of six electronic databases: China National Knowledge Infrastructure, China Science Periodical Database, PubMed, Web of Science, SPORTDiscus and PsycINFO. Effects of rock climbing exercise intervention trials >=4 wk, published in English and Chinese between Jan 1996 and May 2016, including between subject and within subject designs, were reviewed. Nine studies were included in this meta-analysis. Ten selected variables in this meta-analysis were: Body fat percentage, VO2max, Heart rate, Handgrip strength, Lower limb pedaling power, Vertical Jump, Push-Ups, Pull-Ups, Sit-Ups, and Sit and-reach. The effect sizes of these ten variables were calculated (P<0.05) and forest plots along with effective sizes were presented. Results: Rock climbing can significantly improve Handgrip strength, Lower limb pedaling power, Vertical Jump, Push-Ups, Pull-Ups, Sit-Ups and Sit-and-reach (P<0.01), and significantly increase VO2max (P<0.05), however, rock climbing did not show significant improvement on Heart rate and Body fat percentage. Conclusion: As a newly popular physical exercise, rock climbing has a significantly positive impact on the physical fitness among college students. Rock climbing may be more effective if the college students engage in it for a longer term. PMID- 30524974 TI - Next Generation Sequencing in Clinical Oncology: Applications, Challenges and Promises: A Review Article. AB - Background: The aim of this mini-review is to highlight the potential applications of next-generation sequencing technology to the field of clinical oncology with respect to genetic diagnosis, cancer classification, predictive biomarkers and personalized medicine. Methods: Scientific databases were searched to collect relative data. Results: Effective systematic analysis of whole-genome sequence and whole-exome sequence of tumors, targeted genome profiling, transcriptome sequencing and tumor-normal comparisons can be performed using NGS in order to diagnosis of several types of cancer. Conclusion: NGS technology can be powerful enough to discover new and infrequent gene alterations, identify hereditary cancer mutation carriers and provide a reliable molecular portrait of wide range of cancers in a quick and cost-effective manner. PMID- 30524975 TI - The History of Trachoma and Current Prevalence (Spotlight on Iran): A Review Article. AB - Background: Trachoma as a common cause of infectious blindness is caused by Chlamydia trachomatis. This study aimed to review the available data from variety of sources and provide an overview of the epidemiological situation of Trachoma in Iran focused on the past seventy five years. Methods: A literature search of English and Farsi articles regarding trachoma in Iran from the electronic databases and paper documents was performed. Original articles, case reports and letters were included. Results: By the early and mid-20th century, trachoma was widely endemic with the prevalence rate of more than 60% in Iran. Currently, trachoma prevalence is significantly lower than in the past and the elimination of trachoma is achievable in the near future. The decline in active disease is mainly attributed to improvement of socio-economic situation and personal and environmental hygiene rather than targeted interventions for epidemic control. Conclusion: Elimination of trachoma in Iran is achievable. However, trachoma prevalence estimation is required to be interpreted with some caution. Uncertainty around these estimates is partly because of the mismatch between the presence of infection and clinical findings. PMID- 30524976 TI - Oral Health Impact Profile and Associated Variables in Southern Brazilian Drug Users. AB - Background: This study investigated the association between sociodemographic, behavioral, oral health, variables of drug consumption, and the short version of the Oral Health Impact Profile (OHIP-14), in Southern Brazilian drug users. Methods: In this cross-sectional study, 202 drug users aged 18 or over admitted for treatment at the Institute for Research and Treatment of Alcoholism (Instituto de Pesquisa e Tratamento do Alcoolismo -IPTA) from the municipality of Campo Largo, PR, Brazil, from 2012 to 2014, were involved. They answered a questionnaire and were examined by a calibrated researcher. Data were collected and bivariate (Chi-square test) and multivariate (logistic regression and Wald's test) analyses were performed. Results: There was statistical difference (P<0.05) in bivariate analysis and the worst impacts were reported by non-whites, those who reported feeling metallic taste in mouth and tooth mobility, which use cigarettes for over 15 yr and consume more than 3 g of crack/day, with DMFT >10, and number of teeth in mouth <=27. In the multivariate analysis, statistical difference remained, except for ethnicity (P=0.207). Conclusion: Self-perception of oral health was associated with the variables explored, which suggests the need for strategies focused on this population. PMID- 30524977 TI - Exploring the Association between Parental Factors and Age of Onset of Alcohol and Tobacco's Using. AB - Background: There are few reports about relationship between parents' age of onset of substance use and their children's age of onset. The aim of this study was to explore the association between parents' age of onset of substance use and that of their children, the influence of parents' factor on their children's age of onset of substance use. Methods: Overall, 2036 Chinese college students from ten universities in five cities were assessed for their alcohol and tobacco's use, and they reported on their parents' alcohol and tobacco's use, their parents' attitudes towards their substance use and their parental education level. Among current substance users, multiple regression analyses were used to test whether their parents' age of onset of substance use and their parents' attitudes towards their substance use predict their age of onset of substance use. Results: Parents of children who used substances earlier showed significantly more tolerance towards their children's substance use than parents of children with a later onset of substance use. Among current substance users, their parents' age of onset of substance significantly predicted children's age of onset. The parents' attitudes had a significant impact on their children's age of onset of substance use. Conclusion: Parental factors (attitudes towards their children's substance use and parents' age of onset of substance use) are related to age of onset and substance use in children. Prevention program for parents is necessary, especially for those parents who have a tolerant attitude towards their children's substance use. PMID- 30524978 TI - The Prevalence of Lymphatic Filariasis in Elementary School Children Living in Endemic Areas: A Baseline Survey Prior to Mass Drug Administration in Pekalongan District-Indonesia. AB - Background: WHO initiated lymphatic filariasis (LF) elimination globally. Pekalongan District, as LF endemic area, started a program of mass drug administration (MDA) to combat LF in 2015. This study aimed to determine prevalence of Wuchereria bancrofti infection prior to the MDA. Methods: LF infection was detected by the existence of circulating filarial antigen (CFA) W. bancrofti using immunochromatographic card test (ICT). The study population consisted of 1404 elementary school (ES) students living in Pekalongan District. Overall, 1033 were selected as study subjects. Prevalence survey was also conducted on 436 general population in areas where infected students were found. Results: The subjects ranged from 7-17 yr old (mean 9.85+/-1.296) and equally distributed between both sexes. Prevalence of W. bancrofti infection was 1.98% in children. Infection was mostly found in older students (12 yr old), male, in 6th grade, but did not differ significantly (P=0.129, 0.376, and 0.212 respectively). On the other hand, distribution of infection was significantly different by school (P=0.009) and sub-district (P=0000). Most of children with LF infection were found in Tirto Sub District. In general population, the prevalence of W. bancrofti infection in Tirto was 4.4%. Proportion of infection in males (12.2%) was greater than females (3.8%), with 78.9% of positive cases were in adult over 20 yr old. Conclusion: Cases of W. bancrofti infection exist in Pekalongan District, both in children and adults. Implementation of MDA must be carefully monitored in order to achieve elimination target. PMID- 30524979 TI - Analysis of the Factors Influencing Enterprise and Government Participation in the Medicines Patent Pool Based on System Dynamics Model. AB - Background: The participation of enterprises and governments in the Medicines Patent Pool (MPP) improves the disease management levels by enhancing the accessibility of medical resources. Non-participation of the stakeholders restricts the development of the MPP. Hence, systematic analysis of the key factors influencing MPP participation is necessary. Methods: A system dynamics model of the market before and after enterprises and governments join the MPP was constructed by considering the economic benefits of both stakeholders. The effects of generic drug prices, royalty rates, pooling subsidies, and enterprise scale on the relevant benefit difference were analyzed. Data from the China Medical and Economic Network for the period 2003-2016, as well as the 2017 annual report of Celgene Corporation, were used as test data. Results: The proper pooling subsidy coefficient ranges between 0.05 and 0.08 when the generic drug price ratio and royalty rate are lower than 36% and 34%, respectively. These factors could enhance the willingness of both stakeholders to join the MPP. Initial R&D investments and the relative drug patent intensity of enterprises respectively exert positive and negative impacts on their willingness to join the MPP. Conclusion: To encourage stakeholders to join the MPP, generic drug prices should be lowered, license fees and subsidies should be adjusted appropriately, and the R&D scale and strength of original drug enterprises should be taken into account. The research results provide a reference for formulating the rules of MPP and other policies aiming to facilitate the sharing and innovation of medical resources. PMID- 30524980 TI - Computer Game Addiction and Loneliness in Children. AB - Background: We aimed to determine the level of computer game addiction and loneliness among 9-10-yr-old children. Methods: The study was conducted with 4th grade students at a primary school, located at the city center, during 2017-2018 academic years. There was no sampling in the research, all 4th-grade students of the school were reached. "Personal Information Form", "Computer Game Addiction Scale" and "UCLA Loneliness Scale" were used for collecting data. Mann Whitney U test, Kruskal Wallis test, and Correlation Analysis were used to evaluate the data of the research. Results: 50.7% (n=104) of the students were female, most frequent number of sister/brother was one 39.0% (n=80), both their mother 31.7% (n=65) and their father 34.1% (n=69) were mostly high school graduated. The average scores that students got from the scales were; 48.66+/-.27.02 (min.: 21.00, max.: 105) for "Computer Game Addiction Scale" and 40.55+/-8.50 (min: 22.00, max.: 64) for "UCLA Loneliness Scale". A weak, positive and significant relationship was found between students' loneliness scale scores and computer game addiction scale scores (r=0.357; P<0.000). Conclusion: A significant relationship was found between students' computer game addiction and loneliness. It is suggested to perform children's loneliness and computer game addiction assessments, evaluate effectiveness and establish a rehabilitating treatment system among school-hospital-family for abnormal cases. PMID- 30524981 TI - Influence of Nursing Intervention on Recurrent Vulvovaginal Candidiasis Patients Treated with ATP-infrared Bio-effect Technique. AB - Background: We aimed to investigate the influence of nursing intervention on recurrent vulvovaginal candidiasis (RVVC) patients treated with adenosine triphosphate (ATP)-infrared bio-effect technique. Methods: Sixty eight RVVC patients of Women & Children's Health Care Hospital of Linyi were randomly divided into intervention group (n=34) and control group (n=34) from to June, 2016 to June 2017. Patients in intervention group received the one-to-one intervention based on ATP-infrared bio-effect technique; the individualized nursing intervention program was developed. Patients in control group were treated with routine nursing for vaginitis and follow-up. The intervention effect was evaluated via clinical efficacy and MOS 36-item short-form health survey (SF 36) scale. Results: After the total course of treatment, there was significant difference in the cure rate between the two groups of patients (P<0.05). 1 month after all courses of treatment, the scores of physical functioning (PF), mental health (MH), vitality (V) and bodily pain (BP) in intervention group were higher than those in control group, displaying statistically significant differences (P=0.029; P=0.049; P=0.042; P=0.039, respectively). 6 months after the total course of treatment, the score of each dimension in intervention group was higher than that in control group during the same period (P<0.01). Conclusion: Nursing intervention can increase the cure rate, change the adverse cognition and improve the quality of life of RVVC patients treated with ATP-infrared bio-effect technique. PMID- 30524982 TI - The Clustering of World Countries Regarding Causes of Death and Health Risk Factors. AB - Background: We aimed to determine how many clusters, WHO member countries would be grouped based on the causal rates of disease-specific deaths and preventable risk factors, and evaluated the cluster memberships using some sociodemographic and socioeconomic factors. Methods: We constructed a dataset relating to 146 WHO countries using reports and some official websites. An explanatory factor analysis was implemented to reveal the underlying patterns of the dataset. The Ward Hierarchical clustering method and gap statistical analyses were used to group countries that have similar causes of death. Clusters were then compared using subgroup analysis based on some socioeconomic and sociodemographic indicators. Results: We divided 146 countries into six meaningful clusters. In a comparative analysis, the differences between clusters were found to be statistically significant according to disease-specific causes of death, risk factors, socioeconomic, and sociodemographic indicators (P<0.001). Conclusion: Income levels, expenditure rates on health, educational levels, and causes of death in a country are directly proportional to one another. Furthermore, it was surprising that the country clusters regarding causes of death and health risk factors showed regional distributions. PMID- 30524983 TI - Correlation Analysis between Helicobacter pylori Infection Status and Tumor Clinical Pathology as Well as Prognosis of Gastric Cancer Patients. AB - Background: We aimed to investigate the correlation between Helicobacter pylori infection and the development and prognosis of gastric cancer. Methods: Retrospective analysis was used to collect 120 paraffin-embedded specimens and 42 paracancerous specimens of gastric cancer patients archived in Department of Pathology, Weihaiwei People's Hospital from 2010-2012. All patients with gastric cancer were followed for 5 years. Real-time fluorescent quantitative PCR was used to detect the relative H. pylori infection in gastric cancer tissues and paracancerous tissues. The relationship between clinicopathological parameters and H. pylori relative infection was analyzed. Kaplan-Meier was used for survival analysis. Results: The relative amount of H. pylori infection in gastric cancer tissues was significantly higher than that in paracancerous normal tissues (P<0.001). The relative H. pylori infection was related to tumor size, lymph node metastasis, clinical stage, and depth of invasion (P<0.05). The 1-, 3-, and 5 year survival rates of gastric cancer patients were negatively correlated with the relative H. pylori infection. The relative H. pylori infection, age, tumor size, lymph node metastasis, distant metastasis, clinical stage and depth of invasion were positively correlated with the prognosis of patients with gastric cancer. Conclusion: The relative H. pylori infection and clinical stage of patients could increase the risk of death in gastric cancer patients. H. pylori is one of the independent risk factors for the progression and prognosis of gastric cancer. It is also an index to evaluate the development process and prognosis of gastric cancer. PMID- 30524984 TI - On the Frontline: Exploring the Perceptions of Lahore's Inner-city School Teachers Regarding Children Problems. AB - Background: We aimed to explore inner city school teachers' perceptions of problems faced in schools, it causes and role of schools and teachers in promoting child social and emotional well-being, using qualitative approach. Methods: Following ethical approval and informed consent, In-depth interviews were conducted in 2017 with twenty teachers belonging to four private schools in inner city area of Provincial capital, Lahore, Pakistan. Inclusion criteria were at least 12 years of formal education and minimum of 5 years' experience in teaching profession. Framework Analysis was used to analyze data. Results: Teachers identified learning problems, inattention, disobedience, aggression, lying & disrespect as the most commonly encountered problems of children, with very few teachers mentioning emotional difficulties. Teachers view the family, parenting practices and home environment alongside media (in particular social media) as being the main causes of child behavioral problems. With prompts, however, they did identify various school and teacher-related factors having negative impact on children. Fair conceptualization of good school and good teacher was observed. Need for teacher awareness and training for strategies promoting child emotional and social wellbeing was highlighted. Conclusion: As perceived by teachers, children studying in inner city schools have several behaviour problems. Study results and the gaps identified will help in ensuring that teachers receive training targeted towards their needs. Findings of the study also substantiate the need for targeting whole school-wide preventive approach as efforts begin to implement school mental health initiative in Pakistan. PMID- 30524985 TI - Application of Doctor-Nurse-Patient Integration Management Mode in Patients with Endometriosis. AB - Background: To investigate the effect of applying doctor-nurse-patient integration management mode to patients with endometriosis (EMT). Methods: A total of 160 patients with EMT from the Department of Neurology of The Fifth Affiliated Hospital Sun Yat-Sen University from January 2017 to October 2017 were selected. They were divided into control group and experimental group according to the time sequence of hospitalization, with 80 patients in each group. The traditional nursing management mode was implemented in the control group, and doctor-nurse-patient integration mode was implemented in the experimental group. The psychological status, quality of life, and satisfaction of the 2 groups of patients were compared one year after surgery. Results: The anxiety and depression scores in the observation group were (41.89+/-7.50) and (42.40+/-7.40) points, respectively, and those in the control group were (57.55+/-9.68) and (55.00+/-9.35) points, respectively. The differences between the two groups were statistically significant (t=-11.44, -9.42, P<0.05). The improvement rate of quality of life (sleep, work and sexual life) in the observation group was 87.5%, which was higher than that in the control group (63.8%). The difference between the 2 groups was statistically significant (U=583, P<0.01). The satisfaction rate in the observation group was 90.00%, which was higher than that in the control group (78.75%) (U=592.00, P< 0.01). Conclusion: The doctor-nurse-patient integration management mode can effectively improve the negative psychological status and quality of life of patients with EMT and improve patient satisfaction, which is worth popularizing. PMID- 30524986 TI - A Description of the Temporal Pattern of Out-of-Pocket Expenditure Related to Iranian Healthcare Services during 1995-2014. AB - Background: Out-of-pocket (OOP) expenditure directly impacts on poverty and household welfare, especially when there is a decline in healthcare financing. This study was aimed to describe the temporal pattern of OOP expenditures related to Iranian healthcare services during 1995-2014. Methods: For describing the trend of OOP spending in Iran, the database of the World Bank was mined for the period under study. Further, the trend analysis has been complemented by an exhaustive and comprehensive review of the extant literature. Results: From 1995 to 2014, out-of-pocket decreased from 53.59% to 47.8% of the total health expenditure, probably because of the different health reforms implemented throughout the years. However, out-of-pocket expenditure in Iran remains higher than the world average (roughly 3 times higher). Conclusion: It is an onus of the Iranian government to make serious attempts in order to reduce out-of-pocket expenditure, as well as to protect particularly poor and vulnerable subjects against catastrophic health expenditure. In order to ensure an equitable and affordable access to the healthcare system, decision- and policy-makers in Iran should implement a review of health care costs, insurance tariffs, and healthcare services packages covered by insurance organizations as well as introduce a progressive tax-based financing scheme as soon as possible. PMID- 30524987 TI - Prevalence and Costs of Complementary and Alternative Medicine among Traumatic Patients in Iran: A Nationwide Population-based Study. AB - Background: This study was aimed to determine the prevalence, predictors and cost of CAM practitioner use among traumatic patients in Iran. Methods: This cross sectional household survey of a nationally representative sample of Iranians 15 to 64 yr old was conducted in 2011, using a three-stage cluster sampling. Short Form Injury Questionnaire 7 (SFIQ7) was utilized through face-to-face interviews and data on demographics, history of injuries, mechanism, site and type of injury, type and place of the treatment were attained. Via telephone calls, service use and costs of treatment were also collected. Results: The prevalence of CAM practitioner use in injured people and victims seeking medical care was 0.7% and 4.1%, respectively in 3-month interval in 2011. There were no significant sociodemographic differences between victims who seek unconventional settings and those who seek conventional treatment. The most common injury description treated by CAM providers was as follows: fracture (type of injury), upper limb (site of injury), fall (mechanism of injury) and cast, splint, and physiotherapy (type of treatment). The average medical cost of CAM practitioner was US$14.7 while this amount in the conventional setting was US$195.5. Conclusion: Use of CAM is not very common among injured people in Iran. However, due to lack of formal training, CAM usage has possible side effects. PMID- 30524988 TI - Genetic Polymorphisms of Catalase and Glutathione Peroxidase-1 in Keratoconus. AB - Background: Keratoconus (KC) is a degenerative eye disease which results from thinning of the cornea and causes vision distortion. Oxidative stress damage to KC corneas may be because of the failure of corneas to process reactive oxygen species which leads to corneal thinning and loss of vision. Genetic variants in antioxidant defense genes such as catalase (CAT) and glutathione peroxidase (GPX) can decrease antioxidant capacity or increase oxidative stress and alter the risk of KC in patients. We investigated and evaluated the effects of single nucleotide polymorphisms in CAT, GPX-1 on the risk of KC in an Iranian population sample. Methods: This case-control study was performed on 140 patients with KC and 150 healthy control subjects in a sample of Iranian population from Zahedan, southern Iran in 2015. Genotyping of CAT rs7943316 and GPX-1 rs1050450 polymorphisms was done using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Results: CAT rs7943316 A/T, AA genotype and A allele have a protective role against disease (OR =0.28, 95% CI =0.13-0.61, P=0.001 and OR = 0.50, 95% CI =0.35-0.72, P=0.0001, respectively) and decreased the risk of KC. Moreover, GPX-1 rs1050450 T allele increased the risk of KC in comparison with C allele (OR = 1.42, 95% CI = 1.01-2.03, P=0.03). Conclusion: CAT rs7943316 A/T, AA genotype, and A allele decreased the risk of KC. Moreover, in GPX-1 rs1050450 C/T polymorphism, T allele was associated with an increased risk of KC in our population. PMID- 30524989 TI - The Estimation of Economic Burden of Hepatitis C Virus Infection in Iran. AB - Background: One of the major causes of liver-related mortality and morbidity is Hepatitis C Virus (HCV) infection. It is also one of the reasons behinds of chronic liver disease and related complications such as cirrhosis and hepatocellular carcinoma. This autoimmune liver disease imposes a high economic burden on individuals and the society. This study aimed to estimate burden of HCV in Iran. Methods: Overall, 200 patients with HCV infection, referred to hospitals in three cities of Tehran, Karaj and Tabriz, Iran during year 2015, were randomly enrolled. To estimate the total burden of hepatitis, direct and indirect costs, costs of DALYs and social welfare were calculated. Results: Economic burden of HCV infection was obtained 26242.8 purchasing power parity (PPP$). Intangible costs of HCV was calculated 207421.6 PPP$. Conclusion: Total direct costs of HCV for each patient are more than household consumption expenditure. Therefore, it is a reasonable policy to control and increase insurance coverage of HCV patients in order to decrease their costs. PMID- 30524990 TI - Prevalence and Associated Factors of Overweight or Obesity and Abdominal Obesity in Iranian Population: A Population-based Study of Northwestern Iran. AB - Background: This population-based study aimed at investigating the prevalence and associated factors of over-weight /obesity and abdominal obesity in Iran. Methods: The study population consists of 2818 inhabitant of the urban and regional area of East-Azerbaijan, Iran in 2015. The weight, height and waist circumferences were measured and the body mass index (BMI) and conicity index were calculated. The ANCOVA and logistic regression were used for statistical analysis. Results: Prevalence of overweight, obesity and abdominal obesity was 39.6%, 24%, and 76.4% respectively. Women showed the higher prevalence of obesity (32.2%) and abdominal obesity (81.4) than men (obesity: 15.1%; abdominal obesity: 68.6%). Age, marriage and family history of obesity were independent predictors of obesity in the population (P< 0.001). In men and women, nonsmokers (P<0.01) and subjects having more than two kids (P< 0.001) were also more expected to be overweight or obese and abdominally obese respectively. Conclusion: More actions mostly focusing on education and physical activity levels, and changing eating habits are required. PMID- 30524991 TI - Ranking Factors Affecting the Attraction of Foreign Medical Tourists in Hospitals Affiliated to Mashhad University of Medical Sciences Based on Marketing Mix Model. AB - Background: This study was designed to rank factors affecting attraction of foreign medical tourists based on marketing mix model. Methods: In this descriptive study, data were collected through a questionnaire. Foreign patients, hospitalized from Jan 2015 to Sep 2016 in all hospitals of Mashhad were chosen as the study population (13 hospitals). Data analysis was conducted using Friedman test and Wilcoxon test in SPSS 21 at a significance level of 0. 05. Results: Factors of staff, service and process gained the highest score from the perspective of patients; while price, facilities and promotion scored the lowest among parameters affecting the attraction of medical tourists to hospitals of Mashhad. In this context, factors of staff (96%) and price (66%) had the highest and lowest effect on absorption of tourists, respectively. Conclusion: To promote medical tourism, important factors such as staff, service, and process should be further stressed and variables of price, facilities and promotion demand for a revision by the authorities in this industry. PMID- 30524992 TI - Effect of Temporomandibular Disorders on Quality of Life for Elderly Individuals. PMID- 30524993 TI - Kinetic Analysis of Korean Traditional Dance Movements by Using Ground Reaction Force. PMID- 30524994 TI - Construing Interpersonal Meaning through Doctors' Choice of Interrogatives: An Investigation of Doctor-patient Conversations in China. PMID- 30524995 TI - Influences of Nursing Work Environment and Patient Safety Environment on Nurse Outcomes. PMID- 30524996 TI - Two New Therapies in the Cocaine-dependents: Comparison of Topiramate and Contingency Management. PMID- 30524997 TI - The Role of INSR & Diabetes in Polycystic Ovarian Syndrome. PMID- 30524998 TI - Management of Computerized Cognitive Training Programs in Children with ADHD: The Effective Role of Decision Support Systems. PMID- 30524999 TI - Standardization of Health Terminology Systems and the Roles of Responsible Organizations. PMID- 30525000 TI - EXPERIENCE WITH MANAGING PENETRATING ANTERIOR NECK INJURIES IN LAGOS, NIGERIA. AB - Background: Penetrating anterior neck injuries are potentially life threatening and the causes vary across countries of the world. Studies in Nigeria have been mainly isolated case reports and few retrospective studies. Aim: The aim of this study was to assess the causes, severity and management outcome of patients treated in our centre. Methodology: This is a retrospective study of penetrating anterior neck injuries treated at the Lagos University Teaching Hospital over a 25-year period. The case records were retrieved and demographic data as well as the causes, site, extent of injuries and treatment outcome were analyzed. Results: The mean age of the 39 patients in this study was 30.5yrs +/- 7.9 SD with a male: female ratio of 6.8:1. Inflicted cut throat injuries accounted for 46% followed by vehicular accidents in 21%. Zone II site of the neck was the commonest site of injury 61.6% of the patients; while 71.8% of the patients presented within 24hrs of the injury, 46% of them had immediate blood transfusion. Tracheostomy was the main method of securing the airway. Primary soft tissue repair was performed on all the patients. Laryngopharyngeal repair was done in 61.5%. Peri-operative mortality was 7.7% and 83.3% had prolonged hospital admission with wound infection in 27.8% and laryngotracheal stenosis in 22.2% as the commonest complications. Conclusion: This study has shown that penetrating anterior neck injuries is not uncommon in Nigeria and commonly due to cut throat and vehicular accidents. Proper documentation and following established management protocols will improve outcome. PMID- 30525001 TI - EXPERIENCE WITH MANAGING COMPLICATED FRACTURES USING ILIZAROV PRINCIPLE IN LAGOS, NIGERIA. AB - Background: Management of complicated bone fractures in our environment is very challenging. The Ilizarov principle has been found to be a viable management option worldwide, but the use of this method in our environment has been sparsely reported. Aim: To document our use of Ilizarov method to manage patients with complicated long bone fractures and the outcome. Design of study: Prospective observational study. Setting: Lagos State University Teaching Hospital, Ikeja, Nigeria. Methodology: All the patients were treated between June 2009 and December 2012 using the Linear Rail-fixator System (LRS) according to Ilizarov principle. They were followed up for at least two years and data on demography, indications, procedure and outcome were collected and subjected to statistical analysis. Results: Thirty patients whose procedures had been concluded were recruited. The age range was 4 - 57 years with a mean of 38 years ; 17 were male while 13 were female with a male/female ratio of 1.3:1. Specific indications for treatment included infected non-union, failed implant with limb length discrepancy and mal-union. They all had bone defects ranging from 4cm to 12cm and the pre-operative period of morbidity ranged from 2 months to 8 years. Seventeen patients had acute docking and lengthening, 10 had bone transport while 3 had simple limb lengthening. Using the Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria, bone outcome was excellent in 7 patients, good in 20 and poor in 3. Functional outcome was excellent in 8, good in 19 and poor in 3. Complications included pin site infection (grades I & II) in 14 patients, knee stiffness in 6 and regenerate fracture in 1. Conclusion: Ilizarov surgery is a good method of limb reconstruction in our environment. Our major complications are the high rate of pin site infection and knee stiffness. Good pin site care and early physiotherapy is essential. PMID- 30525002 TI - EXPERIENCE WITH MANAGING CHILDHOOD URETHROCUTANEOUS FISTULA AT IBADAN. AB - Background: Urethrocutaneous fistula could be a distressing condition to the child and parents alike. Its management could be challenging and requires adequate expertise. Aim: To review the characteristics and aetiology of urethrocutaneous fistula managed in our division over a ten-year period. Methodology: All children with urethrocutaneous fistulae from July 2006 to June 2015 were subject of this review. The demography, aetiology, type of fistula, operation performed and the outcome were retrieved from the division operation book and case notes of the patients. The data was analyzed using SPSS Inc. version 20 and odd ratio. Results: Thirty-five children were managed over a period of ten tears. The age ranged from 6 months to 13 years with a mean of 4+/ 1.9years. Seventy one percent of urethrocutaneous fistulae resulted from complication of childhood male circumcision procedures performed in private hospitals and by nurses. One child (3%) had isolated perineal urethrocutaneous fistula while 26% complicated hypospadias repair at these locations: glandular in 1% case, subcoronal in 3% cases, penile in 2% cases, and penoscrotal in 3% cases. Ten (29%) children with abnormal haemoglobin AC was noted in 3 (9%) patients and haemoglobin AS in 7 (20%) patients. The odd ratio between abnormal haemoglobin and normal haemoglobin was 3.8. The surgical repair of post-circumcision urethrocutaneous fistulae and post-hypospadias had a recurrent fistulae in 4 (16%) and 3 (33%) respectively. Majority of the fistulae were repaired by simple closure in 80% post-circumcision and in 44% post-hypospadias repair. in the more difficult cases, penile degloving with urethral mobilization was done in 16% post circumcision fistula and 22% post-hypospadias fistula with no recurrence. Conclusion: in this study, post-circumcision urethrocutaneous fistula was the commonest cause of childhood urethrocutaneous fistula, the severe ones could require penile degloving to achieve repair without tension; recurrence was a major complication. PMID- 30525004 TI - HORMONAL PARAMETERS AND SEMEN MICROBIOLOGICAL PATTERN OF INFERTILE MALES: A COMPARATIVE CROSS-SECTIONAL STUDY IN BENIN CITY, SOUTH SOUTH NIGERIA. AB - Background: In many Nigerian studies, male factors were responsible for up to 50 to 70% of infertility. Aim: To evaluate the contribution of endocrinopathy and bacteriospermia to male infertility in Benin. Study design: A comparative cross sectional study. Setting: Department of Obstetrics and Gynecology of Central Hospital, Benin City. Methodology: Male partners of 355 couples who presented with infertility over 8 months were studied. The data collected included socio demographics, clinical features, hormonal assays, semen analysis, and semen culture. These were analyzed using Statistical Package for Social Sciences version 21.0, employing both univariate and bivariate analyses, and multivariate logistic regression to identify independent determinants of abnormal semen analysis. Results: The mean age of the subjects was 34.98+/-4.67 years and mean duration of infertility was 4.5+/-2.17 years. A total of 59.7% patients were of low socioeconomic status. The participants had at least a primary school education, and 81.7% dwelt in the urban areas of the state. Secondary infertility was the commonest (82.3%); while 56.6% of the subjects were overweight and 14.9% obese. 66.5% of participants had abnormal semen parameters. Oligospermia was the commonest (22.8%) abnormality. The commonest hormonal disorders were abnormality of luteinizing hormone (79.1%) and follicle stimulating hormones (26.8%). There was positive semen culture in 162(43.6%) of participants, of which 135(83.3%) had abnormal semen analysis (p=0.000). Men with positive semen culture had more than four-fold odds of having abnormal semen analysis (OR=4.554; 95%CI=2.761-7.513). Conclusion: This study has shown that male endocrinopathy and bacteriospermia contributed significantly to male infertility in our environment. PMID- 30525003 TI - A COMPARISON OF THE OBJECTIVE STRUCTURED CLINICAL EXAMINATION AND THE TRADITIONAL ORAL CLINICAL EXAMINATION IN A NIGERIAN UNIVERSITY. AB - Background: Assessment of clinical skills is essential in medical education. Ideally marks should be based on the student's competence alone. The limitations of the traditional long case examinations such as the patient and examiner variability are well known. The objective structured clinical examination (OSCE) was designed to overcome these limitations. Studies comparing the OSCE and the traditional long case examination in the same group of students are very sparse. Aim: To compare the objective structured clinical examination (OSCE) and the traditional long case examination by determining their correlations with other forms of assessment in undergraduate surgery. Setting: This study was carried out at the College of Medicine, University of Lagos, Nigeria. Methodology: The results of 612 undergraduate students in our medical school of the University of Lagos, Nigeria over a period of 4 years (2012-2015) were analysed. The scores in the long case examination , objective structured clinical examination (OSCE) , multiple choice questions and Essays were analysed and compared using the Pearson's Correlation co-efficient. SPSS version 17 software was used and a P value < 0.01 was regarded as statistically significant. Results: Overall, there was a statistical significant positive correlation among most forms of assessment. The OSCE and the long case examination had a correlation of 0.374. Compared with the long case examination, the OSCE had a higher correlation with all other forms of assessment. The total clinical score (the sum of all long case examination and OSCE) however performed better than the OSCE or the long case examination alone as it had the highest correlation with all other forms of assessment. Conclusion: The OSCE has been shown to be better than the long case examination as an indicator of the student overall knowledge of surgery as it had a superior correlation with other forms of assessments. The total clinical score was however the best indicator of the student overall knowledge in Surgery as it had the best correlation with other forms of assessment. We recommend and encourage institutions that presently combine the OSCE and the long case examination to carry out similar analysis such as ours to determine the desirability of combining LCE and OSCE rather than outright replacement of LCE with OSCE. PMID- 30525005 TI - INTESTINAL OBSTRUCTION CAUSED BY APPENDICITIS: A SYSTEMATIC REVIEW. AB - Background: The known complications of appendicitis include perforated appendicitis with generalised peritonitis, appendiceal mass, appendiceal abscess, sepsis, adhesion formation and in a few occasions, small bowel intestinal obstruction. Aim: To review published cases of intestinal obstruction due to appendicitis with a view to better understand the pathophysiology of this complication. Methodology: A search of the literature in the MEDLINE database, using PubMed and OvidSP, Scopus, Google Scholar and Cochrane Databases with the following MeSH terms: (Appendicitis or appendiceal mass, appendiceal abscess or appendiceal adhesion band) and (intestinal obstruction, intestinal herniation, intestinal strangulation, intestinal knotting and paralytic ileus) was done. Also, these searches were restricted according to the following MeSH limits: (a) January 1, 1950 to July 31, 2016, (b) English articles (c) Human. Results: Overall, 27 articles reported 45 patients with intestinal obstruction due to appendicitis. Of the 30 (66.7%) patients that the gender was indicated, 22 (48.9%) were male while 8 (17.8%) were female. In 38 (84.4%) cases the cause was mechanical obstruction resulting from one or a combination of the following: (a) appendix laid across loops of bowel bound down by adhesions, (b) herniation through a ring or gap formed by the appendix tip being attached to its base, (c) appendix tip attached to the bowel causing a torsion, (d) kinking of the bowel, (e) complex knotting. Pre-operative diagnosis was a major challenge and so, none was approached through incision based on the McBurney's point.The outcome of treatment which was mostly achieved by immediate appendectomy followed by adhesiolysis was sufficient and often gave good results. Conclusion: This study has shown that appendicitis is an important cause of intestinal obstruction. Even though pre-operative diagnosis is still a major challenge, clinical evaluation and a high index of suspicion are key to diagnosis. PMID- 30525006 TI - DIABETES INSIPIDUS IN A PATIENT WITH BRONCHOGENIC CARCINOMA AND SECONDARIES TO THE HYPOTHALAMUS - CASE REPORT. AB - : We present a middle-aged man with features of diabetes insipidus, visual and mental impairments as a result of metastases from bronchogenic carcinoma. This case is being presented because it is uncommon; high index of suspicion and the relevant imaging techniques are required for diagnosis. Surgical resection of the pituitary secondaries with post-operative chemo-radiation brought resolution of symptoms. Conclusion: In conclusion, hypothalamic metastases are uncommon and are often associated with compression of the pituitary gland and optic chiasma leading to diabetes insipidus, visual impairment and mental defects. MRI for diagnosis and surgical resection followed with chemoradiation lead to improvement of symptoms but mortality is high. PMID- 30525008 TI - Peer-Reviewed Abstracts of Scientific Paper Presentation at The 57th Annual Conference Of The West African College Of Surgeons at Ougadougou, Burkina Faso 26th February - 4th March 2017. PMID- 30525007 TI - FOREIGN BODIES IN THE URINARY BLADDER - CASE SERIES. AB - : Foreign bodies get into the bladder by self insertion, migration or as a component of iatrogenic and penetrating injuries. Diagnosis and treatment pose great challenges to the urologist especially if they are radiolucent. A common pattern of presentation is with lower urinary tract symptoms. High index of suspicion is required in patient with lower urinary symptoms. We hereby report 5 cases of foreign bodies in the urinary bladder, 2 (40%) self inflicted, 2(40%) iatrogenic and 1(20%) due to migration of the object; as well as their successful management. Conclusion: Foreign bodies in the urinary bladder still remain a great challenge to the urologist; removal of the foreign body without injury to the urinary bladder or the urethra gives good outcome. PMID- 30525009 TI - Editorial Anterior Neck Injurie. PMID- 30525010 TI - Development of an experimental model for radiation-induced inhibition of cranial bone regeneration. AB - Background: Radiation therapy is widely employed in the treatment of head and neck cancer. Adverse effects of therapeutic irradiation include delayed bone healing after dental extraction or impaired bone regeneration at the irradiated bony defect. Development of a reliable experimental model may be beneficial to study tissue regeneration in the irradiated field. The current study aimed to develop a relevant animal model of post-radiation cranial bone defect. Methods: A lead shielding block was designed for selective external irradiation of the mouse calvaria. Critical-size calvarial defect was created 2 weeks after the irradiation. The defect was filled with a collagen scaffold, with or without incorporation of bone morphogenetic protein 2 (BMP-2) (1 MUg/ml). The non irradiated mice treated with or without BMP-2-included scaffold served as control. Four weeks after the surgery, the specimens were harvested and the degree of bone formation was evaluated by histological and radiographical examinations. Results: BMP-2-treated scaffold yielded significant bone regeneration in the mice calvarial defects. However, a single fraction of external irradiation was observed to eliminate the bone regeneration capacity of the BMP-2-incorporated scaffold without influencing the survival of the animals. Conclusion: The current study established an efficient model for post-radiation cranial bone regeneration and can be applied for evaluating the robust bone formation system using various chemokines or agents in unfavorable, demanding radiation-related bone defect models. PMID- 30525011 TI - Bilateral Neonatal Testicular Torsion; Hidden Surgical Nightmare. AB - Perinatal testicular torsion is a relatively rare event that remains unidentified in many situations and managed only after an avoidable delay of time. Its current management approaches include watchful observation, delayed contralateral orchiopexy, and emergent contralateral orchiopexy. On the other hand, bilateral torsion is now being more frequently reported. However, the assessment of the contralateral testis through physical examination and imaging can be inaccurate in cases of perinatal torsion. We report a case of prenatal testicular torsion with incidentally discovered metachronous contralateral extravaginal testicular torsion. Therefore, immediate surgical intervention is recommended both when uni- or bilateral testicular torsion is suspected. Whenever possible, affected testes should be preserved as some endocrine function may be retained. PMID- 30525012 TI - Prevalence of Target Organ Damage in Chinese Hypertensive Children and Adolescents. AB - Background: Subclinical target organ damage (TOD) has been common in hypertensive children, but there is limited data in the Chinese pediatric population. This study aimed to investigate the prevalence of subclinical TOD in the Chinese hypertensive children and adolescents. Methods: A cross-sectional study was performed in children and adolescents from four schools in Jinan, China between September 2012 and September 2014. The hypertensive status was confirmed based on elevated blood pressure across three different occasions. Those with hypertension were invited to participate in the evaluation of TOD (including heart, arteries, and kidney) and metabolic disorders. A total of 7,840 children and adolescents aged 6-17 years were recruited at baseline, of whom 373 were diagnosed as hypertensive after three separate visits, and 333 (89%) participated in evaluation of TOD. Results: Among 333 hypertensive children, 47.4% had elevated carotid intima-media thickness, 32.4% had left ventricular hypertrophy, 29.2% had dyslipidemia, 7.6% had liver dysfunction, and 4.1% had microalbuminuria. Cardiovascular damages were more prevalent in children aged 9-14 years than the other age groups (i.e., 6-8 and 15-17 years). Girls had higher proportion of microalbuminuria than boys (8.2 vs. 2.6%). No significant sex and age differences were observed for the prevalence of other TODs. Nearly all subclinical TODs were much more prevalent in hypertensive children who were overweight and obese than those with normal weight, except microalbuminuria. Conclusions: The subclinical TOD is prevalent in Chinese hypertensive children and adolescents. Effective measures should be taken to fight against subclinical TOD. PMID- 30525014 TI - Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results. AB - Introduction: Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms. Methods and results: Twenty consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6-10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value -11 (7) ml/kg below the reference blood volume. Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs. 66 [5]; p < 0.05) as were the differences between the measured and the reference blood volume (-14 [2]; vs. -4 [3]; p < 0.02). Conclusions: Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume. PMID- 30525013 TI - Severity of Retrognathia and Glossoptosis Does Not Predict Respiratory and Feeding Disorders in Pierre Robin Sequence. AB - Pierre Robin sequence (PRS) may lead to life-threatening respiratory and feeding disorders. With the aim to analyse the association of the severities of retrognathia and glossoptosis with those of respiratory and feeding disorders, we retrospectively studied a series of 50 infants with retrognathia, glossoptosis, cleft palate, and airway obstruction. The patients were managed from birth to at least 6 years of age by a single pediatric team at the Armand Trousseau Hospital in Paris within a 12 years period (2000-2012). Retrognathia and glossoptosis were graded in the neonatal period according to a specific clinical examination. Ventilation assistance was required for 32/50 (64%) patients, and enteral feeding for 41/50 (82%). The grades of retrognathia and glossoptosis and the severity of respiratory disorders did not differ between patients with isolated PRS and syndromic PRS. Severe respiratory disorders were more common and long-lasting feeding (>12 months) was more frequently required in patients with syndromic PRS compared with isolated PRS (42 vs. 13%, p = 0.04 and 42 vs. 4%, p < 0.01 respectively). Using univariate analysis, neurological impairments and laryngomalacia were associated with severe respiratory disorders [Odds ratio (OR) 5.0, 95% CI 1.3-19.6; and OR 14.6, 95% CI 1.3-161.4; p < 0.05] as well as with long-lasting feeding (>12 months) disorders (OR 18.6, 95% CI 3.9-89.2 and OR 20.4, 95% CI 3,4-122.8; p < 10-2). Syndromic SPR status was also associated with severe respiratory disorders (OR 4.9, 95% CI 1-32.5; p < 0.05). Using multivariate analysis, only syndromic PRS status was predictive for severe respiratory disorders (adjusted OR 8, 95% CI 1.47-44.57; p < 0.05); and only neurological impairments remained a significant risk for long lasting feeding disorders (>12 months) (adjusted OR 21.72, 95% CI 3.4-138.63; p < 10-2). The grades of retrognathia and glossoptosis were not predictive factors for the severity of respiratory and feeding disorders. Conclusion: In children with PRS, the severity of clinical conditions may not correlate with anatomic variables but rather with laryngeal abnormalities, neurological impairement and syndromic PRS status. PMID- 30525015 TI - Monozygotic Twins Suffering From Sodium Taurocholate Cotransporting Polypeptide Deficiency: A Case Report. AB - Sodium taurocholate cotransporting polypeptide (NTCP) is a carrier protein encoded by the human SLC10A1 gene, acting as the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although NTCP was cloned as early as in 1994 and its function has been studied extensively, clinical description of NTCP deficiency remains rather limited thus far. The patients in this paper were 2 female monozygotic twins, who were referred to our hospital at the age 2 years with the complaint of persistently-raised total bile acids (TBA) for 21 months. At age 3 months, they were both diagnosed to have cholestatic liver disease due to raised serum TBA and direct bilirubin (DBIL) with the fraction >20% of the elevated total bilirubin (TBIL). Thereafter, their jaundice subsided and the DBIL levels recovered gradually, while serum TBA remained raised persistently. In view of their refractory hypercholanemia but negative symptoms and signs, SLC10A1 genetic analysis was performed for all family members to evaluate the possibility of NTCP deficiency. As a result, the twins were both homozygotes, while the parents, carriers, of the reportedly pathogenic variant c.800C>T (p.Ser267Phe). These findings suggested that NTCP deficiency may be a unique genetic factor causing transient cholestasis in early infancy, as well as, persistent hypercholanemia in pediatric patients. PMID- 30525016 TI - Late Relapse of Henoch-Schonlein Purpura in an Adolescent Presenting as Severe Gastroduodenitis. AB - Henoch-Schonlein purpura is a systemic vasculitis, commonly affecting children. Gastrointestinal manifestations are observed in 50-75% of patients; it is well known they may occur before skin lesions in about 20% of cases during the first vasculitic episode. Relapses occur in about one third of patients, typically within 4 months from the initial presentation and with milder symptoms. We report the case of a 17-year old girl with an atypical relapse of Henoch-Schonlein purpura, presenting with acute abdominal symptoms 5 years after the first episode. Esophagogastroduodenoscopy showed duodenal multiple hyperemic and hemorrhagic lesions. To our knowledge this is the first case of hemorrhagic erosive duodenitis representing a relapse of Henoch-Schonlein purpura occurring several years after the initial episode. Duodenojejunal inflammation should be considered as primary manifestation of Henoch-Schonlein purpura, not only during the first episode, but also in relapses. Endoscopy can be helpful for differential diagnosis, especially in patients with atypical manifestations. Further studies are needed to evaluate risk factors for Henoch-Schonlein purpura recurrence and the possible role of fecal calprotectin as an early marker for gastrointestinal involvement. PMID- 30525017 TI - Using Point-of-Choice Prompts to Reduce Sedentary Behavior in Sit-Stand Workstation Users. AB - Introduction: Desk-based office workers are at occupational risk for poor health outcomes from excessive time spent sitting. Sit-stand workstations are used to mitigate sitting, but lack of workstation usage has been observed. Point-of choice (PoC) prompts offer a complementary strategy for office workers to break up their sitting time. Study purpose: The purpose of this study was to examine the preliminary efficacy, preference, and acceptability of a theory-driven (i.e., 40 unique prompts encompassing social cognitive theory; TD-PoC) and an atheoretical basic reminder PoC prompt intervention (R-PoC) on reducing sedentary behavior in office workers with self-reported low sit-stand workstation usage (<=4 h per day). Methods: In a cross-over design, participants (N = 19, 78.9% female, 39.4 +/- 10.7 years of age) completed a 5-days no-prompt control condition followed by a random and counterbalanced assignment to one of the TD PoC and R-PoC active conditions with a 1-week washout period between. Preliminary efficacy was assessed during work hours with the activPAL micro accelerometer. Preference was assessed prior to each active condition and acceptability was assessed following each active condition via questionnaire. Results: The R-PoC prompt condition significantly decreased sitting time (b[se] = -49.0 [20.8], p = 0.03) and increased standing time (b[se] = 49.8 [19.7], p = 0.02) and displayed a significant increase in sit-stand transitions (b[se] = 2.3 [1.1], p = 0.04), relative to no-prompt control. Both the R-PoC and TD-PoC prompt conditions significantly decreased time spent in prolonged sitting bouts at b[se] = -68.1 [27.8], (p = 0.02), (b[se] = -76.7 [27.1], p = 0.008) relative to no-prompt control. Overall, the TD-PoC prompt condition displayed higher preference and acceptability ratings; however, these differences were not significant (p's > 0.05). Conclusion: While the R-PoC prompt condition was slightly more efficacious than the TD-PoC prompt condition, the TD-PoC prompt condition was rated with higher preference and acceptability scores. Large variations between participants in preference, acceptability, and intervention feedback may indicate need for tailored messaging which may facilitate sustained use in the long-term. PMID- 30525018 TI - Worksite Physical Activity Barriers and Facilitators: A Qualitative Study Based on the Transtheoretical Model of Change. AB - Background: Many of the studies on worksite physical activity (PA) have investigated either the effectiveness of PA programs for employees and the work related outcomes or health promotion interventions to increase PA. However, studies on barriers and enabling factors for participation are scarce and have generally not been theoretically grounded. The purpose of this qualitative study was to identify worksite PA barriers and facilitators from the perspective of the transtheoretical model of change (TTM). Methods: Thirty employees (15 females and 15 males; Mage = 44.70; SD = 5.20) were recruited to participate in semi structured interviews lasting from 60 to 90 min. Participants came from several organizations that offered PA programs and were at different exercise stages of change. They were invited to describe: (a) general information on the place of PA in their daily lives and in the workplace, and the reasons for (b) worksite PA participation or (c) non-participation. The interview transcripts were analyzed both inductively and deductively with reference to the exercise stages of change. Results: Three categories of barriers and facilitators related to physical, psychological and environmental dimensions were identified. For all exercise stages of change combined, psychological and environmental barriers were significantly more reported than physical barriers, whereas physical and psychological facilitators were more cited than environmental facilitators. Further qualitative analysis suggested that these categories differed with the exercise stage of change. At the precontemplative and contemplative stages, all types of barriers predominated (e.g., physical constraints due to the workstation, fear of management disapproval, time constraints). At the preparation stage, physical, and psychological needs emerged in relation to worksite PA (e.g., need to compensate for sedentary work, stress regulation). At the action and maintenance levels, physical, psychological, and environmental facilitators were reported (e.g., enhanced physical condition, workplace well being, social ties). At the relapse stage, specific life changes or events broke the physically active lifestyle dynamics. Conclusion: This study identified the contribution of different types of worksite PA barriers and facilitators according to the exercise stage of change. The identified facilitators are consistent with the general TTM processes of change, while being specific to the workplace. Practical strategies are discussed. PMID- 30525019 TI - Durability of Polymer Metal Multilayer: Focus on the Adhesive Chemical Degradation. AB - Mechanical toughness and high barriers to air and water may be combined in a polymer-metal multilayer film, provided that the two materials are properly bonded together. Delamination is indeed the most severe flaw observed in service. This suggests that the polyurethane (PU) adhesive at the polymer-metal interface fails to bear the shear forces, as happens principally if a multilayer system is submitted to elevated temperature and humidity. A Raman microscopy of the multilayer revealed a cohesive delamination, with glue on both the surfaces. A detailed investigation of the kinetic of degradation of the polyester was therefore carried out. IR spectroscopy of the standalone PU film hydrolyzed in a controlled manner furnished a series of aging markers. The reference curve was established for approximately a year in continuous severe aging conditions. This curve could be further used to compare the amount of degradation in real systems in a wide range of conditions and time. Moreover, at the metallized interphase, a complex with a free hydroxyl group was detected. The content of this AlIII complex based on terephthalate or carbamate increases with the progress of the ester hydrolysis reactionin the layer. PMID- 30525020 TI - New Pim-1 Kinase Inhibitor From the Co-culture of Two Sponge-Associated Actinomycetes. AB - Saccharomonospora sp. UR22 and Dietzia sp. UR66, two actinomycetes derived from the Red Sea sponge Callyspongia siphonella, were co-cultured and the induced metabolites were monitored by HPLC-DAD and TLC. Saccharomonosporine A (1), a novel brominated oxo-indole alkaloid, convolutamydine F (2) along with other three known induced metabolites (3-5) were isolated from the EtOAc extract of Saccharomonospora sp. UR22 and Dietzia sp. UR66 co-culture. Additionally, axenic culture of Saccharomonospora sp. UR22 led to isolation of six known microbial metabolites (6-11). A kinase inhibition assay results showed that compounds 1 and 3 were potent Pim-1 kinase inhibitors with an IC50 value of 0.3 +/- 0.02 and 0.95 +/- 0.01 MUM, respectively. Docking studies revealed the binding mode of compounds 1 and 3 in the ATP pocket of Pim-1 kinase. Testing of compounds 1 and 3 displayed significant antiproliferative activity against the human colon adenocarcinoma HT-29, (IC50 3.6 and 3.7 MUM, respectively) and the human promyelocytic leukemia HL-60, (IC50 2.8 and 4.2 MUM, respectively). These results suggested that compounds 1 and 3 act as potential Pim-1 kinase inhibitors that mediate the tumor cell growth inhibitory effect. This study highlighted the co cultivation approach as an effective strategy to increase the chemical diversity of the secondary metabolites hidden in the genomes of the marine actinomycetes. PMID- 30525021 TI - Catalytic Liquid-Phase Oxidation of Phenolic Compounds Using Ceria-Zirconia Based Catalysts. AB - Catalytic liquid-phase oxidation using a catalyst and oxygen gas (Catalytic wet air oxidation, CWAO) is one of the most promising technology to remove hazardous organic compounds in wastewater. Up to now, various heterogeneous catalysts have been reported for phenolic compounds decomposition. The CeO2-ZrO2 based catalysts have been recently studied, because CeO2-ZrO2 works as a promoter which supplies active oxygen species from inside the lattice to the active sites. Since it is difficult to dissolve oxygen gas into water, the use of the promoter is effective for realizing the high catalytic activity at moderate conditions. Also, CeO2-ZrO2 shows high resistance for the metal leaching during the catalytic reaction in the liquid-phase. This article reviews the studies of the catalytic liquid-phase oxidation of phenolic compounds using CeO2-ZrO2 based catalysts. PMID- 30525022 TI - Post-Ugi Cyclization for the Construction of Diverse Heterocyclic Compounds: Recent Updates. AB - Multicomponent reactions (MCRs) have proved as a valuable tool for organic and medicinal chemist because of their ability to introduce a large degree of chemical diversity in the product in a single step and with high atom economy. One of the dominant MCRs is the Ugi reaction, which involves the condensation of an aldehyde (or ketone), an amine, an isonitrile, and a carboxylic acid to afford an alpha-acylamino carboxamide adduct. The desired Ugi-adducts may be constructed by careful selection of the building blocks, opening the door for desired post Ugi modifications. In recent times, the post-Ugi transformation has proved an important synthetic protocol to provide a variety of heterocyclic compounds with diverse biological properties. In this review, we have discussed the significant advancements reported in the recent literature with the emphasis to highlight the concepts and synthetic applications of the derived products along with critical mechanistic aspects. PMID- 30525023 TI - Toward Exploiting the Behavior of Niobium-Containing Mesoporous Silicates vs. Polyoxometalates in Catalysis. AB - Classification of polyoxometalates (POMs) is based on their chemical composition, basically represented by two general formulae: a) [MmOy]p- b) [XxMmOy]q-, where M is the main transition metal, O is the oxygen atom and X can be a non-metal atom such as Si. Additionally, in the most cases, the structure of the polyoxometalates is derived from a combination of octahedral units MO6 with a central metal atom M and the oxygen atoms placed at their corners. In such octahedra, oxygen atoms allow the condensation between two octahedral units, while one oxygen atom (or max. two atoms) makes double bond with the central metal atom and is not shared with other metal atoms within the complex (terminal oxygens). On the other hand, niobium-containing mesoporous silicates contain mainly MO4 tetrahedra and reveal superior activity in heterogeneous catalysis. Thus, the proper coordination of niobium is crucial for the catalytic activity and will be deeply discussed. The similarity in the catalytic behavior of niobium polyoxometalates and heterogeneous niobium single-site catalysts in selective oxidations will be demonstrated. PMID- 30525024 TI - Colloidal Synthesis of Bulk-Bandgap Lead Selenide Nanocrystals. AB - Lead selenide quantum dots (QDs) are low-bandgap IV-VI semiconducting nanomaterials that have been studied for a variety of applications. Their preparation using colloidal methods can create small spherical to larger cubic nanocrystals, with an upper limit of ~17 nm reported to date. Here we describe methods for preparing cubic PbSe nanocrystals over a 20-40 nm size range using a twostep procedure. Specifically, ~10 nm PbSe QDs are generated using the rapid injection method, the products from which are overcoated with additional lead and selenium precursors. The use of two lead reagents were studied; lead oleate resulted in a maximum of 20 nm cubes, while more reactive lead hexyldecanoate resulted in much larger nanomaterials with bulk bandgaps. However, PbSe samples prepared with lead hexyldecanoate also contained agglomerates. Special care must be taken when characterizing larger strained nanomaterials with X-ray powder diffraction, for which the Scherrer equation is inadequate. A more rigorous approach using the Williamson-Hall method provides characterizations that are consistent with electron microscopy analysis. PMID- 30525025 TI - Anticancer Activity and Cisplatin Binding Ability of Bis-Quinoline and Bis Isoquinoline Derived [Pd2L4]4+ Metallosupramolecular Cages. AB - New bis-quinoline (L q) and bis-isoquinoline-based (L iq) ligands have been synthesized, along with their respective homoleptic [Pd2(L q or L iq)4]4+ cages (C q and C iq). The ligands and cages were characterized by 1H, 13C and diffusion ordered (DOSY) NMR spectroscopies, high resolution electrospray ionization mass spectrometry (HR-ESIMS) and in the case of the bis-quinoline cage, X-ray crystallography. The crystal structure of the C q architecture showed that the [Pd2(L q)4]4+ cage formed a twisted meso isomer where the [Pd(quinoline)4]2+ units at either end of the cage architecture adopt the opposite twists (left and right handed). Conversely, Density Functional Theory (DFT) calculations on the C iq cage architecture indicated that a lantern shaped conformation, similar to what has been observed before for related [Pd2(L tripy)4]4+ systems (where L tripy = 2,6-bis(pyridin-3-ylethynyl)pyridine), was generated. The different cage conformations manifest different properties for the isomeric cages. The C iq cage is able to bind, weakly in acetonitrile, the anticancer drug cisplatin whereas the C q architecture shows no interaction with the guest under the same conditions. The kinetic robustness of the two cages in the presence of Cl- nucleophiles was also different. The C iq cage was completely decomposed into free L iq and [Pd(Cl)4]2- within 1 h. However, the C q cage was more long lived and was only fully decomposed after 7 h. The new ligands (L iq and L q) and the Pd(II) cage architectures (C iq and C q) were assessed for their cytotoxic properties against two cancerous cell lines (A549 lung cancer and MDA-MB-231 breast cancer) and one non-cancerous cell line (HDFa skin cells). It was found that L q and C q were both reasonably cytotoxic (IC50S ~ 0.5 MUM) against A549, while C iq was slightly less active (IC50 = 7.4 MUM). L iq was not soluble enough to allow the IC50 to be determined against either of the two cancerous cell lines. However, none of the molecules showed any selectivity for the cancer cells, as they were all found to have similar cytotoxicities against HDFa skin cells (IC50 values ranged from 2.6 to 3.0 MUM). PMID- 30525026 TI - Organic-Inorganic Hybrid Planarization and Water Vapor Barrier Coatings on Cellulose Nanofibrils Substrates. AB - Cellulose nanofibrils (CNF) can be produced in the form of thin, transparent and flexible films. However, the permeability of such materials to oxygen and water vapor is very sensitive to moisture, which limits their potential for a variety of packaging and encapsulation applications. Diffusion barrier coatings were thus developed to reduce the access of water molecules to enzymatically pre-treated and carboxymethylated CNF substrates. The coatings were based on UV curable organic-inorganic hybrids with epoxy, tetraethylorthosilicate (TEOS) and 3 glycidoxypropyltrimethylenesilane (GPTS) precursors and additional vapor formed SiNx layers. A total of 14 monolayer and multilayer coatings with various thickness and hybrid composition were produced and analyzed. The water vapor transmission rate (WVTR) of the bilayer epoxy/CNF film was two times lower compared to that of uncoated CNF film. This was partly due to the water vapor permeability of the epoxy, a factor of two times lower than CNF. The epoxy coating improved the transparency of CNF, however it did not properly wet to the CNF surfaces and the interfacial adhesion was low. In contrast hybrid epoxy silica coatings led to high adhesion levels owing to the formation of covalent interactions through condensation reactions with the OH-terminated CNF surface. The barrier and optical performance of hybrid coated CNF substrates was similar to that of CNF coated with pure epoxy. In addition, the hybrid coatings provided an excellent planarization effect, with roughness close to 1 nm, one to two orders of magnitude lower than that of the CNF substrates. The WVTR and oxygen transmission rate values of the hybrid coated CNF laminates were in the range 5 10 g/m2/day (at 38 degrees C and 50% RH) and 3-6 cm3/m2/day/bar (at 23 degrees C and 70% RH), respectively, which matches food and pharmaceutical packaging requirements. The permeability to water vapor of the hybrid coatings was moreover found to decrease with increasing the TEOS/GPTS ratio up to 30 wt% and then increase at higher ratio, and to be much lower for thinner coatings due to further UV-induced silanol condensation and faster evaporation of byproducts. The addition of a single 150 nm thick SiNx layer on the hybrid coated CNF improved its water vapor barrier performance by more than 680 times, with WVTR below the 0.02 g/m2/day detection limit. PMID- 30525027 TI - Co2P Nanoparticles Wrapped in Amorphous Porous Carbon as an Efficient and Stable Catalyst for Water Oxidation. AB - Exploring highly active, enduringly stable, and low-cost oxygen evolution reaction catalysts continues to be a dominant challenge to commercialize renewable electrochemical water-splitting technology. High-active and earth abundant cobalt phosphides are recently considered as promising candidates. However, the poor inherent electron transfer efficiency and instability hinder its further development. In this work, a novel approach was demonstrated to effectively synthesize Co2P nanoparticles wrapped in amorphous porous carbon framework (Co2P/C). Benefiting from extremely high specific surface area of porous carbon, plenty of active sites were adequately exposed. Meanwhile, unique anchoring structure between Co2P nanoparticles and amorphous carbon outerwear insured high charge transfer efficiency and superior stability of Co2P/C. Due to these favorable properties, low overpotential of 281 mV at 10 mA cm-2 and Tafel slope of 69 mV dec-1 were achieved in resultant Co2P/C catalyst. More significantly, it only exhibited a negligible overpotential increase after 30 h stability test, and these performances entirely preceded commercial RuO2 benchmark. In summary, we proposed a simple and feasible strategy to prepare metal phosphides wrapped with amorphous porous carbon outerwear for efficient and durable electrochemical water oxidation. PMID- 30525028 TI - Promoting Effect of Cerium Oxide on the Catalytic Performance of Yttrium Oxide for Oxidative Coupling of Methane. AB - The promoting effect of CeO2 on the catalytic performance of Y2O3, which is moderately active catalyst, for the oxidative coupling of methane (OCM) reaction was investigated. The addition of CeO2 into Y2O3 by coprecipitation method caused a significant increase in not only CH4 conversion but also C2 (C2H6/C2H4) selectivity in the OCM reaction. C2 yield at 750 degrees C was increased from 5.6% on Y2O3 to 10.2% on 3 mol% CeO2/Y2O3. Further increase in the CeO2 loading caused an increase in non-selective oxidation of CH4 to CO2. A good correlation between the catalytic activity for the OCM reaction and the amount of H2 consumption for the reduction of surface/subsurface oxygen species in the H2-TPR profile was observed, suggesting the possibility that highly dispersed CeO2 particles act as catalytically active sites in the OCM reaction. The 16O/18O isotopic exchange reaction suggested that the beneficial role of CeO2 in the OCM reaction is to promote the formation of active oxygen species via the simple hetero-exchange mechanism, resulting in the promotion of CH4 activation. PMID- 30525029 TI - Toward Multi-Parametric Porous Silicon Transducers Based on Covalent Grafting of Graphene Oxide for Biosensing Applications. AB - Graphene oxide (GO) is a two-dimensional material with peculiar photoluminescence emission and good dispersion in water, that make it an useful platform for the development of label-free optical biosensors. In this study, a GO-porous silicon (PSi) hybrid device is realized using a covalent chemical approach in order to obtain a stable support for biosensing applications. Protein A, used as bioprobe for biosensing purposes, is covalently linked to the GO, using the functional groups on its surface, by carbodiimide chemistry. Protein A bioconjugation to GO PSi hybrid device is investigated by atomic force microscopy (AFM), scanning electron microscopy (SEM), water contact angle (WCA) measurements, Fourier transform infrared (FTIR) spectroscopy, steady-state photoluminescence (PL), and fluorescence confocal microscopy. PSi reflectance and GO photoluminescence changes can thus be simultaneously exploited for monitoring biomolecule interactions as in a multi-parametric hybrid biosensing device. PMID- 30525030 TI - A Perfusion Culture System for Assessing Bone Marrow Stromal Cell Differentiation on PLGA Scaffolds for Bone Repair. AB - Biomaterials development for bone repair is currently hindered by the lack of physiologically relevant in vitro testing systems. Here we describe the novel use of a bi-directional perfusion bioreactor to support the long term culture of human bone marrow stromal cells (BMSCs) differentiated on polylactic co-glycolic acid (PLGA). Primary human BMSCs were seeded onto porous PLGA scaffolds and cultured in static vs. perfusion culture conditions for 21 days in osteogenic vs. control media. PLGA scaffolds were osteoconductive, supporting a mature osteogenic phenotype as shown by the upregulation of Runx2 and the early osteocyte marker E11. Perfusion culture enhanced the expression of osteogenic genes Osteocalcin and Osteopontin. Extracellular matrix deposition and mineralisation were spatially regulated within PLGA scaffolds in a donor dependant manner. This, together with the observed upregulation of Collagen type X suggested an environment permissive for the study of differentiation pathways associated with both intramembranous and endochondral ossification routes of bone healing. This culture system offers a platform to assess BMSC behavior on candidate biomaterials under physiologically relevant conditions. Use of this system may improve our understanding of the environmental cues orchestrating BMSC differentiation and enable fine tuning of biomaterial design as we develop tissue engineered strategies for bone regeneration. PMID- 30525031 TI - Diamond/Porous Titanium Nitride Electrodes With Superior Electrochemical Performance for Neural Interfacing. AB - Robust devices for chronic neural stimulation demand electrode materials which exhibit high charge injection (Q inj) capacity and long-term stability. Boron doped diamond (BDD) electrodes have shown promise for neural stimulation applications, but their practical applications remain limited due to the poor charge transfer capability of diamond. In this work, we present an attractive approach to produce BDD electrodes with exceptionally high surface area using porous titanium nitride (TiN) as interlayer template. The TiN deposition parameters were systematically varied to fabricate a range of porous electrodes, which were subsequently coated by a BDD thin-film. The electrodes were investigated by surface analysis methods and electrochemical techniques before and after BDD deposition. Cyclic voltammetry (CV) measurements showed a wide potential window in saline solution (between -1.3 and 1.2 V vs. Ag/AgCl). Electrodes with the highest thickness and porosity exhibited the lowest impedance magnitude and a charge storage capacity (CSC) of 253 mC/cm2, which largely exceeds the values previously reported for porous BDD electrodes. Electrodes with relatively thinner and less porous coatings displayed the highest pulsing capacitances (C pulse), which would be more favorable for stimulation applications. Although BDD/TiN electrodes displayed a higher impedance magnitude and a lower C pulse as compared to the bare TiN electrodes, the wider potential window likely allows for higher Q inj without reaching unsafe potentials. The remarkable reduction in the impedance and improvement in the charge transfer capacity, together with the known properties of BDD films, makes this type of coating as an ideal candidate for development of reliable devices for chronic neural interfacing. PMID- 30525032 TI - 3D Printing-Encompassing the Facets of Dentistry. AB - This narrative review presents an overview on the currently available 3D printing technologies and their utilization in experimental, clinical and educational facets, from the perspective of different specialties of dentistry, including oral and maxillofacial surgery, orthodontics, endodontics, prosthodontics, and periodontics. It covers research and innovation, treatment modalities, education and training, employing the rapidly developing 3D printing process. Research oriented advancement in 3D printing in dentistry is witnessed by the rising number of publications on this topic. Visualization of treatment outcomes makes it a promising clinical tool. Educational programs utilizing 3D-printed models stimulate training of dental skills in students and trainees. 3D printing has enormous potential to ameliorate oral health care in research, clinical treatment, and education in dentistry. PMID- 30525033 TI - Transdifferentiating Astrocytes Into Neurons Using ASCL1 Functionalized With a Novel Intracellular Protein Delivery Technology. AB - Cellular transdifferentiation changes mature cells from one phenotype into another by altering their gene expression patterns. Manipulating expression of transcription factors, proteins that bind to DNA promoter regions, regulates the levels of key developmental genes. Viral delivery of transcription factors can efficiently reprogram somatic cells, but this method possesses undesirable side effects, including mutations leading to oncogenesis. Using protein transduction domains (PTDs) fused to transcription factors to deliver exogenous transcription factors serves as an alternative strategy that avoids the issues associated with DNA integration into the host genome. However, lysosomal degradation and inefficient nuclear localization pose significant barriers when performing PTD mediated reprogramming. Here, we investigate a novel PTD by placing a secretion signal sequence next to a cleavage inhibition sequence at the end of the target transcription factor-achaete scute homolog 1 (ASCL1), a powerful regulator of neurogenesis, resulting in superior stability and nuclear localization. A fusion protein consisting of the amino acid sequence of ASCL1 transcription factor with this novel PTD added can transdifferentiate cerebral cortex astrocytes into neurons. Additionally, we show that the synergistic action of certain small molecules improves the efficiency of the transdifferentiation process. This study serves as the first step toward developing a clinically relevant in vivo transdifferentiation strategy for converting astrocytes into neurons. PMID- 30525034 TI - Numerical Simulation of an Intramedullary Elastic Nail: Expansion Phase and Load Bearing Behavior. AB - The Marchetti-Vicenzi's nail is an intramedullary device where six curved nails are kept straight by a closing ring in order to allow their insertion into the medullary canal of a long bone; in a following step, these nails stabilize the fracture due to the ring withdrawal and to the consequent elastic expansion of the nails. Pre-clinical testing of this sort of device is strongly advocated in order to be able to foresee their stability inside the medullary canal and to quantify their stiffening action on a broken bone. In this numerical work, an MB (Multi Body) model of the device has been developed, with the dual purpose of evaluating forces between the bone and the system components during its progressive opening and verifying the behavior of the stabilized bone when it undergoes external loading. Different solutions, for flexible body modeling (discretization with lumped parameters, "flexible body," "FE Part"), have been analyzed and compared in terms of accuracy of results and required computational resources. Contact parameters have been identified and criteria to simplify geometries and therefore to reduce simulation times have been given. Results have allowed to demonstrate how a moderate lateral force is able to dislocate the fracture and how the final position of the retention nut can be optimized. On the whole, a tool for the pre-clinical testing of elastic intramedullary nails has been given. PMID- 30525035 TI - Editorial: Vascularization for Regenerative Medicine. PMID- 30525036 TI - Workshop on Germ Cells. AB - Germ cell research in vertebrates has traditionally been challenging, but recent breakthroughs have overcome technical difficulties, demonstrating and expanding the power of the zebrafish experimental system for their analysis in vivo. Exploiting the transparency of the zebrafish embryo, germ cell migration was the first topic that moved the germ cells of this organism into the spotlight of modern research. In recent years, research on teleost germ cells has expanded into additional fields, manifested by a session dedicated to this cell type at the European Zebrafish PI meeting in Trento. PMID- 30525037 TI - Disease-Specific Enteric Microbiome Dysbiosis in Inflammatory Bowel Disease. AB - Inflammatory Bowel disease (IBD) is traditionally divided into Crohn's disease (CD) and ulcerative colitis (UC). UC is a relapsing non-transmural inflammatory disease that is restricted to the colon and is characterized by flare-ups of bloody diarrhea. CD is a chronic, segmental localized granulomatous disease that can affect any part of the entire gastrointestinal tract. Ileo-anal pouch is a procedure restoring functionality of the rectum after a colectomy. IBD is a multifactorial disease and flares of IBD are probably triggered by changes in the intestinal microbiota followed by an abnormal immune response. In this study, we aim to analyze the intestinal bacterial diversity in IBD patients during various stages of disease compared with healthy controls. Permission for human experiments and recruitment of participants was obtained from the Ethic Committee for Copenhagen County hospitals (Permission no. KA-03019, Permission no. KA 20060159). Stools from 26 healthy controls, 42 CD, 38 UC and 18 pouch patients were collected. Stool DNA extraction was performed using Qiagen, DNA mini stool kit Denmark. DGGE-PCR amplifying the V2-V3 region of 16S-rDNA gene of the bacteria was amplified by universal primers HDA1 and HDA2. Analysis of DGGE was performed blinded using BioNumerics version 7.5. After normalization, a DGGE gel band matching was performed. The similarities between profiles were calculated with a ranked Pearson correlation coefficient based on the band matching results using band intensities. Simpson's index of diversity and Pielou's species evenness were calculated. Based on the Shannon Diversity Index, UC patients had lower species diversity and bacterial evenness in comparison to healthy persons, p < 0.05. However, only CD and disease pouch patients had lower species diversity compared to those with inactive disease and healthy controls. Well-functioning pouch patients had decreased species evenness in comparison to diseased pouch patients and control group. During the active disease stage in CD and pouch, the patients have a low bacterial diversity in their gut when compared to the inactive stage. In UC patients, a generally low diversity was observed at all stages of the disease compared to healthy controls. PMID- 30525038 TI - Novel Surfaces in Extracorporeal Membrane Oxygenation Circuits. AB - The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2 methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies. PMID- 30525040 TI - Management of Pulmonary Hemorrhage Complicating Pulmonary Thromboendarterectomy. AB - Airway management during pulmonary thromboendarterectomy (PTE) can prove challenging, especially in the face of unexpected intraoperative pulmonary hemorrhage. Utilization of proper airway equipment on induction is crucial for the successful management of intraoperative pulmonary hemorrhage. Our case series describes the preoperative risk factors that can lead to intraoperative pulmonary hemorrhage, the preinduction airway equipment considerations for PTE, and the intraoperative management of pulmonary hemorrhage. We summarize the lessons learned at our institution from four cases of post perfusion pulmonary hemorrhage. PMID- 30525039 TI - Subclinical Cardiac Dysfunction Is Associated With Extracardiac Organ Damages. AB - Background: Several studies conducted in America or Europe have described major cardiac remodeling and diastolic dysfunction in patients with sickle cell disease (SCD). We aimed at assessing cardiac involvement in SCD in sub-Saharan Africa where SCD is the most prevalent. Methods: In Cameroon, Mali and Senegal, SCD patients and healthy controls of the CADRE study underwent transthoracic echocardiography if aged >=10 years. The comparison of clinical and echocardiographic features between patients and controls, and the associations between echocardiographic features and the vascular complications of SCD were assessed. Results: 612 SCD patients (483 SS or Sbeta0, 99 SC, and 19 Sbeta+) and 149 controls were included. The prevalence of dyspnea and congestive heart failure was low and did not differ significantly between patients and controls. While left ventricular ejection fraction did not differ between controls and patients, left and right cardiac chambers were homogeneously more dilated and hypertrophic in patients compared to controls and systemic vascular resistances were lower (p < 0.001 for all comparisons). Three hundred and forty nine SCD patients had extra-cardiac organ damages (stroke, leg ulcer, priapism, microalbuminuria or osteonecrosis). Increased left ventricular mass index, cardiac dilatation, cardiac output, and decreased systemic vascular resistances were associated with a history of at least one SCD-related organ damage after adjustment for confounders. Conclusions: Cardiac dilatation, cardiac output, left ventricular hypertrophy, and systemic vascular resistance are associated with extracardiac SCD complications in patients from sub-Saharan Africa despite a low prevalence of clinical heart failure. The prognostic value of cardiac subclinical involvement in SCD patients deserves further studies. PMID- 30525041 TI - Healthy Food as a New Technology-The Implications of Technological Diffusion and Food Price for Changes in Eating Habits. AB - Diet influences health and poor diets drive up healthcare costs for individuals and society as a whole. Multiple governmental programs in the US have aimed to educate citizens about diet choices, resulting in documented successes, as well as, unintended consequences such as increased food waste. Here we examine some of the relationships between healthy diets, food prices, and wealth by drawing parallels between the diffusion of technological innovation and healthy food diets. We introduce a simple modeling framework to estimate the adoption rates of healthy diets based on income and food prices, and describe the implications of the modeling results for the food industry and for government. PMID- 30525042 TI - Loss of Ca2+/Calmodulin Dependent Protein Kinase Kinase 2 Leads to Aberrant Transferrin Phosphorylation and Trafficking: A Potential Biomarker for Alzheimer's Disease. AB - Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a serine/threonine kinase that is activated following an increase in the intracellular Ca2+ concentration and activates multiple signaling cascades that control physiologically important neuronal processes. CaMKK2 has been implicated in schizophrenia, bipolar disease, neurodegeneration, and cancer. Using isoelectric focusing (IEF) and mass spectrometry-based proteomic analysis, it was found that knockdown (KD) of CaMKK2 in cultured adult primary dorsal root ganglion (DRG) neurons resulted in the reduction of transferrin (TF) phosphorylation at multiple functionally relevant residues which corresponded to loss of an acidic fraction (pH~3-4) of TF. In vitro studies using CRISPR/Cas9 based CaMKK2 knockout (KO) HEK293 and HepG2 cells lines validated previous findings and revealed that loss of CaMKK2 interfered with TF trafficking and turnover. TF is an iron transporter glycoprotein. Abnormal accumulation of iron and/or deregulated Ca2+ homeostasis leads to neurodegeneration in Alzheimer's disease (AD). Therefore, it was hypothesized that aberrant CaMKK2 in AD may lead to aberrant phosphorylated transferrin (P-TF: pH~3-4 fraction) which may serve as a hallmark biomarker for AD. A significant reduction of P-TF in the brain and serum of CaMKK2 KO mice and a triple-transgenic mouse model of AD (3xTg-AD) supported this hypothesis. In addition, analysis of early (< 65 years) and late-stage (>65 years) postmortem human AD cerebrospinal fluid (CSF) and serum samples revealed that aberrant P-TF (pH~3-4 fraction) profile was associated with both early and late-stage AD compared to age-matched controls. This indicates P-TF (pH~3-4 fraction) profile may be useful as a minimally invasive biomarker for AD. In addition, this study provides a link between aberrant CaMKK2 with TF trafficking and turnover which provides a novel insight into the neurodegeneration process. PMID- 30525043 TI - Arterial Stiffness in Balkan Endemic Nephropathy, an Environmental Form of Aristolochic Acid Nephropathy. AB - Balkan endemic nephropathy (BEN), an environmental form of aristolochic acid nephropathy is characterized with later onset and milder forms of hypertension (HT). Thus, we hypothesized that arterial stiffness progresses slower in BEN patients resulting in lower CV mortality. A total of 186 hemodialysed (HD) patients (90 BEN, 96 non-BEN; 67.3 + 13.0 years) were enrolled and followed-up for 25 months. Brachial blood pressure (BP) and pulse wave velocity (PWV) were determined before mid-week dialysis. BEN patients were older (72.1 +/- 37.1 vs. 62.8 +/- 15.1; p < 0.001), had shorter duration of HT prior commencement of HD than non-BEN patients (36 vs. 84 months; p < 0.001). There were no differences in BP, but BEN patients were treated with less antihypertensive drugs (p < 0.01). BEN patients had lower PWV values at baseline and at the end of follow-up period despite being chronologically older (p < 0.001). Baseline PWV > 10 m/s was associated with higher risk for CV mortality (aHR 1.8 [1.4, 2.4]). In multivariate analyses BEN was predictor of lower PWV. During the follow-up period significantly less CV deaths were observed in BEN vs. on-BEN patients (12 vs. 31; p = 0.001). CV mortality adjusted for other risk factors was significantly lower in BEN group (aHR 0.2 [0.1, 0.5]). Overall BEN patients had longer mean survival time on HD (22.3 vs. 18.2 months; p < 0.001). Observed slower vascular aging (i.e., lower PWV) in BEN patients compared to other ESRD patients is related to the later onset of HT and milder stages of HT during predialytic clinical course and better control of BP and phosphate during HD. PMID- 30525044 TI - Single Cell Gene Expression to Understand the Dynamic Architecture of the Heart. AB - The recent development of single cell gene expression technologies, and especially single cell transcriptomics, have revolutionized the way biologists and clinicians investigate organs and organisms, allowing an unprecedented level of resolution to the description of cell demographics in both healthy and diseased states. Single cell transcriptomics provide information on prevalence, heterogeneity, and gene co-expression at the individual cell level. This enables a cell-centric outlook to define intracellular gene regulatory networks and to bridge toward the definition of intercellular pathways otherwise masked in bulk analysis. The technologies have developed at a fast pace producing a multitude of different approaches, with several alternatives to choose from at any step, including single cell isolation and capturing, lysis, RNA reverse transcription and cDNA amplification, library preparation, sequencing, and computational analyses. Here, we provide guidelines for the experimental design of single cell RNA sequencing experiments, exploring the current options for the crucial steps. Furthermore, we provide a complete overview of the typical data analysis workflow, from handling the raw sequencing data to making biological inferences. Significantly, advancements in single cell transcriptomics have already contributed to outstanding exploratory and functional studies of cardiac development and disease models, as summarized in this review. In conclusion, we discuss achievable outcomes of single cell transcriptomics' applications in addressing unanswered questions and influencing future cardiac clinical applications. PMID- 30525045 TI - Teaching Children and Parents to Understand Dog Signaling. AB - Safe human-dog relationships require understanding of dogs' signaling. As children are at particularly high risk of dog bites, we investigated longitudinally how children from 3 to 5 years and parents perceive and interpret dogs' distress signaling gestures. All participants were then taught how to link their perception of the dog with the correct interpretation of dogs' behavioral signals and tested again. Results show a significant increase in learning for children and adults, with them showing greater understanding of dogs' signaling after intervention. Better learning effects were found with increasing age and depended on the type of distress signaling of the dogs. Effects endured over time and it can be concluded that children and adults can be taught to interpret dogs' distress signaling more correctly. Awareness and recognition of dogs' stress signaling can be seen as an important first step in understanding the dog's perspective and are vital to enable safe interactions. PMID- 30525046 TI - Radiographic Identification of Osseous Cyst- Like Lesions in the Distal Phalanx in 22 Lame Thoroughbred Horses Managed Conservatively and Their Racing Performance. AB - Reasons for performing study: To investigate the racing performance of Thoroughbred horses with osseous cyst-like lesions (OCLLs) in the distal phalanx causing lameness and treated conservatively. Objectives: To assess horses' ability to race and perform after radiographic identification of OCLL in the distal phalanx of Thoroughbred horses with lameness at the time of detection and undergoing conservative treatment. Study Design: Retrospective case control study. Methods: The clinical database of one equine clinic was reviewed in a 10 year period for Thoroughbreds showing lameness localized to the foot and a radiographic diagnosis of OCLL in the distal phalanx. Sex, age at time of detection of the OCLL, degree of lameness, affected limb, and treatment were recorded. Successful performance of horses was assessed by racing at least once after detection of the OCLL and maximum racing performance rating (RPR). Radiographic features such as size, location, sclerotic rim of the OCLL and irregularity of the articular surface of the distal phalanx were compared to successful performance using univariable statistical analysis. Successful performance of horses with OCLL was compared to a control group of maternal siblings by parametric testing. Results: Twenty-two horses met the inclusion criteria. Thirteen horses raced after the detection of OCLLs. Eight did not race, one case had not yet reached racing age, resulting in 62% (13/21) of racing age racing at least once. The number of successfully performing horses with an OCCL was significantly lower compared to their maternal siblings [p = 0.03, Odds ratio (OR) = 0.30]. If horses with OCLL in the distal phalanx raced, their RPR was similar to their maternal siblings. No significant association was found between radiographic features of OCLLs and successful performance, but OCLLs in the left forelimb carried a more favorable outcome for racing (p = 0.02, OR = 2.33 95%CI 1.27, 4.27) compared to OCLLs in any other limb. Conclusions: Horses with lameness and an OCLL in the distal phalanx managed conservatively are less likely to race when compared to their maternal siblings. If horses with OCLLs in the distal phalanx are able to race, their performance, measured as RPR, was comparable to their maternal siblings. Due to the small numbers in this study the results should be interpreted carefully. PMID- 30525047 TI - Sustainable Fisheries Management and the Welfare of Bycaught and Entangled Cetaceans. AB - The incidental capture of cetaceans and other protected marine wildlife in fishing gear has significant welfare implications. Many thousands of cetaceans are bycaught in fishing gear in European waters and hundreds of thousands die globally. We can expect many more to survive, but suffer from such interactions. As marine policy focuses on "population level" impact assessments and "sustainability" of fishing to preserve fish populations, the impacts to the bycaught individual, and their wider social group, are often largely underestimated, despite the large numbers affected. The wide range of recorded injuries, including abrasions, cuts, bruising, and broken bones, along with the potential for panic associated with forced submersion, indicate that the welfare of bycaught cetaceans is, individually and collectively, very poor. Commercial fishing is the last human activity targeting wildlife (fish) on a grand scale where slaughter includes incidental killing of other large sapient wildlife on such a regular basis. Here, we review the compelling evidence of the short and long term welfare impacts of bycatch, and the progress made toward implementation of measures to understand and solve this significant welfare issue. We argue that policy decisions surrounding fishing do not adequately consider cetacean bycatch, including welfare impacts. Ultimately, there are welfare issues in all bycatch situations and suffering cannot plausibly be reduced without preventing bycatch. The well-documented welfare implications provide a strong argument for zero tolerance of cetacean bycatch and provide a compelling case for immediate action in fisheries where bycatch is taking place. The only way to reduce the suffering of bycaught cetaceans is to decrease, or ideally eliminate, the number of animals caught in fishing gear. Uncertainties around the scale of bycatch should not delay management, even where individual bycatch estimates are considered "sustainable." Lack of monitoring of sub-lethal impacts on populations may result in flawed impact assessments. We urge that animal welfare considerations should become an integral part of management decision-making in relation to bycatch globally. Enhanced, robust and transparent management systems are urgently required for the range of fisheries within which cetacean bycatch occurs, with the aim to better document and most importantly, work toward eliminating cetacean bycatch altogether. PMID- 30525048 TI - Galectins-1 and-3 Increase in Equine Post-traumatic Osteoarthritis. AB - Galectins are potent regulators of cell adhesion, growth and apoptosis in diverse cell types, including chondrocytes and synovial fibroblasts. Elevations in synovial fluid galectin-3 have been observed in rheumatoid arthritis, juvenile idiopathic arthritis and experimental inflammatory arthritis in animal models, whereas galectin-1 is thought to be protective. Less is known about galectins-1 and-3 in osteoarthritis (OA). Therefore, the purpose of this study was: (1) to determine whether galectin-1 and-3 synovial fluid concentrations and synovial membrane and cartilage histochemical staining were altered following osteochondral injury in an experimental equine osteoarthritis (OA) model and (2) to measure galectin-1 and-3 mRNA expression and synovial fluid concentrations in naturally occurring equine carpal OA. Synovial fluid galectin-1 and-3 concentrations were quantified using custom ELISAs in two research horse cohorts undergoing experimental OA induction (n = 5 and 4) and in a cohort of horses with naturally occurring carpal OA (n = 57). Galectin mRNA expression in synovial membrane and cartilage tissue obtained from carpal joints of horses with naturally occurring OA was measured using RT-qPCR, and galectin immunostaining was assessed in synovial membrane and osteochondral tissues in the experimental model (n = 5). Synovial fluid galectin-1 and-3 concentrations increased following experimental carpal osteochondral fragmentation. Cartilage galectin-1 mRNA expression increased with OA severity in naturally occurring disease. The superficial zone of healthy articular cartilage stained intensely for galectin-3 in sham-operated joints, whereas galectin-1 staining was nearly absent. Chondrocyte galectin-1 and-3 immunoreactivity increased following cartilage injury, particularly in galectin-1 positive chondrones. Galectins-1 and-3 are present in healthy equine synovial fluid and increase following post-traumatic OA. Healthy superficial zone chondrocytes express galectin-3, whereas galectin-1 chondrocyte staining is limited predominantly to chondrones and injured cartilage. Further work is needed to clarify the functions of galectins-1 and-3 in healthy and OA joints. PMID- 30525049 TI - Urinary Exosome-Derived microRNAs Reflecting the Changes in Renal Function in Cats. AB - Increased incidence of kidney disease (KD) is a common concern in human and companion animals. Cats, in particular, are highly susceptible to KD. Novel KD biomarkers would help to address these problems. Therefore, we are focusing on microRNA, a highly conserved nucleic acid, as a KD biomarker for various animals. We previously reported that altered levels of urinary exosome (UExo)-derived microRNAs indicate renal pathologies in dogs. This study comprehensively examined UExo-derived microRNAs, which reflected the KD status in cats. The examined cats were divided into two groups: normal renal function (NR) and KD. Based on our previous data in dogs and cats, as well as the present data on UExo-derived microRNAs in cats by next-generation sequencing, let-7b, let-7f, miR-10a, miR 10b, miR-21a, miR-22, miR-26a, miR-27b, miR-146a, miR-181a, miR-191, and miR-486a were identified as biomarker candidates. In summary, the levels of UExo-derived let-7b, miR-22, and miR-26a significantly decreased in cats with KD from the early stages of the disease. UExo-derived miRNA levels normalized to urinary creatinine or total RNA of miR-21a was significantly higher in the KD group. Importantly, the ratio of UExo-derived miR-21a to let-7b showed a significant and strongest correlation with serum creatinine (rho = 0.751), blood urea nitrogen (rho = 0.754), and urinary creatinine (rho = -0.421) among all examined indices. Further, the ratio of miR-181a to let-7b or miR-10b significantly correlated with the progression of renal dysfunction in the KD group. Thus, we identified that UExo-derived microRNAs in cats, and their raw and normalized levels could indicate altered renal function. PMID- 30525050 TI - A Survey-Based Investigation of Human Factors Associated With Transport Related Injuries in Horses. AB - Injuries resulting from road transport are common in horses and are a potential welfare concern, as well as, a source of economic loss. An online cross sectional survey was used to determine the prevalence of road transport related injuries to horses in New Zealand and the association of human factors including demographics, industry background, training and the horse handling experience of the respondents with transport related injury. The survey generated 1133 valid responses that were analyzed using descriptive statistics, univariate and multivariate logistic regression analysis. At least one injured horse was reported by 201/1133 (17.7%) respondents as occurring during the two previous years. Only 191 respondents chose to provide further information on when the injury occurred and most injuries (133/191; 69.6%) occurred in transit. The respondent perceived possible reason for injury was reported by 190, and was most frequently thought to be either horse-associated (87/190; 45.8%) or associated with a driver mistake (18/190; 9.5%). Variables that remained as significantly associated with injury in a multivariate model focusing on human factors were experience in horse handling, the industry sector, and the amateur or professional involvement with the horse industry. The odds of injury associated with professionals may reflect greater exposure due to more frequent transport and larger numbers of horses in their care than amateurs. Findings confirm that human factors are associated with the risk of an injury during transport. Although further studies are required to determine if any of these relationships are causative, education on transport best practices with consideration of these factors may mitigate their influence. PMID- 30525051 TI - Risk Factors for Deterioration of the Clinical Condition of Cull Dairy Cows During Transport to Slaughter. AB - Cull dairy cows are typically transported to slaughter by road. Across different types of cattle, road transport is recognized as stressful. Cull dairy cows may have different injuries or weaknesses and may thus be more vulnerable to transport stress than other types of cattle. The aim of this study was to investigate whether the clinical condition of cull dairy cows deteriorates during transport (< 8 h), and to evaluate risk factors for potential deterioration of the clinical condition. A total of 411 dairy cows were clinically examined on farm before loading and again after unloading at the slaughter plant. The clinical examination included locomotion, presence of wounds, milk leakage, and general condition. One-fifth of the cows either became lame or more lame during transport, and there was a significant increase in the proportion of lame cows after transport (41% after vs. 31% before, P < 0.0001). A significant increase in the proportion of cows with milk leakage (17% vs. 1%, P < 0.0001) and wounds (34% after vs. 22% before, P < 0.0001) after transport were also found. Low body condition score (BCS) (< 2.75) (P = 0.001), early or late lactation [< 100 days in milk (DIM) or >300 DIM] (P = 0.01), digital dermatitis in the hind feet (P = 0.01), and pelvic asymmetry (P = 0.001) were identified as risk factors for the deterioration in lameness during transport. Early lactation (< 100 DIM) (P = 0.04) and transport distance (>100 km) (P = 0.006) were identified as risk factors for milk leakage. For wounds, no significant risk factors were found. The results demonstrate that cull dairy cows are vulnerable to the strains of transport, even journeys shorter than 8 h, to the extent that the occurrence of clinical findings were increased after transport in cows legally considered fit for transport. These results call for further research into the animal welfare implications and optimization of cattle transport. PMID- 30525052 TI - The Impact of Obesity on the Cardiovascular System. AB - Obesity is a growing health problem worldwide. It is associated with an increased cardiovascular risk on the one hand of obesity itself and on the other hand of associated medical conditions (hypertension, diabetes, insulin resistance, and sleep apnoea syndrome). Obesity has an important role in atherosclerosis and coronary artery disease. Obesity leads to structural and functional changes of the heart, which causes heart failure. The altered myocardial structure increases the risk of atrial fibrillation and sudden cardiac death. However, obesity also has a protective effect on the clinical outcome of underlying cardiovascular disease, the phenomenon called obesity paradox. The improved cardiac imaging techniques allow the early detection of altered structure and function of the heart in obese patients. In this review, we attempt to summarize the relationship between obesity and cardiovascular diseases and outline the underlying mechanisms. The demonstrated new techniques of cardiac diagnostic procedures allow for the early detection and treatment of subclinical medical conditions and, therefore, the prevention of cardiovascular events. PMID- 30525053 TI - Corneal Subbasal Nerve Plexus Changes in Severe Diabetic Charcot Foot Deformity: A Pilot Study in Search for a DNOAP Biomarker. AB - Introduction: Diabetic neuroosteoarthropathy (DNOAP) early symptoms are unspecific, mimicking general infectious symptoms and rendering a diagnosis challenging. Consequently, unfavourable outcomes occur frequently, with recurrent foot ulceration, infectious complications, and eventually amputation. Corneal confocal microscopy (CCM) of the subbasal nerve plexus (SNP) is used to detect early peripheral neuropathy in diabetic patients without diabetic retinopathy. This pilot study was designed to determine if specific SNP changes manifest in severe DNOAP in comparison to a healthy control group. Methods: This pilot study utilized a matched-pair analysis to investigate SNP changes by in vivo CCM for 26 patients (mean patient age 63.7 years, range 27 to 78) with severe DNOAP defined by condition after the need for reconstructive foot surgery (n = 13) and a healthy control group (n = 13). Corneal nerve fibre length (CNFL), nerve fibre density (CNFD), nerve branch density (CNBD), average weighted corneal nerve fibre thickness (CNFTh), nerve connecting points (CNCP), and average weighted corneal nerve fibre tortuosity (CNFTo) were assessed as well as the general clinical status, diabetic status, and ophthalmologic basic criteria. Results: In vivo CCM revealed significantly reduced SNP parameters in the DNOAP group for CNFL (p = 0.010), CNFD (p = 0.037), CNBD (p = 0.049), and CNCP (p = 0.012) when compared to the healthy control group. Six patients (46%) of the DNOAP group suffered from diabetic retinopathy and none of the control group. Conclusions: This pilot study revealed a rarefication of SNP in all measured parameters in patients with severe DNOAP. We see a potential value of CCM providing a SNP-based biomarker for early stages of DNOAP prior to the development of any foot deformities that needs to be evaluated in further studies. This trial is registered with German Clinical Trials Register (DKRS) DRKS00007537. PMID- 30525054 TI - Molecular Modulation of Osteoblasts and Osteoclasts in Type 2 Diabetes. AB - Diabetes is a common disease affecting majority of populations worldwide. Since 1980, there has been an increase in the number of people diagnosed as prediabetic and diabetic. Diabetes is characterized by high levels of circulating glucose and leads to most microvascular and macrovascular complications such as retinopathy, nephropathy, neuropathy, stroke, and myocardial infarction. Bone marrow vascular disruption and increased adiposity are also linked to various complications in type II diabetes mellitus. In addition to these complications, type 2 diabetic patients also have fragile bones caused by faulty mineralization mainly due to increased adiposity among diabetic patients that affects both osteoblast and osteoclast functions. Other factors that increase fracture risk in diabetic patients are increased oxidative stress, inflammation, and drugs administered to diabetic patients. This review reports the modulation of different pathways that affect bone metabolism in diabetic conditions. PMID- 30525055 TI - Administration of RAS Inhibitor before the Onset of Diabetic Nephropathy Counteracts the Adverse Effect of Chronic Hyperglycemia and Reduces the Augmentation of Urinary Albumin Excretion: A Retrospective Clinical Study. AB - It is very important to explore how we can reduce urinary albumin excretion which is an independent risk factor for ischemic heart disease. In this study, we retrospectively evaluated the effects of RAS inhibitor therapy on diabetic nephropathy in Japanese subjects whose urinary albumin levels were within normal range. We enrolled 100 subjects with type 2 diabetes who did not take any renin angiotensin system (RAS) inhibitor. We defined the subjects taking RAS inhibitor for more than 3 years as RAS inhibitor group. RAS inhibitor exerted protective effect on the progression of urinary albumin excretion in subjects with type 2 diabetes without diabetic nephropathy. In addition, RAS inhibitor exerted more protective effects on renal function especially in subjects with poor glycemic control. In conclusion, RAS inhibitor could protect renal function against the deleterious effect of chronic hyperglycemia in Japanese subjects with type 2 diabetes even before the onset of diabetic nephropathy. PMID- 30525056 TI - Corrigendum to "Gmelina arborea Roxb. (Family: Verbenaceae) Extract Upregulates the beta-Cell Regeneration in STZ Induced Diabetic Rats". AB - [This corrects the article DOI: 10.1155/2016/4513871.]. PMID- 30525057 TI - Modulation of Innate Immunity by G-CSF and Inflammatory Response by LBPK95A Improves the Outcome of Sepsis in a Rat Model. AB - Introduction: Sepsis is the primary cause of death from infection. We wanted to improve the outcome of sepsis by stimulating innate immunity in combination with modulating the severity of inflammatory responses in rats. Method: Sepsis was induced by the injection of feces suspension (control). A 5-day course of G-CSF treatment was given before the septic insult (G-CSF). The inflammatory response was decreased using various doses of the LPS-blocking peptide LBPK95A (5 mg/kg = 100% Combi group, 0.5 mg/kg = 10% Combi group, and 0.05 mg/kg = 1% Combi group). Survival rates were observed. Bacterial clearance, neutrophil infiltration, tissue damage, and the induction of hepatic and systemic inflammatory responses were determined 2 h and 12 h after the septic insult. Results: High-dose LBPK95A (100% Combi) reduced the survival rate to 10%, whereas low-dose LBPK95A (10% and 1% Combi) increased the survival rates to 50% and 80%, respectively. The survival rates inversely correlated with multiorgan damage as indicated by the serum levels of ALT and urea. G-CSF treatment increased the white blood cell counts, hepatic neutrophil infiltration, and bacterial clearance in the liver, lung, and blood. The blockade of the LPS-LBP interaction decreased neutrophil infiltration, led to increased white blood cell count, and decreased hepatic neutrophil infiltration, irrespective of dose. However, bacterial clearance improved in the 1% and 10% Combi groups but worsened in the 100% Combi group. G-CSF increased TNF alpha and IL-6 levels. Irrespective of dose, the blockade of the LPS-LBP interaction was associated with low systemic cytokine levels and delayed increases in hepatic TNF-alpha and IL-6 mRNA expression. The delayed increase in cytokines was associated with the phosphorylation of STAT3 and AKT. Conclusion: Our results revealed that increasing innate immunity by G-CSF pretreatment and decreasing inflammatory responses using LBPK95A improved the survival rates in a rat sepsis model and could be a novel strategy to treat sepsis. PMID- 30525058 TI - CD47 Blockade Inhibits Tumor Progression through Promoting Phagocytosis of Tumor Cells by M2 Polarized Macrophages in Endometrial Cancer. AB - There are rapidly emerging efforts to explore tumor-associated macrophages (TAMs) as a tumor therapy target. Tumor cells express CD47, which can interact with the macrophages' SIRPalpha transmitting a "don't eat me" signal to macrophages. The expression of CD47 increases in various tumors to evade immune attack. However, the expression of CD47 in endometrial cancer (EC) and the role of CD47-SIRPalpha in the TAMs which mediate the progression of EC remain unclear. Our study shows that there are increased TAMs in EC which dominantly consist of M2 macrophages and contribute to the progression of EC. We confirm that CD47 is highly expressed in EC tissue using the TCGA database, qPCR, and flow cytometry. Instead of directly promoting the apoptosis of EC cells, anti-CD47 blocking antibody promoted phagocytosis of EC cells by macrophages and the increased phagocytosis ability was mediated by M2 macrophages in a coculture assay. Besides, CD47 blockade inhibited the growth of the EC tumors in vivo and increased the infiltration of macrophages with antitumor ability in the tumor microenvironment (TME). These findings might assist in developing promising strategies that blocked the CD47-SIRPa interaction for EC therapy. PMID- 30525059 TI - In vivo validation of cerebral near-infrared spectroscopy: a review. AB - We summarize the available in vivo validation of cerebral near-infrared spectroscopy (NIRS) oximetry to inform future in vivo validation strategies. In particular, to establish a way forward in the assessment of NIRS instrumentation for future randomized trials, a systematic literature search is performed. The records are screened and abstracts are assessed to select studies fulfilling our inclusion criteria. Twenty-two pediatric and 28 adult studies are analyzed after exclusion of three articles in each group. All studies compare regional cerebral tissue oxygenation measured by cerebral NIRS to invasive measurement of central or jugular venous oxygen saturation. In studies without Bland-Altman plots, we extracted data from scatter plots enabling estimation of mean difference (MD), standard deviation (SD), and limits of agreement (LOA). To assess the agreement between rStO2 (regional cerebral tissue oxygenation) estimated by NIRS and by blood samples, weighted averages of the MDs and SDs from each study are calculated. We found a fair agreement between the overall mean of cerebral tissue oxygenation and the mean of a reference value measured by co-oximetry whatever NIRS instrument or site of blood sampling used. Cerebral oxygenation overestimates the reference at low values, some instruments apparently more than others. Thus, a high degree of scatter and a lack of a good reference method complicate in vivo validation of NIRS. It is difficult to draw any firm conclusions despite the large number of studies, and the result of this review leaves us questioning if more of such validation studies of cerebral NIRS oximetry are really needed. Furthermore, the combination of lack of validation and poor repeatability is an important issue when designing a randomized clinical trial of implementing cerebral NIRS oximetry into clinical care. PMID- 30525060 TI - Deep neural networks for A-line-based plaque classification in coronary intravascular optical coherence tomography images. AB - We develop neural-network-based methods for classifying plaque types in clinical intravascular optical coherence tomography (IVOCT) images of coronary arteries. A single IVOCT pullback can consist of >500 microscopic-resolution images, creating both a challenge for physician interpretation during an interventional procedure and an opportunity for automated analysis. In the proposed method, we classify each A-line, a datum element that better captures physics and pathophysiology than a voxel, as a fibrous layer followed by calcification (fibrocalcific), a fibrous layer followed by a lipidous deposit (fibrolipidic), or other. For A-line classification, the usefulness of a convolutional neural network (CNN) is compared with that of a fully connected artificial neural network (ANN). A total of 4469 image frames across 48 pullbacks that are manually labeled using consensus labeling from two experts are used for training, evaluation, and testing. A 10-fold cross-validation using held-out pullbacks is applied to assess classifier performance. Noisy A-line classifications are cleaned by applying a conditional random field (CRF) and morphological processing to pullbacks in the en-face view. With CNN (ANN) approaches, we achieve an accuracy of 77.7%+/-4.1% ( 79.4%+/-2.9% ) for fibrocalcific, 86.5%+/-2.3% ( 83.4%+/-2.6% ) for fibrolipidic, and 85.3%+/-2.5% ( 82.4%+/-2.2% ) for other, across all folds following CRF noise cleaning. The results without CRF cleaning are typically reduced by 10% to 15%. The enhanced performance of the CNN was likely due to spatial invariance of the convolution operation over the input A-line. The predicted en-face classification maps of entire pullbacks agree favorably to the annotated counterparts. In some instances, small error regions are actually hard to call when re-examined by human experts. Even in worst-case pullbacks, it can be argued that the results will not negatively impact usage by physicians, as there is a preponderance of correct calls. PMID- 30525061 TI - Phantom with multiple active points for ultrasound calibration. AB - Accurate tracking and localization of ultrasound (US) images are used in various computer-assisted interventions. US calibration is a preoperative procedure to recover the transformation bridging the tracking sensor and the US image coordinate systems. Although many calibration phantom designs have been proposed, a limitation that hinders the resulted calibration accuracy is US elevational beam thickness. Previous studies have proposed an active-echo (AE)-based calibration concept to overcome this limitation by utilizing dynamic active US feedback from a single PZT element-based phantom, which assists in placing the phantom within the US elevational plane. However, the process of searching elevational midplane is time-consuming and requires dedicated hardware to enable "AE" functionality. Extending this active phantom, we present a US calibration concept and associated mathematical framework enabling fast and accurate US calibration using multiple "active" points. The proposed US calibration can simplify the calibration procedure by minimizing the number of times midplane search is performed and shortening calibration time. This concept is demonstrated with a configuration mechanically tracking a US probe using a robot arm. We validated the concept through simulation and experiment, and achieved submillimeter calibration accuracy. This result indicates that the multiple active-point phantom has potential to provide superior calibration performance for applications requiring high tracking accuracy. PMID- 30525062 TI - Multireader sample size program for diagnostic studies: demonstration and methodology. AB - The software "Multireader sample size program for diagnostic studies," written by Kevin Schartz and Stephen Hillis, performs sample size computations for diagnostic reader-performance studies. The program computes the sample size needed to detect a specified difference in a reader-performance measure between two imaging modalities when using the analysis methods initially proposed by Dorfman, Berbaum, and Metz, and Obuchowski and Rockette, and later unified and improved by Hillis and colleagues. A commonly used reader-performance measure is the area under the receiver-operating-characteristic curve. The program has an easy-to-use step-by-step intuitive interface that walks the user through the entry of the needed information. It can be used with several different study designs, inference procedures, hypotheses, and input and output formats. The program is functional in Windows, OS X, and Linux. The methodology underlying the software is discussed for the most common diagnostic study design, where each reader evaluates each case using each modality. PMID- 30525063 TI - Moving table magnetic particle imaging: a stepwise approach preserving high spatio-temporal resolution. AB - Magnetic particle imaging (MPI) is a highly sensitive imaging method that enables the visualization of magnetic tracer materials with a temporal resolution of more than 46 volumes per second. In MPI, the size of the field of view (FoV) scales with the strengths of the applied magnetic fields. In clinical applications, those strengths are limited by peripheral nerve stimulation, specific absorption rates, and the requirement to acquire images of high spatial resolution. Therefore, the size of the FoV is usually a few cubic centimeters. To bypass this limitation, additional focus fields and/or external object movements can be applied. The latter approach is investigated. An object is moved through the scanner bore one step at a time, whereas the MPI scanner continuously acquires data from its static FoV. Using a 3-D phantom and dynamic 3-D in vivo data, it is shown that the data from such a moving table experiment can be jointly reconstructed after reordering the data with respect to the stepwise object shifts and heart beat phases. PMID- 30525064 TI - Monochromatic breast computed tomography with synchrotron radiation: phase contrast and phase-retrieved image comparison and full-volume reconstruction. AB - A program devoted to performing the first in vivo synchrotron radiation (SR) breast computed tomography (BCT) is ongoing at the Elettra facility. Using the high spatial coherence of SR, phase-contrast (PhC) imaging techniques can be used. The latest high-resolution BCT acquisitions of breast specimens, obtained with the propagation-based PhC approach, are herein presented as part of the SYRMA-3D collaboration effort toward the clinical exam. Images are acquired with a 60-MUm pixel dead-time-free single-photon-counting CdTe detector. The samples are imaged at 32 and 38 keV in a continuous rotating mode, delivering 5 to 20 mGy of mean glandular dose. Contrast-to-noise ratio (CNR) and spatial resolution performances are evaluated for both PhC and phase-retrieved images, showing that by applying the phase-retrieval algorithm a five-time CNR increase can be obtained with a minor loss in spatial resolution across soft tissue interfaces. It is shown that, despite having a poorer CNR, PhC images can provide a sharper visualization of microcalcifications, thus being complementary to phase-retrieved images. Furthermore, the first full-volume scan of a mastectomy sample ( 9*9*3 cm3 ) is reported. This investigation into surgical specimens indicates that SR BCT in terms of CNR, spatial resolution, scan duration, and scan volume is feasible. PMID- 30525065 TI - Comparison of the efficacy of cryopreserved human platelet lysate and refrigerated lyophilized human platelet lysate for wound healing. AB - Introduction: Human platelet lysate (hPL) part of the growth factor cocktail derived from human platelets, which has been applied as a cell growth supplement. The production process is easier in comparison to platelet-rich plasma; thus, hPL is now considered for use in wound healing therapy. However, methods for preserving hPL for more than several months that maintain its bioactivity must be considered, especially for chronic wound treatment. The present study compared the effects of preservation for 9 months using a refrigerator or deep freezer. Methods: We investigated three preservation conditions. In the C-hPL group, hPL was stored at -80 degrees C in a deep freezer for 9 months; in the CL-hPL group, hPL was cryopreserved for 9 months at -80 degrees C in a deep freezer then lyophilized; in the L-hPL group, lyophilized hPL was refrigerated at 4 degrees C for 9 months. The quantity and quality of growth factors in these three groups were measured by an ELISA and in fibroblast cell cultures. Then, gelatin hydrogel discs were impregnated with hPL and its effects with regard to the promotion of wound healing in mice were evaluated by histologic examinations. Results: The PDGF-BB concentration in C-hPL, CL-hPL and L-hPL was 18,363 +/- 370 pg/ml, 11,325 +/- 171 pg/ml, and 12,307 +/- 348 pg/ml, respectively; the VEGF concentration was 655 +/- 23 pg/ml, 454 +/- 27 pg/ml, and 499 +/- 23 pg/ml, respectively; and the TGF-beta1 concentration was 97,363 +/- 5418 pg/ml, 73,198 +/- 2442 pg/ml, and 78,034 +/- 3885 pg/ml, respectively. In cell culture medium, fibroblast cell cultures were better supported in the hPL groups than in the fetal bovine serum group. In the histologic examination of the wound healing process, no differences were observed among the three preserved hPL groups with regard to epithelialization, or granulation tissue or capillary formation. The wounds in all groups had almost healed by day 14. Conclusions: The stability of growth factors contained in lyophilized hPL is maintained at 4 degrees C for up to 9 months. This was a versatile preservation method that can be applied in clinical practice. PMID- 30525066 TI - A large knee osteochondral lesion treated using a combination of osteochondral autograft transfer and second-generation autologous chondrocyte implantation: A case report. AB - Background: Full-thickness knee cartilage defects greater than 4 cm2 are best treated with autologous chondrocyte implantation (ACI). Since the articular cartilage surrounding the site of implantation does not always have the normal thickness desirable for successful engraftment, there may be benefit in combining ACI with osteochondral autograft transfer, which provides immediate restoration of condylar contour and mechanical function. Case presentation: A 19 year-old male who sustained a traumatic anterolateral femoral condyle osteochondral fracture underwent arthroscopic knee surgery three months after injury to harvest healthy cartilage to be sent to the Japan Tissue Engineering Co., Ltd. (J-TEC) for cartilage culture. The patient was re-admitted after four weeks to undergo a procedure using the Osteochondral Autograft Transfer System (OATS(r)) and the J TEC autologous cultured cartilage (JACC(r)) system. Three 4.75-mm osteochondral cylindrical cores were harvested from non-weight-bearing areas of the knee and were transplanted to the lateral periphery of the lateral femoral condyle defect. The cultured cartilage was implanted to the remaining defect with a periosteal cover harvested from the anterolateral ridge of the lateral femoral condyle. Continuous passive range of motion exercises and gait retraining were immediately initiated, with strict no weight-bearing precaution on the operated limb. Partial weight-bearing was allowed four weeks after surgery, which was progressed to full weight-bearing after another two weeks. Conclusion: ACI must be viewed as a complementary procedure to osteochondral transplantation and this hybrid technique appears to be a promising surgical approach and treatment option for large cartilage lesions, especially in the younger population. PMID- 30525067 TI - Multilineage-differentiating stress-enduring (Muse)-like cells exist in synovial tissue. AB - Introduction: Cartilage regeneration is a promising therapy for restoring joint function in patients with cartilage defects. The limited availability of autologous chondrocytes or chondrogenic progenitor cells is an obstacle to its clinical application. We investigated the existence and chondrogenic potential of synovial membrane-derived multilineage-differentiating stress-enduring (Muse) like cells as an alternative cell source for cartilage regeneration. Methods: Cells positive for stage-specific embryonic antigen-3 (SSEA-3), a marker of Muse cells, were isolated from the synovial membranes of 6 of 8 patients (median age, 53.5 years; range 36-72 years) by fluorescence-activated cell sorting. SSEA-3 positive cells were cultured in methylcellulose to examine their ability to form Muse clusters that are similar to the embryoid bodies formed by human embryonic stem cells. Muse clusters were expanded and chondrogenic potential of M-cluster derived MSCs examined using a pellet culture system. Chondrogenic differentiation was evaluated by proteoglycan, safranin O, toluidine blue and type II collagen staining. To evaluate the practicality of the procedure for isolating Muse-like cells, we compared chondrogenic potential of M-cluster derived MSCs with expanded cells derived from the clusters formed by unsorted synovial cells. Results: Synovial membranes contained SSEA-3-positive cells that after isolation exhibited Muse-like characteristics such as forming clusters that expressed NANOG, OCT3/4, and SOX2. In the pellet culture system, cell pellets created from the M-cluster derived MSCs exhibited an increase in wet weight, which implied an increase in extracellular matrix production, displayed metachromasia with toluidine blue and safranin O staining and were aggrecan-positive and type II collagen-positive by immunostaining. Unsorted synovial cells also formed clusters in methylcellulose culture, and the expanded cell population derived from them exhibited chondrogenic potential. The histological and immunohistochemical appearance of chondrogenic pellet created from unsorted synovial cell-derived cells were comparable with that from M-cluster-derived MSCs. Conclusions: Muse-like cells can be isolated from the human synovial membrane, even from older patients, and therefore may provide a source of multipotent cells for regenerative medicine. In addition, the cluster-forming cell population within synovial cells also has excellent chondrogenic potential. These cells may provide a more practical option for cartilage regeneration. PMID- 30525069 TI - Preparation of iPS cell-derived CD31+ endothelial cells using three-dimensional suspension culture. AB - A well-organised vascular network is essential for metabolic exchange to maintain homoeostasis in the body. Therefore, for progress in regenerative medicine, it is particularly important to establish methods of vascularization in bioengineered three-dimensional (3D) functional tissues. In addition, it is necessary to develop methods to supply a large number of iPS cell-derived endothelial cells for fabricating the vascular network structure. There are already many reports on the method of inducing the differentiation of endothelial cells from iPS cells using 2D culture. However, there are few reports on methods for preparing a large number of iPS cell-derived endothelial cells. Therefore, we developed methods for inducing vascular endothelial cells from human inducible pluripotent stem (hiPS) cells using 3D suspension culture. hiPS cell-derived CD31+ cells expressed several endothelial marker genes and formed endothelial cell network structures, similar to human umbilical vein endothelial cells. These results indicate that hiPS cell-derived CD31+ cells may be a useful cell source for pre-vascularised network structures in 3D functional tissues, and it is important to develop 3D mass culture system for preparing a large number of cells to fabricate bioengineered tissues. PMID- 30525068 TI - Effect of migratory behaviors on human induced pluripotent stem cell colony formation on different extracellular matrix proteins. AB - Introduction: Understanding how extracellular matrix (ECM) protein composition regulates the process of human induced pluripotent stem cell (hiPSC) colony formation may facilitate the design of optimal cell culture environments. In this study, we investigated the effect of migratory behaviors on hiPSC colony formation on various ECM-coated surfaces. Methods: To quantify how different ECM proteins affect migratory behavior during the colony formation process, single cells were seeded onto surfaces coated with varying concentrations of different ECM proteins. Cell behavior was monitored by time-lapse observation, and quantitative analysis of migration rates in relation to colony formation patterns was performed. Actin cytoskeleton, focal adhesions, and cell-cell interactions were detected by fluorescence microscopy. Results: Time-lapse observations revealed that different mechanisms of colony formation were dependent upon the migratory behavior of cells on different ECM surfaces. HiPSCs formed tight colonies on concentrated ECM substrates, while coating with dilute concentrations of ECM yielded more motile cells and colonies capable of splitting into single cells or small clusters. Enhanced migration caused a reduction of cell-cell contacts that enabled splitting or merging between cells and cell clusters, consequently reducing the efficiency of clonal colony formation. High cell-to cell variability in migration responses to ECM surfaces elicited differential focal adhesion formation and E-cadherin expression within cells and colonies. This resulted in variability within focal adhesions and further loss of E cadherin expression by hiPSCs. Conclusions: Migration is an important factor affecting hiPSC colony-forming patterns. Regulation of migratory behavior can be an effective way to improve the expansion of hiPSCs while improving the process of clonal colony formation. We believe that this investigation provides a valuable method for understanding cell phenotypes and heterogeneity during colony formation in culture. PMID- 30525070 TI - A report of the 17th congress of the Japanese Society for Regenerative Medicine. AB - The 17th Congress of the Japanese Society for Regenerative Medicine was held on March 21-23, 2018 at PACIFICO Yokohama (Kanagawa Prefecture) with 3860 participants. The theme of the congress was 'The Integration of Wisdom from All Sectors.' With this theme, this congress aimed to provide people from all sectors (including individuals from various industries, regulatory authorities, academia, and citizens) with opportunities for exchanging views on regenerative medicine under one roof. A broad spectrum of topics related to regenerative medicine was covered by one presidential lecture, one keynote lecture, one collaborative lecture by the Congress Chair and the Governor of Kanagawa Prefecture, three special lectures (six topics), four award lectures, 43 symposia (235 talks), 337 oral presentations (59 sessions), 358 poster presentations (43 sessions), 25 co organized seminars (35 talks), two sessions for junior high school and high school students (basic and advanced), and the state-of-the-art technology showcase (158 organizations). PMID- 30525071 TI - In-process evaluation of culture errors using morphology-based image analysis. AB - Introduction: Advancing industrial-scale manufacture of cells as therapeutic products is an example of the wide applications of regenerative medicine. However, one bottleneck in establishing stable and efficient cell manufacture is quality control. Owing to the lack of effective in-process measurement technology, analyzing the time-consuming and complex cell culture process that essentially determines cellular quality is difficult and only performed by manual microscopic observation. Our group has been applying advanced image-processing and machine-learning modeling techniques to construct prediction models that support quality evaluations during cell culture. In this study, as a model of errors during the cell culture process, intentional errors were compared to the standard culture and analyzed based only on the time-course morphological information of the cells. Methods: Twenty-one lots of human mesenchymal stem cells (MSCs), including both bone-marrow-derived MSCs and adipose-derived MSCs, were cultured under 5 conditions (one standard and 4 types of intentional errors, such as clear failure of handlings and machinery malfunctions). Using time-course microscopic images, cell morphological profiles were quantitatively measured and utilized for visualization and prediction modeling. For visualization, modified principal component analysis (PCA) was used. For prediction modeling, linear regression analysis and the MT method were applied. Results: By modified PCA visualization, the differences in cellular lots and culture conditions were illustrated as traits on a morphological transition line plot and found to be effective descriptors for discriminating the deviated samples in a real-time manner. In prediction modeling, both the cell growth rate and error condition discrimination showed high accuracy (>80%), which required only 2 days of culture. Moreover, we demonstrated the applicability of different concepts of machine learning using the MT method, which is effective for manufacture processes that mostly collect standard data but not a large amount of failure data. Conclusions: Morphological information that can be quantitatively acquired during cell culture has great potential as an in-process measurement tool for quality control in cell manufacturing processes. PMID- 30525072 TI - Cartilage repair and inhibition of the progression of cartilage degeneration after transplantation of allogeneic chondrocyte sheets in a nontraumatic early arthritis model. AB - Introduction: Using a rat model of nontraumatic early arthritis induced by intra articular administration of low-dose monoiodoacetic acid (MIA), we transplanted allogeneic chondrocyte sheets and examined the effects on tissue repair. Methods: MIA (0.2 mg/50 MUl) was injected into the right knee of 20 male Wistar rats. Four weeks later, rats were randomly allocated into three groups: Group A was examined 4 weeks after administration of MIA; Group B, 8 weeks after MIA injection and chondrocyte sheet transplantation, and Group C, 8 weeks after MIA injection but without chondrocyte sheet transplantation. Allogeneic chondrocyte sheets were transplanted into the right knee of Group B rats. Pain was assessed as the weight distribution ratio of the damaged to undamaged limb. The OARSI score was used for histological scoring. Results: The limb weight distribution ratio indicated significantly less pain in Group B. Histological scoring showed significant differences in cartilage repair and inhibition of the progression of cartilage degeneration between Groups B and C, but not between Groups A and B, or Groups A and C. Conclusions: These findings suggest that, in this rat model of nontraumatic early arthritis induced by low-dose MIA injection, allogeneic chondrocyte sheet transplantation induces cartilage repair and suppresses cartilage degeneration. PMID- 30525073 TI - Mesenchymal stromal cells as a potential therapeutic for neurological disorders. AB - Several studies have reported that mesenchymal stromal/stem cells (MSCs) restore neurological damage through their secretion of paracrine factors or their differentiation to neuronal cells. Based on these studies, many clinical trials have been conducted using MSCs for neurological disorders, and their safety and efficacy have been reported. In this review, we provide a brief introduction to MSCs, especially umbilical cord derived-MSCs (UC-MSCs), in terms of characteristics, isolation, and cryopreservation, and discuss the recent progress in regenerative therapies using MSCs for various neurological disorders. PMID- 30525074 TI - Periodontal regeneration with autologous periodontal ligament-derived cell sheets - A safety and efficacy study in ten patients. AB - Background: Periodontitis results in the destruction of tooth-supporting periodontal tissues and does not have the ability to heal spontaneously. Various approaches have been introduced to regenerate periodontal tissues; however, these approaches have limited efficacy for treating severe defects. Cytotherapies combine stem cell biology and tissue engineering to form a promising approach for overcoming these limitations. In this study, we isolated periodontal ligament (PDL)-derived cells from patients and created cell sheets with "Cell Sheet Engineering Technology", using temperature responsive culture dishes, in which all the cultured cells can be harvested as an intact transplantable cell sheet by reducing the temperature of the culture dish. Subsequently, the safety and efficacy of autologous PDL-derived cell sheets were evaluated in a clinical setting. Methods: A single-arm and single-institute clinical study was performed to verify the safety and efficacy of autologous PDL-derived cell sheets in patients with periodontitis. Wisdom teeth were extracted from patients diagnosed with chronic periodontitis, ranging in age from 33 to 63 years (mean [+/-SD], 46 +/- 12), and periodontal tissues were scraped for cell sources. Three-layered PDL derived cell sheets were constructed using temperature-responsive culture dishes and transplanted in an autologous fashion following standard flap surgeries. Bony defects were filled with beta-tricalcium phosphate granules. Clinical variables were evaluated at baseline, 3 months, and 6 months. Cone-beam computed tomography was performed at baseline and 6 months. Additionally, mid-long-term follow-up has been performed with patients' agreements. Results: Our method was found to be safe and no severe adverse events were identified. All the findings, including reduction of periodontal probing depth (mean +/- SD, 3.2 +/- 1.9 mm), clinical attachment gain (2.5 +/- 2.6 mm), and increase of radiographic bone height (2.3 +/- 1.8 mm), were improved in all 10 cases at 6 months after the transplantation. These therapeutic effects were sustained during a mean follow-up period of 55 +/- 19 months, and there were no serious adverse events. Conclusions: The results of this study validate the safety and efficacy of autologous PDL-derived cell sheets in severe periodontal defects, and the stability of this efficacy during mid-long term follow up. This cytotherapeutic approach, based on cell sheet engineering, offers an innovative strategy to treat the recognized unmet need of treating severe periodontal defects. PMID- 30525075 TI - Hepatic cell sheets engineered from human mesenchymal stem cells with a single small molecule compound IC-2 ameliorate acute liver injury in mice. AB - Introduction: We previously reported that transplantation of hepatic cell sheets from human bone marrow-derived mesenchymal stem cells (BM-MSCs) with hexachlorophene, a Wnt/beta-catenin signaling inhibitor, ameliorated acute liver injury. In a further previous report, we identified IC-2, a newly synthesized derivative of the Wnt/beta-catenin signaling inhibitor ICG-001, as a potent inducer of hepatic differentiation of BM-MSCs. Methods: We manufactured hepatic cell sheets by engineering from human BM-MSCs using the single small molecule IC 2. The therapeutic potential of IC-2-induced hepatic cell sheets was assessed by transplantation of IC-2- and hexachlorophene-treated hepatic cell sheets using a mouse model of acute liver injury. Results: Significant improvement of liver injury was elicited by the IC-2-treated hepatic cell sheets. The expression of complement C3 was enhanced by IC-2, followed by prominent hepatocyte proliferation stimulated through the activation of NF-kappaB and its downstream molecule STAT-3. Indeed, IC-2 also enhanced the expression of amphiregulin, resulting in the activation of the EGFR pathway and further stimulation of hepatocyte proliferation. As another important therapeutic mechanism, we revealed prominent reduction of oxidative stress mediated through upregulation of the thioredoxin (TRX) system by IC-2-treated hepatic cell sheets. The effects mediated by IC-2-treated sheets were superior compared with those mediated by hexachlorophene-treated sheets. Conclusion: The single compound IC-2 induced hepatic cell sheets that possess potent regeneration capacity and ameliorate acute liver injury. PMID- 30525076 TI - Application of induced pluripotent stem cells for cartilage regeneration in CLAWN miniature pig osteochondral replacement model. AB - Introduction: Pluripotent stem cells have an advantage that they can proliferate without reduction of the quality, while they have risk of tumorigenesis. It is desirable that pluripotent stem cells can be utilized safely with minimal effort in cartilage regenerative medicine. To accomplish this, we examined the potential usefulness of induced pluripotent stem cells (iPS cells) after minimal treatment via cell isolation and hydrogel embedding for cartilage regeneration using a large animal model. Methods: Porcine iPS-like cells were established from the CLAWN miniature pig. In vitro differentiation was examined for porcine iPS-like cells with minimal treatment. For the osteochondral replacement model, osteochondral defect was made in the quarters of the anteromedial sides of the proximal tibias in pigs. Porcine iPS-like cells and human iPS cells with minimal treatment were seeded on scaffold made of thermo-compression-bonded beta-TCP and poly-L-lactic acid and transplanted to the defect, and cartilage regeneration and tumorigenesis were evaluated. Results: The in vitro analysis indicated that the minimal treatment was sufficient to weaken the pluripotency of the porcine iPS like cells, while chondrogenic differentiation did not occur in vitro. When porcine iPS-like cells were transplanted into osteochondral replacement model after minimal treatment in vitro, cartilage regeneration was observed without tumor formation. Additionally, fluorescent in situ hybridization (FISH) indicated that the chondrocytes in the regenerative cartilage originated from transplanted porcine iPS-like cells. Transplantation of human iPS cells also showed the regeneration of cartilage in miniature pigs under immunosuppressive treatment. Conclusion: Minimally-treated iPS cells will be a useful cell source for cartilage regenerative medicine. PMID- 30525077 TI - Epigenetic-scale comparison of human iPSCs generated by retrovirus, Sendai virus or episomal vectors. AB - Human induced pluripotent stem cells (iPSCs) are established by introducing several reprogramming factors, such as OCT3/4, SOX2, KLF4, c-MYC. Because of their pluripotency and immortality, iPSCs are considered to be a powerful tool for regenerative medicine. To date, iPSCs have been established all over the world by various gene delivery methods. All methods induced high-quality iPSCs, but epigenetic analysis of abnormalities derived from differences in the gene delivery methods has not yet been performed. Here, we generated genetically matched human iPSCs from menstrual blood cells by using three kinds of vectors, i.e., retrovirus, Sendai virus, and episomal vectors, and compared genome-wide DNA methylation profiles among them. Although comparison of aberrant methylation revealed that iPSCs generated by Sendai virus vector have lowest number of aberrant methylation sites among the three vectors, the iPSCs generated by non integrating methods did not show vector-specific aberrant methylation. However, the differences between the iPSC lines were determined to be the number of random aberrant hypermethylated regions compared with embryonic stem cells. These random aberrant hypermethylations might be a cause of the differences in the properties of each of the iPSC lines. PMID- 30525078 TI - Pretreatment with an angiotensin II receptor blocker abolished ameliorating actions of adipose-derived stem cell sheets on cardiac dysfunction and remodeling after myocardial infarction. AB - Introduction: Cell sheets using myoblasts have been developed for the treatment of heart failure after myocardial infarction (MI) bridging to heart transplantation. Stem cells are supposed to be better than myoblasts as a source of cells, since they possess a potential to proliferate and differentiate into cardiomyocytes, and also have capacity to secrete angiogenic factors. Adipose derived stem cells (ASCs) obtained from fat tissues are expected to be a new cell source for ASC sheet therapies. Administration of angiotensin II receptor blockers (ARBs) is a standard therapy for heart failure after MI. However, it is not known whether ARBs affect the cell sheet therapy. This study aimed to examine ameliorating effects of ASC sheets on heart failure and remodeling after MI, and how pretreatment with ARBs prior to the creation of MI and ASC sheet transplantation modifies the effects of ASC sheets. Methods: ASCs were isolated from fat tissues of wild-type rats, and ASC sheets were engineered on temperature responsive dishes. In in vitro studies using cultured cells, mRNA levels of vascular endothelial growth factor (VEGF) in ASCs were determined by RT-PCR in the presence of angiotensin II and/or an ARB, irbesartan, under normoxia and hypoxia; mRNA and protein levels of angiotensin II receptor type 1a (AT1aR), type 1b (AT1bR) and type 2 (AT2R) were also determined by RT-PCR and western blotting. In in vivo studies using a rat MI model, effects of transplanted ASC sheets and/or irbesartan on cardiac functions and remodeling after MI were evaluated by echocardiography, histological analysis and molecular biological techniques. Results: In the in vitro studies, ASCs expressed higher levels of VEGF mRNA under hypoxia. They also expressed mRNA and protein of AT1aR but not AT1bR or AT2R. Under normoxia, angiotensin II increased the level of VEGF mRNA in ASCs, which was abolished by irbesartan. Under hypoxia, irbesartan reduced the level of VEGF mRNA in ASCs regardless of whether angiotensin II was present or not. In the in vivo studies, ASC sheets improved cardiac functions after MI, leading to decreased interstitial fibrosis and increased capillary density in border zones. These effects of ASC sheets were abolished by oral administration of irbesartan before MI and their transplantation. Conclusions: ASC sheets ameliorated cardiac dysfunctions and remodeling after MI via increasing VEGF expression, which was abolished by pretreatment with irbesartan before the creation of MI and transplantation. PMID- 30525079 TI - A novel, flexible and automated manufacturing facility for cell-based health care products: Tissue Factory. AB - Introduction: Current production facilities for Cell-Based Health care Products (CBHPs), also referred as Advanced-Therapy Medicinal Products or Regenerative Medicine Products, are still dependent on manual work performed by skilled workers. A more robust, safer and efficient manufacturing system will be necessary to meet the expected expansion of this industrial field in the future. Thus, the 'flexible Modular Platform (fMP)' was newly designed to be a true "factory" utilizing the state-of-the-art technology to replace conventional "laboratory-like" manufacturing methods. Then, we built the Tissue Factory as the first actual entity of the fMP. Methods: The Tissue Factory was designed based on the fMP in which several automated modules are combined to perform various culture processes. Each module has a biologically sealed chamber that can be decontaminated by hydrogen peroxide. The asepticity of the processing environment was tested according to a pharmaceutical sterility method. Then, three procedures, production of multi-layered skeletal myoblast sheets, expansion of human articular chondrocytes and passage culture of human induced pluripotent stem cells, were conducted by the system to confirm its ability to manufacture CHBPs. Results: Falling or adhered microorganisms were not detected either just after decontamination or during the cell culture processes. In cell culture tests, multi-layered skeletal myoblast sheets were successfully manufactured using the method optimized for automatic processing. In addition, human articular chondrocytes and human induced-pluripotent stem cells could be propagated through three passages by the system at a yield comparable to manual operations. Conclusions: The Tissue Factory, based on the fMP, successfully reproduced three tentative manufacturing processes of CBHPs without any microbial contamination. The platform will improve the manufacturability in terms of lower production cost, improved quality variance and reduced contamination risks. Moreover, its flexibility has the potential to adapt to the modern challenges in the business environment including employment issues, low operational rates, and relocation of facilities. The fMP is expected to become the standard design basis of future manufacturing facilities for CBHPs. PMID- 30525080 TI - Modulatory and regenerative potential of transplanted bone marrow-derived mesenchymal stem cells on rifampicin-induced kidney toxicity. AB - Introduction: Anti-tuberculosis agent rifampicin is extensively used for its effectiveness. Possible complications of tuberculosis and prolonged rifampicin treatment include kidney damage; these conditions can lead to reduced efficiency of the affected kidney and consequently to other diseases. Bone marrow-derived mesenchymal stem cells (BMMSCs) can be used in conjunction with rifampicin to avert kidney damage; because of its regenerative and differentiating potentials into kidney cells. This research was designed to assess the modulatory and regenerative potentials of MSCs in averting kidney damage due to rifampicin induced kidney toxicity in Wistar rats and their progenies. BMMSCs used in this research were characterized according to the guidelines of International Society for Cellular Therapy. Methods: The rats (male and female) were divided into three experimental groups, as follows: Group 1: control rats (4 males & 4 females); Group 2: rats treated with rifampicin only (4 males & 4 females); and Group 3: rats treated with rifampicin plus MSCs (4 males & 4 females). Therapeutic doses of rifampicin (9 mg/kg/day for 3-months) and MSCs infusions (twice/month for 3 months) were administered orally and intravenously respectively. At the end of the three months, the animals were bred together to determine if the effects would carry over to the next generation. Following breeding, the rats were sacrificed to harvest serum for biochemical analysis and the kidneys were also harvested for histological analysis and quantification of the glomeruli size, for the adult rats and their progenies. Results: The results showed some level of alterations in the biochemical indicators and histopathological damage in the rats that received rifampicin treatment alone, while the control and stem cells treated group showed apparently normal to nearly normal levels of both bio indicators and normal histological architecture. Conclusions: Intravenous administration of MSCs yielded sensible development, as seen from biochemical indicators, histology and the quantitative cell analysis, hence implying the modulatory and regenerative properties of MSCs. PMID- 30525081 TI - Effects of residual H2O2 on the growth of MSCs after decontamination. AB - Introduction: Regenerative therapy is a developing field in medicine. In the production of cell products for these therapies, hygienic management is even more critical than in the production of a chemical drug. At the same time, however, care is required with the use of decontamination agents, considering their effects on cell viability and characteristics. To date, hydrogen peroxide (H2O2) is most widely used for decontamination in pharmaceutical plants and cell processing facilities. Methods: In this study, we examined the effects of residual H2O2 in the atmosphere of cell processing units after decontamination on the viability and proliferation of mesenchymal stem cells derived from human bone marrow. Results: We detected residual H2O2 sufficient to affect cell proliferation and survival even more than 30 h after decontamination ended. Our results suggest a longer time period is required before starting operations after decontamination and that the operating time should be as short as possible. Conclusions: Here we show the effects of post-decontamination residual H2O2 on the viability and proliferation of mesenchymal stem cells derived from human bone marrow, which may provide us with important information about the hygienic management of cell processing facilities. PMID- 30525082 TI - Magnetic cell delivery for the regeneration of musculoskeletal and neural tissues. AB - Magnetic targeting is a cell delivery system using the magnetic labeling of cells and the magnetic field; it has been developed for minimally invasive cell transplantation. Cell transplantation with both minimal invasiveness and high efficacy on tissue repair can be achieved by this system. Magnetic targeting has been applied for the transplantation of bone marrow mesenchymal stem cells, blood CD133-positive cells, neural progenitor cells, and induced pluripotent stem cells, and for the regeneration of bone, cartilage, skeletal muscles, and the spinal cord. It enhances the accumulation and adhesion of locally injected cells, resulting in the improvement of tissue regeneration. It is a promising technique for minimally invasive and effective cell transplantation therapy. PMID- 30525083 TI - Aging of mesenchymal stem cells: Implication in regenerative medicine. AB - Multipotent mesenchymal stem cells (MSCs) represent a great candidate for various clinical applications including regenerative medicine. However, aging both in vivo and in vitro can significantly compromise MSC characteristics and performance. This paper highlights current thoughts on senescence-induced damage to MSCs that should be considered prior to their use for regeneration of different cells, tissues or organs. PMID- 30525084 TI - Salmonella risks due to consumption of aquaculture-produced shrimp. AB - The use of aquaculture is increasing to meet the growing global demand for seafood. However, the use of aquaculture for seafood production incurs potential human health risks, especially from enteric bacteria such as Salmonella spp. Salmonella spp. was the most frequently reported cause of outbreaks associated with crustaceans from 1998 to 2004. Among crustacean species, shrimp are the most economically important, internationally traded seafood commodity, and the most commonly aquaculture-raised seafood imported to the United States. To inform safe aquaculture practices, a quantitative microbial risk assessment (QMRA) was performed for wastewater-fed aquaculture, incorporating stochastic variability in shrimp growth, processing, and consumer preparation. Several scenarios including gamma irradiation, proper cooking, and improper cooking were considered in order to examine the relative importance of these practices in terms of their impact on risk. Median annual infection risks for all scenarios considered were below 10-4, however 95th percentile risks were above 10-4 annual probability of infection and 10-6 DALY per person per year for scenarios with improper cooking and lack of gamma irradiation. The greatest difference between microbiological risks for the scenarios tested was observed when comparing proper vs. improper cooking (5 to 6 orders of magnitude) and gamma irradiation (4 to 5 orders of magnitude) compared to (up to less than 1 order of magnitude) for peeling and deveining vs. peeling only. The findings from this research suggest that restriction of Salmonella spp. to low levels (median 5 to 30 per L aquaculture pond water) may be necessary for scenarios in which proper downstream food handling and processing cannot be guaranteed. PMID- 30525085 TI - Carcinoma Cells Reprogram a Wound-healing Switch to Promote Metastasis. AB - Wound healing is a dynamic event where barrier disruption is transient and miR 198/FSTL1 molecular switch orchestrate wound re-epithelialization. However, epithelial carcinomas maintain a prolonged wound-healing phase to promote malignant transformation. Delineating the molecular mechanism we demonstrate, how epidermal growth factor (EGF) hijacks the wound-healing switch to promote metastasis of carcinoma. PMID- 30525086 TI - The role of PLK1 in cancer exhibiting chromosomal instability. AB - Adenomatous polyposis coli (APC) mutations cause aneuploidy and are responsible for familial adenomatous polyposis characterized by chromosomal instability. PLK1 contributes to sustain an intact spindle assembly checkpoint ensuring genomic stability. In our work using independent ApcMin/+ mouse models we revealed that PLK1 functions as tumor suppressor in APC-mutated colorectal cancers. PMID- 30525087 TI - microRNAs: Novel regulators of the TGF-beta pathway in pancreatic ductal adenocarcinoma. AB - We identified that transforming growth factor-beta (TGF-beta) induces long non coding RNA (lncRNA) MIR100HG along with its host microRNAs (miRNAs) miR-100 and miR-125b, to regulate its response in pancreatic ductal adenocarcinoma (PDAC). Importantly let-7a, despite originating from MIR100HG, remains unchanged because post-transcriptionally repressed by lin-28 homolog B (LIN28B). A novel method for global miRNA-target discovery identified that miR-100/125b regulates crucial PDAC pathways. PMID- 30525088 TI - With great power comes great vulnerability. AB - The clinical responses to targeted drugs are often transient and do not always translate into meaningful overall survival due to the development of resistance. We discuss here that the greater power of drug resistant cells can be associated with significant newly-acquired vulnerabilities that can be exploited therapeutically. PMID- 30525089 TI - Functional characterization of the p53 "mutome". AB - Phenotypic characterization of mutations in the tumor protein p53 (TP53) gene has so far focused on a handful of relatively frequent "hotspot" mutations, accounting for only ~ 30% of cases. We expanded the scope and quantitatively measured the impact of thousands of distinct TP53 mutations in vitro and in vivo, providing insights into the connections between structure, function, evolutionary conservation and clinical impact. PMID- 30525090 TI - On your marks, get SET(D1A): the race to protect stalled replication forks. AB - We recently identified that methylation of lysine 4 of histone H3 (H3K4) by SETD1A (SET domain containing 1A) maintains genome stability by protecting newly replicated DNA from degradation. Mechanistically, SETD1A-dependent histone methylation regulates nucleosome mobilisation by FANCD2 (FA complementation group D2), a crucial step in maintaining genome integrity with important implications in chemo-sensitivity. PMID- 30525091 TI - Breaking bad family ties: Pan-ERBB blockers inhibit KRAS driven lung tumorigenesis. AB - Oncogenic K-RAS mutations were believed to lock the molecular switch in the ON state, independent of upstream activation. However, we demonstrate in preclinical models that activity of mutated K-RAS depends on upstream signaling events involving EGF receptor family members. This finding reveals a potential therapeutic vulnerability using pan-ERBB inhibitors to fight K-RAS mutated lung tumors. PMID- 30525092 TI - Wobble uridine tRNA modification: a new vulnerability of refractory melanoma. AB - The enzymes catalysing the modification of the wobble uridine (U34) of tRNAs (U34 enzymes) play an important role in tumor development. We have recently demonstrated that the U34-enzymes are crucial in the survival of glycolytic melanoma cultures through a codon-specific regulation of HIF1alpha mRNA translation. Moreover, depletion of U34-enzymes resensitizes resistant melanoma to targeted therapy. These results indicate that targeting U34-enzymes represents a new therapeutic opportunity for melanoma patients. PMID- 30525093 TI - Timed degradation of Mcl-1 controls mitotic cell death. AB - Mitotic arrest can result in cell death through the process of apoptosis. We have shown by live-cell imaging that the ubiquitin-proteasome dependent proteolysis of the apoptotic regulator Mcl-1 under the control of the anaphase-promoting complex or cyclosome (APC/C) provides a timing mechanism that distinguishes prolonged mitotic arrest from normal mitosis. PMID- 30525094 TI - Oncogenic regulatory circuits driven by 19q13 rs11672691 underlies prostate cancer aggressiveness. AB - The 19q13 allele rs11672691 has been reproducibly found in association with aggressive form of prostate cancer, yet the underlying mechanism remains totally unknown. We have recently uncovered a mechanism by which rs11672691 influenced a novel oncogenic regulatory circuit, including HOXA2, PCAT19 and CEACAM21, thereby contributing to prostate cancer aggressiveness. PMID- 30525095 TI - Controlling the mitochondrial antisense - role of the SUV3-PNPase complex and its co-factor GRSF1 in mitochondrial RNA surveillance. AB - Transcription of the human mitochondrial genome produces a vast amount of non coding antisense RNAs. These RNA species can form G-quadraplexes (G4), which affect their decay. We found that the mitochondrial degradosome, a complex of RNA helicase SUPV3L1 (best known as SUV3) and the ribonuclease PNPT1 (also known as PNPase), together with G4-melting protein GRSF1, is a key player in restricting antisense mtRNAs. PMID- 30525096 TI - Stitching up broken DNA ends by FANCA. AB - RAD52 rejoins resected broken DNA ends by mediating single-strand annealing. Our recent work elucidates that FANCA, a Fanconi anemia protein, also directly repairs double-strand breaks (DSBs) by catalyzing annealing of single-stranded DNA. FANCA and RAD52 likely play complementary roles to each other to prevent deleterious consequences of DSBs. Abbreviations: DSBs: DNA double-strand breaks; ICL: interstrand crosslink; ssDNA: single-stranded DNA; HR: homologous recombination; SSA: single-strand annealing; MMEJ: microhomology-mediated end joining; NHEJ: non-homologous end joining; GFP: green fluorescence protein. PMID- 30525097 TI - Cisplatin resistance coupled to enhanced sensitivity to metabolic interventions. AB - Specific metabolic alterations have recently been observed in cisplatin-resistant cancers. As a result, cisplatin resistance can be overcome by co-administration of pyridoxine, and cisplatin-resistant cancer cells become exquisitely sensitive to killing by inhibitors of poly(ADP-ribose) polymerase, starvation, and antimetabolites targeting nucleotide biosynthesis. PMID- 30525098 TI - ESR1 fusions drive endocrine therapy resistance and metastasis in breast cancer. AB - Estrogen receptor alpha gene (ESR1) fusion transcripts have been identified in breast cancer but their role in breast cancer is not completely understood. Here, we report a causal role for ESR1 fusions in driving both endocrine therapy resistance and metastasis, and describe a therapeutic strategy to target ESR1 fusion-induced growth. PMID- 30525099 TI - Ykt6 mediates autophagosome-vacuole fusion. AB - Studying the mechanism of autophagosome-vacuole fusion has proven difficult in live yeast cells. Developing a novel in vitro fusion assay, we identified Ykt6 as the missing R-SNARE (Soluble N-ethylmaleimide sensitive factor attachment protein receptor) in this process and pinpoint the place of action of all four SNAREs involved. Parallel studies have confirmed our findings in other organisms. PMID- 30525100 TI - TRIM16 controls turnover of protein aggregates by modulating NRF2, ubiquitin system, and autophagy: implication for tumorigenesis. AB - Protein misfolding and protein aggregation are linked to several diseases commonly called as proteinopathies, which include cancer. Understanding the mechanisms of proteostasis could provide newer strategies to combat proteinopathies. We have recently demonstrated a new mechanism where we found that TRIM16 (tripartite motif-containing protein 16) utilizing NRF2-p62 axis and autophagy streamlines the safe disposal of misfolded proteins to maintain protein homeostasis. PMID- 30525101 TI - Expanding the chemotherapeutic potential of an established nucleoside analog with selective targeting of telomerase. AB - The identification of telomerase-mediated telomeric misincorporation of 5-fluoro 2'-deoxyuridine (5-FdU) uncovered a unique approach to telomeric-based therapeutics. Additionally, identification of such a mechanism supports the utility of telomere maintenance mechanisms in guiding therapeutic decisions. Presented here is a unique perspective of 5-FdU and its clinical implications as a telomeric-based therapeutic. PMID- 30525102 TI - Convergent evolution of a metabolic switch between aphid and caterpillar resistance in cereals. AB - Tailoring defense responses to different attackers is important for plant performance. Plants can use secondary metabolites with dual functions in resistance and defense signaling to mount herbivore-specific responses. To date, the specificity and evolution of this mechanism are unclear. Here, we studied the functional architecture, specificity, and genetic basis of defense regulation by benzoxazinoids in cereals. We document that DIMBOA-Glc induces callose as an aphid resistance factor in wheat. O-methylation of DIMBOA-Glc to HDMBOA-Glc increases plant resistance to caterpillars but reduces callose inducibility and resistance to aphids. DIMBOA-Glc induces callose in wheat and maize, but not in Arabidopsis, while the glucosinolate 4MO-I3M does the opposite. We identify a wheat O-methyltransferase (TaBX10) that is induced by caterpillar feeding and converts DIMBOA-Glc to HDMBOA-Glc in vitro. While the core pathway of benzoxazinoid biosynthesis is conserved between wheat and maize, the wheat genome does not contain close homologs of the maize DIMBOA-Glc O-methyltransferase genes, and TaBx10 is only distantly related. Thus, the functional architecture of herbivore-specific defense regulation is similar in maize and wheat, but the regulating biosynthetic genes likely evolved separately. This study shows how two different cereal species independently achieved herbivore-specific defense activation by regulating secondary metabolite production. PMID- 30525103 TI - Fe-oxide concretions formed by interacting carbonate and acidic waters on Earth and Mars. AB - Spherical Fe-oxide concretions on Earth, especially in Utah, USA, have been investigated as an analog of hematite spherules found in Meridiani Planum on Mars to support interpretations of water-rock interactions in early Mars. Although several formation mechanisms have been proposed for the Fe-oxide concretions on Earth, it is still unclear whether these mechanisms are viable because a precise formation process and precursor of the concretions are missing. This paper presents evidence that Fe-oxide concretions in Utah and newly found Fe-oxide concretions in Mongolia had spherical calcite concretions as precursors. Different formation stages of calcite and Fe-oxide concretions observed, both in Utah and Mongolia, indicate that calcite concretions initially formed within eolian sandstone strata and were dissolved by infiltrating Fe-rich acidic waters to form spherical FeO(OH) crusts due to pH buffering. The similarity between these Fe-oxide concretions on Earth and the hematite spherule occurrences in Meridiani Planum, combined with evidence of acid sulfate water influences on Mars, suggest that the hematite spherules also formed from dissolution of preexisting carbonate spherules possibly formed under a dense carbon dioxide early martian atmosphere. PMID- 30525104 TI - Applying ecological resistance and resilience to dissect bacterial antibiotic responses. AB - An essential property of microbial communities is the ability to survive a disturbance. Survival can be achieved through resistance, the ability to absorb effects of a disturbance without a notable change, or resilience, the ability to recover after being perturbed by a disturbance. These concepts have long been applied to the analysis of ecological systems, although their interpretations are often subject to debate. Here, we show that this framework readily lends itself to the dissection of the bacterial response to antibiotic treatment, where both terms can be unambiguously defined. The ability to tolerate the antibiotic treatment in the short term corresponds to resistance, which primarily depends on traits associated with individual cells. In contrast, the ability to recover after being perturbed by an antibiotic corresponds to resilience, which primarily depends on traits associated with the population. This framework effectively reveals the phenotypic signatures of bacterial pathogens expressing extended spectrum beta-lactamases (ESBLs) when treated by a beta-lactam antibiotic. Our analysis has implications for optimizing treatment of these pathogens using a combination of a beta-lactam and a beta-lactamase (Bla) inhibitor. In particular, our results underscore the need to dynamically optimize combination treatments based on the quantitative features of the bacterial response to the antibiotic or the Bla inhibitor. PMID- 30525105 TI - Effective approach to epidemic containment using link equations in complex networks. AB - Epidemic containment is a major concern when confronting large-scale infections in complex networks. Many studies have been devoted to analytically understand how to restructure the network to minimize the impact of major outbreaks of infections at large scale. In many cases, the strategies are based on isolating certain nodes, while less attention has been paid to interventions on the links. In epidemic spreading, links inform about the probability of carrying the contagion of the disease from infected to susceptible individuals. Note that these states depend on the full structure of the network, and its determination is not straightforward from the knowledge of nodes' states. Here, we confront this challenge and propose a set of discrete-time governing equations that can be closed and analyzed, assessing the contribution of links to spreading processes in complex networks. Our approach allows a scheme for the containment of epidemics based on deactivating the most important links in transmitting the disease. The model is validated in synthetic and real networks, yielding an accurate determination of epidemic incidence and critical thresholds. Epidemic containment based on link deactivation promises to be an effective tool to maintain functionality of networks while controlling the spread of diseases, such as disease spread through air transportation networks. PMID- 30525106 TI - The strength of dynamic ties: The ability to alter some ties promotes cooperation in those that cannot be altered. AB - Dynamic networks, where ties can be shed and new ties can be formed, promote the evolution of cooperation. Yet, past research has only compared networks where all ties can be severed to those where none can, confounding the benefits of fully dynamic networks with the presence of some dynamic ties within the network. Further, humans do not live in fully dynamic networks. Instead, in real-world networks, some ties are subject to change, while others are difficult to sever. Here, we consider whether and how cooperation evolves in networks containing both static and dynamic ties. We argue and find that the presence of dynamic ties in networks promotes cooperation even in static ties. Consistent with previous work demonstrating that cooperation cascades in networks, our results show that cooperation is enhanced in networks with both tie types because the higher rate of cooperation that occurs following the dynamics process "spills over" to those relations that are more difficult to alter. Thus, our findings demonstrate the critical role that dynamic ties play in promoting cooperation by altering behavioral outcomes even in non-dynamic relations. PMID- 30525107 TI - Rift Valley fever virus induces fetal demise in Sprague-Dawley rats through direct placental infection. AB - Rift Valley fever virus (RVFV) infections in pregnant livestock cause high rates of fetal demise; miscarriage in pregnant women has also been associated with RVFV infection. To address how RVFV infection during pregnancy causes detrimental effects on the fetus, we developed a pregnant rodent model of RVFV infection. We found that pregnant rats were more susceptible to RVFV-induced death than their nonpregnant counterparts and that RVFV infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a previously unrecognized preference for infection, replication, and tissue damage in the placenta. In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with replication detected in the outermost syncytial layer. Our work identifies direct placental infection by RVFV as a mechanism for vertical transmission. This is the first study to show vertical transmission of RVFV with a lethal outcome in a species other than livestock. This study highlights the potential impact of a future epidemic of this emerging mosquito-borne virus. PMID- 30525108 TI - Radiocarbon re-dating of contact-era Iroquoian history in northeastern North America. AB - A time frame for late Iroquoian prehistory is firmly established on the basis of the presence/absence of European trade goods and other archeological indicators. However, independent dating evidence is lacking. We use 86 radiocarbon measurements to test and (re)define existing chronological understanding. Warminster, often associated with Cahiague visited by S. de Champlain in 1615 1616 CE, yields a compatible radiocarbon-based age. However, a well-known late prehistoric site sequence in southern Ontario, Draper-Spang-Mantle, usually dated ~1450-1550, yields much later radiocarbon-based dates of ~1530-1615. The revised time frame dramatically rewrites 16th-century contact-era history in this region. Key processes of violent conflict, community coalescence, and the introduction of European goods all happened much later and more rapidly than previously assumed. Our results suggest the need to reconsider current understandings of contact-era dynamics across northeastern North America. PMID- 30525109 TI - The development of lower-atmosphere turbulence early in a solar flare. AB - We present the first observational study of the onset and evolution of solar flare turbulence in the lower solar atmosphere on an unprecedented time scale of 1.7 s using the Interface Region Imaging Spectrograph observing plasma at a temperature of 80,000 K. At this time resolution, nonthermal spectral line broadening, indicating turbulent velocity fluctuations, precedes the flare onset at this temperature and is coincident with net blue-shifts. The broadening decreases as the flare brightens and then oscillates with a period of ~10 s. These observations are consistent with turbulence in the lower solar atmosphere at the flare onset, heating that region as it dissipates. This challenges the current view of energy release and transport in the standard solar flare model, suggesting that turbulence partly heats the lower atmosphere. PMID- 30525110 TI - Enacted HIV-related stigma and breast-health beliefs and practices among African American women living with HIV: The mediating roles of internalized HIV-related stigma and depressive symptoms. AB - Reducing HIV-related stigma among African American women living with HIV is a priority to improve HIV-specific health outcomes, but may also impact other health beliefs and practices. Testing this hypothesis is important because African American women experience worse health outcomes, including for breast cancer. This study examines the relationship between enacted HIV-related stigma and breast health beliefs and practices and the mediating effects of depressive symptoms and internalized HIV-related stigma. We use baseline data from a stigma reduction intervention trial for adult African American women living with HIV in Chicago, IL and Birmingham, AL (n = 237). Data were collected using computer assisted self-interviewing software. After adjusting for covariates, enacted HIV related stigma was associated with greater perceived threat of breast cancer, specifically in terms of breast cancer fear (p <0.0001), but not regular breast healthcare engagement (p = .17). Internalized HIV-related stigma and depressive symptoms were associated with enacted HIV-related stigma, perceived threat of breast cancer, and regular breast healthcare engagement (all p <.05). Internalized HIV-related stigma mediated the relationship between enacted HIV related stigma and perceived threat of breast cancer (p = .001); depressive symptoms did not (p = .84). We provide evidence concerning broader influences of internalized HIV-related stigma for the health of African American women living with HIV. Future studies should consider the impact of HIV stigma on other health beliefs and behaviors. PMID- 30525111 TI - Epigenetic inhibitors for the precision treatment of ARID1A-mutant ovarian cancers: what are the next steps? PMID- 30525112 TI - A systematic review and meta-analysis of effects of early life non-cognitive skills on academic, psychosocial, cognitive and health outcomes. AB - Success in school and the labour market relies on more than high intelligence. Associations between "non-cognitive" skills in childhood, such as attention, self regulation, and perseverance, and later outcomes have been widely investigated. In a systematic review of this literature, we screened 9553 publications, reviewed 554 eligible publications, and interpreted results from 222 better quality publications. Better quality publications comprised randomised experimental and quasi-experimental studies (EQIs), and observational studies that made reasonable attempts to control confounding. For academic achievement outcomes there were 26 EQI publications but only 14 were available for meta analysis with effects ranging from 0.16 to 0.37SD. However, within sub-domains effects were heterogeneous. The 95% prediction interval for literacy was consistent with negative, null and positive effects (-0.13 to 0.79). Similarly heterogeneous findings were observed for psychosocial, cognitive and language, and health outcomes. Funnel plots of EQIs and observational studies showed asymmetric distributions and potential for small study bias. There is some evidence that non-cognitive skills associate with improved outcomes. However, there is potential for small study and publication bias that may over-estimate true effects, and heterogeneity of effect estimates spanned negative, null and positive effects. The quality of evidence from EQIs under-pinning this field is lower than optimal and more than a third of observational studies made little or no attempt to control confounding. Interventions designed to develop children's non-cognitive skills could potentially improve outcomes. The inter-disciplinary researchers interested in these skills should take a more strategic and rigorous approach to determine which interventions are most effective. PMID- 30525113 TI - Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps. AB - There is a major unmet need for biomarkers of epilepsy. Biofluids such as blood offer a potential source of molecular biomarkers. MicroRNAs (miRNAs) fulfill several key requirements for a blood-based molecular biomarker being enriched in the brain and dysregulated in epileptic brain tissue, and manipulation of miRNAs can have seizure-suppressive and disease-modifying effects in preclinical models. Biofluid miRNAs also possess qualities that are favorable for translation, including stability and easy and cheap assay techniques. Herein we review findings from both clinical and animal models. Studies have featured a mix of unbiased profiling and hypothesis-driven efforts. Blood levels of several brain enriched miRNAs are altered in patients with epilepsy and in patients with drug resistant compared to drug-responsive seizures, with encouraging receiver operating characteristic (ROC) curve analyses, both in terms of sensitivity and specificity. Both focal and generalized epilepsies are associated with altered blood miRNA profiles, and associations with clinical parameters including seizure burden have been reported. Results remain preliminary, however. There is a need for continued discovery and validation efforts that include multicenter studies and attention to study design, sample collection methodology, and quality control. Studies focused on epileptogenesis as well as associations with covariables such as sex, etiology, and timing of sampling remain limited. We identify 10 knowledge gaps and propose experiments to close these. If adequately addressed, biofluid miRNAs may be an important future source of diagnostic biomarkers that could also support forthcoming trials of antiepileptogenesis or disease-modifying therapies. PMID- 30525114 TI - Methodologic recommendations and possible interpretations of video-EEG recordings in immature rodents used as experimental controls: A TASK1-WG2 report of the ILAE/AES Joint Translational Task Force. AB - The use of immature rodents to study physiologic aspects of cortical development requires high-quality recordings electroencephalography (EEG) with simultaneous video recording (vEEG) of behavior. Normative developmental vEEG data in control animals are fundamental for the study of abnormal background activity in animal models of seizures or other neurologic disorders. Electrical recordings from immature, freely behaving rodents can be particularly difficult because of the small size of immature rodents, their thin and soft skull, interference with the recording apparatus by the dam, and other technical challenges. In this report of the TASK1 Working Group 2 (WG2) of the International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force, we provide suggestions that aim to optimize future vEEG recordings from immature rodents, as well as their interpretation. We focus on recordings from immature rodents younger than 30 days old used as experimental controls, because the quality and correct interpretation of such recordings is important when interpreting the vEEG results of animals serving as models of neurologic disorders. We discuss the technical aspects of such recordings and compare tethered versus wireless approaches. We also summarize the appearance of common artifacts and various patterns of electrical activity seen in young rodents used as controls as a function of behavioral state, age, and (where known) sex and strain. The information herein will hopefully help improve the methodology of vEEG recordings from immature rodents and may lead to results and interpretations that are more consistent across studies from different laboratories. PMID- 30525115 TI - How do we use in vitro models to understand epileptiform and ictal activity? A report of the TASK1-WG4 group of the ILAE/AES Joint Translational Task Force. AB - In vitro brain tissue preparations allow the convenient and affordable study of brain networks and have allowed us to garner molecular, cellular, and electrophysiologic insights into brain function with a detail not achievable in vivo. Preparations from both rodent and human postsurgical tissue have been utilized to generate in vitro electrical activity similar to electrographic activity seen in patients with epilepsy. A great deal of knowledge about how brain networks generate various forms of epileptiform activity has been gained, but due to the multiple in vitro models and manipulations used, there is a need for a standardization across studies. Here, we describe epileptiform patterns generated using in vitro brain preparations, focusing on issues and best practices pertaining to recording, reporting, and interpretation of the electrophysiologic patterns observed. We also discuss criteria for defining in vitro seizure-like patterns (i.e., ictal) and interictal discharges. Unifying terminologies and definitions are proposed. We suggest a set of best practices for reporting in vitro studies to favor both efficient across-lab comparisons and translation to in vivo models and human studies. PMID- 30525116 TI - Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic-clonic seizures: A double-blind, randomized, placebo-controlled trial. AB - Objective: To assess the efficacy, safety, and tolerability of adjunctive levetiracetam (LEV) in Chinese and Japanese adults with generalized tonic-clonic (GTC) seizures (N01159; NCT01228747). Methods: This double-blind, randomized, placebo-controlled, multicenter phase III trial comprised: 4-week retrospective and 4-week prospective baseline, 12-week dose-adjustment, and 16-week evaluation periods. Chinese and Japanese patients >=16 years old with idiopathic generalized, symptomatic generalized, or undetermined epilepsy with GTC seizures received a single-blind placebo during the prospective baseline, and then were randomized 1:1 to placebo or LEV 1,000 mg/day administered twice daily. Patients reporting GTC seizures up to week 8 had the LEV dosage increased to 3,000 mg/day. The primary efficacy variable was percent reduction from combined baseline in GTC seizures/week during the 28-week treatment period. Results: Overall, 251 patients were randomized (208 from China; 43 from Japan); 141 (56.2%) completed the 28 week treatment period. Least-squares mean percent reduction from combined baseline in GTC seizures/week (treatment period) was placebo 12.6% versus LEV 68.8% (95% confidence interval, 44.0-68.2; p < 0.0001). GTC seizure frequency reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. The 50% responder rate (treatment period) was placebo 28.4% versus LEV 77.8%. Freedom from GTC seizures (evaluation period) was placebo 3.1% versus LEV 29.6%. Incidence of treatment-emergent adverse events (TEAEs; treatment period) was placebo 52.0% versus LEV 57.1%; most frequently nasopharyngitis, protein in urine, decreased platelet count, and pyrexia. Incidence of TEAEs leading to discontinuation was 4.8% versus 3.2%; incidence of serious TEAEs was 3.2% versus 0.8% for placebo and LEV, respectively; 3 patients taking placebo died versus none taking LEV. Significance: In this trial, adjunctive LEV 1,000-3,000 mg/day was effective in reducing GTC seizure frequency in Chinese and Japanese patients >=16 years old with GTC seizures. Seizure reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. LEV was well tolerated in this population. PMID- 30525117 TI - Unravelling the brain networks driving spike-wave discharges in genetic generalized epilepsy-common patterns and individual differences. AB - Objective: Genetic generalized epilepsies (GGEs) are characterized by generalized spike-wave discharges (GSWDs) in electroencephalography (EEG) recordings without underlying structural brain lesions. The origin of the epileptic activity remains unclear, although several studies have reported involvement of thalamus and default mode network (DMN). The aim of the current study was to investigate the networks involved in the generation and temporal evolution of GSWDs to elucidate the origin and propagation of the underlying generalized epileptic activity. Methods: We examined 12 patients with GGE and GSWDs using EEG-functional magnetic resonance imaging (fMRI) and identified involved brain areas on the basis of a classical general linear model (GLM) analysis. The activation time courses of these areas were further investigated to reveal their temporal sequence of activations and deactivations. Dynamic causal modeling (DCM) was used to determine the generator of GSWDs in GGE. Results: We observed activity changes in the thalamus, DMN, dorsal attention network (DAN), salience network (SN), basal ganglia, dorsolateral prefrontal cortex, and motor cortex with supplementary motor area, however, with a certain heterogeneity between patients. Investigation of the temporal sequence of activity changes showed deactivations in the DMN and DAN and activations in the SN and thalamus preceding the onset of GSWDs on EEG by several seconds. DCM analysis indicated that the DMN gates GSWDs in GGE. Significance: The observed interplay between DMN, DAN, SN, and thalamus may indicate a downregulation of consciousness. The DMN seems to play a leading role as a driving force behind these changes. Overall, however, there were also clear differences in activation patterns between patients, reflecting a certain heterogeneity in this cohort of GGE patients. PMID- 30525118 TI - PLPBP mutations cause variable phenotypes of developmental and epileptic encephalopathy. AB - Objective: Vitamin B6-dependent epilepsies are treatable disorders caused by variants in several genes, such as ALDH7A1,PNPO, and others. Recently, biallelic variants in PLPBP, formerly known as PROSC, were identified as a novel cause of vitamin B6-dependent epilepsies. Our objective was to further delineate the phenotype of PLPBP mutation. Methods: We identified 4 unrelated patients harboring a total of 4 variants in PLPBP, including 3 novel variants, in a cohort of 700 patients with developmental and epileptic encephalopathies. Clinical information in each case was collected. Results: Each patient had a different clinical course of epilepsy, with seizure onset from the first day of life to 3 months of age. Generalized tonic-clonic seizures were commonly noted. Myoclonic seizures or focal seizures were also observed in 2 patients. Interictal electroencephalography showed variable findings, such as suppression burst, focal or multifocal discharges, and diffuse slow activity. Unlike previous reports, all the patients had some degree of intellectual disability, although some of them had received early treatment with vitamin B6, suggesting that different mutation types influence the severity and outcome of the seizures. Significance: PLPBP variants should be regarded as among the causative genes of developmental and epileptic encephalopathy, even when it occurs after the neonatal period. Early diagnosis and proper treatment with pyridoxine or pyridoxal phosphate is essential to improve the neurologic prognosis in neonates or young children with poorly controlled seizures. PMID- 30525119 TI - A retrospective observational study of EEG findings and antiepileptic drug use among children referred for EEG to Zambia's University Teaching Hospital. AB - Objective: Despite the heavy burden of epilepsy in Sub-Saharan Africa, there remains a relative paucity of neurophysiology services and limited published data on electroencephalography (EEG) features among African children. The aim of this study was to describe clinical characteristics, EEG findings, and antiepileptic drug (AED) use among children referred for EEG to the University Teaching Hospital in Zambia. Methods: EEG referrals and reports from 2013-2015 were reviewed. Within the context of routine care, EEG studies were interpreted by readers with advanced training in child neurology and clinical neurophysiology. Clinical data provided in the referral including seizure semiology and EEG findings were systematically extracted and analyzed. Results: A total of 1,217 EEG reports were reviewed, with 1,187 included in the analysis. Median age was 7 years (interquartile range [IQR] 3-11) and 57% were male. Seventy-three percent of 554 had documented seizure onset before 5 years of age. Among the 23% with seizure etiology documented, 78% were associated with perinatal injuries and central nervous system (CNS) infections. EEG abnormalities were found in 75% of the studies. Clinical semiology per referral identified focal seizures in 29%, but EEG findings increased this proportion to 63% (p = 0.004). Sixty-two percent were taking AEDs, with 85% on monotherapy. The most commonly used AED was carbamazepine (49%).There was no association between the choice of AED and clinical semiology (all p's > 0.05). Significance: This tertiary care center study identified >60% of referred children to have localization-related epilepsies, with at least 18% of epilepsies being from potentially preventable causes. These findings are consistent with multi-country, population-based data from elsewhere in Africa. Seizure semiology assessed in routine, nonspecialist care does not predict AED choice, and the presence of focality is underestimated in routine care. PMID- 30525120 TI - A single seizure selectively impairs hippocampal-dependent memory and is associated with alterations in PI3K/Akt/mTOR and FMRP signaling. AB - Objective: A single brief seizure before learning leads to spatial and contextual memory impairment in rodents without chronic epilepsy. These results suggest that memory can be impacted by seizure activity in the absence of epilepsy pathology. In this study, we investigated the types of memory affected by a seizure and the time course of impairment. We also examined alterations to mammalian target of rapamycin (mTOR) and fragile X mental retardation protein (FMRP) signaling, which modulate elements of the synapse and may underlie impairment. Methods: We induced a single seizure and investigated hippocampal and nonhippocampal memory using trace fear conditioning, novel object recognition (NOR), and accelerating rotarod to determine the specificity of impairment in mice. We used western blot analysis to examine for changes to cellular signaling and synaptic proteins 1 h, 24 h, and 1 week after a seizure. We also included a histologic examination to determine if cell loss or gross lesions might alternatively explain memory deficits. Results: Behavioral results indicated that a seizure before learning leads to impairment of trace fear memory that worsens over time. In contrast, nonhippocampal memory was unaffected by a seizure in the NOR and rotarod tasks. Western analysis indicated increased hippocampal phospho-S6 and total FMRP 1 h following a seizure. Tissue taken 24 h after a seizure indicated increased hippocampal GluA1, suggesting increased alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression. Histologic analysis indicated that neither cell loss nor lesions are present after a single seizure. Significance: The presence of memory impairment in the absence of damage suggests that memory impairment caused by seizure activity differs from general memory impairment in epilepsy. Instead, memory impairment after a single seizure is associated with alterations to mTOR and FMRP signaling, which leads to a disruption of synaptic proteins involved in consolidation of long-term memory. These results have implications for understanding memory impairment in epilepsy. PMID- 30525121 TI - Confirming the pathogenicity of NECAP1 in early onset epileptic encephalopathy. AB - Early onset epileptic encephalopathy (EOEE) has been used to encompass Ohtahara syndrome (early infantile epileptic encephalopathy [EIEE]), early myoclonic epilepsy, and many others. Multiple genes have been established to cause epileptic encephalopathy in the immature brain, and next-generation sequencing has accelerated the process of novel gene discovery. Many of the previously published candidate genes are still pending confirmatory reports or functional studies. Although most of the genes involved are ion channels (channelopathies), multiple other pathways have been implicated as well. NECAP1 is a key element in clathrin-mediated endocytosis and has been reported previously to cause EOEE in a Saudi family. We report another family with the same variant confirming the pathogenicity of this variant as a Saudi founder mutation, further delineate its phenotype, and propose that it causes EOEE instead of EIEE. PMID- 30525122 TI - Running-down phenomenon captured with chronic electrocorticography. AB - The running-down phenomenon refers to 2 analogous but distinct entities that may be seen after epilepsy surgery. The first is clinical, and denotes a progressive diminution in seizures after epilepsy surgery in which the epileptogenic zone could not be completely removed (Modern Problems of Psychopharmacology 1970;4:306, Brain 1996:989). The second is electrographic, and refers to a progressive deactivation of a secondary seizure focus after removal of the primary epileptogenic zone. This progressive decrease in epileptiform activity may represent a reversal of secondary epileptogenesis, where a primary epileptogenic zone is postulated to activate epileptiform discharges at a second site and may become independent.3 The electrographic running-down phenomenon has been reported in only limited numbers of patients, using serial postoperative routine scalp electroencephalography (EEG) (Arch Neurol 1985;42:318). We present what is, to our knowledge, the most detailed demonstration of the electrographic running-down phenomenon in humans, made possible by chronic electrocorticography (ECoG). Our patient's left temporal seizure focus overlapped with language areas, limiting the resection to a portion of the epileptogenic zone, followed by implantation of a direct brain-responsive neurostimulator (RNS System, NeuroPace Inc.) to treat residual epileptogenic tissue. Despite the limited extent of the resection, the patient remains seizure-free more than 2 years after surgery, with the RNS System recording ECoG without delivering stimulation. We reviewed the chronic recordings with automated spike detection and inspection of electrographic episodes marked by the neurostimulator. These recordings demonstrate progressive diminution in spiking and rhythmic discharges, consistent with an electrographic running-down phenomenon. PMID- 30525123 TI - Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro. AB - Inhibition of histone deacetylases (HDACs) and subsequent hyperacetylation of histone proteins lead to altered gene expression associated with therapeutic drug effects, but also with teratogenicity. The only US Food and Drug Administration (FDA)-approved antiepileptic drug that has been consistently shown to induce histone hyperacetylation is valproic acid. More recently, lacosamide was reported to interfere with histone modifications, but histone hyperacetylation was not demonstrated. In the current study we evaluated the effects of lacosamide on histone acetylation in vitro. MDA-MB-231 (triple-negative breast cancer) cells and human placental BeWo cells were exposed for 16 hours to 5-20 MUg/ml (20-80 MUm) lacosamide. Histone acetylation was evaluated by western blot analysis. We additionally measured HDAC1 activity in the presence of lacosamide. At 5, 10, and 20 MUg/ml, lacosamide enhanced histone acetylation in BeWo cells by 1.7-fold (p > 0.05), 3.4-fold (p < 0.05), and 3.0-fold (p > 0.05), respectively. Histone H3 acetylation and total histones H3 and H4 levels were not significantly modified (p > 0.05). The magnitude of change in histone acetylation in MDA-MB-231 cells was smaller (p > 0.05). In contrast to valproic acid, lacosamide did not inhibit HDAC1. Our findings suggest that the effects of lacosamide on gene expression, and the related potential antitumor activity and teratogenicity, may differ from those of valproic acid. PMID- 30525124 TI - Announcements. PMID- 30525125 TI - Xq26.3 Duplication in a Boy With Motor Delay and Low Muscle Tone Refines the X Linked Acrogigantism Genetic Locus. AB - We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, GPR101. The patient's phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs' results are inconsistent with the patient's phenotype. It is also useful for further supporting the contention that GPR101 is the gene responsible for X-LAG. PMID- 30525127 TI - BSR Annual Meeting 2018: Interventional Radiology. PMID- 30525126 TI - Decomposing international gender test score differences. AB - In this paper, we decompose worldwide PISA mathematics and reading scores. While mathematics scores are still tilted towards boys, girls have a larger advantage in reading over boys. Girls' disadvantage in mathematics is increasing over the distribution of talents. Our decomposition shows that part of this increase can be explained by an increasing trend in productive endowments and learning productivity, although the largest part remains unexplained. Countries' general level of gender (in)equality also contributes to girls' disadvantage. For reading, at the upper end of the talent distribution, girls' advantage can be fully explained by differences in learning productivity, but this is not so at lower levels. PMID- 30525128 TI - Editorial Head and Neck Radiology, Annual Meeting of the Belgian Society of Radiology (BSR) 17th November 2018. PMID- 30525130 TI - The 2018 PhD Grant Recipients of the BSR. PMID- 30525129 TI - Annual Meeting of the Belgian Society of Radiology (BSR): Programme by the Young Radiologist Section (YRS). PMID- 30525131 TI - Detailed benchmark ab initio mapping of the potential energy surfaces of the X + C2H6 [X = F, Cl, Br, I] reactions. AB - We investigate three reaction pathways of the X + C2H6 [X = F, Cl, Br, I] reactions: H-abstraction, methyl-substitution, and H-substitution, with the latter two proceeding via either Walden-inversion or front-side-attack mechanisms. We report classical and adiabatic relative energies of unprecedented accuracy for the corresponding stationary points of the reaction potential energy surfaces (PESs) by augmenting the CCSD(T)-F12b/aug-cc-pVQZ energies by core correlation, post-CCSD(T) and spin-orbit corrections. Taking these correction terms into account turns out to be essential to reach subchemical, i.e. <0.5 kcal mol-1, accuracy. Our new benchmark 0 K reaction enthalpies show excellent agreement with experimental data. Spin-orbit coupling in these open-shell systems is also monitored throughout the reaction paths and found to be non-negligible even in some transition-state geometries. Barrier heights corresponding to the different channels of the title reactions appear in the same order with increasing energy: H-abstraction, Walden-inversion methyl-substitution, Walden inversion H-substitution, front-side-attack H-substitution and front-side-attack methyl-substitution, except for X = I where the latter two come in reverse order. Similarly, product channels follow the energy order of the corresponding barrier heights in all four cases. We find strongly reactant-like transition-state structures for the exothermic F + C2H6 reaction paths, while more and more product-like transition states are observed along with increasing endothermicity as going from Cl to I. Several entrance and exit channel minima are also identified for the studied reactions with significant spin-orbit effects for the formers. PMID- 30525132 TI - Slow relaxation of the magnetization observed in mononuclear Ln-radical compounds with D4d geometry configurations. AB - The combination of LnIII ions (GdIII, TbIII or DyIII) and a pyrazole nitronyl nitroxide radical results in three isomorphous complexes, namely, [Ln(hfac)3(NIT Pyz)]2 (Ln = Gd(1), Tb(2), Dy(3); hfac = hexafluoroacetylacetone; NIT-Pyz = 2-{3 pyrazolyl}-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide). Single crystal X-ray diffraction studies revealed that all of them are composed of two crystallographically independent mononuclear systems, in which the central LnIII ions are coordinated by three hfac and one bidentate chelating NIT-Pyz radical. The central LnIII ions are all in square antiprism geometry (D4d) polyhedron configurations. Based on the spin Hamiltonian calculations, there exist antiferromagnetic couplings in the GdIII-NIT radical system in complex 1. Complexes 2 and 3 show frequency-dependent out-of-phase signals in a zero field indicating single-molecule magnetic behavior. Moreover, Tb's complex (2) shows a single thermal relaxation process with an energy barrier of 26 K. For Dy's complex (3), the Orbach and Raman processes both contribute to the magnetic relaxation behaviors. PMID- 30525134 TI - Photoinactivation of uncultured, indigenous enterococci. AB - Enterococci are used to monitor recreational water quality worldwide, so understanding their fate and transport in the environment is essential to the protection of human health. As such, researchers have documented enterococci inactivation under various exposure conditions and in diverse water matrices. However, the majority of studies have been performed using lab-cultured bacteria, which are distinct from indigenous, uncultured bacteria found in the environment. Here we investigate the photoinactivation of indigenous, uncultured enterococci from a range of sources, including wastewater treatment plants (WWTPs), marine beaches, urban streams, and a wastewater-influenced pond. We concentrated indigenous enterococci from their sources using filtration and centrifugation, placed them in a clear buffer solution, and then exposed them to simulated sunlight to measure their photoinactivation rates. First order decay rate constants (k) of indigenous, uncultured enterococci spanned an order of magnitude, from 0.3 to 2.3 m2 kJUVB-1. k values of indigenous enterococci from WWTPs tended to be larger than those from surface waters. The k value of lab cultured Enterococcus faecalis was larger than those of indigenous, uncultured enterococci from most sources. Negative associations between the fraction of pigmented enterococci and sunlight susceptibility were observed. This work suggests that caution should be taken when extending results on bacterial photoinactivation obtained using lab-cultured bacteria to environmental bacteria, and that enterococci pigmentation may be a useful metric for estimating photoinactivation rate constants. PMID- 30525133 TI - Rational design of yolk-shell nanostructures for photocatalysis. AB - Photocatalysis is a promising route to convert solar energy into chemical energy directly, providing an alternative solution to environment and natural resource problems. Theoretically, all photocatalytic reactions are driven by charge carriers whose behavior can be divided into charge generation, separation, migration and surface reactions. Efficiencies of charge utilization in every step determine the overall performance of photocatalysis. Yolk-shell (YS) structures can provide an ideal platform for the efficient utilization of charge carriers. Typically, a YS structure is constructed from a hollow shell and an inner core, which can enhance light scattering in the hollow space and provide a large surface to create sufficient active sites, both of which can significantly improve the efficacy of charge utilization. Additionally, many strategies can be adopted to modify the YS structure for further enhancement of charge behaviors in every step. Existing reviews about YS structures mainly concentrate on the universality of the application of YSs, while the strategies to improve photocatalytic performance based on YSs have not been elaborately illustrated. This review describes the classification, synthesis, formation mechanism of YS structures and the rational regulation of the behaviors of photogenerated charge carriers, aiming at their effective utilization based on YS structures in heterogeneous photocatalytic reactions. PMID- 30525135 TI - Towards rapid prediction of drug-resistant cancer cell phenotypes: single cell mass spectrometry combined with machine learning. AB - Combined single cell mass spectrometry and machine learning methods is demonstrated for the first time to achieve rapid and reliable prediction of the phenotype of unknown single cells based on their metabolomic profiles, with experimental validation. This approach can be potentially applied towards prediction of drug-resistant phenotypes prior to chemotherapy. PMID- 30525136 TI - Kinetic energy densities based on the fourth order gradient expansion: performance in different classes of materials and improvement via machine learning. AB - We study the performance of fourth-order gradient expansions of the kinetic energy density (KED) in semi-local kinetic energy functionals depending on the density-dependent variables. The formal fourth-order expansion is convergent for periodic systems and small molecules but does not improve over the second-order expansion (the Thomas-Fermi term plus one-ninth of the von Weizsacker term). Linear fitting of the expansion coefficients somewhat improves on the formal expansion. The tuning of the fourth order expansion coefficients allows for better reproducibility of the Kohn-Sham kinetic energy density than the tuning of the second-order expansion coefficients alone. The possibility of a much more accurate match with the Kohn-Sham kinetic energy density by using neural networks (NN) trained using the terms of the 4th order expansion as density-dependent variables is demonstrated. We obtain ultra-low fitting errors without overfitting of NN parameters. Small single hidden layer neural networks can provide good accuracy in separate KED fits of each compound, while for joint fitting of KEDs of multiple compounds multiple hidden layers were required to achieve good fit quality. The critical issue of data distribution is highlighted. We also show the critical role of pseudopotentials in the performance of the expansion, where in the case of a too rapid decay of the valence density at the nucleus with some pseudopotentials, numeric instabilities can arise. PMID- 30525137 TI - A nickel(ii) complex under water-oxidation reaction: what is the true catalyst? AB - In the present study, the water-oxidizing activity of nickel(ii) phthalocyanine tetrasulfonate tetrasodium (1), which is a stable Ni(ii) complex under moderate conditions, was investigated. The role of Ni oxide in water oxidation as a true catalyst was investigated. The electrodes after water oxidation by both the complex and Ni salt were analyzed and a relation was proposed between the decomposition of the Ni complex and water oxidation. On the surface of the electrode, there are some areas without any detectable nanoparticles; thus, the detection of such Ni oxides on the surface of the electrode is not easy in the first seconds of the reaction, even using some of the usual methods such as Scanning Electron Microscopy or electrochemical analysis. Such experiments indicated that a precise analysis is necessary to reject the role of nanoparticles in the presence of Ni phthalocyanine under water oxidation. The findings also showed that under water-oxidation conditions and in the presence of the complex, Ni oxide is a good candidate for a true catalyst. PMID- 30525138 TI - Evidence of proton-coupled mixed-valency by electrochemical behavior on transition metal complex dimers bridged by two Ag+ ions. AB - H-Bonded metal complex dimers with reversible redox behaviour, which are connected by a low-barrier hydrogen bond (LBHB) with a very low energy barrier for proton transfer, can provide a unique mixed-valency state stabilized by the proton-coupled electron transfer (PCET) phenomenon. Using cyclic voltammetry measurements, newly prepared [ReIIICl2(PnPr3)2(Hbim)]2 (2) and [OsIIICl2(PnPr3)2(Hbim)]2 (3) existing as H-bonded dimers in a CH2Cl2 solution showed a four-step and four-electron transfer containing two mixed-valency states of ReIIReIII and ReIIIReIV, and OsIIOsIII and OsIIIOsVI, respectively. Furthermore, [ReIIICl2(PnPr3)2(Agbim)]2 (4) and [OsIIICl2(PnPr3)2(Agbim)]2 (5), bridged by two Ag+ ions instead of two H-bonding protons, were prepared, and their electrochemical behaviours changed to a two-step and four-electron transfer. It is clear that the H-bonded complex dimers 2 and 3, connected by an LBHB, can be electrochemically stabilized into unique pairs of mixed-valency states by PCET, and the H-bonding proton transfer also controls the electrochemical redox behaviour. PMID- 30525139 TI - Solar-driven CO2 to CO reduction utilizing H2O as an electron donor by earth abundant Mn-bipyridine complex and Ni-modified Fe-oxyhydroxide catalysts activated in a single-compartment reactor. AB - Photoelectrochemical CO2 to CO reduction was demonstrated with 3.4% solar-to chemical conversion efficiency using polycrystalline silicon photovoltaic cells connected with earth-abundant catalysts: a manganese complex polymer for CO2 reduction and iron oxyhydroxide modified with a nickel compound for water oxidation. The system operated around neutral pH in a single-compartment reactor. PMID- 30525140 TI - A chiral open-framework fluorinated cobalt phosphate consists of distorted F encapsulated double 4-ring units with bulk homochirality. AB - A homochiral open-framework fluorinated cobalt phosphate with a 2-fold interpenetrating diamond topology was ionothermally synthesized. The significant enantiomeric excess of the bulk product was confirmed by strong signals in its solid state circular dichroism (CD) spectrum. PMID- 30525141 TI - Digital nanoliter to milliliter flow rate sensor with in vivo demonstration for continuous sweat rate measurement. AB - Microfluidic flow rate sensors have constraints in both detection limits and dynamic range, and are not often easily integrated into lab-on-chip or wearable sensing systems. We constructed a flow rate sensor that easily couples to the outlet of a microfluidic channel, and measures the flow rate by temporarily shorting periodic droplets generated between two electrodes. The device was tested in a dynamic range as low as 25 nL min-1 and as high as 900 000 nL min-1 (36 000* range). It was tested to continuously operate up to ~200 hours. The device is also simple to fabricate, requiring inexpensive parts, and is small enough to be integrated into wearable devices. The required input pressure is as low as 370 Pascals. An ultra-low flow rate application was demonstrated for wearable sweat biosensing where sweat generation rates (nL min-1 per gland) were accurately measured in human subjects. The digital nanoliter device provides real time flow rates for sweat rates and may have other applications for low flow rates in microfluidic devices. PMID- 30525142 TI - Density functional theory calculations and thermodynamic analysis of bridgmanite surface structure. AB - Bridgmanite, a high temperature and pressure form of MgSiO3, is believed to be Earth's most abundant mineral and responsible for the observed seismic anisotropy in the mantle. Little is known about surfaces of bridgmanite but knowledge of the most stable surface terminations is important for understanding various geochemical processes as well as likely slip planes. A density functional theory based thermodynamic approach is used here to establish the range of stability of bridgmanite as well as possible termination structures of the (001), (010), (100) and (011) surfaces as a function of the chemical potential of oxygen and magnesium. The vibrational contribution to the Gibbs free energy is found to be essential for obtaining a stability region of bridgmanite in the phase diagram. The most stable surface termination of bridgmanite varies between three different atomic structures depending on the chemical potential of oxygen and magnesium. The results presented provide a basis for further theoretical studies of the chemical processes on bridgmanite surfaces in the Earth's mantle and slip plane analysis. PMID- 30525143 TI - Nanostructuring mechanical cracks in a flexible conducting polymer thin film for ultra-sensitive vapor sensing. AB - The swelling of electrically conducting polymer films upon absorption of vapors like alcohol or moisture is widely known. However, this swelling leads to feeble changes in charge transport characteristics. We demonstrate a colossal enhancement (from ~6% to 108%) in the vapor-induced resistance change for a representative system, poly(3,4-ethylene dioxythiophene) polystyrene sulfonate (PEDOT:PSS). This is achieved when the films are nanostructured by strain-induced quasi-periodic parallel cracks, which is then followed by crack engineering. The cracks are nanostructured such that the charge carrier percolation pathways are nearly turned off in the absence of alcohol vapor or at low humidity. These percolation pathways are restored upon alcohol vapor or humidity exposure. When used as an alcohol sensor, this system shows ultra-high sensitivity of 106 for methanol vapors, when compared to ethanol vapors (2 * 102). When used as a humidity sensor in the range 60-100% RH, a resistance ratio of 1.5 * 102 is realized. The different extent of response to alcohol vapors and humidity is attributed to the dominance of the surface ionic conduction process in the former. These sensing characteristics are achieved with short response and recovery time (<5 s). The developed sensing platform outperforms commercial portable breath analyzers. While cracks have been utilized for developing ingenious strain sensors in the literature, here we demonstrate an approach based on the same that substantially amplifies vapor response. PMID- 30525144 TI - Carbon nanotube functionalization as a route to enhancing the electrical and mechanical properties of Cu-CNT composites. AB - Copper-CNT (carbon nanotube) composite materials are promising alternatives to conventional conductors in applications ranging from interconnects in microelectronics to electrical cabling in aircraft and vehicles. Unfortunately, exploiting the full potential of these composites is difficult due to the poor Cu CNT electro-mechanical interface. We demonstrate through large-scale ab initio calculations and sonication experiments that this problem can be addressed by CNT surface modification. Our calculations show that covalent functionalization of CNTs below 6.7 at% significantly improves Cu-CNT wetting and the mechanical properties of the composite. Oxidative pre-treatment of CNTs enhances the Young's modulus of the composite by nearly a factor 3 above that of pure Cu, whereas amination slightly improves the electrical current density with respect to the unmodified Cu-CNT system in the high bias regime. However, only nitrogen doping can effectively improve both the mechanical and electrical properties of the composite. As the experiments show, consistent with the calculations, substitutional doping with nitrogen effectively improves adhesion of the CNT to the Cu matrix. We also predict an improvement in the mechanical properties for the composite containing doped double-wall CNTs. Moreover, the calculations indicate that the presence of nitrogen dopants almost doubles locally the transmission through the nanotube and reduces the back scattering in the Cu matrix around the CNT. The computed electrical conductance of N-doped Cu-CNT "carpets" exceeds that of an undoped system by ~160%. PMID- 30525145 TI - Controlled crystal facet of MAPbI3 perovskite for highly efficient and stable solar cell via nucleation modulation. AB - The crystallization of MAPbI3 perovskite films was purposefully engineered to investigate the governing factors which determine their morphological properties and moisture stability. By modulating nucleation, we obtained a single layer perovskite film with controlled crystal facet orientation and grain size. The lack of perovskite nucleation sites during crystallization allowed us to tailor the resulting crystallization phase. Theoretical calculations indicated that the nucleation sites for perovskite growth are related to the electron density around the oxygen atom (C[double bond, length as m-dash]O and S[double bond, length as m dash]O) in a Lewis base. A single layer of micrometer-sized and (110)-oriented perovskite crystals was achieved in the optimized MAPbI3 films via suppressing the formation of nucleation sites. We fabricated inverted perovskite solar cells with the structure of glass/ITO/PEDOT:PSS/MAPbI3/PC61BM/Al which exhibited a high power conversion efficiency of 17.5% and a high fill factor over 83%. In addition, a study of the moisture stability indicated that the (110) facet orientation of the perovskite grains plays a more important role in film degradation than grain size. PMID- 30525146 TI - From one-dimensional to two-dimensional wurtzite CuGaS2 nanocrystals: non injection synthesis and photocatalytic evolution. AB - Multinary copper-based chalcogenides exhibit significant performance in photocatalytic hydrogen evolution due to their suitable optical bandgap for visible light absorption and environmentally friendly character. Herein, high quality wurtzite CuGaS2 (CGS) nanocrystals (NCs) were synthesized by using a one step heating-up process without any injection, and the morphology could be tuned from one-dimensional (1D) to two-dimensional (2D) by precise choice of surface ligands and gallium precursors. The formation mechanism of CGS NCs was studied comprehensively by means of the temporal-evolution of the morphology, crystal structure and optical absorption results. The reaction started from djurleite Cu31S16 NCs, and then proceeded with the formation of Cu31S16-CGS heteronanostructures (HNS), and finally the transformation from HNS to monophasic CGS nanorods took place with prolonging of the synthesis time. The optical bandgap and the energy level of the different-dimensional CGS NCs exhibited a strong dependence on the morphology change, which correlated with the percentage of the exposed {001} and {100} facets. The theoretical calculation based on density functional theory (DFT) revealed that the (001) surface facilitated the charge transport rather than the (100) surface, which was consistent with the electrochemical impedance spectroscopy (EIS) results. As a result, the 2D CGS nanoplates with more exposed {001} facets exhibited an attractive photocatalytic hydrogen production activity under simulated solar illumination as compared to 1D and quasi-2D counterparts. This study demonstrates that control over the dimension of I-III-V group semiconductor NCs could lead to a significant improvement of the photocatalytic hydrogen evolution. PMID- 30525147 TI - Electrochemical exfoliation of graphene-like two-dimensional nanomaterials. AB - Unlike zero-dimensional quantum dots, one-dimensional nanowires/nanorods, and three-dimensional networks or even their bulk counterparts, the charge carriers in two-dimensional (2D) materials are confined along the thickness while being allowed to move along the plane. They have distinct characteristics like strong quantum confinement, tunable thickness, and high specific surface area, which makes them a promising candidate in a wide range of applications such as electronics, topological spintronic devices, energy storage, energy conversion, sensors, biomedicine, catalysis, and so on. After the discovery of the extraordinary properties of graphene, other graphene-like 2D materials have attracted a great deal of attention. Like graphene, to realize their potential applications, high efficiency and low cost industrial scale methods should be developed to produce high-quality 2D materials. The electrochemical methods usually performed under mild conditions are convenient, controllable, and suitable for mass production. In this review, we introduce the latest and most representative investigations on the fabrication of 2D monoelemental Xenes, 2D transition-metal dichalcogenides, and other important emerging 2D materials such as organic framework (MOF) nanosheets and MXenes through electrochemical exfoliation. The electrochemical exfoliation conditions of the bulk layered materials are discussed. The numerous factors which will affect the quality of the exfoliated 2D materials, the possible exfoliating mechanism and potential applications are summarized and discussed in detail. A summary of the discussion together with perspectives and challenges for the future of this emerging field is also provided in the last section. PMID- 30525148 TI - Electronic structure of Al, Ga, In and Cu doped ZnO/Cu(111) bilayer films. AB - The effect of doping with group-III metals (Al, Ga and In) and Cu free standing and Cu(111) supported ZnO bilayer films has been investigated computationally by using the DFT+U method including dispersion contributions. The changes in the electronic properties of doped ZnO and ZnO/Cu(111) films have been tested by adsorbing CO probe molecules. The replacement of a lattice Zn ion in a free standing ZnO bilayer by a group-III element generates an extra electron whose distribution depends on the dopant. In particular, while the excess electron is delocalized over the conduction band for Al or Ga doping, it is localized on the dopant in the case of In. The situation is different on the supported ZnO/Cu(111) film, where the extra electron is transferred to the underlying Cu support. While the CO adsorption energy at the doped sites in the ZnO bilayer is the same as in the ZnO/Cu(111) ultrathin films, CO exhibits a larger red-shift in the unsupported ZnO bilayer. The oxidation state of Cu replacing Zn in the unsupported ZnO films is 2+, Cu(3d9) state, while it is 1+, Cu(3d10) state, in the ZnO/Cu(111) supported films where a charge transfer from the supporting Cu metal to the Cu impurity occurs. Cu doping results in a stronger interaction with CO and a large red-shift of the CO stretching frequency. In this respect, Cu doping of ZnO/Cu(111) bilayer films could have interesting consequences in gas adsorption while doping with group-III elements does not lead to major changes of the adsorption properties when the free-standing ZnO films are compared to the supported ZnO/Cu(111) counterparts. PMID- 30525149 TI - Red emitting conjugated polymer based nanophotosensitizers for selectively targeted two-photon excitation imaging guided photodynamic therapy. AB - Two-photon excitation (2PE) photodynamic therapy (PDT) is a non-invasive technique for the treatment of cancer. However, its clinical applications are limited by small two-photon absorption cross section values of conventional photosensitizers. Here we designed multifunctional conjugated polymer based nanoparticles consisting of a conjugated polymer, a photosensitizer and a red emitting dye, which can realize simultaneous 2PE red emission imaging and 2PE-PDT activities. The working principle is based on a 2PE fluorescence resonance energy transfer strategy from the conjugated polymer to photosensitizing and imaging agents. In these nanoparticles (NPs), the conjugated polymer, PPBF, was chosen as a two-photon light-harvesting material while the photosensitizer (tetraphenylporphyrin, TPP) and the red-emitting dye (TPD) were chosen as energy acceptors. The 2PE emission of TPP and TPD was enhanced by up to ~161 and ~23 times, respectively. The 2PE-PDT activity of these NPs was significantly improved compared with those NPs without PPBF by up to ~149 times. Further surface functionalization with folic acid (FA) groups allows these nanoparticles to exhibit selective affinity toward KB cancer cells. These NPs could act as novel 2PE conjugated polymer based nanoparticles combined with the advantages of low dark cytotoxicity, selective targeting and imaging-guided 2PE-PDT activities. PMID- 30525150 TI - Microtubule self-healing and defect creation investigated by in-line force measurements during high-speed atomic force microscopy imaging. AB - Microtubules are biopolymers composed of tubulin and play diverse roles in a wide variety of biological processes such as cell division, migration and intracellular transport in eukaryotic cells. To perform their functions, microtubules are mechanically stressed and, thereby, susceptible to structural defects. Local variations in mechanical properties caused by these defects modulate their biological functions, including binding and transportation of microtubule-associated proteins. Therefore, assessing the local mechanical properties of microtubules and analyzing their dynamic response to mechanical stimuli provide insight into fundamental processes. It is, however, not trivial to control defect formation, gather mechanical information at the same time, and subsequently image the result at a high temporal resolution at the molecular level with minimal delay. In this work, we describe the so-called in-line force curve mode based on high-speed atomic force microscopy. This method is directly applied to create defects in microtubules at the level of tubulin dimers and monitor the following dynamic processes around the defects. Furthermore, force curves obtained during defect formation provide quantitative mechanical information to estimate the bonding energy between tubulin dimers. PMID- 30525151 TI - In situ electron microscopy of the self-assembly of single-stranded DNA functionalized Au nanoparticles in aqueous solution. AB - Solution-phase self-assembly of DNA-functionalized nanoparticles into mesoscale structures is a promising strategy for creating functional materials from nanocrystal building blocks. The predominant approach has been the use of Watson Crick base pairing between complementary bases in designated 'sticky ends' to trigger programmable self-assembly into ordered superlattices. Here we demonstrate the ordered self-assembly of Au nanoparticles conjugated with single stranded (ss) DNA in acidic solutions. Au nanoparticles functionalized with thiolated ssDNA are protected against coalescence and the DNA conformation undergoes significant modifications at low pH, which can be associated with the protonation of adenine bases and the formation of a parallel poly-adenine duplex, which govern the interaction between ssDNA-Au nanoparticle conjugates. In situ liquid cell electron microscopy enables real-time imaging of the self-assembly process and the identification of key characteristics, such as the preferred structural motifs and interparticle separations in the native solution environment. Our results highlight alternatives to conventional base-pairing interactions for building DNA-directed nanoparticle superlattices. PMID- 30525152 TI - Chemical sensing of water contaminants by a colloid of a fluorescent imine-linked covalent organic framework. AB - A two-dimensional imine-linked covalent organic framework bearing pyrene has been prepared and exfoliated in water as nanosheets to produce a stable water colloid. As a proof-of-concept, this COF colloid has been used to detect the presence of several organic dyes and polynitro-aromatic derivatives. These results show the high potential of these nanomaterials for applications in chemical sensing of pollutants directly in water. PMID- 30525153 TI - Coupling effect of van der Waals, centrifugal, and frictional forces on a GHz rotation-translation nano-convertor. AB - A nano rotation-translation convertor with a deformable rotor is presented, and the dynamic responses of the system are investigated considering the coupling among the van der Waals (vdW), centrifugal and frictional forces. When an input rotational frequency (omega) is applied at one end of the rotor, the other end exhibits a translational motion, which is an output of the system and depends on both the geometry of the system and the forces applied on the deformable part (DP) of the rotor. When centrifugal force is stronger than vdW force, the DP deforms by accompanying the translation of the rotor. It is found that the translational displacement is stable and controllable on the condition that omega is in an interval. If omega exceeds an allowable value, the rotor exhibits unstable eccentric rotation. The system may collapse with the rotor escaping from the stators due to the strong centrifugal force in eccentric rotation. In a practical design, the interval of omega can be found for a system with controllable output translation. PMID- 30525154 TI - Computational insight into the mechanism and origins of high selectivities in the acylation of polyamines with 5-benzoyl-5-phenyl-1,5-dihydro-4H-pyrazol-4-one. AB - Amide bonds have gained much attention from numerous scientists and acyl transfer is a good way to form amide bonds. The acylation mechanism of polyamines and their high selectivity in dichloromethane were investigated by the use of the density functional theory (DFT), M06-2X/6-311+G (d, p)//M06-2X/6-31G (d, p) method combined with the solvation SMD model. The calculated results suggest that the reaction process involved two steps: an acylation step and a proton-transfer step, with the former being the rate-limiting step. Meanwhile, with the substituent group effects of amines and 5-acyl-5-phenyl-1,5-dihydro-4H-pyrazol-4 one (BCPP) on the acylation step, different substituent groups of amines have little influence on the kinetic properties of the acylation step, and the para substituent groups of the phenyl group in BCPP lead to a linear relationship according to the electronegativity of the substituents. Furthermore, regarding the rate-selectivity of amines, the rate-selectivity of primary amines is higher than that of secondary amines, and polyamines very easily take part in acylation owing to the intramolecular hydrogen bond interaction. Moreover, it is harder for the amine group which has an alpha-position substituent group in polyamines to take part in an acylation reaction compared to the one without an alpha-position substituent group. The site-selectivity of the acylation process in polyamines is determined by steric hindrance. What's more, the auxiliary analysis of the distortion/interaction analysis and the frontier molecular orbital (FMO) analysis is used to investigate the origins of the rate- and site-selectivities. PMID- 30525155 TI - Access to divalent lanthanide NHC complexes by redox-transmetallation from silver and CO2 insertion reactions. AB - Through a redox-transmetallation procedure, divalent NHC-LnII (NHC = N heterocyclic carbene; Ln = Eu, Yb) complexes were obtained from the corresponding NHC-AgI. The lability of the NHC-LnII bond was investigated and treatment with CO2 led to insertion reactions without oxidation of the metal centre. The EuII complex [EuI2(IMes)(THF)3] (IMes = 1,3-dimesitylimidazol-2-ylidene) exhibits photoluminescence with a quantum yield reaching 53%. PMID- 30525156 TI - Intramolecular trapping of ammonium ylides with N-benzoylbenzotriazoles in aqueous medium: direct access to the pseudoindoxyl scaffold. AB - The present work documents an operationally simple, clean and practical method for accessing the 2,2-disubstituted indolin-3-one (pseudoindoxyl) scaffold. The rhodium carbenoid mediated reaction between N-o-alkylamino benzoylbenzotriazoles and aryl diazoacetates occurs smoothly in water and exploits the leaving group ability of the benzotriazole moiety to install the carbonyl function in the product. Other highlights of the methodology are a wide substrate scope and experimental practicality given the re-use of the benzotriazole byproduct for starting material preparation. PMID- 30525157 TI - Proteomic approach underlying the hippocampal neurodegeneration caused by low doses of methylmercury after long-term exposure in adult rats. AB - Methylmercury (MeHg) is an important toxicant that causes cognitive dysfunctions in humans. This study aimed to investigate the proteomic and biochemical alterations of the hippocampus associated with behavioural consequences of low doses of MeHg in a long-term exposure model, and to realistically mimic in vivo the result of human exposure to this toxicant. Adult Wistar male rats were exposed to a dose of MeHg at 0.04 mg kg-1 day-1 by gavage for 60 days. Total mercury (Hg) content was significantly increased in the hippocampal parenchyma. The increase in the Hg levels was capable of reducing neuron and astrocyte cell density in the CA1, CA3, hilus and dentate gyrus regions, increasing both malondialdehyde and nitrite levels and decreasing antioxidant capacity against peroxyl radicals. The proteomic analysis detected 1041 proteins with altered expression due to MeHg exposure, including 364 proteins with no expression, 295 proteins with de novo expression and 382 proteins with up- or down-regulated expression. This proteomic approach revealed alterations in pathways related to chemical synapses, metabolism, amino acid transport, cell energy, neurodegenerative processes and myelin maintenance. Therefore, even at low doses of MeHg exposure, it is possible to cause hippocampal damage in adult rats at many organisational levels, triggering oxidative stress and proteome misbalance, featuring a neurodegenerative process and culminating in long- and short-term memory and learning deficits. PMID- 30525158 TI - Scalable synthesis of a foam-like FeS2 nanostructure by a solution combustion sulfurization process for high-capacity sodium-ion batteries. AB - Pyrite-type FeS2 is regarded as a promising anode material for sodium ion batteries. The synthesis of FeS2 in large quantities accompanied by an improved cycling stability, as well as retaining high theoretical capacity, is highly desirable for its commercialization. Herein, we present a scalable and simple strategy to prepare a foam-like FeS2 (F-FeS2) nanostructure by combining solution combustion synthesis and solid-state sulfurization. The obtained F-FeS2 product is highly uniform and built from interconnected FeS2 nanoparticles (~50 nm). The interconnected feature, small particle sizes and porous structure endow the product with high electrical conductivity, good ion diffusion kinetics, and high inhibition capacity of volume expansion. As a result, high capacity (823 mA h g-1 at 0.1 A g-1, very close to the theoretical capacity of FeS2, 894 mA h g-1), good rate capability (581 mA h g-1 at 5.0 A g-1) and cyclability (754 mA h g-1 at 0.2 A g-1 with 97% retention after 80 cycles) can be achieved. The sodium storage mechanism has been proved to be a combination of intercalation and conversion reactions based on in situ XRD. Furthermore, high pseudocapacitive contribution (i.e. ~87.5% at 5.0 mV s-1) accounts for the outstanding electrochemical performance of F-FeS2 at high rates. PMID- 30525159 TI - Enhanced design and formulation of nanoparticles for anti-biofilm drug delivery. AB - Biofilms are surface-bound, structured microbial communities underpinning persistent bacterial infections. Biofilms often create acidic pH microenvironments, providing opportunities to leverage responsive drug delivery systems to improve antibacterial efficacy. Here, the antibacterial efficacy of novel formulations containing pH-responsive polymer nanoparticle carriers (NPCs) and farnesol, a hydrophobic antibacterial drug, were investigated. Multiple farnesol-loaded NPCs, which varied in overall molecular weight and corona-to-core molecular weight ratios (CCRs), were tested using standard and saturated drug loading conditions. NPCs loaded at saturated conditions exhibited ~300% greater drug loading capacity over standard conditions. Furthermore, saturated loading conditions sustained zero-ordered drug release over 48 hours, which was 3-fold longer than using standard farnesol loading. Anti-biofilm activity of saturated NPC loading was markedly amplified using Streptococcus mutans as a biofilm forming model organism. Specifically, reductions of ~2-4 log colony forming unit (CFU) were obtained using microplate and saliva-coated hydroxyapatite biofilm assays. Mechanistically, the new formulation reduced total biomass by disrupting insoluble glucan formation and increased NPC-cell membrane localization. Finally, thonzonium bromide, a highly potent, FDA-approved antibacterial drug with similar alkyl chain structure to farnesol, was also loaded into NPCs and used to treat S. mutans biofilms. Similar to farnesol-loaded NPCs, thonzonium bromide-loaded NPCs increased drug loading capacity >=2.5-fold, demonstrated nearly zero-order release kinetics over 96 hours, and reduced biofilm cell viability by ~6 log CFU. This work provides foundational insights that may lead to clinical translation of novel topical biofilm-targeting therapies, such as those for oral diseases. PMID- 30525160 TI - Metallo-supramolecular assembly of protic pincer-type complexes: encapsulation of dinitrogen and carbon disulfide into a multiproton-responsive diruthenium cage. AB - Partial dehydrobromination of a diprotic pincer-type ruthenium complex in the presence of a rigid 1,3-bis(diphenylphosphino)benzene linker provided a dinuclear cage containing a guest template KBr surrounded by hydrogen bonds and electrostatic interactions. Dinitrogen and carbon disulfide were encapsulated into the cage with proton channels formed by the pyrazole arms in the pincer ligands. PMID- 30525161 TI - Passivation of the grain boundaries of CH3NH3PbI3 using carbon quantum dots for highly efficient perovskite solar cells with excellent environmental stability. AB - Organic-inorganic hybrid perovskites are prone to defect formation due to iodine and methylamine ion/defect migration, leading to the formation of lots of defects at the perovskite surface and grain boundaries. Passivation of the defects is an effective method to improve the power conversion efficiency (PCE) and stability of perovskite solar cells (PSCs). To achieve stable passivation, the interaction between the perovskite and additive materials should be taken into consideration. In this work, we for the first time introduced carbon quantum dots (CQDs) as an additive for the stabilization of MAPbI3 via passivation of the grain boundaries of the perovskite. Because the carboxylic groups, hydroxyl groups and amino groups on the edge of CQDs can bond with the uncoordinated Pb in MAPbI3, strong and stable interactions between the perovskite and CQDs can be generated, inducing a lower trap-state density and better optoelectronic properties. The typical PCE of the PSCs based on CQD modified MAPbI3 films increases from 17.59% to 18.81% and the PCE of the optimized champion PSCs reaches 19.38%. Furthermore, the hydrophobic CQD molecules can block the contact between water and MAPbI3, and even if the CQD modified perovskite is kept under ambient atmosphere without controlling the humidity for 4 months, the MAPbI3 film still retained its original black color. PMID- 30525162 TI - Highly selective AlCl3 initiated intramolecular alpha-alkylation of alpha,beta unsaturated lactams and lactones. AB - An unprecedented example of AlCl3 initiated intramolecular alpha-alkylation of alpha,beta-unsaturated lactams and lactones is reported. A variety of substrates containing an intramolecular diene yield exclusively regioselective six-membered ring products. This reaction protocol generates a new stereo centre which may be of high interest for the functionalization of bioactive coumarin and quinolinone derivatives. PMID- 30525163 TI - Effect of anisotropic diffusion on spinodal decomposition. AB - We study the phase transition dynamics of a fluid system in which the particles diffuse anisotropically in space. The motivation to study such a situation is provided by systems of interacting magnetic colloidal particles subject to the Lorentz force. The Smoluchowski equation for the many-particle probability distribution then acquires an anisotropic diffusion tensor. We show that in comparison to the isotropic case, anisotropic diffusion results in qualitatively different dynamics of spinodal decomposition. Using the method of dynamical density functional theory, we predict that the intermediate-stage decomposition dynamics are slowed down significantly by anisotropy; the coupling between different Fourier modes is strongly reduced. Numerical calculations are performed for a model (Yukawa) fluid that exhibits gas-liquid phase separation. PMID- 30525164 TI - THz spectroscopy of weakly bound cluster molecules in solid para-hydrogen: a sensitive probe of van der Waals interactions. AB - The present work demonstrates that 99.9% enriched solid para-H2 below 3 K provides an excellent inert and transparent medium for the exploration of large amplitude intermolecular vibrational motion of weakly bound van der Waals cluster molecules in the THz spectral region. THz absorption spectra have been generated for CO2/H2O and CS2/H2O mixtures embedded in enriched solid para-H2 and numerous observed transitions associated with large-amplitude librational motion of the weakly bound binary CO2H2O and CS2H2O van der Waals cluster molecules have been assigned together with tentative assignments for the ternary CS2(H2O)2 system. The interaction strength, directionality and anharmonicity of the weak van der Waals "bonds" between the molecules can be characterized via these THz spectral signatures and yield rigorous benchmarks for high-level ab initio methodologies. It is suggested that even a less stable linear conformation of the ternary CS2(H2O)2 system, where one H2O molecule is linked to each S atom of the CS2 subunit, may be formed due to the kinetics associated with the mobility of free H2O molecules in the soft para-H2 medium. In addition, the spectroscopic observations confirm a linear and planar global intermolecular potential energy minimum for the binary CS2H2O system with C2v symmetry, where the O atom on the H2O molecule is linked to one of the S atoms on the CS2 subunit. A semi experimental value for the vibrational zero-point energy contribution of 1.93 +/- 0.10 kJ mol-1 from the class of large-amplitude intermolecular vibrational modes is proposed. The combination with CCSD(T)/CBS electronic energy predictions provides a semi-experimental estimate of 5.08 +/- 0.15 kJ mol-1 for the binding energy D0 of the CS2H2O van der Waals system. PMID- 30525165 TI - Localization and transient emission properties in InGaN/GaN quantum wells of different polarities within core-shell nanorods. AB - Transient photoluminescence (PL) characteristics and localization phenomena in InGaN/GaN core-shell nanorods (NRs) were investigated from 6 K up to 285 K. The NRs exhibit three well-defined PL bands in the near-UV, blue, and green range ascribed to the emission of quantum well (QW) areas situated at the (1.00) sidewalls, (10.1) top facets, and (00.1) tip, respectively. At low temperature, time-resolved PL shows a fast decay time of about 0.5 ns for the semi- and non polar QWs, while the polar QWs exhibit at least a twice-longer time. Rapid delocalization of carriers above 50 K indicates shallow potential fluctuations in the QWs. At room temperature, the characteristic fast PL decay time of the three QW bands stabilizes around 300 ps. The slow decaying PL components have different characteristic decay times that are explained by additional localization at basal stacking faults (BSFs), taking into account the quantum confined Stark effect. In addition, narrow excitonic luminescence lines are observed in the BSF-enriched polar QWs, providing direct evidence of the impact of the BSF/QW crossings on the optical properties of the NRs. A PL rise time of about 100 ps does not show any deviation between bands. These findings are suggestive of similar transport mechanisms in temperature equilibrium without inter-facet transport between different QWs. We believe that predictable transient characteristics can play a key role in creating uniform NR ensembles for device applications. PMID- 30525167 TI - An in situ assembly strategy for the construction of a sensitive and reusable electrochemical aptasensor. AB - The 5'-end thiolated aptamer is attached on the electrode surface through hybridization with immobilized assistant strands. Then the signal enhancing platform of gold nanoparticles and an electroactive Cu2+-l-cysteine tag are in situ tethered on the 5'-end of the aptamer, through which, a sensitive and reusable aptasensor is facilely constructed. PMID- 30525166 TI - Chemical synthesis of marine saponins. AB - Covering: 1989-2017Saponins are characteristic metabolites of starfish and sea cucumbers, and occasionally are also found in sponges, soft coral, and small fish. These steroid or triterpenoid glycosides often show remarkable biological and pharmacological activities, such as antifungal, antifouling, shark repellent, antitumor and anti-inflammatory activities. Over one thousand marine saponins have been characterized; the majority of them can be categorized into three major structural types, i.e., asterosaponins, polyhydroxysteroid glycosides, and holostane glycosides. Thus far, only 12 marine saponins have been synthesized; those representing the major types were successfully synthesized recently. The syntheses involve preparation of the aglycones from the terrestrial steroid or triterpene materials, installation of the carbohydrate units, and manipulation of the protecting groups. Herein, we provide a comprehensive review on these syntheses. PMID- 30525168 TI - Superior oxygen electrocatalysts derived from predesigned covalent organic polymers for zinc-air flow batteries. AB - Covalent organic polymers (COPs) as emerging porous materials with ultrahigh hydrothermal stability and well-defined and adjustable architectures have aroused great interest in the electrochemical field. Here, we reported a rational design approach for the preparation of a bifunctional electrocatalyst with the assistance of a predesigned bimetallic covalent organic polymer. With the predesigned nitrogen position and structural features of COP materials, the obtained CCOPTDP-FeNi-SiO2 catalyst affords a remarkable bifunctional performance with a positive half-wave potential (0.89 V vs. reversible hydrogen electrode: RHE, superior to the benchmark Pt/C) for ORR activity, and a low overpotential (0.31 V better than the benchmark IrO2) at 10 mA cm-2 for OER activity in alkaline solution. The potential gap between E1/2 and Ej=10 reaches 0.650 V, in line with that observed in the current state-of-the-art bifunctional oxygen electrode materials. Moreover, a homemade rechargeable Zn-air flow battery using the CCOPTDP-FeNi-SiO2 catalyst as an air cathode exhibits an almost twofold power density (112.8 vs. 64.8 mW cm-2) and a lower charge-discharge voltage gap, compared with a commercialized noble Pt/C + IrO2/C-driven Zn-air flow battery. More importantly, the CCOPTDP-FeNi-SiO2-driven battery maintains a better cycling stability compared to a noble metal-driven battery without performance decay. Accordingly, this work will open up new ways for fabricating practical oxygen electrodes for, but not limited to, metal air based battery applications. PMID- 30525169 TI - Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway. AB - Dihydroquercetin (DHQ), a dihydroxyflavone, possesses potent antioxidant properties and is proposed to be useful in the prevention and treatment of cardiovascular disease. In this study, we aimed to investigate whether DHQ has protective effects against MIRI and to elucidate the mechanism of attenuation of oxidative stress-and ERS-induced apoptosis via the PI3K/Akt pathway. Isolated rat hearts and H9c2 cardiomyocytes were treated with or without DHQ, and then subjected to I/R and H/R, respectively. Our results showed that DHQ pretreatment markedly alleviated cardiac dysfunction, scavenged free radicals, reduced lipid peroxidation, and increased the activity of antioxidant enzymes ex vivo and in vitro. The result of western blot analysis showed that DHQ inhibited the apoptotic pathway and the expression of pro-apoptotic proteins CHOP, Caspase-12, and p-JNK. In addition, DHQ delayed the onset of ERs by reducing GRP78, p-PERK, and p-eif2alpha expression levels and by increasing HO-1 expression and Nrf2 binding to antioxidant response elements. These cardioprotective effects of DHQ were partially counteracted by the PI3K/Akt inhibitor LY294002. The protective effects of DHQ on the inhibition of MIRI may be mediated by activating the PI3K/Akt pathway to reduce oxidative stress-and ERS-induced apoptosis. PMID- 30525170 TI - A stochastic model study on the self-assembly process of a Pd2L4 cage consisting of rigid ditopic ligands. AB - The coordination self-assembly process of a Pd2L4 cage including rigid ditopic ligands, L, was studied numerically. A recently developed experimental approach (QASAP: quantitative analysis of self-assembly process) revealed that the rate determining steps in the self-assembly of the Pd2L4 cage are intramolecular ligand exchanges at the late stages of the self-assembly. In this study, the self assembly process before the rate-determining steps, which could not be investigated by experiment, was analyzed based on a minimal reaction network model. Only eight variable parameters of rate constants for ligand exchange reactions are sufficient enough to reproduce the time evolution of substrates and the products during the self-assembly of the cage. With these parameters, the major self-assembly pathway was determined. It was also found that a non negligible amount of an incomplete cage (IC), Pd2L3X2 (X indicates the leaving ligand), which was not suggested by QASAP, should be transiently produced. Numerical tests also suggest that the small rate constant value of the intramolecular ligand exchanges due to a restricted geometry causes the final stage to seemingly become the rate-determining step. PMID- 30525171 TI - Photoredox-catalyzed decarboxylative alkylation/cyclization of alkynylphosphine oxides: a metal- and oxidant-free method for accessing benzo[b]phosphole oxides. AB - By photoredox-catalysis, alkylation/aryl C-H cyclization of readily available alkynylphosphine oxides towards benzo[b]phospholes has been realized under metal- and oxidant-free conditions at room temperature. This reaction readily incorporates various functionalized alkyl groups into the benzo[b]phosphole skeletons, representing a mild and versatile tool for the preparation of valuable phosphole compounds. PMID- 30525172 TI - Straightforward formation of carbocations from tertiary carboxylic acids via CO release at room temperature. AB - We report an unprecedented mode of reactivity of carboxylic acids. A series of tertiary carboxylic acids, containing at least one phenyl alpha-substituent, undergo loss of carbon monoxide at room temperature (295 K), by a one pot reaction with 0.5-1 molar equivalents of WCl6 in dichloromethane. A plausible mechanism for the Ph3CCO2H/WCl6 reaction, leading to [CPh3][WOCl5] and Ph3CCl, is proposed on the basis of DFT calculations. The analogous reactions involving CEt(Ph)2CO2H, CMe(Ph)2CO2H and CMe2(Ph)CO2H selectively afforded stable hydrocarbons (alkene or indene, depending on the case), apparently resulting from the rearrangement of elusive tertiary carbocations. PMID- 30525173 TI - White-light generation from all-solution-processed OLEDs using a benzothiazole salophen derivative reactive to the ESIPT process. AB - A salicylidene derivative, N,N'-bis(salicylidene)-(2-(3',4' diaminophenyl)benzothiazole) (BTS), reactive in the Excited State Intramolecular Proton Transfer (ESIPT) process, was synthesized and its photophysical properties were evaluated, presenting an emission covering the entire range of the visible spectrum. Due to its broad emission band, BTS was successfully tested as an active layer in solution-processed organic light-emitting diodes with white-light emission. These diodes were prepared using solution-based protocols with the dye solubilized in a poly(9-vinylcarbazole) matrix. Different guest : host (polymer : BTS) molar ratios were used to optimize the diode performance. The optimized architecture rendered the best so far all-solution-processed ESIPT OLED with a luminance of 34 cd m-2 at 13.5 V with CIE coordinates 0.31, 0.40. PMID- 30525174 TI - A general and rapid room-temperature synthesis approach for metal sulphide nanocrystals with tunable properties. AB - Colloidal metal sulphide (MS) nanocrystals (NCs) have recently attracted considerable attention because of their tunable properties that can be exploited in various physical, chemical and biological applications. In this work, we present a novel and general method for synthesis of monodispersed binary (CuS, Ag2S, CdS, PbS, and SnS), ternary (Ag-In-S, Cu-In-S and Cu-Sn-S) and quaternary (Cu-Zn-Sn-S) MS NCs. The synthesis is conducted at room temperature, with an immediate crystallization process and up to 60 seconds of growth time, enabling rapid synthesis without external heating. For some of the ternary and quaternary NCs produced with relatively low crystallinity, we then carried out a "colloidal annealing" process to improve their crystallinity without changing their composition. Moreover, we show that the morphology and optical properties of the NCs can be tuned by varying the concentration of precursors and reaction time. The shape evolution and photoluminescence of particular MS NCs were also studied. These results not only provide insights into the growth mechanisms of MS NCs, but also yield a generalized, low cost, and potentially scalable method to fabricate them. PMID- 30525175 TI - Self-assembly of platinum(ii) 6-phenyl-2,2'-bipyridine complexes with solvato- and iono-chromic phenomena. AB - Mono- and di-nuclear organoplatinum(ii) monomers with cyclometalated 6-phenyl 2,2'-bipyridine ligands have been successfully constructed. These systems are capable of displaying intriguing solvato- and iono-chromic phenomena by elaborately manipulating non-covalent PtPt metal-metal and pi-pi stacking interactions for their self-assembly processes. PMID- 30525176 TI - Metal-catalyzed cross-coupling chemistry with polyhedral boranes. AB - Over the past several decades, metal-catalyzed cross-coupling has emerged as a very powerful strategy to functionalize carbon-based molecules. More recently, some of the cross-coupling methodologies have been adapted to inorganic compounds including boron-rich clusters. The development of this chemistry relies on the ability to synthesize halogenated boron-rich clusters which can serve as electrophilic cross-coupling partners with nucleophilic substrates in the presence of a metal catalyst. While the cross-coupling chemistry with boron clusters is conceptually reminiscent of that of its hydrocarbon counterparts, several key aspects including the spheroidal bulk of clusters and the distinct nature of boron-halogen/boron-heteroatom bonds make this chemistry unique. The utility of metal-catalyzed cross-coupling can be extended to several classes of polyhedral boranes including neutral and anionic carboranes, metallaboranes, and carbon-free boranes. Importantly, cross-coupling enables a suite of boron heteroatom (C, N, O, P, S) couplings to prepare boron cluster-based systems that can be used for ligand design, medicinal chemistry, and materials applications. PMID- 30525177 TI - Structural stability and optical properties of two-dimensional perovskite-like CsPb2Br5 microplates in response to pressure. AB - Here, we report the structural stability and visible light response of two dimensional (2D) layered perovskite-like CsPb2Br5 microplates (MPs) under high pressure. In situ high-pressure emission, optical absorption, and angle dispersive synchrotron X-ray diffraction indicated that CsPb2Br5 MPs experienced an isostructural phase transformation at roughly 1.6 GPa. The shrinkage of Pb-Br bond lengths and the marked change of Br-Pb-Br bond angles within the lead bromide pentahedral motif were responsible for the pressure-induced structural modulation and the sudden band-gap change of CsPb2Br5 MPs. PMID- 30525178 TI - Stereoselective synthesis of chromane derivatives via a domino reaction catalyzed by modularly designed organocatalysts. AB - A highly enantio- and diastereoselective method for the synthesis of functionalized chroman-2-ones and chromanes was achieved by using an organocatalytic domino Michael/hemiacetalization reaction of aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols followed by a PCC oxidation and dehydroxylation, respectively. Using the modularly designed organocatalysts (MDOs) self-assembled from cinchona alkaloid derivatives and amino acids in the reaction media, the title products were obtained in good to high yields (up to 97%) and excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 99% ee). PMID- 30525179 TI - Bone biopsy in nephrology practice. AB - Renal osteodystrophy (ROD), a group of metabolic bone diseases secondary to chronic kidney disease (CKD), still represents a great challenge to nephrologists. Its management is tailored by the type of bone lesion - of high or low turnover - that cannot be accurately predicted by serum biomarkers of bone remodeling available in daily clinical practice, mainly parathyroid hormone (PTH) and alkaline phosphatase (AP). In view of this limitation, bone biopsy followed by bone quantitative histomorphometry, the gold-standard method for the diagnosis of ROD, is still considered of paramount importance. Bone biopsy has also been recommended for evaluation of osteoporosis in the CKD setting to help physicians choose the best anti-osteoporotic drug. Importantly, bone biopsy is the sole diagnostic method capable of providing dynamic information on bone metabolism. Trabecular and cortical bones may be analyzed separately by evaluating their structural and dynamic parameters, thickness and porosity, respectively. Deposition of metals, such as aluminum and iron, on bone may also be detected. Despite of these unique characteristics, the interest on bone biopsy has declined over the last years and there are currently few centers around the world specialized on bone histomorphometry. In this review, we will discuss the bone biopsy technique, its indications, and the main information it can provide. The interest on bone biopsy should be renewed and nephrologists should be capacitated to perform it as part of their training during medical residency. PMID- 30525180 TI - Resistant and refractory hypertension: two sides of the same disease? AB - Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment. PMID- 30525181 TI - A comparison of blocked and mixed-trial methods for teaching auditory-visual discriminations. AB - Behavior analysts typically teach conditional discriminations in a mixed-trial format but may switch to a blocked-trial format for learners displaying limited acquisition. No known research has shown that mixed-trial methods are more effective or efficient than blocked-trial methods for teaching discriminations, so it is not clear why this format has been adopted as the "first-line" intervention. We compared blocked and mixed-trial formats for teaching novel auditory-visual discriminations to three adults with intellectual and developmental disabilities (IDD). Results show blocked-trial methods resulted in faster skill acquisition in all cases, suggesting this format may be a preferable starting point for instruction. PMID- 30525182 TI - Sleep-competing behaviours among Australian school-attending youth: Associations with sleep, mental health and daytime functioning. AB - Sleep problems are highly prevalent among school-attending youth, and impact on school performance and outcomes. Sleep-competing behaviours are likely factors in the inadequate sleep time and related functional outcomes observed in this population. We examined a range of sleep-competing behaviours and their associations with sleep variables in Australian school-attending youth. We also assessed whether these behaviours indirectly affected mental health and daytime functioning through poorer sleep quality. A total of 353 school-attending youth (mean age = 14.6 years, 53% female) were recruited from high schools in Australia, and completed a range of self-report measures. Approximately 50% of the youth obtained sub-optimal levels of sleep and reported having a problematically long sleep onset latency. Sleep competing behaviours, related and unrelated to electronic media use, were reported as occurring frequently, and were associated with a range of sleep variables. These behaviours were also related to poorer mental health and daytime sleepiness, with this association explained by indirect effects through sleep quality. Sleep-competing behaviours are prevalent on school nights in Australian youth, and may have adverse associations with mental health and functioning. Prevention and intervention programs might address the risk factors identified in the current study. PMID- 30525183 TI - Exploring geological and topographical controls on low flows with hydrogeological models. AB - This study investigates how catchment properties influence low-flow dynamics. With 496 synthetic models composed of a bedrock and an alluvial aquifer, we systematically assess the impact of the hydraulic conductivity of both lithologies, of the hillslope and of the river slope on catchment dynamics. The physically-based hydrogeological simulator HydroGeoSphere is employed, which allows obtaining a range of low-flow indicators. The hydraulic conductivity of the bedrock Kbedrock , a proxy for transmissivity, is the only catchment property exerting an overall control on low flows and explains 60% of the variance of Q95/Q50. The difference in dynamics of catchments with same Kbedrock depends on hillslope gradients and the alluvial aquifer properties. The buffering capacity of the bedrock is mainly related to Kbedrock and the hillslope gradient. We thus propose the dimensionless bedrock productivity index BPI that combines these characteristics with the mean net precipitation. For bedrock only models, the BPI explains 82% of the variance of the ratio of Q95 to mean net precipitation. The alluvial aquifer can significantly influence low flows when the bedrock productivity is limited. Although our synthetic catchment set-up is simple, it is far more complex than the available analytical approaches or conceptual hydrological models. The direct application of the results to existing catchments requires nevertheless careful consideration of the local geological topographic and climatic conditions. This study provides quantitative insight into the complex interrelations between geology, topography and low-flow dynamics and challenges previous studies which neglect or oversimplify geological characteristics in the assessment of low flows. PMID- 30525184 TI - Development and evaluation of a pan-dermatophyte PCR with species-level identification using sloppy molecular beacon probes. AB - BACKGROUND: Conventional laboratory diagnosis of dermatophyte infection is cumbersome and time-consuming. OBJECTIVES: We aimed to establish a simple, robust, and rapid molecular diagnostic assay for detection of dermatophytes and optionally non-dermatophytes in clinical specimens. METHODS: We developed a two tube pan-dermatophyte PCR assay using six sloppy molecular beacon (SMB) probes. The first PCR uses dermatophyte specific primers and enables detection and identification of most dermatophyte species. The second PCR with pan-fungal primers allows further differentiation of T. interdigitale and T. mentagrophytes/T. quinckeanum, T. violaceum and T. soudanense, and T. tonsurans and T. equinum, and detection of non-dermatophytes. The test was evaluated with 306 clinical specimens by comparing it to the results of microscopy and culture. RESULTS: In melting curve analyses, species-specific Tm signatures of the SMBs were defined. Thus, our new PCR enabled detection and species-level identification of at least 19 dermatophyte species. Sensitivity and specificity of PCR for detection of dermatophytes in clinical samples were estimated to be 96.9% and 90.4%, for culture 46.7% and 98.7%, and for microscopy 91.4% and 84.0%, respectively. The detection of non-dermatophytes by PCR and culture did not correlate. CONCLUSIONS: The new assay showed excellent performance characteristics for the detection of dermatophytes and is significantly faster than culturing techniques what makes it very promising for routine diagnostics of dermatophytosis. We noticed that the detection of non-dermatophytes in our assay currently has no benefit. This article is protected by copyright. All rights reserved. PMID- 30525186 TI - Validity and reliability of a freehand 3D ultrasound system for the determination of triceps surae muscle volume in children with cerebral palsy. AB - This study assessed the validity, intra-rater and inter-rater reliability of segmentation of in vivo medial gastrocnemius (MG), lateral gastrocnemius (LG) and soleus (SOL) muscle volume measurement using a single sweep freehand 3D ultrasound (3DUS) in children with cerebral palsy (CP). The MG, LG and SOL of both limbs of 18 children with CP (age 8 years 4 months +/- 1 year 10 months, 11 males, unilateral CP = 9, bilateral CP = 9, Gross Motor Functional Classification System I = 11, II = 7) were scanned using freehand 3DUS and magnetic resonance imaging (MRI). All freehand 3DUS and MRI images were segmented and volumes rendered by two raters. Validity was assessed using limits of agreement method. Intra-rater and inter-rater reliability was assessed using intra-class correlation (ICC), coefficient of variance (CV) and minimal detectable change (MDC). Freehand 3DUS overestimated muscle volume of the MG and LG by < 0.3 mL (1%) and underestimated SOL by < 1.3 mL (1.5%) compared with MRI. ICCs for intra rater reliability of the segmentation process for the freehand 3DUS system and MRI for muscle volume were > 0.98 and 0.99, respectively, for all muscles. ICCs for inter-rater reliability of the segmentation process for freehand 3DUS and MRI volumes were > 0.96 and 0.98, respectively, for all muscles. MDCs for single rater freehand 3DUS and MRI were < 4.0 mL (14%) and 3.2 mL (11%), respectively, in all muscles. Freehand 3DUS is a valid and reliable method for the measurement of lower leg muscle volume that can be measured with a single sweep in children with CP in vivo. It can be used as an alternative to MRI for the detection of clinically relevant changes in calf muscle volume as the result of growth and interventions. PMID- 30525185 TI - Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures. AB - OBJECTIVE: We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. METHODS: EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. RESULTS: In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10 Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. SIGNIFICANCE: We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis. PMID- 30525187 TI - The effect of light stimuli on dark-adapted visual sensitivity in invasive silver carp Hypophthalmichthys molitrix and bighead carp H. nobilis. AB - Non-physical barriers, including the use of underwater strobe lights alone or paired with sound or bubbles, are being considered as a means to prevent the upstream migration of invasive silver carp Hypophthalmichthys molitrix and bighead carp H. nobilis. To optimize potential optical deterrents, it is necessary to understand the visual sensitivity of the fishes. Dark-adapted H. molitrix and H. nobilis were found to possess broad visual sensitivity between 470 nm to 620 nm with peak spectral sensitivity at 540 nm for H. molitrix and 560 nm in H. nobilis. To assess the effect of a strobe light on vision, dark-adapted H. molitrix, H. nobilis and common carp Cyprinus carpio, were exposed to three different 5 s trains (100, 200, or 500 ms on-off flashes) of white light and the recovery of visual sensitivity was determined by measuring the b-wave amplitude of the electroretinogram (ERG). For all species, the longest recoveries were observed in response to the 500 ms flash trains (H. molitrix mean +/- SE = 702.0 +/- 89.8 s; H. nobilis 648.0 +/- 116.0 s; C. carpio 480 +/- 180.0 s). The results suggest that strobe lights can temporarily depress visual sensitivity, which may render optical barriers less effective. This article is protected by copyright. All rights reserved. PMID- 30525189 TI - Abstraction of tactile properties by individuals with autism and down syndrome using a picture-based communication system. AB - The present study evaluated the efficacy of a set of procedures for bringing tact extensions of abstract tactile properties under stimulus control. Two participants with disabilities who communicated via a picture-based communication system received reinforcement for tacts of tactile properties of four wet/dry and four hard/soft stimuli. Test trials were conducted to evaluate the extent to which the participants' correct responding generalized to novel stimuli with the same tactile properties. The results suggest that the procedures were effective in bringing tact extensions of abstract tactile properties under stimulus control. Both participants' correct responding generalized to a set of novel stimuli. Mastery level responding to training and test targets maintained for 2 weeks following training. The results provide further evidence supporting the use of DTT to teach stimulus abstraction to nonvocal verbal individuals who use augmentative forms of communication. PMID- 30525188 TI - Diagnostic exome sequencing in 100 consecutive patients with both epilepsy and intellectual disability. AB - OBJECTIVE: Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy. METHODS: One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient <= 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines. RESULTS: In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future. SIGNIFICANCE: This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield. PMID- 30525190 TI - Effects of modeling rote versus varied responses on response variability and skill acquisition during discrete-trial instruction. AB - Despite its advantages, discrete-trial instruction (DTI) has been criticized for producing rote responding. Although there is little research supporting this claim, if true, this may be problematic given the propensity of children with autism to engage in restricted and repetitive behavior. One feature that is common in DTI that may contribute to rote responding is the prompting and reinforcement of one correct response per discriminative stimulus. To evaluate the potential negative effects of rote prompts on varied responding, we compared the effects of modeling rote versus varied target responses during the teaching of intraverbal categorization. We also evaluated the effects of these procedures on the efficiency of acquisition of any one correct response. For all four children, any increase in varied responding was fleeting, and for two participants, acquisition was slower in the variable-modeling condition. PMID- 30525191 TI - A Modified Partial Likelihood Score Method for Cox Regression with Covariate Error Under the Internal Validation Design. AB - We develop a new method for covariate error correction in the Cox survival regression model, given a modest sample of internal validation data. Unlike most previous methods for this setting, our method can handle covariate error of arbitrary form. Asymptotic properties of the estimator are derived. In a simulation study, the method was found to perform very well in terms of bias reduction and confidence interval coverage. The method is applied to data from Health Professionals Follow-Up Study (HPFS) on the effect of diet on incidence of Type II diabetes. This article is protected by copyright. All rights reserved. PMID- 30525192 TI - Breaking the intergenerational cycle of obesity with SIRT1. PMID- 30525193 TI - Correction. PMID- 30525195 TI - Correction. PMID- 30525194 TI - Translating the matrix. AB - LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc. PMID- 30525196 TI - A new anatomic approach of the ventricular septal defect in the interruption of the aortic arch. AB - The aim of this study was to analyse the anatomy of the ventricular septal defect (VSD) in heart specimens with interruption of the aortic arch (IAA) in order to explore the hypothesis of different embryologic mechanisms for the different anatomic types of IAA. We examined 42 human heart specimens, 25 with IAA as the main disease with concordant atrioventricular and ventriculo-arterial connections and two distinct great arteries, and 17 hearts with IAA associated with other malformations [six common arterial trunk (CAT), five double-outlet right ventricle (DORV), three transposition of the great arteries (TGA), three atrioventricular septal defect (AVSD)]. The interruption was classified according to Celoria and Patton. We focused on the anatomy of the VSD viewed from the right ventricular side. There were 15 IAA type A, 27 type B, no type C. The VSD in IAA type B was always an outlet VSD, located between the two limbs of the septal band, with posterior malalignment of the outlet septum in hearts with concordant ventriculo-arterial connections, without any fibrous tricuspid-aortic continuity. In addition, the aortic arch was always completely absent. Conversely, the VSD in IAA type A could be of any type (outlet in six, muscular in four, central perimembranous in two, inlet in three) and the aortic arch was either atretic or absent. In addition, IAA type B, when found in the setting of another anomaly, was always associated with neural crest-related anomalies (CAT and DORV), whereas IAA type A was found in association with anomalies not related to the neural crest (TGA and AVSD). These results reinforce the hypothesis that different pathogenic mechanisms are responsible for the two types of IAA, and the inclusion of IAA type B in the group of neural crest defects. Conversely, IAA type A could be due to overlapping mechanisms: flow-related defect (coarctation-like) and neural crest contribution. PMID- 30525197 TI - Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability. PMID- 30525198 TI - Simple discrimination training with differential responses to establish functional and equivalence classes with preschool children. AB - The present study assessed whether simple discrimination training with differential responses would produce functional and equivalence classes with preschool children. In Experiment 1, we exposed 10 children to simple successive discrimination training in which they had to press different buttons (selection based responses). Response 1 (R1) was reinforced only in the presence of A1, B1, or C1, and Response 2 (R2) was reinforced only in the presence of A2, B2, or C2. We assessed the formation of functional classes by training new selection responses in the presence of one member of each class (A1-R3, A2-R4) and testing to see if these responses would occur in the presence of other members. Eight children responded consistently with functional class formation. Four of these eight children also responded consistently with the formation of equivalence classes. Experiment 2 investigated whether differential motor responses (i.e., gestures) would improve equivalence class yields. Three of six children showed both functional and equivalence class formation. In general, the results indicate that the simple discrimination procedure with differential responses yielded functional and equivalence class formation. PMID- 30525200 TI - Anaesthetic research in low- and middle-income countries. PMID- 30525199 TI - Confirmation of the unidimensional structure of the Oral Health Literacy Adults Questionnaire. AB - OBJECTIVES: The Oral Health Literacy Adults Questionnaire (OHL-AQ) was designed to test functional oral health literacy in general populations. Exploratory analyses suggested a unidimensional structure rather than the four constructs proposed (reading comprehension, numeracy, listening and decision-making). The purpose of this study was to conduct a confirmatory analysis of the OHL-AQ. METHODS: A cross-sectional study design used a stratified multistage sampling strategy in 22 districts of Tehran, Iran. The OHL-AQ was administered verbally in its original Persian language. Confirmatory analyses replicated the previous exploratory analyses to determine dimensionality and internal consistency. Data were then randomly assigned to two data sets and item analyses were performed to test reliability. RESULTS: Evidence of unidimensionality was confirmed as the exploratory factor analysis could replicate previous results in a different population. In a confirmatory factor analysis, model fit indicators were mixed because chi-square results were statistically significant and the standard root mean square residual (SRMR) neared guideline values. The comparative fit index (CFI) and the Tucker-Lewis index (TLI) did not meet recommended values but the root mean square error of approximation (RMSEA) was well within standards. Both score validity and reliability were adequate. CONCLUSIONS: While findings overall support that OHL measured using the OHL-AQ can be considered unidimensional and therefore OHL can be characterised with one score, further dimensionality studies are needed to investigate populations in which OHL is low. PMID- 30525201 TI - Mouse neutrophils release extracellular traps in response to Naegleria fowleri. AB - Naegleria fowleri is a free-living amoeba, which is able to infect humans through the nasal mucosa causing a disease in the central nervous system known as primary amoebic meningoencephalitis (PAM). Polymorphonuclear cells (PMNs) play a critical role in the early phase of N. fowleri infection. Recently, a new biological defense mechanism called neutrophil extracellular traps (NETs) has been attracting attention. These structures represent an important strategy to immobilize and kill invading microorganisms. In this work, we evaluate the capacity of N. fowleri to induce the NETs release by PMNs cells in mice in vitro and in vivo. In vitro: Neutrophils from bone marrow were cocultured with N. fowleri trophozoites. In vivo: we employed a mouse model of PAM. We evaluated DNA, histone and myeloperoxidase (MPO) and the formation of NETs by confocal microscopy. Our results showed N. fowleri induce both NETs and MPO release by PMNs cells in mice after trophozoite exposure, which increased through time, in vitro and in vivo. These results demonstrate that NETs are somehow associated with the amoebas. We suggest PMNs release their traps trying to avoid N. fowleri attachment at the apical side of the nasal epithelium. This article is protected by copyright. All rights reserved. PMID- 30525202 TI - Effects of host-derived chemokines on the motility and viability of Trypanosoma brucei. AB - African trypanosomes (Trypanosoma brucei spp.) are extracellular, hemoflagellate, protozoan parasites. Mammalian infection begins when the tsetse fly vector injects trypanosomes into the skin during blood feeding. The trypanosomes then reach the draining lymph nodes before disseminating systemically. Intravital imaging of the skin post-tsetse fly bite revealed that trypanosomes were observed both extravascularly and intravascularly in the lymphatic vessels. Whether host derived cues play a role in the attraction of the trypanosomes towards the lymphatic vessels to aid their dissemination from the site of infection is not known. Since chemokines can mediate the attraction of leukocytes towards the lymphatics, in vitro chemotaxis assays were used to determine whether chemokines might also act as chemoattractants for trypanosomes. Although microarray data suggested that the chemokines CCL8, CCL19, CCL21, CCL27 and CXCL12 were highly expressed in mouse skin, they did not stimulate the chemotaxis of T. brucei. Certain chemokines also possess potent antimicrobial properties. However, none of the chemokines tested exerted any parasiticidal effects on T. brucei. Thus, our data suggest that host-derived chemokines do not act as chemoattractants for T. brucei. Identification of the mechanisms used by trypanosomes to establish host infection will aid the development of novel approaches to block disease transmission. This article is protected by copyright. All rights reserved. PMID- 30525203 TI - NHLRC1 dodecamer repeat expansion demonstrated by whole genome sequencing in a Chihuahua with Lafora disease. PMID- 30525204 TI - Reply to "Racial and Gender Disparities among Patients with Takotsubo Syndrome". AB - We read with great interest the Letter to the Editor titled "Racial and Gender Disparities among Patients with Takotsubo Syndrome" by Khalid et al [1] regarding our recent publication [2]. Their excellent comments and detailed assessment highlights the low prevalence of diabetes mellitus in patients with Takotsubo syndrome (TTS) compared to general population. PMID- 30525205 TI - Orofacial neuralgia associated with a middle cerebral artery aneurysm. AB - Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affect the patient's quality of life. Intracranial aneurysms are a potential cause of stroke, with associated sub-arachnoid haemorrhage leading to high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations excluded odontogenic pain, TMD and other more common causes of facial pain. Magnetic resonance imaging revealed a 7 mm * 6 mm aneurysm in the right middle cerebral artery which was subsequently surgically clipped. Interestingly the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain. This is the first case of facial neuralgia associated with an aneurysm in the middle cerebral artery as far as we are aware, and it emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain. This article is protected by copyright. All rights reserved. PMID- 30525206 TI - System justification theory at 25: Evaluating a paradigm shift in psychology and looking towards the future. AB - Since first being proposed 25 years ago, system justification theory has become a paradigm-shifting framework for understanding intergroup relations and political psychology. Based on the thesis that people are motivated to defend and bolster the societal status quo, system justification theory helps to explain varied phenomena, including resistance to change, outgroup favouritism, and other instances of false consciousness. This paper summarizes four tenets of the theory including the following: (1) antecedents to system justification, (2) palliative effects of system justification, (3) status-based asymmetries in conflict between justification motives, and (4) societal consequences of system justification. Throughout our review, we highlight how system justification theory helps to explain why disadvantaged groups might sometimes support the status quo, emphasizing research conducted outside the United States when possible. We conclude by calling on future research to (1) further utilize nationally representative and multi-level data, (2) investigate the relational motives behind system justification, (3) address social change from a system justification perspective, and (4) extend system justification theory's focus beyond WEIRD societies. PMID- 30525207 TI - Technical Challenges in Generalizing Calibration Techniques for Breast Density Measurements. AB - PURPOSE: We are developing a calibration methodology for full field digital mammography (FFDM). Calibration compensates for the image acquisition technique influences on this pixel representation, ideally producing improved inter-image breast density estimates. This approach relies on establishing references with rigid breast tissue equivalent phantoms (BTEs) and requires an accurate estimate of the compressed breast thickness because the system readout is nominal. There is also an attenuation mismatch between adipose breast tissue and the adipose BTE that was noted in our previous work. It is referred to as the "attenuation anomaly" and is addressed in this report. The objectives are to evaluate methods to correct for the compressed breast thickness and compensate for the attenuation anomaly. METHODS: Thickness correction surfaces were established with a deformable phantom (DP) using both image and physical measurements for three direct x-ray conversion FFDM units. The Cumulative Sum serial quality control procedure was established to ensure the thickness correction measurements were stable over time by imaging and calibrating DPs biweekly in lieu of physical measurements. The attenuation-anomaly was addressed by evaluating adipose image regions coupled with an optimization technique to adjust the adipose calibration data. We compared calibration consistency across matched left and right cranial caudal (CC) mammographic views (n = 199) with and without corrections using Bland Altman plots. These plots were complemented by comparing the right and left breast calibrated average (MUa ) and population distribution mean (ma ) with 95% confidence intervals and difference distribution variances with the F-test for uncorrected and corrected data. RESULTS: Thickness correction surfaces were well approximated as tilted planes and are dependent upon compression force. A correction was developed for the attenuation-anomaly. All paddles (large and small paddles for all units) exhibited similar tilt as a function of force. Without correction, ma = 0.92 (-1.77, 3.62) was not significantly different from zero with many negative MUa samples. The thickness correction produced a significant shift in the MUa distribution in the positive direction with ma = 13.99 (11.17, 16.80) and reduced the difference distribution variance significantly (p < 0.0001). Applying both corrections in tandem gave ma = 22.83 (20.32, 25.34), representing another significant positive shift in comparison with the thickness correction in isolation. Thickness corrections were stable over approximately a two-year timeframe for all units. CONCLUSION: These correction techniques are valid approaches for addressing technical problems with calibration that relies on reference phantoms. The efficacy of the calibration methodology will require validation with clinical endpoints in future studies. This article is protected by copyright. All rights reserved. PMID- 30525208 TI - Application of geographic information systems and simulation modelling to dental public health: Where next? AB - Public health research in dentistry has used geographic information systems since the 1960s. Since then, the methods used in the field have matured, moving beyond simple spatial associations to the use of complex spatial statistics and, on occasions, simulation modelling. Many analyses are often descriptive in nature; however, and the use of more advanced spatial simulation methods within dental public health remains rare, despite the potential they offer the field. This review introduces a new approach to geographical analysis of oral health outcomes in neighbourhoods and small area geographies through two novel simulation methods spatial microsimulation and agent-based modelling. Spatial microsimulation is a population synthesis technique, used to combine survey data with Census population totals to create representative individual-level population datasets, allowing for the use of individual-level data previously unavailable at small spatial scales. Agent-based models are computer simulations capable of capturing interactions and feedback mechanisms, both of which are key to understanding health outcomes. Due to these dynamic and interactive processes, the method has an advantage over traditional statistical techniques such as regression analysis, which often isolate elements from each other when testing for statistical significance. This article discusses the current state of spatial analysis within the dental public health field, before reviewing each of the methods, their applications, as well as their advantages and limitations. Directions and topics for future research are also discussed, before addressing the potential to combine the two methods in order to further utilize their advantages. Overall, this review highlights the promise these methods offer, not just for making methodological advances, but also for adding to our ability to test and better understand theoretical concepts and pathways. PMID- 30525209 TI - miR-145 modulates epithelial-mesenchymal transition and invasion by targeting ZEB2 in non-small cell lung cancer cell lines. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Epithelial mesenchymal transition (EMT) is a major event that drives cancer progression. Here we aim to investigate the role of microRNA, miR-145, in regulating EMT of the highly invasive non-small cell lung cancer (NSCLC). Quantitative real-time polymerase chain reaction analysis indicated that miR-145 was downregulated in cancer tissue compared with that in adjacent normal tissue. NSCLC cell lines, namely H1299, PC7, and SPCA-1, also demonstrated miR-145 downregulation, which is correlated well with their invasive ability, assessed by the Matrigel invasion assay. miR-145 overexpression resulted in downregulation of N-cadherin, and downregulation of vimentin and E-cadherin, suggesting a decreased EMT activity. TargetScan analysis predicted that a binding site exists between miR-145 and an oncogene, ZEB2, which was verified using the dual-luciferase assay. Alteration of miR-145 expression also induced inverse effects on ZEB2 expression, and a negative correlation exists between ZEB2 and miR-145 in human tissues. ZEB2 and miR-145 also exerted antagonizing effects on the invasion of NSCLC cells. Therefore, miR-145 is an important molecule in NSCLC that regulates cancer EMT through targeting ZEB2. PMID- 30525210 TI - Poorly Differentiated Thyroid Cancer in the Context of the Revised 2015 American Thyroid Association Guidelines and the Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (Eighth Edition). AB - OBJECTIVE: Poorly differentiated thyroid cancer (PDTC) is a rare, but aggressive thyroid cancer (TC) and a main cause of death from non-anaplastic follicular cell derived TC. Assessing the risk of PDTC-related death and the risk of recurrence is important for clinicians. The recent American Thyroid Association (ATA) 2015 guidelines and the updated 8th edition of the American Joint Committee on Cancer/Tumor-Node-Metastasis (AJCC/TNM) staging system should support clinicians in the management approach to PDTC patients. PATIENTS: Forty-six consecutive PDTC patients treated in a single oncologic center, 2000-2017. MEASUREMENTS: Retrospective analysis of TNM stage, initial risk, response-to-therapy categories, follow-up, and final disease status incorporating the ATA 2015 criteria and the 8th AJCC/TNM staging system. Disease-specific survival (DSS) using the Kaplan-Meier method. RESULTS: Of the 46 PDTC 21 (45.6%) were ATA high risk (HR), 22 (47.8%), 17 (37%) and seven (15.2%) were TNM stage I, II, and III IV, respectively. During a median follow-up of 55.5 months, two (4.3%) patients were recurrent, 18 (39.1%) died of PDTC. The 5-/10-year DSS were 65/57%, respectively. According to the AJCC/TNM, the 5-/10-year DSS of I, II, and III-IV stage were 83/83%; 77/55%, and 0/0%, respectively. According to the 2015 ATA initial risk, the 5-/10-year DSS were 91/72% for ATA intermediate risk, and 38/38% for ATA HR patients. CONCLUSIONS: In PDTC patients, the updated AJCC/TNM staging system accurately predicts a high risk of death in stage III-IV, whereas it seems to be inadequate for predicting a very low or low risk of death expected for differentiated TC in stage I-II. The ATA initial HR may be also used to predict a high risk of PDTC-related death. This article is protected by copyright. All rights reserved. PMID- 30525211 TI - Skin sensitization: Uncertainties, challenges, and opportunities for improved risk assessment. AB - At the ESCD congress held in Manchester in 2016, a session was organized to encourage more dialogue between clinicians with expertise in skin sensitization and toxicologists seeking to provide effective risk assessment to prevent human health issues. That session focused on the remaining uncertainties regarding the induction and regulation of skin sensitization in humans, and the opportunities and challenges associated with the refinement and improvement of risk assessment methodologies. This short article, prompted by those discussions, debates what the authors regard as being among the most important and most intriguing uncertainties about skin sensitization and allergic contact dermatitis in humans, and the most significant opportunities for improving risk assessment. The aim has been to provide a basis for mapping out the areas that might benefit from a closer alignment between the relevant clinical community and toxicologists charged with the responsibility of ensuring that skin sensitization risks are understood and managed. PMID- 30525212 TI - Can All Major Ros Forming Sites of the Respiratory Chain Be Activated by High FADH2 /NADH Ratios? PMID- 30525213 TI - Calcium-sensing receptor mediates interleukin-1beta-induced collagen expression in mouse collecting duct cells. AB - The mechanisms that underlie the profibrotic effect of interleukin (IL)-1beta are complicated and not fully understood. Recent evidence has suggested the involvement of the calcium-sensing receptor (CaSR) in tubular injury. Therefore, the current study aimed to investigate whether CaSR mediates IL-1beta-induced collagen expression in cultured mouse inner medullary collecting duct cells (mIMCD3) and to determine the possible downstream signaling effector. The results showed that IL-1beta significantly upregulated the expression of type I and III collagens in a concentration- and time-dependent manner. Moreover, CaSR was expressed in mIMCD3 cells, and its expression was increased by increasing the concentrations and times of IL-1beta treatment. Selective inhibitors (Calhex231 or NPS2143) or the siRNA of CaSR attenuated the enhanced expression of type I and III collagens. Furthermore, IL-1beta increased nuclear beta-catenin protein levels and decreased cytoplasmic beta-catenin expression in cells. In contrast, blockage of CaSR by the pharmacological antagonists or siRNA could partially attenuate such changes in the IL-1beta-induced nuclear translocation of beta catenin. DKK1, an inhibitor of beta-catenin nuclear translocation, further inhibited the expression of type I and III collagens in cells treated with IL 1beta plus CaSR antagonist. In summary, these data demonstrated that IL-1beta induced collagen I and III expressions in collecting duct cells might be partially mediated by CaSR and the downstream nuclear translocation of beta catenin. PMID- 30525214 TI - miR-505 acts as a tumor suppressor in gastric cancer progression through targeting HMGB1. AB - Gastric cancer (GC) is a frequent type of malignant tumor worldwide. GC metastasis results in the majority of clinical treatment failures. MicroRNAs (miRNA) are identified to exhibit crucial roles in GC. Our current study aimed to explore the biological roles of miR-505 in GC progression. It was observed that miR-505 was robustly decreased in GC cells compared with human normal gastric epithelial GES-1 cells. Overexpression of miR-505 was able to repress GC progression in AGS and BGC-823 cells. In addition, high-mobility group box 1 (HMGB1) has been identified as a crucial oncogene in several cancer types. By carrying out bioinformatics analysis, HMGB1 was predicted as a direct target of miR-505. Meanwhile, HMGB1 was found to be significantly increased in GC cells and it was confirmed in our study that miR-505 can directly target HMGB1 in vitro. miR-505 mimics can inhibit HMGB1 messenger RNA and protein expression dramatically. Subsequently, knockdown of HMGB1 can inhibit GC cell proliferation, colony formation, and induce cell apoptosis. Furthermore, HMGB1 silence suppressed GC cell migration and invasion greatly in vitro. Finally, it was validated that miR-505 can inhibit GC progression by targeting HMGB1 in vivo. Taken these together, it was indicated that miR-505/HMGB1 axis was involved in the development of GC. miR-505 can serve as a potential prognostic indicator in GC therapy. PMID- 30525215 TI - Upregulation of circular RNA circ_0000502 predicts unfavorable prognosis in osteosarcoma and facilitates cell progression via sponging miR-1238. AB - Growing evidence suggests that circular RNAs (circRNAs) play a significant role in regulating cancer initiation and metastasis. Osteosarcoma (OS) is a sophisticated disease with various genes activated or silenced. In this study, we defined a novel cancer-related circRNA, circ_0000502 in OS progression. qRT-PCR was conducted to detect its expression level in OS tissue samples and cell lines. In addition, the clinical significance of circ_0000502 was investigated. Afterwards, gain-of-function and loss-of-function in vitro assays were performed to detect the cell growth, apoptosis, migration, and invasion altered by circ_0000502 by CCK-8, clone-forming, flow cytometry, and transwell experiments. Xenograft study was performed to validate the in vitro data. The luciferase reporter assay was used to explore the mechanism of circ_0000502. Circ_0000502 was identified upregulated in both OS tissue specimens and cells. In addition, its expression predicts clinical severity and unfavorable prognosis in the 63 recruited patients with OS. Circ_0000502 facilitated cell proliferation, migration, and invasion in OS cells and inhibited cell apoptosis. The animal study further confirmed the in vitro results. For mechanism exploration, circ_0000502 could directly sponge microRNA (miR)-1238, and the oncogenic functions of circ_0000502 is partially dependent on its regulation of miR-1238 proved by rescue assays. In summary, this study might help to develop rational predictive and therapeutic target for patients with OS. PMID- 30525216 TI - Comprehensive characterization of horse genome variation by whole-genome sequencing of 88 horses. AB - Whole-genome sequencing studies are vital to gain a thorough understanding of genomic variation. Here, we summarize the results of a whole-genome sequencing study comprising 88 horses and ponies from diverse breeds at 19.1* average coverage. The paired-end reads were mapped to the current EquCab3.0 horse reference genome assembly, and we identified approximately 23.5 million single nucleotide variants and 2.3 million short indel variants. Our dataset included at least 7 million variants that were not previously reported. On average, each individual horse genome carried ~5.7 million single nucleotides and 0.8 million small indel variants with respect to the reference genome assembly. The variants were functionally annotated. We provide two examples for potentially deleterious recessive alleles that were identified in a heterozygous state in individual genome sequences. Appropriate management of such deleterious recessive alleles in horse breeding programs should help to improve fertility and reduce the prevalence of heritable diseases. This comprehensive dataset has been made publicly available, will represent a valuable resource for future horse genetic studies and supports the goal of accelerating the rates of genetic gain in domestic horse. PMID- 30525217 TI - Racial and Gender Disparities Among Patients with Takotsubo Syndrome. AB - We read with great interest the original article by Lemor et al. in the recent issue of Clinical Cardiology, titled, "Impact of Gender on In-Hospital Outcomes in Patients with Takotsubo syndrome: A Nationwide Analysis from 2006 to 2014" [1]. The authors report important racial and gender disparities among patients with Takotsubo syndrome (TTS) from the large National Inpatient Sample (NIS) database. We wish to highlight a few important points relevant to the article. This article is protected by copyright. All rights reserved. PMID- 30525218 TI - Acclimation and endogenous abscisic acid in the moss Physcomitrella patens during acquisition of desiccation tolerance. AB - The moss Physcomitrella patens has been used as a model organism to study the induction of desiccation tolerance (DT), but links between dehydration rate, the accumulation of endogenous abscisic acid (ABA), and DT remain unclear. In this study, we show that prolonged acclimation of P. patens at 89% relative humidity (RH) (-16 MPa) can induce tolerance of desiccation at 33% RH (-153 MPa) in both protonema and gametophore stages. During acclimation, significant endogenous ABA accumulation occurred after 1 day in gametophores and after 2 days in protonemata. P. patens expressing the ABA-inducible EARLY METHIONINE promoter fused to a cyan fluorescent protein (CFP) reporter gene revealed a mostly uniform distribution of the CFP increasing throughout the tissues during acclimation. DT was measured by day 6 of acclimation in gametophores, but not until 9 days of acclimation for protonemata. These results suggest that endogenous ABA accumulating when moss cells experience moderate water loss requires sufficient time to induce the changes that permit cells to survive more severe desiccation. These results provide insight for ongoing studies of how acclimation induces metabolic changes to enable DT in P. patens. This article is protected by copyright. All rights reserved. PMID- 30525219 TI - AGAP2-AS1 serves as an oncogenic lncRNA and prognostic biomarker in glioblastoma multiforme. AB - Long noncoding RNA (lncRNA) AGAP2 antisense RNA 1 (AGAP2-AS1) has been suggested to function as an oncogenic lncRNA in lung cancer, breast cancer, and anaplastic glioma. However, the expression pattern and molecular mechanism of AGAP2-AS1 in glioblastoma multiforme (GBM) remains unknown. The purpose of this study is to present more evidence about the clinical and biological function of AGAP2-AS1 in GBM. In our results, we found AGAP2-AS1 expression was increased in GBM compared with adjacent normal brain tissues or low-grade glioma tissues, and there was no significantly different between low-grade glioma tissues and normal tissues. Kaplan-Meier survival analysis indicated patients with GBM having high-expression of AGAP2-AS1 had shorter overall survival time than those with low expression of AGAP2-AS1. The loss-of-function studies showed that downregulation of AGAP2-AS1 depressed cell proliferation, migration, and invasion, and promoted cell apoptosis in GBM. In summary, AGAP2-AS1 is a prognostic biomarker for patients with GBM, and functions as an oncogenic lncRNA to modulate GBM cell proliferation, apoptosis, migration, and invasion, which suggests that AGAP2-AS1 is potential therapeutic target for GBM. PMID- 30525220 TI - Warming and water deficit impact leaf photosynthesis and decrease forage quality and digestibility of a C4 tropical grass. AB - Global warming is predicted to cause more intense extreme events such as heat waves, flooding and severe droughts, producing significant effects on agriculture. In tropics, climate change will severely impact livestock production affecting water availability, forage quality and food for cattle. We investigated the isolated and combined effects of soil water deficit (wS) and +2 degrees C increase in canopy temperature (eT) on leaf gas exchange, chlorophyll fluorescence, carbohydrate content, forage quality and in vitro dry matter digestibility (IVDMD) of a field-grown C4 tropical forage grass Panicum maximum Jacq. using a temperature-free air controlled enhancement (T-FACE) system. The wS and eT treatments showed no effects on photosystem II photochemistry. However, wS under ambient temperature decreased net photosynthesis rate (A), stomatal conductance (gs ) and maximum rate of carboxylation of Rubisco (Vcmax ), leading to a reduced starch content in leaves. A 16% reduction in leaf dry mass (LDM) and reduction in forage quality by increasing fibres, reducing crude protein (CP) and decreasing the IVDMD was also observed by effect of wS. Warming under adequate soil moisture (eT) significantly increased LDM by 25% but reduced the forage quality increasing the lignin content and reducing starch, CP and digestibility. The combined wSeT treatment reduced A, gs , Vcmax and the forage quality. When compared to control, the lignin content in leaves increased by 43%, 28% and 17% in wS, eT and wSeT, respectively, causing a significant reduction in IVDMD. We concluded that despite physiological mechanisms to acclimate to warming, both; warming and water deficit will impair the quality and digestibility of C4 tropical pastures. This article is protected by copyright. All rights reserved. PMID- 30525221 TI - The healing of dental extraction sockets in insulin dependent diabetic patients: a prospective controlled observational study. AB - BACKGROUND: The aim of this study was to determine whether there was a difference in delayed healing following dental extractions for insulin-dependent diabetics as compared to non-diabetic patients. METHODS: Prospective patients referred to the Adelaide Dental Hospital exodontia clinic for dental extractions were recruited into two groups: Known insulin-dependent diabetics and healthy non diabetics. All had a random blood glucose level (BGL). Delayed healing cases were identified, and statistical evaluation performed. RESULTS: There were 56 insulin dependent diabetic patients (BGL 10.03, range 4.9-26) and 49 non-diabetic, age and sex matched, patients. Seven patients (12.5%) in the study group showed delayed healing following extraction, while only four patients (8.2%) in the control group suffered delayed healing. This difference was not statistically significant. Two of the study group developed post extraction infections, requiring incision, drainage, and antibiotics. CONCLUSION: The study shows that Type 1 and insulin-dependent Type 2 diabetic patients, if well controlled, tend to heal up well following dental extractions but with a small but not statistically different rate of post extraction complications including infection. This is contrary to what is usually taught. Clinicians should take great care with management of insulin dependent diabetic patients, as compared to non-insulin dependent diabetics or non-diabetic patients. This article is protected by copyright. All rights reserved. PMID- 30525222 TI - 5-Hydroxytryptamine (5-HT)-exacerbated DSS-induced colitis is associated with elevated NADPH oxidase expression in the colon. AB - AIM: This study investigated the impact of 5-hydroxytryptamine (5-HT) on the expression of NOXs in dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: C57BL/6J (B6) mice at 6 to 8 weeks of age were treated with 5-HT, DSS, or DSS + 5-HT. After 6-day treatment, the severity of colitis, infiltration of leukocytes, and messenger RNA (mRNA) and/or protein levels of Nox1, Nox2, Nox4, and Duox2 were analyzed in the colon by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry (IHC), and Western blot analysis. The direct effect of 5-HT on NOX gene and protein expression in HT-29 colon cancer cells and in U-937 macrophage cells were determined by qPCR and Western blot analysis. RESULTS: Mice treated with 5-HT alone did not develop colitis, while those treated with 1.0% DSS or DSS + 5-HT had mild and severe colitis, respectively. All treated mice had more myeloperoxidase-positive cells in the colon compared with untreated control mice. Mice treated with 5-HT or DSS alone had increased Nox2 and Nox4 mRNA and protein levels in the colon determined by qPCR, IHC, and Western blot analysis. These two Nox expressions were even higher in mice treated with DSS + 5-HT, while the expression levels of epithelium localized Nox1 and Duox2 tended to decrease. Additionally, mice treated with 5-HT alone had elevated Nox1 and Duox2 expression as shown by qPCR and IHC. However, these gene expressions were diminished in DSS + 5-HT-treated mice likely due to erosion of epithelium. Furthermore, 5-HT induced NOX1 and DUOX2 gene and protein expression in HT-29 colon cancer epithelial cells, whereas induced NOX2 and NOX4 gene and protein expression in U-937 cells. CONCLUSION: As 5-HT induced NOX1 and DUOX2 gene and protein expression in colon epithelial and HT-29 cells, NOX2 and NOX4 in the infiltrating leukocyte in mouse colon and in U-937 cells, the exacerbate colitis induced by combined 5-HT and DSS treatment might be relevant to increased NOX expression in mice colons. PMID- 30525223 TI - Stroke recovery in rats after 24h-delayed, intramuscular neurotrophin-3 infusion. AB - OBJECTIVES: Neurotrophin-3 (NT3) plays a key role in the development and function of locomotor circuits including descending serotonergic and corticospinal tract (CST) axons and afferents from muscle and skin. We have previously shown that gene therapy delivery of human NT3 into affected forelimb muscles improves sensorimotor recovery after stroke in adult and elderly rats. Here, to move towards the clinic, we tested the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after stroke. METHODS: Rats received unilateral ischemic stroke in sensorimotor cortex. To simulate a clinically feasible time-to-treat, twenty-four hours later rats were randomized to receive NT3 or vehicle by infusion into affected triceps brachii for four weeks using implanted catheters and minipumps. RESULTS: Radiolabelled NT3 crossed from the bloodstream into the brain and spinal cord in rodents with or without strokes. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory impairment of the affected wrist. fMRI during stimulation of the affected wrist showed spontaneous recovery of peri-infarct BOLD signal that NT3 did not further enhance. Rather, NT3 induced neuroplasticity of the spared corticospinal and serotonergic pathways. INTERPRETATION: Our results show that delayed, peripheral infusion of NT3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke. This article is protected by copyright. All rights reserved. PMID- 30525224 TI - Effects of Chemical Speciation on the Bioaccessibility of Zinc in Spiked and Smelter-Affected Soils. AB - Previous studies have suggested that understanding soil metal speciation, rather than relying solely on total metal content, can improve the accuracy and utility of contaminated site risk assessments. Since soil properties and reaction time can alter metal speciation, then speciation should influence metal bioaccessibility. For example, under gastrointestinal conditions, it is expected that metal species will differ in bioaccessibility depending upon their stability in acidic pH environments. We studied the links between metal speciation and bioaccessibility. A combination of synchrotron-based X-ray diffraction (XRD), X ray absorption near edge structure (XANES) were used to identify the Zn speciation in spiked and smelter-affected soils. After conducting in vitro digestion tests on the soil samples, XANES and linear combination fitting (LCF) were carried out on the residual pellets to identify the species of Zn that remained after digesting the soils in the simulated gastric and duodenal fluids. The metal species that were not present in the residual pellets were inferred to have been dissolved and thus are more bioaccessible. Sphalerite (ZnS), ZnO, and outer-sphere Zn contributed more to Zn bioaccessibility than franklinite (ZnFe2 O4 ) and Zn incorporated into a hydroxy interlayer mineral (Zn-HIM). The bioaccessibility of Zn-Al LDH was found to be inversely proportional to its residence time in soil. It was also observed that the relatively high pH of the duodenum favors metal reprecipitation and readsorption, leading to a reduction in bioaccessible metal concentration. These results imply that metal speciation mainly controls metal bioaccessibility. This article is protected by copyright. All rights reserved. PMID- 30525225 TI - Characteristics of sediment affecting monomethylmercury accumulation in benthic fish of the Mekong Delta. AB - The Mekong River Delta is a flat, low-lying area formed by a dense network of main tributaries of the Tien River and the Hau River, providing a nourishing habitat for aquatic organisms. A sediment survey of the total mercury (Hg), monomethylmercury (MMHg), and geochemical variables was carried out from the coast to 131 km upriver to establish an overview of the environmental factors affecting the bioaccumulation of Hg and MMHg in delta fish. The survey results revealed that the total Hg (12-90 ng g-1 ) and MMHg (0.014-1.5 ng g-1 ) concentrations were in the range of uncontaminated sediment. The statistical analysis using various geochemical factors demonstrated that sediment MMHg concentrations and fractions of MMHg over total Hg in sediment are higher at the higher total organic carbon (TOC) and total nitrogen sites. The current levels of TOC in Mekong Delta sediment are relatively low (0.2-1.5%); however, expanding dam constructions and aquacultures related to salinity intrusion are reinforcing the carbon burial rate with increasing fine fractions. Based on the positive relationship found between MMHg and TOC in sediment, proper management efforts are necessary to reduce MMHg production in the Mekong River Delta sediment. This article is protected by copyright. All rights reserved. PMID- 30525226 TI - A prospective randomized clinical trial comparing two doses of AbobotulinumtoxinA for idiopathic overactive bladder. AB - AIMS: To compare 300 U versus 500 U of abobotulinumtoxinA (ABO) intravesical injections for the treatment of idiopathic overactive bladder (OAB) refractory to first and second-line treatments. METHODS: A prospective, randomized, single blind study was performed in female patients with symptoms of OAB, who had failed conservative treatment. Patients were treated with 300 or 500 U of ABO injected into 30 sites, avoiding the trigone. All treatments were evaluated by voiding diary, ICIQ-OAB questionnaire, urodynamic test, visual analogue scale (VAS) for treatment satisfaction and patient global impression of improvement (PGI-I). The primary outcome was change in maximum cistometric capacity (MCC). Secondary outcome included changes in urgency, complete continence, subjective success (VAS and PGI-I), and adverse events (urinary retention, UTI, and CIC). RESULTS: Twenty one patients were included. MCC has increased from 185.0 to 270.9 mL (300 U) and from 240.8 to 311.7 mL (500 U), comparing the baseline with 12 weeks, without statistical difference between the groups (P = 0.270). At 12 weeks, 91% of patients were dry in both groups. At 24 weeks, episodes of incontinence had returned in 50% (300 U) and 0% (500 U) (P = 0.013). Patients were better or much better (PGI-I) in70% (300 U) and 88.9% (500 U) at 12 w; and 50% (300 U) and 100% (500 U), at 24 w (P = 0.027). The peak of PVR was at 4 w, being 71.7 mL (300 U) and 96.5 mL (500 U). General UTI incidence was 35.7%. One patient (500 U) required CIC for 2 weeks. CONCLUSIONS: Intravesical ABO injection at 500 U improves symptoms and quality of life for longer period of time than 300 U for idiopathic OAB. PMID- 30525227 TI - Bone marrow-derived mesenchymal stem cells attenuate tubulointerstitial injury through multiple mechanisms in UUO model. AB - Current evidence supports the use of bone marrow-derived mesenchymal stem cells (MSCs) for a diverse range of clinical applications, and many studies have shown that MSCs have renal-protective effects, but the mechanism is not well understood. Therefore, in this study, we aim to further identify whether MSCs can attenuate renal fibrosis by decreasing tubulointerstitial injury in a unilateral ureteral obstruction (UUO) model. In this study, we cultured MSCs and then transplanted them into a UUO model through the tail vein. Histology, cell proliferation, peritubular capillary (PTC) loss and myofibroblast markers were examined on days 3, 7 and 14 after surgery. We demonstrated that renal interstitial fibrosis in the MSC group was significantly attenuated compared with the UUO and DMEM groups. Moreover, MSC treatment inhibited the loss of PTCs and increased parenchymal cell proliferation. In addition, UUO-induced activation and proliferation of myofibroblasts were suppressed by MSC infusion. Furthermore, MSCs attenuated tubulointerstitial infiltration of macrophages in UUO mice. Tubulointerstitial damage plays a very important role in the progression of chronic kidney disease (CKD). PTC loss, macrophage recruitment, and myofibroblast activation are directly correlated with the development of renal tubulointerstitial fibrosis. Our results suggest that MSC infusion in the UUO model is a promising therapeutic strategy for promoting kidney repair. PMID- 30525228 TI - Induction of Maxillary and Mandibular Squamous Epithelial Cell Proliferation in Mink (Neovison vison) by beta-Naphthoflavone. AB - A jaw lesion reported in mink exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and TCDD-like chemicals has been considered a potential indicator of exposure to these chemicals. TCDD-like chemicals induce many of their effects through interaction with the aryl hydrocarbon receptor. The present report indicates that mink dosed with beta-naphthoflavone, which is an aryl hydrocarbon receptor ligand but not a TCDD-like chemical, also develop the lesion. This article is protected by copyright. All rights reserved. PMID- 30525229 TI - Understanding contact patterns of protein structures from protein contact map and investigation of unique patterns in the globin-like folded domains. AB - Proteins are biochemical compounds made up of one or more polypeptides in a specific order, typically folded into a functionally active form. Proteins are categorized into four different structural classes according to the topology of alpha-helices and beta-strands. In this study, we modeled these four structural classes as an undirected network depicting amino acids as nodes and interaction between them as edges. Results infer that basic protein classes can be easily recognized as well as distinguished by utilizing protein contact maps (PCM). Toward studying the globin-like fold, the helix-loop-helix region contacts were seen to be of a unique pattern, and these remained in all the folds. Further, the averaged diagonal contacts were analyzed and identified those contacts in alpha/beta proteins were higher in comparison with the other class. Interesting, we noticed that anti-parallel beta sheets were dominant in all-beta and alpha + beta classes that lead to similar diagonal patterns. Network properties of all four basic classes were analyzed and found to possess small-world property. Findings infer that PCM may assist classify protein structure classes and it also helps in evaluating the predicted protein structures. PMID- 30525231 TI - Molecular mechanism of miR-153 inhibiting migration, invasion and epithelial mesenchymal transition of breast cancer by regulating transforming growth factor beta (TGF-beta) signaling pathway. AB - OBJECTIVE: To investigate the role and mechanism of action of miR-153 in the migration, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells. METHODS: Quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-153 and transforming growth factor beta receptor 2 (TGFBR2) in tissue specimens and cells. miR-153 overexpression in breast cancer cells was achieved by miR-153 mimic transfection. Mobility and invasiveness of breast cancer cells were evaluated by transwell assay. EMT was evaluated by Western blot detecting the protein level of E-cadherin and Vimentin. Interaction of miR-153 and 3'-untranslated region (UTR) of TGFBR2 messenger RNA (mRNA) was investigated by luciferase reporter assay. RESULTS: The expression of miR-153 in breast cancer tissue specimens and MDA-MB-231 cells was significantly lower than that in nonmalignant counterparts, inversely correlating with that of TGFBR2 mRNA. Transfection with miR-153 mimic significantly increased miR-153 level in MDA-MB-231 cells while inhibiting its migration, invasion, and EMT in vitro, which could be mimicked by TGFBR2 knockdown. Luciferase reporter assay confirmed two targets of miR-153 on the 3'-UTR of TGFBR2 mRNA. Restoring TGFBR2 protein level by transient overexpression largely rescued migration, invasion, and EMT of MDA-MB-231 cells that were repressed by miR-153 mimic transfection. CONCLUSION: miR-153 inhibits breast cancer cell migration, invasion, and EMT by targeting TGFBR2. PMID- 30525230 TI - 4-Deoxyraputindole C induces cell death and cell cycle arrest in tumor cell lines. AB - Several molecules extracted from natural products exhibit different biological activities, such as ion channel modulation, activation of signaling pathways, and anti-inflammatory or antitumor activity. In this study, we tested the antitumor ability of natural compounds extracted from the Raputia praetermissa plant. Among the compounds tested, an alkaloid, here called compound S4 (4-Deoxyraputindole C), showed antitumor effects against human tumor lineages. Compound S4 was the most active against Raji, a lymphoma lineage, promoting cell death with characteristics that including membrane permeabilization, dissipation of the mitochondrial potential, increased superoxide production, and lysosomal membrane permeabilization. The use of cell death inhibitors such as Z-VAD-FMK (caspase inhibitor), necrostatin-1 (receptor-interacting serine/threonine-protein kinase 1 inhibitor), E-64 (cysteine peptidases inhibitor), and N-acetyl- L-cysteine (antioxidant) did not decrease compound S4-dependent cell death. Additionally, we tested the effect of cellular activity on adherent human tumor cells. The highest reduction of cellular activity was observed in A549 cells, a lung carcinoma lineage. In this lineage, the effect on the reduction of the cellular activity was due to cell cycle arrest, without plasma membrane permeabilization, loss of the mitochondrial potential or lysosomal membrane permeabilization. Compound S4 was able to inhibit cathepsin B and L by a nonlinear competitive (negative co operativity) and simple-linear competitive inhibitions, respectively. The potency of inhibition was higher against cathepsin L. Compound S4 promoted cell cycle arrest at G 0 and G 2 phase, and increase the expression of p16 and p21 proteins. In conclusion, compound S4 is an interesting molecule against cancer, promoting cell death in the human lymphoma lineage Raji and cell cycle arrest in the human lung carcinoma lineage A549. PMID- 30525232 TI - TEE-guided transatrial inferior vena cava and hepatic veins thrombectomy during double lung transplantation in a VV ECMO-supported patient. PMID- 30525234 TI - Left main coronary artery aneurysm with a fistula draining into the right atrium. PMID- 30525233 TI - Medical aromatherapy revisited-Basic mechanisms, critique, and a new development. AB - OBJECTIVE: According to a series of recent meta-analyses and systematic reviews, aromatherapy has shown to be effective in treating patients with different medical conditions. However, many of the clinical studies are of rather low methodological quality. Moreover, there is much conceptual ambiguity with regard to what aromatherapy actually constitutes. METHOD: In this paper, we discuss the conditions under which aromatherapy is most likely to be of medical value by outlining the workings of the olfactory system and the necessary requirements of odors to be therapeutic. We then introduce an aromatherapeutic inhaler that was tested in a series of studies involving 465 participants. RESULTS: This inhaler (AromaStick(r)) produced large to very large effects across a variety of physiological target systems (e.g., cardiovascular, endocrine, blood oxygenation, and pain), both short term and long term. DISCUSSION: Inhalation of volatile compounds from essential oils yields almost immediate, large, and clinically relevant effects as long as the scents are delivered highly concentrated from an appropriate device. The changes caused in the body seem side effect-free and can be sustained when inhalation is repeated. PMID- 30525235 TI - Low-dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials. AB - BACKGROUND: The aim of this study was to provide an integrated analysis of safety and efficacy data for brimonidine tartrate ophthalmic solution 0.025 per cent (low-dose; Bausch & Lomb Incorporated), a topical vasoconstrictor for relief of ocular redness. METHODS: Integrated efficacy data from two randomised, double masked, vehicle-controlled studies in subjects with ocular redness as well as safety data from the two efficacy studies, a vehicle-controlled safety study, and a pharmacokinetic study were analysed. Efficacy outcomes analysed included investigator-assessed ocular redness (scale, 0-4) before treatment instillation and at five to 240 minutes post-instillation on Day 1, at five minutes post instillation on Days 15 and 29, and one week after treatment discontinuation (Day 36), and redness self-assessed by subjects recorded daily in diaries. Safety assessments included adverse events, ophthalmic examinations, and rebound redness upon treatment discontinuation. Drop comfort (scale, 0-10) was a tolerability measure. RESULTS: The efficacy population included 117 subjects (brimonidine, n = 78; vehicle, n = 39). The safety population included 635 subjects (brimonidine, n = 426; vehicle, n = 209). Investigator-assessed ocular redness was significantly lower with brimonidine versus vehicle at all post-instillation time points on Day 1 (mean change from pre-instillation of -1.4 units for brimonidine and -0.2 units for vehicle; p < 0.0001). Subject-assessed ocular redness was also significantly lower with brimonidine versus vehicle (mean treatment difference in average daily ratings of -0.9; p < 0.0001). There was no evidence of tachyphylaxis through Day 29 and rebound redness was rare. Incidence of ocular adverse events was low, the most common being reduced visual acuity (brimonidine, 4.0 per cent; vehicle, 4.3 per cent) and conjunctival hyperaemia (2.6 and 2.9 per cent, respectively). Both brimonidine and vehicle were rated as very comfortable (mean post-instillation scores, 0.4-0.5). CONCLUSION: In this integrated analysis, low-dose brimonidine significantly reduced ocular redness with no tachyphylaxis, and minimal rebound redness, and was generally safe and well tolerated. PMID- 30525236 TI - Identification of core genes and outcomes in hepatocellular carcinoma by bioinformatics analysis. AB - Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. However, the mechanistic relationships among various genes and signaling pathways are still largely unclear. In this study, we aimed to elucidate potential core candidate genes and pathways in HCC. The expression profiles GSE14520, GSE25097, GSE29721, and GSE62232, which cover 606 tumor and 550 nontumour samples, were downloaded from the Gene Expression Omnibus (GEO) database. Furthermore, HCC RNA-seq datasets were also downloaded from the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were filtered using R software, and we performed gene ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analysis using the online databases DAVID 6.8 and KOBAS 3.0. Furthermore, the protein-protein interaction (PPI) network complex of these DEGs was constructed by Cytoscape software, the molecular complex detection (MCODE) plug-in and the online database STRING. First, a total of 173 DEGs (41 upregulated and 132 downregulated) were identified that were aberrantly expressed in both the GEO and TCGA datasets. Second, GO analysis revealed that most of the DEGs were significantly enriched in extracellular exosomes, cytosol, extracellular region, and extracellular space. Signaling pathway analysis indicated that the DEGs had common pathways in metabolism-related pathways, cell cycle, and biological oxidations. Third, 146 nodes were identified from the DEG PPI network complex, and two important modules with a high degree were detected using the MCODE plug-in. In addition, 10 core genes were identified, TOP2A, NDC80, FOXM1, HMMR, KNTC1, PTTG1, FEN1, RFC4, SMC4, and PRC1. Finally, Kaplan-Meier analysis of overall survival and correlation analysis were applied to these genes. The abovementioned findings indicate that the identified core genes and pathways in this bioinformatics analysis could significantly enrich our understanding of the development and recurrence of HCC; furthermore, these candidate genes and pathways could be therapeutic targets for HCC treatment. PMID- 30525237 TI - Transesophageal echocardiography induced esophageal ulceration. PMID- 30525239 TI - Abstracts. PMID- 30525238 TI - Double-patch repair of left ventricular outflow tract pseudoaneurysm after aortic valve replacement. PMID- 30525240 TI - Is chronic use of hydroxyurea safe for patients with sickle cell anemia? An account of genotoxicity and mutagenicity. AB - Sickle cell anemia (SCA) is a hereditary hematological disease that is characterized by a point mutation in the beta globin S gene and has no specific treatment; hydroxyurea (HU) is the only therapeutic agent used in clinical practice. In the present study, we evaluated the deoxyribonucleic acid (DNA) damage index (DI) and chromosomal damage in leukocytes of adult patients with SCA with and without HU. The DI was assessed by the comet assay and chromosomal damage by the leukocyte micronucleus test of adult patients treated with HU (SCA HU) and without the use of HU (SCA-NoHU). This is a cross-sectional study with 77 patients with SCA who attended a referral hospital in Fortaleza, Brazil. The control group (CG) consisted of 58 reportedly healthy individuals. The comparisons of means were performed by analysis of variance and Tukey's post test. Values of P < 0.05 were considered statistically significant. SCA-NoHU patients had statistically higher DI values and a statistically significantly higher frequency of micronuclei compared to the CG. In addition, HU treatment accentuated DNA lesions by significantly increasing both parameters in treated patients (SCA-HU). HU potentiates DNA damage and the occurrence of chromosomal damage, which may promote genomic instability, mutation occurrence, and carcinogenesis. Studies are needed to evaluate the involved pathways, repair mechanisms, and the clinical impact that such damage can cause. Environ. Mol. Mutagen. 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30525241 TI - Association between polymorphisms of VKORC1 and CYP2C9 genes with warfarin maintenance dose in a group of warfarin users in Birjand city, Iran. AB - Warfarin is the cardinal anticoagulant drug prescribed around the world. Due to stochastic bleeding in patients, it is essential to adjust the dose for every individual. The aim of the present study was to evaluate the frequency of CYP2C9 and VKORC1 gene polymorphisms and their association with warfarin maintenance dose in a sample of cardiovascular patients in Birjand, South-Khorasan province of Iran. Patients with a history of cardiovascular disorders who take warfarin daily were selected. CYP2C9 and VKORC1 gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism in all participants. A total of 114 patients (mean age: 52.7 +/- 14.9 years, M/F ratio: 0.76) participated in this study. Regarding CYP2C9 gene polymorphisms, the most frequent genotype was 1*/1* (80.4% in females and 62.5% in males). The frequency of 1*/2* and 2*/2* variants was 13% and 6.5% in females and 25% and 12.5% in males, respectively. The frequency of VKORC1 gene (1639 G > A), was 31.5%, 39.5%, and 29% for GG, GA, and AA in males, respectively. Besides, the mentioned genotype frequencies for females were 50%, 40.5%, and 9.5%, respectively. Moreover, there was a statistically significant correlation between VKORC1 gene 1639 G > A variant and warfarin maintenance dose (P < 0.001) but not for CYP2C9 variants. The results of the current study confirmed that the mutant variants of CYP2C9 are not frequent and do not have any impact on warfarin dose. In the case of VKORC1, the mutant allele (A) showed a positive correlation with warfarin dose adjustment. PMID- 30525242 TI - Lack of Association between IL-6 Polymorphisms and Haplotypes with Gastric Cancer. AB - The process of combating neoplasms and mononuclear cells, and during H. pylori infection, several pro-inflammatory and anti-inflammatory cytokines are synthesized. In view of the involvement of the IL-6 law and the presence of H. pylori in the development of gastric diseases, the present study aimed to characterize the promoter-region polymorphism -597 (G/A) (rs1800797), -572 (C/G) (rs1800796), and -174 (G/C) (rs1800795) by PCR-RFLP in 375 gastric biopsy specimens from patients with peptic symptoms. A total of 375 samples were analyzed: 87 patients (without lesion without gastric tissue); 236 patients with gastritis and 52 patients with gastric cancer analyzed the PCR-RFLP techniques. All the results were normalized in relation to the presence of H. pylori. The frequencies of the three polymorphisms were compared in the Control vs Gastritis groups and a statistically significant test observed: -174 (G/C) (OR: 1.27; 95% CI: 0.84-1.93; P = 0.26), 572 (C/G) (OR: 1.42; 95% CI: 0.78-2.59; P = 0.25), and 597 (G/A) (OR: 0.98; 95% CI, 0.64-1.52; P = 0.94). Similar results were obtained when the gastric cancer group was compared to the control group: -174 (G/C) (OR: 1.27; 95% CI: 0.66-2.47; P = 0.47), -572 (C/G) (OR: 1.07; 95% CI: 0.43-2.68; P = 0.88), and -597 (G/A) (OR: 1.01; 95% CI, 0.5-0.9; P = 0.99). The haplotypes were and were not observed statistically significant differences. In conclusion, we found no correlations between any of the three polymorphisms in the IL-6 gene analyzed in this study and a higher risk of gastritis or gastric cancer. PMID- 30525243 TI - CREB/Wnt10b mediates the effect of COX-2 on promoting BMP9-induced osteogenic differentiation via reducing adipogenic differentiation in mesenchymal stem cells. AB - Bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic factors, which may be a potential candidate for bone tissue engineering. However, the osteogenic capacity of BMP9 still need to be further enhanced. In this study, we determined the effect of Wnt10b on BMP9-induced osteogenic differentiation in mesenchymal stem cell (MSCs) and the possible mechanism underlying this process. We introduced the polymerase chain reaction (PCR), Western blot analysis, histochemical stain, ectopic bone formation, and microcomputed tomography analysis to evaluate the effect of Wnt10b on BMP9-induced osteogenic differentiation. Meanwhile, PCR, Western blot analysis, chromatin immunoprecipitation, and immunoprecipitation were used to analyze the possible relationship between BMP9 and Wnt10b. We found that BMP9 upregulates Wnt10b in C3H10T1/2 cells. Wnt10b increases the osteogenic markers and bone formation induced by BMP9 in C3H10T1/2 cells, and silencing Wnt10b decreases these effects of BMP9. Meanwhile, Wnt10b enhances the level of phosphorylated Smad1/5/8 (p Smad1/5/8) induced by BMP9, which can be reduced by silencing Wnt10b. On the contrary, Wnt10b inhibits adipogenic markers induced by BMP9, which can be decreased by silencing Wnt10b. Further analysis indicated that BMP9 upregulates cyclooxygenase-2 (COX-2) and phosphorylation of cAMP-responsive element binding (p-CREB) simultaneously. COX-2 potentiates the effect of BMP9 on increasing p CREB and Wnt10b, while silencing COX-2 decreases these effects. p-CREB interacts with p-Smad1/5/8 to bind the promoter of Wnt10b in C3H10T1/2 cells. Our findings suggested that Wnt10b can promote BMP9-induced osteogenic differentiation in MSCs, which may be mediated through enhancing BMP/Smad signal and reducing adipogenic differentiation; BMP9 may upregulate Wnt10b via the COX-2/p-CREB dependent manner. PMID- 30525244 TI - Esculentoside H inhibits colon cancer cell migration and growth through suppression of MMP-9 gene expression via NF-kB signaling pathway. AB - A water-soluble saponin, Esculentoside H (EsH), 3-O-(O-beta-d-glucopyranosyl-(1 >4)-beta-d-xylopyranosyl)-28-beta-d-glucopyranosylphytolaccagenin has been isolated and purified from the root extract of perennial plant Phytolacca esculenta. EsH is known to be an anticancer compound, having a capacity for TNF alpha release. However, the effects of EsH on migration and growth in tumor cells have not yet been reported. In the current study, the suppressive effects of EsH on phorbol 12-myristate 13-acetate (PMA)-induced cell migration were examined in murine colon cancer CT26 cells and human colon cancer HCT116 cells. Interestingly, the transwell assay and wound healing show that EsH suppresses the PMA-induced migration and growth potential of HCT116 and CT26 colon cancer cells, respectively. EsH dose-dependently suppressed matrix metalloproteinases-9 (MMP-9) expression that was upregulated upon PMA treatment in messenger RNA levels and protein secretion. Since the expression of MMP-9 is correlated with nuclear factor-kappaB (NF-kappaB) signaling, it has been examined whether EsH inhibits PMA-induced IkappaB phosphorylation that leads to the suppression of NK-kappaB nuclear translocation. EsH repressed the phosphorylation level of JNK, but not extracellular signal-regulated kinase and p38 signaling when the cells were treated with PMA. Overall, these results demonstrated that EsH could suppress cancer migration through blockage of the JNK1/2 and NF-kappaB signaling-mediated MMP-9 expression. PMID- 30525245 TI - Construction and analysis of dysregulated lncRNA-associated ceRNA network in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most frequently diagnosed digestive system cancer. The aim of the present study was to investigate the interactions among messenger RNAs (mRNAs), microRNAs (miRNAs), and long noncoding RNAs (lncRNAs) in CRC to reveal the mechanisms of CRC. Differentially expressed genes (DEGs) were identified from public gene expression data sets. One thousand eighty-one common dysregulated mRNAs in two data sets were identified. Gene function analysis and protein-protein interaction network analysis indicated that these DEGs might play important roles in CRC. LINC00365 was selected through coding- noncoding network analysis and its expression was validated upregulated in 22 paired clinical samples and four CRC cell lines. A competing endogenous RNA network composed of 70 miRNAs, nine mRNAs, and LINC00365 was constructed. Eight of nine mRNAs were validated upregulated in The Cancer Genome Atlas data set. Our results suggested that LINC00365 was an oncogene in CRC and it could regulate the expression of several mRNAs through sponging miRNAs. PMID- 30525246 TI - Autologous rectus fascia sling for treatment of stress urinary incontinence in women: A review of the literature. AB - AIMS: Stress urinary incontinence (SUI) is common in the adult females. Surgical treatment options include synthetic mid-urethral sling (MUS), autologous sling, bulking agents, and Burch colposuspension. The autologous pubovaginal sling (PVS) has re-emerged in response to complications of synthetic MUSs and FDA communications regarding the use of vaginal mesh. This resulted in patients' fear related to vaginal mesh and drop in number of patients seeking surgical treatment of SUI. PVS has re-emerged as an option for treatment of primary SUI. The aim of this review is to familiarize, disseminate information, and share tips for the practicing female pelvic surgeons related to the practice of the autologous fascia sling. METHODS: We reviewed the literature related to the autologous sling. We used the following data bases and search engines: GoPubMed (Transinsight), Cochrane reviews (Wiley Interscience), google scholar (google), and Scopus (Elsevier). Because it is the most commonly investigated and utilized, we focused on the autologous rectus fascia sling. We also focused on the retropubic sling approach because the literature on transobturator rectus fascia sling is sparse. RESULTS: Out of 307 articles related to the subject found, 22 articles were included and the rest were excluded. CONCLUSION: ARFS is a valid primary method of treatment for female SUI. Also, it is used in particular indications such as patients with intrinsic sphincter deficiency (ISD), prior pelvic irradiation, failed and/or complicated synthetic MUS, and violated urethral lumen. PMID- 30525247 TI - Early structural valve deterioration and reoperation associated with the mitroflow aortic valve. AB - BACKGROUND: Structural valve deterioration (SVD) is a known limitation of bioprosthetic valves. Recent reports have suggested a concerning rate of early SVD in patients receiving a Mitroflow aortic bioprosthesis. We therefore compared the incidence of SVD and SVD requiring reoperation among patients receiving a Mitroflow versus a common contemporary bioprosthesis. METHODS: A retrospective cohort analysis was performed on 592 patients receiving a Mitroflow aortic bioprosthesis at our institution between 2010 and 2014. Patients were matched 1:1 using a coarsened exact matching algorithm with patients receiving a Carpentier Edwards Magna Ease aortic bioprosthesis (Edwards Lifesciences, Irvine, CA) during the same period. The incidence of SVD (defined as a mean transprosthetic gradient >=30 mmHg or moderate to severe intraprosthetic regurgitation), reoperation for SVD, and cumulative survival were compared between prosthesis types. RESULTS: The cumulative incidence of SVD at 5 years for all patients receiving a Mitroflow aortic bioprosthesis was 16% (13-21%) and 5% underwent reoperation for SVD. Implantation of a Mitroflow valve was associated with an increased risk of SVD compared to the comparator valve (hazard ratio [HR] 2.59 [1.69-3.98], P < 0.01). Older age had a protective effect against SVD (HR 0.95 [0.93-0.96], P < 0.01). Patients who received a Mitroflow valve had reduced long-term survival compared to those who received a comparator valve (P = 0.03). CONCLUSION: The Mitroflow aortic bioprosthesis is associated with increased rates of early SVD and reoperation for valvular dysfunction as well as reduced survival compared to a contemporary valve. Enhanced clinical and echocardiographic follow-up is advisable after Mitroflow implantation. PMID- 30525248 TI - Ghrelin's effects on food motivation in rats are not limited to palatable foods. AB - The "hunger" hormone, ghrelin, is powerfully orexigenic. Even in the absence of hunger, ghrelin delivery to rats increases consumption of chow as well as palatable foods and increases motivated behaviour for palatable food rewards. Inspired by the finding that ghrelin increases the selection of chow in rats offered a choice diet (lard, sucrose or chow) and even in rats bingeing on a high fat diet, we sought to explore whether ghrelin's effects on motivation extend to regular chow. Rats were conditioned to lever press for either chow or sucrose pellets in a progressive ratio (PR) operant conditioning task. The effect of acute intracerebroventricular delivery of ghrelin on both chow and sucrose self administration was determined and compared to overnight fasting (when endogenous ghrelin levels are elevated). We found that ghrelin similarly increased motivated behaviour for chow and sucrose pellets. The effect of fasting on motivated behaviour for both food pellets was comparable in magnitude to that induced by ghrelin, albeit with an earlier ceiling effect during the PR session. Devaluation experiments (in which rats are offered either food reinforcer in excess prior to PR testing) did not support the hypothesis that sucrose pellets would be more difficult to devalue (due to their higher incentive value) than chow pellets. When exchanging the rats' respective pellets during a PR session, chow conditioned rats were more motivated for sucrose pellets than for chow pellets; however, sucrose-conditioned rats were similarly motivated for chow pellets as for sucrose pellets. Thus, using sucrose as a reward may increase the motivation even for less palatable foods. We conclude that the impact of ghrelin on food motivated behaviour in fed rats is not limited to palatable foods but extends to regular chow and also that the magnitude of the effect is considerable when compared to that of an overnight fast. This article is protected by copyright. All rights reserved. PMID- 30525249 TI - Acetylation drives hepatocyte nuclear factor 1beta stability by blocking proteasome-mediated degradation. AB - Hepatocyte nuclear factor 1beta (HNF1beta) is mostly expressed in the liver, but is also expressed in other organs, like kidney, pancreas and genitourinary tract. In fact, HNF1beta, a member of the superfamily of homeodomain-containing transcription factors, has been described as a hallmark in clear cell carcinomas. However, its role as an oncogene or as tumor suppressor gene remains controversial. Here, we disclose a mechanism of HNF1beta stabilization and degradation, using human HNF1beta-expressing cell lines of ovarian clear cell carcinoma (ES2), hepatocellular carcinoma (HEPG2), and normal immortalized kidney tubular cells (HK2). We show that increased levels of HNF1beta is concomitant with an increase in the acetylation load and protein stabilization by interfering with the ubiquitin-proteasome degradation system. This study reinforces that acetylation, besides their role in regulating chromatin conformation and gene expression, could also act in the action, turnover and stability of proteins essential for the survival and progression of certain cancer types. PMID- 30525250 TI - Retrospective study on detection, treatment and clinical outcome of graft thrombosis following pancreas transplantation. AB - INTRODUCTION: Complete graft thrombosis is the leading cause of early graft loss following pancreas transplantation. Partial thrombosis is usually subclinical and discovered on routine imaging. Treatment options may vary in such cases. We describe the incidence and relevance of partial graft thrombosis in a large transplant center. METHODS: All consecutive pancreas transplantation at our center (2004-2015) were included in this study. Radiological follow-up, type and quantity of thrombosis prophylaxis, complications and graft and patient survival were collected. Partial thrombosis and follow-up were also studied. RESULTS: All 230 pancreas transplantations were included in the analysis. Computed tomography was performed in most cases (89.1%). Early graft failure occurred in 23 patients (13/23 due to graft thrombosis, 3/23 bleeding, 1/23 anastomotic leakage, 6/23 secondary to antibody mediated rejection). There was evidence of partial thrombosis in 59 cases (26%), of which the majority was treated with heparin and a vitamin K antagonist with graft preservation in 57/59 patients (97%). CONCLUSION: Thrombosis is the leading cause of early graft loss following pancreas transplantation. Computed tomography allows for early detection of partial thrombosis, which is usually subclinical. Partial graft thrombosis occurs in about 25% of all cases. In this series, treatment with anticoagulant therapy (heparin and vitamin K antagonist) resulted in graft preservation in almost all cases. This article is protected by copyright. All rights reserved. PMID- 30525251 TI - Response to Ghinolfi et al. AB - The authors welcome the discourse presented by Ghinolfi et al. [1] and appreciate the opportunity to respond to their comments on the manuscript "Association between donor age and risk of graft failure after liver transplantation: an analysis of the Eurotransplant database" [2]. The aim of our study was to estimate the effect of donor age on the risk of graft failure in liver transplantation. This article is protected by copyright. All rights reserved. PMID- 30525252 TI - Rhodotorula infection in haematological patient: risk factors and outcome. AB - BACKGROUND: Rhodotorula spp are uncommon yeasts able to cause infections with high mortality rates. Rhodotorula infections have been associated with the presence of central venous catheter (CVC), immunosuppression, exposure to antifungals and the presence of either solid or hematologic malignancies. However, in this latter setting, only a few cases have so far been reported. OBJECTIVES: We have conducted a survey for Rhodotorula infections in hematologic patients. METHODS: Patients' clinical and microbiological data were collected and correlated to the outcome. RESULTS: 27 cases were detected from 13 tertiary care hospitals. 78% and 89% of patients had acute leukemia and a CVC. 70% of patients were exposed to prophylaxis with azoles, mainly posaconazole (37%), 59% were severely neutropenic and 37% underwent allogeneic stem cell transplantation (alloSCT). The most frequent treatments were liposomal amphotericin B (L-AmB) and CVC removal in 17 and 16 patients, respectively. One month post-diagnosis mortality was 26% and was associated with the presence of mucositis (p = 0.034). CONCLUSIONS: Our study shows that Rhodotorula spp should be considered as aetiologic agents of breaktrough infections in acute leukemia patients with a CVC, mucositis, who receive prophylaxis with azoles, including posaconazole, and/or undergo alloSCT. Prompt measures, such as L-AmB administration and CVC removal, should be carried out to avoid the high mortality risk of Rhodotorula infections. This article is protected by copyright. All rights reserved. PMID- 30525253 TI - The Effect of Gastric Electrical Stimulation on Small Bowel Motility in Patients With Gastroparesis and Concomitant Pancreatic and Small Bowel Dysfunction: From Animal Model to Human Application. AB - BACKGROUND/AIMS: Patients with gastroparesis often have biliary/pancreatic and small bowel symptoms but the effects of gastric electrical stimulation on small bowel electrical activity of the mid-gut have not been studied. Animal model aim: Establish gastric and upper small bowel/biliary slow wave activity relationships with electrical stimulation. Human study aim: Demonstrate improvement in symptoms associated with proximal small bowel dysmotility in gastric stimulated patients. MATERIALS AND METHODS: Animal model: In vivo evoked responses of duodenal and Sphincter of Oddi measures recorded during gastric electrical stimulation in a nonsurvival swine model (N = 3). High-resolution electrical slow wave mapping of frequency, amplitude, and their ratio, for duodenal and Sphincter of Oddi electrical activity were recorded. Human study: Patients (N = 8) underwent temporary gastric stimulation with small bowel electrodes. Subjective and objective data was collected before and after temporary gastric stimulation. Symptom scores, gastric emptying times, and mucosal electrograms via low resolution mapping were recorded. RESULTS: Animal gastric stimulation resulted in some changes in electrical activity parameters, especially with the highest energies delivered but the changes were not statistically significant. Human study revealed improvement in symptom and illness severity scores, and changes in small bowel mucosal slow wave activity. CONCLUSIONS: Gastric electrical stimulation in an animal model seems to show nonsignificant effects small bowel slow wave activity and myoelectric signaling, suggesting the existence of intrinsic neural connections. Human data shows more significance, with possible potential for therapeutic use of electrical stimulation in patients with gastroparesis and pancreato-biliary and small bowel symptoms of the mid-gut. This study was limited by the nonsurvival pig model, small sample size, and open label human study. PMID- 30525254 TI - Gene expression is more strongly associated with behavioural specialisation than with age or fertility in ant workers. AB - The ecological success of social insects is based on division of labour, not only between queens and workers, but also among workers. Whether a worker tends the brood or forages is influenced by age, fertility and nutritional status, with brood carers being younger, more fecund and more corpulent. Here, we experimentally disentangle behavioural specialisation from age and fertility in Temnothorax longispinosus ant workers and analyse how these parameters are linked to whole-body gene expression. A total of 3644 genes were associated with behavioural specialisation which is ten times more than associated with age and 50 times more than associated with fertility. Brood carers were characterized by an upregulation of three Vitellogenin (Vg) genes, one of which, Vg-like A, was the most differentially expressed gene that was recently shown experimentally to control the switch from brood- to worker-care. The expression of Conventional Vg was unlinked to behavioural specialisation, age or fertility, which contrasts to studies on bees and some ants. Diversity in Vg/Vg-like copy number and expression bias across ants supports subfunctionalisation of Vitellogenin genes and indicates that some regulatory mechanisms of division of labour diverged in different ant lineages. Simulations revealed that our experimental dissociation of co-varying factors reduced transcriptomic noise, suggesting that confounding factors could potentially explain inconsistencies across transcriptomic studies of behavioural specialisation in ants. Thus, our study reveals that worker gene expression is mainly linked to the worker's function for the colony and provides novel insights into the evolution of sociality in ants. This article is protected by copyright. All rights reserved. PMID- 30525255 TI - Genomic instability in fragile sites - still adding the pieces. AB - Common fragile sites (CFSs) are specific genomic regions in normal chromosomes that exhibit genomic instability under DNA replication stress. Since replication stress is an early feature of cancer development, CFSs are involved in the signature of genomic instability found in malignant tumors. The landscape of CFSs is tissue-specific and differs under different replication stress inducers. Nevertheless, the features underlying CFS sensitivity to replication stress are shared. Here we review the events generating replication stress and discuss the unique characteristics of CFS regions and the cellular responses aimed to stabilizing these regions. This article is protected by copyright. All rights reserved. PMID- 30525256 TI - The prevalence of sleep apnoea in non-dialysis chronic kidney disease patients: a systematic review and meta-analysis. AB - BACKGROUND: The prevalence of sleep apnoea (SA) in chronic kidney disease (CKD) varies greatly across preceding studies. The aim of our study was to provide a summary of the prevalence of SA among non-dialysis CKD patients. METHOD: Medline, Embase, Web of Science, China Knowledge Resource Integrated Database (CNKI), VIP Chinese scientific journal database (VIP) and Wanfang Digital Periodical Full text database were searched up to September 2018 to identify publications related to the prevalence of SA in non-dialysis CKD patients assessed by sleep questionnaires or sleep respiration monitoring. Random-effects meta-analysis was used to estimate pooled prevalence of SA. And subgroup analysis and meta regression were conducted as well. RESULTS: The pooled prevalence of SA in the included26 studies was 38% (95%CI, 21%-70%). In subgroup analyses, the pooled prevalence of SA varied using different diagnostic tools. The pooled prevalence of questionnaire-based SA for CKD was10% (95%CI, 3%-27%), while the prevalence of sleep monitoring-based SA was 56% (95%CI, 49%-66%). Also, advanced CKD patients had a greater chance to suffer from moderate-to-severe SA than early stage CKD patients. Male patients were more likely to be affected by moderate-to-severe SA than female patients (47% versus 30%, P=0.018). CONCLUSION: SA is commonly seen in both early and advanced non-dialysis CKD patients. Sleep related scales provided lower prevalence than instrumental sleep monitoring, therefore, underestimated the presence of SA. The prevalence of SA increases in advanced CKD. And male patients are more likely to be affected by SA than female patients. This article is protected by copyright. All rights reserved. PMID- 30525257 TI - Capping N-Donor Ligands Modulate the Magnetic Dynamics of beta-Diketonate-DyIII Single-Ion Magnets with D4d Symmetry. AB - A family of four mononuclear beta-diketonate-DyIII complexes, with formulas Dy(tmhd)3(Br2-bpy) (1), Dy(tmhd)3(Br-bpy) (2), Dy(tmhd)3(dppz) (3) and Dy(tmhd)3(mcdpq) (4) (tmhd = 2,2,6,6-tetramethyl-3,5-heptanedione, Br2-bpy = 5,5' dibromo-2,2'-bipyridine, Br-bpy = 5-bromo-2,2'-bipyridine, dppz = dipyrido [3,2 a:2',3'-c]phenazine and mcdpq = 2-methoxyl-3-cyano-dipyrido-[3,2-f:2,3'-h] quinoxaline), have been prepared by modifying the capping N-donor coligands. DyIII centers in these complexes feature a N2O6 octa-coordinated environment with a distorted square antiprismatic D4d symmetry. Magnetic investigations evidence a SIM behavior in all complexes with the energy barriers (Ueff) of 42.10 K (1), 61.47 K, (2), 77.53 K (3) and 2.51 K (4) in the absence of static field, as well as 206.03 K (1), 224.13 K (2), 247.76 K (3) and 49.70 K (4) under applied dc fields (Hdc = 1500 Oe for 1 and 2, and 1200 Oe for 3 and 4). The different nature of the N-donor ligand induces changes on both the coordination geometry and their intermolecular interactions, which severely impact on their magnetic dynamics. The disparities in their magnetic behaviors and the uniaxial anisotropies are also explained and substantiated by theoretical calculations. PMID- 30525258 TI - Accelerated partial breast irradiation: Current status with a focus on clinical practice. AB - Accelerated partial breast irradiation (APBI), a radiation technique in which only the tumor bed is treated, has now become an acceptable radiation modality for selected early-stage breast cancer patients. Compared to conventional whole breast irradiation (WBI), APBI has some benefits with regard to the reduced total irradiated breast volume and the shorter treatment time. The role of APBI, which can be delivered using diverse techniques, has been evaluated in several prospective randomized phase III trials. These clinical trials demonstrate diverging outcomes relating to local recurrence, while establishing comparable effect in terms of survival between APBI with WBI. The aim of this study was to review the current status of APBI with a focus on clinical practice. PMID- 30525259 TI - The mechanics of urethral closure, incontinence, and midurethral sling repair Part 3 surgical applications (1990-2016). AB - Part 3 briefly summarizes further development in midurethral sling (MUS) instruments and technique following the 1990 prototype operations, then critically examines the whole MUS surgical methodology, 1990 to present day. The aim is to identify positive and negative aspects of these methodologies which can be usefully applied to improve current MUS surgery. ANIMAL EXPERIMENTS: 1987-1988 proved that a collagenous neoligament could be formed by implantation of a tape. There was a wide variation in tissue reaction to implanted tapes. Inflamamatory tissue reaction was very different from bacterial infection and was safe even when a sinus is formed. MUS METHODOLOGY: The key factor in avoiding major vessel and nerve injuries is to penetrate the perianal membrane with scissors, insert the applicator. Importantly, this reveals any bleeding which could otherwise accumulate in the Space of Retzius and only be controlled by digital pressure. The balance between too tight (retention) and too loose (incontinence) is analyzed in terms of the exponential relationship between urethral diameter and urine flow; why elastic tapes are more likely to cause post-operative urinary retention; how to minimize retention by tightening against an indwelling No18 Foley catheter; the importance of routinely repairing the distal closure mechanism with purse string suture to external ligaments, fascial layer of vagina; why minislings avoid most of the serious MUS complication; why a tensioned minisling allows greater precision when tightening the sling and how anchors and individually knitted tapes give hope that tape erosions may decrease. PMID- 30525260 TI - Modifiable health risk factors, related counselling, and treatment among patients in health centres. AB - Chronic disease burden and its related health risk factors are especially concentrated among the poor. Community health centres reach the nation's most vulnerable population. This study explored the prevalence, racial/ethnic, and gender disparities of five modifiable health risk factors and the receipt of related counselling and treatment among patients in U.S. federally qualified health centres. The 2014 Health Center Patient Survey was used for this study. We performed a cross-sectional study. Measures included tobacco use, excessive alcohol consumption, obese/overweight, high blood pressure, high blood cholesterol, and five related counselling/treatment measures. Logistic regression models were conducted to examine the multivariable-adjusted putative associations of several sociodemographic and health-related factors with modifiable health risk and counselling/treatment measures. Preliminary findings revealed differences in modifiable health risk factors across different racial/ethnic groups, while few racial/ethnic differences existed in related counselling/treatment measures. In the multivariable-adjusted logistic regression models, these differences in health risk factors were still apparent, while associations between race/ethnicity status and counselling/treatment measures were not detected. Gender was also a predictor for four types of health risk measures and two types of counselling/treatment measures. Health centre patients had high rates of modifiable health risk factors. The rates were different across race/ethnicity groups, and the differences found did not always favour non Hispanic Whites. However, the findings reveal equitable access to related counselling/treatment service among patients across race/ethnicity groups. PMID- 30525261 TI - Snap shot view on anaemia in Chronic Kidney Disease of uncertain aetiology. AB - AIM: Anaemia is a well-known complication of Chronic Kidney Disease (CKD) but there are no published studies on the pattern of anaemia in Chronic Kidney Disease of uncertain aetiology (CKDu). This study aims to find out the prevalence, causes and associations of anaemia in CKDu to identify any unique features which are different from already described Anaemia in CKD. METHOD: All (119) biopsy-confirmed CKDu patients in two endemic clinics (Girandurukotte and Wilgamuwa) were selected as cases. Blood samples (10ml) were collected from the peripheral veins into K-EDTA tubes, plain tubes, and Na-citrated tubes. Serum was separated immediately by centrifugation at 3000rpm for 10minutes. Spot urine samples were collected into empty, sterile, polypropylene urine containers. All analyses were performed in IBM SPSS statistics version 23 (IBM Corp, USA). RESULTS: The overall prevalence of anaemia in 119 non-dialysis CKDu patients was 72.3% with the highest prevalence seen in females compared to males (P < 0.001). The prevalence of anaemia in CKDu patients with progression to renal failure was 66.7% -stage1, 60% -stage2, 50% - stage3a, 95% -stage 3b, 79.2% - stage4 and 100% - stage5 (P = 0.005). Of CKDu patients, 44.3% had anaemia of chronic disease with iron deficiency. CKDu patients with anaemia had a high inflammatory score were seen in both early and late stages of CKDu. There were a similar proportion of patients with both early and late CKDu having unexplained anaemia. CONCLUSIONS: The current study showed a significant association of anaemia with disease severity among CKDu patients. Iron deficiency is a crucial aetiology factor of anaemia in CKDu and inflammation likely to effects adversely on anaemia of CKDu. This article is protected by copyright. All rights reserved. PMID- 30525262 TI - Work experiences of Australian cancer survivors with lymphoedema: A qualitative study. AB - Our qualitative study addresses a significant gap in the scholarship on return-to work after cancer by examining the impact of secondary lymphoedema on individuals in paid employment. We undertook an Interpretive Phenomenological Analysis of interviews with 14 cancer survivors (13 women) with secondary lymphoedema in Sydney, Australia. Our interviewees were engaged in paid employment during and after their lymphoedema diagnosis. In addition to difficulties with tasks involving manual or repetitive labour, interviewees highlighted the importance of work for maintaining their identity. They also outlined the critical role that significant others at work, such as supervisors and colleagues, play in maintaining that identity. At the same time, their need for privacy and control over to whom they disclosed their lymphoedema diagnosis emerged strongly from our interviews. Finally, we present the coping mechanisms that our interviewees utilised to manage their lymphoedema in the workplace, including covering the affected limb with long sleeves, changing the tasks they completed, or even changing employers. In addition to our contribution to the scholarship, we highlight implications for employers, future research, and policy makers. PMID- 30525263 TI - Diphenhydramine dependence via Port-A-Cath in a patient with rheumatoid arthritis. AB - Diphenhydramine is a potentially addictive medication. Because the route of administration significantly affects drug delivery to the brain, intramuscular injection of diphenhydramine can trigger more euphoric and rewarding effect, facilitating dependence liability.1 Like narcotics, diphenhydramine is used in a variety of medical conditions, and an underlying disorder may mask the dependence.2 Moreover, diphenhydramine dependence may be overlooked, as it is an over-the-counter medication. This article is protected by copyright. All rights reserved. PMID- 30525265 TI - Primary Graft Dysfunction and Beyond after Lung Transplantation in the Current Era. AB - When encountering early signs of primary graft dysfunction (PGD) at the end of the procedure following lung transplantation in operating rooms, aside from lung protective ventilation strategies, two key players as currently available therapeutic options include inhaled nitric oxide (iNO) and/or extracorporeal membrane oxygenation (ECMO) (1). While iNO plays a unique and relevant therapeutic role in the current clinical lung transplantation, its impact on posttransplant outcomes remains unclear mostly due to a large variety of iNO usage in clinical practice intra-, peri-, and post-operatively among the institutions (2-3). In the December 2018 issue of the Transplant International, Fessler and colleagues (4) from Hospital Foch in France, presented their study to aim to characterize the patients who required prolonged support of iNO following lung transplantation and evaluate the impact of such iNO dependency on posttransplant outcomes in particular with the incidences of severe PGD. Fessler and colleagues nicely demonstrate the strong correlation between iNO dependency and suboptimal short- and long-term outcomes following lung transplantation which will lead to early identification of those high risk patients and moving forward the potential additional treatments in order to improve their subsequent outcomes. This article is protected by copyright. All rights reserved. PMID- 30525264 TI - Phylogeography of a widespread lizard complex reflects patterns of both geographic and ecological isolation. AB - A primary challenge for modern phylogeography is understanding how ecology and geography, both contemporary and historical, shape the spatial distribution and evolutionary histories of species. Phylogeographic patterns are the result of many factors, including geology, climate, habitat, colonization history, and lineage-specific constraints. Assessing the relative influences of these factors is difficult because few species, regions, and environments are sampled in enough detail to compare competing hypotheses rigorously and because a particular phylogeographic pattern can potentially result from different evolutionary scenarios. The silky anoles (Anolis sericeus complex) of Central America and Mexico are abundant and found in all types of lowland terrestrial habitat, offering an excellent opportunity to test the relative influences of the factors affecting diversification. Here, we performed a range-wide statistical phylogeographic analysis on restriction-site associated DNA (RAD) markers from silky anoles and compared the phylogeographic patterns we recovered to historical and contemporary environmental and topographic data. We constructed niche models to compare niche overlap between sister lineages and conducted coalescent simulations to characterize how the major lineages of silky anoles have diverged. Our results revealed that the mode of divergence for major lineage diversification events was geographic isolation, resulting in ecological divergence between lineages, followed by secondary contact. Moreover, comparisons of parapatric sister lineages suggest that ecological niche divergence contributed to isolation by environment in this system, reflecting the natural history differences among populations in divergent environments. This article is protected by copyright. All rights reserved. PMID- 30525266 TI - Monitoring the sleep patterns of people with dementia and their family carers in the community. AB - OBJECTIVES: Gold-standard overnight polysomnography does not reliably capture highly variable sleep patterns across the 24-hour day that are common with dementia and often problematic for carers. We evaluated the reliability of automatically scored actigraphy data as an alternative. METHODS: Actigraphy recordings were analysed from 15 community-dwelling people with dementia (135 days total) and 14 of their family carers (124 days total). Manual scoring used participant sleep diaries to identify sleep periods. Automated scoring used the manufacturer's algorithm to score entire records. RESULTS: For people with dementia, automated scoring identified more sleep fragmentation at night and increased sleep during the day, with comparable sensitivity but lower specificity than for carers. CONCLUSIONS: Automated scoring offers reasonable agreement with manual scoring and may better describe the fragmented nature of dementia-related sleep, which can be challenging to record accurately in a sleep diary. Automated scoring reduces participant burden and could improve research and treatment protocols. PMID- 30525267 TI - Assessing the medical workforces perceived barriers to the prescription of risk reducing medication for women at high-risk of breast cancer. AB - This study aims to determine the attitudes and barriers of Australian oncology health professionals towards using tamoxifen as a breast cancer risk-reducing medication (RRM). Our target group was health professionals involved in breast cancer risk assessment or treatment. Members of relevant medical organizations in Australia and New Zealand were invited to participate in a web-based survey assessing: their attitudes towards tamoxifen as a RRM; which health professionals they felt were responsible for initiating and monitoring women on RRM and their views on workforce issues related to RRM prescription. There were 100 respondents, including 33 genetic health professionals, 32 medical oncologists and 20 surgeons. Respondents perceived tamoxifen to be effective as a RRM (99%). However, only 41% of prescribing health professionals (n = 64) had ever prescribed tamoxifen as a RRM. Overall, survey respondents felt that the initiation of RRM was the role of specialists. Assessing a patient's risk of breast cancer was reported to be the role of cancer geneticists/familial cancer clinicians (74%) and medical oncologists (66%). Discussion about the use of RRM was reported to be the role of these same groups (84% and 85% respectively). Medical oncologists (83%) and breast physicians (70%) were most frequently considered to be responsible for initiating the prescription and monitoring women once commenced on RRM (72% and 71% respectively). Oncology health professionals express confidence in the effectiveness of tamoxifen as a RRM despite reporting low prescription rates. Findings demonstrate that these oncology health professionals felt that initiation of RRM was the role of cancer specialists, despite preventative medicine being seen as a primary care activity. If uptake among at-risk women increases, this will put a significant burden on cancer services and GPs will need to take on a greater role in the delivery of RRM. PMID- 30525268 TI - Role of pyroptosis in cardiovascular disease. AB - Cardiac function is determined by the dynamic equilibrium of various cell types and the extracellular matrix that composes the heart. Cardiovascular diseases (CVDs), especially atherosclerosis and myocardial infarction, are often accompanied by cell death and acute/chronic inflammatory reactions. Caspase dependent pyroptosis is characterized by the activation of pathways leading to the activation of NOD-like receptors, especially the NLRP3 inflammasome and its downstream effector inflammatory factors interleukin (IL)-1beta and IL-18. Many studies in the past decade have investigated the role of pyroptosis in CVDs. The findings of these studies have led to the development of therapeutic approaches based on the regulation of pyroptosis, and some of these approaches are in clinical trials. This review summarizes the molecular mechanisms, regulation and cellular effects of pyroptosis briefly and then discusses the current pyroptosis studies in CVD research. PMID- 30525270 TI - A Water-soluble, NIR-absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy. AB - Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing photothermal agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge in biomedical applications. Herein, we introduce a new photothermal agent based on water-soluble quaterrylenediimide (QDI) that can self assemble into nanoparticles (QDI-NPs) in aqueous solution. Incorporation of polyethylene glycol (PEG) into the QDI core significantly enhances both physiological stability and biocompatibility of QDI-NPs. These highly photostable QDI-NPs exhibit exciting advantages including intense absorption in the near infrared (NIR) and high PTCE of up to 64.7 +/- 4%. This is higher than that of many other organic photothermal agents, such as graphene or commercial indocyanine green (ICG). Their small size of approximately 10 nm enables a sustained retention in deep tumor sites and at the same time proper clearance from the body. QDI-NPs allow high-resolution photoacoustic imaging and efficient 808 nm laser-triggered photothermal therapy of cancer in vivo. The current study opens a promising way for precision phototheranostics. PMID- 30525269 TI - Screening for hepatitis C at the emergency department: should babyboomers also be screened in Belgium? AB - INTRODUCTION: Patients are not screened adequately for hepatitis C virus (HCV) infection in Belgium. In the USA, the CDC recommends screening for patients born in the babyboom period (1945-1965). In Europe, the babyboom cohort was born between 1955-1974, but no screening policy has been targeted to this group. We aimed to study the prevalence of HCV in an emergency department (ED) population in Belgium and the risk factors associated with HCV infection. METHOD: We performed a monocentric, cross-sectional seroprevalence study between January and November 2017 in a large Belgian non-university hospital. Patients aged 18-70 years presenting at the ED were eligible. Patients completed a risk assessment questionnaire and were screened for HCV Ab with reflex HCV RNA testing. RESULTS: Of 2,970 patients, 2,366 (79.7%) agreed to participate. HCV Ab prevalence was 1.31%. Twenty-one (67.7%) HCV Ab positive patients were born between 1955-1974. With a previous treatment uptake of 54.5%, the prevalence of viremia was 0.9% in retrospect; 0.2% were newly diagnosed. The weighted multiple logistic regression model identified males born in the 1955-1974 cohort, intravenous drug use, and high endemic birth country as significant risk factors for HCV infection (p < .05). CONCLUSION: Although the prevalence of HCV Ab at the ED was higher than previously estimated for the general population in Belgium, the number of newly diagnosed patients with viremia was low. To optimize screening strategies, screening should be offered to males born in the 1955-1974 cohort, but especially in drug users, the prison population, and immigrants from high-endemic countries. This article is protected by copyright. All rights reserved. PMID- 30525271 TI - Subsurface Carbon - a General Feature of Noble Metals. AB - Carbon Cn moieties on late transition metals are historically regarded as poisoning agents for their use in heterogeneous catalysis. Recent experimental studies combining ab initio simulations showed the promoting catalytic role of subsurface C atoms in Pd surfaces, plus their existence was well established in Ni and Pt surfaces. Here we show, adjoining energetic and kinetic evidences obtained by accurate density functional simulations on surface and nanoparticle models, that such subsurface C species are a general issue to be considered even in coinage noble metal systems. Subsurface C is the most stable situation in densely packed (111) surfaces of Cu and Ag, with sinking barriers low enough to be overcome at catalytic working temperatures. Low-coordinated sites at nanoparticles edges and corners further stabilize them, even in gold, with negligible subsurface sinking barriers. The malleability of low-coordinated sites appears to be the key aspect in the subsurface C accommodation. The incorporation of C species decreases the electron density of the surrounding metal atoms, thus affecting their chemical and catalytic activity. These results broaden the subsurface C chemistry, so as to be considered a general aspect to be regarded in future studies on heterogeneously catalysed processes by late transition metal systems. PMID- 30525272 TI - User involvement in regulation: A qualitative study of service user involvement in Care Quality Commission inspections of health and social care providers in England. AB - BACKGROUND: High profile failures of care in the NHS have raised concerns about regulatory systems for health-care professionals and organizations. In response, the Care Quality Commission (CQC), the regulator of health and social care in England overhauled its regulatory regime. It moved to inspections which made much greater use of expert knowledge, data and views from a range of stakeholders, including service users. OBJECTIVE: We explore the role of service users and citizens in health and social care regulation, including how CQC involved people in inspecting and rating health and social care providers. DESIGN: We analyse CQC reports and documents, and 61 interviews with CQC staff and representatives of groups of service users and citizens and voluntary sector organizations to explore the place of service user voice in regulatory processes. RESULTS: Care Quality Commission invited comments and facilitated the sharing of existing service user experiences and engaged with representatives of groups of service users and voluntary sector organizations. CQC involved service users in their inspections as "experts by experience." Information from service users informed both the inspection regime and individual inspections, but CQC was less focused on giving feedback to service users who contributed to these activities. DISCUSSION AND CONCLUSIONS: Service users can make an important contribution to regulation by sharing their experiences and having their voices heard, but their involvement was somewhat transactional, and largely on terms set by CQC. There may be scope for CQC to build more enduring relationships with service user groups and to engage them more effectively in the regulatory regime. PMID- 30525273 TI - The impact of apelin and relaxin plasma levels in masked hypertension and white coat hypertension. AB - Masked hypertension (HTN) and white coat hypertension represent two reverse forms of clinical HTN with questionable prognostic significance. Recent evidence supports that low apelin and relaxin plasma levels contribute to vascular damage accelerating atherogenesis and predisposing to HTN and cardiovascular (CV) events. The aim of this study was to compare apelin and relaxin plasma levels between patients with masked hypertension (MH) and those with white coat HTN (WCH). Overall, 130 patients not receiving antihypertensive therapy were studied. All patients underwent 24-hour ambulatory BP monitoring (ABPM) and office BP measurements. Plasma apelin and relaxin levels were measured by ELISA method. According to BP recordings, 24 subjects had MH (group A) and 32 had WCH (group B). Apelin (200 +/- 111 pg/mL vs 305 +/- 127 pg/mL, P < 0.01) and relaxin (35.2 +/- 6.7 pg/mL vs 46.8 +/- 23.6 pg/mL, P < 0.01) plasma levels were significantly lower in patients with MH compared to those with WCH, respectively. In conclusion, our findings showed that patients with MH had significantly lower apelin and relaxin levels compared to those with WCH. This observation implies an additional prognostic role for adipokines supporting the concept that MH is closer to essential HTN whereas WCH is a more benign condition. PMID- 30525274 TI - Cisgenic overexpression of cytosolic glutamine synthetase improves nitrogen utilization efficiency in barley and prevents grain protein decline under elevated CO2. AB - Cytosolic glutamine synthetase (GS1) plays a central role in nitrogen (N) metabolism. The importance of GS1 in N remobilization during reproductive growth has been reported in cereal species but attempts to improve N utilization efficiency (NUE) by overexpressing the GS1 gene have yielded inconsistent results. Here we demonstrate that transformation of barley (Hordeum vulgare L.) plants using a cisgenic strategy to express an extra copy of native HvGS1-1 lead to increased HvGS1.1 expression and GS1 enzyme activity. GS1 overexpressing lines exhibited higher grain yields and NUE than wild-type plants when grown under three different N supplies and two levels of atmospheric CO2 . In contrast to the wild-type, the grain protein concentration in the GS1 overexpressing lines did not decline when plants were exposed to elevated (800-900 MUl L-1 ) atmospheric CO2 . We conclude that an increase in GS1 activity obtained through cisgenic overexpression of HvGS1-1 can improve grain yield and NUE in barley. The extra capacity for N assimilation obtained by GS1 overexpression may also provide a means to prevent declining grain protein levels under elevated atmospheric CO2 . This article is protected by copyright. All rights reserved. PMID- 30525276 TI - Diabetes, body fat, skeletal muscle, and hypertension: The ominous chiasmus? PMID- 30525275 TI - Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir. AB - BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. METHODS: 103 TDF treated patients were included: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R), and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL, and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every four months thereafter. RESULTS: During 46 (4-115) months of ETV treatment, all patients' renal parameters significantly improved: creatinine from 1.30 to 1.10 mg/dL (p<0.0001), eGFRMDRD from 54 to 65 mL/min (p=0.002), P from 2.2 to 2.6 mg/dL (p<0.0001), and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (p<0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and 8 (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV naive patients, and 11% in LMV-R patients (p=0.018). CONCLUSIONS: ETV is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment. This article is protected by copyright. All rights reserved. PMID- 30525277 TI - New vascular biomarkers related to ABPM phenotypes in untreated patients. PMID- 30525278 TI - Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel. AB - OBJECTIVES: The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers. MATERIALS AND METHODS: HeLa cells and fluorescence microscopy were used to analyse the effect of zerumbone on cancer cell lines. Cellular internalization of zerumbone was investigated using FITC-labelled zerumbone. The interaction of zerumbone with tubulin was characterized using fluorescence spectroscopy. The Chou and Talalay equation was used to calculate the combination index. RESULTS: Zerumbone selectively inhibited the proliferation of HeLa cells with an IC50 of 14.2 +/- 0.5 MUmol/L through enhanced cellular uptake compared to the normal cell line L929. It induced a strong mitotic block with cells exhibiting bipolar spindles at the IC50 and monopolar spindles at 30 MUmol/L. Docking analysis indicated that tubulin is the principal target of zerumbone. In vitro studies indicated that it bound to goat brain tubulin with a Kd of 4 MUmol/L and disrupted the assembly of tubulin into microtubules. Zerumbone and colchicine had partially overlapping binding site on tubulin. Zerumbone synergistically enhanced the anti-proliferative activity of vinblastine and paclitaxel through augmented mitotic block. CONCLUSION: Our data suggest that disruption of microtubule assembly dynamics is one of the mechanisms of the anti cancer activity of zerumbone and it can be used in combination therapy targeting cell division. PMID- 30525280 TI - Associations of body fat and skeletal muscle with hypertension. AB - Hypertension is known to be associated with obesity, while its relationship to skeletal muscle, SM (SM; a marker of general health and body function), remains uncertain. We analyzed population-based data of 22 591 men (mean age: 51.6 +/- 16.9 years) and 27 845 nonpregnant women (50.6 +/- 16.9 years) from Scottish Health Surveys (2003, 2008-2011) and Health Surveys for England (2003-2006, 2008 2013) including 2595 non-insulin- and 536 insulin-treated diabetic patients. Compared with normotensive individuals (no hypertension history with normal systolic [SBP < 140 mm Hg] and diastolic blood pressure [DBP < 90 mm Hg]), percent body fat (BF%) was significantly higher and percent SM lower (P < 0.001) in undetected (no hypertension history with raised SBP >= 140 and/or DBP >= 90 mm Hg), controlled (hypertension history with normal BP), uncontrolled (hypertension history with raised BP), and untreated hypertension. The prevalences of hypertension within BF% quintiles were 11.8%, 24.8%, 41.4%, 56.8%, and 71.6% and SM% quintiles were 67.5%, 53.3%, 39.5%, 27.4%, and 18.5%. Compared to referent groups (lowest BF% quintile or highest SM% quintile), odds ratio (age, sex, smoking, ethnicity, country, survey year, and diabetes adjusted) for having all types of hypertension in the highest BF% quintile was 5.5 (95% confidence interval = 5.0-5.9) and lowest SM% quintile was 2.3 (2.2-2.5). Compared with those without diabetes, individuals with diabetes had a 2.3-fold-2.6-fold greater risk of hypertension, independent of confounding factors and BF% or SM%. The associations of hypertension with BF% were higher than those with body mass index (BMI). In conclusion, both BF and SM should be considered when analyzing results from health surveys, rather than relying on BMI which does not discriminate between the two. PMID- 30525279 TI - Morning surge in blood pressure and blood pressure variability in Asia: Evidence and statement from the HOPE Asia Network. AB - Hypertension is a major risk factor for cardiovascular and cerebrovascular diseases. To effectively prevent end-organ damage, maintain vascular integrity and reduce morbidity and mortality, it is essential to decrease and adequately control blood pressure (BP) throughout each 24-hour period. Exaggerated early morning BP surge (EMBS) is one component of BP variability (BPV), and has been associated with an increased risk of stroke and cardiovascular events, independently of 24-hour average BP. BPV includes circadian, short-term and long term components, and can best be documented using out-of-office techniques such as ambulatory and/or home BP monitoring. There is a large body of evidence linking both BPV and EMBS with increased rates of adverse cardio- and cerebrovascular events, and end-organ damage. Differences in hypertension and related cardiovascular disease rates have been reported between Western and Asian populations, including a higher rate of stroke, higher prevalence of metabolic syndrome, greater salt sensitivity and more common high morning and nocturnal BP readings in Asians. This highlights a need for BP management strategies that take into account ethnic differences. In general, long-acting antihypertensives that control BP throughout the 24-hour period are preferred; amlodipine and telmisartan have been shown to control EMBS more effectively than valsartan. Home and ambulatory BP monitoring should form an essential part of hypertension management, with individualized pharmacotherapy to achieve optimal 24-hour BP control particularly the EMBS and provide the best cardio- and cerebrovascular protection. Future research should facilitate better understanding of BPV, allowing optimization of strategies for the detection and treatment of hypertension to reduce adverse outcomes. PMID- 30525281 TI - The organic stratigraphy of Ontong Java Plateau Tuff correlated with the depth related presence and absence of putative microbial alteration structures. AB - Structures in geological samples are often interpreted as fossilised life; however, such interpretations are equivocal, as abiotic processes can be invoked to explain their presence. Thus, additional lines of chemical evidence are invaluable in confirming or refuting such morphological evidence. Glass shards in tuff from the Ontong Java Plateau (OJP) contain microtubular structures that are in close proximity to functionalised nitrogen substituted aromatic compounds that may be indicative of the chemical remnants of biological activity. The organic composition of the OJP tuff containing microtubular alteration structures was compared with tuff without such features. In addition, organic matter associated with horizons with compacted remnants of woody material buried in the OJP tuff and overlying pelagic calcareous foraminifer sediment were also characterised, to ascertain the provenance of the organic matter found in the OJP tuff. As a further control, the organic material in submarine and terrestrial basalts from other locations were also characterised providing further evidence to support the view that the organic matter in the OJP tuff is authigenic. Carbon-nitrogen chemistry was detected across all OJP tuff samples irrespective of the presence or absence of microtubular features, but was not detected in either the wood material, the overlying pelagic sediments or in the basalts from other locations. The results indicate no direct link between the OJP nitrogenous organic compounds and the presence or absence of microtubular features. PMID- 30525282 TI - The metabolic and proteomic signatures of hypoglycemia in type 2 diabetes. AB - AIMS: Hypoglycemia is often related to insulin therapy in both type 1 and type 2 diabetes (T2D) patients. It may result in cardiovascular and neurological sequelae, and increased mortality. The molecular processes underlying the body's response to hypoglycemia, however, require further understanding. Our objective was to determine biochemical changes under hypoglycemia in healthy controls and T2D. MATERIALS AND METHODS: Here we report a hypoglycemic clamp study with seven healthy controls and ten subjects with T2D. Blood was withdrawn at four time points: baseline after an overnight fast, clamping to euglycemia at 90mg/dl, hypoglycemia at 50mg/dl, and 24 hours later after overnight fast. Deep molecular phenotyping using non-targeted metabolomics and the Somalogic aptamer-based proteomics platforms was performed on collected samples. RESULTS: 955 metabolites and 1,125 proteins were identified, with significant alterations in over 90 molecules. A number of metabolites significantly increased during hypoglycemia, but only cortisol, adenosine-3',5'-cyclic monophosphate (cyclic AMP), and pregnenolone sulfate, were independent of insulin. By contrast, identified protein changes were triggered by hypoglycemia rather than insulin. T2D had significantly higher levels of fatty acids including 10-nonadecenoate, linolenate, and dihomo-linoleate during hypoglycemia compared to the control. Molecules contributing to cardiovascular complications such as fatty-acid-binding protein-3 and pregnenolone sulfate were altered in T2D subjects during hypoglycemia. Almost all molecules returned to baseline at 24 hours. CONCLUSIONS: Our study provides a comprehensive description of molecular events that are triggered by insulin-induced hypoglycemia. We identified deregulated pathways in T2D that may play a role in the pathophysiology of hypoglycemia-induced cardiovascular complications. This article is protected by copyright. All rights reserved. PMID- 30525283 TI - Screening for thyroid disease in patients with type 2 diabetes mellitus: an evaluation of current practice. AB - The study is important because many patients with T2DM appear to be tested for thyroid dysfunction on a regular basis, which is not what guidance advocates. Previously we have demonstrated that adherence to guidance is patchy sometimes resulting in thyroid hormone status being tested less than is advised. Nevertheless this testing appears to be worthwhile as we have shown that there is increased likelihood of developing thyroid dysfunction in T2DM - we would therefore propose that screening for thyroid dysfunction should be part of routine practice While there is no specific guidance to support regular thyroid function testing in patients with T2DM, we suggest that annual screening should be considered, in order not to miss developing hypothyroidism in people with T2DM. In reality this is largely happening already in the UK. This article is protected by copyright. All rights reserved. PMID- 30525284 TI - Reconfigurable Bioinspired Framework Nucleic Acid Nanoplatform Dynamically Manipulated in Living Cells for Subcellular Imaging. AB - In nature, the formation of spider silk fibers begins with dimerizing the pH sensitive N-terminal domains of silk proteins (spidroins) upon lowering pH, which provides a natural masterpiece for programmable assembly. Inspired by the similarity of pH-dependent dimerization behaviors, here we introduce an i-motif guided model to mimic the initial step of spidroin assembly at the subcellular level. A framework nucleic acid (FNA) nanoplatform is designed using two tetrahedral DNA nanostructures (TDNs) with different branched vertexes carrying a bimolecular i-motif and a split ATP aptamer. Once TDNs enter acidic lysosomes within living cells, they assemble into a hetero-dimeric architecture thereby enabling the formation of a larger-size framework and meanwhile subcellular imaging in response to endogenous ATP, which can be dynamically manipulated via adjusting intracellular pH and ATP level with external drug stimuli. PMID- 30525285 TI - The meanings of place and space in forensic psychiatric care - A qualitative study reflecting patients' point of view. AB - The outcome of care for patients sentenced to forensic psychiatric care is of importance not only for the patient but also for society, in preventing new crimes. In recent years, a person-centered perspective is influencing the care, recognizing the design of the physical environment as a therapeutic resource. To capture the complexity of patients' experience of the physical environment, a qualitative approach is needed. The aim of this study was to investigate the meanings of the patient room as a place and space in forensic psychiatric in patient care from the patients' perspective. An explorative qualitative design was chosen, data were collected by photovoice; a combination of photographs, taken by the patients, followed by interviews. Eleven (N = 11) patients were interviewed. The interviews were analysed by a thematic analysis method. Four themes emerged from the data revealing the meanings of the patient room as a place and space: (i) striving towards normality; (ii) being anchored and protected; (iii) being at-home and homeness; and (iv) being in communion and meaningfulness. The findings show that the physical environment has a say in patients' basic needs and a role in maintaining normality. Substandard reveals a lack of respect and dignity towards this patient group. Involving patients in the design process of new facilities can be a way to make progress. PMID- 30525286 TI - Predicting strain engineering strategies using iKS1317: a genome-scale metabolic model of Streptomyces coelicolor. AB - Streptomyces coelicolor is a model organism for the Actinobacteria, a phylum known to produce an extensive range of different bioactive compounds that include antibiotics currently used in the clinic. Biosynthetic gene clusters discovered in genomes of other Actinobacteria can be transferred to and expressed in S. coelicolor, making it a factory for heterologous production of secondary metabolites. Genome-scale metabolic reconstructions have successfully been used in several biotechnology applications to facilitate the over-production of target metabolites. Here, we present iKS1317, the most comprehensive and accurate reconstructed genome-scale metabolic model for S. coelicolor. The model reconstruction is based on previous models, publicly available databases, and published literature and includes 1317 genes, 2119 reactions and 1581 metabolites. It correctly predicts wild-type growth in 96.5% of the evaluated growth environments and gene knockout predictions in 78.4% when comparing with observed mutant growth phenotypes, with a total accuracy of 83.3%. However, using a minimal nutrient environment for the gene knockout predictions, iKS1317 has an accuracy of 87.1% in predicting mutant growth phenotypes. Furthermore, we used iKS1317 and existing strain design algorithms to suggest robust gene-knockout strategies to increase the production of acetyl-CoA. Since acetyl-CoA is the most important precursor for polyketide antibiotics, the suggested strategies may be implemented in vivo to improve the function of S. coelicolor as a heterologous expression host. PMID- 30525287 TI - Acceptable "Real-Life" Variability for Lymphocyte Counts by Flow Cytometry. AB - BACKGROUND: As part of quality assurance in laboratories (labs) offering clinical cell analysis by flow cytometry (FCM), cell counting precision and robustness are evaluated but international desirable ranges are still missing. The aim of this study was to provide desirable interlaboratory variability reference values. METHODS: A prospective survey on monthly quality assessment was proposed to all French laboratories routinely performing lymphocyte subpopulation quantification, over one arbitrarily selected month (June 2017), regardless of instrument, counting system and quality controls used. Relative variabilities of the commercially available internal quality control (IQC) used locally were collected. Robust mean, standard deviation and CV were calculated on relative and absolute counts. RESULTS: Sixty-two labs participated, providing 91 sets of data on 82 instruments. All but three were enrolled in external quality assessment (EQA) and 46 in externalized IQA. The mean CV of five repeats ranged from 1.00 +/ 0.33 for T cells to 4.78 +/- 1.92 for NK cells and from 2.88 +/- 1.46 to 5.87 +/ 1.83 for relative and absolute counts, respectively. The precision correlated directly to the concentration of cells rather than the phenotype. Negligible differences were observed between IQC material: MulticheckTM (3.36 +/- 1.30, n = 11); ImmunotrolTM (3.62 +/- 3.24, n = 21) and StatusflowTM (3.63 +/- 1.87, n = 24) on CD4+ T cell, for example. Little difference was observed between counting systems such as FlowcountTM (4.55 +/- 3.45, n = 19), TrucountTM (3.17 +/- 1.40, n = 30) and the fully automated AquiosTM system (1.87 +/- 0.75, n = 5) on single platforms, while dual platform CV was at 2.00 +/- 0.58 (n = 2) on CD4+ T cell, as example. Robustness was measured on 21 +/- 11 consecutive analyses of the same IQC material, providing CVs ranging from 4.45 +/- 1.74 for T cells to 7.57 +/- 2.19 for NK absolute counts. Average residuals calculated from the different low count IQC samples for CD4 T cells (median value below 200 cells/MUl) were below 10 cells/MUl, demonstrating their robustness for medical decisions. CONCLUSIONS: Real life variabilities in cell counting are directly related to the cell concentration and not to their phenotype. Desirable ranges within three SD are proposed according to different cell levels, based on 62 labs, different IQC material and systems. (c) 2018 International Clinical Cytometry Society. PMID- 30525288 TI - Developmental differences in the neural correlates supporting semantics and syntax during sentence processing. AB - School-aged and adolescent children continue to demonstrate improvements in how they integrate and comprehend real-time, auditory language over this developmental time period, which can have important implications for academic and social success. To better understand developmental changes in the neural processes engaged during language comprehension in this age group, we use electroencephalography (EEG) to investigate how 8-9 year old, 12-13 year olds, and adults process semantics and syntax in naturally-paced, auditory sentences. Participants listened to semantically and syntactically correct and incorrect sentences and were asked to complete an acceptability judgment task. When processing a semantic error, developmental differences were observed in theta, but not the N400, suggesting the N400 may be too gross a measure to identify more subtle aspects of semantic development that occur in the school years. For the syntactic task, errors resulted in a larger P600 and greater beta decrease than correct sentences, but the amplitude and location of the P600 and amplitude of beta decreases differed as a function of age, suggesting specialization of syntactic skills is ongoing through adolescence. The current findings shed new light on the development of the neural oscillations supporting language comprehension and suggest that the neural substrates underlying semantic processing reach adult-like levels at a younger age than those underlying syntactic processing. This article is protected by copyright. All rights reserved. PMID- 30525289 TI - Factor VIII with 237 amino acids B-domain has extended half-life in F8-KO mice. AB - BACKGROUND: Factor VIII (FVIII) consists of the A1-A2-B-A3-C1-C2 domains. FVIII with an intermediate length B-domain of 226 amino acids (aa) has previously been evaluated in murine gene therapy studies. OBJECTIVE: To characterize FVIII with intermediate length B-domains in vitro and in vivo in F8-KO mice. METHODS AND RESULTS: FVIII with B-domains of 186 - 240aa had longer half-lives in F8-KO mice than FVIII with shorter or longer B-domains. FVIII with a B-domain containing the 225 N-terminal aa fused to the 12 C-terminal aa of the wild-type B-domain (FVIII 237) had a 1.6-fold extended half-life in F8-KO mice compared to FVIII with a 21aa B-domain (FVIII-21). The in vitro and in vivo activity of FVIII-237 was comparable to that of FVIII-21, as was binding to von Willebrand factor. Cell binding to low density lipoprotein receptor related protein 1 (LRP-1) expressing cells was markedly reduced for FVIII-237 compared to FVIII-21, whereas the affinity for LRP-1 was not reduced in surface plasmon resonance studies. FVIII-21 cell binding and internalization could be inhibited by a fragment consisting of the 226 N-terminal aa of the FVIII B-domain, and SPR analysis suggested that this B-domain fragment might bind with weak affinity to FVIII-21. CONCLUSION: Reduced cell binding of FVIII-237 might explain the observed extended half-life in F8-KO mice. This may contribute to the increased FVIII levels measured in murine gene therapy studies using FVIII constructs with similar B-domain lengths. This article is protected by copyright. All rights reserved. PMID- 30525290 TI - In vitro nematicidal activity of natural and semisynthetic cadinenes from Heterotheca inuloides against plant-parasitic nematode, Nacobbus aberrans (Tylenchida: Pratylenchidae). AB - BACKGROUND: Nacobbus aberrans (Tylenchida: Pratylenchidae) is one of the main plant-parasitic nematodes species that affects crops in Mexico, generating substantial economic losses. Traditionally, the control of the nematodes is carried out using chemical products; however, research efforts are presently focused on the search for new methods for the control of this pest. Natural products derived from plants are an alternative for the control of populations of plant-parasitic nematodes. The genus Heterotheca (Asteraceae) is characterized by containing sesquiterpenes with cadinane skeleton, and some species of this genus exert nematicidal activity RESULTS: We determined the effects of selected Heterotheca inuloides plant metabolites and some semisynthetic derivatives on the hatching of eggs isolated from the gelatinous matrix and infective second-stage juveniles (J2) of the false root-knot nematode, N. aberrans, using an in vitro experimental model. Among the evaluated compounds, nematodes were more susceptible to hydroxylated and quinone compounds, whereas the remaining compounds showed moderate or no activity. The presence of the hydroxyl group is essential for nematicidal potential, with changes at the hydroxyl group modifying the nematicidal activity. CONCLUSION: Flowers of Heterotheca inuloides contain bioactive compounds that showed nematicidal activity against N. aberrans. Here we report the nematicidal activities of cadinenes isolated from the flowers of H. inuloides and their semisynthetic derivatives against the false root-knot nematode N. aberrans. This article is protected by copyright. All rights reserved. PMID- 30525291 TI - Identification of MALDI Imaging Proteolytic Peptides using LC-MS/MS-Based Biomarker Discovery Data - A Proof of Concept. AB - PURPOSE: Identification of proteolytic peptides from matrix-assisted laser desorption/ionization (MALDI) imaging still remains a challenge. In-situ post source decay leads to low fragmentation yields, so identification is often impaired. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is an alternative to in-situ MS/MS, but leads to multiple identification candidates for a given mass. In this proof of concept, we propose to use LC-MS/MS-based biomarker discovery results for reliable identification of MALDI imaging proteolytic peptides. EXPERIMENTAL DESIGN: We established a list of m/z values of interest in a tissue specimen with high grade squamous intraepithelial lesion (HSIL) that was analyzed by MALDI imaging. In parallel we used data from a biomarker discovery study to correlate m/z peaks found by MALDI imaging with masses of identified peptides detected by LC-MS/MS in HSIL. We neglected candidates that were not significantly more abundant in HSIL according to the biomarker discovery investigation. RESULTS: We could assign identifications to three peptides of interest. The number of possible identifiers for MALDI imaging m/z peaks from LC-MS/MS-based biomarker discovery studies was reduced by about tenfold compared with a single LC-MS/MS experiment. Furthermore, one peptide identification candidate was validated by immunohistochemistry. CONCLUSION AND CLINICAL RELEVANCE: This concept combines LC-MS/MS-based shotgun quantitative proteomics with MALDI imaging and allows reliable peptide candidate identification. Public datasets from LC-MS/MS biomarker discovery experiments may be a valuable source to identify MALDI imaging m/z peaks. This article is protected by copyright. All rights reserved. PMID- 30525292 TI - Microwave Intensified Synthesis: Batch and Flow Chemistry. AB - Many studies have been conducted on organic and inorganic synthesis by microwave heating owing to its special heating mechanism, leading to improved reaction rate, higher purity and yields. We specifically demonstrated microwave heating in the fabrication of nanoparticles and polyester. By fine-tuning the microwave and experimental parameters, the materials prepared have shown excellent physical and bio-properties, e. g. narrow particle size distribution, controlled morphology, varied molecular structure and so forth. We further highlight the recent procedure of using fluidic reactors on preparing both metals and metal oxides nanoparticles. The experimental design strategies and fundamentals of the microwave interaction with chemicals are presented. Furthermore, the key factors and issues facing in this area are also discussed. PMID- 30525293 TI - A Bayesian network meta-analysis of the efficacy of targeted therapies and chemotherapy for treatment of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease with poorer prognosis than other subtypes, yet effective therapies are still not available. We aimed to compare the efficacy of various targeted therapies with chemotherapy (CT) in TNBC patients using a network meta-analysis. A systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library. A total of 27 randomized controlled trials (RCTs), involving 6924 TNBC patients, were included. Olaparib significantly improved PFS (0.43, 0.29-0.64) and ORR (2.57, 1.31-5.09) in comparison with CT. As for bevacizumab + CT, it showed a significant improvement of PFS (0.66, 0.55-0.80) and ORR (2.15, 1.16-4.05) compared with CT + placebo. It was also superior to CT alone in PFS (0.48, 0.35-0.65) and pCR (1.30, 1.13-1.49 for breast and axillary nodes and 1.26, 1.11-1.44 for breast). Other targeted agents like iniparib, sorafenib, cetuximab, and ipatasertib combined with CT showed significant superiority in PFS compared with CT alone, and the HRs were 0.75 (0.62-0.90), 0.44 (0.21-0.91), 0.67 (0.47-0.96), and 0.44 (0.24-0.81), respectively, while some other agents such as sunitinib and cetuximab had the lowest SUCRA in OS, PFS, or ORR without any benefits. In conclusion, our results indicated that the addition of bevacizumab to CT was beneficial for TNBC patients, and olaparib had a great effect in PFS and ORR, especially for those with BRCA mutations. When combined with CT, targeted agents including iniparib, sorafenib, cetuximab, and ipatasertib may have better efficacies for treating TNBC. PMID- 30525294 TI - Quality-of-life predictors for men undergoing infertility treatment in Japan. AB - AIM: To dentify the predictors of the quality of life (QOL) of infertile men who are undergoing infertility treatments in Japan and to create a QOL prediction model, with the main variables aimed at providing more adequate support to male patients. METHODS: This cross-sectional study used the quantitative data that were collected from 321 returned self-report questionnaires that had been distributed to the men of 411 couples who were undergoing fertility treatment. The following four scales were used to measure the main outcomes: FertiQoL, psychological distress, spousal support, and workplace support. The data were analyzed by descriptive statistics, multiple regression analyses, and structural equation modeling. RESULTS: The number of returned questionnaires was 321 (78.1%). The QOL that was measured by FertiQoL was significantly lower in those men who were diagnosed with male factor infertility than in the other male patients. The two significant predictors of QOL were: spousal support and the infertility period. The structural equation modeling revealed that the same factors were related to QOL. CONCLUSIONS: Male factor infertility, less spousal support, and a longer period of infertility were associated with a poorer QOL of those men who were undergoing infertility treatment. These results suggest that focusing on infertility causes, the length of the infertility period, and the couples' partnership during treatment is needed to provide full support to men who have been diagnosed with infertility. PMID- 30525295 TI - Becoming and being an editor. PMID- 30525296 TI - Developing leadership and capacity building: Reflections of a nurse leader. AB - Globally, leadership in nursing and healthcare is vital to develop professional skills and knowledge to improve both practice and population health. Much can be learned from the leadership experiences of others, such as Professor Wipada Kunaviktikul from Thailand, a well-known nursing leader. Among her many life achievements, she is a founding member of the Editorial Board of Nursing & Health Sciences and was invited to share her life story with readers. Her life story includes experiences of leadership and capacity building in health, administration and education, across many organizations nationally and internationally. She describes how her early experiences contributed to her later achievements, such as working to establish international relationships, networks and collaborating centers, and English-language nursing degrees and training courses for Thai and international students. Nurses and other health professionals can reflect on how her values and commitment to nursing excellence have shaped her leadership style to the present time. The importance of role models and mentors in capacity building for leadership is emphasized in her personal leadership development and in the development of other leaders. In conclusion, leadership suggestions are given for future and present nursing leaders. PMID- 30525297 TI - Decoration of Dibenzofuran Using Cyanocarbazole via 6- Position As a Molecular Design Approach for High Triplet Energy Bipolar Host Materials. AB - In this study, two new dibenzofuran derivatives featuring one or two cyanocarbazole units, 6-(dibenzo[b,d]furan-4-yl)-9-phenyl-9H-carbazole-3 carbonitrile (mBFCzCN) and 6,6'-(dibenzo[b,d]furan-4,6-diyl)bis(9-phenyl-9H carbazole-3-carbonitrile) (dBFCzCN), were developed as host materials for phosphorescent organic light emitting diodes (PhOLEDs). A new molecular design connecting the cyanocarbazole to the dibenzofuran using the cyanocarbazole 6 position instead of its 9-position was created, and the effects of number of cyanocarbazole units in the dibenzofuran building block on the photophysical and electroluminescence properties were investigated in detail. The mBFCzCN compound revealed high triplet energy (2.78 eV) than that of dBFCzCN (2.68 eV) and good bipolar charge transporting properties. The potential of these materials as hosts for blue and green PhOLEDs was investigated using bis(4,6 (difluorophenyl)pyridinato-N,C2')picolinate iridium(III) (FIrpic) and tris(2 phenylpyridinato)iridium(III) (Ir(ppy)3) dopants, respectively. The results indicated that the mBFCzCN with one cyanocarbazole unit showed better device performance than the dBFCzCN with two cyanocarbazole units in the blue and green devices. High external quantum efficiencies of 19.0 and 21.2% were demonstrated in the blue and green PhOLEDs with the mBFCzCN host due to its high triplet energy and good bipolar charge transporting characteristics. PMID- 30525298 TI - What information do patients want across their cancer journeys? A network analysis of cancer patients' information needs. AB - BACKGROUND: Patients want information across their cancer journeys. We investigated what sort of information they want and at what stage in the cancer journey by examining English patients' satisfaction derived from ratings of their care. METHODS: Using patient experience data from 209 Clinical Commission Groups (CCGs) involving 72 788 respondents in 2016, overall patient satisfaction ratings and information needs questions were extracted. Novel network analysis techniques were used to construct an undirected weighted concentration network to assess the relationship between information needs and patient satisfaction. RESULTS: From the network analysis, we found that patients value information early in the pathway; there were higher associations between patient satisfaction and when information needs are met in earlier phases of the cancer journey. Across the stages of the cancer journey, strong associations between information needs and patient satisfaction emerged during diagnostic testing and also at those points when patients received information provided by the clinical nurse specialists. A mixture of strong and weak associations between patient satisfaction and information needs was found during later phases of the cancer journey, specifically when patients move from treatment to home care. Our study identified that meeting needs for information related to supportive care may be a weaker factor in patient satisfaction than meeting needs for information related to the patient's disease, its treatment and the side effects of treatment. CONCLUSION: If patients have their information needs met, especially during stages within the cancer journey when information needs are highest, they are more likely to be satisfied with their care. Our study has implications for information giving and improving patient satisfaction in cancer care. PMID- 30525299 TI - The Crohn's & Colitis Australia Inflammatory Bowel Disease Audit: Measuring the quality of care in Australia. AB - OBJECTIVES: To audit the quality of care received by patients admitted for inflammatory bowel disease (IBD) across Australia against national IBD Standards. DESIGN: Retrospective cross-sectional survey and clinical audit assessing organisational resources, clinical processes and outcome measures. SETTING: Australian hospitals. PARTICIPANTS: Hospitals that care for inpatients with Crohn's disease or ulcerative colitis. MAIN OUTCOME MEASURES: Adherence to national IBD Standards and comparison of quality of care between hospitals with and without multidisciplinary IBD services. RESULTS: 71 hospitals completed the organisational survey. Only one hospital had a complete multidisciplinary IBD service and 17 had a Partial IBD Service (IBD nurse, helpline and clinical lead). 1440 inpatient records were reviewed from 52 hospitals (mean age 37 years; 51% female, 53% Crohn's disease), approximately 26% of IBD inpatient episodes over a 12-month period in Australia. These patients were chronically unwell with high rates of anaemia (30%) and frequent readmissions (40% within two years). In general, care was inconsistent, and documentation poor. Hospitals with a Partial IBD Service performed better in many process and outcome measures: for example, 22% reduction in admissions via emergency departments and greater adherence to standards for safety monitoring of biologic (89% vs 59%) and immunosuppressive drugs (79% vs 55%) in those hospitals than those without. CONCLUSIONS: Patients admitted to hospital suffering from IBD are young, chronically unwell, and are subject to substantial variations in clinical documentation and quality of care. Only one hospital met accepted Standards for multidisciplinary care; hospitals with even a minimal IBD service provided improved care. This article is protected by copyright. All rights reserved. PMID- 30525300 TI - Ethical issues in susceptibility genetic testing for late-onset neurodegenerative diseases. AB - Genome-wide association studies have revolutionized our understanding of the genetic architecture of complex traits and diseases over the last decade. This knowledge is enabling clinicians, researchers, and direct-to-consumer genetics companies to conduct disease susceptibility testing based on powerful methods such as polygenic risk scoring. However, these technologies raise a set of complex ethical, legal, social, and policy considerations. Here we review and discuss a series of ethical dilemmas associated with susceptibility genetic testing for the two most common late-onset neurodegenerative diseases, Alzheimer's and Parkinson's disease, including testing in asymptomatic individuals. Among others, these include informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. Importantly, appropriate counseling is a deciding factor for the ethical soundness of genetic testing, which poses a challenge for the regulation of these tests and the training of healthcare professionals. As genetic knowledge about these diseases continues growing and genetic testing becomes more widespread, it is increasingly important to raise awareness among researchers, medical practitioners, genetic counselors, and decision makers about the ethical, legal, and social issues associated with genetic testing for polygenic diseases. PMID- 30525301 TI - Development and evaluation of calcium hydroxide-coated, pericardium-based biomembranes for direct pulp capping. AB - AIM: The aim of the present study was to develop a bovine pericardium biomembrane (BPB) and to evaluate pulp response in vivo. METHODS: A double-layer bovine BPB/chitosan was manufactured, and the porous chitosan side was coated with calcium hydroxide. The microstructure of the matrices was evaluated with electron microscopy. To test pulp response, cavities were prepared on the occlusal surface of Wistar rats' mandibular left first molars and capped with matrices, followed by appropriate adhesives/composite restorations. The animals were divided into three groups: group 1, calcium hydroxide alone; group 2, BPB without calcium hydroxide; and group 3, BPB coated with calcium hydroxide. Specimens were processed and histologically evaluated at 7, 14, and 30 days, postoperatively. RESULTS: Electron microscopy showed porous chitosan surface and a cohesive calcium hydroxide layer. Histological analysis showed that groups 1 and 3 had mild odontoblast layer disorganization, but normal pulp tissue appearance at 7, 14, and 30 days. At the same time points, group 2 showed a loss of general pulp tissue, pulp necrosis, and periapical abscess in some teeth. CONCLUSION: Coated bovine pericardium-based biomembranes resulted in favorable outcomes in cases of pulp exposure after a 30-day observation period, and might protect against injuries caused by adhesive systems and composites. PMID- 30525302 TI - Palliative care initiation in pediatric oncology patients: A systematic review. AB - Palliative care (PC) aims to improve quality of life for patients and their families. The World Health Organization and American Academy of Pediatrics recommend that PC starts at diagnosis for children with cancer. This systematic review describes studies that reported PC timing in the pediatric oncology population. The following databases were searched: PubMed, Web of Science, CINAHL, and PsycInfo databases. Studies that reported time of PC initiation were independently screened and reviewed by 2 researchers. Studies describing pilot initiatives, published prior to 1998, not written in English, or providing no empirical time information on PC were excluded. Extracted data included sample characteristics and timing of PC discussion and initiation. Of 1120 identified citations, 16 articles met the inclusion criteria and comprised the study cohort. Overall, 54.5% of pediatric oncology patients received any palliative service prior to death. Data revealed PC discussion does not occur until late in the illness trajectory, and PC does not begin until close to time of death. Despite efforts to spur earlier initiation, many pediatric oncology patients do not receive any palliative care service, and those who do, predominantly receive it near the time of death. Delays occur both at first PC discussion and at PC initiation. Efforts for early PC integration must recognize the complex determinants of PC utilization across the illness timeline. PMID- 30525304 TI - SIRT3 Deficiency Promotes High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease In Correlation With Impaired Intestinal Permeability Through Gut Microbial Dysbiosis. AB - SCOPE: Sirtuin 3 (SIRT3) plays a protective role against non-alcoholic fatty liver disease (NAFLD) by improving hepatic mitochondrial dysfunction. Gut microbiota imbalance contributes to the pathogenesis of NAFLD, yet the underlying mechanism linking SIRT3 with gut microbiota in NAFLD progression remains obscure. METHODS AND RESULTS: Wild-type 129 mice and SIRT3 knockout (SIRT3KO) mice were under a chow diet or high-fat diet (HFD) treatment for 18-weeks. HFD resulted in a significantly increased hepatic steatosis and inflammation, which were exacerbated in SIRT3KO mice. We characterised the gut microbiota by 16s rRNA gene sequencing and phylogenetic reconstruction of unobserved states (PICRUSt) analysis. Lack of SIRT3 facilitates gut microbial dysbiosis in mice following HFD, with increased Desulfovibrio, Oscillibacter and decreased Alloprevotella. SIRT3 deficiency resulted in an impaired intestinal permeability and inflammation in HFD-fed mice, which can be attenuated by sodium butyrate (NaB). SIRT3KO HFD fed mice was followed by an increased lipopolysaccharide into the circulation and dysregulated expressions of cannabinoid receptor 1 and 2 (CB1 and CB2) in colon and liver, which were significantly associated with the alterations of intestinal microbiota. CONCLUSIONS: SIRT3 deficiency promotes NAFLD progression in correlation with impaired intestinal permeability through gut microbiota dysbiosis. This article is protected by copyright. All rights reserved. PMID- 30525303 TI - Association between semen parameters and chance of fatherhood - a long-term follow-up study. AB - BACKGROUND: Evaluation of male fertility includes standard semen analysis; however, there is uncertainty about the value of sperm parameters in predicting fertility. OBJECTIVE: To evaluate the association between semen parameters and fatherhood during a long-time period. MATERIALS AND METHODS: Semen parameters (total sperm count, concentration, motility, and morphology) and sperm DNA fragmentation Index (DFI) assessed on samples collected from 195 Norwegian men from the general population in 2001/2002 were matched with information about fatherhood until 2015, obtained from the Medical Birth Register. The parameters were dichotomized as normal vs. abnormal according to the WHO reference values from 1999 and 2010. Cut-offs at 20% and 30% were used for DFI. RESULTS: Among men who had no children before 2003, those with normal progressive sperm motility had more often become fathers (WHO 1999, cut-off >=50%, adjusted OR 2.8, 95% CI 1.3 6.1 and WHO 2010, cut-off >=32%; aOR 4.2, 95% CI 1.1-15). Based on the WHO 1999 reference value, men with normal sperm concentration (>=20 * 106 /mL) had more often become fathers (aOR 3.1, 95% CI 1.1-8.6). Men with progressive sperm motility >=50% and concentration >=20 * 106 /mL did more often achieve fatherhood (aOR 8.4, 95% CI 2.1-34). For DFI, there was a borderline significance at cut-off 20% in the group of men who had ever been fathers (OR 2.7, 95% CI 1.0-7.0 p < 0.05). DISCUSSION: The results indicate that sperm progressive motility, sperm concentration, and DFI are associated with fatherhood during a longer time period, with sperm motility being most consistent. Although the sample size is relatively small and our results should be replicated in larger studies, they may be of clinical relevance. CONCLUSION: Semen parameters may have a diagnostic value not only in a short time frame but also for predicting future fertility potential. PMID- 30525305 TI - Rapid liver disease progression in a patient with homozygous alpha1-antitrypsin deficiency (Pi*ZZ genotype). AB - With great interest, we read the study by Schaefer et. al. suggesting that the carriage of a heterozygous PiZ variant of alpha1-antitrypsin (AAT) predisposes to a faster development of decompensated liver disease [1]. While the heterozygous PiZ carriage is fairly common, the homozygous genotype (PiZZ) is comparably rare (1:2000-1:4000) [2]. Since the course of PiZZ-related liver disease remains greatly understudied, we report a case of a PiZZ patient with a rapid decompensation of liver disease. This article is protected by copyright. All rights reserved. PMID- 30525306 TI - Use of Electronic and Paper-based Standardized Nursing Care Plans to Improve Nurses' Documentation Quality in a Nigerian Teaching Hospital. AB - PURPOSE: To evaluate the effect of electronic and paper-based standardized nursing care plans (SNCPs) use on quality of nurses' documentation. METHODS: Using quasi-experimental design, two wards were grouped into electronic and paper based wards. Nurses were trained to use electronic- and paper-based SNCPs for care-planning and documentation. Data was collected before, 3, and 6 months postintervention and analyzed with SPSS version 20. FINDINGS: There was improvement in documentation quality in the two wards after introducing SNCPs with higher quality scores in the electronic ward postintervention. CONCLUSION: Providing SNCPs in electronic and paper formats is critical to improving nursing documentation. IMPLICATION FOR NURSING PRACTICE: Adequate training and support for nurses are needed for successful implementation of SNCPs in electronic health records (EHRs) in developing nations. PMID- 30525307 TI - Differential Expression of Genes in Greenbug (Schizaphis graminum Rondani) Treated by Imidacloprid and RNA Interference. AB - BACKGROUND: Insecticides act as toxins, inhibitors of digestion, and deterrents that affect the expression changes of a plenty of genes in insect. To assess the key genes associated with detoxification or regulation of imidacloprid in greenbug, Schizaphis graminum (Rondani), the transcriptome and digital gene expression (DGE) profiling were analyzed by Illumina sequencing. RESULTS: A total of 48,763,494 clean reads were obtained by sequencing. The expression profile analysis showed that 2,782 unigenes were differently expressed between imidacloprid treatment and control groups. After exposure to imidacloprid, the expression levels of 1,846 unigenes were up regulated, whereas 936 were down regulated in comparison to the control groups. Expression patterns of the top 20 highly expressed genes could belong to type of detoxification of imidacloprid. Silencing of multidrug resistance-associated gene (MRA), GATA-binding gene (GAT), and takeout-like precursor gene (TLP) resulted in increasing susceptibility to imidacloprid. CONCLUSIONS: The differential expressed genes in S. graminum play potential regulatory or detoxification roles in the response to imidacloprid. These results should be useful for understanding the molecular mechanisms of greenbug adaption to imidacloprid. This article is protected by copyright. All rights reserved. PMID- 30525308 TI - The commissioning and validation of Monaco treatment planning system on an Elekta VersaHD linear accelerator. AB - Accurate beam modeling is essential to help ensure overall accuracy in the radiotherapy process. This study describes our experience with beam model validation of a Monaco treatment planning system on a Versa HD linear accelerator. Data were collected such that Monaco beam models could be generated using three algorithms: collapsed cone (CC) and photon Monte Carlo (MC) for photon beams, and electron Monte Carlo (eMC) for electron beams. Validations are performed on measured percent depth doses (PDDs) and profiles, for open-field point-doses in homogenous and heterogeneous media, and for obliquely incident electron beams. Gamma analysis is used to assess the agreement between calculation and measurement for intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans, including volumetric modulated arc therapy for stereotactic body radiation therapy (VMAT SBRT). For all relevant conditions, gamma index values below 1 are obtained when comparing Monaco calculated PDDs and profiles with measured data. Point-doses in a water medium are found to be within 2% agreement of commissioning data in 99.5% and 98.6% of the points computed by MC and CC, respectively. All point-dose calculations for the eMC algorithm in water are within 4% agreement of measurement, and 92% of measurements are within 3%. In heterogeneous media of air and cortical bone, both CC and MC yielded better than 3% agreement with ion chamber measurements. eMC yielded 3% agreement to measurement downstream of air with oblique beams of up to 27 degrees , 5% agreement distal to bone, and within 4% agreement at extended source to surface distance (SSD) for all electron energies except 6 MeV. The 6 MeV point of measurement is on a steep dose gradient which may impact the magnitude of discrepancy measured. The average gamma passing rate for IMRT/VMAT plans is 96.9% (+/-2.1%) and 98.0% (+/-1.9%) for VMAT SBRT when evaluated using 3%/2 mm criteria. Monaco beam models for the Versa HD linac were successfully commissioned for clinical use. PMID- 30525309 TI - A regulatory variant in TBX2 promoter is related to the decreased susceptibility of congenital heart disease in the Han Chinese population. AB - BACKGROUND: Tbx2 plays a vital role in the cardiac cushion development. In this study, we aimed to determine the relationship between common genetic variants in the promoter region of TBX2 gene and the risk of congenital heart disease (CHD). METHODS: Blood samples of 516 CHD patients and 587 control subjects were enrolled. Sanger sequencing and SNaPshot analysis were performed for genotyping in our case-control cohort. Luciferase and electrophoretic mobility shift assay (EMSA) were conducted to uncover the potential modulatory mechanism of the related variants. RESULTS: Variant rs4455026(c.-1028G>C) in TBX2 promoter region was found to be associated with significantly lower CHD susceptibility. The risk of CHD in C allele carriers (GC and CC genotypes) decreased by 30% compared to the wild-type GG genotype subjects (OR = 0.70, 95% CI = 0.55-0.89, p = 0.0038). It was revealed that G to C variation resulted in a decrease in the transcriptional activity of luciferase gene, and a potential change in binding affinity with certain nucleoproteins in EMSA data. CONCLUSION: The minor C allele of rs4455026 in TBX2 promoter region was related with lower CHD susceptibility in the Han Chinese population via repressing its transcriptional activity. PMID- 30525310 TI - Molecular characterization of Peste des petits ruminants viruses in the Marmara Region of Turkey. AB - Recent outbreaks of Peste des petits ruminants (PPR) in the Marmara region of Turkey including the European part of Thrace is important due to its proximity to Europe (Greece and Bulgaria) and the potential threat of spread of PPR into mainland Europe. In order to investigate the circulation of PPRV in the region suspect clinical and necropsy samples were collected from domestic sheep (n=211) in the Marmara region of Turkey between 2011 and 2012. PPR virus (PPRV) genome was detected in 10.4% (22 out of 211) of sheep samples by real-time RT-PCR, and PPR virus was isolated from lungs of two sheep that died from infection. Of the 22 positive samples nine were used for partial N gene amplification and sequencing. The phylogenetic analyses indicated that the virus belongs to lineage IV, the same lineage that is circulating in eastern and central part of Turkey since its first official report in 1999. In addition, samples from 100 cattle were collected to investigate potential subclinical circulation of PPRV. However all were found to be negative by real-time RT-PCR, and also in serological tests indicating the large ruminants were likely not exposed or infected with the virus. The impact of these findings on the potential threat of spread of PPR to Europe including the first PPR outbreak in Europe in Bulgaria on 23rd June 2018 is discussed. This article is protected by copyright. All rights reserved. PMID- 30525311 TI - Contributions of dsRNases to differential RNAi efficiencies between the injection and oral delivery of dsRNA in Locusta migratoria. AB - BACKGROUND: The efficiency of RNA interference (RNAi) varies considerably among different insect species, and there is growing evidence to suggest that degradation of double-stranded (dsRNA) prior to uptake is an important factor that limits the efficiency of RNAi in insects. In Locusta migratoria, RNAi is highly efficient when dsRNA is delivered by injection, but not by feeding. However, detailed mechanisms causing such differential RNAi efficiency are still elusive. RESULTS: We identified and characterized the full-length cDNAs of two new dsRNA nuclease (dsRNase) genes from L. migratoria, which were named LmdsRNase1 and LmdsRNase4. Transcript analyses revealed that LmdsRNase1 and LmdsRNase4 were highly expressed in hemolymph with relatively lower expression in other tested tissues. Our study using heterologously expressed LmdsRNase1 and LmdsRNase4 fusion proteins showed that LmdsRNase1 can degrade dsRNA rapidly at optimal pH 5, whereas LmdsRNase4 had no activity in any of the pH conditions examined. In comparing the substrate specificity of the four LmdsRNases, we found that only LmdsRNase1 and 2 digested dsRNA; however, our experiments suggested that the physiological pH of hemolymph (7.0) suppresses LmdsRNase1 activity permitting significant dsRNA stability in this tissue. Conversely, the physiological pH of midgut juice (6.8) is ideal for LmdsRNase2 activity, resulting in degradation of dsRNA in midgut. CONCLUSION: The physiological pH of different insect tissues or compartments can significantly alter the stability of dsRNA by influencing LmdsRNase activity in L. migratoria. Thus, new strategies to overcome such obstacles are expected to help implement RNAi-based technologies for insect pest management. This article is protected by copyright. All rights reserved. PMID- 30525312 TI - Plant-mediated gene silencing of an essential olfactory-related Gqalpha gene enhances resistance to grain aphid in common wheat in greenhouse and field. AB - BACKGROUND: Grain aphid (Sitobion avenae F.) is one of the dominant pests that limit cereal crop production around the globe. Gq proteins play important roles in the signal transduction processes in insect olfaction. Plant-mediated RNA interference (RNAi) has been widely studied in insect control, but its application for wheat aphid control in the field needs to be further explored. In this study, we used dsRNA feeding to verify the potential of selected Gqalpha fragments for host-mediated RNAi, and then evaluated the effect of RNAi on aphid olfaction in transgenic wheat in greenhouse and field. RESULTS: The Gqalpha gene was expressed in aphid lifecycle, and its 540 bp fragment shared 98.1% similarity with the reported sequence. The corresponding dsGqalpha feeding reduced the expression level of Gqalpha gene and reproduction and molting of grain aphid. Feeding on the transgenic lines in greenhouse down-regulated the expression levels of aphid Gqalpha, and significantly reduced the reproduction and molting numbers. Furthermore, our field results indicated that transgenic lines showed less aphid number and higher 1,000-grain weight than the un-sprayed wildtype control. CONCLUSION: Plant-mediated gene silencing of an essential olfactory related Gqalpha gene could enhance resistance to grain aphid in common wheat in greenhouse and field. This article is protected by copyright. All rights reserved. PMID- 30525313 TI - Mouthguard sheet temperature after heating under pressure former. AB - BACKGROUND/AIM: Ethylene vinyl acetate and polyolefin sheets have been used commonly for fabricating mouthguards. However, the change of the sheet temperature during heating of the polyolefin has not been clarified. The aim of this study was to examine the effects of changing the sheet temperature during heating and to examine whether there were any differences between the sheet materials. MATERIALS AND METHODS: The mouthguard materials used were 4.0 mm sheets of ethylene vinyl acetate and polyolefin. The sheet temperature of the two materials was measured when the center of the sheet was displaced by 10, 15, and 20 mm from the baseline after heating. The sheets were pressure-formed when the heating temperatures reached 100 degrees C. Mouthguard thickness and fit was measured at the central incisor and the first molar. Differences in the sheet temperature and the thickness between the sheet materials were analyzed by two way analysis of variance. RESULTS: The sheet temperature of ethylene vinyl acetate and polyolefin sheets became higher as the hanging distance became larger (P < 0.01), and there were statistically significant differences between ethylene vinyl acetate and polyolefin sheets at the hanging distance of 10 and 15 mm (P < 0.01). The thicknesses of the pressure-formed mouthguard at the central incisor and the first molar were greater in the mouthguards formed by ethylene vinyl acetate sheets than those with polyolefin sheets (P < 0.01 and P < 0.05, respectively). The fit of the mouthguard was not different between mouthguards formed by ethylene vinyl acetate sheets and those formed by polyolefin sheets. CONCLUSIONS: The change of mouthguard sheet temperature during heating was different between ethylene vinyl acetate and polyolefin sheets. The ethylene vinyl acetate sheets maintained the mouthguard thickness in comparison with the polyolefin sheets at the same heating temperature. This article is protected by copyright. All rights reserved. PMID- 30525314 TI - A nationwide survey on tracheostomy for very-low-birth-weight infants in Japan. AB - OBJECTIVES: Tracheostomy is indicated for very-low-birth-weight infants (VLBWIs) with prolonged respiratory problems during the perinatal period. The objective of this study is to clarify the epidemiology and risk factors in VLBWIs with tracheostomy after birth in Japan. METHODS: A total of 40 806 VLBWIs were registered in the Neonatal Research Network of Japan database from 2003 to 2012. Among them, 34 674 infants (85%) survived over 28 days after birth and were subjected to this study. The clinical variables at birth, outcomes at hospital discharge and associated factors for tracheostomy were examined. RESULTS: The proportion of VLBWIs with tracheostomy did not increase during the study period (mean 36 cases per year, 0.93%). The rate of in-hospital death over 28 days after birth did not differ between tracheostomized and non-tracheostomized infants (2/324, 0.6% vs 314/34 350, 0.9%). Tracheostomized infants more frequently had severe or moderate bronchopulmonary dysplasia (BPD) (75.5% vs 26.0%, P < 0.01) and longer hospitalization (229 days vs 83 days, P < 0.01) than non tracheostomized infants. Tracheostomized patients showed higher comorbidities with hypoxic ischemic encephalopathy (odds ratio [OR] 10.98, P < 0.01), muscular disease (OR 10.95, P < 0.01), severe or moderate BPD (OR 7.79, P < 0.01), chromosomal abnormality (OR 4.43, P < 0.01) or sepsis (OR 1.78, P < 0.05) at hospital discharge than non-tracheostomized patients. CONCLUSION: We demonstrated the non-increasing rate in tracheostomy for VLBWIs and such cases were associated with an excellent survival in Japan. These data provide evidence that more attentive care must be practiced in order to reduce the pulmonary and neuromuscular burdens of VLBWIs at birth. PMID- 30525315 TI - Expression of the PIM2 gene is associated with more aggressive clinical course in patients with chronic lymphocytic leukemia. AB - BACKGROUND: The PIM2 gene belongs to the PIM family, which encodes serine/threonine kinases involved in cell survival and apoptosis. The relation between the expression of the PIM2 gene and the course of chronic lymphocytic leukemia (CLL) has not been fully determined. OBJECTIVES: The aim of the study was to evaluate the role of the PIM2 gene as a marker of CLL malignancy and its importance as a predictive and prognostic factor. MATERIAL AND METHODS: Sixty seven patients, 35 females and 32 males, aged 49-90 years, with de novo CLL, and 14 healthy individuals were enrolled in the study. Expression of the PIM2 gene was analyzed using TaqMan RQ-PCR assay and western blot test. RESULTS: Median PIM2 gene expression in CLL patients was higher than in controls. Patients with high expression of the PIM2 gene had shorter progression-free survival and time to first treatment than patients with low PIM2 expression. It was found that patients with CR had lower expression of the PIM2 gene than patients without complete remission (CR). Notably, associations between high PIM2 expression and rapid lymphocyte doubling time, the percentage of malignant lymphocytes with ZAP70 expression and the Rai stage were revealed. CONCLUSIONS: We found that the PIM2 gene is associated with a more aggressive clinical course of CLL. PMID- 30525316 TI - Adropin and irisin: New biomarkers of cardiac status in patients with end-stage renal disease? A preliminary study. AB - BACKGROUND: The new polypeptide hormones adropin and irisin have a broad impact on human metabolism and energy homeostasis. They could be potential biomarkers of cardiac injury. In end-stage renal disease (ESRD), the clinical importance of adropin and irisin is yet to be investigated. OBJECTIVES: The aim of this study was to determine the relationship between these peptides and cardiac status in ESRD patients. MATERIAL AND METHODS: Seventy-nine ESRD patients on hemodialysis (HD), peritoneal dialysis (PD) or after renal transplantation (Tx), and 40 healthy, ageand sex-matched controls (CON) were included in this study. Serum concentrations of adropin and irisin were measured with enzyme-linked immunosorbent assay (ELISA). Cardiac status was estimated by transthoracic echocardiography and the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). RESULTS: The levels of irisin were significantly lower in HD patients as compared to CON. During HD sessions, the concentrations of adropin did not change significantly, whereas the concentrations of irisin increased with borderline significance. Positive correlations were evident between adropin concentration and cTnT as well as NT proBNP. Adropin was also correlated with left ventricular systolic internal diameter (LVIDs) (r = 0.375, p = 0.045) and relative wall thickness (RWT) (r = 0.382, p = 0.034). Irisin was correlated with right ventricular diameter (RVd) (r = -0.363, p = 0.045). No correlations were found between irisin and adropin, and blood pressure (BP) measurements. CONCLUSIONS: Adropin could be a new candidate marker of cardiac dysfunction in HD patients. The cause of low levels of irisin found in HD patients is still unclear. These 2 myokines should be further investigated as potential prognostic markers of cardiac status in HD patients. PMID- 30525317 TI - Spontaneous low-frequency fluctuations in the neural system for emotional perception in major psychiatric disorders: amplitude similarities and differences across frequency bands AB - Background: Schizophrenia is a disorder of basic self-disturbance. Evidence suggests that people with schizophrenia may have aberrant experiences of body ownership: they may feel that they are not the subject of their own body experiences. However, little is known about the development of such disturbances. Methods: Using a rubber hand illusion paradigm, we assessed body ownership in patients with schizophrenia (n = 54), healthy controls (n = 56), children/adolescents at increased familial risk of developing schizophrenia (n = 24) or mood disorders (n = 33), and children/adolescents without this risk (n = 18). In this paradigm, a rubber hand (visible) and a participant's real hand (invisible) were stroked synchronously and asynchronously; we then measured subjective illusory experiences and proprioceptive drift. Results: All groups showed the expected effect of the rubber hand illusion: stronger proprioceptive drift and increased subjective illusory experiences after synchronous versus asynchronous stroking. The effect of synchronicity on subjective experiences was significantly weaker in patients with schizophrenia than in healthy controls, and subjective ratings were positively correlated with delusions in patients. We found no significant differences between children/adolescents with and without increased familial risk. Limitations: Large individual differences raised questions for future research. Conclusion: We found subtle disturbances in body ownership experiences in patients with schizophrenia, which were associated with delusions. We found no evidence for impairments in children/adolescents at increased familial risk of developing schizophrenia or a mood disorder. Longitudinal data might reveal whether impairments in body ownership are predictive of psychosis onset. PMID- 30525318 TI - Strength training in children and adolescents: benefits, risks and recommendations AB - In the last decade, there has been a notable increase in the implementation of strength training programs in sports for children andadolescents.This review of strength training includes potential health benefits, fitness, risks and recommendations for the healthy, overweight, obese, or sedentary population in children 7-19 years of age.The general guidelines include supervision, planning and proper learning of the technique. Scientific evidence and clinical experience of strength training in children and adolescents as part of a training program demonstrate that it is useful, effective and safe if properly prescribed and supervised, with potential health benefits on a physical, social and psychological level PMID- 30525319 TI - Adaptation of Monosymptomatic Enuresis Guide in Spanish AB - The general objective is to adapt recommendations on monosymptomatic primary enuresis (ME) to the regional context. The instruments used were "Guide for the Adaptation of Clinical Practice Guidelines" and "Guidelines for creation of Consensus" (Sociedad Argentina de Pediatria).ME is called intermittent urinary incontinence during the sleep of children > 5 years of age, with no other symptoms of the urinary tract. It is differentiated from non-monosymptomatic enuresis, defined by the presence of other symptoms of the lower urinary tract, mainly during the day. The ME is a transitory condition with spontaneous resolution so the decision to start treatment must be agreed with the child and their family environment. The primary care pediatrician should be the first contact with a child with ME, who implements the initial general behaviors and eventual indication of specific first-line medication, such as alarm and desmopressin. PMID- 30525320 TI - Measurement of unstimulated salivary flow rate in healthy children aged 6 to 15 years AB - The aim of the present study was to measure unstimulated saliva flow rate (uSFR), pH value and buffer capacity in healthy children aged 6 to 15 years to serve as reference values for subsequent investigations, in particular to define threshold values for abnormality. Our basic data will power the limited amount of currently available data on salivary flow rate in healthy children. The uSFR was evaluated for correlations with pH value and buffer capacity. The unstimulated saliva of 274 children aged 6 to 15 years was collected (n: 154 v; 120 u) by the spitting method within three minutes. The samples were examined immediately after saliva collection in terms of uSFR, pH value and buffer capacity. From the 274 participating children 18 were excluded due to the intake of medication. The medians (IQR) of uSFR of the tested children were 0.87 (0.54, 1.11) ml/min for boys, 0.65 (0.37, 0.98) ml/min for girls and 0.76 (0.49, 1.05) ml/min in total. The uSFR correlated with the pH value and the buffer capacity (p < 0.001). For different genders there was a statistically significant difference regarding uSFR (p = 0.008) and pH value (p = 0.016). Based on the available data, the pH value and the buffer capacity were closely related to the uSFR. Boys seemed to have a higher uSFR than girls. PMID- 30525321 TI - ? PMID- 30525322 TI - Diabetic nephropathy in the elderly - clinical practice AB - Common health problems of the elderly in the near future will become even more common with aging of the population and longer average life expectancy. The elderly tend to have multiple disorders at one time, some of which may aggravate the course of others. One of the most common diseases, diabetes - "the epidemics of XXI century", treatment of which costs approximately 11% of world health care budget - is the leading reason of chronic kidney disease and end-stage renal disease. Diabetic nephropathy can be a complication of both diabetes mellitus type 1 and 2. The most numerous group of patients with recently-made diagnosis are these above 60 years of age. Albuminuria, which, depending on its intensity, is one of the diagnostic criteria, can appear even in the process of aging itself. Overlapping of structural and functional changes that develop with age and those caused by diabetes is therefore a challenge, both diagnostic and clinical. There are certain methods of early diagnosis and prevention of progression of diabetic kidney disease. There is, however, no targeted treatment and existing therapies are generally based on glycemia and blood pressure control. Some patients in the advanced stage undergo dialyses just like in other kidney failure cases. The course of the disease is influenced by modifiable factors, such as protein and salt intake or cigarette smoking. In the light of the fact that this problem will concern an increasing number of patients, diagnostics and treatment can and should be introduced in the early stages of the disease. This all fits within the recently popular "healthy aging" ideology. Its popularization and implementation can bring measurable benefits of social and economic character. PMID- 30525323 TI - Levels of some heavy metals in vegetables from artisanal mining sites of Dilimi River, Bukuru and Barkin Ladi North Central Nigeria: any public health concern? AB - Background: North Central Nigeria is the food basket of Nigeria but is also known for its artisanal mining with attendant public health consequences which is hitherto unquantified. Vegetables grown close to these mining sites may be contaminated with heavy metals. Objective: This study has estimated health risk associated with heavy metals HM (Cd, Cr, Cu, Zn, Se and Ni) in vegetables harvested inform the mining areas of Dilimi, Bukuru and Barkin Ladi by calculating the Daily intake, Target Hazard Quotient (THQ), Hazard Index (HI) and the Cancer risk (CR) for adults and children in the local population. Material and methods: Vegetable, soil, irrigation water and sediments samples were collected, digested, ashed and analyzed for HM using an Atomic Absorption Spectrometer (AAS). Results: The concentration of heavy metals in vegetables were in the order Cd < Se < Cr < Cu < Ni < Zn. There were higher HM levels in soil than vegetables samples. The daily intake of HM from vegetable consumption decreased in the following order Cd < Se < Cr < Cu < Ni < Zn. At least 62.5% of vegetable samples had THQ values > 1 in Dilimi, Bukuru and Barkin ladi (Adults) while 13% of vegetable samples had THQ values > 1 in children. The THQ of nickel ranged from 0.38-2.73 and 0.21-1.53 in adults and children respectively. The bio concentration factor ranged from 0.026-7.52, 0.01-0.36 and 0.0011-1.23 in Dilimi, Bukuru and Barkin Ladi respectively for all the studied heavy metals. The cancer risk values ranged from 0.011-0.04 and 0.00066-0.02 across all the studied areas for adults and children respectively. HI values for adults were all >1 and also the total cancer risk was above the acceptable range of 10-4. Conclusion: Since THQ is > 1 in most of the samples, HI values > 1 for adults in all the vegetable and cancer risk above the acceptable limit consumption of vegetables from the study areas is not free of risk. PMID- 30525324 TI - Assessment of the frequency of intake of selected sources of dietary fibre among persons competing in marathons AB - Background: The knowledge about nutrition of the marathoners is insufficient. An insightful and personalized approach to the diet of long-distance athletes, including the consumption of important nutrients such as dietary fiber, is needed to improve the efficiency of their performance. Objective: Estimation of the frequency of consumption of food products as a source of dietary fiber by people preparing for the marathon. Material and Methods: The frequency of intake of selected dietary fiber sources by women (n=105) and men (n=87) aged 19 to 73 years, who compete in marathons. The Block questionnaire was used to assess the intake of fiber sources (whole grain cereals, vegetables, fruits, potatoes and legumes). Fiber consumption was expressed on a dot scale. Results: Adequate dietary fiber intake was found in 44% of the marathon runners, but insufficient one - in 50% of the respondents. Diets of about 6% of the subjects were poor in dietary fiber. Lower dietary fiber intake was demonstrated in both men and women in the pre-marathon period, and was due to the recommended dietary fiber intake during this period. Conclusion: The study showed an insufficient intake of dietary fiber in all-day rations of most of the surveyed marathon runners. A statistically significantly lower dietary intake of marathoners (both women and men) was demonstrated before the marathon compared to the post-long distance period. PMID- 30525325 TI - Consumption of different types of bakery products and its effect on visceral fat area in healthy population AB - Background: Bread is one of the world's most consumed food commodity. However, in the last years consumption of breadand bakery products has declined, especially in the Western population. The reason for concern is the weight gain and presence of gluten in these products. Gluten is unacceptable in the diet only in patients with celiac disease who are forced adhere the gluten-free diet all the time. The consequences of gluten-free diet in healthy people are the subject of many recent studies. Objective: The aim of this study was to evaluate the changes of visceral fat area in the general population after 6 weeks of consumption of gluten-free, gluten-containing and whole-grain bread and other bakery products. Material and Methods: The study group consisted of 120 volunteers divided into four subgroups each with 30 subjects. Anthropometric measurements were made using the InBody 720 (Biospace Co. Ltd., Seoul, Republic of Korea). We used the Lookin'Body 3.0 software to process the results. The collected data from anthropometric measurements were evaluated statistically and graphically in Microsoft Office Excel 2010 (Los Angeles, CA, USA). Results: After the intervention we found out that visceral fat area values increased in probands consuming gluten-free and gluten-containing bakery products, but these changes were not significant (P>0.05; 72.7+/-29.18 cm2 vs 73.26+/-30.32 cm2 and 69.6+/-34.06 cm2 vs 70.34+/ 32.33 cm2, respectively). In whole-grain and control group we observed a reduction in visceral fat area, in the control group there was a significant change (P>0.05 - 91.58+/-33 cm2 vs 90.47+/-34.37 cm2 and P<0.05 - 77.3+/-21.65 cm2 vs 75.56+/-21.87 cm2, respectively). After the intervention the visceral fat area values increased in gluten-free group in 57% of subjects, in gluten group in 73% of subjects and in the whole-grain group in 43% of volunteers. Although visceral fat area values had inceased in gluten-free and gluten-containing groups, the number of probands with reference values increased from 80% to 86% in the gluten-free group and from 43% to 66% in the gluten-containing group. In the whole-grain group we found decrease in number of subjects with reference values of visceral fat area (from 70% to 63%). There were no changes in the control group (86% vs. 86%). Conclusions: Consumption of different types of bakery products has mostly changed the visceral fat area values in a positive direction. PMID- 30525326 TI - Correlation between human milk composition and maternal nutritional status AB - Background: Human milk is the optimal nutrition for newborns and infants during the first period of their life - from birth to 6-th month. It contains a uniquely quantitative and qualitative balanced nutrients profile. Composition of breast milk is dynamic and may vary according to maternal nutritional status. Objective: The aim of this study was to investigate associations between human milk composition and maternal nutritional status. Material and methods: One-day milk samples were provided by exclusively breastfeeding mothers (n=40) at the first month of lactation. Protein - total and true, fat, carbohydrate, dry matter and energy content were determined using the Human Milk Analyzer by MIRIS. The anthropometric measurements (current body weight, height) were used to calculate current body mass index (BMI). On this basis, we assessed nutritional status of examined population. Results: For the majority of women (75%, n=30) currently BMI value was in range of 18.5-24.9 kg/m2, for the rest of women it was >= 25 kg/m2. The median macronutrient composition per 100 ml of mature breast milk was 7.0 g for carbohydrate, 1.1 g for protein, 3.5 g for fat, 11.9 for dry matter and energy content was 66.0 kcal. Maternal body mass index was positively related to lipid, dry matter and energy breast milk content (p<0.05). Conclusions: The majority of examined women in the first month of lactation was in normal state of nutrition. For the rest of women BMI values indicated for overweight. Our results confirm correlation between human milk composition and maternal nutritional status, especially in matters of energy value and fat content in human milk. PMID- 30525327 TI - The level of physical activity in elderly persons with overweight and obesity AB - Background: An important factor in maintaining elderly people in good health is an appropriate level of physical activity. The research into physical activity level of the elderly is quite crucial as the low level of such activity may lead to disability and that, in turn, generates the need of additional care which constitutes a serious social problem. As the existing data seem to lack a lot, new research would enrich our knowledge in new conclusions. Objective: The aim of the study is to analyze and estimate the physical activity of the elderly persons with overweight or obesity elderly. Material and methods: The research group consisted of 360 overweight and obese elderly people. The criteria of inclusion into a research group were living in family homes, overweight (BMI=25.0-29.9 kg/m2) or obesity (BMI >= 30 kg/m2), no contraindications to physical activity, age between 60 and 74 and written consent for the participation of the experiment. The control group consisted of 360 people without overweight and obesity. The inclusion criteria included age 60-74 BMI<25.0 kg/m2 and living at family home. The data was gathered with the use of the International Physical Activity Questionnaire (IPAQ). Results: The average age in the test group was 67,03+/-4,264 and in control group 66,59+/-4,050. The research has shown that the level of physical activity of overweight and obese senior citizens was lower than in people with correct body mass. Frequency of high intensity of physical activity undertaken by seniors in the test group was 0.7 day per week and lasted 16.1 minutes a day ( in the control group 2.5 days per day and 32.8 minutes per day, respectively). The IPAQ examination has shown that 95.8% of the test group participants had insufficient level of professional activity, 99.7% in transport related physical activity, 86.1% in household chores and 99.4% in free time physical activity. Conclusions: The level of physical activity of the elderly in the test group was very low, much lower than in people of the same age but with correct body mass. The lowest level of physical activity was noted in transport related physical activity and leisure time physical activity. PMID- 30525328 TI - Differences in eating patterns of middle school students living in urban and rural areas located in the Masovian Voivodeship AB - Background: Proper eating behaviours among youth condition their bodies' optimal growth and development and impact future diet choices, which affects maintenance of health in later years. Studies concerning assessment of the way of eating among adolescents in Poland over the past years indicate a number of errors. Objective: The aim of these studies was to asses diet diversity of middle school students, living in urban and rural areas located in the Masovian Voivodeship. Material and methods: 180 people participated in this study, 90 girls and 90 boys in age between 13 and 15 years. They were middle school students, living in urban and rural areas of Mazowieckie Voivodeship. Assessment of the variety of eating pattern amongst participants were conducted using the Food Intake Diversification Questionnaire (FIVeQ). Results: It was found that 3.3% of respondents from rural areas and 10% of respondents from urban areas were characterized by inappropriate variation of food intake. Sufficient variation of food consumption was found among 35.5% respondents from rural areas and 36.6% from urban areas. Good variation of food consumption was demonstrated in 54.4% of subjects from rural areas and in 42.2% from urban areas. Very good variation of food consumption was found in 6,6% of subjects from rural areas and 11.1% from urban areas. It is worth noticing differences in diet variations observed in these studies. It was shown that diet variety at inadequate, good and very good level was significantly different between groups, which may be puzzling considering the fact that all subjects were living in the same Voivodeship. Conclusion: For reason being, results obtained in these studies indicate the need for education of young people on principles of balanced way of eating. PMID- 30525329 TI - Dietary intake of DHA during pregnancy: a significant gap between the actual intake and current nutritional recommendations AB - Background: Docosahexaenoic acid (DHA) is indispensable to ensure proper development of the fetal central nervous system and pregnancy duration. Daily intake of DHA should be at least 100 mg higher as compared to the pre-pregnancy values. Objectives: The aim of the study was to evaluate DHA intake during pregnancy and compare it to the current recommendations. Material and methods: A total of 100 pregnant women presenting for labor at the Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw, were included in the study. DHA intake from the following sources: fish and eggs, and DHA preparations collected based on the questionnaire was investigated. Results: Low dietary DHA intake (median: 60 mg/day) was observed. The values were only slightly higher (median: 90 mg/day) after DHA preparations were taken into consideration because only 28% of the pregnant women used DHA preparations. Overall, 92% of the subjects consumed <200 mg of DHA a day, which was the result of insufficient fish consumption (mean: 15 g/day). Only 10% of the respondents ate fish twice a week, in which case the DHA dietary intake was statistically significantly higher (median: 160 mg/day) (p=0.0232). Total median dietary DHA and EPA intake in the study population was 79 mg/day. Conclusions: The diet of pregnant women is largely deficient as far as DHA intake is concerned. Importantly, it is not possible to comply with current recommendations without dietary supplementation. PMID- 30525330 TI - Assessment of selected nutritional behaviours among college adolescents from Pomerania Province AB - Background: Adequate nutrition is one of the most important environmental factor that determines the development of children and adolescents. Childhood, as well as puberty significantly take part in forming proper nutritional attitudes and behaviours Objectives: Assessment of selected nutritional behaviors among college adolescents from Pomerania Province. Subjects were students of high schools, trade schools and technical institutes. Material and methods: In the study 198 students participated - 121 girls and 77 boys. A study was conducted during school year 2012/2013. Nutritional behavior was assessed due to an anonymous questionnaire that concerned nutritional self-assessment of adolescents, their interests in healthy dietary patterns, amount and type of daily consumed foods, time of consumption of last meal of the day, snacking between main meals; frequency together with a quality of the snacks, and sources of dietary knowledge acquisition. Results: Data analysis showed that boys ate dinner and supper statistically significantly more frequently than girls. Genderalso defined consumption of products from different food groups. Boys statistically significantly more often were choosing white bread, dumplings, pasta, milk, red meat, poultry and eggs. The amount of underweight girls was three times higher than underweight boys. Snacking was observed in 99.0% of the study group. Diet regimens were conducted statistically more often by girls (37.5%) than boys (6.3%). Conclusions: It has been shown that there are a number of abnormal nutritional behaviors in the study group. This indicates the need for their correction through the education of both young people, but also parents and legal guardians. It is recommended that workshops, youth training by nutritionists in the field of proper nutrition and eating behavior. PMID- 30525331 TI - Selected anti-health behaviours among women with osteoporosis AB - Background: In the prevention of osteoporosis and its treatment, it is important to prevent bone loss by reducing the occurrence of factors determining human health, which reduce the risk of osteoporosis, such as health behaviors. Objective: Characteristics of modifiable risk factors predisposing to osteoporosis, such as: low intake of calcium and vitamin D3 in the diet, smoking, coffee and alcohol abuse. Material and methods: The study involved 400 women aged 50-74 who are suffering from osteoporosis T-score <-2.5 SD and those who are healthy T-score> -1 SD, living in the Malopolska voivodeship. A questionnaire was used to conduct the study. Results: More than half of the respondents with osteoporosis (51%) were drinking coffee several times a day. In the healthy group, the majority of respondents (77.5%) were drinking coffee once a day. None of the healthy subjects drank more than two units of alcohol per day, and in the group of patients 2% of respondents declared consumption of more than two units of alcohol every day. Women with osteoporosis were more likely to smoke cigarettes and declared more frequent intake of calcium-containing products than healthy women. In the group of200 examined women suffering from osteoporosis, 26.5% daily consumed milk, and 21.5% included this product three times a week in their diet. Healthy women did not drink milk every day. One-third (30.5%) of women with osteoporosis provided the daily recommended dose of calcium by consuming a slice of cheese. None of the healthy women examined included yellow cheese in daily meals, but only once (22%) or three times (26.5%) a week. Conclusions: It is important to introduce a health education in order to increase knowledge about the risk factors of osteoporosis , including the principles of proper nutrition with an emphasis on calcium and vitamin D3 intake. PMID- 30525332 TI - Exposure assessment to lead, cadmium, zinc and copper released from ceramic and glass wares intended to come into contact with food AB - Background: One of the important source of food contamination with elements harmful to human health such as lead or cadmium is migration from the articles intended to come into contact with food. Ceramic and glass articles can also be a source of zinc and copper which compounds are used during the production process of vessels. Objective: Determination of migration of lead, cadmium, zinc and copper from ceramic and glass wares available on the market in Poland and assessment of consumer exposure to these elements. Material and methods: Ceramic and glass articles which were available on the retail market and mainly produced in China were tested for release of lead, cadmium, zinc and copper. Samples for testing were prepared in accordance with European Standards: EN 1388-1 and EN 1388-2 and the migration of elements into a food simulant (4% acetic acid) was measured using flame atomic absorption spectrometry (FAAS). Validated and accredited methods according to EN ISO/ IEC 17025:2005 meeting the criteria set in the legislation were applied. Exposure assessment was performed taking into account actual reference doses introduced by the European Food Safety Authority (EFSA) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Results: 736 samples of ceramic and glass wares were tested. Among investigated samples for migration of lead 82% of results were below limit of quantification (LOQ = 0.1 mg/L) of the analytical method used. For cadmium zinc and copper results below LOQ were found in 94%, 79% and 100% tested samples, respectively (Cd LOQ = 0.01mg/L; Zn LOQ = 0.05 mg/L; Cu LOQ = 0.03 mg/L). Only one sample release lead in amount higher than limit set in Polish Standard PN-B-13210:1997, it was rim of the glass mug and migration value was 4.81 mg/article. In case of cadmium there were two samples which exceeded permissible migration limit, it was flat ceramic dish and the rim of the glass mug, migration values were: 0.14 mg/dm2 and 0.42 mg/article respectively. The most measurable results (above LOQ) in case of lead and cadmium were for the samples of ceramic and glass drinking vessels. Quantifiable amounts of zinc were found also in other groups of articles tested: flat and deep ceramic dishes. None of the tested articles released copper in amount higher than LOQ value. The risk assessment showed that lead and cadmium exposure for some of the samples far exceed the reference doses. For children, assuming a single use only of these vessels, these doses may be exceeded: in the case of lead, 69 times and in the case of cadmium, 8 times. Conclusions: It is the urgent need to introduce requirements into the applicable legislation for the rim area of drinking ceramic and glass vessels to reduce exposure especially by the most vulnerable groups of population such as children. PMID- 30525333 TI - Consumer perception of health properties and of other attributes of beef as determinants of consumption and purchase decisions AB - Background: Consumers may feel confused by receiving conflicting information about health-related aspects of beef. Therefore, it is invariably important to assess how consumers perceive the health benefits of beef. Objective: The aim of the study was to assess the impact of consumer perception of beef values on consumer behavior towards this type of meat. Material and methods: The study consisted of a survey conducted among residents of Swietokrzyskie voivodeship in the period February 2013 - September 2014. The research was conducted among 1004 consumers. The questions included in the questionnaire concerned habits associated with consumption of beef, as well as issues related to the process of purchasing decisions, and in particular the place and frequency of purchase of beef. Results: It was found that the frequency of buying beef was also significantly dependent on consumer belief in the health attributes of beef. Consumers consuming beef for this reason more often indicated that they consume beef once a week and 2-3 times a month. On the other hand, consumers who did not eat beef because of its impact on health in which they believed, more often pointed to its occasional/ sporadic consumption, that is once a month and less often. Conclusions: A significant percentage of consumers in the Swietokrzyskie voivodship misinterpret dietary recommendations and conclude that it is necessary to increase the consumption of beef due to medical reasons. Medical recommendations indicating the need to reduce meat consumption for a significant percentage of consumers from the Swietokrzyskie Voivodeship are of little importance and do not contribute to changing their eating behavior. Especially in the case of men, there is often a reluctance to change eating habits if it would involve the need to reduce the consumption of meat. There is a need to verify marketing messages and to carry out general nutrition education so that it is possible to actually reach consumers with information about the need to limit the consumption of meat products. PMID- 30525334 TI - Age-related deficits in intracortical myelination in young adults with bipolar disorder type I AB - Background: Previous studies have implicated white-matter-related changes in the pathophysiology of bipolar disorder. However, most of what is known is derived from in vivo subcortical white-matter imaging or postmortem studies. In this study, we investigated whole-brain intracortical myelin (ICM) content in people with bipolar disorder type I and controls. Methods: Between Sept. 1, 2014, and Jan. 31, 2017, we used a 3 T General Electric scanner to collect T1-weighted images in 45 people with bipolar disorder type I and 60 controls aged 17 to 45 years using an optimized sequence that was sensitive to ICM content. We analyzed images using a surfacebased approach. We used general linear models with quadratic age terms to examine the signal trajectory of ICM across the age range. Results: In healthy controls, the T1-weighted signal followed an inverted-U trajectory over age; in people with bipolar disorder type I, the association between ICM and age followed a flat trajectory (p < 0.05, Bonferroni corrected). Exploratory analyses showed that ICM signal intensity was associated with duration of illness, age of onset, and anticonvulsant and antipsychotic use in people with bipolar disorder type I (p < 0.05, uncorrected). Limitations: Because of the cross-sectional nature of the study, we were unable to comment on whether the effects were due to dysmyelination or demyelination in bipolar disorder. Conclusion: This foundational study is, to our knowledge, the first to show global age-related deficits in ICM maturation throughout the cortex in bipolar disorder. Considering the impact of myelination on the maintenance of neural synchrony and the integrity of neural connections, this work may help us better understand the cognitive and behavioural deficits seen in bipolar disorder. PMID- 30525335 TI - UNAASS: a small or a big step for democracy in health? PMID- 30525336 TI - Effect of Environmental Impedance Surrounding a Radiofrequency Ablation Catheter Electrode on Lesion Characteristics PMID- 30525337 TI - ? PMID- 30525338 TI - Social Security Administration Violence Evaluation and Reporting System. Final rule. AB - We are issuing a final rule to exempt a system of records entitled Social Security Administration Violence Evaluation and Reporting System (SSAvers) from certain provisions of the Privacy Act because this system will contain investigatory material compiled for law enforcement purposes. PMID- 30525339 TI - Patient Protection and Affordable Care Act; Adoption of the Methodology for the HHS-Operated Permanent Risk Adjustment Program for the 2018Benefit Year Final Rule. Final rule. AB - This final rule adopts the HHS-operated risk adjustment methodology for the 2018 benefit year. In February 2018, a district court vacated the use of statewide average premium in the HHS-operated risk adjustment methodology for the 2014 through 2018 benefit years. Following review of all submitted comments to the proposed rule, HHS is adopting for the 2018 benefit year an HHS-operated risk adjustment methodology that utilizesthe statewide average premium and is operated in a budget-neutral manner, as established in the final rules published in the March 23, 2012 and the December 22, 2016 editions of the Federal Register. PMID- 30525343 TI - Poor Oral Health and Blood Pressure Control Among US Hypertensive Adults: Results From the National Health and Nutrition Examination Survey 2009 to 2014 AB - Periodontal disease is a chronic inflammatory disorder of the tissues surrounding the teeth, with evidence of systemic effects. Some studies showed the benefit of periodontal therapy on blood pressure (BP), but the impact of periodontitis on BP control is unknown. We retrospectively analyzed cross-sectional, nationally representative data from treated hypertensive adults aged >=30 years with and without periodontitis. BP was examined as both continuous (mm Hg) and categorical (treatment goal achievement status according to guidelines: at goal and above goal) variable according to the presence or absence of periodontitis and its clinical parameters (probing depth, clinical attachment loss, and disease severity [mild, moderate, and severe]). Systolic BP means and odds ratios for uncontrolled BP according to the presence and severity of periodontitis were calculated using progressively adjusted models. Among treated hypertensive adults, mean systolic BP was about 2.3 to 3 mm Hg higher in the presence of periodontitis (P<0.0001). Periodontitis was associated with unsuccessful antihypertensive treatment after multiple adjustments, with higher odds by disease severity. A good periodontal health is associated with better systolic BP profile during antihypertensive therapy by about 2.3 to 3 mm Hg and with lower odds of antihypertensive treatment failure. Dedicated studies are needed to test the impact of periodontal therapy on BP and the long-term effects on cardiovascular outcomes of this complementary approach to systemic health.